JP2006521400A - Compounds for the treatment of diabetes and related disorders and their use - Google Patents

Abstract

The present invention relates generally to the compounds described herein. More specifically, the present invention relates to compounds and pharmaceutical compositions containing such compounds. The methods of the invention comprise the administration of a compound of the invention for the treatment of diabetes and related disorders.

Description

This application claims the benefit of US Provisional Application No. 60 / 455,194, Mar. 26, 2003, the contents of which are hereby incorporated by reference in their entirety.
The present invention relates to compounds, pharmaceutical compositions containing them and their use for treating diabetes and related disorders in patients.

2. Description of Related Art Diabetes is characterized by impaired glucose metabolism and is manifested by high blood glucose levels in diabetic patients, among other symptoms. Due to the underlying defects, diabetes is divided into two main groups. Type 1 diabetes or insulin-dependent diabetes mellitus (IDDM) occurs when a patient lacks insulin-producing β-cells in its pancreatic gland. Type 2 diabetes or non-insulin dependent diabetes mellitus (NIDDM) occurs in patients with impaired β-cell function and modulation in insulin action.

  Current treatment for type 1 diabetic patients is injection of insulin, but the majority of type 2 diabetic patients are treated with agents that stimulate β-cell function or enhance the patient's tissue sensitivity to insulin. Is done. Agents currently used for the treatment of type 2 diabetes include alpha-glucosidase inhibitors, insulin sensitizers, insulin secretagogues and metformin. Is included.

  Over time, almost half of patients with type 2 diabetes lose their response to these drugs. After diet, exercise, and oral drug administration fail to adequately suppress blood glucose, insulin treatment is initiated. The disadvantages of insulin treatment are the need for drug injection, the possibility of hypoglycemia and weight gain.

  Because of the problems with current treatments, new therapies for the treatment of type 2 diabetes are needed. In particular, new treatments are needed to maintain normal (glucose-dependent) insulin secretion. Such new drugs must have the following properties: dependence on glucose for the promotion of insulin secretion, ie compounds that stimulate insulin secretion only in the presence of high glucose; low primary and secondary failure Rate and primary failure rates; and preservation of islet cell function. Strategies for the development of novel therapies disclosed herein are based on the cyclic adenosine monophosphate (cAMP) signaling mechanism and its effect on insulin secretion.

Glucose metabolism promotes ATP-dependent K ⁺ channel closure, which leads to cell depolarization and subsequent Ca ⁺⁺ channel opening. This in turn results in exocytosis of the insulin granules. cAMP is the main regulator of glucose-stimulated insulin secretion. However, it has little, if any, effect on insulin secretion in the absence or low glucose concentrations (1). The effect of cAMP on insulin secretion is thought to be mediated by the protein kinase A pathway.

  Endogenous secretagogues such as pituitary adenylate cyclase activating peptide (PACAP), VIP and GLP-1 use the cAMP system in a glucose-dependent manner to regulate insulin secretion (2). . Phosphodiesterases (PDEs) are also known to be involved in the regulation of the cAMP system.

PACAP is a potent stimulator of glucose-dependent insulin secretion from pancreatic β-cells. Three types of PACAP receptor types (R1, R2, and R3) have been described (Non-patent Document 3). The insulinotropic action of PACAP is mediated by the GTP binding protein, Gs. Intracellular cAMP deposition, in turn, activates non-selective cation channels in β-cells, improves [Ca ⁺⁺ ] i and promotes exocytosis of insulin-containing secretory granules.

  Vasoactive Intestinal Peptide (VIP) is a 28 amino acid peptide that was first isolated from the upper small intestine of pigs (Non-patent Document 4; Patent Document 1). This peptide belongs to a group of small structurally related polypeptides including herodermin, secretin, somatostatins and glucagon. The biological effects of VIP are mediated by activation of membrane-bound receptor proteins coupled to the intracellular cAMP signaling system. These receptors were first known as VIP-R1 and VIP-R2, but later were found to be the same receptors as PACAP-R2 and PACAP-R3.

  GLP-1 is released from intestinal L-cells after meals and functions as an incretin hormone (ie it powers glucose-induced insulin release from pancreatic β-cells). It is a 37-amino acid peptide that is expressed by various glucagon genes depending on the tissue type. Clinical data supporting the beneficial effects of improving cAMP levels in β-cells were collected using GLP-1. Infusions of GLP-1 in type 2 diabetes with poor suppression normalize their fasting blood glucose levels (Non-Patent Document 5), and longer-term infusions improve β-cell function to that of normal people (Non-patent document 6). Recent reports have shown that GLP-1 improves the ability of β-cells to respond to glucose in patients with impaired glucose tolerance (7). However, all of these effects are short-lived due to the short half-life of the peptide.

1- (3-Chlorophenyl) -4- (dimethylamino) -1,8-naphthyridin-2 (1H) -one is disclosed in Patent Document 2 as 3- (1-hydroxyalkyl) -4- (dimethylamino) -1 , 8-naphthyridin-2 (1H) -one is known as a precursor. This application describes multiple naphthyridine derivatives as anti-inflammatory agents. Non-Patent Document 8 describes 4-amino-1-phenyl-1,8-naphthyridin-2 (1H) -one as 5-phenylimidazo [4,5-c] [1,8, which exhibits potent anti-asthmatic activity. It is described as a precursor for the production of naphthyridin-4 (5H) -one.
US Pat. No. 3,879,371 Japanese Patent Laid-Open No. 07-126268 Weinhaus, et al. , Diabetes 47: 1998, 1426-1435. Komatsu, et al. Author Diabetes 46: 1997, 1928-1938 Harmar, et al. Author, Pharmacol. Reviews 50: 1998, 265-270 Said and Mutt, Science 169: 1970, 1217-1218. Gutniak, et al. Written by New Eng. J. et al. Med. 326: 1992, 1316-1322. Rachman, et al. Author Diabetes 45: 1996, 1524-1530. Byrne, et al. , Diabetes 47: 1998, 1259-1265. Kuge, et al. Written, Synthetic Communications 24 (22): 1994, 3289-96.

SUMMARY OF THE INVENTION The present invention provides compounds, pharmaceutical compositions containing them and methods for their use for the treatment of diabetes and related disorders. The compounds of the present invention include those shown below in the section entitled “Detailed Description of the Invention”.

