WO2011072241A1 - 4 -oxo- ih -quinoline- 3 - carboxamides as modulators of atp -binding cassette transporters - Google Patents

4 -oxo- ih -quinoline- 3 - carboxamides as modulators of atp -binding cassette transporters Download PDF

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Publication number
WO2011072241A1
WO2011072241A1 PCT/US2010/059920 US2010059920W WO2011072241A1 WO 2011072241 A1 WO2011072241 A1 WO 2011072241A1 US 2010059920 W US2010059920 W US 2010059920W WO 2011072241 A1 WO2011072241 A1 WO 2011072241A1
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WIPO (PCT)
Prior art keywords
oxo
carboxamide
phenyl
hydroxy
quinoline
Prior art date
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PCT/US2010/059920
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French (fr)
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WO2011072241A9 (en
Inventor
Urvi Sheth
Tev T.D. Fanning
Mehdi Numa
Hayley Binch
Dennis James Hurley
Jinglan Zhou
Sara S. Hadida Ruah
Anna R. Hazlewood
Alina Silina
Rajendran Vairagoundar
Fredrick F. Van Goor
Peter Diederik Jan Grootenhuis
Martyn C. Botfield
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Vertex Pharmaceuticals Incorporated
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Publication date
Priority to EP10793116A priority Critical patent/EP2509954A1/en
Priority to NZ600707A priority patent/NZ600707A/en
Priority to CA2783314A priority patent/CA2783314A1/en
Priority to CN201080056022XA priority patent/CN102652128A/en
Priority to AU2010327993A priority patent/AU2010327993A1/en
Priority to RU2012129206/04A priority patent/RU2552353C2/en
Application filed by Vertex Pharmaceuticals Incorporated filed Critical Vertex Pharmaceuticals Incorporated
Priority to JP2012543310A priority patent/JP2013513617A/en
Priority to MX2012006764A priority patent/MX2012006764A/en
Publication of WO2011072241A1 publication Critical patent/WO2011072241A1/en
Priority to US13/492,164 priority patent/US8802700B2/en
Priority to IL220283A priority patent/IL220283A0/en
Publication of WO2011072241A9 publication Critical patent/WO2011072241A9/en

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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems

Definitions

  • the present invention relates to modulators of ATP-Bmding Cassette (“ABC”) transporters or fragments thereof, including cystic fibrosis transmembrane conductance regulator (“CFTR”), compositions thereof, and methods therewith.
  • the present invention also relates to methods of treating ABC transporter mediated diseases using such modulators,
  • ABC transporters are a family of membrane transporter proteins that regulate the transport of a wide variety of pharmacological agents, potentially toxic drugs, and xenobioiics, as well as anions, ABC transporters are homologous membrane proteins mat bind and use cellular adenosine triphosphate (ATI 5 ) for their specific activities. Some of these transporters were discovered as multidrug resistance proteins (like the MDR1-P glycoprotein, or tire multidrug resistance protein, MRP! ), defending malignant cancer cells against chemotherapeutic agents. To date, 48 ABC Transporters have been identified and grouped into 7 families based on their sequence identity and function.
  • ABC transporters regulate a variety of important physiological roles within the body and provide defense against harmful environmental compounds. Because of this, they represent important potential drug targets for the treatment of diseases associated with defects in the transporter, prevention of drug transport out of the target cell, and intervention in other diseases in which modulation of ABC transporter activity may be beneficial.
  • CFTR cAMP/ATP-mediated anion channel
  • CFTR is expressed In a variety of cells types, including absorptive and secretory epithelia cells, where It regulates anion flux across the membrane, as well as the activity of other ion channels and proteins. In epithelia ceils, normal functioning of CFTR is critical for the maintenance of electrolyte transport throughout the body, including respiratory and digestive tissue.
  • CFTR is composed of approximately 1480 amino acids that encode a protein made up of a tandem repeat of transmembrane domains, each containing six transmembrane helices and a nucleotide binding domain. Be two transmembrane domains are linked by a large, polar, regulatory (R)-domain with multiple phosphorylation sites that regulate channel activity and cellular trafficking.
  • CFTR cystic fibrosis
  • a defect in this gene causes mutations in CFTR resulting in cystic fibrosis ("CF"), the most common fatal genetic diseas in humans. Cystic fibrosis affects approximately one in every 2,500 infants in the United States. Within the general United Stales population, up to 10 million people carry a single copy of the defective gene without apparent ill effects, in contrast, individuals with two copies of the CF associated gene suffer from the debilitating and fatal effects of CF, including chronic lung disease.
  • Ri I7H-CFTR and G551D-CFTR other disease causing mutations in CFTR that result in defective trafficking, synthesis, and or channel gating could be up- or down-regulated to alter anion secretion and modify disease progression and/or severity.
  • CFTR transports a variety of molecules in addition to anions
  • this role represents one element in an important mechanism of transporting ions and water across the epithelium.
  • the other elements include the epithelia! Na ⁇ channel, ENaC, Na + /2C!YK + co-transporter, a + -K + - ATPase pump and the basolaterai membrane K' channels, that are responsible for the uptake of chloride into the cell.
  • Mutations in CFTR that are associated with moderate CFTR dysfunction are also evident in patients with conditions that share certain disease manifestations with CF but do not meet the diagnostic criteria for CF. These include congenital bilateral absence of die vas deferens, idiopathic chronic pancreatitis, chronic bronchitis, and chronic rhinosinusitis. Other diseases in which mutant CFTR is believed to be a risk factor along with modifier genes
  • environmental factors include primary sclerosing cholangitis, allergic bronchopulmonary aspergillosis, and asthma,
  • Cigarette smoke, hypoxia, and environmental factors that induce hypoxic signaling have also been demonstrated to impair CFT function and may contribute to certain forms of respiratory disease, such as chronic bronchitis. Diseases that ma be due to defective CFTR function but do not meet the diagnostic criteria for CF are characterized as CFTR- related diseases.
  • CFTR in addition to cystic fibrosis, modulation of CFTR activity may be beneficial for other diseases not directly caused by mutations in CFTR, such as secretory diseases and other protein folding diseases mediated by CFTR.
  • CFTR regulates chloride and bicarbonate flux across the epithe!ia of many cells to control fluid movement, protein solubilization, mucus viscosity, and enzyme activity. Defects in CFTR can cause blockage of the airway or ducts in many organs, including the liver and pancreas.
  • Potentiators are compounds that enhance the gating activity of CFTR present in the cell membrane. Any disease which involves thickening of the mucus, impaired fluid regulation, impaired mucus clearance, or blocked ducts leading to inflammation and tissue destruction could be a candidate for potentiators,
  • COPD chronic obstructive pulmonary disease
  • asthma smoke induced COPD
  • chronic bronchitis chronic bronchitis
  • rhinosinusitis constipation
  • dry eye disease dry eye disease
  • Sjogren's Syndrome gastroesophageal reflux disease
  • gallstones rectal prolapse
  • inflammatory bowel disease characterized by airflow limitation that is progressive and not fully reversible.
  • the airflow limitation is due to mucus hypersecretion, emphysema, and bronchiolitis.
  • Activators of mutant or wild-type CFTR offer a potential treatment of mucus hypersecretion and impaired mucociliary clearance that is common in COPD.
  • CFTR modulators may prevent or slow the parenchimal destruction of the airway that characterizes emphysema and reduce or reverse the increase in mucus secreting cell number and size that underiyses mucus hypersecretion in airway diseases. Dry eye disease is characterized by a decrease in tear- aqueous production and abnormal tear film lipid, protein and mucin profiles.
  • Sjogrens's syndrome is an autoimmune disease in which the immune system attacks moisture-producing glands throughout the body, including the eye, mouth, skin, respiratory tissue, liver, vagina, and gut. Symptoms, include, dry eye, mouth, and vagina, as well as lung disease.
  • the disease is also associated with rheumatoid arthritis, systemic lupus, systemic sclerosis, and polymypositis/dermatomyositis. Defective protein trafficking is believed to cause the disease, for which treatment options are limited.
  • Modulators of CFTR activity may hydrate the various organs afflicted by the disease and may help to alleviate the associated symptoms.
  • Individuals with cystic fibrosis have recurrent episodes of intestinal obstruction and higher incidences of rectal polapse, gallstones, gastroesophageal reflux disease, GI malignancies, and inflammatory bowel disease, indicating that CFTR function may play an important role in preventing such diseases.
  • the diseases associated with the first class of ER malfunction are cystic fibrosis (due to misfolded AF5Q8-CFTR as discussed above), hereditary emphysema (due to a 1 -antitrypsin; non Piz variants), hereditar hemochromatosis, coaguiation-fibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia. Type 1 chylor eronernia,
  • abetalipoproteineniia lysosomal storage diseases, such as I-celi disease/pseudo-Hurler, Mucopolysaccharidoses (due to lysosomal processing enzymes), Sandhof/Tay-Sachs (due to ⁇ - hexosaminidase), Crigler-Najjar type II (due to UDP-glucuronyl-sialyc-transferase), polyendocrinopathy/hyperinsulemia, Diabetes mellitus (due to insulin receptor), Laron
  • hypoparathyroidism due to preproparathyroid hormone
  • melanoma due to tyrosinase
  • the diseases associated with the latter class of ER malfunction are Glycanosis CDG type 1, hereditary emphysema (due to al- Antitrypsin (PiZ variant), congenital hyperthyroidism, osteogenesis imperfecta (due to Type I, ⁇ , IV procollagen), hereditary hypofibrinogenemia (due to fibrinogen), ACT deficiency (due to al-antichymotrypsin), Diabetes insipidus (DI), neurophysea!
  • neprogenic DI due to aquaporin II
  • Charcot-Marie Tooth syndrome due to peripheral myelin protein 22
  • Perlizaeus- Merzbacher disease neurodegenerative diseases such as Alzheimer's disease (due to ⁇ and presenilins), Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, several poiyglutamine neurological disorders such as Huntington's, spinocerebullar ataxia type I, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary
  • Creutzfeldt- Jakob disease due to prion protein processing defect
  • Fabry disease due to lysosomal a ⁇ galactosidase A
  • Straussler-Scheinker syndrome due to Prp processing defect
  • infertility pancreatitis pancreatic insufficiency
  • osteoporosis osteopenia, Gorham's
  • PCD Primary Ciliary Dyskinesia
  • PCD with situs inversus also known as Kartagener syndrome
  • PCD without situs inversus and ciliary aplasia and liver disease.
  • CFTR- opathies disease phenotypes associated with cystic fibrosis transmembrane regulator gene mutations
  • CFTR modulators may be beneficial for the treatment of secretory diarrheas, in which epithelial water transport is dramatically increased as a result of secretagogue activated chloride transport.
  • the mechanism involves elevation of cAMP and stimulation of CFTR.
  • Diarrhea is both a significant factor in malnutrition and the leading cause of death (5,000,000 deaths/year) in children less than five years old.
  • Diarrhea in bam animals and pets such as cows, pigs and horses, sheep, goats, cats and dogs, also known as scours, is a major cause of death in these animals. Diarrhea can result from any major transition, such as weaning or physical movement, as well as in response to a variety of bacterial or viral infections and generally occurs within the first few hours of the animal's life.
  • ETEC enterotoxogenic E.coli
  • Common viral causes of diarrhea include rotavirus and coronavirus.
  • Oilier infectious agents include Cryptosporidium, giardia lamblia, and salmonella, among others.
  • Symptoms of rotavirai infection include excretion of watery feces, dehydration and weakness. Coronavirus causes a more severe illness in the newborn animals, and has a higher mortality rate than rotavirai infection. Often, however, a young animal may be infected with more than one virus or with a combination of viral and bacterial microorganisms at one time. This dramatically increases the severity of the disease.
  • R 1 , R 2 , R 3 , R 4 , R 3 , R 6 , R', and Ar l are described generally and in classes and subclasses below.
  • compositions are useful for treating or lessening the severity of a variety of diseases, disorders, or conditions, including, but not limited to, cystic fibrosis, Hereditary emphysema, Hereditar hemochromatosis, Coagulation-Fibrinolysis deficiencies, such as Protein C deficiency, Type 1 hereditary angioedema. Lipid processing deficiencies, such as Familial hypercholesterolemia.
  • Type 1 chylomicronemia Abetalipoproteinemia, Lysosomal storage diseases, such as I-ceS1 disease Pseudo-Hurler, Mucopolysaccharidoses, Sandhof/Tay-Saehs, Crig!er-Najjar type ⁇ , Poiyendocrinopathy/Hyperinsulemia, Diabetes mellitus, Laron dwarfism, Myleoperoxidase deficiency, Primary hypoparathyroidism, Melanoma, Glycanosis CDG type 1, Hereditary emphysema. Congenital hyperthyroidism, Osteogenesis imperfecta, Hereditary
  • hypofibrinogenemia ACT deficiency
  • Diabetes insipidus DI
  • Neurophyseal DI Neprogenic DI
  • Charcot-Marie Tooth syndrome Perlizaeus-Merzbacher disease
  • neurodegenerative diseases such as AlzheimeR's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders asuch as Huntington, Spinocerebuliar ataxia type I, Spinal and bulbar muscular atrophy, Dentatorubai pallidoluysian, and Myotonic dystrophy, as well as Spongiform
  • encephalopathies such as Hereditary Creutzfe!dt- Jakob disease, Fabry disease, Straussler- Scheinker syndrome, COPD, dry-eye disease, and Sjogren's disease.
  • the present i vention relates to compounds of formula I useful as modulators of ABC transporter activity:
  • AT is a 5-6 membered aromatic monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is optionally fused to a 5-12 membered monocyclic or bicyclic, aromatic, partially unsaturated, or saturated ring, wherem each ring contains 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ar ! has m substituents, each independently selected from -WR W ;
  • W is a bond or is an optionally substituted Q-Cg alkylidene chain wherein up to two methylene units of W are optionally and independently replaced by -CO-, -CS-, -COCO-, - CONR'-, -CONR'NR'-, -CO2-, -OCO-, -NR'COr, -0-, -NR'CONR'-, -OCONR'-, -NR.' R.', - NR'NR'CO-, -NR'CO-, -S-, -SO, -SO?.-, -NR'-, -S0 2 NR'-, NR'S0 2 -, or -NR'80 2 NR' ⁇ ;
  • R w is independently R', halo, N0 2 , CN, CF 3 , or OCF3;
  • n 0-5;
  • each of R ! , R 2 , R 3 , R 4 , and R 5 is indendently ⁇ X-R ;
  • X is a bond or is an optionally substituted C C g alkylidene chain wherein up to two methylene units of X are optionally and independently replaced by -CO-, -CS-, -COCO-, - CONR'-, -CONR'NR'-, -CO2-, -OCO-, -NR'COr, -0-, -NR'CONR'-, -OCONR'-, -NR'NR', - NR'NR'CO-, -NR'CO-, -S-, -SO, -SQr, -NR'-, -SO2NR'-, NR'SQr, or -NR'SCfeNR * -;
  • R x is independently R', halo, N0 2 , CN, CF 3 , or OCF3;
  • R 6 is hydrogen, CF3, -OR', -SR', or an optionally substituted Ci-e aliphatic group
  • R 7 is hydrogen or a C;- 6 aliphatic group optionally substituted with -X-R ;
  • R' is independently selected from hydrogen or an optionally substituted group selected from a Cj Cs aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or
  • R' 8544833.1 sulfur; or two occurrences of R' are taken together with the atoro(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heieroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Ar ⁇ is a 5-6 membered aromatic monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is optionally fused to a 5-12 membered monocyclic or bicyclic, aromatic, partially unsaturated, or saturated ring, wherein each ring contains 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ar 1 has m substituents each independently selected from -WR W ;
  • W is a bond or is an optionally substituted C 1 -C6 alkylidene chain wherein up to two methylene units of W are optionally and independently replaced by -CO-, -CS-, -COCO-, - CONR'-, -CONR'NR'-, -CO2-, -OCO-, -NR'CCfe-, -0-, -NR'CONR'-, -OCONR'-, -NR'NR', - NR'NR'CO-, -NR'CO-, -S-, -SO, -SO2-, -NR'-, -80 2 NR' ⁇ , NR'S0 2 -, -NR'SCfcNR'-;
  • R w is independently R', halo, N0 2 , CN, CF 3 , or OCF3;
  • n 0-5;
  • each of R 5 , R 2 , R 3 , R 4 , and R 5 is independentlyTMX-R X ;
  • X is a bond or is an optionally substituted C ⁇ -Cs alkylidene chain wherein up to two methylene units of X are optionally and independently replaced by -CO-, -CS-, -COCO-, - CONR'-, -CONR'NR'-, -CO2-, -OCO-, -NR'COr, -0-, -NR'CONR'-, -OCONR'-, -NR'NR', - NR'NR'CO-, -NR'CO-, -S-, -SO, -SO2-, -NR'-, -80 2 NR ⁇ NR'S0 2 -, or -NR'S0 2 NR'-;
  • R x is independently R', halo, N0 2 , CN, CF 3 , or OCF 3 ;
  • R 6 is hydrogen, CF 3 , -OR', -SR', or an optionally substituted C1-C8 aliphatic group
  • R 7 is hydrogen or a C1-C6 aliphatic group optionally substituted with -X-R ;
  • R' is independently selected from hydrogen or an optionally su stituted group selected from a Q.Cs aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- 12 membered saturated, partially unsaturated, or fully unsaturated
  • bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R * are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • Ar ! is not phenyl, 2- meihoxyphenyl, 4-meihoxyphenyl, 2-methyiphenyi, 2,6-dichlorophenyI, 2,4-dichiorophenyl, 2- bromophenyl, 4-bron ophenyl, 4-hydroxyphenyl, 2,4-dinitrophenyl, 3,5 ⁇ dicarboxyiic acid phenyl, 2,4-dimethy .phenyl, 2,6-dimethylphenyl, 2-ethylphenyi, 3-nitro-4-methyIphenyl, 3- carboxylic-acid phenyl, 2-fiuorophenyl, 3-fiuorophenyi, 3-trifluoromethyIphenyl, 3- ethoxyphenyi, 4-chlorophenyi, 3-methoxyphenyl, 4-dimethyl
  • Ar J is not 4-chiorophenyl, 4-bromophenyl, 4-nitrophenyl, 4- earboethoxyphenyl, 6-ethoxy-benzothiazol-2-yl, 6-carboethoxy-benzothiazol-2-yl, 6-halo- benzothiazo!-2-yl, 6-nitro-benzothiazol-2-yl, or 6-thiocyano-benzothiazoi-2-yl.
  • Ar* is not 4-substituted phenyl wherein said substituent is -S0 2 NHR xx , wherein R xx is 2-pyridinyl, 4-methyi-2-pyrimidinyl, 3,4-dimethyl-5-isoxazoiyi;
  • Ar* is not thiazol-2-yl, IH- l,2,4-triazoI-3-y!, or lH-l,3,4-triazol-2-yl;
  • Ar 5 is not 5-methyl-l ,2-oxazol-3-yl, thiazol-2-yi, 4-fluorophenyl, pyrimidin-2-yl, 1- methyl-l ,2-(lH)-pyrazol-5-yl, pyridine-2-yL phenyl, N-methyl-imidazol-2-yl, imidazoi-2-yl, 5- methyl-imidazol-2-yl, l,3-oxazol-2-yl, or l,3,5-(IH)-triazo!-2-yl:
  • Ar 1 is not pyrimidin-2-yl, 4,6-dimethyl-pyrimidin-2-yl, 4-methoxy-6-methyi- 1 ,3,5-triazin-2-yS; 5-bromo-pyridin-2-yi, pyridin-2-y], or 3,5-dichloro-pyridin-2-yl;
  • Ar 1 is not an optionally substituted ring selected from thiazol-2-yl, pyridyl, phenyl, thiadiazolyl, benzothiazol-2-yl, or indazolyl;
  • Ar 1 is not optionally substituted tetrazolyl
  • R 2 , R 4 , R 5 , R 6 , and R 7 each is hydrogen, and R 1 and R 3 both are
  • Ar 1 is not 4,5-dihydro-l, 3-thiazol-2-yi, thiazol-2-yi, or [3,5-bis(trifluororaethyi)-i/f-pyrazol- 1 -yljphenyl;
  • R 1 , R 4 , R 5 , R 6 , and R 7 each is hydrogen, and Ar 1 is thiazol-2-yl, then neither R 2 nor R J is isopropyl, chloro, or CF 3 ;
  • Ar 1 is 4-methoxy phenyl, 4-trifluororaethyIphenyl, 2-fluorophenyl, phenyl, or 3-chlorophenyl, then:
  • R ! , R 2 , R 4 , R 5 , R 6 , and R 7 each is hydrogen, then R" is not methoxy; or b) when R 1 , R 3 , R 4 , R 5 , R 6 , and R' each is hydrogen, then R' 1 is not chloro; or c) when R ! , R 2 , R 3 , R 5 , R 6 , and R' each is hydrogen, then R 4 is not methoxy; or d) when when R ! , R J , R 4 , R 6 , and R 7 each is hydrogen, and R 5 is ethyl, then R 2 is not chloro;
  • Arl is not a phenyl substituted with -0 € ⁇ 2 03 ⁇ 4 ⁇ 1 ⁇ , -OCH 2 CH 2 (2-trifluorometliyl-phenyI), - OCH 2 CH 2 -(6,7-dimethoxy-l,2,3,4-tetrahydroisoquinolin-2- l), or substituted l f-pyrazoi-3-yl; and
  • ABS-transporter as used herein means an ABC-transporter protein or a fragment thereof comprising at least one binding domain, wherein said protein or fragment, thereof is present in vivo or in vitro.
  • binding domain as used herein means a domain on the ABC-transporter that can bind to a modulator. See, e.g., Hwang, T. C. et l, L Gen. Physiol. (1998): 1 1 1(3), 477-90.
  • CFTR cystic fibrosis transmembrane conductance regulator or a mutation thereof capable of regulator activity, including, but not limited to, AF508 CFTR and G551D CFTR (see, e.g., http://www.genet.sickkids.on.ca/cftr/, for CFTR mutations).
  • modulating means increasing or decreasing by a measurable amount.
  • compounds of the invention may optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by
  • a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
  • aliphatic or "aliphatic group”, as used herein, means a straight- chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocyc!e” "cycloaiiphatic” or “cycloalkyl”), mat has a single point of attachment to the rest of the molecule.
  • aliphatic groups contain 1-20 aliphatic carbon atoms.
  • aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic caibon atoms, in still other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms, and in yet other embodiments aliphatic groups contain 1-4 aliphatic carbon atoms.
  • cycloaiiphatic refers to a monocyclic Cs-Cg hydrocarbon or bicyclic or tricyclic Cg-C ⁇ hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule wherein any individual ring in said bicyclic ring system has 3-7 members.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyi groups and hybrids thereof such as (cycloalkyl)alkyl,
  • Suitable cycloaiiphatic groups include cycloalkyl.
  • bicyclic cycloalkyl e.g., deealin
  • bridged bicycloaikyl such as norbomyl or [2.2.2]bicyek>- octyl
  • bridged tricyclic such as adamantyl
  • heteroaliphatic means aliphatic groups wherein one or two carbon atoms are independently replaced by one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon. Heteroaliphatic groups may be substituted or unsubstiiuied, branched or unbranched, cyclic or acyclic, and include “heterocycle”, “heierocyelyl”,
  • heterocycloaliphatic'' or “heterocyclic” groups.
  • heterocyclic as used herein means non-aromatic, monocyclic, bicyclic, or tricyclic ring systems in which one or more ring members is an independently selected heteroatom.
  • the "heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, or “heterocyclic” group has three to fourteen ring members in which one or more ring members is a heteroatom independently selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the system contains 3 to 7 ring members.
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized fomi of nitrogen, sulfur, phosphorus, or silicon; the quatemszed form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or N * (as in N- substituted pyrrolidinyl)).
  • alkoxy refers to an alkyi group, as previously defined, attached to the principal carbon chain through an oxygen (“alkoxy”) or sulfur (“thioaikyl”) atom.
  • haloaliphatic and haloalkoxy means aliphatic or alkoxy, as the case may be, substituted with one or more halo atoms.
  • halogen or “halo” means F, CI, Br, or L Examples of haloaliphatic incude -CHF 2 , -C3 ⁇ 4F, -CF 3 , -CF 2 -, or perhaloalkyl, such as, -CF 2 CF 3 .
  • aryl used alone or as pari of a larger moiety as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
  • aryl may be used interchangeably with the term “aryl ring”.
  • aryl also refers to heteroaryl ring systems as defined hereinbelow.
  • heteroaryl refers to monocyclic, bicyciic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains 3 to 7 ring members.
  • heteroaryl may be used interchangeably with the term “heteroaryl ring” or the term “heteroaromatic".
  • An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroaryiaikoxy and the like) group may contain one or more substituents.
  • Optional substituents on the aliphatic group of R° are selected from N3 ⁇ 4, (Ci_ 4 aliphatic) 2 , halo, C s , 4 aliphatic, OH, N0 2 , CN, C0 2 0(haloCi_4 aliphatic), or haloCi ⁇ aliphatic, wherein each of the foregoing Ct ⁇ aliphatic groups of R° is unsubstituted.
  • Optional substituents on the aliphatic group of R* are selected from T3 ⁇ 4, NH(Ci-4 aliphatic), aliphatic ) 2 , halo, Ct-4 aliphatic, OH, 0(C aliphatic), N0 2 , CN,
  • substituents on the aliphatic group or the phenyl ring of R + are selected from ⁇ 2 , NH(Cj-4 aliphatic), N(C[. 4 aiiphatic) 2 , halo, C M aliphatic, OH, 0(C t-4 aliphatic), N0 2 , CN, C0 2 H, C0 2 (C M aliphatic), 0(haSo C t .4 aliphatic), or haSo(Ci-4 aliphatic), wherein each of the foregoing €i. 4 aliphatic groups of R + is unsubstituted.
  • alkylidene chain refers to a straight or branched carbon chain mat may be fully saturated or have one or more units of unsaturation and has two points of attachment to the rest of the molecule.
  • spirocycloalkylidene refers to a carbocyclic l ing that may be fully saturated or have one or more units of unsaturation and has two points of attachment from the same ring carbon atom to the rest of the molecule,
  • two independent occurrences of R° are taken together together with the atom ⁇ s) to which each variable is bound to form a 3-8-membered cycloalkyl, heterocyclyl, aryl, or heteroary! ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Exemplar)-' rings that are formed when two independent occurrences of R° (or R ⁇ , or any other variable similarly defined herein) are taken together with the atom(s) to which each variable is bound include, but are not limited to the following: a) two independent occurrences of R° (or R + , or any other variable similarly defined herein) that are bound to the same atom and are taken together with that atom to form a ring, for example, N(R°) 2 , where both occurrences of R° are taken together with the nitrogen atom to form a piperidin-l-yl, piperazin- -yl, or morpholin-4-yl group; and b) two independent occurrences of R° (or R ⁇ , or any other variable similarly defined herein) that are bound to different atoms and are taken
  • a substituent bond in, e.g., a bicycHc ring system, as shown below, means that the substituent can be attached to any substitutahle ring atom on either ring of the bicyclic ring system:
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or tlie replacement of a carbon by a l 3 C- or , C-enriched carbon are within
  • Such compounds are useful, for example, as analytical tools or probes in biological assays.
  • Ar 5 is selected from:
  • a i and A 2 together, is an 8-14 aromatic, hicyclie or tricyclic aryl ring, wherein each ring contains 0-4 heteroaioms independently selected from nitrogen, oxygen, or sulfur.
  • At is an optionally substituted 6 mernbered aromatic ring having 0-4 heteroaioms, wherein said heteroatom is nitrogen.
  • a t is an optionally substituted phenyl.
  • is an optionally substituted pyridyl, pyrimidinyl, pyrazinyl or triazinyl.
  • As is an optionally substituted pyrazinyl or triazinyl.
  • a ⁇ is an optionally substituted pyridyl.
  • At is an optionally substituted 5-membered aromatic ring having 0-3 heteroaioms, wherein said heteroatom is niirogen, oxygen, or sulfur.
  • Aj is an optionally substituted 5-membered aromatic ring having 1-2 nitrogen atoms.
  • a ⁇ is an optionally substituted 5-membered aromatic ring oilier than thiazolyl.
  • a 2 is an optionally substituted 6 mernbered aromatic ring having 0-4 heteroaioms, wherein said heteroatom is niirogen.
  • a 2 is an optionally substituted phenyl.
  • a 2 is an optionally substituted pyridyl, pyrimidinyl, pyrazinyl, or triazinyl.
  • a 2 is an optionally substituted 5-membered aromatic ring having 0-3 heteroaioms, wherein said heieroaiom is nitrogen, oxygen, or sulfur. In some embodiments, A 2 is an optionally substituted 5-membered aromatic ring having 1-2 nitrogen atoms. In certain embodiments, A 2 is an optionally substituted pyrro!yl.
  • a 2 is an optionally substituted 5-7 mernbered saturated or unsatusaied heterocyclic ring having 1-3 heteroaioms independently selected from niirogen,
  • exemplary such rings include piperidyl, piperazyl, morphoiinyl, thiomorpholinyl, pyrrolidinyl, tetrahydrofuranyl, etc.
  • a 2 is an optionally substituted 5- 10 membered saturated or unsaturated carbocyclic ring, in one embodiment, A 2 is an optionally substituted 5-10 membered saturated carbocyclic ring.
  • Exemplary such rings include cyclohexyl, cyc!opentyl, etc.
  • ring A 2 is selected from:
  • W is a bond or is an optionally substituted
  • alkyliderse chain wherein one or two methylene units are optionally and independently replaced by O, NR', S, SO, S0 2 , or COO, CO, S0 2 NR', NR'S0 2 , C(0)NR ⁇ NR'C(O), OC(O), OC(0)NR ⁇ and R w is R' or halo.
  • each occurrence of WR W is independently -C1 -C3 a!kyl, C1 -C3 perhaloalkyl, -0(C1-C3alkyl), -CF 3 , -OCF3, - SCFj, -F, -CI, -Br, or -COOR', -COR' , -0(C3 ⁇ 4) 2 N(R')(R'), -0(CH 2 )N(R')(R'), - CON(R')(R'), -(C3 ⁇ 4) 2 QK ⁇ -(CH 2 )OR ⁇ optionally substituted monocyclic or bicyclic aromatic ring, optionally substituted arylsulfone, optionally substituted 5-membered heteroaryl ring, - N(R')iR'), -(CH ? .) 2 N ⁇ R')(R') 5 or -(CH 2 ) (R')(R 5 ).
  • m is 0. Or, m is 1, Or, m is 2. In some embodiments, m is 3. In yet other embodiments, m is 4.
  • R 5 is X-R x .
  • R 5 is hydrogen.
  • R 5 is an optionally substituted Cj-g aliphatic group.
  • R 5 is optionally substituted CM aliphatic.
  • R 5 is benzyl.
  • R 6 is hydrogen. Or, R 6 is an optionally substituted Cj.g aliphatic group. In some embodiments, R 6 is optionally substituted C aliphatic. In certain other embodiments, R 6 is -(O-CM aliphatic) or -(S-CM aliphatic). Preferably, R 6 is -OMe or - SMe. In certain other embodiments, 6 is CF 3 .
  • R 1 , R 2 , R 3 , and R 4 are
  • R 6 and R 7 are both simultaneously hydrogen.
  • R ⁇ R 2 , R 3 , R 4 , and R 5 are simultaneously hydrogen.
  • R l , R 2 , R ⁇ R 4 , R 5 and R 6 are simultaneously hydrogen,
  • R 2 is X-R x , wherein X is - S0 2 R'-, and R x is R': i.e., R 2 is -S0 2 N(R') 2 .
  • the two R' therein taken together form an optionally substituted 5-7 membered ring with 0-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur.
  • R 1 , R ⁇ R 4 , R 5 and R 6 are simultaneously hydrogen, and R 2 is S0 2 N(R 5 ) 2 .
  • X is a bond or is an optionally substituted Q
  • each occurrence of XR X is independently -C h lky!, -0(Cs- 3 alkyl), -CF 3 , -OCF 3 ⁇ 4 , -SCF 3 , -F, -CI, -Br, OH, -COOR ⁇ -COR', -0(CH 2 )2N(R , )(R'), -0(CH 2 )N(R , )(R') !
  • R 7 is hydrogen, in certain other embodiment, R 7 is €5.4 straight or branched aliphatic,
  • R w is selected from halo, cyano, CF 3 , CHF 2 , OCHF 2 , Me, Et, CH(Me) 2 , CHMeEt, n-propyl, t-butyl, OMe, QEt, OPh, O-fluorophenyl, O- difluorophenyl, O-methoxyphenyl, O-tolyl, O-benzyl, SMe, SCF 3 , SCHF 2( SEt, C3 ⁇ 4CN, NH 2 , NHMe, N(Me) 2 , NHEt, N(Ei) 2 , C(0)CH 3 , C(0)Ph, C(0)N3 ⁇ 4, SPh, S0 2 -(amino-pyridyl), SO2NH2, S0 2 Ph, SQ 2 NHPh, SC -N-morpholino, SCfe-N-pyrrolidyl, N-pyrrolyl
  • R' is hydrogen
  • R' is a C1-C8 aliphatic group, optionally substituted with up to 3 substituenis selected from halo, CN, CF3, CHF 2 , OCF3, or OCHF 2 , wherein up to two methylene units of said C1-C8 aliphatic is optionally replaced with -CO-, -CONH(C1 -C4 alky!)-, -CO2-, -OCO-, -N(C1-C4 alkyl)CO , -0-, -N(C1-C4 alkyl)CON(Cl-C4 alky])-, -OCON(Cl-C4 alkyl)-, -N(C1-C4 alkyl)CO-, -S-, -N(C1-C4 alky!)-, -S(3 ⁇ 4 (C1-C4 alkyl , N(C1-C4 alkyl)SO , or -N(C1
  • R' is a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from
  • R" is optionally substituted with up to 3 substituents selected from halo, CN, CF3, CHF 2 , OCF 3 , OCHF 2 , or C1-C6 alkyl, wherein up to two methylene units of said C1-C6 alkyl is optionally replaced with -CO-, -CONH(Cl-C4 alkyl)-, -CO 2 -, -OCO-, -N(Cl-C alkyI)CO , -0-, ⁇ N(C1-C4 aikyl)CON(Cl -C4 alky!)-, -OCON(Cl- C4 alkyl)-, -N(C1-C4 alkyl)CO-, -S-, -N(C1-C4 alkyl)-, -S0 2 N(C1 ⁇ C4 alkyl)-, N(C1-C4 alkyl)
  • R' is an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein R' is optionally substituted with up to 3 substituents selected from halo, CN, CF 3 , CHF 2 , OCF3, OCHF2, or C1-C6 alkyl, wherein up to two methylene units of said C1-C6 alkyi is optionally replaced with -CO-, -CONH(Cl-C4 alkyl)-, -CO2-, -OCO-, -N(C1-C4 alkyl)C0 2 -, -0-, -N(C1-C4 alkyl)CON(Cl-C4 alkyl)-, -OCGN ⁇ Cl ⁇ C4 alkyi)-, -N(C1-C4 alkyl)CO-, -S-, -N(C1 -C
  • two occurrences of R' are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein R' is optionally substituted with up to 3 substituents selected from halo, CN, CF 3 , CHF 2 , OCF 3 , OCHF 2 , or C1-C6 alkyl, wherein up to two methylene units of said C1-C6 alkyl is optionally replaced with -CO-, - CONH(Cl-C4 alkyi)-, -CO , -OCO-, -N(C1-C4 alkyl)C0 2 -, -0-, -N(C1-C4 alkyl)CON(Cl- C4 alkyl)-, -OCON(Cl-C4 alkyl)
  • the present invention provides compounds of formula IIA or formula IBB:
  • the present invention provides compounds of formula ⁇ , formula HIB, formula IIIC, formula HID, or formula HIE:
  • each of Xi, X 2 , X 3 , X4, and X5 is independently selected from CH or N; and Xe is O, S, or NR' .
  • compounds of formula IIIA, formula ⁇ , formula IIIC, formula MID, OF formula ⁇ have y occurrences of substituent X-R x , wherein y is 0-4. Or, y is 1. Or, y is 2.
  • [ ⁇ 89] is selected from halo, cyano, Q3 ⁇ 4, CHF 2 , OCHF 2 , Me, Et, CH(Me>2, CHMeEt, n-propyl, t-butyl, OMe, OEt, OPh, O-fluorophenyl, O- difluorophenyl.
  • X and R x taken together, is Me, Et, halo, CN, CF 3 , OH, OMe, QEt, S0 2 N(Me)(fluorophenyl), SO -(4-methyl ⁇ piperidin ⁇ l ⁇ yl, or 80 2 -N-pyrrolidinyi. f3 ⁇ 49I] According to another embodiment the present invention provides compounds of formula TV A,
  • compounds of formula IVA, formula IVB, and formula IVC have y occurrences of substituent X-R x , wherein y is 0-4, Or, y is 1. Or, y is 2.
  • the present invention provides compounds of formula IVA, formula IVB, and formula IVC, wherein X is a bond and R x is hydrogen.
  • the present invention provides compounds of formula formula IVB, and formula IVC, wherein ring A 2 is an optionally substituted, saturated, unsaturated, or aromatic seven membered ring with 0-3 heteroatoms selected from O, S, or N.
  • exemplary rings include azepanyl, 5,5-dimeihyl azepanyl, etc.
  • the present invention provides compounds of formula IVB and IVC, wherein ring A 2 is an optionally substituted, saturated, unsaturated, or aromatic six membered ring with 0-3 heteroatoms selected from O, S, or N.
  • exemplary rings include piperidinyl, 4,4-dimethylpiperidinyl, etc.
  • the present invention provides compounds of formula IVB and IVC, wherein ring A 2 is an optionally substituted, saturated, unsaturated, or aromatic five membered ring with 0-3 heteroatoms selected from O, S, or N.
  • the present invention provides compounds of formula IVB and IVC, wherein ring A 2 is an optionally substituted five membered ring with one nitrogen atom, e.g., pyrrolyl or pyrrolidinyL
  • each of WR* 2 and WR W4 is independently selected from hydrogen, CN, CF3, halo, C1-C6 straight or branched alkyl, 3-12 membered cycloaliphatic, phenyl, C5-C10 heteroaryi or C3-C7 heterocyclic, wherein said heteroaryl or heterocyclic has up to 3 heteroatoms selected from O, S, or N, wherein said WR* 2 and WR W4 is independently and
  • - 3 - 44833.1 optionally substituted with up to three substituents selected from -OR', -CF3, -OCF 3 , SR ⁇ S(0)R', SQ 2 R ⁇ -SCF 3 , halo, C , -COOR ⁇ -COR', -0(CH 2 ) 2 N(R')(R'), -0(CH 2 )N(R')(R'), - CON(R')(R'), ⁇ iCH 2 ) 2 OR', -(C3 ⁇ 4)GR ⁇ CH 2 CN, optionally substituted phenyl or phenoxy, - N(R')(R'), -NR'C(0)GR ⁇ -NR'C(0)R ⁇ -(C3 ⁇ 4) 2 N(R')(R 5 ), or -(CH 2 )N(R')(R'); and
  • WR WS is selected from hydrogen, -OH, NH 2> CN, CHF 2 , NHR', N(R') 2 , -NHC(0)R', -NHC(0)OR', NHSO 2 R', -OR ⁇ CH 2 OH, CH2N(R') 2 , C(0)OR ⁇ SG 2 NHR ⁇ SO ⁇ R'h, or CH 2 NHC(0)OR ⁇
  • WR W4 and WR WS taken togetlier form a 5-7 membered ring containing 0-3 three heteroatoms selected from N, O, or S, wherein said ring is optionally substituted with up to three WR W substituents.
  • compounds of formula VA-i have y occurrences of X-R x , wherein y is 0-4. in one embodiment, y is 0.
  • the present invention provides compounds of formula VA- 1, wherein X is a bond and R x is hydrogen.
  • the present invention provides compounds of formula VA- 1, wherein:
  • each of WR W2 and WR W4 is independently selected from hydrogen, CN, CF 3 , halo, C1-C6 straight or branched alky!, 3-12 membered cycioaliphatic, or phenyl, wherein said WR W2 and WR W is independently and optionally substituted with up to three substituents selected from -OR', -CF 3 , -OCF 3 , -SCF 3 , halo, -COOR ⁇ -COR', -0(CH 2 ) 2 N(R')(R'), - 0(C3 ⁇ 4)N(R')(R !
  • WR W5 is selected from hydrogen, -OH, NH 2 , CN, NHR', N(R') 2 , -NHC(0)R', - NHC(0)OR ⁇ NHSO 2 R', -OR', CH 2 OH, C(0)OR', SO 2 NHR', or C3 ⁇ 4 iC ⁇ 0)0-(R').
  • the present invention provides compounds of formula VAIL, wherein:
  • WR W2 is a pheny ring optionally substituted with up to three substituents selected from - OR', -CF 3 , -OCF3, SR ⁇ S(0)R ⁇ S0 2 R', -SCF 3 , halo, CN, -COOR', -COR', - 0(CH 2 ) 2 N(R')(R'), -0(C3 ⁇ 4)N(R')(R'), -CON(R')(R'), -(CH 2 ) 2 OR', -(CH 2 )OR', CH 2 CN, optionally substituted phenyl or phenoxy, -N(R')(R'), -NR'C(0)OR ⁇ -NR'C(0)R', - (CH 2 ) 2 N(R')(R'), or -(CH 2 )N(R')(R');
  • WR W4 is C1-C6 straight or branched alkyl
  • WR WS is OH.
  • each of WR W2 and WR W4 is independently selected from CF 3 or halo, in one embodiment, each of WR W2 and WE? 4 is independently selected from
  • each of of WR W2 and WR W is independently selected from optionally substituted n-propyl, isopropyi, n-b tyl, sec-butyf, t- butyl, l,l-dimethyl-2-hydroxyethyl, l,l-dimethyl ⁇ 2 ⁇
  • each of W W2 and WR W4 is independently selected from optionally substituted 3-12 menibered cycloaliphatic.
  • exemplary embodiments of such eycioaliphaiic include cyclopentyl, eyclohexyl, cycioheptyl, norbornyl, adamantyl,
  • WR W2 is hydrogen and WR W4 is C1-C6 straight or branched alkyl.
  • W W4 is selected from methyl, ethyl, propyl, n-butyi, sec-butyl, or i-butyL
  • WR W4 is hydrogen and W ft,; is C1-C6 straight or branched alkyl.
  • WR W2 is selected from methyl, ethyl, propyl, n-butyl, sec -butyl, t-butyl, or n-pentyl.
  • each of WR W2 and WR 3 ⁇ 44 is CI-C6 straight or branched alkyl.
  • each of WR wi and WR W4 is selected from methyl, ethyl, propyl, n-butyl, sec-butyl, t-butyl, or pentyl.
  • WR Wi is selected from hydrogen, CHF 2 , NH 2 , CN, NHR ⁇ N(R') 2 , C3 ⁇ 4N(R') 2 , -NHC(0)R', -NHC(0)OR ⁇ -OR', C(0)OR', or S0 2 NHR'.
  • WR WS is - OR', e.g., OH.
  • WR W5 is selected from hydrogen, NH 2 , CN, CHF 2 , NH ⁇ Ci-C6 alkyl), N(C1-C6 alkylfc, -NHC(0)(C I-C6 alkyl), -CH 2 NHC(0)0(C1 ⁇ C6 alkyl), - NHC(0)0(C1-C6 alkyl), -OH, -Q(Ci-C6 alkyl), C(0)0(C1 -C6 alkyl), CH 2 Q(C1-C6 alkyl), or S0 2 N3 ⁇ 4.
  • WR W5 is selected from -OH, OMe, NH 2 , -NHMe, -N(Me) 2 , -CH 2 NH 2 , CH 2 OH, NHC(0)OMe, NHC(0)OEt, CN, CHF 2 , -C3 ⁇ 4NHC(0)0(t-butyi), -O- (ethoxyethyl), -O-(hydroxyethyl), -C(0)OMe, or -SO ? N3 ⁇ 4.
  • compound of formula VA-1 has one, preferably more, or more preferably all, of the following features:
  • WR W2 is hydrogen
  • WR W4 is C1-C6 straight or branched alkyl or monocyclic or bicyclic aliphatic; and iii) WR W5 is selected from hydrogen, CN, CHF 2 , N3 ⁇ 4, NHCC1-C6 alkyl), N(C1-C6
  • compound of formula VA-1 has one, preferably more, or more preferably all, of the following features:
  • WR 2 is halo, C1-C6 alky!, CF , CN, or phenyl optionally substituted with up to 3 substituents selected from C1-C4 aikyl, -0(0-C4 alkyi), or halo;
  • WR W4 is CF 3 , halo, C1-C6 aikyl or C6-C10 cycloaliphatic;
  • WR W3 is OH, N3 ⁇ 4, H(C1-C6 aikyl), or N(C1-C6 alkyi).
  • X-R x is at the 6-posiiion of the quinolinyl ring, in certain embodiments, X-R x taken together is C1-C6 alkyi, -0-(O-C6 alkyi), or halo.
  • X-R x is at the 5-position of the quinolinyl ring, in certain embodiments, X-R x taken together is -OH.
  • the present invention provides compounds of formula VA-1, wherein WR W4 and W W5 taken together form a 5-7 membered ring containing 0-3 three heteroaioms selected from N, O, or S, wherein said ring is optionally substituted with up to three WR W substituents.
  • WR W4 and WR 5 taken together form an optionally substituted 5-7 membered saturated, unsatiiraied, or aromatic ring containing 0 heteroatoms.
  • WR W4 and WR 3 ⁇ 45 taken together form an optionally substituted 5-7 membered ring containing 1-3 heteroatoms selected from N, O, or S
  • WR W4 and WR W5 taken together form an optionally substituted saturated, unsaturated, or aromatic 5-7 membered ring containing 1 nitrogen heteroatom.
  • WR 4 and WR W5 taken together form an optionally substituted 5-7 membered ring containing 1 oxygen heteroatom.
  • the present invention provides compounds of formula
  • Y is CH 2 , C(0)0, C(O), or S(0) 2 ;
  • n 0-4;
  • X, R x , W, and R are as defined above.
  • compounds of formula VA-2 have y occurrences of X-R , wherein y is 0-4. In one embodiment, y is 0. Or, y is 1. Or, y is 2.
  • Y is C(O). in another embodiment, Y is C ⁇ 0)0. Or, Y is S(0) 2 , Or, Y s CH 2 .
  • n 1 or 2. Or, m is 1. Or, rn is 0.
  • W is a bond
  • R w is C1-C6 aliphatic, halo, CF 3 , or phenyl optionally substituted with C1-C6 alkyi, halo, cyano, or CF 3 , wherein up to two jneihylene units of said C1-C6 aliphatic or C1-C6 alkyl is optionally replaced with -CO-, -CONR'-, -C0 2 -, -OCO-, -NR'CGr, -0-, -NR'CONR'-, -OCO R'-, -NR'CO-, -S-, -NR'-, -SO2 '-, NR'SOr, or - NR'S ⁇ 3 ⁇ 4NR'-.
  • R" above is C1-C4 alkyl.
  • Exemplary embodiments of WR* include methyl, ethyl, propyl, tert-butyl, or 2-ethoxyphenyl.
  • R w in Y-R* is C1-C6 aliphatic optionally substituted with N(R") 2 , wherein R" is hydrogen, C1-C6 alkyl, or two R" taken together form a 5-7 membered heterocyclic ring with up to 2 additional heteroatoms selected from O, S, or NR'.
  • exemplary such heterocyclic rings include pyrro!idinyt, piperidyl, morpholinyl, or thiomorphoiinyl.
  • the present invention provides compounds of formula -A-3:
  • n 0-4;
  • n 0-4;
  • R x , W, and R w are as defined above.
  • compounds of formula VA-3 have y occurrences of X ⁇ R X , wherein y is 0-4. In one embodiment, y is 0. Or, y is 1. Or, y is 2,
  • n is 0-2.
  • m is 0-2. In one embodiment, m is 0. In one embodiment, m is 1. Or, m is 2.
  • QR Q taken together is halo, CF 3 , OCF 3 , CN, C1-C6 aliphatic, 0-C1-C6 aliphatic, O-phenyl, NH(C1-C6 aliphatic), or N(C1-C6 aliphatic) 2 , wherein said aliphatic and phenyl are optionally substituted with up to three substiiuents selected from C1 -C6 alky I, 0-C1-C6 alkyi, halo, cyano, OH, or CF 3 , wherein up to two methylene units of said C1-C6 aliphatic or C1-C6 alkyi is optionally replaced with -CO-, -CONR'-, -CO 2 -, -OCO-, -NR'COr, -0-, -NR'CONR'-, -OCONR'-, -NR'CO-, -8-, -NR
  • R' above is C1-C4 alkyi.
  • Exemplary QR Q include methyl, isopropyi, sec-buty!, hydroxymethyl, CF 3 , NMe 2 , CN, CH 2 CN, fluoro, chloro, OEt, OMe, SMe, OCF 3 , OPh, C(0)OMe, C(0)0-iPr, S(0)Me, NHC(0)Me, or S(0) 2 Me.
  • the present invention provides compounds of formula
  • compounds of formula VA-4 have y occurrences of X-R , wherein y is 0-4. In one embodiment, y is 0. Or, y is 1. Or, y is 2,
  • R w is C1-C12 aliphatic, C5-C10 cycloaliphatic, or C5-C7 heterocyclic ring, wherein said aliphatic, cycloaliphatic, or heterocyclic ring is optionally substituted with up to three substiiuents selected from C1-C6 alkyi, halo, cyano, oxo, OH, or CF 3 , wherein up to two methylene units of said C1-C6 aliphatic or C1-C6 alkyi is optionally- replaced with -CO-, -CONR'-, -CO2-, -OCO-, -NR'CC , -0-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR * -, -SO2NR'-, NR'SOr, or -NR'S0 2 NR'-.
  • R' above is
  • Exemplary R includes methyl, ethyl, n-propyl, isopropyi, n-butyl, sec-butyi, t- butyl, n-pentyl, vinyl, cyanomethyi, hydroxymethyl, hydroxyethyl, hydroxybutyl, cyclohexyl, adamantyl, or -C(CH 3 ) 2 -NHC(0)0-T, wherein T is C1-C4 alkyi, methoxyethyl, or tetrahydrofuranyl methyl.
  • the present invention provides compounds of foi
  • n 0-4;
  • compounds of formula VA-5 have y occurrences of X-R , wherein y is 0-4, In one embodiment, y is 0. Or, y is 1. Or, y is 2,
  • n is 0-2. Or, m is I, Or, m is 2,
  • both R' are hydrogen.
  • one R' is hydrogen and the other W is C1-C4 alkyl, e.g., methyl
  • both R' are C1-C4 aikyt e.g., methyl.
  • m is I or 2, and is halo, CF 3 , CN, C1-C6 aliphatic, 0-C1-C6 aliphatic, or phenyl, wherein said aliphatic and phenyl are optionally substituted with up to three substituents selected from C1-C6 alkyl, 0-CI-C6 alkyl, halo, cyano, OH, or CF 3 , wherein up to two methylene units of said CI -C6 aliphatic or C1-C6 alky!
  • R' above is C1-C4 alkyl
  • R w include chloro, CF 3 , OCF 3 , methyl, ethyl, n- propyl, isopropyl, n-butyl, t-butyl, methoxy, ethoxy, propyloxy, or 2-ethoxyphenyl.
  • 4 S33.1 ring B is a 5-7 membered monocyclic or bicyclic, heterocyclic or heteroaryl ring optionally substituted with up to n occurrences of ⁇ Q ⁇ R Q , wherein n is 0-4, and Q and R Q are as defined above;
  • compounds of formula VA-6 have y occurrences of X ⁇ R X , wherein y is 0-4. in one embodiment, y is 0, Or, y is 1. Or, y is 2,
  • n is 0-2. Or, m is 0. Or m is 1.
  • n is 0-2. Or, n is 0. Or, n is 1.
  • ring B is a 5-7 membered monocyclic, heterocyclic ring having up to 2 heteroaioms selected from O, S, or N, optionally substituted with up to n occurrences of -Q-R Q .
  • exemplary heterocyclic rings include N-morpholinyl, N-piperidinyS, 4- benzoyl-piperazin-l-y!, pyrrolidm-l-yl, or 4-methyl-piperidin ⁇ 1 -yl.
  • ring B is a 5-6 membered monocyclic, heteroaryl ring having up to 2 heteroaioms selected from O, S, or N, optionally substituted with up to n occurrences of ⁇ Q-R Q .
  • Exemplary such rings include benzimidazol-2-yl, 5-methyl-furan-2-yS, 2,5-dimcthyl-pyrroi-i-yI, pyridine-4-yl, indoi-5-yi, indol-2-yi, 2,4-dimethoxy-pyrimidin-5-yi, furan-2-yl, furan-3-yl, 2-acyl-thien-2-yl, benzothiophen-2-yl, 4-methyl-thien-2-yi, 5-cyano- thien-2-yl, 3-chloro-5-trifluoromethyl-pyridin-2-yl.
  • one of Qs and (3 ⁇ 4 is N(WR ) and the other of Q ⁇ and Q 3 is selected from O, S, or N(WR W );
  • Q 2 is C(0), C3 ⁇ 4-C(0), C(0)-CH 2 , CH 2 , CH 2 -C3 ⁇ 4, CF 2s or CF 2 -CF 2 ;
  • n 0-3;
  • X, W, R x , and R w are as defined above.
  • compounds of formula V-B-l have y occurrences of X- , wherein y is 0-4. in one embodiment, y is 0. Or, y is h Or, y is 2.
  • Q 3 is N(WR*); exemplary WR W include hydrogen, Cl-Ci aliphatic, C(0)C1-C6 aliphatic, or C(0)OC1-C6 aliphatic.
  • ⁇ 3 ⁇ 4 is N(WR W )
  • Q 2 is C(0), CH 2 , CH 2 -CH 2
  • Qi is
  • the present invention provides compounds of formula
  • R is hydrogen or C 1 -C6 aliphatic
  • each of R W3 is hydrogen or C1-C6 aliphatic;
  • n 0-4;
  • compounds of formula V-B-2 have y occurrences of X-R x » wherein y is 0-4. in one embodiment, y is 0. Or, y is 1. Or, y is 2.
  • WR Wi is hydrogen, C1-C6 aliphatic, C(0)C1-C6 aliphatic, or C(0)OCl-C6 aliphatic.
  • each R W3 is hydrogen, C1-C4 alkyl.
  • both R W3 taken togetlier form a C3-C6 cycloaliphatic ring or 5-7 rnembered heterocyclic ring having up to two heteroatoms selected from O, S, or N, wherein said cycloaliphatic or heterocyclic ring is optionally substituted with up to three substitutents selected from WR WI .
  • Exemplary such rings include cyciopropyi, cyclopentyl, optionally substituted piperidyl, etc.
  • the present invention provides compounds of formula
  • Q 4 is a bond, C(0), C(0)0, or S(G>>;
  • R Wi is hydrogen or C1-C6 aliphatic
  • n 0-4;
  • X, W, R w , and R x are as defined above.
  • compoimds of formula V-B-3 have y occurrences of X ⁇ R X , wherein y is 0-4. in one embodiment, y is G.
  • Q 4 is C(O). Or Q 4 is C(0)0, in another embodiment, R i is CI-C6 aikyl.
  • R W1 include methyl, ethyl, or t-butyl.
  • the present invention provides compounds of formula
  • n 0-4;
  • X, x , W, and R w are as defined above,
  • compounds of formula V-B-4 have y occurrences of X-R x , wherein y is 0-4. in one embodiment, y is 0, Or, y is 1. Or, y is 2.
  • n is 0-2. Or, m is 0. Or, m is 1.
  • said cycloaliphatic ring is a 5-menibered ring.
  • said ring is a six-membered ring.
  • the present invention provides compounds of formula
  • ring A 2 is a phenyl or a 5-6 membered heteroaryl ring, wherein ring A 2 and the phenyl ring fused thereto together have up 4 substituents independently selected from WR W ;
  • n 0-4;
  • X, W, R w and R x are as defined above.
  • compounds of formula V-B-5 have y occurrences of X-R x , wherein y is 0-4. In one embodiment, y is 0. Or, y is I . Or, y is 2.
  • ring A 2 is an optionally substituted 5-membered ring selected from pyrroiyi, furanyl, thienyi, pyrazolyl, iraidazoly!, thiazolyl, oxazoiyi, thiadiazolyl, oxadiazo!yl, or triazolyl.
  • ring A is an optionally substituted 5-membered ring selected from pyrroiyi, pyrazolyl, thiadiazolyl, imidazolyl, oxazoiyi, or triazolyl, Exemplary such rings include:
  • ring A 2 is an optionally substituted 6-membered ring.
  • exemplary such rings include pyridyl, pyrazinyl, or triazinyi.
  • said ring is an optionally pyridyl,
  • ring A 2 is phenyl
  • ring A 2 is pyrroiyi, pyrazolyl, pyridyl, or thiadiazolyl
  • Exemplary W in formula V-B-5 includes a bond, C(O), C(0)0 or C1-C6 alkylene.
  • R in formula V-B-5 include cyano, halo, C1-C6 aliphatic, C3-C6 cycloaliphatic, aryl, 5-7 membered heterocyclic ring having up to two heteroatoms selected from O, S, or N, wherein said aliphatic, phenyl, and heterocyclic are independently and optionally substituted with up to three substituents selected from C1-C6 alkyi, 0-C1-C6 alkyi, halo, cyano, OH, or CF 3 , wherein up to two methylene units of said C1-C6 aliphatic or C1-C6 alkyi is optionally replaced with -CO-, -CONR'-, -CO2-, -OCO-, -NR'C0 2 -, -0-, - NR'CONR'-, -OCONR'-, -NR'CO-, -S-, - R'-
  • the present invention provides compounds of formula V-B-
  • G 4 is hydrogen, halo, CN, CF 3 , CHF 2 , CH 2 F, optionally substituted CI -C6 aliphatic, aryl-Cl-C6 alkyi, or a phenyl, wherein G 4 is optionally substituted with up to 4 WR W substituents; wherein up to two methylene units of said CI -C6 aliphatic or C1-C6 alkyi is optionally replaced with -CO-, -CONR'-, -CO2-, -OCO-, -NR'C0 2 -, -0-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -S ⁇ 1 ⁇ 4NR ⁇ NR'SO s -, or -NR'S0 2 NR'-. ;
  • G 5 is hydrogen or an optionally substituted C1-C6 aliphatic
  • indole ring system is further optionally substituted with up to 3 substituents independently selected from WR W .
  • compounds of formula V-B-5-a have y occurrences of X ⁇ R x , wherein y is 0-4. In one embodiment, y is 0. Or, y is 1. Or, y is 2,
  • G 4 is hydrogen.
  • G 5 is hydrogen.
  • G 4 is hydrogen
  • G5 is C1-C6 aliphatic, wherein said aliphatic is optionally substituted with C1-C6 alkyi, halo, cyano, or CF 3 , and wherein up to two methylene units of said C1-C6 aliphatic or C1-C6 alkyi is optionally replaced with - CO-, -CONR'-, -CO 2 -, -OCO-, -NR'CQr, -0-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, - NR'-, -SO2NR'-, NR'SG , or -NR'SQsNR'-.
  • R' above is C1-C4 alkyi.
  • G 4 is hydrogen
  • G5 is cyano, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, cyanomethyl, methoxyethyl, CH 2 C(0)OMe, (CH ) 2 ⁇ NHC(0)0-iert-butyl, or cyclopeniy!.
  • G 5 is hydrogen
  • G4 is halo, C1-C6 aliphatic or phenyl, wherein said aliphatic or phenyl is optionally substituted wife C1-C6 alkyl, halo, cyano, or CF3, wherein up to two methylene units of said C1-C6 aliphatic or C1 -C6 alkyl is optionally replaced wife -CO-, -CONR'-, ⁇ CG 2 ⁇ , -OCO-, -NR'C0 2 -, -0-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -80 2 NR ⁇ NR'S0 2 ⁇ , or ⁇ NR'SQ 2 NR'-.
  • R' above is C 1-C4 alkyl.
  • G 5 is hydrogen
  • G 4 is halo, CFj, ethoxycarbonyl, t- butyl, 2-raethoxyphenyi, 2-ethoxyphenyl, (4 ⁇ C(0)NH(CH 2 ) 2 ⁇ NMe 2 )-phenyl, 2-mefeoxy ⁇ 4- chioro-phenyl, pyridine-3-yl, 4-isopropylphenyl, 2,6-dimethoxyphenyl, sec- butylaminocarbonyl, ethyl, t-butyl, or piperidin-l-ylcarbonyl.
  • G 4 and G5 are both hydrogen, and the nitrogen ring atom of said indole ring is substituted with C1-C6 aliphatic, C(0)(C1-C6 aliphatic), or benzyl, wherein said aliphatic or benzyl is optionally substituted with C1-C6 alkyl, halo, cyano, or CF 3 , wherein up to two methylene units of said C1-C6 aliphatic or CI -C6 alkyl is optionally replaced with -CO-, -CONR'-, -CO2-, -OCO-, -NR'COr, -0-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO 2 NR'-, NR'SOr, or -NR'S0 2 NR'-.
  • R' above is C1-C4 alkyl
  • G 4 and Gj are both hydrogen, and the nitrogen ring atom of said indole ring is substituted with acyl, benzyl, C(0)CH 2 N(Me)C(0)CH 2 NHMe, or ethoxycarbonyl.
  • each of R ⁇ R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and Ar ! in compounds of formula P is independently as defined above for any of the embodiments of compounds of formula I.
  • the present invention provides compounds useful as intermediates in the synthesis of compounds of formula I.
  • such compounds have formula A-I:

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Abstract

The present invention relates to 4 -oxo- lH-quinoline- 3 carboxamides as modulators of ATP -Binding Cassette ("ABC") transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator, compositions thereof, and methods therewith. The present Invention also relates to methods of treating ABC transporter mediated diseases using such modulators.

Description

-OXO- IH -QUINOLINE- 3 - CARBOXAMIDES AS MODULATORS OF ATP
-BINDING CASSETTE
TRANSPORTERS
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority to utility application U.S. Serial No. 12/635,927, filed on December I I, 2009. The contents of which is incorporated herein by reference in its entirety.
TECHNICAL FIELD OF THE INVENTION
[® l 1 The present invention relates to modulators of ATP-Bmding Cassette ("ABC") transporters or fragments thereof, including cystic fibrosis transmembrane conductance regulator ("CFTR"), compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators,
BACKGROUND OF THE INVENTION
[Θ02] ABC transporters are a family of membrane transporter proteins that regulate the transport of a wide variety of pharmacological agents, potentially toxic drugs, and xenobioiics, as well as anions, ABC transporters are homologous membrane proteins mat bind and use cellular adenosine triphosphate (ATI5) for their specific activities. Some of these transporters were discovered as multidrug resistance proteins (like the MDR1-P glycoprotein, or tire multidrug resistance protein, MRP! ), defending malignant cancer cells against chemotherapeutic agents. To date, 48 ABC Transporters have been identified and grouped into 7 families based on their sequence identity and function.
[003] ABC transporters regulate a variety of important physiological roles within the body and provide defense against harmful environmental compounds. Because of this, they represent important potential drug targets for the treatment of diseases associated with defects in the transporter, prevention of drug transport out of the target cell, and intervention in other diseases in which modulation of ABC transporter activity may be beneficial.
[004] One member of the ABC transporter family commonly associated with disease is the cAMP/ATP-mediated anion channel, CFTR. CFTR is expressed In a variety of cells types, including absorptive and secretory epithelia cells, where It regulates anion flux across the membrane, as well as the activity of other ion channels and proteins. In epithelia ceils, normal functioning of CFTR is critical for the maintenance of electrolyte transport throughout the body, including respiratory and digestive tissue. CFTR is composed of approximately 1480 amino acids that encode a protein made up of a tandem repeat of transmembrane domains, each containing six transmembrane helices and a nucleotide binding domain. Be two transmembrane domains are linked by a large, polar, regulatory (R)-domain with multiple phosphorylation sites that regulate channel activity and cellular trafficking.
[005] The gene encoding CFTR has been identified and sequenced (See Gregory, R. J. et al. (1990) Nature 347:382-386; Rich, D. P. et al. (1990) Nature 347:358-362), (Riordan, J. R. et al. (1989) Science 245: 1066-1073). A defect in this gene causes mutations in CFTR resulting in cystic fibrosis ("CF"), the most common fatal genetic diseas in humans. Cystic fibrosis affects approximately one in every 2,500 infants in the United States. Within the general United Stales population, up to 10 million people carry a single copy of the defective gene without apparent ill effects, in contrast, individuals with two copies of the CF associated gene suffer from the debilitating and fatal effects of CF, including chronic lung disease.
[006] in patients with cystic fibrosis, mutations in CFTR endogenously expressed in respiratory epiihelia leads to reduced apical anion secretion causing an imbalance in ion and fluid transport. The resulting decrease in anion transport contributes to enhanced mucus accumulation in the lung and the accompanying microbial infections that ultimately cause death in CF patients. In addition to respiratory disease, CF patients typically suffer from gastrointestinal problems and pancreatic insufficiency that, if left untreated, results in death. In addition, the majority of males with cystic fibrosis are infertile and fertility is decreased among females with cystic fibrosis. In contrast to the severe effects of two copies of the CF associated gene, individuals with a single copy of the CF associated gene exhibit increased resistance to cholera and to dehydration resulting from diarrhea - perhaps explaining the relatively high frequency of the CF gene within the population,
[CW7] Sequence analysis of the CFTR gene of CF chromosomes has revealed a variety of disease causing mutations (Cutting. G. R. et al. (1990) Nature 346:366-369; Dean, M, et al. (1990) Cell 61:863:870; and Kerem, B-S. et al. (1989) Science 245: 1073-1080;
Kerem, B-S et al. (1990) Proc. Natl, Acad. Sci. USA 87:8447-8451 ). To date, > 1000 disease causing mutations in the CF gene have been identified (http://www.genet.sickkids.on.ca cftr/). The most prevalent mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence, and is commonly referred to as AF508-CFTR. This mutation occurs in approximately 70% of the cases of cystic fibrosis and is associated with a severe disease .
[008] The deletion of residue 508 in AF508-CFTR prevents the nascent protein from folding correctly. This results in the inability of the mutant protein to exit the ER, and traffic to the plasma membrane. As a result, the number of channels present in the membrane is far less than observed in cells expressing wild-type CFTR. In addition to impaired trafficking, the mutation results in defective channel gating. Together, the reduced number of
- 2 -44833.1 channels in the membrane and the defective gating lead to reduced anion transport across epithelia leading to defective ion and fluid transport. (Quinton, P. M. (1 90), FASEB J. 4: 2709-2727). Studies have shown, however, that the reduced numbers of AFSOS-CFTR in the membrane are functional, albeit less than wild-type CFTR, (Dolmans et al. (1991), Nature Lend. 354: 526-528; Denning et al, supra; Pasyk and Foskett (1995), J. Cell. Biochem. 270: 12347-50). in addition to AF508-CFFR, Ri I7H-CFTR and G551D-CFTR other disease causing mutations in CFTR that result in defective trafficking, synthesis, and or channel gating could be up- or down-regulated to alter anion secretion and modify disease progression and/or severity.
[009] Although CFTR transports a variety of molecules in addition to anions, it is clear that this role (the transport of anions, chloride and bicarbonate) represents one element in an important mechanism of transporting ions and water across the epithelium. The other elements include the epithelia! Na÷ channel, ENaC, Na+/2C!YK+ co-transporter, a+-K+- ATPase pump and the basolaterai membrane K' channels, that are responsible for the uptake of chloride into the cell.
f ©3 These elements work together to achieve directional transport across the epithelium via their selective expression and localization within the cell. Chloride absorption takes place by the coordinated activity of ENaC and CFTR present on the apical membrane and the Na÷-K+- ATPase pump and CI- ion channels expressed on the basolaterai surface of the cell. Secondary active transport of chloride from the luminal side leads to the accumulation of intracellular chloride, which can then passively leave the cell via Ci" channels, resulting in a vectorial transport. Arrangement of Na72CF/K+ co-transporter, Na+-K~-ATPase pump and the basolaterai membrane + channels on the basolaterai surface and CFTR on fee luminal side coordinate the secretion of chloride via CFTR on the luminal side. Because water is probably never actively transported itself, its flow across epithelia depends on tiny transepithelial osmotic gradients generated by the bulk flow of sodium and chloride.
[§11] Defective bicarbonate transport due to mutations in CFTR is hypothesized to cause defects in certain secretory functions. See, e.g., "Cystic fibrosis: impaired bicarbonate secretion and mucoviscidosis," Paul M. Quinton, Lancet 2008; 372: 415-417.
[012] Mutations in CFTR that are associated with moderate CFTR dysfunction are also evident in patients with conditions that share certain disease manifestations with CF but do not meet the diagnostic criteria for CF. These include congenital bilateral absence of die vas deferens, idiopathic chronic pancreatitis, chronic bronchitis, and chronic rhinosinusitis. Other diseases in which mutant CFTR is believed to be a risk factor along with modifier genes
- 3 -44S33.1 or environmental factors include primary sclerosing cholangitis, allergic bronchopulmonary aspergillosis, and asthma,
[013] Cigarette smoke, hypoxia, and environmental factors that induce hypoxic signaling have also been demonstrated to impair CFT function and may contribute to certain forms of respiratory disease, such as chronic bronchitis. Diseases that ma be due to defective CFTR function but do not meet the diagnostic criteria for CF are characterized as CFTR- related diseases.
[014] in addition to cystic fibrosis, modulation of CFTR activity may be beneficial for other diseases not directly caused by mutations in CFTR, such as secretory diseases and other protein folding diseases mediated by CFTR. CFTR regulates chloride and bicarbonate flux across the epithe!ia of many cells to control fluid movement, protein solubilization, mucus viscosity, and enzyme activity. Defects in CFTR can cause blockage of the airway or ducts in many organs, including the liver and pancreas. Potentiators are compounds that enhance the gating activity of CFTR present in the cell membrane. Any disease which involves thickening of the mucus, impaired fluid regulation, impaired mucus clearance, or blocked ducts leading to inflammation and tissue destruction could be a candidate for potentiators,
[015] These include, but are not limited to, chronic obstructive pulmonary disease (COPD), asthma, smoke induced COPD, chronic bronchitis, rhinosinusitis, constipation, dry eye disease, and Sjogren's Syndrome, gastroesophageal reflux disease, gallstones, rectal prolapse, and inflammatory bowel disease. COPD is characterized by airflow limitation that is progressive and not fully reversible. The airflow limitation is due to mucus hypersecretion, emphysema, and bronchiolitis. Activators of mutant or wild-type CFTR offer a potential treatment of mucus hypersecretion and impaired mucociliary clearance that is common in COPD. Specifically, increasing anion secretion across CFTR may facilitate fluid transport into the airway surface liquid to hydrate the mucus and optimized periciliary fluid viscosity. This would lead to enhanced mucociliary clearance and a reduction in the symptoms associated with COPD. in addition, by preventing ongoing infection and inflammation due to improved airway clearance, CFTR modulators may prevent or slow the parenchimal destruction of the airway that characterizes emphysema and reduce or reverse the increase in mucus secreting cell number and size that underiyses mucus hypersecretion in airway diseases. Dry eye disease is characterized by a decrease in tear- aqueous production and abnormal tear film lipid, protein and mucin profiles. There are many causes of dry eye, some of which include age, Lasik eye surgery, arthritis, medications, chemical/iiiermal bums, allergies, and diseases, such as cystic fibrosis and Sjogrens's syndrome, increasing anion secretion via CFTR would enhance fluid transport from the corneal endothelial cells and secretory glands surrounding the eye to increase corneal hydration. This would help to alleviate the symptoms associated with dry eye disease. Sjogrens's syndrome is an autoimmune disease in which the immune system attacks moisture-producing glands throughout the body, including the eye, mouth, skin, respiratory tissue, liver, vagina, and gut. Symptoms, include, dry eye, mouth, and vagina, as well as lung disease. The disease is also associated with rheumatoid arthritis, systemic lupus, systemic sclerosis, and polymypositis/dermatomyositis. Defective protein trafficking is believed to cause the disease, for which treatment options are limited.
Modulators of CFTR activity may hydrate the various organs afflicted by the disease and may help to alleviate the associated symptoms. Individuals with cystic fibrosis have recurrent episodes of intestinal obstruction and higher incidences of rectal polapse, gallstones, gastroesophageal reflux disease, GI malignancies, and inflammatory bowel disease, indicating that CFTR function may play an important role in preventing such diseases.
[016] As discussed above, it is believed that the deletion of residue 508 in ΔΡ508- CFTR prevents the nascent protein from folding correctly, resulting in the inability of this mutant protein to exit the ER, and traffic to the plasma membrane. As a result, insufficient amounts of the mature protein are present at the plasma membrane and chloride transport within epithelial tissues is significantly reduced. In fact, this celluiar phenomenon of defective ER processing of CFTR by the ER machinery, has been shown to be the underlying basis not only for CF disease, but for a wide range of other isolated and inherited diseases. The two ways that the ER machinery can malfunction is either by loss of coupling to ER export of the proteins leading to degradation, or by the ER accumulation of these defective/misfolded proteins [Aridor M, et al., Nature Med., 5(7), pp 745- 751 (1999); Shastry, B.S., et l, Neurochem. International, 43, pp 1-7 (2003); Rutishauser, J., et a!., Swiss Med Wkly, 132, pp 211-222 (2002); Morello, JP et at, TIPS, 21, pp. 466- 469 (2000); Bross P., et a Human Mut., 14, pp. 186- 198 (1 99)]. The diseases associated with the first class of ER malfunction are cystic fibrosis (due to misfolded AF5Q8-CFTR as discussed above), hereditary emphysema (due to a 1 -antitrypsin; non Piz variants), hereditar hemochromatosis, coaguiation-fibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia. Type 1 chylor eronernia,
abetalipoproteineniia, lysosomal storage diseases, such as I-celi disease/pseudo-Hurler, Mucopolysaccharidoses (due to lysosomal processing enzymes), Sandhof/Tay-Sachs (due to β- hexosaminidase), Crigler-Najjar type II (due to UDP-glucuronyl-sialyc-transferase), polyendocrinopathy/hyperinsulemia, Diabetes mellitus (due to insulin receptor), Laron
- 5 -44833. i dwarfism (due to growth hormone receptor), my!eoperoxidase deficiency, primary
hypoparathyroidism (due to preproparathyroid hormone), melanoma (due to tyrosinase). The diseases associated with the latter class of ER malfunction are Glycanosis CDG type 1, hereditary emphysema (due to al- Antitrypsin (PiZ variant), congenital hyperthyroidism, osteogenesis imperfecta (due to Type I, Π, IV procollagen), hereditary hypofibrinogenemia (due to fibrinogen), ACT deficiency (due to al-antichymotrypsin), Diabetes insipidus (DI), neurophysea! DI (due to vasopvessin homione V2-receptor), neprogenic DI (due to aquaporin II), Charcot-Marie Tooth syndrome (due to peripheral myelin protein 22), Perlizaeus- Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease (due to βΑΡΡ and presenilins), Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, several poiyglutamine neurological disorders such as Huntington's, spinocerebullar ataxia type I, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary
Creutzfeldt- Jakob disease (due to prion protein processing defect), Fabry disease (due to lysosomal a~galactosidase A), Straussler-Scheinker syndrome (due to Prp processing defect), infertility pancreatitis, pancreatic insufficiency, osteoporosis, osteopenia, Gorham's
Syndrome, chloride charmelopathies, myotonia congenita (Thomson and Becker forms), Bartter' s syndrome type Hi, Dent's disease, hyperekplexia, epilepsy, hyperekplexia, lysosomal storage disease, Angelman syndrome. Primary Ciliary Dyskinesia (PCD), PCD with situs inversus (also known as Kartagener syndrome), PCD without situs inversus and ciliary aplasia, and liver disease.
[017] Other diseases implicated by a mutation in CFTR include male infertility caused by congenital bilateral absence of the vas deferens (CBAVD), mild pulmonary disease, idiopathic pancreatitis, and allergic bronchopulmonary aspergillosis (ABPA). See, "CFTR- opathies: disease phenotypes associated with cystic fibrosis transmembrane regulator gene mutations," Peader G. Noone and Michael R. Knowles, Respir. Res. 2001, 2: 328-332
(incorporated herein by reference).
[©18] In addition to up~regulation of CFTR activity, reducing anion secretion by CFTR modulators may be beneficial for the treatment of secretory diarrheas, in which epithelial water transport is dramatically increased as a result of secretagogue activated chloride transport. The mechanism involves elevation of cAMP and stimulation of CFTR.
[019] Although there are numerous causes of diarrhea, the major consequences of diarrheal diseases, resulting from excessive chloride transport are common to all, and include dehydration, acidosis, impaired growth and death. Acute and chronic diarrheas represent a
- 6 -44833.1 major medical problem in many areas of the world. Diarrhea is both a significant factor in malnutrition and the leading cause of death (5,000,000 deaths/year) in children less than five years old.
[020] Secretory diarrheas are also a dangerous condition in patients of acquired immunodeficiency syndrome (AIDS) and chronic inflammatory bowel disease (IBD), 16 million travelers to developing countries from industrialized nations every year develop diarrhea, with the severity and number of cases of diarrhea varying depending on the countiy and area of travel.
[021] Diarrhea in bam animals and pets such as cows, pigs and horses, sheep, goats, cats and dogs, also known as scours, is a major cause of death in these animals. Diarrhea can result from any major transition, such as weaning or physical movement, as well as in response to a variety of bacterial or viral infections and generally occurs within the first few hours of the animal's life.
[©22] The most common diarrheal causing bacteria is enterotoxogenic E.coli (ETEC) having the K99 pilus antigen. Common viral causes of diarrhea include rotavirus and coronavirus. Oilier infectious agents include Cryptosporidium, giardia lamblia, and salmonella, among others.
[023] Symptoms of rotavirai infection include excretion of watery feces, dehydration and weakness. Coronavirus causes a more severe illness in the newborn animals, and has a higher mortality rate than rotavirai infection. Often, however, a young animal may be infected with more than one virus or with a combination of viral and bacterial microorganisms at one time. This dramatically increases the severity of the disease.
[©24] Accordingly, there is a need for modulators of an ABC transporter activity, and compositions thereof, that can be used to modulate the activity of the ABC transporter in the cell membrane of a mammal.
[©25] There is a need for methods of treating ABC transporter mediated diseases using such modulators of ABC transporter activity.
[026] There is a need for methods of modulating an ABC transporter activity in an ex vivo cell membrane of a mammal.
[©27] There is a need for modulators of CFTR activity that can be used to modulate the activity of CFTR in the cell membrane of a mammal
[028] There is also a need for potent and selective CFTR potentiators of wild-type and mutant forms of human CFTR. These mutant CFTR forms include, but are not limited to, AF508del, G551D, Rl 17H, 2789+5G~>A. 44833.! [©29] There is a need for methods of treating CFTR-mediated diseases using such modulators of CFTR activity.
[039] There is a need for methods of modulating CFTR activity in an ex vivo cell membrane of a mammal.
SUMMARY OF THE INVENTION
[031] It has now been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, are useful as modulators of ABC transporter activity. These compounds have the general formula I:
Figure imgf000009_0001
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R3, R6, R', and Arl are described generally and in classes and subclasses below.
[032] These compounds and pharmaceutically acceptable compositions are useful for treating or lessening the severity of a variety of diseases, disorders, or conditions, including, but not limited to, cystic fibrosis, Hereditary emphysema, Hereditar hemochromatosis, Coagulation-Fibrinolysis deficiencies, such as Protein C deficiency, Type 1 hereditary angioedema. Lipid processing deficiencies, such as Familial hypercholesterolemia. Type 1 chylomicronemia, Abetalipoproteinemia, Lysosomal storage diseases, such as I-ceS1 disease Pseudo-Hurler, Mucopolysaccharidoses, Sandhof/Tay-Saehs, Crig!er-Najjar type Π, Poiyendocrinopathy/Hyperinsulemia, Diabetes mellitus, Laron dwarfism, Myleoperoxidase deficiency, Primary hypoparathyroidism, Melanoma, Glycanosis CDG type 1, Hereditary emphysema. Congenital hyperthyroidism, Osteogenesis imperfecta, Hereditary
hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), Neurophyseal DI, Neprogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as AlzheimeR's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders asuch as Huntington, Spinocerebuliar ataxia type I, Spinal and bulbar muscular atrophy, Dentatorubai pallidoluysian, and Myotonic dystrophy, as well as Spongiform
encephalopathies, such as Hereditary Creutzfe!dt- Jakob disease, Fabry disease, Straussler- Scheinker syndrome, COPD, dry-eye disease, and Sjogren's disease. DETAILED DESCRIPTION OF THE INVENTION
[033] L General Description of Compounds of the Invention:
[034] The present i vention relates to compounds of formula I useful as modulators of ABC transporter activity:
Figure imgf000010_0001
I
or a pharmaceutically acceptable salt thereof, wherein:
AT is a 5-6 membered aromatic monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is optionally fused to a 5-12 membered monocyclic or bicyclic, aromatic, partially unsaturated, or saturated ring, wherem each ring contains 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ar! has m substituents, each independently selected from -WRW;
W is a bond or is an optionally substituted Q-Cg alkylidene chain wherein up to two methylene units of W are optionally and independently replaced by -CO-, -CS-, -COCO-, - CONR'-, -CONR'NR'-, -CO2-, -OCO-, -NR'COr, -0-, -NR'CONR'-, -OCONR'-, -NR.' R.', - NR'NR'CO-, -NR'CO-, -S-, -SO, -SO?.-, -NR'-, -S02NR'-, NR'S02-, or -NR'802NR'~;
Rw is independently R', halo, N02, CN, CF3, or OCF3;
m is 0-5;
each of R!, R2, R3, R4, and R5 is indendently ~X-R ;
X is a bond or is an optionally substituted C Cg alkylidene chain wherein up to two methylene units of X are optionally and independently replaced by -CO-, -CS-, -COCO-, - CONR'-, -CONR'NR'-, -CO2-, -OCO-, -NR'COr, -0-, -NR'CONR'-, -OCONR'-, -NR'NR', - NR'NR'CO-, -NR'CO-, -S-, -SO, -SQr, -NR'-, -SO2NR'-, NR'SQr, or -NR'SCfeNR*-;
Rx is independently R', halo, N02, CN, CF3, or OCF3;
R6 is hydrogen, CF3, -OR', -SR', or an optionally substituted Ci-e aliphatic group;
R7 is hydrogen or a C;-6 aliphatic group optionally substituted with -X-R ;
R' is independently selected from hydrogen or an optionally substituted group selected from a Cj Cs aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or
_ 9 _
8544833.1 sulfur; or two occurrences of R' are taken together with the atoro(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heieroatoms independently selected from nitrogen, oxygen, or sulfur.
[935] in certain other embodiments, compounds of formula I are provided:
Figure imgf000011_0001
or a pharmaceutically acceptable salt thereof, wherein:
Ar{ is a 5-6 membered aromatic monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is optionally fused to a 5-12 membered monocyclic or bicyclic, aromatic, partially unsaturated, or saturated ring, wherein each ring contains 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ar1 has m substituents each independently selected from -WRW;
W is a bond or is an optionally substituted C1-C6 alkylidene chain wherein up to two methylene units of W are optionally and independently replaced by -CO-, -CS-, -COCO-, - CONR'-, -CONR'NR'-, -CO2-, -OCO-, -NR'CCfe-, -0-, -NR'CONR'-, -OCONR'-, -NR'NR', - NR'NR'CO-, -NR'CO-, -S-, -SO, -SO2-, -NR'-, -802NR'~, NR'S02-, -NR'SCfcNR'-;
Rw is independently R', halo, N02, CN, CF3, or OCF3;
m is 0-5;
each of R5, R2, R3, R4, and R5 is independently™X-RX;
X is a bond or is an optionally substituted C}-Cs alkylidene chain wherein up to two methylene units of X are optionally and independently replaced by -CO-, -CS-, -COCO-, - CONR'-, -CONR'NR'-, -CO2-, -OCO-, -NR'COr, -0-, -NR'CONR'-, -OCONR'-, -NR'NR', - NR'NR'CO-, -NR'CO-, -S-, -SO, -SO2-, -NR'-, -802NR\ NR'S02-, or -NR'S02NR'-;
Rxis independently R', halo, N02, CN, CF3, or OCF3;
R6 is hydrogen, CF3, -OR', -SR', or an optionally substituted C1-C8 aliphatic group;
R7 is hydrogen or a C1-C6 aliphatic group optionally substituted with -X-R ;
R' is independently selected from hydrogen or an optionally su stituted group selected from a Q.Cs aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8- 12 membered saturated, partially unsaturated, or fully unsaturated
- 10 -
8544833.1 bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R* are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
provided that:
i) when R1, R2, R3, R4, R'\ R6 and R7 are hydrogen, then Ar! is not phenyl, 2- meihoxyphenyl, 4-meihoxyphenyl, 2-methyiphenyi, 2,6-dichlorophenyI, 2,4-dichiorophenyl, 2- bromophenyl, 4-bron ophenyl, 4-hydroxyphenyl, 2,4-dinitrophenyl, 3,5~dicarboxyiic acid phenyl, 2,4-dimethy .phenyl, 2,6-dimethylphenyl, 2-ethylphenyi, 3-nitro-4-methyIphenyl, 3- carboxylic-acid phenyl, 2-fiuorophenyl, 3-fiuorophenyi, 3-trifluoromethyIphenyl, 3- ethoxyphenyi, 4-chlorophenyi, 3-methoxyphenyl, 4-dimethylaminophenyi, 3,4-dimethylphenyl, 2-ethylphenyl, or 4-ethoxycarbonyIphenyi;
ii) when R!, R2, R3, R5, R6 and R7 are hydrogen, and R4 is methoxy, then Ar! is not 2- fiuorophenyl or 3-fluorophenyi;
iii) when R1, R"5, R4, R5, R6 and R7 are hydrogen, Rz is 1 ,2,3,4-ietrahydroisoquinolin-l- yl-sulfonyl, then Ar' is not 3-trifluorornethylphenyl;
iv) when R1, R2, R3, R4, R5 and R7 are hydrogen, R6 is methyl, then Arl is not phenyl; v) when R!, R4, R5, R6 and R7 are hydrogen, R2 and R3, taken together, are
methylenedioxy, then ArJ is not 4-chiorophenyl, 4-bromophenyl, 4-nitrophenyl, 4- earboethoxyphenyl, 6-ethoxy-benzothiazol-2-yl, 6-carboethoxy-benzothiazol-2-yl, 6-halo- benzothiazo!-2-yl, 6-nitro-benzothiazol-2-yl, or 6-thiocyano-benzothiazoi-2-yl.
vi) when R!, R' , R5, R6 and R' are hydrogen, R2 and R3, taken together, are
methylenedioxy, then Ar* is not 4-substituted phenyl wherein said substituent is -S02NHRxx, wherein Rxx is 2-pyridinyl, 4-methyi-2-pyrimidinyl, 3,4-dimethyl-5-isoxazoiyi;
vii) when R!, R2, R3, R4, R5, R6, and R7 are hydrogen, then Ar* is not thiazol-2-yl, IH- l,2,4-triazoI-3-y!, or lH-l,3,4-triazol-2-yl;
viii) when R , R , R , R , R , and R are hydrogen, and R is CF3, OMe, chloro, SCF3, or OCF3, then Ar5 is not 5-methyl-l ,2-oxazol-3-yl, thiazol-2-yi, 4-fluorophenyl, pyrimidin-2-yl, 1- methyl-l ,2-(lH)-pyrazol-5-yl, pyridine-2-yL phenyl, N-methyl-imidazol-2-yl, imidazoi-2-yl, 5- methyl-imidazol-2-yl, l,3-oxazol-2-yl, or l,3,5-(IH)-triazo!-2-yl:
ix) when R\ R2, R3, R4, R5, R6, and R' each is hydrogen, then Ar1 is not pyrimidin-2-yl, 4,6-dimethyl-pyrimidin-2-yl, 4-methoxy-6-methyi- 1 ,3,5-triazin-2-yS; 5-bromo-pyridin-2-yi, pyridin-2-y], or 3,5-dichloro-pyridin-2-yl;
- l i -
8544833,1 x) when R!, R2, R3, R4, R5 and R7each is hydrogen, R6 is hydroxy, then Ar! is not 2,6- dichloro-4-ainiiiosulfonyl-phenyl:
xi) when R2 or R'¾ is an optionally substituted N-piperazyl, N-piperidyl, or N~ morphoiinyl, then Ar1 is not an optionally substituted ring selected from thiazol-2-yl, pyridyl, phenyl, thiadiazolyl, benzothiazol-2-yl, or indazolyl;
xii) when R2 is optionally substituted cyclohexylamino, then Ar3 is not optionally substituted phenyl, pyridyl, or thiadiazolyl;
xiii) Ar1 is not optionally substituted tetrazolyl;
xiv) when R2, R4, R5, R6, and R7 each is hydrogen, and R1 and R3 both are
simultaneously CF¾, chloro, methyl, or methoxy, then Ar1 is not 4,5-dihydro-l, 3-thiazol-2-yi, thiazol-2-yi, or [3,5-bis(trifluororaethyi)-i/f-pyrazol- 1 -yljphenyl;
xv) when R1, R4, R5, R6, and R7 each is hydrogen, and Ar1 is thiazol-2-yl, then neither R2 nor RJ is isopropyl, chloro, or CF3;
xvi) when Ar1 is 4-methoxy phenyl, 4-trifluororaethyIphenyl, 2-fluorophenyl, phenyl, or 3-chlorophenyl, then:
a) when R!, R2, R4, R5, R6, and R7 each is hydrogen, then R" is not methoxy; or b) when R1, R3, R4, R5, R6, and R' each is hydrogen, then R'1 is not chloro; or c) when R!, R2, R3, R5, R6, and R' each is hydrogen, then R4 is not methoxy; or d) when when R!, RJ, R4, R6, and R7 each is hydrogen, and R5 is ethyl, then R2 is not chloro;
e) when R!, R\ R4, R5, R6, and R7 each is hydrogen, then R3 is not chloro; xvi) when Rl, R3, R4, R\ R6, and R7 each is hydrogen, and R2 is CF3 or OCF3, then Ar1 is not E3,5-bis(trifluoromethyl)-iH-pyrazol-l-yl]phenyl;
xvii) when R\ R2, R4, R3, R6, and R7 each is hydrogen, and R3 is hydrogen or CF3, then Arl is not a phenyl substituted with -0€Η20¾Ρ1ι, -OCH2CH2(2-trifluorometliyl-phenyI), - OCH2CH2-(6,7-dimethoxy-l,2,3,4-tetrahydroisoquinolin-2- l), or substituted l f-pyrazoi-3-yl; and
xviii) the following two compounds are excluded:
- 12 -
S544833.1
Figure imgf000014_0001
[036] 2. Compounds and Definitions:
[037] Compounds of this invention include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated.
[038] The term "ABC-transporter" as used herein means an ABC-transporter protein or a fragment thereof comprising at least one binding domain, wherein said protein or fragment, thereof is present in vivo or in vitro. The tenn "binding domain" as used herein means a domain on the ABC-transporter that can bind to a modulator. See, e.g., Hwang, T. C. et l, L Gen. Physiol. (1998): 1 1 1(3), 477-90.
[Θ39] The tenn "CFTR" as used herein means cystic fibrosis transmembrane conductance regulator or a mutation thereof capable of regulator activity, including, but not limited to, AF508 CFTR and G551D CFTR (see, e.g., http://www.genet.sickkids.on.ca/cftr/, for CFTR mutations).
[§40] The term "modulating" as used herein means increasing or decreasing by a measurable amount.
[041] For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.
[042] As described herein, compounds of the invention may optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by
- 13 -44833.! particular classes, subclasses, and species of the invention, it will be appreciated mat the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted." in general, the term "substituted", whether preceded by the term "optionally" or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent, Unless otherwise indicated, an optionally substituted group may have a substituent at each substiiutabk position of the group, and when more than one position in any- given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable", as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein, in some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
[©43J The term "aliphatic" or "aliphatic group", as used herein, means a straight- chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocyc!e" "cycloaiiphatic" or "cycloalkyl"), mat has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic caibon atoms, in still other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms, and in yet other embodiments aliphatic groups contain 1-4 aliphatic carbon atoms. In some embodiments, "cycloaiiphatic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic Cs-Cg hydrocarbon or bicyclic or tricyclic Cg-C^ hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule wherein any individual ring in said bicyclic ring system has 3-7 members. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyi groups and hybrids thereof such as (cycloalkyl)alkyl,
(cycloalkenyl)alkyl or (cycloalkyl)alkenyl. Suitable cycloaiiphatic groups include cycloalkyl.
14 -44833. ! bicyclic cycloalkyl (e.g., deealin), bridged bicycloaikyl such as norbomyl or [2.2.2]bicyek>- octyl, or bridged tricyclic such as adamantyl.
[044] The term "heteroaliphatic", as used herein, means aliphatic groups wherein one or two carbon atoms are independently replaced by one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon. Heteroaliphatic groups may be substituted or unsubstiiuied, branched or unbranched, cyclic or acyclic, and include "heterocycle", "heierocyelyl",
"heterocycloaliphatic'', or "heterocyclic" groups.
[045] The term "heterocycle", "heterocyc!yl", "heterocycloaliphatic", or
"heterocyclic" as used herein means non-aromatic, monocyclic, bicyclic, or tricyclic ring systems in which one or more ring members is an independently selected heteroatom. In some embodiments, the "heterocycle", "heterocyclyl", "heterocycloaliphatic", or "heterocyclic" group has three to fourteen ring members in which one or more ring members is a heteroatom independently selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the system contains 3 to 7 ring members.
[©46] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized fomi of nitrogen, sulfur, phosphorus, or silicon; the quatemszed form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or N * (as in N- substituted pyrrolidinyl)).
[047] The term "unsaturated", as used herein, means that a moiety has one or more units of unsaturation.
[048] The term "alkoxy", or "thioaikyl", as used herein, refers to an alkyi group, as previously defined, attached to the principal carbon chain through an oxygen ("alkoxy") or sulfur ("thioaikyl") atom.
[©49] The terms "haloaliphatic" and "haloalkoxy" means aliphatic or alkoxy, as the case may be, substituted with one or more halo atoms. The term "halogen" or "halo" means F, CI, Br, or L Examples of haloaliphatic incude -CHF2, -C¾F, -CF3, -CF2-, or perhaloalkyl, such as, -CF2CF3.
[05Θ] The term "axyl" used alone or as pari of a larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring". The term "aryl" also refers to heteroaryl ring systems as defined hereinbelow.
- 15 -
8544S33.1 [051] The term "heteroaryl", used alone or as part of a larger moiety as in
"heteroaralkyl" or "heteroaryiaikoxy", refers to monocyclic, bicyciic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains 3 to 7 ring members. The term "heteroaryl" may be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic".
[Θ52] An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroaryiaikoxy and the like) group may contain one or more substituents. Suitable substituents on the unsaturated carbon atom of an aryl or heteroaryl group are selected from halo; -R°; -OR°; -SR°; 1,2-methylene-dioxy; 1,2-ethylenedioxy; phenyl (Ph) optionally substituted with R°; -O(Ph) optionally substituted with R°; -((¾)}- 2(Ph), optionally substituted with R°; -CH=CH(Ph), optionally substituted with R°; -N02; -CN; -N(R°)2; -NR°C(0)R°; -NR°C(0)N(R°)2; -NR°C02R°; -NRcNR°C(0)R°; - NR0NR0C(0)N(R°)2: - R°NR°CQ2R0; -C(0)C(0)R°; -C(0)CH2C(0)R°; -C02R°; ~C(0)R°; - C(0)N(R°)2; -OC(0)N(R°)2; -S(0)2R°; -S02N(R°)2; -S(0)R°; -NR0S02N(R°)2; -NR°S02R°; ~C(=S)N(R°)2; ~C(=NH)-N(R°)2; or ~<CH2)( 2NHC(0)R0 wherein each independent occurrence of R° is selected from hydrogen, optionally substituted C;_6 aliphatic, an tmsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl, -O(Ph), or -C¾(Ph), or, notwithstanding the definition above, two independent occurrences of R°, on the same substituent or different substituents, taken together with the atom(s) to which each R° group is bound, form a 3-8-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Optional substituents on the aliphatic group of R° are selected from N¾, (Ci_4aliphatic)2, halo, Cs, 4aliphatic, OH,
Figure imgf000017_0001
N02, CN, C02 0(haloCi_4 aliphatic), or haloCi ^aliphatic, wherein each of the foregoing Ct^aliphatic groups of R° is unsubstituted.
[Θ53] An aliphatic or heteroaliphatic group, or a non-aromatic heterocyclic ring may contain one or more substituents. Suitable substituents on the. saturated carbon of an aliphatic or heteroaliphatic group, or of a non-aromatic heterocyclic ring are selected from those listed above for the unsaturated carbon of an aryl or heteroaryl group and additionally include the following: =0, =S, =NNHR*, =N (R*)2, =NNHC(0)R*, =NNHC02(alkyl), =NNHS02(alkyl), or ~NR*, where each R* is independently selected from hydrogen or an optionally substituted Ci- aliphatic. Optional substituents on the aliphatic group of R* are selected from T¾, NH(Ci-4 aliphatic),
Figure imgf000017_0002
aliphatic )2, halo, Ct-4 aliphatic, OH, 0(C aliphatic), N02, CN,
■ 16 -44833.1 C02H, C02(Ct^ aliphatic), 0(haio€5.4 aliphatic), or haio(Ci-4 aliphatic), wherein each of the foregoing€1 ^aliphatic groups of R* is unsubstituted.
