EP1786802A1 - Pyrimidinylimidazoles utilises comme inhibiteurs de tgf-beta - Google Patents

Pyrimidinylimidazoles utilises comme inhibiteurs de tgf-beta

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Publication number
EP1786802A1
EP1786802A1 EP05789340A EP05789340A EP1786802A1 EP 1786802 A1 EP1786802 A1 EP 1786802A1 EP 05789340 A EP05789340 A EP 05789340A EP 05789340 A EP05789340 A EP 05789340A EP 1786802 A1 EP1786802 A1 EP 1786802A1
Authority
EP
European Patent Office
Prior art keywords
bicyclo
imidazol
pyrimidin
compound
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05789340A
Other languages
German (de)
English (en)
Inventor
Wen-Cherng Lee
Lihong Sun
Claudio Chuaqui
Juswinder Singh
Feng Shan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Biogen MA Inc
Original Assignee
Biogen Idec Inc
Biogen Idec MA Inc
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Application filed by Biogen Idec Inc, Biogen Idec MA Inc filed Critical Biogen Idec Inc
Publication of EP1786802A1 publication Critical patent/EP1786802A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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.
  • 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.
  • TGFjS signaling pathway underlies many human disorders (e.g., excess deposition of extracellular matrix, an abnormally high level of inflammatory responses, fibrotic 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. 205: 441-448 (1994); Matsuse, T. et ⁇ , Am. J.
  • 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 b and R c independently, can be hydrogen, hydroxy, alkyl, alkoxy, amino, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroaralkyl.
  • p can be 1 or 2
  • q can be 1-4.
  • 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.
  • the pyrimidinyl ring can fuse with a cyclic moiety to form a moiety, that can be optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, heteroaryl, aryloxy, heteroaryloxy, aroyl, heteroaroyl, amino, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylthio, sulfoxy, sulfamoyl, oxo, or carbamoyl.
  • substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as
  • X can be aryl or heteroaryl.
  • X can be an optionally substituted phenyl (e.g., alkyl or cyano).
  • Y can be a bond, -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(OV, -O", -S(O) 2 -N(R b )-, - N(R b )-, -N(R b )-C(O)-O-, -N(R b )-C(O)-N(R c )-, -C(O)-N(R b )-S(O) p -N(R c )-, or -C(O)
  • 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.
  • X can be piperidinyl, piperazinyl, or pyrrolidinyl.
  • the piperdinyl, piperazinyl, or pyrrolidinyl can be bonded to Y via its nitrogen ring atom.
  • Y can be a bond, -C(O)O-, -C(O)-N(R b )-, -S(O) 2 -, or -S(O) 2 -N(R* 3 )-, wherein R b is hydrogen or C M alkyl.
  • X can be cyclohexyl, cyclopentyl, or 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(OV, -O-, -S(O) 2 -N(R b )-, - N(R b )-, -N(R b )-C(0)-0-, -C(O)-N(R b )-O-, or -N(R b )-C(O)-N(R c )-.
  • 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).
  • R 2 can be hydrogen, C 1-6 alkyl, aryl, heteroaryl, aryl-Ci ⁇ alkyl, or heteroaryl-Ci- 4 alkyl.
  • R 2 can be hydrogen, Ci -4 alkyl, phenyl, pyridyl, imidazolyl, furanyl, thienyl, triazolyl, tetrazolyl, benzyl, phenylethyl, benzimidazolyl, benzothiazolyl, naphthylmethyl, naphthylethyl, or -Ci -2 alkyl-pyridyl; each of which, independently, is optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, trifluoromethyl, methyl, ethyl, aminocarbonyl, alkylcarbonylamino, sulfamoyl, alkoxycarbonyl, and alkylcarbony
  • R " can be hydrogen, methyl, ethyl, n-butyl, t-butyl, benzyl or pyridylmethyl.
  • R 2 can be hydrogen, hydroxymethyl, or trifluoromethyl.
