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WO2010001166A1 - Dérivés de thiazole en tant que modulateurs du gpr 119 - Google Patents

Dérivés de thiazole en tant que modulateurs du gpr 119 Download PDF

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Publication number
WO2010001166A1
WO2010001166A1 PCT/GB2009/050770 GB2009050770W WO2010001166A1 WO 2010001166 A1 WO2010001166 A1 WO 2010001166A1 GB 2009050770 W GB2009050770 W GB 2009050770W WO 2010001166 A1 WO2010001166 A1 WO 2010001166A1
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Prior art keywords
thiazol
piperidine
carboxylic acid
triazol
isopropyl
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Lisbeth Elster
Thomas Hoegberg
Anthony Murray
Jean Marie Receveur
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Prosidion Ltd
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Prosidion Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to novel compounds which are GPRl 19 receptor modulators, especially positive modulators (agonists), and to compositions and methods for treating or preventing diseases or conditions which are associated with GPRl 19 receptor signaling, such as diabetes, obesity and metabolic syndrome including associated conditions, such as, glucose intolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypercholesterolemia, dyslipidemia, atherosclerosis, vascular conditions, osteoporosis, pain, demyelination, and nonalcoholic fatty liver disease.
  • the invention also relates to pharmaceutical compositions containing the compounds of the invention, and to the use of the compounds optionally in combination with other treatments, for the treatment or prophylaxis of, for example, diabetes, obesity and for obesity-related diseases.
  • the "identifiable signs and symptoms" of obesity include an excess accumulation of fat or adipose tissue, an increase in the size or number of fat cells (adipocyte differentiation), insulin resistance, increased glucose levels (hyperglycemia), increased blood pressure, elevated cholesterol and triglyceride levels and decreased levels of high-density lipoprotein.
  • Obesity is associated with a significantly elevated risk for type 2 diabetes, coronary heart disease, stroke, hypertension, various types of cancer and numerous other major illnesses, and overall mortality from all causes (Must et al, 1999, JAMA 282:1523-1529, Calle et al, 1999, N. Engl. J. Med. 341:1097-1105).
  • a cluster of metabolic risk factors for cardiovascular disease and Type 2 diabetes is often referred to as metabolic syndrome, syndrome X or insulin resistance syndrome.
  • the major components of metabolic syndrome include excess abdominal fat (also known as visceral, male-pattern or apple-shaped adiposity), atherogenic dyslipidemia (decreased high-density lipoprotein cholesterol (HDL-C)), elevated triglycerides, hypertension, hyperglycaemia (diabetes mellitus type 2 or impaired fasting glucose, impaired glucose tolerance, or insulin resistance), a proinflammatory state and a prothrombotic state (cf. AHA/NHLB I/ADA Conference Proceedings, Circulation 2004; 109:551-556).
  • abdominal fat also known as visceral, male-pattern or apple-shaped adiposity
  • atherogenic dyslipidemia decreased high-density lipoprotein cholesterol (HDL-C)
  • elevated triglycerides hypertension
  • hyperglycaemia diabetes mellitus type 2 or impaired fasting glucose, impaired glucose tolerance, or insulin resistance
  • proinflammatory state cf. AHA/NHLB I/ADA Conference Proceedings
  • apolipoprotein B concentrations include increased apolipoprotein B concentrations, low adiponectin plasma levels, small dense low-density lipoprotein (LDL) particles, hyperuricaemia, non-alcoholic fatty liver disease/hepatic steatosis, elevated liver transaminases, gamma-glutamyl-transferase and microalbuminuria.
  • LDL small dense low-density lipoprotein
  • Diabetes mellitus is a group of disorders characterized by abnormal glucose homeostasis resulting in high levels of blood glucose.
  • Type 1 and Type 2 diabetes are types 1 and Type 2 diabetes of which the latter accounts for approximately 90% of all diabetic cases.
  • the increasing prevalence of obesity together with an ageing population is predicted to rapidly increase the number of people with diabetes.
  • new and novel antidiabetic and antiobesity therapies that are well tolerated with few adverse effects.
  • Type 1 diabetes also known as insulin-dependent diabetes mellitus (IDDM)
  • IDDM insulin-dependent diabetes mellitus
  • Type 1 diabetes usually start in childhood or young adulthood manifesting sudden symptoms of high blood sugar (hyperglycemia).
  • Type 2 diabetes or diabetes mellitus type 2 (formerly called non-insulin-dependent diabetes mellitus (NIDDM), or adult-onset diabetes) is a progressive disease characterized by impaired glucose metabolism resulting in elevated blood glucose levels.
  • T2D may be characterized by a defect in insulin secretion or by insulin resistance, namely those that suffer from T2D have too little insulin or cannot use insulin effectively.
  • Insulin resistance refers to the inability of body tissues to respond properly to endogenous insulin. Insulin resistance develops because of multiple factors, including genetics, obesity, increasing age, and having high blood sugar over long periods of time.
  • T2D is a serious progressive disease that results in the development of microvascular complications (e.g.
  • retinopathy retinopathy, neuropathy, nephropathy
  • macrovascular complications e.g. accelerated atherosclerosis, coronary heart disease, stroke.
  • T2D retinopathy, neuropathy, nephropathy
  • macrovascular complications e.g. accelerated atherosclerosis, coronary heart disease, stroke.
  • More than 75% of people with T2D die of cardiovascular diseases.
  • Current oral medications for T2D have a number of side effects, including hypoglycemia, weight gain and edema, prompting continued efforts to develop therapeutics to improve treatments for patients with diabetes.