[Θ54] Optional substituents on the nitrogen of a non-aromatic heterocyclic ring are selected from -R+, -N(R+> , ~C(0)R+, -C02R÷, -C(0)C(0)R+, ~C(G)CH2C(G)R+, ~S02R+, -S02N(R*)2, -C(=S)N(R+)2, -C(=NH)-N(R+)2) or -NR+S02R+; wherein R+ is hydrogen, an optionally substituted Cj-e aliphatic, optionally substituted phenyl, optionally substituted -O(Ph), optionally substituted -CH2(Ph), optionally substituted -(CH )i-2(Ph); optionally substituted -CH=CH(Ph); or an unsubstituted 5-6 membered heteroaryl or heterocyclic ring having one to four heteroatoms independently selected from oxygen, nitrogen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R+, on the same substituent or different substituents, taken together with the atom(s) to which each R+ group is bound, form a 3-8-membered cycloalkyl, heterocyc!yl, aryl, or heteroary! ring having 0-3 heteroaioms independently selected from nitrogen, oxygen, or sulfur. Optionai substituents on the aliphatic group or the phenyl ring of R+ are selected from Ή2, NH(Cj-4 aliphatic), N(C[.4 aiiphatic)2, halo, CM aliphatic, OH, 0(Ct-4 aliphatic), N02, CN, C02H, C02(CM aliphatic), 0(haSo Ct.4 aliphatic), or haSo(Ci-4 aliphatic), wherein each of the foregoing€i.4aliphatic groups of R+ is unsubstituted.
[§55] The term "alkylidene chain" refers to a straight or branched carbon chain mat may be fully saturated or have one or more units of unsaturation and has two points of attachment to the rest of the molecule. The term "spirocycloalkylidene" refers to a carbocyclic l ing that may be fully saturated or have one or more units of unsaturation and has two points of attachment from the same ring carbon atom to the rest of the molecule,
[056] As detailed above, in some embodiments, two independent occurrences of R° (or R+, or any other variable similarly defined herei ), are taken together together with the atom{s) to which each variable is bound to form a 3-8-membered cycloalkyl, heterocyclyl, aryl, or heteroary! ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Exemplar)-' rings that are formed when two independent occurrences of R° (or R÷, or any other variable similarly defined herein) are taken together with the atom(s) to which each variable is bound include, but are not limited to the following: a) two independent occurrences of R° (or R+, or any other variable similarly defined herein) that are bound to the same atom and are taken together with that atom to form a ring, for example, N(R°)2, where both occurrences of R° are taken together with the nitrogen atom to form a piperidin-l-yl, piperazin- -yl, or morpholin-4-yl group; and b) two independent occurrences of R° (or R÷, or any other variable similarly defined herein) that are bound to different atoms and are taken
- 17 -44833.1 together with both of those atoms to form a ring, for example where a phenyl group is
substituted with two occurrences
Figure imgf000019_0001
these two occurrences of R° are taken together with the oxygen atoms to which they are bound to form a fused 6-niembered oxygen
Figure imgf000019_0002
¾ wjj| appreciated that a variety of other rings can be formed when two independent occurrences of R° (or R+, or any other variable similarly defined herein) are taken together with the atom(s) to which each variable is bound and that the examples detailed above are not intended to be limiting.
[057] A substituent bond in, e.g., a bicycHc ring system, as shown below, means that the substituent can be attached to any substitutahle ring atom on either ring of the bicyclic ring system:
Figure imgf000019_0003
[058] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single
stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. E.g., when R5 in compounds of formula ϊ is hydrogen, compounds of formula Ϊ may exist as tautomers:
Figure imgf000019_0004
ϊ Ϊ
Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or tlie replacement of a carbon by a l 3C- or , C-enriched carbon are within
8544833.1 the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biological assays.
[§59] 3. Description of Exemplary Compounds:
[©6§] to some embodiments of the present invention, Ar5 is selected from:
Figure imgf000020_0001
a-5
wherein ring At 5-6 mernbered aromatic monocyclic ring having 0-4 heteroaioms independently selected from nitrogen, oxygen, or sulfur; or
A i and A2, together, is an 8-14 aromatic, hicyclie or tricyclic aryl ring, wherein each ring contains 0-4 heteroaioms independently selected from nitrogen, oxygen, or sulfur.
[Θ61] In some embodiments, At is an optionally substituted 6 mernbered aromatic ring having 0-4 heteroaioms, wherein said heteroatom is nitrogen. In some embodimenLs, At is an optionally substituted phenyl. Or, A| is an optionally substituted pyridyl, pyrimidinyl, pyrazinyl or triazinyl. Or, As is an optionally substituted pyrazinyl or triazinyl. Or, A{ is an optionally substituted pyridyl.
[062] In some embodiments, At is an optionally substituted 5-membered aromatic ring having 0-3 heteroaioms, wherein said heteroatom is niirogen, oxygen, or sulfur. In some embodiments, Aj is an optionally substituted 5-membered aromatic ring having 1-2 nitrogen atoms. In one embodiment, A\ is an optionally substituted 5-membered aromatic ring oilier than thiazolyl.
[©63] In some embodiments, A2 is an optionally substituted 6 mernbered aromatic ring having 0-4 heteroaioms, wherein said heteroatom is niirogen. In some embodiments, A2 is an optionally substituted phenyl. Or, A2 is an optionally substituted pyridyl, pyrimidinyl, pyrazinyl, or triazinyl.
[064] In some embodiments, A2 is an optionally substituted 5-membered aromatic ring having 0-3 heteroaioms, wherein said heieroaiom is nitrogen, oxygen, or sulfur. In some embodiments, A2 is an optionally substituted 5-membered aromatic ring having 1-2 nitrogen atoms. In certain embodiments, A2 is an optionally substituted pyrro!yl.
[Θ65] in some embodiments, A2 is an optionally substituted 5-7 mernbered saturated or unsatusaied heterocyclic ring having 1-3 heteroaioms independently selected from niirogen,
- 19 -
8544833.1 sulfur, or oxygen. Exemplary such rings include piperidyl, piperazyl, morphoiinyl, thiomorpholinyl, pyrrolidinyl, tetrahydrofuranyl, etc.
[066] in some embodimenis, A2 is an optionally substituted 5- 10 membered saturated or unsaturated carbocyclic ring, in one embodiment, A2 is an optionally substituted 5-10 membered saturated carbocyclic ring. Exemplary such rings include cyclohexyl, cyc!opentyl, etc.
[067] in some embodiments, ring A2 is selected from:
Figure imgf000021_0001
Figure imgf000021_0002
Figure imgf000021_0003
Figure imgf000021_0004
Figure imgf000021_0005
4833.1
Figure imgf000022_0001
Figure imgf000022_0002
xxlx xxx xxxi sorii;
wherein ring A2 is fused to ring Aj through two adjacent ring atoms.
[668] In other embodiments, W is a bond or is an optionally substituted
alkyliderse chain wherein one or two methylene units are optionally and independently replaced by O, NR', S, SO, S02, or COO, CO, S02NR', NR'S02, C(0)NR\ NR'C(O), OC(O), OC(0)NR\ and Rw is R' or halo. In still other embodiments, each occurrence of WRW is independently -C1 -C3 a!kyl, C1 -C3 perhaloalkyl, -0(C1-C3alkyl), -CF3, -OCF3, - SCFj, -F, -CI, -Br, or -COOR', -COR' , -0(C¾)2N(R')(R'), -0(CH2)N(R')(R'), - CON(R')(R'), -(C¾)2QK\ -(CH2)OR\ optionally substituted monocyclic or bicyclic aromatic ring, optionally substituted arylsulfone, optionally substituted 5-membered heteroaryl ring, - N(R')iR'), -(CH?.)2N{R')(R')5 or -(CH2) (R')(R5).
[069] In some embodiments, m is 0. Or, m is 1, Or, m is 2. In some embodiments, m is 3. In yet other embodiments, m is 4.
[070] In one embodiment, R5 is X-Rx. In some embodiments R5 is hydrogen. Or, R5 is an optionally substituted Cj-g aliphatic group. In some embodiments, R5 is optionally substituted CM aliphatic. Or, R5 is benzyl.
[071] In some embodiments R6 is hydrogen. Or, R6 is an optionally substituted Cj.g aliphatic group. In some embodiments, R6 is optionally substituted C aliphatic. In certain other embodiments, R6 is -(O-CM aliphatic) or -(S-CM aliphatic). Preferably, R6 is -OMe or - SMe. In certain other embodiments, 6 is CF3.
[072] In one embodiment of the present invention, R1, R2, R3, and R4 are
simultaneously hydrogen. In another embodiment, R6 and R7 are both simultaneously hydrogen. [©73] In another embodiment of the present invention, R\ R2, R3, R4, and R5 are simultaneously hydrogen. In another embodiment of the present invention, Rl, R2, R~\ R4, R5 and R6 are simultaneously hydrogen,
[074] in another embodiment of the present invention, R2 is X-Rx, wherein X is - S02 R'-, and Rx is R': i.e., R2 is -S02N(R')2. in one embodiment, the two R' therein taken together form an optionally substituted 5-7 membered ring with 0-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur. Or, R1, R\ R4, R5 and R6 are simultaneously hydrogen, and R2 is S02N(R5)2.
[075] In some embodiments, X is a bond or is an optionally substituted Q
alkylidene chain wherein one or two non-adjacent methylene units are optionally and independently replaced by O, NR', S, S02, or COO, CO, and Rx is R' or halo. In still other embodiments, each occurrence of XRX is independently -Ch lky!, -0(Cs-3alkyl), -CF3, -OCF¾, -SCF3, -F, -CI, -Br, OH, -COOR\ -COR', -0(CH2)2N(R,)(R'), -0(CH2)N(R,)(R')! - CON(R'XR'), ~(CH2)2OR\ ~(CH2)OR\ optionally substituted phenyl, -N(R')(R'), - (CH2)2N(R')(R'), or -(CH2)N(R')(R').
[076] in some embodiments, R7 is hydrogen, in certain other embodiment, R7 is€5.4 straight or branched aliphatic,
[©77] in some embodiments, Rw is selected from halo, cyano, CF3, CHF2, OCHF2, Me, Et, CH(Me)2, CHMeEt, n-propyl, t-butyl, OMe, QEt, OPh, O-fluorophenyl, O- difluorophenyl, O-methoxyphenyl, O-tolyl, O-benzyl, SMe, SCF3, SCHF2( SEt, C¾CN, NH2, NHMe, N(Me)2, NHEt, N(Ei)2, C(0)CH3, C(0)Ph, C(0)N¾, SPh, S02-(amino-pyridyl), SO2NH2, S02Ph, SQ2NHPh, SC -N-morpholino, SCfe-N-pyrrolidyl, N-pyrrolyl, N- morpholino, 1-piperidyl, phenyl, benzyl, (cyclohexyl-methylamino)methyl, 4-Methyl-2,4- dihydro-pyrazol-3-one-2-yl, benzimidazol-2yI, furan-2-yl, 4-methyl~4H-[l,2,4jtriazol-3-yl, 3- (4'-cMorophenyl)-[ l,2,4]oxadiazol-5-yl, NHC(0)Me, NHC(0)Et, NHC(0)Ph, NHS02Me, 2- indolyl, 5-indolyl, -CH2CH2OH, -OCF3, 0-(2,3-dimethylphenyl), 5 -methyl fury! , -SO2-N- piperidyl, 2-toiyl, 3-tolyl, 4-tolyl, O-butyl, NHC02C(Me)3, C02C(Me)3, isopropenyl, n-butyl, 0-(2,4-dichiorophenyl), NHS02PhMe, 0-(3-cWoro-5-trifiuoromethyi-2-pyridyl),
phenylhydroxymethyi, 2,5-dimethylpyrrolyl, NHCOCH?C(Me)3, 0-(2-½rf-butyl)phenyl, 2,3- dimethylphenyl, 3,4-dimetiiylphenyl, 4-hydroxymethyl phenyl, 4-dimethylaminophenyl, 2- trifluoromethylphenyl, 3- trifluoromemylphenyl 4- trif!uoromethy!phenyi, 4- cyanomethylphenyl, 4-isobutylphenyi, 3-pyridyl, 4-pyridyl, 4-isopropylphenyl, 3- isopropylphenyl, 2-methoxyphenyS, 3-methoxyphenyl, 4-methoxyphenyI, 3,4- methylenedioxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4~ethoxyphenyl, 2-
- 22 -44833.1 meihyithiophenyl, 4-methyithiophenyI, 2,4-dimeihoxyphenyi, 2,5-dinieihoxyphenyl, 2,6- dimethoxypheny!, 3, 4-dimethox phenyl, 5-chloro-2-methoxyphenyl, 2-OCF3-phenyl, 3- irifluoromeihoxy-phenyl, 4-rrifluoromethoxyphenyl, 2-phen.oxyphenyl, 4-phenoxyp enyl, 2- fluoro-3-methoxy-phenyl, 2,4-dimeAoxy-5-pyrirfiidyI, 5-isopropyl-2-methoxyphenyI, 2- fluorophenyl, 3 -fluorophenyl, 4-fluorophenyI, 3-cyanophenyl, 3-chlorophenyI, 4- chlorophenyl, 2,3-difluorophenyl, 2,4-difiuorophenyi, 2,5-difiuorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3~ch!oro-4-fiuoro-phenyl, 3,5-dichlorophenyl, 2,5-dichlorophenyl, 2,3- dichlorophenyl, 3,4-dic orophenyl, 2,4-dichlorophenyl, 3-met oxycarbonylphenyl, 4- methoxycarbonyi phenyl, 3-isopropyloxycarbonylphenyl, 3-aceianiidophenyl, 4-fiuoro~3- methylphenyl, 4-methanesulfinyl-phenyS, 4-meihanesulfonyl-phenyl, 4-N-(2-N,N- dimethylaminoeihyl)carbamoyiphenyl, 5-acetyl-2-thienyl, 2-benzoihienyl, 3-benzothienyl, furan-3-yl, 4-methyl-2-thienyl, 5-cyano-2-thienyl, N'-phenylcarbonyl-N-piperazinyl, - NHC02Ei, -NHC02Me, N-pyrrolidinyl, -NHS02(CH2)2 N-piperidine, -NHS02(CH2)2 N- morpholine, -NHS02(C¾)2N(Me)2! CQCH2N(Me)COCH2M3Me, -C02Ei, O-propyl, - CH2CH2NHC02C(Me).3, hydroxy, aminomethyl, pentyl, adamantyl, cyc openiyl, ethoxyeihyl, C(Me)2CH2OH, C(Me}2C02Et, -CHOHMe, CH2C02Et, -C(Me)2CH2NHCG2C(Me)3, 0(CH2)2OEt, 0(CH2)2OH, C02Me, hydroxyroethyS, , 1 -methyl- 1-cyclohexyl, 1 -methyl- 1- cyclooctyl, 1 -methyl- 1-cycloheptyl, C(Et)2C(Me)3, C(Et)3f CONHCH2CH(Me)2, 2- aminomethyl-phenyl, ethenyl, 1-piperidinylcarbonyl, ethynyi, cyclohexyl, 4- methylpiperidinyl, -OC<¾Me, -C(Me)2CH2MiC02CH2CH(Me)2, - C(M )2CH2NHC02CH2CH2CH3, -C(Me)2CH2NHC02Et, -C(Me)2CH2NHC02Me, - C(Me)2CH2NHC02CH2C(Me)3, -CH2 HCOCF3, -CH2NHCG2C(Me)3, - C(Me)2CH2 HC02(CH2)3CH35 C(Me)2CH2NHC02(CH2)2OMe, C(OH) (CF3)2, - C(Me)2CH2NHC02CH2-tetrahydrofurane-3-yl, C(Me)2CH20{CH2)2OMe, or 3-ethyl-2,6- dioxopiperidin-3-yl.
[078] In one embodiment, R' is hydrogen.
[079] In one embodiment, R' is a C1-C8 aliphatic group, optionally substituted with up to 3 substituenis selected from halo, CN, CF3, CHF2, OCF3, or OCHF2, wherein up to two methylene units of said C1-C8 aliphatic is optionally replaced with -CO-, -CONH(C1 -C4 alky!)-, -CO2-, -OCO-, -N(C1-C4 alkyl)CO , -0-, -N(C1-C4 alkyl)CON(Cl-C4 alky])-, -OCON(Cl-C4 alkyl)-, -N(C1-C4 alkyl)CO-, -S-, -N(C1-C4 alky!)-, -S(¾ (C1-C4 alkyl , N(C1-C4 alkyl)SO , or -N(C1-C4 alkyl)S02N(CI-C4 alkyl)-.
[080] In one embodiment, R' is a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from
- 23 -44833.1 nitrogen, oxygen, or sulfur, wherein R" is optionally substituted with up to 3 substituents selected from halo, CN, CF3, CHF2, OCF3, OCHF2, or C1-C6 alkyl, wherein up to two methylene units of said C1-C6 alkyl is optionally replaced with -CO-, -CONH(Cl-C4 alkyl)-, -CO2-, -OCO-, -N(Cl-C alkyI)CO , -0-, ~N(C1-C4 aikyl)CON(Cl -C4 alky!)-, -OCON(Cl- C4 alkyl)-, -N(C1-C4 alkyl)CO-, -S-, -N(C1-C4 alkyl)-, -S02N(C1~C4 alkyl)-, N(C1-C4 alkyl)S02-, or -N(C1-C4 alkyl)SQ2N(Cl-C4 alkyl)-.
[081] in one embodiment, R' is an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein R' is optionally substituted with up to 3 substituents selected from halo, CN, CF3, CHF2, OCF3, OCHF2, or C1-C6 alkyl, wherein up to two methylene units of said C1-C6 alkyi is optionally replaced with -CO-, -CONH(Cl-C4 alkyl)-, -CO2-, -OCO-, -N(C1-C4 alkyl)C02-, -0-, -N(C1-C4 alkyl)CON(Cl-C4 alkyl)-, -OCGN{Cl~ C4 alkyi)-, -N(C1-C4 alkyl)CO-, -S-, -N(C1 -C4 alkyl)-, -S02N(C1-C4 alkyl)-, N(C1-C4 a!kyl)SG2-, or -N(C1-C4 alkyl)S02N(Ci-C4 alkyl)-.
[082] In one embodiment, two occurrences of R' are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein R' is optionally substituted with up to 3 substituents selected from halo, CN, CF3, CHF2, OCF3, OCHF2, or C1-C6 alkyl, wherein up to two methylene units of said C1-C6 alkyl is optionally replaced with -CO-, - CONH(Cl-C4 alkyi)-, -CO , -OCO-, -N(C1-C4 alkyl)C02-, -0-, -N(C1-C4 alkyl)CON(Cl- C4 alkyl)-, -OCON(Cl-C4 alkyl)-, -N(C1-C4 alkyl)CO-, -S-, ~N(C1-C4 alkyl)-, -S02N(C1- C4 alkyl)-, N(C1 -C4 alkyl)S02-, or -N(C1-C4 alkyl)S02N(Cl-C4 alkyl)-.
[§83] According to one embodiment, the present invention provides compounds of formula IIA or formula IBB:
Figure imgf000025_0001
[084] According to another embodiment, the present invention provides compounds of formula ΙΠΑ, formula HIB, formula IIIC, formula HID, or formula HIE:
- 24 - 44833.1
Figure imgf000026_0001
Figure imgf000026_0002
wherein each of Xi, X2, X3, X4, and X5 is independently selected from CH or N; and Xe is O, S, or NR' .
[Θ85] In one embodiment, compounds of formula IIIA, formula ΪΙΙ , formula IIIC, formula MID, OF formula ΙΪΙΕ have y occurrences of substituent X-Rx, wherein y is 0-4. Or, y is 1. Or, y is 2.
[086] In some embodiments of formula IIIA, Xj, X2, X3, X4, and X5 taken together with WRW and m is optionally substituted phenyl
[Θ87] In some embodiments of formula IIIA, Xi, X2, X3, X4, and X5 taken together is an optionally substituted ring selected from:
Figure imgf000026_0003
- 25 - 4 S33.1
Figure imgf000027_0001
~xvii a-xviil a-xix a-xx
Figure imgf000027_0002
[088] In some embodiments of formula ΠΪΒ, formula HlC, formula HH>, or formula I!IE, X], X , X3, X4, X5, or Xs, taken together with ring A2 is an optionally substituted ring selected from:
Figure imgf000027_0003
b-iv b-v
Figure imgf000027_0004
- 26 ·■
44833,!
Figure imgf000028_0001
8544833. J
Figure imgf000029_0001
Figure imgf000029_0002
Figure imgf000029_0003
Figure imgf000029_0004
8544833,1
Figure imgf000030_0001
Figure imgf000030_0002
Ħ144S33.1
Figure imgf000031_0001
Figure imgf000031_0002
[§89] In some embodiments, is selected from halo, cyano, Q¾, CHF2, OCHF2, Me, Et, CH(Me>2, CHMeEt, n-propyl, t-butyl, OMe, OEt, OPh, O-fluorophenyl, O- difluorophenyl. O-methoxyphenyl, O-tolyl, O-benzyl, SMe, SCF3, SCHF2f SE CH2CN, NH2, NHMe, N(Me)2, NHEt, (Et)2, C(0)CH3, C(0)Ph, C(0) H2, SPh, SOr(amino~pyridyl), SO2NH2, SO2PI1, S02 HPh, S02-N-morpholmo, S02-N-pyrrolidyl, N-pyrrolyl, N- morpholino, 1-piperidyS, phenyl, benzyl, (cyclohexyl-methylamino)methyl, 4-Methyl-2,4- dihydro-pyrazol-3-one-2-yl, benzimidazol-2yi, furan-2-yL, 4-methyl-4H~[L2,4]triaxol-3-yl, 3~ (4'-chlorophenyl)^[l,2,4]oxadiazol»5-yl, NHC(0)Me, NHC(0)Ei, NHC{0)Ph, or NHS02Me
[§90] In some embodiments, X and Rx, taken together, is Me, Et, halo, CN, CF3, OH, OMe, QEt, S02N(Me)(fluorophenyl), SO -(4-methyl~piperidin~l~yl, or 802-N-pyrrolidinyi. f¾9I] According to another embodiment the present invention provides compounds of formula TV A,
Figure imgf000031_0003
- 30 - 44833.1
Figure imgf000032_0001
[092] In one embodiment compounds of formula IVA, formula IVB, and formula IVC have y occurrences of substituent X-Rx, wherein y is 0-4, Or, y is 1. Or, y is 2.
[093] in one embodiment, the present invention provides compounds of formula IVA, formula IVB, and formula IVC, wherein X is a bond and Rx is hydrogen.
[§94] In one embodiment, the present invention provides compounds of formula formula IVB, and formula IVC, wherein ring A2 is an optionally substituted, saturated, unsaturated, or aromatic seven membered ring with 0-3 heteroatoms selected from O, S, or N. Exemplary rings include azepanyl, 5,5-dimeihyl azepanyl, etc.
[095] In one embodiment, the present invention provides compounds of formula IVB and IVC, wherein ring A2 is an optionally substituted, saturated, unsaturated, or aromatic six membered ring with 0-3 heteroatoms selected from O, S, or N. Exemplary rings include piperidinyl, 4,4-dimethylpiperidinyl, etc.
[©96] In one embodiment, the present invention provides compounds of formula IVB and IVC, wherein ring A2 is an optionally substituted, saturated, unsaturated, or aromatic five membered ring with 0-3 heteroatoms selected from O, S, or N.
[097] in one embodiment, the present invention provides compounds of formula IVB and IVC, wherein ring A2 is an optionally substituted five membered ring with one nitrogen atom, e.g., pyrrolyl or pyrrolidinyL
[§98] According to one embodiment of formula IVA, the following compound of formula VA-1 is provided:
Figure imgf000032_0002
wherein each of WR*2 and WRW4 is independently selected from hydrogen, CN, CF3, halo, C1-C6 straight or branched alkyl, 3-12 membered cycloaliphatic, phenyl, C5-C10 heteroaryi or C3-C7 heterocyclic, wherein said heteroaryl or heterocyclic has up to 3 heteroatoms selected from O, S, or N, wherein said WR*2 and WRW4 is independently and
- 3 - 44833.1 optionally substituted with up to three substituents selected from -OR', -CF3, -OCF3, SR\ S(0)R', SQ2R\ -SCF3, halo, C , -COOR\ -COR', -0(CH2)2N(R')(R'), -0(CH2)N(R')(R'), - CON(R')(R'), ~iCH2)2OR', -(C¾)GR\ CH2CN, optionally substituted phenyl or phenoxy, - N(R')(R'), -NR'C(0)GR\ -NR'C(0)R\ -(C¾)2N(R')(R5), or -(CH2)N(R')(R'); and
WRWS is selected from hydrogen, -OH, NH2> CN, CHF2, NHR', N(R')2, -NHC(0)R', -NHC(0)OR', NHSO2R', -OR\ CH2OH, CH2N(R')2, C(0)OR\ SG2NHR\ SO^R'h, or CH2NHC(0)OR\ Or, WRW4 and WRWS taken togetlier form a 5-7 membered ring containing 0-3 three heteroatoms selected from N, O, or S, wherein said ring is optionally substituted with up to three WRW substituents.
[099] In one embodiment, compounds of formula VA-i have y occurrences of X-Rx, wherein y is 0-4. in one embodiment, y is 0.
[0100] in one embodiment, the present invention provides compounds of formula VA- 1, wherein X is a bond and Rx is hydrogen.
[0101] In one embodiment, the present invention provides compounds of formula VA- 1, wherein:
each of WRW2 and WRW4 is independently selected from hydrogen, CN, CF3, halo, C1-C6 straight or branched alky!, 3-12 membered cycioaliphatic, or phenyl, wherein said WRW2 and WRW is independently and optionally substituted with up to three substituents selected from -OR', -CF3, -OCF3, -SCF3, halo, -COOR\ -COR', -0(CH2)2N(R')(R'), - 0(C¾)N(R')(R!), -CON(R')(R'), -(CH2)2OR\ -(CH2)QR\ optionally substituted phenyl, - N(R')(R'), -NC(0)OR\ -NC(0)R\ -(CH WXR'), or -(CH2)N(R')(R"); and
WRW5 is selected from hydrogen, -OH, NH2, CN, NHR', N(R')2, -NHC(0)R', - NHC(0)OR\ NHSO2R', -OR', CH2OH, C(0)OR', SO2NHR', or C¾ iC{0)0-(R').
[0102] In one embodiment, the present invention provides compounds of formula VAIL, wherein:
WRW2 is a pheny ring optionally substituted with up to three substituents selected from - OR', -CF3, -OCF3, SR\ S(0)R\ S02R', -SCF3, halo, CN, -COOR', -COR', - 0(CH2)2N(R')(R'), -0(C¾)N(R')(R'), -CON(R')(R'), -(CH2)2OR', -(CH2)OR', CH2CN, optionally substituted phenyl or phenoxy, -N(R')(R'), -NR'C(0)OR\ -NR'C(0)R', - (CH2)2N(R')(R'), or -(CH2)N(R')(R');
WRW4 is C1-C6 straight or branched alkyl; and
WRWS is OH.
[0103] In one embodiment, each of WRW2 and WRW4 is independently selected from CF3 or halo, in one embodiment, each of WRW2 and WE? 4 is independently selected from
- 32 - S33.1 optionally substituted hydrogen, C1-C6 straight or branched alkyl. in certain embodiments, each of of WRW2 and WRW is independently selected from optionally substituted n-propyl, isopropyi, n-b tyl, sec-butyf, t- butyl, l,l-dimethyl-2-hydroxyethyl, l,l-dimethyl~2~
(ethoxycarbonyl)-ethyl, l, l-dimethyl-3-(t-butoxycarbonyl-amino) propyl, or n-pentyl,
[0104] In one embodiment, each of W W2 and WRW4 is independently selected from optionally substituted 3-12 menibered cycloaliphatic. Exemplary embodiments of such eycioaliphaiic include cyclopentyl, eyclohexyl, cycioheptyl, norbornyl, adamantyl,
[2.2.2.]bicyclo-octyl, [2.3. L] bicyclo-octyl, or [3.3.I]bicycio-nonyl.
[0105] in certain embodiments WRW2 is hydrogen and WRW4 is C1-C6 straight or branched alkyl. In certain embodiments, W W4 is selected from methyl, ethyl, propyl, n-butyi, sec-butyl, or i-butyL
[0106] In certain embodiments WRW4 is hydrogen and W ft,; is C1-C6 straight or branched alkyl. in certain embodiments, WRW2 is selected from methyl, ethyl, propyl, n-butyl, sec -butyl, t-butyl, or n-pentyl.
[©107] In certain embodiments each of WRW2 and WR¾4 is CI-C6 straight or branched alkyl. in certain embodiments, each of WRwi and WRW4 is selected from methyl, ethyl, propyl, n-butyl, sec-butyl, t-butyl, or pentyl.
[0108] In one embodiment, WRWi is selected from hydrogen, CHF2, NH2, CN, NHR\ N(R')2, C¾N(R')2, -NHC(0)R', -NHC(0)OR\ -OR', C(0)OR', or S02NHR'. Or, WRWS is - OR', e.g., OH.
[0109] in certain embodiments, WRW5 is selected from hydrogen, NH2, CN, CHF2, NH{Ci-C6 alkyl), N(C1-C6 alkylfc, -NHC(0)(C I-C6 alkyl), -CH2NHC(0)0(C1~C6 alkyl), - NHC(0)0(C1-C6 alkyl), -OH, -Q(Ci-C6 alkyl), C(0)0(C1 -C6 alkyl), CH2Q(C1-C6 alkyl), or S02N¾. In another embodiment, WRW5 is selected from -OH, OMe, NH2, -NHMe, -N(Me)2, -CH2NH2, CH2OH, NHC(0)OMe, NHC(0)OEt, CN, CHF2, -C¾NHC(0)0(t-butyi), -O- (ethoxyethyl), -O-(hydroxyethyl), -C(0)OMe, or -SO?N¾.
[§110] In one embodiment, compound of formula VA-1 has one, preferably more, or more preferably all, of the following features:
i) WRW2 is hydrogen;
ii) WRW4 is C1-C6 straight or branched alkyl or monocyclic or bicyclic aliphatic; and iii) WRW5 is selected from hydrogen, CN, CHF2, N¾, NHCC1-C6 alkyl), N(C1-C6
alky!)2, -NHC(0)(C1-C6 alkyl), -NHC(0)0(C1-C6 alkyl), -CH2C(0)0(C1 -C6 alkyl), -OH, -CKC1-C6 alkyl), C(0)0(C1-C6 alkyl), or SQ2NH2. [©111] in one embodiment, compound of formula VA-1 has one, preferably more, or more preferably all, of the following features:
i) WR 2 is halo, C1-C6 alky!, CF , CN, or phenyl optionally substituted with up to 3 substituents selected from C1-C4 aikyl, -0(0-C4 alkyi), or halo;
ii) WRW4 is CF3, halo, C1-C6 aikyl or C6-C10 cycloaliphatic; and
iii) WRW3 is OH, N¾, H(C1-C6 aikyl), or N(C1-C6 alkyi).
[0112] in one embodiment, X-Rx is at the 6-posiiion of the quinolinyl ring, in certain embodiments, X-Rx taken together is C1-C6 alkyi, -0-(O-C6 alkyi), or halo.
[0113] in one embodiment, X-Rx is at the 5-position of the quinolinyl ring, in certain embodiments, X-Rx taken together is -OH.
[§114] in another embodiment, the present invention provides compounds of formula VA-1, wherein WRW4 and W W5 taken together form a 5-7 membered ring containing 0-3 three heteroaioms selected from N, O, or S, wherein said ring is optionally substituted with up to three WRW substituents.
[0115] fa certain embodiments, WRW4 and WR 5 taken together form an optionally substituted 5-7 membered saturated, unsatiiraied, or aromatic ring containing 0 heteroatoms. in oilier embodiments, WRW4 and WR¾5 taken together form an optionally substituted 5-7 membered ring containing 1-3 heteroatoms selected from N, O, or S, In certain other embodiments, WRW4 and WRW5 taken together form an optionally substituted saturated, unsaturated, or aromatic 5-7 membered ring containing 1 nitrogen heteroatom. In certain other embodiments, WR 4 and WRW5 taken together form an optionally substituted 5-7 membered ring containing 1 oxygen heteroatom.
[0116] in another embodiment, the present invention provides compounds of formula
Figure imgf000035_0001
V-A-2
wherein:
Y is CH2, C(0)0, C(O), or S(0)2;
m is 0-4; and
X, Rx, W, and R are as defined above.
34 -44833.1 [0117] In one embodiment, compounds of formula VA-2 have y occurrences of X-R , wherein y is 0-4. In one embodiment, y is 0. Or, y is 1. Or, y is 2.
[0118] In one embodiment, Y is C(O). in another embodiment, Y is C{0)0. Or, Y is S(0)2, Or, Y s CH2.
[§119] In one embodiment, m is 1 or 2. Or, m is 1. Or, rn is 0.
[0120] In one embodiment, W is a bond.
[0121] In another embodiment, Rw is C1-C6 aliphatic, halo, CF3, or phenyl optionally substituted with C1-C6 alkyi, halo, cyano, or CF3, wherein up to two jneihylene units of said C1-C6 aliphatic or C1-C6 alkyl is optionally replaced with -CO-, -CONR'-, -C02-, -OCO-, -NR'CGr, -0-, -NR'CONR'-, -OCO R'-, -NR'CO-, -S-, -NR'-, -SO2 '-, NR'SOr, or - NR'S<¾NR'-. In another embodiment, R" above is C1-C4 alkyl.
Exemplary embodiments of WR* include methyl, ethyl, propyl, tert-butyl, or 2-ethoxyphenyl.
[0122] In another embodiment, Rw in Y-R* is C1-C6 aliphatic optionally substituted with N(R")2, wherein R" is hydrogen, C1-C6 alkyl, or two R" taken together form a 5-7 membered heterocyclic ring with up to 2 additional heteroatoms selected from O, S, or NR'. Exemplary such heterocyclic rings include pyrro!idinyt, piperidyl, morpholinyl, or thiomorphoiinyl.
[0123] In another embodiment, the present invention provides compounds of formula -A-3:
Figure imgf000036_0001
m is 0-4;
n is 0-4; and
X, Rx, W, and Rw are as defined above.
[0124] In one embodiment, compounds of formula VA-3 have y occurrences of X~RX, wherein y is 0-4. In one embodiment, y is 0. Or, y is 1. Or, y is 2,
[0125] In one embodiment, n is 0-2.
- 35 -44833.1 [0126] ¾ another embodiment, m is 0-2. In one embodiment, m is 0. In one embodiment, m is 1. Or, m is 2.
[0127] In one embodiment, QRQ taken together is halo, CF3, OCF3, CN, C1-C6 aliphatic, 0-C1-C6 aliphatic, O-phenyl, NH(C1-C6 aliphatic), or N(C1-C6 aliphatic)2, wherein said aliphatic and phenyl are optionally substituted with up to three substiiuents selected from C1 -C6 alky I, 0-C1-C6 alkyi, halo, cyano, OH, or CF3, wherein up to two methylene units of said C1-C6 aliphatic or C1-C6 alkyi is optionally replaced with -CO-, -CONR'-, -CO2-, -OCO-, -NR'COr, -0-, -NR'CONR'-, -OCONR'-, -NR'CO-, -8-, -NR'-, SOR', 802R\
-SO2NR'-, NR'SOr, or -NR'SC NR'-. In anotlier embodiment, R' above is C1-C4 alkyi.
[0128] Exemplary QRQ include methyl, isopropyi, sec-buty!, hydroxymethyl, CF3, NMe2, CN, CH2CN, fluoro, chloro, OEt, OMe, SMe, OCF3, OPh, C(0)OMe, C(0)0-iPr, S(0)Me, NHC(0)Me, or S(0)2Me.
[0129] In another embodiment, the present invention provides compounds of formula
Figure imgf000037_0001
wherein X, Rx, and Rw are as defined above,
[0130] In one embodiment, compounds of formula VA-4 have y occurrences of X-R , wherein y is 0-4. In one embodiment, y is 0. Or, y is 1. Or, y is 2,
[0131] In one embodiment, Rw is C1-C12 aliphatic, C5-C10 cycloaliphatic, or C5-C7 heterocyclic ring, wherein said aliphatic, cycloaliphatic, or heterocyclic ring is optionally substituted with up to three substiiuents selected from C1-C6 alkyi, halo, cyano, oxo, OH, or CF3, wherein up to two methylene units of said C1-C6 aliphatic or C1-C6 alkyi is optionally- replaced with -CO-, -CONR'-, -CO2-, -OCO-, -NR'CC , -0-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR*-, -SO2NR'-, NR'SOr, or -NR'S02NR'-. In another embodiment, R' above is C1-C4 alkyi.
[0132] Exemplary R includes methyl, ethyl, n-propyl, isopropyi, n-butyl, sec-butyi, t- butyl, n-pentyl, vinyl, cyanomethyi, hydroxymethyl, hydroxyethyl, hydroxybutyl, cyclohexyl, adamantyl, or -C(CH3)2-NHC(0)0-T, wherein T is C1-C4 alkyi, methoxyethyl, or tetrahydrofuranyl methyl.
- 36 -44833. ί [0133] In another embodiment, the present invention provides compounds of foi
Figure imgf000038_0001
V-A-5
wherein:
m is 0-4; and
X, Rx, W, Rw, and ' are as defined above,
[Θ134] In one embodiment, compounds of formula VA-5 have y occurrences of X-R , wherein y is 0-4, In one embodiment, y is 0. Or, y is 1. Or, y is 2,
[Θ135] In one embodiment, m is 0-2. Or, m is I, Or, m is 2,
[Θ136] In another embodiment, both R' are hydrogen. Or, one R' is hydrogen and the other W is C1-C4 alkyl, e.g., methyl Or, both R' are C1-C4 aikyt e.g., methyl.
[Θ137] in another embodiment, m is I or 2, and is halo, CF3, CN, C1-C6 aliphatic, 0-C1-C6 aliphatic, or phenyl, wherein said aliphatic and phenyl are optionally substituted with up to three substituents selected from C1-C6 alkyl, 0-CI-C6 alkyl, halo, cyano, OH, or CF3, wherein up to two methylene units of said CI -C6 aliphatic or C1-C6 alky! is optionally replaced with -CO-, -CONR\ -C<¾-, -OCO-, -NR'COz-, -0-, -NR'CONR'-, -OCONR*-, -NR'CO-, -S-, -NR'-, -SO2 R'-, NR'SO , or -NR'SG2NR'-, In another embodiment, R' above is C1-C4 alkyl
[0138] Exemplary embodiments of Rw include chloro, CF3, OCF3, methyl, ethyl, n- propyl, isopropyl, n-butyl, t-butyl, methoxy, ethoxy, propyloxy, or 2-ethoxyphenyl.
[0139] In another embodimeni, the present, invention provides compounds of formula
Figure imgf000038_0002
wherein: 4 S33.1 ring B is a 5-7 membered monocyclic or bicyclic, heterocyclic or heteroaryl ring optionally substituted with up to n occurrences of ~Q~RQ, wherein n is 0-4, and Q and RQ are as defined above; and
Q, RQ, X, Rx, W, and Rw are as defined above.
[0140] in one embodiment, compounds of formula VA-6 have y occurrences of X~RX, wherein y is 0-4. in one embodiment, y is 0, Or, y is 1. Or, y is 2,
[0141] In one embodiment, m is 0-2. Or, m is 0. Or m is 1.
[0142] in one embodiment, n is 0-2. Or, n is 0. Or, n is 1.
[§143] In another embodiment, ring B is a 5-7 membered monocyclic, heterocyclic ring having up to 2 heteroaioms selected from O, S, or N, optionally substituted with up to n occurrences of -Q-RQ. Exemplary heterocyclic rings include N-morpholinyl, N-piperidinyS, 4- benzoyl-piperazin-l-y!, pyrrolidm-l-yl, or 4-methyl-piperidin~1 -yl.
[0144] In another embodiment, ring B is a 5-6 membered monocyclic, heteroaryl ring having up to 2 heteroaioms selected from O, S, or N, optionally substituted with up to n occurrences of ~Q-RQ. Exemplary such rings include benzimidazol-2-yl, 5-methyl-furan-2-yS, 2,5-dimcthyl-pyrroi-i-yI, pyridine-4-yl, indoi-5-yi, indol-2-yi, 2,4-dimethoxy-pyrimidin-5-yi, furan-2-yl, furan-3-yl, 2-acyl-thien-2-yl, benzothiophen-2-yl, 4-methyl-thien-2-yi, 5-cyano- thien-2-yl, 3-chloro-5-trifluoromethyl-pyridin-2-yl.
present invention provides compounds of formula
Figure imgf000039_0001
wherein:
one of Qs and (¾ is N(WR ) and the other of Q{ and Q3 is selected from O, S, or N(WRW);
Q2 is C(0), C¾-C(0), C(0)-CH2, CH2, CH2-C¾, CF2s or CF2-CF2;
m is 0-3; and
X, W, Rx, and Rw are as defined above.
[0146] in one embodiment, compounds of formula V-B-l have y occurrences of X- , wherein y is 0-4. in one embodiment, y is 0. Or, y is h Or, y is 2.
- 38 -44833.1 [0147] In one embodiment, Q3 is N(WR*); exemplary WRW include hydrogen, Cl-Ci aliphatic, C(0)C1-C6 aliphatic, or C(0)OC1-C6 aliphatic.
[0148] In another embodiment, <¾ is N(WRW), Q2 is C(0), CH2, CH2-CH2, and Qi is
O.
[0149] In another embodiment, the present invention provides compounds of formula
Figure imgf000040_0001
R is hydrogen or C 1 -C6 aliphatic;
each of RW3 is hydrogen or C1-C6 aliphatic; or
both RW3 taken together form a C3-C6 cycloalkyl or heterocyclic ring having up to two heteroatoins selected from O, S, or NR', wherein said ring is optionally substituted with up to two WRW substituertts;
m is 0-4; and
X, Rx, W, and R* are as defined above.
[0150] In one embodiment, compounds of formula V-B-2 have y occurrences of X-Rx» wherein y is 0-4. in one embodiment, y is 0. Or, y is 1. Or, y is 2.
[0151] in one embodiment, WRWi is hydrogen, C1-C6 aliphatic, C(0)C1-C6 aliphatic, or C(0)OCl-C6 aliphatic.
[0152] in another embodiment, each RW3 is hydrogen, C1-C4 alkyl. Or, both RW3 taken togetlier form a C3-C6 cycloaliphatic ring or 5-7 rnembered heterocyclic ring having up to two heteroatoms selected from O, S, or N, wherein said cycloaliphatic or heterocyclic ring is optionally substituted with up to three substitutents selected from WRWI. Exemplary such rings include cyciopropyi, cyclopentyl, optionally substituted piperidyl, etc.
[0153] in another embodiment, the present invention provides compounds of formula
V-B-3:
44833. ί
Figure imgf000041_0001
wherein:
Q4 is a bond, C(0), C(0)0, or S(G>>;
RWi is hydrogen or C1-C6 aliphatic;
m is 0-4; and
X, W, Rw, and Rx are as defined above.
[§154] In one embodiment, compoimds of formula V-B-3 have y occurrences of X~RX, wherein y is 0-4. in one embodiment, y is G.
[0155] in one embodiment, Q4 is C(O). Or Q4 is C(0)0, in another embodiment, R i is CI-C6 aikyl. Exemplary RW1 include methyl, ethyl, or t-butyl.
[0156] In another embodiment, the present invention provides compounds of formula
Figure imgf000041_0002
m is 0-4; and
X, x, W, and Rw are as defined above,
[0157] in one embodiment, compounds of formula V-B-4 have y occurrences of X-Rx, wherein y is 0-4. in one embodiment, y is 0, Or, y is 1. Or, y is 2.
[0158] in one embodiment, m is 0-2. Or, m is 0. Or, m is 1.
[0159] In another embodiment, said cycloaliphatic ring is a 5-menibered ring. Or, said ring is a six-membered ring.
[0160] In another embodiment, the present invention provides compounds of formula
- 40 -
8544833.1
Figure imgf000042_0001
V-B-5
wherein:
ring A2 is a phenyl or a 5-6 membered heteroaryl ring, wherein ring A2 and the phenyl ring fused thereto together have up 4 substituents independently selected from WRW;
m is 0-4; and
X, W, Rw and Rx are as defined above.
[0161] In one embodiment, compounds of formula V-B-5 have y occurrences of X-Rx, wherein y is 0-4. In one embodiment, y is 0. Or, y is I . Or, y is 2.
[Θ162] In one embodiment, ring A2 is an optionally substituted 5-membered ring selected from pyrroiyi, furanyl, thienyi, pyrazolyl, iraidazoly!, thiazolyl, oxazoiyi, thiadiazolyl, oxadiazo!yl, or triazolyl.
[0163] In one embodiment, ring A is an optionally substituted 5-membered ring selected from pyrroiyi, pyrazolyl, thiadiazolyl, imidazolyl, oxazoiyi, or triazolyl, Exemplary such rings include:
Figure imgf000042_0002
wherein said ring is optionally substituted as set forth above.
[0164] In another embodiment, ring A2 is an optionally substituted 6-membered ring. Exemplary such rings include pyridyl, pyrazinyl, or triazinyi. In another embodiment, said ring is an optionally pyridyl,
[01^5] In on embodiment, ring A2 is phenyl
[0166] In another embodiment, ring A2 is pyrroiyi, pyrazolyl, pyridyl, or thiadiazolyl, [0167] Exemplary W in formula V-B-5 includes a bond, C(O), C(0)0 or C1-C6 alkylene.
- 41 -
85 4S33.1 [0168] Exemplary R in formula V-B-5 include cyano, halo, C1-C6 aliphatic, C3-C6 cycloaliphatic, aryl, 5-7 membered heterocyclic ring having up to two heteroatoms selected from O, S, or N, wherein said aliphatic, phenyl, and heterocyclic are independently and optionally substituted with up to three substituents selected from C1-C6 alkyi, 0-C1-C6 alkyi, halo, cyano, OH, or CF3, wherein up to two methylene units of said C1-C6 aliphatic or C1-C6 alkyi is optionally replaced with -CO-, -CONR'-, -CO2-, -OCO-, -NR'C02-, -0-, - NR'CONR'-, -OCONR'-, -NR'CO-, -S-, - R'-, -S02NR'-, NR'SO , or -NR'S02NR'-. in another embodiment, R' above is C1-C4 alkyi.
[0169] in one embodiment, the present invention provides compounds of formula V-B-
Figure imgf000043_0001
wherein:
G4 is hydrogen, halo, CN, CF3, CHF2, CH2F, optionally substituted CI -C6 aliphatic, aryl-Cl-C6 alkyi, or a phenyl, wherein G4 is optionally substituted with up to 4 WRW substituents; wherein up to two methylene units of said CI -C6 aliphatic or C1-C6 alkyi is optionally replaced with -CO-, -CONR'-, -CO2-, -OCO-, -NR'C02-, -0-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -S<¼NR\ NR'SOs-, or -NR'S02NR'-. ;
G5 is hydrogen or an optionally substituted C1-C6 aliphatic;
wherein said indole ring system is further optionally substituted with up to 3 substituents independently selected from WRW.
[Θ17©] In one embodiment, compounds of formula V-B-5-a have y occurrences of X~ Rx, wherein y is 0-4. In one embodiment, y is 0. Or, y is 1. Or, y is 2,
[©171] in one embodiment, G4 is hydrogen. Or, G5 is hydrogen.
[0172] in another embodiment, G4 is hydrogen, and G5 is C1-C6 aliphatic, wherein said aliphatic is optionally substituted with C1-C6 alkyi, halo, cyano, or CF3, and wherein up to two methylene units of said C1-C6 aliphatic or C1-C6 alkyi is optionally replaced with - CO-, -CONR'-, -CO2-, -OCO-, -NR'CQr, -0-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, - NR'-, -SO2NR'-, NR'SG , or -NR'SQsNR'-. In another embodiment, R' above is C1-C4 alkyi.
- 42 -44S33.i [0173] in another embodiment, G4 is hydrogen, and G5 is cyano, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, cyanomethyl, methoxyethyl, CH2C(0)OMe, (CH )2~ NHC(0)0-iert-butyl, or cyclopeniy!.
[0174] in another embodiment, G5 is hydrogen, and G4 is halo, C1-C6 aliphatic or phenyl, wherein said aliphatic or phenyl is optionally substituted wife C1-C6 alkyl, halo, cyano, or CF3, wherein up to two methylene units of said C1-C6 aliphatic or C1 -C6 alkyl is optionally replaced wife -CO-, -CONR'-, ~CG2~, -OCO-, -NR'C02-, -0-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -802NR\ NR'S02~, or ~NR'SQ2NR'-. in another embodiment, R' above is C 1-C4 alkyl.
[0175] in another embodiment, G5 is hydrogen, and G4 is halo, CFj, ethoxycarbonyl, t- butyl, 2-raethoxyphenyi, 2-ethoxyphenyl, (4~C(0)NH(CH2)2~NMe2)-phenyl, 2-mefeoxy~4- chioro-phenyl, pyridine-3-yl, 4-isopropylphenyl, 2,6-dimethoxyphenyl, sec- butylaminocarbonyl, ethyl, t-butyl, or piperidin-l-ylcarbonyl.
[©176] in another embodiment, G4 and G5 are both hydrogen, and the nitrogen ring atom of said indole ring is substituted with C1-C6 aliphatic, C(0)(C1-C6 aliphatic), or benzyl, wherein said aliphatic or benzyl is optionally substituted with C1-C6 alkyl, halo, cyano, or CF3, wherein up to two methylene units of said C1-C6 aliphatic or CI -C6 alkyl is optionally replaced with -CO-, -CONR'-, -CO2-, -OCO-, -NR'COr, -0-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO2NR'-, NR'SOr, or -NR'S02NR'-. in another embodiment, R' above is C1-C4 alkyl,
[0177] Irs another embodiment, G4 and Gj are both hydrogen, and the nitrogen ring atom of said indole ring is substituted with acyl, benzyl, C(0)CH2N(Me)C(0)CH2NHMe, or ethoxycarbonyl.
[0178] in another embodiment, fee present invention provides compounds of formula
F:
Figure imgf000044_0001
r
or pharmaceutically acceptable salts thereof,
wherein R1, R2, R3, R4, R5, R6, R7, and At1 is as defined above for compounds of formula
P.
- 43 -44833.! [©179] in one embodiment, each of R\ R2, R3, R4, R5, R6, R7, and Ar! in compounds of formula P is independently as defined above for any of the embodiments of compounds of formula I.
[0180] Representative compounds of the present invention are set forth below in Table 1 below.
[0181] Table 1
Figure imgf000045_0001
8544833.1 -Oxo-l ^-dihydro-quirioline-S-carboxyiic acid ^-{1 ',2'-dihydrospsio[cyc!opropane-1 ,3'-[3H]indoi]- e'-y!)-amide
-[2-{2-βίho hen l)-5-h drox -4-tert ϊutyl· heπy ~4-oxo-1 H-qu!noi!ne-3~carbo amϊdβ
4-oxo-N-{3-pyrroHdin-1 -ylsu!fony!phenyi5-1 H-quirioiine-3-Gait)Oxamide
N-[2-(3-aceiyiaminopheny§)pheny -4-0X0-1 H-quIno!ine-3~carboxamide
4-oxo-N-[2-{1 -pjperidyS)phenyIj-1 H-quinoSins-3-carboxamide
N-{1 -[2-[mei y¾-{2-methy!aminoacetyl}-amino]aceiy!]-1 H-indo!-6-y!]-4-oxo-1 H-quinoiine-3- carboxamide
[2-methyi-2-[4-[(4-oxo-1 H-qu!no!iri-3-y carboriy!amino]ph8ny!]~propy!]aminoiormic acid 2- methcsxyethyi estor
1 -isopropyM-axo-N-pheny!-l H-quinoiine-S-carboxam de
[2-isopropyl-5-[(4-oxo-1 H-quiiioliri-3-y!)carbonylam!no]phsny!]aminoformiG acid methyl ester
4-oxo-N-{p olyl)-1 H-quinoHne-3-carboxarr¾ide
N-(5-ch!oro~1 H-indo!-6-yS)-4-oxo-1 H-qiiinoiirie-S-carboxamida
N-(1 H-indo!-8~yl)-4-oxo-1 H-quinollne-3-carboxamide
N-[4-(1 , 1 -diethyipropyl)-2-fIuoro-5-hydroxy-pheny ~4-hydroxy-quino!in8-3-carboxamid8
1 ,4-dihydro-N~(2 A4,5-tetrahydr0-5,5-di ethyM ^
carboxamide
3-{2-isopropyiphenyl)-4-oxo-1 H-quinoline-3-carboxamide
N-{1 H-indoi-7-y!}-4-oxo-1 H-quino!ine-3-carboxamide
N'[2-{1 H-indo§-2-yl)pheny!]-4-oxo-1 H-quinoline-S-carboxamide
[3-[{2,4-dima1tioxy-3-quinolyl}carbonylamino]-4-te/t^utyi-phenyi]arr!inoforrr!ic acid tert-buiyl ester
N-[2-{2-hydroxyeihy!}p eny!]-4-oxo- H-qujnoSine-3-carboxanilde 3~{5~amirio-2-propy§-phenyl)-4-oxo-1 H-quino!!ne-3-carboxarriide -[2-[[3-chioro-5-(trif!uorornetbyl)-2-pyr!dy!]oxy3phenyi]-4-oxo-1 H-quinoi!ne-3-carboxarriide -[2-{3-etho ρhβny!5-5-hydroxy-4- βff 5u1yl·pheπ ]-4-oxo-1 H-qϋ!noiiπ -3-car o amidβ
N-(2-methySbenzothiazo!-5-yi)-4-oxo-1 H-quinoi!ne-3-Garboxamid8
N-(2-cyario-3-f iuoro-pheny!)-4-oxo- 1 H-quinoiine-3-carboxamide - 3-chίoro-5-(2-mo ho!iπo th isulfon larn!ΠO) hΘπ l]-4-oxo-1 H-quiπolίrϊθ-3-car oxaΓr!!de
N-[4-isopropyI-2-(ififiuorometr!yl)pheny!]-4~oxo-1 H~quir)oline-3-carboxamide
-{5-chloro-2-f!uoro-phenyl)-4-oxo-1 H-quinoSirie-3-carboxamide -[2-(2,6'dirneihoxyphenyl)phenyl]'4-oxo-1H-qiiino!ine-3-carboxarr!ide
4-oxo-N-(2l4>6-inrriethylphenyi)-1H-quinoline-3-carboxamide
6-[{4~mef yi-1 -piperidyl)suifonyl]-4-oxo-N-{5-fe/t- utyl-1 H-indoS-6-yS)-1 H-quinoline-3- carboxamide
M-[2-{E t-toSy!}phersy -4-oxo- H-quinoS!ne-3-Garboxamide
4-oxo-N-{4-py dyl)-1H-quinoiine-3-cafboxamide
4-oxo-N-{8 hia-7!9-diazabicycio[4.3.0]nona"2,4.6,9 etraen-5-yi)-1H-qu!no]in8-3-carboxamide -(3-amino-2-meihoxy-5-fert 3utyi-pher!yi)-4-oxo-1 H-qusno!irie-3-carboxarnide l ^-dihydro-N-CI ^.S^^etrahydro-e-hydroxynaphthaien^-yiJ^-oxoquinoiine-S-carboxarnide -[4-{3-eihyi-2,6-dioxo-3-piperidy!)phenyi]-4-oxo-1 H-quinoHne-3-carboxamjde
N 3-amino-4-{trifluorornethoxy)pheny!3-4-oxo-1H-quino!in8-3-carboxamide
N-[2-{5-isopropyS-2-methoxy-p enyl)phenyi]-4-oxo- H-quinoiirie"3-carboxamid8
[4-isopropyS-3-i{4-oxo-1 H-quinol!n-3-y!)carbonyiam!no]phenyi]aminoformiC acid tert-buiyi ester
-{2,3-dimethyiphenyi)-4-oxo-1H-quinolSne-3-carboxamSde
4-oxo- -[3-{irifiuorome¾ioxy}phenyi]- H-quinoiine-3-carboxamide
M-[2-{2,4-difSuoropheny!)phenyi]-4-oxo-1 H-quinoHrs8-3-carboxamide
4-oxo-N-{2-oxo-1 !3-dihydrobenzoirnidazoi-5-y -1H-qujnoline-3-carboxamide
4-oxo-N-[5-{3-pyridyi)-1 H-indo!-6-y!]-1 H~quino!ine-3-carboxarnide
M-(2,2-difSuoi-obenzo[1 ,3jdioxoS-5-y!}-4-oxo-1H-quinoline~3-carboxamide
6-elhy!-4-hydroxy-N-{1 H-indol-6-yi)qu!noiine-3-carboxam!d8
3-[2-[{4-oxo-1 H-quino!in-3-yi)carbony!amino]pheriyl]benzo!C acid methyl ester
fSi-(3-amino-4-isopropyl-phertyS)-4-oxo-1H--qii!noiirie-3-carboxarriide
4-oxo- -[2-(4-pyridyi)ph®ny!]"1H-quinoHn8-3-carboxarr!id0
3~[2-[{4-oxo-1 H-qu!noiin-3-yi5carbonyiarrsino]phenyl]benzoic acid isopropy! ester
N-{2-ethylphenyi)-4-oxo-1H-quinoi(n8-3-carboxamide
4-oxo- -{2- hen l·3H-benzoimidazoί-5- !)■·1H-qϋinoHrse-3-car o arriid8
4-oxo- -[5-(trifSuorornethyf)-2-pyridyi]-1H-qumo!ine-3-carboxamide
4-oxo-M-{3-quinoSyi)~1 H-quir!oline-3-carboxamide
- 46 - 78 N-[2-{3,4-diiiiioropheriyi}phenyl]-4-oxo-1H-quifiol!ne-3-carboxamide
77 N-{5-fiuoro-1 H-indo!-8-yl)-4-oxo-1 H-quirso!ine-S-earboxamtde
78 4-oxo-N-(2-sulfamoylphenyi)-1 H-quinoline-3-carboxamide
79 N-[2-(4-fSuoro-3-methyi-phenyi)pheny!]-4-oxo-1 H-quinol!ns-3~carboxam!de
80 -{2-meihoxyph8nyS)-4-oxo-1H-quinoiine-3-carboxamide
81 4-oxo-N-{3-prQpiony!am!nophenyl)-1 H-quinoHne-3-carboxamide
82 N-{4-d!ethyiamino-2-methy!-phenyi}-4-oxo-l H-quinoline-3-carboxamide
83 iS -[2-{3-cyanophenyi)pheny!]-4-oxo-1 H-quirtoline-3-carboxamide
84 N-(4-methyl-2-pyridyi)-4-oxo-1 H-quinonne-3-carboxamide
85 -[2-(3,4- S!ChlorophenyS)phsnyS]~4-oxo-1 H-quinoSSrse-3-carboxamide
86 N-[4-[2-(aminomethy!)p enyl]pheny!]-4-oxo-1 H-quinoSine-3-carboxamid8
87 4-oxo-N-(3-phenoxyphenyl)- H-quinoIine-3-carboxamide
[2-meihy!-2-[4-[{4-oxo-1 H-quinol!n-3-yi}carbonyiam!no]phenyl]-prQpyl aminoformSG acid teri-buty!
88
ester
89 -{2-cyafio-5-rnethy!-phenyl}-4-oxo-1 H-quinolins-3-carboxamide
90 4-oxo-N-{2-terf-buiy!phersyl)'1H-quino!ine-3-carboxamide
91 SSS-{3-chioro-2,8-diethy!-phenyl)-4-oxo-1 H-quinoSirs8-3-cafboxatri!de
92 i-[2-fiuoro-5 iydroxy-4-{1-meth teycIohexy^^
93 ~[2-{5"Cyano-2-ihienyi)pheny!}-4-oxo-1 H-quirioiine-3-carboxarn!de
94 iS3-(5-amino-2-methyI-phenyl)-4-oxo-1 H-quinoSine-3-cafboxatri!de
95 N-(2-cyanophenyi}-4-oxo-1 H~quinoline-3-carboxamide
96 N-p-Ccyanornethy!J-I H-indoi-e-ylH-oxo- H-qu!noiine-S-carboxamide
97 -[2-(2,4-dimeihoxypyrimid!n-5"y p erty -4-oxo-1 H-quir!oiine-3-carboxam!de
98 N-{5-dSfnethy!am!no-2~propyI-pbeny!)-4-oxo-1 H-quinoHrie-3-carboxafnide
99 4-oxo-N-{4-penty!phenyl)-1 H-quinoiin8-3-carboxam!de
100 -{1 H-indol-4-yl)-4-oxo-1 H-quinoiine-S-carboxamide
101 N-(5-arnino-2-(sopropyl~phenyl)-4-Qxo-1 H-qu!noline-3-carboxamide
102 -[2 3-{4-chloropheny!}-1 ,2,4~oxadia2ol-5-y phenyi]-4-oxo-1 H-quinoHne-3-carboxarrside
Figure imgf000049_0001
-48- 4S33.1 130 4-hydroxy~ -{ H-indol-6-y!)~5J-bis{irifluorom
131 N-(3-am!no-5-ch!oro-pheny!}-4-oxo- H-quino!ine-3-carboxamide
132 SSJ-{5-acetySamino-2-eihoxy-pheny!)-4-oxo-1H--quinoiine-3-carboxarr!!de 33 N-[3-cbiQro-5-[2-{1-piperidy!)ethylsuifony!am
134 ^-[2-{4-meihyfeu!finylphenyl)pheny!]-4-oxo-1 H-quino!!n8-3-cafboxamide
135 N-{2-ben2o[1,3]dioxol-5-yipheny!)-4-oxo- H-qu!no!ine-3-carboxamide
138 N-(2-hydroxy-3,5-diteft-buiyi-phenyl)-4-oxo-1H-quinoifne-3-carboxamide
6-[(4-fiuorQphenyl)-methyi-sulfamoy!]-lNH5-h^^
137
3-carboxamide
138 N-[2-{3,5-difSuorophenyi)pheny!]-4-oxo-1H-quinoline"3-car oxamide
139 N-[2-{2,4-dichIorophenyi)phenyi]-4-oxo-1H-qu!noiine"3-carboxamide
140 hJ-(4-cyclQhexyiphenyS)-4-oxo-1H-quinoline-3-carboxamide
141 [2-methyi-5-[{4-oxo~1H-quinoHn-3-yl)carbonylamino]pheny aminoformic acid ethyl ester
142 4-oxo-N-(2-sec-buty!phenyl)-1H-quinol!ne-3-carboxa!Tiide
43 -{2~fIuoro~5-hydroxy"4-ferf-butyl-phenyl}-4-oxo-1H-quinoline-3-carboxamide
144 -(3-hydroxyphenyi)-4-oxo-1H-quinoline-3-carboxamide
145 8-[(4-oxo-1H-quino!iri-3-yi)carbonyiamino]-1H-indoIe-4-carboxy!ic acid ethyi ester
146 4-oxo-N-(17,9 riazabicyc!o[4.3.0}nona-2,4,6 'teiraen-5-yi)-1H-qu!noiine-3-carboxamide
147 lsl-[2-(4-fluorophenoxy)-3-pyridyl]-4-oxo-1H-qu!nol!ne-3-carboxamide
148 4-oxo-N-[5-{1 -piperidylcarbonyl)-1 H-indol-6-yl]-1 H-quino!ine-S-carboxamide 49 N-(3-aceiyIarriinO'4-ethyl-phenyl)-4-oxo-1H-qu!noline-3-carboxarriide
4-oxo-N~[4-[2,2,2-irif !uoro-1 - ydroxy-1 -{trif !uoromethyl)ethyl]phenyi]-1 H-quinoiine-3- 50 carboxamlde
151 2-{4-methyl·2 h!en l) hen i]- -o o-1H-qu!Γίolirlθ-3-carbo amidθ
52 4-oxo-N-{2-oxo~3H~b8nzooxazol-8-yi}-1H-quinoiine-3-carboxamide
N-[4-(1,1-diethyS-2,2-dimeihyi~propyi)-2 !uoro-5^ydroxy-phenyl]-4-hydroxy-quinoSi
153 earboxamide
54 N 3,5-b!s{trif!uorometbyl)phenyi3-4-oxo-1H-quinoIine-3-carboxamide
155 4-oxo-iSi-(2-pyr!dyi)- H-qu!noIine-3-carboxamide
156 4-oxo-N-[2-[2-{tr!f!uoforri8thoxy5phenyl]pbeny!]- H-qu!noiSne-3-carboxamide
- 49 -4833. ϊ 157 N-(2-ethyl·5-mβthy!ar !ino- henyi5-4-oxo-1 H■ uino!ίr5β-3-car oxam!de
158 4-ox0-N-{5-phenyi-1 H-irtdo!-6-y!)-1 H-quino!ine-3-carboxamide
159 [7-[{4-oxo-1 H-quino n-3-yl)carbony!amino]tetralin-1~yilamirsoformic acid methyi ester
160 N-{3-amino-4-propyl-phenyl)-4-oxo-1H-quino!ine-3-carb xamide
61 N-[3-{2-et oxyethoxy)-4-te/i 5uiyi-phenyiJ-4-oxo-1H-quinoline-3-carboxafT!ide 62 M-{6-methoxy-3-pyridy!)-4-oxo-1H-quinoi!ne-3-carboxamide
63 N 5-{am!nomethyl)-2-{2-ethoxyph8nyI)-phenyi]-4-oxo-1H~qu!nolirte-3-carboxamide
164 4-oxo-M-[3-(trif!uoromethyi)p enyl]-1H-quino!ine-3-carboxam'ide
165 4-oxo-N-(4-sulfamoy!phenyS)-1H-quinolne-3-carboxamide
66 4-[2-[(4-oxo- H-quinoSin-3-y!)carbony!am!no]pheny!]ben∑o!C acid methyi ester
167 -{3-amino-4-methyi-pheriyl)-4-oxo-1H-quino!!n8-3-carboxamide
168 4-oxo-N-(3-pyridyS}-1 H-qyino!ine-3-carboxamide
169 -{1 -methyI- H-indoi-6-yt)-4-oxo-1 H-quinoline-3-earboxarrtide
170 N-(5-ch!oro-2-pyr!dy15-4-oxo- H-quinoiine-3-ca!i)oxamid8
171 N-[2-{2,3-dichlorophenyS)phenyi]-4-oxo-1H-qu!noline-3-carboxamids
172 N-{2-{benzo[b3thiophen-2-y3)phenyi)-1,4-dihydro-4-oxoquino!ine-3-carboxamide
173 -{6-methyS-2-pyridy!)-4-oxo-1 H-quiriolins-3-carboxamide
74 N-[2-(5-acetyi-2-thienyl}pheny!]-4-oxo-1H-quinoiine-3-carboxamide
4-Oxo-l ,4-d!hydro-quinoi«ne-3~carboxy!ic acid N-(1 '-Acetyl- ,2'-dihydrospiroicycloproparte-1 ,3'-
175
3H-indol]-6'-yi)-arnide
176 4-oxo-N-[4-{irSf!uoromethoxy}pherfy -1 H-quinoH!ie-3-carboxamid8
177 N-{2-buioxyphenyl5-4-oxo-1H-quino!ine-3-carboxamide
1 8 4-oxo-N-[2-{2-fert-butyiphenoxy)phenyS]-1 H-qiJinoi!ne-3-carboxamide
179 N-(3-carbamoyiphenyi}-4-oxo-1 H-quirioiine-3~carboxarri!de
180 N-{2-ethyS-8-methyl-phenyi)-4-oxo- H-quinoiine-3-carboxamid8
181 4-oxo-N-[2-{p-toiy!}pheny!]-1H-quinoiine-3-carboxamide
182 iM-[2-{4-f!uoropheny!)pher!y!H-oxo-1H-quinoSine-3-carboxam!de
7~[(4-oxo-1 H-quinol!n-3-yl)carbonyiamino]-1 ,2,3,4-tetrahydroquir!Oifne~1 -carboxyHc acid tert-
183
tit i ester
- 50 -4833,! 184 -(1H-!ndol·8-yί)-4-oxo- -{tr!f[uoromβth i)-1H-quSnolίnβ-3■carboxamidβ
185 hJ-(3-!T!orphoiinosuifonyiphenyi}-4-oxo- H-quin Sine-3-carboxamide
188 -{3-cycfopentyl-1H-indol-8-yi)-4--oxo-1H-quinoHne-3-carboxarriide
187 N-{1 -acetyi-1 H-indo!-8-yS)-4-oxo-1 H-quinoiine-S-carboxamide
188 8-[{4-oxo-1H-quinoHn-3-yS)carbonylamir!o]-1H-indote-5-carboxylic acid ethyi ester
189 N-(4-benzytoxyphenyi)-4-Qxo-1H-quinoSine-3-carboxamide
190 N-[2-{3-chioro^-f!uoro-phenyl)phenyi]-4-oxo-1H-quino!ir!e-3-Garboxamide
191 4-oxo- -(5-quinoiy!)-1H-qu!noline-3-carboxamide
192 -{3-methyi-2-pyridyS)-4-oxo-1H-quinoline-3-carboxamide
193 -{2,6-dimethoxy-3'pyridy!)-4-oxo-1H-quino!ine-3-carboxamide
94 N-(4-Gyanopheny§)-4-oxo-1H-qu!no!ine-3-carboxamide
195 N-{5-methyt-2-pyr!dy -4-oxo- H-quinofine-3-carboxarrside
198 N-[5-{3,3-d!nΊΘthyίbuίanoylarnino)-2-ferf 3uΐ l· h8nyl]-4-o O"1H-quϊίoS!πe-3-car oxamidβ
197 4-oxo- f-i8-(trifluorornethyS)-3-pyridy1]-1H--qu!no!ine-3-carbQxarnide
198 M-(4-f!uorophenyS)-4~oxQ-1H-quino!!ne-3-carboxamide
199 N-[2-{o-ioiyi}pheny -4-oxo- H-quinoline-3-carboxamide
200 1 (4-dshydro-N-(1 ,2,3,4 etrabydro-1 -hydroxynaphihaten-7-yI)-4-oxoquinoiine-3-carboxamide
201 N-{2-cyano-3-methy!-phenyl)-4'OXO-1H-quinoi!ne-3-carboxamide
202 -[2-{5-chloro-2-meihoxy-phenyS)phenylj-4-oxo-1H-quinoHris-3-carboxamide
203 !M-{1 -ber yi-l H-indol-8-yl)-4-Qxo-1 H-qusno!tne-3-carbaxamide
204 N-{4,4-dimethytehrornan-7-yi)-4~oxo-1H-qui!iol!ne-3--carboxamide
205 N 2-{4-rnethoxyphenoxy)-5-{trifluoromethyl)pheny!]-4-oxo-1H-quinoSi!ie-3-carboxarr{!de
206 -[2"{2,3-dim©ihy!phenoxy)-3-pyridyl3-4-oxo-1H-quinonne-3- :arboxamide
207 2-[8-[{4-oxo-1 H-quinoln-3-yl)carbonySamino]-1 H-indo!-3~y!]ac8tie acid ethyl ester
208 N 4-(2-adamantyl)-5-hydroxy-2-methyl-phenyi]-4-oxo- H--quino!ine-3-carboxamide
209 -[4-(hydroxyrrfeihyi)phenyI]-4-oxo-1H-quinoline-3-carboxamide
210 2i4-d!meihoxy-N-{2-phenylphenyl)-quinoiine-3-carboxamide
-51- S33.1 211 -{2-rriθίhoxy-5 θft >L!tyl·phenyί)-4-oxo-1H-quinoHne-3~c r oxarπ!de
212 -[3-{3-methyI-5-oxo-1 ,4-dihydropyra2o!-1 -yl)phenyl]-4-oxo-1 H-quinoiine-S-carboxamide
213 -[2-(2,5- lichioropheny phenyS]-4-oxo-1H-quinol!ne-3-carboxamide
214 ^~{3-methylsuifonyiaminopheriyS)-4-oxo-1H-quinoS!ne-3-carboxarri!de
215 4-oxo-M-pheriyi- H-quinoHne-3~carboxamIde
218 -{3H-ben20im!dazoi-2-y!)-4-oxo- H-quinoline-3-ca!-boxamide
217 N~{1 H-indazo!~5-yl)-4-oxG-1 H-quinoiine-S-carboxamide
8-f!uoro- -[2~fiuoro~5-hydroxy~4-{1-rrteihylcycSohexy])-prsenyi3-4-oxo-1H-quino!irt@-3-
218
carboxamide
219 4-oxo- -pyraz!n-2-yi-1H-quinolirfe-3-carboxam!de
220 N-{2,3-dihydroxy-4,8-diiert-buiy}-phenyl}-4-oxo-1 H-quinoHne-3-carboxarr!!de
221 [5-[{4-Gxo-1 H-quinoiin-3-yi)carbonyiamirto]-2-propyi-phenyi]aminoforrnic acid meihyi ester
222 -{3-chioro-2-cyano-pheny!)-4-oxo- H-quinoline-3-carboxamide
223 N-[2-(4-meihyisulfanylphenyI}p eny -4-oxo-1H-quinoiir!e-3-carbQxamide
224 4-oxo~N-[4-[2-[{2,2,2 rifluoroaeetyf)aminorneth^^
225 [2-isopropyi-5-[{4-oxo-1 H-quinolin-3-y carbonyiamino]phenyl]aminoformic acid ethyl ester
226 4-oxo-N-{4-propyIphenyl)-1 H-quinoIine-3-carboxamide
227 !SS 2^3H^enzoimidazoi-2-yi5phenyl]-4-oxo-1 H-quinoiine-3-carboxamide
228 N-[2-{hydroxy-pheny5-met y5)pheny!]-4~oxo-1H-quinoyns-3-carboxamide
229 -{2-methylsulfanyiphenyl)-4-oxo-1 H-quinoiine-3-carboxamide
230 N-{2-methyi-1 H-indo!-5~y!)-4-oxo-1 H-quinoIine-3-carboxamide
3-[4-hydroxy-2-[{4-Gxo-1 H-qu!noIin-3-yi)carbonySamino]-5-fert 3uiyi-ph8nyi]benzoic acid methyl
231
ester
232 N-{5-acetyIam!no-2-propyl-phenyl5-4-oxo-1H-quinoiine-3"Carboxamide
233 -{1 -aceiy!indoiin-8-yS)-4-oxo-1 H-quinoiine-3-cafboxamide
234 4-oxo- -[5-{trifluoromethyi)"1 H-indQS-6-yl]-1H-quinoiIne-3-carboxamide
235 N-{8-isopropyi-3-pyridyl)-4-oxo-1H-quinoHne-3-carboxamide
238 4-oxo-N-[4-{Wflu rornethyl)phenyi]-1H-quir!QHn8-3-carboxamide
237 -[5-{2-niethoxyphenyl)-1H-iridol-e-yS]-4-oxo-1H-quinoiine-3-carboxaro!de
- 52 - 833.S
Figure imgf000054_0001
264 N-(2,5-diethoxyphenyi)-4-oxo-1H-quinoiine~3-carboxamide
-53- 4833 Λ 265 N-{2-benzyiphenyI)-4-oxo-1 H-quinoline-3-carboxainide
266 5-hydroxy-4 efi )uiyl-2-(irifSuoromethyS)phenyi}-4-oxo-1 H-quinoline-3 ;arboxaniide 267 4~ox0-N-{4-phenoxypbenyl)-1 H-quinoiine-3-carboxamide
268 4-Qxo-N-(3-suSfamoyi-4-tert-feuty!-phenyl}-1H-qu!noHne-3-carboxamide
269 [4-isopropyS-3-[{4-oxo-1 H~quino!in-3-yl)carbonyiamino]pher!yl]amSnofornr¾ic acid ethyl ester
270 M-{2-cyano-1 H-irido!~8-y!}-4-oxo~1 H-quinoHne-S-carfooxa ide
271 -(3-amir!o-4-?ert-byiyi-phenyi)-4-oxo- H-quinol!ne-3-carboxam!de
-[3-(2-morphoynoeihyisulfonyiamino}-5 trifluoromeihyl)phenyl]-4-oxo-1 H-quinoS!ne-3-
272
earboxamide
273 [7-[{4-oxo-1 H-quinoi!n-3-yl}carbony!amino]tetraiin-1-yl]aminoformic acid iert-butyi ester
274 4-oxoe-pyrraSidin-1 -ySsuifony1-iNS-{5-tert 5utyl-1 H-irsdoI-6-y!)-1 H-quinoline-3-carboxamSde
275 4-benzyloxy-iSi-(3-hydroxy-4-?e/t-buiyi-phsnyi)-qu!noiine-3-cai'boxamfde
276 N-(4-rnorpholinosuifony!phenyI)-4-oxO'1H~quinoiine-3-carboxamide
277 N-[2-{3-f!uorop enyS)ph8ny¾]-4-oxo~1H-quir!o!ine-3-carboxamide
278 4-oxo-^-[2 3^trif!uoromethyi)phenyl}phenyS]-1 H-quinoSine-3-Garboxamide
279 N-[2-{2-iT5ethySsulfar5y!pheriy!)pher!y -4OXO"1H-quino me-3-carboxamicle
280 4-oxo-N-(6-quinolyI)- H-quinoiine-3-Garboxamide
281 N-(2,4-dimethyIpheny!}-4-oxo- 1 H-quinoiine-3-carboxamide
282 -(5-amino-2-ethy{-phenyS)-4-oxo-1 H-quir!olirie-3-carboxamide
283 N-[2-(3-methoxyphenyi)phenyi]-4-oxo-1H-qu!no!ine-3-carboxamide
284 N-(1 H-indazoi-8-yi)~4-oxo-1 H-qutnoline-3-carboxamide
285 il,>i-[2-{2,3-difluorophenyl)phenyi]-4-oxo-1 H-quinoline-S-carboxamide
286 1,4-dihydro-N-(1 ,2s3,4-tetrahydroriaphihaien-5-yi)-4-oxoquinoline-3-carboxamide
N-[2-fluoro-5-hydroxy-4-{1-rnethyScyciohexyl)-phertyi]-5-hydroxy-4~oxo-1 H-quinoline-3-
287
carboxamide
288 -{5 luoio-2-methoxycarbonyloxy-3 sff 3 tyl-phenyl)-4-oxo-1 H-quinoline-3-carboxamide
289 -(2-fluoro-4-methyi-phenyl)-4-oxo-1H-quino!ine-3-carboxamide
290 -[2-{3-isopropylphenyl}phenyi]-4-oxo-1 H-qu!noHn8-3'Carboxa!r!ide
291 -(2-chioro-5-hydroxy-4-feff-butyS-phenyS)-4-oxo-1 H-quinoi!ne-3~carboxamide
- 54 -
85 4S33.1
Figure imgf000056_0001
-55- 4833.1
Figure imgf000057_0001
-56- 4833.1 348 4-oxo-N-p eny!-7-(trifisjoromet yS)-1 H-quino!ir!e- S-carboxamide
M-[5-{4-{2-di!nethylamino8triyScarbamoy!)phenyi]- H-indoi-6 ~y -4-oxo-1 H-quinoiine-3-
347
carboxamide
348 N-[2-{4~eihoxyphenyl)phenyl]-4-oxo-1 H-quinoyne -3-carboxamide
349 4-oxo-N-{2~prienyisuifonyiphenyi}-1 H-quinoiine-3-carboxam!de
350 N-{ 1 -napbtby!)-4-oxo- 1 H-quinolirse-3-Garboxarrs ids
351 -(5-e†hyi-1 H-indof-8-y!)-4-oxo-1 H-quino!ine-S carboxamide
352 2-[8~{{4-oxo-1 H-quino!in-3-y )carbony§amino]-1 H-indoi-3-y!]8thy!a minoforrrsic acid tert-butyl ester
353 [34^(4-oxo-1 H-quinoiin-3-yl)carbonyiamino]-4-ferf-butyl-phenyS}ai ninoformic acid tert-butyi ester
354 -[2-[(cyctohexyS-methyl-amino)methy!]phenyS]-4-oxo- H- 3|U!nolne-3-carboxamide
355 M-[2-{2-meihoxypheny!)p eny!H-oxo-1 H-quinoiine-3-carboxamide
356 N-{5-meihy!amino-2-propyl-ph8nyi)-4-oxO"1 H-quinoi sne-3-carboxamide
357 -(3-isopropy!-1 H-indoi-6-yl)-4-oxo-1 H-quino!ine -3-carboxamide
358 6-chioro-4-hydroxy-N- 1 H-indoi-6-y!)quinofine-S -carboxamide
N-[3~{2-d!meihySaminoethyisu§fonySamino)-5-{trifSuororr!ethyi)p henyi}-4-oxo~1 H-quino!ine-3-
359
carboxamide
380 -[4-{difiuoromethoxy)phenyi3-4-oxQ-1 H-quinoHn6 i-3-carboxamide
361 N-[2-(2l5-dimethoxyphenyi}phenyS]-4-oxo-1 H-quirior!ne-3-carboxarriide
362 N-(2-ch!oro-4-ieif-butyl-phenyl5-4-oxo-1 H-qyino!in 8-3-earboxamide
363 N-[2-{2-f!uoro-3-methoxy-phenyi)phenyl]-4-Qxo-1 H-qu! ioline-3-carboxamSde
364 N-(2-rnethyi-8-quinofyf)-4-oxo-1 H-quino!ine-3-carboxam!de
365 N-(2-acety!phenyI)-4-oxo-1 H-qu!noline-3-ca rboxamide
366 4-oxo-N 2-[4-{trifiuoromethyi}phany phenyl]-1 H-qu!nQiine-3-carboxarnide
367 N-[2-{3,5-dic iofophenyi)phsr!yi]-4-oxo-1 H-quirsolir re-3-earfooxamide
368 N-{3-aminQ-4-prQpoxy-pbenyl}-4-oxo-1 H-quSno!in« 5-3-carboxamide
369 N-(2,4-d!chioro-6-cyano-pheny -4-oxo-1 H-quino r θ-3-carboxamide
370 N-(3-chlorophenyl)-4-oxo-1 H-quinoSSne-3-carboxamide
371 4-oxo- -[2-{irifluoromethyIsuifany!)phenyi]-1 H-qu!no l!ne-3~carboxamide
372 l-[2-(4-methyl-1 -piper!dyl)phenyi]-4-oxo-1 H-quino!ine~3-carboxarrt!de 373 N-indan-4-yS-4~oxo-1 H-quinolin8-3-carboxamide
374 4-hydfoxy'N-{ H-indol-6*y[)-2-methylsuIfanyS-quinolir!e~3-cafboxamide
375 1 ,4-dihydro-iSHI ,2,3,4 e†rahydrQnaphthaien^^
376 4-oxo-N-{2-phenyl enzooxazo!-5-yl)-1 H-quinoIine-3-carboxamide
377 6.8-dif!uoro~4-hydroxy-ISI-{1 H-indo!-8-yl)quinoHne'3-carboxamide
378 N-(3-amino-4-me1iioxy-pheriyi)-4-oxo-1H-qu!noline-3-GarboxaiTside
379 N-[3-ace5yiamino-5-{irifiuoromethy pheny!]-4-oxo-1H-quirio!ine-3-cairboxamide
380 N-{2-ethoxyphenyS)-4-oxo- H-quinoIina-3-carboxamide
381 4~oxo- -C5-ie?f-butyl-1 H-indol-6-yi)-1 H-quinoline-S-carboxarnide
382 [5-[{4-oxo~1 H-quino!in-S-yiJcarbonyiaminoj^-propy -pheny afr!Ssiofofrr!ic acid ethyl ester
383 N-(3-ethyl-1 H-indol-8-yj)-4-oxo-1 H-quinoSine-S-caffooxamide
384 N-p^.S-difSuoiOphenyiJp snyjJ^-oxo-IH-quinoline-S-carboxamide
385 !N!-[2-(2,4-d!f!uorophenoxy)-3-pyridyi]-4-oxo-1 H-quinoiine-3-carboxamide
388 N-{3,3-dirnethylSndo!!n-8»yl}--4-oxo- H-quinoS!ne-3-carboxam!de
387 N-[2-methyi-3-(irifiuororr!8ihyl)pheriy -4-oxo-1 H-quinoline-S-carboxamide
388 4-oxo-N 2-[4-(tr!f!uorornethoxy}phenyl]phsnyl]-1 H-qu!nolirte-3-carboxamide
389 N-{3-benzyIphenyi)-4-oxo-1H-qu!no!ine-3-carboxamide
390 -[3-{aminomeihy -4-ferf-buiyl-p enyS]-4-oxo-1 H~quinoline-3-carboxarnide
391 -[2-{4-isobutyiphenyi)phenyi]-4-oxo-1 H-quinoline-S-carboxamide
392 N-{6-chloro-3-pyridyS)-4-oxo-1 H-quinol!ne-3~carboxamide
393 N-[5-amino-2-{2-ethoxyphsnyi)-phenyi}-4-oxo-1H-quinoiine-3-carboxarr!ide
394 1.e-dimethyi^-oxo-iSf-p enyi-i H-quinoline-3-cafboxamide
395 N-[4-(1-adamaniy!)-2-liuoro-5-hydroxy-pher!yf3-4-hydroxy-quir!oiin8~3-carboxariside i2-methy 2-[4-[{4-oxo-1H-quinoi!n-3-yi5carbonyamir!o]pheny!]-propyi]aminoforrriic acid
396
tatrahydrofuran-3-ylmethyi ester
397 4-oxo-N-(4-phenyip enyi)-l H-quinoiine-3-carboxarr!ide
398 4-oxo-N-[2-{p-to!yisu!fonyiam!rso)pher!yl]-1 H-qu!noline-3-carboxam!de
399 -{2-Ssopropyi-5-methyiam!no-phenyi)-4-oxo-1 H-quinoline-3-carboxamide 400 -(6-mQrpho!ino~3-pyridy!)-4-oxQ-1 H-quino!ine-3-carboxamide
401 N 2-(2 -dirneih¥jp enyl)phenyl]-4-oxo-1H"qu!rio!ine-3-carboxaniide
402 4-oxo-N-{5-phenyS-2-pyridyl)-1H-qujnoHne-3-carboxamide
403 N-[2~fSuoro-5-hydroxy-4-(1-methyIcyciooctyi}--phenyl]-4-hydroxy-qusno!ine-3-car oxamide
404 N-[5-(2,6-dimeihoxyp eriyl)-1H-indol-8-yi]-4-oxo-1H-quinolr!e-3-carboxafriide
405 N-(4-chloropheny!)-4-oxo-1H-quino!ine-3-carboxamide
8-[{4 !uoropheny!)-methyl-sul1amoy!]-4-oxo-N-{5 ©rt )utyl-1H~indo!-6-y!)-1H-quinoHrje-3-
406
earboxamide
407 -{2-fiuoro-5-hydroxy-4-fert-butyl-ph0nyS}-5-hydroxy-4-oxo-1 H-quinoiine-3-carboxamide
408 SN!-(3-mettioxyphenyl)-4-oxo-1H-quinoline-3-carboxamide
409 -{5-dimeihyiamino-2-ethy!-p enyI)-4-oxo-1 H-quino!ine-3-carboxam!de
410 4-oxo-N-[2-{4-phenoxyphany phenyi]-1H-quino!ine-3-carboxamide
411 7-chioro-4-oxo~N-pheny!-1 H-quirto!ine-3-carboxamide
412 6-[(4-oxo-1 H-qusrsolin-3-yi)carbonyiam!no]-1 H-indoie-7-carboxySic acid ethyi ester
413 4-oxo-N-(2-phenGxyphenyi)-1 H-quino!ine-3-carboxamide
414 N- 3H-berizoirnidazo!-5-yi)-4-oxo- H-qiiinG ir!e'3-carboxamide
415 -(3-hydroxy-4-fefi43utyi-phenyl5-4-rnethoxy-quirio!ine-3-carboxamide
[2-rrseihy!-2-[4-[(4-oxQ-1 H-qu!noIin-3-yi)carbonyiamino]p eny!]-propyl]aminoformic acid propyl
418 ester
417 N-{2-{benzo[b]ihiophen-3-yi)pheny!)-1 ,4-dihydro-4-oxoqu!'no!ine-3-carboxamjde
418 N-(3-dirri8thyiarri!nophenyi)-4-oxo-1 H-quinolne-3~carboxamide
419 -(3~aceiylarrsSnophenyl)-4-oxo-1H~quino!ine-3-carboxamids
420 2-rnetriyi-2-[4-[{4-oxO'1 H-quirio!in-3"yl)carbonyiamino]pheny!]-propanoic acid ethyi ester
421 -[5-m8thoxy-4~fe?i 3uiyl-2-{trif!uoromeihy!}phsnyi]-4-oxo-1H-qu!no!in8-3-carboxam
422 N-(5,6-dirri8thy!-3H-benzoirntdazo!-2--y!)-4-oxo-1 H-quinoHne-3-carboxamide
423 -[3-{2-ethoxyeihyI)-1H-Sndol-8-yI]-4-oxo- H-quinoi!ne-3-carboxamide
424 N-[2-{4-ch!oropheny!)p eny!]-4-oxo-1 H-quinoHrs8-3-carboxam!de
425 N-{4-isopropy!pheny!)-4-oxo-1H-quinoline-3*carboxamid8
426 -(4-c SorG-5- ydroxy-2-teff jutyl-phenyl)-4-oxo-1 H-quinoiin8-3-carboxamide
- 59 -4833.1 5-[(4-GXO-1 H-quinoSin-3-y!)carbonylam!no]- ,2,3,4-tetrahydro!Soquino!ine-2-carboxyIic acid tert-
427
butyi ester
428 N-{3-hydroxy-4-feit-tautyl-phenyl)-4-oxo-1 H-quinoline-3-carboxarnide
429 N 3-amino-5-{irifluororrieihyS}phenyi}-4-oxo-1 H-quinol!ne-3-carboxam!de
430 i i-{2-isopropyl-8-ms !y!-p enyI)-4-oxo- H-qi!inolsne-3-carboxamide
431 N-(3-aminophenyl)-4-oxo- H-quinoHne-3-carboxamide
432 N-[2-{4-isopropySpheny!}pheny!]-4-oxo-1 H-qutnoiine-3-carboxamide
433 ! i-{5-hydroxy-2^-ditert-tautyJ--phenyl)-4-oxo-1 H-quinolSne-3--carboxarr!ide
434 N-{2,5--d!mefriy[p enyS)-4-oxo-1 H-quino[Ine-3-carboxarnide
435 N-[2-(2 luorophenoxy)-3-pyr!dy!]-4-oxo-1 H-quino!ine-3-carboxamide
436 N-[2'{3^-dimethoxyphenyi)pheny!}-4-oxo-1 H-quinoi!ne-3-carboxam!de
437 N-benzo[ ,3]dioxo[-5-yl-4-oxo-1 H-quinoline-3-carboxamide
438 N-[i ^{difluoromeihyi)-2,4-ditert-butyl-p enyl]-4-oxo-1 H-quinoIine-3~carboxamide
439 N-(4-methoxyphenyi)-4-oxo-1 H-quinoIine-3-carboxamide
N~(2,2,S 5,3-tetrafluoro-2,3-dihydroben2Q[b][1 ,4]dioxin-6-y!5*1 ,4-dihydro-4-oxoquinoiine-3-
440
carboxamsde
441 N-[3-meihy!su!fonyiamino~5-(trif!u0ra
442 4-oxo- -[3-(1-piperSdyisuifonyl)phenyi]-1 H-quinoIine-3-carboxamide
443 4-oxo-N-qusnoxa!in-6-yl- 1 H-quinoline-S-carboxamide
444 5-K 4-0X0-1 H-quinoHn-3-yS)carboriy!am!no]-2-feri-¾utyl-benzoic acid methyl ester
445 -(2-isopropenylphenyI}-4-oxo-1 H-quino!in6-3-carboxamide
446 M-( ,1 -dioxobenzQthiophen-8-y!)-4-Qxt 1 H-quinoline-3-carboxamide
447 -{3-cyanophenyl)-4-oxo-1 H-qu!noline-3-carboxamide
448 4-oxo-N-(4-teff-buiyiphenyS)-1 H-qiiinoline-3-carboxamide
449 iS3-{rri-toly!)-4-oxo-1 H-qu!nol!ne-3-carboxamide
450 N-[4-{1 -hydroxyethyi}pheny -4-oxo-1 H-quino!ins-S-carboxamide
451 N-(4-cyano-2-ethyS-phenyi)-4-oxo-1 H-qu!noSine-3-carboxamide
452 4-oxo- -{4-yiny!pbenyi)-1 H-quinoHne-3-carboxarri!ds
453 N-(3"amino-4-€htoro-phenyI)-4-oxo-1 H-quino!ine-3-cafboxarrsid8
•60 -4833.1 454 N-(2-methyl-5-phenyI-phenyO-4-oxo-1 H-quinoline-3-carboxamfde
455 N-[4-(1 -adamantyl)pheny -4-oxo-1 H-quinoline-S-earboxarrode
456 4-oxo-N-[3 trifluoromethylsulfanyi)pheny -1 H-quinoiine-3-carboxarriide
457 N-(4-morpbolinopheny -4-oxo-1 H-quinoHne-3-carboxamide
458 3-{2-hydroxyethoxy)-4-iert 3utyl-ph@nyll-4-oxo-1 H-qu!no!ine-3-carboxamide
459 N-(Q oiyi)-4~QXQ~1 H-quinoline-S-carboxamide
[2-meihyS-2-[4-[(4-oxo-1 H-quinolin-3-y carbonyIamino]pheny!]-propy!]aminoformic acid fauty!
460
ester
461 4-oxo- -{2-pheny!ph@nyi)-1 H-quinoHne-3-carboxamide
462 N-{3-dirriethylamino-4-propyl-pheny -4-oxo-1 H-quinoHne-3-carboxamide
463 M-{4-ethyiphenyi)~4-oxO" 1 H-quinaline-3-carboxamide
464 5-hydroxy- -{5-hydroxy-2,4-d!tert-butyi-phenyS)-4-oxo-1 H-quinoiins-3-carboxamide
[5-[{4-oxo-1 H-quino!in-3-yI)carbonylam!noj-2~fe/i 5utyl-phenylfT!eihyl3arninoformiG acid tert-buty!
