Classifications

• • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • 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
• • 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
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
  • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
  • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
  • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
  • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
  • G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
  • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
  • G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
  • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
  • G01N2333/775—Apolipopeptides
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N2800/00—Detection or diagnosis of diseases
  • G01N2800/28—Neurological disorders
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N2800/00—Detection or diagnosis of diseases
  • G01N2800/28—Neurological disorders
  • G01N2800/2814—Dementia; Cognitive disorders
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N2800/00—Detection or diagnosis of diseases
  • G01N2800/28—Neurological disorders
  • G01N2800/2814—Dementia; Cognitive disorders
  • G01N2800/2821—Alzheimer
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N2800/00—Detection or diagnosis of diseases
  • G01N2800/28—Neurological disorders
  • G01N2800/2814—Dementia; Cognitive disorders
  • G01N2800/2828—Prion diseases
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N2800/00—Detection or diagnosis of diseases
  • G01N2800/28—Neurological disorders
  • G01N2800/2835—Movement disorders, e.g. Parkinson, Huntington, Tourette
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N2800/00—Detection or diagnosis of diseases
  • G01N2800/28—Neurological disorders
  • G01N2800/285—Demyelinating diseases; Multipel sclerosis

Definitions

• SCDs Stearoyl-CoA desaturases introduce a double bond in the C9-C10 position of saturated fatty acids such as palmitoyl-CoA and stearoyl-CoA which are converted to palmitoleoyl-CoA and oleoyl- CoA, respectively.
• SCD1 One SCD gene, SCD1
• SCD5a there are two forms of SCD5, SCD5a and SCD5b, which differ at the C-terminus.
• the present inventors have discovered that inhibition of SCDs is capable of suppressing toxicity in cells related to protein misfolding and/or aggregation. Accordingly, inhibition of SCDs may provide new methods for the treatment of diseases and disorders related to toxicity caused by protein misfolding and/or aggregation. Summary of the Invention
• This disclosure provides compounds that modulate the activity of SCDs (e.g., SCD1 and/or SCD5), pharmaceutical compositions including such compounds, and methods of utilizing such compounds and compositions for modulating the activity of SCDs for the treatment of diseases and disorders related to toxicity caused by proteins such as toxicity related to misfolding and/or aggregation of proteins.
• the disease or disorder is a neurological disorders.
• the disclosure provides a method of treating a neurological disorder in a subject in need thereof. This method includes administering an effective amount of an SCD inhibitor.
• the disclosure provides a method of treating a neurological disorder in a subject in need thereof.
• the method includes administering an SCD inhibitor in an amount sufficient to suppress toxicity in a cell (e.g., in a mammalian neural cell) related to a protein (e.g., toxicity related to misfolding and/or aggregation of a protein such as ⁇ -synuclein or ApoE4).
• a cell e.g., in a mammalian neural cell
• a protein e.g., toxicity related to misfolding and/or aggregation of a protein such as ⁇ -synuclein or ApoE4
• the toxicity is ⁇ -synuclein-related toxicity.
• the toxicity is ApoE4-related toxicity.
• the disclosure provides a method of suppressing toxicity in a cell (e.g., a neural cell) related to a protein (e.g., toxicity related to misfolding and/or aggregation of a protein such as ⁇ - synuclein or ApoE4).
• This method includes contacting a cell with an SCD inhibitor.
• the disclosure provides a method of treating a neurological disorder in a subject in need thereof.
• This method includes (a) determining the level (e.g., in a neural cell) of a protein or a particular form of a protein (e.g., a misfolded form of a protein) related to a neurological disorder (e.g., ⁇ -synuclein, ApoE4, or an undesired form thereof) in the subject; and (b) administering an effective amount of an SCD inhibitor to the subject if the level of the protein or the particular form of the protein (e.g., a misfolded form of the protein) related to a neurological disorder is greater than a predetermined level (e.g., the level in a sample from a subject that does not have a neurological disorder).
• a predetermined level e.g., the level in a sample from a subject that does not have a neurological disorder.
• the disclosure provides a method of treating a neurological disorder in a subject in need thereof, wherein the subject has an elevated level, or is predicted to have an elevated level (e.g., based on genetic markers) of a protein or a particular form of a protein related to a neurological disorder (e.g., ⁇ -synuclein, ApoE4, or an undesired form thereof).
• This method includes administering an effective amount of an SCD inhibitor to the subject.
• the subject has an elevated level of the protein or the particular form of the protein (e.g., a misfolded form of the protein) related to a neurological disorder compared to a predetermined reference value (e.g., a value in a sample from a healthy subject).
• the disclosure provides a method of treating a neurological disorder in a subject, wherein the subject has an elevated level (e.g., the subject has a level about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 150%, about 200%, about 300%, about 400%, about 500%, or more greater as compared to a reference such as the level in a sample from a healthy subject) of a protein or a particular form of a protein (e.g., a misfolded form of a protein) related to a neurological disorder (e.g., ⁇ -synuclein, ApoE4, or an undesired form thereof), the method including administering an effective amount of an SCD inhibitor.
• an SCD inhibitor e.g., ⁇ -synuclein, Apo
• the disclosure provides a method of treating a neurological disorder in a subject in need thereof.
• This method includes (a) administering an effective amount of an SCD inhibitor to the subject; and (b) determining the level (e.g., in a neural cell) of a protein or a particular form of a protein related to a neurological disorder (e.g., ⁇ -synuclein, ApoE4, or an undesired form thereof) in the subject.
• a neurological disorder e.g., ⁇ -synuclein, ApoE4, or an undesired form thereof
• the disclosure provides a method of treating a neurological disorder in a subject in need thereof.
• This method includes (a) administering an effective amount of an SCD inhibitor to the subject; and (b) determining the level of neurite degeneration (e.g., by determining the level of a marker of neurite degeneration) in the subject.
• the disclosure provides a method of suppressing neurite degeneration in a subject.
• This method includes administering an SCD inhibitor to the subject in an amount sufficient to suppress neurite degeneration.
• the SCD inhibitor is an SCD1 inhibitor. In some embodiments of any of the foregoing methods, the SCD inhibitor is an SCD5 inhibitor. In some embodiments, the SCD inhibitor is selective for SCD1 over SCD5. In some embodiments of any of the foregoing methods, the SCD inhibitor has activity for SCD1 that is at least 2.5-fold greater (e.g., at least 5- fold greater, at least 10-fold greater, at least 20-fold greater) than the activity of the inhibitor for SCD5. In some embodiments, the SCD inhibitor is selective for SCD5 over SCD1.
• the SCD inhibitor has activity for SCD5 that is at least 2.5-fold greater (e.g., at least 5-fold greater, at least 10-fold greater, at least 20-fold greater) than the activity of the inhibitor for SCD1.
• the SCD inhibitor is a non-selective SCD inhibitor.
• administering includes contacting a cell with an effective amount of an SCD inhibitor.
• the SCD inhibitor is any compound described herein (e.g., any compound having the structure of any one of Formula I-LXI). In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula I. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula II. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula III. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula IV. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula V.
• the SCD inhibitor is a compound of Formula VI. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula VII. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula VIII. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula IX. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula X. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula XI. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula XII.
• the SCD inhibitor is a compound of Formula XIII. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula XIV. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula XV. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula XVI. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula XVII. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula XVIII. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula XIX.
• the SCD inhibitor is a compound of Formula XX. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula XXI. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula XXII. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula XXIII. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula XXIV. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula XXV.
• the SCD inhibitor is a compound of Formula XXVI. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula XXVII. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula XXVIII. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula XXIX. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula XXX. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula XXI.
• the SCD inhibitor is a compound of Formula XXXII. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula XXXIII. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula XXXIV. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula XXXV. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula XXXVI. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula XXXVII.
• the SCD inhibitor is a compound of Formula XXXVIII. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula XXXIX. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula XL. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula XLI. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula XLII. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula XLIII.
• the SCD inhibitor is a compound of Formula XLIV. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula XLV. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula XLVI. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula XLVII. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula XLVIII. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula XLIX.
• the SCD inhibitor is a compound of Formula L. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula LI. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula LII. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula LIII. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula LIV. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula LV. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula LVI.
• the SCD inhibitor is a compound of Formula LVII. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula LVIII. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula LIX. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula LX. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula LXI.
• the SCD inhibitor is not a compound of Formula I. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula II. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula III. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula IV. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula V. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula VI. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula VII.
• the SCD inhibitor is not a compound of Formula VIII. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula IX. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula X. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula XI. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula XII. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula XIII.
• the SCD inhibitor is not a compound of Formula XIV. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula XV. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula XVI. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula XVII. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula XVIII. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula XIX.
• the SCD inhibitor is not a compound of Formula XX. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula XXI. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula XXII. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula XXIII. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula XXIV. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula XXV.
• the SCD inhibitor is not a compound of Formula XXVI. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula XXVII. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula XXVIII. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula XXIX. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula XXX. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula XXI.
• the SCD inhibitor is not a compound of Formula XXXII. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula XXXIII. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula XXXIV. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula XXXV. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula XXXVI. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula XXXVII.
• the SCD inhibitor is not a compound of Formula XXXVIII. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula XXXIX. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula XL. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula XLI. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula XLII. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula XLIII.
• the SCD inhibitor is not a compound of Formula XLIV. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula XLV. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula XLVI. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula XLVII. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula XLVIII. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula XLIX.
• the SCD inhibitor is not a compound of Formula L. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula LI. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula LII. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula LIII. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula LIV. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula LV. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula LVI.
• the SCD inhibitor is not a compound of Formula LVII. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula LVIII. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula LIX. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula LX. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of Formula LXI.
• the SCD inhibitor is a compound of any one of Formula I-XXX. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of any one of Formula XXXI-XLII. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of any one of Formula XLIII-XLIV. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of any one of Formula XLVI-XLVII. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of any one of Formula L- LX.
• the SCD inhibitor is not a compound of any one of Formula I-XXX. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of any one of Formula XXXI-XLII. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of any one of Formula XLIII-XLIV. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of any one of Formula XLVI-XLVII. In some embodiments of any of the foregoing methods, the SCD inhibitor is not a compound of any one of Formula L-LX.
• a cell expresses ⁇ -synuclein and/or a human apolipoprotein E (ApoE) protein (e.g., ApoE2, ApoE3, or ApoE4).
• ApoE apolipoprotein E
• the subject carries one or two copies of the ApoE4 allele).
• the subject is a human.
• the cell is a neural cell (e.g., a neuron or glial cell).
• the method includes inhibition of neurite degeneration or cell death.
• Neurological disorders include, but are not limited to Alexander disease,
• AD amyotrophic lateral sclerosis
• ataxia telangiectasia Canavan disease
• Cockayne syndrome corticobasal degeneration
• Creutzfeldt-Jakob disease Huntington disease
• Kennedy's disease Krabbe disease
• Lewy body dementia Machado-Joseph disease
• multiple sclerosis PD
• Pelizaeus-Merzbacher disease Pick's disease, primary lateral sclerosis, Ref sum's disease, Sandhoff disease, Schilder's disease, Steele-Richardson-Olszewski disease, tabes dorsalis, frontal temporal
• the neurological disorder is a proteopathy (e.g., a synucleinopathy, AD, Alexander disease, amyotrophic lateral sclerosis (ALS), a prion disease (e.g., Creutzfeldt-Jakob disease), achado-Joseph disease, Pick's disease, or frontotemporal dementia).
• a proteopathy e.g., a synucleinopathy, AD, Alexander disease, amyotrophic lateral sclerosis (ALS), a prion disease (e.g., Creutzfeldt-Jakob disease), achado-Joseph disease, Pick's disease, or frontotemporal dementia.
• the neurological disorder is a synucleinopathy such as Parkinson’s disease (PD), dementia with Lewy bodies, pure autonomic failure, multiple system atrophy, incidental Lewy body disease, pantothenate kinase- associated neurodegeneration, Alzheimer's disease, Down's Syndrome, Gaucher disease, or the Parkinsonism-dementia complex of Guam.
• the neurological disorder is a progressive neurodegenerative disorder (e.g. Alpers’ disease, ataxia telangectsia,
• the neurological disorder is an ApoE-associated neurodegenerative disorder (e.g., AD, vascular cognitive impairment, cerebral amyloid angiopathy, traumatic brain injury, or multiple sclerosis).
• AD ApoE-associated neurodegenerative disorder
• the method further includes administering an additional therapeutic agent (e.g., a small molecule, an antibody or fragment thereof, or a nucleic acid) to the subject.
• an additional therapeutic agent e.g., a small molecule, an antibody or fragment thereof, or a nucleic acid
• the method further includes administering to the subject a cognition-enhancing agent, an antidepressant agent, an anxiolytic agent, an antipsychotic agent, a sedative, a dopamine promoter, or an anti-tremor agent.
• the additional therapeutic agent and the SCD inhibitor are administered within 28 days of each other (e.g., within 21, 14, 10, 7, 5, 4, 3, 2, or 1 days) or within 24 hours (e.g., 12, 6, 3, 2, or 1 hours; or concomitantly) in amounts that together are effective to treat the subject.
