• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    This invention relates to piperidino-pyhmidine derivatives, processes for their preparation, pharmaceutical compositions, and their use in treating viral infections.
    公开号:AU2013218072A1
    申请号:U2013218072
    申请日:2013-02-07
    公开日:2014-07-24
    发明作者:Mourad DAOUBI KHAMLICHI；Tim Hugo Maria Jonckers；David Craig Mc Gowan；Pierre Jean-Marie Bernard Raboisson
    申请人:Janssen R&D Ireland ULC；
    IPC主号:C07D471-04
    专利说明:
    WO 2013/117615 PCT/EP2013/052372 -1 PIPERIDINO-PYRIMIDINE DERIVATIVES FOR THE TREATMENT OF VIRAL INFECTIONS. This invention relates to piperdino-pyrimidine derivatives, processes for their preparation, pharmaceutical compositions, and their use in treating viral 5 infections. The present invention relates to the use of piperidino-pyrimidine derivatives in the treatment of viral infections, immune or inflammatory disorders, whereby the modulation, or agonism, of toll-like-receptors (TLRs) is involved. Toll-Like Receptors are primary transmembrane proteins characterized by an 10 extracellular leucine rich domain and a cytoplasmic extension that contains a conserved region. The innate immune system can recognize pathogen associated molecular patterns via these TLRs expressed on the cell surface of certain types of immune cells. Recognition of foreign pathogens activates the production of cytokines and upregulation of co-stimulatory molecules on 15 phagocytes. This leads to the modulation of T cell behaviour. It has been estimated that most mammalian species have between ten and fifteen types of Toll-like receptors. Thirteen TLRs (named TLR1 to TLR13) have been identified in humans and mice together, and equivalent forms of many of these have been found in other mammalian species. However, 20 equivalents of certain TLR found in humans are not present in all mammals. For example, a gene coding for a protein analogous to TLR10 in humans is present in mice, but appears to have been damaged at some point in the past by a retrovirus. On the other hand, mice express TLRs 11, 12, and 13, none of which are represented in humans. Other mammals may express TLRs which 25 are not found in humans. Other non-mammalian species may have TLRs distinct from mammals, as demonstrated by TLR14, which is found in the Takifugu pufferfish. This may complicate the process of using experimental animals as models of human innate immunity. For detailed reviews on toll-like receptors see the following journal articles. 30 Hoffmann, J.A., Nature, 426, p33-38, 2003; Akira, S., Takeda, K., and Kaisho, T., Annual Rev. Immunology, 21, p335-376, 2003; Ulevitch, R. J., Nature Reviews: Immunology, 4, p512-520, 2004. Compounds indicating activity on Toll-Like receptors have been previously described such as purine derivatives in WO 2006/117670, adenine derivatives 35 in WO 98/01448 and WO 99/28321, and pyrimidines in WO 2009/067081.
    WO 2013/117615 PCT/EP2013/052372 -2 However, there exists a strong need for novel Toll-Like receptor modulators having preferred selectivity, higher potency, higher metabolic stability, and an improved safety profile (for instance a reduced CVS risk) compared to the compounds of the prior art. 5 In accordance with the present invention a compound of formula (1) is provided N N X X.B
    H
    2 N N (I) or a pharmaceutically acceptable salt, tautomer(s), solvate or polymorph thereof, wherein A is selected from the group consisting of CH 2 , NCOR 2 , CHR 3 and CR 3
    R
    3 in 10 any stereo chemical configuration, B is selected from the group consisting of CH 2 , NCOR 4 , CHR 3 and CR 3
    R
    3 in any stereo chemical configuration, with the proviso that when A is NCOR 2 then B is not NCOR 4 and with the proviso that A and B are not both selected from CH 2 , CHR 3 or CR 3
    R
    3 , 15 X is selected from CH 2 or CHR 5 in any stereo chemical configuration,
    R
    1 is selected from C 1
    .
    8 alkyl optionally substituted with one or more of the following: C 1
    .
    6 alkyl, C 3
    .
    7 cycloalkyl, hydroxyl, hydroxyalkyl, amino, nitrile, alkoxy, alkoxy(C 1
    .
    4 )alkyl, carboxylic acid, carboxylic ester, carbamate or sulfone,
    R
    2 is selected from substituted and unsubstituted C 1
    .
    6 alkyl, C 3
    .
    7 cycloalkyl, 20 heterocycle, aryl, heteroaryl, heteroarylalkyl, each of which is optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino, C1.
    6 alkyl, di-(C 1
    .
    6 )alkylamino, C 1
    .
    6 alkylamino, C1.
    6 alkyl, C1.
    6 alkoxy, C3.
    6 cycloalkyl, carboxylic acid, carboxylic ester, carboxylic amide, heterocycle, aryl, alkenyl, alkynyl, arylalkyl, heteroaryl, heteroarylalkyl or nitrile, 25 R 3 is selected from hydrogen, substituted and unsubstituted C1.
    6 alkyl, alkoxy, alkoxy-(C 1
    .
    4 )alkyl, C3.
    7 cycloalkyl, C4.
    7 heterocycle, aromatic, bicyclic heterocycle, arylalkyl, heteroaryl, heteroarylalkyl each of which is optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino, C1.
    6 alkyl, di-(C 1
    .
    6 )alkylamino, C 1
    .
    6 alkylamino, C1.
    6 alkyl, WO 2013/117615 PCT/EP2013/052372 -3
    C
    1
    .
    6 alkoxy, C 3
    .
    6 cycloalkyl, carboxylic acid, carboxylic ester, carboxylic amide, heterocycle, aryl, alkenyl, alkynyl, arylalkyl, heteroaryl, heteroarylalkyl or nitrile,
    R
    4 is selected from substituted or unsubstituted C 1
    .
    7 alkyl, alkoxy, alkoxy
    (C
    1
    .
    4 )alkyl, aryl or C 3
    .
    7 cycloalkyl each of which is optionally substituted by 5 heterocycle, nitrile, heteroarylalkyl or heteroaryl and wherein
    R
    5 is selected from aromatic, bicyclic heterocycle, aryl, heteroaryl, each of which is optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino, C 1
    .
    6 alkyl, di-(C 1
    .
    6 )alkylamino,
    C
    1
    .
    6 alkylamino, C 1
    .
    6 alkyl, C 1
    .
    6 alkoxy, C 3
    .
    6 cycloalkyl, carboxylic acid, carboxylic 10 ester, carboxylic amide, heterocycle, aryl, alkenyl, alkynyl, arylalkyl, heteroaryl, heteroarylalkyl or nitrile. In a first embodiment the present invention provides compounds of formula (1) wherein R1 is butyl and wherein A, B, and X are as specified above. In a further embodiment the invention concerns compounds of formula (1) 15 wherein R 1 is C 4
    .
    8 alkyl substituted with hydroxyl, and wherein A, B, and X are as specified above. Another embodiment relates to compounds of formula I wherein R 1 , being
    C
    4
    .
    8 alkyl substituted with hydroxyl, is one of the following OH HO (S) ,A (S), OH HO 20 Furthermore, the present invention also provides compounds of formula (1) wherein X is CH 2 and wherein A, and B are as specified above. In another embodiment the present invention provides compounds of formula (I) wherein X is CH 2 and wherein A is CH 2 and B are as specified above. Furthermore, the invention relates to compounds of formula (1) wherein R 2 is 25 one of the following examples that can be further substituted with C 1
    .
    3 alkyl, hydroxyl, alkoxy, nitrile, heterocycle, carboxylic ester, or carboxylic amide: WO 2013/117615 PCT/EP2013/052372 -4 Preferred compounds are compound numbers 3 and 1 having the following chemical structures respectively: NH NN 1 N 0NH O H N and H 2 N NN 5 Other preferred compounds according to the invention are the compounds having the following chemical structures: OH OH (S) HO NH HN 0 HN 0 N N 0 N N N N N H2N N N
    H
    2 N N ,H 2 N N and - . The compounds of formula (I) and their pharmaceutically acceptable salt, tautomer(s), solvate or polymorph thereof have activity as pharmaceuticals, in 10 particular as modulators of Toll-Like Receptors (especially TLR7 and/or TLR8) activity. In a further aspect the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof together with one or more 15 pharmaceutically acceptable excipients, diluents or carriers. Furthermore a compound of formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof according to the current invention, or a pharmaceutical composition comprising said compound of formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof can be used as 20 a medicament.
    WO 2013/117615 PCT/EP2013/052372 -5 Another aspect of the invention is that a compound of formula (1) or a pharmaceutically acceptable salt, solvate or polymorph thereof, or said pharmaceutical composition comprising said compound of formula (1) or a pharmaceutically acceptable salt, solvate or polymorph thereof can be used 5 accordingly in the treatment of a disorder in which the modulation of TLR7 and /or TLR8 is involved. The term "alkyl" refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon containing the specified number of carbon atoms. The term "halogen" refers to fluorine, chlorine, bromine or iodine. 10 The term "alkenyl" refers to an alkyl as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond. The term " alkynyl" refers to an alkyl as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond. The term "cycloalkyl" refers to a carbocyclic ring containing the specified 15 number of carbon atoms. The term "heteroaryl" means an aromatic ring structure as defined for the term "aryl" comprising at least 1 heteroatom selected from N, 0 and S, in particular from N and 0. The term "aryl" means an aromatic ring structure optionally comprising one or 20 two heteroatoms selected from N, 0 and S, in particular from N and 0. Said aromatic ring structure may have 4, 5, 6 or 7 ring atoms. In particular, said aromatic ring structure may have 5 or 6 ring atoms. The term "bicyclic heterocycle" means an aromatic ring structure, as defined for the term "aryl" comprised of two fused aromatic rings. Each ring is optionally 25 comprised of heteroatoms selected from N, 0 and S, in particular from N and 0. The term "arylalkyl" means an aromatic ring structure as defined for the term "aryl" optionally substituted with an alkyl group. The term "heteroarylalkyl" means an aromatic ring structure as defined for the 30 term "heteroaryl" optionally substituted by an alkyl group.
    WO 2013/117615 PCT/EP2013/052372 -6 The term "alkoxy" refers to an alkyl (carbon and hydrogen chain) group singular bonded to oxygen like for instance a methoxy group or ethoxy group. Heterocycle refers to molecules that are saturated or partially saturated and include ethyloxide, tetrahydrofuran, dioxane or other cyclic ethers. 5 Heterocycles containing nitrogen include, for example azetidine, morpholine, piperidine, piperazine, pyrrolidine, and the like. Other heterocycles include, for example, thiomorpholine, dioxolinyl, and cyclic sulfones. Heteroaryl groups are heterocyclic groups which are aromatic in nature. These are monocyclic, bicyclic, or polycyclic containing one or more heteroatoms 10 selected from N, 0 or S. Heteroaryl groups can be, for example, imidazolyl, isoxazolyl, furyl, oxazolyl, pyrrolyl, pyridonyl, pyridyl, pyridazinyl, or pyrazinyl. Pharmaceutically acceptable salts of the compounds of formula (1) include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Suitable base salts are formed from 15 bases which form non-toxic salts. The compounds of the invention may also exist in unsolvated and solvated forms. The term "solvate" is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. 20 The term "polymorph" refers to the ability of the compound of the invention to exist in more than one form or crystal structure. The compounds of the present invention may be administered as crystalline or amorphous products. They may be obtained for example as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze 25 drying, spray drying, or evaporative drying. They may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs. Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe any ingredient other 30 than the compound(s) of the invention. The choice of excipient depends largely on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. The compounds of the present invention or any subgroup thereof may be formulated into various pharmaceutical forms for administration purposes. As WO 2013/117615 PCT/EP2013/052372 -7 appropriate compositions there may be cited all compositions usually employed for systemically administering drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate 5 admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, for example, for oral, rectal, or percutaneous administration. For example, in preparing the compositions in oral dosage form, 10 any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions, and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets. 15 Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed. Also included are solid form preparations that can be converted, shortly before use, to liquid forms. In the compositions suitable for percutaneous administration, the carrier optionally comprises a 20 penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered 25 in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment. The compounds of the present invention may also be administered via inhalation or insufflation by means of methods and formulations employed in the art for administration via this way. Thus, in general the compounds of the present invention may be administered to the lungs in the form of a solution, a 30 suspension or a dry powder. It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of 35 active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, WO 2013/117615 PCT/EP2013/052372 -8 powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof. Those of skill in the treatment of infectious diseases will be able to determine the effective amount from the test results presented hereinafter. In general it is 5 contemplated that an effective daily amount would be from 0.01 mg/kg to 50 mg/kg body weight, more preferably from 0.1 mg/kg to 10 mg/kg body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 1 to 1000 mg, and in 10 particular 5 to 200 mg of active ingredient per unit dosage form. The exact dosage and frequency of administration depends on the particular compound of formula (1) used, the particular condition being treated, the severity of the condition being treated, the age, weight and general physical condition of the particular patient as well as other medication the individual may 15 be taking, as is well known to those skilled in the art. Furthermore, it is evident that the effective amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. The effective amount ranges mentioned above are therefore only guidelines and are not 20 intended to limit the scope or use of the invention to any extent.