  • R 1 can be benzo[l,3]dioxolyl, benzo[ ⁇ ]thiophenyl, benzo-oxadiazolyl, benzothiadiazolyl, benzoimidazolyl, benzooxazolyl, benzothiazolyl,
  • 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,
  • the compound of formula (I) can be:
  • a pharmaceutical composition includes a compound of formula (I) and a pharmaceutically acceptable carrier.
  • 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 inhibiting the TGF/3 type I receptor in a cell includes contacting said cell with 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 or preventing fibrotic condition in a subject includes administering to said 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 fibrosis, opthalmic scarring, fibrosclerosis,
  • a method of inhibiting growth or metastasis of tumor cells and/or cancers 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.
  • 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 m-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,/>-bromophenyl-sulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, oxalic acid, malonic acid, salicylic acid, malic 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).
  • the acid addition salt can be converted back to its free base form by treating the salt with a suitable dilute aqueous basic solution (e.g., sodium hydroxide, sodium bicarbonate, potassium carbonate, or ammonia).
  • a suitable dilute aqueous basic solution e.g., sodium hydroxide, sodium bicarbonate, potassium carbonate, or ammonia.
  • Compounds of formula (1) can also be, e.g., in a form of achiral compounds, racemic mixtures, optically active compounds, pure diastereomers, or a mixture of diastereomers.
  • Compounds of formula (I) exhibit surprisingly high affinity to the TGF/3 family type I receptors, AIk 5 and/or AIk 4, e.g., with ICs 0 and Kj values of less than 10 ⁇ M under conditions as described below in Examples 34 and 36, respectively.
  • Some compounds of formula (I) exhibit IC5 0 and K; 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.
  • modifications are known in the art and include those that increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism, and/or alter rate of excretion. Examples of these modifications include, but are not limited to, esterif ⁇ cation with polyethylene glycols, derivatization with pivolates or fatty acid substituents, conversion to carbamates, hydroxylation of aromatic rings, and heteroatom-substitution in aromatic rings.
  • 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 refers to an aliphatic carbon group that contains 2-8 (e.g., 2-6 or 2-4) carbon atoms and at least one double bond. Like an alkyl group, an alkenyl group can be straight or branched. Examples of an alkenyl group include, but are not limited to, allyl, isoprenyl, 2-butenyl, and 2-hexenyl.
  • 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.
  • a heterocycloalkyl or heterocycloalkenyl 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, (cycloalky ⁇ alkylcarbonylamino, arylcarbonylamino, aralkylcarbon
  • a "heteroaryl” group refers to a monocyclic, bicyclic, or tricyclic ring structure having 5 to 15 ring atoms wherein one or more of the ring atoms is a heteroatom, e.g.,
  • heteroaryl examples include pyridyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, tetrazolyl, benzofuryl, benzthiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole, and benzo[l,3]dioxole.
  • a heteroaryl is optionally substituted with one or more substiruents 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, (heterocycloalkyl)carbonylamino, (heterocycloalkyl)alkylcarbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea,
  • heteroarylkyl group refers to an alkyl group (e.g., a C M alkyl group) that is substituted with a heteroaryl group. Both “alkyl” and “heteroaryl” have been defined above.
  • 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.
  • a "carboxy” and a “sulfo” group refer to -COOH and -SO 3 H, respectively.
  • alkoxy refers to an alkyl-O- group where “alkyl” has been defined previously.
  • a "sulfoxy" group refers to -O-SO-R X or -SO-O-R X , where R x has been defined above.
  • halogen or halo group refers to fluorine, chlorine, bromine or iodine.
  • a "sulfamoyl” group refers to the structure -S(O) 2 -NR x R y or -NR X - S(O) 2 -R 2 wherein R x , R y , and R z have been defined above.
  • sulfamide refers to the structure -NR X -S(O) 2 -NR Y R Z wherein R x , R ⁇ , and R z have been defined above.
  • a "urea” group 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 .
