WO2010048149A2 - Heterocyclic modulators of gpr119 for treatment of disease - Google Patents

Heterocyclic modulators of gpr119 for treatment of disease Download PDF

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Publication number
WO2010048149A2
WO2010048149A2 PCT/US2009/061281 US2009061281W WO2010048149A2 WO 2010048149 A2 WO2010048149 A2 WO 2010048149A2 US 2009061281 W US2009061281 W US 2009061281W WO 2010048149 A2 WO2010048149 A2 WO 2010048149A2
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chosen
optionally substituted
heteroaryl
recited
alkyl
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PCT/US2009/061281
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French (fr)
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WO2010048149A3 (en
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Nicholas D. Smith
Celine Bonnefous
Mehmet Kahraman
Stewart A. Noble
Joseph E. Payne
Steven P. Govek
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Kalypsys, Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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

Definitions

  • Obesity is a growing threat to the global health by virtue of its association with a cluster of diseases that include insulin resistance, glucose intolerance, dyslipidemia, and hypertension, collectively known as the metabolic syndrome or syndrome X. It is well documented that patients with metabolic syndrome have a higher risk for cardiovascular diseases such as coronary heart disease and stroke [Grundy S. M. et al. Circulation 112:e285-e290, 2005]. The treatment of obesity will require complex solutions, including increased public awareness to diminish food portions, improved food choices and increased physical activity. However, epidemiologic studies have shown that treating diabetes/insulin resistance in these patients can reduce the risk of cardiovascular diseases such as coronary artery disease.
  • GPRl 19 modulators described herein might represent such an opportunity.
  • Current therapies for diabetes mellitus include: insulin; insulin secretagogues, such as sulphonylureas, which increase insulin secretion from pancreatic ⁇ -cells; glucose-lowering effectors, such as metformin which reduce glucose production from the liver; activators of the peroxisome proliferator-activated receptor- ⁇ (PPAR- ⁇ ), such as the thiazolidinediones, which enhances insulin action; GLP-I mimetics, such as exenatide (Byetta); and ⁇ -glucosidase inhibitors which interfere with gut glucose production.
  • insulin secretagogues such as sulphonylureas, which increase insulin secretion from pancreatic ⁇ -cells
  • glucose-lowering effectors such as metformin which reduce glucose production from the liver
  • activators of the peroxisome proliferator-activated receptor- ⁇ (PPAR- ⁇ ) such as the thiazolidinediones
  • GIP and GLP-I are peptides, known as incretins, secreted from enteroendocrine K- and L-cells respectively in response to ingestion of nutrients, and have a wide variety of physiological effects that have been described in numerous publications over the past two decades. See, for example, Bojanowska, E. et al., Med. Sd. Monit, 2005, Aug 5 11(8): RA271-8; Perry, T. et al., Curr. Alzheimer Res., 2005, July 2(3): 377-85; and Meier, JJ. et al., Diabetes Metab. Res.
  • GIP and GLP-I are potent stimulators of the body's ability to produce insulin in response to elevated levels of blood sugar.
  • GLP-I glucose-lowering effects in addition to GLP- l's ability to stimulate glucose-dependent insulin secretion including, but not limited to, an inhibition of the release of the hormone glucagon following meals, a reduction in the rate at which nutrients are absorbed into the bloodstream, and a reduction of food intake.
  • treatments to increase GLP-I may be used for a variety of conditions and disorders including but not limited to metabolic disorders, gastrointestinal disorders, inflammatory diseases, psychosomatic, depressive, and neuropsychiatric disease including but not limited to diabetes mellitus (Type 1 and Type 2), metabolic syndrome, obesity, appetite control and satiety, weight loss, stress, inflammation, myocardial ischemia/reperfusion injury, Alzheimer's Disease, and other diseases of the central nervous system.
  • Type II diabetes patients display a decreased responsiveness to GIP but not GLP-I, with respect to its ability to stimulate insulin secretion.
  • the mechanism behind the decreased responsiveness to GIP remains unclear since Type II diabetics retain sensitivity to a bolus administration of GIP but not to a continuous infusion (Meier et al. 2004 Diabetes 53 S220-S224).
  • Moreover recent studies with a long-acting fatty-acid derivative of GIP showed beneficial effects on glucose homeostasis in ob/ob mice following 14 days of treatment (Irwin N. et al. (2006) J. Med. Chem. 49, 1047-1 054).
  • a molecule which may stimulate GLPl secretion would provide a therapeutic benefit.
  • a molecule which could stimulate both GLP- 1 secretion and insulin secretion through effects on the L-cell and direct effects on the ⁇ -cell would hold much promise for Type II diabetes therapy.
  • GLP- 1 receptor agonists have proven elusive, a feature that unfortunately is characteristic of Class B GPCRs. Meanwhile, the spectrum of signaling peptides affected by inhibition of DPP-IV remains unclear and could potentially extend significantly beyond GLP-I and GIP (8, 9). It is therefore worthwhile to search for therapeutic approaches which afford both the physiological selectivity of GLP- 1 signaling and the opportunity for orally active treatment modalities.
  • GPRl 19 was identified as a Class A, islet- enriched receptor which could potentially mediate the insulinotropic actions of lysophosphatidylcholine (LPC) observed in vitro (Soga T., et al, Biochem Biophys Res Commun, 2005, 326:744-751), but a later study suggested that oleoylethanolamide (OEA) was a more potent GPRl 19 agonist (Overton H.A., et al., Cell Metab, 2006, 3:167-175). Recently, a small molecule GPRl 19 agonist has been shown to enhance glucose-dependent insulin secretion and improve hyperglycemia in rodent models of diabetes (Chu Z.
  • GPRl 19 is expressed in human gastrointestinal regions and in human islets. Activation of GPRl 19 has been demonstrated to stimulate intracellular cAMP and lead to glucose-dependent GLP-I and insulin secretion. See, T. Soga et al., Biochemical and Biophysical Research Communications 326 (2005) 744-751, herein incorporated by reference with regard to a background understanding of GPRl 19.
  • GPRl 19 activation of GPRl 19 is very unlikely to induce hypoglycemia (Chu Z., et al. Endocrinology, 2007, 148:2601-2609) [011] Agonists to GPRl 19 may be of therapeutic value for diabetes and associated conditions, particularly Type II diabetes, obesity, glucose intolerance, insulin resistance, metabolic syndrome X, hyperlipidemia, hypercholesterolemia, and atherosclerosis.
  • A, B, and D are each independently chosen from heteroaryl, aryl, cycloalkyl, and heterocycloalkyl;
  • Q is chosen from C and N;
  • Q' is chosen from C and N;
  • Z is chosen from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkyl, heteroalkyl, haloalkyl, perhaloalkyl, -CO 2 Rn, and -CO2NR48R1 9 , any of which may be optionally substituted;
  • V is chosen from a bond, O, S, NR 5 , and (CR O R 7 X; W is chosen from a bond, O, S, NRg, and (CRgR 1O ) 5 ; X is chosen from a bond, O, S, NR 11 , and (CR 12 R 13 X;
  • Y is chosen from a bond, O, S, NR 14 , and (CR 15 R 1 O)U; m, n, p, q, r, s, t, and u are each independently an integer from 0 to 4; each R 1 , R 2 , R 3 , and R 4 is independently chosen from hydrogen, null, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, amido, amino, aryl, aryloxy, carbamate, carboxy, cyano, cycloalkyl, halo, heteroalkyl, heteroaryl, heterocycloalkyl, hydroxyl, nitro, perhaloalkoxy, perhaloalkyl, sulfonyl and sulfonamide, any of which may be optionally substituted; or R 2 and R 3 together may form an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or
  • Re, R7, R9, R 1 O, Ri 2 , Ri 3 , Ri5, and R 16 are each independently chosen from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, any of which may be optionally substituted; or R 6 and R 7 , or R 9 and R 10 , or R 12 and R 13 , or R 15 and R 16 are taken together to form oxo; and
  • R 17 , R 18 , and R 19 are each independently chosen from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, any of which may be optionally substituted.
  • Certain compounds disclosed herein may possess useful GPRl 19 modulating activity, and may be used in the treatment or prophylaxis of a disease or condition in which GPRl 19 plays an active role.
  • certain embodiments also provide pharmaceutical compositions comprising one or more compounds disclosed herein together with a pharmaceutically acceptable carrier, as well as methods of making and using the compounds and compositions.
  • Certain embodiments provide methods for modulating GPRl 19.
  • Other embodiments provide methods for treating a GPRl 19-mediated disorder in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound or composition as disclosed herein.
  • Also provided is the use of certain compounds disclosed herein for use in the manufacture of a medicament for the treatment of a disease or condition ameliorated by the modulation of GPRl 19 activity.
  • compounds have Formula (II)
  • A, B, and D are each independently chosen from monocyclic heteroaryl, monocyclic aryl, monocyclic cycloalkyl, and monocyclic heterocycloalkyl;
  • Q is chosen from C and N;
  • Q' is chosen from C and N;
  • Z is chosen from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkyl, heteroalkyl, haloalkyl, perhaloalkyl, -CO 2 Rn, and -CO 2 NR 1S R ⁇ , any of which may be optionally substituted;
  • V is chosen from a bond, O, S, NR5, and (CR O R T X; W is chosen from a bond, O, S, NRg, and (CRgR 1O ) 5 ;
  • Y is chosen from a bond, O, S, NR 14 , and (CR 1S R 16 ); m, n, p, q, r, and s are each independently an integer from 0 to 4; each R 1 , R 2 , R 3 , and R 4 is independently chosen from hydrogen, null, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, amido, amino, aryl, aryloxy, carbamate, carboxy, cyano, cycloalkyl, halo, heteroalkyl, heteroaryl, heterocycloalkyl, hydroxyl, nitro, perhaloalkoxy, perhaloalkyl, sulfonyl and sulfonamide, any of which may be optionally substituted; or R 2 and R 3 together may form an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocyclo
  • R7, R 9 , R 1 O, Ri5, and R 16 are each independently chosen from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, any of which may be optionally substituted; or R 6 and R 7 , or R 9 and R 10 , or R 12 and R 13 , or R 1S and R 16 are taken together to form oxo; and
  • R 17 , Ri 8 , and R 19 are each independently chosen from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, any of which may be optionally substituted. [016] In certain embodiments provided herein,
  • A is chosen from monocyclic aryl, monocyclic cycloalkyl, and monocyclic heterocycloalkyl, any of which may be optionally substituted;
  • B is chosen from monocyclic heteroaryl and monocyclic aryl, any of which may be optionally substituted;
  • Z is chosen from aryl, heteroaryl, alkyl, heteroalkyl, -CO 2 R 17 , and - CO 2 NRi8Ri 9 , any of which may be optionally substituted; and r and s are each independently an integer from 0 to 3.
  • each R 1 , R 2 , R 3 , and R 4 is independently chosen from hydrogen, null, acyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, amido, amino, carboxyl, cyano, halo, hydroxyl, heteroaryl, nitro, perhaloalkoxy, perhaloalkyl, sulfonyl and sulfonamide, any of which may be optionally substituted; or R 2 and R 3 together may form an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl; and each R 5 , Rg, and R 14 is independently chosen from hydrogen, acyl, lower alkyl, lower alkenyl, and lower alkynyl, any of which may be optionally substituted. [019]
  • X is a bond
  • A is chosen from monocyclic aryl, monocyclic cycloalkyl, and monocyclic heterocyclo alkyl ;
  • B is chosen from monocyclic aryl and monocyclic heteroaryl
  • D is chosen from monocyclic aryl, monocyclic cycloalkyl, and monocyclic heteroaryl;
  • Z is chosen from heteroaryl, aryl, alkyl, heteroalkyl, -CO 2 Rn, and - CO2NRi8Ri 9 , any of which may be optionally substituted;
  • Q is chosen from C and N;
  • Q' is chosen from C and N;
  • V is chosen from a bond, O, S, NR5, and W is chosen from a bond, O, NRs, and (CRgR 1 O) 5 ;
  • Y is chosen from a bond, O, S, NR 14 , and (CR 1S R 16 ); m, n, p, and q are each independently an integer from 0 to 4; r and s are each independently an integer from 0 to 2; each R 1 , R 2 , R 3 and R 4 is independently chosen from hydrogen, null, acyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, amido, amino, carboxyl, cyano, halo, hydroxyl, heteroaryl, nitro, perhaloalkoxy, perhaloalkyl, sulfonyl and sulfonamide, any of which may be optionally substituted; or R 2 and R 3 together may form an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl;
  • R 5 and R 14 are each independently chosen from hydrogen, acyl, lower alkyl, lower alkenyl, and lower alkynyl;
  • Re, R7, R 9 , R 1 O, Ri5 and R 16 are each independently chosen from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, any of which may be optionally substituted; or Re and R 7 , or R 9 and R 1O or R 15 and R 16 are taken together to form oxo; and
  • Rn, R 1S , and R 19 are each independently chosen from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, any of which may be optionally substituted.
  • Q' is C.
  • Y is a bond.
  • the compounds have structural Formula (III)
  • Z is chosen from heteroaryl, aryl, alkyl, heteroalkyl, -CO 2 Rn, and - CO 2 NR 1S R 1 C), any of which may be optionally substituted;
  • Q is chosen from C and N;
  • V is chosen from a bond, O, S, NR5, and (CR O R T X ; W is chosen from a bond, O, S, NRg, and (CRgR 1O ) 5 ;
  • m, n, p, and v are each independently an integer from 0 to 4;
  • r is an integer from 0 to 1 ;
  • s is an integer from 0 to 2;
  • each R 1 , R 2 , and R 3 is independently chosen from hydrogen, null, acyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, amido, amino, carboxyl, cyano, halo, hydroxyl, heteroaryl, nitro, perhaloalkoxy, perhaloalkyl, sulfonyl and sulfonamide, any of which may be optionally substituted; or R 2 and R 3 together may form an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycl
  • R 5 and Rg are independently chosen from hydrogen, acyl, lower alkyl, lower alkenyl, and lower alkynyl;
  • R 7 , R 9 , and R 10 are each independently chosen from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, any of which may be optionally substituted; or Re and R 7 , or R 9 and R 1O are taken together to form oxo; and
  • R 17 is chosen from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, any of which may be optionally substituted. [025] In further embodiments:
  • Q is N; s is an integer from 0 to 1 ;
  • V is chosen from a bond, O, NR 5 , and (CR O R 7 X; and R 5 is chosen from hydrogen and lower alkyl.
  • Z is heteroaryl, which may be optionally substituted.
  • Z is a 6-membered heteroaryl, which may be optionally substituted.
  • Z is an optionally substituted 6-membered heteroaryl containing between 1 and 2 nitrogens.
  • Z is pyrimidine, which may be optionally substituted.
  • V is chosen from a bond, O, and NR 5 ; and W is a bond.
  • V is a bond.
  • s is 1;
  • V is chosen from O and NR 5 ; W is (CR 9 R 10 ); and
  • R 9 and R 10 are each independently chosen from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, or R 9 and R 10 are taken together to form oxo.
  • Z is chosen from alkyl, -CO 2 Ri 7 and -CO 2 NR 1 SRi 9 .
  • Z is chosen from -CO 2 Rn and -CO 2 NRi8Ri 9 .
  • Z is -CO 2 Rn.
  • R 17 is chosen from hydrogen, alkyl, aryl, heteroaryl, and heterocycloalkyl.
  • V is chosen from a bond, O, and NR 5 ; and W is a bond.
  • V is a bond. [039] In further embodiments: s is 1;
  • V is chosen from O and NR 5 ; W is (CR 9 Ri 0 ); and
  • R 9 and Rio are each independently chosen from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, or R 9 and Rio are taken together to form oxo. [040] In further embodiments provided herein, compounds have structural
  • Rg and R 1O are each independently chosen from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, any of which may be optionally substituted; or R 9 and R 10 are taken together to form oxo.
  • Y is chosen from O and NR 14 .
  • V is chosen from O, (CR O R T ) 0 and NR5.
  • Y is O.
  • A is chosen from 4- to 6-membered cycloalkyl, lower aryl, 4- to 6-membered heterocycloalkyl, and 4- to 6-membered heteroaryl.
  • A is lower heterocycloalkyl.
  • Z is chosen from CO 2 Rn, optionally substituted phenyl, and optionally substituted heteroaryl.
  • Z is heteroaryl, which may be optionally substituted.
  • Z is a 6-membered heteroaryl, which may be optionally substituted.
  • Z is an optionally substituted six-membered heteroaryl containing between 1 and 2 nitrogens.
  • Z is chosen from pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl, any of which may be optionally substituted.
  • Z is pyrimidine, which may be optionally substituted.
  • Z is chosen from alkyl, -CO 2 Rn and -CO 2 NR 1S R 19 .
  • Z is chosen from -CO 2 R 17 and -CO 2 NR 1S R 19 .
  • Z is -CO 2 R 17 .
  • R 17 is chosen from hydrogen, alkyl, aryl, heteroaryl, and heterocycloalkyl.
  • the compound has structural Formula (IV)
  • B is chosen from phenyl and a 5- or 6 -membered monocyclic heteroaryl
  • D is chosen from phenyl and a 5- or 6-membered monocyclic heteroaryl
  • Z is chosen from lower heteroaryl, lower aryl, lower alkyl, lower heteroalkyl, - CO 2 Rn, and -CO 2 NR 1S R ⁇ , any of which may be optionally substituted;
  • V is chosen from a bond, O, S, NR 5 , and (CR 6 R 7 );
  • W is chosen from a bond, O, NRs, and (CR 9 R 1 O); m, n, p, and q are each independently an integer from 0 to 2; each R 1 , R 2 , R 3 and R 4 is independently selected from the group consisting of hydrogen, null, lower acyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower amido, lower amino, lower carboxyl, cyano, halo, hydroxyl, lower heteroaryl, nitro, lower perhaloalkoxy, lower perhaloalkyl, sulfonyl and sulfonamide, any of which may be optionally substituted; and two R 1 may combine to form a 1-2 carbon bridge;
  • R5, Re, R7, R8, R 9 , and R 1 O are each independently selected from the group consisting of hydrogen and lower alkyl;
  • Rn, R 1S , and R 19 are independently chosen from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower amino, lower aminoalkyl, lower alkoxy, lower alkoxyalkyl, phenyl, lower heteroaryl, lower cycloalkyl, lower heteroaryl, lower heterocycloalkyl, any of which may be optionally substituted. [057] In further embodiments, at least one R 1 is present, and is attached in a position para to V. [058] In further embodiments, Z is -C(O)NH.
  • B is a 9- or 10-membered fused bicyclic heteroaryl having from one to four nitrogens as heteroatoms.
  • B is chosen from phenyl and a 6-membered monocyclic heteroaryl comprising 1 or 2 nitrogens;
  • D is chosen from phenyl and a 6-membered monocyclic heteroaryl
  • V is chosen from a bond, O, S, NR 5 , and (CR 6 R 7 );
  • W is chosen from a bond, O, S, NR 8 , and (CR 9 R 10 );
  • Z is chosen from -CONH, lower heteroaryl, lower aryl, lower alkyl, lower heteroalkyl, -CO 2 Rn, and -CO 2 NR 1 SRi 9 , any of which may be optionally substituted;
  • m is an integer from 0 to 2;
  • n, p, and q are each independently an integer from 0 to 2;
  • each R 2 , R 3 and R 4 is independently selected from the group consisting of hydrogen, null, lower acyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower amido, lower amino, lower carboxyl, cyano, halo, hydroxyl, lower heteroaryl, nitro, lower perhaloalkoxy, lower perhaloalkyl, sulfonyl and sulfonamide, any of which may be optionally substituted; and two Ri may join together to form a 1- or 2- carbon bridge;
  • R la is oriented para to V, and is chosen from
  • R5, Re, R7, R8, R 9 , and R 1 O are each independently selected from the group consisting of hydrogen and lower alkyl;
  • R 17 , R 1S , and R 19 are independently chosen from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower amino, lower aminoalkyl, lower alkoxy, lower alkoxyalkyl, phenyl, lower heteroaryl, lower cycloalkyl, lower heteroaryl, lower heterocycloalkyl, any of which may be optionally substituted.
  • R 17 , R 1S , and R 19 are independently chosen from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower amino, lower aminoalkyl, lower alkoxy, lower alkoxyalkyl, phenyl, lower heteroaryl, lower cycloalkyl, lower heteroaryl, lower heterocycloalkyl, any of which may be optionally substituted.
  • Z is chosen from lower heteroaryl, which may be optionally substituted with one, two or three substituents chosen from halogen, lower alkyl, and lower haloalkyl; and -CO 2 R 17 ;
  • V is chosen from a bond, O, S, NR 5 , and CH 2; ;
  • W is chosen from a bond, C(O), and CH 2 ;
  • R la is chosen from hydrogen, null, acyl, lower alkyl, lower alkenyl, lower alkynyl, C-amido, amino, halo, hydroxyl, heteroaryl, nitro, perhaloalkoxy, perhaloalkyl, sulfonyl and sulfonamide, any of which may be optionally substituted; each R ⁇ , is independently chosen from hydrogen, null, acyl, lower alkyl, lower alkenyl, lower alkynylamido, amino, carboxyl, halo, hydroxyl, heteroaryl, nitro, perhaloalkoxy, perhaloalkyl, sulfonyl and sulfonamide, any of which may be optionally substituted; or R 2 and R 3 together may form an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl; m is 0, or 1;
  • R 5 is chosen from hydrogen, lower alkyl, lower alkenyl, and lower alkynyl; and Rn is chosen from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, phenyl, lower heteroaryl, lower cycloalkyl, and lower heterocycloalkyl, any of which may be optionally substituted.
  • m is 1.
  • Z is chosen from CO 2 Rn and lower heteroaryl, which is substituted with one, two or three substituents chosen from halogen, lower alkyl, and lower haloalkyl; V is chosen from a bond and NR 5 ;
  • R la is chosen from null, lower alkyl, lower amino, lower heteroaryl, and sulfonyl
  • Ri b is chosen from null, halogen, hydroxy, cyano, lower alkyl, lower alkoxy, lower haloalkyl, and lower haloalkoxy;
  • R 5 is hydrogen;
  • R 17 is chosen from lower alkyl and lower cycloalkyl.
  • R la is chosen from lower heteroaryl and sulfonyl.
  • Z is chosen from CO 2 R 17 and pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, any of which may be optionally substituted with one or two substituents chosen from halogen, lower alkyl, and lower haloalkyl.
  • R 17 is lower alkyl.
  • Z is pyrimidinyl.
  • m is 1;
  • Z is chosen from 5-ethyl-pyrimidinyl and CO 2 R 17 ;
  • W-V is chosen from a bond, CH 2 NH, and C(O)NH;
  • R la is chosen from lower alkyl, lower amino, triazolyl, tetrazolyl, and methylsulfonyl;
  • Ri b is chosen from null, halogen, and lower alkyl;
  • Ri7 is tert-butyl
  • B is chosen from phenyl and a 6-membered monocyclic heteroaryl comprising from 1-2 nitrogens;
  • D is chosen from phenyl and a 6-membered monocyclic heteroaryl
  • Z is chosen from CO 2 Rn and lower heteroaryl, which is substituted with one, two or three substituents chosen from halogen, lower alkyl, and lower haloalkyl
  • W is chosen from a bond, C(O), and CH 2
  • V is chosen from a bond and NR 5 ; provided that either each of W and V is a bond, or neither is
  • R la is chosen from lower heteroaryl and sulfonyl
  • Ri b is chosen from null, halogen, hydroxy, cyano, lower alkyl, lower alkoxy, lower haloalkyl, and lower haloalkoxy; m is an integer from 0 to 1 ; R 5 is hydrogen; and;
  • R 17 is chosen from lower alkyl and lower cycloalkyl.
  • Z is chosen from CO 2 R 17 , pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, any of which may be optionally substituted with one or two substituents chosen from halogen, lower alkyl, and lower haloalkyl.
  • R 17 is lower alkyl.
  • Z is pyrimidinyl.
  • m is 1;
  • Z is chosen from 5-ethyl-pyrimidinyl and CO 2 Rn;
  • W-V is chosen from a bond, CH 2 NH, and C(O)NH;
  • R la is chosen from lower alkyl, lower amino, triazolyl, tetrazolyl, and methylsulfonyl;
  • Ri b is chosen from null, halogen, and lower alkyl
  • R 17 is tert-butyl
  • a compound chosen from Examples 1 to 109 is also provided herein.
  • a compound as disclosed herein for use as a medicament is also provided herein.
  • Also provided herein is a compound as disclosed herein for use in the manufacture of a medicament for the prevention or treatment of a disease or condition ameliorated by the modulation of GPRl 19.
  • a pharmaceutical composition comprising a compound as disclosed herein together with a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising at least one compound chosen from those recited in Examples 1 to 109 together with a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is useful for the treatment or prevention of a GPRl 19-mediated disease.
  • Also provided herein is a method of modulating GPRl 19 comprising contacting GPRl 19 with a compound as disclosed herein.
  • Also provided herein is a method of treatment of a GPRl 19-mediated disease, comprising the administration of a therapeutically effective amount of a compound as disclosed herein.
  • said disease is a metabolic disease.
  • said disease is diabetes.
  • a method of treatment of a GPRl 19- mediated disease comprising the administration of: a therapeutically effective amount of a compound as disclosed herein; and a therapeutically effective amount of another therapeutic agent.
  • said agent is chosen from insulin, metformin, Glipizide, glyburide, Amaryl, gliclazide, meglitinides, nateglinide, repaglinide, pramlintide, PTP-112, SB-517955, SB-4195052, SB-216763, NN-57-05441, NN-57- 05445, GW-0791, AGN- 19 4 20 4, T-1095, BAY R3401, acarbose, miglitol, voglibose, Exendin-4, DPP728, LAF237, vildagliptin , BMS477118, PT-100, GSK-823093, PSN- 9301, T-6666, SYR-322, SYR-619, Liraglutide, CJC-1134-PC, naliglutide, MK-0431, saxagliptin, GSK23A, pioglita
  • acyl refers to a carbonyl attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocycle, or any other moiety were the atom attached to the carbonyl is carbon.
  • An “acetyl” group refers to a -C(O)CH 3 group.
  • An “alkylcarbonyl” or “alkanoyl” group refers to an alkyl group attached to the parent molecular moiety through a carbonyl group. Examples of such groups include methylcarbonyl and ethylcarbonyl. Examples of acyl groups include formyl, alkanoyl and aroyl.
  • alkenyl refers to a straight-chain or branched-chain hydrocarbon group having one or more double bonds and containing from 2 to 20 carbon atoms. In certain embodiments, said alkenyl will comprise from 2 to 6 carbon atoms.
  • alkoxy refers to an alkyl ether group, wherein the term alkyl is as defined below.
  • suitable alkyl ether groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso- butoxy, sec-butoxy, tert-butoxy, and the like.
  • alkyl refers to a straight-chain or branched-chain alkyl group containing from 1 to 20 carbon atoms. In certain embodiments, said alkyl will comprise from 1 to 10 carbon atoms. In further embodiments, said alkyl will comprise from 1 to 6 carbon atoms. Alkyl groups may be optionally substituted as defined herein.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, noyl and the like.
  • alkylene refers to a saturated aliphatic group derived from a straight or branched chain saturated hydrocarbon attached at two or more positions, such as methylene (- CH 2 -). Unless otherwise specified, the term “alkyl” may include “alkylene” groups.
  • alkylamino refers to an alkyl group attached to the parent molecular moiety through an amino group. Suitable alkylamino groups may be mono- or dialkylated, forming groups such as, for example, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-ethylmethylamino and the like.
  • alkylidene refers to an alkenyl group in which one carbon atom of the carbon-carbon double bond belongs to the moiety to which the alkenyl group is attached.
  • alkylthio refers to an alkyl thioether (R-S-) group wherein the term alkyl is as defined above and wherein the sulfur may be singly or doubly oxidized.
  • suitable alkyl thioether groups include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso- butylthio, sec-butylthio, tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like.
  • alkynyl refers to a straight-chain or branched chain hydrocarbon group having one or more triple bonds and containing from 2 to 20 carbon atoms. In certain embodiments, said alkynyl comprises from 2 to 6 carbon atoms. In further embodiments, said alkynyl comprises from 2 to 4 carbon atoms.
  • alkynylene refers to a carbon-carbon triple bond attached at two positions such as ethynylene (-C:::C-, -C ⁇ C-).
  • alkynyl groups include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1- yl, 3-methylbutyn-l-yl, hexyn-2-yl, and the like.
  • alkynyl may include "alkynylene” groups.
  • acylamino as used herein, alone or in combination, embraces an acyl group attached to the parent moiety through an amino group.
  • An example of an “acylamino” group is acetylamino (CH 3 C(O)NH-).
  • R and R are independently chosen from hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may themselves be optionally substituted. Additionally, R and R' may combine to form heterocycloalkyl, either of which may be optionally substituted.
  • aryl as used herein, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such polycyclic ring systems are fused together.
  • aryl embraces aromatic groups such as phenyl, naphthyl, anthracenyl, and phenanthryl.
  • arylalkenyl or “aralkenyl,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkenyl group.
  • arylalkoxy or “aralkoxy,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkoxy group.
  • arylalkyl or “aralkyl,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkyl group.
  • arylalkynyl or “aralkynyl,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkynyl group.
  • arylalkanoyl or “aralkanoyl” or “aroyl,”as used herein, alone or in combination, refers to an acyl group derived from an aryl- substituted alkanecarboxylic acid such as benzoyl, napthoyl, phenylacetyl, 3-phenylpropionyl
  • hydrocinnamoyl 4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like.
  • aryloxy refers to an aryl group attached to the parent molecular moiety through an oxy.
  • Boc is shorthand for (tert-butoxy)carbonyl, which has the following structure:
  • carbamate refers to an ester of carbamic acid (-NHCOO-) which may be attached to the parent molecular moiety from either the nitrogen or acid end, and which may be optionally substituted as defined herein.
  • O-carbamyl refers to a -OC(O)NRR', group- with R and R' as defined herein.
  • N-carbamyl as used herein, alone or in combination, refers to a ROC(O)NR'- group, with R and R' as defined herein.
  • carbonyl when alone includes formyl [-C(O)H] and in combination is a -C(O)- group.
  • carboxyl or “carboxy,” as used herein, refers to -C(O)OH or the corresponding “carboxylate” anion, such as is in a carboxylic acid salt.
  • An "O-carboxy” group refers to a RC(O)O- group, where R is as defined herein.
  • a "C-carboxy” group refers to a -C(O)OR groups where R is as defined herein.
  • cyano as used herein, alone or in combination, refers to -CN.
  • cycloalkyl or, alternatively, “carbocycle,” as used herein, alone or in combination, refers to a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl group wherein each cyclic moiety contains from 3 to 12 carbon atom ring members and which may optionally be a benzo fused ring system which is optionally substituted as defined herein.
  • said cycloalkyl will comprise from 5 to 7 carbon atoms.
  • cycloalkyl groups examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronapthyl, indanyl, octahydronaphthyl, 2,3-dihydro-lH-indenyl, adamantyl and the like.
  • "Bicyclic” and "tricyclic” as used herein are intended to include both fused ring systems, such as decahydronaphthalene, octahydronaphthalene as well as the multicyclic (multicentered) saturated or partially unsaturated type. The latter type of isomer is exemplified in general by, bicyclo[l,l,l]pentane, camphor, adamantane, and bicyclo [3 ,2, 1 ] octane.
  • esters refers to a carboxy group bridging two moieties linked at carbon atoms.
  • ether refers to an oxy group bridging two moieties linked at carbon atoms.
  • halo or halogen
  • haloalkoxy refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.
  • haloalkyl refers to an alkyl group having the meaning as defined above wherein one or more hydrogens are replaced with a halogen. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl groups. A monohaloalkyl group, for one example, may have an iodo, bromo, chloro or fluoro atom within the group.
  • Dihalo and polyhaloalkyl groups may have two or more of the same halo atoms or a combination of different halo groups.
  • haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
  • "Haloalkylene” refers to a haloalkyl group attached at two or more positions.
  • heteroalkyl refers to a stable straight or branched chain, or cyclic hydrocarbon group, or combinations thereof, fully saturated or containing from 1 to 3 degrees of unsaturation, consisting of the stated number of carbon atoms and from one to three heteroatoms chosen from O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
  • the heteroatom(s) O, N and S may be placed at any interior position of the heteroalkyl group.
  • heteroaryl refers to a 3 to 7 membered unsaturated heteromonocyclic ring, or a fused monocyclic, bicyclic, or tricyclic ring system in which at least one of the fused rings is aromatic, which contains at least one atom chosen from O, S, and N.
  • said heteroaryl will comprise from 5 to 7 carbon atoms.
  • heterocyclic rings are fused with aryl rings, wherein heteroaryl rings are fused with other heteroaryl rings, wherein heteroaryl rings are fused with heterocycloalkyl rings, or wherein heteroaryl rings are fused with cycloalkyl rings.
  • heteroaryl groups include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, benzothienyl, chromonyl,
  • Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl and the like.
  • heterocycloalkyl and, interchangeably, “heterocycle,” as used herein, alone or in combination, each refer to a saturated, partially unsaturated, or fully unsaturated monocyclic, bicyclic, or tricyclic heterocyclic group containing at least one heteroatom as a ring member, wherein each said heteroatom may be independently chosen from nitrogen, oxygen, and sulfur
  • said hetercycloalkyl will comprise from 1 to 4 heteroatoms as ring members.
  • said hetercycloalkyl will comprise from 1 to 2 heteroatoms as ring members.
  • said hetercycloalkyl will comprise from 3 to 8 ring members in each ring.
  • said hetercycloalkyl will comprise from 3 to 7 ring members in each ring. In yet further embodiments, said hetercycloalkyl will comprise from 5 to 6 ring members in each ring.
  • "Heterocycloalkyl” and “heterocycle” are intended to include sulfones, sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclic fused and benzo fused ring systems; additionally, both terms also include systems where a heterocycle ring is fused to an aryl group, as defined herein, or an additional heterocycle group.
  • heterocycle groups include aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[l,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihy-dropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3- dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like.
  • the heterocycle groups may be optionally substituted unless specifically prohibited.
  • hydrazinyl as used herein, alone or in combination, refers to two amino groups joined by a single bond, i.e., -N-N-.
  • hydroxyalkyl refers to a hydroxy group attached to the parent molecular moiety through an alkyl group.
  • isocyanato refers to a -NCO group.
  • isothiocyanato refers to a -NCS group.
  • linear chain of atoms refers to the longest straight chain of atoms independently selected from carbon, nitrogen, oxygen and sulfur.
  • lower aryl as used herein, alone or in combination, means phenyl or naphthyl, which may be optionally substituted as provided.
  • lower heteroaryl means either 1) monocyclic heteroaryl comprising five or six ring members, of which between one and four said members may be heteroatoms chosen from O, S, and N, or 2) bicyclic heteroaryl, wherein each of the fused rings comprises five or six ring members, comprising between them one to four heteroatoms chosen from O, S, and N.
  • lower cycloalkyl as used herein, alone or in combination, means a monocyclic cycloalkyl having between three and six ring members. Lower cycloalkyls may be unsaturated. Examples of lower cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • lower heterocycloalkyl as used herein, alone or in combination, means a monocyclic heterocycloalkyl having between three and six ring members, of which between one and four may be heteroatoms chosen from O, S, and N.
  • lower heterocycloalkyls include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, and morpholinyl.
  • Lower heterocycloalkyls may be unsaturated.
  • R and R are independently chosen from hydrogen, lower alkyl, and lower heteroalkyl, any of which may be optionally substituted. Additionally, the R and
  • R' of a lower amino group may combine to form a five- or six-membered heterocycloalkyl, either of which may be optionally substituted.
  • nitro refers to -NO 2 .
  • perhaloalkoxy refers to an alkoxy group where all of the hydrogen atoms are replaced by halogen atoms.
  • perhaloalkyl refers to an alkyl group where all of the hydrogen atoms are replaced by halogen atoms.
  • sulfonate refers the -SO 3 H group and its anion as the sulfonic acid is used in salt formation.
  • thia and thio refer to a -S- group or an ether wherein the oxygen is replaced with sulfur.
  • the oxidized derivatives of the thio group namely sulfinyl and sulfonyl, are included in the definition of thia and thio.
  • thiol as used herein, alone or in combination, refers to an -SH group.
  • thiocarbonyl when alone includes thioformyl -
  • N-thiocarbamyl refers to an ROC(S)NR'- group, with R and
  • O-thiocarbamyl refers to a -OC(S)NRR', group with R and
  • thiocyanato refers to a -CNS group.
  • trihalomethanesulfonamido refers to a X 3 CS(O) 2 NR- group with X is a halogen and R as defined herein.
  • trihalomethanesulfonyl refers to a X 3 CS(O) 2 - group where X is a halogen.
  • trihalomethoxy refers to a X 3 CO- group where X is a halogen.
  • trimethysilyl tert- butyldimethylsilyl, triphenylsilyl and the like.
  • Any definition herein may be used in combination with any other definition to describe a composite structural group.
  • the trailing element of any such definition is that which attaches to the parent moiety.
  • the composite group alkylamido would represent an alkyl group attached to the parent molecule through an amido group
  • the term alkoxyalkyl would represent an alkoxy group attached to the parent molecule through an alkyl group.
  • the term "optionally substituted” means the anteceding group may be substituted or unsubstituted.
  • the substituents of an "optionally substituted” group may include, without limitation, one or more substituents independently selected from the following groups or a particular designated set of groups, alone or in combination: lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl, phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester, lower carboxamido, cyano, hydrogen, halogen, hydroxy, amino, lower alkylcarbonyl
  • Two substituents may be joined together to form a fused five-, six-, or seven-membered carbocyclic or heterocyclic ring consisting of zero to three heteroatoms, for example forming methylenedioxy or ethylenedioxy.
  • An optionally substituted group may be unsubstituted (e.g., -CH 2 CH 3 ), fully substituted (e.g., -CF 2 CF 3 ), monosubstituted (e.g., -CH 2 CH 2 F) or substituted at a level anywhere in-between fully substituted and monosubstituted (e.g., -CH 2 CF 3 ).
  • R or the term R' refers to a moiety chosen from hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl and heterocycloalkyl, any of which may be optionally substituted.
  • aryl, heterocycle, R, etc. occur more than one time in a formula or generic structure, its definition at each occurrence is independent of the definition at every other occurrence.
  • certain groups may be attached to a parent molecule or may occupy a position in a chain of elements from either end as written.
  • an unsymmetrical group such as -C(O)N(R)- may be attached to the parent moiety at either the carbon or the nitrogen.
  • Asymmetric centers exist in the compounds disclosed herein. These centers are designated by the symbols “R” or “S,” depending on the configuration of substituents around the chiral carbon atom. It should be understood that the invention encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric, and epimeric forms, as well as d-isomers and 1 -isomers, and mixtures thereof.
  • Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art.
  • Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art.
  • the compounds disclosed herein may exist as geometric isomers.
  • the present invention includes all cis, trans, syn, anti,
  • compounds may exist as tautomers; all tautomeric isomers are provided by this invention. Additionally, the compounds disclosed herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms.
  • bond refers to a covalent linkage between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure.
  • a bond may be single, double, or triple unless otherwise specified.
  • a dashed line between two atoms in a drawing of a molecule indicates that an additional bond may be present or absent at that position.
  • disease as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder” and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.
  • combination therapy means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.
  • GPRl 19 modulator is used herein to refer to a compound that exhibits an EC 50 with respect to GPRl 19 activity of no more than about 100 ⁇ M and more typically not more than about 50 ⁇ M, as measured in the cAMP production assay and glucagon-like peptide- 1 (GLP-I) secretion assays described generally hereinbelow.
  • EC 50 is that concentration of inhibitor which activates the activity of an enzyme (e.g., GPRl 19) to half-maximal level. Certain compounds disclosed herein have been discovered to exhibit modulatory activity against GPRl 19.
  • compounds will exhibit an EC 50 with respect to GPRl 19 of no more than about 10 ⁇ M; in further embodiments, compounds will exhibit an EC 50 with respect to GPRl 19 of no more than about 5 ⁇ M; in yet further embodiments, compounds will exhibit an EC 50 with respect to GPRl 19 of not more than about 1 ⁇ M; in yet further embodiments, compounds will exhibit an EC 50 with respect to GPRl 19 of not more than about 200 nM, as measured in the GPRl 19 assay described herein.
  • the phrase "therapeutically effective” is intended to qualify the amount of active ingredients used in the treatment of a disease or disorder. This amount will achieve the goal of reducing or eliminating the said disease or disorder.
  • the term "therapeutically acceptable” refers to those compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
  • patient means all mammals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, pigs, and rabbits. Preferably, the patient is a human.
  • prodrug refers to a compound that is made more active in vivo.
  • Certain compounds disclosed herein may also exist as prodrugs, as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley- VHCA, Zurich, Switzerland 2003).
  • Prodrugs of the compounds described herein are structurally modified forms of the compound that readily undergo chemical changes under physiological conditions to provide the compound.
  • prodrugs can be converted to the compound by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to a compound when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
  • Prodrugs are often useful because, in some situations, they may be easier to administer than the compound, or parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • a wide variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug.
  • An example, without limitation, of a prodrug would be a compound which is administered as an ester (the "prodrug"), but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound.
  • the compounds disclosed herein can exist as therapeutically acceptable salts.
  • the present invention includes compounds listed above in the form of salts, including acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable salts may be of utility in the preparation and purification of the compound in question. Basic addition salts may also be formed and be pharmaceutically acceptable.
  • Pharmaceutical Salts Properties, Selection, and Use (Stahl, P. Heinrich. Wiley- VCHA, Zurich, Switzerland, 2002).
  • terapéuticaally acceptable salt represents salts or zwitterionic forms of the compounds disclosed herein which are water or oil-soluble or dispersible and therapeutically acceptable as defined herein.
  • the salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound in the form of the free base with a suitable acid.
  • Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenyl
  • basic groups in the compounds disclosed herein can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides.
  • acids which can be employed to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. Salts can also be formed by coordination of the compounds with an alkali metal or alkaline earth ion.
  • the present invention contemplates sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, and the like.
  • Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxy group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine.
  • a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine.
  • the cations of therapeutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, iV,./V-dimethylaniline, N- methylpiperidine, iV-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, iV,./V-dibenzyrphenethylamine, 1-ephenamine, and iV,./V-dibenzylethylenediamine.
  • nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine,
  • a salt of a compound can be made by reacting the appropriate compound in the form of the free base with the appropriate acid.
  • compositions which comprise one or more of certain compounds disclosed herein, or one or more pharmaceutically acceptable salts, esters, prodrugs, amides, or solvates thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Proper formulation is dependent upon the route of administration chosen.
  • compositions disclosed herein may be manufactured in any manner known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.
  • the formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal and topical (including dermal, buccal, sublingual and intraocular) administration although the most suitable route may depend upon for example the condition and disorder of the recipient.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Typically, these methods include the step of bringing into association a compound of the subject invention or a pharmaceutically acceptable salt, ester, amide, prodrug or solvate thereof ("active ingredient”) with the carrier which constitutes one or more accessory ingredients.
  • active ingredient a pharmaceutically acceptable salt, ester, amide, prodrug or solvate thereof
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • Formulations of the compounds disclosed herein suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • Pharmaceutical preparations which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • Tablets may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free- flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • Dragee cores are provided with suitable coatings.
  • concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • the compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use.
  • sterile liquid carrier for example, saline or sterile pyrogen-free water
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Formulations for parenteral administration include aqueous and nonaqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner.
  • Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.
  • Certain compounds disclosed herein may be administered topically, that is by non-systemic administration. This includes the application of a compound disclosed herein externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream.
  • systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
  • Formulations suitable for topical administration include liquid or semi- liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.
  • the active ingredient for topical administration may comprise, for example, from 0.001% to 10% w/w (by weight) of the formulation. In certain embodiments, the active ingredient may comprise as much as 10% w/w. In other embodiments, it may comprise less than 5% w/w. In certain embodiments, the active ingredient may comprise from 2% w/w to 5% w/w. In other embodiments, it may comprise from 0.1% to 1% w/w of the formulation.
  • Gels for topical or transdermal administration may comprise, generally, a mixture of volatile solvents, nonvolatile solvents, and water.
  • the volatile solvent component of the buffered solvent system may include lower (Cl- C6) alkyl alcohols, lower alkyl glycols and lower glycol polymers.
  • the volatile solvent is ethanol.
  • the volatile solvent component is thought to act as a penetration enhancer, while also producing a cooling effect on the skin as it evaporates.
  • the nonvolatile solvent portion of the buffered solvent system is selected from lower alkylene glycols and lower glycol polymers. In certain embodiments, propylene glycol is used.
  • the nonvolatile solvent slows the evaporation of the volatile solvent and reduces the vapor pressure of the buffered solvent system.
  • the amount of this nonvolatile solvent component, as with the volatile solvent, is determined by the pharmaceutical compound or drug being used. When too little of the nonvolatile solvent is in the system, the pharmaceutical compound may crystallize due to evaporation of volatile solvent, while an excess may result in a lack of bioavailability due to poor release of drug from solvent mixture.
  • the buffer component of the buffered solvent system may be selected from any buffer commonly used in the art; in certain embodiments, water is used. A common ratio of ingredients is about 20% of the nonvolatile solvent, about 40% of the volatile solvent, and about 40% water.
  • chelators and gelling agents Appropriate gelling agents can include, but are not limited to, semisynthetic cellulose derivatives (such as hydroxypropylmethylcellulose) and synthetic polymers, and cosmetic agents.
  • Lotions include those suitable for application to the skin or eye.
  • An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops.
  • Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.
  • Creams, ointments or pastes are semi-solid formulations of the active ingredient for external application. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy base.
  • the base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives or a fatty acid such as steric or oleic acid together with an alcohol such as propylene glycol or a macrogel.
  • the formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof.
  • suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof.
  • Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.
  • Drops may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and, in certain embodiments, including a surface active agent.
  • the resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-100 0 C for half an hour.
  • the solution may be sterilized by filtration and transferred to the container by an aseptic technique.
  • bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%).
  • Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.
  • Formulations for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.
  • compounds may be conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray.
  • Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the compounds according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
  • Preferred unit dosage formulations are those containing an effective dose, as herein below recited, or an appropriate fraction thereof, of the active ingredient.
  • the formulations described above may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • Compounds may be administered orally or via injection at a dose of from 0.1 to 500 mg/kg per day. The dose range for adult humans is generally from 5 mg to 2 g/day.
  • Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of one or more compounds which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • the compounds can be administered in various modes, e.g. orally, topically, or by injection.
  • the precise amount of compound administered to a patient will be the responsibility of the attendant physician.
  • the specific dose level 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, diets, time of administration, route of administration, rate of excretion, drug combination, the precise disorder being treated, and the severity of the indication or condition being treated. Also, the route of administration may vary depending on the condition and its severity.
  • one of the side effects experienced by a patient upon receiving one of the compounds herein is hypertension, then it may be appropriate to administer an anti-hypertensive agent in combination with the initial therapeutic agent.
  • the therapeutic effectiveness of one of the compounds described herein may be enhanced by administration of an adjuvant (i.e., by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).
  • the benefit of experienced by a patient may be increased by administering one of the compounds described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
  • combination therapies include use of certain compounds of the invention with agents found in the following pharmacotherapeutic classifications as indicated below. These lists should not be construed to be closed, but should instead serve as illustrative examples common to the relevant therapeutic area at present.
  • combination regimens may include a variety of routes of administration and should include oral, intravenous, intraocular, subcutaneous, dermal, and inhaled topical.
  • compounds disclosed herein may be administered with an agent selected from the group comprising: insulin, insulin derivatives and mimetics, insulin secretagogues, insulin sensitizers, biguanide agents, alpha-glucosidase inhibitors, insulinotropic sulfonylurea receptor ligands, meglitinides, protein tyrosine phosphatase-lB (PTP-IB) inhibitors, GSK3 (glycogen synthase kinase- 3) inhibitors , GLP-I (glucagon like peptide- 1), GLP-I analogs, DPP-IV (dipeptidyl peptidase IV) inhibitors, RXR ligands, sodium-dependent glucose co-transporter (SGLT2) inhibitors, glycogen phosphorylase A inhibitors, an AGE breaker, PPAR modulators, non-glitazone type PPAR ⁇ agonist, HMG-CoA reductase inhibitors, cholesterol
  • compounds disclosed herein may be administered with an agent selected from the group comprising: insulin, metformin, Glipizide, glyburide, Amaryl, gliclazide, meglitinides, nateglinide, repaglinide, amylin mimetics (for example, pramlintide), PTP-112, SB-517955, SB-4195052, SB-216763, NN-57-05441, NN-57-05445, GW-0791, AGN- 19 4 20 4, T-1095, BAY R3401, acarbose, miglitol, voglibose, Exendin-4, DPP728, LAF237, vildagliptin , BMS477118, PT-100, GSK-823093, PSN-9301, T-6666, SYR-322, SYR-619, Liraglutide, CJC-1134-PC, naliglutide, MK
  • compounds disclosed herein may be administered with an agent selected from the group comprising: cholescystokinin-A (CCK-A) agonists, serotonin and norepinephrine reuptake inhibitors (for example sibutramine), dopamine agonists (for example, bromocriptine and like) sympathomimetic agents, ⁇ 3 adrenergic receptor agonists, leptin, leptin analogues, leptin receptor agonists, galanin antagonists, lipase inhibitors (for example Orlistat), Neuropeptide-Y antagonists, glucocorticoid receptor agonists or antagonists, cannabinoid 1 receptor antagonists (for example, rimonabant and like), ciliary neurotropic factors (CNTF, for example Axokine), human agouti-related proteins (AGRP), ghrelin receptor antagonists, histamine 3 receptor antagonists, appetite suppressants (for example, bupro
  • CCK-A cholesc
  • compounds disclosed herein may be administered with an agent selected from the group comprising: corticosteroids, non-steroidal antiinflammatories, muscle relaxants and combinations thereof with other agents, anaesthetics and combinations thereof with other agents, expectorants and combinations thereof with other agents, antidepressants, anticonvulsants and combinations thereof; antihypertensives, opioids, topical cannabinoids, and other agents, such as capsaicin.
  • an agent selected from the group comprising: corticosteroids, non-steroidal antiinflammatories, muscle relaxants and combinations thereof with other agents, anaesthetics and combinations thereof with other agents, expectorants and combinations thereof with other agents, antidepressants, anticonvulsants and combinations thereof; antihypertensives, opioids, topical cannabinoids, and other agents, such as capsaicin.
  • compounds disclosed herein may be administered with an agent selected from the group comprising: betamethasone dipropionate (augmented and nonaugemnted), betamethasone valerate, clobetasol propionate, prednisone, methyl prednisolone, diflorasone diacetate, halobetasol propionate, amcinonide, dexamethasone, dexosimethasone, fluocinolone acetononide, fluocinonide, halocinonide, clocortalone pivalate, dexosimetasone, flurandrenalide, salicylates, ibuprofen, ketoprofen, etodolac, diclofenac, meclofenamate sodium, naproxen, piroxicam, celecoxib, cyclobenzaprine, baclofen, cyclobenzaprine/lidocaine, baclof
  • the multiple therapeutic agents may be administered in any order or even simultaneously. If simultaneously, the multiple therapeutic agents may be provided in a single, unified form, or in multiple forms (by way of example only, either as a single pill or as two separate pills). One of the therapeutic agents may be given in multiple doses, or both may be given as multiple doses. If not simultaneous, the timing between the multiple doses may be any duration of time ranging from a few minutes to four weeks.
  • certain embodiments provide methods for treating GPRl 19-mediated disorders in a human or animal subject in need of such treatment comprising administering to said subject an amount of a compound disclosed herein effective to reduce or prevent said disorder in the subject, in combination with at least one additional agent for the treatment of said disorder that is known in the art.
  • certain embodiments provide therapeutic compositions comprising at least one compound disclosed herein in combination with one or more additional agents for the treatment of GPRl 19-mediated disorders.
  • diabetes type I and type II
  • conditions associated with diabetic diseases which include, but are not limited to, hyperglycemia, hyperlipidemia, hyperinsulinemia, insulin resistance, inadequate glucose tolerance, impaired glucose metabolism, diabetic nephropathy, glomerulosclerosis, diabetic neuropathy, erectile dysfunction, macular degeneration, diabetic retinopathy, chronic microvascular complications, peripheral vascular disease, cataracts, stroke, foot ulcerations, renal failure, kidney disease, ketosis, metabolic acidosis, and related disorders, obesity, myocardial infarction, angina pectoris, coronary artery disease, atherosclerosis, cardiac hypertrophy, allergic diseases, fatty liver disease, nonalcoholic steatohepatitis, liver fibrosis, kidney fibrosis, anorexia nervosa, bulimia vervosa, autoimmune diseases, inflammatory diseases including rheumatoid arthritis, asthma, chronic o
  • the disease is obesity and the effects to be achieved in a human or animal patient include decreasing body weight and controlling weight gain.
  • GPRl 19 agonists might be useful for the treatment of cellulite and other cosmetic conditions which are characterized by subcutaneous fat accumulation.
  • the disease is associated with perturbed bile acid metabolism, including, but not limited to gall bladder stones, cholecystitis, cholangitis, choledocholithiasis, jaundice, and obstetric cholestasis and the itch associated with it.
  • Metabolic diseases other than Type 1 and Type 2 diabetes which may be treated or prevented include, without limitation, metabolic syndrome and insulin resistance.
  • the compounds disclosed herein can be used to treat insulin resistance and other metabolic disorders such as atherosclerosis that are typically associated with an exaggerated inflammatory signaling.
  • the disease is a hyperproliferative condition of the human or animal body, including, but not limited to restenosis, inflammation, immune disorders, cardiac hypertrophy, atherosclerosis, pain, migraine, angiogenesis-related conditions or disorders, proliferation induced after medical conditions, including but not limited to surgery, angioplasty, or other conditions.
  • the compounds disclosed herein may be useful as anti- inflammatory agents with the additional benefit of having significantly less harmful side effects.
  • the compositions may be used to treat arthritis, including but not limited to rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis, acute rheumatic arthritis, enteropathic arthritis, neuropathic arthritis, psoriatic arthritis, and pyogenic arthritis.
  • the compositions may also be used in the treatment of pulmonary inflammation, such as that associated with viral infections and cystic fibrosis.
  • the particular inflammatory disease is rheumatoid arthritis.
  • inflammatory diseases which may be prevented or treated include, without limitation: asthma, allergies, respiratory distress syndrome or acute or chronic pancreatitis.
  • respiratory system diseases may be prevented or treated including but not limited to chronic obstructive pulmonary disease, pulmonary fibrosis, ulcerative colitis, inflammatory bowel disease, Crohn's disease, peptic ulceration, gastritis, psoriasis, and skin inflammation.
  • the disease to be treated by the methods provided herein may be an ophthalmologic disorder.
  • Ophthalmologic diseases and other diseases in which angiogenesis plays a role in pathogenesis may be treated or prevented and include, without limitation, dry eye (including Sjogren's syndrome), macular degeneration, closed and wide angle glaucoma, retinal ganglion degeneration, occular ischemia, retinitis, retinopathies, uveitis, ocular photophobia, and of inflammation and pain associated with acute injury to the eye tissue.
  • the ophthalmologic disease to be treated is glaucomatous retinopathy and/or diabetic retinopathy.
  • the ophthalmologic condition to be treated is post-operative inflammation or pain as from ophthalmic surgery such as cataract surgery and refractive surgery.
  • the disease to be treated by the methods provided herein may be an autoimmune disease.
  • Autoimmune diseases which may be prevented or treated include, but are not limited to: rheumatoid arthritis, inflammatory bowel disease, inflammatory pain, ulcerative colitis, Crohn's disease, periodontal disease, temporomandibular joint disease, multiple sclerosis, diabetes, glomerulonephritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Grave's disease, hemolytic anemia, autoimmune gastritis, autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, myasthenia gravis, atopic dermatitis, graft vs.
  • Inflammatory diseases which may be prevented or treated include, but are not limited to: asthma, allergies, respiratory distress syndrome or acute or chronic pancreatitis.
  • the particular autoimmune disease is rheumatoid arthritis.
  • the compounds provided herein are also useful in treating tissue damage in such diseases as vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, neuromuscular junction disease including myasthenia gravis, white matter disease including multiple sclerosis, sarcoidosis, nephritis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, periodontis, hypersensitivity, swelling occurring after injury, ischemias including myocardial ischemia, cardiovascular ischemia, and ischemia secondary to cardiac arrest, and the like.
  • diseases as vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, neuromuscular junction disease including myasthenia gravis, white matter disease including multiple s
  • the disease to be treated by the methods of the present invention may be a cardiovascular condition.
  • said cardiovascular condition is chosen from atherosclerosis, cardiac hypertrophy, idiopathic cardiomyopathies, heart failure, angiogenesis-related conditions or disorders, and proliferation induced after medical conditions, including, but not limited to restenosis resulting from surgery and angioplasty.
  • the disease to be prevented or treated by the methods of the present invention may be autism.
  • GIP glucose -dependent insulinotropic polypeptide
  • GPRl 19 agonists increase GLP-I and GIP secretion both in vitro and in vivo
  • GPRl 19 agonists in this patent might be important for the prevention or treatment of bone loss induced by age or diseases in which the normal functions of osteobalsts or osteoclasts are altered.
  • Such diseases include, for example, osteopenia and osteoporosis.
  • certain compounds and formulations disclosed herein may also be useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.
  • Reagents (a) NaH, DMF, 100 0 C, 4 h. (b) Pd(PPh 3 ) 4 , Cs 2 CO 3 , toluene/H 2 O, 100 0 C, 18 h. (c) n-BuLi, triisopropyl borate, THF, -80 0 C, 1 h. (d) Acetyl chloride, DCM/MeOH (5:1), 0 0 C to 25°C, 1.5 h or HCl, Et 2 O, 25°C, 4 h. (e) DIEA, DCM, 25°C, 2 h.
  • This compound was purchased from Peakdale Molecular Ltd. (order # 1013265) for uHTS screening.
  • This compound was purchased from Peakdale Molecular Ltd. (order # 1013379) for uHTS screening.
  • This compound was purchased from Peakdale Molecular Ltd. (order # 1013266) for uHTS screening.
  • Step 1 l-(4-Bromo-3-fluorophenyl)-lH-tetrazole
  • n-BuLi (0.81 mL, 2.5M) was added to a solution of tert-butyl 4- (4- bromophenoxy)piperidine-l-carboxylate (600 mg, 1.69 mmol) and triisopropyl borate (350 mg, 1.86 mmol) in THF (30 mL), cooled to -80 0 C under N 2 atmosphere. The mixture was stirred for 1 h at -80 0 C and then was quenched with aqueous HCl (IN, 0.15 mL) to adjust the pH value to 5-6. The solution was concentrated under vacuum. The residue was extracted with EtOAc (3x20 mL).
  • Step 4 tert-butyl 4-(2'-fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yloxy)piperidine-l- carboxylate
  • Step 5 4-(2'-Fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yloxy)piperidine hydrochloride
  • Step 6 5-Ethyl-2-(4-(2'-fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yloxy)piperidin-l- yl)pyrimidine
  • Step 2 tert-Butyl 4-(2'-fluoro-4'-(methylsulfonyl)biphenyl-4-yloxy)piperidine-l- carboxylate
  • Step 4 5-Ethyl-2-(4-(2'-fluoro-4'-(methylsulfonyl)biphenyl-4-yloxy)piperidin-l- yl)pyrimidine
  • Step 3 5-Ethyl-2-(4-(4-(2-methyl-6-(lH-l,2,4-triazol-l-yl)pyridin-3- yl)phenoxy)piperidin-l-yl)pyrimidine
  • n-BuLi (0.81 mL, 2.5M) was added to a solution of tert-butyl 4- (4- bromophenoxy)piperidine-l-carboxylate (600 mg, 1.69 mmol) and triisopropyl borate (350 mg, 1.86 mmol) in THF (30 mL), cooled to -80 0 C under N 2 atmosphere. The mixture was stirred for 1 h at -80 0 C and then was quenched with aqueous HCl (IN, 0.15 mL) to adjust the pH value to 5-6. The solution was concentrated under vacuum. The residue was extracted with EtOAc (3x20 mL).
  • Step 3 tert-butyl 4-(2'-fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yloxy)piperidine-l- carboxylate
  • Step 1 4-(2'-Fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yloxy)piperidine hydrochloride
  • Step 2 Isopropyl 4-(2'-fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yloxy)piperidine-l- carboxylate
  • Step 1 tert-Butyl 4-(4-formylphenoxy)piperidine-l-carboxylate
  • n-BuLi 40 niL, 2.00 equiv
  • ethyl formate 20 g, 270 mmol
  • the reaction was then quenched by the addition of aqueous NH 4 Cl (100 mL) and the aqueous layer was extracted with EtOAc (3 x 100 mL).
  • Step 4 tert-Butyl 4-(4-((2-fluoro-4-(methylsulfonyl)phenylamino)methyl) phenoxy)piperidine-l-carboxylate
  • Step 1 tert-Butyl 4-(4-(Ethoxycarbonyl)phenoxy)piperidine-l-carboxylate
  • Step 4 4-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yloxy)benzoyl chloride
  • Step 1 l-(4-Bromo-2-fluorophenyl)- lH-tetrazole
  • Step 1 4-(3'-Fluoro-4'-(lH-tetrazol- l-yl)biphenyl-4-yloxy)piperidine hydrochloride
  • Step 2 5-Ethyl-2-(4-(3'-fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yloxy)piperidin-l- yl)pyrimidine
  • the title compound was synthesized as described in EXAMPLE 20, using 4-(l-(tert- butoxycarbonyl)piperidin-4-yloxy)phenylboronic acid and 3-bromo-2-methyl-6- (methylsulfonyl)pyridine as the starting materials.
  • Step 3 Tert-butyl 4-((2'-fluoro-4'-(lH-tetrazol- l-yl)biphenyl-4-yl)methoxy)piperidine- 1-carboxylate
  • Step 1 4-((2'-Fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yl)methoxy)piperidine hydrochloride
  • HCl(g) was bubbled into a solution of tert-butyl 4-((2'-fluoro-4'-(lH-tetrazol-l- yl)biphenyl-4-yl)methoxy)piperidine-l-carboxylate (1.20 g, 2.65 mmol, 1.00 equiv) in DCM (40 rnL) for 30 mins at room temperature. The solids were collected by filtration.
  • Step 2 5-Ethyl-2-(4-((2'-fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yl)methoxy)piperidin- l-yl)pyrimidine
  • Step 1 4-(2'-Fluoro-4'-(lH-tetrazol- l-yl)biphenyl-4-yloxy)piperidine- 1-carbonitrile
  • Step 2 5-(4-(2'-Fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yloxy)piperidin-l-yl)-3- isopropyl- 1 ,2,4-oxadiazole
  • Step 2 4-(l-(Tert-butoxycarbonyl)pyrrolidin-3-yloxy)phenylboronic acid
  • Step 3 Tert-butyl 3-(2'-fluoro-4'-(methylsulfonyl)biphenyl-4-yloxy)pyrrolidine-l- carboxylate
  • Step 2 5-Ethyl-2-(3-(2'-fluoro-4'-(methylsulfonyl)biphenyl-4-yloxy)pyrrolidin- 1- yl)pyrimidine
  • Step 3 Tert-butyl 3-(2'-fluoro-4'-(methylsulfonyl)biphenyl-4-yloxy)azetidine-l- carboxylate
  • Step 2 5-Ethyl-2-(3-(2'-fluoro-4'-(methylsulfonyl)biphenyl-4-yloxy)azetidin-l- yl)pyrimidine
  • Step 6 Tert-butyl 4-(4-((2-fluoro-4-(methylsulfonyl)phenoxy)methyl)phenyl) piperidine- 1 -carboxylate
  • Step 1 4-(4-((2-Fluoro-4-(methylsulfonyl)phenoxy)methyl)phenyl)piperidine
  • Step 1 6-(l-(Tert-butoxycarbonyl)piperidin-4-yloxy)pyridazine-3-carboxylic acid
  • the title compound was synthesized as described for EXAMPLE 61 using 5-(l-(tert- butoxycarbonyl)piperidin-4-yloxy)picolinic acid and 2-fluoro-4-(methylsulfonyl) aniline as the starting material.
  • the title compound was synthesized as described for EXAMPLE 61 using 4-(l-(tert- butoxycarbonyl)piperidin-4-yloxy)benzoic acid and 2-methyl-6-(lH-l,2,4-triazol-l- yl)pyridin-3-amine as the starting materials.
  • Step 2 Tert-butyl 4-(4-(l-(2-methyl-6-(methylsulfonyl)pyridin-3-ylamino)ethyl) phenoxy) piperidine-1-carboxylate
  • Step 4 Tert-butyl 4-(3-methyl-4-((2-methyl-6-(methylsulfonyl)pyridin-3-ylamino) methyl)phenoxy)piperidine- 1 -carboxylate
  • the resulting solution was heated to 90 0 C in an oil bath for 16 h. Upon completion, the resulting solution was diluted with DCM (50 mL) and quenched by addition of brine (50 mL). The resulting mixture was then extracted with dichloromethane (3x50 mL). Combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated to give the crude.
  • Step 1 2-Methyl-N-(2-methyl-4-(piperidin-4-yloxy)benzyl)-6-(methylsulfonyl) pyridin-3 -amine
  • the title compound was synthesized as described for EXAMPLE 70 using 6-(l-(5- ethylpyrimidin-2-yl)piperidin-4-yloxy)-N-(2-fluoro-4-(methylsulfonyl)phenyl) nicotinamide as the starting material.
  • Step 1 Methyl 5-hydroxypyrazine-2-carboxylate A l-L 3-necked round-bottom flask was charged with a solution of sodium 5- hydroxypyrazine-2-carboxylate (9.4 g, 56.9 mmol, 1.00 equiv, 98%) in methanol (500 mL). Then, thionyl chloride (32 g, 266 mmol, 4.67 equiv, 98%) was added dropwise at -10 0 C. The resulting solution was stirred at -10 0 C for 30 minutes followed refluxing in an oil bath for 2 hrs.
  • Step 1 Tert-butyl 4-(5-(hydroxymethyl)pyrazin-2-yloxy)piperidine-l-carboxylate
  • Step 3 Tert-butyl 4-(5-((2-fluoro-4-(methylsulfonyl)phenylamino)methyl)pyrazin-2- yloxy)piperidine- 1 -carboxylate
  • the title compound was synthesized as described for EXAMPLE 70 using 5-(l-(5- ethylpyrimidin-2-yl)piperidin-4-yloxy)-N-(2-fluoro-4-(methylsulfonyl)phenyl) pyrazine-2-carboxamide as the starting material.
  • SMILES Simplified Molecular Input Line Entry System
  • SMILES is a modern chemical notation system, developed by David Weininger and Daylight Chemical Information Systems, Inc., that is built into all major commercial chemical structure drawing software packages. Software is not needed to interpret SMILES text strings, and an explanation of how to translate SMILES into structures can be found in Weininger, D., /. Chem. Inf. Comput. ScL 1988, 28, 31-36. All SMILES strings used herein, as well as many IUPAC names, were generated using CambridgeSoft's ChemDraw 10.0 or CambridgeSoft's ChemDraw 11.0.