    WO 2013/117615 PCT/EP2013/052372 -9 General synthetic methods Scheme 1
    NH
    2
    NH
    2 O O N N N N OH C N Guanidine carbonate POCl 3 , neat DMF, butylamine HCI Bn EtOH, 120 0 C N 1 OOC N 100 0 C, 2h Bn Bn II IV NBOC2NBoc2 1. O NH2
    NH
    2 RBoc 2 NR4 C N N N N NN N N R T 0HN 0 C to rt, base R1 N N Boc H Cl-H BoQ2O Boc H 2 , Pd/C, rt Nlt 2. HCI N N DMAP, THE, 80 0 C N H Bn Bn or R4 O O compounds of formula (I) V VI VII
    R
    4 OH coupling agent 5 Compounds of formula (1) wherein B is NCOR 4 were prepared according to scheme 1. In the preparation of III it was found that guanidine carbonate can be used with or without a base (e.g. sodium ethoxide) in an alcoholic solvent such as ethanol. Chlorination of the hydroxypyrimidine ring (III) to afford chloropyrimide IV can be done with a chlorinating agent such as POCl 3 either 10 as a solvent, together with other solvents (i.e. dichloromethane) or in combination with a base, for example NN-dimethylaniline. Displacement of the chlorine to give intermediate V can be done at high temperature in a polar solvent (e.g. acetonitrile or DMF) with excess amine (NH 2
    -R
    1 ) with or without a base (e.g. DIPEA). Boc protection of V to afford intermediate VI can be 15 executed using catalytic NN-dimethylaminopyridine (DMAP) in a non-polar solvent such as dichloromethane or THF. Removal of the N-benzyl (Bn) group can be done via catalytic hydrogenation. Formation of the amide products of formula I can be made by reacting VII with either: an acid chloride in combination with excess base (e.g. triethylamine); a carboxylic acid in 20 combination with a coupling agent (e.g. HBTU) and a base (e.g. triethylamine).
    WO 2013/117615 PCT/EP2013/052372 -10 Examples. Preparation of compounds of formula I. Scheme 2.
    NH
    2 NH 2 O O N N N N Guanidine carbonate POC3, neat DMF, butylamine N EtOH, 12000 Nl POlet M, uylmn HCI n N 1000C N 100 C, 2h Bn Bn A B C 1.
    NH-
    2 NBoc 2 NBoc 2 0NH- 2 N N N Bc2N NBo R 4 CI N N ____ -- I-__ 000 to rt Z_ N N Boc 2HIH H ABoC 2 0 Boc H 2 , Pd/C, Boc 2. Ct N OMAP, THE, 8000C H Bn Bn R 4 0 D E F compounds formula (1) 5 Preparation of B
    NH
    2 O O N N OH N Guanidine carbonate N HCI EtOH, 1200C A B A suspension of A (19.5 g, 68.7 mmol) and guanidine carbonate (19.5 g, 41.23 mmol) in ethanol (170 mL) was heated for 16 hours at 1200C. The 10 solvent was removed under reduced pressure, reconstituted in acetonitril where the crude precipitated and was isolated by filtration. The solid was used as such in the next step without further purification. 1 H NMR (300 MHz, DMSO-d 6 ) 6 ppm 2.35 - 2.46 (m, 2 H), 2.57 - 2.65 (m, 2 H), 3.04 (s, 2 H), 3.60 (s, 2 H), 6.28 (br. s., 2 H), 7.27 (dt, J=8.7, 4.5 Hz, 1 H), 7.31 15 - 7.36 (m, 4 H), 10.74 (br. s., 1 H) MS m/z: 257 [M+H*] WO 2013/117615 PCT/EP2013/052372 -11 Preparation of C
    NH
    2 NH 2 N N N N OH CI N POCl 3 N B C A solution of B (8.2 g, 32 mmol) in phosphoryl oxychloride (POC 3 ) (90 mL) was heated for 16 hours at 1000C. After cooling, the solvent was removed under 5 reduced pressure and the residue was dissolved in ethyl acetate (150 mL), and washed with saturated, aqueous NaHCO 3 (3 x 100 mL). The organic layers were combined, dried over magnesium sulfate, the solids were removed by filtration, and the solvents of the filtrate were removed under reduced pressure. The solid was used in the next step without further purification. 10 MS m/z: 275 [M+H*] Preparation of D
    NH
    2
    NH
    2 N N H2N NN CI N H N dioxane, 120 0 C c D A solution of C (2.78 g, 10.12 mmol) in dioxane (25 mL) and n-butylamine (1.5 15 mL, 15.2 mmol) was heated for 16 hours at 1200C. After cooling to room temperature, the solvent was removed under reduced pressure and the crude was purified via silica gel column chromatography using a dichloromethane to 5% methanol in dichloromethane gradient. 1 H NMR (300 MHz, CHLOROFORM-d) 6 ppm 0.90 - 1.01 (m, 3 H), 1.28 - 1.46 20 (m, 2 H), 1.49 - 1.64 (m, 2 H), 2.70 - 2.81 (m, 4 H), 3.21 (s, 2 H), 3.44 (td, WO 2013/117615 PCT/EP2013/052372 -12 J=7.1, 5.7 Hz, 2 H), 3.74 (s, 2 H), 4.47 (br. s., 1 H), 5.21 - 5.46 (m, 2 H), 7.30 7.40 (m, 5 H) MS m/z: 312 [M+H*] 5 Preparation of E
    NH
    2 NBoc 2 N~ N N INN N H Boc N Boc 2 0 N DMAP/THF D E A solution of D (3 g, 9.63 mmol), di-tert-butyl dicarbonate (12.6 g, 57.8 mmol) and 4-NN-dimethylaminopyridine (0.118 g, 0.1 mmol) in THF (60 mL) was 10 heated to 800C for 4 hours. The reaction cooled to room temperature and the solvent was removed under reduced pressure. The crude was purified via silica gel column chromatography using a heptane to ethyl acetate gradient. MS m/z: 612 [M+H*] 15 Preparation of F NBoc 2 NBoc 2 N N N N Boc Boc N H 2 , Pd/C N F E To a solution of E (0.711g, 1.16 mmol) ethanol (6 mL) was added 0.2 w/w equivalent of Pd/C (10%, wet) (71 mg). The flask was sealed; the atmosphere was removed by vacuum. The flask was equipped with a balloon filled with WO 2013/117615 PCT/EP2013/052372 -13 hydrogen gas. The mixture stirs at room temperature for 16 hours. The mixture was filtered over packed celite and the solvent of the filtrate was removed under reduced pressure. The crude was purified via silica gel column chromatography using a dichloromethane to 5% methanol in dichloromethane 5 gradient. 1 H NMR (300 MHz, CHLOROFORM-d) 6 ppm 0.90 (t, J=7.4 Hz, 3 H), 1.19 1.36 (m, 2 H), 1.41 - 1.50 (m, 27 H), 1.51 - 1.58 (m, 2 H), 1.64 (s, 2 H), 2.91 3.02 (m, 2 H), 3.26 (t, J=6.1 Hz, 2 H), 3.71 - 3.82 (m, 2 H), 3.86 (s, 1 H) MS m/z: 523 [M+H*] 10 Preparation of compound 1 1. Et 3 N/DMAP
    CH
    2 Cl 2 o NH 2 NBoc 2 CI N NN NN N H N Boc 2. HCI N H F To a mixture of F (100 mg, 0.191 mmol), DMAP (2 mg, 0.0.19 mmol) and Et 3 N (0.081 mL, 0.576 mmol) in dichloromethane (2 mL) was added cyclo 15 butanecarbonyl chloride (25 mg, 0.21 mmol) at 00C. The mixture was allowed to reach room temperature and stirred for 16 hours. HCI (1 N, 1 mL) was added and the reaction stirred for further 30 minutes, then was added NaHCO 3 (sat. aq., 10 mL). The mixture was extracted with ethyl acetate (3 x 10 mL) and the combined organic layers were dried over MgSO 4 , the solids were removed via 20 filtration and the solvents of the filtrate were removed under reduced pressure. The crude was purified via silica column chromatography using a heptane to ethyl acetate gradient. The best fractions were pooled, and the solvents were removed under reduced pressure to afford compound 1. MS m/z: 304 [M+H*] 25 WO 2013/117615 PCT/EP2013/052372 -14 Examples. Compounds of formula (1) wherein A is NCOR 2 were prepared according to scheme 3. Scheme 3.
    NH
    2 NH 2 0 0 N N N N 0 N Guanidine carbonate OH P CI M utylamine HOI EtOH, 12000 N, POCl 3 , neat N000, buAmn 1000010c,2 G H
    NH
    2 NBoc 2 NBoc 2 NH 2 N N N N N N N<N N Nl - N Boc HN Boc N Boc 2 O H 2 /Pd/C 0 DMAP/THF R 2 AC R 2 Hunig's base Products or K L 0
    R
    2 OH 5 coupling agent Preparation of H
    NH
    2 O O N N N Guanidine carbonate OH HCI EtOH, 120 0 C N G H A suspension of G (0.5 g, 1.76 mmol) and guanidine carbonate (190 mg, 1.06 mmol) in ethanol (5 mL) was heated to reflux for 16 hours. The solvent 10 was removed under reduced pressure, the crude precipitated in acetonitrile and was isolated via filtration. The solid was used as such in the next step without further purification. MS m/z: 257 [M+H*] WO 2013/117615 PCT/EP2013/052372 -15 Preparation of I
    NH
    2 NH 2 N N N N OH CI N POCl 3 , neat N 1000C H A solution of H (6 g, 23.4 mmol) in phosphoryloxychloride (POC 3 ) (65 mL) was heated for 3 hours at 1000C. After cooling, the solvent was removed under 5 reduced pressure and the residue was dissolved in ethyl acetate (150 mL), washed with saturated, aqueous NaHCO 3 (3 x 100 mL). The organic layers were combined, dried over magnesium sulfate, the solids were removed by filtration, and the solvents of the filtrate were removed under reduced pressure. The crude solid was purified via silica gel column chromatography using a 10 dichloromethane in 5% methanol gradient. MS m/z: 275 [M+H*] Preparation of J
    NH
    2 NH 2 N N N) N CI N N DMA, butylamine N 100 C, 2h J 15 A solution of 1(2.78 g, 10.12 mmol) in DMA (25 mL) and n-butylamine (1.5 mL, 15.2 mmol) was heated for 16 hours at 1200 C. After cooling to room temperature, the solvent was removed under reduced pressure and the crude was purified via silica gel column chromatography using a dichloromethane to 3% methanol in dichloromethane gradient.
