1,8 Naphthyridine derivatives and their use to treat diabetes and related disorders

Description

FIELD OF THE INVENTION

[0001] The present invention relates to 1,8-naphthyridine derivatives, pharmaceutical compositions containing them, and their use for treating diabetes and related disorders in a subject.

DESCRIPTION OF THE RELATED ART

[0002] Diabetes is characterized by impaired glucose metabolism manifesting itself among other things by an elevated blood glucose level in the diabetic patient. Underlying defects lead to a classification of diabetes into two major groups: type 1 diabetes, or insulin dependent diabetes mellitus (IDDM), arises when patients lack insulin-producing beta-cells in their pancreatic glands. Type 2 diabetes, or non-insulin dependent diabetes mellitus (NIDDM), occurs in patients with impaired beta-cell function and alterations in insulin action.

[0003] The current treatment for type 1 diabetic patients is the injection of insulin, while the majority of type 2 diabetic patients are treated with agents that stimulate beta-cell function or with agents that enhance the tissue sensitivity of the patients towards insulin. The drugs presently used to treat type 2 diabetes include alpha-glucosidase inhibitors, insulin sensitizers, insulin secretagogues, and metformin.

[0004] Over time almost one-half of type 2 diabetic subjects lose their response to these agents. Insulin treatment is instituted after diet, exercise, and oral medications have failed to adequately control blood glucose. The drawbacks of insulin treatment are the need for drug injection, the potential for hypoglycemia, and weight gain.

[0005] Because of the problems with current treatments, new therapies to treat type 2 diabetes are needed. In particular, new treatments to retain normal (glucose-dependent) insulin secretion are needed. Such new drugs should have the following characteristics:

[0006] dependency on glucose for promoting insulin secretion, i.e., compounds that stimulate insulin secretion only in the presence of elevated blood glucose; low primary and secondary failure rates; and preservation of islet cell function. The strategy to develop the new therapy disclosed herein is based on the cyclic adenosine monophosphate (cAMP) signaling mechanism and its effects on insulin secretion.

[0007] Metabolism of glucose promotes the closure of ATP-dependent K+ channels, which leads to cell depolarization and subsequent opening of Ca++ channels. This in turn results in the exocytosis of insulin granules. cAMP is a major regulator of glucose-stimulated insulin secretion. However, it has little if any effects on insulin secretion in the absence of or at low glucose concentrations (Weinhaus, A., 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.

[0008] Endogenous secretagogues like pituitary adenylate cyclase activating peptide (PACAP), VIP, and GLP-1 use the cAMP system to regulate insulin secretion in a glucose-dependent fashion (Komatsu, M., et al., Diabetes 46: 1928-1938, (1997)). Also, phosphodiesterases (PDEs) are known to be involved in the regulation of the cAMP system.

[0009] PACAP is a potent stimulator of glucose-dependent insulin secretion from pancreatic beta cells. Three different PACAP receptor types (R1, R2, and R3) have been described (Harmar, A., et al., Pharmacol. Reviews 50: 265-270 (1998)). The insulinotropic action of PACAP is mediated by the GTP binding protein Gs. Accumulation of intracellular cAMP in turn activates nonselective cation channels in beta cells increasing [Ca++]i, and promoting the exocytosis of insulin-containing secretory granules.

[0010] Vasoactive intestinal peptide (VIP) is a 28 amino acid peptide that was first isolated from hog upper small intestine (Said and Mutt, Science 169: 1217-1218, 1970; U.S. Pat. No. 3,879,371). This peptide belongs to a family of structurally related, small polypeptides that includes helodermin, secretin, the somatostatins, and glucagon. The biological effects of VIP are mediated by the activation of membrane-bound receptor proteins that are coupled to the intracellular cAMP signaling system. These receptors were originally known as VIP-R1 and VIP-R2, however, they were later found to be the same receptors as PACAP-R2 and PACAP-R3.

[0011] GLP-1 is released from the intestinal L-cell after a meal and functions as an incretin hormone (i.e., it potentiates glucose-induced insulin release from the pancreatic beta cell). It is a 37-amino acid peptide that is differentially expressed by the glucagon gene, depending upon tissue type. The clinical data that support the beneficial effect of raising cAMP levels in β-cells have been collected with GLP-1. Infusions of GLP-1 in poorly controlled type 2 diabetics normalized their fasting blood glucose levels (Gutniak, M., et al., New Eng. J. Med. 326:1316-1322, (1992)) and with longer infusions improved the beta cell function to those of normal subjects (Rachman, J. et al., Diabetes 45: 1524-1530, (1996)). A recent report has shown that GLP-1 improves the ability of β-cells to respond to glucose in subjects with impaired glucose tolerance (Byrne M., et al., Diabetes 47: 1259-1265 (1998)). All of these effects, however, are short-lived because of the short half-life of the peptide.

SUMMARY OF THE INVENTION

[0012] The invention provides compounds, pharmaceutical compositions, and methods of using the same for treating diabetes and related disorders. Compounds of the invention include compounds of formula (I)

[0013] wherein

[0014] R1 is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, and A-R9, or

[0015] R1 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(═O)0-2 and O, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, wherein said heterocycloalkyl and said heterocycloalkenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), all of which may be substituted with 1-3 of R10;

[0016] R10 is selected from nitro, nitrile, hydroxy, halogen, acyl of 1-6 carbon atoms, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, cycloalkoxy of 3-6 carbon atoms, aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(═O)0-2 and O, NR11R12, C(═O)OR11, C(═O)NHR11, NHC(═O)R13, NHS(═O)2R13, S(═O)0-2R13, S(═O)2NHR11, cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O);

[0017] R13 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, and cycloalkenyl of 4-6 carbon atoms;

[0018] R11 and R12 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, and cycloalkenyl of 4-6 carbon atoms;

[0019] A is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, and haloalkyl of 1-8 carbon atoms;

[0020] R9 is selected from hydroxy, alkoxy of 1-6 carbon atoms, cycloalkoxy of 3-6 carbon atoms, O-A-R14, NR11R12; or

[0021] R9 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(═O)0-2 and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 5-8 carbon atoms, all of which may be substituted with 1-3 of R10, or

[0022] R9 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10;

[0023] R14 is selected from cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 5-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, all of which may be substituted with 1-3 of R10;

[0024] R2 is selected from NR15R16, S(O)0-2R17, and OR17;

[0025] R15 is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, A-R9, C(═O)R18, C(═O)NHR18, S(═O)2NHR18;

[0026] R18 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(═O)0-2 and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, all of which may be substituted with 1-3 of R10, or

[0027] R18 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, and alkynyl of 2-6 carbon atoms, all of which may be substituted with 1-3 of halogen or alkoxy of 1-6 carbon atoms, or

[0028] R18 is A-R9;

[0029] R16 is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, and A-R9, or

[0030] R16 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(═O)0-2 and O, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, all of which may be substituted with 1-3 of R10, or

[0031] R15 and R16 combine, together with the nitrogen atom to which they are attached, to form a heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(═O)0-2 and O, or a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 lo carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), all of which may be substituted with 1-3 of R10;

[0032] R17 is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, and alkynyl of 2-8 carbon atoms, haloalkyl of 1-8 carbon atoms, A-R9, or

[0033] R17 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(═O)0-2 and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, all of which may be substituted with 1-3 of R10;

[0034] R3 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(═O)0-2 and O, cylcoalkyl of 3-8 carbon atoms, heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0-2, and O, cycloalkenyl of 4-8 carbon atoms, and heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0-2 and O, all of which may be substituted with 1-3 of R10, or

[0035] R3 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, hydrogen, nitro, halogen, NR19R20, A-OR19, A-NR19R , and A-R20;

[0036] R19 and R20 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A-R9, or

[0037] R19 and R20 are independently selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(O)0-2 and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 5-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0-2 and O, 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), all of which may be substituted with 1-3 of R10;

[0038] R4 is selected from ═O, ═S, and OR21;

[0039] R21 is hydrogen, or

[0040] R21 is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, all of which may be substituted with 1-3 of R10;

[0041] R5 and R6 are independently selected from cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms, all of which may be substituted with 1-3 of R10, or R5 and R6 are independently selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10, A-R23, A-NR24R25, C(═O)R24, C(═O)OR24, C(═O)NR24R25, S(═O)2R26, A-C(═O)R24, A-C(═O)OR24 or A-C(═O)NR24R25 or

[0042] R5 and R6 are independently selected from hydrogen, halogen, nitrile, nitro, hydroxy, alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, haloalkyl of 1-8 carbon atoms, alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms, cycloalkoxy of 3-8 carbon atoms, A-R23, A(OR22)—R23, NR27R28, A-NR27R28, A-Q-R29, Q-R29, Q-A-NR24R25, C(═O)R24, C(═O)OR24, C(═O)NR24R25, A-C(═O)R24, A-C(═O)OR24, and A-C(═O)NR24R25;

[0043] Q is selected from O and S(═O)0-2;

[0044] R22 is selected from hydrogen, alkyl of 1-8 carbon atoms, haloalkyl of 1-8 carbon atoms, and cycloalkyl of 3-8 carbon atoms;

[0045] R23 is selected from hydroxy, alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms, and cycloalkoxy of 3-8 carbon atoms, or

[0046] R23 is selected from cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or

[0047] R23 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10;

[0048] with the proviso for A(OR22)—R23 that when R23 is selected from hydroxy, alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms, and cycloalkoxy of 3-8 carbon atoms, A is not CH;

[0049] R24 and R25 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A-R23 or

[0050] R24 and R25 are independently selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or

[0051] R24 and R25 are independently selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10, or

[0052] R24 and R25 combine, together with the nitrogen atom to which they are attached, to form a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2, and O, a 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2, and O, or a heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), all of which may be substituted with 1-3 of R10;

[0053] R26 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A(OR22)—R23, and A-R23, or

[0054] R26 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or

[0055] R26 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(=)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10;

[0056] R27 is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A-R23, or

[0057] R27 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or

[0058] R27 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10;

[0059] R28 is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A-R23, C(═O)R24, C(═O)OR, C(═O)NR25R30, S(═O)2R26, A-C(═O)R24, A-C(═O)OR24, and A-C(═O)NR24R25, or

[0060] R28 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or

[0061] R28 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10;

[0062] R30 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A(OR22)—R23, and A-R23, or

[0063] R30 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or

[0064] R30 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10, or

[0065] R25 and R30 combine, together with the nitrogen atom to which they are attached, to form a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2, and O, a 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2, and O, or a heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms, all of which may be substituted with 1-3 of R10;

[0066] R29 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A-R23, A-C(═O)R24, A-C(═O)OR24, A-C(═O)NR24R25, A-NR27R28, or

[0067] R29 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or

[0068] R29 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10;

[0069] R7 is selected from cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms, all of which may be substituted with 1-3 of R10, or

[0070] R7 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10, A(OR22)—R23, A-R23, A-NR24R25, C(═O)R24, C(═O)OR24, C(═O)NR24R25 , S(═O)2R26, A-C(═O)R24, A-C(═O)OR24, or A-C(═O)NR24R25, or

[0071] R7 is selected from hydrogen, nitrile, nitro, hydroxy, alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, haloalkyl of 1-8 carbon atoms, alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms, cycloalkoxy of 3-8 carbon atoms, A-R23, A(OR22)-R23, NR27R28, A-NR27R28, A-Q-R29, Q-R29, Q-A-NR24R25, C(═O)R24, C(═O)OR24, C(═O)NR24R25, A-C(═O)R24, A-C(═O)OR24, and A-C(═O)NR24R25;

[0072] and pharmaceutically acceptable salts thereof, with the provisio that the compound is not: 1,5-dimethyl-2-(methylamino)-7-(4-morpholinyl)-1,8-naphthyridin-4(1H)-one, 1,5-dimethyl-2-(methylamino)-7-(4-methyl-1-piperazinyl)-1,8-naphthyridin-4(1H)-one, 1,5-dimethyl-2-(methylamino)-7-(1-pyrrolidinyl)-1,8-naphthyridin-4(1H)-one, 1,5-dimethyl-2-(methylamino)-7-(1-piperidinyl)-1,8-naphthyridin-4(1H)-one, 1,5-dimethyl-2-(methylamino)-7-(4-methyl-1-piperazinyl)-3-nitro-1,8-naphthyridin-4(1H)-one, 1,5-dimethyl-2-(methylamino)-3-nitro-7-(1-pyrrolidinyl)-1,8-naphthyridin-4(1H)-one, or 1-(3-chlorophenyl)-2-(4-morpholinyl)-1,8-naphthyridin-4(1H)-one.

[0073] Another aspect of the invention includes compounds of formula (I) wherein R1 is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, and A-R9, or

[0074] R1 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(═O)0-2 and O, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, wherein said heterocycloalkyl and said heterocycloalkenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O),all of which may be substituted with 1-3 of R10;

[0075] R10 is selected from nitro, nitrile, hydroxy, halogen, acyl of 1-6 carbon atoms, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, cycloalkoxy of 3-6 carbon atoms, aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(═O)0-2 and O, NR11R12, C(═O)OR11, C(═O)NHR11, NHC(═O)R13, NHS(═O)2R13, S(═O)0-2R13, S(═O)2NHR11, cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O);

[0076] R13 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, and cycloalkenyl of 4-6 carbon atoms;

[0077] R11 and R12 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, and cycloalkenyl of 4-6 carbon atoms;

[0078] A is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, and haloalkyl of 1-8 carbon atoms;

[0079] R9 is selected from hydroxy, alkoxy of 1-6 carbon atoms, cycloalkoxy of 3-6 carbon atoms, O-A-R4, NR11R12; or

[0080] R9 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(═O)0-2 and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 5-8 carbon atoms, all of which may be substituted with 1-3 of R10, or

[0081] R9 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or lo heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10;

[0082] R14 is selected from cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 5-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, all of which may be substituted with 1-3 of R10.

[0083] R2 is NR15R16;

[0084] R15 is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, A-R9, C(═O)R18, C(═O)NHR18, S(═O)2NHR18;

[0085] R18 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(═O)0-2 and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, all of which may be substituted with 1-3 of R10, or

[0086] R18 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, and alkynyl of 2-6 carbon atoms, all of which may be substituted with 1-3 of halogen or alkoxy of 1-6 carbon atoms, or

[0087] R18 is A-R9;

[0088] R16 is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, and A-R9, or

[0089] R16 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(═O)0-2 and O, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, all of which may be substituted with 1-3 of R10, or

[0090] R15 and R16 combine, together with the nitrogen atom to which they are attached, to form a heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(═O)0-2 and O, or a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), all of which may be substituted with 1-3 of R10;

[0091] R3 is selected from cycloalkyl of 3-6 carbon atoms, heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0-2 and O, both of which may be substituted with 1-3 of R10, or

[0092] R3 is selected from alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, hydrogen, nitro, halogen, NR19R20, A-OR19, A-NR19R20 and A-R20;

[0093] R19 and R20 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A-R9, or

[0094] R19 and R20 are independently selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(O)0-2 and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 5-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0-2 and O, 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), all of which may be substituted with 1-3 of R10;

[0095] R4 is selected from ═O, ═S, and OR21;

[0096] R21 is hydrogen, or

[0097] R21 is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, all of which may be substituted with 1-3 of R10;

[0098] R5 and R6 are independently selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 4-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms, all of which may be substituted with 1-3 of R10, or

[0099] R5 and R6 are independently selected from is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10, A-R23, A-NR24R25, C(═O)R24, C(═O)OR24, C(═O)NR24R25, S(═O)2R26, A-C(═O)R24, A-C(═O)OR24, or A-C(═O)NR24R25, or

[0100] R5 and R6 are independently selected from hydrogen, halogen, nitrile, nitro, hydroxy, lo alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, cycloalkoxy of 3-6 carbon atoms, A-R23, A(OR22)—R23, NR27R28, A-NR27R28, A-Q-R29, Q-R2, Q-A-NR24R25, C(═O)R24, C(═O)OR24, C(═O)NR24R25, A-C(═O)R24, A-C(═O)OR24, and A-C(═O)NR24R25;

[0101] Q is selected from O and S(═O)0-2;

[0102] R22 is selected from hydrogen, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and cycloalkyl of 3-6 carbon atoms;

[0103] R23 is selected from hydroxy, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, and cycloalkoxy of 3-6 carbon atoms, or

[0104] R23 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 4-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or

[0105] R23 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10; with the proviso for A(OR22)—R23 that when R23 is selected from hydroxy, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, and cycloalkoxy of 3-6 carbon atoms, A is not CH;

[0106] R24 and R25 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A-R23, or

[0107] R24 and R25 are independently selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10,or

[0108] R24 and R25 are independently selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10, or

[0109] R24 and R25 combine, together with the nitrogen atom to which they are attached, to form a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2, and O, a 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2, and O, or a monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), all of which may be substituted with 1-3 of R10;

[0110] R26 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A(OR22)—R23, and A-R23, or

[0111] R26 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or

[0112] R26 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10;

[0113] R27 is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A-R23, or

[0114] R27 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or

[0115] R27 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10;

[0116] R28 is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A-R23, C(═O)R24, C(═O)OR, C(═O)NR25R30, S(═O)2R26, A-C(═O)R24, A-C(═O)OR24, and A-C(═O)NR24R25, or

[0117] R28 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or

[0118] R28 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10;

[0119] R30 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A(OR22)—R23, and A-R23, or

[0120] R30 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or

[0121] R30 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10, or

[0122] R25 and R30 combine, together with the nitrogen atom to which they are attached, to form a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2, and O, a 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2, and O, or a monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms, all of which may be substituted with 1-3 of R10; and

[0123] R29 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A-R23, A-C(═O)R24, A-C(═O)OR24, A-C(═O)NR24R , A-NR27R28, or

[0124] R29 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or

[0125] R29 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10;

[0126] R7 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 4-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms, all of which may be substituted with 1-3 of R10, or

[0127] R7 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10, AR23, A-NR24R25, C(═O)R24, C(═O)OR24, C(═O)NR24R25, S(═O)2R26, A-C(═O)R24, A-C(═O)OR24, or A-C(═O)NR24R25, or

[0128] R7 is selected from hydrogen, nitrile, nitro, hydroxy, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, cycloalkoxy of 3-6 carbon atoms, A-R23, A(OR22)—R23, NR27R28, A-NR27R28, A-Q-R29, Q-R29, Q-A-NR24R25, C(═O)R24, C(═O)OR24, C(═O)NR24R25, A-C(═O)R24, A-C(═O)OR24, and A-C(═O)NR24R25;

[0129] and pharmaceutically acceptable salts thereof with the provisio that the compound is not: 1,5-dimethyl-2-(methylamino)-7-(4-morpholinyl)-1,8-naphthyridin-4(1H)-one, 1,5-dimethyl-2-(methylamino)-7-(4-methyl-1-piperazinyl)-1,8-naphthyridin-4(1H)-one, 1,5-dimethyl-2-(methylamino)-7-(1-pyrrolidinyl)-1,8-naphthyridin-4(1H)-one, 1,5-dimethyl-2-(methylamino)-7-(1-piperidinyl)-1,8-naphthyridin-4(1H)-one, 1,5-dimethyl-2-(methylamino)-7-(4-methyl-1-piperazinyl)-3-nitro-1,8-naphthyridin-4(1H)-one, 1,5-dimethyl-2-(methylamino)-3-nitro-7-(1-pyrrolidinyl)-1,8-naphthyridin-4(1H)-one, or 1-(3-chlorophenyl)-2-(4-morpholinyl)-1,8-naphthyridin-4(1H)-one.

[0130] Methods of the invention provide for the treatment or prevention of diabetes, inlcuding Type 1 and Type 2 diabetes, and related disorders by administration of a compound of the invention. Related disorders include maturity-onset diabetes of the young (MODY), latent autoimmune diabetes adult (LADA), impaired glucose tolerance (IGT), impaired fasting glucose (IFG), gestational diabetes, and metabolic syndrome X.

[0131] In other embodiments, methods of the invention provide for the administration of a compound of the invention in combination with a PPAR agonist, an insulin sensitizer, a sulfonylurea, an insulin secretagogue, a hepatic glucose output lowering compound, an a-glucosidase inhibitor or insulin. PPAR agonist includes rosiglitazone and pioglitazone. Sulfonylureas include glibenclamide, glimepiride, chlorpropamide, and glipizide. Insulin secretagogues include GLP-1, GIP, PACJVPAC receptor agonists, secretin, nateglinide, meglitinide, repaglinide, glibenclamide, glimepiride, chlorpropamide, and glipizide. α-glucosidase inhibitors include acarbose, miglitol and voglibose. A hepatic glucose output lowering compound is metformin.

[0132] In another embodiment, methods of the invention provide for the administration of a compound of the invention in combination with an HMG-CoA reductase inhibitor, nicotinic acid, a bile acid sequestrant, a fibric acid derivative, antihypertensive drug, or an anti-obesity drug. Anti-obesity drugs include a β-3 agonist, a CB-1 antagonist, and a lipase inhibitor.

[0133] In another embodiment of the invention, methods are provided for the treatment or prevention of secondary causes of diabetes, such as glucocorticoid excess, growth hormone excess, pheochromocytoma, and drug-induced diabetes.

[0134] Finally, methods of the invention provide for increasing the sensitivity of pancreatic beta cells to an insulin secretagogue, by administering a compound of the invention. Insulin secretagogues include GLP-1, GIP, PAC/VPAC receptor agonists, secretin, nateglinide, meglitinide, repaglinide, glibenclamide, glimepiride, chlorpropamide, and glipizide.

[0135] The present invention therefore provides compounds and methods for the treatment of diabetes and related disorders. These and other aspects of the invention will be more apparent from the following description and claims.

DETAILED DESCRIPTION OF THE INVENTION

[0136] The invention relates generally to naphthyridine derivatives of the formula

[0137] wherein one of U, X, Y and Z is nitrogen and the others are C—R, where R is hydrogen or a substituent such as R5, R6 or R7, as described above for formula (I). R1, R2, R3 and R4 are as defined above for formula (I). The invention also relates to compounds of formula (I), described above, and to compounds of formula (II)

[0138] wherein R1′, R2′, R3′, R4′, R5′, R7′ and R8′ correspond to R1, R2, R3, R4, R5, R6 and R7, respectively, of formula (I). Such compounds may be used in the treatment of diabetes and related disorders.

[0139] In one embodiment, the invention relates to compounds of formula (I), as described above. In another embodiment, the invention relates to compounds of formula (I), wherein R1 is phenyl, which may be substituted with 1-3 of R10, R2 is NR15R16, R3 is selected from cycloalkyl of 3-6 carbon atoms, heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0-2 and O, both of which may be substituted with 1-3 of R10, or R3 is selected from alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, hydrogen, nitro, halogen, NR19R20, A-OR19, A-NR19R20 and A-R20, and R4 is ═O.

[0140] In another embodiment, the invention relates to methods of treating diabetes and related disorders by administration of compounds of formula (I). Preferred methods relate to the treatment of Type 2 diabetes. In methods of the invention, compounds of formula (I) may be administered in combination with PPAR agonist, insulin sensitizers, sulfonylureas, insulin secretagogues, metformin, a-glucosidase inhibitors and insulin. In another embodiment, compounds of formula (I) are administered in combination with an HMG-CoA reductase inhibitor, nicotinic acid, a bile acid sequestrant, a fibric acid derivative, an anti-hypertensive drug or an anti-obesity drug.

[0141] In other methods of the invention, compounds of formula (I) are administered to treat or prevent secondary causes of diabetes or to increase the sensitivity of pancreatic beta cells to an insulin secretagogue.

[0142] General Preparative Methods

[0143] The compounds of the invention may be prepared by use of known chemical reactions and procedures. Nevertheless, the following general synthetic schemes are presented to aid the reader in synthesizing compounds of this invention, with more detailed particular examples being presented below in the experimental section describing the working examples.

[0144] In general, compounds of Formula (I) (R4 is ═O) may be prepared from the appropriately substituted nicotinic acid through several routes summarized in Flow Diagram I to IV. Compounds of Formula (II) (R4′ is ═O) may be prepared from the appropriately substituted nicotinic acid through the route summarized in Flow diagram V. The close analogy between Flow Diagram I and V demonstrates that the routes used to synthesize Formula (I) may be applied to synthesize Formula (II). The routes shown in Flow Diagram II to IV maybe used to synthesize Formula (II) from appropriately substituted nicotinic acid.

[0145] The nicotinic acids used in the above flow diagrams could be purchased from commercial sources, prepared according to Flow Diagram VI, or prepared according to literature in this field (Biorg. Med. Chem. Lett. 2001, 475-477; J Prakt. Chem. 2002, 33; Eur. J Org. Chem. 2001, 1371; J Org. Chem. 2000, 65, 4618; J. Med. Chem. 1997, 40, 2674; Bioorg. Med. Chem. Lett. 2000, 10, 1151; U.S. Pat. No. 3,838,156, etc.).

[0146] Further manipulations of Formula (I) (when R4 is ═O) and (II) (when R4′ is ═O) could lead to more diversely substituted compounds. These manipulations include aromatic nucleophilic substitutions, metal-mediated couplings, reductions, oxidations, amide formations, etc.

[0147] Flow Diagram VII illustrates alkylation, and amide, urea, and sulfonamide formations in Formula (I) when R2═NHR16. Similar transformations could be carried out in Formula (II) when R2′═NHR16.

[0148] Flow Diagram VIII and IX illustrate transformations at R3 in Formula (I). These transformations could also be applied to R3′ in Formula (II).

[0149] Flow Diagram X illustrates manipulations of R4 in formula (I), which could also be used on R4′ in formula (II).

[0150] Flow Diagram XI illustrates manipulations of R6 in formnula (I). These manipulations could also be applied to R5 and R7 in formula (I), R5′, R7′, and R8′ in formula (II).

[0151] Flow Diagram XII illustrates manipulations on R7 of formula (I). These manipulations could also be applied to R5 in formula (I), R5′ and R7′ in formula (II).

[0152] Flow Diagram XIII illustrates manipulations on R5 of formula (I). These manipulations could also be applied to R7 in formula (I), R5′ and R7′ in formula (II).

[0153] E+ is alkyl halide, aldehydes, halogen, CO-2, O2, activated ester, etc.

[0154] Flow Diagram XIV illustrates the transformations of some functional groups which are present in Formula (I) or (II).

[0155] Alternative Forms of Novel Compounds

[0156] 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.

[0157] (a) The Stereoisomers

[0158] The stereoisomers of these compounds may include, but are not limited to, enantiomers, diastereomers, racemic mixtures and combinations thereof. Such stereoisomers can be prepared and separated using conventional techniques, either by reacting enantiomeric starting materials, or by separating isomers of compounds of the present invention. Isomers may include geometric isomers. Examples of geometric isomers include, but are not limited to, cis isomers or trans isomers across a double bond. Other isomers are contemplated among the compounds of the present invention. The isomers may be used either in pure form or in admixture with other isomers of the inhibitors described above.

[0159] (b) The Pharmaceutically-Acceptable Salts

[0160] Pharmaceutically-acceptable salts of the compounds of the present invention include salts commonly used to form alkali metal salts or form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically-acceptable. Suitable pharmaceutically-acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic,, heterocyclic, carboxylic and sulfonic classes of organic acids. Examples of organic and sulfonic classes of organic acids includes, but are not limited to, formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicyclic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, algenic, N-hydroxybutyric, salicyclic, galactaric and galacturonic acid and combinations thereof.

[0161] (c) The Tautomers

[0162] Tautomers of the compounds of the invention are encompassed by the present invention. Thus, for example, a carbonyl includes its hydroxy tautomer.

[0163] (d) The Protected Acids and the Conjugate Acids

[0164] The protected acids include, but are not limited to, esters, hydroxyamino derivatives, amides and sulfonamides.

[0165] (e) The Prodrugs

[0166] 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 “Pharmaceutical Dosage Form and Drug Delivery Systems” (Sixth Edition), edited by Ansel et al., publ. by Williams & Wilkins, pgs. 27-29, (1995) which is hereby incorporated by reference). Commonly used prodrugs are designed to take advantage of the major drug biotransformation reactions and are also to be considered within the scope of the invention. Major drug biotransformation reactions include N-dealkylation, O-dealkylation, aliphatic hydroxylation, aromatic hydroxylation, N-oxidation, S-oxidation, deamination, hydrolysis reactions, glucuronidation, sulfation and acetylation (see Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al., publ. by McGraw-Hill, pages 11-13, (1996), which is hereby incorporated by reference).

[0167] Dosages and Treatment Regimen

[0168] Dosage levels of the compounds of this invention typically are from about 0.001 mg to about 10,000 mg daily, preferably from about 0.005 mg to about 1,000 mg daily. On the basis of mg/kg daily dose, either given in a single dose or in divided doses, dosages typically range from about 0.001/75 mg/kg to about 10,000/75 mg/kg, preferably from about 0.005/75 mg/kg to about 1,000/75 mg/kg.

[0169] The total daily dose of each drug 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.

[0170] The 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 with the combinations and compositions of the present invention is selected in accordance with a variety of factors. These factors include, but are not limited to, the type, age, weight, sex, diet, and medical condition of the subject, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetics and toxicology profiles of the particular inhibitors employed, whether a drug delivery system is utilized, and whether the inhibitors are administered with other active ingredients. Thus, the dosage regimen actually employed may vary widely and therefore deviate from the preferred dosage regimen set forth above.

[0171] Pharmaceutical Compositions

[0172] For the prophylaxis or treatment of the conditions and disorders referred to above, the compounds of this invention can be administered as the compound per se. Alternatively, pharmaceutically-acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to that of the parent compound.

