WO2017006295A1 - Dérivés d'hydroxy formamide et leur utilisation - Google Patents

Dérivés d'hydroxy formamide et leur utilisation Download PDF

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WO2017006295A1
WO2017006295A1 PCT/IB2016/054119 IB2016054119W WO2017006295A1 WO 2017006295 A1 WO2017006295 A1 WO 2017006295A1 IB 2016054119 W IB2016054119 W IB 2016054119W WO 2017006295 A1 WO2017006295 A1 WO 2017006295A1
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methyl
hydroxyformamido
heptanamido
carbamoyl
propyl
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PCT/IB2016/054119
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English (en)
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Sarah E. Dowdell
Hilary Schenck Eidam
Mark ELBAN
Ryan Michael Fox
Mark A. Hilfiker
Tram H. Hoang
Lara S. Kallander
Brian Griffin Lawhorn
Sharada Manns
Joanne Philp
David G. Washburn
Guosen Ye
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Glaxosmithkline Intellectual Property (No.2) Limited
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
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    • C07—ORGANIC CHEMISTRY
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    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
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    • C07C309/57—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing carboxyl groups bound to the carbon skeleton
    • C07C309/60—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing carboxyl groups bound to the carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
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    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
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    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
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    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
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    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • the present invention relates to compounds that inhibit BMP1 (also known as BMP-1)
  • the present invention relates to reverse hydroxamate compounds as BMP1 , TLL1 and/or TLL2 inhibitors.
  • Fibrous collagens are integral parts of the extracellular matrix that support tissue integrity and maintain the cellular microenvironment for normal physiological functions.
  • Collagens l-lll the major isoforms of the fibrous collagen protein family, are synthesized as procollagen precursors containing N-terminal and C-terminal propeptides.
  • the procollagens are post-translationally modified by proline hydroxylation, and secreted into the peri-vascular space for further processing.
  • N-terminal propeptides of the collagens are subsequently cleaved by proteinases of the ADAMTS (A Distintegrin And Metalloproteinase with
  • ThromboSpondin repeats family, while the C-terminal propeptides are processed by the Tolloid family of metalloproteases, which include BMP1 , TLL1 and TLL2 (Hopkins, D.R. et al., Matrix Biology, 2007, 26, 508-523).
  • BMP1 BMP1
  • TLL1 TLL2
  • TLL2 Tetra-Lysine
  • the cleavage of both N-terminal and C-terminal propeptides allows further maturation of the collagen, leading to cross-linking at lysine residues and formation of insoluble fibrillar structures (Shoulders, M.D. et al., Annual Review of Biochemistry, 2009, 78, 929-958).
  • this family also includes isoforms of BMP1 , including multiple isofoms of BMP1 that result from alternative splicing of the same gene product (see e.g.,Takahara, K., et al., The Journal of Biological Chemistry, 1994, 269. 32572-32578; and Cvetjeticanin, B. et al., Medical
  • BMP-1-1 or BMP1-1 Other BMP1 isoforms encoded by splice variant RNA transcripts have been described at the transcriptional level and designated with sequential suffixes, e.g., as BMP-1-2, BMP-1-3, BMP-1-4, BMP-1-5, BMP-1-6, and BMP-1-7 (see, e.g., Wozney et al., Science (1988), 242: 1528-1534; Kessler et al., Science, (1996) 271 : 360-362; Li et al., Proc. Natl. Acad. Sci. USA (1996), 93: 5127-5130; Janitz et al., J. Mol. Med. (1998), 76: 141-146; Takahara et al., J. Biol. Chem. (1994), 269: 32572-32578; and Ge and Greenspan, Birth Defect Res. (2006), 78: 47-68).
  • BMP1 isoforms have also been confirmed at the protein level as circulating in the blood of patients with various diseases and in healthy humans (see, e.g., International Patent publication Nos. WO2008/01 1193 A2 and WO2013/163479 A1 , and Grgurevic et al., J. Am. Soc. Nephrol. (201 1), 21 :681-692).
  • BMP1 the role of BMP1 in processing procollagen leading to fibrosis and scar tissue formation in a variety of diseases as well as the discovery of blood profiles comprising individual BMP1 isoforms in patients with various diseases has made BMP1 an attractive target for developing new therapies (see, e.g.
  • RNA splice variants (www.ensembl.orq; gene identifier ENSG00000038295) may exist and at least two expressed proteins (wvvw.uniorot.org.
  • RNA splice variants have been reported for the gene that encodes TLL2 (www. ensem bl . org; gene identifier
  • ENSG00000095587 one of which is thought to encode functional protein ( vvyy unlprotorg, protein identifier Q9Y6L7).
  • ECM extracellular matrix
  • collagen can lead to fibrotic pathologies in various organs or tissues that may be associated with increased tissue rigidity, parenchymal replacement, aberrant electrical conductance, sclerotic wound healing (e.g. infarction and burns), and/or abnormal cell-cell interactions.
  • ECM extracellular matrix
  • sclerotic wound healing e.g. infarction and burns
  • increased fibrosis and collagen production are consistently observed in patients with acute and chronic cardiac diseases, e.g., heart failure, arrhythmias, hypertrophic cardiomyopathy, and myocardial infarction (Lopez, B.
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • NASH nonalcoholic steatohepatitis
  • the Tolloid family of metal loproteases (BMP1 , TLL1 and TLL2) has additional substrates beyond collagens that may also contribute to its role in promoting ECM protein production.
  • BMP1 , TLL1 and TLL2 The Tolloid family of metal loproteases (BMP1 , TLL1 and TLL2) has additional substrates beyond collagens that may also contribute to its role in promoting ECM protein production.
  • LOX1 lysyl oxidase 1
  • BMP1 also has a role in the development of pathological tissue stiffness via this mechanism, for example in glaucoma (Tovar-Vidales, T., et al., Investigative Ophthalmology & Visual Science, 2013, 54, 4741-4748) and in diastolic dysfunction in the heart (Lopez, B., et al., American Journal of Physiology - Heart and Circulatory Physiology,
  • BMP1 also cleaves additional collagens, e.g. procollagens V and XII which influence fibril size and shape, as well as non-fibrillar procollagen VII (Hopkins, D.R. et al., Matrix Biology, 2007, 26, 508-523).
  • Latent TGF-beta binding protein (LTBP) has also been shown to be cleaved by BMP1 , allowing enhanced TGF-beta action to induce further collagen production (Ge, G., et al., Journal of Cell Biology, 2006, 175, 11 1-120).
  • TGF-beta may also play roles in other pathologies, such as control of cancer cell metastasis and invasion (Wu, X., et al. Oncogene, 2014, 33, 1506-1514).
  • BMP1 , TLL1 and/or TLL2 also activate a broader range of other TGF-beta like molecules, such as BMPs 2 and 4, by proteolytically processing interacting proteins (Hopkins, D.R. et al., Matrix Biology, 2007, 26, 508-523).
  • BMP1 The combined actions of BMP1 and its various substrates suggest that BMP1 , TLL1 and TLL2 are key regulators of tissue ECM production/maturation and that the members of the tolloid family of metalloproteases are particularly effective targets for anti-fibrosis therapeutic intervention.
  • BMP1 , TLL1 and TLL2 may also affect other biological pathways via additional substrate processing. In particular, they may affect muscle biology via promoting activation of myostatin.
  • Myostatin is a hormone that negatively regulates muscle growth (Lee, S. J., 2004, Annual Review of Cell & Developmental Biology, 20, 61-86).
  • BMP1 has been demonstrated to cleave an inhibitory pro-peptide of myostatin and thus enhance myostatin activity (Wolfman N.M., et al., Proceedings of the National Academy of Sciences, 2003, 100, 15842-15846).
  • Knockout of TLL2 in mice demonstrated enhanced muscle mass, thereby providing support for the connection between tolloid metalloprotease and myostatin (Lee, S.J., PLoS one, 2008, 3, e1628).
  • An inhibitor of BMP1 , TLL1 and/or TLL2 could therefore be beneficial in diseases where muscle function or muscle mass is diminished, including muscular dystrophy, sarcopenia, and cachexia associated with, e.g., heart failure, CKD, COPD, cancer or old age.
  • BMP1 , TLL1 and TLL2 lends strong support for their key roles in collagen processing, assembly and cross-linking, leading to the formation of a fibrillar collagen network that maintains tissue integrity and proper cellular microenvironment.
  • This family of proteins may also play important roles in the etiology of fibrotic conditions, for example in the heart, lung, skeletal muscle, kidney, liver, skin, vasculature, nervous system, and eye, and inhibitors of these metalloproteases may provide broad benefits as anti-fibrotic agents for the treatment of diseases associated with fibrosis, such as myocardial infarction, heart failure, cardiac arrhythmias, hypertrophic cardiomyopathy, chronic kidney disease (CKD), post-acute kidney injury, diabetic nephropathy, delayed graft function post- transplantation, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), liver cirrhosis, non-alcoholic steatohepatitis (NASH
  • oculopharyngeal distal, and Emery-Dreifuss
  • glaucoma corneal scarring
  • keloids wound healing
  • adhesions hypertrophic scarring
  • other scarring e.g. associated with burns, surgery or other trauma, stroke
  • collagen vascular diseases such as systemic lupus erythematosus, rheumatoid arthritis and scleroderma, spinal cord injury and multiple sclerosis.
  • BMP1 , TLL1 and TLL2 inhibitors may have additional therapeutic applications in muscular disease based on their impact on myostatin biology, in particular muscular dystrophies (e.g., Duchenne, Becker, limb-girdle, congenital, facioscapulohumeral, myotonic, oculopharyngeal, distal, and Emery-Dreifuss), sarcopenia, and cachexia associated with, e.g., heart failure, CKD, COPD, cancer or old age.
  • muscular dystrophies e.g., Duchenne, Becker, limb-girdle, congenital, facioscapulohumeral, myotonic, oculopharyngeal, distal, and Emery-Dreifuss
  • sarcopenia e.g., and cachexia associated with, e.g., heart failure, CKD, COPD, cancer or old age.
