# Patent

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

## Abstract

The invention relates generally to naphthyridine derivatives of the formula




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

## Background
FIELD OF THE INVENTION
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
Diabetes is characterized by impaired glucose metabolism manifesting itself among other things by an elevated blood glucose level in the diabetic patient. Underlying defects lead to a classification of diabetes into two major groups: type 1 diabetes, or insulin dependent diabetes mellitus (IDDM), arises when patients lack insulin-producing beta-cells in their pancreatic glands. Type 2 diabetes, or non-insulin dependent diabetes mellitus (NIDDM), occurs in patients with impaired beta-cell function and alterations in insulin action.
The current treatment for type 1 diabetic patients is 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.
Over time almost one-half of type 2 diabetic subjects lose their response to these agents. Insulin treatment is instituted after diet, exercise, and oral medications have failed to adequately control blood glucose. The drawbacks of insulin treatment are the need for drug injection, the potential for hypoglycemia, and weight gain.
Because of the problems with current treatments, new therapies to treat type 2 diabetes are needed. In particular, new treatments to retain normal (glucose-dependent) insulin secretion are needed. Such new drugs should have the following characteristics: dependency on glucose for promoting insulin secretion, i.e., compounds that stimulate insulin secretion only in the presence of elevated blood glucose; low primary and secondary failure rates; and preservation of islet cell function. The strategy to develop the new therapy disclosed herein is based on the cyclic adenosine monophosphate (cAMP) signaling mechanism and its effects on insulin secretion.
Metabolism of glucose promotes the closure of ATP-dependent K+ channels, which leads to cell depolarization and subsequent opening of Ca++ channels. This in turn results in the exocytosis of insulin granules. cAMP is a major regulator of glucose-stimulated insulin secretion. 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.
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.
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.
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.
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
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)




wherein

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

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

R10 is selected from nitro, nitrile, hydroxy, halogen, acyl of 1–6 carbon atoms, alkyl of 1–6 carbon atoms, alkenyl of 2–6 carbon atoms, alkynyl of 2–6 carbon atoms, haloalkyl of 1–6 carbon atoms, alkoxy of 1–6 carbon atoms, haloalkoxy of 1–6 carbon atoms, cycloalkoxy of 3–6 carbon atoms, aryl of 6–10 carbon atoms, heteroaryl of 2–9 carbon atoms and 1–4 heteroatoms selected from N, S(═O)0-2 and O, 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);

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

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

A is selected from alkyl of 1–8 carbon atoms, alkenyl of 2–8 carbon atoms, alkynyl of 2–8 carbon atoms, and haloalkyl of 1–8 carbon atoms;

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

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

R9 is selected from 5–7 membered heterocycloalkyl of 3–6 carbon atoms and 1–2 heteroatoms selected from N, S(═O)0-2 and O and 5–7 membered heterocycloalkenyl of 3–6 carbon atoms and 1–2 heteroatoms selected from N, S(═O)0-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5–6 membered heteroaryl of 2–5 carbon atoms and 1–3 heteroatoms selected from N, S(═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;

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

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

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

R18 is selected from aryl of 6–10 carbon atoms, heteroaryl of 2–9 carbon atoms and 1–4 heteroatoms selected from N, S(═O)0-2 and O, cylcoalkyl of 3–8 carbon atoms, cycloalkenyl of 4–8 carbon atoms, 5–7 membered heterocycloalkyl of 3–6 carbon atoms and 1–2 heteroatoms selected from N, S(═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

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

R18 is A-R9;

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

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

R15 and R16 combine, together with the nitrogen atom to which they are attached, to form a heteroaryl of 2–9 carbon atoms and 1–4 heteroatoms selected from N, S(═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;

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

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

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

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

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

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

R4 is selected from ═O, ═S, and OR21;

R21 is hydrogen, or

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

R5 and R6 are independently selected from cycloalkyl of 3–8 carbon atoms, cycloalkenyl of 4–8 carbon atoms, aryl of 6–10 carbon atoms, and heteroaryl of 2–9 carbon atoms and 1–4 heteroatoms, all of which may be substituted with 1–3 of R10, or

R5 and R6 are independently selected from 5–7 membered heterocycloalkyl of 3–6 carbon atoms and 1–2 heteroatoms selected from N, S(═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

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;

Q is selected from O and S(═O)0-2;

R22 is selected from hydrogen, alkyl of 1–8 carbon atoms, haloalkyl of 1–8 carbon atoms, and cycloalkyl of 3–8 carbon atoms;

R23 is selected from hydroxy, alkoxy of 1–8 carbon atoms, haloalkoxy of 1–8 carbon atoms, and cycloalkoxy of 3–8 carbon atoms, or

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

R23 is selected from 5–7 membered heterocycloalkyl of 3–6 carbon atoms and 1–2 heteroatoms selected from N, O, S(═O)0-2, and 5–7 membered heterocycloalkenyl of 3–6 carbon atoms and 1–2 heteroatoms selected from N, O, S(═O)0-2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5–6 membered heteroaryl of 2–5 carbon atoms and 1–3 heteroatoms selected from N, S(═O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═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 1–8 carbon atoms, haloalkoxy of 1–8 carbon atoms, and cycloalkoxy of 3–8 carbon atoms, A is not CH;

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

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

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

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

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

R26 is selected from 5–7 membered heterocycloalkyl of 3–6 carbon atoms and 1–2 heteroatoms selected from N, O, S(=)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;

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

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

R27 is selected from 5–7 membered heterocycloalkyl of 3–6 carbon atoms and 1–2 heteroatoms selected from N, O, S(═O)0-2, and 5–7 membered heterocycloalkenyl of 3–6 carbon atoms and 1–2 heteroatoms selected from N, O, S(═O)0-2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5–6 membered heteroaryl of 2–5 carbon atoms and 1–3 heteroatoms selected from N, S(═)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;

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

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

R28 is selected from 5–7 membered heterocycloalkyl of 3–6 carbon atoms and 1–2 heteroatoms selected from N, O, S(═O)0-2, and 5–7 membered heterocycloalkenyl of 3–6 carbon atoms and 1–2 heteroatoms selected from N, O, S(═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;

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

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

R30 is selected from 5–7 membered heterocycloalkyl of 3–6 carbon atoms and 1–2 heteroatoms selected from N, O, S(═O)0-2, and 5–7 membered heterocycloalkenyl of 3–6 carbon atoms and 1–2 heteroatoms selected from N, O, S(═O)0-2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5–6 membered heteroaryl of 2–5 carbon atoms and 1–3 heteroatoms selected from N, S(═O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═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 heteroaryl of 2–9 carbon atoms and 1–4 heteroatoms, all of which may be substituted with 1–3 of R10;

R29 is selected from alkyl of 1–6 carbon atoms, alkenyl of 2–6 carbon atoms, alkynyl of 2–6 carbon atoms, haloalkyl of 1–6 carbon atoms, A-R23, A-C(═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, aryl of 6–10 carbon atoms, heteroaryl of 2–9 carbon atoms and 1–4 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1–3 of R10, or

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

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

R7 is selected from 5–7 membered heterocycloalkyl of 3–6 carbon atoms and 1–2 heteroatoms selected from N, S(═O)0-2 and O and 5–7 membered heterocycloalkenyl of 3–6 carbon atoms and 1–2 heteroatoms selected from N, S(═O)0-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5–6 membered heteroaryl of 2–5 carbon atoms and 1–3 heteroatoms selected from N, S(═O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═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

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;

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.

Another aspect of the invention includes compounds of formula (I) wherein R1 is selected from alkyl of 1–8 carbon atoms, alkenyl of 2–8 carbon atoms, alkynyl of 2–8 carbon atoms, and A-R9, or
R1 is selected from aryl of 6–10 carbon atoms, heteroaryl of 2–9 carbon atoms and 1–4 heteroatoms selected from N, S(═O)0-2 and O, cycloalkyl of 3–8 carbon atoms, cycloalkenyl of 4–8 carbon atoms, 5–7 membered heterocycloalkyl of 3–6 carbon atoms and 1–2 heteroatoms selected from N, S(═O)0-2 and O, and 5–7 membered heterocycloalkenyl of 3–6 carbon atoms and 1–2 heteroatoms selected from N, S(═O)0-2 and O, wherein said heterocycloalkyl and said heterocycloalkenyl may further be fused with phenyl or a 5–6 membered heteroaryl of 2–5 carbon atoms and 1–3 heteroatoms selected from N, S(═O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O),all of which may be substituted with 1–3 of R10;

R10 is selected from nitro, nitrile, hydroxy, halogen, acyl of 1–6 carbon atoms, alkyl of 1–6 carbon atoms, alkenyl of 2–6 carbon atoms, alkynyl of 2–6 carbon atoms, haloalkyl of 1–6 carbon atoms, alkoxy of 1–6 carbon atoms, haloalkoxy of 1–6 carbon atoms, cycloalkoxy of 3–6 carbon atoms, aryl of 6–10 carbon atoms, heteroaryl of 2–9 carbon atoms and 1–4 heteroatoms selected from N, S(═O)0-2 and O, 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);

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

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

A is selected from alkyl of 1–8 carbon atoms, alkenyl of 2–8 carbon atoms, alkynyl of 2–8 carbon atoms, and haloalkyl of 1–8 carbon atoms;

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

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

R9 is selected from 5–7 membered heterocycloalkyl of 3–6 carbon atoms and 1–2 heteroatoms selected from N, S(═O)0-2 and O and 5–7 membered heterocycloalkenyl of 3–6 carbon atoms and 1–2 heteroatoms selected from N, S(═O)0-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5–6 membered heteroaryl of 2–5 carbon atoms and 1–3 heteroatoms selected from N, S(═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;

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

R2 is NR15R16;

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

R18 is selected from aryl of 6–10 carbon atoms, heteroaryl of 2–9 carbon atoms and 1–4 heteroatoms selected from N, S(═O)0-2 and O, cylcoalkyl of 3–8 carbon atoms, cycloalkenyl of 4–8 carbon atoms, 5–7 membered heterocycloalkyl of 3–6 carbon atoms and 1–2 heteroatoms selected from N, S(═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

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

R18 is A-R9;

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

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

R15 and R16 combine, together with the nitrogen atom to which they are attached, to form a heteroaryl of 2–9 carbon atoms and 1–4 heteroatoms selected from N, S(═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;

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;

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

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

R4 is selected from ═O, ═S, and OR21;

R21 is hydrogen, or

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

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

R5 and R6 are independently selected from is selected from 5–7 membered heterocycloalkyl of 3–6 carbon atoms and 1–2 heteroatoms selected from N, S(═O)0-2 and O and 5–7 membered heterocycloalkenyl of 3–6 carbon atoms and 1–2 heteroatoms selected from N, S(═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

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;

Q is selected from O and S(═O)0-2;

R22 is selected from hydrogen, alkyl of 1–6 carbon atoms, haloalkyl of 1–6 carbon atoms, and cycloalkyl of 3–6 carbon atoms;

R23 is selected from hydroxy, alkoxy of 1–6 carbon atoms, haloalkoxy of 1–6 carbon atoms, and cycloalkoxy of 3–6 carbon atoms, or

R23 is selected from cycloalkyl of 3–6 carbon atoms, cycloalkenyl of 4–6 carbon atoms, phenyl, and monocyclic heteroaryl of 2–5 carbon atoms and 1–3 heteroatoms selected from N, S(═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)OR, 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)NR24R , 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;

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

R7 is selected from 5–7 membered heterocycloalkyl of 3–6 carbon atoms and 1–2 heteroatoms selected from N, S(═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

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;

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.

Methods of the invention provide for the treatment or prevention of diabetes, including 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.
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 α-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.
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.
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.
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.
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
The invention relates generally to naphthyridine derivatives of the formula




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)





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.

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.
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, α-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.
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.
General Preparative Methods
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.
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.




















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.).




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.
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.




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








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




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




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




Flow Diagram 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).




E+ is alkyl halide, aldehydes, halogen, CO2, O2, activated ester, etc.
Flow Diagram XIV illustrates the transformations of some functional groups which are present in Formula (I) or (II).