  • combination therapy is being commonly used because a single drug is insufficient to target diabetes and its associated complications.
  • T2D Treatments of T2D aim to reverse insulin resistance, control intestinal glucose absorption, normalize hepatic glucose production, and improve beta-cell glucose sensing and insulin secretion.
  • the sulfonylurea class of oral antihyperglycemic agents promotes insulin secretion from pancreatic beta-islet cells.
  • this enhanced insulin production is not glucose dependent and there is risk for developing hypoglycaemia.
  • Antihyperglycemic agents include: insulin sensitizers that reduce hepatic glucose production by inhibiting gluconeogenesis; alpha-glucosidase inhibitors that inhibit breakdown of complex carbohydrates thus delaying glucose absorption and dampening postprandial glucose and insulin peaks; and activators of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma), such as the thiazolidinediones (TZDs), which enhances insulin action.
  • PPAR-gamma peroxisome proliferator-activated receptor-gamma
  • TZDs thiazolidinediones
  • the incretins, GIP and GLP-I appear to serve as endogenous antidiabetic hormones, stimulating glucose-dependent insulin secretion.
  • GIP and GLP-I are secreted from enteroendocrine K and L cells, respectively, in response to ingestion of nutrients.
  • GLP-I inhibits glucagon release, gastric emptying, and appetite.
  • Continuous infusion of GLP-I into patients with T2D improves glucose control.
  • Both GIP and GLP-I are rapidly degraded by dipeptidylpeptidase-4 (DPP-4) that has prompted the development of DPP-4-resistant GLP-I receptor agonists, e.g.
  • incretin activity can be increased by inhibition of the degrading enzyme DPP-4 (e.g. with sitagliptin or vildagliptin) leading to prolonged antidiabetic effects of GLP-I and GIP (L. Lauffer, R. Iakoubov, and P. L. Brubaker, 2008, Endocrinology, 149(5):2035-2037).
  • DPP-4 degrading enzyme
  • Treatments to increase GLP-I therefore, may be used for a variety of conditions and disorders including metabolic disorders such as diabetes mellitus (Type 1 and Type 2), metabolic syndrome, obesity, appetite control, weight loss and satiety
  • GPRl 19 (GenBank No. NM 178471) is a constitutively active G-protein coupled receptor. GPRl 19 is largely confined to pancreas and intestinal tissues in humans, with extremely low or undetectable expression in all other human tissues examined. The GRPl 19 receptor stimulates insulin production in response to increases in blood glucose and GPRl 19 agonists are not expected to lower normal fasting blood glucose levels or cause hypoglycemia. Moreover, GPRl 19 stimulation has been found to increase the levels and activity of intracellular factors thought to be involved in the preservation of beta cells (Soga et al, 2005, Biochem. Biophys. Res. Commun.
  • GPRl 19 also stimulates incretin hormone release and has been shown to regulate glucose homeostasis by this additional mechanism.
  • GPRl 19 mRNA has been found to be expressed at significant levels in intestinal sub-regions (e.g. entero-endocrine L-cells) that produce GIP and GLP-I. Furthermore, in situ hybridization studies indicated that most GLP-I -producing cells co- express GPRl 19 mRNA.
  • Stimulation with the pharmacological GPRl 19 agonist, AR231453, induces GLP-I secretion from entero-endocrine cell lines (GLUTag and STC-I) and enhances the release of both GLP-I and GIP in vivo in mice.
  • GPRl 19 -specific agonists appear to provide a useful approach to incretin therapy in patients with diabetes mellitus type 2, increasing glucose-dependent insulin secretion through two complementary mechanisms: directly, through actions on the ⁇ -cell, and indirectly, through enhancement of GLP-I and GIP release.
  • GPRl 19 small molecules and the endogenous GPRl 19 ligand oleoylethanolamide improve various metabolic parameters, including weight loss, glucose tolerance and insulin sensitivity and a selective small-molecule agonist of GPRl 19, PSN632408 has been shown to reduce food intake, body weight gain and white adipose tissue deposition in high-fat fed rats (Overton et al., 2006, Cell Metabol 3:167-75).
  • GPR119 agonists have the potential to normalize blood glucose levels in a T2D patient in response to postprandial blood glucose elevation and are potentially useful for treating diabetes and/or obesity.
  • WO 2008/008887 disclose compounds that are modulators of GPRl 19, also referred to as RUP 3, 19 AJ, AXOR 20, and PSl and SNORF25 (Fredriksson et al., 2003, FEBS Lett, 554, 381- 388), and which inter alia may be used for the treatment of
  • Positive modulators or agonists to the GPRl 19 receptor may be used in the treatment or prophylaxis of disorders relating to GPRl 19, e.g. Type 1 and Type 2 diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypercholesterolemia, dyslipidemia, atherosclerosis, metabolic syndrome, obesity, hypertension, vascular conditions, chronic systemic inflammation, pain, retinopathy, neuropathy, nephropathy, osteoporosis, reduced fibrinolysis, demyelination, nonalcoholic fatty liver disease and endothelial dysfunction.