  • the present invention relates to compounds of Formula (I):
  • W1 , W2, W3 and W4 are N and the remainder are CR a , or each of W1 , W2, W3 and W4 are CR a ,
  • each R a is H, or one R a is selected from F, CF 3 , and C0 2 H, and the remainder are H;
  • R1 is selected from H, (C C 4 ) straight chain alkyl, and (C C 4 ) straight chain alkyl substituted with one hydroxy group;
  • R2 is selected from H, (C Cn)alkyl, (CrC 3 )alkyl(C3-C 6 )cycloalkyl, (C C 3 )alkyl-phenyl, (C C 3 )alkyl-naphthyl, and (CrC 3 )alkyl-heterocyclyl, wherein heterocyclyl is a monocyclic ring having 5-6 ring atoms wherein 1-2 of the ring atoms are selected from nitrogen, oxygen and sulfur, and wherein said (d-Cn)alkyl, (CrC 3 )alkyl(C 3 -C 6 )cycloalkyl, (CrC 3 )alkyl-phenyl, (C C 3 )alkyl-naphthyl, and (CrC 3 )alkyl-heterocyclyl are optionally substituted with 1-2 groups independently selected from (C C 4 )alkyl, (C C 4 )alkoxy
  • R3 is selected from phenyl and heteroaryl, wherein said phenyl and heteroaryl are optionally substituted with 1-3 groups independently selected from:
  • (CrC 6 )alkyl optionally substituted with 1-3 groups independently selected from: fluoro (e.g., -CF 3 ); -C0 2 H; -P(0)R f R 9 ; NR a R wherein R a is selected from H and (C C 4 )alkyl and R is selected from (C C 4 )alkyl substituted with 1-3 -C0 2 H or -P(0)R f R 9 ; and - C(0)NR a R wherein R a and R are independently selected from H and (C C 4 )alkyl, wherein the (C C 4 )alkyl is optionally substituted with 1-3 groups independently selected from hydroxy, -C0 2 H, -C(0)0(C C 4 )alkyl and -P(0)R f R 9 ; cyclopropyl, optionally substituted with 1 -C0 2 H;
  • R a and R are independently selected from H and (C C 4 )alkyl, wherein the (C C 4 )alkyl is optionally substituted with 1-3 groups independently selected from hydroxy, -C0 2 H, -C(0)0(C C 4 )alkyl, -P(0)R f R 9 , NR c R d and N + R c R d R e ;
  • (C C 6 )alkoxy optionally substituted with 1-3 substituents independently selected from halo, hydroxy, -C0 2 H, (C 3 -C 6 )cycloalkyl, -C(0)NH 2 and pyrrolidinyl;
  • R a and R are independently selected from H and (C C 4 )alkyl, wherein the (C C 4 )alkyl is optionally substituted with 1-3 groups independently selected from oxo and -C0 2 H;
  • R a is selected from H and (C C 4 )alkyl
  • R c , R d and R e are independently selected from H and (C C 2 )alkyl;
  • R f and R 9 are independently selected from hydroxy, (C C 2 )alkyl and (C C 2 )alkoxy; and n is 0 or 1.
  • the compounds according to Formula (I), or salts, particularly pharmaceutically acceptable salts, thereof, are inhibitors of BMP1 , TLL1 and/or TLL2.
  • the present invention is also directed to a method of inhibiting BMP1 , TLL1 and/or TLL2 which method comprises contacting a biological material comprising the protein(s) with a compound according to Formula (I), or a salt, particularly a
  • the invention is further directed to a method of treating a disease associated with BMP1 , TLL1 and/or TLL2 activity in a subject (e.g., a human or other mammal, particularly a human) in need thereof, including for example treatment of a disease where inhibition of BMP1 , TLL1 and/or TLL2 is of therapeutic benefit, which comprises administering to the subject a therapeutically effective amount of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof.
  • This invention also provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy, e.g. as an active therapeutic substance in the treatment of a disease associated with BMP1 , TLL1 and/or TLL2 activity.
  • the invention also provides for the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a disease associated with BMP1 , TLL1 and/or TLL2 activity.
  • the present invention is further directed to a pharmaceutical composition comprising a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • this invention is directed to a pharmaceutical composition for the treatment of a disease associated with BMP1 , TLL1 and/or TLL2 activity, where the composition comprises a compound according to
  • Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients are included in the pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • the disease associated with BMP1 , TLL1 and/or TLL2 activity is selected from those associated with pathological fibrotic conditions in body organs or tissues, e.g., such conditions of the: heart (e.g., myocardial infarction ("Ml"), heart failure (e.g., heart failure with reduced ejection fraction, heart failure with preserved ejection fraction), cardiac arrhythmias (e.g., atrial fibrillation), hypertrophic cardiomyopathy), lung (e.g. chronic obstructive pulmonary disease ("COPD”), idiopathic pulmonary fibrosis (“IPF”)), kidney (e.g.
  • Ml myocardial infarction
  • COPD chronic obstructive pulmonary disease
  • IPF idiopathic pulmonary fibrosis
  • liver e.g. liver cirrhosis, non-alcoholic steatohepatitis (“NASH”)
  • eye e.g. glaucoma, corneal scarring
  • skeletal muscle e.g.
  • muscular dystrophies including Duchenne, Becker, limb-girdle, congenital,
  • facioscapulohumeral, myotonic, oculopharyngeal, distal, and Emery-Dreifuss skin (e.g. keloids, wound healing, adhesions, hypertrophic scarring and other scarring, e.g., associated with burns, surgery or other trauma), the vasculature (e.g. stroke, and collagen vascular diseases such as systemic lupus erythematosus, rheumatoid arthritis and scleroderma), and the nervous system (e.g. spinal cord injury, multiple sclerosis).
  • skin e.g. keloids, wound healing, adhesions, hypertrophic scarring and other scarring, e.g., associated with burns, surgery or other trauma
  • the vasculature e.g. stroke, and collagen vascular diseases such as systemic lupus erythematosus, rheumatoid arthritis and scleroderma
  • the nervous system e.
  • the disease associated with BMP1 , TLL1 and/or TLL2 activity is selected from muscular diseases characterized by reduced muscle function and/or mass, e.g., muscular dystrophy (e.g., Duchenne, Becker, limb-girdle, congenital, facioscapulohumeral, myotonic, oculopharyngeal, distal, and Emery-Dreifuss), sarcopenia, and cachexia associated with, e.g., heart failure, CKD, COPD, cancer, or old age.
  • muscular dystrophy e.g., Duchenne, Becker, limb-girdle, congenital, facioscapulohumeral, myotonic, oculopharyngeal, distal, and Emery-Dreifuss
  • sarcopenia e.g., CKD, COPD, cancer, or old age.
  • alkyi represents a saturated hydrocarbon moiety which, unless otherwise stated, may be straight or branched.
  • C C 2 alkyi C C 3 alkyi
  • C1-C4 alkyi CrC 6 alkyi
  • d-Cn alkyi refer to an alkyi group or moiety containing 1- 2, 1-3, 1-4, 1-6, or 1-1 1 carbon atoms respectively.
  • Exemplary alkyls include, but are not limited to methyl (Me), ethyl (Et), n-propyl, isopropyl (iPr), n-butyl, s-butyl, isobutyl, t-butyl, pentyl (also known as n-pentyl), and 2-ethylbutyl, as well as hexyl, heptyl, octyl, nonyl, decyl and undecyl, including the branched isomers of these groups.
  • cycloalkyl refers to a non-aromatic, saturated, cyclic hydrocarbon ring moiety.
  • (C3-C 6 )cycloalkyl refers to a non-aromatic cyclic hydrocarbon ring moiety having three to six ring carbon atoms.
  • (C 3 -C 6 )cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • Alkoxy refers to an alkyi radical attached through an oxygen linking atom.
  • the terms “(C C 4 )alkoxy” and “(C C 6 )alkoxy” refer to a straight- or branched-chain hydrocarbon radical containing 1-4 or 1-6 carbon atoms respectively, attached through an oxygen linking atom.
  • “(CrC 4 )alkoxy” and “(CrC 6 )alkoxy” may be alternatively designated as -0(C C 4 alkyi) and -0(C C 6 alkyi) respectively.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, isobutoxy, t-butoxy, pentoxy, and hexoxy, including the branched isomers of these groups.
  • Cycloalkoxy refers to a cycloalkyl radical attached through an oxygen linking atom.
  • the term “(C3-C 6 )cycloalkoxy” refers to a cycloalkyl radical having 3 to 6 ring carbon atoms, attached through an oxygen linking atom.
  • “(C3-C 6 )cycloalkoxy” may be alternatively designated as -0(C 3 -C 6 )cycloalkyl.
  • Exemplary cycloalkoxy groups include cyclopropyloxy, cyclobutyloxy, cyclpentyloxy, and cyclohexyloxy.
  • heterocyclic alternatively referred to as heterocyclyl
  • heterocyclyl group or moiety is a mono- or bi-cyclic group or moiety having as ring members atoms of at least two different elements (carbon and one or more of nitrogen, oxygen and/or sulfur).
  • the ring(s) may be saturated or partially unsaturated (non-aromatic) or fully unsaturated (aromatic).
  • heterocyclic alternatively referred to as heterocyclyl group or moiety is a mono- or bi-cyclic group or moiety having as ring members atoms of at least two different elements (carbon and one or more of nitrogen, oxygen and/or sulfur).
  • the ring(s) may be saturated or partially unsaturated (non-aromatic) or fully unsaturated (aromatic).
  • heterocyclyl may be a cyclic group or moiety having 5-10 ring atoms (i.e. "5-10 membered") wherein 1-4 of the ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, e.g., a monocyclic ring having 5-6 ring atoms wherein 1-2 of the ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, or a bicyclic ring having 9-10 ring atoms wherein 1-4 of the ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur.
  • Heterocycloalkyl represents a group or moiety which is a non-aromatic, monocyclic radical, which is saturated or partially unsaturated, having 5-6 ring atoms wherein 1-2 of the ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur.
  • Illustrative examples of heterocycloalkyl groups include, but are not limited to, piperidyl (or piperidinyl), piperazinyl, morpholinyl, tetrahydrofuryl (or tetrahydrofuranyl), tetrahydropyranyl,
  • Heteroaryl refers to a mono- or bi-cyclic group or moiety wherein at least one ring is aromatic, having 5- 10 ring atoms wherein 1-4 of the ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur.
  • bicyclic heteroaryl at least one ring is aromatic and the other ring may be aromatic, or saturated or unsaturated non-aromatic, and at least one ring is heterocyclic and the other ring may be heterocyclic or carbocyclic.
  • this term encompasses but is not limited to bicyclic heterocyclic compounds containing at least one aromatic carbocyclic or heterocylic ring moiety, e.g., a phenyl ring moiety fused to a heterocycloalkyl ring moiety.
  • heteroaryls include, but are not limited to, thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl (or furanyl), isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridyl (or pyridinyl), pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl, indazolyl, benzothienyl, benzofuranyl, benzothiazolyl, benzimidazolyl, benzoxazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, 2,3- dihydrobenzoisothiazolyl, and 1 ,1-dioxido-2,3-dihydrobenzoisothiazolyl (e.g., 1 ,1-di
  • heterocyclic, heteroalkyl or heteroaryl group e.g., pyridyl
  • it is intended to encompass any one of the various position isomers (e.g., 2-pyridyl, 3-pyridyl, etc).
  • compounds of the invention comprise a 5-membered or
  • 6-membered monocyclic heteroaryl group comprising at least one nitrogen ring atom, e.g., such groups as particularly disclosed herein.
  • Selected 5-membered heteroaryl groups contain one nitrogen, and optionally contain one oxygen ring atom or 1 , 2 or 3 additional nitrogen ring atoms.
  • Selected 6-membered heteroaryl groups contain 1 , 2, or 3 nitrogen ring heteroatoms.
  • compounds of the invention comprise a 9-membered or 10-membered bicyclic heteroaryl group, e.g. such groups as particularly disclosed herein.
  • Selected 9-10 membered heteroaryl groups contain one nitrogen, oxygen or sulfur ring heteroatom, and optionally contain 1 , 2, or 3 additional nitrogen ring atoms.
