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WO2018081276A1 - Composés - Google Patents

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WO2018081276A1
WO2018081276A1 PCT/US2017/058298 US2017058298W WO2018081276A1 WO 2018081276 A1 WO2018081276 A1 WO 2018081276A1 US 2017058298 W US2017058298 W US 2017058298W WO 2018081276 A1 WO2018081276 A1 WO 2018081276A1
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Prior art keywords
amino
compound
methyl
alkyl
independently selected
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Inventor
Philip Jones
Barbara Czako
Jason P. BURKE
Jason Cross
Paul Graham LEONARD
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Tesaro Inc
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Tesaro Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • This disclosure relates to compounds useful as CSF-IR inhibitors, in particular to compounds having favourable activity and/or kinase selectivity for use in the treatment of conditions such as cancers.
  • CSF-IR Cold Stimulating Factor-1 Receptor
  • RTK transmembrane receptor protein tyrosine kinase
  • CSF-IR stem cell growth factor receptor
  • FLT3 fins-like cytokine receptor
  • PDGFR platelet derived growth factor receptors
  • CSF-IR The natural ligand of CSF-IR is CSF, Colony Stimulating Factor (Robinson et al , Blood. (1969) 33(3):396-399). Binding of CSF to CSF-IR results in receptor dimerization and auto- phosphorylation of the kinase domain, and to subsequent activation of downstream signalling pathways such as the PI3K/AKT and Ras/MAPK signalling pathways.
  • CSF-IR signalling has been shown to play a physiological role in the immune response, in bone remodelling, and in the reproductive system. In particular, activation of CSF-IR regulates the proliferation, differentiation and survival of macrophages, osteoclasts, and microglia. These cells and CSF-IR signalling pathways also play an important role in the inflammatory process.
  • CSF-IR knockout mouse models show a range of phenotypes including reduced macrophage density and depletion of microglia and osteoclasts.
  • CSF-IR Consistent with the varied role of CSF-IR, e.g. in different tissues, dysfunction of CSF-IR has been implicated in a number of disease states including cancers, bone osteolysis, and inflammatory disorders such as rheumatoid arthritis and Crohn's disease, renal allograft rejection and obesity.
  • elevated CSF-1 signalling can lead to elevated osteoclast activity and bone loss, resulting in inflammatory bone erosion and the progression of diseases such as arthritis.
  • elevated expression or activation of CSF-IR and/or CSF-1 has been identified in patients with prostate, ovarian, breast, pancreatic and a variety of other cancers. Overexpression of CSF-1 is associated with poor prognosis in certain cancers e.g.
  • TAMs Tumor-Associated Macrophages
  • CSF-IR signalling has been shown to decrease the number of TAMs in a tumor specific manner and correlates with extended survival (Strachan et al., Oncoimmunology (2013) 2(12):e26968). TAMs are important drivers of immune escape in the tumor microenvironment and they can help to generate a favourable environment for tumors by heightening immunosuppression, angiogenesis and invasion.
  • CSF-IR inhibitors have been proposed for the treatment of CSF-IR mediated diseases, especially cancer. Blockage of CSF-l/CSF-lR signalling with small molecules inhibitors or monoclonal antibodies is reported to be effective in preclinical model systems and, more recently, in the clinic.
  • inhibitors have been shown to be multi-target inhibitors which can have a significant inhibitory activity against other type III RTKs such as PDGFR, c-KIT and FLT.
  • RTKs such as PDGFR, c-KIT and FLT.
  • many of the known inhibitors have non-optimal in vivo properties (e.g. pharmacokinetic properties) and/or a low activity against CSF-IR.
  • Burns et al. (Bioorg. Med. Chem. Lett. (2009) 19(4): 1206-9) identify a number of 2-(a- methylbenzylamino) pyrazine compounds as inhibitors of CSF-IR.
  • the tested compounds show little selectivity for CSF-IR over other kinases such as c-Kit, PDGFR and PDGFRa.
  • the study reports that the presence of an amide-containing group at the 3-position of the benzyl ring is required for the potency of the compounds, with both the amide bond proton and the carbonyl group being said to be essential.
  • the present inventors have discovered a family of compounds which are useful as inhibitors of CSF-IR. These compounds are particularly suitable for use in pharmaceutical compositions and in medical treatments in which the activity of CSF-1R needs to be modulated.
  • the invention provides a compound characterised by formula (I),
  • A is a 5- to 10-membered heteroaryl whose ring atoms consist of C, at least one N and, optionally, O or S;
  • n 0, 1, 2 or 3;
  • n 0, 1 or 2;
  • L either denotes a direct bond, or it is a group -(CR 6 R 7 ) P - in which:
  • p 1, 2 or 3
  • each R 6 and each R 7 is independently selected from hydrogen and Ci-4-alkyl, wherein each said alkyl is optionally and independently substituted by 1 to 3 groups independently selected from halogen and hy droxyl;
  • R 1 in each case is independently selected from halogen, carbonitrile, -C(0)N(R 8 R 9 ), -N(R 8 R 9 ), C 2 - 4 -acyl, C 2 -4-acylamino, hydroxyl, -0(Ci-8-alkyl), -C(0)OR 8 , sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl,
  • R 8 and R 9 are independently selected from H, Ci-4-alkyl, cycloalkyl, and heterocycloalkyl, and
  • each said acyl, acylamino, sulfonyl, aminosulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted;
  • R 2 in each case is independently selected from halogen, hydroxyl, carbonitrile, optionally substituted Ci-4-alkyl, and optionally substituted -0(Ci-4-alkyl);
  • R 3 is an optionally substituted group selected from Ci-g-alkyl, C 2 -4-acyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl; and
  • R 4 and R 5 are independently selected from H and Ci-3-alkyl, or R 4 and R 5 taken together with the carbon atom which is bonded thereto form a 3- to 6-membered cycloalkyl or cycloalkoxy group.
  • R 1 in each case is independently selected from halogen, carbonitrile, -C(0)N(R 8 R 9 ), -N(R 8 R 9 ), C 2 - 4 -acyl, C 2 -4-acylamino, hydroxyl, -0(Ci-8-alkyl), -C(0)OR 8 , sulfonyl, aminosulfonyl, Ci-8-alkyl, C 2 -8-alkenyl, C 2 -8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl,
  • R 8 and R 9 are independently selected from H, Ci-4-alkyl, cycloalkyl, and heterocycloalkyl, and
  • each said acyl, acylamino, sulfonyl, aminosulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from:
  • R a and R b are independently selected from hydrogen and R p , -0(Ci-3-alkyl) optionally substituted by 1 to 3 groups independently selected from R m , carbonitrile,
  • C3-8-cycloalkyl optionally substituted by 1 to 3 groups independently selected from R m .
  • Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R m , C3-8-cycloalkenyl optionally substituted by 1 to 3 groups independently selected from
  • R n and R° are independently selected from hydrogen and R p or in which R n and R° taken together with the intervening nitrogen atom form a 3- to 8- membered heterocycloalkyl group;
  • R m in each case is independently selected from halogen, hydroxyl, amino, and Ci-3-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; and wherein R p in each case is independently selected from S0 2 -Ci-4-alkyl, CO-Ci-4-alkyl, C(0)0-Ci-4-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen;
  • R 2 in each case is independently selected from halogen, hydroxyl, carbonitrile,
  • Ci-4-alkyl and -0(Ci -4 -alkyl)
  • each said alkyl is optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl and carbonitrile; and/or
  • R 3 is selected from Ci-g-alkyl, C 2 -4-acyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl,
  • each said alkyl, acyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from:
  • R d and R e are independently selected from hydrogen and R r , -0(Ci-4-alkyl) optionally substituted by 1 to 3 groups independently selected from R q , C3-8-cycloalkyl optionally substituted by 1 to 3 groups independently selected from R q ,
  • R d and R e are independently selected from hydrogen and R r , C3-8-cycloalkenyl optionally substituted by 1 to 3 groups independently selected from R ⁇
  • Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R q , C 2 -6-alkenyl optionally substituted by 1 to 3 groups independently selected from R q , C 2 -6-alkynyl optionally substituted by 1 to 3 groups independently selected from R q , aryl optionally substituted by 1 to 3 groups independently selected from R q , and 3- to 8-membered heterocycloalkyl optionally substituted by 1 to 3 groups independently selected from R q ,
  • heteroaryl optionally substituted by 1 to 3 groups independently selected from R q ; wherein R q in each case is independently selected from halogen, hydroxyl, amino, and Ci-3-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; and wherein R r in each case is independently selected from S0 2 -Ci-3-alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.
  • A is selected from a 5-membered monocyclic heteroaryl, a 6-membered monocyclic heteroaryl, a 9-membered bicyclic heteroaryl and a 10-membered bicyclic heteroaryl.
  • A is selected from the group consisting of pyrrolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, azaindolyl, imidazopyrimidinyl, and pyrazolopyrimidinyl.
  • A is a 6-membered monocyclic heteroaryl, a 9-membered bicyclic heteroaryl, or a 10-membered bicyclic heteroaryl.
  • A is pyramidinyl or pyridinyl.
  • n is 1.
  • R 1 in each case is independently selected from halogen, carbonitrile, -C(0)N(R 8 R 9 ), -N(R 8 R 9 ), C 2 - 4 -acyl, C 2 -4-acylamino, hydroxyl, -0(Ci-4-alkyl), -C(0)OR 8 , sulfonyl, aminosulfonyl, Ci-4-alkyl, C 2 -4-alkenyl, C 2 -8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein R 8 and R 9 are independently selected from H, Ci-4-alkyl, cycloalkyl, and heterocycloalkyl, and
  • each said acyl, acylamino, sulfonyl, aminosulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R a R b ) in which R a and R b are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, and (Ci-4-alkyl)-R c in which R c is selected from hydroxyl, amino and halogen.
  • R 1 in each case is independently selected from phenyl, pyridinyl, pyranyl, pyrazolyl, benzimidazolyl, cyclohexenyl, dihydrofuranyl, cyclopropanyl, cyclohexanyl, tetrahydropyranyl, isoxazolyl, -C(0)NH 2 , carbonitrile, triazolyl, methanesulfonyl and methyl; wherein each may be optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R a R b ) in which R a and R b are independently selected from hydrogen and Ci-3-alkyl, carbonitrile, Ci-4-alkyl, and (Ci-4-alkyl)-R c in which R c is selected from hydroxyl and amino and halogen.
  • R 4 and R 5 are both hydrogen. In embodiments, m is 0.
  • m is 1 and R 2 is selected from halogen, hydroxyl, carbonitrile, Ci-4-alkyl and -0(Ci-4-alkyl), wherein each said alkyl is optionally substituted by 1 to 3 groups independently selected from halogen.
  • L denotes a direct bond.
  • L is -(CR 6 R 7 ) P - in which p is 1 or 2, and in which each R 6 and each R 7 is independently selected from hydrogen and Ci-4-alkyl, wherein each said alkyl is optionally and independently substituted by 1 to 3 groups independently selected from halogen and hydroxyl.
  • each R 6 and each R 7 is hydrogen.
  • R 3 is Ci-g-alkyl, optionally substituted by 1 to 5 groups independently selected from:
  • R d and R e are independently selected from hydrogen and R r , -0(Ci-4-alkyl) optionally substituted by 1 to 3 groups independently selected from R q , C3-8-cycloalkyl optionally substituted by 1 to 3 groups independently selected from R q ,
  • R d and R e are independently selected from hydrogen and R r , C3-8-cycloalkenyl optionally substituted by 1 to 3 groups independently selected from R q ,
  • Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R q , C 2 -6-alkenyl optionally substituted by 1 to 3 groups independently selected from R q , C 2 -6-alkynyl optionally substituted by 1 to 3 groups independently selected from R q , aryl optionally substituted by 1 to 3 groups independently selected from R q , and 3- to 8-membered heterocycloalkyl optionally substituted by 1 to 3 groups independently selected from R q ,
  • heteroaryl optionally substituted by 1 to 3 groups independently selected from R q ; wherein R q in each case is independently selected from halogen, hydroxyl, amino, and Ci-3-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; and wherein R r in each case is independently selected from S0 2 -Ci-3-alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3.
  • R 3 is selected from cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted with 1 to 5 groups independently selected from:
  • R d and R e are independently selected from hydrogen and R r , -0(Ci-4-alkyl) optionally substituted by 1 to 3 groups independently selected from R q , C3-8-cycloalkyl optionally substituted by 1 to 3 groups independently selected from
  • R d and R e are independently selected from hydrogen and R r , C3-8-cycloalkenyl optionally substituted by 1 to 3 groups independently selected from R q ,
  • Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R q ,
  • heteroaryl optionally substituted by 1 to 3 groups independently selected from R q ; wherein R q in each case is independently selected from halogen, hydroxyl, amino, and Ci-3-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; and wherein R r in each case is independently selected from S0 2 -Ci-3-alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3.
  • R 3 is cyclohexyl optionally substituted by 1 to 4 groups independently selected from hydroxyl, Ci-3-alkyl optionally substituted by hydroxyl, F, CI, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, and CONH 2.
  • R 3 is cyclohexyl substituted by hydroxyl and further optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, C 2 -4-acylamino, -C(0)N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.
  • R 3 is cyclohexyl substituted with hydroxyl and with fluorine.
  • R 3 is indanyl optionally substituted by 1 to 4 groups independently selected from hydroxyl, Ci-3-alkyl optionally substituted by hydroxyl, F, CI, carbonitrile, -N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, C2-4-acylamino, and -C(0)N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-3-alkyl.
  • R 3 is indanyl substituted by hydroxyl and further optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, C 2 -4-acylamino, -C(0)N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.
  • R 3 is bicyclo[3.1.0]hexanyl optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R d R e ) in which R d and R e are independently selected from hydrogen and R r , -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, -C(0)N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen;
  • R r in each case is independently selected from S0 2 -Ci-3-alkyl, CO-C 1 -3- alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.
  • R 3 is bicyclo[3.1.0]hexanyl substituted by hydroxyl and further optionally substituted by a group selected from halogen, hydroxyl, carbonitrile, -N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, C 2 -4-acylamino, -C(0)N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.
  • R 3 is tetrahydropyranyl optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R d R e ) in which R d and R e are independently selected from hydrogen and R r , -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, -C(0)N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen;
  • R r in each case is independently selected from S0 2 -Ci-3-alkyl, CO-C1-3- alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.
  • R 3 is pyridinyl optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R d R e ) in which R d and R e are independently selected from hydrogen and R r , -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, -C(0)N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; wherein R r in each case is independently selected from S0 2 -Ci-3-alkyl, CO-C1-3- alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.
  • the invention provides a compound characterized by formula (II
  • Q and Q 4 are independently selected from N, CH and C(R X ), wherein no fewer than one and no more than two of said Q 1 , Q 2 , Q 3 and Q 4 may denote N; and
  • n, m, X 1 , L, and R 1 to R 5 are as described above.
  • Q 1 is N and Q 2 , Q 3 and Q 4 are CH or C(R X ).
  • Q 1 and Q 4 are both N and Q 2 and Q 3 are both CH or CiR 1 ).
  • the invention provides a compound characterized by formula (III
  • X 2 is selected from N and CH;
  • R 10 to R 12 are each independently selected from H and a group R 1 as described above;
  • X 2 is N.
  • R 10 is selected from halogen, -C(0)N(R 1 R 14 ), sulfonyl, Ci-4-alkyl, C2-4-alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R 13 and R 14 are independently selected from H, Ci-4-alkyl, cycloalkyl, and heterocycloalkyl, and wherein each said sulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from: halogen,
  • R a and R b are independently selected from hydrogen and R p , -0(Ci-3-alkyl) optionally substituted by 1 to 3 groups independently selected from R m , carbonitrile,
  • S0 2 -Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R m .
  • C3-8-cycloalkyl optionally substituted by 1 to 3 groups independently selected from R m .
  • Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R m
  • C3-8-cycloalkenyl optionally substituted by 1 to 3 groups independently selected from R m .
  • R n and R° are independently selected from hydrogen and R p or in which R n and R° taken together with the intervening nitrogen atom form a 3- to 8- membered heterocycloalkyl group; wherein R m in each case is independently selected from halogen, hydroxyl, amino, and Ci-3-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; and wherein R p in each case is independently selected from S0 2 -Ci-4-alkyl, CO-Ci-4-alkyl, C(0)0-Ci-4-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.
  • R is selected from phenyl, pyridinyl, pyranyl, pyrazolyl, cyclohexenyl, dihydrofuranyl, cyclopropanyl, cyclohexyl, tetrahydropyranyl, isoxazolyl, aminocarbonyl, carbonitrile, triazolyl, methanesulfonyl, ethynyl, and methyl; wherein each may be optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, carbonitrile, Ci_ 4-alkyl optionally substituted by hydroxyl or by 1 to 3 halogens, C3-8-cycloalkyl optionally substituted by hydroxyl or by 1 to 3 halogens, NH 2 , S0 2 CH 3 , CH 2 NHS0 2 CH 3 , CH 2 NHCOCH 3 , CH 2 NHC(0)0- l Bu, pyrrolidinylmethyl, morpholin-4-ylmethyl, N-
  • R 11 and R 12 are independently selected from H, halogen, carbonitrile, Ci-3-alkyl, hydroxyl, and -0(Ci-3-alkyl), wherein each said alkyl is optionally substituted by 1 to 3 groups independently selected from halogen.
  • R 11 and R 12 are both hydrogen.
