WO2010088518A2 - Heterocyclic modulators of gpr119 for treatment of disease - Google Patents

Heterocyclic modulators of gpr119 for treatment of disease Download PDF

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WO2010088518A2
WO2010088518A2 PCT/US2010/022588 US2010022588W WO2010088518A2 WO 2010088518 A2 WO2010088518 A2 WO 2010088518A2 US 2010022588 W US2010022588 W US 2010022588W WO 2010088518 A2 WO2010088518 A2 WO 2010088518A2
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recited
compound
c1nc2
chosen
optionally substituted
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PCT/US2010/022588
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French (fr)
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WO2010088518A3 (en
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Mehmet Kahraman
Nicholas D. Smith
Celine Bonnefous
Stewart A. Noble
Joseph E. Payne
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Kalypsys, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

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 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).
  • 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-I 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 GPR119 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- 1 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 and D are each independently chosen from heteroaryl, aryl, cycloalkyl, and heterocycloalkyl;
  • B is a bicyclic heteroaryl, which may be optionally substituted
  • Q is chosen from C and N;
  • V is chosen from a bond, O, S, NR5, and (CR 6 R T ) 1 ; W is chosen from a bond, O, S, NRs, and (CRgRiO) 5 ; X is chosen from a bond, O, S, NRn, and (CR 12 R 13 X;
  • Y is chosen from a bond, O, S, NR 14 , and
  • Z is chosen from alkyl, heteroalkyl, haloalkyl, perhaloalkyl, -CO 2 R 1 7, - CO 2 NR 1 8R 19 , aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, any of which may be optionally substituted; 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, halogen, heteroalkyl, heteroaryl, heterocycloalkyl
  • R 6 , R7, R9, Rio, R12, Ri3, Ri5, and R] 6 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 Rio, or R 12 and Ri 3 , or Ri 5 and Ri 6 are taken together to form oxo; and
  • Ri 7 , 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.
  • 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.
  • 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.
  • B is a bicyclic heteroaryl containing between two and four nitrogens.
  • one of said nitrogens occupies a bridge position between the two fused rings.
  • B has the formula:
  • Xi is chosen from CH, C(R 2O ) and N;
  • X 2 is chosen from CH, C(R 21 ) and N;
  • X 3 is chosen from CH, C(R 22 ) and N;
  • X 4 is chosen from CH, C(R 23 ) and N;
  • X 5 is chosen from CH, C(R 24 ) and N;
  • X 6 is chosen from CH, C(R 25 ) and N;
  • X 7 is chosen from CH, C(R 26 ) and N;
  • R 2 o, R 2 I, R 22 , R 2 3, R 24 , R 2 5, and R 26 are each independently chosen from halogen, hydroxy, cyano, lower alkyl, lower alkoxy, trifluoromethyl, trifluoromethoxy, lower cycloalkyl, lower cycloalkylalkyl, lower heterocycloalkyl, lower heterocycloalkylalkyl, phenyl, lower phenylalkyl, lower heteroaryl, and lower heteroarylalkyl, any of which may be optionally substituted with one or more substituents chosen from hydrogen, halogen, hydroxy, cyano, methyl, ethyl, methoxy, trifluoromethyl, and trifluoromethoxy; and the dashed lines in the ring comprising X 4 - X 7 represent additional bonds which may be present or absent.
  • R 2 o, R 2 i, R 22 , R 2 i, R 25 , and R 26 are all hydrogen.
  • X 4 is nitrogen.
  • X 7 is nitrogen.
  • X] is nitrogen.
  • X 6 is nitrogen.
  • X 3 is nitrogen.
  • X 1 , X 4 , and X 6 are each nitrogen; and X 2 , X 3 , X 5 , and X 7 are each CH. [025] In certain embodiments,
  • X 1 , X 4 , X 5 , and X 6 are each nitrogen; and X 2 , X3, and X7 are each CH.
  • X 1 , X 5 , and X 7 are each nitrogen; and X 2 , X 3 , X 4 , and X 6 are each CH.
  • X 1 , X 4 , and X 5 are each nitrogen; and X 2 , X 3 , Xe, and X 7 are each CH.
  • X 4 and X 6 are each nitrogen; and X 1 , X 2 , X 3 , X 5 , and X 7 are each CH.
  • X 4 , X 5 , and X 6 are each nitrogen; and X 1 , X 2 , X 3 , and X 7 are each CH.
  • X 2 , X 4 , and X 6 are each nitrogen; and X 1 , X 3 , X 5 , and X 7 are each CH.
  • X 3 , X 4 , and X 6 are each nitrogen; and X 1 , X 2 , X 5 , and X 7 are each CH.
  • X 1 , X 3 , X 4 , and X 6 are each nitrogen; and X 2 , X 5 , and X 7 are each CH.
  • X 1 , X 6 , and X 7 are each nitrogen; and X 2 , X 3 , X 4 , and X 5 are each CH.
  • X 1 , X 3 , X 6 , and X 7 are each nitrogen; and X 2 , X 4 , and X 5 are each CH.
  • X 3 and X 4 are each nitrogen; and X 1 , X 2 , X 5 , X 6 , and X 7 are each CH.
  • X 1 , X 3 , and X 7 are each nitrogen;
  • X 2 , X 4 , X 5 , and X 6 are each CH. [037] In certain embodiments,
  • X] and X 7 are each nitrogen;
  • X 2 , X 3 , X 4 , Xs, and X 6 are each CH. [038] In certain embodiments,
  • X 3 and X 7 are each nitrogen;
  • Xi, X 2 , X 4 , X 5 , and X 6 are each CH. [039] In certain embodiments,
  • X 2 , X 4 , X 5 , and X 6 are each nitrogen;
  • X 1 , X3, and X 7 are each CH. [040] In certain embodiments,
  • X 2 , X 4 , and X 5 are each nitrogen;
  • Xi, X 3 , X 6 , and X 7 are each CH. [041] In certain embodiments,
  • X 3 , X 4 , and X 5 are each nitrogen;
  • Xi, X 2 , X 6 , and X 7 are each CH.
  • X 4 and X 5 are each nitrogen;
  • Xi, X 2 , X 3 , X 6 , and X 7 are each CH. [043] In certain embodiments,
  • Xi, X 3 , X 4 , and X 5 are each nitrogen;
  • X 2 , X 6 , and X 7 are each CH.
  • X 3 , X 4 , X 5 , and X 6 are each nitrogen;
  • Xi, X 2 , and X 7 are each CH. [045] In certain embodiments,
  • X 2 , X 4 , X 5 , and X 6 are each nitrogen;
  • Xi, X 3 , and X 7 are each CH. [046] In certain embodiments,
  • Xi, X 2 , X 4 , and X 5 are each nitrogen;
  • X 3 , X 6 , and X 7 are each CH. [047] In certain embodiments,
  • X 1 , X 2 , X 4 , and X 6 are each nitrogen;
  • X 3 , X 5 and X 7 are each CH.
  • X 2 , X3, X 6 , and X7 are each nitrogen;
  • X 1 , X 4 and X 5 are each CH. [049] In certain embodiments,
  • X 2 , X3, X5, and X7 are each nitrogen;
  • X 1 , X 4 and X 6 are each CH. [050] In certain embodiments,
  • X 3 , X 6 , and X 7 are each nitrogen;
  • X 1 , X 2 , X 4 , and X 5 are each CH. [051] In certain embodiments ,
  • X 1 , X 5 , and X 7 are each nitrogen;
  • X 2 , X 3 , X 4 , and X 6 are each CH.
  • X 1 , X 3 , and X 4 are each nitrogen;
  • X 2 , X 5 , X 6 , and X 7 are each CH.
  • X 1 , X 6 , and X 7 are each nitrogen;
  • X 2 , X 3 , X 4 , and X 5 are each CH.
  • X 1 , X 3 , X 6 , and X 7 are each nitrogen;
  • X 2 , X 4 , and X 5 are each CH.
  • X 3 and X 4 are each nitrogen;
  • X 1 , X 2 , X 5 , X 6 , and X 7 are each CH.
  • X 1 , X 3 , and X 7 are each nitrogen;
  • X 2 , X 4 , X 5 , and X 6 are each CH. [057] In certain embodiments,
  • X 1 and X 7 are each nitrogen;
  • X 2 , X 3 , X 4 , X 5 , and X 6 are each CH. [058] In certain embodiments,
  • X 3 and X 7 are each nitrogen; and Xi, X 2 , X 4 , Xs, and X 6 are each CH.
  • B is chosen from
  • B is chosen from
  • A is chosen from aryl, cycloalkyl and heterocycloalkyl, any of which may be optionally substituted;
  • Z is chosen from heteroaryl, aryl, and -CO 2 NRi 8 Ri 9 , either of which may be optionally substituted; and
  • r, s, t, and u 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, halogen, 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, Rn, and R] 4 are independently chosen from hydrogen, acyl, lower alkyl, lower alkenyl, and lower alkyny
  • X and Y are each independently a bond.
  • the compounds have structural Formula II:
  • B is a bicyclic heteroaryl, containing between two and four nitrogens;
  • D is chosen from heteroaryl and aryl;
  • Z is chosen from heteroaryl, aryl, and -CO 2 NR 1 8R 19 , which may be optionally substituted;
  • Q is chosen from C and N; V is chosen from a bond, O, S, NR 5, , and (CR 6 Rv) 1,
  • W is chosen from a bond, O, S, NRg, and (CRgRiO) 8 ; 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, halogen, 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 8 are independently chosen from hydrogen, acyl, lower alkyl, lower alkenyl, and lower alkynyl;
  • R 6 , R 7 , R 9 and R] 0 are each independently chosen from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, any of which may be optionally substituted; R 9 and Rio are taken together to form oxo; and
  • Rn is chosen from hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, amido, amino, aryl, aryloxy, carbamate, carboxy, cyano, cycloalkyl, halogen, heteroalkyl, heteroaryl, heterocycloalkyl, hydroxyl, nitro, perhaloalkoxy, perhaloalkyl, and sulfonamide, any of which may be optionally substituted.
  • Q is N; s is an integer from 0 to 1 ;
  • V is chosen from a bond, O, NR5, and (CR 6 R?),-; and R 5 is chosen from hydrogen and lower alkyl.
  • Z is heteroaryl, which may be optionally substituted.
  • Z is a six-membered heteroaryl, which may be optionally substituted.
  • Z is an optionally substituted six- membered heteroaryl containing between 1 and 2 nitrogens.
  • Z is pyrimidine, which may be optionally substituted.
  • V is chosen from O and NR 5 ; and W is a bond.
  • V is a bond
  • W is a bond
  • V is chosen from O and NR 5 ; W is (CR 9 Ri 0 ); and
  • R 9 and R] 0 are each independently chosen from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, or R 9 and Rio are taken together to form oxo.
  • R 9 and R] 0 are each independently chosen from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, or R 9 and Rio are taken together to form oxo.
  • A is chosen from aryl, cycloalkyl, and heterocycloalkyl
  • B is a bicyclic heteroaryl containing between two and four nitrogens
  • D is chosen from heteroaryl and aryl
  • Z is chosen from heteroaryl, aryl, and -CO 2 NR 1 8R 19 , which may be optionally substituted;
  • Q is chosen from C and N;
  • V is chosen from a bond, O, S, NR 5 , and (CR 6 Rv) 1, ;
  • Y is chosen from a bond, O, S, NR 14 , and (CRisRi6) u ; m, n, p, and q are each independently an integer from 0 to 4; r, s, and u are each independently an integer from 0 to 1; 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, halogen, 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] 4 are each independently chosen from hydrogen, acyl, lower alkyl, lower alkenyl, and lower alkynyl;
  • R 6 , R7, R 9 , Rio, Ri5 and R] 6 are each independently chosen from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, any of which may be optionally substituted; or R 9 and Rio are taken together to form oxo.
  • Q is N.
  • Z is heteroaryl, which may be optionally substituted.
  • Z is a six-membered heteroaryl, which may be optionally substituted.
  • Z is an optionally substituted six- membered heteroaryl containing between 1 and 2 nitrogens.
  • Z is pyrimidine, which may be optionally substituted.
  • s is 1; and R 9 and Rio are each independently chosen from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, any of which may be optionally substituted; or R 9 and Rio are taken together to form oxo.
  • Y is chosen from O, (CRisRi6) u , and NRi 4 .
  • V is chosen from O, (CR 6 R 7 ),-, and NR 5 .
  • V is a bond.
  • W is a bond; and D is aryl.
  • Z is heteroaryl, which may be optionally substituted.
  • Z is a six-membered heteroaryl, which may be optionally substituted.
  • Z is an optionally substituted six- membered heteroaryl containing between 1 and 2 nitrogens.
  • Z is pyrimidine, which may be optionally substituted.
  • A is cycloalkyl.
  • Y is O.
  • A is aryl.
  • A is phenyl.
  • Q is N.
  • A is heterocycloalkyl.
  • A is 4- membered, 5- membered, or 6-membered heterocycloalkyl.
  • V is a bond.
  • D is aryl.
  • B is aryl; and R 2 and R 3 together form an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl.
  • B is heteroaryl; and R 2 and R 3 together form an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl.
  • compounds have structural Formula IV:
  • a and D are each independently chosen from heteroaryl, aryl, cycloalkyl, and heterocycloalkyl;
  • B is a bicyclic heteroaryl containing between two and four nitrogens
  • Qi and Q 2 are each independently chosen from C and N;
  • Z is chosen from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, any of which may be optionally substituted;
  • V is chosen from a bond, O, S, NR5, and (CR ⁇ R ⁇ X; W is chosen from a bond, O, S, NRs, and (CRgR 10 X; X is chosen from a bond, O, S, NRn, and (CR 12 R 13 X;
  • Y is chosen from a bond, O, S, NR 14 , and 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, halogen, 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 heterocycloalky
  • R 6 , R7, R9, Rio, R12, Ri3, Ri5, and R] 6 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] 0 , or R] 2 and Ri 3 , or Ri 5 and Ri 6 are taken together to form oxo.
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 are independently chosen from CH, C, and N;
  • Q 2 is chosen from C, CH, and N;
  • Q 3 is chosen from CRi, CH, and N;
  • Z is chosen from hydrogen, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and -CO 2 Ri 7 ;
  • W is chosen from O and NH; m and q are independently an integer from 0 to 4; each Ri and R 4 is independently chosen from hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, amido, amino, aryl, aryloxy, carbamate, carboxy, cyano, cycloalkyl, halogen, heteroalkyl, heteroaryl, heterocycloalkyl, hydroxyl, nitro, perhaloalkoxy, perhaloalkyl, sulfonyl and sulfonamide, any of which may be optionally substituted; and
  • Rn is chosen from alkyl, alkenyl, and alkynyl, any of which may be optionally substituted.
  • Z is chosen from optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and -CO 2 R 17 .
  • X 1 , X 2 , X3, X 4 , X 5 , X 6 , and X 7 are N.
  • said optionally substituted groups are substituted with between 0 and 4 substituents each independently chosen from 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, phenyloxy, 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, arylthi
  • Q 2 is chosen from C and CH.
  • each Rj and R 4 is independently chosen from hydrogen, lower acyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower alkoxyalkyl, lower amido, lower amino, cyano, lower cycloalkyl, lower heterocycloalkyl, phenyl, lower phenylalkyl, lower meteroaryl, halogen, lower heteroalkyl, hydroxyl, nitro, lower perhaloalkoxy, lower perhaloalkyl, lower sulfonyl, and lower sulfonamide, any of which may be optionally substituted.
  • m and q are independently an integer from 0 to 2_
  • each R] and R 4 is independently chosen from lower alkyl, lower alkoxy, cyano, halogen, hydroxyl, nitro, perfluoromethoxy, perfluoromethyl, lower sulfonyl, and lower sulfonamide.
  • m and q are independently an integer from 0 to
  • each R lower alkyl.
  • q is 0.
  • m is an integer from 1 to 2.
  • each R 4 is independently chosen from methyl, halogen, and methylsulfonyl.
  • Z is chosen from optionally substituted optionally substituted heteroaryl and -CO 2 R 1 7.
  • Z is lower heteroaryl, which may be optionally substituted.
  • Z is a six-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 pyrimidine and oxadiazole, either of which may be optionally substituted.
  • Q 3 is N.
  • Q 3 is CH.
  • R n is optionally substituted lower alkyl.
  • Rj 7 is lower alkyl.
  • Z is chosen from optionally substituted monocyclic heteroaryl and -CO 2 R 1 7.
  • X 1 , X 4 , and X 6 are each nitrogen;
  • X 2 , X 3 , X 5 , and X 7 are each CH.
  • X 1 , X 4 , X5, and X 6 are each nitrogen;
  • X 2 , X 3 , and X 7 are each CH.
  • X 1 , X 5 , and X 7 are each nitrogen;
  • X 2 , X 3 , X 4 , and X 6 are each CH. [0129] In certain embodiments ,
  • X 1 , X 4 , and X 5 are each nitrogen;
  • X 2 , X 3 , X 6 , and X 7 are each CH. [0130] In certain embodiments ,
  • X 4 and X 6 are each nitrogen; and Xi, X 2 , X 3 , Xs, and X 7 are each CH.
  • X 4 , X 5 , and X 6 are each nitrogen; and Xi, X 2 , X 3 , and X 7 are each CH.
  • X 2 , X 4 , and X 6 are each nitrogen; and Xi, X 3 , X 5 , and X 7 are each CH.
  • X 3 , X 4 , and X 6 are each nitrogen; and Xi, X 2 , X 5 , and X 7 are each CH.
  • Xi, X 3 , X 4 , and X 6 are each nitrogen; and X 2 , X 5 , and X 7 are each CH.
  • X 1 , X 6 , and X 7 are each nitrogen; and X 2 , X 3 , X 4 , and X 5 are each CH.
  • X 1 , X 3 , Xe, and X 7 are each nitrogen; and X 2 , X 4 , and X 5 are each CH.
  • X 3 and X 4 are each nitrogen; and Xi, X 2 , X 5 , X 6 , and X 7 are each CH.
  • X 1 , X 3 , and X 7 are each nitrogen; and X 2 , X 4 , X 5 , and X 6 are each CH.
  • Xi and X 7 are each nitrogen; and X 2 , X 3 , X 4 , X 5 , and X 6 are each CH.
  • X 3 and X 7 are each nitrogen; and Xi, X 2 , X 4 , X 5 , and X 6 are each CH.
  • X 2 , X 4 , X 5 , and X 6 are each nitrogen;
  • X 1 , X3, and X7 are each CH. [0142] In certain embodiments ,
  • X 2 , X 4 , and X 5 are each nitrogen;
  • Xi, X 3 , X 6 , and X 7 are each CH. [0143] In certain embodiments ,
  • X 3 , X 4 , and X 5 are each nitrogen;
  • Xi, X 2 , X 6 , and X 7 are each CH.
  • X 4 and X 5 are each nitrogen;
  • Xi, X 2 , X 3 , X 6 , and X 7 are each CH.
  • X 1 , X 3 , X 4 , and X5 are each nitrogen;
  • X 2 , X 6 , and X 7 are each CH.
  • X 3 , X 4 , X 5 , and X 6 are each nitrogen;
  • X 1 , X 2 , and X 7 are each CH. [0147] In certain embodiments ,
  • X 2 , X 4 , X 5 , and X 6 are each nitrogen;
  • Xi, X 3 , and X 7 are each CH.
  • X 1 , X 2 , X 4 , and X5 are each nitrogen;
  • X 3 , X 6 , and X 7 are each CH.
  • X 1 , X 2 , X 4 , and X 6 are each nitrogen;
  • X 3 , X 5 and X 7 are each CH.
  • X 2 , X 3 , X 6 , and X 7 are each nitrogen;
  • X 1 , X 4 and X 5 are each CH.
  • X 2 , X 3 , X 5 , and X 7 are each nitrogen;
  • X 1 , X 4 and X 6 are each CH. [0152] In certain embodiments ,
  • X 3 , X 6 , and X 7 are each nitrogen;
  • Xi, X 2 , X 4 , and X 5 are each CH.
  • Xi, X 5 , and X 7 are each nitrogen;
  • X 2 , X 3 , X 4 , and X 6 are each CH. [0154] In certain embodiments ,
  • Xi, X 3 , and X 4 are each nitrogen;
  • X 2 , X 5 , Xe, and X 7 are each CH.
  • Xi, X 6 , and X 7 are each nitrogen;
  • X 2 , X 3 , X 4 , and X 5 are each CH.
  • Xi, X 3 , X 6 , and X 7 are each nitrogen;
  • X 2 , X 4 , and X 5 are each CH.
  • X 3 and X 4 are each nitrogen;
  • Xi, X 2 , X 5 , X 6 , and X 7 are each CH.
  • Xi, X 3 , and X 7 are each nitrogen;
  • X 2 , X 4 , X 5 , and X 6 are each CH.
  • Xi and X 7 are each nitrogen;
  • X 2 , X 3 , X 4 , X 5 , and X 6 are each CH. [0160] In certain embodiments ,
  • X 3 and X 7 are each nitrogen;
  • Xi, X 2 , X 4 , X 5 , and X 6 are each CH.
  • composition comprising a compound as disclosed herein together with a pharmaceutically acceptable carrier.
  • pharmaceutical composition comprises a compound chosen from those recited in Examples 1 to 55 together with a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is useful for the treatment or prevention of a GPR119-mediated disease.
  • 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 to a patient in need thereof.
  • said disease is a metabolic disease.
  • said disease is diabetes.
  • 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; and 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-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,
  • Also provided herein is a method for achieving an effect in a patient comprising the administration of a therapeutically effective amount of a compound as disclosed herein to a patient, wherein the effect is GLP-I secretion, lowering of blood glucose, improve glucose tolerance, decrease in insulin resistance, improvement in glucose-stimulated insulin secretion, preservation or restoration of pancreatic ⁇ -cell function, increased antihyperglycemic efficacy, weight loss, lowering of triglycerides, lowering of LDL, increase of HDL, lowering of blood pressure, and inhibition of bone resorption.
  • said effect is improvement in glucose- stimulated insulin secretion without hypoglycemia.
  • 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.
  • 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.
  • 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 examples 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-).
  • amino 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.
  • 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.
  • 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.
  • carboxyl or “carboxy,” as used herein, refers to -C(O)OH or the corresponding “carboxylate” anion, such as is in a carboxylic acid salt.
  • O-carboxy group refers to a RC(O)O- group, where R is as defined herein.
  • C-carboxy group refers to a -C(O)OR groups where R is as defined herein.
  • 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,l]octane.
  • ester 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.
  • halogen or halo
  • fluorine chlorine, bromine, or iodine
  • 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. Examples include fluoromethylene
  • 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. Up to two heteroatoms may be consecutive, such as, for example, -CH 2 -NH- OCH 3 .
  • 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,
  • heterocycle groups include aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[l,3]oxazolo[4,5-b]pyridinyl, benzo thiazolyl, 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 chosen 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
  • 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,
  • lower heterocycloalkyls include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, and morpholinyl.
  • Lower heterocycloalkyls may be unsaturated.
  • lower amino 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.
  • mercaptyl as used herein, alone or in combination, refers to an RS- group, where R is as defined herein.
  • 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.
  • sulfanyl refers to -
  • 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.
  • 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
  • X is a halogen
  • trihalomethoxy refers to a X 3 CO- group where X is a halogen.
  • trimethysilyl 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.
  • 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.
  • the composite group alkylamido would represent an alkyl group attached to the parent molecule through an amido group
  • the term alkoxy alkyl 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 chosen 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' 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.
  • 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,
  • bonds 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-phenylprop
  • 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, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1- ephenamine, and N.N-dibenzylethylenediamine.
  • nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine,
  • a salt of a compound can be made by reacting the appropriate compound in the form of the free base with the appropriate acid.
  • the compounds of the subject invention 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.
  • 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 nonaqueous 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.
  • compositions 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.
  • 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 (C1-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 chosen 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 chosen 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.
  • 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.
  • lozenges comprising the active ingredient in a flavored basis such as sucrose and acacia or tragacanth
  • 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.
  • compositions 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.
  • the route of administration may vary depending on the condition and its severity.
  • the compounds described herein may be administered in combination with another therapeutic agent.
  • another therapeutic agent such as a pharmaceutically acceptable salt, ester, or prodrug thereof.
  • 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.
  • another therapeutic agent which also includes a therapeutic regimen
  • increased therapeutic benefit may result by also providing the patient with another therapeutic agent for diabetes.
  • the overall benefit experienced by the patient may simply be additive of the two therapeutic agents or the patient may experience a synergistic benefit.
  • 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.
  • 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 chosen 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-lowering agents, and others.
  • compounds disclosed herein may be administered with an agent chosen 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 chosen 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 chosen from the group comprising: corticosteroids, non-steroidal anti-inflammatories, 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 chosen from the group comprising: corticosteroids, non-steroidal anti-inflammatories, 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 chosen 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 GPR119-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.
