WO2009009059A1 - Composés spiro en tant qu'antagonistes du tgf-bêta - Google Patents

Composés spiro en tant qu'antagonistes du tgf-bêta Download PDF

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Publication number
WO2009009059A1
WO2009009059A1 PCT/US2008/008401 US2008008401W WO2009009059A1 WO 2009009059 A1 WO2009009059 A1 WO 2009009059A1 US 2008008401 W US2008008401 W US 2008008401W WO 2009009059 A1 WO2009009059 A1 WO 2009009059A1
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compound
fibrosis
heteroaryl
optionally substituted
aryl
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PCT/US2008/008401
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English (en)
Inventor
Lihong Sun
Deqiang Niu
Feng Shan
Wen-Cherng Lee
Xiaomei Feng
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Biogen Idec Ma Inc.
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Publication of WO2009009059A1 publication Critical patent/WO2009009059A1/fr

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    • 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
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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

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-TGF/3 complex cannot bind to the TGF/3 receptors and is not biologically active.
  • TGF/3 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 (Alk5) in a glycine/serine rich domain, which allows the type I receptor to recruit and phosphorylate downstream signaling molecules, Smad2 or Smad3.
  • 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 TGFjS , that is, by binding to a constitutive serine-threonine receptor kinase, activin type II receptor (ActRIIB), and activating a type I serine-threonine receptor, Alk4, 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.
  • TGF/3 and related factors such as activin regulate a large array of cellular processes, e.g., cell cycle arrest in epithelial and hematopoietic cells, control of mesenchymal cell proliferation and differentiation, inflammatory cell recruitment, immunosuppression, wound healing, and extracellular matrix production.
  • cellular processes e.g., cell cycle arrest in epithelial and hematopoietic cells, control of mesenchymal cell proliferation and differentiation, inflammatory cell recruitment, immunosuppression, wound healing, and extracellular matrix production.
  • TGF/3 signaling pathway underlies many human disorders (e.g., excess deposition of extracellular matrix, an abnormally high level of inflammatory responses, f ⁇ brotic disorders, and progressive cancers).
  • activin signaling and overexpression of activin is linked to pathological disorders that involve extracellular matrix accumulation and fibrosis (see, e.g., Matsuse, T. et al., Am. J. Respir. Cell MoI. Biol., 13: 17- 24 (1995); Inoue, S. et al., Biochem. Biophys. Res. Comm.
  • TGF]S 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 TGF/3 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 potent antagonists of the TGF/3 family type I receptors, Alk5 and/or Alk4.
  • 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 TGF/3 family signaling activity is desirable.
  • diseases such as fibrosis (e.g., renal fibrosis, pulmonary fibrosis, and hepatic fibrosis), progressive cancers, or other diseases for which reduction of TGF/3 family signaling activity is desirable.
  • fibrosis e.g., renal fibrosis, pulmonary fibrosis, and hepatic fibrosis
  • progressive cancers e.g., hepatic fibrosis
  • the present invention provides compounds of Formula (I)
  • each of R 1 and R 2 independently is an optionally substituted aryl or heteroaryl;
  • a 1 is NR 3 or CR 3 ;
  • a 2 is N when A 1 is CR 3 , or A 2 is C when A 1 is NR 3 ;
  • X is O or NR 3 ; each R 3 is independently hydrogen, aliphatic, cycloaliphatic, aryl, or heteroaryl; each of R' and R" is independently an aliphatic, halo, cyano, or alkoxy; each of p and q is independently 0, 1 , or 2, provided that the sum of p and q is 2, 3, or 4; r is 1, 2, or 3; and each of m and n is independently 0, 1, or 2. [08] In some embodiments, R 1 is an optionally substituted aryl.
  • R 1 is phenyl optionally substituted with 1 to 3 substituents each independently selected from the group consisting of 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, cycl
  • R 1 is a heteroaryl optionally substituted with 1 to 3 substitutents each independently selected from the group consisting of 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,
  • R 1 is benzo[l,3]dioxolyl, benzo[b]thiophenyl, benzo oxadiazolyl, benzothiadiazolyl, benzoimidazolyl, benzooxazolyl, benzothiazolyl, 2-oxo- benzooxazolyl, pyridyl, pyrimidinyl, 2,3-dihydrobenzo[l,4]dioxyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzo[b]thiophenyl, 3,4-dihydrobenzo[l,4]oxazinyl, 3-oxo-benzo[l,4]oxazinyl, 1 , 1 -dioxo-2,3-dihydrobenzo[b]thiophenyl, [ 1 ,2,4]triazolo[ 1 ,5- ⁇ ]pyridyl, [ 1 ,2,4
  • R 2 is an optioanlly substituted aryl.
  • R 2 is phenyl optionally substituted with 1 to 3 substitutents each independently selected from the group consisting of 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, urea, thioure
  • R 2 is an heteroaryl optionally substituted with 1 to 3 substitutents each independently selected from the group consisting of 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, urea, thioure
  • the heteroaryl in R 2 is benzo[l,3]dioxolyl, benzo[b]thiophenyl, benzooxadiazolyl, benzothiadiazolyl, benzoimidazolyl, benzooxazolyl, benzothiazolyl, 2- oxo-benzooxazolyl, pyridyl, pyrimidinyl, 2,3-dihydrobenzo[l,4]dioxyl, 2,3- dihydrobenzofuryl, 2,3-dihydrobenzo[b]thiophenyl, 3,4-dihydrobenzo[l,4]oxazinyl, 3-oxo- benzo[ 1 ,4]oxazinyl, 1 , 1 -dioxo-2,3-dihydrobenzo[b]thiophenyl, [ 1 ,2,4]triazolo[ 1 ,5- ⁇ ]pyridyl,
  • each of p, q, and r is independently 1.
  • R 3 is H.
