WO2008004948A1 - 8-oxoadenine derivatives acting as modulators of tlr7 - Google Patents

8-oxoadenine derivatives acting as modulators of tlr7 Download PDF

Info

Publication number
WO2008004948A1
WO2008004948A1 PCT/SE2007/000651 SE2007000651W WO2008004948A1 WO 2008004948 A1 WO2008004948 A1 WO 2008004948A1 SE 2007000651 W SE2007000651 W SE 2007000651W WO 2008004948 A1 WO2008004948 A1 WO 2008004948A1
Authority
WO
WIPO (PCT)
Prior art keywords
amino
methyl
oxo
butoxy
phenyl
Prior art date
Application number
PCT/SE2007/000651
Other languages
French (fr)
Inventor
Anthony Cook
Tom Mcinally
Stephen Thom
Hiroki Wada
Original Assignee
Astrazeneca Ab
Dainippon Sumitomo Pharma Co., Ltd
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 Astrazeneca Ab, Dainippon Sumitomo Pharma Co., Ltd filed Critical Astrazeneca Ab
Priority to JP2009518052A priority Critical patent/JP2009542645A/en
Priority to EP07748310A priority patent/EP2041135A4/en
Priority to US12/305,801 priority patent/US8138172B2/en
Publication of WO2008004948A1 publication Critical patent/WO2008004948A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/08—Antibacterial agents for leprosy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention provides 8-oxoadenine derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy. The 8-oxoadenine derivatives act as modulators of Toll-like Receptor (TLR) 7 and thus may be used in the treatment of asthma, hepatitis, allergic diseases, viral and bacterial infection as well as cancer.