  • the invention provides a compound characterized by formula IV),
  • q 0, 1, 2 or 3;
  • R 17 is independently selected from a group R 1 as described above.
  • the invention provides a compound characterized by formula (IV a ) or (IV b ),
  • R 17 is independently selected from:
  • R 1 and R J are independently selected from hydrogen and R l ,
  • Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R s , C2-6-alkenyl optionally substituted by 1 to 3 groups independently selected from R s , and
  • C2-6-alkynyl optionally substituted by 1 to 3 groups independently selected from R s , wherein R s in each case is independently selected from halogen, hydroxyl, amino, and Ci-3-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; and wherein R l in each case is independently selected from S0 2 -Ci-3-alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.
  • q is 0 or 1.
  • the invention provides a compound characterized by formula V),
  • r 0, 1, 2 or 3;
  • R 18 is independently selected from a group R 1 as described above.
  • the invention provides a compound characterized by formula formula (V a ) or (V b ),
  • R is independently selected from:
  • R 1 and R J are independently selected from hydrogen and R l , -0(Ci-4-alkyl) optionally substituted by 1 to 3 groups independently selected from R s , -C(0)N(R 1 R J ) in which R 1 and R J are independently selected from hydrogen and R l , Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R s , C 2 -6-alkenyl optionally substituted by 1 to 3 groups independently selected from R s , and
  • C 2 -6-alkynyl optionally substituted by 1 to 3 groups independently selected from R s , wherein R s in each case is independently selected from halogen, hydroxyl, amino, and Ci-3-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; and wherein R l in each case is independently selected from S0 2 -Ci-3-alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.
  • r is 0 or 1.
  • the invention provides a compound characterized by formula (VI),
  • R 19 is selected from hydrogen, halogen, hydroxyl, carbonitrile, Ci-4-alkyl, and -0(Ci-4-alkyl), wherein each said alkyl is optionally substituted;
  • R 19 is selected from halogen, Ci-4-alkyl, and -0(Ci-4-alkyl), wherein each said alkyl is optionally substituted by 1 to 3 groups independently selected from halogen and hydroxyl.
  • R 19 is hydrogen
  • the invention provides a compound characterized by formula (X).
  • R , R and R are independently selected from hydrogen and a group R as described above; and L, R 3 , R 4 , R 5 and R 10 are as described above.
  • two of R , R and R are independently selected from hydrogen, and the other is selected from chlorine, fluorine, methyl optionally substituted by 1-3 fluorine, and methoxyl optionally substituted by 1-3 fluorine.
  • the invention provides a compound selected from the group consisting of Compounds 1 to 180, as defined hereinafter, or a pharmaceutically acceptable salt or prodrug thereof.
  • the compound is selected from the group consisting of Compound 1, Compound 15, Compound 21, Compound 35, Compound 49, Compound 50, Compound 51, Compound 70, Compound 88, Compound 103, Compound 106, Compound 107, Compound 111, Compound 113, Compound 114, Compound 117, Compound 119, Compound 127, Compound 133, Compound 134, Compound 146, Compound 147, Compound 148, Compound 160, Compound 165, Compound 171, Compound 173 and Compound 180; or a pharmaceutically acceptable salt or prodrug thereof.
  • the compound has an inhibitory activity (an IC5 0 value) against CSF-IR of less than 100 nM.
  • the compound is selective for CSF-IR over PDGFR by a value of at least 5 times, and/or selective for CSF-IR over PDGFRa by a value of at least 10 times, and/or selective for CSF-IR over c-KIT by a value of at least 20 times, and/or selective for CSF-IR over FLT3 by a value of at least 200 times.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound as described above, and at least one pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises a further active agent selected from the group consisting of anti-proliferative agents, anti-inflammatory agents, anti- angiogenic agents, chemotherapeutic agents and immunotherapeutic agents.
  • the invention provides a compound or a pharmaceutical composition as described above, for use in therapy.
  • the invention provides a method for treating a CSF-IR mediated disease in a subject, the method comprising administering to the subject an effective amount of a compound as described above.
  • the CSF-IR mediated disease is selected from cancer, a bone disorder, an inflammatory disorder, and a neurological disorder.
  • the CSF-IR mediated disease is characterised by overexpression of CSF-IR, by aberrant CSF-IR signalling, by overexpression of CSF-1 and/or IL-34, and/or by mutations in the CSF-IR gene.
  • the CSF-IR mediated disease is a cancer is selected from breast cancer, cervical cancer, glioblastoma multiforme (GBM), Hepatocellular carcinoma, Hodgkin's lymphoma, melanoma, pancreatic cancer pigmented villondular synovitis (PVNS), prostate cancer, ovarian cancer, Tenosynovial giant cell tumors (TGCT), Endometrial cancer, Multiple myeloma, Myelocytic leukemia, Bone cancer, Renal cancer, Brain cancer and myeloproliferative disorder (MPD).
  • GBM glioblastoma multiforme
  • HBM glioblastoma multiforme
  • PVNS pancreatic cancer pigmented villondular synovitis
  • TGCT Tenosynovial giant cell tumors
  • Endometrial cancer Multiple myeloma
  • Myelocytic leukemia Bone cancer, Renal cancer, Brain cancer and myeloproliferative
  • the method is for treating a subject diagnosed as having a cancer or being at risk of developing a cancer.
  • the CSF-IR mediated disease is an inflammatory disorder selected from psoriatic arthritis, arthritis, asthma, thyroiditis, glomerular nephritis, atherosclerosis, psoriasis, Sjogren's syndrome, rheumatoid arthritis, systemic lupus erythematosis (SLE), cutaneous lupus erythematosus, inflammatory bowel disease including Crohn's disease and ulcerative colitis (UC), type 1 diabetes, multiple sclerosis and neuroinflammatory conditions.
  • the CSF-IR mediated disease is a bone disorder selected from osteoporosis, osteoarthritis, periodontitis, periprosthetic osteolysis, and Paget' s disease.
  • the method comprises administering said compound in combination with another therapeutic intervention for said CSF-IR mediated disease.
  • the invention provides a compound as defined above, for use in a method as defined above.
  • the invention provides the use of a compound as described above, in the manufacture of a medicament for use in a method as described above.
  • compositions and methods are intended to mean that the compositions and methods include the recited elements, but not excluding others.
  • Consisting essentially of when used to define compositions and methods shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude contaminants from the isolation and purification method and pharmaceutically acceptable carriers, such as phosphate buffered saline, preservatives and the like.
  • Consisting of shall mean excluding more than trace elements of other ingredients and substantial method steps for administering the compositions of this disclosure or process steps to produce a composition or achieve an intended result.
  • a "subject,” “individual” or “patient” is used interchangeably herein, and refers to a vertebrate, such as a mammal.
  • Mammals include, but are not limited to, rodents, farm animals, sport animals, pets and primates; for example murines, rats, rabbit, simians, bovines, ovines, porcines, canines, felines, equines, and humans.
  • the mammals include horses, dogs, and cats.
  • the mammal is a human.
  • administering is defined herein as a means of providing an agent or a composition containing the agent to a subject in a manner that results in the agent being inside the subject's body.
  • Such an administration can be by any route including, without limitation, oral, transdermal (e.g. by the vagina, rectum, or oral mucosa), by injection (e.g. subcutaneous, intravenous, parenteral, intraperitoneal, or into the CNS), or by inhalation (e.g. oral or nasal).
  • Pharmaceutical preparations are, of course, given by forms suitable for each administration route.
  • Treating" or “treatment” of a disease includes: (1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a patient that may be predisposed to the disease but does not yet experience or display symptoms of the disease; (2) inhibiting the disease, i.e. arresting or reducing the development of the disease or its clinical symptoms; and/or (3) relieving the disease, i.e. causing regression of the disease or its clinical symptoms.
  • the term "suffering” as it relates to the term “treatment” refers to a patient or individual who has been diagnosed with or is predisposed to the disease.
  • a patient may also be referred to being "at risk of suffering” from a disease because of a history of disease in their family lineage or because of the presence of genetic mutations associated with the disease.
  • a patient at risk of a disease has not yet developed all or some of the characteristic pathologies of the disease.
  • An “effective amount” or “therapeutically effective amount” is an amount sufficient to effect beneficial or desired results.
  • An effective amount can be administered in one or more administrations, applications or dosages.
  • Such delivery is dependent on a number of variables including the time period for which the individual dosage unit is to be used, the bioavailability of the therapeutic agent, the route of administration, etc.. It is understood, however, that specific dose levels of the therapeutic agents of the present invention for any particular subject depends upon a variety of factors including, for example, the activity of the specific compound employed, the age, body weight, general health, sex, and diet of the subject, the time of administration, the rate of excretion, the drug combination, and the severity of the particular disorder being treated and form of administration. Treatment dosages generally may be titrated to optimize safety and efficacy. Typically, dosage-effect relationships from in vitro and/or in vivo tests initially can provide useful guidance on the proper doses for patient administration.
  • the term "pharmaceutically acceptable excipient” encompasses any of the standard pharmaceutical excipients, including carriers such as a phosphate buffered saline solution, water, and emulsions, such as an oil/water or water/oil emulsion, and various types of wetting agents.
  • Pharmaceutical compositions also can include stabilizers and preservatives.
  • carriers, stabilizers and adjuvants see Remington's Pharmaceutical Sciences (20th ed., Mack Publishing Co. 2000).
  • prodrug means a pharmacological derivative of a parent drug molecule that requires biotransformation, either spontaneous or enzymatic, within the organism to release the active drug.
  • prodrugs are variations or derivatives of the compounds described herein that have groups cleavable under certain metabolic conditions, which when cleaved, become the compounds described herein, e.g. a compound of formula (I). Such prodrugs then are pharmaceutically active in vivo when they undergo solvolysis under physiological conditions or undergo enzymatic degradation.
  • Prodrug compounds herein may be called single, double, triple, etc. , depending on the number of biotransformation steps required to release the active drug within the organism, and the number of functionalities present in a precursor-type form.
  • Prodrug forms often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (Bundgard, Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985 and Silverman, "The Organic Chemistry of Drug Design and Drug Action” pp. 352-401, Academic Press, San Diego, Calif, 1992).
  • Prodrugs commonly known in the art include well-known acid derivatives, such as, for example, esters prepared by reaction of acid compounds with a suitable alcohol, amides prepared by reaction of acid compounds with an amine, basic groups reacted to form an acylated base derivative, etc..
  • Other prodrug derivatives may be combined with other features disclosed herein to enhance bioavailability.
  • those of skill in the art will appreciate that certain of the presently disclosed compounds having, for example, free amino or hydroxyl groups can be converted into prodrugs.
  • Prodrugs also include compounds having a carbonate, carbamate, amide or alkyl ester moiety covalently bonded to any of the above substituents disclosed herein.
  • pharmaceutically acceptable salt means a pharmaceutically acceptable acid addition salt or a pharmaceutically acceptable base addition salt of a currently disclosed compound that may be administered without any resultant substantial undesirable biological effect(s) or any resultant deleterious interaction(s) with any other component of a pharmaceutical composition in which it may be contained.
  • alkyl means a saturated linear or branched free radical consisting essentially of carbon atoms and a corresponding number of hydrogen atoms.
  • exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, etc.
  • Other alkyl groups will be readily apparent to those of skill in the art given the benefit of the present disclosure.
  • the terms "Ci-3-alkyl”, “Ci-4-alkyl”, etc. have equivalent meanings, i.e. a saturated linear or branched free radical consisting essentially of 1 to 3 (or 1 to 4, or 4 or 8) carbon atoms and a corresponding number of hydrogen atoms.
  • alkenyl means an unsaturated linear or branched free radical consisting essentially of carbon atoms and a corresponding number of hydrogen atoms, which free radical comprises at least one carbon-carbon double bond.
  • alkenyl groups include ethenyl, prop-l-enyl, prop-2-enyl, isopropenyl, but-l-enyl, 2-methyl-prop-l-enyl, 2- methyl-prop-2-enyl, etc.
  • Other alkenyl groups will be readily apparent to those of skill in the art given the benefit of the present disclosure.
  • the terms "C2-6-alkenyl", “C2-8-alkenyl”, etc. have an equivalent meaning, i.e. an unsaturated linear or branched free radical consisting essentially of 2 to 6 (or 2 to 8) carbon atoms and a corresponding number of hydrogen atoms, which free radical comprises at least one carbon-carbon double bond.
  • alkynyl means an unsaturated linear or branched free radical consisting essentially of carbon atoms and a corresponding number of hydrogen atoms, which free radical comprises at least one carbon-carbon triple bond.
  • alkenyl groups include ethynyl, prop-l-ynyl, prop-2-ynyl, but-l-ynyl, 3-methyl-but-l-ynyl, etc.
  • Other alkynyl groups will be readily apparent to those of skill in the art given the benefit of the present disclosure.
  • the terms "C2-6-alkynyl", “C2-8-alkynyl”, etc. have an equivalent meaning, i.e. an unsaturated linear or branched free radical consisting essentially of 2 to 6 (or 2-8) carbon atoms and a corresponding number of hydrogen atoms, which free radical comprises at least one carbon-carbon triple bond.
  • carbocyclic group means a saturated, partially or fully unsaturated, or aromatic free radical having at least 3 to 9 carbon atoms ⁇ i.e. ring atoms) that form a ring.
  • exemplary carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl and phenyl. It will be appreciated that the carbocyclic group may be monocyclic or multicyclic (e.g. fused, bridged or spirocyclic systems). In the case of multicyclic carbocyclic groups, there are further rings, e.g.
  • cycloalkyl has an equivalent meaning in relation to saturated carbocyclic groups.
  • cycloalkyl groups are typically C3-io-cycloalkyl groups, e.g. C 3-8 - or C3-6-cycloalkyl groups.
  • cycloalkyl groups include monocyclic groups such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, as well as multicyclic groups such as bicyclo[3.1.0]hexanyl and bicyclo[3.2.1]octanyl.
  • the term "cycloalkenyl” has an equivalent meaning in relation to unsaturated carbocyclic groups.
  • cycloalkenyl groups are typically C 3 -io-cycloalkenyl groups, e.g. C 3-8 - or C 3 - 6- cycloalkyl groups.
  • Examples of cycloalkyl groups include cyclopropenyl, cyclopentenyl and cyclohexadienyl.
  • aryl has an equivalent meaning in relation to aromatic carbocyclic groups.
  • aryl groups are typically C6-io-aryl groups.
  • Examples of aryl groups include phenyl and naphthalenyl, as well as indenyl and indanyl groups.
  • heterocyclic group means a saturated, partially or fully unsaturated, or aromatic free radical having at least 3 to 6 atoms (i.e. ring atoms) that form a ring, wherein 1 to 5 of said ring atoms are carbon and the remaining 1 to 5 ring atom(s) (i.e. hetero ring atom(s)) are selected independently from the group consisting of nitrogen, sulphur and oxygen.
  • exemplary heterocyclic groups include aziridinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyrrolyl, pyridinyl and imidazolyl.
  • multicyclic heterocyclic groups there are further rings, e.g. 1, 2, 3, or more, further rings, all of which contain from 3 to 6 ring atoms selected from carbon, nitrogen, sulphur and oxygen.
  • Multicyclic heterocyclic rings include fused, bridged and spirocyclic ring systems.
  • Exemplary heterocarbocyclic groups having such further rings include 2-azabicyclo[3.3.0]octanyl, 3,9-diazaspiro[5.5]undecanyl, dihydroindolyl, benzothiophenyl and benzoxazolyl.
  • heterocycloalkyl has an equivalent meaning in relation to saturated heterocyclic groups.
  • Heterocycloalkyl groups typically contain from 3 to 10 ring atoms, e.g. from 3 to 9 ring atoms or from 3 to 8 ring atoms.
  • Exemplary heterocycloalkyl groups include pyrrolidinyl, morpholinyl, piperidinyl, and piperzinyl.
  • the term "heterocycloalkenyl” has an equivalent meaning in relation to unsaturated heterocyclic groups.
  • Heterocycloalkenyl groups typically contain from 3 to 10 ring atoms, e.g. from 3 to 9 ring atoms or from 3 to 8 ring atoms.
  • heterocycloalkenyl groups include 2,5- dihydro-lH-pyrrolyl, 2H-pyranyl, and 3,4-dihydro-2H-pyranyl.
  • heteroaryl has an equivalent meaning in relation to aromatic heterocyclic groups. Heteroaryl groups typically contain from 5 to 10 ring atoms (e.g.
  • ring atoms from 6 to 10 ring atoms
  • groups include monocyclic groups such as pyrrolyl, pyridinyl, pyrazinyl, and pyridazinyl, as well as multicyclic groups such as benzofuranyl, benzothiophenyl, indolyl, pyrrolopyridinyl, quinolinyl and pteridinyl.
  • cyano means a free radical having a carbon atom linked to a nitrogen atom via a triple bond.
  • the cyano radical is attached via its carbon atom.
  • nitro means an NO2 radical which is attached via its nitrogen atom.
  • acyl means a carbon-containing free radical having at least one carbon-oxygen double bond. The acyl radical is attached via the carbon atom of the carbon- oxygen double bond.
  • hydroxy and “hydroxyl” mean an OH radical which is attached via its oxygen atom.
  • thio means an SH radical which is attached via its sulphur atom.
  • amino generally means a free radical having a nitrogen atom and 1 or 2 hydrogen atoms.
  • amino typically refers to primary and secondary amines.