465
ester
468 N-{2,6-dsisopropy!phenyl)-4-oxo-1 H-quinoline-S-carboxamide
467 N-(2.3-dihydrobenzofuran-5-yl)-4-oxo-1 H-quinoifne-3-carboxamide
468 1 -methyi-4-Qxo-N-phenyl-1 H-quinoiine-3-carboxamide
469 4-oxo-N-(2-ph8ny!phenyl)-7-(trifiuoromethyl)-1 H-quinoline-3-carboxarnide
470 4-oxo- -{4-phenyisulfany!phenyi}-1 H-quinoIine-3-carboxamide
471 [3-[(4-oxo-1 H-quinoHn-3-yl)carbonylamino]-4-propyi-ph8nyS]atri!noformic acid methyl ester
472 [4-8ihy!-3- {4-oxo-1 H-quinolin-3-yi)carbonyiamino]phenyi]amir!OformIc acid ethyl ester
473 1 "!Sopropyl-4-oxo-N-{2- eif-butylpheriyl)-1 H-quinoline-3-carboxamid©
474 -(3-methyi-2-oxo-3H-benzooxazo 5-yi)-4-oxo-1 H-qii!noiin8-3-carboxamid8
475 N-{2,5-dich!oro-3-pyridyi)-4-oxo-1 H-quinoline-S-carboxamide
476 -{2-«yano-5-hydroxy-4-?erf-butyi-phenyl)-4-oxo-1 H-quirioline-3-Garboxarnide 477 -{5-fiuoro-2-pyridyS)-4-oxo-1 H-quinoline-3-carboxamide
478 4-Qxo-f>>J-(3-feri )utyl-1 H-Indoi-8-yi}-1 H-quinoline-S-carboxamide
479 N-{1 H-indoi~6-yi}-5-rriethoxy-4-oxo-1 H-quinoline-S-carboxamide
480 1 -8ihyi-8-methoxy-4-oxo-!SI-phenyi~1 H-quinoSine-S-carboxamide
61
4833.1 481 N-{2-naphihy -4-oxo-1H-quinol!fie-3-carboxamide
482 [7-[{4-oxo-1H-quino!!n-3-y!)carbonylamino]tetiaSin-1-yi]aminoformic acid ethyl ester
483 2 luoro-5-hydroxy-4-{1-methyteyclohepty!)-phenyl]-4-hydroxy-quinoHne-3-carboxarriide
484 3-(3-mθίhy!amino-4-tørf 5uίyl· hβπy!)-4-o o-1H- uinol!Πβ-3-c rbo amίdβ
485 N-(3-dimethylamino-4-terf 3utyi^henyi)-4-oxo-1H-quinofoe-3-carboxamid^
488 87-difiuoro~ -(2 IuQro-5-hydroxy-44ert~buiy!-pheny!}-4-oxo-1H-quino!ne-3-carboxam!de
5-h dΓoxy~N 5- ydro y-4 θrt-but l·2-{ίrif!ϋOforriθth !}pheπ -4-oxo-1H- u!nolnθ-3-
487
carboxamide
488 4-Qxo-N-[3-{1^iperidy -5-{trifluoromet^
N 4-{3,3-dSmeihy!pyrro!idin-1-yl)-2-{triiluoromeihy pheny!]-8-methy 4-oxo-1H-quinoiine-3-
489
carboxamide
490 6 !uoro-!Sf-{3-hydroxy-4-tert-buiyl-phenyS)-4-oxo-1H-quinoSine-3-carboxamide
491 N-(3-fSuoro-4 ert-buty!-pheny!)-5-hydroxy-4-oxo-1H-quinoline"3"Carboxamide
methyl 1 -[4-[(4~oxo-1 H-quinoHn-3-yl)carbony[amino]-3-{triiluoromethyS)pheny!]piper!dine-2-
492
earboxytate
5-bydroxy- -[4-[2-hydroxy-1 -(hydroxymeihy!)-l -methy!-eibyi]pheny -4-oxo-1 H-quinoline-3-
493
carboxamide
494 5-hydroxy-4-oxo- 5 πfluorometh l}-1H-!πdol·6- !3-1H-quino!!πe-3 ar oxamίdβ
495 8 !uoro-4-o o-N-[2-{tπfiuorometh -1H-iπdol·6- ~1H~qυ!noHπe-3-carbo amίdθ
496 N-{5-hydroxy-2,4-d!iert-buiy!-pbsnyi)-6-meihoxy-4-oxo-1H-quinoline-3-carboxamide
497 -[5-hydroxy~4-isopropy!-2-{trifluoromeihyS)phenyi]''4-oxo-1H-quSno!in@-3-carboxam!de
N-[ !uoro-5-h dro5< -4-{1-meίh lc clohe -phβn l]-5-mβίh l·4-o o-1H- uinoiinβ-3-
498
carboxamide
499 N-[2 !uoro-5-hydroxy-4 1-methylcyc!obexy!}-pheny!]-7-methyS-4-oxo-1H-qu!noline-3- carboxamide
500 5-hydroxy-4-oxo- -{5 ert-buiyI-1H-indo[-6~yS)-1H-qi!inolSne-3-carboxarnide
501 N 2 iuoro-5-hydroxy-4-{frSf!uorGmethyI)phenyl]^-oxo-1H~qu!no!in8-3-carbQxamide
502 5-hydroxy-N-[3-methQxy-5-{trifiuoronietbyl}pheny -4-oxo-1H-qu!no!ine-3-carboxamide
8-mβt yl·ίSS 4~{ -msΐhyl yrrol!dίn-1- l)-2-{tΓifIuoromΘth i) hθπ -4-o o-^
503
earboxamide
N-[4 3,3-dimethylpyrroiid!n~1-yi)~2-(trifkioromethyl)phenyS]-8-methoxy-4-oxo-1H-qui^
504
carboxamid©
505 S-cyano-M-iS-hydroxy^^-ditert-butyl-pheny ^-oxo-IH-quinoiine-S-carboxamide
506 N-[3-hydroxy-4-{tr!fluoromeihy!}pheny -4-oxo- H-quinoSine-3-carboxam!de
507 N-{2-ethy 5-hydroxy-44er-buty phenyi)-5-hydroxy-4-oxo-1H-quino!ine-3-carboxamide 4833.1 508 4-oxo-N-[3-tert-butyi-5-{tr!fiuoromet y!)-1 H-Sndo!-8- )?!]- H-quinoHne-S-earboxaroide
509 8-fiuoro-iSi~[5-hydrQxy-4-teri-buiyi-2-(trifiuoro!T!eihy!}phen¾ '!]-4-oxo- H-quinoiine-3-ca}ttoxa mide
510 4-oxo~N-[3-(1 -piperidyI}-4-tert-butyi-phenyi]-1 h l-quinoline-3-carboxamide
{S)-5-methyl-N-(4-(2-methyipyrrolidin-1-yi)-2-{trifiL oroi 5eihyI)pheny!)-4-oxo-1 ,4-
511
dihydroquinoIine-S-earbox amids
512 -[4-cyclopeniyl-5-hydroxy-2-(3-hydroxyprap-1-ynyi)phen y[]-4-oxo- H-qi!inoHne-3-carboxamide
(S)-N-(4-(3 dimeihySamino}pyrroydin-1--yl)-2-(t!ifiuoromethyi)pheny!)-4-oxo-1 ,4-
513
dihydroquinolins-S-carfaoxamide
514 4-oxo- -[2-{1-piperidyi)-4-{trifluoromethyl)ph8nyS; -1 H-quinoiine-3-carboxarnide
515 N-(5-hydroxy-2,4-ditert^utyl-pheny -4-ox -6-{trifIuorornethyi}-1 H-quinoHne-3^arboxamide
-(4-({2S!5S5-2l5-dimeihy!pyrroiidin-1-y!)-2-{trif!uoromeihyi5pheny!}-5-meihyl-4-oxo-1 , 4-
516
dihydroquinoiine-S-carboxamide
517 8-ethoxy-M-[4-isopropyl-2-{trifSuoromeihyS)p^®f y "4- 3ΧΟ-1 H-quinoiirse-S-carboxarnids 5
518 N-(5-hydroxy-2-methy^4-tert-butyi~phenyi)-4-oxG -1 H-quino!ine-S-carboxarnide
519 8-cyano- -(2'fiuoio-5-hydroxy-4-tert-buiyS-p eny -4- oxo-1 H-quinoyns-S-carboxamid a
520 N-{5-hydroxy-2,4-diteri-butyS-phenyl}-4-oxo-5-(trifiuoron iethyl)-1 H-quinoiine-3-carboxam ide
521 6-f!uoro-N-[4'(3-methyioxetan-3-yI)ph8nyi]-4-oxo -1 H-quinoSine-3-earboxamide
522 -{4-cycSohexy!-3-hydroxy-phenyS)-5-hydroxy-4-ox 0-1 H-quinoiine-S-carboxamide
523 N-[4~{3-methyioxetan-3-yi)phenyi]-4-oxo-1 H- quinoiine-3-carboxamide
524 6-ethoxy-fSi-{5~hydfoxy-2,4-diiert-buiyi-phenyl5-4-o> to-1 H-quinoHns-S-carboxamide
525 6-cyano- -(5-hydroxy-2,4-ditert-buiy!-pbenyi)-4-ox 0-1 H-quinoline-S-carboxamide
526 8-ethoxy- -(2-f!uoro-5-hydroxy-4-iert-buty!-phenyS)-4 ■oxo-1 H-quinoSine-S-carboxamid β
527 8-f!uoro-N-(3-fluoro-4 ert-butyi-phenyl)-4-oxo-1 H-quinoSine-S-carboxarrside
N-[4-(3,3-dif!uofopyrrolidin~1 -yI)-2-{trifiuoromethyS)pher sy!]-5-meihy!-4-oxo-1 H-qu!r!oHne -3-
528
carboxamide
529 5-hydroxy-N-[4-(3-methySoxetan-3-y!}phenyl]-4~oxo- H-qu!noiine-3-carboxamide
(2S,3S)-me†hyl 3-meihyi~1 -{4-(4-oxo-1 ,4-dihydra quinoiine-3-carboxarnido)-3-
530
{irifluoromeihyl)pheny!)pyrro!idine -2-carboxylate
(IS^S.SRJ-methy! 3-{4-(4-oxo~1.4-dihydroquinoline-3-carboxarnido)-3-(trifiuoromethyl)phenyl}-
531
3~a∑afoicyc!o[3.1.0]hsxane-2-carboxyiate
532 N-[2-chioro-4-{trifiyorom8ihy!)phenyi]-4~oxo-1 } -i-quinoIine-S-carboxamide
533 8-mβ hQ y-4-o o-^S-{5 θrί-but l·1 H^ndol·8■· i)-1 H-quino[ine-3-caΓboxarn!dθ
{R)-N-{4-(3-{dimethylaminG}pyrfoHd'^
534
dihydroqsjinoiine-3-carboxamide 4833.1 535 5-hydroxy-4-oxo-!S3-{3-tert-buty!~1 H-indoi-6-y -1 H-quinoiine-S-carboxamide
536 N"[4-{3,3 Sim8thyipyrrolidin-1-yl}-2-(ir^
537 4-oxo- -[2-{trifiuoromeihyi}-1 H-indol-6-yij-1 H-quino!ine~3-earboxamide
538 -[2-meihyf-4-(irifluoromethoxy)phenyl]-4-oxo-1H-quino[ine-3-carboxarnide
N 4-{{2R,5R)-2 -dimethyIpyrro!id!n-1-yi)-2 trifiuoromethyl}pheny!5-5-meihy 4-oxo-1,^
539
dihydroqusnoline-S-carboxarnide
(R)-iert-butyS 1 ~{4~{4-GXG-1 ,4-dihydroquino!!ns-3-carbaxamido}-3-
540
{triffeor0methy pheny!)pyrrQiidina-2-cafboxyiate
{R)-N-(4-(3 SuorapyrroSidsn-1~yi)-2^
541 S-carboxamide
542 -(5-bydroxy-2,4-d!t8rt-butyi-phenyl)-5-me iyiamino-4-oxo-1 H-quino!ine-3-carboxamide
543 4-oxo- -[4-(1 ~piperidy!)phenyS]~1 H-quinoline-S-carboxamide
544 6-dίmβΐh ίamino- -{5 droxy-2l4-diίert uί l· heπ !)-4-oxo-1 H- u!noIinθ-3~car oxamidθ
545 4-oxo- 3-{irifluoromethyi}-1H-indo!-6-y!3-1H-quino!irie-3-carboxamid8
5-rneihyl-N-[4-{3-methyipyrro!idirs-1-y!)-2-(tnf!uoromsthy!)phenyi]-4'Oxo-1H-quinoline-3-
546
carboxamide
547 J-[4-!sopropoxy-2-{trfluoronieihyS)phenyiJ-5-methyl-4-oxo-1H-qu!noSin8-3~carboxamide
548 7-cyano-iSi-{5-hydroxy-2,4-d!teri-buiy!-phsnyi)-4-oxo-1H-quino!ine-3-carboxamide
549 4-oxo-N-[3-{2-ihienyS)phsny!l-1H-quir!Ol!n8-3"Carboxa!'riide
{2S,4R)-methyl 4-tert-butoxy-1 -{4-{4-oxo-1.4-dihydroqu!noline-3-carboxamido}-3-
550
trifluoromeihyl5pheny pyrro!ldine-2-carboxyiate
551 ~{4~hydroxy-2-naphihyl)-4-oxo-l H-quinolne-3-carboxamide
552 S-fluoro-N-CS-hydroxy^^-ditart-buiyl-pbeny ^-oxo-IH-quino!ine-S-carboxamide
553 6-bropr!0-N-{5-hydroxy-2,4-diiert-butyS-ph©ny!)-4~oxo-1H-quino!ine-3~carboxamid8
554 6-fSuoro-4-oxo-N-{3-iert~butyl~1H-indoi-8-yl)-1H-quinoiine-3-cafboxarnide
555 -[4-{3-m8thyIpyrro!idin-1-y!)-2-{tr¾
^ 4-{2,2-dimethySpropanoylam!no)-2Hirifluoromethy0pheny!]~4-oxo-1 H-quinoi!n8-3-
556
carboxamide
557 6-fiuoro- ~[4-isQ rQ yl·2-{ΐrifluoromeί 0 hen ·4-o o-1H-quίnoline■·3-carboxafT!!de
558 7-cyano-4-oxo- -{54ert-buty!-1 H-indoi-8-yl)-1 H-quinoSine-3-cafboxafrssde
559 4-oxo- -{5 errtuiyi-1 H-indGl-6-yl)-8~{tr$^^
560 -[4-{2,5-dimethySpyrroS-1-y!}-3-meihoxy-phenyS]~4-oxo-1 H-qu!noline-3-carboxaiTiid8
581 8-ch oro-N-{2 Suoro-5-hydroxy-4 ei1-buiyI-pb8nyl)-4-oxo-1 H-quinoiine-3-carboxam!de 4833.! 562 8 iuoro-4~0xa-!SH4~pyrrGSid!n-1~yS-2^
563 N-[3-hydroxy-5-{trif!uoromeihy!}phenyS]-4--oxO'1H-quino!in8-3-€arboxarnide
564 -(4-cyclohexyi-3~hydroxy-phenyl)-4-oxo~1 H-qufno!ine-3-carboxamide
565 5-meihyi-4-oxo-N-{5-tert-buiyI-1 H~indol~8-yi)- 1 H-quinoline-S-carboxamid©
566 6 iu0ro- H1-{2-methoxyelhyl)-5-{irif!uoro
{S)~1-[4~[{4~oxo-1 H-quinoiin-3-yi)carbQ
567
carboxyHc acid
568 N-(5-hydroxy~2,4-diiert~butyl~phenyi)-5-meihyl-4-oxo-1 H-quinoiine-3-carboxamide
N-(4-((2Rl5R)-2,5-diiTiethylpyrroSidir!-1 -yl)-2-{trif!uoromethyl}pheny1}-6-meihyi-4-oxo-1 ,4-
569
dihydroquinofce-S-carboxarrside
570 N-[5-benzyloxy-4-isopropyl-2-{irifSuoromei yS)ph8nyi]-4-oxo-1 H-quino!!ne-3-carboxamide
571 N-[6-methQxy-5 'trifiuoromethyI}-2^yr yl]-4-oxo-1 H-qu!noSine-3-carboxamide iR)-^-{4-{2~meihylpyrroiidin-1-yS)~2-{trifiuoromethyi)phenyl)-4-oxo-1 ,4-dihydroqu!
572
carboxamide
573 8-fluoro- -[4~isopropyl-2-{irifSyoromethyi)pheny -4-oxo-1 H-quinoline-3-carboxamids
574 6-f!uora-N~[3-hydrQxy-5-(trifluoromethyi}phenyl]'4-oxo-1 H-quinoiine-3-carboxamide
575 is!-(3-hydroxy-4-isopropyi-pheny!)-4~oxo-1 H-quinoline-3-carboxamide
576 7-meΐh l·4 > o-N-[5-{trifluoro eib !)-1 ^
577 N-[2-methyi-5-(trifIuoromethyl)phenyl]-4-oxo-1 H-quinoHne-3-cart)oxamide
N~[4-(3,3 jimethy!pyrrolidin-1-y!)-2~{ir^
578
carboxamide
579 4-GXG- -[3^yrroSidin-1 -y!-4-{trif!uorom
580 N-(5-hydroxy-2^-ditert-buiyl~phenyi)-4-oxo-8-(ir1fiuoromethy!}-1 H-quino!ine-3-carboxamide
(S)-5-me†hyhN-(6-i2-methySpyrrofsdin-1 -y!^^
581
dihydroquinoline-S-carboxamide
N-(4-{{1S,4R)-2-azab(cycto[2.2 ]hep†an^
582
dihyd!Oquinoline-S-carboxamide
583 N-(5-rsydroxy-2,4~ditert-butyI-phenyI)-7-meihoxy-4-oxo-1H-quinoiine-3-carboxain!d©
N-[2 luoro-5-hydroxy-4-{1-rriethylcyclohexyi)-phenyi]-6-methoxy-4-oxo-1 H~quinoline'3-
584
carboxamide
585 5-amino-N-{5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo~1 H-quir!oiine-3-caiboxam!de
(R)-N-{4-{2-metby!pyrro!idin-1-yi)-2-(^^
586
dihydroquir!oline-3-carboxamide
587 5~hydroxy- -{3-hydroxy-4-isopropyf-pheny!)-4-oxo-1 H-qu!no!ine-3-carboxamide
588 5-bydroxy-N-{5-hydroxy-2-meίh l·4"tβrt- utyl hΘπ ί)-4-o o-1 H-qυinoίinθ-3-car o amΐdθ
- 65 ·
4833. i 589 87-difSuoro-iSi-[4-!Sopropyi-2-(irifiuora^
590 M~[4-[2-hydroxy-1 -(hydroxymethyS)~1 -methyi-ethyi]pbenySj-4-Qxo~1 H-quinoline-3-carboxamide
591 ^-{5-8ihy!-1 H-indol-6-y!)-5-hydroxy-4-oxo-1H-quinoSine-3-carboxamide
iSK4-{{2R,5S)~2,5-dimetfoyipyrroi!din~1-y^
592
dihydroquinoiine-S-earboxarnide
593 4-oxo-N-[3- rΓolidin-1- l·5 ίrif!uoforriθth S} hθπ i]-1H-qu!noline-3 :arboxam!dθ
594 J-{3-hydroxy-2,4-ditei1-buiy!-pheny!5-4-oxo-1 H-quinoiine-3-carboxamide
595 -[4-cyGtopentoxy-2-{tr!fSuorornethyI)phenyl]-5-methy 4-oxo-1H-quinoiine-3-carboxamide
598 -(5-fSuoro-1 H-indoS-6-yl)-5-hydroxy-4-oxQ"1 H-qu!! o ne-3-carboxamide
597 6-fluoro- -{3-hydroxy-4-!sopropyS-pheny!)"4-oxo-1 H-quinoline-3-carboxamide
598 N-[4-morpholino-2-{trifluoromeihyl)ph8nyS]-4-oxo-1H-quinoiine-3-Garboxamide
599 5-hydroxy^ 3-hydroxy-5-iirif!uororneihyl}phenyl]-4-oxo-1 H-qu!noline-3-carboxam!de
600 tert-buty§ [[4-[{4-oxo-1H-quinoSin-3-y carbonylam!no]-3-(irifIuorornethyI)phenyl]arnino]forrr!aie
{S)-6-methoxy-N-{4-(2-meihySpyrroHdin-1-y!)-2-(triiluoromethy!)ph8nyl)-4-oxo-1 ,4-
601 dihydroquinoiine-3-carboxa ide
602 4-oxD' -{3-iert-buiy!phenyS)-1H-quinoSine-3-carboxamide
803 6-chbro-4-oxo- -{5-tert-buiyl-1 H~indo!~6-yl)-1 H-quinolfne-3-carboxamide
604 7-acetyl-i J-(5-hydroxy-2,4-dSier1-buSyl-phenyS)-4-oxo-1H-quino!ine-3-carboxamide
605 8-ethyl-!Sj-{2-^uoro-5-hydroxy-4-tert-butyl-phenyl5-4"Oxo-1H-quinoHne-3-carboxamide
606 5-hydroxy-iSJ-[3-hydroxy-4-{1-methyScyciohexy -pheny -4-oxo-1H-quinoiine-3-carboxam!de
{S)-7~meihy N-{4-{2-methylpyrrolidin-1-yS)-2-{trifluoromeihyS)phenyl)-4-oxo-1 ,4-
607
dihydroquinoline-S-carboxamide
608 M-{2,4-d!Ch!oro-5-hydroxy-phenyS)-4-oxo-1 H~quinoline-3-carboxamide
609 5-hydroxy- -{5-hydroxy-2-teri-buiyS-phenyl)-4-oxo-1H-quino!ine-3-carboxamide
610 5-fiuoro- -{2-fSuoTO-5-hydroxy-4-t8ri-buiy!-phenyI)-4-oxo-1 H-quinoline-3-carboxamide
611 7 !uoro-6-methoxy-4-oxo-iSi-{5 eri-buty 1HH'ridof-6-yi5-1H-quinoHne-3-carboxamide
612 ^4-{3^<iimethyM^!per!dyi)-2~{trif!uaro
{R)-5-meihyi-!\|-{4-{3-metby!pyrroiid!n-1-y -2-{trif!uoromeihy pheriyI)-4-oxo-1 ,4-
613
dihydroqutnoline-S-carboxarnide
614 4-oxo-N-[4-{3-pyridyfoxy}phenyl]-1 H-quino!ine-3-carboxamide
615 M~{2-methy!-4-pyrrolidin-1 -yS-phenyS)-4-oxo-1H-qu!noiine-3-carboxamide
■ 66 -4833.1
Figure imgf000068_0001
dihydroquinoiine-S-carboxamide
- 67 - 4833.1 5-metbyl- ^4-(3-methy!-1^iperidy!)-2-{W^
643
carboxamide
644 8-mθth ί-4-o o- -(5 ert- uί !-1H~ίπdol·6- !}-1H-qϋinolίne■-3-carbo arnidθ
645 N-{3-fSuoro-4 efi-butyi-pheny -4-oxo-1H-quino!!ne-3-carboxamid8
646 6J-dίflϋoro-4-oxo- -{5-tθrt-buίyl·1H^πdoί-6-y - H-■quiπoHriβ-3-carboxam!dθ
647 N-{4-cyciohexyl-2"methyi-pheny!)-4-oxo-1H-quinoiine-3-carboxamide
648 5-hydroxy- 3-[4-!Sopropyl-2-{trif!uorornethyl)phenyi]-4-oxo-1H-quinoline-3-carboxamide
649 N-{2-ethy!-5-hydroxy-4 ert^uty pheny -6 iuoro-4-oxo-1 H-qumoiirie-3-carboxarnide
650 6 iuoro-N-[3-hydroxy-4-(tr!f!uoromethyl)phenyl]-4--oxo-1H-quinoi!ne-3-carboxarrtide
651 N-(4-cycloh8x¾fi-3-hydroxy-phenyS)-6-f!uoro-4-oxo-1H-quirioiine-3-caii30xamide
652 7-hydroxy- -(5-hydroxy-2,4-ditert-butyl-phenyi)-4-oxo-1 H-quinol!ne-3-carboxarr!ide
653 8-ethy!-4-GXG-N-(54ert-buty!-1 H-indoI-6-yi)-1 H-quinoline-3-carboxarrside
654 N-[5-benzytoxy-4-cyctohexy!"2-{trifluoromethyf)pheny!]-4-oxo-1H-quinoline--3-carboxarTiide
{S)- -{4-{3-hydroxypyrrolidin"1-yl)-2-{trifiuoromethy!)phenyl)-4-oxo-1 «4-d!hydroquinonne-3-
655 carboxamids
656 5-fiuoro-4-oxo- -{5-tert-buiyi-1 H-indol-6-yi)-1 H-qu!noline-3-carboxamide
657 6-chioro-N 4-isopropy 2'{tnf!uoromethyi)ph8nyi3-4-oxo-1H-quinoHne-3-Garboxam'ide
658 4-oxo-N-[4-pyrro!idin-1 -yl-2-(trif!uoromethyl}pheny -1 H-quinoSine-S-earboxamide
659 -{2-ethyS-5-hydroxy-4-tert-butyi-phenyi)-4-oxQ-1H-qu!noline-3-carboxamide
(S)-ethy! 1 -{4-{4-GXO-1 s4-dihydroquinoiine-3-carboxam!do)-3-{trifluoromethy phenyI}piperidine-
660 3-carboxyiate
661 5-ET!8thy!-4-oxo-N-[5-{irifluoromethyi}-1H-sndoi-6-y -1H-quSno!Ine-3-carboxamide
662 N-{5-hydroxy-2-tert-butyl-phenyl)-4-oxo-1H-quinoiine-3-carboxamide
663 8-chioro-N-{5-hydroxy-2,4-diter -butyl-phenyl)-4-Gxo-1H-quinoline-3-carboxamide
664 6-fSuoro-4-oxo- -(3-t8ri-butyipheny!}-1H-quinol!ne-3-carboxamide
665 6 iuoro- -{5-hydfoxy-2-iert-buiyl-ph8nyi}-4-oxo-1H-quinoS!ns-3-castioxaiT!ide
666 6 iuoro-N-[3-methoxy-5-{trifluorom8thyS)phenyl]-4-oxo-1H-quinoi!ne-3-carboxarriide
(R)~ H4 4,4-difluQro-2-methylpyrrQiidin-1~y^
667
dihydfoquino!ine-3-carboxamjde
-[4 4-{hydroxymethyI)-1-piperidy -2-{trifii3oromethy!}phenyl]-4-oxo- H-qu
668
carboxamide
iS)~ -{4-{2-methyipyrrQiidin~1-yO^
669
dihydroquinoiine-3-carboxa !de 4833.1
Figure imgf000070_0001
4833.1
Figure imgf000071_0001
[0182] in another embodiment, the present invention provides compounds useful as intermediates in the synthesis of compounds of formula I. in one embodiment, such compounds have formula A-I:
- 70 -
8544833.!
Figure imgf000072_0001
or a salt thereof;
wherein:
Gi is hydrogen, R\ C(0)R\ C(S)R', S(0)R', S(0)2R\ Si(CH3)2R', P(G)(OR')3, P(S)(OR')3, or B(OR')2;
G2 is halo, CN, CF3, isopropyl, or phenyl wherein said isopropyl or phenyl is optionally substituted with up to 3 substituents independently selected from WRW, wherein W and Rw are as defined above for formuia Ϊ and embodiments thereof;
G3 is an isopropyl or a C3-C10 cydoaliphadc ring, wherein said G3 is optionally substituted with up to 3 substituents independently selected from WRW, wherein W and R are as defined above for formula I and embodiments thereof;
provided that when Gj is methoxv, G3 is tert-butyl, then G2 is not 2~ammo-4-metfooxy-5-fi?? - butyl-phenyl.
[0183] in one embodiment, the present invention provides compounds of formula A-I, provided that when G2 and G each is t-butyl, then Gs is not hydrogen.
[0184] In another embodiment:
Gi is hydrogen;
G2 is halo or isopropyl, wherein said isopropyl is optionally substituted with up to 3 substituents independently selected from R'; and
G3 is an isopropyl or a C3-C10 cyeloaSiphatic ring, wherein said G3 is optionally substituted with up to 3 substituents independently selected from R' .
[0185] In another embodimeni:
Gi is hydrogen;
G2 is halo, preferably f!uoro; and
G3 is a C3-C10 cycloaliphatie ring, wherein said Gj is optionally substituted with up to 3 substituents independently selected from methyl, ethyl, propyl, or butyl.
[β186] in another embodiment:
Gj is hydrogen;
G2 is CN, halo, or CF3; and
- 71 -44833.1 G3 is an isopropyl or a C3-C10 cycloaliphatic ring, wherein said G3 is optionally substituted with up to 3 substituents independently selected from R' ,
[0187] In another embodiment:
G; is hydrogen;
G2 is phenyl is optionally substituted with up to 3 substituents independently selected from -OC1-C4 aikyl, CF3, halo, or CN; and
G3 is an isopropyl or a C3-C1Q cycloaliphatic ring, wherein said G3 is optionally substituted with up to 3 substituents independently selected from R\
[0188] Exemplary G¾ include optionally substituted cyclopentyi, cyclohexyl, cyclohepiyi, or adamaniyl. Or, G3 is C3-C8 branched aliphatic chain. Exemplary G3 include isopropyl, t-butyl, 3,3-diethy!-prop-3-yl, or 3,3~diemyl-2,2-dimethyl-prop~3-yl.
[0189] In another embodiment:
Gj is hydrogen;
G2 is t-butyl; and
G3 is a t-butyl,
[0190] in another embodiment, the present invention provides a compound of formula
Α-Π:
Figure imgf000073_0001
or a salt thereof, wherein:
G4 is hydrogen, halo, CN, CF3, CHF2, C¾F, optionally substituted CI -C6 aliphatic, aralkyl, or a phenyl ring optionally substituted with up to 4 WRW substituents;
G5 is hydrogen or an optionally substituted C1-C6 aliphatic;
provided that both, G and G5, are not simultaneously hydrogen;
wherein said indole ring system is further optionally substituted with up to 3 substituents independently selected from WRW.
[0191] in one embodiment, G is hydrogen. Or, G$ is hydrogen.
[0192] In another embodiment, G4 is hydrogen, and G5 is C1-C6 aliphatic, wherein said aliphatic is optionally substituted with C1-C6 aikyl, halo, cyano, or CF3, and wherein up to two methylene units of said C1-C6 aliphatic or C1-C6 aikyl is optionally replaced with - CO-, -CONR'-, -CO2-, -OCO-, -NR'COr, -0-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, - 4 S33. S. NR'-, -SO2NR'-, NR'SO , or -NR'S02NR'-. In another embodiment, R' above is CS-C4 aikyl
[0193] in another embodiment, G is hydrogen, and G5 is cyano, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, cyanomethyl, methoxyethyi, CH2C(0)OMe, (CH2)2- NHC(0)0-terf-But, or cyclopentyl,
[0194] in another embodiment, G5 is hydrogen, and G is halo, C1-C6 aliphatic or phenyl, wherein said aliphatic or phenyl is optionally substituted with C1-C6 aikyl, halo, cyano, or CF3, wherem up to two methylene unite of said C1-C6 aliphatic or C1-C6 aikyl is optionally replaced with -CO-, -CONR'-, -CO2-, -OCO-, ~NR'C02~, -0-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO2NR'-, NR'SOr, or -NR'S02NR'-. in another embodiment, R' above is C1-C4 aikyl.
[M.9S3 In another embodiment, G5 is hydrogen, and G4 is halo, ethoxycarbonyl, t- butyl, 2-methoxyphenyi, 2-ethoxyphenyl, 4-C(0)NH(CH2)2-NMe2, 2-rnethoxy-4-chIoro- phenyl, pyridine-3-yl, 4-isopropylphenyl, 2,6-dimethoxyphenyl, sec-butylaminocarbonyl, ethyl, t-butyl, or piperidin-l-ylcarbonyi.
[©196] in a related embodiment of formula A-II, the nitrogen ring atom of said indole ring is substituted with C1-C6 aliphatic, C(0)(C1-C6 aliphatic), or benzyl, wherein said aliphatic or benzyl is optionally substituted with C1-C6 aikyl, halo, cyano, or CF3, wherein up to two methylene units of said C1-C6 aliphatic or C1-C6 aikyl is optionally replaced with - CO-, -CONR'-, -CO2-, -OCO-, -NR'COr, -0-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, - NR5-, -SO2NR'-, NR'S02-, or ~NR'SQ2NR'~. in another embodiment, R' above is C1-C4 aikyl.
[0197] in another embodiment the nitrogen ring atom of said indole ring is substituted with acyi, benzyl, C(0)CH2N(Me)C(0)CH2NHMe, or ethoxycarbonyl.
[0198] 4, General Synthetic Schemes
[Θ199] Compounds of the present invention are readily prepared by methods known in the art. illustrated below are exemplar methods for the preparation of compounds of the present invention.
[0200] The scheme below illustrates the synthesis of acid precursors of the compounds of the present invention.
[0201] Synthesis of Acid Precursors P-IV-A, P-IV-B or P-IV-C:
- 73 -44833.1 R6=S¾ R6—H R6=CF3
Figure imgf000075_0001
a) iC02Et)2CH ; b) iCG2Et)2CH==CH(OEt); c) CF3C02H, PPh3, CCI4s Et3N; d) Mel; e) PPA or diphesiyiether; f) NaOH.
[0202] Synthesis of Acid Precursors P-IV-A, P~I¥~B or P-IV-C;
Figure imgf000075_0002
a) ACONH4; b) EtOCHC(C02Et)2, 130°C; c) Ph20, ΔΤ; d) I2, EtOH; e) NaOH.
[0203] Synthesis of Acid Precursors P-IV-A, P-IY-B or P-IV-
- 74 - 4833.1
Figure imgf000076_0001
Figure imgf000076_0002
a; c) n- hEi;
$205] Synthesis of Amine Precursor P-1II-A:
Figure imgf000076_0003
(CH3)2S0 ; b) K3Fe(CN)6, NaOH, H20; c) HNG3, H2S04; d) RCOCH3, MeOH, NH3; e) H2, Ns
[0206] Synthesis of Amine Precursor P-IV-A:
Figure imgf000076_0004
Figure imgf000076_0005
[0207] HNO3, HOAc; b) Na2S204, THF/H20; c) H2, Pd/C.
[§2©8] Synthesis of Amine Precursor P-V-A-l:
- 75 -
8544833.1
Figure imgf000077_0001
Figure imgf000077_0002
[©209] KN03, H2S04; b) NaN02, ¾SQ4- H20; c) NHCO2H, Pd-C; d) R'X; e) 2H, Pd-C
[@210] Synthesis of Amine Precursor P-V-A-l:
-76-
Figure imgf000078_0001
Figure imgf000078_0002
Figure imgf000078_0003
Figure imgf000078_0004
Figure imgf000078_0005
Figure imgf000078_0006
a) SO2CI2, R2= CI; b) R20H, R2=¾lkyl; c) NBS, R T; d) CICO2R, TEA; e) HNO3, H2S04; f) base; g) ArB(OH)2, Ri=Br; h) [HJ; I) R'X, RI= Br; j) ClCF2C02Me; k) [HJ; 1) [HJ.
[0211] Synthesis of Amine Precursor P-V-A-1:
Figure imgf000079_0001
Figure imgf000079_0002
H]; c) K 03; d) AcCl; e) [H]; f) i) of Amine Precursor P-V-A-l:
S54S33.1
Figure imgf000080_0001
Figure imgf000080_0002
[0214] HNO3, H2S04; b) [Hj; c) proieciion; d) R'CHO; e) deproieciion; f) [Hj; g) Na2S, S, ¾0; h) nitration; i) (BOQ2O; j) [H]; k) RX; 1) [H]; PG= protecting group
[0215] Synthesis of Amine Precursors P-V-A-l or P-V-A-2:
- 7} - 44833.1
Figure imgf000081_0001
Figure imgf000081_0002
Figure imgf000081_0003
a) Br2; b) Zr¾(CN)2, Pd(PPh)3; c) [H]; d) B¾; e) (BOC)20; f) [H]; g) H20; h) R5X; i) [H]; j) L1AIH4
[©217] Synthesis of Amine Precursors P-V-A-l or P-V~A~2i
Figure imgf000081_0004
Figure imgf000081_0005
(i)NaN02, HCl; ii) Na2S03, CuS04, HCl; b) H4CI; c)
[0218] Synthesis of Amine Precursors P-V-A-l
- SO -
S544S33J
Figure imgf000082_0001
a) CHCbOMe; b) KN03, ¾SG4; c) Deoxo-F!uor; d) Fe
[0219] Synthesis of Amine Precursors P-V-A-3;
Figure imgf000082_0002
Ar ~ Aryi or Heteroaryl
a) Nitration; b) ArB(OH)2, Pd; c) BH3; d) (BOC)20
[0220] Synthesis of Amine Precursors F-V-B-l:
Figure imgf000082_0003
a) AeCl; b) DEAD; c) AICI3; d) NaOH
[0221] Synthesis of Amine Precursors P-V-B-l:
8544833,1
Figure imgf000083_0001
Figure imgf000083_0002
a) ClOfcCOCl; b) [H]; c) protection; d) [H]
PG= protecting group
[0222] Synthesis of Amine Precursors P-V-B-l:
Figure imgf000083_0003
X=F, Ci
Figure imgf000083_0004
- 82 -
8544833.1 [0223] Synthesis of Amine Precursors P-V-B-2:
Figure imgf000084_0001
a) MCh; b) H]; c) i) RiR2CHCOC¾CH2Cl; ii) MaB¾; d) N¾OH; e) DIBAL-H; f) miration; g) protection; h) [H]
PG~ protecting group
[0224] Synthesis of Amine Precursors P-V-B-3:
Figure imgf000084_0002
a) Nitration; b) Protection; c) [H]
PG~ protecting group
[0225] Synthesis of Amine Precursors P-V-B-5:
-83-
8544833. ί
Figure imgf000085_0001
a) when X=C1, Br, Ϊ: RX, K2C03, DMF or C¾CN; when X=GH: RX, TFFH, DiEA, THF b) H2, Pd-C, EtOH or SnCl2.2H20, EiOH or SnCl2.2H20, DIEA, EtOH.
[0226] Synthesis of Amine Precursors P-V-B-5:
Figure imgf000085_0002
a) RCOCl, Et3N, CH2C12; b) n-BuLi, THF; c) aBH4, AcOH; d) KN03, H2S04; e) DDQ, 1,4- dioxane; f) NaN02, HQ, SnCl2.2H20, H20; g) MeCOR, EiOH; h) PPA; i) LiAIfl , THF or ¾, Raney Ni, EtOH or MeOH
- 84 -
85Ψί833.1 [0227] Synthesis of Amine Precursors
Figure imgf000086_0001
a) NaN02, HCI, SnCl2.2H20, ¾0; b) RCH2COR, AcOH, EiOH; c) H3PO4, toluene; d) H2, Pd- C, EiOH
[0228] S desis of Amine Precursors P-V-B-5:
Figure imgf000086_0002
a) NaN02, HCI, SnCl2.2H20, H20; b) RCH2COH, AcOH, EiOH; c) H3PO4, toluene; d) H2, Pd- C, EtOH
- 85 -
8544833.1 [0229] Synthesis of Amine Precursors P-V-B-5;:
Figure imgf000087_0001
a) RX (X=Br, Ϊ), zinc iriflaie, TB AI, DiE A, toluene; b) ¾, Raney Ni, EtOH or ¾, Pd-C, EtOH or SnCl2.2H20, EtOH; c) C1SQ2MCQ, DMF, C¾CN; d) Me?NH, H2CO, AcOH; e) Mel, DMF, THF, ¾0; f) MNu (M= Na, , Li; Nu= nucleophile)
[©230] Synthesis of Amine Precursors P-V-B-5:
Figure imgf000087_0002
a) HN03, H2SO ; b) Me2 CH(OMe)2, DMF; c) H2, Raney Ni, EtOH
■■86 -
5ί544333.ί [0231] Synthesis of Amine Precursors P-V-B-5;
Figure imgf000088_0001
a) When PG= SC¾Ph: PhS02CIs Et3N, DMAP, C¾Q2; When PG~ Ac: AcCl, NaHC03,
CH2C12; b) When fc= RCO: (RCO)20, AIC13, C¾C12; When R~Bn Br2, AcOH; c) HBr or HC1; d) KNO3, H2SO4; e) MnG2, CH2C12 or DDQ, 1,4-dioxane; f) ¾, Raney Ni, EtOH.
;] Synthesis of Amine Precursors P-V-B-5:
Figure imgf000088_0002
a) NBS, DMF; b) KNO3, H2S0 ; c) HOCSiMe3t PdiPPh3hCl2, Cui, Et3N, Toluene, H20; d) Cul, DMF; e) H2, Raney Ni, MeOH
- 87 -
8544833.1 5] Synthesis of Amine Precursors P-V-A-3 and P-V-A-6:
Ar~ Ary! or heteroaryi
Figure imgf000089_0001
a) ArB(OH>2, Pd(PPh3)4, K2CO3, H20, THF or ArB(OH)2, Pd2(dba)3, P{tBu)3, KF, THF
[0234] Synthesis of Amine Precursors P-V-A-4:
Figure imgf000089_0002
R= CN, CG2EI; a) Mel NaOtBu, DMF; b) HCG2K, Pd-C, EtOH or HC02N¾, Pd-C, EtOH
[0235] Synthesis of Amine Precursors P-V-A-4;
Figure imgf000089_0003
, Pd(OAc)2, PS-PPh.3, K2C03, DMF
[0236] Synthesis of Amine Precursors P-V-B-4;
Figure imgf000089_0004
- 88 -
8544833. J a) H2, Pd-C, MeOH
[0237] Synthesis of Amine Precursors P-V-B-4:
Figure imgf000090_0001
a) NaBH4, MeOH; b) H2, Pd-C, MeOH; c) NH2OH, Pyridine; d) H2, Pd-C, MeOH; e) Boc20,
Figure imgf000090_0002
[0238] Synthesis of Compounds of Formula Ϊ:
Figure imgf000090_0003
a) ATIR7NH, couplixig reagent, base, solvent. Examples of conditions used:
HATO, DiEA; BOP, DIEA, DMF; HBTU, Et3N, CH2C12; PFPTFA, pyridine.
[0239] Synthesis of Compounds of Formula Γ :
Figure imgf000090_0004
R5 = aliphatic: a) R5X (X= Br, Ϊ), Cs2C03, DMF
- 89 -
8544833.! [§240] Syniheis of Compounds of formula V-B-5:
Figure imgf000091_0001
a) NaOH, THF; b) HNR2, HATU, DIEA, DMF
[0241] Syniheis of Compounds of formula V-B-5:
Figure imgf000091_0002
WK.W = aryl or heteroaryl: a) ArB(OH)2s (dppf)PdCl2, K2C03, DMF
- 90 -
8544833.1 [0242] Synthesis of Compounds of Formula V-A-2 & V-A-S:
Figure imgf000092_0001
a) SnCl2.2¾G, EtOH; b) PG= BOC: TFA, CH2C12; c) CH20, NaBH3C , C¾Ci2, MeOH; d) RXCl, DIEA, Tiff or SXCl, NMM, 1 ,4-dioxane or RXCl, CH2CS2, DMF; e) R'R"NH, LiClO, CH2C12, iPrOH
~ 91 ~
8544833.! [Θ243] Synthesis of compounds of formula V-B-2;
Figure imgf000093_0001
a) When PG = BOC: TFA, CH2CI2; When PG = Ac: NaOH or HC1, EiOH
[0244] Synthesis of compounds of formula V-A-2:
Figure imgf000093_0002
a) When PG = BOC: TFA, C¾ ¾
Figure imgf000093_0003
a) When PG = BOC: TFA, CH2C12; b) ROCOC1, EtjN, DMF
(245] Synthesis of compounds of formula V-A-4:
- 92 -
8544833. t
Figure imgf000094_0001
a)When PG = BOC: TFA, C¾C12; b) When Rw - C02R: ROCOC1, DIEA, MeOH
[0246] In the schemes above, the radical employed therein is a substiruent, e.g., R as defined hereinabove. One of skill in the art will readily appreciate that synthetic routes suitable for various substituents of the present invention are such that the reaction conditions and steps employed do not modify the intended substituents.
[0247] 5, Uses, Formulation and Administration
[Θ248] Pharmaceutically acceptable compositions
[©249] As discussed above, the present invention provides compounds that are useful as modulators of ABC transporters and thus are useful in the treatment of disease, disorders or conditions such as cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulatioiv-fibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia. Type 1 chylomicronemia, ahetalipoprotememia, lysosomal storage diseases, such as I-ce!l disease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy/hyperinsulemia, Diabetes mellitus, Laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1 , congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), neurophyseal DI, neprogenic DJ, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as AlzheimeR's disease, Parkinson's disease, amyotrophic lateral scierosis, progressive supranuclear plasy. Pick's disease, several polyglutamine neurological disorders asuch as Huntington, spinocerebellar ataxia type Ϊ, spinal and bulbar muscular atrophy, dentatombal pallidoiuysian, and myotonic
■· 93 -
8544833.1 dystrophy, as well as spongiform encephalopathies, such as hereditary Creuizfeldt-Jakob disease (due to prion protein processing defect), Fabry disease, Siraussler-Scheinker syndrome, COPD, dry-eye disease, or Sjogren's disease,
[0250] Accordingly, in another aspect of the present invention, pharmaceutically acceptable compositions are provided, wherein these compositions comprise any of the compounds as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents.
[0251] it will also be appreciated that certain of the compounds of present invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative or a prodrug thereof. According to the present invention, a pharmaceutically acceptable derivative or a prodrug includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a patient in need thereof is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof,
[02S2] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit risk ratio. A "pharmaceuticaily acceptable salt" means any non-toxic salt or salt of an ester of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof.
[0253J Pharmaceuticaily acceptable salts are well known in the art. For example, S, M. Berge, et L describe pharmaceutically acceptable salts in detail in /. Pharmaceutical
Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsuifate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate,
- 94 -44833.1 gluconate, he nisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, rnalate, maleate, malonate, methanesuSfonate, 2- naphthalenesulfonate, nicotinate, iiitrate, oleaie, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenyIpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thsocyanate, ρ-toluenesulforsate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Ci-4aiky¾ salts. This invention also envisions the quatemizaiion of any basic nitrogen- containing groups of the compounds disclosed herein. Water or oil-soluble or dispersable products may be obtained by such quatemization. Representative alkali or alkaline earth metai salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralky! sulfonate and aryl sulfonate.
[§254] As described above, the pharmaceutically acceptable compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to die particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating
pharmaceutically acceptable compositions and known techniques for the preparation thereof . Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other components) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, poiyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as com starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and
- 95 -44833. J cellulose acetate; powdered tragacanih; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; saffiower oil; sesame oil; olive oil; com oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; algimc acid; pyrogen-free water; isotonic saline; RingeR's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non- toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be presen in the composition, according to the judgment of the formulator,
[025S] Uses qf Compounds and Pharmaceutically Acceptable Compositions
[©256] In yet another aspect, the present invention provides a method of treating or lessening the severity of a condition, disease, or disorder implicated by CFTR mutation, in certain embodiments, the present invention provides a method of treating a condition, disease, or disorder implicated by a deficiency of the CFTR activity, the method comprising administering a composition comprising a compound of Formula (I) to a subject, preferably a mammal, in need thereof.
[0257] Jn certain embodiments, the present invention provides a method of treating diseases associated with reduced CFTR function due to mutations in the gene encoding CFTR or environmental factors (e.g., smoke). These diseases include, cystic fibrosis, chronic bronchitis, recurrent bronchitis, acute bronchitis, male infertility caused by congenital bilateral absence of the vas deferens (CBAVD), female infertility caused by congenital absence of the uterus and vagina (CAUV), idiopathic chronic pancreatitis (ICP), idiopathic recurrent pancreatitis, idiopathic acute pancreatitis, chronic rhinosinusitis, primary sclerosing cholangitis, allergic bronchopulmonary aspergillosis, diabetes, dry eye, constipation, allergic bronchopulmonary aspergillosis (ABPA), bone diseases (e.g., osteoporos s), and asthma.
[§258] in certain embodiments, the present invention provides a method for treating diseases associated with normal CFTR function. These diseases include, chronic obstructive pulmonary disease (COPD), chronic bronchitis, recurrent bronchitis, acute bronchitis, rhinosinusitis, constipation, pancreatitis including chronic pancreatitis, recurrent pancreatitis, and acute pancreatitis, pancreatic insufficiency, male infertility caused by congenital bilateral absence of the vas deferens (CBAVD), mild pulmonary disease, idiopathic pancreatitis, liver disease, hereditary emphysema, gallstones, gasgtro-esophageal reflux disease, gastrointestinal
- 96 -4 S33.1 malignancies, inflammatory bowel disease, constipation, diabetes, arthritis, osteoporosis, and osteopenia.
[0259] in certain embodiments, the present, invention provides a method for treating diseases associated with normal CFTR function including hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-cell disease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Saehs, Crigler-Najjar type Π, polyendocrinopathy hyperinsulemia, Diabetes mellitus, Laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), neurophyseal Di, neprogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, several polyglutamine neurological disorders such as Huntington's, spinocerebullar ataxia type I, spinal and bulbar muscular atrophy, dentatorubai pallidoluysian, and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Creutzfeldt- Jakob disease (due to prion protein processing defect), Fabry disease, Straussler-Scheinker syndrome, Gorham's Syndrome, chloride channelopathies, myotonia congenita (Thomson and Becker forms), Barrier's syndrome type ill. Dent's disease, hyperekplexia, epilepsy, hyperekplexia, lysosomal storage disease, Angelman syndrome, Primary Ciliary Dyskinesia (PCD), PCD with situs inversus (also known as Kartagener syndrome), PCD without situs inversus and ciliary aplasia, or Sjogren's disease, comprising the step of administering to said mammal an effective amount of a composition comprising a compound of the present invention.
[026©] According to an alternative preferred embodiment, the present invention provides a method of treating cystic fibrosis comprising the step of administering to said mammal a composition comprising the step of administering to said mammal an effective amount of a composition comprising a compound of the present invention.
[0261] According to the invention an "effective amount" of the compound or pharmaceutically acceptable composition is that amount effective for treating or lessening the severity of one or more of the diseases, disorders or conditions as recited above,
[0262] The compounds and compositions, according to the method of the present invention, may be administered using any amount and any route of administration effective for
- 97 -44833.1 treating or lessening the severity of one or more of the diseases, disorders or conditions as recited above.
[0263] In certain embodiments, the compounds and compositions of the present invention are useful for treating or lessening the severity of cystic fibrosis in patients who exhibit residual CFTR activity in the apical membrane of respiratory and non-respiratory epithelia. The presence of residual CFTR activity at the epithelial surface can be readily detected using methods known in the art, e.g., standard electrophysiological, biochemical, or histochemical techniques. Such methods identify CFTR activity using in vivo or ex vivo electrophysiological techniques, measurement of sweat or salivary CI" concentrations, or ex vivo biochemical or histochemical techniques to monitor cell surface density. Using such methods, residual CFTR activity can be readily detected in patients heterozygous or homozygous for a variety of different mutations, including patients homozygous or heterozygous for the most common mutation, ΔΡ508.
[0264] In another embodiment, the compounds and compositions of the present invention are useful for treating or lessening the severity of cystic fibrosis in patients who have residual CFTR activity induced or augmented using pharmacological methods or gene therapy. Such methods increase the amount of CFTR present at the cell surface, thereby inducing a hitherto absent CFTR activity in a patient or augmenting the existing level of residual CFTR activity in a patient.
[Θ265] In one embodiment, the compounds and compositions of the present invention are useful for treating or lessening the severity of cystic fibrosis in patients within certain genotypes exhibiting residual CFTR activity, e.g.. class III mutations (impaired regulation or gating), class IV mutations (altered conductance), or class V mutations (reduced synthesis) (Lee R. Choo-Kang, Pamel a L., Zeitlin, Type I II, HI, IV, and V cystic fibrosis Tansmembrane Conductance Regulator Defects and Opportunities of Therapy; Current Opinion in Pulmonary Medicine 6:521 - 529, 2000). Other patient genotypes that exhibit residual CFTR activity- include patients homozygous for one of these classes or heterozygous with any other class of mutations, including class I mutations, class II mutations, or a mutation that lacks
classification.
[0266] In one embodiment, the compounds and compositions of the present invention are useful for treating or lessening the severity of cystic fibrosis in patients within certain clinical phenotypes, e.g., a moderate to mild clinical phenotype that typically correlates with the amount of residual CFTR activity in the apical membrane of epithelia. Such phenotypes
- 98 -
85 4S33.1 include patients exhibiting pancreatic insufficiency or patients diagnosed with idiopathic pancreatitis and congenital bilateral absence of the vas deferens, or mild lung disease,
[0267] The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. The compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "dosage unit form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated, it will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human.
[0268] The pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops or patch), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
[0269] Liquid dosage forms for oral administration include, but are not. limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs, in addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, soiubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyIene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols ar d fatty acid esters of sorbitan, and mixtures
- 99 -44833,1 thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
[0270] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution, in addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglyeerides. in addition, fatty acids such as oleic acid are used in the preparation of injectables.
[027IJ The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
[0272] in order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-poiyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
[0273] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are
- 100 -44833. S solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vagina! cavity and release the active compound,
[0274] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules, in such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof, in the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
[0275] Solid compositions of a similar type may also b employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certai part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like,
[0276] The active compounds can also be in microencapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrysta!Sine cellulose. In the case of capsules, tablets and
- 10! -44833.1 pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferential ly, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can he used include polymeric substances and waxes.
[0277] Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms are prepared by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
[©278] As described generally above, the compounds of the invention are useful as modulators of ABC transporters. Thus, without wishmg to be bound by any particular theory, the compounds and compositions are particularly useful for treating or lessening the severity of a disease, condition, or disorder where hyperactivity or inactivity of ABC transporters is implicated in the disease, condition, or disorder. When hyperactivity or inactivity of an ABC transporter is implicated in a particular disease, condition, or disorder, the disease, condition, or disorder may also be referred to as a "ABC transporter-mediated disease, condition or disorder". Accordingly, in another aspect, the present invention provides a method for treating or lessening the severity of a disease, condition, or disorder where hyperactivity or inactivity of an ABC transporter is implicated in fee disease state.
[Θ279] The activity of a compound utilized in this invention as a modulator of an ABC transporter may be assayed according to methods described generally in the art and in the Examples herein.
[©280] It will also be appreciated that the compounds and pharmaceutically acceptable compositions of the present invention can be employed in combination therapies, that is, the compounds and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a
- 102 -44833.1 combination regimen will take into account compatibility of the desired therapeutics and/or proceduies and the desired therapeutic effect to be achieved, it will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated".
[0281] In one embodiment, the additional agent is selected from a mucolytic agent, bronchodialator, an anti-biotie, an anti-infective agent, an anti-inflammatory agent, a CFTR modulator other than a compound of the present invention, or a nutritional agent. In a further embodiment, the additional agent is a CFTR modulator other than a compound of the present invention.
[©282] in one embodiment, the additional agent is an antibiotic. Exemplary antibiotics useful herein include tobramycin, including tobramycin inhaled powder (TIP), azithromycin, aztreonam, including the aerosolized form of aztreonam, amikacin, including liposomal formulations thereof, ciprofloxacin, including formulations thereof suitable for administration by inhalation, levoflaxacin, including aerosolized formulations thereof, and combinations of two antibiotics, e.g., fosfomycin and tobramycin.
[0283] in another embodiment, the additional agent is a mucolyte. Exemplary mucolytes useful herein includes Pulmozyme®.
[0284J in another embodiment, the additional agent is a bronchodialator. Exemplary bronchodia!tors include albuterol, metaprotenerol sulfate, pirbuterol acetate, salmeterol, or tetrabulme sulfate.
[0285] in another embodiment, th additional agent is effective in restoring lung airway surface liquid. Such agents improve the movement of salt in and out of cells, allowing mucus in the lung airway to be more hydrated and, therefore, cleared more easily. Exemplary such agents include hypertonic saline, denufosol tetrasodium ([[(3S,5R)-5-(4-amino-2- oxopyrimidin- 1 -yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[{2R,3S,4R,5R)~5- (2,4-dioxopyritnidin-l-yl)-3, 4-dihydroxyoxoIan-2-yi]methoxy-hydroxyphosphoryl]oxy- hydroxyphosphoryl] hydrogen phosphate), or bronchitol (inhaled formulation of manrdtol).
[0286] In another embodiment, the additional agent is an anti-inflammatory agent, i.e., an agent that can reduce the inflammation in the lungs. Exemplary such agents useful herein
- 103 -4 S33.1 include ibuprofen, doeosahexanoic acid (DHA), sildenafil, inhaled glutathione, piogiitazone, hydroxychloroquine, or simavastatin.
[0287] in another embodiment, the additional agent reduces the activity of the epitiielial sodium channel blocker (ENaC) either directly by blocking the channel or indirectly by modulation of proteases that lead to an increase in ENaC activity (e.g., seine proteases, channel-activating proteases). Exemplary such agents include camostat (a trypsin-like protease inhibitor), QAU14S, 552-02, GS-9411, ING-4995, Aerolytic, and amiloride.
Additional agents that reduce the activity of the epithelial sodium channel blocker (ENaC) can be found, for example in PCX Publication No. WO2009/074575, the entire contents of which are incorporated herein in their entirety.
[0288] Amongst other diseases described herein, combinations of CFTR modulators, such as compounds of Formula I, and agents that reduce the activity of ENaC are use for treating Liddle's syndrome, an inflammatory or allergic condition including cystic fibrosis, primary ciliary dyskinesia, chronic bronchitis, chronic obstructive pulmonary disease, asthma, respiratory tract infections, lung carcinoma, xerostomia and keratoconjunctivitis sire, respiratory tract infections (acute and chronic; viral and bacterial) and lung carcinoma.
[0289] Combinations of CFTR modulators, such as compounds of Formula I, and agents that reduce the activity of ENaC are also useful for treating diseases mediated by blockade of the epithelial sodium channel also include diseases other than respiratory diseases that are associated with abnormal fluid regulation across an epithelium, perhaps involving abnormal physiology of the protective surface liquids on their surface, e.g., xerostomia (dry mouth) or keratoconjunctivitis sire (dry eye). Furthermore, blockade of the epithelial sodium channel in the kidney could be used to promote diuresis and thereby induce a hypotensive effect.
[0290] Asthma includes both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma induced following bacterial infection. Treatment of asthma is also to be understood as embracing treatment of subjects, e.g., of less than 4 or 5 years of age, exhibiting wheezing symptoms and diagnosed or diagnosable as "wheezy infants", an established patient category of major medical concern and now often identified as incipient or early-phase asthmatics. (For convenience this particular asthmatic condition is referred to as "wheezy-infant syndrome" .) Prophylactic efficacy in the treatment of asthma will be evidenced by reduced frequency or severity of symptomatic attack, e.g., of acute astiimatic or bronchoconstrictor attack, improvement in lung function or improved airways
- 104 -44833.1 hyperreactivity. It may further be evidenced by reduced requirement for other, symptomatic therapy, i.e., therapy for or intended to restrict or abort symptomatic attack when it occurs, e.g., anti-inflammatory (e.g., cortico-steroid) or bronchodilatory. Prophylactic benefit in asthma may, in particular, be apparent in subjects prone to "morning dipping". "Morning dipping" is a recognized asthmatic syndrome, common to a substantial percentage of asthmatics and characterized by asthma attack, e.g., between the hours of about 4-6 am, i.e., at a time normally substantially distant from any previously administered symptomatic asthma therapy.
[0291] Chronic obstructive pulmonary disease includes chronic bronchitis or dyspnea associated therewith, emphysema, as well as exacerbation of airways hyperreactivity consequent to oilier drug therapy, in particular, other inhaled drug therapy. In some embodiments, the combinations of CFFR modulators, such as compounds of Formula I, and agents that reduce the activity of ENaC are useful for the treatment of bronchitis of whatever type or genesis including, e.g., acute, arachidic, catarrhal, croupus, chronic or phthinoid bronchitis.
[0292] in another embodiment, the additional agent is a CFI'R modulator other than a compound of formula I, i.e., an agent that has the effect of modulating CFTR activity.
Exemplary such agents include ataluren ("PTC 124®"; 3-[5-(2-fluorophenyl)-l,2,4-oxadiazol- 3-yl]benzoic acid), sinapultide, iancovutide, depelestat (a human recombinant neutrophil elastase inhibitor), cobiprostone (7-{(2R, 4aR, 5R, 7aR)-2-[(3S)-l,l-difluoro-3-methylpentyl]- 2-hydroxy-6-oxooctahydrocyclopenta[b]pyran-5-y!}heptanoic acid), or (3-(6-( 1 -(2,2- difluoroberizofd] [ i ,3]dioxol~5-yl) cyclopropanecar!x>xamido)-3-memylpyridm-2-yI)benzoic acid. In another embodiment, the additional agent is (3-(6~(i~(2,2-difluorobenzo[d][l,33dioxol- 5-yi) cyclopropanecarboxamido)-3-meihyipyridin-2-yI)benzoic acid.
[0293] In another embodiment, the additional agent is a nutritional agent Exemplary such agents include pancrelipase (pancreating enzyme replacement), including Pancrease®, Pancreacarb®, Ultrase®, or Creon®, Liprotomase® (formerly Trizytek®), Aquadeks®, or glutathione inhalation. In one embodiment, the additional nutritional agent is pancrelipase.
[0294] The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of additional tiierapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
- 105 -44833.1 [©295] The compounds of this Invention or pharmaceutically acceptable compositions thereof may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Accordingly, the present invention, in another aspect, includes a composition for coating an implantable device comprising a compound of the present invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device, in still another aspect, the present invention includes an implantable device coated with a composition comprising a compound of the present invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. Suitable coatings and the general preparation of coated implantable devices are described in US Patents 6,099,562; 5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosi!icone, polysaccarides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.
[©296] Another aspect of the invention relates to modulating ABC transporter activity in a biological sample or a patient (e.g., in vitro or in vivo), which method comprises administering to the patient, or contacting said biological sample with a compound of formula I or a composition comprising said compound. The term "biological sample", as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
[0297] Modulation of ABC transporter activity, e.g., CFTR, in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, the study of ABC transporters in biological and pathological phenomena; and the comparative evaluation of ne modulators of ABC transporters.
[0298] in yet another embodiment, a method of modulating activity of an anion channel in vitro or in vivo, is provided comprising the step of contacting said channel with a compound of formula (I), In preferred embodiments, the anion channel is a chloride channel or a bicarbonate channel, in other preferred embodiments, the anion channel is a chloride channel.
■ 106 -44833. Ί [©299] According to an alternative embodiment, the present invention provides a method of increasing the number of functional ABC transporters in a membrane of a cell, comprising the step of contacting said cell with a compound of formula (I). The term
"functional ABC transporter" as used herein means an ABC transporter that is capable of transport activity. In preferred embodiments, said functional ABC transporter is CFTR.
[03CW] According to another preferred embodiment, the activity of the ABC transporter is measured by measuring the transmembrane voltage potential. Means for measuring the voltage potential across a membrane in the biological sample may employ any of the known methods in the art, such as optical membrane potential assay or other electrophysiological methods.
[0301] The optical membrane potential assay utilizes voltage-sensitive FRET sensors described by Gonzalez and Tsien (See, Gonzalez, J. E. and R. Y. Tsien (1995) "Voltage sensing by fluorescence resonance energy transfer in single ceils" Biophys J 69(4): 1272-80, and Gonzalez, J. E. and R. Y. Tsien (1997) "improved indicators of cell membrane potential that use fluorescence resonance energy transfer" Chein Biol 4(4): 269-77) in combination with instrumentation for measuring fluorescence changes such as the Voltage/ion Probe Reader (VIPR) (See, Gonzalez, J. E., K. Oades, et al. (S 99) "Cell-based assays and instrumentation for screening ion-channel targets" Drug Discov Today 4(9): 431-439).
[03Θ2] These voltage sensitive assays are based on the change in fluorescence resonant energy transfer (FRET) between the membrane-soluble, voltage-sensitive dye, DiSBAC2(3), and a fluorescent phospholipid, CC2-DMFE, which is attached to the outer leaflet of the plasma membrane and acts as a FRET donor. Changes in membrane potential (Vm) cause the negatively charged DiSB AC>(3) to redistribute across the plasma membrane and the amount of energy transfer from CC2-DMPE changes accordingly. The changes in fluorescence emission can be monitored using VIPR™ Π, which is an integrated liquid handler and fluorescent detector designed to conduct cell-based screens in 96- or 384-well microtiter plates.
[©303] In another aspect the present invention provides a kit for use in measuring the activity of a ABC transporter or a fragment thereof in a biological sample in vitro or in vivo comprising (i) a composition comprising a compound of formula (I) or any of the above embodiments; and (ii) instructions for a) contacting the composition with the biological sample and b) measuring activity of said ABC transporter or a fragment thereof. In one embodiment, the kit further comprises instructions for a) contacting an additional composition with the biological sample; b) measuring the activity of said ABC transporter or a fragment thereof in the presence of said additional compound, and c) comparing the activity of the ABC
■■ 107 -44833.1 transporter in the presence of the additional compound with t!ie density of the ABC transporter in the presence of a composition of formula (I), In preferred embodiments, the kit is used to measure the density of CFTR,
[Θ3Θ4] In order that the invention described herein may be snore fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner.
EXAMPLES
[03§5] Example I :
[0306] General scheme to prepare Acid Moi ies:
Figure imgf000109_0001
a) 140-150 °C; b) PPA, PG(¾, 70 °C or diphenyl ether, 220 °C; c) i) 2N NaOH ii) 2N HCS
[§307] S ecific exam le: 2-PheiiyEmnlBometfaylene-maloiiic add dieth l ester
Figure imgf000109_0002
A mixture of aniline (25.6 g, 0.28 mol) and dietliyl 2-(ethoxymethylerie)maionate (62.4 g, 0.29 moi) was heated at 140-150 °C for 2 h. The mixture was cooled to room temperature and dried under reduced pressure to afford 2-phenylaminomethyiene-malonic acid dietliyl ester as a solid, which was used in the next step without further purification. Ή NM ( -DMSO) 8 11.00 (d, 1H), 8.54 (d, 7 = 13.6 Hz, 1H), 7.36-7.39 (m, 2H), 7.13-7.17 (m, 3 H), 4.17-4.33 (m, 4H), 1.18- 1.40 (m, 6H).
[©3§8] 4-HydroxyqataoHae-3-£arboxylk acid ethyl ester
A I L three-necked flask fitted with a mechanical stirrer was charged with 2- phenylaminomethylene-malonic acid diethyl ester (26.3 g, 0.1 moi), poiyphosphoric acid (270 g) and phosphoryl chloride (750 g). The mixture was heated to about 70 °C and stirred for 4 h. The mixture was cooled to room temperature, and filtered. The residue was treated with aqueous N COi solution, filtered, washed with water and dried. 4-Hydroxyquinoline-3-carboxyiic acid
- 108 -
8544833.! ethyl ester was obtained as a pale brown solid (15.2 g, 70 %). Be crude product was used in next step without further purification.
[0309] A-l; 4-Oxo-l,4-dlhydrcjqitiiioi!ne-3-cgrboxyIk acid
4-Hydroxyquinoline-3-carboxylic acid ethyl ester (15 g, 69 mmol) was suspended in sodium hydroxide solution (2N, 150 mL) and stirred for 2 h under reflux. After cooling, the mixture was filtered, and the filtrate was acidified to pH 4 with 2N HCL The resulting precipitate was collected via filtration, washed with water and dried under vacuum to give 4-oxo-l,4- dihydroquinoline-3-carboxylic acid (A-l) as a pale white solid (10.5 g, 92 %). !H NMR (d- DMSO) 515.34 (s, 1 H), 13.42 (s, 1 H), 8.89 (s, 1H), 8.28 (d, J = 8.0 Hz, 1H), 7.88 (m, 1 H), 7.81 (d, J = 8.4 Hz, 1H), 7.60 (m, 1H).
[0310] Specific Example: -2 6-FMoro-4-hydrosy-qaiaoIiise-3-£arbosyllc acid
Figure imgf000110_0001
6-Ruorc~4~hydroxy~qumoline-3-carboxyIic acid (A-2) was synthesized following the general scheme above starting from 4-fiuoro-phenylamine. Overall yield (53 %). Ή NMR (DMSO-<¾) δ 15.2 (br s, 1 H), 8.89 (s, 1 H), 7.93-7.85 (m, 2 H), 7.80-7.74 (m, 1 H); ESI-MS 207.9 m z (MH+).
[0311] Example 2x
Figure imgf000110_0002
109
8544833.1 [0312] 2~Brom0-5-s ei o¾y-phesyIamiae
A mixture of l-bromo-4-methoxy-2-nitro-benzene (10 g, 43 mmoi) and Raney Ni (5 g) in ethanol (100 mL) was stirred under ¾ (1 atm) for 4 h at room temperature. Raney Ni was filtered off and the filtrate was concentrated under reduced pressure. The resulting solid was purified by column chromatography to give 2-bromo-5-niethoxy-pSienyiamine (7.5 g, 86 %).
[§313] 2~[(2~Br©mo~5~meth sy-pheEyismmo)-meihyk¾e]->mal©ak add diethyl ester
A mixture of 2~bromo-5-methoxy~phenylamine (540 nig, 2,64 mmol) and diethyl 2- (ethoxymethylene)malonate (600 mg, 2.7 mmoi) was stirred at 100 °C for 2 h. After cooling, the reaction mixture was reerystallized from methanol (10 inL) to give 2~[(2-bromo~5~methoxy- phenyl amino)-methylene]-maIonic acid diethyl ester as a yellow solid (0.8 g, 81 %).
[§314] 8~Br0m -5-meiho¾y-4-∞o-l,4-dihydro-q ij.i©Iffle--3-carboxylie acid ethyl ester
2-[(2-Bromo-5-methoxy~phenylamino)-methylene]-malonic acid diethyl ester (9 g, 24.2 mmol) was slowly added to polyphosphoric acid (30 g) at 120 °C. The mixture was stirred at this temperature for additional 30 min and then cooled to room temperature. Absolute ethanol (30 mL) was added and the resulting mixture was refluxed for 30 min. The mixture was basified with aqueous sodium bicarbonate at 25 °C and extracted with EtOAc (4 x 100 mL). The organic layers were combined, dried and the solvent evaporated to give 8-bromo 5-niethoxy~4~oxo-l ,4~ dihydro-qumoline-3-carboxylic acid ethyl ester (2.3 g, 30 ).
[©315] S-Meth0xy-4-oso-l,4-dihydrO"qam Mae-3-carij0xyIk acid ethyl ester A mixture of 8-bromo-5-methoxy-4-oxo-l,4-dihydro-quinolme-3-carboxylic acid ethyl ester (2.3 g, 7.1 mmol), sodium acetate (580 mg, 7.1 mmol) and 10 % Pd C (100 mg) in glacial acetic acid (50 mL) was stirred under ¾ (2.5 atm) overnight. The catalyst was removed via filtration, and the reaction mixture was concentrated under reduced pressure. The resulting oil was dissolved in 0¾ί¾ (100 mL) and washed with aqueous sodium bicarbonate solution and water. The organic layer was dried, filtered and concentrated. The crude product was purified by column chromatography to afford 5-methoxy™4-oxo-l,4-dihydro-quinoline-3-carboxylic acid ethyl ester as a yellow solid (1 g, 57 %).
- 1 10 -
854 S33.1 [Θ316] A-4; 5-Methoxy-4~oxo-l, 4-dihydro-quiBe!iae-3-earboxyHc aeid
A mixture of 5-methoxy-4-oxo-l, 4-dihydro-quinoline-3-carboxylic acid ethyl ester (1 g, 7.1 mmoi) in 10% NaOH solution (50 mL) was heated to reflux overnight and then cooled to room temperature. The mixture was extracted with ether. The aqueous phase was separated and acidified with cone. HQ solution to pH 1-2, The resulting precipitate was collected by filtration to give 5-methoxy-4-oxo-l, 4-dihydro-q inoline-3-carboxylic acid (A~4) (530 mg, 52 ), !H NMR (DMSO) δ: 15.9 (s, 1 H), 13.2 (br, 1 H), 8.71 (s, 1 H), 7.71 (t, J ~ 8.1 Hz, 1 H), 7.18 (d, J = 8.4 Hz, 1 H), 6.82 (d, J = 8,4 Hz, 1 H), 3.86 (s, 3 H); ESi-MS 219.9 m/z (MH+).
[©317] Example 3t
Figure imgf000112_0001
A-16
[Θ318] Sodium 2-(mereapio-pheoyIamiiio-rrseihvle e)-malossk add diethyl ester To a suspension of NaH (60% in mineral oil, 6 g, 0.15 mol) in Et20 at room temperature was added dropwise, over a 30 minutes period, ethyl malonate (24 g, 0,15 mol). Phenyl
isothiocyanate (20.3 g, 0.15 mol) was then added dropwise with stirring over 30 min. The mixture was refluxed for 1 h and then stirred overnight at room temperature. The solid was separated, washed with anhydrous ether (200 mL), and dried under vacuum to yield sodium 2- (mercapto-phenylamino-methylene)-malomc acid diethyl ester as a pale yellow powder (46 g, 97 %).
[0319] 2-(MefhylsaIfaEyl-pheHylamlEO-methyIeiJe)- aloKk add diethyl ester Over a 30 min period, methyl iodide (17.7 g, 125 mmol) was added dropwise to a solution of sodium 2-(mercapto-phenylamino-methyiene)-malonic acid diethyl ester (33 g, 104 mmol) in DMF (100 mL) cooled in an ice bath. The mixture was stirred at room temperature for 1 h, and then poured into ice water (300 mL). The resulting solid was collected via filtration, washed
- l i t -
S5 S33.i. with water and dried to give 2-(methyisulfanyl-phenylamino-raeihylene)-maIonic acid diethyl ester as a pale yellow solid (27 g, 84 %).
[0320] 4-Hydr0xy-2-iMethyiseIfa yl-q siTOliiie-3-earboxyMc add ethyl ester A mixture of 2-(methylsulfaiwI-phenyla vino-met y]ene)-malorsic acid diethyl ester (27 g, 87 mmol) in 1,2-dicMorobenzene (100 mL) was heated to reflux for 1.5 h. The solvent was removed under reduced pressure and the oily residue was triturated with hexane to afford a pale yellow solid that was purified by preparative HPLC to yield 4~hydroxy~2-methylsulfanyl- quinoline-3-carboxylic acid ethyl ester (8 g, 35 %).
[0321] A-16 2-MethyIs fe»yl~4~oxo-l,4«dihydro--i iM0liBe-3--carboxylk add 4-Hydroxy~2~mefhylsidfanyi-quinoIme-3 arboxyiie acid ethyl ester (8 g, 30 mmol) was heated under reflux in NaOH solution (10%, 100 mL) for 1 ,5 h. After cooling, the mixture was acidified with concentrated HQ to pH 4. The resulting solid was collected via filtration, washed with water (100 mL) and MeOH (100 mL) to give 2~metliyIsulfanyl-4-oxo~l,4-dihydro- quinoline-3-carboxylic acid (A-16) as a white solid (6 g, 85 ). lH NMR (CDCI3) δ 16.4 (br s, 1 H). 1 1.1 (br s, 1 H), 8.19 (d, 7 = 8 Hz, !H), 8.05 (d, J - 8 Hz, 1H), 7.84 (t, / = 8, 8 Hz, 3H), 7.52 (t, 7 = 8 Hz, SH), 2,74 (s, 3H); ESI-MS 235.9 mJz (MH*).
[©322] Example 4;
Figure imgf000113_0001
A-15 a) PPh3, Et3N, CCU, CF3C02H; b) diethyl ma!onate; c) T~ 200°C; d) 10% NaOH
[0323] 2,2,2~Triil ioro-N-ph€iiyI-ae©tiniidoyI cMorMe
A mixture of Ph3P (138.0 g, 526 mmol), Et3N (21.3 g, 211 mmol), CC14 (170 mL) and TFA (20 g, 175 mmol) was stirred for 10 min in an ice-bath. Aniline (19.6 g, 21 mmol) was dissolved in CCI4 (20 mL) was added. The mixture was stirred at reflux for 3 h. The solvent was removed under vacuum and hexane was added. The precipitates (Ph3PO and Ph3P) were filtered off and washed with hexane. The filtrate was distilled under reduced pressure to yield 2,2,2-trifluoro-iV- phenyl-acetimidoyl chloride (19 g), which was used in the next step without further purification.
- ί 12 -
8544833.1 [0324] 2-(2A2-Trittaoro-l-p eEyllniifflo~eihyl)-maloBk acid diethyl ester
To a suspension of NaH (3.47 g, 145 mmol, 60 % in mineral oil) in THF (200 mL) was added diethyl nialonate (18.5 g, 116 mmol) at.0 °C. The mixture was stirred for 30 rain at this temperature and 2,2,2~trifluoro-N-phenyl-acetiniidoyl chloride (19 g, 92 mmol) was added at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was diluted with CH2CI2, washed with saturated sodium bicarbonate solution and brine. The combined organic layers were dried over Na2S04, filtered and concentrated to provide 2- (2,2,2-trifluoro-l-phenyiimino-ethyl)-malonic acid diethyl ester, which was used directly in the next step without further purification.
[0325] 4-Hydrosy-2-irfflHoromethyi-quMoIiHe-3-carbosylie add ethyl ester 2-(2,2,2"Trifluoro-l-phenySimino-etSiyl)-malonic acid diethyl ester was heated at 210 °C for 1 h with continuous stirring. The mixture was purified by column chromatography (petroleum ether) to yield 4-hydroxy-2-trifluorornethyl-quinoline-3-carboxylic acid ethyl ester (12 g, 24 % over 3 steps),
[©326] A-15; 4-Hydroxy~2-irifl¾ioromethyi»qMsiolisie-3-carbo¾y c acid
A suspension of 4-hyd>oxy-2-trifluororaemyl-quinoIine-3-carboxylic acid ethyl ester (5 g, 17.5 mmol) in 10% aqueous NaOH solution was heated at reflux for 2 h. After cooling,
dichlororaethane was added and the aqueous phase was separated and acidified with concentrated HQ to pH 4. The resulting precipitate was collected via filtration, washed with water and Et Q to provide 4-hydroxy~2 riftuoromemyl-quinoline-3-carboxyiic acid (A-15) (3,6 g, 80 %), Ή NMR (DMSO-de) δ 8.18-8.21 (d, J = 7.8 Hz, 1 H), 7.92-7.94 (d, / = 8.4 Hz, 1 H), 7.79-7.83 (t, J = 14.4 Hz, 1 H), 7.50-7.53 (t, / = 15 Hz, 1 H); ESI-MS 257.0 m/z (MH+).
[©327] Example 5
Figure imgf000114_0001
113 -
8544833,! a) CH3C(0)ONH4, toluene: b) EtOCHC(C02Et)2! 130 °C; c) Ph20; d) i2, EtOH; e) NaOH
[§328] 3-AMli5o~cyd¾fees-2-eTOH®
A mixture of cyciohexane~l,3-dio!ie (56.1 g, 0.5 mol) and AcONlHU (38,5 g, 0,5 mol) in toloene was heated at reflux for 5 h with a Dean-stark apparatus. The resulting oily layer was separated and concentrated under reduced pressure to give 3~amino-cyelohex-2-enone (49,9 g, 90 %), which was used directly in the next step without, further purification.
[0329] 2-[(3-Oxo-eyclohex-l-myIamiiio)-meihyleiie]-fflal0i C. acid diethyl ester
A mixture of 3-aniino-cyclohex-2-enone (3.3 g, 29.7 mmol) and diethyl 2- (etlioxymethylene)malonate (6.7 g, 31,2 mmol) was stirred at 130 °C for 4 h. The reaction mixture was concentrated under reduced pressure and the resulting oil was purified by column chromatography (silica gel, ethyi acetate) to give 2-[(3-oxo-cyclohex-l-enylamino)-methylene]- malonic acid diethyl ester (7.5 g, 90 %).
[033©] ^S-Dioxo-lAS^jTsS-hesaii dro-qiiiiioIine-S-carbo lk acid ethyi ester A mixture of 2-[(3~oxo-cyclohex-l~enylamino)-metliylene]-malonic acid diethyl ester (2.8 g, 1 mmol) and diphenyleiher (20 mL) was refluxed for 15 min. After cooling, «~hexane (80 mL) was added. The resulting solid was isolated via filtration and recrystallized from methanol to give 4,5-dioxo-l,4,5,6,7,8-hexahydro-quinoime-3~carboxylic acid ethyl ester (1.7 g 72 %).
[©331] S-Hydroxy-4-oxo-l,4-dl!iydro~qsimiilIiie--3-earbcsxySi£ add ethyl ester To a solution of 4,5-dioxo-l, 4,5,6 ,7,8-hexahydro-qumolme~3~carboxyiic acid ethyl ester (1 ,6 g, 6.S mmol) in ethanol (100 mL) was added iodine (4.8 g, 19 mmol). The mixture was refluxed for 19 h and then concentrated under reduced pressure. The resulting solid was washed with ethyl acetate, water and acetone, and then recrystallized from DMF to give 5-hydroxy-4-oxo- l,4-dihydro-quinoliEe~3-carboxylic acid ethyl ester (700 mg, 43 %).
[©332] A-3; S-Hydrosy-4-οχο-ϊ, 4-dlhydro~qam liue-3-carboxyli£ acid
A mixture of 5-hydroxy-4~oxo-l,4-di]iydro-quinoline-3-carboxylic acid ethyl ester (700 mg, 3 mmol) in 10% NaOH (20 mL) was heated at reflux overnight. After cooling, the mixture was extracted with ether. The aqueous phase was separated and acidified with cone. HC1 to pH 1-2. The resulting precipitate was collected via filtration to give 5-hydroxy-4-oxo-l, 4-dihydro- quinoline-3-caiboxylic acid (A-3) (540 mg, 87 %). Ή NMR (DMSO- ) δ 13,7 (br, 1 H), 13.5
- 114 -
8544S33.1 (br, ! H), 12.6 (s, 3 H), 8.82 (s, 1 H), 7.68 (t, J = 8.1 Hz, 1 H), 7.18 (d, / = 8.4 Hz, 1 H), 6.82 (d, 7 = 8.4 Hz, 1 H); ESI-MS 205.9 m z (MH+).
Figure imgf000116_0001
a) POC¾; b) MeONa; c) n-BuLi, ClC02Ei; d) NaOH
2,4-Diehior quieoliiie
A suspension of quinoline-2,4-diol (15 g, 92,6 mmol) in POCI3 was heated at reflux for 2 h. After cooling, the solvent was removed under reduced pressure to yield 2,4-dichloroquinoline, which was used without further purification.
[0334] 2,4-Dimethoxyquinoline
To a suspension of 2,4-dichloroquinoline in MeOH (1.00 mL) was added sodium methoxide (50 g). The mixture was heated at reflux for 2 days. After cooling, the mixture was filtered. The filtrate was concentrated under reduced pressure to yield a residue that was dissolved in water and extracted with CH2CI2. The combined organic layers were dried over Na2S04 and concentrated to give 2,4-dimethoxyquinoline as a white solid (13 g, 74 % over 2 steps).
[Θ335] Ethyl 2,4-dimeihoxyqai¾oMne-3-carboxyiate
To a solution of 2,4-dimethoxyquinoiine (1 L5 g, 60.8 mmol) in anhydrous THF was added dropwise n-BuLi (2.5 M in hexane, 48.6 mL, 122 mmol) at 0 °C. After stirring for 1.5 h at 0 °C, the mixture was added to a solution of ethyl chloroformate in anhydrous THF and stirred at 0 °C for additional 30 min and then at room temperature overnight. The reaction mixiure was poured into water and extracted with CH2Q2. The organic layer was dried over Na2SQ and concentrated nder vacuum. The resulting residue was purified by column chromatography
- L IS -
8544833, 1 (petroleum ether / EtOAc = 50 / 1) to give ethyl 2, 4-dimethoxyquinoiisie-3-carbox;y!ate (9,6 g, 60 %).
[0336] A-17; 2,4-Dimeihosyqam0liiie-3-carbosyik add
Ethyl 2,4-dimethoxyquinoline-3-carboxylate (L5 g, 5.7 mmol) was heated at reflux in NaOH solution (10 %, 100 mL) for 1 h. After cooling, the mixture was acidified with concentrated HCl to pH 4, The resulting precipitate was collected via filtration and washed with water and ether to give 2,4-dimethoxyquinoline-3-carboxylic acid (A-17) as a white solid (670 mg, 50 %). lH NMR (CDC13) δ 8.01-8.04 (d, =12 Hz, 1 H), 7.66-7.76 (m, 2 H), 7.42-7.47 (t, / = 22 Hz, 2 H), 4.09 (s, 3 H). 3,97 (s, 3 H); ESI-MS 234.1 m/z (MH*).
[0337] Commercially available adds
Figure imgf000117_0001
- 1 56 -
8544833.! [033S] Amine Moieties
[0339] N-l Sebstl sited 6-am siolMdoI s
[0340] Example 1:
[0341] General Scheme:
Figure imgf000118_0001
a) RX (X = CI, Br, I), K2C<¾, DMF or C¾CN; b) ¾, Pd~C, EiOH or SnCl2-2H20, EtOH. [Q342] Specific example:
Figure imgf000118_0002
To a solution of 6-nitroindole (4.QSg 25 mraol) in DMF (50 mL) was added 2CO3 (8.63 g, 62.5 inmol) and Mel (5.33 g, 37.5 mmol). After stirring at room temperature overnight, the mixture was poured into water and extracted with eihy! acetate. The combined organic layers were dried over N 2S04 and concentrated under vacuum to give the product l-memyl-6-nitro H-indole (4.3 g, 98 9b).
[0344] B-l; l-Methyi-lH-indoI-6~ylamine
A suspension of l-methyl-6-nitro-lH-indole (4.3 g, 24.4 mmol) and 10% Pd-C (0.43 g) in EtOH (50 inL) was stirred under ¾ (1 atm) at room temperature overnight. After filtration, the filtrate was concentrated and acidified with HCl-MeOH (4 moI L) to give 1 -methyl- lH- dol-6-y!amine hydrochloride salt (B-l) (1.74 g, 49 %) as a grey powder. lE NMR (DMSO-tfc): δ 9.10 (s, 2 H), 7.49 (d, J = 8,4 Hz, 1 H), 7.28 (d, J = 2.0 Hz, 1H), 7.15(s, 1 H), 6.84 (d, / = 8.4 Hz, 1 H), 6.38 (d, J = 2.8 Hz, 1H), 3.72 (s, 3 H): ESI-MS 146.08 m z (MH+).
- 117 -
8544833. i [0345] Other examples:
Figure imgf000119_0001
[0346] B-2; l-Betugrl-lH-indol-6-ylaiiiine
1 -Benzyl- lH-indol~0~yIamine (B-2) was synthesized following the general scheme above starting from 6-nitroindoIe and benzyl bromide. Overall yield (~ 40 %). HPLC rei. time 2,19 rain, 10-99 % CFfeCN, 5 min run; ESI-MS 223.3 m/z (MH+).
Figure imgf000119_0002
[§347] B-3; l~(6-AiBiii0-iad0l-i-yi)-eihaB0¾¾e
l-(6-Amino-indol-l-yl)-ethanone (B-3) was synthesized following the general scheme above starting from 6-nifroindoie and acetyl chloride. Overaii yield (~ 40 ). HPLC ret. time 0.54 min, 10-99 % CH3CN, 5 min run; ESI-MS 175.1 m/z (MH+).
[0348] Example 2:
Figure imgf000119_0003
- 1 18 -
8544833.3 [Θ349] {[2-(fer£ ?&to:iycarb68syi~m
ethyl ester
To a stirred solution of (tert-butoxycarbos yl~methyl-aniino)-acetic acid (37 g, 0.2 mo!) and Et3N (60,6 g, 0.6 mol) in CH2C12 (300 mL) was added isobutyl chloroformate (27.3 g, 0.2 mmol) dropwise at -20 °C under argon. After stirring for 0.5 h, methylarnino-acetic acid etSiyl ester hydrochloride (30.5 g, 129 mmol) was added dropwise at -20 °C, The mixture was allowed to warm to room temperature (c.a. 1 h) and quenched with water (500 mL). The organic layer was separated, washed with 10 % citric acid solution, dried over Na280 , filtered and concentrated. The residue was purified by column c!irornatography (petroleum ether / EtOAc 1: 1) to give f [2- (tert-butoxycarbonyl-methyl-amino)-acetyl3-methyl~amino}- acetic acid ethyl ester (12.5 g, 22 %).
[035§] { 2-(te ^ etoxycarboHyl-meihyl-ami¾ )-a€et5l]-metliyl»ammo}~}S£eti€ acid A suspension of { [2-(fer3f'butoxycarbonyl-methyi-arrsino)-acetyij- methyl-amino}-acetic acid ethyl ester (12.3 g, 42.7 mmol) and LiOH (8.9 g, 214 mmol) in H20 (20 mL) and THF (100 mL) was stirred overnight. Volatile solvent was removed under vacuum and the residue was extracted with ether (2 x 100 mL). The aqueous phase was acidified to pH 3 with dilute HQ solution, and then extracted with CH2CI2 (2 x 300 mL), The combined organic layers were washed with brine, dried over Na2S€> and concentrated under vacuum to give { [2-(tert~butoxycarbonyl- methyi-aniino)«aeetyl]-methyl~ammo} -acetic acid as a colorless oil (10 g, 90 %). Ή NMR (CDCI3) δ 7.17 (br s, 1 H), 4.14-4.04 (m, 4 H), 3.04-2,88 (m, 6 H), 1.45-1.41 (m, 9 H); ESI-MS 282.9 m/z (M+Na+).
[0351] MethyK{n½thyl-[2-(6-mtro-indol-l-yl)-2-oxo-et yl]^r^
carbamfc acid ferf-hutyf ester
To a mixture of { [2-(teri-butoxycarbonyl-methyl-ainino)-aceiyl]~methyl-amino}-acetic acid (13.8g, 53 mmol) and TFFH (21.0g, 79.5 mmol) in anhydrous THF (125 mL) was added DfEA (27.7 mL, 159 mmol) at room temperature under nitrogen. The solution was stirred at room temperature for 20 min. A solution of 6-nitroindole (8.6g, 53 mmol) in THF (75 mL) was added and the reaction mixture was heated at 60 °C for 18 h. The solvent was evaporated and the crude mixture was re-partitioned between EtOAc and water. The organic layer was separated, washed with water (x 3), dried over Na2S04 and concentrated. Diethyl ether followed by EtOAc was added. The resulting solid was collected via filtration, washed with diethyl ether and air dried to yield memyl-({memyl-[2-(6-nitro-indol- l-yl)-2-oxo-ethyl]-carbamoyl}-methyl)-
- 1 19 -
8544833.1 carbamic acid _m-butyl ester (6,42 g, 30 ). Ή NMR (400 MHz, DMSO-d6) δ 1.37 (m, 9H), 2.78 (m, 3H), 2.95 (d, J = 1.5 Hz, 1H), 3.12 (d, J = 2.1 Hz, 2H), 4.01 (d, J = 13.8 Hz, 0.6H), 4.18 (d, J = 12.0 Hz, 1.4H), 4.92 (d, J = 3.4 Hz, 1.4H), 5.08 (d, J = 1 1.4 Hz, 0.6H), 7.03 (m, 1H), 7.90 (m, 1H), 8.21 (m, 1H), 8.35 (d, J = 3.8 Hz, lH), 9.18 (m, lH); HPLC ret. time 3.12 min, 10-99 % CH3C , 5 min run; ESI-MS 405.5 m/z (MH+).
[Θ352] B-26; ({[2 6»Ammo~tadoI-i-yI)-2-ox0-ethyI]-m€tfeyl--carbsmojl}«mei¾yI)~ meihyl-carbamlc acid tert -butyl ester
A mixture of methyl-({methyl-[2-(6-nitro-indol- l-yi)-2-oxo-eihyl]-carbamoyl }-methyl)- carbarme acid tert-bui l ester (12.4 g, 30.6 mmol), SnG2-2H20 (34.5g, 153,2 mmol) and DIEA (74.8 mL, 429 mr ol) in ethanoS (112 mL) was heated to 70 °C for 3 h. Water and EtOAc were added and the mixture was filtered through a short plug of Celite. The organic layer was separated, dried over 2SG4 and concentrated to yield ( { [2-(6-Amino-indoI-l~yl)~2-oxo-ethyl]- methyl~carbamoyl}-methyl)-methyl-carbamic acid ferf-butyl ester (B-26) (11.4 g, quant.).
HPLC ret. time 2.1 1 min, 10-99 % CH3C , 5 min run; ESI-MS 375.3 m/z (MS-f ).
Figure imgf000121_0001
8- -b
[0355] B~4~a; {3-Nitro-phenyt)-bydrazme hydrochloride salt
3-Nitro-phenylamine (27.6 g, 0.2 mol) was dissolved in a mixture of H20 (40 mL) and 37% HC1 (40 mL). A solution of NaN02 (13.8 g, 0.2 mol) in H20 (60 mL) was added at 0 °C, followed by the addition of SnCl2-H20 (135.5 g, 0.6 mol) in 37% HQ (100 mL) at that temperature. After
- 120 -
8544833.1 stirring at 0 °C for 0.5 h, the solid was isolated via filtration and washed with water to give (3- nitro-phenyl)-hydrazine hydrochloride salt (B~4~a) (27.6 g, 73 %).
[0356] 2-[(3-Nitro-pheeyI)-hydra¾ K ]~propioiiie add ethyl ester
(3-Nitro~phenyl)~hydrazine hydrochloride salt (B-4-a) (30.2 g, 0.16 mol) and 2-oxo-propionic acid ethyl ester (22.3 g, 0.19 mol) was dissolved in ethanol (300 niL). The mixture was stirred at room temperature for 4 h. The solvent was evaporated under reduced pressure to give 2-[(3- mtro-phenyl)-hydrazono]-propionic acid ethyl ester, which was used directly in the next step,
[0357] B-4-fo; 4-Nitro-lH-mdole-2-carboxyifc acid ethyl ester and 6-Nitro-lH- lisdole -2-carboxyIfc add ethyl ester
2-[(3-Nitro-phenyl)-hydrazonoJ-propionic acid ethyl ester from the preceding step was dissolved in toluene (300 mL). PPA (30 g) was added. The mixture was heated at reflux overnight and then cooled to room temperature. The solvent was removed to give a mixture of 4-nitxo-lH- indo!e-2-carboxylic acid ethyl ester and 6-nitro-lH-indole -2-carboxylic acid ethyl ester (B-4»b) (15 g, 40 ).
[Θ358] B-4; 2- ethyl-lH-indol-6-ylaiiiiiie
To a suspension of LiAlH4 (7.8 g, 0.21 mol) in THF (300 mL) was added dropwise a mixture of 4-nitro-lH-indole-2-carboxylic acid ethyl ester and 6-nitro-lH-mdole -2-carboxylic acid ethyl ester (B-4-b) (6g, 25.7 mmol) in THF (50 mL) at 0 °C under N2. The mixture was heated at reflux overnight and then cooled to 0 °C. H20 (7.8 mL) and 10 % NaOH (7.8 mL) were added to the mixture at 0 °C. The insoluble solid was removed via filtration. The filtrate was dried over Na2S04, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography to afford 2-methyl-lH-indol-6-ylamine (B-4) (0.3 g, 8 %). lH NMR (CDCb) δ 7.57 (br s, 1 H), 7.27 (d, / = 8.8 Hz, 1 H), 6.62 (s, 1 H), 6.51-6.53 (m, 1 H), 6,07 (s, 1 H), 3.59-3.25 (br s, 2 H), 2.37 (s, 3H); ESI-MS 147.2 mix {MR*).
- 121 -
8544833.1 0359] Example 2:
Figure imgf000123_0001
03603 6-NltTO»iH-isidole-2-carboxylk acid nd 4-Niiro-lH- todole-2-earboxyIic acid
A mixture of 4-mtro- lH-indole-2-carboxylic acid ethyl ester and 6-nitro-lH-mdole -2- carboxylic acid ethyl ester (B-4-fe) (0.5 g, 2.13 mmol) in 10 % NaOH (20 m.L) was heated at reflux overnight and then cooled to room temperature. The mixture was extracted with ether. The aqueous phase was separated and acidified with HC1 to pH 1-2. The resulting solid was isolated via filtration to give a mixture of 6-mtro-lH-indole-2-carboxyiic acid and 4-nitro-lH- indoSe~2-carboxySic acid (0.3 g, 68 %).
[0361] 6-Mtro-lH-iiid0le-2-carbosylic acid amide aad 4-Nitro-IH- mdok~2- carboxylk acid amide
A mixture of 6-nitro-lH-indole-2-carboxylic acid and 4-nitro-lH- indoie-2-carboxylic acid (12 g, 58 mmol) and SOCl2 (50 mL, 64 mmol) in benzene (150 mL) was refluxed for 2 h. The benzene and excessive SOQ2 was removed under reduced pressure. The residue was dissolved in CH2C12 (250 mL). NH4OH (21.76 g, 0.32 mol) was added dropwise at 0 °C. The mixture was stirred at room temperature for 1 h. The resulting solid was isolated via filtration to give a crude mixture of 6-mtiO-l H-mdole-2-carbox iic acid amide and 4-nitro-lH~ indoIe-2-carboxyiic acid amide (9 g, 68 %), which was used directly in the next step.
- 122 -
8544833,3 [0362] 6~Nitr -IH~¾doIe-2-€arbi sitrile aad 4- iro-lJt mdok-J-carbomtrile A mixture of 6-nitro-lH-mdole-2-carboxylic acid amide and 4-nitro- lH- indole-2-carboxylic acid amide (5 g, 24 mmol) was dissolved in CH2CI2 (200 raL). Et3N (24.24 g, 0.24 mol) was added, followed by the addition of (€Ρ€0)20 (51,24 g, 0.24 mol) at room temperature. The mixture was stirred for 1 h and poured into water (100 n L). The organic layer was separated. The aqueous layer was extracted with EtOAc ( 100 mL x 3). The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography to give a mixture of 6-nitro H-indole-2-carbomtrile and 4- nitro- lH- indole-2-carbonitrile (2.5 g, 55 %).
[0363] B~S; 6-Amiiici-iH-sEdole-2-carboiiitrl!e
A mixture of 6-nitro-lH-mdo!e-2-carbonitriIe and 4-nitro-lH- indole-2-carbonitri!e (2,5 g, 13.4 mmol) and Raney Ni (500 mg) in EiOH (50 mL) was stirred at room temperature under ¾ (1 aim) for 1 h. Raney Ni was filtered off. The filtrate was evaporated under reduced pressure and purified by column chromatography to give 6-amino~lH-indole-2-carbonitri!e (B-5) (1 g, 49 ).Ή ' NMR (DMSO-rffc) 6 12.75 (br s, 1 H), 7.82 (d, 7 = 8 Hz, 1 H), 7.57 (s, 1 H), 7.42 (s, 1 H), 7.15 (d, 7 = 8 Hz, 1 H); ESI-MS 158.2 m/z (MIT).
[0364] Exam le 3:
Figure imgf000124_0001
Figure imgf000124_0002
8
- 123 -
854 S33.1 [§365] 2,2-DimethyI-N-o-toiyl-propioiiamide
To a solution of o-toiylarnine (21.4 g, 0,20 mol) and EtjN (22,3 g, 0.22 mo!) in C¾C12 was added 2,2-dimethyI-propionyl chloride (25.3 g, 0.21 mol) at 10 °C. The mixture was stirred overnight at room temperature, washed with aq. HCI (5%, 80 mL), saturated NaHCOs solution and brine, dried over N 2S04 and concentrated under vacuum to give 2,2-dimethyi-N-o-tolyl- propionamide (35.0 g, 92 %).
[§366] 24ert-Butyl-lH-iiidale
To a solution of 2,2-dimethyi-N-o-tolyl- propionamide (30.0 g, 159 mmoi) in dry THF (100 mL) was added dropwise n-BuLi (2.5 M, in hexane, 190 mL) at 15 °C. The mixture was stirred overnight at 15 °C, cooled in an ice-water bath and treated with saturated NH4CI solution. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. Be combined organic layers were dried over anhydrous Na2S04, filtered, and concentrated in vacuum. The residue was purified by column chromatography to give 2-fert-butyl-lH-indole (23.8 g, 88 %).