Alternative Forms of Novel Compounds

Also included in the compounds of the present invention are (a) the stereoisomers thereof, (b) the pharmaceutically-acceptable salts thereof, (c) the tautomers thereof, (d) the protected acids and the conjugate acids thereof, and (e) the prodrugs thereof.
(a) The Stereoisomers
The stereoisomers of these compounds may include, but are not limited to, enantiomers, diastereomers, racemic mixtures and combinations thereof. Such stereoisomers can be prepared and separated using conventional techniques, either by reacting enantiomeric starting materials, or by separating isomers of compounds of the present invention. Isomers may include geometric isomers. Examples of geometric isomers include, but are not limited to, cis isomers or trans isomers across a double bond. Other isomers are contemplated among the compounds of the present invention. The isomers may be used either in pure form or in admixture with other isomers of the inhibitors described above.
(b) The Pharmaceutically-Acceptable Salts
Pharmaceutically-acceptable salts of the compounds of the present invention include salts commonly used to form alkali metal salts or form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically-acceptable. Suitable pharmaceutically-acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic, carboxylic and sulfonic classes of organic acids. Examples of organic and sulfonic classes of organic acids includes, but are not limited to, formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicyclic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, algenic, N-hydroxybutyric, salicyclic, galactaric and galacturonic acid and combinations thereof.
(c) The Tautomers
Tautomers of the compounds of the invention are encompassed by the present invention. Thus, for example, a carbonyl includes its hydroxy tautomer.
(d) The Protected Acids and the Conjugate Acids
The protected acids include, but are not limited to, esters, hydroxyamino derivatives, amides and sulfonamides.
(e) The Prodrugs
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).
Dosages and Treatment Regimen
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.
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.
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.
Pharmaceutical Compositions
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Methods of Use
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).
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.
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.
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.
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, α-glucosidase inhibitors, insulin sensitizers, insulin secretagogues, hepatic glucose output lowering compounds, insulin and anti-obesity drugs. Such therapies may be administered prior to, concurrently with or following administration of the 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 include agonists of PPAR-α, PPAR-γ, PPAR-δ or any combination of two or three of the subunits of PPAR. PPAR agonists include, for example, rosiglitazone and pioglitazone. Sulfonylurea drugs include, for example, glyburide, glimepiride, chlorpropamide, and glipizide. α-glucosidase inhibitors that may be useful in treating diabetes when administered with a compound of 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.
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).
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.
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.
Terms
As used herein, various terms are defined below.
When introducing elements of the present invention or the preferred embodiment(s) thereof, the articles “a”, “an”, “the” and “said” are intended to mean that there are one or more of the elements. The terms “comprising”, “including” and “having” are intended to be inclusive and mean that there may be additional elements other than the listed elements.
The term “subject” as used herein includes mammals (e.g., humans and animals).
The term “treatment” includes any process, action, application, therapy, or the like, wherein a subject, including a human being, is provided medical aid with the object of improving the subject's condition, directly or indirectly, or slowing the progression of a condition or disorder in the subject.
The phrase “therapeutically-effective” means the amount of each agent administered that will achieve the goal of improvement in a diabetic condition or disorder severity, while avoiding or minimizing adverse side effects associated with the given therapeutic treatment.
The term “pharmaceutically acceptable” means that the subject item is appropriate for use in a pharmaceutical product.
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.
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.
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.
When symbols such as “A(OR′)—R” is used, it refers to a group which is formed by substituting 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.
The term “halogen” refers to a halogen radical selected from fluoro, chloro, bromo or iodo.
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.
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.
The term “alkenyl” refers to a mono or polyunsaturated 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.
The term “alkynyl” refers to a mono or polyunsaturated 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.
The term “cycloalkyl” refers to the mono- or polycyclic analogs of an alkyl group, as defined above. Unless otherwise specified, the cycloalkyl ring may be attached at any carbon atom that results in a stable structure and, if substituted, may be substituted at any suitable carbon atom which results in a stable structure. Examples of cycloalkyl groups are saturated cycloalkyl groups containing from three to ten carbon atoms. Other examples include cycloalkyl groups containing three to six carbon atoms. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cyclononyl, cyclodecyl, norbornane, adamantyl, and the like.
The term “cycloalkenyl” refers to the mono- or polycyclic analogs of an alkenyl group, as defined above. Unless otherwise specified, the cycloalkenyl ring may be attached at any carbon atom that results in a stable structure and, if substituted, may be substituted at any suitable carbon atom that results in a stable structure. Examples of cycloalkenyl groups are cycloalkenyl groups containing from four to ten carbon atoms. Other examples include cycloalkenyl groups containing four to six carbon atoms. Exemplary cycloalkenyl groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, norbornene, and the like.
The term “heterocycloalkyl” refers to the mono- or polycyclic structures of “cycloalkyl” where one or more of the carbon atoms are replaced by one or more atoms independently chosen from nitrogen, oxygen, or sulfur atoms. Any nitrogen atom maybe optionally oxidized or quanternized, and any sulfur atom maybe optionally oxidized. Unless otherwise specified, the heterocycloalkyl ring may be attached at any carbon atom or heteroatom that results in a stable structure and, if substituted, may be substituted at any suitable carbon atom or heteroatom which results in a stable structure. Examples of heterocycloalkyl groups are saturated heterocycloalkyl groups containing from two to nine carbon atoms and one to four heteroatoms chosen independently from nitrogen, oxygen, or sulfur atoms. Examples of heterocycloalkyl groups include morpholino, pyrazino, tetrahydrofurano, and the like.
The term “heterocycloalkenyl” refers to the mono- or polycyclic structures of “cycloalkenyl” where one or more of the carbon atoms are replaced by one or more atoms independently chosen from nitrogen, oxygen, or sulfur atoms. Any nitrogen atom maybe optionally oxidized or quanternized, and any sulfur atom maybe optionally oxidized. Unless otherwise specified, the heterocycloalkenyl ring may be attached at any carbon atom or heteroatom that results in a stable structure and, if substituted, may be substituted at any suitable carbon atom or heteroatom which results in a stable structure. Examples of heterocycloalkenyl groups are saturated heterocycloalkenyl groups containing from two to nine carbon atoms and one to four heteroatoms chosen independently from nitrogen, oxygen, or sulfur atoms. Examples of heterocycloalkenyl groups include dihydropyran, dihydrofuran, and the like.
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.
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.
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 substitutions 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.
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.
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.
A comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations. The abbreviations contained in said list, and all abbreviations utilized by organic chemists of ordinary skill in the art are hereby incorporated by reference.
For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986–87, inside cover.
Abbreviations and Acronyms
When the following abbreviations are used throughout the disclosure, they have the following meaning:

    
    
        CH2Cl2 methylene chloride
        THF tetrahydrofuran
        CH3CN acetonitrile
        Na2SO4 anhydrous sodium sulfate
        MgSO4 anhydrous magnesium sulfate
        DMSO dimethylsulfoxide
        EtOAc ethyl acetate
        Et2O diethyl ether
        Et3N triethylamine
        H2 hydrogen
        CO carbon monoxide
        HCl hydrochloric acid
        Hex hexanes
        1H NMR proton nuclear magnetic resonance
        HPLC high performance liquid chromatography
        K2CO3 potassium carbonate
        Cs2CO3 cesium carbonate
        NH4Cl ammonium chloride
        LC/MS liquid chromatography/mass spectroscopy
        MeOH methanol
        MS ES mass spectroscopy with electrospray
        NaHCO3 sodium bicarbonate
        NaOH sodium hydroxide
        RT retention time
        h hour
        min minutes
        Pd(OAc)2 palladium acetate
        Ni(dppp)Cl2 [1,3-bis(diphenylphosphino)propane]dichloronickel(II)
        DMF N,N-dimethylformamide
        EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
        LTMP Lithium tetramethylpiperidine
        BuLi butyllithium
        TLC thin layer chromatography
        TFA trifluoacetic acid
        TMEDA tetramethylethylenediamine
        BINAP 2,2′-bis(diphenylphosphino)-1,1′binaphthyl
        HOBt 1-hydroxybenzotriazole hydrate
        NaH sodium hydride
        MeMgBr methylmagnesium bromide
        DPPP (diphenylphosphino)propane
        DME dimethoxyethane
        AlCl3 aluminum chloride
        TEA triethyl amine
        CS2 carbon disulfide
        MeI methyl iodide
        t-BuOK potassium tert-butoxide
        KHMDS potassium hexamethyldisilazide
        LiHMDS lithium hexamethyldisilazide
        NaOBr sodium hypobromite
        Br2 bromine
        Conc. Concentrated
        Pd/C palladium on carbon
        EtOH ethanol
        NH3 ammonia
        NaOMe sodium methoxide
        PPh3 triphenylphosine
        NaH sodium hydride
        LDA lithium diisopropylamide
        SOCl2 thionyl chloride
        MsCl methanesulfonyl chloride
        DMAP 4-dimethylaminopyridine
        NMM 4-methylmorpholine
        AcOH acetic acid
        Na2S2O3 sodium thiosulfate
        H2SO4 sulfuric acid
        CHCl3 chloroform
        MnO2 manganese(IV) oxide
        LAH lithium aluminum hydride
        ADDP 1,1′-(azodicarbonyl)-dipiperidine
        EDTA ethylenediaminetetraacetic acid
        CCl2FCCIF2 1,1,2-trichlorotrifluoroethane
        NaNO2 sodium nitrite
    
    


PREPARATIVE EXAMPLES
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.
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.
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.
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 characterizations, are in agreements with their corresponding structural assignments.
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.
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 characterizations, are in agreements with their corresponding structural assignements.
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.
Intermediate A
2,6-dichloro-4-methyl-nicotinic acid




Method 1

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.
Method 2
Concentrated nitric acid (14 mL) was added to cooled (0° C.) concentrated sulfuric acid (43 mL) maintaining the internal temperature below 10° C. After addition, the acid mixture was heated to 70° C. and commercially available (Avocado) 2,6-dichloro-4-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).
Intermediate B
2,6-dichloro-4-methyl-nicotinoyl chloride




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




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




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




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.
Intermediate F
2,6-dichloro-4-(trifluoromethyl)nicotinic acid




Method 1

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).
Method 2
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).
Intermediate G
2,6-dichloro-4-(trifluoromethyl)nicotinoyl chloride




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




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




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




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.
Intermediate K
2,6-dichloro-5-fluoronicotinoyl chloride




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




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) δ 8.43 (d, 1H, J=8.4 Hz), 7.56 (s, 1H), Rf=0.76 (3:1 Hex:EtOAc).
Intermediate M
3,3-dianilino-1-(2,6-dichloro-5-fluoro-3-pyridinyl)-2-propen-1-one




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




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.
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:
Intermediate N1




LCMS RT: 2.81 min, MH+: 402.3
Intermediate N2




LCMS RT: 2.73 min, MH+: 402.4
Intermediate N3




LCMS RT: 2.30 min, MH+: 298.1
Intermediate N4




LCMS RT: 2.88 min, MH+: 394.3
Intermediate N5




LCMS RT: 2.78 min, MH+: 426.3
Intermediate N6




LCMS RT: 3.09 min, MH+: 434.5
Intermediate N7




LCMS RT: 3.07 min, MH+: 378.2
Intermediate N8




LCMS RT: 3.15 min, MH+: 422.4
Intermediate N9




LCMS RT: 2.90 min, MH+: 486.3
Intermediate N10




LCMS RT: 2.22 min, MH+: 294.2
Intermediate N11




LCMS RT: 3.05 min, MH+: 430.4
Intermediate N12




LCMS RT: 2.51 min, MH+: 468.3
Intermediate N13




LCMS RT: 3.10 min, MH+: 430.4
Intermediate O
2,6-dichloronicotinoyl chloride




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




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




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




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.
Intermediate S
Ethyl 3-(2-chloro-6-methyl(3-pyridyl))-3-oxopropanoate




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




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




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




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




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




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.
Intermediate Y
5-Bromo-2-hydroxy-6-methylnicotine acid




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.
Intermediate Z (Same as Intermediate BA)
2,4-dichloro-6-methylnicotinic acid




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.
Intermediate AA (Same as Intermediate BB)
3,3-dichloro-1-(2,4-dichloro-6-methyl-3-pyridinyl)-2-propen-1-one




The compound was prepared according to the procedure described for Intermediate BB below. LCMS RT: 3.13 min, MH+: 284.6.
Intermediate AB (Same as Intermediate BC)
3,3-dianilino-1-(2,4-dichloro-6-methyl-3-pyridinyl)-2-propen-1-one




The compound was prepared according to the procedure described for Intermediate BC below: LCMS RT: 3.06 min, MH+: 398.7.
Intermediate AC
(2Z)-3-anilino-1-(2,6-dichloro-5-fluoro-3-pyridinyl)-3-(isopropylamino)-2-propen-1-one




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




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




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




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




(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 a white solid: LCMS RT: 2.57 min, MH+: 332.2.
Intermediate AH
2-anilino-7-chloro-6-fluoro-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one




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




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




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




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




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




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




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




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




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




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




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




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




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




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 chromatography (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




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




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




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.
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




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




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




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




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




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




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-carboxamide




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 transformation 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




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




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




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-(trifluoromethyl)-5,8-dihydro-1,8-naphthyridin-2-yl]methanesulfonamide




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




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




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 chromatography 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




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 residue 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




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




And Example 28
2-anilino-7-ethoxy-5-ethyl-3-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one




And Example 29
7-ethoxy-5-ethyl-3-methyl-2-[methyl(phenyl)amino]-1-phenyl-1,8-naphthyridin-4(1H)-one




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: (35 mg, 32%), Example 28: (11 mg, 10%), Example 29: (16 mg, 14%).
Example 30
2-anilino-6-fluoro-7-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one




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




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




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)propenoic acid




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)propenoic acid (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




Example 35
2-anilino-7-ethyl-1-(3-methylphenyl)-1,8-naphthyridin-4(1H)-one




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 MeI (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




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




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




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.
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.
Intermediate BA
2,4-dichloro-6-methylnicotinic acid




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




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




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.
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).
Intermediate BA1
4,6-dichloronicotinic acid




Intermediate BB1
3,3-dichloro-1-(4,6-dichloro-3-pyridinyl)-2-propen-1-one




Intermediate BC1
3,3-dianilino-1-(4,6-dichloro-3-pyridinyl)-2-propen-1-one




Intermediate BA2
4,5-dichloronicotinic acid




Intermediate BB2
3,3-dichloro-1-(4,5-dichloro-3-pyridinyl)-2-propen-1-one




Intermediate BC2
3,3-dianilino-1-(4,5-dichloro-3-pyridinyl)-2-propen-1-one




Example 39
2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one




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.
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




Example 41
2-anilino-8-chloro-1-phenyl-1,6-naphthyridin-4(1H)-one




Example 42
2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one




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




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




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




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




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




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




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




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-carboxamide




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




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




And Example 53
7-methyl-2-[methyl(phenyl)amino]-1-phenyl-5-(trifluoromethyl)-1,6-naphthyridin-4(1H)-one




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




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




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.
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.











