WO2016051193A1 - Composés utiles en tant que modulateurs du facteur 1 de stimulation de colonies - Google Patents

Composés utiles en tant que modulateurs du facteur 1 de stimulation de colonies Download PDF

Info

Publication number
WO2016051193A1
WO2016051193A1 PCT/GB2015/052884 GB2015052884W WO2016051193A1 WO 2016051193 A1 WO2016051193 A1 WO 2016051193A1 GB 2015052884 W GB2015052884 W GB 2015052884W WO 2016051193 A1 WO2016051193 A1 WO 2016051193A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
phenyl
etoac
added
yield
Prior art date
Application number
PCT/GB2015/052884
Other languages
English (en)
Inventor
Richard Armer
Andrew BELFIELD
Matilda Bingham
Alice Johnson
Jean-Francois MARGATHE
Craig AVERY
Shaun HUGHES
Angus Morrison
Original Assignee
Redx Pharma Plc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Redx Pharma Plc filed Critical Redx Pharma Plc
Publication of WO2016051193A1 publication Critical patent/WO2016051193A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • This invention relates to novel compounds and to pharmaceutical compositions comprising the novel compounds. More specifically, the invention relates to compounds useful as Colony Stimulating Factor 1 Receptor (cFMS) modulators (e.g. cFMS inhibitors). This invention also relates to processes for preparing the compounds, uses of the compounds in treatment and methods of treatment employing the compounds. Specifically, the invention relates to the use of the compounds for the treatment of cancer and autoimmune diseases.
  • cFMS Colony Stimulating Factor 1 Receptor
  • Colony Stimulating Factor 1 Receptor also known as CD1 15, CSF-1 R, FMS, MCSFR
  • CD1 15 CSF-1 R
  • FMS FMS
  • MCSFR MCSFR
  • cFMS Colony Stimulating Factor 1 Receptor
  • CSF-1 Colony Stimulating Factor 1
  • IL-34 Interleukin 34
  • IL-34 may substitute for CSF-1 in RANKL stimulated osteoclast formation meaning that only blockade of both cytokines, either via small molecule inhibition of the phosphorylation site or a suitable antibody at the receptor site, would prove effective in inhibiting osteoclast formation.
  • GM CSF has an effect on the impact of CSF-1 on the development of macrophage.
  • macrophages adopt the M1 phenotype
  • macrophages adopt the M2 phenotype (immunomodulatory/immunosuppressive, expressing high levels of I L 10) .
  • M2 phenotype immunomodulatory/immunosuppressive, expressing high levels of I L 10.
  • tumours macrophages represent the highest proportion of the lymphocytic infiltrate and these macrophages are predominantly of the M2 phenotype and potentially contribute to the tumours' strategies for avoiding detection by the immune system.
  • CSF-1 and cFMS are over-expressed in a number of tumours including pancreatic, Hodgkin's lymphoma, AML, breast, cervical, endometrial and ovarian where they may also have an autocrine role.
  • osteoclasts express cFMS and osteoblasts CSF1 and the CSF1/cFMS axis is involved along with RANKL in the dynamics of bone metabolism. Metastatic tumour cells that express cFMS can be recruited into the bone as part of this dynamic metabolism.
  • Inhibition of cFMS has the effect of reducing macrophage population in the tumour environment and is also able to 're-educate' the tumour associated macrophages from the pro- tumourogenic M2 phenotype and potentially recruit them as suppressors of tumourigenesis (Pyonteck, S. M., et. a/., Nature Medicine, 2013, 1264-1275).
  • Inhibition of cFMS in cancers where elevated levels of CSF-1 expression has caused progression of the disease into the bone, caused bone erosion, causes the reduction in number of tumour associated macrophages, and therefore a reduction in the number osteoclasts, in the tumour environment which reduces bone damage in these indications.
  • RA is an autoimmune chronic inflammatory disease characterised by bone and cartilage destruction that is mediated by bone-resorbing osteoclasts which occurs in around 1 % of the adult population worldwide. Elevated levels of CSF-1 have been observed in the synovial fluid of RA patients and synovial fibroblasts from RA patients produce high levels of CSF-1 . As CSF-1 plays an important role in the development of osteoclasts this suggests an important role for CSF-1 in joint degradation in RA.
  • CSF-1 is the primary regulator of the survival, proliferation and differentiation of cells of the monocyte/macrophage lineage and the clear role of macrophages play in the recruitment of osteoclasts resulting in joint destruction, fuelled by autocrine and paracrine signalling of CSF-1 and RANKL
  • inhibition of CSF-1 's receptor - cFMS - seems an attractive option in the treatment of RA.
  • inhibition of cFMS offers a promising method of treating bone erosion in RA by inhibiting osteoclast formation and growth and therefore reducing their ability to cause bone and joint damage.
  • Inhibition of the CSF-1 cytokine itself would not be a suitable option for the inhibition of joint degradation in RA for the reasons outlined below.
  • cFMS is a receptor tyrosine kinase that has two known ligands - CSF-1 and the recently (2008) discovered IL-34. Following its discovery, numerous reports have appeared which describe elevated levels of IL-34 in patients with RA and other inflammatory diseases. It has also been shown that IL-34 is able to activate cFMS in a complimentary manner to CSF-1 , meaning that in the event of CSF-1 inhibition IL-34 is able to activate cFMS and support osteoclast differentiation in a similar manner as CSF-1 .
  • Pharmascience Ltd have filed a patent application - WO 2012/135937 - which discloses inhibitors of tyrosine kinases, including platelet-derived growth factor receptor (PDGFR) and cFMS.
  • PDGFR platelet-derived growth factor receptor
  • cFMS cFMS
  • Pharmascience Ltd disclose compounds similar to those in WO 2012/135937. The compounds are disclosed as being inhibitors of tyrosine kinases, in particular members of the Tec, Src, Btk and Lck protein kinase families.
  • Z is -Y -(CR 4A R 5A )n-R 1 or Y 2 ,
  • Y is -NR 8 C(0)- or -C(0)NR 8 -
  • Y 2 is represented by -C(0)N(R 9 )2 wherein the two R 9 groups taken together form a heterocyclic ring system with the nitrogen atom to which they are attached, wherein the heterocyclic ring system is a 5 or 6 membered monocyclic ring system or a 8, 9, 10 or 1 1 membered bicyclic ring system and which is unsubstituted or substituted by 1 to 4 substituents each independently selected from: halo, -OR A , -NR A R B , -NR A C(0)R c , -C(0)NR A R B , -NR A S0 2 R c , -S0 2 NR A R B , - S0 2 R c , -CN, Ci- alkyl, Ci- haloalkyl and C3-6 cycloalkyl;
  • X is a group selected from: CR 0 R 11 , O, S or NR 2 ;
  • B , B 2 , B 3 and B 4 are independently selected from CR 3 or N, such that not more than two of B , B 2 , B 3 and B 4 are N;
  • R 2 and R 3 are each independently selected from: H, Ci- 4 alkyl and Ci- 4 haloalkyl;
  • R 4 , R 5 R 4A and R 5A are each independently selected at each occurrence from: H, halo, C1-4 alkyl, Ci- 4 haloalkyl, -OR A and -NR A R B ;
  • R 6 , R 7 , R 0 and R are independently selected at each occurrence from: H, halo, C1-4 alkyl, C1-4 haloalkyl, -OR A , -NR A R B , -NR A C(0)R c , -NR A S0 2 R c , -CN and C1-4 alkyl substituted with -OR A ;
  • R 8 is selected from: H, C1-4 alkyl and C1-4 haloalkyl
  • R 2 is selected from: H, C1-4 alkyl, C1-4 haloalkyl and C1-4 alkyl substituted with -OR A ;
  • R 3 is independently selected at each occurrence from: H, halo, C1-4 alkyl, C1-4 haloalkyl, -OR A , -CN, -NR A R B , -SR A , and C1-4 alkyl substituted with -OR A ;
  • n are each independently selected from 0, 1 , 2, 3 or 4,
  • R A and R B are each independently selected at each occurrence from: H, C1-4 alkyl and C1-4 haloalkyl;
  • R c is selected from: C1-4 alkyl and C1-4 haloalkyl
  • m + n is 1 or more when R is unsubstituted phenyl.
  • the present invention also provides compounds of formula (I) and pharmaceutically acceptable salts thereof.
  • R may be substituted or unsubstituted: C5-10 carbocyclic and C5-10 heterocyclic, when substituted R is substituted by 1 to 4 substituents each independently selected from: halo, -OR A , - NR A R B , -NR A C(0)R c , -C(0)NR A R B , -NR A S0 2 R c , -S0 2 NR A R B , -S0 2 R c , -C(0)R c , -CN, -NO2, C1-4 alkyl, C1-4 haloalkyl, C3-6 cyclcoalkyl, C3-6 halocyclcoalkyl, C1-4 alkyl substituted with -OR A , C1-4 alkyl substituted with phenyl, phenyl, -C(0)phenyl, -C(0)CH 2 phenyl, and -C(0)Ophenyl, - C(0)OCH 2 phenyl;
  • R 6 , R 7 , R 0 and R are independently selected from: H, halo, C1-4 alkyl, C1-4 haloalkyl, -OR A , and C1-4 alkyl substituted with -OR A .
  • R A may be as described above.
  • R A may be selected from: H, methyl, ethyl, isopropyl, tert-butyl and trifluoromethyl.
  • R 6 and R 7 are independently selected from: H, chloro, fluoro, methyl, ethyl, trifluoromethyl, trifluorethyl, -OH, -OMe, -OEt, -OCF3, -CH 2 OH and -CH 2 CH 2 OH.
  • R 0 and R are independently selected from: H, chloro, fluoro, methyl, ethyl, trifluoromethyl, trifluorethyl, -OH, -OMe, -OEt, -OCF3, -CH 2 OH and -CH 2 CH 2 OH.
  • R 2 is selected from: H, C1-4 alkyl, C1-4 haloalkyl and C1-4 alkyl substituted with -OR A , wherein R A is selected from: H, methyl, ethyl, isopropyl, tert-butyl and trifluoromethyl. In a preferred embodiment R 2 is selected from: H, methyl, ethyl, trifluoromethyl, trifluoroethyl, -CH 2 OH and -CH 2 CH 2 OH. [0019] In an embodiment R 6 and R 7 are each independently selected from H or methyl. In an embodiment R 6 and R 7 are H . In an embodiment R 6 , R 7 , R 0 and R are each independently selected from H or methyl. In an embodiment R 6 , R 7 , R 0 and R are H.