  • heterocyclic, heteroaryl, and heterocycloalkyl are intended to encompass stable heterocyclic groups where a ring nitrogen heteroatom is optionally oxidized (e.g., heterocyclic groups containing an N-oxide, e.g., pyridine-N-oxide), or where a ring sulfur heteroatom is optionally oxidized (e.g., heterocyclic groups containing sulfones or sulfoxide moieties, e.g., tetrahydrothienyl-1 -oxide [a tetrahydrothienyl sulfoxide], tetrahydrothienyl- 1 , 1 -dioxide [a tetrahydrothienyl sulfone], or 1 ,1-dioxido-2,3- dihydrobenzoisothiazolyl [e.g., 1 , 1-dioxido-2,3-dihydrobenzo[d]isothiazolyl [e.g
  • alkyl When the term “alkyl” is used in combination with other groups, e.g., "(C C 3 )alkyl- (C 3 -C 6 )cycloalkyl", “(Ci-C 3 )alkyl-phenyl” and “(CrC 3 )alkyl-heterocyclyl", the alkyl moiety is intended to encompass a divalent straight or branched-chain hydrocarbon radical and the cycloalkyl, phenyl, and heterocyclyl moieties are as defined herein.
  • (C C 3 )alkyl-phenyl the (C C 3 )alkyl moiety thereof is a divalent straight or branched-chain carbon radical linked to the aryl group phenyl, and is represented by the bonding
  • benzyl group (-CH 2 -phenyl).
  • Particular examples of such groups include (cyclopentyl)methyl, 2-phenylethyl, 3-phenylpropyl, and 2-naphthylethyl.
  • halogen and “halo” represent chloro, fluoro, bromo or iodo substituents.
  • Hydroxo or "hydroxyl” is intended to mean the radical -OH.
  • Cyano means the radical -CN.
  • Niro means the radical -N0 2 .
  • COO" and “C0 2 " may be used interchangeably (e.g., COOH and C0 2 H; COOEt and C0 2 Et are interchangeable respectively).
  • P0 3 H 2 and P(0)(OH) 2 may be used interchangeably.
  • the terms "compound(s) of the invention” or “compound(s) of this invention” mean a compound of Formula (I), as defined above (including more particular embodiments), in any form, i.e., any salt or non-salt form (e.g., as a free acid or base form, or as a salt, particularly a pharmaceutically acceptable salt thereof) and any physical form thereof (e.g., including non-solid forms (e.g., liquid or semi-solid forms), and solid forms (e.g., amorphous or crystalline forms, specific polymorphic forms, solvate forms, including hydrate forms (e.g., mono-, di- and hemi- hydrates)), and mixtures of various forms.
  • any salt or non-salt form e.g., as a free acid or base form, or as a salt, particularly a pharmaceutically acceptable salt thereof
  • any physical form thereof e.g., including non-solid forms (e.g., liquid or semi-solid forms), and solid forms (e
  • the term "optionally substituted” indicates that a group, ring or moiety (such as an alkyl, cycloalkyl, alkoxy, cycloalkoxy, heterocycloalkyl, phenyl, heteroaryl, carbocyclic or heterocyclic group, ring or moiety) may be unsubstituted, or the group, ring or moiety may be substituted with one or more substituent(s) as defined.
  • the selected substituent(s) for each group, ring or moiety may be the same or different, i.e. the substituent(s) are selected independently for each group, ring or moiety.
  • more than one substituent is selected from a number of possible
  • substituents those substituents may be the same or different, i.e. the substituents are selected independently.
  • BMP1 , TLL1 and/or TLL2 encompasses one or more of BMP1 ,
  • BMP1 may include one or more of the isoforms BMP-1-1 , BMP-1-2, BMP-1-3, BMP-1-4, BMP-1-5, BMP-1-6, and BMP-1-7.
  • the present invention is directed to a compound of Formula (I):
  • W1 , W2, W3 and W4 are N and the remainder are CR a , or each of W1 , W2, W3 and W4 are CR a ,
  • each R a is H, or one R a is selected from F, CF 3 , and C0 2 H, and the remainder are H;
  • R1 is selected from H, (C C 4 ) straight chain alkyl, and (C C 4 ) straight chain alkyl substituted with one hydroxy group;
  • R2 is selected from H, (C Cn)alkyl, (CrC 3 )alkyl(C3-C 6 )cycloalkyl, (C C 3 )alkyl-phenyl, (C C 3 )alkyl-naphthyl, and (CrC 3 )alkyl-heterocyclyl, wherein heterocyclyl is a monocyclic ring having 5-6 ring atoms wherein 1-2 of the ring atoms are selected from nitrogen, oxygen and sulfur, and wherein said (d-Cn)alkyl, (CrC 3 )alkyl(C 3 -C 6 )cycloalkyl, (CrC 3 )alkyl-phenyl, (C C 3 )alkyl-naphthyl, and (CrC 3 )alkyl-heterocyclyl are optionally substituted with 1-2 groups independently selected from (C C 4 )alkyl, (C C 4 )alkoxy
  • (C C 6 )alkyl optionally substituted with 1-3 groups independently selected from: fluoro (e.g., -CF 3 ); -C0 2 H; -P(0)R f R 9 ; NR a R wherein R a is selected from H and (C C 4 )alkyl and R is selected from (C C 4 )alkyl substituted with 1-3 -C0 2 H or -P(0)R f R 9 ; and - C(0)NR a R wherein R a and R are independently selected from H and (C C 4 )alkyl, wherein the (C C 4 )alkyl is optionally substituted with 1-3 groups independently selected from hydroxy, -C0 2 H, -C(0)0(C C 4 )alkyl and -P(0)R f R 9 ;
  • R a and R are independently selected from H and (C C 4 )alkyl, wherein the (C C 4 )alkyl is optionally substituted with 1-3 groups independently selected from hydroxy, -C0 2 H, -C(0)0(C C 4 )alkyl, -P(0)R f R 9 , NR c R d and N + R c R d R e ;
  • (C C 6 )alkoxy optionally substituted with 1-3 substituents independently selected from halo, hydroxy, -C0 2 H, (C 3 -C 6 )cycloalkyl, -C(0)NH 2 and pyrrolidinyl;
  • R a and R are independently selected from H and (C C 4 )alkyl, wherein the (C C 4 )alkyl is optionally substituted with 1-3 groups independently selected from oxo and -C0 2 H;
  • R a is selected from H and (C C 4 )alkyl; -CO 2 H; -C(NOH)NH 2; cyano; -C(0)0(C C 4 )alkyl; -C(0)C0 2 H; -P(0)R f R 9 ; - OP(0)R f R 9 ; halo; hydroxy; nitro; -NHS0 2 (CrC 2 )alkyl; -SO 3 H; -S0 2 (C C 2 )alkyl; -S0 2 NR c R d ; - S0 2 NHC(0)(C C 2 )alkyl; -B(OH) 2 ; and oxo;
  • R c , R d and R e are independently selected from H and (C C 2 )alkyl;
  • R f and R 9 are independently selected from hydroxy, (C C 2 )alkyl and (C C 2 )alkoxy; and n is 0 or 1.
  • W1 , W2, W3 and W4 are N and the remainder are CR a .
  • W1 is N and the remainder are CR a .
  • W1 and one of W2 and W3 are N,and W4 is CR a .
  • each of W1 , W2, W3 and W4 are CR a .
  • each R a is H.
  • R1 is H or (C C 4 ) straight chain alkyi, in more particular embodiments H, methyl or ethyl, in even more particular embodiments, H or ethyl and yet more particularly ethyl.
  • R1 is (C C 4 ) straight chain alkyi substituted with one hydroxy group; in particular embodiments -CH 2 OH.
  • R2 is H.
  • R2 is selected from optionally substituted: (d-Cn)alkyl (e.g. C 3 -C 7 alkyi, e.g. C 4 -C 6 alkyi), in more particular embodiments n-pentyl (i.e. pentyl), or 2-ethylbutyl, and even more particularly pentyl.
  • (d-Cn)alkyl e.g. C 3 -C 7 alkyi, e.g. C 4 -C 6 alkyi
  • n-pentyl i.e. pentyl
  • 2-ethylbutyl 2-ethylbutyl
  • R2 is selected from optionally substituted: (CrC 3 )alkyl(C 3 - C 6 )cycloalkyl, in more partucular embodiments cyclopropylmethyl or cyclopentyl methyl.
  • R2 is selected from optionally substituted: (CrC 3 )alkyl-phenyl, in particular embodiments benzyl, 2-phenylethyl (i.e. phenylethyl), or 3-phenylpropyl (i.e.
  • R2 is selected from (CrC 3 )alkyl-naphthyl; iin particular embodiments 2-naphthylethyl.
  • said R2 groups are substituted as defined in accordance with Formula (I). In some embodiments, said R2 groups are unsubstituted.
  • R1 and R2 have (R) stereochemistry.
  • R3 is phenyl, pyridyl, pyridazinyl, pyrimidinyl, oxazolyl, tetrazolyl, pyrazolyl, indazolyl, or 1 , 1-dioxido-2,3-dihydrobenzo[d]isothiazolyl (in more particular embodiments, phenyl, pyridyl, indazolyl, or 1 , 1-dioxido-2,3-dihydrobenzo[d]isothiazolyl), including the various position isomers thereof, where such groups are optionally substituted as defined above in accordance with Formula (I), including more particular embodiments of Formula (I).
  • R3 is phenyl optionally substituted in accordance with the definition of Formula (I), including more particular embodiments of Formula (I).
  • R3 is 3,4- or 3,5- disubstituted phenyl wherein the substituent groups are selected in
  • R3 is phenyl substituted with ethoxy in the 3-position and - P(0)(OH) 2 or -C0 2 H in the 4- or 5- position (especially -P(0)(OH) 2 , particularly in the 5- position) .
  • R3 is phenyl substituted with ethoxy in the 3-position and - OCH 2 C0 2 H, or -C(0)NHCH(C0 2 H)(CH 2 C0 2 H) in the 4- or 5- position (especially - C(0)NHCH(C0 2 H)(CH 2 C0 2 H), particularly in the 4-position).
  • R3 is phenyl substituted with -OCH 2 C0 2 H in the 3-position and -C(0)NHCH(C0 2 H)(CH 2 C0 2 H) in the 4 or 5 position (particularly in the 4-position).
  • R3 is phenyl substituted with 1-3 groups independently selected from: -OCH 3 , - OC 2 H 5 , -OC 3 H 7 , -OCH(CH 3 ) 2 , -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -OCH 2 CHF 2 , -OC 2 H 4 - pyrrolidinyl, -OCH 2 C0 2 H, -OCH 2 C(0)NH 2 , -C0 2 H, -CH 3 , cyclopropanyl-1-carboxylic acid, - CH 2 C0 2 H, -C(CH 3 ) 2 C0 2 H, -CH(CH 3 )C0 2 H, -CF 2 C0 2 H, -CH 2 C(0)NHCH(C0 2 H)(CH 2 C0 2 H), - CH 2 P(0)(OH) 2 ,-
  • R3 is phenyl substituted with 1-3 groups independently selected from: -OC 2 H 5 , OCH 2 C0 2 H, CONHCH(C0 2 H)(CH 2 C0 2 H), P(0)(OH) 2 , C0 2 H, CH 2 C0 2 H, CH 2 CONHCH(C0 2 H)(CH 2 C0 2 H), OH, and S0 3 H, in more particular embodiments independently selected from: : -OC 2 H 5 , OCH 2 C0 2 H, -CONHCH(C0 2 H)(CH 2 C0 2 H), and P(0)(OH) 2 .
  • R3 is phenyl substituted with 1-3 groups independently selected from: methyl, ethyl, isopropyl, CF 3 , CH 2 C0 2 H, CH(CH 3 ) 2 (C0 2 H),
  • R3 is optionally substituted heteroaryl as defined above for Formula (I). In some embodiments, R3 is an optionally substituted monocyclic heteroaryl ring comprising 5-6 ring atoms comprising 1-4
  • R3 is optionally substituted: pyridyl, pyridazinyl, pyrimidinyl, oxazolyl, tetrazolyl, pyrazolyl, indazolyl, or 1 ,1-dioxido-2,3-dihydrobenzo[d]isothiazolyl.
