[go: up one dir, main page]

WO2011080755A1 - Composés hétérocycliques azotés condensés, leur procédé de préparation et leurs utilisations - Google Patents

Composés hétérocycliques azotés condensés, leur procédé de préparation et leurs utilisations Download PDF

Info

Publication number
WO2011080755A1
WO2011080755A1 PCT/IN2010/000844 IN2010000844W WO2011080755A1 WO 2011080755 A1 WO2011080755 A1 WO 2011080755A1 IN 2010000844 W IN2010000844 W IN 2010000844W WO 2011080755 A1 WO2011080755 A1 WO 2011080755A1
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
enantiomers
pyrrolo
alkyl
pyridine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IN2010/000844
Other languages
English (en)
Inventor
Bhavesh Dave
Anil Deshpande
Santosh Kurhade
Balasaheb Kobal
Debnath Bhuniya
Venkata Palle
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eurofins Advinus Ltd
Original Assignee
Advinus Therapeutics Pvt Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Advinus Therapeutics Pvt Ltd filed Critical Advinus Therapeutics Pvt Ltd
Publication of WO2011080755A1 publication Critical patent/WO2011080755A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This disclosure relates to a series of fused nitrogen heterocyclic compounds, their stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof.
  • the disclosure also relates to process of preparation of the fused nitrogen heterocyclic compounds.
  • Glucokinase activators or modulators which are beneficial for the prophylaxis, management, treatment, control of progression, or adjunct treatment of diseases and/or medical conditions where the activation of glucokinase would be beneficial, such as diabetes, metabolic syndrome, and/or diabetes-related complications including retinopathy, nephropathy, neuropathy, ischemic heart disease, arteriosclerosis, ⁇ -cell dysfunction, and as therapeutic and/or prophylactic agents for obesity.
  • Diabetes mellitus is a metabolic disorder characterized by recurrent or persistent hyperglycemia (high blood glucose) and other signs, as distinct from a single disease or condition.
  • Glucose level abnormalities can result in serious long-term complications, which include beta-cell dysfunction, glucotoxicity, cardiovascular disease, chronic renal failure, retinal damage, nerve damage (of several kinds), microvascular damage, macrovascular damage, adipocyte inflammation, vascular inflamation and obesity.
  • Type 1 diabetes also known as Insulin Dependent Diabetes Mellitus (IDDM)
  • IDDM Insulin Dependent Diabetes Mellitus
  • Type-2 diabetes previously known as adult-onset diabetes, maturity-onset diabetes, or Non-Insulin Dependent Diabetes Mellitus (NIDDM) - is due to a combination of increased hepatic glucose output, defective insulin secretion, and insulin resistance or reduced insulin sensitivity (defective responsiveness of tissues to insulin).
  • Glucokinase also known as hexokinase IV or D, is one of four glucose- phosphorylating enzymes called hexokinases that catalyze the first step of glycolysis, the conversion of glucose to glucose 6-phosphate (G6P), in vertebrate tissues.
  • GK functions in a dual role, with distinct functions in the pancreas and liver; (a) as a molecular glucose sensor in the insulin- producing pancreatic ⁇ -cells, and (b) as the high-capacity enzymatic step initiating the storage of glucose in the form of glycogen in the liver and uptake of glucose during hyperglycemia.
  • GK plays a central role in glucose homeostasis, through the phosphorylation of glucose in the liver, and the modulation of insulin secretion in the pancreas (Postic, C. et al ( 1999) J Biol. Chem. 274: 305-31 5). GK also functions as a sensor in other neuroendocrine cells of the gastrointestinal tract and in various brain cells including specific cells in the hypothalamus (Jetton, T. A. et al ( 1994) J. Biol. Chem. 269: 3641 -3654).
  • the physiological concentration of glucose in human plasma is approximately 5.5 m under fasting conditions, and increases to about 12 mM in the fed state. This concentration is dependent on and maintained by the activity of GK, which senses glucose and controls metabolic flux in key cell types.
  • the glucose concentration, at which GK activity is at half of its maximal velocity or V max is defined as its S 0 . 5 .
  • the S 0 . 5 of GK for glucose lies in the middle of the physiological glucose concentration range at approximately 8 mM, allowing this enzyme to act as a molecular glucose sensor crucial for glucose homeostasis.
  • the limited tissue distribution and unique kinetic properties of GK allow it to play a critical role in pancreatic ⁇ -cell insulin secretion and hepatic glucose utilization.
  • GK differs from the other members of the mammalian hexokinase family in its unique sigmoidal kinetics with respect to glucose, a high S 0 5 that lies in the physiological glucose concentration range (the other three mammalian hexokinases have S 0 values less than 0.5 mM), the lack of product inhibition by G6P, and its tissue distribution in cell types that are thought to be responsive to changing plasma glucose levels.
  • GK mutations have a profound influence on glucose homeostasis.
  • About 2000 GK mutations that have been identified in humans result in impaired glucose-mediated insul in secretion and maturity-onset diabetes of the young type 2 (MODY-2). Some of these mutations result in decreased accumulation of hepatic glycogen, while others decrease GK activity by reducing the stability of the enzyme or by decreasing its V max .
  • Mutations that result in activation of GK are implicated in the onset of persistent hyperinsulinemic hypoglycemia of infancy (PHHI).
  • Single point mutations e.g.
  • V62M, D158A, Y214A, V455M, and F456V in regions distinct from the substrate binding site of the enzyme lead to modulation of GK activity (Glaser, B. et al (1998) N. Engl. J. Med. 338: 226-230; Gloyn, A. L. (2003) Hum. Mutat. 22: 353-362; Gloyn, A. L. et al (2003) Diabetes 52: 2433-2440).
  • GK activity can be regulated through allosteric modulation.
  • GKAs small-molecule glucokinase activators
  • the present disclosure provides a novel class of fused nitrogen heterocyclic compounds characterized as glucokinase activators or modulators, and their potential use as medicament for the prophylactic or therapeutic treatment of hyperglycemia, diabetes, obesity, dyslipidemia, metabolic syndrome and like.
  • the present disclosure relates to compounds of formula (I), their stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof;
  • ring A and ring B are independently selected from cycloalkyl, aryl, heterocyclyl or heteroaryl; ring A and ring B is unsubstituted or substituted with up to 4 substituents independently selected from alkyl, alkenyl, alkynyl, halogen, mono, di, tri or perhaloalkyl, nitrile, nitro, oxo, - NR R 5 , -OR 4 , -S(0) p R 4 , -S(0) p NR 4 R 5 , -NR 4 S(0) consentR 5 , -NR 4 C(0)R 5 , -OS(0) p R 5 , - NR 4 C(0)OR 5 , -(CR 6 R 7 ) n C(0)OR 4 , -(CR 6 R 7 ) n C(0)NR 4 R 5 , -(CR 6 R 7 ) n C(0)R 4 , cycloalkyl, cycloalkylalkyl, heterocycl
  • ring C is a heterocyclyl or a heteroaryl each with at least one N-atom;
  • Y is CR or N; wherein R is selected from hydrogen, halogen, alkyl, fluoroalkyl, OR 5 or aryl; R 1 is selected from hydrogen, alkyl, halogen, haloalkyl or perhaloalkyl;
  • R 2 is selected from hydrogen or alkyl
  • R 1 and R 2 taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms selected from O, N or S;
  • R 3 and R 4 are independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, arylalkyi, heteroaryl, heteroarylalkyl, mono, di, tri or perhaloalkyl, nitrile, nitro, -N R 5 , - NR 5 R 6 , -OR 5 , -S(0) p R 5 , -S(0) p NR 5 R 6 , -NR 5 S(0) p R 6 , -NR 5 C(0)R 6 , -OS(0) p R 6 , - NR 5 C(0)OR 6 , -(CR 7 R 8 ) N C
  • R 3 and R 4 taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms selected from O, N or S; the said ring system may be unsubstituted or substituted with 1 to 4 substituents independently selected from halo, alkyl, alkenyl, alkynyl, nito, cyano, -OR 5 , -SR 5 , - NR 5 R 6 , oxo, alkylsulfonyl, -COOR 5 , -C(0)NR 5 R 6 , cycloalkyl, cycloalkylalkyl, aryl, arylalkyi, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl;
  • R 5 and R 6 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyi, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl; or
  • R 5 and R 6 taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms selected from O, N or S; said ring system may be unsubstituted or substituted with 1 to 4 substituents independently selected from halo, alkyl, alkenyl, alkynyl, nito, cyano, -OR 5 , -SR 5 , - NR 5 R 6 , oxo, alkylsulfonyl, -COOR 5 , -C(0)NR 5 R 6 , cycloalkyl, cycloalkylalkyl, aryl, arylalkyi, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl;
  • R 7 and R 8 are independently selected from the group consisting of hydrogen, fluorine, OR 5 , alkyl, and perfluoroalkyl; or R 7 and R 8 taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms selected from O, N or S; said ring system is unsubstituted or substituted with 1 to 4 substituents independently selected from halo, alkyl, alkenyl, alkynyl, nitro, cyano, oxo, -OR 5 , -SR 5 , - NR 5 R 6 , alkylsulfonyl, -COOR 5 , -C(0)NR 5 R 6 , cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
  • the present invention also relates to process of preparation of compounds of formula (I).
  • the compounds of the present invention are useful as glucokinase activators (G As), or modulators, and can be used as medicament for prophylactic or therapeutic treatment of hyperglycemia, diabetes, obesity, dyslipidemia, metabolic syndrome and like.
  • alkyl refers to a monoradical branched or unbranched saturated . hydrocarbon chain having 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 1 or 20 carbon atoms, preferably 1 ,
  • 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms more preferably 1 , 2, 3, 4, 5 or 6 carbon atoms.
  • This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n- hexyl, n-decyl, tetradecyl, and the like.
  • alkylene refers to a diradical of a branched or unbranched saturated hydrocarbon chain, having 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, . 19 or 20 carbon atoms, preferably 1 , 2,
  • substituted alkyl or '"substituted alkylene refers to: 1 ) an alkyl group or alkylene group as defined above, having 1 , 2, 3, 4 or 5 substituents, preferably 1 , 2 or 3 substituents, selected from the group consisting of aikenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, monoalkylamino, dialkylamino, arylamino, heteroarylamino, aminocarbonyl, alkoxycarbonyl amino, azido, cyano, halogen, hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy, carboxyalkyl, -S0 3 H, aryl, aryloxy, heteroaryl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alk
  • substituents may optionally be further substituted by 1 , 2, or 3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and -S(0) p R c , where R c is alkyl, aryl, or heteroaryl and p is 0.1 or 2;