  • the compound of formula (I) is a compound according to formula (I I):
  • X is CR 0 R 11 or O.
  • X is CH 2 or O.
  • R 0 , R and R 2 are each independently selected from H or methyl.
  • R 0 , R and R 2 are H.
  • R 6 , R 7 , R 0 , R and R 2 may all be H.
  • the compound of formula (I) is a compound according to formulae (lla) and (lib):
  • B , B 2 , B 3 and B 4 are independently selected from CR 3 or N, wherein not more than one of B , B 2 , B 3 and B 4 are N. In an embodiment B , B 2 , B 3 and B 4 are CR 13 .
  • R 3 may be independently selected at each occurrence from H, halo, C1-4 alkyl, C1-4 haloalkyl, -OR A , -CN, and C1-4 alkyl substituted with -OR A .
  • R 3 may be independently selected at each occurrence from: H, chloro, fluoro, methyl, ethyl, trifluoromethyl, trifluorethyl, -OH, -OMe, -OEt, -OCF3, -CH2OH and -CH2CH2OH .
  • R 3 is independently at each occurrence H, chloro, fluoro, -OMe, -CF3, or -OCF3.
  • R 3 is independently at each occurrence H, fluoro or -OMe,
  • one of B ⁇ B 2 , B 3 and B 4 is C-OMe and the remaining B , B 2 , B 3 and B 4 are CH. In an embodiment one of B , B 2 , B 3 and B 4 is C-F and the remaining B , B 2 , B 3 and B 4 are CH. In an alternative embodiment B , B 2 , B 3 and B 4 are CH.
  • the compound of formula (I) is a compound according to formulae (Ilia), (lllb) or (lllc):
  • one of B ⁇ B 2 , B 3 and B 4 is C-OCF3 and the remaining B , B 2 , B 3 and B 4 are CH. In an embodiment one of B , B 2 , B 3 and B 4 is C-CI and the remaining B , B 2 , B 3 and B 4 are CH. In an embodiment one of B , B 2 , B 3 and B 4 is C-CF3 and the remaining B , B 2 , B 3 and B 4 are CH.
  • the compound of formula (I) is a compound according to formulae (llld), (llle) or (lllf):
  • the compound of formula (I) is a compound according to formulae (Ilia), (lllb), (lllc), (llld), (llle) or (lllf).
  • Z is -Y -(CR 4A R 5A ) n -R 1 .
  • the compound of formula (I) is a compound according to formula (IV):
  • R 4 , R 5 , R 4A and R 5A are each independently selected from: H, chloro, fluoro, methyl, ethyl, trifluoromethyl, -OH, -OMe, -NH2, -NHMe and - ⁇ 2.
  • one of R 4 , R 5 , R 4A and R 5A is fluoro, methyl and -NH2 and the remainder are H. In an embodiment, one of R 4 , R 5 , R 4A and R 5A is fluoro and the remainder are H. In an embodiment, one of R 4 , R 5 , R 4A and R 5A is methyl and the remainder are H. In an embodiment, one of R 4 , R 5 , R 4A and R 5A is -NH2 and the remainder are H.
  • R 4 and R 5 are H. In an embodiment R 4 and R 5 are H and m is 1 or 2.
  • R 4A is fluoro and R 5A is H. In an embodiment, R 4A is methyl and R 5A is H. In an embodiment, R 4A is -NH2 and R 5A is H. In an embodiment, R 4A is fluoro and R 5A is H and n is 1 or 2. In an embodiment, one of R 4A is methyl and R 5A is H and n is 1 or 2. In an embodiment, R 4A is fluoro and R 5A is -NH2 and n is 1 or 2. [0040] In a preferred embodiment m is 0, 1 or 2, optionally 1 or 2. In a particular embodiment m is 1 . In a preferred embodiment n is 0, 1 or 2, optionally 1 or 2. In a particular embodiment n is 1 . In an embodiment m and n may be selected from 0, 1 or 2.
  • m is 1 or 2 (preferably 1) and n is 0.
  • n is 0 and n is 1 , 2 or 3 (preferably 1 or 2).
  • m is 1 or 2 (preferably 1), n is 0 and Y is - C(0)NR 8 -.
  • m is 0 and n is 1 , 2 or 3 (preferably 1 or 2) and Y is - NR 8 C(0)-.
  • the compound of formula (I) is a compound according to formulae (Va) or (Vb):
  • R may be selected from substituted or unsubstituted: Ce-io aryl, C5-10 heteroaryl, C5-10 cycloalkyl, C5-10 heterocycloalkyl C5-10 cycloalkylene and C5-10 heterocycloalkylene.
  • C5-10 cycloalkyl may represent cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • C5-10 cycloalkenyl may represent cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienly, cycloheptenyl, cycloheptadiene, cyclooctenyl, cyclooctadienyl, indanyl, indenyl or tetralinyl.
  • C5-10 heterocycloalkyl may represent tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, dioxolane, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, dioxane or tetrahydropyran,.
  • C5-10 heterocycloalkenyl may represent pyrroline, imidazoline, pyrazoline, oxazoline, isoxazoline, thiazoline, isothiazoline, dihydropyran, indoline, isoindoline, chromene, chromane, isochromane, dihydroquinoline, tetrahydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, dihydrobenzofuran, benzomorpholine or benzodioxolane.
  • C5-10 heterocycloalkylene is not dihydrobenzofuran, benzomorpholine.
  • Ce-io aryl may represent phenyl or napthyl.
  • C5-10 heteroaryl may represent pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, benzoxadiazolyl and benzimidazolyl.
  • C5-10 heteroaryl is not benzoxadiazolyl.
  • R is a ring selected from unsubstituted or substituted cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienly, cycloheptenyl, cycloheptadiene, cyclooctenyl, cyclooctadienyl, indanyl, indenyl, tetralinyl, tetrahydrofuran, pyrrolidine, pyrroline, imidazolidine, imidazoline, succinimide, pyrazolidine, pyrazoline, oxazolidine, oxazoline, dioxolane, isoxazolidine, isoxazoline, thiazolidine, thiazoline, isothiazolidine, isothiazoline, piperidine,
  • R may be selected from unsubstituted or substituted: phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, imidazolyl, pyrazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, indanyl, indolyl, indolinyl, azaindolyl, benzthiazolyl, benzodioxolane, piperidinyl, piperazinyl, morpholinyl, pyrolidinyl, cyclohexyl, tetrahydroquinoline, dihydrobenzofuran, benzomorpholine, benzoxadiazolyl and tetrahydropyranyl.
  • R may be selected from unsubstituted or substituted: phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, imidazolyl, pyrazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, indanyl, indolyl, indolinyl, azaindolyl, benzthiazolyl, benzodioxolane, tetrahydroquinoline,
  • R may be selected from unsubstituted or substituted: phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, indolyl, indanyl, cyclohexyl and tetrahydropyranyl.
  • R may be substituted by 1 to 4 substituents (optionally 1 , 2 or 3) each independently selected from: halo, -OR A , -NR A R B , -C(0)NR A R B , -C(0)R c , -CN, -NO2, C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, C1-4 alkyl substituted with -OR A , C1-4 alkyl substituted with phenyl, phenyl, -C(0)phenyl, - C(0)CH 2 phenyl, -C(0)Ophenyl, and -C(0)OCH 2 phenyl.
  • R may be substituted by 1 to 4 substituents (optionally 1 , 2 or 3) each independently selected from: halo, -OR A , -NR A R B , -C(0)NR A R B , -C(0)R c , -CN, -N0 2 , Ci- alkyl, Ci- haloalkyl, Ci- alkyl substituted with -OR A , Ci- 4 alkyl substituted with phenyl, phenyl and -C(0)OCH2phenyl.
  • heterocycloalkyl substituted with -OR A , phenyl and -C(0)OCH2phenyl.
  • R may be unsubstituted or substituted with 1 , 2 or 3 groups selected from: chloro, fluoro, bromo, methyl, ethyl, iso-propyl, tert-butyl, trifouromethyl, trifluoroethyl, -OH, -OMe, -OEt, -OCF3, - OCHF2, -NH2, -NHMe, -NMe 2 , -NO2, -CN, -CH2OH , -CH2CH2OH, -C(0)Me, -C(0)NH 2 , hydroxyethyl, hydroxypropyl, phenyl and -C(0)OCH2phenyl.
  • 1 , 2 or 3 groups selected from: chloro, fluoro, bromo, methyl, ethyl, iso-propyl, tert-butyl, trifouromethyl, trifluoroethyl, -OH, -OMe, -OE
  • R may be unsubstituted or substituted with a group or combination of groups selected from: fluoro; bromo; methyl; ethyl; iso-propyl; tert-butyl; trifouromethyl; trifluoroethyl; -OH; -OMe; - OEt; -OCF3; -OCHF2; -NH 2 ; -NHMe; -NMe 2 ; -NO2; -CN; -CH2OH ; -CH2CH2OH; -C(0)Me; -C(0)NH 2 ; hydroxyethyl; hydroxypropyl; phenyl; -C(0)OCH2phenyl; dichloro; fluoro and methyl; fluoro and trifouromethyl; fluoro and methoxy; fluoro and bromo; chloro and trifouromethyl; fluoro and chloro; bromo and methoxy; methyl and methoxy; dime
  • R may be unsubstituted pyridyl, unsubstituted phenyl, unsubstituted pyridazinyl, methylphenyl, ethylphenyl, iso-propylphenyl, tert-butylphenyl, trifluoromethylphenyl, methoxyphenyl, ethyoxyphenyl, aminophenyl, N-methyl-aminophenyl, ⁇ , ⁇ -dimethyl-aminophenyl, nitrophenyl, cyanophenyl, methylpyridyl, ethylpyridyl, iso-propylpyridyl, tert-butylpyridyl, trifluoromethylpyridyl, methoxypyridyl, ethyoxypyridyl, aminopyridyl, N-methyl-aminopyridyl, N,N-dimethyl-
  • aminopyridazinyl N-methyl-aminopyridazinyl, ⁇ , ⁇ -dimethyl-aminopyridazinyl, nitropyridazinyl and cyanopyridazinyl.
  • R is selected from unsubstituted or substituted: phenyl, pyridyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, indanyl, indolyl, indolinyl, azaindolyl, benzthiazolyl, benzodioxolane, piperidinyl, piperazinyl, morpholinyl and pyrolidinyl
  • R is selected from unsubstituted or substituted: phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazolyl, oxazolyl, thiazolyl, indolyl, indanyl, cyclohexyl and tetrahydropyranyl.
  • Z is Y 2 .
  • the compound of formula (I) is a compound according to formula (VI):
  • the two R 9 groups taken together form a heterocyclic ring system with the nitrogen atom to which they are attached, wherein the heterocyclic ring system is a 5 or 6 membered monocyclic ring system which is unsubstituted or substituted.
  • the two R 9 groups taken together form a heterocyclic ring system with the nitrogen atom to which they are attached, wherein the heterocyclic ring system is a 8, 9, 10 or 1 1 membered bicyclic ring system which is unsubstituted or substituted.