[0173] The compounds of the present invention also can be administered with an acceptable carrier in the form of a pharmaceutical composition. The carrier must be acceptable in the sense of being 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.

[0174] The active 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 active compounds and compositions, for example, may be administered orally, sublingually, nasally, pulmonarily, mucosally, parenterally, intravascularly, intraperitoneally, 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.

[0175] For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, a capsule, a suspension, an emulsion, a paste, a solution, a syrup or other liquid form. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. If administered by mouth, the compounds may be admixed with, for example, lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.

[0176] Oral delivery of the compounds of the present invention can include formulations, as are well known in the art, to provide immediate delivery or prolonged or sustained delivery of the 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 the 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 are within the scope of the present invention. Suitable enteric coatings include cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethyl-cellulose phthalate and anionic polymers of methacrylic acid and methacrylic acid methyl ester.

[0177] Pharmaceutical compositions suitable for oral administration can be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the present invention; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. As indicated, such compositions can be prepared by any suitable method of pharmacy which includes the step of bringing into association the inhibitor(s) and the carrier (which can constitute one or more accessory ingredients). In general, the compositions are prepared by uniformly and intimately admixing the inhibitor(s) 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.

[0178] 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.

[0179] Pharmaceutical compositions suitable for buccal (sub-lingual) administration include lozenges comprising a compound of the present invention in a flavored base, usually sucrose, and acacia or tragacanth, and pastilles comprising the inhibitors in an inert base such as gelatin and glycerin or sucrose and acacia.

[0180] Formulations for parenteral administration, for example, may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.

[0181] Pharmaceutically acceptable carriers encompass all the foregoing and the like. The pharmaceutical compositions of the invention can be prepared by any of the well-known techniques of pharmacy, such as admixing the components. The above considerations in regard to effective formulations and administration procedures are well known in the art and are described in standard textbooks.

[0182] Methods of Use

[0183] The present invention also includes methods for the treatment of diabetes and related diseases and conditions. One such method comprises the step of administering to a subject in need thereof, a therapeutically effective amount of one or more compounds of formula (I).

[0184] Compounds of formula (I) may be used in methods of the invention to treat diseases, such as diabetes, including both Type 1 and Type 2 diabetes. Such methods may also delay the onset of diabetes and diabetic complications. Other diseases and conditions that may be treated or prevented using compounds of formula (I) in methods of the invention include: Maturity-Onset Diabetes of the Young (MODY) (Herman, et al., Diabetes 43:40 (1994)), Latent Autoimmune Diabetes Adult (LADA) (Zimmet, et al, Diabetes Med. 11:299 (1994)), impaired glucose tolerance (IGT) (Expert Committee on Classification of Diabetes Mellitus, Diabetes Care 22 (Supp. 1) S5 (1999)), impaired fasting glucose (IFG) (Charles, et al., Diabetes 40:796 (1991)), gestational diabetes (Metzger, Diabetes, 40:197 (1991), and metabolic syndrome X.

[0185] Compounds of formula (I) may also be used in methods of the invention to treat secondary causes of diabetes (Expert Committee on Classification of Diabetes Mellitus, Diabetes Care 22 (Supp. 1), S5 (1999)). Such secondary causes include glucocorticoid excess, growth hormone excess, pheochromocytoma, and drug-induced diabetes. Drugs that may induce diabetes include, but are not limited to, pyriminil, nicotinic acid, glucocorticoids, phenytoin, thyroid hormone, β-adrenergic agents, α-interferon and drugs used to treat HIV infection.

[0186] The methods and compounds of the present invention may be used alone or in combination with additional therapies and/or compounds known to those skilled in the art in the treatment of diabetes and related disorders. Alternatively, the methods and compounds described herein may be used, partially or completely, in combination therapy.

[0187] Compounds of formula (I) may also be administered in combination with other known therapies for the treatment of diabetes, including PPAR agonists, sulfonylurea drugs, non-sulfonylurea secretagogues, cc-glucosidase inhibitors, insulin sensitizers, insulin secretagogues, hepatic glucose output lowering compounds, insulin and anti-obesity drugs. Such therapies may be administered prior to, concurrently with or following administration of the compound of formula (I). Insulin includes both long and short acting forms and formulations of insulin. PPAR agonist may include agonists of any of the PPAR subunits or combinations thereof. For example, PPAR agonist may inlcude agonists of PPAR-α, PPAR-γ, PPAR-δ or any combination of two or three of the subunits of PPAR. PPAR agonists include, for example, rosiglitazone and pioglitazone. Sulfonylurea drugs include, for example, glyburide, glimepiride, chlorpropamide, and glipizide. a-glucosidase inhibitors that may be useful in treating diabetes when administered with a compound of formula (I) include acarbose, miglitol and voglibose. Insulin sensitizers that may be useful in treating diabetes when administered with a compound of formula (I) include thiazolidinediones and non-thiazolidinediones. Hepatic glucose output lowering compounds that may be useful in treating diabetes when administered with a compound of formula (I) include metformin, such as Glucophage and Glucophage XR. Insulin secretagogues that may be useful in treating diabetes when administered with a compound of formula (I) include sulfonylurea and non-sulfonylurea drugs: GLP-1, GIP, PAC/VPAC receptor agonists, secretin, nateglinide, meglitinide, repaglinide, glibenclamide, glimepiride, chlorpropamide, glipizide. GLP-1 includes derivatives of GLP-1 with longer half-lives than native GLP-1, such as, for example, fatty-acid derivatized GLP-1 and exendin. In one embodiment of the invention, compounds of formula (I) are used in combination with insulin secretagogues to increase the sensitivity of pancreatic beta cells to the insulin secretagogue.

[0188] Compounds of formula (I) may also be used in methods of the invention in combination with anti-obesity drugs. Anti-obesity drugs include β-3 agonists, CB-1 antagonists, appetite suppressants, such as, for example, sibutramine (Meridia), and lipase inhibitors, such as, for example, orlistat (Xenical).

[0189] Compounds of formula (1) may also be used in methods of the invention in combination with drugs commonly used to treat lipid disorders in diabetic patients. Such drugs include, but are not limited to, HMG-CoA reductase inhibitors, nicotinic acid, bile acid sequestrants, and fibric acid derivatives. Compounds of formula (I) may also be used in combination with anti-hypertensive drugs, such as, for example, β-blockers and ACE inhibitors.

[0190] Such co-therapies may be administered in any combination of two or more drugs (e.g., a compound of formula (I) in combination with an insulin sensitizer and an anti-obesity drug). Such co-therapies may be administered in the form of pharmaceutical compositions, as described above.

[0191] Terms

[0192] As used herein, various terms are defined below.

[0193] 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.

[0194] The term “subject” as used herein includes mammals (e.g., humans and animals).

[0195] 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.

[0196] The phrase “therapeutically-effective” means the amount of each agent administered that will achieve the goal of improvement in a diabetic condition or disorder severity, while avoiding or minimizing adverse side effects associated with the given therapeutic treatment.

[0197] The term “pharmaceutically acceptable” means that the subject item is appropriate for use in a pharmaceutical product.

[0198] The term “prodrug” includes a compound that is a drug precursor that, following administration to a subject and subsequent absorption, is converted to an active species in vivo. Conversion to the active, species in vivo is typically via some process, such as metabolic conversion. An example of a prodrug is an acylated form of the active compound.

[0199] The following definitions pertain to the structure of the compounds: In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified, for example, alkyl of 1-8 carbon atoms or C1-C8 alkyl. The use of a term designating a monovalent radical where a divalent radical is appropriate shall be construed to designate the divalent radical and vice versa. Unless otherwise specified, conventional definitions of terms controls and conventional stable atom valences are presumed and achieved in all formulas and groups.

[0200] When symbols such as “A-Q-R” is used, it refers to a group which is formed by linking group A, group Q and group R in the designated order and the attachment of this group “A-Q-R” is any position on group A to form a stable structure. Group Q may be linked to any position on group A to form a stable structure and group R may be linked to any position on group Q to form a stable structure.

[0201] When symbols such as “A(OR′)—R” is used, it refers to a group which is formed by susbstituting group A with both group OR1 and group R and the attachment of this group “A(OR′)—R” is any position on group A to form a stable structure. Group OR1 and group R maybe linked to any position on group A to form a stable structure.

[0202] The term “halogen” refers to a halogen radical selected from fluoro, chloro, bromo or iodo.

[0203] The term “alkyl” refers to a saturated aliphatic hydrocarbon radical. “Alkyl” refers to both branched and unbranched alkyl groups. Examples of “alkyl” include alkyl groups that are straight chain alkyl groups containing from one to ten carbon atoms and branched alkyl groups containing from three to ten carbon atoms. Other examples include alkyl groups that are straight chain alkyl groups containing from one to six carbon atoms and branched alkyl groups containing from three to six carbon atoms. This term is examplified by groups such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), 1,1-dimethylethyl (tert-butyl), and the like. It may be abbreviated “Alk”. It should be understood that any combination term using an “alk” or “alkyl” prefix refers to analogs according to the above definition of “alkyl”. For example, terms such as “alkoxy”, “alkylthio”, “alkylamino” refer to alkyl groups linked to a second group via an oxygen, sulfur, or nitrogen atom, respectively.

[0204] The term “haloalkyl” refers to an alkyl group in which one or more hydrogen atoms are replaced with halogen atoms. This term in examplified by groups such as trifluomethyl. The more preferred haloalkyl groups are alkyl groups substituted with one or more fluro or chloro. The term “haloalkoxy” refers to haloalkyl groups linked to a second group via an oxygen atom.

[0205] The term “alkenyl” refers to a mono or polyunsatuarted aliphatic hydrocarbon radical. The mono or polyunsaturated aliphatic hydrocarbon radical contains at least one carbon-carbon double bond. “Alkenyl” refers to both branched and unbranched alkenyl groups, each optionally partially or fully halogenated. Examples of“alkenyl” include alkenyl groups that are straight chain alkenyl groups containing from two to ten carbon atoms and branched alkenyl groups containing from three to ten carbon atoms. Other examples include alkenyl groups that are straight chain alkenyl groups containing from two to six carbon atoms and branched alkenyl groups containing from three to six carbon atoms. This term is exemplified by groups such as ethenyl, propenyl, n-butenyl, isobutenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, decenyl, and the like.

[0206] The term “alkynyl” refers to a mono or polyunsatuarted aliphatic hydrocarbon radical. The mono or polyunsaturated aliphatic hydrocarbon radical contains at least one carbon-carbon triple bond. “Alkynyl” refers to both branched and unbranched alkynyl groups, each optionally partially or fully halogenated. Examples of “alkynyl” include alkynyl groups that are straight chain alkynyl groups containing from two to ten carbon atoms and branched alkynyl groups containing from four to ten carbon atoms. Other examples include alkynyl groups that are straight chain alkynyl groups containing from two to six carbon atoms and branched alkynyl groups containing from four to six carbon atoms. This term is exemplified by groups such as ethynyl, propynyl, octynyl, and the like.

[0207] The term “cycloalkyl” refers to the mono- or polycyclic analogs of an alkyl group, as defined above. Unless otherwise specified, the cycloalkyl ring may be attached at any carbon atom that results in a stable structure and, if substituted, may be substituted at any suitable carbon atom which results in a stable structure. Examples of cycloalkyl groups are saturated cycloalkyl groups containing from three to ten carbon atoms. Other examples include cycloalkyl groups containing three to six carbon atoms. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cyclononyl, cyclodecyl, norbomane, adamantyl, and the like.

[0208] The term “cycloalkenyl” refers to the mono- or polycyclic analogs of an alkenyl group, as defined above. Unless otherwise specified, the cycloalkenyl ring may be attached at any carbon atom that results in a stable structure and, if substituted, may be substituted at any suitable carbon atom that results in a stable structure. Examples of cycloalkenyl groups are cycloalkenyl groups containing from four to ten carbon atoms. Other examples include cycloalkenyl groups containing four to six carbon atoms. Exemplary cycloalkenyl groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, norbomene, and the like.

[0209] The term “heterocycloalkyl” refers to the mono- or polycyclic structures of “cycloalkyl” where one or more of the carbon atoms are replaced by one or more atoms independently chosen from nitrogen, oxygen, or sulfur atoms. Any nitrogen atom maybe S optionally oxidized or quantemized, and any sulfur atom maybe optionally oxidized. Unless otherwise specified, the heterocycloalkyl ring may be attached at any carbon atom or heteroatom that results in a stable structure and, if substituted, may be substituted at any suitable carbon atom or heteroatom which results in a stable structure. Examples of heterocycloalkyl groups are saturated heterocycloalkyl groups containing from two to nine carbon atoms and one to four heteroatoms chosen independently from nitrogen, oxygen, or sulfur atoms. Examples of heterocycloalkyl groups include morpholino, pyrazino, tetrahydrofurano, and the like.

[0210] The term “heterocycloalkenyl” refers to the mono- or polycyclic structures of “cycloalkenyl” where one or more of the carbon atoms are replaced by one or more atoms independently chosen from nitrogen, oxygen, or sulfur atoms. Any nitrogen atom maybe optionally oxidized or quantemized, and any sulfur atom maybe optionally oxidized. Unless otherwise specified, the heterocycloalkenyl ring may be attached at any carbon atom or heteroatom that results in a stable structure and, if substituted, may be substituted at any suitable carbon atom or heteroatom which results in a stable structure. Examples of heterocycloalkenyl groups are saturated heterocycloalkenyl groups containing from two to nine carbon atoms and one to four heteroatoms chosen independently from nitrogen, oxygen, or sulfur atoms. Examples of heterocycloalkenyl groups include dihydropyran, dihydrofuran, and the like.

[0211] The term “cycloalkyloxy” refers to a monovalent radical of the formula —O-cycloalkyl, i.e., a cycloalkyl group linked to a second group via an oxygen atom.

[0212] The term “acyl” refers to a monovalent radical of the formula —C(═O)-alkyl and —C(═O)-cycloalkyl, i.e., an alkyl or cycloakyl group linked to a second group via caronyl group C(═O), wherein said alkyl maybe further substituted with cycloalkyl, aryl, or heteroaryl. Examples of acyl groups include —C(═O)Me (acetyl), —C(═O)CH2-cyclopropyl (cyclopropylacetyl), —C(═O)CH2Ph (phenylacetyl), and the like.

[0213] The term “aryl” refers to 6-10 membered mono- or polycyclic aromatic carbocycles, for example, phenyl and naphthyl. Unless otherwise specified, the aryl ring may be attached at any carbon atom that results in a stable structure and, if substituted, may be substituted at any suitable carbon atom which results in a stable structure. The term “aryl” refers to non-substituted aryls and aryls optionally substituted with one or more of the following groups: halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C4-C6 cycloalkenyl, C2-C6 alkynyl, nitro, cyano, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, amino, C1-C6 alkylamino (for example, —NHMe and —N(Me)2), C1-C6 acyl, thiol, alkylthio, carboxylic acid. All the above subtsitutions can further be substituted with optionally selected groups to form a stable structure. It may be abbreviated “Ar”. It should be understood that any combination term using an “ar” or “aryl” prefix refers to analogs according to the above definition of “aryl”. For example, terms such as “aryloxy”, “arylthio”, “arylamino” refer to aryl groups linked to a second group via an oxygen, sulfur, or nitrogen atom, respectively.

[0214] The term “heteroaryl” refers to a stable 5-8 membered (but preferably, 5 or 6 membered) monocyclic or 8-11 membered bicyclic aromatic heterocycle radical. Each heteroaryl contains 1-10 carbon atoms and from 1 to 5 heteroatoms independently chosen from nitrogen, oxygen and sulfur, wherein any sulfur heteroatom may optionally be oxidized and any nitrogen heteroatom may optionally be oxidized or quaternized. Unless otherwise specified, the heteroaryl ring may be attached at any suitable heteroatom or carbon atom that results in a stable structure and, if substituted, may be substituted at any suitable heteroatom or carbon atom that results in a stable structure. The term “heteroaryl” includes heteroaryl groups that are non-substituted or those optionally substituted with one or more of the following groups: halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C4-C6 cycloalkenyl, C2-C6 alkynyl, nitro, cyano, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, amino, C1-C6 alkylamino (for example, —NHMe and —N(Me)2), C1-C6 acyl, thiol, alkylthio, carboxylic acid. Examples of“heteroaryl” include radicals such as furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzisothiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and phenoxazinyl. Terms such as “heteroaryloxy”, “heteroarylthio”, “heteroarylamino” refer to heteroaryl groups linked to a second group via an oxygen, sulfur, or nitrogen atom, respectively.

[0215] The terms “optional” or “optionally” mean that the subsequently described event or circumstances may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “optionally substituted aryl” means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.

[0216] 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.

[0217] 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, inside cover.

[0218] Abbreviations and Acronyms

[0219] When the following abbreviations are used throughout the disclosure, they have the following meaning:

[0220] CH2Cl2 methylene chloride

[0221] THF tetrahydrofuran

[0222] CH3CN acetonitrile

[0223] Na2SO4 anhydrous sodium sulfate

[0224] MgSO4 anhydrous magnesium sulfate

[0225] DMSO dimethylsulfoxide

[0226] EtOAc ethyl acetate

[0227] Et2O diethyl ether

[0228] Et3N triethylamine

[0229] H2 hydrogen

[0230] CO carbon monoxide

[0231] HCl hydrochloric acid

[0232] Hex hexanes

[0233]

1
H NMR proton nuclear magnetic resonance

[0234] HPLC high performance liquid chromatography

[0235] K2CO3 potassium carbonate

[0236] Cs2CO3 cesium carbonate

[0237] NH4Cl ammonium chloride

[0238] LC/MS liquid chromatography/mass spectroscopy

[0239] MeOH methanol

[0240] MS ES mass spectroscopy with electrospray

[0241] NaHCO3 sodium bicarbonate

[0242] NaOH sodium hydroxide

[0243] RT retention time

[0244] h hour

[0245] min minutes

[0246] Pd(OAc)2 palladium acetate

[0247] Ni(dppp)Cl2 [1,3-bis(diphenylphosphino)propane]dichloronickel(II)

[0248] DMF N,N-dimethylformamide

[0249] EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

[0250] LTMP Lithium tetramethylpiperidine

[0251] BuLi butyllithium

[0252] TLC thin layer chromatography

[0253] TFA trifluoacetic acid

[0254] TMEDA tetramethylethylenediamine

[0255] BINAP 2,2′-bis(diphenylphosphino)-1,1′binaphthyl

[0256] HOBt 1-hydroxybenzotriazole hydrate

[0257] NaH sodium hydride

[0258] MeMgBr methylmagnesium bromide

[0259] DPPP (diphenylphosphino)propane

[0260] DME dimethoxyethane

[0261] AlCl3 aluminum chloride

[0262] TEA triethyl amine

[0263] CS2 carbon disulfide

[0264] MeI methyl iodide

[0265] t-BuOK potassium tert-butoxide

[0266] KHMDS potassium hexamethyldisilazide

[0267] LiHMDS lithium hexamethyldisilazide

[0268] NaOBr sodium hypobromite

[0269] Br2 bromine

[0270] Conc. Concentrated

[0271] Pd/C palladium on carbon

[0272] EtOH ethanol

[0273] NH3 ammonia

[0274] NaOMe sodium methoxide

[0275] PPh3 triphenylphosine

[0276] NaH sodium hydride

[0277] LDA lithium diisopropylamide

[0278] SOCl2 thionyl chloride

[0279] MsCl methanesulfonyl chloride

[0280] DMAP 4-dimethylaminopyridine

[0281] NMM 4-methylmorpholine

[0282] AcOH acetic acid

[0283] Na2S2O3 sodium thiosulfate

[0284] H2SO4 sulfuric acid

[0285] CHCl3 chloroform

[0286] MnO2 manganese(IV) oxide

[0287] LAH lithium aluminum hydride

[0288] ADDP 1,1′-(azodicarbonyl)-dipiperidine

[0289] EDTA ethylenediaminetetraacetic acid

[0290] CCl2FCCIF2 1,1,2-trichlorotrifluoroethane

[0291] NaNO2 sodium nitrite

PREPARATIVE EXAMPLES

[0292] Examples of preparations of compounds of the invention are provided in the following detailed synthetic procedures. In tables 1A and 2A, the synthesis of each compound is referenced back to these exemplary preparative steps. In tables 1B and 2B, the proposed synthesis of each compound is referenced back to these exemplary preparative steps.

[0293] All reactions were carried out under a positive pressure of dry argon or dry nitrogen, and were stirred magnetically unless otherwise indicated. Sensitive liquids and solutions were transferred via syringe or cannula, and introduced into reaction vessels through rubber septa. Commercial grade reagents and solvents were used without further purification.

[0294] Unless otherwise stated, the term ‘concentration under reduced pressure’ refers to use of a Buchi rotary evaporator at approximately 15 mm of Hg. All temperatures are reported uncorrected in degrees Celsius (° C.). Unless otherwise indicated, all parts and percentages are by volume.

[0295] Proton (1H) nuclear magnetic resonance (NMR) spectra were measured with a Varian Mercury (300 MHz) or a Bruker Avance (500 MHz) spectrometer with either Me4Si (δ 0.00) or residual protonated solvent (CHCl3 δ 7.26; MeOH δ 3.30; DMSO δ 2.49) as standard. The NMR data of the synthesized examples, which are not disclosed in the following detailed charaterizations, are in agreements with their corresponding structural assignements.

[0296] The HPLC-MS spectra were obtained using a Hewlett-Packard 1100HPLC equipped with a quaternary pump, a variable wavelength detector set at 254 nm, a YMC pro C-18 column (2×23 mm, 120A), and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 120-1200 amu using a variable ion time according to the number of ions in the source. The eluents were A: 2% CH3CN in water with 0.02% TFA and B: 2% water in CH3CN with 0.018% TFA. Gradient elution from 10% B to 95% over 3.5 minutes at a flow rate of 1.0 mL/min was used with an initial hold of 0.5 minutes and a final hold at 95% B of 0.5 minutes. Total run time was 6.5 minutes.

[0297] Elemental analyses were conducted by Robertson Microlit Labs, Madison N.J. The results of elemental analyses, if conducted but not disclosed in the following detailed charaterizations, are in agreements with their corresponding structural assignements.

[0298] The following specific examples are presented to illustrate the invention related to Formula (I) as described herein, but they should not be construed as limiting the scope of the invention in any way.

[0299] Intermediate A:

2,6-dichloro-4-methyl-nicotinic acid

[0300]

[0301] Method 1

[0302] A solution of sodium nitrite (2.73 g, 39.6 mmol) in water (15 mL) was added slowly to a solution of commercially available (Maybridge) 2,6-dichloro-4-methyl-nicotinamide (4.5 g, 22 mmol) in concentrated sulfuric acid resulting in evolution of heat and brown gas. The mixture was stirred at room temperature for 15 min, and then heated to 60° C. for 7 h. The solution was cooled to 0° C. and then water (15 mL) was added. The resulting white precipitate was collected by filtration and washed with hexane. The aqueous filtrate was extracted with EtOAc (3×) and the combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was combined with the white precipitate to afford 2,6-dichloro-4-methyl-nicotinic acid (4.39 g, 97%) as a white solid: LCMS RT: 1.20 min, MH+: 206.3.

[0303] Method 2

[0304] Concentrated nitric acid (14 mL) was added to cooled (0° C.) concentrated sulfuric acid (43 mL) maintaining the internal temperature below 10° C. After addition, the acid mixture was heated to 70° C. and commercially available (Avocado) 2,6-dichloro-4-methylnicotinonitrile (20.0 g, 107 mmol) was added. The temperature was raised until the internal temperature of the reaction reached 105° C. At this point the heating was stopped and after 2 h, TLC analysis revealed that the reaction was complete. The reaction mixture was cooled to room temperature, and slowly added to ice (100 g) with strong agitation. The solid was filtered and washed with cold water (10 mL). The solid was dissolved in EtOAc (100 mL) and the solution was dried over Na2SO4 and concentrated to give 2,6-dichloro-4-methyl-nicotinic acid (21.0 g, 96%) as a white solid: Rf=0.20 (1:1 EtOAc:Hex).

[0305] Intermediate B:

2,6-dichloro-4-methyl-nicotinoyl chloride

[0306]

[0307] A solution of 2,6-dichloro-4-methyl-nicotinic acid (3.94 g, 19.1 mmol) in thionyl chloride (18 mL) was heated to 80° C. for 2 h. After cooling, the solution was concentrated in vacuo to give 2,6-dichloro-4-methyl-nicotinoyl chloride as yellow oil. It was carried on to the next step without further purification. This transformation can also be accomplished using oxalyl chloride with catalytic DMF in place of thionyl chloride.

[0308] Intermediate C:

3,3-dichloro-1-(2,6-dichloro-4-methyl-pyridin-3-yl)-propenone

[0309]

[0310] A solution of the 2,6-dichloro-4-methyl-nicotinoyl chloride from the previous reaction in CH2Cl2 (10 mL) was added slowly to a cooled (0° C.) and stirred slurry solution of AlCl3 (2.54 g, 19.1 mmol) in CH2Cl2 (54 mL). After 15 min, vinylidene chloride (1.5 mL, 1.85 g, 19.1 mmol) was added to the mixture dropwise. The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was poured over ice and the ice slurry was acidified using 1 N HCl (50 mL). Stirring was continued for 20 min and then the product was extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give 3,3-dichloro-1-(2,6-dichloro-4-methyl-pyridin-3-yl)-propenone (4.22 g, 77 %) as a yellow oil: LCMS RT: 3.25, MH+: 284.3, Rf=0.47 (4:1 Hex:EtOAc).

[0311] Intermediate D:

1-(2,6-Dichloro-4-methyl-pyridin-3-yl)-3,3-bis-phenylamino-propentone

[0312]

[0313] A solution of aniline (4.04 mL, 44.4 mmol) in TEA (6.2 mL, 44.4 mmol) was added slowly to a cooled (0° C.) and stirred solution of 3,3-dichloro-1-(2,6-dichloro-4-methyl-pyridin-3-yl)-propenone (4.22 g, 14.8 mmol) in dioxane (50 mL). The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was concentrated in vacuo until most of the solvent was removed and then the residue was diluted with water and extracted with EtOAc (3×). The combined organic extracts were washed with water, dried over Na2SO4 and concentrated in vacuo. Silica gel flash chromatography of the residue using 7:1 EtOAc:Hex gave 1-(2,6-dichloro-4-methyl-pyridin-3-yl)-3,3-bis-phenylamino-propenone as yellow solid (2.22 g, 40%): LCMS RT: 3.21 min; MH+: 398.2, Rf=0.27 (2:1 Hex:EtOAc).

[0314] Intermediate E:

7-Chloro-5-methyl-1-phenyl-2-phenylamino-1H-[1,8]-naphthyridin-4-one

[0315]

[0316] A mixture of 1-(2,6-dichloro-4-methyl-pyridin-3-yl)-3,3-bis-phenylamino-propenone (2.17 g, 5.45 mmol) and t-BuOK (1.10 g, 9.81 mmol) in dioxane (55 mL) was heated to 80° C. overnight. The reaction was cooled, concentrated in vacuo, diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. Silica gel flash chromatography of the residue using 1:1 EtOAc:Hex provided 7-chloro-5-methyl-1-phenyl-2-phenylamino-1H-[1,8]naphthyridin-4-one (1.297 g, 66%) as an orange solid: LCMS RT: 2.52 min, MH+: 362.3, Rf=0.18 (1:1 EtOAc:Hex) This transformation can also be accomplished by using the combination of other aprotic solvents such as DMF, and THF with other bases such as NaH.

[0317] Intermediate F:

2,6-dichloro-4-(trifluoromethyl)nicotinic acid

[0318]

[0319] Method 1

[0320] A solution of NaNO2 (9.59 g, 139 mmol) in water (95 mL) was added slowly to a solution of commercially available (Oakwood) 2,6-dichloro-4-(trifluoromethyl)nicotinamide (20.0 g, 77 mmol) in conc. H2SO4 resulting in evolution of heat and brown gas. The mixture was stirred at room temperature for 15 min, and then heated to 60° C. for 18 h. The solution was cooled to 0° C. and then water (15 mL) was added. The resulting mixture was extracted with Et2O (3×) and the combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was triturated with hexanes and vacuum-filtered to afford 2,6-dichloro-4-(trifluoromethyl)nicotinic acid (19 g, 95%) as an off-white solid: Rf=0.30 (9:1 CH2Cl2:MeOH), 1H-NMR (d6-DMSO, 300 MHz) δ 8.18 (s, 1H).

[0321] Method 2

[0322] Conc. HNO3 (13.3 mL) was added to cooled (0° C.) conc. H2SO4 (60 mL) maintaining the internal temperature below 10° C. After addition, the acid mixture was heated to 70° C. and commercially available (Maybridge) 2,6-dichloro-4-(trifluoromethyl)nicotinonitrile (20.0 g, 83 mmol) was added. The temperature was raised until the internal temperature of the reaction reached 100° C. After heating for 1 h TLC analysis revealed that the reaction was complete. The reaction mixture was cooled to room temperature, and slowly added to ice (100 g) with strong agitation and extracted with Et2O (3×). The organic layers were combined and washed with brine. The solution was dried over Na2SO4 and concentrated in vacuo to give 2,6-dichloro-4-(trifluoromethyl)nicotinic acid (19.1 g, 89%) as an off-white solid: Rf=0.30 (9:1 CH2Cl2:MeOH), 1H-NMR (d6-DMSO, 300 MHz) δ 8.18 (s, 1H).