  • 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.
  • 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.
  • 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.
  • Further 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. These compounds can also be used to treat allergic rhinitis, respiratory distress syndrome, endotoxic shock syndrome, and atherosclerosis.
  • 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.
  • Reagents a) 2-bromo-l,l-diethoxyethane, IPA, reflux; b) NBS, rt; c) NaH, Ar 102 NH 2 , NMP; d) tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-5,6-dihydropyridine-l(2H)-carboxylate, Pd(PPh 3 ) 2 Cl 2 , K 2 CO 3 e) TFA, DCM. f) DIPEA, DCM g) Ar 103 -X, Cs 2 CO 3 , NMP, microwave, 150 0 C. h) Pd/C, H 2 .
  • Scheme 2 Scheme 2
  • Reagents a) Ar 103 -X, DIPEA, DMF, 100 0 C, 2 h; b)LiOH, THF:H 2 O (6:1), 60 0 C, 16 h; c)HATU, DIPEA, rt, 1 h; d) POCl 3 , reflux, 45 min; e) NaH, DMF, rt, 15 min.
  • Step 4 tert-Butyl 4-(8-(2-fluoro-4-(methylsulfonyl)phenylamino)imidazo[l,2- a]pyrazin-3-yl)-5,6-dihydropyridine-l(2H)-carboxylate
  • Step 4 8-Chloro-3-(l-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-[l,2,4]triazolo[4,3- ajpyrazine
  • TThhee ttiittllee ⁇ c ;oommppcound was synthesized as described for EXAMPLE 3 using N-(2-methyl-6-(methylsulfonyl)pyridin-3-yl)-3-(l,2,3,6-tetrahydropyridin-4- yl)imidazo[l,2-a]pyrazin-8-amine and 2-chloro-5-fluoropyrimidine as the starting materials.
  • Step 2 l-(5-Ethylpyrimidin-2-yl)piperidine-4-carboxylic acid
  • Step 5 N'-(5-Bromopyrimidin-4-yl)-l-(5-ethylpyrimidin-2-yl)piperidine-4- carbohydrazide
  • Step 6 8-Bromo-3-(l-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-[l,2,4]triazolo[4,3- cjpyrimidine
  • Step 7 3-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)-N-(2-fluoro-4-(methylsulfonyl) phenyl)-[l,2,4]triazolo[4,3-c]pyrimidin-8-amine
  • Step 1 4-Bromo-6-chloropyridazin-3 -amine
  • Step 3 6-chloro-N-(2-fluoro-4-(methylsulfonyl)phenyl)imidazo[l,2-b]pyridazin-8- amine flask was placed a solution of 2-fluoro-4- (methylsulfonyl) benzenamine (8.8 g, 46.56 mmol, 1.20 equiv) in tetrahydrofuran (200 mL), potassium butan-1-olate (10.9 g, 97.32 mmol, 2.50 equiv), 8-bromo-6- chloroimidazo [1,2-b] pyridazine (9 g, 38.96 mmol, 1.00 equiv).
  • Step 4 N-(2-Fluoro-4-(methylsulfonyl)phenyl)imidazo[l,2-b]pyridazin-8-amine
  • Step 5 3-Bromo-N-(2-fluoro-4-(methylsulfonyl)phenyl)imidazo[l,2-b]pyridazin-8- amine
  • Step 6 Tert-butyl 4-(8-(2-fluoro-4-(methylsulfonyl)phenylamino)imidazo[l ,2- b]pyridazin-3-yl)-5,6-dihydropyridine-l(2H)-carboxylate
  • Step 1 N-(2-Fluoro-4-(methylsulfonyl)phenyl)-3-(l,2,3,6-tetrahydropyridin-4- yl)imidazo[l,2-b]pyridazin-8-amine
  • Step_l 3-(l-(5-Ethylpyrimidin-2-yl)-l,2,3,6-tetrahydropyridin-4-yl)-N-(2-fluoro-4- (methylsulfonyl)phenyl)imidazo[ 1 ,2-b]pyridazin-8-amine
  • Step 1 Tert-butyl 4-(3-bromoimidazo[l,2-a]pyrazin-8-yl)piperazine-l-carboxylate
  • Step 2 Tert-butyl 4-(3-(2-fluoro-4-(methylsulfonyl)phenylamino)imidazo[l ,2- a]pyrazin-8-yl)piperazine-l-carboxylate
  • Step 2 8-Bromo-3-(l-(5-ethylpyrimidin-2-yl)piperidin-4-yl)imidazo[l,2- a]pyridine
  • Step 3 3-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)-N-(2-methyl-6- (methylsulfonyl) pyridin-3-yl)imidazo[l,2-a]pyridin-8-amine
  • Step 1 Tert-butyl 4-(l-bromo-2-oxoethyl)piperidine-l-carboxylate
  • Step 3 Tert-butyl 4-(8-bromo-6-chloroimidazo[l,2-b]pyridazin-3-yl)piperidine-l- carboxylate
  • Step 4 Tert-butyl 4-(6-chloro-8-(2-methyl-6-(methylsulfonyl)pyridin-3- ylamino)imidazo[l,2-b]pyridazin-3-yl)piperidine-l-carboxylate
  • Step 5 Tert-butyl 4-(8-(2-methyl-6-(methylsulfonyl)pyridin-3- ylamino)imidazo[l,2-b]pyridazin-3-yl)piperidine-l-carboxylate
  • Step 1 3,6-Dichloro-N-(2-methyl-6-(methylsulfonyl)pyridin-3-yl)pyridazin-4- amine
  • Step 2 6-Chloro-3-(l-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-N-(2-methyl-6- (methylsulfonyl)pyridin-3-yl)-[l,2,4]triazolo[4,3-b]pyridazin-8-amine
  • Step 3 3-(l-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-N-(2-methyl-6- (methylsulfonyl) pyridin-3-yl)-[l,2,4]triazolo[4,3-b]pyridazin-8-amine
  • 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 11.0.

Abstract

Disclosed herein are compounds and methods which may be useful as inhibitors of GPRl 19 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 application No. 61/148,956, filed January 31, 2009, the disclosure of which is hereby incorporated by reference as if written herein in its entirety. [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 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- 1 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-I 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-I 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 BYETTA® 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-I 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 GPR119 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- 1 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 GPR119-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 and D are each independently chosen from heteroaryl, aryl, cycloalkyl, and heterocycloalkyl;
B is a bicyclic heteroaryl, which may be optionally substituted;
Q is chosen from C and N;
V is chosen from a bond, O, S, NR5, and (CR6RT)1; W is chosen from a bond, O, S, NRs, and (CRgRiO)5; X is chosen from a bond, O, S, NRn, and (CR12R13X;
Y is chosen from a bond, O, S, NR14, and
Figure imgf000006_0002
Z is chosen from alkyl, heteroalkyl, haloalkyl, perhaloalkyl, -CO2R17, - CO2NR18R19, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, any of which may be optionally substituted; 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, halogen, 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, Rn, 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;
R6, R7, R9, Rio, R12, Ri3, Ri5, and R]6 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 Rio, or R12 and Ri3, or Ri5 and Ri6 are taken together to form oxo; and
Ri7, Ri8, 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 provided herein, B is a bicyclic heteroaryl containing between two and four nitrogens.
[016] In further embodiments, one of said nitrogens occupies a bridge position between the two fused rings. [017] In further embodiments, B has the formula:
Figure imgf000008_0001
wherein:
Xi is chosen from CH, C(R2O) and N;
X2 is chosen from CH, C(R21) and N;
X3 is chosen from CH, C(R22) and N;
X4 is chosen from CH, C(R23) and N;
X5 is chosen from CH, C(R24) and N;
X6 is chosen from CH, C(R25) and N;
X7 is chosen from CH, C(R26) and N;
R2o, R2I, R22, R23, R24, R25, and R26 are each independently chosen from halogen, hydroxy, cyano, lower alkyl, lower alkoxy, trifluoromethyl, trifluoromethoxy, lower cycloalkyl, lower cycloalkylalkyl, lower heterocycloalkyl, lower heterocycloalkylalkyl, phenyl, lower phenylalkyl, lower heteroaryl, and lower heteroarylalkyl, any of which may be optionally substituted with one or more substituents chosen from hydrogen, halogen, hydroxy, cyano, methyl, ethyl, methoxy, trifluoromethyl, and trifluoromethoxy; and the dashed lines in the ring comprising X4 - X7 represent additional bonds which may be present or absent.
[018] In further embodiments, R2o, R2i, R22, R2i, R25, and R26 are all hydrogen. [019] In certain embodiments, X4 is nitrogen. [020] In other embodiments, X7 is nitrogen. [021] In certain embodiments, X] is nitrogen. [022] In certain embodiments, X6 is nitrogen. [023] In certain embodiments, X3 is nitrogen. [024] In certain embodiments,
X1, X4, and X6 are each nitrogen; and X2, X3, X5, and X7 are each CH. [025] In certain embodiments,
X1, X4, X5, and X6 are each nitrogen; and X2, X3, and X7 are each CH.
[026] In certain embodiments,
X1, X5, and X7 are each nitrogen; and X2, X3, X4, and X6 are each CH.
[027] In certain embodiments,
X1, X4, and X5 are each nitrogen; and X2, X3, Xe, and X7 are each CH.
[028] In certain embodiments,
X4 and X6 are each nitrogen; and X1, X2, X3, X5, and X7 are each CH.
[029] In certain embodiments,
X4, X5, and X6 are each nitrogen; and X1, X2, X3, and X7 are each CH.
[030] In certain embodiments,
X2, X4, and X6 are each nitrogen; and X1, X3, X5, and X7 are each CH.
[031] In certain embodiments ,
X3, X4, and X6 are each nitrogen; and X1, X2, X5, and X7 are each CH.
[032] In certain embodiments,
X1, X3, X4, and X6 are each nitrogen; and X2, X5, and X7 are each CH.
[033] In certain embodiments,
X1, X6, and X7 are each nitrogen; and X2, X3, X4, and X5 are each CH.
[034] In certain embodiments,
X1, X3, X6, and X7 are each nitrogen; and X2, X4, and X5 are each CH.
[035] In certain embodiments,
X3 and X4 are each nitrogen; and X1, X2, X5, X6, and X7 are each CH. [036] In certain embodiments,
X1, X3, and X7 are each nitrogen; and
X2, X4, X5, and X6 are each CH. [037] In certain embodiments,
X] and X7 are each nitrogen; and
X2, X3, X4, Xs, and X6 are each CH. [038] In certain embodiments,
X3 and X7 are each nitrogen; and
Xi, X2, X4, X5, and X6 are each CH. [039] In certain embodiments,
X2, X4, X5, and X6 are each nitrogen; and
X1, X3, and X7 are each CH. [040] In certain embodiments,
X2, X4, and X5 are each nitrogen; and
Xi, X3, X6, and X7 are each CH. [041] In certain embodiments,
X3, X4, and X5 are each nitrogen; and
Xi, X2, X6, and X7 are each CH. [042] In certain embodiments,
X4 and X5 are each nitrogen; and
Xi, X2, X3, X6, and X7 are each CH. [043] In certain embodiments,
Xi, X3, X4, and X5 are each nitrogen; and
X2, X6, and X7 are each CH. [044] In certain embodiments,
X3, X4, X5, and X6 are each nitrogen; and
Xi, X2, and X7 are each CH. [045] In certain embodiments,
X2, X4, X5, and X6 are each nitrogen; and
Xi, X3, and X7 are each CH. [046] In certain embodiments,
Xi, X2, X4, and X5 are each nitrogen; and
X3, X6, and X7 are each CH. [047] In certain embodiments,
X1, X2, X4, and X6 are each nitrogen; and
X3, X5 and X7 are each CH. [048] In certain embodiments,
X2, X3, X6, and X7 are each nitrogen; and
X1, X4 and X5 are each CH. [049] In certain embodiments,
X2, X3, X5, and X7 are each nitrogen; and
X1, X4 and X6 are each CH. [050] In certain embodiments,
X3, X6, and X7 are each nitrogen; and
X1, X2, X4, and X5 are each CH. [051] In certain embodiments ,
X1, X5, and X7 are each nitrogen; and
X2, X3, X4, and X6 are each CH. [052] In certain embodiments,
X1, X3, and X4 are each nitrogen; and
X2, X5, X6, and X7 are each CH. [053] In certain embodiments,
X1, X6, and X7 are each nitrogen; and
X2, X3, X4, and X5 are each CH. [054] In certain embodiments,
X1, X3, X6, and X7 are each nitrogen; and
X2, X4, and X5 are each CH. [055] In certain embodiments,
X3 and X4 are each nitrogen; and
X1, X2, X5, X6, and X7 are each CH. [056] In certain embodiments,
X1, X3, and X7 are each nitrogen; and
X2, X4, X5, and X6 are each CH. [057] In certain embodiments,
X1 and X7 are each nitrogen; and
X2, X3, X4, X5, and X6 are each CH. [058] In certain embodiments,
X3 and X7 are each nitrogen; and Xi, X2, X4, Xs, and X6 are each CH.
[059] In certain embodiments, B is chosen from
Figure imgf000012_0001
[060] In further embodiments, B is chosen from
Figure imgf000012_0002
[061] In certain embodiments provided herein,
A is chosen from aryl, cycloalkyl and heterocycloalkyl, any of which may be optionally substituted; Z is chosen from heteroaryl, aryl, and -CO2NRi8Ri9, either of which may be optionally substituted; and r, s, t, and u are each independently an integer from 0 to 2.
[062] In other embodiments provided herein, r, t, and u are each independently an integer from 0 to 1. [063] In yet other 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, halogen, 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, Rn, and R]4 are independently chosen from hydrogen, acyl, lower alkyl, lower alkenyl, and lower alkynyl, any of which may be optionally substituted. [064] In other embodiments provided herein, D is aryl or heteroaryl, any of which may be optionally substituted.
[065] In other embodiments provided herein, X and Y are each independently a bond. [066] In further embodiments, the compounds have structural Formula II:
Figure imgf000013_0001
(H) or a salt, ester, or prodrug thereof, wherein:
B is a bicyclic heteroaryl, containing between two and four nitrogens; D is chosen from heteroaryl and aryl;
Z is chosen from heteroaryl, aryl, and -CO2NR18R19, which may be optionally substituted;
Q is chosen from C and N; V is chosen from a bond, O, S, NR5,, and (CR6Rv)1,
W is chosen from a bond, O, S, NRg, and (CRgRiO)8; 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, halogen, 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 R8 are independently chosen from hydrogen, acyl, lower alkyl, lower alkenyl, and lower alkynyl;
R6, R7, R9 and R]0 are each independently chosen from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, any of which may be optionally substituted; R9 and Rio are taken together to form oxo; and
Rn is chosen from hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, amido, amino, aryl, aryloxy, carbamate, carboxy, cyano, cycloalkyl, halogen, heteroalkyl, heteroaryl, heterocycloalkyl, hydroxyl, nitro, perhaloalkoxy, perhaloalkyl, and sulfonamide, any of which may be optionally substituted. [067] In other embodiments provided herein, Q is N; s is an integer from 0 to 1 ;
V is chosen from a bond, O, NR5, and (CR6R?),-; and R5 is chosen from hydrogen and lower alkyl.
[068] In other embodiments provided herein, Z is heteroaryl, which may be optionally substituted.
[069] In other embodiments provided herein, Z is a six-membered heteroaryl, which may be optionally substituted.
[070] In other embodiments provided herein, Z is an optionally substituted six- membered heteroaryl containing between 1 and 2 nitrogens. [071] In further embodiments provided herein, Z is pyrimidine, which may be optionally substituted. [072] In yet further embodiments provided herein, V is chosen from O and NR5; and W is a bond.
[073] In other embodiments provided herein,
V is a bond; and W is a bond.
[074] In other embodiments provided herein,
V is chosen from O and NR5; W is (CR9Ri0); and
R9 and R]0 are each independently chosen from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, or R9 and Rio are taken together to form oxo. [075] In other embodiments provided herein, the compounds have structural Formula III:
Figure imgf000015_0001
(III) or a salt, ester, or prodrug thereof, wherein:
A is chosen from aryl, cycloalkyl, and heterocycloalkyl;
B is a bicyclic heteroaryl containing between two and four nitrogens;
D is chosen from heteroaryl and aryl;
Z is chosen from heteroaryl, aryl, and -CO2NR18R19, which may be optionally substituted;
Q is chosen from C and N;
V is chosen from a bond, O, S, NR5, and (CR6Rv)1,;
Figure imgf000015_0002
Y is chosen from a bond, O, S, NR14, and (CRisRi6)u ; m, n, p, and q are each independently an integer from 0 to 4; r, s, and u are each independently an integer from 0 to 1; 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, halogen, 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 R]4 are each independently chosen from hydrogen, acyl, lower alkyl, lower alkenyl, and lower alkynyl; and
R6, R7, R9, Rio, Ri5 and R]6 are each independently chosen from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, any of which may be optionally substituted; or R9 and Rio are taken together to form oxo. [076] In yet other embodiments provided herein, Q is N. [077] In further embodiments provided herein, Z is heteroaryl, which may be optionally substituted.
[078] In further embodiments provided herein, Z is a six-membered heteroaryl, which may be optionally substituted.
[079] In other embodiments provided herein, Z is an optionally substituted six- membered heteroaryl containing between 1 and 2 nitrogens. [080] In other embodiments provided herein, Z is pyrimidine, which may be optionally substituted.
[081] In further embodiments provided herein, s is 1; and R9 and Rio are each independently chosen from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, any of which may be optionally substituted; or R9 and Rio are taken together to form oxo.
[082] In other embodiments provided herein, Y is chosen from O, (CRisRi6)u, and NRi4.
[083] In yet other embodiments provided herein, V is chosen from O, (CR6R7),-, and NR5.
[084] In further embodiments provided herein, V is a bond. [085] In yet further embodiments provided herein, W is a bond; and D is aryl. [086] In other embodiments provided herein, Z is heteroaryl, which may be optionally substituted.
[087] In other embodiments provided herein, Z is a six-membered heteroaryl, which may be optionally substituted.
[088] In other embodiments provided herein, Z is an optionally substituted six- membered heteroaryl containing between 1 and 2 nitrogens. [089] In further embodiments provided herein, Z is pyrimidine, which may be optionally substituted.
[090] In yet further embodiments provided herein, A is cycloalkyl. [091] In further embodiments provided herein, Y is O. [092] In further embodiments provided herein, A is aryl. [093] In other embodiments provided herein, A is phenyl. [094] In other embodiments provided herein, Q is N. [095] In other embodiments provided herein, A is heterocycloalkyl. [096] In yet other embodiments provided herein, A is 4- membered, 5- membered, or 6-membered heterocycloalkyl. [097] In further embodiments provided herein, V is a bond. [098] In other embodiments provided herein, D is aryl. [099] In further embodiments provided herein, B is aryl; and R2 and R3 together form an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl.
[0100] In further embodiments provided herein, B is heteroaryl; and R2 and R3 together form an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl. [0101] In certain embodiments of the present invention, compounds have structural Formula IV:
Figure imgf000018_0001
(IV) or a salt, ester, or prodrug thereof, wherein:
A and D are each independently chosen from heteroaryl, aryl, cycloalkyl, and heterocycloalkyl;
B is a bicyclic heteroaryl containing between two and four nitrogens;
Qi and Q2 are each independently chosen from C and N;
Z is chosen from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, any of which may be optionally substituted;
V is chosen from a bond, O, S, NR5, and (CRδRγX; W is chosen from a bond, O, S, NRs, and (CRgR10X; X is chosen from a bond, O, S, NRn, and (CR12R13X;
Y is chosen from a bond, O, S, NR14, and
Figure imgf000018_0002
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, halogen, 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, Rn, and Ru 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; and
R6, R7, R9, Rio, R12, Ri3, Ri5, and R]6 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 R]0, or R]2 and Ri3, or Ri5 and Ri6 are taken together to form oxo.
[0102] In certain embodiments of the present invention, compounds have structural Formula V:
Figure imgf000019_0001
(V) or a salt, ester, or prodrug thereof, wherein: the dashed line indicates an additional bond which may be present or absent;
X1, X2, X3, X4, X5, X6, and X7 are independently chosen from CH, C, and N;
Q2 is chosen from C, CH, and N;
Q3 is chosen from CRi, CH, and N;
Z is chosen from hydrogen, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and -CO2Ri7;
W is chosen from O and NH; m and q are independently an integer from 0 to 4; each Ri and R4 is independently chosen from hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, amido, amino, aryl, aryloxy, carbamate, carboxy, cyano, cycloalkyl, halogen, heteroalkyl, heteroaryl, heterocycloalkyl, hydroxyl, nitro, perhaloalkoxy, perhaloalkyl, sulfonyl and sulfonamide, any of which may be optionally substituted; and
Rn is chosen from alkyl, alkenyl, and alkynyl, any of which may be optionally substituted.
[0103] In certain embodiments, Z is chosen from optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and -CO2R17. [0104] In certain embodiments, between two and four of X1, X2, X3, X4, X5, X6, and X7 are N.
[0105] In certain embodiments, said optionally substituted groups are substituted with between 0 and 4 substituents each independently chosen from 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, phenyloxy, 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, SH, SCH3, C(O)CH3, lower carbamate, and lower urea. [0106] In certain embodiments, Q2 is chosen from C and CH. [0107] In certain embodiments, each Rj and R4 is independently chosen from hydrogen, lower acyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower alkoxyalkyl, lower amido, lower amino, cyano, lower cycloalkyl, lower heterocycloalkyl, phenyl, lower phenylalkyl, lower meteroaryl, halogen, lower heteroalkyl, hydroxyl, nitro, lower perhaloalkoxy, lower perhaloalkyl, lower sulfonyl, and lower sulfonamide, any of which may be optionally substituted. [0108] In certain embodiments, m and q are independently an integer from 0 to 2_
[0109] In certain embodiments, each R] and R4 is independently chosen from lower alkyl, lower alkoxy, cyano, halogen, hydroxyl, nitro, perfluoromethoxy, perfluoromethyl, lower sulfonyl, and lower sulfonamide. [0110] In certain embodiments, m and q are independently an integer from 0 to
2_
[0111] In certain embodiments, each R] lower alkyl. [0112] In certain embodiments, q is 0. [0113] In certain embodiments, m is an integer from 1 to 2. [0114] In certain embodiments, each R4 is independently chosen from methyl, halogen, and methylsulfonyl.
[0115] In certain embodiments, Z is chosen from optionally substituted optionally substituted heteroaryl and -CO2R17.
[0116] In certain embodiments, Z is substituted with a substituent chosen from lower alkyl, lower haloalkyl, lower cycloalkyl, lower alkoxy, lower haloalkoxy, cyano, and halogen.
[0117] In other embodiments provided herein, Z is lower heteroaryl, which may be optionally substituted.
[0118] In other embodiments provided herein, Z is a six-membered heteroaryl, which may be optionally substituted.
[0119] In other embodiments provided herein, Z is an optionally substituted six- membered heteroaryl containing between 1 and 2 nitrogens. [0120] In further embodiments provided herein, Z is chosen from pyrimidine and oxadiazole, either of which may be optionally substituted. [0121] In certain embodiments, Q3 is N. [0122] In certain embodiments, Q3 is CH.
[0123] In certain embodiments, Rn is optionally substituted lower alkyl. [0124] In certain embodiments, Rj7 is lower alkyl. [0125] In certain embodiments, Z is chosen from optionally substituted monocyclic heteroaryl and -CO2R17. [0126] In certain embodiments,
X1, X4, and X6 are each nitrogen; and
X2, X3, X5, and X7 are each CH. [0127] In certain embodiments,
X1, X4, X5, and X6 are each nitrogen; and
X2, X3, and X7 are each CH. [0128] In certain embodiments,
X1, X5, and X7 are each nitrogen; and
X2, X3, X4, and X6 are each CH. [0129] In certain embodiments ,
X1, X4, and X5 are each nitrogen; and
X2, X3, X6, and X7 are each CH. [0130] In certain embodiments ,
X4 and X6 are each nitrogen; and Xi, X2, X3, Xs, and X7 are each CH.
[0131] In certain embodiments ,
X4, X5, and X6 are each nitrogen; and Xi, X2, X3, and X7 are each CH.
[0132] In certain embodiments ,
X2, X4, and X6 are each nitrogen; and Xi, X3, X5, and X7 are each CH.
[0133] In certain embodiments ,
X3, X4, and X6 are each nitrogen; and Xi, X2, X5, and X7 are each CH.
[0134] In certain embodiments,
Xi, X3, X4, and X6 are each nitrogen; and X2, X5, and X7 are each CH.
[0135] In certain embodiments ,
X1, X6, and X7 are each nitrogen; and X2, X3, X4, and X5 are each CH.
[0136] In certain embodiments ,
X1, X3, Xe, and X7 are each nitrogen; and X2, X4, and X5 are each CH.