  • the two R 9 groups taken together form a heterocyclic ring system with the nitrogen atom to which they are attached, wherein the heterocyclic ring system is selected from unsubstituted or substituted: pyrroline, pyrrolidine, pyrazoline, pyrazolidine, imidazoline, imidazolidine, piperidine, piperazine, pyrazole, imidazole, triazole, tetrazole, morpholine, thiomorpholine, pyridine, indoline, indole, isoindole, oxindole, isoxindole, indazole,
  • the two R 9 groups taken together form a heterocyclic ring system with the nitrogen atom to which they are attached, wherein the heterocyclic ring system is selected from unsubstituted or substituted: morpholine, thiomorpholine, pyridine, 1 ,2,3,4-tetrahydroisoquinoline, 1 ,2,3,4-tetrahydroquinoline, 1 ,2,3,4-tetrahydroquinoxaline, 2,3-dihydro-1 H-isoindole, 1 ,3-dihydro- 2,1 -benzoxazole, 2,3-dihydro-1 ,2-benzoxazole, indoline, indole, 3,4-dihydro-2H-1 ,4-benzothiazine, 1 ,2,3,4-tetrahydroquinolin-2-one, 1 ,2,3,4-tetrahydroisoquinolin-1 -one, 1 ,2-dihydro
  • the two R 9 groups taken together form benzomorpholine.
  • R 2 and R 3 are each independently selected from: H or methyl. In an embodiment, R 2 and R 3 are H. In an alternative embodiment R 2 and R 3 are methyl. In an alternative embodiment R 2 is H and R 3 is methyl.
  • R 8 is selected from: H, methyl, ethyl, and trifluoromethyl.
  • R 8 may be H or methyl.
  • the compound according to the invention may be selected from a preferred group consisting of:
  • compounds with one stereocentre have the (R)-configuration at the stereocentre.
  • compounds with one stereocentre have the (S)-configuration at the stereocentre.
  • the present invention provides a compound of the present invention for use as a medicament.
  • the present invention provides a pharmaceutical formulation comprising a compound of the present invention and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition may be a combination product comprising an additional pharmaceutically active agent.
  • the additional pharmaceutically active agent may be an anti-tumor agent described below.
  • a compound of the present invention for use in the treatment of a condition which is modulated by Colony Stimulating Factor 1 Receptor (cFMS).
  • cFMS Colony Stimulating Factor 1 Receptor
  • conditions that are modulated by cFMS are conditions that would be treated by the inhibition of cFMS, using a compound of the present invention.
  • a compound of formula (I) may be for use in the treatment of a condition treatable by the inhibition of cFMS.
  • Modulation of cFMS is relevant for the treatment of many different diseases associated with the inhibition of cFMS.
  • the condition treatable by the inhibition of cFMS may be selected from: cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma, leukemia, central nervous system disorders, inflammatory diseases, autoimmune diseases and immunological diseases.
  • Specific cancers, sarcomas, melanomas, skin cancers, haematological tumors, lymphoma, carcinoma, leukemia, central nervous system disorders, inflammation and immunological diseases treatable by the inhibition of cFMS may be selected from: solid tumors; bone metastases; acute myeloid leukemia; tenosynovial giant cell tumour; breast cancer; metastatic breast cancer; metastatic melanoma; melanoma; gastrc cancer; refractory Hodgkin's lymphoma; glioblastoma; metastatic cancers; endometrial cancer; ovarian cancer; bone cancer; pancreatic cancer; myeloproliferative disorders such as polycythemia vera, essential thrombocytosis, primary or idiopathic myelofibrosis; systemic lupus erythematosus; acute disseminated encephalomyelitis; lupus nephtitis; arthritis; rheum
  • the invention contemplates methods of treating the above mentioned conditions and contemplates compounds of the invention for use in a method of treatment of the above mentioned conditions.
  • a compound of the invention may be for use in the treatment of a condition selected from: cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma, leukemia, central nervous system disorders, neuro-degenerative disorders, inflammation and immunological diseases.
  • Specific cancers, sarcomas, melanomas, skin cancers, haematological tumors, lymphoma, carcinoma, leukemia, central nervous system disorders, inflammation, autoimmune diseases and immunological diseases that may be treated by the compound of the invention may be selected from: solid tumors; bone metastases; acute myeloid leukemia; tenosynovial giant cell tumour; breast cancer; metastatic breast cancer; metastatic melanoma; melanoma; gastrc cancer; refractory Hodgkin lymphoma; Hodgkin lymphoma;
  • glioblastoma metastatic cancers; endometrial cancer; ovarian cancer; bone cancer; pancreatic cancer; myeloproliferative disorders such as polycythemia vera, essential thrombocytosis, primary or idiopathic myelofibrosis; systemic lupus erythematosus; acute disseminated encephalomyelitis; lupus nephtitis; arthritis; rheumatoid arthritis; cardiac hypertrophy; lung fibrosis; hepatic fibrosis; atherosclerosis; restenosis; glomerulonephritis; psoriasis; lupus; multiple sclerosis; macular degeneration; asthma; reactive synoviotides; reactive synoviotides such as pigmented villonodular synovitis; chronic infection; a inflammatory bowel disease; sarcoidosis; immune-mediated nephritis; chronic obstrutive pulmonary disease and S
  • a method of treatment of a condition which is modulated by cFMS comprising administering a therapeutic amount of a compound of the invention, to a patient in need thereof.
  • the method of treatment may be a method of treating a condition treatable by the inhibition of cFMS. These conditions are described above in relation to conditions treatable by the inhibition of cFMS.
  • a method of treatment of a condition selected from: cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma, leukemia, central nervous system disorders, neuro-degenerative disorders, inflammation and immunological diseases wherein the method comprises administering a therapeutic amount of a compound of the invention, to a patient in need thereof.
  • Specific cancers, sarcomas, melanomas, skin cancers, haematological tumors, lymphoma, carcinoma, leukemia, central nervous system disorders, inflammation, autoimmune diseases and immunological diseases that may be treated by the method of treatment may be selected from: solid tumors; bone metastases; acute myeloid leukemia; tenosynovial giant cell tumour; breast cancer; metastatic breast cancer; metastatic melanoma; melanoma; gastrc cancer; refractory Hodgkin's lymphoma; glioblastoma; metastatic cancers; endometrial cancer; ovarian cancer; bone cancer; pancreatic cancer; myeloproliferative disorders such as polycythemia vera, essential thrombocytosis, primary or idiopathic myelofibrosis; systemic lupus erythematosus; acute disseminated encephalomyelitis; lupus nephtitis; arthritis;
  • a use of a compound of the invention in the manufacture of a medicament for the treatment of a condition which is modulated by cFMS in the manufacture of a medicament for the treatment of a condition which is modulated by cFMS.
  • conditions that are modulated by cFMS are conditions that would be treated by the inhibition of cFMS, using a compound of the present invention.
  • the condition may be any of the conditions mentioned above.
  • the present invention provides methods of treating a medical condition that benefits from the inhibition of cFMS comprising administering an effective amount of a compound according to the present invention.
  • the present invention provides methods of enhancing the effectiveness of an anti-cancer treatment comprising administering an anti-cancer agent and a compound according to the present invention.
  • a compound for use in a method of treating a condition that benefits from the inhibition and/or reduction of tumor associated macrophage is provided.
  • the present invention provides a compound of the present invention for use in treating cFMS mediated immunosuppression.
  • the present invention provides a compound of the present invention for use in treating immunosuppression.
  • the present invention provides a compound of the present invention for use in treating immunosuppression associated with cancer, in particular for use in treating tumour-specific immunosuppression associated with cancer.
  • Cancer may refer to any one or more of: solid tumors; bone metastases acute myeloid leukemia; tenosynovial giant cell tumour; breast cancer; metastatic breast cancer; metastatic melanoma; melanoma; gastrc cancer; refractory Hodgkin's lymphoma; glioblastoma; metastatic cancers; cervical cancer; endometrial cancer; ovarian cancer; bone cancer and pancreatic cancer.
  • Inflammatory diseases may refer to any one or more of: myeloproliferative disorders such as polycythemia vera, essential thrombocytosis, primary or idiopathic myelofibrosis; systemic lupus erythematosus; acute disseminated encephalomyelitis; lupus nephtitis; arthritis; rheumatoid arthritis; cardiac hypertrophy; lung fibrosis; hepatic fibrosis; atherosclerosis; restenosis; glomerulonephritis;
  • myeloproliferative disorders such as polycythemia vera, essential thrombocytosis, primary or idiopathic myelofibrosis; systemic lupus erythematosus; acute disseminated encephalomyelitis; lupus nephtitis; arthritis; rheumatoid arthritis; cardiac hypertrophy; lung fibrosis; hepatic