  • Examples of the compound of Formula (I) include, but are not limited to,
  • the invention pertains to a pharmaceutical composition which includes a compound of Formula (I), in a pharmaceutically effective amount, and a pharmaceutically acceptable carrier.
  • the invention in another aspect, relates to a method of inhibiting the TGF/3 signaling pathway in a subject in need of the inhibition.
  • This method includes administering to the subject an effective amount of a compound of Formula (I).
  • the invention in another aspect, relates to a method of inhibiting the TGF/3 type I receptor in a cell, and the method includes contacting the cell with an effective amount of a compound of Formula (I).
  • the invention in another aspect, relates to a method of reducing the accumulation of excess extracellular matrix induced by TGF/3 in a subject in need of the reduction of the accumulation of excess extracellular matrix.
  • the method includes administering to the subject an effective amount of a compound of Formula (I).
  • the invention in another aspect, relates to a method of treating or preventing fibrotic condition in a subject in need thereof.
  • the method includes administering to the subject an effective amount of a compound of Formula (I).
  • the fibrotic condition can be, for example, 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), chronic obstructive pulmonary disease, adult respiratory distress syndrome, drug-induced lung injury, glomerulonephritis, diabetic nephropathy, hypertension- induced nephropathy, alimentary track or gastrointestinal fibrosis, renal fibrosis, hepatic or biliary fibrosis (such as liver cirrhosis, primary biliary cirrhosis, fatty liver disease, primary sclerosing cholangitis), restenosis, cardiac fibros
  • the fibrotic condition can be idiopathic in nature, genetically linked, or induced by radiation.
  • the invention relates to a method of inhibiting growth or metastasis of tumor cells or cancers in a subject in need thereof. The method includes administering to the subject an effective amount of a compound of Formula (I).
  • the invention in another aspect, relates to a method of treating a disease or disorder mediated by an overexpression of TGF/3 in a subject in need thereof.
  • the method 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.
  • N-oxide derivative or a pharmaceutically acceptable salt of each of the compounds of Formula (I) is also within the scope of this invention.
  • a nitrogen ring atom of the imidazole core ring or a nitrogen-containing heterocyclyl substituent can form an oxide in the presence of a suitable oxidizing agent such as /w-chloroperbenzoic acid or H 2 O 2 .
  • a compound of Formula (I) that is acidic in nature e.g., having a carboxyl or phenolic hydroxyl group
  • a pharmaceutically acceptable salt such as a sodium, potassium, calcium, or gold salt.
  • salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, and ⁇ -methylglycamine.
  • a compound of Formula (I) can be treated with an acid to form acid addition salts.
  • acids examples include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, /7-bromophenyl- sulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, oxalic acid, malonic acid, salicylic acid, maleic acid, fumaric acid, ascorbic acid, maleic acid, acetic acid, and other mineral and organic acids well known to those skilled in the art.
  • the acid addition salts can be prepared by treating a compound of Formula (I) in its free base form with a sufficient amount of an acid (e.g., hydrochloric acid) to produce an acid addition salt (e.g., a hydrochloride salt).
  • Compounds of Formula (I) in general exhibit surprisingly high affinity to the TGF/3 family type I receptors, Alk5 or Alk4, e.g., with IC 50 and Ki values of less than 10 ⁇ M under conditions as described below in Examples 8 and 10, respectively. Some compounds of Formula (I) exhibit IC 50 and Kj values of less than 1 ⁇ M (such as below 50 nM).
  • Compounds of Formula (I) can also be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include those that increase biological penetration into a given biological system (e.g., blood, lymphatic system, or central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism, or alter rate of excretion.
  • the present invention also features a pharmaceutical composition including a compound of Formula (I) (or a combination of two or more compounds of Formula (I)) and at least one pharmaceutically acceptable carrier. Also included in the present invention is 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 TGFjS family type I receptors, Alk5 or Alk4 (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, which includes 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 inhibiting the TGF/3 or activin signaling pathway in a cell or in a subject (e.g., a mammal such as a human), which includes 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 in need thereof 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
  • a method of treating or preventing a TGF/3 related disease in a subject in need thereof which includes administering to the subject an effective amount of a compound of Formula (I).
  • Exampels of such diease include, but are not limited to, acute lung injury, adult respiratory distress syndrome, alimentary track or gastrointestinal fibrosis, atherosclerosis, biliary fibrosis, cardiac fibrosis, chemotherapy- induced fibrosis, cholangitis, chronic obstructive pulmonary disease, cirrhosis due to fatty liver disease, CNS scarring, connective tissue disease, corneal scarring, diabetic nephropathy, drug-induced lung injury, fatty liver disease, fibroadenoma, fibroid, fibroma, fibrosarcoma, fibrosclerosis, fibrotic cancer, glomerulonephritis, hepatic or biliary fibrosis, hypertension- induced nephropathy, idiopathic
  • aliphatic encompasses the terms alkyl, alkenyl, and alkynyl, each of which being optionally substituted as set forth below.
  • an "alkyl” group refers to a linear (i.e., noncyclic) saturated aliphatic hydrocarbon group containing 1 to 12 (e.g., 1 to 10, 1 to 8, 1 to 6, or 1 to 4) carbon atoms.
  • An alkyl group can be straight or branched.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec -butyl, tert-butyl, n-pentyl, n- heptyl, or 2-ethylhexyl.
  • An alkyl group can be substituted (i.e., optionally substituted) with one or more substituents such as halo, phospho, cycloaliphatic (e.g., cycloalkyl or cycloalkenyl), heterocycloaliphatic (e.g., heterocycloalkyl or heterocycloalkenyl), aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl (e.g., (aliphatic)carbonyl, (cycloaliphatic)carbonyl, or (heterocycloaliphatic)carbonyl), nitro, cyano, amido (e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaral
  • substituted alkyls include carboxyalkyl (such as HOOC-alkyl, alkoxycarbonylalkyl, and alkylcarbonyloxyalkyl), cyanoalkyl, hydroxyalkyl, alkoxyalkyl, acylalkyl, aralkyl, (alkoxyaryl)alkyl, (sulfonylamino)alkyl (such as (alkyl-SO 2 -amino)alkyl), aminoalkyl, amidoalkyl, (cycloaliphatic)alkyl, or haloalkyl.