[0323] Intermediate G:

2,6-dichloro-4-(trifluoromethyl)nicotinoyl chloride

[0324]

[0325] A solution of 2,6-dichloro-4-(trifluoromethyl)nicotinic acid (3.22 g, 13.2 mmol) in thionyl chloride (9 mL) was heated at reflux for 3 h. After cooling, the solution was concentrated in vacuo to give 2,6-dichloro-4-(trifluoromethyl)nicotinoyl chloride as a yellow oil which was carried on to the next step without further purification. This transformation can also be accomplished using oxalyl chloride with catalytic DMF in place of thionyl chloride.

[0326] Intermediate H:

3,3-dichloro-1-[2,6-dichloro-4-(trifluoromethyl)-3-pyridinyl]-2-propen-1-one

[0327]

[0328] A solution of the 2,6-dichloro-4-(trifluoromethyl)nicotinoyl chloride from the previous reaction in CH2Cl2 (14 mL) was added slowly to a cooled (0° C.) and stirred slurry solution of AlCl3 (4.4 g, 33.0 mmol) in CH2Cl2 (14 mL). After 15 min, vinylidene chloride (2.6 mL, 33.0 mmol) was added to the mixture dropwise. The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was poured over ice and partitioned with CH2Cl2. The organic layer was collected and cooled to 0° C. before TEA (4.6 mL, 33 mmol)was added. After 15 min, the ice bath was removed and the reaction was allowed to warm to room temperature and stirred for an additional 30 min. The solution was washed with 1N HCl, NaHCO3, and water. The organic layer was passed through a pad of silica gel and concentrated in vacuo to afford 3,3-dichloro-1-[2,6-dichloro-4-(trifluoromethyl)-3-pyridinyl]-2-propen-1-one: (4.3 g, 95%) as a brown oil: LCMS RT: 3.59, MH+: 488. 1, Rf=0.44 (EtOAc).

[0329] Intermediate I:

3,3-dianilino-1-[2,6-dichloro-4-(trifluoromethyl)-3-pyridinyl]-2-propen-1-one

[0330]

[0331] A solution of aniline (18.4 mL, 202 mmol) in TEA (28.2 mL, 202 mmol) was added slowly to a cooled (0° C.) and stirred solution of 3,3-dichloro-1-[2,6-dichloro-4-(trifluoromethyl)-3-pyridinyl]-2-propen-1-one (22.9 g, 67.4 mmol) in dioxane (220 mL). The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was treated with 10% HCl and extracted with Et2O (3×). The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo. Silica gel flash chromatography of the residue using 6:1 Hex:EtOAc gave 3,3-dianilino-1-[2,6-dichloro-4-(trifluoromethyl)-3-pyridinyl]-2-propen-1-one as an off-white solid (13.10 g, 43%): 1H-NMR (d6-DMSO, 300 MHz) δ12.24 (br s, 1H), 9.20 (br s, 1H), 7.95 (s, 1H), 7.12-7.42 (m, 10H), 4.82 (s, 1H); Rf=0.60 (6:1 Hex:EtOAc).

[0332] Intermediate J:

2-anilino-7-chloro-1-phenyl-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one

[0333]

[0334] A mixture of 3,3-dianilino-1-[2,6-dichloro-4-(trifluoromethyl)-3-pyridinyl]-2-propen-1-one (12.9 g, 28.5 mmol) and t-BuOK (28.5 mL, 28.5 mmol, 1M in THF) in dioxane (200 mL) was heated at reflux overnight. The reaction was cooled, concentrated in vacuo, treated with saturated NH4Cl and extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over MgSO4, and concentrated in vacuo. Silica gel flash chromatography of the residue using 6:1 Hex:EtOAc provided 2-anilino-7-chloro-1-phenyl-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one (11.2 g, 95%) as an off-white solid: LCMS RT: 3.00 min, MH+: 416.7, Rf=0.25 (3:1 Hex:EtOAc). This transformation can be accomplished by using the combination of other aprotic solvents such as DMF, and THF with other bases such as NaH.

[0335] Intermediate K:

2,6-dichloro-5-fluoronicotinoyl chloride

[0336]

[0337] A solution of commercially available (Aldrich) 2,6-dichloro-5-fluoronicotinic acid (5.00 g, 23.8 mmol) in thionyl chloride (15 mL) was heated at reflux for 3 h. After cooling, the solution was concentrated in vacuo to give 2,6-dichloro-5-fluoronicotinoyl chloride as a brown oil which was carried on to the next step without further purification. This transformation can also be accomplished using oxalyl chloride with catalytic DMF in place of thionyl chloride.

[0338] Intermediate L:

3,3-dichloro-1-(2,6-dichloro-5-fluoro-3-pyridinyl)-2-propen-1-one

[0339]

[0340] A solution of the 2,6-dichloro-5-fluoronicotinoyl chloride from the previous reaction in CH2Cl2 (25 mL) was added slowly to a cooled (0° C.) and stirred slurry solution of AlCl3 (7.9 g, 59.5 mmol) in CH2Cl2 (25 mL). After 15 min, vinylidene chloride (4.75 mL, 59.5 mmol) was added to the mixture dropwise. The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was poured over ice and partitioned with CH2Cl2. The organic layer was collected and cooled to 0° C. before TEA (8.3 mL, 59.5 mmol) was added. After 15 min, the ice bath was removed and the reaction was allowed to warm to room temperature and stirred for an additional 30 min. The solution was washed with 1N HCl, NaHCO3, and water. The organic layer was passed through a pad of silica gel and concentrated in vacuo to afford 3,3-dichloro-1-(2,6-dichloro-5-fluoro-3-pyridinyl)-2-propen-1-one: (6.1 g, 90%) as a brown oil: 1H-NMR (d6-DMSO, 300 MHz) δ8.43 (d, 1H, J=8.4 Hz), 7.56 (s, 1H), Rf=0.76 (3:1 Hex:EtOAc).

[0341] Intermediate M:

3,3-dianilino-1-(2,6-dichloro-5-fluoro-3-pyridinyl)-2-propen-1-one

[0342]

[0343] To a 0° C. solution of 3,3-dichloro-1-(2,6-dichloro-5-fluoro-3-pyridinyl)-2-propen-1-one (6.70 g, 23.2 mmol) in dioxane (50 mL) was added TEA (9.7 mL, 69.6) followed by aniline (6.3 mL, 69.6 mmol). After I h the reaction was allowed to warm to room temperature and was stirred overnight. The mixture was concentrated in vacuo until most of the solvent was removed and then the residue was diluted with water and extracted with CH2Cl2 (2×). The combined organic extracts were washed with water, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by silica gel Biotage chromatography provided 3,3-dianilino-1-(2,6-dichloro-5-fluoro-3-pyridinyl)-2-propen-1-one as yellow solid (4.2 g, 49%): LCMS RT: 3.47 min; MH+: 402.6.

[0344] Intermediate N:

2-anilino-7-chloro-6-fluoro-1-phenyl-1,8-naphthyridin-4(1H)-one

[0345]

[0346] A mixture of 3,3-dianilino-1-(2,6-dichloro-5-fluoro-3-pyridinyl)-2-propen-1-one (2.3 g, 5.7 mmol) and t-BuOK (1.28 g, 11.4 mmol) in dioxane (80 mL) was stirred at 80° C. overnight. The reaction was cooled, concentrated in vacuo, diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. Silica gel flash chromatography of the residue provided 2-anilino-7-chloro-6-fluoro-1-phenyl-1,8-naphthyridin-4(1H)-one (1.0 g, 50%) as a light yellow solid: LCMS RT: 2.60 min, MH+: 366.8. This transformation can be accomplished by using the combination of other aprotic solvents such as DMF, and THF with other bases such as NaH.

[0347] Intermediates N1-N12 were synthesized from 3,3-dichloro-1-(2,6-dichloro-5-fluoro-3-pyridinyl)-2-propen-1-one as above for Intermediate N using the appropriate amine:

[0348] Intermediate N1:

[0349] LCMS RT: 2.81 min, MH+: 402.3

[0350] Intermediate N2:

[0351] LCMS RT: 2.73 min, MH+: 402.4

[0352] Intermediate N3:

[0353] LCMS RT: 2.30 min, MH+: 298.1

[0354] Intermediate N4:

[0355] LCMS RT: 2.88 min, MH+: 394.3

[0356] Intermediate N5:

[0357] LCMS RT: 2.78 min, MH+: 426.3

[0358] Intermediate N6:

[0359] LCMS RT: 3.09 min, MH+: 434.5

[0360] Intermediate N7:

[0361] LCMS RT: 3.07 min, MH+: 378.2

[0362] Intermediate N8:

[0363] LCMS RT: 3.15 min, MH+: 422.4

[0364] Intermediate N9:

[0365] LCMS RT: 2.90 min, MH+: 486.3

[0366] Intermediate N10:

[0367] LCMS RT: 2.22 min, MH+: 294.2

[0368] Intermediate N11:

[0369] LCMS RT: 3.05 min, MH+: 430.4

[0370] Intermediate N12:

[0371] LCMS RT: 2.51 min, MH+: 468.3

[0372] Intermediate N13

[0373] LCMS RT: 3.10 min, MH+: 430.4

[0374] Intermediate O:

2,6-dichloronicotinoyl chloride

[0375]

[0376] A solution of commercially available (Aldrich) 2,6-dichloro-nicotinic acid (2.0 g, 10.4 mmol) in thionyl chloride (10 mL) was heated to 80° C. for 2 h. After cooling, the solution was concentrated in vacuo to give 2,6-dichloro-nicotinoyl chloride as yellow oil which was carried on to the next step without further purification. This transformation can also be accomplished using oxalyl chloride with catalytic DMF in place of thionyl chloride.

[0377] Intermediate P:

3,3-dichloro-1-(2,6-dichloro-3-pyridinyl)-2-propen-1-one

[0378]

[0379] A solution of the 2,6-dichloro-nicotinoyl chloride (1.0 g, 4.76 mmol) from the previous reaction in CH2Cl2 (5 mL) was added slowly to a cooled (0° C.) and stirred slurry solution of AlCl3 (0.64 g, 4.76 mmol) in CH2Cl2 (20 mL). After 15 min, vinylidene chloride (0.38 mL, 0.46 g, 4.76 mmol) was added to the mixture dropwise. The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was then poured over ice and was acidified using 1 N HCl (15 mL). Stirring was continued for 20 min and the product was extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give 3,3-dichloro-1-(2,6-dichloro-3-pyridinyl)-2-propen-1-one (0.88 g, 68% ) as a light yellow oil: 1H-NMR (CDCl3, 300 MHz) δ 8.38, d, J=8.4, 1H). 7.40 (d, J=8.4, 1H), 7.10 (s, 1H); Rf=0.51 (4:1 Hex:EtOAc).

[0380] Intermediate Q:

3,3-dianilino-1-(2,6-dichloro-3-pyridinyl)-2-propen-1-one

[0381]

[0382] A solution of aniline (1.01 mL, 11.1 mmol) in TEA (1.55 mL, 11.1 mmol) was added slowly to a cooled (0° C.) and stirred solution of 3,3-dichloro-1-(2,6-dichloro-3-pyridinyl)-2-propen-1-one (1.0 g, 3.69 mmol) in dioxane (20 mL). The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was concentrated in vacuo until most of the solvent was removed. The residue was diluted with water and extracted with EtOAc (3×). The combined organic extracts were washed with water, dried over Na2SO4 and concentrated in vacuo. Silica gel flash chromatography of the residue using 6:1 EtOAc:Hex gave 3,3-dianilino-1-(2,6-dichloro-3-pyridinyl)-2-propen-1-one as pale yellow solid (0.69 g, 49%): LCMS RT: 3.81 min; MH+: 384.2.

[0383] Intermediate R:

2-anilino-7-chloro-1-phenyl-2,3-dihydro-1,8-naphthyridin-4(1H)-one

[0384]

[0385] A mixture of 3,3-dianilino-1-(2,6-dichloro-3-pyridinyl)-2-propen-1-one (0.08 g, 0.21 mmol) and NaH (0.009 g, 0.23 mmol) in THF (6 mL) was heated to 80° C. overnight. The reaction was cooled, concentrated in vacuo, diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. Silica gel flash chromatography of the residue using 3:1 Hex:EtOAc provided 2-anilino-7-chloro-1-phenyl-2,3-dihydro-1,8-naphthyridin-4(1H)-one (49 mg, 68%) as an off-white solid: LC-MS RT: 2.56 min, MH+: 348.2. This transformation can be accomplished by using the combination of other aprotic solvents such as dioxane and DMF with other bases such as t-BuOK.

[0386] Intermediate S:

Ethyl 3-(2-chloro-6-methyl(3-pyridyl))-3-oxopropanoate

[0387]

[0388] Ethyl 3-(2-chloro-6-methyl(3-pyridyl))-3-oxopropanoate was prepared by the general procedure described in the Journal of Medicinal Chemistry, 1986, 29, 2363. The product had: MH+: 242.1, LCMS RT: 2.33 and 3.06 min (keto-enol).

[0389] Intermediate T:

Ethyl (2Z)-2-[(2-chloro-6-methyl(3-pyridyl))carbonyl]-3,3-dimethylthio-prop-2-enoate

[0390]

[0391] Cs2CO3 (24.0 g, 72.5 mmol) was added to a solution of ethyl 3-(2-chloro-6-methyl(3-pyridyl))-3-oxopropanoate (7.0 g, 29 mmol) in THF (290 mL). The reaction mixture was cooled to −10° C. and after 15 min, CS2 (8.7 mL, 145 mmol) was added. Stirring was continued for 2 h and MeI (4.5 mL, 72.5 mmol) was added. The reaction was slowly warmed to room temperature over 18 h and filtered. The filtrate was concentrated in vacuo to provide ethyl (2Z)-2-[(2-chloro-6-methyl(3-pyridyl))carbonyl]-3,3-dimethylthioprop-2-enoate as a yellow oil that was used without purification. LCMS RT: 2.79 min, MH+: 345.8. A variety of alkyl halides can be used to quench the generated sulfur anion.

[0392] Intermediate U:

Ethyl (2E)-3,3-bis(phenylamino)-2-[(2-chloro-6-methyl(3-pyridyl))-carbonyl]prop-2-enoate

[0393]

[0394] A solution of ethyl (2Z)-2-[(2-chloro-6-methyl(3-pyridyl))carbonyl]-3,3-dimethylthioprop-2-enoate (100. mg, 0.28 mmol) and aniline (0.076 mL, 0.83 mmol) in THF (1.4 mL) was heated at reflux for 18 h. The reaction was cooled to room temperature and concentrated in vacuo. Silica gel flash chromatography of the residue using 1:1 EtOAc:Hex provided ethyl (2E)-3,3-bis(phenylamino)-2-[(2-chloro-6-methyl(3-pyridyl))carbonyl]prop-2-enoate (55.6 mg, 44%): LCMS RT: 3.56 min, MH+: 436.3.

[0395] Intermediate V:

Ethyl 7-methyl-2-methylthio-4-oxo-1-phenylhydropyridino[2,3-b]-pyridine-3-carboxylate

[0396]

[0397] Aniline (3.96 mL, 43.5 mmol) was added to a solution of ethyl (2Z)-2-[(2-chloro-6-methyl(3-pyridyl))carbonyl]-3,3-dimethylthioprop-2-enoate (5.13 g, 14.5 mmol) in DMSO (72.5 mL). The reaction solution was heated to 70° C. for 18 h and then cooled to room temperature. The solution was diluted with EtOAc, washed with water and brine, dried over Na2SO4, and concentrated in vacuo. Trituration of the resulting orange oil with Et2O afforded some desired product as a yellow solid. Additional product was obtained by silica gel flash chromatography of the mother liquor using 1:1 EtOAc:Hex. The two purifications provided ethyl 7-methyl-2-methylthio-4-oxo-1-phenylhydropyridino[2,3-b]pyridine-3-carboxylate (2.87 g, 56%) as a yellow solid: LCMS RT: 2.85 min, MH+: 355.0.

[0398] Intermediate W:

Ethyl 7-methyl-4-oxo-1-phenyl-2-(phenylamino)hydro-pyridino[2,3-b]-pyridine-3-carboxylate

[0399]

[0400] A solution of ethyl (2E)-3,3-bis(phenylamino)-2-((2-chloro-6-methyl(3-pyridyl))carbonyl)prop-2-enoate (85.0 mg, 0.195 mmol) and t-BuOK (67 mg, 0.60 mmol) in dioxane (2 mL) was heated at reflux for 48 h. The reaction was cooled to room temperature and concentrated in vacuo. Silica gel flash chromatography of the residue using 3:1 Hex:EtOAc to 100% EtOAc gave ethyl 7-methyl-4-oxo-1-phenyl-2-(phenylamino)hydropyridino[2,3-b]pyridine-3-carboxylate (39 mg, 49%) as a white solid: LCMS RT: 2.80 min, MH+ 400.0. This transformation can be accomplished by using the combination of other aprotic solvents such as DMF and THF with other bases such as NaH.

[0401] Intermediate X:

Ethyl 2-[(4-chlorophenyl)amino]-7-methyl-4-oxo-1-phenyl-hydropyridino-[2,3-b]pyridine-3-carboxylate

[0402]

[0403] KHMDS (0.5 M in toluene, 0.84 mL, 0.42 mmol) was added to a cooled (−78° C.) solution of 4-chloroaniline (71.4 mg, 0.560 mmol) in THF (0.70 mL). After 2 h, a solution of ethyl 7-methyl-2-methylthio-4-oxo-1-phenylhydropyridino[2,3-b]pyridine-3-carboxylate (100 mg, 0.28 mmol) in THF (0.70 mL) was added resulting in immediate formation of an orange solution. The reaction was slowly warmed to room temperature, stirred for 21 h, and quenched with saturated aqueous NH4Cl. The aqueous solution was extracted with Et2O (3×) and the combined organic extracts were washed with water and brine, dried over Na2SO4, and concentrated in vacuo. Silica gel flash chromatography of the residue using 1:1 EtOAc:Hex gave ethyl 2-[(4-chlorophenyl)amino]-7-methyl-4-oxo-1-phenylhydropyridino[2,3-b]pyridine-3-carboxylate (30.0 mg, 25%) as a white solid: LCMS RT: 2.98 min, MH+ 434.0.

[0404] Intermediate Y:

5-Bromo-2-hydroxy-6-methylnicotine acid

[0405]

[0406] A solution of NaOBr was prepared by adding Br2 (11.4 g, 3.66 mL, 71.3 mmol) to a cooled (0° C.) and stirred solution of NaOH (7.8 g, 196 mmol) in water (90 mL). This solution was warmed to room temperature and was then added to a solution of commercially available (Aldrich) 2-hydroxy-6-methylpyridine-3-carboxylic acid (10.0 g, 65.1 mmol) and NaOH (7.8 g, 196 mmol) in water (30 mL). After stirring for 5 min, the mixture was cooled to 0° C. and carefully acidified with conc. HCl. The precipitate was filtered and dried over MgSO4 to afford 5-bromo-2-hydroxy-6-methylnicotinc acid (15.0 g, 99%): 1H NMR (DMSO-d6) 8.25 (s, 1H), 2.41 (s, 3H); MH+: 232.0. Elemental analysis calculated for C7H6BrNO3: C, 36.23; H, 2.61; N, 6.04; Br, 34.44; Found: C, 36.07; H, 2.44; N, 5.91; Br, 34.43.

[0407] Intermediate Z (Same as Intermediate BA):

2,4-dichloro-6-methylnicotinic acid

[0408]

[0409] A solution of commercially available (Maybridge) ethyl 2,4-dichloro-6-methylpyridine-3-carboxylate (1.0 g, 4.3 mmol) and NaOH (342 mg, 8.6 mmol) in water (1.7 mL) and MeOH (1.5 mL) was heated to 80° C. for 4 h. The mixture was acidified using 50% H2SO4 and filtered. The solid was washed with cold water and dried to give of 2,4-dichloro-6-methylpyridine-3-carboxylic acid (582 mg, 66%): LCMS RT: 0.70 min, MH+: 206.2.

[0410] Intermediate AA (Same as Intermediate BB):

3,3-dichloro-1-(2,4-dichloro-6-methyl-3-pyridinyl)-2-propen-1-one

[0411]

[0412] The compound was prepared according to the procedure described for Intermediate BB below. LCMS RT: 3.13 min, MH+: 284.6.

[0413] Intermediate AB (Same as Intermediate BC):

3,3-dianilino-1-(2,4-dichloro-6-methyl-3-pyridinyl)-2-propen-1-one

[0414]

[0415] The compound was prepared according to the procedure described for Intermediate BC below: LCMS RT: 3.06 min, MH+: 398.7.

[0416] Intermediate AC:

(2Z)-3-anilino-1-(2,6-dichloro-5-fluoro-3-pyridinyl)-3-(isopropylamino)-2-propen-1-one

[0417]

[0418] 3,3-dichloro-1-(2,6-dichloro-5-fluoro-3-pyridinyl)-2-propen-1-one (374.0 mg, 1.29 mmol) was dissolved in CH2Cl2 (5 mL) and cooled to 10° C. Aniline (120.0 mg, 1.29 mmol) and isopropylamine (76.5 mg, 1.29 mmol) were added dropwise as a mixture in 3 mL of 1,4-dioxane. TEA (0.897 mL, 6.45 mmol) was added and the reaction mixture was warmed to room temperature and left to stir for 2 h. The dioxane was removed in vacuo and the brown residue was partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue using Biotage silica gel chromatography eluting with 6:1 to 7:3 Hex:EtOAc provided (2Z)-3-anilino-1-(2,6-dichloro-5-fluoro-3-pyridinyl)-3-(isopropylamino)-2-propen-1-one (45 mg, 10%) as an off-white solid: LCMS RT: 3.63 min, MH+: 368.2.

[0419] Intermediate AD:

4-Nitrophenyl 2-{[3-(trifluoromethyl)phenyl]amino}nicotinate

[0420]

[0421] To a warmed (40° C.) suspension of niflumic acid (10.0 g, 35.4 mmol) and 4-nitrophenol (4.9 g, 35.4 mmol) in CH2Cl2 (80 mL) was added a suspension of EDCI (6.8 g, 35.4 mmol) in CH2Cl2 (20 mL). The reaction was stirred for 16 h, and then cooled to room temperature. The solution was quenched with water (50 mL), and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were washed with water and dried over Na2SO4. The solvent was removed in vacuo, and the residue was purified by trituration with Hex:CH2Cl2 to afford 4-Nitrophenyl 2-{[3-(trifluoromethyl)phenyl]amino}nicotinate (4.5 g, 31%): LCMS RT: 4.03 min, MH+: 404.1.

[0422] Intermediate AE:

Ethyl 2-cyano-3-oxo-3-(2-{[3-(trifluoromethyl)phenyl]amino}-3-pyridinyl)propanoate

[0423]

[0424] To a stirred mixture of NaH (524 mg, 21.8 mmol) in toluene (20 mL) was added dropwise ethyl cyanoacetate (3.7 g, 32.7 mmol, 3.5 mL). The slurry was stirred for 1 h and then 4-nitrophenyl 2-{[3-(trifluoromethyl)phenyl]amino}nicotinate (4.4 g, 10.9 mmol) was added. The reaction mixture was stirred for 1 h and then quenched with water (20 mL). CH2Cl2 (30 mL) was added and the layers were partitioned. The organic layer was washed with brine (2×) and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by silica gel flash chromatography (5:1 to 2:1 Hex:EtOAc) to afford 3 Ethyl 2-cyano-3-oxo-3-(2-{[3-(trifluoromethyl)phenyl]amino}-3-pyridinyl)propanoate.(6 g, 87%): LCMS RT: 2.83 min, MH+: 378.0.

[0425] Intermediate AF:

2-Amino-1-[3-(trifluoromethyl)phenyl]-1,8-naphthyridin-4(1H)-one

[0426]

[0427] Ethyl 2-cyano-3-oxo-3-(2-{[3-(trifluoromethyl)phenyl]amino}-3-pyridinyl) propanoate (2.0 g, 5.3 mmol) was heated to 120° C. in a mixture of conc. HCl (4 mL) and glacial acetic acid (2 mL) for 3 h. The reaction mixture was cooled to room temperature, and neutralized by slow addition of NaOH pellets. The mixture was extracted with CH2Cl2 (3×). The combined organic extracts were washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by prep-HPLC (YMC-Pack Pro C18 Column, 150×20 mm I.D.; 30-70% CH3CN in water, 20 min.) to afford 2-Amino-1-[3-(trifluoromethyl)phenyl]-1,8-naphthyridin-4(1H)-one (880 mg, 55%): LCMS RT: 2.03 min, MH+: 306.3.

[0428] Intermediate AG:

7-chloro-6-fluoro-2-(isopropylamino)-1-phenyl-1,8-naphthyridin-4(1H)-one

[0429]

[0430] (2Z)-3-Anilino-1-(2,6-dichloro-5-fluoro-3-pyridinyl)-3-(isopropylamino)-2-propen-1-one (40.0 mg, 0.109 mmol) was dissolved in 4 mL of DMF. NaH (8.70 mg, 0.217 mmol, 60% dispersion in oil) was added and the reaction was heated to 85° C. under argon for 2 h. The reaction mixture was cooled to room temperature and diluted with water and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue using Biotage silica gel chromatography eluting with 100% EtOAc to 95:5 EtOAc:MeOH provided 7-chloro-6-fluoro-2-(isopropylamino)-1-phenyl-1,8-naphthyridin-4(1H)-one (21 mg, 64%) as awhite solid: LCMS RT: 2.57 min, MH+: 332.2.

[0431] Intermediate AH:

2-anilino-7-chloro-6-fluoro-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one

[0432]

[0433] A solution of LTMP [freshly prepared at 0° C. from tetramethylpiperidine (227.2 mg, 1.62 mmol), TMEDA (188.3 mg, 1.62 mmol) and n-BuLi (1 mL, 1.62 mmol)] in THF (5 mL) was added to a cooled (−40° C.) and stirred solution of 2-anilino-7-chloro-6-fluoro-1-phenyl-1,8-naphthyridin-4(1H)-one (200 mg, 0.54 mmol) in THF (10 mL). The reaction mixture was warmed to 0° C., for 1 h and then re-cooled to −40° C. MeI (766 mg, 5.35 mmol) was added and the reaction mixture was allowed to warm to room temperature and was stirred overnight. The reaction was quenched carefully with water (50 mL) and then extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. Silica gel flash chromatography of the residue using 1:1 EtOAc:Hex afforded 2-anilino-7-chloro-6-fluoro-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (184 mg, 88%) as a white solid: LCMS RT: 2.74 min, MH+: 380.3. This transformation can also be accomplished by using other amide bases such as LDA.

[0434] Intermediate AI:

2-anilino-7-chloro-6-fluoro-1-phenyl-5-(trifluoroacetyl)-1,8-naphthyridin-4(1H)-one

[0435]

[0436] A solution of LTMP [freshly prepared at 0° C. from tetramethylpiperidine (154 mg, 1.10 mmol), TMEDA (127.8 mg, 1.10 mmol) and n-BuLi (0.688 mL, 1.10 mmol)] in THF (5 mL) was added to a cooled (−40° C.) stirred solution of 2-anilino-7-chloro-6-fluoro-1-phenyl-1,8-naphthyridin-4(1H)-one (100 mg, 0.273 mmol) in THF(10 mL). The reaction was stirred for 1 h and then cooled to −78° C. Methyl trifluoroacetate (350 mg, 2.74 mmol) was added and stirring was continued for 2 h. The reaction was quenched carefully with water (50 mL), warmed to room temperature and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. Silica gel flash chromatography of the residue using 3:1 Hex: EtOAc gave 2-anilino-7-chloro-6-fluoro-1-phenyl-5-(trifluoroacetyl)-1,8-naphthyridin-4(1H)-one (71 mg, 56%) as a light yellow solid: LCMS RT: 3.43 min, MH+: 462.3. The anion generated from LTMP deprotonation can be quenched with other electrophiles including carbon dioxide and 4-nitrophenyl acetate.

[0437] Intermediate AJ:

7-chloro-5-methyl-2-[methyl(phenyl)amino]-1-phenyl-1,8-naphthyridin-4(1H)-one

[0438]

[0439] MeI (0.10 mL, 228 mg, 1.6 mmol) was added to a stirred suspension of K2CO3 (23.5 mg, 0.17 mmol) and 2-anilino-7-chloro-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (50 mg, 0.14 mmol) in THF (3 mL). The suspension was heated to 40° C. and stirred was overnight. The reaction was quenched with water (5.0 mL) and extracted with EtOAc. The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. Recrystallization of the residue using EtOAc afforded 7-chloro-5-methyl-2-[methyl(phenyl)amino]-1-phenyl-1,8-naphthyridin-4(1H)-one (18 mg, 35%): LCMS RT: 2.24 min, MH+: 376.6, Rf=0.76 (4:1 Hex:EtOAc).