  • psoriasis lupus
  • multiple sclerosis multiple sclerosis
  • macular degeneration asthma
  • reactive synoviotides reactive synoviotides such as pigmented villonodular synovitis
  • chronic infection inflammatory bowel disease
  • sarcoidosis immune-mediated nephritis
  • chronic obstrutive pulmonary disease chronic obstrutive pulmonary disease and Sjogren's syndrome.
  • halo refers to one of the halogens, group 17 of the periodic table.
  • the term refers to fluorine, chlorine, bromine and iodine.
  • the term refers to fluorine or chlorine.
  • Ci-e alkyl refers to a linear or branched hydrocarbon chain containing 1 , 2, 3, 4, 5 or 6 carbon atoms, for example methyl, ethyl, n-propyl, / ' so-propyl, n-butyl, sec-butyl, fe/ -butyl, n- pentyl and n-hexyl.
  • Alkylene groups may likewise be linear or branched and may have two places of attachment to the remainder of the molecule.
  • an alkylene group may, for example, correspond to one of those alkyl groups listed in this paragraph.
  • alkyl and alkylene groups may be unsubstituted or substituted by one or more substituents. Possible substituents are described below.
  • Substituents for the alkyl group may be halogen, e.g. fluorine, chlorine, bromine and iodine, OH, Ci-e alkoxy.
  • Ci-e alkoxy refers to an alkyl group which is attached to a molecule via oxygen. This includes moieties where the alkyl part may be linear or branched and may contain 1 , 2, 3, 4, 5 or 6 carbon atoms, for example methyl, ethyl, n-propyl, / ' so-propyl, n-butyl, sec-butyl, fe/ -butyl, n- pentyl and n-hexyl.
  • the alkoxy group may be methoxy, ethoxy, n-propoxy, / ' so-propoxy, n- butoxy, sec-butoxy, fe/f-butoxy, ⁇ -pentoxy and ⁇ -hexoxy.
  • the alkyl part of the alkoxy group may be unsubstituted or substituted by one or more substituents. Possible substituents are described below.
  • Substituents for the alkyl group may be halogen, e.g. fluorine, chlorine, bromine and iodine, OH, Ci-e alkoxy.
  • Ci-e haloalkyl refers to a hydrocarbon chain substituted with at least one halogen atom independently chosen at each occurrence, for example fluorine, chlorine, bromine and iodine.
  • the halogen atom may be present at any position on the hydrocarbon chain.
  • Ci-e haloalkyl may refer to chloromethyl, flouromethyl, trifluoromethyl, chloroethyl e.g. 1 - chloromethyl and 2-chloroethyl, trichloroethyl e.g. 1 ,2,2-trichloroethyl, 2,2,2-trichloroethyl, fluoroethyl e.g.
  • C2-6 alkenyl refers to a branched or linear hydrocarbon chain containing at least one double bond and having 2, 3, 4, 5 or 6 carbon atoms.
  • the double bond(s) may be present as the E or Z isomer.
  • the double bond may be at any possible position of the hydrocarbon chain.
  • the "C2-6 alkenyl” may be ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl.
  • C2-6 alkynyl refers to a branched or linear hydrocarbon chain containing at least one triple bond and having 2, 3, 4, 5 or 6 carbon atoms.
  • the triple bond may be at any possible position of the hydrocarbon chain.
  • the "C2-6 alkynyl” may be ethynyl, propynyl, butynyl, pentynyl and hexynyl.
  • C1-6 heteroalkyl refers to a branched or linear hydrocarbon chain containing 1 , 2, 3, 4, 5, or 6 carbon atoms and at least one heteroatom selected from N, O and S positioned between any carbon in the chain or at an end of the chain.
  • the hydrocarbon chain may contain one or two heteroatoms.
  • the C1-6 heteroalkyl may be bonded to the rest of the molecule through a carbon or a heteroatom.
  • the "C1-6 heteroalkyl” may be C1-6 /V-alkyl, C1-6 ⁇ ,/V-alkyl, or C1-6 O-alkyl.
  • Carbocyclic refers to a saturated or unsaturated carbon containing ring system.
  • a “carbocyclic” system may be monocyclic or a fused polycyclic ring system, for example, bicyclic or tricyclic.
  • a “carbocyclic” moiety may contain from 3 to 14 carbon atoms, for example, 5 to 10 carbon atoms in a monocyclic system ai- --7 -to -44 ⁇ &a ⁇ bo& -atoms -mor a polycyclic system.
  • Carbocyclic encompasses cycloalkyl moieties, cycloalkenyl moieties, aryl ring systems and fused ring systems including an aromatic portion.
  • heterocyclic refers to a saturated or unsaturated ring system containing at least one heteroatom selected from N, O or S.
  • a “heterocyclic” system may contain 1 , 2, 3 or 4 heteroatoms, for example 1 or 2.
  • a “heterocyclic” system may be monocyclic or a fused polycyclic ring system, for example, bicyclic or tricyclic.
  • a “heterocyclic” moiety may contain from 3 to 14 carbon atoms, for example, 5 to 10 carbon atoms in a monocyclic system
  • Heterocyclic encompasses heterocycloalkyl moieties, heterocycloalkenyl moieties and heteroaromatic moieties.
  • the heterocyclic group may be: oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, tetrahydropyran, pyrroline, pyrazoline, imidazoline, pyrazole, imidazole, triazole, tetrazole, pyridine, indoline, indole, isoindole, oxindole, isoxindole, indazole, tetrahydroisoquinoline,
  • benzotriazole tetrahydroquinolinone, dihydroisoquinolinone, pyrrolopyridine, benzomorpholine, purine, azaindole, and azaisoindole.
  • cycloalkyl refers to a saturated hydrocarbon ring system.
  • the "cycloalkyl” group may be denoted as a "C3-10 cycloalkyl” containing 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • the ring system may be a single ring or a bi-cyclic or tri-cyclic ring system.
  • the term “cycloalkyl” may also refer to "C3-8 cycloalkyl” refering to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms.
  • C3-8 cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • cycloalkenyl refers to an unsaturated hydrocarbon ring system that is not aromatic.
  • the "cycloalkenyl” group may be denoted as a "C3-10 cycloalkenyl”.
  • a "C3-10 cycloalkenyl” is a ring system containing 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • cycloalkenyl may also refer to "C3-8 cycloalkenyl” refering to an unsaturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms that is not aromatic.
  • the ring may contain more than one double bond provided that the ring system is not aromatic.
  • the ring system may be a single ring or a bi-cyclic or tri-cyclic ring system.
  • C3-8 cycloalkyl may be cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienly, cycloheptenyl, cycloheptadiene, cyclooctenyl and cyclooctadienyl.
  • heterocycloalkyl refers to a saturated hydrocarbon ring system with at least one heteroatom within the ring selected from N, O and S.
  • the "heterocycloalkyl” group may be denoted as a "C5-10 heterocycloalkyl”.
  • a “C5-10 heterocycloalkyl” is a ring system containing 5, 6, 7, 8, 9 or 10 atoms at least one being a heteroatom selected from N, O and S. For example there may be 1 , 2 or 3 heteroatoms, optionally 1 or 2.
  • heterocycloalkyl group may also be denoted as a "3 to 10 membered heterocycloalkyl" which is also a ring system containing 3, 4, 5, 6, 7, 8, 9 or 10 atoms at least one being a heteroatom.
  • the ring system may be a single ring or a bi-cyclic or tricyclic ring system. Where the ring system is bicyclic one of the rings may be an aromatic ring, for example as in indane.
  • the "heterocycloalkyl” may be bonded to the rest of the molecule through any carbon atom or heteroatom.
  • the "C5-10 heterocycloalkyl” may have one or more, e.g.
  • bonds to the rest of the molecule may be through any of the atoms in the ring.
  • the "C5-10 heterocycloalkyl” may be oxirane, aziridine, azetidine, oxetane,
  • heterocycloalkenyl refers to an unsaturated hydrocarbon ring system that is not aromatic, having at least one heteroatom within the ring selected from N, O and S.
  • heterocycloalkenyl group may be denoted as a “C5-10 heterocycloalkenyl”.
  • heterocycloalkenyl is a ring system containing 5, 6, 7, 8, 9 or 10 atoms at least one being a heteroatom selected from N, O and S. For example there may be 1 , 2 or 3 heteroatoms, optionally 1 or 2.
  • the "heterocycloalkenyl” group may also be denoted as a "3 to 10 membered
  • heterocycloalkenyl which is also a ring system containing 3, 4, 5, 6, 7, 8, 9 or 10 atoms at least one being a heteroatom.
  • the ring system may be a single ring or a bi-cyclic or tri-cyclic ring system. Where the ring system is bicyclic one of the rings may be an aromatic ring, for example as in indoline and dihydrobenzofuran.
  • the "heterocycloalkenyl” may be bonded to the rest of the molecule through any carbon atom or heteroatom.
  • the “heterocycloalkenyl” may have one or more, e.g. one or two, bonds to the rest of the molecule: these bonds may be through any of the atoms in the ring.
  • the "C5-10 heterocycloalkenyl” may be bonded to the rest of the molecule through any carbon atom or heteroatom.
  • the "C5-10 heterocycloalkenyl” may have one or more, e.g. one or two, bonds to the rest of the molecule: these bonds may be through any of the atoms in the ring.
  • the "C5-10 heterocycloalkyl” may be tetrahydropyridine, dihydropyran, dihydrofuran, pyrroline.
  • aromatic when applied to a substituent as a whole means a single ring or polycyclic ring system with 4n + 2 electrons in a conjugated ⁇ system within the ring or ring system where all atoms contributing to the conjugated ⁇ system are in the same plane.
  • aryl refers to an aromatic hydrocarbon ring system.
  • the ring system has 4n +2 electrons in a conjugated ⁇ system within a ring where all atoms contributing to the conjugated ⁇ system are in the same plane.
  • the "aryl” may be phenyl and naphthyl.