  • alkyl group or alkylene group as defined above that is interrupted by 1 . 2, 3, 4, 5, 6, 7, 8, 9 or 10 atoms independently selected from oxygen, sulfur and NR d , where R d is selected from hydrogen, alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclyl, carbonylalkyl, carboxyester, carboxyamide and sulfonyl.
  • an alkyl or alkylene as defined above that has 1 , 2, 3, 4 or 5 substituents as defined above, as well as interrupted by 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 atoms as defined above.
  • aikenyl refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 1 7, 1 8, 19 or 20 carbon atoms, more preferably 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and even more preferably 2, 3, 4, 5 or 6 carbon atoms and having 1 , 2, 3, 4, 5 or 6 double bond (vinyl), preferably 1 double bond.
  • alkenylene refers to a diradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 1 5, 16, 1 7, 1 8, 19 or 20 carbon atoms, more preferably 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and even more preferably 2, 3, 4, 5 or 6 carbon atoms and having 1 , 3, 4, 5 or 6 double bond (vinyl), preferably 1 double bond.
  • substituted alkenyl refers to an alkenyl group as defined above having 1 , 2, 3, 4 or 5 substituents, and preferably 1 , 2, or 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, thiocarbonyl, carboxy, carboxyalkyl, S0 3 H, aryl, aryloxy, heteroaryl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, -S(0) 2 NR a R a , -NR a S(0) 2 R a and -S(0) p R b where each R a is independently selected from the group consisting of alkyl,
  • substituents may optionally be further substituted by 1 , 2, or 3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and -S(0) p R c , where R c is alkyl, aryl, or heteroaryl and p is 0, 1 or 2.
  • alkynyl refers to a monoradical of an unsaturated hydrocarbon, preferably having from 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 1 7, 1 8, 1 or 20 carbon atoms, more preferably 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and even more preferably 2, 3, 4, 5 or 6 carbon atoms and having 1 , 2, 3. 4, 5 or 6 sites of acetylene (triple bond) unsaturation, preferably 1 triple bond.
  • Preferred alkynyl groups include ethynyl, (-C ⁇ CH), propargyl (or prop-l-yn-3-yl,-CH 2 C ⁇ CH ). homopropargyl (or but- ] -yn-4-yl, -CH 2 CH 2 C ⁇ CH) and the like.
  • alkynylene refers to a diradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 1 7, 1 8, 19 or 20 carbon atoms, more preferably 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and even more preferably 2, 3, 4, 5 or 6 carbon atoms and having 1 , 3, 4, 5 or 6 sites of acetylene (triple bond) unsaturation, preferably 1 triple bond.
  • substituted alkynyl refers to an alkynyl group as defined above having 1 , 2, 3, 4 or 5 substituents, and preferably 1 , 2, or 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, - S0 3 H, aryl, aryloxy, heteroaryl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, -S(0),NR a R ⁇ -NR a S(0) 2 R a and -S(0) p R b , where each R a
  • substituents may optionally be further substituted by 1 , 2, or 3 substituents selected from alky], carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3, amino, substituted amino, cyano, and-S(O) p R 0 where R c is alkyl, aryl, or heteroaryl and p is 0, 1 or 2.
  • cycloalkyi refers to unless otherwise mentioned, carbocyclic groups of from 3 to 20 carbon atoms having a single cyclic ring, multiple condensed rings or spirocyclic rings which may be saturated or partially unsaturated.
  • Such cycloalkyi groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, bicyclo[2.2.1 ]heptane, bicyclo[2.2.2]octane, 1 ,3,3-trimethylbicyclo[2.2.1 ]hept-2-yl, (2,3,3-trimethylbicyclo[2.2.1 ]hept-2- yl), spiro[4.5]decane, spiro[4.4]nonane or carbocyclic groups to which is fused an aryl group, for example indane, and the like.
  • substituted cycloalkyi refers to cycloalkyi groups having 1 , 2, 3, 4 or 5 substituents, and preferably 1 , 2, or 3 substituents, selected from the group consisting of alkyl, alkoxy, cycloalkyi, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, -C(0)R and - S(0) p R b , where R is hydrogen, hydroxyl, alkoxy, alkyl and cyclocalkyl, heterocyclyloxywhere R b is alkyl,
  • substituents may optionally be further substituted by 1 , 2, or 3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and-S(0) p R c , where R c is alkyl, aryl, or heteroaryl and p is 0, 1 or 2.
  • Halo or “Halogen”, alone or in combination with any other term means halogens such as chloro (CI), fluoro (F), bromo (Br) and iodo (1).
  • Haloalkyl refers to a straight chain or branched chain haloalkyl group with 1 to 6 carbon atoms.
  • the alkyl group may be partly or totally halogenated.
  • Representative examples of haloalkyl groups include but are not limited to fluoromethyl, chloromethyl, bromomethyl, dif!uoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, 2-fluoroethyl, 2-chloroethyl, 2- bromoethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl, 3-chloropropyl, 3-bromopropyl and the like.
  • alkoxy refers to the group R"'-0-, where R'" is optionally substituted alkyl or optionally substituted cycloalkyi, or optionally substituted alkenyl or optionally substituted alkynyl; or optionally substituted cycloalkenyl, where alkyl, alkenyl, alkynyl, cycloalkyi and cycloalkenyl are as defined herein.
  • alkoxy groups include but are not limited to methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1 ,2- dimethylbutoxy, trifluoromethoxy, and the like.
  • aminocarbonyl refers to the group -C(0)NR ' R ' where each R ' is independently hydrogen, alkyl, aryl, heteroaryj, heterocyclyl or both R ' groups are joined to form a heterocyclic group (e. g. morpholino).
  • substituents may optionally be further substituted by 1 -3 substituents selected from alkyl. carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and -S(0) p R c , where R° is alkyl, aryl, or heteroaryl and p is 0, 1 or 2.
  • acylamino refers to the group -NR"C(0)R" where each R" is independently hydrogen, alkyl, aryl, heteroaryl, or heterocyclyl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1 -3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and- S(0) p R c , where R c is alkyl, aryl, or heteroaryl and p is 0, 1 or 2.
  • acyloxy refers to the groups -OC(0)-alkyl, -OC(0)-cycloalkyl, -OC(0)-aryl, -OC(O)- heteroaryl, and -OC(0)-heterocyclyl. Unless otherwise constrained by the definition, all substituents may be optionally further substituted by alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, or -S(0) p R c , where R c is alkyl, aryl, or heteroaryl and p is 0, 1 or 2.
  • Alkoxyalkyl refers to alkyl groups as defined above wherein at least one of the hydrogen atoms of the alkyl group is replaced by an alkoxy group as defined above.
  • Representative examples of alkoxyalkyl groups include but are not limited to methoxymethyl, methoxyethyl, ethoxymethyl and the like.
  • Aryloxyalkyl refers to the group -alkyl-O-aryl.
  • Representative examples of aryloxyalkyl include but are not limited to phenoxymethyl, naphthyloxymethyl, phenoxyethyl, naphthyloxyethyl and the like.
  • Di alkylamino refers to an amino group, to which two same or different straight chain or branched chain alkyl groups with 1 to 6 carbon atoms are bound.
  • Representative examples of di alkylamino include but are not limited to dimethylamino, diethylamino, methylethylamino, dipropylamino, dibutylamino and the like.
  • Cycloalkylalkyl refers to an alkyl radical as defined above which is substituted by a cycloalkyl radical as defined above.
  • Representative examples of cycloalkylalkyl include but are not limited to cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1-cyclopentylethyl, 1 - cyclohexylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, cyclobutyl propyl, cyclopentylpropyl, cyclohexylbutyl and the like.
  • aminoalkyl refers to an amino group that is attached to as defined herein.
  • Representative examples of aminoalkyl include but are not limited to aminomethyl, aminoethyl, 1 - aminopropyl, 2-aminopropyl, and the like.
  • the amino moiety of aminoalkyl may be substituted once or twice with alkyl to provide alkylaminoalkyl and dialkylaminoalkyl respectively.
  • Representative examples of alkylaminoalkyl include but are not limited to methylaminomethyl, methylaminoethyl, methylaminopropyl, ethylaminoethyl and the like.
  • dialkylaminoalkyl include but are not limited to dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, N- methyl-N-ethylaminoethyl and the like.
  • aryl refers to an aromatic carbocyclic group of 6 to 20 carbon atoms having a single ring (e.g. phenyl) or multiple rings (e.g. biphenyl), or multiple condensed (fused) rings (e.g. naphthyl or anthranyl).
  • Preferred aryls include phenyl, naphthyl and the like.
  • arylene refers to a diradical of an aryl group as defined above. This term is exemplified by groups such as 1 ,4-phenylene, 1 ,3-phenylene, 1 ,2-phenylene, 1 ,4'-biphenylene, and the like.
  • the aryl or arylene groups may optionally be substituted with 1 , 2, 3 4 or 5 substituents, preferably 1 , 2 or 3 substituents, selected from the group consisting of alkyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, carboxy, carboxyalkyl, -S0 3 H, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, -S(0) 2 NR a R a , -NR a S(0) 2 R a and -S(0) p R b where each R a is independently selected from the group consisting of hydrogen, alkyl, cyclo
  • substituents may optionally be further substituted by 1 , 2 or 3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and -S(0) p R where R c is hydrogen, alkyl, aryl. or heteroaryl and p is 0, 1 or 2.
  • arylalkyl refers to an aryl group covalently linked to an alkylene group, where aryl and alkylene are defined herein.
  • Optionally substituted arylalkyl refers to an optionally substituted aryl group covalently linked to an optionally substituted alkylene group.
  • arylalkyl groups are exemplified by benzyl, phenethyl, naphthylmethyl, and the like.
  • aryloxy refers to the group aryl-O- wherein the aryl group is as defined above, and includes optionally substituted aryl groups as also defined above.
  • arylthio refers to the group -S-aryl, where aryl is as defined herein including optionally substituted aryl groups as also defined above.
  • substituted amino refers to the group -NR ' R ' where each R' is independently selected from the group consisting of hydrogen, alkyl, cycloalkyi, carboxyalkyl, alkoxycarbonyl, aryl, heteroaryl and heterocyclyl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1, 2 or 3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and -S(0) p R c , where R c is alkyl, aryl, or heteroaryl and p is 0, 1 or 2.
  • carboxyalkyl refers to the groups -alkylene-C(0)OH.