  • disorders relating to GPRl 19 receptor e.g. Type 1 and Type 2 diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypercholesterolemia, dyslipidemia, atherosclerosis, metabolic syndrome, obesity, hypertension, vascular conditions, chronic systemic inflammation, pain, retinopathy, neuropathy, nephropathy, osteoporosis, reduced fibrinolysis, demyelination, nonalcoholic
  • ring A is phenyl or pyridyl
  • R 1 is hydrogen, -CN, -F, -Cl, -Br, -NO 2 , -OR 3 , -NR 7 COR 6 , -NR 7 S(O) 2 R 6 , -COR 6 , -SR 3 , -S(O)R 3 , -CH 2 S(O) 2 R 3 , CH 2 SO 2 NR 4 R 5 , -S(O) 2 R 3 , -SO 2 NR 4 R 5 , C 1 -C 4 alkyl, fully or partially fluorinated C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl, or 5-membered heteroaryl;
  • R 2 is hydrogen, -CN, -F, -Cl, or -OR 3 ;
  • R 8 is hydrogen or -F; provided that R 1 , R 2 and R 8 are not simultaneously hydrogen;
  • R 3 is C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl, or fully or partially fluorinated C 1 -C 4 alkyl;
  • R 6 is C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl, or -NR 4 R 5 ;
  • R 4 and R 5 are independently hydrogen, C 1 -C 4 alkyl or C 3 -C 5 cycloalkyl, or taken together with the nitrogen to which they are attached form a 5- or 6-membered heterocyclic ring;
  • R 7 is hydrogen, C 1 -C 4 alkyl, or C 3 -C 5 cycloalkyl
  • B is -CO 2 R 3 , -COR 6 , -S(O) 2 R 3 , or -V-R 7 ;
  • V is a divalent 5-membered heteroarylene radical.
  • Another aspect of the invention is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers or excipients.
  • (C a -C b )alkyl refers to a straight or branched chain alkyl radical having from a to b carbon atoms.
  • a 1 and b is 4, for example, the term includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec -butyl, and t- butyl.
  • a is 1 and b is 4, for example, the term includes mono-, di- and tri-fluoromethyl, 2-fluoroethyl, 2,2-difluoromethyl, and 2,2,2- trifluoromethyl.
  • C 3 -C 5 cycloalkyl refers to cyclopropyl, cyclobutyl, and cyclopentyl radicals.
  • unqualified term “5-membered heteroaryl” refers to a monocyclic aromatic radical containing one or more, e.g. 1, 2 or 3, heteroatoms selected from S, N and O.
  • Illustrative of such radicals are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, and oxadiazolyl.
  • divalent 5-membered heteroarylene radical means a 5- membered heteroaryl radical having two unsatisfied valencies.
  • 5- or 6-membered heterocyclic means a monocyclic non-aromatic radical having 5 or 6 ring atoms, one or more of which, e.g. 1 or 2 of which, are heteroatoms selected from S, N and O.
  • Illustrative of such radicals are piperidinyl, morpholinyl piperazinyl, and N-(Ci-C 4 alkyl)piperazinyl
  • salt includes base addition, acid addition and quaternary salts.
  • Compounds of the invention which are acidic can form salts, including pharmaceutically acceptable salts, with bases such as alkali metal hydroxides, e.g. sodium and potassium hydroxides; alkaline earth metal hydroxides e.g. calcium, barium and magnesium hydroxides; with organic bases e.g. N-methyl-D-glucamine, choline tris(hydroxymethyl)amino-methane, L- arginine, L-lysine, N-ethylpiperidine, dibenzylamine and the like.
  • bases such as alkali metal hydroxides, e.g. sodium and potassium hydroxides; alkaline earth metal hydroxides e.g. calcium, barium and magnesium hydroxides; with organic bases e.g. N-methyl-D-glucamine, choline tris(hydroxymethyl)amino-methane, L- arginine, L-lysine, N-ethylpiperidine, dibenzylamine and the like.
  • hydrohalic acids such as hydrochloric or hydrobromic acids, sulfuric acid, nitric acid or phosphoric acid and the like
  • organic acids e.g. with acetic, tartaric, succinic, fumaric, maleic, malic, salicylic, citric, methanesulfonic, p-toluenesulfonic, benzoic, benzenesulfonic, glutamic, lactic, and mandelic acids and the like.
  • solvate is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • solvent molecules for example, ethanol.
  • hydrate is employed when said solvent is water.
  • Compounds of the invention which may exist in one or more stereoisomeric form, because of the presence of asymmetric atoms or rotational restrictions, can exist as a number of stereoisomers with R or S stereochemistry at each chiral centre or as atropisomeres with R or S stereochemistry at each chiral axis.
  • the invention includes all such enantiomers and diastereoisomers and mixtures thereof.
  • the compounds of the invention include compounds of formula (I) as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically- labeled compounds of formula (I).
  • prodrugs of the compounds of formula (I) are also within the scope of the invention.
  • certain derivatives of compounds of formula (I) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (I) having the desired activity, for example, by hydrolytic cleavage.
  • Such derivatives are referred to as 'prodrugs'.
  • prodrugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and VJ. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E. B. Roche, American Pharmaceutical Association; CS. Larsen and J. ⁇ stergaard, Design and application of prodrugs, In Textbook of Drug Design and Discovery, 3 rd Edition, 2002, Taylor and Francis ).
  • Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formula (I) with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).
  • (I) that is, compounds formed in vivo upon administration of the drug.
  • Some examples of metabolites include:
  • Ring A is phenyl or pyridyl (i.e. 2-, 3- or 4-pyridyl). Phenyl is preferred.
  • the substituents R 1 , R 2 , and R 8 in ring A have been defined above in relation to formula (I). At least one such substituent other than hydrogen must be present in ring A.