  • the aryl system itself may be substituted with other groups.
  • heteroaryl refers to an aromatic hydrocarbon ring system with at least one heteroatom within a single ring or within a fused ring system, selected from O, N and S.
  • the ring or ring system has 4n +2 electrons in a conjugated ⁇ system where all atoms contributing to the conjugated ⁇ system are in the same plane.
  • the "heteroaryl” may be imidazole, thiene, furane, thianthrene, pyrrol, benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine and indole.
  • alkaryl refers to an aryl group, as defined above, bonded to a C1-4 alkyl, where the C1-4 alkyl group provides attachment to the remainder of the molecule.
  • alkheteroaryl refers to a heteroaryl group, as defined above, bonded to a C1-4 alkyl, where the alkyl group provides attachment to the remainder of the molecule.
  • halogen herein includes reference to F, CI, Br and I. Halogen may be CI. Halogen may be F.
  • a bond terminating in a " - r/ ⁇ r " represents that the bond is connected to another atom that is not shown in the structure.
  • a bond terminating inside a cyclic structure and not terminating at an atom of the ring structure represents that the bond may be connected to any of the atoms in the ring structure where allowed by valency.
  • a moiety may be substituted at any point on the moiety where chemically possible and consistent with atomic valency requirements.
  • the moiety may be substituted by one or more substituents, e.g. 1 , 2, 3 or 4 substituents; optionally there are 1 or 2 substituents on a group. Where there are two or more substituents, the substituents may be the same or different.
  • R may be selected from H, C1-6 alkyl, C3-8 cycloalkyl, phenyl, benzyl or phenethyl group, e.g. R is H or C1-3 alkyl.
  • R is H or C1-3 alkyl.
  • the adjacent substituents may form a C4-8 ring along with the atoms of the moiety on which the substituents are substituted, wherein the C4-8 ring is a saturated or unsaturated hydrocarbon ring with 4, 5, 6, 7, or 8 carbon atoms or a saturated or unsaturated hydrocarbon ring with 4, 5, 6, 7, or 8 carbon atoms and 1 , 2 or 3 heteroatoms.
  • ortho, meta and para substitution are well understood terms in the art.
  • "ortho" substitution is a substitution pattern where adjacent carbons possess a substituent, whether a simple group, for example the fluoro group in the example below, or other portions of the molecule, as indicated by the bond ending in " - r/ ⁇ r ".
  • Metal substitution is a substitution pattern where two substituents are on carbons one carbon removed from each other, i.e with a single carbon atom between the substituted carbons. In other words there is a substituent on the second atom away from the atom with another substituent.
  • substituents are on the groups below are meta substituted.
  • Para substitution is a substitution pattern where two substituents are on carbons two carbons removed from each other, i.e with two carbon atoms between the substituted carbons. In other words there is a substituent on the third atom away from the atom with another substituent.
  • the groups below are para substituted.
  • acyl is meant an organic radical derived from, for example, an organic acid by the removal of the hydroxyl group, e.g. a radical having the formula R-C(O)-, where R may be selected from H, Ci-6 alkyl, C3-8 cycloalkyl, phenyl, benzyl or phenethyl group, eg R is H or C1-3 alkyl.
  • R may be selected from H, Ci-6 alkyl, C3-8 cycloalkyl, phenyl, benzyl or phenethyl group, eg R is H or C1-3 alkyl.
  • acyl is alkyl-carbonyl.
  • Examples of acyl groups include, but are not limited to, formyl, acetyl, propionyl and butyryl. A particular acyl group is acetyl.
  • the compounds of the invention may be present as a single stereoisomer or may be mixtures of stereoisomers, for example racemic mixtures and other enantiomeric mixtures, and diasteroemeric mixtures. Where the mixture is a mixture of enantiomers the enantiomeric excess may be any of those disclosed above. Where the compound is a single stereoisomer the compounds may still contain other diasteroisomers or enantiomers as impurities. Hence a single stereoisomer does not necessarily have an enantiomeric excess (e.e.) or diastereomeric excess (d.e.) of 100% but could have an e.e. or d.e. of about at least 85%
  • the invention contemplates pharmaceutically acceptable salts of the compounds of the invention . These may include the acid addition and base salts of the compounds. These may be acid addition and base salts of the compounds. In addition the invention contemplates solvates of the compounds. These may be hydrates or other solvated forms of the compound.
  • Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 1 ,5- naphthalenedisulfonate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharide,
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts.
  • suitable salts see "Handbook of Pharmaceutical Salts: Properties, Selection , and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
  • the resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised.
  • the compounds of the invention may exist in both unsolvated and solvated forms.
  • the term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • the term 'hydrate' is employed when said solvent is water.
  • complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts.
  • complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non- stoichiometric amounts.
  • the resulting complexes may be ionised, partially ionised, or non- ionised.
  • references to compounds of any formula include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.
  • the compounds of the invention include compounds of a number of formula as herein defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labelled compounds of the invention.
  • the present invention also includes all pharmaceutically acceptable isotopically-labelled compounds of the invention wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as C, 3 C and 4 C, chlorine, such as 36 CI, fluorine, such as 8 F, iodine, such as 23 l and 25 l, nitrogen, such as 3 N and 5 N, oxygen, such as 50, 7 0 and 8 0, phosphorus, such as 32 P, and sulphur, such as 35 S.
  • Radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 4 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • the compounds of the present invention may exist as a mixture of enantiomers depending on the synthetic procedure used.
  • the enantiomers can be separated by conventional techniques known in the art.
  • the invention covers individual enantiomers as well as mixtures thereof.
  • the compounds of the present invention as well as intermediates for the preparation thereof can be purified according to various well-known methods, such as for example
  • One or more compounds of the invention may be combined with one or more
  • anti-viral agents for example anti-viral agents, chemotherapeutics, anti cancer agents, immune enhancers, immunosuppressants, anti-tumour vaccines, anti-viral vaccines, cytokine therapy, or tyrosine kinase inhibitors, for the treatment of conditions modulated by the inhibition of cFMS, for example cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma, leukemia, central nervous system disorders, inflammation and immunological diseases
  • the method of treatment or the compound for use in the treatment of cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma, leukemia, central nervous system disorders, inflammation and immunological diseases as defined hereinbefore may be applied as a sole therapy or be a combination therapy with an additional active agent.
  • the method of treatment or the compound for use in the treatment of cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma, leukemia, and central nervous system disorders may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy.
  • Such chemotherapy may include one or more of the following categories of anti-tumor agents:
  • antiproliferative/antineoplastic drugs and combinations thereof such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, uracil mustard, bendamustin, melphalan, chlorambucil, chlormethine, busulphan, temozolamide, nitrosoureas, ifosamide, melphalan, pipobroman, triethylene-melamine, triethylenethiophoporamine, carmustine, lomustine, stroptozocin, temozolomide and dacarbazine); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, pemetrexed, cytosine arabinoside, floxuridine, cytarabine, 6-mercaptopurine,
  • alkylating agents
  • cytostatic agents such as antiestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a- reductase such as finasteride; and navelbene, CPT-II, anastrazole, letrazole, capecitabine, reloxafme, cyclophosphamide, ifosamide, and droloxa
  • antiestrogens
  • anti-invasion agents for example dasatinib and bosutinib (SKI-606), and metalloproteinase inhibitors, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase;
  • inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies, for example the anti-erbB2 antibody trastuzumab [HerceptinTM], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab, tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as gefitinib, erlotinib, 6-acrylamido-/V-(3-chloro-4- fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib) and antibodies to costimulatory molecules such as CTLA-4, 4-IBB and PD-I, or antibodies to cytokines (IL-I0, TGF-beta);
  • growth factor antibodies and growth factor receptor antibodies for example the
  • antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (AvastinTM); thalidomide; lenalidomide; and for example, a VEGF receptor tyrosine kinase inhibitor such as vandetanib, vatalanib, sunitinib, axitinib and pazopanib;
  • vascular endothelial growth factor for example the anti-vascular endothelial cell growth factor antibody bevacizumab (AvastinTM); thalidomide; lenalidomide; and for example, a VEGF receptor tyrosine kinase inhibitor such as vandetanib, vatalanib, sunitinib, axitinib and pazopanib;
  • immunotherapy approaches including for example antibody therapy such as alemtuzumab, rituximab, ibritumomab tiuxetan (Zevalin®) and ofatumumab; interferons such as interferon a; interleukins such as IL-2 (aldesleukin); interleukin inhibitors for example IRAK4 inhibitors; cancer vaccines including prophylactic and treatment vaccines such as HPV vaccines, for example Gardasil, Cervarix, Oncophage and Sipuleucel-T (Provenge); gp100;dendritic cell-based vaccines (such as Ad.p53 DC); and toll-like receptor modulators for example TLR-7 or TLR-9 agonists; and
  • cytotoxic agents for example fludaribine (fludara), cladribine, pentostatin (NipentTM);
  • steroids such as corticosteroids, including glucocorticoids and mineralocorticoids, for example aclometasone, aclometasone dipropionate, aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasol propionate, cloprednol, cortisone, cortisone acetate, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate, difluorocortolone, fluclorolone, flumethasone, flunisolide, fluocinolone, fluocinolone ace
  • (x) targeted therapies for example PI3Kd inhibitors, for example idelalisib and perifosine; PD-1 , PD-L1 , PD-L2 and CTL4-A modulators, antibodies and vaccines; IDO inhibitors (such as indoximod); Raf enzyme inhibitors for example vemurafenib; anti-PD-1 monoclonal antibodies (such as MK-3475 and nivolumab); anti-PDL1 monoclonal antibodies (such as MEDI- 4736 and RG-7446); anti-PDL2 monoclonal antibodies; and anti-CTLA-4 antibodies (such as ipilimumab);
  • PI3Kd inhibitors for example idelalisib and perifosine
  • PD-1 , PD-L1 , PD-L2 and CTL4-A modulators antibodies and vaccines
  • IDO inhibitors such as indoximod
  • Raf enzyme inhibitors for example vemurafen
  • anti-viral agents such as nucleotide reverse transcriptase inhibitors (for example, zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, adefovir diprovoxil, lobucavir, BCH-10652, emitricitabine, beta-L-FD4 (also called 3'-dicleoxy-5-fluoro-cytidine), (-)-beta-D-2,6- diamino-purine dioxolane, and lodenasine), non-nucleoside reverse transcriptase inhibitors (for example, nevirapine, delaviradine, efavirenz, PNU-142721 , AG-1549, MKC-442 (1 -ethoxy-methyl)- 5-(1 -methylethyl)-6-(phenylmehtyl)-(2,4(1 H,3H)pyrimidineone),
  • the method of treatment or the compound for use in the treatment of inflammation and immunological diseases may involve, in addition to the compound of the invention, additional active agents.
  • the additional active agents may be one or more active agents used to treat the condition being treated by the compound of the invention and additional active agent.
  • the additional active agents may include one or more of the following active agents:-
  • steroids such as corticosteroids, including glucocorticoids and mineralocorticoids, for example aclometasone, aclometasone dipropionate, aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasol propionate, cloprednol, cortisone, cortisone acetate, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate, difluorocortolone, fluclorolone, flumethasone, flunisolide, fluocinolone, fluocinolone ace
  • TNF inhibitors for example etanercept; monoclonal antibodies (e.g. infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi)); fusion proteins (e.g. etanercept (Enbrel)); and 5- ⁇ 2 ⁇ agonists (e.g. 2,5-dimethoxy-4-iodoamphetamine, TCB-2, lysergic acid diethylamide (LSD), lysergic acid dimethylazetidide);
  • monoclonal antibodies e.g. infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi)
  • fusion proteins e.g. etanercept (Enbrel)
  • 5- ⁇ 2 ⁇ agonists e.g
  • anti-inflammatory drugs for example non-steroidal anti-inflammatory drugs
  • dihydrofolate reductase inhibitors/antifolates for example methotrexate, trimethoprim, brodimoprim, tetroxoprim, iclaprim, pemetrexed, ralitrexed and pralatrexate; and
  • immunosuppressants for example cyclosporins, tacrolimus, sirolimus pimecrolimus, angiotensin II inhibitors (e.g. Valsartan, Telmisartan, Losartan, Irbesatan, Azilsartan, Olmesartan, Candesartan, Eprosartan) and ACE inhibitors e.g. sulfhydryl-containing agents (e.g. Captopril, Zofenopril), dicarboxylate-containing agents (e.g.
  • Fosinopril casokinins, lactokinins and lactotripeptides.
  • Such combination treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
  • Such combination products employ the compounds of this invention within a therapeutically effective dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
  • Compounds of the invention may exist in a single crystal form or in a mixture of crystal forms or they may be amorphous.
  • compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, or spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.
  • the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
  • the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight ⁇ g/kg) to 100 milligrams per kilogram body weight (mg/kg).
  • a compound of the invention, or pharmaceutically acceptable salt thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the compounds of the invention, or pharmaceutically acceptable salt thereof, is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a pharmaceutically acceptable adjuvant diluent or carrier.
  • Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example,
  • the pharmaceutical composition which is used to administer the compounds of the invention will preferably comprise from 0.05 to 99 %w (per cent by weight) compounds of the invention, more preferably from 0.05 to 80 %w compounds of the invention, still more preferably from 0.10 to 70 %w compounds of the invention, and even more preferably from 0.10 to 50 %w compounds of the invention, all percentages by weight being based on total composition.
  • compositions may be administered topically (e.g. to the skin) in the form, e.g., of creams, gels, lotions, solutions, suspensions, or systemically, e.g. by oral
  • parenteral administration in the form of a sterile solution, suspension or emulsion for injection including intravenous, subcutaneous, intramuscular, intravascular or infusion
  • rectal administration in the form of suppositories or by inhalation in the form of an aerosol.
  • the compounds of the invention may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets.
  • a carrier for example, lactose, saccharose, sorbitol, mannitol
  • a starch for example, potato starch, corn starch or amylopectin
  • a cellulose derivative for example, gelatine or polyvinylpyrrolidone
  • a lubricant for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and
  • the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.
  • the compounds of the invention may be admixed with, for example, a vegetable oil or polyethylene glycol.
  • Hard gelatine capsules may contain granules of the compound using either the above-mentioned excipients for tablets.
  • liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules.
  • Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol.
  • such liquid preparations may contain colouring agents, flavouring agents, sweetening agents (such as saccharine), preservative agents and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.
  • the compounds of the invention may be administered as a sterile aqueous or oily solution.
  • the size of the dose for therapeutic purposes of compounds of the invention will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.
  • Dosage levels, dose frequency, and treatment durations of compounds of the invention are expected to differ depending on the formulation and clinical indication, age, and co-morbid medical conditions of the patient.
  • the standard duration of treatment with compounds of the invention is expected to vary between one and seven days for most clinical indications. It may be necessary to extend the duration of treatment beyond seven days in instances of recurrent infections or infections associated with tissues or implanted materials to which there is poor blood supply including bones/joints, respiratory tract, endocardium, and dental tissues.
  • T3P refers to propylphosphonic anhydride
  • TBAF refers to
  • TFA tetrabutylammonium fluoride
  • THF tetrahydrofuran
  • the samples were eluted at a flow rate of 0.6mL/min with a mobile phase system composed of A (0.1 % (v/v) Formic Acid in Water) and B (0.1 % (v/v) Formic Acid in Acetonitrile) according to the gradients outlined in Table 1 below. Retention times RT are reported in minutes.
  • the samples were eluted at a flow rate of 0.9ml_/min with a mobile phase system composed of A (0.1 % (v/v) Formic Acid in 95:5 (v/v) Water: Acetonitrile) and B (0.1 % (v/v) Formic Acid in 95:5 (v/v) Acetonitrile: Water) according to the gradients outlined in Table 2 below. Retention times RT are reported in minutes.
  • NMR was also used to characterise final compounds. NMR spectra were obtained on a Bruker AVIII 400 Nanobay with 5mm BBFO probe. Optionally, compound Rf values on silica thin layer chromatography (TLC) plates were measured.