  • carboxyalkyl such as HOOC-alkyl, alkoxycarbonylalkyl, and alkylcarbonyloxyalkyl
  • cyanoalkyl hydroxyalkyl, alkoxyalkyl, acylalkyl, aralkyl, (alkoxyaryl)alkyl, (sulfonylamino)alkyl (such as (alky
  • An alkenyl group can be optionally substituted with one or more substituents such as halo, phospho, cycloaliphatic (e.g., cycloalkyl or cycloalkenyl), heterocycloaliphatic (e.g., heterocycloalkyl or heterocycloalkenyl), aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl (e.g., (aliphatic)carbonyl, (cycloaliphatic)carbonyl, or (heterocycloaliphatic)carbonyl), nitro, cyano, amido (e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino al
  • substituted alkenyls include cyanoalkenyl, alkoxyalkenyl, acylalkenyl, hydroxyalkenyl, aralkenyl, (alkoxyaryl)alkenyl, (sulfonylamino)alkenyl (such as (alkyl-SO 2 -amino)alkenyl), aminoalkenyl, amidoalkenyl, (cycloaliphatic)alkenyl, and haloalkenyl.
  • an "alkynyl” group refers to an aliphatic carbon group that contains 2 to 12 (e.g., 2 to 8, 2 to 6, or 2 to 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 aroyl, heteroaroyl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, nitro, carboxy, cyano, halo, hydroxy, sulfo, mercapto, sulfanyl (e.g., aliphaticsulfanyl or cycloaliphaticsulfanyl), sulfinyl (e.g., aliphaticsulfinyl or cycloaliphaticsulfinyl), sulfonyl (e.g., aliphatic-SO 2 -, aliphaticamino-SO 2 -, or cycloaliphatic- SO 2 -), amido (e.g., aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino, cycloalkylaminocarbonyl
  • an “amido” encompasses both “aminocarbonyl” and “carbonylamino”. These terms when used alone or in connection with another group refers to an amido group such as -N(R X )-C(O)-R Y or -C(O)-N(R X ) 2 , when used terminally, and -C(O)-N(R X )- or -N(R X )-C(O)- when used internally, wherein R x and R ⁇ are defined below.
  • amido groups include, but are not limited to, alkylamido (such as alkylcarbonylamino or alkylaminocarbonyl), (heterocycloaliphatic)amido, (heteroaralkyl)amido, (heteroaryl)amido, (heterocycloalkyl)alkylamido, arylamido, aralkylamido, (cycloalkyl)alkylamido, and cycloalkylamido.
  • alkylamido such as alkylcarbonylamino or alkylaminocarbonyl
  • heterocycloaliphatic such as alkylcarbonylamino or alkylaminocarbonyl
  • heteroaryl heteroaryl
  • an "amino" group refers to -NR X R Y wherein each of R x and R ⁇ is independently hydrogen, aliphatic, cycloaliphatic, (cycloaliphatic)aliphatic, aryl, araliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, heteroaryl, carboxy, sulfanyl, sulfinyl, sulfonyl, (aliphatic)carbonyl, (cycloaliphatic)carbonyl, ((cycloaliphatic)aliphatic)carbonyl, arylcarbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl,
  • amino groups include, but are not limited to, alkylamino, dialkylamino, and arylamino.
  • amino is not the terminal group (e.g., alkylcarbonylamino), it is represented by -NR X -.
  • R x has the same meaning as defined herein.
  • an "aryl” group used alone or as part of a larger moiety such as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl” refers to monocyclic (e.g., phenyl); bicyclic (e.g., indenyl, naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl); and tricyclic (e.g., fluorenyl tetrahydrofluorenyl, or tetrahydroanthracenyl, anthracenyl) ring systems in which the monocyclic ring system is aromatic or at least one of the rings in a bicyclic or tricyclic ring system is aromatic.
  • the bicyclic and tricyclic groups include benzofused systems having 2 to3 carbocyclic rings.
  • a benzofused group includes phenyl fused with two or more C 4-8 carbocyclic moieties.
  • An aryl is optionally substituted with one or more substituents including aliphatic (e.g., alkyl, alkenyl, or alkynyl); cycloaliphatic; (cycloaliphatic)aliphatic; heterocycloaliphatic; (heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy; (cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy; heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl; heteroaroyl; amino; oxo (on a non-aromatic carbocyclic ring of a benzofused bicyclic or tricyclic aryl); nitro; carb
  • sulfonyl e.g., aliphatic-SO 2 - or amino-SO 2 -]; sulfinyl (e.g., aliphatic-S(O)- or cycloaliphatic-S(O)-); sulfanyl (e.g., aliphatic-S-); cyano; halo; hydroxy; mercapto; sulfoxy; urea; thiourea; sulfamoyl; sulfamide; or carbamoyl.
  • an aryl can be unsubstituted.
  • Non-limiting examples of substituted aryls include haloaryl (e.g., mono-, di-(such as /7,r ⁇ -dihaloaryl), and tri-(such as halo) aryl); (carboxy)aryl (e.g., (alkoxycarbonyl)aryl, ((aralkyl)carbonyloxy)aryl, and (alkoxycarbonyl)aryl); (amido)aryl (e.g., (aminocarbonyl)aryl, (((alkylamino)alkyl)aminocarbonyl)aryl, (alkylcarbonyl)aminoaryl, (arylaminocarbonyl)aryl, and (((heteroaryl)amino)carbonyl)aryl); aminoaryl (e.g., ((alkylsulfonyl)amino)aryl or ((dialkyl)amino)aryl); (cyanoalkyl)aryl
  • an "araliphatic” such as an “aralkyl” group refers to an aliphatic group (e.g., a C M alkyl group) that is substituted with an aryl group.