  The present invention has the formula

[Where:
R ¹ is selected from alkyl of ¹ to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms and AR ⁹ ,
Or R ¹ is aryl of 6 to 10 carbon atoms, 2 to 9 carbon atoms and 1 to 4 heteroatoms of heteroaryl selected from N, S (═O) _0-2 and O, 3 Cycloalkyl of 8 carbon atoms, cycloalkenyl of 4 to 8 carbon atoms, 3 to 6 carbon atoms and 1 to 2 heteroatoms selected from N, S (= O) _0-2 and O Selected from 5 to 7-membered heterocycloalkyl and 5 to 7-membered heterocycloalkenyl of 1 to 2 heteroatoms selected from 3 to 6 carbon atoms and N, S (= O) _0-2 and O Wherein the heterocycloalkyl and heterocycloalkenyl are further phenyl or 2-5 carbon atoms and 5-6 of 1-3 heteroatoms selected from N, S (= O) _0-2 and O. Can be condensed with a member heteroaryl. , And / or where it is possible to the one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl are oxidized to C (= O), all of which 1-3 R Can be substituted with ¹⁰ ;
R ¹⁰ is nitro, nitrile, hydroxy, halogen, acyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms 1 to 6 carbon atoms haloalkyl, 1 to 6 carbon atoms alkoxy, 1 to 6 carbon atoms haloalkoxy, 3 to 6 carbon atoms cycloalkoxy, 6 to 10 carbon atoms Of aryl, 2-9 carbon atoms and heteroaryl of 1-4 heteroatoms selected from N, S (═O) _0-2 and O, NR ¹¹ R ¹² , C (═O) OR ¹¹ , C (═O) NHR ¹¹ , NHC (═O) R ¹³ , NHS (═O) ₂ R ¹³ , S (═O) _0-2 R ¹³ , S (═O) ₂ NHR ¹¹ , 3-6 A cycloalkyl of carbon atoms, a cycloalkyl of 3 to 6 carbon atoms Roarukeniru, 3-6 carbon atoms and N, S _{(= O) 0-2} and 1-2 heteroatoms selected from O 5 to 7 membered heterocycloalkyl and 3-6 carbon atoms and N , S (═O) _0-2 and O selected from 5 to 7-membered heterocycloalkenyl of 1 to 2 heteroatoms, wherein the heterocycloalkyl and heterocycloalkenyl are further phenyl or 2- Can be fused with 5 to 6 membered heteroaryl of 5 carbon atoms and 1 to 3 heteroatoms selected from N, S (═O) _0-2 and O, and / or wherein One or more of the carbon atoms in the heterocycloalkyl or heterocycloalkenyl can be oxidized to C (= O);
R ¹³ is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, 3 to 6 carbon atoms Selected from cycloalkyl and cycloalkenyl of 4 to 6 carbon atoms;
R ¹¹ and R ¹² are hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, 3 Independently selected from cycloalkyl of 6 carbon atoms and cycloalkenyl of 4-6 carbon atoms;
A is selected from alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms and haloalkyl of 1 to 8 carbon atoms;
R ⁹ is selected from hydroxy, alkoxy of 1 to 6 carbon atoms, cycloalkoxy of 3 to 6 carbon atoms, O—A—R ¹⁴ , NR ¹¹ R ¹² ; or R ⁹ is 6 to 10 Aryl of 2 carbon atoms, heteroaryl of 1 to 4 heteroatoms selected from N, S (═O) _0-2 and O, cycloalkyl of 3 to 8 carbon atoms , 5 to 8 carbon atoms cycloalkenyl, all of which can be substituted with 1 to 3 R ¹⁰ , or R ⁹ is 3 to 6 carbon atoms and N , S (= O) _0-2 and O, 5 to 7-membered heterocycloalkyl of 1 to 2 heteroatoms and 3 to 6 carbon atoms and N, S (= O) _0-2 and O 5 to 7-membered hetero of 1 to 2 heteroatoms selected from Selected from Kuroarukeniru, wherein said heterocycloalkyl and said heterocycloalkenyl may further phenyl or 2-5 carbon atoms and N, S (= O) 1~3 heteroatoms selected from _0-2 and O Can be fused with a 5-6 membered heteroaryl of the atom and / or wherein one or more of the carbon atoms in the heterocycloalkyl or heterocycloalkenyl are oxidized to C (═O). Wherein the heterocycloalkyl or the heterocycloalkenyl can be substituted with 1 to 3 R ¹⁰ ;
R ¹⁴ is selected from cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 8 carbon atoms, 3 to 6 carbon atoms and N, S (═O) _0-2 and O. 5 to 7 membered heterocycloalkyl of 2 heteroatoms and 5 to 7 membered hetero of 1 to 2 heteroatoms selected from 3 to 6 carbon atoms and N, S (= O) _0-2 and O Selected from cycloalkenyl, wherein all of them can be substituted with 1 to 3 R ¹⁰ ;
R ³ is hydrogen;
R ⁴ is —NR ^4-1 R ^4-2 ;
R ^4-1 is from the group consisting of hydrogen, 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. Chosen;
R ^4-2 is hydrogen, alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, haloalkyl of 1 to 8 carbon atoms, 6 to 10 1 selected from aryl of 2 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms, 3-6 carbon atoms and N, S (= O) _0-2 and O 5 to 7 membered heterocycloalkyl of 2 to 5 heteroatoms and 3 to 6 carbon atoms and 1 to 2 heteroatoms selected from N, S (= O) _0-2 and O Selected from the group consisting of heterocycloalkenyl, wherein said aryl, heteroaryl, heterocycloalkyl or heterocycloalkenyl is nitro, nitrile, hydroxy, halogen, acyl of 1-6 carbon atoms, 1-6 Carbon atom al Alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms and 1 to 6 carbon atoms It can be substituted with 1 to 3 substituents selected from the group consisting of haloalkoxy, or R ^4-1 and R ^4-2 can be 3 to 6 carbon atoms and N, S (= O) forms a 5- to 7-membered heterocycloalkyl of 1-2 heteroatoms selected from _0-2 and O, where the heterocycloalkyl is nitro, nitrile, hydroxy, halogen, 1-6 carbons Atom acyl, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, 1 to 6 carbons Atomic alkoxy and 1-6 Can be substituted with 1-3 substituents selected from the group consisting of haloalkoxy atom,
R ⁵ and R ⁶ are cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 4 to 8 carbon atoms, aryl of 6 to 10 carbon atoms and 2 to 9 carbon atoms and 1 to 4 carbon atoms. Independently selected from heteroaryl of heteroatoms, all of which can be substituted with 1 to 3 R ¹⁰ ,
Alternatively, R ⁵ and R ⁶ are 3 to 6 carbon atoms and 5 to 7 membered heterocycloalkyl of 1 to 2 heteroatoms selected from N, S (═O) _0-2 and O, and 3 to 6 Independently selected from 5 to 7-membered heterocycloalkenyl of 1 to 2 heteroatoms selected from N, S (═O) _0-2 and O, wherein the heterocycloalkyl and the Heterocycloalkenyl is further condensed with phenyl or 2 to 5 carbon atoms and 5 to 6 membered heteroaryl of 1 to 3 heteroatoms selected from N, S (= O) _0-2 and O. And / or wherein one or more of the carbon atoms in the heterocycloalkyl or heterocycloalkenyl can be oxidized to C (═O), where the heterocycloalkyl or the Hetero Kuroarukeniru is 1-3 ^{R 10, A-R 23,} A-NR 24 R 25, C (= O) R 24, C (= O) OR 24, C (= O) NR 24 R 25, S (═O) ₂ R ²⁶ , AC (═O) R ²⁴ , AC (═O) OR ²⁴ or AC (═O) NR ²⁴ R ²⁵
Or R ⁵ and R ⁶ are hydrogen, halogen, nitrile, nitro, hydroxy, alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, 1 to 8 Haloalkyl of 1 carbon atom, alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms, cycloalkoxy of 3-8 carbon atoms, AR ²³ , A (OR ²² ) — R ²³ , NR ²⁷ R ²⁸ , A-NR ²⁷ R ²⁸ , AQR ²⁹ , QR ²⁹ , QA-NR ²⁴ R ²⁵ , C (═O) R ²⁴ , C (═O) OR ²⁴ , C (═O) NR ²⁴ R ²⁵ , A—C (═O) R ²⁴ , A—C (═O) OR ²⁴ and A—C (═O) NR ²⁴ R ²⁵ ;
Q is selected from O and S (= O) _0-2 ;
R ²² is selected from hydrogen, alkyl of 1-8 carbon atoms, haloalkyl of 1-8 carbon atoms and cycloalkyl of 3-8 carbon atoms;
R ²³ is selected from hydroxy, alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms and cycloalkoxy of 3-8 carbon atoms, or R ²³ is 3-8 Selected from cycloalkyl of carbon atoms, cycloalkenyl of 4 to 8 carbon atoms, aryl of 6 to 10 carbon atoms and 2 to 9 carbon atoms and N, S (= O) _0-2 and O Selected from 1 to 4 heteroatoms heteroaryl, all of which can be substituted with 1 to 3 R ¹⁰ , or R ²³ is 3 to 6 carbon atoms and N, From 5 to 7-membered heterocycloalkyl of 1 to 2 heteroatoms selected from O, S (═O) _0-2 and 3 to 6 carbon atoms and N, O, S (═O) _0-2 5 of 1 to 2 heteroatoms selected Membered selected from heterocycloalkenyl, 1-3 to herein selected from the heterocycloalkyl and said heterocycloalkenyl may further phenyl or 2-5 carbon atoms and N, S (= O) _0-2 and O And / or wherein one or more of the carbon atoms in the heterocycloalkyl or heterocycloalkenyl are in C (═O). Can be oxidized, wherein the heterocycloalkyl or the heterocycloalkenyl can be substituted with 1 to 3 R ¹⁰ ;
However, with respect to A (OR ²² ) —R ²³ , R ²³ is selected from hydroxy, alkoxy of 1 to 8 carbon atoms, haloalkoxy of 1 to 8 carbon atoms and cycloalkoxy of 3 to 8 carbon atoms. A is not CH;
R ²⁴ and R ²⁵ are hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms and A- R ²⁴ and R ²⁵ are independently selected from R ²³ or R ²⁴ and R ²⁵ are cycloalkyl of 3 to 6 carbon atoms, cycloalkenyl of 3 to 6 carbon atoms, aryl of 6 to 10 carbon atoms and 2 Independently selected from 1 to 4 heteroatoms of heteroaryl selected from ˜9 carbon atoms and N, S (═O) _0-2 and O, all of which are 1 to 3 R ¹⁰ Or R ²⁴ and R ²⁵ are 3 to 6 carbon atoms and 5 of 1 to 2 heteroatoms selected from N, O, S (═O) _0-2 ~ 7-membered heterocycloalkyl and 3-6 Carbon atoms and N, O, S (= O ) independently of one or two 5- to 7-membered heterocycloalkenyl heteroatoms selected from _0-2 selected, wherein said heterocycloalkyl and said heterocyclo The alkenyl can be further fused to phenyl or 2 to 5 carbon atoms and 5 to 6 membered heteroaryl of 1 to 3 heteroatoms selected from N, S (= O) _0-2 and O. And / or wherein one or more of the carbon atoms in the heterocycloalkyl or heterocycloalkenyl may be oxidized to C (═O), wherein the heterocycloalkyl or heterocyclo or alkenyl may be substituted with 1-3 ^{R 10,} or R ²⁴ and ^{R 25} are linked together with the nitrogen atom to which they are attached, a 3 to 6 Atom and N, S _{(= O)} 5~7 membered heterocycloalkyl 1-2 heteroatoms selected from _0-2 and O, 3 to 6 carbon atoms and N, S (= _{O) 0} Forming a heteroaryl of 5-7 membered heterocycloalkenyl of 1-2 heteroatoms selected from _-2 and O or heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms, wherein said heterocyclo Alkyl and the heterocycloalkenyl are further fused with phenyl or 2 to 5 carbon atoms and 5 to 6 membered heteroaryl of 1 to 3 heteroatoms selected from N, S (= O) _0-2 and O. And / or wherein one or more of the carbon atoms in the heterocycloalkyl or heterocycloalkenyl can be oxidized to C (═O), all of which are 1 ~ 3 R Can be substituted with ¹⁰ ;
R ²⁶ is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, A (OR ²² ) —R ²³ and either selected from ^{a-R 23,} or R ²⁶ is cycloalkyl of 3 to 6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, 6 to 10 carbon atoms of the aryl and 2-9 Selected from 1 to 4 heteroatoms of heteroaryl selected from carbon atoms and N, S (═O) _0-2 and O, all of which are substituted with 1 to 3 R ¹⁰ Or R ²⁶ is a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S (═O) _0-2 and 3 ~ 6 carbon atoms and N, O, S (= ) Is selected from 5-7 membered heterocycloalkenyl of 1-2 heteroatoms selected from _0-2, wherein said heterocycloalkyl and said heterocycloalkenyl may further phenyl or 2-5 carbon atoms and N , S (═O) _0-2 and O can be fused with 5 to 6 membered heteroaryl of 1 to 3 heteroatoms and / or wherein said heterocycloalkyl or heterocycloalkenyl One or more of the carbon atoms in it can be oxidized to C (= O), wherein the heterocycloalkyl or the heterocycloalkenyl is substituted with 1 to 3 R ¹⁰ It is possible;
R ²⁷ is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms and AR ²³ or chosen, or cycloalkyl of R ²⁷ is 3 to 6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, 6 to 10 carbon atoms of the aryl and 2-9 carbon atoms and N, S (= O) selected from 1 to 4 heteroatoms heteroaryl selected from _0-2 and O, all of which can be substituted with 1 to 3 R ¹⁰ , or R ²⁷ is 3 to 6 carbon atoms and 5 to 7-membered heterocycloalkyl of 1 to 2 heteroatoms selected from N, O, S (= O) _0-2 and 3 to 6 carbon atoms and N, O, S (= O) selected from _0-2 From 1 to 2 heteroatoms of 5- to 7-membered heterocycloalkenyl, wherein the heterocycloalkyl and heterocycloalkenyl are further phenyl or 2-5 carbon atoms and N, S (= O) Can be fused with 1 to 6 heteroaryls of 1 to 3 heteroatoms selected from _0-2 and O and / or wherein 1 of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl One or more can be oxidized to C (= O), wherein the heterocycloalkyl or the heterocycloalkenyl can be substituted with 1 to 3 R ¹⁰ ;
R ²⁸ is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, AR ²³ , ^{C (= O) R 24,} C (= O) OR 26, C (= O) NR 25 R 30, S (= O) 2 R 26, A-C (= O) R 24, A-C (= O) OR ²⁴ and A—C (═O) NR ²⁴ R ²⁵ , or R ²⁸ is a cycloalkyl of 3 to 6 carbon atoms, a cycloalkenyl of 3 to 6 carbon atoms, 6 to 10 Selected from aryl of 1 carbon atom, 2-9 carbon atoms and 1 to 4 heteroatoms of heteroaryl selected from N, S (= O) _0-2 and O, all of which are selected from 1 to or may be substituted with 1-3 ^{R 10,} or R ²⁸ is 3-6 Carbon atoms and _{N, O, S (= O} ) 5~7 membered heterocycloalkyl and 3-6 carbon atoms and N 1-2 heteroatoms selected from _0-2, O, S (= O) Selected from 5 to 7-membered heterocycloalkenyl of 1 to 2 heteroatoms selected from _0-2 , wherein the heterocycloalkyl and the heterocycloalkenyl are further phenyl or 2-5 carbon atoms and N, S (= O) can be fused with 5 to 6 membered heteroaryl of 1 to 3 heteroatoms selected from _0-2 and O and / or wherein said heterocycloalkyl or heterocyclo is one or more of the carbon atoms in the alkenyl can optionally be oxidized to C (= O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 R ¹⁰ You can have;
R ³⁰ is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, A (OR ²² ) —R ²³ and either selected from ^{a-R 23,} or R ³⁰ is cycloalkyl of 3 to 6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, 6 to 10 carbon atoms of the aryl and 2-9 Selected from 1 to 4 heteroatoms of heteroaryl selected from carbon atoms and N, S (═O) _0-2 and O, all of which are substituted with 1 to 3 R ¹⁰ Or R ³⁰ is 3 to 6 carbon atoms and 5 to 7 membered heterocycloalkyl of 1 to 2 heteroatoms selected from N, O, S (═O) _0-2 and 3 ~ 6 carbon atoms and N, O, S (= O) Selected from 5 to 7-membered heterocycloalkenyl of 1 to 2 heteroatoms selected from _0-2 , wherein the heterocycloalkyl and heterocycloalkenyl are further phenyl or 2-5 carbon atoms and N; S (= O) can be fused with 5 to 6 membered heteroaryl of 1 to 3 heteroatoms selected from _0-2 and O, and / or wherein in said heterocycloalkyl or heterocycloalkenyl One or more of the carbon atoms of can be oxidized to C (═O), wherein the heterocycloalkyl or heterocycloalkenyl is substituted with 1 to 3 R ¹⁰ or may alternatively R ²⁵ and ^{R 30,} are tied together with the nitrogen atom to which they are attached, 3-6 carbon atoms and N, or S _{(= O) 0-2} and O 5-7 membered heterocycloalkyl of 1-2 heteroatoms selected, three to six carbon atoms and N, 5 of S _{(= O)} 1-2 heteroatoms selected from _0-2 and O Form a 7 to 7 membered heterocycloalkenyl or a heteroaryl of 2 to 9 carbon atoms and 1 to 4 heteroatoms, all of which can be substituted with 1 to 3 R ¹⁰ ;
R ²⁹ is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, A—R ²³ , A— C (═O) R ²⁴ , AC (═O) OR ²⁴ , AC (═O) NR ²⁴ R ²⁵ , A-NR ²⁷ R ²⁸ , or R ²⁹ is 3-6 Selected from cycloalkyl of carbon atoms, cycloalkenyl of 3 to 6 carbon atoms, aryl of 6 to 10 carbon atoms, 2 to 9 carbon atoms and N, S (= O) _0-2 and O Selected from 1 to 4 heteroatoms heteroaryl, all of which can be substituted with 1 to 3 R ¹⁰ , or R ²⁹ is 3 to 6 carbon atoms and N; O, 1-2 heteroatoms selected from S _{(= O) 0-2} 5 7-membered heterocycloalkyl and 3-6 carbon atoms and N, O, selected from 5-7 membered heterocycloalkenyl of S _{(= O)} 1~2 heteroatoms selected from _0-2, wherein The heterocycloalkyl and the heterocycloalkenyl are further phenyl or 2 to 5 carbon atoms and 5 to 6 membered heteroaryl of 1 to 3 heteroatoms selected from N, S (= O) _0-2 and O And / or wherein one or more of the carbon atoms in the heterocycloalkyl or heterocycloalkenyl can be oxidized to C (═O), where The heterocycloalkyl or the heterocycloalkenyl can be substituted with 1 to 3 R ¹⁰ ;
R ⁷ is cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 4 to 8 carbon atoms, aryl of 6 to 10 carbon atoms and 2 to 9 carbon atoms and 1 to 4 heteroatoms Or all of them can be substituted with 1 to 3 R ¹⁰ ,
Or R ⁷ is 3 to 6 carbon atoms and 5 to 7 membered heterocycloalkyl of 1 to 2 heteroatoms selected from N, S (═O) _0-2 and O, and 3 to 6 carbons. Selected from atoms and 5-7 membered heterocycloalkenyl of 1-2 heteroatoms selected from N, S (= O) _0-2 and O, wherein the heterocycloalkyl and heterocycloalkenyl are further phenyl Or may be fused with 2 to 5 carbon atoms and 5 to 6 membered heteroaryl of 1 to 3 heteroatoms selected from N, S (= O) _0-2 and O, and / or Wherein one or more of the carbon atoms in the heterocycloalkyl or heterocycloalkenyl can be oxidized to C (= O), wherein the heterocycloalkyl or heterocycloalkenyl is 1-3 ^{R 10, A (OR 22)} -R 23, A-R 23, A-NR 24 R 25, C (= O) R 24, C (= O) OR 24, C (= O) Substituted with NR ²⁴ R ²⁵ , S (═O) ₂ R ²⁶ , AC (═O) R ²⁴ , AC (═O) OR ²⁴ or AC (═O) NR ²⁴ R ²⁵ Can
Or R ⁷ is hydrogen, nitrile, nitro, hydroxy, alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, 1-8 carbon atoms Haloalkyl, alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms, cycloalkoxy of 3-8 carbon atoms, A—R ²³ , A (OR ²² ) —R ²³ , NR ^{27 R 28, A-NR 27 R} 28, A-Q-R 29, Q-R 29, Q-A-NR 24 R 25, C (= O) R 24, C (= O) OR 24, C (= O) NR ²⁴ R ²⁵ , A—C (═O) R ²⁴ , A—C (═O) OR ²⁴ and A—C (═O) NR ²⁴ R ²⁵ ]
As well as pharmaceutically acceptable salts thereof,
However, the compound is 1- (3-chlorophenyl) -4- (dimethylamino) -1,8-naphthyridin-2 (1H) -one or 4-amino-1-phenyl-1,8-naphthyridine-2 (1H) -Not on.