TABLE 1A







LCMS






RT

Representative


Example
Structure
(min)
[M + H]
Procedure



















56




2.07
413.4
IntermediateZ, AA, ABand Example16, 2


 


57




1.85
357.3
IntermediateZ, AA, ABand Example16, 2


 


58




1.67
412.2
IntermediateZ, AA, ABand Example16, 2


 


59




2.18
411.4
IntermediateZ, AA, ABand Example16, 2


 


60




2.02
358.4
IntermediateZ, AA, ABand Example16, 9


 


61




2.54
382.3
Intermediate F,G, H, I, J andExample 1


 


62




2.58
432.4
IntermediateO, P, Q, R andExample 4


 


63




2.63
296.3
IntermediateO, P, Q, R andExample 4


 


64




2.89
426.2
Intermediate F,G, H, I, J andExample 9


 


65




3.00
426.2
IntermediateIntermediate F,G, H, I, J andExample 4


 


66




3.02
410.4
IntermediateA, B, C, D, Eand Example 5


 


67




3.00
464.2
Intermediate F,G, H, I, J andExample 4


 


68




2.98
500.3
Intermediate F,G, H, I, J andExample 4


 


69




2.57
432.3
IntermediateO, P, Q, R andExample 4


 


70




2.50
471.1
Intermediate F,G, H, I, J andExample 6, 7


 


71




2.73
390.4
IntermediateO, P, Q, R andExample 4


 


72




2.73
408.5
IntermediateO, P, Q, R andExample 4


 


73




3.30
396.4
IntermediateO, P, Q, R andExample 4


 


74




3.41
370.4
IntermediateO, P, Q, R andExample 5


 


75




3.56
396.5
IntermediateO, P, Q, R andExample 5


 


76




3.39
404.4
IntermediateO, P, Q, R andExample 5


 


77




2.69
370.3
IntermediateO, P, Q, R andExample 5


 


78




2.59
356.3
IntermediateO, P, Q, R andExample 5


 


79




2.74
408.4
IntermediateO, P, Q, R andExample 4


 


80




1.60
394.0
IntermediateA, B, C, D, Eand Example1, 10, 11


 


81




2.88
376.4
Intermediate S,T, U, W andExample 15


 


82




2.42
348.3
Intermediate S,T, U, W andExample 15


 


83




1.69
426.2
IntermediateZ, AA, ABand Example16, 2


 


84




3.87
480.4
IntermediateA, B, C, D, E,AL andExample 4


 


85






IntermediateA, B, C, D, E,AL andExample 4


 


86




2.43
283.6
Intermediate S,T, V andExample 15


 


87




2.82
620.4
IntermediateA, B, C, D, Eand Example2, 13


 


88




1.86
389.1
IntermediateK, L, M, N,AM, andExample 1, 13


 


89




2.56
372.3
IntermediateZ, AA, ABand Example16, 17, 7


 


90




2.41
504.2
IntermediateA, B, C, D, Eand Example2, 12


 


91




2.50
518.3
IntermediateA, B, C, D, Eand Example2, 12


 


92




2.71
566.3
IntermediateA, B, C, D, Eand Example2, 12


 


93




2.54
417.4
IntermediateK, L, M, N,and Example 2


 


94




2.27
342.4
Intermediate S,T, U, W andExample 15


 


95




1.71
426.2
IntermediateA, B, C, D, Eand Example 2


 


96




1.74
412.1
IntermediateA, B, C, D, Eand Example 2


 


97




2.75
411.2
IntermediateA, B, C, D, Eand Example 2


 


98




2.70
397.2
IntermediateA, B, C, D, Eand Example 2


 


99




2.52
399.4
IntermediateA, B, C, D, Eand Example 2


 


100




2.80
488.6
IntermediateA, B, C, D, Eand Example 2


 


101




2.89
459.7
IntermediateA, B, C, D, Eand Example 2


 


102




2.54
441.6
IntermediateA, B, C, D, Eand Example 2


 


103




2.40
383.5
IntermediateA, B, C, D, Eand Example 2


 


104




2.44
467.5
Intennediate F,G, H, I, J andExample 8


 


105




2.51
480.4
Intermediate F,G, H, I, J andExample 8


 


106




1.80
466.4
Intermediate F,G, H, I, J andExample 8


 


107




2.65
433.4
IntermediateA, B, C, D, Eand Example 3


 


108




2.60
437.4
IntermediateA, B, C, D, Eand Example 3


 


109




2.71
453.4
IntermediateA, B, C, D, Eand Example 3


 


110




2.53
449.4
IntermediateA, B, C, D, Eand Example 3


 


111




2.65
433.4
IntermediateA, B, C, D, Eand Example 3


 


112




2.84
461.5
IntermediateA, B, C, D, Eand Example 3


 


113




2.08
387.4
IntermediateA, B, C, D, Eand Example 2


 


114




2.46
433.4
IntermediateA, B, C, D, Eand Example 2


 


115




2.64
451.3
IntermediateA, B, C, D, Eand Example 2


 


116




2.61
463.4
IntermediateA, B, C, D, Eand Example 2


 


117




2.03
440.4
IntermediateA, B, C, D, Eand Example 2


 


118




2.58
372.2
IntermediateA, B, C, D, Eand Example 9


 


119




2.20
454.4
IntermediateA, B, C, D, Eand Example2, 13


 


120




2.55
496.4
IntermediateA, B, C, D, Eand Example2, 13


 


121




2.52
552.2
IntermediateA, B, C, D, Eand Example2, 12


 


122




2.44
516.3
IntermediateA, B, C, D, Eand Example2, 13


 


123




2.28
429.3
IntermediateA, B, C, D, Eand Example 3


 


124




2.45
431.4
IntermediateK, L, M, N,AH andExample 2


 


125




2.45
362.3
IntermediateK, L, M, Nand Example 9


 


126




2.51
360.3
IntermediateK, L, M, N,AH andExample 1


 


127




2.30
346.4
IntermediateK, L, M, N,AH andExample 1


 


128




2.70
374.4
IntermediateK, L, M, N,AH andExample 1


 


129




2.69
438.3
IntermediateK, L, M, Nand Example9, 14, 4


 


130




2.64
428.3
IntermediateK, L, M, Nand Example9, 14, 4


 


131




2.74
468.3
Intermediate 2K, L, M, Nand Example9, 14, 4


 


132




2.77
456.4
IntermediateK, L, M, Nand Example9, 14, 4


 


133




2.37
364.3
Intermediate S,T, U, W andExample 15


 


134




2.40
362.3
Intermediate S,T, V, X andExample 15


 


135




2.46
362.2
Intermediate S,T, V, X andExample 15


 


136




2.28
346.3
Intermediate S,T, V, X andExample 15


 


137




2.32
342.3
Intermediate S,T, V, X andExample 15


 


138




2.27
346.3
Intermediate S,T, V, X andExample 15


 


139




2.41
362.3
Intermediate S,T, V, X andExample 15


 


140




2.36
358.3
Intermediate S,T, V, X andExample 15


 


141




2.32
358.3
Intermediate S,T, V, X andExample 15


 


142




2.36
358.3
Intermediate S,T, V, X andExample 15


 


143




2.35
364.3
IntermediateA, B, C, D, Eand Example 1


 


144




2.60
406.3
IntermediateY, S, T, U, Wand Example15


 


145




5.35
434.4
IntermediateY, S, T, U, Wand Example15, 4


 


146




3.43
470.3
Intermediate F,G, H, I, J andExample 6


 


147




3.43
470.3
Intermediate F,G, H, I, J andExample 6


 


148




2.59
541.3
Intermediate F,G, H, I, J andExample 6, 7,13


 


149




2.66
525.2
Intermediate F,G, H, I, J andExample 6, 7,13


 


150




2.49
483.4
Intermediate F,G, H, I, J andExample 8


 


151




2.38
455.3
Intermediate F,G, H, I, J andExample 8, 7


 


152




2.60
499.4
Intermediate F,G, H, I, J andExample 6, 7,13


 


153




2.95
547.4
Intermediate F,G, H, I, J andExample 6, 7,13


 


154




2.19
482.3
Intermediate F,G, H, I, J andExample 8, 7,13


 


155




2.07
482.3
Intermediate F,G, H, I, J andExample 8, 7,13


 


156




1.95
454.3
Intermediate F,G, H, I, J andExample 8, 7,13


 


157




2.18
524.3
Intermediate F,G, H, I, J andExample 8, 7,13


 


158




2.44
530.3
Intermediate F,G, H, I, J andExample 8, 7,13


 


159




1.99
468.3
Intermediate F,G, H, I, J andExample 8, 7,13


 


160




2.74
598.3
Intermediate F,G, H, I, J andExample 8, 7,13


 


161




3.15
442.3
Intermediate F,G, H, I, J andExample 6


 


162




328
456.2
Intermediate F,G, H, I, J andExample 6


 


163




2.26
471.3
Intermediate F,G, H, I, J andExample 6, 7,13


 


164




2.34
485.3
Intermediate F,G, H, I, J andExample 6, 7,13


 


165




2.71
398.4
IntermediateZ, AA, ABExample16


 


166




2.88
542.6
Intermediate F,G, H, I, J andExample 8


 


167




2.66
495.6
Intermediate F,G, H, I, J andExample 8


 


168




2.20
441.5
Intermediate F,G, H, I, J andExample 8


 


169




2.76
453.5
Intermediate F,G, H, I, J andExample 8


 


170




3.05
430.3
IntermediateK, L, M, N, AIand Example 1


 


171




3.14
428.4
IntermediateK, L, M, N, AIand Example 1


 


172




2.72
477.5
IntermediateA, B, C, D, Eand Example 2


 


173




2.72
495.5
Intermediate F,G, H, I, J andExample 8


 


174




2.72
495.6
Intermediate F,G, H, I, J andExample 8


 


175




2.77
487.5
Intermediate F,G, H, I, J andExample 8


 


176




2.43
437.4
IntermediateA, B, C, D, Eand Example 2


 


177




3.13
502.5
Intermediate F,G, H, I, J andExample 6, 21


 


178




2.93
488.3
Intermediate F,G, H, I, J andExample 6, 21


 


179




2.41
426.3
Intermediate F,G, H, I, J andExample 17, 7


 


180




2.56
372.3
IntermediateZ, AA, ABand Example16, 17, 7


 


181




2.19
408.2
IntermediateA, B, C, D, Eand Example17, 7


 


182




2.39
425.4
Intermediate F,G, H, I, J andExample 17,18


 


183




2.18
407.4
IntermediateA, B, C, D, Eand Example17, 18


 


184




2.88
424.4
Intermediate F,G, H, I, J andExample 17, 7,19, 20


 


185




2.27
402.2
IntermediateZ, AA, ABand Example16, 9


 


186




2.41
408.3
IntermediateZ, AA, ABand Example16, 9


 


187




2.50
426.3
IntermediateZ, AA, ABand Example16, 9


 


188




2.43
386.1
IntermediateZ, AA, ABand Example16, 9


 


189




2.66
456.4
Intermediate F,G, H, I, J andExample 9


 


190




2.88
462.5
Intermediate F,G, H, I, J andExample 9


 


191




2.98
452.4
Intermediate F,G, H, I, J andExample 9


 


192




3.12
480.3
Intermediate F,G, H, I, J andExample 9


 


193




3.10
440.1
Intermediate F,G, H, I, J andExample 9


 


194




2.51
398.1
IntermediateZ, AA, ABand Example16, 9


 


195




2.99
505.4
Intermediate F,G, H, I, J andExample 8


 


196




3.05
513.5
Intermediate F,G, H, I, J andExample 8


 


197




2.47
455.4
Intermediate F,G, H, I, J andExample 8


 


198




2.57
453.4
IntermediateK, L, M, N1and Example 2


 


199




2.70
440.2
IntermediateK, L, M, N2and Example17


 


200




2.19
411.3
IntermediateK, L, M, N2and Example17, 18


 


201




2.48
453.4
IntermediateK, L, M, N2and Example 2


 


202




2.76
440.2
IntermediateK, L, M, N1and Example17


 


203




2.76
481.5
IntermediateK, L, M, N1and Example 2


 


204




2.69
481.5
IntermediateK, L, M, N2and Example 2


 


205




2.23
411.3
IntermediateK, L, M, N1and Example17, 18


 


206




2.27
383.4
IntermediateK, L, AC, AGand Example 2


 


207




3.12
490.3
Intermediate F,G, H, I, J andExample 17


 


208




2.55
461.3
Intermediate F,G, H, I, J andExample 17,18


 


209




2.62
503.4
Intermediate F,G, H, I, J andExample 8


 


210




2.82
531.5
Intermediate F,G, H, I, J andExample 8


 


211




2.54
491.4
Intermediate F,G, H, I, J andExample 8


 


212




2.93
531.4
Intermediate F,G, H, I, J andExample 8


 


213




2.47
491.4
Intermediate F,G, H, I, J andExample 8


 


214




3.02
476.3
Intermediate F,G, H, I, J andExample 9


 


215




2.75
492.3
Intermediate F,G, H, I, J andExample 9


 


216




3.14
476.2
Intermediate F,G, H, I, J andExample 9


 


217




2.83
492.3
Intermediate F,G, H, I, J andExample 9


 


218




2.15
349.1
IntermediateK, L, M, N3and Example 2


 


219




2.01
362.3
IntermediateK, L, M, Nand Example17, 25


 


220




2.87
505.4
IntermediateAH, K, L, M,N2


 


221




2.90
396.3
IntermediateAH, K, L, M,N andExample 1


 


222




3.23
424.3
IntermediateAH, K, L, M,N andExample 1


 


223




2.67
396.3
IntermediateAH, K, L, M,N2 andExample 1


 


224




3.02
424.4
IntermediateAH, K, L, M,N2 andExample, 1


 


225




2.12
401.3
IntermediateA, B, C, D, Eand Example3, 7


 


226




2.45
459.4
IntermediateK, L, M, N, AIand Example 2


 