  • "Aliphatic,” “alkyl,” and “aryl” are as defined herein.
  • An example of an araliphatic such as an aralkyl group is benzyl.
  • an "aralkyl” group refers to an alkyl group (e.g., a Ci -4 alkyl group) that is substituted with an aryl group. Both “alkyl” and “aryl” are as defined herien. An example of an aralkyl group is benzyl.
  • An aralkyl is optionally substituted with one or more substituents such as aliphatic (e.g., alkyl, alkenyl, or alkynyl, including carboxyalkyl, hydroxyalkyl, or haloalkyl such as trifluoromethyl); cycloaliphatic (e.g., cycloalkyl or cycloalkenyl); (cycloalkyl)alkyl; heterocycloalkyl; (heterocycloalkyl)alkyl; aryl; heteroaryl; alkoxy; cycloalkyloxy; heterocycloalkyloxy; aryloxy; heteroaryloxy; aralkyloxy; heteroaralkyloxy; aroyl; heteroaroyl; nitro; carboxy; alkoxycarbonyl; alkylcarbonyloxy; amido (e.g., aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloal
  • a "bicyclic ring system” includes 8- to 12- (e.g., 9-, 10-, or H-) membered structures that form two rings, wherein the two rings have at least one atom in common (e.g., 1 atom or 2 atoms in common).
  • Bicyclic ring systems include bicycloaliphatics (e.g., bicycloalkyl or bicycloalkenyl), spiroaliphatics, spiroheteroaliphatics, bicycloheteroaliphatics, bicyclic aryls, and bicyclic heteroaryls.
  • a "cycloaliphatic” group encompasses a “cycloalkyl” group and a “cycloalkenyl” group, each of which being optionally substituted as set forth below.
  • a "cycloalkyl” group refers to a saturated carbocyclic fused or bridged ring system of 3-15 (e.g., 5-12) carbon atoms.
  • Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, cubyl, octahydro-indenyl, decahydro-naphthyl, spiro[5.5]undecanyl, spiro[2.5]octanyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2.]decyl, bicyclo[2.2.2]octyl, adamantyl, or ((aminocarbonyl)cycloalkyl)cycloalkyl.
  • a "cycloalkenyl” group refers to a non-aromatic carbocyclic mono- or bicyclic ring of 3 to 12 (e.g., 4 to 8) carbon atoms having one or more double bonds.
  • cycloalkenyl groups include, but are not limited to, cyclopentenyl, 1,4- cyclohexa-di-enyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl, cyclopentenyl, spiro[5.5]]undec-3-enyl, spiro[2.5]oct-5-enyl, 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 phosphoryl; aliphatic (e.g., alkyl, alkenyl, or alkynyl); cycloaliphatic; (cycloaliphatic) aliphatic; heterocycloaliphatic; (heterocycloaliphatic) aliphatic; aryl; heteroaryl; alkoxy; (cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy; heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl; heteroaroyl; amino; amido (e.g., (aliphatic)carbonylamino, (cycloaliphatic)carbonylamino, ((cycloaliphatic)aliphatic)carbonylamino, (aryl)carbonylamino, (araliphatic)carbonylamino,
  • substituents such as
  • heterocycloaliphatic carbonylamino ((heterocycloaliphatic)aliphatic)carbonylamino, (heteroaryl)carbonylamino, or (heteroaraliphatic)carbonylamino); nitro; carboxy (e.g., HOOC-, alkoxycarbonyl, or alkylcarbonyloxy); acyl (e.g., (cycloaliphatic)carbonyl, ((cycloaliphatic) aliphatic)carbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl, or (heteroaraliphatic)carbonyl); cyano; halo; hydroxy; mercapto; sulfonyl (e.g., alkyl-SO 2 - and aryl-SO 2 -); sulfinyl (e.g., alkyl-S
  • heterocycloalkyl refers to a 3- to 12-membered mono- or bicylic (fused or bridged) (e.g., 5- to 12-membered mono- or bicyclic) saturated ring structure, in which one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof).
  • heterocycloalkyl group examples include piperidyl, piperazyl, tetrahydropyranyl, tetrahydrofuryl, 1 ,4-dioxolanyl, 1 ,4-dithianyl, 1,3-dioxolanyl, oxazolidyl, isoxazolidyl, morpholinyl, thiomorpholyl, octahydrobenzofuryl, octahydrochromenyl, octahydrothiochromenyl, octahydroindolyl, octahydropyrindinyl, decahydroquinolinyl, octahydrobenzo[ ⁇ ]thiopheneyl, 2-oxa-bicyclo[2.2.2]octyl, l-aza-bicyclo[2.2.2]octyl, 3-aza- bicyclo[3.2.1]octyl, 3-oxoc
  • a “heterocycloalkenyl” group refers to a mono- or bicylic (e.g., 5- to 10-membered mono- or bicyclic) 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).
  • a heteroatom e.g., N, O, or S.
  • a heterocycloalkyl or heterocycloalkenyl group can be optionally substituted with one or more substituents such as phosphor; aliphatic (e.g., alkyl, alkenyl, or alkynyl); cycloaliphatic; (cycloaliphatic)aliphatic; heterocycloaliphatic; (heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy; (cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy; heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl; heteroaroyl; amino; amido [e.g., (aliphatic)carbonylamino, (cycloaliphatic)carbonylamino, ((cycloaliphatic) aliphatic)carbonylamino, (aryl)carbonylamino, (araliphatic)carbonylamino, (heterocycloalipha
  • sulfonyl e.g., alkylsulfonyl or arylsulfonyl
  • sulfinyl e.g., alkylsulfinyl
  • sulfanyl e.g., alkylsulfanyl
  • a “heteroaryl” group refers to a monocyclic, bicyclic, or tricyclic ring system having 4 to 15 ring atoms wherein one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof) and in which the monocyclic ring system is aromatic or at least one of the rings in the bicyclic or tricyclic ring systems is aromatic.