In another aspect, the present invention provides
R ¹ is selected from aryl of 6 or 10 carbon atoms, which can be substituted with 1 to 3 R ¹⁰ ;
R ¹⁰ is nitro, nitrile, hydroxy, halogen, acyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms Haloalkoxy of 1 to 6 carbon atoms, cycloalkoxy of 3 to 6 carbon atoms, phenyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzo Heteroaryl selected from thiophenyl, quinolinyl and isoquinolinyl, NR ¹¹ R ¹² , C (═O) OR ¹¹ , C (═O) NHR ¹¹ , NHC (═O) R ¹³ , NHS (═O) ₂ R ¹³ , ^{_{S (= O) 0-2 R 13}} , S (= O) 2 NHR 11, cyclopropyl, consequent Selected from pentyl, cyclohexyl, and heterocycloalkyl selected from tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, piperazinyl, morpholinyl, morpholinyl-N-oxide and thiomorpholinyl Wherein the heterocycloalkyl may be further condensed with phenyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl. Can;
R ¹³ is selected from alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms and cycloalkyl of 3 to 6 carbon atoms;
R ¹¹ and R ¹² are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms and cycloalkyl of 3 to 6 carbon atoms;
A is selected from alkyl of 1 to 8 carbon atoms and haloalkyl of 1 to 8 carbon atoms;
R ³ is hydrogen;
R ⁴ is —NR ^4-1 R ^4-2 ;
R ^4-1 is selected from the group consisting of hydrogen, alkyl of 1-8 carbon atoms and haloalkyl of 1-8 carbon atoms;
R ^4-2 is hydrogen, alkyl of 1 to 8 carbon atoms, haloalkyl of 1 to 8 carbon atoms, aryl of 6 or 10 carbon atoms, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl , Pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl, heteroaryl, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl , Piperazinyl, morpholinyl, morpholinyl-N-oxide and thiomorpholinyl, wherein the aryl, heteroaryl or heterocycloalkyl is nitro, nitrile, hydro Xyl, halogen, acyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms and 1 to 6 carbons Can be substituted with 1 to 3 substituents selected from the group consisting of haloalkoxy of atoms, or R ^4-1 and R ^4-2 are tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2 Forming a heterocycloalkyl selected from dihydropyridinyl, 1,4-dihydropyridinyl, piperazinyl, morpholinyl, morpholinyl-N-oxide and thiomorpholinyl, wherein the heterocycloalkyl is nitro, nitrile, hydroxy, halogen , Acyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, haloal of 1 to 6 carbon atoms Le, can be substituted with 1-3 substituents selected from the group consisting of haloalkoxy of 1-6 alkoxy and 1 to 6 carbon atoms carbon atoms,
R ⁵ and R ⁶ are independently selected from cycloalkyl of 3 to 8 carbon atoms, aryl of 6 to 10 carbon atoms and 2 to 9 carbon atoms and 1 to 4 heteroatoms of heteroaryl. All of them can be substituted with 1 to 3 R ¹⁰ ,
Alternatively, R ⁵ and R ⁶ are heterocycloyl selected from tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, piperazinyl, morpholinyl, morpholinyl-N-oxide and thiomorpholinyl. Where the heterocycloalkyl is further condensed with phenyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl and or isoquinolinyl. Can be
Or R ⁵ and R ⁶ are hydrogen, halogen, nitrile, nitro, hydroxy, alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, 1-8 Haloalkyl of 1 carbon atom, alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms, cycloalkoxy of 3-8 carbon atoms, AR ²³ , A (OR ²² ) — R ²³ , NR ²⁷ R ²⁸ , A-NR ²⁷ R ²⁸ , AQR ²⁹ , QR ²⁹ , QA-NR ²⁴ R ²⁵ , C (═O) R ²⁴ , C (═O) OR ²⁴ , C (═O) NR ²⁴ R ²⁵ , A—C (═O) R ²⁴ , A—C (═O) OR ²⁴ and A—C (═O) NR ²⁴ R ²⁵ ;
Q is selected from O and S (= O) _0-2 ;
R ²² is selected from hydrogen, alkyl of 1 to 8 carbon atoms, haloalkyl of 1 to 8 carbon atoms and cycloalkyl of 3 to 8 carbon atoms;
R ²³ is selected from hydroxy, 1 to 8 carbon atoms alkoxy, 1 to 8 carbon atoms haloalkoxy and 3 to 8 carbon atoms cycloalkoxy, or R ²³ is 3 to 8 carbon atoms From cycloalkyl of carbon atoms, aryl of 6 or 10 carbon atoms and 2 to 9 carbon atoms and 1 to 4 heteroatoms of heteroaryl selected from N, S (= O) _0-2 and O Selected, all of which can be substituted with 1-3 of R ¹⁰ , or R ²³ is tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropyridinyl, 1,4- A heterocycloalkyl selected from dihydropyridinyl, piperazinyl, morpholinyl, morpholinyl-N-oxide and thiomorpholinyl, wherein The heterocycloalkyl can be further condensed with phenyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl. The heterocycloalkyl can be substituted with 1 to 3 R ¹⁰ ;
However, with respect to A (OR ²² ) —R ²³ , R ²³ is selected from hydroxy, alkoxy of 1 to 8 carbon atoms, haloalkoxy of 1 to 8 carbon atoms and cycloalkoxy of 3 to 8 carbon atoms. A is not CH;
R ²⁴ and R ²⁵ are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms and A—R ²³ , or R ²⁴ and R ²⁵ are cyclopropyl, Independently selected from cyclopentyl, cyclohexyl, aryl of 6 to 10 carbon atoms, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl and isoquinolinyl All of which can be substituted with 1 to 3 R ¹⁰ or R ²⁴ and R ²⁵ are tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropyridinyl, 1, 4-dihydropyridinyl, piperazin , Morpholinyl, morpholinyl-N-oxide and thiomorpholinyl, wherein the heterocycloalkyl is further phenyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, It can be fused with indazolyl, benzofuranyl, benzothiophenyl, quinolinyl and or isoquinolinyl, wherein the heterocycloalkyl can be substituted with 1 to 3 R ¹⁰ or R ²⁴ and R ²⁵ together with the nitrogen atom to which they are attached, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, piperazinyl, morpholini Forming a heterocycloalkyl selected from nyl, morpholinyl-N-oxide and thiomorpholinyl, wherein the heterocycloalkyl is further phenyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl , Benzofuranyl, benzothiophenyl, quinolinyl and or isoquinolinyl, all of which can be substituted with 1 to 3 R ¹⁰ ;
R ²⁶ is selected from alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, A (OR ²² ) —R ²³ and A—R ²³ , or R ²⁶ is cyclopropyl, cyclopentyl, Selected from cyclohexyl, aryl of 6 or 10 carbon atoms, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl and isoquinolinyl, all of them Can be substituted with 1 to 3 R ¹⁰ or R ²⁶ can be tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, piperazinyl , Morpholinyl, mol A heterocycloalkyl selected from folinyl-N-oxide and thiomorpholinyl, wherein the heterocycloalkyl is further phenyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, Can be fused with benzothiophenyl, quinolinyl and or isoquinolinyl, wherein the heterocycloalkyl can be substituted with 1 to 3 R ¹⁰ ;
R ²⁷ is selected from hydrogen, alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms and AR ²³ , or R ²⁷ is cyclopropyl, cyclopentyl, cyclohexyl, 6 to 10 carbon atoms Selected from aryl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl of carbon atoms, all of which are 1 to 3 R ¹⁰ or may be substituted, or R ²⁷ is tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, piperazinyl, morpholinyl, morpholinyl -N- Oxides and thiols A heterocycloalkyl selected from morpholinyl, wherein the heterocycloalkyl is further phenyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl and Or can be fused with isoquinolinyl, wherein the heterocycloalkyl can be substituted with 1 to 3 R ¹⁰ ;
R ²⁸ is hydrogen, alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, A—R ²³ , C (═O) R ²⁴ , C (═O) OR ²⁶ , C (═O ) NR ²⁵ R ³⁰ , S (═O) ₂ R ²⁶ , A—C (═O) R ²⁴ , A—C (═O) OR ²⁴ and A—C (═O) NR ²⁴ R ²⁵ Or R ²⁸ is cyclopropyl, cyclopentyl, cyclohexyl, aryl of 6 to 10 carbon atoms, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl is selected from isoquinolinyl, or all of which may be substituted with 1-3 R ^10, or R ²⁸ Gath A heterocycloalkyl selected from lahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, piperazinyl, morpholinyl, morpholinyl-N-oxide and thiomorpholinyl, wherein Cycloalkyls can be further fused with phenyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl and isoquinolinyl. A heterocycloalkyl can be substituted with 1 to 3 R ¹⁰ ;
R ³⁰ is selected from alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, A (OR ²² ) —R ²³ and A—R ²³ , or R ³⁰ is cyclopropyl, cyclopentyl, Selected from cyclohexyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl, all of which are substituted with 1 to 3 R ¹⁰ Or R ³⁰ is tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, piperazinyl, morpholinyl, morpholinyl-N-oxide and thiomorpholini. Wherein the heterocycloalkyl is further phenyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl and the like. Or can be fused with isoquinolinyl, wherein the heterocycloalkyl can be substituted with 1-3 of R ¹⁰ , or R ²⁵ and R ³⁰ can be attached to the nitrogen to which they are attached. Tie together with an atom, selected from tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, piperazinyl, morpholinyl, morpholinyl-N-oxide, thiomorpholinyl Heterocycloalkyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl, all of which are 1-3 R ¹⁰ Can be substituted with;
R ²⁹ is alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, A—R ²³ , A—C (═O) R ²⁴ , A—C (═O) OR ²⁴ , A— C (═O) NR ²⁴ R ²⁵ , A-NR ²⁷ R ²⁸ , or R ²⁹ is cyclopropyl, cyclopentyl, cyclohexyl, aryl having 6 to 10 carbon atoms, thienyl, furyl, pyrrolyl, thiazolyl, Selected from oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl, all of which can be substituted with 1 to 3 R ¹⁰ , or R ²⁹ is tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropi A heterocycloalkyl selected from lysinyl, 1,4-dihydropyridinyl, piperazinyl, morpholinyl, morpholinyl-N-oxide and thiomorpholinyl, wherein the heterocycloalkyl is further phenyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl , Imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl and or isoquinolinyl, wherein the heterocycloalkyl is substituted with 1 to 3 R ¹⁰ Can be;
R ⁷ is cycloalkyl of 3 to 8 carbon atoms, aryl of 6 to 10 carbon atoms, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiol Selected from phenyl, quinolinyl, isoquinolinyl, all of which can be substituted with 1 to 3 R ¹⁰ ,
Or R ⁷ is heterocycloalkyl selected from tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, piperazinyl, morpholinyl, morpholinyl-N-oxide and thiomorpholinyl Where the heterocycloalkyl can be further condensed with phenyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl And / or wherein one or more of the carbon atoms in the heterocycloalkyl can be oxidized to C (═O), wherein the heterocycloalkyl is 1-3 R ¹⁰ , A (OR ²² ) —R ²³ , A—R ²³ , A—NR ²⁴ R ²⁵ , C (═O) R ²⁴ , C (═O) OR ²⁴ , C (═O) NR ²⁴ R ²⁵ , S (═O) ₂ R ²⁶ , AC (═O) R ²⁴ , AC (═O) OR ²⁴ or AC (═O) NR ²⁴ R ²⁵
Or R ⁷ is hydrogen, nitrile, nitro, hydroxy, alkyl of 1 to 8 carbon atoms, haloalkyl of 1 to 8 carbon atoms, alkoxy of 1 to 8 carbon atoms, 1 to 8 carbon atoms haloalkoxy, cycloalkoxy of 3-8 carbon ^{atoms, a-R 23, a (} OR 22) -R 23, NR 27 R 28, a-NR 27 R 28, a-Q-R 29, Q-R ^{29, Q-A-NR 24} R 25, C (= O) R 24, C (= O) OR 24, C (= O) NR 24 R 25, A-C (= O) R 24, A-C With respect to compounds of formula (I) selected from (═O) OR ²⁴ and A—C (═O) NR ²⁴ R ²⁵ and pharmaceutically acceptable salts thereof,
However, the compound is 1- (3-chlorophenyl) -4- (dimethylamino) -1,8-naphthyridin-2 (1H) -one or 4-amino-1-phenyl-1,8-naphthyridine-2 (1H) -Not on.

In another aspect, the invention provides:
R ¹ is phenyl, which can be substituted with 1 to 3 R ¹⁰ ;
R ¹⁰ is selected from nitro, nitrile, hydroxy, halogen, trifluoromethyl, methylcarbonyl, ethylcarbonyl, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, methoxy, ethoxy, propyloxy or isopropyloxy;
R ³ is hydrogen;
R ⁴ is —NR ^4-1 R ^4-2 ;
R ^4-1 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl and t-butyl;
R ^4-2 is phenyl, where the phenyl is nitro, nitrile, hydroxy, fluoro, chloro, methylcarbonyl, ethylcarbonyl, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, methoxy, ethoxy, propyloxy Or can be substituted with 1 to 3 substituents selected from the group consisting of isopropyloxy; or R ^4-1 and R ^4-2 form a heterocycloalkyl selected from piperazinyl, morpholinyl and thiomorpholinyl Where the heterocycloalkyl is nitro, nitrile, hydroxy, fluoro, chloro, methylcarbonyl, ethylcarbonyl, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, methoxy, ethoxy, propyloxy or isopropyloxy. Can be substituted with 1 to 3 substituents selected from the group consisting of:
R ⁵ and R ⁶ are independently selected from hydrogen, fluoro, chloro, nitrile, nitro, hydroxy, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, trifluoromethyl, methoxy, ethoxy, propyloxy and isopropyloxy That;
Compound of formula (I) wherein R ⁷ is selected from hydrogen, nitrile, nitro, hydroxy, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, trifluoromethyl, methoxy, ethoxy, propyloxy and isopropyloxy and pharmaceuticals thereof With respect to salts that are pharmaceutically acceptable,
However, the compound is 1- (3-chlorophenyl) -4- (dimethylamino) -1,8-naphthyridin-2 (1H) -one or 4-amino-1-phenyl-1,8-naphthyridine-2 (1H) -Not on.

In another aspect, the present invention provides
R ¹ is phenyl, which can be substituted with 1 to 3 R ¹⁰ ;
R ¹⁰ is selected from fluoro, chloro and trifluoromethyl;
R ³ is hydrogen;
R ⁴ is —NR ^4-1 R ^4-2 ;
R ^4-1 is selected from the group consisting of hydrogen and methyl;
R ^4-2 is phenyl, wherein the phenyl can be substituted with 1 or 2 substituents selected from the group consisting of nitrile, fluoro, chloro, methyl, ethyl, methoxy and ethoxy; Or R ^4-1 and R ^4-2 form morpholinyl,
R ⁵ and R ⁶ are independently selected from hydrogen, fluoro and chloro;
With respect to compounds of formula (I) and pharmaceutically acceptable salts thereof wherein R ⁷ is selected from hydrogen, fluoro and chloro,
However, the compound is 1- (3-chlorophenyl) -4- (dimethylamino) -1,8-naphthyridin-2 (1H) -one or 4-amino-1-phenyl-1,8-naphthyridine-2 (1H) -Not on.

  In another embodiment, the present invention provides compounds of formula (Ia)

Which can be substituted as described above.

  In another embodiment, the present invention provides compounds of formula (Ib)

Which can be substituted as described above.

  The 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 the compounds of the invention. Related disorders include early-onset diabetics of the young (MODEY), latent autoimmune diabetes (LADA), impaired glucose tolerance (IGT), fasting glucose disorder (Impaired fasting glucose) (IFG), gestational diabetes, and metabolic syndrome X.

  In other embodiments, the methods of the present invention may be used for the compounds of the present invention in combination with PPAR agonists, insulin sensitizers, sulfonylureas, insulin secretagogues, hepatic glucose output lowering compounds, α-glucosidase inhibitors or insulin. Provide administration. PPAR agonists include rosiglitazone and pioglitazone. Sulfonylureas include glibenclamide, glimepiride, chlorpropamide and glipizide. Insulin secretagogues include GLP-1, GIP, PACAP / VPAC receptor agonists, secretin, nateglinide, meglitinide, repaglinide, glibenclamide, glimepiride, chlorpropamide, and chloroproprimide. . Alpha-glucosidase inhibitors include acarbose, miglitol and voglibose. The compound that lowers hepatic glucose output is metformin.

  In other embodiments, the methods of the present invention may include HMG CoA reductase inhibitors (HMG-CoA reductase inhibitors), nicotinic acid, bile acid sequestrants, fibric acid derivatives, antihypertensive antihypertensive drugs and antihypertensive drugs. Administration of a compound of the present invention in combination with an obesity drug is provided. Antiobesity agents include β-3 agonists, CB-1 antagonists and lipase inhibitors.

  In other aspects 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, the method of the present invention improves the sensitivity of pancreatic β-cells to insulin secretagogues by administration of the compounds of the present invention. Insulin secretagogues include GLP-1, GIP, PAC / VPAC receptor agonists, secretin, nateglinide, meglitinide, repaglinide, glibenclamide, glimepiride, chlorpropamide and glipizide.

  The present invention thus provides compounds and methods for the treatment of diabetes and related disorders. These and other aspects of the invention will become more apparent from the following description.

  In other words, the present invention relates to a compound of formula (I) for the treatment and / or prevention of disorders, at least in combination with at least one pharmaceutically acceptable pharmaceutically safe carrier or excipient. Use of a compound of formula (I) for the manufacture of a medicament comprising one compound of formula (I), a medicament for the treatment and / or prevention of diabetes, formula for the treatment and / or prevention of diabetes ( It relates to a medicament containing a compound of I) and to a method of inhibiting diabetes in humans and animals by administering an amount of at least one compound of formula (I) effective in stimulating insulin release.

Detailed Description of the Invention The present invention relates generally to the compounds described in the following table and preparation examples. Such compounds can be used in the treatment of diabetes and related disorders.

  In another aspect, the invention relates to a method for treating diabetes and related disorders by administration of a compound of the invention. A preferred method relates to the treatment of type 2 diabetes. In the method of the present invention, the compound of the present invention can be administered in combination with a PPAR agonist, insulin sensitizer, sulfonylurea, insulin secretagogue, metformin, α-glucosidase inhibitor and insulin. In other embodiments, the compounds of the invention are administered in combination with an HMG CoA reductase inhibitor, nicotinic acid, bile acid sequestrant, fibric acid derivative, antihypertensive agent or anti-obesity agent.

In other methods of the invention, the compounds of the invention are administered to treat or prevent secondary causes of diabetes or to increase the sensitivity of pancreatic β-cells to insulin secretagogues.
Another form of the novel compound also included in the compounds of the present invention is (a) its stereoisomer, (b) its pharmaceutically acceptable salt, (c) its tautomer, (d) A protective acid and a conjugate acid thereof; (e) a prodrug thereof; and (f) a solvate or salt solvate thereof.
(A) Stereoisomers Stereoisomers of these compounds can include, but are not limited to, enantiomers, diastereomers, racemic mixtures, and combinations thereof. Such stereoisomers can be prepared and separated by reacting enantiomeric starting materials or by separating isomers of the compounds of the invention using conventional methods. Isomers can also 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 encompassed within the compounds of the invention. The isomers can be used in pure form or in a mixture with other isomers of the above inhibitors.
(B) Pharmaceutically acceptable salts Pharmaceutically acceptable salts of the compounds of the present invention include salts commonly used for the formation of alkali metal salts or the formation of free acids or free bases. Is included. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts can be made from inorganic or organic acids. Examples of such inorganic acids are hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid and phosphoric acid. Suitable organic acids can be selected from organic acids of the type of aliphatic acids, cycloaliphatic acids, aromatic acids, heterocyclic acids, carboxylic acids and sulfonic acids. Examples of organic acids of the organic and sulfonic acid types include formic acid, acetic acid, furopionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid Acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, mesylic acid, salicylic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid (pamoic acid), methanesulfonic acid, ethanesulfone Acid, benzene sulfonic acid, pantothenic acid, 2-hydroxyethane sulfonic acid, toluene sulfonic acid, sulfanilic acid, cyclohexylamino sulfonic acid, stearic acid, argenic acid, N-hydroxybutyric acid, salicylic acid, galactaric acid and galacturon As well as combinations thereof are not limited thereto.
(C) Tautomers Tautomers of the compounds of the present invention are encompassed by the present invention. Thus, for example, carbonyl includes its hydroxy tautomer.
(D) Protecting acids and conjugate acids Protecting acids include, but are not limited to, esters, hydroxyamino derivatives, amides and sulfonamides.
(E) Prodrugs The present invention also includes prodrugs and prodrug salts. Prodrug formation is well known in the art to enhance the properties of the parent compound; such properties include solubility, absorbability, biological stability and release time ("Pharmaceutical Dosage"). Reference is made to “Form and Drug Delivery Systems” (6th edition), Ansel et al., Williams & Wilkins, 1995, pages 27-29, the contents of which are incorporated herein by reference. Become). Commonly used prodrugs are designed to take advantage of the main drug biotransformation reactions and should also be considered within the scope of the present invention. Major drug bioconversion reactions include N-dealkylation, O-dealkylation, aliphatic hydroxylation, aromatic hydroxylation, N-oxidation, S-oxidation, deamination, hydrolysis reaction, glucuronidation, sulfuric acid (See Goodman and Gilman's The Pharmacological Basis of Therapeutics (9th edition), edited by Molinoff et al., McGraw-Hill, 1996, pp. 11-13). (The description is the contents of this specification).
(F) Solvates The present invention includes solvates and solvates of salts. Solvates for the purposes of the present invention are in the form of compounds that coordinate with solvent molecules to form a complex in the solid or liquid state. Hydrates are a special form of solvates, in which case the coordination is with water. These include but are not limited to monohydrate and hemihydrate.

A comprehensive list of abbreviations used by ordinary skilled organic chemists in the art is in the first edition of each volume of the Journal of Organic Chemistry; this list is typically a table titled Standard List of Abreviations. Shown in. The abbreviations contained in the list and all abbreviations used by ordinary skilled organic chemists in the art are incorporated herein by reference.