Abstract

Disclosed herein are compounds and methods which may be useful as inhibitors of GPR 119 for the treatment or prevention of diseases including cardiovascular and metabolic diseases.

Description

HETEROCYCLIC MODULATORS OF GPR119 FOR TREATMENT OF
DISEASE
[001] This application claims the benefit of priority of United States provisional applications No. 61/106,638, filed October 20, 2008, No. 61/143,854, filed January 12, 2009, and No. 61/154,115, filed February 20, 2009, the disclosures of which are hereby incorporated by reference as if written herein in their entireties.
[002] Disclosed herein are new heterocyclic compounds, compositions, and their application as pharmaceuticals for the treatment of disease. Methods of modulation of GPRl 19 activity in a human or animal subject are also provided for the treatment diseases mediated by GPRl 19.
[003] Obesity is a growing threat to the global health by virtue of its association with a cluster of diseases that include insulin resistance, glucose intolerance, dyslipidemia, and hypertension, collectively known as the metabolic syndrome or syndrome X. It is well documented that patients with metabolic syndrome have a higher risk for cardiovascular diseases such as coronary heart disease and stroke [Grundy S. M. et al. Circulation 112:e285-e290, 2005]. The treatment of obesity will require complex solutions, including increased public awareness to diminish food portions, improved food choices and increased physical activity. However, epidemiologic studies have shown that treating diabetes/insulin resistance in these patients can reduce the risk of cardiovascular diseases such as coronary artery disease. However, there remains a need for additional agents that can perhaps treat the root cause(s) of metabolic syndrome by treating obesity and diabetes. GPRl 19 modulators described herein might represent such an opportunity. [004] Current therapies for diabetes mellitus include: insulin; insulin secretagogues, such as sulphonylureas, which increase insulin secretion from pancreatic β-cells; glucose-lowering effectors, such as metformin which reduce glucose production from the liver; activators of the peroxisome proliferator-activated receptor-γ (PPAR-γ), such as the thiazolidinediones, which enhances insulin action; GLP-I mimetics, such as exenatide (Byetta); and α-glucosidase inhibitors which interfere with gut glucose production. There are, however, deficiencies associated with currently available treatments, including hypoglycemic episodes, weight gain, loss in responsiveness to therapy over time, gastrointestinal problems, and edema. [005] There are several areas at which research is being targeted in order to bring new, more effective, therapies to the marketplace. For example, on-going research includes exploring a reduction in excessive hepatic glucose production, enhancing the pathway by which insulin transmits its signal to the cells such that they take up glucose, enhancing glucose- stimulated insulin secretion from the pancreatic β-cells, and targeting obesity and associated problems with fat metabolism and accumulation. [006] GIP and GLP-I are peptides, known as incretins, secreted from enteroendocrine K- and L-cells respectively in response to ingestion of nutrients, and have a wide variety of physiological effects that have been described in numerous publications over the past two decades. See, for example, Bojanowska, E. et al., Med. Sd. Monit, 2005, Aug 5 11(8): RA271-8; Perry, T. et al., Curr. Alzheimer Res., 2005, July 2(3): 377-85; and Meier, JJ. et al., Diabetes Metab. Res. Rev., 2005, Mar-Apr; 21(2); 91-117 (each herein incorporated by reference with regard to a background understanding of incretins). These peptides act as gut hormones which promote normoglycemia acutely by enhancing glucose-stimulated insulin release and chronically by maintaining pancreatic β-cell mass (Staffers D. A., et al., 2000, Diabetes, 49:741-748; Xu G. et al., 1999, Diabetes, 48:2270-2276; Tourrel C. et al., 2002, Diabetes, 51:1443-1452; Wajchenberg B.L., Endocr Rev., 2007, 28(2):187-218). Although the mechanisms regulating GLP-I secretion remain unclear, the initial rapid rise in GLP-I following a meal may be a result of hormonal stimulation of neuronal afferents involving GIP. See, for example, J.N. Roberge and P. L. Brubaker, Endocrinology 133 (1993), pp. 233 — 240 (herein incorporated by reference with regard to such teaching). Later increases in GLP-I may involve direct activation of L-cells by nutrients in the distal small-intestine and the colon. GIP and GLP-I are potent stimulators of the body's ability to produce insulin in response to elevated levels of blood sugar. These effects occur via β-cell-expressed, Class B G-protein coupled receptors which in turn mediate elevated intracellular cAMP. Decreased GIP responsiveness may contribute to the pathogenesis of type 2 diabetes, resulting in mixed enthusiasm toward GIP receptor agonists as a means to treat the disease (Nauck M.A., et al, 1993, J. Clin. Invest, 91:301-307, Elahi, D., et al, Regul. Pept, 51:63-74). By contrast, strategies that enhance GLP-I receptor function have shown significant therapeutic promise. These strategies have so far consisted of injectable peptidic GLP- 1 receptor agonists, or alternatively, blockade of endogenous GLP- 1 metabolism through selective inhibition of the peptidase DPP-IV (Ahren B., et al., 2000, Eur. J. Pharmacol, 404:239-245; Ahren B., et al., 2002, Diabetes Care, 25:869-875). [007] In Type II diabetes the action of GLP-I on the β-cell is maintained, although GLP- 1 secretion, itself, is reduced. More recently, therefore, much research has been focused on GLP-I. Studies show glucose-lowering effects in addition to GLP- l's ability to stimulate glucose-dependent insulin secretion including, but not limited to, an inhibition of the release of the hormone glucagon following meals, a reduction in the rate at which nutrients are absorbed into the bloodstream, and a reduction of food intake. Studies demonstrate that treatments to increase GLP-I, therefore, may be used for a variety of conditions and disorders including but not limited to metabolic disorders, gastrointestinal disorders, inflammatory diseases, psychosomatic, depressive, and neuropsychiatric disease including but not limited to diabetes mellitus (Type 1 and Type 2), metabolic syndrome, obesity, appetite control and satiety, weight loss, stress, inflammation, myocardial ischemia/reperfusion injury, Alzheimer's Disease, and other diseases of the central nervous system. In Type II diabetes, patients display a decreased responsiveness to GIP but not GLP-I, with respect to its ability to stimulate insulin secretion. The mechanism behind the decreased responsiveness to GIP remains unclear since Type II diabetics retain sensitivity to a bolus administration of GIP but not to a continuous infusion (Meier et al. 2004 Diabetes 53 S220-S224). Moreover recent studies with a long-acting fatty-acid derivative of GIP showed beneficial effects on glucose homeostasis in ob/ob mice following 14 days of treatment (Irwin N. et al. (2006) J. Med. Chem. 49, 1047-1 054).
[008] The use of exogenous GLP-I in clinical treatment is severely limited, however, due to its rapid degradation by the protease DPPIV. There are multiple GLP- 1 mimetics in development for type 2 diabetes that are reported in the literature, all are modified peptides, which display longer half-lives than endogenous GLP-I. For example, the product sold under the tradename BYETT A® is the first FDA-approved agent of this new class of medications. These mimetics, however, require injection. An oral medication that is able to elevate GLP-I secretion is desirable. Orally available inhibitors of DPP-IV, which result in elevation in intact GLP-I, are now available, such as sitagliptin, marketed under the brand name JANUVIA®. Nevertheless, a molecule which may stimulate GLPl secretion would provide a therapeutic benefit. A molecule which could stimulate both GLP- 1 secretion and insulin secretion through effects on the L-cell and direct effects on the β-cell would hold much promise for Type II diabetes therapy.
[009] Orally active, small-molecule GLP- 1 receptor agonists have proven elusive, a feature that unfortunately is characteristic of Class B GPCRs. Meanwhile, the spectrum of signaling peptides affected by inhibition of DPP-IV remains unclear and could potentially extend significantly beyond GLP-I and GIP (8, 9). It is therefore worthwhile to search for therapeutic approaches which afford both the physiological selectivity of GLP- 1 signaling and the opportunity for orally active treatment modalities.
[010] One particular target is GPRl 19. GPRl 19 was identified as a Class A, islet- enriched receptor which could potentially mediate the insulinotropic actions of lysophosphatidylcholine (LPC) observed in vitro (Soga T., et al, Biochem Biophys Res Commun, 2005, 326:744-751), but a later study suggested that oleoylethanolamide (OEA) was a more potent GPRl 19 agonist (Overton H.A., et al., Cell Metab, 2006, 3:167-175). Recently, a small molecule GPRl 19 agonist has been shown to enhance glucose-dependent insulin secretion and improve hyperglycemia in rodent models of diabetes (Chu Z. et al. Endocrinology, 2007, 148:2601-2609). In addition to the "GPRl 19" identifier, several other identifiers exist, including but not limited to RUP 3, Snorf 25, 19 AJ, AXOR 20, GDIR, GPCR2, and PSI. GPRl 19 is expressed in human gastrointestinal regions and in human islets. Activation of GPRl 19 has been demonstrated to stimulate intracellular cAMP and lead to glucose-dependent GLP-I and insulin secretion. See, T. Soga et al., Biochemical and Biophysical Research Communications 326 (2005) 744-751, herein incorporated by reference with regard to a background understanding of GPRl 19. Moreover, activation of GPRl 19 is very unlikely to induce hypoglycemia (Chu Z., et al. Endocrinology, 2007, 148:2601-2609) [011] Agonists to GPRl 19 may be of therapeutic value for diabetes and associated conditions, particularly Type II diabetes, obesity, glucose intolerance, insulin resistance, metabolic syndrome X, hyperlipidemia, hypercholesterolemia, and atherosclerosis.
[012] Novel compounds and pharmaceutical compositions, certain of which have been found to modulate GPRl 19 have been discovered, together with methods of synthesizing and using the compounds including methods for the treatment of GPRl 19-mediated diseases in a patient by administering the compounds. [013] In certain embodiments of the present invention, compounds have structural Formula I:
Figure imgf000006_0001
(I)
Or a salt, ester, or prodrug thereof, wherein:
A, B, and D are each independently chosen from heteroaryl, aryl, cycloalkyl, and heterocycloalkyl;
Q is chosen from C and N;
Q' is chosen from C and N;
Z is chosen from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkyl, heteroalkyl, haloalkyl, perhaloalkyl, -CO2Rn, and -CO2NR48R19, any of which may be optionally substituted;
V is chosen from a bond, O, S, NR5, and (CROR7X; W is chosen from a bond, O, S, NRg, and (CRgR1O)5; X is chosen from a bond, O, S, NR11, and (CR12R13X;
Y is chosen from a bond, O, S, NR14, and (CR15R1O)U; m, n, p, q, r, s, t, and u are each independently an integer from 0 to 4; each R1, R2, R3, and R4 is independently chosen from hydrogen, null, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, amido, amino, aryl, aryloxy, carbamate, carboxy, cyano, cycloalkyl, halo, heteroalkyl, heteroaryl, heterocycloalkyl, hydroxyl, nitro, perhaloalkoxy, perhaloalkyl, sulfonyl and sulfonamide, any of which may be optionally substituted; or R2 and R3 together may form an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl; each R5, R8, R11, and R14 are independently chosen from hydrogen, acyl, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, C-amido, and sulfonyl, any of which may be optionally substituted;
Re, R7, R9, R1O, Ri2, Ri3, Ri5, and R16 are each independently chosen from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, any of which may be optionally substituted; or R6 and R7, or R9 and R10, or R12 and R13, or R15 and R16 are taken together to form oxo; and
R17, R18, and R19 are each independently chosen from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, any of which may be optionally substituted.
[014] Certain compounds disclosed herein may possess useful GPRl 19 modulating activity, and may be used in the treatment or prophylaxis of a disease or condition in which GPRl 19 plays an active role. Thus, in broad aspect, certain embodiments also provide pharmaceutical compositions comprising one or more compounds disclosed herein together with a pharmaceutically acceptable carrier, as well as methods of making and using the compounds and compositions. Certain embodiments provide methods for modulating GPRl 19. Other embodiments provide methods for treating a GPRl 19-mediated disorder in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound or composition as disclosed herein. Also provided is the use of certain compounds disclosed herein for use in the manufacture of a medicament for the treatment of a disease or condition ameliorated by the modulation of GPRl 19 activity. [015] In certain embodiments, compounds have Formula (II)
Figure imgf000008_0001
(H) or a salt thereof, wherein:
A, B, and D are each independently chosen from monocyclic heteroaryl, monocyclic aryl, monocyclic cycloalkyl, and monocyclic heterocycloalkyl;
Q is chosen from C and N;
Q' is chosen from C and N;
Z is chosen from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkyl, heteroalkyl, haloalkyl, perhaloalkyl, -CO2Rn, and -CO2NR1SR^, any of which may be optionally substituted;
V is chosen from a bond, O, S, NR5, and (CRORTX; W is chosen from a bond, O, S, NRg, and (CRgR1O)5;
Y is chosen from a bond, O, S, NR14, and (CR1SR16); m, n, p, q, r, and s are each independently an integer from 0 to 4; each R1, R2, R3, and R4 is independently chosen from hydrogen, null, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, amido, amino, aryl, aryloxy, carbamate, carboxy, cyano, cycloalkyl, halo, heteroalkyl, heteroaryl, heterocycloalkyl, hydroxyl, nitro, perhaloalkoxy, perhaloalkyl, sulfonyl and sulfonamide, any of which may be optionally substituted; or R2 and R3 together may form an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl; each R5, Rg, and R14 are independently chosen from hydrogen, acyl, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, C-amido, and sulfonyl, any of which may be optionally substituted;
Re, R7, R9, R1O, Ri5, and R16 are each independently chosen from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, any of which may be optionally substituted; or R6 and R7, or R9 and R10, or R12 and R13, or R1S and R16 are taken together to form oxo; and
R17, Ri8, and R19 are each independently chosen from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, any of which may be optionally substituted. [016] In certain embodiments provided herein,
A is chosen from monocyclic aryl, monocyclic cycloalkyl, and monocyclic heterocycloalkyl, any of which may be optionally substituted;
B is chosen from monocyclic heteroaryl and monocyclic aryl, any of which may be optionally substituted;
Z is chosen from aryl, heteroaryl, alkyl, heteroalkyl, -CO2R17, and - CO2NRi8Ri9, any of which may be optionally substituted; and r and s are each independently an integer from 0 to 3.
[017] In further embodiments provided herein r is an integer from 0 to 2. [018] In further embodiments provided herein, each R1, R2, R3, and R4 is independently chosen from hydrogen, null, acyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, amido, amino, carboxyl, cyano, halo, hydroxyl, heteroaryl, nitro, perhaloalkoxy, perhaloalkyl, sulfonyl and sulfonamide, any of which may be optionally substituted; or R2 and R3 together may form an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl; and each R5, Rg, and R14 is independently chosen from hydrogen, acyl, lower alkyl, lower alkenyl, and lower alkynyl, any of which may be optionally substituted. [019] In further embodiments provided herein, D is chosen from monocyclic aryl, monocyclic cycloalkyl, and monocyclic heteroaryl, any of which may be optionally substituted.
[020] In further embodiments, X is a bond.
[021] In certain embodiments provided herein, compounds have structural Formula (III)
Figure imgf000010_0001
(III) or a salt thereof, wherein:
A is chosen from monocyclic aryl, monocyclic cycloalkyl, and monocyclic heterocyclo alkyl ;
B is chosen from monocyclic aryl and monocyclic heteroaryl;
D is chosen from monocyclic aryl, monocyclic cycloalkyl, and monocyclic heteroaryl;
Z is chosen from heteroaryl, aryl, alkyl, heteroalkyl, -CO2Rn, and - CO2NRi8Ri9, any of which may be optionally substituted;
Q is chosen from C and N;
Q' is chosen from C and N;
V is chosen from a bond, O, S, NR5, and
Figure imgf000010_0002
W is chosen from a bond, O, NRs, and (CRgR1O)5;
Y is chosen from a bond, O, S, NR14, and (CR1SR16); m, n, p, and q are each independently an integer from 0 to 4; r and s are each independently an integer from 0 to 2; each R1, R2, R3 and R4 is independently chosen from hydrogen, null, acyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, amido, amino, carboxyl, cyano, halo, hydroxyl, heteroaryl, nitro, perhaloalkoxy, perhaloalkyl, sulfonyl and sulfonamide, any of which may be optionally substituted; or R2 and R3 together may form an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl;
R5 and R14 are each independently chosen from hydrogen, acyl, lower alkyl, lower alkenyl, and lower alkynyl;
Re, R7, R9, R1O, Ri5 and R16 are each independently chosen from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, any of which may be optionally substituted; or Re and R7, or R9 and R1O or R15 and R16 are taken together to form oxo; and
Rn, R1S, and R19 are each independently chosen from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, any of which may be optionally substituted. [022] In further embodiments, Q' is C. [023] In further embodiments, Y is a bond.
[024] In certain embodiments provided herein, the compounds have structural Formula (III)
Figure imgf000011_0001
(III) or a salt thereof, wherein: B and D are each independently chosen from monocyclic aryl and monocyclic heteroaryl;
Z is chosen from heteroaryl, aryl, alkyl, heteroalkyl, -CO2Rn, and - CO2NR1SR1C), any of which may be optionally substituted;
Q is chosen from C and N;
V is chosen from a bond, O, S, NR5, and (CRORTX; W is chosen from a bond, O, S, NRg, and (CRgR1O)5; m, n, p, and v are each independently an integer from 0 to 4; r is an integer from 0 to 1 ; s is an integer from 0 to 2; each R1, R2, and R3 is independently chosen from hydrogen, null, acyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, amido, amino, carboxyl, cyano, halo, hydroxyl, heteroaryl, nitro, perhaloalkoxy, perhaloalkyl, sulfonyl and sulfonamide, any of which may be optionally substituted; or R2 and R3 together may form an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl;
R5 and Rg are independently chosen from hydrogen, acyl, lower alkyl, lower alkenyl, and lower alkynyl;
Re, R7, R9, and R10 are each independently chosen from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, any of which may be optionally substituted; or Re and R7, or R9 and R1O are taken together to form oxo; and
R17 is chosen from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, any of which may be optionally substituted. [025] In further embodiments:
Q is N; s is an integer from 0 to 1 ;
V is chosen from a bond, O, NR5, and (CROR7X; and R5 is chosen from hydrogen and lower alkyl.
[026] In further embodiments, Z is heteroaryl, which may be optionally substituted. [027] In further embodiments, Z is a 6-membered heteroaryl, which may be optionally substituted.
[028] In further embodiments, Z is an optionally substituted 6-membered heteroaryl containing between 1 and 2 nitrogens.
[029] In further embodiments, Z is pyrimidine, which may be optionally substituted.
[030] In yet further embodiments:
V is chosen from a bond, O, and NR5; and W is a bond.
[031] In other embodiments, V is a bond. [032] In further embodiments: s is 1;
V is chosen from O and NR5; W is (CR9R10); and
R9 and R10 are each independently chosen from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, or R9 and R10 are taken together to form oxo. [033] In other embodiments, Z is chosen from alkyl, -CO2Ri7and -CO2NR1SRi9. [034] In further embodiments, Z is chosen from -CO2Rn and -CO2NRi8Ri9. [035] In further embodiments, Z is -CO2Rn.
[036] In yet further embodiments, R17 is chosen from hydrogen, alkyl, aryl, heteroaryl, and heterocycloalkyl. [037] In further embodiments:
V is chosen from a bond, O, and NR5; and W is a bond.
[038] In other embodiments, V is a bond. [039] In further embodiments: s is 1;
V is chosen from O and NR5; W is (CR9Ri0); and
R9 and Rio are each independently chosen from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, or R9 and Rio are taken together to form oxo. [040] In further embodiments provided herein, compounds have structural
Formula II wherein Rg and R1O are each independently chosen from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, any of which may be optionally substituted; or R9 and R10 are taken together to form oxo.
[041] In further embodiments, Y is chosen from O and NR14.
[042] In further embodiments, V is chosen from O, (CRORT)0 and NR5.
[043] In further embodiments, Y is O.
[044] In further embodiments, A is chosen from 4- to 6-membered cycloalkyl, lower aryl, 4- to 6-membered heterocycloalkyl, and 4- to 6-membered heteroaryl.
[045] In further embodiments, A is lower heterocycloalkyl.
[046] In further embodiments, Z is chosen from CO2Rn, optionally substituted phenyl, and optionally substituted heteroaryl.
[047] In further embodiments, Z is heteroaryl, which may be optionally substituted.
[048] In further embodiments, Z is a 6-membered heteroaryl, which may be optionally substituted.
[049] In further embodiments, Z is an optionally substituted six-membered heteroaryl containing between 1 and 2 nitrogens.
[050] In further embodiments, Z is chosen from pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl, any of which may be optionally substituted.
[051] In further embodiments, Z is pyrimidine, which may be optionally substituted.
[052] In other embodiments, Z is chosen from alkyl, -CO2Rn and -CO2NR1SR19.
[053] In further embodiments, Z is chosen from -CO2R17 and -CO2NR1SR19.
[054] The In further embodiments, Z is -CO2R17.
[055] In yet further embodiments, R17 is chosen from hydrogen, alkyl, aryl, heteroaryl, and heterocycloalkyl. [056] In further embodiments provided herein, the compound has structural Formula (IV)
Figure imgf000015_0001
or a salt thereof, wherein:
B is chosen from phenyl and a 5- or 6 -membered monocyclic heteroaryl;
D is chosen from phenyl and a 5- or 6-membered monocyclic heteroaryl;
Z is chosen from lower heteroaryl, lower aryl, lower alkyl, lower heteroalkyl, - CO2Rn, and -CO2NR1SR^, any of which may be optionally substituted;
V is chosen from a bond, O, S, NR5, and (CR6R7);
W is chosen from a bond, O, NRs, and (CR9R1O); m, n, p, and q are each independently an integer from 0 to 2; each R1, R2, R3 and R4 is independently selected from the group consisting of hydrogen, null, lower acyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower amido, lower amino, lower carboxyl, cyano, halo, hydroxyl, lower heteroaryl, nitro, lower perhaloalkoxy, lower perhaloalkyl, sulfonyl and sulfonamide, any of which may be optionally substituted; and two R1 may combine to form a 1-2 carbon bridge;
R5, Re, R7, R8, R9, and R1O are each independently selected from the group consisting of hydrogen and lower alkyl; and
Rn, R1S, and R19, are independently chosen from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower amino, lower aminoalkyl, lower alkoxy, lower alkoxyalkyl, phenyl, lower heteroaryl, lower cycloalkyl, lower heteroaryl, lower heterocycloalkyl, any of which may be optionally substituted. [057] In further embodiments, at least one R1 is present, and is attached in a position para to V. [058] In further embodiments, Z is -C(O)NH.
[059] In further embodiments, B is a 9- or 10-membered fused bicyclic heteroaryl having from one to four nitrogens as heteroatoms.
[060] The method as recited in Claim 44, wherein Y is a bond.
[061] In further embodiments, compounds have structural Formula (V)
Figure imgf000016_0001
or a salt thereof, wherein:
B is chosen from phenyl and a 6-membered monocyclic heteroaryl comprising 1 or 2 nitrogens;
D is chosen from phenyl and a 6-membered monocyclic heteroaryl;
V is chosen from a bond, O, S, NR5, and (CR6R7);
W is chosen from a bond, O, S, NR8, and (CR9R10);
Z is chosen from -CONH, lower heteroaryl, lower aryl, lower alkyl, lower heteroalkyl, -CO2Rn, and -CO2NR1SRi9, any of which may be optionally substituted; m is an integer from 0 to 2; n, p, and q are each independently an integer from 0 to 2; each R2, R3 and R4 is independently selected from the group consisting of hydrogen, null, lower acyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower amido, lower amino, lower carboxyl, cyano, halo, hydroxyl, lower heteroaryl, nitro, lower perhaloalkoxy, lower perhaloalkyl, sulfonyl and sulfonamide, any of which may be optionally substituted; and two Ri may join together to form a 1- or 2- carbon bridge; Rla is oriented para to V, and is chosen from hydrogen, null, acyl, lower alkyl, lower alkenyl, lower alkynyl, C-amido, amino, halo, hydroxyl, heteroaryl, nitro, perhaloalkoxy, perhaloalkyl, sulfonyl and sulfonamide, any of which may be optionally substituted; or R2 and R3 together may form an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl; each Rib is independently chosen from hydrogen, null, acyl, lower alkyl, lower alkenyl, lower alkynylamido, amino, carboxyl, halo, hydroxyl, heteroaryl, nitro, perhaloalkoxy, perhaloalkyl, sulfonyl and sulfonamide, any of which may be optionally substituted; or R2 and R3 together may form an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl;
R5, Re, R7, R8, R9, and R1O are each independently selected from the group consisting of hydrogen and lower alkyl; and
R17, R1S, and R19, are independently chosen from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower amino, lower aminoalkyl, lower alkoxy, lower alkoxyalkyl, phenyl, lower heteroaryl, lower cycloalkyl, lower heteroaryl, lower heterocycloalkyl, any of which may be optionally substituted. ] In further embodiments:
Z is chosen from lower heteroaryl, which may be optionally substituted with one, two or three substituents chosen from halogen, lower alkyl, and lower haloalkyl; and -CO2R17;
V is chosen from a bond, O, S, NR5, and CH2;;
W is chosen from a bond, C(O), and CH2;
Rla is chosen from hydrogen, null, acyl, lower alkyl, lower alkenyl, lower alkynyl, C-amido, amino, halo, hydroxyl, heteroaryl, nitro, perhaloalkoxy, perhaloalkyl, sulfonyl and sulfonamide, any of which may be optionally substituted; each R^, is independently chosen from hydrogen, null, acyl, lower alkyl, lower alkenyl, lower alkynylamido, amino, carboxyl, halo, hydroxyl, heteroaryl, nitro, perhaloalkoxy, perhaloalkyl, sulfonyl and sulfonamide, any of which may be optionally substituted; or R2 and R3 together may form an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl; m is 0, or 1;
R5 is chosen from hydrogen, lower alkyl, lower alkenyl, and lower alkynyl; and Rn is chosen from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, phenyl, lower heteroaryl, lower cycloalkyl, and lower heterocycloalkyl, any of which may be optionally substituted. [063] In further embodiments, m is 1. [064] In further embodiments:
Z is chosen from CO2Rn and lower heteroaryl, which is substituted with one, two or three substituents chosen from halogen, lower alkyl, and lower haloalkyl; V is chosen from a bond and NR5;
Rla is chosen from null, lower alkyl, lower amino, lower heteroaryl, and sulfonyl;
Rib is chosen from null, halogen, hydroxy, cyano, lower alkyl, lower alkoxy, lower haloalkyl, and lower haloalkoxy; R5 is hydrogen; and
R17 is chosen from lower alkyl and lower cycloalkyl.
[065] In further embodiments, Rla is chosen from lower heteroaryl and sulfonyl. [066] In further embodiments, Z is chosen from CO2R17 and pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, any of which may be optionally substituted with one or two substituents chosen from halogen, lower alkyl, and lower haloalkyl. [067] In yet further embodiments, R17 is lower alkyl. [068] In further embodiments, Z is pyrimidinyl. [069] In further embodiments: m is 1;
Z is chosen from 5-ethyl-pyrimidinyl and CO2R17; W-V is chosen from a bond, CH2NH, and C(O)NH; Rla is chosen from lower alkyl, lower amino, triazolyl, tetrazolyl, and methylsulfonyl; Rib is chosen from null, halogen, and lower alkyl; and
Ri7 is tert-butyl.
[070] In certain embodiments provided herein, compounds have structural Formula (V):
Figure imgf000019_0001
or a salt thereof, wherein
B is chosen from phenyl and a 6-membered monocyclic heteroaryl comprising from 1-2 nitrogens;
D is chosen from phenyl and a 6-membered monocyclic heteroaryl; Z is chosen from CO2Rn and lower heteroaryl, which is substituted with one, two or three substituents chosen from halogen, lower alkyl, and lower haloalkyl; W is chosen from a bond, C(O), and CH2; V is chosen from a bond and NR5; provided that either each of W and V is a bond, or neither is; Rla is chosen from lower heteroaryl and sulfonyl;
Rib is chosen from null, halogen, hydroxy, cyano, lower alkyl, lower alkoxy, lower haloalkyl, and lower haloalkoxy; m is an integer from 0 to 1 ; R5 is hydrogen; and;
R17 is chosen from lower alkyl and lower cycloalkyl.
[071] In further embodiments, Z is chosen from CO2R17, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, any of which may be optionally substituted with one or two substituents chosen from halogen, lower alkyl, and lower haloalkyl. [072] In further embodiments, R17 is lower alkyl. [073] In further embodiments, Z is pyrimidinyl. [074] In further embodiments: m is 1;
Z is chosen from 5-ethyl-pyrimidinyl and CO2Rn;
W-V is chosen from a bond, CH2NH, and C(O)NH;
Rla is chosen from lower alkyl, lower amino, triazolyl, tetrazolyl, and methylsulfonyl;
Rib is chosen from null, halogen, and lower alkyl; and
R17 is tert-butyl.
[075] Also provided herein is a compound chosen from Examples 1 to 109. [076] Also provided herein is a compound as disclosed herein for use as a medicament.
[077] Also provided herein is a compound as disclosed herein for use in the manufacture of a medicament for the prevention or treatment of a disease or condition ameliorated by the modulation of GPRl 19.
[078] Also provided herein is a pharmaceutical composition comprising a compound as disclosed herein together with a pharmaceutically acceptable carrier. [079] Also provided herein is a pharmaceutical composition comprising at least one compound chosen from those recited in Examples 1 to 109 together with a pharmaceutically acceptable carrier.
[080] In certain embodiments, the pharmaceutical composition is useful for the treatment or prevention of a GPRl 19-mediated disease.
[081] Also provided herein is a method of modulating GPRl 19 comprising contacting GPRl 19 with a compound as disclosed herein.
[082] Also provided herein is a method of treatment of a GPRl 19-mediated disease, comprising the administration of a therapeutically effective amount of a compound as disclosed herein.
[083] In certain embodiments, said disease is a metabolic disease. [084] In further embodiments, said disease is diabetes.
[085] In further embodiments is provided a method of treatment of a GPRl 19- mediated disease, comprising the administration of: a therapeutically effective amount of a compound as disclosed herein; and a therapeutically effective amount of another therapeutic agent.
[086] In further embodiments, said agent is chosen from insulin, metformin, Glipizide, glyburide, Amaryl, gliclazide, meglitinides, nateglinide, repaglinide, pramlintide, PTP-112, SB-517955, SB-4195052, SB-216763, NN-57-05441, NN-57- 05445, GW-0791, AGN-194204, T-1095, BAY R3401, acarbose, miglitol, voglibose, Exendin-4, DPP728, LAF237, vildagliptin , BMS477118, PT-100, GSK-823093, PSN- 9301, T-6666, SYR-322, SYR-619, Liraglutide, CJC-1134-PC, naliglutide, MK-0431, saxagliptin, GSK23A, pioglitazone, rosiglitazone, AVE2268, GW869682, GSK189075, APD668, PSN-119-1, PSN-821, rosuvastatin, atrovastatin, simvastatin, lovastatin, pravastatin, fluvastatin, cerivastatin, rosuvastatin, pitavastatin, fenofibrate, benzafibrate, clofibrate, gemfibrozil, Ezetimibe, eflucimibe, CP-529414, CETi-I, JTT- 705, cholestyramine, colestipol, niacin, implitapide, (R)-l-{4-[5-methyl-2-(4- trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonyl}2,3-dihydro-lH-indole- 2-carboxylic acid, and GI-262570.
[087] As used herein, the terms below have the meanings indicated. [088] When ranges of values are disclosed, and the notation "from ni ... to n2" or "between ni ... and n2" is used, where ni and n2 are the numbers, then unless otherwise specified, this notation is intended to include the numbers themselves and the range between them. This range may be integral or continuous between and including the end values. By way of example, the range "from 2 to 6 carbons" is intended to include two, three, four, five, and six carbons, since carbons come in integer units. Compare, by way of example, the range "from 1 to 3 μM (micromolar)," which is intended to include 1 μM, 3 μM, and everything in between to any number of significant figures (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.). When n is set at 0 in the context of "0 carbon atoms", it is intended to indicate a bond or null.
[089] The term "about," as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term "about" should be understood to mean that range which would encompass the recited value and the range which would be included by rounding up or down to that figure as well, taking into account significant figures.
[090] The term "acyl," as used herein, alone or in combination, refers to a carbonyl attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocycle, or any other moiety were the atom attached to the carbonyl is carbon. An "acetyl" group refers to a -C(O)CH3 group. An "alkylcarbonyl" or "alkanoyl" group refers to an alkyl group attached to the parent molecular moiety through a carbonyl group. Examples of such groups include methylcarbonyl and ethylcarbonyl. Examples of acyl groups include formyl, alkanoyl and aroyl.
[091] The term "alkenyl," as used herein, alone or in combination, refers to a straight-chain or branched-chain hydrocarbon group having one or more double bonds and containing from 2 to 20 carbon atoms. In certain embodiments, said alkenyl will comprise from 2 to 6 carbon atoms. The term "alkenylene" refers to a carbon-carbon double bond system attached at two or more positions such as ethenylene [(-CH=CH- ),(-C::C-)]. Examples of suitable alkenyl groups include ethenyl, propenyl, 2- methylpropenyl, 1,4-butadienyl and the like. Unless otherwise specified, the term "alkenyl" may include "alkenylene" groups.
[092] The term "alkoxy," as used herein, alone or in combination, refers to an alkyl ether group, wherein the term alkyl is as defined below. Examples of suitable alkyl ether groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso- butoxy, sec-butoxy, tert-butoxy, and the like.
[093] The term "alkyl," as used herein, alone or in combination, refers to a straight-chain or branched-chain alkyl group containing from 1 to 20 carbon atoms. In certain embodiments, said alkyl will comprise from 1 to 10 carbon atoms. In further embodiments, said alkyl will comprise from 1 to 6 carbon atoms. Alkyl groups may be optionally substituted as defined herein. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, noyl and the like. The term "alkylene," as used herein, alone or in combination, refers to a saturated aliphatic group derived from a straight or branched chain saturated hydrocarbon attached at two or more positions, such as methylene (- CH2-). Unless otherwise specified, the term "alkyl" may include "alkylene" groups. [094] The term "alkylamino," as used herein, alone or in combination, refers to an alkyl group attached to the parent molecular moiety through an amino group. Suitable alkylamino groups may be mono- or dialkylated, forming groups such as, for example, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-ethylmethylamino and the like.
[095] The term "alkylidene," as used herein, alone or in combination, refers to an alkenyl group in which one carbon atom of the carbon-carbon double bond belongs to the moiety to which the alkenyl group is attached.
[096] The term "alkylthio," as used herein, alone or in combination, refers to an alkyl thioether (R-S-) group wherein the term alkyl is as defined above and wherein the sulfur may be singly or doubly oxidized. Examples of suitable alkyl thioether groups include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso- butylthio, sec-butylthio, tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like. [097] The term "alkynyl," as used herein, alone or in combination, refers to a straight-chain or branched chain hydrocarbon group having one or more triple bonds and containing from 2 to 20 carbon atoms. In certain embodiments, said alkynyl comprises from 2 to 6 carbon atoms. In further embodiments, said alkynyl comprises from 2 to 4 carbon atoms. The term "alkynylene" refers to a carbon-carbon triple bond attached at two positions such as ethynylene (-C:::C-, -C≡C-). Examples of alkynyl groups include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1- yl, 3-methylbutyn-l-yl, hexyn-2-yl, and the like. Unless otherwise specified, the term "alkynyl" may include "alkynylene" groups.
[098] The terms "amido" and "carbamoyl,"as used herein, alone or in combination, refer to an amino group as described below attached to the parent molecular moiety through a carbonyl group, or vice versa. The term "C-amido" as used herein, alone or in combination, refers to a -C(=O)-NR2 group with R as defined herein. The term "N-amido" as used herein, alone or in combination, refers to a RC(=O)NH- group, with R as defined herein. The term "acylamino" as used herein, alone or in combination, embraces an acyl group attached to the parent moiety through an amino group. An example of an "acylamino" group is acetylamino (CH3C(O)NH-). [099] The term "amino," as used herein, alone or in combination, refers to —
NRR , wherein R and R are independently chosen from hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may themselves be optionally substituted. Additionally, R and R' may combine to form heterocycloalkyl, either of which may be optionally substituted.
[0100] The term "aryl," as used herein, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such polycyclic ring systems are fused together. The term "aryl" embraces aromatic groups such as phenyl, naphthyl, anthracenyl, and phenanthryl.
[0101] The term "arylalkenyl" or "aralkenyl," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkenyl group.
[0102] The term "arylalkoxy" or "aralkoxy," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkoxy group.
[0103] The term "arylalkyl" or "aralkyl," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkyl group.
[0104] The term "arylalkynyl" or "aralkynyl," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkynyl group.
[0105] The term "arylalkanoyl" or "aralkanoyl" or "aroyl,"as used herein, alone or in combination, refers to an acyl group derived from an aryl- substituted alkanecarboxylic acid such as benzoyl, napthoyl, phenylacetyl, 3-phenylpropionyl
(hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like.
[0106] The term aryloxy as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an oxy.
[0107] The terms "benzo" and "benz," as used herein, alone or in combination, refer to the divalent group COH4= derived from benzene. Examples include benzothiophene and benzimidazole. [0108] The term "Boc," as used herein, alone or in combination, is shorthand for (tert-butoxy)carbonyl, which has the following structure:
Figure imgf000025_0001
[0109] The term "carbamate," as used herein, alone or in combination, refers to an ester of carbamic acid (-NHCOO-) which may be attached to the parent molecular moiety from either the nitrogen or acid end, and which may be optionally substituted as defined herein.
[0110] The term "O-carbamyl" as used herein, alone or in combination, refers to a -OC(O)NRR', group- with R and R' as defined herein.
[0111] The term "N-carbamyl" as used herein, alone or in combination, refers to a ROC(O)NR'- group, with R and R' as defined herein.
[0112] The term "carbonyl," as used herein, when alone includes formyl [-C(O)H] and in combination is a -C(O)- group.
[0113] The term "carboxyl" or "carboxy," as used herein, refers to -C(O)OH or the corresponding "carboxylate" anion, such as is in a carboxylic acid salt. An "O-carboxy" group refers to a RC(O)O- group, where R is as defined herein. A "C-carboxy" group refers to a -C(O)OR groups where R is as defined herein. [0114] The term "cyano," as used herein, alone or in combination, refers to -CN. [0115] The term "cycloalkyl," or, alternatively, "carbocycle," as used herein, alone or in combination, refers to a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl group wherein each cyclic moiety contains from 3 to 12 carbon atom ring members and which may optionally be a benzo fused ring system which is optionally substituted as defined herein. In certain embodiments, said cycloalkyl will comprise from 5 to 7 carbon atoms. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronapthyl, indanyl, octahydronaphthyl, 2,3-dihydro-lH-indenyl, adamantyl and the like. "Bicyclic" and "tricyclic" as used herein are intended to include both fused ring systems, such as decahydronaphthalene, octahydronaphthalene as well as the multicyclic (multicentered) saturated or partially unsaturated type. The latter type of isomer is exemplified in general by, bicyclo[l,l,l]pentane, camphor, adamantane, and bicyclo [3 ,2, 1 ] octane.
[0116] The term "ester," as used herein, alone or in combination, refers to a carboxy group bridging two moieties linked at carbon atoms.
[0117] The term "ether," as used herein, alone or in combination, refers to an oxy group bridging two moieties linked at carbon atoms.
[0118] The term "halo," or "halogen," as used herein, alone or in combination, refers to fluorine, chlorine, bromine, or iodine.