  • R 1 may be SeIeCtCd IrOm -S(O) 2 R 31 -SO 2 NR 4 R 5 , -CH 2 S(O) 2 R 3 , -CH 2 SO 2 NR 4 R 5 , -COR 6 , -NR 7 COR 6 , or 5-membered heteroaryl, R 3 , R 4 , R 5 , R 6 and R 7 being as defined in relation to formula (I).
  • R 3 may be, for example, hydrogen, methyl ethyl, n- or iso- propyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, or cyclopentyl;
  • R 1 is -SO 2 NR 4 R 5 or -CH 2 SO 2 NR 4 R 5
  • R 4 and R 5 may independently be, for example, hydrogen, methyl or ethyl, or one of R 4 and R 5 may be hydrogen or methyl, and the other may be n- or iso-propyl, cyclopropyl, cyclobutyl or cyclopentyl, or R 4 and R 5 taken with the nitrogen to which they are attached may form a piperidine, morpholine, thiomorpholine, piperazine, or N-substituted piperazine ring, such as an N-(Ci-C
  • R 2 may be, for example, hydrogen, -F, -CN, or -OR 3 wherein R 3 is as defined in relation to formula (I), such as, for example, hydrogen, methyl, ethyl, or cyclopropyl.
  • R 3 is as defined in relation to formula (I), such as, for example, hydrogen, methyl, ethyl, or cyclopropyl.
  • R 8 may be, for example, hydrogen or -F. Often, when R 8 is -F, it will be in an ortho position of ring A relative to the carboxamide bond shown in formula (I).
  • N-substituent B in the piperidine ring shown in formula (I) has been defined in relation to formula (I) as a radical -CO 2 R 3 , -COR 6 , -S(O) 2 R 3 , or -V-R 7 ; wherein V is a divalent 5- membered heteroarylene radical.
  • R 3 may be, for example, methyl, ethyl, n- or iso-propyl, tert-butyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, or cyclopentyl;
  • R 6 may be, for example, methyl, ethyl, n- or iso-propyl, n-sec- or tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or -NR 4 R 5 wherein R 4 and R 5 may independently be, for example, hydrogen, methyl, or ethyl, or one of R 4 and R 5 may be hydrogen or methyl, and the other may be n- or iso-propyl, cyclopropyl, cyclobutyl or cyclopentyl, or R 4 and R 5 taken with the nitrogen to which they are attached may form a piperidine, morpholine, thiomorph
  • the compounds of the present invention are agonists at the GPRl 19 receptor.
  • agonism at that receptor is known to be an indicator of utility in the treatment or prophylaxis of, diseases or conditions which are associated with GPRl 19 receptor signaling, such as diabetes, obesity and metabolic syndrome including associated conditions, such as, glucose intolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypercholesterolemia, dyslipidemia, atherosclerosis, vascular conditions, osteoporosis, pain, demyelination, and nonalcoholic fatty liver disease.
  • Compounds of the invention may be used in combination with agents used for treatment or prophylaxis of diabetes or obesity or in combination with agents used for treatment of diseases related to diabetes or obesity.
  • agents useful in the present methods for treating type 2 diabetes include i) insulin sensitizers (such as PPAR agonists (include PPAR-gamma agonists such as troglitazone, rosiglitazone, pioglitazone and englitazone), DPP-4 inhibitors (such as sitagliptin, saxagliptin, alogliptin, denagliptin and vildagliptin), protein tyrosine phosphatase (PTP)-IB inhibitors and glucokinase activators (e.g.
  • PPAR agonists include PPAR-gamma agonists such as troglitazone, rosiglitazone, pioglitazone and englitazone
  • DPP-4 inhibitors such as sitag
  • glucose absorption inhibitors such as alpha-glucosidase inhibitors (e.g. miglitol, acarbose and voglibose) and sodium-glucose transport protein SGLTl inhibitors
  • insulin secretagogues such as sulfonylureas (e.g.
  • glipizide, tolbutamide, glyburide, glimepiride, chlorpropamide, acetohexamide, gliamilide, gliclazide, glibenclamide and tolazamide) and non-sulfonylurea drugs such as GLP-I, GLP-I peptide analogues, exendin, GIP, secretin, glipizide, chlorpropamide, nateglinide, meglitinide, glibenclamide, repaglinide and glimepiride); iv) glucagon suppressor (such as amylin agonist analog (pramlintide), glucagon receptor antagonists (e.g. NNC-92-1687 and BAY-27-9955); v) hepatic glucose output lowering compounds (such as metformin); vi) renal sodium-glucose transport protein SGLT2 inhibitors (such as dapagliflozin,
  • GW869682 and GSK189075 insulin (including all formulations of insulin, including long acting and short acting forms of insulin and insulin analogues).
  • Compounds of the invention may be administered in combination with anti-obesity agents for the treatment of diabetes.
  • anti-obesity agents for the treatment of diabetes.
  • Several such useful potential anti-obesity agents are currently investigated (for a review, see Bays, 2004, Obesity Research, 12, 1197-1211): i) central nervous system agents that affect neurotransmitters or neural ion channels
  • leptin/insulin/central nervous system pathway agents e.g. antidepressants (bupropion), noradrenaline reuptake inhibitors (GW320659), selective 5HT 2c receptor agonists, antiseizure agents (topiramate, zonisamide), some dopamine antagonists, cannabinoid CB-I receptor antagonists (rimonabant); ii) leptin/insulin/central nervous system pathway agents (e.g.