• the SCD inhibitor is a compound of Formula Ia-Id:
• x and y are each independently 0, 1, 2 or 3;
• each R 1 is independently selected from the group consisting of hydrogen, C1-C12alkyl,
• each R 4 is independently selected from hydrogen, fluoro, chloro, C 1 -C 12 alkyl,
• R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , R 8 and R 8a are each independently selected from hydrogen or
• R 5 and R 5a together, R 6 and R 6a together, or R 7 and R 7a together, or R 8 and R 8a together are an oxo group, provided that when V is -C(O)-, R 6 and R 6a together or R 8 and R 8a together do not form an oxo group, while the remaining R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , R 8 and R 8a are each independently selected from hydrogen or C1-C3alkyl;
• R 5 , R 5a , R 6 and R 6a together with one of R 7 , R 7a , R 8 and R 8a forms a direct bond or an alkylene bridge, while the remaining R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , R 8 and R 8a are each independently selected from hydrogen or C 1 -C 3 alkyl; and
• each R 9 is independently selected from hydrogen or C1-C6alkyl.
• J and K are each independently N or C(R 10 );
• Q is -N(R 4 )-, -O-, -S(O)t (where t is 0, 1 or 2), -C(O)-, -C(S)-, an alkylene chain or an alkenylene chain;
• V is a direct bond, -N(R 1 )-, -N(R 1 )C(O)-, -O-, -C(O)-, -C(O)O-, -C(S)-, -C(O)N(R 1 )-, -S(O)t- (where t is 0, 1 or 2) or -S(O)pN(R 1 )- (where p is 1 or 2);
• W is a direct bond, -N(R 1 )C(O)-, -C(O)N(R 1 )-, -OC(O)N(R 1 )-, -N(R 1 )C(O)N(R 1 )-, -O-, -N(R 1 )-, -S(O)t- (where t is 0, 1 or 2), -N(R 1 )S(O)p- (where p is 1 or 2), -S(O)pN(R 1 )- (where p is 1 or 2), -C(O)-, -OS(O)2N(R 1 )-, -OC(O)-, -C(O)O-, -N(R 1 )C(O)O- or -C(R 1 )2-;
• R 2 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C2-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl, and C3-C12heteroarylalkyl;
• R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• R 3 is selected from the group consisting of hydrogen, C1-C12alkyl, C2-C12alkenyl,
• R 3 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• R 10 is independently selected from hydrogen, fluoro, chloro, C1-C12alkyl or C1-C12alkoxy; or as a stereoisomer, enantiomer or tautomer thereof, as a mixture of stereoisomers, as a pharmaceutically acceptable salt
• G is -N(R 4 )-, -O-, or -S(O)t- (where t is 0, 1 or 2);
• J and K are each independently N or C(R 11 );
• V is -C(O)-, -C(O)O-, -C(S)-, -C(O)N(R 1 )-, -S(O) t - (where t is 0, 1 or 2), -S(O) p N(R 1 )- (where p is 1 or 2), -C(R 10 )H-, -N(R 1 )-, -O-;
• W is a direct bond, -N(R 1 )C(O)-, -C(O)N(R 1 )-, -OC(O)N(R 1 )-, -N(R 1 )C(O)N(R 1 )-, -O-, -N(R 1 )-, -S(O)t- (where t is 0, 1 or 2), -N(R 1 )S(O)p- (where p is 1 or 2), -S(O)pN(R 1 )- (where p is 1 or 2), -C(O)-, -OS(O) 2 N(R 1 )-, -OC(O)-, -C(O)O-, -N(R 1 )C(O)O-;
• R 2 is selected from the group consisting of hydrogen, C1-C12alkyl, C2-C12alkenyl,
• R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• R 3 is selected from the group consisting of hydrogen, C1-C12alkyl, C2-C12alkenyl,
• R 3 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• R 10 is a hydrogen or C1-C3alkyl
• R 11 is independently selected from hydrogen, fluoro, chloro, C1-C12alkyl or C1-C12alkoxy; or a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof.
• J is N or C(R 10 );
• V is a direct bond, -N(R 1 )-, -N(R 1 )C(O)-, -O-, -C(O)-, -C(O)O-, -C(S)-, -C(O)N(R 1 )-, -S(O)p- (where p is 1 or 2), or -S(O)pN(R 1 )- (where p is 1 or 2);
• W is -N(R 1 )C(O)-, -C(O)N(R 1 )-, -OC(O)N(R 1 )-, -N(R 1 )C(O)N(R 1 )-, -O-, -N(R 1 )-, -S(O) t - (where t is 0, 1 or 2), -N(R 1 )S(O)p- (where p is 1 or 2), -S(O)pN(R 1 )- (where p is 1 or 2), -C(O)-, -OS(O)2N(R 1 )-, -OC(O)-, -C(O)O-, -N(R 1 )C(O)O- or -C(R 1 )2-;
• R 2 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C2-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl, and C3-C12heteroarylalkyl; or R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• R 3 is selected from the group consisting of hydrogen, C 1 -C 12 alkyl, C 2 -C 12 alkenyl,
• R 3 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• R 10 is independently selected from hydrogen, fluoro, chloro, C1-C12alkyl or C1-C12alkoxy; or as a stereoisomer, enantiomer or tautomer thereof, as a pharmaceutically acceptable salt thereof, or as a prodrug thereof.
• J and K are each independently N or C(R 10 );
• V is direct bond, -N(R 1 )-, -N(R 1 )C(O)-, -O-, -C(O)-, -C(O)O-, -C(S)-, -C(O)N(R 1 )-, -S(O)p- (where p is 1 or 2), or -S(O)pN(R 1 )- (where p is 1 or 2);
• R 2 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C2-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl, and C3-C12heteroarylalkyl;
• R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• R 3 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C2-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl and C3-C12heteroarylalkyl;
• R 3 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• R 10 is independently selected from hydrogen, fluoro, chloro, C1-C12alkyl or C1-C12alkoxy; or as a stereoisomer, enantiomer or tautomer thereof, as a mixture of stereoisomers, as a pharmaceutically acceptable salt thereof, or as a prodrug thereof.
• the invention provides compounds of Formula Ib having the following Formula Iba:
• x and y are each independently 1, 2 or 3;
• R 12 is hydrogen, -C(O)OR 13 , -C(O)N(R 13 )2, C1-C12alkyl, C2-C12hydroxyalkyl, C4-C12cycloalkylalkyl or C7-C19aralkyl; and
• each R 13 is independently selected from hydrogen, C1-C12alkyl, C2-C12alkenyl,
• C2-C12hydroxyalkyl C2-C12hydroxyalkenyl, C2-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl and C3-C12heteroarylalkyl; or as a stereoisomer, enantiomer or tautomer thereof, as a mixture of stereoisomers, as a pharmaceutically acceptable salt thereof, or as a prodrug thereof.
• Compounds of Formula (I) may be synthesized by methods known in the art, e.g., those described in International Patent Publications No. WO2006/034341, WO2006/034315, WO2006/034338, and WO2006/034440.
• the SCD inhibitor is a compound disclosed in International Patent Publications No. WO2006/034341, WO2006/034315, WO2006/034338, and WO2006/034440, the compounds of which are herein incorporated by reference.
• the SCD inhibitor is a compound of Formula II:
• y is 0, 1, 2, or 3;
• K is N or C(R 10 );
• V is -N(R 1 )-, -O-, -C(R 10 ) 2 -, -C(O)-, -C(O)O-, -C(S)-, -C(O)N(R 1 )-, -S(O) t - (where t is 0, 1 or 2) or -S(O)pN(R 1 )- (wherein p is 1 or 2), provided that when K is N, V cannot be -S-;
• W is a direct bond, -N(R 1 )C(O)-, -C(O)N(R 1 )-, -OC(O)N(R 1 )-, -N(R 1 )C(O)N(R 1 )-, -O-, -N(R 1 )-, -S(O)t- (where t is 0, 1 or 2), -N(R 1 )S(O)p- (where p is 1 or 2), -S(O)pN(R 1 )- (where p is 1 or 2), -C(O)-, -OS(O) 2 N(R 1 )-, -OC(O)-, -C(O)O-, or -N(R 1 )C(O)O-;
• each R 1 is independently selected from the group consisting of hydrogen, C1-C12alkyl, C2-C12hydroxyalkyl, C4-C12cycloalkylalkyl and C7-C19aralkyl;
• R 2 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C2-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C19aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 1 -C 12 heteroaryl, and C 3 -C 12 heteroarylalkyl;
• R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• R 3 is selected from the group consisting of C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 hydroxyalkyl, C2-C12hydroxyalkenyl, C2-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl and C3-C12heteroarylalkyl;
• R 3 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• each R 4 is independently selected from hydrogen, fluoro, chloro, C1-C12alkyl, C1-C12alkoxy, haloalkyl, cyano, nitro or -N(R 9 )2;
• R 4a is hydrogen, fluoro, chloro, C1-C12alkyl, C1-C12alkoxy, haloalkyl, cyano, nitro or -N(R 9 )2; or R 4a is a direct bond to an adjacent carbon;
• R 6 , R 6a , R 7 , R 7a , R 8 and R 8a are each independently selected from hydrogen or C1-C3alkyl;
• R 6 and R 6a together, or R 7 and R 7a together, or R 8 and R 8a together are an oxo group, provided that when V is -C(O)-, R 6 and R 6a together or R 8 and R 8a together do not form an oxo group, while the remaining R 6 , R 6a , R 7 , R 7a , R 8 and R 8a are each independently selected from hydrogen or C1-C3alkyl; or one of R 6 and R 6a together with one of R 7 , R 7a , R 8 and R 8a forms a direct bond or an alkylene bridge, while the remaining R 6 , R 6a , R 7 , R 7a , R 8 and R 8a are each independently selected from hydrogen or C1-C3alkyl;
• each R 9 is independently selected from hydrogen or C1-C6alkyl
• R 10 is independently selected from hydrogen, fluoro, chloro, C1-C12alkyl or C1-C12alkoxy; or as a stereoisomer, enantiomer or tautomer thereof, as a mixture of stereoisomers, as a pharmaceutically acceptable salt thereof, or as a prodrug thereof.
• Compounds of Formula (II) may be synthesized by methods known in the art, e.g., those described in International Patent Publication No. WO2006/034279.
• the SCD inhibitor is a compound disclosed in International Patent Publication No. WO2006/034279, the compounds of which are herein incorporated by reference.
• the SCD inhibitor is a compound of Formula III:
• p 0 to 8.
• each R 1 is independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, cycloalkylalkyl and aralkyl;
• each R 1a is selected from the group consisting of hydrogen, C1-C6alkyl, cycloalkylalkyl, -OR 1 , and cyano;
• R 2 is selected from the group consisting of alkyl, alkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl;
• R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• R 3 is selected from the group consisting of alkyl, alkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl;
• R 3 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• W is -N(R 1 )C(O)-, -C(O)N(R 1 )-, -OC(O)N(R 1 )-, -N(R 1 )C(O)N(R 1 )-, -O-, -N(R 1 )-, -S(O)t- (where t is 0, 1 or 2), -C(O)-, -N(R 1 )S(O)2-, -S(O)2N(R 1 )-, -OS(O)2N(R 1 )-, -OC(O)-, -C(O)O-, -N(R 1 )C(O)O-,
• J is selected from N or C(R 6 );
• each R 4 is alkyl
• R 4 together with another one of R 4 on a different carbon atom forms an alkylene bridge, while the remaining R 4 's are each alkyl;
• R 5 is independently selected from hydrogen, alkyl, fluoro, chloro, or -C(O)OR 7 ;
• R 6 is selected from hydrogen, alkyl, fluoro, or chloro
• R 7 is hydrogen, alkyl, aryl or aralkyl.
• W is -N(R 1 )C(O)-R 9 -, -S(O)t-R 9 - (where t is 1, 2), -C(O)-R 9 -, -OC(O)-R 9 -, -N(R 1 )C(NR 1a )-R 9 -, -C(NR 1a )-R 9 -, -N(R 1 )C(S)-R 9 -, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl or a direct bond;
• K is selected from N or C(R 7 );
• V is -C(O)-, -C(O)O-, -C(S)-, -C(O)N(R 1 )-, -S(O)t (where t is 0, 1 or 2), -S(O)qN(R 1 )- (where q is 1 or 2), -C(R 8 )H- or -C(NR 1a )-;
• V is -O-, -C(O)-, -C(O)O-, -OC(O)-, -C(S)-, -C(O)N(R 1 )-, -N(R 1 )C(O)-, -S(O)t- (where t is 0, 1 or 2), -S(O) q N(R 1 )- (where q is 1 or 2), -N(R 1 )S(O) q - (where q is 1 or 2), -C(R 8 )H- or -C(NR 1a )-;
• J is selected from -O-, -N(R 1 )-, -S(O)t- (where t is 0, 1 or 2) or -C(R 6 )2-;
• R 4 and R 4a are each independently selected from hydrogen or alkyl
• R 4 and R 4a together form an oxo group
• R 5 and 5a are each independently selected from a hydrogen or alkyl
• R 5 and R 5a together form an oxo group
• each R 6 is alkyl
• R 6 or one of R 6 together with another R 6 on different carbon atom from an alkylene bridge and the other R 6 ’s are each alkyl;
• R 7 is selected from hydrogen, alkyl, fluoro, or chloro
• R 8 is selected from hydrogen, alkyl, fluoro, chloro, methoxy, trifluoromethyl, cyano, nitro or -N(R 1 )2;
• each R 9 is independently a direct bond, a straight or branched alkylene chain or a straight or branched alkenylene chain.
