Classifications

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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
  • C07D213/52—Sulfur atoms
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/62—Oxygen or sulfur atoms
  • C07D213/70—Sulfur atoms
  • C07D213/71—Sulfur atoms to which a second hetero atom is attached
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/72—Nitrogen atoms
  • C07D213/73—Unsubstituted amino or imino radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
  • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
  • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
  • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present invention relates to sulfonyl compounds, or pharmaceutically acceptable salts thereof, as defined herein, that interact with glucokinase regulatory protein.
• the present invention relates to methods of treating type 2 diabetes, and other diseases and/or conditions where glucokinase regulatory protein is involved using the compounds, or the pharmaceutically acceptable salts thereof, and pharmaceutical compositions that contain the compounds, or pharmaceutically acceptable salts thereof.
• Glucokinase is a member of a family of four hexokinases that are critical in the cellular metabolism of glucose. Specifically GK, also known as hexokinase IV or hexokinase D, facilitates glucose induced insulin secretion from pancreatic ⁇ -cells as well as glucose conversion into glycogen in the liver. GK has a unique catalytic activity that enables the enzyme to be active within the physiological range of glucose (from 5mM glucose to lOmM glucose).
• mice lacking both copies of the GK gene die soon after birth from severe hyperglycemia, whereas mice lacking only one copy of the GK gene present with only mild diabetes. Mice that are made to overexpress the GK gene in their livers are hypoglycemic.
• GK activity in the liver is transiently regulated by glucokinase regulatory protein (GK P).
• GK catalytic activity is inhibited when GK is bound to GKRP. This interaction is antagonized by increasing concentrations of both glucose and fructose -1 -phosphate (F1P).
• the complex of the two proteins is localized primarily to the nuclear compartment of a cell. Post prandially as both glucose and fructose levels rise, GK released from GKRP translocates to the cytoplasm. Cytoplasmic GK is now free of the inhibitory effects of GKRP and able to kinetically respond to glucose. Evidence from the Zucker diabetic fatty rat (ZDF) indicates that their glucose intolerance may be a result of this mechanism failing to function properly.
• ZDF Zucker diabetic fatty rat
• a compound that acts directly on GKRP to disrupt its interaction with GK and hence elevate levels of cytoplasmic GK is a viable approach to modulate GK activity. Such an approach would avoid the unwanted hypoglycemic effects of over stimulation of GK catalytic activity, which has been seen in the
• GK activators A compound having such an effect would be useful in the treatment of diabetes and other diseases and/or conditions in which GKRP and/or GK plays a role.
• the present invention provides compounds that bind GKRP and disrupts its interaction with GK.
• the present invention provides compounds, or pharmaceutically acceptable salts thereof, selected from:
• the present invention provides methods of treating type 2 diabetes, hyperglycemia, impaired glucose tolerance, insulin resistance, retinopathy, nephropathy, neuropathy, cataracts, glaucoma, Syndrome X, or polycystic ovarian syndrome, the methods comprising administering to a patient in need thereof a therapeutically effective amount of a compound in accordance with embodiment 1 , or a pharmaceutically acceptable salt thereof.
• the present invention provides methods of treating in accordance with embodiment 2 wherein the treatment is for type 2 diabetes.
• the present invention provides pharmaceutical compositions comprising a compound in accordance with embodiment 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
• the present invention provides sulfonyl compounds, as defined above, or pharmaceutically acceptable salts thereof.
• the present invention also provides pharmaceutical compositions comprising a compound of the present invention, or pharmaceutically acceptable salts thereof, and methods of treating diseases and/or conditions, such as diabetes, using compounds of the present invention, or pharmaceutically acceptable salts thereof.
• alkyl means a straight or branched chain hydrocarbon.
• alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl and hexyl.
• Typical alkyl groups are alkyl groups having from 1 to 8 carbon atoms, which groups are commonly represented as Ci- 8 alkyl.
• alkoxy means an alkyl group bonded to an oxygen atom.
• Representative examples of alkoxy groups include methoxy, ethoxy, tert-butoxy, propoxy and isobutoxy. Common alkoxy groups are Ci-galkoxy.
• alkenyl means a branched or straight chain hydrocarbon having one or more carbon-carbon double bonds. Representative examples alkenyl groups include ethenyl, propenyl, allyl, butenyl and 4-methylbutenyl. Common alkenyl groups are C 2 - 8 alkenyl.
• alkynyl means a branched or straight chain hydrocarbon having one or more carbon-carbon triple bonds.
• Representative examples of alkynyl groups include ethynyl, propynyl (propargyl) and butynyl.
• Common alkynyl groups are C 2 - 8 alkynyl.
• cycloalkyl means a cyclic, nonaromatic hydrocarbon.
• cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
• a cycloalkyl group can contain one or more double bond.
• Examples of cycloalkyl groups that contain double bonds include cyclopentenyl, cyclohexenyl, cyclohexadienyl and cyclobutadienyl.
• Common cycloalkyl groups are C3-8 cycloalkyl groups.
• perfluoroalkyl means an alkyl group in which all of the hydrogen atoms have been replaced with fluorine atoms.
• perfluoroalkyl groups are Ci-sperfluoroalkyl.
• An example of a common perfluoroalkyl group is CF 3 .
• acyl means a group derived from an organic acid by removal of the hydroxy group (-OH).
• aryl means a cyclic, aromatic hydrocarbon. Examples of aryl groups include phenyl and naphthyl. Common aryl groups are six to thirteen membered rings.
• heteroatom as used herein means an oxygen, nitrogen or sulfur atom.
• heteroaryl means a cyclic, aromatic hydrocarbon in which one or more carbon atoms of an aryl group have been replaced with a heteroatom. If the heteroaryl group contains more than one heteroatom, the heteroatoms may be the same or different. Examples of heteroaryl groups include pyridyl, pyrimidinyl, imidazolyl, thienyl, furyl, pyrazinyl, pyrrolyl, indolyl, triazolyl, pyridazinyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl,
• heterocycloalkyl means a cycloalkyl group in which one or more of the carbon atoms has been replaced with a heteroatom.
• heterocycloalkyl group contains more than one heteroatom, the heteroatoms may be the same or different.
• heterocycloalkyl groups include tetrahydrofuryl, morpholinyl, piperazinyl, piperidinyl and pyrrolidinyl. It is also possible for the heterocycloalkyl group to have one or more double bonds, but is not aromatic. Examples of heterocycloalkyl groups containing double bonds include dihydrofuran.
• Common heterocycloalkyl groups are three to ten membered rings containing from 1 to 4 heteroatoms. Heterocycloalkyl groups that are five and six membered rings that contain 1 to 2 heterotaoms are particularly common.
• cyclic ring groups i.e., aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, can comprise more than one ring.
• the naphthyl group is a fused bicyclic ring system.
• the present invention include ring groups that have bridging atoms, or ring groups that have a spiro orientation.
• Representative examples of five to six membered aromatic rings, optionally having one or two heteroatoms, are phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyridiazinyl, pyrimidinyl, and pyrazinyl.
• Representative examples of partially saturated, fully saturated or fully unsaturated five to eight membered rings, optionally having one to three heteroatoms are cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and phenyl.
• FIG. 1 Further exemplary five membered rings are furyl, thienyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl, oxazolyl, thiazolyl, imidazolyl, 2H- imidazolyl, 2-imidazolinyl, imidazolidinyl, pyrazolyl, 2-pyrazolinyl,
• FIG. 1 For exemplary six membered rings are 2H-pyranyl, 4H-pyranyl, pyridinyl, piperidinyl, 1 ,2-dioxinyl, 1,3-dioxinyl, 1 ,4-dioxanyl, morpholinyl, 1,4- dithianyl, thiomorpholinyl, pyndazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-trithianyl, 4H-l,2-oxazinyl, 2H-l,3-oxazinyl, 6H-l,3-oxazinyl, 6H-l,2-oxazinyl, 1 ,4-oxazinyl, 2H-1,2- oxazinyl, 4H-l,4-oxazinyl
• exemplary seven membered rings are azepinyl, oxepinyl, thiepinyl and 1,2,4-triazepinyl.
• FIG. 1 Further exemplary eight membered rings are cyclooctyl, cyclooctenyl and cyclooctadienyl.
• Exemplary bicyclic rings consisting of two fused partially saturated, fully saturated or fully unsaturated five and/or six membered rings, optionally having one to four heteroatoms, are indolizinyl, indolyl, isoindolyl, indolinyl, cyclopenta(b)pyridinyl, pyrano(3,4-b)pyrrolyl, benzofuryl, isobenzo furyl, benzo(b)thienyl, benzo(c)thienyl, lH-indazolyl, indoxazinyl, benzoxazolyl, anthranilyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, indenyl, is
• a cyclic ring group may be bonded to another group in more than one way. If no particular bonding arrangement is specified, then all possible arrangements are intended.
