WO2009111277A1 - Imdizo [4. 5-b] pyridine derivatives used as raf inhibitors - Google Patents

Imdizo [4. 5-b] pyridine derivatives used as raf inhibitors Download PDF

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Publication number
WO2009111277A1
WO2009111277A1 PCT/US2009/035379 US2009035379W WO2009111277A1 WO 2009111277 A1 WO2009111277 A1 WO 2009111277A1 US 2009035379 W US2009035379 W US 2009035379W WO 2009111277 A1 WO2009111277 A1 WO 2009111277A1
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WIPO (PCT)
Prior art keywords
alkyl
compound
optionally substituted
halogen
imidazo
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PCT/US2009/035379
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French (fr)
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WO2009111277A9 (en
Inventor
Kateri A. Ahrendt
Alexandre J. Buckmelter
Jonas Grina
Joshua D. Hansen
Ellen R. Laird
Brad Newhouse
Li Ren
Steven M. Wenglowsky
Bainian Feng
Kim Malesky
Simon Mathieu
Joachim Rudolph
Zhaoyang Wen
Wendy B. Young
David A. Moreno
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Array Biopharma Inc.
Genentech, Inc.
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Application filed by Array Biopharma Inc., Genentech, Inc. filed Critical Array Biopharma Inc.
Priority to US12/919,981 priority Critical patent/US20110003809A1/en
Priority to JP2010548884A priority patent/JP2011513329A/en
Priority to CA2716947A priority patent/CA2716947A1/en
Priority to ES09716688T priority patent/ES2392482T3/en
Priority to EP09716688A priority patent/EP2265609B1/en
Publication of WO2009111277A1 publication Critical patent/WO2009111277A1/en
Publication of WO2009111277A9 publication Critical patent/WO2009111277A9/en

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    • 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
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/48—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups having nitrogen atoms of sulfonamide groups further bound to another hetero atom