227




2.69
487.5
IntermediateK, L, M, N, AIand Example 2


 


228




2.37
447.4
IntermediateK, L, M, N, AIand Example 2


 


229




2.60
374.3
IntermediateK, L, M, N, AIand Example 1


 


230




2.78
390.1
IntermediateK, L, M, N,AM andExample 1


 


231




2.09
421.2
IntermediateA, B, C, D, Eand Example22


 


232




2.44
483.2
IntermediateA, B, C, D, Eand Example22


 


233




2.51
497.2
IntermediateA, B, C, D, Eand Example22


 


234




2.44
383.2
IntermediateA, B, C, D, Eand Example 3


 


235




2.84
428.4
IntermediateA, B, C, D, Eand Example17


 


236




2.77
400.3
IntermediateA, B, C, D, Eand Example17


 


237




2.30
372.2
IntermediateA, B, C, D, Eand Example17, 7


 


238




2.50
427.4
IntermediateA, B, C, D, Eand Example17, 7, 13


 


239




2.18
441.5
IntermediateA, B, C, D, Eand Example17, 7, 13


 


240




2.44
399.4
IntermediateA, B, C, D, Eand Example17, 7, 13


 


241




2.66
455.5
IntermediateA, B, C, D, Eand Example17, 7, 13


 


242




2.79
427.3
IntermediateA, B, C, D, Eand Example17, 7, 13


 


243




2.58
411.3
IntermediateA, B, C, D, Eand Example17, 7, 13


 


244




2.58
457.3
IntermediateA, B, C, D, Eand Example17, 7, 13


 


245




2.80
447.5
IntermediateA, B, C, D, Eand Example17, 7, 13


 


246




2.97
481.8
IntermediateA, B, C, D, Eand Example17, 7, 13


 


247




3.30
481.3
IntermediateA, B, C, D, Eand Example17, 7, 13


 


248




3.05
481.7
IntermediateA, B, C, D, Eand Example17, 7, 13


 


249




1.99
371.4
IntermediateA, B, C, D, Eand Example17, 18


 


250




2.82
384.4
IntermediateA, B, C, D, Eand Example17, 7, 19, 20


 


251




2.94
398.4
IntermediateA, B, C, D, Eand Example17, 7, 19, 20


 


252




3.22
426.4
IntermediateA, B, C, D, Eand Example17, 7, 19, 20


 


253




3.05
412.4
IntermediateA, B, C, D, Eand Example17, 7, 19, 20


 


254




3.10
424.4
IntermediateA, B, C, D, Eand Example17, 7, 19, 20


 


255




3.19
438.4
IntermediateA, B, C, D, Eand Example17, 7, 19, 20


 


256




2.96
432.4
IntermediateA, B, C, D, Eand Example17, 7, 19, 20


 


257




3.16
466.4
IntermediateA, B, C, D, Eand Example17, 7, 19, 20


 


258




2.80
398.5
IntermediateA, B, C, D, Eand Example17, 7, 19, 20


 


259




2.95
412.5
IntermediateA, B, C, D, Eand Example17, 7, 19, 20


 


260




2.80
438.6
IntermediateA, B, C, D, Eand Example17, 7, 19, 20


 


261




3.06
450.3
IntermediateA, B, C, D, Eand Example17, 7, 19, 20


 


262




3.05
450.4
IntermediateA, B, C, D, Eand Example17, 7, 19, 20


 


263




1.94
376.2
IntermediateK, L, M, Nand Example17, 7


 


264




2.44
374.4
IntermediateK, L, M, Nand Example17, 7, 19, 20


 


265




2.59
388.3
IntermediateK, L, M, Nand Example17, 7, 19, 20


 


266




2.68
442.4
IntermediateK, L, M, Nand Example17, 7, 19, 20


 


267




2.97
470.5
IntermediateK, L, M, Nand Example17, 7, 19, 20


 


268




2.53
376.3
IntermediateK, L, M, Nand Example 9


 


269




2.28
405.4
IntermediateK, L, M, Nand Example 2


 


270




2.35
406.2
IntermediateK, L, M, Nand Example 9


 


271




2.70
390.2
IntermediateK, L, M, Nand Example 9


 


272




2.20
417.3
IntermediateK, L, M, N, AIand Example17, 18


 


273




2.38
386.3
IntermediateA, B, C, D, Eand Example17, 7, 19, 20,25


 


274




2.63
440.3
IntermediateA, B, C, D, Eand Example17, 7, 19, 20,25


 


275




2.83
468.3
IntermediateA, B, C, D, Eand Example17, 7, 19, 20,25


 


276




2.79
479.3
Intermediate F,G, H, I, J andExample 8


 


277




2.58
451.2
Intermediate F,G, H, I, J andExample 8


 


278




2.58
356.4
IntermediateY, S, T, U, Wand Example15, 34


 


279




2.79
404.4
IntermediateY, S, T, U, Wand Example15, 4


 


280




2.93
422.4
IntermediateY, S, T, U, Wand Example15, 4


 


281




2.78
384.4
IntermediateY, S, T, U, Wand Example15, 34


 


282




2.50
442.2(423 +H2O +1)
IntermediateY, S, T, U, Wand Example15, 34


 


283




2.26
372.4
IntermediateY, S, T, U, Wand Example15, 34


 


284




2.29
427.4
IntermediateY, S, T, U, Wand Example15, 31, 32, 33,13


 


285




2.19
413.4
IntermediateY, S, T, U, Wand Example15, 31, 32, 33,13


 


286




2.15
384.4
IntermediateY, S, T, U, Wand Example15, 31, 32


 


287




2.01
386.4
IntermediateY, S, T, U, Wand Example15, 31, 32, 33


 


288




2.42
396.5
IntermediateY, S, T, U, Wand Example15, 31


 


289




2.97
430.6
IntermediateY, S, T, U, Wand Example15, 31


 


290




2.33
398.6
IntermediateY, S, T, U, Wand Example15, 31, 33


 


291




2.87
432.4
IntermediateY, S, T, U, Wand Example15, 31, 33


 


292




2.01
397.3
IntermediateY, S, T, U, Wand Example15, 31, 32, 13


 


293




2.00
399.5
IntermediateY, S, T, U, Wand Example15, 31, 32, 33,13


 


294




2.63
461.3
Intermediate F,G, H, I, J andExample 17,18


 


295




2.54
445.5
IntermediateK, L, M, Nand Example 2


 


296




2.27
425.3
IntermediateY, S, T, U, Wand Example15, 31, 32, 13


 


297




2.43
392.3
IntermediateY, S, T, U, Wand Example15


 


298




2.40
398.5
IntermediateY, S, T, U, Wand Example15, 31


 


299




2.28
411.4
IntermediateY, S, T, U, Wand Example15, 31, 32, 13


 


300




3.18
490.0
Intermediate F,G, H, I, J andExample 9


 


301




2.90
462.3
Intermediate F,G, H, I, J andExample 9


 


302




2.90
418.3
Intermediate F,G, H, I, J andExample 1


 


303




2.66
418.3
Intermediate F,G, H, I, J andExample 1


 


304




2.70
403.6
IntermediateK, L, M, Nand Example 2


 


305




2.52
503.6
Intermediate F,G, H, I, J andExample 8


 


306




3.03
502.2
Intermediate F,G, H, I, J andExample 8


 


307




2.68
358.0
Intermediate S,T, U, W andExample 25


 


308




2.40
358.4
IntermediateA, B, C, D, Eand Example 9









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.









TABLE 1B







Representative


Example
Structure
Procedure







309




Intermediate Z,AA, AB andExample 16, 4


 


310




Intermediate Z,AA, AB andExample 16, 2


 


311




Intermediate Z,AA, AB andExample 16, 3


 


312




Intermediate Z,AA, AB andExample 16, 2


 


313




Intermediate Z,AA, AB andExample 16, 2, 7


 


314




Intermediate Z,AA, AB andExample 16, 2, 7,13


 


315




Intermediate Z,AA, AB andExample 16, 2, 7,13


 


316




Intermediate Z,AA, AB andExample 16, 2, 7,13


 


317




Intermediate Z,AA, AB andExample 16, 6, 7


 


318




Intermediate Z,AA, AB andExample 16, 6


 


319




Intermediate Z,AA, AB andExample 16, 6, 7,13


 


320




Intermediate Z,AA, AB andExample 16, 6, 7,13


 


321




Intermediate Z,AA, AB andExample 16, 9, 7


 


322




Intermediate Z,AA, AB andExample 16, 9


 


323




Intermediate Z,AA, AB andExample 16, 9, 7,13


 


324




Intermediate Z,AA, AB andExample 16, 9, 7,13


 


325




Intermediate Z,AA, AB andExample 16, 9


 


326




Intermediate Z,AA, AB andExample 16, 9


 


327




Intermediate Z,AA, AB andExample 16, 9


 


328




Intermediate Y,S, T, U, W andExample 15, 34


 


329




Intermediate Y,S, T, U, W andExample 15, 34


 


330




Intermediate Y,S, T, U, W andExample 15, 34


 


331




Intermediate Y,S, T, U, W andExample 15, 34


 


332




Intermediate Y,S, T, U, W andExample 15, 4


 


333




Intermediate Y,S, T, U, W andExample 15, 4


 


334




Intermediate Y,S, T, U, W andExample 15, 34


 


335




Intermediate Y,S, T, U, W andExample 15, 34,13


 


336




Intermediate Y,S, T, U, W andExample 15, 34,13


 


337




Intermediate Y,S, T, U, W andExample 15, 34,13


 


338




Intermediate K,L, M, N Example31, 32


 


339




Intermediate O,P, Q, R andExample 17, 25,26


 


340




Intermediate F,G, H, I, J andExample 31, 32


 


341




Intermediate A,B, C, D, E andExample 1 andIntermediate AK


 


342




Intermediate Z,AA, AB andExample 16, 31,32, 33


 


343




Intermediate A,B, C, D, E andExample 1 andIntermediate AK


 


344




Intermediate A,B, C, D, E andExample 31, 32


 


345




Intermediate A,B, C, D, E andExample 1 andIntermediate AK


 


346




Intermediate O,P, Q, R andExample 17, 25,26


 


347




Intermediate Z,AA, AB, andExample 16, 31,32


 


348




Intermediate F,G, H, I, J andExample 31, 32,33


 


349




Intermediate O,P, Q, R andExample 17, 25,26


 


350




Intermediate K,L, M, N andExample 31


 


351




Intermediate F,G, H, I, J andExample 31


 


352




Intermediate A,B, C, D, E andExample 31


 


353




Intermediate Z,AA, AB andExample 16, 31


 


354




Intermediate A,B, C, D, E andExample 31, 32,33


 


355




Intermediate K,L, M, N andExample 31, 32,33


 


356




Intermediate O,P, Q, R andExample 17, 25,26


 


357




Intermediate A,B, C, D, E AJ andExample 1


 


358




Intermediate A,B, C, D, E andExample 1 andIntermediate AL


 


359




Intermediate Z,AA, AB, andExample 16, 5


 


360




Intermediate Z,AA, AB, andExample 16, 5


 


361




Intermediate Z,AA, AB, andExample 16, 4


 


362




Intermediate K,L, M, N, andExample 2


 


363




Intermediate K,L, M, N, andExample 2


 


364




Intermediate K,L, M, N, andExample 2


 


365




Intermediate K,L, M, N, andExample 2


 


366




Intermediate K,L, M, N, andExample 2


 


367




Intermediate K,L, M, N, andExample 2


 


368




Intermediate K,L, M, N, andExample 2


 


369




Intermediate K,L, M, N, andExample 2


 


370




Intermediate K,L, M, N, andExample 2


 


371




Intermediate A,B, C, D, E andExample 2


 


372




Intermediate A,B, C, D, E andExample 2


 


373




Intermediate A,B, C, D, E andExample 2


 


374




Intermediate A,B, C, D, E andExample 2


 


375




Intermediate A,B, C, D, E andExample 2


 


376




Intermediate A,B, C, D, E andExample 2


 


377




Intermediate A,B, C, D, E andExample 2


 


378




Intermediate A,B, C, D, E andExample 2


 


379




Intermediate S, T,V, X andExample 15


 


380




Intermediate S, T,V, X andExample 15


 


381




Intermediate S, T,V, X andExample 15 andIntermediate AJ


 


382




Intermediate S, T,V, X andExample 15 andIntermediate AJ


 


383




Intermediate S, T,V and Example15


 


384




Intermediate S, T,V and Example15


 


385




Intermediate S, T,V and Example15


 


386




Intermediate S, T,V, X andExample 15


 


387




Intermediate A,B, C, D, E andExample 2


 


388




Intermediate S, T,V and Example15


 


389




Intermediate S, T,V and Example15


 


390




Intermediate S, T,V, X andExample 15


 


391




Intermediate S, T,V, X andExample 15


 


392




Intermediate S, T,V and Example15, 21


 


393




Intermediate S, T,V and Example15, 21


 


394




Intermediate S, T,V and Example15, 21


 


395




Intermediate A,B, C, D, E andExample 1, 12


 


396




Intermediate Z,AA, AB andExample 16, 17,7, 19


 


397




Intermediate Z,AA, AB andExample 16, 17,18


 


398




Intermediate Z,AA, AB andExample 16, 2


 


399




Intermediate Z,AA, AB andExample 16, 2


 


400




Intermediate Z,AA, AB andExample 16, 2,13


 


401




Intermediate Z,AA, AB andExample 16, 2


 


402




Intermediate Z,AA, AB andExample 16, 2


 


403




Intermediate Z,AA, AB andExample 16, 9


 


404




Intermediate A,B, C, D, E andExample 1, 10,11


 


405




Intermediate A,B, C, D, E andExample 1, 10,11


 