To a solution of 2-fert-butyi-lH-indole (5,0 g, 29 mmoi) in AcOH (20 mL) was added NaB¾ at 10 °C. The mixture was stirred for 20 min at 10 °C, treated dropwise with H2G under ice cooling, and extracted with ethyl acetate, The combined organic layers were dried over anhydrous Na2S0 , filtered, and concentrated under vacuum to give a mixture of starting material and 2-/eri-butyl-2,3-dihydro-lH-indole (4.9 g), which was used directly in the next step.
[Θ368] 2^/i-laiyi-6-Hitr« 2^.dihydr -lH ndoi®
To a solution of the mixture of 2-ieri-butyl-2,3-dihydro-lH-indole and 2-ie'ri-butyl-lH-indole (9.7 g ) in H2SO4 (98%, 80 mL) was slowly added KNO3 (5.6 g, 55.7 mmoi) at 0 °C. The reaction mixture was stirred at room temperature for 1 h, carefully poured into cracked ice, basified with Na2CC¾ to pH~8 and extracted with ethyl acetate. The combined extracts were washed with brine, dried over anliydrous Na2S04 and concentrated under vacuum. The residue was purified by column chromatography to give 2-teri-butyl-6-nitro-2,3-dihydro-lH-indole (4.0 g, 32 % over 2 steps).
124 -
8544833.1 [0369] 2-^rjf-B i l-6-iiiir0-lH-iiidoIe
To a solution of 2-ieri-baty!-6-miro-2,3~dihydro-lH ndole (2.0 g, 9,1 mmol) in 1,4-dioxane (20 mL) was added DDQ at room iemperature. After refiuxing for 2.5 h, the mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by column chromatography to give 2-/m-butyl-6-nitro-iH~indole ( 1.6 g, 80 %).
[Θ370] 2-tert~Bii yMH iidol-6.ytemiH
To a solution of 2-ie^buty!~6-mtro-lH~mdoie ( 1.3 g, 6.0 mmoi) in MeOH (10 mL) was added Raney Ni (0,2 g). The mixture was stirred at room temperature under ¾ (i aim) for 3 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was washed with petroleum ether to give 2-ferf-butyl-lH-mdol-6-ylamine (B-6) (1.0 g, 89 %). jH NMR (DMSO- (k) δ 10.19 (s, 1 H), 6.99 (d, / = 8.1 Hz, 1 H), 6.46 (s, 1 H), 6.25 (dd, J - 1.8, 8.1 Hz, i H), 5.79 (d, J = 1.8 Hz, 1 H), 4.52 (s, 2 H), 1.24 (s, 9 H); ESI-MS 189.1 mil (MH+).
[0371] 3-Ssibsiiteled 6-¾mm i jdoIgs
[©372] Example 1:
Figure imgf000126_0001
[Θ373] N-(3-NitrcHphenyI)-N '-propyUdene-hydra^dne
Sodium hydroxide solution (10 %, 15 mL) was added slowly to a stirred suspension of (3-nitro- phenyl)-hydrazine hydrochloride salt (B-4-a) (1.89 g, 10 mmol) in ethanoi (20 mL) until pH 6. Acetic acid (5 mL) was added to the mixture followed by propionaldehyde (0,7 g, 12 mmol). After stirring for 3 h at room iemperature, the mixture was poured into ice-water and the
- 125 -
8544S33J resulting precipitate was isolated via filtration, washed with water and dried in air to obtain N- (3-nitro-phenyl)-N'-propylidene-hydrazine, which was used directly m the next step.
[0374] 3-Met tyl-4-nitro-lH-ind<rie asset 3- etliyl-6-nitro-lH-indole
A mixture of N-(3-nitro-phenyl)-N'-propylidene-hydrazine dissolved in 85 % H3PO4 (20 niL) and toluene (20 mL) was heated at 90-100 °C for 2 h. After cooling, toluene was removed under reduced pressure. The resultant oil was basified with 10 % NaOH to pH 8, The aqueous layer was extracted with EiOAe (100 mL x 3). The combined organic layers were dried, filtered and concentrated under reduced pressure to afford a mixture of 3-methyl- -nitro-lH-indole and 3- methyl-6-nitro H-indole (1.5 g, 86 % over two steps), which was used directly in the next step.
[§375] B-7; 3-Methyl-lH-indol-6-ylamine
A mixture of 3-meihyi-4-nitro-lH-indole and 3-methyl-6-nitro-lH- indole (3 g, 17 mol) and 10 % Pd-C (0.5 g) in ethanoi (30 mL) was stirred overnight under ¾ (1 aim) at room temperature, Pd-C was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give. 3-niethyl-lH-indol-6-yiamine (B-7) (0.6 g, 24 %), !H NMR (CDCI3) δ 7.59 (br s, 1 H), 7.34 (d, J = 8.0 Hz, 1 H), 6.77 (s, 1H), 6.64 (s, 1 H), 6.57 (m, 1 H), 3.57 (br s, 2 H), 2.28 (s, 3H); ESJ-MS 147.2 mlz (MIT).
Figure imgf000127_0001
[Q377] 6-Mtro- lH-indok>3~carbo5ilirHe
To a solution of 6-nitroindole (4.86 g 30 mmol) in DMF (24.3 mL) and CH3CN (243 mL) was added dropwise a solution of ClS02 CO (5 mi.,, 57 mmol) in CH3CN (39 mL) at 0 °C . After addition, the reaction was allowed to warm to room temperature and stirred for 2 h. The mixture was poured into ice-water, basified with sat. NaHC(¾ solution to pH 7-8 and extracted with ethyl acetate. The organic layer was washed with brine, dried over N 280 and concentrated to give 6-mtTO-lH-indole-3-carbomtrile (4.6 g, 82 %).
- 126 -
8544*53.1 [0378] B-8; 6-Amlffio-lH-iiid0le-3-carboisllriI®
A suspension of 6-miro-lH~indole-3~carbo trile (4.6 g, 24.6 mmol) and 10% Pd-C (0.46 g) in EtOH (50 mL) was stirred under H2 (1 aim) at room temperature overnight After filtration, the filtrate was concentrated and the residue was purified by column chromatography (Pet, Ether / EtQAc = 3 / 1) to give 6-amino-!H-indole-3-carbonitrile (B~8) (1 g, 99 %) as a pink powder, !H NMR (DMSG~rf6) δ 1 1.51 (s, 1 H), 7.84 (d, J = 2.4 Hz, I H), 7.22 (d, / = 8.4 Hz, 1 H), 6.62 (s, 1H), 6.56 (d, / = 8.4 Hz, 1 H), 5.0 (s, 2H); ESI-MS 157.1 m z (MH+).
[§379] Example 3:
Figure imgf000128_0001
Figure imgf000128_0002
[0380] Dimeihyl-(6-¾ftro-lH-iffldol-3-yIm©ihyl)-ami¾e
A solution of diraethylarnine (25 g, 0.17 moi) and formaldehyde (14.4 mL, 0.15 moi) in acetic acid (100 mL) was stirred at 0 °C for 30 min. To this solution was added 6-mtro-IH-indole (20 g, 0.1.2 moi). After stirring for 3 days at room temperature, the mixture was poured into 15% aq NaOH solution (500 mL) at 0 °C. The precipitate was collected via filtration and washed with water to give dimethyl-(6-nitro-lH-indol-3-ylmetiiyl)-amine (23 g, 87 %).
[0381] B»9~a; (6-N!iro.lH-MdoI.3-yI)-aceioeitrsle
To a mixture of DMF (35 mL) and Mei (74.6 g, 0.53 moi) in water (35 mL) and THF (400 mL) was added dimethyl-(6-nitro-lH-indol-3-ylrnethyl)-arnine (23 g, 0.105 moi). After the reaction mixture was refluxed for 10 min, potassium cyanide (54.6 g, 0.84 moi) was added and the mixture was kept refluxing overnight. The mixture was then cooled to room temperature and filtered. The filtrate was washed with brine (300 mL x 3), dried over Na2S04, filtered and concentrated. The residue was purified by column chromatography to give (6-nitro- lH-indol-3- yl)-acetonitrile (B-9-a) (7.5 g, 36 %).
- 127 -
S54 833.3 [0382] B«9; (6-Amie0-IH-Indo!-3-yl)-acetofflliree
A mixture of (6-nitro-lH-indol-3-yl)-acetonitrile (B-9-a) (1.5 g, 74.5 mmL) and 10 % Pd-C (300 mg) in EtOH (50 mL) was stirred at room temperature under ¾ (1 aim) for 5 h. Pd-C was removed via filtration and the filtrate was evaporated to give (6-amino-lH-indo!-3-yi)- acetonitrile (B-9) (1.1 g, 90 %). lH NMR (DMSO-flfe) δ 10.4 (br s, 1 H), 7.18 (d, J = 8.4 Hz, 1 H), 6.94 (s, 1H), 6.52 (s, 1 H), 6.42 (dd, J = 8.4, 1.8 Hz, 1 H), 4.76(s, 2 H), 3.88 (s, 2 H); ESI- MS 172.1 m/z (MH+).
Figure imgf000129_0001
8-1 Q
[0384] [2-(6-Niiro-lH- tad«>l-3-yi)-eifcyl]-carbami€ add teri-h iyl ester
To a solution of (6-nitro- lH-indol-3-yl)-acetonitrile (B-9-a) (8.6 g, 42.8 mmol) in dry THF (200 mL) was added a solution of 2 M borane -dimethyl sulfide complex in THF (214 mL. 0.43 mol) at 0 °C. The mixture was heated at reflux overnight under nitrogen. The mixture was then cooled to room temperature and a solution of (Boc^O (14 g, 64,2 mmol) and E.3N (89.0 mL, 0.64 mol) in THF was added. The reaction mixture was kept stirring overnight and then poured into ice-water. The organic layer was separated and the aqueous phase was extracted with EtOAc (200 x 3 mL), The combined organic layers were washed with water and brine, dried over 2S04, filtered and concentrated under reduced pressure. The crude was purified by column chromatography to give [2-(6-nitro-lH- indoi-3-yl)-ethyl]-carbamic acid iert-buty! ester (5 g, 38 %).
[©385] B-l©; [2-(6-AmiEO-lH-ied¾l-3-yl)-eiliyl]-carbamk add terf-butyl ester A mixture of [2-(6-nitro-lH- indol-3-yl)-ethyl]-carbamic acid ½r/-butyl ester (5 g, 16.4 mmol) and Raney Ni (1 g) in EtOH (100 mL) was stirred at room temperature under ¾ (1 aim) for 5 h. Raney Ni was filtered off and the filtrate was evaporated under reduced pressure. The crude product was purified by column chromatography to give [2-(6-amino-lH-indol-3-yi)-ethyl3- carbamic acid ferf-butyl ester (B-10) (3 g, 67 %). *H NMR (DMSO-tf6) δ 10.1 (br s, 1 H), 7.1 1 (d, / = 8.4 Hz, 1 H), 6.77-6.73 (m, 2 H), 6,46 (d, / = 1.5 Hz, 1 H), 6.32 (dd, J = 8.4, 2.1 Hz, 1
- 128 -
8S4 833.1 H), 4,62 (s, 2 H), 3.14-3.08 (m, 2 H), 2.67-2.62 (m, 2 H), 1.35 (s, 9H); ESI-MS 275.
(Mif).
[0386] Example 5;
Figure imgf000130_0001
a) RX (X=Br,l), zinc inflate, TBAI, DIEA, toluene; b) H2, Raney Ni, EtOH or
SnClr2H20, EtOH.
0388] Specific example:
Figure imgf000130_0002
B-11
[©389] 3^er«-But l-6-nItro-lH-iiidole
To a mixture of 6-nitromdole (1 g, 6.2 mmol), zinc inflate (2.06 g, 5.7 romoi) and TBAI (1.7 g, 5.16 mmol) in anhydrous toluene (1 mL) was added DIEA (1.47 g, 11.4 mmol) at room temperature under nitrogen. The reaction mixture was stirred for 10 min at 120 °C, followed by addition of i-butyl bromide (0,707 g, 5.16 mmol). The resulting mixture was stirred for 45 min at 120 °C. The solid was filtered off and the filtrate was concentrated to diyness and purified by column chromatography on silica gel (PetEtherJEtQAc 20: 1) to give 3-ieri-butyl-6-nitro-lH- indole as a yellow solid (0.25 g, 19 %). ¾H NMR (CDC13) δ 8.32 (d, / = 2.1 Hz, 1H), 8,00 (dd, J = 2.1, 14.4 Hz, 1 H), 7.85 (d, J = 8.7 Hz, 1H), 7.25 (s, 1H), 1.46 (s, 9H).
[©390] B-11; 3-ferf-B iyHH-todol-6-ylamme
A suspensio of 3-feri-hutyl-6-nitro-lH-indoie (3.0 g, 13.7mmol) and Raney Ni (0.5g) in ethanol was stirred at room temperature under H2 (1 aim) for 3 h. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was purified by column
- 129 -
S5<M833.i chromatography on silica gei (PetEther. / EtOAc 4 : 1 ) to give 3-½ri-butyHH-indol-6-ylamine (B-ll) (2,0 g, 773%) as a gray solid, EH NMR (CDCi3): δ 7.58 (m, 2H), 6.73 (d, J = 1.2 Hz, 1H), 6.66 (s, 1H), 6.57(dd, / = 0.8, 8.6 Hz, 1H), 3.60 (br s, 2H), 1.42 (s, 9H).
Figure imgf000131_0001
3-Ethyl~lH-indol-6-ylamme (B-12) was synthesized following the general scheme above starting from 6-nitromdole and ethyl bromide. Overall yield (42 %). HPLC ret. time 1.95 min, 10-99 % CH3CN, 5 min run; ESI MS 161.3 m/z (MH*).
Figure imgf000131_0002
[0393] B~13; 3 sopropyi-lH n ol-6-ylamfa-e
3-Isopropyl-lH-indol-6-ylan.ine (B~13) was synthesized following the general scheme above starting from 6-nitroindole and isopropyl iodide. Overall yield (17 %). HPLC ret. time 2.06 min, 10-99 % C¾CN, 5 min am; ESI-MS 175.2 m/z (MH+).
Figure imgf000131_0003
[0394] B-14; 3~sec-B«tyl-lH«todoi-6-y!amme
3~sec~Butyl-1 H ndol~6~ylarmne (B-14) was synthesized following the general scheme above starting from 6-nitroindole and 2-bromobotane. Overall yield (20 %), HPLC ret. time 2.32 min, 10-99 % CH3CN, 5 min ran; ESi-MS 189.5 m z (MH*).
- 130 -
8544833.1
Figure imgf000132_0001
[0395] B-15; 3.Cyctopestyl-lH-tadoI-6-ylamlee
3- Cyclopenlyl ~!H~indol~6~ylamine (B-1S) was synthesized following the general scheme above starting from 6-niiroindole and iodo-cyc opentane. Overall yield (16 %). HPLC ret. time 2.39 min, 10-99 % CH3C , 5 min run; ESI-MS 201.5 m/z (MH+).
Figure imgf000132_0002
[0396] B-16; 3 2-Etiwx -^yl)-lH-indol-6-yIamIne
3-(2-Ethoxy-eihy!)-IH-indol-6-yiamme (B-16) was synthesized following fee general scheme above starting from 6-niiroindole and l-bromo-2-ethoxy-ethane. Overall yield (15 %), HPLC ret. time 1.56 min, 10-99 % C¾CN, 5 min run: ESI-MS 205.1 m z (MH÷).
Figure imgf000132_0003
[©397] B-17; (6-AmlBO-lH-iMdoi-3-yl)-acetic add ethyl ester
(6-Ammo H-indol-3-yl)-acetic acid ethyl ester (B-17) was syntiiesized following the general scheme above starting from 6-nitroindoie and iodo-acetic acid ethyl ester. Overall yield (24 %), HPLC ret. time 0.95 min, 10-99 % CH3CN, 5 min run; ESI-MS 219.2 m/z (MH+).
- 131 -
S5 4S33.I -S¾ibstitiit©d e-amisscrisicfok
Figure imgf000133_0001
[Θ399] 2-Methyl-3^-dis3itro-beii2;0ic acid
To a mixture of HN03 {95%, 80 mL) and H2S04 (98%, 80 mL) was slowly added 2- methylbenzoic acid (50 g, 0.37 mol) at 0 C'C. After addition, the reaction mixture was stirred for 1.5 h while keeping the temperature below 30 °C, poured into ice-water and stirred for 15 min. The resulting precipitate was collected via filtration and washed with water to give 2-methyI- 3,5-dinitro-benzoic acid (70 g, 84 %).
[0400] 2-Methyl-3; -dimtr0-besK©ie acid eifeyl ester
A mi ture of 2-methyI-3,5-dimtro-benzoic acid (50 g, 0.22 mol) in SO€!2 (80 mL) was heated at reflux for 4 h and then was concentrated to dryness. CH2CI2 (50 mL) and EtOH (80 mL) were added. The mixture was stirred at room temperature for 1 h, poured into ice-water and extracted with EtOAc (3 x 100 mL). The combined extracts were washed with sat, Na2C03 (80 mL), water (2 x 100 mL) and brine (100 mL), dried over Na2S04 and concentrated to dryness to give 2-methyl-3,5-dinitro-ben∞ic acid ethyl ester (50 g, 88 %).
[0401] 2~(2~Dimeihy!amiHo-vIsiy!)-3,S-dimtro-beBz; k acid ethyl ester
A mixture of 2-methyl-3,5-dinitro-benzoic acid ethyl ester (35 g, 0.14 mol) and
dimethoxymethyl-dimethyl-amine (32 g, 0.27 mol) in DMF (200 mL) was heated at 100 °C for 5 h. The mixture was poured into ice-water. The precipitate was collected via filtration and washed with water to give 2-(2-dimethylamino-vinyl)-3,5-dinitro-benzoic acid ethyl ester (11.3 g, 48 %}.
- 132 -
8544833.! [0402] B-18; 6~Am R©-iH-Md¾le-4-carbosyIk acid ethyl ester
A mixture of 2-(2~dimethylain o-vmyl)-3,5~dimtro- benzoic acid ethyl ester (1 1.3 g, 0.037 mol) and SnC!2 (83 g. 0.37 mol) in ethanol was heated at reflux for 4 h. The mixture was
concentrated to dryness and the residue was poured into water and basified with sat. a2C03 solution to pH 8. The precipitate was filtered off and the filtrate was extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with water (2 x 100 mL) and brine (150 mL), dried over Na2S04 and concentrated to dryness. The residue was purified by column chromatography on silica gel to give 6-amino-lH-indole-4~carboxylic acid ethyl ester (B-18) (3 g, 40 %), SH MR (DMSO- ) δ 10.76 (br s, 1 H), 7.11-7.14 (m, 2 H), 6.81-6.82 (m, 1 H), 6.67-6.68 (m, 1 H), 4.94 (br s, 2 H), 4.32-4.25 (q, / = 7.2 Hz, 2 H), 1.35-1.31 (t, J = 7.2, 3 H). ESI-MS 205.0 m z (MH+).
[§403] 5 S |b^
[0404] Example 1:
Figure imgf000134_0001
8-20 l~FI«« ro~5~meihyl-2,4-dlaiiro-beH¾esie
To a stirred solution of H O3 (60 mL) and H2SO4 (80 mL), cooled in an ice bath, was added 1- fluoro-3 -methyl-benzene (27.5g, 25 mmol) at such a rate that the temperature did not rise over 35 °C. The mixture was allowed to stir for 30 mm at room temperature and poured into ice water (500 mL). The resulting precipitate (a mixture of the desired product and i-fluoro-3- methyi-2,4-dmitro-benzene, approx, 7:3) was collected via filtration and purified by
recrystallization from 50 mL isopropyi ether to give l-fluoro-5-methyl-2,4-dinitro-benzene as a white solid (18 g, 36 %).
- 133 -
8544833,! [0407] [2-(5-Fleor©-2i4-dlmiro»pferayI)- inyl]-dlmethyl--amIae A mixture of l-fluoro-5-methyl"2,4-dijiiiro-benzene (1.0 g, 50 mmol), dimethoxyraeihyl- dimethylarnme (11.9 g, 100 mmol) and DMF (50 mL) was heated at 100 °C for 4 h. The solution was cooled and poured into water. The red precipitate was collected via filtration, washed with water adequately and dried to give [2-(5~fluoro-2,4-di tn phenyI)~ vinyl]- dimethy!-amme (8 g, 63 ).
[Θ4@§] B-20; 5~F! ro~iH«i¾d !iI-6-yl 5BiBe
A suspension of [2-(5-fluoro-2,4-dimtro-phenyI)-vinyl]-diniethyl-araine (8 g, 31.4 mmol) and Raney Ni (8 g) in EtOH (80 mL) was stirred under I¾ (40 psi) at room temperature for 1 h. After filtration, the filtrate was concentrated and the residue was purified by ctaoraatography (PetEther/ EtOAc ~ 5 / 1) to give 5-fluoro-lH-indol-6-ylamine (1-20) as a brown solid (1 g, 16 %). lH NMR (DMSO- ) δ 10.56 (br s, 1 H), 7.07 (d, i = 12 Hz, 1 H), 7.02 (m, IH), 6,71 (d, / = 8 Hz, IH), 6.17 (s, I H), 3.91 (br s , 2H); ESI-MS 150.1 m z (MH*).
[04Θ9] Other examples:
Figure imgf000135_0001
[0410] B-21; S-Chloro-lH-tadol~6~ylamlis€
5"Chloro- l H-indol-6-yiamine (B-21) was synthesized following the general scheme above starting from l-chloro-3-methyl-benzene. Overall yield (7 %). JH NMR (CDCfe) δ.7.85 (br s, 1 H), 7.52 (s, 1 H), 7.03 (s, IH), 6.79 (s, I H), 6.34 (s, IH), 3.91 (br s, 2H); ESI-MS 166.0 m/z (MH*).
Figure imgf000135_0002
[0411] B-22; S-Tri!1as r methyl-iH-lEdoI-6-ylaKiiiie
5-Trifiuoromethyl-lH-indol-6-ylamine (B-22) was synthesized following the general scheme above starting from l -meihyl-S-trifluoromethyl-benzene. Overall yield (2 ). 'H NMR
(DMSO-t¼) 10.79 (br s, 1 H), 7.55 (s, 1 H), 7.12 (s, 1 H), 6.78 (s, 1 H), 6.27(8, 1 H), 4.92 (s, 2 H); ESI-MS 200.8 m/z (MH+),
- 134 -
85 S33.1 [0412] Example 2:
Figure imgf000136_0001
S-23
[0413] l-Beii¾ersesisIfo5iyI~2,3-dlhydro»lH-iHdoIe
To a mixture of DMAP (i .5 g), benzenesulfonyl chloride (24 g, 136 mmol) and 2,3-dihydro-lH- indole (14.7 g, 124 mmol) in€¾(¾ (200 mL) was added dropwise EtjN (19 g, 186 mmol) in an ice-water bath. After addition, the mixture was stirred at room temperature overnight, washed with water, dried over Na2SC>4 and concentrated to dryness under reduced pressure to provide l-benzenesuifonyl-2,3-dihydro- lH-indole (30.9 g. 96 %).
[0414] i-(l-Be¾¾eiiesiilfosiyI-2,3-dl¾ydro~lH-lad©!«5-yI)--eiha sie
To a stirring suspension of AICI3 (144 g, L08 raol) in CH2CI2 (1070 mL) was added acetic anhydride (54 mL), The mixture was stirred for 15 minutes. A solution of 1-benzenesu fonyl- 2,3-dihydro-lH-indole (46.9 g, 0.18 mol) in CH2C12 (1070 mL) was added dropwise. The mixture was stirred for 5 h and quenched by the slow addition of crushed ice. The organic layer was separated and the aqueous layer was extracted with CH2CI.2. The combined organic layers were washed with saturated aqueous NaHC(¾ and brine, dried over Na2S04 and concentrated under vacuum to yield i-( i-benzenesuifony1.-2,3-dihydro-lH~indoI-5-yl)-e hanone (42.6 g, 79 %).
[0415] i-Bejize-iessilfoEyl-S-et yl-I^-dihy dro- lH-iadole
To magnetically stirred TFA (1600 mL) was added at 0 °C sodium borohydride (64 g, 1.69 mol) over 1 h. To this mixture was added dropwise a solution of l -(i-benzenesulfonyl-2,3-dihydro- lH-indol-5-yl)-ethanone (40 g, 0.13 mol) in TFA (700 mL) over 1 h. The mixture was stirred overnight at 25 °C, diluted with ¾0 (1600 mL), and basified with sodium hydroxide pellets at 0 °C. The organic layer was separated and the aqueous layer was extracted with CH2CI2. The combined organic layers were washed with brine, dried over Na2SQ and concentrated under
- 135 -
8544833.1 reduced pressure. The residue was purif led by column chromatography on silica gel to give 1 - benzenesulfonyl-5-ethyl-2,3-dihydro-lH-indole (16.2 g, 43 ).
[0416] 5-Ethyl-2 dihydre-IH~½dok
A mixture of l -benzenesulfony]-5-ethyl-2,3-dihydro-lH-indoSe (15 g, 0.05 mol) in HBr (48%, 162 mL) was heated at reflux for 6 h. The mixture was basified with sat. NaOH solution to pH 9 and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2S0 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 5-ethyl-2,3-dihydro-lH-indole (2.5 g, 32 %).
[0417] 5-Eth l^nitro-2^dili dro-lH-indole
To a solution of 5-ethyl-2,3-dihydro-lH-indole (2.5 g, 17 mmol) in ¾S0 (98%, 20 mL) was slowly added NO3 (1.7 g, 17 mmol) at 0 °C, After addition, the mixture was stirred at 0 - 10 °C for 10 mm, carefully poured into ice, basified with NaOH solution to pH 9 and extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na?S0 and concentrated to dryness. The residue was purified by column chromatography on silica gel to give 5-ethyl-6-nitro-2,3-dihydro-lH-indoie (1.9 g, 58 %).
[0418] 5-Ethyl-6-nitro-lH-indole
To a solution of 5-ethyl-6~nitro~2,3-dihydro-lH-indole (1.9 g, 9.9 mmol) in CH2CI2 (30 mL) was added Mn02 (4 g, 46 mmol), The mixture was stirred at room temperature for 8 h. The solid was filtered off and the filtrate was concentrated to dryness to give crude 5-ethyl-6-nitro-lH- indole (1.9 g, quant.).
[0419] B-23; 5-Etfayl-m-indol-6-ylamine
A suspension of 5-ethyl-6-nitro-lH-indole (1.9 g, 10 mmol) and Raney Ni (1 g) was stirred under ¾ (1 aim) at room temperature for 2 h. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel to give 5-ethyl-lH-indol-6-ylamine (B-23) (760 nig, 48 %). ¾ NMR (CDC¾)6 7.90 (br s, 1H), 7.41 (s, 1H), 7.00 (s, 1H), 6.78 (s, 2H), 6.39 (s, 1H), 3.39 (br s, 2H), 2.63 (q, J = 7.2 Hz, 2H), 1.29 (t, ./ = 6.9 Hz, 3H); ESi-MS 161.1 m/z (MH+).
- 336 -
S54 S33.1
Figure imgf000138_0001
B-24
[§421] 2-Bro05O~4-ieri-betyI-pheiiylamiHe
To a solution of 4-½ri-butyl~pheEy!amine (447 g, 3 mol) in. DMF (500 mL) was added dropwise NBS (531 g, 3 mol) in DMF (500 rnL) at room temperature. Upon completion, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2S04 and concentrated. The crude product was directly used in the next step without further purification.
[©422] l-Bromo-i -fe i-bisiyl-S-eiiro- heE lam e
2-Bromo-4-ierr-butyl-phenylamiiie (162 g, 0.71 mol) was added dropwise to H2SO4 (410 mL) at room temperature to yield a clear solution. This clear solution was then cooled down to -5 to - 10 °C. A solution of KNO3 (82.5 g, 0.82 mol) in H2S0 (410 mL) was added dropwise while the temperature was maintained between -5 to -10 °C. Upon completion, the reaction mixture was poured into ice / water and extracted with EtOAc. The combined organic layers were washed with 5% Na2C(¾ and brine, dried over Na^SC and concentrated. The residue was purified by a column chromatography (EtOAc / petroleum ether 1 / 10) to give 2-bromo-4-feri- bi!ty!-5-mtro-phenylamine as a yellow so!id (152 g, 78 ).
[Θ423] ^teri-Buiyl-5-Miro-2-trimefhylsil¾¾ylethyiSiyl-phesylamliie
To a mixture of 2-bromo-4-fe/ -butyl-5-nitro-phenylamine (27.3 g, 100 mmol) in toluene (200 mL) and water (100 mL) was added Et3N (27.9 mL, 200 mmol), Pd(PPh3)2Q2 (2.1 1 g, 3 mmol), Cui (950 mg, 0.5 mmol) and trimethylsilyl acetylene (21.2 mL, 150 mmol) under a nitrogen atmosphere. The reaction mixture was heated at 70 °C in a sealed pressure flask for 2.5 h., cooled down to room temperature and filtered through a short plug of Celite, The filter cake was washed with EtOAc. The combined filtrate was washed with 5% N¾OH solution and water,
- 137 -
8544833.1 dried over Na?SQ4 and concentrated. The crude product was purified by column chromatography (0 - 10 % EtOAc / petroleum ether) to provide 4-teri-butyi-5-nitro-2- trimeihyisilany!eihynyl-phenyiamine as a brown viscous liquid (25 g, 8 %).
[0424] 5-ieri-Bi3i i-6-iiitro.lH.mdoie
To a solution of 4-terf-butyl~5-mrfo-2-rrimethylsilaiiylethynyI--pheny]amine (25 g, 86 mmol) in DMF (100 mL) was added Cui (8,2 g, 43 mmol) under a nitrogen atmosphere. The mixture was heated at 135 °C in a sealed pressure flask overnight, cooled down to room temperature and filtered through a short plug of Celite. The filter cake was washed with EtOAc. The combined filtrate was washed with water, dried over Na2SQ and concentrated. The crude product was purified by column chromatography (10 - 20 % EtOAc / Hexane) to provide 5 -½?rf -butyl-6- nitro-lH-indole as a yellow solid (12,9 g, 69 %).
[0425] B-24; 5-tei -Butyl-lH-indol-6-ylainJne
Raney Ni (3 g) was added to 5-terf-butyl-6-nitro-lH-indole (14.7 g, 67 mmol) in methanol (100 mL). The mixture was stirred under hydrogen (1 atm) at 30 °C for 3 h. The catalyst was filtered off. The filtrate was dried over Na2SC>4 a concentrated. The crude dark brown viscous oil was purified by column chromatography (10 - 20 % EtOAc / petroleum ether) to give 5-ieri-butyl- lH-indol-6-ylamine (B-24) as a gray solid ( 11 g, 87 %). 5H NMR (300 MHz, DMSO-d6) δ 10.3 (br s, 1 H), 7.2 (s, 1 H), 6.9 (m, 1H), 6.6 (s, 1H), 6.1 (m, 4.4 (br s, 2H), 1.3 (s, 9H).
[©426] Example 4
Figure imgf000139_0001
[Θ427] S-MethyI-2,4-dImtro.beis¾ok acid
To a mixture of HN03 (95 , 80 mL) and ¾S0 (98 %, 80 mL) was slowly added 3- methylbenzoic acid (50 g, 0,37 mol) at 0 °C. After addition, the mixture was stirred for 1.5 h while maintaining the temperature below 30 °C. The mixture was poured into ice-water and stirred for 15 nun. The precipitate was collected via filtration and washed with water to give a mixture of 3-methyl-2,6-dimtro-benzoic acid and 5-methyl-2,4-dinitro-benzoic acid (70 g, 84 ). To a solution of this mixture in EtOH (150 mL) was added dropwise SQC¾ (53.5 g, 0.45
- 138 -
8544833.1 mol). The mixture was heated at reflux for 2 h and concentrated to dryness under reduced pressure. 'Die residue was dissolved in EtOAc (100 mL) and extracted with 10% Na2CC>3 solution (120 mL). The organic layer was found to contain 5-methyl-2,4~dinitro-ben:zoie acid ethyl ester while the aqueous layer contained 3-methyl-2,6-diratro-benzoic acid. The organic layer was washed with brine (50 mL), dried over Να2804 and concentrated to dryness to provide 5-methyl-2,4-dinitro-benzoic acid ethyl ester (20 g, 20 %).
[0428] ^"(Ι-ΡΜδ^Ι^Μΐϊΐο-νϊ^ - , άΙίΐΙΐΓα-^ΐϊζοίο acid ethyl ester
A mixture of 5-met yl-2,4-dmitro-benzoic acid ethyl ester (39 g, 0.15 mol) and
dimethoxymethyl-dimethylamine (32 g, 0.27 mo!) in DMF (200 mL) was heated at 100 °C for 5 h. The mixture was poured into ice water. The precipitate was collected via filtration and washed with water to afford 5-(2-dimethylamino-vinyl)-2,4-di tro-benzoie acid ethyl ester (15 g, 28 %).
[Θ429] B~25; β-Ammo-lH-indefe-S-carbexy!fc add ethyl ester
A mixture of 5-(2wiimethylamirio-vinyl)-2,4-dinitro-benzoic acid ethyl ester (15 g, 0,05 mol) and Raney Ni (5 g) in EtOH (500 mL) was stirred under ¾ (50 psi) at room temperature for 2 h. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica get to give 6-amino-lH-indofe-5-carboxyiic acid ethyl ester (B-25) (3 g, 30 %). !H NMR (DMSG-<¾ δ 10.68 (s, 1 H), 7.99 (s, 1 H), 7.01-7.06 (m, 1 H), 6.62 (s, 1 H), 6.27-6.28 (m, 1 H), 6.16 (s, 2 H), 4.22 (q, / = 7.2 Hz, 2 H), 1.32-1.27 (t, 7 = 7.2 Hz, 3 H).
Exam le 5;
Figure imgf000140_0001
B-27 l-(2^-Dihydro-li¾ Iol-l~yi)~ethaisoEe
·· B9 -
8544833,5 To a suspension of NaHC03 (504 g, 6.0 mol) and 2,3-dihydro~lH~indole (60 g, 0.5 mol) in CH2CI2 (600 mL) cooled in an ice-water bath, was added dropwise acetyl chloride (78.5 g, 1.0 mol). The mixture was stirred at room temperature for 2 h. The solid was filtered off and the filtrate was concentrated to give l -(2,3~dihydro-mdol~l-yl)-ethanone (82 g, 100 %).
[©431] l-iS-Bromo-l^-dlhydro-Mdol-l-y -eihaHosie
To a solution of l-(2,3-diliydro-indol-l-yS)-ethanone (58.0 g, 0.36 mol) in acetic acid (3000 mL) was added Br2 (87.0 g, 0.54 mol) at 10 °C. The mixture was stirred at room temperature for 4 h. The precipitate was collected via filtration to give crude l-(5~hromo-2,3-d¾ydro~mdol~l-yi>- ethanone (100 g, 96 %), which was used directly in the next step.
[0432] 5-Br©M®-2,3-dihydro-lH Kd©!e
A mixture of crude l-(5-bromo-2,3-diliydiO-indol-l -yI)-ethanone (100 g, 0.34 mol) in HQ (20 %, 1200 mL) was heated at reflux for 6 h. The mixture was basified with Na2C03 to pH 8.5-10 and dien extracted with ethyl acetate. The combined organic layers were washed widi brine, dried over Na2SC>4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 5-bromo-2,3-dihydro-lH-indole (37 g, 55 %).
[0433] S-Broaso-e-Mtr - ^-dlh dris-iH-iKdoIe
To a solution of 5-bromo-2,3-dihydro-lH-indole (45 g, 0.227 mol) in H2S04 (98 %, 200 mL) was slowly added K 03 (23.5 g, 0.23 mol) at 0 °C. After addition, die mixture was stirred at 0 - 10 °C for 4 h, carefully poured into ice, basified with Na2CG3 to pH 8 and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over N 2S04 and concentrated to dryness. The residue was purified by column chromatography on silica gel to give 5-bi mo~6-nitro-2,3-dihydro-lH-indole (42 g, 76 %),
[0434] S-Brom©-6-¾ltro-lH-iisd©le
To a solution of 5-bromo-6-nitro-2,3-dihydro- lH-indole (20 g, 82.3 mmol) in 1,4-dioxane (400 mL) was added DDQ (30 g, 0.13 mol). The mixture was stirred at 80 °C for 2 h. The solid was filtered off and the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel to afford 5-bromo-6-niiro-lH-indole (7.5 g, 38 %).
- 140 -
85Φ3833.Ϊ [0435] B-27; 5-Bromo-lH-I¾dol-6-yiamme
A mixture of 5-bromo-6-nitro-lH-indole (7.5 g, 31.1 mmol) and Raney Ni (1 g) in ethanol was stirred under ¾ (1 aim) at room temperature for 2 h. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel to give 5-bromo-lH-indol-6-ylamine (B-27) (2 g, 30 %). !H NMR (DMSO~<f6) δ 10.6 (s, 1 H), 7.49 (s, 1 H), 6.79-7.02 (m, 1 H), 6.79 (s, 1 H), 6.14-6.16 (m, 1 H), 4.81 (s, 2 H).
[Θ436] 7-Substihited frarotaomdofe
Figure imgf000142_0001
[0437] 3-Meihyi-2,6-di.iiiro-beiiz k acid
To a mixture of HN03 (95 %, 80 mL) and H2S04 (98 , 80 niL) was slowly added 3- methylbenzoic acid (50 g, 0.37 mol) at 0 °C, After addition, the mixture was siirred for 1.5 h while maintaining the temperature below 30 °C. The mixture was poured into ice-water and stirred for 15 mm. The precipitate was collected via filtration and washed with water to give a mixture of 3-metliyl-2,6-dinitro-benzoic acid and 5-methyl~2,4-dinitro-benzoic acid (70 g, 84 %). To a solution of this mixture in EtOH (150 mL) was added dropwise SOC¾ (53.5 g, 0.45 mol). The mixture was heated to reflux for 2 h and concentrated to dryness under reduced pressure. The residue was dissolved in EiOAc (100 mL) and extracted with 10% Na2C(¾ solution (120 mL). The organic layer was found to contain 5-methyl-2,4-diniiro-benzoic acid ethyl ester. The aqueous layer was acidified with HC1 to pH 2 - 3 and the resulting precipitate was collected via filtration, washed with water and dried in air to give 3~methyl-2,6-dinitn benzoic acid (39 g, 47 %).
- 141 -
8544833.1 [0438] 3"Methyl-2,6-dimtro-bea∞k add ethyl ester
A mixture of 3-me yl~2,6~dmiira-faenzoic acid (39 g, 0.15 mol) and SOCI2(80 niL) was heated at reflux for 4 h. The excess SOCl2 was removed under reduced pressure and the residue was added dropwise to a solution of EtOH (100 mL) and Et N (50 mL). The mixture was stirred at 20 °C for 1 h and concentrated to dryness. The residue was dissolved in EtOAc (100 mL), washed with NaaC03 (10 %, 40 mL x 2), water (50 mL x 2) and brine (50 mL), dried over Na2SG4 and concentrated to give 3-methyl-2,6-dinitro-ben2oic acid ethyl ester (20 g, 53 %).
[§439] 3-(2-DimethySamieo-viiiyi)-2?6-diBitro-bem!ok acid ethyl ester
A mixture of 3-memyl-2,6~diniiro-benzoic acid ethyl ester (35 g, 0.14 mol) and
dimethoxymethyl-dimethyl amine (32 g, 0.27 mol) in DMF (200 mL) was heated at 100 °C for 5 h. The mixture was poured into ice water and the precipitate was collected via filtration and washed with water to give 3-(2-dimethylamino-vinyl)-2,6-dinitro-benzoic acid ethyl ester (25 g, 58 %).
[0440] B-19; 6-Amlrao«-lH-iiidoIe-7-carb0xyHc add ethyl ester
A mixture of 3-(2-dimei ylamino-vinyI)-2, 6-dinitro-benzoie acid ethyl ester (30 g, 0.097 mol) and Raney Ni ( 10 g) in EtOH ( 1000 mL) was stirred under ¾ (50 psi) for 2 h. The catalyst was filtered off, and the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel to give 6-amino-lH-indole-7-carboxylic acid ethyl ester (B-19) as an off-white solid (3.2 g, 16 %). Ή NM (DMSO-t¾) δ 10.38 (s, 1 H), 7.44-7.4 (d, 7 = 8.7 Hz, 1 H), 6.98 (t, 1 H), 6.65 (s, 2 H), 6.50-6.46 (m, 1 H), 6.27-6.26 (m, 1 H), 4.43-4.36 (q, 7= 7.2 Hz, 2 H), 1.35 (t, 7= 7.2 Hz, 3 H).
[§441] Phenols
[0442] Example 1:
Figure imgf000143_0001
To a cooled solution of sulfuric acid (90 %, 50 mL) was added dropwise 2-½ri-butyl- phenyiamine (4.5 g, 30 mmol) at 0 °C, Potassium nitrate (4.5 g, 45 mmoi) was added in portions at.0 °C. The reaction mixture was stirred at.0-5 °C for 5 min, poured into ice-water and then
- 142 -
8544833.1 extracted with EtOAc three times. The combined organic layers were washed with brine and dried over Na2S0 . After removal of solvent, the residue was purified by recrystallization using 70 % EtOH - H20 to give 2-terf-butyl-5-nitroaniline (3.7 g, 64 %). lE NMR (400 MHz, CDC13) δ 7.56 (dd, J = 8.7, 2.4 Hz, 1H), 7.48 (d, J = 2.4 Hz, 1H), 7.36 (d, J = 8.7 Hz, 1H), 4.17 (s, 2H), 1.46 (s, 9H); HPLC ret, time 3.27 rain, 10-99 % CH3CN, 5 min run; ESI-MS 195.3 m/z (MtT).
[0444] C-l-a; 2-teri-B tyl-5-nltroph®¾ I
To a mixture of 2-fm-butyl-5~niiroaniline ( 1.94 g, 10 mmol) in 40 mL of 15 % H2SO4 w s added drop wise a solution of NaNG? (763 mg, 11.0 mmol) in water (3 mL) at 0 °C. The resulting mixture was stirred at 0-5 °C for 5 min. Excess NaN02 was neutralized with urea, then 5 mL of H2SO4-H2O (v/v 1 :2) was added and the mixture was refluxed for 5 min. Three additional 5 mL aliquots of H2SO4-H2O (v/v i :2) were added while heating at reflux. The reaction mixture was cooled to room temperature and extracted with EtOAe twice. The combined organic layers were washed with brine and dried over MgS(¾. After removal of solvent, the residue was purified by column chromatograph (0-10 % EtOAc - Hexane) to give 2-tert-butyl-5-nitrophenol (C-l-a) (1.2 g, 62 %). lH NMR (400 MHz, CDC13) δ 7.76 (dd, J = 8.6, 2.2 Hz, 1H), 7.58 (d, J = 2.1 Hz, III), 7,43 (d, J = 8.6 Hz, 1H), 5.41 (s, 1H), 1.45 (s, 9H); HPLC ret. time 3.46 min, 10-99 % CH3C , 5 min run.
[0445] C-l; -ie/ - iityl-S-amiKopfeeisoL To a refluxing solution of 2-½ri-butyI-5- nitrophenol (C~l-a) ( 196 mg, 1.0 mmol) in EtOH (10 mL) was added ammonium formate (200 mg, 3.1 mmol), followed by 140 mg of 10% Pd-C. The reaction mixture was refluxed for additional 30 min, cooled to room temperature and filtered through a plug of CeSite. The filtrate was concentrated to dryness and purified by column chromatography (20-30% EtOAc- Hexane) to give 2-tert-butyl-5-aminophenol (C-l) (144 mg, 87 %). *H NMR (400 MHz, DMSO-de) δ 8.76 (s, lH), 6.74 (d, J = 8,3 Hz, 1H), 6.04 (d, J = 2.3 Hz, 1H), 5.93 (dd, J = 8.2, 2.3 Hz, 1H), 4.67 (s, 2H), 1.26 (s, 9H); HPLC ret. time 2.26 min, 10-99 % C¾CN, 5 min run; ESI-MS 166.1 m/z (MIT).
- 143 -
S5 833.1 [0446] Example 2:
0447] General scheme:
Figure imgf000145_0001
a) RX (X = Br, I), K2C03 or Cs2C03t OMF; b) HC02N¾ or H.C02K, Pd-C, EtOH 0448] Specific example:
Figure imgf000145_0002
[0449] l~tert-Bisiyl-2~methoxy-4-alirobes¾e¾5e
To a mixture of 2~ter?-buty]-5~oitrophenol (C-l-a) (100 mg, 0.52 mmol) and K2C03 (86 mg, 0.62 mmol) in DMF (2 mL) was added C¾I (40 uL, 0.62 mmol). The reaction mixture was stirred at room temperature for 2 h, diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSG4. After filtration, the filtrate was evaporated to dryness to give l-¾rf~butyl~2~me&oxy-4-nitrobenzene (82 mg, 76 %) that was used without further purification. JH NMR (400 MHz, CDC13) δ 7.77 (t, J = 4.3 Hz, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.40 (d, J = 8.6 Hz, 1H), 3.94 (s, 3H), 1.39 (s, 9H).
[0450] C-2; 4-ter->Botyl-3-raethoxyasiiih?e
To a refluxing solution of 1 -ier/-butyl-2-methoxy-4-mtrobenzene (82 mg, 0.4 mmol) in EtOH (2 mL) was added potassium formate (300 mg, 3.6 mmol) in water (1 mL), followed by 10% Pd-C (15 mg). The reaction mixture was refluxed for additional 60 min, cooled to room temperature and filtered through Ceiite. The filtrate was concentrated to dryness to give 4-ferf-butyi-3- methoxyaniiine (C-2) (52 mg, 72 %) that was used without further purification. HPLC ret. time 2.29 min, 10-99 % CH3CN, 5 min run; ESI-MS 180.0 m z (MH+),
- 144 -
8544S33.1 [§451] Other examples;
Figure imgf000146_0001
[0452] C-3; 3-i2-Ethoxyet¾oxy)-4-fei¾-biitylbei¾¾eisarai«e
3-(2-Ethoxyethoxy)-4-¾ri-butyIbenzenaniine (C-3) was synthesized following the general scheme above starting from 2-½ri-buty!-5-niirophenol (C~i-a) and i~bromo~2-ethoxyefchane, 3H NMR (400 MHz, CDC13) δ 6.97 (d, J = 7.9 Hz, 1H), 6.17 (s, 1H), 6.14 (d, J = 2.3 Hz, 1H), 4.00 (t, J = 5.2 Hz, 2H), 3.76 (t, J = 5.2 Hz, 2H), 3.53 (q, J = 7.0 Hz, 2H), 1.27 (s, 9H), 1.16 (t, J = 7.0 Hz, 3H); HPLC ret. time 2.55 min, 10-99 % CH3C , 5 min run; ESI-MS 238.3 m/z (MH+).
Figure imgf000146_0002
[0453] C-4; 2-(2-te i~BMiyI-5-amino lieii∞y)€fh iid
2-(2-teri-Butyl-5-aminophenoxy)ethanoi (C-4) was synthesized following the general scheme above start g from 2-?eri-butyI-5-mtrophenoI (C-l-a) and 2-bromoeihanoL HPLC ret. time 2.08 mm, 10-99 % CH3CN, 5 min rim; ESI-MS 210.3 m/z (MH+).
[§454] Example 3:
Figure imgf000146_0003
- 145 -
8544833.! [0455] N-(3-Hydroxy-phei¾yI)-a£etainMe assd acetic acid 3-forasyIamliio-ptessyl ester
To a well stirred suspension of 3-amino-phenol (50 g, 0.46 mol) and NaHCG3 (193.2 g, 2.3 mol) in chloroform (1 L) was added dropwise chloroacetyl chloride (46.9 g, 0.6 mol) over a period of 30 min at 0 °C. After the addition was complete, the reaction mixture was refiuxed overnight and then cooled to room temperature. The excess NaHCQ was removed via filtration. The filtrate was poured into water and extracted with EtOAc (300 x 3 mL). The combined organic layers were washed with brine (500 rnL), dried over anhydrous Na?S04 and concentrated under reduced pressure to give a mixture of N~(3~hydroxy-phenyl)-acetamide and acetic acid 3- formylamino-phenyl ester (35 g, 4:1 by NMR analysis). The mixture was used directly in the next step.
[§456] N-[3-(3-MethyI-but-3-enyloxy)-phenyI] -aeetamide
A suspension of the mixture of N-(3-hydroxy-phenyl)-acetamide and acetic acid 3-formyIamino- phenyl ester (18.12 g, 0.12 mol), 3-methyl-but-3-en-l-ol (8.6 g, 0.1 mol), DEAD (87 g, 0.2 mol) and Ph3P (31.44 g, 0.12 mol) in benzene (250 mL) was heated, at reflux overnight and then cooled to room temperature. The reaction mixture was poured into water and the organic layer was separated. The aqueous phase was extracted with EtOAc (300 x 3 mL). The combined organic layers were washed with brine, dried over anhydrous 2804 and concentrated. The residue was purified by column chromatography to give N-[3-(3-methyl-but-3-enyloxy)- phenylj-acetamide (1 1 g, 52 %).
[©457] N-(4,4-Dimethyl-chroiBasi-7~yI)-aceiaiiiide
A mixture of N-[3-(3-methyl-but-3-enyloxy)-phenyl]-acetamide (2.5 g, 11.4 mmol) and A1C13 (4.52 g, 34.3 mmol) in fiuoro-benzene (50 mL) was heated at reflux overnight. After cooling, the reaction mixture was poured into water. The organic layer was separated and the aqueous phase was extracted with EtOAc (40 x 3 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SQ4 and concentrated under vacuum. T!ie residue was purified by column chromatography to give N~(4,4-dimethyl~chroman-7-yi)-acetamide (1.35 g, 54 %).
[0458] C-5; 3,4-Dmydro-4,4-dimemyi-2H-chromen-7-amine
A mixture of N-(4,4-dimethyl-chroman-7-yl)-acetamide (1.35 g, 6.2 mmol) in 20 % HC1 solution (30 mL) was heated at reflux for 3 h and then cooled to room temperature. The reaction mixture was basified with 10 % aq. NaOH to pH 8 and extracted with EtOAc (30 x 3 mL). The
- 1.46 -
S544833.1 combined organic layers were washed with brine, dried over anhydrous Na2SG4 and concentrated to give 3,4-dihydro-4,4-dimetliyl-2H-chromen-7-amine (C~5) (1 g, 92 %). Ή NMR (DMSO- ) δ 6,87 (d, / = 8.4 Hz, 1 H), 6.07 (dd, J = 8.4, 2.4 Hz, 1 H), 5.87 (d, J = 2.4 Hz, 1 H), 4.75 (s, 2 H), 3.99 (t, J = 5.4 Hz, 2 H), 1.64 (t, J = 5.1 Hz, 2 H), 1.15 (s, 6 H); ESI-MS 178.1 m/z (Mtf).
[0459] Example 4;
Figure imgf000148_0001
X = F, CI; a) ROH, H2S0 or MeS03H, C¾C12; b) R'CG2Ci, Et3N, 1,4-dioxane or CHCh; c) HN03, H2S04 or K 03, H2S04 or HNCfe, AcOH; d) piperidine, CH2C12; e) HCO2NH4, Pd-C, EtOH or SnCl2.2H2Ot EtOH or ¾, Pd-C, MeOH.
- 147 -
8544833,3 0461] Specific example
Figure imgf000149_0001
[0462] 2-te i-B5ityl~4~flis<.>riipl¾eii«I
4-Fiuorophenoi (5g, 45 mmol) and ft?rf-butanoi (5.9 mL, 63 mmoi) were dissolved in CH2Ch (80 mL) and treated with concentrated sulfuric acid (98 %, 3 mL). The mixture was stirred at room temperature overnight. The organic layer was washed with water, neutralized with NaHC<¼, dried over IvigS04 and concentrated. The residue was purified by column
chromatography (5-15 % EtOAc - Hexane) to give 2-tert-butyl-4-fluorophenol (3.12 g, 42 %). lH NMR (400 MHz, DMSCkfc) δ 9.32 (s, 1H), 6.89 (dd, J = 11.1, 3.1 Hz, 1H), 6.84-6.79 (m, 1H), 6.74 (dd, J = 8.7, 5.3 Hz, 1H), 1.33 (s, 9H).
[©463]
Figure imgf000149_0002
methyl carbonate
To a solution of 2-ieri-butyl-4-fluorophenol (2.63g, 15.7 mmol) and NE13 (3.13 mL, 22.5 mmol) in dioxane (45 mL) was added methyl chloroformate (1.27 mL, 16.5 mmol). The mixture was stirred at room temperature for 1 h. The precipitate was removed via filtration. The filtrate was then diluted with water and extracted with ether. The ether extract was washed with water and dried over MgS04. After removal of sol ent, the residue was purified by column
chromatography to give 2-½ f-butyl-4-fluorophenyl methyl carbonate (2.08g, 59 %). 5H NMR (400 MHz, DMSC s) δ 7.24 (dd, J = 8.8, 5.4 Hz, 1H), 7.17-7.10 (m, 2H), 3.86 (s, 3H), 1.29 (s, 9H).
- 148 -
8544833.5 [©464] 2-tefi-BisiyI-4-fl¾i ro-5- irophei5yI methyl carbonate (C-7-a) mnd 2-iert- taty!~4«flMOTo-6"fflirophesyI methyl earboeate (€~6~a)
To a solution of 2-½r/-butyl-4-fluorophenyl methyl carbonate (1.8 lg, 8 mmol) in H2SO4 (98 %, 1 mL) was added slowly a cooled mixture of H2SO4 (1 mL) and H 03 (1 mL) at 0 °C. Be mixture was stirred for 2 h while warming to room temperature, poured into ice and extracted with diethyl ether. The ether extract was washed with brine, dried over MgSG and
concentrated. The residue was purified by column chromatography (0-10 % EtOAc - Hexane) to give 2-½rf-butyl-4-fluoro-5-rsitrophenyl methyl carbonate (C-7-a) (1.2 g, 55 ) and 2-tert- butyl-4~fluoro-6-nitrophenyl methyl carbonate (C-6-a) (270 mg, 12 %). 2-teri-Butyl-4-fluoro-5- nitrophenyl methyl carbonate (C-7-a): *H NMR (400 MHz, DMSO-40 δ 8.24 (d, J = 7.1 Hz, 1H), 7.55 (d, J = 13,4 Hz, 1H), 3.90 (s, 3H), 1.32 (s, 9H). 2-tert-butyl-4-fluoro-6-nitrophenyl methyl carbonate (C-6-a): H NMR (400 MHz, DMSO- ) δ 8.04 (dd, J = 7,6, 3.1 Hz, lH), 7.69 (dd, J = 10.1, 3.1 Hz, 1H), 3.91 (s, 3H), 1.35 (s, 9H).
[0465] 2-ieri-Bi5tyI-4-fl5soro-S-sitropheiiol
To a solution of 2-teri-butyl-4-fluoro-5-nitrophenyi methyl carbonate (C-7-a) (1,08 g, 4 mmol) in CH2CI2 (40 mL) was added piperidine (3.94 mL, 10 mmol). The mixture was stirred at room temperature for 1 h and extracted with IN NaOH (3x). The aqueous layer was acidified with IN HC1 and extracted with diethyl ether. The ether extract was washed with brine, dried (MgS(¼) and concentrated to give 2-½^butyI~4-fhioro~5~Mtrophenol (530 mg, 62 %). Ή NMR (400 MHz, DMSO-6?6) δ 10.40 (s, 1H), 7.49 (d, J = 6.8 Hz, 1H), 7.25 (d, J™ 13,7 Hz, 1H), 1.36 (s, 9H).
[©466] C-7; 2~teri~Betyl-5-amisi -4-fleoropheBoi
To a refluxing solution of 2-feri-butyI-4-fluoro-5-nitrophenoi (400 mg, 1.88 mmol) and ammonium formate (400 mg, 6.1 mmol) in EtOH (20 mL) was added 5 % Pd-C (260 mg). The mixture was refluxed for additional 1 h, cooled and filtered through Celite. The solvent was removed by evaporation to give 2-ieri-butyl-5-amino-4-fli5orophenol (C-7) (550 mg, 83 %). ¾ NMR (400 MHz, DMSO- ) δ 8.83 (br s, 1H), 6.66 (d, J = 13.7 Hz, 1H), 6.22 (d, J = 8.5 Hz, lH), 4.74 (br s, 2H), 1.26 (s, 9H); HPLC ret. time 2.58 rain, 10-99 % CH3C , 5 min run; ESI- MS 184.0 m/z (MH").
- 149 -
§544833. i [§467] Oilier examples:
Figure imgf000151_0001
[0468] C-10; 2-fert-B¾¾tyl-S-amiffio-4-cMoroph©Hol
2-feri-Buiyl-5-a!nino-4-chlorophenol (C-10) was synthesized following die general scheme above starting from 4-chlorophenol and teri-butanol. Overall yield (6 %). HPLC ret, time 3.07 min, 10-99 % CH3CN, 5 min run; ESI-MS 200.2 m/z (MH+).
Figure imgf000151_0002
[0469] C-13; S-A0iiHO»4-fl«oro~2~(l»meth !cyelohexyl)pheMoI
5-Amino-4-fluoro-2-(l-methylcyclohexyl)phenol (C-13) was synthesized following the general scheme above starting from 4-fluorophenol and 1-methylcyclohexanoL Overall yield (3 %). HPLC ret. time 3.00 min, 10-99 % C¾CN, 5 min ran; ESI-MS 224.2 m z (MH+).
Figure imgf000151_0003
[©470] C-19; 5~AffliBo-2-(3-ethylpeniasi-3-yl).4-flsioro-pheKol
5-Amino-2-(3-etliylpentan-3-yl)-4-fluoro~phenol (C-19) was syntliesized following the general scheme above starting from 4-fluorophenol and 3-ethyl-3-pentanol. Overall yield (1 %).
Figure imgf000151_0004
- 350 -
85 4S33.1 [0471] C-20; 2-AdissaBtyl-S-aiBiisi -4-iliS0 o~pheMol
2-Admantyl-5-amino-4-fluoro-phenol (C~2©> was synthesized following the general scheme above starting from 4-fluorophenol and adamanten-l-oL
Figure imgf000152_0001
5-Amino-4-fiuoro-2-(l-meihy!cycloheptyl)phenol (C-21) was synthesized following the general scheme above starting from 4-fluorophenol and 1 -methyl-cyclohepianoL
Figure imgf000152_0002
[0473] C-22; S-Amlm 4~ leoro--2~(l-m€tliykyclo< tyl)phe oI
5~Amino-4-fluoro-2-(l-met!'iylcycloociyl)phenol (C-22) was synthesized
scheme above starting from 4-fluorophenol and l-methyl-cyclooctanoh
Figure imgf000152_0003
[0474] C-23; 5-Amino«2-(3-ethyI~2,2-diiiieihy!peHiaa-3-yl)-4-flaoF ~pherioi 5-Amino-2-(3~etliyl-2,2"dimethylpentan-3-yl)-4-fluoro-phenol (C-23) was synthesized following the general scheme above storting from 4-fluorophenol and 3-ethy!~2,2-dimethyl~ pentan-3-oL
- 151 -
8544833.1 [Θ475] Exam le 5:
Figure imgf000153_0001
[0476] C-6; 2-terf-Biityl-4- leoro-6~amm p¾®0yI methyl carbonate
To a refluxing solution of 2-terf-buiy!-4-fl oro-6~nitrop eByl methyl carbonate (250 mg, 0.92 mmol) and ammonium formate (250 mg, 4 mmol) in EtOH (10 mL) was added 5 % Pd-C (170 mg). The mixture was refluxed for additional 1 h, cooled and filtered through Celite. The solvent was removed by evaporation and the residue was purified by column chromatography (0-15 %, EtOAc - Hexane) to give 2-¾ri-butyl-4-fluoro-6-aromophenyl methyl carbonate (C-6) (60 mg, 27 %). HPLC ret, time 3.35 min, 10-99 % CH3CN, 5 min run; ESI-MS 242.0 m z (ΜΙΓ). Θ477] Example 6:
Figure imgf000153_0002
[0478] Carbonic add 2,4-dI"ieri»biityl-pheayl ester methyl ester
Metliyi chloroformate (58 mL, 750 mmol) was added dropwise to a solution of 2,4-di-feri-butyl- phenol (103.2g, 500 mmol), Et3N (139 mL, 1000 mmol) and DMAP (3.05g, 25 mmol) in dichloromelhane (400 mL) cooled in an ice-water bath to 0 °C. The mixture was allowed to
- 352 -
8544833. i warm to room temperature while stirring overnight, then filtered through silica gel (approx. 1L) using 10% ethyl acetate - hexasies (~ 4 L) as the eluent. The combined filtrates were concentrated to yield carbonic acid 2,4-di-ierf-butyl-phenyl ester methyl ester as a yellow oil (132 g, quant.)- !H NMR (400 MHz, DMSO-tfc) 5 7.35 (d, J = 2.4 Hz, 1H), 7.29 (dd, J = 8,5, 2.4 Hz, 1H), 7.06 (d, J = 8.4 Hz, IB), 3.85 (s, 3H), 1.30 (s, 9H), 1.29 (s, 9H).
[0479] Carbonic acid 2,4-di-ieri-botyI-5- Mro-pheayl ester methyl ester mid
Carbonic acid 2,4-di-ier#-b»tyl-6-iiitro~pheiiyi ester methyl ester
To a stirring mixture of carbonic acid 2,4-di-tert-butyl-phenyl ester methyl ester (4.76 g, 18 mmoi) in cone, sulfuric acid (2 mL), cooled in an ice- water bath, was added a cooled mixture of sulfuric acid (2 mL) and nitric acid (2 mL). The addition was done slowly so that the reaction temperature did not exceed 50 °C. The reaction was allowed to stir for 2 h while warming to room temperature. The reaction mixture was then added to ice-water and extracted into diethyl ether. The ether layer was dried (Mg804), concentrated and purified by column chromatography (0 - 10% ethyl acetate -- hexanes) to yield a mixture of carbonic acid 2,4-di-f*?rt-butyl-5-nitro- phenyl ester methyl ester and carbonic acid 2,4-di-ierT-butyl-6-nitro-phenyl ester methyl ester as a pale yellow solid (4.28 g), which was used directly in the next step.
[0480] 2,4-Di-terf-batyl-5-iiiiro~pheHol and 2,4-Di-feri.b4ityI-6-¾itro-phenol The mixture of carbonic acid 2,4-di-reri-butyl-5-nitro-phenyl ester methyl ester and carbonic acid 2,4-di-ieri-butyl-6-nitro-phenyl ester methyl ester (4.2 g, 12.9 mmoi) was dissolved in MeOH (65 mL) and KOH (2.0g, 36 mmoi) was added. The mixture was stirred at room temperature for 2 h. The reaction mixture was then made acidic (pH 2-3) by adding cone. HCS and partitioned between water and diethyl ether. The ether layer was dried (Mg804), concentrated and purified by column chromatography (0 - 5 % ethyl acetate - hexanes) to provide 2,4-di-iert-butyl-5-nitro-phenol (1 .31 g, 29 % over 2 steps) and 2,4-di-ierf-butyl-6-nitro- phenol. 2,4-Di-iert-butyl-5-nitro-phenol: Ή NMR (400 MHz, DMSO- ) 5 10.14 (s, 1H, OH), 7.34 (s, 1H), 6.83 (s, 1H), 1.36 (s, 9H), 1 0 (s, 9H). 2,4-Di-tert-butyl-6-nitro-phenoI: !H NMR (400 MHz, CDC13) 5 11.48 (s, 1H), 7.98 (d, J = 2.5 Hz, 1H), 7.66 (d, J = 2.4 Hz, 1H), 1.47 (s, 9H), 1.34 (s, 9H).
[Θ48Ι] C-9 5-Amtoo-2,4-di-fe? -botyI-pheKoi
To a refuxing solution of 2,4-di-½ri~butyl-5-nitro-phenol (1.86 g, 7.4 mmoi) and ammonium formate (1.86 g) in ethanol (75 mL) was added Pd-5% wt. on activated carbon (900 mg). The
- 153 -
8:544833. Ϊ reaction mixture was stirred at reflux for 2 h, cooled to room temperature and filtered through Celite. The Celite was washed with methanol and the combined filtrates were concentrated to yield 5-amino-2,4-di-¾ri-butyl-phenol as a grey solid ( 1.66 g, quant.). !H NMR (400 MHz, DMSC s) δ 8.64 ($, 1H, OH), 6.84 (s, 1H), 6.08 (s, 1H), 4.39 (s, 2H, N¾), 1.27 (m, 18H); HPLC ret. time 2.72 min, 10-99 % CH3CN, 5 min run; ESI-M8 222.4 mix (MH+).
[Θ482] C-8; 6-Amino-2,4-dl»fifrt~bsiiy!-phenoi
A solution.of 2,4~di-iei ~butyl-6-nitro-phenol (27 mg, 0.11 mmol) and SnG2,2¾0 ( 121 mg, 0.54 mmol) in EtOH (1,0 mL) was heated in microwave oven at 100 °C for 30 min. The mixture was diluted with EtOAc and water, basified with sat. NaHC03 and filtered through Celite. The organic layer was separated and dried over Na2S04. Solvent was removed by evaporation to provide 6-amino-2,4-di-teri-butyl-phenol (C-8), which was used without further purification. HPLC ret. time 2.74 min, 10-99 % CH3CN, 5 min run; ESI-MS 222.5 m/z (MH+). 0483] Example 7:
Figure imgf000155_0001
[0484] -fert-boiyl-2-cMoro-pheiiol
To a solution of 4-terf-butyl-phenol (40.0 g, 0.27 mol) and S02C12 (37.5 g, 0,28 mol) in CH2C12 was added MeOH (9.0 g, 0.28 mol) at 0 °C. After addition was complete, the mixture was stirred overnight at room temperature and then water (200 mL) was added. The resulting solution was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2S(>4, filtered and concentrated under vacuum. The residue was purified by column chromatography (Pet. Ether / EtOAc, 50: 1) to give 4-¾rt-buiyl-2-chloro-phenol (47,0 g, 95 %).
- 154 -
8544833.1 [I 85]
Figure imgf000156_0001
methyl e rboHste
To a solution of 4-fert-butyl-2-ch!oropheno! (47.0 g, 0.25 mo!) in didiloroniethane (200 mL) was added Et3N (50,5 g, 0,50 mol), DMAP (1 g) and methyl chloroformate (35.4 g, 0.38 mol) at 0 CC. The reaction was allowed to warm to room temperature and stirred for additional 30 min. The reaction mixture was washed with H20 and the organic layer was dried over Na2S04 and concentrated to give 4-½rf-butyI-2-ch!orophenyl methyl carbonate (56.6 g, 92 ), which was used directly in the next step.
[0486] 4-teri-Boiyl-2-cMore-S-isiiropheiiyS methyl carbooate
4-ii?ri~ButyI-2-chlorophenyl methyl carbonate (36.0 g, 0.15 mol) was dissolved in cone. H2SG (100 mL) at 0 °C. KN<¼ (0.53 g, 5.2 mmoi) was added in portions over 25 min. The reaction was stirred for 1.5 h and poured into ice (200 g). The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with aq. NaHCOa, dried over Na2S04 and concentrated under vacuum to give 4-ii?ri-butyl-2-chIoro-5-nitrophenyl methyl carbonate (41.0 g), which was used without further purification.
Potassium hydroxide (10.1 g, 181 mmo!) was added to 4-ierf-butyl-2-chloro-5-nitrophenyl methyl carbonate (40,0 g, 139 mmol) in MeOH (100 mL). After 30 min, the reaction was acidified with I N HC1 and extracted with dichloromethane. The combined organic layers were combined, dried over Na2S04 and concentrated under vacuum. The crude residue was purified by column chromatography (Pet. Ether / EtOAc, 30: 1) to give 4-ter/-butyl-2-chIoro-5-nitro- phenol (23.0 g, 68 % over 2 steps).
[0488] C-ll; 4~ί^-Βϊί¾Ί-2-€ θΓθ-§-Ηϊ κο- ¾βϊΐοΙ
To a solution of 4-ferf-butyl-2-chloro~5~nitro-phenol (12.6 g, 54.9 mmol) in MeOH (50 mL) was added Ni (1.2 g). The reaction was shaken under ¾ (1 arm) for 4 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column
chromatography (PJE. / EtOAc, 20: 1 ) to give 4-ieri~butyl-2-chloro-5-amino-phenol (C-ll) (8.5 g, 78 %). Ή NMR (DMSC 6) δ 9.33 (s, 1 H), 6.80 (s, 1 H), 6.22 (s, 1 H), 4.76 (s, 1 H), 1.23 (s, 9 H); ESI-MS 200.1 m z (MH+).
- 155 -
¥544833.1 [0489] Example 8:
Figure imgf000157_0001
C-12
2-Adroaffltyl-4-methyl-phe»yI ethyl c&rbcm&te
Ethyl chloroformate (0.64 mL, 6.7 mmol) was added dropwise to a solution of 2-admantyl-4- methyiphenol (1.09 g, 4.5 mmol), EtaN (1.25 mL, 9 mmol) and DMAP (catalytic amount) in dichloromethane (8 mL) cooled in an ice-waier bam to 0 °C. The mixture was allowed to warm to room temperature while stirring overnight, then filtered and the filtrate was concentrated. The residue was purified by column chromatography (10-20 % ethyl acetate - hexanes) to yield 2- admantyl-4-meihyl-phenyl ethyl carbonate as a yellow oil (1.32 g, 94 %).
[049©] 2-Adma0iyI-4-met yl-.5~Mir phe¾yl ethyl carbonate
To a cooled solution of 2-admantyl-4-methyl-phenyl ethyl carbonate (1.32 g, 4.2 mmol) in H2S04 (98 , 10 mL) was added NO3 (510 mg, 5.0 mmol) in small portions at 0 °C, The mixture was stirred for 3 h while warming to room temperature, poured into ice and men extracted with dichloromethane. The combined organic layers were washed with NaHC(¾ and brine, dried over MgS04 and concentrated to dryness. The residue was purified by column chromatography (0-10 % EtOAc - Hexane) to yield 2-admant.yl-4-methyl-5-nitrophenyl ethyl carbonate (378 mg, 25 %).
[©491] 2-Admai¾iyl-4-meihyi-S-Eliropl¾efflol
To a solution of 2-admantyl-4-methyl-5-nitrophenyl ethyl carbonate (378 mg, 1.05 mmol) in CH?C¾ (5 mL) was added piperidine (1.0 mL). The solution was stirred at room temperature for 1 h, adsorbed onto silica gel under reduced pressure and purified by flash chromatography on silica gel (0-15 %, EtOAc - Hexanes) to provide 2-admantyl-4-methyl-5-nitrophenol (231 mg, 77 %).
- 156 -
8544833, ! [0492] C-12; 2-Admaistyl- .methyI-5.a i o teffiol
To a solution of 2-admantyl~4-me&yS-5-nitrophenol (231 mg, 1.6 mmol) in EtOH (2 mL) was added Pd~ 5% wt on carbon (10 mg). The mixture was stirred under ¾ (1 aim) overnight and then filtered through Celite. The filtrate was evaporated to dryness to provide 2-admantyl~4- methyl-S-aminophenol (C-12), which was used without further purification. HPLC ret. time 2.52 min, 10-99 % CH3CN, 5 min run; ESi-MS 258.3 m/z (MH*). 0493] Example 9:
Figure imgf000158_0001
C-1
2-teif-Batyl"4-bromophenol
To a solution of 2-½rf-butylphenoI (250g, 1.67 mol) in CH3CN ( 1500 mL) was added NBS (300 g, 1.67 mol) at room temperature. After addition, the mixture was stirred at room temperature overnight and then the solvent was removed. Petroleum ether (1000 mL) was added, and the resulting white precipitate was filtered off. The filtrate was concentrated under reduced pressure to give the crude 2-ierr-butyl-4-bromophenol (380 g), which was used without further purification.
[0494] Methyl (2-i£rt-ta†yi-4-br©fK0phe*syl) carbonate
To a solution of 2-i~butyl~4-bromophenol (380 g, 1.67 mol) in dichlorometSiane (1000 mL) was added Et3N (202 g, 2 mol) at room temperature. Methyl chlorofomiate (155 mL) was added
- i57 -
8544833. i dropwise to the above solution at 0 °C, After addition, the mixture was stirred at 0 °C for 2 h., quenched with saturated ammonium chloride solution and diluted with water. The organic layer was separated and washed with water and brine, dried over Na2S04, and concentrated to provide the crude methyl (2-½ri-but l-4-bromophenyl) carbonate (470 g), which was used without further purification.
[0495] Methyl (2«ie? -b!styI-4-broMO-5-nIir©ph«iiyI) carboaate
Methyl (2-¾ri-butyI-4-bromophenyl) carbonate (470 g, 1.67 rnol) was dissolved in cone. H2S04 (1000 mL) at 0 °C, KNO3 (253 g, 2.5 mol) was added in portions over 90 min. The reaction mixture was stirred at 0 °C for 2 h arid poured into ice-water (20 L). The resulting precipitate was collected via filtration and washed with water thoroughly, dried and recry stall ized from ether to give methyl (2-teri-but>'l-4-bromo-5-nitrophenyl) carbonate (332 g, 60 % over 3 steps).
[0496] C-14-a; 2-fi?ri-BiiiyI"4~br0mo-S-mir©-phe0oI
To a solution of methyl (2-ieri-butyl-4-bromo-5-nitrophenyl) carbonate (121.5 g, 0.366 mol) in methanol (1000 niL) was added potassium hydroxide (30.75 g, 0.549 mol ) in portions. After addition, the mixture was stirred at room temperature for 3 h and acidified with IN HCi to pH 7. Methanol was removed and water was added. The mixture was extracted with ethyl acetate and the organic layer was separated, dried over Na2S04 and concentrated to give 2-feri-buty!-4- bromo-5-nitro-phenol (C-14-a) (100 g, 99 %).
[0497] l-im-Bsiyl-2-(benzyl©xy)-5-'brom©~4-iiitrobesi2esie
To a mixture of 2-¾ri-butyl-4-bromo-5-nitropheriol (C-14~a) (1.1 g, 4 mmoi) and CS2CO3 (1.56 g, 4.8 mmol) in DMF (8 mL) was added benzyl bromide (500 ί, 4.2 mmol). The mixture was stirred at room temperature for 4 h, diluted with ¾0 and extracted twice with EtOAc. The combined organic layers were washed with brine and dried over MgS04. After removal of solvent, the residue was purified by col mn chloromatography (0-5 % EtOAc - Hexane) to yield l-ie^butyi-2-(benzyloxy)-5-bromo-4-nitrobenzene (1.37 g, 94 %). *Η NM (400 MHz,
CDCI3) 7.62 (s, 1H), 7.53 (s, 1H), 7.43 (m, 5H), 5.22 (s, 2H), 1.42 (s, 9H).
[0498] l-i(e,r^Botyl-2-(ben^1oxy)-S-(iriflw0romeihyI)-4-iiIiroben2eiie
A mixture of l.-fenr-butyl-2-(ben2yloxy)-5-bromo-4-nitrobenzene (913 mg, 2.5 mmol), F (291 mg, 5 mmol), KBr (595 mg, 5 mmol), Cul (570 mg, 3 mmol), methyl chlorodifluoroacetate (1.6 mL, 15 mmol) and DMF (5 mL) was stirred at 125 °C in a sealed tube overnight, cooled to room
- 158 -
8544833.1 temperature, diluted with water and extracted three times with EtOAc. The combined organic layers were washed with brine and dried over anhydrous MgSO.*. After removal of the solvent, the residue was purified by column chromatography (0-5 % EtOAc - Hexane) to yield 1-ieri- but> -2-(benzyIoxy)-5-(frifl oroxnethyl)-4-nitrobenz.ene (591 nig, 67 %). !H NMR (400 MHz, CDCb) 7.66 (s, iH), 7.37 (m, 5H), 7.19 (s, 1H), 5.21 (s, 2H), 1.32 (s, 9H).
[0499] C-14; S-Ammo~2-feri-biit>'l">4-tFiflHoromethyl-phes¾ l
To a refluxiiig solution of l-ieri-butyl-2-(benzyloxy)-5-(trifluororaethyl)-4-niirobenzene (353 mg, 1.0 mmol) and ammonium formate (350 mg, 5.4 mmol) in EtOH (10 mL) was added 10% Pd-C (245 mg). The mixture was refluxed for additional 2 h, cooled to room temperature and filtered through Celite. After removal of solvent, the residue was purified by column chromatography to give 5-Ammo-2-ierf-butyI-4-trifluoramethyl-phenoI (€-14) (120 mg, 52 %). Ή NMR (400 MHz, CDCI3) δ 7.21 (s, 1H), 6.05 (s, 1H), 1.28 (s, 9H); HPLC ret. time 3.46 rain, 10-99 % CH3CN, 5 rniri run; ESI-MS 234.1 mix (MIT).
[0500] Example 10: Θ5Θ1] Genera! scheme:
Figure imgf000160_0001
a) ArB(OH)2, K2CO3, Pd(PPh3)4, H20, DMF or ArB(OIT)2, (dppf)PdCl2, K2C03, EtOH; b) H2, Raney Ni, MeOH or HC02 H4, Pd-C, EtOH or SnCl2.2H20.
Figure imgf000160_0002
- 159 -
S5 S33.I Θ5©3] 2-ierf-Buiyi-4-(2-ethoxypheiiyI)-S-iiiiropheffloI
To a solution of 2-?eri-butyl-4-bromo-5-nitrophenol (C-14-a) (8.22 g, 30 mmol) in DMF (90 mL) was added 2-ethoxyphenyl boronic acid (5.48 g, 33 mmol), potassium carbonate (4.56 g, 33 mmol), water (10 mL) and Pd(PPh3)4 (1.73 g, 1.5 mmol). The mixture was Sieated at 90 °C for 3 under nitrogen. The solvent was removed under reduced pressure. The residue was partitioned between water and ethyl acetate. The combined organic layers were washed with water and brine, dried and purified by column chromatography (petroleum ether - ethyl acetate, 10: 1) to afford 2-tert-butyl-4-(2-eihoxyphenyl)-5-fiitrophenol (9.2 g, 92 %). IH MR (DMSO- d6) δ 10.38 (s, 1 H), 7.36 (s, 1 H), 7.28 (m, 2 H), 7,08 (s, 1 H), 6.99 (t, 1 H, J = 7.35 Hz), 6.92 (d, 1 H, / = 8.1 Hz), 3.84 (q, 2 H, / = 6.6 Hz), 1.35 (s, 9 H), 1.09 (t, 3 H, = 6.6 Hz); ESi-MS 314.3 m/z (MH'!).
[0504] C-i5; 2-ii?r -Bi3tj'!-4-(2-e hoxyp eeyI)-5»amli5 phm l
To a solution of 2-feri-butyl-4-(2-eihoxyphenyl)-5-nitrophenoi (3.0 g, 9.5 mmol) in methanol (30 mL) was added aney Ni (300 mg). The mixture was stirred under H2 (1 aim) at room temperature for 2 h. The catalyst was filtered off and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether - ethyl acetate, 6: 1 ) to afford 2~tert~ butyi^4-(2-ethoxyphenyl)-5-aminophenoI (C-15) (2.35 g, 92 %). 'HNMR (DMSCMs) δ 8.89 (s, l H), 7.19 (t, lH, / = 4.2 Hz), 7.10 (d, 1H, J = 1.8 Hz), 7.08 (d, lH, = 1.8 Hz), 6.94 (t, 1Η, / = 3.6 Hz), 6.67 (s, 1 H), 6.16 (s, 1 H), 4.25 (s, 1 H), 4.00 (q, 2H, J = 6,9 Hz), 1.26 (s, 9H), 1.21 (t, 3 H, J = 6.9 Hz); ESI-MS 286.0 m z (MET),
[0505] Other examples:
Figure imgf000161_0001
[05§6] C-16; 2-teif-BHiyl-4-(3-eth0xyphmyl)~5~amraopheiiol
2-iferi-Butyl-4-(3-ethoxyphenyl)-5-aminophenol (€-16) was synthesized following the general scheme above starting from 2-teri-butyl-4-bromo-5-nitrophenol (C-14-a) and 3-ethoxyphenyi boronic acid, HPLC ret. time 2.77 min, 10-99 % C¾CN, 5 min ran; ESI-MS 286.1 m/z (MKT).
- 160 -
S544833.!
Figure imgf000162_0001
[0507] C-17; 2-ferf-B«t5rl-4-(3»methoxyearboayIphe¾yI)-S-aTO »i pfeeTOl (C-17) 2-it5ri-Buiyl-4-(3-n\eihoxycarborsyIphe!iyl)-5-aminopheiioI (C-17) was synthesized following the genera! scheme above starting from 2-f£sri-butyl-4-bromo-5-mtrophersoI (C«14«a) and 3- (methoxyearbonyi)phenyiboronie acid. HPLC ret. time 2.70 min, 10-99 % C¾CN, 5 min run; ESI-MS 300.5 m/z (MH+).
Figure imgf000162_0002
[0509] l-feri-Bisiyl-2-meihMy-5-bromo-4-Bitrobeiu¾ene
To a mixture of 2-iiri~butyl-4-bromo-5-nitrophenoi (C-14-a) (1.5 g, 5.5 mmol) and CS2CO3 (2.2 g, 6.6 rnmo!) in DMF (6 mL) was added methyl iodide (5150 ,LtL, 8.3 mrrsol). The mixture was stirred at room temperature for 4 h, diluted with H20 and extracted twice with EtOAc. The combined organic layers were washed with brine and dried over MgS€>4. After removal of solvent, the residue was washed with hexane to yield l-ierf-butyi-2-methoxy-5-bromo-4- nitrobenzene (1.1 g, 69 %). JH NMR (400 MHz, CDC13) δ 7.58 (s, 1H), 7.44 (s, 1 H), 3.92 (s, 3H), 1.39 (s, 9H).
[0510] l-^ri-BislyI"-2-meib©xy-S-(trifluor©SBet iyl)-4-aitrobe8¾Ke5se
A mixture of l~ftir/-butyl-2~methoxy-5-bromo-4-nitrobenzene (867 mg, 3.0 mmol), KF (348 mg, 6 rnmol), KBr (714 mg, 6 mmol), Cul (684 mg, 3.6 mmol), methyl chlorodifSuoroacetate (2.2
- 163 -
85ΨΙ833.1 mL, 21.0 mmol) in DMF (5 mL) was stirred at 125 °C in a sealed tube overnight, cooled to room temperature, diluted with water and extracted three times with EtOAc. The combined organic layers were washed with brine and dried over anhydrous MgSOa. After removal of the sol vent, the residue was purified by column chromatography (0-5 % EtOAc - Hexarse) to yield 1 -rerr- buiyl~2-methoxy-5<irifluorarae l)-4-nitrobenz ne (512 mg, 61 %). !H NMR (400 MHz, CDC13) δ 7,60 (s, 1H), 7.29 (s, 1H), 3.90 (s, 3H), 1.33 (s, 9H).
[0511] C-18; l-te^Baiyi-2-m i oxy»S»(trfflm>rometfeyI)-4-aFiiiiio n2 Fie
To a refluxing solution of l -ii^buiyl-2-methoxy-5-( rifluoromeihyl)~4-mtrobenzene (473 mg, 1.7 mmol) and ammonium formate (473 mg, 7.3 mmol) in EtOH (10 mL) was added 10% Pd-C (200 mg). The mixture was refluxed for 1 h, cooled and filtered through Celiie. The solvent was removed by evaporation to give i-i€rt-butyl-2-rnethoxy-5-(trifluoromethyl)-4-amiriobenzene (C- 18) (403 mg, 95 %). ¾ NMR (400 MHz, CDCU) S 7.19 (s, IB), 6.14 (s, 1H), 4.02 (bs, 2H), 3.74 (s, 3H), 1.24 (s, 9H).
[0512] Example 32:
Figure imgf000163_0001
C- 4-a C-27
[0513] C-27; 2-ieri-BuiyI-4-bromo-S-anilno-phenoS
To a solution of 2-ieri-butyl-4-bromo-5-niti'ophenol (C-14-a) (12 g, 43.8 mmol) in MeOH (90 ml.) was added Ni (2.4 g). The reaction mixture was stirred under ¾ (1 aim) for 4 h. The mixture was filtered and the filtrate was concentrated. The crude product was recrystallized from ethyl acetate and petroleum ether to give 2-te? -butyl-4-bromo-5-ammo-phenol (C-27) (7.2 gs 70 %). Ή NMR (DMSC 6) δ 9.15 (s, 1 H), 6.91 (s, 1 H), 6.24 (s, 1 H), 4.90 (br s, 2 H), 1.22 (s, 9 H); ESi-MS 244.0 m/z (MH+).
- 162 ·■
8544833. S 0514] Example 13:
Figure imgf000164_0001
[1)515] C-24; 2,4-Di-ie?i-SiKiyl-6-(N-methjIaEMEo)phessoI
A mixture of 2,4-di-terf-but l-6-amino-phenol (C-9) (5.08 g, 23 mmoi), NaBH3CN (4.41 g, 70 mmoi) and paraformaldehyde (2.1 g, 70 mmoi) in methanol (50 mL) was stirred at reflux for 3 h. After removal of the solvent, the residue was purified by column chromatography (petroleum ether - EtOAc, 30: 1) to give 2,4-di-ieri-butyl-6-(N-methylamino)phenol (C-24) (800 mg, 15 %). 'HNMR (DMSO- ) δ 8.67 (s, 1 H), 6.84 (s, 1 H), 5.99 (s, 1 H), 4.36 (q, J = 4.8 Hz, III), 2.65 (d, J = 4.8 Hz, 3 H), 1.23 (s, 18 H); ESI-MS 236.2 m z (MH+).
[0516] Example 14:
Figure imgf000164_0002
C-25 [0517] 2-Methyl-2-pfee¾yI-prepae~l«eI
To a solution of 2-methyl~2-phenyl- propionic acid (82 g, 0.5 mol) in THF (200 nxL) was added dropwise borane-diraethyl sulfide (2M, 100 mL) at 0-5 °C. The mixture was stirred at this temperature for 30 niin and then heated at reflux for 1 h, After cooling, methanol (150 mL) and water (50 mL) were added. The mixtur was extracted with EtOAc (100 mL x 3), and the combined organic layers were washed with water and brine, dried over Na28G4 and concentrated to give 2-methyl-2-phenyl-propan-l-ol as an oil (70 g, 77 %).
[0518] 2-(2-Meihosy-eth« xy)-ljl-iMmeihyI-eihyl]«beri¾eiie
To a suspension of NaH (29 g, 0.75 raol) in THF (200 mL) was added dropwise a solution of 2- meihyl~2~pheny!~propa3i-l-ol (75 g, 0.5 mol) in THF (50 mL) at 0 °C. The mixture was stirred at 20 °C for 30 min and then a solution of l-bromo-2-methoxy-ethane (104 g, 0.75 mol) in Tiff (100 mL) was added dropwise at 0 °C. The mixture was stirred at 20 °C overnight, poured into water (200 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with water and brine, dried over a2S0 , and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether) to give 2-(2-Methoxy-ethoxy)-1 ,1- dimethyl-ethyl] -benzene as an oil (28 g, 27 %).
[Θ519] 1 2^2-Methifxy-eihoxy)-i,l~dimethyi-ethyI]-4-niir©-beiigesie
To a solution of 2-(2-memoxy-ethoxy)-l ,I-dimethyl-ethyl3-benzene (52 g, 0.25 mol) in CHC¾ (200 mL) was added KNO3 (50,5 g, 0.5 mol) and TMSCl (54 g, 0.5 mol). The mixture was stirred at 20 °C for 30 min and then AICI3 (95 g, 0.7 mol) was added. The reaction mixture was stirred at 20 °C for 1 h and poured into ice-water. The organic layer was separated and the aqueous layer was extracted with CHCI3 (50 mL x 3). The combined organic layers were washed with water and brine, dried over Na2804, and concentrated, The residue was purified by column chromatography (silica gel, petroleum ether) to obtain l-[2-(2-methoxy-ethoxy)-l,l- dimethyl-eihyl]-4-nitiO-benzene (6 g, 10 %).
[0520] 4 242-Methosy-«i OT )^ -diffleihyl-ethyi].ph iiykmiBe
A suspension of l-[2-(2-methoxy-ethoxy)-l,l-dimethyl-ethyi]-4-nitro-benzene (8.1 g, 32 mmol) and aney Ni (1 g) in MeOH (50 mL) was stirred under ¾ (1 aim) at room temperature for 1 h. The catalyst was filtered off and the filtrate was concentrated to obtain 4-[2-(2-methoxy- ethoxy)-i,l~dimethyl-ethyl]-phenyla?nine (5.5 g, 77 %).
- 164 -
SJ44S33.J [0521] 4~[2-(2-Meihoxy-eihoxy)-1 °dimeiiiyI-eihy!3-3-i¾itro-pheiiylamiiie
To a solution of 4-[2-(2-methoxy-ethoxy)-l,!-dimetliyS-eihyl]-phenylamine (5.8 g, 26 inmol) in H2SO4 (20 mL) was added NO3 (2.63 g, 26 minol) at 0 °C. After addition was complete, the mixture was stirred at this temperature for 20 min and then poured into ice-water. The mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water and brine, dried over Na2S04, and concentrated. The residue was purified by column cinematography (petroleum ether - EtO Ac, 100:1) to give 4-[2-(2-methoxy-ethoxy)-l,l- dimethyl-eihyI]-3-mtro-phenyIamine (5 g, 71 %).
[6522] N~f4~[2-{2-Metfeoxy-eth©xy)-! -*M,^
To a suspension of NaHC(¾ (10 g, 0.1 mol) in dichloromethane (50 mL) was added 4-[2-(2- methoxy-ethoxy)-l,l-dimethyl-eihyiJ-3-nitiO-phenylamine (5 g, 30 mmol) and acetyl chloride (3 mL, 20 mmol) at 0-5 °C. The mixture was stirred overnight at 15 °C and then poured into water (200 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (50 mL x 2). The combined organic layers were washed with water and brine, dried over Na2S04, and concentrated to dryness to give N-{4-[2-(2-methoxy-ethoxy)-l,l- dimethyl-ethyl]-3-nitiO-phenyl}-acetamide (5.0 g, 87 ).
[0523] N-{3"AniiMO-.4-[2-(2-metfeoxy~eihoxy)-l,l-"^i∞tliyl-eihyl]-pheHyl}- aeeiamide
A mixture of N-{4-[2-(2-methoxy-ethoxy)-l 5l-dimethy]-ethyl]~3~nitrG-phenyl}-acetamide (5 g, 16 mmol) and Raney Ni (1 g) in MeOH (50 mL) was stirred under ¾ (1 aim) at room temperature 1 h. The catalyst was filtered off and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether - EtOAc, 100: 1 ) to give N~ { 3-amino-4-[2- (2-methoxy-ethoxy)- 1,1 -dimethyl-ethyl] -phenyl }-acetamide (1.6 g, 35 ).
[0524] N-{3-Hydroxy-4"[2-(2-ffleihoxy-etfeoxy)-l,l~dii «thyl-eihyl -pheayl}- acetam!de
To a solution of N-{3-ammo-4-[2- (2-methoxy- eihoxy)-l,l -dimefhyl-ethyl]-phenyl}- acetaroide (1.6 g, 5.7 mmol) in ¾S04 (15 %, 6 mL) was added NaN02 at 0-5 °C. The mixture was stirred at this temperature for 20 min and then poured into ice water. The mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with water and brine, dried over Na2S0 and concentrated. The residue was purified by column chromatography (petroleum
- 165 -
8544833.1 ether - EtOAc, 100: 1) to give N-{3-hydroxy-4-[2-(2-methoxy-ethoxy)-l,l-diinethyl-ethyIJ- phenyl}- acetemide (0.7 g, 38 %).
[©525] C-25; 2-(l-(2-Meiho3syeth« xy)-.2-me hylpropaH«2«yI)-5~ami opheB0l A mixture of N~{3~hydroxy-4'[2-(2-meihoxy-ethoxy)-l,l-dimetiwl-ethyl3-pheEyl }-- aceiamide (1 g, 3.5 mmol) and HC1 (5 mL) was heated at reflux for I h. The mixture was basified with Na2C(¾ solution to pH 9 and then extracted wife EtOAc (20 mL x 3). The combined organic layers were washed with water and brine, dried over Na2SQ and concentrated to dryness. The residue was purified by column chromatography (petroleum ether - EtOAc, 100:1) to obtain 2- (l-(2-metlioxyethoxy)-2-i¾et]>yipropaii-2-yl)-5-aminopheEol (C-25) (61 mg, 6 %). 1HNMR (CDCI3) 6 9.1 1 (br s, 1 H), 6.96-6.98 (d, / = 8 Hz, 1 H), 6.26-6.27 (d, / = 4 Hz, 1 H), 6.17-6.19 (m, 1 H), 3.68-3.69 (m, 2 H), 3.56-3.59 (m, 4 H), 3,39 (s, 3 H), 1.37 (s, 6 H); ESI-MS 239.9 m/z (MH*).
[Θ526 Example 15:
Figure imgf000167_0001
[0527] 4,6-di-i#ri-Biiiyl-3-iiiirocycloh€sa-3,5-dlerie-1^2-dloiie
To a solution of 3,5-di-ierf-butylcyclohexa-3,5-diene-l,2-dione (4.20 g, 19.1 rnmol) in acetic acid (1 15 mL) was slowly added HNO¾ (15 mL). The mixture was heated at 60 °C for 40 min before it was poured into H20 (50 mL). The mixture was allowed to stand at room temperature for 2 h, then was placed in an ice bath for 1 h. The solid was collected and washed with water to provide 4,6-di-ierf-butyl-3-nitrocyclohexa-3,5-diene-i ,2-dione (1.2 g, 24 %). JH NMR (400 MHz, DMSCMg) δ 6.89 (s, 1H), 1.27 (s, 9H), 1.24 (s, 9H).
- 166 -
S344S33.1 In a separaiory funnel was placed THF H20 (1 : 1, 400 mL), 4,0~di-fe^butyl-3-nitrocyciohexa- 3,5-diene-l,2-dione (4,59 g, 17.3 mmol) and Na2S204 (3 g, 17.3 mmol). The separator}' funnel was stoppered and was shaken for 2 min. The mixture was diluted wife EiOAc (20 mL). The layers were separated and the organic layer was washed wiih brine, dried over MgS04 and concentrated to provide 4,6-di-ferf-buiyi-3-niirobenzene-i ,2-diol (3.4 g, 74 %), which was used without further purification. Ή NMR (400 MHz, DMSO-rf6) δ 9.24 (s, 1H), 8.76 (s, 1H), 6.87 (s, 1H), 1.35 (s, 9H), 1.25 (s, 9H).
[0529] C-26; 4,6~DI~te?t~bist I-3-an3lBobeiKe5ie-l?2-iiiol
To a solution of 4,6-di-iert-butyl-3-ratrobenzene-l,2-diol (1.92 g, 7.2 mmol) in EtOH (70 mL) was added Pd-5% wt. on carbon (200 mg). The mixture was stirred under ¾ (1 atm) for 2 h. The reaction was recharged with Pd-5% wt. on carbon (200 mg) and stirred under H2 (1 atm) for another 2 h. The mixture was filtered through Celite and the filtrate was concentrated and purified by column chromatography (10-40 % ethyl acetate - hexanes) to give 4,6-di-is?/?-butyl- 3-aminobenzene-l ,2-diol (C~26) (560 mg, 33 %). !H NMR (400 MHz, CDC¾) δ 7.28 (s, 1H), 1.42 (s, 9H), 1.38 (s, 9H).
[0530] Anilines
[0531] Example 1:
[Θ532] General scheme
Figure imgf000168_0001
X = N(¾ or NB,
[0533] Specific example:
Figure imgf000168_0002
0-1
- I67 -
8544833. i [0534] 15-1; 4-£hior&~benz e'l,3~dmmim
A mixture of l-chloro-2,4"dinitro-benzene (100 trig, 0.5 mmol) and
Figure imgf000169_0001
(1.12 g, 5 mmol) in ethanoi (2.5 mL) was stirred at room temperature overnight. Water was added and then the mixture was basified to pH 7-8 with saturated NaHC03 solution. The solution was extracted with efhyl acetate. The combined organic layers were washed with brine, dried over jS04, filtered and concentrated to yield 4~eh!oro-beiizene~ 1 -diamine (D-1) (79 mg, quant.). HPLC ret. time 0.38 min, 10-99 % CH3CN, 5 min run; ESI-MS 143.1 m/z (MH+)
[Θ535] Other examples:
Figure imgf000169_0002
[0536] D-2; 4)6-DicMo o-bm¾eBe-i,3-dlamlBe
4,6-Dichloro-benzene- l,3-diamine (D-2) was synthesized following the general scheme above starting from l,5-dich!oro-2,4-dinitro-ber!zene. Yield (95 %). HPLC ret. time 1.88 min, 10-99 % CH3CN, 5 min run; ESI-MS 177.1 m/z (MH+).
Figure imgf000169_0003
[0537] D-3; 4-Me hosy-bei¾2eae»l,3-dias lrse
4-Methoxy-benzene-I,3-diamine (D-3) was synthesized following the general scheme above starting from l-methoxy-2,4-dinitro-benzene. Yield (quant). HPLC ret. time 0.31 min, 10-99 % C¾CN, 5 min run.