[0440] Intermediate AK:

N-(7-chloro-5-methyl-4-oxo-1-phenyl-1,4-dihydro-1,8-naphthyridin-2-yl)-N′-(4-fluorophenyl)-N-phenylurea

[0441]

[0442] 4-Fluorophenyl isocyanate (45.0 mg, 0.33 mmol) was added to a stirred solution of 2-anilino-7-chloro-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (100 mg, 0.276 mmol) in CH2Cl2 (3 mL). After 16 h, an additional equivalent of 4-fluorophenyl isocyanate (45.0 mg) was added, and the reaction stirred for an additional 16 h. The reaction was concentrated in vacuo and the residue was dissolved in EtOAc. The solution was washed with 1 N HCl, dried over MgSO4, and concentrated in vacuo. Purification of the residue using reverse phase prep-HPLC afforded N-(7-chloro-5-methyl-4-oxo-1-phenyl-1,4-dihydro-1,8-naphthyridin-2-yl)-N′-(4-fluorophenyl)-N-phenylurea (2.2 mg, 1.6%): LCMS RT: 3.47 min, MH+: 499.1, Rf=0.52 (1:1 EtOAc:Hex).

[0443] Intermediate AL:

2-anilino-7-chloro-3-iodo-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one

[0444]

[0445] K2CO3 (210 mg, 1.52 mmol) and 12 (390 mg, 1.52 mmol,) were added to a solution 2-anilino-7-chloro-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (500 mg, 1.38 mmol) in DMF (10 mL). The mixture was stirred for 30 min and then poured into an aqueous solution of saturated Na2SO2O3 (10 mL). The aqueous solution was extracted with EtOAc. The combined organic extracts were dried over MgSO4, and concentrated in vacuo. Silica gel flash chromatography of the residue using 4:1 to 1:1 Hex:EtOAc afforded 2-anilino-7-chloro-3-iodo-5-methyl-1-phenyl-1,8-naphthyridin-4(1h)-one (380 mg, 56%): LCMS RT: 3.45 min, MH+: 488.2, Rf=0.5 (2:1 Hex:EtOAc).

[0446] Intermediate AM:

2-anilino-7-chloro-6-fluoro-5-(1-hydroxypropyl)-1-phenyl-1,8-naphthyridin-4(1H)-one

[0447]

[0448] A −40° C. solution of 2-anilino-7-chloro-6-fluoro-1-phenyl-1,8-naphthyridin-4(1H)-one (100 mg, 0.274 mmol) in THF (10 mL) was treated with LTMP (1.10 mmol, freshly prepared by mixing 2,2,6,6-Tetramethyl piperidine and n-BuLi at 0° C. for 30 min.). The mixture was then allowed to warm to 0 C. for 2 h. The reaction mixture was cooled to −30° C. and propionaldehyde (159 mg, 2.74 mmol) was added. The reaction was stirred at −30° C. for 2 h before it was slowly quenched with saturated aqueous NH4Cl. The mixture was extracted with EtOAc and the organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel flash chromatography to afford 2-anilino-7-chloro-6-fluoro-5-(1-hydroxypropyl)-1-phenyl-1,8-naphthyridin-4(1H)-one (120 mg, 97%) as a white solid: LCMS RT: 3.14 min, MH+: 424.2. Other electrophiles such as disulfide may be used to quench the anion.

Example 1

2-anilino-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one

[0449]

[0450] A solution of 2-anilino-7-chloro-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (95.0 mg, 0.263 mmol), TEA (0.65 mmol), and 10% Pd/C in EtOAc (2.5 mL) and EtOH (2.5 mL) was stirred under H2 (1 atm) for 3.5 h. The reaction mixture was filtered through a pad of Celite using EtOH and EtOAc to rinse. The combined filtrates were concentrated in vacuo, and purified with Biotage silica gel chromatography using 1:1 EtOAc:Hex to afford 2-anilino-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (84 mg, 98%) as a pale yellow solid. LCMS RT: 2.26 min, MH+: 328.4, Rf=0.1 (1:1 EtOAc:Hex),

Example 2

5-Methyl-7-morpholin-4-yl-1-phenyl-2-phenylamino-1H-[1,8]-naphthyridin-4one

[0451]

[0452] A mixture of 7-chloro-5-methyl-1-phenyl-2-phenylamino-1H-[1,8]naphthyridin-4-one (68.3 mg, 0.189 mmol) and morpholine (0.05 mL, 0.48 mmol) in dioxane (3 mL) was heated to 80° C. for 2 d. The reaction was cooled, concentrated in vacuo, diluted with water and extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo to give 5-methyl-7-morpholin-4-yl-1-phenyl-2-phenylamino-1H-[1,8]naphthyridin-4-one (67 mg, 92%) as yellow solid: LCMS RT: 2.33 min, MH+: 413.4, Rf=0.49 (EtOAc).

Example 3

5-Methyl-1-phenyl-2,7-bis-phenylamino-1H-[1,8]naphthyridin-4-one

[0453]

[0454] A mixture of 7-chloro-5-methyl-1-phenyl-2-phenylamino-1H-[1,8]naphthyridin-4-one (15.1 mg, 0.042 mmol), aniline (2 drops), Pd(OAc)2 (0.27 mg, 0.001 mmol), Cs2CO3 (19.5 mg, 0.06 mmol), and BINAP (1.68 mg, 0.003 mmol) in THF (0.5 mL) was heated at reflux for 16 h. The reaction was quenched with water and extracted with EtOAc (3×). The combined organic extracts were washed brine, dried over Na2SO4, and concentrated in vacuo to give 5-methyl-1-phenyl-2,7-bis-phenylamino-1H-[1,8]naphthyridin-4-one (6.0 mg, 38%): LCMS RT: 2.57 min, MH+: 419.5,Rf=0.18 (EtOAc).

Example 4

2-anilino-1,7-diphenyl-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one

[0455]

[0456] A solution of 2-anilino-7-chloro-1-phenyl-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one (10.0 mg, 0.241 mmol), Ph3P (6.00 mg, 0.024 mmol) and phenylboronic acid (36.0 mg, 0.290 mmol) in DME was treated with 2M K2CO3 (0.482 mL, 0.964 mmol) and Pd(OAc)2 (1.35 mg, 0.006 mmol). The mixture was heated at reflux for 24 h. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by preparative HPLC (10% CH3CN in water with 0.1% TFA to 95% CH3CN in water, 10 mumin, 10 min) provided 2-anilino-1,7-diphenyl-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one (45.0 mg, 41%): LCMS RT: 3.76 min, MH+: 458.4.

Example 5

2-anilino-7-benzyl-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one

[0457]

[0458] To a solution of 2-anilino-7-chloro-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (100 mg, 0.277 mmol) in THF was added Ni(dppp)Cl2 (37.0 mg, 0.069 mmol). After stirring for 5 min, benzylmagnesium chloride (2M, 1.45 mL, 2.90 mmol) was added dropwise via syringe and the mixture was allowed to stir for 24 h. The mixture was quenched with 1 N HCl and extracted with EtOAc. The organic layer was washed brine, dried over MgSO4, and concentrated in vacuo. Purification by preparative HPLC (10% MeNC in water with 0.1 % TFA to 95% CH3CN in water, 10 mL/min, 10 min) provided 2-anilino-7-benzyl-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (47.3 mg, 41%): LCMS RT: 2.85 min, MH+: 418.3.

Example 6

Ethyl{[7-anilino-5-oxo-8-phenyl-4-(trifluoromethyl)-5,8-dihydro-1,8-naphthyridin-2-yl]sulfanyl}acetate

[0459]

[0460] NaH (60% dispersion in oil, 18.0 mg, 0.434 mmol) was added to a cooled (0° C.) and stirred solution of ethyl mercaptoacetate (0.05 mL, 0.434 mmol) in DMF. After 0.5 h, 2-anilino-7-chloro-1-phenyl-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one (150.0 mg, 0.361 mmol) was added as a solid in a single portion. The mixture was allowed to warm to room temperature and was stirred for 24 h. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by preparative HPLC (10% CH3CN in water with 0.1% TFA to 95% CH3CN in water, 10 mL/min, 10 min) provided ethyl {[7-anilino-5-oxo-8-phenyl-4-(trifluoromethyl)-5 ,8-dihydro-1,8-naphthyridin-2-yl]sulfanyl}acetate (50 mg, 53%): LCMS RT: 3.91 min, MH+: 500.2, R=0.24 (1:1 EtOAc:Hex).

Example 7

{[7-anilino-5-oxo-8-phenyl-4-(trifluoromethyl)-5,8-dihydro-1,8-naphthyridin-2-yl]sulfanyl}acetic acid

[0461]

[0462] NaOH (160 mg, 4.0 mmol) was added to a stirred solution of ethyl {[7-anilino-5-oxo-8-phenyl-4-(trifluoromethyl)-5,8-dihydro-1,8-naphthyridin-2-yl]sulfanyl}acetate (30.0 mg, 0.060 mmol) in aqueous EtOH (10 mL EtOH in 4 mL H2O). The mixture was allowed to stir for 4 h and was then concentrated in vacuo. The reaction was acidified with 1N HCl and extracted with CH2Cl2. The organic layer was dried over MgSO4, and concentrated in vacuo. Purification by preparative HPLC (10% CH3CN in water with 0.1% TFA to 95% CH3CN in water, 10 mL/min, 10 min) provided {[7-anilino-5-oxo-8-phenyl-4-(trifluoromethyl)-5,8-dihydro-1,8-naphthyridin-2-yl]sulfanyl}acetic acid (19.0 mg, 66%): LCMS RT: 2.50 min, MH+: 472.1

Example 8

2-anilino-1-phenyl-7-(1-piperidinyl)-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one

[0463]

[0464] To a solution of 2-anilino-7-chloro-1-phenyl-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one (100.0 mg, 0.241 mmol) in dioxane (2.5 mL) was added piperdine (40.9 mg, 0.481 mmol). The mixture was left to stir at 80° C. overnight. The mixture was cooled to room temperature, poured into 1N HCl (1 mL) and extracted with CH2Cl2. The organic extracts were combined, washed with saturated aqueous NaHCO3, dried over Na2SO4, and concentrated in vacuo. The residue was purified by Biotage silica gel chrmoatography (1:1 EtOAc:Hex) to provide 2-anilino-1-phenyl-7-(1-piperidinyl)-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one (89.5 mg, 80%) as a pale yellow solid: LCMS RT: 2.76 min, MH+: 465.5.

Example 9

2-anilino-7-[2-(2-oxo-1-pyrrolidinyl)ethoxy]-1-phenyl-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one

[0465]

[0466] NaH (60% dispersion, 20.0 mg, 0.514 mmol) was added to a cooled (0° C.) and stirred solution of 1-(2-hydroxyethyl)-2-pyrrolidinone (0.06 mL, 0.514 mmol) in DMF. After 0.5 h, 2-anilino-7-chloro-1-phenyl-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one (178 mg, 0.428 mmol) was added as a solid in a single portion and the mixture was heated to 130° C. for 48 h. After cooling to room temperature the mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by preparative HPLC (10% CH3CN in water with 0.1 % TFA to 95% CH3CN in water, 10 mumin, 10 min) provided 2-anilino-7-[2-(2-oxo-1-pyrrolidinyl)ethoxy]-1-phenyl-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one (0.047 g, 64%): LCMS RT: 2.40 min, MH+: 509.2. This transformation can be accomplished by using other aprotic solvents such as DMSO, THF and dioxane with temperatures appropriate for these solvents. Commercially available alkoxides can also be used in the absence of base.

Example 10

2-anilino-5-(hydroxymethyl)-1-phenyl-1,8-naphthyridin-4(1H)-one

[0467]

[0468] A solution of LDA (38.2 mmol, freshly prepared from n-BuLi and diisopropylamine) in THF (53 mL) was added to a cooled (˜78° C.) and stirred suspension of 2-anilino-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (2.50 g, 7.64 mmol) in THF (100 mL). The resulting mixture was stirred for 1 h, and then oxygen gas was bubbled, through a fritted glass tube, into the bottom of the reaction vessel. The mixture was stirred overnight, with continued bubbling of oxygen with slow warming to room temperature. The reaction was quenched with water and 1 M HCl (5 mL), and then extracted with CH2Cl2. The organic phase was dried over Na2SO4 and concentrated in vacuo to afford an orange solid which was recrystalized from EtOAc to obtain 2-anilino-5-(hydroxymethyl)-1-phenyl-1,8-naphthyridin-4(1H)-one (1.38 g, 53%): LCMS RT: 2.01 min, MH+: 344.3, Rf=0.22 (95:5 CH2Cl2:MeOH).

Example 11

2-anilino-1-phenyl-5-(1-piperazinylmethyl)-1,8-naphthyridin-4(1H)-one

[0469]

[0470] A solution of 2-anilino-5-(hydroxymethyl)-1-phenyl-1,8-naphthyridin-4(1H)-one (180 mg, 0.52 mmol), N,N-diisopropylethylamine (0.10 mL, 0.52 mmol) and SOCl2 (0.12 mL, 1.57 mmol) in CH2Cl2 (7 mL) was stirred at room temperature for 2 h. Excess SOCl2 and solvent were removed in vacuo to afford a brownish solid. Crude 2-anilino-5-(chloromethyl)-1-phenyl-1,8-naphthyridin-4(1H)-one was used without further purification: LCMS RT: 2.50 min, MH+: 362.3.

[0471] DMF (1 mL) was added to a stirred suspension of crude 2-anilino-5-(chloromethyl)-1-phenyl-1,8-naphthyridin-4(1H)-one (15.0 mg, 0.041 mmol), N,N-diisopropylethylamine (0.036 mL, 0.21 mmol), and piperazine (36 mg, 0.21 mmol) in 1,4-dioxane (2 mL). The solution was heated to 50° C. overnight, cooled to room temperature and concentrated in vacuo. Reverse phase preparative HPLC (0.1 % TFA in CH3CN and water) of the residue gave 2-anilino-1-phenyl-5-(1-piperazinylmethyl)-1,8-naphthyridin-4(1H)-one (8.0 mg, 37%) as the TFA salt: LCMS RT: 0.71 min, MH+: 412.2.

Example 12:

5-Methyl-1-phenyl-2-phenylamino-7-piperazin-1-yl-1H-[1,8]naphthyridin-4-one

[0472]

[0473] A mixture of 5-methyl-1-phenyl-2-phenylamino-7-piperazin-1-yl-1H-[1,8]naphthyridin-4-one (22.6 mg, 0.055 mmol) and MsCl (0.083 mmol, 0.006 mL) in CH2Cl2 (0.8 mL) was stirred at room temperature overnight at which time the solvent was removed in vacuo. The resulting residue was purified by prep-TLC to give 7-(4-methanesulfonyl-piperazin-1-yl)-5-methyl-1-phenyl-2-phenylamino-1H-[1,8]naphthyridin-4-one (3.4 mg, 6%): LCMS RT: 2.36 min, MH+: 490.3.

Example 13

5-Methyl-1-phenyl-2-phenylamino-7-(4-propionyl-piperazin-1-yl)-1H-[1,8]naphthyridin-4-one

[0474]

[0475] A mixture of 5-methyl-1-phenyl-2-phenylamino-7-piperazin-1-yl-1H-[1,8]naphthyridin-4-one (21.0 mg, 0.052 mmol), propionic acid (0.004 mL, 0.055 mmol), EDCI (11.9 mg, 0.062 mmol), DMAP (7.6 mg, 0.062 mmol), and NMM (0.006 mL, 0.062) in CH2Cl2 (0.8 mL) was stirred at room temperature overnight. The reaction was diluted with water and extracted with CH2Cl2. The combined organic extracts were washed with 0.5 N HCl and brine and concentrated in vacuo. The residue was purified by prep-TLC eluting with 100% EtOAc to give 5-methyl-1-phenyl-2-phenylamino-7-(4-propionyl-piperazin-1-yl)-1H-[1,8]naphthyridin-4-one (9.0 mg, 37%): LCMS RT: 2.29 min, MH+: 468.3.

Example 14

2-anilino-5-bromo-6-fluoro-7-methoxy-1-phenyl-1,8-naphthyridin-4(1H)-one

[0476]

[0477] A solution of LTMP [freshly prepared at 0° C. from tetramethylpiperidine (785.4 mg, 5.6 mmol), TMEDA (651 mg, 5.6 mmol) and n-BuLi (3.5 mL, 5.6 mmol)] in THF (10 mL) was added to a cooled (−40° C.) stirred solution of 2-anilino-6-fluoro-7-methoxy-1-phenyl-1,8-naphthyridin-4(1H)-one (507 mg, 104 mmol) in THF (20 mL). The reaction mixture was warmed to room temperature. After 1 h, the mixture was cooled to −30° C. and 1,2-dibromotetrachloroethane (457 mg, 1.4 mmol) was added. After 30 min, water (50 mL) was added slowly, and then the reaction was warmed to room temperature and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. Silica gel flash chromatography of the residue using EtOAc afforded 2-anilino-5-bromo-6-fluoro-7-methoxy-1-phenyl-1,8-naphthyridin-4(1H)-one (101 mg, 16%) as a light yellow solid: LCMS RT: 2.75 min, MH+: 440.3.

Example 15

7-Methyl-2-phenyl-2-(phenylamino)hydropyridino[2,3-b]pyridin-4-one

[0478]

[0479] Ethyl 7-methyl-4-oxo-1-phenyl-2-(phenylamino)hydropyridino[2,3-b]pyridine-3-carboxylate (67 mg, 0.17 mmol) was dissolved in a 2:1 HCl:AcOH solution (8.5 mL). The reaction was heated to 120° C. for 5 h then cooled to room temperature. The aqueous solution was washed with Et2O and then neutralized with 2 N NaOH and extracted with EtOAc. The combined organic extracts were washed with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, and concentrated in vacuo to provide 7-methyl-1-phenyl-2-(phenylamino)hydropyridino[2,3-b]pyridin-4-one (40 mg, 72%): LCMS RT: 2.28 min, MH+: 328.4.

Example 16

2-anilino-5-chloro-7-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one

[0480]

[0481] A mixture of 3,3-dianilino-1-(2,4-dichloro-6-methyl-3-pyridinyl)-2-propen-1-one(100 mg, 0.25 mmol) and t-BuOK (42 mg, 0.38 mmol) in anhydrous dioxane (4 mL) was heated to 80° C. for 4 h. The solvent was removed in vacuo and the residue was dissolved in EtOAc. The solution was washed with water and brine, dried over MgSO4, and concentrated in vacuo. Silica gel flash chromatography of the residue using 1:1 EtOAc:Hex gave 2-anilino-5-chloro-7-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (13 mg, 14%): LCMS RT: 2.47 min, MH+: 362.6. 2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one was also isolated (68 mg, 75%): LCMS RT: 2.24 min, MH+: 362.6. This transformation can be accomplished by using the combination of other aprotic solvents such as DMF and THF with other bases such as NaH.

Example 17

Ethyl 7-anilino-3-fluoro-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine carboxylate

[0482]

[0483] 2-anilino-7-chloro-6-fluoro-1-phenyl-1,8-naphthyridin-4(1H)-one (200 mg, 0.55 mmol), DPPP (12 mg, 0.030 mmol), Pd(OAc)2 (6.0 mg, 0.028 mmol), and Cs2CO3 (114 mg, 0.42 mmol) was dissolved in a 1:1 mixture of EtOH (3 mL)/DMF (3 mL). A balloon filled with CO was attached to the flask and the solution was stirred vigorously. The solution was saturated with CO by evacuating the flask followed by back filling the flask with CO. This was repeated 3 times before heating the solution to 70° C. After 4 h of stirring all of the starting material had been consumed and the reaction was cooled to room temperature. The solution was diluted with EtOAc and was washed with water. The organic layer was collected, dried over Na2SO4, and concentrated in vacuo. The crude solid was triturated with Et2O, filtered and dried to give ethyl 7-anilino-3-fluoro-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carboxylate as a light brown solid (900 mg, 81%): LCMS RT: 2.63 min, MH+: 404.4

Example 18

7-anilino-3-fluoro-5-oxo-8-phenyl-5,8dihydro-1,8-naphthyridine-2-carboxanide

[0484]

[0485] A suspension of ethyl 7-anilino-3-fluoro-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carboxylate (50 mg, 0.12 mmol), and NH4Cl (10 mg, 0.19 mmol) in concentrated NH3 (3 mL) and MeOH (8 drops) was stirred for 16 h at room temperature. The solid was collected by filtration washing with water. Trituration with Et2O, provided 7-anilino-3-fluoro-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carboxamide as a yellow solid (32 mg, 71%): LCMS RT: 1.93 min, MH+: 375.3. This trasformation can also be accomplished using EDCI/HOBT coupling with NH3.

Example 19

7-anilino-N-methoxy-N,4-dimethyl-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carboxamide

[0486]

[0487] 7-anilino-4-methyl-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carboxylic acid (50 mg, 0.14 mmol), N,O-dimethylhydroxylamine hydrochloride (39 mg, 0.40 mmol), HOBT (28 mg, 0.21 mmol), EDCI (40 mg, 0.21 mmol) were dissolved in CH2Cl2 (3 mL). To this solution was added TEA (78 uL, 0.56 mmol). The reaction was stirred for 1 h and was diluted with CH2Cl2, washed with 0.5N HCl, saturated NaHCO3, and brine. The organic layer was collected, dried over Na2SO4, and concentrated in vacuo. The solid obtained was triturated with Et2O and dried to give 7-anilino-N-methoxy-N,4-dimethyl-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carboxamide as a light yellow solid (34 mg, 59%): LCMS RT: 2.28 min, MH+: 415.2. This transformation can also be accomplished by coupling the appropriate amine with the corresponding acid chloride.

Example 20

7-acetyl-2-anilino-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one

[0488]

[0489] To a suspension of 7-anilino-N-methoxy-N,4-dimethyl-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carboxamide (100 mg, 0.24 mmol) in THF (5 mL) at 0° C. was added MeMgBr (3M in Et2O, 322 uL, 0.97 mmol). The suspension became a red solution. As the reaction proceeded the solution lost its red color. After 1 h the reaction was quenched with saturated NH4Cl, diluted with EtOAc, and washed with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude residue was purified by a Biotage silica gel chromatography using EtOAc to afford 7-acetyl-2-anilino-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one as a light yellow solid (65 mg, 74%): LCMS RT: 2.63 min, MH+: 370.4.

Example 21

2
-anilino-7-(butylsulfonyl)-1-phenyl-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one

[0490]

[0491] To a solution of montmorillonite K10 (107.5 mg) in CHCl3 was added 13 uL of water. 2-anilino-7-(butylsulfanyl)-1-phenyl-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one (25 mg, 0.06 mmol) was then added followed by oxone (85.2 mg, 0.14 mmol). The reaction was allowed to stir for 24 h at room temperature. After 24 h the solution was bright bluish-green in color and was filtered and washed with copious amounts of CHCl3. The filtrate was then concentrated in vacuo. Silica gel flash chromatography using 3:1 Hex:EtOAc provided 2-anilino-7-(butylsulfonyl)-1-phenyl-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one as a yellow oil (13.8 mg, 46%): LCMS RT: 3.14, MH+ 502.2.

Example 22

N-[7-anilino-5-oxo-8-phenyl-4-(trifluoremethyl)-5,8-dihydro-1,8-naphthyridin-2-yl]methanesulfonaimide

[0492]

[0493] To a solution of 2-anilino-7-chloro-1-phenyl-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one (100 mg, 0.241 mmol) in DMSO (5 mL) was added methyl sulfonamide and K2CO3 (76.5 mg, 0.554 mmol). The reaction was stirred at 120° C. for 24 h. The reaction was then cooled to room temperature, quenched with water and extracted with Et2O. The organic layers were dried over MgSO4, and concentrated in vacuo. The crude residue was then passed through a plug of silica gel eluting with 1:1 Hex:EtOAc to 9:1 CH2Cl2:MeOH to afford N-[7-anilino-5-oxo-8-phenyl-4-(trifluoromethyl)-5,8-dihydro-1,8-naphthyridin-2-yl]methanesulfonamide as a white solid (4.4 mg, 4%): LCMS RT: 2.45, MH+: 475.2.

Example 23

7-anilino-3-fluoro-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carbaldehyde

[0494]

[0495] 2-anilino-6-fluoro-7-(hydroxymethyl)-1-phenyl-1,8-naphthyridin-4(1H)-one (100 mg, 0.277 mmol) was dissolved in 4.5 mL CHCl3. MnO2 (311 mg, 3.05 mmol) was added and the reaction was heated to 70° C. under argon for 3 d. The reaction mixture was filtered through celite and concentrated in vacuo. Purification by silica gel flash chromatography eluting with 3:1 to 100:0 EtOAc:Hex provided 7-anilino-3-fluoro-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carbaldehyde (15 mg, 15%) as a white solid: LCMS RT: 2.18 min, MH+: 360.2.

Example 24

7-amino-2-anilino-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one

[0496]

[0497] Pd/C (30 mg, 1.75 mmol, 10%) was added to a 25 mL round bottom flask and was blanketed with argon. 7-(allylamino)-2-anilino-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (150 mg, 0.392 mmol) was dissolved in EtOH (2 mL) and was added to the Pd/C followed by methane sulfonic acid (0.041 mL, 0.63 mmol). The reaction was heated to 80° C. for 3 d at which time it was cooled to room temperature, diluted with EtOAc and filtered through celite. The filtrate was concentrated in vacuo and the residue was purified by Biotage silica gel chromatrography eluting with 100% EtOAc to provide 7-amino-2-anilino-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (182 mg, 41 %) as a yellow solid: LCMS RT: 2.01 min, MH+: 343.3.

Example 25

2-anilino-7-(hydroxymethyl)-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one

[0498]

[0499] To a 0° C. suspension of ethyl 7-anilino-3-fluoro-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carboxylate (100.0 mg, 0.25 mmol) in THF (2.5 mL) was added LAH (0.750 mmol, 1M in THF) dropwise over 10 min. After 5 min. the reaction was slowly quenched with EtOAc (10 mL), was left to stir for 15 min and was concentrated in vacuo. The resiude was taken up in CH2Cl2 (10 mL) and 1N HCl (5 mL) and was left to stir for 30 min. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over MgSO4, and concentrated in vacuo. Trituation with Et2O provided 2-anilino-6-fluoro-7-(hydroxymethyl)-1-phenyl-1,8-naphthyridin-4(1H)-one (55.2 mg, 61%) as a tan solid: LCMS RT: 2.01 min, MH+: 362.3.

Example 26

2-anilino-7-[(4-methoxyphenoxy)methyl]-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one

[0500]

[0501] 2-Anilino-6-fluoro-7-(hydroxymethyl)-1-phenyl-1,8-naphthyridin-4(1H)-one (62 mg, 0.175 mmol) was dissolved in CH2Cl2 (1.2 mL). 4-methoxyphenol (22 mg, 0.175 mmol) was added followed by Ph3P (91.8 mg, 0.35 mmol), and ADDP (88.31 mg, 0.35 mmol). The reaction was left to stir overnight at room temperature under argon. Hexanes (5 mL) were added and the reaction was filtered. The filtrate was concentrated in vacuo. Purification of the residue using Biotage silica gel chromatography eluting with 7:3 to 9:1 EtOAc:Hex provided 2-anilino-6-fluoro-7-[(4-methoxyphenoxy)methyl]-1-phenyl-1,8-naphthyridin-4(1H)-one (30.0 mg, 37%) as a white solid: LCMS RT 2.87 min, MH+: 464.2.

Example 27

7-ethoxy-5-ethyl-2-[methyl(phenyl)amino]-1-phenyl-1,8-naphthyridin-4(1H)-one

[0502]

And Example 28

2-anilino-7-ethoxy-5-ethyl-3-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one

[0503]

And Example 29

7-ethoxy-5-ethyl-3-methyl-2-[methyl(phenyl)amino]-1-phenyl-1,8-naphthyridin-4(1H)-one

[0504]

[0505] To a suspension of 2,2,6,6-tetramethylpiperidine (153 mg, 0.18 mL, 1.08 mmol) in THF (10 mL) at 0° C., was added n-BuLi via syringe (1.6 M, 0.68 mL, 1.08 mmol) and TMEDA. The reaction mixture was stirred for 1 h under argon. The reaction mixture was cooled to −60° C. using an acetone/dry ice bath and 2-anilino-.7-ethoxy-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (100 mg,0.269 mmol) was added via syringe as a solution in THF (5 mL). The mixture was stirred for 1 h. Mel was added via syringe and the reaction was allowed to warm to room temperature and stirred for 18 h. A saturated aqueous solution of NH4Cl (20 mL) and EtOAc (20 mL) was added, and the organic layer was separated, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel flash chromatography using 7:3 to 100:0 EtOAc:Hex to give 3 products as follows:

Example 27

[0506] (35 mg, 32 %),

Example 28

[0507] (11 mg, 10 %),

Example 29

[0508] (16 mg, 14 %).

Example 30

2-anilino-6-fluoro-7-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one

[0509]

100

[0510] To 2-anilino-7-chloro-6-fluoro-1-phenyl-1,8-naphthyridin-4(1H)-one (100 mg, 0.273 mmol) in THF (5 mL) was added Pd(PPh3)4 (13 mg, 0.001 mmol) and methyl zinc chloride (2M, 0.819 mL, 1.64 mmol) and the reaction was heated to 75° C. for 18 h. The reaction was then cooled to room temperature and poured into a solution of EDTA in water (2.5 g/20 mL) and extracted with Et2O. The organic layer was washed with brine and concentrated in vacuo. The residue was then taken up in MeOH and filtered. The filtrate was concentrated in vacuo to give 2-anilino-6-fluoro-7-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (83.0 mg, 89%): LCMS RT: 2.43 min, MH+: 346.4.

