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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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4196—1,2,4-Triazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

• R B2 is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 thioalkyl, C1-C6 alkyl-N(R N )2, phenyl, benzyl, CH2-(C3-C6 cycloalkyl), CH 2 CH2-(C 3 -C6 cycloalkyl), CH 2 -(4 to 6 membered heterocyclyl), CH 2 CH 2 -(4 to 6 membered heterocyclyl), 5 to 6 membered heteroaryl, and CH 2 -(5 to 6 membered heteroaryl); wherein when R B2 is phenyl or benzyl the phenyl ring is optionally substituted by 1 to 3 substituents selected from the group consisting of halogen, C1-C4 alkyl, C1-
• oral formulations of a compound of formula I, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients suitable for oral delivery are also provided herein.
• Cyanoalkyl refers to a C1-C6 alkyl group as defined above wherein one hydrogen atom is replaced by a cyano group ("-CN").
• cyanoalkyl groups include CNCH 2 - and CNCH2CH2-.
• protecting group refers to a substituent that is commonly employed to block or protect a particular functional group on a compound.
• an “amino- protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound.
• Suitable amino-protecting groups include acetyl, trifluoroacetyl, t- butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethylenoxycarbonyl (Fmoc).
• a "hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl.
• mammal includes, but is not limited to, humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows, pigs, and sheep.
• salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge, S. M., et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19).
• Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
• Prodrugs of the invention include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues, is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of a compound of the present invention.
• Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups.
• Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acyl group can be an alkyl ester optionally substituted with groups including, but not limited to, ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed.
• Prodrugs of this type are described in J. Med. Chem., (1996), 39:10.
• Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention. Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present invention.
• composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
• pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
• R 3a and R 3b are H, and the other is selected from the group consisting of H, D, F, CI,
• each R 5 is independently selected from the group consisting of H, F, CI, Ci-C 6 alkyl, Ci-C 6 haloalkyi, Ci- Ce alkoxy and C 1 -C6 haloalkoxy;
• R A is as defined above, and the A ring and the B ring together are:
• each R 5 is selected from the group consisting of H, F, CI, C1-C6 alkyl, C1-C6 haloalkyi, C1-C6 alkoxy and C1-C6 haloalkoxy;
• n 0, 1, 2 or 3.
• R A is selected from the group consisting of:
• R A is selected from the group consisting of:
• R A is selected from the group consisting of:
• R 1 is selected from the group consisting of hydrogen, deutero, fluoro, hydroxyl, cyano, C1-C6 alkyl, C3-C6 cycloalkyi, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C 1 -C6 alkyl substituted with one (R N )2N substituent, C 1 -C6 cyanoalkyi, C 1 -C6 alkylsulfonyl, phenyl, benzyl, 4 to 6 membered heterocyclyl, and 5 to 6 membered heteroaryl;
• each R N is methyl.
• n is 0. In some of the above embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.
• oral formulations of a compound of formula I as described in any one of the above embodiments, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients suitable for oral delivery are also provided herein.
• compositions are formulated, dosed, and administered in a fashion consistent with good medical practice.
• Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.
• the "effective amount" of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to inhibit I P1 kinase activity in order to provide a therapeutic effect in the mammal being treated.
• such an effective amount may be below the amount that is toxic to normal cells, or the mammal as a whole.
• a low dose of the compound of the invention is administered in order to provide therapeutic benefit while minimizing or preventing adverse effects.
• the compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration.
• Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
• the compound of formula I is administered orally.
• the compound of formula I is administered intravenously.
• Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which can contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and nonaqueous sterile suspensions which can include suspending agents and thickening agents.
• Receptor and channel-based methods of transporting a compound of formula I (or an embodiment thereof) across the blood-brain barrier include, but are not limited to, using glucocorticoid blockers to increase permeability of the blood-brain barrier (see, e.g., U.S. Patent Publication Nos. 2002/0065259, 2003/0162695, and 2005/0124533); activating potassium channels (see, e.g., U.S. Patent Publication No. 2005/0089473), inhibiting ABC drug transporters (see, e.g., U.S. Patent Publication No.
• Compounds of the invention may be combined with one or more other compounds of the invention or one or more other therapeutic agent as any combination thereof, in the treatment of the diseases and disorders provided herein.
• a compound of the invention may be administered simultaneously, sequentially or separately in combination with other therapeutic agents known to be useful for the treatment of a disease or disorder selected from those recited above.
• “combination” refers to any mixture or permutation of one or more compounds of the invention and one or more other compounds of the invention or one or more additional therapeutic agent. Unless the context makes clear otherwise, “combination” may include simultaneous or sequentially delivery of a compound of the invention with one or more therapeutic agents. Unless the context makes clear otherwise, “combination” may include dosage forms of a compound of the invention with another therapeutic agent. Unless the context makes clear otherwise, “combination” may include routes of administration of a compound of the invention with another therapeutic agent. Unless the context makes clear otherwise, “combination” may include formulations of a compound of the invention with another therapeutic agent. Dosage forms, routes of administration and pharmaceutical compositions include, but are not limited to, those described herein.
• Step 1 2-(cis-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-yl)butan-2-ol
• Step 2 Cis-2-(l-fluoro-l-methyl-propyl)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b] [1,2,4] triazole
• Step 2 rac-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carbaldehyde
• Step 3 (E)- rac-(5S,7S)-3-(7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-yl)prop- 2-enenitrile and (Z)- rac-(5S,7S)-3-(7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2- yl)prop-2-enenitrile
• Step 2 (5S,7S)-7-fluoro-5-phenyl-2-[rac-(lR,2R)-2-(methoxymethyl)cyclopropyl]-6,7-dihydro-5H- pyrrolo[l,2-b] [l,2,4]triazole
• rac-(lR,2R)-2-[(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro -5H-pyrrolo[l,2- b][l,2,4]triazol-2-yl]cyclopropylmethanol (45 mg, 0.16 mmol) in tetrahydrofuran (2 mL) was added sodium hydride (60%, 13 mg, 0.33 mmol) at 0 °C.
• Prep SFC Information Column: Chiralcel OX 5 ⁇ , (250 x 21.2 mm), Mobile Phase: Carbon Dioxide (A) / 0.1% Ammonium Hydroxide in Isopropanol (B), Elution Program Isocratic: 12% B, Flow Rate: 70 mL/min, Column Temperature: 25°C, Wavelength: 211 nm.
• the reaction mixture was diluted with 100 ml EtOAc, washed with water, filtered over celite, and the organic layer was washed with brine.
• the crude product was purified by column chromatography, flushed with 0-10% MeOH in DCM and further purified by prep-HPLC (Gemini-NX C18 50x30 mm, 5um, 20-60% of 0.1% Formic Acid in Water Acetonitrile) to afford final product (6 mg, 5%) as a white solid.
• Step l (l-((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-yl)-lH-pyrazol-4- yl)methanol
• Step 3 (5S,7S)-7-fluoro-5-phenyl-2-[(lS,2S)-2-methylcyclopropyl]-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazole and (5S,7S)-7-fluoro-5-phenyl-2-[(lR,2R)-2-methylcyclopropyl]-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazole
• Step 2 (5S)-2-(cyclopropylmethyl)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole
• cyclopropyl-[(5S)-5-(2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2- yl]methanol 96 mg, 0.35 mmol
• trifluoroacetic acid 2 mL, 26.93 mmol
• triethylsilane 2 mL, 10.54 mmol

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