[0137] In certain embodiments ,
X3 and X4 are each nitrogen; and Xi, X2, X5, X6, and X7 are each CH.
[0138] In certain embodiments ,
X1, X3, and X7 are each nitrogen; and X2, X4, X5, and X6 are each CH.
[0139] In certain embodiments,
Xi and X7 are each nitrogen; and X2, X3, X4, X5, and X6 are each CH.
[0140] In certain embodiments,
X3 and X7 are each nitrogen; and Xi, X2, X4, X5, and X6 are each CH. [0141] In certain embodiments ,
X2, X4, X5, and X6 are each nitrogen; and
X1, X3, and X7 are each CH. [0142] In certain embodiments ,
X2, X4, and X5 are each nitrogen; and
Xi, X3, X6, and X7 are each CH. [0143] In certain embodiments ,
X3, X4, and X5 are each nitrogen; and
Xi, X2, X6, and X7 are each CH. [0144] In certain embodiments,
X4 and X5 are each nitrogen; and
Xi, X2, X3, X6, and X7 are each CH. [0145] In certain embodiments,
X1, X3, X4, and X5 are each nitrogen; and
X2, X6, and X7 are each CH. [0146] In certain embodiments,
X3, X4, X5, and X6 are each nitrogen; and
X1, X2, and X7 are each CH. [0147] In certain embodiments ,
X2, X4, X5, and X6 are each nitrogen; and
Xi, X3, and X7 are each CH. [0148] In certain embodiments ,
X1, X2, X4, and X5 are each nitrogen; and
X3, X6, and X7 are each CH. [0149] In certain embodiments ,
X1, X2, X4, and X6 are each nitrogen; and
X3, X5 and X7 are each CH. [0150] In certain embodiments ,
X2, X3, X6, and X7 are each nitrogen; and
X1, X4 and X5 are each CH. [0151] In certain embodiments ,
X2, X3, X5, and X7 are each nitrogen; and
X1, X4 and X6 are each CH. [0152] In certain embodiments ,
X3, X6, and X7 are each nitrogen; and
Xi, X2, X4, and X5 are each CH. [0153] In certain embodiments ,
Xi, X5, and X7 are each nitrogen; and
X2, X3, X4, and X6 are each CH. [0154] In certain embodiments ,
Xi, X3, and X4 are each nitrogen; and
X2, X5, Xe, and X7 are each CH. [0155] In certain embodiments ,
Xi, X6, and X7 are each nitrogen; and
X2, X3, X4, and X5 are each CH. [0156] In certain embodiments ,
Xi, X3, X6, and X7 are each nitrogen; and
X2, X4, and X5 are each CH. [0157] In certain embodiments,
X3 and X4 are each nitrogen; and
Xi, X2, X5, X6, and X7 are each CH. [0158] In certain embodiments ,
Xi, X3, and X7 are each nitrogen; and
X2, X4, X5, and X6 are each CH. [0159] In certain embodiments,
Xi and X7 are each nitrogen; and
X2, X3, X4, X5, and X6 are each CH. [0160] In certain embodiments ,
X3 and X7 are each nitrogen; and
Xi, X2, X4, X5, and X6 are each CH.
[0161] Also provided is a pharmaceutical composition comprising a compound as disclosed herein together with a pharmaceutically acceptable carrier. [0162] In certain embodiments, the pharmaceutical composition comprises a compound chosen from those recited in Examples 1 to 55 together with a pharmaceutically acceptable carrier.
[0163] In certain embodiments, the pharmaceutical composition is useful for the treatment or prevention of a GPR119-mediated disease. [0164] Also provided herein is a method of modulating GPRl 19 comprising contacting GPRl 19 with a compound as disclosed herein.
[0165] 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 to a patient in need thereof.
[0166] In certain embodiments, said disease is a metabolic disease.
[0167] In certain embodiments, said disease is diabetes.
[0168] 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; and another therapeutic agent.
[0169] In certain 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)- 1- { 4- [5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4- ylmethoxy]-benzenesulfonyl}2,3-dihydro-lH-indole-2-carboxylic acid, and GI- 262570.
[0170] Also provided herein is a method for achieving an effect in a patient comprising the administration of a therapeutically effective amount of a compound as disclosed herein to a patient, wherein the effect is GLP-I secretion, lowering of blood glucose, improve glucose tolerance, decrease in insulin resistance, improvement in glucose-stimulated insulin secretion, preservation or restoration of pancreatic β-cell function, increased antihyperglycemic efficacy, weight loss, lowering of triglycerides, lowering of LDL, increase of HDL, lowering of blood pressure, and inhibition of bone resorption. [0171] In certain embodiments, said effect is improvement in glucose- stimulated insulin secretion without hypoglycemia. [0172] As used herein, the terms below have the meanings indicated. [0173] 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.
[0174] 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.
[0175] 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.
[0176] 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.
[0177] 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.
[0178] 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.
[0179] 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.
[0180] 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.
[0181] 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.
[0182] 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. [0183] 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 -(X=O)-NR2 group with R as defined herein. The term "N-amido" as used herein, alone or in combination, refers to a RC(=0)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-).
[0184] 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. [0185] 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. [0186] 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.
[0187] 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.
[0188] 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. [0189] 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.
[0190] 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.
[0191] The term aryloxy as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an oxy.
[0192] The terms "benzo" and "benz," as used herein, alone or in combination, refer to the divalent group C6H4= derived from benzene. Examples include benzothiophene and benzimidazole.
[0193] 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.
[0194] 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.
[0195] 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.
[0196] The term "carbonyl," as used herein, when alone includes formyl [-
C(O)H] and in combination is a -C(O)- group.
[0197] 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.
[0198] The term "cyano," as used herein, alone or in combination, refers to -
CN.
[0199] 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,l]octane.
[0200] The term "ester," as used herein, alone or in combination, refers to a carboxy group bridging two moieties linked at carbon atoms. [0201] The term "ether," as used herein, alone or in combination, refers to an oxy group bridging two moieties linked at carbon atoms.
[0202] The term "halogen," or "halo," as used herein, alone or in combination, refers to fluorine, chlorine, bromine, or iodine.
[0203] 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. [0204] 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. [0205] 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.
[0206] 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.
[0207] 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, benzo thiazolyl, 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.
[0208] The term "hydrazinyl" as used herein, alone or in combination, refers to two amino groups joined by a single bond, i.e., -N-N-.
[0209] The term "hydroxy," as used herein, alone or in combination, refers to -
OH.
[0210] 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.
[0211] The term "imino," as used herein, alone or in combination, refer to =N-.
[0212] The term "iminohydroxy," as used herein, alone or in combination, refers to =N(0H) and =N-O-.
[0213] 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.
[0214] The term "isocyanato" refers to a -NCO group.
[0215] The term "isothiocyanato" refers to a -NCS group.
[0216] The phrase "linear chain of atoms" refers to the longest straight chain of atoms independently chosen from carbon, nitrogen, oxygen and sulfur.
[0217] The term "lower," as used herein, alone or in a combination, where not otherwise specifically defined, means containing from 1 to and including 6 carbon atoms.
[0218] The term "lower aryl," as used herein, alone or in combination, means phenyl or naphthyl, which may be optionally substituted as provided.
[0219] 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.
[0220] 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.
[0221] 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.
[0222] 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.
[0223] The term "mercaptyl" as used herein, alone or in combination, refers to an RS- group, where R is as defined herein.
[0224] The term "nitro," as used herein, alone or in combination, refers to -
NO2.
[0225] The terms "oxy" or "oxa," as used herein, alone or in combination, refer to -O-.
[0226] The term "0x0," as used herein, alone or in combination, refers to =0.
[0227] The term "perhaloalkoxy" refers to an alkoxy group where all of the hydrogen atoms are replaced by halogen atoms.
[0228] 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.
[0229] 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. [0230] The term "sulfanyl," as used herein, alone or in combination, refers to -
S-.
[0231] The term "sulfinyl," as used herein, alone or in combination, refers to
-S(O)-.
[0232] The term "sulfonyl," as used herein, alone or in combination, refers to -
S(O)2-.
[0233] The term "N-sulfonamido" refers to a RS(=O)2NR' - group with R and
R' as defined herein.
[0234] The term "S-sulfonamido" refers to a -S(=O)2NRR' , group, with R and
R' as defined herein.
[0235] 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.
[0236] The term "thiol," as used herein, alone or in combination, refers to an -
SH group.
[0237] The term "thiocarbonyl," as used herein, when alone includes thioformyl
-C(S)H and in combination is a -C(S)- group.
[0238] The term "N-thiocarbamyl" refers to an ROC(S)NR'- group, with R and
R' as defined herein.
[0239] The term "O-thiocarbamyl" refers to a -OC(S)NRR' , group with R and
R' as defined herein.
[0240] The term "thiocyanato" refers to a -CNS group.
[0241] The term "trihalomethanesulfonamido" refers to a X3CS(O)2NR- group with X is a halogen and R as defined herein.
[0242] The term "trihalomethanesulfonyl" refers to a X3CS(O)2- group where
X is a halogen.
[0243] The term "trihalomethoxy" refers to a X3CO- group where X is a halogen.
[0244] 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. [0245] 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 alkoxy alkyl would represent an alkoxy group attached to the parent molecule through an alkyl group. [0246] When a group is defined to be "null," what is meant is that said group is absent.
[0247] 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 chosen 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." [0248] 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.
[0249] 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. [0250] 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. [0251] 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.
[0252] 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.
[0253] "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.
[0254] 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. [0255] 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.
[0256] 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.
[0257] 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. [0258] 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).
[0259] 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.
[0260] 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, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1- ephenamine, and N.N-dibenzylethylenediamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine. [0261] A salt of a compound can be made by reacting the appropriate compound in the form of the free base with the appropriate acid. [0262] 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. [0263] 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.
[0264] 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 nonaqueous 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.
[0265] 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.
[0266] 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. [0267] 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.
[0268] 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.
[0269] 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.
[0270] 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. [0271] 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. [0272] 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.
[0273] 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 (C1-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 chosen 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 chosen 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. [0274] 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.
[0275] 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.
[0276] 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.
[0277] 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. [0278] 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. [0279] Preferred unit dosage formulations are those containing an effective dose, as herein below recited, or an appropriate fraction thereof, of the active ingredient. [0280] 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. [0281] 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.
[0282] 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.
[0283] 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.
[0284] 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. [0285] 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. [0286] For the treatment of metabolic disorders, compounds disclosed herein may be administered with an agent chosen 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. [0287] For the treatment of metabolic disorders, compounds disclosed herein may be administered with an agent chosen 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- 1,6-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)-I- {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. [0288] For the treatment of obesity, compounds disclosed herein may be administered with an agent chosen 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.
[0289] For the treatment of inflammatory diseases , compounds disclosed herein may be administered with an agent chosen from the group comprising: corticosteroids, non-steroidal anti-inflammatories, 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. [0290] For the treatment of inflammatory diseases, compounds disclosed herein may be administered with an agent chosen 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. [0291] 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. [0292] Thus, in another aspect, certain embodiments provide methods for treating GPR119-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.
[0293] 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).
[0294] 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.
[0295] 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. [0296] 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.
[0297] 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.
[0298] 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. [0299] 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. [0300] 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. [0301] 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. [0302] 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.
[0303] 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.
[0304] 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. [0305] In certain embodiments, the disease to be prevented or treated by the methods of the present invention may be autism.
[0306] 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.
[0307] 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. [0308] 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.
General Synthetic Methods for Preparing Compounds
[0309] The following schemes can be used to practice the present invention
Scheme 1
Figure imgf000054_0001
[0310] Reagents: a) 2-bromo-l,l-diethoxyethane, IPA, reflux; b) NBS, rt; c) NaH, Ar102NH2, NMP; d) tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-5,6-dihydropyridine-l(2H)-carboxylate, Pd(PPh3)2Cl2, K2CO3 e) TFA, DCM. f) DIPEA, DCM g) Ar103-X, Cs2CO3, NMP, microwave, 150 0C. h) Pd/C, H2. Scheme 2
Figure imgf000055_0001
[0311] Reagents: a) Ar103-X, DIPEA, DMF, 1000C, 2 h; b)LiOH, THF:H2O (6:1), 600C, 16 h; c)HATU, DIPEA, rt, 1 h; d) POCl3, reflux, 45 min; e) NaH, DMF, rt, 15 min.
[0312] The invention is further illustrated by the following examples, set forth below, which can be prepared by methods known in the art and/or by variations on the methods outlined herein. All IUPAC nomenclature was generated using CambridgeSoft's ChemDraw 10.0 or 11.0.
EXAMPLE 1
Tert-butyl 4-(8-(2-fluoro-4-(methylsulfonyl)phenylamino)imidazo[l,2- a]pyrazin-3-yl)-5,6-dihydropyridine-l(2H)-carboxylate
Figure imgf000056_0001
Step 1: 8-Chloroimidazo[l,2-a]pyrazine
Figure imgf000056_0002
[0313] 3-chloropyrazin-2-amine (21.0 g, 161.54 mmol, 1.00 equiv) was dissolved in isopropyl alcohol (200 mL) in a 500 mL round-bottom flask equipped with a reflux condenser. To this solution was added 2-bromo-l,l-diethoxyethane (160.3 g, 813.71 mmol, 5.00 equiv) in small portions over 10 minutes. The resulting mixture was then allowed to reflux for 2 hours in an oil bath. The reaction was monitored by TLC (EtOAc/PE = 1:1). The mixture was cooled down to room temperature and filtered off to give a yellow cake. The solid was added to a saturated solution of NaHCC>3 (200 mL) and DCM (IL). Aqueous layer was separated from organic phase and re-extracted with DCM (2x 250 mL). The combined organics were dried over MgSO4, filtered and evaporated to dryness affording 8-chloroimidazo[l,2-a]pyrazine (25 g) as a yellow solid. Step 2: 3-Bromo-8-chloroimidazo[l,2-a]pyrazine
Figure imgf000057_0001
[0314] A solution of 8-chloroimidazo[l,2-a]pyrazine (15g, 97.4 mmol) in DCM (300 mL) was treated with NBS (19. Ig, 108 mmol) at room temperature and stirred at this temperature for overnight. The reaction was monitored by TLC. After this time, the resulting solution was diluted with 200 mL DCM and washed with saturated solution of Na2CO3 (2x150 mL), and brine (1x150 mL). Organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give the crude product that was purified by a silica gel column chromatography eluted with ethyl acetate in petroleum ether (1:2) to give 3-bromo-8-chloroimidazo[l,2-a]pyrazine (9.5g, 42%) as yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.04 (IH, d, J = 4.6 Hz), 7. 84 (s, IH), 7.82 (2H, d, J = 4.6 Hz).
Step 3: 3-Bromo-N-(2-fluoro-4-(methylsulfonyl)phenyl)imidazo[l,2-a]pyrazin- 8-amine
Figure imgf000057_0002
[0315] To a suspension of NaH (0.130g, 3.2 mmol, 60% dispersion in mineral oil) in NMP (11 mL) was added 2-fluoro-4-(methylsulfonyl)aniline (0.4 g, 2.15 mmol) at room temperature and allowed to stir for 15 minutes. To this mixture was then added a solution of 3-bromo-8-chloroimidazo[l,2-a]pyrazine (0.5g, 2.15 mmol) in 5 mL NMP and allowed to stir for 3 hours at room temperature, then it was warmed up to 100 0C for overnight. The reaction mixture was cooled down to room temperature, and quenched with water. The mixture was rinsed into a seperatory funnel and extracted with ethyl acetate (3x50 mL). Combined organics were washed with water, brine and dried over Na2SO4, filtered and concentrated in vacuo to give the crude product that was purified by a silica gel column chromatography eluted with 0-100% ethyl acetate in petroleum ether to give 3- bromo-N-(2-fluoro-4-(methylsulfonyl)phenyl)imidazo [l,2-a]pyrazin-8-amine (0.15g, 18%).
Step 4: tert-Butyl 4-(8-(2-fluoro-4-(methylsulfonyl)phenylamino)imidazo[l,2- a]pyrazin-3-yl)-5,6-dihydropyridine-l(2H)-carboxylate
Figure imgf000058_0001
[0316] A mixture of 3-bromo-N-(2-fluoro-4-(methylsulfonyl) phenyl)imidazo[l,2-a]pyrazin-8-amine (O.lg, 0.26 mmol), tert-butyl 4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-l(2H)-carboxylate (0.08g, 0.26 mmol), Pd(PPh3)2Cl2 (18 mg, 0.026 mmol), K2CO3 (72 mg, 0.52 mmol) in dioxane (2.6 mL) was degassed three times and purged with nitrogen. Then, the mixture was heated to 100 0C for overnight. It was cooled down to room temperature and quenched with water. The mixture was rinsed into a seperatory funnel and extracted with ethyl acetate (3x50 mL). Combined organics were washed with water, brine and dried over Na2SO4, filtered and concentrated in vacuo to give the crude product that was purified by a silica gel column chromatography eluted with 0-100% ethyl acetate in petroleum ether to give tert-butyl 4-(8-(2- fluoro-4-(methylsulfonyl)phenylamino) imidazo[l,2-a]pyrazin-3-yl)-5,6- dihydropyridine-l(2H)-carboxylate (40 mg, 33%). LCMS 488.32 [M+l]+ . EXAMPLE 2
N-(2-Fluoro-4-(methylsulfonyl)phenyl)-3-(l,2,3,6-tetrahydropyridin-4- yl)imidazo[l,2-a]pyrazin-8-amine
Figure imgf000059_0001
[0317] A solution of tert-butyl 4-(8-(2-fluoro-4-(methylsulfonyl)phenylamino) imidazo[l,2-a]pyrazin-3-yl)-5,6-dihydropyridine-l(2H)-carboxylate (30 mg, 0.06 mmol) in 6 mL DCM was treated with 6 mL 1 : 1 DCM/TFA mixture at room temperature for 6h. LCMS showed a clean conversion to the desired product. The mixture was concentrated in vacuo to give the product as TFA salt. LCMS [M+l]+ 388.22.
EXAMPLE 3
3-(l-(5-Ethylpyrimidin-2-yl)-l,2,3,6-tetrahydropyridin-4-yl-N-(2-fluoro-4- (methylsulfonyl) phenyl)imidazo[l,2-a]pyrazin-8-amine
Figure imgf000059_0002
[0318] A mixture of N-(2-fluoro-4-(methylsulfonyl)phenyl)-3-(l,2,3,6- tetrahydropyridin-4-yl)imidazo[l,2-a]pyrazin-8-amine ( 20mg, 0.05 mmol), 2- chloro-5-ethylpyrimidine (15 mg, 0.1 mmol), N-ethyl-N-isopropylpropan-2-amine ( 1.5 mmol) in 1 mL NMP was placed in a MW tube and irradiated at 150 0C for 5 minutes. LCMS confirms the transformation. This mixture was directly purified by RP column chromatography eluted with 30-100% acetonitrile in water in the presence of 0.1% TFA to afford 3-(l-(5-ethylpyrimidin-2-yl)-l,2,3,6- tetrahydropyridin-4-yl-N-(2-fluoro-4-(methylsulfonyl) phenyl)imidazo[ 1 ,2- a]pyrazin-8-amine (6 mg, 24%). 1H NMR (400 MHz, CDCl3) δ 8.99 (t, IH, J = 7.2 Hz), 8.41 (s, 2H), 7. 86 (d, IH, J = 4.8 Hz), 7.80-7.78 (m, IH), 7.75-7.72 (m, IH), 7.64-7.62(m, 2H), 6.28 (s, IH), 4.57 (d, 2H, J = 3.2 Hz), 4.20 (t, 2H, J = 5.6 Hz), 3.07 (s, 3H), 2.73 (s, br, 2H), 2.61-2.56 (m, 2H), 1.26 (t, 3H, J = 7.2 Hz). LCMS 494.31 [M+l]+.
EXAMPLE 4
3-(l-(5-Chloropyrimidin-2-yl)-l,2,3,6-tetrahydropyridin-4-yl)-N-(2-fluoro-4 (methylsulfonyl)phenyl)imidazo[l,2-a]pyrazin-8-amine
Figure imgf000060_0001
[0319] The title compound was synthesized as described for EXAMPLE 3 using N-(2-fluoro-4-(methylsulfonyl)phenyl)-3-(l,2,3,6-tetrahydropyridin-4- yl)imidazo[l,2-a]pyrazin-8-amine and 2,5-dichloropyrimidine as the starting materials. IH NMR (400 MHz, CDCl3) δ 8.56 (t, IH, J = 7.6 Hz), 8.33 (s, 2H), 7. 89 (d, IH, J = 4.8 Hz), 7.79-7.74 (m, 4H), 6.34 (s, IH), 4.51-4.50 (m, 2H), 4.15 (t, 2H, J = 5.6 Hz), 3.08 (s, 3H), 2.65 (s, br, 2H). LCMS 500.21 [M+l]+ . EXAMPLE 5
N-(2-Fluoro-4-(methylsulfonyl)phenyl)-3-(l-(5-(trifluoromethyl)pyrimidin-2- yl)-l,2,3,6-tetrahydropyridin-4-yl)imidazo[l,2-a]pyrazin-8-amine
Figure imgf000061_0001
[0320] The title compound was synthesized as described for EXAMPLE 3 using N-(2-fluoro-4-(methylsulfonyl)phenyl)-3-(l,2,3,6-tetrahydropyridin-4- yl)imidazo[l,2-a]pyrazin-8-amine and 2-chloro-5-(trifluoromethyl)pyrimidine as the starting materials. IH NMR (400 MHz, CDCl3) δ 8.70 (t, IH, J = 7.6 Hz), 8.57 (s, 2H), 7. 86 (d, IH, J = 4.8 Hz), 7.80-7.71 (m, 4H), 6.32 (s, IH), 4.61 (br, 2H), 4.26-4.23 (m, 2H), 3.08 (s, 3H), 2.68 (s, br, 2H). LCMS 534.24 [M+l]+.
EXAMPLE 6
3-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)-N-(2-fluoro-4- (methylsulfonyl)phenyl)-[l,2,4]triazolo[4,3-a]pyrazin-8-amine
Figure imgf000061_0002
Step 1. Methyl l-(5-ethylpyrimidin-2-yl)piperidine-4-carboxylate
Figure imgf000062_0001
[0321] To a solution of methyl piperidine-4-carboxylate (7.1 g, 50 mmol) in DMF (50 mL), was added 2-chloro-5-ethylpyrimidine (14 g, 100 mmol) and diisopropylethylamine (10 mL). The reaction mixture was heated to 1000C for 2 h. The solution is then poured into ice water (500 mL), and extracted with ethyl acetate (2 x 200 mL). Purification by silica gel chromatography (gradient 10% to 50% ethyl acetate/hexanes) afforded methyl l-(5-ethylpyrimidin-2-yl)piperidine-4- carboxylate as a light yellow oil (8.6 g, 69%). LCMS: 250.2 (M+H)+.
Step 2. l-(5-Ethylpyrimidin-2-yl)piperidine-4-carboxylic acid
Figure imgf000062_0002
[0322] To a solution of methyl l-(5-ethylpyrimidin-2-yl)piperidine-4- carboxylate (8.6g, 34 mmol) in THF (100 mL), was added a solution of lithium hydroxide (0.98 g, 41 mmol) in water (18 mL). The reaction mixture was heated to 600C for 16 h. The THF is then removed by rotary evaporation. To this is added IN HCl (41 mL), and the resulting precipitate is isolated by filtration, washed with water (2 x 20 mL), and dried under vacuum to give l-(5-ethylpyrimidin-2- yl)piperidine-4-carboxylic acid as a white solid (5.8 g, 73%). 1H NMR (400 MHz, DMSOd6) δ 12.21 (s, IH), 8.21 (s, 2H), 4.44 (d, 2H), 2.97 (m, 2H), 2.49 (m, IH), 2.41 (q, 2H), 1.81 (m, 2H), 1.44 (m, 2H), 1.10 (t, 3H). LCMS: 236.2 (M+H)+. Step 3. N'-(3-chloropyrazin-2-yl)-l-(5-ethylpyrimidin-2-yl)piperidine-4- carbohydrazide
Figure imgf000063_0001
[0323] To a solution of l-(5-ethylpyrimidin-2-yl)piperidine-4-carboxylic acid (3.0 g, 13 mmol) in DMF (50 niL), was added 0-(7-Azabenzotriazol-l-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate (5.2 g, 14 mmol), diisopropylethylamine (2.5 mL, 14 mmol), and 2-chloro-3-hydrazinylpyrazine (2.0 g, 14 mmol). After 1 h at rt, the solution is diluted with DCM (200 mL), and washed with brine (100 mL) and water (100 mL), concentrated to residue, and taken up in ethyl acetate (50 mL). The resulting precipitate is isolated by filtration to give Ν'-(3-chloropyrazin-2-yl)-l-(5-ethylpyrimidin-2-yl)piperidine-4- carbohydrazide as off-white solid (3.3 g, 71%). 1H NMR (400 MHz, DMSOd6) δ 9.89 (s, IH), 8.93 (s, IH), 8.22 (s, 2H), 8.06 (d, IH), 7.73 (d, IH), 4.60 (d, 2H), 2.92 (t, 2H), 2.56 (m, IH), 2.40 (q, 2H), 1.78 (m, 2H), 1.49 (m, 2H), 1.10 (t, 3H). LCMS: 362.2 (M+H)+.