Figure imgf000169_0004
[0538] D-4; 4-Trifl5s romethoxy-ben¾;esie-i,3-di¾Mliie
4-Trifluoromethoxy-benzene-l,3-diamine (D-4) was synthesized following the general scheme above starting from 2,4-dinitro-l-trifluoromethoxy-benzene. Yield (89 %). HPLC ret. time 0.91 min, 10-99 % CH3CN, 5 mm run; ESI-MS 193.3 m/z (MH ).
- 168 -
5544833.1
Figure imgf000170_0001
[Θ539] D-S; 4-Fr xyb m€0e-l^-diaml5ie
4-Propoxybenzene-l,3-diaraine (0-5) was synthesized following fee general scheme above starting from 5-nitro~2-propoxy-phenylamme. Yield (79 ). HPLC ret. time 0.54 min, 10-99 % C¾CN, 5 min ran; ESI-MS 167.5 mlz (Mff*).
[§540] Example 2s
Figure imgf000170_0002
a) H C , H2SO4; b) SnCl2-2H20, EtOH or ¾, Pd-C, MeOH
Figure imgf000170_0003
[0543] 2,4~Dtoitro-propyIbea¾effl®
A solution of propylbenzene (10 g, 83 mmol) in cone. H2SO4 (50 mL) was cooled at 0 °C for 30 min, and a solution of cone. H2S04 (50 mL) and fuming HNO3 (25 mL), previously cooled to 0 °C, was added in portions over 15 min. The mixture was stirred at 0 °C for additional 30 min, and then allowed to warm to room temperature. The mixture was poured into ice (200 g) - water (100 mL) and extracted with ether (2 x 100 mL). The combined extracts were washed with H20 (100 mL) and brine (100 mL), dried over MgS04, filtered and concentrated to afford 2,4-dinitro- propylbenzene (15.6 g, 89 %). Ή NMR (CDCI3, 300 MHz) δ 8.73 (d, / = 2.2 Hz, lH), 8.38 (dd,
- 169 -
8544833.1 J = 8.3, / = 2.2, 1H), 7.6 (d, / = 8.5 Hz, 1H), 2.96 (dd, 2H), 1.73 (m, 2H), 1.06 (t, J = 7.4 Hz, 3H).
[0544] D~6; 4~Propyl~beaEeae-l,3-diamiHe
To a solution of 2,4-dinitro-propylbenzene (2.02 g, 9.6 mnio!) in etfaanol (100 mL) was added SnCl2 (9.9 g, 52 mraol) followed by cone. HC1 (10 mL). The mixture was re fluxed for 2 h, poured into ice-water (100 mL), and neutralized with solid sodium bicarbonate. The solution was further basified with 10% NaOH solution to pH - 10 and extracted with ether (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO-j, filtered, and concentrated to provide 4-prop>1 -benzene- 1,3-diairiine (D-6) (1.2 g, 83 %). No further purification was necessary for use in the next step; however, the product was not stable for an extended period of time. !H NMR (CTX¾, 300 MHz) δ 6.82 (d, / = 7.9 Hz, 1H), 6.11 (dd, / = 7.5, J = 2.2 Hz, lH), 6.06 (d, J = 2.2 Hz, 1H), 3.49 (br s, 4H, NH2), 2.38 (t, / = 7.4 Hz, 2H), 1.58 (rn, 2H), 0.98 (t, J = 7.2 Hz, 3H); ESI-MS 151.5 m/z (MIT1").
[©54S] Other examples:
Figure imgf000171_0001
[0546] D-7; 4~EthyIbeffizeHe-l,3- iamine
4-Ethylbenzene-l,3-diamine (D-7) was synthesized following the general scheme above starting from eihylbenezene. Overall yield (76 %).'
Figure imgf000171_0002
[©547] D-8; 4-Is©propyIbeezene-l,3-dkmlae
4-Isopropylbenzene-l ,3-diarnirie (D-8) was synthesized following the general scheme above starting from isopropylbenezene. Overall yield (78 %).
- 170 -
8544833.3
Figure imgf000172_0001
[0548] D-9; 4-&ri-BHtylbm¾:es3e-l,3-diamiHe
4-terf-Burylbenzene- l,3-diamine (D-9) was synthesized following the general scheme above starting from ¾/ -bui lbenzene. Overall yield (48 %). !H NMR (400 MHz, CDC13) δ 7.01 (d, J = 83 Hz, 1H), 6.10 (dd, /= 2.4, 8.3 Hz, 1H), 6.01 (d, J = 2.4 Hz, IK), 3.59 (br, 4H), 1.37 (s, 9H); nC NMR (100 MHz, CD<¾) 8 145.5, 145.3, 127.6, 124.9, 105.9, 104.5, 33.6, 30.1 ; ESI- MS 164.9 m/z (MH*).
[0549] Example 3:
Figure imgf000172_0002
a) KN03, H2SO4; b) (i) HN<¾, ¾S04; (ii) Na2S, S, H20; c) Bcx¾0, NaOH, THF; d) H2, Pd-C, MeOH 0551] Specific example:
Figure imgf000172_0003
To a mixture of 4-fert-butyI-phenylamine (10.0 g, 67.01 mmol) dissolved in H2S04 (98 %, 60 mL) was slowly added KNO3 (8.1 g, 80,41 mmol) at 0 °C. After addition, the reaction was allowed to warm to room temperature and stirred ovemight. The mixture was then poured into ice- water and basified with sat. NaHCQ} solution to pH 8. The mixture was extracted several
- 171 -
8544833.1 times with CH2CI2. The combined organic layers were washed with brine, dried over Na2S0 and concentrated. The residue was purified by column chromatography (petroleum ether - EtOAc, 10: 1 ) to give 4-ier?-butyl-3-nitro-phenySamme (10 g, 77 %).
[§553] (4-teri-¾5slyI-3-mtro~plieiiyl)-carbamle add terMraty! ester
A mixture of 4-fert»butyl-3-nitro-phenylamine (4.0 g, 20.6 mmoS) and Boc Q (4.72 g, 21.6 rnmol) in NaOH (2N, 20 mL) and THF (20 mL) was stirred at room temperature overnight. THF was removed under reduced pressure. The residue was dissolved in water and extracted with CH2CI2. The organic layer was washed with NaHC03 and brine, dried over Na2S04 and concentrated to afford (4-ie'rt~buty!~3~nitro~pheny!)-carbamie acid tert-buiyl ester (4.5 g, 74 %)' .
[0554] D-Ιΰ; (3~Amim}"4~tert~hut !-phe?iyl)-€ark®mi€ acid iert-bu yl ester
A suspension of (4»?ert-butyl-3-niiro-pher3yl)-carbamic acid ferf-butyi ester (3.0 g, 10.19 mol) and 10% Pd-C (1 g) in MeOH (40 mL) was stirred under ¾ (1 aim) at room temperature overnight. After filtration, the filtrate was concentrated and the residue was purified by column chromatograph (petroleum ether - EtOAc, 5: 1) to give (3-amino-4-teri-bi!tyl-phenyi)-carbamic acid tert-bat l ester (D-10) as a brown oil (2.5 g, 93 %). ¾ NMR (CDCi3) δ 7.10 (d, / = 8.4 Hz, 1 H), 6.92 (s, 1 H), 6.50-6.53 (m, 1 H), 6.36 (s, 1 H), 3.62 (br s, 2 H), 1.50 (s, 9 H), 1.38 (s, 9 H); ESI-MS 528.9 m/z (2M+H ).
0555] Other examples:
Figure imgf000173_0001
[Θ556] D-II5 (3-AiBino-4-is spropyl»p!ienyI)-esrbamie add tert-hut l ester (3-Amino-4-isopropyl-phenyl)~carbamic acid ¾ri-butyl ester (D-ll) was synthesized following the genera! scheme above starting from isopropySbenezene. Overall yield (56 %).
Figure imgf000173_0002
- 172 -
8544833.1 [Θ557] D-12; (3-Aim&®-4*ethy!-phmy!)-carbamk add te -bsstyl ester
(3-Amino-4-ethyl-phe!iyl)-caibamic acid ierf-butyl ester (D-12) was synthesized following the general scheme above starting from ethylbenezene. Overall yield (64 %), H NM (CD3OD, 300 MHz) 5 6.87 (d, 7 = 8.0 Hz, 1H), 6.81 (d, 7 = 2.2 Hz, 1H), 6.63 (dd, 7 = 8.1, 7 = 2.2, 1 H), 2.47 (q, 7 = 7.4 Hz, 2H), .50 (s, 9H), 1.19 t, 7 = 7.4 Hz, 3H); ESI-MS 237.1 m/z 1
Figure imgf000174_0001
[0558] D-13; (3«AmiBo-4-propyt-phe&yt)-earbamfc add ferf-butyl ester
(3-Amino-4-propyI-pheny!)-carbamic acid tert-butyl ester (D-13) was synthesized following the general scheme above starting from propylbenezene. Overall yield (48 %). 559] Example 4:
Figure imgf000174_0002
[0560] (3-Amino-4-feri-biiiyl-pheoyl)-e¾rbamic add beaiy! ester
A solution of 4-¾^butylbenzene-l ,3-diamme (D-9) (657 mg, 4 mmol) and pyridine (0.39 mL, 4.8 mmol) in CH2CI2 / MeOH (12 / 1 , 8 mL) was cooled to 0 °C, and a solution of benzyl chlorofomiate (0.51 mL, 3.6 mmol) in€¾02 (8 mL) was added dropwise over 10 min. The mixture was stirred at 0 °C for 15 min, then warmed to room temperature. After 1 h, the mixture was washed with 1M citric acid (2 x 20 mL), saturated aqueous sodium bicarbonate (20 mL), dried (Na2$04), filtered and concentrated in vacuo to afford the crude (3-amino-4-½rf-butyl- phenyl)-carbamic acid benzyl ester as a brown viscous gum (0.97 g), which was used without further purification. *H NMR (400 MHz, CDC13) δ 7.41-7.32 (m, 6H,), 7.12 (d, 7 = 8.5 Hz, 1H), 6.89 (br s, 1H), 6.57 (dd, 7 = 2.3, 8.5 Hz, 1H), 5.17 (s, 2H), 3.85 (br s, 2H), 1.38 (s, 9H); °C
- 173 -
8544833.1 NMR (100 MHz, OX¾, rotameric) δ 153.3 (br), 145.3, 136.56, 136, 18, 129.2, 128.73, 128.59, 128.29, 28.25, 127.14, 108.63 (br), 107.61 (br), 66.86, 33.9, 29.7; ESi-MS 299.1 ra/z (MH+).
[ 561] (^ieri-B^t l-S-form lamiii i-phesyli-carbamlc ¾dd beiszyi ester
A solution of (3-amino-4-½ri-butyl-phenyl)-carbamic acid benzyl ester (0.97 g, 3.25 mmol) and pyridine (0.43 mL, 5.25 mmol) in€H2C12 (7.5 mL) was cooled to 0 °C, and a solution of formic- acetic anhydride (3.5 mmol, prepared by mixing formic acid (158 μϋ, 4.2 mmol, 1.3 equiv) and acetic anhydride (0.32 mL, 3.5 mmol, 1.1 eq.) neat and ageing for 1 hour) in€¾€¾ (2.5 mL) was added dropwise over 2 rain. After the addition was complete, the mixture was allowed to warm to room temperature, whereupon it deposited a precipitate, and the resulting slurry was stirred overnight. The mixture was washed with 1 M citric acid (2 x 20 mL), saturated aqueous sodium bicarbonate (20 mL), dried (Na2S04), and filtered. The cloudy mixture deposited a thin bed of solid above the drying agent, HPLC analysis showed this to be the desired formamide. The filtrate was concentrated to approximately 5 mL, and diluted with hexane (15 mL) to precipitate further formamide. The drying agent ( a2S04> was slurried with methanol (50 mL), filtered, and the filtrate combined with material from the CH2€12 / hexane recrystallisation. The resultant mixture was concentrated to afford (4-ieri-butyl-3-formylamino-phenyl)-carbamic acid benzyl ester as an off-white solid (650 mg, 50 % over 2 steps). JH and ,3C NMR (CD3OD) show the product as a rotameric mixture. *H NMR (400 MHz, CD3OD, rotameric) «5 8.27 (s, lH-a), 8.17 (s, lH-b), 7.42-7.26 (in, 8H), 5.17 (s, lH-a), 5.15 (s, !H-b), 4.86 ($, 2H), 1.37 (s, 9H-a), 1.36 (s, 9H-b); i3C NMR (100 MHz, CD3OD, rotameric) δ 1636.9, 163.5, 155,8, 141.40, 141.32, 139.37, 138.88, 138.22, 138.14, 136.4, 135.3, 129.68, 129.65, 129.31, 129.24, 129.19, 129.13, 128.94, 128.50, 121.4 (br), 118.7 (br), 67.80, 67.67, 35.78, 35.52, 31.65, 31.34; ESI-MS 327.5 m/z (MH*).
[0562] V-CS-AsBiBo-l-feff-li tyl- lieK ^-formamide
A 100 mL flask was charged with (4-ieri-butyl-3-formylamino-phenyl)-carbamic acid benzyl ester (650 mg, 1.99 mmol), methanol (30 mL) and 10% Pd-C (50 mg), and stirred under H2 (1 aim) for 20 h. CH2CI2 (5 mL) was added to quench the catalyst, and the mixture then filtered through Celite, and concentrated to afford iV-(5-amino-2-ferf-butyi-phen.yl)-formamide as an off- white solid (366 mg, 96 %). Rotameric by ¾ and i3C NMR (DMSO-ds). ?H NMR (400 MHz, DMSO-de, rotameric) δ 9.24 (d, / = 10.4 Hz, 1H), 9.15 (s, III), 8.23 (d, J " = 1.5 Hz, 1H), 8.06 (d, / = 10.4 Hz, 1H), 7.06 (d, / = 8.5 Hz, 1H), 7.02 (d, / = 8.5 Hz, 1H), 6.51 (d, 7 = 2.5 Hz, 1H), 6.46 (dd, / = 2,5, 8.5 Hz, 1H), 6.39 (dd, J = 2.5, 8.5 Hz, 1H), 6.29 (d, / = 2.5Hz, 1H), 5,05 (s,
2H), 4.93 (s, 2H), 1.27 (s, 9H); i3C NMR (100 MHz, DMSO-4>, rotameric) δ 164,0, 160.4,
- 174 -
8544833.1 147.37, 146,74, 135.38, 135.72, 132.48, 131.59, 127.31, 126.69, 115.15, 115.01, 112.43, 112,00, 33.92, 33.57, 31.33, 30.92; ESI-MS 193.1 tn/z (MH+).
[0563] D-14; 4-teri-l ¾tyl- VJ-meihyl-beiszeHe-l,3-diss¾toe
A 100 mL flask was charged with iV-(5-araino-2-ierr-butyl-phenyI)-formaraide (340 mg, 1.77 mmo!) and purged with nitrogen. THF (10 mL) was added, and the solution was cooled to 0 WC, A solution of lithium aluminum hydride in THF (4.4 mL, 1M solution) was added over 2 mm. The mixture was then allowed to warm to room temperature. After refluxing for 15 h, the yellow suspension was cooled to 0 °C, quenched with water (170 μί), 15 % aqueous NaOH ( 170 L), and water (510 Ε) which were added sequentially and stirred at room temperature for 30 min. The mixture was filtered through Celite, and ilie filter cake washed with methanol (50 mL). The combined filtrates were concentrated in vacuo to give a gray-brown solid, which was partitioned between chloroform (75 mL) and water (50 mL). The organic layer was separated, washed with water (50 mL), dried (Na2SG4), filtered, and concentrated to afford 4-terf-butyl-iV3-methyi- benzene-l ,3-diamine (D-14) as a brown oil which solidified on standing (313 mg, 98 ). Ή NMR (400 MHz, CDC13) δ 7.01 (d, J = 8.1 Hz, 1H), 6.05 (dd, J = 2.4, 8.1 Hz, 1H), 6.03 (d, J = 2.4 Hz, lH), 3.91 (br s, III), 3.52 (br s, 2H), 2.86 (s, 3H), 1.36 (s, 9H); l3C NMR (100 MHz, CDCI3) 5 148.4, 145.7, 127.0, 124.3, 103.6, 98,9, 33.5, 31.15, 30.31; ESI-MS 179.1 m/z (MOT).
[0564] Example St
Figure imgf000176_0001
- 175 -
8544833.1 05<s<s] Specific example:
Figure imgf000177_0001
[0567] 2,4-Dieiir -propyIbeB2t'»e
A solution of propylbenzene (10 g, 83 mmol) in cone. H2SO4 (50 mL) was cooled at 0 °C for 30 mins, and a solution of cone. H2SO4 (50 mL) and fuming HN(¾ (25 mL), previously cooled to 0 °C, was added in portions over 15 misi. The mixture was stirred at 0 °C for additional 30 mm. and then allowed to warm to room temperature. The mixture was poured into ice (200 g) -water ( 100 mL) and extracted with ether (2 x 100 mL). The combined extracts were washed with H? (100 mL) and brine (100 mL), dried over MgS04, filtered and concentrated to afford 2,4-dinitro- propylbenzene (15.6 g, 89 %). Ή NM (CDC13, 300 MHz) S 8.73 (d, J = 2.2 Hz, IB), 8.38 (dd, J = 8.3, 2.2 Hz, 1H), 7.6 (d, J = 8.5 Hz, t H), 2.96 (m, 2H), 1.73 (m, 2H), 1.06 ( / = 7.4 Hz, 3H).
[0568] 44¥opyI-3-nitroaniliiie
A suspension of 2,4-dinitro-propyl benzene (2 g, 9,5 mmol) in ¾0 (100 mL) was heated near reflux and stirred vigorously. A clear orange-red solution of poly sulfide (300 mL (10 eq.), previously prepared by heating sodium sulfide nanohydrate (10.0 g), sulfur powder (2.60 g) and H20 (400 mL), was added dropwise over 45 mins. The red-brown solution was heated at reflux for 1.5 h. The mixture was cooled to 0 °C and then extracted with ether (2 x 200 mL). The combined organic extracts were dried over MgS<>4, filtered, and concentrated under reduced pressure to afford 4-propyl-3-nitroaniline (1.6 g, 93 %), which was used without further purification.
[0569] (3-Nitro~4~propyl-phenyE)-carbamic acid iert-butyl ester
4-Propyl-3-nitroaniline (1.69 g, 9,4 mmol) was dissolved in pyridine (30 mL) with stirring. Boc anhydride (2.05 g, 9.4 mmol) was added. The mixture was stirred and heated at reflux for 1 h
- 176 -
8544833. ί before the solvent was removed in vacuo. The oil obtained was re-dissolved in (300 mL) and washed with water (300 mL) and brine (300 ixtL), dried over Na2S0 , filtered, and concentrated. The crude oil feat contained both mono- and fe-acylated nitro products was purified by column chromatography (0-10 % CH2CI2 - MeOH) to afford (3-nitro-4-propyl- phenyl)-carbamic acid tert-butyl ester (2.3 g, 87 %).
[Θ570] MethyI-(3-isiiro-4-propyl-phes l)-€arbamic add tert-butyl ester
To a solution of (3-nitro-4-propyl-phenyl)-carbamic acid ii?rf~butyl ester (200 mg, 0.71 mmol) in DMF (5 mL) was added Ag20 (1.0 g, 6.0 mmol) followed by methyl iodide (0,20 niL, 3,2 mmol). The resulting suspension was stirred at room temperature for 18 h and filtered through a pad of Celite. The filter cake was washed with€¾€¾ (10 mL), The filtrate was concentrated in vacuo. The crude oil was purified by column chromatography (0-10 % CH2C12 - MeOH) to afford methyI-(3-nitro-4-propyl-phenyl)-carbamic acid tert-butyl ester as a yellow oil (110 mg, 52 %). !H NMR (CDC , 300 MHz) δ 7.78 (d, / = 2.2 Hz, 1H), 7.42 (dd, / = 8.2, 2.2 Hz, 1H), 7,26 (d, J = 8.2 Hz, IK), 3.27 (s, 3H), 2.81 (t, J = 7.7 Hz, 2H), 1.66 (m, 2H), 1.61 (s, 9H), 0.97 (t, 7 = 7.4 Hz, 3H).
[0571] D-15; (3-Amino-4-propyJ-plieayI)-methyl-carbamic add tert-butyl ester To a solution of methyl-(3-nitro-4-propyl-phenyl)-carbamic acid tert-butyl ester (110 mg, 0.37 mmol) in EtOAc (10 mL) was added 10% Pd-C (100 mg). The resulting suspension was stirred at room temperature under ¾ (1 aim) for 2 days. The progress of the reaction was monitored by TLC, Upon completion, the reaction mixture was filtered through a pad of Celite. The filtrate was concentrated in vacuo to afford (3-Amino-4-propyl-phenyl)~methyl-carbamic acid feri-hutyl ester (D-15) as a colorless crystalline compound (80 mg, 81 %). ESI-MS 265.3 m/z (MH*).
[0572] Other examples:
Figure imgf000178_0001
[0573] D-16; (3-ABiMO-4-eihyl-phessyl)-methyl~carbas ic acid tert-butyl ester (3-Amino-4-ethyl-phenyl)-methyl-carbamic acid tert-butyl ester (D-16) was synthesized following the general scheme above starting from ethylbenezene. Overall yield (57 %).
- 177 -
8544833.!
Figure imgf000179_0001
[©574] D-17; (3-AmlK0~4~is propyI-pfeesiyi)-methy!
(3-Amino-4-isopfopyl-phenyl)-mei!iyl-carbamic acid tert-butyl e D-17) was synthesized following the general scheme above starting from isopropylbenea Overall yield (38 %),
Figure imgf000179_0002
D-18
[0576] 2'-Ethoz -2^ -dinitro-biphenyl
A pressure flask was charged with 2-ethoxypheiiylboronic acid (0.66 g, 4.0 mmol), KF (0.77 g, 13 mnioi), Pd2(dba)3 (16 rng, 0.02 mmol), and 2,4-dinitro-bromobenzene (0.99 g, 4.0 mrnol) in THF (5 mL). The vessel was purged with argon for 1 min followed by the addition of txi tert- butylphosphine (0,15 niL, 0.48 mmol, 10 % solution in hexanes). The reaction vessel was purged with argon for additional 1 min., sealed and heated at 80 °C overnight. After cooling to room temperature, the solution was filtered through a plug of Ceiite. The filter cake was rinsed with CH2CI2 (10 mL), and the combined organic extracts were concentrated under reduced pressure to provide the crude product 2'-ethoxy-2,4-dinitro-biphenyi (0.95 g, 82%), No further purification was performed. JH NMR (300 MHz, CDCI3) δ 8.75 (s, 1H), 8.43 (d, J = 8.7 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.40 (t, J = 7.8 Hz, 1H), 7.31 (d, J = 7.5 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 3.44 (q, J = 6.6 Hz, 2H), 1.24 (t, ./ = 6.6 Hz, 3H); HPLC ret. time 3.14 min, 10-100 % CH3CN, 5 min gradient.
- 178■
8544833.1 [0S77] 2'-Eih©xy-2-mtFoblpfeesisyl-4»y! amine
A clear orange-red solution of polysuifide ( 20 mL, 7.5 eq.), previously prepared by heating sodium sulfide monohydrate (10 g), sulfur (1.04 g) and water (160 mL), was added dropwise at 90 °C over 45 minutes to a suspension of 2'-ethoxy-2,4-diniiro-biphersyl (1.2 g, 4.0 mmol) in water (40 mL), The red-brown solution was heated at reflux for 1.5 h. Be mixture was cooled to room temperature, and solid NaCl (5 g) was added. The solution was extracted with CH2CI2 (3 x 50 mL), and the combined organic extracts was concentrated to provide 2'-ethoxy-2- nitrobiphenyl-4-yl amine (0,98 g, 95 %) that was used in the next step without further purification. !H NMR (300 MHz, CDCI3) δ 7,26 (m, 2H), 7.17 (d, J = 2.7 Hz, 1H), 7.1 1 (d, J = 7.8 Hz, 1H), 7.00 (t, J = 6.9 Hz, 1H), 6.83 (m, 2H), 3.91 (q, J = 6.9 Hz, 2H), 1.23 (t, J = 7.2 Hz, 3H); HPLC ret. time 2.81 min, 10-100 % CH3CN, 5 min gradient; ESI-MS 259.1 m z (NOT).
[0578] (2'-Eih xy-2-isiirobipheKyl-4-yI)-csrbamic acid fert-hutyi ester
A mixture of 2'-ethoxy-2-nitrobipenyl-4-yl amine (0.98 g, 4.0 mmol) and Boc20 (2.6g, 12 mmol) was heated with a heat gun. Upon the consumption of the starting material as indicated by TLC, the crude mixture was purified by flash chromatography (silica gel, CH2CI2) to provide (2'-ethoxy-2-nitrobiphenyl-4-yl)-carbaniic acid terf-butyl ester (1.5 g, 83 %). Ή NMR (300 MHz, CDC13) δ 7.99 (s, IB), 7.55 (d, J = 8.4 Hz, 1H), 7.25 (m, 3H), 6.99 (t, / = 7.5 Hz, IH), 6.82 (m, 2H), 3.88 (q, J = 6.9 Hz, 2H), 1.50 (s, 9 H), 1.18 (t, / = 6.9 Hz, 3H); HPLC ret. time 3.30 min, 10- 100 % CH3CN, 5 min gradient.
[0579] D-18; (2'-eihoxy-2-aminobiph®ayi-4-yI)-carb8raic add ferf-butyi ester To a soloution of NiCl2.6H20 (0.26 g, 1.1 mmol) in EtOH (5 mL) was added NaBH (40 mg, 1.1 mmol) at -10 °C. Gas evolution was observed and a black precipitate was formed. After stirring for 5 min, a solution of 2'-ethoxy-2-nitrobiphenyl-4-yl)carbamic acid ierf-butyl ester (0.50 g, LI mmol) in EtOH (2 mL) was added. Additional NaBrL- (80 mg, 60 mmoi) was added in 3 portions over 20 min. The reaction was stirred at 0 °C for 20 min followed by the addition of NH4OH (4 mL, 25% aq. solution). The resulting solution was stirred for 20 min. The crude mixture was filtered through a short plug of silica. The silica cake was flushed with 5% MeOH in CH2CI2 (10 mL), and the combined organic extracts was concentrated under reduced pressure to provide (2'-ethoxy-2-aminobiphenyl-4-yl)-carbamic acid terf-butyl ester (D~18) (0.36 g, quant.), which was used without further purification. HPLC ret. time 2.41 min, 10-100 % CH3CN, 5 min gradient; ESI-MS 329.3 m/z (MH*).
- 179 -
8544833.1 [0580] Example 7:
Figure imgf000181_0001
[0581] N'(3~Amimi~5~tHfiu&r&meiky^kenyI}~met mmifomimide
A solution of S-tfifluoromethyl-benzene-lJ-diamine (250 mg, 1.42 mmol) in pyridine (0.52 mL) and C¾{¾ (6.5 mL) was cooled to 0 °C. Meihanesuifonyl chloride (171 mg, 1.49 mmol) was slowly added at such a rate mat the temperature of the solution remained below 10 °C. The mixture was stirred at ~ 8 °C and then allowed to warm to room temperature after 30 min. After stiring at room temperature for 4 h, reaction was almost complete as indicated by LCMS analysis. The reaction mixture was quenched with sat. aq. NH4Q (10 mL) solution, extracted with CH2CI2 (4 x 10 mL), dried over Na2S04, filtered, and concentrated to yield N-(3-amino-5- trifluoromeihyi-pheny -methanesulfonamide (D-19) as a reddish semisolid (0.35 g, 97 %), which was used without further purification. Ή-NMR (CDC13, 300 MHz) δ 6.76 (m, 1 H), 6,70 (m, 1H), 6.66 (s, 1H), 3.02 (s, 3H); ESI-MS 255.3 m/z (MH*).
[0582] Cyclic amines
[0583] Exam le 1 :
Figure imgf000181_0002
DC-1
[Θ584] T-Niiro-l^J^-tetrahydro-qisiisoliee
To a mixture of 1,2,3,4-tetraltydro-quinoline (20,0 g, 0.15 moi) dissolved in H2S0 (98 %, 150 mL), KNO3 (18.2 g, 0.18 moi) was slowly added at 0 °C. The reaction was allowed to warm to
- 180 -
8544833.1 room temperature and stirred over night. The mixture was then poured into ice-water and basified with sat. aHC03 solution to pH 8. After extraction with C¾C12, the combined organic layers were washed with brine, dried over Na2SQ and concentrated. The residue was purified by column chromatography (petroleum ether - EtOAc, 10:1) to give 7-nitro- 1,2,3,4-etrahydro-quinoline (6.6 g, 25 %).
[05§5] T- tro-S^-diliydro-lH-qjsmolme-l-c bosylie acid ?r£-tatvl ester A mixture of 7-nitro- 1, 2,3,4-tetrahydro-quinoline (4.0 g, 5.61 mmol), Boe20 { 1.29 g, 5.89 mmol) and DMAP (0.4 g) in CH2CI2 was stirred at room temperature overnight. After diluted with water, the mixture was extracted with CH <¾. The combined organic layers were washed with NaHC03 and brine, dried over Na2S04 and concentrated to provide crude 7~nitro~3,4~ dihydro-2H-quinoiine-l-cai-boxylic acid ierf-butyl ester that was used in the next step wit!iout further purification. 0586] DC-ί; tert-But i 7-m n( 3f4~dikydroqMimlim l(2H)~cs(rb(>xyhte
A suspension of the crude 7-nitro-3,4-dihydro-2H-quinoline-l-cai-boxylic acid tert-h tyl ester (4.5 g, 16.2 mol) and 10% Pd-C (0.45 g) in MeOH (40 mL) was stirred under H2 (1 atm) at room temperature overnight. After filtration, the filtrate was concentrated and the residue was purified by column chromatography (petroleum ether - EtOAc, 5: 1 ) to give tert-butyl 7-amino-3,4- dihydroquinoline- l(2H)-carboxylate (DC-1) as a brown solid (1.2 g, 22 % over 2 steps). lH NM (CDCI3) 5 7.15 (d, J = 2 Hz, 1 H), 6.84 (d, 7 = 8 Hz, 1 H), 6.36-6.38 (m, 1 H), 3.65-3.68 (m, 2 H), 3.10 (br s, 2 H), 2.66 (t, J = 6.4 Hz, 2 H), 1.84-1.90 (m, 2 H), 1.52 (s, 9 H); ESI-MS 496.8 m z (2M+H+).
• 18 !
S5 4S33.; [0587] Example 2:
Figure imgf000183_0001
A siining mixture of oxindole (5,7 g, 43 mmol) and Raney nickel (10 g) in ethane - 1 ,2-diol (100 mL) was heated in an autoclave. After the reaction was complete, the mixture was filtered and the excess of diol was removed under vacuum. The residual oil was triturated with hexane to give 3-(2-hydroxy-ethy!)-1 ,3-dihydro-indol-2-one as a colorless crystalline solid (4,6 g, 70 %).
[Θ589] 1 ,2-Dihydro-3-spIr ~l '-cyeIopr pyI-l i-todok-2-oe®
To a solution of 3-(2-hydroxy-ethyl)-l,3-dihydro-indoI-2-one (4,6 g, 26 mmol) and
triethy!amine (10 mL) in CH2G2 (100 mL) was added MsCl (3.4 g, 30 mmol) dropwise at -20 °C. The mixture was then allowed to warm up to room temperature and stirred overnight The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by column chromatography to give crude l,2-dihydro-3-spiro- -cyclopropyl-lH-indole~2-one as a yellow solid (2.5 g), which was used directly in the next step,
[0590] l,2~DIhydro~3-spiro-I'-cy€!opropyI-llf-Iadoie
To a solution of l,2-dihydro-3-spiro-l'-cyclopropyl-iH-indole-2-one (2.5 g crude) in THF (50 mL) was added L1AIH4 (2 g, 52 mmol) portionwise. After heating the mixture to reflux, it was poured into crushed ice, basified with aqueous ammonia to pH 8 and extracted with EtOAc, The combined organic layers were washed with brine, dried over Na2SC>4 and concentrated to give
- 182 -
S5 4833.I the crude l,2-dihydro-3-spiro-l '-cyclopropyHH-indoIe as a yellow solid (about 2 g), which was used directly in the next step.
[0591] e-Niiro-ljl-difeydro-S-spiro-l'-cyclopropyl-lff-l dole
To a cooled solution (-5 CC to -10 °C) of NaN03 (1.3 g, 15.3 mmol) in H280 (98 , 30 mL) was added 1,2-dihydro- 3-sptfo-P-cyclopropyl- H-indoie (2 g, crude) dropwise over a period of 20 min. After addition, the reaction mixture was stirred for another 40 min and poured over crushed ice (20 g). The cooled mixture was then basified with NH4OH and extracted with EtOAc. The organic layer was washed with brine, dried over Na SG4, and concentrated under reduced pressure to yield 6-nitro- 1, 2-dihydro-3-spiro-l' -cyclopropyl- IH-indole as a dark gray solid (1.3 g)
[0592] l-Aceiyl-^-ssitro-ljl-dlliydro-S-spiro-I^cydopropyl-l/f-ind Ie
NaHC(½ (5 g) was suspended in a solution of 6-nitro-I,2-dihydro-3-spiro-r-cyclopropyl-l H- indole (1.3 g, crude) in CH2Q2 (50 mL). While stirring vigorously, acetyl chloride (720 mg) was added dropwise. The mixture was stirred for 1 h and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel to give l-acetyi-6-nitro-l,2-dmydro-3-spiro-r-cyciopropyl-lH-indoIe (0.9 g, 15 % over 4 steps).
[0593] DC-2; I-Acetyl-e-amliio-l^-dihydro-S-spIro-l'-eyciopropyl-lH-isidol A mixture of l-acetyl-6~nitro-l,2-dihydro-3-spiro-l '-cyclopropyl- IH-indole (383 mg, 2 mmol) and Pd-C (10 %, 100 mg) in EtOH (50 raL) was stirred at room temperature under H2 (1 aim) for 1.5 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was treated with HCi / MeOH to give l-acetyl-6-amino-l,2-dihydro-3-spiro-r- cyclopropyl- IH-indole (DC-2) (300 mg, 90 %) as a hydrochloride salt.
- 183 -
8544833.5 0594] Example 3:
Figure imgf000185_0001
[0595] 3-Methyl-bui-2-e¾olc acid pfamySamide
A mixture of 3~methyI~but-2- enoic acid ( 100 g, 1 mo!) and SO<¾ (119 g, 1 mo!) was heated at reflux for 3 h. The excess SOC was removed under reduced pressure. CH2CI2 (200 mL) was added followed by the addition of aniline (93 g, 1.0 mol) in Et N (101 g, 1 mol) at 0 °C. The mixture was stirred at room temperature for i h and quenched with HC1 (5%, 150 mL). The aqueous layer was separated and extracted with CH2CI2. The combined organic layers were washed with water (2x100 mL) and brine (100 mL), dried over
Figure imgf000185_0002
and concentrated to give 3-methyl-but-2-enoic acid phenylamide (120 g, 80 %).
[0596] 4,4-Dli¾ethyl-3,4-dihydro- lH-quitiolin-2-one
A1C1 (500 g, 3.8 mo!) was carefully added to a suspension of 3~methy!-but-2 -enoic acid phenylamide (105 g, 0.6 mol) in benzene (1000 mL). The reaction mixture was stirred at 80 °C overnight and poured into ice- water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (250 mL x 3). The combined organic layers were washed with water (200 mL x 2) and brine (200 mL), dried over Na2S(¾ and concentrated to give 4,4- dimethyl-3,4-dihydro-lH-quinolin-2-one (90 g, 86 %).
[Θ597] 4,4-Dkneihyl- 1,2 ,3,4-tetrafa dro-qulsollne
A solution of 4,4-dimethyl-3,4-dihydro-lH-quinolin-2-one (35 g, 0.2 mol) in THF (100 mL) was added dropwise to a suspension of L1AIH4 (18 g, 0.47 mol) in THF (200 mL) at 0 °C After
- 184 -
S5 4S33.S addition, the mixture was stirred at room temperature for 30 min and then slowly heated to reflux for 1 h. The mixture was then cooled to 0 °C. Water (18 mL) and NaOH solution (10 %, 100 mL) were carefully added to quench the reaction. The solid was filtered off and the filtrate was concentrated to give 4,4-dimethyl-l>2,3,4-tetrahydro-quinoline,
[©598] 4,4«B!met¾yl»7»Mtr0- 1,2 A etrafa re-qMiBolii¾£
To a mixture of 4,4-dimethyl- 1 ,2,3 ,4-tetrahydro~quinoline (33 g, 0.2 mol) in H2S04 (120 mL) was slowly added KNO3 (20.7 g, 0.2 mol) at 0 °C. After addition, the mixture was stirred at room temperature for 2 h, carefully poured into ice water and basified with Na2C03 to pH 8. The mixture was extracted with ethyl acetate (3 x 200 mL). The combined extracts were washed with water and brine, dried over Na2S04 and concentrated to give 4, 4-dimethyl-7-mtro-l, 2, 3, 4-tetrahydro-quinoiine (21 g, 50 %).
[0599] 4,4-DimethyI-7-¾itro-3,4-dlhydro~2H-q¾smoiirae~l--earbo3»cylk add totf-bsityl ester
A mixture of 4,4-diniethyS-7-mtro-l,2,3,4-tetralwdro-quinoline (25 g, 0.12 mol) and Boc20 (55 g, 0.25 moS) was stirred at 80 °C for 2 days. The mixture was purified by silica gel
chromatography to give 4,4-dimethyi-7-niiro-3,4-dihydro-2H-quinoline-l-carboxylic acid iert- butyl ester(8 g, 22 %).
DC-3; ier -But l 7-aMisi« 3,4-dihyclr0-4,4-dImethylqisIra iie-l(2H)- carboxylate
A mixture of 4,4-dimethyl-7-niirO"3,4-dihydro-2H-quinoline-l carboxylic acid iert-butyl ester (8.3 g, 0.03 mol) and Pd-C (0.5 g) in methanol (100 mL) was stirred under ¾ ( 1 arm) at room temperature overnight. The catalyst was filtered off and the filtrate was concentrated. The residue was washed with petroleum ether to give tert-butyl 7-amino-3,4-dihydro-4,4- dimethylquinoline-l(2H)-carboxylate (DC-3) (7.2 g, 95 %). Ή NMR (CDC13) δ 7.11-7.04 (m, 2 H), 6.45-6.38 (m, ί H), 3.71-3.67 (m, 2 H), 3.50-3.28 (m, 2 H), 1.71-1.67 (m, 2 H), 1.51 (s, 9 H), 1.24 (s, 6 H).
- 185 -
8544833.1 [0601] Exam le 4;
Figure imgf000187_0001
[©6©2] l-CMoro-4-meihylpeHiais-3»ooe
Ethylene was passed through a solution of isobuiyryi chloride (50 g, 0.5 mol) and AICI3 (68.8 g, 0.52 mol) in anhydrous CH2G2 (700 mL) at 5 °C After 4 h, the absorption of ethylene ceased, and die mixture was stirred at room temperature ovemight. The mixture was poured into cold diluted HC1 solution and extracted with CH2CI2. The combined organic phases were washed with brine, dried over Na^SO^, filtered and concentrated to give the crude !-chloro-4- methylpentan-3-one, which was used directly in the next step without further purification,
[0603] 4-Meihyl-l-(pheaylamleo)-peiiiae-3~0Sie
A suspension of the crude l-chloro-4-methylpentan-3-one (about 60 g), aniline (69.8 g, 0.75 mol) and NaHC<¾ (210 g, 2.5 mol) in CH3C (1000 mL) was heated at reflux overnight. After cooling, the insoluble salt was filtered off and the filtrate was concentrated. The residue was diluted with CH2C¾, washed with 10% HCI solution (100 mL) and brine, dried over Na^SG^ filtered and concentrated to give the crude 4-methyl-l-(phenyIamino)-pen.tan-3-one.
[0604] 4-Methyl-l-(p¾esiylaiBiBo)-peiiiaii-3-ol
At -10 °C, NaB¾ (56.7 g, 1.5 mol) was gradually added to a mixture of the crude 4-methyl-l- (phenylammo)-pentan-3-one (about 80 g) in MeOH (500 mL). After addition, the reaction mixture was allowed to warm to room temperature and stirred for 20 rain. The solvent was removed and the residue was repartitioned between water and CH2CI2. The organic phase was separated, washed with brine, dried over Na2SC>4, filtered and concentrated. The resulting gum
;6
8544833.5 was triturated with ether to give 4-meAyl- l-(phenylammo)~peritari-3-o! as a white solid (22 g, 23 %).
[0605] 5,5-DlmeilsyI-2,3 ,4,5-ie rahydro- lH-beiKo[fe Jazepine
A mixture of 4-methyl-l-(p enyiamino)~penian-3-ol (22 g, 0.11 moi) in 98% H2SO4 (250 niL) was stirred at 50 °C for 30 min. The reaction mixture was poured into ice-water basified with sat. NaOH solution to pH 8 and extracted with CH2Q>. The combined organic phases were washed wife brine, dried over Ν¾804, filtered and concentrated. The residue was purified by column chromatography (petroleum ether) to afford 5,5-dimethyl- 2,3,4,5-teteahydro~lH~ benzo[b]azepine as a brown oil (1.5 g, 8 ).
[0606] 5,S-DimethyI»8-miro-2,3,4,5-ietrahydro-lH~bem [b]azeplae
At 0 °C, KNO3 (0.76 g, 7.54 mmol) was added portionwise to a solution of 5,5~dirnelhy!-2,3,4,5- tetrahydro-lH-benzo[b]azepine (1.1 g, 6.28 mmol) in H2SO4 (15 mL). After stirring 15 min at tills temperature, the mixture was poured into ice water, basified with sat. NaHC<¾ to pH 8 and extracted with EtOAc. The organic layer was washed with brine, dried over Na SQ4 and concentrated to give erode 5,5-dimethyl-8-nitro-2,3,4,5-tetrahydro-lH-benzo[b]azepine (1.2 g), which was used directly in the next step without further purification.
[0607] l-(5,5- miethyi-8-nitr©-2,3A5~tt^
Acetyl chloride (0.77 mL, 1 1 mmol) was added to a suspension of crude 5,5-dimethyl-8-nitro- 2,3,4,5~tetrahydro-lH-benzo[b]azepine ( 1.2 g, 5.45 mmol) and NaHCOj (1.37 g, 16.3 mmol) in CH2C1? (20 mL). The mixture was heated at reflux for 1 h. After cooling, the mixture was poured into water and extracted with CH2C12. The organic layer was washed with brine, dried over Na2S04 and concentrated. The residue was purified by column cfiromatography to afford 1- (5,5-dimethyl-8~nitro-2,3,4,5-tetrahydrobenzo[blazepin-l-yl)ethanone (1.05 g, 64 % over two steps).
[0608] DC-4; l-(8-Aoiliso-2,3j4,S»ieirahydro~5,5~dimeihylbemo[b]a¾epl -l- yi)ethaR05ie
A suspension of l-(5,5-dimethyl-8-nitro-2,3,4,5 efr^ (1.05 g5 40 mmol) and 10% Pd~C (0.2 g) in MeOH (20 mL) was stirred under H2 (1 aim) at room temperature for 4 h. After filtration, the filtrate was concentrated to give l-(8-amino-2,3,4,5- tetrahydro-5,5-diniethylbenzo[b]azepin-i-yl)e hanone as a white solid (DC-4) (880 mg, 94 %).
■■ 187 -
S5 4S33.1 Ή NMR (CDCb) δ 7.06 (d, / = 8.0 Hz, 1 H), 6.59 (dd, J= 8.4, 2.4 Hz, 1 H), 6.50 (br s, 1H), 4.18-4.05 (m, 1H), 3.46-3.36 (m, 1 H), 2.23 (s, 3H), 1.92-1.85 (m, 1H), 1.61-1.51 (m, 3H), 1.21 (s, 3H), 0.73 (t, J = 7.2 Hz, 3 H); ESI-MS 233.0 mlz (MH4).
[θ 09] Example 5:
Figure imgf000189_0001
[0618] SpiroClH-indene- '-piperidiiil-aCZH^ne, l'-benzyl
A mixiirre of spiro[lH-indene-l,4'-piperidine3-r-carboxylic acid, 2,3-dihydro-3-oxo-, 1,1- diraethylethyl ester (9.50 g, 31.50 mmol) in saturated HCl MeOH (50 mL) was stirred at 25 °C overnight. The solvent was removed under reduced pressure to yield an off-white solid (7.50 g). To a solution of this solid in dry CH3CN (30 mL) was added anhydrous K2CO3 (7.85 g, 56.80 mmol). The suspension was stirred for 5 min, and benzyl bromide (5.93 g, 34.65 mmol) was added dropwise at room temperature. The mixture was stirred for 2 h, poured into cracked ice and extracted with CH2CI2. The combined organic layers were dried over Na2S0 and concentrated under vacuum, to give cmde spiro[lH-indene~l,4'-piperidin]-3(2H)-one, i '-benzyl (7,93 g, 87 %), which was used without further purification.
- 188 -
8544833.3 [0611J S lro lH-indeHe-l^'- i eridmJ-SClH)-©!!©, -benzyl, oxlme To a solution of spko[lH~mdene~l,4'-piperidin]-3(2H)-one, Γ-benzyi (7.93 g, 27.25 mmo!) in EtOH (50 mL) were added hydroxylamine hydrochloride (3.79 g, 54.50 mmo!) and anhydrous sodium acetate (4.02 g, 49.01 mmoi) in one portion. The mixture was refluxed for 1 h. and then cooled to room temperature. The solvent was removed under reduced pressure and 200 mL of water was added. The mixture was extracted with CH2CI2. The combined organic layers were dried over Na2SG and concentrated to yield spiro[iH-inderae~l ,4'-piperidin]-3(2H)-one, - benzyi, oxime (7.57 g, 91 %), which was used without further purification.
[0612] l^jS^-TeirahydroqK oim-^splro^^i ^beezyl- i ridiEe)
To a solution of spiro[lH-indene-i,4'-piperidin]-3(2H)-Qne, l'-benzyl, oxime (7.57 g, 24.74 mmoi) in dry CH2CI2 (150 mL) was added dropwise DIBAL-H (135.7 mL, 1M in toluene) at 0 °C. The mixture was stirred at 0 °C for 3 h, diluted with C¾Cl2(100 mL), and quenched with NaF (20.78 g, 495 mmoi) and water (6,7 g, 372 mmoi). The resulting suspension was stirred vigorously at 0 °C for 30 min. After filtration, the residue was washed with (¾<¾. The combined filtrates were concentrated under vacuum to give an off-brown oil that was purified by column chromatography on silica gel (€¾(¾ - MeOH, 30:1) to afford 1,2,3,4- tetrahydroquinolin-4-spiro-4'-(N'-benzyl-piperidine) (2.72 g, 38 %).
[0613] l,2 Tetrahydroi|HmoHsi-4-spiro-4*-pip€rjdlne
A suspension of l,2,3,4-Tetrahydroquinolir!-4-spiro-4'-(N'-benzyl-piperidine) (300 mg, 1.03 mmoi) and Pd(OH)2-C (30 mg) in MeOH (3 mL) was stirred under ¾ (55 psi) at 50 °C over night. After cooling, the catalyst was filtered off and washed with MeOH. The combined filtrates were concentrated under reduced pressure to yield l,2,3,4-tetrahydroquinolin-4-spiro- 4'~piperidine as a white solid (176 mg, 85 ), which was used without further purification.
[Θ614] T'-Niiro-s iroi i erldfas -^ l'HJ-qalisolmel, l^-dib dro- earbosyllc acid tert-butyl ester
K O3 (69.97 mg, 0.69 mmoi) was added portion-wise to a suspension of 1,2,3,4- ietrahydroquinolin-4-spiro-4'-piperidine (133 mg, 0.66 mmoi) in 98% H2SO4 (2 mL) at 0 °C. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for additional 2 h. The mixture was then poured into cracked ice and basified with 10% NaOH to pH~ 8. Boc20 (172 mg, 0.79 mmoi) was added dropwise and the mixture was stirred at room temperature for 1 h. The mixture was then extracted with EtOAc and the
. 189 -
8544833.1 combined organic layers were dried over Na2SG4, filtered and concentrated to yield crude T- niiro-spiro[piperidirie-4,4'(rH)-quinoline],
Figure imgf000191_0001
carboxylic acid ?m~butyl ester (230 mg), which was used in the next step without further purification.
[Θ615] ?'-5sltro-splTO[piperidl0«~4,4'(liH)-l-aestyI-qptooIisie]!1 1'^'-diliydro- csrboxylk acid ferf-bistyl ester
Acetyl chloride (260 mg, 3.30 mmoi) was added dropwise to a suspension of 7'-nilro- spiro[piperidine'4,4'(rH)-quirioline]i 2',3'~dihydro- carboxylic acid ferf-butyl ester (230 mg) and aHCOs (1.11 g, 13.17 mmol) in MeCN (5 mL) at room iemperature. The reaction mixture was refluxed for 4 h. After cooling, the suspension was filtered and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether - EtOAc, 10:1) to provide 7'-nitro~spiro[piperidine-4,4t(rH)-l-acetyl-quinoline]J 2',3!-dihydro- carboxylic acid tert-butyl ester (150 mg, 58 % over 2 steps)
[§616] DC~S; 7'-.4mlii©-spiro[piperiilije.4,4 l'H)-1-acelyl~i|iitisoiiiie], 2' '- dlhydre- carboxylic acid tef-tatyl ester
A suspension of 7'~nitro-spiro[piperidine-4,4'(1 'H)-l-acetyl-quinoline], 2',3'-dihydro- carboxylic acid teri-butyi ester (150 mg, 0,39 mmoi) and Raney Ni (15 mg) in MeOH (2 niL) was stirred under ¾ (! atm) at 25 °C overnight. The catalyst was removed via filtration and washed with MeOH. The combined filtrates were dried over Na2S04, filtered, and concentrated to yield 7'- ammo-spiro[piperidffle-4,4'( H)-l-acety'S-quinoIinel, 2\3'-dihydro~ carboxylic acid &?rf-butyl ester (DC-5) (133 mg, 96 %).
[§617] Example 7:
Figure imgf000191_0002
DC-?
[0618] 2-(2,4-Di irophesiyIi o)~acet;k add
Et3N (1.5 g, 15 mmoi) and mercapto-acetic acid (1 g, 1 1 mmol) were added to a solution of 1- chloro-2,4-dinitrobenzene (2.26 g, 10 mmoi) in 1,4-dioxane (50 mL) at room temperature. After stirring at room temperature for 5 h, H20 (100 mL) was added. The resulting suspension was extracted with ethyl acetate (100 mL x 3). The ethyl acetate extract was washed with water and
- 190 - g544833.1 brine, dried over Na2804 and concentrated to give 2-(2,4-dinitrophenyithio)-acetic acid (2.3 g, 74 %), which was used without further purification.
[0619] DC-7; 6-Amlno.2H-beR¾oib][l,4]tliia¾in.3(4H)-.oise
A solution of 2-(2,4-dinitfophenylthio)-acetic acid (2.3 g, 9 mraol) and tin (II) chloride dihydrate (22.6 g, 0.1 moS) in ethanol (30 mL) was refluxed overnight. After removal of the solvent under reduced pressure, the residual slurry was diluted with water (100 mL) and basified with 10 % Na2CO3 solution to pH 8. The resulting suspension was extracted with ethyl acetate (3 x 100 mL). The ethyl acetate extract was washed with water and brine, dried over Na2804, and concentrated. Be residue was washed with€¾<¾ to yield 6-amino-2H-benzo[b][l,4]thiazin- 3(4H)-one (DC~7) as a yellow powder (1 g, 52 %). ¾H NM (DMSO- ) δ 10.24 (s. 1 H), 6.88 (d, 1 H, 7 = 6 Hz), 6.19-6.21 (m, 2H), 5.15 (s, 2 H), 3.28 (s, 2 H); ESi-MS 181.1 m/z (MfT).
[0620] Example 7:
Figure imgf000192_0001
[©621] N-(2-Bromo-5-nItroph®i¾yl)aceiamide
Acetic anhydride (1.4 mL, 13.8 mmol) was added dropwise to a stirring solution of 2-bromo-5- troa line (3 g, 13.8 mmol) in glacial acetic acid (30 mL) at 25 °C. The reaction mixture was stirred at room temperature overnight, and then poured into water. The precipitate was collected via filtration, washed with water and dried under vacuum to provide N-(2-bromo-5- iiitrophenyl)acetamide as an off white solid (3.6 g, 90 %).
[0622] N-(2-BroiBO-5-Eiirophefflyi)-N-(2-meihyIprop~2-erayl)aceiamlde
At 25 °C, a solution of 3-bromo-2-methylpropene (3.4 g, 55.6 mmol) in anhydrous DMF (30 mL) was added dropwise to a solution of N-(2-bromo-5-nitropheny)acetamide (3.6 g, 13.9
■ 191 -
S5 4833.1 mmol) and potassium carbonate (3.9 g, 27.8 mmol) in anhydrous DMF (50 rnL). The reaction raixtiire was stirred at 25 °C overnight. The reaction mixture was then filtered and the filtrate was treated with sat. Na2CG3 solution. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgS04, Filtered and concentrated under vacuum to provide N-(2-bro0Jo-5- nitrophenyI)-N-(2-methylprop-2-enyl)acetamide as a golden solid (3.1 g, 85 %). ESI-MS 313 m/z (MH+),
[§623] 1^3^Dimethyl-6-nitroindolm-l'y!)ethano!ie
A solution of N-(2-bromo-5-nitrophenyl)-N-(2-rnethylprop-2-enyl)acetamide (3.1 g, 10.2 mmol), tetraethyiammonium chloride hydrate (2.4 g, 149 mmol), sodium formate (1.08 g, lSmmol), sodium acetate (2.76 g, 34.2 mmol) and palladium acetate (0.32 g, 13.2 mmol) in anhydrous DMF (50 mL) was stirred at 80 °C for 15 h under N2 atmosphere. After cooling, the mixture was filtered through Celite. The Celite was washed with EtOAc and the combined filtrates were washed with sat. NaHC<¾. The separated organic layer was washed with water and brine, dried over Mg8C>4. filtered and concentrated under reduced pressure to provide l-(3,3- dimethyl-6-nitroindolin-l-yI)ethanone as a brown solid (2.1 g, 88%).
[0624] DC-8; l-(6-Aml¾o-3,3-dlsBethyl-2,3-dihydr0--md i!"'l~yl)-eifeaii iie
10% Pd-C (0.2 g) was added to a suspension of l-(3,3-dimethyl-6-nitroindolm~l-yl)ethanone (2.1 g, 9 mmol) in MeOH (20 mL). The reaction was stirred under ¾ (40 psi) at room temperature overnight. Pd-C was filtered off and the filtrate was concentrated under vacuum to give a crude product, which was purified by column chromatography to yield l-(6-araino-3,3- dimethyl-2,3-dihydro-ii>dol-l-yl)-ethanone (BC-8) (1.3 g. 61 ).
- 192 -
8544833.Ϊ [1)625] Example 8:
Figure imgf000194_0001
[0626] 2,3^4,5-Teirahydro- IH-berai [h]azeptae
DiBAL (90 mL, 90 mmol) was added dropwise to a solution of 4-dihydro~2H~naphthalen-l-one oxime (3 g, 18 mmol) in dichloromethane (50 mL) at 0 CC. The mixture was stirred at this temperature for 2 h. The reaction was quenched with dichloromethane (30 mL), followed by treatment with NaF (2 g. 0.36 mol) and H20 (5 mL, 0.27 mol). Vigorous stirring of the resulting suspension was continued at 0 °C for 30 min. After filtration, the fdtrate was concentrated. The residue was purified by flash column cinematography to give 2,3,4,5-tetrahydro-lH- benzo[b]azepine as a colorless oil (1,9 g, 70 ).
Figure imgf000194_0002
At -10 °C, 2,3,4,5-tetrahydro-lH-benzo[b]azepine (1.9 g, 13 mmoi) was added dropwise to a solution of NO3 (3 g, 30 mmol) in H2SO4 (50 mL). The mixture was stirred for 40 min, poured over crashed ice, basified with aq. ammonia to pH 13, and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na?S04 and concentrated to give 8-nitro-2,3,4,5-tetrahydro~lH-benzo[b]azepine as a black solid (1.3 g, 51 %), which was used without further purification.
[0628] l-(8- iro~2^,4^5-ieirahydro-besi35o[b]a¾ep -l-yl)-ei!iaao0e
Acetyl chloride (1 g, 13 mmol) was added dropwise to a mixture of 8-nitro-2,3,4,5-tetrahydro- lH-benzo[b]azepine (1.3 g, 6.8 mmol) and NaHC03 (1 gs 12 mmol) in CH2C¾ (50 mL). After stirring for 1 h, the mixture was filtered and the filtrate was concentrated. The residue was dissolved in CH2Cl2, washed with brine, dried over Na2804 and concentrated. The residue was
- 193 -
8544833.1 purified by column chromatography to give l-(8-nitro-2,3,4,5-tetrahydro-ben2o[b]azepin~l~yl)- ethanone as a yellow solid (! .3 g, 80 %).
[0629] BC-9; l~{8~Amiiio-2,3,4,5 etrahydro-beH∞[bJs3Kpta-l-yl)->ethaisoii€ A mixiure of l-(8-nltro-2,3,4,5-ietrahyclro-benzo[b]azepiri-l -yl)- ethanone (1.3 g, 5,4 nimol) and Pd-C (10 %, 1 0 mg) in EtOH (200 mL) was stirred under ¾ (1 aim) at room temperature for 1.5 h. The mixture was filtered through a layer of Ce!ite and the filtrate was concentrated to give l-(8-amino-2,3,4,5-tetrahydro-benzo[b]azepin-l-yl)-e.thasione (DC-9) as a white solid (1 g, 90 %). !H NM (CDCI3) δ 7,01 (d, J = 6.0 Hz, 1 H), 6.56 (dd, / = 6.0, 1.8 Hz, 1 H), 6.50 (d, / = 1.8 Hz, 1 H), 4.66-4.61 (m, 1 H), 3.50 (br s, 2 H), 2.64-2.55 (m, 3 H), 1 ,94-1.91 (m, 5 H), 1.77- 1.72 (m, 1 H), 132-1.30 (m, 1 H); ESI-MS 204.1 m z (MH+).
Figure imgf000195_0001
[0631] 6-Nitro~4H-beffi¾o[l,4]osa¾m-3~Oiie
At 0 °C, chloroacetyl chloride (8,75 mL, 0.1 1 moi) was added dropwise to a mixture of 4-nitro- 2-aminophenol (15.4 g, 0.1 mol), benzyltrimethylammonium chloride (18.6 g, 0.1 mol ) and NaHC(¾ (42 g, 0.5 mol) in chloroform (350 mL) over a period of 30 min. After addition, the reaction mixture was stirred at 0 °C for 1 h, then at 50 °C overaight. The solvent was removed under reduced pressure and the residue was treated with water (50 mL). The solid was collected via filtration, washed with water and recrystallized from ethanol to provide 6-mtro-4H~ benzof 1 ,4]oxazin-3-one as a pale yellow solid (8 g, 41 %).
- 194 -
S3 S33.3 [0632] fi- Iiro-S^-dihydr - H-beazoii^Joxassme
A solution of BH3-Me2S in THF (2 M, 7.75 niL, 15.5 mmol) was added dropwise to a suspension of 6-n tro-4H-benzo[l,4]oxazin-3~one (0.6 g, 3.1 mmoi) in THF (10 mL). The mixture was stirred at room temperature overnight. The reaction was quenched with MeOH (5 mL) at 0 °C and then water (20 mL) was added. The mixture was extracted with Et2G and the combined organic layers were washed with brine, dried over Na2S04 and concentrated to give 6- nitro-3,4-dihydro-2H-benzo[1 ,4]oxazine as a red solid (0,5 g, 89 ), which was used without further purification.
[0633] ^Acefyl-e- t o-J^-dlhydro-lH-bemofl^lox z Ke
Under vigorous stirring at room temperature, acetyl chloride (1.02 g, 13 mmol) was added dropwise to a mixture of 6-nitro-3,4-dihydro-2H-benzo[l,4]oxazine (1.8 g, 10 mmol) and NaHC<¾ (7.14 g, 85 mmol) in Q¾Ci2 (50 mL). After addition, the reaction was stirred for 1 h at this temperature. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was treated with Et20: hexane (1:2, 50 mL) under stirring for 30 mm and then filtered to give 4-acetyl-6-nitro-3,4-dihydro-2H-benzo[1 ,4]oxazme as a pale yellow solid (2 g, 90 %).
[Θ634] DC-I0; 4~Acetyi-6.amls -3,4-dihydTO-2H«benzo[l,4joxa¾lne
A mixture of 4-acetyl-6-nitro-3,4-dihydro-2H-benzo[l,43oxazine (1.5 g, 67.6 mmol) and Pd-C (10 %, 100 mg) in EtOH (30 mL) was stirred under ¾ (1 aim) overnight. The catalyst was filtered off and the filtrate was concentrated. The residue was treated with HCl / MeOH to give 4-aceryl-6-amino-3,4-dihydro-2H-benzo[l,43oxazine hydrochloride (DC-10) as an off-white solid (1.1 g, 85 %). !H NMR (DMS€M6) δ 10.12 (br s, 2H), 8.08 (br s, 1H), 6.90-7.03 (m, 2 H), 4.24 (t, J = 4.8 Hz, 2 H), 3.83 (t, J = 4.8 Hz, 2H), 2.23 (s, 3 H); ESI-MS 192.1 mlz (MH*).
Figure imgf000196_0001
- 195 -
8544833.1 [0636] l^J^-Tef ahydro-T-isitroIsoqKmoIisi hydrochloride
1,2,3,4-Teirahydroisoquinoline (6.3 mL, 50.0 mmoi) was added dropwise to a stirred ice-cold solution of concentrated H2SO4 (25 rnL). KNO3 (5.6 g, 55.0 nirnol) was added portionwise while maintaining the temperature below 5 °C. The mixture was stirred at. room temperature overnight, carefully poured into an ice-cold solution of concentrated NH OH, and then extracted three times with CHCI3. The combined organic layers were washed with brine, dried over Na S04 and concentrated. The resulting dark brown oil was taken up into EtOH, cooled in an ice bath and treated with concentrated HC1. The yellow precipitate was collected via filtration and recrystailized from methanol to give 1 ,2,3,4~tetrahydro~7-nitroisoquinoIine hydrochloride as yellow solid (2.5 g, 23 %). Ή NMR (400 MHz, DMSO-d6) δ 9.86 (s, 2H), 8.22 (d, 7 = 1.6 Hz, IH), 8.11 (dd, 7 = 8.5, 2.2 Hz, 1H), 7.53 (d, 7 = 8.5 Ηζ,ΙΗ), 4.38 (s, 2H), 3.38 (s, 2H), 3.17-3.14 (m, 2H); HPLC ret. time 0.51 mm, 10-99 % CH3CN, 5 min run; ESi-MS 179.0 m/z (MH*). f ©637] terf-Butyi 3,4-dihy dro»7-miroisoq¾smolisi€-2( lH)-carbo3S£ylsie
A mixture of 1 ,2,3,4-Tetrahydro-7-nitroisoquinoline (2.5 g, L6 mmoi), 1,4-dioxane (24 mL), H20 (12 mL) and IN NaOH (12 mL) was cooled in an ice-bath, and Boc2Q (2.8 g, 12.8 mmoi) was added. The mixture was stirred at room temperature for 2.5 h, acidified with a 5% KHSO4 solution to pH 2-3, and then extracted with EtOAc. The organic layer was dried over MgS<¼ and concentrated to give lerf-butyl 3,4-dihydro-7-nitroisoquinolirie-2(lH)-carboxylate (3,3 g, quant.), which was used without further purification. JH NMR (400 MHz, DMSO-d6) δ 8.13 (d, 7 = 2.3 Hz, lH), 8.03 (dd, 7 = 8.4, 2.5 Hz, IH), 7.45 (d, J = 8.5 Hz, lH), 4.63 (s, 2H), 3.60-3.57 (m, 2H), 2.90 (t, 7 = 5.9 Hz, 2H), 1.44 (s, 9H); HPLC ret. time 3,51 min, 10-99 % CH3CN, 5 min ran; ESi-MS 279.2 m/z (MET").
[0638] DC-6; fert-Butyl 7-amino-3,4-dihydroisoqumoEine-2(lH)--carboxylate
Pd(OH)2 (330.0 mg) was added to a stirring solution of teri-butyl 3,4-dihydro-7- nitroisoquinoiine-2(lI¾-carboxylate (3.3 g, 12.0 mmoi) in MeOH (56 mL) under N2 atmosphere. The reaction mixture was stirred under H2(l aim) at room temerpature for 72 h. The solid was removed by filtration through Celite. The filtrate was concentrated and purified by column chromatography (15-35 % EtOAc - Hexanes) to provide iert-butyi 7-amino-3,4- dmydroisoquinoline-2(lH)-caiboxylate (DC-6) as a pink" oil (2.0 g, 69 %). Ή NMR (400 MHz, DMSO-d6) δ 6.79 (d, 7 = 8.1 Hz, 1H), 6.40 (dd, 7 = 8.1, 2.3 Hz, lH), 6.31 (s, IH), 4.88 (s, 2H), 4.33 (s, 2H), 3.48 (t, 7 = 5.9 Hz, 2H), 2.58 (t, 7 = 5.9 Hz, 2H), 1.42 (s, 9H); HPLC ret. time 2,13 min, 10-99 % CH3CN, 5 min ran; ESi-MS 249,0 m/z (MH*).
- 196 -
8544833.1 [0639] Other arnines
[0640] Exam le It
Figure imgf000198_0001
E-1
[©641] 4-Bromo-3-iiiirobe ¾© itrile
To a solution of 4-broiTiobenzonitrile (4.0 g, 22 mmol) in cone. H2SO4 (10 mL) was added dropwise at 0 °C nitric acid (6 mL). The reaction mixture was stirred at 0 °C for 30 min, and then at room temperature for 2.5 h. The resulting solution was poored into ice-water. The white precipitate was collected via filtration and washed with water until the washings were neutral The solid was recrystallized from an ethanol/water mixture ( 1 : 1, 20 mL) twice to afford 4- bromo-S-nitrobenzon le as a white crystalline solid (2.8 g, 56 %). *H NMR (300 MHz, DMSCM6) δ 8.54 (s, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H); !3C NMR (75 MHz, DMSO-<¾) δ 150.4, 137.4, 136.6, 129.6, 119.6, 117.0, 112.6; HPLC ret time 1.96 min, 10-100 % C¾CN, 5 min gradient; ESI-MS 227.1 Jz (MH*).
[0642] 2i-Etfeoxy-2- irobiphe yl-4-carboaitriIe
A 50 mL round-bottom flask was charged with 4-bromo-3-nitroberizonitrile (1.0 g 4.4 mmol), 2- ethoxyphenylboronic acid (731 mg, 4.4 mmol), Pd2(dba)s (18 mg, 0,022 mmol) and potassium fluoride (786 mg, 13.5 mmol). The reaction vessel was evacuated and filled with argon. Dry
THF (300 mL) was added followed by the addition of P(f~Bu)3 (0.11 mL, 10% wt. in hexane).
- 197 -
S544S33.1 The reaction mixture was stirred at room temperature for 30 min., and then heated at 80 °C for 16 h. After cooling to room temperature, the resulting mixture was filtered through a CeSite pad and concentrated. 2'-Eihoxy-2-nitrobiphenyi-4-carboniirile was isolated as a yellow solid (1.12 g, 95%). !H NMR (300 MHz, DMSO-£¾) δ 8.51 (s, 1H), 8.20 (d, 7 = 8.1 Hz, 1H), 7.68 (d, 7 =
8.4 Hz, 1H), 7.41 (t, 7 = 8.4 Hz, 1H), 7.37 (d, 7 = 7.5 Hz, IH), 7.08 (t, J ~ 7.5 Hz, IH), 7.03 (d, 7 = 8.1 Hz, IH), 3.91 (q, 7 = 7.2 Hz, 2H), 1.12 (t, 7 = 7.2 Hz, 3H); 13C NMR (75 MHz, DMSCW6) δ 154.9, 149.7, 137.3, 137,2, 134.4, 131.5, 130.4, 128.4, 125.4, 121.8, 117.6, 112.3, 1 1 1.9, 64.1, 14.7; HPLC ret. time 2.43 min, 10-100 % CH3CN, 5 min gradient; ES1-MS 269.3 m/z (MH+).
[0643] 4-A MMometfeyI-2*-"eihoxy-bi heHyI»2-ylai! ii
To a solution of 2*-ethoxy-2-nitrobiphenyl-4-carbonitrile (500 mg, 1.86 mmol) in THF (80 inL) was added a solution of BH3.THF (5.6 mL, 10% wt. in THF, 5.6 mmol) at 0 °C over 30 min. The reaction mixture was stirred at 0 °C for 3 h and then at room temperature for 15 h. The reaction solution was chilled to 0 °C, and a H20/THF mixture (3 mL) was added. After being agitated at room temperature for 6 h, the volatiles were removed under reduced pressure. The residue was dissolved in EtOAc (100 mL) and extracted with IN HC1 (2 x 100 mL). The aqueous phase was basified with IN NaOH solution to pH land extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (50 mL), dried over Na2SC>4, filtered, and evaporated. After drying under vacuum, 4-aminomethyl-2'-ethoxy-biphenyl-2- ylamine was isolated as a brown oil (370 mg, 82 %). Ή NMR (300 MHz, DMSO-tfc) δ 7.28 (dt, 7 = 7.2 Hz, 7 = I .8 Hz, IH), 7.09 (dd, 7 = 7.2 Hz, 7 = 1 ,8 Hz, IH), 7.05 (d, 7 = 7.5 Hz, IH), 6.96 (dt, 7 ~ 7.2 Hz, 7 « 0.9 Hz, IH), 6.83 (d, 7 = 7.5 Hz, IH), 6.66 (d, J = 1.2 Hz, IH), 6.57 (dd, 7 =
7.5 Hz, 7 = 1.5 Hz, IH), 4.29 (s, 2H), 4,02 (q, 7 = 6.9 Hz, 2H), 3.60 (s, 2H), 1.21 (t, 7 = 6.9 Hz, 3H); HPLC ret. time 1.54 min, 10-100 % CH-jCN, 5 min gradient; ESI-MS 243.3 m/z (MH+).
[0644] E-1; (2'Amino>2'-ethoxy-biphenyl-4-ylmethyl)carbatnic acid tori-butyl ester
A solution of Boc20 (123 mg, 0.565 mmol) in 1,4-dioxane (10 mL) was added over a period of 30 min. to a solution of 4-aminomethyI-2'-ethoxy-biphenyl-2-ylamine (274 mg, 1.13 mmol.) in 1,4-dioxane (10 mL). The reaction mixture was stirred at room temperature for 16 h. The volatiles were removed on a rotary evaporator. The residue was purified by flash
chromatography (silica gel, EtOAc - CH2CI2, i :4) to afford (2-Amino-2'-ethoxy-biphenyl-4- ylmethyl)carbamic acid ferf-butyl ester (E-1) as a pale yellow oil (119 mg, 31 %). Ή NMR (300
MHz, DMSO-ds) δ 7.27 (m, 2H), 7.07 (dd, 7 = 7.2 Hz, 7 = 1.8 Hz, IH), 7,03 (d, 7 = 7.8 Hz, ί H),
- 198 -
8544833.1 6,95 (dt, J = 7.2 Hz, 7 = 0.9 Hz, ill), 6.81 (d, 7 = 7.5 Hz, 1H), 6.55 (s, 1H), 6.45 (dd, 7 =
7 = 1 .5 Hz, 1H), 4.47 (s, 2H), 4.00 (q, 7 = 7.2 Hz, 2H), 1.38 (s, 9H), 1.20 (t, 7 = 7.2 Hz, 3
HPLC ret. time 2.34 min, 10400 % CH3CN, 5 rain gradient; ESI-MS 343.1 mix (MH*).
[§645] Example 2s
Figure imgf000200_0001
E-2
[0646] 2-Broisio-l-? ri-bi8tyl-4-!iltrobeii¾es5e
To a solution of 1 -iert-butyl-4-nitrobenzene (8.95 g, 50 mmol) and silver sulfate (10 g, 32 mmol) in 50 n L of 90% sulfuric acid was added dropwise bromine (7.95 g, 50 mmol). Stiring was continued at room temperature overnight, and then the mixture was poured into dilute sodium hydrogen sulfite solution and was extracted with EtOAc three times. The combined organic layers were washed with brine and dried over MgSO^. After filtration, the filtrate was concentrated to give 2-bromo-l-½ri-butyl-4-nitrobenzene (12.7 g, 98 %), which was used without further purification. SH NMR (400 MHz, CDC13) δ 8.47 (d, J = 2.5 Hz, lH), 8.1 1 (dd, J = 8.8, 2.5 Hz, 1H), 7.63 (d, J = 8.8 Hz, 1H), 1 ,57 (s, 9H); HPLC ret time 4,05 min, i 0- 100 % CH3CN, 5 min gradient.
[0647] 2-terf-Beiyl-5-mirobee¾oeliriIe
To a solution of 2-bronio-l -i(£;ri-butyl-4-nitrobenzene (2.13 g, 8.2 mmol) and Zn(CN)2 (770 mg, 6,56 nimol) in DMF (10 mL) was added Pd(PPh3)4 (474 mg, 0.41 mmoi) under a nitrogen atmosphere. The mixture was heated in a sealed vessel at 205 °C for 5 h. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine and dried over MgSC¼. After removal of solvent, the residue was purified by column chromatography (0-10 % EtOAc-Hexane) to give 2-ierf-bufyl-5- nitrobenzonitrile (1,33 g, 80 %). *H NMR (400 MHz, CDC¾) δ 8.55 (d, J = 2.3 Hz, 1H), 8.36 (dd, J = 8.8, 2.2 Hz, 1H), 7.73 (d, J = 8.9 Hz, 1H), 1.60 (s, 9H); HPLC ret. time 3.42 min, 10- 100 % CI¾CN, 5 min gradient.
- 199 -
8544833.5 To a refluxing solution of 2-/t'ri-butyl-5-rdtrobenzoEitrile (816 mg, 4.0 mmol) in EtOH (20 mL ) was added ammonium formate (816 mg, 12.6 mmol), followed by 10% Pd-C (570 mg). The reaction mixture was refluxed for additional 90 mk, cooled to room temperature and filtered through Celite. The filtrate was concentrated to give -iert-butyl-S-aminobenzomtrile (E-2) (630 mg, 91 %), which was used without further purification. HPLC ret. time 2.66 mm, 10-99 % CHjC , 5 min run; ESi-MS 175.2 mlz (MlT).
[©649] Example 3:
Figure imgf000201_0001
[0650] (2~iert~B uiyl-5-niirophesyl)meihaEamme
To a solution of 2-ieri-butyI-5-uitrobenzonitrile (612 mg, 3.0 mmol) in THF (10 mL) was added a solution of BH3 HF (12 mL, 1M in THF, 12.0 mmol) under nitrogen. The reaction mixture was stirred at 70 °C overnight and cooled to 0 °C. Methanol (2 mL) was added followed by the addition of I HQ (2 mL). After refluxing for 30 min, the solution was diluted with water and extracted with EtOAc, The aqueous layer was basified with IN NaOH and extracted with EtOAc twice. The combined organic layers were washed with brine and dried over Mg2S04, After removal of solvent, the residue was purified by column chromatography (0-10 % MeOH - CH2CI2) to give (2-ierl-butyl-5-nitrophenyi)methanamine (268 mg, 43 %), Ή NMR (400 MHz, DMSO-40 δ 8.54 (d, J = 2.7 Hz, 1H), 7.99 (dd, J = 8.8, 2.8 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 4.03 (s, 2H), 2.00 (t, J = 2.1 Hz, 2H), 1.40 (s, 9H); HPLC ret. time 2.05 min, 10-100 % CH3CN, 5 min gradient; ESI-MS 209.3 m/z (MH+).
[©651] terf-Batyl
A solution of (2-ierf-butyl-5-nitsOphenyl)methanamine (208 mg, 1 mmol) and Boc20 (229 mg, 1.05 rnmoi) in THF (5mL) was refluxed for 30 min. After cooling to room temperature, the solution was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over MgS04. After filtration, the filtrate was concentrated to give tert-buty! 2-iert-buryl-5-nitrobenzylearbamate (240 mg, 78 %), which was used without further
- 200 -
8544833.3 purification, Ή NMR (400 MHz, DMSO- ) δ 8.26 (d, J = 2.3 Hz, 1H), 8.09 (dd, J = 8.8, 2.5 Hz, 1H), 7.79 (t, J = 5.9 Hz, 1H), 7.68 (d, J = 8.8 Hz, 1 H), 4.52 (d, J = 6.0 Hz, 2H), 1.48 (s, 18H); HPLC ret. time 3.72 min, 10-100 % CH3CN, 5 rain gradient.
[0652] E-4; teri-Butyl -ter -bHlyl-S-amtoobeiigylcarbamsie
To a solution of tert-butyl 2-½jrr-buiyl-5-nitrobenzylcarbam.ate (20 rag, 0.065 mmol) in 5% AcOH-MeOH (1 mL) was added 10% Pd-C (14 mg) under nitrogen atmosphere. The mixture was stirred under ¾ (I atm) at room temperature for 1 h. Be catalyst was removed via filtration through Ceiite, and the filtrate was concentrated to give tert-butyl 2~fe? ~butyl~5~
aniinobenzylcarbaniate (E-4), which was used without further purification. 5H NMR (400 MHz, CDC13) δ 7.09 (d, J = 8.5 Hz, 1H), 6.62 (d, J = 2.6 Hz, 1H), 6,47 (dd, J ~ 8.5, 2.6 Hz, 1 H), 4.61 (br s, 1H), 4.40 (d, J = 5.1 Hz, 2H), 4.15 (br s, 2H), 1 ,39 (s, 9H), 1.29 (s, 9H); HPLC ret. time 2.47 min, 10- 100 % C¾CN, 5 min gradient; ESI-MS 279.3 m/z (MH*).
Figure imgf000202_0001
[0654] 2-terf-Batyl-5- trobeiMolc acid
A solution of 2-teri-butyl-5-nitrobenzonitrile (204 mg, 1 mmol) in 5 mL of 75% H2SO4 was microwaved at 200 °C for 30 min. T!ie reaction mixture was poured into ice, extracted with EtOAc, washed with brine and dried over MgS04. After filtration, the filtrate was concentrated to give 2-i-?ri-butyl-5-nitroberiizoic acid (200 mg, 90 %), which was used without further purification. 5H NMR (400 MHz, CDC13) S 8.36 (d, J = 2,6 Hz, 1H), 8.24 (dd, J = 8.9, 2.6 Hz, 1H), 7.72 (d, J = 8.9 Hz, 1H) 1.51 (s, 9H); HPLC ret. time 2.97 min, 10-100 % CH3CN, 5 min gradient.
[0655] Methyl 2-^ri~bety!~5-mtrobesi¾oate
To a mixture of 2-teri-butyl-5-nitrobenzoic acid (120 mg, 0.53 mmol) and 2C03 ( 47 mg, 1.1 mmol) in DMF (5.0 mL) was added C¾i (40 jiL, 0,64 mmol). The reaction mixture was stirred at room temperature for 10 min, diluted with water and extracted with EtOAc. The combined
- 201 -
8544833.1 organic layers were washed with brine and dried over MgSO,*. After filtration, the filtrate was concentrated to give methyl 2-½rf-butyl-5-nitrobenzoate, which was used without further purification. ¾H NMR (400 MHz, CDC13) δ 8.20 (d, J = 2.6 Hz, 1H), 8.17 (t, J = i .8 Hz, 1H), 7.66 (d, J = 8.6 Hz, IE), 4.11 (s, 3H), 1.43 (s, 9H).
[0656] E-6; MeihyE 2-fe? -t>isiyl-S-asHlffl0bes¾¾oafe
To a refluxing solution of 2-fe^butyl-5-nitrobenzoate (90 mg, 0,38 mmol) in EtOH (2.0 mL) was added potassium formate (400 mg, 4.76 mmol) in water (1 mL), followed by the addition of 20 mg of 10% Pd-C. The reaction mixture was refluxed for additional 40 min, cooled to room temperature and filtered through Ce!ite. The filtrate was concentrated to give methyl 2-teri- butyi-5-aminobeozoate (E-6) (76 mg, 95 ), which was used without further purification. Ή NMR (400 MHz, CDC13) δ 7.24 (d, J = 8,6 Hz, 1H), 6.67 (dd, J = 8.6, 2.7 Hz, 1H), 6.60 (d, J = 2.7 Hz, 1H), 3.86 (s, 3H), 1.34 (s, 9H); HPLC ret. time 2.19 min, 10-99 % CH3CN, 5 min run; ESI-MS 208.2 m z (MH+).
[Θ657] Example 5;
Figure imgf000203_0001
Έ.-7
[0658] 2-i«ri-Butyi-5-rjiirobefi2;eEe-l-siiIfoiiyl chloride
A suspension of 2-i<?ri-butyl-5-nitrobenzenamine (0.971 g, 5 mmol) in cone. HCl (5 mL) was cooled to 5-10 °C and a solution of NaN02 (0.433g, 6.3 mmol) in H20 (0.83 mL) was added dropwise. Stirring was continued for 0.5 h, after which the mixture was vacuum filtered. The filtrate was added, simultaneously with a solution of Na2S03 (1.57 g, 12.4 mmol) in H20 (2.7 mL), to a stirred solution of CuS04 (0.190 g, 0.76 mmol) and Na2S<¾ (1.57 g, 12.4 mmol) in HQ (ί 1.7 mL) and H20 (2.7 mL) at 3-5 °C. Stirring was continued for 0.5 h and the resulting
- 202 -
S5 4833.1 precipitate was filtered off, washed with water and dried to give 2-teri-butyi-5-nitrobenzene-l- suifeny! chloride (0.235 g, 17 %). Ή NMR (400 MHz, DMSO-tfc) δ 9.13 (d, J = 2.5 Hz, 1H), 8.36 (dd, J = 8.9, 2,5 Hz, 1H), 7.88 (d, J = 8.9 Hz, 1H), 1.59 (s, 9H).
[0659] 2~teri~Muly S-mtmh iene- i -saif oaamlde
To a solution of -i rf-butyl-S-nitrobenzene-l-sulfo!iyl chloride (100 mg, 0.36 mmol) in ether (2 mL) was added aqueous NH4OH (128 jiL, 3,6 mmol) at 0 °C. The mixture was stirred at room temperature overnight, diluted with water and extracted with ether, The combined ether extracts were washed with brine and dried over a2S0 . After removal of solvent, the residue was purified by column cinematography (0-50 % EtOAc-Hexane) to give 2-im~butyl-5- nilrobenzene-1 -sulfonamide (31.6 mg, 34 %).
[0660] E-7; 2-tert-Bisiyl-S~amtj¾obersze8ie-l-sislfonamlde
A solution of 2-ieri-butyl-5~nitrobenzene- 1 -sulfanamide (32 mg, 0.12 mmol) and SnCl2-2H20 (138 mg, 0.61 mmol) in EtOH (1.5 mL) was heated in microwave oven at 100 °C for 30 min. The mixture was diluted with EtOAc and water, basified with sat. NaHCG3 and filtered through Celite. The organic layer was separated from water and dried over Na2SC>4. Solvent was removed by evaporation to provide
Figure imgf000204_0001
(E-7) (28 mg, 100 %), which was used without former purification. HPLC ret. time 1.99 min, 10-99 % CH3CN, 5 rain run; ESI-MS 229.3 m/z (MH+).
[0661] Example 6:
Figure imgf000204_0002
[0662] E-S; (2>teri-B¾tyl-S-asiiisii pfeenyl)methai?« I
To a solution of methyl 2-ffeT?-butyl-5-aminobenzoate (159 mg, 0.72 mmol) in THF (5 mL) was added dropwise LiAl¾ (1.4 mL, 1M in THF, 1.4 mmo!) at 0 CC. The reaction mixture was refluxed for 2 h, diluted with ¾0 and extracted with EtOAc. The combined organic layers were washed with brine and dried over MgS&s. After filtration, the filtrate was concentrated to give
- 203 -
8344833.1 (2-½ri-buiyl-5-amiiiophenyl)meihanoi (E-8) (25 mg, 20 %), which was used without further purification. !H NMR (400 MHz, CDC13) δ 7.17 (d, J - 8.5 Hz, 1H), 6.87 (d, J = 2.6 Hz, lH), 6.56 (dd, J = 8.4, 2,7 Hz, 1H), 4.83 (s, 2H), 1.36 (s, 9H).
[0663] Example 7;
Figure imgf000205_0001
[0664] 1-Methyl-pyridlnium moKomelh l sulfuric acid salt
Methyl sulfate (30 mL, 39.8 g, 0.315 mol) was added dropwise to dry pyridine (25.0 g, 0.316 moi) added dropwise. The mixture was stirred at room temperature for 10 min, then at 100 °C for 2 h. The mixture was cooled to room temperature to give crude 1-methyi-pyridinmra monomethyl sulfuric acid salt (64.7 g, quant), which was used without further purification.
[0665] t-Methyl-2-pyridone
A solution of 1 -methyl-pyridinium monomethyl sulfuric acid salt (50 g, 0.243 mol) in water (54 mL) was cooled to 0 °C. Separate solutions of potassium ferricyanide (160 g, 0.486 mol) in water (320 mL) and sodium hydroxide (40 g, L000 mol) in water (67 mL) were prepared and added dropwise from two separatory funnels to the well-stirred solution of 1 -methyl-pyridinium monomethyl sulfuric acid salt, at such a rate mat the temperature of reaction mixture did not rise above 10 °C. The rate of addition of these two solutions was regulated so that ail the sodium hydroxide solution had been introduced into the reaction mixture when one-half of the potassium Ferric Cyanide solution had beers added. After addition was complete, the reaction mixture was allowed to wann to room temperature and stirred overnight. Dry sodium carbonate (91.6 g) was added, and the mixture was stirred for 10 min. The organic layer was separated, and the aqueous layer was extracted with€¾<¾ (100 mL x 3). The combined organic layers
- 204 -
8544833.! were dried and concentrated to yield l-met yl-2-pyridone (25.0 g, 94 %), which was used without further purification.
[Θ666] 1 -Met foyt~3,5-dmit:r©~2-py tid&m
1- Methyl-2-pyridone (25.0 g, 0.229 mol) was added to sulfuric acid (500 mL) at 0 °C. After stirring for 5 rain., nitric acid (200 mL) was added dropwise at 0 °C. After addition, the reaction temperature was slowly raised to 100 °C, and then maintained for 5 h. The reaction mixture was poured into ice, basified with potassium carbonate to pH 8 and extracted with CH2CI2 (100 mL x 3), The combined organic layers were dried over Na2S0 and concentrated to yield 1 -methyl- 3,5-dinitro-2-pyridone (12.5 g, 28 %), which was used without further purification.
[0667] 2-Isopr®pyl~5~iMtre-pyridMe
To a solution of l-metliyl-3,5-dinitro-2-pyridone (8.0 g, 40 mmol) in methyl alcohol (20 mL) was added dropwise 3-methyl-2-butanone (5,1 mL, 48 mmol), followed by ammonia solution in methyl alcohol ( 10.0 g, 17%, 100 mmol). The reaction mixture was heated at 70 °C for 2.5 h under atmospheric pressure. The solvent was removed under vacuum and the residual oil was dissolved in CH2C¾, and then filtered. The filtrate was dried over Na2S0 and concentrated to afford 2-isopropyl-5-nitro-pyridine (1.88 g, 28 %).
[0668] E~9; 2-IsopropyI-S-amlsio-pyridlee
2- isopropyl-5-nitiO-pyridine (1.30 g, 7.82 mmol) was dissolved in methyl alcohol (20 mL), and Raney Ni (0.25 g) was added. The mixture was stirred under ¾ (1 aim) at room temperature for 2 h. The catalyst was filtered off, and the filtrate was concentrated under vaccum to give 2- isopropyl-5-amino-pyridine (E-9) (0.55 g, 52 %). ¾ MR (CDCI3) δ 8.05 (s, 1 H), 6.93-6.99 (m, 2 H), 3.47 (br s, 2 H), 2.92-3.02 (m, 1 H , 1.24-1.26 (m, 6 H). ESI-MS 137.2 m z (MH+).
- 205 -
S5<i4S33.i
Figure imgf000207_0001
f¾67©3 Phosphoric ¾dd 2,4- i-£0ri-tatyI-pheB l ester diethyl ester
To a suspension of NaH (60% in mineral oil, 6.99 g, 174.7 mmol) in THF (350 mL) was added dropwise a solution of 2,4-di-½rr-butylphenoI (35 g, 169.6 mmol) in THF (150 mL) at 0 °C. The mixture was stirred at 0 °C for 15 min and then phosphorochloridic acid diethyl ester (30.15 g, 174.7 mmol) was added dropwise at 0 °C. After addition, the mixture was stirred at this temperature for 15 min. The reaction was quenched with sat. NH4CI (300 mL). The organic layer was separated and the aqueous phase was extracted with Et2Q (350 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated under vacuum to give crude phosphoric acid 2,4-di-/<?rf-butyl~phenyl ester diethyl ester as a yellow oil (51 g, contaminated with some mineral oil), which was used directly in the next step.
- 206 -
85*1833.3 [0671] l,3~Di-ferf-b«iyI-be&B£5ie
To NI¾ (liquid, 250 mL) was added a solution of phosphoric acid 2,4-di~ieri~biityl~phenyl ester diethyl ester (51 g, crude from last step, about 0,2 raol) in Et G (anhydrous, 150 niL) at -78 °C under N atmosphere. Lithium metal was added to the solution in small pieces until a blue color persisted. The reaction mixture was stirred at -78 °C for 15 min and then quenched with sat. NH CI solution until the mixture turned colorless. Liquid N¾ was evaporated and the residue was dissol ved in water, extracted with Et20 (300 mL x 2). The combined organic phases were dried over Na2SQ4and concentrated to give crude 1,3-di-ferf-butyl-benzene as a yellow oil (30.4 g, 94 % over 2 steps, contaminated with some mineral oil), which was used directly in next step.
[0672] 2,4-Di-teri-boiyl-beo¾aldehyde arad 3,5-di-teri-i>etyl-beE¾¾!dehyde
To a stirred solution of 1,3-di-fert-but l-benzene (30 g, 157.6 mmoS) in dry CH2C12 (700 mL) was added TiC (37.5 g, 197 mmol) at 0 CC, and followed by dropwise addition of MeOCHCl? (27.3 g, 236,4 mmol). The reaction was allowed to warm to room temperature and stirred for 1 h. The mixture was poured into ice-water and extracted with CH2CI2. The combined organic phases were washed with NaHCG3 and brine, dried over Na2S04 and concentrated. The residue was purified by column chromatography (petroleum ether) to give a mixture of 2,4-di-tert-butyl- henzaldehyde and 3,5-di-ferf-butyl-benzaldehyde (21 g, 61 ).
[0673] 2,4~Di-feri-bistyl-5-siiiro-besKald€hyde and
Figure imgf000208_0001
bmxa! tehyde
To a mixture of 2,4-di~ferf~butyl~benzaldehyde and 3,5-di-ierf-butyl-benzaldehyde in H2S04 (250 mL) was added KNO3 (7.64 g, 75.6 mmol) in portions at 0 °C. The reaction mixture was stirred at this temperature for 20 min and then poured into crashed ice. The mixture was basified with NaOH solution to pH 8 and extracted with Et20 (10 mL x 3). The combined organic layers were washed with water and brine and concentrated. The residue was purified by column chromatography (petroleum ether) to give a mixture of 2,4-di-terf-bufyl-5-nitro- benzaldehyde and 3,5-di-½ri-butyi~2~nitro~benzaldehyde (2:1 by NMR) as a yellow solid (14.7 g, 82 %). After further purification by column chromatography (petroleum ether), 2,4-di-ier/- butyl-5-nitro-benzaldehyde (2.5 g, contains 10% 3,5-di-½rt-butyl-2-nitiO-benzaldehyde) was isolated. [0674] i,5-Di-ter^bisiyl~2--difiis romeihyl--4-}iiiro-bm¾effle and l,5-Di-te"£-tatyS~3~ dinuorom®ihyI~2~nitro-bemeiie
2,4~Di-fm~hutyl~5~nitro~benzaldehyde (2.4 g, 9.1 1 mmol, contaminated with 1.0% 3,5~d\~fert- butyl-2-niiro-benzaldehyde) in neat deoxofluor solution was stirred ai room temperature for 5 h, The reaction mixture was poured into cooled sat. aHCG3 solution and extracted with dichloromethane. The combined organics were dried over Na2SC>4, concentrated and purified by column chromatography (petroleum ether) to give l,5-di-ieri-butyl-2-dif!uoromethyl-4-nitro- benzene (1.5 g) and a mixture of l,5-di-terf~butyl-2-dif!uoromethyI-4-nitro-benzene and 1,5-di- ¾r/-but 'l-3-diflisoromethyl-2~nitro-benzene (0.75 g, contains 28 % l,5-di-.«rf-butyl-3- di fluoromethy !~2-mtro-benzene) .
[0675] E-10; l^-DI-te i-but !-2-dIfl¾oromelhyl-4-8 liio-ben¾;i¾e
To a suspension of iron powder (5.1 g, 91.1 mmol) in 50% acetic acid (25 mL) was added 1,5- di-f<?ri-butyl-2-difiuoromethyi~4-nitro-berizene (1.3 g, 4.56 mmol). The reaction mixture was heated at 1 15 °C for 15 min. Solid was filtered off was washed with acetic acid and CH>CI2. The combined filtrate was concentrated and treated with HCl MeOH. The precipitate was collected via filtration, washed with MeOH and dried to give 1 ,5-Di~&?rf-buty!~2~
d?fluGromeihy!-4-amino-benzene HQ salt (E-10) as a white solid (1.20 g, 90 %). }H NM (DMSO- ) δ 7.35-7.70 (t, / = 53.7 Hz, 1 H), 7.56 (s, 1 H), 7.41 (s, 1 H), 1.33-1.36 (d, J = 8.1 Hz, 1H); ESi-MS 256.3 m/z (MET).
[Q676J Example 9
[0677] General scheme:
Figure imgf000209_0001
A) Pd(PPh3)4, 2C03, H20, THF; B) Pd2(dba)3, P(iBu)3, KF, THF
[0678] Method A
in a 2-dram vial, 2-bromoaniline (100 mg, 0.58 mmoi) and the corresponding aryl boronic acid (0.82 mmol) were dissolved in THF (1 mL). H20 (500 aL) was added followed by K2C03 (200 mg, 1.0 mmoi) and Pd(PPh3)4 (100 mg, 0.1 mmol). The vial was purged with argon and sealed. The vial was then heated at 75 °C for 18 h. The crude sample was diluted in EtOAc and filtered
- 208 -
8544833.1 through a silica gel plug. The organics were concentrated via Savant Speed-vac, The crude amine was used without further purification.
[0679] Mei od B
In a 2-dram vial, the corresponding aryi boronic acid (0.58 mmol) was added followed by KF (1 10 mg, 1.9 mmol). The solids were suspended in THF (2 mL), and then 2-bromoaniline (70 μ]_, 0.58 mmol) was added. The vial was purged with argon for 1 min. P(?Bu)3 (100 \iL, 10% sol. in hexanes) was added followed by Pd2(dba)3 (900 jiL, 0.005 M in THF). The via! was purged again with argon and sealed. The vial was agitated on an orbital shaker at room temperature for 30 min and heated in a heating block at 80 °C for 16 h. The vial was then cooled to 20 °C and the suspension was passed through a pad of Celite. The pad was washed with EtOAc (5 mL). The organics were combined and concentrated under vacuum to give a crude amine that was used without further purification.
[6680] The table below includes the amines made following the general scheme above.