    WO 2013/117615 PCT/EP2013/052372 -16 1 H NMR (300 MHz, CHLOROFORM-d) 6 ppm 0.76 - 0.87 (m, 3 H), 1.16 - 1.35 (m, 2 H), 1.38 - 1.71 (m, 2 H), 2.00 (quin, J=6.9 Hz, 2 H), 2.64 (td, J=7.4, 2.4 Hz, 2 H), 3.46 (dd, J=11.4, 2.6 Hz, 1 H), 3.52 (dd, J=5.1, 2.2 Hz, 1 H), 3.72 (s, 2 H), 3.84 (td, J=6.3, 1.8 Hz, 1 H), 4.06 (d, J=2.7 Hz, 1 H), 4.48 (br. s., 2 H), 5 4.89 (d, J=8.7 Hz, 1 H), 6.72 - 6.80 (m, 2 H), 7.02 (d, J=8.7 Hz, 2 H), 7.25 (s, 1 H) MS m/z: 312 [M+H*] Preparation of K
    NH
    2 N N NBoc 2 N' R 1 N N N H N Boc 2 O N Boc N DMAP/THF 10 K A solution of J (3 g, 9.63 mmol), di-tert-butyl dicarbonate (12.6 g, 57.8 mmol) and 4-NN-dimethylamino pyridine (0.118 g, 0.1 mmol) in THF (50 mL) was heated to 800C for 4 hours. The reaction cooled to room temperature and the solvent was removed under reduced pressure. The crude was purified via silica 15 gel column chromatography using a heptane to ethyl acetate gradient. MS m/z: 612 [M+H*] Preparation of L NBoc 2 NBoc 2 N N N N N Boc H 2 , Pd/C HN Boc L
    K
    WO 2013/117615 PCT/EP2013/052372 -17 To a solution of K (0.711 g. 1.16 mmol) ethanol (6 mL) was added 0.2 w/w equivalent of Pd/C (10%, wet) (0.071 g) and stirred under an atmosphere of hydrogen (balloon) for 16 hours. The mixture was filtered over packed celite and the solvent of the filtrate was removed under reduced pressure. The crude 5 was purified via silica gel column chromatography using a heptanes to ethyl acetate gradient. MS m/z: 523 [M+H*] Preparation of compound 2 0 ~ NH2 N Boc2 e CI N N N N -I N N 1. DIPEA, CH 2
    C
    2 0 N H HN Boc rt,16h 2.HCI in isopropanol L 10 2 To a solution of L (100 mg, 0.191 mmol) was added Et 3 N (58 mg, 0.58 mmol) benzoyl chloride (30 mg, 0.211 mmol) in dichloromethane (3 mL), and DMAP (2mg, 0.019 mmol) then stirred at room temperature for 16 hours. To this was added NaHCO 3 (sat., aq., 10 mL) and the mixture was extracted with ethyl 15 acetate (3 x 10 mL). The organic layers were combined, dried over MgSO 4 , the solids were removed via filtration and the solvents of the filtrate were removed under reduced pressure. The crude was purified via silica column chromato graphy using a dichloromethane to 5% methanol in dichloromethane gradient. The purified boc-protected product was deprotected by addition of HCI in 20 isopropanol.
    WO 2013/117615 PCT/EP2013/052372 -18 Preparation of compound 3 0 OH
    NH
    2 NBoc 2 N' N N N N _N 0 N H N Boc 1. HBTU, DIPEA HN DMF, rt, 16 h 2. HCI, isopropanol - N L 3 To a solution of L (90 mg, 0.173 mmol) in DMF (3 mL) was added DIPEA (33 mg, 0.26 mmol), HBTU (72 mg, 0.19 mmol) and 1-methyl-2 5 pyrrolecarboxylic acid (23 mg, 0.18 mmol) was added then stirred at room temperature for 16 hours. To this was added NaHCO 3 (sat., aq., 10 mL) and the mixture was extracted with ethyl acetate (3 x 10 mL). The organic layers were combined, dried (MgSO 4 ), the solids were removed by filtration and the solvents of the filtrate were removed under reduced pressure. The crude was 10 purified via silica column chromatography using a using a dichloromethane to 3% methanol in dichloromethane gradient. The purified boc-protected product was deprotected by addition of HCI in isopropanol. Preparation of compound 4 0
    NH
    2 NBoc 2 CI N H N N N N1 0NNH Boc O N A HN 1. Et3N, DCM, rt, 16 h 2. HCI, isopropanol L 15 4 To a stirring solution of L (110 mg, 0.2 mmol) in dichloromethane (2 mL), triethylamine (60 mg, 0.6 mmol), DMAP (6 mg, 0.05 mmol) and cyclopropanecarbonyl chloride (24 mg, 0.23 mmol) were added and the mixture stirred at room temperature for 16 hours. To this was added NaHCO 3 20 (sat., aq., 50 mL) and the mixture was extracted with ethyl acetate (3 x 10 mL). The organic layers were combined, dried (MgSO 4 ), the solids were removed by WO 2013/117615 PCT/EP2013/052372 -19 filtration and the solvents of the filtrate were removed under reduced pressure. The crude was purified via silica column chromatography using a heptane to ethyl acetate gradient. The purified boc-protected product was deprotected by addition of HCI in isopropanol. 5 Table 1: Compounds of formula (I). Products were prepared by one of the methods described above. Table I A represent compounds wherein A=NCOR 2 while Table I B represents compounds wherein B=NCOR 4 and Table I C contains both region-isomeric 10 compounds respectively. Table I A Exact LC-MS # STRUCTURE Mass (M+H) NMR 1H NMR (300 MHz, CHLOROFORM-d) 6 N N N ppm 0.89 (t, J=7.3 Hz, 3 H), 1.25 - 1.40 (m, 2 H), 1.51 (quin, J=7.3 Hz, 2 H), 1.59 2 325.19 326 N (s, 1 H), 2.34 (br. s., 2 H), 3.37 (td, J=7.0, 5.7 Hz, 2 H), 3.95 (br. s., 1 H), 4.12 - 4.72 (m, 5 H), 7.35 (d, J=2.7 Hz, 5 H) 1H NMR (300 MHz, METHANOL-d4) 6 N ppm 0.86 (t, J=7.4 Hz, 3 H), 1.29 (dd, N N N J=15.1, 7.4 Hz, 2 H), 1.41 - 1.57 (m, 2 H), 3 328.20 329 2.34 (s, 2 H), 3.31 (t, J=7.2 Hz, 2 H), 3.63 N (s, 3 H), 3.85 (t, J=6.0 Hz, 2 H), 4.42 (s, 3 N 0 H), 4.51 - 4.62 (m, 2 H), 6.01 (dd, J=3.8, 2.6 Hz, 1 H), 6.37 (dd, J=3.8, 1.6 Hz, 1 H), 6.74 (d, J=2.2 Hz, 1 H) 1H NMR (300 MHz, CHLOROFORM-d) 6 ppm 0.73 - 0.84 (m, 2 H), 0.92 - 0.99 (m, N N'N 3 H), 1.00 (br. s., 1 H), 1.40 (dq, J=14.9, 7.3 Hz, 2 H), 1.59 (quin, J=7.3 Hz, 2 H), 4 289.19 290 N 1.70 (s, 3 H), 1.78 (br. s., 1 H), 2.25 - 2.48 (m, 2 H), 3.36 - 3.51 (m, 2 H), 3.88 (m, J=5.1 Hz, 2 H), 4.39 - 4.57 (m, 2 H), 4.63 (br. s., 1 H) WO 2013/117615 PCT/EP2013/052372 -20 Exact LC-MS # STRUCTURE Mass (M+H) NMR 1H NMR (300 MHz, DMSO-d6) 6 ppm N N 0.92 (t, J=7.3 Hz, 3 H), 1.24 - 1.42 (m, 2 N H), 1.49 - 1.63 (m, 2 H), 2.31 (s, 2 H), 3.26 9 N 345.16 346 - 3.41 (m, 2 H), 3.74 (s, 2 H), 4.00 (s, 2 H), CO. 4.26 (s, 2 H), 5.39 (br. s., 2 H), 5.93 - 6.10 (m, 1 H), 6.85 - 7.01 (m, 2 H), 7.27 - 7.40 (m, 1 H) 1H NMR (300 MHz, METHANOL-d4) 6 N N 7N ppm 0.85 (t, J=7.3 Hz, 4 H), 1.28 (d, J=7.8 Hz, 3 H), 1.49 (t, J=7.3 Hz, 3 H), 2.15 (s, 3 10 343.21 344 N H), 2.29 - 2.39 (m, 2 H), 3.33 (t, J=7.2 Hz, N N o 2 H), 3.73 (s, 4 H), 3.81 - 3.96 (m, 1 H), 4.22 - 4.51 (m, 2 H), 6.22 (s, 1 H) 1H NMR (300 MHz, DMSO-d6) 6 ppm N 0.85 - 1.00 (m, 3 H), 1.24 - 1.43 (m, 3 H), N N 1.50 - 1.61 (m, 2 H), 1.74 - 1.87 (m, 1 H), 11 303.21 304 1.92 - 2.03 (m, 1 H), 2.09 - 2.23 (m, 3 H), 2.27 - 2.34 (m, 2 H), 3.28 - 3.47 (m, 3 H), 3.54 - 3.69 (m, 2 H), 4.05 - 4.23 (m, 2 H), 5.31 - 5.47 (m, 2 H), 5.92 - 6.07 (m, 1 H) 1H NMR (300 MHz, DMSO-d6) 6 ppm 0.90 (t, J=1.0 Hz, 3 H), 1.21 - 1.38 (m, 2 N N N H), 1.45 - 1.58 (m, 2 H), 2.33 - 2.43 (m, 2 H), 3.23 - 3.32 (m, 2 H), 3.75 - 3.89 (m, 2 12 331.15 332 N H), 4.31 - 4.46 (m, 2 H), 5.67 - 5.83 (m, 2 H), 6.31 - 6.47 (m, 1 H), 7.08 - 7.23 (m, 1 H), 7.40 - 7.52 (m, 1 H), 7.75 - 7.84 (m, 1 H) 1H NMR (300 MHz, DMSO-d6) 6 ppm N 0.84 (t, J=7.3 Hz, 3 H), 0.96 (d, J=6.7 Hz, 6 N N H), 1.26 (d, J=7.4 Hz, 2 H), 1.46 (t, J=7.2 13 291.21 292 Hz, 2 H), 2.25 (br. s., 2 H), 2.75 - 2.89 (m, 1 H), 3.26 (d, J=6.6 Hz, 2 H), 3.62 (t, J=5.8 Hz, 2 H), 4.15 (s, 2 H), 5.29 (br. s., 2 H), 5.82 - 6.04 (m, 1 H) WO 2013/117615 PCT/EP2013/052372 -21 Exact LC-MS # STRUCTURE Mass (M+H) NMR 1H NMR (300 MHz, METHANOL-d4) 6 N ppm 0.86 (t, J=7.3 Hz, 3 H), 1.28 (m, J=7.8 N N Hz, 2 H), 1.50 (s, 2 H), 2.31 - 2.49 (m, 2 14 332.14 333 H), 3.29 - 3.40 (m, 2 H), 3.91 (t, J=5.8 Hz, 2 H), 4.39 - 4.63 (m, 2 H), 8.05 (d, J=1.9 0N Hz, 1 H), 8.97 (d, J=2.1 Hz, 1 H) exchangable protons not shown. 1H NMR (300 MHz, DMSO-d6) 6 ppm N N N 0.92 (t, J=7.3 Hz, 3 H), 1.35 (d, J=7.3 Hz, 2 H), 1.55 (s, 2 H), 2.36 (s, 2 H), 3.34 (d, 15 347.15 348 N J=6.5 Hz, 2 H), 3.86 (s, 2 H), 4.42 (s, 2 H), N N 0 5.36 (s, 2 H), 5.90 - 6.06 (m, 1 H), 6.82 (br. s., 2 H), 6.97 (s, 1 H) 1H NMR (300 MHz, DMSO-d6) 6 ppm N N' N 0.84 (t, J=1.0 Hz, 3 H), 1.16 - 1.20 (m, 1 H), 1.22 - 1.34 (m, 2 H), 1.39 - 1.55 (m, 2 16 293.19 294 N H), 2.18 - 2.33 (m, 2 H), 3.24 (s, 4 H), 3.52 - 3.65 (m, 2 H), 4.04 (s, 2 H), 4.12 (s, 2 H), 5.20 - 5.39 (m, 2 H), 5.85 - 6.01 (m, 1 H) 1H NMR (300 MHz, CHLOROFORM-d) 6 N ppm 0.97 (t, J=7.3 Hz, 3 H), 1.36 - 1.47 N N (m, 2 H), 1.52 - 1.61 (m, 2 H), 2.12 - 2.20 17 263.17 264 (m, 3 H), 2.26 - 2.42 (m, 2 H), 3.35 - 3.52 N (m, 2 H), 3.70 (t, J=5.8 Hz, 1 H), 3.86 (t, J=5.9 Hz, 1 H), 4.31 (s, 2 H), 4.40 - 4.50 (m, 1 H), 4.65 (br. s., 2 H) 1H NMR (300 MHz, METHANOL-d4) 6 N ppm 0.86 (t, J=7.4 Hz, 3 H), 1.28 (m, N _N J=15.2, 7.4 Hz, 2 H), 1.51 (m, J=7.2, 7.2 18 N329.20 330 Hz, 2 H), 2.32 - 2.51 (m, 2 H), 3.38 (t, J=7.2 Hz, 2 H), 3.73 (s, 3 H), 3.91 (d, J=5.4 Hz, 2 H), 4.40 - 4.54 (m, 1 H), 4.67 (br. s., 1 H), 6.96 (s, 1 H), 7.14 (s, 1 H) exchangable protons not shown.