Definitions

  • the present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, to a process for making the compounds and to the use of the compounds in therapy. More particularly, it relates to certain substituted 3H- imidazo[4,5-b]pyridine compounds useful for inhibiting Raf kinase and for treating disorders mediated thereby.
  • Raf/MEK/ERK pathway is critical for cell survival, growth, proliferation and tumorigenesis.
  • Li Nanxin, et al. "B-Raf kinase inhibitors for cancer treatment.”
  • Raf kinases exist as three isoforms, A-Raf, B-Raf and C-Raf. Among the three isoforms, studies have shown that B-
  • Raf functions as the primary MEK activator.
  • B-Raf is one of the most frequently mutated genes in human cancers.
  • B-Raf kinase represents an excellent target for anticancer therapy based on preclinical target validation, epidemiology and drugability.
  • Raf inhibitors are also known, see for example, U.S. Patent Application Publication
  • Patent Application Publication WO 2008/028617 and International Patent Application Publication WO 2009/012283 also disclose kinase inhibitors.
  • the invention relates to compounds that are inhibitors of Raf kinases, particularly B-Raf inhibitors.
  • Certain hyperproliferative disorders are characterized by the over activation of Raf kinase function, for example by mutations or over expression of the protein. Accordingly, the compounds of the invention are useful in the treatment of hyperproliferative disorders such as cancer.
  • one aspect of the present invention provides compounds of
  • Another aspect of the present invention provides methods of preventing or treating a disease or disorder modulated by B-Raf, comprising administering to a mammal in need of such treatment an effective amount of a compound of this invention or a stereoisomer or pharmaceutically acceptable salt thereof.
  • diseases and disorders include, but are not limited to, hyperproliferative disorders (such as cancer, including melanoma and other cancers of the skin), neurodegeneration, cardiac hypertrophy, pain, migraine and neurotraumatic disease.
  • Another aspect of the present invention provides methods of preventing or treating cancer, comprising administering to a mammal in need of such treatment an effective amount of a compound of this invention, or a stereoisomer or pharmaceutically acceptable salt thereof, alone or in combination with one or more additional compounds having anticancer properties.
  • Another aspect of the present invention provides a method of treating a hyperproliferative disease in a mammal comprising administering a therapeutically effective amount of a compound of this invention to the mammal.
  • Another aspect of the present invention provides methods of preventing or treating kidney disease, comprising administering to a mammal in need of such treatment an effective amount of a compound of this invention, or a stereoisomer or pharmaceutically acceptable salt thereof, alone or in combination with one or more additional compounds.
  • Another aspect of the present invention provides methods of preventing or treating polycystic kidney disease, comprising administering to a mammal in need of such treatment an effective amount of a compound of this invention, or a stereoisomer or pharmaceutically acceptable salt thereof, alone or in combination with one or more additional compounds.
  • Another aspect of the present invention provides the compounds of the present invention for use in therapy.
  • Another aspect of the present invention provides the compounds of the present invention for use in the treatment of a hyperproliferative disease.
  • the hyperproliferative disease may be cancer (or still further, a specific cancer as defined herein).
  • kidney disease may be polycystic kidney disease.
  • Another aspect of the present invention provides the use of a compound of this invention in the manufacture of a medicament for the treatment of a hyperproliferative disease.
  • the hyperproliferative disease may be cancer (or still further, a specific cancer as defined herein).
  • Another aspect of the present invention provides the use of a compound of this invention in the manufacture of a medicament for the treatment of a kidney disease.
  • the kidney disease may be polycystic kidney disease.
  • Another aspect of the present invention provides the use of a compound of the present invention in the manufacture of a medicament, for use as a B-Raf inhibitor in the treatment of a patient undergoing cancer therapy.
  • Another aspect of the present invention provides the use of a compound of the present invention in the manufacture of a medicament, for use as a B-Raf inhibitor in the treatment of a patient undergoing polycystic kidney disease therapy.
  • Another aspect of the present invention provides a pharmaceutical composition comprising a compound of the present invention for use in the treatment of a hyperproliferative disease.
  • Another aspect of the present invention provides a pharmaceutical composition comprising a compound of the present invention for use in the treatment of cancer.
  • Another aspect of the present invention provides a pharmaceutical composition comprising a compound of the present invention for use in the treatment of polycystic kidney disease.
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of this invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • Another aspect of the present invention includes methods of preparing, methods of separation, and methods of purification of the compounds of this invention.
  • Another aspect of the present invention provides intermediates for preparing compounds of Formula I. Certain compounds of Formula I may be used as intermediates for other compounds of Formula I.
  • alkyl includes linear or branched-chain radicals of carbon atoms.
  • the alkyl radical is one to six carbon atoms (C 1 -C 6 ). In other examples, the alkyl radical is C 1 -C 5 , C 1 -C 4 or C 1 -C 3 .
  • Some alkyl moieties have been abbreviated, for example, methyl ("Me”), ethyl (“Et”), propyl (“Pr”) and butyl ("Bu”), and further abbreviations are used to designate specific isomers of compounds, for example, 1 -propyl or n-propyl (“n-Pr"), 2-propyl or isopropyl (“i-Pr”), 1 -butyl or n-butyl (“n-Bu”), 2-methyl-l- propyl or isobutyl (“i-Bu”), 1-methylpropyl or s-butyl (“s-Bu”), 1,1-dimethylethyl or t-butyl (“t-Bu”) and the like.
  • alkyl groups include 1-pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2- methyl-2-butyl (-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-l- butyl (-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-l -butyl (-CH 2 CH(CH 3 )CH 2 CH 3 ), 1-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), 3-hexyl
  • alkenyl refers to linear or branched-chain monovalent hydrocarbon radical with at least one site of unsaturation, i.e., a carbon-carbon double bond, wherein the alkenyl radical may be optionally substituted independently with one or more substituents described herein, and includes radicals having "cis” and “trans” orientations, or alternatively, "E” and "Z” orientations.
  • the alkenyl radical is two to six carbon atoms (C 2 - C 6 ). In other examples, the alkenyl radical is C 2 -C 3 .
  • alkynyl refers to a linear or branched monovalent hydrocarbon radical with at least one site of unsaturation, i.e., a carbon-carbon, triple bond, wherein the alkynyl radical may be optionally substituted independently with one or more substituents described herein.
  • the alkynyl radical is two to eighteen carbon atoms (C 2 - C 6 ). In other examples, the alkynyl radical is C 2 -C 3 .
  • Examples include, but are not limited to, ethynyl (-C ⁇ CH), prop-1-ynyl (-C ⁇ CCH 3 ), prop-2-ynyl (propargyl, CH 2 C ⁇ CH), but-1-ynyl, but-2-ynyl and but-3-ynyl.
  • alkenyl and alkynyl also include linear or branched-chain radicals of carbon atoms containing at least one unsaturated bond.
  • Cycloalkyl refers to a non-aromatic, saturated or partially unsaturated hydrocarbon ring group wherein the cycloalkyl group may be optionally substituted independently with one or more substituents described herein.
  • the cycloalkyl group is 3 to 6 carbon atoms (C 3 -C 6 ).
  • cycloalkyl is C 3 -C 4 or C 3 -C 5 .
  • the cycloalkyl group, as a monocycle is C 3 -C 6 or C 5 -C 6 .
  • the cycloalkyl group, as a bicycle is C 7 -C 12 .
  • Examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-l-enyl, l-cyclopent-2-enyl, l-cyclopent-3- enyl, cyclohexyl, 1-cyclohex-l-enyl, l-cyclohex-2-enyl, l-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl.
  • Exemplary arrangements of bicyclic cycloalkyls having 7 to 12 ring atoms include, but are not limited to, [4,4], [4,5], [5,5], [5,6] or [6,6] ring systems.
  • Exemplary bridged bicyclic cycloalkyls include, but are not limited to, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane.
  • heterocyclic or “heterocycle” or “heterocyclyl” refers to a saturated or a partially unsaturated (i.e., having one or more double and/or triple bonds within the ring) cyclic group in which at least one ring atom is a heteroatom independently selected from nitrogen, oxygen, and sulfur, the remaining ring atoms being carbon.
  • heterocyclyl includes saturated or partially unsaturated 4-6 membered heterocyclyl groups.
  • the heterocyclyl group may be optionally substituted with one or more substituents described herein.
  • heterocyclyl groups include, but are not limited to, oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl, piperidinyl, dihydropyridinyl, tetrahydropyridinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, 1,4-oxathianyl, 1,4-dioxepanyl, 1,4-oxathiepanyl, 1,4-oxazepanyl, 1,4- dithiepanyl, 1,4-thiazepanyl and 1,4-diazepane 1 ,
  • heteroaryl refers to an aromatic cyclic group in which at least one ring atom is a heteroatom independently selected from nitrogen, oxygen and sulfur, the remaining ring atoms being carbon. Heteroaryl groups may be optionally substituted with one or more substituents described herein. In one example, heteroaryl includes 5-6 membered heteroaryl groups.
  • heteroaryl groups include, but are not limited to, pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, 1,2,3 -triazolyl, 1,3,4- triazolyl, l-oxa-2,3-diazolyl, l-oxa-2,4-
  • treatment refers to therapeutic, prophylactic, palliative or preventative measures.
  • treatment includes therapeutic and palliative treatment.
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.
  • phrases "therapeutically effective amount” or “effective amount” mean an amount of a compound of the present invention that, when administered to a mammal in need of such treatment, sufficient to (i) treat or prevent the particular disease, condition, or disorder, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, condition, or disorder, or (iii) prevent or delay the onset of one or more symptoms of the particular disease, condition, or disorder described herein.
  • the amount of a compound that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the mammal in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
  • cancer and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by abnormal or unregulated cell growth.
  • a “tumor” comprises one or more cancerous cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies.
  • cancers include squamous cell cancer (e.g., epithelial squamous cell cancer), lung cancer including small-cell lung cancer, non-small cell lung cancer ("NSCLC”), adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, as well as head and neck cancer.
  • the term cancer may be used generically to include various types of cancer or specifically (as listed above).
  • phrases "pharmaceutically acceptable” indicates that the substance or composition is compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
  • pharmaceutically acceptable salt refers to pharmaceutically acceptable organic or inorganic salts of a compound of the invention.
  • the compounds of this invention also include other salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and/or purifying compounds of this invention and/or for separating enantiomers of compounds of this invention.
  • mammal means a warm-blooded animal that has or is at risk of developing a disease described herein and includes, but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters, and primates, including humans.
  • the present invention provides compounds, and pharmaceutical formulations thereof, that are potentially useful in the treatment of diseases, conditions and/or disorders modulated by B-Raf.
  • R 1 and R 2 are independently selected from hydrogen, halogen, CN, C 1 -C 3 alkyl, and C 1 -C 3 alkoxy;
  • R 3 is hydrogen, halogen or C 1 -C 3 alkyl
  • R 4 is C 3 -C 5 cycloalkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl, a 5-6 membered heteroaryl, or NR h R', wherein the cycloalkyl, alkyl, alkenyl, alkynyl and phenyl are optionally substituted with OR 0 , halogen, phenyl, C 3 -C 4 cycloalkyl or C 1 -C 4 alkyl optionally substituted with halogen;
  • R 5 is hydrogen, phenyl optionally substituted with one to three R a groups, -N(R 0 )- phenyl optionally substituted with R a , -CH 2 -phenyl optionally substituted with one to three R b groups, a 5-6 membered heteroaryl optionally substituted with one to three R e groups, saturated or partially unsaturated C 3 -C 6 cycloalkyl optionally substituted with halogen or C 1 - C 4 alkyl, a 5-6 membered heterocyclyl, or C 1 -C 6 alkyl optionally substituted with one or more R s groups; each R a is independently selected from halogen, CN, a 5-6 membered heterocyclyl, NR°R d , -S(O) 2 R f , -0(C 1 -C 4 alkyl), and C 1 -C 4 alkyl, wherein the alkyl or alkoxy are optionally substituted with halogen
  • R e is selected from a 5-6 membered heterocyclyl or NR c R d ;
  • R f is selected from C 1 -C 4 alkyl or NR c R d ; each R 8 is independently selected from halogen, CN, OR C , C 3 -C 6 cycloalkyl or NR c R d ; and
  • R h and R 1 are independently selected from hydrogen and C 1 -C 5 alkyl optionally substituted with halogen, or
  • R h and R 1 together with the nitrogen to which they are attached form a 4 to 6 membered heterocyclic ring.
  • R 1 and R 2 are independently selected from hydrogen, halogen, CN, C 1 -C 3 alkyl, and C 1 -C 3 alkoxy;
  • R 3 is hydrogen, halogen or C 1 -C 3 alkyl
  • R 4 is C 3 -C 5 cycloalkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, wherein the cycloalkyl, alkyl, alkenyl and alkynyl are optionally substituted with OR C , halogen or C 3 -C 4 cycloalkyl;
  • R 5 is hydrogen, phenyl optionally substituted with one to three R a groups, -N(R 0 )- phenyl optionally substituted with R a , -CH 2 -phenyl optionally substituted with one to three R b groups, a 5-6 membered heteroaryl optionally substituted with one to three R e groups, saturated or partially unsaturated C 3 -C 6 cycloalkyl optionally substituted with halogen or C 1 - C 4 alkyl, a 5-6 membered heterocyclyl, or C 1 -C 6 alkyl optionally substituted with one or more R g groups; each R a is independently selected from halogen, CN, a 5-6 membered heterocyclyl, NR°R d , -S(O) 2 R f , -0(C 1 -C 4 alkyl), and C 1 -C 4 alkyl, wherein the alkyl or alkoxy are optionally substituted with halogen
  • R e is selected from a 5-6 membered heterocyclyl or NR°R d ;
  • R f is selected from C 1 -C 4 alkyl or NR c R d ; and each R 8 is independently selected from halogen, CN, OR C , C 3 -C 6 cycloalkyl or NR c R d .
  • R 1 , R 2 and R 3 are independently selected from H, halogen or C 1 -C 3 alkyl
  • R 4 is C 3 -C 4 cycloalkyl, or C 1 -C 6 alkyl optionally substituted with OH, halogen or C 3 - C 4 cycloalkyl;
  • R 5 is hydrogen, phenyl optionally substituted with one to three R a groups, -NH- phenyl, -CH 2 -phenyl optionally substituted with one to three R b groups, a 5-6 membered heteroaryl optionally substituted with one to three R e groups, C 3 -C 6 cycloalkyl, a 5-6 membered heterocyclyl, or C 1 -C 6 alkyl; each R a is independently selected from halogen, CN, a 5-6 membered heterocyclyl, NR c R d , -S(O) 2 R 1 , -0(C 1 -C 4 alkyl) and C 1 -C 4 alkyl, wherein the alkyl or alkoxy are optionally substituted with halogen; each R b is independently selected from halogen, OH or OCH 3 ; each R c and R d are independently selected from hydrogen or C 1 -C 4 alkyl;
  • R e is selected from a 5-6 membered heterocyclyl or NR e R d ;
  • R f is selected from C 1 -C 4 alkyl or NR c R d .
  • R 1 and R 2 are independently selected from hydrogen, halogen, CN, C 1 -C 3 alkyl or C 1 -C 3 alkoxy.
  • R 1 , R 2 and R 3 are independently selected from hydrogen, halogen or C 1 -C 3 alkyl.
  • R 1 , R 2 and R 3 are independently selected from hydrogen, F and Cl.
  • R 1 is hydrogen, halogen, CN, C 1 -C 3 alkyl or C 1 -C 3 alkoxy.
  • R 1 is hydrogen
  • R 1 is halogen. In certain embodiments, R 1 is F or Cl.
  • R 1 is C 1 -C 3 alkyl. In certain embodiments, R 1 is methyl.
  • R 2 is hydrogen, halogen, CN, C 1 -C 3 alkyl or C 1 -C 3 alkoxy.
  • R 2 is hydrogen
  • R 2 is halogen. In certain embodiments, R 2 is F or Cl. [0059] In certain embodiments, R 2 is C 1 -C 3 alkyl. In certain embodiments, R 2 is methyl.
  • R 2 is Cl
  • R 2 is hydrogen
  • R 3 is hydrogen, halogen or C 1 -C 3 alkyl.
  • R 3 is hydrogen
  • R 3 is halogen. In certain embodiments, R 3 is F or Cl.
  • R 1 and R 2 are F and R 3 is hydrogen.
  • R 1 is F and R 2 is Cl and R 3 is hydrogen.
  • R 1 is Cl and R 2 is F and R 3 is hydrogen.
  • R 1 is F and R 2 and R 3 are hydrogen.
  • R and R are hydrogen and R is F.
  • R 2 and R 3 are F and R 1 is hydrogen.
  • R 1 is Cl and R 2 and R 3 are hydrogen.
  • R , R and R are F.
  • R 1 is F and R 2 is methyl and R 3 is hydrogen.
  • R 1 is methyl and R 2 is F and R 3 is hydrogen.
  • R 1 is F and R 2 and R 3 are hydrogen.
  • R 1 is Cl and R 2 and R 3 are hydrogen.
  • R 2 is F and R 1 and R 3 are hydrogen.
  • R 4 is C 3 -C 5 cycloalkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl,
  • R c is independently selected from hydrogen, phenyl and C 1 -C 4 alkyl optionally substituted with oxo. In certain embodiments, R c is hydrogen. [0081] In certain embodiments, R 4 is C 3 -C 5 cycloalkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl,
  • R 4 is C 3 -C 5 cycloalkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or
  • R 4 is cyclopropyl, ethyl, propyl, butyl, isobutyl,
  • R 4 is cyclopropyl, ethyl, propyl, isobutyl,
  • R 4 is propyl, butyl, isobutyl, -CH 2 CH 2 CH 2 F,
  • R 4 is C 3 -C 5 cycloalkyl, or C 1 -C 6 alkyl optionally substituted with OH, halogen or C 3 -C 4 cycloalkyl.
  • R 4 is C 3 -C 5 cycloalkyl. In certain embodiments, R 4 is
  • R 4 is cyclopropyl or cyclobutyl. [0088] In certain embodiments, R 4 is C 3 -C 5 cycloalkyl. In certain embodiments, R 4 is
  • R 4 is cyclopropyl
  • R 4 is C 1 -C 6 alkyl. In certain embodiments, R 4 is ethyl, propyl, butyl or isobutyl.
  • R 4 is C 1 -C 6 alkyl. In certain embodiments, R 4 is propyl, butyl or isobutyl.
  • R 4 is C 1 -C 6 alkyl optionally substituted with OR C .
  • R c is hydrogen.
  • R 4 is C 1 -C 6 alkyl optionally substituted with OH.
  • R 4 is -CH 2 CH 2 CH 2 OH.
  • R 4 is C 1 -C 6 alkyl optionally substituted with halogen.
  • R 4 is -CF 3 , -CH 2 Cl, -CH 2 CF 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CF 3 , -CF 2 CF 3 or -CF 2 CF 2 CF 3 .
  • R 4 is C 1 -C 6 alkyl optionally substituted with halogen.
  • R 4 is -CF 3 , -CH 2 CF 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CF 3 , -CF 2 CF 3 or -CF 2 CF 2 CF 3 . In certain embodiments, R 4 is -CH 2 CH 2 CH 2 F or -CH 2 CH 2 CF 3 . [0094] In certain embodiments, R 4 is C 1 -C 6 alkyl optionally substituted with OR C , halogen or C 3 -C 4 cycloalkyl. In certain embodiments, R 4 is C 1 -C 6 alkyl optionally substituted with OH, halogen or C 3 -C 4 cycloalkyl.
  • R 4 is cyclopropylmethyl (- CH ⁇ cyclopropyl) or cyclobutylmethyl (-CHz-cyclobutyl). In certain embodiments, R 4 is cyclopropylmethyl (-CH ⁇ cyclopropyl).
  • R 4 is C 1 -C 6 alkyl optionally substituted with phenyl.
  • R 4 is phenylmethyl
  • R 4 is phenyl optionally substituted with OR C , halogen,
  • R 4 is phenyl optionally substituted with halogen. In certain embodiments, R 4 is phenyl optionally substituted with C 1 -C 4 alkyl optionally substituted with halogen. In certain embodiments, R 4 is phenyl optionally substituted with halogen and C 1 -C 4 alkyl optionally substituted with halogen, hi certain embodiments, R 4 is phenyl.
  • R 4 is phenyl, 2-fluorophenyl, 3 -fluorophenyl, 4-fluorophenyl, 2,5-difluorophenyl or 4-chloro-3- trifluoromethylphenyl.
  • R 4 is a 5-6 membered heteroaryl optionally substituted with OR C , halogen, C 3 -C 4 cycloalkyl or C 1 -C 4 alkyl optionally substituted with halogen. In certain embodiments, R 4 is a 5-6 membered heteroaryl optionally substituted with C 1 -C 4 alkyl. In certain embodiments, R 4 is a 5-6 membered heteroaryl optionally substituted with OR C , halogen, C 3 -C 4 cycloalkyl or C 1 -C 4 alkyl optionally substituted with halogen, wherein the heteroaryl contains one or two heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur.
  • R 4 is a 5-6 membered heteroaryl optionally substituted with OR 0 , halogen, C 3 -C 4 cycloalkyl or C 1 -C 4 alkyl optionally substituted with halogen, wherein the heteroaryl is imidazolyl, furanyl, pyridinyl or thiophenyl.
  • R 4 is 1 -methyl- lH-imidazol-4-yl, furan-2-yl, pyridin- 2-yl, pyridin-3-yl or thiophen-2-yl.
  • R 4 is NR h R ⁇
  • R h and R 1 are independently selected from hydrogen and C 1 -C 5 alkyl optionally substituted with halogen.
  • R 1 is hydrogen or methyl.
  • R h is C 1 -C 5 alkyl optionally substituted with halogen.
  • R h is methyl, ethyl, propyl, isopropyl, or 2,2-difluoroethyl.
  • R 4 is selected from the group consisting of -NHCH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -NHCH(CH 3 ) 2 , -NHCH 2 CHF 2 , and -N(CH 3 ) 2 .
  • R 4 is NR 11 R 1 , wherein R h and R' together with the nitrogen to which they are attached form a 4 to 6 membered heterocyclic ring.
  • R 4 is NR 11 R 1 , wherein R h and R 1 together with the nitrogen to which they are attached form a 4 to 6 membered heterocyclic ring, wherein the heterocyclic ring contains one or two heteroatoms selected from nitrogen and oxygen.
  • R is NR 11 R 1 , wherein R h and R 1 together with the nitrogen to which they are attached form a 5 membered heterocyclic ring.
  • R 4 is NR 11 R 1 , wherein R h and R 1 together with the nitrogen to which they are attached form a 5 membered heterocyclic ring, wherein the heterocyclic ring contains one nitrogen heteroatom.
  • R 4 is pyrrolidin-1-yl.
  • R 1 and R 2 are F, R 3 is hydrogen and R 4 is propyl, such that the compounds of Formula I, have the structure of Formula Ia:
  • R 1 is Cl
  • R 2 is F
  • R 3 is hydrogen
  • R 4 is propyl
  • R 1 is F
  • R 2 is Cl
  • R 3 is hydrogen
  • R 4 is propyl
  • R 5 is hydrogen, phenyl optionally substituted with one to three R a groups, -N(R c )-phenyl optionally substituted with R a , -CH 2 -phenyl optionally substituted with one to three R b groups, a 5-6 membered heteroaryl optionally substituted with one to three R e groups, saturated or partially unsaturated C 3 -C 6 cycloalkyl optionally substituted with halogen or C 1 -C 4 alkyl, a 5-6 membered heterocyclyl, or C 1 -C 6 alkyl optionally substituted with one or more R s groups.
  • R 5 is hydrogen, phenyl optionally substituted with one to three R a groups, -NH-phenyl, -CH 2 -phenyl optionally substituted with one to three R b groups, a 5-6 membered heteroaryl optionally substituted with one to three R e groups, C 3 -C 6 cycloalkyl, a 5-6 membered heterocyclyl, or C 1 -C 6 alkyl.
  • R 5 is selected from hydrogen, phenyl, 2-fluorophenyl,
  • R 5 is phenyl optionally substituted with one to three
  • each R a is independently selected from halogen, CN, a 5- 6 membered heterocyclyl, NR c R d , -S(O) 2 R f , -0(C 1 -C 4 alkyl), and C 1 -C 4 alkyl, wherein the alkyl or alkoxy are optionally substituted with halogen.
  • R a is a 5-6 membered heterocyclyl, wherein the heterocyclyl is morpholinyl.
  • R 5 is selected from phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3 -fluorophenyl, 3- chlorophenyl, 3-bromophenyl, 3-trifluoromethylphenyl, 3-methoxyphenyl, 4-fluorophenyl, A- chlorophenyl, 4-bromophenyl, 4-cyanophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, A- methoxyphenyl, 4-trifluoromethoxyphenyl, 4-dimethylaminophenyl, A-
  • R 1 and R 2 are F
  • R 3 is hydrogen
  • R 4 is propyl
  • R 5 is phenyl optionally substituted with one to three R a groups, such that the compounds of Formula I, have the structure of Formula Ib:
  • R 5 is phenyl
  • R 5 is phenyl optionally substituted with one R a group.
  • R a is selected from halogen, CN, a 5-6 membered heterocyclyl, NR c R d , -S(O) 2 R f , -0(C 1 -C 4 alkyl), and C 1 -C 4 alkyl, wherein the alkyl or alkoxy are optionally substituted with halogen.
  • R a is -0(C 1 -C 4 alkyl), wherein R a is methoxy.
  • R a is -0(C 1 -C 4 alkyl) optionally substituted with halogen, wherein R a is trifluoromethoxy.
  • R a is C 1 -C 4 alkyl optionally substituted with halogen, wherein R a is trifluoromethyl.
  • R a is a 5-6 membered heterocyclyl, wherein the heterocyclyl is morpholinyl.
  • R c and R d are C 1 -C 4 alkyl.
  • R c and R d are methyl.
  • R a is -S(O) 2 R f .
  • R f is C 1 -C 4 alkyl.
  • R 5 is selected from 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3- fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-trifluoromethylphenyl, 3-methoxyphenyl, 4- fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-cyanophenyl, 4-methylphenyl, 4- trifluoromethylphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 4- dimethylaminophenyl, 4-(methylsulfonyl)phenyl and 4-morpholinophenyl.
  • R 5 is phenyl optionally substituted with two R a groups.
  • R a is selected from halogen and C 1 -C 4 alkyl, wherein the alkyl is optionally substituted with halogen.
  • R a is C 1 -C 4 alkyl, wherein R a is methyl.
  • R a is C 1 -C 4 alkyl optionally substituted with halogen, wherein R a is trifluoromethyl.
  • R is selected from 3,4- dichlorophenyl, 3-trifluoromethyl-4-methylphenyl, 3-trifluoromethyl-4-chlorophenyl and 2- methyl-4-bromophenyl.
  • R 5 is -N(R c )-phenyl optionally substituted with R a .
  • R c is selected from hydrogen or C 1 -C 4 alkyl. In certain embodiments, R c is hydrogen. In certain embodiments, R 5 is -NH-phenyl optionally substituted with R a .
  • R 5 is -NH-phenyl optionally substituted with R a . In certain embodiments, R 5 is -NH-phenyl.
  • R 5 is -CH 2 -phenyl optionally substituted with one to three R b groups.
  • each R b is independently selected from halogen, OH or OCH 3 .
  • R 5 is selected from -CH 2 -4-chlorophenyl, -CH2-3,5- difluorophenyl, -CH 2 -4-methoxyphenyl, -CH 2 -4-bromophenyl and -CH 2 -3,4-difluorophenyl.
  • R 5 is a 5-6 membered heteroaryl optionally substituted with one to three R e groups.
  • R e is selected from a 5-6 membered heterocyclyl or NR c R d .
  • R c and R d are independently selected from hydrogen and C 1 -C 4 alkyl.
  • R 5 is a 5-6 membered heteroaryl optionally substituted with a 5-6 membered heterocyclyl, wherein the heteroaryl is pyridinyl.
  • R 5 is a 5-6 membered heteroaryl optionally substituted with a 5-6 membered heterocyclyl, wherein the heterocyclyl is morpholinyl.
  • R 5 is a 5-6 membered heteroaryl optionally substituted with a 5-6 membered heterocyclyl, wherein the heteroaryl is pyridinyl and the heterocyclyl is morpholinyl.
  • R 5 is selected from pyridin-3-yl, pyridin-4-yl, 6-morpholinopyridin-3- yl and 6-(dimethylamino)pyridin-3-yl.
  • R 5 is saturated or partially unsaturated C 3 -C 6 cycloalkyl optionally substituted with halogen or C 1 -C 4 alkyl.
  • R 5 is saturated or partially unsaturated C 3 -C 6 cycloalkyl.
  • R 5 is saturated C 3 -C 6 cycloalkyl.
  • R 5 is C 3 -C 6 cycloalkyl, wherein the cycloalkyl is cyclobutyl.
  • R 5 is cyclobutyl.
  • R 5 is a 5-6 membered heterocyclyl. In certain embodiments, R 5 is a 5-6 membered heterocyclyl, wherein the heterocyclyl is piperdinyl. In certain embodiments, R 5 is selected from piperdin-3-yl and piperdin-4-yl. [00118] In certain embodiments, R 5 is C 1 -C 6 alkyl optionally substituted with one or more R g groups, hi certain embodiments, each R 8 is independently selected from halogen, CN, OR C , C 3 -C 6 cycloalkyl or NR c R d . [00119] In certain embodiments, R 5 is C 1 -C 6 alkyl. In certain embodiments, R 5 is selected from methyl, ethyl, isopropyl and tert-butyl.
  • stereoisomers are contemplated and included as the compounds of the invention. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is so specified and defined.
  • compounds of Formula I include tautomeric forms. Tautomers are compounds that are interconvertible by tautomerization. This commonly occurs due to the migration of a hydrogen atom or proton, accompanied by the switch of a single bond and adjacent double bond.
  • 3H-imidazo[4,5-b]pyridine is one tautomeric form
  • 4H-imidazo[4,5-b]pyridine is another tautomeric form
  • Other tautomers of Formula I may also form at other positions, including, but not limited to, the sulfonamide or R 5 position depending on the substitution.
  • the compounds of Formula I are intended to include all tautomeric forms.
  • the compounds of Formula I include the tautomer 4H-imidazo[4,5-b]pyridine, shown as Formula II:
  • R 1 , R 2 , R 3 , R 4 and R 5 are as defined herein.
  • R 20 is hydrogen, C 1 -C 6 alkyl, benzyl or phenyl and R 1 , R 2 , R 3 , R 4 are as defined herein.
  • the compounds of the present invention may exist in unsolvated, as well as solvated forms with pharmaceutically acceptable solvents, such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
  • Compounds of the present invention may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein.
  • the starting materials are generally available from commercial sources such as Sigma-Aldrich (St. Louis, MO), Alfa Aesar (Ward Hill, MA), or
  • TCI Portableland, OR
  • TCI are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser,
  • Schemes 1-4 show a general method for preparing the compounds of the present invention, as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. Although specific starting materials and reagents are depicted in the Schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.
  • Scheme 1 shows a general scheme for the synthesis of imidazopyridine 7, wherein R 1 , R 2 , R 3 , R 4 , and R 5 are as defined herein.
  • Dinitropyridine 1 can be treated with ammonium hydroxide to provide compound 2, which then can be selectively reduced to compound 3 using ammonium sulfide as the reducing agent.
  • Imidazopyridine 4 may be prepared using carboxylic acids in a suitable solvent with various additives, such as triphenylphosphite, under microwave conditions or with a carboxylic acid and a dehydrating agent, such as POCl 3 .
  • the nitro group may be reduced by hydrogenation with a suitable catalyst, such as palladium on carbon, tin (II) chloride dehydrate in refluxing methanol, or by zinc or iron in aqueous ammonium chloride, to give compound 5.
  • a suitable catalyst such as palladium on carbon, tin (II) chloride dehydrate in refluxing methanol, or by zinc or iron in aqueous ammonium chloride, to give compound 5.
  • Compound 5 may be coupled with benzoic acid 6 in the presence of a coupling reagent, such as 2-(1H- benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (“HBTU”) or 1-ethyl- (3-dimethylaminopropyl)carbodiimide hydrochloride (“EDCl”), with additives, such as hydroxybenzotriazole monohydrate, in a suitable solvent, such as dichloromethane (“DCM”),
  • Scheme 2 shows another preparation of imidazopyridine 7, wherein R , R , R ,
  • Imidazopyridine 5 may be coupled with bis-sulfonylated benzoate 8 using Weinreb conditions (trimethylaluminum in toluene) to provide compound 10.
  • a suitable base such as aqueous sodium hydroxide, potassium carbonate, or sodium carbonate, and deprotection provides compound 7.
  • Scheme 3 illustrates yet another preparation of imidazopyridine 7, wherein R 1 ,
  • Imidazopyridine 5 may be coupled with bis- sulfonylated benzoic acid 9 using standard amide coupling conditions, such as those described in Scheme 1, to provide compound 10. Hydrolysis with a suitable base, such as aqueous sodium hydroxide or sodium carbonate, provides compound 7.
  • Scheme 4 shows a general method for preparing benzoate 8 and benzoic acid
  • Benzoic acid 10 is esterified by standard methods, such as by Fischer esterification conditions.
  • the nitro group may be reduced by hydrogenation with a suitable catalyst, such as palladium on carbon.
  • Aniline 11 may be sulfonylated with a substituted sulfonyl chloride in the presence of a suitable base, such as triethylamine, to provide benzoate 8.
  • Hydrolysis of benzoate 8 with a base, such as aqueous sodium hydroxide, in an optional solvent, such as an alcohol (e.g., methanol), tetrahydrofuran (“THF”)or a mixture thereof, provides benzoic acid 2.
  • Another embodiment of the present invention provides a process for preparing compounds of Formula I, comprising: (a) coupling a compound of Formula 5:
  • R 5 is as defined herein, with a compound of Formula 6:
  • R 1 , R 2 , R 3 and R 4 are as defined herein, to provide a compound of Formula I; or (b) coupling a compound of Formula 5:
  • Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butyloxycarbonyl ("Boc”), benzyloxycarbonyl ("CBz”) and 9- fluorenylmethyleneoxycarbonyl ("Fmoc”).
  • Boc t-butyloxycarbonyl
  • Fmoc 9- fluorenylmethyleneoxycarbonyl
  • reaction products may be advantageous to separate reaction products from one another and/or from starting materials.
  • the desired products of each step or series of steps is separated and/or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art.
  • separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography.
  • Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed (SMB) and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography.
  • SMB simulated moving bed
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • Enantiomers can also be separated by use of a chiral HPLC column.
  • a single stereoisomer e.g., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, C. H., et al. "Chromatographic resolution of enantiomers: Selective review.” J. Chromatogr.. 113(3) (1975): pp. 283-302).
  • Racemic mixtures of chiral compounds of the invention can be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. See: Wainer, Irving W., Ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.
  • diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, ⁇ -methyl- ⁇ -phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid.
  • the diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography.
  • the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994, p. 322).
  • Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the pure or enriched enantiomer.
  • a method of determining optical purity involves making chiral esters, such as a menthyl ester, e.g., (-) menthyl chloroformate in the presence of base, or Mosher ester, ⁇ -methoxy- ⁇ - (trifluoromethyl)phenyl acetate (Jacob III, Peyton. "Resolution of ( ⁇ )-5-Bromonornicotine. Synthesis of (R)- and (S)-Nornicotine of High Enantiomeric Purity.” J. Qrg. Chem. Vol. 47, No. 21 (1982): pp.
  • chiral esters such as a menthyl ester, e.g., (-) menthyl chloroformate in the presence of base, or Mosher ester, ⁇ -methoxy- ⁇ - (trifluoromethyl)phenyl acetate (Jacob III, Peyton. "Resolution of ( ⁇ )-5-Bromonornicotine. Synthesis of (R)-
  • Stable diastereomers of atropisomeric compounds can be separated and isolated by normal- and reverse-phase chromatography following methods for separation of atropisomeric naphthyl-isoquinolines (WO 96/15111).
  • a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase Lough, WJ., Ed. Chiral Liquid Chromatography. New York: Chapman and Hall, 1989; Okamoto, Yoshio, et al. "Optical resolution of dihydropyridine enantiomers by high-performance liquid chromatography using phenylcarbamates of polysaccharides as a chiral stationary phase.” J. of Chromatogr. Vol. 513 (1990): pp. 375-378).
  • Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism. BIOLOGICAL EVALUATION
  • B-Raf mutant protein 447-717 (V600E) was co-expressed with the chaperone protein Cdc37, complexed with Hsp90 (Roe, S. Mark, et al. "The Mechanism of Hsp90
  • Activity of human recombinant B-Raf protein may be assessed in vitro by assay of the incorporation of radio labeled phosphate to recombinant MAP kinase (MEK), a known physiologic substrate of B-Raf, according to US 2004/0127496 and WO 03/022840.
  • MEK MAP kinase
  • the activity/inhibition of V600E full-length B-Raf was estimated by measuring the incorporation of radio labeled phosphate from [ ⁇ - 33 P]ATP into FSBA-modified wild-type MEK (see Example A).
  • ADMINISTRATION AND PHARMACEUTICAL FORMULATIONS [00143]
  • the compounds of the invention may be administered by any convenient route appropriate to the condition to be treated.
  • Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), transdermal, rectal, nasal, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary and intranasal.
  • the compounds may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc.