• W is -N(R 1 )C(O)-, -C(O)N(R 1 )-, -OC(O)N(R 1 )-, -N(R 1 )C(O)N(R 1 )-, -O-, -N(R 1 )-, -S(O)t- (where t is 0, 1 or 2), -C(O)-, -N(R 1 )S(O)2-, -S(O)2N(R 1 )-, -OS(O)2N(R 1 )-, -OC(O)-, -C(O)O-, -N(R 1 )C(O)O-, -N(R 1 )C(NR 1a )N(R 1 )-, -N(R 1 )C(S)N(R 1 )-, -N(R 1 )C(NR 1a )-, -C(NR 1a )N(R 1
• K is selected from N or C(R 9 );
• V is -C(O)-, -C(O)O-, -C(S)-, -C(O)N(R 1 )-, -S(O)t (where t is 0, 1 or 2), -S(O)qN(R 1 )- (where q is 1 or 2), -C(R 8 )H- or -C(NR 1a )-;
• V is -O-, -C(O)-, -C(O)O-, -OC(O)-, -C(S)-, -C(O)N(R 1 )-, -N(R 1 )C(O)-, -S(O)t- (where t is 0, 1 or 2), -S(O)qN(R 1 )- (where q is 1 or 2), -N(R 1 )S(O)q- (where q is 1 or 2), -C(R 8 )H- or -C(NR 1a )-;
• R 4 and R 4a are each independently selected from the group consisting of hydrogen, alkyl, aryl, fluoro or chloro;
• R 4 and R 4a together form an oxo group
• R 5 is selected from alkyl, aryl, heteroaryl, cyano or -N(R 1 )2;
• each R 6 is alkyl
• R 6 or one of R 6 together with another R 6 on different carbon atom from an alkylene bridge and the other R 6 ’s are each alkyl;
• R 7 and R 7a are independently selected from hydrogen and alkyl;
• R 8 is selected from hydrogen, alkyl, fluoro, chloro, methoxy, trifluoromethyl, cyano, nitro or -N(R 1 )2;
• R 9 is selected from hydrogen, alkyl, fluoro or chloro.
• Compounds of Formula (III) may be synthesized by methods known in the art, e.g., those described in International Patent Publications No. WO2006/125181, WO2007/046868, and
• the SCD inhibitor is a compound disclosed in International Patent Publications No. WO2006/125181, WO2007/046868, and WO2006/125194, the compounds of which are herein incorporated by reference.
• the SCD inhibitor is a compound of Formula IVa-IVb:
• each R 1 is independently selected from the group consisting of hydrogen, C1-C12alkyl,
• R 2 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C2-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl, and C3-C12heteroarylalkyl;
• R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• R 3 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C2-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl and C3-C12heteroarylalkyl;
• R 3 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 10 , and R 10a are each independently selected from hydrogen or C1-C3alkyl;
• R 7 and R 7a together, or R 8 and R 8a together, or R 9 or R 9a together, or R 10 and R 10a together are an oxo group, provided that when V is -C(O)-, R 7 and R 7a together or R 8 and R 8a together do not form an oxo group, while the remaining R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 10 and R 10a are each independently selected from hydrogen or C1-C3alkyl;
• R 10 , R 10a , R 7 and R 7a together with one of R 8 , R 8a , R 9 and R 9a form an alkylene bridge, while the remaining R 10 , R 10a , R 7 , R 7a , R 8 , R 8a , R 9 and R 9a are each independently selected from hydrogen or C1-C3alkyl;
• R 11 is a hydrogen or C1-C3alkyl; and each R 13 is independently selected from hydrogen or C1-C6alkyl; or
• W is -O-, -N(R 1 )-, -C(R 1 )2-, -C(O)-, -OC(O)-, -S(O)t- (where t is 0, 1 or 2), -N(R 1 )S(O)t- (where t is 1 or 2), -S(O)2N(R 1 )-, -C(O)N(R 1 )-, -C(S)N(R 1 )-, -OS(O)2N(R 1 )-, -OC(O)N(R 1 )-, -OC(S)N(R 1 )-, -OC(S)N(R 1 )-,
• V is -C(O)-, -C(S)-, -C(O)N(R 1 )-, -C(O)O-, -C(S)O-, -S(O) t - (where t is 1 or 2), -S(O) t N(R 1 )- (where t is 1 or 2) or -C(R 11 )H;
• R 4 , R 5 , and R 6 are each independently selected from hydrogen, bromo, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro, or -N(R 13 )2;
• W is -O-, -N(R 1 )-, -C(O)-, -S(O)t- (where t is 0, 1 or 2), -N(R 1 )S(O)2-, -S(O)2N(R 1 )-, -OS(O)2N(R 1 )-, -C(O)N(R 1 )-, -OC(O)N(R 1 )-, -C(S)N(R 1 )-, -OC(S)N(R 1 )-, -N(R 1 )C(O)-, -N(R 1 )C(O)N(R 1 )-;
• V is -C(O)-, -C(S)-, -C(O)N(R 1 )-, -C(O)O-, -S(O)2-, -S(O)2N(R 1 )- or -C(R 11 )H-;
• R 4 , R 5 , and R 6 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro, or -N(R 13 )2;
• the invention provides compounds of Formula (IVa) having the following Formula (IVca):
• R 2 is selected from the group consisting of C7-C12alkyl, C3-C12alkenyl, C7-C12hydroxyalkyl, C2-C12alkoxyalkyl, C3-C12hydroxyalkenyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, C13-C19aralkyl,
• R 2 is not pyrazinyl, pyridinonyl, pyrrolidinonyl or imidazolyl;
• R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, where some or all of the rings may be fused to each other;
• R 3 is selected from the group consisting of C3-C12alkyl, C3-C12alkenyl, C3-C12hydroxyalkyl, C3-C12hydroxyalkenyl, C3-C12alkoxy, C3-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl and C3-C12heteroarylalkyl; or R 3 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• R 9 or R 9a together, or R 10 and R 10a together form an oxo group, while the remaining R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 10 and R 10a are each independently selected from hydrogen or C1-C3alkyl;
• the invention provides compounds of Formula IVa having the following Formula IVcb:
• R 2 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C1-C6alkoxy, C3-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl,
• R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• R 3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C1-C6alkyl, C1-C6trihaloalkyl, C1-C6trihaloalkoxy, C1-C6alkylsulfonyl, -N(R 12 )2, -OC(O)R 12 , -C(O)OR 12 , -S(O)2N(R 12 )2, cycloalkyl, heterocyclyl, heteroaryl and
• R 3 is not phenyl substituted with optionally substituted thienyl
• each R 12 is independently selected from hydrogen, C1-C6alkyl, C3-C6cycloalkyl, aryl or aralkyl.
• the invention provides compounds of Formula IVa having the following Formula IVd:
• Va is -C(O)-, -C(S)-, -C(O)N(R 1 )-, -C(S)N(R 1 )-, -C(O)O-, -C(S)O-, -S(O)t- (where t is 1 or 2), or -S(O)tN(R 1 )- (where t is 1 or 2);
• R 2 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C1-C6alkoxy, C3-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C 7 -C 19 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 1 -C 12 heteroaryl, and C 3 -C 12 heteroarylalkyl; or R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other.
• the invention provides compounds of Formula IVa having the following Formula IVe:
• Va is -C(O)-, -C(S)-, -C(O)N(R 1 )-, -C(S)N(R 1 )-, -C(O)O-, -C(S)O-, -S(O)t- (where t is 1 or 2), or -S(O)tN(R 1 )- (where t is 1 or 2);
• R 2 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C3-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl, and C3-C12heteroarylalkyl;
• R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other.
• the invention provides compounds of Formula IVa having the following Formula IVf:
• Wa is -O-, -N(R 1 )-, -S(O)t- (where t is 0, 1 or 2);
• Va is -C(O)-, -C(S)-, -C(O)N(R 1 )-, -C(S)N(R 1 )-, -C(O)O-, -C(S)O-, -S(O)t- (where t is 1 or 2), or -S(O)tN(R 1 )- (where t is 1 or 2);
• R 2 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C3-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl, and C3-C12heteroarylalkyl;
• R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other.
• the invention provides compounds of Formula IVa having the following Formula IVaa:
• W is -N(R 1 )S(O)t- (where t is 1 or 2);
• V is -C(O)-, -C(S)-, -C(O)N(R 1 )-, -C(S)N(R 1 )-, -C(O)O-, -C(S)O-, -S(O)t- (where t is 1 or 2), -S(O) t N(R 1 )- (where t is 1 or 2) or -C(R 11 )H.
• the invention provides compounds of Formula IVb having the following Formula IVha:
• R 2 is selected from the group consisting of C7-C12alkyl, C3-C12alkenyl, C7-C12hydroxyalkyl, C1-C12alkoxy, C2-C12alkoxyalkyl, C3-C12hydroxyalkenyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl,
• R 2 is not pyrazinyl, pyridinonyl, pyrrolidinone or imidazolyl;
• R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, where some or all of the rings may be fused to each other;
• R 3 is selected from the group consisting of C 3 -C 12 alkyl, C 3 -C 12 alkenyl, C 3 -C 12 hydroxyalkyl, C3-C12hydroxyalkenyl, C3-C12alkoxy, C3-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl and C3-C12heteroarylalkyl; or R 9 or R 9a together, or R 10 and R 10a together form an oxo group, while the remaining R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 10 and R 10a are each independently selected from hydrogen or C1-C3alkyl.
• the invention provides compounds of Formula IVb having the following Formula IVhb:
• R 2 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C1-C6alkoxy, C3-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl,
• R 2 is phenyl optionally substituted with one or more substituents selected from halo and C1-C6trihaloalkyl;
• R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, where some or all of the rings may be fused to each other;
• R 3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxyl, C1-C6alkyl, C1-C6trihaloalkyl, C1-C6trihaloalkoxy, C1-C6alkylsulfonyl, -N(R 12 )2, -OC(O)R 12 , -C(O)OR 12 , -S(O)2N(R 12 )2, cycloalkyl, heterocyclyl, heteroaryl and
• R 3 is not phenyl substituted with optionally substituted thienyl
• each R 12 is independently selected from hydrogen, C1-C6alkyl, C3-C6cycloalkyl, aryl or aralkyl.
• the invention provides compounds of Formula IVb having the following Formula IVi:
• Va is -C(O)-, -C(S)-, -C(O)N(R 1 )-, -C(O)O-, -S(O)2- or -S(O)2N(R 1 )-;
• R 2 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C1-C6alkoxy, C3-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl, and C3-C12heteroarylalkyl; or R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other.
• the invention provides compounds of Formula IVb having the following Formula IVj:
• Va is -C(O)-, -C(S)-, -C(O)N(R 1 )-, -C(O)O-, -S(O)2- or -S(O)2N(R 1 )-;
• R 2 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C3-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl, and C3-C12heteroarylalkyl;
• R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other.
• the invention provides compounds of Formula IVb having the following Formula IVk:
• Wa is -O-, -N(R 1 )- or -S(O)t- (where t is 0, 1 or 2);
• Va is -C(O)-, -C(S)-, -C(O)N(R 1 )-, -C(O)O-, -S(O)2- or -S(O)2N(R 1 )-;
• R 2 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C 2 -C 12 hydroxyalkenyl, C 3 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C 7 -C 19 aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl, and C3-C12heteroarylalkyl;
• R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other.
• the invention provides compounds of Formula IVb having the following Formula IVla:
• R 2 is selected from the group consisting of C7-C12alkyl, C3-C12alkenyl, C7-C12hydroxyalkyl, C2-C12alkoxyalkyl, C3-C12hydroxyalkenyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, C13-C19aralkyl, C3-C12heterocyclylalkyl, and C3-C12heteroarylalkyl;
• R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, where some or all of the rings may be fused to each other;
• R 3 is selected from the group consisting of C3-C12alkyl, C3-C12alkenyl, C3-C12hydroxyalkyl, C3-C12hydroxyalkenyl, C3-C12alkoxy, C3-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C5-C12heteroaryl and C3-C12heteroarylalkyl; or R 3 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other.
• the invention provides compounds of Formula IVb having the following Formula IVlb:
• R 2 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C3-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl and C3-C12heteroarylalkyl;
• R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• R 3 is naphthyl or phenyl, each optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C1-C6alkyl, C1-C6trihaloalkyl, C1-C6trihaloalkoxy, C1-C6alkylsulfonyl, -N(R 12 )2, -OC(O)R 12 , -C(O)OR 12 , -S(O)2N(R 12 )2, cycloalkyl, heterocyclyl, heteroaryl and heteroarylcycloalkyl, provided that R 3 is not phenyl substituted with optionally substituted thienyl, and provided that when R 3 is naphthyl, R 2 cannot be C1-C6alkyl, C2-C6hydroxyalkyl or phenyl substituted by amino;
• each R 12 is independently selected from hydrogen, C1-C6alkyl, C3-C6cycloalkyl, aryl or aralkyl.
• Compounds of Formula (IV) may be synthesized by methods known in the art, e.g., those described in International Patent Publications No. WO2005/011656 and WO2005/011654.
• the SCD inhibitor is a compound disclosed in International Patent Publications No.