    WO 2013/117615 PCT/EP2013/052372 -22 Exact LC-MS # STRUCTURE Mass (M+H) NMR 1H NMR (300 MHz, DMSO-d6) 6 ppm 0.92 (t, J=7.3 Hz, 3 H), 1.30 - 1.43 (m, 2 N H), 1.55 (m, J=7.1, 7.1 Hz, 2 H), 2.40 (t, N N J=5.5 Hz, 2 H), 3.35 (m, J=6.5 Hz, 2 H), 19 326.19 327 3.51 - 3.98 (m, 2 H), 4.23 - 4.45 (m, 2 H), 5.40 (br. s., 2 H), 5.94 - 6.14 (m, 1 H), N 0 7.42 - 7.52 (m, 1 H), 7.60 (d, J=7.8 Hz, 1 H), 7.83 - 8.00 (m, 1 H), 8.61 (d, J=4.7 Hz, 1 H) 1H NMR (300 MHz, CHLOROFORM-d) 6 N N ppm 0.97 (t, J=7.3 Hz, 3 H), 1.40 (dq, N N J=14.9, 7.3 Hz, 2 H), 1.51 - 1.67 (m, 2 H), 20 365.11 366 2.44 (t, J=5.8 Hz, 2 H), 3.45 (td, J=7.1, 5.6 Hz, 2 H), 3.79 - 4.11 (m, 2 H), 4.34 - 4.55 CI (m, 3 H), 4.66 (br. s., 2 H), 6.92 (d, J=5.2 Hz, 1 H), 7.38 (d, J=5.2 Hz, 1 H) 1H NMR (300 MHz, CHLOROFORM-d) 6 ppm 0.96 (t, J=7.3 Hz, 3 H), 1.34 - 1.48 N N N (m, 2 H), 1.51 - 1.66 (m, 2 H), 1.98 (br. s., 2 H), 2.41 (t, J=5.7 Hz, 2 H), 3.36 - 3.51 21 331.15 332 8N (m, 2 H), 3.76 - 4.11 (m, 2 H), 4.49 (br. s., 2 H), 4.66 (br. s., 1 H), 7.23 (dd, J=4.9, 1.1 Hz, 1 H), 7.34 (dd, J=4.9, 3.0 Hz, 1 H), 7.58 (dd, J=2.9, 1.2 Hz, 1 H) 1H NMR (300 MHz, CHLOROFORM-d) 6 ppm 0.96 (t, J=7.3 Hz, 3 H), 1.40 (dq, N N N J=15.0, 7.3 Hz, 2 H), 1.52 - 1.67 (m, 2 H), 1.88 (br. s., 2 H), 2.49 (q, J=6.0 Hz, 2 H), 22 327.18 328 N N 3.35 - 3.51 (m, 2 H), 4.07 (t, J=5.9 Hz, 1 H), 4.51 - 4.69 (m, 3 H), 4.77 (br. s., 1 H), 8.57 (m, J=2.2, 1.4 Hz, 1 H), 8.62 - 8.70 (m, 1 H), 8.96 - 9.05 (m, 1 H) WO 2013/117615 PCT/EP2013/052372 -23 Exact LC-MS # STRUCTURE Mass (M+H) NMR 1H NMR (300 MHz, DMSO-d6) 6 ppm N 0.89 (t, J=7.3 Hz, 3 H), 1.30 (dq, J=14.9, N NN 7.3 Hz, 2 H), 1.50 (quin, J=7.3 Hz, 2 H), 23 288.17 289 2.26 (t, J=5.6 Hz, 1 H), 2.36 (t, J=5.6 Hz, 1 N H), 3.24 - 3.33 (m, 2 H), 3.57 (t, J=5.8 Hz, / 'o 1 H), 3.67 (t, J=5.7 Hz, 1 H), 4.11 (s, 1 H), N 4.13 (s, 2 H), 4.19 (s, 1 H), 5.76 (d, J=7.3 Hz, 2 H), 6.40 (t, J=5.4 Hz, 1 H) 1H NMR (300 MHz, CHLOROFORM-d) 6 N ppm 0.96 (t, J=7.3 Hz, 3 H), 1.40 (dq, N N N J=15.0, 7.2 Hz, 2 H), 1.59 (quin, J=7.3 Hz, 24 331.16 332 2 H), 1.85 (br. s., 2 H), 2.34 (t, J=5.9 Hz, 1 N H), 2.41 (t, J=5.8 Hz, 1 H), 3.20 - 3.37 (m, F F o 2 H), 3.45 (td, J=7.0, 5.7 Hz, 2 H), 3.73 (t, J=5.8 Hz, 1 H), 3.91 (t, J=5.9 Hz, 1 H), 4.31 (s, 1 H), 4.58 - 4.81 (m, 2 H) Table I B Exact LC-MS # STRUCTURE NMR Mass (M+H) 1H NMR (300 MHz, DMSO-d6) 6 ppm 0.94 N (t, J=1.0 Hz, 3 H), 1.29 - 1.43 (m, 2 H), 1.51 N - 1.64 (m, 2 H), 1.73 - 1.84 (m, 1 H), 1.90 2.02 (m, 1 H), 2.08 - 2.29 (m, 4 H), 2.39 1 303.21 304 2.47 (m, 1 H), 3.19 - 3.25 (m, 1 H), 3.29 3.48 (m, 3 H), 3.52 - 3.63 (m, 2 H), 4.05 4.27 (m, 2 H), 5.33 - 5.49 (m, 2 H), 6.03 6.23 (m, 1 H) 1H NMR (300 MHz, CHLOROFORM-d) 6 N ppm 0.90 - 0.98 (m, 3 H), 1.39 (dq, J=14.9, N'N 7.3 Hz, 2 H), 1.50 - 1.65 (m, 2 H), 2.19 (s, 3 5 263.17 264 H), 2.69 (t, J=5.8 Hz, 2 H), 3.43 (td, J=7.1, 5.6 Hz, 2 H), 3.68 (t, J=5.9 Hz, 2 H), 4.29 (s, 2 H), 4.46 - 4.57 (m, 1 H), 4.67 - 4.85 (m, 2
    H)
    WO 2013/117615 PCT/EP2013/052372 -24 Exact LC-MS # STRUCTURE NMR Mass (M+H) 1H NMR (300 MHz, DMSO-d6) 6 ppm 0.90 N ( -, J=6.6 Hz, 3 H), 1.18 - 1.37 (m, 2 H), N 1.44 - 1.59 (m, 2 H), 2.32 - 2.40 (m, 2 H), 6 N 345.16 346 3.21 - 3.29 (m, 2 H), 3.61 - 3.76 (m, 2 H), 4.03 (s, 2 H), 4.16 - 4.34 (m, 2 H), 5.61 5.78 (m, 2 H), 6.24 - 6.45 (m, 1 H), 6.85 7.03 (m, 2 H), 7.30 - 7.46 (m, 1 H) N 1H NMR (300 MHz, DMSO-d6) 6 ppm 0.75 N N (t, J=7.4 Hz, 3 H), 0.87 (d, J=6.7 Hz, 6 H), 7 291.21 292 1.19 (s, 2 H), 1.38 (s, 2 H), 2.24 - 2.30 (m, 2 N H), 2.74 - 2.77 (m, 1 H), 3.18 (d, J=6.6 Hz, 2 H), 3.50 (s, 2 H), 4.06 (s, 2 H), 5.18 (br. s., 2 H), 5.86 - 6.02 (m, 1 H) 1H NMR (300 MHz, DMSO-d6) 6 ppm 0.96 N (td, J=7.3, 3.6 Hz, 3 H), 1.07 (t, J=7.4 Hz, 3 N -N H), 1.37 (s, 2 H), 1.56 (br. s., 2 H), 2.45 (dd, 8 N 277.19 278 J=7.4, 3.0 Hz, 3 H), 2.50 - 2.54 (m, 1 H), 3.29 - 3.34 (m, 2 H), 3.68 (d, J=8.0 Hz, 2 H), 4.23 (d, J=7.6 Hz, 2 H), 4.31 - 4.31 (m, 0 H), 5.80 (d, J=8.2 Hz, 2 H), 6.34 - 6.57 (m, 1 H) Table I C Exact LC-MS STRUCTURE # Mass (M+H) NMR IH NMR (300 MHz, CHLOROFORM-d) 6 ppm 0.68 - 1.01 (m, 7 H), 1.32 (dq, N N J=14.9, 7.3 Hz, 2 H), 1.43 - 1.62 N -N (m, 6 H), 1.76 (dd, J=12.5, 6.3 320.2 321 Hz, 1 H), 2.26 (td, J=14.2, 6.1 N N Hz, 2 H), 3.36 (q, J=6.6 Hz, 2 H), 3.42 (s, 1 H), 3.49 (d, J=5.2 Hz, 1 H), 3.66 (br. s., 1 H), 3.71 - 3.95 (m, 1 H), 4.17 - 4.30 (m, 25 1 H), 4.32 - 4.46 (m, 1 H), 4.53 (br. s., 2 H) WO 2013/117615 PCT/EP2013/052372 -25 Exact LC-MS STRUCTURE # Mass (M+H) NMR IH NMR (300 MHz, CHLOROFORM-d) 6 ppm 0.89 (t, J=7.3 Hz, 3 H), 1.08 - 1.25 N N (m, 3 H), 1.32 (dq, J=14.9, 7.3 N N Hz, 2 H), 1.44 - 1.65 (m, 6 H), 292.2 293 2.24 (t, J=5.6 Hz, 1 H), 3.31 N, N 3.40 (m, 2 H), 3.42 (s, 1 H), 3.71 - 3.91 (m, 2 H), 4.25 (d, J=8.2 Hz, 1 H), 4.31 - 4.46 (m, 26 1 H), 4.53 (br. s., 2 H) IH NMR (300 MHz, DMSO-d 6 ) 6 ppm 0.90 (t, J=7.3 Hz, 3 H), N 1.31 (dq, J=14.9, 7.3 Hz, 2 H), N N N 1.51 (quin, J=7.3 Hz, 2 H), 2.42 333.1 334 (t, J=5.2 Hz, 2 H), 3.18 - 3.28 (m, 2 H), 3.75 (t, J=5.4 Hz, 1 H), 3.96 (t, J=5.4 Hz, 1 H), 4.29 N - 4.60 (m, 2 H), 5.65 - 6.00 (m, 27 2 H), 6.33 - 6.66 (m, 1 H), 9.52 - 9.70 (m, 1 H) IH NMR (300 MHz, DMSO-d 6 ) N 6 ppm 0.93 (t, J=7.3 Hz, 3 H), 1.20 - 1.43 (m, 5 H), 1.48 - 1.62 N. N (m, 2 H), 2.38 (br. s., 2 H), 3.35 326.2 327 (q, J=6.5 Hz, 1 H), 3.51 - 3.80 N( (m, 1 H), 4.24 (br. s., 1 H), 5.40 (br. s., 2 H), 6.04 (br. s., 1 H), 28 7.39 (d, J=5.8 Hz, 2 H), 8.69 (d, J=5.8 Hz, 2 H) H NMR (300 MHz, DMSO-d 6 ) 6 ppm 0.92 (t, J=7.3 Hz, 3 H), N 1.19 - 1.44 (m, 3 H), 1.47 - 1.77 N / N (m, 6 H), 2.33 (t, J=5.8 Hz, 2 333.2 334 H), 2.94 (t, J=4.3 Hz, 2 H), 3.28 - 3.38 (m, 2 H), 3.44 (td, J=11.4, 2.4 Hz, 2 H), 3.72 (t, J=5.9 Hz, 2 H), 3.80 - 3.93 (m, 29 2 H), 5.38 (br. s., 2 H), 6.00 (br. s., 1 H) WO 2013/117615 PCT/EP2013/052372 -26 Exact LC-MS STRUCTURE # Mass (M+H) NMR IH NMR (300 MHz, DMSO-d 6 ) N 6 ppm 0.90 (t, J=7.3 Hz, 3 H), N1.00 (q, J=7.7 Hz, 3 H), 1.19 N N 1.38 (m, 2 H), 1.50 (quin, J=7.3 277.2 278 Hz, 2 H), 2.23 (t, J=5.5 Hz, 1 N H), 2.27 - 2.45 (m, 3 H), 3.27 /A (br. s., 2 H), 3.56 - 3.73 (m, 2 30 H), 4.18 (s, 2 H), 5.71 (br. s., 2 H), 6.16 - 6.42 (m, 1 H) N N N N 333.2 334 not available 31 * N I H NMR (300 MHz, DMSO-d 6 ) NN N 6 ppm 0.93 (t, J=7.3 Hz, 3 H), - 21.20 - 1.43 (m, 4 H), 1.56 (quin, N2882 28 J7.3 Hz, 2 H), 3.36 (q, J=6.2 Hz, 2 H), 3.63 (br. s., 2 H), 4.00 32 (s, 2 H), 4.21 (br. s., 2 H), 5.44 N (br. s., 2 H), 6.16 (br. s., 1 H) N N 331.1 332 not available 33 /S IH NMR (300 MHz, DMSO-d 6 ) N 6ppm 0.83 - 0.98 (m, 3 H), 1.22 N/NNN- 1.43 (m, 2 H), 1.48 - 1.65 (m, 2 H), 2.48 (s, 3 H), 3.02 - 3.07 N 330.2 331 (m, 2 H), 3.25 - 3.55 (m, 2 H), 3.64 - 3.96 (m, 2 H), 4.39 (br. s., / N 2 H), 5.42 (br. s., 2 H), 5.91 34 0 6.34 (m, 1 H), 6.36 - 6.49 (m, 1 H) IH NMR (300 MHz, DMSO-d 6 ) N 6ppm 0.93 (s, 3 H), 1.25 - 1.46 N N (m, 2 H), 1.49 - 1.64 (m, 2 H), 6 2.53 - 2.61 (m, 2 H), 3.28 - 3.44 N3162 317 (m, 2 H), 3.86 - 4.03 (m, 2 H), 4.30 - 4.51 (m, 2 H), 5.27 - 5.52 (m, 2 H), 6.02 - 6.25 (m, 1 H), 35 8.39 - 8.44 (m, 1 H), 8.46 - 8.50 (m,1 H) WO 2013/117615 PCT/EP2013/052372 -27 Exact LC-MS STRUCTURE # Mass (M+H) NMR IH NMR (300 MHz, DMSO-d 6 ) N 6 ppm 0.94 (t, J=7.4 Hz, 3 H), N N N1.37 (d, J=7.6 Hz, 2 H), 1.57 (s, 316.2 317 2 H), 2.43 (s, 2 H), 3.37 (d, N7 J=6.6 Hz, 2 H), 3.98 (br. s., 2 H), 4.52 (br. s., 2 H), 5.42 (br. N O s., 2 H), 5.97 - 6.14 (m, 1 H), 8.44 (s, 1 H), 8.50 (s, 1 