WO2006026306A1 - Pyrimidinylimidazoles utilises comme inhibiteurs de tgf-beta - Google Patents

Pyrimidinylimidazoles utilises comme inhibiteurs de tgf-beta Download PDF

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WO2006026306A1
WO2006026306A1 PCT/US2005/030133 US2005030133W WO2006026306A1 WO 2006026306 A1 WO2006026306 A1 WO 2006026306A1 US 2005030133 W US2005030133 W US 2005030133W WO 2006026306 A1 WO2006026306 A1 WO 2006026306A1
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bicyclo
imidazol
pyrimidin
compound
alkyl
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PCT/US2005/030133
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Wen-Cherng Lee
Lihong Sun
Claudio Chuaqui
Juswinder Singh
Feng Shan
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Biogen Idec Ma Inc.
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Application filed by Biogen Idec Ma Inc. filed Critical Biogen Idec Ma Inc.
Priority to AU2005280168A priority Critical patent/AU2005280168A1/en
Priority to JP2007530093A priority patent/JP2008511631A/ja
Priority to CA002578630A priority patent/CA2578630A1/fr
Priority to EP05789340A priority patent/EP1786802A1/fr
Publication of WO2006026306A1 publication Critical patent/WO2006026306A1/fr

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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
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • TGF/3 Transforming Growth Factor /3 is a member of a large family of dimeric polypeptide growth factors that includes, for example, activins, inhibins, bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs) and mullerian inhibiting substance (MIS).
  • BMPs bone morphogenetic proteins
  • GDFs growth and differentiation factors
  • MIS mullerian inhibiting substance
  • TGF/3 exists in three isoforms (TGF/31, TGF/32, and TGF/33) and is present in most cells, along with its receptors. Each isoform is expressed in both a tissue-specific and developmentally regulated fashion.
  • Each TGF/3 isoform is synthesized as a precursor protein that is cleaved intracellularly into a C-terminal region (latency associated peptide (LAP)) and an N-terminal region known as mature or active TGF/3.
  • LAP latency associated peptide
  • LAP is typically non-covalently associated with mature TGF/3 prior to secretion from the cell.
  • the LAP-TGF/3 complex cannot bind to the TGF ' ⁇ receptors and is not biologically active.
  • TGF ⁇ is generally released (and activated) from the complex by a variety of mechanisms including, for example, interaction with thrombospondin-1 or plasmin.
  • TGF/3 binds at high affinity to the type II receptor (TGF/3RII), a constitutively active serine/threonine kinase.
  • TGF/3RII type II receptor
  • the ligand-bound type II receptor phosphorylates the TGF/3 type I receptor (AIk 5) in a glycine/serine rich domain, which allows the type I receptor to recruit and phosphorylate downstream signaling molecules, Smad2 or Smad3.
  • TGF/3RII type II receptor
  • AIk5 TGF/3 type I receptor
  • Phosphorylated Smad2 or Smad3 can then complex with Smad4, and the entire hetero-Smad complex translocates to the nucleus and regulates transcription of various TGF/3-responsive genes. See, e.g., Massague, J. Ann. Rev .Biochem. Med. 67: 773 (1998).
  • Activins are also members of the TGF/3 superfamily, which are distinct from TGF/3 in that they are homo- or heterodimers of activin /3a or /3b. Activins signal in a manner similar to TGF/3 , that is, by binding to a constitutive serine-threonine receptor kinase, activin type II receptor (ActRIIB), and activating a type I serine-threonine receptor, AIk 4, to phosphorylate Smad2 or Smad3. The consequent formation of a hetero-Smad complex with Smad4 also results in the activin-induced regulation of gene transcription.
  • Pathol. 148 707- 713 (1996); De Bleser et al., Hepatology 26: 905-912 (1997); Pawlowski, J.E., et al., J. Clin. Invest. 100: 639-648 (1997); Sugiyama, M. et al., Gastroenterology 114: 550-558 (1998); Munz, B. et al., EMBOJ. 18: 5205-5215 (1999)), inflammatory responses (see, e.g., Rosendahl, A. et al., Am. J. Repir. Cell MoI. Biol. 25: 60-68 (2001)), cachexia or wasting (see Matzuk, M. M.