• the SCD inhibitor is a compound of Formula V:
• each R 1 is independently selected from the group consisting of hydrogen, C1-C12alkyl,
• R 2 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C2-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C19aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 1 -C 12 heteroaryl, and C 3 -C 12 heteroarylalkyl;
• R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• each R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , R 8 and R 8a is independently selected from hydrogen or C1-C3alkyl; or R 5 and R 5a together, or R 6 and R 6a together, or R 7 and R 7a together, or R 8 and R 8a together are an oxo group, provided that when V is -C(O)-, R 6 and R 6a together or R 8 and R 8a together do not form an oxo group, while the remaining R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , R 8 and R 8a are each independently selected from hydrogen or C 1 -C 3 alkyl;
• each R 9 is independently selected from hydrogen or C1-C6alkyl.
• x and y are each independently 1, 2 or 3;
• R 3 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C2-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl and C3-C12heteroarylalkyl;
• R 3 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• each R 4 is independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or -N(R 9 )2;
• R 5 , R 5a , R 6 , and R 6a together with one of R 7 , R 7a , R 8 and R 8a form an alkylene bridge, while the remaining R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , R 8 , and R 8a are each independently selected from hydrogen or C1-C3alkyl;
• R 10 is hydrogen or C1-C3alkyl
• x and y are each independently 0, 1, 2 or 3;
• J and K are each independently N or C(R 10 );
• V is a direct bond, -N(R 1 )-, -N(R 1 )C(O)-, -O-, -C(O)-, -C(O)O-, -C(S)-, -C(O)N(R 1 )-, -S(O)p- (where p is 0, 1 or 2) or -S(O)pN(R 1 )- (where p is 1 or 2);
• W is a direct bond, -N(R 1 )C(O)-, -C(O)N(R 1 )-, -OC(O)N(R 1 )-, -N(R 1 )C(O)N(R 1 )-, -O-, -N(R 1 )-, -S(O)t- (where t is 0, 1 or 2), -N(R 1 )S(O)p- (where p is 1 or 2), -S(O)pN(R 1 )- (where p is 1 or 2), -C(O)-, -OS(O)2N(R 1 )-, -OC(O)-, -C(O)O-, -N(R 1 )C(O)O-;
• R 3 is selected from the group consisting of hydrogen, C1-C12alkyl, C2-C12alkenyl,
• R 3 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• each R 4 is independently selected from hydrogen, fluoro, chloro, C 1 -C 12 alkyl, C 1 -C 12 alkoxy, haloalkyl, cyano, nitro or -N(R 9 )2;
• R 5 , R 5a , R 6 , and R 6a together with one of R 7 , R 7a , R 8 and R 8a forms a direct bridge or an alkylene bridge, while the remaining R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , R 8 , and R 8a are each independently selected from hydrogen or C 1 -C 3 alkyl;
• R 10 is independently selected from hydrogen, fluoro, chloro, C1-C12alkyl or C1-C12alkoxy;
• the invention provides compounds of Formula Va having the following Formula Vc:
• W is -N(R 1 )C(O)-, -C(O)N(R 1 )-, -OC(O)N(R 1 )-, -N(R 1 )C(O)N(R 1 )-, -O-, -N(R 1 )-, -S(O) t - (where t is 0, 1 or 2), -N(R 1 )S(O)2-, -S(O)2N(R 1 )-, -C(O)-, -OS(O)2N(R 1 )-, -OC(O)-, -C(O)O- or -N(R 1 )C(O)O-;
• V is -C(O)-, -C(O)O-, -C(S)-, -C(O)N(R 1 )-, -S(O)2-, -S(O)2N(R 1 )-, -C(R 10 )H-;
• the invention provides compounds of Formula Va having the following Formula Vd:
• W is -N(R 1 )C(O)-, -C(O)N(R 1 )-, -OC(O)N(R 1 )-, -N(R 1 )C(O)N(R 1 )-, -O-, -N(R 1 )-, -S(O)t- (where t is 0, 1 or 2), -N(R 1 )S(O)2-, -S(O)2N(R 1 )-, -C(O)-, -OS(O)2N(R 1 )-, -OC(O)-, -C(O)O- or -N(R 1 )C(O)O-;
• V is -C(O)-, -C(O)O-, -C(S)-, -C(O)N(R 1 )-, -S(O)2-, -S(O)2N(R 1 )-, -C(R 10 )H-;
• the invention provides compounds of Formula Va having the following Formula Ve:
• W is -N(R 1 )C(O)-, -C(O)N(R 1 )- or -OC(O)N(R 1 )-;
• R 2 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C3-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, C7-C19aralkyl,
• R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• R 3 is phenyl optionally substituted by one or more substituents selected from the group of halo, cyano, nitro, hydroxy, C1-C6alkyl, C1-C6trihaloalkyl, C1-C6trihaloalkoxy, C1-C6alkylsulfonyl, -N(R 12 )2, -OC(O)R 12 , -C(O)OR 12 , -S(O)2N(R 12 )2, cycloalkyl, heterocyclyl, heteroaryl and heteroarylcycloalkyl, provided that R 3 is not phenyl substituted with optionally substituted thienyl;
• each R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , R 8 and R 8a is independently selected from hydrogen or C1-C3alkyl; or R 5 and R 5a together or R 7 and R 7a together form an oxo group, while the remaining R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , R 8 and R 8a are each independently selected from hydrogen or C1-C3alkyl;
• each R 12 is independently selected from hydrogen, C1-C6alkyl, C3-C6cycloalkyl, aryl or aralkyl; a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof.
• the invention provides compounds of Formula Va having the following Formula Vf:
• W is -N(R 1 )C(O)-, -C(O)N(R 1 )- or -OC(O)N(R 1 )-;
• R 2 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C 2 -C 12 hydroxyalkenyl, C 3 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, C 7 -C 19 aralkyl,
• R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• R 3 is phenyl optionally substituted by one or more substituents selected from the group of halo, cyano, nitro, hydroxy, C1-C6alkyl, C1-C6trihaloalkyl, C1-C6trihaloalkoxy, C1-C6alkylsulfonyl, -N(R 12 )2, -OC(O)R 12 , -C(O)OR 12 , -S(O)2N(R 12 )2, cycloalkyl, heterocyclyl, heteroaryl and heteroarylcycloalkyl, provided that R 3 is not phenyl substituted with optionally substituted thienyl;
• each R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , R 8 and R 8a is independently selected from hydrogen or C1-C3alkyl; or R 5 and R 5a together or R 7 and R 7a together form an oxo group, while the remaining R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , R 8 and R 8a are each independently selected from hydrogen or C1-C3alkyl;
• each R 12 is independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, aryl or aralkyl; a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof.
• the invention provides compounds of Formula Va having the following Formula Vca:
• W is -N(R 1 )C(O)N(R 1 )-, -O-, -N(R 1 )-, -S(O)t- (where t is 0, 1 or 2), -N(R 1 )S(O)2-, -S(O)2N(R 1 )-, -C(O)O- or -N(R 1 )C(O)O-;
• V is -C(O)-, -C(O)O-, -C(S)-, -C(O)N(R 1 )-, -S(O)2-, -S(O)2N(R 1 )-;
• Compounds of Formula (V) may be synthesized by methods known in the art, e.g., those described in International Patent Publications No. WO2006/086445, WO2006/034446 and
• the SCD inhibitor is a compound disclosed in International Patent Publications No. WO2006/086445, WO2006/034446 and WO2005/011657, the compounds of which are herein incorporated by reference. In some embodiments of any of the foregoing methods, the SCD inhibitor is a compound of Formula VI:
• x and y are each independently 1, 2 or 3;
• W is -C(O)N(R 1 )-, -C(O)N[C(O)R 1a ]-, -N(R 1 )C(O)N(R 1 )- or -N(R 1 )C(O)-;
• V is -C(O)-, -C(S)-, -C(R 10 )H-;
• each R 1 is independently selected form the group consisting of hydrogen; C 1 -C 6 alkyl optionally substituted with one or more substituents selected from the group consisting of halo, methyl or trifluoromethyl; and C2-C6alkyl optionally substituted with one or more substituents selected from the group consisting of methoxy and hydroxyl;
• R 1a is selected from the group consisting of hydrogen, C 1 -C 6 alkyl and cycloalkyl;
• R 2 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C1-C12alkoxy, C2-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl, and C3-C12heteroarylalkyl; or R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• R 3 is selected from the group consisting of C2-C12alkenyl, C2-C12hydroxyalkyl, C 2 -C 12 hydroxyalkenyl, C 1 -C 12 alkoxy, C 2 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C7-C12aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl and C3-C12heteroarylalkyl; or R 3 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• R 4 and R 5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or -N(R 12 )2;
• R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 9 and R 9a are each independently selected from hydrogen or
• R 6 and R 6a together, or R 7 and R 7a together, or R 8 and R 8a together, or R 9 and R 9a together are an oxo group, provided that when V is -C(O)-, R 7 and R 7a together or R 8 and R 8a together do not form an oxo group, while the remaining R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 9 and R 9a are each independently selected from hydrogen or C1-C3alkyl;
• R 6 , R 6a , R 7 and R 7a together with one of R 8 , R 8a , R 9 and R 9a form an alkylene bridge, while the remaining R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 9 and R 9a are each independently selected from hydrogen or C1-C3alkyl;
• R 10 is hydrogen or C1-C3alkyl; and each R 12 is independently selected from hydrogen or C1-C6alkyl;
• the invention provides compounds of Formula VI having the following Formula VIa:
• W is -C(O)N(R 1 )- or -N(R 1 )C(O)-;
• R 2 is selected from the group consisting of C7-C12alkyl, C3-C12alkenyl, C7-C12hydroxyalkyl, C2-C12alkoxyalkyl, C3-C12hydroxyalkenyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, C13-C19aralkyl, C3-C12heterocyclylalkyl, and C3-C12heteroarylalkyl;
• R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, where some or all of the rings may be fused to each other;
• R 3 is selected from the group consisting of C3-C12alkyl, C3-C12alkenyl, C3-C12hydroxyalkyl, C3-C12hydroxyalkenyl, C3-C12alkoxy, C3-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C12aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C5-C12heteroaryl and C3-C12heteroarylalkyl; or R 3 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• R 4 and R 5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, and trifluoromethyl.
• the invention provides compounds of Formula VI having the following Formula VIb:
• A is oxygen or sulfur
• W is -C(O)N(R 1 )- or -N(R 1 )C(O)-;
• R 2 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C1-C6alkoxy, C3-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C12aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl, and C3-C12heteroarylalkyl; or R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• R 3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C1-C6alkyl, C1-C6trihaloalkyl, C1-C6trihaloalkoxy, C1-C6alkylsulfonyl, -N(R 11 )2, -OC(O)R 11 , -C(O)OR 11 , -S(O)2N(R 11 )2, cycloalkyl, heterocyclyl, heteroaryl and
• R 3 is not phenyl substituted with optionally substituted thienyl
• R 4 and R 5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, and trifluoromethyl.
• each R 11 is independently selected from hydrogen, C1-C6alkyl, C3-C6cycloalkyl, aryl or aralkyl.
• the invention provides compounds of Formula VI having the following Formula VIc:
• R 2 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C2-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, C3-C12heterocyclyl, C 3 -C 12 heterocyclylalkyl, aryl, C 7 -C 19 aralkyl, C 1 -C 12 heteroaryl, and C 3 -C 12 heteroarylalkyl;
• R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• R 4 and R 5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, and trifluoromethyl.
• the invention provides compounds of Formula VI having the following Formula VIda:
• W is -C(O)N(R 1 )-, -N(R 1 )C(O)N(R 1 )- or -N(R 1 )C(O)-;
• R 2 is selected from the group consisting of C7-C12alkyl, C2-C12alkenyl, C7-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C1-C12alkoxy, C2-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl,
• R 10 is hydrogen or C1-C3alkyl; and each R 12 is independently selected from hydrogen or C1-C6alkyl;
• R 2 cannot be pyrazinyl, pyridinonyl, pyrrolidinonyl or imidazolyl.
• the invention provides compounds of Formula VI having the following Formula VIdb:
• W is -C(O)N(R 1 )-, -N(R 1 )C(O)N(R 1 )- or -N(R 1 )C(O)-;
• R 3 is selected from the group consisting of C7-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C1-C12alkoxy or C2-C12alkoxyalkyl.
• the invention provides compounds of Formula VI having the following Formula VIe:
• W is a direct bond, -C(O)N(R 1 )-, -C(O)N[C(O)R 1a ]-, -N(R 1 )C(O)N(R 1 )-, -N(R 1 )C(O)-,
• R 1a is selected from the group consisting of hydrogen, -OR 1 , cyano, C1-C6alkyl and
• Compounds of Formula (VI) may be synthesized by methods known in the art, e.g., those described in International Patent Publications No. WO2005/011655, WO2006/086447 and WO2009/106991.
• the SCD inhibitor is a compound disclosed in International Patent Publications No.
