2-Amino-quinoline derivatives

Abstract

Described herein are 2-amino-quinoline derivatives as agonists of toll-like receptor 7 and toll-like receptor 8 (TLR7 and TRL8), pharmaceutical compositions, and methods of using the compounds and compositions to treat various diseases (e.g., viral diseases, cancer, and allergic diseases), the methods comprising administering a therapeutically effective amount of the 2-amino-quinoline derivative as needed.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to Chinese application CN201710287322.2 filed on April 27, 2017, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present invention relates to 2-amino-quinoline derivatives, such as imidazoquinoline analogs and pyrazoloquinoline analogs as agonists of toll-like receptor 7 and toll-like receptor 8 (TLR7 and TRL8), and pharmaceutical compositions comprising the 2-amino-quinoline derivatives. The present invention also relates to the use of the compounds and the compositions and methods for activating TLR7 and TRL8 in the treatment of various diseases. Background Art

[0004] The TLR family plays a fundamental role in pathogen recognition and activation of innate immunity. TLR7 and TLR8 are toll-like receptor 7 and toll-like receptor 8, respectively, and they are close to each other on the human X chromosome. Both TLR7 and TLR8 recognize single-stranded RNA of viruses (e.g., HIV virus and HCV virus). TLR7 has been shown to play an important role in the pathogenesis of autoimmune diseases (e.g., systemic lupus erythematosus (SLE)) and antiviral immune regulation. Recently, genetic variants of TLR8 have been associated with susceptibility to tuberculosis. TLR7 works in humans and mice, while TLR8 only works in humans, but TLR8 seems to offset the activity of TLR7. The main advantage of TLR7 / 8 agonists as immune response enhancers is that they stimulate multiple cell types at the same time. TLR7 and TLR8 are mainly expressed on immune cells such as antigen presenting cells (including plasmacytoid dendritic cells (pDC) and myeloid dendritic cells (mDC)) and natural killer cells and macrophages. Activation of TLR7 / 8 on pDC and mDC leads to the induction and release of type I interferon (IFN), tumor necrosis factor α (TNFα) and interleukin 12 (IL-12), which is an important step in initiating innate and adaptive immunity to kill cancer cells. For these reasons, TLR7 and TLR8 have become targets of interest in antiviral therapy and cancer therapy. The field is also increasingly focusing on the targeting of toll-like receptors, for example, TLR7 / 8 for the treatment of allergic diseases.

[0005] Since TLR7 and TLR8 have strong antiviral and antitumor activities, there has been a great interest in small molecule agonists of TLR7 and TLR8 in antiviral and cancer research. Imiquimod, the lead compound of the imidazoquinoline family, is effective against many primary skin tumors and skin metastases, and is marketed as a topical preparation. Resiquimod (R-848), from the same imidazoquinoline family, is a low molecular weight synthetic molecule that activates immune cells through the TLR7 / TLR8 MyD88-dependent signaling pathway. Resiquimod (R-848) acts as an immune response modifier and has antiviral and antitumor activities. Resiquimod (R-848) has multiple mechanisms of action and can act as an agonist of toll-like receptors 7 and 8 and an upregulator of opioid growth factor receptors. R-848 is used as a topical gel for treating skin lesions, such as those caused by herpes simplex virus and cutaneous T-cell lymphoma, as an adjuvant to improve the effectiveness of vaccines, and as an immunotherapy adjuvant for patients with allergic rhinitis (AR). Therefore, TLR7 / 8 agonists are expected to become adjuvants for cancer vaccines or adjuvants in T cell adoptive transfer procedures in addition to being independent immunotherapeutic agents. As described above, the expansion of the known synthetic TLR7 / 8 agonist family has paved the way for the research and discovery of TLR7 / 8 agonists, which are well tolerated, have higher selectivity for effective anti-tumor and antiviral activity, are widely applicable and can be used as more effective adjuvants. Summary of the invention

[0006] Described herein are 2-amino-quinoline derivatives, pharmaceutically acceptable salts, solvates, prodrugs and active metabolites thereof, which are agonists of toll-like receptors 7 and 8 (TLR7 / 8). These compounds can be used to treat viral (e.g., HCV) infection, cancer and allergic diseases in a subject in need thereof by administering a therapeutically effective amount of a 2-amino-quinoline derivative.

[0007] Some embodiments include compounds represented by Formula 1:

[0008]

[0009] The dotted line indicates the presence or absence of a chemical bond; A 1 CR 1 , NR 1A or N; A 2 CR 2 , NR 2A , O, or S; B 1 CR 5 or N; B 2 CR 6or N; B 3 CR 7 or N; R 1 and R 2 F, Cl, Br, I, NO independently 2 , CN, R a , -OR a , -NR a R b , -NHCOR a , -NHSO 2 R a , -OCOR a , or -SO 2 R a ; X is a chemical bond, O, NR a , -CO-, -SO-, or -SO 2 -,-CONR a , hydrocarbon group, and R 3 H or C 1-30 Organic group; or XR 3 is F or Cl; R 1A , R 2A , R 4 , R a and R b are independently H or C 1-30 Organic group; R 5 , R 6 and R 7 F, Cl, Br, I, NO independently 2 , CN, R a , -OR a , -NR a R b , -NHCOR a , -NHSO 2 R a , -OCOR a , -SO 2 R a , -SO 2 NHR a , or -X 1 -(C m H 2m O 0-1 )-Z-(C n H 2n+1 ), -(C m H 2m O 0-1 )-Z-(C n H 2n+1 ), where R 5 and R 6 or R6 and R 7 can be optionally linked to form a ring; wherein X 1 is a chemical bond, O, NR a , -CO-, -SO-, or -SO 2 -; Z is a chemical bond, O, NHSO 2 , or NHCO; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23.

[0010] Some embodiments include pharmaceutical dosage forms comprising the above compounds. The above compounds or compositions can be used to activate TLR7 / 8. In addition to being used as independent immunotherapeutic agents (e.g., antiviral and anticancer agents), the above compounds or compositions can also be used as adjuvants for cancer vaccines or adjuvants in T cell adoptive transfer procedures.

[0011] Some embodiments include methods of treating a disease or disorder associated with TLR7 / 8 agonists, comprising administering to a mammal in need of such treatment an effective amount of a compound described above.

[0012] Some embodiments include use of the above compounds in the manufacture of a medicament for treating a disease or disorder associated with a TLR7 / 8 agonist. DETAILED DESCRIPTION

[0013] Unless otherwise indicated, when a compound or chemical structural feature (e.g., alkyl, alkenyl, alkynyl, aryl, heteroaryl, etc.) is referred to as "optionally substituted", it includes features without substituents (i.e., unsubstituted) or substituted features (meaning that the feature has one or more substituents). The term "substituent" has the broadest meaning known to those of ordinary skill in the art, and includes the following groups: the group occupies the position usually occupied by one or more hydrogen atoms connected to the parent compound or parent structural feature. In some embodiments, the substituent can be a common organic group known in the art, and the organic group can have the following molecular weight (e.g., the sum of the atomic masses of the atoms of the substituent): 15-50 g / mol, 15-100 g / mol, 15-150 g / mol, 15-200 g / mol, 15-300 g / mol, or 15-500 g / mol. In some embodiments, the substituent includes or consists of: 0-30, 0-20, 0-10 or 0-5 carbon atoms; and 0-30, 0-20, 0-10 or 0-5 heteroatoms, wherein each heteroatom can independently be: N, O, S, Si, F, Cl, Br, or I; provided that the substituent includes one C, N, O, S, Si, F, Cl, Br, or I atom. Examples of substituents include, but are not limited to, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, acyl, acyloxy, alkylcarboxylate, thiol, alkylthio, cyano, halo, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amide, N-amide, S-sulfonamido, N-sulfonamido, isocyanate, thiocyanate, isothiocyanate, nitro, silyl, thio, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, and the like.

[0014] Even though a group or portion of a molecule may not be a complete molecule, for convenience the term "molecular weight" is used for a group or portion of a molecule to represent the sum of the atomic masses of the atoms in the group or portion of a molecule.

[0015] The term "alkyl" as used herein has the broadest meaning generally understood in the art, and may include groups consisting of carbon and hydrogen without double or triple bonds. The alkyl group may be a straight chain alkyl group, a branched chain alkyl group, a cycloalkyl group, or a combination thereof; in some embodiments, the alkyl group may contain 1 to 35 carbon atoms. In some embodiments, the alkyl group may contain C 1-10 Straight chain alkyl groups, such as methyl (-CH 3 ), methylene (-CH 2-), ethyl (-CH 2 CH 3 ), ethylene (-C 2 H 4 -), propylene (-C 3 CH 6 -), n-butyl (-CH 2 CH 2 CH 2 CH 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 2 CH 3 ), n-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ) etc.; C 3-10 Branched chain alkyl, such as C 3 H 7 (e.g., isopropyl), C 4 H 9 (e.g., branched butyl isomers), C 5 H 11 (e.g., branched-chain pentyl isomers), C 6 H 13 (e.g., branched hexyl isomers), C 7 H 15 (e.g., heptyl isomers), etc.; C 3-10 Cycloalkyl, such as C 3 H 5 (e.g., cyclopropyl), C 4 H 7 (e.g., cyclobutyl isomers, such as cyclobutyl, methylcyclopropyl, etc.), C 5 H 9 (e.g., cyclopentyl isomers such as cyclopentyl, methylcyclobutyl, dimethylcyclopropyl, etc.), C 6 H 11 (e.g., cyclohexyl isomers), C 7 H 13 (e.g., cycloheptyl isomers), etc.

[0016] The term "aryl" as used herein includes groups derived from monocyclic aromatic hydrocarbons and polycyclic aromatic hydrocarbons by removing a hydrogen atom from a ring carbon atom. The "aryl" may include an aromatic ring or an aromatic ring system, such as phenyl, naphthyl, and the like.

[0017] The term "heteroaryl" has the broadest meaning understood by those of ordinary skill in the art, and includes "aryl" groups having one or more heteroatoms in a ring or ring system, for example, pyridyl, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, oxadiazolyl, isoxazolyl, indolyl, quinolinyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, and the like.

[0018] Unless otherwise indicated, compounds referred to herein by structure, name, or any other means include: pharmaceutically acceptable salts (e.g., hydrochlorides, bromates, iodates, sulfates, acetates, citrates, phosphates, sodium salts, potassium salts, and ammonium salts); prodrugs (e.g., ester prodrugs); alternative solid dosage forms (e.g., polymorphs, solvates, hydrates, etc.); tautomers; or any other chemical species that can be readily converted into a compound described herein under the conditions of use of the compound described herein.

[0019] If no stereochemistry is indicated, the name or structural diagram includes any stereoisomer or any mixture of stereoisomers.

[0020] For the purposes disclosed herein, "treat," "treating" or "treatment" includes the use of a compound, composition, therapeutic agent or drug in the diagnosis, cure, mitigation, treatment or prevention of disease or other undesirable condition.

[0021] With respect to any relevant structural diagram, such as Formula 1, dashed lines represent the presence or absence of a chemical bond. For example, compounds represented by Formula 1A and 1B are included herein.

[0022]

[0023] With respect to any relevant structural diagram, for example, Formula 1, Formula 1A or Formula 1B, A 1 CR 1 ,NR 1A , or N. In some embodiments, A 1 CR 1 In some embodiments, A 1 NR 1A In some embodiments, A 1 is N.

[0024] With respect to any relevant structural diagram, for example, Formula 1, Formula 1A or Formula 1B, A 2 CR 2 ,NR 2A , O or S. In some embodiments, A 2 CR 2In some embodiments, A 2 NR 2A In some embodiments, A 2 is 0. In some embodiments, A 2 For S.

[0025] With respect to any relevant structural diagram, for example, Formula 1, Formula 1A or Formula 1B, X is a chemical bond, O, NR a ,-C(=O)-,-S(=O)-,-S(=O) 2 -,-CONR a , hydrocarbon group; R 3 H or C 1-30 Organic group; or XR 3 In some embodiments, X is F or Cl. In some embodiments, X is a chemical bond. In some embodiments, X is O. In some embodiments, X is NR a In some embodiments, X is -C(=O)-. In some embodiments, X is -S(=O)-. In some embodiments, X is -S(=O) 2 -. In some embodiments, XR 3 is F. In some embodiments, XR 3 For Cl.

[0026] For any relevant structural diagram, such as R in Formula 1, 1A or 1B a , NR a , -OR a , -OCOR a , or -SO 2 R a , -NR a R b , R a or R b are independently H or an organic group, such as C 1-30 Organic groups include any organic substituent groups (whether functional or not) having free valences at carbon atoms, for example, optionally substituted alkyl groups, for example, optionally substituted C 1-30 Alkyl, C 1-12 Alkyl, C 1-6 Alkyl, or C 1-3 Alkyl groups, including methyl, ethyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl, C 6 Alkyl, C 7 Alkyl, C 8 Alkyl, C 9 Alkyl, C 10 Alkyl, C 11Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl, C 16 Alkyl, C 17 Alkyl, C 18 Alkyl, C 19 Alkyl, C 20 Alkyl, C 21 Alkyl, C 22 Alkyl, C 23 Alkyl, C 24 Alkyl, C 25 Alkyl, C 26 Alkyl, C 27 Alkyl, C 28 Alkyl, C 29 Alkyl, C 30 Alkyl, C 3 Cycloalkyl, C 4 Cycloalkyl, C 5 Cycloalkyl, C 6 Cycloalkyl, C 7 Cycloalkyl, C 8 Cycloalkyl, C 9 Cycloalkyl, C 10 Cycloalkyl, C 11 Cycloalkyl, C 12 cycloalkyl, etc.; optionally substituted alkenyl, for example, optionally substituted C 2-12 or C 2-6 Alkenyl, including vinyl, C 3 Alkenyl, C 4 Alkenyl, C 5 Alkenyl, C 6 Alkenyl, C 7 Alkenyl, C 8 Alkenyl, C 9 Alkenyl, C 10 Alkenyl, C 11 Alkenyl, C 12 Alkenyl, C 4 Cycloalkenyl, C 5 Cycloalkenyl, C 6 Cycloalkenyl, C 7 Cycloalkenyl, C 8 Cycloalkenyl, C 9 Cycloalkenyl, C 10 Cycloalkenyl, C 11 Cycloalkenyl, C 12 cycloalkenyl, etc.; optionally substituted alkynyl, for example, optionally substituted C 2-12 or C 2-6 Alkynyl, including ethynyl, C 3 Alkynyl, C 4 Alkynyl, C5 Alkynyl, C 6 Alkynyl, C 7 Alkynyl, C 8 Alkynyl, C 9 Alkynyl, C 10 Alkynyl, C 11 Alkynyl, C 12 Alkynyl, C 5 Cycloalkynyl, C 6 Cycloalkynyl, C 7 Cycloalkynyl, C 8 Cycloalkynyl, C 9 Cycloalkynyl, C 10 Cycloalkynyl, C 11 Cycloalkynyl, C 12 cycloalkynyl, etc.; optionally substituted aryl, for example, optionally substituted phenyl, optionally substituted naphthyl, etc.; optionally substituted heterocyclic, optionally substituted heteroaryl, etc.; organic groups also include CN, -C(O)R a , -C(O)OR a , -C(O)NHR a , -C(O)NR a R b , -C(O)-Z-organic group, where Z is a chemical bond, O, S, or NR a R b , -C(R a R b )-OR a , -C(R a R b )-NR a R b In some embodiments, R a or R b are independently H or C 1-30 In some embodiments, C 1-30 The organic group may be substituted with halogen, hydroxy, amine, alkoxy, aryl, heteroaryl, sulfone, sulfonamide, carboxylic acid, amide, retroamide, ester, cycloalkyl, heterocycloalkyl, carbonyl, alkyl, alkenyl, alkynyl, phosphonamide acid, phosphinamide or phosphine oxide.