  • TGF ⁇ and activin can act synergistically to induce extracellular matrix production (see, e.g., Sugiyama, M. et al., Gastroenterology 114: 550-558, (1998)). It is therefore desirable to develop modulators (e.g., antagonists) to members of the TGFjS family to prevent and/or treat disorders involving this signaling pathway.
  • modulators e.g., antagonists
  • the invention is based on the discovery that compounds of formula (I) are unexpectedly potent antagonists of the TGF ⁇ family type I receptors, Alk5 and/or AIk 4.
  • compounds of formula (I) can be employed in the prevention and/or treatment of diseases such as fibrosis (e.g., renal fibrosis, pulmonary fibrosis, and hepatic fibrosis), progressive cancers, or other diseases for which reduction of TGFjS family signaling activity is desirable.
  • fibrosis e.g., renal fibrosis, pulmonary fibrosis, and hepatic fibrosis
  • progressive cancers e.g., hepatic fibrosis
  • Each R a can be alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, oxo, thioxo, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulf
  • X can be cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or a bond.
  • Y can be a bond, -C(O)-, -C(O)-O-, -O-C(O)-, -S(O) P -O-, -O-S(O) P -, -C(O)-N(R b )-, -N(R b )-C(O)-, -O-C(O)-N(R b )-, -N(R b )-C(O)-O-, -C(O)-N(R b )-O-, -O-N(R b )-C(O)-, -O-S(O) p -N(R b )-, -N(R b )-S(O) p -N(R b )-, -N(R b )
  • R 2 can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, aralkyl, arylalkenyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heterocycloalkenyl, (heterocycloalkenyl)alkyl, heteroaryl, heteroaralkyl, or (heteroaryl)alkenyl.
  • Each of A 1 and A 2 independently, can be N or NR b .
  • a 1 is NR b
  • a 2 is N, and vice versa.
  • the variable, m can be 0, 1, 2, or 3.
  • the pyrimidinyl ring cari be unsubstituted or substituted with 1-3 R a groups. Note that when m >2, two adjacent R a groups can join together to form a 4- to 8-membered optionally substituted cyclic moiety.
  • R 2 can be hydrogen, Ci -6 alkyl, aryl, heteroaryl, aryl-Ci ⁇ alkyl, or heteroaryl-C ⁇ alkyl.
  • X can be a 4- to 8-membered monocyclic cycloalkyl or heterocycloalkyl, or X can be a 4- to 8-membered bicyclic cycloalkyl or heterocycloalkyl.
  • X can be piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuran, cyclohexyl, cyclopentyl, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.1]octane, 2-oxa-bicyclo[2.2.2]octane, 2-aza-bicyclo[2.2.2]octane, 3-aza-bicyclo[3.2.1]octane, or 1 -aza-bicyclo[2.2.2]octane.
  • Y can be -N(R b )-C(0)-, -N(R b )-S(O) 2 -, -C(O)-, -C(O)-O-, -0-C(O)-, -C(O)-N(R b )-, -S(OV, -O-, -S(O) 2 -N(R b )-, - N(R b )-, -N(R b )-C(O)-O-, -C(O)-N(R b )-O-, -N(R b )-C(0)-N(R c )-, -C(O)-N(R b )-S(O) p -N(R c )-, or -C(O)-O-S(O) p -N(R b )-.
  • X and Y are each a bond;
  • R 2 can be hydrogen or C 1-6 alkyl (e.g., Ci -4 alkyl such as methyl or t-butyl);
  • m can be 1 or 2 (e.g., m can be 1);
  • at least one R a is substituted at the 2-pyrimidinyl position and this R a can be Ci -4 alkyl, C 3-6 cycloalkyl, or amino (e.g, -CH 3 , - CF 3 , cyclopropyl, -NH 2 , -NH-C 1-4 alkyl, or -NH-cycloalkyl such as -NH-cyclopropyl).
  • m can be 0-2.