  • leptin analogues leptin transport and/or receptor promoters
  • CNTF Axokine
  • NPY antagonists AgRP antagonists
  • POMC promoters CART promoters
  • MSH analogues MSH analogues
  • MC4 receptor agonists agents that affect insulin metabolism/activity [PTP-IB inhibitors, PPAR receptor antagonists, short-acting D2 agonist (ergoset), somatostatin agonists (octreotide), and adiponectin/Acrp30 (Famoxin or Fatty Acid Metabolic OXidation INducer)]); iii) gastrointestinal-neural pathway agents (e.g.
  • agents that increase CCK and PYY activity agents that increase GLP-I activity (extendin 4, liraglutide, dipeptidyl peptidase IV inhibitor), agents that decrease ghrelin activity, amylin (pramlinitide), neuropeptide Y agonists); iv) agents that may increase resting metabolic rate (beta-3 agonists, UCP homologues, thyroid receptor agonists); v) other more diverse agents, such as for example including (MCH) melanin concentrating hormone antagonists, phytostanol analogues, functional oils, P57, amylase inhibitors, growth hormone fragments, synthetic analogues of DHEAS (fluasterone), antagonists of adipocyte 1 lbeta-hydroxysteroid dehydrogenase type 1 activity, CRH agonists, carboxypeptidase inhibitors, inhibitors of fatty acid synthesis (cerulenin and C75), indanones/indanols, aminosterols (trodusquemine),
  • Drugs effective in obesity treatment may act by various mechanisms such as by: a reduction of food intake (e.g. by inducing satiety or satiety signals), altering metabolism (e.g. by modifying the absorption of nutrients e.g. by inhibition of fat absorption), increasing energy expenditure (e.g. increase thermogenesis), inhibition of lipogenesis or stimulation of adipocyte apoptosis.
  • a reduction of food intake e.g. by inducing satiety or satiety signals
  • altering metabolism e.g. by modifying the absorption of nutrients e.g. by inhibition of fat absorption
  • increasing energy expenditure e.g. increase thermogenesis
  • inhibition of lipogenesis or stimulation of adipocyte apoptosis i.e.
  • sibutramine a centrally acting mixed inhibitor of serotonin and norepinephrine presynaptic re-uptake; orlistat an inhibitor of gastrointestinal lipases which reduces fat absorption in the gut; and rimonabant a centrally and peripherally acting cannabinoid CB 1 modulator (for a review see Pagotto et al, 2006, Endocrine Reviews, 27, 73-100).
  • cardiovascular hypertension, congestive cardiomyopathy, varicosities, pulmonary embolism, coronary heart disease [CHD], neurological (stroke, idiopathic intracranial hypertension, meralgia parethetica); ii) respiratory (dyspnea, obstructive sleep apnea, hypoventilation syndrome,
  • GPRl 19 agonist of the invention it is also useful to combine a GPRl 19 agonist of the invention with medications used for treatment of such diseases.
  • compounds of the invention may also be administered in combination with antihypertensive agents, for example beta-blockers and calcium channel blockers, ACE inhibitors, AT-I receptor antagonists, renin inhibitors and endothelin receptor antagonists.
  • antihypertensive agents for example beta-blockers and calcium channel blockers, ACE inhibitors, AT-I receptor antagonists, renin inhibitors and endothelin receptor antagonists.
  • other agents used for treatment of above mentioned diseases may be combined with GPRl 19 agonists of the invention.
  • GPRl 19 agonist of the invention may also be combined with drugs used for treatment of Type 2 diabetes, e.g. by lowering blood glucose levels by stimulating the release of insulin from the pancreas, or with antidiabetic agents that sensitize the body to the insulin that is already present (e.g. certain biguanides, glitazones or thiazolidinediones), or with peptides increasing insulin production (e.g. amlintide, pramlintide, exendin, and liraglutide), or with DPP-4 inhibitors increasing levels of GLP-I and GIP (e.g.
  • drugs used for treatment of Type 2 diabetes e.g. by lowering blood glucose levels by stimulating the release of insulin from the pancreas, or with antidiabetic agents that sensitize the body to the insulin that is already present (e.g. certain biguanides, glitazones or thiazolidinediones), or with peptides increasing insulin production (e.g.
  • sitagliptin sitagliptin, saxagliptin, alogliptin, denagliptin and vildagliptin); or combined with compounds potentially useful with novel mechanisms such as modulators of G-protein coupled receptors TGR5 (G protein-coupled bile acid receptor 1 (GPBARl)), Y2, Y4, GPR39, GPR40, GPR43, and GPR120, ghrelin receptor antagonists, glucagon receptor antagonists, insulin receptor kinase stimulants (e.g. L-783281), tripeptidyl peptidase Il inhibitors (e.g. UCL-1397), glycogen phosphorylase inhibitors (e.g.
  • fructose-bisphosphatase inhibitors e.g. R-132917
  • pyruvate dehydrogenase inhibitors e.g. AZD-7545
  • hepatic gluconeogenesis inhibitors e.g. FR-225659
  • aldose reductase inhibitors e.g. epalrestat, fidarestat, imirestat, lindolrestat, minalrestat, ponalrestat, risarestat, tolrestat, zenarestat, zopolrestat
  • advanced glycation endproducts formation inhibitors e.g.