[0119] The term "haloalkoxy," as used herein, alone or in combination, refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom. [0120] The term "haloalkyl," as used herein, alone or in combination, refers to an alkyl group having the meaning as defined above wherein one or more hydrogens are replaced with a halogen. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl groups. A monohaloalkyl group, for one example, may have an iodo, bromo, chloro or fluoro atom within the group. Dihalo and polyhaloalkyl groups may have two or more of the same halo atoms or a combination of different halo groups. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. "Haloalkylene" refers to a haloalkyl group attached at two or more positions. Examples include fluoromethylene (-CFH-), difluoromethylene (-CF2 -), chloromethylene (-CHC1-) and the like. [0121] The term "heteroalkyl," as used herein, alone or in combination, refers to a stable straight or branched chain, or cyclic hydrocarbon group, or combinations thereof, fully saturated or containing from 1 to 3 degrees of unsaturation, consisting of the stated number of carbon atoms and from one to three heteroatoms chosen from O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N and S may be placed at any interior position of the heteroalkyl group. Up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3. [0122] The term "heteroaryl," as used herein, alone or in combination, refers to a 3 to 7 membered unsaturated heteromonocyclic ring, or a fused monocyclic, bicyclic, or tricyclic ring system in which at least one of the fused rings is aromatic, which contains at least one atom chosen from O, S, and N. In certain embodiments, said heteroaryl will comprise from 5 to 7 carbon atoms. The term also embraces fused polycyclic groups wherein heterocyclic rings are fused with aryl rings, wherein heteroaryl rings are fused with other heteroaryl rings, wherein heteroaryl rings are fused with heterocycloalkyl rings, or wherein heteroaryl rings are fused with cycloalkyl rings. Examples of heteroaryl groups include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, benzothienyl, chromonyl, coumarinyl, benzopyranyl, tetrahydroquinolinyl, tetrazolopyridazinyl, tetrahydroisoquinolinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl and the like. [0123] The terms "heterocycloalkyl" and, interchangeably, "heterocycle," as used herein, alone or in combination, each refer to a saturated, partially unsaturated, or fully unsaturated monocyclic, bicyclic, or tricyclic heterocyclic group containing at least one heteroatom as a ring member, wherein each said heteroatom may be independently chosen from nitrogen, oxygen, and sulfur In certain embodiments, said hetercycloalkyl will comprise from 1 to 4 heteroatoms as ring members. In further embodiments, said hetercycloalkyl will comprise from 1 to 2 heteroatoms as ring members. In certain embodiments, said hetercycloalkyl will comprise from 3 to 8 ring members in each ring. In further embodiments, said hetercycloalkyl will comprise from 3 to 7 ring members in each ring. In yet further embodiments, said hetercycloalkyl will comprise from 5 to 6 ring members in each ring. "Heterocycloalkyl" and "heterocycle" are intended to include sulfones, sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclic fused and benzo fused ring systems; additionally, both terms also include systems where a heterocycle ring is fused to an aryl group, as defined herein, or an additional heterocycle group. Examples of heterocycle groups include aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[l,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihy-dropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3- dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like. The heterocycle groups may be optionally substituted unless specifically prohibited.
[0124] The term "hydrazinyl" as used herein, alone or in combination, refers to two amino groups joined by a single bond, i.e., -N-N-.
[0125] The term "hydroxy," as used herein, alone or in combination, refers to -OH.
[0126] The term "hydroxyalkyl," as used herein, alone or in combination, refers to a hydroxy group attached to the parent molecular moiety through an alkyl group.
[0127] The term "imino," as used herein, alone or in combination, refers to =N-.
[0128] The term "iminohydroxy," as used herein, alone or in combination, refers to
=N(OH) and =N-O-.
[0129] The phrase "in the main chain" refers to the longest contiguous or adjacent chain of carbon atoms starting at the point of attachment of a group to the compounds of any one of the formulas disclosed herein.
[0130] The term "isocyanato" refers to a -NCO group.
[0131] The term "isothiocyanato" refers to a -NCS group.
[0132] The phrase "linear chain of atoms" refers to the longest straight chain of atoms independently selected from carbon, nitrogen, oxygen and sulfur.
[0133] The term "lower," as used herein, alone or in a combination, where not otherwise specifically defined, containing from 1 to and including 6 carbon atoms.
[0134] The term "lower aryl," as used herein, alone or in combination, means phenyl or naphthyl, which may be optionally substituted as provided.
[0135] The term "lower heteroaryl," as used herein, alone or in combination, means either 1) monocyclic heteroaryl comprising five or six ring members, of which between one and four said members may be heteroatoms chosen from O, S, and N, or 2) bicyclic heteroaryl, wherein each of the fused rings comprises five or six ring members, comprising between them one to four heteroatoms chosen from O, S, and N.
[0136] The term "lower cycloalkyl," as used herein, alone or in combination, means a monocyclic cycloalkyl having between three and six ring members. Lower cycloalkyls may be unsaturated. Examples of lower cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
[0137] The term "lower heterocycloalkyl," as used herein, alone or in combination, means a monocyclic heterocycloalkyl having between three and six ring members, of which between one and four may be heteroatoms chosen from O, S, and N. Examples of lower heterocycloalkyls include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, and morpholinyl. Lower heterocycloalkyls may be unsaturated.
[0138] The term "lower amino," as used herein, alone or in combination, refers to
— NRR , wherein R and R are independently chosen from hydrogen, lower alkyl, and lower heteroalkyl, any of which may be optionally substituted. Additionally, the R and
R' of a lower amino group may combine to form a five- or six-membered heterocycloalkyl, either of which may be optionally substituted.
[0139] The term "mercaptyl" as used herein, alone or in combination, refers to an
RS- group, where R is as defined herein.
[0140] The term "nitro," as used herein, alone or in combination, refers to -NO2.
[0141] The terms "oxy" or "oxa," as used herein, alone or in combination, refer to
-O-.
[0142] The term "oxo," as used herein, alone or in combination, refers to =0.
[0143] The term "perhaloalkoxy" refers to an alkoxy group where all of the hydrogen atoms are replaced by halogen atoms.
[0144] The term "perhaloalkyl" as used herein, alone or in combination, refers to an alkyl group where all of the hydrogen atoms are replaced by halogen atoms.
[0145] The terms "sulfonate," "sulfonic acid," and "sulfonic," as used herein, alone or in combination, refer the -SO3H group and its anion as the sulfonic acid is used in salt formation.
[0146] The term "sulfanyl," as used herein, alone or in combination, refers to -S-. [0147] The term "sulfinyl," as used herein, alone or in combination, refers to
-S(O)-.
[0148] The term "sulfonyl," as used herein, alone or in combination, refers to -
S(O)2-.
[0149] The term "N-sulfonamido" refers to a RS(=O)2NR'- group with R and R' as defined herein.
[0150] The term "S-sulfonamido" refers to a -S(=O)2NRR\ group, with R and R' as defined herein.
[0151] The terms "thia" and "thio," as used herein, alone or in combination, refer to a -S- group or an ether wherein the oxygen is replaced with sulfur. The oxidized derivatives of the thio group, namely sulfinyl and sulfonyl, are included in the definition of thia and thio.
[0152] The term "thiol," as used herein, alone or in combination, refers to an -SH group.
[0153] The term "thiocarbonyl," as used herein, when alone includes thioformyl -
C(S)H and in combination is a -C(S)- group.
[0154] The term "N-thiocarbamyl" refers to an ROC(S)NR'- group, with R and
R' as defined herein.
[0155] The term "O-thiocarbamyl" refers to a -OC(S)NRR', group with R and
R' as defined herein.
[0156] The term "thiocyanato" refers to a -CNS group.
[0157] The term "trihalomethanesulfonamido" refers to a X3CS(O)2NR- group with X is a halogen and R as defined herein.
[0158] The term "trihalomethanesulfonyl" refers to a X3CS(O)2- group where X is a halogen.
[0159] The term "trihalomethoxy" refers to a X3CO- group where X is a halogen.
[0160] The term "trisubstituted silyl," as used herein, alone or in combination, refers to a silicone group substituted at its three free valences with groups as listed herein under the definition of substituted amino. Examples include trimethysilyl, tert- butyldimethylsilyl, triphenylsilyl and the like. [0161] Any definition herein may be used in combination with any other definition to describe a composite structural group. By convention, the trailing element of any such definition is that which attaches to the parent moiety. For example, the composite group alkylamido would represent an alkyl group attached to the parent molecule through an amido group, and the term alkoxyalkyl would represent an alkoxy group attached to the parent molecule through an alkyl group.
[0162] When a group is defined to be "null," what is meant is that said group is absent.
[0163] The term "optionally substituted" means the anteceding group may be substituted or unsubstituted. When substituted, the substituents of an "optionally substituted" group may include, without limitation, one or more substituents independently selected from the following groups or a particular designated set of groups, alone or in combination: lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl, phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester, lower carboxamido, cyano, hydrogen, halogen, hydroxy, amino, lower alkylamino, arylamino, amido, nitro, thiol, lower alkylthio, lower haloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonic acid, trisubstituted silyl, N3, SH, SCH3, C(O)CH3, CO2CH3, CO2H, pyridinyl, thiophene, furanyl, lower carbamate, and lower urea. Two substituents may be joined together to form a fused five-, six-, or seven-membered carbocyclic or heterocyclic ring consisting of zero to three heteroatoms, for example forming methylenedioxy or ethylenedioxy. An optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and monosubstituted (e.g., -CH2CF3). Where substituents are recited without qualification as to substitution, both substituted and unsubstituted forms are encompassed. Where a substituent is qualified as "substituted," the substituted form is specifically intended. Additionally, different sets of optional substituents to a particular moiety may be defined as needed; in these cases, the optional substitution will be as defined, often immediately following the phrase, "optionally substituted with."
[0164] The term R or the term R', appearing by itself and without a number designation, unless otherwise defined, refers to a moiety chosen from hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl and heterocycloalkyl, any of which may be optionally substituted. Such R and R' groups should be understood to be optionally substituted as defined herein. Whether an R group has a number designation or not, every R group, including R, R' and Rn where n=(l, 2, 3, ...n), every substituent, and every term should be understood to be independent of every other in terms of selection from a group. Should any variable, substituent, or term (e.g. aryl, heterocycle, R, etc.) occur more than one time in a formula or generic structure, its definition at each occurrence is independent of the definition at every other occurrence. Those of skill in the art will further recognize that certain groups may be attached to a parent molecule or may occupy a position in a chain of elements from either end as written. Thus, by way of example only, an unsymmetrical group such as -C(O)N(R)- may be attached to the parent moiety at either the carbon or the nitrogen.
[0165] Asymmetric centers exist in the compounds disclosed herein. These centers are designated by the symbols "R" or "S," depending on the configuration of substituents around the chiral carbon atom. It should be understood that the invention encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric, and epimeric forms, as well as d-isomers and 1 -isomers, and mixtures thereof. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art. Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art. Additionally, the compounds disclosed herein may exist as geometric isomers. The present invention includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof. Additionally, compounds may exist as tautomers; all tautomeric isomers are provided by this invention. Additionally, the compounds disclosed herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms.
[0166] The term "bond" refers to a covalent linkage between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure. A bond may be single, double, or triple unless otherwise specified. A dashed line between two atoms in a drawing of a molecule indicates that an additional bond may be present or absent at that position.
[0167] The term "disease" as used herein is intended to be generally synonymous, and is used interchangeably with, the terms "disorder" and "condition" (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.
[0168] The term "combination therapy" means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.
[0169] "GPRl 19 modulator" is used herein to refer to a compound that exhibits an EC50 with respect to GPRl 19 activity of no more than about 100 μM and more typically not more than about 50 μM, as measured in the cAMP production assay and glucagon-like peptide- 1 (GLP-I) secretion assays described generally hereinbelow. "EC50" is that concentration of inhibitor which activates the activity of an enzyme (e.g., GPRl 19) to half-maximal level. Certain compounds disclosed herein have been discovered to exhibit modulatory activity against GPRl 19. In certain embodiments, compounds will exhibit an EC50 with respect to GPRl 19 of no more than about 10 μM; in further embodiments, compounds will exhibit an EC50 with respect to GPRl 19 of no more than about 5 μM; in yet further embodiments, compounds will exhibit an EC50 with respect to GPRl 19 of not more than about 1 μM; in yet further embodiments, compounds will exhibit an EC50 with respect to GPRl 19 of not more than about 200 nM, as measured in the GPRl 19 assay described herein.
[0170] The phrase "therapeutically effective" is intended to qualify the amount of active ingredients used in the treatment of a disease or disorder. This amount will achieve the goal of reducing or eliminating the said disease or disorder. [0171] The term "therapeutically acceptable" refers to those compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
[0172] As used herein, reference to "treatment" of a patient is intended to include prophylaxis. The term "patient" means all mammals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, pigs, and rabbits. Preferably, the patient is a human.
[0173] The term "prodrug" refers to a compound that is made more active in vivo. Certain compounds disclosed herein may also exist as prodrugs, as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley- VHCA, Zurich, Switzerland 2003). Prodrugs of the compounds described herein are structurally modified forms of the compound that readily undergo chemical changes under physiological conditions to provide the compound. Additionally, prodrugs can be converted to the compound by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to a compound when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful because, in some situations, they may be easier to administer than the compound, or parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. A wide variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. An example, without limitation, of a prodrug would be a compound which is administered as an ester (the "prodrug"), but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound.
[0174] The compounds disclosed herein can exist as therapeutically acceptable salts. The present invention includes compounds listed above in the form of salts, including acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable salts may be of utility in the preparation and purification of the compound in question. Basic addition salts may also be formed and be pharmaceutically acceptable. For a more complete discussion of the preparation and selection of salts, refer to Pharmaceutical Salts: Properties, Selection, and Use (Stahl, P. Heinrich. Wiley- VCHA, Zurich, Switzerland, 2002). [0175] The term "therapeutically acceptable salt," as used herein, represents salts or zwitterionic forms of the compounds disclosed herein which are water or oil-soluble or dispersible and therapeutically acceptable as defined herein. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound in the form of the free base with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, phosphonate, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para-toluenesulfonate (p-tosylate), and undecanoate. Also, basic groups in the compounds disclosed herein can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids which can be employed to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. Salts can also be formed by coordination of the compounds with an alkali metal or alkaline earth ion. Hence, the present invention contemplates sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, and the like.
[0176] Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxy group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine. The cations of therapeutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, iV,./V-dimethylaniline, N- methylpiperidine, iV-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, iV,./V-dibenzyrphenethylamine, 1-ephenamine, and iV,./V-dibenzylethylenediamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine. [0177] A salt of a compound can be made by reacting the appropriate compound in the form of the free base with the appropriate acid.
[0178] While it may be possible for the compounds of the subject invention to be administered as the raw chemical, it is also possible to present them as a pharmaceutical formulation. Accordingly, provided herein are pharmaceutical formulations which comprise one or more of certain compounds disclosed herein, or one or more pharmaceutically acceptable salts, esters, prodrugs, amides, or solvates thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., in Remington's Pharmaceutical Sciences. The pharmaceutical compositions disclosed herein may be manufactured in any manner known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes. [0179] The formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal and topical (including dermal, buccal, sublingual and intraocular) administration although the most suitable route may depend upon for example the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Typically, these methods include the step of bringing into association a compound of the subject invention or a pharmaceutically acceptable salt, ester, amide, prodrug or solvate thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
[0180] Formulations of the compounds disclosed herein suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste. [0181] Pharmaceutical preparations which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free- flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses. [0182] The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. [0183] Formulations for parenteral administration include aqueous and nonaqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. [0184] In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
[0185] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner. Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.
[0186] The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.
[0187] Certain compounds disclosed herein may be administered topically, that is by non-systemic administration. This includes the application of a compound disclosed herein externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration. [0188] Formulations suitable for topical administration include liquid or semi- liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient for topical administration may comprise, for example, from 0.001% to 10% w/w (by weight) of the formulation. In certain embodiments, the active ingredient may comprise as much as 10% w/w. In other embodiments, it may comprise less than 5% w/w. In certain embodiments, the active ingredient may comprise from 2% w/w to 5% w/w. In other embodiments, it may comprise from 0.1% to 1% w/w of the formulation.
[0189] Gels for topical or transdermal administration may comprise, generally, a mixture of volatile solvents, nonvolatile solvents, and water. In certain embodiments, the volatile solvent component of the buffered solvent system may include lower (Cl- C6) alkyl alcohols, lower alkyl glycols and lower glycol polymers. In further embodiments, the volatile solvent is ethanol. The volatile solvent component is thought to act as a penetration enhancer, while also producing a cooling effect on the skin as it evaporates. The nonvolatile solvent portion of the buffered solvent system is selected from lower alkylene glycols and lower glycol polymers. In certain embodiments, propylene glycol is used. The nonvolatile solvent slows the evaporation of the volatile solvent and reduces the vapor pressure of the buffered solvent system. The amount of this nonvolatile solvent component, as with the volatile solvent, is determined by the pharmaceutical compound or drug being used. When too little of the nonvolatile solvent is in the system, the pharmaceutical compound may crystallize due to evaporation of volatile solvent, while an excess may result in a lack of bioavailability due to poor release of drug from solvent mixture. The buffer component of the buffered solvent system may be selected from any buffer commonly used in the art; in certain embodiments, water is used. A common ratio of ingredients is about 20% of the nonvolatile solvent, about 40% of the volatile solvent, and about 40% water. There are several optional ingredients which can be added to the topical composition. These include, but are not limited to, chelators and gelling agents. Appropriate gelling agents can include, but are not limited to, semisynthetic cellulose derivatives (such as hydroxypropylmethylcellulose) and synthetic polymers, and cosmetic agents.
[0190] Lotions include those suitable for application to the skin or eye. An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops. Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.
[0191] Creams, ointments or pastes are semi-solid formulations of the active ingredient for external application. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy base. The base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives or a fatty acid such as steric or oleic acid together with an alcohol such as propylene glycol or a macrogel. The formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof. Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.
[0192] Drops may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and, in certain embodiments, including a surface active agent. The resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-1000C for half an hour. Alternatively, the solution may be sterilized by filtration and transferred to the container by an aseptic technique. Examples of bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol. [0193] Formulations for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising the active ingredient in a flavored basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.
[0194] For administration by inhalation, compounds may be conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray. Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compounds according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
[0195] Preferred unit dosage formulations are those containing an effective dose, as herein below recited, or an appropriate fraction thereof, of the active ingredient. [0196] It should be understood that in addition to the ingredients particularly mentioned above, the formulations described above may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents. [0197] Compounds may be administered orally or via injection at a dose of from 0.1 to 500 mg/kg per day. The dose range for adult humans is generally from 5 mg to 2 g/day. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of one or more compounds which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg. [0198] The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
[0199] The compounds can be administered in various modes, e.g. orally, topically, or by injection. The precise amount of compound administered to a patient will be the responsibility of the attendant physician. The specific dose level 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, diets, time of administration, route of administration, rate of excretion, drug combination, the precise disorder being treated, and the severity of the indication or condition being treated. Also, the route of administration may vary depending on the condition and its severity. [0200] In certain instances, it may be appropriate to administer at least one of the compounds described herein (or a pharmaceutically acceptable salt, ester, or prodrug thereof) in combination with another therapeutic agent. By way of example only, if one of the side effects experienced by a patient upon receiving one of the compounds herein is hypertension, then it may be appropriate to administer an anti-hypertensive agent in combination with the initial therapeutic agent. Or, by way of example only, the therapeutic effectiveness of one of the compounds described herein may be enhanced by administration of an adjuvant (i.e., by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Or, by way of example only, the benefit of experienced by a patient may be increased by administering one of the compounds described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit. By way of example only, in a treatment for diabetes involving administration of one of the compounds described herein, increased therapeutic benefit may result by also providing the patient with another therapeutic agent for diabetes. In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient may simply be additive of the two therapeutic agents or the patient may experience a synergistic benefit. [0201] Specific, non-limiting examples of possible combination therapies include use of certain compounds of the invention with agents found in the following pharmacotherapeutic classifications as indicated below. These lists should not be construed to be closed, but should instead serve as illustrative examples common to the relevant therapeutic area at present. Moreover, combination regimens may include a variety of routes of administration and should include oral, intravenous, intraocular, subcutaneous, dermal, and inhaled topical.
[0202] For the treatment of metabolic disorders, compounds disclosed herein may be administered with an agent selected from the group comprising: insulin, insulin derivatives and mimetics, insulin secretagogues, insulin sensitizers, biguanide agents, alpha-glucosidase inhibitors, insulinotropic sulfonylurea receptor ligands, meglitinides, protein tyrosine phosphatase-lB (PTP-IB) inhibitors, GSK3 (glycogen synthase kinase- 3) inhibitors , GLP-I (glucagon like peptide- 1), GLP-I analogs, DPP-IV (dipeptidyl peptidase IV) inhibitors, RXR ligands, sodium-dependent glucose co-transporter (SGLT2) inhibitors, glycogen phosphorylase A inhibitors, an AGE breaker, PPAR modulators, non-glitazone type PPARδ agonist, HMG-CoA reductase inhibitors, cholesterol-lowering drugs and anti-obesity agents.
[0203] For the treatment of metabolic disorders, compounds disclosed herein may be administered with an agent selected from the group comprising: insulin, metformin, Glipizide, glyburide, Amaryl, gliclazide, meglitinides, nateglinide, repaglinide, amylin mimetics (for example, pramlintide), PTP-112, SB-517955, SB-4195052, SB-216763, NN-57-05441, NN-57-05445, GW-0791, AGN-194204, T-1095, BAY R3401, acarbose, miglitol, voglibose, Exendin-4, DPP728, LAF237, vildagliptin , BMS477118, PT-100, GSK-823093, PSN-9301, T-6666, SYR-322, SYR-619, Liraglutide, CJC-1134-PC, naliglutide, MK-0431, saxagliptin, GSK23A, pioglitazone, rosiglitazone, AVE2268, GW869682, GSK189075, GPRl 19 agonists including, but not limited to APD668, PSN-119-1 and PSN-821, HMG-CoA reductase inhibitors (for example, rosuvastatin, atorvastatin, simvastatin, lovastatin, pravastatin, fluvastatin, cerivastatin, rosuvastatin, pitavastatin and like), cholesterol-lowering drugs (for example, fibrates which include: fenofibrate, benzafibrate, clofibrate, gemfibrozil and like; cholesterol absorption inhibitors such as Ezetimibe, eflucimibe and like compounds), cholesterol ester transfer protein inhibitors (for example, CP-529414, CETi-I, JTT-705 and like compounds), bile acid sequestrants (for example, cholestyramine, colestipol, and like compounds), niacin, microsomal triglyceride transfer protein inhibitors (for example, implitapide), insulin signaling pathway modulators, like inhibitors of protein tyrosine phosphatases (PTPases) and inhibitors of glutamine-fructose-6-phosphate amidotransferase (GFAT), inhibitors of glucose-6-phosphatase (G6 Pase), inhibitors of fructose- 1,6- bisphosphatase (F-l,6-BPase), inhibitors of glycogen phosphorylase, glucagon receptor antagonists, inhibitors of phosphoenolpyruvate carboxylase (PEPCK), inhibitors of pyruvate dehydrogenase kinase, activators AMP- activated protein kinase (AMPK), (R)-l-{4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]- benzenesulfonyl}2,3-dihydro-lH-indole-2-carboxylic acid described in the patent application WO 03/043985, as compound 19 of Example 4, and GI-262570. [0204] For the treatment of obesity, compounds disclosed herein may be administered with an agent selected from the group comprising: cholescystokinin-A (CCK-A) agonists, serotonin and norepinephrine reuptake inhibitors (for example sibutramine), dopamine agonists (for example, bromocriptine and like) sympathomimetic agents, β3 adrenergic receptor agonists, leptin, leptin analogues, leptin receptor agonists, galanin antagonists, lipase inhibitors (for example Orlistat), Neuropeptide-Y antagonists, glucocorticoid receptor agonists or antagonists, cannabinoid 1 receptor antagonists (for example, rimonabant and like), ciliary neurotropic factors (CNTF, for example Axokine), human agouti-related proteins (AGRP), ghrelin receptor antagonists, histamine 3 receptor antagonists, appetite suppressants (for example, bupropion), urocortin binding protin antagonists, orexin receptor antagonists, and bombesin agonists.
[0205] For the treatment of inflammatory diseases , compounds disclosed herein may be administered with an agent selected from the group comprising: corticosteroids, non-steroidal antiinflammatories, muscle relaxants and combinations thereof with other agents, anaesthetics and combinations thereof with other agents, expectorants and combinations thereof with other agents, antidepressants, anticonvulsants and combinations thereof; antihypertensives, opioids, topical cannabinoids, and other agents, such as capsaicin. [0206] For the treatment of inflammatory diseases, compounds disclosed herein may be administered with an agent selected from the group comprising: betamethasone dipropionate (augmented and nonaugemnted), betamethasone valerate, clobetasol propionate, prednisone, methyl prednisolone, diflorasone diacetate, halobetasol propionate, amcinonide, dexamethasone, dexosimethasone, fluocinolone acetononide, fluocinonide, halocinonide, clocortalone pivalate, dexosimetasone, flurandrenalide, salicylates, ibuprofen, ketoprofen, etodolac, diclofenac, meclofenamate sodium, naproxen, piroxicam, celecoxib, cyclobenzaprine, baclofen, cyclobenzaprine/lidocaine, baclofen/cyclobenzaprine, cyclobenzaprine/lidocaine/ketoprofen, lidocaine, lidocaine/deoxy-D-glucose, prilocaine, EMLA Cream (Eutectic Mixture of Local Anesthetics (lidocaine 2.5% and prilocaine 2.5%), guaifenesin, guaifenesin/ketoprofen/cyclobenzaprine, amitryptiline, doxepin, desipramine, imipramine, amoxapine, clomipramine, nortriptyline, protriptyline, duloxetine, mirtazepine, nisoxetine, maprotiline, reboxetine, fluoxetine, fluvoxamine, carbamazepine, felbamate, lamotrigine, topiramate, tiagabine, oxcarbazepine, carbamezipine, zonisamide, mexiletine, gabapentin/clonidine, gabapentin/carbamazepine, carbamazepine/cyclobenzaprine, antihypertensives including clonidine, codeine, loperamide, tramadol, morphine, fentanyl, oxycodone, hydrocodone, levorphanol, butorphanol, menthol, oil of wintergreen, camphor, eucalyptus oil, turpentine oil; CB1/CB2 ligands, acetaminophen, infliximab; n) nitric oxide synthase inhibitors, particularly inhibitors of inducible nitric oxide synthase; anti-TNFα agents including, but not limited to etanerecept and infliximab, and other agents, such as capsaicin.
[0207] In any case, the multiple therapeutic agents (at least one of which is a compound disclosed herein) may be administered in any order or even simultaneously. If simultaneously, the multiple therapeutic agents may be provided in a single, unified form, or in multiple forms (by way of example only, either as a single pill or as two separate pills). One of the therapeutic agents may be given in multiple doses, or both may be given as multiple doses. If not simultaneous, the timing between the multiple doses may be any duration of time ranging from a few minutes to four weeks. [0208] Thus, in another aspect, certain embodiments provide methods for treating GPRl 19-mediated disorders in a human or animal subject in need of such treatment comprising administering to said subject an amount of a compound disclosed herein effective to reduce or prevent said disorder in the subject, in combination with at least one additional agent for the treatment of said disorder that is known in the art. In a related aspect, certain embodiments provide therapeutic compositions comprising at least one compound disclosed herein in combination with one or more additional agents for the treatment of GPRl 19-mediated disorders.
[0209] Specific diseases to be treated by the compounds, compositions, and methods disclosed herein include: diabetes (type I and type II) and conditions associated with diabetic diseases which include, but are not limited to, hyperglycemia, hyperlipidemia, hyperinsulinemia, insulin resistance, inadequate glucose tolerance, impaired glucose metabolism, diabetic nephropathy, glomerulosclerosis, diabetic neuropathy, erectile dysfunction, macular degeneration, diabetic retinopathy, chronic microvascular complications, peripheral vascular disease, cataracts, stroke, foot ulcerations, renal failure, kidney disease, ketosis, metabolic acidosis, and related disorders, obesity, myocardial infarction, angina pectoris, coronary artery disease, atherosclerosis, cardiac hypertrophy, allergic diseases, fatty liver disease, nonalcoholic steatohepatitis, liver fibrosis, kidney fibrosis, anorexia nervosa, bulimia vervosa, autoimmune diseases, inflammatory diseases including rheumatoid arthritis, asthma, chronic obstructive pulmonary disease (COPD), psoriasis, ulcerative colitis, proliferative disorders, infectious diseases, angiogenic disorders, reperfusion/ischemia in stroke, vascular hyperplasia, organ hypoxia, cardiac hypertrophy, thrombin-induced platelet aggregation, and conditions associated with prostaglandin endoperoxidase synthetase-2 (COX-2).
[0210] In certain embodiments, the disease is obesity and the effects to be achieved in a human or animal patient include decreasing body weight and controlling weight gain.
[0211] In addition, topical application of GPRl 19 agonists might be useful for the treatment of cellulite and other cosmetic conditions which are characterized by subcutaneous fat accumulation. [0212] In certain embodiments, the disease is associated with perturbed bile acid metabolism, including, but not limited to gall bladder stones, cholecystitis, cholangitis, choledocholithiasis, jaundice, and obstetric cholestasis and the itch associated with it. [0213] Metabolic diseases other than Type 1 and Type 2 diabetes which may be treated or prevented include, without limitation, metabolic syndrome and insulin resistance. In addition, the compounds disclosed herein can be used to treat insulin resistance and other metabolic disorders such as atherosclerosis that are typically associated with an exaggerated inflammatory signaling.
[0214] In certain embodiments, the disease is a hyperproliferative condition of the human or animal body, including, but not limited to restenosis, inflammation, immune disorders, cardiac hypertrophy, atherosclerosis, pain, migraine, angiogenesis-related conditions or disorders, proliferation induced after medical conditions, including but not limited to surgery, angioplasty, or other conditions.
[0215] The compounds disclosed herein may be useful as anti- inflammatory agents with the additional benefit of having significantly less harmful side effects. The compositions may be used to treat arthritis, including but not limited to rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis, acute rheumatic arthritis, enteropathic arthritis, neuropathic arthritis, psoriatic arthritis, and pyogenic arthritis. The compositions may also be used in the treatment of pulmonary inflammation, such as that associated with viral infections and cystic fibrosis. In certain embodiments, the particular inflammatory disease is rheumatoid arthritis.
[0216] Further inflammatory diseases which may be prevented or treated include, without limitation: asthma, allergies, respiratory distress syndrome or acute or chronic pancreatitis. Furthermore, respiratory system diseases may be prevented or treated including but not limited to chronic obstructive pulmonary disease, pulmonary fibrosis, ulcerative colitis, inflammatory bowel disease, Crohn's disease, peptic ulceration, gastritis, psoriasis, and skin inflammation.
[0217] In certain embodiments, the disease to be treated by the methods provided herein may be an ophthalmologic disorder. Ophthalmologic diseases and other diseases in which angiogenesis plays a role in pathogenesis, may be treated or prevented and include, without limitation, dry eye (including Sjogren's syndrome), macular degeneration, closed and wide angle glaucoma, retinal ganglion degeneration, occular ischemia, retinitis, retinopathies, uveitis, ocular photophobia, and of inflammation and pain associated with acute injury to the eye tissue. In certain embodiments, the ophthalmologic disease to be treated is glaucomatous retinopathy and/or diabetic retinopathy. In certain embodiments, the ophthalmologic condition to be treated is post-operative inflammation or pain as from ophthalmic surgery such as cataract surgery and refractive surgery.
[0218] In certain embodiments, the disease to be treated by the methods provided herein may be an autoimmune disease. Autoimmune diseases which may be prevented or treated include, but are not limited to: rheumatoid arthritis, inflammatory bowel disease, inflammatory pain, ulcerative colitis, Crohn's disease, periodontal disease, temporomandibular joint disease, multiple sclerosis, diabetes, glomerulonephritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Grave's disease, hemolytic anemia, autoimmune gastritis, autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, myasthenia gravis, atopic dermatitis, graft vs. host disease, and psoriasis. Inflammatory diseases which may be prevented or treated include, but are not limited to: asthma, allergies, respiratory distress syndrome or acute or chronic pancreatitis. In certain embodiments, the particular autoimmune disease is rheumatoid arthritis.
[0219] The compounds provided herein are also useful in treating tissue damage in such diseases as vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, neuromuscular junction disease including myasthenia gravis, white matter disease including multiple sclerosis, sarcoidosis, nephritis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, periodontis, hypersensitivity, swelling occurring after injury, ischemias including myocardial ischemia, cardiovascular ischemia, and ischemia secondary to cardiac arrest, and the like. These compounds can also be used to treat allergic rhinitis, respiratory distress syndrome, endotoxic shock syndrome, and atherosclerosis. [0220] In certain embodiments, the disease to be treated by the methods of the present invention may be a cardiovascular condition. In certain embodiments, said cardiovascular condition is chosen from atherosclerosis, cardiac hypertrophy, idiopathic cardiomyopathies, heart failure, angiogenesis-related conditions or disorders, and proliferation induced after medical conditions, including, but not limited to restenosis resulting from surgery and angioplasty.
[0221] In certain embodiments, the disease to be prevented or treated by the methods of the present invention may be autism.
[0222] Glucose -dependent insulinotropic polypeptide (GIP) knock out mice showed a decreased bone size, lower bone mass (1). In contrast, GIP-overexpressing transgenic mice have increased bone mass compared to control mice (2). In addition, recent data suggested that the glucagone-like peptide- 1 (GLP-I) receptor is essential for control of bone resorption as GLP-IR (-/-) mice have cortical osteopenia and bone fragility (3). Since GPRl 19 agonists increase GLP-I and GIP secretion both in vitro and in vivo, GPRl 19 agonists in this patent might be important for the prevention or treatment of bone loss induced by age or diseases in which the normal functions of osteobalsts or osteoclasts are altered. (Xie D et al. Bone. 2005, 37: 759-769; Ding KH et al. J Bone Miner Res. 2008, 23: 536-543; Yamada C et al. Endocrinology. 2008, 149:574-9.) Such diseases include, for example, osteopenia and osteoporosis. [0223] Besides being useful for human treatment, certain compounds and formulations disclosed herein may also be useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.
[0224] All references, patents or applications, U.S. or foreign, cited in the application are hereby incorporated by reference as if written herein in their entireties. Where any inconsistencies arise, material literally disclosed herein controls. [0225] The invention is further illustrated by the following Examples 1-15, set forth below, which can be prepared by methods known in the art and/or by variations on the method outlined below. All IUPAC nomenclature was generated using CambridgeSoft's ChemDraw 10.0. General Synthetic Methods for Preparing Compounds
[0226] The following schemes can be used to practice the present invention.
[0227] Scheme 1
Figure imgf000051_0001
Reagents: (a) NaH, DMF, 1000C, 4 h. (b) Pd(PPh3)4, Cs2CO3, toluene/H2O, 1000C, 18 h. (c) n-BuLi, triisopropyl borate, THF, -800C, 1 h. (d) Acetyl chloride, DCM/MeOH (5:1), 00C to 25°C, 1.5 h or HCl, Et2O, 25°C, 4 h. (e) DIEA, DCM, 25°C, 2 h. (f) Ar103-X, K2CO3, 1,4-dioxane / H2O, 900C, 3 h. (g) Ar103-X, Cs2CO3, DMF, 100°C, 4 h. [0228] The invention is further illustrated by the following examples.