  • Such compositions may contain components conventional in pharmaceutical preparations, e.g. diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents. If parenteral administration is desired, the compositions will be sterile and in a solution or suspension form suitable for injection or infusion.
  • a typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient.
  • Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C, et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005.
  • the formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
  • buffers stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing
  • One embodiment of the present invention includes a pharmaceutical composition comprising a compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof.
  • the present invention provides a pharmaceutical composition comprising a compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.
  • Another embodiment of the present invention provides a pharmaceutical composition comprising a compound of Formula I for use in the treatment of a hyperproliferative disease.
  • Another embodiment of the present invention provides a pharmaceutical composition comprising a compound of Formula I for use in the treatment of cancer.
  • METHODS OF TREATMENT WITH COMPOUNDS OF THE INVENTION The invention includes methods of treating or preventing disease or condition by administering one or more compounds of this invention, or a stereoisomer or pharmaceutically acceptable salt thereof.
  • a human patient is treated with a compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle in an amount to detectably inhibit B-Raf activity.
  • a human patient is treated with a compound of
  • Formula I or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle in an amount to detectably inhibit B- Raf activity.
  • a method of treating a hyperproliferative disease in a mammal comprising administering a therapeutically effective amount of the compound of Formula I, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, to the mammal is provided.
  • a method of treating a hyperproliferative disease in a mammal comprising administering a therapeutically effective amount of the compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof, to the mammal is provided.
  • kidney disease in another embodiment, a method of treating kidney disease in a mammal comprising administering a therapeutically effective amount of the compound of Formula I, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, to the mammal is provided.
  • the kidney disease is polycystic kidney disease.
  • a method of treating or preventing cancer in a mammal in need of such treatment comprises administering to said mammal a therapeutically effective amount of a compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof.
  • the cancer is selected from breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, NSCLC, small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney carcinoma, myeloid disorders, lymphoid disorders, hairy cells, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, colon-rectum, large intestine, rectum, brain and central nervous system, Hodgkin's and leukemia.
  • a method of treating or preventing cancer in a mammal in need of such treatment comprises administering to said mammal a therapeutically effective amount of a compound of Formula I, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.
  • Another embodiment of the present invention provides the use of a compound of Formula I, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.
  • Another embodiment of the present invention provides the use of a compound of Formula I, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of kidney disease.
  • the kidney disease is polycystic kidney disease.
  • a method of preventing or treating cancer comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula I, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, alone or in combination with one or more additional compounds having anti-cancer properties.
  • a method of preventing or treating cancer comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof, alone or in combination with one or more additional compounds having anti-cancer properties.
  • the cancer is a sarcoma.
  • the cancer is a carcinoma.
  • the carcinoma is squamous cell carcinoma.
  • the carcinoma is an adenoma or adenocarcinoma.
  • a method of treating or preventing a disease or disorder modulated by B-Raf comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof.
  • diseases and disorders include, but are not limited to, cancer.
  • the cancer is selected from breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, NSCLC, small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney carcinoma, myeloid disorders, lymphoid disorders, hairy cells, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, colon-rectum, large intestine, rectum, brain and central nervous system, Hodgkin's and leukemia.
  • a method of treating or preventing a disease or disorder modulated by B-Raf comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula I, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.
  • a method of preventing or treating kidney disease comprising administering to a mammal in need of such treatment an effective amount of Formula I, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, alone or in combination with one or more additional compounds.
  • a method of preventing or treating polycystic kidney disease comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula I, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, alone or in combination with one or more additional compounds.
  • Another embodiment of the present invention provides the use of a compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.
  • the cancer is selected from breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, NSCLC, small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney carcinoma, myeloid disorders, lymphoid disorders, hairy cells, buccal cavity and pharynx (oral), lip, tongue, mouth,
  • Another embodiment of the present invention provides the use of a compound of Formula I, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.
  • Another embodiment of the present invention provides the use of a compound of Formula I, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of polycystic kidney disease.
  • the kidney disease is polycystic kidney disease.
  • Another embodiment of the present invention provides the compounds of
  • Another embodiment of the present invention provides the compounds of
  • the hyperproliferative disease is cancer (as further defined and may be individually selected from those above).
  • Another embodiment of the present invention provides the compounds of
  • kidney disease is polycystic kidney disease.
  • the compounds of this invention and stereoisomers and pharmaceutically acceptable salts thereof may be employed alone or in combination with other therapeutic agents for treatment.
  • the compounds of the present invention can be used in combination with one or more additional drugs, for example an anti-hyperproliferative, anti-cancer or chemotherapeutic agent.
  • the second compound of the pharmaceutical combination formulation or dosing regimen preferably has complementary activities to the compound of this invention such that they do not adversely affect each other.
  • agents are suitably present in combination in amounts that are effective for the purpose intended.
  • the compounds may be administered together in a unitary pharmaceutical composition or separately and, when administered separately this may occur simultaneously or sequentially in any order. Such sequential administration may be close in time or remote in time.
  • a "chemotherapeutic agent” is a chemical compound useful in the treatment of cancer, regardless of mechanism of action.
  • Chemotherapeutic agents include compounds used in "targeted therapy” and conventional chemotherapy.
  • a number of suitable chemotherapeutic agents to be used as combination therapeutics are contemplated for use in the methods of the present invention.
  • the present invention contemplates, but is not limited to, administration of numerous anticancer agents, such as: agents that induce apoptosis; polynucleotides (e.g., ribozymes); polypeptides (e.g., enzymes); drugs; biological mimetics; alkaloids; alkylating agents; antitumor antibiotics; antimetabolites; hormones; platinum compounds; monoclonal antibodies conjugated with anticancer drugs, toxins, and/or radionuclides; biological response modifiers (e.g., interferons [e.g., IFN-a, etc.] and interleukins [e.g., IL-2, etc.], etc.); adoptive immunotherapy agents; hematopoietic growth factors; agents that induce tumor cell differentiation (e.g., all-trans-retinoic acid, etc.); gene therapy reagents; antisense therapy reagents and nucleotides; tumor vaccines; inhibitors of angiogenesis, and the like.
  • chemotherapeutic agents include Erlotinib (T ARCEV A®,
  • dynemicin including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6- diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, e
  • chemotherapeutic agent also included in the definition of "chemotherapeutic agent” are: (i) anti- hormonal agents that act to regulate or inhibit hormone action on tumors such as anti- estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, 4- hydroxytamoxifen, trioxifene, keoxifene, LYl 17018, onapristone, and FARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR® (vorozole), FEMARA®
  • chemotherapeutic agent therapeutic antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen pie), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), and the antibody drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth).
  • therapeutic antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RIT
  • Humanized monoclonal antibodies with therapeutic potential as chemotherapeutic agents in combination with the Raf inhibitors of the invention include: alemtuzumab, apolizumab, aselizumab, atlizumab, bapineuzumab, bevacizumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, moto
  • Activity of human recombinant B-Raf protein may be assessed in vitro by assay of the incorporation of radio labeled phosphate to recombinant MAP kinase (MEK), a known physiologic substrate of B-Raf, according to US 2004/0127496 and WO 03/022840.
  • Catalytically active human recombinant B-Raf protein is obtained by purification from sf9 insect cells infected with a human B-Raf recombinant baculovirus expression vector.
  • V600E full-length B-Raf The activity/inhibition of V600E full-length B-Raf was estimated by measuring the incorporation of radio labeled phosphate from [ ⁇ - 33 P]ATP into FSBA-modified wild-type MEK.
  • the 30- ⁇ L assay mixtures contained 25mM Na Pipes, pH 7.2, 10OmM KCl, 1OmM MgCl 2 , 5mM ⁇ -glycerophosphate, lOO ⁇ M Na Vanadate, 4 ⁇ M ATP, 500 nCi [ ⁇ - 33 P]ATP, l ⁇ M FSBA-MEK and 2OnM V600E full-length B-Raf. Incubations were carried out at 22°C in a Costar 3365 plate (Corning).
  • the B-Raf and FSBA-MEK were preincubated together in assay buffer at 1.5x (20 ⁇ L of 3OnM and 1.5 ⁇ M, respectively) for 15 minutes, and the assay was initiated by the addition of 10 ⁇ L of lO ⁇ M ATP.
  • the assay mixtures were quenched by the addition of 100 ⁇ L of 25% TCA, the plate was mixed on a rotary shaker for 1 minute, and the product was captured on a Perkin-Elmer GF/B filter plate using a Tomtec Mach III Harvester. After sealing the bottom of the plate, 35 ⁇ L of Bio-Safe II (Research Products International) scintillation cocktail were added to each well and the plate was top-sealed and counted in a TopcountNXT (Packard).
  • Step A A 1 L flask was charged with 2,6-difluoro-3-nitrobenzoic acid (17.0 g, 83.7 mmol) and MeOH (170 mL, 0.5M). The flask was placed in a cold water bath, and an addition funnel charged with a 2M solution of trimethylsilyl (“TMS”) diazomethane in hexanes (209 mL, 419 mmol) was attached to the flask. The TMS diazomethane solution was added slowly to the reaction flask over the course of 2 hours.
  • TMS trimethylsilyl
  • Step B 10% (wt.) Pd on activated carbon (4.46 g, 4.19 mmol) was added to a
  • Step C Propane- 1-sulfonyl chloride (23.46 niL, 209.3 mmol) was slowly added to a solution of methyl 3-amino-2,6-difluorobenzoate (15.66 g, 83.7 mmol) and triethylamine (35.00 mL, 251.1 mmol) in CH 2 Cl 2 (175 mL, 0.5M) maintained in a cool water bath. The reaction mixture was stirred for 1 hour at room temperature.
  • the mixture was then partitioned between saturated NaHCO 3 (100 mL) and ethyl acetate (75 mL).
  • the aqueous layer was washed with ethyl acetate (50 mL) and then acidified with concentrated HCl to a pH of about 1.
  • the acidified aqueous layer was extracted with ethyl acetate (2 X 50 mL), and the combined ethyl acetate extracts were dried (Na 2 SO 4 ), filtered and concentrated.
  • 6-fluoro-2-methyl-3- ⁇ S[-(propylsulfonyl)propylsulfonamido)benzoic acid [00190] 6-Fluoro-2-methyl-3-(N-(propylsulfonyl)propylsulfonamido)benzoic acid
  • Step A 2-Chloro-6-fluorobenzoic acid (2.00 g, 11.5 mmol) was dissolved in sulfuric acid (20 mL) and cooled to 0°C. Nitric acid (0.529 mL, 12.6 mmol) was added, and the reaction mixture was warmed to room temperature for one hour. The reaction mixture was diluted with water, and the aqueous portion was extracted with DCM (3 X), dried over Na 2 SO 4 , concentrated to a solid, 2-chloro-6-fluoro-3-nitrobenzoic acid (97%), which was used directly in the next step without further purification.
  • Step B 2-Chloro-6-fluoro-3-nitrobenzoic acid (0.100 g, 0.455 mmol) and Zn dust (0.298 g, 4.55 mmol) were taken up in tetrahydrofuran (4 mL) and saturated aqueous NH 4 Cl (2 mL) and stirred at room temperature overnight. The reaction mixture was filtered through Celite, concentrated to a solid, and dissolved in water. The pH was adjusted to 2 with IN HCl, and the aqueous portion was extracted with DCM (3 X). The organic portion was dried over Na 2 SO 4 and concentrated to a solid, 3-amino-2-chloro-6-fluorobenzoic acid (49%), which was used directly in the next step without further purification.
  • Step C 2-Chloro-6-fluoro-3-(propylsulfonamido)benzoic acid (13%) was prepared according to the general procedure for Example H, substituting 3-amino-2-chloro-6- fluorobenzoic acid for 5-amino-2-fluorobenzoic acid.
  • Step A A flame dried flask equipped with a stir bar and rubber septum was charged with 4-chloro-2-fluoroaniline (5.00 g, 34.35 mmol) and dry THF (170 mL). This solution was chilled to -78°C, and n-BuLi (14.7 mL, 1.07 eq. of 2.5M solution in hexanes) was then added over a 15 minute period.
  • Benzyl chloroformate (7.40 g, 1.2 eq.) was then added slowly, and the mixture was stirred at -78°C for one hour. The cooling bath was then removed. The mixture was allowed to warm for 30 minutes and then quenched with water (70 mL) and concentrated HCl (25 mL). The mixture was allowed to continue to warm to room temperature. The mixture was then extracted with EtOAc. The extracts were washed twice with a saturated NaHCO 3 solution, once with water, dried over sodium sulfate and concentrated.
  • Step B Benzyl 3-amino-6-chloro-2-fluorobenzoate (4.3 g, 15.37 mmol) was dissolved in dry dichloromethane (270 mL). Triethylamine (5.36 mL, 2.5 eq.) was added, and the mixture was chilled to 0°C. Propane- 1-sulfonyl chloride (3.63 mL, 32.3 mmol, 2.1 eq.) was then added via syringe, and a precipitate resulted. Once the addition was complete, the mixture was allowed to warm to room temperature, and the starting material was consumed as determined by TLC (3:1 hexane:ethyl acetate).
  • Step A Cyclopropylmethanesulfonyl chloride (1.27 g, 8.20 mmol) was added to a mixture of 3-amino-2,6-difluorobenzoic acid (0.430 g, 2.48 mmol), triethylamine (1.52 mL, 10.9 mmol) and CH 2 Cl 2 (12 mL, 0.2M) cooled to 0 0 C. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The mixture was then partitioned between saturated NaHCO 3 (75 mL) and ethyl acetate (50 mL).
  • the aqueous layer was washed with ethyl acetate (50 mL) and then acidified to a pH of 1 with concentrated HCl.
  • the acidified aqueous layer was extracted twice with ethyl acetate (2 X 50 mL), and the combined ethyl acetate extracts were dried (Na 2 SO 4 ), filtered and concentrated to provide crude 3-(l-cyclopropyl-N-(cyclopropylmethylsulfonyl)methylsulfonamido)-2,6- difluorobenzoic acid (380 mg, 37%).
  • Step B A solution of IN NaOH (2.78 mL, 2.78 mmol) was added to a solution of crude 3-(l-cyclopropyl-N-(cyclopropylmethylsulfonyl)methylsulfonamido)-2,6- difluorobenzoic acid (380 mg, 0.928 mmol) in 4:1 THF/MeOH (5 niL, 0.2M). The reaction mixture was stirred at room temperature for 1 hour, after which most of the organic solvents were removed. IN HCl (3 mL) was slowly added to the mixture to acidify to a pH of 1. The acidified aqueous layer was extracted with ethyl acetate (75 mL). The ethyl acetate extract was washed with water (2 X 20 mL), brine (20 mL), dried (Na 2 SO 4 ), filtered and concentrated. Trituration of the residue with Et 2 O afforded 3-
  • 2,6-Difluoro-3-(3-fluoropropylsulfonamido)benzoic acid was prepared according to the general procedure for Example C, substituting methyl 2,6-difluoro-3-(N-(3- fluoropropylsulfonyl)-3-fluoropropylsulfonamido)benzoate for methyl 2,6-difluoro-3-(N- (propylsulfonyl)-propylsulfonamido)benzoate.
  • 2,6-Difluoro-3-(2-methylpropylsulfonamido)benzoic acid was prepared according to the general procedure for Example C, substituting methyl-2,6-difluoro-3-(N-(2- methylpropylsulfonyl)-2-methylpropylsulfonamido)benzoate for methyl 2,6-difluoro-3-(N- (propylsulfonyl)-propylsulfonamido)benzoate.
  • Benzyl 6-chloro-2-fluoro-3-( ' 3-fluoro-N-(3-fluoropropylsulfonyl)propylsulfonamido)benzoate [00209] Benzyl 6-chloro-2-fluoro-3 -(3 -fluoro-N-(3 -fluoropropylsulfonyl)propylsulfon- amido)benzoate (92%) was prepared according to the general procedure for Example K, Step B substituting 3-fluoropropane- 1-sulfonyl chloride for propane- 1-sulfonyl chloride.
  • 6-Chloro-2-fluoro-3-(3-fluoropropylsulfonamido)benzoic acid (71%) was prepared according to the general procedure for Example L substituting benzyl 6-chloro-2- fluoro-3-(3-fluoro-N-(3-fluoropropylsulfonyl)propylsulfonamido)benzoate for benzyl 6- chloro-2-fluoro-3-(N-(propylsulfonyl)propylsulfonamido)benzoate.
  • 2-Fluoro-3-(3-fluoropropylsulfonamido)benzoic acid (81%) was prepared according to the general procedure for Example M substituting 6-chloro-2-fluoro-3-(3- fluoropropylsulfonamido)benzoic acid for 6-chloro-2-fluoro-3-(propylsulfonamido)benzoic acid.
  • Step A 2,5-Difluorobenzoic acid (2.01 g, 9.90 mmol, 31.3% yield) was dissolved in concentrated sulfuric acid (25 mL) and cooled to 0°C. Nitric Acid (1.46 mL, 34.8 mmol) was added, and the reaction mixture was stirred at room temperature for one hour. The solution was extracted with DCM (3 X), and the combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by column chromatography (1:1 hexanes:l%HCOOH/EtOAc) giving 2,5-difluoro-3-nitrobenzoic acid (2.01 g, 31.3%) as a solid.
  • Step B 2,5-Difluoro-3-nitrobenzoic acid (2.00 g, 9.847 mmol) was dissolved in MeOH (60 mL). TMSCl (6.220 mL, 49.24 mmol) was added, and the reaction mixture was stirred at reflux for 4 hours. The reaction mixture was concentrated to about 20 mL, and the crystals produced were filtered and dried under high vacuum providing methyl 2,5- difluoro-3-nitrobenzoate (1.55 g, 72.4%) as a crystalline solid.
  • Step C Methyl 3-amino-2,5-difluorobenzoate (96.5%) was prepared according to the general procedure for Example B, Step B, substituting methyl 2,5-difluoro- 3-nitrobenzoate for methyl 2,6-difluoro-3-nitrobenzoate.
  • Step D Methyl 2,5-difluoro-3-(N-(propylsulfonyl)propylsulfon- amido)benzoate was prepared according to the general procedure for Example B, Step C, substituting methyl 3-amino-2,5-difluorobenzoate for methyl 3-amino-2,6-difluorobenzoate.
  • Step E 2,5-Difluoro-3-(propylsulfonamido)benzoic acid (83.8%, two steps) was prepared according to the general procedure for Example C substituting methyl 2,5- difluoro-3-(N-(propylsulfonyl)propylsulfonamido)benzoate for methyl 2,6-difluoro-3-(N- (propylsulfonyl)propylsulfonamido)benzoate.
  • Step A 2,2,2-Trifluoroethyl-sulfonyl chloride (459 mL, 4.15 mmol) was slowly added to a solution of methyl 3-amino-2,6-difluorobenzoate (311 g, 1.66 mmol) and pyridine (0.806 mL, 9.97 mmol) in dichloromethane (8.92 mL, 139 mmol), while applying external cooling using an acetone dry ice bath. The reaction mixture was stirred for 45 minutes, and the dry ice bath was removed. The reaction mixture was kept stirring for another hour.
  • Step B 2,6-Difluoro-3-(2-trifluoroethylsulfonamido)benzoic acid was prepared according to the general procedure for Example C, substituting methyl 2,6-difluoro- 3-(2-trifluoroethylsulfonamido) benzoate for methyl 2,6-difluoro-3-(N-(propylsulfonyl)- propylsulfonamido)benzoate.
  • Step A Methyl 2,6-difluoro-3-(N-(3,3,3-trifluoropropylsulfonyl)-3,3,3- trifluoropropyl-sulfonamido) benzoate was made according to the general procedure for Example B, substituting 3,3,3-trifluoropropyl sulfonyl chloride for propane- 1-sulfonyl chloride.
  • Step B 2,6-Difluoro-3-(3,3,3-trifluoropropylsulfonamido)benzoic acid was prepared according to the general procedure for Example C, substituting methyl 2,6-difluoro- 3-(N-(3 ,3 ,3 -trifluoropropylsulfonyl)-3 ,3 ,3 -trifluoropropylsulfonamido)benzoate for methyl 2,6-difluoro-3-(N-(propylsulfonyl)-propylsulfonamido)benzoate.
  • Step A Methyl 2,6-difluoro-3-(N-(2-chloromethylsulfonyl)-2-chloromethyl- sulfonamido) benzoate was made according to the general procedure for Example B, substituting 2-chloromethyl sulfonyl chloride for propane- 1-sulfonyl chloride.
  • 1 H NMR 400 MHz, d 6 -DMSO
  • ⁇ 8.08-7.97 m, IH
  • 7.45 t, IH
  • 4.55 (s, 2H) 4.02(s, 3H).
  • Step B 2,6-Difluoro-3-(2-chloromethylsulfonamido)benzoic acid was prepared according to the general procedure for Example C, substituting methyl 2,6-difluoro- 3-(N-(2-chloromethylsulfonyl)-2-chloromethylsulfonamido)benzoate for methyl 2,6-difluoro- 3-(N-(propylsulfonyl)-propylsulfonamido)benzoate.
  • Step A Benzyl 3-amino-2-chloro-6-fluorobenzoate (56%) was prepared according to the general procedure for Example K, substituting 2-chloro-4-fluoroaniline for 4-chloro-2-fluoroaniline.
  • Step B Benzyl 3-amino-2-chloro-6-fluorobenzoate (330 mg, 1.2 mmol) was dissolved in dry dichloromethane (11.8 mL). Triethylamine (0.494 mL, 3.54 mmol) was added, and the mixture was chilled to 0°C. Propane- 1-sulfonyl chloride (0.332 mL, 2.95 mmol) was then added via syringe. Once the addition was complete, the mixture was allowed to warm to ambient temperature and stir for 16 hours.
  • Step A Benzyl 2-chloro-6-fluoro-3-(N-(propylsulfonyl)propylsulfon- amido)benzoate (413.2 mg, 0.840 mmol) was dissolved in THF (8.4 mL) and 2.0M aqueous LiOH (1.26 mL). The mixture was refluxed for 16 hours and then allowed to cool to ambient temperature. The mixture was acidified to a pH of 0 with l.OM HCl (5.0 mL) and then adjusted to a pH of 4 using saturated sodium bicarbonate. The mixture was extracted with EtOAc (2 X).
  • Step A 2,6-Dichloro-3-nitrobenzoic acid (2.13 g, 9.03 mmol) was dissolved in 2:1 THF:saturated aqueous NH 4 Cl and cooled to 0°C. The mixture was treated with zinc (11.8 g, 181 mmol). The reaction mixture was allowed to warm to ambient temperature and stir for 24 hours. The reaction mixture was filtered through GF/F paper while rinsing with THF. The mixture was acidified to a pH of 1 using 1.0M HCl and extracted with 15% 2- propanol:DCM (3 X).
  • Step B 3-Amino-2,6-dichlorobenzoic acid (1.40 g, 6.82 mmol) was dissolved in dry dichloromethane (66.7 mL). Triethylamine (4.09 mL, 29.4 mmol) was added, and the mixture was chilled to 0°C. Propane- 1-sulfonyl chloride (2.48 mL, 22 mmol) was then added via syringe. Once the addition was complete, the mixture was allowed to warm to ambient temperature and stir for 1 hour. The mixture was concentrated in vacuo and diluted with diethyl ether.
  • Step A 2-Chloro-3,5-dinitropyridine (6.8 g, 33.41 mmol) was taken up in ethanol (200 mL), and ammonium hydroxide solution (19.5 mL, 167 mmol, 5 eq.) was then dripped in slowly, which resulted in a mixture/precipitate. An exotherm was observed, so the reaction mixture was placed in an ice bath for 10 minutes and then removed. After stirring for about 20 minutes, the solids were collected by filtration and dried under vacuum.
  • Step C 5-Nitropyridine-2,3-diamine (0.050 g, 0.32 mmol) was dissolved in formic acid (10 mL) and heated to 100°C for 6 hours. The reaction was diluted with water (10 mL) and brought to a pH of 7 with 3N NaOH. The aqueous portion was extracted with 25% isopropyl alcohol (“IPA”)/DCM (6 X), dried over Na 2 SO 4 and concentrated to give 6- nitro-3H-imidazo[4,5-b]pyridine (52 mg, 98%) as a solid.
  • IPA isopropyl alcohol
  • 6 X isopropyl alcohol
  • Step D 6-Nitro-3H-imidazo[4,5-b]pyridine (0.026 g, 0.158 mmol) was taken up as a slurry in EtOH. 10% PdVC (0.00843 g, 0.00792 mmol) was added, and hydrogen gas was bubbled through for 10 minutes. The reaction was stirred under a balloon of hydrogen at room temperature overnight. The reaction was filtered through celite, and the filtrate was concentrated to give 3H-imidazo[4,5-b]pyridin-6-amine as a solid that was used without further purification. [00235] Step E: 3H-Imidazo[4,5-b]pyridin-6-amine (29 mg, 0.22 mmol), 2,6-difluoro-
  • Step A 5-Nitropyridine-2,3-diamine (100 mg, 0.65 mmol, see Example 1) and benzoic acid (87 mg, 0.71 mmol, 1.1 eq.) were combined in POCl 3 (5 mL) and heated to reflux for 16 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure, and the resulting residue was taken up in saturated sodium bicarbonate solution, and extracted with 25% IPA/DCM (2 X).
  • Step B 2-Phenyl-3H-imidazo[4,5-b]pyridin-6-amine (71%) was prepared according to the general procedure in Example 1, step D, substituting 6-nitro-2-phenyl-3H- imidazo[4,5-b]pyridine for 6-nitro-3H-imidazo[4,5-b]pyridine, and was carried forward to the next step without further purification.
  • Step C 2,6-Difluoro-N-(2-phenyl-3H-imidazo[4,5-b]pyridin-6-yl)-3-
  • Step D Alternative formation of 2,6-difluoro-N-(2-phenyl-3H-imidazo[4,5- b]pyridin-6-yl)-3-(propylsulfonamido)benzamide: A reaction vial containing 2-phenyl-3H- imidazo[4,5-b]pyridin-6-amine (5.3 mg, 0.026 mmol) was taken up in dry toluene (0.25 mL). Trimethyl aluminum (36 mL, 0.075 mmol, 2M in toluene) was then added by syringe, and the mixture was stirred at room temperature for 20 minutes.
  • Step E Alternative formation of 2,6-difluoro-N-(2-phenyl-3H-imidazo[4,5- b]pyridin-6-yl)-3-(propylsulfonamido)benzamide: 2,6-Difluoro-N-(2-phenyl-3H- imidazo[4,5-b]pyridin-6-yl)-3-(N-(propylsulfonyl)propylsulfonamido)benzamide was prepared according to the general procedure in Example 1, Step E, substituting 2-phenyl-3H- imidazo[4,5-b]pyridin-6-amine for 3H-imidazo[4,5-b]pyridin-6-amine and 2,6-difluoro-3-(N- (propylsulfonyl)propylsulfonamido)benzoic acid for 2,6-difluoro-3-
  • Step A N,N-Dimethyl-4-(6-nitro-3H-imidazo[4,5-b]pyridin-2-yl)aniline
  • Step C N-(2-(4-(Dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-6-yl)-
  • Step A A scintillation vial was charged with 5-nitropyridine-2,3-diamine (44 mg, 0.285 mmol), phenyl isothiocyanate (250 ⁇ L, 2.09 mmol) and THF (5 mL). The reaction vessel was sealed and heated to 70°C for 30 minutes. The vessel was then cooled to room temperature, and PS-carbodiimide (1.25 mmol/g; 1.20 g, 1.50 mmol) was added. The vessel was re-sealed and heated to 70°C for 24 hours. The reaction mixture was filtered through GF/F paper, and the solids were rinsed with excess CH 2 Cl 2 and MeOH alternately. The filtrate was concentrated in vacuo, and the residue was triturated with 5% MeOH/CH 2 Cl 2 to afford 6-nitro-N-phenyl-3H-imidazo[4,5-b]pyridin-2-amine.
  • Step B N2-Phenyl-3H-imidazo[4,5-b]pyridine-2,6-diamine was prepared according to Example 1, Step D, substituting 6-nitro-N-phenyl-3H-imidazo[4,5-b]pyridin-2- amine for 6-nitro-3H-imidazo[4,5-b]pyridine.
  • Step C 2,6-Difluoro-N-(2-(phenylamino)-3H-imidazo[4,5-b]pyridin-6-yl)-3-
  • Step A A 10-20 mL Biotage Microwave reaction vial was charged with 5- nitropyridine-2,3 -diamine (85 mg, 0.55 mmol, Example 1, Step B) and acetic acid (5 mL). This mixture was subjected to microwave irradiation at 175°C for 75 minutes and then poured into a saturated sodium bicarbonate solution (200 mL). The solution was extracted with 25% IPA/DCM (2 X), and the extracts were dried over sodium sulfate.
  • Step B 2-Methyl-3H-imidazo[4,5-b]pyridin-6-amine (87%) was prepared according to the general procedure Example 1, Step D, substituting 2-methyl-6-nitro-3H- imidazo[4,5-b]pyridine for 6-nitro-3H-imidazo[4,5-b]pyridine.
  • Step C 2,6-Difluoro-N-(2-methyl-3H-imidazo[4,5-b]pyridin-6-yl)-3-
  • Step A A 2-5 mL Biotage Microwave reaction vial was charged with 5- nitropyridine-2,3 -diamine (100 mg, 0.65 mmol), isonicotinic acid (80 mg, 0.65 mmol, 1 eq.), and triphenyl phosphite (204 ⁇ L, 0.78 mmol, 1.2 eq.) in pyridine (3 mL). This mixture was heated in the microwave at 200°C for 15 minutes and then concentrated under reduced pressure.
  • Step B 2-(Pyridin-4-yl)-3H-imidazo[4,5-b]pyridin-6-amine (50%) was prepared according to the general procedure in Example 1, Step D (using 1 weight equivalent of 20% Pd(OH) 2 as the catalyst), substituting 6-nitro-2-(pyridin-4-yl)-3H-imidazo[4,5- b]pyridine for 6-Nitro-3H-imidazo[4,5-b]pyridine.
  • Step C 2,6-Difluoro-3-(propylsulfonamido)-N-(2-(pyridin-4-yl)-3H- imidazo[4,5-b]pyridin-6-yl)benzamide (35%) was prepared according to the general procedure in Example 1, Step E, substituting 2-(pyridin-4-yl)-3H-imidazo[4,5-b]pyridin-6- amine for 3H-imidazo[4,5-b]pyridin-6-amine.
  • Step A 6-Nitro-2-(pyridin-3-yl)-3H-imidazo[4,5-b]pyridine (20%) was prepared according to Example 6, Step A, substituting nicotinic acid for isonicotinic acid.
  • Step B 2-(Pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-6-amine (61%) was prepared according to Example 6, Step B, substituting 6-nitro-2-(pyridin-3-yl)-3H- imidazo[4,5-b]pyridine for 6-nitro-2-(pyridin-4-yl)-3H-imidazo[4,5-b]pyridine.
  • Step C 2,6-Difluoro-3-(propylsulfonamido)-N-(2-(pyridin-3-yl)-3H- imidazo[4,5-b]pyridin-6-yl)benzarnide (42%) was prepared according to the general procedure in Example 1, Step E, substituting 2-(pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-6- amine for 3H-imidazo[4,5-b]pyridin-6-amine.
  • Step A Benzyl 4-(6-nitro-3H-imidazo[4,5-b]pyridin-2-yl)piperidine-l- carboxylate (34%) was prepared according to the general procedure in Example 6, Step 1, substituting l-(benzyloxycarbonyl)piperidine-4-carboxylic acid for isonicotinic acid.
  • Step B Benzyl 4-(6-nitro-3H-imidazo[4,5-b]pyridin-2-yl)piperidine-l- carboxylate (80 mg, 0.21 mmol) was dissolved in methanol (2 mL). Tin (II) chloride di- hydrate (237 mg, 1.05 mmol, 5 eq.) was added, and the mixture was warmed to 70°C for 2 hours. The mixture was then allowed to cool to room temperature. The reaction mixture was diluted with EtOAc and washed once with saturated sodium bicarbonate solution (an emulsion formed, which was filtered through GF/F filter paper). The organics were isolated, dried and concentrated under reduced pressure.
  • Step C Benzyl 4-(6-(2,6-difluoro-3-(propylsulfonamido)benzamido)-3H- imidazo[4,5-b]pyridin-2-yl)piperidine-l-carboxylate (46%) was prepared according to the general procedure in Example 1, Step E, substituting benzyl 4-(6-amino-3H-imidazo[4,5- b]pyridin-2-yl)piperidine-l-carboxylate for 3H-imidazo[4,5-b]pyridin-6-amine.
  • Step D Benzyl 4-(6-(2,6-difluoro-3-(propylsulfonamido)benzamido)-3H- imidazo[4,5-b]pyridin-2-yl)piperidine-l-carboxylate (29 mg, 0.047 mmol) was dissolved in methanol (approximately 1 mL), and 20% palladium hydroxide (30 mg, 1 eq.) was added. The mixture was hydrogenated under a balloon of hydrogen for 1.5 hours.
  • Step A Benzyl 3-(6-nitro-3H-imidazo[4,5-b]pyridin-2-yl)piperidine-l- carboxylate (27%) was prepared according to the general procedure in Example 6, Step 1, substituting l-(benzyloxycarbonyl)piperidine-3-carboxylic acid for isonicotinic acid.
  • Step B Benzyl 3-(6-amino-3H-imidazo[4,5-b]pyridin-2-yl)piperidine-l- carboxylate (75%) was prepared according to the general procedure in Example 8, Step B, substituting benzyl 3-(6-nitro-3H-imidazo[4,5-b]pyridin-2-yl)piperidine-l-carboxylate for benzyl 4-(6-nitro-3H-imidazo[4,5-b]pyridin-2-yl)piperidine-l-carboxylate.
  • Step C Benzyl 3-(6-(2,6-difluoro-3-(propylsulfonamido)benzamido)-3H- imidazo[4,5-b]pyridin-2-yl)piperidine-l-carboxylate (25%) was prepared according to the general procedure in Example 1, Step E, substituting 3-(6-amino-3H-imidazo[4,5-b]pyridin- 2-yl)piperidine-l-carboxylate for 3H-imidazo[4,5-b]pyridin-6-amine.
  • m/z (APCI-neg) M-I 611.2
  • (APCI-pos) M+l 613.1.
  • Step D 2,6-Difluoro-N-(2-(piperidin-3-yl)-3H-imidazo[4,5-b]pyridin-6-yl)-3-
  • Step A 2-(4-Chlorophenyl)-6-nitro-3H-imidazo[4,5-b]pyridine (49%) was prepared as in the general procedure in Example 2, Step A, substituting 4-chlorobenzoic acid for benzoic acid.
  • Step B 2-(4-Chlorophenyl)-6-nitro-3H-imidazo[4,5-b]pyridine (50 mg, 0.182 mmol) was dissolved in THF (2 mL), and a saturated ammonium chloride solution (2 mL) was added followed by zinc powder (119 mg, 1.82 mmol, 10 eq.). This mixture was vigorously stirred at room temperature for 15 minutes, when TLC indicated complete consumption of starting material. The reaction mixture was then filtered through GF/F filter paper. The filtrate was diluted with water and extracted with EtOAc (with a little methanol, 2 X). The extracts were dried over sodium sulfate and concentrated to 2-(4-chlorophenyl)-3H- imidazo[4,5-b]pyridin-6-amine (41 mg, 92%) as a solid.
  • Step C N-(2-(4-Chlorophenyl)-3H-imidazo[4,5-b]pyridin-6-yl)-2,6-difluoro-
  • Step A 2-(4-Methoxyphenyl)-6-nitro-3H-imidazo[4,5-b]pyridine (64%) was prepared as in the general procedure in Example 2, Step A, substituting 4-methoxybenzoic acid for benzoic acid.
  • 1 H NMR 400 MHz, DMSOd 6 ) ⁇ 9.19-9.22 (m, IH), 8.72 (br s, IH), 8.21-8.26 (m, 2H), 7.16-7.20 (m, 2H), 3.87 (s, 3H); m/z (APCI-neg) M-I - 269.3.
  • Step B 2-(4-Methoxyphenyl)-3H-imidazo[4,5-b]pyridin-6-amine (96%) was prepared as in the general procedure in Example 10, Step B, substituting 2-(4- methoxyphenyl)-6-nitro-3H-imidazo[4,5-b]pyridine for 2-(4-chlorophenyl)-6-nitro-3H- imidazo[4,5-b]pyridine.
  • Step C 2,6-Difluoro-N-(2-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridin-6- yl)-3-(propylsulfonamido)benzamide (22%) was prepared according to the general procedure in Example 1, Step E, substituting 2-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridin-6-amine for 3H-imidazo[4,5-b]pyridin-6-amine.
  • Step A 2-(4-Fluorophenyl)-6-nitro-3H-imidazo[4,5-b]pyridine (30%) was prepared according to the general procedure in Example 2, Step A, substituting 4- fluorobenzoic acid for benzoic acid.
  • Step B 2-(4-Fluorophenyl)-3H-imidazo[4,5-b]pyridin-6-amine (59%) was prepared according to Example 10, Step B, substituting 2-(4-fluorophenyl)-6-nitro-3H- imidazo[4,5-b]pyridine for 2-(4-chlorophenyl)-6-nitro-3H-imidazo[4,5-b]pyridine.
  • Step C 2,6-Difluoro-N-(2-(4-fluorophenyl)-3H-imidazo[4,5-b]pyridin-6-yl)-
  • Step B 2-p-Tolyl-3H-imidazo[4,5-b]pyridin-6-amine was prepared according to the general procedure in Example 3, Step B, substituting 6-nitro-2-p-tolyl-3H-imidazo[4,5- b]pyridine for N,N-dimethyl-4-(6-nitro-3H-imidazo[4,5-b]pyridin-2-yl)aniline.
  • Step C N-(2-(4-Bromophenyl)-3H-imidazo[4,5-b]pyridin-6-yl)-2,6-difluoro-
  • Step C N-(2-(3-Chlorophenyl)-3H-imidazo[4,5-b]pyridm-6-yl)-2,6-difluoro-
  • Step A 6-Nitro-2-(3-(trifluoromethoxy)phenyl)-3H-imidazo[4,5-b]pyridine
  • Step C 2,6-Difluoro-3-(propylsulfonamido)-N-(2-(4-)
  • Step A 6-Nitro-2-(4-(trifluoromethyl)phenyl)-3H-imidazo[4,5-b]pyridine
  • Step C 2,6-Difluoro-3-(propylsulfonamido)-N-(2-(4-)
  • Step A 6-Nitro-2-(3-(trifluoromethyl)phenyl)-3H-imidazo[4,5-b]pyridine
  • Step B 2-(3-(Trifiuoromethyl)phenyl)-3H-imidazo[4,5-b]pyridin-6-amine was prepared according to the general procedure in Example 3, Step B, substituting 6-nitro-2- (3 -(trifluoromethyl)phenyl)-3 H-imidazo [4,5 -bjpyridine for N,N-dimethyl-4-(6-nitro-3 H- imidazo[4,5-b]pyridin-2-yl)aniline.
  • Step C 2,6-Difluoro-N-(2-(2-fluorophenyl)-3H-imidazo[4,5-b]pyridin-6-yl)-
  • Step C N-(2-(3-Bromophenyl)-3H-imidazo[4,5-b]pyridin-6-yl)-2,6-difluoro-
  • Step C N-(2-(4-Cyanophenyl)-3H-imidazo[4,5-b]pyridin-6-yl)-2,6-difluoro-
  • Step C N-(2-(2-Chlorophenyl)-3H-imidazo[4,5-b]pyridin-6-yl)-2,6-difluoro-
  • Step C N-(2-(4-Chlorobenzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-2,6-difluoro-
  • Step C N-(2-(2-Bromophenyl)-3H-imidazo[4,5-b]pyridin-6-yl)-2,6-difluoro-
  • Step C N-(2-(4-Bromobenzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-2,6-difluoro-
  • Step C N-(2-tert-Butyl-3H-imidazo[4,5-b]pyridin-6-yl)-2,6-difluoro-3-
  • Step C 2,6-Difluoro-N-(2-isopropyl-3H-imidazo[4,5-b]pyridin-6-yl)-3-
  • Step C N-(2-Ethyl-3H-imidazo[4,5-b]pyridin-6-yl)-2,6-difluoro-3-
  • Step C N-(2-Cyclopropyl-3H-imidazo[4,5-b]pyridin-6-yl)-2,6-difluoro-3-
  • Step A 4-(4-(6-Nitro-3H-imidazo[4,5-b]pyridin-2-yl)phenyl)morpholine
  • Step C 2,6-Difluoro-N-(2-(4-morpholinophenyl)-3H-imidazo[4,5-b]pyridin-
  • Step A 2-(4-Bromo-2-methylphenyl)-6-nitro-3H-imidazo[4,5-b]pyridine