• the SCD inhibitor is a compound of Formula VII:
• each R 1 is independently selected from the group consisting of hydrogen, C1-C12alkyl,
• R 2 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C2-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl, and C3-C12heteroarylalkyl;
• R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , R 8 and R 8a are each independently selected from hydrogen or C1- C3alkyl;
• R 5 and R 5a together, R 6 and R 6a together, or R 7 and R 7a together, or R 8 and R 8a together are an oxo group, provided that when V is -C(O)-, R 6 and R 6a together or R 8 and R 8a together do not form an oxo group, while the remaining R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , R 8 and R 8a are each independently selected from hydrogen or C1-C3alkyl;
• R 5 , R 5a , R 6 and R 6a together with one of R 7 , R 7a , R 8 and R 8a forms a direct bond or an alkylene bridge, while the remaining R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , R 8 and R 8a are each independently selected from hydrogen or C1-C3alkyl;
• each R 9 is independently selected from hydrogen or C1-C6alkyl
• x and y are each independently 1, 2 or 3;
• J and K are each independently N or C(R 11 );
• L is N or C(R 4 );
• W is a direct bond, -N(R 1 )C(O)-, -C(O)N(R 1 )-, -OC(O)N(R 1 )-, -N(R 1 )C(O)N(R 1 )-, -O-, -N(R 1 )-, -S(O)t- (where t is 0, 1 or 2), -N(R 1 )S(O)p- (where p is 1 or 2), -S(O)pN(R 1 )- (where p is 1 or 2), -C(O)-, -OS(O)2N(R 1 )-, -OC(O)-, -C(O)O-, -N(R 1 )C(O)O- or -C(R 1 )2-;
• V is -N(R 1 )-, -N(R 1 )C(O)-, -C(O)-, -C(O)O-, -C(S)-, -C(O)N(R 1 )-, -S(O)p- (where p is 0, 1 or 2) or -S(O)pN(R 1 )- (wherein p is 1 or 2) or -C(R 10 )H;
• R 3 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C2-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl and C3-C12heteroarylalkyl; or R 3 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• each R 4 is independently selected from hydrogen, fluoro, chloro, C 1 -C 12 alkyl,
• R 10 is a hydrogen or C1-C3alkyl
• R 11 is independently selected from hydrogen, fluoro, chloro, C1-C12alkyl or C1-C12alkoxy;
• x and y are each independently 0, 1, 2 or 3;
• J and K are each independently N or C(R 10 );
• V is a direct bond, -N(R 1 )-, -N(R 1 )C(O)-, -O-, -C(O)-, -C(O)O-, -C(S)-, -C(O)N(R 1 )-, -S(O)p- (where p is 0, 1 or 2) or -S(O) p N(R 1 )- (where p is 1 or 2);
• W is R 2 -N(R 1 )C(O)-, R 2 -C(O)N(R 1 )-, R 2 -OC(O)N(R 1 )-, R 2 -N(R 1 )C(O)N(R 1 )-, R 2 -O-, R 2 -N(R 1 )-, R 2 -S(O)t- (where t is 0, 1 or 2), R 2 -N(R 1 )S(O)p- (where p is 1 or 2), R 2 -S(O)pN(R 1 )- (where p is 1 or 2), R 2 -C(O)-, R 2 -OS(O)2N(R 1 )-, R 2 -OC(O)-, R 2 -C(O)O-, R 2 -N(R 1 )C(O)O- or R 2 -C(R 1 )2-;
• R 3 is selected from the group consisting of hydrogen, C 1 -C 12 alkyl, C 2 -C 12 alkenyl,
• R 3 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• R 4 is hydrogen, fluoro, chloro, hydroxyl, C1-C12alkyl, C1-C12alkoxy, haloalkyl, cyano, nitro or -N(R 9 )2;
• each R 10 is independently selected from hydrogen, fluoro, chloro, C1-C12alkyl or C1-C12alkoxy.
• the invention provides compounds of Formula VIIa having the following Formula VIIc:
• A, D, E, G, Z, L, and M are each independently N, NH or C(R 4 );
• T and Q are each independently C or N.
• the invention provides compounds of Formula VIIb having the following Formula VIId:
• W is -CN, R 2 -N(R 1 )C(O)-, R 2 -C(O)N(R 1 )-, R 2 -OC(O)N(R 1 )-, R 2 -N(R 1 )C(O)N(R 1 )-, R 2 -O-, R 2 -N(R 1 )-, R 2 -S(O)t- (where t is 0, 1 or 2), R 2 -N(R 1 )S(O)p- (where p is 1 or 2), R 2 -S(O)pN(R 1 )- (where p is 1 or 2), R 2 - C(O)-, R 2 -OS(O)2N(R 1 )-, R 2 -OC(O)-, R 2 -C(O)O-, R 2 -N(R 1 )C(O)O- or R 2 -C(R 1 )2-.
• Compounds of Formula (VII) may be synthesized by methods known in the art, e.g., those described in International Patent Publications No. WO2006/034312 and WO2006/034441.
• the SCD inhibitor is a compound disclosed in International Patent Publications No.
• the SCD inhibitor is a compound of Formula VIII:
• K is selected from N or C(R 6 );
• each R 1 is independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, cycloalkylalkyl and aralkyl;
• each R 5 is alkyl
• R 5 together with one of R 5 on a diufferent carbon atom form an alkylene bridge, while the remaining R 5 ’s are each alkyl;
• R 6 is hydrogen, alkyl, fluoro or chloro
• R 7 is hydrogen, alkyl, fluoro, chloro, methoxy, trifluoromethyl, cyano, nitro or -N(R 1 )2;
• p 0 to 7;
• Q is an optionally substituted alkylene bridge or -(CH2)xA(CH2)y- where x and y are independently selected from 0, 1, 2, or 3 and A is selected from -O-, -C(O)-, -N(R 1 )-, -N(R 1 )C(O)-, -C(O)N(R 1 )-, -S(O)t- (where t is 0, 1 or 2);
• W is -N(R 1 )C(O)-, -C(O)N(R 1 )-, -OC(O)N(R 1 )-, -N(R 1 )C(O)N(R 1 )-, -O-, -N(R 1 )-, -S(O)t- (where t is 0, 1 or 2), -C(O)-, -N(R 1 )S(O)2-, -S(O)2N(R 1 )-, -OS(O)2N(R 1 )-, -OC(O)-, -C(O)O-, -N(R 1 )C(O)O-, -N(R 1 )C(NR 1a )N(R 1 )-, -N(R 1 )C(S)N(R 1 )-, -N(R 1 )C(NR 1a )-, -C(NR 1a )N(R 1
• V is -O-, -C(O)-, -C(O)O-, -OC(O)-, -C(S)-, -C(O)N(R 1 )-, -N(R 1 )C(O)-, -S(O)t- (where t is 0, 1 or 2), -S(O) q N(R 1 )- (where q is 1 or 2), -N(R 1 )S(O) q - (where q is 1 or 2), -C(R 7 )H- or -C(NR 1a )-;
• each R 1a is selected from the group consisting of hydrogen, C1-C6alkyl, cycloalkylalkyl, -OR 1 and cyano;
• R 2 is selected from the group consisting of alkylene, cycloalkyl, aryl, heterocyclyl, and heteroaryl; or R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• R 3 is alkyl, alkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl;
• R 3 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• R 4 is hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or -N(R 1 )2.
• p 0 to 2;
• q 0 to 8.
• W is -N(R 1 )C(O)-, -C(O)N(R 1 )-, -OC(O)N(R 1 )-, -N(R 1 )C(O)N(R 1 )-, -O-, -N(R 1 )-, -S(O)t- (where t is 0, 1 or 2), -C(O)-, -N(R 1 )S(O)2-, -S(O)2N(R 1 )-, -OS(O)2N(R 1 )-, -OC(O)-, -C(O)O-, -N(R 1 )C(O)O-,
• Q is an optionally substituted C8-C20alkylene bridge, or -(CH2)xA(CH2)y- where x and y are independently selected from 0 to 10 provided that the sum of x and y is 8 to 20, and A is selected from -O-, -C(O)-, -N(R 1 )C(O)-, -C(O)N(R 1 )-, -N(R 1 )-, -S(O)t- (where t is 0, 1 or 2), -S(O)pN(R 1 )- (where p is 1 or 2), aryl, heterocyclyl, or heteroaryl;
• R 1a is selected from the group consisting of hydrogen, C1-C6alkyl and cycloalkylalkyl, -OR 1 , nitro, -S(O)2R 1b , and cyano;
• R 1b is C1-C6alkyl
• R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• R 3 is selected from the group consisting of cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl;
• R 3 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other; each R 4 is independently selected from alkyl, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or -N(R 1 )2.
• Compounds of Formula (VIII) may be synthesized by methods known in the art, e.g., those described in International Patent Publications No. WO2006/125179 and WO2007/136746.
• the SCD inhibitor is a compound disclosed in International Patent Publications No.
• the SCD inhibitor is a compound of Formula IX:
• W is -N(R 1 )C(O)-, -C(O)N(R 1 )-, -OC(O)N(R 1 )-, -N(R 1 )C(O)N(R 1 )-, -O-, -N(R 1 )-, -S(O)t- (where t is 0, 1 or 2), -C(O)-, -N(R 1 )S(O)2, -S(O)2N(R 1 )-, -OS(O)2N(R 1 )-, -OC(O)-, -C(O)O-, -N(R 1 )C(O)O-, -,
• V is -O-, -C(O)-, -C(O)O-, -OC(O)-, -C(S)-, -C(O)N(R1)-, -N(R 1 )C(O)-, -S(O)t- (where t is 0, 1 or 2), -S(O)qN(R 1 )- (where q is 1 or 2), -N(R 1 )S(O)q- (where q is 1 or 2), -C(R 5 )H- or -C(NR 1a )-; is selected from cycloalkyl, aryl, heterocyclyl, or heteroaryl;
• each R 1 is independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, cycloalkylalkyl and aralkyl;
• each R 1a is selected from the group consisting of hydrogen, C1-C6alkyl, cycloalkylalkyl, -OR 1 , and cyano;
• R 2 is selected from the group consisting of alkyl, alkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl;
• R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• R 3 is selected from the group consisting of alkyl, alkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl;
• R 3 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other; and
• R 4 is selected from hydrogen, alkyl, fluoro, chloro, methoxy, trifluoromethyl, cyano, nitro or -N(R 1 )2; or a stereoisomer, enantiomer or tautomer thereof, or a racemic or non-racemic mixture thereof, or a pharmaceutically acceptable salt or prodrug thereof.
• Compounds of Formula (IX) may be synthesized by methods known in the art, e.g., those described in International Patent Publication No. WO2007/044085.
• the SCD inhibitor is a compound disclosed in International Patent Publication No. WO2007/044085, the compounds of which are herein incorporated by reference.
• the SCD inhibitor is a compound of Formula X
• n 1, 2 or 3;
• n 1, 2, 3 or 4;
• p 2, 3 or 4;
• V is -C(O)-, -S(O)- or -S(O)2;
• R 1 is hydrogen, alkyl, alkenyl, aryl, heteroaryl, aralkyl, aralkenyl or cycloalkyl;
• R 2 is selected from the group consisting of hydrogen, -R 7 -OR 8 , -R 7 -N(R 8 ) 2 , -R7-S(O) t R 10 (where t is 0, 1 or 2), alkyl, alkenyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl and optionally substituted heteroarylalkenyl;
• R 3 is selected from the group consisting of hydrogen, -R 9 -OR 8 , -R 9 -N(R 8 )2, alkyl, alkenyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl and optionally substituted heteroarylalkenyl;
• each R 4 is independently hydrogen, alkyl, alkenyl, halo, haloalkyl, aryl, cyano, nitro, -R 9 -OR 8 , -R 9 -N(R 8 )2 or -S(O)tR 10 (where t is 0, 1 or 2);
• each R 5 and R 6 is independently hydrogen, oxo, alkyl, alkenyl, halo, haloalkyl or aryl;
• R 5 and one R 6 may together form an straight or branched alkylene bridge
• each R 7 is independently a straight or branched alkylene or alkenylene chain
• each R 8 is independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocylylalkyl, heteroaryl or heteroarylalkyl;
• each R 9 is independently a direct bond or a straight or branched alkylene or alkenylene chain; and R 10 is alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocylylalkyl, heteroaryl or heteroarylalkyl;
• Compounds of Formula (X) may be synthesized by methods known in the art, e.g., those described in International Patent Publication No. WO2006/014168.
• the SCD inhibitor is a compound disclosed in International Patent Publication No. WO2006/014168, the compounds of which are herein incorporated by reference.
• the SCD inhibitor is a compound of Formula XI
• X is CH or N
• Y is NH, N-CH3, O or S
• W is selected from -N(R 5 )C(O)-, -C(O)N(R 5 )-, -OC(O)N(R 5 )-, -N(R 5 )C(O)O-, -N(R 5 )C(O)N(R 5 )-, -O-, -S-, -N(R 5 )-, -S(O)t, -N(R 5 )S(O)t, -S(O)tN(R 5 )-, -OS(O)tN(R 5 )-, C(O)-, -OC(O)-, -C(O)O-,
• V is selected from -N(R 5 )C(O)-, -C(O)N(R 5 )-, -OC(O)N(R 5 )-, -N(R 5 )C(O)O-, -N(R 5 )C(O)N(R 5 )-, -O-, -S-, -N(R 5 )-, -S(O)t, -N(R 5 )S(O)t, -S(O)tN(R 5 )-, -OS(O)tN(R 5 )-, C(O)-, -OC(O)-, -C(O)O-,
• n 0, 1, 2 or 3;
• p is an integer from 0 to 9;
• t 1 or 2;
• R 1 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl;
• R 1 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl;
• R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, halo, haloalkyl, haloalkoxy, cyano and -N(R 5 )2;
• each R 4 is independently selected from the group consisting of alkyl, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxy, -N(R 5 )2, cycloalkylalkyl and aralkyl;
• each R 5 is independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, hydroxyalkyl, cycloalkylalkyl and aralkyl;
• R 5a is selected from the group consisting of hydrogen, alkyl, cycloalkylalkyl and cyano; or a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof.