  • alkylcarboxyalkyi refers to the groups -alkylene-C(0)OR d where R d is alkyl, cycloalkyi, where alkyl, cycloalkyi are as defined herein, and may be optionally further substituted by alkyl, halogen, CF 3 , amino, substituted amino, cyano, or -S(0) p R c , in which R c is alkyl, aryl, or heteroaryl and p is 0, 1 or 2.
  • heteroaryl refers to an aromatic cyclic group having 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, or 15 carbon atoms and 1, 2, 3 or 4 heteroatoms selected from oxygen, nitrogen and sulfur within at least one ring.
  • Such heteroaryl groups can have a single ring (e.g. pyridyl or furyl) or multiple condensed rings (e.g. indolizinyl, benzothiazolyl, or benzothienyl).
  • heteroaryls include, but are not limited to, [1,2,4] oxadiazole, [1,3,4] oxadiazole, [1,2,4] thiadiazole, [1,3,4] thiadiazole, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, furan, thiophene, oxazole, thiazole, triazole, triazine,
  • heteroarylene refers to a diradical of a heteroaryl group as defined above. Unless otherwise constrained the heteroaryl or heterarylene groups can be optionally substituted with 1 , 2, 3, 4 or 5 substituents, preferably 1 , 2 or 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyi, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl.
  • alkoxycarbonylamino azido, cyano, halogen, hydroxy, thiocarbonyl, carboxy, carboxyalkyl, -S0 3 H, aryl, aryloxy, heteroaryl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, -S(0) 2 NR a R a , -NR a S(0) 2 R a and -S(0) p R b , where each R a is independently selected from the group consisting of hydrogen, alkyl, cycloalkyi, cycloalkylalkyl, aryl, arylalkyl, heteroaryl heteroarylalkyl, heterocyclyl and heterocyclylalkyl; where R b is hydrogen, alkyl, aryl, heterocyclyl or heteroaryl, and p is 0, 1 or 2.
  • substituents may optionally be further substituted by 1 -3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and-S(0) n R c , where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
  • heteroarylalkyl refers to a heteroaryl group covalently linked to an alkylene group, where heteroaryl and alkylene are defined herein.
  • Optionally substituted heteroarylalkyl refers to an optionally substituted heteroaryl group covalently linked to an optionally substituted alkylene group.
  • Such heteroarylalkyl groups are exemplified by 3-pyridylmethyl, quinolin-8-ylethyl, 4-methoxythiazol-2-ylpropyl, and the like.
  • heterocyclyl refers to a saturated or partially unsaturated group having a single ring, multiple condensed rings or spirocyclic rings, unless otherwise mentioned, having from 1 to 40 carbon atoms and from 1 to 10 hetero atoms, preferably 1 , 2, 3 or 4 heteroatoms, selected from nitrogen, sulfur, phosphorus, and/or oxygen within the ring.
  • Heterocyclic groups can have a single ring or multiple condensed rings, and include tetrahydrofuranyl, morpholinyl, piperidinyl, piperazinyl, dihydropyridinyl, tetrahydroquinolinyl, 7-oxa-spiro[4.5]decane, 7-aza-spiro[4.5]decane and the like. Unless otherwise constrained by the definition for the heterocyclic substituent, such heterocyclic groups can be optionally substituted with 1 , 2, 3, 4 or 5, and preferably 1 .
  • substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, -C(0)R where R is hydrogen, hydroxyl, alkoxy, alkyl and cyclocalkyl, thiocarbonyl, carboxy, carboxyalkyl, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, and -S(0) p R b , where R b is hydrogen, alkyl, aryl, heterocyclyl or heteroaryl and p is 0, 1 or 2.
  • substituents may optionally be further substituted by 1 -3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and -S(0)R c , where R c is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
  • heterocyclylalkyl refers to a heterocyclyl group covalently linked to an alkylene group, where heterocyclyl and alkylene are defined herein.
  • Optionally substituted heterocyclylalkyl refers to an optionally substituted heterocyclyl group covalently linked to an optionally substituted alkylene group.
  • heteroaryloxy refers to the group heteroaryl-O-.
  • thiol refers to the group -SH.
  • substituted alkylthio refers to the group -S-substituted alkyl.
  • heteroarylthio refers to the group -S-heteroaryl wherein the heteroaryl group is as defined above including optionally substituted heteroaryl groups as also defined above.
  • sulfoxide refers to a group -S(O).
  • Substituted sulfoxide refers to a group -S(0) , in which R is substituted alkyl, substituted aryl, or substituted heteroaryl, as defined herein.
  • substituted sulfone refers to a group -S(0) 2 R, in which R is alkyl, aryl, or heteroaryl.
  • the compounds of the present invention may have the ability to crystallize in more than one form, a characteristic known as polymorphism, and all such polymorphic forms (“polymorphs”) are encompassed within the scope of the invention.
  • Polymorphism generally can occur as a response to changes in temperature or pressure or both, and can also result from variations in the crystallization process. Polymorphs can be distinguished by various physical characteristics, and typically the x-ray diffraction patterns, solubility behavior, and melting point of the compound are used to distinguish polymorphs.
  • the compounds described herein may contain one or more chiral centers and/or double bonds and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), regioisomers, enantiomers or diastereomers. Accordingly, the chemical structures depicted herein encompass all possible enantiomers and stereoisomers of the illustrated or identified compounds including the stereoisomerically pure form (e.g.,geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures.
  • stereoisomerically pure form e.g.,geometrically pure, enantiomerically pure or diastereomerically pure
  • Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the person skilled in the art.
  • the compounds may also exist in several tautomeric forms including the enol form, the keto form and mixtures thereof. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated or identified compounds.
  • Compounds may exist in unsolvated forms as well as solvated forms, including hydrated forms and as N-oxides. In general, compounds may be hydrated, solvated or N-oxides. Certain compounds may exist in multiple crystalline or amorphous forms. Also contemplated within the scope of the invention are congeners, analogs, hydrolysis products, metabolites and precursor or prodrugs of the compound. In general, unless otherwise indicated, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of the present invention.
  • Prodrug refers to a derivative of a drug molecule as, for example, esters, carbonates, carbamates, ureas, amides or phosphates that requires a transformation within the body to release the active drug. Prodrugs are frequently, although not necessarily, pharmacologically inactive until converted to the parent drug. Prodrugs may be obtained by bonding a promoiety (defined herein) typically via a functional group, to a drug.
  • Promoiety refers to a group bonded to a drug, typically to a functional group of the drug, via bond(s) that are cleavable under specified conditions of use.
  • the bond(s) between the drug and promoiety may be cleaved by enzymatic or non-enzymatic means. Under the conditions of use, for example following administration to a patient, the bond(s) between the drug and promoiety may be cleaved to release the parent drug.
  • the cleavage of the promoiety may proceed spontaneously, such as via a hydrolysis reaction, or it may be catalyzed or induced by another agent, such as by an enzyme, by light, by acid, or by a change of or exposure to a physical or environmental parameter, such as a change of temperature, pH, etc.
  • the agent may be endogenous to the conditions of use, such as an enzyme present in the systemic circulation to which the prodrug is administered or the acidic conditions of the stomach or the agent may be supplied exogenously.
  • “Pharmaceutically acceptable salt” embraces salts with a pharmaceutically acceptable acid or base.
  • Pharmaceutically acceptable acids include both inorganic acids, for example hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic, hydroiodic and nitric acid and organic acids, for example citric, fumaric, maleic, malic, mandelic, ascorbic, oxalic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p-toluenesulphonic acid.
  • Pharmaceutically acceptable bases include alkali metai (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases, for example alkyl amines, arylalkyl amines and heterocyclic amines.
  • X- may be an anion of various mineral acids such as, for example, chloride, bromide, iodide, sulphate, nitrate, phosphate, or an anion of an organic acid such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulphonate and p-toluenesulphonate.
  • mineral acids such as, for example, chloride, bromide, iodide, sulphate, nitrate, phosphate
  • organic acid such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulphonate and p-toluenesulphonate.
  • X- is preferably an anion selected from chloride, bromide, iodide, sulphate, nitrate, acetate, maleate, oxalate, succinate or trifluoroacetate. More preferably X- is chloride, bromide, trifluoroacetate or methanesulphonate.
  • the present disclosure relates to compounds of formula (I), their stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof,
  • ring A and ring B are independently selected from cycloalkyl, aryl, heterocyciyl or heteroaryl;
  • ring A and ring B is unsubstituted or substituted with up to 4 substituents independently selected from alkyl, alkenyl, alkynyl, halogen, mono, di, tri or perhaloalkyl, nitrile, nitro, oxo, - NR 4 R 5 , -OR 4 , -S(0) p R 4 , -S(0) p NR 4 R 5 , -NR 4 S(0) p R 5 , -NR C(0)R 5 , -OS(0) P R 5 , - NR 4 C(0)OR 5 , -(CR 6 R 7 ) N C(0)OR 4 , - (CR 6 R 7 ) N C(0)NR 4 R 5 , -(CR 6 R 7 ) N C(0)R 4 , cycloalkyl, cycloalkylalkyl, heterocyciyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl
  • ring C is a heterocyciyl or a heteroaryl each with at least one N-atom;
  • Y is CR or N; wherein R is selected from hydrogen, halogen, alkyl, fluoroalkyl, OR 5 or aryl;
  • R 1 is selected from hydrogen, alkyl, halogen, haloalkyl or perhaloalkyl
  • R 2 is selected from hydrogen or alkyl
  • R 1 and R 2 taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms selected from O, N or S;
  • R' and R 4 are independently selected from a group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyciyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, mono, di, tri or perhaloalkyl, nitrile, nitro, -NR 5 , - NR 5 R 6 , -OR 5 , -S(0) P R 5 , -S(0) P NR 5 R 6 , -NR 5 S(0) P R 6 , -NR 5 C(0)R 6 , -OS(0) P R 6 , - NR 5 C(0)OR 6 , -(CR 7 R 8 ) radicalC(0)
  • R 5 and R 6 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl, or