Step 4. 8-Chloro-3-(l-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-[l,2,4]triazolo[4,3- ajpyrazine
Figure imgf000063_0002
[0324] A mixture of N'-(3-chloropyrazin-2-yl)- l-(5-ethylpyrimidin-2- yl)piperidine-4-carbohydrazide (2.4 g, 6.6 mmol) in phosphorus(V) oxychloride (24 mL) was heated to reflux for 45 min and then poured into ice water (250 mL). Sodium hydroxide (5 N) solution was carefully added in portions to until pH 7. The resulting precipitate was collected by filtration and washed with water (2 x 50 mL) to give 8-chloro-3-(l-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-[l,2,4]triazolo[4,3- ajpyrazine as an off-white solid (2.0 g, 88%). 1H NMR (400 MHz, DMSOd6) δ 8.74 (d, IH), 8.25 (s, 2H), 7.77 (d, IH), 4.67 (d, 2H), 3.64 (m, IH), 3.13 (t, 2H), 2.41 (q, 2H), 2.03 (m, 2H), 1.76 (m, 2H), 1.12 (t, 3H). LCMS: 344.2 (M+H)+.
Step 5. 3-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)-N-(2-fluoro-4-(methylsulfonyl) phenyl)-[l,2,4]triazolo[4,3-a]pyrazin-8-amine
Figure imgf000064_0001
[0325] To a solution of 2-fluoro-4-(methylsulfonyl)aniline (227 mg, 1.2 mmol) in DMF (5 mL), was added sodium hydride (50 mg, 1.3 mmol, 60%). After 3 min, 8-chloro-3-(l-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-[l,2,4]triazolo[4,3-a]pyrazine (343 mg, 1.0 mmol) was added. After an additional 15 min at rt, the reaction mixture was poured into water (50 mL) and the precipitate was collected by filtration and washed with water (10 mL) to give 3-(l-(5-ethylpyrimidin-2- yl)piperidin-4-yl)-N-(2-fluoro-4-(methylsulfonyl)phenyl)-[l,2,4]triazolo[4,3- a]pyrazin-8-amine as an off-white solid (350 mg, 71%). 1H NMR (400 MHz, DMSOd6; HCl salt) δ 8.42 (s, IH), 88.16 (d, IH), 8.11 (t, IH), 7.85 (m, IH), 7.78 (m, IH), 7.41 (d, IH), 4.70 (d, 2H), 3.66 (m, IH), 3.30 (m, 2H), 3.27 (s, 3H), 2.11 (m, 2H), 1.86 (m, 2H), 1.14 (t, 3H). LCMS: 497.3 (M+H)+. EXAMPLE 7
Tert-butyl 4-(8-(2-fluoro-4-(methylsulfonyl)phenylamino)imidazo[l,2- a]pyrazin-3-yl)piperidine-l-carboxylate
Figure imgf000065_0001
[0326] To a solution of tert-butyl 4-(8-(2-fluoro-4-
(methylsulfonyl)phenylamino) imidazo[l,2-a]pyrazin-3-yl)-5,6-dihydropyridine- l(2H)-carboxylate (100 mg, 0.2 mmol) in EtOAc (20 mL), was added Pd/C (4 mg, 0.04 mmol, 10%). The, the reaction vessel was equipped with a hydrogen balloon and allowed to stir at room temperature for 3 hours. Upon completion, the mixture was filtered through Celite and concentrated to give the crude that was purified by C18 RP column chromatography eluted with 30-100% MeCN in H2O in the presence of 0.1% TFA affording tert-butyl 4-(8-(2-fluoro-4- (methylsulfonyl)phenylamino)imidazo[l,2-a]pyrazin-3-yl)piperidine-l-carboxylate as off-white solid (70 mg). LCMS: 490 (M+H)+.
EXAMPLE 8
N-(2-Fluoro-4-(methylsulfonyl)phenyl)-3-(piperidin-4-yl)imidazo[l,2- a]pyrazin-8-amine
Figure imgf000065_0002
[0327] The title compound was synthesized as described for EXAMPLE 2 using tert-butyl 4-(8-(2-fluoro-4-(methylsulfonyl)phenylamino)imidazo[l,2- a]pyrazin-3-yl)piperidine-l-carboxylate as the starting material. LCMS 390 [M+l]+ .
EXAMPLE 9
3-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)-N-(2-fluoro-4- (methylsulfonyl)phenyl) imidazo[l,2-a]pyrazin-8-amine
Figure imgf000066_0001
[0328] The title compound was synthesized as described for EXAMPLE 3 using N-(2-fluoro-4-(methylsulfonyl)phenyl)-3-(piperidin-4-yl)imidazo[l,2- a]pyrazin-8-amine and 2-chloro-5-ethylpyrimidine as the starting materials. LCMS 496 [M+l]+.
EXAMPLE 10
3-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)-N-(2-fluoro-4- (methylsulfonyl)phenyl) imidazo[l,5-a]pyrazin-8-amine
Figure imgf000067_0001
[0329] The title compound was synthesized as described for EXAMPLE 6, in step 3, using l-(5-ethylpyrimidin-2-yl)piperidine-4-carboxylic acid and (3- chloropyrazin-2-yl)methanamine hydrochloride as the starting materials. LCMS 496 [M+l]+.
EXAMPLE 11
Tert-butyl 4-(8-(2-chloro-4-(methylsulfonyl)phenylamino)imidazo[l,2- a]pyrazin-3-yl)-5,6-dihydropyridine-l(2H)-carboxylate
Figure imgf000067_0002
[0330] The title compound was synthesized as described for EXAMPLE 1, in step 3, using 2-chloro-4-(methylsulfonyl)aniline and 3-bromo-8-chloroimidazo[l,2- a]pyrazine as the starting materials. LCMS 504 [M+l]+. EXAMPLE 12
Tert-butyl 4-(8-(2-methyl-6-(methylsulfonyl)pyridin-3-ylamino)imidazo[l,2- a]pyrazin-3-yl)-5,6-dihydropyridine-l(2H)-carboxylate
Figure imgf000068_0001
[0331] The title compound was synthesized as described for EXAMPLE 1, in step 3, using 2-methyl-6-(methylsulfonyl)pyridin-3-amine and 3-bromo-8- chloroimidazo [l,2-a]pyrazine as the starting materials. 1H NMR (400 MHz, DMSOd6) δ 9.68 (s, IH), 8.62 (d, IH), 8.14 (d, IH), 7.92 (d, IH), 7.76 (s, IH), 7.42 (d, IH), 6.23 (s, IH), 4.08 (br, 2H), 3.58 (br, 2H), 2.60 (s, 3H), 2.54 (br, 2H), 1.42 (s, 9H). LCMS 485 [M+l]+.
EXAMPLE 13
Tert-butyl 4-(8-(2-methyl-6-(methylsulfonyl)pyridin-3-ylamino)imidazo[l,2- a]pyrazin-3-yl)piperidine-l-carboxylate
Figure imgf000068_0002
[0332] The title compound was synthesized as described for EXAMPLE 7 using tert-butyl 4-(8-(2-methyl-6-(methylsulfonyl)pyridin-3-ylamino)imidazo[l,2- a]pyrazin-3-yl)-5,6-dihydropyridine-l(2H)-carboxylate as the starting materials. LCMS 487 [M+l]+.
EXAMPLE 14
3-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)-N-(2-methyl-6-(methylsulfonyl) pyridin-3-yl)imidazo[l,5-a]pyrazin-8-amine
Figure imgf000069_0001
[0333] The title compound was synthesized as described for EXAMPLE 10, using 8-chloro-3-(l-(5-ethylpyrimidin-2-yl)piperidin-4-yl)imidazo[l,5-a]pyrazine and 2-methyl-6-(methylsulfonyl)pyridin-3-amine as the starting materials. 1H NMR (400 MHz, CD3OD) δ 8.54 (s, 2H), 8.49 (s, IH), 8.20 (d, IH), 8.10 (d, 2H), 7.03 (s, IH), 4.72 (d, 2H), 3.86 (t, IH), 3.56 (t, 2H), 2.70-2.65 (m, 5H), 2.26 (d, 2H), 2.10 (m, 2H), 1.28 (t, 3H). LCMS 493 [M+l]+.
EXAMPLE 15
3-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)-N-(2-methyl-6-(lH-l,2,4-triazol-l- yl)pyridin-3-yl)imidazo[l,5-a]pyrazin-8-amine
Figure imgf000070_0001
[0334] The title compound was synthesized as described for EXAMPLE 10, using 8-chloro-3-(l-(5-ethylpyrimidin-2-yl)piperidin-4-yl)imidazo[l,5-a]pyrazine and 2-methyl-6-(lH-l,2,4-triazol-l-yl)pyridin-3-amine as the starting materials. 1H NMR (400 MHz, CD3OD) δ 9.54 (s, IH), 8.53 (d, 2H), 8.46 (s, IH), 8.32 (s, IHO, 8.15-8.13 (m, 2H), 8.02 (d, IH), 6.99 (m, IH), 4.72 (d, 2H), 3.82 (t, IH), 3.57 (t, 2H), 2.70-2.63 (m, 5H), 2.24 (d, 2H), 2.09 (m, 2H), 1.28 (t, 3H). LCMS 482 [M+l]+.
EXAMPLE 16
N-(2-Chloro-4-(methylsulfonyl)phenyl)-3-(l,2,3,6-tetrahydropyridin-4- yl)imidazo[l,2-a]pyrazin-8-amine
Figure imgf000070_0002
[0335] The title compound was synthesized as described for EXAMPLE 2, using tert-butyl 4-(8-(2-chloro-4-(methylsulfonyl)phenylamino)imidazo[l,2- a]pyrazin-3-yl)-5,6-dihydropyridine-l(2H)-carboxylate as the starting materials. LCMS 404 [M+l]+.
EXAMPLE 17
N-(2-Chloro-4-(methylsulfonyl)phenyl)-3-(l-(5-ethylpyrimidin-2-yl)-l,2,3,6- tetrahydropyridin-4-yl)imidazo[l,2-a]pyrazin-8-amine
Figure imgf000071_0001
[0336] The title compound was synthesized as described for EXAMPLE 3 using N-(2-chloro-4-(methylsulfonyl)phenyl)-3-(l,2,3,6-tetrahydropyridin-4- yl)imidazo[l,2-a]pyrazin-8-amine and 2-chloro-5-ethylpyrimidine as the starting materials. LCMS 510 [M+l]+.
EXAMPLE 18
3-(l-(5-Ethylpyrimidin-2-yl)-l,2,3,6-tetrahydropyridin-4-yl)-N-(2-methyl-6- (methylsulfonyl)pyridin-3-yl)imidazo[l,2-a]pyrazin-8-amine
Figure imgf000071_0002
[0337] The title compound was synthesized as described for EXAMPLE 3 using N-(2-methyl-6-(methylsulfonyl)pyridin-3-yl)-3-(l,2,3,6-tetrahydropyridin-4- yl)imidazo[l,2-a]pyrazin-8-amine and 2-chloro-5-ethylpyrimidine as the starting materials. 1H NMR (400 MHz, CDCl3) δ 9.31 (d, IH), 8.25 (s, 2H), 8.17 (s, IH), 8.01 (d, IH), 7.84 (d, IH), 7.58 (s, IH), 7.54 (d, IH), 6.25 (s, IH), 4.49 (m, 2H), 4.13 (d, 2H), 3.22 (s, 3H), 2.80 (s, 3H), 2.68 (m, 2H), 2.51 (q, 2H), 1.22 (t, 3H). LCMS 491 [M+l]+.
EXAMPLE 19
Tert-butyl 4-(8-(2-methyl-6-(lH-l,2,4-triazol-l-yl)pyridin-3- ylamino)imidazo[l,2-a]pyrazin-3-yl)-5,6-dihydropyridine-l(2H)-carboxylate
Figure imgf000072_0001
[0338] The title compound was synthesized as described for EXAMPLE 1 using 3-bromo-8-chloroimidazo[l,2-a]pyrazine and 2-methyl-6-(lH-l,2,4-triazol- l-yl)pyridin-3-amine as the starting materials. 1H NMR (400 MHz, DMSOd6) δ 9.29 (s, IH), 9.20 (s, Ih), 8.31-8.27 (m, 2H), 8.04 (d, IH), 7.74-7.71 (m, 2H), 7.33 (d, IH), 6.21 (s, IH), 4.08 (s, 2H), 3.58 (br, 2H), 2.54 (br, 2H), 1.42 (s, 9H). LCMS 474 [M+ 1]+.
EXAMPLE 20
3-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)-N-(2-methyl-6-(methylsulfonyl) pyridin-3-yl)-[l,2,4]triazolo[4,3-a]pyrazin-8-amine
Figure imgf000073_0001
[0339] The title compound was synthesized as described for EXAMPLE 6, in step 5, using 8-chloro-3-(l-(5-ethylpyrimidin-2-yl)piperidin-4-yl)- [l,2,4]triazolo[4,3-a]pyrazine and 2-methyl-6-(methylsulfonyl)pyridin-3-amine as the starting materials. LCMS 494 [M+ 1]+.
EXAMPLE 21
Isopropyl 4-(8-(2-methyl-6-(methylsulfonyl)pyridin-3-ylamino)imidazo[l,2- a]pyrazin-3-yl)-5,6-dihydropyridine-l(2H)-carboxylate
Figure imgf000073_0002
[0340] To a solution of N-(2-methyl-6-(methylsulfonyl)pyridin-3-yl)-3- (1,2,3, 6-tetrahydropyridin-4-yl)imidazo[l,2-a]pyrazin-8-amine ( 100 mg, 0.2 mmol) in DCM (2 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.1 mL, 0.6 mmol). To this mixture was then added isopropyl carbonochloridate (0.24 mL, IM in toluene, 0.24 mmol). Then the resulting mixture was allowed to stir at room temperature for 2 hours. Upon completion, the mixture was concentrated to give a residue that was purified by RP Cl 8 column chromatography eluted with 50-100 % MeCN in H2O in the presence of 0.1% TFA affording Isopropyl 4-(8-(2-methyl-6- (methylsulfonyl)pyridin-3-ylamino)imidazo[l,2-a]pyrazin-3-yl)-5,6- dihydropyridine-l(2H)-carboxylate. LCMS 471 [M+l]+.
EXAMPLE 22
N-(2-Methyl-6-(methylsulfonyl)pyridin-3-yl)-3-(l-(pyrimidin-2-yl)-l,2,3,6- tetrahydropyridin-4-yl)imidazo[l,2-a]pyrazin-8-amine
Figure imgf000074_0001
[0341] The title compound was synthesized as described for EXAMPLE 3 using N-(2-methyl-6-(methylsulfonyl)pyridin-3-yl)-3-(l,2,3,6-tetrahydropyridin-4- yl)imidazo[l,2-a]pyrazin-8-amine and 2-chloro-pyrimidine as the starting materials. LCMS 463 [M+l]+.
EXAMPLE 23
3-(l-(5-Fluoropyrimidin-2-yl)-l,2,3,6-tetrahydropyridin-4-yl)-N-(2-methyl-6- (methylsulfonyl)pyridin-3-yl)imidazo[l,2-a]pyrazin-8-amine
Figure imgf000075_0001
[0342] TThhee ttiittllee < c ;oommppcound was synthesized as described for EXAMPLE 3 using N-(2-methyl-6-(methylsulfonyl)pyridin-3-yl)-3-(l,2,3,6-tetrahydropyridin-4- yl)imidazo[l,2-a]pyrazin-8-amine and 2-chloro-5-fluoropyrimidine as the starting materials. 1H NMR (400 MHz, CDCl3) δ 8.60 (d, IH), 8.29 (s, 2H), 7.99 (d, IH), 7.86 (d, IH), 7.74-7.69 (m, 2H), 6.35 (m, IH), 4.49 (m, 2H), 4.15 (m, 2H), 3.24 (s, 3H), 2.72 (s, 3H), 2.66 (m, 2H). LCMS 481 [M+l]+.
EXAMPLE 24
3-(l-(5-Chloropyrimidin-2-yl)-l,2,3,6-tetrahydropyridin-4-yl)-N-(2-methyl-6- (methylsulfonyl)pyridin-3-yl)imidazo[l,2-a]pyrazin-8-amine
Figure imgf000075_0002
was synthesized as described for EXAMPLE 3 using N-(2-methyl-6-(methylsulfonyl)pyridin-3-yl)-3-(l,2,3,6-tetrahydropyridin-4- yl)imidazo[l,2-a]pyrazin-8-amine and 2,5-dichloropyrimidine as the starting materials. 1H NMR (400 MHz, CDCl3) δ 8.62 (d, IH), 8.32 (s, 2H), 8.01 (d, IH), 7.86 (d, IH), 7.72-7.69 (m, 2H), 6.33 (m, IH), 4.51 (m, 2H), 4.15 (m, 2H), 3.24 (s, 3H), 2.72 (s, 3H), 2.66 (m, 2H). LCMS 497 [M+l]+.
EXAMPLE 25
3-(l-(5-Bromopyrimidin-2-yl)-l,2,3,6-tetrahydropyridin-4-yl)-N-(2-methyl-6- (methylsulfonyl)pyridin-3-yl)imidazo[l,2-a]pyrazin-8-amine
Figure imgf000076_0001
[0344] The title compound was synthesized as described for EXAMPLE 3 using N-(2-methyl-6-(methylsulfonyl)pyridin-3-yl)-3-(l,2,3,6-tetrahydropyridin-4- yl)imidazo[l,2-a]pyrazin-8-amine and 5-bromo-2-chloropyrimidine as the starting materials. LCMS 543 [M+l]+.
EXAMPLE 26
3-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)-N-(2-methyl-6-(lH-l,2,4-triazol-l- yl)pyridin-3-yl)-[l,2,4]triazolo[4,3-a]pyrazin-8-amine
Figure imgf000077_0001
[0345] The title compound was synthesized as described for EXAMPLE 6 using S-chloro-S-Cl-CS-ethylpyrimidin^-y^piperidin^-y^-fl^^ltriazolo^^- a]pyrazine and 2-methyl-6-(lH-l,2,4-triazol-l-yl)pyridin-3-amine as the starting materials. LCMS: 483 (M+H)+.
EXAMPLE 27
3-(l-(5-Ethylpyrimidin-2-yl)-l,2,3,6-tetrahydropyridin-4-yl)-N-(2-methyl-6- (lH-l,2,4-triazol-l-yl)pyridin-3-yl)imidazo[l,2-a]pyrazin-8-amine
Figure imgf000077_0002
[0346] The title compound was synthesized as described for EXAMPLE 3 using N-(2-methyl-6-(lH-l,2,4-triazol-l-yl)pyridin-3-yl)-3-(l,2,3,6- tetrahydropyridin-4-yl)imidazo[l,2-a]pyrazin-8-amine and 2-chloro-5- ethylpyrimidine as the starting materials. LCMS 480 [M+l]+.
EXAMPLE 28
N-(2-Methyl-6-(methylsulfonyl)pyridin-3-yl)-3-(l-(5-
(trifluoromethyl)pyrimidin-2-yl)-l,2,3,6-tetrahydropyridin-4-yl)imidazo[l,2- a]pyrazin-8-amine
Figure imgf000078_0001
[0347] The title compound was synthesized as described for EXAMPLE 3 using N-(2-methyl-6-(methylsulfonyl)pyridin-3-yl)-3-(l,2,3,6-tetrahydropyridin-4- yl)imidazo[l,2-a]pyrazin-8-amine and 2-chloro-5-(trifluoromethyl)pyrimidine as the starting materials. 1H NMR (400 MHz, CDCl3) δ 9.30 (d, IHO, 8.5 (s, 2H), 8.16 (s, IH), 8.00 (d, IH), 7.82 (d, 2H), 7.56 (s, IH), 7.55 (d, IH), 6.24 (br, IH), 4.58 (br, 2H), 4.23 (br, 2H), 3.21 (s, 3H), 2.79 (s, 3H), 2.69 (br, 2H). LCMS 531 [M+l]+.
EXAMPLE 29
N-(2-Methyl-6-(methylsulfonyl)pyridin-3-yl)-3-(l-(5-propylpyrimidin-2-yl)- l,2,3,6-tetrahydropyridin-4-yl)imidazo[l,2-a]pyrazin-8-amine
Figure imgf000079_0001
[0348] The title compound was synthesized as described for EXAMPLE 3 using N-(2-methyl-6-(methylsulfonyl)pyridin-3-yl)-3-(l,2,3,6-tetrahydropyridin-4- yl)imidazo[l,2-a]pyrazin-8-amine and 2-chloro-5-propylpyrimidine as the starting materials. 1H NMR (400 MHz, CDCl3) δ 8.57 (d, IH), 8.50 (s, 2H), 8.02 (d, IH), 7.97 (d, IH), 7.84 (s, IH), 7.75 (d, IH), 6.40 (br, IH), 4.66 (d, 2H), 4.31 (t, 2H), 3.26 (s, 3H), 2.80 (br, 2H), 2.74 (s, 3H), 1.69 (q, 2H), 1.03 (t, 3H). LCMS 505 [M+l]+.
EXAMPLE 30
3-(l-(5-Chloropyridin-2-yl)-l,2,3,6-tetrahydropyridin-4-yl)-N-(2-methyl-6- (methylsulfonyl)pyridin-3-yl)imidazo[l,2-a]pyrazin-8-amine
Figure imgf000079_0002
[0349] The title compound was synthesized as described for EXAMPLE 3 using N-(2-methyl-6-(methylsulfonyl)pyridin-3-yl)-3-(l,2,3,6-tetrahydropyridin-4- yl)imidazo[l,2-a]pyrazin-8-amine and 2,5-dichloropyridine as the starting materials. LCMS 496 [M+l]+.
EXAMPLE 31
Isopropyl 4-(8-(2-methyl-6-(methylsulfonyl)pyridin-3-ylamino)imidazo[l,2- a]pyrazin-3-yl)piperidine-l-carboxylate
Figure imgf000080_0001
[0350] The title compound was synthesized as described for EXAMPLE 21 using N-(2-methyl-6-(methylsulfonyl)pyridin-3-yl)-3-(piperidin-4-yl)imidazo[l,2- a]pyrazin-8-amine as the starting material. LCMS 473 [M+l]+.
EXAMPLE 32
Tert-butyl 4-(8-(2-chloro-4-(methylsulfonyl)phenylamino)imidazo[l,2- a]pyrazin-3-yl)piperidine-l-carboxylate
Figure imgf000080_0002
[0351] The title compound was synthesized as described for EXAMPLE 7 using tert-butyl 4-(8-(2-chloro-4-(methylsulfonyl)phenylamino)imidazo[l,2- a]pyrazin-3-yl)-5,6-dihydropyridine-l(2H)-carboxylate as the starting material. 1H NMR (400 MHz, CDCl3) δ 8.97 (d, IH), 8.92 (s, IH), 8.18 (d, IH), 8.07 (d, IH), 7.93 (dd, IH), 7.57 (s, IH), 7.55 (d, IH), 4.05 (d, 2H), 3.25 (s, 3H), 2.90 (br, 2H), 1.97 (d, 2H), 1.53 (m, 2H), 1.40 (s, 9H). LCMS 506 [M+l]+.
EXAMPLE 33
N-(2-chloro-4-(methylsulfonyl)phenyl)-3-(l-(5-ethylpyrimidin-2-yl)piperidin-4- yl)imidazo[l,2-a]pyrazin-8-amine
Figure imgf000081_0001
[0352] The title compound was synthesized as described for EXAMPLE 3 using N-(2-chloro-4-(methylsulfonyl)phenyl)-3-(piperidin-4-yl)imidazo[l,2- a]pyrazin-8-amine and 2-chloro-5-ethylpyrimidine as the starting materials. LCMS 512 [M+l]+.