• Compounds of Formula (XI) may be synthesized by methods known in the art, e.g., those described in International Patent Publication No. WO2008/036715.
• the SCD inhibitor is a compound disclosed in International Patent Publication No. WO2008/036715, the compounds of which are herein incorporated by reference.
• the SCD inhibitor is a compound of Formula XII,
• W is selected from -O-, -OC(O)-, -OC(O)N(R 5 )-, -OS(O)2N(R 5 )-, -C(O)-, -C(O)O-, -C(O)N(R 5 )-, -N(R 5 )-, -N(R 5 )C(O)-, -N(R 5 )C(O)O-, -N(R 5 )C(O)N(R 5 )-, -N(R 5 )S(O)2, -S(O)t- (where t is 0, 1 or 2), or -S(O)2N(R 5 )-;
• V is selected from -C(O)-, -C(O)N(R 5 )-, -C(O)O-, -S(O)t- (where t is 1 or 2) or a direct bond;
• R 1 is selected from the group consisting of alkyl, alkenyl, -R 6 -OR 7 , hydroxyalkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl; or R 1 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• R 2 is selected from the group consisting of alkyl, alkenyl, -R 6 -OR 7 , hydroxyalkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; or R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• R 3 is selected from hydrogen, alkyl, alkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, fluoro, chloro, bromo, trihaloalkyl, trihaloalkoxy, cyano, nitro, -OR 4 , -OC(O)R 2 , -N(R 5 )C(O)OR 5 , -N(R 5 )C(O)N(R 4 )(R 5 ) or -N(R 5 )S(O)2R 2 ; each R 4 and R 5 is independently selected from the group consisting of
• each R 6 is a straight or branched alkylene chain
• each R 7 is hydrogen, alkyl, aryl or aralkyl
• Compounds of Formula (XII) may be synthesized by methods known in the art, e.g., those described in International Patent Publication No. WO2007/130075.
• the SCD inhibitor is a compound disclosed in International Patent Publication No. WO2007/130075, the compounds of which are herein incorporated by reference.
• the SCD inhibitor is a compound of Formula XIII,
• W is selected from -N(R 5 )C(O)-, -C(O)N(R 5 ) ⁇ , -OC(O)N(R 5 )-, -N(R 5 )C(O)O-, -N(R 5 )C(O)N(R 5 )-, -O-, -N(R 5 )-, -S ⁇ , -S(O)t-, -N(R 5 )S(O)t-, ⁇ S(O)tN(R 5 )-, -OS(O)2N(R 5 )-, -C(O)-, -OC(O) ⁇ , -C(O)O-,
• X is selected from C(H) or N;
• Y is selected from S, O, N(H) or N(CH3);
• p 0, 1, 2, or 3;
• t 1 or 2;
• R 1 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl;
• R 1 is a multi-rins structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, haloalkyl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; or R 2 is a multi-ting structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, halo, haloalkyl, trihaloalkoxyl, cyano and -N(R 5 )2;
• R 4 is selected from the group consisting of alkyl, hydroxyalkyl, cycloalkylalkyl, aralkyl, halo, haloalkyl, -OCF 3 , -OC(H)F 2 , and cyano;
• R 4 groups may form a cycloalkyl, heterocyclyl, aryl or heteroaryl and the remaining R 4 groups, if present, are as described above;
• R 5 is selected from the group consisting of hydrogen, aryl, alkyl, heteroaryl, heterocyclyl, haloalkyl, hydroxyalkyl, cycloalkylalkyl and aralkyl;
• R 5a is selected from the group consisting of hydrogen, alkyl, cycloalkylalkyl and cyano;
• Compounds of Formula (XIII) may be synthesized by methods known in the art, e.g., those described in International Patent Publication No. WO2007/143597.
• the SCD inhibitor is a compound disclosed in International Patent Publication No. WO2007/143597, the compounds of which are herein incorporated by reference.
• the SCD inhibitor is a compound of Formula XIV,
• W is -N(R 8 )C(O)-, -C(O)N(R 8 )-, C1-C6alkylene, C2-C6alkeneylene, C2-C6alkynylene or a direct bond;
• V is selected from a C1-C6alkylene
• n 1, 2, or 3;
• p 1, 2, 3, 5, or 6;
• R 1 is hydrogen, an optionally substituted C1-C7alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C7alkoxy, hydroxyC1-C4alkyl, C1-C7alkoxyC1-C4alkyl, an optionally substituted C3-C7cycloalkyl, an optionally substituted C3-C7cycloalkylC1-C4alkyl, an optionally substituted C6-C10aryl, haloC1-C4alkyl, an optionally substituted C6-C10arylC1-C4alkyl, an optionally substituted C2-C10heterocyclyl, an optionally substituted C2-C10heterocyclylC1-C4alkyl, an optionally substituted C1-C10heteroaryl, or an optionally substituted C1-C10heteroarylC1-C4alkyl;
• R 2 is C3-C7alkyl, haloC1-C4alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C7alkoxy, hydroxyl,
• V-R 2 is not quinolin-4-ylmethyl when R 1 is an alkyl
• R 3 is hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, hydroxyC1-C4alkyl, C 1 -C 6 alkoxyC 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkylC 1 -C 4 alkyl, C 2 -C 10 heterocyclyl, C 6 -C 10 aryl, C6-C10arylC1-C4alkyl, C1-C10heteroaryl, halo, haloC1-C4alkyl, trifluoromethoxy, cyano, hydroxy, or -N(R 8 )2;
• R 5 and R 5a are independently selected from hydrogen, C1-C6alkyl, haloC1-C4alkyl, hydroxy, hydroxyC1-C4alkyl, C1-C6alkoxy, C3-C7cycloalkylC1-C4alkyl and C6-C10arylC1-C4alkyl;
• R 6 for each occurrence, is independently selected from C1-C6alkyl, C6-C10aryl, C3-C7cycloalkyl, C1-C10heteroaryl, C2-C10heterocyclyl, hydroxyC1-C4alkyl, haloC1-C4alkyl, C1-C6alkoxy,
• R 7 is hydrogen, C1-C7alkyl, haloC1-C4alkyl, C8-C10aryl, C3-C7cycloalkyl, C1-C10heteroaryl, C2-C10heterocyclyl, hydroxyC1-C4alkyl, C3-C7cycloalkylC1-C4alkyl or aralkyl;
• R 8 for each occurrence, is independently selected from hydrogen, C1-C7alkyl, hydroxyC1-C4alkyl, C3-C7cycloalkyl, C3-C7cycloalkylC1-C4alkyl, C6-C10aryl, C1-C10heteroaryl, C2-C10heterocyclyl and aralkyl; and
• R 8a for each occurrence, is independently selected from hydrogen, C1-C7alkyl, C3-C7cycloalkyl, C3-C7cycloalkylC1-C4alkyl, and cyano;
• R 12 for each occurrence, is independently selected from hydrogen, C3-C7alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C7alkoxy, hydroxy, hydroxyC1-C4alkyl, C1-C6alkoxyC1-C4alkyl, C3-C7cycloalkyl,
• Compounds of Formula (XIV) may be synthesized by methods known in the art, e.g., those described in International Patent Publication No. WO2011/039358.
• the SCD inhibitor is a compound disclosed in International Patent Publication No. WO2011/039358, the compounds of which are herein incorporated by reference.
• the SCD inhibitor is a compound of Formula XV
• X is N or CH
• Y is NH, O, S or N-CH3;
• V is selected from -N(R 5 )C(O)-, -C(O)N(R 5 )-, -OC(O)N(R 5 )-, -N(R 5 )C(O)O-, -N(R 5 )C(O)N(R 5 )-, -O-, -N(R 5 )-, -S-, -S(O)t-, -N(R 5 )S(O)2-, -S(O)2N(R 5 )-, -OS(O)2N(R 5 )-, -C(O)-, -O(C)O, -C(O)O-, -CR 5 C(O)N(R 5 )-, -(CR 5 2)nC(O)-, -(CR 5 2)nO-, -(CR 5 2)nN(R 6 )-, -(CR 5 2)nN(R 5 )C(O)-, -
• t 1 or 2;
• p 0, 1 or 2;
• n is an integer from 1 to 6;
• R 1 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl;
• R 1 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl;
• R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, halo, trifluoromethyl, trifluoromethoxyl, cyano and -N(R 6 )2;
• R 4 is selected from the group consisting of alkyl, halo, -N(R 6 )2, haloalkyl, hydroxyl, alkoxy, -N(R 2 )2, cycloalkylalkyl and aralkyl;
• R 5 and R 6 are independently selected from the group consisting of hydrogen, alkyl, halo, aryl, heteroaryl, cycloalkyl, hydroxyalkyl, cycloalkylalkyl and aralkyl; R 5a and R 6a are independently selected from the group consisting of hydrogen, alkyl, cycloalkylalkyl and cyano.
• V is selected from -C(O)N(R 5 )-, -S(O)t-, -S(O)2N(R 5 )-, -C(O)-, -C(C)O, -CR 5 2C(O)N(R 5 )-, -(CR 5 2)nC(O)-, -(CR 5 2)nO-,-(CR 5 2)nN(R 6 )-, -(CR 5 2)nN(R 5 )C(O)-, -(CR 5 2)nN(R 5 )C(O)O-,-(CR 5 2)nN(R 5 )S(O)t-, an aryl, a heteroaryl, a heterocyclyl, an alkynylene, an alkenylene, an alkylene or a direct bond;
• r 0, 1 or 2;
• R 4 is selected from the group consisting of alkyl, haloalkyl, hydroxyl, alkoxy, -N(R 2 )2,
• R 5a and R 6a are independently selected from the group consisting of hydrogen, alkyl, cycloalkylalkyl and cyano.
• Compounds of Formula (XV) may be synthesized by methods known in the art, e.g., those described in International Patent Publication No. WO2008/024390.
• the SCD inhibitor is a compound disclosed in International Patent Publication No. WO2008/024390, the compounds of which are herein incorporated by reference.
• the SCD inhibitor is a compound of Formula XVI,
• V is -N(R 7 )C(O)-, -N(R 7 )C(O)O-, -N(R 7 )C(O)N(R 7 )-, -N(R 7 )-, -N(R 7 )S(O)2-, -O-, -S-, -S(O)t, -N(R 7 )S(O)t, -S(O)2N(R 7 )-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R 7 )-, -OC(O)N(R 7 )-, -C(R 7 2)nC(O)N(R 7 )-, -(CR 7 2)nC(O)-, -(CR 7 2)nO-, -(CR 7 2)nO-, -(CR 7 2)nO-, -(CR 7 2)nN(R 7 )-,
• X is N or CH
• Y is NH, O, S or N-CH3;
• t 1 or 2;
• n is an integer from 1 to 6;
• R 1 is selected from the group consisting of hydrogen, alkyl, alkenyl, hydroxyalkyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl;
• R 1 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, hydroxyalkyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl;
• R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, hydroxyalkyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, halo, trifluoromethyl, trifluoromethoxyl, cyano, nitro and -N(R 7 )2;
• R 6 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl and aralkyl; each R 7 is the same or different and independently selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkenyl, alkynyl, aryl, alkoxyalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl and aralkyl;
• R 7a is selected from the group consisting of hydrogen, alkyl, cycloalkylalkyl and cyano; and R 8 is hydrogen or alkyl; or
• Compounds of Formula (XVI) may be synthesized by methods known in the art, e.g., those described in International Patent Publication No. WO2008/074835.
• the SCD inhibitor is a compound disclosed in International Patent Publication No. WO2008/074835, the compounds of which are herein incorporated by reference.
• the SCD inhibitor is a compound of Formula XVII
• W is -N(R 7 )C(O)-, -C(O)N(R 7 )-, -N(R 7 )C(O)N(R 7 )-, -N(R 7 )S(O)t-, -S(O)tN(R 7 )-, or a direct bond;
• Z is -C(R 4 )u-, -C(O)-, -O-, -N(R 7 )-, -S(O)t-, -O- or -S-;
• k 0 or 1
• n 0 to 8.
• n 0, 1, 2, 3 or 4;
• p 0, 1, 2, 3 or 4;
• q 1, 2, or 3;
• t 1 or 2;
• u 1 or 2;
• R 1 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, haloalkyl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;
• R 1 is a multi-ring structure having 2 to 4 rings wherein the rings are independently cycloalkyl, heterocyclyl, aryl or heteroaryl and where some or all of the rings may be fused to each other;
• R 2 is hydrogen, or alkyl
• R 3 is independently alkyl, halo, haloalkyl, hydroxy, or -N(R 7 )2;
• R 4 is independently alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, halo, haloalkyl, haloalkoxy, cyano, hydroxy or -N(R 7 )2;
• R 5 is independently alkyl, halo, haloalkyl, hydroxy, cycloalkyl or-N(R 7 )2;
• R 6 is independently alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, halo, haloalkyl, haloalkoxy, cyano, hydroxy or -N(R 7 )2; and
• R 7 is independently hydrogen, alkyl, alkenyl, hydroxyalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl; or
• Compounds of Formula (XVII) may be synthesized by methods known in the art, e.g., those described in International Patent Publication No. WO2010/112520.
• the SCD inhibitor is a compound disclosed in International Patent Publication No. WO2010/112520, the compounds of which are herein incorporated by reference.