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Abstract

Compounds of Formula I are useful for inhibition of Raf kinases. Methods of using compounds of Formula I and stereoisomers and pharmaceutically acceptable salts thereof, for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions are disclosed.

Description

IMDIZO [4 . 5-B] PYRIDINE DERIVATIVES USED AS RAF INHIBITORS
BACKGROUND OF THE INVENTION
[0001] FIELD OF THE INVENTION
[0002] The present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, to a process for making the compounds and to the use of the compounds in therapy. More particularly, it relates to certain substituted 3H- imidazo[4,5-b]pyridine compounds useful for inhibiting Raf kinase and for treating disorders mediated thereby.
[0003] DESCRIPTION OF THE STATE OF THE ART
[0004] The Raf/MEK/ERK pathway is critical for cell survival, growth, proliferation and tumorigenesis. Li, Nanxin, et al. "B-Raf kinase inhibitors for cancer treatment." Current
Opinion in Investigational Drugs. Vol. 8, No. 6 (2007): 452-456. Raf kinases exist as three isoforms, A-Raf, B-Raf and C-Raf. Among the three isoforms, studies have shown that B-
Raf functions as the primary MEK activator. B-Raf is one of the most frequently mutated genes in human cancers. B-Raf kinase represents an excellent target for anticancer therapy based on preclinical target validation, epidemiology and drugability.
[0005] Small molecule inhibitors of B-Raf are being developed for anticancer therapy. Nexavar® (sorafenib tosylate) is a multikinase inhibitor, which includes inhibition of
B-Raf, and is approved for the treatment of patients with advanced renal cell carcinoma and unresectable hepatocellular carcinoma. Other Raf inhibitors have also been disclosed or have entered clinical trials, for example SB-590885, RAF-265, PLX-4032 and XL-281. Other B-
Raf inhibitors are also known, see for example, U.S. Patent Application Publication
2006/0189627, U.S. Patent Application Publication 2006/0281751, U.S. Patent Application
Publication 2007/0049603, International Patent Application Publication WO 2007/002325 and International Patent Application Publication WO 2007/002433.
[0006] Imidazopyridines are known, see for example, International Patent Application
Publication WO 2007/017143, International Patent Application Publication WO
2006/066913, International Patent Application Publication WO 2004/108133 and
International Patent Application Publication WO 2004/024897.
[0007] Kinase inhibitors are known, see for example, International Patent Application
Publication WO 2005/062795 and International Patent Application Publication WO
2007/013896. [0008] International Patent Application Publication WO 2006/066913, International
Patent Application Publication WO 2008/028617 and International Patent Application Publication WO 2009/012283 also disclose kinase inhibitors.
SUMMARY OF THE INVENTION
[0009] In one aspect, the invention relates to compounds that are inhibitors of Raf kinases, particularly B-Raf inhibitors. Certain hyperproliferative disorders are characterized by the over activation of Raf kinase function, for example by mutations or over expression of the protein. Accordingly, the compounds of the invention are useful in the treatment of hyperproliferative disorders such as cancer.
[0010] More specifically, one aspect of the present invention provides compounds of
Formula I:
Figure imgf000003_0001
I and stereoisomers, tautomers and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4 and R5 are as defined herein.
[0011] Another aspect of the present invention provides methods of preventing or treating a disease or disorder modulated by B-Raf, comprising administering to a mammal in need of such treatment an effective amount of a compound of this invention or a stereoisomer or pharmaceutically acceptable salt thereof. Examples of such diseases and disorders include, but are not limited to, hyperproliferative disorders (such as cancer, including melanoma and other cancers of the skin), neurodegeneration, cardiac hypertrophy, pain, migraine and neurotraumatic disease.
[0012] Another aspect of the present invention provides methods of preventing or treating cancer, comprising administering to a mammal in need of such treatment an effective amount of a compound of this invention, or a stereoisomer or pharmaceutically acceptable salt thereof, alone or in combination with one or more additional compounds having anticancer properties. [0013] Another aspect of the present invention provides a method of treating a hyperproliferative disease in a mammal comprising administering a therapeutically effective amount of a compound of this invention to the mammal.
[0014] Another aspect of the present invention provides methods of preventing or treating kidney disease, comprising administering to a mammal in need of such treatment an effective amount of a compound of this invention, or a stereoisomer or pharmaceutically acceptable salt thereof, alone or in combination with one or more additional compounds. Another aspect of the present invention provides methods of preventing or treating polycystic kidney disease, comprising administering to a mammal in need of such treatment an effective amount of a compound of this invention, or a stereoisomer or pharmaceutically acceptable salt thereof, alone or in combination with one or more additional compounds. [0015] Another aspect of the present invention provides the compounds of the present invention for use in therapy.
[0016] Another aspect of the present invention provides the compounds of the present invention for use in the treatment of a hyperproliferative disease. In a further embodiment, the hyperproliferative disease may be cancer (or still further, a specific cancer as defined herein).
[0017] Another aspect of the present invention provides the compounds of the present invention for use in the treatment of a kidney disease. In a further embodiment, the kidney disease may be polycystic kidney disease.
[0018] Another aspect of the present invention provides the use of a compound of this invention in the manufacture of a medicament for the treatment of a hyperproliferative disease. In a further embodiment, the hyperproliferative disease may be cancer (or still further, a specific cancer as defined herein).
[0019] Another aspect of the present invention provides the use of a compound of this invention in the manufacture of a medicament for the treatment of a kidney disease. In a further embodiment, the kidney disease may be polycystic kidney disease. [0020] Another aspect of the present invention provides the use of a compound of the present invention in the manufacture of a medicament, for use as a B-Raf inhibitor in the treatment of a patient undergoing cancer therapy.
[0021] Another aspect of the present invention provides the use of a compound of the present invention in the manufacture of a medicament, for use as a B-Raf inhibitor in the treatment of a patient undergoing polycystic kidney disease therapy. [0022] Another aspect of the present invention provides a pharmaceutical composition comprising a compound of the present invention for use in the treatment of a hyperproliferative disease.
[0023] Another aspect of the present invention provides a pharmaceutical composition comprising a compound of the present invention for use in the treatment of cancer.
[0024] Another aspect of the present invention provides a pharmaceutical composition comprising a compound of the present invention for use in the treatment of polycystic kidney disease.
[0025] Another aspect of the present invention provides a pharmaceutical composition comprising a compound of this invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
[0026] Another aspect of the present invention includes methods of preparing, methods of separation, and methods of purification of the compounds of this invention. [0027] Another aspect of the present invention provides intermediates for preparing compounds of Formula I. Certain compounds of Formula I may be used as intermediates for other compounds of Formula I.
DETAILED DESCRIPTION OF THE INVENTION
[0028] Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. While the invention will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present invention as defined by the claims. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described. In the event that one or more of the incorporated literature and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, this application controls. DEFINITIONS
[0029] The term "alkyl" includes linear or branched-chain radicals of carbon atoms.
In one example, the alkyl radical is one to six carbon atoms (C1-C6). In other examples, the alkyl radical is C1-C5, C1-C4 or C1-C3. Some alkyl moieties have been abbreviated, for example, methyl ("Me"), ethyl ("Et"), propyl ("Pr") and butyl ("Bu"), and further abbreviations are used to designate specific isomers of compounds, for example, 1 -propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1 -butyl or n-butyl ("n-Bu"), 2-methyl-l- propyl or isobutyl ("i-Bu"), 1-methylpropyl or s-butyl ("s-Bu"), 1,1-dimethylethyl or t-butyl ("t-Bu") and the like. Other examples of alkyl groups include 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2- methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-l- butyl (-CH2CH2CH(CH3)2), 2-methyl-l -butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl
(-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2- pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3- methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3- dimethyl-2-butyl (-C(CH3)2CH(CH3)2) and 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3. The abbreviations are sometimes used in conjunction with elemental abbreviations and chemical structures, for example, methanol ("MeOH") or ethanol ("EtOH").
[0030] Additional abbreviations used throughout the application include, for example, benzyl ("Bn"), phenyl ("Ph") and acetyl ("Ac").
[0031] The term "alkenyl" refers to linear or branched-chain monovalent hydrocarbon radical with at least one site of unsaturation, i.e., a carbon-carbon double bond, wherein the alkenyl radical may be optionally substituted independently with one or more substituents described herein, and includes radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. In one example, the alkenyl radical is two to six carbon atoms (C2- C6). In other examples, the alkenyl radical is C2-C3. Examples include, but are not limited to, ethenyl or vinyl (-CH=CH2), prop-1-enyl (-CH=CHCH3), prop-2-enyl (-CH2CH=CH2), 2- methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-l,3-dienyl, 2-methylbuta-l,3- diene, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hexa-l,3-dienyl. [0032] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical with at least one site of unsaturation, i.e., a carbon-carbon, triple bond, wherein the alkynyl radical may be optionally substituted independently with one or more substituents described herein. In one example, the alkynyl radical is two to eighteen carbon atoms (C2- C6). In other examples, the alkynyl radical is C2-C3. Examples include, but are not limited to, ethynyl (-C≡CH), prop-1-ynyl (-C≡CCH3), prop-2-ynyl (propargyl, CH2C≡CH), but-1-ynyl, but-2-ynyl and but-3-ynyl.
[0033] The terms "alkenyl" and "alkynyl" also include linear or branched-chain radicals of carbon atoms containing at least one unsaturated bond.
[0034] "Cycloalkyl" refers to a non-aromatic, saturated or partially unsaturated hydrocarbon ring group wherein the cycloalkyl group may be optionally substituted independently with one or more substituents described herein. In one example, the cycloalkyl group is 3 to 6 carbon atoms (C3-C6). In other examples, cycloalkyl is C3-C4 or C3-C5. In other examples, the cycloalkyl group, as a monocycle, is C3-C6 or C5-C6. In another example, the cycloalkyl group, as a bicycle, is C7-C12. Examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-l-enyl, l-cyclopent-2-enyl, l-cyclopent-3- enyl, cyclohexyl, 1-cyclohex-l-enyl, l-cyclohex-2-enyl, l-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Exemplary arrangements of bicyclic cycloalkyls having 7 to 12 ring atoms include, but are not limited to, [4,4], [4,5], [5,5], [5,6] or [6,6] ring systems. Exemplary bridged bicyclic cycloalkyls include, but are not limited to, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. [0035] The terms "heterocyclic" or "heterocycle" or "heterocyclyl" refers to a saturated or a partially unsaturated (i.e., having one or more double and/or triple bonds within the ring) cyclic group in which at least one ring atom is a heteroatom independently selected from nitrogen, oxygen, and sulfur, the remaining ring atoms being carbon. In one embodiment, heterocyclyl includes saturated or partially unsaturated 4-6 membered heterocyclyl groups. The heterocyclyl group may be optionally substituted with one or more substituents described herein. Exemplary heterocyclyl groups include, but are not limited to, oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl, piperidinyl, dihydropyridinyl, tetrahydropyridinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, 1,4-oxathianyl, 1,4-dioxepanyl, 1,4-oxathiepanyl, 1,4-oxaazepanyl, 1,4- dithiepanyl, 1,4-thiazepanyl and 1,4-diazepane 1 ,4-dithianyl, 1,4-azathianyl, oxazepinyl, diazepinyl, thiazepinyl, dihydrothienyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3- pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, 1,4-dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinylimidazolinyl, imidazolidinyl, pyrimidinonyl, 1,1-dioxo-thiomoφholinyl, 3-azabicyco[3.1.0]hexanyl, 3- azabicyclo[4.1.0]heptanyl and azabicyclo[2.2.2]hexanyl. Heterocycles include 4 to 6 membered rings containing one or two heteroatoms selected from oxygen, nitrogen and sulfur.
[0036] The term "heteroaryl" refers to an aromatic cyclic group in which at least one ring atom is a heteroatom independently selected from nitrogen, oxygen and sulfur, the remaining ring atoms being carbon. Heteroaryl groups may be optionally substituted with one or more substituents described herein. In one example, heteroaryl includes 5-6 membered heteroaryl groups. Other examples of heteroaryl groups include, but are not limited to, pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, 1,2,3 -triazolyl, 1,3,4- triazolyl, l-oxa-2,3-diazolyl, l-oxa-2,4-diazolyl, l-oxa-2,5-diazolyl, l-oxa-3,4-diazolyl, 1- thia-2,3-diazolyl, l-thia-2,4-diazolyl, l-thia-2,5-diazolyl, l-thia-3,4-diazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. Heteroaryls include 5 to 6 membered aromatic rings containing one, two or three heteroatoms selected from oxygen, nitrogen and sulfur. [0037] "Halogen" refers to F, Cl, Br or I.
[0038] The terms "treat" or "treatment" refer to therapeutic, prophylactic, palliative or preventative measures. In one example, treatment includes therapeutic and palliative treatment. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.
[0039] The phrases "therapeutically effective amount" or "effective amount" mean an amount of a compound of the present invention that, when administered to a mammal in need of such treatment, sufficient to (i) treat or prevent the particular disease, condition, or disorder, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, condition, or disorder, or (iii) prevent or delay the onset of one or more symptoms of the particular disease, condition, or disorder described herein. The amount of a compound that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the mammal in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
[0040] The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by abnormal or unregulated cell growth. A "tumor" comprises one or more cancerous cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More particular examples of such cancers include squamous cell cancer (e.g., epithelial squamous cell cancer), lung cancer including small-cell lung cancer, non-small cell lung cancer ("NSCLC"), adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, as well as head and neck cancer. The term cancer may be used generically to include various types of cancer or specifically (as listed above).
[0041] The phrase "pharmaceutically acceptable" indicates that the substance or composition is compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith. [0042] The phrase "pharmaceutically acceptable salt," as used herein, refers to pharmaceutically acceptable organic or inorganic salts of a compound of the invention. [0043] The compounds of this invention also include other salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and/or purifying compounds of this invention and/or for separating enantiomers of compounds of this invention.
[0044] The term "mammal" means a warm-blooded animal that has or is at risk of developing a disease described herein and includes, but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters, and primates, including humans. B-RAF INHIBITOR COMPOUNDS
[0045] The present invention provides compounds, and pharmaceutical formulations thereof, that are potentially useful in the treatment of diseases, conditions and/or disorders modulated by B-Raf.
[0046] One embodiment of this invention provides compounds of Formula I:
Figure imgf000010_0001
I and stereoisomers and pharmaceutically acceptable salts thereof, wherein:
R1 and R2 are independently selected from hydrogen, halogen, CN, C1-C3 alkyl, and C1-C3 alkoxy;
R3 is hydrogen, halogen or C1-C3 alkyl;
R4 is C3-C5 cycloalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, a 5-6 membered heteroaryl, or NRhR', wherein the cycloalkyl, alkyl, alkenyl, alkynyl and phenyl are optionally substituted with OR0, halogen, phenyl, C3-C4 cycloalkyl or C1-C4 alkyl optionally substituted with halogen;
R5 is hydrogen, phenyl optionally substituted with one to three Ra groups, -N(R0)- phenyl optionally substituted with Ra, -CH2-phenyl optionally substituted with one to three Rb groups, a 5-6 membered heteroaryl optionally substituted with one to three Re groups, saturated or partially unsaturated C3-C6 cycloalkyl optionally substituted with halogen or C1- C4 alkyl, a 5-6 membered heterocyclyl, or C1-C6 alkyl optionally substituted with one or more Rs groups; each Ra is independently selected from halogen, CN, a 5-6 membered heterocyclyl, NR°Rd, -S(O)2Rf, -0(C1-C4 alkyl), and C1-C4 alkyl, wherein the alkyl or alkoxy are optionally substituted with halogen; each Rb is independently selected from halogen, OH or OCH3; each Rc and Rd are independently selected from hydrogen or C1-C4 alkyl;
Re is selected from a 5-6 membered heterocyclyl or NRcRd;
Rf is selected from C1-C4 alkyl or NRcRd; each R8 is independently selected from halogen, CN, ORC, C3-C6 cycloalkyl or NRcRd; and
Rh and R1 are independently selected from hydrogen and C1-C5 alkyl optionally substituted with halogen, or
Rh and R1 together with the nitrogen to which they are attached form a 4 to 6 membered heterocyclic ring. [0047] One embodiment of this invention provides compounds of Formula I:
Figure imgf000011_0001
I and stereoisomers and pharmaceutically acceptable salts thereof, wherein:
R1 and R2 are independently selected from hydrogen, halogen, CN, C1-C3 alkyl, and C1-C3 alkoxy;
R3 is hydrogen, halogen or C1-C3 alkyl;
R4 is C3-C5 cycloalkyl, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the cycloalkyl, alkyl, alkenyl and alkynyl are optionally substituted with ORC, halogen or C3-C4 cycloalkyl;
R5 is hydrogen, phenyl optionally substituted with one to three Ra groups, -N(R0)- phenyl optionally substituted with Ra, -CH2-phenyl optionally substituted with one to three Rb groups, a 5-6 membered heteroaryl optionally substituted with one to three Re groups, saturated or partially unsaturated C3-C6 cycloalkyl optionally substituted with halogen or C1- C4 alkyl, a 5-6 membered heterocyclyl, or C1-C6 alkyl optionally substituted with one or more Rg groups; each Ra is independently selected from halogen, CN, a 5-6 membered heterocyclyl, NR°Rd, -S(O)2Rf, -0(C1-C4 alkyl), and C1-C4 alkyl, wherein the alkyl or alkoxy are optionally substituted with halogen; each Rb is independently selected from halogen, OH or OCH3; each Rc and R are independently selected from hydrogen or C1-C4 alkyl;
Re is selected from a 5-6 membered heterocyclyl or NR°Rd;
Rf is selected from C1-C4 alkyl or NRcRd; and each R8 is independently selected from halogen, CN, ORC, C3-C6 cycloalkyl or NRcRd. [0048] Compounds of Formula I include compounds wherein:
R1, R2 and R3 are independently selected from H, halogen or C1-C3 alkyl;
R4 is C3-C4 cycloalkyl, or C1-C6 alkyl optionally substituted with OH, halogen or C3- C4 cycloalkyl;
R5 is hydrogen, phenyl optionally substituted with one to three Ra groups, -NH- phenyl, -CH2-phenyl optionally substituted with one to three Rb groups, a 5-6 membered heteroaryl optionally substituted with one to three Re groups, C3-C6 cycloalkyl, a 5-6 membered heterocyclyl, or C1-C6 alkyl; each Ra is independently selected from halogen, CN, a 5-6 membered heterocyclyl, NRcRd, -S(O)2R1, -0(C1-C4 alkyl) and C1-C4 alkyl, wherein the alkyl or alkoxy are optionally substituted with halogen; each Rb is independently selected from halogen, OH or OCH3; each Rc and Rd are independently selected from hydrogen or C1-C4 alkyl;
Re is selected from a 5-6 membered heterocyclyl or NReRd; and
Rf is selected from C1-C4 alkyl or NRcRd.
[0049] In certain embodiments, R1 and R2 are independently selected from hydrogen, halogen, CN, C1-C3 alkyl or C1-C3 alkoxy.
[0050] In certain embodiments, R1, R2 and R3 are independently selected from hydrogen, halogen or C1-C3 alkyl.
[0051] In certain embodiments, R1, R2 and R3 are independently selected from hydrogen, F and Cl.
[0052] In certain embodiments, R1 is hydrogen, halogen, CN, C1-C3 alkyl or C1-C3 alkoxy.
[0053] In certain embodiments, R1 is hydrogen.
[0054] In certain embodiments, R1 is halogen. In certain embodiments, R1 is F or Cl.
[0055] In certain embodiments, R1 is C1-C3 alkyl. In certain embodiments, R1 is methyl.
[0056] In certain embodiments, R2 is hydrogen, halogen, CN, C1-C3 alkyl or C1-C3 alkoxy.
[0057] In certain embodiments, R2 is hydrogen.
[0058] In certain embodiments, R2 is halogen. In certain embodiments, R2 is F or Cl. [0059] In certain embodiments, R2 is C1-C3 alkyl. In certain embodiments, R2 is methyl.
[0060] In certain embodiments of Formula I, R2 is Cl.
[0061] In certain embodiments of Formula I, R2 is hydrogen.
[0062] In certain embodiments, R3 is hydrogen, halogen or C1-C3 alkyl.
[0063] In certain embodiments, R3 is hydrogen.
[0064] In certain embodiments, R3 is halogen. In certain embodiments, R3 is F or Cl.
[0065] In certain embodiments, R1 and R2 are F and R3 is hydrogen.
[0066] In certain embodiments, R1 is F and R2 is Cl and R3 is hydrogen.
[0067] In certain embodiments, R1 is Cl and R2 is F and R3 is hydrogen.
[0068] In certain embodiments, R1 is F and R2 and R3 are hydrogen.
[0069] In certain embodiments, R and R are hydrogen and R is F.
[0070] In certain embodiments, R2 and R3 are F and R1 is hydrogen.
[0071] In certain embodiments, R1 is Cl and R2 and R3 are hydrogen.
[0072] In certain embodiments, R , R and R are F.
[0073] In certain embodiments, R1 is F and R2 is methyl and R3 is hydrogen.
[0074] In certain embodiments, R1 is methyl and R2 is F and R3 is hydrogen.
[0075] In certain embodiments, R1 is F and R2 and R3 are hydrogen.
[0076] In certain embodiments, R1 is Cl and R2 and R3 are hydrogen.
[0077] In certain embodiments, R2 is F and R1 and R3 are hydrogen.
[0078] In certain embodiments, the residue:
Figure imgf000013_0001
of Formula I, wherein the wavy line represents the point of attachment of the residue in Formula I, is selected from:
Figure imgf000013_0002
Figure imgf000014_0001
[0079] In certain embodiments, R4 is C3-C5 cycloalkyl, C1-C6 alkyl, C2-C6 alkenyl,
C2-C6 alkynyl, phenyl, a 5-6 membered heteroaryl, or NRhR', wherein the cycloalkyl, alkyl, alkenyl, alkynyl and phenyl are optionally substituted with ORC, halogen, phenyl, C3-C4 cycloalkyl or C1-C4 alkyl optionally substituted with halogen.
[0080] In certain embodiments, Rc is independently selected from hydrogen, phenyl and C1-C4 alkyl optionally substituted with oxo. In certain embodiments, Rc is hydrogen. [0081] In certain embodiments, R4 is C3-C5 cycloalkyl, C1-C6 alkyl, C2-C6 alkenyl,
C2-C6 alkynyl, phenyl, a 5-6 membered heteroaryl, or NRhR', wherein the cycloalkyl, alkyl, alkenyl, alkynyl and phenyl are optionally substituted with OH, halogen, phenyl, C3-C4 cycloalkyl or C1-C4 alkyl optionally substituted with halogen.
[0082] In certain embodiments, R4 is C3-C5 cycloalkyl, C1-C6 alkyl, C2-C6 alkenyl, or
C2-C6 alkynyl, wherein the cycloalkyl, alkyl, alkenyl and alkynyl are optionally substituted with OR0, halogen or C3-C4 cycloalkyl. [0083] In certain embodiments, R4 is cyclopropyl, ethyl, propyl, butyl, isobutyl,
-CH2CH2CH2OH, -CH2Cl, -CH2CF3, -CH2CH2CH2F, -CH2CH2CF3, phenylmethyl, cyclopropylmethyl, phenyl, 2-fluorophenyl, 3 -fluorophenyl, 4-fluorophenyl, 2,5- difluorophenyl, 4-chloro-3-trifluoromethylphenyl, 1 -methyl- lH-imidazol-4-yl, furan-2-yl, pyridin-2-yl, pyridin-3-yl, thiophen-2-yl, -NHCH2CH3, -NHCH2CH2CH3, -N(CH3)CH2CH3, -NHCH(CH3)2, -NHCH2CHF2, -N(CH3)2 or pyrrolidin-1-yl.
[0084] In certain embodiments, R4 is cyclopropyl, ethyl, propyl, isobutyl,
-CH2CH2CH2OH, -CH2CH2CH2F, phenylmethyl, cyclopropylmethyl, phenyl, 2- fluorophenyl, 3 -fluorophenyl, 4-fluorophenyl, 2,5-difluorophenyl, 4-chloro-3- trifluoromethylphenyl, 1 -methyl- lH-imidazol-4-yl, furan-2-yl, pyridin-2-yl, pyridin-3-yl, thiophen-2-yl or -NHCH2CH3.
[0085] In certain embodiments, R4 is propyl, butyl, isobutyl, -CH2CH2CH2F,
-CH2CH2CF3 or cyclopropylmethyl.
[0086] In certain embodiments, R4 is C3-C5 cycloalkyl, or C1-C6 alkyl optionally substituted with OH, halogen or C3-C4 cycloalkyl.
[0087] In certain embodiments, R4 is C3-C5 cycloalkyl. In certain embodiments, R4 is
C3-C4 cycloalkyl. In certain embodiments, R4 is cyclopropyl or cyclobutyl. [0088] In certain embodiments, R4 is C3-C5 cycloalkyl. In certain embodiments, R4 is
C3-C4 cycloalkyl. In certain embodiments, R4 is cyclopropyl.
[0089] In certain embodiments, R4 is C1-C6 alkyl. In certain embodiments, R4 is ethyl, propyl, butyl or isobutyl.
[0090] In certain embodiments, R4 is C1-C6 alkyl. In certain embodiments, R4 is propyl, butyl or isobutyl.
[0091] In certain embodiments, R4 is C1-C6 alkyl optionally substituted with ORC. In certain embodiments, Rc is hydrogen. In certain embodiments, R4 is C1-C6 alkyl optionally substituted with OH. In certain embodiments, R4 is -CH2CH2CH2OH. [0092] In certain embodiments, R4 is C1-C6 alkyl optionally substituted with halogen.
In certain embodiments, R4 is -CF3, -CH2Cl, -CH2CF3, -CH2CH2CH2F, -CH2CH2CF3, -CF2CF3 or -CF2CF2CF3.
[0093] In certain embodiments, R4 is C1-C6 alkyl optionally substituted with halogen.
In certain embodiments, R4 is -CF3, -CH2CF3, -CH2CH2CH2F, -CH2CH2CF3, -CF2CF3 or -CF2CF2CF3. In certain embodiments, R4 is -CH2CH2CH2F or -CH2CH2CF3. [0094] In certain embodiments, R4 is C1-C6 alkyl optionally substituted with ORC, halogen or C3-C4 cycloalkyl. In certain embodiments, R4 is C1-C6 alkyl optionally substituted with OH, halogen or C3-C4 cycloalkyl. In certain embodiments, R4 is cyclopropylmethyl (- CH^cyclopropyl) or cyclobutylmethyl (-CHz-cyclobutyl). In certain embodiments, R4 is cyclopropylmethyl (-CH^cyclopropyl).
[0095] In certain embodiments, R4 is C1-C6 alkyl optionally substituted with phenyl.
In certain embodiments, R4 is phenylmethyl.
[0096] In certain embodiments, R4 is phenyl optionally substituted with ORC, halogen,
C3-C4 cycloalkyl or C1-C4 alkyl optionally substituted with halogen. In certain embodiments, R4 is phenyl optionally substituted with halogen. In certain embodiments, R4 is phenyl optionally substituted with C1-C4 alkyl optionally substituted with halogen. In certain embodiments, R4 is phenyl optionally substituted with halogen and C1-C4 alkyl optionally substituted with halogen, hi certain embodiments, R4 is phenyl. In certain embodiments, R4 is phenyl, 2-fluorophenyl, 3 -fluorophenyl, 4-fluorophenyl, 2,5-difluorophenyl or 4-chloro-3- trifluoromethylphenyl.
[0097] In certain embodiments, R4 is a 5-6 membered heteroaryl optionally substituted with ORC, halogen, C3-C4 cycloalkyl or C1-C4 alkyl optionally substituted with halogen. In certain embodiments, R4 is a 5-6 membered heteroaryl optionally substituted with C1-C4 alkyl. In certain embodiments, R4 is a 5-6 membered heteroaryl optionally substituted with ORC, halogen, C3-C4 cycloalkyl or C1-C4 alkyl optionally substituted with halogen, wherein the heteroaryl contains one or two heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. In certain embodiments, R4 is a 5-6 membered heteroaryl optionally substituted with OR0, halogen, C3-C4 cycloalkyl or C1-C4 alkyl optionally substituted with halogen, wherein the heteroaryl is imidazolyl, furanyl, pyridinyl or thiophenyl. In certain embodiments, R4 is 1 -methyl- lH-imidazol-4-yl, furan-2-yl, pyridin- 2-yl, pyridin-3-yl or thiophen-2-yl.
[0098] In certain embodiments, R4 is NRhR\ In certain embodiments, Rh and R1 are independently selected from hydrogen and C1-C5 alkyl optionally substituted with halogen. In certain embodiments, R1 is hydrogen or methyl. In certain embodiments, Rh is C1-C5 alkyl optionally substituted with halogen. In certain embodiments, Rh is methyl, ethyl, propyl, isopropyl, or 2,2-difluoroethyl. In certain embodiments, R4 is selected from the group consisting of -NHCH2CH3, -NHCH2CH2CH3, -N(CH3)CH2CH3, -NHCH(CH3)2, -NHCH2CHF2, and -N(CH3)2. [0099] In certain embodiments, R4 is NR11R1, wherein Rh and R' together with the nitrogen to which they are attached form a 4 to 6 membered heterocyclic ring. In certain embodiments, R4 is NR11R1, wherein Rh and R1 together with the nitrogen to which they are attached form a 4 to 6 membered heterocyclic ring, wherein the heterocyclic ring contains one or two heteroatoms selected from nitrogen and oxygen. In certain embodiments, R is NR11R1, wherein Rh and R1 together with the nitrogen to which they are attached form a 5 membered heterocyclic ring. In certain embodiments, R4 is NR11R1, wherein Rh and R1 together with the nitrogen to which they are attached form a 5 membered heterocyclic ring, wherein the heterocyclic ring contains one nitrogen heteroatom. In certain embodiments, R4 is pyrrolidin-1-yl.
[00100] In certain embodiments, R1 and R2 are F, R3 is hydrogen and R4 is propyl, such that the compounds of Formula I, have the structure of Formula Ia:
Figure imgf000017_0001
Ia wherein R5 is as defined herein.
[00101] In certain embodiments, R1 is Cl, R2 is F, R3 is hydrogen and R4 is propyl, such that the compounds of Formula I, have the structure of Formula IaI:
Figure imgf000017_0002
IaI wherein R5 is as defined herein.
[00102] In certain embodiments, R1 is F, R2 is Cl, R3 is hydrogen and R4 is propyl, such that the compounds of Formula I, have the structure of Formula Ia2:
Figure imgf000017_0003
Ia2 wherein R is as defined herein. [00103] In certain embodiments, R5 is hydrogen, phenyl optionally substituted with one to three Ra groups, -N(Rc)-phenyl optionally substituted with Ra, -CH2-phenyl optionally substituted with one to three Rb groups, a 5-6 membered heteroaryl optionally substituted with one to three Re groups, saturated or partially unsaturated C3-C6 cycloalkyl optionally substituted with halogen or C1-C4 alkyl, a 5-6 membered heterocyclyl, or C1-C6 alkyl optionally substituted with one or more Rs groups.
[00104] In certain embodiments, R5 is hydrogen, phenyl optionally substituted with one to three Ra groups, -NH-phenyl, -CH2-phenyl optionally substituted with one to three Rb groups, a 5-6 membered heteroaryl optionally substituted with one to three Re groups, C3-C6 cycloalkyl, a 5-6 membered heterocyclyl, or C1-C6 alkyl.
[00105] In certain embodiments, R5 is selected from hydrogen, phenyl, 2-fluorophenyl,
2-chlorophenyl, 2-bromophenyl, 3 -fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3- trifluoromethylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, A- cyanophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, A- trifluoromethoxyphenyl, 4-dimethylaminophenyl, 4-(methylsulfonyl)phenyl, A- morpholinophenyl, 3,4-dichlorophenyl, 3-trifluoromethyl-4-methylphenyl, 3-trifluoromethyl- 4-chlorophenyl, 2-methyl-4-bromophenyl, -NH-phenyl, -CH2-4-chlorophenyl, -CH2-3,5- difluorophenyl, -CH2-4-methoxyphenyl, -CH2-4-bromophenyl, -CH2-3,4-difluorophenyl, pyridin-3-yl, pyridin-4-yl, 6-morpholinopyridin-3-yl, 6-(dimethylamino)pyridin-3-yl, cyclobutyl, piperdin-3-yl, piperdin-4-yl, methyl, ethyl, isopropyl and tert-butyl. [00106] In certain embodiments, R5 is hydrogen.
[00107] In certain embodiments, R5 is phenyl optionally substituted with one to three
Ra groups. In certain embodiments, each Ra is independently selected from halogen, CN, a 5- 6 membered heterocyclyl, NRcRd, -S(O)2Rf, -0(C1-C4 alkyl), and C1-C4 alkyl, wherein the alkyl or alkoxy are optionally substituted with halogen. In certain embodiments, Ra is a 5-6 membered heterocyclyl, wherein the heterocyclyl is morpholinyl. In certain embodiments, R5 is selected from phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3 -fluorophenyl, 3- chlorophenyl, 3-bromophenyl, 3-trifluoromethylphenyl, 3-methoxyphenyl, 4-fluorophenyl, A- chlorophenyl, 4-bromophenyl, 4-cyanophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, A- methoxyphenyl, 4-trifluoromethoxyphenyl, 4-dimethylaminophenyl, A-
(methylsulfonyl)phenyl, 4-morpholinophenyl, 3,4-dichlorophenyl, 3-trifluoromethyl-4- methylphenyl, 3-trifluoromethyl-4-chlorophenyl and 2-methyl-4-bromophenyl. [00108] In certain embodiments, R1 and R2 are F, R3 is hydrogen, R4 is propyl and R5 is phenyl optionally substituted with one to three Ra groups, such that the compounds of Formula I, have the structure of Formula Ib:
Figure imgf000019_0001
Ib wherein n is 0, 1, 2 or 3, and Ra is as defined herein. [00109] In certain embodiments, R5 is phenyl.
[00110] In certain embodiments, R5 is phenyl optionally substituted with one Ra group.
In certain embodiments, Ra is selected from halogen, CN, a 5-6 membered heterocyclyl, NRcRd, -S(O)2Rf, -0(C1-C4 alkyl), and C1-C4 alkyl, wherein the alkyl or alkoxy are optionally substituted with halogen. In certain embodiments, Ra is -0(C1-C4 alkyl), wherein Ra is methoxy. In certain embodiments, Ra is -0(C1-C4 alkyl) optionally substituted with halogen, wherein Ra is trifluoromethoxy. In certain embodiments, Ra is C1-C4 alkyl optionally substituted with halogen, wherein Ra is trifluoromethyl. In certain embodiments, Ra is a 5-6 membered heterocyclyl, wherein the heterocyclyl is morpholinyl. In certain embodiments, Rc and Rd are C1-C4 alkyl. In certain embodiments, Rc and Rd are methyl. In certain embodiments, Ra is -S(O)2Rf. In certain embodiments, Rf is C1-C4 alkyl. In certain embodiments, R5 is selected from 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3- fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-trifluoromethylphenyl, 3-methoxyphenyl, 4- fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-cyanophenyl, 4-methylphenyl, 4- trifluoromethylphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 4- dimethylaminophenyl, 4-(methylsulfonyl)phenyl and 4-morpholinophenyl. [00111] In certain embodiments, R5 is phenyl optionally substituted with two Ra groups. In certain embodiments, Ra is selected from halogen and C1-C4 alkyl, wherein the alkyl is optionally substituted with halogen. In certain embodiments, Ra is C1-C4 alkyl, wherein Ra is methyl. In certain embodiments, Ra is C1-C4 alkyl optionally substituted with halogen, wherein Ra is trifluoromethyl. In certain embodiments, R is selected from 3,4- dichlorophenyl, 3-trifluoromethyl-4-methylphenyl, 3-trifluoromethyl-4-chlorophenyl and 2- methyl-4-bromophenyl. [00112] In certain embodiments, R5 is -N(Rc)-phenyl optionally substituted with Ra.
In certain embodiments, Rc is selected from hydrogen or C1-C4 alkyl. In certain embodiments, Rc is hydrogen. In certain embodiments, R5 is -NH-phenyl optionally substituted with Ra.
[00113] In certain embodiments, R5 is -NH-phenyl optionally substituted with Ra. In certain embodiments, R5 is -NH-phenyl.