For the purposes of the present invention, chemical elements are identified according to Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th edition, 1986-87, inner cover.
General manufacturing methods are generally commercially available by routine methods known in the art, by similar known methods, and / or by the methods described herein, or routinely The compounds used in the present invention can be prepared using starting materials that can be prepared according to conventional chemical methods. In order to assist the reader in the synthesis of the compounds of the present invention, the following preparation method is shown. If necessary, active groups present in the substrate will be protected against reaction with reagents or reaction under reaction conditions. This is the Theodore W. Greene, Peter G. M.M. According to standard methods such as in Wuts, Protective Groups in Organic Synthesis, 3rd edition, Wiley-Interscience, NY, NY, 1999.

In general, compounds of formula (I) can be prepared from appropriately substituted nicotinic acid via several routes summarized in Schemes IV.
Scheme I
Nicotinic acid used in Scheme I can be purchased from commercial sources or can be prepared according to literature in the field (Biorg. Med. Chem. Lett., 2001, 475-477; Prakt.Chem.33.2002; Eur.J.Org.Chem.1371, 2001; J.Org.Chem.6: 2000,4618; Med. Chem. Lett. 10: 2000, 1151; U.S. Pat.

Scheme II
Scheme II shows the operation of R ⁶ in formula (I). These operations should also be applicable to R ⁵ and R ⁷ in formula (I).

Scheme III
Scheme III shows the operation of R ⁷ in formula (I). These operations should also be applicable to R ⁵ in formula (I).

Scheme IV
Scheme IV shows the operation of R ⁵ in formula (I). These operations should also be applicable to R ⁷ in formula (I).

Scheme V
Scheme V illustrates the transformation of some functional groups present in formula (I).

  Thus, the present application provides a compound of formula (I)

[Wherein R ⁴ represents a leaving group such as halogen, tosylate, mesylate or triflate, preferably chlorine]
Of the formula HNR ^4-1 R ^4-2 in the presence of a base, preferably lithium bis (trimethylsilyl) amide.
It is related also with the manufacturing method of the compound of this invention made to react with this compound.

Specific Examples of the Invention In order to illustrate the invention described herein, the following specific examples are given but should not be construed as limiting the scope of the invention in any way.
Abbreviations and acronyms When the following abbreviations are used throughout this disclosure, they have the following meanings:
CH ₂ Cl ₂ methylene chloride THF tetrahydrofuran Na ₂ SO ₄ anhydrous sodium sulfate DMSO dimethyl sulfoxide EtOAc ethyl acetate Et ₃ N triethylamine HCl hydrochloric acid
¹ H NMR proton nuclear magnetic resonance HPLC high performance liquid chromatography K ₂ CO ₃ potassium carbonate NH ₄ Cl ammonium chloride LC / MS liquid chromatography / mass spectrometry MeOH methanol NaHCO ₃ sodium bicarbonate NaOH sodium hydroxide RT retention time h hours min min DMF N, N-dimethylformamide BuLi butyllithium TLC thin layer chromatography TFA trifluoroacetic acid LiHMDS lithium hexamethyldisilazide LDA lithium diisopropylamide SOCl ₂ all thionyl chloride AcOH acetic reactions, dry argon unless otherwise indicated Or under a positive pressure of dry nitrogen and magnetically stirred. Sensitive liquids and solutions were transferred via a syringe and introduced into the reaction vessel via a rubber septum. Commercial grade reagents and solvents were used without further purification.

  Unless otherwise noted, the term “concentration under reduced pressure” refers to the use of a Buchi rotary evaporator at about 15 mm Hg. All temperatures are reported in degrees Celsius (° C) without correction. Unless otherwise noted, all parts and percentages are by volume.

Proton ( ¹ H) nuclear magnetic resonance (NMR) spectra were obtained using a Varian Mercury (300 MHz) or Bruker Avance (500 MHz) spectrometer, with Me ₄ Si (δ 0.00) or residual protonated solvent (CHCl ₃ δ as standard). 7.26; MeOH δ 3.30; DMSO δ 2.49). The NMR data of the synthesized examples that are not disclosed in the detailed characterization below are consistent with their corresponding structural assignments.

HPLC-MS spectra were obtained from a Hewlett-Packard equipped with a quaternary pump, a variable wavelength detector set at 254 nm, a YMC pro C-18 column (2 × 23 mm, 120 A) and a Finnigan LCQ ion trap mass spectrometer using electrospray ionization. Obtained using a Packard 1100 HPLC. The spectrum was scanned from 120 to 1200 amu using a variable ion time according to the number of ions in the source. The eluents were A: 2% CH ₃ CN in water containing 0.02% TFA and B: 2% water in CH ₃ CN containing 0.018% TFA. Gradient elution from 10% 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 experiment time was 6.5 minutes.

The IUPAC name was obtained using the ACD / ILab web service.
Preparation Examples Intermediate 1: 2-{[3- (trifluoromethyl) phenyl] amino} nicotinoyl chloride

A solution of 2- [3- (trifluoromethyl) phenyl] amino] nicotinic acid (Niflumic acid, 10 g, 35.43 mmol) in thionyl chloride (31 ml, 12 eq) was heated at reflux for 2 hours. . Excess thionyl chloride was evaporated and the residue was dissolved in dichloromethane and filtered through a plug of silica gel. The filtrate was concentrated to give the desired product (7.6 g, 71%) as a yellow solid: R _f = 0.67 (6: 1 hexane: EtOAc).
Intermediate 2: ethyl 3-oxo-3- (2-{[3- (trifluoromethyl) phenyl] amino} -3-pyridinyl) propanoate

To a solution of ethyl hydrogen manolate (4.6 ml, 39.0 mmol) in THF (190 ml) cooled at −78 ° C. was added a solution of n-BuLi in hexane (2.5 M, 32 ml, 78.38 mmol) was added slowly. The reaction mixture became a milky white solution. To the above reaction mixture was slowly added a solution of intermediate 1 (7.6 g, 32.66 mmol) in THF (10 ml) at −78 ° C. It became an orange solution and then turned into a yellow solution. After the addition, the cooling bath was removed and the resulting reaction mixture was stirred at room temperature for 2 hours. It was quenched with saturated NH ₄ Cl and extracted with ethyl acetate. The organic phase was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give a brownish oil, which was flash column (silica gel, hexane: EtOAc = 6: 1 to 4: 1 to 2: 1). Purified. The desired product (3.52 g, 38%) was obtained as a yellow oil that became a yellow solid on standing. LCMS RT: 3.62 min, MH ^<+> = 353.1, _Rf = 0.14 (6: 1 hexane: EtOAc).
Intermediate 3: 4-hydroxy-1- [3- (trifluoromethyl) phenyl] -1,8-naphthyridin-2 (1H) -one

A solution of intermediate 2 (3.52 g, 9.99 mmol) in xylene (50 ml) was heated at 130 ° C. overnight (18 hours). It became a suspension when heated. The reaction mixture was cooled to room temperature and the desired product that precipitated was collected by filtration as a white solid. It was washed with ethyl acetate. The filtrates were combined, concentrated, dissolved in xylene and again heated at 130 ° C. overnight. The desired product was collected again by filtration. A total of 2 g of the desired product (65%) was obtained: LCMS RT = 2.45 min, MH ⁺ = 307.2.
Intermediate 4: 4-Chloro-1- [3- (trifluoromethyl) phenyl] -1,8-naphthyridin-2 (1H) -one

Intermediate 3 (1 g, 3.27 mmol) was dissolved in a mixture of a solution of 2M oxalyl chloride in oxalyl chloride (13 ml) and dichloromethane (13 ml). The reaction mixture was stirred at room temperature overnight (18 hours). The solvent and excess oxalyl chloride were evaporated and the residue was suspended in a small amount of ethyl acetate and filtered to remove unreacted starting material. The filtrate was concentrated and purified by flash column (silica gel, hexane: EtOAc = 3: 1). The desired product (633 mg, 66%) was obtained as a white solid: LCMS RT = 2.74, MH ⁺ = 325.4, R _f = 0.10 (6: 1 hexane: EtOAc).
Final product:

A reaction mixture of Intermediate 4 in 1,4-dioxane (30 mg, 0.0924 mmol, 1 eq), amine (2 eq) and 1M lithium bis (trimethylsilyl) amide (LiHMDS, 2 eq) in hexane at room temperature. Or at reflux overnight (18 hours). It was quenched with saturated NH ₄ Cl and extracted with dichloromethane. The organic phase was dried over anhydrous Na ₂ SO ₄ , filtered, concentrated and purified by flash column (silica gel, hexane: EtOAc = 2: 1). The desired product was obtained in a yield of 18% -60%.

  Compounds that can be synthesized via the methods described above include:

Is included.

  The compounds of the invention can be used in the treatment of diabetes, including both type 1 and type 2 diabetes (non-insulin dependent diabetes). Such treatment can also delay the onset of diabetes and diabetic complications. Compounds can be used to prevent patients with impaired glucose tolerance from progressing to developing type 2 diabetes. Other diseases and conditions that can be treated or prevented with the compounds of the invention in the methods of the invention include: early-onset adult type diabetes (MODY) (Herman, et al., Diabetes 43: 1994, 40). Adult latent autoimmune diabetes (LADA) (Zimmet, et al., Diabetes Med. 11: 1994, 299); Glucose intolerance (IGT) (Expert Committee on Classification of Mellitus, Diabetes Scape. 22) 1): S5, 1999); Fasting glucose disorder (IFG) (Charles, et al., Diabetes 40: 1991, 796); Gestational diabetes (by Metzger, Diabe) tes, 40: 1991, 197); and metabolic syndrome X.

  The compounds of the present invention are useful in disorders such as obesity as well as atherosclerosis, hyperlipidemia, hypercholesterolemia, low HDL levels, hypertension, cardiovascular disease (atherosclerosis, coronary heart disease) , Including coronary artery disease and hypertension), cerebrovascular disease and peripheral vascular disease.

  The compounds of the present invention can be used for example for cell differentiation resulting in lipid deposited cells, eg abnormal pancreatic beta cell function, insulin-secreting tumors and / or autoantibodies to insulin, autoantibodies to insulin receptors or autoantibodies stimulating to pancreatic beta cells. Regulation of insulin sensitivity and blood glucose level in autoimmune hypoglycemia, macrophage differentiation leading to atherosclerotic plaque formation, inflammatory response, carcinogenesis, hyperplasia, adipocyte gene expression, adipocyte differentiation, pancreatic β -Decrease in cell mass, insulin secretion, tissue sensitivity to insulin, liposarcoma cell growth, polycystic ovarian disease, chronic anovulation, hyperandrogenism, progesterone production, steroidogenesis, redox potential and oxidative stress in cells, oxidation Nitrogen synthase (NOS) production, gamma Le Tamil trans peptidase, catalase, plasma triglycerides, also for the treatment of physiological disorders associated with such HDL and increased LDL cholesterol levels may be useful.

  The compounds of the invention can also be used in the methods of the invention for the treatment of 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. Agents that can induce diabetes include pyriminil, nicotinic acid, glucocorticoid, phenytoin, thyroid hormone, β-adrenergic drugs, α-interferon and drugs used to treat HIV infection. It is not limited to these.

  The compounds of the present invention can 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 can be used partially or fully in combination therapy.

  A compound of the present invention comprising a PPAR agonist, a sulfonylurea drug, a non-sulfonylurea secretagogue, an α-glucosidase inhibitor, an insulin sensitizer, an insulin secretagogue, a liver glucose excretion reducing compound, insulin and an anti-obesity drug It can also be administered in combination with other known therapies for the treatment of diabetes. Such treatment can be administered prior to, concurrently with, or subsequent to administration of the compounds of the present invention. Insulin includes both long-term and short-acting forms as well as preparations of insulin. PPAR agonists can include agonists of any of the PPAR subunits or combinations thereof. For example, PPAR agonists can include agonists of PPAR-α, PPAR-γ, PPAR-δ or any combination of two or three subunits of PPAR. PPAR agonists include, for example, rosiglitazone, troglitazone, and pioglitazone. Sulfonylurea drugs include, for example, glyburide, glimepiride, chlorpropamide, tolbutamide and glipizide. Alpha-glucosidase inhibitors that may be useful in the treatment of diabetes when administered with the compounds of the present invention include acarbose, miglitol and voglibose. Insulin sensitizers that may be useful in the treatment of diabetes include PPAR-γ agonists such as glitazones (eg troglitazone, pioglitazone, englititazone, MCC-555, rosiglitazone, etc.); biguanides such as metformin and fenfor Protein tyrosine phosphatase-1B (PTP-1B) inhibitors; dipeptidyl peptidase IV (DP-IV) inhibitors; and thiazolidinediones and non-thiazolidinediones. Hepatic glucose output lowering compounds that may be useful in the treatment of diabetes when administered with the compounds of the present invention include metformin, such as Glucophage and Glucophage XR. Insulin secretagogues that may be useful in the treatment of diabetes when administered with the compounds of the present invention include sulfonylureas and non-sulfonylureas: GLP-1, GIP, secretin, nateglinide, meglitinide, Repaglinide, glibenclamide, glimepiride, chlorpropamide, glipizide are included. GLP-1 includes derivatives of GLP-1 that have a longer half-life than native GLP-1, such as fatty acid derivatized GLP-1 and exendin. In one embodiment of the invention, the compounds of the invention are used in combination with an insulin secretagogue to improve pancreatic β-cell sensitivity to an insulin secretagogue.

  The compounds of the present invention can also be used in the methods of the present invention in combination with anti-obesity agents. Anti-obesity drugs include β-3 agonists; CB-1 antagonists; neuropeptide Y5 inhibitors; appetite suppressants such as sibutramine (Meridia); and lipase inhibitors such as orlistat (xenical) (Xenical)).

  The compounds of the invention can also be used in the methods of the invention in combination with drugs commonly used to treat lipid disorders in diabetic patients. Such agents include HMG-CoA reductase inhibitors, nicotinic acid, lipid-lowering drugs (eg stanol esters, sterol glycosides such as tiqueside and azetidinones such as ezetimibe, ACAT inhibitors (eg abashimibe) (Vasimib), bile acid sequestrants, bile acid reabsorption inhibitors, microsomal triglyceride transport inhibitors and fibric acid derivatives, including but not limited to HMG-CoA reductase inhibitors such as lovastatin, simvastatin (Simvastatin), pravastatin, fluvastatin, atorvastatin, rivasta Rivastatin, itavastatin, cerivastatin, and ZD-4522, including fibric acid derivatives such as clofibrate, fenofibrate, bezafibrate, bezafibrate, bezafibrate Examples include cprofibrate, beclofibrate, etofibrate, and gemfibrozil, such as cholestyramine, colestipol and colestipol cross-linked cholestipol. Contains aminoalkyl derivatives

  The compounds of the present invention can also be used in combination with antihypertensive agents such as β-blockers and ACE inhibitors. Examples of additional antihypertensive agents for use in combination with the compounds of the present invention include calcium channel blockers (L-type and T-type; such as diltiazem, verapamil, nifedipine, amlodipine ( amlodipine and mibefradil), diuretics (eg, chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendrofludithiazide) Ethacrylic acid triclinaphene (ethacrylic acid t ricryafene, chlorthalidone, furosemide, musolimine, bumetanide, triamtrene, aspirone, piragon, amidolide, p Zofenopril, fosinopril, enalapril, ceranopril, silazopril, delapril, pentopril ril), lisinopril), AT-1 receptor antagonists (eg, losartan, irbesartan, valsartan), ET receptor antagonists (eg, sitaxsentan, atrsentan, atrsentan) Neutral endopeptidase (NEP) inhibitors, vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g. omapatrilat and gemopatrilat) and nitrates are included.

  Such co-therapy can be administered in any combination of two or more drugs (eg, a compound of the invention in combination with an insulin sensitizer and an anti-obesity drug). Such co-treatment can be administered in the form of a pharmaceutical composition as described above.

  As used herein, various terms are defined below.

  When introducing elements of the present invention or preferred embodiments thereof, the articles “a”, “an”, “the” and “the” have one or more elements. Is meant to mean The terms “comprising”, “including” and “having” are intended to be inclusive and mean that there may be additional elements other than the listed elements.

  As used herein, the term “patient” includes mammals (eg, humans and animals).

  The term “treatment” refers to any process, action, that provides medical assistance to a patient, including a human, for the purpose of directly or indirectly improving the patient's condition or slowing the progression of the condition or disorder in the patient. Includes application, treatment, etc.

  The term “combination therapy” or “co-therapy” means the administration of two or more therapeutic agents for the treatment of diabetic conditions and / or disorders. Such administration can be performed in a substantially simultaneous manner, for example in a single capsule with a fixed ratio of active ingredients, or in two or more individual capsules for each inhibitor. Includes co-administration of therapeutic agents. Furthermore, such administration encompasses the use of each type of therapeutic agent in a sequential manner.