Description

υ o ~\yι- LWi i
NOVEL COMPOUNDS M \ S
The present invention relates to adenine derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
The immune system is comprised of innate and acquired immunity, both of which work cooperatively to protect the host from microbial infections. It has been shown that innate immunity can recognize conserved pathogen-associated molecular patterns through toll-like receptors (TLRs) expressed on the cell surface of immune cells. Recognition of invading pathogens then triggers cytokine production (including interferon alpha(IFNα)) and upregulation of co-stimulatory molecules on phagocytes, leading to modulation of T cell function. Thus, innate immunity is closely linked to acquired immunity and can influence the development and regulation of an acquired response.
TLRs are a family of type I transmembrane receptors characterized by an NH2-terminal extracellular leucine-rich repeat domain (LRR) and a COOH-terminal intracellular tail containing a conserved region called the Toll/IL-1 receptor (TIR) homology domain. The extracellular domain contains a varying number of LRR, which are thought to be involved in ligand binding. Eleven TLRs have been described to date in humans and mice. They differ from each other in ligand specificities, expression patterns, and in the target genes they can induce.
Ligands which act via TLRs (also known as immune response modifiers (IRMS)) have been developed, for example, the imidazoquinoline derivatives described in US Patent No. 4689338 which include the product Imiquimod for treating genital warts, and the adenine derivatives described in WO 98/01448 and WO 99/28321.
This patent application describes a class of 9-substituted-8-oxoadenine compounds having immuno-modulating properties which act via TLR7 that are useful in the treatment of viral or allergic diseases and cancers. In accordance with the present invention, there is therefore provided a compound of formula (I)
wherein
Figure imgf000003_0001
.1 R represents hydrogen, hydroxyl, or a Cj-Cg alkoxy, C2-C5 alkoxycarbonyl,
Cj-Cg haloalkyl, Cj-Cg haloalkoxy, Cg-Cjo aryl, C5-C10 heteroaryl or Cβ-Cg cycloalkyl group, each group being optionally substituted by one or more substiruents independently selected from halogen, hydroxyl, a Cj-Cg alkyl, Cj-Cg haloalkyl, Cj-Cg alkoxy,
Cj-Cg haloalkoxy, C2-C5 alkoxycarbonyl, amino (NH2), (mono)- Cj-Cg alkylamino and (di)-Cj-Cg alkylamino group;
Y represents a single bond or Cj-Cg alkylene;
X represents a single bond, an oxygen, sulphur atom, sulphonyl (S O2) or NR ;
Z represents a C2-Cg alkylene or C3-C8 cycloalkylene group, each group being optionally substituted by at least one hydroxyl;
2 4 X represents NR ;
Y represents a single bond or Cj-Cg alkylene;
3
Y represents a single bond or Cj-Cg alkylene; n is an integer 0, 1 or 2;
R represents halogen or a Cj-Cg alkyl, Cj-Cg hydroxyalkyl, Cj-Cg haloalkyl, Cj-Cg alkoxy, Cj-Cg hydroxyalkoxy, Cj-Cg haloalkoxy, amino (NH2), (mono)- Cj-Cβ alkylamino, (di)-Cj-Cg alkylamino group or a C3-C§ saturated heterocyclic ring comprising a ring nitrogen atom and optionally one or more further heteroatoms independently selected from nitrogen, oxygen and sulphur, the heterocyclic ring being optionally substituted by one or more substituents independently selected from halogen, hydroxy 1, oxo, CJ-CO alkyl, Cj-Cg alkoxy, C2-C5 alkylcarbonyl and C2-C5 alkoxycarbonyl;
2 R represents hydrogen or a Cj-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl or
C3-Cg cycloalkyl group, each group being optionally substituted by one or more substituents independently selected from halogen, hydroxyl or a Cj-Cg alkoxy, C2-CJ0 acyloxy, amino
(NH2), (mono)- Cj-Cg alkylamino, (di)-Cj-Cg alkylamino group and a C3-C8 saturated heterocyclic ring comprising a ring nitrogen atom and optionally one or more further heteroatoms independently selected from nitrogen, oxygen and sulphur, the heterocyclic ring in turn being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, oxo, Cj-Cg alkyl, Cj-Cg alkoxy, C2-C5 alkylcarbonyl and C2-C5 alkoxycarbonyl group;
3 R represents hydrogen or Cj-Cg alkyl;
R4 represents CO2R5, SO2R5, COR5, SO2NR6R7 and CONR6R7;
R independently represents
(i) a 3- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms comprising ring group NR , S(0)m or oxygen, each ring may being optionally substituted by one or more substituents independently selected from halogen, hydroxyl or a Cj-Cg alkyl and Cj-Cg alkoxy group, or
(ii) a Cg-Cjo aryl or C5-CJ0 heteroaryl group, each of which may be optionally substituted by one or more substituents independently selected from halogen, cyano, Cj-Cg alkyl, C1-C3 haloalkyl, carboxyl, S(O)1nR9, OR10, CO2R10, SO2NR10R1^ CONR10R11, NR10R11, NR10SO2R9, NR10CO2R9, NR10COR9, or (iii) a Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl or C3-C8 cycloalkyl group, each of which may be optionally substituted by one or more substituents independently selected from halogen, CN, C3-C8 cycloalkyl, S(O)pR12, OR13, COR13, CO2R13, SO2NR13R14, i ς Λ Λ Λ 'l 14 I Q T 9 I Q 1 9 Λ 7. 1 9 I 'l 19
CONR R , M R , NR SO2R , NR CO2R , NR COR , NR SO2R or a Cg-Cio aryl or C5-C10 heteroaryl group or a heterocyclic ring, the latter three groups may be optionally substituted by one or more substituents independently selected from Ci-Cg alkyl (optionally substituted by hydroxy, Ci-Cg alkoxy, Ci-Cg alkoxycarbonyl, amino, Ci-Cg alkylamino, di-Ci-Cg alkylamino, amido, Ci-Cg alkylamido, di-Ci-Cg alkylamido, -OCH2CH2OH, pyrrolidinyl, pyrrolidinylcarbonyl, furanyl, piperidyl, methylpiperidyl or phenyl), Ci-Cg alkenyl (optionally substituted by phenyl), halogen, hydroxy, cyano, carboxy, amino, Ci-Cg alkylamino, di-Ci-Cg alkylamino, amido, Ci-Cg alkylamido, di-Ci-Cg alkylamido, Ci-Cg alkoxycarbonyl,
Ci-Cg alkylsulphonyl, Ci-Cg alkylcarbonylamino, Ci-Cg alkylcarbonylmethylamino, phenyl (optionally substituted by hydroxy, fluoro or methyl), pyrrolidinyl, pyridyl, piperidinyl, benzothiazolyl or pyrimidinyl;
R represents hydrogen or a Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, C3-Cg cycloalkyl group or heterocyclic ring, each of which may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, oxo, cyano, Ci-Cg alkyl,
C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, OR15, S(O)qR15, CO2R16, COR16, NR16R17, CONR16R17, NR16COR17, NR16CO2R15, SO2NR16R17, NR16SO2R15, or a Cg-Cio aryl or C5-C10 heteroaryl group or heterocyclic ring, the latter three groups being optionally substituted by one or more substituents independently selected from, Ci-Cg alkyl,
C3-C8 cycloalkyl, halogen, S(O)qR , CO2R , COR , hydroxy or cyano; and
7 R represents hydrogen, a Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, or C3-C8 cycloalkyl group, each group may be optionally substituted by one or more substituents independently selected from halogen, C3-C8 cycloalkyl, a C6-Ci0 aryl or C5- Cio heteroaryl group, carboxy, cyano, OR , hydroxy or NR R , or
R and R together with the nitrogen atom to which they are attached form a 3- to 8- membered saturated or partially saturated heterocyclic ring, optionally containing further heteroatoms or heterogroups selected from nitrogen, S(O)m or oxygen. The heterocyclic ring, may be optionally substituted by one or more substituents independently selected from
90 91 99 93 94 94 halogen, hydroxy., carboxyl, cyano, OR , NR R 1 S(O)qR , COR , CO2R ,
94 95 94 95 94 93
NR/4R , CONR R ,
Figure imgf000006_0001
NR SO2R , C6-C10 aryl , C5-C10 heteroaryl group, heterocyclic ring, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-Cg cycloalkyl group, the latter seven groups being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, oxo,
90 93 94 94 94 95 94 95 94 93 cyano, OR , S(O)qR , COR , CO2R , NR R , CONR R , NR CO2R ,
24 25 24 25 24 93
NR COR , SO2NR R , NR SO2R , a heterocyclic ring or a C6-Ci0 aryl or C5-Ci0 heteroaryl group, the latter three groups being optionally substituted by one or more substituents independently selected from Ci-C6 alkyl, halogen, hydroxy or cyano;
R8 represents hydrogen, CO2R26, COR26, SO2R26, Ci-C6 alkyl or C3-C6 cycloalkyl group, each group may be optionally substituted by one or more substituents independently
97 9R selected from halogen, hydroxyl, and NR R ;
„ 10 ,, 11 Ώ 16 ,, 17 ^ 18 _, 19 -.21 Ώ22 ,,26 „27 „28 „29 „30 , . , , .. R , R , R , R , R , R , R , R , R , R , R , R or R each independently represents hydrogen, and a Ci-C6 alkyl or C3-C6 cycloalkyl group;
24 25
R and R each independently represents hydrogen, and a Ci-C6 alkyl or
C3-C6 cycloalkyl group; or
24 25
R and R together with the nitrogen atom to which they are attached form a 3- to 8- membered saturated or partially saturated heterocyclic ring, optionally containing further heteroatoms or heterogroups selected from nitrogen, S(0)m or oxygen; 9 12 15 23
R 5 R , R and R represent Ci-Cg alkyl or C3-C6 cycloalkyl;
R and R are defined as for R and R respectively;
20 R represents a Ci-Cg alkyl optionally substituted by one or more substituents
23 independently selected from halogen, hydroxyl or OR ; m, p, q and r each independently represent an integer 0, 1 or 2; and
A represents a Cg-Cjo aryl or C5-C12 heteroaryl group; or a pharmaceutically acceptable salt thereof.
In the context of the present specification, unless otherwise stated, an alkyl substituent group or an alkyl moiety in a substituent group may be linear or branched. Examples of C^ -Cg alkyl groups/moieties include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl. Similarly, an alkylene group/moiety may be linear or branched.
Examples of Ci-Cg alkylene groups/moieties include methylene, ethylene, n-propylene, n- butylene, n-pentylene, n-hexylene, 1-methylethylene, 2-methylethylene, 1,2- dimethylethylene, 1-ethylethylene, 2-ethylethylene, 1-, 2- or 3-methylpropylene and 1-, 2- or
3-ethylpropylene. A Ci-Cg haloalkyl or Ci-Cg haloalkoxy substituent group/moiety will comprise at least one halogen atom, e.g. one, two, three, four or five halogen atoms, examples of which include trifluoromethyl, trifluoromethoxy or pentafluoroethyl. The alkyl groups in a di-Ci-Cg alkylamino group/moiety may be the same as, or different from, one another. A Ci- Cg hydroxyalkyl or Ci-Cg hydroxyalkoxy substituent group/moiety will comprise at least one hydroxyl group, e.g. one, two or three hydroxyl groups. An aryl or heteroaryl substituent group/moiety may be monocyclic or polycyclic (e.g. bicyclic or tricyclic) in which the two or more rings are fused. A heteroaryl group/moiety will comprise at least one ring heteroatom (e.g. one, two, three or four ring heteroatoms independently) selected from nitrogen, oxygen and sulphur. Examples of aryl and heteroaryl groups/moieties include phenyl, 1-naphthyl, 2- naphthyl, furyl, thienyl, pyrrolyl, pyridyl, indolyl, isoindolyl, quinolyl, isoquinolyl, pyrazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl and oxazolyl. A heterocyclic ring is defined as a saturated or partially saturated 3-8 membered ring containing at least one hetero atom or group selected from nitrogen, sulphur, SO, SO2 or oxygen. The ring may be fused with a Cg-Cio aryl or C5-C12 heteroaryl group. Examples include morpholine, azetidine, pyrrolidine, piperidine, piperazine, 3-pyrroline, isoindoline, tetrahydroquinoline and thiomoφholine.
A C2-C10 acyloxy group/moiety is exemplified by a C2-C5 alkylcarbonyloxy group, a C2-C5 alkenylcarbonyloxy group, a C2-C5 alkynylcarbonyloxy group, a C6-C9 arylcarbonyloxy group or a C5-C9 heteroarylcarbonyloxy group, each of which may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, C1-C3 alkoxy or phenyl providing that the total number of carbon atoms in the acyloxy group does not exceed 10.
Preferably X represents oxygen.
Preferably Y represents Cj-Cg alkylene and R represents hydrogen
Preferably Z represents C2-Cg alkylene, more preferably (CH2)3.
2 Preferably Y represents C]-Cg alkylene, more preferably a CH2 group.
Preferably A represents a Cg-C 10 aryl, more preferably phenyl.
Preferably Y represents Ci-Cg alkylene, more preferably CH2.
2 Preferably R represents Ci-Cg alkyl more preferably methyl.
Preferably R represents SO2R5 or COR5. Examples of compounds of the invention include:
Methyl [4-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9Hr-purm-9-yl)propyl][(4- methylpiperazin-l-yl)acetyl]amino}methyl)phenyl]acetate, Methyl (4-{[[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)proρyl](N,N- dimethylglycyl)amino]methyl}phenyl)acetate,
Methyl [4-( { [3 -(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl] [(I - methylpiperidin-4-yl)carbonyl]amino}methyl)phenyl]acetate,
Methyl [4-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][4- (dimethylamino)butanoyl]amino}methyl)phenyl]acetate,
Methyl (4-{[[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)proρyl](N;^V-dimethyl- β-alanyl)amino]methyl}phenyl)acetate,
Methyl [4-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-ρurin-9-yl)propyl][N^V-bis(2- hydroxyethyl)glycyl]amino}methyl)phenyl]acetate, Methyl {4-[([3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-ρurin-9-yl)proρyl] {[4-(2- hydroxyethyl)piperazin- 1 -yl] acetyl} amino)methyl]phenyl} acetate,
Methyl {4-[([3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]{[4-
(methylsulfonyl)piperazin- 1 -yl]acetyl} amino)methyl]phenyl} acetate,
Methyl [3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)proρyl][(l- methylpiperidin-4-yl)carbonyl]amino}methyl)phenyl]acetate,
Methyl [3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)proρyl][(l- methylpiperidin-4-yl)carbonyl]amino}methyl)phenyl]acetate,
Methyl (3- {[[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9- yl)propyl](glycyl)amino]methyl}phenyl)acetate, Methyl [3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9- yl)propyl][(methylthio)acetyl]amino}methyl)phenyl]acetate,
Methyl [3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9- yl)propyl][(methylsulfinyl)acetyl]amino}methyl)phenyl]acetate,
Methyl [3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9- yl)propyl][(methylsulfonyl)acetyl]amino}methyl)phenyl]acetate,
Methyl [3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H"-purin-9-yl)propyl][3-
(methylthio)propanoyl] amino } methyl)phenyl] acetate, Methyl [3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-
(methylsulfonyl)propanoyl]amino}methyl)phenyl]acetate,
Methyl [3-({[3-(6-ammo-2-butoxy-8-oxo-758-dihydro-9H-purin-9-yl)propyl][N-
(methylsulfonyl)glycyl]amino}methyl)phenyl]acetate, tert-Butyl 4- {[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-ρurin-9-yl)propyl][3-(2-methoxy-
2-oxoethyl)benzyl] amino } -4-oxobutanoate,
4-{[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)ρropyl][3-(2-methoxy-2- oxoethyl)ben2yl]amino} -4-oxobutanoic acid,
Methyl 3-{[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(2-methoxy-2- oxoethyl)benzyl]amino}-3-oxopropanoate,
Methyl [3-({acetyl[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9- yl)propyl]amino}methyl)phenyl]acetate,
Methyl (3- {[[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-ρurin-9- yl)propyl](methylsulfonyl)amino]methyl}phenyl)acetate, (4-{[[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-purin-9-yl)[2R]-propyl]-(pyrrolidine-2- carbonyl)-amino]-methyl}-phenyl)-acetic acid methyl ester,
(4- { [[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-ρurin-9-yl)-ρropyl] [2S,4R](4-hydroxy- pyrrolidine^-carbony^-aminoj-methylj-pheny^-acetic acid methyl ester,
(4-{[[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-purin-9-yl)-ρropyl][2S]-(l-methyl- pyrrolidine-2-carbonyl)-amino]-methyl}-phenyl)-acetic acid methyl ester,
(4-{[[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-purin-9-yl)-propyl]-(3-piperazin-l-yl- propionyl)-amino]-methyl}-phenyl)-acetic acid methyl ester,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7Η-ρurin-9-yl)propyl-[2-[4-[3-(l- piperidyl)propyl]piperazin-l-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[3-(diethylcarbamoyl)-l- piperidyl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-phenyl-l- piperidyl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(2-oxo-2-pyrrolidin-l- y l-ethyl)piperazin- 1 -yl] acetyl] amino]methyl]phenyl] acetate, Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(l- piperidyl)acetyl]amino]methyl]phenyl]acetate,
Ethyl 4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)proρyl-[[4-
(methoxycarbonylmethy^phenyljmethyljcarbamoyymethyypiperazine-l-carboxylate,
2- [[3 -(6-Amino-2-butoxy- 8-oxo-7H-purin-9-yl)propyl- [[4- (methoxycarbonylmethyl)phenyl]methyl]carbamoyl]methyl-(2-cyanoethyl)amino]acetic acid,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(ben2yl-(2- dimethylaminoethyl)amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-carbamoyl-l- piperidyl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)ρropyl-[2-[(3R)-3- hydroxypyrrolidin- 1 -yl] acetyl] amino]methyl]phenyl] acetate, tert-Butyl (2S)-l-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[[4- (methoxycarbonylmethy^phenyymethy^carbamoy^methyljpyrrolidine^-carboxylate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(2-cyanoethyl-(oxolan-2- ylmethyl)amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(ethyl-(pyridin-4- ylmethyl)amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-ethylpiperazin-l- yl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-ρurin-9-yl)propyl-[2-(methyl-(2-pyridin-4- ylethyl)amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-pyrrolidin-l-yl-l- piperidyl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)ρropyl-[2-[(2S)-2- carbamoylpyrrolidin- 1 -yl] acetyl] amino]methyl]phenyl] acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(3,6-dihydro-2H-pyridin- l-yl)acetyl]amino]methyl]phenyl]acetate, Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-ρurin-9-yl)proρyl-[2-(ethyl-(2- hydroxyethyl)amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)ρropyl-[2-(cyclohexyl-(2- hydroxyethyl)amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(hydroxymethyl)-l- piperidy 1] acetyl] amino]methyl]phenyl] acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(2- aminoethyl)piperazin-l-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(2-hydroxyethyl)-l- piperidyl] acetyl] amino]methyl]phenyl] acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[methyl-(l-methyl-4- piperidyl)amino]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-ben2yl-4-hydroxy- 1 - piperidyl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-cinnamylpiperazin-l- yl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-ρurin-9-yl)ρropyl-[2-[4-[2-(2- hydroxyethoxy)ethyl]piperazin-l-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(3-dimethylaminopropyl- methyl-amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-ρurin-9-yl)ρropyl-[2- (dimethylcarbamoylmethyl-methyl-amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)ρropyl-[2-[(2R)-2- carbamoylpyrrolidin- 1 -y 1] acetyl] amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-ρurin-9-yl)propyl-[2-[(2S,6R)-2,6- dimethylmorpholin-4-yl]acetyl]aniino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-methyl-l,4-diazepan- 1 -yl)acetyl] amino]niethy l]phenyl] acetate, Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-puxin-9-yl)ρropyl-(2-morpholin-4- ylacetyl)amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-ρurin-9-yl)ρropyl-[2-[4-(3- hydroxyphenyl)piperazin- 1 -yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[[2-[3-(acetyl-methyl-amino)pyrrolidin-l-yl]acetyl]-[3-(6-amino-2-butoxy-8- oxo-7H-purin-9-yl)propyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-ρurin-9-yl)ρropyl-[2-[(3S)-3- dimethylaminopyrrolidin- 1 -yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-pyridin-4-ylpiperazin- 1 -yl)acetyl] amino]methyl]phenyl] acetate