Example 31

Methyl (2E)-3-(7-anilino-2-methyl-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridin-3-yl)-2-propenoate

[0511]

101

[0512] To a suspension of 2-anilino-6-bromo-7-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (41 mg, 0.1 mmol) in DMF (2.0 mL) were successively added Pd(OAc)2 (0.70 mg, 0.003 mmol), Ph3P (5.2 mg, 0.02 mmol), TEA (0.03 mL) and methyl acrylate (17.2 mg, 0.2 mmol). The suspension was heated at 120° C. in a sealed tube for 64 h. The residue obtained after concentration in vacuo was washed with water and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated in vacuo. Purification by prep-HPLC provided methyl (2E)-3-(7-anilino-2-methyl-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridin-3-yl)-2-propenoate (10.0 mg, 24%): LCMS RT: 2.61 min, MH+: 412.3, Rf=0.26 (1:1 EtOAc:Hex).

Example 32

(2E)-3-(7-anilino-2-methyl-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridin-3-yl)-2-propenoic acid

[0513]

102

[0514] To a suspension of 2-anilino-6-[(E)-3-methoxy-3-oxo-1-propenyl]-7-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (10 mg, 0.025 mmol) in CH3CN (2.0 mL) was added 1N NaOH (2.0 mL). The suspension was stirred at room temperature for 18 h. The mixture was diluted with water (10 mL) and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated in vacuo to afford (2E)-3-(7-anilino-2-methyl-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridin-3-yl)-2-propenoic acid (6.2 mg, 63%): LCMS RT: 2.37 min, MH+: 398.3, Rf=0.51 (EtOAc).

Example 33

3-(7-anilino-2-methyl-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridin-3-yl)propanoicacid

[0515]

103

[0516] To a stirred suspension of 2-anilino-6-[(E)-3-hydroxy-3-oxo-1-propenyl]-7-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (40.0 mg, 0.100 mmol) in MeOH (2.0 mL), was added Pd/C (5.3 mg, 10% weight on carbon) under an argon atmosphere, followed by the addition of ammonia formate (19.0 mg, 0.30 mmol) in a single portion. The reaction mixture was heated at reflux for 2 h, cooled and filtered. The filtrate was diluted with water (10 mL) and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was washed with water and dried in vacuo to afford 3-(7-anilino-2-methyl-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridin-3-yl)propanoicacid (34.5 mg, 86 %): LCMS RT: 2.31 min, MH+: 400.4, Rf=0.61 (4:1 EtOAc:MeOH).

Example 34

2-anilino-6,7-dimethyl-1-phenyl-1,8-naphthyridin-4(1H)-one

[0517]

104

Example 35

2-anilino-7-ethyl-1-(3-methylphenyl)-1,8-naphthyridin-4(1H)-one

[0518]

105

[0519] A suspension of 2-anilino-6-bromo-7-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (203 mg, 0.5 mmol) in THF (10 mL) in an atmosphere of argon was cooled to −78° C. A solution of n-BuLi in hexanes (1.0 mL, 1.6 mmol, 1.6 M) was added and the suspension was stirred for 10 min at 0° C. until it became a clear solution. Excessive Mel (0.2 mL, 3.2 mmol) was added, and the reaction was stirred for another 10 min. The reaction was quenched with saturated aqueous NH4Cl (2.0 mL) and water (10 mL) and the mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by prep-HPLC to afford 2-anilino-6,7-dimethyl-1-phenyl-1,8-naphthyridin-4(1H)-one (55 mg, 32%): LCMS RT: 2.33 min, MH+: 342.4, Rf=0.39 (EtOAc). 2-anilino-7-ethyl-1-(3-methylphenyl)-1,8-naphthyridin-4(1H)-one (13.3 mg, 7.5%) was also obtained as a side product: LCMS RT: 2.54 min, MH+: 356.3, Rf=0.40 (EtOAc). Other electrophiles such as aldehydes, carbon dioxide, disulfides, trifluoroacetates acid chlorides and other alkyl halides can also be used to quench the generated aryl lithium.

Example 36

Ethyl 7-anilino4-chloro-3-fluoro-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carboxylate

[0520]

106

[0521] A suspension of ethyl 7-anilino-3-fluoro-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carboxylate (40.0 mg, 0.099 mmol) in anhydrous THF (10 mL) in an atmosphere of argon was cooled to −78° C. LiHMDS (5 mL, 5 mmol) was then added to the suspension, and the suspension was stirred for 2 h at 0° C. and then cooled to −78° C. and treated with CCl2FCClF2 (94 mg, 0.5 mmol). The reaction was stirred for another hour at 0° C. before being quenched with saturated aqueous NH4Cl (2.0 mL) and water (10 mL) and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated in vacuo. Purification of the residue by prep-HPLC provided Ethyl 7-anilino-4-chloro-3-fluoro-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carboxylate (13.2 mg, 31%): LCMS RT: 2.80 min, MH+: 437.1, Rf=0.78 (EtOAc).

Example 37

7-anilino-4-chloro-3-fluoro-N,N-diisopropyl-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carboxamide

[0522]

107

[0523] LDA was made by adding n-BuLi (0.31 mL, 0.5 mmol, 1.6 M) to diisopropylamine (50 mg, 0.5 mmol) in THF (15 mL) at −15° C. A suspension of ethyl 7-anilino-3-fluoro-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carboxylate (40.0 mg, 0.915 mmol) in anhydrous THF (10 mL) in an atmosphere of argon was cooled to −78° C. LDA was added and the suspension was stirred for 2 h at 0° C. and then cooled to −78° C. and treated with CCl2FCClF2 (94 mg, 0.5 mmol). The reaction was stirred for another hour at 0° C. before being quenched with saturated aqueous NH4Cl (2.0 mL) and water (10 mL). The aqueous solution was extracted with EtOAc and the organic layer was dried over MgSO4 and concentrated in vacuo. Purification of the residue by prep-HPLC provided 7-anilino-3-bromo-4-chloro-N,N-diisopropyl-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carboxamide (20 mg, 41%): LCMS RT: 3.02 min, MH+: 493.3, Rf=0.78 (EtOAc).

Example 38

2-[(4-Methylbenzyl)amino]-1-[3-(trifluoromethyl)phenyl]-1,8-naphthyridin-4(1H)-one

[0524]

108

[0525] A mixture of 2-amino-1-[3-(trifluoromethyl)phenyl]-1,8-naphthyridin-4(1H)-one (50 mg, 0.16 mmol), CsCO3 (160 mg, 0.49 mmol) and 4-methylbenzyl bromide (35 mg, 0.25 mmol) in THF (3 mL) was heated to 80° C. in a sealed tube for 16 h. The reaction was cooled to room temperature and quenched with water (3 mL). The mixture was extracted with CH2Cl2 (3×), and the combined organic extracts were dried with Na2SO4 and concentrated in vacuo. The residue was purified by prep-HPLC (YMC-Pack Pro C 18 Column, 150×20 mm I.D.; first run: 20-80% CH3CN in water, 11 min.; second run: 50-90% MeOH in water, 20 min.) to afford 2-[(4-Methylbenzyl)amino]-1-[3-(trifluoromethyl)phenyl]-1,8-naphthyridin-4(1H)-one (2.2 mg, 3%): LCMS RT: 2.75 min, MH+: 410.2.

[0526] The following specific examples are presented to illustrate the invention related to Formula (II) as described herein, but they should not be construed as limiting the scope of the invention in any way.

[0527] Intermediate BA:

2,4-dichloro-6-methylnicotinic acid

[0528]

109

[0529] A solution of commercially available (Maybridge) ethyl 2,4-dichloro-6-methylpyridine-3-carboxylate (1.0 g, 4.3 mmol) and NaOH (342 mg, 8.6 mmol) in water (1.7 mL) and MeOH (1.5 mL) was heated to 80° C. for 4 h. The mixture was acidified using 50% H2SO4 and then filtered. The solid collected was washed with cold water and dried to give of 2,4-dichloro-6-methylpyridine-3-carboxylic acid (582 mg, 66%): LCMS RT: 0.70 min, MH+: 206.2.

[0530] Intermediate BB:

3,3-dichloro-1-(2,4-dichloro-6-methyl-3-pyridinyl)-2-propen-1-one

[0531]

110

[0532] 2,4-Dichloro-6-methylnicotinic acid (8.7 g, 43.0 mmol) was mixed with SOCl2 (31 mL). The resulting mixture was heated to 80° C. for 2 h and concentrated in vacuo to give the acid chloride as yellow oil. The oil was then dissolved in CH2Cl2 (10 mL) and the solution was added to a cooled suspension of AlCl3 (21.3 g, 160.0 mmol) in CH2Cl2 (50 mL) at 0° C. After 2 h at 0° C., vinylidene chloride (2.16 mL, 80.0 mmol) was added to the above suspension. The resulting mixture was then left to warm to room temperature and stirred overnight. The reaction mixture was poured into crushed ice and the resulting mixture was extracted with CH2Cl2. The combined organic layers were cooled to 0° C. and TEA (14.9 mL) was added. After 1 h of stirring, the organic layer was washed with 10% aqueous HCl (100 mL), water (200 mL), brine (100 mL), and dried over Na2SO4. Solvents were removed in vacuo and the residue was purified by passing it through a pad of silica gel with 15% EtOAc in Hex as the eluent to provide 3,3-dichloro-1-(2,4-dichloro-6-methyl-3-pyridinyl)-2-propen-1-one (5.2 g, 46%): LCMS RT: 3.13 min, MH+: 284.6. Alternatively, the acid chloride could be prepared by using oxalyl chloride with a catalytic amount of DMF.

[0533] Intermediate BC:

3,3-dianilino-1-(2,4-dichloro-6-methyl-3-pyridinyl)-2-propen-1-one

[0534]

111

[0535] A solution of 3,3-dichloro-1-(2,4-dichloro-6-methyl-3-pyridinyl)-2-propen-1-one (5.2 g, 18.0 mmol) in 1,4-dioxane (25 mL) was cooled to 0° C. and aniline (5.1 mL, 55.0 mmol) and TEA (7.7 mL, 55.0 mmol) were added dropwise. The reaction mixture was stirred at 0° C. for 1 h and at room temperature for 2 h. The solvents were removed in vacuo. The residue was purified by passing it through a pad of silica gel with EtOAc:Hex (1:5) as the eluent to provide 3,3-dianilino-1-(2,4-dichloro-6-methyl-3-pyridinyl)-2-propen-1-one (7.1 g, 99%): LCMS RT: 3.06 min, MH+: 398.7.

[0536] Intermediates BA1, BB1, BC1, BA2, BB2, BC2 can be prepared in the same manner shown above for BA, BB and BC starting with the appropriate known starting nicotinic acid (Eur. J Org. Chem. 2001, 1371).

[0537] Intermediate BA1:

4,6-dichloronicotinic acid

[0538]

112

[0539] Intermediate BB1:

3,3-dichloro-1-(4,6-dichloro-3-pyridinyl)-2-propen-1-one

[0540]

113

[0541] Intermediate BC1:

3,3-dianilino-1-(4,6-dichloro-3-pyridinyl)-2-propen-1-one

[0542]

114

[0543] Intermediate BA2:

4,5-dichloronicotinic acid

[0544]

115

[0545] Intermediate BB2:

3,3-dichloro-1-(4,5-dichloro-3-pyridinyl)-2-propen-1-one

[0546]

116

[0547] Intermediate BC2:

3,3-dianilino-1-(4,5-dichloro-3-pyridinyl)-2-propen-1-one

[0548]

117

Example 39

2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one

[0549]

118

[0550] A mixture of 3,3-dianilino-1-(2,4-dichloro-6-methyl-3-pyridinyl)-2-propen-1-one (100 mg, 0.25 mmol) and t-BuOK (42 mg, 0.38 mmol) in anhydrous dioxane (4 mL) was heated to 80° C. for 4 h. The solvent was removed in vacuo and the residue was dissolved in EtOAc. The solution was washed with water and brine, dried over MgSO4, and concentrated in vcaco. Silica gel flash chromatography of the residue using 1:1 EtOAc:Hex gave 2-anilino-5-chloro-7-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (13 mg, 14%): LCMS RT: 2.47 min, MH+: 362 and 2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (68 mg, 75%): LCMS RT: 2.24 min, MH+: 362.3. Alternatively, the cyclization could be achieved by using other bases such as NaH and other aprotic solvents such as THF and DMF.

[0551] Examples 40 and 41 can be prepared in the same manner as that for Example 39 above.

Example 40

2-anilino-7-chloro-1-phenyl-1,6-naphthyridin-4(1H)-one

[0552]

119

Example 41

2-anilino-8-chloro-1-phenyl-1,6-naphthyridin-4(1H)-one

[0553]

120

Example 42

2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one

[0554]

121

[0555] To a solution of 2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (80 mg, 0.22 mmol) in THF (3mL) was added Ni(dppp)Cl2 (24 mg, 0.044 mmol) at room temperature. After stirring for a few minutes MeMgBr (3M, 0.59 mL, 1.76 mmol) was added and the mixture was allowed to stir for 24 h. The mixture was quenched with 1N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by reverse-phase preparative HPLC (10% CH3CN in water with 0.1% TFA to 95% CH3CN in water, 10 mL/min, 10 min) provided 2-anilino-5,7-dimethyl-1-phenyl-1,6-naphthyridin-4(1H)-one (31 mg, 40%): LCMS RT: 1.51 min, MH+: 342.4.

Example 43

2-anilino-5-(dimethylamino)-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one

[0556]

122

[0557] A mixture of 2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (80 mg, 0.22 mmol) and dimethylamine (3M in THF, 0.73 mL, 2.20 mmol) in dioxane (3 mL) was heated to 80 C. for 24 h. The reaction mixture was cooled, concentrated in vacuo, diluted with water and the resulting mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo to give 2-anilino-5-(dimethylamino)-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (74 mg, 91%): LCMS RT: 1.86 min, MH+: 371.3

Example 44

Ethyl[(2-anilino-7-methyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridin-5-yl)sulfanyl]acetate

[0558]

123

[0559] A solution of 2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (200 mg, 0.55 mmol) in EtOH (10 mL) was added ethyl 2-mercaptoacetate (0.12 mL, 1.10 mmol) and TEA (0.23 mL, 1.65 mmol). The reaction was heated at reflux for 24 h. The reaction mixture was cooled, concentrated in vacuo, diluted with water and extracted with EtOAc. The combined organic extracts were washed with water, brine, and dried over Na2SO4. Solvents were removed in vacuo and the residue was purified by reverse-phase preparative HPLC (10% CH3CN in water with 0.1 % TFA to 95% CH3CN in water, 10 mL/min, 10 min) to provide ethyl[(2-anilino-7-methyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridin-5-yl)sulfanyl]acetate (120 mg, 49%): LCMS RT: 3.07 min, MH+: 446.2.

Example 45

[(2-anilino-7-methyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridin-5-yl)sulfanyl]acetic acid

[0560]

124

[0561] Aqueous NaOH (2N, 1 mL) was added to a stirred solution of ethyl[(2-anilino-7-methyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridin-5-yl)sulfanyl]acetate (100 mg, 0.23 mmol) in EtOH (8 mL) at room temperature. The mixture was allowed to stir for 4 h and was concentrated in vacuo. The reaction mixture was acidified with 1N HCl and extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated in vacuo. Purification by reverse-phase preparative HPLC (10% CH3CN in water with 0.1% TFA to 95% CH3CN in water, 10 mL/min, 10 min) provided [(2-anilino-7-methyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridin-5-yl)sulfanyl]acetic acid (56 mg, 60%): LCMS RT: 2.61 min, MH+: 418.2.

Example 46

Ethyl N-(2-anilino-7-methyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridin-5-yl)glycinate

[0562]

125

[0563] To a solution of 2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (80 mg, 0.22 mmol) in EtOH (8 mL) was added glycine ethyl ester hydrochloride (46 mg, 0.44 mmol) and TEA (0.23 mL, 1.65 mmol). The reaction was heated at reflux for 3 d. The reaction mixture was cooled, concentrated in vacuo, diluted with water and extracted with EtOAc. The combined organic extracts were washed with water, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by reverse-phase preparative HPLC (10% CH3CN in water with 0.1% TFA to 95% CH3CN in water, 10 mL/min, 10 min) to provide ethyl N-(2-anilino-7-methyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridin-5-yl)glycinate (43 mg, 46%): LCMS RT: 2.16 min, MH+: 429.3.

Example 47

2-[(2-anilino-7-methyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridin-5-yl)sulfanyl]-N-cyclopropylacetamide

[0564]

126

[0565] To a mixture of [(2-anilino-7-methyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridin-5-yl)sulfanyl]acetic acid (20 mg, 0.05 mmol), EDCI (18 mg, 0.10 mmol), HOBT (13 mg, 0.10 mmol) and cyclopropylamine (0.004 mL, 0.06 mmol) in CH2Cl2 (5 mL) was added TEA (0.02 mL, 0.14 mmol). The reaction solution was stirred at room temperature for 24 h before the mixture was diluted with CH2Cl2, washed with 0.5N HCl, saturated aqueous NaHCO3, brine and dried over Na2SO4. Solvents were removed in vacuo and the residue was purified by reverse-phase preparative HPLC (10% CH3CN in water with 0.1 % TFA to 95% CH3CN in water, 10 mL/min, 10 min) to provide 2-[(2-anilino-7-methyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridin-5-yl)sulfanyl]-N-cyclopropylacetamide (13 mg, 59%): LCMS RT: 2.55 min, MH+: 457.1.

Example 48

2-anilino-7-methyl-1-phenyl-5-(2,2,2-trifluoroethoxy)-1,6-naphthyridin-4(1H)-one

[0566]

127

[0567] Trifluoroethanol (0.08 mL, 1.1 mmol) was added to a suspension of NaH (60% oil dispersion, 44 mg, 1.1 mmol) in DMSO (4 mL) at 0° C., and the mixture was heated at 60° C. for 1 h. The mixture was cooled to room temperature and a solution of 2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (200 mg, 0.55 mmol) in DMSO (2 mL) was added. The resulting mixture was stirred at 50° C. for 16 h. The reaction mixture was cooled, poured into ice water and extracted with CH2Cl2. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by a Biotage silica gel chromatography (2:1 EtOAc:Hex) to provide 2-anilino-7-methyl-1-phenyl-5-(2,2,2-trifluoroethoxy)-1,6-naphthyridin-4(1H)-one (159 mg, 68%): LCMS RT: 2.65 min, MH+: 426.4. This transformation can be accomplished by using other aprotic solvents such as DMF, THF and dioxane with temperatures appropriate for these solvents. Commercially available alkoxides can also be used in the absence of base.

Example 49

2-anilino-7-methyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridine-5-carboxylic acid

[0568]

128

[0569] 2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (1.0 g, 2.8 mmol), DPPP (64 mg, 0.15 mmol), Pd(OAc)2 (31 mg, 0.14 mmol), Cs2CO3 (580 mg, 4.20 mmol) were dissolved in EtOH (10 mL) and DMF (10 mL). A balloon filled with CO was attached to the flask and the solution was stirred vigorously. The flask was purged with CO for 5 min before it was heated to 70° C. After 4 h the mixture was cooled to room temperature and diluted with EtOAc. The mixture was washed with water, brine, and dried over Na2SO4. Solvents were removed in vacuo and the residue was triturated with Et2O to give ethyl 2-anilino-7-methyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridine-5-carboxylate (800 mg, 71%). The ethyl ester was then dissolved in MeOH (5 mL), and THF (20 mL). To this stirring solution was added KOH (3N, 10 mL) and the mixture was stirred at room temperature for 6 h before it was extracted with Et2O. The aqueous layer was acidified with 2N HCl to pH=1 and the product precipitated out of the solution. The solid was filtered and dried to give 2-anilino-7-methyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridine-5-carboxylic acid as a white solid (683 mg, 92%): LCMS RT: 1.75 min, MH+: 372.9.

Example 50

2-anilino-N-methoxy-N,7-dimethyl-4-oxo-1-phenyl-1,4-dihydro-1,6naphthyridine-5-carboxamnide

[0570]

129

[0571] 2-anilino-7-methyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridine-5-carboxylic acid (80 mg, 0.22 mmol), N,O-dimethylhydroxylamine hydrochloride (64 mg, 0.66 mmol), HOBT (89 mg, 0.66 mmol) and EDCI (126 mg, 0.66 mmol) were dissolved in CH2Cl2 (9 mL). To this solution was added TEA (120 uL, 0.88 mmol). The reaction was stirred for 1 h and was diluted with CH2Cl2, washed with 0.5N HCl, saturated NaHCO3, and brine. The organic layer was collected, dried over Na2SO4, and concentrated in vacuo. The solid obtained was triturated with Et2O and dried to give 2-anilino-N-methoxy-N,7-dimethyl-4-oxo-1-phenyl-1,4-dihydro-1,6 naphthyridine-5-carboxamide as a light yellow solid (50 mg, 55%): LCMS RT: 2.08 min, MH+: 414.9. This transformation can also be accomplished by coupling the appropriate amine with the corresponding acid chloride.

Example 51

5-acetyl-2-anilino-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one

[0572]

130

[0573] 2-Anilino-N-methoxy-N,7-dimethyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridine-5-carboxamide (60 mg, 0.14 mmol) was suspended in THF (5 mL). To this stirring suspension at 0° C. was added MeMgBr (0.19 mL, 0.56 mmol, 3M in Et2O). The reaction was stirred at room temperature for 6 h and quenched with saturated aqueous NH4Cl, diluted with EtOAc, and washed with brine. The organic layer was collected, dried over Na2SO4, and concentrated in vacuo. The residue was purified by Biotage silica gel chromatography using EtOAc as the eluent to provide 5-acetyl-2-anilino-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one as a light yellow solid (34 mg, 66%): LCMS RT: 2.20 min, MH+: 370.4.

Example 52

2-anilino-7-methyl-1-phenyl-5-(trifluoromethyl)-1,6-naphthyridin-4(1H)-one

[0574]

131

And Example 53

7-methyl-2-[methyl(phenyl)amino]-1-phenyl-5-(trifluoromethyl)-1,6-naphthyridin-4(1H)-one

[0575]

132

[0576] A mixture of methyl fluorosulphonyldifluoroacetate (0.78 mL, 6.10 mmol) and 2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (2.0 g, 5.50 mmol) in DMF (15 mL) was mixed with Copper(I) iodide (1.05 g, 5.50 mmol) at 80° C. for 6 h before the mixture was filtered and concentrated in vacuo. The residue was diluted with CH2Cl2, washed with water and brine, and dried over MgSO4. Solvents were removed in vacuo and the residue was purified by Biotage silica gel chromatography using 1:1 EtOAc:Hex to provide 2-anilino-7-methyl-1-phenyl-5-(trifluoromethyl)-1,6-naphthyridin-4(1H)-one as a light yellow solid (477 mg 22%): LCMS RT: 2.68 min, MH+: 396.2. 7-Methyl-2-[methyl(phenyl)amino]-1-phenyl-5-(trifluoromethyl)-1,6-naphthyridin-4(1H)-one (270 mg, 12%) was also isolated: LCMS RT: 2.32 min, MH+: 410.4.

Example 54

2-anilino-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one

[0577]

133

[0578] To a flask containing 2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (10 mg, 0.03 mmol) in EtOAc (2 mL) and EtOH (2 mL) at room temperature was added a drop of TEA, and Pd/C (10 weight % on activated carbon Degussa type E101, 2 mg). The system was purged with H2 and left stirring at room temperature overnight. The reaction mixture was filtered and concentrated in vacuo to provide 2-anilino-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (8 mg, 91%): LCMS RT: 1.22 min, MH+: 328.3.

Example 55

2-anilino-5-(4-methoxyphenyl)-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one

[0579]

134

[0580] An 8-mL amber vial was charged with 2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (72 mg, 0.20 mmol), 4-methoxyphenylboronic acid (36 mg, 0.24 mmol), Pd(OAc)2 (1 mg, 0.02 mmol), Ph3P (5 mg, 0.02 mmol), K2CO3 (110 mg, 0.8 mmol, 2 M), and DME (2 mL). The mixture was heated to 90° C. 2 d. Water was added to the reaction mixture and it was extracted with CH2Cl2. The organic layer was dried over Na2SO4. The residue after concentration in vacuo was triturated with Et2O to provide 2-anilino-5-(4-methoxyphenyl)-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (54 mg, 63%): LCMS RT: 1.92 min, MH+: 434.5.

[0581] Utilizing the above described procedures for intermediates and examples alone or in combination, a variety of Formula I compounds were prepared using the appropriate starting material and the representative procedure described. These results are summarized in Table 1A.