• pyridyl includes 2-, 3-, or 4- pyridyl
• thienyl includes 2-, or 3-thienyl.
• substituted means that a hydrogen atom on a molecule or group is replaced with a group or atom.
• a group or atom that replaces a hydrogen atom is also called a substituent.
• Any particular molecule or group can have one or more substituent depending on the number of hydrogen atoms that can be replaced.
• the symbol "-" represents a covalent bond and can also be used in a radical group to indicate the point of attachment to another group. In chemical structures, the symbol is commonly used to represent a methyl group in a molecule.
• terapéuticaally effective amount means an amount of a compound that ameliorates, attenuates or eliminates one or more symptom of a particular disease or condition, or prevents or delays the onset of one of more symptom of a particular disease or condition.
• patient means animals, such as dogs, cats, cows, horses, sheep and humans. Particular patients are mammals.
• patient includes males and females.
• pharmaceutically acceptable means that the referenced substance, such as a compound of the present invention or a formulation containing a compound of the present invention, or a particular excipent, are suitable for administration to a patient.
• treating include preventative (e.g., prophylactic) and palliative treatment.
• patient in need thereof means a patient who has or is at risk of having a GKRP/GK mediated disease or condition, such as type 2 diabetes.
• excipient means any pharmaceutically acceptable additive, carrier, diluent, adjuvant, or other ingredient, other than the active pharmaceutical ingredient (API), which is typically included for formulation and/or
• the compounds of the present invention are administered to a patient in a therapeutically effective amount.
• the compounds can be administered alone or as part of a pharmaceutically acceptable composition or formulation.
• the compounds or compositions can be administered all at once, as for example, by a bolus injection, multiple times, such as by a series of tablets, or delivered substantially uniformly over a period of time, as for example, using transdermal delivery. It is also noted that the dose of the compound can be varied over time.
• the compounds of the present invention can be administered alone, in combination with other compounds of the present invention, or with other pharmaceutically active compounds.
• the other pharmaceutically active compounds can be intended to treat the same disease or condition as the compounds of the present invention or a different disease or condition. If the patient is to receive or is receiving multiple pharmaceutically active compounds, the compounds can be administered simultaneously, or sequentially.
• the active compounds may be found in one tablet or in separate tablets, which can be administered at once or sequentially in any order.
• the compositions may be different forms. For example, one or more compound may be delivered via a tablet, while another is administered via injection or orally as a syrup. All combinations, delivery methods and administration sequences are contemplated.
• the compounds of the present invention may be used in the manufacture of a medicament for the treatment of a disease and/or condition mediated by GKRP/GK, such as type 2 diabetes.
• the compounds of the present invention may be used in combination with other pharmaceutically active compounds. It is noted that the term
• pharmaceutically active compounds can include biologies, such as proteins, antibodies and peptibodies.
• examples of other pharmaceutically active compounds include, but are not limited to: (a) dipeptidyl peptidase IV (DPP-IV) inhibitors such as Vildagliptin (Novartis), Sitagliptin (Merck&Co.), Saxagliptin (BMS) Alogliptin (Takeda); (b) insulin sensitizers including (i) PPARy agonists such as the glitazones (e.g., troglitazone, pioglitazone, edaglitazone,
• DPP-IV dipeptidyl peptidase IV
• glitazones e.g., troglitazone, pioglitazone, edaglitazone
• PPARa/ ⁇ dual agonists such as muraglitazar (BMS) and tesaglitazar (AstraZeneca), and PPARa agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate), (ii) biguanides such as metformin and phenformin, and (iii) protein tyrosine phosphatase-lB (PTP-1B) inhibitors; (c) insulin or insulin mimetics; (d) incretin and incretin mimetics such as (i) Exenatide available from Amylin Pharmaceuticals, (i) amylin and amylin mimetics such as pramlintide acetate, available as Symlin ® , (iii) GLP-1, GLP-1 mimetics, and GLP-1
• dialkylaminoalkyl derivatives of a cross-linked dextran (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPARa agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate), (v) PPARa/ ⁇ dual agonists such as muraglitazar (BMS) and tesaglitazar (AstraZeneca), (vi) inhibitors of cholesterol absorption, such as beta-sitosterol and ezetimibe, (vii) acyl CoAxholesterol acyltransferase inhibitors such as avasimibe, and (viii) antioxidants such as probucol; (j) PPAR5 agonists such as GW-501516 from GSK; (k) anti-obesity compounds such as fenfluramine, dexfenflur
• glucokinase activators that can be used in combination with the compounds of the present invention include those set forth in published PCT patent application no. WO 2009/042435, published April 2, 2009.
• ILl-Rl compounds set forth in U.S. patent no. 7,438,910.
• a particular disease that can be treated with the combination is type 2 diabetes.
• the compounds of the present invention can also be used in combination with FGF-21 compounds, and particularly for the treatment of type 2 diabetes.
• FGF-21 compounds are disclosed in U.S. patent no. 7,671,180; U.S. patent no. 7,667,008; U.S. patent no. 7,459,540; U.S. patent no. 7,696,172; PCT application publication no. WO 2010/042747; and PCT application publication no. WO 2009/149171.
• the compounds of the present invention can be also be used in combination with anakinra, particularly for the treatment of type 2 diabetes.
• the compounds of the present invention may be used in combination with metformin.
• the compounds of the present invention are used in the treatment diseases or symptoms mediated by GKRP and/or GK (GKRP/GK).
• diseases or symptoms mediated by GKRP/GK include, but are not limited to, Type II (type 2) diabetes and related disorders, such as hyperglycemia, low or impaired glucose tolerance, insulin resistance, obesity, lipid disorders such as
• dyslipidemia hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDL levels, atherosclerosis, and vascular restenosis, irritable bowel syndrome, inflammatory bowel disease, including Crohn's disease and ulcerative colitis, other inflammatory conditions, pancreatitis, abdominal obesity, neurodegenerative disease, retinopathy, nephropathy, neuropathy, cataracts, glaucoma, glomerulosclerosis, foot ulcerations and unlcerative colitis, altered gastrointestinal motility, Syndrome X, ovarian hyperandrogenism, polycystic ovarian syndrome, premenstrual syndrome, other disorders where insulin resistance is a component.
• Syndrome X also known as Metabolic Syndrome
• obesity is thought to promote insulin resistance, diabetes, dyslipidemia, hypertension, and increased cardiovascular risk, growth hormone deficiency, neutropenia, neuronal disorders, tumor invasion and metastasis, benign prostatic hypertrophy, gingivitis, osteoporosis, frailty of aging, intestinal injury, benign prostatic hypertrophy (BPH), and sperm motility/male contraception.
• BPH benign prostatic hypertrophy
• cardiovascular diseases or damages e.g. cardiac hypertrophy, cardiac remodelling after myocardial infarction, pulmonary congestion and cardiac fibrosis in dilated or in hypertrophic cardiomyopathy, cardiomyopathy such as dilated cardiomyopathy or hypertrophic
• cardiomyopathy mesanglial hypertrophy, or diabetic cardiomyopathy, left or right ventricular hypertrophy, arrhythmia, cardiac dysrhythmia, syncopy, angina pectoris, cardiac bypass reocclusion, intermittent claudication, diastolic and/or systolic dysfunction, diabetic myopathy, stroke prevention in congestive heart failure, hypertrophic medial thickening in arteries and/or large vessels, mesenteric vasculature hypertrophy or artherosclerosis, preferably
• kidney diseases or damages like renal hyperfiltration such as after portal renal ablation, proteinuria in chronic renal disease, renal arteriopathy as a consequence of hypertension, nephrosclerosis, hypertensive nephrosclerosis or mesanglial hypertrophy;
• Heart Failure to be treated is secondary to idiopathic dilated cardiomyopathy and/or coronary ischemic disease.
• the compounds of the present invention can also be used for the prevention, the delay of the onset, the delay of progression or the treatment of neurodegenerative disorders, cognitive disorders and for improving memory (both short term and long term) and learning ability wherin the (i)
• neurodegenerative disorder is dementia, senile dementia, schizophrenia, mild cognitive impairment, Alzheimer related dementia, Huntington's chores, tardive dyskinesia, hyperkinesias, mania, Morbus Parkinson, Steel-Richard syndrome, Down's syndrome, myasthenia gravis, nerve and brain trauma, vascular amyloidosis, cerebral haemorrhage I with amyloidosis, brain inflammation, Friedrich ataxia, acute confusion disorders, acute confusion disorders with apoptotic necrocytosis, amyotrophic lateral sclerosis, glaucoma, and Alzheimer's disease; (ii) cognitive disorders like cognitive deficits associated with
• the compounds of the present invention can also be used for stimulating an immune response in a subject having or at risk of having cancer wherein the cancer is selected from the group consisting of basal cell carcinomas including cancers of the binary tract, bladder, urinary system, bone, brain, breast, cervical, endometrial, ovarian, uterine, choriocarcinoma, central nervous system, colon and rectal cancers, connective tissue cancer, cancer of the digestive system, esophageal, gastric, stomach, larynx, liver, pancreatic, colorectal, renal cancers; cancers of the urinary system; cancers of eye, head and neck, oral cavity, skin, prostate; cancers of biliary tract, testicular, thyroid; intra- epithelial neoplasm, leukemia, acute myeloid leukemia, acute lymphoid leukemia, chronic myeloid leukemia, chronic lymphoid leukemia; and other cancers of the respiratory system, lung, small cell lung, non-small cell lung; lymphom
• rhabdomyosarcoma and other cancers including neoplastic conditions, adipose cell tumors, adipose cell carcinomas, such as liposarcoma.