EXAMPLE 1 4'-(l-(Pyrimidin-2-yl)piperidin-4-yloxy)biphenyl-4-carbonitrile
Figure imgf000052_0001
This compound was purchased from Peakdale Molecular Ltd. (order # 1013265) for uHTS screening.
EXAMPLE 2
2-(4-(4'-(Methoxymethyl)biphenyl-4-yloxy)piperidin-l-yl)pyrimidine
Figure imgf000052_0002
This compound was purchased from Peakdale Molecular Ltd. (order # 1013417) for uHTS screening. EXAMPLE 3
N,N-Dimethyl-5-(4-(l-(pyrimidin-2-yl)piperidin-4-yloxy)phenyl)pyridin-2-amine
Figure imgf000053_0001
This compound was purchased from Peakdale Molecular Ltd. (order # 1013379) for uHTS screening.
EXAMPLE 4
4'-(l-(4-Methoxypyrimidin-2-yl)piperidin-4-yloxy)biphenyl-4-carbonitrile
Figure imgf000053_0002
This compound was purchased from Peakdale Molecular Ltd. (order # 1013266) for uHTS screening.
EXAMPLE 5
5-Ethyl-2-(4-(2'-fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yloxy)piperidin-l- yl)pyrimidine
Figure imgf000054_0001
Step 1: l-(4-Bromo-3-fluorophenyl)-lH-tetrazole
Figure imgf000054_0002
To a solution of 4-bromo-3-fluoroaniline (10.0 g, 52.63 mmol) in AcOH (30 niL), was placed NaN3 (4.1 g, 63.08 mmol) and triethoxymethane (11.7 g, 79.05 mmol). The mixture was stirred at 900C for 3 h until the starting material was completely consumed. The reaction mixture was cooled to 25°C and iced water (300 mL) was added. The precipitate was filtered and dried to give l-(4-bromo-3-fluorophenyl)-lH- tetrazole as a light yellow solid.
Step 2: tert-Butyl 4-(4-bromophenoxy)piperidine-l-carboxylate
Figure imgf000054_0003
To a solution of tert-butyl 4-hydroxypiperidine-l-carboxylate (5.22 g, 25.97 mmol) in DMF (150 mL) were added NaH (1.40 g, 60%) and l-bromo-4-fluorobenzene (6.03 g, 34.66 mmol). The mixture was stirred for 4 h at 1000C and concentrated under vacuum. The resulting residue was dissolved in EtOAc (300 rnL) and the organic layer was washed with brine (2x100 rnL), dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified on silica gel column (ethyl acetate/hexane =1/50-1/10) to afford tert-butyl 4-(4-bromophenoxy)piperidine-l-carboxylate as a white solid.
Step 3: 4-(l-(tert-Butoxycarbonyl)piperidin-4-yloxy)phenylboronic acid
Figure imgf000055_0001
n-BuLi (0.81 mL, 2.5M) was added to a solution of tert-butyl 4- (4- bromophenoxy)piperidine-l-carboxylate (600 mg, 1.69 mmol) and triisopropyl borate (350 mg, 1.86 mmol) in THF (30 mL), cooled to -800C under N2 atmosphere. The mixture was stirred for 1 h at -800C and then was quenched with aqueous HCl (IN, 0.15 mL) to adjust the pH value to 5-6. The solution was concentrated under vacuum. The residue was extracted with EtOAc (3x20 mL). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated to give 4-(l-(tert- butoxycarbonyl)piperidin-4-yloxy)phenylboronic acid as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 7.85 (s, 2H), 7.75 (m, 2H), 6.95 (m, 2H), 4.60 (m, IH), 3.65 (m, 2H), 3.18 (m, 2H), 1.95 (m, 2H), 1.52 (m, 2H), 1.42 (s, 9H).
Step 4: tert-butyl 4-(2'-fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yloxy)piperidine-l- carboxylate
Figure imgf000055_0002
A mixture of 4-(l-(tert-butoxycarbonyl)piperidin-4-yloxy)phenylboronic acid (100 mg, 0.31 mmol), l-(4-bromo-3-fluorophenyl)-lH-tetrazole (75 mg, 0.31 mmol), Cs2CO3 (101 mg, 0.31 mmol), Pd(PPh3)4 (36 mg, 0.03 mmol) and water (1 mL) in toluene (10 mL) was heated to 1000C for 4 h. The solution was concentrated under vacuum and the residue was dissolved in EtOAc (30 mL). The precipitate was filtered and the filtrate was concentrated under vacuum. The crude product was recrystallized from PE/EA (2:1) to afford tert-butyl 4-(2'-fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4- yloxy)piperidine-l-carboxylate as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.17 (s, IH), 8.02 (d, IH), 7.99-7.78 (m, 2H), 7.56 (m, 2H), 7.13 (d, 2H), 4.67 (m, IH), 3.68 (m, 2H), 3.22 (m, 2H), 1.97 (m, 2H), 1.56 (m, 2H), 1.42 (9H, s).
Step 5: 4-(2'-Fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yloxy)piperidine hydrochloride
Figure imgf000056_0001
To a solution of tert-butyl 4-(2'-fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4- yloxy)piperidine-l-carboxylate (1.51 g, 3.44 mmol) in DCM / MeOH (5:1) (60 mL) was added acetyl chloride (20 mL) dropwise at 00C. The mixture was stirred for 1.5 h at 25°C and then concentrated under vacuum. The resulting solid was filtered, washed with CH2Cl2(2xl0 mL) and dried to afford 4-(2'-fluoro-4'-(lH-tetrazol-l-yl)biphenyl- 4-yloxy)piperidine hydrochloride as a white solid. LCMS: 340 (M+H)+.
Step 6: 5-Ethyl-2-(4-(2'-fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yloxy)piperidin-l- yl)pyrimidine
Figure imgf000057_0001
A mixture of 4-(2'-fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yloxy)piperidine hydrochloride (270 mg, 0.72 mmol), K2CO3 (199 mg, 1.44 mmol), water (1.2 niL), and 2-chloro-5-ethylpyrimidine (107 mg, 0.75 mmol) in 1,4-dioxane (12 mL) was heated to 900C for 3 h. After cooling to 25°C, the mixture was concentrated under vacuum. The resulting residue was purified on silica gel column (PE:EA=10: 1-3: 1-5:4) to afford 5- ethyl-2-(4-(2'-fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yloxy)piperidin-l-yl)pyrimidine was obtained as a white solid. 1H NMR (400 MHz, DMSOd6) δ 10.15 (s, IH), 8.25 (s, 2H), 7.98 (d, IH), 7.79-7.87 (m, 2H), 7.56 (d, 2H), 7.14 (d, 2H), 4.74 (m, IH), 4.20 (m, 2H), 3.50 (m, 2H), 2.43 (m, 2H), 2.01 (m, 2H), 1.60 (m, 2H), 1.08 (t, 3H). LCMS: 446 (M+H)+.
EXAMPLE 6
5-Ethyl-2-(4-(2'-fluoro-4'-(methylsulfonyl)biphenyl-4-yloxy)piperidin-l- yl)pyrimidine
Figure imgf000057_0002
Step 1: l-Bromo-2-fluoro-4-(methylsulfonyl)benzene
Figure imgf000058_0001
A mixture of 2-fluoro-4-(methylsulfonyl)benzenamine (5 g, 26.0 mmol), CuBr (7.5 mg, 0.05 mmol), and t-BuONO (13.6 g, 132.0 mmol) in CH3CN (150 mL) was refluxed for 3 h. The resulting mixture was concentrated under vacuum. The residue was dissolved in 200 mL of EtOAc. The resulting mixture was washed with H2O (3x100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum to afford l-bromo-2-fluoro-4-(methylsulfonyl)benzene as a light yellow solid.
Step 2: tert-Butyl 4-(2'-fluoro-4'-(methylsulfonyl)biphenyl-4-yloxy)piperidine-l- carboxylate
Figure imgf000058_0002
The title compound was synthesized as described in EXAMPLE 1, Step 4 using 4-(l- (tert-butoxycarbonyl)piperidin-4-yloxy)phenylboronic acid and l-bromo-2-fluoro-4- (methylsulfonyl)benzene as the starting materials.
Step 3: 4-(2'-Fluoro-4'-(methylsulfonyl)biphenyl-4-yloxy)piperidine hydrochloridex
Figure imgf000058_0003
HCl (36%) (2 niL) was added to a solution of tert-butyl 4-(2'-fluoro-4'- (methylsulfonyl)biphenyl-4-yloxy)piperidine-l-carboxylate (590 mg, 1.31 mmol,) in 1,4-dioxane (10 niL). The resulting solution was stirred at 25°C for 30 min. The resulting mixture was concentrated under vacuum and the residue was washed with EtOAc (2x10 rnL) to afford 200 mg (38%) of 4-(2'-fluoro-4'-(methylsulfonyl)biphenyl- 4-yloxy)piperidine hydrochloride as a white solid.
Step 4: 5-Ethyl-2-(4-(2'-fluoro-4'-(methylsulfonyl)biphenyl-4-yloxy)piperidin-l- yl)pyrimidine
Figure imgf000059_0001
A mixture of 4-(2'-fluoro-4'-(methylsulfonyl)biphenyl-4-yloxy)piperidine hydrochloride (200 mg, 0.49 mmol,), 2-chloro-5-ethylpyrimidine (70 mg, 0.49 mmol), and Cs2CO3 (322 mg, 0.99 mmol) in DMF (20 mL) was heated to 1000C for 4 h. The resulting mixture was concentrated under vacuum and the residue was diluted with 50 mL of EtOAc and washed with brine (2x20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with EtOAc/hexanes (1:20-1:5) to afford 5-ethyl-2-(4-(2'- fluoro-4'-(methylsulfonyl)biphenyl-4-yloxy)piperidin-l-yl)pyrimidine as a white solid. LCMS: 456 (M+H)+. EXAMPLE 7
5-Ethyl-2-(4-(4-(2-methyl-6-(lH-l,2,4-triazol-l-yl)pyridin-3-yl)phenoxy)piperidin- l-yl)pyrimidine
Figure imgf000060_0001
3-Bromo-2-methyl-6-(lH-l,2,4-triazol-l-yl)pyridine
Figure imgf000060_0002
A mixture of 3-bromo-6-chloro-2-methyrpyridine (10.3 g, 50.00 mmol), 1H-1,2,4- triazole (5.18 g, 75.07 mmol), and K2CO3 (10.35 g, 75.00 mmol) in DMF (80 mL) was heated to 1200C for 18 h. The resulting solution was diluted with H2O (200 mL) then filtered. The solid was washed with H2O(3x30 mL) and dried to afford 3-bromo-2- methyl-6-(lH-l,2,4-triazol-l-yl)pyridine as a yellow solid. LCMS: 239 (M+H)+.
Step 2: 2-Methyl-3-(4-(piperidin-4-yloxy)phenyl)-6-(lH-l,2,4-triazol-l-yl)pyridine hydrochloride
Figure imgf000060_0003
The title compound was synthesized as described for EXAMPLE 5, Steps 4 and 5 using 4-(l-(tert-butoxycarbonyl)piperidin-4-yloxy)phenylboronic acid and 3-bromo-2- methyl-6-(lH-l,2,4-triazol-l-yl)pyridine in Step 4 and tert-butyl 4-(4-(2-methyl-6-(lH- l,2,4-triazol-l-yl)pyridin-3-yl)phenoxy)piperidine-l-carboxylate in Step 5. LCMS:
336 (M+H)+.
Step 3: 5-Ethyl-2-(4-(4-(2-methyl-6-(lH-l,2,4-triazol-l-yl)pyridin-3- yl)phenoxy)piperidin-l-yl)pyrimidine
Figure imgf000061_0001
A mixture of 2-methyl-3-(4-(piperidin-4-yloxy)phenyl)-6-(lH-l,2,4-triazol-l- yl)pyridine hydrochloride, 2-chloro-5-ethylpyrimidine (280 mg, 1.96 mmol), and K2CO3 (550 mg, 3.99 mmol) (740 mg, 1.99 mmol) in DMF (10 mL) was heated to 1200C for 3 h. The resulting solution was diluted with H2O (40 mL), extracted with EtOAc (3x50 mL). The organics were combined, washed with brine (100 mL), dried, filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel (EtOAc/PE) to give 5-ethyl-2-(4-(4-(2-methyl-6-(lH- l,2,4-triazol-l-yl)pyridin-3-yl)phenoxy)piperidin-l-yl)pyrimidine as a white solid. LCMS: 442 (M+H)+.
EXAMPLE 8 4-Chloro-2-(4-(2'-fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yloxy)piperidin-l- yl)pyrimidine
Figure imgf000062_0001
The title compound was synthesized as one regioisomer as described for EXAMPLE 5, Step 5 using 4-(2'-fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yloxy)piperidine hydrochloride and 2,4-dichloropyrimidine as the starting materials. 1H NMR (400 MHz, DMSOd6) δ 10.15 (s, IH), 8.30 (d, IH), 7.97 (dd, IH), 7.86-7.77 (m, 2H), 7.55 (d, 2H), 7.13 (d, 2H), 6.71 (d, IH), 4.77 (m, IH), 4.13 (m, 2H), 3.59 (m, 2H), 2.02 (m, 2H), 1.65 (m, 2H). LCMS: 452 (M+H)+.
EXAMPLE 9
2-Chloro-4-(4-(2'-fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yloxy)piperidin-l- yl)pyrimidine
Figure imgf000062_0002
The title compound was synthesized as the other regioisomer as described for EXAMPLE 5, Step 5 using 4-(2'-fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4- yloxy)piperidine hydrochloride and 2,4-dichloropyrimidine as the starting materials. 1H NMR (400 MHz, DMSOd6) δ 10.15 (s, IH), 8.06 (d, IH), 7.98 (dd, IH), 7.87-7.77 (m, 2H), 7.57 (d, 2H), 7.14 (d, 2H), 6.88 (d, IH), 4.77 (m, IH), 3.99 (m, 2H), 3.55 (m, 2H), 2.02 (m, 2H), 1.69 (m, 2H). LCMS: 452 (M+H)+.
EXAMPLE 10 tert-Butyl 4-(4'-cyanobiphenyl-4-yloxy)piperidine-l-carboxylate
Figure imgf000063_0001
Step 1: tert-Butyl 4-(4-bromophenoxy)piperidine-l-carboxylate
Figure imgf000063_0002
To a solution of tert-butyl 4-hydroxypiperidine-l-carboxylate (5.22 g, 25.97 mmol) in DMF (150 niL) were added NaH (1.40 g, 60%) and l-bromo-4-fluorobenzene (6.03 g, 34.66 mmol). The mixture was stirred for 4 h at 1000C and concentrated under vacuum. The resulting residue was dissolved in EtOAc (300 mL) and the organic layer was washed with brine (2x100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel column (EtOAc/hexanes) to afford tert-butyl 4-(4-bromophenoxy)piperidine- 1-carboxylate as a white solid. tert-Butyl 4-(4'-cyanobiphenyl-4-yloxy)piperidine-l-carboxylate
Figure imgf000064_0001
A mixture of tert-butyl 4-(4-bromophenoxy)piperidine-l-carboxylate (710 mg, 2.00 mmol), 4-cyanophenylboronic acid (294 mg, 2.00 mmol), Pd(PPh3)4 (230 mg, 0.20 mmol), and Cs2CO3 (652 mg, 2.00 mmol) in toluene/H2O (10:1, 33 mL) was stirred at 100 C for 18 h. The resulting mixture was concentrated under vacuum and the residue was dissolved in EtOAc (100 mL). The organic layer was washed with brine (2x50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel (EtO Ac/petroleum ether) to afford tert-butyl 4-(4'-cyanobiphenyl-4-yloxy)piperidine-l-carboxylate as a white solid. LCMS: 279 (M+H-BOC)+.
EXAMPLE 11
Tert-butyl 4-(2'-fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yloxy)piperidine-l- carboxylate
Figure imgf000064_0002
l-(4-Bromo-3-fluorophenyl)-lH-tetrazole
Figure imgf000064_0003
To a solution of 4-bromo-3-fluoroaniline (10.0 g, 52.63 mmol) in AcOH (30 niL), was placed NaN3 (4.1 g, 63.08 mmol) and triethoxymethane (11.7 g, 79.05 mmol). The mixture was stirred at 900C for 3 h until the starting material was completely consumed. The reaction mixture was cooled to 25°C and ice water (300 mL) was added. The precipitate was filtered and dried to give l-(4-bromo-3-fluorophenyl)-lH- tetrazole as a light yellow solid.
4-(l-(tert-Butoxycarbonyl)piperidin-4-yloxy)phenylboronic acid
Figure imgf000065_0001
n-BuLi (0.81 mL, 2.5M) was added to a solution of tert-butyl 4- (4- bromophenoxy)piperidine-l-carboxylate (600 mg, 1.69 mmol) and triisopropyl borate (350 mg, 1.86 mmol) in THF (30 mL), cooled to -800C under N2 atmosphere. The mixture was stirred for 1 h at -800C and then was quenched with aqueous HCl (IN, 0.15 mL) to adjust the pH value to 5-6. The solution was concentrated under vacuum. The residue was extracted with EtOAc (3x20 mL). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated to give 4-(l-(tert- butoxycarbonyl)piperidin-4-yloxy)phenylboronic acid as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 7.85 (s, 2H), 7.75 (m, 2H), 6.95 (m, 2H), 4.60 (m, IH), 3.65 (m, 2H), 3.18 (m, 2H), 1.95 (m, 2H), 1.52 (m, 2H), 1.42 (s, 9H).
Step 3: tert-butyl 4-(2'-fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yloxy)piperidine-l- carboxylate
Figure imgf000065_0002
A mixture of 4-(l-(tert-butoxycarbonyl)piperidin-4-yloxy)phenylboronic acid (100 mg, 0.31 mmol), l-(4-bromo-3-fluorophenyl)-lH-tetrazole (75 mg, 0.31 mmol), Cs2CO3 (101 mg, 0.31 mmol), Pd(PPh3)4 (36 mg, 0.03 mmol) and water (1 mL) in toluene (10 mL) was heated to 1000C for 4 h. The solution was concentrated under vacuum and the residue was dissolved in EtOAc (30 mL). The precipitate was filtered and the filtrate was concentrated under vacuum. The crude product was recrystallized from PE/EtOAc (2:1) to afford 91 mg (53%) of tert-butyl 4-(2'-fluoro-4'-(lH-tetrazol-l- yl)biphenyl-4-yloxy)piperidine-l-carboxylate as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.14 (s, IH), 7.98 (d, IH), 7.86-7.76 (m, 2H), 7.56 (d, 2H), 7.11 (d, 2H), 4.64 (m, IH), 3.66 (m, 2H), 3.18 (m, 2H), 1.93 (m, 2H), 1.53 (m, 2H), 1.39 (9H, s).
EXAMPLE 12
Isopropyl 4-(2'-fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yloxy)piperidine-l- carboxylate
Figure imgf000066_0001
Step 1: 4-(2'-Fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yloxy)piperidine hydrochloride
Figure imgf000066_0002
To a solution of tert-butyl 4-(2'-fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4- yloxy)piperidine-l-carboxylate (1.51 g, 3.44 mmol) in DCM / MeOH (5:1) (60 mL) was added acetyl chloride (20 mL) dropwise at 00C. The mixture was stirred for 1.5 h at 25°C and then concentrated under vacuum. The resulting solid was filtered, washed with DCM (2x10 rnL) and dried to afford of 4-(2'-fluoro-4'-(lH-tetrazol-l-yl)biphenyl- 4-yloxy)piperidine hydrochloride as a white solid. LCMS: 340 (M+H)+.
Step 2: Isopropyl 4-(2'-fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yloxy)piperidine-l- carboxylate
Figure imgf000067_0001
A mixture of 4-(2'-fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yloxy)piperidine hydrochloride (175 mg, 0.48 mmol) and DIEA (0.17 mL, 1.03 mmol) in DCM (10 mL) was cooled to 00C. Isopropyl carbonochloridate (IM in toluene, 0.7 mL, 0.7 mmol) was then added dropwise and the resulting mixture was stirred at 25°C for 2 h. The solvent was removed and the residue was purified by column chromatography on silica gel to afford isopropyl 4-(2'-fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yloxy)piperidine-l- carboxylate as a white solid. 1H NMR (400 MHz, DMSOd6) δ 10.14 (s, IH), 7.97 (dd, IH), 7.86-7.76 (m, 2H), 7.54 (d, 2H), 7.11 (d, 2H), 4.76 (m, IH), 4.65 (m, IH), 3.68 (m, 2H), 3.23 (m, 2H), 1.94 (m, 2H), 1.56 (m, 2H), 1.17 (d, 6H).
EXAMPLE 13 tert-Butyl 4-(4-((2-fluoro-4-(methylsulfonyl)phenylamino)methyl) phenoxy)piperidine-l-carboxylate
Figure imgf000067_0002
Step 1: tert-Butyl 4-(4-formylphenoxy)piperidine-l-carboxylate
Figure imgf000068_0001
n-BuLi (40 niL, 2.00 equiv) was added dropwise to a solution of tert-butyl 4-(4- bromophenoxy) piperidine-1-carboxylate (20 g, 56.2 mmol) in THF (500 niL) cooled to -78°C and it was stirred for 30 min at this temperature. To this was added ethyl formate (20 g, 270 mmol) and the resulting solution was stirred for 30 min at -78°C. The reaction was then quenched by the addition of aqueous NH4Cl (100 mL) and the aqueous layer was extracted with EtOAc (3 x 100 mL). The organics were combined, dried, filtered, and the residue was purified by silica gel chromatography (EtOAc/PE) to afford tert-butyl 4-(4-formylphenoxy) piperidine-1-carboxylate as a yellow oil.
Step 2: tert-Butyl 4-(4-(hydroxymethyl)phenoxy)piperidine-l-carboxylate
Figure imgf000068_0002
A mixture of tert-butyl 4-(4-formylphenoxy)piperidine-l-carboxylate (3 g, 9.8 mmol) and NaBH4 (700 mg, 18.4 mmol) in MeOH (50 mL) was stirred at rt for 30 min. The reaction was then quenched by the addition of H2OACe (30 mL) and the aqueous layer was extracted with EtOAc (3 x 30 mL). The organics were combined, dried, and concentrated under reduced pressure to afford tert-butyl 4-(4-(hydroxymethyl) phenoxy)piperidine-l-carboxylate as a white solid. Step 3: tert-Butyl 4-(4-(bromomethyl)phenoxy)piperidine-l-carboxylate
Figure imgf000069_0001
A mixture of tert-butyl 4-(4-(hydroxymethyl)phenoxy)piperidine-l-carboxylate (6 g, 19.5 mmol), CBr4 (8 g, 24.49 mmol), and PPh3 (6.6 g, 25.2 mmol) in DCM (50 niL) was stirred at rt for 1 h. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (EtOAc/PE) to afford tert-butyl 4-(4- (bromomethyl)phenoxy)piperidine-l-carboxylate as a white solid.
Step 4: tert-Butyl 4-(4-((2-fluoro-4-(methylsulfonyl)phenylamino)methyl) phenoxy)piperidine-l-carboxylate
Figure imgf000069_0002
Sodium hydride (424 mg, 17.7 mmol) was added to a solution of 2-fluoro-4- (methylsulfonyl)aniline (1 g, 4.88 mmol) in DMF (50 mL) and the mixture was stirred at rt for 1 h. This was followed by the addition tert-butyl 4-(4-(bromomethyl) phenoxy)piperidine-l-carboxylate (976 mg, 2.6 mmol) and the mixture was stirred at rt for an additional 1 h. The reaction was then diluted with H2O (100 mL) and the aqueous layer was extracted with EtOAc (3 x 100 mL). The organics were combined, dried, concentrated under reduced pressure, and the residue was purified by silica gel chromatography (EtOAc/PE) to afford tert-butyl 4-(4-((2-fluoro-4-(methylsulfonyl) phenylamino)methyl)phenoxy)piperidine-l-carboxylate as a yellow solid. LCMS: 379 (M-Boc+H)+. EXAMPLE 14 N-(4-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yloxy)benzyl)-2-fluoro-4-
(methylsulfonyl)aniline
Figure imgf000070_0001
The title compound was synthesized as described in EXAMPLE 5 using tert-butyl 4- (4-((2-fluoro-4-(methylsulfonyl)phenylamino)methyl) phenoxy)piperidine-l- carboxylate in Step 5 and 2-fluoro-4-(methylsulfonyl)-N-(4-(piperidin-4- yloxy)benzyl)aniline in Step 6. 1H NMR (300 MHz, DMSOd6) δ 8.25 (s, 2H), 7.53 (d, IH), 7.43 (d, IH), 7.26 (m, 3H), 6.97-6.91 (m, 2H), 6.75 (m, IH), 4.60 (m, IH), 4.36 (d, 2H), 4.20-4.15 (m, 2H), 3.49-3.36 (m, 2H), 3.09 (s, 3H), 2.51-2.39 (m, 2H), 1.97- 1.94 (m, 2H), 1.58-1.50 (m, 2H), 1.12 (t, 3H). LCMS: 485 (M+H)+.
EXAMPLE 15
4-(l-(5-ethylpyrimidin-2-yl)piperidin-4-yloxy)-N-(2-fluoro-4-(methylsulfonyl) phenyl)benzamide
Figure imgf000070_0002
Step 1: tert-Butyl 4-(4-(Ethoxycarbonyl)phenoxy)piperidine-l-carboxylate
Figure imgf000071_0001
A mixture of ethyl 4-hydroxybenzoate (16.6 g, 100 mmol), PPh3 (39.3 g, 150 mmol), and tert-butyl 4-hydroxypiperidine-l-carboxylate (30.15 g, 150 mmol) in THF (400 mL) was stirred at 00C for 2 h. DEAD (26.1 g, 150 mmol) was then added and the resulting mixture was stirred at rt for 18 h. The reaction mixture was diluted with EtOAc (500 mL) and it was washed with NaHCO3 (200 mL) and brine (brine). The organic layer was dried, concentrated under reduced pressure, and the residue was purified by silica gel chromatography (EtOAc/PE) to afford tert-butyl 4- (4- (ethoxycarbonyl)phenoxy)piperidine-l-carboxylate as a white solid.
Step 2: Ethyl 4-(l-(5-ethylpyrimidin-2-yl)piperidin-4-yloxy)benzoate
Figure imgf000071_0002
The title compound was synthesized as described in EXAMPLE 5 using tert-butyl 4- (4-(ethoxycarbonyl)phenoxy)piperidine-l-carboxylate in Step 5 and ethyl 4-(piperidin- 4-yloxy)benzoate in Step 6. Step 3: 4-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yloxy)benzoic acid
Figure imgf000072_0001
A mixture of ethyl 4-(l-(5-ethylpyrimidin-2-yl) piperidin-4-yloxy) benzoate (6.0 g, 16.9 mmol) and KOH (12 g, 175.7 mmol) in MeOH/H2O (100/5 niL) was stitrred at rt for 18 h. The pH value of the solution was adjusted to 3 with HCl (5 % aq. solution) and the aqueous layer was extracted with DCM (3 x 100 rnL). The organics were combined, dried, and concentrated under reduced pressure to afford 4-(l-(5- ethylpyrimidin-2-yl) piperidin-4-yloxy)benzoic acid as a white solid.
Step 4: 4-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yloxy)benzoyl chloride
Figure imgf000072_0002
Oxalyl chloride (470 mg, 3.73 mmol) was added to a solution of 4-(l-(5- ethylpyrimidin-2-yl)piperidin-4-yloxy)benzoic acid (800 mg, 2.45 mmol) and DMF (0.1 mL) in DCM (30 mL) and the resulting mixture was stirred at rt for 18 h. The solvent was removed under reduced pressure to give 4-(l-(5-ethylpyrimidin-2- yl)piperidin-4-yloxy)benzoyl chloride as a white solid. Step 5: 4-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yloxy)-N-(2-fluoro-4- (methylsulfonyl)phenyl)benzamide
Figure imgf000073_0001
4-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yloxy)benzoyl chloride (840 mg, 2.4 mmol) in DCM (50 niL) was added to a solution of 2-fluoro-4-(methylsulfonyl)benzenamine (460 mg, 2.4 mmol) and TEA (296 mg, 2.9 mmol) in THF (50 mL) maintained at 00C and the resulting mixture was heated to 700C for 18 h. The solvents were removed under reduced pressure and the residue was purified by reverse phase chromatography (ACN/H2O:TFA) to afford 4-(l-(5-ethylpyrimidin-2-yl) piperidin-4-yloxy)-N-(2- fluoro-4-(methylsulfonyl)phenyl)benzamide as a white solid. 1H NMR (300 MHz, DMSOd6) δ 10.31 (s, IH), 8.28 (s, 2H), 8.00 (m, 3H), 7.91-7.79 (m, 2H), 7.16 (m, 2H), 4.84 (s, IH), 4.21 (s, 2H), 3.52 (s, 3H), 3.36-3.31 (m, 2H), 2.52-2.44 (m, 2H), 2.02 (m, 2H), 1.63 (m, 2H), 1.25-1.15 (t, 3H). LCMS: 499 (M+H)+.
EXAMPLE 16
5-Fluoro-2-(4-(2'-fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yloxy)piperidin-l- yl)pyrimidine
Figure imgf000073_0002
The title compound was synthesized as described for EXAMPLE 5, Step 5 using 4-(2'- fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yloxy)piperidine hydrochloride and 2-chloro-5- fluoropyrimidine as the starting materials. 1H NMR (400 MHz, DMSOd6) δ 10.15 (s, IH), 8.43 (s, 2H), 7.97 (dd, IH), 7.86-7.77 (m, 2H), 7.55 (d, 2H), 7.13 (d, 2H), 6.71 (d, IH), 4.75-4.72 (m, IH), 4.17-4.13 (m, 2H), 3.55-3.30 (m, 2H), 2.01-1.96 (m, 2H), 1.65-1.58 (m, 2H). LCMS: 436 (M+H)+.
EXAMPLE 17
Tert-butyl 4-(3'-fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yloxy)piperidine-l- carboxylate
Figure imgf000074_0001
Step 1: l-(4-Bromo-2-fluorophenyl)- lH-tetrazole
Figure imgf000074_0002
A 250-mL round-bottom flask was charaged with a solution of 4-bromo-2- fluorobenzenamine (10 g, 52.63 mmol) in AcOH (100 mL). To this was added NaN3 (4.5 g, 69.23 mmol). To the mixture was added triethoxymethane (11.7 g, 79.05 mmol) and the resulting solution was stirred for 4 hr at 900C. The resulting mixture was concentrated under vacuum and diluted with 150 mL of H2O. The solids were collected by filtration and washed with 100 ml of H2O affording l-(4-bromo-2-fluorophenyl)- lH-tetrazole as a light yellow solid (11.3 g, 88%). Step 2: Tert-butyl 4-(3'-fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yloxy)piperidine-l- carboxylate
Figure imgf000075_0001
A 250-mL round-bottom flask purged and maintained with an inert atmosphere of N2, was charged with a solution of 4-(l-(tert-butoxycarbonyl)piperidin-4- yloxy)phenylboronic acid (2 g, 6.23 mmol) , l-(4-bromo-2-fluorophenyl)-lH-tetrazole (1.8 g, 7.44 mmol) , Pd(PPh3)4 (700 mg, 0.61 mmol) ,Cs2CO3 (2 g, 6.13 mmol) in toluene and H2O (100:5 mL). The resulting solution was stirred for 4 hr at 1000C. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=l:5). Upon completion, the resulting mixture was concentrated under vacuum and the resulting solution was diluted with 100 mL of EtOAc, washed with water (1x50 mL), and brine (1x50 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with DCM/PE (1:20-1:4) affording tert-butyl 4-(3'-fluoro-4'-(lH-tetrazol-l- yl)biphenyl-4-yloxy)piperidine-l-carboxylate (2 g, 73%). LCMS: 440 (M+H)+.
EXAMPLE 18
5-Ethyl-2-(4-(3'-fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yloxy)piperidin-l- yl)pyrimidine
Figure imgf000075_0002
Step 1: 4-(3'-Fluoro-4'-(lH-tetrazol- l-yl)biphenyl-4-yloxy)piperidine hydrochloride
Figure imgf000076_0001
A 50-mL round-bottom flask was charged with a solution of tert-butyl 4-(3'-fluoro-4'- (lH-tetrazol-l-yl)biphenyl-4-yloxy)piperidine-l-carboxylate from EXAMPLE 17, Step 2 (2 g, 4.56 mmol) in DCMiCH3OH (10+10 mL). To this solution was added CH3COCl (5 mL) dropwise with stirring. The resulting solution was stirred for 1 hr at room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by re-crystallization from DCM affording 4-(3'-fluoro-4'-(lH- tetrazol-l-yl)biphenyl-4-yloxy)piperidine hydrochloride as white solid (1.6 g, 94%). LCMS: 340 (M+H)+.
Step 2: 5-Ethyl-2-(4-(3'-fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yloxy)piperidin-l- yl)pyrimidine
Figure imgf000076_0002
A 100-mL round bottomed flask was charged with a solution of 4-(3'-fluoro-4'-(lH- tetrazol-l-yl)biphenyl-4-yloxy)piperidine hydrochloride (678 mg, 1.81 mmol) in toluene/H2O (50/2 mL). To this solution was added 2-chloro-5-ethylpyrimidine (852 mg, 6.00 mmol) and Cs2CO3 (717 mg, 2.20 mmol). The resulting mixture was stirred at 95°C for overnight. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 50 rnL of DCM. The residue was washed with 1x20 rnL of water and 1x20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by a silica gel column chromatography eluted with DCM/MeOH (1:1) affording 5-ethyl-2-(4-(3'- fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yloxy)piperidin-l-yl)pyrimidine as white solid (0.22 g). 1H NMR (300 MHz, DMSOd6) δ 9.96 (s, IH), 8.25 (s, 2H), 7.91 (t, IH), 7.76 (d, 2H), 7.13 (d, 2H), 4.75 (m, IH), 4.18 (m, 2H), 3.49 (t, 2H), 2.43 (m, 2H), 2. 00 (m, 2H), 1.65-1.58 (m, 2H), 1.12 (t, 3H). LCMS: 446 (M+H)+.
EXAMPLE 19
Tert-butyl 4-(4-(2-methyl-6-(lH-l,2,4-triazol-l-yl)pyridin-3-yl)phenoxy) piperidine- 1 -carboxylate
Figure imgf000077_0001
To a solution of 3-bromo-2-methyl-6-(lH-l,2,4-triazol-l-yl)pyridine (110 mg, 0.46 mmol) in toluene (10 mL) were added 4-(l-(tert-butoxycarbonyl)piperidin-4- yloxy)phenylboronic acid (222 mg, 0.69 mmol), a solution Of Cs2CO3 (225 mg, 0.69 mmol) in H2O (1 mL) and Pd(PPh3)4 (10 mg). The resulting solution was stirred at 100 for overnight. The resulting mixture was evaporated, diluted with water (10 mL), extracted with ethyl acetate (2x15 mL) .The combined extracts were dried over anhydrous sodium sulfate, purified by silica gel column chromatography (silica gel, 1/10-1/5 ethyl acetate/petroleum ether), followed by recrystallization from ethoxyethane to give tert-butyl 4-(4-(2-methyl-6-(lH-l,2,4-triazol-l-yl)pyridin-3- yl)phenoxy)piperidine-l -carboxylate as a white solid (113 mg, 55%). 1H NMR (300 MHz, DMSO-d6) δ 9.36(s, IH), 8.31(s, IH), 7.86-7.88(d, IH), 7.73-7.75(d, IH), 7.08- 7.1 l(d, 2H), 3.67-3.72 (t, 2H), 3.20-3.23 (d, 2H), 1.93 (s, 2H), 1.54-1.57 (t, 2H), 1.41 (s, 9H). LCMS: 436 (M+H)+. EXAMPLE 20 Tert-butyl 4-(4'-(lH-tetrazol-l-yl)biphenyl-4-yloxy)piperidine-l-carboxylate
Figure imgf000078_0001
To a solution of tert-butyl 4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenoxy)piperidine-l-carboxylate (650 mg, 1.61 mmol) ) in DMEiH2O (5:1, 15 niL) were added l-(4-bromophenyl)-lH-tetrazole (469 mg, 2.09 mmol), K2CO3 (333 mg, 2.41 mmol) and Pd(PPh3)2Cl2 (56mg, 0.08 mmol). The resulting solution was stirred at 85 for overnight. The resulting mixture was evaporated, diluted with water (10 mL), extracted with ethyl acetate (2x15 mL) .The combined extracts were dried over anhydrous sodium sulfate, purified by silica gel column chromatography (EtOAc: Hexanes, 0-100%) to give Tert-butyl 4-(4'-(lH-tetrazol-l-yl)biphenyl-4- yloxy)piperidine-l-carboxylate as white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, IH), 7.96-7.87 (m, 4H), 7.67 (d, 2H), 7.01 (d, 2H), 4.63 (m, IH), 3.67-3.64 (m, 2H), 3.19 (m, 2H), 1.91 (m, 2H), 1.55 (m, 2H), 1.39 (s, 9H). LCMS: 422 (M+H)+.
EXAMPLE 21 Tert-butyl 4-(3'-(lH-tetrazol-l-yl)biphenyl-4-yloxy)piperidine-l-carboxylate
Figure imgf000078_0002
The title compound was synthesized as described for EXAMPLE 20 using tert-butyl 4- (4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenoxy)piperidine- 1 -carboxylate and l-(3-bromophenyl)-lH-tetrazole as the starting materials. 1H NMR (400 MHz, DMSO-d6) δ 10.17 (s, IH), 8.13-8.12 (m, IH), 7.83-7.80 (m, 2H), 7.73-7.65 (m, 3H), 7.11-7.09 (m, 2H), 4.64-4.61 (m, IH), 3.68-3.64 (m, 2H), 3.19 (m, 2H), 1.90 (m, 2H), 1.57-1.54 (m, 2H), 1.39 (s, 9H). LCMS: 422 (M+H)+.
EXAMPLE 22 2-(4-(4'-(lH-Tetrazol-l-yl)biphenyl-4-yloxy)piperidin-l-yl)-5-ethylpyrimidine
Figure imgf000079_0001
The title compound was synthesized as described for EXAMPLE 18 using tert-butyl 4- (4'-(lH-tetrazol-l-yl)biphenyl-4-yloxy)piperidine-l-carboxylate as the starting material. 1H NMR (400 MHz, DMSOd6) δ 10.07 (s, IH), 8.19 (s, 2H), 7.91-7.83 (m, 4H), 7.64 (d, 2H), 7.05 (d, 2H), 4.68-4.66 (m, IH), 4.15-4.12 (m, 2H), 3.47-3.45 (m, 2H), 3.37 (q, 2H), 1.96-1.93 (m, 2H), 1.57-1.53 (m, 2H), 1.68 (s, 3H). LCMS: 428 (M+H)+.
EXAMPLE 23 Tert-butyl 4-(2'-fluoro-4'-(methylsulfonyl)biphenyl-4-yloxy)piperidine-l- carboxylate
Figure imgf000079_0002
The title compound was synthesized as described in EXAMPLE 20, using 4-(l-(tert- butoxycarbonyl)piperidin-4-yloxy)phenylboronic acid and l-bromo-2-fluoro-4- (methylsulfonyl)benzene as the starting materials. 1H NMR (300 MHz, DMSOd6) δ 7.88-7.79 (m, 3H), 7.56 (d, 2H), 7.13 (d, 2H), 4.67-4.65 (m, IH), 3.72-3.64 (m, 2H), 3.33 (s, 3H), 3.23-3.16 (m, 2H), 1.96-1.93 (m, 2H), 1.57-1.53 (m, 2H), 1.41 (s, 9H).
EXAMPLE 24
Tert-butyl 4-(4-(2-methyl-6-(methylsulfonyl)pyridin-3-yl)phenoxy)piperidine-l- carboxylate
Figure imgf000080_0001
The title compound was synthesized as described in EXAMPLE 20, using 4-(l-(tert- butoxycarbonyl)piperidin-4-yloxy)phenylboronic acid and 3-bromo-2-methyl-6- (methylsulfonyl)pyridine as the starting materials. 1H NMR (300 MHz, DMSOd6) δ 7.92 (s, 2H), 7.41 (d, 2H), 7.11 (d, 2H), 4.66-4.63 (m, IH), 3.73-3.65 (m, 2H), 3.33 (s, 3H), 3.23-3.16 (m, 2H), 2.55 (s, 3H), , 1.96-1.93 (m, 2H), 1.57-1.53 (m, 2H), 1.41 (s, 9H). LCMS: 447 (M+H)+.
EXAMPLE 25 2-(4-(3'-(lH-tetrazol-l-yl)biphenyl-4-yloxy)piperidin-l-yl)-5-ethylpyrimidine
Figure imgf000080_0002
The title compound was synthesized as described for EXAMPLE 18 using Tert-butyl 4-(3'-(lH-tetrazol-l-yl)biphenyl-4-yloxy)piperidine-l-carboxylate as the starting material. 1H NMR (400 MHz, DMSOd6) δ 10.18 (s, IH), 8.23 (s, 2H), 8.13 (m, IH), 7.84-7.81 (m, 2H), 7.74-7.66 (m, 3H), 7.13 (d, 2H), 4.75-4.71 (m, IH), 4.19-4.16 (m, 2H), 3.52-3.46 (m, 2H), 2.41 (q, 2H), 1.96-1.93 (m, 2H), 1.61-1.55 (m, 2H), 1.11 (t, 3H). LCMS: 428 (M+H)+.
EXAMPLE 26
Tert-butyl 4-((2'-fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yl)methoxy)piperidine-l- carboxylate
Figure imgf000081_0001
Stepl: Tert-butyl 4-(4-bromobenzyloxy)piperidine-l-carboxylate
Figure imgf000081_0002
A 100-mL round-bottom flask was charged with a solution of NaH (1.2 g, 30 mmol, 1.00 equiv, 60%) in DMF (100 rnL). To this was added tert-butyl 4-hydroxypiperidine- 1-carboxylate (6.1 g, 30.3 mmol, 1.00 equiv) and allowed to stir at at 500C in an oil bath for 30 min. To this mixture was added l-bromo-4-(bromomethyl)benzene (7.5 g, 30.2 mmol, 1.00 equiv). The resulting solution was allowed to stir for 30 min at room temperature. Upon completion, the resulting solution was quenched with water (200 mL). The resulting mixture was extracted with ethyl acetate (3x200 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with ethyl acetate/petroleum ether (1:50-1:10) affording tert-butyl 4-(4- bromobenzyloxy)piperidine-l-carboxylate as a white solid (8.0 g, 65%).
4-((l-(Tert-butoxycarbonyl)piperidin-4-yloxy)methyl)phenylboronic acid
Figure imgf000081_0003
A 100 niL round bottomed flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of tert-butyl 4-(4-bromobenzyloxy)piperidine-l- carboxylate (4.00 g, 10.8 mmol, 1.00 equiv) in THF (100 mL) and triisopropyl borate (2.4 g, 12.8 mmol, 1.20 equiv). To this was added n-BuLi(2.5M) (8 mL, 2.00 equiv) at -800C dropwise and resulting mixture was allowed to stir for 1 h at this temperature. The reaction was then quenched by the addition of water (40 mL). The pH of the solution was adjusted to 5-6 with 2N HCl. The resulting solution was extracted with ethyl acetate (4x100 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum affording 4-((l-(tert-butoxycarbonyl) piperidin-4-yloxy)methyl)phenylboronic acid as light yellow oil (3.5 g).
Step 3: Tert-butyl 4-((2'-fluoro-4'-(lH-tetrazol- l-yl)biphenyl-4-yl)methoxy)piperidine- 1-carboxylate
Figure imgf000082_0001
A 100 mL round bottomed flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 4-((l-(tert-butoxycarbonyl)piperidin-4- yloxy)methyl)phenylboronic acid (335 mg, 1.00 mmol, 1.00 equiv) in toluene/H2O (50/5 mL), l-(4-bromo-3-fluorophenyl)-lH-tetrazole (242 mg, 1.00 mmol, 1.00 equiv), Cs2CO3 (326 mg, 1.00 mmol, 1.00 equiv), Pd(PPh3 )4 (230 mg, 0.20 mmol, 0.20 equiv). The resulting solution was stirred at 95°C in an oil bath overnight. The resulting mixture was diluted with ethyl acetate (100 mL). Then, it was washed with water (2x20 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column chromatography eluted with ethyl acetate/petroleum ether (1:20-1:5) affording tert-butyl 4-((2'-fluoro-4'-(lH-tetrazol-l- yl)biphenyl-4-yl)methoxy)piperidine-l-carboxylate as a white solid (178 mg, 37%). . 1H NMR (400 MHz, DMSOd6) δ 10.18 (s, IH), 8.00 (m, IH), 7.84-7.81 (m, 2H), 7.59 (d, 2H), 7.47 (d, 2H), 4.60 (s, 2H), 3.60 (m, 3H), 3.06 (m, 2H), 1.83 (m, 2H), 1.42 (m, 2H0, 1.39 (m, 2H). LCMS: 354 (M+H-Boc)+. EXAMPLE 27 5-Ethyl-2-(4-((2'-fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yl)methoxy)piperidin-l- yl)pyrimidine
Figure imgf000083_0001
Step 1: 4-((2'-Fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yl)methoxy)piperidine hydrochloride
Figure imgf000083_0002
HCl(g) was bubbled into a solution of tert-butyl 4-((2'-fluoro-4'-(lH-tetrazol-l- yl)biphenyl-4-yl)methoxy)piperidine-l-carboxylate (1.20 g, 2.65 mmol, 1.00 equiv) in DCM (40 rnL) for 30 mins at room temperature. The solids were collected by filtration. The resulting white solid was washed with EtOAc (2x10 mL) affording 4-((2'-Fluoro- 4'-(lH-tetrazol-l-yl)biphenyl-4-yl)methoxy)piperidine hydrochloride as a white solid (950 mg, 92%). 1H NMR (400 MHz, DMSOd6) δ 10.20 (s, IH), 8.26 (s, 2H), 8.01 (m, IH), 7.84-7.81 (m, 2H), 7.60 (m, 2H), 7.49 (d, 2H), 4.60 (s, 2H), 3.72 (s, IH), 2.99 (m, 2H), 1.99 (m, 2H), 1.77 (m, 2H). LCMS: 354 (M+H)+.
Step 2: 5-Ethyl-2-(4-((2'-fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yl)methoxy)piperidin- l-yl)pyrimidine
Figure imgf000083_0003
A 100 niL round bottomed flask was placed a solution of 4-((2'-fluoro-4'-(lH-tetrazol- l-yl)biphenyl-4-yl)methoxy)piperidine hydrochloride (600 mg, 1.54 mmol, 1.00 equiv) in toluene/water (50/2 rnL), 2-chloro-5-ethylpyrimidine (438 mg, 3.08 mmol, 2.00 equiv), Cs2CO3 (1.05 g, 3.22 mmol, 2.00 equiv). The resulting mixture was heated to 900C in an oil bath for overnight. The resulting mixture was concentrated under vacuum and diluted with dichloromethane (100 mL). The organic layer was then washed with with water (2x30 mL) and dried over anhydrous sodium sulfate, filtered and concentrated to give a residue that was purified by a silica gel column chromatography eluted with ethyl acetate/petroleum ether (1:20-1:4) affording 5-ethyl- 2-(4-((2'-fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yl)methoxy)piperidin-l-yl)pyrimidine as a white solid (178 mg, 25%). 1H NMR (300 MHz, DMSOd6) δ 10.18 (s, IH), 8.24 (s, 2H), 8.01 (m, IH), 7.84-7.81 (m, 2H), 7.49 (m, 4H), 4.63 (s, 2H), 4.15 (m, IH), 3.67 (m, IH), 3.30 (m, 2H), 2.38 (m, 2H), 1.92 (m, 2H), 1.46 (m, 2H), 1.10 (t, 3H). LCMS: 460 (M+H)+.
EXAMPLE 28
5-(4-(2'-Fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yloxy)piperidin-l-yl)-3-isopropyl-
1,2,4-oxadiazole
Figure imgf000084_0001
Step 1: 4-(2'-Fluoro-4'-(lH-tetrazol- l-yl)biphenyl-4-yloxy)piperidine- 1-carbonitrile
Figure imgf000084_0002
A 100 niL round bottomed flask was placed a solution of 4-(2'-fluoro-4'-(lH-tetrazol- l-yl)biphenyl-4-yloxy)piperidine hydrochloride (1.00 g, 2.66 mmol, 1.00 equiv) in THF (50 rnL), bromoformonitrile (422 mg, 3.98 mmol, 1.50 equiv) and Et3N (800 mg, 7.92 mmol, 2.98 equiv). The resulting solution was stirred at 0-5 0C for 3 hrs at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum affording 4-(2'-fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yloxy)piperidine- 1-carbonitrile as a white solid (0.98 g).
Step 2: 5-(4-(2'-Fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yloxy)piperidin-l-yl)-3- isopropyl- 1 ,2,4-oxadiazole
Figure imgf000085_0001
A 100 mL round bottomed flask was placed a solution of 4-(2'-fluoro-4'-(lH-tetrazol- l-yl)biphenyl-4-yloxy)piperidine-l-carbonitrile (980 mg, 2.69 mmol, 1.00 equiv) in EtOAc/Et2O (40/20 mL), N-hydroxyisobutyramidine (329 mg, 3.23 mmol, 1.20 equiv), ZnCl2 (440 mg, 3.24 mmol, 1.20 equiv). The resulting solution was stirred for 1 hr at room temperature. Then, the resulting mixture was concentrated under vacuum. To the mixture was added 4N HCl in EtOH (50 mL). The resulting solution was heated to reflux for an additional 2 hrs. Upon completion, the resulting mixture was concentrated under vacuum to give a residue that was purified by a silica gel column chromatography eluted with THF/PE (1:1) affording 5-(4-(2'-Fluoro-4'-(lH-tetrazol-l- yl)biphenyl-4-yloxy)piperidin-l-yl)-3-isopropyl-l,2,4-oxadiazole as a white solid (209 mg, 17%). %). 1H NMR (300 MHz, DMSOd6) δ 10.17 (s, IH), 8.02 (m, IH), 7.87- 7.82 (m, 2H), 7.60-7.57 (d, 2H), 7.18-7.15 (d, 2H), 4.75 (m, IH), 3.81-3.79 (m, 2H), 3.55-3.52 (m, 2H), 2.83 (m, IH), 2.06-2.05 (m, 2H), 1.77-1.74 (m, 2H), 1.19 (d, 6H). LCMS: 450 (M+H)+. EXAMPLE 29 Tert-butyl 3-(2'-fluoro-4'-(methylsulfonyl)biphenyl-4-yloxy)pyrrolidine-l- carboxylate
Figure imgf000086_0001
Step 1: Tert-butyl 3-(4-bromophenoxy)pyrrolidine-l-carboxylate
Figure imgf000086_0002
A 100 niL round bottomed flask was placed a solution of NaH (60%) (1.32 g, 55 mmol) in DMF (50 rnL) and tert-butyl 3-hydroxypyrrolidine-l-carboxylate (5.61 g, 30 mmol) was added in several batches. To the mixture was added l-bromo-4- fluorobenzene (5.22 g, 30 mmol). The resulting solution was stirred for 3 hrs at 100 0C. The reaction was then quenched by the addition of water (100 mL), extracted with EtOAc (3x200 mL), combined organic layers were washed with brine (1x100 mL), dried over anhydrous sodium sulfate and purified by recrystallization from Et2O affording tert-butyl 3-(4-bromophenoxy)pyrrolidine-l-carboxylate as a white solid (5.8 g, 57%).
Step 2: 4-(l-(Tert-butoxycarbonyl)pyrrolidin-3-yloxy)phenylboronic acid
Figure imgf000086_0003
A 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of N2 was charged with a solution of tert-butyl 3-(4- bromophenoxy)pyrrolidine-l-carboxylate (5.81 g, 17 mmol) in tetrahydrofuran (100 mL), triisopropyl borate (3.84 g, 20.4 mmol). This was mixture was added n-BuLi (8.2 niL) dropwise while stirring at -800C. The resulting solution was stirred for 3 hrs at - 800C. The reaction was then quenched with water (100 rnL), concentrated under vacuum, pH was adjusted to 5-6 with hydrogen chloride (6N), extracted with EtOAc (3x200 rnL), combined organic layers were dried over anhydrous sodium sulfate and purified by re-crystallization from ether affording 4-(l-(tert-butoxycarbonyl)pyrrolidin- 3-yloxy)phenylboronic acid as a white solid (3.2 g, 61%).
Step 3: Tert-butyl 3-(2'-fluoro-4'-(methylsulfonyl)biphenyl-4-yloxy)pyrrolidine-l- carboxylate
Figure imgf000087_0001
A 100 mL round bottomed flask was placed a solution of 4-(l-(tert- butoxycarbonyl)pyrrolidin-3-yloxy)phenylboronic acid (I g, 3.26 mmol), l-bromo-2- fluoro-4-(methylsulfonyl)benzene (820 mg, 3.25 mmol), Pd(PPh3)4 (376 mg, 0.33 mmol), Cs2CO3 (1.06 g, 3.25 mmol) in toluene/H2O (50/5 mL). The resulting solution was stirred overnight at 1000C. The resulting mixture was concentrated under vacuum, diluted with EtOAc (100 mL), washed with water (1x50 mL) and brine (1x50 mL), dried over anhydrous sodium sulfate and purified by a silica gel column chromatography eluted with ethyl acetate/petroleum ether (1:10-1:1) affording tert- butyl 3-(2'-fluoro-4'-(methylsulfonyl)biphenyl-4-yloxy)pyrrolidine-l-carboxylate as a white solid (0.8 g, 56%). LCMS: 436 (M+H)+.
EXAMPLE 30
5-Ethyl-2-(3-(2'-fluoro-4'-(methylsulfonyl)biphenyl-4-yloxy)pyrrolidin-l- yl)pyrimidine
Figure imgf000088_0001
3-(2'-Fluoro-4'-(methylsulfonyl)biphenyl-4-yloxy)pyrrolidine hydrochloride
Figure imgf000088_0002
A 50 rnL round bottomed flask was placed a solution of tert-butyl 3-(2'-fluoro-4'- (methylsulfonyl)biphenyl-4-yloxy)pyrrolidine-l-carboxylate (800 mg, 1.84 mmol) in 1,4-dioxane (20 rnL), hydrogen chloride(36%, 2 mL). The resulting solution was stirred for 2 hrs at room temperature. Then, the resulting mixture was concentrated under vacuum. The crude product was purified by re-crystallization from ether/MeOH affording 3-(2'-fluoro-4'-(methylsulfonyl)biphenyl-4-yloxy)pyrrolidine hydrochloride as a white solid (0.47 g, 69%).
Step 2: 5-Ethyl-2-(3-(2'-fluoro-4'-(methylsulfonyl)biphenyl-4-yloxy)pyrrolidin- 1- yl)pyrimidine
Figure imgf000088_0003
A 50 niL round bottomed flask was placed a solution of 3-(2'-fluoro-4'- (methylsulfonyl)biphenyl-4-yloxy)pyrrolidine hydrochloride (230 mg, 0.62 mmol), potassium carbonate (180 mg, 1.30 mmol), 2-chloro-5-ethylpyrimidine (180 mg, 1.26 mmol) in DMF (6 mL). The resulting solution was stirred for 2 hrs at 120 0C. The resulting solution was diluted with 30 mL of water, extracted with ethyl acetate (2x50 mL), combined organic layers were washed with brine (1x50 mL) and purified by a silica gel column chromatography eluted with ethyl acetate/petroleum ether (1/50-1/5) affording 5-ethyl-2-(3-(2'-fluoro-4'-(methylsulfonyl)biphenyl-4-yloxy)pyrrolidin-l- yl)pyrimidine as a white solid (173 mg, 61%). 1H NMR (300 MHz, DMSOd6) δ 8.21 (s, 2H), 7.24 (m, 2H), 7.62 (t, IH), 7.51 (d, 2H), 7.01 (d, 2H), 5.12 (s, IH), 3.90 ( m, 2H), 3.85 (m, IH), 3.76 (m, IH), 3.11 (s, 3H), 2.48 (m, 2H), 2.34 (m, 2H), 1.19 (t, 3H). LCMS: 442 (M+H)+.
EXAMPLE 31
3-Isopropyl-5-(4-(4-(2-methyl-6-(lH-l,2,4-triazol-l-yl)pyridin-3-yl)phenoxy) piperidin- 1 -yl) - 1 ,2,4-oxadiazole
Figure imgf000089_0001
The title compound was synthesized as described for EXAMPLE 28 using 2-methyl-3-