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-ρurin-9-yl)propyl-[2-[4-(3- dimethylaminopropyl)piperazin-l-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2- [4- [ [3 -(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl- [2-(4-propan-2-ylpiperazin- l-yl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4- (dimethylcarbamoylmethy^piperazin-l-y^acety^aminojmethy^phenyljacetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(2-hydroxy-2-phenyl- ethyl)-methyl-amino]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(aminomethyl)-l- piperidyl] acetyl] amino]methyl]phenyl] acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(methyl-(2- methylaminoethyl)amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-(2-thiomorpholin-4- ylacetyl)amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-phenylpiperazin-l- yl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(l,3-dihydroisoindol-2- yl)acetyl]amino]methyl]phenyl]acetate, Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-(2-piperazin-l- ylacetyl)amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(l-piperidyl)-l- piperidyl] acetyl] amino]methyl]phenyl] acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-pyridin-2-ylpiperazin- 1 -yl)acetyl] amino]methyl]phenyl] acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-hydroxy-l- piperidyl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-ρurin-9-yl)ρropyl-[2-[4-(4- fluorophenyl)piperazin-l-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-methyl-l- piperidyl)acetyl] amino]methyl]phenyl] acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(2,5-dihydropyrrol-l- yl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-benzothiazol-2- ylpiperazin-l-yl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-ρurin-9-yl)propyl-[2-[4- (ethoxycarbonylmethy^-l-piperidyllacetyljaminojmethy^pheny^acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(2- dimethylaminoethyl)piperazin- 1 -yl] acetyl] amino]methyl]phenyl] acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-ρurin-9-yl)ρropyl-[2-[4-(2- methylphenyl)piperazin-l-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-ethylsulfonylpiperazin- l-yl)acetyl]amino]methyl]phenyl]acetate,
(2S,4R)-l-[[3-(6-Amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[[4- (methoxycarbonylmethyl)phenyl]methyl]carbamoyl]methyl]-4-hydroxy-pyrrolidine-2- carboxylic acid, (2S)-2-[[3-(6-Amino-2-butoxy-8-oxo-7H-ρurin-9-yl)proρyl-[[4- (methoxycarbonylmethyl)phenyl]methyl] carbamoyljmethyl-methyl-amino] -3 -phenyl- propanoic acid,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(2S)-2- (hy droxymethyl)pyrrolidin- 1 -yl] acetyl] amino]methyl]phenyl] acetate,
3-[[3-(6-Amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[[4- (methoxycarbonylmethyl)phenyl]methyl]carbamoyl]methyl-(l , 1 -dioxothiolan-3- yl)amino]propanoic acid,
3-[[3-(6-Amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[[4-
(methoxycarbonylmethyl)phenyl]methyl]carbamoyl]methyl-cyclohexyl-amino]propanoic acid,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-ρurin-9-yl)propyl-[2-(ethyl-(2- ethylaminoethyl)amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(ethyl-(3- ethylaminopropyl)amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(3,4-dihydro-lH- isoquinolin-2-yl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-ρurin-9-yl)ρropyl-[2-[(2S)-2-(ρyrrolidin-l- ylmethyl)pyrrolidin- 1 -yl] acetyl] amino]methyl]phenyl] acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-[(l-methyl-4- piperidyl)methyl]piperazin-l-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(methyl-prop-2-ynyl- amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(l-methyl-4-piperidyl)- phenethyl-amino]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(oxolan-2- ylmethyl)piperazin- 1 -yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(3R)-3-aminopyrrolidin- l-yl]acetyl]amino]methyl]phenyl]acetate, tert-Butyl (2R)-l-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[[4- (methoxycarbonylmethy^phenyymethyljcarbamoyljmethyypyrrolidine^-carboxylate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-pyrimidin-2- ylpiperazin-l-yl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-(2-pyrrolidin-l- ylacetyl)amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-p\jrin-9-yl)propyl-[2-[(2S)-2-
(methoxymethyl)pyrrolidin-l-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(2R)-2- (methoxymethyl)pyrrolidin-l-yl]acetyl]amino]methyl]phenyl]acetate,
and pharmaceutically acceptable salts thereof. c
The present invention further provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above which comprises,
4 5
(a) when R represents COR , reacting a compound of formula (II)
Figure imgf000016_0001
wherein n, A, Y1, Y2, Y3, X1, Z1, R, R and R are as defined in formula (I), with a compound of formula (III), wherein R is as defined in formula (I), using an appropriate coupling reagent (for example, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC) or O-(7- azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU)), in the presence of a base such as diisopropyl ethylamine, triethylamine or pyridine in an organic solvent (for example dimethylformamide, dichloromethane or acetonitrile) at a temperature in the range, for example, from 0 to 150°C [alternatively, the acid (III) may be activated by formation of an acid halide using a halogenating reagent such as oxalyl chloride or thionyl chloride; the acid chloride may then be reacted with a compound of formula (II) in the presense of a base such as diisopropyl ethylamine, triethylamine or pyridine in an organic solvent (for example dimethylformamide, dichloromethane or acetonitrile) at a temperature in the range, for example, from 0 to 1500C];
4 5 5 13 14
(b) when R represents COR and R represents Ci-Cg alkyl substituted by NR R , reacting a compound of formula (IV)
Figure imgf000017_0001
wherein L2 represents a leaving group such as a halogen, mesylate or triflate, t is an integer from 1 to 6, and n, A, Y1, Y2, Y3, X1, Z1, R, R1 and R2 are as defined in formula (I), with a compound of formula
13
H-N 14
(V)
wherein R13 and R14 are as defined in formula (I) [the reaction may be carried out in the presense of a base (for example diisopropyl ethylamine, triethylamine or pyridine) in an organic solvent such as dimethylformamide, dimethylsulphoxide or acetonitrile at a temperature, for example, in the range from 0 to 15O0C]; 4 5
(c) when R represents a group SO2R , reacting a compound of formula (II) as defined in (a)
3 5 3 above with a compound of formula (VI), L -S(O)2~R , wherein L represents a leaving group (e.g. halogen) and R is as defined in formula (I), in the presence of a base;
4 5
(d) when R represents a group CO2R , reacting a compound of formula (II) as defined in (a)
4 5 4 above with a compound of formula (VII), L -C(O)-OR , wherein L represents a leaving group (e.g. halogen) and R is as defined in formula (I), in the presence of a base;
4 6 7 (e) when R represents a group SO2NR R , reacting a compound of formula (II) as defined in (a) above with a compound of formula (VIII), L -S(O)2-NR R , wherein L represents a leaving group (e.g. halogen) and R and R are as defined in formula (I), in the presence of a base;
or
4 6 7
(f) when R represents a group CONR R , reacting a compound of formula (II) as defined in
(a) above with a compound of formula (IX), L -C(O)-NR R , wherein L represents a leaving group (e.g. halogen) and R and R are as defined in formula (I), in the presence of a base;
and optionally thereafter carrying out one or more of the following procedures:
• converting a compound of formula (I) into another compound of formula (I),
• removing any protecting groups, • forming a pharmaceutically acceptable salt.
In each of processes (c), (d), (e) and (f) above, the reaction is conveniently carried out in an organic solvent such as dimethylformamide, dichloromethane or acetonitrile at a temperature in the range from 0°C to 150°C. Suitable bases include diisopropyl ethylamine, triethylamine and pyridine.
A compound of formula (IV) may be prepared by reacting a compound of formula (II) with a compound of formula (X)
Figure imgf000019_0001
wherein L2 and t are as defined in formula (IV). The reaction may be carried out using similar conditions to couple compounds of formulae (II) and (III).
A compound of formula (II) may be obtained by the treatment of a compound of formula (XI)
Figure imgf000019_0002
wherein n, A, Y1, Y2, Y3, X1, Z1, R, R and R are as defined in formula (I) with an acid. The reaction may be carried out in an organic solvent such as methanol, tetrahydrofuran or dioxane using either an inorganic acid such as hydrochloric acid, hydrobromic acid or sulfuric acid, or an organic acid such as trifluoroacetic acid.
A compound of formula (XI) may be obtained by the treatment of a compound of formula (XII)
Figure imgf000020_0001
wherein Z1, X1, Y1 and R are as defined in formula (I) with a compound of formula (XIII), wherein Y4 represents a bond or a C1-C5 alkylene group and n, A, Y3, R and R are as defined in formula (I). The reaction may be carried out in the presense of a suitable reducing agent (for example sodium triacetoxyborohydride or sodium borohydride), in an organic solvent such as l-methyl-2-pyrrolidinone, 1,2-dichloroethane, tetrahydrofuran or methanol at a temperature, for example, in the range from 0 to 150°C.
A compound of formula (XII) above may be obtained by treatment of a compound of formula
Figure imgf000020_0002
wherein Z1 , X1, Y1 and R are as defined in formula (I) and PG1 represents a protecting group, e.g. phthalimide or Fmoc, which may be deprotected using hydrazine in ethanol or an organic base such as piperidine.
A compound of formula (XIV) may be prepared by reacting a compound of formula (XV)
Figure imgf000020_0003
(XV) wherein X1, Y1 and R are as defined in formula (I), with a compound of formula (XVI)5
Figure imgf000021_0001
wherein L7 represents a leaving group such as a halogen, mesylate or triflate, and Z1 is as defined in formula (I) and PG1 is as defined above. The reaction may conveniently be carried out in an organic solvent such as dimethylformamide, dimethylsulphoxide or acetonitrile in the presense of a base such as an alkali metal carbonate (for example sodium carbonate or potassium carbonate) or an alkaline earth metal carbonate (for example calcium carbonate), a metal hydroxide (for example sodium hydroxide or potassium hydroxide) at a temperature, for example, in the range from 0 to 1500C, preferably at room temperature (2O0C).
The protection and deprotection of functional groups is described in 'Protective Groups in Organic Chemistry', edited by J.W.F. McOmie, Plenum Press (1973) and 'Protective Groups in Organic Synthesis', 3rd edition, T.W. Greene and P.G.M. Wuts, Wiley-Interscience (1999).
The compounds defined in the formula (XV) may be obtained following the procedure described in the patent WO2005/092893.
Compounds of formulae (III), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XIII) and (XVI) are either commercially available, are well known in the literature or may be prepared using known techniques.
The compounds of formula (I) above may be converted to a pharmaceutically acceptable salt thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, trifluoroacetate, sulphate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methanesulphonate or^»-toluenesulphonate.
Compounds of formula (I) is capable of existing in stereoisomeric forms. It will be understood that the invention encompasses the use of all geometric and optical isomers (including atropisomers) of the compounds of formula (I) and mixtures thereof including racemates. The use of tautomers and mixtures thereof also form an aspect of the present invention. Enantiomerically pure forms are particularly desired. The compounds of formula (I) and their pharmaceutically acceptable salts have activity as pharmaceuticals, in particular as modulators of toll-like receptor (especially TLR7) activity, and thus may be used in the treatment of: 1. respiratory tract: obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced) and dust-induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature, and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS) and adenovirus;
2. skin: psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber-Christian syndrome, erythema multiforme; cellulitis, both infective and non-infective; panniculitis;cutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions; drug-induced disorders including fixed drug eruptions; 3. eyes: blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; iritis; anterior and posterior uveitis; choroiditis; autoimmune, degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infections including viral , fungal, and bacterial;
4. genitourinary: nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystitis and Hunner's ulcer; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvo-vaginitis; Peyronie's disease; erectile dysfunction (both male and female);
5. allograft rejection: acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or following blood transfusion; or chronic graft versus host disease; 6. other auto-immune and allergic disorders including rheumatoid arthritis, irritable bowel syndrome, systemic lupus erythematosus, multiple sclerosis, Hashimoto's thyroiditis, Graves' disease, Addison's disease, diabetes mellitus, idiopathic thrombocytopaenic purpura, eosinophilic fasciitis, hyper-IgE syndrome, antiphospholipid syndrome and Sazary syndrome;
7. oncology: treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes; and,
8. infectious diseases: virus diseases such as genital warts, common warts, plantar warts, respiratory syncytial virus (RSV), hepatitis B, hepatitis C, herpes simplex virus, molluscum contagiosum, variola, human immunodeficiency virus (HIV), human papilloma virus (HPV), cytomegalovirus (CMV), varicella zoster virus (VZV), rhinovirus, adenovirus, coronavirus, influenza, para-influenza; bacterial diseases such as tuberculosis and mycobacterium avium, leprosy; other infectious diseases, such as fungal diseases, chlamydia, Candida, aspergillus, cryptococcal meningitis, Pneumocystis carnii, cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosome infection and leishmaniasis.
Thus, the present invention provides a compound of formula (I) or a pharmaceutically- acceptable salt thereof as hereinbefore defined for use in therapy. In a further aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined in the manufacture of a medicament for use in therapy.
In the context of the present specification, the term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be construed accordingly.
Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question. Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.
In particular, the compounds of the invention may be used in the treatment of asthma, COPD, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, cancer, hepatitis B, hepatitis C, HIV, HPV, respiratory syncytial virus (RSV), bacterial infections and dermatosis.
The invention still further provides a method of treating, or reducing the risk of, an obstructive airways disease or condition (e.g. asthma or COPD) which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined.
For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. For example, the daily dosage of the compound of the invention, if inhaled, may be in the range from 0.05 micrograms per kilogram body weight (μg/kg) to 100 micrograms per kilogram body weight (μg/kg). Alternatively, if the compound is administered orally, then the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight (μg/kg) to 100 milligrams per kilogram body weight (mg/kg). The compounds of formula (I) and pharmaceutically acceptable salts thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.
Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.05 to 80 %w, still more preferably from 0.10 to 70 %w, and even more preferably from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.
The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.
The pharmaceutical compositions may be administered topically (e.g. to the skin or to the lung and/or airways) in the form, e.g., of creams, solutions, suspensions, heptafluoroalkane (PIF A) aerosols and dry powder formulations, for example, formulations in the inhaler device known as the Turbuhaler®; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of solutions or suspensions; or by subcutaneous administration; or by rectal administration in the form of suppositories; or transdermally.
Dry powder formulations and pressurized HFA aerosols of the compounds of the invention (including pharmaceutically acceptable salts) may be administered by oral or nasal inhalation. For inhalation, the compound is desirably finely divided. The finely divided compound preferably has a mass median diameter of less than 10 micrometres (μm), and may be suspended in a propellant mixture with the assistance of a dispersant, such as a C§-C20 fatty acid or salt thereof, (for example, oleic acid), a bile salt, a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated surfactant, or other pharmaceutically acceptable dispersant.
The compounds of the invention may also be administered by means of a dry powder inhaler. The inhaler may be a single or a multi dose inhaler, and may be a breath actuated dry powder inhaler.
One possibility is to mix the finely divided compound of the invention with a carrier substance, for example, a mono-, di- or polysaccharide, a sugar alcohol, or another polyol. Suitable carriers are sugars, for example, lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol; and starch. Alternatively the finely divided compound may be coated by another substance. The powder mixture may also be dispensed into hard gelatine capsules, each containing the desired dose of the active compound.
Another possibility is to process the finely divided powder into spheres which break up during the inhalation procedure. This spheronized powder may be filled into the drug reservoir of a multidose inhaler, for example, that known as the Turbuhaler® in which a dosing unit meters the desired dose which is then inhaled by the patient. With this system the active ingredient, with or without a carrier substance, is delivered to the patient.
For oral administration the compound 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. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide. Alternatively, the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.
For the preparation of soft gelatine capsules, the compound 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. Also 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. Optionally such liquid preparations may contain colouring agents, flavouring agents, saccharine and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.