EXAMPLE 34
3-(l-(5-Cyclopropylpyrimidin-2-yl)-l,2,3,6-tetrahydropyridin-4-yl)-N-(2- methyl-6-(methylsulfonyl)pyridin-3-yl)imidazo[l,2-a]pyrazin-8-amine
Figure imgf000082_0001
[0353] A mixture of 3-(l-(5-bromopyrimidin-2-yl)-l,2,3,6-tetrahydropyridin-4- yl)-N-(2-methyl-6-(methylsulfonyl)pyridin-3-yl)imidazo[l,2-a]pyrazin-8-amine (25 mg, 0.046 mmol), cyclopropylzinc(II) chloride (0.18 mL of 1 M in THF, 0.092 mmol), Pd(PPh3)Cl2 (3 mg, 0.0046 mmol), and CuI (1.7 mg, 0.0092 mmol) in THF ( ImL) was degassed and purged with nitrogen. Then, the mixture was irradiated in a microwave at 90 0C for 10 minutes. Upon completion, the mixture was quenched with water (10 ml), extracted with EtOAc (2x10 ml). Combined organic layers were dried on sodium sulfate, filtered and concentrated to give the crude that was purified by RP C 18 column chromatography eluted with 20-100 % MeCN in water in the presence of 0.1% TFA affording 3-(l-(5-cyclopropylpyrimidin-2-yl)-l,2,3,6- tetrahydropyridin-4-yl)-N-(2-methyl-6-(methylsulfonyl)pyridin-3-yl)imidazo[l,2- a]pyrazin-8-amine. LCMS 503 [M+l]+.
EXAMPLE 35
Tert-butyl 4-(8-(4-cyano-2-fluorophenylamino)imidazo[l,2-a]pyrazin-3-yl)-5,6- dihydropyridine-l(2H)-carboxylate
Figure imgf000083_0001
[0354] The title compound was synthesized as described for EXAMPLE 1 using 3-bromo-8-chloroimidazo[l,2-a]pyrazine and 4-amino-3-fluorobenzonitrile as the starting materials. LCMS 435 [M+ 1]+.
EXAMPLE 36
4-(3-(l-(5-Ethylpyrimidin-2-yl)-l,2,3,6-tetrahydropyridin-4-yl)imidazo[l,2- a]pyrazin-8-ylamino)-3-fluorobenzonitrile
Figure imgf000083_0002
[0355] The title compound was synthesized as described for EXAMPLE 3 using tert-butyl 4-(8-(4-cyano-2-fluorophenylamino)imidazo[l,2-a]pyrazin-3-yl)- 5,6-dihydropyridine-l(2H)-carboxylate and 2-chloro-5-ethylpyrimidine as the starting materials. LCMS 441 [M+l]+. EXAMPLE 37
Tert-butyl 4-(8-(4-cyano-2-fluorophenylamino)imidazo[l,2-a]pyrazin-3- yl) piper idine- 1 -carboxylate
Figure imgf000084_0001
[0356] The title compound was synthesized as described for EXAMPLE 7 using tert-butyl 4-(8-(4-cyano-2-fluorophenylamino)imidazo[l,2-a]pyrazin-3-yl)- 5,6-dihydropyridine-l(2H)-carboxylate as the starting material. LCMS 437 [M+l]+.
EXAMPLE 38
3-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)-N-(2-methyl-6-(methylsulfonyl) pyridin-3-yl)imidazo[l,2-a]pyrazin-8-amine
Figure imgf000084_0002
[0357] The title compound was synthesized as described for EXAMPLE 3 using N-(2-methyl-6-(methylsulfonyl)pyridin-3-yl)-3-(piperidin-4-yl)imidazo[l,2- a]pyrazin-8-amine and 2-chloro-5-ethylpyrimidine as the starting materials. LCMS 493 [M+l]+. EXAMPLE 39
3-(l-(5-Chloropyrimidin-2-yl)piperidin-4-yl)-N-(2-methyl-6-(methylsulfonyl) pyridin-3-yl)imidazo[l,2-a]pyrazin-8-amine
Figure imgf000085_0001
[0358] The title compound was synthesized as described for EXAMPLE 3 using N-(2-methyl-6-(methylsulfonyl)pyridin-3-yl)-3-(piperidin-4-yl)imidazo[l,2- a]pyrazin-8-amine and 2,-5dichloropyrimidine as the starting materials. . 1H NMR (400 MHz, CDCl3) δ 9.30 (d, IH), 8.26 (s, 2H), 8.12 (s, IH), 8.00 (d, IH), 7.60 (d, IHO, 7.55 (d, IH), 7.40 (s, IH), 4.90 (m, 2H), 3.21 (s, 3H), 5.15-3.07 (m, 2H), 2.78 (s, 3H), 2.18-2.15 (m, 2H), 1.81-1.79 (m, 2H). LCMS 499 [M+l]+.
EXAMPLE 40
3-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)-N-((2-methyl-6- (methylsulfonyl)pyridin-3-yl)methyl)-[l,2,4]triazolo[4,3-a]pyrazin-8-amine
[0359] The title compound was synthesized as described for EXAMPLE 6, in step 5, using 8-chloro-3-(l-(5-ethylpyrimidin-2-yl)piperidin-4-yl)- [l,2,4]triazolo[4,3-a]pyrazine and (2-methyl-6-(methylsulfonyl)pyridin-3- yl)methanamine as the starting materials. LCMS 508 [M+l]+.
EXAMPLE 41
3-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)-N-(2-fluoro-4-(methylsulfonyl) phenyl)-[l,2,4]triazolo[4,3-c]pyrimidin-8-amine
Figure imgf000086_0001
Step 1: Ethyl l-(5-ethylpyrimidin-2-yl)piperidine-4-carboxylate
Figure imgf000086_0002
[0360] A 250-mL round-bottomed flask was charged with a solution of ethyl piperidine-4-carboxylate (14.79 g, 94.20 mmol, 1.00 equiv) in N,N- dimethylformamide (100 mL), 2-chloro-5-ethylpyrimidine (13.78 g, 97.04 mmol, 1.03 equiv), Cs2CO3 (32.24 g, 98.90 mmol, 1.05 equiv). The resulting solution was stirred at 1000C in an oil bath for 4 hrs. The reaction progress was monitored by TLC (EtOAc: PE = 1:5). Then, the reaction mixture was cooled down to room temperature. The solids were filtered out and filtrate was concentrated under vacuum. The resulting mixture was diluted with EtOAc (IL), washed with water (2x500 mL) and brine (2x500 mL). Organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum affording ethyl l-(5-ethylpyrimidin-2- yl)piperidine-4-carboxylate as yellow oil (23 g, 93%). LCMS 264 [M+l]+.
Step 2: l-(5-Ethylpyrimidin-2-yl)piperidine-4-carboxylic acid
Figure imgf000087_0001
[0361] A 500-mL round-bottomed flask was charged with a solution of ethyl 1- (5-ethylpyrimidin-2-yl)piperidine-4-carboxylate (23 g, 87.45 mmol, 1.00 equiv) in ethanol (150 mL) and sodium hydroxide (17.49 g, 437.2 mmol, 5.00 equiv) in water (150 mL). The resulting solution was stirred at 400C in an oil bath overnight. The reaction progress was monitored by TLC (EtOAc: PE=I :5). The resulting mixture was extracted with ethyl acetate (2x200 mL). The pH of aqueous layer was adjusted to 3 with 12N hydrogen chloride. The solids were collected by filtration and dried in air affording l-(5-ethylpyrimidin-2-yl)piperidine-4-carboxylic acid as white solid (18 g, 88%). LCMS 236 [M+l]+.
Step 3: 5-Bromo-4-chloropyrimidine
Figure imgf000087_0002
[0362] Into a 500-mL round-bottomed flask was charged with 5- bromopyrimidin-4-ol (22 g, 63.22 mmol, 1.00 equiv, 50 %), N,N- dimethylbenzenamine (4 mL), POCI3 (266.8 g). The resulting solution was stirred at 1300C in an oil bath overnight. The mixture was cooled down to room temperature and diluted with ether (1 L). The pH was adjusted to 9 with sodium bicarbonate/water. The resulting mixture was extracted with ether (4x1 L). Combined organic layers were washed with brine (2x1 L), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum affording 5-bromo-4- chloropyrimidine as black liquid (15 g, 124%).
Step 4: 5-Bromo-4-hydrazinylpyrimidine
Figure imgf000088_0001
[0363] A 100-mL round-bottomed flask was charged with a solution of 5- bromo-4-chloropyrimidine (8 g, 25.00 mmol, 1.00 equiv, 60%) in ethanol (50 mL). To this solution was added hydrazine (10 mL, 99%) drop wise with stirring. The resulting solution was stirred overnight at room temperature. The reaction progress was monitored by TLC (MeOH: DCM = 1: 10). The solids were collected by filtration affording 5-bromo-4-hydrazinylpyrimidine as yellow solid (0.83 g, 18%).
Step 5: N'-(5-Bromopyrimidin-4-yl)-l-(5-ethylpyrimidin-2-yl)piperidine-4- carbohydrazide
Figure imgf000088_0002
[0364] A 100-mL 3-necked round-bottomed flask was charged with a solution of l-(5-ethylpyrimidin-2-yl)piperidine-4-carboxylic acid (830 mg, 3.53 mmol, 1.00 equiv) in dichloromethane (60 mL), 5-bromo-4-hydrazinylpyrimidine (830 mg, 3.53 mmol, 1.00 equiv, 80%). To this was added EDCHCl (930 mg, 4.87 mmol, 1.10 equiv), in portions at -100C. The resulting mixture was stirred -10 0C for 2 hours and warmed up to room temperature and stirred overnight. The reaction progress was monitored by TLC (MeOH: DCM = 1:10). The resulting solution was diluted with DCM (200 mL), washed with water (1x200 mL) and brine (1x300 mL). Organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column chromatography eluted with dichloromethane/methanol (30:1) affording N'-(5-bromopyrimidin-4- yl)-l-(5-ethylpyrimidin-2-yl)piperidine-4-carbohydrazide as white solid (0.27 g, 18%). LCMS 406 [M+ 1]+.
Step 6: 8-Bromo-3-(l-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-[l,2,4]triazolo[4,3- cjpyrimidine
Figure imgf000089_0001
[0365] A 50-mL round-bottom flask was charged with a solution of N'-(5- bromopyrimidin-4-yl)-l-(5-ethylpyrimidin-2-yl)piperidine-4-carbohydrazide (240 mg, 0.57 mmol, 1.00 equiv, 96%) in PPA (15 mL). The resulting solution was stirred at 150 0C in an oil bath for 10 hrs. The reaction progress was monitored by TLC (MeOH: DCM = 1:10). The reaction was then quenched by the addition of water/ice. pH was adjusted to 9 with ammonia. The resulting precipitate was collected by filtration affording 8-bromo-3-(l-(5-ethylpyrimidin-2-yl)piperidin-4- yl)-[l,2,4]triazolo[4,3-f]pyrimidine as white solid (200 mg, 91%).
Step 7: 3-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)-N-(2-fluoro-4-(methylsulfonyl) phenyl)-[l,2,4]triazolo[4,3-c]pyrimidin-8-amine
Figure imgf000090_0001
[0366] A 100-mL 3 -neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with a solution of 8-bromo-3-(l-(5- ethylpyrimidin-2-yl)piperidin-4-yl)-[l,2,4]triazolo[4,3-f]pyrimidine (225 mg, 0.58 mmol, 1.00 equiv) in toluene (20 mL), 2-fluoro-4-(methylsulfonyl)benzenamine (121 mg, 0.64 mmol, 1.10 equiv), Pd2(dba)3 (320 mg, 0.35 mmol, 0.60 equiv), BINAP (434 mg, 0.70 mmol, 1.20 equiv), t-BuONa (88 mg, 0.92 mmol, 1.40 equiv). The resulting solution was stirred at 80 0C in an oil bath overnight. The reaction progress was monitored by TLC (DCM: MeOH = 20:1). The resulting solution was diluted with EtOAc (300 mL), washed with water (1x200 mL) and brine (1x200 mL). Organic later was dried over sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column chromatography with EtOAc: PE (1:1) affording 3-(l-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-N-(2- fluoro-4-(methylsulfonyl)phenyl)-[l,2,4]triazolo[4,3-f]pyrimidin-8-amine as light pink solid (94 mg, 33%). 1H NMR (300 MHz, CDCl3) δ 9.05 (s, IH) 8.23 (d, 3H), 7.79 (d, 2H), 7.65 (t, IH), 7.01 (s, IH), 4.80-4.85 (d, 2H), 3.16-3.34 (m, 3H), 2.45- 2.55 (m, 2H), 3.11 (s, 3H), 2.23-2.27 (d, 2H), 1.94-2.07 (m, 2H), 1.23 (t, 3H). LCMS 497 [M+l]+. EXAMPLE 42
3-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)-8-(2-methylpyridin-3-yloxy)- [l,2,4]triazolo[4,3-a]pyrazine
Figure imgf000091_0001
[0367] The title compound was synthesized as described for EXAMPLE 6, in step 5, using 8-chloro-3-(l-(5-ethylpyrimidin-2-yl)piperidin-4-yl)- [l,2,4]triazolo[4,3-a]pyrazine and 2-methylpyridin-3-ol as the starting materials. LCMS 417 [M+l]+.
EXAMPLE 43
Tert-butyl 4-(8-(2-fluoro-4-(methylsulfonyl)phenylamino)imidazo[l,2-b] pyridazin-3-yl)-5,6-dihydropyridine-l(2H)-carboxylate
Figure imgf000091_0002
Step 1: 4-Bromo-6-chloropyridazin-3 -amine
Figure imgf000092_0001
[0368] A 500-ml round-bottomed flask was charged with a solution of 6- chloropyridazin-3-amine (90 g, 697.67 mmol, 1.00 equiv) in methanol (2500 ml) and sodium bicarbonate (117.2 g, 1.40 mol, 1.84 equiv). To this mixture was added Br2 (111.62 g, 697.62 mmol, 1.10 equiv) drop wise with stirring at 0-10 0C and allowed to stir at room temperature overnight. The resulting mixture was quenched with water and extracted with EtOAc (5x1 L). Combined organic layers were washed with water (3x2 L), brine (1x2 L) dried over sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column chromatography eluted with EA: PE (1:2) affording 4-bromo-6-chloropyridazin-3- amine as red solid (55 g, 36%).
Step 2: 8-Bromo-6-chloroimidazo[l,2-b]pyridazine hydrochloride
ΛrS HCI VN-A;,
[0369] A 500-mL 3-necked round-bottomed flask was charged with a solution of 4-bromo-6-chloropyridazin-3-amine (10 g, 48.31 mmol, 1.00 equiv) in ethanol (150 mL) and 2-chloroacetaldehyde (41.1 g, 526.92 mmol, 5.20 equiv). The resulting solution was stirred at 500C overnight. Upon completion, the resulting mixture was concentrated under vacuum and washed with acetone (3x25 mL) affording 8-bromo-6-chloroimidazo[l,2-b]pyridazine hydrochloride as light yellow solid (H g, 80%).
Step 3: 6-chloro-N-(2-fluoro-4-(methylsulfonyl)phenyl)imidazo[l,2-b]pyridazin-8- amine
Figure imgf000093_0001
flask was placed a solution of 2-fluoro-4- (methylsulfonyl) benzenamine (8.8 g, 46.56 mmol, 1.20 equiv) in tetrahydrofuran (200 mL), potassium butan-1-olate (10.9 g, 97.32 mmol, 2.50 equiv), 8-bromo-6- chloroimidazo [1,2-b] pyridazine (9 g, 38.96 mmol, 1.00 equiv). The resulting solution was stirred at 50 0C for 3 hrs. The resulting mixture was quenched with water and diluted with EtOAc (1 L). The resulting mixture was washed with water (3x200 mL), brine (1x300 mL) dried over sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column chromatography eluted with EtOAc: PE (1:1) affording 6-chloro-N- (2-fluoro-4- (methylsulfonyl) phenyl) imidazo [1,2-b] pyridazin-8-amine as a yellow solid (12 g, (86%).
Step 4: N-(2-Fluoro-4-(methylsulfonyl)phenyl)imidazo[l,2-b]pyridazin-8-amine
Figure imgf000093_0002
[0371] A 500-mL round-bottomed flask was purged, flushed and maintained with a hydrogen atmosphere was added a solution of 6-chloro-N-(2-fluoro-4- (methylsulfonyl)phenyl)imidazo[l,2-b]pyridazin-8-amine (12 g, 35.29 mmol, 1.00 equiv) in methanol (300 mL). To this mixture was added palladium carbon (2.4 g). The resulting solution was stirred at room temperature for 36 hrs. Upon completion, the mixture was filtered through Celite and concentrated in vacuo to give N- (2-fluoro-4-(methylsulfonyl)phenyl)imidazo[l,2-b]pyridazin-8-amine as a light yellow solid (9.5 g, 83.5%).
Step 5: 3-Bromo-N-(2-fluoro-4-(methylsulfonyl)phenyl)imidazo[l,2-b]pyridazin-8- amine
Figure imgf000094_0001
[0372] A 500-mL three-necked round-bottomed flask was placed a solution of N-(2-fluoro-4-(methylsulfonyl)phenyl)imidazo[l,2-b]pyridazin-8-amine (8 g, 26.14 mmol, 1.00 equiv) in N,N-dimethylformamide (300 mL). To this was added NBS (2.313 g, 13.07 mmol, 0.50 equiv) in several batches at -10-200C and allowed to stir for 10 minutes. The reaction was then quenched by the addition of ice water (1 L). The resulting mixture was extracted with ethyl acetate (3x300 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 EA: PE (2:3) affording 3-bromo-N- (2-fluoro-4- (methylsulfonyl) phenyl) imidazo [1,2-b] pyridazin-8-amine as white solid (0.5 g, 5%).
Step 6: Tert-butyl 4-(8-(2-fluoro-4-(methylsulfonyl)phenylamino)imidazo[l ,2- b]pyridazin-3-yl)-5,6-dihydropyridine-l(2H)-carboxylate
Figure imgf000094_0002
[0373] A 100-mL sealed tube purged and maintained with an inert atmosphere of nitrogen was placed a solution of 3-bromo-N- (2-fluoro-4- (methylsulfonyl) phenyl) imidazo [1,2-b] pyridazin-8-amine (180 mg, 0.47 mmol, 1.00 equiv) in toluene/EtOH/H2O (1:1:0.6) (39 mL), triethylamine (142 mg, 1.41 mmol, 3.00 equiv), tert-butyl 4-(4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl)-5,6- dihydropyridine-1 (2H)-carboxylate (173.8 mg, 0.56 mmol, 1.20 equiv), Pd (PPh3)4 (36 mg). The resulting solution was stirred at 125°C overnight. Upon completion, the resulting mixture was concentrated under vacuum. The residue was purified by a silica gel column chromatography eluted with EtOAc: PE (1:1) affording tert- butyl 4-(8-(2-fluoro-4- (methylsulfonyl) phenylamino)imidazo[l,2-b]pyridazin-3- yl)-5,6-dihydropyridine-l(2H)-carboxylate as white solid (19 mg, 8.1%) 1H NMR (300 MHz, CDCl3) δ 7.63-8.33 (m, 5 H), 7.18 (s, IH), 6.71 (d, IH), 4.24 (s, 2H), 3.74 (m, 2H), 3.13 (s, 3H), 2.68 (s, 2H), 1.52 (s, 9H). LCMS 488 [M+l]+.
EXAMPLE 44
3-(l-(5-Ethylpyrimidin-2-yl)-l,2,3,6-tetrahydropyridin-4-yl)-N-(2-fluoro-4- (methylsulfonyl)phenyl)imidazo[l,2-b]pyridazin-8-amine
Figure imgf000095_0001
Step 1: N-(2-Fluoro-4-(methylsulfonyl)phenyl)-3-(l,2,3,6-tetrahydropyridin-4- yl)imidazo[l,2-b]pyridazin-8-amine
Figure imgf000095_0002
[0374] A solution of tert-butyl 4-(8-(2-fluoro-4-(methylsulfonyl)phenylamino) imidazo[l,2-b]pyridazin-3-yl)-5,6-dihydropyridine-l(2H)-carboxylate (10 mg, 0.02 mmol) in 1 mL DCM was treated with 1 mL 1 : 1 DCM/TFA mixture at room temperature for 6h. LCMS showed a clean conversion to the desired product. The mixture was concentrated in vacuo to give the product as TFA salt. LCMS [M+l]+ 388.
Step_l: 3-(l-(5-Ethylpyrimidin-2-yl)-l,2,3,6-tetrahydropyridin-4-yl)-N-(2-fluoro-4- (methylsulfonyl)phenyl)imidazo[ 1 ,2-b]pyridazin-8-amine
Figure imgf000096_0001
[0375] A mixture of N-(2-fluoro-4-(methylsulfonyl)phenyl)-3-(l,2,3,6- tetrahydropyridin-4-yl)imidazo[l,2-b]pyridazin-8-amine ( lOmg, 0.02 mmol), 2- chloro-5-ethylpyrimidine (4 mg, 0.03 mmol), N-ethyl-N-isopropylpropan-2-amine ( 0.6 mmol) in 1 mL NMP was placed in a MW tube and irradiated at 150 0C for 5 minutes. LCMS confirms the transformation. This mixture was directly purified by RP column chromatography eluted with 30-100% acetonitrile in water in the presence of 0.1% TFA to afford 3-(l-(5-Ethylpyrimidin-2-yl)-l,2,3,6- tetrahydropyridin-4-yl)-N-(2-fluoro-4-(methylsulfonyl)phenyl)imidazo[l,2- b]pyridazin-8-amine. LCMS 494 [M+l]+. EXAMPLE 45
3-(l-(5-Methoxypyrimidin-2-yl)-l,2,3,6-tetrahydropyridin-4-yl)-N-(2-methyl-6- (methylsulfonyl)pyridin-3-yl)imidazo[l,2-a]pyrazin-8-amine
Figure imgf000097_0001
[0376] The title compound was synthesized as described for EXAMPLE 3 using N-(2-methyl-6-(methylsulfonyl)pyridin-3-yl)-3-(l,2,3,6-tetrahydropyridin-4- yl)imidazo[l,2-a]pyrazin-8-amine and 2-chloro-5-methoxypyrimidine as the starting materials. 1H NMR (400 MHz, CDCl3) δ 8.96 (d, IH), 8.21 (s, 2H), 8.00 (d, IH), 7.85 (d, IH), 7.65 (s, IH), 7.61 (d, IH), 6.30 (m, IH), 4.47 (m, 2H), 4.11 (t, 2H), 3.85 (s, 3H), 3.23 (s, 3H), 2.76 (s, 3H), 2.67 (m, 2H). LCMS 493 [M+l]+.
EXAMPLE 46
3-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)-8-(2-fluoro-4-(lH-tetrazol-l- yl)phenoxy)-[l,2,4]triazolo[4,3-a]pyrazine
Figure imgf000097_0002
[0377] The title compound was synthesized as described for EXAMPLE 6, in step 5, using 8-chloro-3-(l-(5-ethylpyrimidin-2-yl)piperidin-4-yl)- [l,2,4]triazolo[4,3-a]pyrazine and 2-fluoro-4-(lH-tetrazol-l-yl)phenol as the starting materials. LCMS 487 [M+l]+.
EXAMPLE 47
3-(l-(5-Ethylpyrimidin-2-yl)-l,2,3,6-tetrahydropyridin-4-yl)-8-(2-fluoro-4-(lH- tetrazol-l-yl)phenoxy)imidazo[l,2-a]pyrazine
Figure imgf000098_0001
J_: 3-Bromo-8-(2-fluoro-4-(lH-tetrazol-l-yl)phenoxy)imidazo[l,2-a]pyrazine
Figure imgf000098_0002
[0378] A mixture of 3-bromo-8-chloroimidazo[l,2-a]pyrazine (0.13 g, 0.56 mmol), 2-fluoro-4-(lH-tetrazol-l-yl)phenol (0.1 g, 0.56 mmol) and Cs2CO3 in NMP (5 mL) (0.18, 0.56 mmol) was heated to 80 0C for 6 hours. Upon completion, the resulting mixture was diluted with water (10 mL), extracted with EtOAc (3x10 mL), washed with water (2x10 mL), and brine (1x10 mL). Organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by a silica gel column chromatography eluted with EtOAc: PE (1: 1) affording 3-bromo-8-(2- fluoro-4-(lH-tetrazol-l-yl)phenoxy)imidazo[l,2-a]pyrazine (90 mg). Step 2: 3-(l-(5-Ethylpyrimidin-2-yl)-l,2,3,6-tetrahydropyridin-4-yl)-8-(2-fluoro-4- ( 1 H-tetrazol- 1 -yl)phenoxy)imidazo [ 1 ,2-a]pyrazine
Figure imgf000099_0001
[0379] A mixture of 3-bromo-8-(2-fluoro-4-(lH-tetrazol-l- yl)phenoxy)imidazo[l,2-a]pyrazine (50 mg, 0.13 mmol), 5-ethyl-2-(4-(4,4,5,5- tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-5 ,6-dihydropyridin- 1 (2H)-yl)pyrimidine (42 mg, 0.13 mmol), Pd(PPh3)2Cl2 (9 mg, 0.013 mmol), K2CO3 (36 mg, 0.26 mmol) in dioxane (1.3 mL) was degassed three times and purged with nitrogen. Then, the mixture was heated to 100 0C for overnight. It was cooled down to room temperature and quenched with water. The mixture was rinsed into a seperatory funnel and extracted with ethyl acetate (3x50 mL). Combined organics were washed with water, brine and dried over Na2SO4, filtered and concentrated in vacuo to give the crude product that was purified by a RP C 18 column chromatography eluted with 10-100% MeCN in water in the presence of 0.1% TFA to give 3-(l-(5- Ethylpyrimidin-2-yl)- 1,2,3, 6-tetrahydropyridin-4-yl)-8-(2-fluoro-4-(lH-tetrazol-l- yl)phenoxy)imidazo[l,2-a]pyrazine (30 mg). LCMS 485 [M+l]+ .