Figure imgf000210_0001
8544833.1 F-18 I 3'-Methoxy-biphenyl-2-yiamine B
F-19 2-Benzo[l,3]dioxol-5-yi-phenylamine B
¥~2Q 3'-Ethoxy-biphenyl-2-ykmiiie B
F-21 4'-Ethoxy-biphenyi-2-y1amine B
F~22 2'-Ethoxy-biphenyl-2-ylamme B
F-23 4'-Methylsulfanyl-biphenyl-2-yIamine B
F-24 3\4'-Dimethoxy-biphenyl~2~yiamine B
F-25 2',6'-Dimethoxy-biphenyl-2-yiamine B
F-26 2',5'-Dimei oxy-biphenyl-2-ylamine B
F-27 2',4'-Dimeihoxy-biphenyl-2-ylamine B
F-28 5'-Chloro-2'-methoxy-biphenyI-2-ylamine B
F-29 4'~Trifluoromethoxy-biphenyl-2-yiamine B
F-30 3'-Trifluoromeihoxy-biphenyl-2-ylanune B
F-31 4'-Phenoxy-biphenyl-2-ylamine B
F-32 2VFluoro-3'-met Gxy-biphenyl-2-ylamine B
F-33 2'-Phenoxy-biphenyl-2-ylamine B
F-34 2-(2,4-Dimeihoxy-pyrimidin-5-yi)-phenylamine B
F-35 5'-Isopropyl-2!-metlioxy-biphenyl-2~yIaniine B
F-36 2'-Trifluoromethoxy-biphenyl.-2-yiamine B
F-37 4'-Fluoro-biphenyl-2~ylamine B
F-38 3 '-Fluoro-bipheny ί-2-ylamine B
F-39 2'-Fiuoro-biphenyl-2-ylamine B
F- 0 2'-Ammo-b!pheny!~3-carboniirile B
F-41 4'-Fiuoro-3'-methyl-biphenyi~2-ylamine B
F-42 4"-Chioro-biphenyl-2-yiamine B
F-43 3'-Chloro-biphenyI-2-ylamine B
F-44 3',5,-Difluoro-biphenyl-2-ylamine B
F-45 2,,3'-Difl oro-biphenyl-2-yIamine B
F-46 3',4'-Difluoro-bjphenyl-2-ylamine B
F-47 2\4'-Dif.uoro-biphenyl-2-yiamine B
F-4S 2' .5 '-Difluoro-bipheny! -2-yIamme B
¥-49 3'-Chloro-4'-fluoro-biphenyl-2-ylainine B
F-50 3',5'-D chioro-biphenyl-2-ylamine
210 ·
33. i F-Sl 2',5'-Dichloro-biphenyl-2-ylamine B
F-52 2',3,-Djchloro-bfphenyl~2-ylaniine B
F-53 3 ',4'-Dichloro~biphenyl-2-yI amine B
F-54 2'-Amino-biphenyl-4-carboxylic acid methyl ester B
F-55 2!-Amino-biphenyI-3-carboxy!ic acid methyl ester B
F-56 2'-Methylsiilfariyl-biphenyi-2-yIarnine B
F-57 N-(2'-Amino-biphenyl-3-yI)-acetamide B
F-58 4i-Memane$uiimyl-biphenyl-2~ylamine B
F-59 2\4VDichloro-biphenyl-2-ylamine B
F-60 4'-Methariesulfonyl-biphenyl-2-ylamine B
F-61 2'-Amino-biphenyl-2-carboxylic acid isopropyl ester B
F-62 2-Furan-2-yl-phenylamine B
F~63 l-[5-(2-Amino~pheny!)-thiophen-2-yl3-ethaj5.one B
F-64 2-Benzo[b]ihiophen-2-yl-phenylamine B
F-65 2-Benzo[b]thiophen-3-y1-phenylamine B
2-Furan-3-yl-phenylamine B
F-67 2-(4-Meihyl-thiophen-2~yl)-phenyiamine B
F-68 5-(2-Ammo-pheny1)-thiophene-2-carbomtrile B
[0681.1 Example 10:
Figure imgf000212_0001
G-1
[0682] Ethyl 2-(4-mirophe jI)-2-Methylpropa oaie
Sodium t-butoxide (466 mg, 4.85 mmol) was added to DMF (20 mL) at 0 °C. The cloudy- solution was re-cooled to 5 °C. Ethyl 4-nitrophenyIacetate (1.0 g, 4.78 mmol) was added. The purple slurry was cooled to 5 °C and methyl iodide (0.688 niL, 4,85 mmol) was added over 40 min. The mixture was stirred at 5-10 °C for 20 min, and then re-charged with sodium t-butoxide (466 mg, 4.85 mmol) and methyl iodide (0.699 mL, 4.85 mmol). The mixture was stirred at 5-10 °C for 20 min and a third charge of sodium t-butoxide (47 mg, 0.48 mmol) was added followed
- 211. -
S544S33.1 by methyl iodide (0.057 mL, 0,9 mmol). Ethyl acetate (100 rnL) and HQ (0.1 N, 50 mL) were added. The organic layer was separated, washed with brine and dried over
Figure imgf000213_0001
After filtration, the filtrate was concentrated to provide ethyl 2-(4-nitrophenyI)-2-methylpropanoate (900 nig, 80 %), which was used without further purification.
[0683] G«l; Ethyl 2-(4~amiisopheiiyi)-2-isief ylpr0paB©ate
A solution of ethyl 2-(4-mtrophenyI)-2-methylpropanoate (900 mg, 3.8 mmol) in EtOH (10 mL) was treated with 10% Pd-C (80 mg) and heated to 45 °C. A solution of potassium formate (4.10 g, 48.8 mmol) in ¾Q (1 1 mL) was added over a period of IS min. The reaction mixture was stirred at 65 °C for 2 h and then treated wit additional 300 mg of Pd/C. The reaction was stirred for 1.5 h and then filtered through Celite. The solvent volume was reduced by approximately 50 % under reduced pressure and extracted with EtOAc. The organic layers were dried over M aSC^. and die solvent was removed under reduced pressure to yield ethyl 2-(4- aminophenyl)-2-methylpropanoate (G-l) (670 mg, 85 %). Ή NMR (400 MHz, CDC! 3) δ 7.14 (d, J = 8.5 Hz, 2H), 6.65 (d, J - 8.6 Hz, 2H), 4.10 (q, J = 7.1 Hz, 2H), 1.53 (s, 6H), 1.18 (t, J = 7.1 Hz, 3H).
[0684] Example 11:
Figure imgf000213_0002
[0685] G-2; 2-(4«AsBiMophe»yl)~2-meihylpropasi-l-©l
A solution of ethyl 2-(4-aminophenyl)-2-methylpropanoate (30 nig, 0.145 mmol) in THF (1 mL) was treated with LiAi¾ (IM solution in THF', 0.226 mL, 0.226 mmol) at 0 °C and stirred for 15 min. The reaction was treated with 0.1N NaOH, extracted with EtOAc and the organic layers were dried over a?S04. The solvent was removed under reduced pressure to yield 2-(4- aminophenyl)-2-methylpropan~l-ol (G-2), which was used withoutfurther purification: *H NMR (400 MHz, CDC¾) δ 7.17 (d, J = 8.5 Hz, 2H), 6.67 (d, J = 8.5 Hz, 2H), 3.53 (s, 2H), 1.28 (s, 6H).
- 212 -
8544833.; 0686] Exam le 12;
Figure imgf000214_0001
[0687] 2~meihyI-2-(4»mtTOpheisyl)propsrie trile
A suspension of sodium j¾?t~butoxide (662 mg, 6.47 mmol) in DMF (20 mL) at 0 °C was treated with 4- irophenylacetoniiriIe (1000 mg, 6.18 mmol) and stirred for 10 min. Methyl iodide (400 μΐ,, 6.47 mmol) was added dropwise over 15 min. Be solution was stirred at Q~1G °C for 15 mm and then at room temperature for additional 15 min. To this purple solution was added sodium i«??t~butoxide (662 mg, 6.47 mmol) and the solution was stirred for 15 min. Methyl iodide (400 μΧ-, 6.47 mmol) was added dropwise over 15 min and the solution was stirred overnight. Sodium feri-butoxide (192 mg, 1.94 mmol) was added and the reaction was stirred at 0 °C for 10 minutes. Methyl iodide (186 μ£, 2.98 mmol) was added and the reaction was stirred for Ih. The reaction mixture was then partitioned between IN HC1 (50 mL) and EtOAc (75 mL). The organic layer was washed with 1 N HQ and brine, dried over Na2.S04 and concentrated to yield 2-methyi-2-(4-mtrophenyi)propa5ienitrile as a green waxy solid (1.25 g, 99 %). SH NM (400 MHz, CD€¾) δ 8,24 (d, J = 8.9 Hz, 2H), 7.66 (d, J = 8.9 Hz, 2H), 1.77 (s, 6H).
[0688] 2-Methy!-2-(4-mtroplie¾yl)pTOpaffi~ I -amies
To a cooled solution of 2-methyl-2-(4-nitrophenyl)propanenitrile (670 mg, 3.5 mmol) in THF (1.5 mL) was added BH3 ( l M in THF, 14 mL, 14 mmol) dropwise at 0 °C. The mixture was warmed to room temperature and heated at. 70 °C for 2 h. IN HC1 solution (2 mL) was added, followed by the addition of NaOH until H > 7, The mixture was extracted with ether and ether extract was concentrated to give 2-methyl-2-(4-nitrophenyl)propan-I -aniine (610 mg, 90 %), which was used without further purification. {H NMR (400 MHz, CDCS3) δ 8.20 (d, J = 9.0 Hz, 2B), 7.54 (d, J = 9.0 Hz, 2H), 2.89 (s, 2H), 1.38 (s, 6H).
- 213 -
8544833.1 [0689] teri-B tyi 2-iiS€ihyl-2-{4-niir©phe8iyl)propylcarbai aie
To a cooled solution of 2-methyl-2-(4~nitropheny!)propan-l -amine (600 mg, 3.1 mmol) and IN NaOH (3 mL, 3 mmol) in 1,4-dioxane (6 mL) and waier (3 mL) was added Boc20 (742 mg, 3.4 mmol) at 0 °C. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was made acidic with 5% KHS04 solution and then extracted with ethyl acetate. The organic layer was dried over MgS04 and concentrated to give tert-butyl 2-methyi-2-(4- nitrophenyl)propylcarbamate (725 mg, 80 %), which was used without further purification, lH NMR (400 MHz, CDC13) δ 8.1 1 (d, ί = 8.9 Hz, 2H), 7.46 (d, J = 8.8 Hz, 2H), 3.63 (s, 2H), 1.31- 1.29 (m, 15H).
[0699] G-3; ter^-B¾t l 2-methyI-2-(4-amtnopfee¾5yl)propyIcar >aMate
To a reflu ing solution of tert-butyl 2-methyl-2-(4-nitrophenyi)propyIcarbamate (725 mg, 2.5 mmol) and ammonium formate (700 mg, 10.9 mmol) in EtOH (25 mL) was added Pd-5%wt on carbon (400 mg). The mixture was refluxed for 1 h, cooled and filtered through Celite. The filtrate was concentrated to give tert-butyl 2-meihyl-2-(4-aminophenyl)propylcarbamate (G-3) (550 mg, 83 %), which was used without further purification. Ή NMR (400 MHz, DMSO-de) 5 6,99 (d, J = 8.5 HE, 2H), 6.49 (d, J = 8.6 Hz, 2H), 4,85 (s, 2H), 3.01 (d, J = 6.3 Hz, 2H), 1.36 (s, 9H), 1.12 (s, 6H); HPLC ret. time 2.02 min, 10-99 % CH3CN, 5 min run; ESI-MS 265.2 m/z (MH*).
[0691] Example 13;
Figure imgf000215_0001
H-
[0692] 7-Nitro>l^, -tetrahydro-naphthalen-l-oi
7-Nitro-3,4-dihydro-2H-naphthalen-l-on.e (200 mg, 1.05 mmol) was dissolved in methanol (5 mL) and NaB¾ ((78 mg, 2,05 mmol) was added in portions. The reaction was stirred at room temperature for 20 min and then concentrated and purified by column chromatography (10-50 % ethyl acetate - hexanes) to yield 7-nitro-l,2,3,4-tetrahydro-naphthalen-l-ol (163 mg, 80 ). !H NMR (400 MHz, CD3CN) δ 8.30 (d, J = 2.3 Hz, 1H), 8.02 (dd, J = 8.5, 2.5 Hz, 1H), 7.33 (d.
- 214 -
8544833.1 J = 8,5 Hz, 1H), 4.76 (t, J = 5.5 Hz, lH), 2.96-2.80 (m, 2H), 2.10-1.99 (m, 2H), 1 ,86-1.77 (m, 2H); HPLC ret. time 2,32 min, 10-99 % CH3C , 5 min run.
[0693] H-l; T-Amisio-l^^^-ieirafe dro-^a hateH-l-ol
7-mtro-l,2,3,4-teirahydro-naphthalen-l-ol (142 mg, 0.73 mmol) was dissolved in methanol (10 mL) and the flask was flushed with N2 (g). 10% Pd-C (10 mg) was added and the reaction was stirred under ¾ (1 aim) at room temperature overnight. The reaction was filtered and the filtrate concentrated to yield 7-amino-l ,2,3,4-tetrahydro-naphthalen-l-ol (H-l) (113 mg, 95 %), HPLC ret. time 0.58 min, 10-99 % CH3CN, 5 min run; ESI-MS 164.5 m/z (MH+).
Figure imgf000216_0001
[0695 J 7-Nitro-3,4»dihydro~2H-5iaphihaiea-l->osie oxime
To a solution of 7-nitro-3,4-dihydro-2H-naphthalen-i-one (500 mg, 2.62 mmo!) in pyridine (2 mL) was added hydroxylamine solution (1 mL, -50% solution in water). The reaction was stirred at room temperature for 1 h, then concentrated and purified b column chromatography ( 10-50 % ethyl acetate - hexanes) to yield 7-nitro-3,4-dihydro-2H-naphthalen-l-one oxime (471 mg, 88 %). HPLC ret, time 2,67 min, 10-99 % CH3CN, 5 min run; ESI-MS 207,1 m/z (MFT).
[©696] l,2,3,4-Tetrahydro-¾aphl iak!ie- 1,7-diamijie
7-Nitro-3!4-dihydro-2H-naphthalen-l-one oxime (274 mg, 1.33 mmol) was dissolved in methanol (10 mL) and the flask was flushed with N2 (g). 10 % Pd-C (50 mg) was added and the reaction was stirred under ¾ (1 aim) at room temperature overnight. The reaction was filtered and the filtrate was concentrated to yield l,2,3,4-tetrahydro-naphthalene- l,7 -diamine (207 mg, ). Ή MR (400 MHz, DMSC 6) δ 6.61 -6.57 (m, 2H), 6.28 (did, J = 8.0, 2.4 Hz, 1H), 4.62 3.58 (m, 1H), 2.48-2.44 (m, 2H), 1.78- 1.70 (m, 2H), 1.53-1.37 (m, 2H).
[0697] H-2; (7-Amlrao-l,2 ,4-ieirahydro-siaphthales-i-yI)-€arbamk add feri-
To a solution of l ,2,3,4-tetrahydro-naphthalene-l ,7-diamine (154 mg, 0.95 mmoi) and triethy!amme (1.39 μΐ.., LO mmoi) in methanol (2 mL) cooled to 0 °C was added di-ferr-butyi dicarbonate (207 mg, 0,95 mmoi). The reaction was stirred at 0 °C and then concentrated and purified by column chromatography (5-50 % methanol - dichloromethane) to yield (7-amino- l,2,3,4-teirahydro-naphihalen~l.-yl)-carbamic acid tert-butyl ester (H-2) (327 mg, quant).
HPLC ret. time 1.95 min, 10-99 % C¾CN, 5 mm ran; ESI-MS 263.1 m/z (MH*).
Figure imgf000217_0001
[0699] N-(2-Br0mo»beM¾y!)-2f2^-trifluoro-a€eiaii de
To a solution of 2-bromobenzylamme (1.3 mL, 10.8 mmoi) in methanol (5 mL) was added ethyl trifluoroacetate ( 1.54 mL, 2 .6 mmoi) and triethylarnine (1.4 mL, 10.8 mmoi) under a nitrogen atmosphere. The reaction was stirred at room temperature for 1 h. The reaction mixture was then concentrated under vacuum to yield N-(2-bromo-benzy!)-2,2,2-trifiuoro~acetamide (3.15g, quant.). HPLC ret time 2,86 min, 10-99 % CH3CN, 5 min run; ESI-MS 283.9 m/z (MH+).
J] 1-1; N-(4'-AmiBO»Mphes-y!-2-yl0seihyl)-2,2j2-trifluoro-8cetanside
A mixture of N-(2-bromo-benzyl)-2,2,2-trifluoro-acetamide (282 mg, 1.0 mmoi), 4-(4,4,5,5- tetramethyl-l,3,2-dioxaboiOlan-2-yl)aniline (284 mg, 1.3 mmoi), Pd(OAe)2 (20 mg, 0.09 mmoi) and PS-PPh3 (40 mg, 3 mmoi / g, 0.12 mmoi) was dissolved in DMF (5 mL) and 4M K2C(¼ solution (0,5 mL) was added. The reaction was heated at 80 °C overnight. The mixture was filtered, concentrated and purified by column chromatography (0-50 % ethyl acetate - hexanes) to yield N-(4'-amino-biphenyl-2-ylmemyl)-2,2,2-trifluoro-acetamide (1-1) (143 mg, 49 %). HPLC ret. time 1.90 min, 10-99 % CH3CN, 5 min run; ESI-MS 295.5 m/z (MH+).
- 216 -
8544833.1 [0701] Commercially available amines
Amino ame
J-l 2-methoxy-5-meihylbenzenamme
J-2 2,6~diisopropylbenzenaniine
J-3 pyridin-2-amine
J~4 4-pentylbenzenamine
J-5 isoquinol -3-amine
aniline
J-7 4-phenoxybenzenamine
J-8 2-(2,3-dixnediyiphenoxy)pyridin-3-amine
J-9 4-ethynylbenzenamine
J-10 2-sec-butylbenzenamine
J-ll 2-ammo-4,5-dimethoxybenzoniirile
2-ii.;rf-buiylbenzenainine
J-13 I -(7-amino-3,4~dihydroisoquino!in-2( lH)-yi)ethanone
J-14 4-(4-methyl-4H~ 1 ,2,4-iriaEol-3-yl)benzenamine
J-15 2'-Aminomeihyl-bipheEyi-4-yiamine
J-16 1 H-indazol-6-ylamine
J-17 2-(2-meihoxyphenoxy)-5-(trifluoromethyl)benzenamine
J-18 2-feri-butyibenzenamine
J-19 2,4,6-irinieihylbenze!iainine
J-20 5,6~dimethyl~ lH~benzo[d]imidazoI-2»anMne
J-21 2,3-dihydro- lH-inden~4~ amine
2-sec-butyl-6-ethylbenzenamine
J-23 quinolin-5-amine
J-24 4-(benzyioxy)benzenamine
J-25 2'-Methoxy~biphenyl-2-ylamine
J~26 enzoic] [ 1 ,2,5] thiadiazol-4-aniine
J-27 3 -benzy Ibenzenamine
J-28 4-isopropylbenzenamine
Figure imgf000219_0001
-218-
854 S33.1 J-62 2 S»dimet yIbenzenamine
J-63 5-fluoropyridin~2-amine
J-64 4-cyclohexylbenzenamine
J-65 4~Amino-benzenesi!lfonaniide
J-66 2-ei ylbenzenamine
4-fluoro-3-methylbeiiz namine
J -68 2,6-dimethoxypyridin-3-amine
J-69 4-½rf-buiylbenzenaniine
J-70 4~sec-buiylbenzenamine
J-71 5,6,7,8-ietrahydronaphthaien-2-amine
J-72 3-(Pyrrolidine- i -sulfonyl)-phenylamine
J-73 4- Adamantan- 1 -y!-phenylamine
J-74 3-amino~5,6,7,8-telrahydronaphthalen-2-ol
J-75 benzo[d][ 13]dioxoI-5-amine
J-76 5-chloro~2-phenoxybenzenamine
J-77 N 1 -tosyibenzene- 1 ,2~diamine
J-78 3,4-dime hylbenzenamine
J-79 2-(trifiuoromethyIthio)benzenamine lH-indol-7-amine
J-81 3-methoxybenzenamine
J-82 quinolin-S-amine
J-83 2-(2,4-difluorophenoxy)pyridin-3-amine
J-84 2-{4-aminophenyl)aceioniirile
J«85 2,6-dichlorobenzenamine
J -86 2,3 -dihydrobenzofuran-5 -amine
J~87 p-toluidine
J-88 2-methylquinoiin-8-annrie
J-89 2-fert-butylbenzenamine
J-90 3-chlorobenzenamine
J-91 4-ieri-buiyl-2-chiorobenzen amine
J-92 2-Amino-benzenesuifonamide
J-93 i ~(2-aminopheny i)ethanone
J-94 m-toluidine
219 - J-95 2-(3-chloro-5-(lTifluoromeihyl)pyridii--2-yloxy)ben2enamine
J-96 2-amino-6~me fiylbe!izoniirile
J-97 2~(prop~ 1 -en-2-yl)benzenamine
J-98 4-Amino-N-pyridin-2-yl-benzenesulfonamide
J-99 2-eihoxybenzenamine
J-100 naphthalen- 1 -amine
J-101 Biphenyl-2-yIamine
J-102 2-(trifluoromethyi)-4-isopropylbenzenaniine
J-103 2,0-diethyibenzenarmne
J-104 5-(trifluorome£hyl)pyridin-2-amine
J-105 2-aminobenzamide
J-106 3-(frifluoromeihoxy)benzena ine
J-107 3,5-bis(irifluoromethyl)benzenamine
J-108 4-vinylbenzenamine
J-109 4-(trifluoroffie hyl)benzenamine
J-110 2-moipholinobenzenainine
J-lll 5-amino-lH-benzo[d]imidazol-2(3H)-one
J-112 quinolin-2-amine
J-113 3-meihyl-lH-mdol-4-amine
J-114 pyrazin-2-amine
J-115 1 -(3-aminophenyl)eihanone
J-lld 2-ethyl-6-isopropylbenze-iamine
J-117 2-(3-(4-chlorophenyl)-l,2,4-oxadiazol-5-yl)benzenamiiie
J-118 N-(4-araino-2,5-diethoxyphenyl)benzamide
J-119 5,6,7,8-tetrahydro!iaphihalen- 1 -amine
J-120 2-( 1 H-be!i2o[d]imidazoI-2-yl)benzenamffie
J-121 1 , 1-Dioxo-IH- llambda*6*-benzo[bjthiophen-6-ylamine
2,5-diethoxybenzenamine
J-123 2-isopropyl-6-met ylbenzenamine
J-124 tert-buiyl 5-amino-3,4-dihydroisoq inoline-2(lH)~carboxylate
2-(2-aminophenyl)ethanol
J-126 (4-aminophenyl)methanol
J-127 5-niethylpyridin-2-amine J"12§ 2-(pyrroHdin- 1 -yl)benzenamine
J-129 4-propylbenzenamine
J-130 3 ,4-diehlorobenzenamine
2-phenoxybenzenamine
B iphenyl-2~y lamine
J-133 2-chlorobenzenamine
J-134 2-amino-4-raethylbenzonitrile
(2~aminophenyl)(phenyi)methanone
J-136 aniline
J-137 3-(trifluoK>methylthio)benzenamine
J-138 2-(2,5-dimethyl-lH-pyrroi-i-yl)bei3zenamine
J-139 4-(MoφhoIine- -sulfonyl)- heny!aInine
J-140 2-methylbenzo[d]thiazoi-5~amme
J-141 2-amino-3,5-dicMorobe«zoraiTile
J* 142 2-fluoto-4-methyibenzenamine
J-143 6-ethylpyridin-2-amkse
J- 144 2-( IH-pyrrol- 1 -yl)benzenamine |
J-145 2-methyl-iH-indoi-5-amine
i quinolin-0-amine
J-147 lH-beozo[dlimida ol~2-amine
J-148 2-o-toIylbenzo[d]oxazol-5-amine
J-149 5~phenylpyridin-2-amine
J-150 Bjphenyl-2~ylamine
J-151 4-(difluoromethoxy)benzenamine
5-ierf-butyi-2-methoxybenzenamine
2-(2-ieri-buiylphenoxy)benzenaniine
J-154 3~aminobenzamide
4-morphol i nobenzenamine
J-1S6 6-aminobenzQ[d]oxazol-2(3H}-orie
J-157 2-phenyl~3H-benzo[d3imidazol-5-amine
J-158 2,5-dichloropyridin-3-amine
J-159 2,5-dimethyl benzenamine
J-160 4-(pheny1thio)benzenamine J-161 9H-fiuoren- 1 -amine
J-162 2-(4~ammophenyl)- 1,1,1 ,3,3 -hexafluoropropan-2-ol
J-163 4-bromo~2-ethyibenzenamine
J-164 4-me&oxybenzenaroine
J-165 3 -(Pi peridine- 1 -sulf ony l)~pheny lamine
J-166 quinoxaiin-6-amine
J-167 6-(trifluoromethyl)pyridin-3-ai ne
J-16S 3-(bifluoromeihyl)-2-methyIbenzenamine
J-169 (2-aminophenyl)(phenyl)methanoI
J-170 aniline
J-171 6-methoxypyridm-3-amine
J-172 4-butylbenzenamine
J-173 3-(Morpholine-4-s lfonyl)-phenylamine
J-174 2,3-dimethylbenzenamine
J-175 aniline
J-176 Biphenyl~2~ylamine
J-177 2-(2,4-dichiorophenoxy)benzenamme
J-178 pyridin-4-amine
J-179 2-(4-memoxyphenoxy)-5-(trifluoro-neihyi)benzenamine
J-ISO 6-methy I pyridin-2-am i ne
J~181 5-chloro-2-fluorobenzenamme
J" 182 1 H~indo!~4-amine
J-183 6-morpholinopyridin-3-amme
J-184 aniline
J-185 1 H-indazol-5 -amine
J-186 2-[(Cyclohexyl-methyl-amino)-methylJ-phenyIamine
J-187 2-phenylbenzo[d]oxazol-5-amine
J-188 naphthalen-2-amine
J-189 2-aminobenzoniixiIe
J-190 N 1 ,N I -dieihyI-3-meihylbenzene~ 1 ,4-diamine
J-191 aniline
1-192 2-butylbenzenamine
J-193 1 -(4-ami nophenyl)ei anol J-194 2-amino-4-meihylbenzamide
J-195 quinoiin-3 -amine
J-196 2-(piperidin- 1 -yl)benzenamine
J-197 3-Amino-benzenesu!fonamide
J-19S 2-ethyl-6-methyIbeiizenanikie
J-199 B iphenyl-4-y lamine
3-2M 2-(o-tolyloxy)benzenamine
J-201 5 -amino-3 -methylbenzo[d3 oxazol-2(3H)-one
3-202 4-ethyibenzenaniine
J-203 2-isopropylbenzenamine
J-204 3-(frifluon methyl)benzenamiiie
J-205 2-amino-0-fluorobenzonitri3.e
J~2§6 2-(2-aminophenyl)acetonitrile
J-207 2-(4-fiuorophenoxy)pyridin~3-amine
J-208 aniline
J-209 2-(4~methyi piperidin- i -yl)benzenamme
J-210 4-fl uoFobenzenamine
2-propyibenzenamine
J-212 4-(trifluorome hoxy)benzenamine
3-ammophenol
J-214 2,2-difluorobenzo[d][I,3]dioxoi-5~amine
J-215 2,2,3.3-teirafluoro-2,3-dihydroben¾o[b] [ 1 ,4]dioxin-6~amine j-216 N-(3-aminophenyl)acetamide
J-217 ί -(3-aminophenyl)~3~meihyl- lH-pyrazo!~5(4H)-one
J-218 5-(irif!uoromethyl)benzene- 1 ,3~diamine
J-219 5 -rer?-butyl-2-me hoxybenzene- 1 ,3-diamine
J-220 N~(3-aitiino-4-ethoxyphenyl)aceiamide
N-(3-Ammo~phenyl)-meihanesuIfonaniide
J°222 N-(3 -am inopheny l)proptonamide
N 1 ,N 1 -dimethylbenzene- i ,3 -diami n
N~(3-amino-4-methoxyphenyl)aceiamide
J-225 benzene- 1 ,3-diamine
J-226 4-methylbenzene- 1 ,3-diamine J-227 lH-indol-6-amine
J-228 6,7,8,9-ieixah dro-5H-carbazol-2~amine
J-229 1 H-indol-6-amine
1 H-indol-6~amirie
J-231 lH-mdol-6-afnine
lH-indol-6-amine
J «233 1 H-indol-6~amine
j-234 1 H-indol-6-amine
J-235 lH-indol-6-aniine
J-236 iH-indoI-6~amine
J-237 1 H-indol-6-amine
J "238 lH-indol-6~amine
J-239 1 -(6-Amino-2,3-dihydro-indo!- l-yi)-ethanone
J-24D 5-Chloro-benzene- 1 ,3~diamine
[0702] Amides (Com ounds of fo mula I) [0703] General scheme:
Figure imgf000225_0001
[07Θ5] 215; 4-Oxo-N-phe¾yI-lH-qt in ise~3~carbo3¾ansIde
To a soluiion of 4-hydroxy-q inoline-3-carboxylic acid (A-1) ( 1.9 mg, 0.1 mmol), HATU (38 rog, O. lmraol) and DIEA (34,9 fiL, 0.2mmol) in DMF (1 mL) was added aniline ( 18.2 uL, 0.2 mmol) and the reaction mixture was stirred at room temperature for 3 h. The resulting solution was filtered and purified by BPLC (10-99 % CH3CN / H20) to yield 4-oxo-N-phenyl- lH- quinoline-3-caiboxamide (215) (12 mg, 45 %). lR NMR (400 MHz, DMSO*¼) δ 12.97 (s, 1H), 12.50 (s, 1H), 8.89 ($, 1H), 8.34 (dd, J = 8.1 , 1.1 Hz, 1H), 7.83 (t, J = 8,3 Hz, 1H), 7.75 (m, 3H), 7.55 (t, J = 8.1 Hz, 1 H), 7.37 (t, J = 7.9 Hz, 2H), 7.10 (t, J = 6.8 Hz, 1H); HPLC ret. time 3.02 min, 10-99 % CFfcCN, 5 min run; ESI-MS 265.1 m/z (MH+).
[0706] The table below lists other examples synthesized by the general scheme above.
Figure imgf000226_0001
- 225 -
85 4S33.i
Figure imgf000227_0001
Figure imgf000228_0001
121 A~1 J-1 8
122 A-1 -49
123 A-1 F-S0
124 A-2 B-24
12S A-1 J-143
1 § A-1 C-2S 2S A-22 J-176
130 A-14 J-233
131 A-1 J-24Q
132 A-1 d-220
134 A~1 F-SS
135 A-1 F-19
13® A-1 C-S
137 A-@ C-§
135 A-1 F-44
1 9 A-1 F-59
140 A-1 J-S4
1 2 A-1 J-10
143 A-1 C-7
144 A-1 J-213
145 A-1 B-18
148 A-1
147 A-1 J-2S7
150 A-1 J- 82
1S1 A-1 F-87
1S2 A-1 J-1SS
153 A-1 C-23
1S4 A-1 J-107
1SS A-1 J-3
15S A-1 F-36
1β0 A-1 D-i
1i1 A-1 C-3
1S2 A-1 J-17 i4 A~1 J-2G4
1§5 A-1 J-8S
1@S A-1 F-S4
1ST A-1 J-22S
1iS A~1 J-48
1S9 A-1 B- 170 A-1 J-42
171 A-1 F-S2
172 A-1 F-84
173 A-1 J-1 0
1 4 A-1 F-§3
178 -1 OC-2
1 S A-1 J-212
177 A-1 J-S7
1 S -1 J-1S3
179 A-1 J-154
18Q A-1 J-1 8
181 A-1 F~1
182 A-1 F-37
183 A-1 DC-1
184 A-15 J-231
18S A-1 J-1 3
186 A-1 8-1 S
187 A-1 B-3
188 A-1 B-28 9 A-1 J-24
190 A-1 F-4S
191 A~1 J-23 92 A-1 J-38
193 A-1 J-68
1 4 A-1 J-37
198 A-1 J- 27
197 A-1 J-187 98 A-1 J-210
199 A-1 F-3
20® A-1 H-1
201 A-1
202 A-1 F-28
203 A-1 e-2
204 A~1 OS
20S A-1 J-179
200 A-1 J-8
207 A-1 8-17
208 A-1 C-12
209 A-1 J-126
229-
85 S33J 210 A-17 J-101
211 A-1 J-1S2
212 A-1 J-21
213 A«1 F-S1
214 A-1 J-221
21 § A-1 J-138
21§ A-1 J-147
217 A-1 J-18S
218 A-2 C-1
21 i A-1 J-114
220 A-1 C-2S
222 A-1 J-35
223 A-1 F-23
224 A-1 1-1
22§ A-1 J~12§
22? A-1 J-120
228 A-1 J-1§9
22i A-1 J-5§
230 A-1 J-14S
231 A-1 C-17
233 A-1 J-23§
234 A-1 B-22
238 A-1 E-i
23i A-1 J-10§
240 A-1 J-34
241 A-1 J-S2
242 A-1 0-2
244 A-1 J-22S
24§ A-1 J-177
2 i A-1 J-78
247 A-1 F-33
280 A-1 J-224
2S2 A-1 J-13S
2S3 A-1 F-30
2S4 A-2 B-20
2SS A~8 C-§
2SS A-1 J-4§
257 A-1 J-6?
2§§ A-1 8-14 261 A-1 F-13
2§2 A-1 DC-7
263 A-1 J-163
284 A~1 J-1 2
2m A- J- 0
2m A-1 C-1
267 A-1 J-7
258 A-1 E-7
270 A-1 e-s
271 A-1 D-9
273 A-1 H-2
274 A-8 B-2
2 6 A-1 J-139
277 A-1 F-38
270 A-1 F-10
270 A-1 F-Se
280 A-1 J- 6
281 A-1 J~«2
283 A-1 F-18
284 A-1 J-1S
28S A-1 F-4S
28® A-1 J-11S
287 A-3 C-13
288 A-1 C-s
289 A-1 J-1 2
2§0 A-1 F-1§
291 A-1 C-1Q
292 A-1 J-78
2S3 A~1 J-144
294 A-1
29S A-1 J-1 8
28® A-1 J-12
297 A-1 J-138
301 A-1 J- 4
302 A-1 F-S
303 A~1 J- 3
3M A-1 E-1
305 A-1 F-17
3S8 A-1 F-20 307 A~1 F-43
308 A-1 J-20S
309 A-1 J-6
310 A-1 J~70
311 A-1 J-iS
312 A-1 F-27
313 A-1 F~3§
314 A-1 J-1 8
31 § A-1 J-SS
317 A-1
319 A-2 C-7
320 A-1 S~8
321 A-1 J- 4
322 A-1 4-22
324 A-1 J- 2
32§ A-1 J-103
326 A-1 F-@0
328 A-1 J- 1S
32S A-1 J-143
330 A-1 J-133
331 A-1 J-105
332 A-1 J-i
333 A-1 F~8
334 A-1 DC-S
33S A~1 J-1 4
338 A-1 J-102
337 A-1 C-24
33S A~1 J-113
339 A-1 B-S
344 A-1 F-22
345 &~2 J-234
348 A-12 J-§
348 A-1 F-21
340 A-1 J-29
350 A-1 J-180
3S1 A-1 B-23
352 A-1 B-10
3S3 A-1 D-10
3S4 A-1 J-188 3S§ A-1 J-2S
357 A-1 B-13
35® A-24 J-232
368 A-1 J-1S1
381 A-1 F-28
3S2 A-1 J-S1
3S3 A-1 F-32
3S4 A-1 J-88
A-1 J-§3
3 8 A-1 F-18
3i? A-1 F-S8
3S8 A-1 O-S
3β9 A-1 J-1 1
370 A-1 J-80
371 A-1 J-79
372 A-1 J-2®§
373 A-1 J-21
374 A~1§ J-238
37S A-1 J-7
376 A-1 J-187
377 A~§ J-237
378 A-1 D-3
380 A-1 J-iS
381 A-1 B-24
383 A-1 -12
384 A-1 F-4S
388 A~1 J-83
3S7 A-1 J-188
3SS A-1 F-2i
38S A~1 J-27
3§1 A-1 F~S
3§2 A-1 J-S2
394 A-22 J- 0
3§S A-1 C-20
387 A-1 J~1S§
398 A-1 J-77
480 A-1 J-183
401 A-1 F~4
402 A-1 J- 4®
Figure imgf000235_0001
44§ A-1 J-121
44? A-1 J-S1
448 A-1
44® A-1 J~i4
4S0 A-1 J-1S3
4S1 A-1 d-31 S2 A-1 d-188
453 A-1 D-1
4S4 A-1 d-47
4SS A~1 J-73
4S8 A-1 J-1 7
4S7 A-1 J-1SS
4S8 A-1 C-4
4S§ A-1 J-SS
461 A-1 J-1S0
483 A-1 J-202
404 A-3 C-9
46S A-1 E-4
4®a A-1 d-2
487 A-1 J-88
46S A~20 J-184
48§ A-12 J-132
470 A-1 d-180
473 A~21
474 A-1 J-201
47S A-1 d-188
477 A-1 d-83
478 A-1 8-1
479 A-4 J-230
480 A-23 J- 75
481 A-1 d-188
483 A-1 C-21
484 A-1 D-1
B-ae-s A-1 B-28
Β-27-Ϊ A-1 B-27
C-27-ϊ A-1 C-27
0-12-S A-1 D-12
D- 3-S A-1 9- 3
D-1S-S A-1 D-1S
2.35 -
Figure imgf000237_0001
[©711] 188-1; 6~[(4-Os -lH-qoiisoiia-3-yl)carboKylaisiiao]-lii~mdole-5-carboxyli£ acid
A mixture of 6- (4-oxo-lH-quinolm-3-yi}carbonylaniino]-lH-indoie-5-carboxylic acid ethyl ester (188) (450 mg, 1.2 mmol) and IN NaOH solution (5 mL) in THF (10 mL) was heated at 85
°C overnight. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was acidified with IN HCi solution to pH 5, and the precipitate was filtered, washed wid water and air dried to yield 6-[(4-oxo-lH-qumolin--3-yl)carbonylamino]-lH-indole-5-carboxyHc acid (188-1) (386 mg, 93 %). 'H-NMR (400 MHz, DMSO-rf6) δ 12.92-12.75 (m, 2H), 1 1.33 (s,
1H), 8.84 (s, 1H), 8.71 (s, 1H), 8.30 (dd, J = 8.1, 0.9 Hz, !H), 8.22 (s, lH), 7.80-7.72 (m, 2H),
7.49 (t, J = 8.0 Hz, lH), 7.41 (t, J = 2.7 Hz, 1H), 6.51 (m, 1H); HPLC ret. time 2.95 min, 10-99
% CH3CN, 5 rain run: ESI-MS 376.2 m z (MH*).
- 236 -
8544833.5 [0712] 343; N-[S-(lsob«iylearbamoyS)«lH-mdol~6~yI}-4-oxo--lH--qiHMoliHe-3- earbesamide
To a solution of 6-[(4-oxo-lH-quinolin--3-yl)carbonyIaroino]-lH-indoie-5-cai-boxylic acid (188- I) (26 mg, 0.08 mmol), HATU (38 mg, 0.1 mmol) and DIEA (35 pL, 0,2 mmol) in DMF (1 mL) was added isobutylamine (7 mg, 0.1 mmol) and the reaction mixture was stirred at 65 °C overnight. The resulting solution was filtered and purified by HPLC (10-99 % C¾CN / ¾0) to yield the product, N-[5-(isobutylcarbamoyl)-lH-indol-6-yl]~4-oxo-lH-quinoline-3-carboxamide (343) (20 mg, 66 %). Ή-NMR (400 MHz, DMSO-tfc) δ 12.66 (d, J = 7.4 Hz, IH), 12.42 (s, IH), 11.21 (s, IH), 8.81 (d, J = 6.6 Hz, IH), 8.47 (s, IH), 8.36 (t, J = 5.6 Hz, IH), 8.30 (d, J = 8.4 Hz, IH), 7.79 (t, J = 7.9 Hz, IH), 7.72-7.71 (m, 2H), 7.51 (t, J = 7.2 Hz, IH), 7.38 (m, IH), 6.48 (m, IH), 3.10 (t, J = 6.2 Hz, 2H), 1.88 (m, IH), 0.92 (d, J = 6.7 Hz, 6H); HPLC ret. time 2.73 mm, 10-99 % CH3C , 5 mm run; ESI-MS 403.3 m/z (MH+).
[0713] Another example:
Figure imgf000238_0001
[©714] 148; 4-Oxo-N-[5-(l-piperidylcarbonyi)-lH-indol-6-yl]-lH-quinoline-3- carboxamide
4-Oxo-N-[5-(l -piperidy!carbosiyl)-lH-indol~6-yi]-lH-quinoline-3-carboxamide (148) was synthesized following the general scheme above, coupling the acid (188-1) with piperidine. Overall yield (12 %). HPLC ret. time 2.79 min, 10-99 % CH3CN, 5 min run; ES!-MS 415.5 m/z (MH*).
237
8544833.!
Figure imgf000239_0001
Figure imgf000239_0002
[©718] 158; 4-Ox -N-(S-phesiyl-iH-ii oI-6- !)~lH-qisI iolliie'>3-earl osamMe A mixture of N-(5-bromo-lH-indol-6-yl)-4-oxo-lH-quinolme-3-carboxamide (B-2?-i) (38 mg, 0.1 mol), phenyl boronic acid (18 mg, 0.15 mmol), (dpp PdCia (cat.), and K2CO3 (1(X> pL, 2M solution) in DMF (1 mL) was heated in the microwave at 180 °C for 10 min. The reaction was filtered and purified by HPLC (10-99 % CH3CN / H20) to yield the product, 4-oxo-N-(5-phen I lH-indol-6-yI)-iH-quinoiine-3-carboxamide (158) (5 mg, 13 ). HPLC ret. time 3.05 min, 10- 99 % CH3CN, 5 min run; ESI-MS 380.2 m/z (MH+).
[Θ719] The table below lists other examples synthesized following the general scheme above.
Figure imgf000239_0003
- 238 -
S544S33.1 [0720] Exam le 3;
Figure imgf000240_0001
27
Figure imgf000240_0002
To a solution of methyl-{ [methyi-(2-oxo-2- {6-[(4-oxo~l,4-dihydro-quinol3ne-3-carbo ami5io]-indoS-l-yl }-eihyl)-carbamoyl]-meiliyl }-carbamic acid tert-buiyl ester (B-26 ) (2.0 g, 3.7 mmol) dissolved in a mixiure of (¾<¾ (50 mL) and methanol (15 mL) was added HQ
(60 mL, 1.25 M in methanol). The reaction was stirred at room temperature for 64 h. The precipitated product was collected via filtration, washed with diethyl ether and dried under hi vacuum to provide the HCI salt of the product, N-[l -[2-[methyl-(2-rr!ethylaminoacetyI)- amino]aceiyl]- lH-indol-6-yl]-4-oxo-lH-quinolme-3-carboxarnide (27) as a greyish white s ( 1.25 g, 70 %). 'H-NMR (400 MHz, DMSO-d6) δ 13.20 (d, J = 6.7 Hz, 1 H), 12.68 (s, 1H), 8.96-8.85 (m, lH), 8.35 (d, J ~ 7.9 Hz; 1H), 7.91-7.77 (m, 3H), 7.64-7.54 (m, 3H), 6.82 (m, 5.05 (s, 0.7H), 4.96 (s, 1.3H), 4.25 (t, J = 5.6 Hz, 1311), 4.00 (t, J = 5.7 Hz, 0.7H), 3.14 (s, 2 3.02 (s, 1H), 2.62 (t, J = 5.2 Hz, 2H), 2.54 (t, J = 5.4 Hz, IH); HPLC ret time 2.36 min, 10-ί Q¾CN, 5 min run; ESI-MS 446.5 m z (MIT).
[0723] Example 1 :
0724] General scheme:
Figure imgf000240_0003
0725] Specific example:
Figure imgf000241_0001
27S
[§726] 275; 4«Be?i2ylosy-N-(3-hydrosy- -fert- tyI-phesiyI)- 5sla Iiiie~3~ earboxasmcfe
To a mixture of N-(3-hyckoxy-4-¾rf-butyl-phenyl)-4-oxo- !H-quinoIine-3-carboxamide (428) (6.7 n g, 0.02 mmol) and Cs2C03 (13 mg, 0,04 mmol) in DMF (0.2 mL ) was added BnBr (10 uL, 0.08 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was filtered and purified using HPLC to give 4-benzyloxy-N-(3-hydroxy-4-feri-butyl- phenyi)-qumoline~3-carboxamide (275). 5H NMR (400 MHz, DMSO-<¾) δ 12,23 (s, IH), 9.47 (s, 1 H), 9.20 (s, 1 H), 8.43 (d, J = 7.9 Hz, IH), 7,79 (t, J = 2,0 Hz, 2H), 7.56 (m, IH), 7.38-7.26 (m, 6H), 7.1 1 (d, J = 8.4 Hz, 1H), 6.99 (dd, J = 8.4, 2.1 Hz, 1H), 5.85 (s, 2H), 1.35 (s, 9H). HPLC ret. time 3.93 min, 10-99 % CH3CN, 5 min run; ESI-MS 427.1 m/z (MH+),
[0727] Another example:
Figure imgf000241_0002
[0728] 415 ; N-(3-Mydroxy- ~ieri-batyI-pheisyl)-4-methoxy-qiiliioline-3- carb xamMe
N-(3-Hydroxy-4~ieri-butyI-phenyl)-4-methoxy-q inolirse-3-carboxamide (415) was synthesized following the general scheme above reacting N-(3-hydroxy-4-teri-butyl-phenyl)-4-oxo-lH- quinoline-3-carfx>xamide (428) with methyl iodide. lH NMR (400 MHz, DMSC fe) 8 12.26 (s,
■240 -
«544833.1 1H), 9.46 (s, 1H), 8.99 (s, lH), 8.42 (t, J = 4.2 Hz, !H), 7.95-7.88 (m, 2H), 7.61-7.69 (m, 1H), 7.38 (d, J = 2.1 Hz, 1 H), 7.10 (d, J = 8.4 Hz, 1H), 6.96 (dd, J = 8.4, 2.1 Hz, 1H), 4.08 (s, 3H), 1.35 (s, 9H); HPLC ret time 3.46 min, 10-99 % C¾CN, 5 rain ran; ESI-MS 351.5 m/z (MH+).
[0729] Example 2:
Figure imgf000242_0001
[Θ73§] 476; N-C^^ri-Biity!-l-cyaao-S-hyilroxyp eisyi)-! ,4~df hydro-4~
oxoqMinolisie-3-csrb xamMe
To a suspension of N-(4-i rf-buiyi-2-bronxo-5-hydroxyphenyl)-] 54-dihydro-4-oxoquinoline-3- cai oxamide (C-27-I) (84 mg, 0.2 mmol), Zn(CN)2 (14 mg, 0.12 mmol) in MP ( 1 mL) was added Pd(PPh3).i ( 16 mg, 0.014 mmol) under nitrogen. The mixture was heated in a microwave oven at 200 °C for 1 h, filtered and purified using prepative HPLC to give N~(4-.«rr-butyi-2- cyano-5-hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-3-carboxamide (476). ¾ NMR (400 MHz, DMSO- ) δ 13.00 (d, J =6.4 Hz, III), 12.91 (s, 1H), 10.72 (s, 1H), 8.89 (d, J =6.8Hz, 1H), 8.34 (d, J ~8.2Hz, 1H), 8.16 (s, 1H), 7.85-7.75 (rn, 2H), 7.56-7.54 (m, 1H), 7.44 (s, !H), time 3.42 min, 10-100 % CH3C , 5 min gradient; ESI-MS 362.1 m/z
Figure imgf000242_0002
[0732] Ex m le 1;
Figure imgf000242_0003
- 241 -
8544833.1 [0734 Specific example:
Figure imgf000243_0001
[073S] 26$; N~(S~Ammo~2-fert-bi!tyI«phe!syl)-4-^^
A mixture of [3-[(4-oxo- iH-quinolin-3- yl)carbonylamino]~4-ie?i-butyl-p enyl]a3iiinofonBic acid tert-buiyl ester (353) (33 mg, 0.08 mmoi), TFA (! mL) and CH2G2 ( 1 mL) was stirred at room temperature overnight. The solution was concentrated and the residue was dissolved in DMSO (1 mL) and purified by HPLC (10-99 % CH3C / H20) to yield the product, N-(5- amino-2-½ri-butyl-phenyl)-4-oxo-lH-qmiioHne-3-carboxamide (260) (15 mg, 56 %), !H NMR (400 MHz, DMSO- ) δ 13.23 (d, J = 6.6 Hz, lH), 12.20 (s, 1H), 10.22 (br s, 2H), 8.88 (d, J = 6.8 Hz, 1H), 8.34 (d, J = 7.8 Hz, 1H), 7.86-7.80 (m, 3H), 7.56-7.52 (m, 2H), 7.15 (dd, J = 8.5, 2.4 Hz, IH), 1.46 (s, 9H); HPLC ret. time 2.33 mm, 10-99 % CH3CN, 5 min ran; ESi-MS 336.3 m/z (MtT).
[0736] The table below lists other examples synthesized following the general scheme above.
Figure imgf000243_0002
- 242 -
854-1833.1 [0737] Example 2:
[07381 Genera! Scheme:
Figure imgf000244_0001
[0739] Specific example:
Figure imgf000244_0002
[0740] 485 ; N-(3-DimethyksBiii« - -tert-b«iy I-pheiiyI)-4- so- IH-qwtaoMsie-S-
To a suspension of N-(3-amino-4-½ri-butyl-phenyl)-4-oxo-lH-quinoline-3-carboxamide (271) (600 rag, 1 ,8 mrrsol) in CH2C12 (15 mL) and methanol (5 mL) were added acetic acid (250 μί) and formaldehyde (268 μί, 3.6 mmol, 37 wt % in water). After 10 min, sodium
cyanoborohydride (407 mg, 6.5 mmol) was added in one portion. Additional formaldehyde (135 μΐ,, 1 .8 mmol, 37 wt% in water) was added at 1.5 and 4.2 h. After 4.7 h, the mixture was diluted with ether (40 mL), washed with water (25 mL) and brine (25 mL), dried
Figure imgf000244_0003
filtered, and concentrated. The resulting red-brown foam was purified by preparative HPLC to afford N-(3- dimetltylammo-4-ieri-but>'l--phenyi)--4-oxo-lH-quinoline-3-carboxamide (485) (108 mg, 17 %). Ή NM (300 MHz, CDQ3) δ 13.13 (br s, 1H), 12.78 (s, 1.H), 8.91 (br s, 1H), 8.42 (br s, 1H), 8.37 (d, / = 8.1 Hz, 1H), 7.72-7.58 (m, 2H), 7.47-7.31 (m, 3H), 3.34 (s, 6H), 1.46 (s, 9H); HPLC ret. time 2.15 min, 10-100 % C¾CN, 5 min ran; ESI-MS 364.3 m z (MBf).
[0741] The table below lists other examples synthesized following the general scheme
■· 243 -
8544833,;
Figure imgf000245_0001
[0742] Example 3i
Figure imgf000245_0002
[§744] Specific example:
Figure imgf000245_0003
[§745] 94; -(S-Aimi¾o-2-meiliyl-phe!iyl)«4-oxo-iH-qeiH¾lMe-3-earbosaimde To a solution of 4-hydroxy-quinoline-3-carboxylic acid (A-l) (50 rag, 0,26 nimol), HBTU (99 mg, 0.26 mmol) and DffiA (138 pL, 0.79 mraol) in THF (2.6 mL) was added 2-methyl-5-nitro- pheny!amine (40 mg, 0.26 mmol). The mixture was heated at 150 °C in the microwave for 20 min and the resulting solution was concentrated. The residue was dissolved in EtOH (2 mL) and SnCl2-2H20 (293 mg, 1.3 mmol) was added. The reaction was stirred at room temperature overnight. The reaction mixture was basified with sat. NaHCQi solution to pH 7-8 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated. The residue was dissolved in DMSO and purified by HPLC (10-99 % C¾CN / H2Q) to yield the product, N-(5-amino-2-methyf-phenyl)-4-oxo-lH- quinoline-3-carboxaniide (94) (6 mg, 8 ). HPLC ret. time 2,06 min, 10-99 % CH3CN, 5 min run; ESI-MS 294.2 mlz (MH+).
- 244 -
85448».! [Θ746] Another example:
Figure imgf000246_0001
[0747] 17; N S-Ammo-2- rop sy-phe!i l)-4-oxo-lH- BiBoliiie-3-c rboxamide N-(5-Amino-2-propox "pheny!)--4-oxo-i H-quinoline-3-carboxamide (17) was made following the genera! scheme above starting from 4-hydroxy-quinolme~3-carboxylic acid (A-l) and 5~ oitro-2-propoxy~phenyIamirse. Yield (9 %). HPLC ret. time 3.74 min, 10-99 % CH3CN, 5 min run; ESI-MS 338.3 m/z (MIT).
[§748] Example 4;
[
Figure imgf000246_0002
X= CO, CO-2, S02: a) R2XC1, DIEA, ΤΉΡ or R2XC1, NMM, 1,4-dioxane or R2XC1, Et3N,
Figure imgf000246_0003
[0750 Specific example:
Figure imgf000246_0004
167 248
[0751] 2 8 N-(3-Aceiy!amii30-4--Bieihyl-phesyl)-4-ox -iII-qiimo Be-3- earboxsmide
To a solution of N-(3-amino-4-methyl-phenyl)-4-oxo-lH-quinoline-3-carboxamide (167) (33rag, 0.11 mmol) and DIEA (49 μ-L, 0.28 mmol) in THF (1 mL) was added acetyl chloride (16
- 245 -
8544833.! }JL, 0,22 mraol). The reaction was stirred at room temperature for 30 min, LCMS analysis indicated that diacyiation had occiirred. A solution of piperidine (81 jiL, 0.82mmol) in€¾(¾ (2 mL) was added and the reaction stirred for a further 30 rain at which time only the desired product was detected by LCMS. The reaction solution was concentrated and the residue was dissolved in DMSO and purified by HPLC (10-99 % CH3CN / ¾0) to yield the product, N-(3- acetylamino-4-raeihyl-phenyl)-4-oxo-lH-quinoline~3-carboxamide (248) (4 mg, 1 1 %). Ή NMR (400 MHz, DMSO-<¾) δ 12.95 (d, J * 6.6 Hz, lH), 12.42 (s, 1H), 9.30 (s, IH), 8.86 (d, J = 6.8 Hz, IH), 8.33 (dd, J = 8.1 , 1.3 Hz, IH), 7.85-7.81 (m, 2H), 7.76 (d, J = 7.8 Hz, 1H), 7.55 (t, J = 8.1 Hz, IH), 7.49 (dd, J = 8.2, 2.2 Hz, H), 7.18 (d, J = 8.3 Hz, IH), 2.18 (s, 3H), 2.08 (s, 3H); HPLC ret. time 2.46 mm, 10-99 % CH3CN, 5 min run; ESI-MS 336.3 m/z (MH+),
[0752] The table below lists other examples synthesized following the general scheme above.
Figure imgf000247_0001
246-
8544g33.i
Figure imgf000248_0001
[0754] General Scheme:
Figure imgf000248_0002
[Θ755] Specific example:
Figure imgf000248_0003
[0756] 4~Oxo-iV~[3-(irlfluoromeihyI)-S-(¥ii^!saIfoiraMMo)p eeyl]-i,4~ dIhydroqistaoliise-3-earboxafflM le
To a suspension of N-[3-amino-5-(trifluorometiiyl)phenyi]-4-oxo-lH-quinoiine-3-carboxamide
(429) (500 mg 1.4 mrnol) in l,4~dioxane (4 mL) was added NMM (0.4 mL, 3.6 mmoi). β-
Chloroethylsulfonyl chloride (0, 16 mL, 1.51 mmol) was added under an argon atmosphere. The mixture was stirred at room temperature for 6 ½ h, after which TLC (CH2CI2 - EtOAc, 8:2) showed a new spot with a very similar Rf to the starting material. Another 0.5 eq. of NMM was added, and the mixture was stirred at room temperature overnight. LCMS analysis of the crude mixture showed >85 conversion to the desired product. The mixture was concentrated, treated with IM HC1 (5 mL), and extracted with EtOAc (3 x 10 mL) and CH2C12 (3 x 10 mL). The combined organic extracts were dried over Na2S0 , filtered, and concentrated to yield 4-oxo-N-
[3~(trifiuoroineihyi)~S-(vmy!sulfonam as an orange foam (0.495 g, 79 %), which was used in the next step without further purification. !H-
NMR (<4-Acetone, 300 MHz) δ 8.92 (s, 1H), 8.41-8.38 (m, !H), 7.94 (m, 2H), 7,78 {br s, 2H),
- 247 -
85<M833.i 7,53-7.47 (m, 1H), 7.30 (s, 1H), 6.87-6.79 (dd, 7 = 9,9 Hz, 1H), 6.28 (d, J = 16,5 Hz, 1H), 6.09 (d, 7 = 9.9 Hz, 1H); ESI-MS 436,4 mlz (MH")
[0757] 318; 4-Ox -N-[3-[2-(l-piperidyi)ethyMfoE l¾mis¾o]~5- (triflisorometh I)ptes I3-lH»qo oIme--3~carb samlde
A mixture of 4-oxo-iV-[3-(trifluorome&yl)-5-( vinyls^
3-carboxamide (50 mg, 0.1 1 inmoi), piperidine ( 8 jiL, L6 eq) and LiCi04 (20 mg, 1.7 eq) was suspended in a 1 :1 solution of€¾€¾: isopropanoi (1,5 rnL). The mixture was refiuxed at 75 °C for 18 h. After this time, LCMS analysis showed >95 conversion to the desired product. The crude mixture was purified by reverse-phase HPLC to provide 4-oxo-N-[3-[2-( l~ piperidyi)et ylsulfonylamino]-5-(irifluoroniethy l)phenyl]- 1 H-quinoline-3-carboxamide (318) as a yellowish solid (15 mg, 25 ¾). lH-NMR (<fc-Acetone, 300 MHz) δ 8.92 (br s, 1H), 8.4 (d, = 8.1 Hz, 1H), 8.05 (br s, IH), 7,94 (br s, 1H), 7.78 (br s, 2H), 7.53-751 (m, 1H), 7.36 (br s, 1H), 3.97 (t, 7= 7.2 Hz, 2H), 3.66 (t, 7= 8 Hz, 2H), 3,31-3.24 (m, 6H), 1.36-1.31 (m, 4H); ESI-MS 489.1 m z (MH*).
[075§] The table below lists other examples synthesized following die general scheme above.
Figure imgf000249_0001
- 248 -
8544833. S [§759] Example 6t
Figure imgf000250_0001
§761] Specific example:
Figure imgf000250_0002
[§762] 258; N-Issdolm-6-yl-4-oxo-lH-quinoIIse-3-earb©samide
A mixture of N-(l-acetyiindoHri~6-yi)-4-oxo~lH-quinoiine-3-carboxairiide (233) (43mg. 0.12 rnmol), I N NaOH soluiion (0.5 mL) and eihanoi (0.5 mL) was heated to reflux for 48 h. The solution was concentrated and the residue was dissolved in DMSO (.1 mL) and purified by HPLC (10-99 % CH3CN - H20) to yield the product, N-indolin-6-yl-4-oxo- lH-quinoline-3- carboxamide (258) (10 mg, 20 %). HPLC ret. time 2.05 min, 10-99 % CH3CN, 5 min run; ESI- MS 306.3 m z (MH*),
[0763] The table below lists other examples synthesized following the general scheme above.
Figure imgf000250_0003
- 249 -
8544833. J [0764] Example 2:
Figure imgf000251_0001
[0766] S ecific example:
Figure imgf000251_0002
[©767] 299; 4-Oxo-N-(l ^^^-teirahydr qoMoIisi^-yli-lH-qy moMrse-3- carboxam de
A mixture of 7-[(4-oxo- iH-quinoSin-3-yI)carbonylamino]- 1 ,2,3,4-tetrahydroquinoline- 1 - carboxylic acid tert-bulyl ester (183) (23 mg, 0,05 mmoS), ITA ( 1 mL) and CH2CI2 {1 inL) was stirred at room temperature overnight. The solution was concentrated and the residue was dissolved in DMSO (1 mL) and purified by HPLC (10-99 % C¾CN - H20) to yield the product, 4-oxo-N-(l ,2,3,4-tetrahydroquinolin-7-yl)-lH-quinoline-3-carboxamide (299) (7 mg, 32 %). HPLC ret time 2.18 min, 10-99 % C¾CN, 5 min run; ESI-MS 320.3 ra/z (ΜϊΓ).
[©768] Anotlier example:
Figure imgf000251_0003
- 250 -
8544833.3 [0769] 3O0; -(4^-D!me hyI-li2,3,4 €lrahydroqwiEdm-7-yl)~4~ox0-lH-q iliiolisi€-. 3-carboxamMe
N (4,4-Dimethyl-!,2 ,4-tetr^ (300) was synthesized following the general scheme above starting from 4,4-diraethyl-7-[(4-oxo-lH- quinoHn~3~yl)carfaonylaminoj- 1 ,2,3,4-tetraliydroquinoline- i -carboxyiic acid text-butyl ester (108). Yield (33 %). Ή MR (400 MHz, DMSC 6) 8 13.23 (d, J = 6.6 Hz, 1H), 12.59 (s, Hi), 8.87 (d, J = 6.8 Hz, 1H), 8.33 (d, J = 7.7 Hz, 1H), 7.86-7.79 (m, 3H), 7.58-7.42 (m, 3H), 3.38 (m, 2H), 1.88 (m, 2H), 1.30 (s, 6H); HPLC ret. time 2.40 min, 10-99 % CH3C , 5 rain run; ESI- MS 348.2 m/z (MH+).
[077Θ] Other
[0771] Example 1 :
Figure imgf000252_0001
[Θ773] Specific example:
Figure imgf000252_0002
- 253 -
8544833,1 [0774] 163; 4-Ox -l,4-dihydr0-qeMoifaie-3-carb& y c ¾cid (4~asBinomsl¾yi~2i- {2'-EmGxy~2-[(4-Qxo ,4-dihydrGquinoline-3-carbony^
acid tert-butyl ester (304) (40 rag, 0,078 ramol) was stirred in a (¾€¾ / TFA mixture (3:1 , 20 mL) at room temperature for I h. The voiatiles were removed on a rotary evaporator. The crude product was purified by preparative HPLC to afford 4-oxo-l ,4-dihydroquinoline-3-carboxylix acid (4-ai inoineAyl-2'-ethoxybipheEyl-2-yl)amine (163) as a tan solid (14 mg. 43 %), !H NMR (300 MHz, DMSO-</<$) δ 12.87 (d, 7 = 6.3 Hz, 1H), 11,83 (s, 1H), 8.76 (d, J = 6.3 Hz, 1H), 8.40 (s, SH), 8.26 (br s, 2H), 8.01 (dd, = 8.4 Hz, 7 = 1.5 Hz, IH), 7.75 (dt, 7 = 8.1 Hz, = 1.2 Hz, IH), 7.67 (d, 7 = 7.8 Hz, IH), 7.47-7.37 (m, 2H), 7.24 (s, 2H), 7.15 (dd, 7 = 7.5 Hz, 7 = 1.8 Hz, IH), 7.10 (d, 7 = 8.1 Hz, IH), 7.02 (dt, 7 = 7.5 Hz, 7 = 0.9 Hz, IH), 4.09 (m, 2H), 4.04 (q, 7 = 6.9 Hz, 2H), 1.09 (t, 7 = 6.9 Hz, 3H); HPLC ret. time 1.71 rain, 10-100 % CH3CN, 5 rain gradient; ESI-MS 414.1 m z (MH÷).
[0775] Another example:
Figure imgf000253_0001
[0776] 39©; N-[3-(A leomethyI)»4-tert-b«iyl-pfeesiyI]-4-ox 5~lH-qMta0 Ke--3- carboxamide
N-[3-(Aminomediyl)~4~½r?-butyl-phenyl]-4-oxo- lH-quinoline-3-carboxamide (39Θ) was synthesized following the general scheme above starting from [5-[(4-oxo-lH-quinolin-3- yl)carbonylamino]-2-i r?-butyl-phenyl]raethy!ammoformic acid tert-butyl ester (465). HPLC ret. time 2,44 min, 10-99 % CH3CN, 5 min gradient; ESi-MS m/z 350.3 (M + H)+.
- 252 -
8544833.1 [Θ777] Example 2:
§77i| General scheme:
Figure imgf000254_0001
§779] Specific example:
Figure imgf000254_0002
[0780] 3-{2-(4-(l-Ammo-2-methyIpri^aii«2-yI)pheiiyl)aeeh1)qiiiffi IiE-4(iH)-osse (2-Mefhyl-2- {4 2-GXQ-2-(4-oxo- 1
acid tert-butyi ester (88) (0.50 g, 1.15 mmol), TFA (5 mL) and CH2CI2 (5 mL) were combined and stirred at room iemerpaiiire overnight. The reaction mixture was then neutralized with IN NaOH. The precipitate was collected via filtration to yield the product 3-(2~(4-(l-amino-2- methyipropan-2~yl)phenyi)acetyi)quinoiin-4( lH)-one as a brown solid (651 mg, 91 %). HPLC ret. time 2.26 min, 10-99 % CH3CN, 5 min ran; ESI-MS 336.5 m/z (MH+).
[Θ781] 323; [2-Meihyl-2-[4 (4-oso-iH-qi8l olm~3~yl)earboByIamliio]pfeeffiyi]- propyljsrmnotormic acid methyl ester
Methyl chloroformate (0.032 g, 0.150 mmol) was added to a solution of 3-(2~(4-(l-amino-2- methyIpropan-2-yl)phenyi)acetyI)quinoiiE-4( l H)-orse (0.025 g, 0.075 mmol), TEA (0.150 mmol, 0.021 mL) and DMF (1 mL) and stirred at room temperature for 1 h. Then piperidine (0.074 mL, 0.750 mmoi) was added and the reaction was stirred for another 30 min. The reaction mixture was filtered and purified by preparative HPLC (10-99 % CH3CN-¾Q) to yield the product [2- methyl-2-[4-[(4-GXQ-lH-quinolm-3~yi)c^ acid methyl ester (323). !H NMR (400 MHz, DMSO-d6) δ 12.94 (br s, 1H), 12,44 (s, I E), 8,89 (s, 1H), 8.33 (dd, ,/ = 8.2, 1.1 Hz, 1H), 7,82 (t, J = 8.3 Hz, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.67 (d, / = 8.8 Hz, 2H), 7.54 (t, J " = 8.1 Hz, 1H), 7.35 (d, = 8.7 Hz, 2H), 7.02 (t, J = 6.3 Hz, 1H), 3.50 (s, 3H), 3.17 (d, J = 6.2 Hz, 2H), 1.23 (s, 6H): HPLC ret. time 2.93 min, 10-99 % CH3CN, 5 mm ran; ESI-MS 394.0 m/z (MH*).
- 253 -
8544833.1 [0782] The table below lists other examples synthesized following the genera! scheme above.
Ethyl chioroformate
Propyl chioroformate
Bu vl chioroformate
Isobutyl chioroformate
Neopentyl chioroformate
2-met oxvethvi chioroformate
(tetrahydrofuran-3-yl)niethyl chloroforaiate
[0783] Exam le 3:
[Θ784] Genera! Scheme:
Figure imgf000255_0001
ific example:
Figure imgf000255_0002
[0786] 273-!; N-{l-Amlaoii raim-7-yl)-4-oxo-lH-qiiisMis¾e-3-earbosais d¾
To a solution of [7-[(4-oxo-lH-q inolin-3-yl)carbonyIamino]tetralin-l-yl]amiiiofoi-mic acid tert- butyl ester (273) (250 mg, 0.6 mmol) in dichloromethane (2 mL) was added TFA (2 rnL). The reaction was stirred at room temperatiire for 30 min. More dichloromethane (10 mL) was added to the reaction mixture and the solution was washed with sat. NaHCOj solution (5 raL). A precipitate began to fonn in the organic layer so the combined organic layers were concentrated to yield N-(i-aminoterfaIm-7-yl)-4-oxO"lH-quiiioIine~3-carboxamide (273-1) ( 185 mg, 93 %). HPLC ret. time 1.94 min, 10-99 % CH3CN, 5 min run; ESI-MS 334.5 m/z (MH+).
• 254 ·
S544S33.5 [0787] 159; [7~[(4~OTO~lH~q« oIlB-3-yl)carbsKylamlEoJtetrailH-l-yl]amlm>formic ac d methyl ester
To a solution of N-i l-aminoteiralin-7-yi)-4-oxo-lH-quinoiii'8e-3-carboxamide (273-1) (65 mg, 0.20 mmol) and DJEA (52 $iL« 0,29 ramol) in methanol (1 mL) was added methyl chiorofomiate (22 jiL, 0,29 rrsmol). The reaction was stirred at room temperature for 1 h. LCMS analysis of the reaction mixture showed peaks corresponding to both the single and bis addition products. Piperidme (2 mL) was added and the reaction was stirred overnight after which only the single addition product was observed, The resulting solution was filtered and purified by HPLC (10-99 % C¾CN - ¾0) to yield the product, [7-[(4-oxo-lH-quinoiin~3-yl)carbonylaminojietraiin-i- yijaminoforniic acid methyl ester (159) (27 rag, 35 ). HPLC ret, time 2.68 min, 10-99 % CH3CN, 5 min run; ESI-MS 392.3 m/z (MH4"),
[0788] Another exam le:
Figure imgf000256_0001
[0789] 482; [7-t(4-Oxo-lH-quinolin-3-yi)carbonylamino]terralin-l-yl]aminoformic acid ethyl ester
[7-[(4-Oxo- lH-quinoIin-3-yi)carbonylaraino]tetralin- l -yl]aminoformic acid ethyl ester (482) was synthesized following the general scheme above, from amine (273-1) and ethyl
chloroformate. Overall yield (18 %). HPLC ret, time 2.84 min, 10-99 % CH3CN, 5 min run; ESI-MS 406,5 m/z (MH+).
[0790] Farther Examples
[0791] Acid Intermediate Example 1 : Synthesis of 7-H«oro-6-methoxy-4-oxo-l,4- dihydroquino ee-3-carb xylic aeid
- 255 -
&544S33.1
Figure imgf000257_0001
[0792] A mixture of 3-fluGro-4-medioxy~anilme (0.7 g, 4.96 mmoi) and diethyl 2- (edioxymethylene)propanedioate (1.1 g, 4.96 mmoi) was heated at 100 °C for 4 h. The mixture was cooled to room temperature and concentrated under reduced pressure, and then purified via silica gel column chromatography using 1 to 60% EtOAc in hexanes to yield diethyl 2-((3- fiuoro-4-met oxypheny!amino)methyiene)rnalonate (1.2 g, 78%). LC M.S: m/z 312.3 (M+H)+ at 1.69 min (10%-99% C¾CN (0.035% TFA)/H2G (0.05% TFA)).
[0793] A flask charged with diethyl 2-((3-fiuoro~4~
methoxyphenylamino)raethyIene)malonate (1.2 g, 3.86 mmoi) and polyphosphoric acid (4.8 g) was heated at 120 °C for 4 h. The reaction was then cooled to room temperature and filtered. The residue was treated with aqueous NaHC03 solution, filtered, washed with water and dried. The solid was then purified via silica gel column chromatography using 20 to 70% EtOAc in hexanes to yield ethyl 7'fluoro-6-metho.Ky-4-oxo- l,4-dihydroqumoline-3-carboxylate (410 mg, 40%). LC/M8: m/z 266.3 (M+H)+ at 0.91 min (10%-99% C¾CN (0.035% TFA)/H20 (0.05% TFA)).
[§794] Ethyl 7-fluoro-6-methoxy-4-oxo-l,4-dihydroquinoline-3-carboxyIate (409 mg, 1.54 mmoi) was suspended in a solution of NaOH (3.55mL of 4 %w/v, 3.55 mmoi) and tlie reaction was stirred under reflux for 2 h. After cooling, the reaction mixture was acidified with cone. HCl. The resulting precipitated was collected via filtration, washed with water and dried to yield 7-fluoro-6-methoxy-4-oxo-l,4-dihy<lroqumoliiie-3-carboxylic acid (50 mg, 14%). LC/MS: m/z 238.3 (M+H)+ at 0.95 min (10%-99% CH3CN (0.035% TFA)/¾0 (0,05% TFA)).
- 256 -4833.1 [©795] 6»flMOF0-7-metfeo%y-4-0X0- 1 ,4-difeydroqHiaol e-3-carljosy lie acid
Figure imgf000258_0001
[0796] 6-fluoro-7-meihoxy-4-oxo-I ,4-dihydroquinofine-3-carboxylic acid can be synthesized following the general scheme above starting from 4-fluoro-3-metlioxyamlme
[§797] Acid Intermediate Example 2: Synthesis of 5-meihyi-4~ KO~l,4- dlhydroqiitaolioe-S-earfo xyllc add
Figure imgf000258_0002
[0798] A mixture of 2-bromo-5-methyl-aniline (1.0 g, 5.34 mmol) and diethyl 2- (ethoxymethylene)propanedioate (1.23 g, 5.90 mmol) was heated at 100 °C for 4 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was then purified via silica gel column chromatography using 1 to 60% EtOAc in hexanes to yield diethyl 2-[[(2-bromo-5-methyI-phenyl)amino]methylene]propanedioate ( 1.6 g, 84%). !H NMR (300 MHz, CDC13) 5 1.19 (d, J = 13.2 Hz, 1H), 8.48 (d, J = 13.2 Hz, lH), 7.43 (d, J = 8.1 Hz, 1H), 7.08 (s, lH), 6.81 (d, 7 = 8.1 Hz, III), 4.37-4.23 (m, 4H), 2.35 (s, 3H), 1.42- 1.25 (m, 6H).
[0799] A flask charged with diethyl 2-[[(2-bromo-5-methyl- phenyl)amino] methylene] ropanedioate (1.6 g, 4.49 mmol) and polyphosphoric acid (5.6 g) was heated at 120 °C for 4 h. The reaction was then cooled to room temperature and filtered. The residue was ixeated with aqueous NaHC03 solution, filtered, washed with water and dried. The residue was then purified via silica gel column chromatography using 20 to 70% EtOAc in hexanes to yield ethyl 8-bromo-5-methyl-4-oxo-lH-quinoline-3-carboxylate (895 mg, 64%). !H NMR (300 MHz, DMSO-< ) δ 11.22 (s, 1H), 8.32 (s, 1H) , 7.82 (d, J = 7.8 Hz, 3H), 7.04 (d, / = 7.8 Hz, 1 H), 4.19 (q, J = 7.2, 14.4 Hz, 2H), 2.72 (s, 3H), 1.23 (t, J = 10.2 Hz, 3H).
■ 257 ·
4833.1 [080®] A flask charged with ethyl 8~bromo-5-methyl-4~oxo H~quinoline-3- carbox late (895 mg, 2.89 mmol), sodium acetate (237 mg, 2.89 mmol) and Pd C (180 mg, 1.69 mmol) was flushed under a N2 followed by evacuating under vacuum. Acetic acid (21 mL) was added under an inert atmosphere followed by evacuating under vacuum. The reaction was then stirred for 4 h in an atmosphere of ¾. The reaction was filtered to remove the Pd catalyst and the solvent was evaporated to give ethyl 5-met yi-4-oxo-lH-quinoIine-3- carboxylate (145 mg, 22%).
[0801] Ethyl 5~methyI-4-oxo-lH-quinoiine-3-carboxyIate (142 mg, 0,61 mmol) was suspended in an aqueous solution of NaOH (1.54 mL of" 4%w/v, 1.54 mmol) and the reaction was stirred under reflux for 2 h. After cooling, the reaction mixture was acidified with cone. HQ. The resulting precipitate was collected via filtration, washed with water and dried to yield 5~methyl-4-oxo-lH-quinoline~3-carboxyiic acid (42 mg, 34%). !H NMR (400 MHz, DMSO-4 δ 15.69 (brs, 1H), 13.81 (brs, lH), 8.68 (d, 7 = 6.4 Hz, 1H), 7.70-7.64 (m, 2H) , 7.27(d, 7 = 6.4 Hz, 1H), 2.84 (s, 3H). MS (ESI) m/z: 202.2 [ -H]\
[0802] T-m thyl-^ xo-l^-dihydroi Missolisie-S-carhoxy e acid
Figure imgf000259_0001
[0803] 7-methyl-4-oxo-l,4-dihydroquinoline-3-carboxylic acid can be synthesized following the general scheme above starting from 2-hromo-3-methy!amline, Overall yield (16%). Ή NMR (400 MHz, DMSO-ifc) S 15.24 (s, 1 H), 12.30 (s, IH)5 8.63 (s, 1 H), 8.07 (d, 7 = 8.0 Hz, 2H), 7.28 (d, 7 = 8.0 Hz, lH), 2.85 £s, 3H).
[Θ8Θ4] §-bromo-5-eitr -4-o - l^dlhydroqulnolme-J-carb xyltc add
Figure imgf000259_0002
[0805] 8-brorao-5-niiro-4-oxo~l,4-dihydroquinoline-3-carboxylic acid can be synthesized following the general scheme above starting from 2~bromo~5~mtroanifine.
LC MS: m/z 314.9 (M+H)+ at 1. min (10%~99% CH3CN (0.035% TFA)/¾0 (0.05% TFA)).
- 258 -44833.1 [0806] Acid Intermediate Example 3: Synthesis of 4~oxo-5-(triflisoromethyI)-l,4-
Figure imgf000260_0001
[0807] 2-chloro-5-(trifluoromethyl)aniline (52 g, 260 mmol) and diethyl 2- (ethoxymethylene)propanedioate (85g, 389 mmol) were combined in a 250 mL flask and fitted with a Dean-Stark condenser. The mixture was heated to 1 10 °C for 4 h. The reaction mixture was cooled to - 80 °C and hexane was slowly added (-150 mL). The resulting precipitate was stirred until room temperature was reached, then filtered to obtain a white crystalline solid. The solid was washed with hexane and air dried (93 g, 94%). Ή NMR (400 MHz, DMSO-de) δ 1 1.28 (d, 7 = 13.0 Hz, 1H), 8.63 (d, J = 13.0 Hz, 1H), 8.10 (s, 1H), 7.80 (d, 7 - 8.3 Hz, 1H), 7.50 (dd, J = 8.4, 1.5 Hz, 1H), 4.21 (dq, J = 28.3, 7.1 Hz, 4H), L27 (td, 7 = 7.1, 2.9 Hz, 6H).
[08Θ8] 6 niL of Dowiherm was added to a long-neck 25 mL flask, fitted with a reflux condenser. The Dowiherm was heated to 200 °C and degassed for 20 minutes. Diethyl 2-((2- chk)ro-5-(trifiuoromethyl)phenylamino)methylene)malonate (Ig, 2.73 mmol) was then added and the solution was then heated to reflux for 2.5 h under N?. The reaction mixture was cooled after 2.5 h, then diluted with hexane (12 mL) to produce a fine, light brown precipitate. The reaction mixture was filtered, and the precipitate washed with hexane until the color was removed. The product was air dried to obtain ethyl 8-chIoro-4-oxo-5-(trifluoromethyl)-l, 4- dihydroquinoline-3-carboxylate as a light brown solid (0.57 g, 65%). !H NMR (400 MHz, DMSO-i¾) δ 1 1.91 (s, ill), 8.39 (s, 1H), 8.06 (d, 7 = 8.3 Hz, 1H), 7.81 (d, 7 = 8,4 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 1 ,29 (t, 7 = 7.1 Hz, 3H).
[0809] Ethyl 8-chloro-4-oxo-5 -(trifluoromethy 1)- 1 ,4-dihydroqumoline-3-carboxylate (500 mg, 1.56 mmol) was dissolved in NaOH (16 mL of 2.0 M, 31 mmol) and ethanol (3 mL) and heated to 100 °C for 2 h. The clear, light yellow solution was cooled to 50 °C, the reaction mixture was degassed with N2, and then treated with 10% Pd C (65 mg, 0.03 mmol). The
- 259 - 44833.1 reaction mixture was heated at 70 °C for 3 h under an atmosphere of ¾. The reaction mixture was cooled and then filtered, acidified with cone. HQ until a white precipitate was formed, then allowed to stir overnight. The reaction mixture was filtered, washed with water and dried with CH3CN to yield a white powder (350 mg, 87%). !H NMR (400 MHz, DMSOri6) δ 15.26 (s, IB), 13.68 (s, 1H), 8.98 (s, 1H), 8.16 - 8.09 (m, 1H), 8,08 - 7.97 (m, 2H).
[0810] Commercially avaliabk Acids as¾ Esters
8-chloro-4~oxo~ 1 ,4-dihydroquinoiine-3-carboxylic acid
4-oxo-6-(trifluoromethy 1)- 1 ,4-dihydroquinoline-3-carboxylic acid
8~fiuoro-4~oxo- 1 ,4-diliydroquinoline-3-carboxylic acid
4- oxo-7-(trifluoromethoxy)- 1 t4-dihydroqumoHne-3-carboxylic acid
Ethyl 5,8-difluoro-4-oxo- 1 ,4-dihydroquinoline-3-carboxylate
5- fluoro-4-oso- Ϊ ,4-dihydroqumoHn -3-carboxylic acid
6J-difluoro-4-oxo- l,4-dihydroquinoline-3-carboxylic acid
4-oxo-8-(irifi uoromethyl)- 1 ,4-dihydroquinoline-3-carboxylic acid
i-methyl-4-oxo- 1 ,4-dihydroqumoIine-3-earhoxylic acid
Ethyl 8-cyano-4-oxo- 1 ,4-d¾ydroquinoHne-3-carboxylate
7- cyano-4-oxo~ 1 ,4-dihydroquinoline-3»carboxylic acid
6- methy 1-4-OXO-1 ,4-dihydroqumoiine-3-carboxylic acid
8- ethoxy-4-oxo- i ,4"-dihydroquinoline-3-carboxylic acid
6-chioro-4~oxo- 1 ,4-dihydroquinoline-3-carboxylic acid
8-ethyl-4-oxo- i ,4-dihydroquinoIine-3-earboxylic acid
6-bromo-4-oxo- 1 ,4-dihydroquinoHne-3-carboxylic acid
6-methoxy-4-oxo- 1 ,4-dihydroquinoline-3-carbox lie acid
Ethyl 7~raethoxy-4-oxo~ 1 ,4-dihydroquinoline-3-carboxyIate
6-(dimethylamino)-4-axo- 1 ,4-dihydroquinoiine-3-carboxylic acid
6- ethoxy-4-oxo- 1 ,4-dihydroquinoline-3-carboxy!ic acid
7- acetyl-4-oxo- 1 ,4-dihydroquinoiine-3-carbox lie acid
7-methyi-4-oxo~ i ,4-dihydroquinoluie-3"Carboxylic acid
- 260 -
8544833.1 [©811] Amine Intermediate Example 1 : Synthesis of 5-amin©-2- (iriflii®romeihyl)pheBol
Figure imgf000262_0001
[0812] A mixture of l-bromo-2-meAoxy-4~nitro~benzene (20 g, 86.2 mmol), methyl 2,2-difluoro-2-fluorosuIfonyl-acetate (100 g, 520.5 mmol) and Cul (65 g, 341.3 mmol) in dry DMF (200 mL) was stirred at 75 °C under an atmosphere of N2 overnight. The solvent was evaporated under reduced pressure. EtOAc was added to the residue and the solid was removed by filtration. The filtrate was washed with water (100 mL x 2), brine (100 mL)s dried over anhydrous Na2S0 and purified by silica gel column chromatography (petroleum as eluant) to afford a mixture of l-hromo-2-methoxy-4~nitro-benzene and 2-methoxy-4-nitro~ 1 - (trifluoromethy benzene (16 g). !H NMR (300 MHz, CDCI3 ) δ 7.90-7,86 (m, III), 7.85 (s, 1 H), 7.77-7.69 (m, 1H), 4.02 (s, 3H)
[0813] A mixture of 2-methoxy-4-nirro-l-(riifluoromeihy])benzene and l~bromo-2- methoxy-4-nitro-benzene (16 g, 72 mmol) and pyridine hydrochloride (100 g, 865.3 mmol) was stirred at 210 °C for 40 min. Then the reaction mixture was poured into ice-water and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with water (100 mL x 2) and brine (50 mL), dried over anhydrous Na2S0 , filtered, concentrated and purified by silica gel column chromatography (5% EtOAc in petroleum as eluant) to afford a mixture of 5-nitro-2-(trifluoromethyl)phenol and 2-bromo~5-nitro-pheooI (10 g). lH NMR (400 MHz, CDCI3 ) δ 9.16 (s, 1 H), 7.00 (d, J = 8.4 Hz, 1 H), 6.06 (s, 1 H), 5,95 (d, J = 8.4 Hz, 1 H), 4.07 (brs, 1 H).
[0814] To a solution of 5-nitro-2-(tritluoromethyl)phenol and 2-bromo-5-nitro-phenol (10 g, 48.28 mmol) in methanol (60 mL) was added Raney Nickel (2.83 g, 318 μί, 48.28 mmol) under an atmosphere of nitrogen. The reaction mixture was then stirred for 4h at room temperature under an atmosphere of hydrogen (1 atm). The catalyst was removed by filtration through a pad of celite and the filtrate was evaporated under vacuum. The crude product was purified by preparative HPLC to obtain 5-amino-2-(trifluoromethyl)phenol (1 ,7 g, 20%). Ή
- 261 -44833. ! NMR (400 MHz, DMSO-d6) 5 9.79 (s, 1H), 7.04 (d, J = 8.8 Hz, 1H), 6 JO (s, 1H), 6.01 (d, i = 8.4 Hz, I H), 5,58 (br s, 2H).
[0815] Amine intermediate Example 2: Synthesis of 5~ammo-2»
(irIfl5soromeilsyl)pheiiol
Figure imgf000263_0001
[0816] 2-Isopropylaniline (13.5 g, 99.85 mmol) was added portionwise to cone, ¾SG4 (100 mL) to generate a yellow homogeneous solution. The solution was then cooled to 0 °C and KNOj ( 15.2 g, 150.3 mmol) was added portionwise maintaining the internal temperature below 5 °C. The reaction was stirred for 2 h and then poured on ice water, then basified with 10% NaOH sol tion. The aqueous layer was extracted with EtOAc, dried over MgSG4, filtered and concentrated to obtain 2~isopropyi-5-nitroaniline (14.9 g, 83%). lR NMR (400 MHz, CDC¾) δ 7.60 (dd, J = 8.4, 2.2 Hz, 1H), 7.50 (d, / = 2.4 Hz, 1H), 7.27 - 7.21 (m, 1H), 3.96 (s, 2H), 2.98 - 2.79 (m, 1H), 1.29 (d, J = 6.8 Hz, 6H).
[0817] 2-Isopropyl-5-nitro-aniline ( 1.89 g, 10.49 mmol) was added dropwise to a mixture of conc.HaSQ* (9 mL) and H20 (50 mL), This reaction mixture was cooled to 0 °C and a solution of NaNG2 (763 mg, i 1.06 mmol) in ¾0 (2 mL) was added. The reaction mixture was stirred for 10 minutes and then 1 g of urea was added to decompose the excess NaNC½, followed by the addition of 10 mL of 1 : 2 eonc.HsSC^: ¾0. The reaction mixture was then refluxed for 10 minutes, cooled to room temperature and extracted with EtOAc, washed with brine, dried over MgS04, filtered and concentrated. The residue was then purified via silica gel column chromatography using 10 to 20% EtOAc in hexanes to obtain 2- isopropyl-5-methyl-phenol (1 ,41 g, 89%). !H NMR (400 MHz, CDC13) δ 7.79 (dd, J = 8.5, 2.3 Hz, 1H), 7.63 (d, 7 = 2.3 Hz, 1H), 7.33 (d, 7 = 8.5 Hz, IE), 7.26 (s, 1H), 3,39 - 3.18 (m, 1H), 1.29 - 1.26 (m, 6H).
- 262 -4 S33.1 [0818] To a refluxing solution of 2 sopropyl-5-methyl-phenol (1.3 g, 8,65 mmol) and ammonium formate ( 1.3 g, 20.62 mmol) in ethanol (50 roL) was added 10% Pd C (887 rag, 8,33 mmol). The mixture was refluxed for an additional 5 minutes, cooled and filtered through a pad of eelite. The solvent was removed by evaporation to give 5-ammo~2~isopropylpheiioI which was used without further purification. Ή NMR (400 MHz, DMSG~i¾) δ 8.70 (s, 1H), 6.71 (d, 7 = 8.1 Hz, 1H), 6.04 (d, 7 = 2.2 Hz, 1H), 5.97 (dd, 7 = 8.1, 2.2 Hz, 1H), 4.65 (s, 2H), 3.08 - = 6.9 Hz, 6H).
Figure imgf000264_0001
[§82§] 3-amino-4-teri-butylphenoi can be synthesized following the general scheme above starting from 4~tert-butylaniline.
[§821] Amine Intermediate Example 3: Synthesis of S-amtao-l-eydohexyipfaesaol
Figure imgf000264_0002
[0822] 4-cyclohexylaniline (15 g, 85.58 mmol) was added portionwise to cone, sulfuric acid (85 rrsL, 1.6 mol) to generate a homogeneous solution. The solution was then cooled to 0 °C and KNO3 (13 g, 128.6 mmol) was added portionwise maintaining the internal temperature below 5 °C, The reaction was stirred for 5 minutes at -10 °C and then poured on ice water, basified with 6N NaOH solution and the aqueous layer was extracted with EtOAc, dried over MgSG4, filtered and concentrated to obtain 4~cyciohexyi-3-eitroamline (17 g, 921%). !H NMR (400 MHz, CDC¾) δ 7.20 (d, 7 = 8.5 Hz, 1H), 6.97 (d, 7 = 2,5 Hz, 1H), 6,82 (dd, 7 = 8.4, 2.5 Hz, 1H), 2,85 (ddd, 7 = 1 1.4, 8.3, 3.2 Hz, 1H), 1.89 - 1.69 (m, 6H), 1.49 - 1.29 (m, 4H).
■ 263 -4833.1 [0823] To a solution of 4-cyclohexyl-3-nitro-aniIine (1.54 g, 6.99 mmol) in DCM (15 raL) was added Et3N (1.9 mL, 13.63 mmol), followed by the addition of acetic anhydride (3,3 mL, 34.98 mmol). The reaction mixture was stirred at room temperature for 2 h, quenched with water, the layers separated and the organic layer was washed with 0. IN HCI, followed by washing with H20. The organic layer was dried over MgSQ4, filtered and concentrated to obtain N-(4-cydohexyl-3-nitrophenyl)acetamide (1.7 g, 93%). *H NMR (400 MHz, CDC13) δ 7.91 (d, / = 2.2 Hz, 1H), 7.69 (dd, J = 8.6, 2,2 Hz, 1H), 7.52 (s, IH), 7.40 (d, J = 8.6 Hz, 1H), 3.01 - 2.87 (m, IH), 2.22 (s, 3H), 1.95 - 1.78 (m, 5H), 1.42 (t, / = 10.4 Hz, 4H), 1.32 - 1.21 (m, iH).
[0824] To a refluxing solution of N-(4-eyclohexyl-3~nitro-phenyl)acetamide (1.8 g, 6.86 mmol) and ammonium formate (1.8 g, 28,55 mmol) in ethanol (50 mL) was added 10% Pd/C (1.3 g, 12,22 mmol). The mixture was refluxed for additional 5 minutes, cooled and filtered through a pad of celite. The solvent was removed by evaporation to give N-(3-amino- 4~cyclohexylphenyl)acetamide (1.4 g, 90%) which was used without further purification. !H NMR (400 MHz, CDC13) 6 7.15 (d, / = 2.1 Hz, 2H), 7.03 (d, J - 8.3 Hz, IH), 6.67 (dd, J = 8.2, 2.1 Hz, 1H), 3.72 (d, J = 9.8 Hz, 2H), 2.42 (d, J™ 8.5 Hz, lH), 2J5 (s, 3H), 1.88 (d, / = 9.5 Hz, 4H), 1.78 (d, / = 12.1 Hz, IH), 1.51 - 1.33 (m, 5H).
[082S] N-(3-amino-4-cydohexyl-phenyl)aeetarmde (696 mg, 3,0 mmol) was added dropwise to a mixture of conc.H2S04 (3 mL, 56.28 mmol) and ¾0 (17 mL). This reaction mixture was cooled to 0 °C and a solution of aN02 (229 mg, 3.32 mmol) in H20 (2 mL) was added. The reaction mixture was stirred for 5 minutes at 0 °C and then 1 g of urea was added, followed by the addition of tO mL of 1 : 2 H2S04: H 0. The reaction mixture was then refluxed for lhour, cooled to room temperature and extracted with EtOAc, The aqueous layer was basified with solid NaOH and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgS04, filtered and concentrated to obtain 5-amino-2- cyclohexylphenol (426 mg, 74%), which was used wit!iout further purification.
[0826] Amine intermediate Example 4: Synthesis of 5-ami.iQ-2 erf-butyI-4- ethylphenol
- 264 -
85 Ί8 .3
Figure imgf000266_0001
[0827] To a solution of 2-fc>J -butyi-4-ethyl-phenoi (10 g, 56.1 mmol) in DCM (50 mL) was added 1¾N (17 g, 168.0 mmol) and methyl cl loroforaiate (1 1 g, 1 16.4 mmoi) at 0 °C, The mixture was stirred overnight at room temperature. Water was added to quench the reaction and the mixture was extracted with EtOAc (200 mLx3). The combined organic layers were dried over anhydrous NajSi filtered and evaporated under vacuum to give 2-ierf-butyl-4- ethyipheny! methyl carbonate (12 g, 91%). !H NMR (300 MHz, CDC13 ), 7.06-7.02 (m, 2H), 7.02 (s, 1H), 3.92 (s, 3H), 2.64 (q, 7 = 7.5 Hz, 2H), 1.37 (s, 9H), 1.54 (t, 7 = 7.5 Hz, 3H)
[0828] To a solution of NO3 (3.9 g, 38.57 mmol) in DCM (50 mL) was added TMSC1 (5.5 g, 50.62 mmol) and 2-ierf-butyl-4-ethylphenyi methyl carbonate (6 g, 25.39 mmol) at 0 °C. After stirring for 15 minutes, Ai(¾ (10 g, 0.08 moi) was added and then the reaction mixture was stirred for 2 h. The reaction mixture was poured onto ic water and extracted with EtOAc (50 mLx3). The combined organic layers were dried over anhydrous N ^SO^ filtered and evaporated under vacuum to give the crude compound, which was purified by silica gei column chromatography (10-15 % EtOAc in petroleum ether as eluant) to yield 2-ieri-butyl-4-ethyI-5-nitrophenyl methyl carbonate (5 g, 70%). Ή NMR (400 MHz, CDC13 ) 7.69 (s, 1H), 7.25 (s, 1H), 3.82 (s, 3H), 2,54 (q, 7 = 7.6 Hz, 2H)S 1.26 (s, 9H), 1.15 (d, 7 = 7.6 Hz, 3H).
[0829] To a .solution of (2-ieri-b tyl-4-ethyl-5-nitro-phenyl)methyl carbonate (3.9 g, 13.86 mmoi) in methanol (100 mL) was added KOH (1.8 g, 32.08 mxnol) at room
temperature. The mixture was stirred overnight. Water was added and the reaction mixture was extracted with EtOAc (50 mLx3). The combined organic layers were dried over anhydrous Na2S04. filtered and evaporated under vacuum to give 2-fcri-butyl-4-ethyl-5- nitrophenoi (2.8 g, 91 %), which was used in the next step without further purification,
[083©] To a solution of 2-feri-butyl-4-ethyi-5-niiro-phenoi (3.2 g, 14.3 mmol) in methanol (20 mL) was added Raney Nickel (200 mg, 3.4 mmol) under nitrogen
atmosphere. The reaction mixture was then stirred overnight at room temperature under an atmosphere, of hydrogen (1 aim). The catalyst was removed by filtration through a pad of
- 265 - 44833.1 celite and the filtrate was evaporated under vacuum to give 5-amino-2-ierr-butyl-4~ethyl- phenol (1.2 g, 43%). Ή NMR (400 MHz, CDC13 ) δ 6.92 (s, i H), 6.06 (s, 1 H), 2.45 (q, 7 = 7.6 Hz, 2 H), 137 (s, 9 H), 1.21 (t, 7 = 7.6 Hz, 3 H). MS (ESI) m/e (M+H ÷ ) 194.2
[0831] 5-amleo~2~iifri~b iyi-4-ii5€ihylphe0o!
Figure imgf000267_0001
[0832] 5-aniino-2-r^butyl~4-methy!pheno3 can be synthesized following the general scheme above starting from 2-ie^butyl-4-methyiphenol. !H NMR (400 MHz, CDCI3) δ 6.91 (s, 1 H), 6.05 (s, 1 H), 4.73 (br s, 1 H), 3.44 (br s, 2 H), 2.09 (s, 3 H), 1.37 (s, 9 H). MS (ESI) m z (M+H*) 179.3.
[0833] Amine Intermediate Example 5: Synthesis of 4-feri-b¾styl-3-fluor asiiilae
Figure imgf000267_0002
[0834] KNO3 (7.5 g, 74,18 mmol) in cone. H2SO4 (50 mL) was slowly added to a mixture of 2-£erf~bety!amime (1 1 g, 73.71 mmol) in cone. H2SO4 (50 mL) at -10 °C. The mixture was stirred at -10 °C for i hour and poured into ice-water. The mixture was extracted with EtOAc ( 150 mL x 3). The combined organics were washed with brine, dried over anhydrous Na2S04 , and purified by silica gel column chromatography to obtain 2-terf-butyl- 5-nitro-aniline (9 g, 63%). lE NMR (400 MHz, CDC13 ) S 7.53 (dd, 7 = 2.8, 8.8 Hz, 1 H), 7.46 (d, 7 = 2.8 Hz, 1 H), 7.34 (d, 7 = 8.8 Hz, 1 H), 4.12 (br s, 2 H), 1.44 (s, 9 H).
[0835] To a stirred solution of 2-ieri-butyI-5-nitro-aniline (5,0 g, 25.74 mmol) in H20 (20 mL) was added cone. HC1 (10 mL). Once dissolved, the mixture was cooled to 0 °C followed by the slow addition of NaNQ2 (1.8 g, 819 L, 25.74 mmol) in ¾0 (10 mL). The reaction mixture was stirred at 0 °C for another 0.5 h. Then HPFg solution was added (2 x 20 mL) batch wise. The precipitate formed was obtained by filtration, which was then heated under infrared light at approximately 130- 150 °C. The grey solid slowly turned to a dark viscous oil, which was purified by silica gel column chromatography to afford 1 -iert-butyl-2- fluoro-4-nitrobenzene (0.6 g, 12%). 5H NMR (400 MHz, CDC13 ) δ 7,96 (dd, 7 = 2.4, 8.8 Hz, 1 H), 7.87 (dd, J = 2.4, 12.0 Hz, 1 H), 7.48 (t, 7 = 8.0 Hz, 1 H), 1.43 (s, 9 H).