• the compounds of the present invention can also be used for the treatment or prophylaxis of chronic inflammatory diseases such as autoimmune disorders like rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, allergies or asthma.
• chronic inflammatory diseases such as autoimmune disorders like rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, allergies or asthma.
• the compounds of the present invention can also be used in the treatment of pain, neuropathic pain, rheumatoid pain, osteoarthritis pain, anesthesia adjunct in mammalian patients undergoing surgery, chronic pain in advanced cancer, treatment of refractory diarrhea, biliary pain caused by gallstones.
• the compounds of the present invention can also be used for the treatment of mammalian patients undergoing islet/pancreas transplantation, for the prevention or the delay of transplant rejection, or allograft rejection in transplantation, for improving pancreatic function by increasing the number and size of pancreatic beta-cells in the treatment of Type 1 diabetes patients, and for improving pancreatic function by increasing the number and size of pancreatic beta-cells in general.
• the compounds of the present invention can be used for the treatment of mammalian patients with acne, skin disorders (e.g. pigmentation disorders or psoriasis), scleroderma, mycoses; anxiety, anxiety neurosis, major depression disorder, drug abuse, alcohol addiction, insomnia, chronic fatigue, sleep apnea; anorexia nervosa; epilepsy; migrane; encephalomyelitis;
• osteoarthritis osteoporosis, calcitonin-induced osteoporosis; male and female sexual dysfunction, infertility; Type 1 diabetes; immunosuppression, HIV infection; hematopoiesis, anemia; and for weight reduction.
• the compounds of the present invention are useful for the prevention, delay of progression or treatment of (i) bacterial infections from Escherichia coli, Staphylococcus, Streptoococcus, Pseudomonas, Clostridium difficile infection, Legionella, Pneumococcus, Haemophilus, Klebsiella,
• cryptococcosis aspergillosis, chromomycosis, mycetoma infections
• kits comprises two separate pharmaceutical compositions: a compound of the present invention, and a second pharmaceutical compound.
• the kit comprises a container for containing the separate compositions such as a divided bottle or a divided foil packet.
• kits include syringes, boxes and bags.
• the kit comprises directions for the use of the separate components.
• the kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are
• Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
• a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested.
• a memory aid is a calendar printed on the card, e.g., as follows "First Week, Monday, Tuesday, . . . etc . . . Second Week, Monday, Tuesday, . . . " etc.
• a “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day.
• a daily dose of a compound of the present invention can consist of one tablet or capsule, while a daily dose of the second compound can consist of several tablets or capsules and vice versa.
• the memory aid should reflect this and aid in correct administration of the active agents.
• a dispenser designed to dispense the daily doses one at a time in the order of their intended use.
• the dispenser is equipped with a memory-aid, so as to further facilitate compliance with the regimen.
• a memory-aid is a mechanical counter which indicates the number of daily doses that has been dispensed.
• a battery-powered microchip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.
• the compounds of the present invention and other pharmaceutically active compounds can be administered to a patient either orally, rectally, parenterally, (for example, intravenously, intramuscularly, or subcutaneously) intracisternally, intravaginally, intraperitoneally, intravesically, locally (for example, powders, ointments or drops), or as a buccal or nasal spray. All methods that are used by those skilled in the art to administer a patient.
• compositions suitable for parenteral injection may comprise
• aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
• a coating such as lecithin
• surfactants for reconstitution into sterile injectable solutions or dispersions.
• compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents.
• adjuvants such as preserving, wetting, emulsifying, and dispersing agents.
• Microorganism contamination can be prevented by adding various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like.
• isotonic agents for example, sugars, sodium chloride, and the like.
• Prolonged absorption of injectable pharmaceutical compositions can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
• Solid dosage forms for oral administration include capsules, tablets, powders, and granules.
• the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or
• fillers or extenders as for example, starches, lactose, sucrose, mannitol, and silicic acid;
• binders as for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia;
• humectants as for example, glycerol;
• disintegrating agents as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate;
• solution retarders as for example, paraffin;
• absorption accelerators as for example, quaternary ammonium compounds;
• wetting agents as for example, paraffin
• compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like.
• Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may also contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
• Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
• the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame seed oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, or mixtures of these substances, and the like.
• inert diluents commonly used in the art, such as water or other solvents, solubilizing
• the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
• adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
• Suspensions in addition to the active compound, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances, and the like.
• compositions for rectal administration are preferable suppositories, which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary room temperature, but liquid at body temperature, and therefore, melt in the rectum or vaginal cavity and release the active component.
• suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary room temperature, but liquid at body temperature, and therefore, melt in the rectum or vaginal cavity and release the active component.
• Dosage forms for topical administration of a compound of the present invention include ointments, powders, sprays and inhalants.
• the active compound or fit compounds are admixed under sterile condition with a physiologically acceptable carrier, and any preservatives, buffers, or propellants that may be required.
• Opthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
• the compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 3,000 mg per day.
• dosage levels in the range of about 0.1 to about 3,000 mg per day.
• a dosage in the range of about 0.01 to about 100 mg per kilogram body weight is typically sufficient.
• the specific dosage and dosage range that can be used depends on a number of factors, including the requirements of the patient, the severity of the condition or disease being treated, and the pharmacological activity of the compound being administered. The determination of dosage ranges and optimal dosages for a particular patient is within the ordinary skill in the art.
• the compounds of the present invention can be administered as pharmaceutically acceptable salts, esters, amides or prodrugs.
• salts refers to inorganic and organic salts of compounds of the present invention.
• the salts can be prepared in situ during the final isolation and purification of a compound, or by separately reacting a purified compound in its free base or acid form with a suitable organic or inorganic base or acid and isolating the salt thus formed.
• Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, palmitiate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like.
• the salts may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium,
• esters of the compounds of the present invention include Ci-Cg alkyl esters. Acceptable esters also include C5-C7 cycloalkyl esters, as well as arylalkyl esters such as benzyl. C 1 -C4 alkyl esters are commonly used. Esters of compounds of the present invention may be prepared according to methods that are well known in the art.
• Examples of pharmaceutically acceptable amides of the compounds of the present invention include amides derived from ammonia, primary Ci-Cs alkyl amines, and secondary Ci-Cg dialkyl amines. In the case of secondary amines, the amine may also be in the form of a 5 or 6 membered heterocycloalkyl group containing at least one nitrogen atom. Amides derived from ammonia, C 1 -C3 primary alkyl amines and C 1 -C 2 dialkyl secondary amines are commonly used. Amides of the compounds of the present invention may be prepared according to methods well known to those skilled in the art.
• prodrug means compounds that are transformed in vivo to yield a compound of the present invention. The transformation may occur by various mechanisms, such as through hydrolysis in blood.
• a discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and in
• a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (Ci-Cg alkyl, (C 2 - Cl 2 )alkanoyloxymethyl, l-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1 -methyl- l-(alkanoyloxy)ethyl having from 5 to 10 carbon atoms,
• alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- 1- (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N- (alkoxycarbonyl)aminomethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4- crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(C 1 -C 2 )alkylamino(C 2 - C 3 )alkyl (such as ⁇ -dimethylaminoethyl), carbamoyl-(Ci-C 2 )alkyl, N,N-di(C 1 - C 2 )alkylcarbamoyl-(Ci-C 2
• a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (Ci-C6)alkanoyloxymethyl, 1- ((Ci-C6)alkanoyloxy)ethyl, 1 -methyl- l-((Ci-C6)alkanoyloxy)ethyl, (Ci- C6)alkoxycarbonyloxymethyl, N-(C i -C6)alkoxycarbonylaminomethyl, succinoyl, (Ci-C 6 )alkanoyl, a-amino(Ci-C4)alkanoyl, arylacyl and a-aminoacyl, or a- aminoacyl-a-aminoacyl, where each a-aminoacyl group is independently selected from the naturally occurring L-amino acids, -P(0)(OH) 2 , -P(0)(0(Ci-C6)
• the compounds of the present invention may contain asymmetric or chiral centers, and therefore, exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention contemplates all geometric and positional isomers. For example, if the compound contains a double bond, both the cis and trans forms (designated as S and E, respectively), as well as mixtures, are
• stereoisomers such as diastereomeric mixtures
• Enantiomers can also be separated by converting the enantiomeric mixture into a diasteromeric mixture by reaction with an appropriate optically active compound (e.g., an alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
• an appropriate optically active compound e.g., an alcohol
• the compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water (hydrate), ethanol, and the like.