  • R 5 and R 6 taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms selected from O, N or S; said ring system is unsubstituted or substituted with 1 to 4 substituents independently selected from halo, alkyl, alkenyl, alkynyl, nito, cyano, - OR 5 , -SR 5 , - NR 5 R 6 , oxo, alkylsulfonyl, -COOR 5 , -C(0)NR 5 R 6 , cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl;
  • R 7 and R 8 are independently selected from the group consisting of hydrogen, fluorine, OR 5 , alkyl, and peril uoroalkyl; or
  • R 7 and R 8 taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms selected from O, N or S; said ring system is unsubstituted or substituted with 1 to 4 substituents independently selected from halo, alkyl, alkenyl, alkynyl, nitro, cyano, oxo, -OR 5 , -SR 5 .
  • - NR 5 R 6 alkylsulfonyl, -COOR 5 , -C(0)NR 5 R 6 , cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl heteroaryl or heteroarylalkyl.
  • the present disclosure relates to compounds of formula (1) wherein: ring A and ring B are independently selected from cycloalkyl, aryl, heterocyclyl or heteroaryl; ring A and ring B are unsubstituted or substituted with up to 4 substituents independently selected from alkyl, alkenyl, alkynyl, halogen, mono, di, tri or perhaloalkyl, nitrile, nitro, oxo, -NR 4 R 5 , -OR 4 , -S(0) p R 4 , -S(0) p NR 4 R 5 , -NR 4 S(0) p R 5 , -NR 4 C(0)R 5 , - OS(0) p R 5 , -NR 4 C(0)OR 5 , -(CR 6 R 7 ) n C(0)OR 4 , - (CR 6 R 7 ) n C(0)OR 4 , - (CR 6 R 7 ) n C(0)NR 4 R 5 , - (CR 6 R
  • ring C is a heterocyclyl or a heteroaryl each with at least one N-atom;
  • Y is CR or N; wherein R is selected from hydrogen, halogen, alkyl or fluoroalkyl;
  • R 1 is selected from hydrogen, alkyl, halogen, haloalkyl or perhaloalkyl
  • R 2 is selected from hydrogen or alkyl
  • R 1 and R 2 taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms selected from O, N or S;
  • R ' and R* are independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyi, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, mono, di, tri or perhaloalkyl, nitrile, nitro, -NR 3 , -NR 5 R 6 , -OR 5 , - S(0) P R 5 , -S(0) P NR 5 R ⁇ -NR 5 S(0) P R 6 , -NR 5 C(0)R 6 , -OS(0) P R 6 , -NR 5 C(0)OR 6 , - (CR 7 R 8 ) conflictC(0)OR 5 , -(
  • R 5 and R 6 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyi, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl;
  • R 7 and R 8 are independently selected from the group consisting of hydrogen, fluorine, OR 5 , alkyl, and perfluoroalkyl.
  • Y is CR; wherein R is selected from hydrogen, halogen, alkyl or fluoroalkyl;
  • R 1 is selected from hydrogen, alkyl, halogen, haloalkyl or perhaloalkyl
  • R 2 is selected from hydrogen or alkyl
  • R 1 and R 2 taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms selected from O, N or S;
  • R 3 and R 4 are independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyi, heterocyclyl, aryl, heteroaryl, mono, di, tri or perhaloalkyl, nitrile, -S(0) p R 5 , - S(0) p NR 5 R 6 , -(CR 7 R 8 ) n C(0)OR 5 , -(CR 7 R 8 ) n (CO)NR 5 R 6 , -(CR 7 R 8 ) n S(0) p NR 5 R 6 , - (CR 7 R 8 ) n OR 5 , C(R 7 R 8 ) n NR 5 R 6 and C(R 7 R 8 ) n CO(R 5 ).
  • R s and R 6 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl. aryl, heteroaryl, cycloalkyi and heterocyclyl;
  • R' and R are independently selected from the group consisting of hydrogen, fluorine, OR 5 , alkyl, and perfluoroalkyl.
  • ring C is a heterocyclyl or a heteroaryl each with at least one N-atom;
  • Y is N
  • R' is selected from hydrogen, alkyl, halogen, haloalkyl or perhaloalkyl
  • R 2 is selected from hydrogen or alkyl; or R 1 and R 2 taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms selected from O, N or S;
  • R 3 and R 4 are independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, mono, di, tri or perhaloalkyl, nitrile, -S(0) p R 5 , - S(0) p NR 5 R 6 , -(CR 7 R 8 ) n C(0)OR 5 , -(CR 7 R 8 ) n (CO)NR 5 R 6 , -(CR 7 R 8 ) consumerS(0) p NR 5 R 6 , - (CR 7 R 8 ) n OR 5 , C(R 7 R 8 ) complicatNR 5 R 6 and C(R 7 R 8 ) n CO(R 5 ) ; wherein each of
  • R 5 and R 6 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclyl;
  • R 7 and R 8 are independently selected from the group consisting of hydrogen. fluorine, OR 5 , alkyl, and perfluoroalkyl.
  • the resulting intermediate may be subjected for deprotection of N-boc group followed by cyclization in one pot using suitable reagents such as trifluoroacetic acid, HC1, and the like to provide compounds of formula I wherein X is CHR 2 , R 1 and R 2 form a cycloalkyl ring and all other symbols are as defined herein above.
  • Compounds of formula IX may be converted to compounds of formula IX under amide coupling methods and using ammonia as reported in literature.
  • Compounds of formula IX may be dehydrated using suitable dehydrating agents such as trifluoroactic anhydride, acetic anhydride, oxalyl chloride, thionyl chloride and the like in presence or absence of any suitable organic solvents at temperature ranging from -10 °C to 100°C to provide compounds of formula III wherein X is CHR 2 or O and all other symbols are as defined herein above.
  • Scheme-8 Intermediate of formula IV may be synthesized as outlined below in Scheme-8.
  • Compounds of formula XIV may be cyclized to compounds of formula XV under basic condition using a suitable base such as potassium tertiary butoxide, sodium hydride, potassium hydride and the like at temperature ranging from -78 °C to 100 °C.
  • a suitable base such as potassium tertiary butoxide, sodium hydride, potassium hydride and the like at temperature ranging from -78 °C to 100 °C.
  • Compounds of formula XV may be deprotected to obtain intermediate of formula IV wherein Y is C, R 1 is H and all other symbols are defined herein above.
  • Scheme-10 Compounds of formula I can also be synthesized as outlined below in Scheme-1 1 when X is C, Y is N and ring C is aromatic.
  • amide coupling of carboxylic acid with amine or ammonia may be carried out using any suitable amide coupling regents such as oxailyl chloride, thionyl chloride, BOP-Cl, DCC, HOBt, HOAt, HATU, EDCI, alkylchloroformate and the like in the presence of organic non-nucleophillic bases such as triethyl amine, di- isopropylethyl amine, pyridine, N-methyl pyrrolidine, ⁇ , ⁇ -dimethylaminopyridine, DBU, DABCO, other hindered amines and pyridines.
  • suitable amide coupling regents such as oxailyl chloride, thionyl chloride, BOP-Cl, DCC, HOBt, HOAt, HATU, EDCI, alkylchloroformate and the like in the presence of organic non-nucleophillic bases such as triethyl amine
  • the amide coupling reaction may be carried out in the presence of solvents such as dichloromethane, dichloroethane, DMF, dimethylacetamide, THF, acetonitri le or mixture of them may be used at a temperature ranging from -5 to 1 50 °C.
  • the reaction may be carried out optionally in presence of catalytic amount of DMF.
  • Condition-II Amide coupling on carboxylic acid ester may be carried out by heating the ester and amine either in the absence of solvent or in presence of high boiling solvent like toluene, xylene, DMSO. Amide coupling may be carried out in presence of trialkyl aluminium (Chem. Commun., 2008, 1 100-1 102).
  • Halogenation reaction may be carried out using reagents such as N-halosuccinimide, dihalogens and the like, in presence of radical generating reagents like peroxides such as benzoylperoxide.
  • Solvents used for this reaction include, but are not limited to, carbontetrachloride and ethers or mixtures thereof. The reaction may be carried out at a temperature ranging from -5 to 80 °C.
  • Nucleophilic substitution reaction may be carried out using any suitable organic or inorganic bases.
  • Organic bases may be selected from a group consisting of mono, di or trialkyl amines particularly methylamine. ethylamine, dimethylamine, diethylamine or triethylamine.
  • Inorganic bases may be selected from a group consisting of alkali and alkaline earth metal hydrides, hyroxides, carbonates and bicarbonates or mixtures thereof.
  • Solvents used for this reaction may be selected from a group consisting of lower alcohols, acetone, acetonitrile, DMSO, DMF, dimethylacetamide, THF and toluene, or mixtures thereof.
  • the reaction may be carried out at a temperature in the range of 0 to 150 °C.
  • Condition 2 For Carbon centered nucleophile.
  • the reactions can be carried out using strong non nucleophilic bases like, BuLi, LDA, LiHMDS, OtBu, NaHMDS to generate carbon centered nucleophile. Reactions can be done in anhydrous condition and using aprotic solvents like THF, diethylether, dioxane, benzene etc.
  • the Mitsunobu reaction between alcohol and phenol, to obtain the corresponding ether may be carried out in THF using triphenylphosphine (TPP) and diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD) as reagents.
  • TPP triphenylphosphine
  • DEAD diethyl azodicarboxylate
  • DIAD diisopropyl azodicarboxylate
  • any of the compounds of formula (I) may be converted into a pharmaceutically acceptable salt or vice versa or converting one salt form into another pharmaceutically acceptable salt form.
  • the present disclosure relates to compounds of formula (I) their stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof, which are glucokinase activators, and are beneficial for the prophylaxis, management, treatment, control of progression, or adjunct treatment of diseases and/or medical conditions where the activation of glucokinase would be beneficial, such as diabetes, dyslipidemia, metabolic syndrome, and/or diabetes-related complications including retinopathy, nephropathy, neuropathy, ischemic heart disease, arteriosclerosis, ⁇ -cell dysfunction, and as therapeutic and/or prophylactic agents for obesity.
  • the present disclosure relates to compounds of formula (I) their stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof, which are liver selective Glucokinase activators, useful for the treatment of hyperglycemia, diabetes, obesity, dyslipidemia, metabolic syndrome and like, in mammals and have minimum hypoglycemic potential.
  • a further embodiment of the disclosure includes a method of treatment of glucokinase activator mediated disease by administering a therapeutically effective amount of a compound of formula (I) to a mammal in need of such treatment.
  • salts as used herein, it covers salts of compounds of formula (1) prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.
  • Inorganic bases salts include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like.
  • Salts derived from pharmaceutically acceptable organic nontoxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, ⁇ , ⁇ '-dibenzylethylene-diamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion exchange resins such
  • Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates.
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids, such as acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
  • Particularly preferred are hydrochloric, maleic, phosphoric, citric, hydrobromic, sulfuric, fumaric, and tartaric acids.