H) H NMR (300 MHz, DMSO-d 6 ) 6 ppm 0.82 (d, J=7.4 Hz, 3 H), 1.11 - 1.31 (m, 2 H), 1.34 - 1.55 N (m, 2 H), 2.07 - 2.17 (m, 1 H), N N 3.16 - 3.21 (m, 2 H), 3.69 - 3.78 -7(m, 1 H), 3.87 - 4.01 (m, 1 H), N 376.2 3 4.47 (s, 2 H), 5.43 - 5.58 (m, 1 H), 5.69 - 5.80 (m, 2 H), 6.11 6.26 (m, 1 H), 7.54 - 7.69 (m, 1 H), 7.71 - 7.91 (m, 1 H), 7.72 7.82 (m, 1 H), 7.84 - 7.91 (m, 1 H), 7.97 - 8.06 (m, 1 H), 8.37 8.53 (m, 1 H) H NMR (300 MHz, DMSO-d 6 ) N 6 ppm 0.92 (t, J=7.3 Hz, 3 H), /-N 1.24 - 1.43 (m, 2 H), 1.55 (t, N. N1 J=7.3 Hz, 2 H), 2.40 (t, J=5.8 330.2 331 Hz, 2 H), 2.48 (s, 3 H), 3.35 (d, J=6.6 Hz, 2 H), 3.84 (br. s., 2 H), 4.38 (s, 2 H), 5.42 (br. s., 2 38 NH), 5.95 - 6.19 (m, 1 H), 6.42 (s, 1 H) IH NMR (300 MHz, DMSO-d 6 ) N 6 ppm 0.75 - 0.96 (m, 3 H), 1.14 N N - 1.39 (m, 3 H), 1.43 - 1.79 (m, 369.2 370 5 H), 3.38 - 3.51 (m, 2 H), 3.55 N - 3.73 (m, 2 H), 3.99 - 4.16 (m, 1 H), 4.21 - 4.39 (m, 3 H), 5.32 - 5.49 (m, 2 H), 5.68 - 5.83 (m, 1 H), 7.27 - 7.59 (m, 5 H) WO 2013/117615 PCT/EP2013/052372 -28 Exact LC-MS STRUCTURE # Mass (M+H) NMR IH NMR (300 MHz, DMSO-d 6 ) 6 ppm 0.91 (t, J=7.3 Hz, 3 H), 1.23 - 1.42 (m, 2 H), 1.54 (d, N N J=6.7 Hz, 2 H), 1.66 - 1.76 (m, N'N 2 H), 2.57 (t, J=5.8 Hz, 2 H), 376.2 377 3.49 (br. s., 2 H), 3.86 (d, J=5.9 N Hz, 1 H), 4.04 - 4.19 (m, 1 H), 4.22 - 4.37 (m, 1 H), 4.44 (s, 2 H), 5.43 (br. s., 2 H), 5.70 (s, 1 H), 5.75 - 5.91 (m, 1 H), 8.13 40 (d, J=1.9 Hz, 1 H), 9.15 (d, J=1.8 Hz, 1 H) IH NMR (300 MHz, DMSO-d 6 ) 6 ppm 0.92 (t, J=7.3 Hz, 3 H), 1.17 - 1.41 (m, 2 H), 1.57 (dt, N N J=14.2, 7.0 Hz, 2 H), 1.66 - 1.82 N N (m, 2 H), 2.60 (t, J=5.8 Hz, 2 359.2 360 H), 3.24 (br. s., 1 H), 3.51 (br. N s., 2 H), 3.89 (t, J=5.9 Hz, 2 H), 4.13 (br. s., 1 H), 4.43 (s, 2 H), 5.43 (s, 2 H), 5.84 (d, J=8.4 Hz, 1 H), 6.64 (dd, J=3.2, 1.5 Hz, 1 41 H), 7.04 (d, J=3.4 Hz, 1 H), 7.71 - 7.91 (m, 1 H) IH NMR (300 MHz, DMSO-d 6 ) 6 ppm 0.89 (t, J=7.3 Hz, 3 H), N N 1.12 (t, J=7.0 Hz, 1 H), 1.24 N N 1.40 (m, 2 H), 1.44 - 1.61 (m, 2 H), 1.62 - 1.78 (m, 2 H), 2.54 N 390.2 391 2.58 (m, 2 H), 2.71 (s, 3 H), 3.36 - 3.53 (m, 2 H), 3.85 (q, C, /N J=6.7 Hz, 1 H), 4.11 (br. s., 1 H), 4.20 - 4.35 (m, 1 H), 4.44 (s, 42 2 H), 5.40 (br. s., 2 H), 5.78 (d, J=6.7 Hz, 1 H), 7.87 (s, 1 H) IH NMR (300 MHz, DMSO-d 6 ) 6 ppm 0.85 (t, J=6.5 Hz, 3 H), o 1.25 (d, J=4.1 Hz, 4 H), 1.43 N 1.77 (m, 4 H), 2.57 (br. s., 2 H), N 3.40 (q, J=6.2 Hz, 2 H), 3.74 373.2 3 3.98 (m, 2 H), 4.15 - 4.30 (m, 1 H), 4.32 - 4.49 (m, 3 H), 5.80 - c (br. s, 2 H), 6.17 (br. s., 1 H), 6.66 (dd, J=3.4, 1.8 Hz, 1 H), 7.08 (d, J=3.3 Hz, 1 H), 7.86 (d, J=1.0 Hz, 1 H) WO 2013/117615 PCT/EP2013/052372 -29 Exact LC-MS STRUCTURE # Mass (M+H) NMR IH NMR (300 MHz, DMSO-d 6 ) 6 ppm 0.88 (t, J=6.2 Hz, 3 H), 1.31 (br. s., 4 H), 1.46 - 1.62 (m, N 2 H), 1.69 (dt, J=13.2, 6.6 Hz, 2 N N H), 2.53 - 2.59 (m, 2 H), 2.71 (s, N404.2 405 3 H), 3.48 (br. s., 2 H), 3.85 (dq, J=13.1, 6.8 Hz, 2 H), 4.11 (br. s., 1 H), 4.19 - 4.34 (m, 1 H), 4.44 (s, 2 H), 5.41 (br. s., 2 H), 5.79 (d, J=6.7 Hz, 1 H), 7.87 (s, 1 H) H NMR (300 MHz, DMSO-d 6 ) 6 ppm 0.87 (t, J=6.4 Hz, 3 H), 1.29 (d, J=3.3 Hz, 4 H), 1.45 1.60 (m, 2 H), 1.63 - 1.79 (m, 2 N NH), 2.58 (t, J=5.8 Hz, 2 H), 3.47 389.2 390 (d, J=4.8 Hz, 2 H), 3.84 (q, J=6.6 Hz, 2 H), 4.11 (br. s., 1 H), 4.19 - 4.34 (m, 1 H), 4.42 (s, s s2 H), 5.41 (s, 2 H), 5.81 (d, J=8.4 Hz, 1 H), 7.14 (t, J=4.3 Hz, 1 H), 7.48 (d, J=3.6 Hz, 1 H), 7.72 (d, J=4.9 Hz, 1 H) IH NMR (300 MHz, DMSO-d 6 ) 6 ppm 0.80 (t, J=6.8 Hz, 3 H), 1.11 - 1.30 (m, 3 H), 1.48 (br. s., N 2 H), 1.56 - 1.69 (m, 2 H), 2.48 N -- N (t, J=6.0 Hz, 2 H), 3.13 (d, - 390.2 391 J=5.1 Hz, 1 H), 3.39 (d, J=5.1 N Hz, 2 H), 3.76 (d, J=6.3 Hz, 2 H), 3.93 - 4.06 (m, 1 H), 4.09 S/N 4.24 (m, 1 H), 4.34 (s, 2 H), 5.32 (br. s., 2 H), 5.64 - 5.80 (m, 46 1 H), 8.03 (d, J=2.1 Hz, 1 H), 9.05 (d, J=1.9 Hz, 1 H) WO 2013/117615 PCT/EP2013/052372 -30 Exact LC-MS STRUCTURE # Mass (M+H) NMR IH NMR (300 MHz, DMSO-d 6 ) 6 ppm 0.76 - 0.99 (m, 3 H), 1.16 - 1.23 (m, 1 H), 1.27 - 1.39 (m, N N 2 H), 1.44 - 1.61 (m, 2 H), 1.65 - 1.81 (m, 2 H), 2.55 - 2.62 (m, 375.2 376 2 H), 3.18 - 3.28 (m, 2 H), 3.41 N - 3.53 (m, 1 H), 3.79 - 3.92 (m, 2 H), 4.40 - 4.47 (m, 2 H), 5.34 - 5.50 (m, 2 H), 5.81 - 5.89 (m, 1 H), 7.10 - 7.25 (m, 1 H), 7.41 - 7.54 (m, 1 H), 7.68 - 7.79 (m, 1 H) IH NMR (300 MHz, DMSO-d 6 ) o 6 ppm 0.87 (t, J=6.7 Hz, 3 H), N 1.29 (br. s., 4 H), 1.54 (br. s., 2 N NH), 1.67 (s, 2 H), 2.53 (br. s., 2 383.2 384 H), 3.46 (br. s., 2 H), 3.53 - 3.77 N (m, 2 H), 4.00 - 4.14 (m, 1 H), 48 e c= 4.20 - 4.28 (m, 1 H), 4.32 (s, 2 H), 5.40 (br. s., 2 H), 5.67 - 5.86 (m, 1 H), 7.27 - 7.53 (m, 5 H) IH NMR (300 MHz, DMSO-d 6 ) 6 ppm 0.70 - 0.83 (m, 3 H), 1.09 - 1.29 (m, 3 H), 1.32 - 1.71 (m, N N 4 H), 2.26 - 2.37 (m, 2 H), 3.32 N - 3.40 (m, 2 H), 3.56 - 3.64 (m, 372.2 373 3 H), 3.71 - 3.82 (m, 2 H), 4.10 N - 4.22 (m, 1 H), 4.26 - 4.32 (m, 2 H), 4.33 - 4.45 (m, 1 H), 5.61 - 5.74 (m, 1 H), 5.84 - 5.94 (m, 1 H), 5.96 - 6.04 (m, 1 H), 6.27 - 6.36 (m, 1 H), 6.81 - 6.88 (m, 1 H) IH NMR (300 MHz, DMSO-d 6 ) 6 ppm 0.77 - 0.92 (m, 3 H), 1.13 - 1.36 (m, 4 H), 1.39 - 1.74 (m, 4 H), 2.32 - 2.43 (m, 2 H), 3.38 N N .N- 3.47 (m, 2 H), 3.63 - 3.71 (m, N N 386.2 387 3 H), 3.77 - 3.90 (m, 2 H), 4.17 - 4.26 (m, 1 H), 4.32 - 4.38 (m, 2 H), 4.39 - 4.45 (m, 1 H), 5.65 - 5.76 (m, 2 H), 5.91 - 6.01 (m, 1 H), 6.02 - 6.10 (m, 1 H), 6.34 50 - 6.43 (m, 1 H), 6.89 - 6.95 (m, S1H) WO 2013/117615 PCT/EP2013/052372 -31 Exact LC-MS STRUCTURE # Mass (M+H) NMR IH NMR (300 MHz, DMSO-d 6 ) 6 ppm 0.68 (t, J=6.5 Hz, 3 H), 1.10 (d, J=3.3 Hz, 4 H), 1.27 1.40 (m, 2 H), 1.49 (dt, J=13.2, N 6.6 Hz, 2 H), 2.33 - 2.39 (m, 2 N H), 3.28 (t, J=6.2 Hz, 2 H), 3.50 386.2 387 (s, 3 H), 3.54 - 3.73 (m, 2 H), N 3.84 - 3.97 (m, 1 H), 4.07 (d, J=7.6 Hz, 1 H), 4.18 (s, 2 H), 5.28 (br. s., 2 H), 5.66 (d, J=8.4 Hz, 1 H), 5.81 - 5.91 (m, 1 H), 51 6.17 (dd, J=3.7, 1.5 Hz, 1 H), 6.67 (d, J=1.6 Hz, 1 H) IH NMR (300 MHz, DMSO-d 6 ) 6 ppm 0.80 - 1.01 (m, 3 H), 1.16 - 1.39 (m, 3 H), 1.44 - 1.78 (m, N 3 H), 2.26 - 2.46 (m, 2 H), 3.43 N N -3.56 (m, 2 H), 3.86 - 3.98 (m, 370.2 371 1 H), 4.06 - 4.13 (m, 1 H), 4.22 N - 4.34 (m, 1 H), 4.38 - 4.49 (m, N O 2 H), 5.64 - 5.73 (m, 1 H), 5.80 - 5.89 (m, 2 H), 5.93 - 6.15 (m, 52 1 H), 7.40 - 7.58 (m, 2 H), 8.69 - 8.81 (m, 2 H) Analytical Methods. All compounds were characterized by LC-MS. The following LC-MS methods were used: 5 All analyses were performed using an Agilent 1100 series LC/MSD quadrupole coupled to an Agilent 1100 series liquid chromatography (LC) system consisting of a binary pump with degasser, autosampler, thermostated column compartment and diode array detector. The mass spectrometer (MS) was operated with an atmospheric pressure electro-spray ionisation (API-ES) 10 source in positive ion mode. The capillary voltage was set to 3000 V, the fragmentor voltage to 70 V and the quadrupole temperature was maintained at 1000C. The drying gas flow and temperature values were 12.0 L/min and 3500C respectively. Nitrogen was used as the nebulizer gas, at a pressure of 35 psig. Data acquisition was performed with Agilent Chemstation software.