1TABLE 1ALCMSRTRepresentativeExampleStructure(min)[M + H]Procedure56

135

2.07413.4Intermediate Z, AA, AB and Example 16, 257

136

1.85357.3Intermediate Z, AA, AB and Example 16, 258

137

1.67412.2Intermediate Z, AA, AB and Example 16, 259

138

2.18411.4Intermediate Z, AA, AB and Example 16, 260

139

2.02358.4Intermediate Z, AA, AB and Example 16, 961

140

2.54382.3Intermediate F, G, H, I, J and Example 162

141

2.58432.4Intermediate O, P, Q, R and Example 463

142

2.63296.3Intermediate O, P, Q, R and Example 464

143

2.89426.2Intermediate F, G, H, I, J and Example 965

144

3.00426.2Intermediate Intermediate F, G, H, I, J and Example 466

145

3.02410.4Intermediate A, B, C, D, E and Example 567

146

3.00464.2Intermediate F, G, H, I, J and Example 468

147

2.98500.3Intermediate F, G, H, I, J and Example 469

148

2.57432.3Intermediate O, P, Q, R and Example 470

149

2.50471.1Intermediate F, G, H, I, J and Example 6, 771

150

2.73390.4Intermediate O, P, Q, R and Example 472

151

2.73408.5Intermediate O, P, Q, R and Example 473

152

3.30396.4Intermediate O, P, Q, R and Example 474

153

3.41370.4Intermediate O, P, Q, R and Example 575

154

3.56396.5Intermediate O, P, Q, R and Example 576

155

3.39404.4Intermediate O, P, Q, R and Example 577

156

2.69370.3Intermediate O, P, Q, R and Example 578

157

2.59356.3Intermediate O, P, Q, R and Example 579

158

2.74408.4Intermediate O, P, Q, R and Example 480

159

1.60394.0Intermediate A, B, C, D, E and Example 1, 10, 1181

160

2.88376.4Intermediate S, T, U, W and Example 1582

161

2.42348.3Intermediate S, T, U, W and Example 1583

162

1.69426.2Intermediate Z, AA, AB and Example 16, 284

163

3.87480.4Intermediate A, B, C, D, E, AL and Example 485

164

Intermediate A, B, C, D, E, AL and Example 486

165

2.43283.6Intermediate S, T, V and Example 1587

166

2.82620.4Intermediate A, B, C, D, E and Example 2, 1388

167

1.86389.1Intermediate K, L, M, N, AM, and Example 1, 1389

168

2.56372.3Intermediate Z, AA, AB and Example 16, 17, 790

169

2.41504.2Intermediate A, B, C, D, E and Example 2, 1291

170

2.50518.3Intermediate A, B, C, D, E and Example 2, 1292

171

2.71566.3Intermediate A, B, C, D, E and Example 2, 1293

172

2.54417.4Intermediate K, L, M, N, and Example 294

173

2.27342.4Intermediate S, T, U, W and Example 1595

174

1.71426.2Intermediate A, B, C, D, E and Example 296

175

1.74412.1Intermediate A, B, C, D, E and Example 297

176

2.75411.2Intermediate A, B, C, D, E and Example 298

177

2.70397.2Intermediate A, B, C, D, E and Example 299

178

2.52399.4Intermediate A, B, C, D, E and Example 2100

179

2.80488.6Intermediate A, B, C, D, E and Example 2101

180

2.89459.7Intermediate A, B, C, D, E and Example 2102

181

2.54441.6Intermediate A, B, C, D, E and Example 2103

182

2.40383.5Intermediate A, B, C, D, E and Example 2104

183

2.44467.5Intennediate F, G, H, I, J and Example 8105

184

2.51480.4Intermediate F, G, H, I, J and Example 8106

185

1.80466.4Intermediate F, G, H, I, J and Example 8107

186

2.65433.4Intermediate A, B, C, D, E and Example 3108

187

2.60437.4Intermediate A, B, C, D, E and Example 3109

188

2.71453.4Intermediate A, B, C, D, E and Example 3110

189

2.53449.4Intermediate A, B, C, D, E and Example 3111

190

2.65433.4Intermediate A, B, C, D, E and Example 3112

191

2.84461.5Intermediate A, B, C, D, E and Example 3113

192

2.08387.4Intermediate A, B, C, D, E and Example 2114

193

2.46433.4Intermediate A, B, C, D, E and Example 2115

194

2.64451.3Intermediate A, B, C, D, E and Example 2116

195

2.61463.4Intermediate A, B, C, D, E and Example 2117

196

2.03440.4Intermediate A, B, C, D, E and Example 2118

197

2.58372.2Intermediate A, B, C, D, E and Example 9119

198

2.20454.4Intermediate A, B, C, D, E and Example 2, 13120

199

2.55496.4Intermediate A, B, C, D, E and Example 2, 13121

200

2.52552.2Intermediate A, B, C, D, E and Example 2, 12122

201

2.44516.3Intermediate A, B, C, D, E and Example 2, 13123

202

2.28429.3Intermediate A, B, C, D, E and Example 3124

203

2.45431.4Intermediate K, L, M, N, AH and Example 2125

204

2.45362.3Intermediate K, L, M, N and Example 9126

205

2.51360.3Intermediate K, L, M, N, AH and Example 1127

206

2.30346.4Intermediate K, L, M, N, AH and Example 1128

207

2.70374.4Intermediate K, L, M, N, AH and Example 1129

208

2.69438.3Intermediate K, L, M, N and Example 9, 14, 4130

209

2.64428.3Intermediate K, L, M, N and Example 9, 14, 4131

210

2.74468.3Intermediate 2 K, L, M, N and Example 9, 14, 4132

211

2.77456.4Intermediate K, L, M, N and Example 9, 14, 4133

212

2.37364.3Intermediate S, T, U, W and Example 15134

213

2.40362.3Intermediate S, T, V, X and Example 15135

214

2.46362.2Intermediate S, T, V, X and Example 15136

215

2.28346.3Intermediate S, T, V, X and Example 15137

216

2.32342.3Intermediate S, T, V, X and Example 15138

217

2.27346.3Intermediate S, T, V, X and Example 15139

218

2.41362.3Intermediate S, T, V, X and Example 15140

219

2.36358.3Intermediate S, T, V, X and Example 15141

220

2.32358.3Intermediate S, T, V, X and Example 15142

221

2.36358.3Intermediate S, T, V, X and Example 15143

222

2.35364.3Intermediate A, B, C, D, E and Example 1144

223

2.60406.3Intermediate Y, S, T, U, W and Example 15145

224

5.35434.4Intermediate Y, S, T, U, W and Example 15, 4146

225

3.43470.3Intermediate F, G, H, I, J and Example 6147

226

3.43470.3Intermediate F, G, H, I, J and Example 6148

227

2.59541.3Intermediate F, G, H, I, J and Example 6, 7, 13149

228

2.66525.2Intermediate F, G, H, I, J and Example 6, 7, 13150

229

2.49483.4Intermediate F, G, H, I, J and Example 8151

230

2.38455.3Intermediate F, G, H, I, J and Example 8, 7152

231

2.60499.4Intermediate F, G, H, I, J and Example 6, 7, 13153

232

2.95547.4Intermediate F, G, H, I, J and Example 6, 7, 13154

233

2.19482.3Intermediate F, G, H, I, J and Example 8, 7, 13155

234

2.07482.3Intermediate F, G, H, I, J and Example 8, 7, 13156

235

1.95454.3Intermediate F, G, H, I, J and Example 8, 7, 13157

236

2.18524.3Intermediate F, G, H, I, J and Example 8, 7, 13158

237

2.44530.3Intermediate F, G, H, I, J and Example 8, 7, 13159

238

1.99468.3Intermediate F, G, H, I, J and Example 8, 7, 13160

239

2.74598.3Intermediate F, G, H, I, J and Example 8, 7, 13161

240

3.15442.3Intermediate F, G, H, I, J and Example 6162

241

3.28456.2Intermediate F, G, H, I, J and Example 6163

242

2.26471.3Intermediate F, G, H, I, J and Example 6, 7, 13164

243

2.34485.3Intermediate F, G, H, I, J and Example 6, 7, 13165

244

2.71398.4Intermediate Z, AA, AB Example 16166

245

2.88542.6Intermediate F, G, H, I, J and Example 8167

246

2.66495.6Intermediate F, G, H, I, J and Example 8168

247

2.20441.5Intermediate F, G, H, I, J and Example 8169

248

2.76453.5Intermediate F, G, H, I, J and Example 8170

249

3.05430.3Intermediate K, L, M, N, AI and Example 1171

250

3.14428.4Intermediate K, L, M, N, AI and Example 1172

251

2.72477.5Intermediate A, B, C, D, E and Example 2173

252

2.72495.5Intermediate F, G, H, I, J and Example 8174

253

2.72495.6Intermediate F, G, H, I, J and Example 8175

254

2.77487.5Intermediate F, G, H, I, J and Example 8176

255

2.43437.4Intermediate A, B, C, D, E and Example 2177

256

3.13502.5Intermediate F, G, H, I, J and Example 6, 21178

257

2.93488.3Intermediate F, G, H, I, J and Example 6, 21179

258

2.41426.3Intermediate F, G, H, I, J and Example 17, 7180

259

2.56372.3Intermediate Z, AA, AB and Example 16, 17, 7181

260

2.19408.2Intermediate A, B, C, D, E and Example 17, 7182

261

2.39425.4Intermediate F, G, H, I, J and Example 17, 18183

262

2.18407.4Intermediate A, B, C, D, E and Example 17, 18184

263

2.88424.4Intermediate F, G, H, I, J and Example 17, 7, 19, 20185

264

2.27402.2Intermediate Z, AA, AB and Example 16, 9186

265

2.41408.3Intermediate Z, AA, AB and Example 16, 9187

266

2.50426.3Intermediate Z, AA, AB and Example 16, 9188

267

2.43386.1Intermediate Z, AA, AB and Example 16, 9189

268

2.66456.4Intermediate F, G, H, I, J and Example 9190

269

2.88462.5Intermediate F, G, H, I, J and Example 9191

270

2.98452.4Intermediate F, G, H, I, J and Example 9192

271

3.12480.3Intermediate F, G, H, I, J and Example 9193

272

3.10440.1Intermediate F, G, H, I, J and Example 9194

273

2.51398.1Intermediate Z, AA, AB and Example 16, 9195

274

2.99505.4Intermediate F, G, H, I, J and Example 8196

275

3.05513.5Intermediate F, G, H, I, J and Example 8197

276

2.47455.4Intermediate F, G, H, I, J and Example 8198

277

2.57453.4Intermediate K, L, M, N1and Example 2199

278

2.70440.2Intermediate K, L, M, N2and Example 17200

279

2.19411.3Intermediate K, L, M, N2and Example 17, 18201

280

2.48453.4Intermediate K, L, M, N2and Example 2202

281

2.76440.2Intermediate K, L, M, N1and Example 17203

282

2.76481.5Intermediate K, L, M, N1and Example 2204

283

2.69481.5Intermediate K, L, M, N2and Example 2205

284

2.23411.3Intermediate K, L, M, N1and Example 17, 18206

285

2.27383.4Intermediate K, L, AC, AG and Example 2207

286

3.12490.3Intermediate F, G, H, I, J and Example 17208

287

2.55461.3Intermediate F, G, H, I, J and Example 17, 18209

288

2.62503.4Intermediate F, G, H, I, J and Example 8210

289

2.82531.5Intermediate F, G, H, I, J and Example 8211

290

2.54491.4Intermediate F, G, H, I, J and Example 8212

291

2.93531.4Intermediate F, G, H, I, J and Example 8213

292

2.47491.4Intermediate F, G, H, I, J and Example 8214

293

3.02476.3Intermediate F, G, H, I, J and Example 9215

294

2.75492.3Intermediate F, G, H, I, J and Example 9216

295

3.14476.2Intermediate F, G, H, I, J and Example 9217

296

2.83492.3Intermediate F, G, H, I, J and Example 9218

297

2.15349.1Intermediate K, L, M, N3and Example 2219

298

2.01362.3Intermediate K, L, M, N and Example 17, 25220

299

2.87505.4Intermediate AH, K, L, M, N2221

300

2.90396.3Intermediate AH, K, L, M, N and Example 1222

301

3.23424.3Intermediate AH, K, L, M, N and Example 1223

302

2.67396.3Intermediate AH, K, L, M, N2 and Example 1224

303

3.02424.4Intermediate AH, K, L, M, N2 and Example, 1225

304

2.12401.3Intermediate A, B, C, D, E and Example 3, 7226

305

2.45459.4Intermediate K, L, M, N, AI and Example 2227

306

2.69487.5Intermediate K, L, M, N, AI and Example 2228

307

2.37447.4Intermediate K, L, M, N, AI and Example 2229

308

2.60374.3Intermediate K, L, M, N, AI and Example 1230

309

2.78390.1Intermediate K, L, M, N, AM and Example 1231

310

2.09421.2Intermediate A, B, C, D, E and Example 22232

311

2.44483.2Intermediate A, B, C, D, E and Example 22233

312

2.51497.2Intermediate A, B, C, D, E and Example 22234

313

2.44383.2Intermediate A, B, C, D, E and Example 3235

314

2.84428.4Intermediate A, B, C, D, E and Example 17236

315

2.77400.3Intermediate A, B, C, D, E and Example 17237

316

2.30372.2Intermediate A, B, C, D, E and Example 17, 7238

317

2.50427.4Intermediate A, B, C, D, E and Example 17, 7, 13239

318

2.18441.5Intermediate A, B, C, D, E and Example 17, 7, 13240

319

2.44399.4Intermediate A, B, C, D, E and Example 17, 7, 13241

320

2.66455.5Intermediate A, B, C, D, E and Example 17, 7, 13242

321

2.79427.3Intermediate A, B, C, D, E and Example 17, 7, 13243

322

2.58411.3Intermediate A, B, C, D, E and Example 17, 7, 13244

323

2.58457.3Intermediate A, B, C, D, E and Example 17, 7, 13245

324

2.80447.5Intermediate A, B, C, D, E and Example 17, 7, 13246

325

2.97481.8Intermediate A, B, C, D, E and Example 17, 7, 13247

326

3.30481.3Intermediate A, B, C, D, E and Example 17, 7, 13248

327

3.05481.7Intermediate A, B, C, D, E and Example 17, 7, 13249

328

1.99371.4Intermediate A, B, C, D, E and Example 17, 18250

329

2.82384.4Intermediate A, B, C, D, E and Example 17, 7, 19, 20251

330

2.94398.4Intermediate A, B, C, D, E and Example 17, 7, 19, 20252

331

3.22426.4Intermediate A, B, C, D, E and Example 17, 7, 19, 20253

332

3.05412.4Intermediate A, B, C, D, E and Example 17, 7, 19, 20254

333

3.10424.4Intermediate A, B, C, D, E and Example 17, 7, 19, 20255

334

3.19438.4Intermediate A, B, C, D, E and Example 17, 7, 19, 20256

335

2.96432.4Intermediate A, B, C, D, E and Example 17, 7, 19, 20257

336

3.16466.4Intermediate A, B, C, D, E and Example 17, 7, 19, 20258

337

2.80398.5Intermediate A, B, C, D, E and Example 17, 7, 19, 20259

338

2.95412.5Intermediate A, B, C, D, E and Example 17, 7, 19, 20260

339

2.80438.6Intermediate A, B, C, D, E and Example 17, 7, 19, 20261

340

3.06450.3Intermediate A, B, C, D, E and Example 17, 7, 19, 20262

341

3.05450.4Intermediate A, B, C, D, E and Example 17, 7, 19, 20263

342

1.94376.2Intermediate K, L, M, N and Example 17, 7264

343

2.44374.4Intermediate K, L, M, N and Example 17, 7, 19, 20265

344

2.59388.3Intermediate K, L, M, N and Example 17, 7, 19, 20266

345

2.68442.4Intermediate K, L, M, N and Example 17, 7, 19, 20267

346

2.97470.5Intermediate K, L, M, N and Example 17, 7, 19, 20268

347

2.53376.3Intermediate K, L, M, N and Example 9269

348

2.28405.4Intermediate K, L, M, N and Example 2270

349

2.35406.2Intermediate K, L, M, N and Example 9271

350

2.70390.2Intermediate K, L, M, N and Example 9272

351

2.20417.3Intermediate K, L, M, N, AI and Example 17, 18273

352

2.38386.3Intermediate A, B, C, D, E and Example 17, 7, 19, 20, 25274

353

2.63440.3Intermediate A, B, C, D, E and Example 17, 7, 19, 20, 25275

354

2.83468.3Intermediate A, B, C, D, E and Example 17, 7, 19, 20, 25276

355

2.79479.3Intermediate F, G, H, I, J and Example 8277

356

2.58451.2Intermediate F, G, H, I, J and Example 8278

357

2.58356.4Intermediate Y, S, T, U, W and Example 15, 34279

358

2.79404.4Intermediate Y, S, T, U, W and Example 15, 4280

359

2.93422.4Intermediate Y, S, T, U, W and Example 15, 4281

360

2.78384.4Intermediate Y, S, T, U, W and Example 15, 34282

361

2.50442.2 (423 +H2O +1)Intermediate Y, S, T, U, W and Example 15, 34283

362

2.26372.4Intermediate Y, S, T, U, W and Example 15, 34284

363

2.29427.4Intermediate Y, S, T, U, W and Example 15, 31, 32, 33, 13285

364

2.19413.4Intermediate Y, S, T, U, W and Example 15, 31, 32, 33, 13286

365

2.15384.4Intermediate Y, S, T, U, W and Example 15, 31, 32287

366

2.01386.4Intermediate Y, S, T, U, W and Example 15, 31, 32, 33288

367

2.42396.5Intermediate Y, S, T, U, W and Example 15, 31289

368

2.97430.6Intermediate Y, S, T, U, W and Example 15, 31290

369

2.33398.6Intermediate Y, S, T, U, W and Example 15, 31, 33291

370

2.87432.4Intermediate Y, S, T, U, W and Example 15, 31, 33292

371

2.01397.3Intermediate Y, S, T, U, W and Example 15, 31, 32, 13293

372

2.00399.5Intermediate Y, S, T, U, W and Example 15, 31, 32, 33, 13294

373

2.63461.3Intermediate F, G, H, I, J and Example 17, 18295

374

2.54445.5Intermediate K, L, M, N and Example 2296

375

2.27425.3Intermediate Y, S, T, U, W and Example 15, 31, 32, 13297

376

2.43392.3Intermediate Y, S, T, U, W and Example 15298

377

2.40398.5Intermediate Y, S, T, U, W and Example 15, 31299

378

2.28411.4Intermediate Y, S, T, U, W and Example 15, 31, 32, 13300

379

3.18490.0Intermediate F, G, H, I, J and Example 9301

380

2.90462.3Intermediate F, G, H, I, J and Example 9302

381

2.90418.3Intermediate F, G, H, I, J and Example 1303

382

2.66418.3Intermediate F, G, H, I, J and Example 1304

383

2.70403.6Intermediate K, L, M, N and Example 2305

384

2.52503.6Intermediate F, G, H, I, J and Example 8306

385

3.03502.2Intermediate F, G, H, I, J and Example 8307

386

2.68358.0Intermediate S, T, U, W and Example 25308

387

2.40358.4Intermediate A, B, C, D, E and Example 9

[0582] Utilizing the above described procedures for intermediates and examples alone or in combination, a variety of Formula I compounds can be prepared using the appropriate starting material and the representative procedure described. These compounds are in Table 1B.

2TABLE 1BRepresentativeExampleStructureProcedure309

388

Intermediate Z, AA, AB and Example 16, 4310

389

Intermediate Z, AA, AB and Example 16, 2311

390

Intermediate Z, AA, AB and Example 16, 3312

391

Intermediate Z, AA, AB and Example 16, 2313

392

Intermediate Z, AA, AB and Example 16, 2, 7314

393

Intermediate Z, AA, AB and Example 16, 2, 7, 13315

394

Intermediate Z, AA, AB and Example 16, 2, 7, 13316

395

Intermediate Z, AA, AB and Example 16, 2, 7, 13317

396

Intermediate Z, AA, AB and Example 16, 6, 7318

397

Intermediate Z, AA, AB and Example 16, 6319

398

Intermediate Z, AA, AB and Example 16, 6, 7, 13320

399

Intermediate Z, AA, AB and Example 16, 6, 7, 13321

400

Intermediate Z, AA, AB and Example 16, 9, 7322

401

Intermediate Z, AA, AB and Example 16, 9323

402

Intermediate Z, AA, AB and Example 16, 9, 7, 13324

403

Intermediate Z, AA, AB and Example 16, 9, 7, 13325

404

Intermediate Z, AA, AB and Example 16, 9326

405

Intermediate Z, AA, AB and Example 16, 9327

406

Intermediate Z, AA, AB and Example 16, 9328

407

Intermediate Y, S, T, U, W and Example 15, 34329

408

Intermediate Y, S, T, U, W and Example 15, 34330

409

Intermediate Y, S, T, U, W and Example 15, 34331

410

Intermediate Y, S, T, U, W and Example 15, 34332

411

Intermediate Y, S, T, U, W and Example 15, 4333

412

Intermediate Y, S, T, U, W and Example 15, 4334

413

Intermediate Y, S, T, U, W and Example 15, 34335

414

Intermediate Y, S, T, U, W and Example 15, 34, 13336

415

Intermediate Y, S, T, U, W and Example 15, 34, 13337

416

Intermediate Y, S, T, U, W and Example 15, 34, 13338

417

Intermediate K, L, M, N Example 31, 32339

418

Intermediate O, P, Q, R and Example 17, 25, 26340

419

Intermediate F, G, H, I, J and Example 31, 32341

420

Intermediate A, B, C, D, E and Example 1 and Intermediate AK342

421

Intermediate Z, AA, AB and Example 16, 31, 32, 33343

422

Intermediate A, B, C, D, E and Example 1 and Intermediate AK344

423

Intermediate A, B, C, D, E and Example 31, 32345

424

Intermediate A, B, C, D, E and Example 1 and Intermediate AK346

425

Intermediate O, P, Q, R and Example 17, 25, 26347

426

Intermediate Z, AA, AB, and Example 16, 31, 32348

427

Intermediate F, G, H, I, J and Example 31, 32, 33349

428

Intermediate O, P, Q, R and Example 17, 25, 26350

429

Intermediate K, L, M, N and Example 31351

430

Intermediate F, G, H, I, J and Example 31352

431

Intermediate A, B, C, D, E and Example 31353

432

Intermediate Z, AA, AB and Example 16, 31354

433

Intermediate A, B, C, D, E and Example 31, 32, 33355

434

Intermediate K, L, M, N and Example 31, 32, 33356

435

Intermediate O, P, Q, R and Example 17, 25, 26357

436

Intermediate A, B, C, D, E AJ and Example 1358

437

Intermediate A, B, C, D, E and Example 1 and Intermediate AL359

438

Intermediate Z, AA, AB, and Example 16, 5360

439

Intermediate Z, AA, AB, and Example 16, 5361

440

Intermediate Z, AA, AB, and Example 16, 4362

441

Intermediate K, L, M, N, and Example 2363

442

Intermediate K, L, M, N, and Example 2364

443

Intermediate K, L, M, N, and Example 2365

444

Intermediate K, L, M, N, and Example 2366

445

Intermediate K, L, M, N, and Example 2367

446

Intermediate K, L, M, N, and Example 2368

447

Intermediate K, L, M, N, and Example 2369

448

Intermediate K, L, M, N, and Example 2370

449

Intermediate K, L, M, N, and Example 2371

450

Intermediate A, B, C, D, E and Example 2372

451

Intermediate A, B, C, D, E and Example 2373

452

Intermediate A, B, C, D, E and Example 2374

453

Intermediate A, B, C, D, E and Example 2375

454

Intermediate A, B, C, D, E and Example 2376

455

Intermediate A, B, C, D, E and Example 2377

456

Intermediate A, B, C, D, E and Example 2378

457

Intermediate A, B, C, D, E and Example 2379

458

Intermediate S, T, V, X and Example 15380

459

Intermediate S, T, V, X and Example 15381

460

Intermediate S, T, V, X and Example 15 and Intermediate AJ382

461

Intermediate S, T, V, X and Example 15 and Intermediate AJ383

462

Intermediate S, T, V and Example 15384

463

Intermediate S, T, V and Example 15385

464

Intermediate S, T, V and Example 15386

465

Intermediate S, T, V, X and Example 15387

466

Intermediate A, B, C, D, E and Example 2388

467

Intermediate S, T, V and Example 15389

468

Intermediate S, T, V and Example 15390

469

Intermediate S, T, V, X and Example 15391

470

Intermediate S, T, V, X and Example 15392

471

Intermediate S, T, V and Example 15, 21393

472

Intermediate S, T, V and Example 15, 21394

473

Intermediate S, T, V and Example 15, 21395

474

Intermediate A, B, C, D, E and Example 1, 12396

475

Intermediate Z, AA, AB and Example 16, 17, 7, 19397

476

Intermediate Z, AA, AB and Example 16, 17, 18398

477

Intermediate Z, AA, AB and Example 16, 2399

478

Intermediate Z, AA, AB and Example 16, 2400

479

Intermediate Z, AA, AB and Example 16, 2, 13401

480

Intermediate Z, AA, AB and Example 16, 2402

481

Intermediate Z, AA, AB and Example 16, 2403

482

Intermediate Z, AA, AB and Example 16, 9404

483

Intermediate A, B, C, D, E and Example 1, 10, 11405

484

Intermediate A, B, C, D, E and Example 1, 10, 11406

485

Intermediate A, B, C, D, E and Example 1, 10, 11407

486

Intermediate A, B, C, D, E and Example 1, 10, 11408

487

Intermediate Z, AA, AB and Example 16, 2, 7, 13409

488

Intermediate Z, AA, AB and Example 16, 6, 7, 13410

489

Intermediate Z, AA, AB and Example 16, 9, 7, 13411

490

Intermediate Z, AA, AB and Example 16, 9, 7, 13412

491

Intermediate Z, AA, AB and Example 16, 2, 7, 13413

492

Intermediate Z, AA, AB and Example 16, 6, 7, 13414

493

Intermediate Z, AA, AB and Example 16, 17, 7, 13415

494

Intermediate Z, AA, AB and Example 16, 17, 7, 13416

495

Intermediate Z, AA, AB and Example 16, 17, 7, 13417

496

Intermediate Z, AA, AB and Example 16, 17, 7, 13418

497

Intermediate Z, AA, AB and Example 16, 17419

498

Intermediate Z, AA, AB and Example 16, 6420

499

Intermediate Z, AA, AB and Example 16, 6, 21421

500

Intermediate Z, AA, AB and Example 16, 6422

501

Intermediate Z, AA, AB and Example 16, 6423

502

Intermediate Z, AA, AB and Example 16, 6, 21424

503

Intermediate Z, AA, AB and Example 16, 6425

504

Intermediate Z, AA, AB and Example 16, 3, 24426

505

Intermediate K, L, M, N, AM and Example 1 and Intermediate AJ427

506

Intermediate K, L, M, N, AM and Example 1 and Intermediate AJ428

507

Intermediate K, L, M, N, AM and Example 1, 26429

508

Intermediate K, L, M, N, AM and Example 1, 26430

509

Intermediate K, L, M, N, AM and Example 1 and Intermediate AJ431

510

Intermediate Z, AA, AB and Example 16, 31432

511

Intermediate Z, AA, AB and Example 16, 31, 32, 13433

512

Intermediate Z, AA, AB and Example 16, 31, 33434

513

Intermediate Z, AA, AB and Example 16, 31, 32, 33, 13435

514

Intermediate Z, AA, AB and Example 16, 31, 33436

515

Intermediate Z, AA, AB and Example 16, 31, 32, 33, 13437

516

Intermediate Z, AA, AB and Example 16, 31, 32, 33, 13438

517

Intermediate Z, AA, AB and Example 16, 17, 7, 19, 20439

518

Intermediate Z, AA, AB and Example 16, 17, 7, 19, 20440

519

Intermediate Z, AA, AB and Example 16, 17, 7, 19, 20441

520

Intermediate Z, AA, AB and Example 16, 2, 13442

521

Intermediate Z, AA, AB and Example 16, 2 and Intermediate AK443

522

Intermediate Z, AA, AB and Example 16, 2, 12444

523

Intermediate Z, AA, AB and Example 16, 2, 13445

524

Intermediate Z, AA, AB and Example 16, 3, 24, 13446

525

Intermediate Z, AA, AB and Example 16, 2, 13447

526

Intermediate Z, AA, AB and Example 16, 22448

527

Intermediate Z, AA, AB and Example 16, 22449

528

Intermediate Z, AA, AB and Example 16, 3, 24 and Intermediate AK450

529

Intermediate S, T, U, W and Example 25 and Intermediate AJ451

530

Intermediate S, T, U, W and Example 25 and Intermediate AJ452

531

Intermediate S, T, U, W and Example 25, 26453

532

Intermediate S, T, U, W and Example 25, 26454

533

Intermediate S, T, U, W and Example 25 and Intermediate AJ455

534

Intermediate S, T, U, W and Example 15 and Intermediate AL and Example 3456

535

Intermediate S, T, U, W and Example 15 and Intermediate AL and Example 3457

536

Intermediate S, T, U, W and Example 15 and Intermediate AL and Example 3458

537

Intermediate Y, S, T, U, W and Example 15, 31, 32, 33, 19, 20459

538

Intermediate Y, S, T, U, W and Example 15, 31, 33460

539

Intermediate Y, S, T, U, W and Example 15, 31, 32, 33, 19, 20461

540

Intermediate Y, S, T, U, W and Example 15, 17, 7, 19, 20462

541

Intermediate Y, S, T, U, W and Example 15, 17, 7, 19, 20463

542

Intermediate Y, S, T, U, W and Example 15, 17, 7, 19, 20464

543

Intermediate Y, S, T, U, W and Example 15, 17, 25465

544

Intermediate Y, S, T, U, W and Example 15, 17, 25 and Intermediate AJ466

545

Intermediate Y, S, T, U, W and Example 15, 17, 25, 26467

546

Intermediate Y, S, T, U, W and Example 15, 3468

547

Intermediate Y, S, T, U, W and Example 15, 3469

548

Intermediate Y, S, T, U, W and Example 15, 3470

549

Intermediate Y, S, T, U, W and Example 15, 3471

550

Intermediate Y, S, T, U, W and Example 15, 3472

551

Intermediate Y, S, T, U, W and Example 15, 3, 13473

552

Intermediate Y, S, T, U, W and Example 15, 3 and Intermediate AK474

553

Intermediate Y, S, T, U, W and Example 15, 3, 12475

554

Intermediate Y, S, T, U, W and Example 15, 3476

555

Intermediate Y, S, T, U, W and Example 15, 3477

556

Intermediate Y, S, T, U, W and Example 15, 3478

557

Intermediate Y, S, T, U, W and Example 15, 3, 24479

558

Intermediate Y, S, T, U, W and Example 15, 3480

559

Intermediate Y, S, T, U, W and Example 15, 3481

560

Intermediate Y, S, T, U, W and Example 15, 3482

561

Intermediate Y, S, T, U, W and Example 15, 3483

562

Intermediate Y, S, T, U, W and Example 15, 3484

563

Intermediate Y, S, T, U, W and Example 15, 3485

564

Intermediate Y, S, T, U, W and Example 15, 3, 7486

565

Intermediate Y, S, T, U, W and Example 15, 3, 18487

566

Intermediate Y, S, T, U, W and Example 15, 3, 7, 13488

567

Intermediate Y, S, T, U, W and Example 15, 3, 7, 13489

568

Intermediate Y, S, T, U, W and Example 15, 3, 7, 13490

569

Intermediate Y, S, T, U, W and Example 15, 3, 13491

570

Intermediate Y, S, T, U, W and Example 15, 3, 12492

571

Intermediate Y, S, T, U, W and Example 15, 3, 24 and Intermediate AK493

572

Intermediate Y, S, T, U, W and Example 15, 34494

573

Intermediate Y, S, T, U, W and Example 15, 34495

574

Intermediate Y, S, T, U, W and Example 15, 34, 21496

575

Intermediate Y, S, T, U, W and Example 15, 34, 21497

576

Intermediate Y, S, T, U, W and Example 15, 34498

577

Intermediate S, T, U, W and Example 15499

578

Intermediate Y, S, T, U, W and Example 15, 31, 32, 33, 13500

579

Intermediate Y, S, T, U, W and Example 15, 31, 32, 33, 13501

580

Intermediate Y, S, T, U, W and Example 15, 31, 32, 33, 13502

581

Intermediate F, G, H, I, J and Example 17, 25 and Intermediate AJ503

582

Intermediate F, G, H, I, J and Example 17, 25 and Intermediate AJ504

583

Intermediate F, G, H, I, J and Example 17, 25 and Intermediate AJ505

584

Intermediate F, G, H, I, J and Example 8506

585

Intermediate F, G, H, I, J and Example 8507

586

Intermediate F, G, H, I, J and Example 8508

587

Intermediate F, G, H, I, J and Example 9509

588

Intermediate F, G, H, I, J and Example 9510

589

Intermediate F, G, H, I, J and Example 9511

590

Intermediate F, G, H, I, J and Example 9512

591

Intermediate F, G, H, I, J and Example 6, 21513

592

Intermediate F, G, H, I, J and Example 6514

593

Intermediate F, G, H, I, J and Example 6515

594

Intermediate F, G, H, I, J and Example 9516

595

Intermediate F, G, H, I, J and Example 8 and Intermediate AK517

596

Intermediate F, G, H, I, J and Example 8 and Intermediate AK518

597

Intermediate F, G, H, I, J and Example 31, 33519

598

Intermediate F, G, H, I, J and Example 31, 33520

599

Intermediate F, G, H, I, J and Example 31, 32, 33, 13521

600

Intermediate F, G, H, I, J and Example 31, 32, 33, 13522

601

Intermediate F, G, H, I, J and Example 31, 32, 33, 13523

602

Intermediate F, G, H, I, J and Example 31, 32, 33, 13524

603

Intermediate F, G, H, I, J and Example 31, 33525

604

Intermediate F, G, H, I, J and Example 3, 24, 13526

605

Intermediate F, G, H, I, J and Example 3, 24, 13527

606

Intermediate F, G, H, I, J and Example 3, 24 and Intermediate AK528

607

Intermediate F, G, H, I, J and Example 3, 24 and Intermediate AK529

608

Intermediate F, G, H, I, J and Example 9, 7530

609

Intermediate F, G, H, I, J and Example 9531

610

Intermediate F, G, H, I, J and Example 9, 7, 13532

611

Intermediate F, G, H, I, J and Example 9, 7, 13533

612

Intermediate F, G, H, I, J and Example 9, 7, 13

[0583] Utilizing the above described procedures for intermediates and examples and Flow Diagrams I-XIV alone or in combination, a variety of Formula I compounds can be prepared using the appropriate starting material. These compounds are summarized in Table 1C.