  • pyridoxamine ALT-946, ALT-711, pimagedine
  • protein kinase C inhibitors e.g. LY-333531 and midostaurin
  • glucagon-like peptide-1 analogues e.g. exendin-4 and CJC-1131
  • glucagon-like peptide 1 agonists e.g. AZM-134 and LY-315902
  • amylin agonists e.g. AZM-134 and LY-315902
  • amylin agonists e.g. AZM-134 and LY-315902
  • Another object of the present invention is a method for the treatment or prophylaxis of disorders related to GPRl 19, such as but not limited to, Type 1 and Type 2 diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypercholesterolemia, dyslipidemia, atherosclerosis, metabolic syndrome, obesity, hypertension, vascular conditions, chronic systemic inflammation, pain, retinopathy, neuropathy, nephropathy, osteoporosis, reduced fibrinolysis, demyelination, nonalcoholic fatty liver disease and endothelial dysfunction.
  • disorders related to GPRl 19 such as but not limited to, Type 1 and Type 2 diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypercholesterolemia, dyslipidemia, atherosclerosis, metabolic syndrome, obesity, hypertension, vascular conditions, chronic systemic inflammation, pain, retinopathy, neuropathy, nephropathy, osteoporosis, reduced fibrinolysis, demyelination, nonalcoholic fatty liver disease and end
  • the specific dose level of a compound of the invention for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing treatment. Optimum dose levels and frequency of dosing will be determined by clinical trial, as is required in the pharmaceutical art.
  • the total daily dose of the compounds of the invention may typically be in the range 1 mg to 1000 mg depending, of course, on the mode of administration.
  • oral administration may require a total daily dose of from 10 mg to 1000 mg, while an intravenous dose may only require from 1 mg to 500 mg.
  • the total daily dose may be administered in single or divided doses and may, at the physician' s discretion, fall outside of the typical range given herein.
  • These dosages are based on an average human subject having a weight of about 60 kg to 100 kg.
  • the physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly, and especially obese patients.
  • the compounds with which the invention is concerned may be prepared for administration by any route consistent with their pharmacokinetic properties.
  • the orally administrable compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical, or sterile parenteral solutions or suspensions.
  • Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrrolidone; fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricant, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants for example potato starch, or acceptable wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p- hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats
  • emulsifying agents for example lecithin, sorbitan monooleate, or acacia
  • non-aqueous vehicles which may include edible oils
  • almond oil fractionated coconut oil
  • oily esters such as glycerine, propy
  • the active ingredient may also be administered parenterally in a sterile medium.
  • the drug can either be suspended or dissolved in the vehicle.
  • adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • DCC dicyclohexylcarbodiimide
  • HOBT 1- hydroxybenzotriazole
  • the carboxylic acid can be synthesized according to procedures described in the standard literature e.g. upon hydrolysis of a nitrile, ester or amide moiety in either basic or acidic conditions, or upon conversion of an aromatic halide in presence of carbon monoxide and a suitable metal catalyst (e.g. palladium acetate) and ligand (e.g. 1,3- bis(diphenylphosphino)propane) or upon treatment of an aromatic halide for instance with a strong base (e.g. butyllithium), at low temperature in presence of carbon dioxide.
  • a suitable metal catalyst e.g. palladium acetate
  • ligand e.g. 1,3- bis(diphenylphosphino)propane
  • a strong base e.g. butyllithium
  • the 2-aminothiazole derivative can be synthesized according to the procedure outlined in Bioorganic & Medicinal Chemistry Letters (2005), 15(8), 2129-2134 as outlined in Scheme B:
  • Such a procedure may include for instance the synthesis of compounds of general formula (Ia), (Ib), (Ic) and (Id):
  • compounds of formula (Ia) may be obtained by treatment of the unsubstituted piperidine intermediate with e.g. an alkylchloroformate or an alkyldicarbonate, in presence of an organic (e.g. triethylamine) or inorganic base (e.g. cesium carbonate), in polar (e.g. tetrahydrofuran, acetonitrile) or apolar (e.g. dichloromethane) aprotic solvents.
  • an organic e.g. triethylamine
  • inorganic base e.g. cesium carbonate
  • polar e.g. tetrahydrofuran, acetonitrile
  • apolar e.g. dichloromethane
  • compounds of formula (Ib) may be obtained by treatment of the unsubstituted piperidine intermediate with a carboxylic acid.
  • DCC dicyclohexylcarbodiimide
  • HOBT 1-hydroxybenzotriazole
  • a carbonylating agent e.g. phosgene, trisphosgene, carbonyldiimidazole
  • compounds of formula (Ic) may be obtained by treatment of the unsubstituted piperidine intermediate with an alkylsulfonyl chloride, in presence of an organic or inorganic base, in polar or apolar aprotic solvents.
  • a sulfonylating agent e.g. sulfonyl chloride
  • compounds of formula (Id) wherein V is a 5-membered heteroarylene may be obtained by treatment of the unsubstituted piperidine intermediate with a suitable activated heteroaryl moiety.
  • a suitable activated heteroaryl moiety may be:
  • the coupling reaction usually takes place in presence of a mild or strong base, in aprotic polar solvent, with or without use of metal-coupling catalyst (e.g. CuI), depending upon the nature of the activated heteroaryl moiety.
  • metal-coupling catalyst e.g. CuI
  • compounds of formula (Id) may be obtained by in situ formation of the heteroaryl moiety.
  • compounds of formula (Id) wherein V is an oxadiazole may be synthesized synthesized as outlined below:
  • the unsubstituted piperidine intermediate may first be reacted with cyanogen bromide to give an intermediate which, upon treatment with a suitable alkylamidoxime, may lead to the formation of an oxadiazole of formula (Id), as described in WO 2005/007647.