[0027] Some embodiments include compounds of Formula 2 or Formula 2A.

[0028]

[0029] With respect to any related structural diagram, for example, Formula 1, Formula 1A, Formula 1B, Formula 2, or Formula 2A, B 1 CR 5 Or N. In some embodiments, B 1 CR5 In some embodiments, B 1 is N.

[0030] With respect to any related structural diagram, for example, Formula 1, Formula 1A, Formula 1B, Formula 2, or Formula 2A, B 2 CR 6 Or N. In some embodiments, B 2 CR 6 In some embodiments, B 2 is N.

[0031] With respect to any related structural diagram, for example, Formula 1, Formula 1A, Formula 1B, Formula 2, or Formula 2A, B 3 CR 7 Or N. In some embodiments, B 3 CR 7 In some embodiments, B 3 is N.

[0032] Some embodiments include compounds of Formula 3A, Formula 3B, Formula 3C, Formula 3D, Formula 3E, Formula 4, Formula 5, Formula 6, Formula 7, Formula 8, Formula 9, Formula 10, Formula 11, Formula 12, or Formula 13.

[0033]

[0034]

[0035] With respect to any related structural diagram, for example, Formula 1, Formula 1A, Formula 1B, Formula 2, Formula 2A, Formula 3A, Formula 3B, Formula 3C, Formula 3D, Formula 3E, Formula 4, Formula 5, Formula 6, Formula 7, Formula 8, Formula 9, Formula 10, Formula 11, Formula 12 or Formula 13, R 1 or R 1A are independently H or any substituent, for example, F, Cl, Br, I, NO 2 , CN, R a , -OR a , -NR a R b , -NHCOR a , -NHSO 2 R a , -OCOR a , or -SO 2 R a In some embodiments, R 1 or R 1A C r H 2r+1 O, wherein r is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, including: C2 H 5 O(e.g., -(CH 2 ) 2 OH); C 3 H 7 O (e.g. -CH 2 OCH 2 CH 3 ,-(CH 2 ) 2 OCH 3 etc.); R 1 or R 1A C 1-12 Alkyl groups, such as -(CH 2 ) 3 CH 3 , -CH 2 CH 2 CH(CH 3 ) 2 wait.

[0036] In some embodiments, R 1 or R 1A For -(CH 2 ) 2 OH. In some embodiments, R 1 or R 1A -CH 2 OCH 2 CH 3 In some embodiments, R 1 or R 1A For -(CH 2 ) 2 OCH 3 In some embodiments, R 1 or R 1A For -(CH 2 ) 3 CH 3 In some embodiments, R 1 or R 1A -CH 2 CH 2 CH(CH 3 ) 2 .

[0037] With respect to any related structural diagram, for example, Formula 1, Formula 1A, Formula 1B, Formula 2, Formula 2A, Formula 3A, Formula 3B, Formula 4, Formula 5, Formula 6, Formula 7, Formula 8, Formula 9, or Formula 10, R 2 or R 2A are independently H or any substituent, for example, -CH 3 , -CH 2 CH(CH3 ) 2 , -CH 2 C(CH 3 ) 2 R 8 , -CH 2 CH 2 C(CH 3 ) 2 R 8 , -C 4 H 9 O,-CH 2 CH 2 OCH(CH 3 ) 2 .

[0038] In some embodiments, R 2 or R 2A is H. In some embodiments, R 2 or R 2A CH 3 In some embodiments, R 2 or R 2A -CH 2 CH(CH 3 ) 2 In some embodiments, R 2 or R 2A -CH 2 C(CH 3 ) 2 R 8 In some embodiments, R 2 or R 2A -CH 2 C(CH 3 ) 2 OH. In some embodiments, R 2 or R 2A -CH 2 CH 2 C(CH 3 ) 2 OH. In some embodiments, R 2 or R 2A -CH 2 CH 2 OCH(CH 3 ) 2 .

[0039] With respect to any related structural diagram, for example, Formula 1, Formula 1A, Formula 1B, Formula 2, Formula 2A, Formula 3A, Formula 3B, Formula 3C, Formula 3D, Formula 4, Formula 5, Formula 6, Formula 7, Formula 8, Formula 9, or Formula 10, R 3 is any substituent, for example: C1-30 Optionally substituted alkyl; -C w H 2w+1 O or its ester (wherein, w is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10); -(C u H 2u O 0-1 )-Z-(C v H 2v+1 )(where Z is a chemical bond, O, NHSO 2 , or NHCO, u is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 and v is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24); or -(C t H 2t O 0-1 )-Ht (wherein t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, and Ht is an optionally substituted C 3-10 heterocyclic group).

[0040] In some embodiments, R 3 is H. In some embodiments, R 3 CH 3 In some embodiments, R 3 -CH 2 CH(CH 3 ) 2 In some embodiments, R 3 For -(CH 2 ) 2 CH(CH 3 ) 2 In some embodiments, R 3 -CH 2 CH(OH)CH 3 In some embodiments, R 3 For -(CH 2 ) 2 CH(OH)CH 3 In some embodiments, R 3 For -(CH 2 ) 2 C(CH 3 ) 2 OH. In some embodiments, R 3 for (CH 2 ) 2 OCH(CH 3 ) 2,-(CH 2 ) 3 NHSO 2 CH 3 ,-(CH 2 ) 4 NHSO 2 CH 3 ,-(CH 2 ) 2 O(CH 2 ) 2 NHSO 2 CH 3 ,-(CH 2 ) 3 NHCOC 17 H 35 ,-(CH 2 ) 3 NHCOCH 3 ,-(CH 2 ) 4 NHCOCH 3 ,-(CH 2 ) 4 NHCOC 17 H 35 ,-(CH 2 ) 3 NH 2 ,

[0041] or

[0042] For any relevant structural diagram, for example, Formula 3E, R 3 1 to 6 identical or different R 8A Optionally substituted C 1-3 Alkyl, where R 8A OH, oxide, C 1-6 Organic group, or -O-(C 1-6 organic groups).

[0043] With respect to any related structural diagram, for example, Formula 1, Formula 1A, Formula 1B, Formula 2, Formula 2A, Formula 3A, Formula 3B, Formula 3C, Formula 3D, Formula 3E, Formula 4, Formula 5, Formula 6, Formula 7, Formula 8, Formula 9, Formula 10, Formula 11, Formula 12, or Formula 13, R 4 is H or any substituent, for example, a hydrocarbon group.

[0044] In some embodiments, R 4 For H.

[0045] With respect to any related structural diagram, for example, Formula 1, Formula 1A, Formula 1B, Formula 2, Formula 2A, Formula 3A, Formula 3B, Formula 3C, Formula 3D, Formula 3E, Formula 4, Formula 5, Formula 6, Formula 7, Formula 8, Formula 9, Formula 10, Formula 11, Formula 12, or Formula 13, R 5 is H or any substituent, for example, F, Cl, R a , -CO 2 R a , -CONR a R b ,CN,-OR a , -NR a R b , -NHCOR a , -NHSO 2 R a , -OCOR a , or -SO 2 R a , where R a or R b are independently H or C 1-30 In some embodiments, R 5 For-(C m H2 m O 0-1 )-Z-(C n H 2n+1 ), where Z is a chemical bond, O, -NHSO 2 , or -NHCO, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24. In some embodiments, R 5 For H.

[0046] With respect to any related structural diagram, for example, Formula 1, Formula 1A, Formula 1B, Formula 2, Formula 2A, Formula 3A, Formula 3B, Formula 3C, Formula 3D, Formula 3E, Formula 4, Formula 5, Formula 6, Formula 7, Formula 8, Formula 9, Formula 10, Formula 11, Formula 12, or Formula 13, R 6 is H or any substituent, for example, F, Cl, R a , -CO 2 R a , -CONR a R b ,CN,-OR a , -NR a R b , -NHCOR a , -NHSO 2 Ra , -OCOR a , or -SO 2 R a , where R a or R b are independently H or C 1-30 In some embodiments, R 6 For-(C m H 2m O 0-1 )-Z-(C n H 2n+1 ), where Z is a chemical bond, O, -NHSO 2 , or -NHCO, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24. In some embodiments, R 6 For H.

[0047] With respect to any related structural diagram, for example, Formula 1, Formula 1A, Formula 1B, Formula 2, Formula 2A, Formula 3A, Formula 3B, Formula 3C, Formula 3D, Formula 3E, Formula 4, Formula 5, Formula 6, Formula 7, Formula 8, Formula 9, Formula 10, Formula 11, Formula 12, or Formula 13, R 7 is H or any substituent, for example, F, Cl, R a , -CO 2 R a , -CONR a R b ,CN,-OR a , -NR a R b , -NHCOR a , -NHSO 2 R a , -OCOR a , or -SO 2 R a , where R a or R b are independently H or C 1-30 In some embodiments, R 7 For-(C m H 2m O 0-1 )-Z-(C n H 2n+1 ), where Z is a chemical bond, O, -NHSO 2, or -NHCO, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24. In some embodiments, R 7 For H.

[0048] With respect to any related structural diagram, for example, Formula 4, Formula 5, Formula 6, Formula 7, Formula 8, Formula 9, or Formula 10, R 8 H, OH, or C 1-6 In some embodiments, R 8 is H. In some embodiments, R 8 In some embodiments, R 8 CH 3 .

[0049] For any relevant structural diagram, for example, Formula 3E, R 8A OH, oxide, C 1-6 Organic group, or -O-(C 1-6 1 to 6 identical or different R 8A Can be attached to any ring C atom. In some embodiments, R 8A In some embodiments, R 8A CH 3 In some embodiments, two different R 8A (For example, CH 3 and OH) are attached to the same ring C atom. In some embodiments, R 8A -C(CH 3 ) 2 OH.

[0050] With respect to any related structural diagrams, for example, Formula 1, Formula 1A, Formula 1B, Formula 2, Formula 2A, Formula 3A, Formula 3B, Formula 3C, Formula 3D, Formula 4, Formula 5, Formula 6, Formula 7, Formula 8, Formula 9, or Formula 10, in some embodiments, R 3 and R 4 are independently H or C 1-12 Organic group; R 1 , R 2 , R 5 , R 6 , and R 7 F, Cl, Br, I, NO independently 2 ,CN,-OR a , -NR a R b , -OCOR a, or -SO 2 R a ; R 1A and R 2A For R a ; R a and R b are independently H or C 1-12 an organic group; and R 8 is H or OH. In some embodiments, R 5 and R 6 or R 6 and R 7 They may be optionally linked to form a saturated or unsaturated ring.

[0051] Some embodiments include optionally substituted 9-methoxy-1H-imidazo[4,5-c]quinolin-4-amine or a salt thereof.