  • R a can be substituted at the 2-pyrimidinyl position.
  • R a can be C 1-4 alkyl, C 1-4 alkoxy, Ci -4 alkylthio, halo, amino, aminocarbonyl, or alkoxycarbonyl.
  • a 1 can be N and A 2 is NR b , or A 1 is NR b and A 2 is N; wherein R b is hydrogen or Ci -4 alkyl.
  • m can be 0-2;
  • R 1 can be heteroaryl;
  • R 2 can be hydrogen, C 1 ⁇ alkyl, aryl, heteroaryl, -Ci -4 alkyl-aryl, Or -Ci -4 alkyl-heteroaryl;
  • X can be a 4- to 8-membered monocyclic or bicyclic cycloalkyl or heterocycloalkyl; and
  • Y can be -N(R b )-C(O)-,
  • m can be 0-2;
  • R 1 can be heteroaryl;
  • R 2 can be hydrogen, Ci -6 alkyl, aryl, heteroaryl, -Ci -4 alkyl-aryl, or -Ci -4 alkyl-heteroaryl;
  • X can be piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuran, cyclohexyl, cyclopentyl, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.1]octane, 2-oxa-bicyclo[2.2.2]octane,
  • Y can be -N(R b )-C(O)-, -N(R b )-S(O) 2 -, -C(O)-, -C(O)-O-, -0-C(O)-, -C(O)-N(R b )-, -S(O) P -, -O-,
  • m can be 0-2;
  • R 1 can be heteroaryl;
  • R 2 can be hydrogen, Ci -6 alkyl, aryl, heteroaryl, -Ci -4 alkyl-aryl, Or -Ci -4 alkyl-heteroaryl; and
  • -X-Y- can be
  • a 1 can be N and A 2 can be NH.
  • a 1 can be NH and A 2 can be N.
  • R 2 can be hydrogen, Ci -4 alkyl, benzyl, or pyridylmethyl; m can be 1 and R a can be substituted at the 2-pyrimidinyl position.
  • m can be 0-2;
  • R 1 can be heteroaryl;
  • R 2 can be hydrogen, Ci -6 alkyl, aryl, heteroaryl, aryl-Ci ⁇ alkyl, or heteroaryl-C M alkyl;
  • X can be cyclohexyl, cyclopentyl, or bicyclo[2.2.2]octane;
  • Y can be -N(R b )-C(0)-, -N(R b )-S(O) 2 -, -C(O)-, -C(O)-O-, -0-C(O)-,
  • R b and R c independently, can be hydrogen or Ci -4 alkyl.
  • a 1 can be N and A 2 can be NH, or alternatively, A 1 can be NH and A 2 can be N.
  • R 2 can be hydrogen, Ci -4 alkyl, benzyl, or pyridylmethyl; m can be 1 and R a can be substituted at the 2-pyrimindyl position.
  • X and Y can each be a bond;
  • R 2 can be hydrogen or Ci -4 alkyl;
  • m can be 1;
  • R a can be -CH 3 , -CF 3 , cyclopropyl, -NH 2 , -NH-Ci -4 alkyl, or -NH-cycloalkyl;
  • R 1 can be benzo[l,3]dioxolyl, benzo[6]thiophenyl, benzooxadiazolyl, benzothiadiazolyl, benzoimidazolyl, benzooxazolyl, benzothiazolyl, 2-oxo-benzooxazolyl, pyridyl, pyrimidinyl,
  • a method of inhibiting the TGF/3 signaling pathway in a subject includes administering to said subject an effective amount of a compound of formula (I).
  • a method of reducing the accumulation of excess extracellular matrix induced by TGF/3 in a subject includes administering to said subject an effective amount of a compound of formula (I).
  • a method of treating a disease or disorder mediated by an overexpression of TGF ⁇ includes administering to a subject in need of such treatment an effective amount of a compound of formula (I).