  • therapeutically effective amount in this disclosure, it means an amount of compound of formula (I), its polymorphs, stereoisomers, pharmaceutically acceptable salt, solvate or pro-drug thereof, that is sufficient for effective treatment of obesity and/or type II diabetes.
  • the therapeutically effective amount or dosage of a compound according to this disclosure can vary within wide limits. The dosage will depend on individual requirements in each particular case including the specific compound(s) being administered, the manner of administration, the severity of condition being treated, as well as the patient being treated, which is readily determinable by a person skilled in the art.
  • a daily dose in the range for example, about 0.01 mg to 100 mg per kg body weight is received, given if required in divided doses.
  • a parenteral route is employed.
  • a dose in the range for example, about 0.01 mg to 30 mg per kg body weight will generally be used.
  • a dose in the range for example, about 0.01 mg to 30 mg per kg body weight will be used.
  • the disclosure also relates to compound of formula (I), or its polymorph, stereoisomer, prodrug, solvate or a pharmaceutically acceptable salt thereof, for treating a disease through Glucokinase activation.
  • the disclosure also relates to compounds of formula (I), or its polymorph, stereoisomer, prodrug, solvate or a pharmaceutically acceptable salt thereof, for treating a disease through Glucokinase modulation or regulation.
  • the disclosure also relates to compounds of formula (1), or its polymorph, stereoisomer, prodrug, solvate or a, pharmaceutically acceptable salt thereof, for treating a disease through Glucokinase deinhibition.
  • the disclosure also relates to compounds of formula (I), or its polymorph, stereoisomer, prodrug, solvate or a pharmaceutically acceptable salt thereof, for prophylactic or therapeutic treatment of hyperglycemia or diabetes, particularly type II diabetes.
  • the disclosure also relates to compounds of formula (I), or its polymorph, stereoisomer, prodrug, solvate or a pharmaceutically acceptable salt thereof, for preventing diabetes, particularly type II diabetes, in a human demonstrating pre-diabetic hyperglycemia or impaired glucose tolerance.
  • the disclosure also relates to compounds of formula (I), or its polymorph, stereoisomer, prodrug, solvate or a pharmaceutically acceptable salt thereof, for combined treatment or preventing diabetes and obesity.
  • the disclosure also relates to compounds of formula (I), or its polymorph, stereoisomer, prodrug, solvate or a pharmaceutically acceptable salt thereof, for treating or preventing obesity.
  • the disclosure also relates to compounds of formula (I), or its polymorph, stereoisomer, prodrug, solvate or a pharmaceutically acceptable salt thereof, for enhancing the secretion of enteroincretins, like GLP-1 and GIP, thereby managing diseases or disorders associated with modulation of secretions of enteroincretins, such as hyperglycemia, insulin resistance, impaired glucose tolerance, obesity, gastric emptying, gastroparesis, satiety, leptin resistance, dyslipidemia, wound healing, diabetic complications, such as nephropathy, retinopathy, neuropathy and cataracts.
  • enteroincretins like GLP-1 and GIP
  • the disclosure also relates to the use of compounds of formula (1), or its polymorphs, stereoisomers, pharmaceutically acceptable salt, solvate or pro-drug thereof, in the prophylactic or therapeutic treatment of dyslipidemia.
  • the disclosure also relates to compound of formula (I), or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof, for treating hyperglycemia, IGT, Syndrome X, type 2 diabetes, type 1 diabetes, dyslipidemia or hyperlipidemia, hypertension, for the treatment or prophylaxis of obesity, for lowering of food intake, for appetite regulation, for regulating feeding behaviour.
  • the disclosure further relates to compounds of formula (1), its polymorphs, stereoisomers, pharmaceutically acceptable salt, solvate or pro-drug thereof, for use in the manufacture of medicament for the treatment of diabetes, obesity, metabolic syndrome X, insulin resistance, impaired glucose tolerance and dyslipidemia.
  • the disclosure also relates to the use of a compounds of formula (I), its polymorphs, stereoisomers, pharmaceutically acceptable salt, solvate or pro-drug thereof, in the manufacture of a medicament for the activation of Glucokinase.
  • the disclosure also relates to the use of a compounds of formula (I), its polymorphs, stereoisomers, pharmaceutically acceptable salt, solvate or pro-drug thereof, in the manufacture of a medicament for the prevention of diabetes, particularly type ⁇ diabetes, in a human demonstrating pre-diabetic hyperglycemia or impaired glucose tolerance.
  • the disclosure also relates to a method of prophylactic or therapeutic treatment of hyperglycemia or diabetes, particularly type II diabetes, comprising a step of administering an effective amount of a compound of formula (I), its polymorphs, stereoisomers, pharmaceutically acceptable salt, solvate or pro-drug thereof.
  • the disclosure also relates to a method for the prevention of diabetes, particularly type II diabetes, in a human demonstrating pre-diabetic hyperglycemia or impaired glucose tolerance comprising a step of administering an effective prophylactic amount of a compound of formula (I), its polymorphs, stereoisomers, pharmaceutically acceptable salt, solvate or pro-drug thereof.
  • the disclosure also relates to a method of combined treatment of diabetes and obesity by administering an effective amount of a compound of formula (I), its polymorph, stereoisomer, prodrug, solvate or a pharmaceutically acceptable salt thereof, to a mammal in need of such treatment.
  • the disclosure also relates to the use of a compound of formula (I), its polymorphs, stereoisomers, pharmaceutically acceptable salt, solvate or pro-drug thereof, for the prevention of diabetes, particularly type II diabetes, in a human demonstrating pre-diabetic hyperglycemia or impaired glucose tolerance.
  • the disclosure also relates to the use of a compound of formula (I), its polymorphs, stereoisomers, pharmaceutically acceptable salt, solvate or pro-drug thereof, for use as medicament, for the prophylactic or therapeutic treatment of hyperglycemia or diabetes, particularly type II diabetes.
  • the disclosure also relates to the use of a compound of formula (I), its polymorphs, stereoisomers, pharmaceutically acceptable salt, solvate or pro-drug thereof, in the manufacture of a medicament for the prophylactic or therapeutic treatment of hyperglycemia or diabetes, particularly type II diabetes.
  • the disclosure also relates to the use of a compound of formula (I), their stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, and solvates, in the manufacture of a medicament for use in combined treatment or prevention of diabetes and obesity.
  • the disclosure also relates to the use of a compound of formula (I), their stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof for prophylactic or therapeutic treatment of a disease selected from a group consisting of a disease needing Glucokinase activation, a disease needing Glucokinase deinhibition, hyperglycemia, 1GT, Syndrome X, type 2 diabetes, type 1 diabetes, dyslipidemia, hyperlipidemia, hypertension, insulin resistance, impaired glucose tolerance, obesity, gastric emptying, gastroparesis, satiety, leptin resistance, dyslipidemia, wound healing, nephropathy, retinopathy, neuropathy and cataracts.
  • a disease selected from a group consisting of a disease needing Glucokinase activation, a disease needing Glucokinase deinhibition, hyperglycemia, 1GT, Syndrome X, type 2 diabetes, type 1 diabetes, dys
  • the disclosure also relates to the use of a compound of formula (I), their stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof for lowering of food intake, for appetite regulation, for regulating feeding behaviour, for enhancing the secretion of enteroincretins like GLP-1 and GIP.
  • the disclosure also relates to the use of a compound of formula (I), their stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof for preventing diabetes, particularly type II diabetes, in a human demonstrating pre-diabetic hyperglycemia or impaired glucose tolerance, preventing obesity and preventing dyslipidemia.
  • the disclosure also relates to the use of a compound of formula (I), their stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof for combined treatment or prevention of diabetes and obesity.
  • the disclosure also relates to pharmaceutical composition
  • pharmaceutical composition comprising, as an active ingredient, at least one compound of formula (I), or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, and solvates thereof, together with one or more pharmaceutically acceptable carriers or excipients.
  • the compounds and compositions of the present disclosure may be optionally employed in combination with one or more, from current or future therapy, other anti-diabetic agents or anti- hyperglycemic agents, which include, for example, (a) insulin secretagogues such as sulfonylureas (e.g. Amaryl, glyburide, glimepiride, glipyride, glipizide, etc.); (b) Insulinotropic sulfonyl urea receptor ligands such as meglitinides (e.g. nateglinide, rapaglinide); (c) biguanides (e.g. metformin etc.); (d) glucagon antagonists (e.g.
  • glucosidase inhibitors e.g. acarbose, miglitol, etc.
  • glucose sensitive insulinotropic agents e.g. GLP- 1 , GLP- 1 mimetics e.g Exendin-4; GLP- 1 , GPR- 1 19, GPR-40, GPR 120 and like other receptor modulators chosen from small molecule or from peptides
  • insulin sensitizers e.g. rosiglitazone, pioglitazone, balaglitazone etc.
  • Dipeptidyl peptidase-IV inhibitors e.g.
  • the said additional therapeutic agent is added in a dose range of about 0.01 mg to 100 mg per kg body weight.
  • compositions of the present disclosure may also be optionally employed in combination with one or more, from current or future therapy, anti-obesity agents (e.g. sibutramine, orlistat, rimonabant etc.) and the like.
  • anti-obesity agents e.g. sibutramine, orlistat, rimonabant etc.
  • dyslipidemic agents which include, for example: (a) fibrates (e.g. gemfibrozil, fenofibrate); (b) Niacin; (c) Statins (e.g. rosuvatatin, atorvastatin, simvastatin); (d) cholesterol absorption inhibitors (e.g. Ezetimibe); (e) bile acid sequestrants (e.g. cholestyramine) and the likes.
  • fibrates e.g. gemfibrozil, fenofibrate
  • Niacin e.g. rosuvatatin, atorvastatin, simvastatin
  • Statins e.g. rosuvatatin, atorvastatin, simvastatin
  • cholesterol absorption inhibitors e.g. Ezetimibe
  • bile acid sequestrants e.g. cholestyramine