The compounds of the invention may also be administered in conjunction with other compounds used for the treatment of the above conditions.
The invention therefore further relates to combination therapies wherein a compound of the invention or a pharmaceutical composition or formulation comprising a compound of the invention is administered concurrently or sequentially or as a combined preparation with another therapeutic agent or agents, for the treatment of one or more of the conditions listed.
In particular, for the treatment of the inflammatory diseases COPD, asthma and allergic rhinitis the compounds of the invention may be combined with agents such as tumour necrosis factor alpha (TNF-alpha) inhibitors such as anti-TNF monoclonal antibodies (for example Remicade, CDP-870 and adalimumab) and TNF receptor immunoglobulin molecules (such as Enbrel); non-selective cyclo-oxygenase COX-l/COX-2 inhibitors whether applied topically or systemically (such as piroxicam, diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin), COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib, lumarocoxib, parecoxib and etoricoxib); glucocorticosteroids (whether administered by topical,oral, intramuscular, intravenous, or intra-articular routes); methotrexate, lefunomide; hydroxychloroquine, d-penicillamine, auranofin or other parenteral or oral gold preparations.
The present invention still further relates to the combination of a compound of the invention and a leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein (FLAP) antagonist such as; zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761; a N-(5-substituted)-thiophene-2-alkylsulfonamide; 2,6-di-tert- butylphenolhydrazones; a methoxytetrahydropyrans such as Zeneca ZD-2138; the compound SB-210661; a pyridinyl-substituted 2-cyanonaphthalene compound such as L-739,010; a 2- cyanoquinoline compound such as L-746,530; or an indole or quinoline compound such as MK-591, MK-886, and BAY x 1005.
The present invention further relates to the combination of a compound of the invention and a receptor antagonist for leukotrienes (LT B4, LTC4, LTD4, and LTE4) selected from the group consisting of the phenothiazin-3-ls such as L-651,392; amidino compounds such as CGS-25019c; benzoxalamines such as ontazolast; benzenecarboximidamides such as BIIL 284/260; and compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195.
The present invention still further relates to the combination of a compound of the invention and a phosphodiesterase (PDE) inhibitor such as a methylxanthanine including theophylline and aminophylline; a selective PDE isoenzyme inhibitor including a PDE4 inhibitor an inhibitor of the isoform PDE4D, or an inhibitor of PDE5.
The present invention further relates to the combination of a compound of the invention and a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine; applied orally, topically or parenterally. The present invention still further relates to the combination of a compound of the invention and a gastroprotective histamine type 2 receptor antagonist.
The present invention further relates to the combination of a compound of the invention and an antagonist of the histamine type 4 receptor.
The present invention still further relates to the combination of a compound of the invention and an alpha- l/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride or ethylnorepinephrine hydrochloride.
The present invention further relates to the combination of a compound of the invention and an anticholinergic agent including muscarinic receptor (Ml, M2, and M3) antagonists such as atropine, hyoscine, glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.
The present invention still further relates to the combination of a compound of the invention together with a beta-adrenoceptor agonist (including beta receptor subtypes 1-4) such as isoprenaline, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, and pirbuterol.
The present invention further relates to the combination of a compound of the invention and a chromone, such as sodium cromoglycate or nedocromil sodium.
The present invention still further relates to the combination of a compound of the invention together with an insulin-like growth factor type I (IGF-I) mimetic.
The present invention still further relates to the combination of a compound of the invention and a glucocorticoid, such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate. The present invention still further relates to the combination of a compound of the invention together with an inhibitor of matrix metalloproteases (MMPs), i.e., the stromelysins, the collagenases, and the gelatinases, as well as aggrecanase; especially collagenase-1 (MMP-I), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-IO), and stromelysin-3 (MMP-Il) andMMP-9 and MMP-12.
The present invention still further relates to the combination of a compound of the invention together with modulators of chemokine receptor function such as antagonists of CCRl, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO and CCRl 1 (for the C-C family); CXCRl, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX3CR1 for the C-X3-C family.
The present invention still further relates to the combination of a compound of the invention together with a cytokine or modulator of cytokine function, including alpha-, beta-, and gamma-interferon; interleukins (IL) including ILl to 15, and interleukin antagonists or inhibitors, including agents which act on cytokine signalling pathways.
The present invention still further relates to the combination of a compound of the invention together with an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE (omalizumab).
The present invention further relates to the combination of a compound of the invention and another systemic or topically-applied anti-inflammatory agent, such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol.
The present invention further relates to the combination of a compound of the invention together with an antibacterial agent such as a penicillin derivative, a tetracycline, a macrolide, a beta-lactam, a fluoroquinolone, metronidazole, an inhaled aminoglycoside; an antiviral agent including acyclovir, famciclovir, valaciclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin, zanamavir and oseltamavir; a protease inhibitor such as indinavir, nelfϊnavir, ritonavir, and saquinavir; a nucleoside reverse transcriptase inhibitor such as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; or a non-nucleoside reverse transcriptase inhibitor such as nevirapine or efavirenz.
The anti-cancer treatment defined hereinbefore may be applied as a sole therapy or may
5 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-tumour agents:-
(i) an antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, io cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, is dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere and polokinase inhibitors); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin); (ii) cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene,
20 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 5α-reductase such as finasteride;
25 (iii) anti-invasion agents (for example c-Src kinase family inhibitors like 4-(6-chloro-2,3- methylenedioxyanilino)-7-[2-(4-methylpiperazin-l-yl)ethoxy]-5-tetrahydropyran-4- yloxyquinazoline (AZD0530; International Patent Application WO 01/94341) andiV-(2- chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-l-yl]-2-methylpyrimidin-4- ylamino}thiazole-5-carboxamide (dasatinib, BMS-354825; J. Med. Cherou 2004, 47, 6658-
30 6661), and metalloproteinase inhibitors like marimastat, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase); (iv) inhibitors of growth factor function: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [Herceptin™], the anti-EGFR antibody panitumumab, the anti-erbBl antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. Critical reviews in oncology/haematology, 2005, Vol. 54, ppl 1-29); such inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZDl 839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3- morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib, inhibitors of the hepatocyte growth factor family, inhibitors of the platelet-derived growth factor family such as imatinib, inhibitors of serine/threonine kinases (for example Ras/Raf signalling inhibitors such as farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006)), inhibitors of cell signalling through MEK and/or AKT kinases, inhibitors of the hepatocyte growth factor family, c-kit inhibitors, abl kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors (for example AZDl 152, PH739358, VX-680, MLΝ8054, R763, MP235, MP529, VX-528 AND AX39459) and cyclin dependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors; (v) 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 (Avastin™) and VEGF receptor tyrosine kinase inhibitors such as 4-(4-bromo- 2-fluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline (ZD6474; Example 2 within WO 01/32651), 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3- pyrrolidin- 1 -ylpropoxy)quinazoline (AZD2171; Example 240 within WO 00/47212), vatalanib (PTK787; WO 98/35985) and SUl 1248 (sunitinib; WO 01/60814), compounds such as those disclosed in International Patent Applications WO97/22596, WO 97/30035, WO 97/32856 and WO 98/13354 and compounds that work by other mechanisms (for example linomide, inhibitors of integrin αvβ3 function and angiostatin)]; (vi) vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213; (vii)antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
(viii) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug s therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and
(ix) immunotherapy approaches, including for example ex- vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines sucho as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies. s The present invention will be further explained by reference to the following illustrative examples.
The following abbreviations are used; 0 EtOAc ethyl acetate
DCM dichloromethane
NMP N-methylpyrrolidine
NB S N-bromosuccinimide
DMF ΛζiV-dimethylformamide 5 DMSO dimethylsulfoxide
THF tetrahydrofuran
TFA trifluoroacetic acid
K2CO3 potassium carbonate
NaHCO3 sodium hydrogen carbonate 0 MeCN acetonitrile mCPBA 3-chloroperoxybenzoic acid (Aldrich 77% max) rt room temperature h hours min minutes
M molar
N normal
MS mass spectrometry
APCI atmospheric chemical ionisation method
ESI electron spray ionisation method
NMR nuclear magnetic resonance
HCl hydrochloric acid
BOC fertzαry-butoxycarbonyl
HOBt 1-hydroxybenzotriazole
EDC l-(3-dimethylamino propyl)-3-ethylcarbodiimide hydrochloride
HATU <9-(7-azabenzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphonate
Unless otherwise stated organic solutions were dried over magnesium sulphate. RPHPLC denotes Reversed Phase Preparative High Performance Liquid Chromatography using Waters Symmetry C8, Xterra or Phenomenex Gemini columns using acetonitrile and either aqueous ammonium acetate, ammonia, formic acid or trifluoroacetic acid as buffer where appropriate. Column chromatography was carried out on silica gel. SCX denotes solid phase extraction with a sulfonic acid sorbent whereby a mixture was absorbed on a sulfonic acid sorbent and eluted with an appropriate solvent such as methanol or acetonitrile and then the free base product was eluted with aqueous ammonia/an appropriate solvent such as methanol or acetonitrile.
Example 1
Figure imgf000034_0001
Methyl [4-({ [3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9Jϊ-purin-9-yl)propyl] [(4- methylpiperazin-l-yl)acetyl] amino} methyl)phenyl] acetate
(i) 2-Chloro-9-(tetrahydro-2H-pyran-2-yl)- 9H-purin-6-amine 2,6-Dichloro-9-(tetrahydxo-2H-pyran-2-yl)- 9H-purine (55g) was dissolved in 7N-aqueous ammonia in methanol (500ml) and heated at 1000C in a sealed flask for 6h. The reaction mixture was cooled to rt and left overnight. Filtration afforded the subtitle compound. Yield
4Og.
1H NMR δ (CDCl3) 8.02 (IH, s), 5.94 (2H, brs), 5.71 (IH, dd), 4.15 - 4.22 (IH, m), 3.75 - 3.82 (IH, m), 1.27 - 2.12 (6H, m).
(ii) 2-Butoxy-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine
The product from step (i) (4Og) was dissolved in 19%(w/w)-sodium butoxide in butanol (250ml). The reaction mixture was stirred under reflux for 6h. The resultant suspension was cooled to rt, diluted with water and extracted with diethyl ether. The combined organic phase was washed with water, dried and concentrated in vacuo. The subtitle compound was crystallized from diethyl ether/isohexane (1/1, 300ml) and obtained by filtration. Yield 19g. 1H NMR δ (CDCl3) 7.87 (IH, s), 5.56 - 5.68 (3H, m), 4.31 - 4.35 (2H, t), 4.14 - 4.17 (IH, m), 3.76 - 3.80 (IH, m), 1.49 - 2.08 (1OH, m), 0.98 (3H, t).
(iii) 8-Bromo-2-butoxy-9-(tetrahydro-2H-pyran-2-yl) 9H-purin-6-amine The product from step (ii) (30g) was dissolved in dry DCM (200ml). The solution was stirred at rt whilst iV-bromosuccinimide (27g) was added portion wise. The mixture was stirred at rt overnight. 20%(w/v)-Sodium sulfate (200ml) was added and the separated aqueous phase extracted with DCM. The combined organic phase was washed with saturated NaHCO3 solution and brine. After concentration in vacuo, the residue was dissolved in EtOAc, washed with water, brine and dried. The solution was filtered through silica gel. The filtrate was concentrated in vacuo and dissolved in a mixture of diethyl ether and isohexane (1/1, 200ml) to give the subtitle compound (26g). The solvent was removed to give a residue, which was purified by column chromatography (EtOAc/isohexane), which afforded 2.5g. The solids were combined to give the subtitle compound as a yellow solid. Yield 28.5g. mp 148-5O0C 1H NMR δ (CDCl3) 5.59-5.64 (3H, m), 4.32 (2H, m), 4.17 (IH, m), 3.74 (IH, m), 3.08 (IH, m), 2.13 (IH, d), 1.48 - 1.83 (8H, m), 0.98 (3H, t).
(iv) 2-Butoxy-8-methoxy-9-(tetrahydro-2H-pyran-2-yl) 9H-purin-6-amine Sodium (3.7g) was added to absolute methanol (400ml) under a nitrogen atmosphere. To this solution was added the product (28.5g) from step (iii) and the mixture was stirred at 650C for 9h. The mixture was concentrated in vacuo and 500ml of water added. The aqueous phase was extracted with EtOAc and washed with brine and dried. The subtitle compound was obtained after crystallisation from diethyl ether. Yield 14.2g. 1H NMR δ (CDCl3) 5.51(1H, dd), 5.28 (2H, brs), 4.29 (2H, t), 4.11 - 4.14 (4H, m), 3.70 (IH, m), 2.76 - 2.80 (IH, m), 2.05 (IH, d), 1.47 - 1.81 (8H, m), 0.97 (3H, t).
(v) 2-Butoxy-8-methoxy-9H-purin-6-amine, TFA salt
The product from step (iv) (24g) was dissolved in absolute methanol (300ml) and 30ml of TFA was added. The reaction mixture was stirred at rt for 3 days and concentrated in vacuo. The subtitle compound was obtained as a white crystalline solid after trituration with methanol/EtOAc. Yield 2 Ig.
1H NMR δ (CD3OD) 4.48 (2H, t), 4.15 (3H, s), 1.80 (2H, quintet), 1.50 (2H, sextet), 0.99 (3H, t).
(vi) 2-[3-(6-Amino-2-butoxy-8-methoxy-9H-purin-9-yl)propyl]-lH-isoindole- l,3(2H)-dione
The product from step (v) (15g) was dissolved in dry DMF (200ml) and 18g of K2CO3 added. After the suspension was stirred at rt for 15min, 2-(3-bromopropyl)-lH-isoindole-l,3(2H)- dione (14g) was added the the suspension vigorously stirred at rt for 10 h. The reaction mixture was extracted with EtOAc, washed with water and brine and dried. The subtitle compound was obtained after crystallisation from EtOAc/diethyl ether. Yield 16g. 1H NMR δ (DMSO-d6) 7.83 (4H, m), 6.73 (2H, brs), 4.06 (2H, t,), 4.01 (3H, s), 3.89 (2H, t), 3.58 (2H, t), 2.07-2.14 (2H, m), 1.55-1.62 (2H, m), 1.31-1.40 (2H5 m), 0.90 (3H, t).
(vii) 9-(3-Aminopropyl)-2-butoxy-8-methoxy-9H-ρurin-6-amine The product from step (vi) (Ig) was dissolved in ethanol (10ml) and hydrazine monohydrate (ImI) was added and stirred at ambient temperature for 1Oh. The resultant was concentrated under reduced pressure and the residue suspended in DCM (10ml) and stirred for Ih. The suspension was filtered, washed with DCM. The solution was washed with water and dried. The solution was concentrated under reduced pressure to give the subtitled compound. Yield 700mg.
1H NMR δ (DMSO-d6) 6.77 (2H, brs), 4.16 (2H, t), 4.05 (3H, s), 3.89 (2H, t), 2.46-2.52 (2H, m), 1.61-1.76 (4H, m), 1.35-1.45 (2H, m), 0.92 (3H, t).
(viii) [4-({[3-(6-Amino-2-butoxy-8-methoxy-9H-purin-9- y l)propy 1] amino } methy l)phenyl] acetic acid
The product from step (vii) (9.7g) and (4-formylphenyl)acetic acid (5.4g) were dissolved in TΗF (100ml) and stirred at rt for 4h. Sodium borohydride (1.9g) and 5 drops of methanol was added and stirred at a rt overnight. The mixture was quenched with water and concentrated under reduced pressure. Water was added and washed with diethyl ether. 0. IN- HCl was added to acidify the solution to pΗ 6. The suspension was filtered and the solid collected and dried under reduced pressure to give the subtitle compound. Yield 13g. 1H NMR δ (DMSO-d6) 7.14 - 7.22 (4Η, m), 6.75 (2H, brs), 4.12 (2H, t), 4.03 (3H, s), 3.88 (2H, t), 3.62 (2H, s), 3.38 (2H, s), 1.34 - 2.47 (8H, m), 0.91 (3H, t).
(ix) Methyl [4-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9- yl)propyl]amino}methyl)phenyl]acetate
The product from step (viii) (13g) was dissolved in methanol (100ml) and 4N-ΗC1 in dioxane (10ml) added. The reaction mixture was stirred at rt for 24h. The resultant was concentrated under reduced pressure and aqueous NaHCO3 added to pH 8. The suspension was filtered and the solid collected and dried under reduced pressure to give the subtitle compound. Yield 1 Ig. 1HNMR δ (DMSO-d6) 7.15 - 7.25 (4H, m), 6.35 (2H, brs6), 4.12 (2H, t), 3.71 (2H, t), 3.62 (3H, s), 3.62 (2H5 s), 3.60 (2H5 s), 2.47 (2H5 m), 1.34 - 1.80 (6H, m), 0.90 (3H5 1).
(x) Methyl [4-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9- yl)propyl] [(4-methylpiperazin- 1 -yl)acetyl] amino } methyl)phenyl] acetate The product from step (ix) (200mg) was suspended in MeCN. Chloroacetyl chloride (0.02ml) added and the mixture stirred at rt for 4h. The mixture was concentrated under reduced pressure, piperazine (0.02 ml) in DMSO (ImI) was added and the mixture heated at 60 0C for 24h. The mixture was purified by RPHPLC. Yield 80mg. s 1R NMR δ (DMSO-dg) 10.02 (IH, brs), 7.10 - 7.20 (4H, m), 6.30 (2H, brs), 4.52 (2H, m), 4.15 (3H, t), 3.60 - 3.66 (7H, m), 3.27 (4H, m), 2.98 (4H, m), 2.73 (4H, m), 2.61 (3H, s), 1.33 - 1.94 (6H, m), 0.92 (3H, t). MS: APCI (+ve): 583 (M+H). o Example 2
Figure imgf000038_0001
Methyl (4-{ [ [3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl] (ΛyV- dimethylglycyl)amino]methyl}phenyl)acetate s
The product of example 1, step (ix) (200mg) was suspended in MeCN. AζN-dimethylglycyl chloride hydrochloride (1 lOmg) and triethylamine (0.19ml) were added and the mixture stirred at rt for 1Oh. The mixture was purified by RPΗPLC. Yield lOOmg. 1H ΝMR δ (DMSO-de) 7.07 - 7.22 (4H, m), 6.43 (2H, brs), 4.55 (2H, s), 4.13 (2H, t), 3.63 -0 3.69 (4H, m), 3.60 (3H, s), 3.29 (2H3 m), 3.01 (2H, s), 2.14 (2H, s), 1.31 - 1.97 (6H, in), 0.90 (3H, t). MS: APCI (+ve): 528 (M+H).
Example 3 5
Figure imgf000039_0001
Methyl [4-({ [3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)pr opyl] [(1- methyIpiperidin-4-yl)carbonyl] amino}methyl)phenyl] acetate