[00114] In certain embodiments, R5 is -CH2-phenyl optionally substituted with one to three Rb groups. In certain embodiments, each Rb is independently selected from halogen, OH or OCH3. In certain embodiments, R5 is selected from -CH2-4-chlorophenyl, -CH2-3,5- difluorophenyl, -CH2-4-methoxyphenyl, -CH2-4-bromophenyl and -CH2-3,4-difluorophenyl. [00115] In certain embodiments, R5 is a 5-6 membered heteroaryl optionally substituted with one to three Re groups. In certain embodiments, Re is selected from a 5-6 membered heterocyclyl or NRcRd. In certain embodiments, Rc and Rd are independently selected from hydrogen and C1-C4 alkyl. In certain embodiments, R5 is a 5-6 membered heteroaryl optionally substituted with a 5-6 membered heterocyclyl, wherein the heteroaryl is pyridinyl. In certain embodiments, R5 is a 5-6 membered heteroaryl optionally substituted with a 5-6 membered heterocyclyl, wherein the heterocyclyl is morpholinyl. In certain embodiments, R5 is a 5-6 membered heteroaryl optionally substituted with a 5-6 membered heterocyclyl, wherein the heteroaryl is pyridinyl and the heterocyclyl is morpholinyl. In certain embodiments, R5 is selected from pyridin-3-yl, pyridin-4-yl, 6-morpholinopyridin-3- yl and 6-(dimethylamino)pyridin-3-yl.
[00116] In certain embodiments, R5 is saturated or partially unsaturated C3-C6 cycloalkyl optionally substituted with halogen or C1-C4 alkyl. hi certain embodiments, R5 is saturated or partially unsaturated C3-C6 cycloalkyl. In certain embodiments, R5 is saturated C3-C6 cycloalkyl. In certain embodiments, R5 is C3-C6 cycloalkyl, wherein the cycloalkyl is cyclobutyl. In certain embodiments, R5 is cyclobutyl.
[00117] In certain embodiments, R5 is a 5-6 membered heterocyclyl. In certain embodiments, R5 is a 5-6 membered heterocyclyl, wherein the heterocyclyl is piperdinyl. In certain embodiments, R5 is selected from piperdin-3-yl and piperdin-4-yl. [00118] In certain embodiments, R5 is C1-C6 alkyl optionally substituted with one or more Rg groups, hi certain embodiments, each R8 is independently selected from halogen, CN, ORC, C3-C6 cycloalkyl or NRcRd. [00119] In certain embodiments, R5 is C1-C6 alkyl. In certain embodiments, R5 is selected from methyl, ethyl, isopropyl and tert-butyl.
[00120] It will be appreciated that certain compounds of the invention may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention.
[00121] In the structures shown herein, where the stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included as the compounds of the invention. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is so specified and defined. [00122] It will also be appreciated that compounds of Formula I include tautomeric forms. Tautomers are compounds that are interconvertible by tautomerization. This commonly occurs due to the migration of a hydrogen atom or proton, accompanied by the switch of a single bond and adjacent double bond. For instance, 3H-imidazo[4,5-b]pyridine is one tautomeric form, while 4H-imidazo[4,5-b]pyridine is another tautomeric form. Other tautomers of Formula I may also form at other positions, including, but not limited to, the sulfonamide or R5 position depending on the substitution. The compounds of Formula I are intended to include all tautomeric forms.
[00123] The compounds of Formula I include the tautomer 4H-imidazo[4,5-b]pyridine, shown as Formula II:
Figure imgf000021_0001
II wherein R1, R2, R3, R4 and R5 are as defined herein.
[00124] In another embodiments of the present invention, intermediates of Formula III are provided:
Figure imgf000022_0001
III wherein R20 is hydrogen, C1-C6 alkyl, benzyl or phenyl and R1, R2, R3, R4 are as defined herein.
[00125] It will also be appreciated that certain compounds of Formula I may be used as intermediates for further compounds of Formula I.
[00126] It will be further appreciated that the compounds of the present invention may exist in unsolvated, as well as solvated forms with pharmaceutically acceptable solvents, such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
SYNTHESIS OF COMPOUNDS
[00127] Compounds of the present invention may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein. The starting materials are generally available from commercial sources such as Sigma-Aldrich (St. Louis, MO), Alfa Aesar (Ward Hill, MA), or
TCI (Portland, OR), or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser,
Reagents for Organic Synthesis, v. 1-23, New York: Wiley 1967-2006 ed. (also available via the Wiley InterScience® website), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer- Verlag, Berlin, including supplements (also available via the Beilstein online database)).
[00128] For illustrative purposes, Schemes 1-4 show a general method for preparing the compounds of the present invention, as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. Although specific starting materials and reagents are depicted in the Schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.
Reduction
Figure imgf000023_0001
Figure imgf000023_0002
1 2 3
Figure imgf000023_0003
Scheme 1
[00129] Scheme 1 shows a general scheme for the synthesis of imidazopyridine 7, wherein R1, R2, R3, R4, and R5 are as defined herein. Dinitropyridine 1 can be treated with ammonium hydroxide to provide compound 2, which then can be selectively reduced to compound 3 using ammonium sulfide as the reducing agent. Imidazopyridine 4 may be prepared using carboxylic acids in a suitable solvent with various additives, such as triphenylphosphite, under microwave conditions or with a carboxylic acid and a dehydrating agent, such as POCl3. The nitro group may be reduced by hydrogenation with a suitable catalyst, such as palladium on carbon, tin (II) chloride dehydrate in refluxing methanol, or by zinc or iron in aqueous ammonium chloride, to give compound 5. Compound 5 may be coupled with benzoic acid 6 in the presence of a coupling reagent, such as 2-(1H- benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate ("HBTU") or 1-ethyl- (3-dimethylaminopropyl)carbodiimide hydrochloride ("EDCl"), with additives, such as hydroxybenzotriazole monohydrate, in a suitable solvent, such as dichloromethane ("DCM"), N,N-dimethylformamide ("DMF") or mixtures thereof, to prepare compound 7.
Figure imgf000024_0001
AIMe3, Toluene
Figure imgf000024_0002
Scheme 2
[00130] Scheme 2 shows another preparation of imidazopyridine 7, wherein R , R , R ,
R4 and R5 are as defined herein. Imidazopyridine 5 may be coupled with bis-sulfonylated benzoate 8 using Weinreb conditions (trimethylaluminum in toluene) to provide compound 10. Hydrolysis with a suitable base, such as aqueous sodium hydroxide, potassium carbonate, or sodium carbonate, and deprotection provides compound 7.
Figure imgf000024_0003
Scheme 3
[00131] Scheme 3 illustrates yet another preparation of imidazopyridine 7, wherein R1,
R2, R3, R4 and R5 are as defined herein. Imidazopyridine 5 may be coupled with bis- sulfonylated benzoic acid 9 using standard amide coupling conditions, such as those described in Scheme 1, to provide compound 10. Hydrolysis with a suitable base, such as aqueous sodium hydroxide or sodium carbonate, provides compound 7.
Figure imgf000025_0001
hydrolysis
Figure imgf000025_0002
Scheme 4
[00132] Scheme 4 shows a general method for preparing benzoate 8 and benzoic acid
2, wherein R1, R2, R3 and R4 are as defined herein. Benzoic acid 10 is esterified by standard methods, such as by Fischer esterification conditions. The nitro group may be reduced by hydrogenation with a suitable catalyst, such as palladium on carbon. Aniline 11 may be sulfonylated with a substituted sulfonyl chloride in the presence of a suitable base, such as triethylamine, to provide benzoate 8. Hydrolysis of benzoate 8 with a base, such as aqueous sodium hydroxide, in an optional solvent, such as an alcohol (e.g., methanol), tetrahydrofuran ("THF")or a mixture thereof, provides benzoic acid 2.
[00133] Accordingly, another embodiment of the present invention provides a process for preparing compounds of Formula I, comprising: (a) coupling a compound of Formula 5:
Figure imgf000025_0003
wherein R5 is as defined herein, with a compound of Formula 6:
Figure imgf000025_0004
wherein R1, R2, R3 and R4 are as defined herein, to provide a compound of Formula I; or (b) coupling a compound of Formula 5:
Figure imgf000026_0001
5 wherein R5 is as defined herein, with a compound of Formula III:
Figure imgf000026_0002
III wherein R1, R2, R3, R4 and R20 are as defined herein, to provide a compound of Formula I. [00134] In preparing compounds of Formula I, protection of remote functionalities
(e.g., primary or secondary amines, etc.) of intermediates may be necessary. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. Suitable amino-protecting groups (NH-Pg) include acetyl, trifluoroacetyl, t-butyloxycarbonyl ("Boc"), benzyloxycarbonyl ("CBz") and 9- fluorenylmethyleneoxycarbonyl ("Fmoc"). The need for such protection is readily determined by one skilled in the art. For a general description of protecting groups and their use, see T. W. Greene, et al. Greene's Protective Groups in Organic Synthesis. New York: Wiley Interscience, 2006. METHODS OF SEPARATION
[00135] It may be advantageous to separate reaction products from one another and/or from starting materials. The desired products of each step or series of steps is separated and/or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art. Typically such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed (SMB) and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography. One skilled in the art will apply techniques most likely to achieve the desired separation. [00136] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers. Enantiomers can also be separated by use of a chiral HPLC column.
[00137] A single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, C. H., et al. "Chromatographic resolution of enantiomers: Selective review." J. Chromatogr.. 113(3) (1975): pp. 283-302). Racemic mixtures of chiral compounds of the invention can be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. See: Wainer, Irving W., Ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.
[00138] Under method (1), diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, α-methyl- β-phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid. The diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography. For separation of the optical isomers of amino compounds, addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts.
[00139] Alternatively, by method (2), the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994, p. 322). Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the pure or enriched enantiomer. A method of determining optical purity involves making chiral esters, such as a menthyl ester, e.g., (-) menthyl chloroformate in the presence of base, or Mosher ester, α-methoxy-α- (trifluoromethyl)phenyl acetate (Jacob III, Peyton. "Resolution of (±)-5-Bromonornicotine. Synthesis of (R)- and (S)-Nornicotine of High Enantiomeric Purity." J. Qrg. Chem. Vol. 47, No. 21 (1982): pp. 4165-4167), of the racemic mixture, and analyzing the 1H NMR spectrum for the presence of the two atropisomeric enantiomers or diastereomers. Stable diastereomers of atropisomeric compounds can be separated and isolated by normal- and reverse-phase chromatography following methods for separation of atropisomeric naphthyl-isoquinolines (WO 96/15111).
[00140] By method (3), a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase Lough, WJ., Ed. Chiral Liquid Chromatography. New York: Chapman and Hall, 1989; Okamoto, Yoshio, et al. "Optical resolution of dihydropyridine enantiomers by high-performance liquid chromatography using phenylcarbamates of polysaccharides as a chiral stationary phase." J. of Chromatogr. Vol. 513 (1990): pp. 375-378). Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism. BIOLOGICAL EVALUATION
[00141] B-Raf mutant protein 447-717 (V600E) was co-expressed with the chaperone protein Cdc37, complexed with Hsp90 (Roe, S. Mark, et al. "The Mechanism of Hsp90
Regulation by the Protein Kinase-Specific Cochaperone p50cdc37." Cell. Vol. 116 (2004): pp. 87-98; Stancato, LF, et al. "Raf exists in a native heterocomplex with Hsp90 and p50 that can be reconstituted in a cell free system." J. Biol. Chem. 268(29) (1993): pp. 21711-21716). [00142] Determining the activity of Raf in the sample is possible by a number of direct and indirect detection methods (US 2004/0082014). Activity of human recombinant B-Raf protein may be assessed in vitro by assay of the incorporation of radio labeled phosphate to recombinant MAP kinase (MEK), a known physiologic substrate of B-Raf, according to US 2004/0127496 and WO 03/022840. The activity/inhibition of V600E full-length B-Raf was estimated by measuring the incorporation of radio labeled phosphate from [γ-33P]ATP into FSBA-modified wild-type MEK (see Example A). ADMINISTRATION AND PHARMACEUTICAL FORMULATIONS [00143] The compounds of the invention may be administered by any convenient route appropriate to the condition to be treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), transdermal, rectal, nasal, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary and intranasal.
[00144] The compounds may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g. diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents. If parenteral administration is desired, the compositions will be sterile and in a solution or suspension form suitable for injection or infusion.
[00145] A typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C, et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
[00146] One embodiment of the present invention includes a pharmaceutical composition comprising a compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof. In a further embodiment, the present invention provides a pharmaceutical composition comprising a compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient. [00147] Another embodiment of the present invention provides a pharmaceutical composition comprising a compound of Formula I for use in the treatment of a hyperproliferative disease.
[00148] Another embodiment of the present invention provides a pharmaceutical composition comprising a compound of Formula I for use in the treatment of cancer. METHODS OF TREATMENT WITH COMPOUNDS OF THE INVENTION [00149] The invention includes methods of treating or preventing disease or condition by administering one or more compounds of this invention, or a stereoisomer or pharmaceutically acceptable salt thereof. In one embodiment, a human patient is treated with a compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle in an amount to detectably inhibit B-Raf activity.
[00150] In another embodiment, a human patient is treated with a compound of
Formula I, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle in an amount to detectably inhibit B- Raf activity.
[00151] In another embodiment of the present invention, a method of treating a hyperproliferative disease in a mammal comprising administering a therapeutically effective amount of the compound of Formula I, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, to the mammal is provided.
[00152] In another embodiment of the present invention, a method of treating a hyperproliferative disease in a mammal comprising administering a therapeutically effective amount of the compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof, to the mammal is provided.
[00153] In another embodiment of the present invention, a method of treating kidney disease in a mammal comprising administering a therapeutically effective amount of the compound of Formula I, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, to the mammal is provided. In a further embodiment, the kidney disease is polycystic kidney disease.
[00154] In another embodiment, a method of treating or preventing cancer in a mammal in need of such treatment, wherein the method comprises administering to said mammal a therapeutically effective amount of a compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof. The cancer is selected from breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, NSCLC, small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney carcinoma, myeloid disorders, lymphoid disorders, hairy cells, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, colon-rectum, large intestine, rectum, brain and central nervous system, Hodgkin's and leukemia. Another embodiment of the present invention provides the use of a compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.
[00155] In another embodiment, a method of treating or preventing cancer in a mammal in need of such treatment, wherein the method comprises administering to said mammal a therapeutically effective amount of a compound of Formula I, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.
[00156] Another embodiment of the present invention provides the use of a compound of Formula I, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.
[00157] Another embodiment of the present invention provides the use of a compound of Formula I, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of kidney disease. In a further embodiment, the kidney disease is polycystic kidney disease.
[00158] In another embodiment, a method of preventing or treating cancer, comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula I, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, alone or in combination with one or more additional compounds having anti-cancer properties. [00159] In another embodiment, a method of preventing or treating cancer, comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof, alone or in combination with one or more additional compounds having anti-cancer properties. [00160] In one further embodiment, the cancer is a sarcoma. [00161] In another further embodiment, the cancer is a carcinoma. In one further embodiment, the carcinoma is squamous cell carcinoma. In another further embodiment, the carcinoma is an adenoma or adenocarcinoma.
[00162] In another embodiment, a method of treating or preventing a disease or disorder modulated by B-Raf, comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof. Examples of such diseases and disorders include, but are not limited to, cancer. The cancer is selected from breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, NSCLC, small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney carcinoma, myeloid disorders, lymphoid disorders, hairy cells, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, colon-rectum, large intestine, rectum, brain and central nervous system, Hodgkin's and leukemia.
[00163] In another embodiment, a method of treating or preventing a disease or disorder modulated by B-Raf, comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula I, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.
[00164] In another embodiment of the present invention, a method of preventing or treating kidney disease, comprising administering to a mammal in need of such treatment an effective amount of Formula I, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, alone or in combination with one or more additional compounds. In another embodiment of the present invention, a method of preventing or treating polycystic kidney disease, comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula I, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, alone or in combination with one or more additional compounds. [00165] Another embodiment of the present invention provides the use of a compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer. The cancer is selected from breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, NSCLC, small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney carcinoma, myeloid disorders, lymphoid disorders, hairy cells, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, colon-rectum, large intestine, rectum, brain and central nervous system, Hodgkin's and leukemia. In a further embodiment, the use of a compound of Formula I in the manufacture of a medicament, for use as a b-Raf inhibitor in the treatment of a patient undergoing cancer therapy.
[00166] Another embodiment of the present invention provides the use of a compound of Formula I, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.
[00167] Another embodiment of the present invention provides the use of a compound of Formula I, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of polycystic kidney disease. In a further embodiment, the kidney disease is polycystic kidney disease.
[00168] Another embodiment of the present invention provides the compounds of
Formula I for use in therapy.
[00169] Another embodiment of the present invention provides the compounds of
Formula I for use in the treatment of a hyperproliferative disease. In a further embodiment, the hyperproliferative disease is cancer (as further defined and may be individually selected from those above).
[00170] Another embodiment of the present invention provides the compounds of
Formula I for use in the treatment of kidney disease. In a further embodiment, the kidney disease is polycystic kidney disease. COMBINATION THERAPY
[00171] The compounds of this invention and stereoisomers and pharmaceutically acceptable salts thereof may be employed alone or in combination with other therapeutic agents for treatment. The compounds of the present invention can be used in combination with one or more additional drugs, for example an anti-hyperproliferative, anti-cancer or chemotherapeutic agent. The second compound of the pharmaceutical combination formulation or dosing regimen preferably has complementary activities to the compound of this invention such that they do not adversely affect each other. Such agents are suitably present in combination in amounts that are effective for the purpose intended. The compounds may be administered together in a unitary pharmaceutical composition or separately and, when administered separately this may occur simultaneously or sequentially in any order. Such sequential administration may be close in time or remote in time. [00172] A "chemotherapeutic agent" is a chemical compound useful in the treatment of cancer, regardless of mechanism of action. Chemotherapeutic agents include compounds used in "targeted therapy" and conventional chemotherapy. A number of suitable chemotherapeutic agents to be used as combination therapeutics are contemplated for use in the methods of the present invention. The present invention contemplates, but is not limited to, administration of numerous anticancer agents, such as: agents that induce apoptosis; polynucleotides (e.g., ribozymes); polypeptides (e.g., enzymes); drugs; biological mimetics; alkaloids; alkylating agents; antitumor antibiotics; antimetabolites; hormones; platinum compounds; monoclonal antibodies conjugated with anticancer drugs, toxins, and/or radionuclides; biological response modifiers (e.g., interferons [e.g., IFN-a, etc.] and interleukins [e.g., IL-2, etc.], etc.); adoptive immunotherapy agents; hematopoietic growth factors; agents that induce tumor cell differentiation (e.g., all-trans-retinoic acid, etc.); gene therapy reagents; antisense therapy reagents and nucleotides; tumor vaccines; inhibitors of angiogenesis, and the like.
[00173] Examples of chemotherapeutic agents include Erlotinib (T ARCEV A®,
Genentech/OSI Pharm.), Bortezomib (VELCADE®, Millennium Pharm.), Fulvestrant (FASLODEX®, AstraZeneca), Sunitinib (SUTENT®, Pfizer), Letrozole (FEMARA®, Novartis), Imatinib mesylate (GLEEVEC®, Novartis), PTK787/ZK 222584 (Novartis), Oxaliplatin (Eloxatin®, Sanofi), 5-FU (5-fluorouracil), Leucovorin, Rapamycin (Sirolimus, RAPAMUNE®, Wyeth), Lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), Lonafamib (SCH 66336), Sorafenib (NEXAV AR®, Bayer), Irinotecan (CAMPTOSAR®, Pfizer) and Gefitinib (IRESSA®, AstraZeneca), AG1478, AGl 571 (SU 5271; Sugen), alkylating agents such as thiotepa and CYTOXAN® cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analog topotecan); bryostatin; callystatin; CC- 1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogs, KW-2189 and CBl-TMl); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin omegall (Angew Chem. Intl. Ed. Engl. (1994) 33:183-186); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6- diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6- mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE™ (Cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, Illinois), and TAXOTERE® (doxetaxel; Rhόne-Poulenc Rorer, Antony, France); chloranmbucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP- 16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELOD A®); ibandronate; CPT-I l; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above.
[00174] Also included in the definition of "chemotherapeutic agent" are: (i) anti- hormonal agents that act to regulate or inhibit hormone action on tumors such as anti- estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, 4- hydroxytamoxifen, trioxifene, keoxifene, LYl 17018, onapristone, and FARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; as well as troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those which inhibit expression of genes in signaling pathways implicated in aberrant cell proliferation, such as, for example, PKC -alpha, RaIf and H-Ras; (vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN®, LEUVECTIN®, and VAXID®; PROLEUKIN® rIL-2; a topoisomerase 1 inhibitor such as LURTOTECAN®; ABARELIX® rmRH; (ix) anti-angiogenic agents such as bevacizumab (AVASTIN®, Genentech); and (x) pharmaceutically acceptable salts, acids and derivatives of any of the above.
[00175] Also included in the definition of "chemotherapeutic agent" are therapeutic antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idee), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), and the antibody drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth).
[00176] Humanized monoclonal antibodies with therapeutic potential as chemotherapeutic agents in combination with the Raf inhibitors of the invention include: alemtuzumab, apolizumab, aselizumab, atlizumab, bapineuzumab, bevacizumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pertuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, trastuzumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab, urtoxazumab, and visilizumab.
EXAMPLES
[00177] In order to illustrate the invention, the following Examples are included.
However, it is to be understood that these Examples do not limit the invention and are only meant to suggest a method of practicing the invention. Persons skilled in the art will recognize that the chemical reactions described may be readily adapted to prepare a number of other compounds of the invention, and alternative methods for preparing the compounds of this invention are deemed to be within the scope of this invention. For example, the synthesis of non-exemplified compounds according to the invention may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, and/or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the invention.
[00178] In the Examples described below, unless otherwise indicated all temperatures are set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar, or TCI, and were used without further purification unless otherwise indicated.
[00179] The reactions set forth below were done generally under a positive pressure of nitrogen or argon or with a drying tube (unless otherwise stated) in anhydrous solvents, and the reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried. [00180] Column chromatography purification was done on a Biotage system
(Manufacturer: Dyax Corporation) having a silica gel column or on a silica SepPak cartridge (Waters) or on a Teledyne Isco Combiflash purification system using prepacked silica gel cartridges. 1H NMR spectra were recorded on a Varian instrument operating at 400 MHz. 1H-NMR spectra were obtained as CDCl3, CD2Cl2, CD3OD, D2O, d6-DMSO or d6-acetone solutions (reported in ppm), using tetramethylsilane (0.00 ppm) or residual solvent (CDCl3: 7.25 ppm; CD3OD: 3.31 ppm; D2O: 4.79 ppm; d6-DMSO: 2.50 ppm; d6-acetone: 2.05 ppm) as the reference standard. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), qn (quintuplet), sx (sextuplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, when given, are reported in Hertz (Hz).
Example A
B-Raf ICs0 Assay Protocol
[00181] Activity of human recombinant B-Raf protein may be assessed in vitro by assay of the incorporation of radio labeled phosphate to recombinant MAP kinase (MEK), a known physiologic substrate of B-Raf, according to US 2004/0127496 and WO 03/022840. Catalytically active human recombinant B-Raf protein is obtained by purification from sf9 insect cells infected with a human B-Raf recombinant baculovirus expression vector. [00182] The activity/inhibition of V600E full-length B-Raf was estimated by measuring the incorporation of radio labeled phosphate from [γ-33P]ATP into FSBA-modified wild-type MEK. The 30-μL assay mixtures contained 25mM Na Pipes, pH 7.2, 10OmM KCl, 1OmM MgCl2, 5mM β-glycerophosphate, lOOμM Na Vanadate, 4μM ATP, 500 nCi [γ- 33P]ATP, lμM FSBA-MEK and 2OnM V600E full-length B-Raf. Incubations were carried out at 22°C in a Costar 3365 plate (Corning). Prior to the assay, the B-Raf and FSBA-MEK were preincubated together in assay buffer at 1.5x (20 μL of 3OnM and 1.5μM, respectively) for 15 minutes, and the assay was initiated by the addition of 10 μL of lOμM ATP. Following the 60-minute incubation, the assay mixtures were quenched by the addition of 100 μL of 25% TCA, the plate was mixed on a rotary shaker for 1 minute, and the product was captured on a Perkin-Elmer GF/B filter plate using a Tomtec Mach III Harvester. After sealing the bottom of the plate, 35 μL of Bio-Safe II (Research Products International) scintillation cocktail were added to each well and the plate was top-sealed and counted in a TopcountNXT (Packard).
[00183] The compounds of Examples 1-42 were tested in the above assay and found to have an IC5O of less than 1 μM.
Example B
Figure imgf000039_0001
methyl 2,6-difluoro-3-(N-(propylsulfonvπpropylsulfonamido)benzoate [00184] Step A: A 1 L flask was charged with 2,6-difluoro-3-nitrobenzoic acid (17.0 g, 83.7 mmol) and MeOH (170 mL, 0.5M). The flask was placed in a cold water bath, and an addition funnel charged with a 2M solution of trimethylsilyl ("TMS") diazomethane in hexanes (209 mL, 419 mmol) was attached to the flask. The TMS diazomethane solution was added slowly to the reaction flask over the course of 2 hours. A large excess of reagent was required in order for the reaction to reach completion as determined by the ceased evolution of N2 upon further addition of reagent. The volatiles were removed in vacuo to afford methyl 2,6-difluoro-3-nitrobenzoate as a solid (18.2 g, 99%). The material was taken directly onto Step B.
[00185] Step B: 10% (wt.) Pd on activated carbon (4.46 g, 4.19 mmol) was added to a
1 L flask charged with methyl 2,6-difluoro-3-nitrobenzoate (18.2 g, 83.8 mmol) under a nitrogen atmosphere. EtOH (350 mL, 0.25 M) was added, and then H2 was passed through the reaction mixture for 15 minutes. The reaction mixture was stirred under two H2 balloons overnight. The following day the reaction mixture was re-flushed with fresh H2 balloons and stirred an additional 4 hours. Upon consumption of the starting material and intermediate hydroxylamine as determined by thin layer chromatography ("TLC"), N2 gas was flushed through the reaction mixture. The mixture was then filtered through glass microfibre filter ("GF/F") paper twice. The volatiles were removed to afford methyl 3-amino-2,6- difluorobenzoate as an oil (15.66 g, 99%). The material was taken directly onto the next step. [00186] Step C: Propane- 1-sulfonyl chloride (23.46 niL, 209.3 mmol) was slowly added to a solution of methyl 3-amino-2,6-difluorobenzoate (15.66 g, 83.7 mmol) and triethylamine (35.00 mL, 251.1 mmol) in CH2Cl2 (175 mL, 0.5M) maintained in a cool water bath. The reaction mixture was stirred for 1 hour at room temperature. Water (300 mL) was added and the organic layer was separated, washed with water (2 X 300 mL) and brine (200 mL), then dried (Na2SO4), filtered and concentrated to an oil. The crude product was purified by column chromatography, eluting with 15% ethyl acetate/hexanes. The isolated fractions were triturated with hexanes to afford methyl 2,6-difluoro-3-(N-(propylsulfonyl) propylsulfonamido)benzoate as a solid (24.4 g, 73% yield for 3 steps). 1H NMR (400 MHz, CDCl3) δ 7.52-7.45 (m, IH), 7.08-7.02 (m, IH), 3.97 (s, 3H), 3.68-3.59 (m, 2H), 3.53-3.45 (m, 2H), 2.02-1.89 (m, 4H), 1.10 (t, J = 7.4 Hz, 6H). m/z (APCI-neg) M-(SO2Pr) = 292.2.
Example C
Figure imgf000040_0001
2,6-difluoro-3-(propylsulfonamido)benzoic acid
[00187] A IN aqueous NaOH solution (150 mL, 150 mmol) was added to a solution of methyl 2,6-difluoro-3-(N-(propylsulfonyl)propylsulfonamido)benzoate (20.0 g, 50.1 mmol) in 4:1 THF/MeOH (250 mL, 0.2M). The reaction mixture was stirred at room temperature overnight. The majority of the organic solvents were then removed in vacuo (water bath temperature 35°C). IN HCl (150 mL) was slowly added to the mixture, and the resulting solid was filtered and rinsed with water (4 X 50 mL). The material was then washed with Et2O (4 X 15 mL) to give 2,6-difluoro-3-(propylsulfonamido)benzoic acid as a solid (10.7 g, 77% yield). 1H NMR (400 MHz, d6-DMSO) δ 9.74 (s, IH), 7.57-7.50 (m, IH), 7.23-7.17 (m, IH), 3.11-3.06 (m, 2H), 1.79-1.69 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H). m/z (APCI-neg) M-I = 278.0.
Example D
Figure imgf000040_0002
2,6-difluoro-3-flSKpropylsulfonyl)propylsulfonamido)benzoic acid [00188] Propane- 1-sulfonyl chloride (1.225 mL, 10.92 mmol) was added to a mixture of 3-amino-2,6-difluorobenzoic acid (0.573 g, 3.310 mmol), triethylamine (2.030 mL, 14.56 mmol) and CH2Cl2 (17 mL, 0.2M) cooled to O0C. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The mixture was then partitioned between saturated NaHCO3 (100 mL) and ethyl acetate (75 mL). The aqueous layer was washed with ethyl acetate (50 mL) and then acidified with concentrated HCl to a pH of about 1. The acidified aqueous layer was extracted with ethyl acetate (2 X 50 mL), and the combined ethyl acetate extracts were dried (Na2SO4), filtered and concentrated. The resulting residue was triturated with hexanes to afford 2,6-difluoro-3-(N-(propylsulfonyl)propyl- sulfonamido)benzoic acid as a solid (0.948 g, 74% yield). 1H NMR (400 MHz, d6-DMSO) δ 7.90-7.84 (m, IH), 7.39-7.34 (m, IH), 3.73-3.58 (m, 4H), 1.88-1.74 (m, 4H), 1.01 (t, J = 7.5 Hz, 6H). m/z (APCI-neg) M-(SO2Pr) = 278.1.
Example E
Figure imgf000041_0001
2,3.6-trifluoro-5-(propylsulfonamido)benzoic acid
[00189] 2,3,6-Trifluoro-5-(propylsulfonamido)benzoic acid (8.5%) was prepared according to the general procedure of Example D, substituting 3-amino-2,5,6-trifluorobenzoic acid for 3-amino-2,6-difluorobenzoic acid.
Example F
Figure imgf000041_0002
6-fluoro-2-methyl-3-πS[-(propylsulfonyl)propylsulfonamido)benzoic acid [00190] 6-Fluoro-2-methyl-3-(N-(propylsulfonyl)propylsulfonamido)benzoic acid
(11%) was prepared according to the general procedure of Example D, substituting 3-amino- 6-fluoro-2-methylbenzoic acid for 3-amino-2,6-difluorobenzoic acid. Example G
Figure imgf000042_0001
l-fluoro-ό-methyl-B-πSf-CpropylsulfonvDpropylsulfonaniidolbenzoic acid [00191] 2-Fluoro-6-methyl-3-(N-(propylsulfonyl)propylsulfonamido)benzoic acid
(3%) was prepared according to the general procedure of Example D, substituting 3-amino-2- fluoro-6-methylbenzoic acid for 3-amino-2,6-difluorobenzoic acid.
Example H
Figure imgf000042_0002
2-fluoro-5-(propylsulfonamido)benzoic acid
[00192] Propane- 1-sulfonyl chloride (0.0871 mL, 0.774 mmol) was dissolved in 10%
Na2CO3 (1.65 mL, 1.55 mmol) at room temperature. 5-Amino-2-fluorobenzoic acid (0.100 g, 0.645 mmol) was added and heated to 60°C overnight. Propane- 1-sulfonyl chloride (0.0871 mL, 0.774 mmol) was added again, and the reaction mixture was heated at 60°C for another hour. The reaction mixture was cooled to room temperature, diluted with water, taken to a pH of 10 with 10% Na2CO3 and extracted with DCM (2 X). The reaction mixture was then taken to a pH of 2 with IN HCl, extracted with DCM (3 X) and concentrated to a solid, 2- fluoro-5-(propylsulfonamido)benzoic acid (29%).
Example I
Figure imgf000042_0003
2-chloro-5-(propylsulfonamido)benzoic acid