3TABLE 1CExampleStructure534

613

535

614

536

615

537

616

538

617

539

618

540

619

541

620

542

621

543

622

544

623

545

624

546

625

547

626

548

627

549

628

550

629

551

630

552

631

553

632

554

633

555

634

556

635

557

636

558

637

559

638

560

639

561

640

562

641

563

642

564

643

565

644

566

645

567

646

568

647

569

648

570

649

571

650

572

651

573

652

574

653

575

654

576

655

577

656

578

657

579

658

580

659

581

660

[0584] Utilizing the above described procedures for intermediates and examples alone or in combination, a variety of Formula II compounds were prepared using the appropriate starting material and the representative procedure described. These results are summarized in Table 2A.

4TABLE 2ALCMS RTRepresentativeExampleStructure(min)[M + H]Procedure582

661

2.39372.3Intermediate BA, BB, BC and Example 39, 48583

662

2.05401.2Intermediate BA, BB, BC and Example 39, 46, 45584

663

1.93401.3Intermediate BA, BB, BC and Example 39, 43585

664

2.04418.3Intermediate BA, BB, BC and Example 39, 42586

665

2.25358.4Intermediate BA, BB, BC and Example 39, 48587

666

2.89412.1Intermediate BA, BB, BC and Example 39, 48588

667

1.89415.3Intermediate BA, BB, BC and Example 39, 48589

668

2.57398.3Intermediate BA, BB, BC and Example 39, 48590

669

1.92457.2Intermediate BA, BB, BC and Example 39, 48591

670

2.41408.4Intermediate BA, BB, BC and Example 39, 48592

671

2.52386.1Intermediate BA, BB, BC and Example 39, 48593

672

2.46402.2Intermediate BA, BB, BC and Example 39, 48594

673

2.12441.1Intermediate BA, BB, BC and Example 39, 48595

674

1.79371.9Intermediate BA, BB, BC and Example 39, 49, 47596

675

2.36398.3Intermediate BA, BB, BC and Example 39597

676

2.57390.4Intermediate BA, BB, BC and Example 39598

677

3.28400.2Intermediate BA, BB, BC and Example 39, 48599

678

2.56422.0Intermediate BA, BB, BC and Example 39, 48600

679

2.74414.1Intermediate BA, BB, BC and Example 39, 48601

680

2.43398.4Intermediate BA, BB, BC and Example 39602

681

2.57422.1Intermediate BA, BB, BC and Example 39, 48603

682

2.45408.2Intermediate BA, BB, BC and Example 39, 48604

683

2.02396.3Intermediate BA, BB, BC and Example 39, 42605

684

2.15410.3Intermediate BA, BB, BC and Example 39, 42606

685

1.96383.3Intermediate BA, BB, BC and Example 39, 43607

686

2.20484.3Intermediate BA, BB, BC and Example 39, 43608

687

2.19411.3Intermediate BA, BB, BC and Example 39, 43609

688

2.33419.4Intermediate BA, BB, BC and Example 39, 43610

689

1.86454.3Intermediate BA, BB, BC and Example 39, 43611

690

1.22483.2Intermediate BA, BB, BC and Example 39, 43612

691

2.11411.4Intermediate BA, BB, BC and Example 39, 43613

692

1.55426.0Intermediate BA, BB, BC and Example 39, 43614

693

1.98413.0Intermediate BA, BB, BC and Example 39, 43615

694

1.88370.3Intermediate BA, BB, BC and Example 39, 42616

695

1.73356.3Intermediate BA, BB, BC and Example 39, 42617

696

2.53488.3Intermediate BA, BB, BC and Example 39, 43618

697

2.30427.3Intermediate BA, BB, BC and Example 39, 43619

698

1.68405.4Intermediate BA, BB, BC and Example 39, 55620

699

2.25449.2Intermediate BA, BB, BC and Example 39, 55621

700

2.00418.5Intermediate BA, BB, BC and Example 39, 55622

701

2.19438.3Intermediate BA, BB, BC and Example 39, 55

[0585] Utilizing the above described procedures for intermediates and examples alone or combination, a variety of Formula II compounds can be prepared using the appropriate starting material and the representative procedure described. These compounds are summarized in Table 2B.

5TABLE 2BRepresentativeExampleStuctureProcedure623

702

Intermediate BA1, BB1, BC1 and Example 40, 49, 47624

703

Intermediate BA1, BB1, BC1 and Example 40, 31, 32625

704

Intermediate BA1, BB1, BC1 and Example 40, 43626

705

Intermediate BA1, BB1, BC1 and Example 40, 43 and Intermediate AK627

706

Intermediate BA1, BB1, BC1 and Example 40, 43 and Intermediate AK628

707

Intermediate BA1, BB1, BC1 and Example 40, 17, 25 and Intermediate AJ629

708

Intermediate BA1, BB1, BC1 and Example 40, 31, 33630

709

Intermediate BA1, BB1, BC1 and Example 40, 31, 33631

710

Intermediate BA1, BB1, BC1 and Example 40, 31, 32, 33, 47632

711

Intermediate BA1, BB1, BC1 and Example 40, 31, 32, 33, 47633

712

Intermediate BA1, BB1, BC1 and Example 40, 31, 32, 33, 47634

713

Intermediate BA1, BB1, BC1 and Example 40, 31, 32, 33, 47635

714

Intermediate BA1, BB1, BC1 and Example 40, 31, 33636

715

Intermediate BA1, BB1, BC1 and Example 40, 17, 25 and Intermediate AJ637

716

Intermediate BA1, BB1, BC1 and Example 40, 17, 25 and Intermediate AJ638

717

Intermediate BA1, BB1, BC1 and Example 40, 48639

718

Intermediate BA1, BB1, BC1 and Example 40, 48640

719

Intermediate BA1, BB1, BC1 and Example 40, 48641

720

Intermediate BA1, BB1, BC1 and Example 40, 48642

721

Intermediate BA1, BB1, BC1 and Example 40, 44, 21643

722

Intermediate BA1, BB1, BC1 and Example 40, 44644

723

Intermediate BA1, BB1, BC1 and Example 40, 44645

724

Intermediate BA1, BB1, BC1 and Example 40, 43646

725

Intermediate BA1, BB1, BC1 and Example 40, 49, 47647

726

Intermediate BA1, BB1, BC1 and Example 40, 43648

727

Intermediate BA, BB, BC and Example 39, 17, 25, 26649

728

Intermediate BA, BB, BC and Example 39, 31, 32, 33650

729

Intermediate BA1, BB1, BC1 and Example 40, 43651

730

Intermediate BA1, BB1, BC1 and Example 40, 43652

731

Intermediate BA2, BB2, BC2 and Example 40, 31, 32653

732

Intermediate BA1, BB1, BC1 and Example 40, 43654

733

Intermediate BA1, BB1, BC1 and Example 40, 49, 47655

734

Intermediate BA1, BB1, BC1 and Example 40, 49, 50, 51656

735

Intermediate BA1, BB1, BC1 and Example 40, 44657

736

Intermediate BA1, BB1, BC1 and Example 40, 43658

737

Intermediate BA1, BB1, BC1 and Example 40, 49, 50, 51659

738

Intermediate BA1, BB1, BC1 and Example 40, 43660

739

Intermediate BA1, BB1, BC1 and Example 40, 44661

740

Intermediate BA1, BB1, BC1 and Example 40, 49, 47662

741

Intermediate BA1, BB1, BC1 and Example 40, 44, 21663

742

Intermediate BA, BB, BC and Example 39, 31664

743

Intermediate BA1, BB1, BC1 and Example 40, 43665

744

Intermediate BA, BB, BC and Example 39, 17, 25, 26666

745

Intermediate BA1, BB1, BC1 and Example 40, 44, 21667

746

Intermediate BA1, BB1, BC1 and Example 40, 49, 50, 51668

747

Intermediate BA1, BB1, BC1 and Example 40, 43, 12669

748

Intermediate BA1, BB1, BC1 and Example 40, 3670

749

Intermediate BA, BB, BC and Example 39, 3671

750

Intermediate BA1, BB1, BC1 and Example 40, 55672

751

Intermediate BA1, BB1, BC1 and Example 40, 44, 21673

752

Intermediate BA1, BB1, BC1 and Example 40, 43, 12674

753

Intermediate BA1, BB1, BC1 and Example 40, 31675

754

Intermediate BA1, BB1, BC1 and Example 40, 49, 50, 51676

755

Intermediate BA, BB, BC and Example 39, 17, 25, 26677

756

Intermediate BA, BB, BC and Example 39, 54 and Intermediate AL678

757

Intermediate BA1, BB1, BC1 and Example 40, 3679

758

Intermediate BA1, BB1, BC1 and Example 40, 43, 12680

759

Intermediate BA1, BB1, BC1 and Example 40, 48681

760

Intermediate BA1, BB1, BC1 and Example 40, 49, 50, 51682

761

Intermediate BA, BB, BC and Example 39, 43, 12683

762

Intermediate BA, BB, BC and Example 39, 54 and Intermediate AJ684

763

Intermediate BA1, BB1, BC1 and Example 40, 3685

764

Intermediate BA, BB, BC and Example 39, 3, 24686

765

Intermediate BA1, BB1, BC1 and Example 40, 17687

766

Intermediate BA1, BB1, BC1 and Example 40, 49, 47688

767

Intermediate BA2, BB2, BC2 and Example 40, 31, 32, 33689

768

Intermediate BA1, BB1, BC1 and Example 40, 22690

769

Intermediate BA1, BB1, BC1 and Example 40, 3691

770

Intermediate BA2, BB2, BC2 and Example 41, 55692

771

Intermediate BA1, BB1, BC1 and Example 40, 44, 21693

772

Intermediate BA1, BB1, BC1 and Example 40, 17, 25, 26694

773

Intermediate BA1, BB1, BC1 and Example 40, 17, 25, 23695

774

Intermediate BA1, BB1, BC1 and Example 40, 17, 18696

775

Intermediate BA1, BB1, BC1 and Example 40, 3, 24697

776

Intermediate BA, BB, BC and Example 39, 17, 25698

777

Intermediate BA, BB, BC and Example 39, 17, 25, 26699

778

Intermediate BA2, BB2, BC2 and Example 41, 55700

779

Intermediate BA1, BB1, BC1 and Example 40, 49, 50701

780

Intermediate BA, BB, BC and Example 39 54, and Intermediate AK702

781

Intermediate BA1, BB1, BC1 and Example 40, 3703

782

Intermediate BA1, BB1, BC1 and Example 40, 49, 50, 51704

783

Intermediate BA2, BB2, BC2 and Example 41, 34705

784

Intermediate BA2, BB2, BC2 and Example 41, 3706

785

Intermediate BA1, BB1, BC1 and Example 40, 17, 25, 26707

786

Intermediate BA1, BB1, BC1 and Example 40, 44708

787

Intermediate BA1, BB1, BC1 and Example 40, 43, 47709

788

Intermediate BA, BB, BC and Example 39, 17, 25, 26710

789

Intermediate BA1, BB1, BC1 and Example 40, 48711

790

Intermediate BA2, BB2, BC2 and Example 41, 31712

791

Intermediate BA1, BB1, BC1 and Example 40, 3713

792

Intermediate BA, BB, BC and Example 39 54 and Intermediate AK714

793

Intermediate BA2, BB2, BC2 and Example 41, 34715

794

Intermediate BA1, BB1, BC1 and Example 40, 3716

795

Intermediate BA1, BB1, BC1 and Example 40, 17, 25, 26717

796

Intermediate BA1, BB1, BC1 and Example 40, 48718

797

Intermediate BA1, BB1, BC1 and Example 40, 49, 50, 51719

798

Intermediate BA2, BB2, BC2 and Example 41, 3720

799

Intermediate BA2, BB2, BC2 and Example 41, 34721

800

Intermediate BA1, BB1, BC1 and Example 40, 55722

801

Intermediate BA1, BB1, BC1 and Example 40, 44, 45723

802

Intermediate BA1, BB1, BC1 and Example 40, 3724

803

Intermediate BA1, BB1, BC1 and Example 40, 43, 47725

804

Intermediate BA, BB, BC and Example 39, 54 and Intermediate AK726

805

Intermediate BA1, BB1, BC1 and Example 40, 17, 25, 26727

806

Intermediate BA1, BB1, BC1 and Example 40, 3728

807

Intermediate BA2, BB2, BC2 and Example 41, 34729

808

Intermediate BA2, BB2, BC2 and Example 41, 3730

809

Intermediate BA1, BB1, BC1 and Example 40, 55731

810

Intermediate BA1, BB1, BC1 and Example 40, 3732

811

Intermediate BA1, BB1, BC1 and Example 40, 48733

812

Intermediate BA1, BB1, BC1 and Example 40, 3734

813

Intermediate BA, BB, BC and Example 39, 31, 32735

814

Intermediate BA1, BB1, BC1 and Example 40, 3736

815

Intermediate BA1, BB1, BC1 and Example 40, 3737

816

Intermediate BA1, BB1, BC1 and Example 40, 31, 32, 33738

817

Intermediate BA1, BB1, BC1 and Example 40, 3739

818

Intermediate BA, BB, BC and Example 39, 49, 50, 51, 25740

819

Intermediate BA, BB, BC and Example 39, 17, 25, 11741

820

Intermediate BA, BB, BC and Example 39, 17, 25, 11742

821

Intermediate BA1, BB1, BC1 and Example 40, 42743

822

Intermediate BA1, BB1, BC1 and Example 40, 42744

823

Intermediate BA1, BB1, BC1 and Example 40, 42745

824

Intermediate BA1, BB1, BC1 and Example 40, 42746

825

Intermediate BA1, BB1, BC1 and Example 40, 17, 25747

826

Intermediate BA1, BB1, BC1 and Example 40, 49, 50, 51, 25748

827

Intermediate BA1, BB1, BC1 and Example 40, 49, 50, 51, 25749

828

Intermediate BA1, BB1, BC1 and Example 40, 49, 50, 51, 25750

829

Intermediate BA1, BB1, BC1 and Example 40, 17, 25, 26751

830

Intermediate BA1, BB1, BC1 and Example 40, 55752

831

Intermediate BA1, BB1, BC1 and Example 40, 55753

832

Intermediate BA1, BB1, BC1 and Example 40, 55754

833

Intermediate BA1, BB1, BC1 and Example 40, 49, 50, 51755

834

Intermediate BA1, BB1, BC1 and Example 40, 49, 50, 51756

835

Intermediate BA1, BB1, BC1 and Example 40, 49757

836

Intermediate BA1, BB1, BC1 and Example 40, 43758

837

Intermediate BA1, BB1, BC1 and Example 40, 43759

838

Intermediate BA1, BB1, BC1 and Example 40, 43760

839

Intermediate BA1, BB1, BC1 and Example 40, 43761

840

Intermediate BA1, BB1, BC1 and Example 40, 43762

841

Intermediate BA1, BB1, BC1 and Example 40, 43763

842

Intermediate BA1, BB1, BC1 and Example 40, 43, 47764

843

Intermediate BA1, BB1, BC1 and Example 40, 43, 12765

844

Intermediate BA1, BB1, BC1 and Example 40, 43, 12766

845

Intermediate BA1, BB1, BC1 and Example 40, 43767

846

Intermediate BA1, BB1, BC1 and Example 40, 43768

847

Intermediate BA1, BB1, BC1 and Example 40, 3769

848

Intermediate BA1, BB1, BC1 and Example 40, 43770

849

Intermediate BA1, BB1, BC1 and Example 40, 22771

850

Intermediate BA1, BB1, BC1 and Example 40, 46, 45772

851

Intermediate BA1, BB1, BC1 and Example 40, 46773

852

Intermediate BA1, BB1, BC1 and Example 40, 46, 45, 47774

853

Intermediate BA1, BB1, BC1 and Example 40, 46, 45, 47775

854

Intermediate BA1, BB1, BC1 and Example 40, 46, 45, 47776

855

Intermediate BA1, BB1, BC1 and Example 40, 44, 45, 47777

856

Intermediate BA1, BB1, BC1 and Example 40, 44, 45, 47778

857

Intermediate BA1, BB1, BC1 and Example 40, 44, 45, 47779

858

Intermediate BA1, BB1, BC1 and Example 40, 48, 45780

859

Intermediate BA1, BB1, BC1 and Example 40, 48781

860

Intermediate BA1, BB1, BC1 and Example 40, 48, 45, 47782

861

Intermediate BA1, BB1, BC1 and Example 40, 48, 45, 47783

862

Intermediate BA1, BB1, BC1 and Example 40, 44784

863

Intermediate BA1, BB1, BC1 and Example 40, 44, 21785

864

Intermediate BA1, BB1, BC1 and Example 40, 48786

865

Intermediate BA1, BB1, BC1 and Example 40, 48787

866

Intermediate BA1, BB1, BC1 and Example 40, 48788

867

Intermediate BA1, BB1, BC1 and Example 40, 48789

868

Intermediate BA1, BB1, BC1 and Example 40, 48790

869

Intermediate BA, BB, BC and Example 39, 48791

870

Intermediate BA, BB, BC and Example 39, 48792

871

Intermediate BA, BB, BC and Example 39, 48793

872

Intermediate BA, BB, BC and Example 39, 48794

873

Intermediate BA, BB, BC and Example 39, 48795

874

Intermediate BA, BB, BC and Example 39, 48796

875

Intermediate BA, BB, BC and Example 39, 48797

876

Intermediate BA, BB, BC and Example 39, 48798

877

Intermediate BA, BB, BC and Example 39, 48799

878

Intermediate BA, BB, BC and Example 39, 48800

879

Intermediate BA, BB, BC and Example 39, 48801

880

Intermediate BA, BB, BC and Example 39, 48802

881

Intermediate BA, BB, BC and Example 39, 48803

882

Intermediate BA, BB, BC and Example 39, 48804

883

Intermediate BA, BB, BC and Example 39, 48805

884

Intermediate BA, BB, BC and Example 39, 48806

885

Intermediate BA, BB, BC and Example 39, 48807

886

Intermediate BA, BB, BC and Example 39, 48808

887

Intermediate BA, BB, BC and Example 39, 48809

888

Intermediate BA, BB, BC and Example 39, 48810

889

Intermediate BA, BB, BC and Example 39, 48811

890

Intermediate BA, BB, BC and Example 39, 54, 47812

891

Intermediate BA, BB, BC and Example 39, 54 and Intermediate AJ813

892

Intermediate BA, BB, BC and Example 39, 54 and Intermediate AK814

893

Intermediate BA, BB, BC and Example 39, 54, 12815

894

Intermediate BA, BB, BC and Example 39, 54, 12816

895

Intermediate BA, BB, BC and Example 39, 54, 12817

896

Intermediate BA, BB, BC and Example 39, 54, 12818

897

Intermediate BA, BB, BC and Example 39, 54, 12819

898

Intermediate BA, BB, BC and Example 39, 54 and Intermediate AL and Example 42820

899

Intermediate BA, BB, BC and Example 39, 54 and Intermediate AL821

900

Intermediate BA, BB, BC and Example 39, 54 and Intermediate AL and Example 17, 25822

901

Intermediate BA, BB, BC and Example 39, 54 and Intermediate AL and example 55823

902

Intermediate BA, BB, BC and Example 39, 54 and Intermediate AL and Example 55824

903

Intermediate BA, BB, BC and Example 39, 54 and Intermediate AL and Example 17, 25 and Intermediate AJ825

904

Intermediate BA, BB, BC and Example 39, 54 and Intermediate AL and Example 17, 25 and Intermediate AJ826

905

Intermediate BA, BB, BC and Example 39, 54 and Intermediate AL and Example 17, 25, 26827

906

Intermediate BA, BB, BC and Example 39, 54 and Intermediate AL and Example 17, 25, 26828

907

Intermediate BA, BB, BC and Example 39, 54 and Intermediate AL and Example 3829

908

Intermediate BA, BB, BC and Example 39, 54 and Intermediate AL and Example 3830

909

Intermediate BA, BB, BC and Example 39, 54 and Intermediate AL and Example 3831

910

Intermediate BA, BB, BC and Example 39, 43832

911

Intermediate BA, BB, BC and Example 39, 43833

912

Intermediate BA, BB, BC and Example 39, 46, 45, 47834

913

Intermediate BA, BB, BC and Example 39, 46, 45, 47835

914

Intermediate BA, BB, BC and Example 39, 44, 45, 47836

915

Intermediate BA, BB, BC and Example 39, 44, 45, 47837

916

Intermediate BA, BB, BC and Example 39, 48, 45, 47838

917

Intermediate BA, BB, BC and Example 39, 48, 45, 47839

918

Intermediate BA, BB, BC and Example 39, 49, 47840

919

Intermediate BA, BB, BC and Example 39, 49, 47841

920

Intermediate BA, BB, BC and Example 39, 49, 47842

921

Intermediate BA, BB, BC and Example 39, 49, 47843

922

Intermediate BA, BB, BC and Example 39, 17844

923

Intermediate BA, BB, BC and Example 39, 44845

924

Intermediate BA, BB, BC and Example 39, 44846

925

Intermediate BA, BB, BC and Example 39, 44847

926

Intermediate BA, BB, BC and Example 39, 44848

927

Intermediate BA, BB, BC and Example 39, 44, 21849

928

Intermediate BA, BB, BC and Example 39, 44, 21850

929

Intermediate BA, BB, BC and Example 39, 48851

930

Intermediate BA, BB, BC and Example 39, 48852

931

Intermediate BA, BB, BC and Example 39, 49, 50, 51, 25 and Intermediate AJ853

932

Intermediate BA, BB, BC and Example 39, 49, 50, 51, 25 and Intermediate AJ854

933

Intermediate BA, BB, BC and Example 39, 49, 50, 51, 25, 26855

934

Intermediate BA, BB, BC and Example 39, 49, 50, 51, 25, 26856

935

Intermediate BA, BB, BC and Example 39, 31, 33857

936

Intermediate BA, BB, BC and Example 39, 31, 33858

937

Intermediate BA, BB, BC and Example 39, 31, 32, 33, 47859

938

Intermediate BA, BB, BC and Example 39, 31, 32, 33, 47860

939

Intermediate BA, BB, BC and Example 39, 31, 33861

940

Intermediate BA, BB, BC and Example 39, 31, 32, 33, 47862

941

Intermediate BA, BB, BC and Example 39, 31, 32, 33, 47863

942

Intermediate BA, BB, BC and Example 39, 49, 50, 51864

943

Intermediate BA, BB, BC and Example 39, 49, 50, 51865

944

Intermediate BA, BB, BC and Example 39, 49, 50, 51866

945

Intermediate BA, BB, BC and Example 39, 43, 47867

946

Intermediate BA, BB, BC and Example 39, 43 and Intermediate AK868

947

Intermediate BA, BB, BC and Example 39, 3869

948

Intermediate BA, BB, BC and Example 39, 43, 47870

949

Intermediate BA, BB, BC and Example 39, 43, 47871

950

Intermediate BA, BB, BC and Example 39, 22872

951

Intermediate BA, BB, BC and Example 39, 3, 24, 12873

952

Intermediate BA, BB, BC and Example 39, 3, 24 and Intermediate AK874

953

Intermediate BA2, BB2, BC2 and Example 41, 34875

954

Intermediate BA2, BB2, BC2 and Example 41, 34876

955

Intermediate BA2, BB2, BC2 and Example 41, 34877

956

Intermediate BA2, BB2, BC2 and Example 41, 34878

957

Intermediate BA2, BB2, BC2 and Example 41, 34879

958

Intermediate BA2, BB2, BC2 and Example 41, 31, 33880

959

Intermediate BA2, BB2, BC2 and Example 41, 31, 33881

960

Intermediate BA2, BB2, BC2 and Example 41, 31, 32, 33, 47882

961

Intermediate BA2, BB2, BC2 and Example 41, 31, 32, 33, 47883

962

Intermediate BA2, BB2, BC2 and Example 41, 31, 32, 33, 47884

963

Intermediate BA2, BB2, BC2 and Example 41, 31, 32, 33, 47885

964

Intermediate BA2, BB2, BC2 and Example 41, 31, 32, 33, 47886

965

Intermediate BA2, BB2, BC2 and Example 41, 31, 33887

966

Intermediate BA2, BB2, BC2 and Example 41, 55888

967

Intermediate BA2, BB2, BC2 and Example 41, 55889

968

Intermediate BA2, BB2, BC2 and Example 41, 55890

969

Intermediate BA2, BB2, BC2 and Example 41, 49891

970

Intermediate BA2, BB2, BC2 and Example 41, 34892

971

Intermediate BA2, BB2, BC2 and Example 41, 17893

972

Intermediate BA2, BB2, BC2 and Example 41, 49, 47894

973

Intermediate BA2, BB2, BC2 and Example 41, 49, 47895

974

Intermediate BA2, BB2, BC2 and Example 41, 49, 47896

975

Intermediate BA2, BB2, BC2 and Example 41, 49, 47897

976

Intermediate BA2, BB2, BC2 and Example 41, 49, 47898

977

Intermediate BA2, BB2, BC2 and Example 41, 34899

978

Intermediate BA2, BB2, BC2 and Example 41, 34900

979

Intermediate BA2, BB2, BC2 and Example 41, 34, 21901

980

Intermediate BA2, BB2, BC2 and Example 41, 34, 21902

981

Intermediate BA2, BB2, BC2 and Example 41, 31, 32, 33, 50, 51903

982

Intermediate BA2, BB2, BC2 and Example 41, 31, 33904

983

Intermediate BA2, BB2, BC2 and Example 41, 31, 32, 33, 50, 51905

984

Intermediate BA2, BB2, BC2 and Example 41, 49, 50, 51906

985

Intermediate BA2, BB2, BC2 and Example 41, 49, 50, 51907

986

Intermediate BA2, BB2, BC2 and Example 41, 49, 50, 51908

987

Intermediate BA2, BB2, BC2 and Example 41, 31, 33, 25909

988

Intermediate BA2, BB2, BC2 and Example 41, 31, 33, 25 and Intermediate AJ910

989

Intermediate BA2, BB2, BC2 and Example 41, 17, 25, 26911

990

Intermediate BA2, BB2, BC2 and Example 41, 17, 25912

991

Intermediate BA2, BB2, BC2 and Example 41, 17, 25 and Intermediate AJ913

992

Intermediate BA2, BB2, BC2 and Example 41, 3914

993

Intermediate BA2, BB2, BC2 and Example 41, 3915

994

Intermediate BA2, BB2, BC2 and Example 41, 3916

995

Intermediate BA2, BB2, BC2 and Example 41, 3917

996

Intermediate BA2, BB2, BC2 and Example 41, 3918

997

Intermediate BA2, BB2, BC2 and Example 41, 3919

998

Intermediate BA2, BB2, BC2 and Example 41, 3 and Intermediate AK920

999

Intermediate BA2, BB2, BC2 and Example 41, 3, 12921

1000

Intermediate BA2, BB2, BC2 and Example 41, 3922

1001

Intermediate BA2, BB2, BC2 and Example 41, 3923

1002

Intermediate BA2, BB2, BC2 and Example 41, 3924

1003

Intermediate BA2, BB2, BC2 and Example 41, 3, 24925

1004

Intermediate BA2, BB2, BC2 and Example 41, 3926

1005

Intermediate BA2, BB2, BC2 and Example 41, 3927

1006

Intermediate BA2, BB2, BC2 and Example 41, 3928

1007

Intermediate BA2, BB2, BC2 and Example 4l, 3929

1008

Intermediate BA2, BB2, BC2 and Example 41, 3, 45930

1009

Intermediate BA2, BB2, BC2 and Example 41, 3, 18931

1010

Intermediate BA2, BB2, BC2 and Example 41, 3, 45, 47932

1011

Intermediate BA2, BB2, BC2 and Example 41, 3, 45, 47933

1012

Intermediate BA2, BB2, BC2 and Example 41, 3, 24, 47934

1013

Intermediate BA2, BB2, BC2 and Example 41, 3, 47935

1014

Intermediate BA2, BB2, BC2 and Example 41, 3, 12936

1015

Intermediate BA2, BB2, BC2 and Example 41, 3, 24 and Intermediate AK

[0586] Utilizing the above described procedures for intermediates and examples, and Flow Diagrams I-XIV alone or in combination, a variety of Formula II compounds can be prepared using the appropriate starting material. These compounds are summarized in Table 2C.

6TABLE 2CEx-am-pleStructure937

1016

938

1017

939

1018

940

1019

941

1020

942

1021

943

1022

944

1023

945

1024

946

1025

947

1026

948

1027

949

1028

950

1029

951

1030

952

1031

953

1032

954

1033

955

1034

956

1035

957

1036

958

1037

959

1038

960

1039

961

1040

962

1041

963

1042

964

1043

965

1044

966

1045

967

1046

968

1047

969

1048

970

1049

971

1050

972

1051

973

1052

974

1053

975

1054

976

1055

977

1056

978

1057

979

1058

980

1059

981

1060

982

1061

983

1062

984

1063

985

1064

986

1065

987

1066

988

1067

989

1068

990

1069

991

1070

992

1071

993

1072

994

1073

995

1074

996

1075

997

1076

998

1077

999

1078

1000

1079

1001

1080

1002

1081

1003

1082

1004

1083

[0587] Biological Evaluation

[0588] Demonstration of the activity of the compounds of this invention is accomplished through in vitro, ex vivo and in vivo assays that are well known in the art.