  • a tertiary amine is represented by the general formula RR ⁇ N-, wherein R and R ⁇ are carbon radicals that may or may not be identical.
  • RR ⁇ N- a tertiary amine
  • R and R ⁇ are carbon radicals that may or may not be identical.
  • amino may be used herein to describe a primary, secondary, and/or tertiary amine, and those of skill in the art will readily be able to ascertain how the term is being used in view of the context of that term.
  • the term is intended, generally, to encompass primary, secondary and tertiary amide radicals, “amido” and “amide” radicals are attached via their carbonyl carbon atom.
  • acylamino means a free radical containing at least one carbon- oxygen double bond, having an amino group attached to the carbonyl carbon.
  • the acylamino radical is attached via the nitrogen atom of the amino group.
  • the "sulfonyl” radical is attached via the said sulphur atom.
  • aminonosulfonyl means a sulfonyl group which is directly bonded to an amino group as defined herein.
  • R* and S* denote that the stereochemical designation is racemic. Where two such terms appear in a chemical name, this can denote that the relative configuration at the chiral centers in question is either the same (e.g. "1R*,2R*”) or different (e.g. "1R*,2S*”).
  • the prefix “rel-” is used to denote relative configuration in cases where more than two chiral centres are present within the compound.
  • compositions and methods provided herein may be combined with one or more of any of the other compositions and methods provided herein.
  • DIBAL diisobutylaluminum hydride
  • DIBAL-D diisobutylaluminum deuteride
  • DIEA N.N-diisopropy lethy lamine
  • DIPEA N,N-diisopropylethylamine
  • DMSO-d 6 dimethyl sulfoxide hexadeuterated
  • HATU l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate
  • NBS N-bromosuccinimide
  • Rochelles salt Potassium sodium tartrate tetrahydrate
  • tBuONO tert-butyl nitrite.
  • TBSC1 fc/V-butyldimethylsilyl chloride
  • the present invention relates to compounds useful as CSF-IR inhibitors.
  • the invention provides a compound characterised by formula (I),
  • A is a 5- to 10-membered heteroaryl whose ring atoms consist of C, at least one N and, optionally, O or S;
  • n 0, 1. 2 or 3;
  • n 0, 1 or 2;
  • L either denotes a direct bond, or it is a group -(CR 6 R 7 ) P - in which:
  • each R 6 and each R 7 is independently selected from hydrogen and Ci-4-alkyl, wherein each said alkyl is optionally and independently substituted by 1 to 3 groups independently selected from halogen and hydroxyl;
  • R 1 in each case is independently selected from halogen, carbonitrile, -C(0)N(R 8 R 9 ), -N(R 8 R 9 ), C 2 - 4 -acyl, C 2 -4-acylamino, hydroxyl, -0(Ci-8-alkyl), -C(0)OR 8 , sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl,
  • R 8 and R 9 are independently selected from H, Ci-4-alkyl, cycloalkyl, and heterocycloalkyl, and
  • each said acyl, acylamino, sulfonyl, aminosulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted;
  • R 2 in each case is independently selected from halogen, hydroxyl, carbonitrile, optionally substituted Ci-4-alkyl, and optionally substituted -0(Ci-4-alkyl);
  • R 3 is an optionally substituted group selected from Ci-g-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl; and
  • R 4 and R 5 are independently selected from H and Ci-3-alkyl, or R 4 and R 5 taken together with the carbon atom which is bonded thereto form a 3- to 6-membered cycloalkyl or cycloalkoxy group.
  • R 1 in each case is independently selected from halogen, carbonitrile, -C(0)N(R 8 R 9 ), -N(R 8 R 9 ), C 2 - 4 -acyl, C 2 -4-acylamino, hydroxyl, -0(Ci-8-alkyl), -C(0)OR 8 , sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl,
  • R 8 and R 9 are independently selected from H, Ci-4-alkyl, cycloalkyl, and heterocycloalkyl, and wherein each said acyl, acylamino, sulfonyl, aminosulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from:
  • R a and R b are independently selected from hydrogen and R p , -0(Ci-3-alkyl) optionally substituted by 1 to 3 groups independently selected from R m , carbonitrile,
  • S02-Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R m .
  • C3-8-cycloalkyl optionally substituted by 1 to 3 groups independently selected from R m .
  • Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R m
  • C3-8-cycloalkenyl optionally substituted by 1 to 3 groups independently selected from R m .
  • R n and R° are independently selected from hydrogen and R p or in which R n and R° taken together with the intervening nitrogen atom form a 3- to 8- membered heterocycloalkyl group;
  • R m in each case is independently selected from halogen, hydroxyl, amino, and Ci-3-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; and wherein R p in each case is independently selected from S0 2 -Ci-4-alkyl, CO-Ci-4-alkyl, C(0)0-Ci-4-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; R 2 in each case is independently selected from halogen, hydroxyl, carbonitrile, C h alky 1, and -0(Ci -4 -alkyl),
  • each said alkyl is optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl and carbonitrile; and/or
  • R 3 is selected from Ci-8-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl,
  • each said alkyl, acyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from:
  • R d and R e are independently selected from hydrogen and R r , -0(Ci-4-alkyl) optionally substituted by 1 to 3 groups independently selected from R q , C3-8-cycloalkyl optionally substituted by 1 to 3 groups independently selected from R q ,
  • R d and R e are independently selected from hydrogen and R r , C3-8-cycloalkenyl optionally substituted by 1 to 3 groups independently selected from R q ,
  • Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R q , C2-6-alkenyl optionally substituted by 1 to 3 groups independently selected from R q , C2-6-alkynyl optionally substituted by 1 to 3 groups independently selected from R q , aryl optionally substituted by 1 to 3 groups independently selected from R q , and 3- to 8-membered heterocycloalkyl optionally substituted by 1 to 3 groups independently selected from R q ,
  • heteroaryl optionally substituted by 1 to 3 groups independently selected from R q ; wherein R q in each case is independently selected from halogen, hydroxyl, amino, and Ci-3-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; and wherein R r in each case is independently selected from S02-Ci-3-alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.
  • R 1 in each case is independently selected from halogen, carbonitrile, -C(0)N(R 8 R 9 ), -N(R 8 R 9 ), C 2 - 4 -acyl, C 2 -4-acylamino, hydroxyl, -0(Ci-8-alkyl), -C(0)OR 8 , sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl,
  • R 8 and R 9 are independently selected from H, Ci-4-alkyl, cycloalkyl, and heterocycloalkyl, and
  • each said acyl, acylamino, sulfonyl, aminosulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R a R b ) in which R a and R b are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, and (Ci-4-alkyl)-R c in which R c is selected from hydroxyl, amino and halogen;
  • R 2 in each case is independently selected from halogen, hydroxyl, carbonitrile, Ci-4-alkyl, and -0(Ci -4 -alkyl),
  • each said alkyl is optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl and carbonitrile; and/or
  • R 3 is selected from Ci-g-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl,
  • each said alkyl, acyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, C3-8-cycloalkyl, C2-4-acylamino, -C(0)N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-3-alkyl, C3-8-cycloalkenyl, Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen, aryl and heteroaryl.
  • A is selected from a 5-membered monocyclic heteroaryl, a 6-membered monocyclic heteroaryl, a 9-membered bicyclic heteroaryl and a 10-membered bi cyclic heteroaryl.
  • A is selected from the group consisting of pyrrolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, azaindolyl, imidazopyrimidinyl, and pyrazolopyrimidinyl.
  • A is a 6-membered monocyclic heteroaryl, e.g. pyramidinyl, pyridinyl or pyrazinyl (e.g. pyramidinyl or pyridinyl).
  • A is a 9-membered bicyclic heteroaryl, e.g. imidazo[l,2-c]pyrimidinyl.
  • A is a 10-membered bicyclic heteroaryl, e.g. quinazolinyl.
  • n is 1 or 2. In other embodiments, n is 1. In other embodiments, n is 2. In other embodiments, n is 0. In other embodiments, n is 0 or 1.
  • R 1 in each case is independently selected from halogen, carbonitrile, -C(0)N(R 8 R 9 ), -N(R 8 R 9 ), C 2 - 4 -acyl, C 2 -4-acylamino, hydroxyl, -0(Ci-8-alkyl), -C(0)OR 8 , sulfonyl, aminosulfonyl, Ci-g-alkyl, C 2 -8-alkenyl, C 2 -8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl,
  • R 8 and R 9 are independently selected from H, Ci-4-alkyl, cycloalkyl, and heterocycloalkyl, and
  • each said acyl, acylamino, sulfonyl, aminosulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from:
  • R a and R b are independently selected from hydrogen and R p , -0(Ci-3-alkyl) optionally substituted by 1 to 3 groups independently selected from R m , carbonitrile,
  • C3-8-cycloalkyl optionally substituted by 1 to 3 groups independently selected from Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R m , C3-8-cycloalkenyl optionally substituted by 1 to 3 groups independently selected from R m .
  • R n and R° are independently selected from hydrogen and R p or in which R n and R° taken together with the intervening nitrogen atom form a 3- to 8- membered heterocycloalkyl group;
  • R m in each case is independently selected from halogen, hydroxyl, amino, and Ci-3-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; and wherein R p in each case is independently selected from S0 2 -Ci-4-alkyl, CO-Ci-4-alkyl, C(0)0-Ci-4-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.
  • R 1 in each case is independently selected from halogen, carbonitrile, -C(0)N(R 8 R 9 ), -N(R 8 R 9 ), C 2 - 4 -acyl, C 2 -4-acylamino, hydroxyl, -0(Ci-4-alkyl), -C(0)OR 8 , sulfonyl, aminosulfonyl, Ci-4-alkyl, C 2 -4-alkenyl, C 2 -8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl,
  • R 8 and R 9 are independently selected from H, Ci-4-alkyl, cycloalkyl, and heterocycloalkyl, and
  • each said acyl, acylamino, sulfonyl, aminosulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from: halogen,
  • R a and R b are independently selected from hydrogen and C 1-3 - alkyl
  • C3-8-cycloalkyl optionally substituted by 1 to 3 groups independently selected from R m .
  • Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R m , 3- to 8-membered heterocycloalkyl optionally substituted by 1 to 3 groups independently selected from R m ,
  • R n and R° are independently selected from hydrogen and R p or in which R n and R° taken together with the intervening nitrogen atom form a 3- to 8- membered heterocycloalkyl group;
  • R m in each case is independently selected from halogen, hydroxyl, amino and Ci-3-alkyl; and wherein R p in each case is independently selected from S0 2 -Ci -4 -alkyl, CO-C M -alkyl, C(0)0-C M -alkyl, and C M -alk l.
  • R 1 in each case is independently selected from halogen, carbonitrile, -C(0)N(R 8 R 9 ), -N(R 8 R 9 ), C 2 - 4 -acyl, C 2-4 -acylamino, hydroxyl, -0(Ci-4-alkyl), -C(0)OR 8 , sulfonyl, aminosulfonyl, Ci-4-alkyl, C 2- 4-alkenyl, C 2 -8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl,
  • R 8 and R 9 are independently selected from H, Ci-4-alkyl, cycloalkyl, and heterocycloalkyl, and
  • each said acyl, acylamino, sulfonyl, aminosulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R a R b ) in which R a and R b are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, and (Ci-4-alkyl)-R c in which R c is selected from hydroxyl, amino and halogen.
  • R 1 in each case is independently selected from halogen, -C(0)N(R 8 R 9 ), -0(Ci -4 -alkyl), -C(0)OR 8 , sulfonyl, Ci -4 -alkyl, C 2 - 8 -alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,
  • R 8 and R 9 are independently selected from H, Ci-4-alkyl, cycloalkyl, and heterocycloalkyl, and
  • each said sulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from:
  • R a and R b are independently selected from hydrogen and C1-3- alkyl
  • C3-8-cycloalkyl optionally substituted by 1 to 3 groups independently selected from R m .
  • Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R m , 3- to 8-membered heterocycloalkyl optionally substituted by 1 to 3 groups independently selected from R m ,
  • R n and R° are independently selected from hydrogen and R p or in which R n and R° taken together with the intervening nitrogen atom form a 3- to 8- membered heterocycloalkyl group;
  • R m in each case is independently selected from halogen, hydroxyl, amino and Ci-3-alkyl; and wherein R p in each case is independently selected from S0 2 -Ci -4 -alkyl, CO-Ci -4 -alkyl, and C(0)0-Ci -4 -alkyl.
  • R 1 in each case is independently selected from halogen, -C(0)N(R 8 R 9 ), -0(Ci -4 -alkyl), -C(0)OR 8 , sulfonyl, Ci -4 -alkyl, C 2-8 -alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R 8 and R 9 are independently selected from H, Ci-4-alkyl, cycloalkyl, and heterocycloalkyl, and
  • each said sulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R a R b ) in which R a and R b are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, and (Ci-4-alkyl)-R c in which R c is selected from hydroxyl and amino and halogen.
  • R 1 in each case is independently selected from halogen, C 2 -8-alkynyl, aryl, and heteroaryl,
  • each said alkynyl, aryl or heteroaryl is optionally substituted by 1 or 2 groups independently selected from:
  • R a and R b are independently selected from hydrogen and C 1-3 - alkyl
  • C3-8-cycloalkyl optionally substituted by 1 to 3 groups independently selected from R m .
  • Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R m , 3- to 8-membered heterocycloalkyl optionally substituted by 1 to 3 groups independently selected from R m ,
  • R n and R° are independently selected from hydrogen and R p or in which R n and R° taken together with the intervening nitrogen atom form a 3- to 8- membered heterocycloalkyl group;
  • R m in each case is independently selected from halogen, hydroxyl and Ci-3-alkyl; and wherein R p in each case is independently selected from S0 2 -Ci-4-alkyl, CO-Ci-4-alkyl, and C(0)0-Ci -4 -alkyl.
  • R 1 in each case is independently selected from phenyl, pyridinyl, pyranyl, pyrazolyl, benzimidazolyl, cyclohexenyl, dihydrofuranyl, cyclopropanyl, cyclohexanyl, tetrahydropyranyl, isoxazolyl, -C(0)NH 2 , carbonitrile, ethynyl, triazolyl, methanesulfonyl and methyl; wherein each may be optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R a R b ) in which R a and R b are independently selected from hydrogen and Ci-3-alkyl, carbonitrile, -0(Ci-3-alkyl) optionally substituted by 1-3 halogen, Ci-4-alkyl, (Ci-4-alkyl)-R c in which R c is selected from hydroxyl and amino and halogen,
  • R 1 in each case is independently selected from phenyl, pyridinyl, pyranyl, pyrazolyl, benzimidazolyl, cyclohexenyl, dihydrofuranyl, cyclopropanyl, cyclohexanyl, tetrahydropyranyl, isoxazolyl, -C(0)NH 2 , carbonitrile, triazolyl, methanesulfonyl and methyl; wherein each may be optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R a R b ) in which R a and R b are independently selected from hydrogen and Ci-3-alkyl, carbonitrile, Ci-4-alkyl, and (Ci-4-alkyl)-R c in which R c is selected from hydroxyl and amino and halogen.
  • n is 1 and R 1 is independently selected from phenyl, pyridinyl and ethynyl; wherein each may be optionally substituted by up to 3 groups independently selected from: halogen,
  • R a and R b are independently selected from hydrogen and R p , -0(Ci-3-alkyl) optionally substituted by 1 to 3 groups independently selected from R m .
  • C3-8-cycloalkyl optionally substituted by 1 to 3 groups independently selected from R m .
  • Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R m , 3- to 8-membered heterocycloalkyl optionally substituted by 1 to 3 groups independently selected from R m ,
  • 5- to 10-membered heteroaryl optionally substituted by 1 to 3 groups independently selected from R m , and CH 2 NR n R° in which R n and R° are independently selected from hydrogen and R p or in which R n and R° taken together with the intervening nitrogen atom form a 3- to 8- membered heterocycloalkyl group;
  • R m in each case is independently selected from halogen, hydroxyl, amino, and Ci-3-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; and wherein R p in each case is independently selected from S0 2 -Ci-4-alkyl, CO-Ci-4-alkyl, C(0)0-Ci-4-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.
  • n is 1 and R 1 is selected from phenyl, pyridinyl, and methyl, each optionally substituted by 1 to 3 groups selected independently from halogen, Ci-3-alkyl and -0(Ci -3 -alkyl).
  • n is 1 and R 1 is selected from phenyl, pyridinyl, and ethynyl, wherein each may be optionally substituted by up to 2 groups independently selected from halogen, methyl, methoxyl, carbonitrile, CH 2 NHSO 2 CH 3 , and N-methylpyrazolyl.
  • n is 1 and R 1 is phenyl optionally substituted by 1 to 3 halogen. In another embodiment, n is 1 and R 1 is pyridine optionally substituted with 1 to 3 halogen. In another embodiment, n is 1 and R 1 is methyl optionally substituted by 1 to 3 halogen. In another embodiment, n is 1 and R 1 is carbonitrile. In another embodiment, n is 1 and R 1 is CI. In another embodiment, n is 1 and R 1 is Br. In another embodiment, n is 1 and R 1 is -C(0)NH2. In another embodiment, n is 1 and R 1 is 2,3-dihydro-6H-pyranyl. In another embodiment, n is 1 is 2,3-dihydrofuranyl.
  • n is 1 and R 1 is phenyl optionally substituted by 1 or 2 substituents selected from fluorine, carbonitrile and methoxyl. In another embodiment, n is 1 and R 1 is pyridinyl optionally substituted by 1 or 2 substituents selected from fluorine and methoxyl. In other embodiments, n is 0.