• the SCD inhibitor is a compound of Formula XVIII,
• Y is NH, O, S or N-CH3;
• W is selected from -N(R 6 )C(O)-, -C(O)N(R 6 )-, -OC(O)N(R 6 )-, -N(R 6 )C(O)O-, -N(R 6 )C(O)N(R 6 )-, -O-, -S-, -N(R 6 )-, -S(O)t-, -N(R 6 )S(O)t-, -S(O)tN(R 6 )-, -OS(O)tN(R 6 )-, -C(O)-, -O(C)O, -C(O)O-,
• V is selected from -R 8 -C(O)N(R 6 )-, -R 8 -OC(O)N(R 6 )-, -S(O)t-, -S(O)2N(R 6 )-, -R 8 -C(O)-,
• n 1, 2, or 3;
• p 0, 1, 2, to 2n:
• t 1 or 2;
• R 1 is selected from the group consisting of halo, hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;
• R 1 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, haloalkyl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl;
• R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, halo, haloalkyl, haloalkoxyl, cyano, or -N(R 6 )2;
• each of R 4 and R 4a are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyl, hydroxyalkyl, alkoxy, cycloalkylalkyl or aralkyl;
• R 5 is selected from the group consisting of alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, hydroxyalkyl, alkoxy, cycloalkylalkyl, aralkyl, -N(R 6 )C(O)R 2 -, -C(O)N(R 6 )R 2 -, -OC(O)N(R 6 )R 2 -,
• each R 6 is independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl or aralkyl;
• each R 6a is independently selected from the group consisting of hydrogen, alkyl, cycloalkylalkyl, or cyano;
• each R 7 is independently selected from the group consisting of hydrogen, alkyl, trifluoromethyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, hydroxyalkyl, cycloalkylalkyl or aralkyl;
• each R 8 is independently a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain or an optionally substituted straight or branched alkynylene chain; or
• Compounds of Formula (XVIII) may be synthesized by methods known in the art, e.g., those described in International Patent Publication No. WO2008/127349.
• the SCD inhibitor is a compound disclosed in International Patent Publication No. WO2008/127349, the compounds of which are herein incorporated by reference.
• the SCD inhibitor is a compound of Formula XIX,
• W is -N(R 6 )C(O)-, -R 8 -C(O)N(R 6 )-, -R 8 -OC(O)N(R 6 )-, -N(R 6 )C(O)O-, -N(R 6 )C(O)N(R 6 )-, -O-, -S-, -N(R 6 )-, -S(O)t-, -N(R 6 )S(O)t-, -S(O)tN(R 6 )-, -OS(O)tN(R 6 )-, -R 8 -C(O)-, -O(C)O, -C(O)O-,
• t 1 or 2;
• R 1 is halo, hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; or R 1 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• R 2 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, haloalkyl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl;
• R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
• R 3 is hydrogen or alkyl
• R 4 and R 4a are independently hydrogen, alkyl, haloalkyl, hydroxyl, hydroxyalkyl, alkoxy, cycloalkylalkyl or aralkyl;
• R 5 and R 5a are independently hydrogen, alkyl or haloalkyl
• R 4 and R 5 are taken from a cycloalkyl, aryl, heteroaryl or heterocyclyl, and the remaining R 4a and R 5a are as described above;
• R 6 is independently hydrogen, alkyl, hydroxyalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl or aralkyl;
• R 6a are independently hydrogen, alkyl cycloalkylalkyl, or cyano
• R 7 is hydrogen, alkyl, trifluoromethyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, hydroxyalkyl, cycloalkylalkyl or aralkyl;
• R 8 is independently a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain or an optionally substituted straight or branched alkynylene chain; or
• Compounds of Formula (XIX) may be synthesized by methods known in the art, e.g., those described in International Patent Publication No. WO2009/103739.
• the SCD inhibitor is a compound disclosed in International Patent Publication No. WO2009/103739, the compounds of which are herein incorporated by reference.
• the SCD inhibitor is a compound of Formula XX, W is selected from -N(R 8 )C(O)-, -C(O)N(R 8 )- or a direct bond;
• n 1, 2, or 3;
• p 0, 1, 2, to 2n
• q 0, 1, 2, or 3;
• R 1 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, haloalkyl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;
• R 2 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, haloalkyl, aralkyl, aralkyloxy, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl;
• R 3 is alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, halo, haloalkyl, trifluoromethoxyl, cyano, hydroxy, or -N(R 6 )2;
• R 5 and R 5a are independently hydrogen, alkyl, haloalkyl, hydroxyl, hydroxyalkyl, alkoxy, cycloalkylalkyl or aralkyl;
• R 6 is alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, hydroxyalkyl, haloalkyl, alkoxy,
• R 5 and R 6 on adjacent carbons are together to form a cycloalkyl, or to form an aryl;
• R 7 is hydrogen, alkyl, haloalkyl, aryl, cyclolkyl, heteroaryl, heterocyclyl, hydroxyalkyl,
• R 8 is hydrogen, alkyl, hydroxyalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, or aralkyl; or a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof.
• Compounds of Formula (XX) may be synthesized by methods known in the art, e.g., those described in International Patent Publication No. WO2009/156484.
• the SCD inhibitor is a compound disclosed in International Patent Publication No. WO2009/156484, the compounds of which are herein incorporated by reference.
• the SCD inhibitor is a compound of Formula XXI
• A is selected from the group consisting of:
• J and K are each independently selected from the group consisting of: S, O, NH, CH and CH2, wherein each NH is unsubstituted or substituted with R g , and wherein each CH and CH2 is unsubstituted or substituted with R2, provided that when g is a single bond at least one of J and K is CH2 unsubstituted or substituted with R 2 , and further provided that when g is a double bond then both J and K are CH;
• L and M are each independently selected from the group consisting of: S, O, NH and CH2, wherein each NH is unsubstituted or substituted with R g , and wherein each CH2 is unsubstituted or substituted with R 2 ;
• T, U, V and W are each independently selected from N and CH, wherein each CH is
• X is CH2, wherein CH2 is unsubstituted or substituted with R 2 ;
• Y is independently selected from the group consisting of: O, NH and CH2, wherein each NH is unsubstituted or substituted with R g , and wherein each CH 2 is unsubstituted or substituted with R 2 ;
• Z is independently selected from the group consisting of: S, S(O), S(O)2, O, NH and CH2, wherein each NH is unsubstituted or substituted with R g , and wherein each CH2 is unsubstituted or substituted with R 2 ;
• each R 1 is independently selected from the group consisting of: hydrogen, halogen, and
• alkyl is unsubstituted or substituted with one to three substituents independently selected from halogen and hydroxy;
• each R 2 is independently selected from the group consisting of: hydrogen, halogen, oxo, C1-6alkyl, (CH2)nOR e , (CH2)nN(R e )2, (CH2)nC ⁇ N, (CH2)nCOR e , and (CH2)nS(O)qR e ,
• alkyl is unsubstituted or substituted with hydroxy or one to three halogens, and wherein any CH2 in R 2 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C1-4alkyl unsubstituted or substituted with one to five fluorines;
• each R a is independently selected from the group consisting of:
• each R b is independently selected from the group consisting of: hydrogen, and C1-4alkyl, wherein alkyl is unsubstituted or substituted with one to five fluorines;
• each R c is independently selected from the group consisting of: -(CH2)mCO2H, -(CH2)mCO2C1-3 alkyl, -(CH2)m-NR b -(CH2)pCO2H, -(CH2)m-NR b -(CH2)pCO2C1-3alkyl, -(CH2)m-O-(CH2)pCO2H, -(CH2)m-O-(CH2)pCO2C1-3alkyl, -(CH2)m-S-(CH2)pCO2H, and wherein any CH2 in R c is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C1-4alkyl unsubstituted or substituted with one to five fluorines;
• each R d is independently selected from the group consisting of: -(CH 2 ) n CO 2 H,
• any CH2 in R d is unsubstituted or substituted with one to two groups independently selected from the group consisting of: halogen, hydroxy, and C 1-4 alkyl unsubstituted or substituted with one to five fluorines;
• each R e is independently selected from the group consisting of: hydrogen, and C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents independently selected from the group consisting of: halogen, cyano, -C 1-4 alkoxy, -C 1-4 alkylthio, -C 1-4 alkylsulfonyl, -CO 2 H, and -CO2C1-4alkyl;
• each R g is independently selected from the group consisting of: hydrogen, and C1-6alkyl, m is an integer from 1 to 3;
• n is an integer from 0 to 3;
• p is an integer from 1 to 3;
• q is an integer from 1 to 2;
• t is an integer from 0 to 8.
• d is an integer from 0 to 2;
• e is an integer from 0 to 2
• B is a 5 membered heteroaryl ring containing 1, 2 or 3 heteroatoms selected from NH, O and S, wherein any CH is unsubstituted or substituted with one substituent selected from R a , and wherein any NH is unsubstituted or substituted with one substituent selected from R b ;
• each R 3 is independently selected from the group consisting of: hydrogen, halogen, -C1-6alkyl, -C1-6alkenyl, -OC1-6alkyl, (CH2)nOR e , (CH2)nN(R e )2, (CH2)nC ⁇ N, (CH2)nCOR e , and (CH2)nS(O)qR e ,
• alkyl is unsubstituted or substituted with one to three substituents selected from: hydroxy, halogen, C1-4alkyl, C3-6cycloalkyl, C2-5cycloheteroalkyl, aryl, and heteroaryl,
• alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl are unsubstituted or substituted with one to three substituents selected from: halogen, hydroxy, and C1-4alkyl unsubstituted or substituted with one to five fluorines, and wherein any CH2 in R 3 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C1-4alkyl unsubstituted or substituted with one to five fluorines;
• R 4 is selected from the group consisting of:
• B is selected from the group consisting of:
• each R 3 is independently selected from the group consisting of: hydrogen, halogen, -C1-6alkyl, -OC1-6alkyl, (CH2)nOR e , (CH2)nN(R e )2, (CH2)nC ⁇ N, (CH2)nCOR e , and (CH2)nS(O)qR e ,
• alkyl is unsubstituted or substituted with hydroxy or one to three halogens, and wherein any CH2 in R 3 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C1-4alkyl unsubstituted or substituted with one to five fluorines;
• R 4 is selected from the group consisting of:
• Compounds of Formula (XXI) may be synthesized by methods known in the art, e.g., those described in International Patent Publications No. WO2010/094120 and WO2011/047481.
• the SCD inhibitor is a compound disclosed in International Patent Publications No. WO2010/094120 and WO2011/047481, the compounds of which are herein incorporated by reference.
• the SCD inhibitor is a compound of Formula XXII,
• X and Y are each independently CH or N;
• W is heteroaryl selected from the group consisting of:
• R 1 is heteroaryl selected from the group consisting of:
• R d is -(CH2)nCO2H, -(CH2)nCO2C1-3alkyl, -(CH2)n-Z-(CH2)pCO2H, or -(CH2)nZ-(CH2)pCO2C1-3alkyl;
• R e is -(CH2)mCO2H, -(CH2)mCO2C1-3alkyl, -(CH2)m-Z-(CH2)pCO2H, or
• n is an integer from 1 to 3;
• p is an integer from 1 to 3;
• n is an integer from 0 to 3;
• Z is O or S
• each R 2 is independently selected from the group consisting of:
• R 3 is hydrogen or C 1-4 alkyl wherein alkyl is optionally substituted with one to five fluorines;
• Ar is phenyl or pyridyl each of which is optionally substituted with one to five substituents independently selected from the group consisting of:
• R a is hydrogen or C1-4 alkyl wherein alkyl is optionally substituted with one to five fluorines; and R b and R c are each independently hydrogen, fluorine, or C1-4 alkyl wherein alkyl is optionally substituted with one to five fluorines;
• R b and R e are taken together to form a 3- to 6-membered saturated carbocyclic ring optionally containing a heteroatom selected from the group consisting of O, S, and N.
• Compounds of Formula (XXII) may be synthesized by methods known in the art, e.g., those described in International Patent Publication No. WO2010/025553.
• the SCD inhibitor is a compound disclosed in International Patent Publication No. WO2010/025553, the compounds of which are herein incorporated by reference.
• the SCD inhibitor is a compound of Formula XXIII,
• X and Y are each independently CH or N;
• W is heteroaryl selected from the group consisting of:
• W is further optionally substituted with one to two substituents independently selected from R 4 ;
• R 1 is selected from the group consisting of: -(CH2)pCO2H, -(CH2)pCO2C1-4alkyl, -Z(CH2)mCO2H, -Z(CH2)mCO2C1-4alkyl, -(CH2)nOR 6 , -(CH2)n-CONR 6 R 7 , -(CH2)n-OCONR 6 R 7 , -(CH2)n-SO2NR 6 R 7 , -(CH2)n- SO 2 R 8 , -(CH 2 ) n -NR 9 SO2R 8 , -(CH 2 ) n -NR 9 CONR 6 R 7 , -(CH 2 ) n -NR 9 COR 9 , and -(CH 2 ) n -NR 9 CO 2 R 8 ;
• R 2 is -(CH2)mCO2H or -(CH2)mCO2C1-3alkyl
• each m is independently an integer from 1 to 3;
• each n is independently an integer from 0 to 3;
• each p is independently an integer from 0 to 3;
• T is O, S, or NR 5 ;
• Z is O, S, or NR 5 ;
• each R 4 is independently selected from the group consisting of:
• R 5 is hydrogen or C1-4alkyl wherein alkyl is optionally substituted with one to five fluorines;
• R 6 and R 7 are each independently selected from the group consisting of hydrogen
• alkyl is optionally substituted with one to five substituents independently selected from fluorine and hydroxy and wherein phenyl and cycloalkyl are optionally substituted with one to five substituents independently selected from halogen, hydroxy, C1-6alkyl, and C1-6alkoxy, wherein alkyl and alkoxy are optionally substituted with one to five fluorines;
• R 6 and R 7 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from azetidine, pyrrolidine, piperidine, piperazine, and morpholine wherein said heterocyclic ring is optionally substituted with one to three substituents independently selected from halogen, hydroxy, C1-6alkyl, and C1-6alkoxy, wherein alkyl and alkoxy are optionally substituted with one to five fluorines; each R 8 is independently C1-6alkyl, wherein alkyl is optionally substituted with one to five substituents independently selected from fluorine and hydroxyl;
• R 9 is hydrogen or R 8 ;
• Ar is phenyl or pyridyl each of which is optionally substituted with one to five substituents independently selected from the group consisting of:
• R a is hydrogen or C1-4alkyl wherein alkyl is optionally substituted with one to five fluorines; and R b and R c are each independently hydrogen, fluorine, or C1-4alkyl wherein alkyl is optionally substituted with one to five fluorines;
• R b and R c are taken together to form a 3- to 6-membered saturated carbocyclic ring optionally containing a heteroatom selected from the group consisting of O, S, and N.