[0052] Some embodiments include: optionally substituted 1-(4-amino-2-(ethoxymethyl)-9-methoxy-1H-imidazo[4,5-c]quinolin-1-yl)-2-methyl-2-propanol or a salt thereof; optionally substituted 2-(ethoxymethyl)-1-isobutyl-9-methoxy-1H-imidazo[4,5-c]quinolin-4-amine or a salt thereof; optionally substituted 1-(4-amino-9-methoxy-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methyl-2-propanol or a salt thereof; optionally substituted 1-(4-amino-2-(2-hydroxyethyl)-9-methoxy-1H-imidazo[4,5-c]quinolin-1 -yl)-2-methyl-2-propanol or a salt thereof; optionally substituted 4-((4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-9-yl)oxy)-2-methyl-2-butanol or a salt thereof; optionally substituted 2-(ethoxymethyl)-9-(isopentyloxy)-1H-imidazo[4,5-c]quinolin-4-amine or a salt thereof; optionally substituted 4-((4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-9-yl)oxy)-2-butanol or a salt thereof; optionally substituted 1-((4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-9-yl)oxy)-2-propanol or a salt thereof; Optionally substituted 4-((4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-9-yl)oxy)-2-methyl-2-butanol or a salt thereof; optionally substituted 4-((4-amino-2-(ethoxymethyl)-1-methyl-1H-imidazo[4,5-c]quinolin-9-yl)oxy)-2-methyl-2-butanol or a salt thereof; optionally substituted 2-(ethoxymethyl)-9-(2-isopropoxyethoxy)-1H-imidazo[4,5-c]quinolin-4-amine or a salt thereof; or optionally substituted 4-((4-amino-2-(ethoxymethyl)-1-isobutyl-1H-imidazo[4,5-c]quinolin-9-yl)oxy)-2 -methyl-2-butanol or a salt thereof; optionally substituted 2-(ethoxymethyl)-1-(2-isopropoxyethyl)-9-methoxy-1H-imidazo[4,5-c]quinolin-4-amine or a salt thereof; optionally substituted 4-(4-amino-2-(ethoxymethyl)-9-methoxy-1H-imidazo[4,5-c]quinolin-1-yl)-2-methyl-2-butanol or a salt thereof; optionally substituted 2-(ethoxymethyl)-9-isobutoxy-1H-imidazo[4,5-c]quinolin-4-amine or a salt thereof; optionally substituted 2-(ethoxymethyl)-9-(2-isopropoxyethoxy)-1-methyl-1H-imidazo[4,5-c]quinolin-4-amine or a salt thereof;Optionally substituted 2-(ethoxymethyl)-9-(isopentyloxy)-1-methyl-1H-imidazo[4,5-c]quinolin-4-amine or a salt thereof; Optionally substituted 2-(ethoxymethyl)-9-isobutoxy-1-methyl-1H-imidazo[4,5-c]quinolin-4-amine or a salt thereof; Optionally substituted N-(3-((4-amino-2-(ethoxymethyl)-1-methyl-1H-imidazo[4,5-c]quinolin-9-yl)oxy)propyl)methanesulfonamide or a salt thereof; Optionally substituted N-(2-(2-((4-amino-2-(ethoxymethyl)-1-methyl-1H-imidazo[4,5-c]quinolin-9-yl)oxy)ethoxy)ethyl)-methanesulfonamide or a salt thereof; Optionally substituted N-(3-((4-amino-2-(ethoxymethyl)-1-methyl-1H-imidazo[4,5-c]quinolin-9-yl)oxy)propyl)acetamide or a salt thereof; optionally substituted N-(4-((4-amino-2-(ethoxymethyl)-1-methyl-1H-imidazo[4,5-c]quinolin-9-yl)oxy)butyl)methanesulfonamide or a salt thereof; optionally substituted N-(3-((4-amino-2-(ethoxymethyl)-1-methyl-1H-imidazo[4,5-c]quinolin-9-yl)oxy)propyl)stearamide or a salt thereof; optionally substituted N-(4-((4-amino-2-(ethoxymethyl)-1-methyl-1H-imidazo[4,5-c]quinolin-9-yl)oxy)propyl) )butyl)acetamide or a salt thereof; optionally substituted N-(4-((4-amino-2-(ethoxymethyl)-1-methyl-1H-imidazo[4,5-c]quinolin-9-yl)oxy)butyl)-stearamide or a salt thereof; optionally substituted 2-(ethoxymethyl)-1-methyl-9-(2-morpholinethoxy)-1H-imidazo[4,5-c]quinolin-4-amine or a salt thereof; optionally substituted 2-(ethoxymethyl)-1-methyl-9-((tetrahydrofuran-3-yl)oxy)-1H-imidazo[4,5-c]quinolin-4-amine or a salt thereof; optionally substituted 2-(ethoxymethyl)-1-methyl-9-(pyrrolidin-3-yloxy)-1H-imidazo[4,5-c]quinolin-4-amine or a salt thereof; optionally substituted 2-(ethoxymethyl)-1-methyl-9-(piperidin-4-yloxy)-1H-imidazo[4,5-c]quinolin-4-amine or a salt thereof; optionally substituted N-(3-((4-amino-2-(ethoxymethyl)-1-methyl-1H-imidazo[4,5-c]quinolin-9-yl)oxy)propyl)palmitamide or a salt thereof; optionally substituted N-(4-((4-amino-2-(ethoxymethyl)-1-methyl-1H-imidazo[4,5-c]quinolin-9-yl)oxy)butyl)palmitamide or a salt thereof; optionally substituted 9-(3-aminopropoxy)-2-(ethoxymethyl)-1-methyl-1H-imidazo[4,5-c]quinolin-4-amine or a salt thereof;Optionally substituted 2-(ethoxymethyl)-9-isopropoxy-1-methyl-1H-imidazo[4,5-c]quinolin-4-amine or a salt thereof; Optionally substituted 1-((4-amino-2-(ethoxymethyl)-1-methyl-1H-imidazo[4,5-c]quinolin-9-yl)oxy)-2-methyl-2-propanol or a salt thereof; Optionally substituted 2-(ethoxymethyl)-3,4-dihydro-5-oxa-1,2a,9-triazinapho[2,1,8-cde]azulene-10-amine or a salt thereof; Optionally substituted (R)-2-(10-amino-2-(ethoxymethyl)-3 ,4-dihydro-5-oxa-1,2a,9-triazine[2,1,8-cde]azulen-3-yl)-2-propanol or a salt thereof; optionally substituted (S)-2-(10-amino-2-(ethoxymethyl)-3,4-dihydro-5-oxa-1,2a,9-triazine[2,1,8-cde]azulen-3-yl)-2-propanol or a salt thereof; optionally substituted (S)-2-amino-12-(ethoxymethyl)-6-methyl-6,7-dihydro-5H-3,4-(azenometheno)[1,5]oxazocine-3-yl)- azocino)[4,3,2-de]quinolin-6-ol or a salt thereof; optionally substituted (R)-2-amino-12-(ethoxymethyl)-6-methyl-6,7-dihydro-5H-3,4-(nitrilomethine bridge)[1,5]oxazocino[4,3,2-de]quinolin-6-ol or a salt thereof; optionally substituted (R)-2-amino-12-(ethoxymethyl)-6,7-dihydro-5H-3,4-(nitrilomethine bridge)[1,5]oxazocino[4,3,2-de]quinolin-6-ol or a salt thereof; optionally substituted (S)-2-amino- 12-(ethoxymethyl)-6,7-dihydro-5H-3,4-(nitrilomethine bridge)[1,5]oxazocino-[4,3,2-de]quinolin-6-ol or a salt thereof; optionally substituted 2-amino-12-(ethoxymethyl)-5H-3,4-(nitrilomethine bridge)[1,5]oxazocino[4,3,2-de]quinolin-6(7H)-one or a salt thereof; or optionally substituted tert-butyl 4-((4-amino-2-(ethoxymethyl)-1-methyl-1H-imidazo[4,5-c]quinolin-9-yl)oxy)piperidine-1-carboxylate or a salt thereof. ;

[0053] Table 3

[0054]

[0055]

[0056]

[0057]

[0058]

[0059]

[0060]

[0061]

[0062] Some embodiments include: optionally substituted 4-amino-2H-pyrazolo[3,4-c]quinolin-9-ol or a salt thereof; or optionally substituted 4-amino-2-isopentyl-2H-pyrazolo[3,4-c]quinolin-9-ol or a salt thereof; optionally substituted 2-isopentyl-9-(isopentyloxy)-2H-pyrazolo[3,4-c]quinolin-4-amine or a salt thereof; or optionally substituted 2-butyl-9-(isopentyloxy)-2H-pyrazolo[3,4-c]quinolin-4-amine or a salt thereof.

[0063] Table 4

[0064]

[0065] The following embodiments are particularly contemplated herein.

[0066] Embodiment 1: A compound represented by the following formula or a salt thereof:

[0067]

[0068] Among them, the dotted line indicates the presence or absence of a chemical bond;

[0069] A 1 CR 1 , NR 1A or N;

[0070] A 2 CR 2 , NR 2A , O, or S;

[0071] B 1 CR 5 or N;

[0072] B 2 CR 6 or N;

[0073] B 3 CR 7 or N;

[0074] R 1 and R 2F, Cl, Br, I, NO independently 2 , CN, R a , -OR a , -NR a R b , -NHCOR a , -NHSO 2 R a , -OCOR a , or -SO 2 R a ;

[0075] X is a chemical bond, O, NR a , -CO-, -SO-, or -SO 2 -,-CONR a , hydrocarbon group, and R 3 H or C 1-30 Organic group; or XR 3 is F or Cl;

[0076] R 1A , R 2A , R 4 , R a and R b are independently H or C 1-30 Organic groups;

[0077] R 5 , R 6 and R 7 F, Cl, Br, I, NO independently 2 , CN, R a , -OR a , -NR a R b , -NHCOR a , -NHSO 2 R a , -OCOR a , -SO 2 R a , or -X 1 -(C m H 2m O 0-1 )-Z-(C n H 2n+1 ), -(C m H 2m O 0-1 )-Z-(C n H 2n+1 ), where R 5 and R 6 or R 6 and R 7may be optionally linked to form a ring;

[0078] Among them, X 1 is a chemical bond, O, NR a , -CO-, -SO-, or -SO 2 -;

[0079] Z is a chemical bond, O, NHSO 2 , or NHCO;

[0080] m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

[0081] n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23.

[0082] Embodiment 2: The compound according to Embodiment 1, which is further a compound represented by the following formula or a salt thereof:

[0083] or

[0084]

[0085] Among them, R 3 C 1-30 In some embodiments, R 3 1-6 R 8A The group optionally substituted C 1-3 Alkyl, where R 8A The groups are independently -OH, oxide, C 1-6 Organic group, or -O-(C 1-6 organic groups).

[0086] Embodiment 3: The compound according to Embodiment 1, which is further a compound represented by the following formula or a salt thereof:

[0087]

[0088] Among them, R 4 is hydrogen, C 1-30 A non-aromatic organic group or a C containing an aromatic group not directly attached to a nitrogen atom 1-30 Aromatic organic group.

[0089] Embodiment 4: A compound according to Embodiment 1, 2 or 3, wherein R 1 or R 1A C 1-12 Optionally substituted alkyl.

[0090] Embodiment 5: The compound of embodiment 4, wherein R 1 or R 1A For -C r H 2r+1 O or an ester thereof, wherein r is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0091] Embodiment 6: The compound of embodiment 5, wherein R 1 or R 1A For -C 3 H 7 O.

[0092] Embodiment 7: The compound of embodiment 6, wherein R 1 or R 1A -CH 2 OCH 2 CH 3 .

[0093] Embodiment 8: A compound according to Embodiment 1, 2, 3, 4, 5, 6, or 7, wherein R 2 or R 2A H or C 1-12 Optionally substituted alkyl.

[0094] Embodiment 9: The compound of embodiment 8, wherein R 2 or R 2A C 1-6 Alkyl, or -C y H 2y+1 O or an ester thereof, wherein y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0095] Embodiment 10: The compound of embodiment 9, wherein R 2 or R 2A For -C 4 H 9 O.

[0096] Embodiment 11: The compound of embodiment 10, wherein R 2 or R 2A -CH 2 -CH(CH 3 ) 2 -OH.

[0097] Embodiment 12: The compound of embodiment 8, wherein R 2 or R 2A For H.

[0098] Embodiment 13: A compound according to Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, wherein R 3 C 1-30 Optionally substituted alkyl.

[0099] Embodiment 14: The compound of embodiment 13, wherein R 3 C 1-10 Alkyl, or -C w H 2w+1 O or an ester thereof, wherein w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0100] Embodiment 15: A compound according to Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13, wherein R 3 For-(C t H 2t O 0-1 )-Ht, wherein t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and Ht is an optionally substituted C 3-6 Heterocyclic group.

[0101] Embodiment 16: A compound according to Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13, wherein R 3 For-(C u H 2u O 0-1 )-Z-(C v H 2v+1 ), where Z is a chemical bond, O, NHSO 2 , or NHCO, u is 0, 1, 2, 3, 4, 5, or 6, and v is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23.

[0102] Embodiment 17: A compound according to Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13, wherein R 3 For-(C u H 2u O 0-1 )-NR a R b , and u is 1, 2, 3, 4, 5, or 6, where R a and R b are independently H or C 1-6 alkyl.

[0103] Embodiment 18: The compound of embodiment 14, wherein R 3 C 5 H 11 O.

[0104] Embodiment 19: The compound of embodiment 18, wherein R 3 -CH 2 -CH 2 -CH(CH 3 ) 2 OH.

[0105] Embodiment 20: The compound of embodiment 17, wherein R 3 -CH 2 -CH 2 -CH 2 -NH 2 .

[0106] Embodiment 21: A compound according to Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, wherein R 4 H or C 1-6 alkyl.

[0107] Embodiment 22: The compound of embodiment 21, wherein R 4 For H.

[0108] Embodiment 23: A compound according to Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22, wherein R 5 For R a , F, Cl, -CO 2 R a , -CONR a R b ,CN,-OR a , -NR a R b , -OCOR a , or -SO 2 R a , where R a and R b are independently H or C 1-6 alkyl.

[0109] Embodiment 24: The compound of embodiment 23, wherein R 5 For H.

[0110] Embodiment 25: A compound according to Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22, wherein R 5 For-(C m H 2m O 0-1 )-Z-(C n H 2n+1 ), where Z is a chemical bond, O, NHSO 2 , or NHCO, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25.

[0111] Embodiment 26: A compound according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25, wherein R 6 For R a , F, Cl, -CO 2 R a , -CONR a R b ,CN,-OR a , -NR a R b , -OCOR a , or -SO 2 R a , where R a or R b are independently H or C 1-6 alkyl.

[0112] Embodiment 27: The compound of embodiment 26, wherein R 6 For H.

[0113] Embodiment 28: A compound according to Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25, wherein R 6 For-(C m H 2m O 0-1 )-Z-(C n H 2n+1 ), where Z is a chemical bond, O, NHSO 2, or NHCO, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23.

[0114] Embodiment 29: A compound according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28, wherein R 7 For R a , F, Cl, -CO 2 R a , -CONR a R b ,CN,-OR a , -NR a R b , -OCOR a , or -SO 2 R a , where R a or R b are independently H or C 1-6 alkyl.

[0115] Embodiment 30: The compound of embodiment 29, wherein R 7 For H.

[0116] Embodiment 31: A compound according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28, wherein R 7 For-(C m H 2m O 0-1 )-Z-(C n H 2n+1 ), where Z is a chemical bond, O, NHSO 2 , or NHCO, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23.

[0117] Embodiment 32: A compound according to Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31, wherein R 8 H, OH or CH 3 .

[0118] Embodiment 33: The compound of embodiment 32, wherein R 8 For OH.

[0119] Embodiment 34: The compound of embodiment 32, wherein R 8 For H.

[0120] Embodiment 35: The following compounds or salts of these compounds, or esters of these compounds having a -OH group:

[0121]

[0122]

[0123]

[0124]

[0125] or Embodiment 36: The compound is optionally substituted 9-methoxy-1H-imidazo[4,5-c]quinolin-4-amine. Embodiment 37: The compound is optionally substituted 9-methoxy-2H-pyrazolo[3,4-c]quinolin-4-amine. Embodiment 38: The compound of Embodiment 36 is:

[0126] Optionally substituted 1-(4-amino-2-(ethoxymethyl)-9-methoxy-1H-imidazo[4,5-c]quinolin-1-yl)-2-methyl-2-propanol or a salt thereof;

[0127] Optionally substituted 2-(ethoxymethyl)-1-isobutyl-9-methoxy-1H-imidazo[4,5-c]quinolin-4-amine or a salt thereof;

[0128] Optionally substituted 1-(4-amino-9-methoxy-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methyl-2-propanol or a salt thereof;

[0129] Optionally substituted 1-(4-amino-2-(2-hydroxyethyl)-9-methoxy-1H-imidazo[4,5-c]quinolin-1-yl)-2-methyl-2-propanol or a salt thereof;

[0130] Optionally substituted 4-((4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-9-yl)oxy)-2-methyl-2-butanol or a salt thereof;

[0131] Optionally substituted 2-(ethoxymethyl)-9-(isopentyloxy)-1H-imidazo[4,5-c]quinolin-4-amine or a salt thereof;

[0132] Optionally substituted 4-((4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-9-yl)oxy)-2-butanol or a salt thereof;

[0133] Optionally substituted 1-((4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-9-yl)oxy)-2-propanol or a salt thereof;

[0134] Optionally substituted 4-((4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-9-yl)oxy)-2-methyl-2-butanol or a salt thereof;

[0135] Optionally substituted 4-((4-amino-2-(ethoxymethyl)-1-methyl-1H-imidazo[4,5-c]quinolin-9-yl)oxy)-2-methyl-2-butanol or a salt thereof;

[0136] Optionally substituted 2-(ethoxymethyl)-9-(2-isopropoxyethoxy)-1H-imidazo[4,5-c]quinolin-4-amine or a salt thereof;

[0137] Optionally substituted 4-((4-amino-2-(ethoxymethyl)-1-isobutyl-1H-imidazo[4,5-c]quinolin-9-yl)oxy)-2-methyl-2-butanol or a salt thereof;

[0138] Optionally substituted 2-(ethoxymethyl)-1-(2-isopropoxyethyl)-9-methoxy-1H-imidazo[4,5-c]quinolin-4-amine or a salt thereof;

[0139] Optionally substituted 4-(4-amino-2-(ethoxymethyl)-9-methoxy-1H-imidazo[4,5-c]quinolin-1-yl)-2-methyl-2-butanol or a salt thereof;

[0140] Optionally substituted 2-(ethoxymethyl)-9-isobutoxy-1H-imidazo[4,5-c]quinolin-4-amine or a salt thereof;

[0141] Optionally substituted 2-(ethoxymethyl)-9-(2-isopropoxyethoxy)-1-methyl-1H-imidazo[4,5-c]quinolin-4-amine or a salt thereof;