406




Intermediate A,B, C, D, E andExample 1, 10,11


 


407




Intermediate A,B, C, D, E andExample 1, 10,11


 


408




Intermediate Z,AA, AB andExample 16, 2, 7,13


 


409




Intermediate Z,AA, AB andExample 16, 6, 7,13


 


410




Intermediate Z,AA, AB andExample 16, 9, 7,13


 


411




Intermediate Z,AA, AB andExample 16, 9, 7,13


 


412




Intermediate Z,AA, AB andExample 16, 2, 7,13


 


413




Intermediate Z,AA, AB andExample 16, 6, 7,13


 


414




Intermediate Z,AA, AB andExample 16, 17,7, 13


 


415




Intermediate Z,AA, AB andExample 16, 17,7, 13


 


416




Intermediate Z,AA, AB andExample 16, 17,7, 13


 


417




Intermediate Z,AA, AB andExample 16, 17,7, 13


 


418




Intermediate Z,AA, AB andExample 16, 17


 


419




Intermediate Z,AA, AB andExample 16, 6


 


420




Intermediate Z,AA, AB andExample 16, 6,21


 


421




Intermediate Z,AA, AB andExample 16, 6


 


422




Intermediate Z,AA, AB andExample 16, 6


 


423




Intermediate Z,AA, AB andExample 16, 6,21


 


424




Intermediate Z,AA, AB andExample 16, 6


 


425




Intermediate Z,AA, AB andExample 16, 3,24


 


426




Intermediate K,L, M, N, AM andExample 1 andIntermediate AJ


 


427




Intermediate K,L, M, N, AM andExample 1 andIntermediate AJ


 


428




Intermediate K,L, M, N, AM andExample 1, 26


 


429




Intermediate K,L, M, N, AM andExample 1, 26


 


430




Intermediate K,L, M, N, AM andExample 1 andIntermediate AJ


 


431




Intermediate Z,AA, AB andExample 16, 31


 


432




Intermediate Z,AA, AB andExample 16, 31,32, 13


 


433




Intermediate Z,AA, AB andExample 16, 31,33


 


434




Intermediate Z,AA, AB andExample 16, 31,32, 33, 13


 


435




Intermediate Z,AA, AB andExample 16, 31,33


 


436




Intermediate Z,AA, AB andExample 16, 31,32, 33, 13


 


437




Intermediate Z,AA, AB andExample 16, 31,32, 33, 13


 


438




Intermediate Z,AA, AB andExample 16, 17,7, 19, 20


 


439




Intermediate Z,AA, AB andExample 16, 17,7, 19, 20


 


440




Intermediate Z,AA, AB andExample 16, 17,7, 19, 20


 


441




Intermediate Z,AA, AB andExample 16, 2,13


 


442




Intermediate Z,AA, AB andExample 16, 2and IntermediateAK


 


443




Intermediate Z,AA, AB andExample 16, 2,12


 


444




Intermediate Z,AA, AB andExample 16, 2,13


 


445




Intermediate Z,AA, AB andExample 16, 3,24, 13


 


446




Intermediate Z,AA, AB andExample 16, 2,13


 


447




Intermediate Z,AA, AB andExample 16, 22


 


448




Intermediate Z,AA, AB andExample 16, 22


 


449




Intermediate Z,AA, AB andExample 16, 3,24 andIntermediate AK


 


450




Intermediate S, T,U, W andExample 25 andIntermediate AJ


 


451




Intermediate S, T,U, W andExample 25 andIntermediate AJ


 


452




Intermediate S, T,U, W andExample 25, 26


 


453




Intermediate S, T,U, W andExample 25, 26


 


454




Intermediate S, T,U, W andExample 25 andIntermediate AJ


 


455




Intermediate S, T,U, W andExample 15 andIntermediate ALand Example 3


 


456




Intermediate S, T,U, W andExample 15 andIntermediate ALand Example 3


 


457




Intermediate S, T,U, W andExample 15 andIntermediate ALand Example 3


 


458




Intermediate Y,S, T, U, W andExample 15, 31,32, 33, 19, 20


 


459




Intermediate Y,S, T, U, W andExample 15, 31,33


 


460




Intermediate Y,S, T, U, W andExample 15, 31,32, 33, 19, 20


 


461




Intermediate Y,S, T, U, W andExample 15, 17,7, 19, 20


 


462




Intermediate Y,S, T, U, W andExample 15, 17,7, 19, 20


 


463




Intermediate Y,S, T, U, W andExample 15, 17,7, 19, 20


 


464




Intermediate Y,S, T, U, W andExample 15, 17,25


 


465




Intermediate Y,S, T, U, W andExample 15, 17,25 andIntermediate AJ


 


466




Intermediate Y,S, T, U, W andExample 15, 17,25, 26


 


467




Intermediate Y,S, T, U, W andExample 15, 3


 


468




Intermediate Y,S, T, U, W andExample 15, 3


 


469




Intermediate Y,S, T, U, W andExample 15, 3


 


470




Intermediate Y,S, T, U, W andExample 15, 3


 


471




Intermediate Y,S, T, U, W andExample 15, 3


 


472




Intermediate Y,S, T, U, W andExample 15, 3,13


 


473




Intermediate Y,S, T, U, W andExample 15, 3and IntermediateAK


 


474




Intermediate Y,S, T, U, W andExample 15, 3,12


 


475




Intermediate Y,S, T, U, W andExample 15, 3


 


476




Intermediate Y,S, T, U, W andExample 15, 3


 


477




Intermediate Y,S, T, U, W andExample 15, 3


 


478




Intermediate Y,S, T, U, W andExample 15, 3,24


 


479




Intermediate Y,S, T, U, W andExample 15, 3


 


480




Intermediate Y,S, T, U, W andExample 15, 3


 


481




Intermediate Y,S, T, U, W andExample 15, 3


 


482




Intermediate Y,S, T, U, W andExample 15, 3


 


483




Intermediate Y,S, T, U, W andExample 15, 3


 


484




Intermediate Y,S, T, U, W andExample 15, 3


 


485




Intermediate Y,S, T, U, W andExample 15, 3, 7


 


486




Intermediate Y,S, T, U, W andExample 15, 3,18


 


487




Intermediate Y,S, T, U, W andExample 15, 3, 7,13


 


488




Intermediate Y,S, T, U, W andExample 15, 3, 7,13


 


489




Intermediate Y,S, T, U, W andExample 15, 3, 7,13


 


490




Intermediate Y,S, T, U, W andExample 15, 3,13


 


491




Intermediate Y,S, T, U, W andExample 15, 3,12


 


492




Intermediate Y,S, T, U, W andExample 15, 3,24 andIntermediate AK


 


493




Intermediate Y,S, T, U, W andExample 15, 34


 


494




Intermediate Y,S, T, U, W andExample 15, 34


 


495




Intermediate Y,S, T, U, W andExample 15, 34,21


 


496




Intermediate Y,S, T, U, W andExample 15, 34,21


 


497




Intermediate Y,S, T, U, W andExample 15, 34


 


498




Intermediate S, T,U, W andExample 15


 


499




Intermediate Y,S, T, U, W andExample 15, 31,32, 33, 13


 


500




Intermediate Y,S, T, U, W andExample 15, 31,32, 33, 13


 


501




Intermediate Y,S, T, U, W andExample 15, 31,32, 33, 13


 


502




Intermediate F,G, H, I, J andExample 17, 25and IntermediateAJ


 


503




Intermediate F,G, H, I, J andExample 17, 25and IntermediateAJ


 


504




Intermediate F,G, H, I, J andExample 17, 25and IntermediateAJ


 


505




Intermediate F,G, H, I, J andExample 8


 


506




Intermediate F,G, H, I, J andExample 8


 


507




Intermediate F,G, H, I, J andExample 8


 


508




Intermediate F,G, H, I, J andExample 9


 


509




Intermediate F,G, H, I, J andExample 9


 


510




Intermediate F,G, H, I, J andExample 9


 


511




Intermediate F,G, H, I, J andExample 9


 


512




Intermediate F,G, H, I, J andExample 6, 21


 


513




Intermediate F,G, H, I, J andExample 6


 


514




Intermediate F,G, H, I, J andExample 6


 


515




Intermediate F,G, H, I, J andExample 9


 


516




Intermediate F,G, H, I, J andExample 8 andIntermediate AK


 


517




Intermediate F,G, H, I, J andExample 8 andIntermediate AK


 


518




Intermediate F,G, H, I, J andExample 31, 33


 


519




Intermediate F,G, H, I, J andExample 31, 33


 


520




Intermediate F,G, H, I, J andExample 31, 32,33, 13


 


521




Intermediate F,G, H, I, J andExample 31, 32,33, 13


 


522




Intermediate F,G, H, I, J andExample 31, 32,33, 13


 


523




Intermediate F,G, H, I, J andExample 31, 32,33, 13


 


524




Intermediate F,G, H, I, J andExample 31, 33


 


525




Intermediate F,G, H, I, J andExample 3, 24,13


 


526




Intermediate F,G, H, I, J andExample 3, 24,13


 


527




Intermediate F,G, H, I, J andExample 3, 24and IntermediateAK


 


528




Intermediate F,G, H, I, J andExample 3, 24and IntermediateAK


 


529




Intermediate F,G, H, I, J andExample 9, 7


 


530




Intermediate F,G, H, I, J andExample 9


 


531




Intermediate F,G, H, I, J andExample 9, 7, 13


 


532




Intermediate F,G, H, I, J andExample 9, 7, 13


 


533




Intermediate F,G, H, I, J andExample 9, 7, 13









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.








TABLE 1C





Example
Structure
















534






 


535






 


536






 


537






 


538






 


539






 


540






 


541






 


542






 


543






 


544






 


545






 


546






 


547






 


548






 


549






 


550






 


551






 


552






 


553






 


554






 


555






 


556






 


557






 


558






 


559






 


560






 


561






 


562






 


563






 


564






 


565






 


566






 


567






 


568






 


569






 


570






 


571






 


572






 


573






 


574






 


575






 


576






 


577






 


578






 


579






 


580






 


581













Utilizing the above described procedures for intermediates and examples alone or in combination, a variety of Formula II compounds were prepared using the appropriate starting material and the representative procedure described. These results are summarized in Table 2A.











TABLE 2A







LCMS RT

Representative


Example
Structure
(min)
[M + H]
Procedure



















582




2.39
372.3
IntermediateBA, BB, BCand Example39, 48


 


583




2.05
401.2
IntermediateBA, BB, BCand Example39, 46, 45


 


584




1.93
401.3
IntermediateBA, BB, BCand Example39, 43


 


585




2.04
418.3
IntermediateBA, BB, BCand Example39, 42


 


586




2.25
358.4
IntermediateBA, BB, BCand Example39, 48


 


587




2.89
412.1
IntermediateBA, BB, BCand Example39, 48


 


588




1.89
415.3
IntermediateBA, BB, BCand Example39, 48


 


589




2.57
398.3
IntermediateBA, BB, BCand Example39, 48


 


590




1.92
457.2
IntermediateBA, BB, BCand Example39, 48


 


591




2.41
408.4
IntermediateBA, BB, BCand Example39, 48


 


592




2.52
386.1
IntermediateBA, BB, BCand Example39, 48


 


593




2.46
402.2
IntermediateBA, BB, BCand Example39, 48


 


594




2.12
441.1
IntermediateBA, BB, BCand Example39, 48


 


595




1.79
371.9
IntermediateBA, BB, BCand Example39, 49, 47


 


596




2.36
398.3
IntermediateBA, BB, BCand Example39


 


597




2.57
390.4
IntermediateBA, BB, BCand Example39


 


598




3.28
400.2
IntermediateBA, BB, BCand Example39, 48


 


599




2.56
422.0
IntermediateBA, BB, BCand Example39, 48


 


600




2.74
414.1
IntermediateBA, BB, BCand Example39, 48


 


601




2.43
398.4
IntermediateBA, BB, BCand Example39


 


602




2.57
422.1
IntermediateBA, BB, BCand Example39, 48


 


603




2.45
408.2
IntermediateBA, BB, BCand Example39, 48


 


604




2.02
396.3
IntermediateBA, BB, BCand Example39, 42


 


605




2.15
410.3
IntermediateBA, BB, BCand Example39, 42


 


606




1.96
383.3
IntermediateBA, BB, BCand Example39, 43


 


607




2.20
484.3
IntermediateBA, BB, BCand Example39, 43


 


608




2.19
411.3
IntermediateBA, BB, BCand Example39, 43


 


609




2.33
419.4
IntermediateBA, BB, BCand Example39, 43


 


610




1.86
454.3
IntermediateBA, BB, BCand Example39, 43


 


611




1.22
483.2
IntermediateBA, BB, BCand Example39, 43


 


612




2.11
411.4
IntermediateBA, BB, BCand Example39, 43


 


613




1.55
426.0
IntermediateBA, BB, BCand Example39, 43


 


614




1.98
413.0
IntermediateBA, BB, BCand Example39, 43


 


615




1.88
370.3
IntermediateBA, BB, BCand Example39, 42


 


616




1.73
356.3
IntermediateBA, BB, BCand Example39, 42


 


617




2.53
488.3
IntermediateBA, BB, BCand Example39, 43


 


618




2.30
427.3
IntermediateBA, BB, BCand Example39, 43


 


619




1.68
405.4
IntermediateBA, BB, BCand Example39, 55


 


620




2.25
449.2
IntermediateBA, BB, BCand Example39, 55


 


621




2.00
418.5
IntermediateBA, BB, BCand Example39, 55


 


622




2.19
438.3
IntermediateBA, BB, BCand Example39, 55









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.