(4-(piperidin-4-yloxy)phenyl)-6-(lH-l,2,4-triazol-l-yl)pyridine hydrochloride as the starting material. 1H NMR (400 MHz, DMSOd6) δ 9.25 (s, IHO, 8.13 (s, IH),
7.78-7.68 (m, 2H), 7.30-7.27 (d, 2H), 7.03-7.00 (d, 2H), 4.65 (s, IH), 3.88-3.66 (m,
4H), 2.96-2.87 (m, IH), 2.55 (s, 3H), 2.07-2.00 (m, 4H), 1.32 (d, 6H). LCMS: 446
(M+H)+. EXAMPLE 32 Tert-butyl 4-(3'-(methylsulfonyl)biphenyl-3-yloxy)piperidine-l-carboxylate
Figure imgf000090_0001
The title compound was synthesized as described for EXAMPLE 29 using 3-(l-(tert- butoxycarbonyl)piperidin-4-yloxy)phenylboronic acid and l-bromo-3- (methylsulfonyl)benzene as the starting material.. LCMS: 332 (M+H-Boc)+.
EXAMPLE 33 5-Ethyl-2-(4-(3'-(methylsulfonyl)biphenyl-3-yloxy)piperidin-l-yl)pyrimidine
Figure imgf000090_0002
The title compound was synthesized as described for EXAMPLE 30 using tert-butyl 4- (3'-(methylsulfonyl)biphenyl-3-yloxy)piperidine- 1-carboxylate and 2-chloro-5- ethylpyrimidine as the starting material. 1H NMR (400 MHz, DMSOd6) δ 8.26 (s, 2H), 8.16 (d, IH), 8.06-8.04 (d, IH), 7.93-7.91 (d, IH), 7.77-7.72 (t, IH), 7.47- 7.42 (t, IH), 7.36-7.31 (m, 2H), 7.12-7.07 (m, IH), 4.81 (s, IH), 4.17-4.22 (m, 2H), 3.57-3.49 (m, 2H), 3.33-3.31 (m, 3H), 2.51-2.40 (m, 2H), 2.04-1.99 (t, 2H), 1.65-1.60 (m, 2H), 1.16-1.11 (t, 3H). LCMS: 438 (M+H)+. EXAMPLE 34 Tert-butyl 4-(4'-(methylsulfonyl)biphenyl-3-yloxy)piperidine-l-carboxylate
Figure imgf000091_0001
The title compound was synthesized as described for EXAMPLE 29 using 3-(l-(tert- butoxycarbonyl)piperidin-4-yloxy)phenylboronic acid and l-bromo-4- (methylsulfonyl)benzene as the starting material.. LCMS: 332 (M+H-Boc)+.
EXAMPLE 35 5-Ethyl-2-(4-(4'-(methylsulfonyl)biphenyl-3-yloxy)piperidin-l-yl)pyrimidine
Figure imgf000091_0002
The title compound was synthesized as described for EXAMPLE 30 using tert-butyl 4- (4'-(methylsulfonyl)biphenyl-3-yloxy)piperidine- 1-carboxylate and 2-chloro-5- ethylpyrimidine as the starting material. 1H NMR (400 MHz, DMSOd6) δ 8.25 (s, 2H), 8.00-7.94 (m, 4H), 7.45-7.41 (t, IH), 7.33-7.30 (t, 2H), 7.10-7.08 (d, IH), 4.881-4.78 (m, IH), 4.23-4.19 (t, 2H), 3.52-3.47 (t, 2H), 3.26 (s, 3H), 2.44-2.40 (m, 2H), 2.02-2.00 (d, 2H), 1.63-1.51 (m, 2H), 1.15-1.11 (t, 3H). LCMS: 438 (M+H)+. EXAMPLE 36 Tert-butyl 4-(3'-(methylsulfonyl)biphenyl-4-yloxy)piperidine-l-carboxylate
Figure imgf000092_0001
The title compound was synthesized as described for EXAMPLE 29 using 4-(l-(tert- butoxycarbonyl)piperidin-4-yloxy)phenylboronic acid and l-bromo-3- (methylsulfonyl)benzene as the starting material.. LCMS: 432 (M+H)+.
EXAMPLE 37 5-Ethyl-2-(4-(3'-(methylsulfonyl)biphenyl-4-yloxy)piperidin-l-yl)pyrimidine
Figure imgf000092_0002
The title compound was synthesized as described for EXAMPLE 30 using tert-butyl 4-
(3'-(methylsulfonyl)biphenyl-4-yloxy)piperidine- 1-carboxylate and 2-chloro-5- ethylpyrimidine as the starting material. 1H NMR (400 MHz, DMSOd6) δ
8.26 (s, 2H), 8.10 (s, IH), 8.00-7.97 (d, IH), 7.86 (d, IH), 7.73-7.68 (m, 3H), 7.15-7.12
(d, 2H), 4.76-4.73 (m, IH), 4.22-4.16 (m, 2H), 3.55-3.47 (m, 2H), 3.29 (s, 3H), 2.40-
2.39 (m, 2H), 2.02-1.98 (m, 2H), 1.64-1.57 (m, 2H), 1.17-1.11 (t, 3H). LCMS: 438
(M+H)+. EXAMPLE 38 2-Methyl-6-(methylsulfonyl)-3-(4-(piperidin-4-yloxy)phenyl)pyridine
Figure imgf000093_0001
The title compound was synthesized as described in EXAMPLE 18, using tert-butyl 4- (4-(2-methyl-6-(methylsulfonyl)pyridin-3-yl)phenoxy)piperidine- 1-carboxylate as the starting materials. 1H NMR (300 MHz, DMSOd6) δ 7.91 (s, 2H), 7.40-7.37 (d, 2H), 7.08-7.05 (d, 2H), 4.50-4.44 (m, IH), 3.29 (s, 3H), 2.97-2.93 (m, 2H), 2.61-2.55 (m, 5H), 1.96-1.93 (m, 2H), 1.52-1.40 (m, 2H). LCMS: 347 (M+H)+.
EXAMPLE 39 4-(2'-Fluoro-4'-(methylsulfonyl)biphenyl-4-yloxy)piperidine
Figure imgf000093_0002
The title compound was synthesized as described in EXAMPLE 18, using tert-butyl 4- (2'-fluoro-4'-(methylsulfonyl)biphenyl-4-yloxy)piperidine- 1-carboxylate as the starting materials. 1H NMR (300 MHz, DMSOd6) δ 7.82 (m, 3H), 7.55 (d, 2HO, 7.10 (d, 2H), 4.49 (s, IH), 3.32 (s, 3H), 2.96 (m, 2H), 2.59 (t, 2H), 1.96 (m, 2H), 1.48 (m, 2H). LCMS: 350 (M+H)+.
EXAMPLE 40
5-Ethyl-2-(4-(4-(2-methyl-6-(methylsulfonyl)pyridin-3-yl)phenoxy)piperidin-l- yl)pyrimidine
Figure imgf000094_0001
The title compound was synthesized as described for EXAMPLE 30 using tert-butyl 4- (4-(2-methyl-6-(methylsulfonyl)pyridin-3-yl)phenoxy)piperidine- 1-carboxylate and 2- chloro-5-ethylpyrimidine as the starting material. LCMS: 453 (M+H)+.
EXAMPLE 41 Tert-butyl 4-(4-(2-fluoro-4-(lH-tetrazol-l-yl)phenyl)naphthalen-l- yloxy)piperidine-l-carboxylate
Figure imgf000094_0002
The title compound was synthesized as described for EXAMPLE 17 using tert-butyl 4- (4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-l-yloxy)piperidine-l- carboxylate and l-(4-bromo-3-fluorophenyl)-lH-tetrazole as the starting material. LCMS: 490 (M+H)+. EXAMPLE 42
3-Isopropyl-5-(4-(4-(2-methyl-6-(methylsulfonyl)pyridin-3-yl)phenoxy)piperidin-
1 -yl) - 1 ,2,4-oxadiazole
Figure imgf000095_0001
The title compound was synthesized as described for EXAMPLE 28 using 2-methyl-6- (methylsulfonyl)-3-(4-(piperidin-4-yloxy)phenyl)pyridine as the starting material. 1H NMR (400 MHz, DMSOd6) δ 7.92 (s, 2H), 7.44-7.41 (d, 2H), 7.15-7.12 (d, 2H), 4.75- 4.72 (m, IH), 3.83-3.77 (m, 2H), 3.54-3.46 (m, 2H), 3.29 (s, 3H), 2.84-2.80 (m, IH), 2.55 (s, 3H), 2.09-2.05 (m, 2H), 1.78-1.69 (m, 2H), 1.20-1.18 (m, 6H). LCMS: 457 (M+H)+.
EXAMPLE 43 Tert-butyl 4-(4-(2-fluoro-4-(methylsulfonyl)phenylamino)phenoxy)piperidine-l- carboxylate
Figure imgf000095_0002
A 100-mL 3-necked round-bottom flask was charged with a solution of 4-(l-(tert- butoxycarbonyl)piperidin-4-yloxy)phenylboronic acid (1.16 g, 3.61 mmol) in dichloromethane (20 mL). This was followed by the addition of TEA (243 mg, 2.41 mmol). Then the mixture was stirred for 5 min. To this was added Cupric Acetate (48 mg, 0.24 mmol), 2-fluoro-4-(methylsulfonyl)benzenamine (455 mg, 2.41 mmol). The resulting solution was bubbled with air and stirred for 24 hrs at 300C. The reaction mixture was cooled to room temperature. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether: 1:1). The solids were filtered out. The filtrate was concentrated under vacuum. The residue was purified by a silica gel column chromatography eluted with petroleum ether/ethyl acetate (3:1) affording tert-butyl 4- (4-(2-fluoro-4-(methylsulfonyl)phenylamino)phenoxy)piperidine-l-carboxylate as a white solid (180 mg, 16%). . 1H NMR (300 MHz, DMSOd6) δ 8.43 (s, IH), 7.61- 7.66 (q, IH), 7.48-7.51 (q, IH), 7.15-7.18 (d, 2H), 7.04-7.09 (t, IH), 6.98-7.01 (d, 2H), 4.49-4.54 (m, IH), 3.65-3.70 (m, 2H), 3.26-3.14 (m, 2H), 3.14 (s, 3H), 1.89 (m, 2H), 1.46-1.56 (m, 2H), 1.41 (s, 9H). LCMS: 365 (M+H-Boc)+.
EXAMPLE 44
N-(4-(l-(5-ethylpyrimidin-2-yl)piperidin-4-yloxy)phenyl)-2-fluoro-4-
(methylsulfonyl)aniline
Figure imgf000096_0001
The title compound was synthesized as described for EXAMPLE 30 using tert-butyl 4- (4-(2-fluoro-4-(methylsulfonyl)phenylamino)phenoxy)piperidine-l-carboxylate and 2- chloro-5-ethylpyrimidine as the starting material. 1H NMR (400 MHz, DMSOd6) δ 8.44 (s, IH), 8.27 (s, 2H), 7.62-7.67 (q, IH), 7.49-7.52 (q, IH), 7.17-7.20 (d, 2H), 7.06- 7.11 (t, IH), 7.01-7.04 (d, 2H), 4.59-4.65 (m, IH), 4.18-4.24 (q, 2H), 3.44-3.52 (m, 2H), 3.15 (s, 3H), 2.41-2.46 (m, 2H), 1.98 (m, 2H), 1.54-1.64 (m, 2H), 1.12-1.17 (t, 3H). LCMS: 471 (M+H)+. EXAMPLE 45
2-(4-(2'-Fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yloxy)piperidin-l-yl)-5-
(trifluoromethyl)pyrimidine
Figure imgf000097_0001
The title compound was synthesized as described for EXAMPLE 5, Step 5 using 4-(2'- fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yloxy)piperidine hydrochloride and 2-chloro-5- trifluoromethylpyrimidine as the starting materials. 1H NMR (300 MHz, CDCl3) δ 9.03 (s, IH), 8.51 (s, 2H), 7.68-7.53(m, 5H), 7.08-7.05 (m, 2H), 1.06 (m, IH), 4.20- 4.11 (m, 2H), 4.02-3.94 (m, 2H), 2.10-1.91 (m, 4H). LCMS: 486 (M+H)+.
EXAMPLE 46 5-(4-(2'-Fluoro-4'-(methylsulfonyl)biphenyl-4-yloxy)piperidin-l-yl)-3-isopropyl-
1,2,4-oxadiazole
Figure imgf000097_0002
The title compound was synthesized as described for EXAMPLE 28 using 4-(2'-fluoro- 4'-(methylsulfonyl)biphenyl-4-yloxy)piperidine as the starting material. 1H NMR (300 MHz, DMSOd6) δ 7.77 (m, 3H), 7.56 (d, 2H), 7.14 (d, 2H), 4.75 (s, IH), 3.77 (m, 2H), 3.46 (m, 2H), 3.31 (s, 3H), 2.77 (m, IH), 2.04 (m, 2H), 1.72 (m, 2H), 1.18 (d, 6H). LCMS: 460 (M+H)+. EXAMPLE 47 Tert-butyl 3-(2'-fluoro-4'-(methylsulfonyl)biphenyl-4-yloxy)azetidine-l- carboxylate
Figure imgf000098_0001
Step 1: Tert-butyl 3-(4-bromophenoxy)azetidine-l-carboxylate
Figure imgf000098_0002
A 250 niL round bottomed flask purged and maintained with an inert atmosphere of N2 was charged with a solution of tert-butyl 3-hydroxyazetidine-l-carboxylate (6 g, 34.7 mmol) in DMF (80 mL). To this was added sodium hydride (1.65 g, 41.2 mmol) and 1- bromo-4-fluorobenzene (12.04 g, 69.20 mmol). The resulting solution was stirred for overnight at 95 0C. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (3x100 mL) and combined organic layers were washed with water (2x100 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column chromatography eluted with ethyl acetate/petroleum ether (1:10) affording tert-butyl 3-(4-bromophenoxy)azetidine-l-carboxylate as a white solid (8.7 g, 77%).
4-(l-(Tert-butoxycarbonyl)azetidin-3-yloxy)phenylboronic acid
Figure imgf000098_0003
A 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of N2 was charged with a solution of tert-butyl 3-(4- bromophenoxy)azetidine-l-carboxylate (6.5 g, 19.9 mmol), triisopropyl borate (4.5 g, 23.9 mmol) in THF (100 mL). This was followed by the addition of n-BuLi (10 mL) dropwise with stirring at -80 0C. The resulting solution was stirred at -800C for 4 hrs. The reaction was then quenched by the addition of water (100 mL). The resulting mixture was concentrated under vacuum. The pH was adjusted to 5-6 with hydrogen chloride (2N). The resulting solution was extracted with ether (3x200 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by re-crystallization from ether affording 4-(l-(tert-butoxycarbonyl)azetidin-3-yloxy)phenylboronic acid as a white solid (4.4 g, 76%).
Step 3: Tert-butyl 3-(2'-fluoro-4'-(methylsulfonyl)biphenyl-4-yloxy)azetidine-l- carboxylate
Figure imgf000099_0001
A 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with a solution of 4-(l-(tert-butoxycarbonyl)azetidin-3- yloxy)phenylboronic acid (1.2 g, 4.10 mmol) in toluene and H2O (50:3 mL), 1-bromo- 2-fluoro-4-(methylsulfonyl)benzene (1 g, 3.97 mmol), Pd(PPh3)4 (460 mg, 0.40 mmol), Cs2CO3 (1.3 g, 3.99 mmol). The resulting solution was stirred at 100 0C for 4 hrs. The resulting mixture was concentrated under vacuum and diluted with EtOAc (50 mL). The resulting mixture was washed with water (1x30 mL) and brine (1x30 mL). The mixture was dried over anhydrous sodium sulfate. The crude product was purified by re-crystallization from methanol affording tert-butyl 3-(2'-fluoro-4'-(methylsulfonyl) biphenyl-4-yloxy)azetidine-l-carboxylate as a white solid (Ig). LCMS: 322 (M+H- Boc)+. EXAMPLE 48 5-Ethyl-2-(3-(2'-fluoro-4'-(methylsulfonyl)biphenyl-4-yloxy)azetidin-l- yl)pyrimidine
Figure imgf000100_0001
Step 1: 3-(2'-Fluoro-4'-(methylsulfonyl)biphenyl-4-yloxy)azetidine hydrochloride
Figure imgf000100_0002
A 50-mL round-bottom flask was charged a solution of 3-(2'-fluoro-4'-(methylsulfonyl) biphenyl-4-yloxy)azetidine-l-carboxylate (500 mg, 1.19 mmol) in 1,4-dioxane (20 rnL) and hydrogen chloride(36%, 2 rnL). The resulting solution was stirred at room temperature for 2 hrs. Then, the mixture was concentrated under vacuum. The crude product was purified by re-crystallization from ether affording 3-(2'-fluoro-4'- (methylsulfonyl)biphenyl-4-yloxy)azetidine hydrochloride as a white solid (0.3 g). LCMS: 322 (M+H)+.
Step 2: 5-Ethyl-2-(3-(2'-fluoro-4'-(methylsulfonyl)biphenyl-4-yloxy)azetidin-l- yl)pyrimidine
Figure imgf000101_0001
A 100-mL round-bottom flask was charged a solution of 3-(2'-fluoro-4'- (methylsulfonyl)biphenyl-4-yloxy)azetidine hydrochloride (300 mg, 0.84 mmol) in DMF (20 niL), 2-chloro-5-ethylpyrimidine (400 mg, 2.82 mmol), and Cs2CO3 (320 mg, 0.98 mmol). The resulting solution was stirred at 120 0C for 2 hrs. The resulting solution was diluted with water (100 mL) and extracted with ethyl acetate (3x200 mL). Combined organic layers were washed with brine (1x100 mL) and dried over anhydrous sodium sulfate to give the crude after filtration followed by concentration. The crude product was purified by re-crystallization from ether affording 5-Ethyl-2-(3- (2'-fluoro-4'-(methylsulfonyl)biphenyl-4-yloxy)azetidin-l-yl)pyrimidine as a white solid (133 mg, 37%). 1H NMR (300 MHz, DMSOd6) δ 8.28 (s, 2H), 7.88 (d, 2H), 7.80 (m, 2H), 7.60 (d, 2H), 7.04 (d, 2H), 5.22 (s, IH), 4.52 (m, 2H), 3.98 (m, 2H), 3.33 (d, 3H), 2.46 (m, 2H), 1.35 (t, 3H). LCMS: 428 (M+H)+.
EXAMPLE 49
Tert-butyl 4-(4-(4-(methylsulfonyl)phenoxy)phenyl)-5,6-dihydropyridine-l(2H)- carboxylate
Figure imgf000101_0002
A 25 niL round bottom falsk was charged with tert-butyl 4-(4-hydroxyphenyl)-5,6- dihydropyridine-l(2H)-carboxylate (293 mg, 1.06 mmol), l-fluoro-4- (methylsulfonyl)benzene (222 mg, 1.28 mmol), and K2CO3 ( 219 mg, 1.59 mmol) in NMP (10 mL). The resulting mixture was heated to 120 0C overnight. Upon completion, the mixture was quenched with water (50 mL), and extracted with ethyl acetate (2x50 mL). Combined organics were dried over sodium sulfate, filtered and concentarated in vacuo to give the crude. The crude material was purified by silica gel column chromatography eluted with 10-70% EtOAc in hexanes affording tert-butyl 4- (4-(4-(methylsulfonyl)phenoxy)phenyl)-5,6-dihydropyridine- 1 (2H)-carboxylate as foamy white solid. LCMS: 430 (M+H)+.
EXAMPLE 50
N-(4-(4-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yloxy)naphthalen-l-yl)-3- fluorophenyl)cyanamide
Figure imgf000102_0001
The title compound was synthesized as described for EXAMPLE 5 using tert-butyl 4- (4-(2-fluoro-4-(lH-tetrazol- l-yl)phenyl)naphthalen- l-yloxy)piperidine- 1-carboxylate and 2-chloro-5-ethylpyrimidine as the starting material. LCMS: 468 (M+H)+.
EXAMPLE 51 5-Ethyl-2-(4-(4-(2-fluoro-4-(lH-tetrazol-l-yl)phenyl)naphthalen-l- yloxy)piperidin-l-yl)pyrimidine
Figure imgf000103_0001
The title compound was synthesized as described for EXAMPLE 5 using tert-butyl 4- (4-(2-fluoro-4-(lH-tetrazol- l-yl)phenyl)naphthalen- l-yloxy)piperidine- 1-carboxylate and 2-chloro-5-ethylpyrimidine as the starting material. LCMS: 496 (M+H)+.
EXAMPLE 52 Tert-butyl 4-(4-(4-(methylsulfonyl)phenoxy)phenyl)piperidine-l-carboxylate
Figure imgf000103_0002
A solution of tert-butyl 4-(4-(4-(methylsulfonyl)phenoxy)phenyl)-5,6-dihydropyridine- l(2H)-carboxylate (100 mg) in EtOAc ( 10 mL) was treated with catalytic PtO2 ( 5 mg) at ambient temperature for 8 hrs. Upon completion, the mixture was filtered through Celite and concentrated to give tert-butyl 4-(4-(4-(methylsulfonyl)phenoxy)phenyl) piperidine- 1-carboxylate. LCMS: 432 (M+H)+. EXAMPLE 53
Tert-butyl 4-(4-((2-fluoro-4-(methylsulfonyl)phenoxy)methyl)phenyl)piperidine-l- carboxylate
Figure imgf000104_0001
Step 1: 1 ,2-Difluoro-4-(methylsulfonyl)benzene
Figure imgf000104_0002
A 250-mL round-bottomed flask was charged with 1,2-difluorobenzene (45.6 g, 400.00 mmol, 2.00 equiv), methanesulfonyl chloride (23.1 g, 200.87 mmol, 1.00 equiv), AlCl3 (26.4 g, 198.50 mmol, 1.00 equiv). The resulting solution was heated to reflux overnight in an oil bath. The reaction progress was monitored by TLC (EA: PE=I :1). The resulting mixture was concentrated, quenched with 100 mL of water/ice. The crude product was collected by filtration, re-crystallized from EA:PE (1:10) to give of 1,2- difluoro-4-(methylsulfonyl)benzene as a white solid (21 g, 54%).
Step 2: 2-Fluoro- l-methoxy-4-(methylsulfonyl)benzene
Figure imgf000104_0003
A 250-mL 3-necked round-bottomed flask was charged with a solution of 1,2-difluoro- 4-(methylsulfonyl)benzene (8.9 g, 46.35 mmol, 1.00 equiv) in methanol (30 mL). Then potassium hydroxide (3.1 g, 55.36 mmol, 1.20 equiv) in methanol (50 mL) was added dropwise. The resulting mixture was heated to reflux for 3 hrs. Upon completion, the resulting mixture was concentrated under vacuum, quenched with water (100 mL). The solids were collected by filtration to give 2-fluoro-l-methoxy-4-(methylsulfonyl) benzene as a light yellow solid (9.0 g, 95%).
Step 3: 2-Fluoro-4-(methylsulfonyl)phenol
Figure imgf000105_0001
A 500-mL 3-necked round-bottomed flask was charged with a solution of 2-fluoro-l- methoxy-4-(methylsulfonyl)benzene (5 g, 24.51 mmol, 1.00 equiv) in dichloromethane (50 mL). Then tribromoborane (30.4 g, 122.58 mmol, 5.00 equiv) in dichloromethane (100 mL) was added dropwised with stirring at -78°C. The resulting solution was warmed to room temperature overnight. The reaction progress was monitored by TLC (DCM: MeOH = 20:1). Upon completion, the resulting mixture was concentrated under vacuum, quenched with 80 ml of ice water and extracted with dichloromethane (8x50 mL). Then, combined organic layers were dried over anhydrous sodium sulfate and concentrated to give 2-fluoro-4-(methylsulfonyl)phenol as a light yellow solid (4.4 g, 93%).
Step 4: Tert-butyl 4-(4-(hydroxymethyl)phenyl)piperidine-l-carboxylate
Figure imgf000105_0002
A 500-mL round-bottomed flask was purged, flushed and maintained with hydrogen atmosphere. To this was added a solution of tert-butyl 4-(4-formylphenyl)-5,6- dihydropyridine-l(2H)-carboxylate (8 g, 27.87 mmol, 1.00 equiv) in EtOH (160 niL) and palladium on carbon (1.6 g, 10%). The resulting solution was stirred at room temperature for 24 hrs. Upon completion, the mixture was filtered through Celite and concentarated to give the crude that was purified by silica gel column chromatography eluted with EA: PE (1:5) to give tert-butyl 4-(4-(hydroxymethyl)phenyl)piperidine-l- carboxylate as a white solid (6.3 g, 76.1%).
Step 5: Tert-butyl 4-(4-((methylsulfonyloxy)methyl)phenyl)piperidine- 1-carboxylate
Figure imgf000106_0001
A 250-ml 3-necked round-bottomed flask was charged with a solution of tert-butyl 4- (4- (hydroxymethyl)phenyl)piperidine- 1-carboxylate (4.8 g, 16.49 mmol, 1.00 equiv) in dichloromethane (50 mL) and TEA (2.498 g, 24.73 mmol, 1.50 equiv). To this mixture was then added (CH3SOi)2O (574 mg, 3.30 mmol, 1.20 equiv) in dichloromethane (30 mL at 0 0C. The resulting mixture was stirred at room temperature overnight. Upon completion, the resulting mixture was concentrated and diluted with EtOAc (100 mL). The mixture was washed with water (3x30 mL). Then the organic layer was dried over sodium sulfate and concentrated to give tert-butyl 4-(4-((methylsulfonyloxy)methyl) phenyl)piperidine- 1-carboxylate as a white solid (3.2 g, 52%).
Step 6: Tert-butyl 4-(4-((2-fluoro-4-(methylsulfonyl)phenoxy)methyl)phenyl) piperidine- 1 -carboxylate
Figure imgf000107_0001
A 50-mL round-bottomed flask was charged with a solution of 2-fluoro-4- (methylsulfonyl)phenol (772 mg, 4.06 mmol, 1.00 equiv) in N,N-dimethylformamide (35 rnL). To this was added sodium hydride (203 mg, 8.12 mmol, 2.00 equiv, 96%) in several batches at 0 0C. After 10 minutes, tert-butyl 4-(4-((methylsulfonyloxy)methyl) phenyl)piperidine-l -carboxylate (1.5 g, 4.07 mmol, 1.00 equiv) was added and the resulting solution was stirred for 1 hr at room temperature. The reaction was then quenched with water (150 mL) and the mixture was extracted with ethyl acetate (3x50 mL). Combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give tert-butyl 4-(4-((2-fluoro-4-(methylsulfonyl) phenoxy)methyl)phenyl)piperidine-l -carboxylate as a white solid (0.9 g, 46%). 1H NMR (300 MHz, DMSOd6) δ 7.81 (t, IH), 7.72 (t, IH), 7.52 (t, IH) 4.41 (d, 2H), 7.30 (d, 2H), 4.07 (d, 2H), 5.27 (s, 2H) 2.72 (m, 3H), 3.20 (s, 3H), 1.75 (d, 2H), 1.48 (s, 9H). LCMS: 464 (M+H)+.
EXAMPLE 54
5-Ethyl-2-(4-(4-((2-fluoro-4-(methylsulfonyl)phenoxy)methyl)phenyl)piperidin-l- yl)pyrimidine
Figure imgf000108_0001
Step 1: 4-(4-((2-Fluoro-4-(methylsulfonyl)phenoxy)methyl)phenyl)piperidine
Figure imgf000108_0002
A 50-mL round-bottomed flask was charged with a solution of tert-butyl 4-(4-((2- fluoro-4-(methylsulfonyl)phenoxy)methyl)phenyl)piperidine-l-carboxylate (700 mg, 1.51 mmol, 1.00 equiv) in 1,4-dioxane (25 rnL) and 4N hydrogen chloride (3 rnL). The resulting solution was stirred at 50 0C for 1 hr. The resulting mixture was concentrated and washed with EtOAc( 3x15 mL) to give 4-(4-((2-fluoro-4-(methylsulfonyl )phenoxy)methyl)phenyl)piperidine hydrochloride as a white solid (0.4 g, 61.0%). Step 2: 5-Ethyl-2-(4-(4-((2-fluoro-4-(methylsulfonyl)phenoxy)methyl)phenyl) piperidin- 1 -yl)pyrimidine
Figure imgf000109_0001
A 50-mL round-bottomed flask was charged with a solution of 4-(4-((2-fluoro-4- (methylsulfonyl)phenoxy)methyl)phenyl)piperidine hydrochloride (400 mg, 1.00 mmol, 1.00 equiv) in n-BuOH (15 niL) and DIPEA (258 mg, 2.00 mmol, 2.00 equiv). Then, to this mixture was added 2-chloro-5-ethylpyrimidine (142 mg, 1.00 mmol, 1.00 equiv). The resulting solution was stirred at 85 0C in an oil bath overnight. The resulting mixture was concentrated and purified by silica gel column chromatography eluted with EtOAc:PE (1:10) affording 5-ethyl-2-(4-(4-((2-fluoro-4-(methylsulfonyl) phenoxy)methyl)phenyl)piperidin-l-yl)pyrimidine as a white solid (14 mg, 3%). 1H NMR (300 MHz, DMSOd6) δ 8.26 (s, 2H), 7.80 (m, 2H), 7.52 (t, IH), 7.41 (d, 2H), 7.31 (d, 2H), 5.28 (s, 2H), 4.79 (d, 2H), 2.86 (m, 4H), 3.22 (s, 3H), 2.50 (s, 3H), 1.83 (d, 2H), 1.55 (t, 2H), 1.15 (t, 3H). LCMS: 470 (M+H)+.
EXAMPLE 55
Tert-butyl 4-(4-((2-fluoro-4-(methylsulfonyl)phenylamino)methyl)phenyl) piperidine- 1 -carboxylate
Figure imgf000110_0001
The title compound was synthesized as described for EXAMPLE 53 using tert-butyl 4- (4- ((methylsulfonyloxy)methyl)phenyl)piperidine-l -carboxylate and 2-fluoro-4- (methylsulfonyl)aniline as the starting material. 1H NMR (300 MHz, DMSOd6) δ 7.41-7.53 (m, 5H) 6.71 (m, IH), 4.40 (d, 2H), 4.05 (d, 2H), 3.34 (s, 3H), 3.09 (s, 3H), 2.78 (s, 2H), 2.51 (m, IH), 1.72 (d, 2H), 1.47 (m, 9H). LCMS: 464 (M+H)+.
EXAMPLE 56
N-(4-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)benzyl)-2-fluoro-4- (methylsulfonyl)aniline
Figure imgf000110_0002
The title compound was synthesized as described for EXAMPLE 54 using tert-butyl 4- (4-((methylsulfonyloxy)methyl)phenyl)piperidine-l-carboxylate and 2-chloro-5- ethylpyrimidine as the starting material. 1H NMR (300 MHz, DMSOd6) δ 8.25 (s, 2H), 7.22-5.53 (m, 7H), 6.72 (t, 2H), 4.78 (d, 2H), 4.41 (s, 2H), 4.79 (d, 2H), 3.09 (s, 3H), 2.83 (m, 3H), 2.47 (m, 2H), 1.81 (d, 2H), 1.52 (d, 2H), 1.34 (m, 3H). LCMS: 491 (M+Na)+.
EXAMPLE 57
Tert-Butyl 4-((2'-fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yl)methyl)piperidine-l- carboxylate
Figure imgf000111_0001
The title compound was synthesized as described in EXAMPLE 5 using tert-butyl 4- (4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzyl)piperidine-l-carboxylate and 1- (4-bromo-3-fluorophenyl)-lH-tetrazole as the starting materials. LCMS: 338 (M+H- Boc)+.
EXAMPLE 58
5-Ethyl-2-(4-((2'-fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yl)methyl)piperidin-l- yl)pyrimidine
Figure imgf000111_0002
The title compound was synthesized as described in EXAMPLE 5 using tert-Butyl 4- ((2'-fluoro-4'-(lH-tetrazol-l-yl)biphenyl-4-yl)methyl)piperidine-l-carboxylate and l-chloro-5-ethylpyrimidine as the starting materials. LCMS: 446 (M+H)+.
EXAMPLE 59
5-Chloro-2-(4-(4-(2-methyl-6-(methylsulfonyl)pyridin-3-yl)phenoxy)piperidin-l- yl)pyrimidine
Figure imgf000112_0001
The title compound was synthesized as described for EXAMPLE 30 using tert-butyl 4- (4-(2-methyl-6-(methylsulfonyl)pyridin-3-yl)phenoxy)piperidine-l-carboxylate and 2,5-dichloropyrimidine as the starting material. LCMS: 459 (M+H)+.
EXAMPLE 60 4-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yloxy)benzoic acid
Figure imgf000112_0002
Step 1: Ethyl 4-(l-(5-ethylpyrimidin-2-yl)piperidin-4-yloxy)benzoate
Figure imgf000113_0001
A 250-mL round-bottom flask was charged with a solution of ethyl 4-(piperidin-4- yloxy)benzoate hydrochloride (3 g, 10.5 mmol) in N,N-dimethylformamide (80 rnL), 2-chloro-5-ethylpyrimidine (3 g, 20.98 mmol), potassium carbonate (4.14 g, 30 mmol). The resulting solution was stirred at 120 0C for 1 overnight. The resulting mixture was concentrated under vacuum. The residue was purified by a silica gel column chromatography eluted with ethyl acetate/petroleum ether (1:40) affording ethyl 4-(l- (5-ethylpyrimidin-2-yl)piperidin-4-yloxy)benzoate as a white solid (3 g, 81%).
Step 2: 4-(l-(5-ethylpyrimidin-2-yl)piperidin-4-yloxy)benzoic acid
Figure imgf000113_0002
A 100-mL round-bottom flask was charged with a solution of ethyl 4-(l-(5- ethylpyrimidin-2-yl)piperidin-4-yloxy)benzoate (1.5 g, 4.23 mmol) in methanol (50 mL) and sodium hydroxide(2N) (10 mL). The resulting solution was stirred at 60 0C for 3 h. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether = 1:2). The resulting mixture was concentrated under vacuum. The resulting solution was diluted with water (30 mL) and pH was adjusted to 3 with hydrogen chloride(2N). The solids were collected by filtration and dried in an oven affording 4-(l-(5- ethylpyrimidin-2-yl)piperidin-4-yloxy)benzoic acid as a white solid (1.15 g, 82%). 1H NMR (300 MHz, DMSOd6) δ 8.26 (s, IH), 7.87-7.90 (d, 2H), 7.06-7.09 (d, 2H), 4.75- 4.80 (m, IH), 4.17-4.25 (m, 2H), 3.43-3.52 (m, 2H), 2.40-2.52 (m, 2H), 1.99-2.03 (m, 2H), 1.60-1.64 (m, 2H), l.l l-1.15(m, 3H). LCMS: 328 (M+H)+.
EXAMPLE 61
Tert-butyl 4-(6-(2-fluoro-4-(methylsulfonyl)phenylcarbamoyl)pyridazin-3- yloxy)piperidine-l-carboxylate
Bo
Figure imgf000114_0001
Step 1: 6-(l-(Tert-butoxycarbonyl)piperidin-4-yloxy)pyridazine-3-carboxylic acid
Bo
Figure imgf000114_0002
To a solution of tert-butyl 4-hydroxypiperidine-l-carboxylate (1 g, 5 mmol) in THF (10 niL) was added β-chloropyridazine-S-carboxylic acid (792 mg, 5 mmol) followed by addition of KOtBu (1.12g, 10 mmol). The mixture was stirred at room temperature for overnight. Upon completion, the mixture was diluted with EtOAc, washed with H2O (85 mL), and IN HCl (15 mL). Organic layers were concentarated to give the crude that was purified by silica gel column chromatography eluted with 10-40 mL ethyl acetate in hexanes affording 6-(l-(tert-butoxycarbonyl)piperidin-4- yloxy)pyridazine-3-carboxylic acid. LCMS: 324 (M+H)+. Step 2: Tert-butyl 4-(6-(2-fluoro-4-(methylsulfonyl)phenylcarbamoyl)pyridazin-3- yloxy)piperidine- 1 -carboxylate
Figure imgf000115_0001
To a solution of 6-(l-(tert-butoxycarbonyl)piperidin-4-yloxy)pyridazine-3-carboxylic acid (323 mg, 1 mmol) in DMF (2 niL) was added 2-fluoro-4-(methylsulfonyl)aniline (189 mg, 1 mmol). To this mixture was then added TEA (700 mL, 5 mmol), followed by addition of HATU (450 mg, 1.2 mmol) in one portion at room temperature. Upon completion, the reaction mixture was diluted with EtOAc (50 mL), washed with K2CO3 (10%, 40 mL) and IN HCl (2x40 mL). Organic layers were concentrated in vacuo to give the crude that was prufied by silica gel column chraomatograhy eluted with 20- 80% EtOAc in hexanes to afford tert-butyl 4-(6-(2-fluoro-4-(methylsulfonyl) phenylcarbamoyl)pyridazin-3-yloxy)piperidine-l -carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, IH), 8.30-8.23 (m, 2H), 7.93 (dd, IH), 7.83 (dd, IH), 7.45 (d, IH), 5.51-5.49 (m, IH), 3.76-3.70 (m, 2H), 3.29 (s, 3H), 3.42 (m, 2H), 2.09-2.05 (m, 2H), 1.72-1.67 (m, 2H), 1.42 (s, 9H). LCMS: 495 (M+H)+.
EXAMPLE 62
SH-tl^^triazolo^S-btøyridin-S-yl ό-Cl-Ctert-butoxycarbony^piperidin-^ yloxy)pyridazine-3-carboxylate
Figure imgf000115_0002
The title compound was synthesized as described for EXAMPLE 61 was obtained as a side product under the reaction condition. LCMS: 442 (M+H)+. EXAMPLE 63
Tert-butyl 4-(6-(2-methyl-6-(methylsulfonyl)pyridin-3-ylcarbamoyl)pyridazin-3- yloxy)piperidine-l-carboxylate
Bo
Figure imgf000116_0001
The title compound was synthesized as described for EXAMPLE 61 using 6-(l-(Tert- butoxycarbonyl)piperidin-4-yloxy)pyridazine-3-carboxylic acid and 2-methyl-6- (methylsulfonyl)pyridin-3-amine as the starting material. LCMS: 492 (M+H)+.
EXAMPLE 64 l-(Tert-butoxycarbonyl)piperidin-4-yl 6-(l-(tert-butoxycarbonyl)piperidin-4- yloxy)pyridazine-3-carboxylate
Bo
Figure imgf000116_0002
The title compound was synthesized as described for EXAMPLE 61 and was obtained as a side product under the reaction condition. LCMS: 507 (M+H)+.
EXAMPLE 65
Tert-butyl 4-(4-(2-fluoro-4-(methylsulfonyl)phenylcarbamoyl)phenoxy)piperidine-
1-carboxylate
Figure imgf000116_0003
The title compound was synthesized as described for EXAMPLE 61 using 4-(l-(tert- butoxycarbonyl)piperidin-4-yloxy)benzoic acid and 2-fluoro-4-(methylsulfonyl)aniline as the starting material. 1H NMR (400 MHz, DMSOd6) δ 10.26 (s, IH), 7.99-7.93 (m, 3H), 7.85 (dd, IH), 7.77 (dd, IH), 7.10 (dd, IH), 4.71-4.67 (m, IH), 3.69-3.63 (m, 2H), 3.18 (s, 3H), 3.18 (m, 2H), 1.94-1.91(m, 2H), 1.55-1.50 (m, 2H), 1.39 (s, 9H). LCMS: 393 (M+H-Boc)+.
EXAMPLE 66
Tert-butyl 4-(4-(2-methyl-6-(methylsulfonyl)pyridin-3-ylcarbamoyl)phenoxy) piperidine- 1 -carboxylate
Figure imgf000117_0001
The title compound was synthesized as described for EXAMPLE 61 using 4-(l-(tert- butoxycarbonyl)piperidin-4-yloxy)benzoic acid and 2-methyl-6-(methylsulfonyl) pyridine-3-amine as the starting material. 1H NMR (400 MHz, DMSOd6) δ 10.09 (s, IH), 8.16 (d, IH), 7.96-7.90 (m, 3H), 7.13 (dd, IH), 4.72-4.69 (m, IH), 3.69-3.63 (m, 2H), 3.25 (s, 3H), 3.18 (m, 2H), 2.54 (s, 3H), 1.97-1.90 (m, 2H), 1.57-1.50 (m, 2H), 1.39 (s, 9H). LCMS: 490 (M+H)+.
EXAMPLE 67
Tert-butyl 4-(5-(2-fluoro-4-(methylsulfonyl)phenylcarbamoyl)pyridin-2- yloxy)piperidine-l-carboxylate
Figure imgf000117_0002
The title compound was synthesized as described for EXAMPLE 61 using 6-(l-(tert- butoxycarbonyl)piperidin-4-yloxy)nicotinic acid and 2-fluoro-4- (methylsulfonyl)aniline as the starting material. LCMS: 438 (M+H-tBu)+.
EXAMPLE 68
4-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yloxy)-N-(2-methyl-6-(methylsulfonyl) pyridin-3-yl)benzamide
Figure imgf000118_0001
The title compound was synthesized as described for EXAMPLE 30 using tert-butyl 4- (4-(2-methyl-6-(methylsulfonyl)pyridin-3-ylcarbamoyl)phenoxy) piperidine-1- carboxylate and 2-chloro-5-ethylpyrimidine as the starting materials. 1H NMR (400 MHz, DMSOd6) δ δ 10.09 (s, IH), 8.25 (s, 2H), 8.17 (d, IH), 7.97-7.90 (m, 3H), 7.14 (d, 2H), 4.81-4.79 (m, IH), 4.21-4.15 (m, 2H), 3.52-3.45 (m, 2H), 3.25 (s, 3H), 2.55 (s, 3H), 2.44 (q, 2H), 2.07-1.97 (m, 2H), 1.62-1.57 (m, 2H), 1.13 (s, 3H). LCMS: 496 (M+H)+.
EXAMPLE 69
Tert-butyl 4-(6-(2-fluoro-4-(methylsulfonyl)phenylcarbamoyl)pyridin-3- yloxy)piperidine-l-carboxylate
Figure imgf000118_0002
The title compound was synthesized as described for EXAMPLE 61 using 5-(l-(tert- butoxycarbonyl)piperidin-4-yloxy)picolinic acid and 2-fluoro-4-(methylsulfonyl) aniline as the starting material. 1H NMR (400 MHz, DMSOd6) δ 10.44 (d, IH), 7.49- 7.44 (m, 2H), 8.13 (d, IH), 7.89 (dd, IH), 7.81 (dd, IH), 7.71 (dd, IH), 4.82-4.78 (m, IH), 3.71-3.65 (m, 2H), 3.25 (s, 3H), 3.18 (m, 2H), 1.98-1.93 (m, 2H), 1.60-1.53 (m, 2H), 1.39 (s, 9H). LCMS: 438 (M+H-tBu)+.
EXAMPLE 70
Tert-butyl 4-(6-((2-fluoro-4-(methylsulfonyl)phenylamino)methyl)pyridin-3- yloxy)piperidine-l-carboxylate
Figure imgf000119_0001
To a solution of tert-butyl 4-(6-(2-fluoro-4-(methylsulfonyl)phenylcarbamoyl)pyridin- 3-yloxy)piperidine-l-carboxylate ( 56 mg) in THF (1.5 mL) was added BF3OEt2 (0.36 mL, IM in THF, 0.34 mmol). The resulting mixture was heated to 50 0C overnight. Upon completion, the reaction mixture was diluted with water (10 mL), washed with K2CO3 (10%). Organic layers were concentrated in vacuo to give the crude that was prufied by RP HPLC eluted with 0-80% acetonitrile in water affording tert-butyl 4-(6- ((2-fluoro-4-(methylsulfonyl)phenylamino)methyl)pyridin-3-yloxy)piperidine-l- carboxylate. LCMS: 424 (M+H-tBu)+.
EXAMPLE 71
Tert-butyl 4-(2-(2-fluoro-4-(methylsulfonyl)phenylcarbamoyl)pyrimidin-5- yloxy)piperidine-l-carboxylate
Bo
Figure imgf000119_0002
The title compound was synthesized as described for EXAMPLE 61 using 5-(l-(tert- butoxycarbonyl)piperidin-4-yloxy)pyrimidine-2-carboxylic acid and 2-fluoro-4- (methylsulfonyl)aniline as the starting materials. 1H NMR (400 MHz, DMSOd6) δ 10.55 (s, IH), 8.82 (s, 2H), 8.42 (t, IH), 7.92 (d, IH), 7.83 (d, IH), 4.96-4.91 (m, IH), 3.72-3.66 (m, 2H), 3.28 (s, 3H), 3.21 (m, 2H), 2.07-1.99 (m, 2H), 1.65-1.58 (m, 2H), 1.41 (s, 9H). LCMS: 495 (M+H)+.
EXAMPLE 72 Tert-butyl 4-(5-(2-fluoro-4-(methylsulfonyl)phenylcarbamoyl)pyrazin-2- yloxy)piperidine-l-carboxylate
Figure imgf000120_0001
The title compound was synthesized as described for EXAMPLE 61 using 5-(l-(tert- butoxycarbonyl)piperidin-4-yloxy)pyrazine-2-carboxylic acid and 2-fluoro-4- (methylsulfonyl)aniline as the starting materials. 1H NMR (400 MHz, DMSOd6) δ 10.80 (s, IH), 8.30-8.23 (m, 2H), 7.93 (dd, IH), 7.83 (dd, IH), 7.45 (d, IH), 5.51-5.49 (m, IH), 3.75-3.70 (m, 2H), 3.29 (s, 3H), 3.23 (m, 2H), 2.10-2.06 (m, 2H), 171-1.67 (m, 2H), 1.41 (s, 9H). LCMS: 495 (M+H)+.
EXAMPLE 73
Tert-butyl 4-(5-(2-fluoro-4-(methylsulfonyl)phenylcarbamoyl)pyrimidin-2- yloxy)piperidine-l-carboxylate
Figure imgf000120_0002
The title compound was synthesized as described for EXAMPLE 61 using 2-(l-(tert- butoxycarbonyl)piperidin-4-yloxy)pyrimidine-5-carboxylic acid and 2-fluoro-4- (methylsulfonyl)aniline as the starting materials. LCMS: 495 (M+H)+.
EXAMPLE 74
Tert-butyl 4-(5-((2-fluoro-4-(methylsulfonyl)phenylamino)methyl)pyridin-2- yloxy)piperidine-l-carboxylate
Figure imgf000121_0001
The title compound was synthesized as described for EXAMPLE 70 using tert-butyl 4- (5-(2-fluoro-4-(methylsulfonyl)phenylcarbamoyl)pyridin-2-yloxy)piperidine-l- carboxylate as the starting material. LCMS: 495 (M+H)+.
EXAMPLE 75
Tert-butyl 4-(6-(2-methyl-6-(methylsulfonyl)pyridin-3-ylcarbamoyl)pyridin-3- yloxy)piperidine-l-carboxylate
Bo
Figure imgf000121_0002
The title compound was synthesized as described for EXAMPLE 61 using 5-(l-(tert- butoxycarbonyl)piperidin-4-yloxy)picolinic acid and 2-methyl-6- (methylsulfonyl)pyridin-3-amine as the starting materials. 1H NMR (400 MHz, DMSOd6) δ 10.42 (s, IH), 8.53 (d, IH), 8.45 (d, IH), 8.13 (d, IH), 7.94 (d, IH), 7.71 (dd, IH), 4.83-4.79 (m, IH), (m, IH), 3.71-3.70 (m, 2H), 3.24 (s, 3H), 3.18 (m, 2H), 2.61 (s, 3H), 1.96-1.94 (m, 2H), 1.60-1.53 (m, 2H), 1.39 (s, 9H). LCMS: 491 (M+H)+. EXAMPLE 76
5-(l-(5-ethylpyrimidin-2-yl)piperidin-4-yloxy)-N-(2-fluoro-4-(methylsulfonyl) phenyl)picolinamide
Figure imgf000122_0001
The title compound was synthesized as described for EXAMPLE 30 using tert-butyl 4- (6-((2-fluoro-4-(methylsulfonyl)phenylamino)methyl)pyridin-3-yloxy)piperidine-l- carboxylate and 2-chloro-5-ethylpyrimidine as the starting materials. 1H NMR (400 MHz, DMSOd6) δ δ 10.43 (d, IH), 8.49-8.45 (m, 2H), 8.24 (s, 2H), 8.16 (d, IH), 7.90 (dd, IH), 7.81 (dd, IH), 7.74 (dd, 2H), 4.92-4.88 (m, IH), 4.24-4.18 (m, 2H), 3.50-3.48 (m, 2H), 3.25 (s, 3H), 2.42 (q, 2H), 2.05-2.02 (m, 2H), 1.65-1.57 (m, 2H), 1.11 (s, 3H). LCMS: 500 (M+H)+.
EXAMPLE 77
Tert-butyl 4-(4-(2-methyl-6-(lH-l,2,4-triazol-l-yl)pyridin-3-ylcarbamoyl) phenoxy)piperidine-l-carboxylate
Figure imgf000122_0002
The title compound was synthesized as described for EXAMPLE 61 using 4-(l-(tert- butoxycarbonyl)piperidin-4-yloxy)benzoic acid and 2-methyl-6-(lH-l,2,4-triazol-l- yl)pyridin-3-amine as the starting materials. 1H NMR (400 MHz, DMSOd6) δ 10.02 (s, IH), 9.30 (s, IH), 8.28 (s, IH), 8.01-7.95 (m, 3H), 7.72 (d, IH), 7.11 (d, IH), 4.70- 4.67 (m, IH), 3.69-3.64 (m, 2H), 3.18 (m, 2H), 1.95-1.90 (m, 2H), 1.56-1.49 (m, 2H), 1.39 (s, 9H). LCMS: 479 (M+H)+.
EXAMPLE 78
Tert-butyl 4-(6-((2-methyl-6-(methylsulfonyl)pyridin-3-ylamino)methyl)pyridin-3- yloxy)piperidine-l-carboxylate
Bo
Figure imgf000123_0001
The title compound was synthesized as described for EXAMPLE 70 using tert-butyl 4- (5-(2-fluoro-4-(methylsulfonyl)phenylcarbamoyl)pyridin-2-yloxy)piperidine-l- carboxylate as the starting material. LCMS: 421 (M+H-tBu)+.
EXAMPLE 79
5-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yloxy)-N-(2-methyl-6-(methylsulfonyl) pyridin-3-yl)picolinamide
Figure imgf000123_0002
The title compound was synthesized as described for EXAMPLE 30 using tert-butyl 4- (6-(2-methyl-6-(methylsulfonyl)pyridin-3-ylcarbamoyl)pyridin-3-yloxy)piperidine-l- carboxylate and 2-chloro-5-ethylpyrimidine as the starting materials. 1H NMR (400 MHz, DMSOd6) δ 10.43 (d, IH), 8.54 (d, IH), 8.46 (d, IH), 8.49 (s, 2H), 8.14 (d, IH), 7.94 (d, IH), 7.74 (dd, IH), 4.92-4.89 (m, IH), 4.24-4.18 (m, 2H), 3.51-3.49 (m, 2H), 3.24 (s, 3H), 2.61 (s, 3H), 2.42 (q, 2H), 2.05-2.02 (m, 2H), 1.65-1.58 (m, 2H), 1.11 (s, 3H). LCMS: 497 (M+H)+. EXAMPLE 80
N-((5-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yloxy)pyridin-2-yl)methyl)-2-fluoro-
4- (methylsulf onyl)aniline
Figure imgf000124_0001
The title compound was synthesized as described for EXAMPLE 70 using 5-(l-(5- ethylpyrimidin-2-yl)piperidin-4-yloxy)-N-(2-fluoro-4-(methylsulfonyl) phenyl)picolinamide as the starting material. LCMS: 486 (M+H)+.
EXAMPLE 81
Tert-butyl 4-(5-(2-methyl-6-(methylsulfonyl)pyridin-3-ylcarbamoyl)pyridin-2- yloxy)piperidine-l-carboxylate
Bo
Figure imgf000124_0002
The title compound was synthesized as described for EXAMPLE 61 using 6-(l-(tert- butoxycarbonyl)piperidin-4-yloxy)nicotinic acid and 2-methyl-6- (methylsulfonyl)pyridin-3-amine as the starting materials. LCMS: 491 (M+H)+.
EXAMPLE 82 N-(2-Fluoro-4-(methylsulfonyl)phenyl)-6-(piperidin-4-yloxy)nicotinamide
Figure imgf000124_0003
The title compound was synthesized as described for EXAMPLE 6, Step 3 using tert- butyl 4-(5-(2-fluoro-4-(methylsulfonyl)phenylcarbamoyl)pyridin-2-yloxy)piperidine-l- carboxylate as the starting material. LCMS: 394 (M+H)+.
EXAMPLE 83
Tert-butyl 4-(4-((2-methyl-6-(lH-l,2,4-triazol-l-yl)pyridin-3-ylamino)methyl) phenoxy)piperidine-l-carboxylate
Figure imgf000125_0001
The title compound was synthesized as described for EXAMPLE 70 using tert-butyl 4- (4-(2-methyl-6-(lH-l,2,4-triazol-l-yl)pyridin-3-ylcarbamoyl)phenoxy)piperidine-l- carboxylate as the starting material. 1H NMR (400 MHz, DMSOd6) δ 9.04 (s, IH), 8.11 (s, IH), 7.37 (d, IH), 7.25 (d, 2H), 6.89 (d, 3H), 4.49-4.45 (m, IH), 4.31 (s, 2H), 3.65-3.59 (m, 2H), 3.13 (m, 2H), 2.47 (s, 3HO, 1.87-1.82 (m, 2H), 1.49-1.45 (m, 2H), 1.37 (s, 9H). LCMS: 465 (M+H)+.
EXAMPLE 84
4-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yloxy)-N-(2-methyl-6-(lH-l,2,4-triazol-l- yl)pyridin-3-yl)benzamide
Figure imgf000125_0002
The title compound was synthesized as described for EXAMPLE 30 using tert-butyl 4- (4-(2-methyl-6-(lH-l,2,4-triazol-l-yl)pyridin-3-ylcarbamoyl)phenoxy)piperidine-l- carboxylate and 2-chloro-5-ethylpyrimidine as the starting materials. 1H NMR (400 MHz, DMSOd6) δ 10.02 (d, IH), 9.30 (s, IH), 8.28 (s, IHO, 8.24 (s, 2H), 8.02-7.96 (m, 3H), 7.73 (d, IH), 7,13 (d, 2H), 4.80-4.78 (m, IH), 4.20-4.16 (m, 2H), 3.51-3.50 (m, 2H), 2.47 (s, 3H), 2.42 (q, 2H), 2.01-1.99 (m, 2H), 1.60-1.57 (m, 2H), 1.11 (t, 3H). LCMS: 485 (M+H)+.
EXAMPLE 85
Tert-butyl 4-(4-((2-fluoro-4-(lH-tetrazol-l-yl)phenoxy)methyl) phenoxy)piperidine-l-carboxylate
Figure imgf000126_0001
The title compound was synthesized as described for EXAMPLE 53 using tert-butyl 4- (4-((methylsulfonyloxy)methyl)phenoxy)piperidine-l-carboxylate and 2-fluoro-4-(lH- tetrazol-l-yl)phenol as the starting material. 1H NMR (400 MHz, DMSOd6) δ 9.99 (s, IHO, 7.89 (dd, IH), 7.70-7.67 (m, IH), 7.51 (t, IH), 7.39 (d, 2H), 7.00-6.98 (m, 3H), 5.17 (s, 2H), 4.57-4.53 (m, IH), 3.66-3.61 (m, 2H), 3.14 (m, 2H), 1.90-1.86 (m, 2H), 1.53-1.45 (m, 2H), 1.38 (s, 9H). LCMS: 470 (M+H)+.
EXAMPLE 86 Ethyl 6-(l-(tert-butoxycarbonyl)piperidin-4-yloxy)nicotinate
Figure imgf000126_0002
A solution of tert-butyl 4-hydroxypiperidine- 1 -carboxylate (10.0 g, 49.7 mmol, 1.00 equiv) in N,N-dimethylformamide (100 mL) was added NaH (60%) (2.2 g, 91.7 mmol, 1.10 equiv) followed by addition of ethyl 6-chloronicotinate (9.2 g, 49.7 mmol, 1.00 equiv). This mixture was stirred at room temperature for 30 min. The reaction was then quenched by the addition of water/ice (40 niL). The resulting mixture was concentrated under vacuum and extracted with ethyl acetate (3x100 mL). Combined organic layers were dried over sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column chromatography eluted with ethyl acetate/petroleum ether (1:10-1:30) affording ethyl 6-(l-(tert-butoxycarbonyl)piperidin -4-yloxy)nicotinate as light yellow oil (9.8 g, 55%). LCMS: 351 (M+H)+.
EXAMPLE 87
6-(l-(5-ethylpyrimidin-2-yl)piperidin-4-yloxy)-N-(2-fluoro-4-(methylsulfonyl) phenyl)nicotinamide
Figure imgf000127_0001
The title compound was synthesized as described for EXAMPLE 30 using tert-butyl 4- (5-(2-fluoro-4-(methylsulfonyl)phenylcarbamoyl)pyridin-2-yloxy)piperidine-l- carboxylate and 2-chloro-5-ethylpyrimidine as the starting materials. LCMS: 500
(M+H)+.
EXAMPLE 88
Tert-butyl 4-(4-(l-(2-methyl-6-(methylsulfonyl)pyridin-3-ylamino)ethyl)phenoxy) piperidine- 1 -carboxylate
Figure imgf000127_0002
J_: Tert-butyl 4-(4-(l-aminoethyl)phenoxy)piperidine-l-carboxylate
Figure imgf000128_0001
A 250-mL round-bottom flask was charged with a solution of tert-butyl 4-(4- acetylphenoxy) piperidine-1-carboxylate (2 g, 6.27 mmol, 1.00 equiv) in NH3/EtOH (100 niL), acetic acid (3.76 g, 62.67 mmol, 10.00 equiv) and NaBH3CN (790 mg, 12.54 mmol, 2.00 equiv). The resulting solution was stirred at 90 0C for 3 hrs. The reaction progress was monitored by TLC (DCM:MeOH=20:l). The pH was adjusted to 8 with sodium hydroxide/H2O (3 mol/L). The resulting solution was extracted with dichloromethane (4x30 mL). Combined organic layers were dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum affording tert-butyl 4-(4-(l-aminoethyl) phenoxy) piperidine-1- carboxylate as pale yellow oil (1.9 g, 95%).
Step 2: Tert-butyl 4-(4-(l-(2-methyl-6-(methylsulfonyl)pyridin-3-ylamino)ethyl) phenoxy) piperidine-1-carboxylate
Figure imgf000128_0002
A solution of 3-bromo-2-methyl-6-(methylsulfonyl)pyridine (1 g, 4.02 mmol, 1.00 equiv) in tetrahydrofuran (30 mL), tert-butyl 4-(4-(l-aminoethyl)phenoxy)piperidine-l- carboxylate (1.8 g, 5.62 mmol, 1.50 equiv), Pd2(dba)3 chloroform (400 mg, 0.39 mmol, 0.10 equiv), BINAP (400 mg, 0.60 mmol, 0.20 equiv), t-BuONa (1.14 g, 11.88 mmol, 3.00 equiv) was heated to 90 0C in an oil bath for 16 h. The reaction progress was monitored by TLC (PE:EtOAc=l:l). The reaction was then quenched by the addition of 40 mL of sodium chloride/water. The resulting mixture was extracted with ethyl acetate (3x50 mL). Comibined organic layers were dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was purified by a silica gel column chromatography eluted with ethyl acetate/petroleum ether (1/1) affording tert-butyl 4-(4-(l-(2-methyl-6- (methylsulfonyl) pyridin-3-ylamino)ethyl)phenoxy)piperidine-l-carboxylate as a pale yellow solid (0.4 g, 20%). 1H NMR (300 MHz, CDCl3) δ 7.67 (d,lH) 7.19 (d, 2H), 6.87 (d, 2H), 6.64 (d, IH), 4.44 (m, 2H), 3.67 (m, 2H), 3.30 (m, 2H), 3.15 (s, 3H), 2.55 (s, 3H), 1.91 (m, 2H), 1.738 (m, 2H), 1.61 (d, 2H), 1.48(s, 9H). LCMS: 490 (M+H)+.
EXAMPLE 89
Tert-butyl 4-(3-methyl-4-((2-methyl-6-(methylsulfonyl)pyridin-3-ylamino)methyl) phenoxy)piperidine-l-carboxylate
Figure imgf000129_0001
J_: Tert-butyl 4-(4-bromo-3-methylphenoxy)piperidine- 1-carboxylate
Figure imgf000129_0002