EXAMPLE 48
3-(l-(5-Ethylpyrimidin-2-yl)-l,2,3,6-tetrahydropyridin-4-yl)-8-(2-methyl-6- (methylsulfonyl)pyridin-3-yloxy)imidazo[l,2-a]pyrazine
Figure imgf000100_0001
[0380] The title compound was synthesized as described for EXAMPLE 47 using 2-methyl-6-(methylsulfonyl)pyridin-3-ol and 3-bromo-8-chloroimidazo[l,2- ajpyrazine as the starting materials. 1H NMR (400 MHz, CD3OD) δ 8.48-8.43 (m, 3H), 8.07-7.98 (m, 3H), 7.49 (d, IH), 6.46 (s, IH), 4.52 (m, 2H), 4.19 (t, 2H), 3.27 (s, 3H), 2.80 (m, 2H), 2.63-2.60 (m, 2H), 2.55 (s, 3H), 1.25 (t, 3H). LCMS 492 [M+l]+.
EXAMPLE 49
3-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)-N-(2-methyl-6-(methylsulfonyl) pyridin-3-yl)-[l,2,4]triazolo[4,3-c]pyrimidin-8-amine
[0381] The title compound was synthesized as described for EXAMPLE 41, in step 7, using 8-bromo-3-(l-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-[l,2,4]triazolo [4,3-c]pyrimidine and 2-methyl-6-(methylsulfonyl)pyridin-3-amine as the starting materials. 1H NMR (300 MHz, CDCl3) δ 9.03 ( s, IH ), 8.26 (s, 2H ), 8.05 (s, IH ), 7.98 - 8.01 (d, IH), 7.86 - 7.89 (d, IH ), 6.62 (s, IH ), 4.82 - 8.86 (q, 2H ), 3.30- 3.35 (m, 3H), 3.26 (s, 3H ), 2.74 (s, 3H ), 2.48-2.56 (m, 2H), 2.24-2.28 (m, 2H), 2.01-2.08 (m, 2H), 1.20-1.23 (t, 3H). LCMS 493 [M+l]+.
EXAMPLE 50
Tert-butyl 4-(3-(2-fluoro-4-(methylsulfonyl)phenylamino)imidazo[l,2- a]pyrazin-8-yl)piperazine-l-carboxylate
Figure imgf000101_0002
Step 1: Tert-butyl 4-(3-bromoimidazo[l,2-a]pyrazin-8-yl)piperazine-l-carboxylate
Figure imgf000102_0001
[0382] A mixture of tert-butyl piperazine-1-carboxylate (9.7 mmol) and 3- bromo-8-chloroimidazo[l,2-a]pyrazine (4.3 mmol) in 10 mL DMSO was heated to 100 0C for 45 minutes. The reaction mixture was cooled down to room temperature, and quenched with water. The mixture was rinsed into a seperatory funnel and extracted with ethyl acetate (3x50 mL). Combined organics were washed with water, brine and dried over Na2SO4, filtered and concentrated in vacuo to give tert-butyl 4-(3-bromoimidazo[l,2-a]pyrazin-8-yl)piperazine-l-carboxylate as tan solid (1.5 g).
Step 2: Tert-butyl 4-(3-(2-fluoro-4-(methylsulfonyl)phenylamino)imidazo[l ,2- a]pyrazin-8-yl)piperazine-l-carboxylate
Figure imgf000102_0002
[0383] A mixture of tert-butyl 4-(3-bromoimidazo[l,2-a]pyrazin-8- yl)piperazine-l-carboxylate (0.5 mmol), 2-fluoro-4-(methylsulfonyl)phenylboronic acid (0.6 mmol), Pd(PPh3)2Cl2 (0.07 mmol), K2CO3 (2 mL, 10 % aqueous solution) in dioxane (6 mL) was degassed three times and purged with nitrogen. Then, the mixture was heated to 100 0C for overnight. It was cooled down to room temperature and quenched with water. The mixture was rinsed into a seperatory funnel and extracted with ethyl acetate (3x50 mL). Combined organics were washed with water, brine and dried over Na2SO4, filtered and concentrated in vacuo to give the crude product that was purified by a silica gel column chromatography eluted with 20-60% ethyl acetate in hexanes to give tert-butyl 4-(3-(2-fluoro-4- (methylsulfonyl)phenylamino)imidazo [l,2-a]pyrazin-8-yl)piperazine-l-carboxylate as beige solid (100 mg, 40%). LCMS 491 [M+l]+ .
EXAMPLE 51
Tert-butyl 4-(8-(2-methyl-6-(methylsulfonyl)pyridin-3-ylamino)imidazo[l,2- b]pyridazin-3-yl)-5,6-dihydropyridine-l(2H)-carboxylate
Figure imgf000103_0001
[0384] The title compound was synthesized as described for EXAMPLE 43 using 8-bromo-6-chloroimidazo[l,2-b]pyridazine hydrochloride and 2-methyl-6- (methylsulfonyl) pyridin-3-amine as the starting materials. 1H NMR (300 MHz, CDCl3) δ 8.85 (s, 1 H) 8.18 (s, 2 H), 7.74 (d, 2 H), 7.63 (s, IH), 7.46 (d, 1 H), 5.75 (s, 1 H), 3.69 (s, 2H), 3.17 (s, 3H), 3.02 (s, 2H), 2.60 (s, 4H), 1.29 (s, 9H). LCMS 485 [M+l]+.
EXAMPLE 52
3-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)-N-(2-methyl-6-(methylsulfonyl) pyridin-3-yl)imidazo[l,2-a]pyridin-8-amine
Figure imgf000104_0001
Step 1: 8-bromo-3-(piperidin-4-yl)imidazo[l,2-a]pyridine hydrobromide
Figure imgf000104_0002
[0385] A 50-mL round-bottom flask was charged with a solution of 3- bromopyridin-2-amine (100 mg, 0.58 mmol, 1.00 equiv), tert-butyl 4-(l-bromo-2- oxoethyl)piperidine-l-carboxylate (350 mg, 1.14 mmol, 1.97 equiv) in ethanol (20 mL). The resulting solution was heated to reflux overnight. The solids were collected by filtration affording 8-bromo-3-(piperidin-4-yl)H-imidazo[l,2- ajpyridine hydrogen bromide as brown solid (150 mg, 68%).
Step 2: 8-Bromo-3-(l-(5-ethylpyrimidin-2-yl)piperidin-4-yl)imidazo[l,2- a]pyridine
Figure imgf000105_0001
[0386] A 50-mL round-bottom flask was charged with a solution of 8-bromo-3- (piperidin-4-yl)H-imidazo[l,2-a]pyridine hydrogen bromide (150 mg, 0.42 mmol, 1.00 equiv), 2-chloro-5-ethylpyrimidine (150 mg, 1.05 mmol, 2.50 equiv), and potassium carbonate (300 mg) in N,N-dimethylformamide (10 mL). The resulting solution was stirred at 90 0C overnight. The residue purified by a silica gel column chromatography eluted with ethyl acetate/petroleum ether (1: 1) affording 8-bromo- 3-(l-(5-ethylpyrimidin-2-yl)piperidin-4-yl)H-imidazo[l,2-a]pyridine as white solid (210 mg, 97%).
Step 3: 3-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)-N-(2-methyl-6- (methylsulfonyl) pyridin-3-yl)imidazo[l,2-a]pyridin-8-amine
Figure imgf000105_0002
[0387] A 50-mL round-bottom flask was placed with a solution of 8-bromo-3- (l-(5-ethylpyrimidin-2-yl)piperidin-4-yl)H-imidazo[l,2-a]pyridine (300 mg, 0.78 mmol, 1.00 equiv), 2-methyl-6-(methylsulfonyl)pyridin-3-amine (160 mg, 0.86 mmol, 1.10 equiv), Pd2(dba)3 (136 mg), BINAP (150 mg), potassium 2- methylpropan-2-olate (400 mg) in toluene (25 mL). The resulting solution was stirred at 700C overnight. Upon completion, the mixture was cooled down to room temperature and quenched with water. The mixture was rinsed into a seperatory funnel and extracted with ethyl acetate (3x50 mL). Combined organics were washed with water, brine and dried over Na2SO4, filtered and concentrated in vacuo to give the crude product that was purified by a silica gel column chromatography eluted with ethyl acetate in hexanes (1:1) to give 3-(l-(5-ethylpyrimidin-2- yl)piperidin-4-yl)-N-(2-methyl-6-(methylsulfonyl)pyridin-3-yl)H-imidazo[l,2- a]pyridin-8-amine as a white solid (350 mg, 90%). 1H NMR (300 MHz, DMSOd6) δ 8.29 (m, 4H), 7.76 (d, IH), 7.47 (t, 2H), 6.99 (d, 2H), 4.80 (d, 2H), 3.36 (t, 2H), 3.21 (s, 3H), 3.09 (t, 2H), 2.60 (s, 3H), 2.45 (m, 2H), 2.08 (d, 2H), 1.60 (m, 2H), 1.14 (t, 3H). LCMS 492 [M+l]+.
EXAMPLE 53
Tert-butyl 4-(8-(2-methyl-6-(methylsulfonyl)pyridin-3-ylamino)imidazo[l,2- b]pyridazin-3-yl)piperidine-l-carboxylate
Figure imgf000106_0001
Step 1: Tert-butyl 4-(l-bromo-2-oxoethyl)piperidine-l-carboxylate
Figure imgf000106_0002
[0388] A l L round-bottom flask was charged with a solution of tert-butyl 4-(2- oxoethyl)piperidine-l-carboxylate (23 g, 101.32 mmol, 1.00 equiv), PTAP (40 g) in tetrahydrofuran (500 mL). The resulting solution was stirred at 100C for 3 h. Upon completion, the reaction was quenched with brine (IL). The resulting mixture was extracted with ethyl acetate (3x300 mL). Combine organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum affording tert-butyl 4-(l- bromo-2-oxoethyl)piperidine-l-carboxylate as yellow oil (25 g, 65%).
Step 2: 8-Bromo-6-chloro-3-(piperidin-4-yl)imidazo[l,2-b]pyridazine hydrobromide
Figure imgf000107_0001
[0389] A 100-mL round-bottom flask was charged with a solution of 4-bromo- 6-chloropyridazin-3-amine (2.1 g, 10.1 mmol, 1.35 equiv), tert-butyl 4-(l-bromo-2- oxoethyl)piperidine-l-carboxylate (2.3 g, 7.54 mmol, 1.00 equiv) in ethanol (50 mL). The resulting solution was heated to reflux overnight. The precipitate was collected by filtration affording 8-bromo-6-chloro-3-(piperidin-4-yl)imidazo[l,2- b]pyridazine hydrogen bromide as brown solid (2.3 g 52%). LCMS 317 [M+l]+.
Step 3: Tert-butyl 4-(8-bromo-6-chloroimidazo[l,2-b]pyridazin-3-yl)piperidine-l- carboxylate
Figure imgf000107_0002
[0390] A 100-mL round-bottom flask was charged with a solution of 8-bromo- 6-chloro-3-(piperidin-4-yl)imidazo[l,2-b]pyridazine hydrogen bromide (230 mg, 0.58 mmol, 1.00 equiv), (Boc)2O (500 mg), potassium carbonate (300 mg) in ethanol (50 mL). The resulting solution was stirred h at room temperature for 2. Upon completion, the resulting mixture was quenched with water (200 mL). The precipitate was collected by filtration affording tert-butyl 4-(8-bromo-6- chloroimidazo[l,2-b]pyridazin-3-yl)piperidine-l-carboxylate as brown solid (300 mg, 98%).
Step 4: Tert-butyl 4-(6-chloro-8-(2-methyl-6-(methylsulfonyl)pyridin-3- ylamino)imidazo[l,2-b]pyridazin-3-yl)piperidine-l-carboxylate
Figure imgf000108_0001
[0391] A 100-mL round-bottom flask was charged with a solution of tert-butyl 4-(8-bromo-6-chloroimidazo[l,2-b]pyridazin-3-yl)piperidine-l-carboxylate (1 g, 2.40 mmol, 1.00 equiv), 2-methyl-6-(methylsulfonyl)pyridin-3-amine (700 mg, 3.76 mmol, 1.57 equiv), potassium 2-methylpropan-2-olate (450 mg) in tetrahydrofuran (50 mL). The resulting mixture was stirred at 500C for 2 h. Upon completion, the reaction was quenched with brine (IL). The resulting mixture was extracted with ethyl acetate (3x300 mL). Combine organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give the crude that was purified by a silica gel column chromatography eluted with ethyl acetate/petroleum ether (1:1) affording tert-butyl 4-(6-chloro-8-(2-methyl-6- (methylsulfonyl)pyridin-3-ylamino)imidazo[l,2-b]pyridazin-3-yl)piperidine-l- carboxylate as yellow solid (1.5 g, 84%).
Step 5: Tert-butyl 4-(8-(2-methyl-6-(methylsulfonyl)pyridin-3- ylamino)imidazo[l,2-b]pyridazin-3-yl)piperidine-l-carboxylate
Figure imgf000109_0001
[0392] A 100-mL round-bottom flask was charged with a solution of tert-butyl 4-(6-chloro-8-(2-methyl-6-(methylsulfonyl)pyridin-3-ylamino)imidazo[l,2- b]pyridazin-3-yl)piperidine-l-carboxylate (1 g, 1.92 mmol, 1.00 equiv) and palladium carbon (1 g) in methanol (50 mL). The flask was equipped with H2 balloon and was allowed stir at 500C overnight. Upon completion, the mixture was filtered through Celite and concentrated to give a residue that was purified by silica gel column chromatography eluted with ethyl acetate/petroleum ether (1:1) affording tert-butyl 4-(8-(2-methyl-6-(methylsulfonyl)pyridin-3- ylamino)imidazo[l,2-b]pyridazin-3-yl)piperidine-l-carboxylate as white solid (0.7 g, 74%). 1H NMR (300 MHz, DMSOd6) δ 9.35 (s, IH), 8.15 (d, IH), 8.06 (d, IH), 7.94 (d, IH), 7.49 (s, IH), 6.17 (d, IH), 4.08 (m, 2H), 3.29 (s, 3H), 2.92 (m, 2H), 2.55 (s, 3H), 2.07 (d, 2H), 1.61 (m, 2H), 1.42 (s, 9H). LCMS 487 [M+l]+.
EXAMPLE 54
3-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)-N-(2-methyl-6-(methylsulfonyl) pyridin-3-yl)imidazo[l,2-b]pyridazin-8-amine
Figure imgf000110_0001
[0393] The title compound was synthesized as described for EXAMPLE 3 using N-(2-methyl-6-(methylsulfonyl)pyridin-3-yl)-3-(piperidin-4-yl)imidazo[l,2- b]pyridazin-8-amine and 2-chloro-5-ethylpyrimidine as the starting materials. 1H NMR (300 MHz, DMSOd6) δ 8.19 (m, 3H), 8.02 (m, 2H), 7.72 (s, IH), 7.42 (s, IH), 6.50 (d, IH), 4.92 (d, 2H), 3.51 (m, IH), 3.28 (s, 3H), 3.13 (t, 2H), 2.73 (s, 3H), 2.51 (m, 2H), 2.30 (d, 2H), 1.79 (m, 2H), 1.22 (t, 3H). LCMS 493 [M+l]+.
EXAMPLE 55
3-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)-N-(2-methyl-6-(methylsulfonyl) pyridin-3-yl)-[l,2,4]triazolo[4,3-b]pyridazin-8-amine
Figure imgf000110_0002
Step 1: 3,6-Dichloro-N-(2-methyl-6-(methylsulfonyl)pyridin-3-yl)pyridazin-4- amine
Figure imgf000111_0001
[0394] A 100-mL round-bottom flask was charged with a solution of 2-methyl- 6-(methylsulfonyl)pyridin-3-amine (500 mg, 2.69 mmol) in tetrahydrofuran (50 mL), sodium hydride (269 mg, 11.2 mmol), and 3,4,6-trichloropyridazine (1 g, 5.49 mmol). The resulting solution was stirred for 16 hrs at room temperature. The reaction was then quenched with brine (50 mL), extracted with ethyl acetate (4x50 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. This residue was purified by a silica gel column chromatography eluted with dichloromethane/ethyl acetate (2/1) affording 3,6-dichloro-N-(2-methyl-6-(methylsulfonyl)pyridin-3-yl)pyridazin-4-amine as pale yellow solid (0.75 g, 84%).
Step 2: 6-Chloro-3-(l-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-N-(2-methyl-6- (methylsulfonyl)pyridin-3-yl)-[l,2,4]triazolo[4,3-b]pyridazin-8-amine
Figure imgf000111_0002
[0395] A 250-mL round-bottom flask was charged with a solution of 3,6- dichloro-N-(2-methyl-6-(methylsulfonyl)pyridin-3-yl)pyridazin-4-amine (500 mg, 1.51 mmol) in p-xylene (150 mL), triethylamine hydrochloride (600 mg, 4.38 mmol), l-(5-ethylpyrimidin-2-yl)piperidine-4-carbohydrazide (375 mg, 1.51 mmol). The resulting solution was stirred at 145°C in an oil bath for 16 h. Upon completion, the reaction was cooled down to room temperature. Then quenched with brine (50 mL) and extracted with ethyl acetate (4x50 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. This residue was purified by a silica gel column chromatography eluted with dichloromethane/methanol (50: 1) affording 6-chloro-3-(l-(5-ethylpyrimidin- 2-yl)piperidin-4-yl)-N-(2-methyl-6-(methylsulfonyl)pyridin-3-yl)- [l,2,4]triazolo[4,3-b]pyridazin-8-amine as pale yellow solid (0.4 g, 50%).
Step 3: 3-(l-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-N-(2-methyl-6- (methylsulfonyl) pyridin-3-yl)-[l,2,4]triazolo[4,3-b]pyridazin-8-amine
Figure imgf000112_0001
[0396] A 100-mL round-bottom flask purged, flushed and maintained with a N2 (g) was charged with a solution of 6-chloro-3-(l-(5-ethylpyrimidin-2-yl)piperidin- 4-yl)-N-(2-methyl-6-(methylsulfonyl)pyridin-3-yl)-[l,2,4]triazolo[4,3-b]pyridazin- 8-amine (100 mg, 0.19 mmol) in methanol (50 mL). To this was added palladium carbon (0.3 g). The resulting solution was stirred at room temperature for 1 under H2 atmosphere. The resulting mixture was filtered through Celite and concentrated to give the crude material that was purified by a silica gel column chromatography eluted with dichloromethane/methanol (80/1) affording 3-(l-(5-ethylpyrimidin-2- yl)piperidin-4-yl)-N-(2-methyl-6-(methylsulfonyl)pyridin-3-yl)-[l,2,4]triazolo[4,3- b]pyridazin-8-amine as white solid (42 mg, 44%). 1H NMR (300 MHz, DMSOd6) δ 9.98 (s, IH), 8.28 (s, 2H), 8.18 (d, IH), 8.08 (d, IH), 7.95 (d, IH), 6.10 (d, IH), 4.79 (d, 2H), 3.61 (m, IH), 3.31 (d, 3H), 3.17 (t, 2H), 2.55 (s, 4H), 2.44 (m, 3H), 2.12 (d, 2H), 1.87 (m, 2H), 1.14 (t, 3H). LCMS 494 [M+l]+.
I ll [0397] 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 11.0.