  • R3 is optionally substituted: pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, tetrazolyl, or oxazolyl.
  • R3 groups may be optionally substituted as defined in accordance with Formula (I).
  • the heteroaryl ring is substituted with 1-3 groups independently selected from: - OCH 3 , -OC 2 H 5 , -OC 3 H 7 , -OCH(CH 3 ) 2 , -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -OCH 2 CHF 2 , -OC 2 H 4 - pyrrolidinyl, -OCH 2 C0 2 H, -OCH 2 C(0)NH 2 , -C0 2 H, -CH 3 , cyclopropanyl-1-carboxylic acid, - CH 2 C0 2 H, -C(CH 3 ) 2 C0 2 H, -CH(CH 3 )C0 2 H, -CF 2 C0 2 H, -CH 2 C(0)NHCH(C0 2 H)(CH 2 C0 2 H), - CH 2 P(0)(OH) 2 ,-
  • the heteroaryl R3 group is substituted with 1-3 groups independently selected from: -OC 2 H 5 , OCH 2 C0 2 H, CONHCH(C0 2 H)(CH 2 C0 2 H), P(0)(OH) 2 , C0 2 H, CH 2 C0 2 H, CH 2 CONHCH(C0 2 H)(CH 2 C0 2 H), OH, and S0 3 H, in more particular embodiments selected from: -OC 2 H 5 , OCH 2 C0 2 H, CONHCH(C0 2 H)(CH 2 C0 2 H), and
  • R3 is heteroaryl substituted with 1-3 groups independently selected from: methyl, ethyl, isopropyl, CF 3 , CH 2 C0 2 H, CH(CH 3 ) 2 (C0 2 H),
  • n is 0.
  • n 1
  • R1 is (C C 4 ) straight chain alkyl; R2 is (C Cn) alkyl; R3 is phenyl substituted as defined in accordance with Formula (I); and n is 0.
  • R3 phenyl is substituted with 1-2 groups or 1-3 groups independently selected from -OC 2 H 5 , OCH 2 C0 2 H, - CONHCH(C0 2 H)(CH 2 C0 2 H), and P(0)(OH)2.
  • R3 phenyl is 3,4- or 3,5-disubstituted with 2 groups independently selected from -OC 2 H 5 , OCH 2 C0 2 H, -CONHCH(C0 2 H)(CH 2 C0 2 H), and P(0)(OH) 2.
  • a compound of the invention includes a compound of Formula (I), or a salt thereof, particularly a pharmaceutically acceptable salt thereof.
  • Representative compounds of this invention include the specific compounds described herein, e.g., the compounds of the Examples, as well as any alternative stereoisomers, free acid/base forms, salt forms, and alternative salt forms thereof (particularly pharmaceutically acceptable salt or alternative salt forms thereof), as applicable.
  • the compound of the invention is a compound selected from the group consisting of:
  • the compound of the invention is a compound selected from the group consisting of:
  • the compound of the invention is a compound selected from the group consisting of:
  • the invention is directed to a method of inhibiting BMP1 , TLL1 and/or TLL2 comprising contacting a biological material comprising the protein(s) with a compound of the invention.
  • a biological material comprising the protein(s)
  • the contact is made in-vitro
  • the biological material is, e.g., cell culture or cellular tissue.
  • the contact is made in-vivo.
  • the invention is directed to a method of treating a disease associated with BMP1 , TLL1 and/or TLL2 activity in a subject (e.g., a human or other mammal) in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the invention (particularly a compound of Formula (I) or a pharmaceutically acceptable salt thereof).
  • a subject e.g., a human or other mammal
  • the invention is still further directed to the use of a compound of the invention or a pharmaceutical composition comprising a compound of the invention (particularly a compound of Formula (I) or a pharmaceutically acceptable salt thereof) to treat a disease associated with BMP1 , TLL1 and/or TLL2 activity.
  • the invention is further directed to a compound of the invention ((particularly a compound of Formula (I) or a pharmaceutically acceptable salt thereof) for use in therapy, particularly as an active therapeutic substance in the treatment of a disease associated with BMP1 , TLL1 and/or TLL2 activity.
  • the invention is further directed to the use of a compound of the invention (particularly a compound of Formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for use in treating a disease associated with BMP1 , TLL1 and/or TLL2 activity.
  • the disease associated with BMP1 , TLL1 and/or TLL2 activity is selected from those associated with pathological fibrotic conditions in body organs or tissues, e.g., such conditions of the heart, lung, kidney, liver, eye, skeletal muscle, skin, the vasculature, and the nervous system, e.g., myocardial infarction ("Ml"), heart failure (e.g., heart failure with reduced ejection fraction, heart failure with preserved ejection fraction), cardiac arrhythmias (e.g., atrial fibrillation), hypertrophic cardiomyopathy, chronic obstructive pulmonary disease (“COPD”), idiopathic pulmonary fibrosis (“IPF”), diabetic nephropathy, post-acute kidney injury, chronic kidney disease (“CKD”), delayed graft function posttransplantation, liver cirrhosis, non-alcoholic steatohepatitis (“NASH”), glaucoma, corneal scarring, muscular dystrophies (including Duch), a path
  • the disease associated with BMP1 , TLL1 and/or TLL2 activity is selected from muscular diseases characterized by reduced muscle function and/or mass, e.g., muscular dystrophy (e.g., Duchenne, Becker, limb-girdle, congenital,
  • muscular dystrophy e.g., Duchenne, Becker, limb-girdle, congenital
  • the compounds according to Formula (I) may contain one or more asymmetric center(s) (also referred to as a chiral center(s)) and may, therefore, exist as individual enantiomers, diastereomers, or other stereoisomeric forms, or as mixtures thereof.
  • Chiral centers such as a chiral carbon, sulfur or phosphorus, may also be present in the compounds of this invention.
  • the stereochemistry of a chiral center present in a compound of this invention e.g., compound name or in any chemical structure illustrated herein
  • the compound, compound name, or structure is intended to encompass all individual stereoisomers and all mixtures thereof.
  • compounds according to Formula (I) containing one or more chiral center(s) may be present as racemic mixtures, enantiomerically enriched mixtures, or as enantiomerically pure individual stereoisomers.
  • Individual stereoisomers of a compound according to Formula (I) which contain one or more asymmetric center(s) may be resolved by methods known to those skilled in the art. For example, such resolution may be carried out (1) by formation of diastereoisomeric salts, complexes or other derivatives; (2) by selective reaction with a stereoisomer-specific reagent, for example by enzymatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent.
  • stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.
  • a solid form of a compound of the invention may exist in crystalline forms, non-crystalline forms or a mixture thereof. Such crystalline forms may also exhibit polymorphism (i.e. the capacity to occur in different crystalline forms). These different crystalline forms are typically known as "polymorphs.” Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. One of ordinary skill in the art will appreciate that different polymorphs may be produced, for example, by changing or adjusting the conditions used in crystallizing/recrystallizing the compound.
  • the salts of the compounds of Formula (I) are preferably pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts include those described by Berge, S.M. et al., Journal of Pharmaceutical Sciences, 1977, 66, 1-19.
  • a desired salt form may be prepared by any suitable method known in the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, and the like, or with a pyranosidyl acid, such as glucuronic acid or galacturonic acid, or with an alpha-hydroxy acid, such as citric acid or tartaric acid, or with an amino acid, such as aspartic acid or glutamic acid, or with an aromatic acid, such as benzoic acid or cinnamic acid, or with a sulfonic acid, such as p
  • Suitable acid addition salts include acetate, p-aminobenzoate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bismethylenesalicylate, bisulfate, bitartrate, borate, calcium edetate, camsylate, carbonate, clavulanate, citrate, cyclohexylsulfamate, edetate, edisylate, estolate, esylate, ethanedisulfonate, ethanesulfonate, formate, fumarate, gluceptate, gluconate, glutamate, glycollate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, dihydrochloride, hydrofumarate, hydrogen phosphate, hydroiodide, hydromaleate, hydrosuccinate, hydroxynaphthoate, isethionate
  • methylsulfate monopotassium maleate, mucate, napsylate, nitrate, /V-methylglucamine, oxalate, oxaloacetate, pamoate (embonate), palmate, palmitate, pantothenate,
  • phosphate/diphosphate pyruvate, polygalacturonate, propionate, saccharate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, triethiodide, trifluoroacetate and valerate.
  • exemplary acid addition salts include pyrosulfate, sulfite, bisulfite, decanoate, caprylate, acrylate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, suberate, sebacate, butyne-1 ,4-dioate, hexyne-1 ,6-dioate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, phenylacetate,
  • phenylpropionate phenyl butrate, lactate, ⁇ -hydroxybutyrate, mandelate, and sulfonates, such as xylenesulfonate, propanesulfonate, naphthalene-1-sulfonate and
  • an inventive basic compound is isolated as a salt
  • the corresponding free base form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic base, suitably an inorganic or organic base having a higher pK a than the free base form of the compound.
  • a desired salt may be prepared by any suitable method known to the art, including treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary, tertiary or quaternary), an alkali metal or alkaline earth metal hydroxide, alkoxide (e.g. (d.
  • alkyl ester e.g., (Ci -4 )alkyl ester, e.g. acetate
  • suitable salts include organic salts derived from amino acids such as glycine, lysine, and arginine, ammonia, primary, secondary, tertiary, and quaternary amines, cyclic amines, and amino sugars, e.g., 2-amino-2-deoxysugars, such as /V-methyl-D-glucamine, diethylamine, isopropylamine, trimethylamine, ethylene diamine, dicyclohexylamine, ethanolamine, choline, piperidine, morpholine, piperazine, Tris (also known as THAM, or
  • Treatment of a compound of Formula (I) containing a free acid with an inorganic or organic base, or containing a free base with an acid, to form a salt of the compound of Formula (I) may be done by methods known in the art.
  • the free acid may be admixed with a suitable solvent (e.g. in which the free acid is soluble) and treated with the base, with stirring, and optionally with heating and/or temperature cycling.
  • the free base may be admixed with a suitable solvent (e.g. in which the free base is soluble) and treated with the acid, with stirring, and optionally with heating and/or temperature cycling.
  • Certain of the compounds of the invention may form salts with one or more equivalents of an acid (if the compound contains a basic moiety) or a base (if the compound contains an acidic moiety).
  • the present invention includes within its scope all possible stoichiometric and non-stoichiometric salt forms.
  • Compounds of the invention having both a basic and acidic moiety may be in the form of zwitterions, acid-addition salts of the basic moiety or base salts of the acidic moiety.
  • This invention also provides for the conversion of one pharmaceutically acceptable salt of a compound of this invention into another pharmaceutically acceptable salt of a compound of this invention.
  • the compound of the invention is a salt, e.g., a
  • the compounds of Formula (I) and salts (including pharmaceutically acceptable salts) thereof may be in the form of a solvate.
  • solvates of the compounds of Formula (I), including solvates of salts of the compounds of Formula (I), that are in crystalline form the skilled artisan will appreciate that pharmaceutically acceptable solvates may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallization.
  • Solvates may involve nonaqueous solvents such as ethanol, isopropanol, dimethylsulfoxide, acetic acid, ethanolamine, and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice.