  • the disease or disorder can be, for example, demyelination of neurons in multiple sclerosis, Alzheimer's disease, cerebral angiopathy, squamous cell carcinomas, multiple myeloma, melanoma, glioma, glioblastomas, leukemia, sarcomas, leiomyomas, mesothelioma, or carcinomas of the lung, breast, ovary, cervix, liver, biliary tract, gastrointestinal tract, pancreas, prostate, and head and neck.
  • the present invention also features a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) (or a combination of two or more compounds of formula (I)) and at least one pharmaceutically acceptable carrier.
  • a medicament composition including any of the compounds of formula (I), alone or in a combination, together with a suitable excipient.
  • the invention also features a method of inhibiting the TGF/3 family type I receptors, AIk 5 and/or AIk 4 (e.g., with an IC 50 value of less than 10 ⁇ M; such as, less than 1 ⁇ M; and for example, less than 5 nM) in a cell, including the step of contacting the cell with an effective amount of one or more compounds of formula (I). Also within the scope of the invention is a method of inihibiting the TGF/3 and/or activin signaling pathway in a cell or in a subject (e.g., a mammal such as a human), including the step of contacting the cell with or administering to the subject an effective amount of one or more of the compounds of formula (I).
  • a subject e.g., a mammal such as a human
  • Also within the scope of the present invention is a method of treating a subject or preventing a subject from suffering a condition characterized by or resulted from an elevated level of TGF/3 and/or activin activity.
  • the method includes the step of administering to the subject an effective amount of one or more of a compound of formula (I).
  • the conditions include an accumulation of excess extracellular matrix; a fibrotic condition (which can be induced by drug or radiation), e.g., scleroderma, lupus nephritis, connective tissue disease, wound healing, surgical scarring, spinal cord injury, CNS scarring, acute lung injury, pulmonary fibrosis (such as idiopathic pulmonary fibrosis and radiation-induced pulmonary fibrosis), chronic obstructive pulmonary disease, adult respiratory distress syndrome, acute lung injury, drug-induced lung injury, glomerulonephritis, diabetic nephropathy, hypertension-induced nephropathy, alimentary track or gastrointestinal fibrosis, renal fibrosis, hepatic or biliary fibrosis, liver cirrhosis, primary biliary cirrhosis, cirrhosis due to fatty liver disease (alcoholic and nonalcoholic steatosis), primary sclerosing cholangitis, restenosis, cardiac fibrosis
  • an "alkyl” group refers to a saturated aliphatic hydrocarbon group containing 1-8 (e.g., 1-6 or 1-4) carbon atoms.
  • An alkyl group can be straight or branched. Examples of an alkyl group include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, and 2-ethylhexyl.
  • An alkyl group can be optionally substituted with one or more substituents such as alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, amino, nitro, carboxy, cyano, halo, hydroxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, cycloalkyl-alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, heterocycloalkyl-carbonylamino, heterocycloalkyl- alkylcarbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, urea, thiourea, sulfamoyl,
  • An alkenyl group can be optionally substituted with one or more substituents such as alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, amino, nitro, carboxy, cyano, halo, hydroxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, cycloalkyl-alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, heterocycloalkyl-carbonylamino, heterocycloalkyl-alkylcarbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, urea, thiourea, sulfamoyl,
  • an "alkynyl” group refers to an aliphatic carbon group that contains 2-8 (e.g., 2-6 or 2-4) carbon atoms and has at least one triple bond.
  • An alkynyl group can be straight or branched. Examples of an alkynyl group include, but are not limited to, propargyl and butynyl.
  • An alkynyl group can be optionally substituted with one or more substituents such as alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, amino, nitro, carboxy, cyano, halo, hydroxy, sulfo, mercapto, alkylsulfanyl, alkylsulfmyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, cycloalkyl-alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, heterocycloalkyl- carbonylamino, heterocycloalkyl-alkylcarbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, urea, thiourea, sulfamoyl,
  • an “amino” group refers to -NR X R Y wherein each of R x and R ⁇ is independently hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heteroaryl, or heteroaralkyl.
  • R x has the same meaning as defined above.
  • an "aryl” group refers to phenyl, naphthyl, or a benzofused group having 2 to 3 rings.