    WO 2013/117615 PCT/EP2013/052372 -32 Analyses were carried out on a YMC pack ODS-AQ C18 column (50 mm x 4.6 mm; 3pm particles) at 350C, with a flow rate of 2.6 mL/min. A gradient elution was performed from 95% (water + 0.1% formic acid) / 5% Acetonitrile to 5% (water + 0.1% formic acid) / 95% Acetonitrile in 4.80 minutes, then the final 5 mobile phase composition was held for an additional 1.00 min. The standard injection volume was 2 pL. Acquisition ranges were set to 190-400nm for the UV-PDA detector and 100-1400 m/z for the MS detector. NMR analysis performed using a BRUKER Avance III Spectrometer with a 300MHz Ultrashield magnet. 10 Description of Biological Assays Assessment of TLR7 and TLR8 activity The ability of compounds to activate human TLR7 and/or TLR8 was assessed in a cellular reporter assay using HEK293 cells transiently transfected with a 15 TLR7 or TLR8 expression vector and NFKB-luc reporter construct. In one instance the TLR expression construct expresses the respective wild type sequence or a mutant sequence comprising a deletion in the second leucine rich repeat of the TLR. Such mutant TLR proteins have previously been shown to be more susceptible to agonist activation (US 7498409). 20 Briefly, HEK293 cells were grown in culture medium (DMEM supplemented with 10% FCS and 2 mM Glutamine). For transfection of cells in 10 cm dishes, cells were detached with Trypsin-EDTA, transfected with a mix of CMV-TLR7 or TLR8 plasmid (750 ng), NFKB-luc plasmid (375 ng) and a transfection reagent and incubated overnight at 370C in a humidified 5% C02 atmosphere. 25 Transfected cells were then detached with Trypsin-EDTA, washed in PBS and resuspended in medium to a density of 1.67 x 105 cells/mL. Thirty microliters of cells were then dispensed into each well in 384-well plates, where 10 pL of compound in 4% DMSO was already present. Following 6 hours incubation at 370C, 5% C02, the luciferase activity was determined by adding 15 pl of 30 Steady Lite Plus substrate (Perkin Elmer) to each well and readout performed on a ViewLux ultraHTS microplate imager (Perkin Elmer). Dose response curves were generated from measurements performed in quadruplicates. Lowest effective concentrations (LEC) values, defined as the concentration that induces an effect which is at least two fold above the standard deviation of the 35 assay, were determined for each compound.
    WO 2013/117615 PCT/EP2013/052372 -33 Compound toxicity was determined in parallel using a similar dilution series of compound with 30 pL per well of cells transfected with the CMV-TLR7 construct alone (1.67 x 105 cells/mL), in 384-well plates. Cell viability was measured after 6 hours incubation at 370C, 5% C02 by adding 15 pL of ATP 5 lite (Perkin Elmer) per well and reading on a ViewLux ultraHTS microplate imager (Perkin Elmer). Data was reported as CC50. Biological activity of compounds of formula (I). All compounds showed CC50 of >24uM in the HEK 293 TOX assay described above. 10 Table 2. Biological Activity of compounds of formula (I). Table II A represent compounds wherein A=NCOR 2 while Table II B represents compounds wherein B=NCOR 4 and Table II C contains both region-isomeric compounds respectively. 15 Table II A Human TLR7 Human TLR8 # STRUCTURE (LEC, pM) (LEC, pM) 2 3.96 0.75 N N 3 0.79 0.60 N N 4 8,6.82 0.47
    N-
    WO 2013/117615 PCT/EP2013/052372 -34 Human TLR7 Human TLR8 # STRUCTURE (LEC, pM) (LEC, pM) N NN N 9N 1.-0 0-46 N N~ N N l 10 2.04 0.71 N 1- N N N'N N 1N >N N N 15 ,N -N400A3 12 82.40 0.36 N 13 >8N3.21 0.85 N N 14 8,4.43 0.90 N N 15 4.66 1.31 N
    N
    WO 2013/117615 PCT/EP2013/052372 -35 Human TLR7 Human TLR8 # STRUCTURE (LEC, pM) (LEC, pM) N NN 16 5.37 1.49 N N N N 17 5.82 0.43 N N 18 6.16 0.96 NN N N' 19 6.59 0.83 N N N 20 7.15 0.68 N ) -N N 21 8.13 1.85 N 22 9.35 1.37 WO 2013/117615 PCT/EP2013/052372 -36 Human TLR7 Human TLR8 # STRUCTURE (LEC, pM) (LEC, pM) N N N 23 11.62 2.67 N N N N N 24 12.93 2.29 F Table II B Human TLR7 Human TLR8 # STRUCTURE (LEC, pM) (LEC, pM) N N N N _ N0.83 0.32 N 5 4.90 0.50 >0 N 6 N 3.45 0.88 N N N 7 8.13 1.62 0 WO 2013/117615 PCT/EP2013/052372 -37 Human TLR7 Human TLR8 # STRUCTURE (LEC, pM) (LEC, pM) N N N 8 2.34 0.40 Table II C Human TLR7 Human TLR8 PBMC-IFNa # (LEC, pM) (LEC, pM) (LEC, pM) 25 20.0 1.8 1.1 26 16.8 2.1 0.6 27 >25 1.9 1.2 28 8.6 2.2 1.9 29 >25 7.5 8.7 30 5.0 0.5 0.5 31 7.7 0.6 1.3 32 7.1 0.6 0.9 33 0.3 0.2 0.2 34 0.8 0.4 0.2 35 0.7 0.2 0.2 36 4.7 0.9 0.6 WO 2013/117615 PCT/EP2013/052372 -38 Human TLR7 Human TLR8 PBMC-IFNa # (LEC, pM) (LEC, pM) (LEC, pM) 37 7.2 1.7 1.8 38 5.2 0.8 0.6 39 2.5 4.2 0.5 40 2.2 4.5 0.2 41 0.4 0.4 0.1 42 2.2 2.1 0.2 43 0.1 0.7 0.04 44 1.0 6.6 0.2 45 0.2 1.7 0.2 46 0.6 3.5 0.2 47 0.2 1.1 0.2 48 1.2 3.9 0.3 49 2.7 4.0 0.3 50 1.7 3.9 0.3 51 0.5 0.4 0.1 52 12.1 15 NA
    权利要求:
    Claims (10)
    [1] 1. A compound of formula (1) RNH R-N H - A H
    [2] 2 N N (I) or a pharmaceutically acceptable salt, tautomer(s), solvate or polymorph 5 thereof, wherein A is selected from the group consisting of CH 2 , NCOR 2 , CHR 3 and CR 3 R 3 in any stereo chemical configuration, B is selected from the group consisting of CH 2 , NCOR 4 , CHR 3 and CR 3 R 3 in any stereo chemical configuration, 10 with the proviso that when A is NCOR 2 then B is not NCOR 4 and with the proviso that A and B are not both selected from CH 2 , CHR 3 or CR 3 R 3 , X is selected from CH 2 or CHR 5 in any stereo chemical configuration, R 1 is selected from C 1 . 8 alkyl optionally substituted with one or more of the following: C 1 . 6 alkyl, C 3 . 7 cycloalkyl, hydroxyl, hydroxyalkyl, amino, nitrile, alkoxy, 15 alkoxy-(C 1 . 4 )alkyl, carboxylic acid, carboxylic ester, carbamate or sulfone, R 2 is selected from substituted and unsubstituted C 1 . 6 alkyl, C 3 . 7 cycloalkyl, heterocycle, aryl, heteroaryl, heteroarylalkyl, each of which is optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino, C1. 6 alkyl, di-(C 1 . 6 )alkylamino, C1. 6 alkylamino, C1. 6 alkyl, 20 C1. 6 alkoxy, C3. 6 cycloalkyl, carboxylic acid, carboxylic ester, carboxylic amide, heterocycle, aryl, alkenyl, alkynyl, arylalkyl, heteroaryl, heteroarylalkyl or nitrile, R 3 is selected from hydrogen, substituted and unsubstituted C1. 6 alkyl, alkoxy, alkoxy-(C 1 . 4 )alkyl, C3. 7 cycloalkyl, C4. 7 heterocycle, aromatic, bicyclic heterocycle, arylalkyl, heteroaryl, heteroarylalkyl each of which is optionally 25 substituted by one or more substituents independently selected from halogen, hydroxyl, amino, C1. 6 alkyl, di-(C 1 . 6 )alkylamino, C1. 6 alkylamino, C1. 6 alkyl, C1. 6 alkoxy, C3. 6 cycloalkyl, carboxylic acid, carboxylic ester, carboxylic amide, heterocycle, aryl, alkenyl, alkynyl, arylalkyl, heteroaryl, heteroarylalkyl or nitrile, WO 2013/117615 PCT/EP2013/052372 -40 R 4 is selected from substituted or unsubstituted C 1 . 7 alkyl, alkoxy, alkoxy (C 1 . 4 )alkyl, aryl or C 3 . 7 cycloalkyl each of which is optionally substituted by heterocycle, nitrile, heteroarylalkyl or heteroaryl and wherein R 5 is selected from aromatic, bicyclic heterocycle, aryl, heteroaryl, each of 5 which is optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino, C 1 . 6 alkyl, di-(C 1 . 6 )alkylamino, C 1 . 6 alkylamino, C 1 . 6 alkyl, C 1 . 6 alkoxy, C 3 . 6 cycloalkyl, carboxylic acid, carboxylic ester, carboxylic amide, heterocycle, aryl, alkenyl, alkynyl, arylalkyl, heteroaryl, heteroarylalkyl or nitrile. 10 2. A compound of formula (1) according to claim 1 wherein R 1 is butyl and wherein A, B, and X are as specified above.