A 100-mL round-bottom flask was charged with tert-butyl 4-hydroxypiperidine-l- carboxylate (2.01 g, 10 mmol), sodium hydride (480 mg, 12 mmol, 60%), and a solution of l-bromo-4-fluoro-2-methylbenzene (1.88 g, 10 mmol) in DMF (40 mL). The resulting solution was stirred at 100 0C for 1 h. Upon completion, the resulting mixture was quenched with water (100 mL) and extracted with ethyl acetate (2x100 mL). Combined organic layers were washed with brine (2x30 mL), dried over anhydrous sodium sulfate and concentrated to give the crude. The crude material was then prufied with a silica gel column chromatography eluted with ethyl acetate/petroleum ether (1:10-1:20) affording tert-butyl 4-(4-bromo-3- methylphenoxy)piperidine-l-carboxylate as light yellow oil (2.1 g, 57%). LCMS: 370 (M+H)+.
Tert-butyl 4-(4-formyl-3-methylphenoxy)piperidine-l-carboxylate
Figure imgf000130_0001
A 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of tert-butyl 4-(4-bromo-3- methylphenoxy)piperidine-l-carboxylate (14 g, 37.9 mmol) in tetrahydrofuran (200 mL). To this solution was added n-BuLi (30 mL) dropwise and allowed to stir at -800C for 30 min. To this was added ethyl formate (14 g, 189 mmol, 4.99 equiv) dropwise at - 800C and stirred for additional 30 min. Upon completion, the reaction was then quenched by the addition NH4Cl (100 mL) and extracted with ethyl acetate (3x200 mL). Combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated to give the crude. The crude material was then prufied with a silica gel column chromatography eluted with ethyl acetate/petroleum ether (1:50-1:20) affording tert-butyl 4-(4-formyl-3- methylphenoxy)piperidine-l-carboxylate as colorless oil (7 g, 58%).
Tert-butyl 4-(4-(aminomethyl)-3-methylphenoxy)piperidine-l-carboxylate
Figure imgf000130_0002
A 250-mL round-bottom flask was charged with a solution of tert-butyl 4-(4-formyl-3- methylphenoxy)piperidine-l-carboxylate (2 g, 6.27 mmol) in NH3ZEtOH (100 mL), acetic acid (3.76 g, 62.67 mmol), NaBH3CN (790 mg, 12.54 mmol). The resulting mixture was stirred at 90 0C in an oil bath for 16 h. Upon completion, the resulting mixture was concentrated under vacuum. The pH was adjusted to 8 with sodium hydroxide/water (3 mol/L), extracted with dichloromethane (4x30 mL). Combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated to give tert-butyl 4-(4-(aminomethyl)-3-methylphenoxy)piperidine-l- carboxylate as pale yellow oil (1.5 g, 75%).
Step 4: Tert-butyl 4-(3-methyl-4-((2-methyl-6-(methylsulfonyl)pyridin-3-ylamino) methyl)phenoxy)piperidine- 1 -carboxylate
Figure imgf000131_0001
A 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with a solution of tert-butyl 4-(4-(aminomethyl)-3- methylphenoxy)piperidine- 1 -carboxylate (1.0 g, 3.12 mmol) in tetrahydrofuran (100 mL), 3-bromo-2-methyl-6-(methylsulfonyl)pyridine (520 mg, 2.09 mmol,), Pd2(dba)3CHCl3 (215 mg, 0.21 mmol), BINAP (280 mg, 0.42 mmol) and t-BuONa (600 mg, 6.25 mmol). The resulting solution was heated to 900C in an oil bath for 16 h. Upon completion, the resulting solution was diluted with DCM (50 mL) and quenched by addition of brine (50 mL). The resulting mixture was then extracted with dichloromethane (3x50 mL). Combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated to give the crude. The crude material was then prufied with a silica gel column chromatography eluted with ethyl acetate/petroleum ether (2:1) affording tert-butyl 4-(3-methyl-4-((2-methyl-6- (methylsulfonyl)pyridin-3-ylamino)methyl)phenoxy)piperidine- 1 -carboxylate as a white solid (126 mg, 12%). 1H NMR (300 MHz, DMSOd6) δ 7.85 (d, IH), 7.16 (d, IH), 6.90 (d, IH), 6.83 (s, IH), 6.74 (d, IH), 4.48(m, IH), 4.31 (s, 2H), 3.68 (m, 2H), 3.33 (m, 2H), 3.20 (s, 3H), 2.48 (s, 3H), 2.35 (s, 3H), 1.90(m, 2H), 1.70(m, 2H,), 1.49 (s, 9H). LCMS: 512 (M+Na)+.
EXAMPLE 90
N-(4-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yloxy)-2-methylbenzyl)-2-methyl-6-
(methylsulfonyl)pyridin-3-amine
Figure imgf000132_0001
Step 1: 2-Methyl-N-(2-methyl-4-(piperidin-4-yloxy)benzyl)-6-(methylsulfonyl) pyridin-3 -amine
Figure imgf000132_0002
A 250-mL round-bottom flask was charged with a solution of tert-butyl 4-(3-methyl-4- ((2-methyl-6-(methylsulfonyl)pyridin-3-ylamino)methyl)phenoxy)piperidine-l- carboxylate (1 g, 2.04 mmol) in dichloromethane (100 mL) and CF3COOH (10 mL). The resulting solution was stirred at room temperature for 1 h. The reaction progress was monitored by TLC (CH2Cl2IMeOH=S: 1). The reaction mixture was quenched with a water/ice and pH value was adjusted to 9 with sodium hydroxide (5 mol/L). The resulting solution was extracted with dichloromethane (4x50 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give N- (2-methyl-4-(piperidin-4-yloxy)benzyl)-2-methyl-6-(methylsulfonyl)pyridin-3-amine as a yellow solid (0.5 g, 57%). Step 2: N-(4-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yloxy)-2-methylbenzyl)-2-methyl- 6-(methylsulfonyl)pyridin-3-amine
Figure imgf000133_0001
A 250-mL round-bottom flask was charged with a solution of N-(2-methyl-4- (piperidin-4-yloxy)benzyl)-2-methyl-6-(methylsulfonyl)pyridin-3-amine (750 mg, 1.93 mmol) in n-BuOH (150 rnL). This was followed by the addition of 2-chloro-5- ethylpyrimidine (330 mg, 2.32 mmol) and 2-isopropyl-3-methylbutan-l -amine (750 mg, 5.81 mmol). The resulting solution was stirred at 900C in an oil bath for 16 h. The resulting mixture was concentrated under vacuum. The residue was purified by a silica gel column chromatography eluted with dichloromethane/methanol (80/1) affording N- (4-(l-(5-ethylpyrimidin-2-yl)piperidin-4-yloxy)-2-methylbenzyl)-2-methyl-6- (methylsulfonyl)pyridin-3-amine as a white solid (164 mg, 17%). %). 1H NMR (300 MHz, DMSOd6) δ 8.24 (s, 2H), 7.84 (d, IH), 7.18 (d, IH), 6.85 (m, 2H), 6.78 (d, IH), 4.60 (m, IH), 4.30 (d, 2H), 4.17 (m, 3H), 3.77 (m, 2H), 3.17 (s, 3H), 2.50 (m, 2H), 2.46 (s, 3H), 2.36 (s, 3H), 2.03 (m, 2H), 1.87 (m, 2H), 1.20 (m, 3H). LCMS: 496 (M+H)+.
EXAMPLE 91
Tert-butyl 4-(2-methyl-4-((2-methyl-6-(methylsulfonyl)pyridin-3-ylamino)methyl) phenoxy)piperidine-l-carboxylate
Figure imgf000133_0002
The title compound was synthesized as described for EXAMPLE 89 using tert-butyl A- (4-bromo-2-methylphenoxy)piperidine- 1 -carboxylate and 3-bromo-2-methyl-6- (methylsulfonyl)pyridine as the starting materials. 1H NMR (300 MHz, CDCl3) δ 7.81 (d, IH), 7.12 (m, 2H), 6.85 (m, 2H), 4.52 (s, IH), 1.28 (s, IH), 4.33 (s, 2H), 3.64 (m, 2H), 3.34 (m, 2H), 3.17 (s, 3H), 2.26 (s, 3H), 1.78-1.95 (m, 4H), 1.49 (s, 9H). LCMS: 512 (M+Na)+.
EXAMPLE 92
N-(4-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yloxy)-3-methylbenzyl)-2-methyl-6- (methylsulfonyl)pyridin-3-amine
Figure imgf000134_0001
The title compound was synthesized as described for EXAMPLE 90 using tert-butyl A- (2-methyl-4-((2-methyl-6-(methylsulfonyl)pyridin-3-ylamino)methyl)phenoxy) piperidine-1 -carboxylate and 2-chloro-5-methylpyrimidine as the starting materials. 1H NMR (300 MHz, CDCl3) δ 8.24 (s, 2H), 7.57 (d, IH), 7.12 (m, 2H), 6.96 (d, IH), 6.82 (d, 2H), 4.60 (m, IH), 4.34 (s, 2H), 4.02 (m, 2H), 3.59 (m, 2H), 3.07 (s, 3H), 2.49 (m, 5H), 2.13 (s, 3H), 1.91 (m, 2H), 1.60 (m, 2H), 1.13 (t, 3H). LCMS: 496 (M+H)+.
EXAMPLE 93
Tert-butyl 4-(4-((methyl(2-methyl-6-(methylsulfonyl)pyridin-3-yl)amino)methyl) phenoxy)piperidine-l-carboxylate
Figure imgf000134_0002
The title compound was synthesized as described for EXAMPLE 89 using tert-butyl 4- (4-formylphenoxy)piperidine-l-carboxylate and methanamine in Step 3 as the starting materials. 1H NMR (300 MHz, CDCl3) δ 7.76-7.79 (d,, IH), 7.53-7.56 (d, IH), 7.20- 7.23 (d, 2H), 6.93-6.96 (d, 2H), 4.51-4.54 (m, IH), 4.17 (s, 2H), 3.64-3.70 (m, 2H), 3.34 (m, 3H), 3.20 (m, 2H), 2.67 (s, 3H), 2.61 (s, 3H), 2.22 (m, 2H), 1.14-1.54 (m, 2H), 1.14 (s, IH). LCMS: 490 (M+H)+.
EXAMPLE 94
N-(4-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yloxy)benzyl)-N,2-dimethyl-6- (methylsulfonyl)pyridin-3-amine
Figure imgf000135_0001
The title compound was synthesized as described for EXAMPLE 90 using tert-butyl 4- (4-((methyl(2-methyl-6-(methylsulfonyl)pyridin-3-yl)amino)methyl) phenoxy)piperidine-l-carboxylate and 2-chloro-5-methylpyrimidine as the starting materials. 1H NMR (300 MHz, DMSOd6) δ 8.25 (s, 2H), 7.77 (d, IH), 7.55 (d, IH), 7.22 (d, 2H), 6.96 (d, 2H), 6.61 (m, IH), 4.19 (s, 4H), 3.45 (m, 2H), 3.19 (s, 3H), 2.67 (s, 3H), 2.60 (s, 3H), 2.43 (m, 2H), 1.96 (m, 2H), 1.55 (m, 2H), 1.12 (t, 3H). LCMS: 496 (M+H)+.
EXAMPLE 95
N-(l-(4-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yloxy)phenyl)ethyl)-2-methyl-6-
(methylsulfonyl)pyridin-3-amine
Figure imgf000136_0001
The title compound was synthesized as described for EXAMPLE 90 using tert-butyl 4- (4-(l-(2-methyl-6-(methylsulfonyl)pyridin-3-ylamino)ethyl)phenoxy)piperidine-l- carboxylate and 2-chloro-5-methylpyrimidine as the starting materials. 1H NMR (300 MHz, DMSOd6) δ 8.24 (s, 2H), 7.52 (d, IH), 7.31 (d, 2H), 6.92 (d, 2H), 6.74 (d, IH), 6.27 (d, IH), 4.59 (m, 2H), 4.16 (m, 2H), 3.44 (t, 2H), 3.2 (d, 2H), 3.06 (s, 3H), 2.41 (m, 2H), 1.92 (m, 2H), 1.52 (d, 4H), 1.12 (t, 3H). LCMS: 496 (M+H)+.
EXAMPLE 96
Tert-butyl 4-(4-((2-methyl-6-(methylsulfonyl)pyridin-3-ylamino)methyl)phenoxy) piperidine- 1 -carboxylate
Figure imgf000136_0002
The title compound was synthesized as described for EXAMPLE 89 using tert-butyl 4- (4- (aminomethyl)phenoxy)piperidine- 1 -carboxylate and 3-bromo-2-methyl-6- (methylsulfonyl)pyridine as the starting materials. 1H NMR (300 MHz, DMSOd6) δ 7.56 (d, IH), 7.26 (d, 2H), 6.92 (d, 2H), 6.89 (m, IH), 6.81 (d, IH), 4.49 (m, IH), 4.37 (d, 2H), 3.64 (m, 2H), 3.15 (m, 2H), 3.07 (s, 3H), 2.44 (s, 3H), 1.85 (m, 2H), 1.49 (m, 2H), 1.40 (s, 9H). LCMS: 498 (M+Na)+.
EXAMPLE 97
N-(4-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yloxy)benzyl)-2-methyl-6- (methylsulfonyl)pyridin-3-amine
Figure imgf000137_0001
The title compound was synthesized as described for EXAMPLE 90 using tert-butyl 4- (4-((2-methyl-6-(methylsulfonyl)pyridin-3-ylamino)methyl)phenoxy) piperidine-1- carboxylate and 2-chloro-5-methylpyrimidine as the starting materials. 1H NMR (300 MHz, DMSOd6) δ 8.20 (s, 2H), 7.57 (d, IH), 7.27 (d, 2H), 6.94 (d, 2H), 6.85 (m, IH), 6.82 (d, IH), 4.59 (m, IH), 4.38 (d, 2H), 4.16 (m, 2H), 3.45 (m, 2H), 3.07 (s, 3H), 2.41 (m, 5H), 1.94 (m, 2H), 1.53 (m, 2H), 1.12 (t, 3H). LCMS: 482 (M+H)+.
EXAMPLE 98
N-(4-(l-(5-ethylpyrimidin-2-yl)piperidin-4-yloxy)benzyl)-2-methyl-6-(lH-l,2,4- triazol-l-yl)pyridin-3-amine
Figure imgf000137_0002
The title compound was synthesized as described for EXAMPLE 90 using tert-butyl 4- (4-((2-methyl-6-(lH-l,2,4-triazol-l-yl)pyridin-3-ylamino)methyl)phenoxy)piperidine- 1-carboxylate and 2-chloro-5-methylpyrimidine as the starting materials. 1H NMR (300 MHz, DMSOd6) δ 9.05 (s, 2H), 8.24 (s, 2H), 8.13 (s, 2H), 7.39 (d, IH), 7.29 (d, 2H), 6.94 (m, 3H), 6.22 (m, IH), 4.59 (m, IH), 4.34 (d, 2H), 4.16 (m, 2H), 3.46 (m, 2H), 2.41 (m, 5H), 1.94 (m, 2H), 1.55 (m, 2H), 1.12 (t, 3H). LCMS: 493 (M+Na)+.
EXAMPLE 99
6-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yloxy)-N-(2-methyl-6-(methylsulfonyl) pyridin-3-yl)nicotinamide
Figure imgf000138_0001
The title compound was synthesized as described for EXAMPLE 79 using tert-butyl 4- (5-(2-methyl-6-(methylsulfonyl)pyridin-3-ylcarbamoyl)pyridin-2-yloxy)piperidine-l- carboxylate and 2-chloro-5-ethylpyrimidine as the starting materials. 1H NMR (400 MHz, DMSOd6) δ 10.24 (s, IH), 8.82 (d, IH), 8.20 (m, 3H), 7.93 (d, IH), 6.96 (d, IH), 5.37 (m, IH), 4.22 (m, 2H), 3.45 (m, 2H), 3.27 (s, 3H), 2.58 (s, 3H), 2.40 (m, 2H), 2.04 (m, 2HJ, 1.60 (m, 2H), 1.11 (t, 3H). LCMS: 497 (M+H)+.
EXAMPLE 100
N-((6-(l-(5-ethylpyrimidin-2-yl)piperidin-4-yloxy)pyridin-3-yl)methyl)-2-fluoro-4-
(methylsulfonyl)aniline
Figure imgf000139_0001
The title compound was synthesized as described for EXAMPLE 70 using 6-(l-(5- ethylpyrimidin-2-yl)piperidin-4-yloxy)-N-(2-fluoro-4-(methylsulfonyl)phenyl) nicotinamide as the starting material. 1H NMR (300 MHz, DMSOd6) δ 8.25 (s, 2H), 8.18-8.18 (d, IH), 7.67-7.71 (d, IH), 7.43-7.54 (m, 2H), 7.17 (s, IH), 6.76-6.87 (m, 2H), 5.20-5.25 (m, IH), 4.37 (s, 2H), 4.20-4.24 (m, 2H), 3.42-3.48 (m, 2H), 3.10 (s, 3H), 2.40-2.45 (t, 2H), 1.98-2.01 (m, 2H), 1.53-1.60 (m, 2H), 1.11 (t, 3H,). LCMS: 486 (M+H)+.
EXAMPLE 101
Tert-butyl 4-(5-(2-methyl-6-(methylsulfonyl)pyridin-3-ylcarbamoyl)pyrazin-2- yloxy)piperidine-l-carboxylate
Bo
Figure imgf000139_0002
Step 1: Methyl 5-hydroxypyrazine-2-carboxylate
Figure imgf000139_0003
A l-L 3-necked round-bottom flask was charged with a solution of sodium 5- hydroxypyrazine-2-carboxylate (9.4 g, 56.9 mmol, 1.00 equiv, 98%) in methanol (500 mL). Then, thionyl chloride (32 g, 266 mmol, 4.67 equiv, 98%) was added dropwise at -100C. The resulting solution was stirred at -100C for 30 minutes followed refluxing in an oil bath for 2 hrs. The resulting mixture was concentrated under vacuum to give a residue that was purified by a silica gel column chromatography eluted with dichloromethane/methanol (10:1) affording methyl 5-hydroxypyrazine-2-carboxylate as a yellow solid (5.2 g, 59%).
Step 2: Methyl 5-(l-(tert-butoxycarbonyl)piperidin-4-yloxy)pyrazine-2-carboxylate
Figure imgf000140_0001
A 100-mL 3-necked round-bottom flask was charged with a solution of PPh3 (5.2 g, 19.4 mmol, 1.5 equiv, 98%) in tetrahydrofuran (30 mL). Tto this solution was added DEAD (3.4 g, 19.1 mmol, 1.5 equiv, 98%). The resulting solution was stirred for 5 min at -100C in an ice/salt bath. Then, to this solution was added methyl 5- hydroxypyrazine-2-carboxylate (2 g, 12.7 mmol, 1.00 equiv, 98%) and tert-butyl A- hydroxypiperidine-1-carboxylate (3.2 g, 15.6 mmol, 1.2 equiv, 98%). The resulting solution was stirred for 2 h at room temperature. Upon completion, the reaction was then quenched by the addition of 300 mL of NaHCO3 (aq). The resulting solution was extracted with ethyl acetate (3x100 mL). Combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by a silica gel column chromatography eluted with ethyl acetate/petroleum ether (1:10) affording methyl 5-(l-(tert-butoxycarbonyl) piperidin-4-yloxy)pyrazine-2-carboxylate as a yellow solid (1.3 g, 30%). Step 3: Tert-butyl 4-(5-(2-methyl-6-(methylsulfonyl)pyridin-3-ylcarbamoyl)pyrazin-2- yloxy)piperidine- 1 -carboxylate
B
Figure imgf000141_0001
A 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with a solution of methyl 5-(l-(tert-butoxycarbonyl)piperidin-4- yloxy)pyrazine-2-carboxylate (I g, 2.91 mmol, 1.00 equiv, 98%), 2-methyl-6- (methylsulfonyl)pyridin-3-amine (610 mg, 3.21 mmol, 1.11 equiv, 98%), and AlMe3 (2moL/L) (2 mL, 2M in 1,2-dichloroethane (10 mL)). The resulting solution was stirred for 10 min at room temperature. Then, it was heated to 88 0C for 3 h. Upon completion, The resulting mixture was then quenched by the addition of 100 mL of sodium bicarbonate (aq). The resulting solution was extracted with ethyl acetate (3x100 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the crude that was purified by a silica gel column chromatography eluted with ethyl acetate/petroleum ether (1:10) affording tert-butyl 4- (5-((2-methyl-6-(methylsulfonyl)pyridin-3-yl)carbamoyl)pyrazin-2-yloxy)piperidine-l- carboxylate as a white solid (352 mg, 24%). . 1H NMR (300 MHz, DMSOd6) δ 10.41 (s, IH), 8.92 (d, IH), 8.40-8.45 (m, 2H), 7.96 (d, IH), 5.30-5.36 (m, IH), 3.70-3.75 (m, 2H), 3.20-3.28 (m, 5H), 2.61 (s, 3H), 2.03 (d, 2H), 1.63-1.69 (m, 2H), 1.42 (s, 9H). LCMS: 492 (M+H)+.
EXAMPLE 102
5-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yloxy)-N-(2-methyl-6-(methylsulfonyl) pyridin-3-yl)pyrazine-2-carboxamide
Figure imgf000142_0001
The title compound was synthesized as described for EXAMPLE 79 using tert-butyl 4- (5-(2-methyl-6-(methylsulfonyl)pyridin-3-ylcarbamoyl)pyrazin-2-yloxy)piperidine-l- carboxylate and 2-chloro-5-ethylpyrimidine as the starting materials. 1H NMR (400 MHz, DMSOd6) δ 10.42 (s, IH), 8.94 (d, IH), 8.40-8.46 (m, 2H), 8.28 (s, 2H), 7.96 (d, IH), 5.40-5.44 (m, IH), 4.21-4.27 (m, 2H), 3.49-3.57 (m, 2H), 3.31 (t, 3H), 2.61 (s, 3H), 2.43 (t, 2H), 2.07 (d, 2H), 1.66-1.76 (m, 2H), 1.14 (d, 3H). LCMS: 498 (M+H)+.
EXAMPLE 103
5-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yloxy)-N-(2-fluoro-4-(methylsulfonyl) phenyl)pyrazine-2-carboxamide
Figure imgf000142_0002
The title compound was synthesized as described for EXAMPLE 79 using tert-butyl 4- (5-(2-fluoro-4-(methylsulfonyl)phenylcarbamoyl)pyrazin-2-yloxy)piperidine-l- carboxylate and 2-chloro-5-ethylpyrimidine as the starting materials. 1H NMR (400 MHz, DMSOd6) δ 10.38 (s, IH), 8.94 (d, IH), 8.45 (s, IH), 8.38 (m, IH), 8.27 (s, 2H), 7.91 (m, 2H), 5.42 (m, IH), 4.56 (m, 2H), 3.56 (m, 2H), 3.31 (s, 3H), 2.44 (m, 2H), 2.10 (m, 2H), 1.71 (m, 2H), 1.14 (t, 3H). LCMS: 501 (M+H)+.
EXAMPLE 104
Tert-butyl 4-(5-((2-fluoro-4-(methylsulfonyl)phenylamino)methyl)pyrazin-2- yloxy)piperidine-l-carboxylate
Figure imgf000143_0001
Step 1: Tert-butyl 4-(5-(hydroxymethyl)pyrazin-2-yloxy)piperidine-l-carboxylate
Figure imgf000143_0002
A solution of methyl 5-(l-(tert-butoxycarbonyl)piperidin-4-yloxy)pyrazine-2- carboxylate (8 g, 21.4 mmol, 1.00 equiv, 90%) in tetrahydrofuran (200 niL) and LiBH4 (1.04 g, 46.8 mmol, 2.00 equiv, 99%) was stirred at 800C in an oil bath overnight. The reaction was then quenched by the addition of water (200 mL). The resulting solution was extracted with ethyl acetate (3x200 mL). Combined organic layers were dried over sodium sulfate, filtered and concentrated to give tert-butyl 4-(5- (hydroxymethyl)pyrazin-2-yloxy)piperidine-l-carboxylate as yellow oil (7 g). Step 2: Tert-butyl 4-(5-(bromomethyl)pyrazin-2-yloxy)piperidine- 1-carboxylate
Bo
Figure imgf000144_0001
A solution of tert-butyl 4-(5-(hydroxymethyl)pyrazin-2-yloxy)piperidine- 1-carboxylate (7 g, 11.3 mmol, 1.00 equiv, 50%) in dichloromethane (100 niL), CBr4 (11 g, 33.20 mmol, 1.45 equiv, 99%) and PPh3 (8.9 g, 33.5 mmol, 1.50 equiv, 99%) was stirred at 0 0C in a water/ice bath for 1 h. The resulting mixture was concentrated under vacuum. The residue was purified by a silica gel column chromatography eluted with ethyl acetate/petroleum ether (20:80) affording tert-butyl 4-(5-(bromomethyl)pyrazin-2- yloxy)piperidine- 1-carboxylate as a white solid (2 g, 48%).
Step 3: Tert-butyl 4-(5-((2-fluoro-4-(methylsulfonyl)phenylamino)methyl)pyrazin-2- yloxy)piperidine- 1 -carboxylate
Figure imgf000144_0002
A solution of tert-butyl 4-(5-(bromomethyl)pyrazin-2-yloxy)piperidine- 1-carboxylate (1 g, 2.43 mmol, 1.00 equiv, 90%) in MeCN (15 mL), 2-fluoro-4- (methylsulfonyl)benzenamine (760 mg, 3.98 mmol, 1.50 equiv, 99%) and Cs2CO3 (2.6 g, 7.90 mmol, 3.00 equiv, 99%) was irradiated in a microwave at 80 0C for 1 h. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC using a C-18 column eluted with MeCNiH2O = 1:100 to 50:50 affording tert-butyl 4-(5-((2-fluoro-4-(methylsulfonyl)phenylamino)methyl)pyrazin-2- yloxy)piperidine- 1-carboxylate as a yellow solid (600 mg, 52%). 1H NMR (300 MHz, DMSO-d6) δ 8.25 (d, IH), 8.18 (s, IH), 7.45-7.56 (m, 2H), 7.15 (s, IH), 6.86 (t, IH), 5.11-5.17 (m, IH), 4.51 (d, 2H), 3.65-3.71 (m, 2H), 3.18 (t, 2H), 3.11 (s, 3H), 1.94 (d, 2H), 1.54-1.60 (m, 2H), 1.41 (s, 9H). LCMS: 503 (M+Na)+. EXAMPLE 105
Tert-butyl 4-(5-((2-methyl-6-(methylsulfonyl)pyridin-3-ylamino)methyl)pyridin-2- yloxy)piperidine-l-carboxylate
Bo
Figure imgf000145_0001
The title compound was synthesized as described for EXAMPLE 70 using tert-butyl 4- (5-(2-methyl-6-(methylsulfonyl)pyridin-3-ylcarbamoyl)pyridin-2-yloxy)piperidine-l- carboxylate as the starting material. 1H NMR (300 MHz, DMSOd6) δ 8.15-8.16 (d, IH), 7.67-7.70 (m, IH), 7.58-7.60 (d,, IH), 6.74-6.92 (m, 3H), 5.10-5.159 (m, IH), 4.38-4.40 (d, 2H), 3.65-3.71 (m, 2H), 3.11-3.18 (t, 2H), 3.07 (s, 3H), 2.43 (s, 3H), 1.90-1.93 (m, 2H), 1.45-1.57 (m, 2H), 1.40 (s, 9H). LCMS: 499 (M+Na)+.
EXAMPLE 106
Tert-butyl 4-(5-((2-methyl-6-(methylsulfonyl)pyridin-3-ylamino)methyl)pyrazin-2- yloxy)piperidine-l-carboxylate
Bo
Figure imgf000145_0002
The title compound was synthesized as described for EXAMPLE 104 using tert-butyl 4-(5-(bromomethyl)pyrazin-2-yloxy)piperidine-l -carboxylate and 2-methyl-6- (methylsulfonyl)pyridin-3-amine as the starting materials. 1H NMR (300 MHz, DMSOd6) δ 8.24 (s, IH), 8.19 (s, IH), 7.61 (d, IH), 6.94 (d, IH), 6.88 (s, IH), 5.13 (m, IH), 4.52 (d, 2H), 3.69 (d, 2H), 3.17 (s, 2H), 3.09 (s, 3H), 2.44 (s, 3H), 1.93 (s, 2H), 1.57 (d, 2H), 1.41 (s, 9H). LCMS: 478 (M+H)+. EXAMPLE 107
N-((6-(l-(5-ethylpyrimidin-2-yl)piperidin-4-yloxy)pyridin-3-yl)methyl)-2-methyl-
6-(methylsulfonyl)pyridin-3-amine
Figure imgf000146_0001
The title compound was synthesized as described for EXAMPLE 70 using 6-(l-(5- ethylpyrimidin-2-yl)piperidin-4-yloxy)-N-(2-methyl-6-(methylsulfonyl)pyridin-3- yl)nicotinamide as the starting material. 1H NMR (300 MHz, DMSOd6) δ 8.18-8.25 (m, 3H), 7.67-7.71 (m, IH), 7.58-7.61 (d, IH), 6.75-6.93 (m, 3H), 5.19-5.25 (m, IH), 4.39-4.40 (d, 2H), 4.20-4.25 (m, 2H), 3.39-3.46 (t, 2H), 3.08 (s, 3H), 2.39-2.47 (m, 5H), 1.98-2.01 (m, 2H), 1.52-1.63 (m, 2H), 1.10-1.15 (t, 3H).LCMS: 483 (M+H)+.
EXAMPLE 108
N-((5-(l-(5-ethylpyrimidin-2-yl)piperidin-4-yloxy)pyrazin-2-yl)methyl)-2-fluoro-4-
(methylsulfonyl)aniline
Figure imgf000146_0002
The title compound was synthesized as described for EXAMPLE 70 using 5-(l-(5- ethylpyrimidin-2-yl)piperidin-4-yloxy)-N-(2-fluoro-4-(methylsulfonyl)phenyl) pyrazine-2-carboxamide as the starting material. 1H NMR (300 MHz, DMSOd6) δ 8.26 (s, 2H), 8.20 (s, IH), 7.46-7.56 (m, 2H), 7.17 (s, IH), 6.87 (t, IH), 5.23 (s, IH), 4.51 (d, 2H), 4.22 (d, 2H), 3.47 (t, 2H), 3.12 (s, 3H), 2.43 (t, 2H), 2.01 (s, 2H), 1.63 (d, 2H), 1.12-1.25 (m, 3H). LCMS: 487 (M+H)+.
EXAMPLE 109
N-((5-(l-(5-ethylpyrimidin-2-yl)piperidin-4-yloxy)pyrazin-2-yl)methyl)-2-methyl-
6-(methylsulfonyl)pyridin-3-amine
Figure imgf000147_0001
The title compound was synthesized as described for EXAMPLE 70 using 5-(l-(5- ethylpyrimidin-2-yl)piperidin-4-yloxy)-N-(2-methyl-6-(methylsulfonyl)pyridin-3- yl)pyrazine-2-carboxamide as the starting material. 1H NMR (300 MHz, DMSO-dβ) δ
8.20-8.26 (m, 4H), 7.61 (d, IH), 6.95 (d, IH), 6.87 (t, IH), 5.22 (d, IH), 4.52 (d 2H), 4.18-4.24 (m, 2H), 3.42-3.50 (m, 2H), 3.09 (s, 3H), 2.40-2.52 (m, 5H), 2.02 (t, 2H), 1.60-1.68 (m, 2H), 1.14 (t, 3H). LCMS: 484 (M+H)+.
[0229] The following compounds can generally be made using the methods described above and methods known in the art, and may not have been synthesized yet or tested. It is expected that these compounds when made will have activity similar to those that have been made in the examples above. The following compounds are represented herein using the Simplified Molecular Input Line Entry System, or SMILES. SMILES is a modern chemical notation system, developed by David Weininger and Daylight Chemical Information Systems, Inc., that is built into all major commercial chemical structure drawing software packages. Software is not needed to interpret SMILES text strings, and an explanation of how to translate SMILES into structures can be found in Weininger, D., /. Chem. Inf. Comput. ScL 1988, 28, 31-36. All SMILES strings used herein, as well as many IUPAC names, were generated using CambridgeSoft's ChemDraw 10.0 or CambridgeSoft's ChemDraw 11.0.
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4CCN(CC%14)C%15=NC=C(C(F)(F)F)C=N%15 FC% 16=CC(S(=O)(C)=O)=CC=C% 16C(C=C% 17)=C(CCCC% 18)C% 18=C% 17OC%
19CCN(CC% 19)C%20=NC=C(C(F)(F)F)C=N%20 FC%21=CC(S(=O)(C)=O)=CC=C%21C(C=C%22)=C(C=CC=C%23)C%23=C%22O
C%24CCN(CC%24)C%25=NC=C(C(F)(F)F)C=N%25 FC%26=CC(S(=O)(C)=O)=CC=C%26C(C=C%27)=C(NC=C%28)C%28=C%27OC%
29CCN(CC%29)C%30=NC=C(C(F)(F)F)C=N%30 CCC%31=CN=C(N=C%31)N(CC%32)CCC%32OC%33=CN(C%34=C(F)C=C(S(=O)
(C)=O)C=C%34)C%35=C%33N=CC=C%35 CCC%36=CN=C(N=C%36)N(CC%37)CCC%37OC%38=CN(C%39=C(F)C=C(S(=O)
(C)=O)C=C%39)C%40=C%38C=CC=C%40 CCC%41=CN=C(N=C%41)N(CC%42)CCC%42OC%43=CN=C(N%44C%43=NC=C
%44)C%45=CC=C(S(=O)(C)=O)C=C%45F CCC%46=CN=C(N=C%46)N(CC%47)CCC%47OC%48=C%49C(CCCC%49)=C(C%
50=CC=C(S(=O)(C)=O)C=C%50F)C=C%48 CCC%51=CN=C(N=C%51)N(CC%52)CCC%52OC%53=C%54C(C=CC=C%54)=C(
C%55=CC=C(S(=O)(C)=O)C=C%55F)C=C%53 CCC%56=CN=C(N=C%56)N(CC%57)CCC%57OC%58=C%59C(NC=C%59)=C(C%
60=CC=C(S(=O)(C)=O)C=C%60F)C=C%58 C1C1=CN=C(N=C1)N(CC2)CCC2OC3=CC=C(C(C(F)=C4)=CC=C4N5C=NN=N5)C
=C3 FC6=CC(N7C=NN=N7)=CC=C6C(C=C8)=CC=C8OC9CCN(CC9)C% 1O=NC=C(C(F
)(F)F)C=N%10 FC% 11=CC(N% 12C=NN=N% 12)=CC=C% 11C(C=C% 13)=CC=C% 13OC% 14CCN(
CC% 14)C% 15=NC(C(C)C)=NO% 15 C1C%16=CN=C(N=C%16)N(CC%17)CCC%17OC%18=CC=C(C(C(F)=C%19)=CC=
C% 19S (=O)(C)=O)C=C% 18 FC%20=CC(S(=O)(C)=O)=CC=C%20C(C=C%21)=CC=C%21OC%22CCN(CC%22)
C%23=NC(C(C)C)=NO%23 FC%24=CC(S(=O)(C)=O)=CC=C%24C(C=C%25)=CC=C%25OC%26CCN(CC%26)
C%27=NC=C(C(F)(F)F)C=N%27 ClC%28=CN=C(N=C%28)N(CC%29)CCC%29OC%30=CC=C(C(C(C)=N%31)=CC=
C%31N%32C=NC=N%32)C=C%3O CC%33=NC(N%34C=NC=N%34)=CC=C%33C(C=C%35)=CC=C%35OC%36CCN(
CC%36)C%37=NC=C(C(F)(F)F)C=N%37 CC%38=NC(N%39C=NC=N%39)=CC=C%38C(C=C%40)=CC=C%40OC%41CCN(
CC%41)C%42=NC(C(C)C)=NO%42 C1C%43=CN=C(N=C%43)N(CC%44)CCC%44OC%45=CC=C(C(C(C)=N%46)=CC=
C%46S(=O)(C)=O)C=C%45 CC%47=NC(S(=O)(C)=O)=CC=C%47C(C=C%48)=CC=C%48OC%49CCN(CC%49)
C%50=NC(C(C)C)=NO%50 CCC%51=CN=C(N=C%51)N(CC%52)CCC%52OC%53=CC=C(C(C(C)=N%54)=CC
=C%54S(=O)(C)=O)C=C%53 CC%55=NC(S(=O)(C)=O)=CC=C%55C(C=C%56)=CC=C%56OC%57CCN(CC%57)
C%58=NC=C(C(F)(F)F)C=N%58 CCC I=CN=C(N=C 1 )C(CC2)CCN2CC3=CC=C(C4=CC=C(S (=O)(C)=O)C=C4F)C=C
3 CCC5=CN=C(N=C5)C(CC6)CCN6CC7=CC=C(C8=CC=C(N9N=NN=C9)C=C8F)C=
C7 CCC% 10=CN=C(N=C% 10)N(CC% 11)CCN% 11CC% 12=CC=C(C% 13=CC=C(N% 14
N=NN=C% 14)C=C% 13F)C=C% 12 FC%15=CC(S(=O)(C)=O)=CC=C%15C(C=C%16)=CC=C%16OC%17CCN(CC%17)
C% 18=NC(CC)=CC=N% 18 FC% 19=CC(N%20N=NN=C%20)=CC=C% 19C(C=C%21 )=CC=C%21 OC%22CCN(
CC%22)C%23=NC(CC)=CC=N%23 FC%24=CC(S(=O)(C)=O)=CC=C%24C(C=C%25)=CC=C%25OC%26CCN(CC%26)
C%27=NC=C(CC(C)C)C=N%27 FC%28=CC(N%29N=NN=C%29)=CC=C%28C(C=C%30)=CC=C%30OC%31CCN(
CC%31)C%32=NC=C(CC(C)C)C=N%32 FC%33=CC(S(=O)(C)=O)=CC=C%33C(C=C%34)=CC=C%34CC%35CCN(CC%35)
C%36=NC=C(CC)C=N%36 FC%37=CC(N%38N=NN=C%38)=CC=C%37C(C=C%39)=CC=C%39CC%40CCN(
CC%40)C%41=NC=C(CC)C=N%41 FC%42=CC(S(=O)(C)=O)=CC=C%42C(C=C%43)=CC=C%43NC%44CCN(CC%44)
C%45=NC=C(CC)C=N%45 FC%46=CC(N%47N=NN=C%47)=CC=C%46C(C=C%48)=CC=C%48NC%49CCN(
CC%49)C%50=NC=C(CC)C=N%50 FC%51=CC(S(=O)(C)=O)=CC=C%51C(C=C%52)=CC=C%52N(C)C%53CCN(CC%
53)C%54=NC=C(CC)C=N%54 FC%55=CC(N%56N=NN=C%56)=CC=C%55C(C=C%57)=CC=C%57N(C)C%58CC
N(CC%58)C%59=NC=C(CC)C=N%59 FC1=CC(N2C=NN=N2)=CC=C1C(C=C3)=CC=C3OC4CCN(CC4)C5=NC=C(C(C)C)
C=N5 FC6=CC(N7C=NN=N7)=CC=C6C(C=C8)=CC=C8OC9CCN(CC9)C% 1O=NC=C(CC)
C=C%10 FC% 1 I=CC(S (=O)(C)=O)=CC=C% 11C(C=C% 12C)=CC=C% 12OC% 13CCN(CC% 1
3)C% 14=NC=C(CC)C=N% 14 FC% 15=CC(N% 16N=NN=C% 16)=CC=C% 15C(C=C% 17C)=CC=C% 17OC% 18CCN
(CC% 18)C% 19=NC=C(CC)C=N% 19 FC%20=CC(S (=O)(C)=O)=CC=C%20C(C(C)=C%21 )=CC=C%21 OC%22CCN(CC%
22)C%23=NC=C(CC)C=N%23 FC%24=CC(N%25N=NN=C%25)=CC=C%24C(C(C)=C%26)=CC=C%26OC%27CC
N(CC%27)C%28=NC=C(CC)C=N%28 FC%29=CC(S(=O)(C)=O)=CC=C%29C(C=C%30)=CC=C%30OC%31CC(C)N(C(C)
C%31)C%32=NC=C(CC)C=N%32 FC%33=CC(N%34N=NN=C%34)=CC=C%33C(C=C%35)=CC=C%35OC%36CC(C)
N(C(C)C%36)C%37=NC=C(CC)C=N%37 FC%38=CC(S(=O)(C)=O)=CC=C%38C(C=C%39)=CC=C%39OCC%40CCN(CC%4
0)C%41=NC=C(CC)C=N%41 FC%42=CC(N%43C=NN=N%43)=CC=C%42C(C=C%44)=CC=C%44OCC%45CCN
(CC%45)C%46=NC=C(CC)C=N%46 FC%47=CC(S(=O)(C)=O)=CC=C%47C(C=C%48)=CC=C%48COC%49CCN(CC%4
9)C%50=NC=C(CC)C=N%50 FC%51=CC(N%52C=NN=N%52)=CC=C%51C(C=C%53)=CC=C%53COC%54CCN
(CC%54)C%55=NC=C(CC)C=N%55 CCC%56=CN=C(N=C%56)N(CC%57)CCC%57OC%58=CC=C(CC%59=CC=C(S(=
O)(C)=O)C=C%59F)C=C%58 CCC%60=CN=C(N=C%60)N(CC%61)CCC%61OC%62=CC=C(CC%63=CC=C(N%
64C=NN=N%64)C=C%63F)C=C%62
FC1=CC(N2C=NN=N2)=CC=C1C3=CSC(CC4CCN(CC4)C5=NC=C(CC)C=N5)=N3 FC6=CC(NVC=NN=NV)=CC=C6C8=CC(N(C)C9CCN(CC9)C%10=NC=C(C(F)(F)F)
C=N%10)=NS8 FC% 11=CC(N% 12C=NN=N% 12)=CC=C% 11C% 13=NC(CC% 14CCN(CC% 14)C% 1
5=NC=C(CC)C=N% 15)=CS% 13 FC% 16=CC(N% 1VC=NN=N% 1V)=CC=C% 16N% 18N=NC(NC% 19CCN(CC% 19)C
%20=NC=C(CC)C=N%20)=C% 18 C1C%21=CN=C(N=C%21)N(CC%22)CCC%22CC%23=NN(C(C(F)=C%24)=CC=C
%24N%25C=NN=N%25)N=C%23 FC%26=CC(N%2VC=NN=N%2V)=CC=C%26N%28C=NC(OC%29CCN(CC%29)C%
30=NC=C(C(F)(F)F)C=N%30)=C%28 FC%31=CC(N%32C=NN=N%32)=CC=C%31N%33N=CC(CC%34CCN(CC%34)C%
35=NC=C(CC)C=N%35)=C%33 FC%36=CC(N%3VC=NN=N%3V)=CC=C%36N%38C=CC(NC%39CCN(CC%39)C%
40=NC=C(CC)C=N%40)=N%38 FC%41=CC(N%42C=NN=N%42)=CC=C%41N%43C=CC(CC%44CCN(CC%44)C%
45=NC=C(C(F)(F)F)C=N%45)=C%43 CCC%46=CN=C(N=C%46)N(CC%4V)CCC%4VCC%48=NC(C(C(F)=C%49)=CC=C
%49N%50C=NN=N%50)=NO%48 CCC%51=CN=C(N=C%51)N(CC%52)CCC%52OC%53=NC(C(C(F)=C%54)=CC=C
%54N%55C=NN=N%55)=CS%53 CCC%56=CN=C(N=C%56)N(CC%5V)CCC%5VOC%58=NSC(C(C(F)=C%59)=CC=
C%59N%60C=NN=N%60)=C%58 CCC%61=CN=C(N=C%61)N(CC%62)CCC%62OC%63=CSC(C(C(F)=C%64)=CC=
C%64N%65C=NN=N%65)=N%63 CCC%66=CN=C(N=C%66)N(CC%6V)CCC%6VOC%68=NN=C(C(C(F)=C%69)=CC
=C%69N%V0C=NN=N%V0)O%68 CCC%71=CN=C(N=C%71)N(CC%72)CCC%72OC%73=NC=C(C(C(F)=C%74)=CC
=C%74N%75C=NN=N%75)0%73 CCC%76=CN=C(N=C%76)N(CC%77)CCC%77OC%78=CN=C(C(C(F)=C%79)=CC
=C%79N%80C=NN=N%80)O%78 CCC% 81=CN=C(N=C% 81 )N(CC%82)CCC% 82OC% 83=NN=C(C(C(F)=C% 84)=CC
=C%84N%85C=NN=N%85)S%83 CCC%86=CN=C(N=C%86)N(CC%87)CCC%87OC%88=NC=C(C(C(F)=C%89)=CC
=C%89N%90C=NN=N%90)S%88 CCC%91=CN=C(N=C%91)N(CC%92)CCC%92OC%93=CN(C(C(F)=C%94)=CC=C
%94N%95C=NN=N%95)N=N%93 CCC%96=CN=C(N=C%96)N(CC%97)CCC%97OC%98=NN(C(C(F)=C%99)=CC=C
%99N%100C=NN=N%100)N=C%98 CCC%101=CN=C(N=C%101)N(CC%102)CCC%102OC%103=CN(C(C(F)=C%104)
=CC=C% 104N% 105C=NN=N% 105)C=N% 103 CCC%106=CN=C(N=C%106)N(CC%107)CCC%107OC%108=CN(C(C(F)=C%109)
=CC=C% 109N% 110C=NN=N% 110)N=C% 108 CCC% 111=CN=C(N=C% 111)N(CC% 112)CCC% 112OC% 113=NN(C(C(F)=C% 114)
=CC=C% 114N% 115C=NN=N% 115)C=C% 113 CCC% 116=CN=C(N=C% 116)N(CC% 117)CCC% 117OC% 118=CN=C(C(C(F)=C% 11
9)=CC=C% 119N% 120C=NN=N% 120)S% 118 CCC%121=CN=C(N=C%121)N(CC%122)CCC%122OC%123=CN(C(C(F)=C%124)
=CC=C% 124N% 125C=NN=N% 125)C=C% 123
FC1=CC(S(=O)(C)=O)=CC=C1C(C=C2)=CC=C2CN3CCN(CC3)C(OC(C)C)=O FC4=CC(N5N=NN=C5)=CC=C4C(C=C6)=CC=C6CN7CCN(CC7)C(OC(C)C)=O FC8=CC(S(=O)(C)=O)=CC=C8C(C=C9)=CC=C9CC%10CCN(C(OC(C)C)=O)CC%l
0 FC% 11=CC(N% 12N=NN=C% 12)=CC=C% 11C(C=C% 13)=CC=C% 13CC% 14CCN(
C(OC(C)C)=O)CC%14 FC% 15=CC(S (=O)(C)=O)=CC=C% 15C(C=C% 16)=CC=C% 16NC% 17CCN(CC% 17)
C(OC(C)C)=O FC%18=CC(N%19N=NN=C%19)=CC=C%18C(C=C%20)=CC=C%20NC%21CCN(
C(OC(C)C)=O)CC%21 FC%22=CC(S(=O)(C)=O)=CC=C%22C(C=C%23)=CC=C%23N(C)C%24CCN(CC%
24)C(OC(C)C)=O FC%25=CC(N%26N=NN=C%26)=CC=C%25C(C=C%27)=CC=C%27N(C)C%28CC
N(CC%28)C(OC(C)C)=O FC%29=CC(S(=O)(C)=O)=CC=C%29C(C=C%30)=CC=C%30OC%31CCN(CC%31)
C(OC(C)(C)C)=O FC%32=CC(S(=O)(C)=O)=CC=C%32C(C=C%33)=CC=C%33CC%34CCN(C(OC(C)
(C)C)=O)CC%34 FC%35=CC(N%36N=NN=C%36)=CC=C%35C(C=C%37)=CC=C%37CC%38CCN(
C(OC(C)(C)C)=O)CC%38 FC%39=CC(S(=O)(C)=O)=CC=C%39C(C=C%40)=CC=C%40NC%41CCN(CC%41)
C(OC(C)(C)C)=O FC%42=CC(N%43N=NN=C%43)=CC=C%42C(C=C%44)=CC=C%44NC%45CCN(
C(OC(C)(C)C)=O)CC%45 FC%46=CC(S(=O)(C)=O)=CC=C%46C(C=C%47)=CC=C%47N(C)C%48CCN(CC%
48)C(OC(C)(C)C)=O FC%49=CC(N%50N=NN=C%50)=CC=C%49C(C=C%51)=CC=C%51N(C)C%52CC
N(CC%52)C(OC(C)(C)C)=O
CC1=NC(N2C=NN=N2)=CC=C1C(C=C3)=CC=C3OC4CCN(CC4)C(OC(C)C)=O FC5=CC(C(C=C6)=CC=C6OC7CCN(CC7)C(OC(C)C)=O)=CC=C5S(=O)(C)=O O=C(OC(C)C)N(CC8)CCC8OC9=CC=C(C% 1 O=CC=C(S (=O)(C)=O)C=C% 10)C=C9 O=C(OC(C)C)N(CC% 11)CCC% 11OC% 12=CC=C(C(C=C% 13)=CC=C% 13N% 14C=
NN=N%14)C=C%12 FC% 15=CC(S (=O)(C)=O)=CC=C% 15C(C=C% 16)=CC=C% 16OC(CC% 17)CN% 17C
(OC(C)C)=O FC%18=CC(N%19N=NN=C%19)=CC=C%18C(C=C%20)=CC=C%20OC(CC%21)C
N%21C(OC(C)C)=O FC%22=CC(S(=O)(C)=O)=CC=C%22C(C=C%23C)=CC=C%23OC%24CCN(CC%2
4)C(OC(C)C)=O FC%25=CC(N%26N=NN=C%26)=CC=C%25C(C=C%27C)=CC=C%27OC%28CCN
(CC%28)C(OC(C)C)=O FC%29=CC(S(=O)(C)=O)=CC=C%29C(C(C)=C%30)=CC=C%30OC%31CCN(CC%
3I)C(OC(C)C)=O FC%32=CC(N%33N=NN=C%33)=CC=C%32C(C(C)=C%34)=CC=C%34OC%35CC
N(CC%35)C(OC(C)C)=O FC%36=CC(S(=O)(C)=O)=CC=C%36C(C=C%37)=CC=C%37OC%38C(C)CN(CC%
38C)C(OC(C)C)=O FC%39=CC(N%40N=NN=C%40)=CC=C%39C(C=C%41 )=CC=C%41 OC%42C(C)C
N(CC%42C)C(OC(C)C)=O FC%43=CC(S(=O)(C)=O)=CC=C%43C(C=C%44)=CC=C%44OC%45CC(C)N(C(C)
C%45)C(OC(C)C)=O FC%46=CC(N%47N=NN=C%47)=CC=C%46C(C=C%48)=CC=C%48OC%49CC(C)
N(C(C)C%49)C(OC(C)C)=O FC%50=CC(S(=O)(C)=O)=CC=C%50C(C=C%51)=CC=C%51OC(CC%52)CN%52C
(OC(C)(C)C)=O FC%53=CC(N%54N=NN=C%54)=CC=C%53C(C=C%55)=CC=C%55OC(CC%56)C
N%56C(OC(C)(C)C)=O CC%57=NC(N%58C=NN=N%58)=CC=C%57C(C=C%59)=CC=C%59OC%60CCN(
CC%60)C(OC(C)(C)C)=O FC%61=CC(C(C=C%62)=CC=C%62OC%63CCN(CC%63)C(OC(C)(C)C)=O)=CC=
C%61S(=0)(C)=0
O=C(OC(C)C)N(CC 1 )CCC 1 OC2=CC=C(C3=CC(S (=O)(C)=O)=CC=C3)C=C2 O=C(OC(C)C)N(CC4)CCC4OC5=CC=C(C6=CC(N7C=NN=N7)=CC=C6)C=C5 O=C(OC(C)C)N(CC8)CCC8OC9=CC(C%10=CC=C(S(=O)(C)=O)C=C%10)=CC=C9 0=C(0C(C)C)N(CC% 11)CCC% 110C% 12=CC(C% 13=CC=C(N% 14C=NN=N% 14)
C=C%13)=CC=C%12 0=C(0C(C)C)N(CC% 15)CCC% 150C% 16=CC(C% 17=CC(S(=0)(C)=0)=CC=C% 17
)=CC=C%16 0=C(0C(C)C)N(CC% 18)CCC% 180C% 19=CC(C%20=CC(N%21N=NN=C%21 )=C
C=C%20)=CC=C%19 FC%22=CC(S(=O)(C)=O)=CC=C%22NC(C=C%23)=CC=C%23OC%24CCN(CC%2
4)C(OC(C)C)=O FC%25=CC(S(=O)(C)=O)=CC=C%25C(C=C%26)=CC=C%26OC(C%27)CN%27C(
OC(C)C)=O O=C(OC(C)(C)C)N(CC1)CC=C1C2=CN=C3N2C=CN=C3NC4=CC(F)=C(S(C)(=O)=
O)C=C4 O=C(OC(C)(C)C)N(CC1)CCC1C2=CN=C3N2C=CN=C3NC4=C(C)N=C(N5C=NN=
N5)C=C4 O=C(OC(C)(C)C)N(CC1)CCC1C2=CN=C3N2C=CN=C3NC4=CC(F)=C(S(C)(=O)=
O)C=C4 FC(C=C(S (C)C=O)=O)C=C 1 )=C 1NC2=NC=CN3C2=CN=C3C4=CCN(C(OC(C)C)=O
)CC4 FC(C=C(S (C)C=O)=O)C=C 1 )=C 1NC2=NC=CN3C2=CN=C3C4CCN(C(OC(C)C)=O)
CC4 FC(C=C(S (CX=O)=O)C=C 1 )=C 1NC2=CC=CN3C2=NC=C3C4CCN(C(OC(C)C)=O)
CC4 O=C(OC(C)C)N(CC1)CC=C1C2=CN=C3N2C=CN=C3NC4=C(C)N=C(S(C)(=O)=O)
C=C4 O=C(OC(C)C)N(CC1)CC=C1C2=CN=C3N2C=CN=C3NC4=C(F)C=C(N5C=NN=N5
)C=C4 O=C(OC(C)C)N(CC1)CCC1C2=CN=C3N2C=CN=C3NC4=C(C)N=C(S(C)(=O)=O)C
=C4 O=C(OC(C)(C)C)N(CC1)CC=C1C2=NC=C3N2C=CN=C3NC4=CC(F)=C(S(C)(=O)=
0)C=C4 O=C(OC(C)(C)C)N(CC1)CCC1C2=NC=C3N2C=CN=C3NC4=CC(F)=C(S(C)(=O)=
0)C=C4 O=C(OC(C)(C)C)N(CC1)CCC1C2=CN=C3N2C=CC=C3NC4=CC(F)=C(S(C)(=O)=
0)C=C4 O=C(OC(C)(C)C)N(CC1)CCC1C2=CN=C3N2C=CC=C3NC4=CC(F)=C(S(C)(=O)=
0)C=C4 O=C(OC(C)C)N(CC1)CC=C1C2=CN=C3N2C=CN=C3NC4=CC(F)=C(N5C=NN=N5
)C=C4 O=C(OC(C)(C)C)N(CC1)CCC1C2=CN=C3N2C=CN=C3NC4=C(C)N=C(N5C=NC=
N5)C=C4 O=C(OC(C)C)N(CC1)CC=C1C2=NC=C3N2C=CN=C3NC4=C(C)N=C(S(C)(=O)=O)
C=C4 O=C(OC(C)C)N(CC1)CCC1C2=NC=C3N2C=CN=C3NC4=C(C)N=C(S(C)(=O)=O)C
=C4 O=C(OC(C)C)N(CC1)CCC1C2=CN=C3N2C=CC=C3NC4=C(C)N=C(S(C)(=O)=O)C
=C4 O=C(OC(C)C)N(CC1)CC=C1C2=CN=C3N2C=CN=C3NC4=C(C)N=C(N5C=NC=N5
)C=C4 O=C(OC(C)C)N(CC1)CCC1C2=CN=C3N2C=CN=C3NC4=C(C)N=C(N5C=NC=N5)
C=C4 O=C(OC(C)(C)C)N(CC1)CC=C1C2=NC=C3N2C=CN=C3NC4=C(C)N=C(N5C=NC
=N5)C=C4 O=C(OC(C)(C)C)N(CC1)CCC1C2=NC=C3N2C=CN=C3NC4=C(C)N=C(N5C=NC=
N5)C=C4 O=C(OC(C)(C)C)N(CC1)CCC1C2=CN=C3N2C=CC=C3NC4=C(C)N=C(N5C=NC=
N5)C=C4 FC(C=C(S (C)C=O)=O)C=C 1 )=C 1NC2=CC=CN3C2=NC=C3C4CCN(C(OC(C)(C)C)=
O)CC4 O=C(OC(C)C)N(CC1)CC=C1C2=CN=C3N2C=CN=C3NC4=C(C)N=C(N5C=NN=N
5)C=C4 O=C(OC(C)(C)C)N(CC1)CC=C1C2=NC=C3N2C=CN=C3NC4=C(C)N=C(N5C=NN
=N5)C=C4 O=C(OC(C)C)N(CC1)CC=C1C2=CN=C3N2C=CC=C3NC4=C(C)N=C(N5C=NN=N5
)C=C4 FC(C=C(S (C)C=O)=O)C=C 1 )=C 1NC2=NC=CN3C2=NN=C3C4CCN(C(OC(C)C)=O)
CC4 O=C(OC(C)C)N(CC1)CCC1C2=CN=C3N2C=CC=C3NC4=CC(F)=C(S(C)(=O)=O)C
=C4 O=C(OC(C)(C)C)N(CC1)CCC1C2=CN=C3N2C=CN=C3NC4=C(F)C=C(N5C=NN=
N5)C=C4 O=C(OC(C)(C)C)N(CC1)CC=C1C2=NC=C3N2C=CN=C3NC4=C(F)C=C(N5C=NN=
N5)C=C4 O=C(OC(C)(C)C)N(CC1)CCC1C2=CN=C3N2C=CC=C3NC4=C(F)C=C(N5C=NN=
N5)C=C4 O=C(OC(C)(C)C)N(CC1)CC=C1C2=NN=C3N2C=CN=C3NC4=CC(F)=C(S(C)(=O)=
O)C=C4 O=C(OC(C)(C)C)N(CC1)CC=C1C2=CN=C3N2C=CC=C3NC4=C(C)N=C(S(C)(=O)
=O)C=C4 O=C(OC(C)C)N(CC1)CCC1C2=CN=C3N2C=CN=C3NC4=CC(F)=C(N5C=NN=N5)
C=C4 O=C(OC(C)(C)C)N(CC1)CC=C1C2=NC=C3N2C=CN=C3NC4=CC(F)=C(N5C=NN=
N5)C=C4 O=C(OC(C)C)N(CC1)CCC1C2=CN=C3N2C=CC=C3NC4=CC(F)=C(N5C=NN=N5)
C=C4 O=C(OC(C)C)N(CC1)CC=C1C2=NN=C3N2C=CN=C3NC4=C(C)N=C(S(C)(=O)=O)
C=C4 O=C(OC(C)C)N(CC1)CC=C1C2=CN=C3N2C=CC=C3NC4=C(C)N=C(N5C=NC=N5
)C=C4 O=C(OC(C)(C)C)N(CC1)CCC1C2=NN=C3N2C=CN=C3NC4=C(C)N=C(N5C=NC=
N5)C=C4 FC(C=C(S (C)C=O)=O)C=C 1 )=C 1NC2=NC=CN3C2=NN=C3C4CCN(C(OC(C)C)=O)
CC4 O=C(OC(C)C)N(CC1)CC=C1C2=NN=C3N2C=CN=C3NC4=C(C)N=C(N5C=NN=N
5)C=C4 FC(C=C(S (C)C=O)=O)C=C 1 )=C 1NC2=CC=CN3C2=NN=C3C4=CCN(C(OC(C)C)=O
)CC4 FC(C=C(S (C)C=O)=O)C=C 1 )=C 1NC2=NC=CC(N2C=N3)=C3C4=CCN(C(OC(C)C)=
O)CC4 FC(C=C(S (C)C=O)=O)C=C 1 )=C 1NC2=CN=CN3C2=NC=C3C4=CCN(C(OC(C)C)=O
)CC4 FC(C=C(S (C)(=O)=O)C=C 1 )=C 1NC2=CC=NN3C2=NC=C3C4=CCN(C(OC(C)C)=O
)CC4 O=C(OC(C)(C)C)N(CC1)CCC1C2=NN=C3N2C=CN=C3NC4=CC(F)=C(S(C)(=O)=
O)C=C4 O=C(OC(C)(C)C)N(CC1)CCC1C2=NN=C3N2C=CN=C3NC4=C(F)C=C(N5C=NN=
N5)C=C4 O=C(OC(C)(C)C)N(CC1)CC=C1C2=NN=C3N2C=CC=C3NC4=CC(F)=C(S(C)(=O)=
O)C=C4 O=C(OC(C)(C)C)N(CC1)CC=C1C2=C3C=CN=C(NC4=CC(F)=C(S(C)(=O)=O)C=C
4)N3C=N2 O=C(OC(C)(C)C)N(CC1)CC=C1C2=CN=C3N2C=NC=C3NC4=CC(F)=C(S(C)(=O)=
O)C=C4 O=C(OC(C)(C)C)N(CC1)CC=C1C2=CN=C3N2N=CC=C3NC4=CC(F)=C(S(C)(=O)=
O)C=C4 O=C(OC(C)C)N(CC1)CC=C1C2=NN=C3N2C=CN=C3NC4=C(C)N=C(S(C)(=O)=O)
C=C4 O=C(OC(C)C)N(CC1)CCC1C2=NN=C3N2C=CN=C3NC4=CC(F)=C(N5C=NN=N5)
C=C4 O=C(OC(C)C)N(CC1)CCC1C2=NN=C3N2C=CC=C3NC4=C(C)N=C(S(C)(=O)=O)C
=C4 CC(N=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CC(N2C=N3)=C3C4CCN(C(OC(C)C)=
O)CC4 O=C(OC(C)C)N(CC1)CCC1C2=CN=C3N2C=NC=C3NC4=C(C)N=C(S(C)(=O)=O)C
=C4 O=C(OC(C)C)N(CC1)CCC1C2=CN=C3N2N=CC=C3NC4=C(C)N=C(S(C)(=O)=O)C
=C4 O=C(OC(C)(C)C)N(CC1)CC=C1C2=NN=C3N2C=CN=C3NC4=C(C)N=C(N5C=NC
=N5)C=C4 O=C(OC(C)(C)C)N(CC1)CC=C1C2=NN=C3N2C=CN=C3NC4=C(F)C=C(N5C=NN
=N5)C=C4 O=C(OC(C)(C)C)N(CC1)CCC1C2=NN=C3N2C=CC=C3NC4=C(C)N=C(N5C=NC=
N5)C=C4 O=C(OC(C)(C)C)N(CC1)CCC1C2=CN=C3N2C=NC=C3NC4=C(C)N=C(N5C=NC=
N5)C=C4 O=C(OC(C)(C)C)N(CC1)CCC1C2=CN=C3N2N=CC=C3NC4=C(C)N=C(N5C=NC=
N5)C=C4 O=C(OC(C)(C)C)N(CC1)CCC1C2=CN=C3N2C=NC=C3NC4=C(C)N=C(N5C=NN=
N5)C=C4 O=C(OC(C)C)N(CC1)CC=C1C2=CN=C3N2N=CC=C3NC4=C(C)N=C(N5C=NN=N
5)C=C4 O=C(OC(C)C)N(CC1)CCC1C2=CN=C3N2N=CN=C3NC4=C(F)C=C(S(=O)(C)=O)C
=C4 FC(C=C(S (=O)(C)=O)C=C 1 )=C 1NC2=NC=NN3C2=CC=C3C4CCN(C(OC(C)C)=O)
CC4 FC(C=C(S (=O)(C)=O)C=C 1 )=C 1NC2=NC=CN3C2=CC=C3C4CCN(C(OC(C)(C)C)=
O)CC4 FC1=C(NC2=CC=NN3C2=CC=C3C4CCN(C(OC(C)(C)C)=O)CC4)C=CC(S(=O)(C)=
O)=Cl O=C(OC(C)(C)C)N(CC1)CC=C1C2=CN=C3N2C=NC=C3NC4=C(F)C=C(N5C=NN=
N5)C=C4 O=C(OC(C)C)N(CC1)CCC1C2=CN=C3N2N=CC=C3NC4=C(F)C=C(N5C=NN=N5)
C=C4 FC(C=C(S(=O)(C)=O)C=C1)=C1NC2=NC=CC(N2N=C3)=C3C4CCN(C(OC(C)(C)C
)=O)CC4 FC(C=C(S(=O)(C)=O)C=C1)=C1NC2=NC=NC(N2N=C3)=C3C4CCN(C(OC(C)(C)C
)=O)CC4 FC(C=C(S(=O)(C)=O)C=C1)=C1NC2=NC=NC(N2C=C3)=C3C4CCN(C(OC(C)(C)C
)=O)CC4 FC(C=C(S (=O)(C)=O)C=C 1 )=C 1NC2=NC=CC(N2C=C3)=C3C4CCN(C(OC(C)(C)C)
=O)CC4 FC(C=C(S (=O)(C)=O)C=C 1 )=C 1NC2=CC=NC(N2C=C3)=C3C4CCN(C(OC(C)(C)C)
=O)CC4 O=C(OC(C)C)N(CC1)CCC1C2=CN=C3N2C=NC=C3NC4=CC(F)=C(N5C=NN=N5)
C=C4 O=C(OC(C)(C)C)N(CC1)CC=C1C2=CN=C3N2N=CC=C3NC4=CC(F)=C(N5C=NN=
N5)C=C4 FC(C=C(S (C)C=O)=O)C=C 1 )=C 1NC2=NC=CN3C2=NC=C3C4CCC(C(OC5CCCC5)
=0)CC4 FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=NN=C3N4CCC(C(OC(C)(C)C)=
0)CC4 FC(C=C(S (C)C=O)=O)C=C 1 )=C 1NC2=NC=CC(N2C=N3)=C3N4CCN(C(OCCCC(C)
C)=0)CC4 FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=NC(N2C=N3)=C3N4CCN(C(OC5CC5)=
0)CC4 FC(C=C(S (C)(=0)=0)C=C 1 )=C 1NC2=NC=CN3C2=NC=C3C4CC5N(C(OC(C)C)=O
)C(C5)C4 FC(C=C(S (C)(=0)=0)C=C 1 )=C 1NC2=NC=CN3C2=NC=C3C4CC5N(C(OCC6=CC=
CC=C6)=O)C(CC5)C4 FC(C=C(S (C)(=0)=0)C=C 1 )=C 1NC2=NC=CN3C2=NN=C3C4=CCN(C(OC(C)C)=O
)CC4 FC(C=C(S (CX=O)=O)C=C 1 )=C 1NC2=NC=CN3C2=NN=C3C4CCN(C(OC(C)C)=O)
CC4 FC(C=C(S (C)(=0)=0)C=C 1 )=C 1NC2=NC=CN3C2=CN=C3N4CCN(C(OC(CC)CC)=
0)CC4 FC(C=C(S (C)(=0)=0)C=C 1 )=C 1NC2=NC=CN3C2=CN=C3N4CCC(C(OC(C)C)=O)
CC4 FC(C=C(S (C)C=O)=O)C=C 1 )=C 1NC2=NC=CN3C2=CN=C3C4CCC(C(OCCOC)=O)
CC4 FC(C=C(S (C)C=O)=O)C=C 1 )=C 1NC2=NC=CN3C2=NC=C3C4C5CN(C(OC(C)C)=O
)CC4C5 FC(C=C(S (C)C=O)=O)C=C 1 )=C 1NC2=NC=CN3C2=NC=C3C4C5CN(C(OCCC6=CC
=CN=C6)=O)CC4CC5 CC(C=C(N1N=CN=C1)C=C2)=C2NC3=NC=CN4C3=CN=C4C5CCN(C(OC(C)C)=O
)C5 FC(C=C(S (C)(=0)=0)C=C 1 )=C 1NC2=NC=CN3C2=CN=C3C4CN(C(OCCN(C)C)=
0)C4 FC(C=C(S (C)(=0)=0)C=C 1 )=C 1NC2=NC=CN3C2=NC=C3N4C5CN(C(OC(C)C)=O
)CC4CC5 CC(N=C(S (CX=O)=O)C=C 1 )=C 1NC2=NC=CN3C2=NN=C3N4CCC(C(OCCC[N+] (
C)(C)C)=0)CC4 CC(N=C(S (C) (=0)=0)C=C I)=Cl NC2=NC=CN3C2=NN=C3C4=CCN(C(OC(C)C)=
0)CC4 CC(N=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=NN=C3C4CCN(C(OC(C)C)=O)
CC4 CC(N=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=CC=C3N4CCC(C(OC(C)C)=O)
CC4 CC(N=C(S(C)(=O)=O)C=C1)=C1NC2=CC=CN3C2=CC=C3N4CCC(C(OC(C)C)=O)
CC4 CC(N=C(N1N=CN=C1)C=C2)=C2NC3=NC=CN4C3=NN=C4C5=CCN(C(OC(C)C)=
0)CC5 CC(N=C(N1N=CN=C1)C=C2)=C2NC3=NC=CN4C3=NN=C4C5CCN(C(OC(C)C)=
0)CC5 CC(N=C(S (C)(=0)=0)C=C 1 )=C 1NC2=NC=CN3C2=CN=C3C4=CCN(C(OC(C)C)=
0)CC4 CC(N=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=CN=C3C4CCN(C(OC(C)C)=O)
CC4 FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=NN3C2=NC=C3C4CCN(C(OC(C)(C)C)=
O)CC4 FC(C=C(S (C)C=O)=O)C=C 1 )=C 1NC2=NC=NN3C2=CC=C3C4CCN(C(OC(C)C)=O)
CC4 FC(C=C(S (C)C=O)=O)C=C 1 )=C 1NC2=CC=NN3C2=CC=C3C4CCN(C(OCCCC)=O)
CC4 FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CC(N2N=C3)=C3C4CCN(C(OC(C)(C)C
)=O)CC4 FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=NC(N2N=C3)=C3C4CCN(C(OC(C)C)=
O)CC4 FC(C=C(S (C)C=O)=O)C=C 1 )=C 1NC2=NC=NC(N2C=C3)=C3C4CCN(C(OCCCC)=O
)CC4 FC(C=C(S (C)(=0)=0)C=C 1 )=C 1NC2=NC=CC(N2C=C3)=C3C4CCN(C(NCC)=O)C
C4 FC(C=C(S (C)(=0)=0)C=C 1 )=C 1NC2=CC=NC(N2C=C3)=C3C4CCN(C(OC(C)(C)C)
=0)CC4 FC1=C(N2C=NN=N2)C=CC(CNC3=NC=CN4C3=NC=C4C5CCN(C(OC(C)(C)C)=O
)CC5)=C1 FC1=C(N2C=NN=N2)C=CC(OCC3=NC=CN4C3=NC=C4C5=CCN(C(OC(C)(C)C)=
0)CC5)=Cl FC(C=C(S (C)(=0)=0)C=C 1 )=C 1NC2=NC=CN3C2=NC=C3NC4CCN(C(NC(C)C)=
0)CC4 FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=NC=C3C4C(C)CN(C(OC(C)(C)
C)=0)CC4C FC(C=C(S (C)(=0)=0)C=C 1 )=C 1 OC2=NC=CN3C2=NC(CC)=C3C4CCN(C(OCC)=O
)CC4 FC(C=C(S (C)(=0)=0)C=C 1 )=C 1NC2=NC=CN3C2=NC=C3C4CCN(C(NC(C)C)=O)
CC4 FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=NC=C3C4CCC(C(NC(C)(C)C)=
0)CC4 FC(C=C(S (C)C=O)=O)C=C 1 )=C 1NC2=NC=CN3C2=NC=C3C4CCN(C(NCC5=CC=C
N=C5)=O)CC4
FC(C=C(S (C)C=O)=O)C=C 1 )=C 1NC2=NC=CN3C2=NC=C3C4CCC(C(NCC(O)CO)= O)CC4
[0230] The activity of the compounds in Examples 1-109 as GPRl 19 modulators is illustrated in the following assay. The other compounds listed above, which have not yet been made and/or tested, are predicted to have activity in this assay as well.
Biological Activity Assay
cAMP Production Assay:
[0231] HEK293 cells stably expressing GPRl 19 (HEK293-GPR119) were established by stably transfecting HEK-293 cells with an expression vector (pcDNA 3.1, Invitrogen) inserted with human GPRl 19 cDNA using Fugeneβ (Roche, Indianapolis, IN) according to conventional methods. Cells were grown in DMEM (Invitrogen, Carlsbad, CA) supplemented with 10% FBS, 1% penicillin/streptomycin under geneticin selection. The presence of GPRl 19 transcripts in these cells was confirmed using branched DNA (bDNA, Panomics Inc., Fremont CA) following the manufacturer's protocol and using specific probes for human GPRl 19. cAMP production assay was performed in high throughput 1536 well format using Cisbio c AMP detection kit (Cisbio Inc., Bedford, MA) according to the manufacturer's protocol. Briefly, HEK293-GPR119 cells were harvested using non-enzymatic cell dissociation buffer (Invitrogen, Carlsbad, CA), suspended in DMEM supplemented with 2% FBS at a density of 3200 cells/well dispensed in white opaque tissue culture treated Greiner 1536 well plates (USA Scientific, Inc., Ocala, FL). After an overnight incubation at 370C in an atmosphere of 10% CO2 and 95% humidity, 1 ul of 5 mM IBMX (Sigma, St. Louis, MO) solution in DMEM was dispensed for a final concentration of 1 mM. Cells were then stimulated with test compounds for 30 minutes, after which time cAMP detection reagents were added and incubated for 1 h at room temperature. TR-FRET signal was detected using the Viewlux (Perkin Elmer Inc., Boston MA) or the Analyst GT (Molecular Devices, Sunnyvale, CA) plate reader. EC50 values for cAMP production were determined using Graph Pad Prizm analysis (Graph Pad Software, La Jolla, CA) or proprietary Kalypsys KNET software. GPRl 19-specific mechanism of action was determined by the lack of cAMP production when compounds were tested in HEK-293 cells that were transfected with an empty vector. Results are shown below in Table 1.
Table 1. Biological Activity
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
[0232] From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