• pharmaceutically acceptable solvents such as water (hydrate), ethanol, and the like.
• the present invention contemplates and encompasses both the solvated and unsolvated forms.
• compounds of the present invention may exist in different tautomeric forms. All tautomers of compounds of the present invention are contemplated. For example, all of the tautomeric forms of the tetrazole moiety are included in this invention. Also, for example, all keto-enol or imine- enamine forms of the compounds are included in this invention.
• the present invention encompass compounds that are synthesized in vitro using laboratory techniques, such as those well known to synthetic chemists; or synthesized using in vivo techniques, such as through metabolism, fermentation, digestion, and the like. It is also contemplated that the compounds of the present invention may be synthesized using a combination of in vitro and in vivo techniques.
• the present invention also includes isotopically-labelled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 16 0, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 C1.
• the compounds of the present invention contain one or more deuterium atoms (2H) in place of one or more hydrogen atoms.
• Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detection. Further, substitution with heavier isotopes such as deuterium, i.e., 2 H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some
• Isotopically labelled compounds of this invention can generally be prepared by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
• the compounds of the present invention may exist in various solid states including crystalline states and as an amorphous state.
• crystalline states also called polymorphs, and the amorphous states of the present compounds are contemplated as part of this invention.
• LG generally refer to groups that are displaceable by a nucleophile.
• Such leaving groups are known in the art.
• Examples of leaving groups include, but are not limited to, halides (e.g., I, Br, F, CI), sulfonates (e.g., mesylate, tosylate), sulfides (e.g., SCH 3 ), N- hydroxsuccinimide, N-hydroxybenzotriazole, and the like.
• nucleophiles include, but are not limited to, amines, thiols, alcohols, Grignard reagents, anionic species (e.g., alkoxides, amides, carbanions) and the like.
• This assay is used to directly measure the formation of 13 C-glucose-6- phosphate from 13 C-glucose by liquid chromatography-mass spectrometry (LC MS/MS).
• CB Compound Buffer
• EB Enzyme Buffer
• EB 50mM Tris, pH 7.5 / 4mM MgCl 2 / 6% DMSO / fresh 0.1% BSA / fresh 0.01% Brij-35 (10% BSA and 1% Brij-35 stock).
• GK (Glucokinase) Working Stock (5X): Dilute human His-hepatic GK to 30nM in EB buffer.
• Substrate Working Stock (1.47X): Dilute 13C-D-glucose (Sigma-Aldrich, St. Louis, MO) to 7.35mM from 1M stock (1M 13 C-D-glucose 186.1 1 mg/ml in 50mM Tris pH 7.5, 4mM MgCl 2 ) and dilute ATP (EMD Chemical Inc., Gibbstown, NJ) to 0.3528mM from frozen lOOmM stock and dilute 20mM fructose-6-phosphate (F6P) (Sigma-Aldrich, St.
• GKRP Glucokinase Regulatory Protein
• G6P glucose-6-phosphate
• Assay format is the same as for GKRP LC MS/MS Biochemical Assay with the following exceptions.
• This assay is used to directly measure the interaction between glucokinase (GK) and glucokinase regulatory protein (GKRP).
• GK glucokinase
• GKRP glucokinase regulatory protein
• Assay Buffer 20mM Tris, pH 7.5 / 0.05% BSA / ImM DTT / ⁇ sorbitol-6-phosphate.
• Assay Procedure Dilute avi-tagged GKRP to 10.7 nM in assay buffer. Combine the following reagents in a white 96-well half area plate. Pipette 14 ⁇ 1 of the diluted avi-tagged GKRP into each well. Add ⁇ of compound to be tested and incubate at room temperature for 20 minutes.
• This assay is used to directly measure the formation of 13 C-glucose-6- phosphate from 13 C-glucose by LC MS/MS.
• CB Compound Buffer
• EB Enzyme Buffer
• EB 50mM Tris, pH 7.5 / 4mM MgCl 2 / 6% DMSO / fresh 0.1% BSA / fresh 0.01% Brij-35 (10% BSA and 1% Brij-35 stock).
• GK (Glucokinase) Working Stock (5X): Dilute human His-hepatic GK to 30nM in EB buffer.
• Substrate Working Stock (1.47X): Dilute 13 C-D-glucose (Sigma- Aldrich,St. Louis, MO) to 7.35mM from 1M stock and dilute ATP (EMD Chemical, Gibbstown, NJ) to 0.3528mM from frozen lOOmM stock in CB buffer (1M 13 C-D-glucose 186.1 1 mg/ml in water).
• Dilute 20mM fructose-6-phosphate (F6P) (Sigma- Aldrich, St. Louis, MO) to 441 ⁇ in the substrate working stock.
• GKRP Glucokinase Regulatory Protein
• NIS l-iodo-2,5-pyrrolidinedione It is noted that when a percent (%) is used with regard to a liquid, it is a percent by volume with respect to the solution. When used with a solid, it is the percent with regard to the solid composition.
• chromatography columns are used for separations and purifications. Below are some representative suppliers of columns: Phenomenex, Torrance,CA (e.g., Gemini); Diacel Inc., Fort Lee, NJ (e.g.,Chiralcel ® , Chiralpak ® ); Krackeler Scientific, Albany, NY (e.g., AccuBOND).
• STEP 2 N,N-Bis(4-methoxybenzyl)-5-(((3S)-3-(l-propyn-l-yl)-l- piperazinyl)sulfonyl)-2-pyridinamine
• a 1-L pressure tube was charged with benzyl (3 S)-3-(l -propyn- l-yl)-l- piperazinecarboxylate (9.89 g, 38.3 mmol, Intermediate A), 2-(4-bromophenyl)- l,l,l,3,3,3-hexafluoropropan-2-ol (16.11 g, 49.9 mmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009), RuPhos Palladacycle (1.57 g, 1.93 mmol, Strem Chemical Inc, Newburyport, MA), RuPhos (1.83 g, 3.92 mmol, Strem Chemical Inc,
• STEP 2 l,l,l,3,3,3-Hexafiuoro-2-(4-((2S)-2-(l-propyn-l-yl)-l- piperazinyl)phenyl)-2-propanol
• a 1-L pressure vessel was charged with 2-(4-bromophenyl)- 1,1,1 - trifluoropropan-2-ol (43.8 g, 163 mmol, Intermediate O), (3R)-3- ((benzyloxy)methyl)-l-(2-thiophenylsulfonyl)piperazine (47.8 g, 136 mmol), 200 mL of toluene, and sodium tert-butoxide (32.6 g, 339 mmol).
• a 1-L pressure vessel was charged with 2-(4-bromophenyl)-l, 1,1,3, 3,3- hexafluoropropan-2-ol (70.8 g, 219 mmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009), tert-butyl piperazine-l-carboxylate (40.0 g, 215 mmol, Sigma- Aldrich, St. Louis, MO), 200 mL of toluene, and sodium tert-butoxide (43.3 g, 451 mmol).
• the isomeric mixture obtained above was separated using the following chiral SFC method: Chiralcel ® OJH column (250 x 30 mm) using 5% isopropanol in supercritical C0 2 (total flow was 120 mL/min). This produced two products with enantiomeric excesses over 95%.
• the absolute stereochemistry was assigned based on vibrational circular dichroism (VCD) methodology ⁇ Chirality 2008, 20, 643) which furnished an assignment consistent with that assumed in a literature example (Org. Lett. 2007, 9(18), 3707).
• a 150-mL reaction vessel was charged with benzyl 3-(prop-l-yn-l-yl)piperazine- 1-carboxylate (2.88 g, 11.2 mmol), 2-(4-bromophenyl)-l, 1,1, 3,3,3- hexafluoropropan-2-ol (4.36 g, 13.5 mmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009), dicyclohexyl(2',6'-diisopropoxy-[ 1 , 1 '-biphenyl]-2-yl)phosphine, RuPhos (0.530 g, 1.14 mmol, Sigma- Aldrich, St.
• Trifluoromethanesulfonic acid (1.25 mL, 14.1 mmol, Acros/Fisher Scientific, Waltham, MA) was added dropwise at room temperature. After 5 min, additional TfOH (0.45 mL, 5.1 mmol) was added. After an additional 10 min, solid
• the volume of the reaction mixture was reduced to approximately 10 mL under a vacuum then the mixture was purified twice by column chromatography (100 g of silica, 0 to 50% EtOAc in hexanes) to afford 2-(4-(4-((6-chloro-3- pyridinyl)sulfonyl)-2-( 1 -propyn- 1 -yl)- 1 -piperazinyl)phenyl)- 1,1,1,3,3,3- hexafluoro-2-propanol (3.46 g) as an off-white solid.