[00193] 2-Chloro-5-(propylsulfonamido)benzoic acid (14%) was prepared according to the general procedure for Example H, substituting 5-amino-2-chlorobenzoic acid for 5- amino-2-fluorobenzoic acid. Example J
Figure imgf000043_0001
2-chloro-6-fluoro-3 -(propylsulfonamido)benzoic acid
[00194] Step A: 2-Chloro-6-fluorobenzoic acid (2.00 g, 11.5 mmol) was dissolved in sulfuric acid (20 mL) and cooled to 0°C. Nitric acid (0.529 mL, 12.6 mmol) was added, and the reaction mixture was warmed to room temperature for one hour. The reaction mixture was diluted with water, and the aqueous portion was extracted with DCM (3 X), dried over Na2SO4, concentrated to a solid, 2-chloro-6-fluoro-3-nitrobenzoic acid (97%), which was used directly in the next step without further purification.
[00195] Step B: 2-Chloro-6-fluoro-3-nitrobenzoic acid (0.100 g, 0.455 mmol) and Zn dust (0.298 g, 4.55 mmol) were taken up in tetrahydrofuran (4 mL) and saturated aqueous NH4Cl (2 mL) and stirred at room temperature overnight. The reaction mixture was filtered through Celite, concentrated to a solid, and dissolved in water. The pH was adjusted to 2 with IN HCl, and the aqueous portion was extracted with DCM (3 X). The organic portion was dried over Na2SO4 and concentrated to a solid, 3-amino-2-chloro-6-fluorobenzoic acid (49%), which was used directly in the next step without further purification. [00196] Step C: 2-Chloro-6-fluoro-3-(propylsulfonamido)benzoic acid (13%) was prepared according to the general procedure for Example H, substituting 3-amino-2-chloro-6- fluorobenzoic acid for 5-amino-2-fluorobenzoic acid.
Example K
Figure imgf000043_0002
benzyl 6-chloro-2-fluoro-3-(N-(propylsulfonyl)propylsulfonamido)benzoate [00197] Step A: A flame dried flask equipped with a stir bar and rubber septum was charged with 4-chloro-2-fluoroaniline (5.00 g, 34.35 mmol) and dry THF (170 mL). This solution was chilled to -78°C, and n-BuLi (14.7 mL, 1.07 eq. of 2.5M solution in hexanes) was then added over a 15 minute period. This mixture was stirred at -78°C for 20 minutes, and then a THF solution (25 mL) of l,2-bis(chlorodimethylsilyl)ethane (7.76 g, 1.05 eq.) was added slowly (over a 10 minute period) to the reaction mixture. This was stirred for 1 hour, and then 2.5M n-BuLi in hexanes (15.11 mL, 1.1 eq.) was added slowly. After allowing the mixture to warm to room temperature for one hour, the mixture was chilled back to -78°C. A third allotment of n-BuLi (15.66 mL, 1.14 eq.) was added slowly, and the mixture was stirred at -78°C for 75 minutes. Benzyl chloroformate (7.40 g, 1.2 eq.) was then added slowly, and the mixture was stirred at -78°C for one hour. The cooling bath was then removed. The mixture was allowed to warm for 30 minutes and then quenched with water (70 mL) and concentrated HCl (25 mL). The mixture was allowed to continue to warm to room temperature. The mixture was then extracted with EtOAc. The extracts were washed twice with a saturated NaHCO3 solution, once with water, dried over sodium sulfate and concentrated. The resulting residue was flashed on a 65 Biotage (30% ethyl acetate/hexane) to produce benzyl 3-amino-6-chloro-2-fluorobenzoate (4.3 g, 45%) as an oil. 1H NMR (DMSO-d6, 400 MHz) δ 7.37-7.48 (m, 5H), 7.07 (dd, IH, J = 8, 2), 6.87 (t, IH, J = 8), 5.61 (br s, 2H), 5.40 (s, 2H).
[00198] Step B: Benzyl 3-amino-6-chloro-2-fluorobenzoate (4.3 g, 15.37 mmol) was dissolved in dry dichloromethane (270 mL). Triethylamine (5.36 mL, 2.5 eq.) was added, and the mixture was chilled to 0°C. Propane- 1-sulfonyl chloride (3.63 mL, 32.3 mmol, 2.1 eq.) was then added via syringe, and a precipitate resulted. Once the addition was complete, the mixture was allowed to warm to room temperature, and the starting material was consumed as determined by TLC (3:1 hexane:ethyl acetate). The mixture was then diluted with dichloromethane (200 mL), washed with 2M aqueous HCl (2 X 100 mL), saturated NaHCO3 solution, dried over sodium sulfate and concentrated. The resulting residue was purified on a 65 Biotage chromatography system (40% ethyl acetate/hexane) to produce benzyl 6-chloro-2-fluoro-3-(N-(propylsulfonyl)propylsulfonamido)benzoate (5.5 g, 72%) as an oil that slowly solidified upon standing. NMR (CDCl3, 400 MHz) δ 7.28-7.45 (m, 7H), 5.42 (s, 2H), 3.58-3.66 (m, 2H), 3.43-3.52 (m, 2H), 1.08 (t, 6H, J=8).
Example L
Figure imgf000044_0001
6-chloro-2-fluoro-3 -(propylsulfonamido)benzoic acid
[00199] Benzyl 6-chloro-2-fluoro-3 -(N-(propylsulfonyl)propylsulfonamido)benzoate
(5.4 g, 10.98 mmol) was dissolved in THF (100 mL) and IM aqueous KOH (100 mL). This mixture was refluxed for 16 hours and then allowed to cool to room temperature. The mixture was then acidified to a pH of 2 with 2M aqueous HCl and extracted with EtOAc (2 X). The extracts were washed with water, dried over sodium sulfate and concentrated to a solid that was triturated with hexanes/ether to give 6-chloro-2-fluoro-3- (propylsulfonamido)benzoic acid (2.2 g, 68%) as a solid. NMR (DMSO-d6, 400 MHz) δ 9.93 (s, IH), 7.49 (t, IH, J=8), 7.38 (dd, IH, J = 8, 2), 3.11-3.16 (m, 2H), 1.68-1.78 (m, 2H), 0.97 (t, 3H, J = 8).
Example M
Figure imgf000045_0001
2-fluoro-3-(propylsulfonamido)benzoic acid
[00200] 6-Chloro-2-fluoro-3-(propylsulfonamido)benzoic acid (0.5 g, 1.69 mmol) was dissolved in methanol (15 mL), and Pearlman's catalyst (one weight equivalent, 0.5 g, 20% Pd(OH)2 on carbon, 50% by weight water) was added. This mixture was subjected to a balloon of hydrogen for 3 hours and then filtered through GF/F filter paper. The filtrate was concentrated to 2-fluoro-3-(propylsulfonamido)benzoic acid (396 mg, 90%) as a solid. MS (M-H+) 262. NMR (DMSOd6, 400 MHz) δ 13.36 (s, IH), 9.76 (s, IH), 7.58-7.70 (m, 2H), 7.26 (t, IH, J = 8), 3.10 (t, 2H, J = 8), 1.69-1.80 (m, 2H), 0.98 (t, 3H, J = 8).
Example N
Figure imgf000045_0002
3-(cvclopropylmethylsulfonamidoV2.6-difluoroberizoic acid
[00201] Step A: Cyclopropylmethanesulfonyl chloride (1.27 g, 8.20 mmol) was added to a mixture of 3-amino-2,6-difluorobenzoic acid (0.430 g, 2.48 mmol), triethylamine (1.52 mL, 10.9 mmol) and CH2Cl2 (12 mL, 0.2M) cooled to 00C. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The mixture was then partitioned between saturated NaHCO3 (75 mL) and ethyl acetate (50 mL). The aqueous layer was washed with ethyl acetate (50 mL) and then acidified to a pH of 1 with concentrated HCl. The acidified aqueous layer was extracted twice with ethyl acetate (2 X 50 mL), and the combined ethyl acetate extracts were dried (Na2SO4), filtered and concentrated to provide crude 3-(l-cyclopropyl-N-(cyclopropylmethylsulfonyl)methylsulfonamido)-2,6- difluorobenzoic acid (380 mg, 37%).
[00202] Step B: A solution of IN NaOH (2.78 mL, 2.78 mmol) was added to a solution of crude 3-(l-cyclopropyl-N-(cyclopropylmethylsulfonyl)methylsulfonamido)-2,6- difluorobenzoic acid (380 mg, 0.928 mmol) in 4:1 THF/MeOH (5 niL, 0.2M). The reaction mixture was stirred at room temperature for 1 hour, after which most of the organic solvents were removed. IN HCl (3 mL) was slowly added to the mixture to acidify to a pH of 1. The acidified aqueous layer was extracted with ethyl acetate (75 mL). The ethyl acetate extract was washed with water (2 X 20 mL), brine (20 mL), dried (Na2SO4), filtered and concentrated. Trituration of the residue with Et2O afforded 3-
(cyclopropylmethylsulfonamido)-2,6-difluorobenzoic acid as a solid (139 mg, 51%). 1H NMR (400 MHz, d6-DMSO) δ 9.76 (s, IH), 7.60-7.54 (m, IH), 7.22-7.16 (m, IH), 3.10 (d, J = 7.0 Hz, 2H), 1.10-0.99 (m, IH), 0.58-0.53 (m, 2H), 0.36-0.31 (m, 2H); m/z (APCI-neg) M- 1 = 289.9.
Example O
Figure imgf000046_0001
2,6-difluoro-3-(3-fluoropropylsulfonamido)benzoic acid
[00203] Methyl 2,6-difluoro-3-(N-(3-fluoropropylsulfonyl)-3- fluoropropylsulfonamido)benzoate was made according to the general procedure for Example B, substituting 3-fluoropropyl sulfonyl chloride for propane- 1-sulfonyl chloride. 1H NMR (400 MHz, DMSO-d6) δ 8.05-7.99 (m, IH), 7.44 (t, IH), 4.62 (t, 2H), 4.50 (t, 2H), 3.93 (s, 3H), 3.89-3.74 (m, 4H), 2.26-2.11 (m, 4H).
[00204] 2,6-Difluoro-3-(3-fluoropropylsulfonamido)benzoic acid was prepared according to the general procedure for Example C, substituting methyl 2,6-difluoro-3-(N-(3- fluoropropylsulfonyl)-3-fluoropropylsulfonamido)benzoate for methyl 2,6-difluoro-3-(N- (propylsulfonyl)-propylsulfonamido)benzoate. 1H NMR (500 MHz, DMSO-d6) δ 14.05 (br s, IH), 9.71 (s, IH), 7.56-7.50 (m, IH), 7.20 (t, IH), 3.12-3.08 (m, 2H), 1.73-1.66 (m, 2H), 1.39 (sx, 2H), 0.87 (t, 3H).
Example P
Figure imgf000046_0002
3-(butylsulfonamidoV2,6-difluorobenzoic acid
[00205] Methyl 2,6-difluoro-3-(N-(butylsulfonyl)-butylsulfonamido)benzoate was made according to the general procedure for Example B, substituting butane- 1-sulfonyl chloride for propane- 1-sulfonyl chloride. 1H NMR (500 MHz, DMSOd6) δ 7.99-7.94 (m, IH), 7.42 (t, IH), 3.92 (s, 3H), 3.74-3.62 (m, 4H), 1.81-1.68 (m, 4H), 1.42 (sx, 4H), 0.89 (t, 6H).
[00206] 3-(Butylsulfonamido)-2,6-difluorobenzoic acid was prepared according to the general procedure for Example C, substituting methyl 2,6-difluoro-3-(N-(butylsulfonyl)- butylsulfonamido)benzoate for methyl 2,6-difluoro-3-(N-(propylsulfonyl)- propylsulfonamido)benzoate. 1H NMR (400 MHz, DMSOd6) δ 14.05 (br s, IH), 9.71 (s, IH), 7.56-7.50 (m, IH), 7.20 (t, IH), 3.12-3.08 (m, 2H), 1.73-1.66 (m, 2H), 1.39 (sx, 2H), 0.87 (t, 3H).
Example Q
Figure imgf000047_0001
2,6-difluoro-3 -(2-methylpropylsulfonamido)benzoic acid
[00207] Methyl-2,6-difluoro-3-(N-(2-methylpropylsulfonyl)-2-methylpropyl- sulfonamido)benzoate was made according to the general procedure for Example B, substituting 2-methylpropyl sulfonyl chloride for propane- 1-sulfonyl chloride, m/z (LC-MS) M+l = 428.4.
[00208] 2,6-Difluoro-3-(2-methylpropylsulfonamido)benzoic acid was prepared according to the general procedure for Example C, substituting methyl-2,6-difluoro-3-(N-(2- methylpropylsulfonyl)-2-methylpropylsulfonamido)benzoate for methyl 2,6-difluoro-3-(N- (propylsulfonyl)-propylsulfonamido)benzoate. 1H NMR (400 MHz, DMSOd6) δ 14.01 (s, IH), 9.71 (s, IH), 7.56 (dd, IH), 7.22(dd , IH), 3.02 (d, 2H), 2.18-2.15 (m, IH), 1.03 (d, 6H); m/z (LC-MS) M+l = 294.3.
Example R
Figure imgf000047_0002
benzyl 6-chloro-2-fluoro-3-('3-fluoro-N-(3-fluoropropylsulfonyl)propylsulfonamido)benzoate [00209] Benzyl 6-chloro-2-fluoro-3 -(3 -fluoro-N-(3 -fluoropropylsulfonyl)propylsulfon- amido)benzoate (92%) was prepared according to the general procedure for Example K, Step B substituting 3-fluoropropane- 1-sulfonyl chloride for propane- 1-sulfonyl chloride.
Figure imgf000048_0001
6-chloro-2-fluoro-3-(3-fluoropropylsulfonamido)benzoic acid
[00210] 6-Chloro-2-fluoro-3-(3-fluoropropylsulfonamido)benzoic acid (71%) was prepared according to the general procedure for Example L substituting benzyl 6-chloro-2- fluoro-3-(3-fluoro-N-(3-fluoropropylsulfonyl)propylsulfonamido)benzoate for benzyl 6- chloro-2-fluoro-3-(N-(propylsulfonyl)propylsulfonamido)benzoate.
Example T
Figure imgf000048_0002
2-fluoro-3-(3-fluoropropylsulfonamido)benzoic acid
[00211] 2-Fluoro-3-(3-fluoropropylsulfonamido)benzoic acid (81%) was prepared according to the general procedure for Example M substituting 6-chloro-2-fluoro-3-(3- fluoropropylsulfonamido)benzoic acid for 6-chloro-2-fluoro-3-(propylsulfonamido)benzoic acid.
Example U
Figure imgf000048_0003
methyl 2.6-difluoro-3-(3-fluoro-N-(3-fluoropropylsulfonyl)propylsulfonamido')benzoate [00212] 3-Fluoropropane-l-sulfonyl chloride (14.3 mL, 129 mmol) was slowly added to a solution of methyl 3-amino-2,6-difluorobenzoate (24.1 g, 129 mmol) and pyridine (31.2 mL, 386 mmol) in CH2Cl2 (360 mL). The reaction mixture was stirred for over two days at room temperature. The reaction mixture was diluted with methylene chloride. The reaction mixture was then washed with an aqueous solution of saturated sodium bicarbonate, IN HCl, and brine, then dried (Na2SO4), filtered and concentrated to an oil to give methyl 2,6- difluoro-3-(3-fluoro-N-(3-fluoropropylsulfonyl)propylsulfonamido)benzoate (38.1 g). H NMR (400 MHz, CDCl3, ppm) 7.69 (dt, IH), 7.00 (dt, IH), 6.55 (s, IH), 4.56 (dd, 2H), 3.28- 3.17 (m, 2H), 2.32-2.15 (m, 2H). Example V
Figure imgf000049_0001
2,6-difluoro-3-(3-fluoropropylsulfonamido)benzoic acid
[00213] 2,6-Difluoro-3-(N-(3-fluoropropylsulfonyl)propylsulfonamido)benzoate (38 g,
120 mmol) was dissolved in 5:2 THF/MeOH (250 niL), and a solution of lithium hydroxide (8.77g, 366 mmol) in water (50 mL) was added. The reaction mixture was stirred at room temperature for four hours. The majority of the organic solvents were then removed in vacuo. 2.5N HCl (500 mL) was slowly added to the mixture, and the resulting solid was filtered and rinsed with cold ether to give 2,6-difluoro-3-(3-fluoropropylsulfonamido)benzoic acid as a solid (29.3 g, 81% yield). 1H NMR (400 MHz, CDCl3 ppm) 9.85 (s, IH), 7.54 (dt, IH), 7.21 (dt, IH), 4.54 (td, 2H), 2.20-2.00 (m, 2H), 3.24-3.18 (m, 2H).
Example W
Figure imgf000049_0002
2,5-difluoro-3-(propylsulfonamido)benzoic acid
[00214] Step A: 2,5-Difluorobenzoic acid (2.01 g, 9.90 mmol, 31.3% yield) was dissolved in concentrated sulfuric acid (25 mL) and cooled to 0°C. Nitric Acid (1.46 mL, 34.8 mmol) was added, and the reaction mixture was stirred at room temperature for one hour. The solution was extracted with DCM (3 X), and the combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by column chromatography (1:1 hexanes:l%HCOOH/EtOAc) giving 2,5-difluoro-3-nitrobenzoic acid (2.01 g, 31.3%) as a solid.
[00215] Step B: 2,5-Difluoro-3-nitrobenzoic acid (2.00 g, 9.847 mmol) was dissolved in MeOH (60 mL). TMSCl (6.220 mL, 49.24 mmol) was added, and the reaction mixture was stirred at reflux for 4 hours. The reaction mixture was concentrated to about 20 mL, and the crystals produced were filtered and dried under high vacuum providing methyl 2,5- difluoro-3-nitrobenzoate (1.55 g, 72.4%) as a crystalline solid.
[00216] Step C: Methyl 3-amino-2,5-difluorobenzoate (96.5%) was prepared according to the general procedure for Example B, Step B, substituting methyl 2,5-difluoro- 3-nitrobenzoate for methyl 2,6-difluoro-3-nitrobenzoate. [00217] Step D: Methyl 2,5-difluoro-3-(N-(propylsulfonyl)propylsulfon- amido)benzoate was prepared according to the general procedure for Example B, Step C, substituting methyl 3-amino-2,5-difluorobenzoate for methyl 3-amino-2,6-difluorobenzoate. [00218] Step E: 2,5-Difluoro-3-(propylsulfonamido)benzoic acid (83.8%, two steps) was prepared according to the general procedure for Example C substituting methyl 2,5- difluoro-3-(N-(propylsulfonyl)propylsulfonamido)benzoate for methyl 2,6-difluoro-3-(N- (propylsulfonyl)propylsulfonamido)benzoate. 1H NMR (400 MHz, d6-DMSO) δ 13.67 (br s, IH), 10.07 (s, IH), 7.46-7.50 (m, IH), 7.38-7.42 (m, IH), 3.17-3.21 (m, 2H), 1.70-1.76 (m, 2H), 0.95-0.99 (m, 3H); m/z (APCI-neg) M-I - 278.1.
Example X
Figure imgf000050_0001
2,6-difluoro-3-(2,2,2-trifluoroethylsulfonamido)benzoic acid
[00219] Step A: 2,2,2-Trifluoroethyl-sulfonyl chloride (459 mL, 4.15 mmol) was slowly added to a solution of methyl 3-amino-2,6-difluorobenzoate (311 g, 1.66 mmol) and pyridine (0.806 mL, 9.97 mmol) in dichloromethane (8.92 mL, 139 mmol), while applying external cooling using an acetone dry ice bath. The reaction mixture was stirred for 45 minutes, and the dry ice bath was removed. The reaction mixture was kept stirring for another hour. The mixture was diluted with EtOAc (100 mL), washed with water (2 X 25 mL) and brine (25 mL), dried (Na2SO4), filtered, and then concentrated to an oil. The crude product was purified by column chromatography, eluting with 15% EtOAc/hexane to afford methyl 2,6-difluoro-3-(2-trifluoroethylsulfonamido) benzoate as a solid (513 mg, 92.6% yield). 1H NMR (400 MHz, d6-DMSO) δ 8.10-8.01 (m, IH), 7.48 (t, IH), 4.68 (s, 2H), 4.58 (s, 2H), 3.98 (s, 3H).
[00220] Step B: 2,6-Difluoro-3-(2-trifluoroethylsulfonamido)benzoic acid was prepared according to the general procedure for Example C, substituting methyl 2,6-difluoro- 3-(2-trifluoroethylsulfonamido) benzoate for methyl 2,6-difluoro-3-(N-(propylsulfonyl)- propylsulfonamido)benzoate. 1H NMR (500 MHz, d6-DMSO) δ 14.08 (br s, IH), 9.75 (s, IH), 7.58-7.52 (m, IH), 7.25 (t, IH), 3.15-3.11 (s, 2H). Example Y
Figure imgf000051_0001
2,6-difluoro-3-(3,3,3-trifluoropropylsulfonamido)benzoic acid
[00221] Step A: Methyl 2,6-difluoro-3-(N-(3,3,3-trifluoropropylsulfonyl)-3,3,3- trifluoropropyl-sulfonamido) benzoate was made according to the general procedure for Example B, substituting 3,3,3-trifluoropropyl sulfonyl chloride for propane- 1-sulfonyl chloride. 1H NMR (400 MHz, d6-DMSO) δ 8.05-7.99 (m, IH), 7.44 (t, IH), 4.62 (t, 2H), 4.50 (t, 2H), 3.93 (s, 3H), 3.89-3.74 (m, 4H), 2.26-2.11 (m, 4H).
[00222] Step B: 2,6-Difluoro-3-(3,3,3-trifluoropropylsulfonamido)benzoic acid was prepared according to the general procedure for Example C, substituting methyl 2,6-difluoro- 3-(N-(3 ,3 ,3 -trifluoropropylsulfonyl)-3 ,3 ,3 -trifluoropropylsulfonamido)benzoate for methyl 2,6-difluoro-3-(N-(propylsulfonyl)-propylsulfonamido)benzoate. 1H NMR (500 MHz, Cl6- DMSO) δ 14.05 (br s, IH), 9.71 (s, IH), 7.56-7.50 (m, IH), 7.20 (t, IH), 3.12-3.08 (m, 2H), 1.73-1.66 (m, 2H).
Example Z
Figure imgf000051_0002
2,6-difluoro-3 -(2-chloromethylsulfonamido)benzoic acid
[00223] Step A: Methyl 2,6-difluoro-3-(N-(2-chloromethylsulfonyl)-2-chloromethyl- sulfonamido) benzoate was made according to the general procedure for Example B, substituting 2-chloromethyl sulfonyl chloride for propane- 1-sulfonyl chloride. 1H NMR (400 MHz, d6-DMSO) δ 8.08-7.97 (m, IH), 7.45 (t, IH), 4.65 (s, 2H), 4.55 (s, 2H), 4.02(s, 3H). [00224] Step B: 2,6-Difluoro-3-(2-chloromethylsulfonamido)benzoic acid was prepared according to the general procedure for Example C, substituting methyl 2,6-difluoro- 3-(N-(2-chloromethylsulfonyl)-2-chloromethylsulfonamido)benzoate for methyl 2,6-difluoro- 3-(N-(propylsulfonyl)-propylsulfonamido)benzoate. 1H NMR (500 MHz, d6-DMSO) δ 14.10 (br s, IH), 9.78 (s, IH), 7.62-7.56 (m, IH), 7.28 (t, IH), 3.19-3.15 (s, 2H).
Figure imgf000052_0001
benzyl 2-chloro-6-fluoro-3-(N-(propylsulfonyl)propylsulfonamido)benzoate [00225] Step A: Benzyl 3-amino-2-chloro-6-fluorobenzoate (56%) was prepared according to the general procedure for Example K, substituting 2-chloro-4-fluoroaniline for 4-chloro-2-fluoroaniline. 1H NMR (400 MHz, d6-DMSO) δ 7.48-7.32 (m, 5H), 7.11-7.05 (t, IH), 6.94-6.89 (q, IH), 5.53-5.49 (s, 2H), 5.41-5.39 (s, 2H).
[00226] Step B: Benzyl 3-amino-2-chloro-6-fluorobenzoate (330 mg, 1.2 mmol) was dissolved in dry dichloromethane (11.8 mL). Triethylamine (0.494 mL, 3.54 mmol) was added, and the mixture was chilled to 0°C. Propane- 1-sulfonyl chloride (0.332 mL, 2.95 mmol) was then added via syringe. Once the addition was complete, the mixture was allowed to warm to ambient temperature and stir for 16 hours. The mixture was diluted with dichloromethane (11 mL) and washed with water (2 X 50 mL) and brine (25 mL), dried over sodium sulfate, and concentrated. The resulting residue was applied directly to a silica gel column and eluted with a gradient (5% to 40%) of ethyl acetate-hexanes to provide benzyl 2- chloro-6-fluoro-3-(N-(propylsulfonyl)propylsulfonamido)benzoate (413 mg, 0.840 mmol, 71.1% yield). 1H NMR (400 MHz, d6-DMSO) δ 8.00-7.94 (q, IH), 7.59-7.52 (t, IH), 7.50- 7.35 (m, 5H), 5.48-5.44 (s, 2H), 3.80-3.60 (m, 4H), 1.89-1.75 (m, 4H), 1.05-0.98 (t, 6H).
Example AC
Figure imgf000052_0002
2-chloro-6-fluoro-3 -(propylsulfonamido)benzoic acid
[00227] Step A: Benzyl 2-chloro-6-fluoro-3-(N-(propylsulfonyl)propylsulfon- amido)benzoate (413.2 mg, 0.840 mmol) was dissolved in THF (8.4 mL) and 2.0M aqueous LiOH (1.26 mL). The mixture was refluxed for 16 hours and then allowed to cool to ambient temperature. The mixture was acidified to a pH of 0 with l.OM HCl (5.0 mL) and then adjusted to a pH of 4 using saturated sodium bicarbonate. The mixture was extracted with EtOAc (2 X). The extracts were washed with water (2 X) and brine (1 X), dried over sodium sulfate and concentrated to afford benzyl 2-chloro-6-fluoro-3-(propylsulfonamido)benzoate (174.5 mg, 0.4523 mmol, 53.9% yield). MS (APCI-neg) m/z = 384.1 (M-H). [00228] Step B: Benzyl 2-chloro-6-fluoro-3-(propylsulfonamido)benzoate (174.5 mg,
0.4523 mmol) was dissolved in 3:1 dioxane: water (7.5 mL) and treated with barium hydroxide (100.7 mg, 0.5879 mmol). The reaction mixture was heated to 80°C for 16 hours and then allowed to cool to ambient temperature. The mixture was acidified to a pH of 0 with concentrated HCl. The reaction mixture was allowed to stir for 10 minutes, after which the pH was adjusted to a pH of 4 using saturated sodium bicarbonate. The mixture was extracted with EtOAc (2 X). The extracts were washed with water (2 X) and brine (1 X), dried over sodium sulfate, and concentrated to afford 2-chloro-6-fluoro-3- (propylsulfonamido)benzoic acid (75.7 mg, 0.2560 mmol, 56.6% yield). MS (APCI-neg) m/z = 293.9 (M-H).
Example AD
Figure imgf000053_0001
2,6-dichloro-3 -(propylsulfonamido)benzoic acid
[00229] Step A: 2,6-Dichloro-3-nitrobenzoic acid (2.13 g, 9.03 mmol) was dissolved in 2:1 THF:saturated aqueous NH4Cl and cooled to 0°C. The mixture was treated with zinc (11.8 g, 181 mmol). The reaction mixture was allowed to warm to ambient temperature and stir for 24 hours. The reaction mixture was filtered through GF/F paper while rinsing with THF. The mixture was acidified to a pH of 1 using 1.0M HCl and extracted with 15% 2- propanol:DCM (3 X). The extracts were washed with water and brine, dried over sodium sulfate and concentrated to afford 3-amino-2,6-dichlorobenzoic acid (1.40 g, 6.82 mmol, 75.5% yield). MS (APCI-neg) m/z = 203.6 (M-H).
[00230] Step B: 3-Amino-2,6-dichlorobenzoic acid (1.40 g, 6.82 mmol) was dissolved in dry dichloromethane (66.7 mL). Triethylamine (4.09 mL, 29.4 mmol) was added, and the mixture was chilled to 0°C. Propane- 1-sulfonyl chloride (2.48 mL, 22 mmol) was then added via syringe. Once the addition was complete, the mixture was allowed to warm to ambient temperature and stir for 1 hour. The mixture was concentrated in vacuo and diluted with diethyl ether. The mixture was washed with 0.25M NaOH (80 mL), and the aqueous layer was acidified to a pH of 1 using 1.0M HCl. The aqueous layer was extracted with 15% 2- propanol:DCM (2 X 300 mL). The organic layer was collected, dried over sodium sulfate, and concentrated to afford 2,6-dichloro-3-(propylsulfonamido)benzoic acid (1.55 g, 4.96 mmol, 74.4% yield). 1H NMR (400 MHz, d6-DMSO) δ 9.77-9.75 (s, IH), 7.84-7.80 (d, IH), 7.71-7.68 (d, IH), 3.82-3.72 (m, 2H), 1.89-1.70 (m, 2H), 1.05-1.03 (m, 3H).
Example 1
Figure imgf000054_0001
2,6-difluoro-N-(3H-imidazo|"4,5-blpyridin-6-yl)-3-rpropylsulfonamido)benzamide [00231] Step A: 2-Chloro-3,5-dinitropyridine (6.8 g, 33.41 mmol) was taken up in ethanol (200 mL), and ammonium hydroxide solution (19.5 mL, 167 mmol, 5 eq.) was then dripped in slowly, which resulted in a mixture/precipitate. An exotherm was observed, so the reaction mixture was placed in an ice bath for 10 minutes and then removed. After stirring for about 20 minutes, the solids were collected by filtration and dried under vacuum. 3,5- Dinitropyridin-2-amine (4.8 g, 78%) was obtained as a solid. 1H NMR (400 MHz, DMSO- d6) δ 9.26 (br s, IH), 9.17-9.18 (m, IH), 8.95-8.97 (m, IH), 8.70 (br s, IH). [00232] Step B: 3,5-Dinitropyridin-2-amine (4.0 g, 21.7 mmol) was suspended in methanol (150 mL), and a 20% aqueous solution of ammonium sulfide (31.7 mL, 109 mmol, 5 eq.) was then added. A mixture resulted as the temperature was raised to 75°C for 30 minutes. The mixture was allowed to cool and then placed in an ice bath, where a precipitate formed. The solids were collected by filtration, yielding 5-nitropyridine-2,3-diamine (3.4 g, 100%) as a solid. 1H NMR (400 MHz, DMSOd6) δ 8.28-8.29 (m, IH), 7.35-7.37 (m, IH), 6.99 (br s, 2H), 5.32 (br s, 2H).
[00233] Step C: 5-Nitropyridine-2,3-diamine (0.050 g, 0.32 mmol) was dissolved in formic acid (10 mL) and heated to 100°C for 6 hours. The reaction was diluted with water (10 mL) and brought to a pH of 7 with 3N NaOH. The aqueous portion was extracted with 25% isopropyl alcohol ("IPA")/DCM (6 X), dried over Na2SO4 and concentrated to give 6- nitro-3H-imidazo[4,5-b]pyridine (52 mg, 98%) as a solid.
[00234] Step D: 6-Nitro-3H-imidazo[4,5-b]pyridine (0.026 g, 0.158 mmol) was taken up as a slurry in EtOH. 10% PdVC (0.00843 g, 0.00792 mmol) was added, and hydrogen gas was bubbled through for 10 minutes. The reaction was stirred under a balloon of hydrogen at room temperature overnight. The reaction was filtered through celite, and the filtrate was concentrated to give 3H-imidazo[4,5-b]pyridin-6-amine as a solid that was used without further purification. [00235] Step E: 3H-Imidazo[4,5-b]pyridin-6-amine (29 mg, 0.22 mmol), 2,6-difluoro-
3-(propylsulfonamido)benzoic acid (60 mg, 0.22 mmol, 1 eq.), EDCI (46 mg, 0.24 mmol, 1.1 eq.), and 1-hydroxybenzotriazole ("HOBT")Η2O (33 mg, 0.22 mmol, 1 eq.) were combined in dry DMF (2 mL) and stirred at room temperature for 16 hours. The reaction mixture was then diluted with brine and extracted with ethyl acetate ("EtOAc"; 2 X). The extracts were washed with water (1 X), dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by preparative TLC (2 X 0.5 mm plates, 10% MeOH/DCM) to give 2,6-difluoro-N-(3H-imidazo[4,5-b]pyridin-6-yl)-3-
(propylsulfonamido)benzamide (7.4 mg, 9%). 1H NMR (400 MHz, DMSOd6) δ 12.63 (br s, IH), 11.03 (br s, IH), 9.81 (br s, IH), 8.43-8.53 (m, 3H), 7.53-7.59 (m, IH), 7.26-7.30 (m, IH), 3.11-3.15 (m, 2H), 1.74-1.80 (m, 2H), 0.98-1.02 (m, 3H); m/z (APCI-pos) M+l = 394.3.
Example 2
Figure imgf000055_0001
2,6-difluoro-N-(2-phenyl-3H-imidazo[4,5-blpyridin-6-ylV3-(propylsulfonamido)benzamide [00236] Step A: 5-Nitropyridine-2,3-diamine (100 mg, 0.65 mmol, see Example 1) and benzoic acid (87 mg, 0.71 mmol, 1.1 eq.) were combined in POCl3 (5 mL) and heated to reflux for 16 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure, and the resulting residue was taken up in saturated sodium bicarbonate solution, and extracted with 25% IPA/DCM (2 X). The extracts were dried over sodium sulfate and concentrated to 6-nitro-2-phenyl-3H-imidazo[4,5-b]pyridine (67 mg, 43%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ 9.24-9.27 (m, IH), 8.81 (br s, IH), 8.27-8.32 (m, 2H), 7.61-7.67 (m, 3H); m/z (APCI-neg) M-I = 239.3.
[00237] Step B: 2-Phenyl-3H-imidazo[4,5-b]pyridin-6-amine (71%) was prepared according to the general procedure in Example 1, step D, substituting 6-nitro-2-phenyl-3H- imidazo[4,5-b]pyridine for 6-nitro-3H-imidazo[4,5-b]pyridine, and was carried forward to the next step without further purification.
[00238] Step C: 2,6-Difluoro-N-(2-phenyl-3H-imidazo[4,5-b]pyridin-6-yl)-3-
(propylsulfonamido)benzamide (10%) was prepared according to the general procedure in Example 1, Step E, substituting 2-phenyl-3H-imidazo[4,5-b]pyridin-6-amine for 3H- imidazo[4,5-b]pyridin-6-amine. 1H NMR (400 MHz, DMSO-d6) δ 13.61 and 13.17 (broad singlets, IH), 11.17 and 11.07 (broad singlets, IH), 9.84 (br s, IH), 8.42-8.57 (m, 2H), 8.17- 8.26 (m, 2H), 7.53-7.64 (m, 4H), 7.25-7.33 (m, IH), 3.10-3.17 (m, 2H), 1.71-1.83 (m, 2H), 0.98-1.03 (m, 3H); m/z (APCI-neg) M-I = 470.2, (APCI-pos) M+l = 472.1. [00239] Step D: Alternative formation of 2,6-difluoro-N-(2-phenyl-3H-imidazo[4,5- b]pyridin-6-yl)-3-(propylsulfonamido)benzamide: A reaction vial containing 2-phenyl-3H- imidazo[4,5-b]pyridin-6-amine (5.3 mg, 0.026 mmol) was taken up in dry toluene (0.25 mL). Trimethyl aluminum (36 mL, 0.075 mmol, 2M in toluene) was then added by syringe, and the mixture was stirred at room temperature for 20 minutes. 2,6-Difluoro-3-(N- (propylsulfonyl)propylsulfonamido)-benzoate was added to this mixture, and the mixture was warmed to 90°C for 4 hours. The mixture was then allowed to stir at room temperature overnight. The mixture was then quenched with 30% aqueous sodium potassium tartrate, extracted with EtOAc (2 X), dried over sodium sulfate and concentrated to crude 2,6- difluoro-N-(2-phenyl-3H-imidazo[4,5-b]pyridin-6-yl)-3-(N-
(propylsulfonyl)propylsulfonamido)benzamide. m/z (APCI-neg) M-I = 470.1 (M-SO2Pr), (APCI-pos) M+l = 577.9. The crude product was then dissolved in methanol (0.5 mL), and aqueous 2M potassium carbonate (0.5 mL) was added. The mixture was warmed to 60°C for 4 hours and then stirred at room temperature overnight. The mixture was then diluted with EtOAc (5 mL), washed with 10% aqueous citric acid solution, dried over sodium sulfate and concentrated to give 2,6-difluoro-N-(2-phenyl-3H-imidazo[4,5-b]pyridin-6-yl)-3- (propylsulfonamido)benzamide. (APCI-pos) M+l = 472.1.
[00240] Step E: Alternative formation of 2,6-difluoro-N-(2-phenyl-3H-imidazo[4,5- b]pyridin-6-yl)-3-(propylsulfonamido)benzamide: 2,6-Difluoro-N-(2-phenyl-3H- imidazo[4,5-b]pyridin-6-yl)-3-(N-(propylsulfonyl)propylsulfonamido)benzamide was prepared according to the general procedure in Example 1, Step E, substituting 2-phenyl-3H- imidazo[4,5-b]pyridin-6-amine for 3H-imidazo[4,5-b]pyridin-6-amine and 2,6-difluoro-3-(N- (propylsulfonyl)propylsulfonamido)benzoic acid for 2,6-difluoro-3-
(propylsulfonamido)benzoic acid. (APCI-neg) M-I = 470.1 (M-SO2Pr), (APCI-pos) M+l = 577.9. This material was then taken up in methanol (0.5 mL) and 2M aqueous potassium carbonate (0.5 mL), and the mixture was warmed to 60°C for 3 hours. The mixture was then diluted with EtOAc, washed with 10% aqueous citric acid, dried and concentrated to give 2,6-difluoro-N-(2-phenyl-3H-imidazo[4,5-b]pyridin-6-yl)-3-(propylsulfonamido)benzamide. (APCI-pos) M+l = 472.1. Example 3
Figure imgf000057_0001
N-(2-(4-(dimethylamino)phenyls)-3H-imidazo[4,5-blpyridin-6-vD-2.,6-difluoro-3-
(propylsulfonamido)benzamide
[00241] Step A: N,N-Dimethyl-4-(6-nitro-3H-imidazo[4,5-b]pyridin-2-yl)aniline
(97%) was prepared according to the general procedure in Example 2, Step A, substituting 4- (dimethylamino)benzoic acid for benzoic acid, m/z (LC-MS) M+l = 284.3. [00242] Step B: N,N-Dimethyl-4-(6-nitro-3H-imidazo[4,5-b]pyridin-2-yl)aniline (155 mg, 0.55 mmol) in ethanol (10 niL) and water (3 niL), Fe (122 mg, 2.19 mmol) and NH4Cl (293 mg, 5.47 mmol) were stirred at 80°C for 4 hours. Then the mixture was cooled down to room temperature and diluted with 20% MeOH in CH2Cl2. The mixture was then filtrated through a celite pad and concentrated. The mixture was used in the next step without further purification, m/z (LC-MS) M+l = 254.3.
[00243] Step C: N-(2-(4-(Dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-6-yl)-
2,6-difluoro-3-(propylsulfonamido)benzamide (26%) was prepared according to the general procedure in Example 1, Step E, substituting 2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5- b]pyridin-6-amine for 3H-imidazo[4,5-b]pyridin-6-amine. m/z (LC-MS) M+l = 515.5.
Example 4
Figure imgf000057_0002
2,6-difluoro-N-r2-(phenylamino)-3H-imidazor4.5-b]pyridin-6-yl)-3-
(propylsulfonamido)benzamide
[00244] Step A: A scintillation vial was charged with 5-nitropyridine-2,3-diamine (44 mg, 0.285 mmol), phenyl isothiocyanate (250 μL, 2.09 mmol) and THF (5 mL). The reaction vessel was sealed and heated to 70°C for 30 minutes. The vessel was then cooled to room temperature, and PS-carbodiimide (1.25 mmol/g; 1.20 g, 1.50 mmol) was added. The vessel was re-sealed and heated to 70°C for 24 hours. The reaction mixture was filtered through GF/F paper, and the solids were rinsed with excess CH2Cl2 and MeOH alternately. The filtrate was concentrated in vacuo, and the residue was triturated with 5% MeOH/CH2Cl2 to afford 6-nitro-N-phenyl-3H-imidazo[4,5-b]pyridin-2-amine.
[00245] Step B: N2-Phenyl-3H-imidazo[4,5-b]pyridine-2,6-diamine was prepared according to Example 1, Step D, substituting 6-nitro-N-phenyl-3H-imidazo[4,5-b]pyridin-2- amine for 6-nitro-3H-imidazo[4,5-b]pyridine.
[00246] Step C: 2,6-Difluoro-N-(2-(phenylamino)-3H-imidazo[4,5-b]pyridin-6-yl)-3-
(propylsulfonamido)benzamide was prepared according to Example 1, Step E, substituting N2-phenyl-3H-imidazo[4,5-b]pyridine-2,6-diamine for 3H-imidazo[4,5-b]pyridin-6-amine. 1H NMR (400 MHz, CD3OD) δ 8.19 (br s, IH), 7.70-7.56 (m, 4H), 7.40-7.33 (m, 3H), 7.16- 7.10 (m, IH), 7.10-7.05 (m, IH), 3.14-3.08 (m, 2H), 1.92-1.82 (m, 2H), 1.06 (t, J = 7.4 Hz, 3H). m/z (APCI-pos) M+l = 487.1.
Example 5
Figure imgf000058_0001
2,6-difluoro-N-(2-methyl-3H-imidazo[4,5-blpyridin-6-yl)-3-('propylsulfonamido)benzamide [00247] Step A: A 10-20 mL Biotage Microwave reaction vial was charged with 5- nitropyridine-2,3 -diamine (85 mg, 0.55 mmol, Example 1, Step B) and acetic acid (5 mL). This mixture was subjected to microwave irradiation at 175°C for 75 minutes and then poured into a saturated sodium bicarbonate solution (200 mL). The solution was extracted with 25% IPA/DCM (2 X), and the extracts were dried over sodium sulfate. The extracts were concentrated to a solid, 2-methyl-6-nitro-3H-imidazo[4,5-b]pyridine (85 mg, 87%). 1H NMR (400 MHz, DMSOd6) δ 13.43 (br s, IH), 9.15-9.17 (m, IH), 8.67-8.69 (m, IH), 2.61 (s, 3H); m/z (APCI-neg) M-I = 177.1.
[00248] Step B: 2-Methyl-3H-imidazo[4,5-b]pyridin-6-amine (87%) was prepared according to the general procedure Example 1, Step D, substituting 2-methyl-6-nitro-3H- imidazo[4,5-b]pyridine for 6-nitro-3H-imidazo[4,5-b]pyridine.
[00249] Step C: 2,6-Difluoro-N-(2-methyl-3H-imidazo[4,5-b]pyridin-6-yl)-3-
(propylsulfonamido)benzamide (19%) was prepared according to the general procedure in Example 1, Step E, substituting 2-methyl-3H-imidazo[4,5-b]pyridin-6-amine for 3H- imidazo[4,5-b]pyridin-6-amine. 1H NMR (400 MHz, DMSOd6) δ 12.82, 12.42 (broad singlets, IH), 10.93-11.10 (m, IH), 9.80 (br s, IH), 8.21-8.46 (m, 2H), 7.50-7.59 (m, IH), 7.23-7.29 (m, IH), 3.08-3.19 (m, 3H), 1.72-1.83 (m, 2h), 0.96 - 1.03 (m, 3H); m/z (APCI- neg) M-I = 408.1, (APCI-pos) M+l = 410.1.
Example 6
Figure imgf000059_0001
2,6-difluoro-3-(propylsulfonamidoVN-(2-(pyridin-4-yl)-3H-imidazo[4,5-blpyridin-6- vPbenzamide
[00250] Step A: A 2-5 mL Biotage Microwave reaction vial was charged with 5- nitropyridine-2,3 -diamine (100 mg, 0.65 mmol), isonicotinic acid (80 mg, 0.65 mmol, 1 eq.), and triphenyl phosphite (204 μL, 0.78 mmol, 1.2 eq.) in pyridine (3 mL). This mixture was heated in the microwave at 200°C for 15 minutes and then concentrated under reduced pressure. Preparative TLC of the resulting material (4 X 1.0 mm plates, 100% EtOAc as the eluant) afforded 6-nitro-2-(pyridin-4-yl)-3H-imidazo[4,5-b]pyridine (40 mg, 25%) as a solid. 1H NMR (400 MHz, DMSOd6) δ 9.30-9.31 (m, IH), 8.91-8.94 (br m, IH), 8.83-8.88 (br m, 2H), 8.18-8.21 (m, 3H); m/z (APCI-neg) M-I = 240.4, (APCI-pos) M+l = 242.2. [00251] Step B: 2-(Pyridin-4-yl)-3H-imidazo[4,5-b]pyridin-6-amine (50%) was prepared according to the general procedure in Example 1, Step D (using 1 weight equivalent of 20% Pd(OH)2 as the catalyst), substituting 6-nitro-2-(pyridin-4-yl)-3H-imidazo[4,5- b]pyridine for 6-Nitro-3H-imidazo[4,5-b]pyridine.
[00252] Step C: 2,6-Difluoro-3-(propylsulfonamido)-N-(2-(pyridin-4-yl)-3H- imidazo[4,5-b]pyridin-6-yl)benzamide (35%) was prepared according to the general procedure in Example 1, Step E, substituting 2-(pyridin-4-yl)-3H-imidazo[4,5-b]pyridin-6- amine for 3H-imidazo[4,5-b]pyridin-6-amine. 1H NMR (400 MHz, DMSO-d6) δ 11.19 (br s, IH), 9.83 (br s), IH), 8.76-8.83 (m, 2H), 8.52-8.61 (br m, 2H), 8.09-8.16 br m, 2H), 7.53- 7.61 (m, IH), 7.24-7.31 (m, IH), 3.08-3.18 (m, 2H), 1.71-1.82 (m, 2H), 0.98-1.03 (m, 3H); m/z (APCI-neg) M-I = 471.2, (APCI-pos) M+l = 473.1.
Example 7
Figure imgf000059_0002
2,6-difluoro-3-(propylsulfonamido')-N-(2-(pyridin-3-yl)-3H-imidazor4,5-blpyridin-6- yl)benzamide [00253] Step A: 6-Nitro-2-(pyridin-3-yl)-3H-imidazo[4,5-b]pyridine (20%) was prepared according to Example 6, Step A, substituting nicotinic acid for isonicotinic acid. 1H NMR (400 MHz, DMSO-d6) δ 9.43-9.45 (m, IH), 9.27-9.29 (m, IH), 8.90 (br s, IH), 8.78- 8.82 (m, IH), 8.59-8.63 (m, IH), 7.65-7.71 (m, IH); m/z (APCI-neg) M-I = 240.4. [00254] Step B: 2-(Pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-6-amine (61%) was prepared according to Example 6, Step B, substituting 6-nitro-2-(pyridin-3-yl)-3H- imidazo[4,5-b]pyridine for 6-nitro-2-(pyridin-4-yl)-3H-imidazo[4,5-b]pyridine. [00255] Step C: 2,6-Difluoro-3-(propylsulfonamido)-N-(2-(pyridin-3-yl)-3H- imidazo[4,5-b]pyridin-6-yl)benzarnide (42%) was prepared according to the general procedure in Example 1, Step E, substituting 2-(pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-6- amine for 3H-imidazo[4,5-b]pyridin-6-amine. 1H NMR (400 MHz, DMSO-d6) δ 13.81 and 13.37 (broad singlets, IH), 11.07-11.22 (br m, IH), 9.77-9.86 (br s, IH), 9.34-9.41 (br s, IH), 8.71-8.74 (m, IH), 8.45-8.61 (br m, 3H), 7.54-7.66 (m, 2H), 7.26-7.31 (m, IH), 3.09-3.19 (m, 2H), 1.73-1.83 (m, 2H), 0.97-1.04 (m, 3H); m/z (APCI-neg) M-I = 471.2, (APCI-pos) M+l = 473.1.