[0142] Optionally substituted 2-(ethoxymethyl)-9-(isopentyloxy)-1-methyl-1H-imidazo[4,5-c]quinolin-4-amine or a salt thereof;

[0143] Optionally substituted 2-(ethoxymethyl)-9-isobutoxy-1-methyl-1H-imidazo[4,5-c]quinolin-4-amine or a salt thereof;

[0144] Optionally substituted N-(3-((4-amino-2-(ethoxymethyl)-1-methyl-1H-imidazo[4,5-c]quinolin-9-yl)oxy)propyl)methanesulfonamide or a salt thereof;

[0145] Optionally substituted N-(2-(2-((4-amino-2-(ethoxymethyl)-1-methyl-1H-imidazo[4,5-c]quinolin-9-yl)oxy)ethoxy)ethyl)-methanesulfonamide or a salt thereof;

[0146] Optionally substituted N-(3-((4-amino-2-(ethoxymethyl)-1-methyl-1H-imidazo[4,5-c]quinolin-9-yl)oxy)propyl)acetamide or a salt thereof;

[0147] Optionally substituted N-(4-((4-amino-2-(ethoxymethyl)-1-methyl-1H-imidazo[4,5-c]quinolin-9-yl)oxy)butyl)methanesulfonamide or a salt thereof;

[0148] Optionally substituted N-(3-((4-amino-2-(ethoxymethyl)-1-methyl-1H-imidazo[4,5-c]quinolin-9-yl)oxy)propyl)stearamide or a salt thereof;

[0149] Optionally substituted N-(4-((4-amino-2-(ethoxymethyl)-1-methyl-1H-imidazo[4,5-c]quinolin-9-yl)oxy)butyl)acetamide or a salt thereof;

[0150] Optionally substituted N-(4-((4-amino-2-(ethoxymethyl)-1-methyl-1H-imidazo[4,5-c]quinolin-9-yl)oxy)butyl)-stearamide or a salt thereof;

[0151] Optionally substituted 2-(ethoxymethyl)-1-methyl-9-(2-morpholinethoxy)-1H-imidazo[4,5-c]quinolin-4-amine or a salt thereof;

[0152] Optionally substituted 2-(ethoxymethyl)-1-methyl-9((tetrahydrofuran-3-yl)oxy)-1H-imidazo[4,5-c]quinolin-4-amine or a salt thereof;

[0153] Optionally substituted 2-(ethoxymethyl)-1-methyl-9-(pyrrolidin-3-yloxy)-1H-imidazo[4,5-c]quinolin-4-amine or a salt thereof;

[0154] Optionally substituted 2-(ethoxymethyl)-1-methyl-9-(piperidin-4-yloxy)-1H-imidazo[4,5-c]quinolin-4-amine or a salt thereof;

[0155] Optionally substituted N-(3-((4-amino-2-(ethoxymethyl)-1-methyl-1H-imidazo[4,5-c]quinolin-9-yl)oxy)propyl)palmitamide or a salt thereof;

[0156] Optionally substituted N-(4-((4-amino-2-(ethoxymethyl)-1-methyl-1H-imidazo[4,5-c]quinolin-9-yl)oxy)butyl)palmitamide or a salt thereof;

[0157] Optionally substituted 9-(3-aminopropoxy)-2-(ethoxymethyl)-1-methyl-1H-imidazo[4,5-c]quinolin-4-amine or a salt thereof;

[0158] Optionally substituted 2-(ethoxymethyl)-9-isopropoxy-1-methyl-1H-imidazo[4,5-c]quinolin-4-amine or a salt thereof;

[0159] Optionally substituted 1-((4-amino-2-(ethoxymethyl)-1-methyl-1H-imidazo[4,5-c]quinolin-9-yl)oxy)-2-methyl-2-propanol or a salt thereof;

[0160] Optionally substituted 2-(ethoxymethyl)-3,4-dihydro-5-oxa-1,2a,9-triazinap[2,1,8-cde]azul-10-amine or a salt thereof;

[0161] Optionally substituted (R)-2-(10-amino-2-(ethoxymethyl)-3,4-dihydro-5-oxa-1,2a,9-triazinap[2,1,8-cde]azul-3-yl)-2-propanol or a salt thereof;

[0162] Optionally substituted (S)-2-(10-amino-2-(ethoxymethyl)-3,4-dihydro-5-oxa-1,2a,9-triazinap[2,1,8-cde]azul-3-yl)-2-propanol or a salt thereof;

[0163] Optionally substituted (S)-2-amino-12-(ethoxymethyl)-6-methyl-6,7-dihydro-5H-3,4-(nitrilomethine bridge)[1,5]oxazocino[4,3,2-de]quinolin-6-ol or a salt thereof;

[0164] Optionally substituted (R)-2-amino-12-(ethoxymethyl)-6-methyl-6,7-dihydro-5H-3,4-(nitrilomethine bridge)[1,5]oxazocino[4,3,2-de]quinolin-6-ol or a salt thereof;

[0165] Optionally substituted (R)-2-amino-12-(ethoxymethyl)-6,7-dihydro-5H-3,4-(nitrilomethine bridge)[1,5]oxazocino[4,3,2-de]quinolin-6-ol or a salt thereof;

[0166] Optionally substituted (S)-2-amino-12-(ethoxymethyl)-6,7-dihydro-5H-3,4-(nitrilomethine bridge)[1,5]oxazocino-[4,3,2-de]quinolin-6-ol or a salt thereof;

[0167] Optionally substituted 2-amino-12-(ethoxymethyl)-5H-3,4-(nitrilomethine bridge)[1,5]oxazocino[4,3,2-de]quinolin-6(7H)-one or a salt thereof;

[0168] Optionally substituted tert-butyl 4-((4-amino-2-(ethoxymethyl)-1-methyl-1H-imidazo[4,5-c]quinolin-9-yl)oxy)piperidine-1-carboxylate or a salt thereof.

[0169] Embodiment 39: The compound of embodiment 37 is:

[0170] Optionally substituted 4-amino-2H-pyrazolo[3,4-c]quinolin-9-ol or a salt thereof;

[0171] Optionally substituted 4-amino-2-isopentyl-2H-pyrazolo[3,4-c]quinolin-9-ol or a salt thereof;

[0172] Optionally substituted 2-isopentyl-9-(isopentyloxy)-2H-pyrazolo[3,4-c]quinolin-4-amine or a salt thereof;

[0173] Optionally substituted 2-butyl-9-(isopentyloxy)-2H-pyrazolo[3,4-c]quinolin-4-amine or a salt thereof.

[0174] Embodiment 40: A method for treating a viral infection, cancer or an allergic disease, the method comprising administering a compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, or 39 to a mammal in need of such treatment.

[0175] Embodiment 41: Use of a compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, or 39 in the manufacture of a medicament for treating viral infection, cancer or allergic disease.

[0176] Embodiment 42: The method of Embodiment 40 or the use of Embodiment 41, wherein the viral infection comprises HCV infection.

[0177] Embodiment 43: A dosage form suitable for administration to a mammal, comprising a compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, or 39.

[0178] Example:

[0179] In the synthetic schemes described below, all temperatures are in degrees Celsius and all parts and percentages are by weight unless otherwise stated. Reagents and solvents were purchased from suppliers such as Aldrich Chemical Company and were used without further purification unless otherwise stated. Tetrahydrofuran (THF) and N,N-dimethylformamide (DMF) purchased from commercial sources were stored in sealed bottles and used as received.

[0180] The reactions listed below were generally performed at ambient temperature (unless otherwise indicated) in anhydrous solvents under a positive pressure of argon or nitrogen. Glassware was oven dried and / or heat dried. The reactions were analyzed by TLC and / or LC-MS, and termination of the reactions was determined by consumption of the starting materials. Analytical thin layer chromatography (TLC) was performed on glass plates pre-coated with 0.25 mm silica gel 60 F254 plates (EM Sciences) and visualized with UV light (254 nm) and / or heated with commercially available ethanolic phosphomolybdic acid. Preparative thin layer chromatography (TLC) was performed on glass plates pre-coated with 0.5 mm silica gel 60 F254 plates (20 x 20 cm, from commercial sources) and visualized with UV light (254 nm).

[0181] Reactions were usually carried out by doubling the reaction volume using the reaction solvent or extraction solvent, and then, unless otherwise stated, washing operations were performed using the indicated aqueous solution (25% by volume of the extraction volume). 2 SO 4 and / or MgSO 4 The product solution was dried on a plate and then filtered, and the solvent was evaporated on a rotary evaporator under reduced pressure, and it should be noted that the solvent was removed under vacuum. Column chromatography was performed under positive pressure using 230-400 mesh silica gel.

[0182] 1 H-NMR and 13 C-NMR spectra were recorded on a Varian Mercury-VX400 instrument operating at 400 MHz. NMR spectra were recorded using CDCl 3 Solution (chloroform as reference standard (7.27 ppm for protons, 77.00 ppm for C)); CD 3 OD (3.4ppm and 4.8ppm represent protons, 49.3ppm represents C), DMSO-d 6 (2.49 ppm for protons) or, where appropriate, tetramethylsilane as an internal reference (0.00 ppm). Other NMR solvents may be used as desired.

[0183] Embodiment 1:

[0184] Synthesis of 1-[4-amino-2-(ethoxymethyl)-9-methoxy-imidazo[4,5-c]quinolin-1-yl]-2-methyl-2-propanol

[0185] Solution 1

[0186]

[0187] Step 1: Synthesis of 1-[(5-methoxy-3-nitro-4-quinolyl)amino]-2-methyl-2-propanol

[0188] 4-Chloro-5-methoxy-3-nitro-quinoline (1.00 g, 4.19 mmol, 1.0 equiv) was added to 1-amino-2-methyl-2-propanol (747.10 mg, 8.38 mmol, 2.0 equiv) and triethylamine (Et 3 N) (2.12 g, 20.95 mmol, 2.90 mL, 5.0 equiv) in DCM (50.00 mL). The resulting mixture was stirred at 25 °C for 0.5 h. The reaction mixture was washed by extraction with water (30 mL) and brine (30 mL). 2 SO 4 The organic phase was dried, filtered, and concentrated under vacuum. The residue was purified by column chromatography (DCM: DCM / MeOH = 20 / 1). The desired product was obtained: 1-[(5-methoxy-3-nitro-4-quinolyl)amino]-2-methyl-2-propanol (1.00 g, 3.43 mmol, yield 81.86%), as a yellow solid. 1 H NMR (400 MHz, CDCl 3 )δppm: 9.51 (s, 1H), 9.03 (s, 1H), 7.63 (t, J = 8.0Hz, 1H), 7.58 (d, J = 8.4Hz, 1H), 6.94 (d, J=7.2Hz, 1H), 4.10 (s, 3H), 2.95 (d, J=4.8Hz, 2H), 1.29 (s, 6H); ES-LCMS m / z 292.3[M+H] + .

[0189] Step 2: Synthesis of 1-[(3-amino-5-methoxy-4-quinolyl)amino]-2-methyl-2-propanol

[0190] In N 2 Under the conditions, Raney-Ni (626.42 mg, 7.31 mmol, 2.1 eq.) was added to a solution of 1-[(5-methoxy-3-nitro-4-quinolyl)amino]-2-methyl-2-propanol (1.00 g, 3.43 mmol, 1.0 eq.) in MeOH (100.00 mL). The suspension was degassed under vacuum and heated to 40 °C with H 2 Purify several times. 2The resulting mixture was stirred at 25°C for 3 h under conditions of (15 psi). The reaction mixture was filtered. The filtrate was concentrated under vacuum. The desired product was obtained: 1-[(3-amino-5-methoxy-4-quinolyl)amino]-2-methyl-2-propanol) (870.00 mg, 3.33 mmol, 97.08% yield) as a yellow solid. 1 H NMR (400 MHz, CD 3 OD) δppm: 8.26 (s, 1H), 7.38 (d, J=8.0Hz, 1H), 7.31 (t, J=8.0Hz, 1H), 6.88 (d, J=7.6Hz, 1H), 4.02 (s, 3H), 3.22 (s, 2H), 1.29 (s, 6H); ES-LCMSm / z 262.3[M+H] + .

[0191] Step 3: Synthesis of 1-[2-(ethoxymethyl)-9-methoxy-imidazo[4,5-c]quinolin-1-yl]-2-methyl-2-propanol

[0192] At 120°C, 1-[(3-amino-5-methoxy-4-quinolyl)amino]-2-methyl-2-propanol (400.00 mg, 1.53 mmol, 1.0 equiv) and MS (200 mg) in 2-ethoxyacetic acid (3.30 g, 31.7 mmol, 3 mL, 20.7 equiv) was continued for 4 h. The reaction mixture was then filtered. The filtrate was dissolved in DCM (80 mL) and adjusted to pH = 8 with 2M NaOH. The organic layer was separated and the mixture was heated to 40 °C in anhydrous Na 2 SO 4 The mixture was dried over medium, filtered and concentrated under vacuum. The mixture was purified by column chromatography (DCM: DCM / MeOH = 10 / 1). The desired product was obtained: 1-[2-(ethoxymethyl)-9-methoxy-imidazo[4,5-c]quinolin-1-yl]-2-methyl-2-propanol (230.00 mg, 698.26 μmol, yield 45.62%), as a yellow solid. 1 H NMR (400 MHz, CD 3OD) δppm: 9.09 (s, 1H), 7.79 (d, J = 8.0Hz, 1H), 7.67 (t, J = 8.2Hz, 1H), 7.25 (d, J = 7.2Hz, 1H), 5.68 (s, 1H), 5.3 9 (s, 1H), 4.63 (m, 2H), 4.14 (s, 3H), 3.62 (m, 2H), 1.32-1.26 (m, 3H), 1.25-1.23 (m, 3H), 0.76 (m, 3H); ES-LCMS m / z:330.3[M+H] + .

[0193] Step 4: Synthesis of 1-[2-(ethoxymethyl)-9-methoxy-5-oxido-imidazo[4,5-c]quinolin-5-yl-1-yl]-2-methyl-2-propanol

[0194] m-CPBA (212.64 mg, 1.05 mmol, 85% purity, 1.5 eq) was added to a solution of 1-[2-(ethoxymethyl)-9-methoxy-imidazo[4,5-c]quinolin-1-yl]-2-methyl-2-propanol (230.00 mg, 698.26 μmol, 1.0 eq) in DCM (30.00 mL). The resulting mixture was stirred at 25 °C for 1 h. K 2 CO 3 The reaction mixture was adjusted to pH = 8 with aqueous solution and partitioned between DCM (50 mL) and water (20 mL). The organic layer was separated, washed with brine (20 mL) and concentrated in anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under vacuum. Preparative TCL (DCM / MeOH=8 / 1, R f =0.3) to purify the residue to obtain the desired product: 1-[2-(ethoxymethyl)-9-methoxy-5-oxido-imidazo[4,5-c]quinolin-5-yl-1-yl]-2-methyl-2-propanol) (150.00 mg, 434.29 μmol, yield 62.20%) as a yellow solid. 1 H NMR (400MHz, CD 3 OD) δppm: 9.10 (s, 1H), 8.52 (d, J = 8.8Hz, 1H), 7.85 (t, J = 8.6Hz, 1H), 7.45 (d, J = 7.6Hz, 1H), 5.54 (s , 1H), 5.31 (s, 1H), 4.58 (s, 2H), 4.19 (s, 3H), 3.62 (m, 2H), 1.28-1.23 (m, 6H), 0.84 (m, 3H); ES-LCMS m / z:346.3[M+H]+ .