• Step 6 2-(4-(4-((6- Amino-3 -pyridinyl)sulfonyl)-2-( 1 -propyn- 1 -yl)- 1 - piperazinyl)phenyl)- 1,1,1 ,3 ,3 ,3 -hexafluoro-2-propanol
• the individual enantiomers were isolated using chiral SFC.
• the method used was as follows: Chiralpak ® ADH column (21 x 250 mm, 5 ⁇ ) using 35% methanol in supercritical C0 2 (total flow was 70 mL/min). This produced the two enantiomers with enantiomeric excesses greater than 98%.
• STEP 5 ' 2-(4-(4-((6-Amino-3-pyridinyl)sulfonyl)-2-(l-propyn-l-yl)-l- piperazinyl)phenyl)- 1,1,1 ,3 ,3 ,3 -hexafluoro-2-propanol
• 2-(4-(4-((6-Amino-3-pyridinyl)sulfonyl)-2-( 1 -propyn- 1 -yl)- l-piperazinyl)phenyl)-l,l,l,3,3,3-hexafluoro-2-propanol was synthesized from benzyl 3-( 1 -propyn- 1 -yl)-4-(4-(2,2,2-trifluoro- 1 -hydroxy- 1 - (trifluoromethyl)ethyl)phenyl)- 1 -piperazinecarboxylate as follows.
• Trifluoromethanesulfonic acid (11.6 mL, 131 mmol, Acros/Fisher Scientific, Waltham, MA) was added slowly at rt resulting orange cloudy mixture. After stirring at rt for 10 min, the volume of the reaction mixture was reduced to half under a vacuum. Solid NaHC0 3 was added in portions until the mixture became sludge. Saturated aqueous NaHC0 3 (800 mL) was added slowly until the pH was about 8. The aqueous phase was extracted with EtOAc (3 x 250 mL). The combined organic phases were washed with water (500 mL) and saturated aqueous NaCl (500 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under a vacuum.
• the reaction mixture was stirred at room temperature for 18h.
• the reaction mixture was carefully diluted with saturated aqueous sodium bicarbonate (about 10 mL) and extracted with EtOAc (2 x 30 mL).
• the organic extract was washed with brine, dried (Na 2 S0 4 ), filtered, and concentrated in vacuum.
• the crude material was absorbed onto a plug of silica gel and purified by chromatography through a silica gel column (40 g), eluting with a gradient of 0 % to 10% EtOAc in hexanes, to provide 2-(5,6-dichloro-3-pyridinyl)- 1,1,1 - trifluoro-2-propanol (812 mg) as a colorless oil.
• Example 1 2-(6-(4-((6-Amino-3-pyridinyl)sulfonyl)-2-(l-propyn-l-yl)-l- piperazinyl)-3-pyridinyl)- 1,1,1 -trifluoro-2-propanol
• tetramethylammonium fluoride (0.363 g, 3.90 mmol, Sigma- Aldrich, St. Louis, MO) was added portionwise. The mixture was allowed to warm to rt and was stirred for 15 h. Aqueous saturated NaHC0 3 (20 mL) was added and the aqueous phase was extracted with EtOAc (3 x 30 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated under a vacuum.
• reaction mixture was concentrated and the resulting product was purified by column chromatography twice (25 g and 10 g of silica, 30 to 90% EtOAc in hexanes) to afford 2-(6-(4-((6- amino-3 -pyridinyl)sulfonyl)-2-( 1 -propyn- 1 -yl)- 1 -piperazinyl)-3 -pyridinyl)- 1,1,1- trifluoro-2-propanol (0.0320 g) as a mixture of 4 stereoisomers.
• Trifluoromethanesulfonic acid (0.71 mL, 8.00 mmol, Alfa Aesar, Ward Hill, MA) was added dropwise at room temperature. The mixture was stirred at room temperature for 2 min. Solid NaHC0 3 was added followed by saturated aqueous NaHC0 3 until a pH of about 7. The aqueous phase was extracted with EtOAc (2 x 30 mL). The combined organic phases were washed with water (50 mL) and saturated aqueous sodium chloride (50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under a vacuum.
• the reaction mixture was allowed to cool to room temperature and then partitioned between water (120 mL) and EtOAc (80 mL). The aqueous phase was extracted with EtOAc (60 mL). The combined organic phases were washed with water (80 mL) and saturated aqueous sodium chloride (80 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under a vacuum to afford.
• the individual diastereomers were isolated using chiral SFC.
• the method used was as follows: Chiralpak ® AS-H column (21 x 250 mm, 5 ⁇ ) using 25% (40 mM NH 3 in methanol) in supercritical C0 2 (total flow was 75 mL/min). This produced the two diastereomers with diastereomeric and enanteomeric excesses greater than 98%.
• the reaction mixture was partitioned between saturated aqueous sodium bicarbonate (50 mL) and EtOAc (30 mL). The aqueous phase was extracted with EtOAc (40 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated under a vacuum. The resulting product was purified by column chromatography (25 g of silica gel, 0 to 40% EtOAc in hexanes) to afford 2-(6-chloro-3-pyridinyl)-l, 1,1,3, 3,3- hexafluoro-2-propanol (0.556 g) as a flaky glassy solid.
• STEP 3 2-(6-((2S)-4-((6-Amino-3-pyridinyl)sulfonyl)-2-( 1 -propyn- 1 -yl)- 1 - piperazinyl)-3-pyridinyl)- 1,1,1 ,3 ,3 ,3-hexafluoro-2-propanol
• Trifluoromethanesulfonic acid (0.080 mL, 0.90 mmol, Alfa Aesar, Ward Hill, MA) was added dropwise at room temperature. The mixture was stirred for 3 min. The reaction mixture was concentrated under a vacuum to dryness and DCM (2.5 mL) was added followed by triethylamine (0.400 mL, 2.87 mmol). The mixture was stirred for 3 min then tert-butyl (5-(chlorosulfonyl)-2- pyridinyl)carbamate (0.0856 g, 0.292 mmol, Intermediate B) was added. The mixture was stirred for 5 min. The reaction mixture was concentrated under a vacuum and taken into DCM (2 mL).
• Trifluoromethanesulfonic acid (0.020 mL, 0.23 mmol, Alfa Aesar, Ward Hill, MA) was added dropwise at room temperature. The mixture was stirred at room temperature for 3 min and then concentrated under a vacuum. To the residue DCM (1 mL) was added followed by triethylamine (0.087 mL, 0.62 mmol). The mixture was stirred at room temperature for 5 min then tert-butyl (5- (chlorosulfonyl)pyridin-2-yl)carbamate (0.0267 g, 0.091 mmol, Intermediate B) was added. After 2 h of stirring, additional TEA (0.30 mL) was added. After stirring for 10 min the reaction mixture was concentrated.
• the individual diastereomers were isolated using chiral SFC.
• the method used was as follows: Chiralpak ® AS-H column (21 x 250 mm, 5 ⁇ ) using 25% (20 mM NH 3 in methanol) in supercritical C0 2 (total flow was 70 mL/min). This produced the two diastereomers with diastereomeric excesses greater than 98%>.
• Imidazole (30.2 g, 444 mmol) was taken up in 240 mL of DCM and chilled to 0 °C.
• Thionyl chloride (9.76 mL, 134 mmol) was added slowly to the mixture. After 5 min, the mixture was warmed to room temperature and stirred for 1 h. The mixture was then cooled to -78 °C.
• t-Butyl (3R)-3- (hydroxymethyl)-l-piperazinecarboxylate (10.33 g, 47.8 mmol, Tetrahedron, 2007, 63, 3057-3065) was added dropwise in 240 mL of DCM via addition funnel. The mixture was then warmed to room temperature and stirred for 18 h.
• RuPhos Palladacycle methyl-t-butyl ether adduct (0.076 g, 0.094 mmol, Sigma-Aldrich, St. Louis, MO), and RuPhos (0.044 g, 0.094 mmol, Strem Chemicals, Inc., Newburyport, MA) were taken up in 5 mL of dioxane and heated to 80 °C. After 1 hour, the reaction was cooled to room temperature. The mixture was diluted with 40 mL of EtOAc and washed with 10 mL of aq NH 4 C1 and 10 mL of brine, then dried over MgS0 4 .
• Lithium aluminum hydride (1.0 M solution in diethyl ether, 0.48 mL, 0.48 mmol, Sigma-Aldrich, St. Louis, MO) was added to the mixture. After 18 h, the reaction was carefully quenched with 2 mL of aq. Rochelle's salt. The mixture was then diluted with 2 mL of water and 6 mL of EtOAc and stirred for 15 min. The mixture was extracted with 10 mL of EtOAc and the combined organic extracts were washed with 10 mL of brine and dried over MgS0 4 .