CC(C)C(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3C=CC=C4NC5=C(C)N=C(N6C=NC=N6)C=C5
CC(C)C(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3C=CC=C4NC5=C(C)N=C(N6C=NN=N6)C=C5
CC(C)C(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3C=CC=C4NC5=C(F)C=C(N6C=NN=N6)C=C5
CC(C)C(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3C=CC=C4NC5=CC(F)=C(N6C=NN=N6)C=C5
CC(C)C(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3C=CN=C4NC5=C(C)N=C(N6C=NC=N6)C=C5
CC(C)C(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3C=CN=C4NC5=C(C)N=C(N6C=NN=N6)C=C5
CC(C)C(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3C=CN=C4NC5=C(F)C=C(N6C=NN=N6)C=C5
CC(C)C(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3C=CN=C4NC5=CC(F)=C(N6C=NN=N6)C=C5
CC(C)C(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3C=NC=C4NC5=C(C)N=C(N6C=NC=N6)C=C5
CC(C)C(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3C=NC=C4NC5=C(C)N=C(N6C=NN=N6)C=C5
CC(C)C(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3C=NC=C4NC5=C(F)C=C(N6C=NN=N6)C=C5
CC(C)C(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3C=NC=C4NC5=CC(F)=C(N6C=NN=N6)C=C5
CC(C)C(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3N=CC=C4NC5=C(C)N=C(N6C=NC=N6)C=C5
CC(C)C(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3N=CC=C4NC5=C(C)N=C(N6C=NN=N6)C=C5
CC(C)C(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3N=CC=C4NC5=C(F)C=C(N6C=NN=N6)C=C5
CC(C)C(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3N=CC=C4NC5=CC(F)=C(N6C=NN=N6)C=C5
CC(C)C(C=N1)=CN=C1N(CC2)CCC2C3=NC=C4N3C=CN=C4NC5=C(C)N=C(N6C=NC=N6)C=C5
CC(C)C(C=N1)=CN=C1N(CC2)CCC2C3=NC=C4N3C=CN=C4NC5=C(C)N=C(N6C=NN=N6)C=C5
CC(C)C(C=N1)=CN=C1N(CC2)CCC2C3=NC=C4N3C=CN=C4NC5=C(F)C=C(N6C=NN=N6)C=C5
CC(C)C(C=N1)=CN=C1N(CC2)CCC2C3=NC=C4N3C=CN=C4NC5=C(F)C=C(N6C=NN=N6)C=C5
CC(C)C(C=N1)=CN=C1N(CC2)CCC2C3=NC=C4N3C=CN=C4NC5=CC(F)=C(N6C=NN=N6)C=C5
CC(C)C(C=N1)=CN=C1N(CC2)CCC2C3=NN=C4N3C=CC=C4NC5=C(C)N=C(N6C=NC=N6)C=C5
CC(C)C(C=N1)=CN=C1N(CC2)CCC2C3=NN=C4N3C=CN=C4NC5=C(C)N=C(N6C=NC=N6)C=C5
CC(C)C(C=N1)=CN=C1N(CC2)CCC2C3=NN=C4N3C=CN=C4NC5=C(C)N=C(N6C=NN=N6)C=C5
CC(C)C(C=N1)=CN=C1N(CC2)CCC2C3=NN=C4N3C=CN=C4NC5=C(F)C=C(N6C=NN=N6)C=C5
CC(C)C(C=N1)=CN=C1N(CC2)CCC2C3=NN=C4N3C=CN=C4NC5=CC(F)=C(N6C=NN=N6)C=C5
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CC(C)C1=NOC(N(CC2)CCC2C3=CN=C4N3C=CC=C4NC5=C(C)N=C(N6C=NN=N6)C=C5)=N1 CC(C)C1=NOC(N(CC2)CCC2C3=CN=C4N3C=CC=C4NC5=C(F)C=C(N6C=NN=N6)C=C5)=N1 CC(C)C1=NOC(N(CC2)CCC2C3=CN=C4N3C=CC=C4NC5=CC(F)=C(N6C=NN=N6)C=C5)=N1
CC(C)C1=NOC(N(CC2)CCC2C3=CN=C4N3C=CN=C4NC5=C(C)N=C(N6C=NC=N6)C=C5)=N1
CC(C)C1=NOC(N(CC2)CCC2C3=CN=C4N3C=CN=C4NC5=C(C)N=C(N6C=NN=N6)C=C5)=N1
CC(C)C1=NOC(N(CC2)CCC2C3=CN=C4N3C=CN=C4NC5=C(F)C=C(N6C=NN=N6)C=C5)=N1
CC(C)C1=NOC(N(CC2)CCC2C3=CN=C4N3C=CN=C4NC5=CC(F)=C(N6C=NN=N6)C=C5)=N1
CC(C)C1=NOC(N(CC2)CCC2C3=CN=C4N3C=NC=C4NC5=C(C)N=C(N6C=NC=N6)C=C5)=N1
CC(C)C1=NOC(N(CC2)CCC2C3=CN=C4N3C=NC=C4NC5=C(C)N=C(N6C=NN=N6)C=C5)=N1
CC(C)C1=NOC(N(CC2)CCC2C3=CN=C4N3C=NC=C4NC5=C(F)C=C(N6C=NN=N6)C=C5)=N1
CC(C)C1=NOC(N(CC2)CCC2C3=CN=C4N3C=NC=C4NC5=CC(F)=C(N6C=NN=N6)C=C5)=N1
CC(C)C1=NOC(N(CC2)CCC2C3=CN=C4N3N=CC=C4NC5=C(C)N=C(N6C=NC=N6)C=C5)=N1
CC(C)C1=NOC(N(CC2)CCC2C3=CN=C4N3N=CC=C4NC5=C(C)N=C(N6C=NN=N6)C=C5)=N1
CC(C)C1=NOC(N(CC2)CCC2C3=CN=C4N3N=CC=C4NC5=C(F)C=C(N6C=NN=N6)C=C5)=N1
CC(C)C1=NOC(N(CC2)CCC2C3=CN=C4N3N=CC=C4NC5=CC(F)=C(N6C=NN=N6)C=C5)=N1
CC(C)C1=NOC(N(CC2)CCC2C3=NC=C4N3C=CN=C4NC5=C(C)N=C(N6C=NC=N6)C=C5)=N1
CC(C)C1=NOC(N(CC2)CCC2C3=NC=C4N3C=CN=C4NC5=C(C)N=C(N6C=NN=N6)C=C5)=N1
CC(C)C1=NOC(N(CC2)CCC2C3=NC=C4N3C=CN=C4NC5=C(F)C=C(N6C=NN=N6)C=C5)=N1
CC(C)C1=NOC(N(CC2)CCC2C3=NC=C4N3C=CN=C4NC5=CC(F)=C(N6C=NN=N6)C=C5)=N1
CC(C)C1=NOC(N(CC2)CCC2C3=NN=C4N3C=CC=C4NC5=C(C)N=C(N6C=NC=N6)C=C5)=N1
CC(C)C1=NOC(N(CC2)CCC2C3=NN=C4N3C=CN=C4NC5=C(C)N=C(N6C=NC=N6)C=C5)=N1
CC(C)C1=NOC(N(CC2)CCC2C3=NN=C4N3C=CN=C4NC5=C(C)N=C(N6C=NN=N6)C=C5)=N1
CC(C)C1=NOC(N(CC2)CCC2C3=NN=C4N3C=CN=C4NC5=C(F)C=C(N6C=NN=N6)C=C5)=N1
CC(C)C1=NOC(N(CC2)CCC2C3=NN=C4N3C=CN=C4NC5=CC(F)=C(N6C=NN=N6)C=C5)=N1
CC(C=C(N1N=CN=C1)C=C2)=C2NC3=NC=CN4C3=CN=C4C5CCN(C(OC(C)C)=O)C5
CC(N=C(N1C=NC=N1)C=C2)=C2NC3=CC=CN4C3=NC=C4C5CCN(C6=NC=C(C(F)(F)F)C=N6)CC5
CC(N=C(N1C=NC=N1)C=C2)=C2NC3=CC=CN4C3=NN=C4C5CCN(C6=NC=C(C(F)(F)F)C=N6)CC5
CC(N=C(N1C=NC=N1)C=C2)=C2NC3=CC=NN4C3=NC=C4C5CCN(C6=NC=C(C(F)(F)F)C=N6)CC5
CC(N=C(N1C=NC=N1)C=C2)=C2NC3=CN=CN4C3=NC=C4C5CCN(C6=NC=C(C(F)(F)F)C=N6)CC5
CC(N=C(N1C=NC=N1)C=C2)=C2NC3=NC=CC(N3C=N4)=C4C5=CCN(C6=NC=C(CC)C=N6)CC5
CC(N=C(N1C=NC=N1)C=C2)=C2NC3=NC=CC(N3C=N4)=C4C5CCN(C6=NC=C(CC)C=N6)CC5
CC(N=C(N1C=NC=N1)C=C2)=C2NC3=NC=CN4C3=CN=C4C5CCN(C6=NC=C(C(F)(F)F)C=N6)CC5
CC(N=C(N1C=NC=N1)C=C2)=C2NC3=NC=CN4C3=NC=C4C5CCN(C6=NC=C(C(F)(F)F)C=N6)CC5
CC(N=C(N1C=NC=N1)C=C2)=C2NC3=NC=CN4C3=NN=C4C5CCN(C6=NC=C(C(F)(F)F)C=N6)CC5
CC(N=C(N1C=NN=N1)C=C2)=C2NC3=CC=CN4C3=NC=C4C5CCN(C6=NC=C(C(F)(F)F)C=N6)CC5
CC(N=C(N1C=NN=N1)C=C2)=C2NC3=CC=NN4C3=NC=C4C5CCN(C6=NC=C(C(F)(F)F)C=N6)CC5
CC(N=C(N1C=NN=N1)C=C2)=C2NC3=CN=CN4C3=NC=C4C5CCN(C6=NC=C(C(F)(F)F)C=N6)CC5
CC(N=C(N1C=NN=N1)C=C2)=C2NC3=NC=CC(N3C=N4)=C4C5=CCN(C6=NC=C(CC)C=N6)CC5
CC(N=C(N1C=NN=N1)C=C2)=C2NC3=NC=CC(N3C=N4)=C4C5CCN(C6=NC=C(CC)C=N6)CC5
CC(N=C(N1C=NN=N1)C=C2)=C2NC3=NC=CN4C3=CN=C4C5CCN(C6=NC=C(C(F)(F)F)C=N6)CC5
CC(N=C(N1C=NN=N1)C=C2)=C2NC3=NC=CN4C3=NC=C4C5CCN(C6=NC=C(C(F)(F)F)C=N6)CC5 CC(N=C(N1C=NN=N1)C=C2)=C2NC3=NC=CN4C3=NN=C4C5CCN(C6=NC=C(C(F)(F)F)C=N6)CC5
CC(N=C(N1N=CN=C1)C=C2)=C2NC3=NC=CN4C3=NN=C4C5=CCN(C(OC(C)C)=O)CC5
CC(N=C(N1N=CN=C1)C=C2)=C2NC3=NC=CN4C3=NN=C4C5CCN(C(OC(C)C)=O)CC5
CC(N=C(S(C)(=O)=O)C=C1)=C1NC2=CC=CN3C2=CC=C3N4CCC(C(OC(C)C)=O)CC4
CC(N=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CC(N2C=N3)=C3C4=CCN(C5=NC=C(CC)C=N5)CC4
CC(N=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CC(N2C=N3)=C3C4CCN(C(OC(C)C)=O)CC4
CC(N=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CC(N2C=N3)=C3C4CCN(C5=NC=C(CC)C=N5)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=NC=CN3C2=CN=C3C4=CCN(C(OC(C)C)=O)CC4
CC(N=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=CN=C3C4CCN(C(OC(C)C)=O)CC4
CC(N=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=NN=C3C4=CCN(C(OC(C)C)=O)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=NN=C3N4CCC(C(OCCC[N+](C)(C)C)=O)CC4
CCC(C=N1)=CN=C1N(CC2)CC=C2C3=CN=C4N3C=CC=C4NC5=C(C)N=C(N6C=NC=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CC=C2C3=CN=C4N3C=CC=C4NC5=C(C)N=C(N6C=NN=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CC=C2C3=CN=C4N3C=CC=C4NC5=C(F)C=C(N6C=NN=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CC=C2C3=CN=C4N3C=CC=C4NC5=CC(F)=C(N6C=NN=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CC=C2C3=CN=C4N3C=CN=C4COC5=CC(F)=C(N6C=NN=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CC=C2C3=CN=C4N3C=CN=C4NC5=C(C)N=C(N6C=NC=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CC=C2C3=CN=C4N3C=CN=C4NC5=C(C)N=C(N6C=NN=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CC=C2C3=CN=C4N3C=CN=C4NC5=C(F)C=C(N6C=NN=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CC=C2C3=CN=C4N3C=CN=C4NC5=CC(F)=C(N6C=NN=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CC=C2C3=CN=C4N3C=NC=C4NC5=C(C)N=C(N6C=NC=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CC=C2C3=CN=C4N3C=NC=C4NC5=C(C)N=C(N6C=NN=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CC=C2C3=CN=C4N3C=NC=C4NC5=C(F)C=C(N6C=NN=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CC=C2C3=CN=C4N3C=NC=C4NC5=CC(F)=C(N6C=NN=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CC=C2C3=CN=C4N3N=CC=C4NC5=C(C)N=C(N6C=NC=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CC=C2C3=CN=C4N3N=CC=C4NC5=C(C)N=C(N6C=NN=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CC=C2C3=CN=C4N3N=CC=C4NC5=C(F)C=C(N6C=NN=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CC=C2C3=CN=C4N3N=CC=C4NC5=CC(F)=C(N6C=NN=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CC=C2C3=NC=C4N3C=CN=C4NC5=C(C)N=C(N6C=NC=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CC=C2C3=NC=C4N3C=CN=C4NC5=C(C)N=C(N6C=NN=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CC=C2C3=NC=C4N3C=CN=C4NC5=C(F)C=C(N6C=NN=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CC=C2C3=NC=C4N3C=CN=C4NC5=CC(F)=C(N6C=NN=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CC=C2C3=NN=C4N3C=CC=C4NC5=C(C)N=C(N6C=NC=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CC=C2C3=NN=C4N3C=CN=C4NC5=C(C)N=C(N6C=NC=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CC=C2C3=NN=C4N3C=CN=C4NC5=C(C)N=C(N6C=NN=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CC=C2C3=NN=C4N3C=CN=C4NC5=C(F)C=C(N6C=NN=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CC=C2C3=NN=C4N3C=CN=C4NC5=CC(F)=C(N6C=NN=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3C=CC=C4NC5=C(C)N=C(N6C=NC=N6)C=C5 CCC(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3C=CC=C4NC5=C(C)N=C(N6C=NN=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3C=CC=C4NC5=C(F)C=C(N6C=NN=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3C=CC=C4NC5=CC(F)=C(N6C=NN=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3C=CN=C4NC5=C(C)N=C(N6C=NC=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3C=CN=C4NC5=C(C)N=C(N6C=NN=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3C=CN=C4NC5=C(F)C=C(N6C=NN=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3C=CN=C4NC5=CC(F)=C(N6C=NN=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3C=CN=C4NCC5=CC(F)=C(N6C=NN=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3C=NC=C4NC5=C(C)N=C(N6C=NC=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3C=NC=C4NC5=C(C)N=C(N6C=NN=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3C=NC=C4NC5=C(F)C=C(N6C=NN=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3C=NC=C4NC5=CC(F)=C(N6C=NN=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3N=CC=C4NC5=C(C)N=C(N6C=NC=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3N=CC=C4NC5=C(C)N=C(N6C=NN=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3N=CC=C4NC5=C(F)C=C(N6C=NN=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3N=CC=C4NC5=CC(F)=C(N6C=NN=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CCC2C3=NC=C4N3C=CN=C4NC5=C(C)N=C(N6C=NC=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CCC2C3=NC=C4N3C=CN=C4NC5=C(C)N=C(N6C=NN=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CCC2C3=NC=C4N3C=CN=C4NC5=C(F)C=C(N6C=NN=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CCC2C3=NC=C4N3C=CN=C4NC5=CC(F)=C(N6C=NN=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CCC2C3=NN=C4N3C=CC=C4NC5=C(C)N=C(N6C=NC=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CCC2C3=NN=C4N3C=CN=C4NC5=C(C)N=C(N6C=NC=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CCC2C3=NN=C4N3C=CN=C4NC5=C(C)N=C(N6C=NN=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CCC2C3=NN=C4N3C=CN=C4NC5=C(F)C=C(N6C=NN=N6)C=C5
CCC(C=N1)=CN=C1N(CC2)CCC2C3=NN=C4N3C=CN=C4NC5=CC(F)=C(N6C=NN=N6)C=C5
C1C(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3C=CC=C4NC5=C(C)N=C(N6C=NC=N6)C=C5
C1C(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3C=CC=C4NC5=C(C)N=C(N6C=NN=N6)C=C5
C1C(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3C=CC=C4NC5=C(F)C=C(N6C=NN=N6)C=C5
C1C(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3C=CC=C4NC5=CC(F)=C(N6C=NN=N6)C=C5
C1C(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3C=CN=C4NC5=C(C)N=C(N6C=NC=N6)C=C5
C1C(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3C=CN=C4NC5=C(C)N=C(N6C=NN=N6)C=C5
C1C(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3C=CN=C4NC5=C(F)C=C(N6C=NN=N6)C=C5
C1C(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3C=CN=C4NC5=CC(F)=C(N6C=NN=N6)C=C5
C1C(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3C=NC=C4NC5=C(C)N=C(N6C=NC=N6)C=C5
C1C(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3C=NC=C4NC5=C(C)N=C(N6C=NN=N6)C=C5
C1C(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3C=NC=C4NC5=C(F)C=C(N6C=NN=N6)C=C5
C1C(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3C=NC=C4NC5=CC(F)=C(N6C=NN=N6)C=C5
C1C(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3N=CC=C4NC5=C(C)N=C(N6C=NC=N6)C=C5
C1C(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3N=CC=C4NC5=C(C)N=C(N6C=NN=N6)C=C5
C1C(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3N=CC=C4NC5=C(F)C=C(N6C=NN=N6)C=C5 C1C(C=N1)=CN=C1N(CC2)CCC2C3=CN=C4N3N=CC=C4NC5=CC(F)=C(N6C=NN=N6)C=C5
C1C(C=N1)=CN=C1N(CC2)CCC2C3=NC=C4N3C=CN=C4NC5=C(C)N=C(N6C=NC=N6)C=C5
C1C(C=N1)=CN=C1N(CC2)CCC2C3=NC=C4N3C=CN=C4NC5=C(C)N=C(N6C=NN=N6)C=C5
C1C(C=N1)=CN=C1N(CC2)CCC2C3=NC=C4N3C=CN=C4NC5=C(F)C=C(N6C=NN=N6)C=C5
C1C(C=N1)=CN=C1N(CC2)CCC2C3=NC=C4N3C=CN=C4NC5=CC(F)=C(N6C=NN=N6)C=C5
C1C(C=N1)=CN=C1N(CC2)CCC2C3=NN=C4N3C=CC=C4NC5=C(C)N=C(N6C=NC=N6)C=C5
C1C(C=N1)=CN=C1N(CC2)CCC2C3=NN=C4N3C=CN=C4NC5=C(C)N=C(N6C=NC=N6)C=C5
C1C(C=N1)=CN=C1N(CC2)CCC2C3=NN=C4N3C=CN=C4NC5=C(C)N=C(N6C=NN=N6)C=C5
C1C(C=N1)=CN=C1N(CC2)CCC2C3=NN=C4N3C=CN=C4NC5=C(F)C=C(N6C=NN=N6)C=C5
C1C(C=N1)=CN=C1N(CC2)CCC2C3=NN=C4N3C=CN=C4NC5=CC(F)=C(N6C=NN=N6)C=C5
CS(C(C=C1)=C(F)C=C1NC2=CC=CN3C2=NC=C3C4=CCN(C5=NC=C(CC)C=N5)CC4)(=O)=O
CS(C(C=C1)=C(F)C=C1NC2=CC=CN3C2=NC=C3C4CCN(C5=NC(C(C)C)=NO5)CC4)(=O)=O
CS(C(C=C1)=C(F)C=C1NC2=CC=CN3C2=NC=C3C4CCN(C5=NC=C(C(C)C)C=N5)CC4)(=O)=O
CS(C(C=C1)=C(F)C=C1NC2=CC=CN3C2=NC=C3C4CCN(C5=NC=C(C(F)(F)F)C=N5)CC4)(=O)=O
CS(C(C=C1)=C(F)C=C1NC2=CC=CN3C2=NC=C3C4CCN(C5=NC=C(CC)C=N5)CC4)(=O)=O
CS(C(C=C1)=C(F)C=C1NC2=CC=CN3C2=NC=C3C4CCN(C5=NC=C(C1)C=N5)CC4)(=O)=O
CS(C(C=C1)=C(F)C=C1NC2=CC=CN3C2=NN=C3C4=CCN(C5=NC=C(CC)C=N5)CC4)(=O)=O
CS(C(C=C1)=C(F)C=C1NC2=CC=CN3C2=NN=C3C4CCN(C5=NC(C(C)C)=NO5)CC4)(=O)=O
CS(C(C=C1)=C(F)C=C1NC2=CC=CN3C2=NN=C3C4CCN(C5=NC=C(C(C)C)C=N5)CC4)(=O)=O
CS(C(C=C1)=C(F)C=C1NC2=CC=CN3C2=NN=C3C4CCN(C5=NC=C(C(F)(F)F)C=N5)CC4)(=O)=O
CS(C(C=C1)=C(F)C=C1NC2=CC=CN3C2=NN=C3C4CCN(C5=NC=C(CC)C=N5)CC4)(=O)=O
CS(C(C=C1)=C(F)C=C1NC2=CC=CN3C2=NN=C3C4CCN(C5=NC=C(C1)C=N5)CC4)(=O)=O
CS(C(C=C1)=C(F)C=C1NC2=CC=NN3C2=NC=C3C4=CCN(C5=NC=C(CC)C=N5)CC4)(=O)=O
CS(C(C=C1)=C(F)C=C1NC2=CC=NN3C2=NC=C3C4CCN(C5=NC(C(C)C)=NO5)CC4)(=O)=O
CS(C(C=C1)=C(F)C=C1NC2=CC=NN3C2=NC=C3C4CCN(C5=NC=C(C(C)C)C=N5)CC4)(=O)=O
CS(C(C=C1)=C(F)C=C1NC2=CC=NN3C2=NC=C3C4CCN(C5=NC=C(C(F)(F)F)C=N5)CC4)(=O)=O
CS(C(C=C1)=C(F)C=C1NC2=CC=NN3C2=NC=C3C4CCN(C5=NC=C(CC)C=N5)CC4)(=O)=O
CS(C(C=C1)=C(F)C=C1NC2=CC=NN3C2=NC=C3C4CCN(C5=NC=C(C1)C=N5)CC4)(=O)=O
CS(C(C=C1)=C(F)C=C1NC2=CN=CN3C2=NC=C3C4=CCN(C5=NC=C(CC)C=N5)CC4)(=O)=O
CS(C(C=C1)=C(F)C=C1NC2=CN=CN3C2=NC=C3C4CCN(C5=NC(C(C)C)=NO5)CC4)(=O)=O
CS(C(C=C1)=C(F)C=C1NC2=CN=CN3C2=NC=C3C4CCN(C5=NC=C(C(C)C)C=N5)CC4)(=O)=O
CS(C(C=C1)=C(F)C=C1NC2=CN=CN3C2=NC=C3C4CCN(C5=NC=C(C(F)(F)F)C=N5)CC4)(=O)=O
CS(C(C=C1)=C(F)C=C1NC2=CN=CN3C2=NC=C3C4CCN(C5=NC=C(CC)C=N5)CC4)(=O)=O
CS(C(C=C1)=C(F)C=C1NC2=CN=CN3C2=NC=C3C4CCN(C5=NC=C(C1)C=N5)CC4)(=O)=O
CS(C(C=C1)=C(F)C=C1NC2=NC=CC(N2C=N3)=C3C4=CCN(C5=NC=C(CC)C=N5)CC4)(=O)=O
CS(C(C=C1)=C(F)C=C1NC2=NC=CC(N2C=N3)=C3C4CCN(C5=NC=C(CC)C=N5)CC4)(=O)=O
CS(C(C=C1)=C(F)C=C1NC2=NC=CN3C2=CN=C3C4=CCN(C5=NC=C(CC)C=N5)CC4)(=O)=O
CS(C(C=C1)=C(F)C=C1NC2=NC=CN3C2=CN=C3C4CCN(C5=NC(C(C)C)=NO5)CC4)(=O)=O
CS(C(C=C1)=C(F)C=C1NC2=NC=CN3C2=CN=C3C4CCN(C5=NC=C(C(C)C)C=N5)CC4)(=O)=O
CS(C(C=C1)=C(F)C=C1NC2=NC=CN3C2=CN=C3C4CCN(C5=NC=C(C(F)(F)F)C=N5)CC4)(=O)=O CS(C(C=C1)=C(F)C=C1NC2=NC=CN3C2=CN=C3C4CCN(C5=NC=C(CC)C=N5)CC4)(=O)=O
CS(C(C=C1)=C(F)C=C1NC2=NC=CN3C2=CN=C3C4CCN(C5=NC=C(C1)C=N5)CC4)(=O)=O
CS(C(C=C1)=C(F)C=C1NC2=NC=CN3C2=NC=C3C4=CCN(C5=NC=C(CC)C=N5)CC4)(=O)=O
CS(C(C=C1)=C(F)C=C1NC2=NC=CN3C2=NC=C3C4CCN(C5=NC(C(C)C)=NO5)CC4)(=O)=O
CS(C(C=C1)=C(F)C=C1NC2=NC=CN3C2=NC=C3C4CCN(C5=NC=C(C(C)C)C=N5)CC4)(=O)=O
CS(C(C=C1)=C(F)C=C1NC2=NC=CN3C2=NC=C3C4CCN(C5=NC=C(C(F)(F)F)C=N5)CC4)(=O)=O
CS(C(C=C1)=C(F)C=C1NC2=NC=CN3C2=NC=C3C4CCN(C5=NC=C(CC)C=N5)CC4)(=O)=O
CS(C(C=C1)=C(F)C=C1NC2=NC=CN3C2=NC=C3C4CCN(C5=NC=C(C1)C=N5)CC4)(=O)=O
CS(C(C=C1)=C(F)C=C1NC2=NC=CN3C2=NN=C3C4=CCN(C5=NC=C(CC)C=N5)CC4)(=O)=O
CS(C(C=C1)=C(F)C=C1NC2=NC=CN3C2=NN=C3C4CCN(C5=NC(C(C)C)=NO5)CC4)(=O)=O
CS(C(C=C1)=C(F)C=C1NC2=NC=CN3C2=NN=C3C4CCN(C5=NC=C(C(C)C)C=N5)CC4)(=O)=O
CS(C(C=C1)=C(F)C=C1NC2=NC=CN3C2=NN=C3C4CCN(C5=NC=C(C(F)(F)F)C=N5)CC4)(=O)=O
CS(C(C=C1)=C(F)C=C1NC2=NC=CN3C2=NN=C3C4CCN(C5=NC=C(CC)C=N5)CC4)(=O)=O
CS(C(C=C1)=C(F)C=C1NC2=NC=CN3C2=NN=C3C4CCN(C5=NC=C(C1)C=N5)CC4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=CC=CN3C2=NC=C3C4=CCN(C5=NC=C(CC)C=N5)CC4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=CC=CN3C2=NC=C3C4CCN(C5=NC(C(C)C)=NO5)CC4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=CC=CN3C2=NC=C3C4CCN(C5=NC=C(C(C)C)C=N5)CC4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=CC=CN3C2=NC=C3C4CCN(C5=NC=C(C(F)(F)F)C=N5)CC4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=CC=CN3C2=NC=C3C4CCN(C5=NC=C(CC)C=N5)CC4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=CC=CN3C2=NC=C3C4CCN(C5=NC=C(C1)C=N5)CC4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=CC=CN3C2=NN=C3C4=CCN(C5=NC=C(CC)C=N5)CC4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=CC=CN3C2=NN=C3C4CCN(C5=NC(C(C)C)=NO5)CC4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=CC=CN3C2=NN=C3C4CCN(C5=NC=C(C(C)C)C=N5)CC4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=CC=CN3C2=NN=C3C4CCN(C5=NC=C(C(F)(F)F)C=N5)CC4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=CC=CN3C2=NN=C3C4CCN(C5=NC=C(CC)C=N5)CC4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=CC=CN3C2=NN=C3C4CCN(C5=NC=C(C1)C=N5)CC4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=CC=NN3C2=NC=C3C4=CCN(C5=NC=C(CC)C=N5)CC4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=CC=NN3C2=NC=C3C4CCN(C5=NC(C(C)C)=NO5)CC4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=CC=NN3C2=NC=C3C4CCN(C5=NC=C(C(C)C)C=N5)CC4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=CC=NN3C2=NC=C3C4CCN(C5=NC=C(C(F)(F)F)C=N5)CC4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=CC=NN3C2=NC=C3C4CCN(C5=NC=C(CC)C=N5)CC4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=CC=NN3C2=NC=C3C4CCN(C5=NC=C(C1)C=N5)CC4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=CN=CN3C2=NC=C3C4=CCN(C5=NC=C(CC)C=N5)CC4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=CN=CN3C2=NC=C3C4CCN(C5=NC(C(C)C)=NO5)CC4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=CN=CN3C2=NC=C3C4CCN(C5=NC=C(C(C)C)C=N5)CC4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=CN=CN3C2=NC=C3C4CCN(C5=NC=C(C(F)(F)F)C=N5)CC4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=CN=CN3C2=NC=C3C4CCN(C5=NC=C(CC)C=N5)CC4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=CN=CN3C2=NC=C3C4CCN(C5=NC=C(C1)C=N5)CC4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=NC=CN3C2=CN=C3C4=CCN(C5=NC=C(CC)C=N5)CC4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=NC=CN3C2=CN=C3C4CCN(C5=NC(C(C)C)=NO5)CC4)(=O)=O CS(C(C=C1)=NC(C)=C1NC2=NC=CN3C2=CN=C3C4CCN(C5=NC=C(C(C)C)C=N5)CC4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=NC=CN3C2=CN=C3C4CCN(C5=NC=C(C(F)(F)F)C=N5)CC4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=NC=CN3C2=CN=C3C4CCN(C5=NC=C(CC)C=N5)CC4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=NC=CN3C2=CN=C3C4CCN(C5=NC=C(C1)C=N5)CC4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=NC=CN3C2=NC=C3C(CCN(C4=NC=C(CC)C=N4)C5)C5=O)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=NC=CN3C2=NC=C3C4(O)C(C)(C)CN(C5=NC=C(CC)C=N5)CC4)(=O)
=O
CS(C(C=C1)=NC(C)=C1NC2=NC=CN3C2=NC=C3C4(O)C(C)CN(C5=NC=C(CC)C=N5)CC4C)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=NC=CN3C2=NC=C3C4(O)CC(C)N(C5=NC=C(CC)C=N5)C(C)C4)(=O)
=o
CS(C(C=C1)=NC(C)=C1NC2=NC=CN3C2=NC=C3C4(O)CCN(C5=NC=C(CC)C=N5)CC4)(=O)=O CS(C(C=C1)=NC(C)=C1NC2=NC=CN3C2=NC=C3C4=CCN(C5=NC=C(CC)C=N5)CC4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=NC=CN3C2=NC=C3C4C(C)(C)CN(C5=NC=C(CC)C=N5)CC4(C)C)(=O)
=o
CS(C(C=C1)=NC(C)=C1NC2=NC=CN3C2=NC=C3C4C(C)(C)CN(C5=NC=C(CC)C=N5)CC4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=NC=CN3C2=NC=C3C4C(C)C(C)N(C5=NC=C(CC)C=N5)C(C)C4C)(=O)
=o
CS(C(C=C1)=NC(C)=C1NC2=NC=CN3C2=NC=C3C4C(C)C(C)N(C5=NC=C(CC)C=N5)CC4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=NC=CN3C2=NC=C3C4C(C)CN(C5=NC=C(CC)C=N5)C(C)C4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=NC=CN3C2=NC=C3C4C(C)CN(C5=NC=C(CC)C=N5)CC4=O)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=NC=CN3C2=NC=C3C4C(C)CN(C5=NC=C(CC)C=N5)CC4C)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=NC=CN3C2=NC=C3C4CC(C)N(C5=NC=C(CC)C=N5)C(C)C4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=NC=CN3C2=NC=C3C4CCN(C5=NC(C(C)C)=NO5)CC4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=NC=CN3C2=NC=C3C4CCN(C5=NC=C(C(C)C)C=N5)CC4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=NC=CN3C2=NC=C3C4CCN(C5=NC=C(C(F)(F)F)C=N5)CC4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=NC=CN3C2=NC=C3C4CCN(C5=NC=C(CC)C=N5)C(C)C4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=NC=CN3C2=NC=C3C4CCN(C5=NC=C(CC)C=N5)CC4(C)C)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=NC=CN3C2=NC=C3C4CCN(C5=NC=C(CC)C=N5)CC4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=NC=CN3C2=NC=C3C4CCN(C5=NC=C(CC)C=N5)CC4C)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=NC=CN3C2=NC=C3C4CCN(C5=NC=C(CC)C=N5)CC4O)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=NC=CN3C2=NC=C3C4CCN(C5=NC=C(C1)C=N5)CC4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=NC=CN3C2=NC=C3N(CCN(C4=NC=C(CC)C=N4)C5)C5=O)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=NC=CN3C2=NN=C3C4=CCN(C5=NC=C(CC)C=N5)CC4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=NC=CN3C2=NN=C3C4CCN(C5=NC(C(C)C)=NO5)CC4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=NC=CN3C2=NN=C3C4CCN(C5=NC=C(C(C)C)C=N5)CC4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=NC=CN3C2=NN=C3C4CCN(C5=NC=C(C(F)(F)F)C=N5)CC4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=NC=CN3C2=NN=C3C4CCN(C5=NC=C(CC)C=N5)CC4)(=O)=O