  • Solvates wherein water is the solvent that is incorporated into the crystalline lattice are typically referred to as "hydrates.”
  • Solvates include stoichiometric solvates as well as compositions containing variable amounts of the incorporated solvent(s), e.g. a hydrate includes stoichiometic hydrates and compositions containing variable amounts of water.
  • the invention includes all such solvates, particularly hydrates.
  • a salt, particularly a pharmaceutically acceptable salt, thereof, or solvate thereof encompasses a salt of a compound of Formula (I), a pharmaceutically acceptable salt of a compound of Formula (I), a solvate of a compound of Formula (I), a solvate of a salt of a compound of Formula (I), and a solvate of a pharmaceutically acceptable salt of a compound of Formula (I) (for example, where water is the incorporated solvent, said solvates are hydrates).
  • the compounds of the invention are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions.
  • the compounds of Formula (I) may be obtained by using synthetic procedures illustrated in the Schemes below or by drawing on the knowledge of a skilled organic chemist.
  • the syntheses provided in these Schemes are applicable for producing
  • React (II) and (III) in the presence of an amide coupling reagent e.g. EDC/HOBT, HATU or HBTU
  • an amide coupling reagent e.g. EDC/HOBT, HATU or HBTU
  • suitable solvent either at room temperature or at elevated temperature
  • Debenzylation may be achieved via hydrogenation using a catalyst such as Pd/C and a hydrogen source (e.g. hydrogen gas or ammonium formate).
  • re- formylation may be achieved utilizing a pre-mixed solution of CDI/formic acid in a solvent such as DCM at room temperature to form (I).
  • re-formylation may be achieved via reaction with 5-methyl-2-thioxo-1 ,3,4-thiadiazole-3(2H)-carbaldehyde (Yazawa, H., et al., Tetrahedron Letters, 1985, 26(31), 3703-6) in a solvent such as DCM at room temperature. Reformylation may be needed following all debenzylation steps discussed below but for brevity it will be left out of the future schemes. As appreciated by those skilled in the art, the order of the synthetic steps may be varied or omitted if unnecessary.
  • compounds of Formula (I) wherein R3 contains a carboxylic acid (e.g., Formula (Ic or lh)) or phosphonic acid (e.g., Formula (Id or li)) may be prepared according to Schemes 1-5 and/or as outlined in Scheme 6 from their corresponding ester functionalities (Xc), (Xd), (Xh), and (Xg)
  • the transformations in Scheme 6 are illustrated with a phenyl ring R3 however Scheme 6 applies analogously to preparation of corresponding molecules of Formula (1c-d) with all embodiments of R3 disclosed herein. 1.
  • Debenzylation may be achieved as described in Scheme 1. 2.
  • ester hydrolysis may be achieved by reaction with lithium hydroxide in a solvent and ester deprotection could be achieved via reaction with acid in a solvent and for compounds of Formula (Xd) and Formula (Xg), hydrolysis may be alternatively achieved by reaction with TMS-Br in a suitable solvent. Additionally, the order of these steps can be changed, wherein 1. ester hydrolysis and then 2. debenzylation can lead to (Ic) or (Id) when starting with the appropriate starting material. Additionally, a global debenzylation can be utilized if appropriate esters (e.g., benzyl esters) are being utilized. As appreciated by those skilled in the art the order of the synthetic steps may be varied or omitted if unecessary.
  • compounds of Formula (I) wherein R3 contains an amine may be prepared according to Schemes 1-5 and/or as outlined in Scheme 7 from their corresponding protected amine (Xe).
  • Xe protected amine
  • compounds of Formula (I) wherein the distal ring contains a thiol may be prepared according to Schemes 1-5 and/or as outlined in Scheme 9. 1. React amine (VI) with (XII) with coupling reagent and base in solvent (Scheme 9). 2.
  • compounds of Formula (II), wherein R1 is H may be prepared according to the following Schemes 10 or 1 1.
  • compounds of Formula (II) may be alternatively prepared according to the following Schemes 12 or 13.
  • Fmoc deprotection may be achieved by reaction with a secondary amine such as piperidine, or pyrollidine in a solvent such as DCM to form compounds of the structure (III).
  • a secondary amine such as piperidine, or pyrollidine
  • a solvent such as DCM
  • Amide formation may be achieved by reaction with oxalyl chloride in a solvent such as DMF followed by reaction with (XXX) in the presence of a base such as DIPEA in a solvent such as DCM.
  • amide formation may be achieved by reaction with (XXXI) in the presence of a coupling reagent such as HATU, base, solvent and (XXX).
  • Fmoc deprotection may be achieved by reaction with a secondary amine such as pyrollidine or morpholine in a suitable solvent such as DCM.
  • compounds of Formula (III) may be prepared according to reaction Scheme 16. 1. React compound (XXXII) with (XXXIII) in the presence of a base and solvent. 2. Rearrangement with PIFA in a solvent to form (III).
  • compounds of Formula (VI) may be prepared according to reaction Scheme 18.
  • PG Cbz or Fmoc
  • debenzylation may be achieved under similar conditions described in Scheme 1 to yield the amine (VI)
  • the compounds of this invention are inhibitors of BMP1 , TLL1 and/or TLL2 activity, and may be particularly useful for treatment of diseases associated with BMP1 , TLL1 and/or TLL2 activity, including for example treatment of diseases where inhibition of BMP1 , TLL1 and/or TLL2 is of therapeutic benefit.
  • compounds of the invention may be particularly useful for treatment of diseases where inhibition of tissue ECM (extracellular matrix) production and/or maturation would be beneficial, or where inhibition of myostatin activity would be beneficial.
  • the disease associated with BMP1 , TLL1 and/or TLL2 activity is selected from diseases associated with pathological fibrotic conditions in body organs or tissues, e.g., such conditions of the:
  • heart e.g., myocardial infarction ("Ml")
  • heart failure e.g., heart failure with reduced ejection fraction, heart failure with preserved ejection fraction
  • cardiac arrhythmias e.g., atrial fibrillation
  • hypertrophic cardiomyopathy e.g., hypertrophic cardiomyopathy
  • COPD chronic obstructive pulmonary disease
  • IPF idiopathic pulmonary fibrosis
  • kidney e.g. diabetic nephropathy, post-acute kidney injury, chronic kidney disease (“CKD”), delayed graft function post-transplantation
  • CKD chronic kidney disease
  • liver e.g. liver cirrhosis, non-alcoholic steatohepatitis (“NASH”)
  • NASH non-alcoholic steatohepatitis
  • eye e.g. glaucoma, corneal scarring
  • skeletal muscle e.g. muscular dystrophies, including Duchenne, Becker, limb-girdle, congenital, facioscapulohumeral, myotonic, oculopharyngeal, distal, and Emery-Dreifuss
  • skin e.g. keloids, wound healing, adhesions, hypertrophic scarring and other scarring, e.g., associated with burns, surgery or other trauma
  • vasculature e.g. stroke, and collagen vascular diseases such as systemic lupus erythematosus, rheumatoid arthritis and scleroderma
  • vasculature e.g. stroke, and collagen vascular diseases such as systemic lupus erythematosus, rheumatoid arthritis and scleroderma
  • the nervous system e.g. spinal cord injury, multiple sclerosis.
  • the disease associated with BMP1 , TLL1 and/or TLL2 activity is selected from muscular diseases characterized by reduced muscle function and/or mass, e.g., muscular dystrophy (e.g., Duchenne, Becker, limb-girdle, congenital,
  • muscular dystrophy e.g., Duchenne, Becker, limb-girdle, congenital
  • this invention provides a method of treating a disease associated with BMP1 , TLL1 and/or TLL2 activity in a subject in need thereof (e.g. a human or other mammal, particularly a human), for example the diseases recited herein, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a salt thereof, particularly a pharmaceutically acceptable salt thereof.
  • a compound of the invention is administered post-MI (i.e. to a subject who has suffered an Ml), e.g. to treat fibrosis associated with myocardial infarction.
  • a compound of the invention is administered post-MI, e.g. to prevent fibrosis associated with myocardial infarction.
  • the method of treating comprises administering a specific compound described herein, e.g., a compound of the Examples, or any alternative stereoisomer, free acid/base form, salt form, or alternative salt form (particularly
  • the method of treating comprises administering (S)-2-(5-ethoxy-3'- ((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)-[1 , T-biphenyl]- 3-ylcarboxamido)succinic acid; (S)-2-(2-(carboxymethoxy)-4-(6-(((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2-yl)benzamido)succinic acid; or (3-ethoxy-5-(6-(((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methyl) carbamoyl)pyridin-2-yl)phenyl)phosphonic acid.
  • the method of treating comprises administering a pharmaceutically acceptable salt of (S)-2-(5-ethoxy-3'- ((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)-[1 , T-biphenyl]- 3-ylcarboxamido)succinic acid; (S)-2-(2-(carboxymethoxy)-4-(6-(((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2-yl)benzamido)succinic acid; or (3-ethoxy-5-(6-(((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methyl) carbamoyl)pyridin-2-yl)phenyl)phosphonic
  • This invention also provides a compound of Formula (I), or a salt thereof, particularly a pharmaceutically acceptable salt thereof, for use in therapy.
  • This invention specifically provides for the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as an active therapeutic substance in the treatment of a disease associated with BMP1 , TLL1 and/or TLL2 activity, for example the diseases recited herein.
  • the compound for use in therapy e.g. for use in the treatment of a disease associated with BMP1 , TLL1 and/or TLL2 activity
  • the compound for use in therapy is (S)-2-(5-ethoxy-3'-((((R)-2- ((R)-1-(N-hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)-[1 ,1 '-biphenyl]-3- ylcarboxamido)succinic acid; (S)-2-(2-(carboxymethoxy)-4-(6-(((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2-yl)benzamido)succinic acid; or (3-ethoxy-5-(6-(((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methyl) carbamoyl)pyridin-2-yl)phenyl)phosphonic acid.
  • the compound for use in therapy is a pharmaceutically acceptable salt of (S)-2-(5-ethoxy-3'-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)-[1 , T-biphenyl]-3- ylcarboxamido)succinic acid; (S)-2-(2-(carboxymethoxy)-4-(6-(((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2-yl)benzamido)succinic acid; or (3-ethoxy-5-(6-(((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methyl) carbamoyl)pyridin-2-yl)phenyl)
  • the invention also provides for the use of a compound of Formula (I), or a salt thereof, particularly a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a disease associated with BMP1 , TLL1 and/or TLL2 activity, for example the diseases recited herein.
  • the invention provides for the use of a specific compound described herein, e.g., a compound of the Examples, or any alternative stereoisomer, free acid/base form, salt form, or alternative salt form (particularly pharmaceutically acceptable salts or alternative pharmaceutically acceptable salt forms) thereof, as applicable, in the manufacture of a medicament for use in the treatment of a disease associated with BMP1 , TLL1 and/or TLL2 activity.
  • a specific compound described herein e.g., a compound of the Examples, or any alternative stereoisomer, free acid/base form, salt form, or alternative salt form (particularly pharmaceutically acceptable salts or alternative pharmaceutically acceptable salt forms) thereof, as applicable, in the manufacture of a medicament for use in the treatment of a disease associated with BMP1 , TLL1 and/or TLL2 activity.