• STEP 7 2-(4-((2S)-4-((6-Amino-3-pyridinyl)sulfonyl)-2-((4- (hydroxymethyl)tetrahydro-2H-pyran-4-yl)methyl)-l-piperazinyl)phenyl)- 1,1,1 ,3 ,3 ,3 -hexafluoro-2-propanol
• methanesulfonate (0.200 g, 0.378 mmol, Intermediate H), potassium carbonate (0.110 g, 0.757 mmol, J.T.Baker, Phillipsburg, NJ), 2-propanethiol (0.071 mL, 0.757 mmol, Sigma-Aldrich, St. Louis, MO), and MeCN (3.0 mL).
• the vial was sealed and heated at 140 °C for 40 min. The reaction mixture was filtered and the filtrate was concentrated.
• STEP 2 1,1,1 -Trifluoro-2-(4-((2R)-2-(((l -methylethyl)sulfonyl)methyl)-4-(2- thiophenylsulfonyl)- 1 -piperazinyl)phenyl)-2-propanol
• DCM 2.0 mL
• MCPBA 0.070 g, 0.295 mmol, Aldrich, St.
• the resulting product was purified by silica gel column chromatography (24 g, 10% to 20%> acetone in hexanes) to afford l,l,l-trifluoro-2-(4-((2R)-2-(((l- methylethyl)sulfonyl)methyl)-4-(2-thiophenylsulfonyl)- 1 -piperazinyl)phenyl)-2- propanol (0.040 g) as a mixture of two isomers.
• methyl phenylphosphonium bromide (25.4 g, 71.1 mmol, Sigma-Aldrich, St. Louis, MO) and toluene (75 mL). The resulting mixture was stirred for 5 min then concentrated and dried under a high vacuum for 30 min. To this residue was added THF (300 mL) followed by adding butyllithium (2.5 M in hexanes, 29.0 mL, 71.1 mmol, Aldrich, St. Louis, MO) dropwise via an addition funnel at room temperature.
• STEP 4 4-(4-(2,2-Dimethyl-4-(trifluoromethyl)-l,3-dioxolan-4-yl)phenyl)-3-(l- propyn- 1 -yl)- 1 -piperazinecarboxylate
• the reaction mixture was concentrated to dryness and the residue was neutralized by adding saturated aqueous NaHCOs (40 mL) then extracted with EtOAc (3 x 70 mL) and 10% IP A in CHCI 3 (3 x 70 mL). The combined organic layers were dried over MgS0 4 , filtered and concentrated. The resulting intermediate was redissolved in DCM (15 mL). Triethylamine (0.230 mL, 1.60 mmol, Sigma-Aldrich, St. Louis, MO) and 6-chloropyridine-3-sulfonyl chloride (0.080 g, 0.360 mmol, Organic Process Research & Development 2009, 13, 875) were added. The reaction mixture was stirred at rt for 1 h.
• the reaction mixture was partitioned between DCM (60 mL) and water (30 mL). The aqueous layer was extracted with DCM (2 x 40 mL). The combined organic layers were dried over MgS0 4 , filtered and concentrated. The resulting product was purified by column chromatography (40 g of silica gel, 10% to 40% acetone in hexanes) to afford 2-(4-(4-((6-chloro-3- pyridinyl)sulfonyl)-2-( 1 -propyn- 1 -yl)- 1 -piperazinyl)phenyl)-3 ,3 ,3 -trifluoro- 1 ,2- propanediol (0.090 g) as a white solid.
• a 20-mL vial was charged with 2-(4-(4-((6-amino-3-pyridinyl)sulfonyl)- 2-( 1 -propyn- 1 -yl)- 1 -piperazinyl)phenyl)-3 ,3 ,3-trifluoro- 1 ,2-propanediol (0.090 g, 0.180 mmol), EtOH (3.0 mL), and concentrated ammonium hydroxide (, 3.0 mL, 77.0 mmol, Sigma-Aldrich, St. Louis, MO). The vial was sealed and heated at 120 °C for 7 h.
• reaction mixture was concentrated and the resulting product was partitioned between water (30 mL) and DCM (70 mL). The aqueous layer was extracted with DCM (2 x 30 mL) and the combined organic layers were dried over MgS0 4 , filtered and concentrated.
• STEP 1 (3S)-3-(l-Propyn-l-yl)-4-(5-((lR)-2,2,2-Trifluoro-l-hydroxy-l- methylethyl)-2-pyrimidinyl)- 1 -piperazmecarboxylate; or (3 S)-3 -( 1 -propyn- 1 -yl)- 4-(5-(( 1 S)-2,2,2-trifluoro- 1 -hydroxy- 1 -methylethyl)-2-pyrimidinyl)- 1 - piperazmecarboxylate
• a 1-L pressure vessel was charged with benzyl (3 S)-3-(l -propyn- l-yl)-l- piperazinecarboxylate (11.0 g, 43.0 mmol, Intermediate A), (2R)- 1,1,1 -trifluoro- 2-(2-((2S)-2-(l -propyn- 1 -yl)- 1 -piperazinyl)-5-pyrimidinyl)-2-propanol or (2S)- 1,1,1 -trifluoro-2-(2-((2S)-2-( 1 -propyn- 1 -yl)- 1 -piperazinyl)-5-pyrimidinyl)-2- propanol (12.0 g, 51.6 mmol, Intermediate F, peak 1), NMP (200 mL), and DIEA (27.0 mL, 155 mmol, Sigma- Aldrich, St.
• the vial was sealed and heated at 70 °C for 20 h.
• the reaction mixture was cooled to rt and concentrated.
• the residue was neutralized with saturated aqueous NaHC0 3 (10 mL).
• the resulting mixture was extracted with DCM (3 x 50 mL). The combined organic layers were dried over MgS0 4 and concentrated.
• step 3 Ho L_ - Br step 1
• the resulting product was purified by column chromatography (80 g of silica gel, 10 to 30% acetone in hexanes) to afford l-(6-bromo-3-pyridinyl)-2,2,2-trifluoroethanone (1.1 g) as a light yellow paste.
• EXAMPLE 12 2-(4-((25)-4-((6- Amino-3 -pyridazinyl)sulfonyl)-2-( 1 -propyn- 1 - yl)- 1 -piperazinyl)phenyl)- 1,1,1 ,3 ,3 ,3-hexafluoro-2-propanol
• the isolated solid was treated with aq sodium hydroxide (a solution made from 4 g NaOH in 80 mL H 2 0) until the solution was homogeneous (about 40 mL). The solution was stirred for 5 min at rt and then was acidified with cone HCl until a pH of about 5. A precipitate had formed and this was filtered, washed with H 2 0 and then dried under a vacuum to afford 6- chloro-3(2H)-pyridazinethione (4.2 g) as a yellow solid.
• aq sodium hydroxide a solution made from 4 g NaOH in 80 mL H 2 0
• 6-chloro-3(2H)- pyridazinethione (2.6 g, 17.6 mmol), water (1 10 ml) and acetic acid (1 1 ml).
• the solution was cooled to 0 °C and chlorine gas (Sigma-Aldrich, St. Louis, MO) was bubbled into the reaction mixture at a minimal rate with the internal temperature being kept below 5 °C.
• Cl 2 was added for 75 min and then N 2 was bubbled through the reaction mixture.
• the mixture was filtered and the filtercake was washed with ice cold water and then dried under vacuum to afford 6-chloro-3- pyridazinesulfonyl chloride (1.2 g,) as a yellow sticky solid that was used immediately.
• STEP 3 2-(4-((2S)-4-((6-Chloro-3-pyridazinyl)sulfonyl)-2-(l -propyn- 1-yl)- 1 - piperazinyl)phenyl)- 1 ,1 , 1 ,3 ,3 ,3 -hexafluoro-2-propanol
• STEP 4 2-(4-((25)-4-((6-Amino-3-pyridazinyl)sulfonyl)-2-(l -propyn- 1 -yl)- 1 - piperazinyl)phenyl)- 1,1,1 ,3 ,3 ,3 -hexafluoro-2-propanol
• STEP 2 3-Chloro-6-(((35)-4-(4-(2,2-dimethyl-4-(trifluoromethyl)-l ,3-dioxolan- 4-yl)phenyl)-3 -( 1 -propyn- 1 -yl)- 1 -piperazinyl)sulfonyl)pyridazine
• STEP 3 6-(((3S)-4-(4-(2,2-Dimethyl-4-(trifiuoromethyl)-l,3-dioxolan-4- yl)phenyl)-3 -( 1 -propyn- 1 -yl)- 1 -piperazinyl)sulfonyl)-3 -pyridazinamine
• Step 4 2-(4-((2S)-4-((6-Amino-3 -pyridazinyl)sulfonyl)-2-( 1 -propyn- 1 -yl)- 1 - piperazinyl)phenyl)-3,3,3-trifluoro-l,2-propanediol
• STEP 2 2-(2-Sulfanyl-l,3-thiazol-5-yl)-lH-isoindole-l,3(2H)-dione
• STEP 4 2-(2-((4-(4-(2,2,2-Trifluoro- 1 -hydroxy- 1 -(trifluoromethyl)ethyl)phenyl)- 1 -piperazinyl)sulfonyl)- 1 ,3-thiazol-5-yl)- lH-isoindole- 1 ,3(2H)-dione
• the reaction mixture was concentrated and then purified by HPLC (Gemini ® -NX (Phenomenex, Torrance, CA) 10 ⁇ Ci 8 110 A LC Column, 2 to 100% CH 3 CN (0.1% TFA)/H 2 0 (0.1% TFA) over 15 min then 100% CH 3 CN (0.1% TFA) for 5 minutes at 20 mL/min) to obtain a mixture of the phthalimide (minor) and its open form carboxylic acid (major). To a resealable vial was added a portion of the phthalimide/carboxylic acid mixture (0.052 g) and TFA (1.5 mL). The solution was stirred and heated at 70 °C for 16 h.