Example 8
Figure imgf000060_0001
2,6-difluoro-N-(2-(piperidin-4-yl)-3H-imidazo[4.5-b]pyridin-6-yl)-3-
(propylsulfonamido)benzamide
[00256] Step A: Benzyl 4-(6-nitro-3H-imidazo[4,5-b]pyridin-2-yl)piperidine-l- carboxylate (34%) was prepared according to the general procedure in Example 6, Step 1, substituting l-(benzyloxycarbonyl)piperidine-4-carboxylic acid for isonicotinic acid. 1H NMR (400 MHz, DMSOd6) δ 13.53 (br s, IH), 9.17-9.21 (m, IH), 8.70-8.76 (br s, IH), 7.30-7.42 (m, 5H), 5.11 (s, 2H), 4.05-4.14 (m, 2H), 2.96-3.28 (m, 3H), 2.02-2.12 (m, 2H), 1.69-1.82 (m, 2H); m/z (APCI-neg) M-I = 380.4.
[00257] Step B: Benzyl 4-(6-nitro-3H-imidazo[4,5-b]pyridin-2-yl)piperidine-l- carboxylate (80 mg, 0.21 mmol) was dissolved in methanol (2 mL). Tin (II) chloride di- hydrate (237 mg, 1.05 mmol, 5 eq.) was added, and the mixture was warmed to 70°C for 2 hours. The mixture was then allowed to cool to room temperature. The reaction mixture was diluted with EtOAc and washed once with saturated sodium bicarbonate solution (an emulsion formed, which was filtered through GF/F filter paper). The organics were isolated, dried and concentrated under reduced pressure. Preparative TLC (2 X 0.5 mm plates, 10% MeOH/DCM as the eluant) afforded benzyl 4-(6-ammo-3H-imidazo[4,5-b]pyridin-2- yl)piperidine-l-carboxylate (42 mg, 57%) as a solid. 1H NMR (400 MHz, DMSOd6) δ 7.70- 7.73 (m, IH), 7.29-7.41 (m, 5H), 6.97-7.01 (br s, IH), 5.11 (s, 2H), 4.02-4.11 (m, 2H), 3.15- 3.18 (m, IH), 2.93-3.07 (m, 2H), 1.94-2.02 (m, 2H), 1.63-1.75 (m, 2H); m/z (APCI-neg) M-I = 350.4, (APCI-pos) M+l = 352.1.
[00258] Step C: Benzyl 4-(6-(2,6-difluoro-3-(propylsulfonamido)benzamido)-3H- imidazo[4,5-b]pyridin-2-yl)piperidine-l-carboxylate (46%) was prepared according to the general procedure in Example 1, Step E, substituting benzyl 4-(6-amino-3H-imidazo[4,5- b]pyridin-2-yl)piperidine-l-carboxylate for 3H-imidazo[4,5-b]pyridin-6-amine. 1H NMR (400 MHz, DMSO-d6) δ 12.87 and 12.46 (br singlets, IH), 11.07 and 10.97 (br singlets), 9.78-9.83 (br s, IH), 8.39-8.42 (m, IH), 8.28 and 8.46 (br singlets, IH), 7.28-7.59 (m , 7H), 5.11 (s, 2H), 4.05-4.14 (m, 2H), 2.96-3.19 (m, 5H), 2.00-2.08 (m, 2H), 1.69-1.81 (m, 4H), 0.96-1.04 (m, 3H); m/z (APCI-neg) M-I = 611.3, (APCI-pos) M+l = 613.1. [00259] Step D: Benzyl 4-(6-(2,6-difluoro-3-(propylsulfonamido)benzamido)-3H- imidazo[4,5-b]pyridin-2-yl)piperidine-l-carboxylate (29 mg, 0.047 mmol) was dissolved in methanol (approximately 1 mL), and 20% palladium hydroxide (30 mg, 1 eq.) was added. The mixture was hydrogenated under a balloon of hydrogen for 1.5 hours. The mixture was filtered through GF/F paper, and the filtrate was concentrated to 2,6-difluoro-N-(2-(piperidin- 4-yl)-3H-imidazo[4,5-b]pyridin-6-yl)-3-(propylsulfonamido)benzamide (14 mg, 62%). 1H NMR (400 MHz, DMSOd6) δ 12.57 (very broad s, IH), 11.02 (br s, IH), 8.33-8.49 (m, 3H), 7.49-7.56 (m, IH), 7.16-7.23 (m, IH), 4.05-4.15 (m, 2H), 2.87-3.06 (m, 4H), 2.09-2.15 (m, 2H), 1.69-1.94 (m, 4H), 0.95-1.02 (m, 3H); m/z (APCI-neg) M-I = 477.3, (APCI-pos) M+l = 479.2.
Example 9
Figure imgf000061_0001
2,6-difluoro-N-(2-(piperidin-3-ylV3H-imidazo[4,5-blpyridin-6-yl)-3-
(propylsulfonamidoibenzamide
[00260] Step A: Benzyl 3-(6-nitro-3H-imidazo[4,5-b]pyridin-2-yl)piperidine-l- carboxylate (27%) was prepared according to the general procedure in Example 6, Step 1, substituting l-(benzyloxycarbonyl)piperidine-3-carboxylic acid for isonicotinic acid. H NMR (400 MHz, DMSO-(I6) δ 13.61 (br s, IH), 9.18-9.21 (m, IH), 8.71-8.77 (br s, IH), 7.27-7.41 (m, 5H), 5.10 (s, 2H), 4.25-4.38 (m, IH), 3.91-4.02 (m, IH), 3.06-3.18 (m, IH), 2.93-3.07 (m, IH), 2.16 -2.25 (m, IH), 1.77-1.91 (m, 2H), 1.47-1.60 (m, 2H); m/z (APCI- neg) M-I = 380.4, (APCI-pos) M+l = 382.0.
[00261] Step B: Benzyl 3-(6-amino-3H-imidazo[4,5-b]pyridin-2-yl)piperidine-l- carboxylate (75%) was prepared according to the general procedure in Example 8, Step B, substituting benzyl 3-(6-nitro-3H-imidazo[4,5-b]pyridin-2-yl)piperidine-l-carboxylate for benzyl 4-(6-nitro-3H-imidazo[4,5-b]pyridin-2-yl)piperidine-l-carboxylate. m/z (APCI-neg) M-I = 350.3, (APCI-pos) M+l = 352.2.
[00262] Step C: Benzyl 3-(6-(2,6-difluoro-3-(propylsulfonamido)benzamido)-3H- imidazo[4,5-b]pyridin-2-yl)piperidine-l-carboxylate (25%) was prepared according to the general procedure in Example 1, Step E, substituting 3-(6-amino-3H-imidazo[4,5-b]pyridin- 2-yl)piperidine-l-carboxylate for 3H-imidazo[4,5-b]pyridin-6-amine. m/z (APCI-neg) M-I = 611.2, (APCI-pos) M+l = 613.1.
[00263] Step D: 2,6-Difluoro-N-(2-(piperidin-3-yl)-3H-imidazo[4,5-b]pyridin-6-yl)-3-
(propylsulfonamido)benzamide (53%) was prepared according to the general procedure in Example 8, Step D, substituting benzyl 3-(6-(2,6-difluoro-3-(propylsulfonamido)benzamido)- 3H-imidazo[4,5-b]pyridin-2-yl)piperidine-l-carboxylate for benzyl 4-(6-(2,6-difluoro-3- (propylsulfonamido)benzamido)-3H-imidazo[4,5-b]pyridin-2-yl)piperidine-l-carboxylate. 1H NMR (400 MHz, DMSOd6) δ 10.97 (s, IH), 8.42-8.44 (m, IH), 8.35-8.37 (m, IH), 7.47- 7.56 )m, m, IH), 7.15-7.21 (m, IH), 3.51 (s, 2H), 2.88-3.06 (m, 4H), 2.61-2.69 (m, IH), 2.09- 2.16 (m, IH), 1.68-1.82 (m, 4H), 0.95-1.01 (m, 3H); m/z (APCI-neg) M-I = 477.3, (APCI- pos) M+l = 479.2.
Example 10
Figure imgf000062_0001
N-(2-(4-chlorophenylV3H-imidazor4.5-b1pyridin-6-ylV2.6-difluoro-3-
(propylsulfonamido)benzamide
[00264] Step A: 2-(4-Chlorophenyl)-6-nitro-3H-imidazo[4,5-b]pyridine (49%) was prepared as in the general procedure in Example 2, Step A, substituting 4-chlorobenzoic acid for benzoic acid. 1H NMR (400 MHz, DMSO-d6) δ 9.25-9.26 (m, IH), 8.81-8.32 (m, IH), 8.27-8.32 (m, 2H), 7.70-7.74 (m, 2H); m/z (APCI-neg) M-I = 273.3. [00265] Step B: 2-(4-Chlorophenyl)-6-nitro-3H-imidazo[4,5-b]pyridine (50 mg, 0.182 mmol) was dissolved in THF (2 mL), and a saturated ammonium chloride solution (2 mL) was added followed by zinc powder (119 mg, 1.82 mmol, 10 eq.). This mixture was vigorously stirred at room temperature for 15 minutes, when TLC indicated complete consumption of starting material. The reaction mixture was then filtered through GF/F filter paper. The filtrate was diluted with water and extracted with EtOAc (with a little methanol, 2 X). The extracts were dried over sodium sulfate and concentrated to 2-(4-chlorophenyl)-3H- imidazo[4,5-b]pyridin-6-amine (41 mg, 92%) as a solid.
[00266] Step C: N-(2-(4-Chlorophenyl)-3H-imidazo[4,5-b]pyridin-6-yl)-2,6-difluoro-
3-(propylsulfonamido)benzamide (20%) was prepared according to the general procedure in Example 1, Step E, substituting 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridin-6-amine for 3H-imidazo[4,5-b]pyridin-6-amine. 1H NMR (400 MHz, DMSOd6) δ 13.67 and 13.25 (broad singlets, IH), 11.18 and 11.07 (broad singlets, IH), 9.81 (br s, IH), 8.42-8.56 (m, 2H), 8.16 - 8.28 (m, 2H), 7.63 - 7.70 (br m, 2H), 7.52-7.60 (m, IH), 7.26-7.32 (m, IH), 3.11-3.17 (m, 2H), 1.72-1.82 (m, 2H), 0.98-1.04 (m, 3H); m/z (APCI-neg) M-I = 506.2, 504.2, (APCI- pos) M+l = 506.1, 508.1.
Example 11
Figure imgf000063_0001
2,6-difluoro-N-(2-(4-methoxyphenylV3H-imidazo[4,5-blpyridin-6-yl)-3-
Figure imgf000063_0002
[00267] Step A: 2-(4-Methoxyphenyl)-6-nitro-3H-imidazo[4,5-b]pyridine (64%) was prepared as in the general procedure in Example 2, Step A, substituting 4-methoxybenzoic acid for benzoic acid. 1H NMR (400 MHz, DMSOd6) δ 9.19-9.22 (m, IH), 8.72 (br s, IH), 8.21-8.26 (m, 2H), 7.16-7.20 (m, 2H), 3.87 (s, 3H); m/z (APCI-neg) M-I - 269.3. [00268] Step B: 2-(4-Methoxyphenyl)-3H-imidazo[4,5-b]pyridin-6-amine (96%) was prepared as in the general procedure in Example 10, Step B, substituting 2-(4- methoxyphenyl)-6-nitro-3H-imidazo[4,5-b]pyridine for 2-(4-chlorophenyl)-6-nitro-3H- imidazo[4,5-b]pyridine.
[00269] Step C: 2,6-Difluoro-N-(2-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridin-6- yl)-3-(propylsulfonamido)benzamide (22%) was prepared according to the general procedure in Example 1, Step E, substituting 2-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridin-6-amine for 3H-imidazo[4,5-b]pyridin-6-amine. 1H NMR (400 MHz, MeOH-(I4) δ 8.57 (br s, IH), 8.44 (m, IH), 8.08-8.13 (m, 2H), 7.62-7.69 (m, IH), 7.10-7.17 (m, 3H), 3.90 (s, 3H), 3.08- 3.14 (m, 2H), 1.82-1.93 (m, 2H), 1.03-1.09 (m, 3H); m/z (APCI-neg) M-I = 500.3, (APCI- pos) M+l = 502.1.
Example 12
Figure imgf000064_0001
2,6-difluoro-N-(2-(4-fluorophenylV3H-imidazo[4,5-blpyridin-6-yl)-3-
(propylsulfonamido)benzamide
[00270] Step A: 2-(4-Fluorophenyl)-6-nitro-3H-imidazo[4,5-b]pyridine (30%) was prepared according to the general procedure in Example 2, Step A, substituting 4- fluorobenzoic acid for benzoic acid. 1H NMR (400 MHz, MeOH-dj) δ 8.17-8.22 (m, 2H), 7.96-7.99 (m, IH), 7.63-7.72 (m, 2H), 7.24-7.38 (m, 3H), 7.12-7.18 (m, IH), 3.10-3.14 (m, 2H), 1.79-1.93 (m, 2H), 1.01-1.09 (m, 3H); m/z (APCI-neg) M-I = 480.2, (APCI-pos) M+l - 490.1.
[00271] Step B: 2-(4-Fluorophenyl)-3H-imidazo[4,5-b]pyridin-6-amine (59%) was prepared according to Example 10, Step B, substituting 2-(4-fluorophenyl)-6-nitro-3H- imidazo[4,5-b]pyridine for 2-(4-chlorophenyl)-6-nitro-3H-imidazo[4,5-b]pyridine. [00272] Step C: 2,6-Difluoro-N-(2-(4-fluorophenyl)-3H-imidazo[4,5-b]pyridin-6-yl)-
3-(propylsulfonamido)benzamide (30%) was prepared according to the general procedure in Example 1, Step E, substituting 2-(4-fluorophenyl)-3H-imidazo[4,5-b]pyridin-6-amine for 3H-imidazo[4,5-b]pyridin-6-amine. 1H NMR (400 MHz, MeOH-d4) δ 8.17-8.22 (m, 2H), 7.96-7.99 (m, IH), 7.63-7.72 (m, 2H), 7.24-7.38 (m, 3H), 7.12-7.18 (m, IH), 3.10-3.14 (m, 2H), 1.79-1.93 (m, 2H), 1.01-1.09 (m, 3H); m/z (APCI-neg) M-I = 480.2, (APCI-pos) M+l = 490.1.
Example 13
Figure imgf000064_0002
N-(2-(3,4-dichlorophenylV3H-imidazor4.5-blpyridin-6-yl)-2.6-difluoro-3- (propylsulfonamido)benzamide [00273] Step A: 2-(3,4-Dichlorophenyl)-6-nitro-3H-imidazo[4,5-b]pyridine was prepared according to the general procedure in Example 2, Step A, substituting 3,4- dichlorobenzoic acid for benzoic acid, m/z (LC-MS) M+l = 310.1.
[00274] Step B: 2-(3,4-Dichlorophenyl)-3H-imidazo[4,5-b]pyridin-6-amine was prepared according to the general procedure in Example 3, Step B, substituting 2-(3,4- dichlorophenyl)-6-nitro-3H-imidazo[4,5-b]pyridine for N,N-dimethyl-4-(6-nitro-3H- imidazo[4,5-b]pyridin-2-yl)aniline. m/z (LC-MS) M+l = 280.1.
[00275] Step C: N-(2-(3,4-Dichlorophenyl)-3H-imidazo[4,5-b]pyridin-6-yl)-2,6- difluoro-3-(propylsulfonamido)benzamide (19%) was prepared according to the general procedure in Example 1, Step E, substituting 2-(3,4-dichlorophenyl)-3H-imidazo[4,5- b]pyridin-6-amine for 3H-imidazo[4,5-b]pyridin-6-amine. m/z (LC-MS) M+l = 541.3.
Example 14
Figure imgf000065_0001
2,6-difluoro-3-(propylsulfonamido)-N-('2-p-tolyl-3H-imidazor4.5-b1pyridin-6-yl)benzamide [00276] Step A: 6-Nitro-2-p-tolyl-3H-imidazo[4,5-b]pyridine (82%) was prepared according to the general procedure in Example 2, Step A, substituting p-toluic acid for benzoic acid, m/z (LC-MS) M+l = 255.2.
[00277] Step B: 2-p-Tolyl-3H-imidazo[4,5-b]pyridin-6-amine was prepared according to the general procedure in Example 3, Step B, substituting 6-nitro-2-p-tolyl-3H-imidazo[4,5- b]pyridine for N,N-dimethyl-4-(6-nitro-3H-imidazo[4,5-b]pyridin-2-yl)aniline. [00278] Step C: 2,6-Difluoro-3-(propylsulfonamido)-N-(2-p-tolyl-3H-imidazo[4,5- b]pyridin-6-yl)benzamide (30%) was prepared according to the general procedure in Example 1, Step E, substituting 2-p-tolyl-3H-imidazo[4,5-b]pyridin-6-amine for 3H-imidazo[4,5- b]ρyridin-6-amine. m/z (LC-MS) M+l = 486.5.
Example 15
Figure imgf000065_0002
N-(2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridin-6-yl)-2,6-difluoro-3- (propylsulfonamido)benzamide [00279] Step A: 2-(4-Bromophenyl)-6-nitro-3H-imidazo[4,5-b]pyridine (59%) was prepared according to the general procedure in Example 2, Step A, substituting 4- bromobenzoic acid for benzoic acid, m/z (LC-MS) M+l = 321.
[00280] Step B: 2-(4-Bromophenyl)-3H-imidazo[4,5-b]pyridin-6-amine was prepared according to the general procedure in Example 3, Step B, substituting 2-(4-bromophenyl)-6- nitro-3 H-imidazo [4,5 -b]pyridine for N,N-dimethyl-4-(6-nitro-3 H-imidazo [4,5 -b]pyridin-2- yl)aniline. m/z (LC-MS) M+l = 291.
[00281] Step C: N-(2-(4-Bromophenyl)-3H-imidazo[4,5-b]pyridin-6-yl)-2,6-difluoro-
3-(propylsulfonamido)benzamide (54%) was prepared according to the general procedure in Example 1, Step E, substituting 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridin-6-amine for 3H-imidazo[4,5-b]pyridin-6-amine. m/z (LC-MS) M+l = 552.
Example 16
Figure imgf000066_0001
N-(2-(3-chlorophenyl)-3H-imidazo[4,5-blpyridin-6-ylV2,6-difluoro-3-
(propylsulfonamido*)benzamide
[00282] Step A: 2-(3-Chlorophenyl)-6-nitro-3H-imidazo[4,5-b]pyridine (83%) was prepared according to the general procedure in Example 2, Step A, substituting 3- chlorobenzoic acid for benzoic acid, m/z (LC-MS) M+l = 275.6.
[00283] Step B: 2-(3-Chlorophenyl)-3H-imidazo[4,5-b]pyridin-6-amine was prepared according to the general procedure in Example 3, Step B, substituting 2-(3-chlorophenyl)-6- nitro-3H-imidazo[4,5-b]pyridine for N,N-dimethyl-4-(6-nitro-3H-imidazo[4,5-b]pyridin-2- yl)aniline. m/z (LC-MS) M+l = 245.6.
[00284] Step C: N-(2-(3-Chlorophenyl)-3H-imidazo[4,5-b]pyridm-6-yl)-2,6-difluoro-
3-(propylsulfonamido)benzamide (18%) was prepared according to the general procedure in Example 1, Step E, substituting 2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridin-6-amine for 3H-imidazo[4,5-b]pyridin-6-amine. m/z (LC-MS) M+l = 506.9.
Example 17
Figure imgf000066_0002
2,6-difluoro-3-(propylsulfonamidoVN-(2-(4-('trifluoromethoxy)phenylV3H-imidazo[4,5- b1pγridin-6-yl)benzamide
[00285] Step A: 6-Nitro-2-(3-(trifluoromethoxy)phenyl)-3H-imidazo[4,5-b]pyridine
(75%) was prepared according to the general procedure in Example 2, Step A, substituting 4- trifluoromethoxybenzoic acid for benzoic acid, m/z (LC-MS) M+l = 325.2. [00286] Step B: 2-(3-(Trifluoromethoxy)phenyl)-3H-imidazo[4,5-b]pyridin-6-amine was prepared according to the general procedure in Example 3, Step B, substituting 6-nitro-2- (3-(trifluoromethoxy)phenyl)-3H-imidazo[4,5-b]pyridine for N,N-dimethyl-4-(6-nitro-3H- imidazo[4,5-b]pyridin-2-yl)aniline. m/z (LC-MS) M+l = 295.2.
[00287] Step C: 2,6-Difluoro-3-(propylsulfonamido)-N-(2-(4-
(trifluoromethoxy)phenyl)-3H-imidazo[4,5-b]pyridin-6-yl)benzamide (28%) was prepared according to the general procedure in Example 1, Step E, substituting 2-(3- (trifluoromethoxy)phenyl)-3H-imidazo[4,5-b]pyridin-6-amine for 3H-imidazo[4,5-b]pyridin- 6-amine. m/z (LC-MS) M+l = 556.5.
Example 18
Figure imgf000067_0001
2,6-difluoro-3-(propylsulfonamido)-N-(2-(4-rtrifluoromethvDphenylV3H-imidazo[4,5- blpyridin-6-vDbenzamide
[00288] Step A: 6-Nitro-2-(4-(trifluoromethyl)phenyl)-3H-imidazo[4,5-b]pyridine
(64%) was prepared according to the general procedure in Example 2, Step A, substituting 4- trifluoromethylbenzoic acid for benzoic acid, m/z (LC-MS) M+l = 309.2. [00289] Step B: 2-(4-(Trifluoromethyl)phenyl)-3H-imidazo[4,5-b]pyridin-6-amine was prepared according to the general procedure in Example 3, Step B, substituting 6-nitro-2- (4-(trifluoromethyl)phenyl)-3H-imidazo[4,5-b]pyridine for N,N-dimethyl-4-(6-nitro-3H- imidazo[4,5-b]pyridin-2-yl)aniline. m/z (LC-MS) M+l = 279.2.
[00290] Step C: 2,6-Difluoro-3-(propylsulfonamido)-N-(2-(4-
(trifluoromethyl)phenyl)-3H-imidazo[4,5-b]pyridin-6-yl)benzamide (27%) was prepared according to the general procedure in Example 1, Step E, substituting 2-(4- (trifluoromethyl)phenyl)-3H-imidazo[4,5-b]pyridin-6-amine for 3H-imidazo[4,5-b]pyridin-6- amine. m/z (LC-MS) M+l = 540.4. Example 19
Figure imgf000068_0001
2,6-difluoro-N-('2-(4-methyl-3-(trifluoromethyl)phenyl)-3H-imidazo[4.5-blpyridin-6-vπ-3-
(propylsulfonamido)benzamide
[00291] Step A: 2-(4-Methyl-3-(trifluoromethyl)phenyl)-6-nitro-3H-imidazo[4,5- bjpyridine (87%) was prepared according to the general procedure in Example 2, Step A, substituting 4-methyl-3-(trifluoromethyl)benzoic acid for benzoic acid, m/z (LC-MS) M+l = 323.
[00292] Step B: 2-(4-Methyl-3-(trifluoromethyl)phenyl)-3H-imidazo[4,5-b]pyridin-6- amine was prepared according to the general procedure in Example 3, Step B, substituting 2- (4-methyl-3-(trifluoromethyl)phenyl)-6-nitro-3H-imidazo[4,5-b]pyridine for N,N-dimethyl-4- (6-nitro-3H-imidazo[4,5-b]pyridin-2-yl)aniline. m/z (LC-MS) M+l = 293. [00293] Step C: 2,6-Difluoro-N-(2-(4-methyl-3-(trifluoromethyl)phenyl)-3H- imidazo[4,5-b]pyridin-6-yl)-3-(propylsulfonamido)benzamide (30%) was prepared according to the general procedure in Example 1, Step E, substituting 2-(4-methyl-3- (trifluoromethyl)phenyl)-3H-imidazo[4,5-b]pyridin-6-amine for 3H-imidazo[4,5-b]pyridin-6- amine. m/z (LC-MS) M+l = 554.
Example 20
Figure imgf000068_0002
2,6-difluoro-3-rpropylsulfonamido)-N-(2-('3-(trifluoromethvπphenyl)-3H-imidazo[4,5- blpyridin-6-yl)benzamide
[00294] Step A: 6-Nitro-2-(3-(trifluoromethyl)phenyl)-3H-imidazo[4,5-b]pyridine
(78%) was prepared according to the general procedure in Example 2, Step A, substituting 3- (trifluoromethyl)benzoic acid for benzoic acid, m/z (LC-MS) M+l = 309.2. [00295] Step B: 2-(3-(Trifiuoromethyl)phenyl)-3H-imidazo[4,5-b]pyridin-6-amine was prepared according to the general procedure in Example 3, Step B, substituting 6-nitro-2- (3 -(trifluoromethyl)phenyl)-3 H-imidazo [4,5 -bjpyridine for N,N-dimethyl-4-(6-nitro-3 H- imidazo[4,5-b]pyridin-2-yl)aniline. m/z (LC-MS) M+l = 279.2. [00296] Step C: 2,6-Difluoro-3-(propylsulfonamido)-N-(2-(3-(trifluoromethyl) phenyl)-3H-imidazo[4,5-b]pyridin-6-yl)benzamide (27%) was prepared according to the general procedure in Example 1, Step E, substituting 2-(3-(trifluoromethyl)phenyl)-3H- imidazo[4,5-b]pyridin-6-amine for 3H-imidazo[4,5-b]pyridin-6-amine. m/z (LC-MS) M+l = 540.4.
Example 21
Figure imgf000069_0001
2,6-difluoro-N-('2-(2-fluorophenyl')-3H-imidazo[4,5-blpyridin-6-yl)-3-
(propylsulfonamido)benzamide
[00297] Step A: 2-(2-Fluorophenyl)-6-nitro-3H-imidazo[4,5-b]pyridine (88%) was prepared according to the general procedure in Example 2, Step A, substituting 2- fluorobenzoic acid for benzoic acid, m/z (LC-MS) M+l = 259.2.
[00298] Step B: 2-(2-Fluorophenyl)-3H-imidazo[4,5-b]pyridin-6-amine was prepared according to the general procedure in Example 3, Step B, substituting 2-(2-fluorophenyl)-6- nitro-3H-imidazo[4,5-b]pyridine for N,N-dimethyl-4-(6-nitro-3H-imidazo[4,5-b]pyridin-2- yl)aniline. m/z (LC-MS) M+l = 229.2.
[00299] Step C: 2,6-Difluoro-N-(2-(2-fluorophenyl)-3H-imidazo[4,5-b]pyridin-6-yl)-
3-(propylsulfonamido)benzamide (43%) was prepared according to the general procedure in Example 1, Step E, substituting 2-(2-fluorophenyl)-3H-imidazo[4,5-b]pyridin-6-amine for 3H-imidazo[4,5-b]pyridin-6-amine. m/z (LC-MS) M+l = 490.4.
Example 22
Figure imgf000069_0002
N-(2-(3-bromophenylV3H-imidazo[4,5-blpyridin-6-ylV2.6-difluoro-3-
(propylsulfonamido)benzamide
[00300] Step A: 2-(3-Bromophenyl)-6-nitro-3H-imidazo[4,5-b]pyridine (71%) was prepared according to the general procedure in Example 2, Step A, substituting 3- bromobenzoic acid for benzoic acid, m/z (LC-MS) M+l = 320.1.
[00301] Step B: 2-(3-Bromophenyl)-3H-irnidazo[4,5-b]pyridin-6-amine was prepared according to the general procedure in Example 3, Step B, substituting 2-(3-bromophenyl)-6- nitro-3H-imidazo[4,5-b]pyridine for N,N-dimethyl-4-(6-nitro-3H-imidazo[4,5-b]pyridin-2- yl)aniline. m/z (LC-MS) M+l = 290.1.
[00302] Step C: N-(2-(3-Bromophenyl)-3H-imidazo[4,5-b]pyridin-6-yl)-2,6-difluoro-
3-(propylsulfonamido)benzamide (17%) was prepared according to the general procedure in Example 1, Step E, substituting 2-(3-bromophenyl)-3H-imidazo[4,5-b]pyridin-6-amine for 3H-imidazo[4,5-b]pyridin-6-amine. m/z (LC-MS) M+l = 551.4.
Example 23
Figure imgf000070_0001
N-(2-(4-cvanophenylV3H-imidazo[4,5-b]pyridin-6-yl)-2.,6-difluoro-3-
(propylsulfonamido)benzamide
[00303] Step A: 4-(6-Nitro-3H-imidazo[4,5-b]pyridin-2-yl)benzonitrile (71%) was prepared according to the general procedure in Example 2, Step A, substituting 4- cyanobenzoic acid for benzoic acid, m/z (LC-MS) M+l = 266.2.
[00304] Step B: 4-(6-Amino-3H-imidazo[4,5-b]pyridin-2-yl)benzonitrile was prepared according to the general procedure in Example 3, Step B, substituting 4-(6-nitro-3H- imidazo[4,5-b]pyridin-2-yl)benzonitrile for N,N-dimethyl-4-(6-nitro-3H-imidazo[4,5- b]pyridin-2-yl)aniline. m/z (LC-MS) M+l = 236.2.
[00305] Step C: N-(2-(4-Cyanophenyl)-3H-imidazo[4,5-b]pyridin-6-yl)-2,6-difluoro-
3-(propylsulfonamido)benzamide (21%) was prepared according to the general procedure in Example 1, Step E, substituting 4-(6-amino-3H-imidazo[4,5-b]pyridin-2-yl)benzonitrile for 3H-imidazo[4,5-b]pyridin-6-amine. m/z (LC-MS) M+l = 497.4.
Example 24
Figure imgf000070_0002
N-(2-(2-chlorophenylV3H-imidazo[4,5-blpyridin-6-ylV2,6-difluoro-3-
(propylsulfonamido)benzamide
[00306] Step A: 2-(2-Chlorophenyl)-6-nitro-3H-imidazo[4,5-b]pyridine (88%) was prepared according to the general procedure in Example 2, Step A, substituting 2- chlorobenzoic acid for benzoic acid, m/z (LC-MS) M+l = 275.6. [00307] Step B: 2-(2-Chlorophenyl)-3H-imidazo[4,5-b]pyridin-6-amine was prepared according to the general procedure in Example 3, Step B, substituting 2-(2-chlorophenyl)-6- nitro-3H-imidazo[4,5-b]pyridine for N,N-dimethyl-4-(6-nitro-3H-imidazo[4,5-b]pyridin-2- yl)aniline. m/z (LC-MS) M+l =245.6.
[00308] Step C: N-(2-(2-Chlorophenyl)-3H-imidazo[4,5-b]pyridin-6-yl)-2,6-difluoro-
3-(propylsulfonamido)benzamide (32%) was prepared according to the general procedure in Example 1, Step E, substituting 2-(2-chlorophenyl)-3H-imidazo[4,5-b]pyridin-6-amine for 3H-imidazo[4,5-b]pyridin-6-amine. m/z (LC-MS) M+l = 506.9.
Example 25
Figure imgf000071_0001
N-(2-(4-chlorobenzyl)-3H-imidazo[4.5-b]pyridin-6-yl)-2.6-difluoro-3-
(propylsulfonamido)benzamide
[00309] Step A: 2-(4-Chlorobenzyl)-6-nitro-3H-imidazo[4,5-b]pyridine (99%) was prepared according to the general procedure in Example 2, Step A, substituting 4- chlorophenyl acetic acid for benzoic acid, m/z (LC-MS) M+l = 289.7. [00310] Step B: 2-(4-Chlorobenzyl)-3H-imidazo[4,5-b]pyridin-6-amine was prepared according to the general procedure in Example 3, Step B, substituting 2-(4-chlorobenzyl)-6- nitro-3H-imidazo[4,5-b]pyridine for N,N-dimethyl-4-(6-nitro-3H-imidazo[4,5-b]pyridin-2- yl)aniline. m/z (LC-MS) M+l =259.7.
[00311] Step C: N-(2-(4-Chlorobenzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-2,6-difluoro-
3-(propylsulfonamido)benzamide (52%) was prepared according to the general procedure in Example 1, Step E, substituting 2-(4-chlorobenzyl)-3H-imidazo[4,5-b]pyridin-6-amine for 3H-imidazo[4,5-b]pyridin-6-amine. m/z (LC-MS) M+l - 520.9.
Example 26
Figure imgf000071_0002
N-(2-(3.,5-difluorobenzyl)-3H-imida2o[4.,5-blpyridin-6-yl)-2,6-difluoro-3-
(propylsulfonamido)benzamide
[00312] Step A: 2-(3,5-Difluorobenzyl)-6-nitro-3H-imidazo[4,5-b]pyridine (91%) was prepared according to the general procedure in Example 2, Step A, substituting 4- chlorophenyl acetic acid for benzoic acid, m/z (LC-MS) M+l = 291.2. [00313] Step B: 2-(3,5-Difluorobenzyl)-3H-imidazo[4,5-b]pyridin-6-amine was prepared according to the general procedure in Example 3, Step B, substituting 2-(3,5- difluorobenzyl)-6-nitro-3H-imidazo[4,5-b]pyridine for N,N-dimethyl-4-(6-nitro-3H- imidazo[4,5-b]pyridin-2-yl)aniline. m/z (LC-MS) M+l =261.2.
[00314] Step C: N-(2-(3,5-Difluorobenzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-2,6- difluoro-3-(propylsulfonamido)benzamide (23%) was prepared according to the general procedure in Example 1, Step E, substituting 2-(3,5-difluorobenzyl)-3H-imidazo[4,5- b]pyridin-6-amine for 3H-imidazo[4,5-b]pyridin-6-amine. m/z (LC-MS) M+l = 522.4.
Example 27
Figure imgf000072_0001
N-(2-(2-bromophenyl)-3H-imidazo[4.5-blpyridin-6-yl)-2.6-difluoro-3-
(propylsulfonamido)benzamide
[00315] Step A: 2-(2-Bromophenyl)-6-nitro-3H-imidazo[4,5-b]pyridine (81%) was prepared according to the general procedure in Example 2, Step A, substituting 2- bromobenzoic acid for benzoic acid, m/z (LC-MS) M+l = 320.1.
[00316] Step B: 2-(2-Bromophenyl)-3H-imidazo[4,5-b]pyridin-6-amine was prepared according to the general procedure in Example 3, Step B, substituting 2-(2-bromophenyl)-6- nitro-3H-imidazo[4,5-b]pyridine for N,N-dimethyl-4-(6-nitro-3H-imidazo[4,5-b]pyridin-2- yl)aniline. m/z (LC-MS) M+l =290.1.
[00317] Step C: N-(2-(2-Bromophenyl)-3H-imidazo[4,5-b]pyridin-6-yl)-2,6-difluoro-
3-(propylsulfonamido)benzamide (30%) was prepared according to the general procedure in Example 1, Step E, substituting 2-(2-bromophenyl)-3H-imidazo[4,5-b]pyridin-6-amine for 3H-imidazo[4,5-b]pyridin-6-amine. m/z (LC-MS) M+l = 551.4.
Example 28
Figure imgf000073_0001
2,6-difluoro-N-(2-(4-methoxybenzyl)-3H-imidazor4.,5-b1pyridin-6-ylV3-
(propylsulfonamido)benzamide
[00318] Step A: 2-(4-Methoxybenzyl)-6-nitro-3H-imidazo[4,5-b]pyridine (90%) was prepared according to the general procedure in Example 2, Step A, substituting 2- bromobenzoic acid for benzoic acid, m/z (LC-MS) M+l = 285.2.
[00319] Step B: 2-(4-Methoxybenzyl)-3H-imidazo[4,5-b]pyridin-6-amine was prepared according to the general procedure in Example 3, Step B, substituting 2-(4- methoxybenzyl)-6-nitro-3H-imidazo[4,5-b]pyridine for N,N-dimethyl-4-(6-nitro-3H- imidazo[4,5-b]pyridin-2-yl)aniline. m/z (LC-MS) M+l = 255.2.
[00320] Step C: 2,6-Difluoro-N-(2-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-6- yl)-3-(propylsulfonamido)benzamide (47%) was prepared according to the general procedure in Example 1, Step E, substituting 2-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-6-amine for 3H-imidazo[4,5-b]pyridin-6-amine. m/z (LC-MS) M+l = 516.5.
Example 29
Figure imgf000073_0002
N-(2-(4-bromobenzyl)-3H-imidazor4.5-blpyridin-6-yl)-2.6-difluoro-3-
(propylsulfonamido'tøenzamide
[00321] Step A: 2-(4-Bromobenzyl)-6-nitro-3H-imidazo[4,5-b]pyridine (70%) was prepared according to the general procedure in Example 2, Step A, substituting 4- bromophenyl acetic acid for benzoic acid, m/z (LC-MS) M+l = 334.1. [00322] Step B: 2-(4-Bromobenzyl)-3H-imidazo[4,5-b]pyridin-6-amine was prepared according to the general procedure in Example 3, Step B, substituting 2-(4-bromobenzyi)-6- nitro-3H-imidazo[4,5-b]pyridine for N,N-dimethyl-4-(6-nitro-3H-imidazo[4,5-b]pyridin-2- yl)aniline. m/z (LC-MS) M+l =304.2. [00323] Step C: N-(2-(4-Bromobenzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-2,6-difluoro-
3-(propylsulfonamido)benzamide (70%) was prepared according to the general procedure in Example 1, Step E, substituting 2-(4-bromobenzyl)-3H-imidazo[4,5-b]pyridin-6-amine for 3H-imidazo[4,5-b]pyridin-6-amine. m/z (LC-MS) M+l = 565.4.
Example 30
Figure imgf000074_0001
N-(2-tert-butyl-3H-imidazor4,5-blpyridin-6-vπ-2,6-difluoro-3-
(propylsulfonamido)benzamide
[00324] Step A: 2-tert-Butyl-6-nitro-3H-imidazo[4,5-b]pyridine (54%) was prepared according to the general procedure in Example 2, Step A, substituting pivalic acid for benzoic acid, m/z (LC-MS) M+l = 221.2.
[00325] Step B: 2-tert-Butyl-3H-imidazo[4,5-b]pyridin-6-amine was prepared according to the general procedure in Example 3, Step B, substituting 2-tert-butyl-6-nitro-3H- imidazo[4,5-b]pyridine for N,N-dimethyl-4-(6-nitro-3H-imidazo[4,5-b]pyridin-2-yl)aniline. m/z (LC-MS) M+l =191.2.
[00326] Step C: N-(2-tert-Butyl-3H-imidazo[4,5-b]pyridin-6-yl)-2,6-difluoro-3-
(propylsulfonamido)benzamide (33%) was prepared according to the general procedure in Example 1, Step E, substituting 2-tert-butyl-3H-imidazo[4,5-b]pyridin-6-amine for 3H- imidazo[4,5-b]pyridin-6-amine. m/z (LC-MS) M+l = 452.4.
Example 31
Figure imgf000074_0002
2,6-difluoro-N-(2-isopropyl-3H-imidazor4,5-blpyridin-6-ylV3-
(propylsulfonamido'tøenzamide
[00327] Step A: 2-Isopropyl-6-nitro-3H-imidazo[4,5-b]pyridine (87%) was prepared according to the general procedure in Example 2, Step A, substituting isobutyric acid for benzoic acid, m/z (LC-MS) M+l = 207.2.
[00328] Step B: 2-Isopropyl-3H-imidazo[4,5-b]pyridin-6-amine was prepared according to the general procedure in Example 3, Step B, substituting 2-isopropyl-6-nitro- 3H-imidazo[4,5-b]pyridine for N,N-dimethyl-4-(6-nitro-3H-imidazo[4,5-b]pyridin-2- yl)aniline. m/z (LC-MS) M+l =177.2.
[00329] Step C: 2,6-Difluoro-N-(2-isopropyl-3H-imidazo[4,5-b]pyridin-6-yl)-3-
(propylsulfonamido)benzamide (71%) was prepared according to the general procedure in Example 1, Step E, substituting 2-isopropyl-3H-imidazo[4,5-b]pyridin-6-amine for 3H- imidazo[4,5-b]pyridin-6-amine. m/z (LC-MS) M+l = 438.4.
Example 32
Figure imgf000075_0001
N-(2-ethyl-3H-imidazo[4,5-blpyridin-6-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide [00330] Step A: 2-Ethyl-6-nitro-3H-imidazo[4,5-b]pyridine (80%) was prepared according to the general procedure in Example 2, Step A, substituting propionic acid for benzoic acid, m/z (LC-MS) M+l = 193.1.
[00331] Step B: 2-Ethyl-3H-imidazo[4,5-b]pyridin-6-amine was prepared according to the general procedure in Example 3, Step B, substituting 2-ethyl-6-nitro-3H-imidazo[4,5- b]pyridine for N,N-dimethyl-4-(6-nitro-3H-imidazo[4,5-b]pyridin-2-yl)aniline. m/z (LC-MS) M+l =163.1.
[00332] Step C: N-(2-Ethyl-3H-imidazo[4,5-b]pyridin-6-yl)-2,6-difluoro-3-
(propylsulfonamido)benzamide (33%) was prepared according to the general procedure in Example 1, Step E, substituting 2-ethyl-3H-imidazo[4,5-b]pyridin-6-amine for 3H- imidazo[4,5-b]pyridin-6-amine. m/z (LC-MS) M+l = 424.4.
Example 33
Figure imgf000075_0002
N-(2-(3,4-difluorobenzylV3H-imidazo[4.5-blpyridin-6-vD-2,6-difluoro-3-
(propylsulfonamido)benzamide
[00333] Step A: 2-(3,4-Difluorobenzyl)-6-nitro-3H-imidazo[4,5-b]pyridine (82%) was prepared according to the general procedure in Example 2, Step A, substituting 3,4- difluorophenyl acetic acid for benzoic acid, m/z (LC-MS) M+l = 291.2. [00334] Step B: 2-(3,4-Difluorobenzyl)-3H-imidazo[4,5-b]pyridin-6-amine was prepared according to the general procedure in Example 3, Step B, substituting 2-(3,4- difluorobenzyl)-6-nitro-3H-imidazo[4,5-b]pyridine for N,N-dimethyl-4-(6-nitro-3H- imidazo[4,5-b]pyridin-2-yl)aniline. m/z (LC-MS) M+l =261.2.
[00335] Step C: N-(2-(3,4-Difluorobenzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-2,6- difluoro-3-(propylsulfonamido)benzamide (40%) was prepared according to the general procedure in Example 1, Step E, substituting 2-(3,4-difluorobenzyl)-3H-imidazo[4,5- b]pyridin-6-amine for 3H-imidazo[4,5-b]pyridin-6-amine. m/z (LC-MS) M+l = 522.4.
Example 34
Figure imgf000076_0001
N-(2-cvclobutyl-3H-imidazo[4,5-blpyridin-6-yl)-2,6-difluoro-3-
(propylsulfonamido)benzamide
[00336] Step A: 2-Cyclopropyl-6-nitro-3H-imidazo[4,5-b]pyridine (70%) was prepared according to the general procedure in Example 2, Step A, substituting cyclobutanecarboxylic acid for benzoic acid, m/z (LC-MS) M+l = 219.2. [00337] Step B: 2-Cyclopropyl-3H-imidazo[4,5-b]pyridin-6-amine was prepared according to the general procedure in Example 3, Step B, substituting 2-cyclopropyl-6-nitro- 3H-imidazo[4,5-b]pyridine for N,N-dimethyl-4-(6-nitro-3H-imidazo[4,5-b]pyridin-2- yl)aniline. m/z (LC-MS) M+l =189.2.
[00338] Step C: N-(2-Cyclopropyl-3H-imidazo[4,5-b]pyridin-6-yl)-2,6-difluoro-3-
(propylsulfonamido)benzamide (79%) was prepared according to the general procedure in Example 1, Step E, substituting 2-cyclopropyl-3H-imidazo[4,5-b]pyridin-6-amine for 3H- imidazo[4,5-b]pyridin-6-amine. m/z (LC-MS) M+l = 450.4.
Example 35
Figure imgf000076_0002
2,6-difluoro-N-(2-(6-morpholinopyridin-3-yl)-3H-imidazo[4.5-b1pyridin-6-yl)-3-
(propylsulfonamido)benzamide [00339] Step A: 4-(5-(6-Nitro-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-yl)morpholine
(99%) was prepared according to the general procedure in Example 2, Step A, substituting 6- morpholinonicotinic acid for benzoic acid, m/z (LC-MS) M+l = 327.3. [00340] Step B: 2-(6-Moφholinopyridin-3-yl)-3H-imidazo[4,5-b]pyridin-6-amine was prepared according to the general procedure in Example 3, Step B, substituting 4-(5-(6-nitro- 3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-yl)morpholine for N,N-dimethyl-4-(6-nitro-3H- imidazo[4,5-b]pyridin-2-yl)aniline. m/z (LC-MS) M+l =297.3.
[00341] Step C: 2,6-Difluoro-N-(2-(6-morpholinopyridin-3-yl)-3H-imidazo[4,5- b]pyridin-6-yl)-3-(propylsulfonamido)benzamide (8%) was prepared according to the general procedure in Example 1, Step E, substituting 2-(6-morpholinopyridin-3-yl)-3H-imidazo[4,5- b]pyridin-6-amine for 3H-imidazo[4,5-b]pyridin-6-amine. m/z (LC-MS) M+l = 558.5.
Example 36
Figure imgf000077_0001
2,6-difluoro-N-('2-('4-morpholinophenyl)-3H-imidazo[4,5-blpyridin-6-yl)-3-
(propylsulfonamido)benzamide
[00342] Step A: 4-(4-(6-Nitro-3H-imidazo[4,5-b]pyridin-2-yl)phenyl)morpholine
(99%) was prepared according to the general procedure in Example 2, Step A, substituting 4- morpholinobenzoic acid for benzoic acid, m/z (LC-MS) M+l = 326.3. [00343] Step B: 2-(4-Moφholinophenyl)-3H-imidazo[4,5-b]pyridin-6-amine was prepared according to the general procedure in Example 3, Step B, substituting 4-(4-(6-nitro- 3H-imidazo[4,5-b]pyridin-2-yl)phenyl)morpholine for N,N-dimethyl-4-(6-nitro-3H- imidazo[4,5-b]pyridin-2-yl)aniline. m/z (LC-MS) M+l =296.3.
[00344] Step C: 2,6-Difluoro-N-(2-(4-morpholinophenyl)-3H-imidazo[4,5-b]pyridin-
6-yl)-3-(propylsulfonamido)benzamide (8%) was prepared according to the general procedure in Example 1, Step E, substituting 2-(4-morpholinophenyl)-3H-imidazo[4,5- b]pyridin-6-amine for 3H-imidazo[4,5-b]pyridin-6-amine. m/z (LC-MS) M+l = 557.5.
Example 37
Figure imgf000077_0002
N-(2-(4-chloro-3-(trifluoromethyl)phenyl)-3H-imidazo[4,5-blpyridin-6-yl)-2.6-difluoro-3-
(propylsulfonamido)benzamide
[00345] Step A: 2-(4-Chloro-3-(trifluoromethyl)phenyl)-6-nitro-3H-imidazo[4,5- b]pyridine (91%) was prepared according to the general procedure in Example 2, Step A, substituting 4-chloro-3-trifluoromethyl benzoic acid for benzoic acid, m/z (LC-MS) M+l = 343.6.
[00346] Step B: 2-(4-Chloro-3-(trifluoromethyl)phenyl)-3H-imidazo[4,5-b]pyridin-6- amine was prepared according to the general procedure in Example 3, Step B, substituting 2- (4-chloro-3-(trifluoromethyl)phenyl)-6-nitro-3H-imidazo[4,5-b]pyridine for N,N-dimethyl-4- (6-nitro-3H-imidazo[4,5-b]pyridin-2-yl)aniline. m/z (LC-MS) M+l =312.6. [00347] Step C: N-(2-(4-chloro-3-(trifluoromethyl)phenyl)-3H-imidazo[4,5-b]pyridin-
6-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (14%) was prepared according to the general procedure in Example 1, Step E, substituting 2-(4-chloro-3-(trifluoromethyl)phenyl)- 3H-imidazo[4,5-b]pyridin-6-amine for 3H-imidazo[4,5-b]pyridin-6-amine. m/z (LC-MS) M+l = 574.9.
Example 38
Figure imgf000078_0001
N-(2-(4-bromo-2-methylphenyl)-3H-imidazo[4,5-b1pyridin-6-yl)-2,6-difluoro-3-
(propylsulfonamidolbenzamide
[00348] Step A: 2-(4-Bromo-2-methylphenyl)-6-nitro-3H-imidazo[4,5-b]pyridine
(78%) was prepared according to the general procedure in Example 2, Step A, substituting 4- bromo-2 -methyl benzoic acid for benzoic acid, m/z (LC-MS) M+l = 334.1. [00349] Step B: 2-(4-Bromo-2-methylphenyl)-3H-imidazo[4,5-b]pyridin-6-amine was prepared according to the general procedure in Example 3, Step B, substituting 2-(4-bromo-2- methylphenyl)-6-nitro-3 H-imidazo [4,5 -b]pyridine for N,N-dimethyl-4-(6-nitro-3 H- imidazo[4,5-b]pyridin-2-yl)aniline. m/z (LC-MS) M+l =304.2.
[00350] Step C: N-(2-(4-Chloro-3-(trifluoromethyl)phenyl)-3H-imidazo[4,5- b]pyridin-6-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (21%) was prepared according to the general procedure in Example 1, Step E, substituting 2-(4-bromo-2-methylphenyl)-3H- imidazo[4,5-b]pyridin-6-amine for 3H-imidazo[4,5-b]pyridin-6-amine. m/z (LC-MS) M+l = 565.4. [00351] The following compounds in Table 1 were prepared following the above procedures.
Table 1
Figure imgf000079_0001
Figure imgf000080_0001
[00352] While the invention has been described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the present invention as defined by the claims. Thus, the foregoing description is considered as illustrative only of the principles of the invention.
[00353] The words "comprise," "comprising," "include," "including," and "includes" when used in this specification and in the following claims are intended to specify the presence of stated features, integers, components, or steps, but they do not preclude the presence or addition of one or more other features, integers, components, steps, or groups thereof.