  • a benzofused group includes phenyl fused with one or two C 4-8 carbocyclic moieties, e.g., 1, 2, 3, 4-tetrahydronaphthyl, indanyl, or fluorenyl.
  • An aryl is optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, amino, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkyl)alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloal
  • an "aralkyl” group refers to an alkyl group (e.g., a C 1-4 alkyl group) that is substituted with an aryl group. Both “alkyl” and “aryl” have been defined above. An example of an aralkyl group is benzyl.
  • a "cycloalkyl” group refers to an aliphatic carbocyclic ring of 3-10 (e.g., 4-8) carbon atoms.
  • Examples of cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, cubyl, octahydro-indenyl, decahydro-naphthyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, and bicyclo[3.2.3]nonyl.
  • a "cycloalkenyl” group refers to a non-aromatic carbocyclic ring of 3-10 (e.g., 4- 8) carbon atoms having one or more double bond.
  • Examples of cycloalkenyl groups include cyclopentenyl, 1,4-cyclohexa-di-enyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, bicyclo[2.2.2]octenyl, and bicyclo[3.3.1]nonenyl.
  • a cycloalkyl or cycloalkenyl group can be optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, amino, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkyl)alkylcarbonylamino, arylcarbonylamino, aralkyl
  • heterocycloalkyl refers to a 3- to 10-membered (e.g., 4- to 8- membered) saturated ring structure, in which one or more of the ring atoms is a heteroatom, e.g., N, O, or S.
  • heterocycloalkyl group examples include piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrofuryl, dioxolanyl, oxazolidinyl, isooxazolidinyl, morpholinyl, octahydro-benzofuryl, octahydro-chromenyl, octahydro-thiochromenyl, octahydro-indolyl, octahydro-pyrindinyl, decahydro-quinolinyl, octahydro-benzo[Z>]thiophenyl, 2-oxa- bicyclo[2.2.2]octyl, l-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, anad 2,6-dioxa- tricyclo[3.3.1.0 3 ' 7 ]non
  • heterocycloalkenyl group refers to a 3- to 10- membered (e.g., 4- to 8-membered) non-aromatic ring structure having one or more double bonds, and wherein one or more of the ring atoms is a heteroatom, e.g., N, O, or S.
  • heteroaryl examples include pyridyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, tetrazolyl, benzofuryl, benzthiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole, and benzo[l,3]dioxole.
  • heterocycloalkyl alkyl
  • aryl, heteroaryl alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, amino, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkyl)alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkyl)alkylcarbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea,
  • cyclic moiety includes cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl, each of which has been defined previously.
  • a "carbamoyl” group refers to a group having the structure -O-CO-
  • NR x R y or -NR X -CO-O-R Z wherein R x and R y have been defined above and R z can be alkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroaralkyl.
  • Body surface area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, New York, 537 (1970).
  • patient refers to a mammal, including a human.
  • An antagonist as used herein, is a molecule that binds to the receptor without activating the receptor. It competes with the endogenous ligand(s) or substrate(s) for binding site(s) on the receptor and, thus inhibits the ability of the receptor to transduce an intracellular signal in response to endogenous ligand binding.
  • fibrotic conditions for which preventive treatment with compounds of formula (I) can have therapeutic utility include radiation-induced fibrosis, chemotherapy- induced fibrosis, and surgically-induced scarring including surgical adhesions, laminectomy, and coronary restenosis.
  • Triethylphosphite (0.343 uL, 2.0 mmol) was added to a solution of 4-[l-hydroxy-4-(2- methyl-pyrimidin-4-yl)-5-[l,2,4]triazolo[l,5-a]pyridin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester (0.40 g, 0.87 mmol; see Example 1 above) in DMF (10 mL). The mixture was heated at 110 0 C for 18 hours. The solvent was removed. The residue was portioned between ethyl acetate and brine.