• thionyl chloride (7.5 mL, Spectrochem, India) was added dropwise to water (45 mL) maintained at 0 to 5 °C, over a period of 15 minutes. The resulting solution was stirred at 20 °C for 17 h.
• the solution of 6-chloro-5- methylpyridin-3 -amine (3.0 g, 21.12 mmol, S2Sbiochemsys, India) in acetonitrile (60 mL) was cooled to 0 °C and concentrated HCl (24 mL, SD Fine-Chem India) was added drop wise.
• the resulting solution was stirred at the same temperature for 5 min.
• An aqueous solution of NaN0 2 (1.73 g, 25.1 mmol, Spectrochem, India, dissolved in 5 mL of water) was added drop wise over a period of 15 minutes.
• the resulting mixture was stirred for 30 min at 0 °C and added to the solution in the first flask at 0 °C.
• the resulting mixture was stirred at 0 °C for 45 min.
• the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (200 mL). The organic layer was separated and dried over anhydrous Na 2 S0 4 .
• STEP 2 2-(4-((2S)-4-((6-Chloro-5-methyl-3-pyridinyl)sulfonyl)-2-(l-propyn-l- yl)- 1 -piperazinyl)phenyl)- 1,1,1 ,3 ,3 ,3-hexafluoro-2-propanol
• EXAMPLE 16 2-(4-((2S)-4-((6-Amino-5-bromo-3-pyridinyl)sulfonyl)-2-(l- propyn- 1 -yl)- 1 -piperazinyl)phenyl)- 1,1,1 ,3 ,3 ,3 -hexafluoro-2-propanol and 3 - bromo-5 -(((3 S)-3 -( 1 -propyn- 1 -yl)-4-(4-(2,2,2-trifluoro- 1 -hydroxy- 1 - (trifluoromethy l)ethyl)phenyl)- 1 -piperazinyl)sulfonyl)-2-pyridinol (tautomeric form's name (S)-3-bromo-5-((4-(4-(l , 1 ,1 ,3,3,3-hexafluoro-2-hydroxypropan-2- yl)phen
• the resulting material was absorbed onto a plug of silica gel and purified by chromatography through a silica gel column (12 g), eluting with a gradient of 0% to 7% 2M NHs MeOH in CH 2 C1 2 , to provide 3-bromo-5-(((3S)-3-(l-propyn-l-yl)-4-(4-(2,2,2-trifiuoro-l- hydroxy- 1 -(trifluoromethyl)ethyl)phenyl)- 1 -piperazinyl)sulfonyl)-2-pyridinol (7 mg) as a white solid.
• a glass microwave reaction vessel was charged with 2-(4-((2S)-4-((6- amino-5 -bromo-3 -pyridinyl)sulfonyl)-2-( 1 -propyn- 1 -yl)- 1 -piperazinyl)phenyl)- l,l,l,3,3,3-hexafluoro-2-propanol (54 mg, 0.090 mmol) and zinc cyanide (21.1 mg, 0.180 mmol, Sigma- Aldrich, St. Louis, MO) and Pd(PPh 3 ) 4 (5.19 mg, 4.49 ⁇ , Strem Chemical Inc, Newburyport, MA) in DMF (1.5 mL).
• the reaction mixture was stirred and heated in a microwave reactor (Biotage AB, Inc., Upssala, Sweden) at 140 °C for 30 min. After being cooled to rt, the reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 15 mL) and the combined organic extracts were washed with saturated aqueous NaCl (30 mL) and dried over Na 2 S0 4 . The solution was filtered and concentrated under a vacuum.
• a microwave reactor Biotage AB, Inc., Upssala, Sweden
• the resulting material was absorbed onto a plug of silica gel and purified by chromatography through a pre-packed silica gel column (12 g), eluting with a gradient of 0% to 5% 2M NH 3 MeOH in CH 2 C1 2 , to provide 2- amino-5 -(((3 S)-3-(l -propyn- 1 -yl)-4-(4-(2,2,2-trifluoro- 1 -hydroxy- 1 - (trifluoromethyl)ethyl)phenyl)-l-piperazinyl)sulfonyl)-3-pyridinecarbonitrile (34 mg) as off-white solid.
• STEP 1 tert-Butyl (2-(((6-chloro-3-pyridinyl)sulfonyl)(2-oxo(5,5,5- 2 H)-3- pentyn- 1 -yl)amino)ethyl)carbamate
• a stirring bar was placed a stirring bar and THF (2 mL) under nitrogen.
• the flask was cooled in an dry ice-acetone bath and a stream of (3,3,3- 2 H)-l-propyne (1 mL, 12 mmol, Sigma-Aldrich, St. Louis, MO) from a lecture bottle was introduced through a needle immersed to the THF.
• STEP 2 1 -((6-Chloro-3-pyridinyl)sulfonyl)-3-( 2 H 3 )- 1 -propyn- 1 -ylpiperazine
• tert-butyl (2-(((6-chloro-3-pyridinyl)sulfonyl)(2- oxo(5,5,5- 2 H)-3-pentyn-l-yl)amino)ethyl)carbamate (1.78 g, 4.25 mmol) in DCM (3 mL) was added sodium triacetoxyborohydride (3 g, 14 mmol, Sigma- Aldrich, St.
• WO2007/109810A2 in 'BuOH (1 mL) was heated at 132 °C in a microwave reactor (Biotage AB, Inc., Uppsala, Sweden) for 3 h. The mixture was partitioned between DCM (30 mL) and aqueous NaHC0 3 (half saturated, 30 mL). The organic layer was dried over Na 2 S0 4 , filtered, and concentrated.
• STEP 4 (2R)-2-(4-(4-((6-(Bis(4-methoxybenzyl)amino)-3-pyridinyl)sulfonyl)-2- ( 2 H 3 )- 1 -propyn- 1 -yl- 1 -piperazinyl)phenyl)- 1,1,1 -trifluoro-2-propanol
• a stream of N 2 was passed through a mixture of N,N-bis(4- methoxybenzyl)-5-((3-( 2 H 3 )- 1 -propyn-1 -yl- 1 -piperazinyl)sulfonyl)-2- pyridinamine (0.55 g, 1.050 mmol) and (2R)-2-(4-bromophenyl)- 1,1,1 -trifluoro- 2-propanol (0.400 g, 1.487 mmol, Intermediate N) in dioxane (5 mL) for 5 min.
• the individual diastereomers were isolated using chiral SFC.
• the method used was as follows: Chiralpak ® AD-H column (21 x 150 mm, 5 ⁇ ) using 40% (20 mM NH 3 in ethanol) in supercritical C0 2 (total flow was 70 mL/min). This produced the two diastereomers with diastereomeric and enanteomeric excesses greater than 99%.
• STEP 2 2-(4-(4-((2,6-Dichloro-3-pyridinyl)sulfonyl)-l-piperazinyl)phenyl)- 1,1,1 ,3 ,3 ,3 -hexafluoro-2-propanol
• the reaction mixture was diluted with water (20 mL) and DCM (30 mL). The organic layer was separated, washed with water, brine and dried over anhydrous Na 2 S0 4 . The solution was concentrated under reduced pressure and the residue obtained was purified by silica gel (60 to 120 mesh) column chromatography (eluent, 20% EtOAc-hexanes) to give 2-(4-(4-((2,6- dichloro-3-pyridinyl)sulfonyl)- 1 -piperazinyl)phenyl)- 1,1,1 ,3 ,3 ,3-hexafluoro-2- propanol (300 mg) as a yellow solid.
• STEP 3 2-(4-(4-((6-Amino-2-chloro-3-pyridinyl)sulfonyl)-l- piperazinyl)phenyl)- 1,1,1 ,3 ,3 ,3 -hexafluoro-2-propanol
• STEP 4 2-(4-(4-((6-Amino-2-(methylamino)-3-pyridinyl)sulfonyl)-l - piperazinyl)phenyl)- 1,1,1 ,3 ,3 ,3 -hexafluoro-2-propanol
• the reaction mixture was cooled to rt and opened carefully.