- 266 - 44833.1 [0836] NaB¾ (144 mg, 152 μΐ,, 3.8 mmoi) was added to a solution of l-feri-butyl-2- fiuoro-4-nitro-benzene (750 mg, 3.8 mmoi) and Ν1(¾.όΗ2 3 (2.6 g, 1 1 mmol) in methanol (15 mL) at -15 °C. After addition, the mixture was stirred for 2 minutes and water was added to quench the reaction. The reaction mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and evaporated in vacuo to afford 4-ferf-butyI-3-flisoro~aniline (470 mg, 74%) which was used without further purification. !H NMR (300 MHz, CDCI3 ) δ 7.08-7.02 (m, 1 H), 6.42-6,34 (m, 2 H), 1.32 (s, 9 H). MS (ESI) m z: 168.2 [M+H]
[0837] Amine Intermediate Example 6: Synthesis of 4^rf-butyl-3-fluoroaniliiie
Figure imgf000268_0001
oluene
Figure imgf000268_0002
[Θ838] Cone, nitric acid (15.8 mL, 376.9 mmol) was added to a solution of 4- hromoamline (40 g, 232.5 mmol) in H2S04 CH2CI2 (400 mL, 1: 1, v/v) dropwise at 0 °C under an atmosphere of N2. The cooling bath was removed and the mixture was stirred at 20 °C until the starting material was consumed (about 1 h). The reaction mixture was poured onto water and neutralized with NaOH solution to pH~9 and extracted with DCM. The organic layer was dried, filtered and evaporated in vacuo to afford the crude product 4-bromo-3-nitiO-anilines which was used directly in the next step.
[Θ839] 2,2-dimethylpropanoyl chloride (28 g, 232.2 mmol) was added to a stirred solution of 4~hromo-3-nitro-aniiine (42 g, 193.5 mmol) and Et-$N (51 mL, 366 mmol) in anhydrous DCM (200 mL) at 0 °C under an atmosphere of N2. The cooling bath was removed and the stirring was continued at room temperature for 2 h. Be reaction mixture was poured
- 267 -44833. i into ice (500 g) and extracted with CH2CI2. The combined organic layer was dried over Na2SG4 and evaporated in vacuo to afford crude product N-(4-bromo-3- nitropheny pivalamide (55 g, 94%) which was used directly in the next step. !H NMR (300 MHz, CDCI3 ) 5: 8.18-8, 17 (m, 1 H), 7.64-7.63 (m, 2 H), 7.50 (br s, 1 H), 1.32 (s, 9 H).
[084©] Cul (69.8 g, 366.5 mmol) and methyl 2,2-difluoro-2-fluorosulfonyl-acetate (70.4 g, 366.4 mmol) was added to a stirred solution of N-(4~bromo-3-nitro-phenyl)-2,2- dimethyl-propanamide (55.0 g, 182.6 mmol) in anhydrous DMF (300 mL) at room
temperature. The reaction mixture was stirred at 100 °C until the starting material was consumed (about 12 h).The solvent was evaporated in vacuo to afford crude product N-(3- nitro-4-(trifluororaethyl)phenyI)pivalamide (45.0 g, 85%) ), which was used directly in next step without purification. !H NMR (400 MHz, CDC13 ) δ: 8.21 (d, J = 2.0 Hz, 1 H), 7.87 (dd, J = 2.0, 8.8 Hz, 1 H), 7.74 (d, J = 8.8 Hz, 1 H), 7.64 (br s, 1 H), 1.34 (s, 9 H). 19F NMR (282.4 MHz, CDCI3 ): -60,62 (S).
[0841] 2,2-dimethyl-N-[3-nitro-4-(trifluoromethyl)phenyl3propanamide (45.0 g, 155.0 mmol) in 6N HCl (200 ml,) was stirred at 100 °C overnight. The reaction mixture was cooled to room temperature and was carefully neutraiized with solid NaHC03 to pH~9. The reaction mixture was extracted with CH2CI2 and dried over Na2S04. The solvent was evaporated in vacuo to obtain the crude product 3-nitro-4-(trifluoromethyl)anilme (31.0 g, 97%), which was used directly for the next step.
[0842] To a solution of 3-mtro-4-(trifluoromethyl)anUine (31.0 g, 150.4 mmol) in HO Ac (200 mL) was added bromine (9,3 mL, ί 80,5 mmol) at 0 °C under an atmosphere of N2. The cooling bath was removed and the mixture was stirred at 20 °C for 1 h. The solvent was removed in vacuo to afford the crude product 2-bromo-5-nitro-4-(trifluoromethyl)aniline (40.0 g, 93%) , which was used directly in the next step.
[0843] To a solution of 2-bromo-5-nitro-4-(trifluoromethyi)aniline (10.0 g, 35.1 rnmoi) in toiuene/H20 (100 mL, 1: 1, v/v) was added Cul (0.4 g, 2.10 mmol), Et3N (9.5 mL, 68.16 mmol), Pd(PPh3)2Cl2 (5,0 g, 7.12 mmol) and ethynyltrimethylsilane (5.2 g, 53 mmol) successively under an atmosphere of nitrogen at room temperature. The reaction mixture was transferred to a sealed pressure flask and heated at 70 °C for 10 h. The reaction mixture was cooled down to room temperature, filtered, evaporated in vacuo and purified by silica gel column chromatography (1 to 20% EtOAc in petroleum ether as eiuant) to afford 5-nitro-4- (trifluoromemyI)-2-((trimethyIsilyi)ethynyl)aniline (6.0 g, 57%) as yellow solid. !H NMR (300 MHz. CDCS3 ): δ 7.67 is, 1H), 7.13 (s, 1H), 4.86 (br s, 2H), 0.29 (s, 9H),
- 268 -44833. J [0844] To a solution of 5-niiro-4-(trifluoromelhyi)-2~((irimethyisilyl)eihynyl)ariiliRe (6.0 g, 19.85 mmol) in DMF (30 mL) was added Cul ( 1.9 g, 9.976 mmol) under an atmosphere of nitrogen. The reaction mixture was heated at 135 °C in a sealed pressure flask overnight. The reaction mixture was then filtered and the filtrate was washed with water, dried over Na2S0 and concentrated. The crude product was purified by silica gel column
chromatography (5 to 20% EtOAc in petroleum as eluant) to obtain 6-nitro-S- (trifluoramethyl)-lH-indole ( 1.4 g, 31%), !H NMR (400 MHz, CDC13): δ 8.83 (br s, 1 H), 8,15 (s, 1H), 8.1 1 (s, IH), 7.58-7.57 (m, lH), 6.80-6.79 (m, 1H); !9F NMR (282.4 MHz, CDC13 ) : δ -57.82; MS (ESI): m/z [M-H] " 229.
[0845] A microwave via! charged with 6-nicro-5-(trifluoromethyl)- lH-indole (100 mg, 0.43 mmol), t-hutyi bromide (30 mg, 0.22 mmol), zinc triflate (95 mg, 0.26 mmol), TBAI (80 mg, 0.22 mmol), DTEA (63 mg, 0.49 mmol) and toluene (1 mL.) was sealed and heated in the microwave for 10 minutes at 120 °C, The reaction mixture was quenched with water, the layers separated and the aqueous layer was extracted with DCM. The combined organic layer was dried over Na2S04, filtered and concentrated. It was then purified by silica gel column chromatography using 0 to 20% EtOAc in hexanes to obtain 3-£erf~hutyl-0-nitro-5- (trifluoromethyl)- l H-indole. Ή NMR (400.0 MHz, CDC¾) δ 8.25 (s, 1H), 8.10 (s, 1H), 7.33 (d, J = 2.5 Hz, 1H), 7.28 (s, 1H) and 1.50 (s, 9H) ppm.
[0846] A microwave vial charged with 3-ii?ri-butyl-6-niiro-5-(trifiuoromethyi)-iH- indole (95 mg, 0.3319 mmol), SnCl2,2H20 (375 mg, 1.66 mmol) and ethanol (I mL), was sealed and heated at 62 °C for 3 h. The reaction was cooled to room temperature, diluted with EtOAc and quenched with saturated NaHCOs solution until the pH was 7. The reaction mixture was then filtered through a plug of celite. The layers were separated and the organic layer was dried over Na2SQ4, filtered and concentrated. The residue was purified via silica gel column chromatography using 0 to 40% EtOAc in hexanes to obtain 3-teri-butyl-5- (trifluoromethyl)- lH-indol-6-amine. LC MS: m/z 257.3 (M+H)+ at 1.54 min (10%-99%
CH3CN (0.035% TFA)/¾0 (0.05% TFA)).
- 269 -4S33.3 [0847 General Scheme: Preparation of Meta-Substituted Anilines
Figure imgf000271_0001
Suitable solvents include: benzene, toluene, DMSO; suitable cyciization conditions include: NaOAc, AcjO or thionyi chloride, NaOAc; suitable reduction S conditions include: B¾ or L1ALH4 in Et2Q or THF; suitable nitration conditions include: H O3, H2SO4 or KN<¾, ¾S04-, suitable reduction 2 conditions include: Pd/C, H2 or Zn, AcOH or Fe, AcOH
[0848] 3»Cpy rr ildm- l-yI)-S~(tritlTOroia€tliyl)aMlfMe
Figure imgf000271_0002
[0849] 3-(pyrrolidin-I-y!)-5~(trifluoromet!iyl)aniiine can be synthesized following the general scheme above starting from 3-mtro~5-itrifluoromethy anilme and tetrahydrofuran-2,5- dione. LC MS: m/z 230.9 (M+H)+ at 1.22 mm (10%~99% CH3CN (0,035% TFA)/¾0 (0.05% TFA»
Figure imgf000271_0003
- 270 -
8544833.1 [0851] 3-(piperidin-I-yl)-5-(trifluoromethyI)aniiine can be synthesized following fee general scheme above starting from 4-nitro-3-(trifluororaeihyi)antIine and dihydro-2H-pyran- 2,6(3H)-dione. LC/MS: m/z 245.1 (M+H)+ at 0.77 min (I0%-99% CH3CN (0,035%
TFA)/¾0 (0.05% TFA)).
[0852] 3-(piperiiliii->l»yI)-4-(triflisoromethijsy)as¾ilme
Figure imgf000272_0001
[§853] 3-(piperidin-l-yl)-4-(irifluoromeihoxy)aniline can be synthesized following the general scheme above startmg from 4-(trifluoromethoxy)benzene-l,3-dianiine and dihydro- 2H-pyran-2,6(3H)-dione. LC MS: /z 361.3 (M+H)÷ at. 1.15 min ( 10%-99% CH3CN (0.035% TFA)/H20 (0.05% TFA)),
[0854] 3-(py rr ! Ia- l-y!)- -(trl0iioromeihoxy)aiillme
Figure imgf000272_0002
[0855] 3-(pyrrolidin-i-yl)-4-(trifluoroinethoxy)aniline can be synthesized following the general scheme above starting from 4-(trifluororaethoxy)benzene-l,3-diamine and tetrahydrofuran-2,5-dione. LC/MS: m/z 247.1 (M+H)+ at 1.13 min (10%~99% C¾CN (0.035% TFA)/¾G (0.05% TFA)).
- 27! -44833.! Amine intermediate Example 7: Synthesis of 4-ter -biit}rl-3-(pyrro dIsi-i-
Figure imgf000273_0001
[Θ857] To a solution of 2-.¾rt-hutylaniline (1.0 g, 6.7 mmol) in toluene (15 rnL) was added tetrahydrofuran-2,5-dione (0.81 g, 8.1 mniol) and the reaction mixture was ref!uxed for Ih. The reaction mixture was cooled and filtered to obtain
Figure imgf000273_0002
oxobutanoic acid, which was dissolved in acetic acid (20 mL) and sodium acetate (3.02 g, 36.86 mmol) and was stirred at 80 °C overnight. The reaction was quenched with water, the layers separated and the aqueous layer was extracted with DCM. The combined organic layer was dried over MgSO,*, filtered and concentrated. The resulting solid was recrystallized from ethanol, to obtain pure l-(2"iert-butylphenyl)pyrrolidioe-2,5-diorie (930 mg, 60 ). LC/MS: Jz 232.3 (M+Hf at 1.264 mm (10%-99% C¾CN (0.035% TFA)/H20 (0.05% TFA)).
[0858] To a solution of l-(2-terf-butylphenyI)pyrroiidine-2,5-dione (500 mg, 2.16 mmol) in THF (10 mL) was added B¾ in toluene (350 mg, 1.72 mmol) dropwise and the reaction mixture was heated to reflux overnight. The reaction was cooled to room temperature and quenched with methanol (until the evolution of ¾ ceased). The solvent was evaporated to obtain l-(2-feri-butyIphenyl)pyrrolidine (350 mg, 80%) as an oil. !H NMR (400 MHz, CDC¾) δ 7.30 (s, 1H), 7.28 (s, 1H), 7.15 (d, / = 0.9 Hz, 1H), 7.07 - 7.01 (m, IH), 2.90 (s, 4H), 1.88 - 1.78 (m, 4H), 1.35 (s, 9H). LC/MS: mfz 204.1 (M+H)+ at 0.88 min (10%~99% CH3CN
(0.035% TFA)/¾G (0,05% TFA)).
[©§59] l -(2-/eri-butyIphenyl)pyrroIidine (350 mg, 1.72 mmol) was added portionwise to cone. H2S04 (1 mL) to generate a yellow homogeneous solution. The solution was then cooled to 0 °C and O3 (191 mg, 1.9 mmol) was added portionwise maintaining the internal temperature below 5 °C. The reaction was stirred for 2 h and then poured on ice-water and
- 272 -
8544S33.i extracted with DCM, dried over Na2S(>4, filtered and concentrated. The residue was purified by silica gel column chromatography to obtain l-(2~feri-butyl-5~nitrophenyl)pyrroSidine (325 mg, 76%). LC/MS: m/z 248.9 (M+H)+ at 2.39 min (10 -9 % CH3CN (0.035% TFA)/H20 (0.05% TFA)).
A flask charged with l~(2~fe^butyl~5~mtrophenyl)pyrTolidme (150 n g, 0.60 mmol) and Pd/C (15 mg, 0.14 mmol) was flushed imder N2 followed by evacuating under vacuum. Methanol (2 roL) was added under inert atmosphere followed by evacuating under vacuum. The reaction mixture was stirred overnight under an atmosphere of ¾. The reaction mixture was filtered and the solvent was evaporated to give 4-½rt-butyl-3-(pyrrolidin-l- yi)amliiie (119 mg, 90%). LC/MS: m z 218.5 (M+H)+ at 2 rain (10%-99 CH3CN (0.035% TFA)/H20 (0.05% TFA)),
Figure imgf000274_0001
[0862] 4-½rf4>uiyi-3-(piperidin-l-yl)amHne can be synthesized following the general scheme above starting from 2~½rf-butylanilme and dihydro-2H-pyran-2,6(3H)-dione . LC/MS: m/z 232.9 (M+H)+ at 1.23 min (10%-99% CH3C (0.035% TFA)/H20 (0.05% TFA)).
[0863] Preparation of Para-Substituted Anilines
s
Suitable solvents include:
Figure imgf000274_0002
benzene, tolue iization conditions include:
NaOAc, Ac 0 or thionyl chloride. NaOAc; suitable reduction 1 conditions include: BH3 or
- 273 -
S544S33.1 LiALHLj in Et20 or THF; suitable nitration conditions include: HNO3, H2SO4 or K O3, H2SO4; suitable reduction 2 conditions include: Pd/C, ¾ or Zn, AcOH or Fe, AcOH.
¾864] Preparation of Para-Substituted Anilines via SNAT Chemistry
Figure imgf000275_0001
Suitable bases include: triethylamine, potassium terl-biiioxkle, diisopropyiethylamine, potassium carbonate; suitable solvents include: DMSO, DMF, CH3CN, THF; suitable reduction conditions include: Pd/C, H2; Zn, AcOH, Fe, AcOH. is of 4-CpyrroIidta»l-y!)-2~
Figure imgf000275_0002
[0866] To a solution of 4~ni†ro~3~(trifluoro) aniline (2.0 g, 9,7 mmol) in toluene (30 mL) was added dihydrofuran-2,5-dione (1 ,16 g, 1 1.6 mmol) and reaction was reflux for 5 h The reaction mixture was cooled to room temperature and filtered. The precipitate was w with ether and dried to provide 4-(4-nitro-3~(rrifluoron ethyl)phenylaraino)-4-oxobutanoic (Li g, 37%). LC/MS: tnfz 307,3 (M+H)+.
- 274 -
S5 4S33.i [0867] A solution of 4-(4-ni ro-3-(irifjuoromethyl)p esiy!amino)-4-oxobutanoic acid (L g, 3.6 mmol) and NaOAc ( 1.62 g, 19.75 mmol) in acetic anhydride (15 mL) was stirred overnight at 80 °C. The reaction mixture was diluted with water and extracted twice with dichlorometharie. The organic layers were combined and washed with NaOH (1 ) until pH was 9. The organic layer was separated, dried with MgSQ*. filtered and concentrated in vacuo to provide l-(4-nitro-3-(triflisoromethyi)pheEyI)pytTolidine-2,5-dione (0.4 g, 39%), LC/MSi m/z 288.9 (M+H)+.
[ 86S] To a solution of l-(4-nitro-3-(trifiuoromethyl)phenyi)pynOlidine-2,5-dione (400 mg, 1.38 mmol) in THF (10 mL) was added 1 M BH3 solution in THF (1 1.10 ml) dropwise over 5 min. The reaction mixture was refluxed for 16 h under inert atmosphere, cooled, then quenched with MeOH and concentrated in vacuo. The crude product was used for the next step without purification. LC MS: trs z 261.1 (M+H)+.
[0869] A solution of i-(4-nitro-3-(tritluoromethyl)phenyS)pyrrolidme (350 mg, 1 ,34 mmol) in methanol (2 mL) and Pd C (30 mg, 0.3 mmol) were stirred for 16 h under ¾. The reaction mixture was filtered and the solvent evaporated in vacuo to provide 4-(pyrroIidin-l- yl 2-(trifluoromethyl)aniline (0.3 g, 97%). LC/MS: m/z 231.3 (M+H)+. Ή NMR (400 MHz, DMSO-dd) δ 6.84 (d, J = 8.8 Hz, 1H), 6.72 (dd, J = 8.8, 2.5 Hz, 1H), 6.53 (d, J = 2.7 Hz, IB), 4.74 (s, - 3.11 (m, 4H), 2.00 - 1.93 (m, 4H).
Figure imgf000276_0001
[0871] 4-(piperidin-l-yl)-2-(trifluoromethyl)aniline can be synthesized following the general scheme above starting from 4-nitro-3-(trifluoromethyl) aniline and dihydro-2H-pyran- 2,6(3H)-dione. Ή NMR (400.0 MHz, DM$0-d6) δ 7.08 (dd, = 2.7, 8.8 Hz, 1H), 6,88 (d, J = 2.8 Hz, 1H), 6.83 (d, = 8.9 Hz, 1H), 5.09 (s, 2H), 2.96 (t, / = 5.4 Hz, 4H), 1.67 (q, / = 5.5 Hz, 4H) and 1.55 - 1.42 (m, 2H) ppm. LC MS: m/z 244.9 (M+H)+ at 0.67 min (10%-99% CH3CN (0.035% TFA)/¾Q (0.05% TFA)).
- 275 -44833. ί [§872] 2»mef fayi-4-(pyrroii hi- 1- ijamlisie
Figure imgf000277_0001
[0873] 2-methyi-4-(pyrrolidin-i-yl)aniline can be synthesized following the general scheme above starting from 3~methyI~4~nitroaniline and tetrahydrofuran-2,5-dione. 'H NMR (400.0 MHz, OMSO-de) δ 6.56 (d, / = 8.4 Hz, 1H), 633 (d, J = 2.6 Hz, 1H), 6.27 (dd, / = 2.7, 8.4 Hz, 1H), 4.10 (s, 2H), 3.13 (t, J = 6,5 Hz, 4H), 2.09 - 2.04 (m, 3H) and 1.99 - 1.90 (m, 4H) ppm. LC/MS: m/z 177.3 (M+H)+ at 0.35 min ( J 0%-999 CH3CN (0.035% TFA)/¾0 (0.05% TFA)).
[0874] Amine Jntennediate Example 8; Synthesis of l,4,4-trimethyl-l,2,3,4-
Figure imgf000277_0002
[0875] To a solution of ierf-butyl 7-amino-4,4-dimethyl-2,3-dihydroquinoline- l- carboxyfate (100 nig, 0.36 mmol) in THF (2.2 mL) under an inert atmosphere was added UAIH4 (1.8 mL of 1 M, 1.8 mmol) dropwise. The reaction mixture was heated to reflux and stirred for 4 h. The reaction was cooled to room temperature and quenched with of 0.4 M NaOH solution (0.6 mL), the aqueous layer was extracted with DCM, dried over a2S04, filtered and concentrated to an orange oil. The residue was purified via reverse phase HPLC. LC/MS: m/z 191.5 (M+H) ÷ at 0.92 min (10%-99% CH3CN (0.035% TFA)/H20 (0.05% TFA)).
- 276 -
8544S33.1 [0S76] Amine Intermediate .Example .9: Synthesis of 5-(besKyI∞y)»4-cycIohexyf»2- oromethy!)afflll5ie
Figure imgf000278_0001
[0877] To a stirring solution of 2~eycSohexylphenol (26.0g, 146,8 mraoi) in glacial acetic acid (100 mL) was added HBr in acetic acid (150 mL of 33 %w/w, ) and ¾0 (52 mL), followed by the dropwise addition of DMSO ( 100 mL) over 10 mm. The reaction was then carefully quenched with saturated NaHC<¾ and concentrated in vacuo. The residue was brought up in ether (400 mL), washed with water (2 x 100 mL) and brine (1 x 100 mL), and dried over anhydrous Na2SC>4, filtered and concentration to yield a crude oil that was purified by silica gel column chromatography, using 15-30% EtOAc/hexane gradient to yield 4~bromo- 2-eyclohexyS-phenoi (35.0 g, 93%)
[0878] 4-Bromo-2-cyclohexyl-phenol (35.0 g, 137,2 mmol) was dissolved in DCM (200 mL) and Et3N (38 mL, 272.6 mmol), cooled to 0 °C, then treated with methyl chloroformate (15.0 g, 153.4 mmol) and allowed to warm to room temperature over 16 h. The reaction was quenched with 30 mL saturated NaHCC , washed with 50% saturated NaHCOj ( 1 x 100 niL) and brine (1 x 100 mL), then dried over anhydrous Na2SC>4, filtered and concentrated to yield a crude oil that was purified by silica gel column chromatography, using 20% EtOAc/hexane gradient to yield (4~bromo~2-cyclohexyl-phe!iyI) methyl carbonate (38.0 g, 88%) as a colorless oil. lB NMR (400 MHz, CDC13) 8 7.41 (d, J = 2.3 Hz, 1H), 7.32-7.29
), 6.98 (d, J = 8.6 Hz, 1H), 3.92 (s, 3H), 2.71-2.64 (m, 1H), 1.85- 1.74 (m, 5H), 1.39- 1.20 (m, 5H).
[0879] (4-Bromo-2-cyclohexyl-phenyl) methyl carbonate (5.0 g, 15.96 mmol) was added portionwise to cone. H28G4 ( 15 mL) to generate a colorless homogeneous solution. This solution was then cooled to 0 °C and KNO3 (1.77 g, 17.51 mmol) was added portionwise maintaining the internal temperature below 5 °C. Be reaction was stirred for 2 h and then
- 277 -
8544833.! poured on ice water and the aqueous layer was extracted with DCM (3 x 10 mL). The combined organic layer was dried over Na2SC>4, filtered and concentrated. The residue was then purified by silica gel column chromatography using 10% EtOAc hexane gradient, to yield 4-brorno-2-cydohexyl-5-nitro- phenyl methyl carbonate (3,25 g, 58%). Ή NMR (400 MHz, CDC1 3 ) δ 7.80 (s, lH), 7.69 (s, 1H), 3.98 (s. 3H), 2.81-2.75 (m, 1H), 1.90-1.79 (m, 5H), 1.44- 1.26 (m, 5H)
[088©] To a solution of (4-bromo-2-cyclohexyl-5-nitro-phenyI) methyl carbonate (1.5 g. 4.2 mmol) in methanol (15 mL) was added OH (353 mg, 6.3 mmol) portionwise at 0 °C. After addition, the reaction mixture was allowed to warm to room temperature and stirred for 3 h. The reaction mixture was acidified with IN HQ. The solvent was evaporated and water was added. The aqueous layer was extracted with DCM (3 x 10 mL). The combined organic layer was dried over Na2S0 , filtered and concentrated to give 4-bromo-2-cyclohexyl-5- nitrophenol (1.2 g, 95%). *H NMR (400 MHz, CDQ3 ) δ 7.50 (s, 1 H), 7.39 (s, 1H), 5.10 (s, 1H), 2.90-2.83 (m, 1H), 1.91-1.89 (m, 4H), 1.83- 1.80 (m, 1 H), 1.51-1.24 (m, 5H)
[0881] To a solution of 4-bromo-2-cyclohexyl~5-nitro-phenol (1.19 g, 4.0 mmol) and CS2CO3 (1.54 g, 4.72 mmol) in DMF (10 mL) was added benzyl bromide (1.02 g, 707 μί, 6,0 mmol) dropwise. The reaction mixture was stirred at room temperature under an inert atmosphere for 2 h. The reaction was quenched with water and the aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layer was dried over Na2S04, filtered and concentrated. The residue was purified by silica gel column chromatography using 5% EtOAc hexane gradient gave i-(benzyloxy)-4-bromo-2-cyciohexyl-5-nittObenzene (1.35 g, 87%). Ή NMR (400 MHz, CDC13 ) δ 7.42 (s, 1H), 7.39 (s, 1H), 7.36-7.25 (m, 5H), 5.06 (s, 2H), 2.99-2.93 (m, 1H), 1.79 (d, / = 1 1.5 Hz, 4H), 1.70 (d, / = 13.4 Hz, lH), 1.39-1.14 (m, 5H)
[0882] To a solution of l-benzyloxy-4-bromo-2-cyclohexyl-5-nitro-benzene (500 mg, 1.28 mmol) and Cul (487.0 mg, 2.56 mmol) in DMF (5 mL) at room temperature was added methyl 2,2-difluoro-2-fluorosulfonyi-acetate (492 mg, 326.0 mL, 2.56 mmol) dropwise under an inert atmosphere. The reaction mixture was then heated at 105 °C for 2 h. The reaction mixture was cooled to room temperature, quenched with NaHC03 and filtered through a plug of celite (to remove Cu salts). The aqueous layer was extracted with ethyl acetate, dried over 2S04, filtered and concentrated. The residue was purified by silica gel column
chromatography using 10% EtOAc hexane gradient to yield l-(benzyloxy)-2-cyclohexyl-5- nitro-4-(trifluoromethyl)benzene (435 mg, 90%). ¾ NMR (400 MHz, CDCI3 ) δ 7.77 (s, 1H),
- 278 -44833.1 7.62 (s, IK), 7.42-7.28 (m, 5H), 5.27 (s, 2H), 2.98-2.92 (m, 1H), 1.75-1.62 (m, 5H), 1.47-1.13 (m, 5H)
[§883] To a solution of l-(benzyloxy)-2-cyc!ohexyl-5-nitro-4- (trifluoromethyl)benzeiie (250 mg, 0.66 mmol) and NiC!2 (170 mg, 1.31 mmol) in methanol (2.5 mL) was added NaB¾ (50 mg, 1.32 mmol) poriionwise at 0 °C. The reaction mixture turned black after 5 minutes. The reaction mixture was quenched with NaHC03 and diluted with EtOAc. The reaction mixture was filtered through a plug of celite, the layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layer was dried over Na2SC¼, filtered and concentrated. The residue was then purified by silica gel column chromatography using 10% EtQAc hexane gradient to give 5-benzyioxy-4- cyclohexyl-2-(trifluoromethyl)aniline (150 mg, 65%). LC/MS: m z 350.3 (M+H)+ at 2.40 min (10%-99% CH3CN (0.035% TFA)/H 2 O (0.05% TFA)).
[0884] 5-(beiK l0xy)"-4-Isopropyl'-2-(triflMoromethyI)aiilIiffie
Figure imgf000280_0001
[§885] 5-(benzyloxy)-4-isopropyI-2-(trifluoromethyi)amline can be synthesized following the general scheme above starting from 2-isopropylphenol. LC MS: m/z 310.3 (M+H)+ at 2.21 min (10%-99% CH3CN (0.035% TFA)/¾0 (0.05% TFA)).
[Θ886] 4-bromo-2-cyd ethyl carbonate
Figure imgf000280_0002
[0887] 4-bromo-2-cyclopeniyl-5-nitrophenyl methyl carbonate can be synthesized following the general scheme above starting from 2-cyc!openiyiphenoI). !H MR (400,0 MHz, DMSOi¾ δ 8.12 (s, 1H), 7.88 (s, 1H), 3.88 (d, J = 5.7 Hz, 3H), 3.13 (dd, J = 9.4, 17.2 Hz, 1H), 1.96 - 1.92 (m, 2H), 1.80 - 1.75 (m, 2H), 1.68 - 1.54 (m, 4H).
- 279 -
8544S33.1 [0888] Amine Intermediate Example 10: Synthesis of 5-(bera;yIosy)-2- !5S0ro~4-
Figure imgf000281_0001
[0889] A solution of 2-bromo-4-fluoro-phenol (7.0 g, 36.65 mraol) and DMAP (224 mg, 1.83 mmol) in DCM (15 mL) and Et3N (7.42 g, 10 mL, 73.30 mmol) was cooled to 0 °C, then treated with methyl chloroformate (14,5 g, 153.4 mmol) dropwise and allowed to wann to room temperature over 16 h. The reaction mixture was quenched with 30 mL saturated NaHC03, washed with 50% saturated NaHCQj ( 1 x 100 mL) and brine ( 1 x 100 mL). The organic layer was then dried over anhydrous Na2SG4, filtered and concentrated to yield a crude oil that was purified by silica gel column chromatography, using 15% EiQAc/hexane gradient to yield (2-bromo-4-fluoro-phenyl) methyl carbonate (8.25 g, 90%). Ή NMR (400 MHz, CDC13) δ 7.38 (dd, J = 7.7, 2,9 Hz, 1H), 7.23 (dd, J = 9.0, 5.0 Hz, 1H), 7.08 (ddd, J = 9.0, 7.6, 2.9 Hz, IH), 3.97 (s, 3H). i9F NMR (376 MHz, CDC13) δ -1 13.78 (td, J = 7.9, 5.2 HE, 1H).
[0890] (2-Bromo-4-fiuoro-phenyl) metliyi carbonate (8.25 g, 33.13 mmol) was added portionwise to cone. H2SG4 (45 mL) to generate a colorless homogeneous solution. This solution was then cooled to 0 °C and KNO3 (3.7 g, 36.44 mmol) was added portionwise maintaining the internal temperature below 5 °C. The reaction was stirred for 2 h and then poured on ice-water and the aqueous layer was extracted with DCM (3 x 10 mL). The combined organic layer was dried over Na2SG , filtered and concentrated. The residue was then purified by silica ge! column chromatography using 15% EtOAc hexane gradient to yield
2-brorao-4-fluoro-5-nitrophenyl methyl carbonate (8.93 g, 92%) !H NMR (400 MHz, CDC13)
S 8.05 (d, J = 6.7 Hz, 1H), 7.65 (d, / = 9.6 Hz, 1H), 4.01 (s, 3H).
- 280 -4833.1 [0891] To a solution of 2-brorao-4-fluoro-5-nitrophenyl methyl carbonate (8.90 g. 30.27 mmol) in methanol (100 mL) was added KOH (4,25 g, 75.68 mmoi) portiomvise at 0 °C. After the addition was complete the reaction mixture was allowed to warm to room
temperature and stirred for 1.5 h. The reaction mixture was acidified by IN HC1. The solvent was evaporated and water was added. The aqueous layer was extracted with DCM (3 10 mL). The combined organic layer was dried over Na2S04, filtered and concentrated to give 2- bromo-4-fluoro-5-nitro-phenol (7.05 g, 99%). *H NMR (400 MHz, CDC13) δ 7.75 (d, J = 6.6 Hz, 1H), 7.51 (d, J = 9.6 Hz, 1 H), 5.62 (s, !H).
[0892] To a solution of 2-bromo-4-fiuoro-5~nitro- phenol (3.5 g, 14.83 mmol) and
CS2CO3 (5.80 g, 17.80 mmol) in DMF (26 mL) was added benzyl bromide (2.80 g, 1.94 mL, 16,31 mmol) dropwise. The reaction was stirred at room temperature under an inert atmosphere for 2 h. The reaction was quenched with water and the aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layer was dried over Na2S04, filtered and concentrated. The residue was purified by silica gel column chromatography using 40% DCM/hexane gradient to yield l-(benzySoxy)-2-bromo-4-fluoro-5-nitrobenzene. !H NMR (400 MHz, CDCI3) δ 7.65 (d, J = 6.4 Hz, lH), 7.59 (d, J = 9.9 Hz, lH), 7.52 - 7.34 (m, 5H), 5.23 (s, 2H).
[0893] To a solution of l-benzySoxy-2-bromo-4 1uoro-5-nitro-benzene (500 mg, 1 ,53 mmoi) and Cui (584 mg, 3.07 mmol) in DMF (5 mL) at room temperature was added methyl 2,2-difluoro-2-fluorosulfonyl-acetate (589.0 mg, 3.07 mmol) dropwise under an inert atmosphere. The reaction mixture was then heated at 105 °C for 3 h, then cooled to room temperature, quenched with NaHC<¾ and filtered through a plug of celite (to remove Cu salts). The aqueous layer was extracted with ethyl acetate, dried over N&2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography using 10% EtOAc/hexane gradient to give l-(benzyloxy)-4-fluoro-5-m^-2-(trifluoromethyl)benzene (400 mg, 83%). [H NMR (400 MHz, CDC¾) δ 7.71 (d, J = 5.7 Hz, 1H), 7.62 - 7.57 (m, 1H), 7.48 - 7,37 (m, 5H), 5.27 (s, 2H). !9F NMR (376 MHz, CDC13) 8 -63.28 (s, 3H), -126.02 (dd, J = 10.2, 5.7 Hz, 1H).
[0894] To a solution of l-(benzyloxy)-4~fluoro-5-nitro-2-(trifSuoromethyl)benzerie (382 mg, 1.21 mmol) and NiCl2 (3 4 mg, 2.42 mmol) in methanol (40 mL) was added MaBEL* (50 mg, 1 ,32 mmol) portionwise at 0 °C. The reaction turned black after 20 minutes. The reaction mixture was quenched with NaHC03 and diluted with EtOAc. The reaction mixture was then filtered through a plug of celite, the layers separated and fee aqueous layer was extracted with EtOAc. The combined organic layer was dried over Na2SC>4, filtered and
- 281 -44833.1 concentrated. Be residue was then purified by silica gel column chromatography using 15% EtOAc/hexane gradient to give 5-(benzyloxy)-2-fiuoro-4-(trifluoroJTietliyl)ariiIine (150 mg, 43%). LC/MS: m/z 286, 1 (M+H)÷ at 1.89 mm (10%-99 CH3CN (0.035% TFA)/H2G (0.05% TFA)).
|OS9§] Amine Intermediate Example 1 1 : Synthesis of (1S,4^)"2- a¾aMcyclo[2,2.1 Jfee tasie
Figure imgf000283_0001
[0896] A cooled solution of ( IS)- l-phenylethanamine (19.0 g, 156.8 mmol) in H2Q (60 mL) at 0 °C was treated with a solution of glacial acetic acid (9 mL) in water (20 mL), followed by the addition of freshly distilled cyciopentadiene (20.73 g, 26.01 mL, 313.6 mmol) and formaldehyde (7.06 g, 6.5 mL, 235.2 mmol). The resulting reaction mixture was stirred for 48 h at 5 °C. The reaction mixture was then poured onto ice water (100 mL) and 50% ethyl acetate in hexane (100 mL) and then basified with NaOH pallets (pH -10) at 0 CC. The layers were separated and the aqueous layer was extracted with 50% ethyl acetate/hexane (2x 100 mL). The combined organic layer was dried over Na2SC>4, filtered and concentrated under reduced pressure to get a mixture of (li?,4^)-2-((S)-l -phenylethyl)-2-azabicyclo[2,2Jlhept-5- ene and (1.5,4iS)-2-((S)-l-phenylethyl)-2-azabicyclo[2.2.l]hept-5-ene as an oil (33,0 g). The product is prone to undergo retro-Dieis-Alder reaction, so it was directly used for the next step. LC/MS: m/z 199.8 (M+H)* at 0.38 min (!0%-99% CH3CN (0.035% TFA)/H20 (0.05% TFA)).
[0897] To a solution of (2i?,3.R)-2,3-dibenzoyloxybutanedioic 3£.{^ (55,75 gs 155.6 mmol) in acetone (500 mL) was added a solution of (li?,4/?)-5-[(15)-l-phenylethyl]-5- azabicyclo[2.2.1 ]hept-2-ene and ( 1 S,45)~5- [( S)- 1 -phenyiethyl] -5-azabicyclo[2,2.1 ]hept-2-ene (31,01 g, 155.6 mmol) in acetone (200 mL) dropwise. The reaction mixture was stirred for 15 h at room temperature. The precipitate formed was collected by filtration and washed with acetone (2x 75 mL) and dried under reduced pressure. The residue was slowly added to cooled (0 °C) 10 % NaOH (350 mL) and ethyl acetate (300 mL) solution and stirred for 15 minutes (pH 10). The layers were separated and aqueous layer was extracted with ethyl acetate (3x 150
- 282 -44833. t mL). The combined organic layer was dried over Na SQ4; filtered and concentrated under reduced pressure to obtain (l/?,4i?)-2-((S)-l-phenylethyl)-2-azabicyclo[2.2.1]hept-5-ene, which was used directly used for the next step. LC/MS: m/z 199.8 (M+H)+ at 0.38 mm (10%- 99% CH3CN (0.035% TFA)/H20 (0.05% TFA)).
[0898] A flask charged with (liJ^-S-filSJ-l-p enykthylj-S-azabicycloll aihept- 2-ene (19 g5 95.34 mmol) and palladium on carbon (4 g, 133.0 mmol) was flushed with N2 followed by evacuating under vacuum. EtOAc (50 mL) and EtOH (200 mL) were added under inert atmosphere followed by evacuating under vacuum. The reaction mixture was then stirred overnight under an atmosphere of ¾. AcOH (60 mL) was added and then the reaction mixture was stirred overnight at 55 °C under an atmosphere of ¾. The reaction mixture was cooled to room temperature and filtered through a plug of ce!ite to remove the palladium catalyst, washed with ethyl acetate, concentrated in vacuo and the residue was treated with IN HC1 solution in ether. The solvents were evaporated under reduced pressure to obtain ( iS,4J?)-2~ azabicyclo[2.2.1]heptane .
089 ] Amine intermediate Example 12: Synthesis of (S)-4-(2-methy!pyrroI te-l-
Figure imgf000284_0001
To a solution of 5-fiuoro-2-nitrobenzotrifluoride (2.0 g, 9.56 nimol) in C¾CN (20 mL) was added Et3N (2.41 g, 23.90 mmol) followed by the addition of (5 2- methylpyrrolidine tosylate (3.18 g, 12.43 mmol). The reaction was stirred at 80 °C overnight. The reaction was then quenched with water and the aqueous layer was extracted with DCM. The combined organics were washed with IN HCi, dried over MgSO-s, filtered and concentrated to give (S)-2-methyI-l-(4-nitro-3-(trifluorornethyl) phenyl) pyrrolidine (2.45 g, 94% yield). Ή NM (400 MHz, DM80-<¾) δ 8.11 (d, J = 9.1 Hz, lH), 6.88 (s, lH), 6.85 (d, /
= 2.6 Hz, 1H), 4.17-4.13 (m, ill), 3.59-3.54 (m, 1H), 3.33-3.28 (m, 1H), 2.14-2.00 (m,
1.80-1.71 (m, 1H), 1.14 (d, / = 6.3 Hz, 3H). LC MS: m/z 275.3 (M+H)+ at 1.98 min (10%-
99% C¾CN (0.035% TFA)/H20 (0.05% TFA)).
[0901] A flask charged with (S)-2-rnethyl-l-(4-nitro-3-(trifluoromethyI) phenyl) pyrrolidine (2.45 g, 8.9 mmol) and palladium on carbon (245 mg. 10 wt %) was flushed with N2 followed by evacuating under vacuum. Methanol (15 mL) was added under inert
- 283 -44S33.! atmosphere followed by evacuatin under vacuum. The reaction mixture was stirred overnight under an atmosphere of H2. The palladium catalyst was removed by filtration and solvent was removed under reduced pressure to give (5 4-(2-methylpyrrolidin- l-yl)-2-(irifluorornethyi) aniline in quantitative yield, {H NMR (400 MHz, DMSO-de) δ 6.78 (d, J = 8.8 Hz, IH), 6.70- 6.67 (m, IH), 6.47 (d, J = 2.1 Hz, IH), 4.68 (s, 2H), 3.76-3.69 (m, 1H), 3.32-3.27 (m, 1H), 3.02-2.96 (m, IH), 2.05-1.94 (ra, 2H), 1.93-1.84 (m, IH), 1.64-1.58 (m, IH), 1.05 (<L / = 6.1 Hz, 3H). LC/MS: ro% 245,1 (M+H)+ at 0.48 min (1Q%™99% CH3CN (0.035% TFA) H20 (0.05% TFA)).
[09023 The following compounds can be prepared following the general scheme above.
[0903] (^)~4 2~Methylpyrro!id rifliior©metfe l)aiiilme
Figure imgf000285_0001
[0904] (i?)-4-(2-Methylpyrrolidin- l-yl)-2-(trifluoromethyl)amline can be synthesized following the general scheme above starting from 5-fiuoro-2-nitrobenzotrifluoride and (R}-2~ methylpyrrolidine. 5H NMR (400.0 MHz, DMSO-t¼) 3 6.79 (d, J = 8.8 Hz, IH), 6.68 (dd, ./ = 2.3, 8.7 Hz, IH), 6.47 (d, ./ = 2.5 Hz, IH), 4.69 (s, 2H), 3.73 (t, J = 5,6 Hz, I H), 333 - 3.27 (m, IH), 2.99 (q, / = 8.0 HE, IH), 2.03 - 1.87 (m, 3H), 1.64 - 1 ,60 (m, IH) and 1.05 (d, J = 6.1 Jiz, 3H). LCMS: rn/z 245.3 (M+H)* at 0.57 min (10%~99 CH3CN (0.035% TFA)/¾G (0.05% TFA)).
[0905] 4*M0rph lmo~2-(trifl¾or msthyl)¾BillBe
Figure imgf000285_0002
[Θ906] 4-Morpholino-2-(trifluoromethyl)aniline can be synthesized following the general scheme above starting from 5-fluoro-2-nitrobenzotrifluoride and morpholine. ¾ NMR (400.0 MHz, DMSG-6Q «5 7.04 (dd, J = 2.6, 8.9 Hz, IH), 6.84 - 6.79 (m, 2H), 5.07 (s, 2H), 3.71 (t, J = 4,7 Hz, 4H) and 2.93 (l, J = 4.7 Hz, 4H). LC MS: n*¾ 247.1 (M+H)+ at 0.43 min (I0%-99% CH3CN (0.035% TFA)/¾0 (0.05% TFA)). [0907] 4-(3 "B5melhylpyrroHd rll eoromeihyl)aisilii5e
Figure imgf000286_0001
[§908] 4-(3 -Dimethyipyrroiidin-l-yi)-2-(irifluoromethyl)aniiine can be synthesized following tlie general scheme above starting from 5-fluoro-2-nitrobenzotrifS oride and 3,3- dimethylpyrrolidine. LC M.S: m/z 259.1 (M+H)+ at 1.18 min (lG%-99% CH3CN (0,035% TFA)/H20 (0,05% TFA)).
[0909] 4-(3~Meihylpyrrolid¾->l- iioromethyl)aelitae
Figure imgf000286_0002
[0910] 4-(3-MethyipynOiidin-l-yl)-2-(trifluofomethy1)ani!ine can be synthesized following tlie general scheme above starting from 5-fluoro~2~nitxobenzotrif!uoride and 3- methylpynolidine. *H NMR (400.0 MHz, DMSG~£¾ δ 6.78 (d, 7 = 8.8 Hz, 1H), 6.64 (dd, 7 = 2.5, 8.8 Hz, 1H), 6.44 (d, 7 = 2.7 Hz, 1H), 4.67 (s, 2H), 3.31 (t, 7 = 7.6 Hz, 1H), 3.20 - 3.15 (m, 2H), 2.73 - 2.69 (m, 1H), 2,33 (dd, 7 = 7.0, 15, 1 Hz, lH), 2.10 - 2.04 (m, 1H), 1.54 (id, 7 = 8.2, 4,0 Hz, 1H) and 1.06 (d, 7 = 6,7 Hz, 3H) ppm. LC/MS: m z 245.1 (M+H)+ at 0.94 min ( 10%-99% CH3CN (0.035% TFA)/H20 (0.05% TFA)).
[0911] 4-(Azeiidis-l-y!)»2-(trlfl oromeihyI)aeaisse
Figure imgf000286_0003
[0912] 4-(Azetidin-l-yl)-2-(trifiuoromethyl)aniline can be synthesized following the general scheme above starting from 5-fluoro-2-nitrobenzotrifluoride and azetidine. LC/MS: m/z 217.3 (M+H)+ at 0.34 min (10%-99% CH3CN (0.035% TFA)/H20 (0.05% TFA)).
- 285 -4 S33.I
Figure imgf000287_0001
[§914] (JK)-l-(4-Amino-3-(tiifl orome&yl)phenyl)-N,N-dimethylpyrroSidin-3-an ine can be synthesized following the general scheme above starting from 5-fluoro-2- nitrobenzoirifluoride and i^)-N,N-dimethylpyrroiidin-3-amine. LC MS: /z 274.5 (M+H)"' at 1.32 min (1Q%~99% CH3CN (0.035% TFA)/H20 (0,05% TFA)).
[0915] (E)~teri-B tyl 1-(4"S5miio~3-(irifl 5oroMethyi)pfee¾yl)pyrro liiie»2- carbosylate
Figure imgf000287_0002
[0916] (R)-tert-Eutyl l-(4-amino~3-(trifluoroineihyl)phenyl)pyrrolidine-2-carboxylate can be synthesized following the general scheme above starting from 5-fluoro~2- niirobenzotrif!uoride and (R}-tert-buiy\ pyrrolidine-2-earboxylate. LC/MS: m/z 331.5 (M -H)+ at 1.70 min (10%-99% CH3CN (0.035% TFA)/H20 (Q.05% TFA)).
[0917] (S)-ferMkstyl l-i4-¾imffi -3»(irItlii rom«ihj'l)phei5yl)pyrrolidme-2- carboxylate
Figure imgf000287_0003
[§918] (S)-iert~Bui ] 1 -(4-amino-3~(trifiuoromethyl)phenyl)pyrrolidine-2-carboxylaie can be synthesized following the general scheme above starting from 5-fiuoro-2-
- 286 -44833.! mtrohenzoirifluoride and (S)-te rt-bu yi pyrro!idine-2-carboxylate, LC/MS: m z 331,5 (M+H) at 1.70 roin (10%-99% CH3CN (0.035% TFA)/H20 (0.05% TFA)).
[Θ 19] 4-(4-Is< propyipipera¾iis--i-yI)-2-(trillisoromethy!)aallisie
Figure imgf000288_0001
[§920] 4-(4-Isopropylpiperazin- l -yl)-2-(irif!uoromethyI)ani!ine can be synthesized following the general scheme above starting from 5~fluoro-2~mtrobenzotrifluoride and 1- isopropylpiperazine. Ή NMR (400.0 MHz. DMSOK¾) δ 7.02 (dd, J = 2.6, 8.8 Hz, 1 H), 6.82 - 6.77 (m, 2H), 5.03 (s, 2H), 2.95 - 2.92 (m, 4H), 2.65 (t, J = 6.5 Hz, 1 H), 2.56 - 2.50 (m, 4H) and 0.99 (d, / = 6.5 Hz, 6H) ppm. LC/MS: m/z 288.3 (M+H)+ at 0.97 mm ( 10%~-99% CH3CN (0.035% TFA)/H2G (0.05% TFA)),
[0921] ( ?)-(l-(4-aralno~3~(infl¾oromeihyi)pheHyi)pyrroIidm-2-yI)m«t aisol
Figure imgf000288_0002
[§922] (/?)-( l-(4~amino-3-(frifiuoiOmeihyI)phenyl)pyrroiidin-2-yl)methanoI can be synthesized following the general scheme above starting from 5-fluoro-2-nifrobenzotrifluoride and (R)-pyiTOlidin-2-ylmethanol. LC/MS: m/z 261 .1 (M+H)+ at 0.90 min (10%-99% C¾CN (0,035% TFA)/H20 (0.05% TFA)).
[0923] (S)-(l-(4-Aml¾< -3-(trifloor0mefhyI)phesiyI)pyrroIidiii-2-yI)m®thaE I
Figure imgf000288_0003
[Θ 24] (5)-(i-(4-Amino-3-(trifluoromethyi)phenyi)pyn lidm-2-yl)methanol can be synthesized following the general scheme above starting from 5-fluoro-2-nitrobenzotrifluoride and (S)-pyiTOlidin-2-ylmethanol. LC/MS: /z 261.1 (M+H)+ at 0.91 min (10%~99% G¾CN (0.035% TFA)/H20 (0.05% TFA)).
• 287 -
854 S33.I [Θ925] (l-(4-Amteo-3-(trifl oroMeihy!)p e¾yI)p!peridls5~4~yl)meihais©l
Figure imgf000289_0001
[Θ926] (l-(4~Amino-3-(iTifluoromet yl)phenyi)piperidin-4-yl)niethaiiol can be synthesized following the general scheme above stalling from 5-fluoro-2-nitrobenzotrifluoride and piperidin-4-ylmethanol. LC/MS: m/z 275.3 (M+H)+ at 0.91 min (10%-99% CH3CN (0.035% TFA)/H20 (0.05% TFA)).
[Θ927] (S)-1^4-Amlno-3-(trif!iioromethyi)pheiiyl)~N,N-dlmeihyipyrrolldin~3- amitie
Figure imgf000289_0002
[0928] ($)- 1 -(4-Amino-3-(trifluoromei yl)phenyi)-N,N-dimethylpym>i idm-3-amine can be synthesized following the general scheme above starting from 5-fluoro-2~
nitrobenzotrifluoride and (5)-N,N-diinethy!pyrroiidin-3-amine. LC MS: m/z 274.1 (M+H)+ at 0.78 min (10%- 9% CH3CN (0.035% TFA)/H20 (0.05% TFA)).
[0929] (S)-l-(4-AriMKO-3-{ rifl oromeihyl)phe55yl)pyrroI iis-3-> l
Figure imgf000289_0003
[0930] (S)-l-(4-Amino-3-(trifluoromethyl)phenyl)pyrrolidin-3-oi can be synthesized following the general scheme above starting from 5~fluoro-2~mtrobenzotrifluoride and (5)~ pyrrolidin-3-ol. LC/MS: m/z 277.1 (M+H at 1.28 rain (lG%-99% CH3CN (0.035%
TFA) ¾0 (0.05% TFA)).
- 288 -4833.1 [0931] (^)-l»(4-Amisio-3-{trIflisor©s effeyl)pbenyl)pyrro! Iffi-3-ol
Figure imgf000290_0001
[§932] (i?)-l-(4-Am.mo-3-(trifluoromethyl)phenyl)pyrrolidm-3-ol can be synthesized following the general scheme above starting from 5-fluoro-2-!iiirobenzotrifiuoride arsd (R)~ pyrrolidin-3-ol. LC MS: m/z 277.1 (M+H)+ at 1.28 mm (10%~99% CH3C (0.035%
TFA)/H20 (0.05% TFA)).
[0933] (S)-4-{2-M€thy!piperid -l-yI)-2-{triflaoromefhyl)aellme
Figure imgf000290_0002
[0934] (S)-4-(2-Methylpiperidin-l-yI)-2-(trifluoromethyl)amline can be synthesized following the general scheme above starting from 5-fluofo~2-nitrobenzoirifluoride and (S)-2- methylpiperidine. LC/MS: m/z 259.1 (M- H)+ at 0.66 min ( !0%-99% CH3CN (0.035% TFA)/H20 (0.05% TFA)).
[0935] (S)-Ethyl l-(4-aniiii0-3-(iriflsi«OMeiliyI)pheoyl)piperMi0e-3-earboxyIate
Figure imgf000290_0003
[0936] (S)-Ethyl l-(4-amino-3-(trifluoromethyl)phenyl)piperidsne-3-carbox Sate can be synthesized following the general scheme above starting from 5~fiuoro-2- mtrobenzotnfluoride and (S)~ethyl piperidine-3-earboxylate. LC MS: m z 317.1 (M+H)+ at 1.01 mm (i0%-99% CH3CN (0.035% TFA)/H20 (0.05% TFA)).
■· 289■
44833, J [Θ937] 4-{3^-Dimethylpiper is Hu0Fomethy I)amlhte
Figure imgf000291_0001
[§938] 4-(3,3-Dimemylpiperidm-i-yI)-2-(irifluorometliyl)anili5¾e can be synthesized following the general scheme above starting from 5~fluoro~2~miFobenzo£rifiuoride and 3,3- dimethylpiperidine. LC MS: m/z. 273.1 (M+H)÷ at 0.96 min (10%--99% CH3CN (0.035% TFA) H20 (0.05% TFA)).
[0939] (J?)-Met¾yi l-(4-a dsso~ ~(trifleororaeihyl)pheiiyl)piperidisie-2-carbosylate
Figure imgf000291_0002
[ 94Θ] (i?)-Methyl l-(4-amino-3-(irifluoromethyl)phenyl)piperidine-2-carboxyIaie can be synthesized following the general scheme above starting from 5-fiuoro~2- mtrobenzotrifluoride and (i?)-methyi piperidine-2-carboxylate. LC/MS: m/z 303.3 (M+H)+ at 1 ,03 rain (10%~99% C¾CN (0.035% TFA)/H20 (0.05% TFA)).
[0941] (S)-Methyl l-(4-amiiio- -(trffl¾ r i eihyi)pfeesiyI)piperidlHe~2~carb xyIate
Figure imgf000291_0003
[Θ942] (S)~Methyl l-(4-amino-3-(trifiuoromethyl)phenyl)piperidine-2-carboxylate can be synthesized following the general scheme above starting from 5~fluoro-2- nitrobenzotri fluoride and (S)-raeihyl piperidine-2-carboxylate. LC/MS: m/z 303.3 (M+H)+ at 1.03 mio ( 10%~99% C¾CN (0.035% TFA)/¾0 (0,05% TFA)).
- 290 -44833.1 [0943] (S)-Meihyi l-(4-¾mta©-3-(iriflaoromethyl)phei?yI)»2-Mell¾ylpyrr dfae»2« carboxylate
Figure imgf000292_0001
[0944] (S)-Methyl 1 -{4-amino-3-(trifluoromethyl)phenyI)~2-methylpyrrolidine-2- carboxy ate can be synthesized following the general scheme above starting from S-fluoro~2~ nitrobenzotrifSuoride and (S)-methyl 2-methylpyrrolidine-2~carboxylaie. LC/MS: m/z 303.1 (M+H)+ at 1.27 min ( I0%-9 % CI¾CN (0.035% TFA)/H20 (0.05% TFA)).
[0945] (2S,35)-Methyl l-(4.amfaio-3.(trlllraorcsmethyI)pheiiiyI)-3- meihyIpyrroIidine-2-csrboxy!afe
Figure imgf000292_0002
[0946] (25,3S)~Methyl 1 -(4-amino~3-(irifluoromethyl)phenyl)-3-meihyIpyrroIidirie-2- carboxylate can be synthesized followi g the general scheme above starting from 5-fluoro-2- nitrobenzotrifiuoride and (2S,3S)-methyl 3-methyIpynOiidine-2-carboxylate. LC/MS: rtv'z 303.3 (M+H)+ at 1.30 min (10%~99% C¾CN (0.035% TFA)/¾0 (0.05% TFA)).
[0947] (li??¾?,5S)-M€!tb.yl 3.(4-amlso-3.(trifliioromet yI)phes5yl)-3~
azabi€ydo[3.L0]l.exaiie-2-csrboxylat
Figure imgf000292_0003
[094S] ( 1 R,2R,5S)-Methyl 3-(4-amino-3-(trifluoiomethyl)phenyl)-3- azabicyclo[3. I.0]hexane-2-carboxylate can be synthesized following me general scheme above starting from 5-fiuoro-2-niirobenzotrifluoride and (1 ?,2i?,55)-methyl 3-
- 291 -4483X1 azabicyclo[3.1.0]hexane-2-carboxylate. LC/MS: m/z 301.5 (M+H)÷ at 1.31 min (1G%~99% CH3CN (0.035% TFA)/¾0 (0.05% TFA)).
[0949] (2S,4¾)-Methyl i~(4~a isi -3-{triflis rom€ihyi)phesiy!)-4-feri- l istoxypyrroi me~2-earl oxylate
Figure imgf000293_0001
[Q950] (2S,4 ?)-Methyl i -<4-amino-3-(trifluoromethyl)pheny L)-4-fert- butoxypyrro ne-2~earboxylaie can be synthesized following the general scheme above starting from 5~fluoro~2~nifrobenzotrifluoride- and (2S,41?)-methyl 4-ieri-buioxypyrroiidine-2- carboxylate. LC MS: m z 301.5 (M+H)÷ at 1.31 min (I0%~99% CH3CN (0.035% TFA)/¾0 (0.05% TFA)).
[0951] N-(4-Amtao-3-(irifliioromeihyl)pheisyl)pivaIanilde
Figure imgf000293_0002
[0952] N-(4-Amino~3-(trifiuoromethyl)phenyl)pivalai-nide can be synthesized following the genera! scheme above starting from 5-fluQFO~2~mtrobenzotrifh3oride and pivalamide. LC/MS: m z 261.1 (M+H)+ at 1 .28 min (10%~-99% CH3CN (0.035% TFA)/¾0 (0.05% TFA)).
[0953] feri-Baiyl 4-aramo-3-(iriflit<iromeihyI)pheiiylcarbam8ie
Figure imgf000293_0003
- 292 -44833. ί [0954] ίέτί-Butyl 4-amino-3-(frifl oromeihyl)phenylcarbaniaie can be synthesized following the general scheme above starting from 5-fluoro-2-nitrobenzotrifluoride and ten- butyl carbamate. LC/MS: m/z 277.3 (M+H)+ at 1.56 min (10%-99% CH3C (0.035%
TFA)/H20 (0.05% TFA)).
[0955] (JK)~4~(3~FI a ropyrrolldl - l-yl)-2-(triflTOro5Bethyi)sisllia€
Figure imgf000294_0001
[0956] (i?)-4'(3-Fluoropyrroiidm-l-yl)-2-(tsiiluorometiiyl)aniline can be synthesized foilowing the genera! scheme above starting from 5-fluoro-2-mtrobenzotrifl.uoride and (R)~3- fluoropyrrolidine. LC/MS: /z 249.3 (M+H)+ at 0.92 min (10%™99% CH3CN (0.035% TFA)/H20 (0.05% TFA)),
[0957] (S)-4-(3-Fta ropyrrolid -i-yl)-2~(irlfl¾iiirome hyl)am iie
Figure imgf000294_0002
[0958] (S)-4-(3~FluoropynOlidin-l -yl)-2-(trifiuoromethyl)aniline can be synthesized following the general scheme above stalling from 5-fluoro-2-nitrobenzotrifluoride and (S)-3- fluoropyrrolidme. Ή NMR (400.0 MHz, DMSO- 6) δ 6.81 (d, J = 8.8 Hz, 1H), 6.72 (dd, J = 2.6, 8.8 Hz, 1 H), 6,51 (d, J = 2.8 Hz, 1H), 5.48 (d, J ' = 3.1 Hz, 1H)( 4.76 (s, 2H), 3,50 (dd, J = 3.9, 1 1.8 Hz, lH), 3.43 - 338 (m, 1H), 3.33 - 3.24 (m, 2H), 2.24 - 2.21 (m, 1H) and 2.15 (dd, J = 3.9, 7.9 Hz, 1H) ppm LOMS: m/z 249.2 (M+H)+ at 0.92 min ( 10%~-99% C¾CN (0.035% TFA)/¾0 (0,05% TFA)).
[0959] (*)-4 3-Msthy!pyrroKd -yl)-2-( r «« romeihyl)asiilme
Figure imgf000294_0003
- 293 -44833.1 [0960] ( ?)-4~{3-Methy!pyrrolidin-l-yl)-2-{trifSuorometh l)aniline can be synthesized following the general scheme above stalling from 5-fluoro-2-niirobenzotrifluoride and (R)-3- methylp rrolidine. LC MS: m/z 245.1 (M+H)+ at 0.92 min (lG%-99% C¾CN (0.035% TFA)/¾G (0.05% TEA)).
[0961] (S)~4-(3-Methy!pyrr IId rifliSOTomethyl)aHMme
Figure imgf000295_0001
[0962] (S)-4-(3-MethylpyiTolidin-l-yl)-2-(irirluoromeihyi)aniiine can be synthesized following the general scheme above starting from 5-fluoro-2-niirobenzo$rifluoride and (5)-3- methylpyrrolidine. LC/MS: m/z 245.1 (M+H)+ at 0.93 min (i0%~-99% C¾CN (0.035% TFA)/¾0 (0.05% TFA)).
[0963] 4 (M^J?)-2^.DImei yIpyrrolM -l-yi)»2 toflisoromefl5y!)ara!i e
Figure imgf000295_0002
[0964] 4-((2J?t5^)-2,5-DiniethylpynOiidm- l-yl)-2-(trifluoromethyl)aniline can be synthesized following the general scheme above starting from 5~fluoro-2-nitrobenzotrifluoride and (2i?,5^)-2,5-dimeAyipyrroIidine, ¾ NMR (400.0 MHz, DMSO-40 δ 6.77 (d, / = 8.8 Hz, 1H), 6.70 (d, J = 9.0 Hz, 1H), 6.49 (s, 1H), 4.70 (s, 2H), 3.88 (t, J = 5.9 Hz, 2H), 2.18 - 2.14 (m, 2H), 1.56 (s, 2H) and 0.96 (d, J = 6.1 Hz, 6H) ppm. LC/MS: ro¾ 259.3 (M+H)+ at 0.66 min ( IO%-99% CH3C (0.035% TFA) H20 (0.05% TFA)).
[Θ965] 4-(33-Difliior py rrolidto- l-yl)-2-(trlflHoromethyi)anilme
Figure imgf000295_0003
- 294 - S33J [0966] 4-(3s3-Difluoropyrrolidin~i-yl)-2-(trifluofomei yl)aniiine can be synthesized following the general scheme above starting from 5-fluGro~2~nitxohenzoirifluoride and 3,3- difluoropynolidine. Ή NMR (400,0 MHz, DMSO-rf6) 5 6.83 - 6.76 (m, 2H), 6.58 (d, / = 2.6 Hz, IH), 4.89 (s, 2H), 3.59 (t, / = 13.5 Hz, 2H), 3.36 (q, = 7.0 Hz, 3H), and 1.18 (t, / = 7.3 Hz, IH) ppm. LC/MS: m/z 267.2 (M+H)+ at i.35 min (10%-99% CH3CN (0.035% TFA)/¾G (0.05% TFA)).
[0967] 4 (2S,5S)-2,S-Dimethy -yl)»2-itrffliiorometi5yl)as3i se
Figure imgf000296_0001
[Θ9681 4-((2S,5S)-2,5-Dimethylpyrroiidin-l-yl)-2-(trifluoromethyl)anilme can be synihesized following the general scheme above starting from 5-fiuoro-2-nitrobenzotrifluoride and (2S,55)-2,5-dimethylpynoIidine. LC/MS: m/z 259 Λ (M+H)+ at 0.79 min (1Q%~99%
CH3CN (0.035% TFA)/H20 (0,05% TFA)).
[0969] 4.{(2Si5«)~2?S-DlmeihylpyrroIMi -i.y!)-2Ktrfflaoro!Beihyl)g!iame
Figure imgf000296_0002
[0970] 4-((25,5i?)-2,5-Dimethylpyrrolidin- i-yl)-2-(tiii]uoron3etl¾,l)aniline can be synthesized following the general scheme above starting from 5-f!uoro-2-nitrobenzotrifiuoride and (2S,5R)-2,5-dimethylpyrrolidine. LC MS: m/z 259.1 (M+H)* at 0.79 min (10%™99% C¾CN (0.035% TFA)/H20 (0.05% TFA)).
[0971] 4 (2S?5A)«2i5-Dimef ylpyrroIMra-i"-yI)-2--(trIfli5orosBeihyl)affillme
Figure imgf000296_0003
[0972] 4-((2S,5^)-2,5-DimemyIpyrrolidin-l-yl)-2-(trifluoromethyI)aniline can be synthesized following the general scheme above starting from 5~fluoro-2-niirobenzotrifluoride
- 295 -44833. ί and (2S,5¾-2,5-dimethylpyrrdidine. LC/MS: m/z 259.1 (M+H)+ at 0.79 min ( 1096-99%
CH3CN (0,035% TFA)/¾G (0.05% TFA)).
[0973] 4~(C^ydop€¾tyl xy)*2-(iriflisaromethyl)aiilliae
Figure imgf000297_0001
[0974] 4-(Cyclopentyloxy)-2-(irifluoromethyl)aniline can be synthesized following the general scheme above starting from 5-fluoro-2-niirobenzotrifiuoride and cyclopenianoL !H NMR (400.0 MHz, CD ¾) 8 6.96 (d, J = 2.8 Hz, 1H), 6,88 (dd, J = 2.8, 8.7 Hz, lH), 6.69 - 6.67 (m, 1H), 4.68 - 4.63 (m, 1H), 4.12 (d, / = 7.1 Hz, 2H) and 1.90 - 1.56 (m, 8H) ppm.
[Θ 75] 4-feopr po3sy~2-(ir!flsi r iBe
Figure imgf000297_0002
[1)976] 4-Isopropoxy-2-(trifiuoromethyl)aniline can be synthesized following the general scheme above starting from 5-fluoro-2-nitrobenzotrifluoride and propan~2~oi. ¾ NMR (400.0 MHz, CDC¾) δ 6.99 (d, / = 2.8 Hz, 1H), 6.90 (dd, J = 2.7, 8.7 Hz, 1H), 6.68 (d, ,/ = 8,7 Hz, 1H), 4,39 (t, / = 6.1 Hz, 1H), 3.88 (s, 2H) and 1.30 - 1.26 (m, 6H) ppm.
[0977] 2- Amieo-5-(py rroiidin- -yl)besK sslirile
Figure imgf000297_0003
[0978] 2-Amino-5-{pynOUdin-l-yl)benzonitrile can be synthesized following the general scheme above starting from 2-ammo-5-fluorobenzonitrile and pyrrolidine. H NMR (400.0 MHz, DMSO-*¾) δ 6.74 (d, / = L i Hz, 2H), 6.48 (s, 1H), 5.16 (s, 2H), 3.10 (m, 4H), 1.90 (m, 4H). LC MS: m z 188.5 (M+H)+ at 0.44 min ( 10%-99% CH3CN (0.035% TFA)/H20 (0.05% TFA)).
- 296 -44833. J [0979] 2~Meitay~4~(pjrr Hdm-l-y!)amliae
Figure imgf000298_0001
[0980] 2-Methoxy-4-(pyrrolidin-l-yl)amHne can be synthesized following the general scheme above starting from 4~fluoro~2~methoxyamline and pyrrolidine. 1 H NMR (400.0 MHz, DMSO-ifc) δ 6.51 (d, J - 8.3 Hz, IH), 6.14 (d, J = 2.4 Hz, 1H), 5.95 (dd, J = 2.4, 8.3 Hz, 1H), 3.91 (s, 2H), 3.74 (s, 3H), 3.1 1 (m, 4H), 1.90 (m, 4H). LC MS: m z 193.5 (M+H)+ at 1.06 min (10%-99% CH3CN (0.035% TFA)/¾G (0.05% TFA)).
[0981] 4-(3-Methy !ptperidln-i -yS)~2~(ir iiHiuo 0meils I)a Ime
Figure imgf000298_0002
[0982] 2-Methoxy-4-(pyrroHdin- l-yl)aniline cars be synthesized following the general scheme above starting from 5-fiuoro-2-nitrobenzotrifluoride and 3-methyipiperidine. !H NMR (400 MHz, CDC13) δ 7.05 - 6.93 (m, 2H), 6.69 (d, J = 8.7 Hz, 1H), 3.85 (s, 2H), 3.42 - 3,29 (m, 2H), 2.52 (td, J ~ 11 ,5, 3.1 Hz, lH), 2.25 - 2.15 (m, lH), 1.86 - 1.62 (m, 5H), 0.94 (d, i = 6.4 Hz, 3H). LC/MS: m/z 259.0 (M+H)+ at 0.79 min (10%-99% CH3CN (0.035% TFA)/H20 (0.05% TFA)),
[0983] 4 (lS,4«)-2-A2aMcyc[o ri.2.yI)-2-(irtflBoromeihyl)a8same
Figure imgf000298_0003
4-((lS,4i?)-2-Azabicyclo[2,2.13hepian-2-yl)-2-(trifluoromethyl)aiiiline can be synthesized following the general scheme above starting from 5-fluoro-2-nitrobenzotrifluoride and (1S,4R)- 2-azabicyclo[2.2.1]heptane. lH NMR (400 MHz, CDC13) δ 6.68 (d, / = 8.5 Hz, 1H), 6.58 (dt, J = 8,7, 2.5 Hz, 2H), 4,02 (s, IH), 3.65 (s, 2H), 3.49 (dt, / = 5.9, 3.2 Hz, 1H), 2.64 (d, / = 8.0 Hz, 1H), 2.56 (s, H), 1.83 - 1.53 (m, 5H), 1.48 (d, J = 9.3 Hz, 1H), 1.37 - 1.22 (m, 2H)
- 297 -
S544S33.1 [0984] 2-(4-(4-Amtoo-3-(iriflaoromethyI)pheiiyl)pipera¾lB~l»yl)ethaH0l
Figure imgf000299_0001
[0985] 2-(4-(4-Amino-3-(irifluoromet yl)phenyl)piperazin-l-yl)ethanol can be synthesized following the general scheme above starting from 5-fluoro-2-nitrobenzotrifluoride and 2-(piperazm-l-yl)ethanol,
[0986] Amine intermediate Example 13: Synthesis of S-amiiso~2-IsoproposypfeesioI
Figure imgf000299_0002
[0987] To a stirred solution of sodium hydroxide (387 mg, 9.67 mmol) in anhydrous DMSO was added 4-nitrobenzene-l,2-diol (500 mg, 3.22 mmol) at 0 °C. After stirring for 5 min, 2-iodo-propane (603 mg, 3.55 mmol) was added dropwise. The resulting dark mixture was stirred for 1 h at room temperature. The reaction mixture was quenched with water and then acidified with 1M HC1 (pH ~ 4) and then the aqueous layer was extracted with ethyl acetate (3x20 mL). The combined organic layer was washed with sat. NaCl and then dried over MgS04, filtered and concentrated under reduced pressure to dryness. The crude product was purified by silica gel column chromatography using a gradient of 0-20% EtOAc in hexanes to obtain 2-isopropoxy-5-nitro-phenoi (163 mg, 51 %) Ή NMR (400,0 MHz, CDC¾) δ 7.86 (dd, J = 2.5, 8.8 Hz, 1H), 7.76 (d, ./ = 2.5 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 4.73 (qn, J = 6.1 Hz, lH) and 1.43 (d, i = 6.1 Hz, 6H),
[1)988] A flask charged with 2-isopropoxy-5-niiro-phenol ( 100 mg, 0.47 mmol) and palladium on carbon (50 mg, 0.47 mmol) was flushed with N2 followed by evacuating under vacuum. EtOAc (2 mL) and methanol (2 mL) were added under an inert atmosphere followed by evacuating under vacuum. The reaction mixture was then stirred overnight under an atmosphere of hydrogen. The palladium catalyst was removed by filtration and solvent was removed under reduced pressure to give 5-ammo~2~isopropoxyphenol (65 mg, 76%). Ή NMR
- 298 -44833. ί .0 MHz, CDCI3) δ 6,73 (d, / ^= 8.3 Hz, 1 H), 6.31 (d, J = 2.5 Hz, 1H), 6.22 (dd, / = 2.5 Hz, 1H), 5.22 (s, lH), 4.50 (qn, J = 6.1 Hz, 1H), 3.37 (s, 2H) and 1.37 - 1.26 (m, 6H) ppm
[©989] Amine Intermediate Example 14: S nthesis of 6~m thoxy-5- (trffl»0rometfeyl)pyridin«2~&mkse
Figure imgf000300_0001
Figure imgf000300_0002
>] A mixture of 2,6-dichioro-3-(trifluoromethyl)pyridine ( 1.0 g, 4.63 mmol) , dibenzyiamine (913 ing, 890 L, 4.63 mmol), trieihylamhie (1.2 mL, 8.61 mmol) and 1- methyl-2-pyrrolidone (6 mL, 62.22 mmol) was heated at 120 °C for 9 h. The reaction mixture was cooled to the room temperature and poured into ice-water, extracted with EtOAc (20 mLx3), the combined organic layers were dried over anhydrous Na2SC>4, filtered, concentrated and purified by silca gel column chromatography (2%~I0% EtOAc in petroleum ether as eluant) to give N,N-diberizyl-6-chIoro-5-(trifluoromethyl)pyridin-2-amine (1.5 g, 86%) as an oil. Ή NMR (300 MHz, CDC13 ) δ 7.59 (d, J = 8,7 Hz, 1H), 7.37-7.21 (m, 10H), 6.32 (d, J = 8.7 Hz, 1H), 4.80 (s, 4H).
[0991J To a stirred solution of N,N-dibenzyl-6-chloro-5-(trifluoromethyl)pyridin-2- amine ( 100 mg, 0,27 mmol) in THF (5 mL) was added freshly produced CH3ONa (42 mg, 0.78 mmoi) at room temperature. The mixture was heated to reflux for 10 h and then cooled to the room temperature, diluted with water (5 mL) and extracted with CH2CI2 (6 mLx3). The combined organic layers were dried over anhydrous Na2S04, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography using 2%- 10% EtOAc in petroleum ether as eluant to obtain N,N-dibenzyl-6-methoxy-5-(trifluoromethyI)pyridin-2- amine (90 mg, 91 %), Ή NMR (400 MHz, CDC¾ ) 8 7.53 (d, / = 8.4 Hz, 1H), 7.35-7.22 (m, 10H), 6.02 (d, / = 8.4 Hz, 1H), 4.79 (s, 4H), 3.90 (s, 3H).
[0992] To a solution of N,N-dibenzyl-6-memoxy-5-(trifluoromethyl)pyrid n-2-amine (3.0 g, 8.056 mmol) in a mixture of methanol (30 mL) and AcOH (3 mL) was added palladium hydroxide (0.3 g, 0.43 mmol) under a nitrogen atmosphere. The mixture was stirred under hydrogen atmosphere (55 psi, 25 °C) overnight. The catalyst was removed by filtration
- 299 -44833. i through a pad of ceiite and the filtrate was neutralized by saturated a2COj. The aqueous layer was extracted with€¾(¾ (30 mLx3) and the combined organic layers were concentrated under vacuum to give 6-metiioxy-5-(trifiuQrome&yl)pyridm-2-amme (1.4 g, 90 %) as a pale yellow solid. !H NMR (400 MHz, CDC13) δ 7.56 (d, J = 8,4 Hz, 1H), 6.03 (d, i = 8.0 Hz, lH), 4.64 (bis, 2H), 3.93 (s, 3H). MS (ESI) m/ε (M+H + ) 193. i3C NMR (100 MHz, CDC13) 159,4, 138.0 (d, 7 = 5.9 Hz), 125.9, 122.3, 101.9 (d, 7 = 44.4 Hz), 98.3, 53.6. l9F NMR (282.4 MHz, CDCI3) -62.6.
[0993] Amine Intermediat Example ¾ : Synthesis of (£)-4-(4,4~ά!£Ιϋοπ»-2- ¾ieiliylpyrr0lMI¾-l-yI)-2-(trifteoromethy!)amlIae
Figure imgf000301_0001
yi5-4,4-difiuoro-1-{4-nitro-3-(irifiuorom8thy pheny pyrrondsfi^
Figure imgf000301_0002
(/¾-4-{4,4-difiuGrQ-2-meiftyipyrrQ&fdsn^
[0994] (S)-l-(ieri-btitoxycarbonyl)~4,4-difluoropyrroHdine-2-carboxylic acid (500 mg, 2.0 mmoi) was dissolved in dichloroniethane and treated dropwise with TFA (227 rng, 153 ,uL, 2 mmol). The reaction was stirred for 3 h at room temperature, the solvents evaporated to obtain (S)-4,4-difluoropyrrolidme-2-carboxyiic acid, which was used in the next step without further purification. LC/MS: m/z 152.2 (M+B)+ at 0.53 min (10 -99% CH3C (0.035% TFA)/H20 (0.05% TFA)).
- 300 -
8544833.; [§995] To 4-fluoro-l-nitro-2-(trifiuoromethyl)33enzene (416 mg, 2 mmol), (S)-4,4- difluoropyrrolidine-2-carboxylic acid (301 mg, 2 mmol), and sodium carbonate (633 mg, 574 μί, 6.0 mmol) was added 1:1 water Et anoi (8 mL) and the reaction mixture was heated at 90 °C for 72 h. The reaction mixture was diluted with water (50 mL) then acidified with 1 N HQ and the product was extracted with ethyl acetate. The organic layer was dried over Na2SC¼, filtered and concentrated under reduced pressure to yield (5)-4,4-difluoro- l -(4-nitro-3- (trifluorometJiyl)phenyl)pyrrolidine-2-carboxyHc acid as a brown oil (600 mg, 89%), which was used directly in the next reaction. LC MS: m/z 341.00 (M+H)÷ at 1 ,49 min (10%-99 CH3CN (0.035% TFA)/¾0 (0.05% TFA)).
[0996] (5)-4,4-difiuoro- 1 -(4-nitro-3 -(trifluorometh l)phenyl)pyrrolidine-2-carboxylic acid (600 mg, 1.76 mmol) was dissolved in methanol (10 mL), cooled to 0 °C, and treated dropwise with thionyl chloride (840 mg, 515 ih, 7.08 mmol). The reaction mixture was heated at 50 "C over 48 h. The reaction mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (0-60% ethyl acetate in hexane) to obtain (S)- methyl 4,4-dif!uoro-l-(4-nitro-3-(trifluoromethyl)phenyl)pyrroIidine-2-carboxyIate (300 mg, 48% yield). Ή NMR (400 MHz, OM80~d6) δ 8.12 (d, J = 9.2 Hz, 1H), 7.04 (d, J = 2,6 Hz, IH), 6.97 (dd, J = 9.2, 2.7 Hz, 1H), 5.19 (dd, J = 9.8, 1.9 Hz, 1H), 4.14-3.99 (m, 2H), 3.69 (s, 3H), 3.11-2.95 (m, 1H), 2.78 (t, / = 14.6 Hz, 1H).
[0997] To a suspension of LiB¾ (55 mg, 2,54 mmol) in anhydrous THF (3 mL) was added a solution of (S)-methyl 4,4-difluoro-l-(4-nitro-3-(trifluoromemyl)phenyl)pyrroiidine- 2-carboxylate (300 mg, 0.85 mmoi) in anhydrous THF at 0 °C. The reaction mixture was stirred at 0 °C for 20 min then aiiowed to come to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (50 mL), and then brine. The layers were separated, and the organic layer was dried over Na2SC¼, filtered, and concentrated to afford (S)-(4,4-difluoro-l-(4™nitro-3-(trifluoromemyl)phenyl)pyrroIidin-2- yl)methanol as a yellow, viscous oil (275 mg, 100%). LC/MS: m/z 327.2 (M+H)* at 1.54 min (10%-99% C¾CN (0.035% TFA)/H?0 (0.05% TFA)).
[0998] To a solution of (5)-(4,4-difluoro~l-(4-nitro-3- (tTifluoromemyl)phenyl)pyrrolidin-2-yl)methanoi (275 mg, 0.84 mmol) in anhydrous DCM was added triethylamine (171 mg, 235 μL, 1.7 mmol) followed by methane sulfonyl chloride (106 mg, 72 y/L, 0.93 mmol) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction was diluted with DCM and quenched with 3 mL saturated NaHC<¾. The organic layer was separated and washed with brine, dried over Na?S04, filtered, and concentrated to obtain (S)-(4,4-difluoro-l-(4-nitro-3-
- 301 -44833.1 (irifluoronKthyI)phenyl)pyrrolidin-2-yf)methyl methanesuSfonate as a yellow solid (330 mg, 96%), LC/MS: m z 405 (M+H)+ at 1.71 min (10%-99% CH3CN (0.035% TFA)/H20 (0.05% TFA)).
[0999] NaBr (420 mg, 131 μί, 4.08 mmol) was added to a solution of (S)-(4,4- difluoro- 1 -(4-niti -3-(trifluoromethyl)phenyl)pyrrolidin-2-yi)methyl methanesulfonate (330 mg, 0.82 mmol) in acetonitriie (2.0 mL) and heated at 80 °C for 16 h. The reaction mixture was diluted with ethyl acetate (10 mL) and water (5 mL). The organic layer was separated, dried over Na2SC>4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography ( 15-50% ethyl acetate/hex ane) to obtain (5)-2-(bromomethyl)-4,4- difluoro-i-(4-nit£O-3-(trifluoromethyl)phenyl)pyrrolidir!e (230 mg, 72%) as a yellow oil. *H NMR (400 MHz, OM8Q-d6) δ 8.14 (d, 7 - 8.7 Hz, 1H), 7.09-7.07 (m, 2H), 4.76-4.71 (m, 1H), 4.16-3.99 (m, 2H), 3.74 (dd, 7 = 10.6, 3.0 Hz, 1H), 3.60 (t, 7 = 9.7 Hz, 1H), 2.94-2.80 (m, 1H), 2.66-2.55 (m, 1H).
[01000] (S)-2-(bromomethyl)-4,4-difluoro- 1 -(4-nitro-3- (trifluoromethyl)phenyl)pyrroHdine (230 mg, 0.59 mmol) was dissolved in ethyl acetate (5 mL) and TEA (90 mg, 124 L, 0.89 mmol) and the flask was flushed with nitrogen. 10% Pd/C (58 mg, 0.05 mmol) catalyst was added and the reaction mixture was stirred overnight under an atmosphere of hydrogen. The reaction mixture was filtered, treated with 50% saturated NaHC03, and extracted with ethyl acetate. The organic layer was dried over Na2S04, filtered and concentrated to provide (i?)-4-(4,4-difluoro-2-methylpyrrolidin-l-yl)-2- (trifluoromemyl)aniline as a purple oil (164 mg, 99% yield). !H NMR (400 MHz, DMSO-rffi) δ 6.81 (s, 2H), 6.58 (s, 1H), 4.92 (s, 2H), 4.07-4.01 (m, 1 H), 3.74-3,63 (m, 1H), 3.60-3.50 (m, 1H), 2.75-2.60 (m, 1H), 2.22-2.1 1 (m, 1H), 1.10 (d, J = 6.2 Hz, 3H).
[01001] Amine Intermediate Example 16: Synthesis of l-(2-meiisoxyeihyl)-S- (trIflisor0meihyl)-lH-i¾d©I-6-amiise
Figure imgf000303_0001
[01002] 6-nitro-5-(trifluoromethyl)- lH-indole (50 mg, 0.22 mmol) was dissolved in DMF (2 niL) and treated with sodium hydride (35 mg, 0.87 mmol) to form a dark red opaque solution. The solution was stirred for 20 minutes and then added dropwise to a solution of 2- bromoethyl methyl ether (121 mg, 82 ,uL, 0.87 mmol) in 1 mL DMF. The reaction mixture was heated at 50 °C for 30 minutes. The reaction mixture was diluted with ethyl acetate (50
302 -44833. J n L) and washed with 50% saturated NaH€<¾ (2 x 10 mL) and brine. The organic layer was dried over Na S(>4, filtered and dried to obtain l-(2-methoxyethyi)-6-nitro-5-(trifluofomethyl)- IH-indole, which was used in the next step without further purification.
[010(13] l-(2-nie&oxyethyi)-6-nitro-5-(trifluoromethyl)-lH"indole was dissolved in 10 mL EtOH, and hydrogenated using aney Ni as a catalyst (H-cube: 1.2 mL/min 30 °C) to obtain in l~(2-methoxyethyi)-5-(trifluoromethyl)-lH-indol-6-arnine in quantitative yield. LC/MS: m/z 259.0 (M+H)+ at 1.12 min ( 10%~99% CH3CN (0.035% TFA)/¾Q (0.05% TEA)).
[Θ10 ] Amine .Intermediate Example 17: Synthesis off N~(4~ammo-3- (trlHeorometfeyi)pfeenyI)pi¥alamlde
Figure imgf000304_0001
[ΘΙΘ05] To a solution of 4-nitro-3-(trifluoromethyl)aniline (1.0 g, 4.85 mmoi) in
CH2CI2 (15 mL) and TEA (2.95 g, 4.1 mL, 29.11 mmoi) in a round-bottom flask at 0 °C was added trimethylacetyl chloride (1.75 g, 1.8 mL, 14.55 mmoi) dropwise. The reaction mixture was warmed to room temperature and was quenched by pouring into water. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layer was dried over sodium sulfate, filtered and concentrated. The residue was then purified by silica gel column chromatography using (0-100% EtO Ac/Hex.) to obtain N-(4-nitro-3- (trifluoromet yl)phenyl)pivalamide (1.64 g, 81%). LC/MS: m/z 291.1 (M+Hf at. 1.83 min (10%-99% CH3CN (0.035% TFA) H20 (0.05% TEA)).
[OlODfi] To a solution of 2,2-dimethyl-n-(4-nitro-3-trifluoromethyl-phenyl)- propionamide (1,64 g, 5,65 mmoi) in MeOH (50 mL) was added Pd/C (150 mg, 0.14 mmoi) under a nitrogen atmosphere. The mixture was stirred under a hydrogen atmosphere for 4 h. The catalyst was removed by filtration through a pad of ce!ite and the solvent was evaporated under vacuum to give N-(4-amino-3-(trifiuoromethyl)phenyl)pivalamide (1.2 g, 78%).
LC MS: /z 261.5 (M+B.† at 1.83 min (1G%~99% CH3CN (0.035% TFA)/H20 (0.05% TEA)).
- 303 -44833.J 01007] iCTf-Bsity! 4-anMHo-3- )pfee?3ykarbamai€
Figure imgf000305_0001
[01008] ferf-Buty! 4-amiEO~3~(trifluoromemyl)phenylcarbamate can be synthesized following the genera! scheme above starting from 4-nitro-3-(trifluoromethyl)aniline and di- ferr-but l dicarbonate, LC MS: rn/z 277.35 (M÷H)+ at 1.56 min (10%-99% C¾CN (0.035% TFA)/¾0 (0.05% TFA)).
[01009]
Figure imgf000305_0002
-l-Ctriilssorometfey^ yridis-^^
Figure imgf000305_0003
[OIOIOJ To a solution of 2,6-dihromopyridme (10.0 g, 42.6 mmoL) in anhydrous C¾CN (100 mL) was slowly added N02 +Bp4 (1 1.3 g, 85.2 mmoL). The reaction mixture was heated to 80 °C under an atmosphere of nitrogen for 24 h. The mixture was then evaporated in vacuo to give the crude product. The residue was purified by silica gel column
chromatography to afford 2,6-dibiOmo-3-nitropyridine (5,7 g, 48 %). !H NMR (400 MHz, CDC13) δ 8.03 (d, / = 8.4 Hz, 1 H), 7.65 (d, / = 8.4 Hz, 1H).
[01011] To a solution of 2,6-dibromo-3-nitropyridine (5,7 g, 20.4 mmoL) in DMF (40 mL) was added Cul (3.9 g, 20.4 mmoL) and FS02CF2C02Me (4.7 g, 24.5 mmoL). The reaction mixture was stirred at 80 °C for 1 h. After cooling to room temperature, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layer was washed with brine, dried over anhydrous Na2S(¼ and purified by silica gel column chromatography to afford 6-bromo-3-nitro-2-(trifiuoromethyl)pyridine (3.0 g, 53%, 70% purity). lll NMR (400 MHz, CDCh) δ 8.12 (d, / = 8.4 Hz, 1H), 7.94 (d, J ^ 8.4 Hz, 1H),
- 304 ·
44833.! [01012] A suspension of 6-bromo-3-mtro-2-(iriflooromethyl)pyridine (400 mg, 1.5 mmoL), (S)-2-methylpyrrolidme tosylaie salt (381 mg, 1.5 mmoL) and K2C03 (620 mg, 4,5 mmoL) in H20 (4 mL) was heated at 140 °C under microwave irradiation for 30 minutes. The solution was extracted with EtOAc (50 mL x 3) and the combined organic layer was washed with brine, dried over anhydrous Na2S0 and purified by silica gel column chromatography to afford (5)-6-(2-methylpyrrolidin-l-yl)-3-nitro-2-(trifluoromediyl)pyridine (350 mg, 88 % yield). !H NMR (400 MHz, CDC13) «5 8.14 (d, = 9.2 Hz, 1H), 6.44 (d, / = 8.4 Hz, 1H), 4,55- 4.42 (m, lH), 4.02-3,30 (m, 2H), 2.30-2.00 (m, 3H), 1.81 (brs, 1H), 1.27 (d, J - 6.4 Hz, 3H).
[01013] To a solution of f5)-6-(2-methylpyrroiidin- 1 -yl)-3-nitro-2- (trifluoromethyl)pyridine (300 mg, L mmoL) in 5 mL methanol was added NiCl2'6H20 (772 mg, 3.3 mmoL), After stirring for 5mm, NaB¾ (84 mg, 2.2 mmoL) was added in three portions at 0°C. The reaction mixture was stirred for 5 min and quenched with water (10 mL) and was extracted with EtOAc (15 mL x 3). The combined organic layer was washed with brine, dried over anhydrous Na2SC>4, concentrated and purified by silica gel chromatographyon silica gel to afford f5 -6-(2-methyipyrrolidin-l-yl)-2-(trifluoromethyl)pyridin-3-amine (260 mg, 92.6 % yield).
[01§14] Amine Intermediate Example 19: Synthesis of* 3-amtao-2,6-di-ii?ri- hutylpbenol
Figure imgf000306_0001
[0101SJ DMAP (885 mg, 7.24 mmol) was added to a solution of 2,6-di-terf- butylphenol (30 g, 145.4 mmol) and di-ferf-butyi dicarbonate (38 g, 174.1 mmol) in Et3N
(29.43 g, 40,5 mL, 290.8 mmol) and hexane (700 mL). The reaction mixture was stirred overnight and quenched with water and extracted with EtOAc. The organic layer was washed with aqueous NaHCQ , dried over Na2SQ and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether eluent) to give ½rf-butyl (2,6- di-½rf-but lphenyl) carbonate (30 g, 67%). ¾H NMR (400 MHz, CDC13 ) 8: 7.31 (d, J = 8.0
Hz, 2H), 7.12 (t, J = 8.0 Hz, lH), 1.54 (s, 9H), 1.38 (s, 8H).
- 305 -4833J [01016] TMSC1 (8.5 g, 78.24 mmol) and fert-butyl (2,6-di-tef -butylphenyl) carbonate (12.0 g, 39,16 mmol) was added to a suspension of K (¼ (5.9 g, 58,36 mmoi) in CHt¾ (100 mL) successively at Q°C. The reaction mixture was stirred for 0.5 h and A1C¾ (15,5 g, 1 16.20 ramol) was added. The stirring was continued for 2 h and the resulting mixture was poured into ice-water and extracted with€H2€S2. The combined organic layers were washed with sat.NaHC<¾ solution and brine, dried over Na^SQ* and evaporated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether) to give 2,6-di- fert-butyl-3-nitrophenol (2,5 g, 25%). Ή NMR (300 MHz, CDC13 ) δ 7.18 (d, J = 8.4 Hz, 1H), 6.79 (d, / = 8.4 Hz, 1H), 5.57 (s, 1H), 1.51 (s, 9H), 1.44 (s, 9H).
[01017] N BH4 (433 mg, 1 1.45 mmol) was added to a solution of 2,6-di-terf-butyl-3- niirophenol (950 rag, 3,780 mmol) and NiC (1.24 g, 9,568 mmol) in methanol ( 15 mL) at - 15°C. After the addition was complete, the reaction mixture was stirred for 20 seconds and water was added immediately and the reaction mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SG and evaporated in vacuo to afford 3-amino-2,6-di-«ri-butyl-phenol (650 mg, 78%). lH NMR (300 MHz, CDC¾ ) δ 6.92 (d, J = 8,4 Hz, 1H), 6,24 (d, J = 8.4 Hz, 1H), 5.39 (s, 1H), 1.62 (s, 9H), ! .39 (s, 9H); MS (ESI) m z: 222.2 [M+H ].
[01018] Amine Intermediate Example 20: Synthesis of 3-(trifluoromeihyI)-lH~ ffld l~6~¾mme
Figure imgf000307_0001
[01019] To a solution of 1 ,4-diratroiodobenzene (2.12 g, 7.21 mmol) in
tetrahydrofuran (1 1 mL) at -78 °C under an atmosphere of N2 was added phenylmagnesium chloride (2M irs THF) (4 mL, 8.0 mmol, i . i eq) dropwise. The dark red solution was stirred for 30 min at -78 °C then methyitrifluoropyruvate (0.75 mL, 8.65 mmol) was added dropwise. The reaction mixture was stirred for 30 min at -78 °C and then for 2 h at room temperature. The reaction was cooled to -10 °C and quenched by addition of 1 M HCl (6 mL). The reaction
- 306 -44833.1 mixture was diluted with water (10 mL) and dichloronietha te (30 mL). Tiie organic phase was separated and the aqueous phase was extracted with dichioromethane (3 x 30 mL). The combined organic phase was dried over Na2S0 , filtered, and concentrated. The residue was purified by silica gel column chromatography (0.5-30% ethyl acetate/hexanes) to yield methyl 2-i2,4-dimtrophenyl)-3,3,3-trifluoro-2-hydroxypropanoaie (1.34 g, 60%)
[01020] To a solution of methyl 2-(2,4-dimtrophenyl)-3,3!3-trifluoro-2- hydroxypropanoate (1.3 g, 4,01 mmol) in ethyl acetate (18 mL) was added (pH3) HQ (5.2 mL) followed by 10% Pd/C (350 mg) in ethyl acetate (3 mL)- The reaction mixture was stirred overnight, under an atmosphere of ¾. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo. The crude residue obtained was partitioned between dichioromethane (25 mL) and aqueous saturated NaHC03 (15 mL), The organic phase was separated and the aqueous phase was extracted dichioromethane (2 x 25 mL). The combined organic phase was dried over Na^ O.^ filtered, and concentrated. The residue was purified by silica gel column chromatography (50-100% ethyl acetate/ hexanes) to give 6- amino-3-hydroxy-3-(trifluoromethyl)indolin~2-one (921 mg, 99%)
[01021] To a solution of 6-amino-3-hydroxy-3-(trifluoromeihyl)indolin-2-one (58 mg, 0.25 mmol) in THF (0,5 mL) at 0 °C was added BH3THF complex (1 M in THF, 1 mL, 0,95 mmol) dropwise. The reaction mixture was stirred for 5 min at 0 °C then for 3 h at room temperature. The reaction mixture was quenched by adding very carefully 6M HC1 (3.5 mL) until no more gas release was observed. The reaction mixture, was thers stirred at 80 °C for 2 h. The solvent was removed under reduce pressure and the solid residue obtained was dissolved in DMF (3 mL), filtered and purified by reverse phase HPLC (10-99% CH3CN/H2O) to provide 3-(trifluoromethyl)- 1 H-indol-6-arnine (30 mg , 54%, TFA salt).
[ ΙΘ22] Amine intermediate Example 21 ; Synthesis of 2-(tr ¾oromethyI)-IH- indd-6-amiiie
Figure imgf000308_0001
- 307 -44833. i [0ΙΘ23] To a solution of 4- eihyibenzene-i,3-diamine (500 mg, 4.1 mmoi) in dry pyridine (25 mL) at 0 °C under a N2 atmosphere was added trifiuoroacetic anhydride ( 1.2 mL) dropwise. The cooling bath was removed and the reaction mixture was stirred at room temperature until complete conversion of the starting material to the desired product was observed. The reaction mixture was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (10-45% AcOEt in hexanes) to obtain N,N'-(4-methyl-l,3-phenylene)bis(2,2,2-trifluoroacetarnide) (807 mg, 63%). LC/MS: m/z 315,3 (M+H)+ at S .39 rain (10%-99 CH3CN (0.035% TFA) H20 (0.05% TFA)).