  • HATU (0.265 g, 0.70 mmol) was added to a solution of 4-[4-(2-methyl-pyrimidin-4-yl)- 5-[l ,2,4]triazolo[l ,5-a]pyridin-6-yl-lH-imidazol-2-yl]-bicyclo[2.2.2]octane-l-carboxylic acid (0.150 g, 0.35 mmol) and potassium carbonate (0.1242 g, 1.75 mmol) in DMF (5 mL). The mixture was stirred for 10 minutes. NH 3 was bubbled into the reaction mixture for 10 minutes. The mixture was stirre for an additional 2 hours. The mixture was filtered, and DMF was removed under reduced pressure.
  • 1,2-dione 2-oxime (0.6 g, 2.1 mmol) and ammonium acetate (3.1 g, 40 mmol) in acetic acid (30 mL). The mixture was reflux for 2 hours. Solvent was removed under reduced pressure.
  • Lithium hydroxide monohydrate (0.10 g, 2.44 mmol) was added to 4-[5-(2- Cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester (0.28 g, 0.61 mmol) in a mixture of THFMeOHTH 2 O (2/1/1, 5 mL). The mixture was stirred for 3 h. Solvent was removed. Residue was diluted with water (30 mL). Citric acid was added to the solution to make the pH lower than 7.
  • HATU (0.17 g, 0.45 mmol) was added to a solution of 4-[5-(2-Cyclopropylamino- pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-bicyclo[2.2.2]octane-l-carboxylic acid (0.10 g, 0.225 mmol; see Example 10 above) and potassium carbonate (0.155 g, 1.13 mmol) in anhydrous DMF (5 mL). The mixture was stirred for 30 minutes. Ammonia was bubbled through the mixture for 10 minutes. The mixture was continued to stir for 2 hours. The mixture was then filtered and concentrated.
  • TGF/3 inhibitory activity of compounds of formula (I) can be assessed by methods described in the following examples.
  • the serine-threonine kinase activity of TGFjS type I receptor was measured as the autophosphorylation activity of the cytoplasmic domain of the receptor containing an N-terminal poly histidine, TEV cleavage site-tag, e.g., His-TGF/3RI.
  • the His-tagged receptor cytoplasmic kinase domains were purified from infected insect cell cultures using the Gibco-BRL FastBac
  • TopCount Packard. Total binding (no inhibition) was defined as counts measured in the presence of DMSO solution containing no test compound and non-specific binding was defined as counts measured in the presence of EDTA or no-kinase control.
  • Compounds of formula (I) typically exhibited IC 50 values of less than 10 ⁇ M; some exhibited IC 50 values of less than 1 ⁇ M; and some even exhibited IC50 values of less than 50 nM.
  • His-TGFjS Type I receptor in the same assay buffer Hepes, NaCl 2 , MgCl 2 , MnCl 2 , DTT, and 30% Brij ® added fresh
  • Biological activity of the compounds of formula (I) was determined by measuring their ability to inhibit TGF/3-induced PAI-Luciferase reporter activity in HepG2 cells.
  • HepG2 cells were stably transfected with the PAI-luciferase reporter grown in DMEM medium containing 10% FBS, penicillin (100 U/mL), streptomycin (100 ⁇ g/mL), L-glutamine (2 mM), sodium pyruvate (1 mM), and non-essential amino acids (Ix).
  • the transfected cells were then plated at a concentration of 2.5 x 10 4 cells/well in 96 well plates and starved for 3-6 hours in media with 0.5% FBS at 37 0 C in a 5% CO 2 incubator.
  • the cells were then stimulated with 2.5 ng/mL TGF/3 ligand in the starvation media containing 1% DMSO either in the presence or absence of a test compound of formula (I) and incubated as described above for 24 hours.
  • the media was washed out the following day and the luciferase reporter activity was detected using the LucLite Luciferase Reporter Gene Assay kit (Packard, cat. no. 6016911) as recommended.
  • the plates were read on a Wallac Microbeta plate reader, the reading of which was used to determine the IC 50 values of " compounds of formula (I) for inhibiting TGF/3-induced
  • test compounds of formula (I) The cellular inhibition of activin signaling activity by the test compounds of formula (I) is determined in a similar manner as described above in Example 37 except that 100 ng/mL of activin is added to serum starved cells in place of the 2.5 ng/mL TGF/3.