  • R x , R ⁇ , and R z have been defined above.
  • 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. The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described by Freireich et al., Cancer Chemother. Rep., 50: 219 (1966).
  • 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.
  • 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).
  • the compounds of formula (I) are useful for studying and researching the role of TGFjS receptor type I (Alk5) and/or activin receptor type I (Alk4), such as their role in cellular processes, for example, signal transduction, production of extracellular matrix, the differentiation of stromal cells to myofibroblasts, and the stimulation of and migration of inflammatory cells.
  • TGFjS receptor type I Alk5
  • activin receptor type I Alk4
  • the compounds of formula (I) are useful for studying and researching the role of TGFjS receptor type I (Alk5) and/or activin receptor type I (Alk4), such as their role in cellular processes, for example, signal transduction, production of extracellular matrix, the differentiation of stromal cells to myofibroblasts, and the stimulation of and migration of inflammatory cells.
  • the invention features compounds of formula (I), which exhibit surprisingly high affinitiy for the TGF ⁇ family type I receptors, AIk 5 and/or AIk 4. Synthesis of the Compounds of formula (I)
  • Compounds of formula (I) may be prepared by a number of known methods from commercially available or known starting materials.
  • compounds of formula (I) are prepared according to Schemes Ia, Ib, or Ic below.
  • optionally substituted 2-methylpyrimidine (II) is deprotonated by LDA before reacting with R 1 -substituted carboxylic acid methoxy-methyl-amide (V) to form an R 1 -(6-methylpyrimidinyl)-ketone (III).
  • R 1 has been defined above.
  • the methoxy-methyl-amide can be prepared by reacting a corresponding acid chloride (i.e., R'-CO-CI) with N, 0-dimethylhydroxylamine hydrochloride.
  • R'-CO-CI acid chloride
  • the R 1 -(6-methylpyrimidinyl)-ketone (III) can then be treated with sodium nitrite in acetic acid to afford an ⁇ -keto-oxime (IV), which can undergo further reaction with an appropriate substituted (and optionally protected) aldehyde (VI) in the presence of ammonium acetate to yield a compound of formula (I).
  • the above-described compounds of formula (I) can be prepared according to Scheme Ib below. Specifically, l,l-dimethoxy-propan-2-one can first react with dimethoxymethyl-dimethyl-amine at an elevated temperature to produce the intermediate 4- dimethylamino-l,l-dimethoxy-but-3-en-2-one, which can then react with an R a -substituted amidine to form an R a -substituted pyrimidine-2-carbaldehyde (Ila).
  • This carbaldehyde (Ha) can then reacted with aniline and diphenyl phosphite to form a resulting N.P-acetal, which can further couple with an R 1 -substituted aldehyde to produced an (R'-methyty-pyrirnidinyl-ketone ( ⁇ ia). See, e.g., Journet et al., Tetrahedron Lett 39: 1717-1720 (1998).
  • a compound of formula (I) can be prepared by reacting intermediate (IV) or (FVa) with an aldehyde (VII) to yield a further intermediate (VIII), which can then react with compound (IX) to yield a compound of formula (I).
  • moieties Y' and Y" are precursors of moiety Y. See Scheme 2 below.
  • desired substitutions at R a can be obtained by selecting, for example, the appropriate compound (Ha) intermediate.
  • moiety X in compound (VTI) is a nitrogen-containing heterocycloalkyl (e.g., piperidine).
  • the nitrogen ring atom can be protected by a nitrogen protecting group (e.g., Cbz, Boc, or FMOC) before coupling to compound (IV) or (IVa) and deprotected afterwards (see first step of Scheme 3) to yield compound (Villa).
  • This compound can further react with various compounds (IX) to produce a compound of formula (I). See second steps of Scheme 3 below.
  • compound (VIII) or compound (Villa) can be a compound of formula (I) as well.
  • TGF]S family signaling pathways can result in excess deposition of extracellular matrix and increased inflammatory responses, which can then lead to fibrosis in tissues and organs (e.g., lung, kidney, and liver) and ultimately result in organ failure.