Claims

CLAIMSWhat is claimed is:
1. A method of treatment of a GPRl 19-mediated disease, comprising the administration of a therapeutically effective amount of a compound of structural
Formula (I)
Figure imgf000173_0001
(I) or a salt thereof, wherein:
A, B, and D are each independently chosen from monocyclic heteroaryl, monocyclic aryl, monocyclic cycloalkyl, and monocyclic heterocycloalkyl;
Q is chosen from C and N;
Q' is chosen from C and N;
Z is chosen from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkyl, heteroalkyl, haloalkyl, perhaloalkyl, -CO2Rn, and -CO2NR1SR^, any of which may be optionally substituted;
V is chosen from a bond, O, S, NR5, and (CRORTX; W is chosen from a bond, O, S, NRg, and (CRgR1O)5; X is a bond;
Y is chosen from a bond, O, S, NR14, and (CR1SR16); m, n, p, q, r, and s are each independently an integer from 0 to 4; each R1, R2, R3, and R4 is independently chosen from hydrogen, null, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, amido, amino, aryl, aryloxy, carbamate, carboxy, cyano, cycloalkyl, halo, heteroalkyl, heteroaryl, heterocycloalkyl, hydroxyl, nitro, perhaloalkoxy, perhaloalkyl, sulfonyl and sulfonamide, any of which may be optionally substituted; or R2 and R3 together may form an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl; each R5, R8, and R14 are independently chosen from hydrogen, acyl, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, C-amido, and sulfonyl, any of which may be optionally substituted;
Re, R7, R9, R1O, Ri5, and R16 are each independently chosen from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, any of which may be optionally substituted; or Re and R7, or R9 and R1O, or R12 and R13, or R15 and R16 are taken together to form oxo; and
Rn, R18, and R19 are each independently chosen from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, any of which may be optionally substituted.
2. The method as recited in Claim 1, wherein:
A is chosen from monocyclic aryl, monocyclic cycloalkyl, and monocyclic heterocycloalkyl, any of which may be optionally substituted;
B is chosen from monocyclic heteroaryl and monocyclic aryl, any of which may be optionally substituted;
Z is chosen from aryl, heteroaryl, alkyl, heteroalkyl, -CO2Rn, and - CO2NR1SR19, any of which may be optionally substituted; and r and s are each independently an integer from 0 to 3.
3. The method as recited in Claim 2, wherein r is an integer from 0 to 2.
4. The method as recited in Claim 3, wherein: each R1, R2, R3, and R4 is independently chosen from hydrogen, null, acyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, amido, amino, carboxyl, cyano, halo, hydroxyl, heteroaryl, nitro, perhaloalkoxy, perhaloalkyl, sulfonyl and sulfonamide, any of which may be optionally substituted; or R2 and R3 together may form an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl; and each R5, R8, and R14 is independently chosen from hydrogen, acyl, lower alkyl, lower alkenyl, and lower alkynyl, any of which may be optionally substituted.
5. The method as recited in Claim 4, wherein D is chosen from monocyclic aryl, monocyclic cycloalkyl, and monocyclic heteroaryl, any of which may be optionally substituted.
6. The method as recited in Claim 5, wherein the compound has structural Formula (III)
Figure imgf000175_0001
(III) or a salt thereof, wherein:
A is chosen from monocyclic aryl, monocyclic cycloalkyl, and monocyclic heterocyclo alkyl ;
B is chosen from monocyclic aryl and monocyclic heteroaryl;
D is chosen from monocyclic aryl, monocyclic cycloalkyl, and monocyclic heteroaryl;
Z is chosen from heteroaryl, aryl, alkyl, heteroalkyl, -CO2Rn, and - CO2NR1SRiC), any of which may be optionally substituted;
Q is chosen from C and N;
Q' is chosen from C and N;
V is chosen from a bond, O, S, NR5, and
Figure imgf000175_0002
W is chosen from a bond, O, NRs, and (CR9Rio)s;
Y is chosen from a bond, O, S, NRi4, and (CR1SR16); m, n, p, and q are each independently an integer from 0 to 4; r and s are each independently an integer from 0 to 2; each R1, R2, R3 and R4 is independently chosen from hydrogen, null, acyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, amido, amino, carboxyl, cyano, halo, hydroxyl, heteroaryl, nitro, perhaloalkoxy, perhaloalkyl, sulfonyl and sulfonamide, any of which may be optionally substituted; or R2 and R3 together may form an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl;
R5 and R14 are each independently chosen from hydrogen, acyl, lower alkyl, lower alkenyl, and lower alkynyl;
Re, R7, R9, R1O, Ri5 and R16 are each independently chosen from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, any of which may be optionally substituted; or Re and R7, or R9 and R1O or R15 and R16 are taken together to form oxo; and
Rn, R1S, and R19 are each independently chosen from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, any of which may be optionally substituted.
7. The method as recited in Claim 6, wherein Q' is C.
8. The method as recited in Claim 7, wherein Y is a bond.
9. The method as recited in Claim 8, wherein the compound has structural Formula (III)
Figure imgf000176_0001
(III) or a salt thereof, wherein: B and D are each independently chosen from monocyclic aryl and monocyclic heteroaryl;
Z is chosen from heteroaryl, aryl, alkyl, heteroalkyl, -CO2Rn, and - CO2NR1SR1C), any of which may be optionally substituted;
Q is chosen from C and N;
V is chosen from a bond, O, S, NR5, and (CRORTX; W is chosen from a bond, O, S, NRg, and (CRgR1O)5; m, n, p, and v are each independently an integer from 0 to 4; r is an integer from 0 to 1 ; s is an integer from 0 to 2; each R1, R2, and R3 is independently chosen from hydrogen, null, acyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, amido, amino, carboxyl, cyano, halo, hydroxyl, heteroaryl, nitro, perhaloalkoxy, perhaloalkyl, sulfonyl and sulfonamide, any of which may be optionally substituted; or R2 and R3 together may form an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl;
R5 and Rg are independently chosen from hydrogen, acyl, lower alkyl, lower alkenyl, and lower alkynyl;
Re, R7, R9, and R10 are each independently chosen from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, any of which may be optionally substituted; or Re and R7, or R9 and R1O are taken together to form oxo; and
R17 is chosen from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, any of which may be optionally substituted.
10. The method as recited in Claim 9, wherein:
Q is N; s is an integer from 0 to 1 ;
V is chosen from a bond, O, NR5, and (CROR7X; and R5 is chosen from hydrogen and lower alkyl.
11. The method as recited in Claim 10, wherein Z is heteroaryl, which may be optionally substituted.
12. The method as recited in Claim 11, wherein Z is a 6-membered heteroaryl, which may be optionally substituted.
13. The method as recited in Claim 12, wherein Z is an optionally substituted 6- membered heteroaryl containing between 1 and 2 nitrogens.
14. The method as recited in Claim 13, wherein Z is pyrimidine, which may be optionally substituted.
15. The method as recited in Claim 14, wherein:
V is chosen from a bond, O, and NR5; and W is a bond.
16. The method as recited in Claim 15, wherein V is a bond.
17. The method as recited in Claim 14, wherein: s is 1;
V is chosen from O and NR5; W is (CR9R10); and
R9 and R10 are each independently chosen from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, or R9 and R10 are taken together to form oxo.
18. The method as recited in Claim 10, wherein Z is chosen from alkyl, -CO2Rπand - CO2NRi8Ri9.
19. The method as recited in Claim 18, wherein Z is chosen from -CO2Rn and - CO2NRi8Ri9.
20. The method as recited in Claim 19, wherein Z is -CO2Rn.
21. The method as recited in Claim 20, wherein Rn is chosen from hydrogen, alkyl, aryl, heteroaryl, and heterocycloalkyl.
22. The method as recited in Claim 21, wherein:
V is chosen from a bond, O, and NR5; and W is a bond.
23. The method as recited in Claim 22, wherein V is a bond.
24. The method as recited in Claim 21, wherein: s is 1;
V is chosen from O and NR5; W is (CR9Ri0); and Rg and R1O are each independently chosen from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, or Rg and R1O are taken together to form oxo.
25. The method as recited in Claim 7, wherein R9 and R10 are each independently chosen from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, any of which may be optionally substituted; or Rg and R1O are taken together to form oxo.
26. The method as recited in Claim 25, wherein Y is chosen from O and NR14.
27. The method as recited in Claim 26, wherein V is chosen from O, (CRORT)1, and NR5.
28. The method as recited in Claim 27, wherein Y is O.
29. The method as recited in Claim 28, wherein A is chosen from 4- to 6-membered cycloalkyl, lower aryl, 4- to 6-membered heterocycloalkyl, and 4- to 6-membered heteroaryl.
30. The method as recited in Claim 29, wherein A is lower heterocycloalkyl.
31. The method as recited in Claim 30, wherein Z is chosen from CO2Rn, optionally substituted phenyl, and optionally substituted heteroaryl.
32. The method as recited in Claim 31, wherein Z is heteroaryl, which may be optionally substituted.
33. The method as recited in Claim 32, wherein Z is a 6-membered heteroaryl, which may be optionally substituted.
34. The method as recited in Claim 33, wherein Z is an optionally substituted six- membered heteroaryl containing between 1 and 2 nitrogens.
35. The method as recited in Claim 34, wherein Z is chosen from pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl, any of which may be optionally substituted.
36. The method as recited in Claim 35, wherein Z is pyrimidine, which may be optionally substituted.
37. The method as recited in Claim 31, wherein Z is chosen from alkyl, -CO2Rn and - CO2NRi8Ri9.
38. The method as recited in Claim 37, wherein Z is chosen from -CO2Rn and - CO2NRi8Ri9.
39. The method as recited in Claim 38, wherein Z is -CO2Rn.
40. The method as recited in Claim 39, wherein R17 is chosen from hydrogen, alkyl, aryl, heteroaryl, and heterocycloalkyl.
41. A method as recited in claim 31, wherein the compound has structural Formula
(IV)
Figure imgf000180_0001
or a salt thereof, wherein:
B is chosen from phenyl and a 5- or 6 -membered monocyclic heteroaryl;
D is chosen from phenyl and a 5- or 6-membered monocyclic heteroaryl;
Z is chosen from lower heteroaryl, lower aryl, lower alkyl, lower heteroalkyl, - CO2Rn, and
Figure imgf000180_0002
any of which may be optionally substituted;
V is chosen from a bond, O, S, NR5, and (CROR7);
W is chosen from a bond, O, NRg, and (CRgR1O); m, n, p, and q are each independently an integer from 0 to 2; each R1, R2, R3 and R4 is independently selected from the group consisting of hydrogen, null, lower acyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower amido, lower amino, lower carboxyl, cyano, halo, hydroxyl, lower heteroaryl, nitro, lower perhaloalkoxy, lower perhaloalkyl, sulfonyl and sulfonamide, any of which may be optionally substituted; and two R1 may combine to form a 1-2 carbon bridge;
R5, Re, R7, R8, R9, and R10 are each independently selected from the group consisting of hydrogen and lower alkyl; and
R17, Ri8, and R^, are independently chosen from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower amino, lower aminoalkyl, lower alkoxy, lower alkoxyalkyl, phenyl, lower heteroaryl, lower cycloalkyl, lower heteroaryl, lower heterocycloalkyl, any of which may be optionally substituted.
42. The method as recited in Claim 41, wherein at least one R1 is present, and is attached in a position para to V.
43. The method as recited in Claim 42, wherein Z is -C(O)NH.
44. The method as recited in Claim 27, wherein B is a 9- or 10-membered fused bicyclic heteroaryl having from one to four nitrogens as heteroatoms.
45. The method as recited in Claim 44, wherein Y is a bond.
46. A method as recited in claim 42, wherein the compound has structural Formula (V)
Figure imgf000181_0001
or a salt thereof, wherein:
B is chosen from phenyl and a 6-membered monocyclic heteroaryl comprising 1 or 2 nitrogens;
D is chosen from phenyl and a 6-membered monocyclic heteroaryl;
V is chosen from a bond, O, S, NR5, and (CR6R7);
W is chosen from a bond, O, S, NRg, and (CRgR1O);
Z is chosen from -CONH, lower heteroaryl, lower aryl, lower alkyl, lower heteroalkyl, -CO2Rn, and -CO2NR1SR^, any of which may be optionally substituted; m is an integer from O to 2; n, p, and q are each independently an integer from O to 2; each R2, R3 and R4 is independently selected from the group consisting of hydrogen, null, lower acyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower amido, lower amino, lower carboxyl, cyano, halo, hydroxyl, lower heteroaryl, nitro, lower perhaloalkoxy, lower perhaloalkyl, sulfonyl and sulfonamide, any of which may be optionally substituted; and two R1 may join together to form a 1- or 2- carbon bridge;
Rla is oriented para to V, and is chosen from hydrogen, null, acyl, lower alkyl, lower alkenyl, lower alkynyl, C-amido, amino, halo, hydroxyl, heteroaryl, nitro, perhaloalkoxy, perhaloalkyl, sulfonyl and sulfonamide, any of which may be optionally substituted; or R2 and R3 together may form an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl; each Rib is independently chosen from hydrogen, null, acyl, lower alkyl, lower alkenyl, lower alkynylamido, amino, carboxyl, halo, hydroxyl, heteroaryl, nitro, perhaloalkoxy, perhaloalkyl, sulfonyl and sulfonamide, any of which may be optionally substituted; or R2 and R3 together may form an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl;
R5, Re, R7, R8, R9, and R10 are each independently selected from the group consisting of hydrogen and lower alkyl; and
Ri7, Ri8, and R^, are independently chosen from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower amino, lower aminoalkyl, lower alkoxy, lower alkoxyalkyl, phenyl, lower heteroaryl, lower cycloalkyl, lower heteroaryl, lower heterocycloalkyl, any of which may be optionally substituted.
47. The method as recited in Claim 46, wherein:
Z is chosen from lower heteroaryl, which may be optionally substituted with one, two or three substituents chosen from halogen, lower alkyl, and lower haloalkyl; and -CO2R17;
V is chosen from a bond, O, S, NR5, and CH2;;
W is chosen from a bond, C(O), and CH2;
Rla is chosen from hydrogen, null, acyl, lower alkyl, lower alkenyl, lower alkynyl, C-amido, amino, halo, hydroxyl, heteroaryl, nitro, perhaloalkoxy, perhaloalkyl, sulfonyl and sulfonamide, any of which may be optionally substituted; each R^, is independently chosen from hydrogen, null, acyl, lower alkyl, lower alkenyl, lower alkynylamido, amino, carboxyl, halo, hydroxyl, heteroaryl, nitro, perhaloalkoxy, perhaloalkyl, sulfonyl and sulfonamide, any of which may be optionally substituted; or R2 and R3 together may form an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl; m is 0, or 1;
R5 is chosen from hydrogen, lower alkyl, lower alkenyl, and lower alkynyl; and
Ri7 is chosen from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, phenyl, lower heteroaryl, lower cycloalkyl, and lower heterocycloalkyl, any of which may be optionally substituted.
48. The method as recited in Claim 47, wherein m is 1.
49. The method as recited in Claim 48, wherein:
Z is chosen from CO2Rn and lower heteroaryl, which is substituted with one, two or three substituents chosen from halogen, lower alkyl, and lower haloalkyl;
V is chosen from a bond and NR5;
Rla is chosen from null, lower alkyl, lower amino, lower heteroaryl, and sulfonyl;
Rib is chosen from null, halogen, hydroxy, cyano, lower alkyl, lower alkoxy, lower haloalkyl, and lower haloalkoxy;
R5 is hydrogen; and
Ri7 is chosen from lower alkyl and lower cycloalkyl.
50. The method as recited in Claim 49, wherein Rla is chosen from lower heteroaryl and sulfonyl.
51. The method as recited in Claim 50, wherein Z is chosen from CO2R17 and pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, any of which may be optionally substituted with one or two substituents chosen from halogen, lower alkyl, and lower haloalkyl.
52. The method as recited in Claim 51, wherein R17 is lower alkyl.
53. The method as recited in Claim 52, wherein Z is pyrimidinyl.
54. The method as recited in Claim 50, wherein: m is 1;
Z is chosen from 5-ethyl-pyrimidinyl and CO2Rn; W-V is chosen from a bond, CH2NH, and C(O)NH; Rla is chosen from lower alkyl, lower amino, triazolyl, tetrazolyl, and methylsulfonyl;
Rib is chosen from null, halogen, and lower alkyl; and R17 is tert-butyl.
55. The method as recited in claim 1, wherein said compound is chosen from Examples 1 to 109.
56. The method as recited in Claim 1, wherein said disease is a metabolic disease.
57. The method as recited in Claim 56, wherein said disease is diabetes.
58. The method as recited in Claim 1, additionally comprising the administration of a therapeutically effective amount of another therapeutic agent.
59. The method as recited in Claim 58, wherein said agent is chosen from insulin, metformin, Glipizide, glyburide, Amaryl, gliclazide, meglitinides, nateglinide, repaglinide, pramlintide, PTP-112, SB-517955, SB-4195052, SB-216763, NN-57- 05441, NN-57-05445, GW-0791, AGN-194204, T-1095, BAY R3401, acarbose, miglitol, voglibose, Exendin-4, DPP728, LAF237, vildagliptin , BMS477118, PT- 100, GSK-823093, PSN-9301, T-6666, SYR-322, SYR-619, Liraglutide, CJC- 1134-PC, naliglutide, MK-0431, saxagliptin, GSK23A, pioglitazone, rosiglitazone, AVE2268, GW869682, GSK189075, APD668, PSN-119-1, PSN-821, rosuvastatin, atrovastatin, simvastatin, lovastatin, pravastatin, fluvastatin, cerivastatin, rosuvastatin, pitavastatin, fenofibrate, benzafibrate, clofibrate, gemfibrozil, Ezetimibe, eflucimibe, CP-529414, CETi-I, JTT-705, cholestyramine, colestipol, niacin, implitapide, (R)-l-{4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4- ylmethoxy]-benzenesulfonyl}2,3-dihydro-lH-indole-2-carboxylic acid, and GI- 262570.
60. A compound of Formula (V):
Figure imgf000185_0001
or a salt thereof, wherein
B is chosen from phenyl and a 6-membered monocyclic heteroaryl comprising from 1-2 nitrogens;
D is chosen from phenyl and a 6-membered monocyclic heteroaryl;
Z is chosen from CO2Rn and lower heteroaryl, which is substituted with one, two or three substituents chosen from halogen, lower alkyl, and lower haloalkyl;
W is chosen from a bond, C(O), and CH2;
V is chosen from a bond and NR5; provided that either each of W and V is a bond, or neither is;
Rla is chosen from lower heteroaryl and sulfonyl;
Rib is chosen from null, halogen, hydroxy, cyano, lower alkyl, lower alkoxy, lower haloalkyl, and lower haloalkoxy; m is an integer from 0 to 1 ;
R5 is hydrogen; and;
R17 is chosen from lower alkyl and lower cycloalkyl.
61. The compound as recited in Claim 60, wherein Z is chosen from CO2R17, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, any of which may be optionally substituted with one or two substituents chosen from halogen, lower alkyl, and lower haloalkyl.
62. The compound as recited in Claim 61, wherein R17 is lower alkyl.
63. The compound as recited in Claim 62, wherein Z is pyrimidinyl.
64. The compound as recited in Claim 60, wherein m is 1;
Z is chosen from 5-ethyl-pyrimidinyl and CO2R17; W-V is chosen from a bond, CH2NH, and C(O)NH; Rla is chosen from lower alkyl, lower amino, triazolyl, tetrazolyl, and methylsulfonyl;
Rib is chosen from null, halogen, and lower alkyl; and Ri7 is tert-butyl.
65. A compound chosen from Examples 1 to 109.
66. A compound as recited in Claim 60 for use as a medicament.
67. A compound as recited in Claim 60 for use in the manufacture of a medicament for the prevention or treatment of a disease or condition ameliorated by the modulation of GPRl 19.
68. A pharmaceutical composition comprising a compound as recited in Claim 60 together with a pharmaceutically acceptable carrier.
69. A pharmaceutical composition comprising at least one compound chosen from those recited in Examples 1 to 109 together with a pharmaceutically acceptable carrier.
70. The pharmaceutical composition as recited in Claim 68, useful for the treatment or prevention of a GPRl 19-mediated disease.
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Cited By (123)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011113947A1 (en) 2010-03-18 2011-09-22 Boehringer Ingelheim International Gmbh Combination of a gpr119 agonist and the dpp-iv inhibitor linagliptin for use in the treatment of diabetes and related conditions
US20110294836A1 (en) * 2008-06-20 2011-12-01 Metabolex, Inc. Aryl gpr119 agonists and uses thereof
WO2012006955A1 (en) * 2010-07-14 2012-01-19 Zhejiang Beta Pharma Inc. Compounds for treatment of metabolic disorders
WO2012046249A1 (en) 2010-10-08 2012-04-12 Cadila Healthcare Limited Novel gpr 119 agonists
US20120184572A1 (en) * 2011-01-13 2012-07-19 Metabolex, Inc. Aryl gpr119 agonists and uses thereof
US8273900B2 (en) 2008-08-07 2012-09-25 Novartis Ag Organic compounds
US8293729B2 (en) 2009-06-24 2012-10-23 Boehringer Ingelheim International Gmbh Compounds, pharmaceutical composition and methods relating thereto
US8410127B2 (en) 2009-10-01 2013-04-02 Metabolex, Inc. Substituted tetrazol-1-yl-phenoxymethyl-thiazol-2-yl-piperidinyl-pyrimidine salts
JP2013519701A (en) * 2010-02-17 2013-05-30 エフ．ホフマン−ラ ロシュ アーゲー Piperidine derivatives
US8481731B2 (en) 2009-06-24 2013-07-09 Boehringer Ingelheim International Gmbh Compounds, pharmaceutical composition and methods relating thereto
US8557826B2 (en) 2009-10-08 2013-10-15 Merck Sharp & Dohme Corp. Pentafluorosulfur imino heterocyclic compounds as BACE-1 inhibitors, compositions, and their use
US8563543B2 (en) 2009-10-08 2013-10-22 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as bace inhibitors, compositions, and their use
WO2013157022A1 (en) 2012-04-20 2013-10-24 Advinus Therapeutics Limited Substituted hetero-bicyclic compounds, compositions and medicinal applications thereof
US8569310B2 (en) 2009-10-08 2013-10-29 Merck Sharp & Dohme Corp. Pentafluorosulfur imino heterocyclic compounds as BACE-1 inhibitors, compositions and their use
US8580762B2 (en) 2010-12-03 2013-11-12 Epizyme, Inc. Substituted purine and 7-deazapurine compounds
WO2014011926A1 (en) 2012-07-11 2014-01-16 Elcelyx Therapeutics, Inc. Compositions comprising statins, biguanides and further agents for reducing cardiometabolic risk
US8633319B2 (en) 2010-04-29 2014-01-21 Glaxo Group Limited 7-(1H-pyrazol-4-yl)-1,6-naphthyridine compounds as Syk inhibitors
WO2014056938A1 (en) 2012-10-09 2014-04-17 Sanofi Pyrrolidinone derivatives as gpr119 modulators for the treatment of diabetes, obesity, dyslipidemia and related disorders
JP2014509600A (en) * 2011-03-14 2014-04-21 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング N-cyclopropyl-N-piperidinylbenzamide as a GPR119 modulator
US8716282B2 (en) 2009-10-30 2014-05-06 Janssen Pharmaceutica Nv Imidazo[1,2-b]pyridazine derivatives and their use as PDE10 inhibitors
US8722877B2 (en) 2010-12-03 2014-05-13 Epizyme, Inc. 7-deazapurine modulators of histone methyltransferase, and methods of use thereof
US8846746B2 (en) 2011-08-31 2014-09-30 Japan Tobacco Inc. Pyrazole compound and pharmaceutical use thereof
US8846675B2 (en) 2007-07-19 2014-09-30 Cymabay Therapeutics, Inc. N-linked heterocyclic receptor agonists for the treatment of diabetes and metabolic disorders
US8859543B2 (en) 2010-03-09 2014-10-14 Janssen Pharmaceutica Nv Imidazo[1,2-a]pyrazine derivatives and their use for the prevention or treatment of neurological, psychiatric and metabolic disorders and diseases
KR20140127758A (en) * 2013-04-25 2014-11-04 주식회사유한양행 Novel triazolone derivatives or salts thereof and pharmaceutical composition comprising the same
US8921350B2 (en) 2006-12-28 2014-12-30 Cymabay Therapeutics, Inc. Heterocyclic receptor agonists for the treatment of diabetes and metabolic disorders
US9018214B2 (en) 2011-04-21 2015-04-28 Astex Therapeutics Limited Bicyclic heterocycle compounds and their uses in therapy
US9029362B2 (en) 2009-10-08 2015-05-12 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as brace inhibitors, compositions, and their use
WO2015150565A1 (en) 2014-04-04 2015-10-08 Sanofi Isoindolinone compounds as gpr119 modulators for the treatment of diabetes, obesity, dyslipidemia and related disorders
US9175032B2 (en) 2013-03-15 2015-11-03 Epizyme, Inc. Methods of synthesizing substituted purine compounds
US9242969B2 (en) 2013-03-14 2016-01-26 Novartis Ag Biaryl amide compounds as kinase inhibitors
US9241924B2 (en) 2010-06-23 2016-01-26 Cymabay Therapeutics, Inc. Compositions of 5-ethyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine
US9273077B2 (en) 2008-05-21 2016-03-01 Ariad Pharmaceuticals, Inc. Phosphorus derivatives as kinase inhibitors
US9296701B2 (en) 2012-04-24 2016-03-29 Vertex Pharmaceuticals Incorporated DNA-PK inhibitors
US9328096B2 (en) 2014-05-07 2016-05-03 Pfizer Inc. Tropomyosin-related kinase inhibitors
US9334286B2 (en) 2012-09-07 2016-05-10 Cancer Research Technology Limited Pharmacologically active compounds
US9340557B2 (en) 2013-03-12 2016-05-17 Vertex Pharmaceuticals Incorporated Substituted quinoxaline DNA-PK inhibitors
US20160168096A1 (en) * 2013-06-27 2016-06-16 Lg Life Sciences Ltd. Biaryl derivatives as gpr120 agonists
US9371319B2 (en) 2011-03-14 2016-06-21 Cancer Research Technology Limited Pyrrolopyridineamino derivatives as MPS1 inhibitors
US9458175B2 (en) 2014-09-17 2016-10-04 Celgene Avilomics Research, Inc. MK2 inhibitors and uses thereof
US9493450B2 (en) 2014-02-13 2016-11-15 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US9493442B2 (en) 2014-02-13 2016-11-15 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US9499536B2 (en) 2010-07-06 2016-11-22 Novartis Ag Tetrahydro-pyrido-pyrimidine derivatives
RU2603346C2 (en) * 2012-06-12 2016-11-27 Чхон Кхун Дан Фармасьютикал Корп. Piperidine derivatives as gpr119 agonists
US9527835B2 (en) 2014-02-13 2016-12-27 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US9550784B2 (en) 2012-07-09 2017-01-24 Beerse Pharmaceutica NV Inhibitors of phosphodiesterase 10 enzyme
US9573969B2 (en) 2014-09-12 2017-02-21 Novartis Ag Compounds and compositions as kinase inhibitors
JP2017505808A (en) * 2014-01-06 2017-02-23 ライゼン・ファーマシューティカルズ・エスアー Novel glutaminase inhibitor
US9611283B1 (en) 2013-04-10 2017-04-04 Ariad Pharmaceuticals, Inc. Methods for inhibiting cell proliferation in ALK-driven cancers
US9617283B2 (en) 2012-10-19 2017-04-11 Astex Therapeutics Limited Bicyclic heterocycle compounds and their uses in therapy
US9617248B2 (en) 2012-10-19 2017-04-11 Astex Therapeutics Limited Bicyclic heterocycle compounds and their uses in therapy
US9663486B2 (en) 2013-10-14 2017-05-30 Eisai R&D Management Co., Ltd. Selectively substituted quinoline compounds
US9663512B2 (en) 2012-10-19 2017-05-30 Astex Therapeutics Limited Bicyclic heterocycle compounds and their uses in therapy
US9670210B2 (en) 2014-02-13 2017-06-06 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US9669035B2 (en) 2012-06-26 2017-06-06 Janssen Pharmaceutica Nv Combinations comprising PDE 2 inhibitors such as 1-aryl-4-methyl-[1,2,4]triazolo-[4,3-A]]quinoxaline compounds and PDE 10 inhibitors for use in the treatment of neurological of metabolic disorders
US9695180B2 (en) 2014-07-10 2017-07-04 Incyte Corporation Substituted imidazo[1,2-a]pyrazines as LSD1 inhibitors
US9695167B2 (en) 2014-07-10 2017-07-04 Incyte Corporation Substituted triazolo[1,5-a]pyridines and triazolo[1,5-a]pyrazines as LSD1 inhibitors
US9695168B2 (en) 2014-07-10 2017-07-04 Incyte Corporation Substituted imidazo[1,5-α]pyridines and imidazo[1,5-α]pyrazines as LSD1 inhibitors
US9732094B2 (en) 2013-05-11 2017-08-15 Merck Patent Gmbh Arylquinazolines
US9732080B2 (en) 2006-11-03 2017-08-15 Vertex Pharmaceuticals Incorporated Azaindole derivatives as CFTR modulators
US9758520B2 (en) 2014-04-04 2017-09-12 Sanofi Substituted fused heterocycles as GPR119 modulators for the treatment of diabetes, obesity, dyslipidemia and related disorders
US9758523B2 (en) 2014-07-10 2017-09-12 Incyte Corporation Triazolopyridines and triazolopyrazines as LSD1 inhibitors
US9775841B2 (en) 2011-05-04 2017-10-03 Rhizen Pharmaceuticals Sa Compounds as modulators of protein kinases
US9776987B2 (en) 2013-11-26 2017-10-03 Chong Kun Dang Pharmaceutical Corp Amide derivatives for GPR119 agonist
US9783538B2 (en) 2013-12-20 2017-10-10 Astex Therapeutics Limited Bicyclic heterocycle compounds and their uses in therapy
US9815813B2 (en) 2014-01-17 2017-11-14 Novartis Ag 1-(triazin-3-yl/pyridazin-3-yl)-piper(-azine)idine derivatives and compositions therefor for inhibiting the activity of SHP2
US9834571B2 (en) 2012-05-05 2017-12-05 Ariad Pharmaceuticals, Inc. Compounds for inhibiting cell proliferation in EGFR-driven cancers
US9834518B2 (en) 2011-05-04 2017-12-05 Ariad Pharmaceuticals, Inc. Compounds for inhibiting cell proliferation in EGFR-driven cancers
US9896434B2 (en) 2014-04-04 2018-02-20 Sanofi Substituted indanone compounds as GPR119 modulators for the treatment of diabetes, obesity, dyslipidemia and related disorders
US9902730B2 (en) 2014-05-01 2018-02-27 Novartis Ag Compounds and compositions as toll-like receptor 7 agonists
CN107847765A (en) * 2015-06-18 2018-03-27 赛福伦公司 The piperidine derivative of 1,4 substitutions
US9944649B2 (en) 2014-05-01 2018-04-17 Novartis Ag Compounds and compositions as toll-like receptor 7 agonists
US9944647B2 (en) 2015-04-03 2018-04-17 Incyte Corporation Heterocyclic compounds as LSD1 inhibitors
US9975886B1 (en) 2017-01-23 2018-05-22 Cadent Therapeutics, Inc. Potassium channel modulators
US9980973B2 (en) 2012-10-19 2018-05-29 Astex Therapeutics Limited Bicyclic heterocycle compounds and their uses in therapy
US10039761B2 (en) 2013-10-17 2018-08-07 Vertex Pharmaceuticals Incorporated Co-crystals and pharmaceutical compositions comprising the same
WO2018153849A1 (en) 2017-02-21 2018-08-30 Sanofi Azetidine compounds as gpr119 modulators for the treatment of diabetes, obesity, dyslipidemia and related disorders
US10064868B2 (en) 2011-03-28 2018-09-04 Mei Pharma, Inc. (Alpha-substituted aralkylamino and heteroarylalkylamino) pyrimidinyl and 1,3,5-triazinyl benzimidazoles, pharmaceutical compositions thereof, and their use in treating proliferative diseases
US10071979B2 (en) 2010-04-22 2018-09-11 Vertex Pharmaceuticals Incorporated Process of producing cycloalkylcarboxamido-indole compounds
US10077276B2 (en) 2014-01-17 2018-09-18 Novartis Ag N-azaspirocycloalkane substituted N-heteroaryl compounds and compositions for inhibiting the activity of SHP2
US10081621B2 (en) 2010-03-25 2018-09-25 Vertex Pharmaceuticals Incorporated Solid forms of (R)-1(2,2-difluorobenzo[D][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide
US10087174B2 (en) 2013-10-14 2018-10-02 Eisai R&D Management Co., Ltd. Selectively substituted quinoline compounds
US10093646B2 (en) 2014-01-17 2018-10-09 Novartis Ag 1-pyridazin-/triazin-3-yl-piper(-azine)/idine/pyrolidine derivatives and compositions thereof for inhibiting the activity of SHP2
US10112968B2 (en) 2012-08-10 2018-10-30 Epizyme, Inc. Inhibitors of protein methyltransferase DOT1L and methods of use thereof
US10159712B2 (en) 2013-08-13 2018-12-25 Ostara Biomedical Ltd. Embryo implantation
US10166221B2 (en) 2016-04-22 2019-01-01 Incyte Corporation Formulations of an LSD1 inhibitor
US10206877B2 (en) 2014-04-15 2019-02-19 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions for the treatment of cystic fibrosis transmembrane conductance regulator mediated diseases
US10287266B2 (en) 2015-06-19 2019-05-14 Novartis Ag Compounds and compositions for inhibiting the activity of SHP2
US10292983B2 (en) 2016-08-03 2019-05-21 Cymabay Therapeutics, Inc. Oxymethylene aryl compounds for treating inflammatory gastrointestinal diseases or gastrointestinal conditions
US10293029B2 (en) 2015-01-27 2019-05-21 Ostara Biomedical Ltd. Embryo implantation
US10308660B2 (en) 2015-06-19 2019-06-04 Novartis Ag Compounds and compositions for inhibiting the activity of SHP2
US10329255B2 (en) 2015-08-12 2019-06-25 Incyte Corporation Salts of an LSD1 inhibitor
US10450269B1 (en) 2013-11-18 2019-10-22 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10588944B2 (en) 2015-10-05 2020-03-17 Ostara Biomedical Ltd. Methods and compositions for managing reproduction
US10604523B2 (en) 2011-06-27 2020-03-31 Janssen Pharmaceutica Nv 1-aryl-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline derivatives
US10647661B2 (en) 2017-07-11 2020-05-12 Vertex Pharmaceuticals Incorporated Carboxamides as modulators of sodium channels
US10774064B2 (en) 2016-06-02 2020-09-15 Cadent Therapeutics, Inc. Potassium channel modulators
US10881680B2 (en) 2012-09-06 2021-01-05 Epizyme, Inc. Method of treating leukemia
US10894797B2 (en) 2018-09-18 2021-01-19 Nikang Therapeutics, Inc. Fused tricyclic ring derivatives as SRC homology-2 phosphatase inhibitors
US10934285B2 (en) 2016-06-14 2021-03-02 Novartis Ag Compounds and compositions for inhibiting the activity of SHP2
US10968200B2 (en) 2018-08-31 2021-04-06 Incyte Corporation Salts of an LSD1 inhibitor and processes for preparing the same
US10975056B2 (en) 2016-06-13 2021-04-13 Glaxosmithkline Intellectual Property Development Limited Substituted pyridines as inhibitors of DNMT1
US10973817B2 (en) 2014-02-10 2021-04-13 Sentinel Oncology Limited Pharmaceutical compounds
US10973826B2 (en) 2015-10-29 2021-04-13 Novartis Ag Antibody conjugates comprising toll-like receptor agonist
US10975080B2 (en) 2015-06-19 2021-04-13 Novartis Ag Compounds and compositions for inhibiting the activity of SHP2
US11053195B2 (en) 2013-03-15 2021-07-06 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US11110108B2 (en) 2016-09-27 2021-09-07 Vertex Pharmaceuticals Incorporated Method for treating cancer using a combination of DNA-damaging agents and DNA-PK inhibitors
CN113480522A (en) * 2021-08-19 2021-10-08 守恒(厦门)医疗科技有限公司 Novel phenylpyrazole derivative and application thereof in hypoglycemic drugs
US11208399B2 (en) 2019-05-17 2021-12-28 Novartis Ag NLRP3 inflammasome inhibitors
US11247987B2 (en) 2017-10-06 2022-02-15 Forma Therapeutics, Inc. Inhibiting ubiquitin specific peptidase 30
CN114072408A (en) * 2019-07-08 2022-02-18 南京明德新药研发有限公司 Compound serving as porcupine inhibitor and application thereof
US11279702B2 (en) 2020-05-19 2022-03-22 Kallyope, Inc. AMPK activators
US11304953B2 (en) 2017-05-23 2022-04-19 Mei Pharma, Inc. Combination therapy
US11351176B2 (en) 2017-08-14 2022-06-07 Mei Pharma, Inc. Combination therapy
US11407768B2 (en) 2020-06-26 2022-08-09 Kallyope, Inc. AMPK activators
US11535618B2 (en) 2018-10-05 2022-12-27 Forma Therapeutics, Inc. Fused pyrrolines which act as ubiquitin-specific protease 30 (USP30) inhibitors
WO2023016567A1 (en) * 2021-08-13 2023-02-16 Ascentage Pharma (Suzhou) Co., Ltd. Methods of treating a disease or disorder
US11603523B2 (en) 2019-01-18 2023-03-14 Astrazeneca Ab PCSK9 inhibitors and methods of use thereof
US11613548B2 (en) 2021-02-19 2023-03-28 Sudo Biosciences Limited Substituted pyridines, pyridazines, pyrimidines, and 1,2,4-triazines as TYK2 inhibitors
US11827627B2 (en) 2021-06-04 2023-11-28 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels
US11834441B2 (en) 2019-12-06 2023-12-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
US11873290B2 (en) 2018-11-06 2024-01-16 Edgewise Therapeutics, Inc. Pyridazinone compounds and uses thereof
US11878966B2 (en) 2015-06-18 2024-01-23 89Bio Ltd Substituted 4-benzyl and 4-benzoyl piperidine derivates