Claims

What is claimed is:
1. A compound selected from Formula I:
Figure imgf000081_0001
and stereoisomers and pharmaceutically acceptable salts thereof, wherein:
R1 and R2 are independently selected from hydrogen, halogen, CN, C1-C3 alkyl, and C1-C3 alkoxy;
R3 is hydrogen, halogen or C1-C3 alkyl;
R4 is C3-C5 cycloalkyl, C1-C6 alkyl, C1-C6 alkenyl, or C1-C6 alkynyl, wherein the cycloalkyl, alkyl, alkenyl and alkynyl are optionally substituted with ORC, halogen or C3- C4 cycloalkyl;
R5 is hydrogen, phenyl optionally substituted with one to three Ra groups, -N(R0)- phenyl optionally substituted with Ra, -CH2-phenyl optionally substituted with one to three Rb groups, a 5-6 membered heteroaryl optionally substituted with one to three Re groups, saturated or partially unsaturated C3-C6 cycloalkyl optionally substituted with halogen or C1-C4 alkyl, a 5-6 membered heterocyclyl, or C1-C6 alkyl optionally substituted with one or more R8 groups; each Ra is independently selected from halogen, CN, a 5-6 membered heterocyclyl, NRcRd, -S(O)2Rf, -0(C1-C4 alkyl), and C1-C4 alkyl, wherein the alkyl or alkoxy are optionally substituted with halogen; each Rb is independently selected from halogen, OH or OCH3; each Rc and Rd are independently selected from hydrogen or C1-C4 alkyl; Re is selected from a 5-6 membered heterocyclyl or NRcRd; Rf is selected from C1-C4 alkyl or NRcRd; and each Rg is independently selected from halogen, CN, OR0, C3-C6 cycloalkyl or
NR°Rd
2. A compound of Claim 1, wherein:
R1, R2 and R3 are independently selected from H, halogen or C1-C3 alkyl; R4 is C3-C4 cycloalkyl, or C1-C6 alkyl optionally substituted with OH, halogen or C3-C4 cycloalkyl;
R5 is hydrogen, phenyl optionally substituted with one to three Ra groups, -NH- phenyl, -CH2-phenyl optionally substituted with one to three Rb groups, a 5-6 membered heteroaryl optionally substituted with one to three Re groups, C3-C6 cycloalkyl, a 5-6 membered heterocyclyl, or C1-C6 alkyl; each Ra is independently selected from halogen, CN, a 5-6 membered heterocyclyl, NRcRd, -S(O)2Rf, -0(C1-C4 alkyl), and C1-C4 alkyl, wherein the alkyl or alkoxy are optionally substituted with halogen; each Rb is independently selected from halogen, OH or OCH3; each Rc and Rd are independently selected from hydrogen or C1-C4 alkyl;
Re is selected from a 5-6 membered heterocyclyl or NRcRd; and
Rf is selected from C1-C4 alkyl or NRcRd.
3. A compound as claimed in any one of Claims 1 or 2, wherein R , R and R are independently selected from hydrogen, halogen or C1-C3 alkyl.
4. A compound as claimed in any one of Claims 1 to 3, wherein the residue:
Figure imgf000082_0001
of Formula I, wherein the wavy line represents the point of attachment of the residue in Formula I, is selected from:
Figure imgf000082_0002
Figure imgf000083_0001
5. A compound as claimed in any one of Claims 1 to 4, wherein R1 and R2 are
F and R3 is hydrogen.
6. A compound as claimed in any one of Claims 1 to 4, wherein R , R and R are F.
7. A compound as claimed in any one of Claims 1 to 4, wherein R1 is F and R2 is Cl and R3 is hydrogen.
8. A compound as claimed in any one of Claims 1 to 4, wherein R1 is Cl and R is F and R is hydrogen.
9. A compound as claimed in any one of Claims 1 to 4, wherein R1 is F and R is methyl and R is hydrogen.
10. A compound as claimed in any one of Claims 1 to 4, wherein R1 is methyl and R2 is F and R3 is hydrogen.
11. A compound as claimed in any one of Claims 1 to 4, wherein R1 is F and R and R are hydrogen.
12. A compound as claimed in any one of Claims 1 to 4, wherein R1 is Cl and R and R are hydrogen.
13. A compound as claimed in any one of Claims 1 to 4, wherein R is F and R and R3 are hydrogen.
14. A compound as claimed in any one of Claims 1 to 13, wherein R4 is propyl, butyl, isobutyl, -CH2CH2CH2F, -CH2CH2CF3 or cyclopropylmethyl.
15. A compound as claimed in any one of Claims 1 to 14, wherein R4 is propyl.
16. A compound as claimed in any one of Claims 1 to 13, wherein R is -CF3, -CH2CF3, -CH2CH2CH2F, -CH2CH2CF3, -CF2CF3 or -CF2CF2CF3.
17. A compound as claimed in any one of Claims 1 to 16, wherein R is hydrogen.
18. A compound as claimed in any one of Claims 1 to 16, wherein R5 is phenyl optionally substituted with one to three Ra groups.
19. A compound as claimed in any one of Claims 1 to 16, wherein R5 is -NH- phenyl.
20. A compound as claimed in any one of Claims 1 to 16, wherein R5 is -CH2- phenyl optionally substituted with one to three Rb groups.
21. A compound as claimed in any one of Claims 1 to 16, wherein R5 is a 5-6 membered heteroaryl optionally substituted with one to three Re groups.
22. A compound as claimed in any one of Claims 1 to 16, wherein R is saturated C3-C6 cycloalkyl.
23. A compound as claimed in any one of Claims 1 to 16, wherein R5 is a 5-6 membered heterocyclyl.
24. A compound as claimed in any one of Claims 1 to 16, wherein R5 is C1-C6 alkyl.
25. A compound as claimed in any one of Claims 1 or 16, wherein R5 is selected from hydrogen, phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3- fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-trifluoromethylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-cyanophenyl, 4-methylphenyl, 4- trifluoromethylphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 4- dimethylaminophenyl, 4-(methylsulfonyl)phenyl, 4-morpholinophenyl, 3,4- dichlorophenyl, 3-trifluoromethyl-4-methylphenyl, 3-trifluoromethyl-4-chlorophenyl, 2- methyl-4-bromophenyl, -NH-phenyl, -CH2-4-chlorophenyl, -CH2-3,5-difluorophenyl, -CH2-4-methoxyphenyl, -CH2-4-bromophenyl, -CH2-3,4-difluorophenyl, pyridin-3-yl, pyridin-4-yl, 6-morpholinopyridin-3-yl, 6-(dimethylamino)pyridin-3-yl, cyclobutyl, piperdin-3-yl, piperdin-4-yl, methyl, ethyl, isopropyl and tert-butyl.
26. A compound of Formula I as defined in Claim 1 and named in any one of Examples 1 to 42 herein.
27. A pharmaceutical composition, comprising a compound as claimed in any one of Claims 1 to 26, and a pharmaceutically acceptable carrier or excipient.
28. A method of preventing or treating a disease or disorder modulated by b- Raf, comprising administering to a mammal in need of such treatment an effective amount of a compound of any one of Claims 1 to 26.
29. A method of preventing or treating cancer, comprising administering to a mammal in need of such treatment an effective amount of a compound of any one of Claims 1 to 26, alone or in combination with one or more additional compounds having anti-cancer properties.
30. The method of Claim 29, wherein the cancer is a sarcoma.
31. The method of Claim 29, wherein the cancer is a carcinoma.
32. The method of Claim 31, wherein the carcinoma is squamous cell carcinoma.
33. The method of Claim 31, wherein the carcinoma is adenoma or adenocarcinoma.
34. The method of Claim 29, wherein the cancer is breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, NSCLC, small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney carcinoma, myeloid disorders, lymphoid disorders, hairy cells, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, colon- rectum, large intestine, rectum, brain and central nervous system, Hodgkin's and leukemia.
35. A method of treating a hyperproliferative disease in a mammal comprising administering a therapeutically effective amount of a compound of any one of Claims 1 to
26 to the mammal.
36. A compound as claimed in any one of Claims 1 to 26 for use in therapy.
37. A compound as claimed in any one of Claims 1 to 26 for use in the treatment of a hyperproliferative disease.
38. Use of a compound of any one of Claims 1 to 26 in the manufacture of a medicament for the treatment of a hyperproliferative disease.
39. Use of a compound as claimed in any one of Claims 1 to 26, in the manufacture of a medicament, for use as a b-Raf inhibitor in the treatment of a patient undergoing cancer therapy.
40. A method of preventing or treating kidney disease, comprising administering to a mammal in need of such treatment an effective amount of a compound of any one of Claims 1 to 26, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, alone or in combination with one or more additional compounds.
41. The method of Claim 40, wherein the kidney disease is polycystic kidney disease.
42. A compound of any one of Claims 1 to 26 for use in the treatment of a kidney disease.
43. The compound of Claim 42, wherein the kidney disease is polycystic kidney disease.
44. Use of a compound of any one of Claims 1 to 26 in the manufacture of a medicament for the treatment of a kidney disease.
45. The use of Claim 44, wherein the kidney disease is polycystic kidney disease.
46. A pharmaceutical composition comprising a compound as claimed in any one of Claims 1 to 26 for use in the treatment of a hyperproliferative disease.
47. A pharmaceutical composition comprising a compound as claimed in any one of Claims 1 to 26 for use in the treatment of cancer.
48. A pharmaceutical composition comprising a compound as claimed in any one of Claims 1 to 26 for use in the treatment of kidney disease.
49. The composition of Claim 48, wherein the kidney disease is polycystic kidney disease.
50. A compound selected from Formula III:
Figure imgf000087_0001
in wherein R20 is hydrogen, C1-C6 alkyl, benzyl or phenyl;
R1 and R2 are independently selected from hydrogen, halogen, CN, C1-C3 alkyl and C1-C3 alkoxy;
R3 is hydrogen, halogen or C1-C3 alkyl;
R4 is C3-C5 cycloalkyl, C1-C6 alkyl, C1-C6 alkenyl, or C1-C6 alkynyl, wherein the cycloalkyl, alkyl, alkenyl and alkynyl are optionally substituted with ORC, halogen or C3- C4 cycloalkyl; and Rc is hydrogen or C1-C4 alkyl.
51. A compound of Claim 50, wherein:
R1, R2 and R3 are independently selected from H, halogen or C1-C3 alkyl; and R4 is C3-C4 cycloalkyl, or C1-C6 alkyl optionally substituted with OH, halogen or C3-C4 cycloalkyl.
52. A process for preparing compounds of Formula I, comprising:
(a) coupling a compound of Formula 5 :
Figure imgf000087_0002
5 wherein R5 is hydrogen, phenyl optionally substituted with one to three Ra groups, -N(R0)- phenyl optionally substituted with Ra, -CH2-phenyl optionally substituted with one to three R groups, a 5-6 membered heteroaryl optionally substituted with one to three Re groups, saturated or partially unsaturated C3-C6 cycloalkyl optionally substituted with halogen or C1-C4 alkyl, a 5-6 membered heterocyclyl, or C1-C6 alkyl optionally substituted with one or more Rg groups; each Ra is independently selected from halogen, CN, a 5-6 membered heterocyclyl, NRcRd, -S(O)2Rf, -0(C1-C4 alkyl), and C1-C4 alkyl, wherein the alkyl or alkoxy are optionally substituted with halogen; each Rb is independently selected from halogen, OH or OCH3; each Rc and Rd are independently selected from hydrogen or C1-C4 alkyl; Re is selected from a 5-6 membered heterocyclyl or NRcRd; Rf is selected from C1- C4 alkyl or NRcRd; and each R8 is independently selected from halogen, CN, ORC, C3-C6 cycloalkyl or NRcRd; with a compound of Formula 6:
Figure imgf000088_0001
6 wherein R1 and R2 are independently selected from hydrogen, halogen, CN, C1-C3 alkyl, and C1-C3 alkoxy; R3 is hydrogen, halogen or C1-C3 alkyl; R4 is C3-C5 cycloalkyl, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the cycloalkyl, alkyl, alkenyl and alkynyl are optionally substituted with ORC, halogen or C3-C4 cycloalkyl; and Rc is hydrogen or C1-C4 alkyl; to provide a compound of Formula I:
Figure imgf000088_0002
(b) coupling a compound of Formula 5:
Figure imgf000088_0003
wherein R5 is hydrogen, phenyl optionally substituted with one to three Ra groups, -N(R0)- phenyl optionally substituted with Ra, -CH2-phenyl optionally substituted with one to three Rb groups, a 5-6 membered heteroaryl optionally substituted with one to three Re groups, saturated or partially unsaturated C3-C6 cycloalkyl optionally substituted with halogen or C1-C4 alkyl, a 5-6 membered heterocyclyl, or C1-C6 alkyl optionally substituted with one or more Rg groups; each Ra is independently selected from halogen, CN, a 5-6 membered heterocyclyl, NRcRd, -S(O)2Rf, -0(C1-C4 alkyl), and C1-C4 alkyl, wherein the alkyl or alkoxy are optionally substituted with halogen; each Rb is independently selected from halogen, OH or OCH3; each Rc and Rd are independently selected from hydrogen or C1-C4 alkyl; Re is selected from a 5-6 membered heterocyclyl or NRcRd; Rf is selected from C1- C4 alkyl or NRcRd; and each Rg is independently selected from halogen, CN, ORC, C3-C6 cycloalkyl or NRcRd; with a compound of Formula III:
Figure imgf000089_0001
III wherein R1 and R2 are independently selected from hydrogen, halogen, CN, C1-C3 alkyl, and C1-C3 alkoxy; R3 is hydrogen, halogen or C1-C3 alkyl; R4 is C3-C5 cycloalkyl, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the cycloalkyl, alkyl, alkenyl and alkynyl are optionally substituted with ORC, halogen or C3-C4 cycloalkyl; and Rc is hydrogen or C1-C4 alkyl; to provide a compound of Formula I:
Figure imgf000089_0002
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Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012118492A1 (en) * 2011-03-01 2012-09-07 Array Biopharma Inc. Heterocyclic sulfonamides as raf inhibitors
CN102659778A (en) * 2012-03-22 2012-09-12 盛世泰科生物医药技术(苏州)有限公司 Novel synthesis technology of 6-amino-2-methyl-3H-imidazo [4, 5-b] pyridine
CN102746241A (en) * 2012-07-02 2012-10-24 西安交通大学 2, 3, 5-trisubstituted benzamide compound, and preparation method and application thereof
WO2013043715A1 (en) 2011-09-19 2013-03-28 Genentech, Inc. Combination treatments comprising c-met antagonists and b-raf antagonists
US20140134133A1 (en) * 2012-11-14 2014-05-15 Sunshine Lake Pharma Co., Ltd. Heteroaromatic compounds as pi3 kinase modulators and methods of use
US8741920B2 (en) 2009-08-03 2014-06-03 Hoffmann-La Roche, Inc. Process for the manufacture of pharmaceutically active compounds
WO2014128235A1 (en) 2013-02-22 2014-08-28 F. Hoffmann-La Roche Ag Methods of treating cancer and preventing drug resistance
WO2014144850A1 (en) 2013-03-15 2014-09-18 Genentech, Inc. Methods of treating cancer and preventing cancer drug resistance
US9150570B2 (en) 2012-05-31 2015-10-06 Plexxikon Inc. Synthesis of heterocyclic compounds
US9169250B2 (en) 2006-11-22 2015-10-27 Plexxikon Inc. Compounds modulating c-fms and/or c-kit activity and uses therefor
WO2015191986A1 (en) 2014-06-13 2015-12-17 Genentech, Inc. Methods of treating and preventing cancer drug resistance
WO2016011160A1 (en) 2014-07-15 2016-01-21 Genentech, Inc. Compositions for treating cancer using pd-1 axis binding antagonists and mek inhibitors
US9447089B2 (en) 2009-04-03 2016-09-20 Plexxikon Inc. Compositions and uses thereof
US9624213B2 (en) 2011-02-07 2017-04-18 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
WO2017087851A1 (en) 2015-11-19 2017-05-26 Genentech, Inc. Methods of treating cancer using b-raf inhibitors and immune checkpoint inhibitors
US9844539B2 (en) 2007-07-17 2017-12-19 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
WO2018011138A1 (en) 2016-07-11 2018-01-18 Kancera Ab 2-phenylimidazo[4,5-b]pyridin-7-amine derivates useful as inhibitors of mammalian tyrosine kinase ror1 activity
WO2018146253A1 (en) 2017-02-10 2018-08-16 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for the treatment of cancers associated with activation of the mapk pathway
CN108602821A (en) * 2015-12-14 2018-09-28 齐尼思表观遗传学有限公司 1H- imidazos [4,5-B] pyridyl group and 2- oxos -2,3- dihydro -1H- imidazos [4,5-B] pyridinyl heterocycle BET bromine structural domain inhibitor
WO2019133810A1 (en) 2017-12-28 2019-07-04 Tract Pharmaceuticals, Inc. Stem cell culture systems for columnar epithelial stem cells, and uses related thereto
US10550113B2 (en) 2015-02-02 2020-02-04 Kancera Ab 2-phenyl-3H-imidazo[4,5-B]pyridine derivates useful as inhibitors of mammalian tyrosine kinase ROR1 activity
US10646567B2 (en) 2011-08-01 2020-05-12 Genentech, Inc. Methods of treating cancer using PD-1 axis binding antagonists and MEK inhibitors
WO2020188015A1 (en) 2019-03-21 2020-09-24 Onxeo A dbait molecule in combination with kinase inhibitor for the treatment of cancer
WO2021089791A1 (en) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for the treatment of cancers that have acquired resistance to kinase inhibitors
WO2021148581A1 (en) 2020-01-22 2021-07-29 Onxeo Novel dbait molecule and its use
US11087354B2 (en) 2012-08-17 2021-08-10 Genentech, Inc. Combination therapies
US11660303B2 (en) 2016-07-11 2023-05-30 Kancera Ab 2-phenylimidazo[4,5-b]pyridin-7-amine derivates useful as inhibitors of mammalian tyrosine kinase ROR1 activity
US12123019B2 (en) 2020-10-15 2024-10-22 Whitehead Institute For Biomedical Research Uses of kinase inhibitors for inducing and maintaining pluripotency

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2716949A1 (en) * 2008-02-29 2009-09-11 Array Biopharma Inc. N- (6-aminopyridin-3-yl) -3- (sulfonamido) benzamide derivatives as b-raf inhibitors for the treatment of cancer
AR072657A1 (en) * 2008-02-29 2010-09-15 Genentech Inc RAF INHIBITING COMPOUNDS AND METHODS FOR USE
PE20091561A1 (en) * 2008-02-29 2009-10-30 Array Biopharma Inc RAF INHIBITING COMPOUNDS AND METHODS FOR THEIR USE
WO2011057022A1 (en) 2009-11-06 2011-05-12 Plexxikon, Inc. Compounds and methods for kinase modulation, and indications therefor
TWI558702B (en) 2011-02-21 2016-11-21 普雷辛肯公司 Solid forms of a pharmaceutically active substance
MX2014000452A (en) * 2011-07-15 2014-03-21 Shionogi & Co Azabenzimidazole derivative having ampk-activating activity.
CN103772317B (en) * 2014-01-06 2016-04-06 西安山川医药科技有限公司 2-methoxyl group-3-replaces sulfonamido-5-(2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl) benzamide compound and preparation method thereof and purposes

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4328155A (en) * 1977-01-27 1982-05-04 Shionogi & Co., Ltd. Meta-sulfonamido-benzamides
WO2006040039A1 (en) * 2004-10-13 2006-04-20 Merck Patent Gmbh N,n'-dithenylurea derivatives used in the form of kinase inhibitors
WO2006042599A1 (en) * 2004-10-13 2006-04-27 Merck Patent Gmbh Phenylurea derivatives used as inhibitors of tyrosinkinase for treating tumors
WO2006066913A2 (en) * 2004-12-23 2006-06-29 F. Hoffmann-La Roche Ag Benzamide substituted imidazo- and pyrolo-pyridines as protein kinase inhibitors
WO2007017143A1 (en) * 2005-07-29 2007-02-15 F. Hoffmann-La Roche Ag Azabenzimidazole derivatives, their manufacture and use as anti-cancer agents
WO2009012283A1 (en) * 2007-07-17 2009-01-22 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor

Family Cites Families (67)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7928239B2 (en) * 1999-01-13 2011-04-19 Bayer Healthcare Llc Inhibition of RAF kinase using quinolyl, isoquinolyl or pyridyl ureas
CA2359244C (en) * 1999-01-13 2013-10-08 Bayer Corporation .omega.-carboxy aryl substituted diphenyl ureas as p38 kinase inhibitors
US8124630B2 (en) * 1999-01-13 2012-02-28 Bayer Healthcare Llc ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
EP1140840B1 (en) * 1999-01-13 2006-03-22 Bayer Pharmaceuticals Corp. -g(v)-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
ME00275B (en) * 1999-01-13 2011-02-10 Bayer Corp ?-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US7235576B1 (en) * 2001-01-12 2007-06-26 Bayer Pharmaceuticals Corporation Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US20030207914A1 (en) * 2001-04-20 2003-11-06 Bayer Corporation Inhibition of raf kinase using quinolyl, isoquinolyl or pyridyl ureas
US7071216B2 (en) * 2002-03-29 2006-07-04 Chiron Corporation Substituted benz-azoles and methods of their use as inhibitors of Raf kinase
US7135575B2 (en) * 2003-03-03 2006-11-14 Array Biopharma, Inc. P38 inhibitors and methods of use thereof
MXPA05013349A (en) * 2003-06-13 2006-03-09 Novartis Ag 2-aminopyrimidine derivatives as raf kinase inhibitors.
US7691870B2 (en) * 2003-07-11 2010-04-06 Merck Patent Gmbh Benzimidazole carboxamides as raf kinase inhibitors
ATE538787T1 (en) * 2003-07-11 2012-01-15 Merck Patent Gmbh BENZIMIDAZOLE DERIVATIVES AS RAF-KINASE INHIBITORS
DE10337942A1 (en) * 2003-08-18 2005-03-17 Merck Patent Gmbh aminobenzimidazole derivatives
DE10344223A1 (en) * 2003-09-24 2005-04-21 Merck Patent Gmbh New 2-anilino-1,3-benzoxazole derivatives, are inhibitors of kinases, especially tyrosine- or Raf-kinases, useful e.g. for treating solid tumors, angiogenesis, diabetic retinopathy, inflammation or psoriasis
JP4758349B2 (en) * 2003-10-08 2011-08-24 アイアールエム・リミテッド・ライアビリティ・カンパニー Compounds and compositions as protein kinase inhibitors
US7691866B2 (en) * 2003-10-16 2010-04-06 Novartis Vaccines And Diagnostics, Inc. 2,6-disubstituted quinazolines, quinoxalines, quinolines and isoquinolines and methods of their use as inhibitors of Raf kinase
ATE435015T1 (en) * 2003-10-16 2009-07-15 Novartis Vaccines & Diagnostic SUBSTITUTED BENZAZOLES AND THEIR USE AS RAF-KINASE INHIBITORS
EP1696920B8 (en) * 2003-12-19 2015-05-06 Plexxikon Inc. Compounds and methods for development of ret modulators
DE102004009238A1 (en) * 2004-02-26 2005-09-08 Merck Patent Gmbh New aryl amide compounds are kinase inhibitors useful for the treatment and/or prophylaxis of e.g. tumors, psoriasis, rheumatoid arthritis, contact dermatitis, inflammations, endometriosis, scar and benign prostatic hyperplasia
TW200616974A (en) * 2004-07-01 2006-06-01 Astrazeneca Ab Chemical compounds
BRPI0514691A (en) * 2004-08-31 2008-06-17 Astrazeneca Ab compound or a pharmaceutically acceptable salt thereof, process for preparing it, pharmaceutical composition, and use of a compound or pharmaceutically acceptable salt thereof
CN101010303A (en) * 2004-09-01 2007-08-01 阿斯利康(瑞典)有限公司 Quinazolinone derivatives and their use as B-RAF inhibitors
US20070054916A1 (en) * 2004-10-01 2007-03-08 Amgen Inc. Aryl nitrogen-containing bicyclic compounds and methods of use
AU2005293384A1 (en) * 2004-10-15 2006-04-20 Astrazeneca Ab Quinoxalines as B Raf inhibitors
GB0423554D0 (en) * 2004-10-22 2004-11-24 Cancer Rec Tech Ltd Therapeutic compounds
JP5197016B2 (en) * 2004-12-23 2013-05-15 デシファラ ファーマスーティカルズ， エルエルシー Enzyme modulators and therapy
WO2006079791A1 (en) * 2005-01-25 2006-08-03 Astrazeneca Ab Chemical compounds
US20090105250A1 (en) * 2005-01-26 2009-04-23 Irm Llc Compounds and compositions as protein kinase inhibitors
TW200639163A (en) * 2005-02-04 2006-11-16 Genentech Inc RAF inhibitor compounds and methods
BRPI0606281A2 (en) * 2005-03-17 2009-06-09 Novartis Ag organic compounds
RU2411242C2 (en) * 2005-05-13 2011-02-10 Айрм, Ллк. Compounds and compositions as proteinkinase inhibitors
NZ563444A (en) * 2005-05-17 2011-04-29 Plexxikon Inc Pyrrolo(2,3-b)pyridine derivatives as protein kinase inhibitors
EP1902056A2 (en) * 2005-05-20 2008-03-26 Array Biopharma, Inc. Raf inhibitor compounds and methods of use thereof
RU2008108898A (en) * 2005-08-09 2009-09-20 Айрм Ллк (Bm) COMPOUNDS AND COMPOSITIONS AS PROTEINKINASE INHIBITORS
WO2007027855A2 (en) * 2005-09-01 2007-03-08 Array Biopharma Inc. Raf inhibitor compounds and methods of use thereof
JP4908511B2 (en) * 2005-09-15 2012-04-04 エフ．ホフマン−ラ ロシュ アーゲー 4-Amino-thieno [3,2-c] pyridine-7-carboxylic acid derivative
WO2007056625A2 (en) * 2005-11-04 2007-05-18 Smithkline Beecham Corporation Thienopyridine b-raf kinase inhibitors
RU2008127486A (en) * 2005-12-08 2010-01-20 Милленниум Фармасьютикалз, Инк. (Us) BICYCLIC COMPOUNDS WITH INHIBITOR ACTIVITY AGAINST KINASE
EP1966159A2 (en) * 2005-12-22 2008-09-10 AstraZeneca AB Chemical compounds
TW200804349A (en) * 2005-12-23 2008-01-16 Kalypsys Inc Novel substituted pyrimidinyloxy ureas as inhibitors of protein kinases
WO2007076474A1 (en) * 2005-12-23 2007-07-05 Kalypsys, Inc. Novel substituted pyridinyloxy and pyrimidinyloxy amides useful as inhibitors of protein kinases
CN101415689A (en) * 2006-04-05 2009-04-22 阿斯利康(瑞典)有限公司 Substituted quinazolines with anti-cancer activity
WO2007113558A2 (en) * 2006-04-05 2007-10-11 Astrazeneca Ab Quinazolinone derivatives having b-raf inhibitory activity
US20090149484A1 (en) * 2006-04-18 2009-06-11 Astrazeneca Ab Quinazolin-4-one derivatives, process for their preparation and pharmaceutical compositions containing them
WO2008028617A1 (en) * 2006-09-06 2008-03-13 F. Hoffmann-La Roche Ag Heteroaryl derivatives as protein kinase inhibitors
US7897762B2 (en) * 2006-09-14 2011-03-01 Deciphera Pharmaceuticals, Llc Kinase inhibitors useful for the treatment of proliferative diseases
US8188113B2 (en) * 2006-09-14 2012-05-29 Deciphera Pharmaceuticals, Inc. Dihydropyridopyrimidinyl, dihydronaphthyidinyl and related compounds useful as kinase inhibitors for the treatment of proliferative diseases
MX2009003456A (en) * 2006-10-02 2009-04-14 Irm Llc Compounds and compositions as protein kinase inhibitors.
EP1914234A1 (en) * 2006-10-16 2008-04-23 GPC Biotech Inc. Pyrido[2,3-d]pyrimidines and their use as kinase inhibitors
WO2008079909A1 (en) * 2006-12-21 2008-07-03 Plexxikon, Inc. Pyrrolo [2,3-b] pyridines as kinase modulators
PE20121126A1 (en) * 2006-12-21 2012-08-24 Plexxikon Inc PIRROLO [2,3-B] PYRIDINES COMPOUNDS AS KINASE MODULATORS
US7872018B2 (en) * 2006-12-21 2011-01-18 Plexxikon, Inc. Compounds and methods for kinase modulation, and indications therefor
CN101707863A (en) * 2007-06-15 2010-05-12 Irm责任有限公司 protein kinase inhibitors and methods for using thereof
WO2008157575A1 (en) * 2007-06-21 2008-12-24 Irm Llc Protein kinase inhibitors and methods for using thereof
WO2009025358A1 (en) * 2007-08-23 2009-02-26 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
EP2184285B1 (en) * 2007-08-29 2015-11-04 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
CA2716949A1 (en) * 2008-02-29 2009-09-11 Array Biopharma Inc. N- (6-aminopyridin-3-yl) -3- (sulfonamido) benzamide derivatives as b-raf inhibitors for the treatment of cancer
AR072657A1 (en) * 2008-02-29 2010-09-15 Genentech Inc RAF INHIBITING COMPOUNDS AND METHODS FOR USE
PE20091561A1 (en) * 2008-02-29 2009-10-30 Array Biopharma Inc RAF INHIBITING COMPOUNDS AND METHODS FOR THEIR USE
HUE032873T2 (en) * 2008-03-17 2017-11-28 Ambit Biosciences Corp 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea as raf kinase modulator in the treatment of cancer diseases
GB0807609D0 (en) * 2008-04-25 2008-06-04 Cancer Rec Tech Ltd Therapeutic compounds and their use
UA103319C2 (en) * 2008-05-06 2013-10-10 Глаксосмитклайн Ллк Thiazole- and oxazole-benzene sulfonamide compounds
WO2009143018A2 (en) * 2008-05-19 2009-11-26 Plexxikon, Inc. Compounds and methods for kinase modulation, and indications therefor
PE20091846A1 (en) * 2008-05-19 2009-12-16 Plexxikon Inc PIRROLO [2,3-d] -PYRIMIDINE DERIVATIVES AS KINE MODULATORS
US8110576B2 (en) * 2008-06-10 2012-02-07 Plexxikon Inc. Substituted pyrrolo[2,3b]pyrazines and methods for treatment of raf protein kinase-mediated indications
CN102112478A (en) * 2008-06-10 2011-06-29 普莱希科公司 5H-pyrr0l0 [2, 3-B] pyrazine derivatives for kinase modulation, and indications therefor
KR101061599B1 (en) * 2008-12-05 2011-09-02 한국과학기술연구원 Novel indazole derivatives that are protein kinase inhibitors for the treatment of abnormal cell growth diseases, pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing the same as active ingredients

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4328155A (en) * 1977-01-27 1982-05-04 Shionogi & Co., Ltd. Meta-sulfonamido-benzamides
WO2006040039A1 (en) * 2004-10-13 2006-04-20 Merck Patent Gmbh N,n'-dithenylurea derivatives used in the form of kinase inhibitors
WO2006042599A1 (en) * 2004-10-13 2006-04-27 Merck Patent Gmbh Phenylurea derivatives used as inhibitors of tyrosinkinase for treating tumors
WO2006066913A2 (en) * 2004-12-23 2006-06-29 F. Hoffmann-La Roche Ag Benzamide substituted imidazo- and pyrolo-pyridines as protein kinase inhibitors
WO2007017143A1 (en) * 2005-07-29 2007-02-15 F. Hoffmann-La Roche Ag Azabenzimidazole derivatives, their manufacture and use as anti-cancer agents
WO2009012283A1 (en) * 2007-07-17 2009-01-22 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor

Cited By (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9169250B2 (en) 2006-11-22 2015-10-27 Plexxikon Inc. Compounds modulating c-fms and/or c-kit activity and uses therefor
US10426760B2 (en) 2007-07-17 2019-10-01 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9844539B2 (en) 2007-07-17 2017-12-19 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9663517B2 (en) 2009-04-03 2017-05-30 Plexxikon Inc. Compositions and uses thereof
US9447089B2 (en) 2009-04-03 2016-09-20 Plexxikon Inc. Compositions and uses thereof
US8741920B2 (en) 2009-08-03 2014-06-03 Hoffmann-La Roche, Inc. Process for the manufacture of pharmaceutically active compounds
US12076322B2 (en) 2011-02-07 2024-09-03 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US11337976B2 (en) 2011-02-07 2022-05-24 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9624213B2 (en) 2011-02-07 2017-04-18 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
WO2012118492A1 (en) * 2011-03-01 2012-09-07 Array Biopharma Inc. Heterocyclic sulfonamides as raf inhibitors
US10646567B2 (en) 2011-08-01 2020-05-12 Genentech, Inc. Methods of treating cancer using PD-1 axis binding antagonists and MEK inhibitors
WO2013043715A1 (en) 2011-09-19 2013-03-28 Genentech, Inc. Combination treatments comprising c-met antagonists and b-raf antagonists
CN102659778A (en) * 2012-03-22 2012-09-12 盛世泰科生物医药技术(苏州)有限公司 Novel synthesis technology of 6-amino-2-methyl-3H-imidazo [4, 5-b] pyridine
US9695169B2 (en) 2012-05-31 2017-07-04 Plexxikon Inc. Synthesis of heterocyclic compounds
US9150570B2 (en) 2012-05-31 2015-10-06 Plexxikon Inc. Synthesis of heterocyclic compounds
CN102746241A (en) * 2012-07-02 2012-10-24 西安交通大学 2, 3, 5-trisubstituted benzamide compound, and preparation method and application thereof
US11087354B2 (en) 2012-08-17 2021-08-10 Genentech, Inc. Combination therapies
US11783366B2 (en) 2012-08-17 2023-10-10 Genentech, Inc. Combination therapies
US20140134133A1 (en) * 2012-11-14 2014-05-15 Sunshine Lake Pharma Co., Ltd. Heteroaromatic compounds as pi3 kinase modulators and methods of use
US9926324B2 (en) * 2012-11-14 2018-03-27 Calitor Sciences, Llc Heteroaromatic compounds as PI3 kinase modulators and methods of use
WO2014128235A1 (en) 2013-02-22 2014-08-28 F. Hoffmann-La Roche Ag Methods of treating cancer and preventing drug resistance
WO2014144850A1 (en) 2013-03-15 2014-09-18 Genentech, Inc. Methods of treating cancer and preventing cancer drug resistance
WO2015191986A1 (en) 2014-06-13 2015-12-17 Genentech, Inc. Methods of treating and preventing cancer drug resistance
US10946093B2 (en) 2014-07-15 2021-03-16 Genentech, Inc. Methods of treating cancer using PD-1 axis binding antagonists and MEK inhibitors
EP3563870A1 (en) 2014-07-15 2019-11-06 F. Hoffmann-La Roche AG Methods of treating cancer using pd-1 axis binding antagonists and mek inhibitors
WO2016011160A1 (en) 2014-07-15 2016-01-21 Genentech, Inc. Compositions for treating cancer using pd-1 axis binding antagonists and mek inhibitors
US10550113B2 (en) 2015-02-02 2020-02-04 Kancera Ab 2-phenyl-3H-imidazo[4,5-B]pyridine derivates useful as inhibitors of mammalian tyrosine kinase ROR1 activity
WO2017087851A1 (en) 2015-11-19 2017-05-26 Genentech, Inc. Methods of treating cancer using b-raf inhibitors and immune checkpoint inhibitors
CN108602821A (en) * 2015-12-14 2018-09-28 齐尼思表观遗传学有限公司 1H- imidazos [4,5-B] pyridyl group and 2- oxos -2,3- dihydro -1H- imidazos [4,5-B] pyridinyl heterocycle BET bromine structural domain inhibitor
CN108602821B (en) * 2015-12-14 2021-06-29 恒元生物医药科技(苏州)有限公司 1H-imidazo [4,5-B ] pyridinyl BET bromodomain inhibitors
WO2018011138A1 (en) 2016-07-11 2018-01-18 Kancera Ab 2-phenylimidazo[4,5-b]pyridin-7-amine derivates useful as inhibitors of mammalian tyrosine kinase ror1 activity
US11008318B2 (en) 2016-07-11 2021-05-18 Kancera Ab 2-phenylimidazo[4,5-b]pyridin-7-amine derivates useful as inhibitors of mammalian tyrosine kinase ROR1 activity
US11660303B2 (en) 2016-07-11 2023-05-30 Kancera Ab 2-phenylimidazo[4,5-b]pyridin-7-amine derivates useful as inhibitors of mammalian tyrosine kinase ROR1 activity
WO2018146253A1 (en) 2017-02-10 2018-08-16 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for the treatment of cancers associated with activation of the mapk pathway
WO2019133810A1 (en) 2017-12-28 2019-07-04 Tract Pharmaceuticals, Inc. Stem cell culture systems for columnar epithelial stem cells, and uses related thereto
WO2020188015A1 (en) 2019-03-21 2020-09-24 Onxeo A dbait molecule in combination with kinase inhibitor for the treatment of cancer
WO2021089791A1 (en) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for the treatment of cancers that have acquired resistance to kinase inhibitors
WO2021148581A1 (en) 2020-01-22 2021-07-29 Onxeo Novel dbait molecule and its use
US12123019B2 (en) 2020-10-15 2024-10-22 Whitehead Institute For Biomedical Research Uses of kinase inhibitors for inducing and maintaining pluripotency

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