[0589] In vivo Test Procedure:

[0590] Male Wistar rats (270-330 g) were fasted overnight and then given either vehicle or compound by oral gavage. Two or three hours later, the rats were given an intraperitoneal dose of glucose (2 g/kg). The rats were tail-bled for glucose using a Glucometer (Bayer Corporation, Mishawaka, Ind.) just prior to the glucose dose and 15, 30 and 60 minutes afterward. The area under the glucose curve was calculated by the trapezoidal method for both the vehicle and treated animals, and the percent reduction in the glucose AUC by the compound calculated. A typical positive effect of the compound results in a 12-20% reduction in the AUC relative to the AUC of the vehicle-treated group. Compounds of present invention were found to have a bloodglucose lowering effect in this in vivo assay.

[0591] The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing examples are included by way of illustration only. Accordingly, the scope of the invention is limited only by the scope of the appended claims.

Claims

1. A compound of the formula 1
2. The compound of claim 1, wherein R4 is ═O.
3. The compound of claim 1, wherein R3is selected from cycloalkyl of 3-6 carbon atoms, heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0-2 and O, both of which may be substituted with 1-3 of R10, or R3is selected from alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, hydrogen, nitro, halogen, NR19R20, A-OR19, A-NR19R20 and A-R20.
4. The compound of claim 3, wherein R19 and R20 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms and A-R9, or wherein R19 and R20 are independently selected from phenyl, monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(O)0-2 and O, cycloalkyl of 3-6 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0-2 and O, wherein one or more of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), all of which may be substituted with 1-3 of R10.
5. The compound of claim 1, wherein R3 is selected from cycloalkyl of 3-6 carbon atoms, heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0-2 and O, both of which may be substituted with 1-3 of R10, or R3 is selected from alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, hydrogen, nitro, halogen, NR19R20, A-OR19, A-NR19R20 and A-R20; and R4 is ═O.
6. The compound of claim 5, wherein R19 and R20 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms and A-R9, or wherein R19 and R20 are independently selected from phenyl, monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(O)0-2 and O, cycloalkyl of 3-6 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0-2 and O, wherein one or more of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), all of which may be substituted with 1-3 of R10.
7. The compound of claim 1, wherein R2 is NR15R16.
8. The compound of claim 7, wherein R15 is selected from hydrogen, alkyl of 1-6 carbon atoms, cylcoalkyl of 3-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, A-R9, C(═O)R18, C(═O)NHR18, and S(═O)2NHR18; R18 is selected from phenyl, monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2 and O, cylcoalkyl of 3-6 carbon atoms, and 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, all of which may be substituted with 1-3 of R10, or R18 is alkyl of 1-6 carbon atoms, which may be substituted with 1-3 of halogen or alkoxy of 1-6 carbon atoms, or R18 is A-R9; and R16 is selected from alkyl of 1-6 carbon atoms and A-R9, or R16 is selected from phenyl, monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2 and O, cycloalkyl of 3-8 carbon atoms, and 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, all of which may be substituted with 1-3 of R10, or R15 and R16 combine, together with the nitrogen atom to which they are attached, to form a monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2 and O, or a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), all of which may be substituted with 1-3 of R10.
9. The compound of claim 1, wherein R2 is NR15R16; R3 is selected from cycloalkyl of 3-6 carbon atoms, heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0-2 and O, both of which may be substituted with 1-3 of R10, or R3 is selected from alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, hydrogen, nitro, halogen, NR19R20, A-OR19, A-NR19R20 and A-R20; and R4 is ═O.
10. The compound of claim 9, wherein R15 is selected from hydrogen, alkyl of 1-6 carbon atoms, cylcoalkyl of 3-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, A-R9, C(═O)R18, C(═O)NHR18, and S(═O)2NHR18; R18 is selected from phenyl, monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2 and O, cylcoalkyl of 3-6 carbon atoms, and 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, all of which may be substituted with 1-3 of R10, or R18 is alkyl of 1-6 carbon atoms, which may be substituted with 1-3 of halogen or alkoxy of 1-6 carbon atoms, or R18is A-R9; and R16 is selected from alkyl of 1-6 carbon atoms and A-R9, or R16 is selected from phenyl, monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2 and O, cycloalkyl of 3-8 carbon atoms, and 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, all of which may be substituted with 1-3 of R10, or R15 and R16 combine, together with the nitrogen atom to which they are attached, to form a monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2 and O, or a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), all of which may be substituted with 1-3 of R10.
11. The compound of claim 10, selected from the group consisting of:
12. The compound of claim 9, wherein R19 and R20 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms and A-R9, or wherein R19 and R20 are independently selected from phenyl, monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(O)0-2 and O, cycloalkyl of 3-6 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0-2 and O, wherein one or more of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), all of which may be substituted with 1-3 of R10.
13. The compound of claim 1 or 9, wherein R5 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 4-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms, all of which may be substituted with 1-3 of R10, or R5 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and 0 and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10, A-R23, A-NR24R25, C(═O)R, C(═O)OR24, C(═O)NR24R25, S(═O)2R26, A-C(═O)R24, A-C(═O)OR24, or A-C(═O)NR24R25, or R5 is selected from hydrogen, halogen, nitrile, nitro, hydroxy, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, cycloalkoxy of 3-6 carbon atoms, A-R23, A(OR22)—R23, NR27R28, A-NR27R28, A-Q-R29, Q-R29, Q-A-NR24R25, C(═O)R24, C(═O)OR24, C(═O)NR24R25, A-C(═O)R24, A-C(═O)OR24, and A-C(═O)NR24R25; R22 is selected from hydrogen, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and cycloalkyl of 3-6 carbon atoms; R23 is selected from hydroxy, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, and cycloalkoxy of 3-6 carbon atoms, or R23 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 4-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R23 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10; with the proviso for A(OR22)—R23 that when R23 is selected from hydroxy, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, and cycloalkoxy of 3-6 carbon atoms, A is not CH; R24 and R25 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A-R23, or R24 and R25 are independently selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R24 and R25 are independently selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10, or R24 and R25 combine, together with the nitrogen atom to which they are attached, to form a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2, and O, a 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2, and O, or a monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), all of which may be substituted with 1-3 of R10; R26 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A(OR22)—R23, and A-R23, or R26 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R26 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10; R27 is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A-R23, or R27 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R27 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10; R28 is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A-R23, C(═O)R24, C(═O)OR26, C(═O)NR25R30, S(═O)2R26, A-C(═O)R24, A-C(═O)OR24, and A-C(═O)NR24R25, or R28 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R28 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10; R30 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A(OR22)—R23, and A-R23, or R30 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R30 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10, or R25 and R30 combine, together with the nitrogen atom to which they are attached, to form a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2, and O, a 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2, and O, or a monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms, all of which may be substituted with 1-3 of R10; and R29 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A-R23, A-C(═O)R24, A-C(═O)OR24, A-C(═O)NR24R25, A-NR27R28, or R29 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R29 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10.
14. The compound of claim 13, wherein R5 is selected from cycloalkyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms, all of which may be substituted with 1-3 of R10, or R5 is 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), wherein said heterocycloalkyl may be substituted with 1-3 of R10, A-R23, A-NR24R25, C(═O)R24, C(═O)OR24, C(═O)NR24R25, S(═O)2R26, A-C(═O)R24, A-C(═O)OR24, or A-C(═O)NR24R25, or R5 is selected from hydrogen, halogen, nitrile, nitro, hydroxy, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, cycloalkoxy of 3-6 carbon atoms, A-R23, A(OR22)—R23, NR27R28, A-NR27R28, A-Q-R29, Q-R29, Q-A-NR24R25, C(═O)R24,and A-C(═O)R24; R22 is selected from hydrogen, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and cycloalkyl of 3-6 carbon atoms; R23 is selected from hydroxy, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, and cycloalkoxy of 3-6 carbon atoms, or R23 is selected from cycloalkyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R23is 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), wherein said heterocycloalkyl may be substituted with 1-3 of R10; with the proviso for A(OR22)—R23 that when R23 is selected from hydroxy, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, and cycloalkoxy of 3-6 carbon atoms, A is not CH; R24 and R25 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A-R23, or R24 and R25 are independently selected from cycloalkyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R24 and R25 are independently selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), wherein said heterocycloalkyl may be substituted with 1-3 of R10, or R24 and R25 combine, together with the nitrogen atom to which they are attached, to form a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2, and O, or a monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms, wherein one or more of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), all of which may be substituted with 1-3 of R10; R26 is selected from alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A(OR22)—R23, and A-R23, or R26 is selected from cycloalkyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R26 is 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), wherein said heterocycloalkyl may be substituted with 1-3 of R10; R27 is selected from hydrogen, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A-R23, or R27 is selected from cycloalkyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R27 is 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), wherein said heterocycloalkyl may be substituted with 1-3 of R10; R28 is selected from hydrogen, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A-R23 C(═O)R24, C(═O)OR26, C(═O)NR25R30, S(═O)2R26, A-C(═O)R24, A-C(═O)OR24, and A-C(═O)NR24R25, or R28 is selected from cycloalkyl of 3-6 carbon atoms, phenyl, monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R28 is 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), wherein said heterocycloalkyl may be substituted with 1-3 of R10; R30 is selected from alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A(OR22)—R23, and A-R23, or R30 is selected from cycloalkyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R30 is 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), wherein said heterocycloalkyl may be substituted with 1-3 of R10, or R25 and R30 combine, together with the nitrogen atom to which they are attached, to form a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2, and O, or a monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms, all of which may be substituted with 1-3 of R10; and R29 is selected from alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A-R23, A-C(═O)R24, A-C(═O)OR24, A-C(═O)NR24R25, A-NR27R28, or R29 is selected from cycloalkyl of 3-6 carbon atoms, phenyl, monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R29 is 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), wherein said heterocycloalkyl may be substituted with 1-3 of R10.
15. The compound of claim 14 selected from the group consisting of:
16. The compound of claim 1 or 9, wherein R6 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 4-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms, all of which may be substituted with 1-3 of R10, or R6 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10, A-R23, A-NR24R25, C(═O)R24, C(═O)OR24, C(═O)NR24R25, S(═O)2R26, A-C(═O)R24, A-C(═O)OR24, or A-C(═O)NR24R25, or R6 is selected from hydrogen, halogen, nitrile, nitro, hydroxy, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, cycloalkoxy of 3-6 carbon atoms, A-R23, A(OR22)—R23, NR27R28, A-NR27R28, A-Q-R29, Q-R29, Q-A-NR24R25, C(═O)R24, C(═O)OR24, C(═O)NR24R25, A-C(═O)R24, A-C(═O)OR24, and A-C(═O)NR24R25; R22 is selected from hydrogen, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and cycloalkyl of 3-6 carbon atoms; R23 is selected from hydroxy, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, and cycloalkoxy of 3-6 carbon atoms, or R23 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 4-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R23 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10; with the proviso for A(OR22)—R23 that when R23 is selected from hydroxy, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, and cycloalkoxy of 3-6 carbon atoms, A is not CH; R24 and R25 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A-R23, or R24 and R25 are independently selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R24 and R25 are independently selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10, or R24 and R25 combine, together with the nitrogen atom to which they are attached, to form a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2, and O, a 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2, and O, or a monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), all of which may be substituted with 1-3 of R10; R26 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A(OR22)—R23, and A-R23, or R26 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R26 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S({dot over (═)}O)0-2, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10; R27 is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A-R23, or R27 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R27 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10; R28 is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A-R23, C(═O)R24, C(═O)OR26, C(═O)NR R30, S(═O)2R26, A-C(═O)R24, A-C(═O)OR24, and A-C(═O)NR24R25, or R28 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R28 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10; R30 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A(OR22)—R23, and A-R23, or R30 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R30 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10, or R25 and R30 combine, together with the nitrogen atom to which they are attached, to form a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2, and O, a 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2, and O, or a monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms, all of which may be substituted with 1-3 of R10; and R29 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A-R23, A-C(═O)R24, A-C(═O)OR24, A-C(═O)NR24R25, A-NR27R28, or R29 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R29 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10.
17. The compound of claim 16, wherein R6 is selected from cycloalkyl of 3-6 carbon atoms, all of which may be substituted with 1-3 of R10, or R6 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), wherein said heterocycloalkyl may be substituted with 1-3 of R10, A-R23, A-NR24R25, C(═O)R24, C(═O)OR24, C(═O)NR24R25, S(═O)2R26, A-C(═O)R24, A-C(═O)OR24, or A-C(═O)NR24R25, or R6 is selected from hydrogen, halogen, nitrile, nitro, hydroxy, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A-R23, A(OR22)—R23, NR27R28, A-NR27R28, A-Q-R29, S(═O)0-2-R29, S(═O)0-2-A-NR24R25, C(═O)OR24, C(═O)NR24R25, A-C(═O)R24, A-C(═O)OR24, and A-C(═O)NR24R25; R22 is selected from hydrogen, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and cycloalkyl of 3-6 carbon atoms; R23 is selected from hydroxy, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, and cycloalkoxy of 3-6 carbon atoms, or R23 is selected from cycloalkyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R23 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), wherein said heterocycloalkyl may be substituted with 1-3 of R10; with the proviso for A(OR22)—R23 that when R23 is selected from hydroxy, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, and cycloalkoxy of 3-6 carbon atoms, A is not CH; R24 and R25 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A-R23, or R24 and R25 are independently selected from cycloalkyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R24 and R25 are independently selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), wherein said heterocycloalkyl may be substituted with 1-3 of R10, or R24 and R25 combine, together with the nitrogen atom to which they are attached, to form a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2, and O, monocyclic heteroaryland/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), all of which may be substituted with 1-3 of R10; R26 is selected from alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A(OR22)—R23, and A-R23, or R26 is selected from cycloalkyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R26 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), wherein said heterocycloalkyl may be substituted with 1-3 of R10; R27 is selected from hydrogen, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A-R23, or R27 is selected from cycloalkyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R27 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), wherein said heterocycloalkyl may be substituted with 1-3 of R10; R28 is selected from hydrogen, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A-R23, C(═O)R24, C(═O)OR26, C(═O)NR25R30, S(═O)2R26, A-C(═O)R24, A-C(═O)OR24, and A-C(═O)NR24R25, or R28 is selected from cycloalkyl of 3-6 carbon atoms, phenyl, monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R28 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), wherein said heterocycloalkyl may be substituted with 1-3 of R10; R30 is selected from alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A(OR22)—R23, and A-R23, or R30 is selected from cycloalkyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R30 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), wherein said heterocycloalkyl may be substituted with 1-3 of R10, or R25 and R30 combine, together with the nitrogen atom to which they are attached, to form a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2, and O, or a monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms, all of which may be substituted with 1-3 of R10; R29 is selected from alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A-R23, A-C(═O)R24, A-C(═O)OR24, A-C(═O)NR24R25, A-NR27R28, or R29 is selected from cycloalkyl of 3-6 carbon atoms, phenyl, monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R29 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), wherein said heterocycloalkyl may be substituted with 1-3 of R10.
18. The compound of claim 17 selected from the group consisting of:
19. The compound of claim 1 or 9, wherein R7is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 4-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms, all of which may be substituted with 1-3 of R10, or R7 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10, A-R23, A-NR24R25, C(═O)R24, C(═O)OR24, C(═O)NR24R25, S(═O)2R26, A-C(═O)R24, A-C(═O)OR24, or A-C(═O)NR24R25, or R7 is selected from hydrogen, nitrile, nitro, hydroxy, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, cycloalkoxy of 3-6 carbon atoms, A-R23, A(OR22)—R23, NR27R28, A-NR27R28, A-Q-R29, Q-R29, Q-A-NR24R25, C(═O)R24, C(═O)OR24, C(═O)NR24R25, A-C(═O)R24, A-C(═O)OR24, and A-C(═O)NR24R25; R22 is selected from hydrogen, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and cycloalkyl of 3-6 carbon atoms; R23 is selected from hydroxy, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, and cycloalkoxy of 3-6 carbon atoms, or R23 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 4-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R23 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10; with the proviso for A(OR22)—R23 that when R23 is selected from hydroxy, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, and cycloalkoxy of 3-6 carbon atoms, A is not CH; R24 and R25 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A-R23, or R24 and R25 are independently selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R24 and R25 are independently selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10, or R24 and R25 combine, together with the nitrogen atom to which they are attached, to form a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2, and O, a 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2, and O, or a monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), all of which may be substituted with 1-3 of R10; R26 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A(OR22)—R23, and A-R23, or R26 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R26 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10; R27 is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A-R23, or R27 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R27 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10; R28 is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A-R23, C(═O)R24, C(═O)OR26, C(═O)NR25R30, S(═O)2R26, A-C(═O)R24, A-C(═O)OR24, and A-C(═O)NR24R25, or R28 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R28 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10; R30 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A(OR22)—R23, and A-R23, or R30 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R30 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10, or R25 and R30 combine, together with the nitrogen atom to which they are attached, to form a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2, and O, a 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2, and O, or a monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms, all of which may be substituted with 1-3 of R10; R29 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A-R23, A-C(═O)R24, A-C(═O)OR24, A-C(═O)NR24R25, A-NR27R28, or R29 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R29 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10.
20. The compound of claim 19, wherein R7 is selected from cycloalkyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms, all of which may be substituted with 1-3 of R10, or R7 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), wherein said heterocycloalkyl may be substituted with 1-3 of R10, A-R23, A-NR24R25, C(═O)R24, C(═O)OR24, C(═O)NR24R25, S(═O)2R26, A-C(═O)R24, A-C(═O)OR24, or A-C(O)NR24R25, or R7 is selected from hydrogen, nitrile, nitro, hydroxy, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, cycloalkoxy of 3-6 carbon atoms, A-R23, A(OR22)—R23, NR27R28, A-NR27R28, A-Q-R29, Q-R29, Q-A-NR24R25, C(═O)R24, C(═O)OR24, C(═O)NR24R25, A-C(═O)R24, A-C(═O)OR24, and A-C(═O)NR24R25; R22 is selected from hydrogen, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and cycloalkyl of 3-6 carbon atoms; R23 is selected from hydroxy, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, and cycloalkoxy of 3-6 carbon atoms, or R23 is selected from cycloalkyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R23 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), wherein said heterocycloalkyl may be substituted with 1-3 of R10; with the proviso for A(OR22)—R23 that when R23 is selected from hydroxy, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, and cycloalkoxy of 3-6 carbon atoms, A is not CH; R24 and R25 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A-R23, or R24 and R25 are independently selected from cycloalkyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R24 and R25 are independently selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), wherein said heterocycloalkyl may be substituted with 1-3 of R10, or R24 and R25 combine, together with the nitrogen atom to which they are attached, to form a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2, or a monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), all of which may be substituted with 1-3 of R10; R26 is selected from alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A(OR22)—R23, and A-R23, or R26 is selected from cycloalkyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R26 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), wherein said heterocycloalkyl may be substituted with 1-3 of R10; R27 is selected from hydrogen, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A-R23, or R27 is selected from cycloalkyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R27 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), wherein said heterocycloalkyl may be substituted with 1-3 of R10; R28 is selected from hydrogen, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A-R23, A-C(═O)R24, A-C(═O)OR24, and A-C(═O)NR24R25, or R28 is selected from cycloalkyl of 3-6 carbon atoms, phenyl, monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R28 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), wherein said heterocycloalkyl may be substituted with 1-3 of R10; R30 is selected from alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A(OR22)—R23, and A-R23, or R30 is selected from cycloalkyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R30 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), wherein said heterocycloalkyl may be substituted with 1-3 of R10, or R25 and R30 combine, together with the nitrogen atom to which they are attached, to form a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2, and O, or a monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms, all of which may be substituted with 1-3 of R10; R29 is selected from alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A-R23, A-C(═O)R24, A-C(═O)OR24, A-C(═O)NR24R25, A-NR27R28, or R29 is selected from cycloalkyl of 3-6 carbon atoms, phenyl, monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R29 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), wherein said heterocycloalkyl may be substituted with 1-3 of R10.
21. The compound of claim 20 selected from the group consisting of:
22. A compound of the formula I
23. The compound of claim 22, wherein R4 is ═O; R15 is selected from hydrogen, alkyl of 1-6 carbon atoms, cylcoalkyl of 3-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, A-R9, C(═O)R18, C(═O)NHR18, and S(═O)2NHR18; R18 is selected from phenyl, monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2 and O, cylcoalkyl of 3-6 carbon atoms, and 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, all of which may be substituted with 1-3 of R10, or R18 is alkyl of 1-6 carbon atoms, which may be substituted with 1-3 of halogen or alkoxy of 1-6 carbon atoms, or R18 is A-R9; and R16 is selected from alkyl of 1-6 carbon atoms and A-R9, or R16 is selected from phenyl, monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2 and O, cycloalkyl of 3-8 carbon atoms, and 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, all of which may be substituted with 1-3 of R10, or R15 and R16 combine, together with the nitrogen atom to which they are attached, to form a monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2 and O, or a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), all of which may be substituted with 1-3 of R10; R19 and R20 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms and A-R9, or wherein R19 and R20 are independently selected from phenyl, monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(O)0-2 and O, cycloalkyl of 3-6 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0-2 and O, wherein one or more of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), all of which may be substituted with 1-3 of R10; and R5 is selected from cycloalkyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms, all of which may be substituted with 1-3 of R10, or R5 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), wherein said heterocycloalkyl may be substituted with 1-3 of R10, A-R23, A-NR24R25, C(═O)R25, C(═O)OR24, C(═O)NR24R25, S(═O)2R26, A-C(═O)R24, A-C(═O)OR24, or A-C(═O)NR24R25, or R5 is selected from hydrogen, halogen, nitrile, nitro, hydroxy, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, cycloalkoxy of 3-6 carbon atoms, A-R23, A(OR22)—R23, NR27R28, A-NR27R28, A-Q-R29, Q-R29, Q-A-NR24R25, C(═O)R24, and A-C(═O)R; R22 is selected from hydrogen, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and cycloalkyl of 3-6 carbon atoms; R23 is selected from hydroxy, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, and cycloalkoxy of 3-6 carbon atoms, or R23 is selected from cycloalkyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R23 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), wherein said heterocycloalkyl may be substituted with 1-3 of R10; with the proviso for A(OR22)—R23 that when R23 is selected from hydroxy, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, and cycloalkoxy of 3-6 carbon atoms, A is not CH; R24 and R25 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A-R23, or R24 and R25 are independently selected from cycloalkyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R24 and R25 are independently selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), wherein said heterocycloalkyl may be substituted with 1-3 of R10, or R24 and R25 combine, together with the nitrogen atom to which they are attached, to form a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2, and O, or a monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), all of which may be substituted with 1-3 of R10; R26 is selected from alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A(OR22)—R23, and A-R23, or R26 is selected from cycloalkyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R26 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), wherein said heterocycloalkyl may be substituted with 1-3 of R10; R27 is selected from hydrogen, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A-R23, or R27 is selected from cycloalkyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R27 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), wherein said heterocycloalkyl may be substituted with 1-3 of R10; R28 is selected from hydrogen, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A-R23, C(═O)R24, C(═O)OR26, C(═O)NR25R30, S(═O)2R26, A-C(═O)R24, A-C(═O)OR24, and A-C(═O)NR24R25, or R28 is selected from cycloalkyl of 3-6 carbon atoms, phenyl, monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R28 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), wherein said heterocycloalkyl may be substituted with 1-3 of R10; R30 is selected from alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A(OR22)—R23, and A-R23, or R30 is selected from cycloalkyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1-3 of R10, or R30 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), wherein said heterocycloalkyl may be substituted with 1-3 of R10, or R25 and R30 combine, together with the nitrogen atom to which they are attached, to form a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2, or a monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms, all of which may be substituted with 1-3 of R10; R29 is selected from alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A-R23, A-C(═O)R24, A-C(═O)OR24, A-C(═O)NR24R25, A-NR27R28, or R29 is selected from cycloalkyl of 3-6 carbon atoms, phenyl, monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2, and O, all of which maybe substituted with 1-3 of R10, or R29 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)0-2, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), wherein said heterocycloalkyl may be substituted with 1-3 of R10; R6 is selected from cycloalkyl of 3-6 carbon atoms, all of which may be substituted with 1-3 of R10, or R6 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2 and O, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), wherein said heterocycloalkyl may be substituted with 1-3 of R10, A-R23, A-NR24R25, C(═O)R24, C(═O)OR24, C(═O)NR24R25, S(═O)2R26, A-C(═O)R24, A-C(═O)OR24, or A-C(═O)NR24R25, or R6 is selected from hydrogen, halogen, nitrile, nitro, hydroxy, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A-R23, A(OR22)—R23, NR27R28, A-NR27R28, A-Q-R29, S(═O)0-2-R29, S(═O)0-2-A-NR24R25, C(═O)OR24, C(═O)NR24R25, A-C(═O)R24, A-C(═O)OR24, and A-C(═O)NR24R25; R7 is selected from cycloalkyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms, all of which may be substituted with 1-3 of R10, or R7 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)0-2, and/or wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(═O), wherein said heterocycloalkyl may be substituted with 1-3 of R10, A-R23, A-NR24R25, C(═O)R24, C(═O)OR24, C(═O)NR24R25, S(═O)2R26, A-C(═O)R24, A-C(═O)OR24, or A-C(═O)NR24R25, or R7 is selected from hydrogen, nitrile, nitro, hydroxy, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, cycloalkoxy of 3-6 carbon atoms, A-R23, A(OR22)—R23, NR27R28, A-NR27R28, A-Q-R29, Q-R29, Q-A-NR24R25, C(═O)R24, C(═O)OR24, C(═O)NR24R25, A-C(═O)R24, A-C(═O)OR24, and A-C(═O)NR24R25.
24. The compound of claim 23, wherein R1 is selected from alkyl of 1-8 carbon atoms, and A-R9, or R1 is selected from phenyl, monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2 and O, cycloalkyl of 3-6 carbon atoms, all of which may be substituted with 1-3 of R10; A is selected from alkyl of 1-6 carbon atoms, and haloalkyl of 1-8 carbon atoms; R9 is selected from hydroxy, alkoxy of 1-6 carbon atoms, cycloalkoxy of 3-6 carbon atoms, O-A-R14, NR11R12; or R9 is selected from phenyl, monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)0-2 and O, cylcoalkyl of 3-6 carbon atoms, all of which may be substituted with 1-3 of R10.
25. The compound of claim 24, wherein R1 is phenyl, which may be substituted with 1-3 of R10.
26. A method of treating or preventing a disease or condition selected from the group consisting of diabetes (Type 1 or Type 2), maturity-onset diabetes of the young (MODY), latent autoimmune diabetes adult (LADA), impaired glucose tolerance (IGT), impaired fasting glucose (IFG), gestational diabetes, and metabolic syndrome X, comprising administering to a mammal an effective amount of a compound of claim 1 or 22.
27. The method of claim 26, wherein said disease or condition is diabetes (Type 1 or Type 2).
28. The method of claim 27, wherein said disease or condition is Type 2 diabetes.
29. The method of claim 26, further comprising administering a PPAR-agonist, an insulin sensitizer, a sulfonylurea, an insulin secretagogue, a hepatic glucose output lowering compound, an α-glucosidase inhibitor or insulin in combination with said compound of claim 1 or 22.
30. The method of claim 29, wherein said PPAR-agonist is selected from rosiglitazone and pioglitazone.
31. The method of claim 29, wherein said sulfonylurea is selected from glibenclamide, glimepiride, chlorpropamide, and glipizide.
32. The method of claim 29, wherein said insulin secretagogue is selected from GLP-1, GIP, PACNVPAC receptor agonists, secretin, nateglinide, meglitinide, repaglinide, glibenclamide, glimepiride, chlorpropamide, and glipizide.
33. The method of claim 29, wherein said α-glucosidase inhibitor is selected from acarbose, miglitol and voglibose.
34. The method of claim 29, wherein said hepatic glucose output lowering compound is metformin.
35. The method of claim 26, further comprising administering an HMG-CoA reductase inhibitor, nicotinic acid, a bile acid sequestrant, a fibric acid derivative, antihypertensive drug, or an anti-obesity drug in combination with said compound of claim 1 or 22.
36. The method of claim 35, wherein said anti-obesity drug is selected from a β-3 agonist, a CB-1 antagonist, and a lipase inhibitor.
37. A method of treating or preventing secondary causes of diabetes selected from glucocorticoid excess, growth hormone excess, pheochromocytoma, and drug-induced diabetes, comprising administering to a mammal an effective amount of a compound of claim 1 or 22.
38. A method of increasing the sensitivity of pancreatic beta cells to an insulin secretagogue, comprising administering to a mammal an effective amount of a compound of claim 1 or 22.
39. The method of claim 38, wherein said insulin secretagogue is selected from GLP-1, GIP, PACNVPAC receptor agonists, secretin, nateglinide, meglitinide, repaglinide, glibenclamide, glimepiride, chlorpropamide, and glipizide.
40. A pharmaceutical composition, comprising a compound according to claim 1 or 22 and a pharmaceutically acceptable carrier.

Provisional Applications (1)

	Number	Date	Country
	60324511	Sep 2001	US

Divisions (1)

	Number	Date	Country
Parent	10253104	Sep 2002	US
Child	10834357	Apr 2004	US

1,8 Naphthyridine derivatives and their use to treat diabetes and related disorders

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Provisional Applications (1)

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