  • Table 1 The Examples shown in Table 1 were prepared using the method described for Example 1. Table 1
  • Table 2 shows results for compounds of the invention, synthesized as above.
  • the cDNA (GenBank accession number: AY288416) encoding the human GPRl 19 receptor (synonyms: GDIR, RUP3, SNORF25, ATRA receptor, GPR2, GPCR2, 19AJ, SMT3, OSGPRl 16) was cloned from a human pancreas cDNA library (Clontech BD-biosciences, 7410-1) and cloned into the inducible expression vector pcDNATM4/TO (Invitrogen), which is a tetracycline-regulated expression system for mammalian cells.
  • Chinese Hamster Ovary cells (CHO-T-Rex) stably expressing recombinant human
  • GPRl 19 were generated by transfecting the plasmid containing the coding sequence of the human GPRl 19 receptor N-terminally flagged with Ml (Met-Lys-Thr-Ile-Ile-Ala-Leu-Ser-Tyr-Ile-Phe- Cys-Leu-Val-Phe-Ala-Asp-Tyr-Lys-Asp-Asp- Asp-Asp), using lipofectaminTM 2000 reagent, according to the manufacturer instructions. Resistant clones were selected in the presence of 100 ⁇ g/ml Zeocin and 5 ⁇ g/ml Blasticidin S HCl (Invitrogen).
  • Stably transfected CHO-T-Rex cells were maintained in Ham's F- 12 culture medium (Invitrogen), supplemented with 10 % fetal calf serum (Invitrogen), 100 U/ml penicillin, 100 ⁇ g/ml streptomycin (Life Technology), 100 ⁇ g/ml Zeocin, and 5 ⁇ g/ml Blasticidin S HCl and incubated at 37°C in a humidified atmosphere 5% (v/v) CO 2 in air.
  • GPR119-CHO-T-Rex cells were incused with 0.01 ⁇ g/ml tetracycline for 24 hrs after which the cells were frozen following a standard freezing procedure. Frozen cells were thawed one day prior day of assay and recovered in culture for 24hrs.
  • ALPHAscreen cAMP assay The ALPHAscreen technology has thoroughly been described in "PerkinElmer ALPHAscreen cAMP assay Kit manual". Briefly, the production of intracellular cAMP will generate a competition between unlabeled cAMP and exogenously added biotinylated cAMP for anti-cAMP antibodies conjugated to a bead (Acceptor bead). A streptavidin coated Donor bead will recognize the biotinylated cAMP bead complex forming a stable unit where the two beads are brought into close proximity. Upon laser excitation at 680 nm, a photosensitizer in the Donor bead converts ambient triplet oxygen to the more excited singlet state.
  • This step is responsible for very high signal amplification. If the beads are in close proximity, energy will be trans-located to the acceptor bead and a cascade of chemical reactions will finally lead to emission of fluorescent light at 520-620 nm.
  • Assay conditions were slightly changed from the standard PerkinElmer procedure. All buffers were as per manufacture instructions (including 0.5 mM IBMX final concentration). The assay was performed in 384-well microplates (OptiPlate-384, PerkinElmer). 0.5 ⁇ l of test compound (DMSO solution, 2% final DMSO concentration) were added to empty wells and stored until day of assay. One the day of assay 25 ⁇ l of cells (15.000 cells/well) was added and incubated for 60 min.
  • the biotinylated cAMP (1 units/well) was pre-incubated with donor beads (1 units/well) for 30 min. 5 ⁇ l of acceptor beads (1 units/well) was added followed by 5 ⁇ l of the donor bead/bio tinylated cAMP suspension after 10 min of incubation. The plates were read on a Fusion plate reader after three hours of incubation. In parallel with compound screening on the GPRl 19 receptor all compounds were counter screened on the GLPl receptor using the cAMP ALPHAscreen technology to eliminate pathway selective, promiscuous or signaling quenching compounds. Data analysis

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Abstract

L'invention porte sur des composés de formule (I) ou des sels, hydrates, solvates ou N-oxydes de ces composés, formule (I) : dans laquelle A, B, R1, R2 et R8 sont tels que définis dans la description, ces composés étant utiles pour traiter ou prévenir des maladies ou états pathologiques qui sont associés à une signalisation du récepteur GPR119, tels que le diabète, l'obésité et le syndrome métabolique.