  • R 4 and R 5 taken together with the carbon atom which is bonded thereto form a cyclopropyl group.
  • one of R 4 and R 5 is hydrogen and the other is selected from Ci-3-alkyl (e.g. methyl).
  • R 4 and R 5 are both independently selected from Ci-3-alkyl (e.g. both methyl).
  • R 4 and R 5 are both hydrogen.
  • isotopically labelled compounds are within the scope of the present disclosure and invention.
  • the present compounds may have one or more hydrogen atoms replaced with e.g. deuterium.
  • R 4 and/or R 5 may optionally be deuterium.
  • R 4 and R 5 are both deuterium.
  • n is 1. In a preferred embodiment, m is 0.
  • each R 2 is independently selected from halogen, hydroxyl, carbonitrile, Ci-4-alkyl and -0(Ci-4-alkyl), wherein each said alkyl is optionally substituted by 1 to 3 groups independently selected from halogen.
  • each R 2 is independently selected from halogen, Ci-3-alkyl and - 0(Ci-3-alkyl), wherein each said alkyl is optionally substituted by 1 to 3 groups independently selected from fluorine.
  • m is 1 and R 2 is selected from halogen, hydroxyl, carbonitrile, Ci-4-alkyl and -0(Ci-4-alkyl), wherein each said alkyl is optionally substituted by 1 to 3 groups independently selected from halogen.
  • n is 1 and R 2 is selected from fluorine, chlorine, methyl and methoxyl.
  • L is -(CR 6 R 7 ) P - in which p is preferably 1 or 2 (especially in which p is 1) and in which each R 6 and each R 7 is independently selected from hydrogen and Ci-4-alkyl, wherein each said alkyl is optionally and independently substituted by 1 to 3 groups independently selected from halogen (e.g. fluorine) and hydroxyl.
  • p is preferably 1 or 2 (especially in which p is 1) and in which each R 6 and each R 7 is independently selected from hydrogen and Ci-4-alkyl, wherein each said alkyl is optionally and independently substituted by 1 to 3 groups independently selected from halogen (e.g. fluorine) and hydroxyl.
  • one of an R 6 and R 7 attached to the same carbon atom is hydrogen and the other is C 1-4 alkyl, optionally substituted with hydroxyl. In other embodiments, one of an R 6 and R 7 attached to the same carbon atom is hydrogen and the other is methyl. In still other embodiments, one of an R 6 and R 7 attached to the same carbon atom is hydrogen and the other is hydroxymethyl. In yet other embodiments, all R 6 and R 7 groups present are hydrogen. In one embodiment, L is -CH 2 -.
  • L denotes a direct bond
  • R 3 is Ci-g-alkyl optionally substituted by 1 to 5 groups independently selected from:
  • R d and R e are independently selected from hydrogen and R r , -0(Ci-4-alkyl) optionally substituted by 1 to 3 groups independently selected from R q , C3-8-cycloalkyl optionally substituted by 1 to 3 groups independently selected from R q ,
  • R d and R e are independently selected from hydrogen and R r , C3-8-cycloalkenyl optionally substituted by 1 to 3 groups independently selected from R q ,
  • Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R q , C 2 -6-alkenyl optionally substituted by 1 to 3 groups independently selected from R q , C2-6-alkynyl optionally substituted by 1 to 3 groups independently selected from R q , aryl optionally substituted by 1 to 3 groups independently selected from R q , and 3- to 8-membered heterocycloalkyl optionally substituted by 1 to 3 groups independently selected from R q ,
  • heteroaryl optionally substituted by 1 to 3 groups independently selected from R q ; wherein R q in each case is independently selected from halogen, hydroxyl, amino, and Ci-3-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; and wherein R r in each case is independently selected from S0 2 -Ci-3-alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.
  • R 3 is Ci-g-alkyl, optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen, and -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen.
  • R 3 is Ci-5-alkyl, optionally substituted with 1 to 3 groups independently selected from halogen and hydroxyl.
  • R 3 is C 2 -6-alkyl, optionally substituted with 1 to 3 groups independently selected from halogen and hydroxyl.
  • R 3 is 4-methylpentan-l -ol.
  • R 3 is selected from cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted with 1 to 5 groups independently selected from:
  • R d and R e are independently selected from hydrogen and R r ,
  • R d and R e are independently selected from hydrogen and R r , C3-8-cycloalkenyl optionally substituted by 1 to 3 groups independently selected from
  • Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R q , C 2 -6-alkenyl optionally substituted by 1 to 3 groups independently selected from R q , C 2 -6-alkynyl optionally substituted by 1 to 3 groups independently selected from R q , aryl optionally substituted by 1 to 3 groups independently selected from R q , and
  • heteroaryl optionally substituted by 1 to 3 groups independently selected from R q ; wherein R q in each case is independently selected from halogen, hydroxyl, amino, and Ci-3-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; and wherein R r in each case is independently selected from S0 2 -Ci-3-alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.
  • R 3 is selected from cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted with 1 to 5 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, C2-4-acylamino, -C(0)N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.
  • R 3 is selected from cyclohexyl, bicyclo[3.1.0]hexanyl, phenyl, pyridinyl, tetrahydrofuranyl, tetrahydropyranyl and indanyl (2,3-dihydro-lH-indenyl), each optionally substituted with 1 to 5 groups selected from:
  • R d and R e are independently selected from hydrogen and R r , -0(Ci-4-alkyl) optionally substituted by 1 to 3 groups independently selected from R q , C3-8-cycloalkyl optionally substituted by 1 to 3 groups independently selected from R q ,
  • Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R q , C2-6-alkenyl optionally substituted by 1 to 3 groups independently selected from R q , C2-6-alkynyl optionally substituted by 1 to 3 groups independently selected from R q , aryl optionally substituted by 1 to 3 groups independently selected from R q , and 3- to 8-membered heterocycloalkyl optionally substituted by 1 to 3 groups independently selected from R q ,
  • heteroaryl optionally substituted by 1 to 3 groups independently selected from R q ; wherein R q in each case is independently selected from halogen, hydroxyl, amino, and Ci-3-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; and wherein R r in each case is independently selected from S0 2 -Ci-3-alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.
  • R 3 is selected from cyclohexyl, bicyclo[3.1.0]hexanyl, phenyl, pyridinyl, tetrahydrofuranyl, tetrahydropyranyl and indanyl (2,3-dihydro-lH-indenyl), each optionally substituted with 1 to 3 groups selected from:
  • R d and R e are independently selected from hydrogen and R r , -0(Ci-4-alkyl) optionally substituted by 1 to 3 groups independently selected from R q , C3-8-cycloalkyl optionally substituted by 1 to 3 groups independently selected from R q ,
  • R d and R e are independently selected from hydrogen and R r , C3-8-cycloalkenyl optionally substituted by 1 to 3 groups independently selected from R q ,
  • Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R q , aryl optionally substituted by 1 to 3 groups independently selected from R q , and heteroaryl optionally substituted by 1 to 3 groups independently selected from R q ;
  • R q in each case is independently selected from halogen, hydroxyl, amino, and Ci-3-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; and wherein R r in each case is independently selected from SO2-C1-3- alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.
  • R 3 is selected from cyclohexyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl and indanyl (2,3-dihydro-lH-indenyl), optionally substituted with 1 to 5 groups selected from halogen, hydroxyl, carbonitrile, -N(R d R e ) in which R d and R e are independently selected from hydrogen and R r , -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, -C(0)N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; wherein R r in each case is independently selected from S0 2 -Ci-3-alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl
  • R 3 is selected from cyclohexyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl and indanyl (2,3-dihydro-lH-indenyl), optionally substituted with 1 to 5 groups selected from halogen, hydroxyl, carbonitrile, -N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, C 2 -4-acylamino, -C(0)N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.
  • R 3 is C3-8-cycloalkyl, optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R d R e ) in which R d and R e are independently selected from hydrogen and R r , -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, -C(0)N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; wherein R r in each case is independently selected from S0 2 -Ci-3-alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.
  • R 3 is cyclohexyl optionally substituted by 1 to 4 groups independently selected from hydroxyl, Ci-3-alkyl optionally substituted by hydroxyl or by 1 to 3 halogen, F, CI, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, CONH 2 , and -NHS0 2 CH 3.
  • R 3 is C3-8-cycloalkyl, optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, C 2 -4-acylamino, -C(0)N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.
  • R 3 is cyclohexyl optionally substituted by 1 to 4 groups independently selected from hydroxyl, Ci-3-alkyl optionally substituted by hydroxyl, F, CI, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, and CONH 2.
  • R 3 is cyclohexyl substituted with hydroxyl.
  • R 3 is cyclohexyl substituted with hydroxymethyl.
  • R 3 is cyclohexyl optionally substituted by 1 to 4 groups independently selected from hydroxyl, Ci-3-alkyl optionally substituted by hydroxyl, F, CI, carbonitrile, -N(R d R e ) in which R d and R e are independently selected from hydrogen and R r , -0(Ci -4 -alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, and -C(0)N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-3-alkyl; wherein R r in each case is independently selected from S0 2 -Ci-3-alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.
  • R 3 is cyclohexyl substituted with -NHSO2CH 3 .
  • R 3 is cyclohexyl substituted by hydroxyl and further optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, C 2 -4- acylamino, -C(0)N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.
  • R 3 is cyclohexyl substituted with hydroxyl and with fluorine.
  • R 3 is cyclohexyl substituted by hydroxyl and further optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R d R e ) in which R d and R e are independently selected from hydrogen and R r , -0(Ci -4 -alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, -C(0)N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; wherein R r in each case is independently selected from S0 2 -Ci-3-alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.
  • R 3 is cyclohexyl substituted by
  • R 3 is bicyclo[3.1.0]hexanyl optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R d R e ) in which R d and R e are independently selected from hydrogen and R r , -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, -C(0)N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; wherein R r in each case is independently selected from S0 2 -Ci-3-alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.
  • R 3 is bicyclo[3.1.0]hexan-3-yl optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R d R e ) in which R d and R e are independently selected from hydrogen and R r , -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, -C(0)N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; wherein R r in each case is independently selected from S0 2 -Ci-3-alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.
  • R 3 is (2- hydroxy)bicyclo
  • R 3 is bicyclo[3.1.0]hexanyl substituted by hydroxyl and further optionally substituted by a group selected from halogen, hydroxyl, carbonitrile, -N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, C 2 -4-acylamino, -C(0)N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.
  • R 3 is (2- hydroxy)bicyclo[3.1.0]hexan-3-yl substituted by a group selected from halogen, hydroxyl, carbonitrile, -N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, C 2 -4- acylamino, -C(0)N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.
  • R 3 is heterocycloalkyl, optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R d R e ) in which R d and R e are independently selected from hydrogen and R r , -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, -C(0)N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; wherein R r in each case is independently selected from S0 2 -Ci-3-alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.
  • R 3 is heterocycloalkyl, optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, C 2 -4-acylamino, -C(0)N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.
  • R 3 is tetrahydropyranyl (e.g. tetrahydropyran-3-yl or tetrahydropyran- 4-yl) optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R d R e ) in which R d and R e are independently selected from hydrogen and R r , -0(Ci -4 -alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, -C(0)N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; wherein R r in each case is independently selected from S0 2 -Ci-3-alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by 1 to 3
  • R 3 is 4-hydroxytetrahydropyran-3- yi.
  • R 3 is tetrahydropyrany 1 (e.g. tetrahydropyran-3-yl or tetrahydropyran-
  • R 3 is indanyl (2,3-dihydro-lH-indenyl) optionally substituted by 1 to 4 groups independently selected from hydroxyl, Ci-3-alkyl optionally substituted by hydroxyl, F, CI, carbonitrile, -N(R d R e ) in which R d and R e are independently selected from hydrogen and R r , -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, and -C(0)N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-3-alkyl; wherein R r in each case is independently selected from S0 2 -Ci-3-alkyl, CO-C 1 -3- alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.
  • R 3 is indanyl (2,3-dihydro-lH-indenyl) optionally substituted by 1 to 4 groups independently selected from hydroxyl, Ci-3-alkyl optionally substituted by hydroxyl, F, CI, carbonitrile, -N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, C 2 -4- acylamino, and -C(0)N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-3-alkyl.
  • R 3 is indanyl substituted with hydroxyl.
  • R 3 is indanyl substituted with hydroxymethyl.
  • R 3 is 2-hydroxyindan-l-yl.
  • R 3 is indanyl substituted by hydroxyl and further optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R d R e ) in which R d and R e are independently selected from hydrogen and R r , -0(Ci -4 -alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, -C(0)N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; wherein R r in each case is independently selected from S0 2 -Ci.3-alkyl, CO-Ci -3 -alkyl, C(0)0-Ci -3 -alkyl, and Ci -4 -alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.
  • R 3 is indanyl substituted by hydroxyl and further optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, C 2 -4- acylamino, -C(0)N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.
  • R 3 is heteroaryl, optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R d R e ) in which R d and R e are independently selected from hydrogen and R r , -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, -C(0)N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; wherein R r in each case is independently selected from S0 2 -Ci-3-alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.
  • R 3 is pyridinyl (e.g. pyridine-3-yl) optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R d R e ) in which R d and R e are independently selected from hydrogen and R r , -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, -C(0)N(R d R e ) in which R d and R e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; wherein R r in each case is independently selected from SO 2 - Ci-3-alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.
  • R 3 is pyridinyl (e.g
  • A is a 6-membered monocyclic heteroaryl; n is 1, 2 or 3; R 1 is selected from halogen, -C(0)N(R 8 R 9 ) wherein R 8 and R 9 are independently selected from H and Ci-4-alkyl, sulfonyl, Ci-4-alkyl, C2-4-alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein each said sulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R a R b ) in which R a and R b are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, and
  • A is a 6-membered monocyclic heteroaryl; n is 1, 2 or 3; R 1 is selected from halogen, -C(0)N(R 8 R 9 ) wherein R 8 and R 9 are independently selected from H and Ci-4-alkyl, sulfonyl, Ci-4-alkyl, C2-4-alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein each said sulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R a R b ) in which R a and R b are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, and
  • the compound is characterized by formula (VII),
  • the compound is characterized by formula (II),
  • Q ⁇ Q 2 , Q M & Q 4 are independently selected from N, CH and C(R X ), wherein no fewer than one and no more than two of said Q 1 , Q 2 , Q 3 and Q 4 may denote N;
  • n, m, X 1 , L, and R 1 to R 5 are as defined herein.
  • Q 1 is N and Q 2 , Q 3 and Q 4 are CH or C(R X ). In other embodiments, Q 2 is N, and Q 1 , Q 3 and Q 4 are CH or C(R X ). In other embodiments, Q 1 and Q 3 are both N and Q 2 and Q 4 are both CH or CiR 1 ). In preferred embodiments, Q 1 and Q 4 are both N and Q 2 and Q 3 are both CH or CiR 1 ).
  • the compound is characterized by formula (VIII),
  • the compound is characterized by formula (III),
  • X 2 is selected from N and CH;
  • R 10 to R 12 are each independently selected from H and a group R 1 as defined herein; and m, X 1 , L, and R 2 to R 5 are as defined herein.
  • R 10 is selected from H, halogen, carbonitrile, -C(0)N(R 1 R 14 ), -N(R 1 R 14 ), C 2 - 4 -acyl, C2-4-acylamino, -0(Ci-8-alkyl), -C(0)OR 13 , sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl,
  • R 13 and R 14 are independently selected from H, Ci-4-alkyl, cycloalkyl, and heterocycloalkyl, and
  • each said acyl, acylamino, sulfonyl, aminosulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted;
  • R 11 and R 12 are independently selected from H, halogen, carbonitrile, -N(R 15 R 16 ), -C(0)N(R 15 R 16 ), Ci -4 -alkyl, C 2 - 4 -alkynyl, C 2 - 4 -acyl, C 2 -4-acylamino, hydroxy 1, -0(Ci-4-alkyl), -C(0)OR 15 , sulfonyl, and aminosulfonyl,
  • R 15 and R 16 are independently selected from H, Ci-4-alkyl, cycloalkyl, and heterocycloalkyl, and
  • alkyl, alkynyl, acyl, acylamino, sulfonyl or aminosulfonyl is optionally substituted.
  • R 10 is selected from H, halogen, carbonitrile, -C(0)N(R 1 R 14 ), -N(R 1 R 14 ), C2-4-acyl, C2-4-acylamino, -0(Ci-8-alkyl), -C(0)OR 13 , sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl,
  • R 13 and R 14 are independently selected from H, Ci-4-alkyl, cycloalkyl, and heterocycloalkyl, and
  • each said acyl, acylamino, sulfonyl, aminosulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from: halogen,
  • R a and R b are independently selected from hydrogen and R p , -0(Ci-3-alkyl) optionally substituted by 1 to 3 groups independently selected from R m , carbonitrile,
  • S0 2 -Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R m .
  • C3-8-cycloalkyl optionally substituted by 1 to 3 groups independently selected from R m .
  • Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R m ,
  • R n and R° are independently selected from hydrogen and R p or in which R n and R° taken together with the intervening nitrogen atom form a 3- to 8- membered heterocycloalkyl group;
  • R m in each case is independently selected from halogen, hydroxyl, amino, and Ci-3-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; and wherein R p in each case is independently selected from S0 2 -Ci-4-alkyl, CO-Ci-4-alkyl, C(0)0-Ci-4-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; and
  • R 11 and R 12 are independently selected from H, halogen, carbonitrile, -N(R 15 R 16 ), -C(0)N(R 15 R 16 ), Ci -4 -alkyl, C 2 - 4 -alkynyl, C 2 - 4 -acyl, C 2 -4-acylamino, hydroxyl, -0(Ci-4-alkyl), -C(0)OR 15 , sulfonyl, and aminosulfonyl,
  • R 15 and R 16 are independently selected from H and Ci-3-alkyl, and wherein said alkyl, alkynyl, acyl, acylamino, sulfonyl or aminosulfonyl is optionally substituted by 1 to 3 groups independently selected from halogen and Ci-3-alkyl.
  • R 10 is selected from H, halogen, carbonitrile, C(0)N(R 1 R 14 ), -N(R 1 R 14 ), C 2 - 4 -acyl, C 2 -4-acylamino, -0(Ci -8 -alkyl), -C(0)OR 13 , sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl,
  • R 13 and R 14 are independently selected from H, Ci-4-alkyl, cycloalkyl, and heterocycloalkyl, and
  • each said acyl, acylamino, sulfonyl, aminosulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R f R ) in which R f and R are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, and (Ci-4-alkyl)-R h in which R h is selected from hydroxyl and amino and halogen; and
  • R 11 and R 12 are independently selected from H, halogen, carbonitrile, -N(R 15 R 16 ), -C(0)N(R 15 R 16 ), Ci -4 -alkyl, C 2 - 4 -alkynyl, C 2 - 4 -acyl, C 2 -4-acylamino, hydroxyl, -0(Ci-4-alkyl), -C(0)OR 15 , sulfonyl, and aminosulfonyl,
  • R 15 and R 16 are independently selected from H and Ci-3-alkyl, and wherein said alkyl, alkynyl, acyl, acylamino, sulfonyl or aminosulfonyl is optionally substituted by 1 to 3 groups independently selected from halogen and Ci-3-alkyl.
  • X 2 is N. In other embodiments, X 2 is CH.
  • R 10 is selected from a group R 1 as defined herein.
  • R 10 is selected from halogen, -C(0)N(R 1 R 14 ), sulfonyl, Ci -4 -alkyl, C 2 -4-alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R 13 and R 14 are independently selected from H, Ci-4-alkyl, cycloalkyl, and heterocycloalkyl, and wherein each said sulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from: halogen,
  • R a and R b are independently selected from hydrogen and R p , -0(Ci-3-alkyl) optionally substituted by 1 to 3 groups independently selected from R m , carbonitrile,
  • S0 2 -Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R m .
  • C3-8-cycloalkyl optionally substituted by 1 to 3 groups independently selected from R m .
  • Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R m ,
  • R n and R° are independently selected from hydrogen and R p or in which R n and R° taken together with the intervening nitrogen atom form a 3- to 8- membered heterocycloalkyl group; wherein R m in each case is independently selected from halogen, hydroxyl, amino, and Ci-3-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; and wherein R p in each case is independently selected from S0 2 -Ci-4-alkyl, CO-Ci-4-alkyl, C(0)0-Ci-4-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.
  • R 10 is selected from halogen, -C(0)N(R 1 R 14 ), sulfonyl, Ci -4 -alkyl, C 2 -4-alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R 13 and R 14 are independently selected from H, Ci-4-alkyl, cycloalkyl, and heterocycloalkyl, and wherein each said sulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R f R ) in which R f and R are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, and (Ci-4-alkyl
  • R 10 is selected from halogen, phenyl, pyridinyl, pyranyl, pyrazolyl, cyclohexenyl, dihydrofuranyl, cyclopropanyl, cyclohexyl, tetrahydropyranyl, isoxazolyl, aminocarbonyl, carbonitrile, triazolyl, methanesulfonyl, ethynyl, and methyl; wherein each may be optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, carbonitrile, Ci-4-alkyl optionally substituted by hydroxyl or by 1 to 3 halogens, C3- 8-cycloalkyl optionally substituted by hydroxyl or by 1 to 3 halogens, NH 2 , SO2CH 3 , CH2NHSO2CH 3 , CH2NHCOCH 3 , CH2NHC(0)0- l Bu, pyrrolidinylmethyl, morpholin-4-
  • R 10 is ethynyl optionally substituted by 1 or 2 groups selected from halogen, Ci-3-alkyl optionally substituted by hydroxyl or by 1 to 3 halogens, cyclopropanyl, tetrahydropyranyl, CH 2 NHC(0)0- l Bu, and pyrrolidinylmethyl.
  • R 10 is ethynyl substituted by methyl.
  • R 10 is selected from halogen, phenyl, pyridinyl, pyranyl, pyrazolyl, cyclohexenyl, dihydrofuranyl, cyclopropanyl, cyclohexyl, tetrahydropyranyl, isoxazolyl, aminocarbonyl, carbonitrile, triazolyl, methanesulfonyl and methyl; wherein each may be optionally substituted by 1 to 5 groups independently selected from hydroxyl, Ci-4-alkyl, NH 2 or halogen.
  • R 10 is fluorophenyl.
  • R 10 is pyridinyl.
  • R 10 is phenyl.
  • R 10 is bromine.
  • R 10 is chlorine.
  • R 10 is -C(0)NH 2 .
  • R 10 is selected from phenyl and pyridinyl, each optionally substituted by 1 to 3 groups selected independently from halogen, hydroxyl, amino, carbonitrile, Ci-3-alkyl optionally substituted by 1 to 3 groups independently selected from halogen, -0(Ci-3-alkyl) optionally substituted by 1 to 3 groups independently selected from halogen, S0 2 CH 3 , CH 2 NHC(0)CH 3 , and CH 2 NHS0 2 CH 3 .
  • R 10 is phenyl optionally substituted by 1 or 2 groups selected from fluorine, methyl, methoxyl and CH 2 NHSO 2 CH 3 .
  • R 10 is pyridinyl optionally substituted by 1 or 2 groups selected from fluorine, methyl, methoxyl and CH 2 NHSO 2 CH 3 .
  • R 10 is pyridinyl substituted by methoxyl.
  • R is selected from phenyl, pyridinyl, and methyl, each optionally substituted by 1 to 3 groups selected independently from halogen, Ci-3-alkyl and -0(Ci-3-alkyl).
  • R 10 is phenyl optionally substituted by 1 to 3 halogen.
  • R 10 is pyridine optionally substituted with 1 to 3 halogen.
  • R 10 is methyl optionally substituted by 1 to 3 halogen. In another embodiment, R 10 is carbonitrile. In another embodiment, R 10 is CI. In another embodiment, R 10 is 2,3-dihydro-6H-pyranyl. In another embodiment, R 10 is 2,3-dihydrofuranyl.
  • R 10 is hydrogen
  • R 11 is selected from H, halogen, carbonitrile, -C(0)N(R 15 R 16 ), C 1-3 -alkyl, hydroxyl, and -0(Ci-3-alkyl), wherein R 15 and R 16 are independently selected from H and Ci-3-alkyl, and wherein each said alkyl is optionally substituted by 1 to 3 groups independently selected from halogen.
  • R 11 is selected from H, halogen, carbonitrile, Ci-3-alkyl, hydroxyl, and -0(Ci-3-alkyl), wherein each said alkyl is optionally substituted by 1 to 3 groups independently selected from halogen.
  • R 11 is -C(0)NH 2 . In preferred embodiments R 11 is hydrogen.
  • R 12 is selected from H, halogen, carbonitrile, Ci-3-alkyl, hydroxyl, and -0(Ci-3-alkyl), wherein said alkyl is optionally substituted by 1 to 3 groups independently selected from halogen.
  • R 12 is hydrogen.
  • both R 11 and R 12 are hydrogen.
  • L is -(CR 6 R 7 ) P -, in which p is 1 and R 6 and R 7 are both hydrogen; and R 3 is selected from heterocycloalkyl or heteroaryl, optionally substituted by 1 to 3 groups independently selected from hydroxyl, Ci-3-alkyl optionally substituted by 1-3 halogen or hydroxyl, F, CI, -0(C M -alkyl) and CONH 2.
  • L is -(CR 6 R 7 ) P -, in which p is 1 and one of R 6 and R 7 is hydrogen and the other is Ci-4-alkyl optionally substituted by hydroxyl; and R 3 is selected from cycloalkyl or heteroaryl, optionally substituted by 1 to 3 groups independently selected from hydroxyl, Ci-3-alkyl optionally substituted by halogen or hydroxyl, F, CI, -0(Ci-4-alkyl) and CONH 2.
  • L denotes a direct bond and R 3 is selected from cycloalkyl or heteroaryl, optionally substituted by 1 to 4 groups independently selected from hydroxyl, Ci_ 3-alkyl optionally substituted by halogen or hydroxyl, F, CI, -0(Ci-4-alkyl) and CONH 2 .
  • L denotes a direct bond
  • R 3 is cyclohexyl optionally substituted by 1 to 4 groups independently selected from hydroxyl, Ci-3-alkyl optionally substituted by hydroxyl, F, -0(Ci-4-alkyl) and CONH 2 .
  • L denotes a direct bond
  • R 3 is cyclohexyl substituted by hydroxyl and further optionally substituted by 1 to 3 groups independently selected from Ci-3-alkyl optionally substituted by hydroxyl, F, -0(Ci-4-alkyl) and CONH 2 .
  • L denotes a direct bond
  • R 3 is (2- hydroxy)cyclohexanyl.
  • L denotes a direct bond
  • R 3 is 2- methyl(2-hydroxy)cyclohexanyl.
  • L denotes a direct bond
  • R 3 is indanyl, optionally substituted by 1 to 4 groups independently selected from hydroxyl, Ci-3-alkyl optionally substituted by halogen or hydroxyl, F, CI, -0(Ci-4-alkyl) and CONH 2 .
  • L denotes a direct bond
  • R 3 is indanyl substituted by hydroxyl and further optionally substituted by 1 to 3 groups independently selected from Ci-3-alkyl optionally substituted by hydroxyl, F, -0(Ci-4-alkyl) and CONH 2 .
  • L denotes a direct bond
  • R 3 is (1 -hydroxy )indanyl or (2-hydroxy)indanyl.
  • L denotes a direct bond
  • R 3 is tetrahydropyranyl optionally substituted by 1 to 4 groups independently selected from hydroxyl, Ci-3-alkyl optionally substituted by halogen or hydroxyl, F, CI, -0(Ci-4-alkyl) and CONH 2 .
  • L denotes a direct bond
  • R 3 is tetrahydropyranyl substituted by hydroxyl and further optionally substituted by 1 to 3 groups independently selected from Ci-3-alkyl optionally substituted by hydroxyl, F, -0(Ci-4-alkyl) and CONH 2 .
  • L denotes a direct bond
  • R 3 is (3-hydroxy)tetrahydropyran-4-yl or (4- hydroxy)tetrahydropyran-3-yl.
  • the compound is characterized by formula (IX),
  • the compound is characterized by formula (IV),
  • q 0, 1, 2 or 3;
  • R 17 is independently selected from a group R 1 as defined herein;
  • X 1 , X 2 , R 2 , R 4 , R 5 , R 10 and R 11 are as defined herein.
  • R 17 is independently selected from halogen, hydroxyl, carbonitrile, -I ⁇ R'R 1 ) in which R 1 and R J are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, C3-8-cycloalkyl, C2-4-acylamino, -C(0)N(R 1 R J ) in which R 1 and R J are independently selected from hydrogen and Ci-3-alkyl, C3-8-cycloalkenyl, Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen, aryl and heteroaryl.
  • R 11 is hydrogen.
  • q is 0, 1 or 2. In other embodiments, q is 0. In other embodiments, q is 1. In other embodiments, q is 2. In other embodiments, q is 0 or 1.
  • R 17 is independently selected from:
  • R 1 and R J are independently selected from hydrogen and R l ,
  • Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R s , C 2 -6-alkenyl optionally substituted by 1 to 3 groups independently selected from R s , and
  • C 2 -6-alkynyl optionally substituted by 1 to 3 groups independently selected from R s , wherein R s in each case is independently selected from halogen, hydroxyl, amino, and Ci-3-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; and wherein R l in each case is independently selected from S0 2 -Ci-3-alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.
  • R 17 is independently selected from:
  • R 1 and R J are independently selected from hydrogen and R l , -0(Ci-3-alkyl) optionally substituted by 1 to 3 groups independently selected from R s , and
  • Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R s , wherein R s in each case is independently selected from halogen, hydroxyl, and
  • Ci-3-alkyl optionally substituted by 1 to 3 halogen; and wherein R l in each case is independently selected from S0 2 -Ci-3-alkyl and Ci-3-alkyl optionally substituted by 1 to 3 halogen.
  • R 17 is independently selected from halogen, hydroxyl, carbonitrile, -I ⁇ R'R 1 ) in which R 1 and R J are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, C 2 -4- acylamino, -C(0)N(R 1 R J ) in which R 1 and R J are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.
  • q is 0, or q is 1 and R 17 is selected from:
  • R 1 and R J are independently selected from hydrogen and R l , -0(Ci-3-alkyl) optionally substituted by 1 to 3 halogen, and
  • Ci-4-alkyl optionally substituted by 1 to 3 halogen
  • R l in each case is independently selected from SO2CH 3 and Ci-3-alkyl optionally substituted by 1 to 3 halogen.
  • q is 1 and R 17 is independently selected from halogen, hydroxyl, carbonitrile, -I ⁇ R'R 1 ) in which R 1 and R J are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, C 2 -4- acylamino, -C(0)N(R 1 R J ) in which R 1 and R J are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.
  • the compound is characterized by formula (X),
  • the compound is characterized by formula (IV a ),
  • R 10 is selected from halogen, C2-4-alkynyl, aryl, and heteroaryl, wherein each said alkynyl, aryl or heteroaryl is optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, -NH 2 , -0(Ci-3-alkyl) optionally substituted by 1-3 halogen, carbonitrile, C3-8-cycloalkyl and Ci-4-alkyl optionally substituted by 1-3 halogen; R 11 is hydrogen; X 2 is N or CH; R 4 and R 5 are independently selected from H; m is 0 or 1 ; R 2 is selected from halogen, Ci-4-alkyl optionally substituted by 1-3 halogen, and -0(Ci-4-alkyl) optionally substituted by 1-3 halogen; and X 1 is S. In a preferred embodiment, q is 0.
  • R 10 is selected from halogen, -C(0)NH 2 , sulfonyl, Ci-4-alkyl, C2-4- alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each said sulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, -NH 2 , -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl and Ci-4-alkyl; R 11 is hydrogen; X 2 is N or CH; R 4 and R 5 are independently selected from H and Ci-3-alkyl; m is 0 or 1 ; R 2 is selected from halogen, hydroxyl, carbonitrile, Ci-4-alkyl, and -0(Ci-4-alkyl); and X 1 is S
  • R is selected from halogen, -C(0)NH 2 , sulfonyl, Ci-4-alkyl, C2-4- alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each said sulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, -NH 2 , -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl and Ci-4-alkyl; R 11 is hydrogen; X 2 is N or CH, one of R 4 and R 5 is hydrogen and the other is Ci-3-alkyl; m is 0 or 1; R 2 is selected from halogen, hydroxyl, carbonitrile, Ci_ 4-alkyl, and -0(Ci-4-
  • R 10 is selected from halogen, -C(0)NH 2 , sulfonyl, Ci-4-alkyl, C 2-8 - alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each said sulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, -NH 2 , -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl and Ci-4-alkyl; R 11 is hydrogen; X 2 is N or CH; R 4 and R 5 are both hydrogen; m is 0 or 1 ; R 2 is selected from halogen, hydroxyl, carbonitrile, Ci-4-alkyl, and -0(Ci-4-alkyl); and X 1 is S, O or NH.
  • the compound is characterized by formula (X a ),
  • the compound is characterized by formula (IV b ),
  • Compounds characterized by formula (IV b ) display inter alia a good selectivity for CSF-IR over other kinases, such as c-KIT, PDGFRa, PDGFR and/or FLT-3.
  • R 10 is selected from halogen, C 2 -4-alkynyl, aryl, and heteroaryl, wherein each said alkynyl, aryl or heteroaryl is optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, -NH 2 , -0(Ci-3-alkyl) optionally substituted by 1-3 halogen, carbonitrile, C3-8-cycloalkyl, CH 2 NHS0 2 -Ci-3-alkyl, S0 2 -Ci-3-alkyl, Ci-4-alkyl optionally substituted by 1-3 halogen, 3- to 8-membered heterocycloalkyl optionally substituted by 1-3 halogen, and heteroaryl optionally substituted by 1 to 3 groups independently selected from halogen and methyl;
  • R 11 is hydrogen;
  • X 2 is N or CH;
  • R 4 and R 5 are independently selected from H;
  • m is 0 or 1;
  • R 2 is selected from halogen, Ci
  • R 10 is selected from halogen, -C(0)NH 2 , sulfonyl, Ci-4-alkyl, C 2 -4-alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each said sulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, -NH 2 , -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl and Ci-4-alkyl; R 11 is hydrogen; X 2 is N or CH; R 4 and R 5 are independently selected from H and Ci-3-alkyl; m is 0 or 1 ; R 2 is selected from halogen, hydroxyl, carbonitrile, Ci-4-alkyl, and -0(Ci-4-alkyl); and X 1 is
  • R is selected from halogen, -C(0)NH 2 , sulfonyl, Ci-4-alkyl, C2-4- alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each said sulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, -NH 2 , -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl and Ci-4-alkyl; R 11 is hydrogen; X 2 is N or CH, one of R 4 and R 5 is hydrogen and the other is Ci-3-alkyl; m is 0 or 1; R 2 is selected from halogen, hydroxyl, carbonitrile, Ci_ 4-alkyl, and -0(Ci-4-
  • R 10 is selected from halogen, -C(0)NH 2 , sulfonyl, Ci-4-alkyl, C2-4- alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each said sulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, -NH 2 , -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl and Ci-4-alkyl; R 11 is hydrogen; X 2 is N or CH; R 4 and R 5 are both hydrogen; m is 0 or 1 ; R 2 is selected from halogen, hydroxyl, carbonitrile, Ci-4-alkyl, and -0(Ci-4-alkyl); and X 1 is S, O or NH.