TABLE 2B







Representative


Example
Stucture
Procedure

















623




IntermediateBA1, BB1,BC1 andExample 40,49, 47


 


624




IntermediateBA1, BB1,BC1 andExample 40,31, 32


 


625




IntermediateBA1, BB1,BC1 andExample 40,43


 


626




IntermediateBA1, BB1,BC1 andExample 40,43 andIntermediateAK


 


627




IntermediateBA1, BB1,BC1 andExample 40,43 andIntermediateAK


 


628




IntermediateBA1, BB1,BC1 andExample 40,17, 25 andIntermediateAJ


 


629




IntermediateBA1, BB1,BC1 andExample 40,31, 33


 


630




IntermediateBA1, BB1,BC1 andExample 40,31, 33


 


631




IntermediateBA1, BB1,BC1 andExample 40,31, 32, 33, 47


 


632




IntermediateBA1, BB1,BC1 andExample 40,31, 32, 33, 47


 


633




IntermediateBA1, BB1,BC1 andExample 40,31, 32, 33, 47


 


634




IntermediateBA1, BB1,BC1 andExample 40,31, 32, 33, 47


 


635




IntermediateBA1, BB1,BC1 andExample 40,31, 33


 


636




IntermediateBA1, BB1,BC1 andExample 40,17, 25 andIntermediateAJ


 


637




IntermediateBA1, BB1,BC1 andExample 40,17, 25 andIntermediateAJ


 


638




IntermediateBA1, BB1,BC1 andExample 40,48


 


639




IntermediateBA1, BB1,BC1 andExample 40,48


 


640




IntermediateBA1, BB1,BC1 andExample 40,48


 


641




IntermediateBA1, BB1,BC1 andExample 40,48


 


642




IntermediateBA1, BB1,BC1 andExample 40,44, 21


 


643




IntermediateBA1, BB1,BC1 andExample 40,44


 


644




IntermediateBA1, BB1,BC1 andExample 40,44


 


645




IntermediateBA1, BB1,BC1 andExample 40,43


 


646




IntermediateBA1, BB1,BC1 andExample 40,49, 47


 


647




IntermediateBA1, BB1,BC1 andExample 40,43


 


648




IntermediateBA, BB, BCand Example39, 17, 25, 26


 


649




IntermediateBA, BB, BCand Example39, 31, 32, 33


 


650




IntermediateBA1, BB1,BC1 andExample 40,43


 


651




IntermediateBA1, BB1,BC1 andExample 40,43


 


652




IntermediateBA2, BB2,BC2 andExample 40,31, 32


 


653




IntermediateBA1, BB1,BC1 andExample 40,43


 


654




IntermediateBA1, BB1,BC1 andExample 40,49, 47


 


655




IntermediateBA1, BB1,BC1 andExample 40,49, 50, 51


 


656




IntermediateBA1, BB1,BC1 andExample 40,44


 


657




IntermediateBA1, BB1,BC1 andExample 40,43


 


658




IntermediateBA1, BB1,BC1 andExample 40,49, 50, 51


 


659




IntermediateBA1, BB1,BC1 andExample 40,43


 


660




IntermediateBA1, BB1,BC1 andExample 40,44


 


661




IntermediateBA1, BB1,BC1 andExample 40,49, 47


 


662




IntermediateBA1, BB1,BC1 andExample 40,44, 21


 


663




IntermediateBA, BB, BCand Example39, 31


 


664




IntermediateBA1, BB1,BC1 andExample 40,43


 


665




IntermediateBA, BB, BCand Example39, 17, 25, 26


 


666




IntermediateBA1, BB1,BC1 andExample 40,44, 21


 


667




IntermediateBA1, BB1,BC1 andExample 40,49, 50, 51


 


668




IntermediateBA1, BB1,BC1 andExample 40,43, 12


 


669




IntermediateBA1, BB1,BC1 andExample 40,3


 


670




IntermediateBA, BB, BCand Example39, 3


 


671




IntermediateBA1, BB1,BC1 andExample 40,55


 


672




IntermediateBA1, BB1,BC1 andExample 40,44, 21


 


673




IntermediateBA1, BB1,BC1 andExample 40,43, 12


 


674




IntermediateBA1, BB1,BC1 andExample 40,31


 


675




IntermediateBA1, BB1,BC1 andExample 40,49, 50, 51


 


676




IntermediateBA, BB, BCand Example39, 17, 25, 26


 


677




IntermediateBA, BB, BCand Example39, 54 andIntermediateAL


 


678




IntermediateBA1, BB1,BC1 andExample 40,3


 


679




IntermediateBA1, BB1,BC1 andExample 40,43, 12


 


680




IntermediateBA1, BB1,BC1 andExample 40,48


 


681




IntermediateBA1, BB1,BC1 andExample 40,49, 50, 51


 


682




IntermediateBA, BB, BCand Example39, 43, 12


 


683




IntermediateBA, BB, BCand Example39, 54 andIntermediateAJ


 


684




IntermediateBA1, BB1,BC1 andExample 40,3


 


685




IntermediateBA, BB, BCand Example39, 3, 24


 


686




IntermediateBA1, BB1,BC1 andExample 40,17


 


687




IntermediateBA1, BB1,BC1 andExample 40,49, 47


 


688




IntermediateBA2, BB2,BC2 andExample 40,31, 32, 33


 


689




IntermediateBA1, BB1,BC1 andExample 40,22


 


690




IntermediateBA1, BB1,BC1 andExample 40,3


 


691




IntermediateBA2, BB2,BC2 andExample 41,55


 


692




IntermediateBA1, BB1,BC1 andExample 40,44, 21


 


693




IntermediateBA1, BB1,BC1 andExample 40,17, 25, 26


 


694




IntermediateBA1, BB1,BC1 andExample 40,17, 25, 23


 


695




IntermediateBA1, BB1,BC1 andExample 40,17, 18


 


696




IntermediateBA1, BB1,BC1 andExample 40,3, 24


 


697




IntermediateBA, BB, BCand Example39, 17, 25


 


698




IntermediateBA, BB, BCand Example39, 17, 25, 26


 


699




IntermediateBA2, BB2,BC2 andExample 41,55


 


700




IntermediateBA1, BB1,BC1 andExample 40,49, 50


 


701




IntermediateBA, BB, BCand Example39 54, andIntermediateAK


 


702




IntermediateBA1, BB1,BC1 andExample 40,3


 


703




IntermediateBA1, BB1,BC1 andExample 40,49, 50, 51


 


704




IntermediateBA2, BB2,BC2 andExample 41,34


 


705




IntermediateBA2, BB2,BC2 andExample 41,3


 


706




IntermediateBA1, BB1,BC1 andExample 40,17, 25, 26


 


707




IntermediateBA1, BB1,BC1 andExample 40,44


 


708




IntermediateBA1, BB1,BC1 andExample 40,43, 47


 


709




IntermediateBA, BB, BCand Example39, 17, 25, 26


 


710




IntermediateBA1, BB1,BC1 andExample 40,48


 


711




IntermediateBA2, BB2,BC2 andExample 41,31


 


712




IntermediateBA1, BB1,BC1 andExample 40,3


 


713




IntermediateBA, BB, BCand Example39 54 andIntermediateAK


 


714




IntermediateBA2, BB2,BC2 andExample 41,34


 


715




IntermediateBA1, BB1,BC1 andExample 40,3


 


716




IntermediateBA1, BB1,BC1 andExample 40,17, 25, 26


 


717




IntermediateBA1, BB1,BC1 andExample 40,48


 


718




IntermediateBA1, BB1,BC1 andExample 40,49, 50, 51


 


719




IntermediateBA2, BB2,BC2 andExample 41, 3


 


720




IntermediateBA2, BB2,BC2 andExample 41,34


 


721




IntermediateBA1, BB1,BC1 andExample 40,55


 


722




IntermediateBA1, BB1,BC1 andExample 40,44, 45


 


723




IntermediateBA1, BB1,BC1 andExample 40,3


 


724




IntermediateBA1, BB1,BC1 andExample 40,43, 47


 


725




IntermediateBA, BB, BCand Example39, 54 andIntermediateAK


 


726




IntermediateBA1, BB1,BC1 andExample 40,17, 25, 26


 


727




IntermediateBA1, BB1,BC1 andExample 40,3


 


728




IntermediateBA2, BB2,BC2 andExample 41,34


 


729




IntermediateBA2, BB2,BC2 andExample 41, 3


 


730




IntermediateBA1, BB1,BC1 andExample 40,55


 


731




IntermediateBA1, BB1,BC1 andExample 40,3


 


732




IntermediateBA1, BB1,BC1 andExample 40,48


 


733




IntermediateBA1, BB1,BC1 andExample 40,3


 


734




IntermediateBA, BB, BCand Example39, 31, 32


 


735




IntermediateBA1, BB1,BC1 andExample 40,3


 


736




IntermediateBA1, BB1,BC1 andExample 40,3


 


737




IntermediateBA1, BB1,BC1 andExample 40,31, 32, 33


 


738




IntermediateBA1, BB1,BC1 andExample 40,3


 


739




IntermediateBA, BB, BCand Example39, 49, 50, 51,25


 


740




IntermediateBA, BB, BCand Example39, 17, 25, 11


 


741




IntermediateBA, BB, BCand Example39, 17, 25, 11


 


742




IntermediateBA1, BB1,BC1 andExample 40,42


 


743




IntermediateBA1, BB1,BC1 andExample 40,42


 


744




IntermediateBA1, BB1,BC1 andExample 40,42


 


745




IntermediateBA1, BB1,BC1 andExample 40,42


 


746




IntermediateBA1, BB1,BC1 andExample 40,17, 25


 


747




IntermediateBA1, BB1,BC1 andExample 40,49, 50, 51, 25


 


748




IntermediateBA1, BB1,BC1 andExample 40,49, 50, 51, 25


 


749




IntermediateBA1, BB1,BC1 andExample 40,49, 50, 51, 25


 


750




IntermediateBA1, BB1,BC1 andExample 40,17, 25, 26


 


751




IntermediateBA1, BB1,BC1 andExample 40,55


 


752




IntermediateBA1, BB1,BC1 andExample 40,55


 


753




IntermediateBA1, BB1,BC1 andExample 40,55


 


754




IntermediateBA1, BB1,BC1 andExample 40,49, 50, 51


 


755




IntermediateBA1, BB1,BC1 andExample 40,49, 50, 51


 


756




IntermediateBA1, BB1,BC1 andExample 40,49


 


757




IntermediateBA1, BB1,BC1 andExample 40,43


 


758




IntermediateBA1, BB1,BC1 andExample 40,43


 


759




IntermediateBA1, BB1,BC1 andExample 40,43


 


760




IntermediateBA1, BB1,BC1 andExample 40,43


 


761




IntermediateBA1, BB1,BC1 andExample 40,43


 


762




IntermediateBA1, BB1,BC1 andExample 40,43


 


763




IntermediateBA1, BB1,BC1 andExample 40,43, 47


 


764




IntermediateBA1, BB1,BC1 andExample 40,43, 12


 


765




IntermediateBA1, BB1,BC1 andExample 40,43, 12


 


766




IntermediateBA1, BB1,BC1 andExample 40,43


 


767




IntermediateBA1, BB1,BC1 andExample 40,43


 


768




IntermediateBA1, BB1,BC1 andExample 40,3


 


769




IntermediateBA1, BB1,BC1 andExample 40,43


 


770




IntermediateBA1, BB1,BC1 andExample 40,22


 


771




IntermediateBA1, BB1,BC1 andExample 40,46, 45


 


772




IntermediateBA1, BB1,BC1 andExample 40,46


 


773




IntermediateBA1, BB1,BC1 andExample 40,46, 45, 47


 


774




IntermediateBA1, BB1,BC1 andExample 40,46, 45, 47


 


775




IntermediateBA1, BB1,BC1 andExample 40,46, 45, 47


 


776




IntermediateBA1, BB1,BC1 andExample 40,44, 45, 47


 


777




IntermediateBA1, BB1,BC1 andExample 40,44, 45, 47


 


778




IntermediateBA1, BB1,BC1 andExample 40,44, 45, 47


 


779




IntermediateBA1, BB1,BC1 andExample 40,48, 45


 


780




IntermediateBA1, BB1,BC1 andExample 40,48


 


781




IntermediateBA1, BB1,BC1 andExample 40,48, 45, 47


 


782




IntermediateBA1, BB1,BC1 andExample 40,48, 45, 47


 


783




IntermediateBA1, BB1,BC1 andExample 40,44


 


784




IntermediateBA1, BB1,BC1 andExample 40,44, 21


 


785




IntermediateBA1, BB1,BC1 andExample 40,48


 


786




IntermediateBA1, BB1,BC1 andExample 40,48


 


787




IntermediateBA1, BB1,BC1 andExample 40,48


 


788




IntermediateBA1, BB1,BC1 andExample 40,48


 


789




IntermediateBA1, BB1,BC1 andExample 40,48


 


790




IntermediateBA, BB, BCand Example39, 48


 


791




IntermediateBA, BB, BCand Example39, 48


 


792




IntermediateBA, BB, BCand Example39, 48


 


793




IntermediateBA, BB, BCand Example39, 48


 


794




IntermediateBA, BB, BCand Example39, 48


 


795




IntermediateBA, BB, BCand Example39, 48


 


796




IntermediateBA, BB, BCand Example39, 48


 


797




IntermediateBA, BB, BCand Example39, 48


 


798




IntermediateBA, BB, BCand Example39, 48


 


799




IntermediateBA, BB, BCand Example39, 48


 


800




IntermediateBA, BB, BCand Example39, 48


 


801




IntermediateBA, BB, BCand Example39, 48


 


802




IntermediateBA, BB, BCand Example39, 48


 


803




IntermediateBA, BB, BCand Example39, 48


 