CS(C(C=C1)=NC(C)=C1NC2=NC=CN3C2=NN=C3C4CCN(C5=NC=C(C1)C=N5)CC4)(=O)=O
FC(C=C(N1C=NN=N1)C=C2)=C2NC3=CC=CN4C3=NC=C4C5CCN(C6=NC=C(C(F)(F)F)C=N6)CC5
FC(C=C(N1C=NN=N1)C=C2)=C2NC3=CC=NN4C3=NC=C4C5CCN(C6=NC=C(C(F)(F)F)C=N6)CC5 FC(C=C(N1C=NN=N1)C=C2)=C2NC3=CN=CN4C3=NC=C4C5CCN(C6=NC=C(C(F)(F)F)C=N6)CC5
FC(C=C(N1C=NN=N1)C=C2)=C2NC3=NC=CC(N3C=N4)=C4C5=CCN(C6=NC=C(CC)C=N6)CC5
FC(C=C(N1C=NN=N1)C=C2)=C2NC3=NC=CC(N3C=N4)=C4C5CCN(C6=NC=C(CC)C=N6)CC5
FC(C=C(N1C=NN=N1)C=C2)=C2NC3=NC=CN4C3=CN=C4C5CCN(C6=NC=C(C(F)(F)F)C=N6)CC5
FC(C=C(N1C=NN=N1)C=C2)=C2NC3=NC=CN4C3=NC=C4C5CCN(C6=NC=C(C(F)(F)F)C=N6)CC5
FC(C=C(N1C=NN=N1)C=C2)=C2NC3=NC=CN4C3=NN=C4C5CCN(C6=NC=C(C(F)(F)F)C=N6)CC5
FC(C=C(S(=O)(C)=O)C=C1)=C1NC2=CC=NC(N2C=C3)=C3C4CCN(C(OC(C)(C)C)=O)CC4
FC(C=C(S(=O)(C)=O)C=C1)=C1NC2=NC=CC(N2C=C3)=C3C4CCN(C(OC(C)(C)C)=O)CC4
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=CN3C2=CC=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=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=NN3C2=CC=C3C4CCN(C(OC(C)C)=O)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=CC=CN3C2=NC=C3C4=CCN(C5=NC=C(CC)C=N5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=CC=CN3C2=NC=C3C4CCN(C(OC(C)(C)C)=O)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=CC=CN3C2=NC=C3C4CCN(C(OC(C)C)=O)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=CC=CN3C2=NC=C3C4CCN(C5=NC(C(C)C)=NO5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=CC=CN3C2=NC=C3C4CCN(C5=NC=C(C(C)C)C=N5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=CC=CN3C2=NC=C3C4CCN(C5=NC=C(C(F)(F)F)C=N5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=CC=CN3C2=NC=C3C4CCN(C5=NC=C(CC)C=N5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=CC=CN3C2=NC=C3C4CCN(C5=NC=C(C1)C=N5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=CC=CN3C2=NN=C3C4=CCN(C(OC(C)C)=O)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=CC=CN3C2=NN=C3C4=CCN(C5=NC=C(CC)C=N5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=CC=CN3C2=NN=C3C4CCN(C5=NC(C(C)C)=NO5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=CC=CN3C2=NN=C3C4CCN(C5=NC=C(C(C)C)C=N5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=CC=CN3C2=NN=C3C4CCN(C5=NC=C(C(F)(F)F)C=N5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=CC=CN3C2=NN=C3C4CCN(C5=NC=C(CC)C=N5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=CC=CN3C2=NN=C3C4CCN(C5=NC=C(C1)C=N5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=CC=NC(N2C=C3)=C3C4CCN(C(OC(C)(C)C)=O)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=CC=NC(N2C=C3)=C3C4CCN(C5=NC=C(CC)C=N5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=CC=NN3C2=CC=C3C4CCN(C(OCCCC)=O)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=CC=NN3C2=CC=C3C4CCN(C5=NC=C(CC)C=N5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=CC=NN3C2=NC=C3C4=CCN(C(OC(C)C)=O)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=CC=NN3C2=NC=C3C4=CCN(C5=NC=C(CC)C=N5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=CC=NN3C2=NC=C3C4CCN(C5=NC(C(C)C)=NO5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=CC=NN3C2=NC=C3C4CCN(C5=NC=C(C(C)C)C=N5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=CC=NN3C2=NC=C3C4CCN(C5=NC=C(C(F)(F)F)C=N5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=CC=NN3C2=NC=C3C4CCN(C5=NC=C(CC)C=N5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=CC=NN3C2=NC=C3C4CCN(C5=NC=C(C1)C=N5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=CN=CN3C2=NC=C3C4=CCN(C(OC(C)C)=O)CC4 FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=CN=CN3C2=NC=C3C4=CCN(C5=NC=C(CC)C=N5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=CN=CN3C2=NC=C3C4CCN(C5=NC(C(C)C)=NO5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=CN=CN3C2=NC=C3C4CCN(C5=NC=C(C(C)C)C=N5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=CN=CN3C2=NC=C3C4CCN(C5=NC=C(C(F)(F)F)C=N5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=CN=CN3C2=NC=C3C4CCN(C5=NC=C(CC)C=N5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=CN=CN3C2=NC=C3C4CCN(C5=NC=C(C1)C=N5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CC(N2C=C3)=C3C4CCN(C(NCC)=O)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CC(N2C=N3)=C3C4=CCN(C(OC(C)C)=O)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CC(N2C=N3)=C3C4=CCN(C5=NC=C(CC)C=N5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CC(N2C=N3)=C3C4CCN(C5=NC=C(CC)C=N5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CC(N2C=N3)=C3N4CCN(C(OCCCC(C)C)=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=CC(N2N=C3)=C3C4CCN(C5=NC=C(CC)C=N5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=CN=C3C4=CCN(C(OC(C)C)=O)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=CN=C3C4=CCN(C5=NC=C(CC)C=N5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=CN=C3C4CCC(C(OCCOC)=O)CC4
FC(C=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=CN3C2=CN=C3C4CCN(C5=NC(C(C)C)=NO5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=CN=C3C4CCN(C5=NC=C(C(C)C)C=N5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=CN=C3C4CCN(C5=NC=C(C(F)(F)F)C=N5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=CN=C3C4CCN(C5=NC=C(CC)C=N5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=CN=C3C4CCN(C5=NC=C(C1)C=N5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=CN=C3C4CN(C(OCCN(C)C)=O)C4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=CN=C3N4CCC(C(OC(C)C)=O)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=CN=C3N4CCN(C(OC(CC)CC)=O)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=NC=C3C4C(C)CN(C(OC(C)(C)C)=O)CC4C
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=NC=C3C4C(C)CN(C5=NC=C(CC)C=N5)CC4C
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=NC=C3C4C5CN(C(OC(C)C)=O)CC4C5
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=NC=C3C4C5CN(C(OCCC6=CC=CN=C6)=O)CC4
CC5
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=NC=C3C4CC5N(C(OC(C)C)=O)C(C5)C4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=NC=C3C4CC5N(C(OCC6=CC=CC=C6)=O)C(CC5)
C4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=NC=C3C4CCC(C(NC(C)(C)C)=O)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=NC=C3C4CCC(C(NCC(O)CO)=O)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=NC=C3C4CCC(C(OC5CCCC5)=O)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=NC=C3C4CCN(C(NC(C)C)=O)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=NC=C3C4CCN(C(NCC5=CC=CN=C5)=O)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=NC=C3C4CCN(C5=NC(C(C)C)=NO5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=NC=C3C4CCN(C5=NC=C(C(C)C)C=N5)CC4 FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=NC=C3C4CCN(C5=NC=C(C(F)(F)F)C=N5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=NC=C3C4CCN(C5=NC=C(CC)C=N5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=NC=C3C4CCN(C5=NC=C(C1)C=N5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=NC=C3N4C5CN(C(OC(C)C)=O)CC4CC5
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=NC=C3NC4CCN(C(NC(C)C)=O)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=NC=C3NC4CCN(C5=NC=C(C1)C=N5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=NN=C3C4=CCN(C(OC(C)C)=O)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=NN=C3C4=CCN(C5=NC=C(CC)C=N5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=NN=C3C4CCN(C(OC(C)C)=O)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=NN=C3C4CCN(C5=NC(C(C)C)=NO5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=NN=C3C4CCN(C5=NC=C(C(C)C)C=N5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=NN=C3C4CCN(C5=NC=C(C(F)(F)F)C=N5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=NN=C3C4CCN(C5=NC=C(CC)C=N5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=NN=C3C4CCN(C5=NC=C(C1)C=N5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=CN3C2=NN=C3N4CCC(C(OC(C)(C)C)=O)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=NC(N2C=C3)=C3C4CCN(C(OCCCC)=O)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=NC(N2C=C3)=C3C4CCN(C5=NC=C(CC)C=N5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=NC(N2C=N3)=C3N4CCN(C(OC5CC5)=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)(=O)=O)C=C1)=C1NC2=NC=NC(N2N=C3)=C3C4CCN(C5=NC=C(CC)C=N5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=NN3C2=CC=C3C4CCN(C(OC(C)C)=O)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1NC2=NC=NN3C2=CC=C3C4CCN(C5=NC=C(CC)C=N5)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)(=O)=O)C=C1)=C1NC2=NC=NN3C2=NC=C3C4CCN(C5=NC=C(CC)C=N5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1OC2=NC=CN3C2=NC(CC)=C3C4CCN(C(OCC)=O)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1OC2=NC=CN3C2=NC(CC)=C3C4CCN(C5=NC=C(CC)C=N5)CC4
FC(C=C(S(C)(=O)=O)C=C1)=C1OC2=NC=CN3C2=NC=C3C4=CCN(C5=NC=C(CC)C=N5)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(NC3=CC=CN4C3=NC=C4C5CCN(C6=NC=C(C(F)(F)F)C=N6)CC5)=C1
FC1=C(N2C=NN=N2)C=CC(NC3=CC=NN4C3=NC=C4C5CCN(C6=NC=C(C(F)(F)F)C=N6)CC5)=C1
FC1=C(N2C=NN=N2)C=CC(NC3=CN=CN4C3=NC=C4C5CCN(C6=NC=C(C(F)(F)F)C=N6)CC5)=C1
FC1=C(N2C=NN=N2)C=CC(NC3=NC=CN4C3=CN=C4C5CCN(C6=NC=C(C(F)(F)F)C=N6)CC5)=C1
FC1=C(N2C=NN=N2)C=CC(NC3=NC=CN4C3=NC=C4C5CCN(C6=NC=C(C(F)(F)F)C=N6)CC5)=C1
FC1=C(N2C=NN=N2)C=CC(NC3=NC=CN4C3=NN=C4C5CCN(C6=NC=C(C(F)(F)F)C=N6)CC5)=C1
FC1=C(N2C=NN=N2)C=CC(OCC3=NC=CN4C3=NC=C4C5=CCN(C(OC(C)(C)C)=O)CC5)=C1
FC1=C(NC2=CC=NN3C2=CC=C3C4CCN(C(OC(C)(C)C)=O)CC4)C=CC(S(=O)(C)=O)=C1
O=C(OC(C)(C)C)N(CC1)CC=C1C2=C3C=CN=C(NC4=CC(F)=C(S(C)(=O)=O)C=C4)N3C=N2
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)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)CC=C1C2=CN=C3N2C=NC=C3NC4=C(F)C=C(N5C=NN=N5)C=C4 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(N5C=NN=N5)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)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)CC=C1C2=NC=C3N2C=CN=C3NC4=C(C)N=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)CC=C1C2=NC=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(S(C)(=O)=O)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=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)CC=C1C2=NN=C3N2C=CN=C3NC4=CC(F)=C(S(C)(=O)=O)C=C4
O=C(OC(C)(C)C)N(CC1)CCC1C2=CN=C3N2C=CC=C3NC4=C(C)N=C(N5C=NC=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)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(C)N=C(N5C=NC=N5)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=C(F)C=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
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=C3N2C=NC=C3NC4=C(C)N=C(N5C=NN=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=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=CC(F)=C(S(C)(=O)=O)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=NN=C3N2C=CN=C3NC4=C(C)N=C(N5C=NC=N5)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)CCC1C2=NN=C3N2C=CN=C3NC4=CC(F)=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)N(CC1)CC=C1C2=CN=C3N2C=CC=C3NC4=C(C)N=C(N5C=NN=N5)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)CC=C1C2=CN=C3N2C=CN=C3NC4=C(C)N=C(N5C=NN=N5)C=C4
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)CC=C1C2=CN=C3N2C=CN=C3NC4=CC(F)=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=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)CC=C1C2=NN=C3N2C=CN=C3NC4=C(C)N=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)CCC1C2=CN=C3N2C=CC=C3NC4=C(C)N=C(S(C)(=O)=O)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)CCC1C2=CN=C3N2C=CC=C3NC4=CC(F)=C(S(C)(=O)=O)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)N(CC1)CCC1C2=CN=C3N2C=CN=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)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=C3N2C=NC=C3NC4=CC(F)=C(N5C=NN=N5)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)N(CC1)CCC1C2=CN=C3N2N=CC=C3NC4=C(F)C=C(N5C=NN=N5)C=C4
O=C(OC(C)C)N(CC1)CCC1C2=CN=C3N2N=CN=C3NC4=C(F)C=C(S(=O)(C)=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=NN=C3N2C=CC=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
[0398] The activity of the compounds in Examples 1-55 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:
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 Fugeneό (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 cAMP 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 37°C 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.
Table 1. Biological Activity
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
[0399] 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 compound Formula V
Figure imgf000128_0001
(V) or a salt, ester, or prodrug thereof, wherein: the dashed line indicated an additional bond which may be present or absent;
X1, X2, X3, X4, X5, Xe, and X7 are independently chosen from CH, C, and N;
Q2 is chosen from C, CH, and N;
Q3 is chosen from CRi, CH, and N;
Z is chosen from hydrogen, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and -CO2Rn;
W is chosen from O and NH; m and q are independently an integer from 0 to 4; each Ri and R4 is independently chosen from hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, amido, amino, aryl, aryloxy, carbamate, carboxy, cyano, cycloalkyl, halogen, heteroalkyl, heteroaryl, heterocycloalkyl, hydroxyl, nitro, perhaloalkoxy, perhaloalkyl, sulfonyl and sulfonamide, any of which may be optionally substituted; and
Rn is chosen from alkyl, alkenyl, and alkynyl, any of which may be optionally substituted.
2. The compound as recited in claim 1, wherein Z is chosen from optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and -CO2Rn.
3. The compound as recited in claim 2, wherein between two and four of X1, X2, X3, X4, Xs, Xe, and X7 are N.
4. The compound as recited in claim 3, wherein said optionally substituted groups are substituted with between 0 and 4 substituents each independently chosen from 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, phenyloxy, 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 perhaloalkyl thio, arylthio, sulfonate, sulfonic acid, SH, SCH3, C(O)CH3, lower carbamate, and lower urea.
5. The compound as recited in claim 4, wherein Q2 is chosen from C and CH.
6. The compound as recited in claim 5, wherein each Ri and R4 is independently chosen from hydrogen, lower acyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower alkoxyalkyl, lower amido, lower amino, cyano, lower cycloalkyl, lower heterocycloalkyl, phenyl, lower phenylalkyl, lower meteroaryl, halogen, lower heteroalkyl, hydroxyl, nitro, lower perhaloalkoxy, lower perhaloalkyl, lower sulfonyl, and lower sulfonamide, any of which may be optionally substituted; and
Rn is chosen from lower alkyl, lower alkenyl, and lower alkynyl, any of which may be optionally substituted.
7. The compound as recited in claim 6, wherein m and q are independently an integer from 0 to 2.
8. The compound as recited in claim 7, wherein each Ri and R4 is independently chosen from lower alkyl, lower alkoxy, cyano, halogen, hydroxyl, nitro, perfluoromethoxy, perfluoromethyl, lower sulfonyl, and lower sulfonamide.
9. The compound as recited in claim 8, wherein m and q are independently an integer from 0 to 2.
10. The compound as recited in claim 9, wherein each Ri lower alkyl.
11. The compound as recited in claim 9, wherein q is 0.
12. The compound as recited in claim 9, wherein m is an integer from 1 to 2.
13. The compound as recited in claim 12, wherein each R4 is independently chosen from methyl, halogen, and methylsulfonyl.
14. The compound as recited in claim 12, wherein Z is chosen from optionally substituted optionally substituted heteroaryl and -CO2R17.
15. The compound as recited in claim 14, wherein Z is substituted with a substituent chosen from lower alkyl, lower haloalkyl, lower cycloalkyl, lower alkoxy, lower haloalkoxy, cyano, and halogen.
16. The compound as recited in claim 14, wherein Z is lower heteroaryl, which may be optionally substituted.
17. The compound as recited in claim 16, wherein Z is a six-membered heteroaryl, which may be optionally substituted.
18. The compound as recited in claim 17, wherein Z is an optionally substituted six- membered heteroaryl containing between 1 and 2 nitrogens.
19. The compound as recited in claim 16, wherein Z is chosen from pyrimidine and oxadiazole, either of which may be optionally substituted.
20. The compound as recited in claim 14, wherein Z is -CO2R17.
21. The compound as recited in claim 20, wherein R]7 is optionally substituted lower alkyl.
22. The compound as recited in claim 21, wherein R17 is lower alkyl.
23. The compound as recited in claim 14, wherein Q3 is N.
24. The compound as recited in claim 14, wherein Q3 is CH.
25. The compound as recited in claim 14, wherein W is NH.
26. The compound as recited in claim 14, wherein W is O.
27. The compound as recited in claim 14, wherein:
X1, X4, and X6 are each nitrogen; and X2, X3, X5, and X7 are each CH.
28. The compound as recited in claim #, wherein:
X1, X4, X5, and X6 are each nitrogen; and X2, X3, and X7 are each CH.
29. The compound as recited in claim 14, wherein: X1, X5, and X7 are each nitrogen; and
X2, X3, X4, and X6 are each CH.
30. The compound as recited in claim 14, wherein: X1, X4, and X5 are each nitrogen; and X2, X3, Xδ, and X7 are each CH.
31. The compound as recited in claim 14, wherein: X4 and Xe are each nitrogen; and
Xi, X2, X3, Xs, and X7 are each CH.
32. The compound as recited in claim 14, wherein: X4, X5, and X6 are each nitrogen; and
X1, X2, X3, and X7 are each CH.
33. The compound as recited in claim 14, wherein: X2, X4, and X6 are each nitrogen; and
Xi, X3, X5, and X7 are each CH.
34. .A compound chosen from Examples 1 to 55.
35. A compound as recited in Claim 1 for use as a medicament.
36. A compound as recited in Claim 1 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.
37. A pharmaceutical composition comprising a compound as recited in Claim 1 together with a pharmaceutically acceptable carrier.
38. A pharmaceutical composition comprising at least one compound chosen from those recited in Examples 1 to 55 together with a pharmaceutically acceptable carrier.
39. The pharmaceutical composition as recited in Claim 37, useful for the treatment or prevention of a GPRl 19-mediated disease.
40. A method of modulating GPRl 19 comprising contacting GPRl 19 with a compound as recited in Claim 1.
41. A method of treatment of a GPRl 19-mediated disease comprising the administration of a therapeutically effective amount of a compound as recited in Claim 1 to a patient in need thereof.
42. The method as recited in Claim 41 wherein said disease is a metabolic disease.
43. The method as recited in Claim 42 wherein said disease is diabetes.
44. A method of treatment of a GPRl 19-mediated disease comprising the administration of: a. a therapeutically effective amount of a compound as recited in Claim 1 ; and b. another therapeutic agent.
45. The method as recited in Claim 44, 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- 1, JTT-705, cholestyramine, colestipol, niacin, implitapide, (7?)-l-{4-[5-methyl- 2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonyl}2,3- dihydro-lH-indole-2-carboxylic acid, and GI-262570.
46. A method for achieving an effect in a patient comprising the administration of a therapeutically effective amount of a compound as recited in Claim 1 to a patient, wherein the effect is GLP-I secretion, lowering of blood glucose, improve glucose tolerance, decrease in insulin resistance, improvement in glucose-stimulated insulin secretion, preservation or restoration of pancreatic β- cell function, increased antihyperglycemic efficacy, weight loss, lowering of triglycerides, lowering of LDL, increase of HD L, lowering of blood pressure, and inhibition of bone resorption.
47. The method as recited in claim 46 wherein said effect is improvement in glucose-stimulated insulin secretion without hypoglycemia.
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