  • the compound is characterized by formula (X b ),
  • the compound is characterized by formula (V),
  • r 0, 1, 2 or 3;
  • R 18 is independently selected from a group R 1 as defined herein;
  • R 11 is hydrogen.
  • R 18 is independently selected from halogen, hydroxyl, carbonitrile, -N(R k R') in which R k and R 1 are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, C3-8-cycloalkyl, C2-4- acylamino, -C(0)N(R k R') in which R k and R 1 are independently selected from hydrogen and Ci-3-alkyl, C3-8-cycloalkenyl, Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen, aryl and heteroaryl.
  • r is 0, 1 or 2. In other embodiments, r is 0. In other embodiments, r is 1. In other embodiments, r is 2. In other embodiments, r is 0 or 1.
  • R 18 is independently selected from:
  • R 1 and R J are independently selected from hydrogen and R l , -0(Ci-4-alkyl) optionally substituted by 1 to 3 groups independently selected from R s , -C(0)N(R 1 R J ) in which R 1 and R J are independently selected from hydrogen and R l , Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R s , C 2 -6-alkenyl optionally substituted by 1 to 3 groups independently selected from R s , and
  • C 2 -6-alkynyl optionally substituted by 1 to 3 groups independently selected from R s , wherein R s in each case is independently selected from halogen, hydroxyl, amino, and Ci-3-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; and wherein R l in each case is independently selected from S0 2 -Ci-3-alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.
  • R 18 is independently selected from:
  • R 1 and R J are independently selected from hydrogen and R l , -0(Ci-3-alkyl) optionally substituted by 1 to 3 groups independently selected from R s , and
  • Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R s , wherein R s in each case is independently selected from halogen, hydroxyl, and Ci-3-alkyl optionally substituted by 1 to 3 halogen; and wherein R l in each case is independently selected from S0 2 -Ci-3-alkyl and Ci-3-alkyl optionally substituted by 1 to 3 halogen.
  • R 18 is independently selected from halogen, hydroxyl, carbonitrile, -N(R k R') in which R k and R 1 are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, C2-4-acylamino, -C(0)N(R k R') in which R k and R 1 are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.
  • each R 18 is attached to a saturated carbon atom within the indane moiety. In other embodiments each R 18 is attached to an unsaturated carbon atom within the indane moiety. In other embodiments at least one R 18 is attached to a saturated carbon atom within the indane moiety and at least one R 18 is attached to an unsaturated carbon atom within the indane moiety.
  • the compound is characterized by formula (XI),
  • the compound is characterized by formula (V a ),
  • the compound is characterized by formula (XI a ),
  • the compound is characterized by formula (V b ),
  • the compound is characterized by formula (X3 ⁇ 4),
  • R 10 is selected from halogen, -C(0)NH 2 , sulfonyl, Ci-4-alkyl, C2-4-alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each said sulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 3 groups independently selected from halogen, hydroxy 1, -NH 2 , -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl and Ci-4-alkyl; R 11 is hydrogen; X 2 is N or CH; R 4 and R 5 are independently selected from H and Ci-3-alkyl; m is 0 or 1 ; R 2 is selected from halogen, hydroxyl, carbonitrile, Ci-4-alkyl, and -0(Ci-4-alkyl); and X 1 is S, O
  • R 10 is selected from halogen, -C(0)NH 2 , sulfonyl, Ci-4-alkyl, C2-4- alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each said sulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, -NH 2 , -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl and Ci-4-alkyl; R 11 is hydrogen; X 2 is N or CH, one of R 4 and R 5 is hydrogen and the other is Ci-3-alkyl; m is 0 or 1; R 2 is selected from halogen, hydroxyl, carbonitrile, Ci_ 4-alkyl, and -0(Ci-4-alkyl); and X 1 is
  • R 10 is selected from halogen, -C(0)NH 2 , sulfonyl, Ci-4-alkyl, C2-4- alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each said sulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, -NH 2 , -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl and Ci-4-alkyl; R 11 is hydrogen; X 2 is N or CH; R 4 and R 5 are both hydrogen; m is 0 or 1 ; R 2 is selected from halogen, hydroxyl, carbonitrile, Ci-4-alkyl, and -0(Ci-4-alkyl); and X 1 is S, O or NH.
  • the compound is characterized by formula (VI),
  • R 19 is selected from hydrogen and a group R 2 as defined herein;
  • R 11 and R 12 are as defined herein.
  • R 11 and R 12 are both hydrogen.
  • R 19 is selected from hydrogen, halogen, hydroxyl, carbonitrile, Ci-4-alkyl, and -0(Ci-4-alkyl), wherein each said alkyl is optionally substituted.
  • R is selected from hydrogen, halogen, hydroxyl, carbonitrile, Ci-4-alkyl, and -0(Ci-4-alkyl), wherein each said alkyl is optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl and carbonitrile.
  • R 19 is selected from halogen, Ci-4-alkyl, and -0(Ci-4-alkyl), wherein each said alkyl is optionally substituted by 1 to 3 groups independently selected from halogen and hydroxyl. In other embodiments, R 19 is hydrogen.
  • R 19 is -0(Ci-3-alkyl) optionally substituted by 1 to 3 groups independently selected from halogen.
  • R 19 is methoxyl.
  • R 19 is ethoxyl.
  • R is halogen (e.g. fluorine).
  • R is methyl.
  • the compound is characterized by formula (XII),
  • the compound is characterized by formula (XIII),
  • R , R and R are independently selected from hydrogen and a group R as defined herein;
  • R , R and R are independently selected from hydrogen, halogen, hydroxyl, carbonitrile, Ci-4-alkyl, and -0(Ci-4-alkyl), wherein each said alkyl is optionally substituted.
  • R , R and R are all independently selected from hydrogen.
  • two of R , R and R are independently selected from hydrogen, and the other is selected from halogen, hydroxyl, Ci-3-alkyl, and -0(Ci-3-alkyl), wherein each said alkyl is optionally substituted by 1-3 halogen.
  • two of R , R and R are independently selected from hydrogen, and the other is selected from chlorine, fluorine, methyl optionally substituted by 1-3 fluorine, and methoxyl optionally substituted by 1-3 fluorine.
  • L is -CH 2 - or a direct bond
  • R 3 is cyclohexyl substituted by hydroxyl and further optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, carbonitrile, -0(Ci-4-alkyl) optionally substituted by 1-3 halogen, and Ci-4-alkyl optionally substituted by 1-3 halogen
  • R 4 and R 5 are independently selected from hydrogen
  • R 19 is selected from hydrogen, halogen, hydroxyl, carbonitrile, Ci-3-alkyl, and -0(Ci-3-alkyl), wherein each said alkyl is optionally substituted by 1-3 halogen
  • R 20 and R 21 are both hydrogen.
  • L is -CH 2 - or a direct bond
  • R 3 is cyclohexyl substituted by hydroxyl and further optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, carbonitrile, -0(Ci-4-alkyl) optionally substituted by 1-3 halogen, and Ci-4-alkyl optionally substituted by 1-3 halogen
  • R 4 and R 5 are independently selected from hydrogen
  • R 21 is selected from hydrogen, halogen, hydroxyl, carbonitrile, Ci-3-alkyl, and -0(Ci-3-alkyl), wherein each said alkyl is optionally substituted by 1-3 halogen
  • R 19 and R 20 are both hydrogen.
  • the compound is characterized by formula (XIV),
  • the compound is characterized by formula (XIV a ) or formula (XlV b ),
  • q is 0.
  • the compound is a compound of formula (XIV a ) in which R 19 and R 20 are both hydrogen; and in which R 21 is halogen (e.g. fluorine).
  • the compound is a compound of formula (XlV b ) in which R 19 is selected from fluorine, chlorine, methyl and methoxyl; and in which R 20 and R 21 are both hydrogen.
  • the compound is a compound of formula (XlV b ) in which R 19 and R 20 are both hydrogen; and in which R 21 is halogen (e.g. fluorine).
  • the compound is characterized by formula (XV),
  • the compound is characterized by formula (XV a ) or formula (XV b ),
  • q is 0.
  • the compound is a compound of formula (XV a ) in which R 19 is selected from fluorine and methoxyl; and in which R 20 and R 21 are both hydrogen.
  • the compound is a compound of formula (XV a ) in which R 19 and R 20 are both hydrogen; and in which R 21 is halogen (e.g. fluorine).
  • the compound is selected from the group consisting of Compounds 1 to 180:
  • Compound 162 4-methoxy-6-(((6-phenylpyrazin-2-yl)amino)methyl)-N-((6- (trifluoromethyl)pyridin-3-yl)methyl)benzo[d]thiazol-2-amine
  • the compound is selected from the group consisting of Compounds 1 to 81 or a pharmaceutically acceptable salt or prodrug thereof.
  • the compound is selected from the group consisting of: Compounds 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 28, 30, 31, 32, 33, 34, 35, 36, 38, 39, 40, 43, 45, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 61, 62, 63, 64, 65, 67, 68, 69, 70, 73, 74, 75, 76, 80 and 81; or a pharmaceutically acceptable salt or prodrug thereof.
  • the compound is selected from the group consisting of: Compounds 1, 2, 3, 5, 7, 8, 9, 10, 11, 14, 15, 16, 17, 19, 20, 21, 22, 26, 30, 33, 34, 35, 36, 38, 45, 47, 48, 49, 50, 51, 52, 53, 54, 56, 57, 61, 62, 63, 64, 65, 67, 68, 70, 76, 80 and 81; or a pharmaceutically acceptable salt or prodrug thereof.
  • the compound is selected from the group consisting of: Compounds 3, 7, 8, 9, 10, 11, 14, 19, 21, 30, 35, 36, 38, 48, 49, 50, 51, 52, 53, 54, 61, 62, 63, 64, 67, 80 and 81; or a pharmaceutically acceptable salt or prodrug thereof.
  • the compound is selected from the group consisting of: Compounds 3, 10, 11, 35, 48, 49, 50, 52, 54, 62, 63, 64, 67, 81, 82, 83, 84, 85, 86, 88, 90, 91, 93, 94, 95, 96, 97, 98, 99, 101, 102, 103, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 118, 120, 121, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 145, 146, 147, 148, 151, 153, 158, 160, 161, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 174, 175, 177, 178 and
  • the compound is selected from the group consisting of: Compounds 1, 3, 11, 14, 15, 21, 30, 35, 38, 49, 50, 51, 64, 67, 70 and 71; or a pharmaceutically acceptable salt or prodrug thereof.
  • the compound is selected from the group consisting of: Compounds 1, 15, 21, 35, 50, 51, 64, 70 and 71; or a pharmaceutically acceptable salt or prodrug thereof.
  • the compound is selected from the group consisting of: Compounds 1, 3, 8, 11, 14, 15, 16, 21, 22, 35, 49, 50, 51, 67 and 71 ; or a pharmaceutically acceptable salt or prodrug thereof.
  • the compound is selected from the group consisting of: Compounds 1, 15, 35, 38, 50, 51 and 70; or a pharmaceutically acceptable salt or prodrug thereof. In another embodiment, the compound is selected from the group consisting of: Compounds 1, 35, 50, 51 and 70; or a pharmaceutically acceptable salt or prodrug thereof.
  • the compound is selected from the group consisting of: Compounds 62, 85, 88, 90, 108, 110, 113, 114, 115, 120, 125, 127, 130, 138, 139, 140, 141, 142, 146, 151, 161, 166, 170 and 179; or a pharmaceutically acceptable salt or prodrug thereof.
  • the compound is selected from the group consisting of: Compounds 1, 15, 21, 35, 49, 50, 51 and 70; or a pharmaceutically acceptable salt or prodrug thereof. In another embodiment, the compound is selected from the group consisting of: Compounds 1, 35, 50 and 51 ; or a pharmaceutically acceptable salt or prodrug thereof. In another embodiment, the compound is selected from the group consisting of: Compounds 35, 50 and 51 ; or a pharmaceutically acceptable salt or prodrug thereof.
  • the compound is selected from the group consisting of: Compounds 1, 15, 21, 35, 49, 50, 51, 70, 88, 103, 106, 107, 111, 113, 114, 117, 119, 127, 133, 134, 146, 147, 148, 160, 165, 171, 173 and 180; or a pharmaceutically acceptable salt or prodrug thereof.
  • the compound is selected from the group consisting of: Compounds 1, 35, 50, 51, 106, 111, 113, 114, 119, 127, 134, 146, 147, 160, 165, 171, 173 and 180; or a pharmaceutically acceptable salt or prodrug thereof.
  • the compounds of the invention are useful as kinase inhibitors.
  • compounds of the invention are useful as inhibitors of CSF-1R.
  • Assays for determining the inhibitory activity of compounds against CSF-1R are known in the art and are also set out in the following Examples. The activity values listed below may, for example, be determined according to an assay as set out in the following Examples.
  • compounds of the invention have an IC5 0 value (e.g.
  • an inhibitory activity against CSF-IR in a cell-free assay of less than 1 ⁇ , less than 750 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 150 nM, less than 100 nM, less than 75 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 25 nM, less than 20 nM, less than 15 nM, less than 10 nM or less than 5 nM.
  • compounds of the invention have an IC5 0 value (e.g. an inhibitory activity against CSF-IR in a cell-based assay), of less than 2 ⁇ , less than 1 ⁇ , less than 750 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 150 nM, less than 100 nM, less than 75 nM, or less than 50 nM.
  • IC5 0 value e.g. an inhibitory activity against CSF-IR in a cell-based assay
  • the compounds of the invention may be selective for CSF-IR over other kinases, e.g. c-KIT, PDGFRa, PDGFR and/or FLT3.
  • the compounds of the invention may selectively inhibit the activity of CSF-IR over other kinases, e.g. c-KIT, PDGFRa, PDGFR and/or FLT3.
  • Assays for determining the selectivity of a compound for CSF-IR over other kinases are known in the art. Examples of assays for determining the selectivity of a compound for CSF-IR over other kinases are also set out in the following Examples. The selectivity values listed below may, for example, be determined according to the assays set out in the following Examples.
  • the compounds of the invention are selective for CSF-IR over another kinase by a value of at least 10 times, at least 11 times, at least 12 times, at least 13 times, at least 14 times, at least 15 times, at least 16 times, at least 17 times, at least 18 times, at least 19 times, at least 20 times, at least 25 times, at least 30 times, at least 35 times, at least 40 times, at least 45 times, at least 50 times, at least 55 times, at least 60 times, at least 65 times, at least 70 times, at least 75 times, at least 80 times, at least 85 times, at least 90 times, at least 95 times, at least 100 times, at least 150 times, at least 200 times, at least 250 times, at least 300 times, at least 350 times, at least 400 times, at least 450 times, at least 500 times, at least 1000 times, or at least 1500 times .
  • a compound having an IC5 0 value of 10 nM against CSF-IR, and having an IC5 0 value of 200 nM against another kinase is selective for CSF-IR over said another kinase by a value of 20 times.
  • the compounds of the invention are selective for CSF-IR over PDGFR by a value of at least 2.5 times, at least 5 times, at least 10 times, at least 15 times, at least 20 times, at least 25 times or at least 30 times.
  • the compounds of the invention are selective for CSF-IR over PDGFRa at a value of at least 5 times, at least 10 times, at least 15 times, at least 20 times, at least 30 times, at least 40 times, at least 50 times, at least 60 times, at least 70 times, at least 80 times, at least 90 times, or at least 100 times.
  • the compounds of the invention are selective for CSF-IR over c-KIT by a value of at least 10 times, at least 20 times, at least 30 times, at least 40 times, at least 50 times, at least 100 times, at least 150 times, at least 200 times, at least 300 times, at least 400 times, at least 500 times, or at least 1000 times more.
  • the compounds of the invention are selective for CSF-IR over FLT3 by a value of at least 100 times, at least 200 times, at least 500 times, at least 1000 times, at least 1500 times, or at least 2000 times.
  • Presently disclosed compounds that are basic in nature are generally capable of forming a wide variety of different salts with various inorganic and/or organic acids.
  • such salts are generally pharmaceutically acceptable for administration to animals and humans, it is often desirable in practice to initially isolate a compound from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent, and subsequently convert the free base to a pharmaceutically acceptable acid addition salt.
  • the acid addition salts of the base compounds can be readily prepared using conventional techniques, e.g. by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as, for example, methanol or ethanol.
  • Acids which can be used to prepare pharmaceutically acceptable salts of compounds are those which can form non-toxic acid addition salts, e.g. salts containing pharmacologically acceptable anions, such as chloride, bromide, iodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, malate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate and pamoate [i.e. 1,1'- methylene-bis-(2-hydroxy-3-naphthoate)] salts.