  • a heteroaryl group includes a benzofused ring system having 2 to 3 rings.
  • a benzofused group includes benzo fused with one or two 4 to 8 membered heterocycloaliphatic moieties (e.g., indolizyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[6]furyl, benzo[ ⁇ ]thiophenyl, quinolinyl, or isoquinolinyl).
  • heterocycloaliphatic moieties e.g., indolizyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[6]furyl, benzo[ ⁇ ]thiophenyl, quinolinyl, or isoquinolinyl.
  • heteroaryl examples include azetidinyl, pyridyl, IH- indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzthiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole, 1,2,3,4- tetrahydroisoquinoline, isoindoline, benzo[l,3]dioxole, benzo[b]furyl, benzo[b]thiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, puryl, cinnolyl, quinolyl, quinazolyl,cinnolyl, phthalazyl, quinazolyl, quinoxalyl, isoquinolyl,
  • monocyclic heteroaryls include furyl, thiophenyl, 2H-pyrrolyl, pyrrolyl, oxazolyl, thazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4-H-pranyl, pyridyl, pyridazyl, pyrimidyl, pyrazolyl, pyrazyl, or 1,3,5-triazyl.
  • Monocyclic heteroaryls are numbered according to standard chemical nomenclature.
  • bicyclic heteroaryls include indolizyl, indolyl, isoindolyl, 3H- indolyl, indolinyl, benzo[6]furyl, benzo[6]thiophenyl, quinolinyl, isoquinolinyl, indolizyl, isoindolyl, indolyl, benzo[6]furyl, bexo[ ⁇ ]thiophenyl, indazolyl, benzimidazyl, benzthiazolyl, purinyl, 4H-quinolizyl, quinolyl, isoquinolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, 1,8-naphthyridyl, or pteridyl.
  • Bicyclic heteroaryls are numbered according to standard chemical nomenclature.
  • a heteroaryl is optionally substituted with one or more substituents such as aliphatic [e.g., alkyl, alkenyl, or alkynyl]; cycloaliphatic; (cycloaliphatic)aliphatic; heterocycloaliphatic; (heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy; (cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy; heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl; heteroaroyl; amino; oxo (on a non-aromatic carbocyclic or heterocyclic ring of a bicyclic or tricyclic heteroaryl); carboxy; amido; acyl [e.g., aliphaticcarbonyl; (cycloaliphatic)carbonyl; ((cycloaliphatic)aliphatic)carbonyl;
  • heterocycloaliphatic aliphatic
  • carbonyl or (heteroaraliphatic)carbonyl]
  • sulfonyl e.g., aliphaticsulfonyl or aminosulfonyl
  • sulfinyl e.g., aliphaticsulfinyl
  • sulfanyl e.g., aliphaticsulfanyl
  • a heteroaryl can be unsubstituted.
  • heteroarylkyl refers to an alkyl group (e.g., a Ci -4 alkyl group) that is substituted with a heteroaryl group. Both “alkyl” and “heteroaryl” are as defined herien.
  • a heteroaralkyl 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, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloal
  • an "acyl” group refers to a formyl group or R X -C(O)- (such as alkyl-C(O)-, also referred to as “alkylcarbonyl”) wherein R x and "alkyl” are as defined herein.
  • Acetyl and pivaloyl are examples of acyl groups.
  • an “aroyl” or “heteroaroyl” refers to an aryl-C(O)- or a heteroaryl-
  • aryl and heteroaryl portion of the aroyl or heteroaroyl is optionally substituted as previously defined.
  • alkoxy refers to an alkyl-O- group where “alkyl” are as defined herein.
  • a "carbamoyl” group refers to a group having the structure -O-CO-
  • R x and R ⁇ are as defined herein, and R z can be aliphatic, aryl, araliphatic, heterocycloaliphatic, heteroaryl, or heteroaraliphatic.
  • a "carboxy” group refers to -COOH, -C00R x , -OC(O)H, or
  • haloaliphatic refers to an aliphatic group substituted with 1 to 3 halogen atoms.
  • haloalkyl includes the group -CF 3 .
  • mercapto refers to -SH.
  • a "sulfo" group refers to -SO 3 H or -SO 3 R X when used terminally or
  • a "sulfamide” group refers to the structure -NR X -S(O) 2 -NR Y R Z when used terminally or -NR X -S(O) 2 -NR Y - when used internally, wherein R x , R ⁇ , and R z are as defined above.
  • a "sulfonamide” group refers to the structure -S(O) 2 -NR X R Y or
  • sulfanyl group refers to -S-R x when used terminally or -S- when used internally, wherein R is as defined herein.
  • sulfanyls include aliphatic-S-, cycloaliphatic-S-, aryl-S-, or the like.
  • sulfinyl refers to -S(O)-R X when used terminally or -S(O)- when used internally, wherein R x is as defined above.
  • exemplary sulfinyl groups include, but are not limited to, aliphatic-S(O)-, aryl-S(O)-, (cycloaliphatic(aliphatic))-S(O)-, cycloalkyl-S(O)-, heterocycloaliphatic-S(O)-, heteroaryl-S(O)-, and the like.