804




IntermediateBA, BB, BCand Example39, 48


 


805




IntermediateBA, BB, BCand Example39, 48


 


806




IntermediateBA, BB, BCand Example39, 48


 


807




IntermediateBA, BB, BCand Example39, 48


 


808




IntermediateBA, BB, BCand Example39, 48


 


809




IntermediateBA, BB, BCand Example39, 48


 


810




IntermediateBA, BB, BCand Example39, 48


 


811




IntermediateBA, BB, BCand Example39, 54, 47


 


812




IntermediateBA, BB, BCand Example39, 54 andIntermediateAJ


 


813




IntermediateBA, BB, BCand Example39, 54 andIntermediateAK


 


814




IntermediateBA, BB, BCand Example39, 54, 12


 


815




IntermediateBA, BB, BCand Example39, 54, 12


 


816




IntermediateBA, BB, BCand Example39, 54, 12


 


817




IntermediateBA, BB, BCand Example39, 54, 12


 


818




IntermediateBA, BB, BCand Example39, 54, 12


 


819




IntermediateBA, BB, BCand Example39, 54 andIntermediateAL andExample 42


 


820




IntermediateBA, BB, BCand Example39, 54 andIntermediateAL


 


821




IntermediateBA, BB, BCand Example39, 54 andIntermediateAL andExample 17,25


 


822




IntermediateBA, BB, BCand Example39, 54 andIntermediateAL andexample 55


 


823




IntermediateBA, BB, BCand Example39, 54 andIntermediateAL andExample 55


 


824




IntermediateBA, BB, BCand Example39, 54 andIntermediateAL andExample 17,25 andIntermediateAJ


 


825




IntermediateBA, BB, BCand Example39, 54 andIntermediateAL andExample 17,25 andIntermediateAJ


 


826




IntermediateBA, BB, BCand Example39, 54 andIntermediateAL andExample 17,25, 26


 


827




IntermediateBA, BB, BCand Example39, 54 andIntermediateAL andExample 17,25, 26


 


828




IntermediateBA, BB, BCand Example39, 54 andIntermediateAL andExample 3


 


829




IntermediateBA, BB, BCand Example39, 54 andIntermediateAL andExample 3


 


830




IntermediateBA, BB, BCand Example39, 54 andIntermediateAL andExample 3


 


831




IntermediateBA, BB, BCand Example39, 43


 


832




IntermediateBA, BB, BCand Example39, 43


 


833




IntermediateBA, BB, BCand Example39, 46, 45, 47


 


834




IntermediateBA, BB, BCand Example39, 46, 45, 47


 


835




IntermediateBA, BB, BCand Example39, 44, 45, 47


 


836




IntermediateBA, BB, BCand Example39, 44, 45, 47


 


837




IntermediateBA, BB, BCand Example39, 48, 45, 47


 


838




IntermediateBA, BB, BCand Example39, 48, 45, 47


 


839




IntermediateBA, BB, BCand Example39, 49, 47


 


840




IntermediateBA, BB, BCand Example39, 49, 47


 


841




IntermediateBA, BB, BCand Example39, 49, 47


 


842




IntermediateBA, BB, BCand Example39, 49, 47


 


843




IntermediateBA, BB, BCand Example39, 17


 


844




IntermediateBA, BB, BCand Example39, 44


 


845




IntermediateBA, BB, BCand Example39, 44


 


846




IntermediateBA, BB, BCand Example39, 44


 


847




IntermediateBA, BB, BCand Example39, 44


 


848




IntermediateBA, BB, BCand Example39, 44, 21


 


849




IntermediateBA, BB, BCand Example39, 44, 21


 


850




IntermediateBA, BB, BCand Example39, 48


 


851




IntermediateBA, BB, BCand Example39, 48


 


852




IntermediateBA, BB, BCand Example39, 49, 50,51, 25 andIntermediateAJ


 


853




IntermediateBA, BB, BCand Example39, 49, 50,51, 25 andIntermediateAJ


 


854




IntermediateBA, BB, BCand Example39, 49, 50,51, 25, 26


 


855




IntermediateBA, BB, BCand Example39, 49, 50,51, 25, 26


 


856




IntermediateBA, BB, BCand Example39, 31, 33


 


857




IntermediateBA, BB, BCand Example39, 31, 33


 


858




IntermediateBA, BB, BCand Example39, 31, 32,33, 47


 


859




IntermediateBA, BB, BCand Example39, 31, 32,33, 47


 


860




IntermediateBA, BB, BCand Example39, 31, 33


 


861




IntermediateBA, BB, BCand Example39, 31, 32,33, 47


 


862




IntermediateBA, BB, BCand Example39, 31, 32,33, 47


 


863




IntermediateBA, BB, BCand Example39, 49, 50, 51


 


864




IntermediateBA, BB, BCand Example39, 49, 50, 51


 


865




IntermediateBA, BB, BCand Example39, 49, 50, 51


 


866




IntermediateBA, BB, BCand Example39, 43, 47


 


867




IntermediateBA, BB, BCand Example39, 43 andIntermediateAK


 


868




IntermediateBA, BB, BCand Example39, 3


 


869




IntermediateBA, BB, BCand Example39, 43, 47


 


870




IntermediateBA, BB, BCand Example39, 43, 47


 


871




IntermediateBA, BB, BCand Example39, 22


 


872




IntermediateBA, BB, BCand Example39, 3, 24, 12


 


873




IntermediateBA, BB, BCand Example39, 3, 24 andIntermediateAK


 


874




IntermediateBA2, BB2,BC2 andExample 41,34


 


875




IntermediateBA2, BB2,BC2 andExample 41,34


 


876




IntermediateBA2, BB2,BC2 andExample 41,34


 


877




IntermediateBA2, BB2,BC2 andExample 41,34


 


878




IntermediateBA2, BB2,BC2 andExample 41,34


 


879




IntermediateBA2, BB2,BC2 andExample 41,31, 33


 


880




IntermediateBA2, BB2,BC2 andExample 41,31, 33


 


881




IntermediateBA2, BB2,BC2 andExample 41,31, 32, 33, 47


 


882




IntermediateBA2, BB2,BC2 andExample 41,31, 32, 33, 47


 


883




IntermediateBA2, BB2,BC2 andExample 41,31, 32, 33, 47


 


884




IntermediateBA2, BB2,BC2 andExample 41,31, 32, 33, 47


 


885




IntermediateBA2, BB2,BC2 andExample 41,31, 32, 33, 47


 


886




IntermediateBA2, BB2,BC2 andExample 41,31, 33


 


887




IntermediateBA2, BB2,BC2 andExample 41,55


 


888




IntermediateBA2, BB2,BC2 andExample 41,55


 


889




IntermediateBA2, BB2,BC2 andExample 41,55


 


890




IntermediateBA2, BB2,BC2 andExample 41,49


 


891




IntermediateBA2, BB2,BC2 andExample 41,34


 


892




IntermediateBA2, BB2,BC2 andExample 41,17


 


893




IntermediateBA2, BB2,BC2 andExample 41,49, 47


 


894




IntermediateBA2, BB2,BC2 andExample 41,49, 47


 


895




IntermediateBA2, BB2,BC2 andExample 41,49, 47


 


896




IntermediateBA2, BB2,BC2 andExample 41,49, 47


 


897




IntermediateBA2, BB2,BC2 andExample 41,49, 47


 


898




IntermediateBA2, BB2,BC2 andExample 41,34


 


899




IntermediateBA2, BB2,BC2 andExample 41,34


 


900




IntermediateBA2, BB2,BC2 andExample 41,34, 21


 


901




IntermediateBA2, BB2,BC2 andExample 41,34, 21


 


902




IntermediateBA2, BB2,BC2 andExample 41,31, 32, 33,50, 51


 


903




IntermediateBA2, BB2,BC2 andExample 41,31, 33


 


904




IntermediateBA2, BB2,BC2 andExample 41,31, 32, 33,50, 51


 


905




IntermediateBA2, BB2,BC2 andExample 41,49, 50, 51


 


906




IntermediateBA2, BB2,BC2 andExample 41,49, 50, 51


 


907




IntermediateBA2, BB2,BC2 andExample 41,49, 50, 51


 


908




IntermediateBA2, BB2,BC2 andExample 41,31, 33, 25


 


909




IntermediateBA2, BB2,BC2 andExample 41,31, 33, 25 andIntermediateAJ


 


910




IntermediateBA2, BB2,BC2 andExample 41,17, 25, 26


 


911




IntermediateBA2, BB2,BC2 andExample 41,17, 25


 


912




IntermediateBA2, BB2,BC2 andExample 41,17, 25 andIntermediateAJ


 


913




IntermediateBA2, BB2,BC2 andExample 41,3


 


914




IntermediateBA2, BB2,BC2 andExample 41,3


 


915




IntermediateBA2, BB2,BC2 andExample 41,3


 


916




IntermediateBA2, BB2,BC2 andExample 41,3


 


917




IntermediateBA2, BB2,BC2 andExample 41,3


 


918




IntermediateBA2, BB2,BC2 andExample 41,3


 


919




IntermediateBA2, BB2,BC2 andExample 41,3 andIntermediateAK


 


920




IntermediateBA2, BB2,BC2 andExample 41,3, 12


 


921




IntermediateBA2, BB2,BC2 andExample 41,3


 


922




IntermediateBA2, BB2,BC2 andExample 41,3


 


923




IntermediateBA2, BB2,BC2 andExample 41,3


 


924




IntermediateBA2, BB2,BC2 andExample 41,3, 24


 


925




IntermediateBA2, BB2,BC2 andExample 41,3


 


926




IntermediateBA2, BB2,BC2 andExample 41,3


 


927




IntermediateBA2, BB2,BC2 andExample 41,3


 


928




IntermediateBA2, BB2,BC2 andExample 4l,3


 


929




IntermediateBA2, BB2,BC2 andExample 41,3, 45


 


930




IntermediateBA2, BB2,BC2 andExample 41,3, 18


 


931




IntermediateBA2, BB2,BC2 andExample 41,3, 45, 47


 


932




IntermediateBA2, BB2,BC2 andExample 41,3, 45, 47


 


933




IntermediateBA2, BB2,BC2 andExample 41,3, 24, 47


 


934




IntermediateBA2, BB2,BC2 andExample 41,3, 47


 


935




IntermediateBA2, BB2,BC2 andExample 41,3, 12


 


936




IntermediateBA2, BB2,BC2 andExample 41,3, 24 andIntermediateAK









Utilizing the above described procedures for intermediates and examples, and Flow Diagrams I–XIV alone or in combination, a variety of Formula II compounds can be prepared using the appropriate starting material. These compounds are summarized in Table 2C.









TABLE 2C





Ex-



am-


ple
Structure







937






 


938






 


939






 


940






 


941






 


942






 


943






 


944






 


945






 


946






 


947






 


948






 


949






 


950






 


951






 


952






 


953






 


954






 


955






 


956






 


957






 


958






 


959






 


960






 


961






 


962






 


963






 


964






 


965






 


966






 


967






 


968






 


969






 


970






 


971






 


972






 


973






 


974






 


975






 


976






 


977






 


978






 


979






 


980






 


981






 


982






 


983






 


984






 


985






 


986






 


987






 


988






 


989






 


990






 


991






 


992






 


993






 


994






 


995






 


996






 


997






 


998






 


999






 


1000






 


1001






 


1002






 


1003






 


1004













Biological Evaluation

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.
In vivo Test Procedure:
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 blood glucose lowering effect in this in vivo assay.
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 I



wherein
R1 is selected from alkyl of 1–8 carbon atoms, alkenyl of 2–8 carbon atoms, alkynyl of 2–8 carbon atoms, and A-R9, or
R1 is selected from aryl of 6–10 carbon atoms, cycloalkyl of 3–8 carbon atoms, and cycloalkenyl of 4–8 carbon atoms, all of which may be substituted with 1–3 of R10;
R10 is selected from nitro, nitrile, hydroxy, halogen, acyl of 1–6 carbon atoms, alkyl of 1–6 carbon atoms, alkenyl of 2–6 carbon atoms, alkynyl of 2–6 carbon atoms, haloalkyl of 1–6 carbon atoms, alkoxy of 1–6 carbon atoms, haloalkoxy of 1–6 carbon atoms, cycloalkoxy of 3–6 carbon atoms, aryl of 6–10 carbon atoms, heteroaryl of 2–9 carbon atoms and 1–4 heteroatoms selected from N, S(═O)0-2 and O, 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);
R13 is selected from alkyl of 1–6 carbon atoms, alkenyl of 2–6 carbon atoms, alkynyl of 2–6 carbon atoms, haloalkyl of 1–6 carbon atoms, cycloalkyl of 3–6 carbon atoms, and cycloalkenyl of 4–6 carbon atoms;
R11 and R12 are independently selected from hydrogen, alkyl of 1–6 carbon atoms, alkenyl of 2–6 carbon atoms, alkynyl of 2–6 carbon atoms, haloalkyl of 1–6 carbon atoms, cycloalkyl of 3–6 carbon atoms, and cycloalkenyl of 4–6 carbon atoms;
A is selected from alkyl of 1–8 carbon atoms, alkenyl of 2–8 carbon atoms, alkynyl of 2–8 carbon atoms, and haloalkyl of 1–8 carbon atoms;
R9 is selected from hydroxy, alkoxy of 1–6 carbon atoms, cycloalkoxy of 3–6 carbon atoms, O-A-R14, NR11R12; or
R9 is selected from aryl of 6–10 carbon atoms, heteroaryl of 2–9 carbon atoms and 1–4 heteroatoms selected from N, S(═O)0-2 and O, cylcoalkyl of 3–8 carbon atoms, cycloalkenyl of 5–8 carbon atoms, all of which may be substituted with 1–3 of R10, or
R9 is selected from 5–7 membered heterocycloalkyl of 3–6 carbon atoms and 1–2 heteroatoms selected from N, S(═O)0-2 and O and 5–7 membered heterocycloalkenyl of 3–6 carbon atoms and 1–2 heteroatoms selected from N, S(═O)0-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5–6 membered heteroaryl of 2–5 carbon atoms and 1–3 heteroatoms selected from N, S(═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;
R14 is selected from cylcoalkyl of 3–8 carbon atoms, cycloalkenyl of 5–8 carbon atoms, 5–7 membered heterocycloalkyl of 3–6 carbon atoms and 1–2 heteroatoms selected from N, S(═O)0-2 and O, and 5–7 membered heterocycloalkenyl of 3–6 carbon atoms and 1–2 heteroatoms selected from N, S(═O)0-2 and O, all of which may be substituted with 1–3 of R10;