  • non-toxic acid addition salts e.g. salts containing pharmacologically acceptable anions, such as chloride, bromide, iodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate
  • Presently disclosed compounds that are acidic in nature are generally capable of forming a wide variety of different salts with various inorganic and/or organic bases.
  • such salts are generally pharmaceutically acceptable for administration to animals and humans, it is often desirable in practice to initially isolate a compound from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free acid compound by treatment with an acidic reagent, and subsequently convert the free acid to a pharmaceutically acceptable base addition salt.
  • These base addition salts can be readily prepared using conventional techniques, e.g.
  • Bases which can be used to prepare the pharmaceutically acceptable base addition salts of compounds are those which can form non-toxic base addition salts, e.g. salts containing pharmacologically acceptable cations, such as, alkali metal cations (e.g. potassium and sodium), alkaline earth metal cations (e.g. calcium and magnesium), ammonium or other water-soluble amine addition salts such as N-methylglucamine (meglumine), lower alkanolammonium, and other such bases of organic amines.
  • pharmacologically acceptable cations such as, alkali metal cations (e.g. potassium and sodium), alkaline earth metal cations (e.g. calcium and magnesium), ammonium or other water-soluble amine addition salts such as N-methylglucamine (meglumine), lower alkanolammonium, and other such bases of organic amines.
  • prodrugs for use according to the present disclosure are derivatives of CSF-1R inhibitors, e.g. compounds characterized by formula (I), which can be converted in vivo into the compounds described herein.
  • the prodrugs which may themselves have some activity, become fully pharmaceutically active in vivo when they undergo, for example, solvolysis under physiological conditions or through enzymatic degradation. Methods for preparing prodrugs of compounds as described herein would be apparent to one of skill in the art based on the present disclosure. Stereochemistry
  • Stereoisomers e.g. cis and trans isomers
  • optical isomers of a presently disclosed compound e.g. R- and S- enantiomers
  • racemic, diastereomeric and other mixtures of such isomers are within the scope of the present disclosure.
  • the compounds of the invention may exist predominantly as a single enantiomer (or diastereomer), or as a mixture of isomers (e.g. enantiomers or diastereomers).
  • the compounds of the invention are present as a racemic mixture, e.g. said R- and S- isomers (or all enantiomers or diastereomers) are present in approximately equal amounts.
  • the compounds of the invention are present as a mixture of isomers in which one enantiomer (or diastereomer) is present in an enantiomeric excess of at least about 5%, 10%, 25%, 40%, 70%, 80%, 90%, 95%, 97%, 98% or 99%, e.g. about 100%.
  • Tautomers exist as mixtures of a tautomeric set in solution. In solid form, usually one tautomer predominates. Even though one tautomer may be described, all tautomers are within the scope of the present disclosure.
  • the invention extends to mixtures of one or more of said compounds characterized by the said structural formulae.
  • the invention provides a mixture of compounds characterized by formulae (IV a ) and (IVb), or pharmaceutically acceptable salts or prodrugs of one or more thereof.
  • the invention provides a mixture of compounds characterized by formulae (V a ) and (1 ⁇ 4,), or pharmaceutically acceptable salts or prodrugs of one or more thereof.
  • an "isotopically-labeled compound” refers to a presently disclosed compound including pharmaceutical salts and prodrugs thereof, each as described herein, in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds presently disclosed include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, H, 1 C, 14 C, 15 N, 18 0, 17 0,
  • Deuterated compounds e.g. compounds of the invention which have one or more hydrogen atoms replaced by deuterium, are preferred.
  • compositions comprising at least one compound of the invention, e.g. a compound characterized by formula (I), and at least one pharmaceutically acceptable excipient, e.g. for use according to the methods disclosed herein.
  • the pharmaceutically acceptable excipient can be any such excipient known in the art including those described in, for example, Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985).
  • Pharmaceutical compositions of the compounds presently disclosed may be prepared by conventional means known in the art including, for example, mixing at least one presently disclosed compound with a pharmaceutically acceptable excipient.
  • a pharmaceutical composition or dosage form of the invention can include an agent and another carrier, e.g. compound or composition, inert or active, such as a detectable agent, label, adjuvant, diluent, binder, stabilizer, buffers, salts, lipophilic solvents, preservative, adjuvant or the like.
  • Carriers also include pharmaceutical excipients and additives, for example, proteins, peptides, amino acids, lipids, and carbohydrates (e.g.
  • sugars including monosaccharides, di-, tri-, tetra-, and oligosaccharides; derivatized sugars such as alditols, aldonic acids, esterified sugars and the like; and polysaccharides or sugar polymers), which can be present singly or in combination, comprising alone or in combination 1 to 99.99% by weight or volume.
  • exemplary protein excipients include serum albumin such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, and the like.
  • amino acid/antibody components which can also function in a buffering capacity, include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, and the like.
  • Carbohydrate excipients are also intended within the scope of this invention, examples of which include but are not limited to monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides, such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides, such as raffinose, melezitose, maltodextrins, dextrans, starches, and the like; and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol) and myoinositol.
  • monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like
  • disaccharides such as lactose, sucrose
  • Carriers which may be used include a buffer or a pH adjusting agent; typically, the buffer is a salt prepared from an organic acid or base.
  • Representative buffers include organic acid salts such as salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid; Tris, tromethamine hydrochloride, or phosphate buffers.
  • Additional carriers include polymeric excipients/additives such as polyvinylpyrrolidones, ficolls (a polymeric sugar), dextrates (e.g.
  • cyclodextrins such as 2-hydroxypropyl- - cyclodextrin
  • polyethylene glycols such as 2-hydroxypropyl- - cyclodextrin
  • flavoring agents such as 2-hydroxypropyl- - cyclodextrin
  • antimicrobial agents such as "STYPES”
  • sweeteners such as "STYPES”
  • antioxidants such as "TWEEN 20" and "TWEEN 80”
  • surfactants e.g. polysorbates such as "TWEEN 20" and "TWEEN 80”
  • lipids e.g. phospholipids, fatty acids
  • steroids e.g. cholesterol
  • chelating agents e.g. EDTA
  • compositions, and kits comprising said compositions, which contain at least one compound as described herein, e.g. a compound characterized by formula (I), and at least one further pharmaceutically-active agent.
  • These pharmaceutical compositions and kits may be adapted to allow simultaneous, subsequent and/or separate administration of the compound and the further active agent.
  • the compound and the further active agent may be formulated in separate dosage forms, e.g. in separate tablets, capsules, lyophilisates or liquids, or they may be formulated in the same dosage form, e.g. in the same tablet, capsule, lyophilisate or liquid.
  • the compound and the further active agent are formulated in the same dosage form
  • the compound and the further active agent may be present substantially in admixture, e.g. within the core of a tablet, or they may be present substantially in discrete regions of the dosage form, e.g. in separate layers of the same tablet.
  • a further aspect of the present invention provides a pharmaceutical composition comprising: (i) a compound as described herein, e.g. a compound characterized by formula (I); (ii) a further active agent; and (iii) a pharmaceutically acceptable excipient.
  • a kit comprising (i) a compound as described herein, e.g. a compound characterized by formula (I); (ii) instructions for the use of the compound in therapy, e.g. in a method as described herein; and (iii) optionally a further active agent.
  • the further active agent is an anti-proliferative agent, an anti-inflammatory agent, an anti-angiogenic agent, a chemotherapeutic agent, or an immunotherapeutic agent.
  • the pharmaceutical compositions can be formulated so as to provide slow, extended, or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • the pharmaceutical compositions can also optionally contain opacifying agents and may be of a composition that releases the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner, e.g. by using an enteric coating.
  • Examples of embedding compositions include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more pharmaceutically acceptable carriers, excipients, or diluents well known in the art (see, e.g. , Remington's).
  • the compounds presently disclosed may be formulated for sustained delivery according to methods well known to those of ordinary skill in the art. Examples of such formulations can be found in United States Patents 3,119,742; 3,492,397; 3,538,214; 4,060,598; and 4,173,626.
  • step (i) of Scheme I the compound A (which may be commercially available, or prepared according to general synthetic methodology known to the person of skill in the art) is reduced, e.g. using DIBAL. Nucleophilic aromatic substitution, e.g. using sodium methanethiolate, leads to intermediate B. In step (ii), hydroxyl substitution, e.g. using DPPA and DBU, and subsequent hydrogenation using e.g. a Lindlar catalyst yields intermediate C. In step (iii), cyclic group A (which may be protected if necessary, e.g. if substituted), which carries a leaving group "LG", participates in a nucleophilic substitution or coupling reaction to yield intermediate D.
  • DIBAL nucleophilic aromatic substitution, e.g. using sodium methanethiolate
  • step (ii) hydroxyl substitution, e.g. using DPPA and DBU, and subsequent hydrogenation using e.g. a Lindlar catalyst yields intermediate C.
  • the nucleophilic substitution reaction in step (iii) may, for example, be a nucleophilic aromatic substitution using an appropriate aryl halide in the case where the cyclic group A is aromatic or heteroaromatic and LG is a halogen.
  • oxidation e.g. using mCPBA, and treatment with a selective amine, gives the target compound E.
  • compounds as disclosed herein may be prepared using the following synthetic methodology:
  • step (i) of Scheme II the compound A is reduced to intermediate F.
  • step (ii) hydroxyl substitution, e.g. using DPP A and DBU, yields organic azide intermediate G.
  • step (iii) Subsequent nucleophilic aromatic substitution or coupling with amine H2N-L-R 3 leads to intermediate H in step (iii) that, upon hydrogenation, gives amine I in step (iv).
  • Schemes I and II may be varied to obtain other compounds as disclosed herein.
  • the target compound may be obtained using the substituted cyclic group R X -A-LG in step (iii) of Scheme I or in step (v) of Scheme II.
  • the target compound may be prepared using a cyclic group A-LG which is substituted by a halide or a pseudohalide ⁇ e.g. a triflate, or alkoxy group) at the position to be substituted by R 1 .
  • the group "Y” is a halide or a pseudohalide (e.g. a triflate, or alkoxy group).
  • Coupling under conditions appropriate for Suzuki, Negishi or Sonogashira reaction yields the product E, in which R 1 is typically a group that contains at least one carbon-carbon double or triple bond. Unsaturated bonds in an R 1 group may be reduced, e.g. as illustrated in Scheme IV in which a compound E is catalytically hydrogenated to yield the corresponding product.
  • step (i) of Scheme V the intermediate B (which may be prepared according to Scheme I above) is oxidised to the corresponding aldehyde J, e.g. using MnC>2 in DCM.
  • Intermediate J is reacted in step (ii) with a Grignard reagent in which the alkyl group corresponds to a group R 4 , e.g. with R 4 -MgBr in a solvent such as THF.
  • This reaction yields intermediate K which is converted in step (iii) into the corresponding chloride, L, e.g. using SOCI2 or PCI 3 in a solvent such as pyridine.
  • step (iv) cyclic group A (which may be protected if necessary, e.g. if substituted), which carries a primary amine group, is reacted with L to yield intermediate M.
  • oxidation e.g. using mCPBA, and treatment with a selective amine, gives the target compound N.
  • Scheme VI provides a route to compounds of Formula (VI) in which group X 1 is S and R 4 and R 5 are both hydrogen:
  • step (i) of Scheme VI compound O is converted into benzothiazole P, e.g. by treatment with potassium thiocyanate and bromine in acetic acid.
  • step (ii) intermediate P is transformed to bromide Q, e.g. by treatment with copper bromide and t-BuONO.
  • Reduction in step (iii), e.g. using DIBAL, and substitution in step (iv), e.g. with DPP A in DBU leads to intermediate azide S.
  • Nucleophilic aromatic substitution or coupling in step (v), e.g. using H 2 N-L-R 3 in DIEA, followed by reduction in step (vi), e.g. using PdVC and H 2 gives intermediate amine U.
  • step (vii) Introduction of the heterocycle in step (vii) leads to product V.
  • V contains halogen atoms on the aromatic ring (e.g. at position R 10 )
  • a further coupling step e.g. using a Pd catalyst, may be employed to obtain other compounds of formula (VI).
  • step (i) of Scheme VII the aniline compound W (which may be commercially available, or prepared according to general synthetic methodology known to the person of skill in the art) is converted to its corresponding benzothiazole, e.g. using KSCN and Br 2 , which is subsequently brominated in step (ii), e.g. using CuBr 2 and tBuONO, to yield compound X.
  • step (ii) is further brominated in step (iii), e.g. using NBS and benzoic peroxyanhydride, to yield compound Y, which is then converted to the corresponding azide compound Z, e.g. using NaN 3 .
  • Nucleophilic aromatic substitution or coupling in step (v) e.g.
  • step (vi) using H 2 N-L-R 3 under elevated temperature, followed by reduction in step (vi), e.g. using PdVC and H 2 , gives intermediate amine AB.
  • step (vii) Introduction of the heterocycle in step (vii) leads to product AC.
  • a further coupling step e.g. using a Pd catalyst, may be employed to obtain other compounds of formula (XIII).
  • step (i) the isoindoline compound AD (acting as a protected aminocyclopentene) is hydroxylated, e.g. using SeC>2, to yield an anti product AE.
  • the cyclopentenol portion is converted to the corresponding bicyclo[3.1.0]hexanol AF, e.g. using diethylzine and diiodomethane, and the isoindoline function is removed, e.g. using hydrazine in ethanol, to yield the free amine AG which can be used directly in the reactions illustrated herein.
  • the compounds described herein, and pharmaceutical compositions containing them, are useful in therapy, in particular in the therapeutic treatment of CSF-IR mediated disorders in a subject.
  • Subjects to be treated according to the methods described herein include vertebrates, such as mammals. In preferred embodiments the mammal is a human patient.
  • the present invention provides a method for treating a CSF-IR mediated disease in a subject, the method comprising administering to the subject an effective amount of a compound as defined herein, e.g. a compound characterised by formula (I). Also provided is a compound as defined herein, e.g. a compound characterised by formula (I), for use in a method of treating a CSF-IR mediated disease in a subject. Further provided is the use of a compound as defined herein, e.g. a compound characterised by formula (I), in the manufacture of a medicament for use in a method of treating a CSF-IR mediated disease in a subject.
  • CSF-IR and its ligands have been implicated in a number of disease states, including cancers; bone disorders such as osteolysis; inflammatory disorders such as rheumatoid arthritis, atherosclerosis and inflammatory bowel disease; and neurological disorders such as Alzheimer's disease, ALS and brain injury.
  • the CSF-IR mediated disease is selected from cancer, a bone disorder, an inflammatory disorder, and a neurological disorder.
  • CSF-IR can mediate the development and/or progression of disease in a number of ways including: aberrant signalling, overexpression of CSF-IR, CSF-IR gene mutations, overexpression of its ligands CSF-1 and IL-34, and/or through its role in the development and proliferation of macrophages, microglia and osteoclasts.
  • the CSF-IR mediated disease is characterised by overexpression of CSF-IR. In embodiments, the CSF-IR mediated disease is characterised by aberrant CSF-IR signalling. In embodiments, the CSF-IR mediated disease is characterised by overexpression of CSF-1 and/or IL-34. In embodiments, the CSF-IR mediated disease is characterised by mutations in the CSF-IR gene.
  • CSF-IR and its ligand CSF-1 occurs in a significant number of cancer types, for example in tenosynovial giant-cell tumors, breast, ovarian, prostate and endometrial cancers.
  • Levels of CSF-IR and CSF-1 correlate with tumor progression, cell invasiveness and adverse prognosis.
  • CSF-IR expression can be associated with decreased overall survival patients (Kluger et al, Clin. Cancer Res. (2004) 10(l,Pt. l): 173-7).
  • a high level of expression of CSF-IR in tumor stromal cells, but not cancer cells themselves, may be a marker for lower survival in Hodgkin lymphoma (Koh et al, Am. J. Clin.
  • TAMs are associated with a number of cancers and high TAM levels can correlate with angiogenesis and malignancy progression.
  • high numbers of TAMs have been identified as a poor prognostic factor in several cancer types including breast cancer, prostate cancer, ovarian cancer, cervical cancer, pancreatic cancer and Hodgkin's lymphoma (Bingle et al , 2002, supra; Pollard et al, Nat. Rev. Cancer. (2004) 4(l):71-78).
  • Reduction in the number of TAMs in a variety of preclinical models has been demonstrated to correlate with extended survival.
  • CSF-IR signalling Inhibition of CSF-IR signalling is reported to reduce angiogensis, decrease growth of malignant cells, improve prognosis, prevent or reduce tumor progression and reduce the number of TAMs, in various cancer models, such as models of gastrointestinal stromal tumor, breast cancer, osteosarcoma, lung carcinoma and prostate cancer (Pyonteck et al , Nat. Med. (2013) 19(10): 1264-1272; Strachan et al, 2013, supra; Laoui et al, Front. Immunol. (2014) 5:a.489).
  • the CSF-IR mediated disease is a cancer.
  • the cancer is associated with high levels of tumor associated macrophages (TAMs).
  • TAMs tumor associated macrophages
  • the cancer is associated with overexpression of CSF-IR and/or CSF-1.
  • the cancer is associated with CSF-IR mutations. Methods for assessing TAMs, CSF-IR, CSF-1 and CSF-IR mutations are described herein and/or known to the skilled person.