5
The title compound was prepared by the method of example 2 using l-methylpiperidine-4- carbonyl chloride hydrochloride, yield 50mg.
1R NMR δ (DMSO-d6) 7.04 - 7.24 (4H, m), 6.45 (2H, brs), 4.51 (2H, s), 4.13 (2H, t), 3.60 -
3.65 (7H, m), 3.17 - 3.31 (4H, m), 2.66 (2H, s), 2.07 (3H, s), 1.35 - 2.02 (1 IH, m), 0.90 (3H,o t).
MS: APCI (+ve): 568 (M+H).
Example 4
Figure imgf000039_0002
Methyl [4-({ [3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl] [4- (dimethylamino)butanoyl] amino} methyl)phenyl] acetate o The title compound was prepared by the method of example 2 using 4- (dimethylamino)butanoyl chloride hydrochloride, yield 30mg.
1H NMR δ (DMSO-de) 7.05 - 7.24 (4H, m), 6.40 (2H5 brs), 4.55 (2H, s), 4.12 (2H, t), 3.39 - 3.65 (7H3 m), 3.23 (2H, m), 2.10 - 2.27 (4H, m), 2.04 (6H, s), 1.33 - 1.93 (8H, m), 0.91 (3H, t). MS: APCI (+ve): 556 (M+H).
Example 5
Figure imgf000040_0001
Methyl (4-{[[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl](iV;Λ- dimethyl-β-alanyl)amino]methyl}phenyl)acetate
The title compound was prepared by the method of example 2 using N,N-dimethyl-β-alanyl chloride hydrochloride, yield 55mg.
1H ΝMR δ (DMSO-d6) 7.06 - 7.24 (4H, m), 6.40 (2H, brs), 4.51 (2H, s), 4.12 (2H, t), 3.62 -
3.69 (7H3 m), 3.60 (3H, s), 3.23 (2H, m ), 2.40 (4H, m), 2.05 (6H, s), 1.34 - 1.93 (6H, m),
0.90 (3H, t). MS: APCI (+ve): 542 (M+H).
Example 6
Figure imgf000040_0002
Methyl [4-({ [3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9J?-purin-9-yl)propyl] [ΛyV-bis(2- hydroxyethyl)glycyl]amino}methyl)phenyl]acetate The title compound was prepared by the method of example 1 using 2,2'-iminodiethanol, yield 30mg.
1H NMR δ (DMSOd6) 7.09 - 7.20 (4H, m), 4.59 (2H, brs), 4.22 (2H, m), 3.78 (2H, t), 3.64 (3H5 s), 3.45 - 3.61 (10H5 m), 2.71 (4H, m), 1.44 - 2.10 (6H, m), 0.95 (3H, t). MS: APCI (+ve): 588 (M+H).
Example 7
Figure imgf000041_0001
Methyl {4-[([3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]{[4-(2- hydroxyethyl)piperazin-l-yl]acetyl}amino)methyl]phenyl}acetate
The title compound was prepared by the method of example 1 using 2-piperazin-l-ylethanol, yield 52mg.
1H NMR δ (DMSO-de) 9.87 (IH, brs), 7.06 - 7.21 (4H, m), 6.41 (2H, brs), 4.55 (2H, s), 4.22 (2H5 m), 3.63 - 3.69 (4H5 m), 3.60 (3H5 s), 3.20 (2H5 m), 3.04 (2H, s), 1.36 - 2.37 (18H, m), 0.90 (3H5 1). MS: APCI (+ve): 613 (M+H).
Example 8
Figure imgf000042_0001
Methyl {4-[([3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]{[4- (methylsulfonyl)piperazin-l-yl]acetyl}amino)methyl]phenyl}acetate
5
The title compound was prepared by the method of example 1 using 1- (methylsulfonyl)piperazine, yield 25mg.
1H NMR δ (DMSO-de) 7.07 - 7.24 (4H, m), 6.44 (2H, brs), 4.54 (2H, s), 4.12 (2H, m), 3.63 - 3.67 (4H, m), 3.60 (3H, s), 3.15 (2H, s), 3.03 (4H, m), 2.83 (2H, s), 2.40 (4H, m), 1.33 - 1.90 io (6H, m), 0.90 (3H, t).
MS: APCI (+ve): 647 (M+H).
Example 9
Figure imgf000042_0002
Methyl [3-({ [3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9#-purin-9-yl)propyl] [(1- methylpiperidin-4-yl)carbonyl]amino}methyl)phenyl]acetate
20 (i) tert-Butyl [3-(6-amino-2-butoxy-8-methoxy-9H'-purin-9-yl)propyl]carbamate
The product from example 1 step (v) (1.5g), 1.4g of K2CO3 and tert-bntyl (3- bromopropyl)carbamate (Ig) were heated at 5O0C in DMF (10ml) for 3h. The reaction mixture was cooled to rt, extracted with EtOAc, washed with water and dried. The solvent was removed to give a residue, which was purified by column chromatography (methanol/DCM), which afforded the subtitle compound. Yield l.lg. 1H NMR δ (DMSO-d6) 6.82 (IH, t), 6.77 (2H, s), 4.17 (2H, t,), 4.04 (3H, s), 3.83 (2H, t), 2.90 (2H, m), 1.79 (2H, m), 1.65 (2H, m), 1.41 (2H, m), 1.37 (9H, s), 0.92 (3H, t). s
(ii) 6-Amino-9-(3-aminopropyl)-2-butoxy-7,9-dihydro-8H-purin-8-one The product from step (i) (l.lg) was dissolved in methanol/DCM (1/1, 40ml). 4N-ΗC1 in dioxane (10ml) was added and the mixture stirred at rt for 2Oh. The resultant was concentrated under reduced pressure, which afforded the subtitle compound. Yield 0.9g.o 1H NMR 6 (DMSOd6) 10.71 (IH, brs), 7.88 (2H, brs), 4.22 (2H, t,), 3.75 (2H, t), 2.77 (2H, m), 1.96 (2H, m), 1.36 - 1.70 (4H, m), 0.92 (3H, t).
(iii) Methyl [3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9- yl)propyl]amino}methyl)phenyl]acetate s The product from step (ii) (3.Ig) and methyl (3-formylphenyl)acetate (1.6g) were dissolved in NMP (30ml) and stirred for 15min. Sodium triacetoxyborohydride (3.7g) was added and the mixture stirred at rt for 20 h. After addition of methanol (1 ml), the mixture was purified by SCX, which afforded the subtitle compound. Yield 3.1g.
1H NMR δ (DMSO-d6) 7.27 - 7.21 (3H, m), 7.13 (IH, m), 6.46 (2H, brs), 4.12 (2H, t), 3.730 (2H, t), 3.70 (2H, s), 3.64 (2H, s), 3.61 (3H, s), 2.54 (2H, t), 1.82 (2H, m), 1.62 (2H, m), 1.37 (2H, m), 0.90 (3H, t).
(iv) Methyl [3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9- yl)propyl][(l-methylpiperidin-4-yl)carbonyl]amino}methyl)phenyl]acetate5 The product from step (iii) (O.lg), diisopropyl ethylamine (0.1ml) and l-methylpiperidine-4- carboxylic acid hydrochloride (45mg) were dissolved in NMP (3ml) then ΗATU (130mg) added to the mixture. The mixture was stirred at rt for 5h then purified by SCX and RPΗPLC, which afforded the title compound. Yield 70mg.
1H NMR δ (DMSO- d6) 7.23 (IH, t), 7.12 (IH, d), 7.03 (IH, s), 7.02 (IH, d), 6.15 (2H, brs),o 4.50 (2H, s), 4.16 (2H, t), 3.65 (2H, t), 3.61 (2H, s), 3.60 (3H, s), 3.25 (2H, t), 2.68 (2H, m),
2.10 (3H, s), 1.86- 1.96 (2H, m), 1.63 (5H, m), 1.42 (4H, m), 0.91 (3H, t).
MS: APCI (+ve): 568 (M+l). Example 10
Figure imgf000044_0001
Methyl [3-({ [3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9iT-purin-9-yl)propyl] [(1- methylpiperidin-4-yl)carbonyl] amino}methyl)phenyl] acetate
The title compound was prepared by the method of example 10 using N-(tert- butoxycarbonyl) glycine, yield 160mg.
1H NMR δ (DMSO- d6) 9.69 (IH, s), 7.27 (IH, m), 7.17 (IH, m), 7.09 (2H, m), 6.35 - 6.25 (IH, m), 6.14 (2H, brs), 4.54 (2H, s), 4.20 (2H, t), 3.83 (2H, d), 3.69 (2H, t), 3.65 (2H, s), 3.64 (3H, s), 3.31 (2H, t), 1.95 (2H, m), 1.68 (2H, m), 1.43 (2H, m), 1.40 (9H, s), 0.95 (3H, t). MS: APCI (+ve): 600 (M+l).
Example 11
Figure imgf000044_0002
Methyl (3-{[[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9Jϊ-purin-9- yl)propyl] (glycyl)amino] methyl}phenyl)acetate The product from example 10 (150mg) was dissolved in methanol (2ml) and 4N HCl in dioxane added. The mixture was stirred at rt for 3h and purified by RPHPLC, which afforded the title compound. Yield 20mg.
1HNMR δ (DMSO- d6) 7.24 (IH, m), 7.13 (IH, m), 7.05 (2H, m), 6.13 (2H, brs), 4.50 (2H, s), 4.17 (2H, s), 3.66 (2H, t), 3.62 (2H, s), 3.61 (3H, s), 3.33 (2H, s), 3.24 - 3.31 (2H, m), 1.92 (2H, m), 1.65 (2H, m), 1.40 (2H, m), 0.93 (3H, t). MS: APCI (+ve): 500 (M+l).
Example 12
Figure imgf000045_0001
Methyl [3-({ [3-(6-amino-2-butoxy-8-oxo-7,8-dihydr o-9H-purm-9- yl)propyl][(methylthio)acetyl]amino}methyl)phenyl] acetate
The title compound was prepared by the method of example 10 using (methylthio)acetic acid, yield 170mg.
1H NMR δ (DMSO- d6) 7.24 (IH, m), 7.14 (IH, m), 7.07 (2H, m), 6.13 (2H, brs), 4.48 - 4.60
(2H, m), 4.17 (2H, t), 3.67 (2H, t), 3.62 (2H, s), 3.61 (3H, s), 3.33 (2H, s), 3.30 (2H, t), 2.09 (3H, s), 1.90 - 2.02 (2H5 m), 1.65 (2H, m), 1.40 (2H, m), 0.92 (3H, t).
MS: APCI (+ve): 531 (M+l).
Example 13
Figure imgf000046_0001
Methyl [3-({ [3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9ϋ-purin-9- yl)propyl] [(methylsulfinyl)acetyl] amino}methyl)phenyl] acetate s
The product from example 12 (150mg) was dissolved in DCM (10ml) and methanol (2ml) and mCPBA (0. Ig) added. The mixture was stirred at rt for 3h then purified by RPHPLC, which afforded the title compound. Yield 50 mg.
1H NMR δ (DMSO- d6) 7.00 - 7.31 (4H, m), 6.14 (2H, brs), 4.46 - 4.70 (2H, m), 4.17 (2H, t), iϋ 3.92 (2H, s), 3.67 (2H, s), 3.61 (3H, s), 3.02 (4H, m), 2.62 (3H, s), 1.85 - 2.11 (2H, m), 1.65
(2H, m), 1.41 (2H, m), 0.93 (3H, t).
MS: APCI (+ve): 547 (M+l).
Example 14
15
Figure imgf000046_0002
Methyl [3-({ [3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9-ff-purin-9- yl)propyl][(methylsulfonyl)acetyl]amino}methyl)phenyl]acetate 0
The product from example 12 (150mg) was dissolved in DCM (10ml) and methanol (2ml) and mCPBA (0. Ig) added. The mixture was stirred at rt for 3h then purified by RPHPLC, which afforded the title compound. Yield 40mg. 1B. NMR δ (DMSO- d6) 7.05 - 7.39 (4H, m), 6.15 (2H, brs), 4.60 (2H, m), 4.35 (2H, m), 4.17 (2H, t), 3.68 (2H, s), 3.62 (3H, s), 3.11 (3H, s), 3.03 (4H, m), 1.84 - 2.05 (2H, m), 1.65 (2H, m), 1.41 (2H, m), 1.10 (3H, t). MS: APCI (+ve): 563 (M+l).
Example 15
Figure imgf000047_0001
Methyl [3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9Jy-purin-9-yl)propyl] [3- (methylthio)propanoyl] amino} methyl)phenyl] acetate
The title compound was prepared by the method of example 10 using 3- (methylthio)propanoic acid, yield 130mg. 1H NMR δ (DMSO- d6) 7.25 (IH, m), 7.14 (IH, m), 7.07 (2H, m), 6.13 (2H, brs), 4.53 (2H, s), 4.17 (2H, t), 3.67 (2H, t), 3.62 (2H, s), 3.61 (3H, s), 3.31 (2H, t), 2.68 (2H, m), 2.58 (2H, m), 2.01 (3H, s), 1.99 - 1.89 (2H, m), 1.65 (2H, m), 1.41 (2H, m), 0.93 (3H, t). MS: APCI (+ve): 545 (M+l).
Example 16
Figure imgf000047_0002
Methyl [3-({ [3-(6-amino-2-butoxy-8-oxo~7,8-dihydro-9H-purin-9-yl)propyl] [3- (methylsulfonyl)propanoyl] amino}methyl)phenyl] acetate
The title compound was prepared by the method of example 14 using the product from example 15, yield 60mg.
1H NMR δ (DMSO- d6) 7.24 (IH, m), 7.14 (IH, m), 7.06 (2H, m), 6.13 (2H, brs), 4.61 - 4.50 (2H, m), 4.16 (2H, t), 3.67 (2H, t), 3.62 (2H, s), 3.61 (3H, s), 3.34 (4H, m), 2.92 (3H, s), 2.80 (2H, t), 1.89 - 2.00 (2H, m), 1.65 (2H, m), 1.40 (2H, m), 0.92 (3H, t). MS: APCI (+ve): 577 (M+l).
Example 17
Figure imgf000048_0001
Methyl [3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl] [N- (methylsulfonyl)glycyl] amino} methyl)phenyl] acetate
The product from example 11 (50mg) was dissolved in NMP (ImI), then pyridine (0.07ml) and methanesulfonic anhydride (29mg) added. The mixture was stirred at rt for 2Oh then purified by RPHPLC, which afforded the title compound. Yield 15mg
1B. NMR δ (DMSO- d6) 7.25 (IH, m), 7.15 (IH, m), 7.07 (2H, m), 6.15 (2H, brs), 4.53 (2H, s), 4.17 (2H, t), 3.91 (2H, s), 3.67 (2H, t), 3.63 (2H, s), 3.62 (3H, s), 3.31 (2H, t), 2.92 (3H, s), 1.89 - 1.99 (2H, m), 1.65 (2H, m), 1.41 (2H, m), 0.93 (3H, t). MS: APCI (+ve): 576 (M+l).
Example 18
Figure imgf000049_0001
tert-Butyl 4-{ [3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl] [3-(2- methoxy-2-oxoethyl)benzyl]amino}-4-oxobutanoate
The title compound was prepared by the method of example 10 using 4-tert-butoxy-4- oxobutanoic acid, yield 17mg.
1H NMR δ (DMSO- d6) 7.22 (IH, m), 7.12 (IH, m), 7.05 (2H, m), 6.11 (2H, brs), 4.51 (2H, s), 4.16 (2H, t), 3.65 (2H, t), 3.60 (2H, s), 3.60 (3H, s), 3.29 (2H, m), 2.50 (2H, m), 2.42 (2H, m), 1.85 - 1.98 (2H, m), 1.64 (2H, m), 1.39 (2H, m), 1.36 (9H, s), 0.91 (3H, t). MS: APCI (+ve): 599 (M+ 1).
Example 19
Figure imgf000049_0002
4-{[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9JH-purin-9-yI)propyl][3-(2-methoxy-2- oxoethyl)benzyl] amino}-4-oxobutanoic acid
The product from example 18 (140mg) was dissolved in DCM (ImI) and TFA (0.2ml) added. The mixture was stirred at rt for 2h. The solution was washed with saturated aqueous NaHCO3 solution and dried. The mixture was purified by RPHPLC, which afforded the title compound. Yield 80mg. 1HNMR δ (DMSO- d6) 9.66 (IH, s), 7.22 (IH, m), 7.12 (IH, m), 7.05 (2H, m), 4.52 (2H, brs), 4.16 (2H, t), 3.65 (2H, t), 3.61 (2H, s), 3.60 (3H, s), 3.29 (2H, m), 2.54 (2H, m), 2.46 (2H, m), 1.85 - 1.98 (2H, m), 1.64 (2H, m), 1.39 (2H, m), 0.91 (3H, t). MS: APCI (+ve): 543 (M+l).
Example 20
Figure imgf000050_0001
Methyl 3-{ [3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl] [3-(2-methoxy- 2-oxoethyl)benzyl]amino}-3-oxopropanoate
(i) tert-Butyl 3-{[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9- yl)propyl][3-(2-methoxy-2-oxoethyl)benzyl]amino}-3-oxopropanoate The subtitle compound was prepared by the method of example 10 using 3~tert-butoxy-3- oxopropanoic acid. Yield lOOmg. MS: APCI (+ve): 585 (M+l).
(ii) Methyl 3-{[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3- (2-methoxy-2-oxoethyl)benzyl]amino} -3-oxopropanoate
The product from step (i) (lOOmg) was dissolved in methanol (3ml) and 4N-ΗC1 in dioxane added. The mixture was stirred at rt for 5h and purified by RPHPLC, which afforded the title compound. Yield 80mg
1H NMR δ (DMSO- d6) 9.68 (IH, s), 7.23 (IH, m), 7.13 (IH, m), 7.06 (2H, m), 6.11 (2H, brs), 4.51 (2H, s), 4.16 (2H, t), 3.65 (2H, t), 3.60 (6H, s), 3.27 (2H, t), 3.00 (2H, s), 2.99 (2H, m), 1.85 - 1.98 (2H, m), 1.64 (2H5 m), 1.39 (2H, m), 0.91 (3H, t).
MS: APCI (-We): 543 (M+l). Example 21
Figure imgf000051_0001
Methyl [3-({acetyl[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9- yl)propyl]amino}methyl)phenyl]acetate
The product from example 20 step (i) (lOOmg) was dissolved in DCM (ImI) and TFA (0.2ml) added. The mixture was stirred at rt for 2h. The solution was washed with saturated aqueous
NaHCO3 and dried. The mixture was purified by RPHPLC, which afforded the title compound.
Yield 30mg
1H NMR δ (DMSO- d6) 7.01 - 7.29 (4H, m), 6.12 (2H, brs), 4.50 (2H, s), 4.15 (2H, t), 3.65
(2H, t), 3.61 (2H, s), 3.60 (3H, s), 3.26 (2H, t), 2.00 (3H, s), 1.83 - 1.99 (2H, m), 1.64 (2H, m), 1.39 (2H, m), 0.91 (3H, t).
MS: APCI (+ve): 485 (M+l).
Example 22
Figure imgf000051_0002
Methyl (34[[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9#-purin-9- yl)propyl] (methylsulfonyl)amino] methyl}phenyl)acetate The title compound was prepared by the method of example 17 using product example 9 step (iii) (lOOmg) and methanesulfonic anhydride (76mg). yield 60mg. s 1H NMR δ (DMSO- d6) 7.33 - 7.49 (4H, m), 6.33 (2H, brs), 4.53 (2H, s), 4.38 (2H, t), 3.84 (2H, s), 3.82 (2H, m), 3.82 (3H, s), 3.37 (2H, t), 3.12 (3H, s), 2.10 (2H, m), 1.86 (2H m), 1.62 (2H, m), 1.14 (3H, t). MS: APCI (+ve): 521 (M+l). o Example 23
Figure imgf000052_0001
(4-{[[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-purin-9-yl)[2R]-propyI]-(pyrrolidine-2-5 carbonyl)-amino]-methyl}-phenyl)-acetic acid methyl ester
The product of example 1, step (ix) (300mg) and pyrrolidine- 1,2-dicarboxylic acid l-(R)-teτt- butyl ester (146mg) were dissolved in DCM (10ml) and HATU (258mg) added. After Ih, more HATU (258mg) and ^-pyrrolidine- 1,2-dicarboxylic acid 1-tert-butyl ester (146mg)0 were added to the miture. The mixture was stirred at rt for 16h and TFA (5ml) added and stirred for 4h. The reaction mixture was concentrated in vacuo to dryness then redissolved in methanol before being purified by RPHPLC5 to give the title compound. Yield 19mg. 1H NMR δ (DMSO- d6) 8.19 (IH, s), 7.27 - 7.03 (5H, m), 6.46 (2H5 d5 J= 14.9 Hz), 4.71 - 4.49 (2H5 m), 4.41 (IH5 d)5 4.20 - 4.04 (4H5 m)5 3.71 - 3.60 (4H, m)5 3.47 - 3.33 (2H5 m), 3.345 - 3.26 (2H, m), 3.26 - 3.18 (2H, m)5 3.17 - 3.07 (2H5 m), 2.92 - 2.81 (IH5 m), 2.19 - 2.02 (2H, m), 2.02 - 1.86 (2H, m), 1.82 - 1.69 (2H, m), 1.69 - 1.56 (2H, m), 1.45 - 1.32 (2H, m), 0.94
0.88 (3H, m).
MS: APCI (+ve): 540 (M+l).
Example 24
Figure imgf000053_0001
(4-{[[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-purin-9-yl)-propyl][2S,4R](4-hydroxy- pyrrolidine^-carbonyty-aminoj-methylj-phenyty-acetic acid methyl ester
The product of example 1, step (ix) (0.27 g) was dissolved in DCM (10ml) and treated with (2?)-4-triethylsilanyloxy-pyrrolidine-l,2-dicarboxylic acid 1-fS^-tert-butyl ester (211mg) and HATU (232mg).The reaction was stirred at rt for 16h and TFA (2ml) added and stirred for 4h. The reaction mixture was concentrated to dryness in vacuo purifed by RPHPLC to give the title compound. Yield 114mg.
1H NMR δ (DMSO- d6) 8.22 (IH5 s), 7.28 - 7.02 (4H, m), 6.46 (2H, d), 4.61 (IH, s), 4.60 - 4.36 (IH, m), 4.27 - 4.19 (2H, m), 4.17 - 4.06 (3H, m), 3.70 - 3.61 (4H, m), 3.34 - 3.23 (2H, m), 3.19 - 3.06 (2H, m), 2.00 - 1.86 (2H, m), 1.87 - 1.73 (2H, m), 1.70 - 1.56 (2H, m), 1.44 - 1.31 (2H, m), 0.96 - 0.84 (3H, m). MS: APCI (+ve): 556 (M+l).
Example 25
Figure imgf000054_0001
(4-{ [ [3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-purin-9-yI)-propyl] [2S] -(1-methyl- pyrroIidine-2-carbonyl)-amino]-methyl}-phenyl)-acetic acid methyl ester
The product of example 1, step (ix) (0.43 g), l-methyl-pyrrolidine-2-carboxylic acid (0.13g) and HATU (0.37g) were stirred in DCM (5ml) at rt for 7 days. The reaction mixture was purified by SCX and RPHPLC, to give the title compound. Yield 24mg. 1H NMR δ (DMSO- d6) 9.92 (IH, d), 9.61 (IH, s), 7.30 - 7.03 (5H, m), 6.44 (2H, s), 4.67 - 4.56 (2H, m), 4.54 - 4.42 (2H, m), 4.15 - 4.05 (4H, m), 3.69 - 3.58 (4H, m), 2.84 - 2.73 (4H, m), 2.05 (3H, s), 2.10 - 1.97 (2H, m), 1.97 - 1.84 (2H, m), 1.86 - 1.73 (2H, m), 1.66 - 1.53 (2H, m), 1.37 - 1.24 (2H, m), 0.96 - 0.83 (3H, m). MS: APCI (+ve): 554 (M+ 1).
Example 26
Figure imgf000054_0002
(4-{[[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-purin-9-yl)-propyl]-(3-piperazin-l-yl- propionyl)-amino]-methyl}-phenyl)-acetic acid methyl ester The product of example 1, step (ix) (0.27 g) was dissolved in DCM (10ml) and treated with 4-
(2-carboxy-ethyl)-piperazine-l-carboxylic acid tert-butyl ester (0.16 g) and HATU (0.23g).
The reaction was stirred at rt for 16h, before 2mls of TFA added. The mixture was purifed by
RPHPLC, to give the title compound. Yield 3mg.
1H NMR δ (DMSO- d6) 9.93 (IH, d), 7.27 - 7.06 (4H, m), 6.52 - 6.41 (2H, m), 4.60 (IH, s),
4.48 (IH, s), 4.13 (2H, s), 3.71 - 3.59 (4H, m), 3.61 (3H, s), 3.43 - 3.16 (1OH, m), 2.87 - 2.75
(2H, m), 2.02 - 1.91 (2H, m), 1.91 - 1.80 (2H, m), 1.68 - 1.58 (2H, m), 1.42 - 1.31 (2H, m),
0.91 (3H, t).
MS: APCI (+ve): 583 (M+l).
The compounds of Examples 27 to 103 were prepared by processes analogous to Example 1, step (x) using commercially available amines.
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Biological Assay
Human TLR7 assay
Recombinant human TLR7 was stably expressed in a HEK293 cell line already stably s expressing the pNiFty2-SEAP reporter plasmid; integration of the reporter gene was maintained by selection with the antibiotic zeocin. The most common variant sequence of human TLR7 (represented by the EMBL sequence AF240467) was cloned into the mammalian cell expression vector pUNO and transfected into this reporter cell-line. Transfectants with stable expression were selected using the antibiotic blasticidin. In thiso reporter cell-line, expression of secreted alkaline phosphatase (SEAP) is controlled by an NFkB/ELAM-1 composite promoter comprising five NFkB sites combined with the proximal ELAM-I promoter. TLR signaling leads to the translocation of NFkB and activation of the promoter results in expression of the SEAP gene. TLR7-specific activation was assessed by determining the level of SEAP produced following overnight incubation of the cells at 37°Cs with the standard compound in the presence of 0.1 % (v/v) dimethylsulfoxide (DMSO). Concentration dependent induction of SEAP production by compounds was expressed as the log of the minimal effective concentration of compound to induce SEAP release (pMEC). For example Compounds of Examples : 1, 4, 7 and 18 have pMEC >7.7