  • tissues and organs e.g., lung, kidney, and liver
  • fibrosis in tissues and organs (e.g., lung, kidney, and liver) and ultimately result in organ failure.
  • TGFjS and/or activin mR ⁇ A and the level of TGFjS and/or activin are increased in patients suffering from various fibrotic disorders, e.g., fibrotic 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.
  • fibrotic disorders e.g., fibrotic 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
  • Compounds of formula (I), which are antagonists of the TGFjS family type I receptors AIk 5 and/or AIk 4, 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 TGFjS 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 /xM; and for example, less than 5 nM) to a receptor of the pathway (e.g., AIk 5 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., AIk 5 and/or AIk 4
  • the aforementioned disorders or diseases include any condition (a) marked by the presence of an abnormally high level of TGFjS 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.
  • fibrotic conditions such as scleroderma, glomerulonephritis, diabetic nephropathy, lupus nephritis, hypertension-induced nephropathy, ocular or corneal scarring, alimentary track or gastrointestinal fibrosis, renal fibrosis,
  • 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.
  • TGF/3 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.
  • 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/5 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 TGF/3 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 TGF/3 receptors, e.g., anti-TGF/3, anti-TGF/3 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.
  • the invention will be further described in the following examples, which do not limit the scope of the invention described in the claims.
  • 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.
  • Lithium hydroxide monohydrate (0.046 g, 1.12 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 methyl ester (0.25 g, 0.56 mmol) in a mixture of THF/MeOH/H 2 O (2/1/1, 4 mL). The mixture was stirred for 3 hours, and the solvent was removed. The residue was diluted with water (30 mL). Citric acid was added to the solution to make the pH lower than 7.
  • 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.
  • Trimethylphosphite (1.0 mL, 9.7 mmol) was added to a solution of 4-[l-hydroxy-4-(6- methyl-pyridin-2-yl)-5-(2-methylsulfanyl-pyrimidin-4-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester (0.9 g, 1.93 mmol; see Example 6 above) in
  • 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 (

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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.
EP05789340A 2004-08-31 2005-08-24 Pyrimidinylimidazoles utilises comme inhibiteurs de tgf-beta Withdrawn EP1786802A1 (fr)

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US9446175B2 (en) 2011-06-03 2016-09-20 Yale University Compositions and methods for treating and preventing neointimal stenosis
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JP6433974B2 (ja) 2013-03-14 2018-12-05 トレロ ファーマシューティカルズ， インコーポレイテッド Ｊａｋ２およびａｌｋ２阻害剤およびその使用方法
US9242969B2 (en) 2013-03-14 2016-01-26 Novartis Ag Biaryl amide compounds as kinase inhibitors
EP3116512B1 (fr) * 2014-03-11 2020-06-10 Dai Niann-tzyy Composition pharmaceutique et méthode pour réduire la formation de cicatrices
UY36294A (es) 2014-09-12 2016-04-29 Novartis Ag Compuestos y composiciones como inhibidores de quinasa
ES3038189T3 (en) 2015-12-11 2025-10-10 Res Inst Nationwide Childrens Hospital Systems and methods for optimized patient specific tissue engineering vascular grafts
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WO2020023910A1 (fr) 2018-07-26 2020-01-30 Tolero Pharmaceuticals, Inc. Procédés de traitement de maladies associées à l'expression anormale d'acvr1 et inhibiteurs d'acvr1 destinés à être utilisés dans ceux-ci
US20220177978A1 (en) 2019-04-02 2022-06-09 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods of predicting and preventing cancer in patients having premalignant lesions
ES3025633T3 (en) 2019-05-13 2025-06-09 Novartis Ag New crystalline forms of n-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methvlphenyl)-2(trifluoromethyl)isonicotinamide as raf inhibitors for the treatment of cancer
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AU2005280168A1 (en) 2006-03-09

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