R2 is selected from NR15R16, S(O)0-2R17, and OR17;
R15 is selected from hydrogen, alkyl of 1–6 carbon atoms, alkenyl of 2–6 carbon atoms, alkynyl of 2–6 carbon atoms, cylcoalkyl of 3–8 carbon atoms, and cycloalkenyl of 4–8 carbon atoms,
R16 is selected from alkyl of 1–8 carbon atoms, alkenyl of 2–8 carbon atoms, alkynyl of 2–8 carbon atoms, and A-R9, or
R16 is selected from aryl of 6–10 carbon atoms, cycloalkyl of 3–8 carbon atoms, and cycloalkenyl of 4–8 carbon atoms, all of which may be substituted with 1–3 of R10, or
R17 is selected from alkyl of 1–8 carbon atoms, alkenyl of 2–8 carbon atoms, and alkynyl of 2–8 carbon atoms, haloalkyl of 1–8 carbon atoms, A-R9, or
R17 is selected from aryl of 6–10 carbon atoms, cylcoalkyl of 3–8 carbon atoms, and cycloalkenyl of 4–8 carbon atoms, all of which may be substituted with 1–3 of R10;

R3 is selected from aryl of 6–10 carbon atoms, and cylcoalkyl of 3–8 carbon atoms, all of which may be substituted with 1–3 of R10, or
R3 is selected from alkyl of 1–6 carbon atoms, alkenyl of 2–6 carbon atoms, alkynyl of 2–6 carbon atoms, haloalkyl of 1–6 carbon atoms, hydrogen, nitro, halogen, NR19R20, A-OR19, A-NR19R20, and A-R20;
R19 and R20 are independently selected from hydrogen, alkyl of 1–6 carbon atoms, alkenyl of 2–6 carbon atoms, alkynyl of 2–6 carbon atoms, haloalkyl of 1–6 carbon atoms, and A-R9, or
R19 and R20 are independently selected from aryl of 6–10 carbon atoms, heteroaryl of 2–9 carbon atoms and 1–4 heteroatoms selected from N, S(O)0-2 and O, cylcoalkyl of 3–8 carbon atoms, cycloalkenyl of 5–8 carbon atoms, 5–7 membered heterocycloalkyl of 3–6 carbon atoms and 1–2 heteroatoms selected from N, S(O)0-2 and O, 5–7 membered heterocycloalkenyl of 3–6 carbon atoms and 1–2 heteroatoms selected from N, S(O)0-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5–6 membered heteroaryl of 2–5 carbon atoms and 1–3 heteroatoms selected from N, S(═O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), all of which may be substituted with 1–3 of R10;

R4 is ═O;
R5 and R6 are independently selected from cycloalkyl of 3–8 carbon atoms, cycloalkenyl of 4–8 carbon atoms, and aryl of 6–10 carbon atoms, all of which may be substituted with 1–3 of R10, or
R5 and R6 are independently selected from hydrogen, halogen, nitrile, nitro, hydroxy, alkyl of 1–8 carbon atoms, alkenyl of 2–8 carbon atoms, alkynyl of 2–8 carbon atoms, haloalkyl of 1–8 carbon atoms, alkoxy of 1–8 carbon atoms, haloalkoxy of 1–8 carbon atoms, cycloalkoxy of 3–8 carbon atoms, A-R23, A(OR22)—R23, NR27R28, A-NR27R28, A-Q—R29, Q—R29, Q-A-NR24R25, C(═O)R24, C(═O)OR24, C(═O)NR24R25, A-C(═O)R24, A-C(═O)OR24, and A-C(═O)NR24R25;
Q is selected from O and S(═O)0-2;
R22 is selected from hydrogen, alkyl of 1–8 carbon atoms, haloalkyl of 1–8 carbon atoms, and cycloalkyl of 3–8 carbon atoms;
R23 is selected from hydroxy, alkoxy of 1–8 carbon atoms, haloalkoxy of 1–8 carbon atoms, and cycloalkoxy of 3–8 carbon atoms, or
R23 is selected from cycloalkyl of 3–8 carbon atoms, cycloalkenyl of 4–8 carbon atoms, aryl of 6–10 carbon atoms, and heteroaryl of 2–9 carbon atoms and 1–4 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1–3 of R10, or
R23 is selected from 5–7 membered heterocycloalkyl of 3–6 carbon atoms and 1–2 heteroatoms selected from N, O, S(═O)0-2, and 5–7 membered heterocycloalkenyl of 3–6 carbon atoms and 1–2 heteroatoms selected from N, O, S(═O)0-2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5–6 membered heteroaryl of 2–5 carbon atoms and 1–3 heteroatoms selected from N, S(═O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═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 1–8 carbon atoms, haloalkoxy of 1–8 carbon atoms, and cycloalkoxy of 3–8 carbon atoms, A is not CH;
R24 and R25 are independently selected from hydrogen, alkyl of 1–6 carbon atoms, alkenyl of 2–6 carbon atoms, alkynyl of 2–6 carbon atoms, haloalkyl of 1–6 carbon atoms, and A-R23, or
R24 and R25 are independently selected from cycloalkyl of 3–6 carbon atoms, cycloalkenyl of 3–6 carbon atoms, aryl of 6–10 carbon atoms, and heteroaryl of 2–9 carbon atoms and 1–4 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1—3 of R10, or
R24 and R25 are independently selected from 5–7 membered heterocycloalkyl of 3–6 carbon atoms and 1–2 heteroatoms selected from N, O, S(═O)0-2, and 5–7 membered heterocycloalkenyl of 3–6 carbon atoms and 1–2 heteroatoms selected from N, O, S(═O)0-2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5–6 membered heteroaryl of 2–5 carbon atoms and 1–3 heteroatoms selected from N, S(═O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═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 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;
R26 is selected from alkyl of 1–6 carbon atoms, alkenyl of 2–6 carbon atoms, alkynyl of 2–6 carbon atoms, haloalkyl of 1–6 carbon atoms, A(OR22)—R23, and A-R23, or
R26 is selected from cycloalkyl of 3–6 carbon atoms, cycloalkenyl of 3–6 carbon atoms, aryl of 6–10 carbon atoms, and heteroaryl of 2–9 carbon atoms and 1–4 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1–3 of R10, or
R26 is selected from 5–7 membered heterocycloalkyl of 3–6 carbon atoms and 1–2 heteroatoms selected from N, O, S(═O)0-2, and 5–7 membered heterocycloalkenyl of 3–6 carbon atoms and 1–2 heteroatoms selected from N, O, S(═O)0-2, wherein said heterocycloalkyl and said 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), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1–3 of R10;
R27 is selected from hydrogen, alkyl of 1–6 carbon atoms, alkenyl of 2–6 carbon atoms, alkynyl of 2–6 carbon atoms, haloalkyl of 1–6 carbon atoms, and A-R23, or
R27 is selected from cycloalkyl of 3–6 carbon atoms, cycloalkenyl of 3–6 carbon atoms, aryl of 6–10 carbon atoms, and heteroaryl of 2–9 carbon atoms and 1–4 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1–3 of R10, or
R27 is selected from 5–7 membered heterocycloalkyl of 3–6 carbon atoms and 1–2 heteroatoms selected from N, O, S(═O)0-2, and 5–7 membered heterocycloalkenyl of 3–6 carbon atoms and 1–2 heteroatoms selected from N, O, S(═O)0-2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5–6 membered heteroaryl of 2–5 carbon atoms and 1–3 heteroatoms selected from N, S(═O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═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, aryl of 6–10 carbon atoms, heteroaryl of 2–9 carbon atoms and 1–4 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1–3 of R10, or
R28 is selected from 5–7 membered heterocycloalkyl of 3–6 carbon atoms and 1–2 heteroatoms selected from N, O, S(═O)0-2, and 5–7 membered heterocycloalkenyl of 3–6 carbon atoms and 1–2 heteroatoms selected from N, O, S(═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;
R30 is selected from alkyl of 1–6 carbon atoms, alkenyl of 2–6 carbon atoms, alkynyl of 2–6 carbon atoms, haloalkyl of 1–6 carbon atoms, A(OR22)—R23, and A-R23, or
R30 is selected from cycloalkyl of 3–6 carbon atoms, cycloalkenyl of 3–6 carbon atoms, aryl of 6–10 carbon atoms, and heteroaryl of 2–9 carbon atoms and 1–4 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1–3 of R10, or
R30 is selected from 5–7 membered heterocycloalkyl of 3–6 carbon atoms and 1–2 heteroatoms selected from N, O, S(═O)0-2, and 5–7 membered heterocycloalkenyl of 3–6 carbon atoms and 1–2 heteroatoms selected from N, O, S(═O)0-2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5–6 membered heteroaryl of 2–5 carbon atoms and 1–3 heteroatoms selected from N, S(═O)0-2 and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═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 heteroaryl of 2–9 carbon atoms and 1–4 heteroatoms, all of which may be substituted with 1–3 of R10;
R29 is selected from alkyl of 1–6 carbon atoms, alkenyl of 2–6 carbon atoms, alkynyl of 2–6 carbon atoms, haloalkyl of 1–6 carbon atoms, A-R23, A-C(═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, aryl of 6–10 carbon atoms, heteroaryl of 2–9 carbon atoms and 1–4 heteroatoms selected from N, S(═O)0-2, and O, all of which may be substituted with 1–3 of R10, or
R29 is selected from 5–7 membered heterocycloalkyl of 3–6 carbon atoms and 1–2 heteroatoms selected from N, O, S(═O)0-2, and 5–7 membered heterocycloalkenyl of 3–6 carbon atoms and 1–2 heteroatoms selected from N, O, S(═O)0-2, wherein said heterocycloalkyl and said 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), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1–3 of R10;

R7 is selected from cycloalkyl of 3–8 carbon atoms, cycloalkenyl of 4–8 carbon atoms, and aryl of 6–10 carbon atoms, all of which may be substituted with 1–3 of R10, or
R7 is selected from hydrogen, nitrite, 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;
and pharmaceutically acceptable salts thereof.

2. The compound of claim 1, wherein R3 is cycloalkyl of 3–6 carbon atoms, 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.

3. The compound of claim 2, 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.

4. The compound of claim 1, wherein R3 is cycloalkyl of 3–6 carbon atoms, 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.

5. The compound of claim 4, 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.

6. The compound of claim 1, wherein R2 is NR15R16.

7. The compound of claim 6, wherein
R15 is selected from hydrogen, alkyl of 1–6 carbon atoms, and cylcoalkyl of 3–8 carbon atoms, and
R16 is selected from alkyl of 1–6 carbon atoms and A-R9, or
R16 is selected from phenyl, and cycloalkyl of 3–8 carbon atoms, all of which may be substituted with 1–3 of R10.

8. The compound of claim 1, wherein R2 is NR15R16;
R3 is selected from cycloalkyl of 3–6 carbon atoms, 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.

9. The compound of claim 8, wherein
R15 is selected from hydrogen, alkyl of 1–6 carbon atoms, and cylcoalkyl of 3–8 carbon atoms, and
R16 is selected from alkyl of 1–6 carbon atoms and A-R9, or
R16 is selected from phenyl, and cycloalkyl of 3–8 carbon atoms, all of which may be substituted with 1–3 of R10.

10. The compound of claim 9, selected from the group consisting of:

11. The compound of claim 8, 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 maybe substituted wit 1–3 of R10.

12. The compound of claim 1 or 8, wherein R5 is selected from cycloalkyl of 3–6 carbon atoms, cycloalkenyl of 4–6 carbon atoms, and phenyl, all of which may be substituted with 1–3 of R10, 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)OR24, 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 or 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 R25are 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 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
R27is 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 1–3of R10.

13. The compound of claim 12, wherein R5 is selected from cycloalkyl of 3–6 carbon atoms, and phenyl, all of which may be substituted with 1–3 of R10, 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
R23 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;
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
R27is 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.

14. The compound of claim 1 or 8, wherein R6 is selected from cycloalkyl of 3–6 carbon atoms, cycloalkenyl of 4–6 carbon atoms, and phenyl, all of which may be substituted with 1–3 of R10, 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(═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.

15. The compound of claim 14, wherein R6 is selected from cycloalkyl of 3–6 carbon atoms, which may be substituted with 1–3 of R10, or
R6is 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 wit 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 heteroaryl 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, 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.

16. The compound of claim 15 selected from the group consisting of:

17. The compound of claim 1 or 8, wherein R7 is selected from cycloalkyl of 3–6 carbon atoms, cycloalkenyl of 4–6 carbon atoms, and phenyl, all of which may be substituted with 1–3 of R10, 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.

18. The compound of claim 17, wherein R7 is selected from cycloalkyl of 3–6 carbon atoms, and phenyl, all of which may be substituted with 1–3 of R10, 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(0)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.

19. The compound of claim 18 selected from the group consisting of:

20. A pharmaceutical composition, comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.