  The phrase “therapeutically effective” refers to each administered dose that will achieve the goal of improvement in the severity of the diabetic condition or disorder while avoiding or minimizing adverse side effects associated with the given therapeutic treatment. Means the amount of drug.

  The term “pharmaceutically acceptable” means that the modified term is suitable for use in a pharmaceutical product.

  Based on well-known assays used to determine the efficacy for treatment of the above-identified conditions in mammals and comparing these results with the results of known drugs used to treat these conditions Thus, an effective dose of the compounds of the present invention can be readily determined for each desired indication treatment. The amount of active ingredient (eg, compound) to be administered in one treatment of these conditions depends on the particular compound and dosage unit used, the mode of administration, the duration of treatment, the age and sex of the patient being treated and the treatment. It can vary widely according to considerations such as the nature and extent of the condition being performed.

  The total amount of active ingredient to be administered can generally range from about 0.0001 mg / kg to about 200 mg / kg body weight per day, preferably from about 0.01 mg / kg to about 200 mg / kg body weight. A unit dosage can contain from about 0.05 mg to about 1500 mg of active ingredient, and can be administered one or more times per day. Daily dosages for administration by infusion, including intravenous, intramuscular, subcutaneous and parenteral infusions, and use of infusion techniques can be from about 0.01 to about 200 mg / kg. Daily rectal dosage management can be 0.01-200 mg / kg of total body weight. The transdermal concentration can be that required to maintain a daily dosage of 0.01 to 200 mg / kg.

  Of course, the specific initial and continuing dosage management for each patient will depend on the nature and severity of the condition as determined by the treating physician, the activity of the particular compound used, the age of the patient, the patient's diet, It will vary according to time, route of administration, rate of drug excretion, drug combination, and the like. The desired mode of treatment and number of doses of the compound of the present invention can be ascertained by those skilled in the art using routine treatment tests.

  By administering in a suitably prepared pharmaceutical composition to a patient in need, the compounds of the invention can be used to achieve a desired pharmacological effect. For purposes of the present invention, a patient is a mammal, including a human in need of treatment for a particular condition or disease. Accordingly, the present invention includes a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound. A pharmaceutically acceptable carrier is relatively non-toxic and harmless to the patient at a concentration consistent with the active activity of the active ingredient and any side effects that can be attributed to the carrier do not impair the beneficial effects of the active ingredient. It is such a carrier. A therapeutically effective amount of a compound is that amount which produces a result or affects the particular condition being treated. Effective conventional dosage unit forms, including, for example, immediate and timed release preparations, oral, parenteral, topical, etc., are used herein together with a pharmaceutically acceptable carrier. Can be administered.

  For oral administration, the compounds can be prepared into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions or emulsions. Can be prepared according to methods known in the art for the production of pharmaceutical compositions. The solid unit dosage form can be a capsule, which is a conventional hard- or soft-shell gelatin type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate and corn starch. Can be.

  In other embodiments, binders such as gum arabic, corn starch or gelatin; disintegrants intended to aid tablet breakage and dissolution following administration, such as potato starch, alginic acid, corn starch and guar gum; tablet granulation flow Lubricants intended to improve the adhesion of the tablet material to the surface of the tablet die and punch, such as talc, stearic acid or magnesium stearate, calcium or zinc; dyes; colorants; and aesthetics of the tablets Tableting the compounds of the invention using conventional tablet bases such as lactose, sucrose and corn starch in combination with flavors intended to enhance the quality and make the tablet acceptable to the patient Can do. Excipients suitable for use in oral liquid dosage forms include diluents such as water, with or without the addition of pharmaceutically acceptable surfactants, suspending agents or emulsifiers. And alcohols such as ethanol, benzyl alcohol and polyethylene alcohol. Various other materials can be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules can be coated with shellac, sugar or both.

  Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are represented by those already mentioned above. Additional excipients may also be present, for example sweetening, flavoring and coloring agents such as those mentioned above.

  The pharmaceutical composition of the present invention may be in the form of an oil-in-water emulsion. The oily phase can be a vegetable oil, for example liquid paraffin or a mixture of vegetable oils. Suitable emulsifiers are (1) naturally occurring gums such as gum arabic and tragacanth, (2) naturally occurring phosphatides such as soy and lecithin, (3) esters or partial esters derived from fatty acids and anhydrous hexitol. For example, sorbitan monooleate and (4) condensation products of the partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsion can also contain sweetening and flavoring agents.

  Oily suspensions can be prepared by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil; or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Suspending agents are one or more preservatives such as ethyl p-hydroxybenzoate or n-propyl; one or more colorants; one or more flavors; and one or more Sweetening agents such as sucrose or saccharin can also be included.

  Syrups and elixirs can be prepared with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent and a preservative, flavoring and coloring agents.

  Administration of the compounds of the invention parenterally, ie subcutaneously, intravenously, intramuscularly or intraperitoneally, as an injectable dosage of the compound in a physiologically acceptable diluent together with a pharmaceutical carrier. The carrier can be water, saline, aqueous dextrose and related sugar solutions; alcohols such as ethanol, isopropanol or hexadecyl alcohol; glycols such as propylene glycol or polyethylene glycol; glycerol ketals such as 2,2-dimethyl- 1,1-dioxolane-4-methanol, ethers such as poly (ethylene glycol) 400; oils; fatty acids; fatty acid esters or glycerides; or aseptic liquids or mixtures of liquids such as acetylated fatty acid glycerides Pharmaceutically acceptable surface activity , For example, soap or detergent, suspending agent, such as pectin, carbomers, methylcellulose, not or added hydroxypropylmethylcellulose or carboxymethylcellulose, or emulsifying agents and other pharmaceutical additives are added.

  Examples of oils that can be used in the parenteral preparations of the present invention are of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum and mineral oil. Suitable fatty acids include oleic acid, stearic acid and isostearic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate. Suitable soaps include fatty alkali metal, ammonium and triethanolamine salts; suitable detergents include cationic detergents such as dimethyldialkylammonium halides, alkylpyridinium halides and alkylamine acetates; anionic detergents such as alkyl, aryl And olefin sulfonates, alkyls, olefins, ethers and monoglyceride sulfates and sulfosuccinates; nonionic detergents such as fatty amine oxides, fatty acid alkanolamides and polyoxyethylene polypropylene copolymers; and amphoteric detergents such as alkyl-beta-aminopropio Nate and 2-alkylimidazoline quaternary ammonium salts and mixtures.

  The parenteral compositions of the present invention can typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffering agents can also be used advantageously. In order to minimize or eliminate irritation at the site of infusion, such compositions may contain non-ionic surfactants having a hydrophilic-lipophilic balance (HLB) of about 12 to about 17. it can. The amount of surfactant in such formulations ranges from about 5% to about 15% by weight. The surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB.

  Examples of surfactants used in parenteral formulations are polyethylene sorbitan fatty acid ester types such as sorbitan monooleate and high molecular weight adducts of ethylene oxide and hydrophobic bases formed by condensation of propylene oxide and propylene glycol.

  The pharmaceutical compositions can be in the form of a sterile injectable aqueous suspension. Such suspending agents follow known methods and are suitable dispersing or wetting agents and suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and gum arabic; natural Derived from phosphatides present in water, such as lecithin, condensation products of alkylene oxide and fatty acids, such as polyoxyethylene stearate, condensation products of ethylene oxide and long chain aliphatic alcohols, such as heptadecaethyleneoxycetanol, ethylene oxide and fatty acids and hexitol Products derived from partial esters, such as polyoxyethylene sorbitol monooleate or ethylene oxide with fatty acids and anhydrous hexitol Condensation products of the partial specific esters, such may be prepared using a dispersing or wetting agents may be a polyoxyethylene sorbitan monooleate.

  The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Diluents and solvents that can be used are, for example, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are usually used as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. It can also be used in the preparation of injectable fatty acids such as oleic acid.

  The compositions of the invention can also be administered in the form of suppositories for rectal administration of the drug. These compositions are prepared by mixing the drug (eg, compound) with a suitable non-irritating excipient that is solid at room temperature but liquid at the rectal temperature, and therefore melts in the rectum to release the drug. Can be done. Such materials are, for example, cocoa butter and polyethylene glycol.

  Other formulations used in the methods of the invention employ transdermal delivery devices (“patches”). Such transdermal patches can be used to infuse the compound of the invention continuously or discontinuously in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art (eg, US Pat. No. 5,023,252, the contents of which are incorporated herein by reference). See the description). Such patches can be configured for continuous, pulsed or on-demand delivery of pharmaceutical agents.

  It may be desirable or necessary to introduce the pharmaceutical composition to the patient via a mechanical delivery device. The construction and use of mechanical delivery devices for the delivery of pharmaceutical agents is well known in the art. For example, direct methods for administering a drug directly to the brain typically involve placing a drug delivery catheter within the patient's ventricular system to bypass the blood-brain barrier. One such implantable delivery system used to deliver drugs to specific anatomical regions of the body is described in US Pat. No. 5,011, the contents of which are incorporated herein by reference. 472, which is incorporated herein by reference.

  The compositions of the present invention can also contain other conventional pharmaceutically acceptable compounding ingredients, commonly referred to as carriers or diluents, as needed or desired. Any of the compositions of the present invention can be preserved by the addition of an antioxidant such as ascorbic acid or by other suitable preservatives. Conventional methods for the preparation of such compositions in suitable dosage forms can be used.

  Commonly used pharmaceutical ingredients that can be used to appropriately prepare the composition for its intended route of administration include: acidifying agents such as, but not limited to, acetic acid, citric acid, fumaric acid, Hydrochloric acid, nitric acid; and alkalinizing agents such as, but not limited to, aqueous ammonia, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine It is.

Other pharmaceutical ingredients include, for example, adsorbents (eg, powdered cellulose and activated carbon); aerosol propellants (eg, carbon dioxide, CCl ₂ F ₂ , F ₂ ClC—CClF ₂ and CClF ₃ ); air displacement agents (eg, nitrogen) And antibacterial / fungal preservatives (for example, benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate); antimicrobial preservatives (for example, benzalkonium chloride, benzethonium chloride, benzyl alcohol) , Cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate, thimerosal; antioxidants (eg ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butyrate) Hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite); binding materials (eg block polymers, natural and synthetic rubbers, poly Acrylates, polyurethanes, silicones and styrene-butadiene copolymers); buffering agents (eg potassium metaphosphate, monobasic potassium phosphate, sodium acetate, anhydrous sodium citrate and sodium citrate dihydrate); carrying agents. (For example, acacia syrup, aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil, antibacterial sodium chloride Chelating agents (eg edetate disodium and edetic acid); colorants (eg FD & C Red No. 3, FD & C Red No. 20, FD & C Yellow No. 6, FD & C Blue No) .2, D & C Green No. 5, D & C Orange No. 5, D & C Red No. 8, caramel and ferric oxide red); clearing agents (eg bentonite); emulsifiers (but not limited to gum arabic, cetomacrogol) (Cetomacrogor), cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyethylene 50 stearate); encapsulants (eg gelatin and cellulose acetate phthalate); flavors (eg anise oil, cinnamon oil, cocoa, menthol) Humectants (eg glycerin, propylene glycol and sorbitol); emollients (eg mineral oil and glycerin); oils (eg arachis oil, mineral oil, olive oil, peanut oil, sesame oil and vegetable oil); Ointment bases (eg lanolin, hydrophilic ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white ointment, yellow ointment and rose water ointment); penetration enhancers (transdermal delivery) (eg monohydroxy or polyhydroxy) Hydroxy alcohols, saturated or unsaturated fatty alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl derivatives, cephalins, terpenes, amides, ethers, ketones and ureas); plasticizers (eg phthalates) Solvent (eg alcohol, corn oil, cottonseed oil, glycerin, isopropyl alcohol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection and sterile water for irrigation); curing; Agents (eg cetyl alcohol, cetyl ester wax, microcrystalline wax, paraffin, stearyl alcohol, white wax and yellow wax); suppository bases (eg cocoa butter and polyethylene glycol (mixtures)); surfactants (eg benzalkonium) Chloride, nonoxynol 10, oxoxynol 9, polysorbate 80, sodium lauryl sulfate and sorbitan monopalmitate); suspending agents (eg agar, bentonite, carbomer, sodium carboxymethylcellulose, hydro Sweeteners such as aspartame, dextrose, glycerin, mannitol, propylene glycol, sodium saccharin, sorbitol and sucrose); tablet anti-adhesives (eg stearin) Tablet binders (eg gum arabic, alginic acid, sodium carboxymethylcellulose, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, povidone and pregelatinized starch); tablets and capsule dilutions Agents (eg dibasic calcium phosphate, kaolin, lactose, man Nitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol and starch); tablet coatings (eg liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, acetic acid) Tablet direct compression excipients (eg dibasic calcium phosphate); tablet disintegrants (eg alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrilin potassium, sodium alginate, sodium starch glycolate and starch) ); Tablet lubricants (eg colloidal silica, corn starch and talc); tablet lubricants (eg potassium stearate) Tablets / capsule opacifiers (eg titanium dioxide); tablet abrasives (eg carnauba wax and white wax); thickeners (eg beeswax, cetyl alcohol); And tonicity agents (eg, dextrose and sodium chloride); viscosity improvers (eg, alginic acid, bentonite, carbomer, sodium carboxymethylcellulose, methylcellulose, povidone, sodium alginate and tragacanth); and wetting agents (eg, hepta). Decaethyleneoxycetanol, lecithin, polyethylene sorbitol monooleate, polyoxyethylene sorbitol monooleate and polyoxyethylene stearate). Not limited.

  The compounds described herein can be administered as a single pharmaceutical agent or in combination with one or more other pharmaceutical agents, where the combination is unacceptable adverse effect Does not cause. For example, the compounds of the present invention can be combined with known anti-obesity drugs, or with known anti-diabetic drugs or other indication agents, and the like and mixtures and combinations thereof.

  The compounds described herein can also be used in the form or composition of the free base, in research and diagnosis, or as a reference standard for analysis. Accordingly, the present invention includes compositions comprising an inert carrier and an effective amount of a compound or salt or ester thereof identified by the methods described herein. An inert carrier is any material that does not interact with the compound to be supported and that provides support, means of transport, bulk, traceable materials, etc. to the compound to be supported. An effective amount of a compound is that amount which produces a result or influences the particular method being performed.

  Formulations suitable for subcutaneous, intravenous, intramuscular, etc .; suitable pharmaceutical carriers; and methods for preparation and administration can be prepared by any of the methods well known in the art (eg Remington ' s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 20th edition, 2000).

  It should be apparent to those skilled in the art that changes and modifications can be made to the present invention without departing from the spirit or scope of the invention as set forth herein.

Biological Evaluation The following examples are provided so that the invention might be better understood. These examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way. All published documents cited in this specification are incorporated herein by reference in their entirety.

  The activity of the compounds of the present invention can be verified through in vitro, in vitro and in vivo assays well known in the art. For example, the following assays can be used to demonstrate the effectiveness of pharmaceutical agents for the treatment of diabetes and related disorders such as syndrome X, impaired glucose tolerance, fasting glucose disorder and hyperinsulinemia.

Example 1: Preparation of pseudo islets in 96-well plates Pancreas from four Sprague Dawley rats were divided into small pieces of dimensions about 1 mm ² or smaller. The tissue was then treated with Hanks-Hepes buffer (127 mM NaCl, 5.4 mM KCl, 0.34 mM Na ₂ HPO ₄ , 4.4 mM KH ₂ PO ₄ , 20 mM HEPES (4- (2-hydroxyethyl) piperazine-1-ethanesulfone). acid), rinsed 3 times with 1.2 mM CaCl _2/5 mM glucose), collagenase (Liberase, 0.25mg / ml, Roche Diagnostic Corp., Indianapolis, iN, with USA), at 37 ° C. in a water bath shaker 10 Digested for a minute.

  Digested pancreatic tissue was rinsed 3 times with 50 mL Hanks-Hepes buffer to remove collagenase. The tissue pellet was then filtered through a 250 μm filter and the filtrate was mixed with 16 ml of 27% Ficoll (Sigma, St. Louis, MO, USA) w / v in Hanks-Hepes buffer. Three Ficoll layers (23%, 20.5% and 11%, respectively; 8 mL each) were then placed on top of the mixture of islet tissues in 27% Ficoll to form a gradient.

The Ficoll gradient was then centrifuged at 1,600 rpm for 10 minutes at room temperature. Islets of Langerhans were concentrated at an interface between 11% and 20.5% and between 20.5% and 23% depending on the size of the island. Islands were collected from the two interfaces and rinsed twice with Ca ⁺⁺ -free Hanks-Hepes buffer. The islets were then suspended in 5 ml Ca ⁺⁺ -free Hanks-Hepes buffer containing 1 mM EDTA and incubated for 8 minutes at room temperature.