• the solution was diluted with cold water (10 mL) and EtOAc (20 mL) at rt.
• the organic layer was separated, washed with water, brine and dried over anhydrous Na 2 S04.
• Pd(dppf)Cl 2 14 mg, 0.019 mmol was added to the above mixture at rt under argon atmosphere.
• the reaction tube was sealed under argon atmosphere and contents were heated at 80 °C for 4 h.
• the reaction mixture was cooled to rt and diluted with cold water (10 mL) and EtOAc (20 mL). The organic layer was separated, washed with water, brine and dried over anhydrous Na 2 S0 4 .
• tert-butyl (5-amino-6-bromo-2- pyridinyl)carbamate 300 mg, 1.04 mmol
• triethylamine 0.29 mL, 2.08 mmol
• Pd(PPh 3 ) 2 Cl 2 36 mg, 0.052 mmol
• Cul 3. mg, 0.002 mmol
• the solution was homogenized by stirring at same temperature for 5 min and cooled to -10 °C before purging propyne gas through the solution for 5 minutes.
• the reaction tube was sealed and resulting reaction mixture was heated at 80 °C for 4 h.
• the reaction mixture was cooled to rt and filtered through a diatomaceous earth pad.
• the filtrate was diluted with cold water (30 mL) and ethyl acetate (30 mL).
• the organic layer was separated, washed with water, brine and dried over anhydrous Na 2 S0 4 .
• the resulting reaction mixture was stirred for 1 h at 0 °C. 2 mL of glacial acetic acid, CuCl 2 2H 2 0 (69 mg, 0.4 mmol) and CuCl (2 mg, 0.016 mol) were added sequentially to the above mixture and purged with S0 2 gas for 15 min at 0 °C. The resulting reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was diluted with cold water (20 mL) and ethyl acetate (50 mL). The organic layer was separated, washed with water, brine and dried over anhydrous Na 2 S0 4 .
• the resulting reaction mixture was stirred at rt under nitrogen atmosphere for 1 h.
• the reaction mixture was diluted with water (20 mL) and DCM (30 mL).
• the organic layer was separated, washed with water, brine and dried over anhydrous Na 2 S0 4 .
• the solution was
• STEP 7 2-(4-(4-((6- Amino-2-( 1 -propyn- 1 -yl)-3 -pyridinyl)sulfonyl)- 1 - piperazinyl)phenyl)- 1,1,1 ,3 ,3 ,3 -hexafluoro-2-propanol
• tert-butyl (6-(l -propyn- l-yl)-5-((4-(4- (2,2,2-trifluoro- 1 -hydroxy- 1 -(trifluoromethyl)ethyl)phenyl)- 1 - piperazinyl)sulfonyl)-2-pyridinyl)carbamate (100 mg, 0.16 mmol) was dissolved in DCM (5 mL) and cooled to 0 °C. A solution of HC1 in 1,4-dioxane (4M, 1 mL, Sigma-Aldrich, India) was added to the above solution at 0 °C.
• reaction mixture was gradually warmed to rt and stirred at rt for 2 h.
• the reaction mixture was basified with saturated NaHC0 3 solution and diluted with ethyl acetate (20 mL).
• the organic layer was separated, washed with water, brine and dried over anhydrous Na 2 S0 4 .
• STEP 2 Benzyl 3-(2-methyl-l-propen-l-yl)-l-piperazinecarboxylate
• benzyl (2-((tert- butoxycarbonyl)amino)ethyl)(4-methyl-2-oxo-3-penten- 1 -yl)carbamate 0.8 g, 2.0 mmol
• TFA 1.5 ml, 20 mmol
• Sodium triacetoxyborohydride (1.74 g, 8.20 mmol) was then added portionwise over 10 min.
• aqueous phase was extracted with EtOAc (3 x 100 mL) and the combined organic phases were washed with saturated aqueous sodium chloride (150 mL). The organic extracts were dried over sodium sulfate, filtered and concentrated under a vacuum. The resulting product was purified by silica gel column chromatography (0 to 100% EtOAc in hexanes) to afford benzyl 3-(2-methyl-l-propen-l-yl)-4-(4-(2,2,2-trifluoro-l- hydroxy- l-(trifluoromethyl)ethyl)phenyl)-l-piperazinecarboxylate (350 mg) as a yellow solid.
• Trifluoromethanesulfonic acid (0.2 ml, 2.252 mmol) was added dropwise at room temperature. After 10 min, solid NaHC0 3 was carefully added in portions.
• 6-Chloropyridine-3-sulfonyl chloride (159 mg, 0.748 mmol, Organic Process Research & Development 2009, 13, 875) was added at room temperature. The reaction was diluted with water (100 mL) and the aqueous phase was extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with water (100 mL) and saturated aqueous sodium chloride (100 mL).
• Step 5 2-(4-(4-((6-Amino-3-pyridinyl)sulfonyl)-2-(2 -methyl- 1 -propen- 1 -yl)- 1 - piperazinyl)phenyl)- 1,1,1 ,3 ,3 ,3 -hexafluoro-2-propano
• a sealable tube was charged with 2-(4-(4-((6-chloro-3- pyridinyl)sulfonyl)-2-(2 -methyl- 1 -propen- 1 -yl)- 1 -piperazinyl)phenyl)- l,l,l,3,3,3-hexafluoro-2-propanol (340 mg, 0.609 mmol), concentrated ammonium hydroxide (10 ml, 154 mmol) and EtOH (10 mL).
• the reaction mixture was heated at 110 °C overnight.
• the reaction was diluted with water (100 mL) and the aqueous phase was extracted with EtOAc (3 x 100 mL).
• the combined organic phases were washed with water (100 mL) and saturated aqueous sodium chloride (100 mL).
• EXAMPLE 26 2-(4-(4-((6-Amino-3-pyridinyl)sulfonyl)-2-(3,3-dimethyl-l- butyn- 1 -yl)- 1 -piperazinyl)phenyl)- 1,1,1 ,3 ,3 ,3 -hexafluoro-2-propanol
• Example 24 Prepared via the method described for Example 24 substituting bromo(3,3-dimethyl-l-butyn-l-yl)magnesium, generated from 3,3-dimethyl-l- butyne (Sigma-Aldrich, St. Louis, MO) and 'PrMgCl (Sigma-Aldrich, St. Louis, MO), in place of prop-l-yn-l-ylmagnesium chloride. The compound was isolated as a mixtue of two enantiomers.
• EXAMPLE 27 2-(4-((2S)-4-((6- Amino-3 -pyridinyl)sulfonyl)-2-(( 1 Z)- 1 -propen- 1 -yl)- 1 -piperazinyl)phenyl)- 1,1,1 ,3 ,3 ,3-hexafluoro-2-propanol
• the reaction was evacuated and flushed with hydrogen three times before stirring under a balloon of hydrogen for lh. After that time, the reaction was filtered through a pad of diatomaceous earth, washing with EtOH and the filtrate was concentrated. The resulting product was purified via column chromatography on silica gel (0 to 100% EtOAc in hexanes) to give 2-(4-((2S)-4-((6-amino-3- pyridinyl)sulfonyl)-2-(( 1 Z)- 1 -propen- 1 -yl)- 1 -piperazinyl)phenyl)- 1,1,1,3,3,3- hexafluoro-2-propanol (75 mg).
• EXAMPLE 28 2-(4-(4-((6-Amino-3-pyridinyl)sulfonyl)-2-propyl-l- piperazinyl)phenyl)- 1,1,1 ,3 ,3 ,3 -hexafluoro-2-propanol
• the resulting material was purified by reverse-phase preparative HPLC using a Gemini 30 x 150 mm, 0.1% TFA in CH 3 CN/H 2 0, gradient 40% to 60% over 15 min.
• the dried material was then filtered through a carbonate silica plug to provide 2-(4-(4-((6-amino-3- pyridinyl)sulfonyl)-2-propyl- 1 -piperazinyl)phenyl)- 1,1,1 ,3 ,3 ,3-hexafluoro-2- propanol (13 mg) as a mixture of two enantiomers.
• STEP 2 Benzyl 3-(3-((tert-butyl(diphenyl)silyl)oxy)-l-propyn-l-yl)-l- piperazinecarboxylate
• the resulting orange oil was purified via column chromatography (330 g of silica gel, 0 to 10% (2M NH 3 in MeOH) in CH 2 C1 2 ) to give benzyl benzyl 3-(3-((tert-butyl(diphenyl)silyl)oxy)-l- propyn-l-yl)-l-piperazinecarboxylate (12.6 g) as a brown oil.
• This material was taken up in CH 2 C1 2 (100 mL) and di-tert-butyl dicarbonate (6.20 mL, 27.0 mmol), triethylamine (10.25 ml, 73.7 mmol) and DMAP (0.300 g, 2.458 mmol) added.

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