  • antihypertensive agents such as: (a) diuretics (e.g hydrochlorothiazides, mannitol, indapamide, furosemide); (b) angiotensin converting enzyme (ACE) inhibitors (e.g. captopril, enalapril); (c) Angiotensin-II receptor type-I blockers (ARB) (e.g. losartan, irbesartan); (d) rennin inhibitors (e.g aliskerin); (e) ⁇ -adrenergic receptor blockers (e.g.
  • diuretics e.g hydrochlorothiazides, mannitol, indapamide, furosemide
  • ACE angiotensin converting enzyme
  • ARB Angiotensin-II receptor type-I blockers
  • rennin inhibitors e.g aliskerin
  • ⁇ -adrenergic receptor blockers e.g.
  • the said additional therapeutic agent is added in a dose range of about 0.01 mg to 100 mg per kg body weight.
  • compositions of the present disclosure and the other therapeutic agents such as described above may be administered simultaneously, sequentially or separately.
  • compositions of the present disclosure comprise a compound of formula (I), polymorphs, stereoisomers, pharmaceutically acceptable salt, solvate or pro-drug thereof, as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic active agent in any suitable ratios.
  • the disclosure also relates to pharmaceutical composition
  • pharmaceutical composition comprising, as an active ingredient, at least one compound of formula (I), or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, and solvates thereof, wherein the pharmaceutically acceptable therapeutically active agent is selected from anti-diabetic agents, anti-hyperglycemic agents, anti-obesity agents, anti-hypertensive agents or anti-dyslipidemic agents.
  • compositions of the present disclosure comprising compounds of formula (I), polymorphs, stereoisomers, pharmaceutically acceptable salt, solvate or prodrugs thereof, may be manufactured in a manner that is known in the art, e.g. by means of conventional mixing, encapsulating, dissolving, granulating, emulsifying, entrapping, dragee making, or lyophilizing processes.
  • These pharmaceutical preparations can be formulated with therapeutically inert, inorganic or organic carriers such as lactose, corn starch or derivatives thereof, talc, steric acid or its salts as carriers for tablets, coated tablets, dragees and hard gelatin capsules.
  • suitable carriers include vegetable oils, waxes and fats.
  • Suitable carriers for the manufacture of solutions and syrups are water, polyols, saccharose, invert sugar and glucose.
  • Suitable carriers for injection are water, alcohols, polyols, glycerine, vegetable oils, phospholipids and surfactants.
  • Suitable carriers for suppositories are natural or hardened oils, waxes, fats and semi- liquid polyols.
  • the pharmaceutical preparations can also contain preserving agents, solubilizing agents, stabilizing agents, wetting agents, emulsifying agents, sweetening agents, coloring agents, flavoring agents, salts for varying the osmotic pressure, buffers, coating agents or antioxidants. They can also contain other therapeutically valuable substances, including additional active ingredients other than those of formula (I), its polymorphs, stereoisomers, pharmaceutically acceptable salt, solvate or prodrugs thereof.
  • compositions containing the active ingredient of compound of formula (1), its polymorphs, stereoisomers, pharmaceutically acceptable salt, solvate or prodrugs thereof maybe in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs; sterile injectable aqueous or oleaginous suspension; suppositories; topical use, for example creams, ointments, jellies, solutions or suspension etc including mouth washes and gargles.
  • These compositions can be manufactured by any method known in the art with the active ingredient combined with non-toxic pharmaceutically acceptable excipients.
  • diastereomeric or enantiomeric products When diastereomeric or enantiomeric products are obtained as mixtures, they can be separated by conventional methods for example, chromatographic separation or fractional crystallization or through diasteriomeric salt formation. When intended, a desired enantiomer or diasteriomer can also be obtained by following appropriate enantioselective or diastereoselective reactions.
  • Step I p-ToIuene sulfonyl hydrazone (4-cycIopropyl sulfonyl) phenyl acetic acid ethyl ester:
  • Step II (4-Cyclopropanesulfonyl-phenyl) diazo acetic acid ethyl ester:
  • Step III (4-Cyclopropanesulfonyl-phenyl)-[(tetrahydro-pyran-4-yloxy)]-acetic acid ethyl ester:
  • Step IV 2-
  • Example A2 was obtained.
  • Example-Bl 2-[(2,4-Difluoro-phenoxy)-(4-methanesulfonyl-phenyl)-methyl]-lH-pyrrolo[2,3- b] pyridine
  • Step I Synthesis of l-(4-Methylsulfanyl-phenyl)-3-trimethyIsilanyl-prop-2-yn-l-ol:
  • n-BuLi (54.88 mL, 87.82 mmol, 1.6M in hexanes) was added to the solution of trimethylsilyl acetylene (7.9 gm, 80.5 mmol) in anhydrous THF (100 mL) at -78 °C under inert atmosphere.
  • the reaction mixture was stirred at -78 °C for 1 hr and 4-methylthio benzaldehyde ( 10 mL, 73.1 8 mmol) was slowly added to the reaction mixture at -78 °C.
  • the reaction mixture was then stirred at 25 °C for 2 hr, reaction mixture was diluted with satd. aq.
  • Step IV Synthesis of tert-Butyl-[l-(4-methanesulfonyl-phenyl)-prop-2-ynyIoxy]-dimethyl- silane.
  • Step V Synthesis of 3-
  • Step VI Synthesis of 2-[(tert-Butyl-dimethyl-silanyloxy)-(4-methanesulfonyI-phenyl)-methyl]- lH-pyrrolo[2,3-b)pyridine.
  • the reaction mixture was concentrated and diluted with ethylacetate (25 mL), washed with water (25 mL) followed by brine, dried over anhydrous sodium sulfate, sodium sulfate was filtered and washed with ethylacetate and the solvent was removed under reduced pressure to provide the crude product.
  • the crude compound was purified by column chromatography (silica gel 60-120 mesh, 10-40% ethylacetate in hexanes as eluent) to give the pure product (0.6 gm).
  • Step VII Synthesis of (4-MethanesuIfonyl-phenyl)-(lH-pyrrolo[2,3-b]pyridin-2-yl)-methanol.
  • reaction mixture was diluted with water (20 mL), mixture was then extracted with ethyl acetate (3X25 mL), combined organic layer was washed with water followed by brine, dried over anhydrous sodium sulfate. Sodium sulfate was filtered and washed with ethylacetate and solvent was removed under reduced pressure to provide the product (0.2 gm).
  • Step VIII Synthesis 2-[(2,4-Difluoro-phenoxy)-(4-methanesulfonyl-phenyl)-methyl]-lH- pyrrolo
  • reaction mixture was diluted with water (10 mL), mixture was then extracted with ethyl acetate (3X15 mL), combined organic layer was washed with water followed by brine, dried over anhydrous sodium sulfate, sodium sulfate was filtered and washed with ethyl acetate and solvent was removed under reduced pressure to provide the crude product.
  • the crude compound was purified by column chromatography (silica gel 60-120 mesh) followed by preparative HPLC to give the pure product (0.03 gm).
  • Example B2 was prepared following procedure used for Exampie-Bl from appropriate starting materials.
  • Reaction mixture was quenched by addition of 20 ml water, extracted with DCM (3 X 30 ml), combined organic layer was washed with brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude intermediate.
  • the crude was dissolved in 2 ml dry DCM, to this solution 10 ml TFA was added slowly and stirred overnight at 25 °C.
  • Reaction mixture was concentrated under reduced pressure, neutralized by aq. sat. solution of NaHC0 3 , extracted with ethyl acetate (3 X 20ml).
  • Example Dl 2-[l-(4-CyclopropanesuIfonyl-phenyI)-2-(2,4-difluoro-phenyl)-ethyl]-lH- pyrrolo[2,3-b]pyridine:
  • Step I Synthesis of 2-(4-Cyclopropanesulfonyl-phenyl)-3-(2,4-difluoro-phenyl)- propionic acid ethyl ester:
  • Step II 2-[l-(4-Cyclopropanesulfonyl-phenyl)-2-(2,4-difluoro-phenyl)-ethyI]-lH- pyrrolo[2,3-b]pyridine:
  • Example D2 to D5 were, prepared following procedure used for Example-Dl from appropriate starting materials.
  • the glucokinase (GK) assay is a coupled enzymatic assay.
  • GK catalyzes the first step of glycolysis, the conversion of glucose to glucose-6-phosphate (G6P) in the presence of ATP.
  • G6P in turn is converted by glucose-6-phosphate dehydrogenase (G6PD) to 6-phosphogluconate, a process that requires NAD, resulting in NADH formation.
  • G6PD glucose-6-phosphate dehydrogenase
  • the GK-catalyzed step is the rate-limiting step of this coupled enzymatic process, the rate of accumulation of 6-phosphogluconate and NADH is directly proportional to the rate of glucose phosphorylation by GK.
  • the rate of the GK-catalyzed reaction can therefore be measured by monitoring the increase in NADH absorbance at 340 nm.
  • the assay is carried out according to the protocol outlined in Hariharan et al ( 1 997), Diabetes 46: 1 1 - 16. Briefly, the test compounds are incubated in a reaction mix containing 25 mM HEPES (pH 7.2), 10 mM MgCl 2 , 100 mM KC1, 5 mM ATP, 2 mM DTT, 0.5 mM NAD, 1 U/ml Leuconostoc mesenteroides G6PD, 0.3 U/ml of purified human recombinant GK, and different concentrations of glucose. Enzymatic activity is calculated from the initial reaction velocity, measured from the change in NADH absorbance as a function of time.
  • the change in the S 0 .5 of glucokinase (AS 0 s) for glucose is calculated by subtracting the S 0 5 at each concentration of the compound from the S 0 s in the vehicle control.
  • the AS 0. s is then normalized to a percent scale, where the S 0 .5 in the vehicle control is set to 0% and 0 mM glucose is set to 100%.
  • the % AS 0 5 is then plotted against the log of the compound concentration.
  • the EC 50 and E max of % change in S 0 .5 is obtained from the sigmoidal fit of the data.
  • Characterization data of some representative glucokinase activators of the present disclosure, which are illustrative but not limiting, are given in table I below.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Diabetes (AREA)
  • General Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur des composés hétérocycliques azotés condensés, sur leurs stéréoisomères, tautomères, promédicaments, sels pharmaceutiquement acceptables, polymorphes, solvates et sur leurs formulations, utiles comme activateurs ou modulateurs de glucokinase, qui sont bénéfiques pour la prophylaxie, la gestion, le traitement, la maîtrise de la progression ou le traitement complémentaire de maladies et/ou d'états pathologiques où l'activation de la glucokinase serait bénéfique, tels que le diabète, le syndrome métabolique et/ou des complications liées au diabète dont une rétinopathie, une néphropathie, une neuropathie, une cardiopathie ischémique, l'artériosclérose, un dysfonctionnement des cellules β, et comme agents thérapeutiques et/ou prophylactiques pour l'obésité. L'invention porte également sur un procédé de préparation des composés hétérocycliques azotés condensés.
PCT/IN2010/000844 2009-12-29 2010-12-22 Composés hétérocycliques azotés condensés, leur procédé de préparation et leurs utilisations Ceased WO2011080755A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN3212CH2009 2009-12-29
IN3212/CHE/2009 2009-12-29