  • sulfonyl refers to-S(O) 2 -R x when used terminally or
  • sulfonyl groups include, but are not limited to, aliphatic-S(0)2-, aryl-S(O) 2 -, (cycloaliphatic(aliphatic))-S(O) 2 -, cycloaliphatic-S(O) 2 -, heterocycloaliphatic-S(O) 2 -, heteroaryl-S(O) 2 -,
  • a "sulfoxy" group refers to -O-SO-R X or -SO-O-R* when used terminally, or -0-S(O)- or -S(O)-O- when used internally, where R x as as defined herein.
  • halogen or halo group refers to fluorine, chlorine, bromine, or iodine.
  • alkoxycarbonyl which is encompassed by the term carboxy, used alone or in connection with another group, refers to a group such as alkyl-O-
  • alkyl is as defined herein.
  • alkoxyalkyl refers to an alkyl group such as alkyl-O-alkyl-, wherein alkyl is as defined herein.
  • phosphor refers to phosphinates and phosphonates.
  • phosphinates and phosphonates include, but are not limited to, -P(O)(R P ) 2 , wherein R p is aliphatic, alkoxy, aryloxy, heteroaryloxy, (cycloaliphatic)oxy,
  • heterocycloaliphatic oxy aryl, heteroaryl, cycloaliphatic or amino.
  • aminoalkyl refers to the structure (R x ) 2 N-alkyl- wherein
  • cyanoalkyl refers to the structure (NC)-alkyl-.
  • urea refers to the structure -NR X -CO-NR Y R Z and a
  • thiourea group refers to the structure -NR X -CS-NR Y R Z when used terminally and -NR X -
  • the term "vicinal” refers to the placement of substituents on a group that includes two or more carbon atoms, wherein the substituents are attached to adjacent carbon atoms.
  • the term “geminal” refers to the placement of substituents on a group that includes two or more carbon atoms, wherein the substituents are attached to the same carbon atom.
  • terminal refers to the location of a group within a substituent.
  • a group is terminal when the group is present at the end of the substituent not further bonded to the rest of the chemical structure.
  • Carboxyalkyl i.e., R x O(O)C-alkyl, is an example of a carboxy group used terminally.
  • a group is internal when the group is present in the middle of a substituent of the chemical structure.
  • Alkylcarboxy e.g., alkyl-C(O)O- or alkyl-OC(O)-
  • alkylcarboxyaryl e.g., alkyl-C(O)O-aryl- or alkyl- O(CO)-aryl-
  • a "bridged cyclic ring system” refers to a cyclic heterocycloalipahtic ring system or cyclic cycloaliphatic ring system in which at least two rings have two atoms in common.
  • bridged cyclic ring systems include, but are not limited to, adamantanyl, norbornanyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.2.3]nonyl, 2-oxabicyclo[2.2.2]octyl, l-azabicyclo[2.2.2]octyl, 3- azabicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.0 3>7 ]nonyl.
  • a bridged cyclic ring system 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, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heter
  • an "aliphatic chain” refers to a branched or straight aliphatic group (e.g., alkyl groups, alkenyl groups, or alkynyl groups).
  • a straight aliphatic chain has the structure -(CH 2 ) V -, where v is 1-6.
  • a branched aliphatic chain is a straight aliphatic chain that is substituted with one or more aliphatic groups.
  • a branched aliphatic chain has the structure -(CHQ)v- where Q is hydrogen or an aliphatic group; however, Q shall be an aliphatic group in at least one instance.
  • aliphatic chain includes alkyl chains, alkenyl chains, and alkynyl chains, where alkyl, alkenyl, and alkynyl are defined above.
  • the term “optionally substituted” is used interchangeably with the term “substituted or unsubstituted.”
  • compounds of the invention can optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention.
  • the variables A, B, R 1 , R 2 , R 3 , Y and Y', and other variables contained in formulae described herein encompass specific groups, such as alkyl and aryl.
  • each of the specific groups for the variables A, B, Ri, R 2 , R 3 , Y and Y', and other variables contained therein can be optionally substituted with one or more substituents described herein.
  • Each substituent of a specific group is further optionally substituted with one to three of halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, cycloaliphatic, heterocycloaliphatic, heteroaryl, haloalkyl, and alkyl.
  • an alkyl group can be substituted with alkylsulfanyl and the alkylsulfanyl can be optionally substituted with one to three of halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl.
  • the cycloalkyl portion of a (cycloalkyl)carbonylamino can be optionally substituted with one to three of halo, cyano, alkoxy, hydroxy, nitro, haloalkyl, and alkyl.
  • the term "substituted”, whether preceded by the term “optionally” or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Specific substituents are described above in the definitions and below in the description of compounds and examples thereof. Unless otherwise indicated, an optionally substituted group can have a substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position.
  • a ring substituent such as a heterocycloalkyl
  • substituents envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds.
  • stable or chemically feasible refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein.
  • a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40 0 C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
  • an "antagonist,” as used herein, refers to 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.
  • compounds of Formula (I) are antagonists of TGF/3 receptor type I (Alk5) and/or activin receptor type I (Alk4), these compounds are useful in inhibiting the consequences of TGF/3 and/or activin signal transduction such as the production of extracellular matrix (e.g., collagen and fibronectin), the differentiation of stromal cells to myofibroblasts, and the stimulation of and migration of inflammatory cells.
  • TGF/3 receptor type I Alk5
  • activin receptor type I Alk4
  • these compounds of Formula (I) inhibit pathological inflammatory and fibrotic responses and possess the therapeutic utility of treating and/or preventing disorders or diseases for which reduction of TGF/3 and/or activin activity is desirable (e.g., various types of fibrosis or progressive cancers).
  • an effective amount is defined as the amount required to confer a therapeutic effect on the treated patient, and is typically determined based on age, surface area, weight, and condition of the patient.
  • 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.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention.