• Compounds of Formula (XXIII) may be synthesized by methods known in the art, e.g., those described in International Patent Publication No. WO2010/037225.
• the SCD inhibitor is a compound disclosed in International Patent Publication No. WO2010/037225, the compounds of which are herein incorporated by reference.
• the SCD inhibitor is a compound of Formula XXIV,
• X is NH, Y is C, and Z is N or CR 5 ;
• X and Z are each CR 5 , and Y is N;
• W is a residue selected from the group consisting of:
• each R a is independently selected from the group consisting of:
• R 3 , R 4 , and each R 5 are each independently selected from the group consisting of:
• R 2 is selected from the group consisting of:
• SC1-3alkyl optionally substituted with one to five fluorines
• SO2C1-3alkyl optionally substituted with one to five fluorines, and
• R b is independently hydrogen or C 1-3 alkyl
• R 1 is selected from the group consisting of: cyclopentenyl, cyclohexenyl, phenyl, and heteroaryl selected from the group consisting of: pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, furyl, thienyl, thiazolyl, oxazolyl,isoxazolyl, isothiazolyl, imidazolyl, and pyrazolyl;
• aryl and heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, cyano, and C1-3alkyl wherein alkyl is optionally substituted with one to five fluorines.
• Compounds of Formula (XXIV) may be synthesized by methods known in the art, e.g., those described in International Patent Publication No. WO2009/129625.
• the SCD inhibitor is a compound disclosed in International Patent Publication No. WO2009/129625, the compounds of which are herein incorporated by reference.
• the SCD inhibitor is a compound of Formula XXV,
• Z is independently selected from the group consisting of: S, S(O), S(O)2, O, NH and CH2, wherein each NH is unsubstituted or substituted with R g , and wherein CH 2 is unsubstituted or substituted with R 2 ;
• B is a 5 membered heteroaryl ring containing 1, 2 or 3 heteroatoms selected from NH, O and S, wherein any CH is unsubstituted or substituted with one substituent selected from R a , and wherein any NH is unsubstituted or substituted with one substituent selected from R b ;
• each R 1 is independently selected from the group consisting of: hydrogen, halogen, and C1-3alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents independently selected from halogen and hydroxy;
• each R 2 is independently selected from the group consisting of: hydrogen, halogen, aryl, heteroaryl, biphenyl, C1-6alkyl, (CH2)nOR e , (CH2)nN(R e )2, (CH2)nC ⁇ N, (CH2)nCOR e , and (CH2)nS(O)qR e , wherein CH2, alkyl, phenyl, aryl and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from R f ;
• each R 3 is independently selected from the group consisting of: hydrogen, halogen, -C1-6alkyl, -OC1-6alkyl, (CH2)nOR e , (CH2)nN(R e )2, (CH2)nC ⁇ N, (CH2)nCOR e , and (CH2)nS(O)qR e ,
• alkyl is unsubstituted or substituted with hydroxy or one to three halogens, and wherein any CH2 in R 3 is unsubstituted or substituted with one to two groups independently selected
• R 4 is selected from the group consisting of:
• each R a is independently selected from the group consisting of:
• each R b is independently selected from the group consisting of: hydrogen, and C1-4alkyl, wherein alkyl is unsubstituted or substituted with one to five fluorines;
• each R c is independently selected from the group consisting of: -(CH2)mCO2H,
• any CH2 in R d is unsubstituted or substituted with one to two groups independently selected from the group consisting of: halogen, hydroxy, and C1-4alkyl unsubstituted or substituted with one to five fluorines;
• each R e is independently selected from the group consisting of: hydrogen, and C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents independently selected from the group consisting of: halogen, cyano, -C1-4alkoxy, -C1-4alkylthio, -C1-4alkylsulfonyl, -CO2H, and -CO 2 C 1-4 alkyl;
• each R f is independently selected from the group consisting of: hydrogen, halogen, -C1-6alkyl, -OC1-6alkyl, (CH2)nOR e , (CH2)nN(R e )2, (CH2)nC ⁇ N, (CH2)nCOR e , (CH2)nS(O)qR e , and aryl,
• alkyl and aryl are unsubstituted or substituted with one, two or three groups independently selected from halogen, hydroxy, and C 1-4 alkyl unsubstituted or substituted with one to five fluorines;
• each R g is independently selected from the group consisting of: hydrogen, and C1-6alkyl
• n is an integer from 1 to 3;
• n is an integer from 0 to 3;
• p is an integer from 1 to 3;
• q is an integer from 1 to 2;
• r is an integer from 0 to 2;
• s is an integer from 0 to 4.
• t is an integer from 0 to 8.
• d is an integer from 0 to 2;
• e is an integer from 0 to 2
• Compounds of Formula (XXV) may be synthesized by methods known in the art, e.g., those described in International Patent Publication No. WO2011/011872.
• the SCD inhibitor is a compound disclosed in International Patent Publication No. WO2011/011872, the compounds of which are herein incorporated by reference.
• the SCD inhibitor is a compound of Formula XXVI,
• each n is independently 0, 1 or 2;
• W and Z are each independently CH or N, with the proviso that at least one of W and Z is N;
• X-Y is N-C(O), N-S(O)2, N-CR 1 R 2 , CH-O, CH-S(O)p, CH-NR 5 , or CH-CR 1 R 2 ;
• Ar is phenyl, benzyl, naphthyl, or heteroaryl each of which is optionally substituted with one to five R 3 substituents;
• R a is phenyl, naphthyl, or a heteroaromatic ring selected from the group consisting of: oxazolyl, thiazolyl, imidazolyl, pyrrolyl, pyrazolyl, isoxazolyl,
• phenyl, naphthyl, and the heteroaromatic ring are optionally substituted with one to three substituents independently selected from R 6 ;
• R 1 and R 2 are each independently hydrogen or C1-3alkyl, wherein alkyl is optionally substituted with one to three substituents independently selected from halogen and hydroxy;
• each R 6 is independently selected from the group consisting of: C 1-6 alkyl, C 2-4 alkenyl, (CH 2 ) n OR 4 , (CH2)n-phenyl, (CH2)n-naphthyl, (CH2)n-heteroaryl, (CH2)n-heterocyclyl, (CH2)nC3-7cycloalkyl, halogen, (CH2)nN(R 4 )2, (CH2)nC ⁇ N, (CH2)nCO2R 4 , (CH2)nOC(O)R 4 , (CH2)nCOR 4 , NO2, (CH2)nNR 4 SO2R 4 ,
• phenyl, naphthyl, heteroaryl, cycloalkyl, and heterocyclyl are optionally substituted with one to three substituents independently selected from halogen, hydroxy, C1-4alkoxy, C1-4alkylsulfonyl, C3-6cycloalkyl, and C1-4alkyl wherein alkyl is optionally substituted with hydroxy or one to three fluorines; and wherein any methylene (CH2) carbon atom in R 6 is optionally substituted with one to two groups independently selected from fluorine, hydroxy, and C1-4alkyl optionally substituted with one to five fluorines; or two substituents when on the same methylene (CH2) group are taken together with the carbon atom to which they are attached to form a cyclopropyl group;
• each R 3 is independently selected from the group consisting of: C1-6alkyl, (CH2)nOR 4 ,
• phenyl, naphthyl, heteroaryl, cycloalkyl, and heterocyclyl are optionally substituted with one to three substituents independently selected from halogen, hydroxy, C1-4alkoxy, C3-6cycloalkyl, and C1-4alkyl wherein alkyl is optionally substituted with hydroxy or one to three fluorines; and wherein any methylene (CH2) carbon atom in R 3 is optionally substituted with one to two groups independently selected from fluorine, hydroxy, and C1-4alkyl optionally substituted with one to five fluorines; or two substituents when on the same methylene (CH2) group are taken together with the carbon atom to which they are attached to form a cyclopropyl group; each R 4 is independently selected from the group consisting of: hydrogen, C1-6alkyl, (CH2)n-phenyl, (CH2)n-heteroaryl, (CH2)n-naphthyl, and (CH2)nC3-7cycloalkyl;
• alkyl, phenyl, heteroaryl, and cycloalkyl are optionally substituted with one to three groups independently selected from halogen, C 1-4 alkyl, and C 1-4 alkoxy; or two R 4 groups together with the atom to which they are attached form a 4- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and NC1-4alkyl; and
• R 5 is hydrogen or C1-6 alkyl optionally substituted with one to five fluorines.
• Compounds of Formula (XXVI) may be synthesized by methods known in the art, e.g., those described in International Patent Publication No. WO2007/009236.
• the SCD inhibitor is a compound disclosed in International Patent Publication No. WO2007/009236, the compounds of which are herein incorporated by reference.
• the SCD inhibitor is a compound of Formula XXVII
• X is -O-, -S-, -S(O)-, -S(O)2-, -NR 9 -, or-CR 10 R 11 ;
• W is selected from the group consisting of:
• HetAr is heteroaryl selected from the group consisting of:
• R 1 is heteroaryl selected from the group consisting of:
• R b is -(CH2)rCO2H, -(CH2)rCO2C1-3alkyl, -(CH2)r-Z-(CH2)pCO2H, or -(CH2)r-Z-(CH2)pCO2C1-3alkyl;
• R C is -(CH2)mCO2H, -(CH2)mCO2C1-3alkyl, -(CH2)m-Z-(CH2)pCO2H, or
• R 1 heteroaryl ring is optionally substituted with a substituent selected from the group consisting of cyano, halogen, C1-4alkyl, C1-4alkoxy, C1-4alkylthio, C1-4alkylsulfonyl, and trifluoromethyl;
• each R 2 is independently selected from the group consisting of:
• Ar is phenyl or naphthyl optionally substituted with one to five R 3 substituents; each R 3 is independently selected from the group consisting of: C1-6alkyl, C2-6alkenyl, (CH2)n-phenyl,
• phenyl, naphthyl, heteroaryl, cycloalkyl, and heterocyclyl are optionally substituted with one to three substituents independently selected from halogen, hydroxy, C1-4alkyl,
• any methylene (CH2) carbon atom in R 3 is optionally substituted with one to two groups independently selected from fluorine, hydroxy, and
• Z is O, S, or NR 4 ;
• each R 4 is independently selected from the group consisting of: hydrogen, C1-6alkyl,
• alkyl, phenyl, heteroaryl, and cycloalkyl are optionally substituted with one to three groups independently selected from halogen, C1-4alkyl, and C1-4alkoxy; or two R 4 groups together with the atom to which they are attached form a 4- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, NH, and NC1-4alkyl;
• each R 6 and R 7 are independently hydrogen or C1-3alkyl, wherein alkyl is optionally substituted with one to five fluorines;
• each R 8 is independently selected from the group consisting of hydrogen, halogen, and C1-4alkyl wherein alkyl is optionally substituted with one to five fluorines;
• R 9 , R 10 , and R 11 are each independently hydrogen or C1-3alkyl, wherein alkyl is optionally substituted with one to five fluorines;
• u is an integer from 0 to 2;
• r is an integer from 0 to 3;
• n is an integer from 1 to 3;
• each s is independently an integer from 1 to 3;
• each t is independently an integer from 1 to 3.
• Compounds of Formula (XXVII) may be synthesized by methods known in the art, e.g., those described in International Patent Publication No. WO2009/073973.
• the SCD inhibitor is a compound disclosed in International Patent Publication No. WO2009/073973, the compounds of which are herein incorporated by reference.
• the SCD inhibitor is a compound of Formula XXVIII,
• any methylene (CH2) carbon atom in (CH2)u is optionally substituted with one to two R 5 substituents independently selected from fluorine, hydroxy, oxo, hydroxyrnethyl, and C1-4alkyl; or two R 5 substituents, when on the same (CH2) carbon atom, are taken together with the carbon atom to which they are attached to form a C3-6cycloalkyl group; or any two methylene (CH2) carbon atoms are taken together to form a saturated or monounsaturated five- or six-membered cycloalkyl group;
• X and Y are each independently a bond, -O-, -S-, -S(O)-, -S(O)2-, -NR 6 -,
• W is heteroaryl selected from the group consisting of:
• R 1 is heteroaryl selected from the group consisting of:

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