Publications (1)

Publication Number Publication Date
WO2011080755A1 true WO2011080755A1 (fr) 2011-07-07

Family

ID=43709023

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2010/000844 Ceased WO2011080755A1 (fr) 2009-12-29 2010-12-22 Composés hétérocycliques azotés condensés, leur procédé de préparation et leurs utilisations

Country Status (1)

Country Link
WO (1) WO2011080755A1 (fr)

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9266892B2 (en) 2012-12-19 2016-02-23 Incyte Holdings Corporation Fused pyrazoles as FGFR inhibitors
US9388185B2 (en) 2012-08-10 2016-07-12 Incyte Holdings Corporation Substituted pyrrolo[2,3-b]pyrazines as FGFR inhibitors
US9533954B2 (en) 2010-12-22 2017-01-03 Incyte Corporation Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3
US9533984B2 (en) 2013-04-19 2017-01-03 Incyte Holdings Corporation Bicyclic heterocycles as FGFR inhibitors
US9580423B2 (en) 2015-02-20 2017-02-28 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US9611267B2 (en) 2012-06-13 2017-04-04 Incyte Holdings Corporation Substituted tricyclic compounds as FGFR inhibitors
US9708318B2 (en) 2015-02-20 2017-07-18 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US9890156B2 (en) 2015-02-20 2018-02-13 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10611762B2 (en) 2017-05-26 2020-04-07 Incyte Corporation Crystalline forms of a FGFR inhibitor and processes for preparing the same
US10710986B2 (en) 2018-02-13 2020-07-14 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10774071B2 (en) 2018-07-13 2020-09-15 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10851105B2 (en) 2014-10-22 2020-12-01 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10899735B2 (en) 2018-04-19 2021-01-26 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11174257B2 (en) 2018-05-04 2021-11-16 Incyte Corporation Salts of an FGFR inhibitor
US11236085B2 (en) 2018-10-24 2022-02-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11407750B2 (en) 2019-12-04 2022-08-09 Incyte Corporation Derivatives of an FGFR inhibitor
US11466004B2 (en) 2018-05-04 2022-10-11 Incyte Corporation Solid forms of an FGFR inhibitor and processes for preparing the same
CN115364110A (zh) * 2022-09-16 2022-11-22 复旦大学 6-磷酸葡萄糖酸及其衍生物在制备预防或治疗糖代谢紊乱性疾病药物中的应用
US11566028B2 (en) 2019-10-16 2023-01-31 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US11591329B2 (en) 2019-07-09 2023-02-28 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US11607416B2 (en) 2019-10-14 2023-03-21 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US11628162B2 (en) 2019-03-08 2023-04-18 Incyte Corporation Methods of treating cancer with an FGFR inhibitor
CN116675689A (zh) * 2023-05-05 2023-09-01 五邑大学 一种β-咔啉类衍生物及其制备方法和应用
US11897891B2 (en) 2019-12-04 2024-02-13 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors
US11939331B2 (en) 2021-06-09 2024-03-26 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors
US12012409B2 (en) 2020-01-15 2024-06-18 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US12065494B2 (en) 2021-04-12 2024-08-20 Incyte Corporation Combination therapy comprising an FGFR inhibitor and a Nectin-4 targeting agent
US12122767B2 (en) 2019-10-01 2024-10-22 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US12428420B2 (en) 2021-06-09 2025-09-30 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors
WO2025247390A1 (fr) * 2024-05-31 2025-12-04 福佑泰生物制药公司 Composés hétérobicycliques utilisables en tant qu'agonistes de glp-1r
US12534463B2 (en) 2023-10-20 2026-01-27 Incyte Corporation Substituted tricyclic compounds as FGFR inhibitors

Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6320050B1 (en) 1999-03-29 2001-11-20 Hoffmann-La Roche Inc. Heteroaromatic glucokinase activators
WO2002008209A1 (fr) 2000-07-20 2002-01-31 F. Hoffmann-La Roche Ag Composes de benzene acetamide substitues par alpha-acyle et des alpha-heteroatomes en tant qu'activateurs de glucokinase
WO2003055482A1 (fr) 2001-12-21 2003-07-10 Novo Nordisk A/S Derives amide utiles en tant qu'activateurs de la glucokinase
WO2004002481A1 (fr) 2002-06-27 2004-01-08 Novo Nordisk A/S Activateurs de la glycokinase
EP1460067A1 (fr) * 2001-11-26 2004-09-22 Takeda Chemical Industries, Ltd. Derive bicyclique, procede de production de ce derive et utilisation correspondante
WO2005049019A1 (fr) * 2003-11-24 2005-06-02 Novo Nordisk A/S N-heteroaryl indole carboxamides et leurs analogues, activateurs de la glucokinase, pour le traitement du diabete
WO2005123132A2 (fr) 2004-06-17 2005-12-29 Novo Nordisk A/S Utilisation d'activateurs de glucokinase selectifs du foie
WO2006016178A1 (fr) 2004-08-12 2006-02-16 Prosidion Limited Procédé énantiosélectif
WO2006040528A1 (fr) 2004-10-16 2006-04-20 Astrazeneca Ab Composes de phenoxy benzamide ayant une utilite dans le traitement du diabete de type 2 et de l'obesite
WO2006125958A1 (fr) 2005-05-24 2006-11-30 Astrazeneca Ab Derives d’imidazol[4,5b]pyridine/pyrazine et purine substitues en 2-phenyl en tant que modulateurs de la glucokinase
WO2007031739A1 (fr) 2005-09-16 2007-03-22 Astrazeneca Ab Composés hétérobicycliques utilisés comme activateurs de la glucokinase
WO2008104994A2 (fr) 2007-02-28 2008-09-04 Advinus Therapeutics Private Limited Dérivés d'acétamide 2,2,2-tri-substitué en tant qu'activateurs de la glucokinase, leur procédé de préparation et leur application pharmaceutique
WO2009047798A2 (fr) 2007-10-08 2009-04-16 Advinus Therapeutics Private Limited Dérivés acétamide comme activateur de la glucokinase, leur procédé et applications médicinales

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6320050B1 (en) 1999-03-29 2001-11-20 Hoffmann-La Roche Inc. Heteroaromatic glucokinase activators
WO2002008209A1 (fr) 2000-07-20 2002-01-31 F. Hoffmann-La Roche Ag Composes de benzene acetamide substitues par alpha-acyle et des alpha-heteroatomes en tant qu'activateurs de glucokinase
US6486184B2 (en) 2000-07-20 2002-11-26 Hoffmann-La Roche Inc. α-acyl- and α-heteroatom-substituted benzene acetamide glucokinase activators
EP1460067A1 (fr) * 2001-11-26 2004-09-22 Takeda Chemical Industries, Ltd. Derive bicyclique, procede de production de ce derive et utilisation correspondante
WO2003055482A1 (fr) 2001-12-21 2003-07-10 Novo Nordisk A/S Derives amide utiles en tant qu'activateurs de la glucokinase
WO2004002481A1 (fr) 2002-06-27 2004-01-08 Novo Nordisk A/S Activateurs de la glycokinase
WO2005049019A1 (fr) * 2003-11-24 2005-06-02 Novo Nordisk A/S N-heteroaryl indole carboxamides et leurs analogues, activateurs de la glucokinase, pour le traitement du diabete
WO2005123132A2 (fr) 2004-06-17 2005-12-29 Novo Nordisk A/S Utilisation d'activateurs de glucokinase selectifs du foie
WO2006016178A1 (fr) 2004-08-12 2006-02-16 Prosidion Limited Procédé énantiosélectif
WO2006040528A1 (fr) 2004-10-16 2006-04-20 Astrazeneca Ab Composes de phenoxy benzamide ayant une utilite dans le traitement du diabete de type 2 et de l'obesite
WO2006125958A1 (fr) 2005-05-24 2006-11-30 Astrazeneca Ab Derives d’imidazol[4,5b]pyridine/pyrazine et purine substitues en 2-phenyl en tant que modulateurs de la glucokinase
WO2007031739A1 (fr) 2005-09-16 2007-03-22 Astrazeneca Ab Composés hétérobicycliques utilisés comme activateurs de la glucokinase
WO2008104994A2 (fr) 2007-02-28 2008-09-04 Advinus Therapeutics Private Limited Dérivés d'acétamide 2,2,2-tri-substitué en tant qu'activateurs de la glucokinase, leur procédé de préparation et leur application pharmaceutique
WO2009047798A2 (fr) 2007-10-08 2009-04-16 Advinus Therapeutics Private Limited Dérivés acétamide comme activateur de la glucokinase, leur procédé et applications médicinales