  • Formamidine acetate (53.59g, 514.72mmol) was added to a stirred solution of EtOH (300ml_) and benzyl N-[4-(3-amino-2-cyano-5,6-dihydro-4H-cyclopenta[b]pyrrol-1 -yl)phenyl]carbamate (47.92g, 128.68mmol) at room temperature.
  • the reaction was heated to 80 °C and stirred for 3 hours.
  • the reaction was then cooled to room temperature and solvent removed in vacuo. The residue was partitioned between sat. aq. NaHC03 and EtOAc (500mL/500ml_).
  • Benzyl N-[4-(4-amino-7,8-dihydro-6H-cyclopenta[2,3]pyrrolo[2,4-d]pyrimidin-5-yl)phenyl]carbamate (51 .40g, 128.68mmol) was dissolved in EtOAc (500ml_) and the resulting solution stirred at room temperature. Palladium, 10 wt. % on carbon powder, dry (5.00g, 46.98mmol) was added and then the reaction was fitted with a hydrogen balloon and subjected to 3 x vacuum/hydrogen cycles and then left to stir under a hydrogen atmosphere for 72 hours. After this time the reaction had not gone to completion and more palladium (2.5g) was added.
  • Benzyl chloroformate (32.80ml_, 229.80mmol) was added to a stirred mixture of 2- methoxy-4-nitroaniline (27.60g, 164.1 mmol), magnesium oxide (5.62g, 139.51 mmol) and acetone (350mL) at room temperature under a nitrogen atmosphere. The reaction was stirred at room temperature for 18 hours, after which time it had gone around 50%. More benzyl chloroformate was added (20ml_) and the reaction allowed to stir for a further 24 hours. After this time it had gone to completion. Water (300ml_) was added which caused a yellow solid to crash out which was filtered and dried.
  • MeOH 50ml_ was added to aid solubility as well as more palladium on carbon, 10 wt. % loading (1 .35g) and the reaction back filled 3 times with nitrogen before evacuating and back filling 3 times with hydrogen.
  • the reaction was left to stir at room temperature for 48 hours.
  • the reaction was then evacuated and back filled 3 times with nitrogen before filtering through a plug of celite.
  • the filtrate was concentrated under reduced pressure to afford a brown oil.
  • DIPEA 8.12ml_, 46.61 mmol
  • methyl 2-(4-amino-2-methoxy- phenyl)acetate 9.1 g, 46.61 mmol
  • bromoacetonitrile 3.25ml_, 46.61 mmol
  • THF 5ml_
  • the reaction solution was heated at 80 °C overnight.
  • the reaction mixture was cooled to room temperature and the bulk THF was removed in vacuo to give a brown gum.
  • the brown gum was diluted with EtOAc (200ml_).
  • the organic layer was washed twice with sat. aq.
  • Ethyl 4-pyridylacetate (0.94ml_, 6.1 1 mmol) was dissolved in EtOH (15 mL) and distilled water (1 15 ⁇ _, 6.42mmol) and heated to 60 °C. A solution of potassium fe/ -butoxide (720mg, 6.42mmol) in EtOH (5ml_) was then added dropwise and the reaction was stirred at 60 °C overnight. The EtOH was removed in vacuo and the resulting residue triturated with ether and dried in the vac oven to yield potassium 2-(4-pyridyl)acetate (538mg, 3.92mmol, 64% yield) as a colourless solid.
  • Morpholine (261 ⁇ _, 2.99mmol) was added to a stirred solution of ethyl bromoacetate (332 ⁇ _, 2.99mmol) and DIPEA (639 ⁇ _, 3.59mmol) in THF (5ml_) which was then refluxed for 120 minutes.
  • the product was partitioned between sat. aq. NaHC03 and EtOAc, the aqueous fraction was back extracted with EtOAc. The combined organic fractions were washed with brine, dried over
  • LiHMDS 1 M in toluene (7.98ml_, 7.98mmol) was added to a stirred solution of 2-bromo-5- methoxypyridine (0.35ml_, 2.66mmol), te/ -butyl acetate (0.54ml_, 3.99mmol) and 'BuXPhos Pd G1 (18mg, 0.03mmol) in a 3 neck flask evacuated/backfilled with nitrogen.
  • the reaction mixture was allowed to stir for 24 hours at 0 °C. Sat. aq. NhUCI (6ml_) was added and the mixture was extracted three times with EtOAc. The combined organic fractions were dried over Na2S04, and the solvents were then removed in vacuo.
  • the product was purified via column chromatography using an eluent of 10-20% EtOAc in heptane to yield te/ -butyl 2-(5-methoxy-2-pyridyl)acetate (201 mg, 0.90mmol, 34% yield) as a yellow oil.
  • Zinc Powder (331 mg, 5.06mmol) and a stirrer bar was added to a dry 3-neck flask and the flask sealed and flushed with nitrogen. The zinc was then suspended in dry THF (12ml_), the suspension stirred and fe/ -butyl bromoacetate (0.67ml_, 4.56mmol) added to the vessel.
  • Diisobutylaluminium hydride (1 M in toluene) (0.08ml_, 0.51 mmol) was then added. Stirring was continued for 2 hours with heating to 40 °C, until the zinc had mostly dissolved giving a grey solution. This solution was then allowed to cool and to the vessel was added 5-bromo-1 -methyl- indole (531 mg, 2.53mmol) and QPhos (180mg, 0.25mmol). Nitrogen was then bubbled through the resulting stirred solution before tris(dibenzylideneacetone)dipalladium (0) (231 mg, 0.25mmol) was added, the vessel re-sealed, flushed with nitrogen again, and heated to reflux overnight.
  • Morpholine (262 ⁇ _, 2.99mmol) was added to a stirred solution of ethyl 4-bromobutanoate (428 ⁇ _, 2.99mmol) and DIPEA (639 ⁇ _, 3.59mmol) in THF (5ml_) which was then refluxed for 16 hours.
  • the product was partitioned between sat. aq. NaHC03 and EtOAc, the aqueous fraction was back extracted with EtOAc.
  • the product was separated via SCX eluting with 2M Nhh in methanol.
  • the combined organic fractions were washed with brine, dried over Na2S04 and the solvents removed under vacuum to yield ethyl 4-morpholinobutanoate (230mg, 1 .14mmol, 38% yield) as a yellow oil.
  • Zinc powder (466mg, 7.14mmol) was suspended in dry THF (25ml_) before evacuating and back filling the flask with nitrogen.
  • fe/f-Butyl bromoacetate (0.95ml_, 6.43mmol) was then added followed by diisobutylaluminium hydride (1 M in toluene) (0.12ml_, 0.71 mmol) which was added dropwise.
  • the mixture was heated to 40 °C and stirred at this temperature for 2 hours. During this time the mixture had turned from a suspension to a grey solution. The solution was allowed to cool.
  • the compound was purified via column chromatography using an eluent of 0-75% EtOAc in petroleum ether to yield 5-bromo-1 -methyl-pyrrolo[2,3-b]pyridine (1 .00mg, 4.76mmol, 47% yield) as a yellow solid.
  • Zinc Powder (619mg, 9.48mmol) and a stirrer bar was added to a dry 3-neck flask and the flask sealed and flushed with nitrogen. The powder was then suspended in dry THF (20ml_), the suspension stirred and fe/ -butyl bromoacetate (1 .26ml_, 8.53mmol) added to the vessel.
  • Zinc Powder (519mg, 7.93mmol) and a stirrer bar were added to a dry 3-neck flask and the flask sealed and flushed with nitrogen. The powder was then suspended in dry THF (20ml_), the suspension stirred and fe/ -butyl bromoacetate (1 .05ml_, 7.14mmol) added to the vessel.
  • LiHMDS 1 M in toluene (15.96ml_, 15.96mmol) was added to a stirred solution of 5-bromo- 2-methoxy-pyridine (0.69ml_, 5.32mmol), fe/f-butyl acetate (1 .08ml_, 7.98mmol) and chloro[2-(di- fe/?-butylphosphino)-2',4',6'-triisopropyl-1 ,1 '-biphenyl][2-(2-aminoethyl)phenyl)]palladium(ll) (36mg, 0.05mmol) in toluene (3ml_) under nitrogen.
  • LiHMDS 1 M in toluene (8.26mL, 8.26mmol) was added to a stirred solution of 4-chloro-2- trifluoromethylpyridine (500mg, 2.75mmol), fe f-butyl acetate (0.56mL, 4.13mmol) and fBuXPhos Pd G1 (19mg, 0.03mmol) in toluene (3mL) in a 3 neck flask evacuated/backfilled with N2 held at 0 °C. The reaction mixture was allowed to stir for 16 hours at 0 °C. Sat. aq. NH4CI (6mL) was then added and the reaction mixture was extracted in EtOAc (3 x 15mL).
  • Ethyl 2-(1 ,3-benzothiazol-2-yl)acetate (627 ⁇ _, 3.07mmol) was dissolved in EtOH (8ml_) and water (58 ⁇ _, 3.23mmol) and heated to 60 °C. A solution of sodium fe/ -butoxide (295mg, 3.07mmol) in EtOH (2ml_) was then added dropwise and the reaction was stirred at 60 °C overnight. The EtOH was removed in vacuo and the resulting residue triturated with ⁇ 0 and dried in the vac oven to yield sodium 2-(1 ,3-benzothiazol-2-yl)acetate (412mg, 1 .91 mmol, 62% yield) as a yellow powder.
  • a flask containing benzyl 2-(3-oxo-1 ,4-benzoxazin-4-yl)acetate (270mg, 0.91 mmol) in EtOAc (5ml_) was degassed with nitrogen before the addition of palladium, 10 wt. % on carbon powder, wet support (19mg, 0.18mmol).
  • the reaction mixture was hydrogenated overnight while heating at 50 °C.
  • the reaction mixture was left to cool to room temperature before being degassed with nitrogen and filtered through celite.
  • the filter cake was washed with EtOAc (200ml_) and MeOH (50ml_).
  • Tris(dibenzylideneacetone)dipalladium(0) (77mg, 0.08mmol), 4,5-bis(diphenylphosphino)- 9,9-dimethylxanthene (65mg, 0.1 1 mmol), 3-(4-bromophenyl)oxetan-3-ol (319mg, 1 .39mmol), caesium carbonate (1 .36g, 4.18mmol), 1 ,4-Dioxane (7ml_) and benzophenone imine (0.28ml_, 1 .67mmol) were combined in a round bottomed flask.
  • Phosphoric acid 85 wt-%, 4ml_, 68.78mmol was added to a suspension of 2-[4-bromo-2- (hydroxymethyl)phenyl]propan-2-ol (906mg, 3.7mmol) in toluene (12ml_) and the mixture was heated at 80 °C for 3 hours. The mixture was cooled to room temperature and diluted with water. The two layers were separated and the aqueous layer neutralized with 1 M NaOH and then extracted with EtOAc (2 x 20ml_).
  • the flask was evacuated/backfilled with nitrogen and the mixture was heated at 100 °C overnight. The mixture was then cooled to room temperature and filtered through a plug of celite and the solid was washed with EtOAc. The filtrate was concentrated in vacuo and the residue purified by flash