[0195] Step 5: Synthesis of 1-[4-amino-2-(ethoxymethyl)-9-methoxy-imidazo[4,5-c]quinolin-1-yl]-2-methyl-2-propanol

[0196] TsCl (99.36 mg, 521.15 μmol, 1.2 eq.) was added to 1-[2-(ethoxymethyl)-9-methoxy-5-oxido-imidazo[4,5-c]quinolin-5-yl-1-yl]-2-methyl-2-propanol (150.00 mg, 434.29 μmol, 1.0 eq.) and NH 3 ·H 2 O (543.64 mg, 4.34 mmol, 597.41 μL, 28% purity, 10.0 equiv) in CHCl 3 (20.00 mL) solution. The resulting mixture was stirred at 20°C for 0.5 h. The solvent was removed under vacuum. The product was purified by preparative HPLC (MeCN / H 2 O as eluent, acidic conditions) to purify the residue. After freeze-drying, the desired product was obtained: 1-[4-amino-2-(ethoxymethyl)-9-methoxy-imidazo[4,5-c]quinolin-1-yl]-2-methyl-2-propanol (50.00 mg, 131.28 μmol, yield 30.23%, purity 100%, as hydrochloride) as a white solid. 1 H NMR (400 MHz, CD 3 OD) δppm: 7.63 (t, J=8.2Hz, 1H), 7.30 (d, J=8.0Hz, 1H), 7.13 (d, J=8.0Hz, 1H), 5.50 (s, 1H), 5.21 (s , 1H), 4.76 (s, 1H), 4.55 (s, 1H), 4.09 (s, 3H), 3.59 (m, 2H), 1.23-1.20 (m, 6H), 0.82 (m, 3H); ES-LCMS m / z:345.3[M+H] + .

[0197] Embodiment 2:

[0198] Synthesis of 2-(ethoxymethyl)-1-isobutyl-9-methoxy-imidazo[4,5-c]quinolin-4-amine

[0199] Solution 2

[0200]

[0201] Step 1: Synthesis of 2-(ethoxymethyl)-1-isobutyl-9-methoxy-imidazo[4,5-c]quinoline

[0202] 2-Ethoxyacetyl chloride (99.91 mg, 815.26 μmol, 2.0 equiv) was added to N 4 -isobutyl-5-methoxy-quinoline-3,4-diamine (100.00 mg, 407.63 μmol, 1.0 equiv) and pyridine (322.44 mg, 4.08 mmol, 329.02 μL, 10.0 equiv) in DCM (4.00 mL). The resulting mixture was stirred at 25 °C for 1 h. The solvent was removed under vacuum. The residue was dissolved in NaOH (2M, 4.95 mL, 24.3 equiv) and stirred at 100 °C for 5 h. The mixture was dissolved in water (10 mL) and extracted with DCM (50 mL x 2). The combined organic phases were washed with brine (20 mL) and concentrated in anhydrous Na 2 SO 4 The mixture was dried over medium, filtered and concentrated under vacuum. The residue was purified by preparative TCL (DCM / MeOH=15 / 1) to obtain the desired product: 2-(ethoxymethyl)-1-isobutyl-9-methoxy-imidazo[4,5-c]quinoline (80.00 mg, 255.27 μmol, yield 62.62%) as a brown solid. 1 HNMR (400MHz, CDCl 3 )δppm: 9.27 (s, 1H), 7.70 (d, J = 8.4Hz, 1H), 7.60 (t, J = 8.2Hz, 1H), 7.04 (d, J = 8.0Hz, 1H), 4.89 (s, 2H), 4.62 (br ,s.2H), 4.08(s,3H), 3.65-3.59(m,2H), 2.11-2.02(m,1H), 1.26(t,J=7.0Hz,3H),0.75-0.72(m,6H); ES-LCMS m / z:314.3[M+H] + .

[0203] Step 2: Synthesis of 2-(ethoxymethyl)-1-isobutyl-9-methoxy-5-oxido-imidazo[4,5-c]quinolin-5-yl

[0204] m-CPBA (48.59 mg, 239.33 μmol, 85% purity, 1.5 eq) was added to a solution of 2-(ethoxymethyl)-1-isobutyl-9-methoxy-imidazo[4,5-c]quinoline (50.00 mg, 159.55 μmol, 1.0 eq) in DCM (5.00 mL). The resulting mixture was stirred at 25 °C for 0.5 h. DCM (40 mL) and water (10 mL) were added to the mixture, and the pH was adjusted to 8 by adding an aqueous solution of NaOH. The organic layer was then separated, washed with brine (10 mL), and stirred in anhydrous Na 2 SO 4 The mixture was dried on ice and filtered. The filtrate was concentrated under vacuum to obtain the desired product: 2-(ethoxymethyl)-1-isobutyl-9-methoxy-5-oxido-imidazo[4,5-c]quinolin-5-yl (50.00 mg, 151.80 μmol, yield 95.14%) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 )δppm: 9.05 (s, 1H), 8.71 (d, J = 8.8Hz, 1H), 7.70 (t, J = 8.2Hz, 1H), 7.17 (d, J = 7.2Hz, 1H), 4.56 (s, 2H), 4.44 (br ,s.2H), 4.11(s,3H), 3.65-3.59(m,2H), 2.06-1.99(m,1H), 1.27(t,J=7.0Hz,3H), 0.76-0.72(m,6H); ES-LCMS m / z:330.2[M+H] + .

[0205] Step 3: Synthesis of 2-(ethoxymethyl)-1-isobutyl-9-methoxy-imidazo[4,5-c]quinolin-4-amine

[0206] TsCl (34.73 mg, 182.16 μmol, 1.2 eq.) was added to 2-(ethoxymethyl)-1-isobutyl-9-methoxy-5-oxido-imidazo[4,5-c]-quinolin-5-yl (50.00 mg, 151.80 μmol, 1.0 eq.) and NH 3 ·H 2 O (190.27 mg, 1.52 mmol, 209.09 μL, 28% purity, 10.0 equiv) in CHCl 3 (10.00 mL) solution. The resulting mixture was stirred at 25°C for 0.5 h. The solvent was removed under vacuum. The product was purified by preparative HPLC (MeCN / H 2O as eluent, acidic conditions) and the residue was purified. After freeze-drying, the desired product was obtained: 2-(ethoxymethyl)-1-isobutyl-9-methoxy-imidazo[4,5-c]quinolin-4-amine (30.00 mg, 78.31 μmol, 51.59% yield, purity 95.24%, as hydrochloride) as a white solid. 1 H NMR (400MHz, CD 3 OD)δppm:7.69(t,J=8.2Hz,1H),7.36(d,J=8.0Hz,1H),7.18(d,J=8.4Hz,1H),4.87(s,2H),4.62(br,s.2 ES-LCMS m / z:329.4[M+H] + .

[0207] The following compounds were prepared in the same manner as in Example 1 or 2 using corresponding reagents.

[0208]

[0209] The hydrochloride salt of 1-[4-amino-9-methoxy-2-(2-methoxyethyl)imidazo[4,5-c]quinolin-1-yl]-2-methyl-2-propanol was obtained as a white solid with a yield of 9.18% and a purity of 98.5%. 1 H NMR (400MHz, CD 3 OD) δppm: 7.67 (t, J = 8.4Hz, 1H), 7.35 (d, J = 8.4Hz, 1H), 7.18 (d, J = 8.4Hz, 1H), 5.60 (m, 1H), 4.48 (m ,1H), 4.14(s,3H), 3.97(m,2H), 3.47-3.44(m,2H), 3.42(s,3H), 1.26(s,3H), 0.89(s,3H); ES-LCMS m / z:345.3[M+H] + .

[0210]

[0211] The hydrochloride salt of 1-[4-amino-2-(2-hydroxyethyl)-9-methoxy-imidazo[4,5-c]quinolin-1-yl]-2-methyl-2-propanol was obtained as a white solid with a yield of 3.47% and a purity of 100%. 1 H NMR (400MHz, CD 3OD)δppm:7.61(t,J=8.4Hz,1H),7.28(d,J=8.0Hz,1H),7.12(d,J=7.6Hz,1H),5.54(m,1H),4 .41(m,1H),4.08(s,3H),4.07-4.05(m,2H),3.27(m,2H),1.20(s,3H),0.85(s,3H); ES-LCMS m / z:331.2[M+H] + .

[0212]

[0213] The hydrochloride salt of 4-[[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-9-yl]oxy]-2-methyl-2-butanol was obtained as a white solid in a yield of 40.57%. 1 H NMR (400MHz, CD 3 OD)δppm: 7.68(t,J=8.4Hz,1H), 7.34(d,J=8.4Hz,1H), 7.15(d,J=8.4Hz,1H), 4.84(s,2H), 4.50(t, ES-LCMS m / z:345.3[M+H] + .

[0214] Embodiment 3:

[0215] Synthesis of 2-(ethoxymethyl)-9-isopentyloxy-1H-imidazo[4,5-c]quinolin-4-amine

[0216] Solution 3

[0217]

[0218] Step 1: Synthesis of 5-isopentyloxy-3-nitro-quinolin-4-amine

[0219] A solution of isopentyl-4-methylbenzenesulfonate (1.06 g, 4.38 mmol, 3.0 equiv) in DCM (4.00 mL) was added to a solution of 4-amino-3-nitro-quinolin-5-ol (300.00 mg, 1.46 mmol, 1.0 equiv), TBAB (470.66 mg, 1.46 mmol, 1.0 equiv) and KI (242.36 mg, 1.46 mmol, 1.0 equiv) in NaOH (1 M, 4.38 mL, 3.0 equiv). The resulting mixture was stirred at 20 °C for 40 h. The reaction mixture was diluted with water (10 mL) and extracted with DCM (30 mL x 2). The combined organic layers were washed with brine (10 mL) and heated in anhydrous Na 2 SO 4 The product was dried on 4% paraformaldehyde, filtered and concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography (PE: PE / EA = 1 / 2) to obtain the desired product: 5-isopentyloxy-3-nitro-quinolin-4-amine (140.00 mg, 508.54 μmol, yield 34.83%) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 )δppm: 9.33 (s, 1H), 9.25 (s, 1H), 9.10 (s, 1H), 7.66 (t, J = 8.2Hz, 1H), 7.57 (d, J = 8.4Hz, 1H) , 6.94(d,J=7.6Hz,1H), 4.28(t,J=6.2Hz,2H), 1.88(m,3H), 1.05(d,J=6.0Hz,6H); ES-LCMS m / z:276.3[M+H] + .

[0220] Step 2: Synthesis of 5-isopentyloxyquinoline-3,4-diamine

[0221] In N 2 Under the conditions, Raney-Ni (100.00 mg, 1.17 mmol, 2.3 equiv) was added to a solution of 5-isopentyloxy-3-nitro-quinolin-4-amine (140.00 mg, 508.54 μmol, 1.0 equiv) in MeOH (50.00 mL). The suspension was degassed under vacuum and heated to 40 °C. 2 Purify 3 times. 2 The resulting mixture was stirred at 20°C for 2 h under the conditions of (15 psi). The reaction mixture was filtered. The filtrate was concentrated under vacuum to obtain the desired product: 5-isopentyloxyquinoline-3,4-diamine (120.00 mg, 489.16 μmol, yield 96.19%), as a green solid. 1 H NMR (400MHz, CD3 OD) δppm: 8.01 (s, 1H), 7.53 (t, J = 8.2Hz, 1H), 7.27 (d, J = 8.8Hz, 1H), 6.96 (d, J = 8. 0Hz, 1H), 4.30 (t, J = 6.2Hz, 2H), 1.89-1.87 (m, 3H), 1.04 (d, J = 6.4Hz, 6H); ES-LCMS m / z:246.3[M+H] + .

[0222] Step 3: Synthesis of 2-(ethoxymethyl)-9-isopentyloxy-1H-imidazo[4,5-c]quinoline

[0223] 5-isopentyloxyquinoline-3,4-diamine (110.00 mg, 448.39 μmol, 1.0 eq.), 2-ethoxyacetic acid (1.21 g, 11.62 mmol, 1.10 mL, 25.9 eq.) and MS (150.00 mg) was placed in a microwave tube. The sealed tube was heated in a microwave at 130 °C for 1 h. The solid was filtered off. The filtrate was diluted with DCM (50 mL) and water (20 mL). The pH of the mixture was adjusted to 7 with an aqueous solution of NaOH (1 M). The layers were separated. The organic phase was washed with brine (20 mL) and heated in anhydrous Na 2 SO 4 The mixture was dried on 4% paraffin wax, filtered and concentrated under vacuum. The residue was purified by preparative TLC (DCM / MeOH=20 / 1) to obtain the desired product: 2-(ethoxymethyl)-9-isopentyloxy-1H-imidazo[4,5-c]quinoline (130.00 mg, 414.82 μmol, yield 92.51%) as a yellow solid. 1 H NMR (400MHz, CD 3 OD) δppm: 9.10 (s, 1H), 7.73 (d, J = 8.8Hz, 1H), 7.66 (t, J = 8.4Hz, 1H), 7.20 (d, J = 7.6Hz, 1H), 4.80 (s, 2H), 4.48 (t,J=6.6Hz,2H), 3.73-3.68(m,2H), 1.95-1.88(m,3H), 1.29(t,J=7.0Hz,3H), 1.05(d,J=6.0Hz,6H); ES-LCMS m / z:314.3[M+H] + .

[0224] Step 4: Synthesis of 2-(ethoxymethyl)-9-isopentyloxy-5-oxido-1H-imidazo[4,5-c]quinolin-5-yl

[0225] m-CPBA (126.33 mg, 622.23 μmol, 85% purity, 1.5 eq) was added to a solution of 2-(ethoxymethyl)-9-isopentyloxy-1H-imidazo[4,5-c]quinoline (130.00 mg, 414.82 μmol, 1.0 eq) in DCM (30.00 mL). The resulting mixture was stirred at 20 °C for 0.5 h. The reaction mixture was diluted with DCM (20 mL) and washed with saturated K 2 CO 3 The reaction mixture was washed with water (10 mL) and the combined organic layers were washed with brine (15 mL) and stirred in anhydrous Na 2 SO 4 The mixture was dried over medium, filtered and concentrated under reduced pressure to obtain the desired product: 2-(ethoxymethyl)-9-isopentyloxy-5-oxido-1H-imidazo[4,5-c]quinolin-5-yl (130.00 mg, 394.67 μmol, yield 95.14%) as a brown solid. 1 H NMR (400MHz, CD 3 OD) δppm: 9.11 (s, 1H), 8.31 (d, J = 8.4Hz, 1H), 7.82 (t, J = 8.8Hz, 1H), 7.41-7.38 (m, 1H), 4.88 (s, 2H), 4.54 (t ,J=6.6Hz,2H), 3.73-3.67(m,2H), 1.94-1.86(m,3H), 1.29(t,J=7.0Hz,3H), 1.04(d,J=6.0Hz,6H); ES-LCMS m / z:330.3[M+H] + .