Claims

1. A compound of formula (I)
Figure imgf000063_0001
R represents hydrogen, hydroxy 1, or a Cj-Cg alkoxy, C2-C5 alkoxycarbonyl,
Cj-Cg haloalkyl, Cj-Cg haloalkoxy, C6-C10 aryl, C5-C10 heteroaryl or C3-C8 cycloalkyl group, each group being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, a Cj-Cg alkyl, Cj-Cβ haloalkyl, Cj-Cg alkoxy,
Cj-Cg haloalkoxy, C2-C5 alkoxycarbonyl, amino (NH2), (mono)- Cj-Cg alkylamino and (di)-Cj-Cg alkylamino group;
Y represents a single bond or Cj-Cg alkylene;
X represents a single bond, an oxygen, sulphur atom, sulphonyl (SO2) or NR ; Z represents a C2-C6 alkylene or C3-C8 cycloalkylene group, each group being optionally substituted by at least one hydroxyl; X represents NR ;
Y represents a single bond or Cj-Cg alkylene;
Y represents a single bond or Cj-Cg alkylene; n is an integer 0, 1 or 2; R represents halogen or a Ci-Cg alkyl, Ci-Cg hydroxyalkyl, Ci-Cg haloalkyl, Ci-Cg alkoxy, Ci-Cg hydroxyalkoxy, Ci-Cg haloalkoxy, amino (NH2), (mono)-
Ci-Cg alkylamino, (di)-Ci-Cg alkylamino group or a C3-C8 saturated heterocyclic ring comprising a ring nitrogen atom and optionally one or more further heteroatoms 5 independently selected from nitrogen, oxygen and sulphur, the heterocyclic ring being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, oxo, Ci-Cg alkyl, Ci-Cg alkoxy, C2-C5 alkylcarbonyl and C2-C5 alkoxycarbonyl;
2 R represents hydrogen or a Ci -Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl or 0 C3-C8 cycloalkyl group, each group being optionally substituted by one or more substituents independently selected from halogen, hydroxyl or a Ci-Cg alkoxy, C2-C10 acyloxy, amino
(NH2), (mono)- Ci-Cg alkylamino, (di)-Ci-Cg alkylamino group and a C3-C8 saturated heterocyclic ring comprising a ring nitrogen atom and optionally one or more further heteroatoms independently selected from nitrogen, oxygen and sulphur, the heterocyclic rings in turn being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, oxo, Ci-Cg alkyl, Ci-Cg alkoxy, C2-C5 alkylcarbonyl and C2-C5 alkoxycarbonyl group;
3 R represents hydrogen or Ci-Cg alkyl;
R4 represents CO2R5, SO2R5, COR5, SO2NR6R7 and CONR6R7; 0 R independently represents
(i) a 3- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms comprising ring group NR , S(0)m or oxygen, each ring may being optionally substituted by one or more substituents independently selected from halogen, hydroxyl or a Ci-Cg alkyl and Ci-Cg alkoxy group, or s (ii) a Cg-Cio aryl or C5-C10 heteroaryl group, each of which may be optionally substituted by one or more substituents independently selected from halogen, cyano, Ci-Cg alkyl, C1-C3 haloalkyl, carboxyl, S(O)1nR9, OR10, CO2R10, SO2NR10R1^ CONR10R11, NR10R11, NR10SO2R9, NR10CO2R9, NR10COR9, or
(iii) a Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl or C3-Cs cycloalkyl group, each of which may be optionally substituted by one or more substituents independently selected from halogen, CN, C3-C8 cycloalkyl, S(O)pR12, OR13, COR13, CO2R13, SO2NR13R14,
CONR13R14, NR13R14, NR13SO2R12, NR13CO2R12, NR13COR12, NR13SO2R12 or a Cg-Cio aryl or C5-C10 heteroaryl group or a heterocyclic ring, the latter three groups may be optionally substituted by one or more substituents independently selected from Ci -Cg alkyl (optionally substituted by hydroxy, Ci-Cg alkoxy, Ci-Cg alkoxycarbonyl, amino, Ci-Cg alkylamino, di-Ci-Cg alkylamino, amido, Ci-Cg alkylamido, di-Ci-C6 alkylamido, -OCH2CH2OH, pyrrolidinyl, pyrrolidinylcarbonyl, furanyl, piperidyl, methylpiperidyl or phenyl), Ci-Cg alkenyl (optionally substituted by phenyl), halogen, hydroxy, cyano, carboxy, amino, Ci-Cg alkylamino, di-Ci-Cg alkylamino, amido, Ci-Cg alkylamido, di-Ci-Cg alkylamido, Ci-Cg alkoxycarbonyl, Ci-Cg alkylsulphonyl, Ci-Cg alkylcarbonylamino, Ci-Cg alkylcarbonylmethylamino, phenyl (optionally substituted by hydroxy, fluoro or methyl), pyrrolidinyl, pyridyl, piperidinyl, benzothiazolyl or pyrimidinyl;
R represents hydrogen or a Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, C3-C8 cycloalkyl group or heterocyclic ring, each of which may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, oxo, cyano, Ci-Cg alkyl,
C2-C6 alkenyl, C2-Cg alkynyl, C3-C8 cycloalkyl, OR15, S(O)qR15, CO2R16, COR16, NR16R17, CONR16R17, NR16COR17, NR16CO2R15, SO2NR16R17, NR16SO2R15, or a Cg-Cio aryl or C5-C10 heteroaryl group or heterocyclic ring, the latter three groups being optionally substituted by one or more substituents independently selected from, Ci-Cg alkyl, C3-C8 cycloalkyl, halogen, S(O)qR , CO2R , COR , hydroxy or cyano; and 7 R represents hydrogen, a Cj-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or
C3-C8 cycloalkyl group, each group may be optionally substituted by one or more substituents independently selected from halogen, C3-C8 cycloalkyl, a C6-Ci0 aryl or C5-
15 18 19
Cjo heteroaryl group, carboxy, cyano, OR , hydroxy or NR R , or R and R together with the nitrogen atom to which they are attached form a 3- to 8- membered saturated or partially saturated heterocyclic ring, optionally containing further heteroatoms or heterogroups selected from nitrogen, S(O)m or oxygen. The heterocyclic ring, may be optionally substituted by one or more substituents independently selected from
90 91 99 01 OA OA halogen, hydroxyl, carboxyl, cyano, OR , NR R , S(O)qR , COR , CO2R ,
OA 95 OA 95 OA 95 OA 0% OA OS OA 0% NRZ V , CONR R , NR COR , NR CO2R , SO2NR R , NR SO2R , C6-Ci0 aryl , C5-C10 heteroaryl group, heterocyclic ring, Ci-C6 alkyl, C2-C6 alkenyl,
C2-C6 alkynyl or C3-C8 cycloalkyl group, the latter seven groups being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, oxo,
90 93 OA OA OA 95 OA OS OA 93 cyano, OR , S(O)qR , COR , CO2R , NR R , CONR R , NR CO2R ,
OA 95 94 95 OA 93 NR COR , SO2NR R , NR SO2R , a heterocyclic ring or a C6-Ci0 aryl or C5-Ci0 heteroaryl group, the latter three groups being optionally substituted by one or more substituents independently selected from Ci-C6 alkyl, halogen, hydroxy or cyano;
R8 represents hydrogen, CO2R26, COR26, SO2R26, Ci-C6 alkyl or C3-C6 cycloalkyl group, each group may be optionally substituted by one or more substituents independently
97 9R selected from halogen, hydroxyl, and NR R ;
Ώ 10 T3 Il „ 16 ^ 17 ^ 18 D 19 ^21 D22 ^26 ,,27 „28 „29 -,3O , . - , Λ R , R , R , R , R , R , R , R , R , R , R , R or R each independently represents hydrogen, and a Ci-C6 alkyl or C3-C6 cycloalkyl group;
24 25
R and R each independently represents hydrogen, and a Ci-C6 alkyl or
C3-C6 cycloalkyl group; or 24 25
R and R together with the nitrogen atom to which they are attached form a 3- to 8- membered saturated or partially saturated heterocyclic ring, optionally containing further heteroatoms or heterogroups selected from nitrogen, S(O)m or oxygen;
9 12 15 23
R , R , R and R represent C^-Cg alkyl or C3-C6 cycloalkyl;
5 R and R are defined as for R and R respectively;
20 R represents a Cj-Cg alkyl optionally substituted by one or more substituents
23 independently selected from halogen, hydroxyl or OR ; m, p, q and r each independently represent an integer 0, 1 or 2; and A represents a Cβ-Cio aryl or C5-C12 heteroaryl group; I0 or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1, wherein X represents oxygen.
3. A compound according to claim 1 or claim 2, wherein Y represents Cj-Cg alkylene and is R represents hydrogen.
4. A compound according to any one of the preceding claims, wherein Z represents C2-C6 alkylene
20 5. A compound according to any one of the preceding claims, wherein Y represents C1-C6 alkylene.
6. A compound according to any one of the preceding claims wherein A represents Cg-C10 aryl.
25
3
7. A compound according to any one of the preceding claims wherein Y represents Cj-Cg alkylene. 2
8. A compound according to any one of the preceding claims wherein R represents
Ci-Ce alkyl.
4 5
9. A compound according to any one of the preceding claims wherein R represents SO2R .
4 5
10. A compound according to any one of claims 1 to 8 wherein R represents COR .
11. A compound of formula (I) according to claim 1 selected from:
Methyl [4-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][(4- methylpiperazin-l-yl)acetyl]amino}methyl)phenyl]acetate,
Methyl (4-{[[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl](N^- dimethylglycyl)amino]methyl}phenyl)acetate,
Methyl [4-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-ρurin-9-yl)proρyl][(l- methylpiperidin-4-yl)carbonyl]amino}methyl)phenyl]acetate,
Methyl [4-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][4-
(dimethylamino)butanoyl]amino}methyl)phenyl]acetate,
Methyl (4-{[[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl](N;jV-dimethyl- β-alanyl)amino]methyl}phenyl)acetate, Methyl [4-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][i\ζN-bis(2- hydroxyethyl)glycyl]amino}methyl)phenyl]acetate,
Methyl {4-[([3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-ρurin-9-yl)ρroρyl]{[4-(2- hydroxy ethyl)piperazin- 1 -yl] acetyl} amino)methyl]phenyl} acetate,
Methyl {4-[([3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]{[4- (methylsulfonyl)piperazin- 1 -yl]acetyl} amino)methyl]phenyl} acetate,
Methyl [3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)ρropyl][(l- methylpiperidin-4-yl)carbonyl]amino}methyl)phenyl]acetate,
Methyl [3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][(l- methylpiperidin-4-yl)carbonyl]amino}methyl)phenyl]acetate, Methyl (3-{[[3-(6-amino-2-butoxy-8-oxo-758-dihydro-9H-purin-9- yl)propyl](glycyl)amino]methyl}phenyl)acetate, Methyl [3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9- yl)propyl][(methylthio)acetyl]amino}methyl)phenyl]acetate,
Methyl [3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9- yl)propyl] [(methylsulfinyl)acetyl] amino} methyl)phenyl] acetate, Methyl [3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9- yl)propyl][(methylsulfonyl)acetyl]amino}methyl)phenyl]acetate,
Methyl [3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)ρroρyl][3-
(methylthio)propanoyl] amino} methyl)phenyl] acetate,
Methyl [3 -( { [3 -(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)ρroρyl] [3- (methylsulfonyl)propanoyl]amino}methyl)phenyl]acetate,
Methyl [3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-ρurin-9-yl)propyl][N-
(methylsulfonyl)gly cyl] amino } methyl)phenyl] acetate, tert-Butyl 4-{[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(2-methoxy-
2-oxoethyl)benzyl] amino } -4-oxobutanoate, 4-{[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(2-methoxy-2- oxoethyl)benzyl]amino} -4-oxobutanoic acid,
Methyl 3-{[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(2-methoxy-2- oxoethyl)benzyl]amino}-3-oxopropanoate,
Methyl [3-({acetyl[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9- y l)propy 1] amino } methy l)pheny 1] acetate,
Methyl (3-{[[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9- yl)propyl](methylsulfonyl)amino]methyl}phenyl)acetate,
(4-{[[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-purin-9-yl)[2R]-propyl]-(pyrrolidine-2- carbonyl)-amino]-methyl}-phenyl)-acetic acid methyl ester, (4-{[[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-purin-9-yl)-propyl][2S,4R](4-hydroxy- pyrrolidine-2-carbonyl)-amino]-methyl}-phenyl)-acetic acid methyl ester,
(4-{[[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-purin-9-yl)-propyl][2S]-(l-methyl- pyrrolidine-2-carbonyl)-amino]-methyl}-phenyl)-acetic acid methyl ester,
(4-{[[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-purin-9-yl)-propyl]-(3-piperazin-l-yl- propionyl)-amino]-methyl}-phenyl)-acetic acid methyl ester, Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-ρurin-9-yl)proρyl-[2-[4-[3-(l- piperidyl)propyl]piperazin-l-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[3-(diethylcarbamoyl)-l- piperidyl] acetyl] amino]methyl]phenyl] acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-phenyl-l- piperidyl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(2-oxo-2-pyrrolidin-l- yl-ethyl)piperazin- 1 -yl] acetyl] amino]methyl]phenyl] acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(l- piperidyl)acetyl]amino]methyl]phenyl]acetate,
Ethyl 4-[[3-(6-amino-2-butoxy-8-oxo-7H-ρurin-9-yl)propyl-[[4- (methoxycarbonylmethyl)phenyl]methyl] carbamoyl]methyl]piperazine- 1 -carboxylate,
2-[[3-(6-Amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[[4- (methoxycarbonylmethyl)phenyl]methyl]carbamoyl]methyl-(2-cyanoethyl)amino]acetic acid,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(benzyl-(2- dimethylaminoethyl)amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-carbamoyl-l- piperidyl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(3R)-3- hy droxypyrrolidin- 1 -yl] acetyl] amino]methyl]phenyl] acetate, tert-Butyl (2S)-l-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)proρyl-[[4- (methoxycarbonylmethyl)phenyl]methyl]carbamoyl]methyl]pyrrolidine-2-carboxylate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(2-cyanoethyl-(oxolan-2- ylmethyl)amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(ethyl-(pyridin-4- ylmethyl)amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-ethylpiperazin-l- yl)acetyl]amino]methyl]phenyl]acetate, Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(methyl-(2-ρyridin-4- ylethyl)amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-pyrrolidin-l-yl-l- piperidyl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-ρurin-9-yl)propyl-[2-[(2S)-2- carbamoylpyrrolidin-l-y^acetyljammojmethyljphenyljacetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(3,6-dihydro-2H-pyridin- l-yl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-pυrin-9-yl)propyl-[2-(ethyl-(2- hydroxyethyl)amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(cyclohexyl-(2- hydroxyethyl)amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(hydroxymethyl)-l- piperidyl] acetyl] amino]methyl]phenyl] acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(2- aminoethyl)piperazin- 1 -yl] acetyl] amino]methyl]phenyl] acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-pυrin-9-yl)propyl-[2-[4-(2-hydroxyethyl)-l- piperidyl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[methyl-(l-methyl-4- piperidyl)amino]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-benzyl-4-hydroxy-l- piperidyl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-cinnamylpiperazin-l- yl)acetyl] amino]methyl]phenyl] acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-[2-(2- hydroxyethoxy)ethyl]piperazin-l-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(3-dimethylaminopropyl- methyl-amino)acetyl]amino]methyl]phenyl]acetate, Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)ρroρyl-[2- (dimethylcarbamoylmethyl-methyl-amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)ρropyl-[2-[(2R)-2- carbamoylpyrrolidin-l-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-ρurin-9-yl)ρropyl-[2-[(2S,6R)-2,6- dimethylmorpholin-4-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)ρropyl-[2-(4-methyl-l,4-diazepan- l-yl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-(2-morpholin-4- ylacetyl)amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(3- hydroxyphenyl)piperazin-l-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[[2-[3-(acetyl-methyl-amino)pyrrolidin-l-yl]acetyl]-[3-(6-amino-2-butoxy-8- oxo-7H-purin-9-yl)propyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)ρropyl-[2-[(3S)-3- dimethylaminopyrrolidin-l-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-pyridin-4-ylpiperazin- 1 -yl)acetyl] amino]methyl]phenyl] acetate
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)ρropyl-[2-[4-(3- dimethylaminopropyl)piperazin-l-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-propan-2-ylpiperazin- l-yl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4- (dimethylcarbamoylmethy^piperazin-l-yyacetyljaminojmethy^phenyyacetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(2-hydroxy-2-phenyl- ethyl)-methyl-amino]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(aminomethyl)-l- piperidyl] acetyl] amino]methyl]phenyl] acetate, Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(methyl-(2- methylaminoethyl)amino)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-(2-thiomorpholin-4- ylacetyl)amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-phenylpiperazin-l- yl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(l,3-dihydroisoindol-2- yl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-(2-piperazin-l- ylacetyl)amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(l-piperidyl)-l- piperidyl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-pyridin-2-ylpiperazin- 1 -yl)acetyl] amino]methyl]phenyl] acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-hydroxy- 1 - piperidyl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(4- fluorophenyl)piperazin-l-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-methyl-l- piperidyl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-ρurin-9-yl)ρroρyl-[2-(2,5-dihydroρyrrol-l- yl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-benzothiazol-2- ylpiperazin-l-yl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4- (ethoxycarbonylmethy^-l-piperidyyacety^aminojmethyypheny^acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(2- dimethylaminoethyl)piperazin-l-yl]acetyl]amino]methyl]phenyl]acetate, Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-(2- methylphenyl)piperazin-l-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-ethylsulfonylpiperazin- l-yl)acetyl]amino]methyl]phenyl]acetate,
(2S,4R)-l-[[3-(6-Amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[[4- (methoxycarbonylmethyl)phenyl]methyl]carbamoyl]methyl]-4-hydroxy-pyrrolidine-2- carboxylic acid,
(2S)-2-[[3-(6-Amino-2-butoxy-8-oxo-7H-ρurin-9-yl)propyl-[[4- (methoxycarbonylmethyl)phenyl]methyl] carbamoyl]methyl-methyl-amino] -3 -phenyl- propanoic acid,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(2S)-2- (hydroxymethyl)pyrrolidin-l-yl]acetyl]amino]methyl]phenyl]acetate,
3-[[3-(6-Amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[[4- (methoxycarbonylmethyl)phenyl]methyl] carbamoyl]methyl-( 1 , 1 -dioxothiolan-3 - yl)amino]propanoic acid,
3-[[3-(6-Amino-2-butoxy-8-oxo-7H-ρurin-9-yl)propyl-[[4-
(methoxycarbonylmethyl)phenyl]methyl]carbamoyl]methyl-cyclohexyl-amino]propanoic acid,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(ethyl-(2- ethylaminoethyl)amino)acetyl]amήio]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-ρurin-9-yl)propyl-[2-(ethyl-(3- ethylaminopropyl)amino)acetyl] amino]methyl]phenyl] acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(3,4-dihydro-lH- isoquinolin-2-yl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)proρyl-[2-[(2S)-2-(ρyrrolidin-l- ylmethyl)pyrrolidin-l-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[4-[(l-methyl-4- piperidyl)methyl]piperazin-l-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(methyl-prop-2-ynyl- amino)acetyl] amino]methyl]phenyl] acetate, Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(l-methyl-4-piperidyl)- phenethyl-amino]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)ρropyl-[2-[4-(oxolan-2- ylmethyl)piperazin-l-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(3R)-3-aminopyrrolidin- 1 -yl] acetyl] amino]methyl]phenyl] acetate, tert-Butyl (2R)-l-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[[4- (methoxycarbonylmethyl)phenyl]methyl]carbamoyl]methyl]pyrrolidine-2-carboxylate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-(4-pyrimidin-2- ylpiperazin-l-yl)acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-(2-pyrrolidin-l- ylacetyl)amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-ρurin-9-yl)propyl-[2-[(2S)-2- (methoxymethyl)pyrrolidin-l-yl]acetyl]amino]methyl]phenyl]acetate,
Methyl 2-[4-[[3-(6-amino-2-butoxy-8-oxo-7H-purin-9-yl)propyl-[2-[(2R)-2- (methoxymethyl)pyrrolidm-l-yl]acetyl]amino]methyl]phenyl]acetate,
and pharmaceutically acceptable salts thereof.
12. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 11 in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
13. A process for the preparation of a pharmaceutical composition as claimed in claim 12 which comprises mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 11 with a pharmaceutically acceptable adjuvant, diluent or carrier.
14. A compound of formula (I) or a pharmaceutically-acceptable salt thereof as claimed in any one of claims 1 to 11 for use in therapy.
15. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 11 in the manufacture of a medicament for the treatment of human diseases or conditions in which modulation of TLR7 activity is beneficial. s
16. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 11 in the manufacture of a medicament for the treatment of allergic or viral diseases or cancers.
io 17. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 11 in the manufacture of a medicament for use in treating asthma, COPD, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, cancer, hepatitis B, hepatitis C, BD[V, HPV, respiratory syncytial virus (RSV), bacterial infections and dermatosis.
15 18. A method of treating, or reducing the risk of, a disease or condition in which modulation of TLR7 activity is beneficial which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 11.
20 19. A method of treating, or reducing the risk of, an allergic or viral disease or cancer which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 11.
25 20. A method of treating, or reducing the risk of, an obstructive airways disease or condition which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 11. 16
21. A combination of a compound of formula (I) as claimed in any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, and one or more agents independently selected from:
• a non-steroidal glucocorticoid receptor agonist;
• a selective β2 adrenoceptor agonist; • a phosphodiesterase inhibitor;
• a protease inhibitor;
• a glucocorticoid;
• an anticholinergic agent;
• a modulator of chemokine receptor function; and • an inhibitor of kinase function .
22. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 which comprises,
4 5 (a) when R represents a group COR , reacting a compound of formula
Figure imgf000077_0001
1 2 1 1 1 2 3 wherein n, R, R , R , A, X , Z , Y , Y and Y are as defined in formula (I), with a compound of formula (III), R -C(O)-L , wherein L represents halogen or hydroxy and R is as defined in formula (I), in the presence of a base or a coupling reagent as required;
4 5 5 13 14
(b) when R represents a group COR and R represents a group C^-Cδ alkyl-NR R , reacting a compound of formula
Figure imgf000078_0001
wherein L2 represents a leaving group, t is an integer from 1 to 6, and n, A, Y1, Y2, Y3, X1,
Z1, R, R and R are as defined in formula (I), with a compound of formula (V), NHR R ,
13 14 wherein R and R are as defined in formula (I), in the presence of a base;
4 5
(c) when R represents a group SO2R , reacting a compound of formula (II) as defined in (a)
3 5 3 above with a compound of formula (VI), L -S(O)2-R , wherein L represents a leaving group and R is as defined in formula (I), in the presence of a base;
4 5 (d) when R represents a group CO2R , reacting a compound of formula (II) as defined in (a)
4 5 4 above with a compound of formula (VII), L -C(O)-OR , wherein L represents a leaving group and R is as defined in formula (I), in the presence of a base;
4 6 7
(e) when R represents a group SO2NR R , reacting a compound of formula (II) as defined in (a) above with a compound of formula (VIII),
Figure imgf000078_0002
L represents a leaving group and R and R are as defined in formula (I), in the presence of a base;
or 4 6 7
(f) when R represents a group CONR R , reacting a compound of formula (II) as defined in
(a) above with a compound of formula (IX), L -C(O)-NR R , wherein L represents a leaving group and
Figure imgf000079_0001
are as defined in formula (I), in the presence of a base;
and optionally thereafter carrying out one or more of the following procedures:
• converting a compound of formula (I) into another compound of formula (I),
• removing any protecting groups,
• forming a pharmaceutically acceptable salt.
PCT/SE2007/000651 2006-07-05 2007-07-03 8-oxoadenine derivatives acting as modulators of tlr7 WO2008004948A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP2009518052A JP2009542645A (en) 2006-07-05 2007-07-03 8-oxoadenine derivatives acting as modulators of TLR7
EP07748310A EP2041135A4 (en) 2006-07-05 2007-07-03 8-oxoadenine derivatives acting as modulators of tlr7
US12/305,801 US8138172B2 (en) 2006-07-05 2007-07-03 8-oxoadenine derivatives acting as modulators of TLR7

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US81855406P 2006-07-05 2006-07-05
US60/818,554 2006-07-05

Publications (1)