  • the invention provides for the use of (S)-2-(5-ethoxy-3'-((((R)- 2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)-[1 , T-biphenyl]-3- ylcarboxamido)succinic acid; (S)-2-(2-(carboxymethoxy)-4-(6-(((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2-yl)benzamido)succinic acid; or (3-ethoxy-5-(6-(((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methyl) carbamoyl)pyridin-2-yl)phenyl)phosphonic acid, in the manufacture of
  • the invention provides for the use of a pharmaceutically acceptable salt of (S)- 2-(5-ethoxy-3'-(((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)- [1 , T-biphenyl]-3-ylcarboxamido)succinic acid; (S)-2-(2-(carboxymethoxy)-4-(6-((((R)-2-((R)- 1-(N-hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2- yl)benzamido)succinic acid; or (3-ethoxy-5-(6-(((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl) carbamoyl)pyridin-2-yl)phenyl)phospho
  • Treatment of a disease associated with BMP1 , TLL1 and/or TLL2 activity may be achieved using a compound of this invention as a monotherapy, or in dual or multiple combination therapy.
  • the compounds of this invention may be administered in combination with one or more therapeutically active agents selected from the group consisting of: anticoagulants, angiotensin-converting-enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), beta(' ⁇ ")-blockers, aldosterone antagonists, diuretics,
  • ACE angiotensin-converting-enzyme
  • ARBs angiotensin II receptor blockers
  • beta(' ⁇ ")-blockers beta(' ⁇ ")-blockers
  • aldosterone antagonists diuretics
  • vasodilators e.g., statins, fibrates, niacin, resins), statins, platelet antagonists, anti-arrhythmics, calcium channel blockers, erythropoiesis-stimulating agents (ESAs), iron, beta agonists, inhaled or oral steroids, anticholinergics, theophylline, PDE4 inhibitors, antibiotics, other antifibrotic agents, PDE5 inhibitors, immune modulators, neprilysin inhibitors, and digitalis preparations, e.g., any such agents as are known in the art, and combinations thereof.
  • Particular therapeutic agents in these classes include those in the United States Pharmacopeia (USP).
  • agents may fall within one or more of the foregoing classes.
  • Such agents may be administered in therapeutically effective amounts, e.g., as is known in the art, or lesser or greater amounts than known in the art provided that the amount administered is therapeutically effective.
  • treatment of cardiac diseases may include administration of one or more agents selected from the group: anticoagulants, ACE inhibitors, ARBs, ⁇ -blockers, aldosterone antagonists, diuretics, vasodilators (e.g. nitrates), cholesterol lowering drugs (e.g., statins, fibrates, niacin, resins), platelet antagonists, anti-arrhythmics, calcium channel blockers, neprilysin inhibitors, digitalis preparations, and combinations thereof.
  • treatment of atrial fibrillation, heart failure, or hypertrophic cardiomyopathy may comprise administration of one or more such agents.
  • treatment of CKD may include administration of one or more agents selected from ESAs, iron, ACE inhibitors, ARBs, ⁇ -blockers, diuretics, calcium channel blockers, statins, and combinations thereof.
  • treatment of COPD may include administration of one or more agents selected from the group: beta agonists, inhaled or oral steroids, anticholinergics, theophylline, PDE4 inhibitors, antibiotics, and combinations thereof.
  • idiopathic pulmonary fibrosis may include administration of one or more agents selected from the group: antifibrotics, PDE5 inhibitors, immune modulators, and combinations thereof.
  • therapeutically active agents which may be used in combination with one or more compounds of the invention, for example to treat cardiac diseases, include:
  • anticoagulants such as: dalteparin (FRAGMIN), danaparoid (ORGARAN), enoxaparin (LOVENOX), heparin, tinzaparin (INNOHEP), warfarin (COUMADIN), alteplase, aspirin, ardeparin, fondaparinux, lepirudin, desirudin, bivalirudin, urokinase, rivaroxaban, apixaban, dabigatran, argatroban;
  • ACE inhibitors such as benazepril (LOTENSIN), captopril (CAPOTEN), enalapril (VASOTEC), fosinopril (MONOPRIL), lisinopril (PRINIVIL, ZESTRIL), moexipril (UNIVASC), perindopril (ACEON), quinapril (ACCUPRIL), Ramipril (ALTACE), trandolapril (MAVIK), imidapril;
  • ARBs such as candesartan (ATACAND), eprosartan (TEVETEN), irbesartan (AVAPRO), losartan (COZAAR), telmisartan (MICARDIS), valsartan (DIOVAN), olmesartan, azilsartan;
  • beta-blockers such as acebutolol (SECTRAL), atenolol (TENORMIN), betaxolol (KERLONE), bisoprolol/hydrochlorothiazide (ZIAC), bisoprolol (ZEBETA), carteolol
  • aldosterone antagonists such as spironolactone, eplerenone, Canrenone
  • diuretics such as amiloride (MIDAMOR), bumetanide (BUMEX), chlorothiazide (DIURIL), chlorthalidone (HYGROTON), furosemide (LASIX), hydro-chlorothiazide
  • vasodilators such as nitroglycerin, isosorbide dinitrate (ISORDIL), isosorbide mononitrate, nesiritide (NATRECOR), hydralazine (APRESOLINE)
  • statins such as atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, including combination products, such as ADVICOR (lovastatin/niacin extended-release), SIMCOR (simvastatin/niacin extended- release), and VYTORIN (simvastatin/ezetimibe); nicotinic acid (niacin), fibrates such as gemfibrozil (LOPID), fenofibrate (TRICOR, FIBRICOR), clofibrate;
  • statins such as atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, including combination products, such as ADVICOR (lovastatin/niacin extended-release), SIMCOR (simvastatin/niacin extended- release), and VYTORIN (sim
  • platelet antagonists such as aspirin, ticlopidine, clopidogrel (PLAVIX), dipyridamole; anti-arrhythmics such as quinidine, procainamide, disopyramide, lidocaine, phenytoin, mexiletine, tocainide, encainide, flecainide, propafenone, moricizine, carvedilol, propranolol, esmolol, timolol, metoprolol, atenolol, bisoprolol, amiodarone, sotalol, ibutilide, dofetilide, dronedarone, verapamil, diltiazem, adenosine, digoxin, magnesium sulfate;
  • anti-arrhythmics such as quinidine, procainamide, disopyramide, lidocaine, phenytoin, mexiletine, tocainide, encainide,
  • calcium channel blockers such as amlodipine (NORVASC, LOTREL), bepridil (VASCOR), diltiazem (CARDIZEM, TIAZAC), felodipine (PLENDIL), nifedipine (ADALAT, PROCARDIA), nimodipine (NIMOTOP), nisoldipine (SULAR), verapamil (CALAN, ISOPTIN, VERELAN), isradipine, nicardipine;
  • neprilysin inhibitors such as sacubitril, including, e.g., a combination of sacubitril and valsartan, such as LCZ696;
  • digitalis preparations such as digoxin, digitoxin.
  • Combination therapy includes administration of the therapeutically active agents ' separate dosage forms or together in a single dosage form.
  • Combination therapy may involve simultaneous administration or separate administration of the therapeutically active agents, which may be substantially simultaneous or substantially separate administration.
  • combination therapy will involve administration of each agent such that therapeutically effective amounts of each agent are present in the subject's body in at least an overlapping period.
  • combination therapy comprises administering a specific compound described herein, e.g., a compound of the Examples, or any alternative stereoisomer, free acid/base form, salt form, or alternative salt form (particularly
  • combination therapy comprises administering (S)-2-(5- ethoxy-3'-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)-[1 , T- biphenyl]-3-ylcarboxamido)succinic acid; (S)-2-(2-(carboxymethoxy)-4-(6-(((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2-yl)benzamido)succinic acid; or (3-ethoxy-5-(6-(((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methyl) carbamoyl)pyridin-2-yl)phenyl)phosphonic acid, and one or more additional therapeutically
  • combination therapy comprises administering a pharmaceutically acceptable salt of (S)-2-(5-ethoxy-3'-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)-[1 , T-biphenyl]-3- ylcarboxamido)succinic acid; (S)-2-(2-(carboxymethoxy)-4-(6-(((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2-yl)benzamido)succinic acid; or (3-ethoxy-5-(6-(((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methyl) carbamoyl)pyridin-2-yl)phenyl)phosphonic
  • the present invention provides a composition
  • a composition comprising a) a compound of formula (I) or a pharmaceutically acceptable salt thereof and b) a combination partner.
  • suitable combination partners include one or more other therapeutically active agents such as those described above by classification or more particularly.
  • the present invention further provides a method for treating a disease associated with BMP1 , TLL1 and/or TLL2 activity in a subject (e.g. a human or other mammal, particularly a human) in need thereof comprising administering to said subject a subject (e.g. a human or other mammal, particularly a human) in need thereof comprising administering to said subject a subject (e.g. a human or other mammal, particularly a human) in need thereof comprising administering to said subject a subject (e.g. a human or other mammal, particularly a human) in need thereof comprising administering to said subject a subject (e.g. a human or other mammal, particularly a human) in need thereof comprising administering to said subject a subject (e.g. a human or other mammal, particularly a human) in need thereof comprising administering to said subject a subject (e.g. a human or other mammal, particularly a human) in need thereof comprising administering to said
  • the individual components of the combination may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations by any convenient route.
  • the invention further provides a combination of a) a compound of formula (I) or a pharmaceutically acceptable salt thereof and b) a combination partner.
  • suitable combination partners include other therapeutically active agents such as described above by classification or more particularly.
  • compositions, methods and combinations of the inventions comprising a combination partner, the compound of formula (I) or a
  • pharmaceutically acceptable salt thereof is a specific compound described herein, e.g., a compound of the Examples, or any alternative stereoisomer, free acid/base form, pharmaceutically acceptable salt form or alternative pharmaceutically acceptable salt form thereof, as applicable; in various more particular embodiments the compound of formula (I) or a pharmaceutically acceptable salt thereof is (S)-2-(5-ethoxy-3'-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)-[1 , T-biphenyl]-3- ylcarboxamido)succinic acid; (S)-2-(2-(carboxymethoxy)-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2-yl)benzamido)succinic acid; (3-e
  • a “therapeutically effective amount” is intended to mean that amount of a compound that, when administered to a subject in need of such treatment, is sufficient to effect treatment, as defined herein.
  • a therapeutically effective amount of a compound of the invention e.g. a compound of Formula (I) or a pharmaceutically acceptable salt thereof, is a quantity of such agent that, when administered to a subject (e.g., human) in need thereof, is sufficient to modulate or inhibit the activity of BMP1 , TLL1 and/or TLL2 such that a disease condition which is mediated or inhibited by that activity is reduced, alleviated or prevented.
  • the amount of a given compound that will correspond to such an amount will vary depending upon factors such as the particular compound (e.g., the potency (plC 50 ) and the biological half-life of the particular compound), disease condition and its severity, and the identity (e.g., age, size and weight) of the subject in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
  • the particular compound e.g., the potency (plC 50 ) and the biological half-life of the particular compound
  • disease condition and its severity e.g., age, size and weight
  • the duration of treatment and the time period of administration (time period between dosages and the timing of the dosages, e.g., before/with/after meals) of the compound will vary according to the identity of the subject in need of treatment (e.g., weight), the particular compound and its properties (e.g., pharmaceutical characteristics), disease and its severity and the specific composition and method being used, but can nevertheless be determined by one of skill in the art.
  • 0.1 mg to 1000 mg e.g., 0.1 - 500 mg, or 0.1 - 100 mg
  • a compound of the invention, particularly a compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered at a frequency of twice a day, once a day, once a week, or frequencies therebetween.