  • the invention features compounds of Formula (I), which exhibit surprisingly high affinitiy for the TGF/3 family type I receptors, Alk5 and/or Alk4. Synthesis of the Compounds of Formula (T)
  • reaction of the aldehyde 1 with ethylene glycol in the presence of a catalytic amound of/>-toluenesulfonic acid provides the acetal 2.
  • Alkylation of 2 with a bromochloro alkane, e.g. l-bromo-2-chloroethane provides the alkylated acetal 3.
  • Treatment of 3 with silver nitrate in water at elevated temperature results in acetal hydrolysis and ring closure to provide the spirolactone 5.
  • Reaction of 5 with a dione 6 and ammonium acetate provides imidazole compounds of the invention (i.e., Formula (I)).
  • TGF/3 and/or activin mRNA and the level of TGFjS and/or activin are increased in patients suffering from various fibrotic disorders, e.g., f ⁇ brotic kidney diseases, alcohol-induced and autoimmune hepatic fibrosis, myelofibrosis, bleomycin- induced pulmonary fibrosis, and idiopathic pulmonary fibrosis. Elevated TGF ⁇ and/or activin is has also been demonstrated in cachexia, demyelination of neurons in multiple sclerosis, Alzheimer's disease, cerebral angiopathy and hypertension.
  • Compounds of Formula (I), which are antagonists of the TGF/3 family type I receptors Alk5 and/or Alk4, and inhibit TGFjS and/or activin signaling pathway, are therefore useful for treating and/or preventing fibrotic disorders or diseases mediated by an increased level of TGF/3 and/or activin activity.
  • a compound inhibits the TGFjS family signaling pathway when it binds (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) to a receptor of the pathway (e.g., Alk5 and/or AIk 4), thereby competing with the endogenous ligand(s) or substrate(s) for binding site(s) on the receptor and reducing the ability of the receptor to transduce an intracellular signal in response to the endogenous ligand or substrate binding.
  • a receptor of the pathway e.g., Alk5 and/or AIk 4
  • the aforementioned disorders or diseases include any condition (a) marked by the presence of an abnormally high level of TGF/3 and/or activin; and/or (b) an excess accumulation of extracellular matrix; and/or (c) an increased number and synthetic activity of myofibroblasts.
  • fibrotic conditions such as scleroderma, glomerulonephritis, diabetic nephropathy, lupus nephritis, hypertension-induced nephropathy, ocular or corneal scarring, alimentary track or gastrointestinal fibrosis, renal fibrosis, hepatic or biliary fibrosis, acute lung injury, pulmonary fibrosis (such as idiopathic pulmonary fibrosis and radiation- induced pulmonary fibrosis), post-infarction cardiac fibrosis, fibrosclerosis, fibrotic cancers, fibroids, fibroma, fibroadenomas, and fibrosarcomas.
  • Other 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.
  • TGFjS activity is also found to manifest in patients with progressive cancers.
  • the tumor cells, stromal cells, and/or other cells within a tumor generally overexpress TGF/3. This leads to stimulation of angiogenesis and cell motility, suppression of the immune system, and/or increased interaction of tumor cells with the extracellular matrix.
  • TGF tumor growth factor
  • the tumors grow more readily, become more invasive and metastasize to distant organs. See, e.g., Maehara, Y.
  • compounds of Formula (I) which are antagonists of the TGF/3 type I receptor and inhibit TGF/3 signaling pathways, are also useful for treating and/or preventing various cancers which overexpress TGF/3 or benefit from TGF/3's above-mentioned pro- tumor activities.
  • Such cancers include carcinomas of the lung, breast, liver, biliary tract, gastrointestinal tract, head and neck, pancreas, prostate, cervix as well as multiple myeloma, melanoma, glioma, and glioblastomas.
  • TGF/3 and/or activin e.g., fibrosis or cancers
  • small molecule treatments are favored for long-term treatment.
  • the levels of TGF/3 and/or activin in serum and of TGF/3 and/or activin mRNA in tissue can be measured and used as diagnostic or prognostic markers for disorders or diseases mediated by overexpression of TGF/3 and/or activin, and polymorphisms in the gene for TGFjS that determine the production of TGF/3 and/or activin can also be used in predicting susceptibility to disorders or diseases. See, e.g., Blobe, G.C. et al., N. Engl. J. Med. 342(18): 1350-1358 (2000); Matsuse, T. et al., Am. J. Respir. Cell MoI. Biol. 13: 17-24 (1995); Inoue, S.
  • an effective amount is the amount required to confer a therapeutic effect on the treated patient.
  • an effective amount can range, for example, from about 1 mg/kg to about 150 mg/kg (e.g., from about 1 mg/kg to about 100 mg/kg).
  • Effective doses will also vary, as recognized by those skilled in the art, dependant on route of administration, excipient usage, and the possibility of co-usage with other therapeutic treatments including use of other therapeutic agents and/or radiation therapy.
  • Compounds of Formula (I) can be administered in any manner suitable for the administration of pharmaceutical compounds, including, but not limited to, pills, tablets, capsules, aerosols, suppositories, liquid formulations for ingestion or injection or for use as eye or ear drops, dietary supplements, and topical preparations.
  • the pharmaceutically acceptable compositions include aqueous solutions of the active agent, in an isotonic saline, 5% glucose or other well-known pharmaceutically acceptable excipient.
  • Solubilizing agents such as cyclodextrins, or other solubilizing agents well-known to those familiar with the art, can be utilized as pharmaceutical excipients for delivery of the therapeutic compounds.
  • the compositions can be administered orally, intranasally, transdermally, intradermally, vaginally, intraaurally, intraocularly, buccally, rectally, transmucosally, or via inhalation, implantation (e.g., surgically), or intravenous administration.
  • the compositions can be administered to an animal (e.g., a mammal such as a human, non-human primate, horse, dog, cow, pig, sheep, goat, cat, mouse, rat, guinea pig, rabbit, hamster, gerbil, or ferret, or a bird, or a reptile, such as a lizard).