    [3] 3. A compound of formula (1) according to claim 1 wherein R 1 is C 4 . 8 alkyl substituted with hydroxyl, and wherein A, B, and X are as specified above. 15
    [4] 4. A compound of formula (1) according to claim 3 wherein R 1 , being C 4 . 8 alkyl substituted with hydroxyl, is one of the following OH HO (S) ,A (S), OH HO 20
    [5] 5. A compound of formula (1) according to claim 1 wherein X is CH 2 and wherein A, and B are as specified above.
    [6] 6. A compound of formula (1) according to claims wherein X is CH 2 and 25 wherein A is CH 2 and B is as specified above.
    [7] 7. A compound of formula (1) according to claim 1 wherein R 2 is one of the following examples that can be further substituted with C 1 . 3 alkyl, hydroxyl, alkoxy, nitrile, heterocycle, carboxylic ester, or carboxylic amide: 30 WO 2013/117615 PCT/EP2013/052372 -41 NN
    [8] 8. A pharmaceutical composition comprising a compound of formula (1) or a pharmaceutically acceptable salt, tautomer, solvate or polymorph thereof 5 according to one of the claims 1-7 together with one or more pharmaceutically acceptable excipients, diluents or carriers.
    [9] 9. A compound of formula (1) or a pharmaceutically acceptable salt, tautomer, solvate or polymorph thereof according to one of the claims 1-7, or a 10 pharmaceutical composition according to claim 8 for use as a medicament.
    [10] 10. A compound of formula (1) or a pharmaceutically acceptable salt, tautomer, solvate or polymorph thereof according to one of the claims 1-7, or a pharmaceutical composition according to claim 8 for use in the 15 treatment of a disorder in which the modulation of TLR7 and /or TLR8 is involved.
    类似技术:
    公开号 | 公开日 | 专利标题
    US9365571B2|2016-06-14|Piperidino-pyrimidine derivatives for the treatment of viral infections
    AU2018236703B2|2020-09-17|Pyrimidine derivatives for the treatment of viral infections
    AU2018274911B2|2020-05-14|Pyrrolo[3,2-c]Pyrimidine derivatives for the treatment of viral infections and other diseases
    EP2882721B1|2018-12-05|Alkylpyrimidine derivatives for the treatment of viral infections and further diseases
    AU2013346793B2|2018-03-08|Heterocyclic substituted 2-amino-quinazoline derivatives for the treatment of viral infections
    AU2014298540B2|2018-08-09|Thieno[3,2-d]pyrimidines derivatives for the treatment of viral infections
    CA2886630C|2021-01-26|1,2,4-triazine derivatives for the treatment of viral infections
    AU2013328732A1|2015-03-19|Pyrrolo[3,2-d]pyrimidine derivatives for the treatment of viral infections and other diseases
    AU2014220717A1|2015-07-23|2-aminopyrimidine derivatives for the treatment of viral infections
    CA2912338C|2022-01-25|Pyridone derivatives for the treatment of viral infections and further diseases
    BR112014019699B1|2021-12-07|PIPERIDINO-PYRIMIDINE DERIVATIVES, THEIR USE IN THE TREATMENT OF VIRAL INFECTIONS AND THE PHARMACEUTICAL COMPOSITION THAT COMPRISES THEM
    NZ709769B2|2021-02-02|2-aminopyrimidine derivatives for the treatment of viral infections
    同族专利:
    公开号 | 公开日
    IL233499D0|2014-08-31|
    DK2812331T3|2019-04-08|
    PH12014501738B1|2014-11-10|
    KR102064807B1|2020-01-10|
    NZ627036A|2016-03-31|
    WO2013117615A1|2013-08-15|
    JP2015506380A|2015-03-02|
    UA112668C2|2016-10-10|
    JP6283320B2|2018-02-21|
    AU2013218072B2|2017-08-31|
    SG11201404743TA|2014-09-26|
    HK1201254A1|2015-08-28|
    CL2014002093A1|2014-11-21|
    MX357296B|2018-07-03|
    ES2716811T3|2019-06-17|
    PH12014501738A1|2014-11-10|
    EP2812331A1|2014-12-17|
    CN104245695A|2014-12-24|
    US9365571B2|2016-06-14|
    EA033907B1|2019-12-09|
    CA2862823A1|2013-08-15|
    MX2014009556A|2014-11-10|
    EA201992133A1|2020-02-05|
    US20140350031A1|2014-11-27|
    IL233499A|2018-12-31|
    ZA201405820B|2016-05-25|
    US9133192B2|2015-09-15|
    US20150336955A1|2015-11-26|
    EP2812331B1|2019-01-02|
    MY169159A|2019-02-19|
    CA2862823C|2020-09-22|
    EA201491486A1|2014-11-28|
    IN2014MN01736A|2015-07-10|
    KR20140129011A|2014-11-06|
    CN104245695B|2017-06-06|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    ZA975946B|1996-07-03|1998-04-16|Japan Energy Corp|Purine derivative.|
    US6329381B1|1997-11-28|2001-12-11|Sumitomo Pharmaceuticals Company, Limited|Heterocyclic compounds|
    JP2000012487A|1998-06-19|2000-01-14|Sanyo Electric Co Ltd|Semiconductor device and its monitoring method|
    JP4497340B2|1998-08-27|2010-07-07|大日本住友製薬株式会社|Pyrimidine derivatives|
    WO2002088079A2|2001-05-01|2002-11-07|Bristol-Myers Squibb Company|Dual inhibitors of pde 7 and pde 4|
    JP4691865B2|2001-09-28|2011-06-01|マツダ株式会社|Front body structure of the vehicle|
    WO2003104230A1|2002-06-07|2003-12-18|協和醱酵工業株式会社|Bicyclic pyrimidine derivatives|
    US7498409B2|2005-03-24|2009-03-03|Schering Corporation|Screening assay for TLR7, TLR8 and TLR9 agonists and antagonists|
    KR20080006004A|2005-05-04|2008-01-15|화이자 리미티드|2-amido-6-amino-8-oxopurine derivatives as toll-like receptor modulators for the treatment of cancer and viral infections, such as hepatitis c|
    PE20091236A1|2007-11-22|2009-09-16|Astrazeneca Ab|PYRIMIDINE DERIVATIVES AS IMMUNOMODULATORS OF TLR7|
    JP2011511073A|2008-02-07|2011-04-07|ザリージェンツオブザユニバーシティオブカリフォルニア|Treatment of bladder disease with TLR7 activator|
    CN102482233A|2009-05-21|2012-05-30|阿斯利康有限公司|Novel Pyrimidine Derivatives And Their Use In The Treatment Of Cancer And Further Diseases|
    US8637525B2|2009-07-31|2014-01-28|Bristol-Myers Squibb Company|Compounds for the reduction of beta-amyloid production|
    TWI468402B|2009-07-31|2015-01-11|Squibb Bristol Myers Co|Compounds for the reduction of β-amyloid production|
    JP2013032290A|2009-11-20|2013-02-14|Dainippon Sumitomo Pharma Co Ltd|Novel fused pyrimidine derivative|
    WO2013117615A1|2012-02-08|2013-08-15|Janssen R&D Ireland|Piperidino-pyrimidine derivatives for the treatment of viral infections|JP2001068326A|1999-08-30|2001-03-16|Tdk Corp|MnZn BASED FERRITE|
    EP3590928B1|2011-04-08|2021-06-09|Janssen Sciences Ireland Unlimited Company|Pyrimidine derivatives for the treatment of viral infections|
    CN104066733A|2011-11-09|2014-09-24|爱尔兰詹森研发公司|Purine derivatives for the treatment of viral infections|
    WO2013117615A1|2012-02-08|2013-08-15|Janssen R&D Ireland|Piperidino-pyrimidine derivatives for the treatment of viral infections|
    CA2874800C|2012-07-13|2021-04-06|Janssen R&D Ireland|Macrocyclic purines for the treatment of viral infections|
    CN104837840B|2012-10-10|2017-08-08|爱尔兰詹森科学公司|Pyrrolo- [3,2 d] pyrimidine derivatives for treating virus infection and other diseases|
    NZ748345A|2012-11-16|2020-04-24|Janssen Sciences Ireland Uc|Heterocyclic substituted 2-amino-quinazoline derivatives for the treatment of viral infections|
    US9598378B2|2013-02-21|2017-03-21|Janssen Sciences Ireland Uc|2-aminopyrimidine derivatives for the treatment of viral infections|
    AU2014242954B2|2013-03-29|2018-03-15|Janssen Sciences Ireland Uc|Macrocyclic deaza-purinones for the treatment of viral infections|
    US10377738B2|2013-05-24|2019-08-13|Janssen Sciences Ireland Unlimited Company|Pyridone derivatives for the treatment of viral infections and further diseases|
    SI3030563T1|2013-06-27|2017-12-29|Janssen Sciences Ireland Uc|Pyrrolopyrimidine derivatives for the treatment of viral infections and other diseases|
    NZ714519A|2013-07-30|2021-07-30|Janssen Sciences Ireland Uc|Thieno[3,2-d]pyrimidines derivatives for the treatment of viral infections|
    RS56787B1|2015-03-04|2018-04-30|Gilead Sciences Inc|Toll-like receptor modulating 4,6-diamino-pyrido[3,2-d]pyrimidine compounds|
    AU2016312508A1|2015-08-26|2018-02-15|Gilead Sciences, Inc.|Deuterated toll-like receptor modulators|
    AU2016322763A1|2015-09-15|2018-04-19|Gilead Sciences, Inc.|Modulators of toll-like recptors for the treatment of HIV|
    SG11201804787UA|2015-12-15|2018-07-30|Gilead Sciences Inc|Human immunodeficiency virus neutralizing antibodies|
    CA3025633C|2016-05-27|2021-02-23|Gilead Sciences, Inc.|Methods for treating hepatitis b virus infections using ns5a, ns5b or ns3 inhibitors|
    BR102017010009A2|2016-05-27|2017-12-12|Gilead Sciences, Inc.|COMPOUNDS FOR THE TREATMENT OF HEPATITIS B VIRUS INFECTION|
    WO2018002319A1|2016-07-01|2018-01-04|Janssen Sciences Ireland Uc|Dihydropyranopyrimidines for the treatment of viral infections|