  • a compound of the invention, particularly a compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered sub-cutaneously in an amount of less than 100 mg per dose (e.g., 0.1 - ⁇ 100 mg per dose).
  • Treatment is intended to mean at least the mitigation of a disease in a subject.
  • the methods of treatment for mitigation of a disease include the use of the compounds in this invention in any conventionally acceptable manner, for example for prevention, retardation, prophylaxis, therapy, improvement or cure of a disease.
  • treatment may involve at least the mitigation of one or more symptoms of a disease.
  • the compounds of the invention may be administered by any suitable route of administration, including both systemic administration and topical administration.
  • Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation.
  • Oral administration includes enteral (digestive tract) and buccal or sublingual administration.
  • Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion into tissue or blood.
  • Parenteral administration includes intravenous, intramuscular, subcutaneous, intradermal, and transdermal implant injection or infusion.
  • Inhalation refers to administration into the subject's lungs whether inhaled through the mouth or through the nasal passages.
  • Topical administration includes application to the skin.
  • the compounds of the invention will be normally, but not necessarily, formulated into a pharmaceutical composition prior to administration to a subject. Accordingly, the invention also is directed to pharmaceutical compositions comprising a compound of the invention, particularly a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • compositions of the invention may be prepared and packaged in bulk form wherein an effective amount of a compound of the invention can be extracted and then given to the subject such as with powders, syrups, and solutions for injection.
  • the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form.
  • one or more tablets or capsules may be administered.
  • a dose of the pharmaceutical composition contains at least a therapeutically effective amount of a compound of this invention (i.e., a compound of Formula (I), or a salt, particularly a pharmaceutically acceptable salt, thereof).
  • the pharmaceutical compositions may contain from 0.1 mg to 1000 mg (e.g., 0.1 - 500 mg, or 0.1 - 100 mg) of a compound of this invention.
  • the pharmaceutical composition may include one or more compounds of the invention and/or one or more pharmaceutically acceptable excipients.
  • the pharmaceutical compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention.
  • the pharmaceutical compositions of the invention may optionally further comprise one or more additional pharmaceutically active compounds, e.g., the therapeutically active agents described above by classification or more particularly.
  • the pharmaceutical composition comprises a) 0.01-100 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof and b) 0.001-900 mg of one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition comprises a) 0.01-100 mg/mL of a compound of formula (I) or a pharmaceutically acceptable salt thereof and b) 0.001-900 mg/mL of one or more
  • the pharmaceutical composition comprises a specific compound described herein, e.g., a compound of the Examples, or any alternative stereoisomer, free acid/base form, pharmaceutically acceptable salt form, or alternative pharmaceutically acceptable salt form thereof, as applicable.
  • the pharmaceutical composition comprises (S)-2-(5-ethoxy-3'- ((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)-[1 , T-biphenyl]- 3-ylcarboxamido)succinic acid; (S)-2-(2-(carboxymethoxy)-4-(6-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2-yl)benzamido)succinic acid; or (3-ethoxy-5-(6-(((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methyl) carbamoyl)pyridin-2-yl)phenyl)phosphonic acid, and one or more pharmaceutically acceptable ex
  • the pharmaceutical composition comprises a pharmaceutically acceptable salt of (S)-2-(5-ethoxy-3'-(((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)-[1 , T-biphenyl]-3- ylcarboxamido)succinic acid; (S)-2-(2-(carboxymethoxy)-4-(6-(((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)pyridin-2-yl)benzamido)succinic acid; or (3-ethoxy-5-(6-(((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methyl) carbamoyl)pyridin-2-yl)phenyl)phosphonic acid
  • pharmaceutically acceptable excipient means a material, composition or vehicle other than a pharmaceutical active ingredient(s) intended for treating a disease (e.g., a compound of the invention).
  • Pharmaceutically acceptable excipients are involved in providing a property or function useful to a pharmaceutical composition, for example an excipient may be involved in modifying physical, sensory, stability, or pharmaco-kinetic properties of the composition, for example in giving form or consistency to the composition, in bulking up the active ingredient (e.g. for convenient and accurate dispensation), in enhancing therapy (e.g. facilitating drug absorption or solubility, or other pharmacokinetic properties), in the manufacturing process (e.g.
  • each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention (or any other active ingredient, if present) when administered to a subject and interactions which would result in pharmaceutical compositions that are sufficiently high purity to render it
  • the compounds of the invention and the pharmaceutically acceptable excipient or excipients will typically be formulated into a dosage form adapted for administration to the subject by the desired route of administration.
  • Conventional dosage forms include those adapted for (1) oral administration such as tablets, capsules, caplets, pills, lozenges, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, lyophiles, microparticles, nanocarriers, implants, preformed implants and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as aerosols and solutions; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, gels, dermal patches, and transdermal patches or sprays.
  • Suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form chosen.
  • suitable pharmaceutically acceptable excipients may be chosen for a particular function that they may serve in the composition.
  • certain pharmaceutically acceptable excipients may be chosen for their ability to: facilitate the production of uniform dosage forms, to facilitate the production of stable dosage forms, to facilitate the carrying or transporting the compound or compounds of the invention once administered to the subject from one organ, or portion of the body, to another organ, or portion of the body, and/or to enhance subject compliance.
  • Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, carriers, and buffering agents.
  • excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation.
  • Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically acceptable excipients in appropriate amounts for use in the invention.
  • resources that are available to the skilled artisan which describe pharmaceutically acceptable excipients and may be useful in selecting suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press), including current and past editions.
  • compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
  • the invention is directed to a solid oral dosage form such as a tablet or capsule comprising an effective amount of a compound of the invention and a diluent or filler, and optionally a binder, disintegrant, and/or lubricant.
  • Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate.
  • Suitable binders include starch (e.g.
  • Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose.
  • Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc.
  • the invention is directed to a parenteral formulation, e.g., in-situ gels, microspheres, nanospheres, nanosuspensions, or lyophilized products to control the release of a compound following subcutaneous and/or intramuscular administration, comprising a compound of the invention, a surfactant and/or a polymeric carrier and/or a solubilising excipient and/or an excipient to control osmolality.
  • Suitable surfactants include polysorbates, polyvinyl alcohol, polyvinyl pyrrolidone and combinations thereof.
  • Suitable polymeric carriers include polyethylene glycol, polymethacrylate, ethylene vinyl acetate copolymer, polyglactin, polyoxyethylene fatty acid esters, poly(lactic-co-glycolic acid), poly(epsilon-caprolactone), poly(p-dioxanone), poly(anhydride esters) and combinations thereof.
  • Suitable solubilising excipients include n-methyl pyrollidone, polyethoxylated castor oil (e.g., CREMOPHOR such as CREMOPHOR EL), polysorbates, Solutol® (Macrogol 15 Hydroxystearate Ph. Eur; Polyoxyl 15 Hydroxystearate USP), ethanol and combinations thereof.
  • Suitable excipients to control osmolality include mannitol, sucrose, glycine, and polyvinyl pyrrolidone.
  • In-situ gels can be prepared by solubilising a compound of the invention in solvent phase and water-insoluble polymeric carrier(s). The solution is then sterilized, e.g., by gamma irradiation.
  • Nanosuspensions or micron-sized suspensions can be prepared by combining a compound of the invention, a surfactant, a polymeric carrier and an excipient to control osmolality in aqueous phase, then bead milling or microfluidising the combination in aqueous phase to deliver particles of the compound sized less than 5 ⁇ , e.g., less than 1 ⁇ , or e.g., between 100nm to less than 5 ⁇ or to less than 1 ⁇ .
  • the nanosuspension is sterilized, e.g., by utilizing terminal heat sterilization or gamma irradiation techniques.
  • Microspheres and nanospheres can be prepared by various methods known in the art including water/oil/water emulsion methods, solvent/oil/water emulsion methods, oil/water emulsion methods, organic phase separation or melt extrusion/cryomilling techniques which involve inclusion of the compound of the invention and polymer(s) to control drug delivery.
  • the particles are delivered to less than 100 ⁇ for microspheres and between 100nm to less than 1 ⁇ for nanospheres.
  • the microspheres and nanospheres can go through further processing, including lyophilization, and require sterilization, e.g., through gamma irradiation.
  • a lyophilized product may suitably include a compound of the invention in a concentration of from 0.01 - 100 mg/mL, a surfactant, a polymeric carrier, and a solubilizing excipient.
  • General conditions to provide a lyophilized product involve forming a solution or suspension of the product ingredients, reducing the solution or suspension below the glass transition, providing differential pressure to pull off aqueous and/or solvent phase, and slowly increasing temperature to form a lyophilized cake.
  • Acetonitrile (1250 ml) and sodium iodide (931 g, 6213 mmol) were charged to a 6 I reactor vessel under nitrogen at room temperature. The mixture was stirred vigorously for 10 minutes and chlorotrimethylsilane (790 ml, 6224 mmol) was then added. After stirring at room temperature for 15 minutes, the reaction was cooled to 15 °C. Triethylamine (870 ml, 6242 mmol) was added. Heptanoic acid (264 ml, 1864 mmol) was then added slowly, maintaining the temperature below 35 °C. The addition funnel was rinsed with acetonitrile (50 ml).
  • the addition vessel was rinsed with toluene (400 ml).
  • the biphasic mixture was stirred at 35 °C for 30 minutes. The layers were left to separate, and the aqueous layer was drained.
  • the organic phase was held at 3 °C overnight and warmed up to 35 °C the next morning before proceeding with the workup.
  • the organic phase was washed sequentially with a mixed solution of concentrated HCI (123 ml) and 10 % brine (1400 ml) to prevent emulsion formation, 10 % brine solution (900 ml), 5 % NaHC0 3 solution (900 ml) stirring for 10 minutes and then 10 % brine solution (900 ml).
  • the organic phase was separated and concentrated to give the crude product as a yellow oil.
  • Step 1 4-phenylbutanoyl chloride
  • Oxalyl chloride (6 ml, 68.5 mmol) was added to a solution of 4-phenylbutanoic acid (7 g, 42.6 mmol) in DCM (207 ml) and a few drops of DMF at 0 °C. The reaction was allowed to warm to room temperature overnight then concentrated to give the title compound as a yellow oil which was used without further purification or characterization.
  • Step 3 (S)-4-benzyl-3-((R)-2-((benzyloxy)methyl)-4-phenylbutanoyl)oxazolidin-2-one DIPEA (8.28 ml, 47.4 mmol) was added dropwise to a solution of (S)-4-benzyl-3-(4- phenylbutanoyl)oxazolidin-2-one (13.9 g, 43.1 mmol) and TiCI 4 (4.99 ml, 45.3 mmol) in DCM (122 ml) at 0 °C.
  • Step 8 (R)-2-(((benzyloxy)amino)methyl)-4-phenylbutanoic acid (R)-1-(benzyloxy)-3-phenethylazetidin-2-one (5.06 g, 18.0 mmol) in THF (54 ml), methanol (18 ml) and water (18 ml) was treated with lithium hydroxide (4.30 g, 180 mmol) at room temperature for 1.5 days. The volatiles were removed under reduced pressure and the residue was acidified to ⁇ pH 5-6 via addition of 6 N HCI. The mixture was extracted with EtOAc (2 x) and the combined organic layers were dried over Na 2 S0 4 , filtered and concentrated to give the title compound as a clear oil (5.7 g). MS (m/z) 300.1 (M+H + ). Step 9: (R)-2-((N-(benzyloxy)formamido)methyl)-4-phenylbutanoic acid
  • Step 1 (R)-4-benzyl-3-heptanoyloxazolidin-2-one
  • Aqueous Rochelles salt was added followed by aq. HCI (50 % v/v) to dissolve any solids.