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EA029131B1 (en) 2008-05-21 2018-02-28 Ариад Фармасьютикалз, Инк. Phosphorous derivatives as kinase inhibitors

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050070562A1 (en) * 2003-07-11 2005-03-31 Jones Robert M. Trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto
WO2005121121A2 (en) * 2004-06-04 2005-12-22 Arena Pharmaceuticals, Inc. Substituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto
US20080058339A1 (en) * 2006-08-30 2008-03-06 Biovitrum New compounds
WO2008070692A2 (en) * 2006-12-06 2008-06-12 Smithkline Beecham Corporation Bicyclic compounds and use as antidiabetics

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050070562A1 (en) * 2003-07-11 2005-03-31 Jones Robert M. Trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto
WO2005121121A2 (en) * 2004-06-04 2005-12-22 Arena Pharmaceuticals, Inc. Substituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto
US20080058339A1 (en) * 2006-08-30 2008-03-06 Biovitrum New compounds
WO2008070692A2 (en) * 2006-12-06 2008-06-12 Smithkline Beecham Corporation Bicyclic compounds and use as antidiabetics

Cited By (237)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9732080B2 (en) 2006-11-03 2017-08-15 Vertex Pharmaceuticals Incorporated Azaindole derivatives as CFTR modulators
US8975258B2 (en) 2006-12-28 2015-03-10 Cymabay Therapeutics, Inc. Heterocyclic receptor agonists for the treatment of diabetes and metabolic disorders
US9925189B2 (en) 2006-12-28 2018-03-27 Cymabay Therapeutics, Inc. Heterocyclic receptor agonists for the treatment of diabetes and metabolic disorders
US9737537B2 (en) 2006-12-28 2017-08-22 Cymabay Therapeutics, Inc. Heterocyclic receptor agonists for the treatment of diabetes and metabolic disorders
US8921350B2 (en) 2006-12-28 2014-12-30 Cymabay Therapeutics, Inc. Heterocyclic receptor agonists for the treatment of diabetes and metabolic disorders
US8846675B2 (en) 2007-07-19 2014-09-30 Cymabay Therapeutics, Inc. N-linked heterocyclic receptor agonists for the treatment of diabetes and metabolic disorders
US9273077B2 (en) 2008-05-21 2016-03-01 Ariad Pharmaceuticals, Inc. Phosphorus derivatives as kinase inhibitors
US20110294836A1 (en) * 2008-06-20 2011-12-01 Metabolex, Inc. Aryl gpr119 agonists and uses thereof
US8273900B2 (en) 2008-08-07 2012-09-25 Novartis Ag Organic compounds
US8614213B2 (en) 2008-08-07 2013-12-24 Novartis Ag Cyclohexyl amide derivatives and their use as CRF-1 receptor antagonists
US8481731B2 (en) 2009-06-24 2013-07-09 Boehringer Ingelheim International Gmbh Compounds, pharmaceutical composition and methods relating thereto
US8293729B2 (en) 2009-06-24 2012-10-23 Boehringer Ingelheim International Gmbh Compounds, pharmaceutical composition and methods relating thereto
US8815886B2 (en) 2009-10-01 2014-08-26 Cymabay Therapeutics, Inc. Substituted tetrazol-1-yl-phenoxymethyl-thiazol-2-yl-piperidinyl-pyrimidine salts
US8410127B2 (en) 2009-10-01 2013-04-02 Metabolex, Inc. Substituted tetrazol-1-yl-phenoxymethyl-thiazol-2-yl-piperidinyl-pyrimidine salts
US9150567B2 (en) 2009-10-01 2015-10-06 Cymabay Therapeutics, Inc. Substituted tetrazol-1-yl-phenoxymethyl-thiazol-2-yl-piperidinyl-pyrimidine salts
US9475785B2 (en) 2009-10-08 2016-10-25 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as BACE inhibitors, compositions and their use
US8563543B2 (en) 2009-10-08 2013-10-22 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as bace inhibitors, compositions, and their use
US9029362B2 (en) 2009-10-08 2015-05-12 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as brace inhibitors, compositions, and their use
US8569310B2 (en) 2009-10-08 2013-10-29 Merck Sharp & Dohme Corp. Pentafluorosulfur imino heterocyclic compounds as BACE-1 inhibitors, compositions and their use
US8557826B2 (en) 2009-10-08 2013-10-15 Merck Sharp & Dohme Corp. Pentafluorosulfur imino heterocyclic compounds as BACE-1 inhibitors, compositions, and their use
US9687494B2 (en) 2009-10-08 2017-06-27 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as BACE inhibitors, compositions, and their use
US8716282B2 (en) 2009-10-30 2014-05-06 Janssen Pharmaceutica Nv Imidazo[1,2-b]pyridazine derivatives and their use as PDE10 inhibitors
JP2013519701A (en) * 2010-02-17 2013-05-30 エフ．ホフマン−ラ ロシュ アーゲー Piperidine derivatives
US8859543B2 (en) 2010-03-09 2014-10-14 Janssen Pharmaceutica Nv Imidazo[1,2-a]pyrazine derivatives and their use for the prevention or treatment of neurological, psychiatric and metabolic disorders and diseases
WO2011113947A1 (en) 2010-03-18 2011-09-22 Boehringer Ingelheim International Gmbh Combination of a gpr119 agonist and the dpp-iv inhibitor linagliptin for use in the treatment of diabetes and related conditions
US10081621B2 (en) 2010-03-25 2018-09-25 Vertex Pharmaceuticals Incorporated Solid forms of (R)-1(2,2-difluorobenzo[D][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide
US10071979B2 (en) 2010-04-22 2018-09-11 Vertex Pharmaceuticals Incorporated Process of producing cycloalkylcarboxamido-indole compounds
US8633319B2 (en) 2010-04-29 2014-01-21 Glaxo Group Limited 7-(1H-pyrazol-4-yl)-1,6-naphthyridine compounds as Syk inhibitors
US9241924B2 (en) 2010-06-23 2016-01-26 Cymabay Therapeutics, Inc. Compositions of 5-ethyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine
US10098843B2 (en) 2010-06-23 2018-10-16 Cymabay Therapeutics, Inc. Compositions of 5-ethyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine
US9499536B2 (en) 2010-07-06 2016-11-22 Novartis Ag Tetrahydro-pyrido-pyrimidine derivatives
WO2012006955A1 (en) * 2010-07-14 2012-01-19 Zhejiang Beta Pharma Inc. Compounds for treatment of metabolic disorders
WO2012046249A1 (en) 2010-10-08 2012-04-12 Cadila Healthcare Limited Novel gpr 119 agonists
US9096634B2 (en) 2010-12-03 2015-08-04 Epizyme, Inc. Substituted purine and 7-deazapurine compounds
US9145438B2 (en) 2010-12-03 2015-09-29 Epizyme, Inc. 7-deazapurine modulators of histone methyltransferase, and methods of use thereof
US8580762B2 (en) 2010-12-03 2013-11-12 Epizyme, Inc. Substituted purine and 7-deazapurine compounds
US8722877B2 (en) 2010-12-03 2014-05-13 Epizyme, Inc. 7-deazapurine modulators of histone methyltransferase, and methods of use thereof
US20120184572A1 (en) * 2011-01-13 2012-07-19 Metabolex, Inc. Aryl gpr119 agonists and uses thereof
US9371319B2 (en) 2011-03-14 2016-06-21 Cancer Research Technology Limited Pyrrolopyridineamino derivatives as MPS1 inhibitors
JP2014509600A (en) * 2011-03-14 2014-04-21 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング N-cyclopropyl-N-piperidinylbenzamide as a GPR119 modulator
US10335415B2 (en) 2011-03-28 2019-07-02 Mei Pharma, Inc. (Alpha-substituted aralkylamino and heteroarylalkylamino) pyrimidinyl and 1,3,5-triazinyl benzimidazoles, pharmaceutical compositions thereof, and their use in treating proliferative diseases
US10603324B2 (en) 2011-03-28 2020-03-31 Mei Pharma, Inc. (Alpha-substituted aralkylamino and heteroarylalkylamino) pyrimidinyl and 1,3,5-triazinyl benzimidazoles, pharmaceutical compositions thereof, and their use in treating proliferative diseases
US11400097B2 (en) 2011-03-28 2022-08-02 Mei Pharma, Inc. (Alpha-substituted aralkylamino and heteroarylalkylamino) pyrimidinyl and 1,3,5-triazinyl benzimidazoles, pharmaceutical compositions thereof, and their use in treating proliferative diseases
US10064868B2 (en) 2011-03-28 2018-09-04 Mei Pharma, Inc. (Alpha-substituted aralkylamino and heteroarylalkylamino) pyrimidinyl and 1,3,5-triazinyl benzimidazoles, pharmaceutical compositions thereof, and their use in treating proliferative diseases
US11866428B2 (en) 2011-04-21 2024-01-09 Astex Therapeutics Limited Bicyclic heterocycle compounds and their uses in therapy
US9676768B2 (en) 2011-04-21 2017-06-13 Astex Therapeutics Limited Bicyclic heterocycle compounds and their uses in therapy
US9018214B2 (en) 2011-04-21 2015-04-28 Astex Therapeutics Limited Bicyclic heterocycle compounds and their uses in therapy
US9775841B2 (en) 2011-05-04 2017-10-03 Rhizen Pharmaceuticals Sa Compounds as modulators of protein kinases
US11020399B2 (en) 2011-05-04 2021-06-01 Rhizen Pharmaceuticals Sa Intermediates useful in the synthesis of compounds as modulators of protein kinases
US10322130B2 (en) 2011-05-04 2019-06-18 Rhizen Pharmaceuticals Sa Substituted chromenones as modulators of protein kinases
US9834518B2 (en) 2011-05-04 2017-12-05 Ariad Pharmaceuticals, Inc. Compounds for inhibiting cell proliferation in EGFR-driven cancers
US10220035B2 (en) 2011-05-04 2019-03-05 Rhizen Pharmaceuticals Sa Compounds as modulators of protein kinases
US10604523B2 (en) 2011-06-27 2020-03-31 Janssen Pharmaceutica Nv 1-aryl-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline derivatives
US8846746B2 (en) 2011-08-31 2014-09-30 Japan Tobacco Inc. Pyrazole compound and pharmaceutical use thereof
US9233983B2 (en) 2012-04-20 2016-01-12 Advinus Therapeutics Limited Substituted hetero-bicyclic compounds, compositions and medicinal applications thereof
WO2013157022A1 (en) 2012-04-20 2013-10-24 Advinus Therapeutics Limited Substituted hetero-bicyclic compounds, compositions and medicinal applications thereof
US10391095B2 (en) 2012-04-24 2019-08-27 Vertex Pharmaceuticals Incorporated DNA-PK inhibitors
US11008305B2 (en) 2012-04-24 2021-05-18 Vertex Pharmaceuticals Incorporated DNA-PK inhibitors
US11021465B2 (en) 2012-04-24 2021-06-01 Vertex Pharmaceuticals Incorporated DNA-PK inhibitors
US10442791B2 (en) 2012-04-24 2019-10-15 Vertex Pharmaceuticals Incorporated DNA-PK inhibitors
US9878993B2 (en) 2012-04-24 2018-01-30 Vertex Pharmaceuticals Incorporated DNA-PK inhibitors for treatment of cancer
US9592232B2 (en) 2012-04-24 2017-03-14 Vertex Pharmaceuticals Incorporated DNA-PK inhibitors
US10501439B2 (en) 2012-04-24 2019-12-10 Vertex Pharmaceuticals Incorporated DNA-PK inhibitors
US9376448B2 (en) 2012-04-24 2016-06-28 Vertex Pharmaceuticals Incorporated DNA-PK inhibitors
US9296701B2 (en) 2012-04-24 2016-03-29 Vertex Pharmaceuticals Incorporated DNA-PK inhibitors
US9925188B2 (en) 2012-04-24 2018-03-27 Vertex Pharmaceuticals Incorporated DNA-PK inhibitors and uses thereof
US10076521B2 (en) 2012-04-24 2018-09-18 Vertex Pharamceuticals Incorporated DNA-PK inhibitors
US9834571B2 (en) 2012-05-05 2017-12-05 Ariad Pharmaceuticals, Inc. Compounds for inhibiting cell proliferation in EGFR-driven cancers
US9944600B2 (en) 2012-06-12 2018-04-17 Chong Kun Dang Pharmaceutical Corp. Piperidine derivatives for GPR119 agonist
RU2603346C2 (en) * 2012-06-12 2016-11-27 Чхон Кхун Дан Фармасьютикал Корп. Piperidine derivatives as gpr119 agonists
US9669035B2 (en) 2012-06-26 2017-06-06 Janssen Pharmaceutica Nv Combinations comprising PDE 2 inhibitors such as 1-aryl-4-methyl-[1,2,4]triazolo-[4,3-A]]quinoxaline compounds and PDE 10 inhibitors for use in the treatment of neurological of metabolic disorders
US9550784B2 (en) 2012-07-09 2017-01-24 Beerse Pharmaceutica NV Inhibitors of phosphodiesterase 10 enzyme
WO2014011926A1 (en) 2012-07-11 2014-01-16 Elcelyx Therapeutics, Inc. Compositions comprising statins, biguanides and further agents for reducing cardiometabolic risk
US10112968B2 (en) 2012-08-10 2018-10-30 Epizyme, Inc. Inhibitors of protein methyltransferase DOT1L and methods of use thereof
US11633420B2 (en) 2012-09-06 2023-04-25 Epizyme, Inc. Method of treating leukemia
US10881680B2 (en) 2012-09-06 2021-01-05 Epizyme, Inc. Method of treating leukemia
US9895364B2 (en) 2012-09-07 2018-02-20 Cancer Research Technology Limited Pharmacologically active compounds
US10188642B2 (en) 2012-09-07 2019-01-29 Cancer Research Technology Limited Pharmacologically active compounds
US9334286B2 (en) 2012-09-07 2016-05-10 Cancer Research Technology Limited Pharmacologically active compounds
WO2014056938A1 (en) 2012-10-09 2014-04-17 Sanofi Pyrrolidinone derivatives as gpr119 modulators for the treatment of diabetes, obesity, dyslipidemia and related disorders
US8853412B2 (en) 2012-10-09 2014-10-07 Sanofi Pyrrolidinone derivatives as GPR119 modulators for the treatment of diabetes, obesity, dyslipidemia and related disorders
US9980973B2 (en) 2012-10-19 2018-05-29 Astex Therapeutics Limited Bicyclic heterocycle compounds and their uses in therapy
US9663512B2 (en) 2012-10-19 2017-05-30 Astex Therapeutics Limited Bicyclic heterocycle compounds and their uses in therapy
US9617248B2 (en) 2012-10-19 2017-04-11 Astex Therapeutics Limited Bicyclic heterocycle compounds and their uses in therapy
US9617283B2 (en) 2012-10-19 2017-04-11 Astex Therapeutics Limited Bicyclic heterocycle compounds and their uses in therapy
US10786512B2 (en) 2013-03-12 2020-09-29 Vertex Pharmaceuticals Incorporated DNA-PK inhibitors
US10973830B2 (en) 2013-03-12 2021-04-13 Vertex Pharmaceuticals Incorporated Substituted quinoxaline DNA-PK inhibitors
US10258627B2 (en) 2013-03-12 2019-04-16 Vertex Pharmaceutical Incorporated DNA-PK inhibitors
US11813267B2 (en) 2013-03-12 2023-11-14 Vertex Pharmaceuticals Incorporated DNA-PK inhibitors
US9340557B2 (en) 2013-03-12 2016-05-17 Vertex Pharmaceuticals Incorporated Substituted quinoxaline DNA-PK inhibitors
US9359380B2 (en) 2013-03-12 2016-06-07 Vertex Pharmaceuticals Incorporated DNA-PK inhibitors
US9987284B2 (en) 2013-03-12 2018-06-05 Vertex Pharmaceuticals Incorporated Substituted benzooxadiazole DNA-PK inhibitors
US9694016B2 (en) 2013-03-14 2017-07-04 Novartis Ag Biaryl amide compounds as kinase inhibitors
US10245267B2 (en) 2013-03-14 2019-04-02 Novartis Ag Biaryl amide compounds as kinase inhibitors
US10709712B2 (en) 2013-03-14 2020-07-14 Novartis Ag Biaryl amide compounds as kinase inhibitors
US9242969B2 (en) 2013-03-14 2016-01-26 Novartis Ag Biaryl amide compounds as kinase inhibitors
US11572383B2 (en) 2013-03-15 2023-02-07 Epizyme, Inc. Methods of synthesizing substituted purine compounds
US9701707B2 (en) 2013-03-15 2017-07-11 Epizyme, Inc. Methods of synthesizing substituted purine compounds
US10968247B2 (en) 2013-03-15 2021-04-06 Epizyme, Inc. Methods of synthesizing substituted purine compounds
US9175032B2 (en) 2013-03-15 2015-11-03 Epizyme, Inc. Methods of synthesizing substituted purine compounds
US9738679B2 (en) 2013-03-15 2017-08-22 Epizyme, Inc. Methods of synthesizing substituted purine compounds
US11053195B2 (en) 2013-03-15 2021-07-06 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US11753433B2 (en) 2013-03-15 2023-09-12 Epizyme, Inc. Methods of synthesizing substituted purine compounds
US9611283B1 (en) 2013-04-10 2017-04-04 Ariad Pharmaceuticals, Inc. Methods for inhibiting cell proliferation in ALK-driven cancers
EP2989093A4 (en) * 2013-04-25 2016-12-14 Yuhan Corp Novel triazolone derivatives or salts thereof and pharmaceutical composition comprising the same
KR101720937B1 (en) 2013-04-25 2017-03-29 주식회사유한양행 Novel triazolone derivatives or salts thereof and pharmaceutical composition comprising the same
CN105143210A (en) * 2013-04-25 2015-12-09 柳韩洋行 Novel triazolone derivatives or salts thereof and pharmaceutical composition comprising the same
KR20140127758A (en) * 2013-04-25 2014-11-04 주식회사유한양행 Novel triazolone derivatives or salts thereof and pharmaceutical composition comprising the same
US10383874B2 (en) 2013-05-11 2019-08-20 Merk Patent Gmbh Arylquinazolines
US9732094B2 (en) 2013-05-11 2017-08-15 Merck Patent Gmbh Arylquinazolines
US11065253B2 (en) 2013-05-11 2021-07-20 Merck Patent Gmbh Arylquinazolines
US10172859B2 (en) 2013-05-11 2019-01-08 Merck Patent Gmbh Arylquinazolines
US10221138B2 (en) * 2013-06-27 2019-03-05 Lg Chem, Ltd. Biaryl derivatives as GPR120 agonists
US20160168096A1 (en) * 2013-06-27 2016-06-16 Lg Life Sciences Ltd. Biaryl derivatives as gpr120 agonists
AU2017203392B2 (en) * 2013-06-27 2018-05-10 Lg Chem, Ltd. Biaryl derivatives as GPR120 agonists
US10159712B2 (en) 2013-08-13 2018-12-25 Ostara Biomedical Ltd. Embryo implantation
US9663486B2 (en) 2013-10-14 2017-05-30 Eisai R&D Management Co., Ltd. Selectively substituted quinoline compounds
US10087174B2 (en) 2013-10-14 2018-10-02 Eisai R&D Management Co., Ltd. Selectively substituted quinoline compounds
USRE47193E1 (en) 2013-10-14 2019-01-08 Eisai R&D Management Co., Ltd. Selectively substituted quinoline compounds
US10039761B2 (en) 2013-10-17 2018-08-07 Vertex Pharmaceuticals Incorporated Co-crystals and pharmaceutical compositions comprising the same
US10716789B2 (en) 2013-10-17 2020-07-21 Vertex Pharmaceuticals Incorporated Co-crystals and pharmaceutical compositions comprising the same
US10450269B1 (en) 2013-11-18 2019-10-22 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US9776987B2 (en) 2013-11-26 2017-10-03 Chong Kun Dang Pharmaceutical Corp Amide derivatives for GPR119 agonist
US11643410B2 (en) 2013-12-20 2023-05-09 Astex Therapeutics Limited Bicyclic heterocycle compounds and their uses in therapy
US10618895B2 (en) 2013-12-20 2020-04-14 Astex Therapeutics Limited Bicyclic heterocycle compounds and their uses in therapy
US11225476B2 (en) 2013-12-20 2022-01-18 Astex Therapeutics Limited Bicyclic heterocycle compounds and their uses in therapy
US9783538B2 (en) 2013-12-20 2017-10-10 Astex Therapeutics Limited Bicyclic heterocycle compounds and their uses in therapy
JP2017505808A (en) * 2014-01-06 2017-02-23 ライゼン・ファーマシューティカルズ・エスアー Novel glutaminase inhibitor
US10611759B2 (en) 2014-01-06 2020-04-07 Rhizen Pharmaceuticals Sa Glutaminase inhibitors
US10774065B2 (en) 2014-01-17 2020-09-15 Novartis Ag 1-pyridazin-/triazin-3-yl-piper(-azine)/idine/pyrolidine derivatives and compositions thereof 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
US10077276B2 (en) 2014-01-17 2018-09-18 Novartis Ag N-azaspirocycloalkane substituted N-heteroaryl compounds and compositions for inhibiting the activity of SHP2
US11401259B2 (en) 2014-01-17 2022-08-02 Novartis Ag 1-Pyridazin-/triazin-3-yl-piper(-azine)/idine/pyrolidine derivatives and compositions thereof for inhibiting the activity of SHP2
US10968235B2 (en) 2014-01-17 2021-04-06 Novartis Ag N-azaspirocycloalkane substituted N-heteroaryl compounds and compositions for inhibiting the activity of SHP2
US10093646B2 (en) 2014-01-17 2018-10-09 Novartis Ag 1-pyridazin-/triazin-3-yl-piper(-azine)/idine/pyrolidine derivatives and compositions thereof for inhibiting the activity of SHP2
US10336774B2 (en) 2014-01-17 2019-07-02 Novartis Ag N-azaspirocycloalkane substituted N-heteroaryl compounds and compositions for inhibiting the activity of SHP2
US10301278B2 (en) 2014-01-17 2019-05-28 Novartis Ag 1-(triazin-3-yl/pyridazin-3-yl)-piper(-azine)idine derivatives and compositions therefor for inhibiting the activity of SHP2
US9815813B2 (en) 2014-01-17 2017-11-14 Novartis Ag 1-(triazin-3-yl/pyridazin-3-yl)-piper(-azine)idine derivatives and compositions therefor for inhibiting the activity of SHP2
US11786524B2 (en) 2014-02-10 2023-10-17 Sentinel Oncology Limited Pharmaceutical compounds
US10973817B2 (en) 2014-02-10 2021-04-13 Sentinel Oncology Limited Pharmaceutical compounds
US9493442B2 (en) 2014-02-13 2016-11-15 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US10513493B2 (en) 2014-02-13 2019-12-24 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US10300051B2 (en) 2014-02-13 2019-05-28 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US9527835B2 (en) 2014-02-13 2016-12-27 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US9493450B2 (en) 2014-02-13 2016-11-15 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US11247992B2 (en) 2014-02-13 2022-02-15 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US10717737B2 (en) 2014-02-13 2020-07-21 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US11155532B2 (en) 2014-02-13 2021-10-26 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US9670210B2 (en) 2014-02-13 2017-06-06 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US10676457B2 (en) 2014-02-13 2020-06-09 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US9994546B2 (en) 2014-02-13 2018-06-12 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US10174030B2 (en) 2014-02-13 2019-01-08 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US9908868B2 (en) 2014-04-04 2018-03-06 Sanofi Isoindolinone compounds as GPR119 modulators for the treatment of diabetes, obesity, dyslipidemia and related disorders
WO2015150565A1 (en) 2014-04-04 2015-10-08 Sanofi Isoindolinone compounds as gpr119 modulators for the treatment of diabetes, obesity, dyslipidemia and related disorders
US9758520B2 (en) 2014-04-04 2017-09-12 Sanofi Substituted fused heterocycles as GPR119 modulators for the treatment of diabetes, obesity, dyslipidemia and related disorders
US9896434B2 (en) 2014-04-04 2018-02-20 Sanofi Substituted indanone compounds as GPR119 modulators for the treatment of diabetes, obesity, dyslipidemia and related disorders
US10206877B2 (en) 2014-04-15 2019-02-19 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions for the treatment of cystic fibrosis transmembrane conductance regulator mediated diseases
US10407431B2 (en) 2014-05-01 2019-09-10 Novartis Ag Compounds and compositions as toll-like receptor 7 agonists
US10844068B2 (en) 2014-05-01 2020-11-24 Novartis Ag Compounds and compositions as toll-like receptor 7 agonists
US9944649B2 (en) 2014-05-01 2018-04-17 Novartis Ag Compounds and compositions as toll-like receptor 7 agonists
US9902730B2 (en) 2014-05-01 2018-02-27 Novartis Ag Compounds and compositions as toll-like receptor 7 agonists
US9328096B2 (en) 2014-05-07 2016-05-03 Pfizer Inc. Tropomyosin-related kinase inhibitors
US10968221B2 (en) 2014-07-10 2021-04-06 Incyte Corporation Substituted [1,2,4]triazolo[1,5-a]pyrazines as LSD1 inhibitors
US10125133B2 (en) 2014-07-10 2018-11-13 Incyte Corporation Substituted [1,2,4]triazolo[1,5-a]pyridines and substituted [1,2,4]triazolo[1,5-a]pyrazines as LSD1 inhibitors
US10047086B2 (en) 2014-07-10 2018-08-14 Incyte Corporation Imidazopyridines and imidazopyrazines as LSD1 inhibitors
US9695180B2 (en) 2014-07-10 2017-07-04 Incyte Corporation Substituted imidazo[1,2-a]pyrazines as LSD1 inhibitors
US10640503B2 (en) 2014-07-10 2020-05-05 Incyte Corporation Imidazopyridines and imidazopyrazines as LSD1 inhibitors
US9695167B2 (en) 2014-07-10 2017-07-04 Incyte Corporation Substituted triazolo[1,5-a]pyridines and triazolo[1,5-a]pyrazines as LSD1 inhibitors
US10112950B2 (en) 2014-07-10 2018-10-30 Incyte Corporation Substituted imidazo[1,2-a]pyrazines as LSD1 inhibitors
US9695168B2 (en) 2014-07-10 2017-07-04 Incyte Corporation Substituted imidazo[1,5-α]pyridines and imidazo[1,5-α]pyrazines as LSD1 inhibitors
US10556908B2 (en) 2014-07-10 2020-02-11 Incyte Corporation Substituted imidazo[1,2-a]pyrazines as LSD1 inhibitors
US10138249B2 (en) 2014-07-10 2018-11-27 Incyte Corporation Triazolopyridines and triazolopyrazines as LSD1 inhibitors
US9758523B2 (en) 2014-07-10 2017-09-12 Incyte Corporation Triazolopyridines and triazolopyrazines as LSD1 inhibitors
US9573969B2 (en) 2014-09-12 2017-02-21 Novartis Ag Compounds and compositions as kinase inhibitors
US9809610B2 (en) 2014-09-12 2017-11-07 Novartis Ag Compounds and compositions as kinase inhibitors
US10577380B2 (en) 2014-09-17 2020-03-03 Celgene Car Llc MK2 inhibitors and uses thereof
US10253040B1 (en) 2014-09-17 2019-04-09 Celgene Car Llc MK2 inhibitors and uses thereof
US9458175B2 (en) 2014-09-17 2016-10-04 Celgene Avilomics Research, Inc. MK2 inhibitors and uses thereof
US11584757B2 (en) 2014-09-17 2023-02-21 Celgene Car Llc MK2 inhibitors and uses thereof
US9790235B2 (en) 2014-09-17 2017-10-17 Celgene Car Llc MK2 inhibitors and uses thereof
US10987406B2 (en) 2015-01-27 2021-04-27 Ostara Biomedical Ltd. Embryo implantation
US10293029B2 (en) 2015-01-27 2019-05-21 Ostara Biomedical Ltd. Embryo implantation
US11401272B2 (en) 2015-04-03 2022-08-02 Incyte Corporation Heterocyclic compounds as LSD1 inhibitors
US9944647B2 (en) 2015-04-03 2018-04-17 Incyte Corporation Heterocyclic compounds as LSD1 inhibitors
US10800779B2 (en) 2015-04-03 2020-10-13 Incyte Corporation Heterocyclic compounds as LSD1 inhibitors
US11878966B2 (en) 2015-06-18 2024-01-23 89Bio Ltd Substituted 4-benzyl and 4-benzoyl piperidine derivates
CN107847765A (en) * 2015-06-18 2018-03-27 赛福伦公司 The piperidine derivative of 1,4 substitutions
CN107847765B (en) * 2015-06-18 2021-05-04 89生物有限公司 1, 4-substituted piperidine derivatives
US11702388B2 (en) 2015-06-18 2023-07-18 89Bio Ltd 1,4-substituted piperidine derivatives
US10308660B2 (en) 2015-06-19 2019-06-04 Novartis Ag Compounds and compositions for inhibiting the activity of SHP2
US10975080B2 (en) 2015-06-19 2021-04-13 Novartis Ag Compounds and compositions for inhibiting the activity of SHP2
US10287266B2 (en) 2015-06-19 2019-05-14 Novartis Ag Compounds and compositions for inhibiting the activity of SHP2
US10329255B2 (en) 2015-08-12 2019-06-25 Incyte Corporation Salts of an LSD1 inhibitor
US10723700B2 (en) 2015-08-12 2020-07-28 Incyte Corporation Salts of an LSD1 inhibitor
US11498900B2 (en) 2015-08-12 2022-11-15 Incyte Corporation Salts of an LSD1 inhibitor
US10588944B2 (en) 2015-10-05 2020-03-17 Ostara Biomedical Ltd. Methods and compositions for managing reproduction
US10973826B2 (en) 2015-10-29 2021-04-13 Novartis Ag Antibody conjugates comprising toll-like receptor agonist
US10166221B2 (en) 2016-04-22 2019-01-01 Incyte Corporation Formulations of an LSD1 inhibitor
US10774064B2 (en) 2016-06-02 2020-09-15 Cadent Therapeutics, Inc. Potassium channel modulators
US10975056B2 (en) 2016-06-13 2021-04-13 Glaxosmithkline Intellectual Property Development Limited Substituted pyridines as inhibitors of DNMT1
US11905283B2 (en) 2016-06-14 2024-02-20 Novartis Ag Compounds and compositions for inhibiting the activity of SHP2
US10934285B2 (en) 2016-06-14 2021-03-02 Novartis Ag Compounds and compositions for inhibiting the activity of SHP2
US10292983B2 (en) 2016-08-03 2019-05-21 Cymabay Therapeutics, Inc. Oxymethylene aryl compounds for treating inflammatory gastrointestinal diseases or gastrointestinal conditions
US11110108B2 (en) 2016-09-27 2021-09-07 Vertex Pharmaceuticals Incorporated Method for treating cancer using a combination of DNA-damaging agents and DNA-PK inhibitors
US9975886B1 (en) 2017-01-23 2018-05-22 Cadent Therapeutics, Inc. Potassium channel modulators
US10717728B2 (en) 2017-01-23 2020-07-21 Cadent Therapeutics, Inc. Potassium channel modulators
US10351553B2 (en) 2017-01-23 2019-07-16 Cadent Therapeutics, Inc. Potassium channel modulators
WO2018153849A1 (en) 2017-02-21 2018-08-30 Sanofi Azetidine compounds as gpr119 modulators for the treatment of diabetes, obesity, dyslipidemia and related disorders
US10392366B2 (en) 2017-02-21 2019-08-27 Sanofi Azetidine compounds as GPR119 modulators for the treatment of diabetes, obesity, dyslipidemia and related disorders
US11304953B2 (en) 2017-05-23 2022-04-19 Mei Pharma, Inc. Combination therapy
US11603351B2 (en) 2017-07-11 2023-03-14 Vertex Pharmaceuticals Incorporated Carboxamides as modulators of sodium channels
US10647661B2 (en) 2017-07-11 2020-05-12 Vertex Pharmaceuticals Incorporated Carboxamides as modulators of sodium channels
US11351176B2 (en) 2017-08-14 2022-06-07 Mei Pharma, Inc. Combination therapy
US11247987B2 (en) 2017-10-06 2022-02-15 Forma Therapeutics, Inc. Inhibiting ubiquitin specific peptidase 30
US11512064B2 (en) 2018-08-31 2022-11-29 Incyte Corporation Salts of an LSD1 inhibitor and processes for preparing the same
US10968200B2 (en) 2018-08-31 2021-04-06 Incyte Corporation Salts of an LSD1 inhibitor and processes for preparing the same
US10894797B2 (en) 2018-09-18 2021-01-19 Nikang Therapeutics, Inc. Fused tricyclic ring derivatives as SRC homology-2 phosphatase inhibitors
US11034705B2 (en) 2018-09-18 2021-06-15 Nikang Therapeutics, Inc. Fused tricyclic ring derivatives as Src homology-2 phosphate inhibitors
US11459340B2 (en) 2018-09-18 2022-10-04 Nikang Therapeutics, Inc. Tri-substituted heteroaryl derivatives as Src homology-2 phosphatase inhibitors
US11518772B2 (en) 2018-09-18 2022-12-06 Nikang Therapeutics, Inc. Fused tricyclic ring derivatives as Src homology-2 phosphate inhibitors
US11814386B2 (en) 2018-10-05 2023-11-14 Forma Therapeutics, Inc. Fused pyrrolines which act as ubiquitin-specific protease 30 (USP30) inhibitors
US11535618B2 (en) 2018-10-05 2022-12-27 Forma Therapeutics, Inc. Fused pyrrolines which act as ubiquitin-specific protease 30 (USP30) inhibitors
US11873290B2 (en) 2018-11-06 2024-01-16 Edgewise Therapeutics, Inc. Pyridazinone compounds and uses thereof
US11603523B2 (en) 2019-01-18 2023-03-14 Astrazeneca Ab PCSK9 inhibitors and methods of use thereof
US11208399B2 (en) 2019-05-17 2021-12-28 Novartis Ag NLRP3 inflammasome inhibitors
US11254653B2 (en) 2019-05-17 2022-02-22 Novartis Ag NLRP3 inflammasome inhibitors
CN114072408B (en) * 2019-07-08 2023-05-12 南京明德新药研发有限公司 Compounds as inhibitors of porcupine and uses thereof
CN114072408A (en) * 2019-07-08 2022-02-18 南京明德新药研发有限公司 Compound serving as porcupine inhibitor and application thereof
US11834441B2 (en) 2019-12-06 2023-12-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
US11919887B2 (en) 2019-12-06 2024-03-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
US11279702B2 (en) 2020-05-19 2022-03-22 Kallyope, Inc. AMPK activators
US11851429B2 (en) 2020-05-19 2023-12-26 Kallyope, Inc. AMPK activators
US11407768B2 (en) 2020-06-26 2022-08-09 Kallyope, Inc. AMPK activators
US11613548B2 (en) 2021-02-19 2023-03-28 Sudo Biosciences Limited Substituted pyridines, pyridazines, pyrimidines, and 1,2,4-triazines as TYK2 inhibitors
US11827627B2 (en) 2021-06-04 2023-11-28 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels
WO2023016567A1 (en) * 2021-08-13 2023-02-16 Ascentage Pharma (Suzhou) Co., Ltd. Methods of treating a disease or disorder
CN113480522A (en) * 2021-08-19 2021-10-08 守恒(厦门)医疗科技有限公司 Novel phenylpyrazole derivative and application thereof in hypoglycemic drugs

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