  • Fibroblasts are derived from the skin of adult transgenic mice expressing Green
  • GFP Fluorescent Protein
  • Cells are thawed, plated in complete DMEM (contains non-essential amino acids, ImM sodium pyruvate and 2mM L-glutamine) with 10 % fetal calf serum, and then incubated for overnight at 37 0 C, 5% CO 2 . The cells are trypsinized in the following day and transferred into complete DMEM (contains non-essential amino acids, ImM sodium pyruvate and 2mM L-glutamine) with 10 % fetal calf serum, and then incubated for overnight at 37 0 C, 5% CO 2 . The cells are trypsinized in the following day and transferred into complete DMEM (contains non-essential amino acids, ImM sodium pyruvate and 2mM L-glutamine) with 10 % fetal calf serum, and then incubated for overnight at 37 0 C, 5% CO 2 . The cells are trypsinized in the following day and transferred into complete DMEM (

Abstract

Les composés représentés par la formule (I) possèdent de manière inattendue une haute affinité pour Alk 5 et/ou pour Alk 4 et peuvent convenir comme antagonistes de ceux-ci pour prévenir et/ou traiter de nombreuses maladies, notamment des troubles fibrotiques. Cette invention concerne les composés représentés par la formule (I) et des utilisations de ceux-ci.
PCT/US2005/030133 2004-08-31 2005-08-24 Pyrimidinylimidazoles utilises comme inhibiteurs de tgf-beta WO2006026306A1 (fr)

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WO2008134693A1 (fr) * 2007-04-30 2008-11-06 Abbott Laboratories Inhibiteurs d'enzyme diacylglycérol o-acyltransférase de type 1
WO2009087224A1 (fr) * 2008-01-11 2009-07-16 Novartis Ag Pyrimidines utilisés en tant qu'inhibiteurs de kinase
WO2013014262A1 (fr) 2011-07-27 2013-01-31 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes de diagnostic et de traitement du syndrome de myhre
WO2012167261A3 (fr) * 2011-06-03 2013-05-16 Yale University Compositions et méthodes de traitement et de prévention d'une sténose néointimale
US8642034B2 (en) 2006-10-03 2014-02-04 Genzyme Corporation Use of TGF-β antagonists to treat infants at risk of developing bronchopulmonary dysplasia
US8865732B2 (en) 2008-03-21 2014-10-21 Novartis Ag Heterocyclic compounds and uses thereof
US9242969B2 (en) 2013-03-14 2016-01-26 Novartis Ag Biaryl amide compounds as kinase inhibitors
US9468612B2 (en) 2011-10-26 2016-10-18 Seattle Children's Hospital Cysteamine in the treatment of fibrotic disease
US9573969B2 (en) 2014-09-12 2017-02-21 Novartis Ag Compounds and compositions as kinase inhibitors
US10752594B2 (en) 2013-03-14 2020-08-25 Sumitomo Dainippon Pharma Oncology, Inc. JAK1 and ALK2 inhibitors and methods for their use
WO2020201362A2 (fr) 2019-04-02 2020-10-08 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes de prédiction et de prévention du cancer chez des patients ayant des lésions prémalignes
US11040038B2 (en) 2018-07-26 2021-06-22 Sumitomo Dainippon Pharma Oncology, Inc. Methods for treating diseases associated with abnormal ACVR1 expression and ACVR1 inhibitors for use in the same
US11541149B2 (en) 2015-12-11 2023-01-03 Research Institute At Nationwide Children's Hospital Systems and methods for optimized patient specific tissue engineering vascular grafts

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WO2006044509A2 (fr) * 2004-10-15 2006-04-27 Biogen Idec Ma Inc. Procede pour traiter des lesions vasculaires
WO2006044509A3 (fr) * 2004-10-15 2006-08-17 Biogen Idec Inc Procede pour traiter des lesions vasculaires