  • the layers were then separated and the aqueous phase extracted with additional DCM.
  • the combined organic extracts were treated with aq. NaHS0 3 for 30 minutes then the layers allowed to settle in a separation funnel overnight.
  • the organic layer was then separated and filtered through a plug of silica ( ⁇ 3 cm), the filtrates were combined, concentrated and dried under vacuum to give the title compound (19 g, 87 % yield) which was used without further purification.
  • Trimethylaluminum 50 ml, 2 M in toluene, 100 mmol was then added slowly. The white slurry was stirred for 15 minutes to obtain a clear solution.
  • O-benzylhydroxylamine hydrochloride (5 g, 31 mmol) was dissolved in THF (100 ml) and treated with trimethylaluminum (17 ml, 2 M in toluene, 34 mmol) at 0 °C. The mixture was stirred until a solution was obtained and then added to primary reaction via cannula. The reaction was then quenched by the addition of sat. aq. KHS0 4 . A HCI solution (500 ml water, 500 ml cone. HCI) was added and the layers separated. The organic layer was reduced in volume and re-combined with the aqueous phase, the volatiles were removed via rotovap and a white precipitate formed.
  • THF 100 ml
  • trimethylaluminum 17 ml, 2 M in toluene, 34 mmol
  • Carbonyldiimidazole (822 g, 5.07 mol) was suspended in 2-methyltetrahydrofuran (5340 ml) and cooled to 0 °C.
  • Formic acid (88 %, 276 ml, 6.33 mol) was added dropwise via addition funnel. The reaction was stirred at 5 °C for 10 minutes and then warmed to room temperature for an additional 30 minutes. The reaction was cooled back to 5 °C and (R)-2- ((R)-1-((benzyloxy)amino)propyl)heptanoic acid acid in 2-methyltetrahydrofuran (1780 ml solution from previous step) was added. The reaction was warmed to room temperature and stirred for 40 minutes.
  • Steps 5 and 6 were repeated with (3R,4R)-1-(benzyloxy)-4-ethyl-3-pentylazetidin-2- one (365 g) scale to provide a second batch (R)-2-((R)-1-(N-
  • Intermediate 5 may be prepared according to procedures detailed for Intermediate A in WO2009061879, page 55.
  • Step 1 (9H-fluoren-9-yl)methyl (2-amino-2-oxoethyl)carbamate
  • Step 1 (R)-(9H-fluoren-9-yl)methyl -((N-(benzyloxy)formamido)methyl)heptanamido) methyl)carbamate
  • Step 1 (R)-N-(2-amino-2-oxoethyl)-3-(N-(benzyloxy)formamido)-2- (cyclopentylmethyl)propanamide
  • Step 1 (S)-4-benzyl-3-heptanoyloxazolidin-2-one
  • Step 2 (R)-1-((S)-4-benzyl-2-oxooxazolidin-3-yl)-2-pentylpentane-1 ,3-dione
  • Step 3 (S)-4-benzyl-3-((R)-2-((E)-1-((benzyloxy)imino)propyl)heptanoyl)oxazolidin-2-one
  • Step 4 (4S)-4-benzyl-3-((2R)-2-(1-((benzyloxy)amino)propyl)heptanoyl)oxazolidin-2-one
  • (S)-4-benzyl-3-((R)-2-((E)-1-((benzyloxy)imino)propyl)heptanoyl)oxazolidin-2-one (8.51 g, 18.9 mmol) was disolved in acetic acid (62.9 ml) and cooled to 0°C before sodium cyanoborohydride (1.20 g, 18.9 mmol) was added in one portion.
  • Step 7 (9H-fluoren-9-yl)methyl (((R)-2-((R)-1-(N- (benzyloxy)formamido)propyl)heptanamido)methyl)carbamate
  • Step 1 benzyl (aminomethyl)carbamate, trifluoroacetic acid salt
  • benzyl (2-amino-2- oxoethyl)carbamate 300 g, 1442 mmol
  • DCM 8400 ml
  • PI FA PI FA (682 g, 1586 mmol) was added and the mixture was maintained at 23 °C for 1 hour. Seeding material of product (2 wt %) was added and the reaction mixture was maintained for an additional 1 hour.
  • Step 3 (R)-N-(aminomethyl)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamide
  • benzyl (((R)-2-((R)-1-(N- (benzyloxy)formamido)propyl)heptanarnido)rnethyl)carbarnate (180 g, 372 mmol) and ethanol (3600 ml) were charged.
  • Palladium on carbon 10 wt % (18.0 g, 16.9 mmol) was added and the reaction vessel was purged with nitrogen and degassed.
  • the reaction mixture was pressurized with 5.0 kg/cm 2 hydrogen gas at 20-25 °C for 4 hours.
  • Step 1 2-methyl-6-phenyl-4-(trifluoromethyl)pyridine
  • tetrabutylammonium permanganate (1.67 g, 4.50 mmol) was added and the reaction was stirred overnight. The reaction was then poured into a mixture of water and ice and then NaHS0 3 solution (40 % in water) was added until the reaction turned light yellow. The mixture was then acidified by addition of 2 N HCI and extracted with EtOAc. The combined organic layers were then washed with 1 N HCI and brine, dried over Na 2 S0 4 , filtered and concentrated.
  • phenylboronic acid (0.48 g, 3.96 mmol)
  • PdCl 2 (dppf)-CH 2 Cl 2 adduct (0.14 g, 0.17 mmol)
  • sodium carbonate (1 M, 9.91 ml, 9.91 mmol) in 1 ,4-dioxane (6.61 ml)
  • the reaction was then filtered through a pad of Celite® and then extracted with EtOAc.
  • the aqueous phase was acidified to ⁇ pH 2-3 via addition of 1 N HCI.
  • the resultant precipitate was collected.
  • the aqueous phase was then concentrated and the resultant solid was suspended in methanol (10 ml).
  • Step 1 methyl 3-((3-oxobutan-2-yl)carbamoyl)benzoate
  • Step 1 methyl 3-(2-methyloxazol-5-yl)benzoate
  • the reaction was reduced in volume and then diluted by the addition of 1 M NaOH solution (150 ml) and washed with diethyl ether (150 ml). The layers were separated and the aqueous layer was cooled to 0 °C and acidified by addition of HCI (37 %). The aqueous phase was filtered and the collected solid was dissolved in EtOAc (400 ml), washed with brine (100 ml), dried over Na 2 S0 4 then filtered through a silica gel plug, washing with EtOAc. The organic phase was concentrated to give a solid which was triturated with a mixture of
  • Step 1 methyl 3-((6-methoxypyridin-3-yl)oxy)benzoate
  • Step 1 (3-bromophenyl)(2,4,6-trimethoxybenzyl)sulfane
  • Step 3 3'-((2,4,6-trimethoxybenzyl)thio)-[1 , 1 '-biphenyl]-3-carboxylic acid
  • Step 4 3'-mercapto-[1 , T-biphenyl]-3-carboxylic acid
  • Step 1 N-(2-amino-2-oxoethyl)-6-bromopicolinamide
  • Step 1 N-(2-amino-2-oxoethyl)-6-phenylpicolinamide
  • Step 1 (9H-fluoren-9-yl)methyl ((6-phenyl-4-(trifluoromethyl)picolinamido)methyl)carbamate To a solution of 6-phenyl-4-(trifluoromethyl)picolinic acid (0.88 g, 3.29 mmol) in DMF
  • N-(aminomethyl)-6-bromopicolinamide 200 mg, 0.87 mmol
  • 2-ethoxy-4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoic acid (279 mg, 0.96 mmol)
  • PdCl 2 (dppf)-CH 2 Cl 2 adduct 71 mg, 0.09 mmol
  • sodium carbonate (1 M, 2.61 ml, 2.61 mmol
  • reaction was diluted by the addition of water and extracted with DCM and ethyl acetate.
  • aqueous phase was then reduced to ⁇ 1/3 volume and purified by OASIS column (6 g, washed with water, eluted with methanol).
  • the methanol fractions were concentrated and the residue dissolved in DCM and purified by Si SPE (0-10 %
  • Step 1 (9H-fluoren-9-yl)methyl ((3-(1 H-pyrazol-1-yl)benzamido)methyl)carbamate
  • Intermediate 40 was prepared from (9H-fluoren-9-yl)methyl (aminomethyl)carbamate, trifluoroacetic acid salt and the indicated acid by methods analogous to those described for Intermediate 35 using pyrollidine in Step 2 instead of piperidine.
  • Step 1 N-(2-amino-2-oxoethyl)-2,2'-difluoro-3'-methoxy-[1 , 1 '-biphenyl]-3-carboxamide
  • Step 2 N-(aminomethyl)-2,2'-difluoro-3'-methoxy-[1 , 1 '-biphenyl]-3-carboxamide
  • Step 1 N-(2-amino-2-oxoethyl)-3-((6-methoxypyridin-3-yl)oxy)benzamide
  • Step l N-(2-amino-2-oxoethyl)-[1 , T-biphenyl]-3-carboxamide
  • Step 2 N-(aminomethyl)-[1 , T-biphenyl]-3-carboxamide hydrochloride

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Abstract

L'invention concerne des composés de formule (I) dans laquelle R1, R2 et R3 sont tels que définis dans la description, ainsi que des procédés de fabrication et d'utilisation de ces composés, y compris leur utilisation en tant qu'inhibiteurs de BMP1, TLL1 et/ou TLL2 et pour traiter des maladies associées à l'activité de BMP1, TLL1 et/ou TLL2.
PCT/IB2016/054119 2015-07-08 2016-07-08 Dérivés d'hydroxy formamide et leur utilisation WO2017006295A1 (fr)

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US10450288B2 (en) 2014-01-10 2019-10-22 Glaxosmithkline Intellectual Property (No. 2) Limited Hydroxy formamide derivatives and their use
CN110799498A (zh) * 2017-01-23 2020-02-14 深圳大学 一种对非靶生物体具有低毒性的新型天然灭藻剂
EP3820861A1 (fr) * 2018-04-20 2021-05-19 Bayer Aktiengesellschaft Composés hétéroaryle-triazole et hétéroaryle-tétrazole utilisés en tant que pesticides

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US10450288B2 (en) 2014-01-10 2019-10-22 Glaxosmithkline Intellectual Property (No. 2) Limited Hydroxy formamide derivatives and their use
CN110799498A (zh) * 2017-01-23 2020-02-14 深圳大学 一种对非靶生物体具有低毒性的新型天然灭藻剂
CN110799498B (zh) * 2017-01-23 2023-10-27 深圳大学 一种对非靶生物体具有低毒性的新型天然灭藻剂
EP3820861A1 (fr) * 2018-04-20 2021-05-19 Bayer Aktiengesellschaft Composés hétéroaryle-triazole et hétéroaryle-tétrazole utilisés en tant que pesticides
CN109293696A (zh) * 2018-11-20 2019-02-01 上海应用技术大学 一步法合成棉用n-羟甲基-3-（二甲氧基磷酰基）丙酰胺阻燃剂的方法

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