Abstract

La présente invention concerne de nouveaux composés et des compositions pharmaceutiques comprenant les nouveaux composés. Plus particulièrement, l'invention concerne des composés utiles en tant que modulateurs du récepteur du facteur 1 de stimulation des colonies (cFMS) des modulateurs (par exemple des inhibiteurs de cFMS). L'invention porte également sur des procédés pour préparer les composés, des utilisations des composés dans le traitement et des procédés de traitement utilisant les composés. En particulier, l'invention concerne l'utilisation des composés pour le traitement du cancer et de maladies auto-immunes.
PCT/GB2015/052884 2014-10-03 2015-10-02 Composés utiles en tant que modulateurs du facteur 1 de stimulation de colonies WO2016051193A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB1417561.6 2014-10-03
GBGB1417561.6A GB201417561D0 (en) 2014-10-03 2014-10-03 Compounds

Publications (1)

Publication Number Publication Date
WO2016051193A1 true WO2016051193A1 (fr) 2016-04-07

Family

ID=51946845

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2015/052884 WO2016051193A1 (fr) 2014-10-03 2015-10-02 Composés utiles en tant que modulateurs du facteur 1 de stimulation de colonies

Country Status (2)

Country Link
GB (1) GB201417561D0 (fr)
WO (1) WO2016051193A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018130437A1 (fr) 2017-01-10 2018-07-19 Bayer Aktiengesellschaft Dérivés hétérocycliques utilisés comme pesticides
WO2018130443A1 (fr) 2017-01-10 2018-07-19 Bayer Aktiengesellschaft Dérivés hétérocycliques utilisés comme pesticides
WO2019053182A1 (fr) 2017-09-18 2019-03-21 Syngenta Participations Ag Dérivés hétérocycliques à activité pesticide comportant des substituants contenant du soufre
CN109503473A (zh) * 2019-01-07 2019-03-22 上海慧川生物医药科技有限公司 2-甲氧基-3-氨基-5-吡啶硼酸频哪醇酯及其中间体的合成方法
GB2568549A (en) * 2017-11-21 2019-05-22 Univ Leicester New compounds and uses
WO2020038755A1 (fr) * 2018-08-21 2020-02-27 Huntsman International Llc Catalyseur pour la production de mousse pir/pur
US11084825B2 (en) 2018-12-31 2021-08-10 Biomea Fusion, Llc Substituted pyridines as irreversible inhibitors of menin-MLL interaction
US11174263B2 (en) 2018-12-31 2021-11-16 Biomea Fusion, Inc. Inhibitors of menin-MLL interaction
WO2023137307A1 (fr) * 2022-01-14 2023-07-20 Enko Chem, Inc. Inhibiteurs de la protoporphyrinogène oxydase

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012135937A1 (fr) * 2011-04-04 2012-10-11 Pharmascience Inc. Inhibiteurs de protéine kinase

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012135937A1 (fr) * 2011-04-04 2012-10-11 Pharmascience Inc. Inhibiteurs de protéine kinase

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018130443A1 (fr) 2017-01-10 2018-07-19 Bayer Aktiengesellschaft Dérivés hétérocycliques utilisés comme pesticides
WO2018130437A1 (fr) 2017-01-10 2018-07-19 Bayer Aktiengesellschaft Dérivés hétérocycliques utilisés comme pesticides
WO2019053182A1 (fr) 2017-09-18 2019-03-21 Syngenta Participations Ag Dérivés hétérocycliques à activité pesticide comportant des substituants contenant du soufre
GB2568549A (en) * 2017-11-21 2019-05-22 Univ Leicester New compounds and uses
WO2020038755A1 (fr) * 2018-08-21 2020-02-27 Huntsman International Llc Catalyseur pour la production de mousse pir/pur
CN112805312A (zh) * 2018-08-21 2021-05-14 亨茨曼国际有限公司 用于pir/pur泡沫生产的催化剂
US11702421B2 (en) 2018-12-31 2023-07-18 Biomea Fusion, Llc Substituted pyridines as irreversible inhibitors of menin-MLL interaction
US11845753B2 (en) 2018-12-31 2023-12-19 Biomea Fusion, Inc. Inhibitors of menin-mll interaction
US11084825B2 (en) 2018-12-31 2021-08-10 Biomea Fusion, Llc Substituted pyridines as irreversible inhibitors of menin-MLL interaction
US11174263B2 (en) 2018-12-31 2021-11-16 Biomea Fusion, Inc. Inhibitors of menin-MLL interaction
CN109503473A (zh) * 2019-01-07 2019-03-22 上海慧川生物医药科技有限公司 2-甲氧基-3-氨基-5-吡啶硼酸频哪醇酯及其中间体的合成方法
CN109503473B (zh) * 2019-01-07 2020-07-07 上海慧川生物医药科技有限公司 2-甲氧基-3-氨基-5-吡啶硼酸频哪醇酯及其中间体的合成方法
WO2023137307A1 (fr) * 2022-01-14 2023-07-20 Enko Chem, Inc. Inhibiteurs de la protoporphyrinogène oxydase

Also Published As

Publication number Publication date
GB201417561D0 (en) 2014-11-19

Similar Documents

Publication Publication Date Title
JP6482629B2 (ja) Ｔｒｋａキナーゼ阻害剤としてのｎ−ピロリジニル、ｎ’−ピラゾリル尿素、チオ尿素、グアニジン、およびシアノグアニジン化合物
WO2016051193A1 (fr) Composés utiles en tant que modulateurs du facteur 1 de stimulation de colonies
CN108431007B (zh) 用于治疗癌症的作为btk抑制剂的吡唑并嘧啶衍生物
US20200138827A1 (en) Small molecule modulators of human sting
US11643408B2 (en) N-pyridinyl acetamide derivatives as inhibitors of the WNT signaling pathway
US20200172483A1 (en) Heterocyclic small molecule modulators of human sting
ES2649144T3 (es) Compuestos heteroaromáticos y su uso como ligandos de dopamina D1
JP2022120013A (ja) キナーゼ阻害剤として有用な化合物
JP2021193099A (ja) 置換４−アザインドール及びｇｌｕｎ２ｂ受容体調節因子としてのそれらの使用
USRE49361E1 (en) Fused bicyclic (hetero)aromatic compounds useful for the treatment of cancers
CN111655681A (zh) 杂环基氨基取代的三唑类化合物作为Rho相关蛋白激酶的调节剂
US9163021B2 (en) Pyrrolo[3,2-c]pyridine tropomyosin-related kinase inhibitors
EP4188552A2 (fr) Inhibiteurs de raf bicycliques fusionnés et leurs procédés d'utilisation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15782022

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15782022

Country of ref document: EP

Kind code of ref document: A1