Non-Patent Citations (14)

* Cited by examiner, † Cited by third party
Title
BROCKLEHURST, K. J. ET AL., DIABETES, vol. 53, 2004, pages 535 - 541
CHEM. COMMUN., 2008, pages 1100 - 1102
EFANOV, A. M. ET AL., ENDOCRINOLOGY, vol. 146, 2005, pages 3696 - 3701
FYFE, M. C. T., DIABETOLOGIA, vol. 50, 2007, pages 1277 - 1287
GLASER, B. ET AL., N. ENGL. J MED., vol. 338, 1998, pages 226 - 230
GLOYN, A. L. ET AL., DIABETES, vol. 52, 2003, pages 2433 - 2440
GLOYN, A. L., HUM. MUTAT., vol. 22, 2003, pages 353 - 362
GRIMSBY, J. ET AL., SCIENCE, vol. 301, 2003, pages 370 - 373
HARIHARAN ET AL., DIABETES, vol. 46, 1997, pages 11 - 16
JETTON, T. A. ET AL., J. BIOL. C'HEM., vol. 269, 1994, pages 3641 - 3654
KAMATA, K. ET AL., STRUCTURE, vol. 12, 2004, pages 429 - 438
MCKERRECHER, D. ET AL., BIOORG. MED. CHEM. LETT., vol. 15, 2005, pages 2103 - 2106
POSTIC, C. ET AL., J. BIOL. CHEM., vol. 274, 1999, pages 305 - 315
PRINTZ, R. L.; GRANNER, D. K., ENDOCRINOLOGY, vol. 146, 2005, pages 3693 - 3695

Cited By (59)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10213427B2 (en) 2010-12-22 2019-02-26 Incyte Corporation Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3
US10813930B2 (en) 2010-12-22 2020-10-27 Incyte Corporation Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3
US9533954B2 (en) 2010-12-22 2017-01-03 Incyte Corporation Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3
US10131667B2 (en) 2012-06-13 2018-11-20 Incyte Corporation Substituted tricyclic compounds as FGFR inhibitors
US11840534B2 (en) 2012-06-13 2023-12-12 Incyte Corporation Substituted tricyclic compounds as FGFR inhibitors
US9611267B2 (en) 2012-06-13 2017-04-04 Incyte Holdings Corporation Substituted tricyclic compounds as FGFR inhibitors
US11053246B2 (en) 2012-06-13 2021-07-06 Incyte Corporation Substituted tricyclic compounds as FGFR inhibitors
US9745311B2 (en) 2012-08-10 2017-08-29 Incyte Corporation Substituted pyrrolo[2,3-b]pyrazines as FGFR inhibitors
US9388185B2 (en) 2012-08-10 2016-07-12 Incyte Holdings Corporation Substituted pyrrolo[2,3-b]pyrazines as FGFR inhibitors
US9266892B2 (en) 2012-12-19 2016-02-23 Incyte Holdings Corporation Fused pyrazoles as FGFR inhibitors
US11530214B2 (en) 2013-04-19 2022-12-20 Incyte Holdings Corporation Bicyclic heterocycles as FGFR inhibitors
US10947230B2 (en) 2013-04-19 2021-03-16 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US10040790B2 (en) 2013-04-19 2018-08-07 Incyte Holdings Corporation Bicyclic heterocycles as FGFR inhibitors
US10450313B2 (en) 2013-04-19 2019-10-22 Incyte Holdings Corporation Bicyclic heterocycles as FGFR inhibitors
US9533984B2 (en) 2013-04-19 2017-01-03 Incyte Holdings Corporation Bicyclic heterocycles as FGFR inhibitors
US10851105B2 (en) 2014-10-22 2020-12-01 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US11173162B2 (en) 2015-02-20 2021-11-16 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10016438B2 (en) 2015-02-20 2018-07-10 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10632126B2 (en) 2015-02-20 2020-04-28 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US9708318B2 (en) 2015-02-20 2017-07-18 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10738048B2 (en) 2015-02-20 2020-08-11 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US9580423B2 (en) 2015-02-20 2017-02-28 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10251892B2 (en) 2015-02-20 2019-04-09 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10214528B2 (en) 2015-02-20 2019-02-26 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US9801889B2 (en) 2015-02-20 2017-10-31 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US11667635B2 (en) 2015-02-20 2023-06-06 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US11014923B2 (en) 2015-02-20 2021-05-25 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US9890156B2 (en) 2015-02-20 2018-02-13 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10611762B2 (en) 2017-05-26 2020-04-07 Incyte Corporation Crystalline forms of a FGFR inhibitor and processes for preparing the same
US11472801B2 (en) 2017-05-26 2022-10-18 Incyte Corporation Crystalline forms of a FGFR inhibitor and processes for preparing the same
US12338233B2 (en) 2018-02-13 2025-06-24 Gilead Sciences, Inc. PD-1/Pd-L1 inhibitors
US11555029B2 (en) 2018-02-13 2023-01-17 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10710986B2 (en) 2018-02-13 2020-07-14 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10899735B2 (en) 2018-04-19 2021-01-26 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US12473286B2 (en) 2018-05-04 2025-11-18 Incyte Corporation Salts of an FGFR inhibitor
US11466004B2 (en) 2018-05-04 2022-10-11 Incyte Corporation Solid forms of an FGFR inhibitor and processes for preparing the same
US12024517B2 (en) 2018-05-04 2024-07-02 Incyte Corporation Salts of an FGFR inhibitor
US11174257B2 (en) 2018-05-04 2021-11-16 Incyte Corporation Salts of an FGFR inhibitor
US12269812B2 (en) 2018-07-13 2025-04-08 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10774071B2 (en) 2018-07-13 2020-09-15 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11236085B2 (en) 2018-10-24 2022-02-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11628162B2 (en) 2019-03-08 2023-04-18 Incyte Corporation Methods of treating cancer with an FGFR inhibitor
US11591329B2 (en) 2019-07-09 2023-02-28 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US12122767B2 (en) 2019-10-01 2024-10-22 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US11607416B2 (en) 2019-10-14 2023-03-21 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US12083124B2 (en) 2019-10-14 2024-09-10 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US11566028B2 (en) 2019-10-16 2023-01-31 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US11897891B2 (en) 2019-12-04 2024-02-13 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors
US12168660B2 (en) 2019-12-04 2024-12-17 Incyte Corporation Derivatives of an FGFR inhibitor
US11407750B2 (en) 2019-12-04 2022-08-09 Incyte Corporation Derivatives of an FGFR inhibitor
US12012409B2 (en) 2020-01-15 2024-06-18 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US12065494B2 (en) 2021-04-12 2024-08-20 Incyte Corporation Combination therapy comprising an FGFR inhibitor and a Nectin-4 targeting agent
US11939331B2 (en) 2021-06-09 2024-03-26 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors
US12428420B2 (en) 2021-06-09 2025-09-30 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors
CN115364110B (zh) * 2022-09-16 2024-05-07 复旦大学 6-磷酸葡萄糖酸及其衍生物在制备预防或治疗糖代谢紊乱性疾病药物中的应用
CN115364110A (zh) * 2022-09-16 2022-11-22 复旦大学 6-磷酸葡萄糖酸及其衍生物在制备预防或治疗糖代谢紊乱性疾病药物中的应用
CN116675689A (zh) * 2023-05-05 2023-09-01 五邑大学 一种β-咔啉类衍生物及其制备方法和应用
US12534463B2 (en) 2023-10-20 2026-01-27 Incyte Corporation Substituted tricyclic compounds as FGFR inhibitors
WO2025247390A1 (fr) * 2024-05-31 2025-12-04 福佑泰生物制药公司 Composés hétérobicycliques utilisables en tant qu'agonistes de glp-1r

Similar Documents

Publication Publication Date Title
WO2011080755A1 (fr) Composés hétérocycliques azotés condensés, leur procédé de préparation et leurs utilisations
EP2195304B1 (fr) Dérivés acétamide comme activateurs de la glucokinase, leur procédé et applications médicinales
JP6099753B2 (ja) スピロ環化合物、その組成物及びその医薬応用
EP2155720B1 (fr) Nouveaux dérivés de pyrrole-2-carboxamide en tant qu'activateurs de la glucokinase, leur procédé d'obtention et leur application pharmaceutique
CA2877550C (fr) Derives d'imidazopyridine utilisables en tant que modulateurs de l'activite tnf
JP7447089B2 (ja) 心筋サルコメア阻害剤
AU2011256444B2 (en) Spiro isoxazoline compounds as SSTR5 antagonists
AU2024227155A1 (en) Carboxy-benzimidazole GLP-1R modulating compounds.
JP2022528251A (ja) 置換複素環式アミド化合物、その調製方法、及びその医薬的使用
WO2012044567A2 (fr) Dérivés d'imidazole
AU2011205483A1 (en) Oxadiazole beta carboline derivatives as antidiabetic compounds
WO2015112465A1 (fr) Dérivés d'isoquinoline utilisés comme inhibiteurs de mgat2
US20100184799A1 (en) Oxadiazole beta carboline derivatives as antidiabetic compounds
WO2012015693A1 (fr) Dérivés d'imidazole
WO2013074387A1 (fr) Dérivés d'imidazole
WO2012020357A1 (fr) Composés d'acétamide, leur procédé de préparation et leur application pharmaceutique
TW202440091A (zh) Ｎａｍｐｔ調節劑
TWI525088B (zh) 新穎之苯基吡啶衍生物及含有該衍生物之醫藥
WO2011095997A1 (fr) Composés de benzamide à titre d'activateurs de glucokinase et leur application pharmaceutique
TWI500611B (zh) 新穎苯基吡啶衍生物及含有該衍生物之醫藥
EP4161919A2 (fr) Amides d'amino-pyrimidine

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10808945

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10808945

Country of ref document: EP

Kind code of ref document: A1