  Trypsin and DNAse I were added to the islet suspension to final concentrations of 25 μg / mL and 2 μg / mL, respectively. This suspension was incubated at 30 ° C. for 10 minutes with shaking. Trypsin digestion was stopped by adding 40 ml RPMI 1640 (GIBCO Life Technologies, Invitrogen, Carlsbad, Calif.) Containing 10% FBS. Trypsin digested islet cells were then filtered through a 63 μm nylon filter (PGC Scientific, Frederick, MD) to remove large cell clusters.

The dispersed islet cells were then washed, counted with a hemocytometer under a microscope, and seeded in “V-bottom” 96-well plates (2,500 cells per well). The dispersed islet cell suspension was then centrifuged at 1,000 rpm for 5 minutes. Hanks-Hepes buffer was removed and replaced with 200 μL RPMI 1640 medium containing 10% FBS, 1% penicillin-streptomycin and 2 mM L-glutamine. The 96-well plate was then centrifuged at 1,000 rpm for 5 minutes to collect the dispersed islet cells that were concentrated at the V-bottom of the plate to form pseudo islets. These pseudo islets were then cultured overnight in a cell culture incubator at 37 ° C. with 5% CO ₂ and then used for the assay.

[Example 2]: Pseudoislet incubation with 3T3-L1 cells Dispersed islet cells (prepared by the method described in Example 1) were washed with customary RPMI 1640 medium containing 10% FBS under a microscope. And then seeded together with 3T3-L1 cells in “V-bottom” 96-well plates (2,500 islet cells and 1,250 3T3-L1 cells per well). . The cell suspension was then centrifuged at 1,000 rpm for 5 minutes to collect the dispersed islet cells that were concentrated at the V-bottom of the plate to form pseudo islets. These pseudo islets were then co-cultured with 3T3-L1 cells overnight in a cell culture incubator at 37 ° C. with 5% CO ₂ and then used for the assay.

[Example 3]: Frozen islets frozen and thawed Dispersed islet cells (prepared by the method described in Example 1) were counted as described above, and a typical RPMI containing 10% FBS and 10% DMSO 1640 × Dilute to a concentration of 2 × 10 ⁵ cells per mL in the ground. An aliquot (1 mL) was transferred to a cryotube and the cryotube was placed on a shelf in the vapor phase in a liquid nitrogen tank and then frozen in liquid nitrogen.

Cells were thawed and then washed with customary media and seeded in “V-bottom” 96-well plates (5,000 cells per well). The 96-well plate was then centrifuged at 1,000 rpm for 5 minutes to collect the dispersed islet cells that were concentrated at the V-bottom of the plate to form pseudo islets. These pseudo islets were then cultured overnight in a cell culture incubator at 37 ° C. with 5% CO ₂ and then used for the assay.

[Example 4]: Static pseudoislet incubation for insulin release assay Pseudoislets were prepared by the method described in Example 1. Following overnight incubation, RPMI 1640 medium was removed and 100 μL of Krebs-Ringer-Hepes buffer (115 mM NaCl, 5.0 mM KCl, 24 mM NaHCO ₃ , 2.2 mM CaCl ₂ , 1 mM MgCl ₂ , 20 mM HEPES, 0. 25% BSA (bovine serum albumin), 0.002% Phenol Red, pH 7.35-7.40). The cell suspension was then centrifuged at 1,000 rpm for 5 minutes to pellet the dispersed islet cells.

For a 30 minute pre-incubation, pseudoislets in 96-well plates were incubated in a water bath at 37 ° C. with continuous 95% O ₂ /5% CO ₂ gassed. Pre-incubation buffer was removed and replaced with 50 μL of incubation buffer (Krebs-Ringer-Hepes buffer, pH 7.35-7.40) containing various test substrates.

The 96-well plate was again centrifuged at 1,000 rpm for 5 minutes to form pseudo islets. The pseudoislets in these 96-well plates were incubated in a water bath at 37 ° C. with continuous aeration of 95% O ₂ /5% CO ₂ and left to stand for 60 minutes. After 60-minute incubation, incubation buffer (25 μL) was collected and used for insulin content assay (ELISA assay, ALPCO, NH, USA).

Example 5: Stationary pseudoislet incubation for insulin biosynthesis Pseudoislets were prepared as described in Example 1. After overnight culture, KRBH containing 3 mM glucose (Krebs-Ringer-Hepes buffer, 135 mM NaCl, 3.6 mM KCl, 10 mM HEPES, 5 mM NaHCO ₃ , 0.5 mM NaH ₂ PO ₄ , 0.5 mM MgCl ₂ , Preincubation of pseudoislets for 30 minutes at 37 ° C. in 1.5 mM CaCl ₂ , 0.1% bovine serum albumin) followed by test compound and 2 μM ³ H-leucine (100 μL) (Amersham, Piscataway, NJ, USA) And incubated at 37 ° C. for 90 minutes. The pseudo islets were then washed 3 times with KRBH containing 1 mM leucine (Sigma, St. Louis, MO, USA), lysed in 2 mM acetic acid (100 μL), sonicated for 15 seconds, and using 10N NaOH (20 μL). Neutralized. HEPES (50 mM) containing 0.1% Triton X-100 (Calbiochem, San Diego, Calif., USA) was added to bring the volume to 1 mL and the sample was spun at 1750 × g for 10 minutes at high speed. Protein A Agarose (50 μL per sample) was preincubated with anti-insulin antibody (Linco, St. Charles, MO, USA) (100 μL per sample) for 2 hours and washed twice. Antibody bead mixture (50 μL) was added to 750 μL of sample and incubated at 4 ° C. overnight. The immunoprecipitate was washed 3 times with HEPES (50 mM) containing 0.1% Triton X-100. The beads were then counted in a scintillation counter.

Example 6: Pseudoislet incubation for glucagon release Pseudoislets were prepared as described in Example 1. Following overnight incubation, RPMI 1640 medium was removed and 100 μL of Krebs-Ringer-Hepes buffer (115 mM NaCl, 5.0 mM KCl, 24 mM NaHCO ₃ , 2.2 mM CaCl ₂ , 1 mM MgCl ₂ , 20 mM HEPES, 0. 25% BSA, 0.002% Phenol Red, pH 7.35-7.40). The cell suspension was then centrifuged at 1,000 rpm for 5 minutes to pellet the dispersed islet cells.

For 30 min pre-incubation, pseudoislets in 96-well plates were incubated in a water bath at 37 ° C. with continuous aeration of 95% O ₂ /5% CO ₂ . The pre-incubation buffer was removed and replaced with 50 μl of incubation buffer (Krebs-Ringer-Hepes buffer, pH 7.35-7.40) containing various test compounds.

The 96-well plate was again centrifuged at 1,000 rpm for 5 minutes to form pseudo islets. The pseudoislets in these 96-well plates were incubated in a water bath at 37 ° C. with continuous aeration of 95% O ₂ /5% CO ₂ and left to stand for 60 minutes. After 60-minute incubation, incubation buffer (25 μL) was collected and used for glucagon content assays (Glucagon RIA kit; Linco, St. Charles, MO, USA).

Example 7: Assay for Identification of Insulinotropic Compounds Pseudoislets were prepared as described in Example 1. The dispersed islet cells were then washed and counted using a hemacytometer and "V-bottom" 96- with 200 μL RPMI 1640 medium containing 10% FBS, 1% penicillin-streptomycin and 2 mM L-glutamine. Seeded in well plates (2,500 cells per well). The 96-well plate was then centrifuged at 1,000 rpm for 5 minutes to collect the dispersed islet cells that were concentrated at the V-bottom of the plate to form pseudo islets. These pseudo islets were then cultured overnight in a cell culture incubator at 37 ° C. with 5% CO ₂ .

Following overnight incubation, RPMI 1640 medium is removed and 100 μL Krebs-Ringer-Hepes buffer containing 115 mM NaCl (115 mM NaCl, 5.0 mM KCl, 24 mM NaHCO ₃ , 2.2 mM CaCl ₂ , 1 mM MgCl ₂ , 20 mM HEPES, 0.25% BSA, 0.002% Phenol Red, pH 7.35-7.40). The cell suspension was then centrifuged at 1,000 rpm for 5 minutes to pellet the dispersed islet cells.

For 30 min pre-incubation, pseudoislets in 96-well plates were incubated in a water bath at 37 ° C. with continuous aeration of 95% O ₂ /5% CO ₂ . The pre-incubation buffer was removed and replaced with 50 μL of incubation buffer (Krebs-Ringer-Hepes buffer, pH 7.35-7.40) containing the test compound. The 96-well plate was again centrifuged at 1,000 rpm for 5 minutes to form pseudo islets. These pseudoislets were then incubated in a water bath at 37 ° C. with continuous aeration of 95% O ₂ /5% CO ₂ and left to stand for 30 minutes. After a 30-minute incubation, incubation buffer (25 μL) was collected and used for the insulin content assay.

The compounds of the present invention stimulate insulin release beyond basic levels. For example, compounds 2, 6-10 and 12 have been found to stimulate insulin release about 1.3-2 times over basic insulin release.
Pharmaceutical compositions The compounds according to the invention can be converted into pharmaceutical preparations as follows:
tablet:
composition:
100 mg of the compound of Example 1, 50 mg lactose (monohydrate), 50 mg corn starch (domestic), 10 mg polyvinylpyrrolidone (PVP 25) (from BASF, Ludwigshafen, Germany) and 2 mg magnesium stearate. Tablet weight: 212 mg, diameter 8 mm, curvature radius 12 mm.
Preparation:
The mixture of active ingredient, lactose and starch is granulated with a 5% solution of PVP in water (m / m). After drying, the granules are mixed with magnesium stearate for 5 minutes. The mixture is formed using a conventional tablet press (see above for tablet type). The molding force applied is typically 15 kN.
Orally administrable suspensions:
composition:
1000 mg of the compound of Example 1, 1000 mg ethanol (96%), 400 mg Rhodigel (xanthan gum from FMC, Pennsylvania, USA) and 99 g water.

10 ml of oral suspension gives a single dose of 100 mg of the compound according to the invention.
Preparation:
Rhodigel is suspended in ethanol and the active ingredient is added to the suspension. Add water with stirring. Stirring is continued for about 6 hours until Rhodigel swelling is complete.

Claims (22)