  • an animal e.g., a mammal such as a human, non-human primate, horse, dog, cow, pig, sheep, goat, cat, mouse, rat, guinea pig, rabbit, hamster, gerbil, or ferret, or a bird, or a reptile, such as a
  • compounds of Formula (I) can be administered in conjunction with one or more other agents that inhibit the TGF/3 signaling pathway or treat the corresponding pathological disorders (e.g., fibrosis or progressive cancers) by way of a different mechanism of action.
  • agents include angiotensin converting enzyme inhibitors, nonsteroid and steroid anti-inflammatory agents, immunotherapeutics, chemotherapeutics, as well as agents that antagonize ligand binding or activation of the TGFjS receptors, e.g., anti-
  • TGFjS anti-TGFjS receptor antibodies, or antagonists of the TGF/3 type II receptors.
  • Compounds of Formula (I) can also be administered in conjunction with other treatments, e.g., radiation.
  • Example 1 8-(5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-4-(6-methylpyridin-2-yl)-lH- imidazol-2-yl)-2-oxaspiro[4.5]decan-l-one
  • Step 1 Dioxolan-2-yl-cyclohexanecarboxylic acid methyl ester.
  • Step 2 methyl l-(2-chloroethyl)-4-(l,3-dioxolan-2-yl)cyclohexanecarboxylate.
  • Step 3 l-oxo-2-oxaspiro[4.51decane-8-carbaldehyde.
  • Step 4 8-(5-([l,2,4]triazolo[l,5-alpyridin-6-yl)-4-(6-methylpyridin-2-yl)-lH-imidazol-2- yl)-2-oxaspiro [4.5] decan-1-one.
  • Step 1 ethyl 4-(tert-butyldimethyIsilyloxy)cyclohexanecarboxylate.
  • Step 2 8-hydroxy-2-oxaspiro[4.5]decan-l-one.
  • the ethyl acetate phase was washed with brine, dried over sodium sulfate, filtered, and then concentrated to give yellow oil.
  • the yellow oil was purified by HPLC eluting with acetonitrile/water (with 0.1% TFA) to give 30 mg of the title compound as a yellow solid.
  • the serine-threonine kinase activity of TGF/3 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-TGFjSRI.
  • the His-tagged receptor cytoplasmic kinase domains were purified from infected insect cell cultures using the Gibco- BRL FastBac HTb baculovirus expression system.
  • Inhibition of the Activin type I receptor (AIk 4) kinase autophosphorylation activity by test compounds of Formula (I) can be determined in a similar manner to that described above in Example 8 except that a similarly His-tagged form of Alk4 (His-Alk 4) is used in place of the His-TGF/3RI.
  • His-TGF/3 Type I receptor in the same assay buffer Hepes, NaCl 2 , MgCl 2 , MnCl 2 , DTT, and 30% Brij ® added fresh
  • PE nickel coated FlashPlate
  • the premixed solution of tritiated 4-(3- pyridin-2-yl-lH-pyrazol-4-yl)-quinoline and test compound of Formula (I) was then added to the wells.
  • the wells were aspirated after an hour at room temperature and radioactivity in wells (emitted from the tritiated compound) was measured using TopCount (PerkinElmer Lifesciences, Inc., Boston MA).
  • 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 PAI-Luciferase reporter activity in HepG2 cells.
  • Compounds of Formula (I) typically exhibited IC 50 values of less 10 ⁇ M.
  • Cytotoxicity was determined using the same cell culture conditions as described above. Specifically, cell viability was determined after overnight incubation with the CytoLite cell viability kit (Packard, Cat. No. 6016901). Compounds of Formula (I) typically exhibited LD 25 values greater than 10 ⁇ M.
  • 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 11 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 Fluorescent Protein (GFP) under the control of the collagen IAl promoter (see Krempen, K. et al., Gene Exp. 8: 151-163 (1999)). Cells are immortalized with a temperature sensitive large T antigen that is in an active stage at 33 0 C. Cells are expanded at 33 0 C and then transferred to 37 0 C at which temperature the large T antigen becomes inactive (see Xu, S. et al., Exp. Cell Res. 220: 407-414 (1995)). Over the course of about 4 days and one split, the cells cease proliferating. Cells are then frozen in aliquots sufficient for a single 96 well plate.
  • GFP Green 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 96 well format with 30,000 cells per well in 50 ⁇ L complete DMEM containing 2 % fetal calf serum, but without phenol red.
  • the cells are incubated at 37 0 C for 3 to 4 hours to allow them to adhere to the plate.
  • Solutions containing a test compound of Formula (I) are then added to wells with no TGF/3 (in triplicates), as well as wells with 1 ng/mL TGF/3 (in triplicates).
  • DMSO is also added to all of the wells at a final concentration of 0.1%.
  • GFP fluorescence emission at 530 nm following excitation at 485 run is measured at 48 hours after the addition of solutions containing a test compound on a CytoFluor microplate reader (PerSeptive Biosystems). The data are then expressed as the ratio of TGF/3-induced to non-induced for each test sample.

Abstract

La présente invention concerne des composés de formule (I). Ces composés peuvent être utilisés en tant qu'antagonistes des récepteurs de la famille des facteurs de croissance transformants bêta (TGF-bêta) de type I, ALK5 ou ALK4. Les composés répondant à la formule (I) peuvent être utilisés pour la prévention et/ou le traitement de maladies telles qu'une fibrose (notamment une fibrose rénale, une fibrose pulmonaire et une fibrose hépatique), de cancers progressifs ou d'autres maladies dans lesquelles une réduction de l'activité du signal de la famille des TGF-bêta est souhaitable.
PCT/US2008/008401 2007-07-09 2008-07-09 Composés spiro en tant qu'antagonistes du tgf-bêta WO2009009059A1 (fr)

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