Publication Number Publication Date
WO2008004948A1 true WO2008004948A1 (en) 2008-01-10

Family

ID=38894827

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE2007/000651 WO2008004948A1 (en) 2006-07-05 2007-07-03 8-oxoadenine derivatives acting as modulators of tlr7

Country Status (4)

Country Link
US (1) US8138172B2 (en)
EP (1) EP2041135A4 (en)
JP (1) JP2009542645A (en)
WO (1) WO2008004948A1 (en)

Cited By (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008114006A1 (en) * 2007-03-19 2008-09-25 Astrazeneca Ab 9-substituted-8-oxo-adenine compounds as toll-like receptor (tlr7) modulators
WO2009091032A1 (en) * 2008-01-17 2009-07-23 Dainippon Sumitomo Pharma Co., Ltd. Method for producing adenine compound
US7968544B2 (en) * 2007-06-29 2011-06-28 Gilead Sciences, Inc. Modulators of toll-like receptor 7
US7977344B2 (en) * 2007-02-19 2011-07-12 Glaxosmithkline Llc Compounds
US8012964B2 (en) * 2004-03-26 2011-09-06 Dainippon Sumitomo Pharma Co., Ltd. 9-substituted 8-oxoadenine compound
US8044056B2 (en) * 2007-03-20 2011-10-25 Dainippon Sumitomo Pharma Co., Ltd. Adenine compound
US8067426B2 (en) * 2008-08-11 2011-11-29 Glaxosmithkline Llc 6-amino-purin-8-one compounds
US8067413B2 (en) * 2007-03-19 2011-11-29 Astrazeneca Ab 9-substituted-8-oxo-adenine compounds as toll-like receptor (TLR7 ) modulators
US8067411B2 (en) * 2006-12-14 2011-11-29 Astrazeneca Ab Compounds
WO2012031140A1 (en) 2010-09-01 2012-03-08 Novartis Ag Adsorption of immunopotentiators to insoluble metal salts
US8138172B2 (en) * 2006-07-05 2012-03-20 Astrazeneca Ab 8-oxoadenine derivatives acting as modulators of TLR7
US8268990B2 (en) 2007-11-22 2012-09-18 Astrazeneca Ab Compounds
WO2013030378A1 (en) 2011-09-01 2013-03-07 Novartis Ag Adjuvanted formulations of staphylococcus aureus antigens
WO2013072518A1 (en) 2011-11-20 2013-05-23 Glaxosmithkline Biologicals S.A. Vaccine comprising a tlr-5 agonist as adjuvant for use in cutaneous immunisation
WO2013072519A1 (en) 2011-11-20 2013-05-23 Glaxosmithkline Biologicals S.A. Vaccine
US8466167B2 (en) 2008-03-03 2013-06-18 Irm Llc Compounds and compositions as TLR activity modulators
US8476288B2 (en) 2009-05-21 2013-07-02 Astrazeneca Ab Salts 756
US8507507B2 (en) 2009-10-22 2013-08-13 Gilead Sciences, Inc. Modulators of toll-like receptors
WO2013132041A2 (en) 2012-03-08 2013-09-12 Novartis Ag Adjuvanted formulations of booster vaccines
WO2013131984A1 (en) 2012-03-07 2013-09-12 Novartis Ag Adjuvanted formulations of rabies virus immunogens
WO2013131983A1 (en) 2012-03-07 2013-09-12 Novartis Ag Adjuvanted formulations of streptococcus pneumoniae antigens
WO2014037472A1 (en) 2012-09-06 2014-03-13 Novartis Ag Combination vaccines with serogroup b meningococcus and d/t/p
US8895570B2 (en) 2010-12-17 2014-11-25 Astrazeneca Ab Purine derivatives
US9045472B2 (en) 2010-12-16 2015-06-02 Astrazeneca Ab Imidazoquinoline compounds
WO2016004876A1 (en) 2014-07-09 2016-01-14 Shanghai Birdie Biotech, Inc. Anti-pd-l1 combinations for treating tumors
WO2016004875A1 (en) 2014-07-09 2016-01-14 Shanghai Birdie Biotech, Inc. Combination therapy compositions and methods for treating cancers
US9376398B2 (en) 2012-05-18 2016-06-28 Sumitomo Dainippon Pharma Co., Ltd Carboxylic acid compounds
US9428512B2 (en) 2012-11-20 2016-08-30 Glaxosmithkline Llc Compounds
US9540383B2 (en) 2012-11-20 2017-01-10 Glaxosmithkline Llc Pyrrolopyrimidines as therapeutic agents for the treatment of diseases
US9550785B2 (en) 2012-11-20 2017-01-24 Glaxosmithkline Llc Pyrrolopyrimidines as therapeutic agents for the treatment of diseases
US9555036B2 (en) 2012-08-24 2017-01-31 Glaxosmithkline Llc Pyrazolopyrimidine compounds
US9950062B2 (en) 2009-09-02 2018-04-24 Glaxosmithkline Biologicals Sa Compounds and compositions as TLR activity modulators
EP2881393B1 (en) * 2010-11-16 2018-06-06 Texas Heart Institute Agonists that enhance binding of integrin-expressing cells to integrin receptors
US10112946B2 (en) 2011-07-22 2018-10-30 Glaxosmithkline Llc Composition
US10202384B2 (en) 2014-09-16 2019-02-12 Gilead Sciences, Inc. Solid forms of a toll-like receptor modulator
CN109715214A (en) * 2016-09-13 2019-05-03 豪夫迈·罗氏有限公司 The combined therapy of TLR7 agonist and HBV Mouth Disease Virus Proteins inhibitor
US10603369B2 (en) 2011-03-02 2020-03-31 Glaxosmithkline Biologicals Sa Combination vaccines with lower doses of antigen and/or adjuvant
EP3763742A1 (en) 2014-09-01 2021-01-13 Birdie Biopharmaceuticals Inc. Anti-pd-l1 conjugates for treating tumors
US11110091B2 (en) 2008-12-09 2021-09-07 Gilead Sciences, Inc. Modulators of toll-like receptors
US11116774B2 (en) 2014-07-11 2021-09-14 Gilead Sciences, Inc. Modulators of toll-like receptors for the treatment of HIV
WO2022084417A1 (en) 2020-10-21 2022-04-28 Univerza V Ljubljani Conjugated tlr7 and nod2 agonists

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AR065784A1 (en) * 2007-03-20 2009-07-01 Dainippon Sumitomo Pharma Co DERIVATIVES OF 8-OXO ADENINE, DRUGS THAT CONTAIN THEM AND USES AS THERAPEUTIC AGENTS FOR ALLERGIC, ANTIVIRAL OR ANTIBACTERIAL DISEASES.
CA2686163A1 (en) * 2007-05-08 2008-11-13 Astrazenca Ab Imidazoquinolines with immuno-modulating properties
PE20091156A1 (en) 2007-12-17 2009-09-03 Astrazeneca Ab SALTS OF (3 - {[[3- (6-AMINO-2-BUTOXY-8-OXO-7,8-DIHIDRO-9H-PURIN-9-IL) PROPYL] (3-MORFOLIN-4-ILPROPIL) AMINO] METHYL} PHENYL) METHYL ACETATE
WO2009091031A1 (en) * 2008-01-17 2009-07-23 Dainippon Sumitomo Pharma Co., Ltd. Method for producing adenine compound
WO2011068233A1 (en) * 2009-12-03 2011-06-09 Dainippon Sumitomo Pharma Co., Ltd. Imidazoquinolines which act via toll - like receptors (tlr)
WO2011079016A1 (en) * 2009-12-22 2011-06-30 Gilead Sciences, Inc. Methods of treating hbv and hcv infection
EP2674170B1 (en) 2012-06-15 2014-11-19 Invivogen Novel compositions of TLR7 and/or TLR8 agonists conjugated to lipids
CN112587658A (en) 2012-07-18 2021-04-02 博笛生物科技有限公司 Targeted immunotherapy for cancer
EP2732825B1 (en) 2012-11-19 2015-07-01 Invivogen Conjugates of a TLR7 and/or TLR8 agonist and a TLR2 agonist
EP2769738B1 (en) 2013-02-22 2016-07-20 Invivogen Conjugated TLR7 and/or TLR8 and TLR2 polycationic agonists
AU2015205756A1 (en) 2014-01-10 2016-07-21 Birdie Biopharmaceuticals Inc. Compounds and compositions for treating EGFR expressing tumors
CN106943598A (en) 2016-01-07 2017-07-14 博笛生物科技（北京）有限公司 Anti- HER2 for treating tumour is combined
CN115554406A (en) 2016-01-07 2023-01-03 博笛生物科技有限公司 anti-CD 20 combinations for the treatment of tumors
CN106943597A (en) 2016-01-07 2017-07-14 博笛生物科技（北京）有限公司 Anti-EGFR for treating tumour is combined
CN108794467A (en) 2017-04-27 2018-11-13 博笛生物科技有限公司 2- amino-quinoline derivatives
BR112019027025A2 (en) 2017-06-23 2020-06-30 Birdie Biopharmaceuticals, Inc. pharmaceutical compositions
US10857153B2 (en) 2018-06-04 2020-12-08 Apros Therapeutics, Inc. Pyrimidine compounds containing acidic groups
JP7233809B2 (en) * 2018-09-04 2023-03-07 エフ． ホフマン－ラ ロシュ アーゲー Benzothiazole compounds for the treatment of autoimmune diseases

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1550662A1 (en) * 2002-09-27 2005-07-06 Sumitomo Pharmaceuticals Company, Limited Novel adenine compound and use thereof
EP1728793A1 (en) * 2004-03-26 2006-12-06 Dainippon Sumitomo Pharma Co., Ltd. 9-substituted 8-oxoadenine compound
WO2007031726A1 (en) * 2005-09-16 2007-03-22 Astrazeneca Ab Purine derivatives having immuno-modulating properties
WO2007034173A1 (en) * 2005-09-22 2007-03-29 Astrazeneca Ab Purine derivatives for the treatment of viral or allergic diseases and cancers
WO2007034881A1 (en) * 2005-09-22 2007-03-29 Dainippon Sumitomo Pharma Co., Ltd. Novel adenine compound
WO2007034882A1 (en) * 2005-09-22 2007-03-29 Dainippon Sumitomo Pharma Co., Ltd. Novel adenine compound
WO2007034917A1 (en) * 2005-09-22 2007-03-29 Dainippon Sumitomo Pharma Co., Ltd. Novel adenine compound

Family Cites Families (69)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1375162A (en) 1970-10-22 1974-11-27
GB1546937A (en) * 1976-07-29 1979-05-31 Beecham Group Ltd 2,4-diaminopyrimidine derivatives
SE8404768L (en) 1983-09-27 1985-03-28 Ceskoslovenska Akademie Ved 9- (AMINOALKYL) -8-HYDROXIADENINES AND SETS FOR THEIR PREPARATION
IL73534A (en) * 1983-11-18 1990-12-23 Riker Laboratories Inc 1h-imidazo(4,5-c)quinoline-4-amines,their preparation and pharmaceutical compositions containing certain such compounds
ZA848968B (en) * 1983-11-18 1986-06-25 Riker Laboratories Inc 1h-imidazo(4,5-c)quinolines and 1h-imidazo(4,5-c)quinolin-4-amines
IL78643A0 (en) * 1985-05-02 1986-08-31 Wellcome Found Purine derivatives,their preparation and pharmaceutical compositions containing them
DE3603577A1 (en) * 1986-02-06 1987-08-13 Joachim K Prof Dr Seydel NEW SUBSTITUTED 2,4-DIAMINO-5-BENZYLPYRIMIDINE, THEIR PRODUCTION AND USE THEREOF AS A MEDICINE WITH ANTIBACTERIAL EFFECTIVENESS
JPH08165292A (en) 1993-10-07 1996-06-25 Techno Res Kk Adenine derivative,its production and application
US5994361A (en) 1994-06-22 1999-11-30 Biochem Pharma Substituted purinyl derivatives with immunomodulating activity
US5736549A (en) * 1994-10-05 1998-04-07 Chiroscience Limited Hypoxanthine and guanine compounds
TW552261B (en) 1996-07-03 2003-09-11 Japan Energy Corp Novel purine derivative
DE69817393T2 (en) * 1997-11-28 2004-06-17 Sumitomo Pharmaceuticals Co., Ltd. NEW HETEROCYCLIC CONNECTIONS
JPH11180981A (en) 1997-12-19 1999-07-06 Sumitomo Pharmaceut Co Ltd Heterocyclic derivative
TW572758B (en) 1997-12-22 2004-01-21 Sumitomo Pharma Type 2 helper T cell-selective immune response inhibitors comprising purine derivatives
JP4160645B2 (en) 1997-12-24 2008-10-01 大日本住友製薬株式会社 Novel adenine derivatives and their pharmaceutical use
JP4189048B2 (en) 1997-12-26 2008-12-03 大日本住友製薬株式会社 Heterocyclic compounds
WO2000012487A1 (en) 1998-08-27 2000-03-09 Sumitomo Pharmaceuticals Co., Ltd. Pyrimidine derivatives
JP2000159767A (en) 1998-11-26 2000-06-13 Sumitomo Pharmaceut Co Ltd New production process for 8-hydroxyadenine derivative
CZ27399A3 (en) 1999-01-26 2000-08-16 Ústav Experimentální Botaniky Av Čr Substituted nitrogen heterocyclic derivatives process of their preparation, the derivatives employed as medicaments, pharmaceutical composition and a compound pharmaceutical preparation in which these derivatives are comprised as well as use of these derivatives for preparing medicaments
US6573273B1 (en) * 1999-06-10 2003-06-03 3M Innovative Properties Company Urea substituted imidazoquinolines
US6331539B1 (en) 1999-06-10 2001-12-18 3M Innovative Properties Company Sulfonamide and sulfamide substituted imidazoquinolines
US6756382B2 (en) * 1999-06-10 2004-06-29 3M Innovative Properties Company Amide substituted imidazoquinolines
GB9924361D0 (en) 1999-10-14 1999-12-15 Pfizer Ltd Purine derivatives
US20020040032A1 (en) * 2000-07-07 2002-04-04 Glasky Michelle S. Methods for stimulation of synthesis of synaptophysin in the central nervous system
US6630478B2 (en) * 2000-07-07 2003-10-07 Neotherapeutics, Inc. Methods for treatment of drug-induced peripheral neuropathy
US20020128264A1 (en) * 2000-07-07 2002-09-12 Taylor Eve M. Methods for treatment of conditions affected by activity of multidrug transporters
US6887880B2 (en) * 2000-11-20 2005-05-03 Millennium Pharmaceuticals, Inc. Adenine based inhibitors of adenylyl cyclase, pharmaceutical compositions, and method of use thereof
US6677348B2 (en) * 2000-12-08 2004-01-13 3M Innovative Properties Company Aryl ether substituted imidazoquinolines
ATE404561T1 (en) * 2001-04-17 2008-08-15 Dainippon Sumitomo Pharma Co NEW ADENINE DERIVATIVES
ITRM20010465A1 (en) * 2001-07-31 2003-01-31 Sigma Tau Ind Farmaceuti DERIVATIVES OF TRIAZOLYL-IMIDAZOPYRIDINE AND OF TRIAZOLYLPURINES USEFUL AS LIGANDS OF THE ADENOSINE A2A RECEPTOR AND THEIR USE AS MEDICAM
US20060252774A1 (en) * 2002-05-02 2006-11-09 Vatner Stephen F Regulation of type 5 adenylyl cyclase for treatment of neurodegenerative and cardiac diseases
US7115373B2 (en) * 2002-06-27 2006-10-03 Genox Research, Inc. Method of testing for atopic dermatitis by measuring expression of the NOR-1 gene
WO2004011481A1 (en) 2002-07-30 2004-02-05 Sankyo Co Phosmidosine derivative and process for producing the same
JP2004137157A (en) 2002-10-16 2004-05-13 Sumitomo Pharmaceut Co Ltd Medicine comprising new adenine derivative as active ingredient
EP1599726A4 (en) 2003-02-27 2009-07-22 3M Innovative Properties Co Selective modulation of tlr-mediated biological activity
JP2006523452A (en) 2003-03-25 2006-10-19 スリーエム イノベイティブ プロパティズ カンパニー Selective activation of cellular activity mediated through a common Toll-like receptor
CA2528774A1 (en) * 2003-06-20 2005-01-27 Coley Pharmaceutical Gmbh Small molecule toll-like receptor (tlr) antagonists
AU2004271972B2 (en) * 2003-09-05 2010-06-03 Anadys Pharmaceuticals, Inc. TLR7 ligands for the treatment of hepatitis C
JP2005089334A (en) 2003-09-12 2005-04-07 Sumitomo Pharmaceut Co Ltd 8-hydroxyadenine compound
WO2005092892A1 (en) 2004-03-26 2005-10-06 Dainippon Sumitomo Pharma Co., Ltd. 8-oxoadenine compound
EP1784180A4 (en) 2004-09-02 2009-07-22 3M Innovative Properties Co 2-amino 1h imidazo ring systems and methods
EP1845988A2 (en) 2005-02-11 2007-10-24 3M Innovative Properties Company Substituted imidazoquinolines and imidazonaphthyridines
CA2607780A1 (en) 2005-05-04 2006-11-09 Pfizer Limited Purine derivatives
JPWO2006129784A1 (en) 2005-06-03 2009-01-08 独立行政法人理化学研究所 Interferon-α regulator
US20090324551A1 (en) * 2005-08-22 2009-12-31 The Regents Of The University Of California Office Of Technology Transfer Tlr agonists
EP1939202A4 (en) 2005-09-22 2010-06-16 Dainippon Sumitomo Pharma Co Novel adenine compound
EP1939200A4 (en) * 2005-09-22 2010-06-16 Dainippon Sumitomo Pharma Co Novel adenine compound
US20090281075A1 (en) * 2006-02-17 2009-11-12 Pharmacopeia, Inc. Isomeric purinones and 1h-imidazopyridinones as pkc-theta inhibitors
WO2008004948A1 (en) * 2006-07-05 2008-01-10 Astrazeneca Ab 8-oxoadenine derivatives acting as modulators of tlr7
DK2038290T3 (en) * 2006-07-07 2013-12-02 Gilead Sciences Inc Modulators of toll-like receptor 7
TW200831105A (en) * 2006-12-14 2008-08-01 Astrazeneca Ab Novel compounds
DK2125792T3 (en) * 2007-02-19 2011-03-07 Glaxosmithkline Llc Purine derivatives as immunomodulators
ATE530549T1 (en) * 2007-03-19 2011-11-15 Astrazeneca Ab 9-SUBSTITUTED 8-OXOADENINE COMPOUNDS AS MODULATORS OF THE TOLL-LIKE RECEPTOR (TLR7)
EP2132209B8 (en) * 2007-03-19 2014-04-16 AstraZeneca AB 9-substituted-8-oxo-adenine compounds as toll-like receptor (tlr7 ) modulators
AR065784A1 (en) * 2007-03-20 2009-07-01 Dainippon Sumitomo Pharma Co DERIVATIVES OF 8-OXO ADENINE, DRUGS THAT CONTAIN THEM AND USES AS THERAPEUTIC AGENTS FOR ALLERGIC, ANTIVIRAL OR ANTIBACTERIAL DISEASES.
JPWO2008114819A1 (en) * 2007-03-20 2010-07-08 大日本住友製薬株式会社 New adenine compounds
CA2686163A1 (en) * 2007-05-08 2008-11-13 Astrazenca Ab Imidazoquinolines with immuno-modulating properties
CN101784548B (en) * 2007-06-29 2013-07-17 吉里德科学公司 Purine derivatives and their use as modulators of Toll-like receptor 7
PE20091236A1 (en) * 2007-11-22 2009-09-16 Astrazeneca Ab PYRIMIDINE DERIVATIVES AS IMMUNOMODULATORS OF TLR7
EP2246353A4 (en) 2008-01-17 2011-04-20 Dainippon Sumitomo Pharma Co Method for producing adenine compound
WO2009091031A1 (en) * 2008-01-17 2009-07-23 Dainippon Sumitomo Pharma Co., Ltd. Method for producing adenine compound
WO2009151910A2 (en) * 2008-05-25 2009-12-17 Wyeth Combination product of receptor tyrosine kinase inhibitor and fatty acid synthase inhibitor for treating cancer
BRPI0917458A2 (en) * 2008-08-11 2015-12-01 Glaxosmithkline Llc compound, method of treating disease and conditions, pharmaceutical composition, method for treating or preventing disease, and use of a compound
UA103195C2 (en) * 2008-08-11 2013-09-25 Глаксосмитклайн Ллк Purine derivatives for use in the treatment of allergic, inflammatory and infectious diseases
KR101616396B1 (en) * 2008-08-11 2016-04-28 글락소스미스클라인 엘엘씨 Novel adenine derivatives
US8575181B2 (en) * 2008-08-11 2013-11-05 Glaxosmithkline Llc Purine derivatives for use in the treatment of allergic, inflammatory and infectious diseases
WO2010018132A1 (en) * 2008-08-11 2010-02-18 Smithkline Beecham Corporation Compounds
GB0908772D0 (en) * 2009-05-21 2009-07-01 Astrazeneca Ab New salts 756
WO2011068233A1 (en) * 2009-12-03 2011-06-09 Dainippon Sumitomo Pharma Co., Ltd. Imidazoquinolines which act via toll - like receptors (tlr)