[0226] Step 5: Synthesis of 2-(ethoxymethyl)-9-isopentyloxy-1H-imidazo[4,5-c]quinolin-4-amine

[0227] TsCl (112.87 mg, 592.00 μmol, 1.5 eq.) was added to 2-(ethoxymethyl)-9-isopentyloxy-5-oxido-1H-imidazo[4,5-c]-quinolin-5-yl (130.00 mg, 394.67 μmol, 1.0 eq.) and NH 3 ·H 2 O (494.04 mg, 3.95 mmol, 542.90 μL, 28% purity, 10.0 equiv) in CHCl 3 (6.00 mL) solution. The resulting mixture was stirred at 25 °C for 0.5 h. The solvent was then removed under vacuum. The product was purified by preparative HPLC (MeCN / H 2O as eluent, acidic conditions) to purify the residue. After freeze-drying, the desired product was obtained: 2-(ethoxymethyl)-9-isopentyloxy-1H-imidazo[4,5-c]quinolin-4-amine (75.00 mg, 196.61 μmol, yield 49.82%, purity 95.65%, hydrochloride solid) as a white solid. 1 H NMR (400MHz, CD 3 OD) δppm: 7.68(t,J=8.2Hz,1H), 7.33(d,J=8.4Hz,1H), 7.17(d,J=8.4Hz,1H), 4.86(s,2H), 4.51(t,J=6 .8Hz,2H), 3.75-3.70(m,2H), 1.94-1.86(m,3H), 1.31(t,J=7.0Hz,3H), 1.05(d,J=6.4Hz,6H); ES-LCMS m / z:329.3[M+H] + .

[0228] The following compounds were prepared in the same manner as described in Example 3 using the corresponding reagents.

[0229]

[0230] The hydrochloride salt of 4-[[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-9-yl]oxy]2-butanol was obtained as a white solid with a yield of 20.06% and a purity of 100%. 1 H NMR (400MHz, CD 3 OD) δppm: 7.65 (t, J = 8.4Hz, 1H), 7.31 (d, J = 8.0Hz, 1H), 7.13 (d, J = 8.4Hz, 1H), 4.79 (s, 2H), 4.54-4.53 (m, 1H), 4.42-4.4 0(m,1H), 4.25-4.16(m,1H), 3.72-3.66(m,2H), 2.15-2.09(m,2H), 1.35(d,J=6.4Hz,3H), 1.27(t,J=7.0Hz,3H); ES-LCMS m / z:330.9[M+H] + .

[0231] Embodiment 4:

[0232] Synthesis of 1-((4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-9-yl)oxy)-2-propanol Scheme 4

[0233]

[0234] Step 1: Synthesis of 1-[(4-amino-3-nitro-5-quinolyl)oxy]propan-2-one

[0235] A solution of acetylmethyl-4-methylbenzenesulfonate (3.33 g, 14.61 mmol, 3.0 equiv) in DCM (8.00 mL) was added to a solution of 4-amino-3-nitro-quinolin-5-ol (1.00 g, 4.87 mmol, 1.0 equiv), TBAB (1.57 g, 4.87 mmol, 1.0 equiv), KI (809.09 mg, 4.87 mmol, 1.0 equiv) in NaOH (2M, 7.31 mL, 3.0 equiv) at 25 °C. The mixture was stirred for 48 h at 25 °C. The reaction mixture was diluted with water (20 mL) and extracted with DCM (50 mL x 2). The combined organic layers were washed with brine (20 mL) and washed with anhydrous Na 2 SO 4 The mixture was dried over medium, filtered and concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography (DCM: DCM / MeOH=20 / 1). The desired product was obtained: 1-[(4-amino-3-nitro-5-quinolyl)oxy]propan-2-one (220.00 mg, 842.17 μmol, yield 17.29%), as a yellow solid. 1 HNMR (400MHz, CDCl 3 )δppm:9.84(br s,1H),9.41(br s,1H),9.35(s,1H),7.66-7.60(m,2H),6.80-6.77(m,1H),4.92(s,2H),2.37(s,3H); ES-LCMS m / z:262.2[M+H] + .

[0236] Step 2: Synthesis of 1-[(3,4-diamino-5-quinolyl)oxy]-2-propanol

[0237] In N 2 Under the conditions, Raney-Ni (100.29 mg, 1.17 mmol, 1.39 equiv) was added to a solution of 1-[(4-amino-3-nitro-5-quinolyl)oxy]propan-2-one (220.00 mg, 842.17 μmol, 1.0 equiv) in MeOH (100.00 mL). The suspension was degassed under vacuum and heated to 40 °C with H 2 Purify several times. 2(15 psi) and stirred the mixture at 25 °C for 1 h. The solid was filtered off. The filtrate was concentrated under vacuum to obtain the desired product: 1-[(3,4-diamino-5-quinolyl)oxy]-2-propanol (160.00 mg, 685.90 μmol, yield 81.44%) as a green solid. 1 H NMR (400MHz, CD 3 OD)δppm:7.95(s,1H),7.64-7.60(m,1H),7.28-7.26(m,1H),7.02-6.90(m ,1H), 4.32-4.29(m,2H), 4.07-4.04(m,1H), 1.33(d,J=6.4Hz,3H); ES-LCMS m / z:234.1[M+H] + .

[0238] Step 3: Synthesis of 1-[[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-9-yl]oxy]2-propanol

[0239] 1-[(3,4-diamino-5-quinolyl)oxy]2-propanol (150.00 mg, 643.03 μmol, 1.0 eq.), 2-ethoxyacetic acid (1.10 g, 10.57 mmol, 1.00 mL, 16.4 eq.) and MS (50.00 mg) was placed in a microwave tube. The sealed tube was heated in a microwave at 120°C for 0.5 h. A 3M NaOH (10 mL) aqueous solution and THF (3 mL) were added to the reaction mixture. The resulting mixture was stirred at 50°C for 2 h. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (10 mL) and washed with anhydrous Na 2 SO 4 The product was dried over medium, filtered and concentrated under reduced pressure to provide a residue. The residue was purified by preparative TLC (DCM / MeOH=15 / 1). The desired product was obtained: 1-[[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-9-yl]oxy]2-propanol (23.00 mg, 76.33 μmol, yield 11.87%), as a yellow solid. 1 H NMR (400 MHz, CDCl 3)δppm: 11.52(s,1H), 9.20(s,1H), 7.81(d,J=8.4Hz,1H), 7.50(t,J=8.0Hz,1H), 6.97(d,J=7.6Hz,1H), 4.83(s,2 ES-LCMS m / z:302.2[M+H] + .

[0240] Step 4: Synthesis of 1-[[2-(ethoxymethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-5-yl-9-yl]oxy]-2-propanol

[0241] m-CPBA (30.99 mg, 152.65 μmol, 85% purity, 2.0 eq) was added in one portion to a mixture of 1-[[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-9-yl]oxy]-2-propanol (23.00 mg, 76.33 μmol, 1.0 eq) in DCM (8.00 mL) at 25 °C. The mixture was stirred for 1 h at 25 °C. The solvent was removed under vacuum. The crude product was used in the next step without further purification. The crude product: 1-[[2-(ethoxymethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-5-yl-9-yl]oxy]-2-propanol (20.00 mg, 63.02 μmol, 82.57% yield) was obtained as a brown solid. 1 H NMR (400 MHz, CDCl 3 )δppm:9.17(s,1H),8.39(d,J=8.8Hz,1H),7.47-7.45(m,1H),7.05-7.01(m,1H),4.8 6(s,2H),4.48(m,1H),4.37(m,1H),4.06(d,J=8.4Hz,1H),3.74-3.71(m,2H),1.47(br d,J=6.4Hz,3H), 1.35(t,J=7.2Hz,3H); ES-LCMSm / z:=318.2[M+H] + .

[0242] Step 5: Synthesis of 1-[[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-9-yl]oxy]-2-propanol

[0243] At 25 °C, TsCl (24.03 mg, 126.05 μmol, 2.0 equiv) was added to 1-[[2-(ethoxymethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-5-yl-9-yl]oxy]-2-propanol (20.00 mg, 63.02 μmol, 1.0 equiv) and NH 3 ·H 2 O (78.89 mg, 630.24 μmol, 86.69 μL, 28% purity, 10.0 equiv) in CHCl 3 (6.00 mL). The mixture was stirred at 25°C for 3 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The reaction mixture was purified by preparative HPLC (MeCN / H 2 O as eluent, acidic conditions) to purify the residue. After freeze-drying, the desired product was obtained: 1-[[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-9-yl]oxy]-2-propanol (4.68 mg, 13.26 μmol, yield 21.04%, hydrochloride) as a white solid. 1 H NMR (400MHz, CD 3 OD) δppm: 7.66 (t, J = 8.4Hz, 1H), 7.35 (d, J = 8.4Hz, 1H), 7.20 (d, J = 8.4Hz, 1H), 4.83 (s, 2H), 4.42-4.39 (m, 1H) ), 4.36(m,1H), 4.18-4.16(m,1H), 3.71-3.68(m,2H), 1.36(d,J=6.4Hz,3H), 1.29(t,J=7.2Hz,3H); ES-LCMS m / z:317.2[M+H] + .

[0244] Example 5 :

[0245] Synthesis of 4-[[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-9-yl]oxy]-2-methyl-2-butanol

[0246] Solution 5

[0247]

[0248] Step 1: Synthesis of 4-[[2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-9-yl]oxy]-2-methyl-2-butanol

[0249] 3-Methoxypropanoyl chloride (80.66 mg, 658.20 μmol, 2.0 equiv) was added to a solution of 4-[(3,4-diamino-5-quinolyl)oxy]-2-methyl-2-butanol (179.17 mg, 329.10 μmol, 1.0 equiv) and pyridine (260.32 mg, 3.29 mmol, 265.63 μL, 10.0 equiv) in DCM (2.00 mL). The resulting mixture was stirred at 25 °C for 16 h. The solvent was removed under vacuum. The residue was dissolved in NaOH (2M, 4.00 mL, 24.3 equiv) and stirred at 100 °C for 1 h. The mixture was diluted with water (10 mL) and extracted with DCM (50 mL x 2). The combined organic phases were washed with brine (30 mL) and washed with anhydrous Na 2 SO 4 The mixture was dried over medium, filtered and concentrated under vacuum. The residue was purified by preparative TLC (DCM / MeOH=15 / 1). The desired product was obtained: 4-[[2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-9-yl]oxy]-2-methyl-2-butanol (90.00 mg, 273.23 μmol, yield 83.02%), as a brown solid. 1 H NMR (400MHz, CD 3 OD) δppm: 9.08 (s, 1H), 7.73 (d, J = 8.4Hz, 1H), 7.65 (t, J = 8.0Hz, 1H), 7.18 (d, J = 7.2Hz, 1H), 4.51 (t, J = 6.0H z,2H), 3.93(t,J=6.4Hz,2H), 3.42(s,3H), 3.33-3.28(m,2H), 2.23(t,J=6.0Hz,2H), 1.44(s,6H); ES-LCMS m / z:330.3[M+H] + .

[0250] Step 2: Synthesis of 4-[[2-(2-methoxyethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-5-yl-9-yl]oxy]-2-methyl-2-butanol

[0251] m-CPBA (83.21 mg, 409.85 μmol, 85% purity, 1.5 eq.) was added to a solution of 4-[[2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-9-yl]oxy]-2-methyl-2-butanol (90.00 mg, 273.23 μmol, 1.0 eq.) in DCM (10.00 mL). The resulting mixture was stirred at 25 °C for 0.5 h. The solvent was removed under vacuum. The residue was purified by preparative TLC (DCM / MeOH=15 / 1). The desired product: 4-[[2-(2-methoxyethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-5-yl-9-yl]oxy]-2-methyl-2-butanol (60.00 mg, 173.72 μmol, yield 63.58%) was obtained as a yellow solid. 1 H NMR (400 MHz, CDCl 3 )δppm: 8.97 (s, 1H), 8.36 (d, J = 8.8Hz, 1H), 7.54 (t, J = 8.4Hz, 1H), 6.94 (d, J = 8.0Hz, 1H), 4.38 (t, J = 5.6Hz, 2H), 3.81(t,J=6.2Hz,2H), 3.40(s,3H), 3.17(t,J=6.0Hz,2H), 2.24(t,J=5.6Hz,2H), 1.48(s,6H); ES-LCMS m / z:345.9[M+H] + .

[0252] Step 3: Synthesis of 4-[[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-9-yl]oxy]-2-methyl-2-butanol

[0253] TsCl (66.24 mg, 347.44 μmol, 2.0 equiv) was added to 4-[[2-(2-methoxyethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-5-yl-9-yl]oxy]-2-methyl-2-butanol (60.00 mg, 173.72 μmol, 1.0 equiv) and NH 3 ·H 2 O (217.81 mg, 1.74 mmol, 239.35 μL, 28% purity, 10.0 equiv) in CHCl 3 (6.00 mL) solution. The resulting mixture was stirred at 25°C for 0.5 h. The solvent was removed under vacuum. The product was purified by preparative HPLC (MeCN / H 2O as eluent, acidic conditions) and the residue was purified. After freeze-drying, the desired product was obtained: 4-[[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-9-yl]oxy]-2-methyl-2-butanol (24.95 mg, 63.20 μmol, yield 36.38%, purity 96.48%, hydrochloride solid), white solid. 1 H NMR (400MHz, CD 3 OD)δppm:7.66(t,J=8.2Hz,1H), 7.32(d,J=8.0Hz,1H), 7.13(d,J=8.0Hz,1H), 4.49(t,J=6.0Hz,2H), 3 .93(t,J=6.6Hz,2H), 3.42(s,3H), 3.26(t,J=6.2Hz,2H), 2.19(t,J=5.8Hz,2H), 1.43(s,6H); ES-LCMS m / z:345.3[M+H] + .

[0254] Embodiment 6:

[0255] Synthesis of 4-[4-amino-2-(ethoxymethyl)-1-methyl-imidazo[4,5-c]quinolin-9-yl]oxy-2-methyl-2-butanol

[0256] Solution 6

[0257]

[0258] Step 1: Synthesis of 4-(methylamino)-3-nitro-quinolin-5-ol

[0259] At -78℃, BBr 3 The product was added dropwise to a solution of 5-methoxy-N-methyl-3-nitro-quinoline-4-amine (300.00 mg, 1.29 mmol, 1.0 equiv) in DCM (15.00 mL). The resulting mixture was stirred at 60 °C for 2 h. The mixture was added dropwise to MeOH (100 mL) at -30 °C. The solvent was removed under vacuum. The desired product was obtained: 4-(methylamino)-3-nitro-quinoline-5-ol (300.00 mg, crude product), as a brown solid. 1 H NMR (400MHz, CD 3OD)δppm:9.22(s,1H),7.79(m,1H),7.33(m,1H),7.15-7.13(m,1H),3.08(s,3H); ES-LCMS m / z:220.2[M+H] + .