formula

[Where:
R ¹ is selected from alkyl of ¹ to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms and AR ⁹ ,
Or R ¹ is aryl of 6 to 10 carbon atoms, 2 to 9 carbon atoms and 1 to 4 heteroatoms of heteroaryl selected from N, S (═O) _0-2 and O, 3 Cycloalkyl of 8 carbon atoms, cycloalkenyl of 4 to 8 carbon atoms, 3 to 6 carbon atoms and 1 to 2 heteroatoms selected from N, S (= O) _0-2 and O Selected from 5 to 7-membered heterocycloalkyl and 5 to 7-membered heterocycloalkenyl of 1 to 2 heteroatoms selected from 3 to 6 carbon atoms and N, S (= O) _0-2 and O Wherein the heterocycloalkyl and heterocycloalkenyl are further phenyl or 2-5 carbon atoms and 5-6 of 1-3 heteroatoms selected from N, S (= O) _0-2 and O. Can be condensed with a member heteroaryl. , And / or where it is possible to the one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl are oxidized to C (= O), all of which 1-3 R Can be substituted with ¹⁰ ;
R ¹⁰ is nitro, nitrile, hydroxy, halogen, acyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms 1 to 6 carbon atoms haloalkyl, 1 to 6 carbon atoms alkoxy, 1 to 6 carbon atoms haloalkoxy, 3 to 6 carbon atoms cycloalkoxy, 6 to 10 carbon atoms Of aryl, 2-9 carbon atoms and heteroaryl of 1-4 heteroatoms selected from N, S (═O) _0-2 and O, NR ¹¹ R ¹² , C (═O) OR ¹¹ , C (═O) NHR ¹¹ , NHC (═O) R ¹³ , NHS (═O) ₂ R ¹³ , S (═O) _0-2 R ¹³ , S (═O) ₂ NHR ¹¹ , 3-6 A cycloalkyl of carbon atoms, a cycloalkyl of 3 to 6 carbon atoms Roarukeniru, 3-6 carbon atoms and N, S _{(= O) 0-2} and 1-2 heteroatoms selected from O 5 to 7 membered heterocycloalkyl and 3-6 carbon atoms and N , S (═O) _0-2 and O selected from 5 to 7-membered heterocycloalkenyl of 1 to 2 heteroatoms, wherein the heterocycloalkyl and heterocycloalkenyl are further phenyl or 2- Can be fused with 5 to 6 membered heteroaryl of 5 carbon atoms and 1 to 3 heteroatoms selected from N, S (═O) _0-2 and O, and / or wherein One or more of the carbon atoms in the heterocycloalkyl or heterocycloalkenyl can be oxidized to C (= O);
R ¹³ is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, 3 to 6 carbon atoms Selected from cycloalkyl and cycloalkenyl of 4 to 6 carbon atoms;
R ¹¹ and R ¹² are hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, 3 Independently selected from cycloalkyl of 6 carbon atoms and cycloalkenyl of 4-6 carbon atoms;
A is selected from alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms and haloalkyl of 1 to 8 carbon atoms;
R ⁹ is selected from hydroxy, alkoxy of 1 to 6 carbon atoms, cycloalkoxy of 3 to 6 carbon atoms, O—A—R ¹⁴ , NR ¹¹ R ¹² ; or R ⁹ is 6 to 10 Aryl of 2 carbon atoms, heteroaryl of 1 to 4 heteroatoms selected from N, S (═O) _0-2 and O, cycloalkyl of 3 to 8 carbon atoms , 5 to 8 carbon atoms cycloalkenyl, all of which can be substituted with 1 to 3 R ¹⁰ , or R ⁹ is 3 to 6 carbon atoms and N, From 5 to 7-membered heterocycloalkyl of 1 to 2 heteroatoms selected from S (= O) _0-2 and O, and 3 to 6 carbon atoms and N, S (= O) _0-2 and O 5-7 membered heterosidies of 1-2 heteroatoms selected Selected from Roarukeniru, wherein said heterocycloalkyl and said heterocycloalkenyl may further phenyl or 2-5 carbon atoms and N, S (= O) 1~3 heteroatoms selected from _0-2 and O And / or wherein one or more of the carbon atoms in the heterocycloalkyl or heterocycloalkenyl are oxidized to C (═O). Wherein the heterocycloalkyl or the heterocycloalkenyl can be substituted with 1 to 3 R ¹⁰ ;
R ¹⁴ is selected from cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 8 carbon atoms, 3 to 6 carbon atoms and N, S (═O) _0-2 and O. 5 to 7 membered heterocycloalkyl of 2 heteroatoms and 5 to 7 membered hetero of 1 to 2 heteroatoms selected from 3 to 6 carbon atoms and N, S (= O) _0-2 and O Selected from cycloalkenyl, wherein all of them can be substituted with 1 to 3 R ¹⁰ ;
R ³ is hydrogen;
R ⁴ is —NR ^4-1 R ^4-2 ;
R ^4-1 is from the group consisting of hydrogen, 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. Chosen;
R ^4-2 is hydrogen, alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, haloalkyl of 1 to 8 carbon atoms, 6 to 10 1 selected from aryl of 2 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms, 3-6 carbon atoms and N, S (= O) _0-2 and O 5 to 7 membered heterocycloalkyl of 2 to 5 heteroatoms and 3 to 6 carbon atoms and 1 to 2 heteroatoms selected from N, S (= O) _0-2 and O Selected from the group consisting of heterocycloalkenyl, wherein said aryl, heteroaryl, heterocycloalkyl or heterocycloalkenyl is nitro, nitrile, hydroxy, halogen, acyl of 1-6 carbon atoms, 1-6 carbons Atomic alk , Alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms and halo of 1 to 6 carbon atoms Can be substituted with 1 to 3 substituents selected from the group consisting of alkoxy, or R ^4-1 and R ^4-2 can be 3 to 6 carbon atoms and N, S (= O) Forms a 5- to 7-membered heterocycloalkyl of 1-2 heteroatoms selected from _0-2 and O, wherein the heterocycloalkyl is of nitro, nitrile, hydroxy, halogen, 1-6 carbon atoms Acyl, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, 1 to 6 carbon atoms Alkoxy and 1-6 carbons Can be substituted with 1-3 substituents selected from the group consisting of haloalkoxy child,
R ⁵ and R ⁶ are cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 4 to 8 carbon atoms, aryl of 6 to 10 carbon atoms and 2 to 9 carbon atoms and 1 to 4 carbon atoms. Independently selected from heteroaryl of heteroatoms, all of which can be substituted with 1 to 3 R ¹⁰ ,
Or R ⁵ and R ⁶ are 3 to 6 carbon atoms and 5 to 7-membered heterocycloalkyl of 1 to 2 heteroatoms selected from N, S (═O) _0-2 and O, and 3 to 6 Independently selected from 5 to 7-membered heterocycloalkenyl of 1 to 2 heteroatoms selected from N, S (═O) _0-2 and O, wherein the heterocycloalkyl and the hetero The cycloalkenyl is further fused with phenyl or 2 to 5 carbon atoms and 5 to 6 membered heteroaryl of 1 to 3 heteroatoms selected from N, S (= O) _0-2 and O. And / or wherein one or more of the carbon atoms in the heterocycloalkyl or heterocycloalkenyl can be oxidized to C (═O), wherein the heterocycloalkyl or heterocycle Roarukeniru is 1-3 ^{R 10, A-R 23,} A-NR 24 R 25, C (= O) R 24, C (= O) OR 24, C (= O) NR 24 R 25, S ( ═O) ₂ R ²⁶ , A—C (═O) R ²⁴ , A—C (═O) OR ²⁴ or A—C (═O) NR ²⁴ R ²⁵ ,
Or R ⁵ and R ⁶ are hydrogen, halogen, nitrile, nitro, hydroxy, alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, 1 to 8 Haloalkyl of 1 carbon atom, alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms, cycloalkoxy of 3-8 carbon atoms, AR ²³ , A (OR ²² ) — R ²³ , NR ²⁷ R ²⁸ , A-NR ²⁷ R ²⁸ , AQR ²⁹ , QR ²⁹ , QA-NR ²⁴ R ²⁵ , C (═O) R ²⁴ , C (═O) OR ²⁴ , C (═O) NR ²⁴ R ²⁵ , A—C (═O) R ²⁴ , A—C (═O) OR ²⁴ and A—C (═O) NR ²⁴ R ²⁵ ;
Q is selected from O and S (= O) _0-2 ;
R ²² is selected from hydrogen, alkyl of 1-8 carbon atoms, haloalkyl of 1-8 carbon atoms and cycloalkyl of 3-8 carbon atoms;
R ²³ is selected from hydroxy, alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms and cycloalkoxy of 3-8 carbon atoms, or R ²³ is 3-8 Selected from cycloalkyl of carbon atoms, cycloalkenyl of 4 to 8 carbon atoms, aryl of 6 to 10 carbon atoms and 2 to 9 carbon atoms and N, S (= O) _0-2 and O Selected from 1 to 4 heteroatoms heteroaryl, all of which can be substituted with 1 to 3 R ¹⁰ , or R ²³ is 3 to 6 carbon atoms and N, O , S (= O) _0-2 selected from 1 to 2 heteroatoms 5-7 membered heterocycloalkyl and 3-6 carbon atoms and N, O, S (= O) _0-2 1 to 2 heteroatoms 5-7 Selected from heterocycloalkenyl, wherein said heterocycloalkyl and said heterocycloalkenyl may further phenyl or 2-5 carbon atoms and N, S (= O) 1~3 amino selected from _0-2 and O Can be fused with a 5-6 membered heteroaryl of a heteroatom and / or wherein one or more of the carbon atoms in the heterocycloalkyl or heterocycloalkenyl are oxidized to C (= O) Wherein the heterocycloalkyl or the heterocycloalkenyl can be substituted with 1 to 3 R ¹⁰ ;
However, with respect to A (OR ²² ) —R ²³ , R ²³ is selected from hydroxy, alkoxy of 1 to 8 carbon atoms, haloalkoxy of 1 to 8 carbon atoms and cycloalkoxy of 3 to 8 carbon atoms. A is not CH;
R ²⁴ and R ²⁵ are hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms and A- R ²⁴ and R ²⁵ are independently selected from R ²³ or R ²⁴ and R ²⁵ are cycloalkyl of 3 to 6 carbon atoms, cycloalkenyl of 3 to 6 carbon atoms, aryl of 6 to 10 carbon atoms and 2 Independently selected from 1 to 4 heteroatoms of heteroaryl selected from ˜9 carbon atoms and N, S (═O) _0-2 and O, all of which are 1 to 3 R ¹⁰ Or R ²⁴ and R ²⁵ are 3 to 6 carbon atoms and 5 to 1 to 2 heteroatoms selected from N, O, S (═O) _0-2. 7-membered heterocycloalkyl as well as 3-6 Atom and N, O, is independently selected from 5-7 membered heterocycloalkenyl of 1-2 heteroatoms selected from S (= O) _0-2, wherein said heterocycloalkyl and said heterocyclo The alkenyl can be further fused to phenyl or 2 to 5 carbon atoms and 5 to 6 membered heteroaryl of 1 to 3 heteroatoms selected from N, S (= O) _0-2 and O. And / or wherein one or more of the carbon atoms in the heterocycloalkyl or heterocycloalkenyl may be oxidized to C (═O), wherein the heterocycloalkyl or heterocyclo or alkenyl may be substituted with 1-3 R ^10, or R ²⁴ and R ²⁵ are linked together with the nitrogen atom to which they are attached, 3-6 carbon Kooyobi N, S _{(= O)} 5~7 membered heterocycloalkyl 1-2 heteroatoms selected from _0-2 and O, 3 to 6 carbon atoms and N, S (= _{O) 0-} Forming a 5-7 membered heterocycloalkenyl of 1-2 heteroatoms selected from ₂ and O or a heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms, wherein said heterocycloalkyl And the heterocycloalkenyl is further condensed with phenyl or 2 to 5 carbon atoms and 5 to 6 membered heteroaryl of 1 to 3 heteroatoms selected from N, S (= O) _0-2 and O. And / or wherein one or more of the carbon atoms in the heterocycloalkyl or heterocycloalkenyl can be oxidized to C (═O), all of which are 1 to three of ^{R 1} In can be substituted;
R ²⁶ is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, A (OR ²² ) —R ²³ and either selected from ^{a-R 23,} or R ²⁶ is cycloalkyl of 3 to 6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, 6 to 10 carbon atoms of the aryl and 2-9 Selected from 1 to 4 heteroatoms of heteroaryl selected from carbon atoms and N, S (═O) _0-2 and O, all of which are substituted with 1 to 3 R ¹⁰ Or R ²⁶ is 3 to 6 carbon atoms and 5 to 7 membered heterocycloalkyl of 1 to 2 heteroatoms selected from N, O, S (═O) _0-2 and 3 to 3 6 carbon atoms and N, O, S (= O Is selected from 1-2 5-7 membered heterocycloalkenyl heteroatoms selected from _0-2, wherein said heterocycloalkyl and said heterocycloalkenyl may further phenyl or 2-5 carbon atoms and N, S (= O) can be fused with 5 to 6 membered heteroaryl of 1 to 3 heteroatoms selected from _0-2 and O, and / or wherein in said heterocycloalkyl or heterocycloalkenyl One or more of the carbon atoms of can be oxidized to C (═O), wherein the heterocycloalkyl or heterocycloalkenyl is substituted with 1 to 3 R ¹⁰ Can do;
R ²⁷ is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms and AR ²³ or chosen, or cycloalkyl of R ²⁷ is 3 to 6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, 6 to 10 carbon atoms of the aryl and 2-9 carbon atoms and N, S (= O) selected from 1 to 4 heteroatoms heteroaryl selected from _0-2 and O, all of which can be substituted with 1 to 3 R ¹⁰ , or R ²⁷ represents 3 to 6 carbon atoms and 5 to 7-membered heterocycloalkyl of 1 to 2 heteroatoms selected from N, O, S (= O) _0-2 and 3 to 6 carbon atoms and N , O, S (═O) selected from _0-2 Selected from 1-2 heteroheterocycloalkenyls of 1-2 heteroatoms, wherein the heterocycloalkyl and heterocycloalkenyl are further phenyl or 2-5 carbon atoms and N, S (= O) ₀ Can be fused with 5 to 6 membered heteroaryl of 1 to 3 heteroatoms selected from _-2 and O, and / or one of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl Or more can be oxidized to C (= O), wherein the heterocycloalkyl or the heterocycloalkenyl can be substituted with 1 to 3 R ¹⁰ ;
R ²⁸ is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, AR ²³ , ^{C (= O) R 24,} C (= O) OR 26, C (= O) NR 25 R 30, S (= O) 2 R 26, A-C (= O) R 24, A-C (= O) OR ²⁴ and A—C (═O) NR ²⁴ R ²⁵ , or R ²⁸ is a cycloalkyl of 3 to 6 carbon atoms, a cycloalkenyl of 3 to 6 carbon atoms, 6 to 10 Selected from aryl of 1 carbon atom, 2-9 carbon atoms and 1 to 4 heteroatoms of heteroaryl selected from N, S (= O) _0-2 and O, all of which are selected from 1 to or may be substituted with 1-3 ^{R 10,} or R ²⁸ is 3-6 Carbon atoms and _{N, O, S (= O} ) 1-2 heteroatoms selected from _0-2 5-7 membered heterocycloalkyl and 3-6 carbon atoms and N, O, S (= O ) Selected from 5 to 7-membered heterocycloalkenyl of 1 to 2 heteroatoms selected from _0-2 , wherein the heterocycloalkyl and heterocycloalkenyl are further phenyl or 2-5 carbon atoms and N , S (═O) _0-2 and O can be fused with 5 to 6 membered heteroaryl of 1 to 3 heteroatoms and / or wherein said heterocycloalkyl or heterocycloalkenyl can is one or more of the carbon atoms in the is oxidized to C (= O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 R ¹⁰ Rukoto can be;
R ³⁰ is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, A (OR ²² ) —R ²³ and either selected from ^{a-R 23,} or R ³⁰ is cycloalkyl of 3 to 6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, 6 to 10 carbon atoms of the aryl and 2-9 Selected from 1 to 4 heteroatoms of heteroaryl selected from carbon atoms and N, S (═O) _0-2 and O, all of which are substituted with 1 to 3 R ¹⁰ Or R ³⁰ is 3 to 6 carbon atoms and 5 to 7 membered heterocycloalkyl of 1 to 2 heteroatoms selected from N, O, S (═O) _0-2 and 3 to 3 6 carbon atoms and N, O, S (= O) ₀ Selected from 5 to 7-membered heterocycloalkenyl of 1 to 2 heteroatoms selected from _-2 , wherein the heterocycloalkyl and heterocycloalkenyl are further phenyl or 2-5 carbon atoms and N, S (= O) can be fused with 5 to 6 membered heteroaryl of 1 to 3 heteroatoms selected from _0-2 and O, and / or wherein in said heterocycloalkyl or heterocycloalkenyl One or more of the carbon atoms can be oxidized to C (═O), wherein the heterocycloalkyl or heterocycloalkenyl is substituted with 1 to 3 R ^10. may or R ²⁵ and ^{R 30,} are tied together with the nitrogen atom to which they are attached, 3-6 carbon atoms and N, S _{(= O) 0-2} and O 1-2 5-7 membered heterocycloalkyl heteroatoms barrel 3 to 6 carbon atoms and N, S _{(= O)} 5~ 1-2 heteroatoms selected from _0-2 and O Form a 7-membered heterocycloalkenyl or a heteroaryl of 2 to 9 carbon atoms and 1 to 4 heteroatoms, all of which can be substituted with 1 to 3 R ¹⁰ ;
R ²⁹ is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, A—R ²³ , A— C (═O) R ²⁴ , AC (═O) OR ²⁴ , AC (═O) NR ²⁴ R ²⁵ , A-NR ²⁷ R ²⁸ , or R ²⁹ is 3-6 Selected from cycloalkyl of carbon atoms, cycloalkenyl of 3 to 6 carbon atoms, aryl of 6 to 10 carbon atoms, 2 to 9 carbon atoms and N, S (= O) _0-2 and O Selected from 1 to 4 heteroatoms of heteroaryl, all of which can be substituted with 1 to 3 R ¹⁰ , or R ²⁹ is 3 to 6 carbon atoms and N, O , 5 1-2 heteroatoms selected from S _{(= O) 0-2} Membered heterocycloalkyl and 3-6 carbon atoms and N, O, selected from 5-7 membered heterocycloalkenyl of S _{(= O)} 1~2 heteroatoms selected from _0-2, wherein the Heterocycloalkyl and said heterocycloalkenyl are further phenyl or 2 to 5 carbon atoms and 5 to 6 membered heteroaryl of 1 to 3 heteroatoms selected from N, S (= O) _0-2 and O Can be fused and / or wherein one or more of the carbon atoms in the heterocycloalkyl or heterocycloalkenyl can be oxidized to C (= O), wherein the A heterocycloalkyl or the heterocycloalkenyl can be substituted with 1 to 3 R ¹⁰ ;
R ⁷ is cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 4 to 8 carbon atoms, aryl of 6 to 10 carbon atoms and 2 to 9 carbon atoms and 1 to 4 heteroatoms Or all of them can be substituted with 1 to 3 R ¹⁰ ,
Or R ⁷ is 3-6 carbon atoms and 5-7 membered heterocycloalkyl of 1-2 heteroatoms selected from N, S (═O) _0-2 and O and 3-6 carbon atoms And N, S (═O) _0-2 and O selected from 5 to 7-membered heterocycloalkenyl of 1 to 2 heteroatoms, wherein the heterocycloalkyl and the heterocycloalkenyl are further phenyl or Can be fused with 2 to 5 carbon atoms and 5 to 6 membered heteroaryl of 1 to 3 heteroatoms selected from N, S (= O) _0-2 and O and / or And one or more of the carbon atoms in the heterocycloalkyl or heterocycloalkenyl can be oxidized to C (= O), wherein the heterocycloalkyl or heterocycloalkenyl is 1 To three ^{R 10, A (OR 22)} -R 23, A-R 23, A-NR 24 R 25, C (= O) R 24, C (= O) OR 24, C (= O) NR ²⁴ R ²⁵ , S (═O) ₂ R ²⁶ , A—C (═O) R ²⁴ , A—C (═O) OR ²⁴ or A—C (═O) NR ²⁴ R ²⁵ Can
Or R ⁷ is hydrogen, nitrile, nitro, hydroxy, alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, 1-8 carbon atoms Haloalkyl, alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms, cycloalkoxy of 3-8 carbon atoms, A—R ²³ , A (OR ²² ) —R ²³ , NR ^{27 R 28, A-NR 27 R} 28, A-Q-R 29, Q-R 29, Q-A-NR 24 R 25, C (= O) R 24, C (= O) OR 24, C (= O) NR ²⁴ R ²⁵ , A—C (═O) R ²⁴ , A—C (═O) OR ²⁴ and A—C (═O) NR ²⁴ R ²⁵ ]
As well as pharmaceutically acceptable salts thereof,