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1550662A1 (en) * 2002-09-27 2005-07-06 Sumitomo Pharmaceuticals Company, Limited Novel adenine compound and use thereof
EP1728793A1 (en) * 2004-03-26 2006-12-06 Dainippon Sumitomo Pharma Co., Ltd. 9-substituted 8-oxoadenine compound
WO2007031726A1 (en) * 2005-09-16 2007-03-22 Astrazeneca Ab Purine derivatives having immuno-modulating properties
WO2007034173A1 (en) * 2005-09-22 2007-03-29 Astrazeneca Ab Purine derivatives for the treatment of viral or allergic diseases and cancers
WO2007034881A1 (en) * 2005-09-22 2007-03-29 Dainippon Sumitomo Pharma Co., Ltd. Novel adenine compound
WO2007034882A1 (en) * 2005-09-22 2007-03-29 Dainippon Sumitomo Pharma Co., Ltd. Novel adenine compound
WO2007034917A1 (en) * 2005-09-22 2007-03-29 Dainippon Sumitomo Pharma Co., Ltd. Novel adenine compound

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LEE J. ET AL.: "Activation of anti-hepatitis C virus responses via Toll-like receptor 7", PNAS, vol. 13, no. 6, 7 February 2006 (2006-02-07), pages 1828 - 1833, XP003018389 *
See also references of EP2041135A4 *

Cited By (81)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8575180B2 (en) 2004-03-26 2013-11-05 Astrazeneca Aktiebolag 9-substituted 8-oxoadenine compound
US8969362B2 (en) 2004-03-26 2015-03-03 Astrazeneca Aktiebolag 9-substituted 8-oxoadenine compound
US8012964B2 (en) * 2004-03-26 2011-09-06 Dainippon Sumitomo Pharma Co., Ltd. 9-substituted 8-oxoadenine compound
US20110306610A1 (en) * 2004-03-26 2011-12-15 Astrazeneca Aktiebolag 9-substituted 8-oxoadenine compound
US8138172B2 (en) * 2006-07-05 2012-03-20 Astrazeneca Ab 8-oxoadenine derivatives acting as modulators of TLR7
US8067411B2 (en) * 2006-12-14 2011-11-29 Astrazeneca Ab Compounds
US7977344B2 (en) * 2007-02-19 2011-07-12 Glaxosmithkline Llc Compounds
WO2008114006A1 (en) * 2007-03-19 2008-09-25 Astrazeneca Ab 9-substituted-8-oxo-adenine compounds as toll-like receptor (tlr7) modulators
US8063051B2 (en) 2007-03-19 2011-11-22 Astrazeneca Ab 9-substituted-8-oxo-adenine compounds as toll-like receptor (TLR7) modulators
JP2010522150A (en) * 2007-03-19 2010-07-01 アストラゼネカ・アクチエボラーグ 9-Substituted-8-oxo-adenine compounds as TOLL-like receptor (TLR7) modulators
US8067413B2 (en) * 2007-03-19 2011-11-29 Astrazeneca Ab 9-substituted-8-oxo-adenine compounds as toll-like receptor (TLR7 ) modulators
US8044056B2 (en) * 2007-03-20 2011-10-25 Dainippon Sumitomo Pharma Co., Ltd. Adenine compound
US7968544B2 (en) * 2007-06-29 2011-06-28 Gilead Sciences, Inc. Modulators of toll-like receptor 7
US8993755B2 (en) 2007-06-29 2015-03-31 Gilead Sciences, Inc. Modulators of toll-like receptor 7
US9611268B2 (en) 2007-06-29 2017-04-04 Gilead Sciences, Inc. Modulators of toll-like receptor 7
US20110236348A1 (en) * 2007-06-29 2011-09-29 Gilead Sciences, Inc. Modulators of toll-like receptor 7
US8268990B2 (en) 2007-11-22 2012-09-18 Astrazeneca Ab Compounds
US8765939B2 (en) 2007-11-22 2014-07-01 Astrazeneca Ab Pyrimidline derivatives having immune modulating properties that act via TLR7 for the treatment of viral or allergic diseases and cancers
US8865896B2 (en) 2008-01-17 2014-10-21 Astrazeneca Aktiebolag Method for preparing adenine compound
WO2009091032A1 (en) * 2008-01-17 2009-07-23 Dainippon Sumitomo Pharma Co., Ltd. Method for producing adenine compound
US8466167B2 (en) 2008-03-03 2013-06-18 Irm Llc Compounds and compositions as TLR activity modulators
US8895577B2 (en) 2008-03-03 2014-11-25 Tom Yao-Hsiang Wu Compounds and compositions as TLR activity modulators
US9233962B2 (en) 2008-08-11 2016-01-12 Glaxosmithkline Llc Purine derivatives for use in the treatment of allergic, inflammatory and infectious diseases
US9346806B2 (en) 2008-08-11 2016-05-24 Glaxosmithkline Llc 6-amino-purin-8-one compounds
US9877968B2 (en) 2008-08-11 2018-01-30 Glaxosmithkline Llc 6-amino-purin-8-one compounds
US10117873B2 (en) 2008-08-11 2018-11-06 Glaxosmithkline Llc 6-amino-purin-8-one compounds
US8067426B2 (en) * 2008-08-11 2011-11-29 Glaxosmithkline Llc 6-amino-purin-8-one compounds
US11110091B2 (en) 2008-12-09 2021-09-07 Gilead Sciences, Inc. Modulators of toll-like receptors
US8476288B2 (en) 2009-05-21 2013-07-02 Astrazeneca Ab Salts 756
US9950062B2 (en) 2009-09-02 2018-04-24 Glaxosmithkline Biologicals Sa Compounds and compositions as TLR activity modulators
US8507507B2 (en) 2009-10-22 2013-08-13 Gilead Sciences, Inc. Modulators of toll-like receptors
US9161934B2 (en) 2009-10-22 2015-10-20 Gilead Sciences, Inc. Derivatives of purine or deazapurine useful for the treatment of (inter alia) viral infections
US8962652B2 (en) 2009-10-22 2015-02-24 Gilead Sciences, Inc. Derivatives of purine or deazapurine useful for the treatment of (inter alia) viral infections
US9315530B2 (en) 2010-09-01 2016-04-19 Novartis Ag Adsorption of immunopotentiators to insoluble metal salts
WO2012031140A1 (en) 2010-09-01 2012-03-08 Novartis Ag Adsorption of immunopotentiators to insoluble metal salts
US10098949B2 (en) 2010-09-01 2018-10-16 Glaxosmithkline Biologicals S.A. Adsorption of immunopotentiators to insoluble metal salts
EP2719395A1 (en) 2010-09-01 2014-04-16 Novartis AG Adsorption of immunopotentiators to insoluble metal salts
US10287264B2 (en) 2010-11-16 2019-05-14 Texas Heart Institute Agonists that enhance binding of integrin-expressing cells to integrin receptors
US10035784B2 (en) 2010-11-16 2018-07-31 Texas Heart Institute Agonists that enhanced binding of integrin-expressing cells to integrin receptors
EP2881393B1 (en) * 2010-11-16 2018-06-06 Texas Heart Institute Agonists that enhance binding of integrin-expressing cells to integrin receptors
US10071980B2 (en) 2010-11-16 2018-09-11 Texas Heart Institute Agonists that enhanced binding of integrin-expressing cells to integrin receptors
US9045472B2 (en) 2010-12-16 2015-06-02 Astrazeneca Ab Imidazoquinoline compounds
US8895570B2 (en) 2010-12-17 2014-11-25 Astrazeneca Ab Purine derivatives
US10603369B2 (en) 2011-03-02 2020-03-31 Glaxosmithkline Biologicals Sa Combination vaccines with lower doses of antigen and/or adjuvant
US10112946B2 (en) 2011-07-22 2018-10-30 Glaxosmithkline Llc Composition
WO2013030378A1 (en) 2011-09-01 2013-03-07 Novartis Ag Adjuvanted formulations of staphylococcus aureus antigens
WO2013072518A1 (en) 2011-11-20 2013-05-23 Glaxosmithkline Biologicals S.A. Vaccine comprising a tlr-5 agonist as adjuvant for use in cutaneous immunisation
WO2013072519A1 (en) 2011-11-20 2013-05-23 Glaxosmithkline Biologicals S.A. Vaccine
WO2013131983A1 (en) 2012-03-07 2013-09-12 Novartis Ag Adjuvanted formulations of streptococcus pneumoniae antigens
WO2013131984A1 (en) 2012-03-07 2013-09-12 Novartis Ag Adjuvanted formulations of rabies virus immunogens
US9931399B2 (en) 2012-03-08 2018-04-03 Glaxosmithkline Biologicals Sa Adjuvanted formulations of booster vaccines
WO2013132041A2 (en) 2012-03-08 2013-09-12 Novartis Ag Adjuvanted formulations of booster vaccines
US9375471B2 (en) 2012-03-08 2016-06-28 Glaxosmithkline Biologicals Sa Adjuvanted formulations of booster vaccines
US10842868B2 (en) 2012-03-08 2020-11-24 Glaxosmithkline Biologicals Sa Adjuvanted formulations of booster vaccines
US10150743B2 (en) 2012-05-18 2018-12-11 Sumitomo Dainippon Pharma Co., Ltd. Carboxylic acid compounds
US11299465B2 (en) 2012-05-18 2022-04-12 Sumitomo Dainippon Pharma Co., Ltd. Carboxylic acid compounds
US10562861B2 (en) 2012-05-18 2020-02-18 Sumitomo Dainippon Pharma Co., Ltd. Carboxylic acid compounds
US9376398B2 (en) 2012-05-18 2016-06-28 Sumitomo Dainippon Pharma Co., Ltd Carboxylic acid compounds
US10022442B2 (en) 2012-08-24 2018-07-17 Glaxosmithkline Llc Pyrazolopyrimidine compounds
US9662336B2 (en) 2012-08-24 2017-05-30 Glaxosmithkline Llc Pyrazolopyrimidine compounds
US9555036B2 (en) 2012-08-24 2017-01-31 Glaxosmithkline Llc Pyrazolopyrimidine compounds
US9526776B2 (en) 2012-09-06 2016-12-27 Glaxosmithkline Biologicals Sa Combination vaccines with serogroup B meningococcus and D/T/P
WO2014037472A1 (en) 2012-09-06 2014-03-13 Novartis Ag Combination vaccines with serogroup b meningococcus and d/t/p
US9540383B2 (en) 2012-11-20 2017-01-10 Glaxosmithkline Llc Pyrrolopyrimidines as therapeutic agents for the treatment of diseases
US9907847B2 (en) 2012-11-20 2018-03-06 Glaxosmithkline Llc Pyrrolopyrimidines as therapeutic agents for the treatment of diseases
US9428512B2 (en) 2012-11-20 2016-08-30 Glaxosmithkline Llc Compounds
US9550785B2 (en) 2012-11-20 2017-01-24 Glaxosmithkline Llc Pyrrolopyrimidines as therapeutic agents for the treatment of diseases
EP4001311A1 (en) 2014-07-09 2022-05-25 Birdie Biopharmaceuticals Inc. Anti-pd-l1 combinations for treating tumors
WO2016004875A1 (en) 2014-07-09 2016-01-14 Shanghai Birdie Biotech, Inc. Combination therapy compositions and methods for treating cancers
WO2016004876A1 (en) 2014-07-09 2016-01-14 Shanghai Birdie Biotech, Inc. Anti-pd-l1 combinations for treating tumors
US11116774B2 (en) 2014-07-11 2021-09-14 Gilead Sciences, Inc. Modulators of toll-like receptors for the treatment of HIV
EP4148069A1 (en) 2014-09-01 2023-03-15 Birdie Biopharmaceuticals Inc. Anti-pd-l1 conjugates for treating tumors
EP3763742A1 (en) 2014-09-01 2021-01-13 Birdie Biopharmaceuticals Inc. Anti-pd-l1 conjugates for treating tumors
US10202384B2 (en) 2014-09-16 2019-02-12 Gilead Sciences, Inc. Solid forms of a toll-like receptor modulator
US11773098B2 (en) 2014-09-16 2023-10-03 Gilead Sciences, Inc. Solid forms of a toll-like receptor modulator
US11072615B2 (en) 2014-09-16 2021-07-27 Gilead Sciences, Inc. Solid forms of a toll-like receptor modulator
US10508117B2 (en) 2014-09-16 2019-12-17 Gilead Sciences, Inc. Solid forms of a toll-like receptor modulator
CN109715214A (en) * 2016-09-13 2019-05-03 豪夫迈·罗氏有限公司 The combined therapy of TLR7 agonist and HBV Mouth Disease Virus Proteins inhibitor
US11337982B2 (en) 2016-09-13 2022-05-24 Hoffmann-La Roche, Inc. Combined treatment with a TLR7 agonist and an HBV capsid assembly inhibitor
CN109715214B (en) * 2016-09-13 2022-03-04 豪夫迈·罗氏有限公司 Combination therapy of a TLR7 agonist and an HBV capsid assembly inhibitor
WO2022084417A1 (en) 2020-10-21 2022-04-28 Univerza V Ljubljani Conjugated tlr7 and nod2 agonists

Also Published As

Publication number Publication date
EP2041135A1 (en) 2009-04-01
US8138172B2 (en) 2012-03-20
JP2009542645A (en) 2009-12-03
US20100240623A1 (en) 2010-09-23
EP2041135A4 (en) 2010-12-01

Similar Documents

Publication Publication Date Title
US8138172B2 (en) 8-oxoadenine derivatives acting as modulators of TLR7
EP2155743B1 (en) Imidazoquinolines with immuno-modulating properties
EP2121693B1 (en) 8-oxoadenine derivatives as immuno-modulators
EP2139894B1 (en) 9-substituted-8-oxo-adenine compounds as toll-like receptor (tlr7) modulators
EP2132209B1 (en) 9-substituted-8-oxo-adenine compounds as toll-like receptor (tlr7 ) modulators
US8044056B2 (en) Adenine compound
US20090082332A1 (en) Purine derivatives for the treatment of viral or allergic diseases and cancers
US20110136801A1 (en) Novel Compounds
WO2007031726A1 (en) Purine derivatives having immuno-modulating properties
WO2012080730A1 (en) Purine derivatives
NZ580622A (en) Imidazoquinolines with immuno-modulating properties

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: 07748310

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2009518052

Country of ref document: JP

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2007748310

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: RU

WWE Wipo information: entry into national phase

Ref document number: 12305801

Country of ref document: US