    UY37374A|2016-08-26|2018-03-23|Gilead Sciences Inc|SUBSTITUTED PIRROLIZINE COMPOUNDS AND USES OF THE SAME|
    US10640499B2|2016-09-02|2020-05-05|Gilead Sciences, Inc.|Toll like receptor modulator compounds|
    WO2018045144A1|2016-09-02|2018-03-08|Gilead Sciences, Inc.|Toll like receptor modulator compounds|
    CN109641899A|2016-09-09|2019-04-16|诺华股份有限公司|Compound and composition as inner body Toll-like receptor inhibitor|
    KR20190053200A|2016-09-29|2019-05-17|얀센 사이언시즈 아일랜드 언리미티드 컴퍼니|Pyrimidine prodrugs for the treatment of viral infections and further diseases|
    KR20210118240A|2016-10-14|2021-09-29|프리시젼 바이오사이언시스 인코포레이티드|Engineered meganucleases specific for recognition sequences in the hepatitis b virus genome|
    AR110768A1|2017-01-31|2019-05-02|Gilead Sciences Inc|CRYSTAL FORMS OF TENOFOVIR ALAFENAMIDA|
    JOP20180008A1|2017-02-02|2019-01-30|Gilead Sciences Inc|Compounds for the treatment of hepatitis b virus infection|
    JOP20180040A1|2017-04-20|2019-01-30|Gilead Sciences Inc|Pd-1/pd-l1 inhibitors|
    US11229638B2|2017-08-22|2022-01-25|Gilead Sciences, Inc.|Therapeutic heterocyclic compounds|
    WO2019057158A1|2017-09-22|2019-03-28|江苏恒瑞医药股份有限公司|Condensed heteroaryl derivatives, preparation method therefor, and application thereof in medicines|
    WO2019084060A1|2017-10-24|2019-05-02|Silverback Therapeutics, Inc.|Conjugates and methods of use thereof for selective delivery of immune-modulatory agents|
    CA3084667A1|2017-12-15|2019-06-20|Silverback Therapeutics, Inc.|Antibody construct-drug conjugate for the treatment of hepatitis|
    AU2018392213B2|2017-12-20|2021-03-04|Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I.|3'3' cyclic dinucleotides with phosphonate bond activating the STING adaptor protein|
    AU2018392212B9|2017-12-20|2021-03-18|Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I.|2'3' cyclic dinucleotides with phosphonate bond activating the STING adaptor protein|
    PE20210640A1|2018-02-13|2021-03-23|Gilead Sciences Inc|INHIBITORS PD-1 / PD-L1|
    US10836769B2|2018-02-26|2020-11-17|Gilead Sciences, Inc.|Substituted pyrrolizine compounds and uses thereof|
    WO2019195181A1|2018-04-05|2019-10-10|Gilead Sciences, Inc.|Antibodies and fragments thereof that bind hepatitis b virus protein x|
    TW202005654A|2018-04-06|2020-02-01|捷克科學院有機化學與生物化學研究所|2'2'-cyclic dinucleotides|
    TW202010503A|2018-04-06|2020-03-16|捷克科學院有機化學與生物化學研究所|3’3’－cyclic dinucleotides|
    TW202005655A|2018-04-06|2020-02-01|捷克科學院有機化學與生物化學研究所|2'3'-cyclic dinucleotides|
    US11142750B2|2018-04-12|2021-10-12|Precision Biosciences, Inc.|Optimized engineered meganucleases having specificity for a recognition sequence in the Hepatitis B virus genome|
    CN112041311A|2018-04-19|2020-12-04|吉利德科学公司|PD-1/PD-L1 inhibitors|
    WO2019211799A1|2018-05-03|2019-11-07|Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I.|2'3'-cyclic dinucleotide analogue comprising a cyclopentanyl modified nucleotide|
    EP3817819A1|2018-07-03|2021-05-12|Gilead Sciences, Inc.|Antibodies that target hiv gp120 and methods of use|
    WO2020010223A1|2018-07-06|2020-01-09|Gilead Sciences, Inc.|Therapeutic heterocyclic compounds|
    EP3818052A1|2018-07-06|2021-05-12|Gilead Sciences, Inc.|Therapeutic heterocyclic compounds|
    TW202136244A|2018-07-13|2021-10-01|美商基利科學股份有限公司|Pd-1/pd-l1 inhibitors|
    WO2020028097A1|2018-08-01|2020-02-06|Gilead Sciences, Inc.|Solid forms of -11--12--3,3-dimethyl-8-0x0-2,3,8,13b-tetrahydro-1h-pyrido[2,1-a]pyrrolo[1,2-c] phthalazine-7-c arboxylic acid|
    CN113164618A|2018-09-12|2021-07-23|希沃尔拜克治疗公司|Methods and compositions for treating diseases with immunostimulatory conjugates|
    US11179397B2|2018-10-03|2021-11-23|Gilead Sciences, Inc.|Imidazopyrimidine derivatives|
    CA3117199A1|2018-10-24|2020-04-30|Gilead Sciences, Inc.|Pd-1/pd-l1 inhibitors|
    US11071730B2|2018-10-31|2021-07-27|Gilead Sciences, Inc.|Substituted 6-azabenzimidazole compounds|
    PE20211655A1|2018-10-31|2021-08-24|Gilead Sciences Inc|6-AZABENZIMIDAZOLE COMPOUNDS SUBSTITUTED AS HPK1 INHIBITORS|
    WO2020162705A1|2019-02-08|2020-08-13|성균관대학교산학협력단|Toll-like receptor 7 or 8 agonist-cholesterol complex, and use of same|
    WO2020176505A1|2019-02-25|2020-09-03|Gilead Sciences, Inc.|Protein kinase c agonists|
    WO2020176510A1|2019-02-25|2020-09-03|Gilead Sciences, Inc.|Protein kinase c agonists|
    WO2020178770A1|2019-03-07|2020-09-10|Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I.|3'3'-cyclic dinucleotides and prodrugs thereof|
    EP3935065A1|2019-03-07|2022-01-12|Institute of Organic Chemistry and Biochemistry ASCR, V.V.I.|3'3'-cyclic dinucleotide analogue comprising a cyclopentanyl modified nucleotide as sting modulator|
    WO2020178769A1|2019-03-07|2020-09-10|Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I.|2'3'-cyclic dinucleotides and prodrugs thereof|
    KR20210151942A|2019-04-17|2021-12-14|길리애드 사이언시즈, 인코포레이티드|Solid Forms of Toll-Like Receptor Modulators|
    EP3956328A1|2019-04-17|2022-02-23|Gilead Sciences, Inc.|Solid forms of a toll-like receptor modulator|
    TW202110481A|2019-05-21|2021-03-16|美商基利科學股份有限公司|Methods of identifying hiv patients sensitive to therapy with gp120 v3 glycan-directed antibodies|
    US20200392153A1|2019-05-23|2020-12-17|Gilead Sciences, Inc.|Substituted eneoxindoles and uses thereof|
    WO2020255038A1|2019-06-18|2020-12-24|Janssen Sciences Ireland Unlimited Company|Combination of hepatitis b virusvaccines and pyridopyrimidine derivatives|
    AU2020298222A1|2019-06-19|2022-01-20|Silverback Therapeutics, Inc.|Anti-mesothelin antibodies and immunoconjugates thereof|
    AU2020301161A1|2019-06-25|2022-01-06|Gilead Sciences, Inc.|FLT3L-Fc fusion proteins and methods of use|
    US20210017255A1|2019-07-16|2021-01-21|Gilead Sciences, Inc.|Hiv vaccines and methods of making and using|
    WO2021011891A1|2019-07-18|2021-01-21|Gilead Sciences, Inc.|Long-acting formulations of tenofovir alafenamide|
    WO2021034804A1|2019-08-19|2021-02-25|Gilead Sciences, Inc.|Pharmaceutical formulations of tenofovir alafenamide|
    US20210093712A1|2019-09-30|2021-04-01|Gilead Sciences, Inc.|Hbv vaccines and methods treating hbv|
    WO2021067644A1|2019-10-01|2021-04-08|Silverback Therapeutics, Inc.|Combination therapy with immune stimulatory conjugates|
    US20210115140A1|2019-10-18|2021-04-22|Forty Seven, Inc.|Combination therapies for treating myelodysplastic syndromes and acute myeloid leukemia|
    US20210147568A1|2019-10-31|2021-05-20|Forty Seven, Inc.|Anti-cd47 based treatment of blood cancer|
    TW202128714A|2019-11-12|2021-08-01|美商基利科學股份有限公司|Mcl1 inhibitors|
    WO2021113765A1|2019-12-06|2021-06-10|Precision Biosciences, Inc.|Optimized engineered meganucleases having specificity for a recognition sequence in the hepatitis b virus genome|
    WO2021130638A1|2019-12-24|2021-07-01|Carna Biosciences, Inc.|Diacylglycerol kinase modulating compounds|
    US20210277129A1|2020-02-14|2021-09-09|Jounce Therapeutics, Inc.|Antibodies and fusion proteins that bind to ccr8 and uses thereof|
    WO2021168274A1|2020-02-21|2021-08-26|Silverback Therapeutics, Inc.|Nectin-4 antibody conjugates and uses thereof|
    WO2021188959A1|2020-03-20|2021-09-23|Gilead Sciences, Inc.|Prodrugs of 4'-c-substituted-2-halo-2'-deoxyadenosine nucleosides and methods of making and using the same|
    WO2021222522A1|2020-05-01|2021-11-04|Gilead Sciences, Inc.|Cd73 inhibiting 2,4-dioxopyrimidine compounds|
    WO2021236944A1|2020-05-21|2021-11-25|Gilead Sciences, Inc.|Pharmaceutical compositions comprising bictegravir|
    WO2021262990A1|2020-06-25|2021-12-30|Gilead Sciences, Inc.|Capsid inhibitors for the treatment of hiv|
    WO2022006327A1|2020-07-01|2022-01-06|Silverback Therapeutics, Inc.|Anti-asgr1 antibody conjugates and uses thereof|
    WO2022031894A1|2020-08-07|2022-02-10|Gilead Sciences, Inc.|Prodrugs of phosphonamide nucleotide analogues and their pharmaceutical use|
    法律状态:
    2015-03-26| PC1| Assignment before grant (sect. 113)|Owner name: JANSSEN SCIENCES IRELAND UC Free format text: FORMER APPLICANT(S): JANSSEN R&D IRELAND |
    2018-01-04| FGA| Letters patent sealed or granted (standard patent)|
    优先权:
    申请号 | 申请日 | 专利标题
    EP12154474||2012-02-08||
    EP12154474.6||2012-02-08||
    PCT/EP2013/052372|WO2013117615A1|2012-02-08|2013-02-07|Piperidino-pyrimidine derivatives for the treatment of viral infections|
    [返回顶部]