However, the compound is 1- (3-chlorophenyl) -4- (dimethylamino) -1,8-naphthyridin-2 (1H) -one or 4-amino-1-phenyl-1,8-naphthyridine-2 (1H) -Not on. R ¹ is selected from aryl of 6 or 10 carbon atoms, which can be substituted with 1 to 3 R ¹⁰ ;
R ¹⁰ is nitro, nitrile, hydroxy, halogen, acyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms Haloalkoxy of 1 to 6 carbon atoms, cycloalkoxy of 3 to 6 carbon atoms, phenyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzo Heteroaryl selected from thiophenyl, quinolinyl and isoquinolinyl, NR ¹¹ R ¹² , C (═O) OR ¹¹ , C (═O) NHR ¹¹ , NHC (═O) R ¹³ , NHS (═O) ₂ R ¹³ , ^{_{S (= O) 0-2 R 13}} , S (= O) 2 NHR 11, cyclopropyl, consequent Selected from pentyl, cyclohexyl, and heterocycloalkyl selected from tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, piperazinyl, morpholinyl, morpholinyl-N-oxide and thiomorpholinyl Wherein the heterocycloalkyl may be further condensed with phenyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl. Can;
R ¹³ is selected from alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms and cycloalkyl of 3 to 6 carbon atoms;
R ¹¹ and R ¹² are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms and cycloalkyl of 3 to 6 carbon atoms;
A is selected from alkyl of 1 to 8 carbon atoms and haloalkyl of 1 to 8 carbon atoms;
R ³ is hydrogen;
R ⁴ is —NR ^4-1 R ^4-2 ;
R ^4-1 is selected from the group consisting of hydrogen, alkyl of 1-8 carbon atoms and haloalkyl of 1-8 carbon atoms;
R ^4-2 is hydrogen, alkyl of 1 to 8 carbon atoms, haloalkyl of 1 to 8 carbon atoms, aryl of 6 or 10 carbon atoms, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl , Pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl, heteroaryl, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl , Piperazinyl, morpholinyl, morpholinyl-N-oxide and thiomorpholinyl, wherein the aryl, heteroaryl or heterocycloalkyl is nitro, nitrile, hydro Xyl, halogen, acyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms and 1 to 6 carbons Can be substituted with 1 to 3 substituents selected from the group consisting of haloalkoxy of atoms, or R ^4-1 and R ^4-2 are tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2 Forming a heterocycloalkyl selected from dihydropyridinyl, 1,4-dihydropyridinyl, piperazinyl, morpholinyl, morpholinyl-N-oxide and thiomorpholinyl, wherein the heterocycloalkyl is nitro, nitrile, hydroxy, halogen , Acyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, haloal of 1 to 6 carbon atoms Le, can be substituted with 1-3 substituents selected from the group consisting of haloalkoxy of 1-6 alkoxy and 1 to 6 carbon atoms carbon atoms,
R ⁵ and R ⁶ are independently selected from cycloalkyl of 3 to 8 carbon atoms, aryl of 6 to 10 carbon atoms and 2 to 9 carbon atoms and 1 to 4 heteroatoms of heteroaryl. All of them can be substituted with 1 to 3 R ¹⁰ ,
Alternatively, R ⁵ and R ⁶ are heterocycloyl selected from tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, piperazinyl, morpholinyl, morpholinyl-N-oxide and thiomorpholinyl. Where the heterocycloalkyl is further condensed with phenyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl and or isoquinolinyl. Can be
Or R ⁵ and R ⁶ are hydrogen, halogen, nitrile, nitro, hydroxy, alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, 1-8 Haloalkyl of 1 carbon atom, alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms, cycloalkoxy of 3-8 carbon atoms, AR ²³ , A (OR ²² ) — R ²³ , NR ²⁷ R ²⁸ , A-NR ²⁷ R ²⁸ , AQR ²⁹ , QR ²⁹ , QA-NR ²⁴ R ²⁵ , C (═O) R ²⁴ , C (═O) OR ²⁴ , C (═O) NR ²⁴ R ²⁵ , A—C (═O) R ²⁴ , A—C (═O) OR ²⁴ and A—C (═O) NR ²⁴ R ²⁵ ;
Q is selected from O and S (= O) _0-2 ;
R ²² is selected from hydrogen, alkyl of 1 to 8 carbon atoms, haloalkyl of 1 to 8 carbon atoms and cycloalkyl of 3 to 8 carbon atoms;
R ²³ is selected from hydroxy, 1 to 8 carbon atoms alkoxy, 1 to 8 carbon atoms haloalkoxy and 3 to 8 carbon atoms cycloalkoxy, or R ²³ is 3 to 8 carbon atoms From cycloalkyl of carbon atoms, aryl of 6 or 10 carbon atoms and 2 to 9 carbon atoms and 1 to 4 heteroatoms of heteroaryl selected from N, S (= O) _0-2 and O Selected, all of which can be substituted with 1-3 of R ¹⁰ , or R ²³ is tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropyridinyl, 1,4- A heterocycloalkyl selected from dihydropyridinyl, piperazinyl, morpholinyl, morpholinyl-N-oxide and thiomorpholinyl, wherein The heterocycloalkyl can be further condensed with phenyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl. The heterocycloalkyl can be substituted with 1 to 3 R ¹⁰ ;
However, with respect to A (OR ²² ) —R ²³ , R ²³ is selected from hydroxy, alkoxy of 1 to 8 carbon atoms, haloalkoxy of 1 to 8 carbon atoms and cycloalkoxy of 3 to 8 carbon atoms. A is not CH;
R ²⁴ and R ²⁵ are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms and A—R ²³ , or R ²⁴ and R ²⁵ are cyclopropyl, Independently selected from cyclopentyl, cyclohexyl, aryl of 6 to 10 carbon atoms, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl and isoquinolinyl All of which can be substituted with 1 to 3 R ¹⁰ or R ²⁴ and R ²⁵ are tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropyridinyl, 1, 4-dihydropyridinyl, piperazin , Morpholinyl, morpholinyl-N-oxide and thiomorpholinyl, wherein the heterocycloalkyl is further phenyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, It can be fused with indazolyl, benzofuranyl, benzothiophenyl, quinolinyl and or isoquinolinyl, wherein the heterocycloalkyl can be substituted with 1 to 3 R ¹⁰ or R ²⁴ and R ²⁵ together with the nitrogen atom to which they are attached, tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, piperazinyl, morpholini Forming a heterocycloalkyl selected from nyl, morpholinyl-N-oxide and thiomorpholinyl, wherein the heterocycloalkyl is further phenyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl , Benzofuranyl, benzothiophenyl, quinolinyl and or isoquinolinyl, all of which can be substituted with 1 to 3 R ¹⁰ ;
R ²⁶ is selected from alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, A (OR ²² ) —R ²³ and A—R ²³ , or R ²⁶ is cyclopropyl, cyclopentyl, Selected from cyclohexyl, aryl of 6 or 10 carbon atoms, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl and isoquinolinyl, all of them Can be substituted with 1 to 3 R ¹⁰ or R ²⁶ can be tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, piperazinyl , Morpholinyl, mol A heterocycloalkyl selected from folinyl-N-oxide and thiomorpholinyl, wherein the heterocycloalkyl is further phenyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, Can be fused with benzothiophenyl, quinolinyl and or isoquinolinyl, wherein the heterocycloalkyl can be substituted with 1 to 3 R ¹⁰ ;
R ²⁷ is selected from hydrogen, alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms and AR ²³ , or R ²⁷ is cyclopropyl, cyclopentyl, cyclohexyl, 6 to 10 carbon atoms Selected from aryl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl of carbon atoms, all of which are 1 to 3 R ¹⁰ or may be substituted, or R ²⁷ is tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, piperazinyl, morpholinyl, morpholinyl -N- Oxides and thiols A heterocycloalkyl selected from morpholinyl, wherein the heterocycloalkyl is further phenyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl and Or can be fused with isoquinolinyl, wherein the heterocycloalkyl can be substituted with 1 to 3 R ¹⁰ ;
R ²⁸ is hydrogen, alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, A—R ²³ , C (═O) R ²⁴ , C (═O) OR ²⁶ , C (═O ) NR ²⁵ R ³⁰ , S (═O) ₂ R ²⁶ , A—C (═O) R ²⁴ , A—C (═O) OR ²⁴ and A—C (═O) NR ²⁴ R ²⁵ Or R ²⁸ is cyclopropyl, cyclopentyl, cyclohexyl, aryl of 6 to 10 carbon atoms, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl is selected from isoquinolinyl, or all of which may be substituted with 1-3 R ^10, or R ²⁸ Gath A heterocycloalkyl selected from lahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, piperazinyl, morpholinyl, morpholinyl-N-oxide and thiomorpholinyl, wherein Cycloalkyls can be further fused with phenyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl and isoquinolinyl. A heterocycloalkyl can be substituted with 1 to 3 R ¹⁰ ;
R ³⁰ is selected from alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, A (OR ²² ) —R ²³ and A—R ²³ , or R ³⁰ is cyclopropyl, cyclopentyl, Selected from cyclohexyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl, all of which are substituted with 1 to 3 R ¹⁰ Or R ³⁰ is tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, piperazinyl, morpholinyl, morpholinyl-N-oxide and thiomorpholini. Wherein the heterocycloalkyl is further phenyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl and the like. Or can be fused with isoquinolinyl, wherein the heterocycloalkyl can be substituted with 1-3 of R ¹⁰ , or R ²⁵ and R ³⁰ can be attached to the nitrogen to which they are attached. Tie together with an atom, selected from tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, piperazinyl, morpholinyl, morpholinyl-N-oxide, thiomorpholinyl Heterocycloalkyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl, all of which are 1-3 R ¹⁰ Can be substituted with;
R ²⁹ is alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, A—R ²³ , A—C (═O) R ²⁴ , A—C (═O) OR ²⁴ , A— C (═O) NR ²⁴ R ²⁵ , A-NR ²⁷ R ²⁸ , or R ²⁹ is cyclopropyl, cyclopentyl, cyclohexyl, aryl having 6 to 10 carbon atoms, thienyl, furyl, pyrrolyl, thiazolyl, Selected from oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl, all of which can be substituted with 1 to 3 R ¹⁰ , or R ²⁹ is tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropi A heterocycloalkyl selected from lysinyl, 1,4-dihydropyridinyl, piperazinyl, morpholinyl, morpholinyl-N-oxide and thiomorpholinyl, wherein the heterocycloalkyl is further phenyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl , Imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl and or isoquinolinyl, wherein the heterocycloalkyl is substituted with 1 to 3 R ¹⁰ Can be;
R ⁷ is cycloalkyl of 3 to 8 carbon atoms, aryl of 6 to 10 carbon atoms, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiol Selected from phenyl, quinolinyl, isoquinolinyl, all of which can be substituted with 1 to 3 R ¹⁰ ,
Or R ⁷ is heterocycloalkyl selected from tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, piperazinyl, morpholinyl, morpholinyl-N-oxide and thiomorpholinyl Where the heterocycloalkyl can be further condensed with phenyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl And / or wherein one or more of the carbon atoms in the heterocycloalkyl can be oxidized to C (═O), wherein the heterocycloalkyl is 1-3 R ¹⁰ , A (OR ²² ) —R ²³ , A—R ²³ , A—NR ²⁴ R ²⁵ , C (═O) R ²⁴ , C (═O) OR ²⁴ , C (═O) NR ²⁴ R ²⁵ , S (═O) ₂ R ²⁶ , AC (═O) R ²⁴ , AC (═O) OR ²⁴ or AC (═O) NR ²⁴ R ²⁵
Or R ⁷ is hydrogen, nitrile, nitro, hydroxy, alkyl of 1 to 8 carbon atoms, haloalkyl of 1 to 8 carbon atoms, alkoxy of 1 to 8 carbon atoms, 1 to 8 carbon atoms haloalkoxy, cycloalkoxy of 3-8 carbon ^{atoms, a-R 23, a (} OR 22) -R 23, NR 27 R 28, a-NR 27 R 28, a-Q-R 29, Q-R ^{29, Q-A-NR 24} R 25, C (= O) R 24, C (= O) OR 24, C (= O) NR 24 R 25, A-C (= O) R 24, A-C The compound of Claim 1 selected from (= O) OR ²⁴ and A-C (= O) NR ²⁴ R ²⁵ and pharmaceutically acceptable salts thereof,
However, the compound is 1- (3-chlorophenyl) -4- (dimethylamino) -1,8-naphthyridin-2 (1H) -one or 4-amino-1-phenyl-1,8-naphthyridine-2 (1H) -Not on. R ¹ is phenyl, which can be substituted with 1 to 3 R ¹⁰ ;
R ¹⁰ is selected from nitro, nitrile, hydroxy, halogen, trifluoromethyl, methylcarbonyl, ethylcarbonyl, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, methoxy, ethoxy, propyloxy or isopropyloxy;
R ³ is hydrogen;
R ⁴ is —NR ^4-1 R ^4-2 ;
R ^4-1 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl and t-butyl;
R ^4-2 is phenyl, where the phenyl is nitro, nitrile, hydroxy, fluoro, chloro, methylcarbonyl, ethylcarbonyl, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, methoxy, ethoxy, propyloxy Or can be substituted with 1 to 3 substituents selected from the group consisting of isopropyloxy; or R ^4-1 and R ^4-2 form a heterocycloalkyl selected from piperazinyl, morpholinyl and thiomorpholinyl Where the heterocycloalkyl is nitro, nitrile, hydroxy, fluoro, chloro, methylcarbonyl, ethylcarbonyl, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, methoxy, ethoxy, propyloxy or isopropyloxy. Can be substituted with 1 to 3 substituents selected from the group consisting of:
R ⁵ and R ⁶ are independently selected from hydrogen, fluoro, chloro, nitrile, nitro, hydroxy, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, trifluoromethyl, methoxy, ethoxy, propyloxy and isopropyloxy That;
The compound according to claim 1, wherein R ⁷ is selected from hydrogen, nitrile, nitro, hydroxy, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, trifluoromethyl, methoxy, ethoxy, propyloxy and isopropyloxy and pharmaceutical preparation thereof Acceptable salts,
However, the compound is 1- (3-chlorophenyl) -4- (dimethylamino) -1,8-naphthyridin-2 (1H) -one or 4-amino-1-phenyl-1,8-naphthyridine-2 (1H) -Not on. R ¹ is phenyl, which can be substituted with 1 to 3 R ¹⁰ ;
R ¹⁰ is selected from fluoro, chloro and trifluoromethyl;
R ³ is hydrogen;
R ⁴ is —NR ^4-1 R ^4-2 ;
R ^4-1 is selected from the group consisting of hydrogen and methyl;
R ^4-2 is phenyl, wherein the phenyl can be substituted with 1 or 2 substituents selected from the group consisting of nitrile, fluoro, chloro, methyl, ethyl, methoxy and ethoxy; Or R ^4-1 and R ^4-2 form morpholinyl,
R ⁵ and R ⁶ are independently selected from hydrogen, fluoro and chloro;
The compound of claim 1 and pharmaceutically acceptable salts thereof, wherein R ⁷ is selected from hydrogen, fluoro and chloro,
However, the compound is 1- (3-chlorophenyl) -4- (dimethylamino) -1,8-naphthyridin-2 (1H) -one or 4-amino-1-phenyl-1,8-naphthyridine-2 (1H) -Not on.   A pharmaceutical composition comprising an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier.   A pharmaceutical comprising a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier and one or more pharmaceutical agents. Composition.   The pharmaceutical agent is a PPAR agonist, a sulfonylurea drug, a non-sulfonylurea secretagogue, an α-glucosidase inhibitor, an insulin sensitizer, an insulin secretagogue, a liver glucose excretion reducing compound, insulin, an anti-obesity drug, Group consisting of HMG CoA reductase inhibitor, nicotinic acid, bile acid sequestrants, bile acid reabsorption inhibitor, microsomal triglyceride transport inhibitor, fibric acid derivative, lipid lowering drug, ACAT inhibitor and blood pressure lowering drug The pharmaceutical composition of claim 6 selected from.   A method of treating diabetes and diabetes-related disorders comprising administering to a patient in need a therapeutically effective amount of a compound of claim 1.   9. The method of claim 8, wherein the diabetes is selected from the group consisting of type 1 diabetes, type 2 diabetes, juvenile-onset adult diabetes, adult latent autoimmune diabetes and gestational diabetes.   A method of treating syndrome X comprising administering to a patient in need a therapeutically effective amount of the compound of claim 1.   A method of treating a diabetes-related disorder comprising administering to a patient in need a therapeutically effective amount of the compound of claim 1.   The diabetes-related disorder is selected from the group consisting of hyperglycemia, hyperinsulinemia, impaired glucose tolerance, fasted glucose, dyslipidemia, hypertriglyceridemia and insulin resistance 12. The method of claim 11, wherein:   A method of treating diabetes comprising administering to a patient in need a therapeutically effective amount of a compound of claim 1 in combination with one or more pharmaceutical agents.   The pharmaceutical agent is a PPAR agonist, a sulfonylurea drug, a non-sulfonylurea secretagogue, an α-glucosidase inhibitor, an insulin sensitizer, an insulin secretagogue, a liver glucose excretion reducing compound, insulin, an anti-obesity drug, Claims selected from the group consisting of HMG CoA reductase inhibitors, nicotinic acid, bile acid sequestrants, bile acid reabsorption inhibitors, microsomal triglyceride transport inhibitors, fibric acid derivatives, lipid lowering drugs, ACAT inhibitors and blood pressure lowering drugs 13 methods.   A compound according to claim 1 for the treatment and / or prevention of diabetes and diabetes-related disorders.   A medicament comprising at least one compound according to claim 1 in combination with at least one pharmaceutically acceptable pharmaceutically safe carrier or excipient.   Use of a compound according to claim 1 for the manufacture of a medicament for the treatment and / or prevention of diabetes and diabetes-related disorders.   A medicament according to claim 16 for the treatment and / or prevention of diabetes. Formula (I)

[Wherein R ⁴ represents a leaving group]
In the presence of a base of the formula HNR ^4-1 R ^4-2
The manufacturing method of the compound of this invention made to react with the compound of this.   20. The method of claim 19, wherein the leaving group is selected from halogen, tosylate, mesylate and triflate.   21. The method of claim 20, wherein the leaving group is chlorine.   20. The method of claim 19, wherein the base is lithium bis (trimethylsilyl) amide.