[0260] Step 2: Synthesis of 2-methyl-4-[[4-(methylamino)-3-nitro-5-quinolyl]oxy]2-butanol

[0261] A solution of (3-hydroxy-3-methyl-butyl) 4-methylbenzenesulfonate (883.49 mg, 3.42 mmol, 3.0 equiv) in DCM (3.00 mL) was added to a solution of 4-(methylamino)-3-nitro-quinolin-5-ol (250.00 mg, 1.14 mmol, 1.0 equiv), TBAB (367.67 mg, 1.14 mmol, 1.0 equiv) and KI (189.32 mg, 1.14 mmol, 1.0 equiv) in NaOH (2M, 1.71 mL, 3.0 equiv). The resulting mixture was stirred at 25 °C for 64 h. The reaction mixture was diluted with water (10 mL) and extracted with DCM (30 mL x 2). The combined organic layers were washed with brine (10 mL) and washed with anhydrous Na 2 SO 4 The product was dried over medium, filtered and concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography (DCM / MeOH=20 / 1). The desired product was obtained: 2-methyl-4-[[4-(methylamino)-3-nitro-5-quinolyl]oxy]2-butanol) (100.00 mg, 327.51 μmol, 28.73% yield), as a yellow solid. 1 H NMR (400 MHz, CDCl 3 )δppm: 9.36 (s, 1H), 9.02 (s, 1H), 7.61-7.55 (m, 2H), 6.91 (d, J = 6.8Hz, 1H), 4.36 (t ,J=5.8Hz,2H), 2.84(d,J=5.2Hz,3H), 2.13(t,J=5.8Hz,2H), 1.41(s,6H); ES-LCMS m / z:306.0[M+H] + .

[0262] Step 3: Synthesis of 4-[[3-amino-4-(methylamino)-5-quinolyl]oxy]-2-methyl-2-butanol

[0263] In N 2Under the conditions, Raney-Ni (100.00 mg, 1.17 mmol, 3.6 equiv) was added to a solution of 2-methyl-4-[[4-(methylamino)-3-nitro-5-quinolyl]oxy]2-butanol (100.00 mg, 327.51 μmol, 1.0 equiv) in MeOH (50.00 mL). The resulting suspension was degassed under vacuum and heated with H 2 Purify several times. 2 The resulting mixture was stirred at 25°C for 1 h under conditions of 15 psi. The mixture was filtered. The filtrate was concentrated under vacuum. The desired product was obtained: 4-[[3-amino-4-(methylamino)-5-quinolyl]oxy]-2-methyl-2-butanol (80.00 mg, 290.54 μmol, 88.71% yield) as a green solid. 1 H NMR (400MHz, CD 3 OD) δppm: 8.07 (s, 1H), 7.44 (t, J = 8.0Hz, 1H), 7.29 (d, J = 8.4Hz, 1H), 6.95 (d, J = 7.6Hz, 1H), 4.35(t,J=6.4Hz,2H), 3.19(d,J=10.4Hz,3H), 2.10(d,J=6.4Hz,2H), 1.33(s,6H); ES-LCMS m / z:276.3[M+H] + .

[0264] Step 4: Synthesis of 4-[2-(ethoxymethyl)-1-methyl-imidazo[4,5-c]quinolin-9-yl]oxy-2-methyl-2-butanol

[0265] 4-[[3-amino-4-(methylamino)-5-quinolyl]oxy]-2-methyl-2-butanol (70.00 mg, 254.22 μmol, 1.0 equivalent), 2-ethoxyacetic acid (1.65 g, 15.85 mmol, 1.50 mL, 62.4 equivalent) and MS (100.00 mg) was placed in a microwave tube. The sealed tube was heated in a microwave at 120°C for 30 minutes. The mixture was filtered. The filtrate was diluted with DCM (50 mL) and water (10 mL), and the pH was adjusted to 7 with an aqueous solution of NaOH (2 M). The organic layer was separated, washed with brine (10 mL), and heated in anhydrous Na 2 SO 4The mixture was dried on 4% paraformaldehyde, filtered and concentrated under vacuum. The crude product was purified by preparative TLC (DCM / MeOH=15 / 1). The desired product was obtained: 4-[2-(ethoxymethyl)-1-methyl-imidazo[4,5-c]quinolin-9-yl]oxy-2-methyl-2-butanol (20.00 mg, 58.24 μmol, yield 22.91%), as a yellow solid. 1 H NMR (400 MHz, CDCl 3 )δppm: 9.25 (s, 1H), 7.88 (d, J = 7.6Hz, 1H), 7.59 (t, J = 8.2Hz, 1H), 7.10 (d, J = 7.2Hz, 1H), 4.89 (s, 2H), 4.48 (t,J=7.6Hz,2H), 4.32(s,3H), 3.66-3.61(m,2H), 2.20(t,J=7.6Hz,2H), 1.38(s,6H), 1.26(m,3H); ES-LCMS m / z:344.3[M+H] + .

[0266] Step 5: Synthesis of 4-[2-(ethoxymethyl)-1-methyl-5-oxido-imidazo[4,5-c]quinolin-5-yl-9-yl]oxy-2-methyl-2-butanol

[0267] m-CPBA (23.65 mg, 116.48 μmol, purity 85%, 2.0 eq.) was added to a solution of 4-[2-(ethoxymethyl)-1-methyl-imidazo[4,5-c]quinolin-9-yl]oxy-2-methyl-2-butanol (20.00 mg, 58.24 μmol, 1.0 eq.) in DCM (5.00 mL). The resulting mixture was stirred at 25 °C for 0.5 h. The solvent was removed under vacuum. The residue was purified by preparative TLC (DCM / MeOH=10 / 1). The desired product: 4-[2-(ethoxymethyl)-1-methyl-5-oxido-imidazo[4,5-c]quinolin-5-yl-9-yl]oxy-2-methyl-2-butanol (20.00 mg, crude product) was obtained as a white solid. 1 H NMR (400 MHz, CDCl 3)δppm: 9.28 (s, 1H), 8.70 (d, J = 8.8Hz, 1H), 7.71 (t, J = 8.2Hz, 1H), 7.22 (d, J = 8.0Hz, 1H), 4.86 (s, 2H), 4.52 -4.48(m,2H),4.28(s,3H),3.67-3.61(m,2H),2.23-2.16(m,2H),1.35(s,6H),1.29-1.27(m,3H); ES-LCMS m / z:360.3[M+H] + .

[0268] Step 6: Synthesis of 4-[4-amino-2-(ethoxymethyl)-1-methyl-imidazo[4,5-c]quinolin-9-yl]oxy-2-methyl-2-butanol

[0269] TsCl (15.91 mg, 83.47 μmol, 1.5 eq.) was added to 4-[2-(ethoxymethyl)-1-methyl-5-oxido-imidazo[4,5-c]quinolin-5-yl-9-yl]oxy-2-methyl-2-butanol (20.00 mg, 55.65 μmol, 1.0 eq.) and NH 3 ·H 2 O (69.66 mg, 556.45 μmol, 76.54 μL, 28% purity, 10.0 equiv) in CHCl 3 (2.00 mL) solution. The resulting mixture was stirred at 25°C for 0.5 h. The solvent was removed under vacuum. The product was purified by preparative HPLC (MeCN / H 2 O as eluent, acidic conditions) to purify the residue. After freeze-drying, the desired product was obtained: 4-[4-amino-2-(ethoxymethyl)-1-methyl-imidazo[4,5-c]quinolin-9-yl]oxy-2-methyl-2-butanol (6.00 mg, 15.19 μmol, yield 27.30%, hydrochloride) as a white solid. 1 H NMR (400MHz, CD 3 OD) δppm: 7.65(t,J=8.2Hz,1H), 7.31(d,J=8.4Hz,1H), 7.18(d,J=8.0Hz,1H), 4.85(s,2H), 4.48(t,J=7.8H z,2H), 4.26(s,3H), 3.68-3.63(m,2H), 2.16(t,J=7.8Hz,2H), 1.31(s,6H), 1.26(t,J=6.8Hz,3H); ES-LCMS m / z:359.3[M+H] + .

[0270] The following compounds were prepared by similar procedures to those described in Examples 5 and 6 using the corresponding reagents.

[0271]

[0272] 2-(Ethoxymethyl)-9-(2-isopropoxyethoxy)-1H-imidazo[4,5-c]quinolin-4-amine was obtained as a white solid hydrochloride with a yield of 40.79% and a purity of 100%. 1 H NMR (400MHz, CD 3 OD)δppm:7.63(t,J=8.2Hz,1H), 7.30(d,J=8.4Hz,1H), 7.18(d,J=8.0Hz,1H), 4.79(s,2H), 4.54-4.51(m,2H), 3.94-3.91(m,2H), 3.75-3.69(m,1H), 3.66-3.64(m,2H), 1.24(t,J=7.0Hz,3H), 1.15(d,J=6.0Hz,6H); ES-LCMS m / z:345.3[M+H] + .

[0273] Example 7 :

[0274] Synthesis of 4-[4-amino-2-(ethoxymethyl)-1-isobutyl-imidazo[4,5-c]quinolin-9-yl]oxy-2-methyl-2-butanol

[0275] Solution 7

[0276]

[0277] Step 1: Synthesis of 3-amino-4-(isobutylamino)quinolin-5-ol

[0278] At -78℃, BBr 3 (2.30 g, 9.17 mmol, 883.73 μL, 5.0 equiv) was added dropwise to N 4 -isobutyl-5-methoxy-quinoline-3,4-diamine (450.00 mg, 1.83 mmol, 1.0 equiv) in DCM (30.00 mL). The resulting mixture was stirred at 60 ° C for 2 h. The mixture was added dropwise to MeOH (100 mL) at -30 ° C. The solvent was removed under vacuum. The desired product was obtained: 3-amino-4-(isobutylamino)quinoline-5-ol) (500.00 mg, 1.64 mmol, 89.81% yield, hydrochloric acid (2HCl) salt), brown solid. 1 H NMR (400MHz, CD3 OD) δppm: 8.19 (s, 1H), 7.65 (t, J = 8.2Hz, 1H), 7.24 (d, J = 8.4Hz, 1H), 6.97 (d, J = 7. 2Hz,1H),3.80(d,J=6.4Hz,2H),2.07-2.02(m,1H),1.10(d,J=6.4Hz,6H); ES-LCMS m / z:232.3[M+H] + .

[0279] Step 2: Synthesis of 2-(ethoxymethyl)-1-isobutyl-imidazo[4,5-c]quinolin-9-ol

[0280] 2-Ethoxyacetyl chloride (271.92 mg, 2.22 mmol, 1.5 eq) was added to a solution of 3-amino-4-(isobutylamino)quinolin-5-ol (450.00 mg, 1.48 mmol, 1.0 eq, hydrochloric acid (2HCl) salt) in pyridine (4.90 g, 61.95 mmol, 5.0 mL, 41.9 eq). The resulting mixture was stirred at 25°C for 1 h. The solvent was removed under vacuum. The residue was dissolved in NaOH (2M, 7.40 mmol, 3.0 mL, 5.0 eq) and stirred at 100°C for 2 h. The mixture was partitioned between DCM (40 mL) and water (10 mL). The organic layer was separated, washed with brine (10 mL), and precipitated in anhydrous NaOH. 2 SO 4 The mixture was dried on 4% paraformaldehyde, filtered, and concentrated under vacuum. The residue was purified by column chromatography (DCM: DCM / MeOH = 10 / 1) to obtain the desired product: 2-(ethoxymethyl)-1-isobutyl-imidazo[4,5-c]quinolin-9-ol (100.00 mg, 334.03 μmol, yield 2.58%), as a red solid. 1 H NMR (400MHz, CD 3 OD) δppm: 9.06 (s, 1H), 7.69-7.67 (m, 1H), 7.56 (t, J = 8.0Hz, 1H), 7.11-7.08 (m, 1H), 4.89 (s, 2H), 4.65 ES-LCMS m / z:300.3[M+H] + .

[0281] Step 3: Synthesis of 4-[2-(ethoxymethyl)-1-isobutyl-imidazo[4,5-c]quinolin-9-yl]oxy-2-methyl-2-butanol

[0282] A solution of (3-hydroxy-3-methyl-butyl) 4-methylbenzenesulfonate (155.32 mg, 601.26 μmol, 3.0 equiv) in DCM (3.00 mL) was added to a solution of 2-(ethoxymethyl)-1-isobutyl-imidazo[4,5-c]quinolin-9-ol (60.00 mg, 200.42 μmol, 1.0 equiv), TBAB (64.61 mg, 200.42 μmol, 1.0 equiv) and KI (33.27 mg, 200.42 μmol, 1.0 equiv) in NaOH (2M, 300.63 μL, 3.0 equiv). The resulting mixture was stirred at 25 °C for 64 h. The reaction mixture was diluted with water (20 mL) and extracted with DCM (50 mL x 2). The combined organic layers were washed with brine (20 mL) and washed with anhydrous Na 2 SO 4 The mixture was dried over medium, filtered, and concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography (DCM: DCM / MeOH = 10 / 1). The desired product was obtained: 4-[2-(ethoxymethyl)-1-isobutyl-imidazo[4,5-c]quinolin-9-yl]oxy-2-methyl-2-butanol (60.00 mg, 155.64 μmol, 77.66% yield), a red solid. 1 H NMR (400 MHz, CDCl 3 )δppm: 9.26 (s, 1H), 7.88 (d, J = 8.4Hz, 1H), 7.59 (t, J = 8.2Hz, 1H), 7.09 (d, J = 7.2Hz, 1H), 4.88 (s, 2H), 4.68 (br, s.2H), 4.48 (t, J = 7.4 Hz,2H), 3.65-3.59(m,2H), 2.19(t,J=7.6Hz,2H), 2.06-2.02(m,1H), 1.34(s,6H), 1.28-1.24(m,3H), 0.66(d,J=6.0Hz,6H); ES-LCMS m / z:386.4[M+H] + .

[0283] Step 4: Synthesis of 4-[2-(ethoxymethyl)-1-isobutyl-5-oxido-imidazo[4,5-c]quinolin-5-yl-9-yl]oxy-2-methyl-2-butanol

[0284] m-CPBA (47.40 mg, 233.46 μmol, 85% purity, 1.5 eq.) was added to a solution of 4-[2-(ethoxymethyl)-1-isobutyl-imidazo[4,5-c]quinolin-9-yl]oxy-2-methyl-2-butanol (60.00 mg, 155.64 μmol, 1.0 eq.) in DCM (10.00 mL). The resulting mixture was stirred at 25 °C for 0.5 h. The solvent was removed under vacuum. The residue was purified by preparative TLC (DCM / MeOH=10 / 1). The desired product: 4-[2-(ethoxymethyl)-1-isobutyl-5-oxido-imidazo[4,5-c]quinolin-5-yl-9-yl]oxy-2-methyl-2-butanol (50.00 mg, 124.53 μmol, yield 80.01%) was obtained as a yellow solid. 1 H NMR (400 MHz, CDCl 3 )δppm: 9.07 (s, 1H), 8.68 (d, J = 8.0Hz, 1H), 7.68 (t, J = 8.4Hz, 1H), 7.22 (d, J = 8.0Hz, 1H), 4.84 (s, 2H), 4.61 (br, s.2H), 4.51 (t, J = 7.8 Hz,2H), 3.65-3.59(m,2H), 2.19(t,J=7.6Hz,2H), 1.99-1.94(m,1H), 1.35(s,6H), 1.29-1.27(m,3H), 0.67(d,J=6.0Hz,6H); ES-LCMS m / z:402.4[M+H] + .