EP3254696A1 (fr) 2006-10-03 2017-12-13 Genzyme Corporation Utilisation d'antagonistes de tgf-bêta pour traiter des nourrissons risquant de développer une dysplasie broncho-pulmonaire
EP2918288A1 (fr) 2006-10-03 2015-09-16 Genzyme Corporation Utilisation d'antagonistes de TGF-BETA pour traiter des nourrissons risquant de développer une dysplasie broncho-pulmonaire
US8642034B2 (en) 2006-10-03 2014-02-04 Genzyme Corporation Use of TGF-β antagonists to treat infants at risk of developing bronchopulmonary dysplasia
US8242139B2 (en) 2007-04-30 2012-08-14 Abbott Laboratories Inhibitors of diacylglycerol O-acyltransferase type 1 enzyme
US8901152B2 (en) 2007-04-30 2014-12-02 Abbvie Inc. Inhibitors of diacylglycerol O-acyltransferase type 1 enzyme
EP2452937A1 (fr) * 2007-04-30 2012-05-16 Abbott Laboratories Inhibiteurs de l'enzyme diacylglycérol o-acyltransférase de type 1
AU2008245461B2 (en) * 2007-04-30 2012-12-06 Abbvie Inc. Inhibitors of diacylglycerol O-acyltransferase type 1 enzyme
WO2008134693A1 (fr) * 2007-04-30 2008-11-06 Abbott Laboratories Inhibiteurs d'enzyme diacylglycérol o-acyltransférase de type 1
AU2009203693B2 (en) * 2008-01-11 2012-06-07 Novartis Ag Pyrimidines as kinase inhibitors
CN101910153A (zh) * 2008-01-11 2010-12-08 诺瓦提斯公司 作为激酶抑制剂的嘧啶类
WO2009087224A1 (fr) * 2008-01-11 2009-07-16 Novartis Ag Pyrimidines utilisés en tant qu'inhibiteurs de kinase
US8865732B2 (en) 2008-03-21 2014-10-21 Novartis Ag Heterocyclic compounds and uses thereof
US9782522B2 (en) 2011-06-03 2017-10-10 Yale University Compositions and methods for treating and preventing neointimal stenosis
WO2012167261A3 (fr) * 2011-06-03 2013-05-16 Yale University Compositions et méthodes de traitement et de prévention d'une sténose néointimale
US9446175B2 (en) 2011-06-03 2016-09-20 Yale University Compositions and methods for treating and preventing neointimal stenosis
WO2013014262A1 (fr) 2011-07-27 2013-01-31 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes de diagnostic et de traitement du syndrome de myhre
US9468612B2 (en) 2011-10-26 2016-10-18 Seattle Children's Hospital Cysteamine in the treatment of fibrotic disease
US9925154B2 (en) 2011-10-26 2018-03-27 Seattle Children's Hospital Cysteamine in the treatment of fibrotic disease
US10245267B2 (en) 2013-03-14 2019-04-02 Novartis Ag Biaryl amide compounds as kinase inhibitors
US9694016B2 (en) 2013-03-14 2017-07-04 Novartis Ag Biaryl amide compounds as kinase inhibitors
US9242969B2 (en) 2013-03-14 2016-01-26 Novartis Ag Biaryl amide compounds as kinase inhibitors
US10709712B2 (en) 2013-03-14 2020-07-14 Novartis Ag Biaryl amide compounds as kinase inhibitors
US10752594B2 (en) 2013-03-14 2020-08-25 Sumitomo Dainippon Pharma Oncology, Inc. JAK1 and ALK2 inhibitors and methods for their use
US9809610B2 (en) 2014-09-12 2017-11-07 Novartis Ag Compounds and compositions as kinase inhibitors
US9573969B2 (en) 2014-09-12 2017-02-21 Novartis Ag Compounds and compositions as kinase inhibitors
US11541149B2 (en) 2015-12-11 2023-01-03 Research Institute At Nationwide Children's Hospital Systems and methods for optimized patient specific tissue engineering vascular grafts
US11040038B2 (en) 2018-07-26 2021-06-22 Sumitomo Dainippon Pharma Oncology, Inc. Methods for treating diseases associated with abnormal ACVR1 expression and ACVR1 inhibitors for use in the same
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