  • the cancer is selected from breast cancer, cervical cancer, glioblastoma multiforme (GBM), Hepatocellular carcinoma, Hodgkin's lymphoma, melanoma, pancreatic cancer pigmented villondular synovitis (PVNS), prostate cancer, ovarian cancer, Tenosynovial giant cell tumors (TGCT), Endometrial cancer, Multiple myeloma, Myelocytic leukemia, Bone cancer, Renal cancer, Brain cancer and myeloproliferative disorder (MPD).
  • administration of the compounds as disclosed herein can treat subjects diagnosed as having a cancer or being at risk of developing a cancer.
  • administration of compounds as disclosed herein improves prognosis, reduces angiogenesis, reduces number of tumor associated macrophages (TAMs), decreases growth of malignant cells and/or prevents or reduces tumor progression.
  • CSF-IR chronic myeloma
  • rheumatoid arthritis for example, rheumatoid arthritis, atherosclerosis, Crohn's disease, inflammatory bowel diseases, sarcoidosis, glomerulonephritis, allograft rejection and arteriosclerosis.
  • Macrophages play a key role in chronic inflammation and increased levels of these cells can correlate with disease severity. They are an important source of pro-inflammatory cytokines such as TNFa and IL-lb, which can induce CSF-1 expression in different cell types. This contributes to monocyte recruitment, differentiation and proliferation and further TNFa and IL-lb expression, resulting in a positive feedback loop which may help to drive chronic inflammation.
  • pro-inflammatory cytokines such as TNFa and IL-lb
  • Rheumatoid arthritis is an inflammatory autoimmune disease caused by the accumulation of macrophages in the connective tissue and synovial fluid.
  • CSF-lR/CSF-1 mediated signalling has been suggested to contribute to macrophage proliferation and infiltration into the synovial tissue.
  • Inhibition of CSF-IR can decrease disease progression, decrease the destruction of bone and cartilage, and decrease the number of macrophages present in the joints of patients with collagen-induced arthritis.
  • Increased numbers of renal macrophage and high expression of CSF-1 is associated with several forms of immune mediate nephritis such as lupus nephritis. Reduced creatinine clearance is related to high renal CSF-1 levels.
  • a CSF-IR antibody decreased macrophage recruitment and proliferation at sites of renal inflammation.
  • Microglia cells play an important role in the immune response within the central nervous system and are thought to play a role in regulating the neuroinflammatory response associated with brain disease.
  • CSF-IR signalling is important for the proliferation and survival of microglial in the adult brain, and CSF-IR knockout mice are devoid of microglia.
  • Proliferation and activation of microglia is a hallmark of several neuroinflammatory diseases including experimental autoimmune encephalomyelitis (EAE), HIV encephalitis, neurodegenerative conditions such as Alzheimer's disease and ALS, stroke and brain injury.
  • EAE experimental autoimmune encephalomyelitis
  • HIV encephalitis HIV encephalitis
  • neurodegenerative conditions such as Alzheimer's disease and ALS
  • stroke and brain injury atypicallyceridel
  • Increased microglial proliferation correlates with increased upregulation of CSF-IR and with disease severity in some cases.
  • CSF-1 has been reported to promote inflammation in Alzheimer's disease and ALS.
  • the CSF-1 R mediated disease is an inflammatory disorder.
  • the inflammatory disorder is associated with high levels of macrophages or microglia.
  • the inflammatory disorder is associated with increased expression of CSF-1R and/or CSF-1.
  • the inflammatory disorder is selected from psoriatic arthritis, arthritis, asthma, thyroiditis, glomerular nephritis, atherosclerosis, psoriasis, Sjogren's syndrome, rheumatoid arthritis, systemic lupus erythematosis (SLE), cutaneous lupus erythematosus, inflammatory bowel disease including Crohn's disease and ulcerative colitis (UC), type 1 diabetes, multiple sclerosis and neuroinflammatory conditions such as HIV encephalitis, Alzheimer's disease and ALS.
  • Osteoclasts are multinucleated cells of hematopoietic origin which are able to resorb bone and play a key role in several skeletal diseases including osteoporosis, inflammatory osteolysis and bone erosion.
  • An increase in the number of osteoclast cells and an imbalance in the number of osteoclast-osteoblasts cells results in an abnormally high bone resorption rate.
  • CSF-1 and CSF-1R play an important role in osteoclast survival and differentiation.
  • Mice with a single point mutation in CSF-1 are reported to have decreased levels of osteoclast cells and developed osteopetrosis; whilst removal of CSF-1 from osteoclast cultures results in osteoclast apoptosis.
  • Osteoporosis is a bone disease mediated by loss of osteoblasts and increased osteoclast dependent bone resorption.
  • Treatment of an osteoporosis mouse model with an anti-CSF-1 antibody was reported to preserve bone density and inhibit bone resorption (Sauter et al, J. Leukoc. Biol. (2014) 96(2):265-274).
  • Paget's disease is a bone metabolism disorder associated with increased bone turnover.
  • CSF-1 CSF-1
  • CSF-1R a potential role in the pathogenesis of periodontitis, an inflammatory disease of teeth which is associated with bone reabsorption.
  • Studies have also shown that inhibition of CSF-1R contributes to bone protection.
  • treatment with an inhibitor of CSF-IR is reported to inhibit bone degradation in osteoclast cultures, rat calvaria and rat fetal long bones (Conway et al, Proc. Natl. Acad. Sci. USA (2005) 102(44): 16078-16083).
  • the CSF-IR mediated disease is a bone disorder selected from osteoporosis, osteoarthritis, periodontitis, periprosthetic osteolysis, and Paget' s disease.
  • the treatment of a CSF-IR mediated disease as disclosed herein is achieved by administering a compound of the invention in combination with another therapeutic intervention for said CSF-IR mediated disease.
  • the other therapeutic intervention may be performed before, during and/or after administering the compound of the invention.
  • the other therapeutic intervention includes the administration of a pharmaceutical agent as disclosed herein, especially an anti-proliferative agent, an antiinflammatory agent, an anti-angiogenic agent, a chemotherapeutic agent, or an immunotherapeutic agent.
  • the other therapeutic intervention is adoptive t- cell transfer.
  • the other therapeutic intervention is radiotherapy.
  • a presently disclosed compound can be formulated as a pharmaceutical composition for oral, buccal, parenteral (e.g. intravenous, intraperitoneal, intramuscular or subcutaneous), topical, rectal or intranasal administration or in a form suitable for administration by inhalation or insufflation.
  • the compound or pharmaceutical composition is formulated for systemic administration, e.g. via a non-parenteral route.
  • the compound or pharmaceutical composition is formulated for oral administration, e.g. in solid form.
  • Such modes of administration and the methods for preparing appropriate pharmaceutical compositions are described, for example, in Gibaldi's Drug Delivery Systems in Pharmaceutical Care (1st ed., American Society of 15 Health-System Pharmacists 2007).
  • the active ingredient is mixed with one or more pharmaceutically acceptable carriers, excipients, or diluents, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, microcrystalline cellulose, calcium phosphate and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, pregelatinized maize starch, polyvinyl pyrrolidone, hydroxypropyl methylcellulose, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, sodium starch glycolate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbon
  • compositions can also comprise buffering agents.
  • Solid compositions of a similar type can also be prepared using fillers in soft and hard-filled gelatin capsules, and excipients such as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet can be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets can be prepared using binders (for example, gelatin or hydroxypropylmethyl cellulose), lubricants, inert diluents, preservatives, disintegrants (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface- actives, and/ or dispersing agents.
  • Molded tablets can be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.
  • the tablets and other solid dosage forms, such as dragees, capsules, pills, and granules can optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the art.
  • the pharmaceutical compositions are administered orally in a liquid form.
  • Liquid dosage forms for oral administration of an active ingredient include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • Liquid preparations for oral administration may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • the liquid dosage forms can contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (e.g. cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol
  • the liquid pharmaceutical compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents, and the like.
  • Suspensions in addition to the active ingredient(s) can contain suspending agents such as, but not limited to, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Suitable liquid preparations may be prepared by conventional means with a pharmaceutically acceptable additive(s) such as a suspending agent (e.g.
  • sorbitol syrup methyl cellulose or hydrogenated edible fats
  • emulsifying agent e.g. lecithin or acacia
  • nonaqueous vehicle e.g. almond oil, oily esters or ethyl alcohol
  • preservative e.g. methyl or propyl p-hydroxybenzoates or sorbic acid
  • the active ingredient(s) can also be administered as a bolus, electuary, or paste.
  • the composition may take the form of tablets or lozenges formulated in a conventional manner.
  • the pharmaceutical compositions are administered by non-oral means such as by topical application, transdermal application, injection, and the like.
  • the pharmaceutical compositions are administered parenterally by injection, infusion, or implantation (e.g. intravenous, intramuscular, intra-arterial, subcutaneous, and the like).
  • Presently disclosed compounds may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion.
  • Formulations for injection may be presented in unit dosage form, e.g. in ampules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain a formulating agent such as a suspending, stabilizing and/or dispersing agent recognized by those of skill in the art.
  • the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
  • the pharmaceutical compositions can be in the form of sterile injections.
  • the pharmaceutical compositions can be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • the active ingredient is dissolved or suspended in a parenterally acceptable liquid vehicle.
  • exemplary vehicles and solvents include, but are not limited to, water, water adjusted to a suitable pH by addition of an appropriate amount of hydrochloric acid, sodium hydroxide or a suitable buffer, 1 ,3-butanediol, Ringer's solution and isotonic sodium chloride solution.
  • the pharmaceutical composition can also contain one or more preservatives, for example, methyl, ethyl or n-propyl p-hydroxybenzoate.
  • a dissolution enhancing or solubilising agent can be added or the solvent can contain 10-60% w/w of propylene glycol or the like.
  • the pharmaceutical compositions can contain one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders, which can be reconstituted into sterile inj ectable solutions or dispersions just prior to use.
  • Such pharmaceutical compositions can contain antioxidants; buffers; bacteriostats; solutes, which render the formulation isotonic with the blood of the intended recipient; suspending agents; thickening agents; preservatives; and the like.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • Controlled release parenteral compositions can be in form of aqueous suspensions, microspheres, microcapsules, magnetic microspheres, oil solutions, oil suspensions, emulsions, or the active ingredient can be incorporated in biocompatible carrier(s), liposomes, nanoparticles, implants or infusion devices.
  • Materials for use in the preparation of microspheres and/or microcapsules include, but are not limited to, biodegradable/bioerodible polymers such as polyglactin, poly-(isobut l cyanoacrylate), poly(2-hydroxyethyl-L- glutamine) and poly(lactic acid).
  • Biocompatible carriers which can be used when formulating a controlled release parenteral formulation include carbohydrates such as dextrans, proteins such as albumin, lipoproteins or antibodies.
  • Materials for use in implants can be non- biodegradable, e.g. polydimethylsiloxane, or biodegradable such as, e.g., poly(caprolactone), poly(lactic acid), poly(gly colic acid) or poly(ortho esters).
  • a presently disclosed compound may be formulated as an ointment or cream.
  • Presently disclosed compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
  • presently disclosed compounds may be conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g. dichlorodifiuoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g. dichlorodifiuoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the pressurized container or nebulizer may contain a solution or suspension of the presently disclosed compound.
  • Capsules and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix of a presently disclosed compound and a suitable powder base such as lactose or starch.
  • the agents and compositions described herein are administered in an effective amount or quantity sufficient to inhibit CSF-1R in the subject receiving the agent or composition.
  • the dose can be adjusted based on, e.g., age, physical condition, body weight, sex, diet, time of administration, and other clinical factors.
  • the effective amount may also vary depending on the mode of administration, e.g. intravenous versus oral, as well as on the nature of the composition, e.g. rapidly disintegrating versus slow release compositions. Determination of an effective amount is within the capability of those skilled in the art.
  • an effective amount for administration to a subject is in the range of about 0.1 to 1000 mg/kg.
  • the invention provides a dosage form or pharmaceutical composition as described herein for use in therapy, e.g. for use in a method as defined herein.
  • 6-carboxylate (1.00 g, 3.49 mmol) in DCM (17 ml) at -78 °C was added DIBAL-H in toluene (7.5 ml, 7.5 mmol, 1.0 M) slowly over 5 min and the resulting mixture was stirred at -78 °C for 2 h.
  • the reaction was quenched at -78 °C with 1 M Rochelle salt (10 mL) and allowed to warm to rt over 30 min.
  • the aqueous layer was extracted with 1 : 10 IPA/DCM (3 x 10 mL) and the combined organics were dried over MgS04, filtered, and concentrated.
  • the title compound was isolated as a pale yellow solid (841 mg, 99%).
  • 6-(Azidomethyl)-2-(methylthio)benzo[d]thiazole To a solution of (2-(methylthio)benzo [d]thiazol-6-yl)methanol (650 mg, 3.08 mmol) in THF (10 mL) at 0 °C were added diphenyl phosphorazidate (796 ⁇ , 3.69 mmol) and l,8-diazabicyclo[5.4.0]undec-7-ene (556 ⁇ , 3.69 mmol) and the resulting mixture was stirred at rt for 15 h. The volatiles were removed under reduced pressure.
  • 6-Chloro-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyrazin-2-amine To a solution of 2,6-dichloropyrazine (283 mg, 1.90 mmol) and (2-(methylthio)benzo[d]thiazol-6- yl)methanamine (200 mg, 0.951 mmol) in dioxane (3.2 mL) was added K 2 CO 3 (263 mg, 1.90 mmol) and the resulting mixture was stirred at 120 °C for 12 h. The mixture was concentrated.
  • 6-Chloro-N-((2-(methylsulfinyl)benzo[d]thiazol-6-yl)methyl)pyrazin-2-amine To a suspension of 6-chloro-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyrazin-2-amine (270 mg, 0.836 mmol) in DCM (8.4 mL) at 0 °C was added m-CPBA (206 mg, 0.836 mmol) in DCM (0.5 mL) and the resulting mixture was stirred at 0 °C for 6 h. The solution was diluted with sat. NaHCC (3 mL) and extracted with DCM (3 x 3 mL).
  • N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyrazin-2-amine To a suspension of 2- iodopyrazine (110 mg, 0.53 mmol) and (2-(methylthio)benzo[d]thiazol-6-yl)methanamine (75 mg, 0.36 mmol) in DMSO (713 ⁇ ) were added copper (2.3 mg, 0.036 mmol) and cesium acetate (137 mg, 0.713 mmol) and the resulting mixture was stirred at 90 °C for 1 h.
  • N-Cyclohexyl-6-((pyrazin-2-ylamino)methyl)benzo[d]thiazol-2-amine TFA salt The title compound was prepared according to step (iv) of Scheme I using cyclohexylamine as the amine. Briefly, N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyrazin-2-amine was oxidised using mCPBA and then treated with cyclohexylamine to yield the title compound. MS (ES+) C1 8 H21N5S requires: 339, found: 340 [M+H] + .

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Abstract

L'invention concerne des composés de formule (I), qui sont utiles en tant qu'inhibiteurs de CSF-1R. L'invention concerne également des compositions pharmaceutiques et des kits comprenant lesdits composés, ainsi que des procédés et des utilisations se rapportant auxdits composés.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019113469A1 (fr) 2017-12-07 2019-06-13 The Regents Of The University Of Michigan Inhibiteurs de la famille nsd et méthodes de traitement comprenant ces derniers
WO2021198981A1 (fr) 2020-04-01 2021-10-07 Janssen Biopharma, Inc. Composés antiviraux et leurs utilisations

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US20040014774A1 (en) * 1991-05-10 2004-01-22 Myers Michael R. Aryl and heteroaryl quinazoline compounds which inhibit CSF-1R receptor tyrosine kinase
US20100130490A1 (en) * 2007-05-21 2010-05-27 Ng Simon C Csf-1r inhibitors,compositions, and methods of use
US20150368210A1 (en) * 2012-06-26 2015-12-24 Chroma Therapeutics Ltd. 2-aminopyrazine derivatives as csf-1 r kinase inhibitors

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Publication number Priority date Publication date Assignee Title
US20040014774A1 (en) * 1991-05-10 2004-01-22 Myers Michael R. Aryl and heteroaryl quinazoline compounds which inhibit CSF-1R receptor tyrosine kinase
US20100130490A1 (en) * 2007-05-21 2010-05-27 Ng Simon C Csf-1r inhibitors,compositions, and methods of use
US20150368210A1 (en) * 2012-06-26 2015-12-24 Chroma Therapeutics Ltd. 2-aminopyrazine derivatives as csf-1 r kinase inhibitors

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019113469A1 (fr) 2017-12-07 2019-06-13 The Regents Of The University Of Michigan Inhibiteurs de la famille nsd et méthodes de traitement comprenant ces derniers
EP3720439A4 (fr) * 2017-12-07 2021-09-08 The Regents Of The University Of Michigan Inhibiteurs de la famille nsd et méthodes de traitement comprenant ces derniers
US11324729B2 (en) 2017-12-07 2022-05-10 The Regents Of The University Of Michigan NSD family inhibitors and methods of treatment therewith
AU2018378935B2 (en) * 2017-12-07 2024-10-31 The Regents Of The University Of Michigan NSD family inhibitors and methods of treatment therewith
US12364688B2 (en) 2017-12-07 2025-07-22 The Regents Of The University Of Michigan NSD family inhibitors and methods of treatment therewith
WO2021198981A1 (fr) 2020-04-01 2021-10-07 Janssen Biopharma, Inc. Composés antiviraux et leurs utilisations

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