PCT/GB2009/050770 2008-07-01 2009-07-01 Dérivés de thiazole en tant que modulateurs du gpr 119 Ceased WO2010001166A1 (fr)

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WO2011113947A1 (fr) 2010-03-18 2011-09-22 Boehringer Ingelheim International Gmbh Combinaisons d'agonistes de gpr119 et d'inhibiteurs de dpp-iv, linagliptine, pour le traitement du diabète et d'états apparentés
WO2011128394A1 (fr) 2010-04-14 2011-10-20 Prosidion Limited 5-(pyrrolidine-1-carbonyl) pyrrolidine 3-substituée et ses dérivés à usage dans le traitement de troubles métaboliques
WO2011128395A1 (fr) 2010-04-14 2011-10-20 Prosidion Limited 3-amino 4-(pyrrolidine-1-carbonyl) pyrrolidine n-substituée et ses dérivés à usage dans le traitement de troubles métaboliques
WO2011147951A1 (fr) 2010-05-28 2011-12-01 Prosidion Limited Dérivés de cycloamino comme antagonistes du gpr119
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012066077A1 (fr) 2010-11-18 2012-05-24 Prosidion Limited Dérivés 1,4 di substitués pyrolidine-3-yl-amine et leur utilisation pour le traitement de troubles métaboliques
WO2012170867A1 (fr) 2011-06-09 2012-12-13 Rhizen Pharmaceuticals Sa Nouveaux composes utilises comme modulateurs de gpr-119
WO2013026587A1 (fr) 2011-08-22 2013-02-28 Prosidion Limited Dérivés de pyrolidin-3-yl-amine 1,4 disubstituée et leur utilisation pour le traitement de troubles métaboliques
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
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JP2018526413A (ja) * 2015-09-09 2018-09-13 ダナ−ファーバー キャンサー インスティテュート， インコーポレイテッド サイクリン依存性キナーゼの阻害剤
US10968235B2 (en) 2014-01-17 2021-04-06 Novartis Ag N-azaspirocycloalkane substituted N-heteroaryl compounds and compositions for inhibiting the activity of SHP2
US11325910B2 (en) 2015-03-27 2022-05-10 Dana-Farber Cancer Institute, Inc. Inhibitors of cyclin-dependent kinases
US11826365B2 (en) 2009-12-29 2023-11-28 Dana-Farber Cancer Institute, Inc. Type II raf kinase inhibitors
US12168663B2 (en) 2014-12-23 2024-12-17 Dana-Farber Cancer Institute, Inc. Inhibitors of cyclin-dependent kinase 7 (CDK7)
US12187701B2 (en) 2018-06-25 2025-01-07 Dana-Farber Cancer Institute, Inc. Taire family kinase inhibitors and uses thereof

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Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8883714B2 (en) 2008-04-07 2014-11-11 Arena Pharmaceuticals, Inc. Pharmaceutical compositions comprising GPR119 agonists which act as peptide YY (PYY) secretagogues
US11826365B2 (en) 2009-12-29 2023-11-28 Dana-Farber Cancer Institute, Inc. Type II raf kinase inhibitors
WO2011113947A1 (fr) 2010-03-18 2011-09-22 Boehringer Ingelheim International Gmbh Combinaisons d'agonistes de gpr119 et d'inhibiteurs de dpp-iv, linagliptine, pour le traitement du diabète et d'états apparentés
WO2011128394A1 (fr) 2010-04-14 2011-10-20 Prosidion Limited 5-(pyrrolidine-1-carbonyl) pyrrolidine 3-substituée et ses dérivés à usage dans le traitement de troubles métaboliques
WO2011128395A1 (fr) 2010-04-14 2011-10-20 Prosidion Limited 3-amino 4-(pyrrolidine-1-carbonyl) pyrrolidine n-substituée et ses dérivés à usage dans le traitement de troubles métaboliques
WO2011147951A1 (fr) 2010-05-28 2011-12-01 Prosidion Limited Dérivés de cycloamino comme antagonistes du gpr119
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012066077A1 (fr) 2010-11-18 2012-05-24 Prosidion Limited Dérivés 1,4 di substitués pyrolidine-3-yl-amine et leur utilisation pour le traitement de troubles métaboliques
WO2012170867A1 (fr) 2011-06-09 2012-12-13 Rhizen Pharmaceuticals Sa Nouveaux composes utilises comme modulateurs de gpr-119
WO2013026587A1 (fr) 2011-08-22 2013-02-28 Prosidion Limited Dérivés de pyrolidin-3-yl-amine 1,4 disubstituée et leur utilisation pour le traitement de troubles métaboliques
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
WO2014011926A1 (fr) 2012-07-11 2014-01-16 Elcelyx Therapeutics, Inc. Compositions comportant des statines, des biguanides et d'autres agents pour réduire un risque cardiométabolique
US10968235B2 (en) 2014-01-17 2021-04-06 Novartis Ag N-azaspirocycloalkane substituted N-heteroaryl compounds and compositions for inhibiting the activity of SHP2
US11952386B2 (en) 2014-01-17 2024-04-09 Novartis Ag N-azaspirocycloalkane substituted N-heteroaryl compounds and compositions for inhibiting the activity of SHP2
US12209098B2 (en) 2014-01-17 2025-01-28 Novartis Ag N-azaspirocycloalkane substituted N-heteroaryl compounds and compositions for inhibiting the activity of SHP2
US12168663B2 (en) 2014-12-23 2024-12-17 Dana-Farber Cancer Institute, Inc. Inhibitors of cyclin-dependent kinase 7 (CDK7)
US11325910B2 (en) 2015-03-27 2022-05-10 Dana-Farber Cancer Institute, Inc. Inhibitors of cyclin-dependent kinases
US12098154B2 (en) 2015-03-27 2024-09-24 Dana-Farber Cancer Institute, Inc. Inhibitors of cyclin-dependent kinases
JP2018526413A (ja) * 2015-09-09 2018-09-13 ダナ−ファーバー キャンサー インスティテュート， インコーポレイテッド サイクリン依存性キナーゼの阻害剤
US11142507B2 (en) 2015-09-09 2021-10-12 Dana-Farber Cancer Institute, Inc. Inhibitors of cyclin-dependent kinases
JP7028766B2 (ja) 2015-09-09 2022-03-02 ダナ－ファーバー キャンサー インスティテュート， インコーポレイテッド サイクリン依存性キナーゼの阻害剤
US12187701B2 (en) 2018-06-25 2025-01-07 Dana-Farber Cancer Institute, Inc. Taire family kinase inhibitors and uses thereof

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