[01024] A mixture of NsN,-(4-methyl" I,3-phenylene)bis(2,2,2~trifluoroace amide) (1.02 g, 3.25 mmol), NBS (0,80 g, 4.5 mmol) in CC14 (6 mL) was stirred overnight at room temperature under irradiation of a 300 W lamp. The precipitate formed was collected by filtration and washed with CC .The crade residue was taken up in dry toluene (9,7 ml.,) in the presence of PPh3 (1.3 g, 4.96 mmol) and stirred at 60°C for 16 h. The phosphonium precipitate was collected by filtration, then dissolved in dry DMF ( 10 mL) and stirred at 65 °C until complete conversion to die product (6.5 h). The solvent was removed in vacuo and the residue obtained was purified by silica gel column chromatography (5-25% AcOEt in hexanes) to obtain 2,2,2-trifluoro-N-(2-(trifluoromethyl)-lH-indol-6-yi)acetamide (243 mg, 25%).
LC/MS: m/z 297.3 (M+H)+ at 1.68 min (10%~99% CH3CN (0.035% TFA)/¾0 (0.05% TFA)).
[01025] 2,2,2-irifluoro- -(2-(iriiluoromethyl)~ lH-indoi-6-yl)acetamide (28 mg, 0.09 mmol) was dissolved in MeOH (0,9 rnL) and water (0.4 mL) in the presence of 2CO3 (90 mg, 0.65 mmol) and stirred overnight at room temperature. Purification (10 to 99% ACN in water) by LC-MS provided 3-(trifluoromethyi)-lH-indol-6-amine 2,2,2~trifluoroacetate (30 mg, quantitative yield). LC/MS: m z 201.1 (M+H)+ at 0.90 min (!0%-99% C¾CN (0,035% TFA)/¾0 (0.05% TFA)).
[01026] Amin Intermediate Example 22: Syisttasts of 4-(3-methyIose ¾5i-3-
Figure imgf000309_0001
- 308
44833.1 [01027] To a solution of diethyl 2-methyipropanedioate (21.8 g, 125.0 mmol) m anhydrous DMF (125 mL) was slowly added NaH (5.2 g, 130 mmol) at 0 °C under an atmosphere of nitrogen. The resulting reaction mixture was allowed to stir for 10 minutes at 0 °C, and then at room temperature for 10 minutes. 2-bromo~!-fluoro-4-nirro~benzene (25,0 g, 1 13.6 mmol) was quickly added and the reaction mixture turned bright red. After stirring for 10 minutes at room temperature, the crude mixture was evaporated to dryness and then partitioned between dichloromethane and brine. The layers were separated and the combined organic layers were dried over anhydrous Na2SQ and evaporated under vacuum to give the crude product, which was purified by silica gel column chromatography (petroleum ether EtOAc 10: 1) to give diethyl 2-(2-hromo-4-nitrophenyl)-2-meftylmaionate (33.0 g, 78%)
[Θ1Θ28] To a solution of diethyl 2~(2-bromo-4~nitrophenyl)-2-methylmalonate (7.5 g, 20.0 mmol) in anhydrous tetrahydrofuran (80 mL) was slowly added a solution of lithium aluminum hydride (22 mL, 22.0 mmol, 1.0 M in THF) at 0 °C under an atmosphere of nitrogen. After stirring for 10 minutes the reaction was completed. The reaction mixture was quenched by the slow addition of methanol at 0 °C. The reaction mixture was then partitioned between dichloromethane and 1 N hydrochloric acid. The layers were separated and the aqueous layer was extracted three times with dichloromethane. The combined organic layers were dried over anhydrous Na^SQ* and evaporated under vacuum to give crude product, which was purified by silica gel column chromatography (petroleum ether/EtOAc 2: 1 ) to give
2- (2-bromo-4-nitrophenyl)-2-methylpropane-l,3-diol (1.4 g, 24%) as a red solid. lH NM (400 MHz, DMSQ-i¾) δ 8.31 (d, J = 2.4 Hz, 1H), 8.13 (dd, J = 2.4, 8.8 Hz, 1H), 7.74 (d, / = 8.8 Hz, lH), 4.74 (t, J = 5.2 Hz, 2H), 3.93 (q, J = 5.2 Hz, 2H), 3.79 (m, q, / = 5.2 Hz, 2H ), 1.38 (s, 3H).
[©1029] To a solution of 2-(2-bromo-4-nitrophenyl)-2-methylpropane-l,3-dioI (7.2 g, 24,82 mmol) in anhydrous benzene (75 mL) was added cyanomethylenetributylphosphorane (9.0 g, 37.29 mmol) at room temperature. The reaction mixture was stirred for 72 h, then evaporated to dryness and re-dissolved in ethano! (100 mL). Tin (ΪΙ) chloride diliydrate (28 g, 94.42 mmol) was then added and the resulting solution was heated to 70 °C for I hour. The reaction mixture was cooled to room temperature and then quenched with a saturated aqueous solution of sodium bicarbonate. The reaction mixture was then extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous Na2S04 and evaporated under vacuum to give the crude product, which was purified by reverse phase HPLC to afford
3- bromo-4-(3-methyloxetan-3-yl)anUine (1.5 g, 18%) TFA salt. ¾H NMR (400 MHz, CI¾CN)
- 309 -ΦίΒ33. ί δ 6.93 (d, J = 2.4 Hz, 1H), 6.78 (d, J - 8.4 Hz, 1H), 6.71 (dd, J = 2.4, 8.4 Hz, 1H), 4.94 (d, / = 5.6 Hz, 2H), 4.46 (d, / = 6.0 Hz, 2H), 1.70 (s, 3H).
[01030] To a refluxing solution of 3-(2-bromo-4-nitrophenyl)-3-methyloxetane (68 rag, 0.2499 mmol) in ethane! (5 mL) was added ammonium formate (68 nig, 1.078 mraol) followed by the addition of Pd/C (32 mg, 0.3007 mmol). The reaction mixture was refluxed for an additional 5 minutes, cooled to room temperature and filtered through a plug of celite. The solvent was evaporated to get 4-(3-methyloxetan-3-yl)aniline. !H NMR (400 MHz, DMSO-tfc) 5 6.93 - 6.90 (m, 2H), 6.56 (d, J = 8.5 Hz, 2H), 4.70 (d, J = 5.4 Hz, 2H), 4,45 (d, / = 5.6 Hz, 2H), 1.55 (s, 3H).
o h«iyl)-2-
[Θ1Θ32] To a refluxing solution of 2-(2-bromo-4-nitrophenyl)-2-methylpropane-l,3- diol (21 1 mg, 0.73 mmol) in ethanol (15.5 mL) was added ammonium formate (21 1 mg, 3.35 mmol) followed by the addition of Pd C (140 mg, 1.32 mmol). The reaction mixture was refluxed for an additional 10 minutes, cooled to room temperature and filtered through a plug of celite. The solvent, was evaporated under reduced pressure to give 2-(4-aminophenyi)-2- methyIpropane-l,3-dio! (1 12 mg, 85%).
[01033] Specific Examples
[01034] Synthesis of 4-oxo-N-(3-teri-butylpheityi)-lH-qHlsjolSiie-3-carbo samlde (Table 1, Compound 603)
Figure imgf000311_0002
[01035] A flask charged with 4-oxo-lH-quinoline-3-carboxylic acid (38 mg, 0.20 mmol), HBTU (76 mg, 0.20 mmol), Et3N (61 mg, 84 L, 0,60 mmol) and DMF (2 mL) was heated at 60 °C for 15 minutes. To the reaction mixture was then added 3-ieri-butylaniline (29.98 mg, 0.2009 mmol) and the reaction mixture was stirred at 60 °C for an additional 30 minutes. The reaction mixture was cooled to room temperature, filtered and purified via
- 310 -44833.1 reverse phase HPLC using 10 to 99% C¾CN in I¾0 to obtain N~(3~/m~butytphenyl)-4-QXo- lH-quinoline-3-carboxamide. *H NMR (400 MHz, DMSG- 8 12.94 (s, IH), 12.45 (s, IH), 8.89 ($, IH), 8.34 (dd, 7 = 1.1, 8.2 Hz, IH), 7.84 - 7.80 (m, IH), 7.76 - 7.71 (m, 2H), 7.62 - 7.53 Cm, 2H), 7.29 (t, 7 = 7.9 Hz, IH), 7.15 - 7.12 (m, 111), 1.31 (s, 9H>. LC/MS: w¾ 321.5 (M+H)+ at 1.8 min (10%-99% CH3CN (0.035% TFA)/H20 (0.05% TFA)).
[01036] Synthesis of N-[4-eyci peiityl-5-liydr©sy-2~(3~hydr iypr p-l- ynyl)pheisyl]-4-oso-lH-qiiIaolMe-3-£arboxamMs (Table 1, Compound 512)
Figure imgf000312_0001
[0ΙΘ37] 4-bromo-2-cyclopenty J-5~(4~oxo- 1 ,4-dihydroquinoIine-3- carhoxamido)phen l methyl carbonate (50 mg, 0.10 mmol), PdiPPIi3)2C!2 (4 mg, 0.005 mmoi), and cuprous iodide (1 mg. 0,10 μϊ_, 0.003 mmol) were added to a microwave tube which was flushed with N2 and capped. A degassed solution of DMF (1 mL), triethylamine (2 mL), and prop-2-yn-l -ol (57.75 mg, 59.97 pL, 1 .030 mmol) was added and the reaction mixture was heated at 80 °C for 16 h. The reaction mixture was filtered and purified by HPLC (20-99% CH3CN/0.05% TFA) to give 2-cyclopentyi-4-(3-hydroxyprop-i-ynyl)-5-(4~oxo-l,4- dihydroquinoline-3-carboxamido)phenyl methyl carbonate N-(4~cyclopentyl-5-hydroxy-2-(3- hydroxyprop- 1 -ynyl)phenyl)-4-oxo- 1 ,4-dih droquinof ine-3-carboxamide. These product fractions were combined, concentrated to remove aceto itrile, and treated with 5N NaOH (2 mL). The H of the solution was adjusted to 7 and the reaction mixture was extracted with ethyl acetate. The organic layer was washed wife 50% saturated sodium bicarbonate solution (2 x 20 mL) and brine. The solution was dried over anhydrous Na2Si>4, filtered, and dried to obtain N-(4-cycIopentyl-5-hydroxy-2-(3-hydroxyprop- 1 -ynyl)phenyl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide. LC MS: m/z 403.2 (M+H)+ at 0.92 min (10%-99 C¾CN (0.035% TFA) H20 (0.05% TFA)).
11■
854*833.! [01038] Synthesis of N-(4-cyclo esyl-2-melhyl-pheMyI)-4-i xO'>lH-qatno iie-3- ear oxamide (Table 1, Com oiissd 648)
Figure imgf000313_0001
[§1039] To N-{4-bromo-2-methyl-phenyl)-4-oxo-l H-quinoline-3-carboxamide (50 nig, 0.14 mmol), cyclobesen-l-yiboronic acid (35mg, 0.28), and Pci(dpp£)ClrDCM (1 1 mg, 0.01 mmoi) was added Na2CG3 (980 μh of 2 M, 1.96 mmol) and acetonitri!e (2 mL). The reaction mixture was heated under microwave irradiation for 10 min at 150 °C under a N2 atmosphere. The reaction mixture was diluted with ethyl acetate, washed with 50% saturated sodium bicarbonate solution (2 x 20 mL), water, and brine. The organic layer was dried over anhydrous Na2SC>4, filtered, and concentrated in vacuo. The crude product was purified via siicia gel column chromatography (30-100% ethyl acetate/hexane) to obtain N-(4-cyclohexen~ l-yl-2-methyl-phenyI)-4-oxo-iH-quinoline-3-carboxamide as a white solid (35 mg, 70%). - (4-cyclohexen-l-yI-2-methy!-phenyi)-4-oxo-lH-quinoiine-3-carboxaraide (35 mg, 0.10 mmol) was stirred vigorously with 10% Pd/C (wet) (30 mg, 0.01 mmol) under an atmosphere of S¾ for 30 min at 50 °C. The reaction mixture was filtered, concentrated in vacuo, and purified by HPLC (30-95% CH3CN/ 5 mM HC1) to yield N-(4-cyclohexyl-2-methylphenyl)-4-oxo-l, - dihydroqmnoliiie-3-carboxamide (20 mg, 57% yield). LC MS m/z 361.4 [M- Hf. Ή NMR (400.0 Milz, OM$0-d6) δ 12.94 (d, J = 6.0 Hz, IE), 12.24 (s, 1H), 8.89 (d, J = 6.5 Hz, 1H), 8.35 (d, J = 7.7 Hz, 1H), 8.22 (d, J = 8.3 Hz, lH), 7.82 (t, / = 7.6 Hz, 1H), 7.76 (d, / = 7.8 Hz, 1H), 7.55 - 7.51 (m, / = 7.6 Hz, 1H), 7.1 1 (s, 1H), 7.05 (d, 7 = 8.4 Hz, 1H), 2.45 (m, 1H), 2,38 (s, 3H), 1.80 - 1.69 (m, 5H), 1.42 - 1.21 (m, 5H).
[01040] Synthesis of N-(4-hydrosy-2-eapbihyl)-4- s0-lH-qaiBolfee-3» carboxamide (Table 1, Compound 552)
Figure imgf000313_0002
- 38.2 -44833.5 [01§41] To a solution of N-(4~methoxy-2-naphthyl)-4-oxo- lH-quinoIine-3- carboxamide (73 mg, 0,21 mmol) in DCM (4 mL) was added BBr (1 ,1 mL, 11,64 mmol) dropwise at -78 °C. After me addition was complete the cooling bath was removed and the resulting reaction mixture was warmed to room temperature and then was heated to 50 °C for 2 h, cooled to -10 °C and quenched with saturated solution of NaHC(¾ . The aqueous layer was extracted with DCM and the combined organic layer was dried over MgSQ4, filtered and concentrated in vacuo. The residue was purified via reverse phase HPLC to get N-(4-hydroxy~ 2-naphthyl)-4~oxo-lH"quinoline-3-carboxamide. LC/MS: m'z 331 (M+H)÷ at 1.47 min (10%- 99% CHjCN (0.035% TFA)/H20 (0.05% TFA)).
[01042] Synthesis of N-[5-hydrosy-4-lsopr0pyi»2-(trffl«ioromef hyl)phesiy!]-4-oxo- lH- -3-ear osamide (Table 1, Compmmd 497)
Figure imgf000314_0001
[01043] A flask charged with N-[5-benzyloxy-4-isopropyl-2-(trifluoromethyl)phenyl]- 4-oxo- 1 H-quinoline-3-carboxamide (118 mg, 0.25 mmol) and Pd/C ( 12 mg, 0.1 mmoi) was evacuated under vacuum, followed by purging with N2. Methanol (2 mL) was added under inert atmosphere, followed by evacuating under vacuum. The reaction was stirred overnight under an atmosphere of hydrogen, filtered through a plug of eelite and concentrated to give N- [5-hydroxy-4-isopropyl-2-(rrifluoromethyS)phenyS|-4-oxo-l H-qumoline--3~carboxamide, !H NMR (400.0 MHz, DMSO-ife) δ 12.93 (s, 1H), 12.59 (s, 1 H), 10.29 (s, SH), 8.87 (s, 1H), 8.32 (dd, J = 1.0, 8.1 Hz, 1H), 7.95 (s, 1H), 7.83 - 7.74 (m, 2H), 7.52 (t, J = 8,0 Hz, SH), 7.36 (s, 1H), 3.20 (qn, / = 6.9 Hz, 1 H) and 1.24 - 1.19 (m, 6H) ppm. LC/MS: m z 391.36 (M+H)+ at 1.77 min (!Q%~99% CH3CN (0.035% TFA)/H20 (0.05% TFA)).
[01044] Synthesis of N~[4~cyelohexyI-5-hydi°osy-2-(triflaoromethy )phe»yl]~4~ oso-lH-q molme-3-carfeoxamide (Table 1» Compoimd 620)
Figure imgf000314_0002
313 -44833.! [01045] (N-(4-cyciohexyl-5-hydroxy-2-(irifluorornethyI)phenyl)~4-oso- 1 ,4- dihydroquinoline-3-carbox amide can be synthesized following the general scheme above starting from N~(5-(benzyioxy)-4~cyclohexyl-2-(trifluoromeih l)phenyI)-4-oso- 1 ,4- dihydroquinoline-3-cai oxamide. !H NMR (400 MHz, DMSO-<fe) δ 12.93 (d, J = 6.6 Hz, IE), 12.54 (s, 1H), 10.28 (s, 1H), 8.87 (d, 7 = 6.8 Hz, 1H), 8.32 (d, 7 = 7.3 Hz, 1 H), 7,95 (s, 1H), 7.81 (ddd, 7 = 23.1, 15.0, 4.7 Hz, 2H), 7.53 (dd, 7 = 1 1.5, 4,6 Hz, lH), 7.34 (s, 1H), 2.84 (s, l H), 1.85 - 1.69 (m, 5H), 1.38 (t, 7 = 10.3 Hz, 5H). LC/MS: wv¾ 431.5 (M+H)+ at 2.Ql min (10%-99% CH3CN (0.035% TFA)/¾0 (0.05% TFA)).
[01046] Synthesis of N-[2-fliioro-S-hydroxj'~4~(iriflisoromethyI)phesyl]-4-oso-lH- qulsioIme-3-carbosai¾ilcle (Ta
Figure imgf000315_0001
[01047] N-(2-fluoro-5-hydroxy-4-(irif!uoromeihyl)phenyl)-4-oxo-l,4- dihydroquinoline-3-carboxainide can be synthesized following the general scheme above starting from N-(5-(benzyIoxy)~2~fluoro-4-(irifluoromethyl)phenyl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide. LC MS: m z 367.10 (M+H)+ at 1.65 min (10%-99% C¾CN (0.035% TFA)/¾0 (0.05% TFA)).
[01048] Synthesis of 6-[(4-ox< lH- ttssiolffl-3-yl)€arhoi}yl8miiio]-lH-i doIe-4~ carfeoxylie acid (Table 1, Compousid 712)
Figure imgf000315_0002
[01049] Ethyl 6-(4-oxo- 1 ,4-dihydroquinoline-3-carboxamido)- 1 H-indole-4- carboxylate (6 nig, 0.02 mmol) was suspended in 1 M NaOH (400 μί, 0.40 mmol) and heated to 50 °C for 30 min. The clear brown solution was diluted with water (1 mL) and acidified with IN HC1 (450 uL). The solution was washed with water (3 x 1 mL), and purified via reverse phase HPLC (75% acetonitrile/water) to give 6-(4-oxo-I ,4-dihydroquinoline-3-
- 314 -
S.¾ 833.t carboxainido)-lH-indole-4-carboxylic acid, LC/MS: m/z 347.8 (M+H)+ at 1.07 min ( 10%- 99% C¾CN (0.035% TFA)/¾0 (0.05% TFA))
[Θ1050] Synthesis of S-ami0 ~N-(5--hydrosy-2!,4«dilert-b5sty!-phe jI)'-4-©xo~lH- qsi
Figure imgf000316_0001
[01051] A flask charged with 8-bromo-N-(2,4-di-½ri-butyl-5-hydroxyphenyl)-5-iiiiro- 4-oxo ,4-dihydroquinoiiiie-3-carboxarnide (430 mg, 0.83 mmoi) ) and Pd/C (60 mg, 0.56 mmoi) was evacuated under vacuum, followed by purging with N . ElOAc (4 mL) and HQ (1 mL of 1 M, 1.000 mmol) were added foliowed by evacuating under vacuum. The reaction was stirred overnight under an atmosphere of hydrogen, filtered through a plug of celite and concentrated to get 5~amino-N-(2,4-diieri-butyl-5-hydroxy-phenyl)-4-oxo-lH-quinoiine-3- carboxamide (164 mg, 48%). LC/MS: m/z 408.5 (M+H)+ at 1.98 min (10%~99% CH3CN (0.035% TFA)/¾0 (0.05% TFA)).
[Θ1Θ52] Synthesis of N-(S-hydr©sy-2,4~dIteri->biityl-phe0yl)-5-iiiet yMMljio~4~oxo- lH-qulffiolme-3-carboxaniide (Table 1, Compotmd 543)
Figure imgf000316_0002
[01053] A flask charged with 5-ammo-N-(2,4-diieri-butyi-5 -hydrox -phenyi)-4-oxo- lH-quinoline-3-carboxamide (23 mg, 0.06 mmol), Pd C (5 mg, 0.05 mmoi) and formaldehyde (5 μL· of 38 %w/v, 0.06 mmol) was evacuated under vacuum, foliowed by purging with N2. Methanol (1 mL) was added followed by evacuating under vacuum. The reaction mixture was stirred overnight under an atmosphere of hydrogen, filtered through a plug of celite and concentrated to get N-(2,4-diferi-butyl-5-hydroxy-phenyl)-5-methylamino-4-oxo~lH- quinoline-3-carboxamide. LC MS: m z 422.5 (M+H)+ at 2.24 min (10%-99% CH3C
(0.035% TFA)/¾G (0.05% TFA)).
- 315 -44833, J [§1054] Synthesis of N-(2,4-di-terf-biityI-5-hydroxy-phsiiyI)-7»hydr xy-4-oso-lH"' uiH liM ~3~car oxamid (Table 1, Com ose 653)
Figure imgf000317_0001
[01055] To a solution of N-(2,4-di-^ri-bur>'l-5-hydroxy-phenyl)-7-metlioxy-4-oxo- lH-qumoiine-3-carboxarmde (120 mg, 0.28 mmol) in DCM (L5 n L) was added BBr3 (1.5 oiL, 15.23 mmol) drop ise at -78 °C. After the addition was complete the cooling bath was removed and the resulting reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was quenched with sat. solution of NaHCOs. The aqueous layer was extracted with DCM and the combined organic layer was dried over MgS04, filtered and concentrated. The residue was purified via reverse phase HPLC to give N-(2,4~dii_?ri- butyl-5-hydroxy-phenyl)-7-hydroxy-4-oxo-lH-quinoline-3-carboxamide . LC/MS: m/z 409.5 (M+H)+ at 1.83 min ( 1G%~99% CH 3 CN (0,035% TFA)/H 2 O (0.05% TFA)).
[§1§56] Synthesis of 6-hydrosy-4-oxo-N-(S-feri-bssiyi-lH»iisdol-6-yl)-lH- isiss ltee-J-carboxsfflide (Table 1, Compound 680)
Figure imgf000317_0002
[01057] 6-hydroxy-4-oxo-N-(5 ert~butyI~lH-indoS-6-yl) H-quinonne-3- carboxamide can be synthesized following the general scheme above starting from N-(5-ieri- butyl- iH-indoi-6-yl)-6-methoxy-4-oxo- 1 ,4-dihydroquinoiine-3-carboxamide. LC/MS: m/z 378.00 (M+H)+ at 1.38 min (10%-99% CH3CN (0.035% TFA)/¾0 (0.05% TFA)).
[©!§§§] Synthesis of 6-hydr sy- -(S-hydroxy-2,4~dlteri~bsityl-pheiiyI)-4-oxo-lH- qniaoIiiie-3-carboxamide (Table 1, Com ound 7Θ3)
Figure imgf000317_0003
- 316 -44833, J [§1059] 6-hydroxy-N-(5-hydroxy-2,4-ditert-buiyl-phenyI)-4-oxo- 1 H-qumoline~3~ carboxamide can be synthesized following the general scheme above starting from N-(2,4-di- ?g^butyl-5~hydroxyphenyl)-6-methoxy-4-oxo- 1 ,4~dihydroqukolme-3~carboxamide. LC/MS: m/z 409.00 (M+H)+ at 1.73 min (10%~99% CH3CN (0.035% TFA) H20 (0.05% TFA)).
Synthesis of (R)»l-[4-[(4» so»lH~q«is5oli8i»3"'Yl)£arboiiylamiiio3-3- (trifln romethyI)phe55yI]pyrroiIdhse-2-€arboxyllc acid (Table I, Compound 699)
Figure imgf000318_0001
01061] To a solution of teri-butyl (2i?)- l-[4-[(4-oxolH-quinoline-3-carbonyl)amino]- 3-(trifSuoromethyi)phenyrjpyrrolidirie-2-carboxykie (35 mg, 0.06979 nirnol) in DCM (500 μ!_) was added TFA (1 niL) at room temperature and the reaction mixture was stirred for 3h,The solvents were evaporated under reduced pressure and the residue was purified via reverse phase HPLC to give (2i?)~l-[4-[(4-oxo-l H-q moline-3-carbonyl)amino]-3~
(trifluoromethyl)phenyl]pyrrolidine-2-carboxyiic acid. LC MS: m/z 466.3 (M+H)+ at 1.46 min (10%-99% CH3CN (0.035% TFA) H20 (0.05% TFA)).
[01062] Synthesis f (S)~i-[4~[(4~oxo- lH-quinoliii-3-yl)carbonylarnmo]-3- (trit1ooromemyl)phenyl]pyrrolidine-2-carboxylic acid (Table 1, C®mpe¾md 56§)
Figure imgf000318_0002
[01063] (5 1 ~(4~(4-oxo- 1 ,4-dihydroquinoline-3-carboxauudo)-3- (trifl oromethyI)phenyl)pyrrolidine-2-carboxylic acid can be synthesized following the general scheme above starting from ieri-butyl (2S)~l-[4~[(4-oxolH-quinoline-3- cai¾oiiyl)amino]-3-(irifluoromeihyl)phenyl3p> rolidine-2-carboxylate. LC/MS: m/z 466.3 (M+H)+ at 1.47 min (10%~-99% CH3CN (0.035% TFA)/H20 (0.05% TFA)).
§106 ] Set forth below is fee characterizing data for compounds of the present invention prepared according to the above Examples.
[01065] T¾bte 2
- 317 -
85 }83Ϊ.Ϊ 223306/VPiG4~ 125WOCPl/tbd
Figure imgf000319_0001
Figure imgf000319_0002
Figure imgf000319_0003
-3!8-
8544833.1 M . M+1 mlfi Mo. *i rrsin o.
139 408,0 3.17 _J85_ 414.1 2.98 231 471.3 3.41
140 346,1 4 188 372.3 3.59 383.1 2.57
141 366.3 2.89 187 348.3 2.9 233 348.5 2.75
142 321.3 3.58 88 378.2 2,95 234 372.3 3.2
143 355.2 3.45 189 370.9 3.38 235 308.4 J2.12
144 281.3 2.49 190 392.0 3.09 236 333.1 3.35
145 " 376.2 2.98 191 318.3 2.1 237 410.3 2,96
148 308.3 2.51 192 280.3 2.13 238 489.4 2.78
147 376.3 3.27 193 328,3 3.02 239 379.0 2.82
148 415.5 2.79 194 290.1 2.98 240 370JL 3.85
149 349.1 1.45 195 280.3 2.14 241 318.3 2.61
150 430.0 3.29 196 434.5 3.38 242 348.3 3.08
151 380.0 3 97 334.1 3.15 243 363,0 2.44
152 322.3 2.31 198 283 1 3 244 358.1 3.48
153 425.1 4.52 199 354.1 2.98 425.1 3.89 54 401.3 3.77 200 335.5 2,49 248 292,9 3.2
155 286.1 2.11 201 303.9 3.08 247 432,1 3.23
156 424.1 3,12 202 404.0 3.19 248 336.3 2.46
157 321.0 2.13 203 394.3 3.42 249 365.0 2.54
158 380.2 3.05 204 349.3 3.32 250 352.3 2.53 59 392.3 2.68 205 455.5 3,74 251 438.2 3.38
160 321.1 1 ,34 206 386.1 3.5 252 368.9 3.17
181 409,2 3.82 207 390.3 2.71 253 424.1 3.25 82 296.3 2.81 208 429.7 3.89 254 340.1 3.08
183 413.1 1.71 209 294.1 2,39 255 528.5 3.89
184 333.1 3.33 210 385.2 3,72 258 306,1 2.4
185 344,1 2,41 211 351.3 3.53 257 297.3 3.28
186 398,1 2.83 212 380.9 2.45 258 " 306.3 2.05
187 294.3 2.12 213 408.0 3.3 259 380.3 3.46
168 265.9 1.96 214 358.1 2.7 280 336.3 2.33
189 318 2.98 215 285.3 3.07 281 388.1 3.08
170 300.3 3.08 218 305.3 2.27 282 352.3 2,7
171 408.0 3.08 217 305.3 2.41 263 372.9 3,89
1 2 396.0 3.14 218 413.2 3.98 264 353.1 3.42
1 3 280.3 2.14 219 266.9 2.48 265 354.9 3.4
174 388.0 2.58 220 409,0 3.35 286 405,3 4.05
175 374.2 2.85 221 379.1 2.88 267 357.1 3.43
176 349.1 3.38 222 324.3 3.27 268 400.3 _6,01__
177 337.1 223 388.1 3.14 289 393.0 2.75
178 413.3 4 224 468,3 3.08 270 329.3 J3.G2
179 308.5 2.33 225 393.1 2.75 271 338.5 2.75 80 307.3 3.08 226 308.1 3.8 272 524.1 1 ,87
181 354.1 2.97 227 381.1 2.24 273 434.5 3.17 82 358.1 2.89 228 371.1 2.84 274 493,5 3.46
183 420.3 229 311.1 2.93 275 427.1 3.93
184 372.3 2.86 230 „.!!§:! 2.81 278 414.3 2,81
- 319 -
S5<MS33,i
Figure imgf000321_0001
-320-
854-1833. ί
Figure imgf000322_0001
S544833.!
Figure imgf000323_0001
- 322 -
8544833.1 Cmd
■Ά 'M+l: "
711 347.8 1.07
712 351.5 1.84
713 430.5 1.12
714 434.5 1.85
715 474.2 1.76
716 383 1.71
717 345 1.73
718 429 1.97
Figure imgf000324_0001
NMR data for selected compounds is shown below in Table 2-A:
Figure imgf000324_0002
- 323 -
8544833.1
Figure imgf000325_0001
- 324-
S54S33.f
Figure imgf000326_0001
Figure imgf000327_0001
Figure imgf000328_0001
Figure imgf000329_0001
1H SMMR (CD30D, 300 UHz) δ 8.90 (s, 1H), 8.51 (s, 1H), 8.44 {d, J = 7.9 Hz, 1H), 7.82 (t, J = 8.3 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.58 (t, J = 7.7
282
Hz, 2H), 7.42 (d. J = 7.9 Hz.1H), 7.07 (d, J = 5.8 Hz, 1H), 2.93 (q, J ~
7.4 Hz, 2H), 1.36 (t, J = 7.5 Hz, 3H).
H- MR (CDCi3, 300 MHz) δ 8.82 (d, J 6.8 Hz, 1 H), 8.29 (d, J = 8.2
283 Hz, 1 H), 8.06 <d, J = 7.9 Hz, 1 H), 7.43 - 7,24 (m, 6H), 7.02 (m, 2H), 6.87
- 6.81 (dd, 2H), 3.76 (s, 3H).
H NMR (400 MHz, DMS0-d6) δ 13.51 (s.1 H), 13.28 (d, J = 8.8 Hz, 1 H), 11.72 (d, J = 2.2 Hz, 1 H).9.42 (s, 1 H), 8,87 (d, J = 6.9 Hz, 1 H).8.04 (d, J
287 = 7.4 Hz, 1H), 7.67 (i, J = 8.2 Hz, 1H), 7.17 {dd, J = 8.3, 0.8 Hz, 1H),
7.01 (d, J = 13.7 Hz, 1H), 6.81 (dd. J = 8.1, 0.8 Hz, 1H), 2. 0 (m, 2H),
1.63-1.34 (m, 8H), 1.26 (s, 3H)
H NMR (400 MHz, DMSG~d8) 513.18 (s, 1H), 12.85 (s, 1H), 8.98 (s, 1H), 8.43 (dd, J = 8.1 , 1.1 Hz, 1H), 8.34 (dd, J ~ 10.3, 3.1 Hz, 1H), 7.93
288
<t, J = 8.4 Hz, 1 H), 7.86 (d, J = 7.7 Hz, 1 H), 7.66 (t, J = 8.1 Hz, 1 H), 7.03 (dd, J = 10.7, 3,2 Hz, 1H), 4.06 (s, 3H), 1.42 (s, 9H)
H NMR (400 MHz, DMS0-d6) δ 1.98 (m, 4H), 3.15 (m.4H), 7.04 (m. 2H).7.17 (d, J = 7.8 Hz, 1H), 7.52 (rn, 1H), 7.74 {d, J = 7.8 Hz, 1H), 7.81
295
(m, 1 H), 8.19 (dd, J = 7.9, 1.4 Hz, H), 8.33 (d. J = 8.1 Hz, 1 H), 8,88 (d,
J = 6.7 Hz, 1 H), 12.19 (s, 1 H), 12.87 (s, 1 H)
1H NMR (400 MHz, D S0-d6) 512.93-12.88 {m, 1H), 12.18 (s, 1H), 8.83 (d, J = 6.8 Hz, 1H), 8.38-8.31 (m.1H), 7.85-7.67 (m, 2H), 7.57-7.51
299
(m, 1H), 6.94 (s, 1H).6.81-6.74 (m, 2H), 3.19-3.16 (m, 2H), 2.68-2.61
(m, 2H), 1.80- .79 (m, 2H)
H NMR (400 MHz, DMS0-d6) δ 13.23 (d, J = 6.6 Hz, 1H), 12.59 (s, 1H),
300 8.87 (d, J = 6,8 Hz, 1 H), 8.33 (d, J = 7.7 Hz, H), 7.86-7.79 (m, 3H),
7.58-7.42 (m, 3H), 3.38 (m, 2H), 1,88 (m, 2H), 1.30 (s, 6H)
H NMR (400 MHz, DMS0-d6) δ 12.96 (d, J = 6.5 Hz, 1H), 12.47 (s. 0.4H), 12,43 (s, 0.6H), 8.87 (dd, J = 6.7, 2.3 Hz, 1H), 8.33 (d. J = 8.1 Hz,
303 1 H), 7,82 ( J = 8.2 Hz, 1 H), 7.75 (d, J = 8.3 Hz, 1 H), 7.82-7.52 (m, 3H),
7. 7 (d, J = 8.3 Hz, H), 4.88 (s, 0.8H), 4.80 (s, 1.2H), 3.66 (t, J = 5.9 Hz, 2H5, 2.83 (i, J = 5.8 Hz, 1.2H), 2.72 (t, J = 5.9 Hz, 0.8H), 2.09 (m, 3H)
1H NMR (300 MHz, DMS0-d6) δ 11.70 (s, 1H), 8.74 {s.1H), 8.15 (s, H).8.07 (m, 1H).7.72 (m, 1H).7.83 (d, J = 8.4 Hz, 1H), 7.45-7.31 (m,
304
3H), 7.15-8.95 (m, 5H), 4. 7 (d, J = 6.0 Hz, 2H)« 4.02 (q, J = 6.9 Hz, 2H),
1.40 (s, 9H), 1.09 (t, J = 8.9 Hz, 3H).
1 H-NMR (CDCI3, 300 MHz) δ 8.81 (d, J = 6,8 Hz, H), 8.30 (d, J = 6.2
307 Hz, 1 H), 8.02 (d, J = 7.9 Hz, 1 H).7.44-7.28 (m.9H), 6.79 (d, J = 7.5 Hz,
1H).
1 H-NMR (d6-Acstone, 300 MHz) δ 8.92 (bs, 1H), 8.40 (d, J= 8.1 Hz.1H), 8.05 (bs, 1H), 7.94 (bs, 1H), 7.78 (bs, 2H), 7.52 (m, 1H), 7.36 (bs, 1H),
318
3.97 (t, J = 7.2 Hz, 2H), 3,68 {t, J= 8 Hz, 2H), 3.31-3.24 (m, 6H), .36-
1.31 (m,4H).
1H NMR (400 MHz, DMS0-d6) δ 12.90 (s. H), 12.44 (s. H), 10.86 (s. 1H), 8.90 (s, H), 8.35 (dd, J = 8.2, 1.0 Hz.1H , 8.12 (t, J = 0.8 Hz, 1H),
320
7.84-7.75 (m, 2H), 7.56-7.52 (m, 1H), 7.3 (d, J = 8.3 Hz, H), 8.99 (dd, j = 8.4, 1.9 Hz, 1H), 6.08-6.07 (m, 1H), 1.35 (s, 9H)
H NIMR (400 MHz, DMS0-d6) δ 2.93 (m, 4H), 3.72 {m, 4H), 7.10 {m. 2H), 7.27 (d, J = 7.8 Hz, 1H), 7.51 (m, 6H), 7.74 (d, J = 8.2 Hz, H), 7.81
321
(m, 1H), 8.40 (d, J = 8.1 Hz, 1H), 8.58 (d, J ^ 8.0 Hz, 1H), 8.88 (d, J =
8.7 Hz, H), 12.69 {s, H), 12.86 (s, 1H)
Figure imgf000331_0001
- 330 -
8544833.1
Figure imgf000332_0001
Figure imgf000333_0001
Figure imgf000334_0001
'Η NMR (400.0 MHz, DMSO-<¾) δ 12.94 (d, = 6,0 Hz. 1 H), 12.24 (s, 1 H), 8.89 (d, J = 6.5 Hz, 1 H), 8.35 (d. J = 7.7 Hz, 1 H), 8.22 (d, J = 8.3
848 Hz. H), 7.82 (t, J = 7.6 Hz, 1 H). 7.76 (d, J = 7.8 Hz, 1 H), 7.55 - 7.51 (m.
J - 7.6 Hz, 1 H), 7.1 1 (s, 1 H), 7.05 (d, J = 8.4 Hz, 1 H), 2.45 (m, 1 H), 2.38
(s, 3H), 1.80 - 1 .69 (m, 5H), 1 .42■ 1.21 (m, 5H).
¾H MR (400 MHz, DMSO) 13.03 (br s, 1 H), 12.34 (s, 1 H), 8.92 {s, 1 H). 7.98 (dd, J 2.9, 9.2 Hz, 1 H), 7.84 (m, 1 H), 7.77 - 7.70 (m, 2H), 7.80 (d,
665
J = 7.4 Hz, 1 H), 7.30 (t. J = 7.9 Hz, 1 H), 7.14 (d, J = 7.9 Hz, 1 H), 1.34 (s,
9H)
1H N R (400 MHz, DMSO-d8) 13.04 (d, J = 6.6 Hz, 1 H), 11.76 {s, 1 H), 9.25 (s, 1 H), 8.90 (d, J = 8.8 Hz, H), 7.98 (dd, J = 9,2, 2.9 Hz, 1 H), 7.88
686
(d, J = 4.6 Hz, 1 H), 7.74 (Id, J = 8.8, 3.0 Hz. H), 7.18 ( , J = 8.7 Hz, 1 H), 7.08 (d, J = 2.7 Hz, 1 H), 8.56 (dd, J = 8.7, 2.7 Hz, 1 H), 1.37 (s, 9H} H NMR (400 MHz, DMSO-d6) 13.06 (d, J = 6.6 Hz, 1 H), 12.07 (s, 1 H), 9.19 (s, H), 8,91 id, J = 8,7 Hz, 1 H), 8.00 (dd, J = 9.2, 2.9 Hz, 1 H), 7.95
684
(s, 1 H), 7.85 (dd, J = 9.1 , 4.7 Hz, H), 7.73 (td, J = 8,6, 2.9 Hz, 1 H), 6,97
(s, 1 H), 2.29 (8, 3H), 1.34 (s, 9H)
[01066] B) Assays for Detecting sad Measurtag AF508-CFTR Correction Properties of Com ounds
[111067] i) Membrane potential optical methods for assaying AF508~€FTR modulation properties of compounds
[01068] The optical membrane potential assay utilized voltage-sensitive FRET sensors described by Gonzalez and Tsien (See* Gonzalez, J, E. and R. Y. Tsien (1995) "Voltage sensing by fluorescence resonance energy transfer in single cells" Biophys J 69(4): 1272-80, and Gonzalez, J. E. and R, Y. Tsien (1997) "improved indicators of cell membrane potential that use fluorescence resonance energy transfer" Chem Biol 4(4): 269-77) in combination with instrumentation for measuring fluorescence changes such as the Voltage/ion Probe Reader (VIPR) (See, Gonzalez, J. E., K. Oades, et al. (1999) "Cell-based assays and instrumentation for screening ion-channel targets" Drug Discov Today 4(9): 431-439).
[01069] These voltage sensitive assays are based on the change in fluorescence resonant energy transfer (FRET) between the membrane-soluble, voltage-sensitive dye, DiSBAC2(3), and a fluorescent phospholipid, CC2-DMPE, which is attached to the outer leaflet of the plasma membrane and acts as a FRET donor. Changes in membrane potential (Vm) cause the negatively charged DiSBAC2(3) to redistribute across die plasma membrane and the amount of energy transfer from CC2-DMPE changes accordingly. The changes in fluorescence emission were monitored using VIPR™ II, which is an integrated liquid handier and fluorescent detector designed to conduct cell-based screens in 96- or 384-well microtiier plates.
- 334 -44833.1 [011)70] Identification of Correction Compounds
[01071] To identify small molecules that correct the trafficking defect associated with AF508-CFTR; a single-addition HTS assay format was developed. The cells were incubated in serum-free medium for 16 hrs at 37 °C in the presence or absence (negative control) of test compound, As a positive control, cells plated in 384-well plates were incubated for 16 hrs at 27 °C to "temperature-correct" AF5Q8~CFTR, The cells were subsequently rinsed 3X with Krebs Ringers solution and loaded with the voltage-sensitive dyes. To activate AF508-CFTR, 10 μΜ forskolin and the CFTR potentiator, genistein (20 μΜ), were added along with CF-free medium to each well. The addition of CF-free medium promoted CI" efflux in response to AF508-CFTR activation and the resulting membrane depolarization was optically monitored using the FRET-based voltage-sensor dyes,
[01072] identification of Potentiator Compounds
[§1073] To identify potentiators of AF5Q8~CFTR, a double-addition HTS assay format was developed. During the first addition, a CF-free medium with or without test compound was added to each well. After 22 sec, a second addition of CF-free medium containing 2 - 10 μ.Μ forskolin was added to activate AF508-CFTR. The extracellular CF concentration following both additions was 28 mM, which promoted CF efflux in response to AF508~CFTR activation and the resulting membrane depolarization was optically monitored using die FRET-based voltage-sensor dyes.
Solutions
Bath Solution #1 : (in mM) NaCS 160, KCS 4.5, CaCl2 2, MgCl2 1 , HEPES 10, pH 7.4 with
NaOH.
Chloride-free bath solution: Chloride salts in Bath Solution #1 are substituted with gluconate salts.
CC2-DMPE: Prepared as a 10 mM stock solution in DMSO and stored at -20°C.
DiSBAC2(3): Prepared as a 10 mM stock in DMSO and stored at -20°C
[ 10 4] Cell Culture
[Θ1075] ΝΪΗ3Τ3 mouse fibroblasts stably expressing AF508-CFTR are used for optical measurements of membrane potential. The cells are maintained at 37 °C in 5% C02 and 90 % humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10 % fetal bovine serum, 1 X NEAA, β-ΜΕ, 1 X pen/strep, and 25 mM HEPES In 175 cm2 culture flasks. For ail optical assays, the cells were seeded at 30,000/well in 384-well
- 335 -
8544833. i matrigel -coated plates and cultured for 2 hrs at 37 °C before culturing at 27 °C for 24 hrs. for the potentiator assay. For the correction assays, the cells are cultured at 27 °C or 37 °C with and without compounds for 16 - 24 hoursB) Electrophysiological Assays for assaying ΔΡ508- CFTR. modulation properties of compounds
[©1077] 1.Ussing Chamber Assay
[01078] Ussing chamber experiments were performed on polarized epithelial cells expressing AF508~CFTR to further characterize the AF508-CFTR modulators identified in the optical assays, ^ ^503-*-^ epithelial cells grown on Costar Snapwel! eel! culture inserts were mounted in an Ussing chamber (Physiologic Instruments, Inc., San Diego, CA), and the monolayers were continuously short-circuited using a Voltage-clamp System (Department of Bioengineering, University of Iowa, IA, and, Physiologic Instruments, Inc., San Diego, CA). Transepithelial resistance was measured by applying a 2-mV pulse. Under these conditions, the FRT epithelia demonstrated resistances of 4 ΚΩ/ cm2 or more. The solutions were maintained at 27 °C and bubbled with air. The electrode offset potential and fluid resistance were corrected using a cell-free insert, Under these conditions, the current reflects the flow of CI" through AF508-CFTR expressed in the apical membrane. The i$c was digitally acquired using an MPIOOA-CE interface and AcqKnowledge software (v3.2.6; BIOPAC Systems, Santa Barbara, CA).
[01079] Identification of Correction Compounds
[01080] Typical protocol utilized a basolateral to apical membrane CI* concentration gradient. To set up this gradient, normal ringer was used on the basolateral membrane, whereas apical NaCi was replaced by equimoSar sodium gluconate (titrated to pH 7.4 with NaOH) to give a large CF concentration gradient across the epithelium. All experiments were performed with intact monolayers. To fully activate AF508-CFT , forskolin (10 fiM) and the PDE inhibitor, ΪΒΜΧ (100 μΜ), were applied followed by the addition of the CFTR potentiator, gemstem (50 μΜ).
[01081] As observed in other cell types, incubation at low temperatures of FRT cells stably expressing AF508~CFTR increases the functional density of CFTR in the plasma membrane. To determine the activity of correction compounds, the cells were incubated with 10 μΜ of the test compound for 24 hours at 37°C and were subsequently washed 3X prior to recording. The cAMP- and genistein-mediated ¾ if* compound-treated cells was normalized to the 27°C and 37°C controls and expressed as percentage activity. Preincubation of the cells
• 336 -44833.! with the correction compound significantly increased the cAMP- and genistein-mediated ¾c compared to the 37°C controls.
[01082] Identification of Potentiator Compounds
[01083] Typical protocol utilized a basolateral to apical membrane Ci" concentration gradient. To se up this gradient, normal ringers was used on the basolateral membrane and was permeabilized with nystatin (360 §/Ηΐ1. whereas apical NaCl was replaced by equimoiar sodium gluconate (titrated to pH 7.4 with NaOH) to give a large CY concentration gradient across the epithelium. All experiments were performed 30 min after nystatin permeabilization. Forskoiin (10 μΜ) and all test compounds were added to both sides of the cell culture inserts. The efficacy of the putative AF5G8~CFT potentiators was compared to that of the known potentiator, genistein.
[01084] So!wtiiffls
Basolateral solution (in mM): NaCl (135), CaC¾ (1.2), MgC¾ (1.2), ¾HP0 (2,4),
KHPO4 (0,6), N-2-hydroxyethylpiperazine-N'-2- ethanesulfonic acid (HEPES) (10), and dextrose (10). The solution was titrated to pH 7.4 with NaOH.
Apical solution (in mM): Same as basolateral solution with NaCl replaced with Na
Gluconate (135),
[01085] Cell Culture
[01086] Fisher rat epithelial (FRT) cells expressing AF508-CFTR (FRT¾F508'CF R) were used for Ussing chamber experiments for the putative AF508-CFTR modulators identified from our optical assays. The cells were cultured on Costar Snapwell cell culture inserts and cultured for five days at 37 ύ€. and 5% C<½ in Coon's modified Ham's F-12 medium supplemented with 5% fetal calf serum, 100 U/mL penicillin, and 100 pg mL streptomycin. Prior to use for characterizing the potentiator activity of compounds, the cells were incubated at 27 °C for 16 - 48 hrs to correct for the AF508-CFTR. To determine the activity of corrections compounds, the cells were incubated at 27 °C or 37 °C with and without the compounds for 24 hours.
[01087] 2.Whol -ceU ecordings
[01088] The macroscopic AF508-CFTR current (IAFSOS) in temperature- and test compound-corrected NIH3T3 cells stably expressing AF5Q8-CFTR were monitored using the perforated-patch, whole-cell recording. Briefly, voltage-clamp recordings of IAF O* were
- 337 -
8544833.1 performed at room temperature using an Axopatch 200B patch-damp amplifier (Axon instruments inc., Foster City, CA). All recordings were acquired at a sampling frequency of 10 kHz and low-pass filtered at 1 kHz, Pipettes had a resistance of 5 - 6 ΜΩ when filled with the intracellular solution. Under these recording conditions, the calculated reversal potential for CI" (Eci) at room temperature was -28 raV, All recordings Siad a seal resistance > 20 GO and a series resistance < 15 ΜΩ. Pulse generation, data acquisition, and analysis were performed using a PC equipped with a Digidata 1320 A D interface in conjunction with Clampex 8 (Axon instruments Inc.). The bath contained < 250 μί of saline and was continuously perifused at a rate of 2 nilJmin using a gravity-driven perfusion system.
[01089] Identification of Correction Compounds
[01090] To determine the activity of correction compounds for increasing the density of functional AF508-CFTR in the plasma membrane, vve used the above-described perforated- patch-recording techniques to measure the current density following 24-hr treatment with the correction compounds. To fully activate AF508-CFTR, 10 μΜ forskolin and 20 μΜ genistein were added to the cells. Under our recording conditions, the current density following 24-hr incubation at 27°C was higher than that observed following 24-hr incubation at 37 °C. These results are consistent with the known effects of low-temperature incubation on the density of AF508-CFTR in the plasma membrane. To determine the effects of correction compounds on CFTR current density, the cells were incubated with 10 μΜ of the test compound for 24 hours at 37°C and the current density was compared to the 27°C and 37°C controls (% activity). Prior to recording, the cells were washed 3X with extracellular recording medium to remove any remaining test compound. Preincubation with 10 μΜ of correction compounds significantly increased the cAMP- and genistein-dependent current compared to the 37°C controls.
[01091] Identification of Potentiator Compounds
[01092] The ability of AF508-CFTR potentiators to increase the macroscopic ΔΡ508- CFTR CI" current (i& os) n NIH3T3 cells stably expressing AF508-CFTR was also investigated using perforated-patch-recording techniques. The potentiators identified from the optical assays evoked a dose-dependent increase in IAFSOS with similar potency and efficacy observed in the optical assays. In all cells examined, the reversal potential before and during potentiator application was around -30 mV, which is the calculated Ea (-28 mV). [01093] Solutions
Intracellular solution (in mM): Cs-aspartate (90), CsCl (50), MgCl2 (1), HEPES (10), and
240 /ίίΐ£ amphotericin-B (pH adjusted to 7.35 with CsOH).
Extracellular solution (in mM): N-raethyl-D-glucamine (NMDG)-Cl (150), Mg(¾ (2),
CaCl2 (2), HEPES (10) (pH adjusted to 7.35 with HC1).
[01094] Cell Culture
[01© 5] ΝΪΗ3Τ3 mouse fibroblasts stably expressing AF508-CFTR are used for whole-cell recordings, The cells are maintained at 37 °C in 5% C<¾ and 90 % humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10 % fetal bovine serum, 1 X NEAA, β-ΜΕ, 1 X pen strep, and 25 mM HEPES in 175 cm2 culture flasks. For whole-cell recordings, 2,500 - 5,000 cells were seeded on poly-L-lysine-coated glass covers!ips and cultured for 24 - 48 hrs at 27 °C before use to test the activity of potentiators; and incubated with or without the correction compound at 37 °C for measuring the activity of correctors.
[01096] 3. Single-channel recordings
[©1097] The single-channel activities of temperature-corrected AF508-CFTR stably- expressed in NIH3T3 cells and activities of potentiator compounds were observed using excised inside-out membrane patch. Briefly, voltage-clamp recordings of single-channel activity were performed at room temperature with an Axopatch 200B patch-clamp amplifier (Axon Instruments Inc.). All recordings were acquired at a sampling frequency of 10 kHz and low-pass filtered at 400 Hz, Patch pipettes were fabricated from Corning Kovar Sealing #7052 glass (World Precision Instruments, Inc., Sarasota, FL) and had a resistance of 5 - 8 ΜΩ when filled with the extracellular solution. The AF508-CFTR was activated after excision, by adding i mM Mg-ATP, and 75 nM of the cAMP-dependent protein kinase, catalytic subunit (PKA; Promega Corp. Madison, Wi). After channel activity stabilized, the patch was perifused using a gravity-driven microperfusion system. The inflow was placed adjacent to the patch, resulting in complete solution exchange within 1 - 2 sec. To maintain AF508~CFfR activity during the rapid perifusion, the nonspecific phosphatase inhibitor F (10 mM NaF) was added to the bath solution. Under these recording conditions, channel activity remained constant throughout the duration of the patch recording (up to 60 min). Currents produced by positive charge moving from the intra- to extracellular solutions (anions moving
- 339 -
8544833.1 in the opposite direction) are shown as positive currents. The pipette potential (Vp) was maintained at 80 mV.
[0109S] Channel activity was analyzed from membrane patches containing < 2 active channels. The maximum number of simultaneous openings determined the number of active channels during the course of an experiment. To determine the single-channel current amplitude, the data recorded from 120 sec of
Figure imgf000341_0001
activity was filtered "off-line" at 100 Hz and then used to construct all-point amplitude histograms that were fitted with multigaussian functions using Bio-Patch Analysis software (Bio-Logic Comp. France). The total microscopic current and open probability (P0) were determined from 120 sec of channel activity. The P0 was determined using the Bio-Patoh software or from the relationship P0 ~ I/i(N), where I ~ mean current i = single-channel current ampSifude, and N ~ number of active channels in patch,
[01099] Solutions
Extracellular solution (in mM): NMDG (150), aspartic acid (150), CaCl2 (5), MgCl2 (2), and HEPES ( 10) (pH adjusted to 7.35 with Tris base).
Intracellular solution (in mM): NMDG-C1 ( 150), MgC¾ (2), EGTA (5), TES ( 10), and
Tris base (14) (pH adjusted to 7.35 with HC1).
[01100] Cdl Culture
[01101] NIH3T3 mouse fibroblasts stably expressing AF5Q8-CFTR are used for excised-membrane patch-clamp recordings. The cells are maintained at 37 °C in 5% C02 and 90 % humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10 % fetal bovine serum, 1 X NEAA, β-ΜΕ, 1 X pen/strep, and 25 mM HEPES in 175 era2 culture flasks. For single channel recordings, 2,500 - 5,000 cells were seeded on poiy-L- lysine-coated glass coverslips and cultured for 24 - 48 hrs at 27 °C before use.
[01102] Compounds of the invention are useful as modulators of ATP binding cassette transporters. Table 3 below illustrates the EC50 and relative efficacy of certain embodiments in Table 1.
[01103] in Table 3 below, the following meanings apply:
EC50: "+·++" means <10 uM; "++" means between lOuM to 25 uM; "+" means between 25 uM to 60uM.
% Efficacy: "+" means < 25%; "++" means between 25% to 100%; "+++" means > 100%.
- 340 -
S544833.I 223306/VPI04- l25WOCPI/tbd
Figure imgf000342_0001
854-1833.1
Figure imgf000343_0001
-342-
8544833.1
Figure imgf000344_0001
- 343 - 4 S33.i
Figure imgf000345_0001
-344-
8544833. S
Figure imgf000346_0001
-345-
8544833.1

Claims

What is claimed is:
1. A compound selected from:
6,7-d!fluoro-N-(2-fluoro-5-hydroxy-4-iert-butyi-phenyi)-4-oxo-lH-quinolme-3-- carboxamide;
5- hydroxy-N-[5-hyckoxy-4-teri-butyl-2-(^^
carboxamide;
4- oxo-N-[3-(l-piperidyI)-5-(trifliioromethyl)phenyll-lH-quinoline-3--cai-boxaraide; N-[4-(3,3~dimethylpyrro!idin- 1 -yl)-2-(trifluoromeiliyl)phenyl]-6-iT5eiliyl-4-oxo- 1H~ qiiinoline-3-carboxamide;
6- fluoro-N-(3-hydroxy-4-ter -butyl-phenyl)-4-oxo-lii-qumoline-3-carboxaniide;
N-(3-fluoro-4-tert~butyl-phenyl)-5-hydroxy-4--oxo-lH-quinoiine-3-carboxamide;
methyl l-[4-[(4-oxo- lH-quinolin-3-yl)carbonyiamino]-3-
(trifiuorometliyl)phenyI]piperidine-2-earboxylate;
5- hydroxy-N-[4-[2-hydroxy- i -(hydroxymethyi)- 1 -niethyl-ethyljpheny !]-4-oxo- 1 H- quinoline-3-carboxamide;
5~hydroxy-4-Qxo~N-[5-{trifluorGmeffiyl^^^
6- f luoro-4-oxo- N- [2-(trifluoromethy I)- 1 H- indol-6-y 1]- 1 H-quinoline-3-carboxamide; N-(5-hydroxy-2,4-diiert-buiyl~phenyl)-6-medioxy-4-oxo-lH-quinoline-3-carboxaraide; N-[5-hydroxy-4-isopropyl-2-(trifluorometliyl)phenyI]-4-oxo-lH-quinoline-3- carboxamide;
N-[2-fluoro-5-hydroxy-4-( 1 -me&^
3-carboxamide;
N-[2-fluoro-5-hydroxy-4-( 1 -meihylcyclohexyl)-phenyl]-7-methyI~4~oxo- IH-quinoline- 3-carboxamide;
5-hydroxy~4~oxG-N-(5-tert-buty 1- 1 H-indol-6-yl)- 1 H-quinoline-3-carboxamide;
N-[2-fluoro-5-hydroxy-4-(irifIuoromeihyl)phenylJ-4-oxo--SH-quiEoliiie-3-carboxa!nide;
5- hydroxy-N-[3-methoxy-5-(trifIuoromethyi)phenyl]-4-oxo-lH-quinoline-3- carboxamide;
6- methyl-N-[4-(2-methylpyrrolidin- 1 -yi)-2-(trifl oromethyl)plienyl]-4-oxo- 1H- quinoiine-3-carboxamide;
N-[4-(3.3-dimethylpyrrolidin ^
qumoline~3~carboxamide:
8-cyano-N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4--oxo-lH-quinoline-3-carboxamide; N-[3-hydroxy-4-{irifluorGmethyl)phenyl]-4-oxo-lH-quinoline-3-cai-boxan-iide;
- 346 -
8544833. ί N-(2~e†hyl~5~hydroxy-4-tert^
carboxaraide;
4H xo-N~[3~iert~butyl~5~i fluorome^
6-fluoro-N-[5-hycfroxy-4-iert-buiyl-2-(iniluofomethy!)pheiiyl]-4-oxo-lH-quinoline-3- carboxamide;
4-oxo-N-[3-( 1 -piperidyi)-4-tert~buiy!~phenyl]- 1 H-quinoIme-3-car boxamide;
(S)-5~memy!~N-{4-(2-raethylpyrro!idm~ ί ~yl)-2-{irifluoromethyl)phenyi)-4-oxo- 1 ,4- dihydroqu inoline · 3 -carboxamide;
N-[4-cyclopentyl-5-hydroxy~2-(3- ydroxyprop- 1 -ynyl)phenyl]~4-oxo- iH-quinoSine-3- earboxamide;
(S)~N-i4-(3-(dimethyiamino)pym>ik1in- 1 -yI)-2-(trifl oromeihyl)phenyl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide;
4-oxo-N-[2-(I-piperidyl)-4-(irifluororaeiliyi)pheny]l-lH-quiiio!ine-3-carboxaniide;
N-(5-hydroxy~2,4~ditert-butyl-pe^^
carboxamide;
N-i4~((2S S)-2,5~dinie ylpym3lidin~i-yl)-2^
l,4-dihydroqiiinolme~3-carboxamide;
8-efeoxy-N-[4-isopropy!-2-( fluoroniethyl)pheeyi]-4-oxo-lH-qmnoline"3- carhoxamide;
N-(5-hy€koxy-2-raemyl-4-ter^buty!-phenyl)-4-oxo-lH-quinoline-3-carboxaniide;
8-cyano-N-(2-fluoro-5-hydroxy~4- ert-b tyl-pheny!)-4-oxo-lH-quinoline~3- carboxamide;
N~(5~hydrQxy-2,4-diiert~butyI-phe^^
carboxamide;
6-fluoro-N-[4-(3-meihyloxefan-3-yl)phenyl]~4-oxo-ni-quino!me-3-carboxamide; N-(4-cyclohexyl-3-hydroxy-phenyl)-5-hydroxy-4-oxo-IH-quinoIiiie-3-cai-boxaniide; N- [4-(3 -meihyloxetan-3 -yl)phenyl] -4-oxo- 1 H-quinoline-3 -carboxamide ;
6-ethoxy-N-(5-hydroxy-2,4-diiert-butyl-phenyl)~4-oxo-lH-quinoIine-3-carboxamide; 6-cyano-N-(5-hydroxy-2,4-diieri~bu yl-phenyI)-4-oxo-lH-quinoliiie-3-carboxaniide; 8-eihoxy-N-(2-fluofo-5-hydroxy-4-iert-butyl-phenyl)-4-oxo-lH-qoinoline-3- carboxamide;
6-fluoro-N-(3-fluoro-4-terl-buiyi-phenyl)-4-oxo-lH-quinolii e-3-carboxamide;
N-[4-(3,3-difluoropyiTolidm-l-yl)-2-(trifluoromethyl)phenyl]-5~methyI-4-oxo-lH quinoline-3-carboxan ide;
- 347 -
8544833.1 5 -hydrox y-N- [4-{3 -rnethy loxetan-3 -y l)phenyl] -4-o xo- 1 H-quinol ine-3 -carbox amide ;
(2S,3S)-meihyl 3~meihyl-l-(4-(4H xo-l ,4-dihydroquinoline--3-carboxainide)-3- (trifluoromeihyl)pSienyl)pyn'oiidine-2-carboxylate;
(lS,2S,5R)~methyl 3-(4-(4-oxo-i,4-dihydroq inoline-3-carboxaniide)-3- (trifluororneihyl)phenyl)~3-azabicyclo[3.1,0]hexane-2-carboxylate;
N~[2-c oro-4-(irifluoromethyI)phenyl]-4~oxo-lH-quinoline-3-carboxamide;
6'meAoxy-4H^xo-N-(5-iert~buSyl'lH-indol-6-yl)- SH-quinoiine-3--cai-boxaEiide;
(R)-N-(4-(3-(dimeihylamino)pyrro!idin- 1 -yI)-2-(frifluoromeihyl)phenyI)-4-oxo- 1 ,4- dihydroqumoline~3~carboxamide;
5- hydroxy-4-oxo-N-(3-tert-butyl- lH-indol-6-yl)- 1 H-quinoline-S-carboxamide;
N-[4-(3,3-dimethylpyrroIidin- l-yl)-2-(trifluoromethyl)phenyl]-4-oxo- 1 H-quinoline-3- carboxamide;
4-oxo-N~[2-(trifluoix>meihyl)-lH-indol-6-yi]-lH-quinoline-3-carboxaniide;
N-[2~meihyl-4-(irifluoromeiiioxy)phenyl3-4-oxo- IH-q inoHne-3-carboxamide;
N-(4-((2 ,5R)-2,5-dimeihylpyn,olidin-l-yi)-2-(trifluoromethyl)phenyi)-5-methyl^ i,4-dihydroquinoline-3-carboxamide;
(R)-tert~butyl 1 -(4-(4~oxo- 1 ,4-dIhydroquinoline-3-cai-boxan'side)-3~
(trifluoromethyl)phenyl)pyiTolidme-2-carboxylaie;
(R)-N-(4-(3-0uofopyrrol.idin- 1 -yl)-2-(irifluoromethy l.)phenyl)-5-methyl-4-oxo- 3 ,4- dihydroquinoline-3-carboxamide;
N-(5-hydroxy-2,4-ditert-butyl-phenyl)-5-meihyIamino-4-oxo- lH-quinoline~3- carboxamide;
4-oxo~N-[4-( 1 -piperidyl)phenyl]~ IH~quinoline-3-carboxamide;
6- dimeili>1aniino-N-(5-hydroxy~2,4-ditert-buiyl-pheriyi)-4-oxo-iH-q inol3ne-3- carboxamide;
4- oxo-N- [3 -(trif iuoromeifay 1)- 1 H-i ndol-6-y I] - 1 H-quinoline-3 -carboxamide ;
5- memyl-N-[4-(3-nieihylpyrrolidin-l-yl)-2-(iiif!uoromeihyl)phenyl]-4-oxo- iH- quinoline-3-carboxamide;
N-[4-isopropoxy-2-(trifluoromethy3)phenyl]-5~methyl-4-oxo-lH-qmnoline-3- carboxamide;
7- cyano-N-(5-hydTOxy-2,4-ditert-butyl-phenyl)-4-oxo-lH-quinoline-3-caxboxamide; 4-oxo-N-[3-(2-ihienyI)phenyl]- lH-quinoline-3-carboxaraide;
(2S,4R)-methyl 4- eri butoxy- 1 -(4-(4-oxo- 1 ,4-dihydroqumoline-3-carboxainide)-3-
(trifluoromeihyl)phenyl)pynOlidine~2-carboxylalje;
- 348 -
85-14833.1 N-(4-hydroxy-2-naphthyl)-4~oxo-lH-quinoIine-3-carboxamide;
5- fluoro-N-(5-hydroxy-2,4-diteri-butyi-pheiiyl)-4-oxo-lH-quinoSine-3-carboxaniide;
6- bromo-N-(5-hydroxy-2,4-di iert~butyl-phenyl)-4-oxo- 1 H-quinoline-3-carboxamide; 6-fluoro-4-oxo-N-(3-iert-butyl-lH-indol-6-yl)-lH-q inoline-3-carboxamide;
N-[4-{3-methylpyrrolidm- 1 -yl)-2-(tri fluoromethyl)phenyi]-4-oxo- lH-quinoline-3- carboxamide;
N-[4 (2,2-dimethyipropanoylaminQ)-2-(m
carboxaraide;
6- fluoro-N~[4-isopropyl-2-{trifl oromethyl)phenyl3-4-oxo-lH-quinoHne-3-carboxamide;
7- cyano-4-oxo-N-(5-iert-butyl- 1 H-indol-6-yl)- 1 H-quinoline-3-carboxamide;
4- oxo-N-(5-iert-butyl-lH-indol-6-yl)-8-(tiifluoromethyI)-lH-quinoline-3-cai-boxaniide; N~[4~(2,5-dimethylpyiTGl -yl)-3-nretto
6-chIoro-N-(2-fluoro-5-hydroxy-4-tert~butyl-phenyl)-4-oxo-]H-quirioline-3- carboxamide;
6-fluoro-4-oxo-N-[4-pyiTolidin- l-yl-2-(lTifluoronieihyl)phenyll-lH-q molme-3- carboxanude;
N-[3-hydroxy-5-(trifSuorometiiyl)p enyl]-4-oxo-lH-quinoline-3-carboxamide;
N-(4-cyclohexyl-3-hydroxy-phenyl)-4-oxo-lH-quinoline-3-carboxamide;
5- rae hyl-4-oxo-N-(5-iert-butyl-lH-indol-6-yl)-iH-quinolme-3-carboxamide;
6- fluoro~KHH2~m6thoxyethyl)-5-(t^
carboxamide;
(S)-l-[4-[{4-oxO"iH-quinolin-3-yl)carbony3amino]-3- (irifluoromeihyl)phenylJpyn'oSidme-2-carboxylic acid;
N-(5-hydroxy-2,4~ditert-butyl-phenyI)-5^
N~(4~i(2R,5R)~2,5-dimethyIpyrroIidin^^
I54-dihydroquinoline-3-carboxamide;
N-[5-benzyioxy-4-isopropyl~2-(irifluoromeihyl)phenyl]-4-oxo-lH-quinoline-3- carboxanude;
N-[6-met oxy~5-(irifluoromeihyl)-2-pyridyll~4-oxo-lH-quinoline-3-carboxamide;
(R)-N-(4-(2-methylpyrrolidin- l-yl)-2-(trifiuoromethyl)phenyl)-4-oxo- 1 ,4- dihydroq inoline-3-carboxamide;
8- fl oro-N~[4~isopropyl-2-(trifl orometlwl)phenyl]-4-oxo-iH-quiiioHne-3-carboxamide; 6-fluoro-N-[3-hydiOxy-5-(irifluoromeihyl)p enyl]-4-oxo-lH-q inoline-3-carboxamide; N-(3-hydroxy-4-3sopropyl-phenyl)-4-oxo-3H-quinoSine-3-carboxamide;
- 349 -
8544833.1 7~methyl-4-oxQ-N-[5~(tnfiuorome&^
N-[2-meiliyl-5"(triflMoronie hyI)phenyl]-4-oxo-lH-quinoniie-3-cai'boxanMde;
N- [4-(3 , 3 -diraeihylpy rrol idin- 1 -y l)-2-(trifluoroi5ie hyl )pheny 1] -5-meihy 1-4-oxo- 1 H- quinoline~3~carboxamide;
4- oxo-N-[3-pyrrolidin- 1 ~yl-4-(trifiuoromethoxy)phenyl]~ lH-quinoIine-3-carboxamide; N-(5-hydroxy-2,4-ditert-bu(yl~phenyl)-4~oxo-8-(trifluofomethyi)-lH~quinolme- carboxamide;
(S)~5~methyl~N-(6-(2-methylpynOlidm^
dihydroquinoiine-3-carboxamide;
N-(4-(( lS,4R)-2-azabicyclo[2.2.1 ]heptan-2-yl)^2-(Srifluoromethyl)phenyl)--5-methyl-4- oxo- 1 ,4-dihydroquinoline-3-carboxamide;
N-(5--hydroxy-2,4-diiert-butyl--phenyI)-7-methoxy-4--oxo-lH-qutnoHrie-3-carboxaniide;
N-[2-fluoro-5-hydroxy-4-(l-methylcyclohexyl)-phenyl]-6-me1¾oxy~4-oxo- lH-quino]ine- 3-carboxarnide;
5- am3no-N-{5-hydroxy-2,4-diiert-buiyl-phenyl)-4-oxo- lH-quinoiine-3-carboxainide; (R)-N-i4-(2-met ylpyiTolidin-l-yl)-2-(irifluorome hy!)phenyl)-4-oxo-5-
(Sxifiuoromethyl)- 1 ,4-dihydroquinoline-3-carboxamide;
5-hydroxy-N-(3-hydroxy-4-isopropyl-phenyl)-4-oxo- lH-quinoline-3-carboxamide;
5- hydroxy-N-(5-hydroxy-2-me hyi-4-tert-bistyl-phenyl)-4~oxo-lH-quinoline-3- carboxamide;
6,7-difluoro-N--[4-isopropyl-2-( rif3 oromethyi)phenyl]-4-oxo-lH-quinoline-3- carboxamide;
N-[4 2-hydroxy- l-(hydroxyme^^
carboxamide;
N-(5-eihyl- lH-indol-6-yl)-5-hydroxy-4-oxo-lH-quiiioHne-3-carboxaniide;
N-(4-((2R,5S)-2,5-dim thylpym^idin-l-yl)"2-{ fluoromeihyl)phenyl)--5-niethyl-4-oxo- l,4-dihydroquinoline-3-carboxamide;
4-oxo-N-[3-pyrrolidin- 1 -yl-5-(trifluoromethy phenyi]- lH-quinoline~3-carboxamide;
N-(3-hydroxy-2,4-diiert-butyI-phenyl)-4~oxo-iH-quinoline-3-carboxamide;
N-[4'Cyclopenioxy-2-(trif3uoromeihyI)phenyl]-5-methyl-4-oxo-lH-quinoiine-3- caiboxamide;
N-(5-fluoro~lH-indol~6-yl)-5 iydroxy-4-oxo-lH-quinoline-3-carboxamide;
6- fluoro-N-(3-hydroxy-4-is propyl-pheny!)-4-oxo-iH-qumoIine-3-carboxan'iide;
N-[4-rao h.o! πo-2-(triflιsoromeίhyl)phenyl3-4-o o-lH-quirloline-3-carbo araide;
- 350 -
8544833.1 5- hydroxy-N-[3-hydroxy-5~(trifluoromeihyl)phenyS]-4-oxo-lH-quinoline-3- carboxamide;
tert-butyl [[4 (4-oxo-lH-q molin-3~yI)carbonylainino]-3- (t£-ifluororoethyl)phenyllamino]formate;
(S)-6-methoxy-N~(4-(2-meiliyIpyrrolidin- 1 -yl)-2-(irifSi3oroniethyS)phenyl)-4-oxo- 1 ,4- dihydFGqumoltae-3-earbGxainide;
4- oxo-N-(3-tert-bulylp eiiyI)-lH-qumoline-3-cai-boxamide;
6- chloro-4-oxo~N-(5 ert-bt yS-lH-indol-6-y])-iH-quinoline-3--carboxaniide;
7- acetyl-N-(5 iydroxy-2,4-ditert-buiyl-phenyI)-4-oxo-lH-qui!ioSine-3-carboxaniide;
8 -eihyS-N-(2'fl oro-5-hydroxy-4-iert-buiyl-phenyl)-4-oxo- 1 H-quinoline-3-carboxamide;
5- hydroxy-N-[3-hydroxy-4~(l-meti ylcyclohexyl)-phenyl]-4-oxo~lH~quii oSine-3- carboxamide;
(S)-7-metliyl-N-(4-(2-raethylpynOlidin- 1 -yl)~2~(irifiuoromeihyi)phenyS)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide;
N-(2,4-dichforo-5-hydroxy-phenyl)-4-oxo-lH-quinoline-3-carboxamide;
5-hydroxy-N-(5-hydroxy-2-iert-buiyl-phenyl)-4-oxo-lH-quinoline--3-cai-boxaraide;
5- fl oro-N-(2-fluoro-5-hydroxy--4-tert-buiyl-pheiiyl)-4-oxo-lH-qumoliTse-3- carboxamide;
7-fl oro-6-ineihoxy-4-oxo~N~(5-teri-butyl- lH-indol-6- !)~ 1 H-quii oline-3-cai'boxaniide; N-[4-(3,3-dimethyl- 1 -piperidyl)-2-itrifl oromethy l)phenyl]-4-oxo~ 1 H-quinoline-3- carboxamkle:
(R)-5-methyl-N-(4-(3-methylpyrrolidin- 1 -yl)-2-(crifluororoeihyl)phenyl)-4-oxo- 1 ,4- dihydroquinoIine-S-carboxarnide;
4- oxo-N- [4-(3 -pyridyiox y )pheny I] - 1 H-qumol ine-3 -carboxamide;
N~(2~methy 1-4-pyrrolidiii- 1 -yl-phenyl)-4-oxo- lH-quinoline-3 -carboxamide;
8~eihoxy-N-(5-hy<iroxy-2t4-diiert-bu^
6- fluoro-N-(5-hydroxy-2,4-diteri~but}4~pheiiyl)-7-memoxy-4-oxo-lH-quinoline-3- earboxamide;
{S)-N-(4-(2-methy!pynOlidin- 1 -yl)-2-(trifluoromeihyl)phenyl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide;
N-[4-cyclohexyl-5-hydroxy-2-(triiluoromethyl)phenyl]-4-oxo~iH-quinoline-3- carboxamide;
5- hydroxy-4-oxo-N-(3"tert-butylpheiiyl)-lH-quinoline-3--carboxamide;
N-(5-hy koxy-2,4- itert~butyI-ph^
- 351 -
S544S33.1 N-(2-cyajio-4-pyn,olidin- l-yi-phenyl)-4-oxo-lH-quinoiine-3-carboxaimde;
6-chiGFO-N~(5~hydrQxy-2,4~ditert~butyl^
N-[2-fluoro-5-hydroxy-4-(l-methylcycSohexyl)-pheny!]-6-meihyl-4-oxo-lH-quinoline- 3-carboxamide;
N-(2-fluoro-5 -hydrox y-4-tert-b iyl-pheny l)-8 -meiliyI-4-oxo- 1 H-quinoline- 3 - earboxamide;
(S)-N-(4-(3-fiuoropym>Iidin- 1 -yl)-2-(trifluoromethyi)pheEyl)-5-metl¾yI-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide;
6-fl uoro-N- [4- [2~hy droxy- 1 -{hydroxymethy 1)- 1 -methyl-ethyl] phenyl] -4-oxo- 1 H- quinoline-3~carboxaffiide;
-[2 hloro-4-(irifluoromethoxy)phenyI]-4"Oxo-lH-quinoiiiie-3-carboxamide;
(S)-tert-butyl 1 -(4-(4-oxo- 1 ,4-dihydroquinoline-3-carboxamide)-3- (tri luoromethy])pheny!)pyrrofidine-2-carboxylate;
N-[2,5-bis(trifluoromethyl)phenyl3-4-oxo-lH-quinoiine-3-carboxamide;
(S)-methyl 2-methyI- 1 -(4-(4-oxo- 1 ,4-dihydroquinoline-3-carboxamide)-3- (trifluoromethyl)phenyl)pyrroiidine-2-carboxylate;
4- oxo-N-(5-tert-butyI-lH-indol-6-yl)-7-(i^
5- hydroxy-N-(3-hydroxy-4-teit-butyl-phenyl)-4-oxo-lH-quinoiine-3-carboxami<le; (S)-N-(4-(2-(hydroxyniethyl)pyrrolidin-l-yl)-2-(irifiuoromethyi)phenyl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxajnide;
N 2-chloro-4-(irifiuoromeihyl)phenyi]-5-hydroxy-4-oxo-lH-quinoline-3-carboxamide;
N-[2-ch!oro-4-(irif]uoromeihyi)phenyl]-6-fluoro-4-oxo-lH~quinoline-3-carboxajTiide;
N-[4-isopropyl-2-(irifiuoromeihy!)phenyl]-8-meihyl-4--oxo-lH-quino!iiie-3- carboxamide;
N-(2-fluoro-5-hydroxy-4-tert-butyl-phenyl)-4-oxo-8-(irifluoromeiliyl)-lH-quinoline-3- carboxamide;
N~[4-(4-isopropyIpiperazin- l-yl)-2-(irifluoromethyl)phenyl]-4--oxo-lH--quiEolme~3- carboxamide;
N-(5-hydroxy-2 -diiert-buiyl-phenyl)-7-metiiyi-4-oxo-] H-quinoline-3-caxboxamide;
8-ethoxy-4-oxo-N~(5-tert-buiyl-lH-indoi-6-yl)-lH-quinoline-3-carboxamide;
(S)-7-methoxy-N-(4-(2-methylpyrroi idin- 1 -yl)-2-(trifluoromethyl)phenyl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide;
5-methyl-N-[4-(3-methyl- 1 -piperidyl)-2-(trifluoromethyl)phenyI] -4-oxo- 1 H-quinoIine-3- carboxamide;
- 352 -
85 1333.1 8-meihyl-4-oxo-N-(5-tert-b iyl- lH-iiidof-6-yi)- 1 H~quinoiine-3-carboxamide;
N-(3~fluoro-4-tert-buiy'I-phenyr)-4-oxo-lH-quinoIine-3-carboxamide;
6,7-difSi3.oro-4-oxo-N-(5-tert-buiyI'lH-indoI-6-yi)- 1 H-quinoline-3-carboxamide;
N-(4-cyclohexyl-2-methy{-phenyi)-4-oxo-lH-quinolme-3-carboxamide;
5- hydroxy-N-[4-isopropyl-2-(trifluoromeihyi)phenyl]-4-oxo-lH-q inoline-3- carhoxamide;
N-(2-eibyl-5-hydroxy~4-tert-butyl-phenyl)-6-fluoro-4-oxo~lH-quinolijie-3-carboxami
6- fluoro-N-[3-hydroxy-4-(trifluoromethyl)phenyl]-4-oxo-lH-quinoline-3-carboxamide; N-(4-cyclohexyl -3-hydroxy-phenyl)-6-fluoro-4-oxo- 1 H-quinoline-3-carboxamide;
7- hydfOxy-N-(5-hydroxy-2,4-diieri-butyi-phenyI)-4-oxo-lH-quinoline-3-carboxatTiide;
8- eihyl-4-oxo-N-(5-tert-buiyI-lH-indol-6~yl)-lH-quinoline-3-carboxainide;
N-[5-benzyloxy-4-cyclohexyl--2-(!rifluoromethyl)phenyI]--4-oxo-lH-quinoSine-3- carboxaniide;
(S)-N-(4-{3-hydroxypyrrolidin- 1 -yl)-2-(trifluoromeihyl)phenyl)-4-oxo- 1 ,4- dihydroq irsoHne-3-carboxamide;
5- fiuoro-4-oxo-N-(5-teri-butyl- 1 H-indol-6-y 1)- 1 H-quinoline-3-carboxamide;
6- chloro-N-[4-isopropyi-2-(trifluoromeihyl)phenyl]-4-oxo-lH-quinoline-3-carboxamide;
4- oxo-N-[4-pyrrolidin- 1 ~yl-2-iirifluoromethyl)phenyl]- 1 H-quinoline-3-carboxamide; N-(2-einyI-5-hydroxy~4"tert-b tyl-phenyl)-4-oxo--lH-qtiinoline-3-carboxamide;
(S)~ethyl I -(4-(4-oxo- 1 ,4-dihydroquinoline-3-carboxamide)-3-
(trif!uoromethyl)phenyl)piperidine-3-carboxylate;
5- methyl-4-oxo-N-[5-(tri luoromethyl)- 1 H-indol-6-yi]- 1 H-quinoline-S-carboxainide; N-(5-Siydroxy-2-iert-buiyi-phenyI)-4-oxo-lH-quinoline~3-carboxamide;
8-chloro-N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-lH-quinoIine-3-carboxami 6~fluoro-4-oxo-N~(3-tert-buiyiphenyl)-IH-quinoIine-3-carboxamide;
6- fluoro~N-(5-hydroxy-2-tert-buty!-pheEyl)~4-oxo-lH-qiimoline-3-carboxamide;
6-fluoro-N-[3-methoxy-5-(trifluorometliyl)phenyl]-4-oxo~lH-quiiioiine-3-carboxamide; {R)~N-(4~(4,4-difluoro-2~meihylpynO m-^
oxo- 1 ,4-dihydroquinoline-3-carboxamide;
N-[4-[4-(hydroxymet yl)-l-piperidyl]-2-(trifluoromeihyl)phenyl3-4-oxo-IH- carboxamide;
(S)-N-(4-(2-methylpyrrondin-l-yi)-2-(tTifSuoromethyl)p enyl)-4-oxo-5~
(trifluoromethyl)- ,4-dihydroqumoline-3-carboxamide;
- 353 -
S544Sr>.i (R)- -(4-(2-(hydroxy methyI)pyrrolidin- 1 -yl)-2-(trifluororaethyl)phenyl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxamide;
N-(2-aminobenzothiazol-6-yl)-4-oxo-lH-quinoSme-3-carboxamide;
6s7-difl oro-N-(5-hydroxy-2,4-diiert-bulyS-phei yS)-4-oxo-IH-q inoline-3-carboxani
N-[4-[4-(2-hydroxyethyl)piperazin- 1 -yi]-2-(trif!uoromeihyl)phe!iyi]-4-oxo- 1 H- q moline-3~carboxamide;
4- oxo-N-(4-pyrrolidin- 1 -ySphenyl)- lH-qumoIine-3-carboxamide;
N-(2-metj:\oxy-4-pyrTolidin-l~yl'phenyl)-4-oxo-lH-quinoiine-3-carboxamide;
5- hydroxy-N-[2-meihyl-5-( fluoromethyl)phenyl]-4-oxo-lH-quinoline-3-carboxamide;
7- cyano-N-(2-fluoro-5-hydroxy-4-tert-buiyI"p enyl)-4-oxo-lH-quinoSine-3- carboxamide;
6- fluoro-N-[2-meihyI-5-(irifluoromeihyI)phenyl]-4-oxo-lH-quinoline~3-carboxainide; 6~hydroxy-4-oxo-N-(5~tert-butyl- ί H-indol-6-yl)- lH-qutnoline-3-carboxamide;
8- fluoro-4-oxo-N-(5-iert-butyS-lH-mdol-6-yS)-iH-quinolme-3-caiboxamide;
6-eihoxy-4-oxo-N-(5-tert-buty!-iH-indoi-6-yl)-lH-quinoHne-3-carboxamide;
8-eihyl-N-[4-isopropyl-2-itrifli3oromeihyl)phenyI3-4-oxo-lH-quinofine-3-carboxamide: 6-fluoro-N~(5-hydroxy-2-meihyl-4-iert--butyl~phenyl)-4--oxo--lH-quinoline-3- carboxamide;
(R)-6-fluoro-N-(4-(2-meihy Ipyrrolidin- 1 -y!)-2 trifiuoromeihyi)phenyl)~4~oxo- 1 ,4- dihydroquinoIine-3-carboxamide;
N-(4~((2R,5R)~2s5~dimethylpynOSidin^^
oxo- 1 ,4-dihydroquinoline-3-carboxamide;
4-oxo-N-[4-( i -piperidyf )-2~itriflu^^
8 -fluoro-N-(5-hy drox y-2,4-di tert-buty I-phesiy l)-4-oxo- 1 H-quinol ί ne-3-earboxaraide ; N-(5-hydroxy-2,4-diteri-buiyS-phenyl)-6-mediyl-4-oxo-lH~quinoline-3-carboxamide; N-[4-azetidin- 1 -yl-2~(trifluoromethyi)phe«yS]-4-oxo- iH-quinolme-3-carboxamide methyl 4-[(4-oxo-lH-qumolin-3-yl)carbonylamino]-2-tert-butyl-ihiop ene-3- carboxylate;
N-[3-raeihoxy-5-(trifluororoeihyl)pheiiyl]-4-oxo-lH-quinoIine-3-cm-boxamide;
4- oxo~N~[2~{2-pyridyl)phen.yI]- i H-quinoline-3-carboxamide;
5- hydroxy-4-oxo-N-[2-(trifluoromeihyl) H ndoi-6-yl]-lH-quinolme-3-caiboxaniide; N-(5-hydroxy-2,4-diiert-bi}t)4-phenyl)-4-oxo-7-(irifluoromeihoxy)-lH-quinoIine-3- carboxamide;
N-(4-cMoro-2-fluoro-5-hydroxy--pheJiyI)~4-oxo-lH-quinoHne-3-carboxamide;
- 354 -
8544833.1 4- oxo-N-[3-( 1 -pjperidyl)-4-(irifl oromeihoxy)phenylj" lH-quinoline-3-carboxamide; (R)-5-methyl-N-(4-(2-methylpynOlidin- 1 -yl)-2-(trifluoromethyl)phenyl)-4-oxo- 1 ,4- dihydroquinoIine-3-carboxamide;
(R)- 1 -[4-[(4-oxo- 1 H-quinolin-3-yl)carbonylammo]-3- (trifluoromethyl)phenyl]pyrrolidine-2-carboxyiic acid;
5- fluoro-N-[4-isopropyl-2-(irifluoromethyi)phenyI]-4-oxo-lH"quinoline-3-carboxaiBide; 5~hydroxy-N-[3-hydroxy--4-(trifluoromethyl)pheiiylJ-4-oxo-lH-quinoline-3- carboxaniide;
N-(3-hydroxy-4-isopropoxy-phenyl)-5-meihyl-4-oxo-lH-qi!inoSine-3-carboxanHde;
6- hydroxy-N-(5-hydroxy-2,4-diieri-buiyl-phenyi)-4-oxo-lH-quinoIine-3-carboxaraide;
6- fl uGro-4-oxo-N- [5 ~{iri fluoromefty I)- 1
7- meihyl-4-oxo-N-(5~iert-buiyl-lH-indol-6-y!)-lH-quinolme-3-carboxamide;
(R)-N~(4~(3-hydroxypyrrolidin- 1 -yl)-2-(trifluoromethyl)phenyl)-4-oxo- 1 ,4- dihydroquinofine-3-carboxamide;
N-[2-fluoro-5-hydroxy-4-( 1 -methylcyclohexyl)-phenyl]-4-oxo-5-(trifluoromethyl)- 1H- quinoIine-3-carboxaniide;
4-oxo-N-(3^yrrolidin-l-yl"4~iert-buiyi-phenyl)-lH-quinoline-3-carboxaniide;
4-oxo-N-[4-phenyl-5-(irifluoromeiliyi)-3-iljieny!l-lH-quinoiine-3-carboxainide;
7- fluoro-N-(5-hydroxy-2,4-dif.ert-buiyl-phenyi)-6-meihoxy-4-oxo-l H-quinoline-3- carboxaniide;
4-oxo-N-( 1 ,4,4-trimethyl-2,3-dihydroquinolin-7-yl)- lH-quinoSine-3 :arboxarnide;
6-[(4-oxo-lH-quinolin-3-yl)carbonyiamino]-lH-indole-4-carboxylic acid;
N-[3-fluoro-4-(triiluoromethyI)phenyl]-4-oxo-lH-quinoline-3-carix)xamide;
(S)-N-(4-(2-methylpiperidin- 1 -y!)-2-(trifluoromethyl)phenyi)-4-oxo- 1 ,4- dihydroquijioline-3-carboxamide;
(S)-6-fluoro-N-(4-(2-methyipyiToIidin-i -yl)-2-(irifluoromethyl)ph^
dihydroquinofme-3-carboxamide;
(S)-methyl 1 -(4-(4-oxo- 1 ,4-dihydroquinoiine-3-carboxamide)-3- (trifluoromethyl)phenyI)piperidine-2-carboxylaie;
8- chloro-N-[3'hydroxy"4-(irif1uoromediyl)phenyl]-4-oxo-lH-quinoii!ie-3-carboxamide; N-(4-methoxy-2-naphthyi)-4-oxo- 1 H-quinoiine-3-carboxamide; and
5,8-difluoro-N-(5-hydroxy-2.4-ditert-bui) -pheny!)-4-oxo-lH-quinoline-3-carboxainide or a pharmaceutically acceptable salt thereof.
2. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or adjuvant.
3. The pharmaceutical composition according to claim 2,†½ther comprising an additional agent selected from a mucolytic agent, a bronehodialater, an antibiotic, an anti-infective agent, an anti-inflammatory agent, a CFTR modulator, or a nutritional agent.
4. The pharmaceutical composition according to claim 3, wherein said additional agent is a CFTR modulator other than a compound according to claim 1 ,
5. A method of treating or lessening the severity of a disease in a patient, wherein said disease is selected from cystic fibrosis, asthma, smoke induced COPD, chronic bronchitis, rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility caused by congenital bilateral absence of the vas deferens (CBAVD), mild pulmonary disease, idiopatliic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA), fiver disease, hereditary emphysema, hereditary hemochi matosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoprotememia, lysosomal storage diseases, such as i-cell disease/pseudo-Hurler, mucopolysaccharidoses, Sandhof Tay-Sachs, Crigler- ajjar type II, polyendocrinopamy hyperinsulemia, Diabetes meilitus, Laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1 , congenita! hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), neurophyseal DI, neprogenic DI, Chareot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, several polyglutamine neurological disorders such as Huntington's,
spinocerebu!Iar ataxia type I, spinal and bulbar muscular atrophy, dentatorubal palfidoluysian, and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary
Creutzfeidt- Jakob disease (due to prion protein processing defect), Fabry disease, Straussler- Scheinker syndrome, COPD, dry-eye disease, pancreatic insufficiency, osteoporosis, osteopenia, Gorham's Syndrome, chloride channelopathies, myotonia congenita (Thomson and Becker forms), Bartter's syndrome type ill, Dent's disease, hyperekplexia, epilepsy, hyperekplexia, lysosomal storage disease, Angelman syndrome. Primary Ciliary Dyskinesia (PCD), PCD with situs inversus (also known as Kartagener syndrome), PCD without situs inversus and ciliary
- 356 -
S.144S33.5 aplasia, or Sjogren's disease, said method comprising the step of administering to said patient an effective amount of a compound according to claim 1.
6. The method according to claim 5, wherein said disease is cystic fibrosis.
7. A method of treating or lessening the severity of a disease in a patient, wherein said disease is associated with reduced CFTR function due to mutations in the gene encoding CFTR or environmental factors, said method comprising the step of admmistenng to said patient an effective amount of a compound according to claim 1.
8. The method of claim 7, wherein disease is cystic fibrosis, chronic bronchitis, recurrent bronchitis, acute bronchitis, male infertility caused by congenital bilateral absence of the vas deferens (CBAVD), female infertility caused by congenital absence of the uterus and vagina (CAUV), idiopathic chrome pancreatitis (ICP), idiopathic recurrent pancreatitis, idiopatliic acute pancreatitis, chronic rhinosinusitis, primary sclerosing cholangitis, allergic bronchopulmonary aspergillosis, diabetes, dry eye, constipation, allergic bronchopulmonary aspergillosis (ABPA), hone diseases, and asthma.
9. A method of treating or lessening the severity of a disease in a patient, wherein said disease is associated with normal CFTR function, said method comprising the step of administering to said patient an effective amount of a compound according to claim 1.
10. The method of claim 9, wherein disease is chronic obstructive pulmonary disease (COPD), chronic bronchitis, recurrent bronchitis, acute bronchitis, rhinosinusitis, constipation, chronic pancreatitis, recurrent pancreatitis, and acute pancreatitis, pancreatic insufficiency, male infertility caused by congenital bilateral absence of the vas deferens (CBAVD), mild pulmonary disease, idiopathic pancreatitis, liver disease, hereditary emphysema, gallstones, gasgtro- esophageal reflux disease, gastrointestinal malignancies, inflammatory bowel disease, constipation, diabetes, arthritis, osteoporosis, and osteopenia,
1 1. The method of claim 9, wherein die disease is hereditary hemochromatosis, coagulation- fibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chyiomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-cell disease/pseudo-Hurier,
- 357 -
8544833.3 mucopolysaccharidoses, Sandhof/Tay-Sachs, Crig!er-Najjar type Π,
polyendocrinopathy/hyperinsulemia, Diabetes meilitus, Laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinagenemia, ACT deficiency, Diabetes insipidus (DI), neurophyseal DI, neprogenic DI, Chareot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic laterai sclerosis, progressive supranuclear palsy, Pick's disease, several poiyg!utamme neurological disorders such as Huntington's, spinocerebullar ataxia type I, spinal and bulbar muscular atrophy, dentatorubal paliidoluysian, and myotonic dystrophy, as well as spongifonn encephalopathies, such as hereditary Creuizfeldt- Jakob disease (due to prion protein processing defect), Fabry disease, Straussler-Scheinker syndrome, Gorham's Syndrome, chloride channelopatliies, myotonia congenita (Thomson and Becker forms), Bartter's syndrome type ΠΪ, Dent's disease, hyperekplexia, epilepsy, hyperekplexia, lysosomal storage disease, Angelman syndrome, Primary Ciliary Dyskinesia (PCD), PCD with situs inversus (also known as Kartagener syndrome), PCD without situs inversus and ciliary aplasia, or Sjogren's disease.
12, A kit for use in measuring the activity of CFTR or a fragment thereof in a biological sample in vitro or in vivo, comprising:
a composition comprising a compound according to claim 1;
instructions for:
contacting the composition with the biological sample;
measuring activity of said CFTR or a fragment thereof.
The kit. of claim 12, further comprising instructions for:
contacting an additional compound with the biological sample;
measuring the activity of said CFTR or a fragment thereof in the presence of said additional compound, and
comparing the activity of said CFTR or a fragment thereof in the presence of said additional compound with the activity of said CFTR or a fragment thereof in the presence of a composition comprising a compound according to claim 1.
358 -
3344833.1 14, A method of modulating CFTR activity in a biological sample comprising the step of contacting said CFTR with a compound according claim I.
15. The kit according to claim 13, wherein the step of comparing the activity of said CFTR or a fragment tiiereof provides a measure of the density of said CFTR or a fragment thereof.
1.6. A method of treating or lessening the severity of cystic fibrosis (CF) in a patient, said method comprising the step of administering to said patient an effective amount of a compound according to claim L
17. The method of claim 16, wherein the patient possesses a cystic fibrosis transmembrane receptor (CFTR) with a homozygous ΔΡ508 mutation.
18. The method of claim 16, wherein the patient possesses a cystic fibrosis transmembrane receptor (CFTR) with a homozygous G55 I.D mutation.
19. The method of claim 16, wherein the patient possesses a cystic fibrosis transmembrane receptor (CFTR) with a heterozygous ΔΡ508 mutation.
20. The method of claim 16, wherein the patient possesses a cystic fibrosis transmembrane receptor (CFTR) with a heterozygous G55 ID mutation.
- 359 -
8544833.1
PCT/US2010/059920 2009-12-11 2010-12-10 4 -oxo- ih -quinoline- 3 - carboxamides as modulators of atp -binding cassette transporters WO2011072241A1 (en)

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CN201080056022XA CN102652128A (en) 2009-12-11 2010-12-10 4 -oxo- iH -quinoline- 3 - carboxamides as modulators of ATP -binding cassette transporters
AU2010327993A AU2010327993A1 (en) 2009-12-11 2010-12-10 4-oxo-1H-quinoline-3-carboxamides as modulators of ATP-Binding cassette transporters
RU2012129206/04A RU2552353C2 (en) 2009-12-11 2010-12-10 Modulators of atp-binding transporters
EP10793116A EP2509954A1 (en) 2009-12-11 2010-12-10 4 -oxo- 1h -quinoline- 3 - carboxamides as modulators of atp -binding cassette transporters
JP2012543310A JP2013513617A (en) 2009-12-11 2010-12-10 4-oxo-1H-quinoline-3-carboxamide as modulator of ATP-binding cassette transporter
MX2012006764A MX2012006764A (en) 2009-12-11 2010-12-10 4 -oxo- ih -quinoline- 3 - carboxamides as modulators of atp -binding cassette transporters.
US13/492,164 US8802700B2 (en) 2010-12-10 2012-06-08 Modulators of ATP-Binding Cassette transporters
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