[0285] Step 5: Synthesis of 4-[4-amino-2-(ethoxymethyl)-1-isobutyl-imidazo[4,5-c]quinolin-9-yl]oxy-2-methyl-2-butanol

[0286] TsCl (28.49 mg, 149.44 μmol, 1.2 eq.) was added to 4-[2-(ethoxymethyl)-1-isobutyl-5-oxido-imidazo[4,5-c]quinolin-5-yl-9-yl]oxy-2-methyl-2-butanol (50.00 mg, 124.53 μmol, 1.0 eq.) and NH 3 ·H 2 O (155.89 mg, 1.25 mmol, 171.31 μL, 28% purity, 10.0 equiv) in CHCl 3 (5.00 mL) solution. The resulting mixture was stirred at 25°C for 0.5 h. The solvent was removed under vacuum. The product was purified by preparative HPLC (MeCN / H 2O as eluent, acidic conditions) and the residue was purified. After freeze-drying, the desired product was obtained: 4-[4-amino-2-(ethoxymethyl)-1-isobutyl-imidazo[4,5-c]quinolin-9-yl]oxy-2-methyl-2-butanol (26.50 mg, 60.38 μmol, 48.48% yield, purity 99.56%, hydrochloride) as a white solid. 1 H NMR (400MHz, CD 3 OD)δppm:7.69(t,J=8.2Hz,1H), 7.34(t,J=8.0Hz,1H), 7.22(d,J=8.4Hz,1H), 4.87(s,2H), 4.71(br,s.2H), 4.53(t,J=7.6Hz,1H) , 3.69-3.63(m,2H), 2.18(t,J=7.6Hz,2H), 2.02-1.97(m,1H), 1.29(s,6H), 1.26(t,J=7.0Hz,3H), 0.74(d,J=4.2Hz,6H); ES-LCMS m / z:401.4[M+H] + .

[0287] Example 8

[0288] Preparation of intermediates

[0289] Intermediate 1: 4-Chloro-5-methoxy-3-nitro-quinoline

[0290] Solution 8

[0291]

[0292] Step 1: Synthesis of 2-methoxy-6-[[(E)-2-nitrovinyl]amino]benzoic acid

[0293] At 0℃, CH 3 NO 2 (23.73 g, 388.84 mmol, 21.00 mL, 1.3 eq) was added to a solution of NaOH (40.20 g, 1.01 mol, 3.4 eq) in water (100 mL). The mixture was heated to 40 °C and an additional amount of CH 3 NO 2(23.73 g, 388.84 mmol, 21.00 mL, 1.3 eq.). The temperature was maintained at 40 °C until all solids dissolved and a clear red solution was obtained. The solution was cooled to 30 °C by pouring 300 g of crushed ice and acidified with concentrated HCl (100 mL). The mixture was immediately added to a solution of 2-amino-6-methoxy-benzoic acid (50.00 g, 299.11 mmol, 1.0 eq.) and concentrated HCl (35 mL) in water (1400 mL). The solution was stirred at 20 °C for 16 h. The mixture was filtered. The lumps were washed with water (300 mL x 3) and dried under vacuum. The desired product was obtained: 2-methoxy-6-[[(E)-2-nitrovinyl]amino]benzoic acid) (67.00 g, 281.28 mmol, 94.04% yield), as a yellow solid. 1 HNMR (400MHz, CD 3 OD)δppm:7.70(d,J=6.0Hz,1H), 7.51(t,J=8.4Hz,1H), 7.11(d,J=8.4Hz,1H), 6.93(d, J=8.4Hz,1H), 6.68(d,J=6.0Hz,1H), 3.89(d,J=4.4Hz,3H); ES-LCMSm / z:261.1[M+Na] + .

[0294] Step 2: Synthesis of 5-methoxy-3-nitro-quinolin-4-ol

[0295] At 105°C, 2-methoxy-6-[[(E)-2-nitrovinyl]amino]benzoic acid (56.00 g, 235.10 mmol, 1.0 equivalent) was heated in Ac 2 O (300.00mL) solution for 0.5h, and obtain a clear solution. To the solution was added AcOK (27.69g, 282.12mmol, 1.2 eq). The resulting mixture was stirred at 105°C for 2h. The mixture was filtered. The block was washed with acetic acid (30mL x 2) and water (100mL x 3). The block was dried on an oil pump. The desired product was obtained: 5-methoxy-3-nitro-quinoline-4-ol (19.00g, 86.29mmol, 36.70% yield), off-white solid. 1 H NMR (400 MHz, DMSO-d 6)δppm: 12.59(s,1H), 8.96(s,1H), 7.62(t,J=8.2Hz,1H), 7.16(d,J=8.0Hz,1H), 6.95(d,J=8.0Hz,1H), 3.83(s,3H); ES-LCMS m / z: 221.2[M+H] + .

[0296] Step 3: Synthesis of 4-chloro-5-methoxy-3-nitro-quinoline

[0297] DMF (66.39 mg, 908.35 μmol, 69.89 μL, 0.1 eq.) was added to a solution of 5-methoxy-3-nitro-quinolin-4-ol (2.00 g, 9.08 mmol, 1.0 eq.) in SOCl 2 (8.20 g, 68.92 mmol, 5.00 mL, 7.6 equiv) suspension. The resulting mixture was stirred at 80 °C for 4 h. The solvent was removed under vacuum. The desired product was obtained: 4-chloro-5-methoxy-3-nitro-quinoline (2.10 g, 8.80 mmol, yield 96.92%) as a brown solid. 1 H NMR (400 MHz, CDCl 3 )δppm:9.12(s,1H),8.08(t,J=8.8Hz,1H),7.96-7.92(m,1H),7.20(d,J=8.4Hz,1H),4.08(s,3H); ES-LCMS m / z:239.2[M+H] + .

[0298] Intermediate 2: 4-Amino-3-nitro-quinolin-5-ol

[0299] Solution 9

[0300]

[0301] Step 1: Synthesis of 5-methoxy-3-nitro-quinolin-4-amine

[0302] At 0°C, a solution of 4-chloro-5-methoxy-3-nitro-quinoline (5.28 g, 22.13 mmol, 1.0 equiv) in THF (50 mL) was added dropwise to NH 3 ·H 2O (91.00g, 726.96mmol, 100.00mL, purity 28%, 32.9 equivalents) in THF (100mL). The mixture was stirred at 25°C for 2h. The reaction mixture was filtered. The residue was washed with water (50mL x 3) and dried under vacuum. The desired product was obtained: 5-methoxy-3-nitro-quinoline-4-amine (4.83g, 22.03mmol, yield 99.55%), yellow solid. 1 H NMR (400MHz, CD 3 OD) δppm: 9.17 (s, 1H), 7.75 (t, J = 8.4Hz, 1H), 7.46 (d, J = 8.4Hz, 1H), 7.15 (d, J = 8.0Hz, 1H), 4.13 (s, 3H); ES-LCMS m / z: 220.2 [M+H] + .

[0303] Step 2: Synthesis of 4-amino-3-nitro-quinolin-5-ol

[0304] At -78℃, BBr 3 (22.86g, 91.20mmol, 8.79mL, 10.0 equivalents) was added dropwise to a DCM (100.00mL) solution of 5-methoxy-3-nitro-quinoline-4-amine (2.00g, 9.12mmol, 1.0 equivalents). The reaction mixture was stirred for 16h at 60°C. The reaction mixture was added to MeOH (200mL) at -30°C and then concentrated under reduced pressure to provide a residue. The residue was suspended in DCM and filtered. The block was dried under vacuum. The desired product was obtained: 4-amino-3-nitro-quinoline-5-ol (2.53g, crude product), a green solid. 1 H NMR (400MHz, CD 3 OD) δppm: 9.41 (s, 1H), 7.83 (t, J = 8.4Hz, 1H), 7.33 (d, J = 8.4Hz, 1H), 7.13 (d, J = 8.4Hz, 1H); ES-LCMS m / z: 206.2 [M+H] + .

[0305] Intermediate 3: N 4 -Isobutyl-5-methoxy-quinoline-3,4-diamine

[0306] Solution 10

[0307]

[0308] Step 1: Synthesis of N-isobutyl-5-methoxy-3-nitro-quinolin-4-amine

[0309] 4-Chloro-5-methoxy-3-nitro-quinoline (1.00 g, 4.19 mmol, 1.0 equiv) was added to 2-methylpropane-1-amine (612.91 mg, 8.38 mmol, 828.26 μL, 2.0 equiv) and Et 3 N (2.12 g, 20.95 mmol, 2.90 mL, 5.0 equiv) in DCM (50.00 mL). The resulting mixture was stirred at 25 °C for 0.5 h. The reaction mixture was washed with water (30 mL) and brine (30 mL) by extraction. The organic phase was concentrated into anhydrous Na 2 SO 4 The mixture was dried on 4% paraformaldehyde, filtered, and concentrated under vacuum. The residue was purified by column chromatography (PE: PE / EtOAc=1 / 1) to obtain the desired product: N-isobutyl-5-methoxy-3-nitro-quinolin-4-amine (1.00 g, 3.63 mmol, yield 86.69%) as a yellow solid. 1 H NMR (400 MHz, CD 3 OD) δppm: 8.85 (s, 1H), 7.70 (t, J = 8.2Hz, 1H), 7.47 (d, J = 7.6Hz, 1H), 7.16 (d, J = 8.0Hz, 1H ), 4.14(s,3H), 2.85(d,J=6.4Hz,2H), 2.04-1.94(m,1H), 1.00(d,J=6.8Hz,6H); ES-LCMS m / z:276.2[M+H] + .

[0310] Step 2: Synthesize N 4 -Isobutyl-5-methoxy-quinoline-3,4-diamine

[0311] In N 2 Under the conditions, Raney-Ni (100.00 mg, 1.17 mmol, 1.1 equiv) was added to a solution of N-isobutyl-5-methoxy-3-nitro-quinolin-4-amine (300.00 mg, 1.09 mmol, 1.0 equiv) in MeOH (50.00 mL). The resulting suspension was degassed under vacuum and heated to 40 °C with H 2 Purify several times. 2 The mixture was stirred at 25°C for 1 h under the condition of (15 psi). The reaction mixture was filtered. The filtrate was concentrated under vacuum to obtain the desired product: N 4-isobutyl-5-methoxy-quinoline-3,4-diamine (250.00 mg, 1.02 mmol, yield 93.49%), yellow solid. 1 H NMR (400MHz, CD 3 OD) δppm: 8.28 (s, 1H), 7.42-7.40 (m, 1H), 7.33 (t, J = 8.2Hz, 1H), 6.91 (d, J = 7.6Hz, 1H) , 4.03(s,3H), 3.08(d,J=6.8Hz,2H), 1.90-1.80(m,1H), 1.02(d,J=6.8Hz,6H); ES-LCMS m / z:246.3[M+H] + .

[0312] Intermediate 4: 4-[(3,4-Diamino-5-quinolyl)oxy]-2-methyl-2-butanol

[0313] Solution 11

[0314]

[0315] Step 1: Synthesis of 4-[(4-amino-3-nitro-5-quinolyl)oxy]-2-methyl-2-butanol

[0316] A solution of (3-hydroxy-3-methyl-butyl) 4-methylbenzenesulfonate (5.67 g, 21.93 mmol, 3.0 equiv) in DCM (15.00 mL) was added to a solution of 4-amino-3-nitro-quinolin-5-ol (1.50 g, 7.31 mmol, 1.0 equiv), TBAB (2.36 g, 7.31 mmol, 1.0 equiv) and KI (405.04 mg, 2.44 mmol, 1.0 equiv) in NaOH (2M, 3.66 mL, 3.0 equiv). The resulting mixture was stirred at 25 °C for 64 h. The reaction mixture was diluted with water (10 mL) and extracted with DCM (50 mL x 2). The combined organic layers were washed with brine (10 mL) and washed with anhydrous Na 2 SO 4 The product was dried over 40 °C, filtered and concentrated under reduced pressure to provide a residue. 2 , DCM / MeOH=100 / 1 to 20 / 1) to obtain the desired product: 4-[(4-amino-3-nitro-5-quinolyl)oxy]-2-methyl-2-butanol (646.00 mg, 2.22 mmol, 30.34% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl 3)δppm:9.59(br s,1H), 9.29(s,1H), 9.22(br s,1H), 7.63(t,J=8.2Hz,1H), 7.54(dd,J=8.4,0.8Hz,1H), 6.92(d,J=7.6Hz,1H), 4.38(t,J=6.2Hz,2H), 2.14(t,J=6.2Hz,2H), 1.41(s,6H); ES-LCMS m / z:292.3[M+H] + .

[0317] Step 2: Synthesis of 4-[(3,4-diamino-5-quinolyl)oxy]-2-methyl-2-butanol

[0318] In N 2 Under the conditions, Raney-Ni (200.00 mg, 2.33 mmol, 1.1 eq.) was added to a solution of 4-[(4-amino-3-nitro-5-quinolyl)oxy]-2-methyl-2-butanol) (640.00 mg, 2.20 mmol, 1.0 eq.) in MeOH (150.00 mL). The suspension was degassed under vacuum and heated to 40 ℃ for 2 h. 2 Purify several times. 2 (15psi) at 25 ° C. The mixture was stirred for 1 h. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to provide a residue. The product was used directly in the next step without further purification. The desired product was obtained: 4-[(3,4-diamino-5-quinolyl)oxy]-2-methyl-2-butanol (570.00 mg, 2.18 mmol, yield 99.15%), a dark brown solid. 1 H NMR (400 MHz, CDCl 3 )δppm: 8.24 (s, 1H), 7.47 (d, J = 8.4Hz, 1H), 7.30 (t, J = 8.0Hz, 1H), 6.68 (d, J = 7.6Hz, 1H), 5.89 (br s, 2H), 4.28 (t, J = 6.4Hz, 2H), 2.11 (t, J = 6.4Hz, 2H), 1.36 (s, 6H); ES-LCMS m / z: 262.2 [M+H].

[0319] Intermediate 5: 5-Methoxy-N-methyl-3-nitro-quinolin-4-amine

[0320] Solution 12

[0321]

[0322] A solution of 4-chloro-5-methoxy-3-nitro-quinoline (1.00 g, 4.19 mmol, 1.0 equiv) in DCM (30.00 mL) was added to MeNH 2 (2M in THF, 40.00 mL, 19.1 eq.). The mixture was stirred at 25 °C for 2 h. The mixture was concentrated to provide a residue. Column chromatography ((SiO 2 The residue was purified by HPLC-MS / MS (50 / 1 to 20 / 1) to obtain the desired product: 5-methoxy-N-methyl-3-nitro-quinolin-4-amine (400.00 mg, 1.72 mmol, 40.93% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 )δppm:9.03(s,1H),8.79(s,1H),7.62-7.60(m,2H),6.94-6.92(m,1H),4.09(s,3H),2.94(d,J=5.6Hz,3H); ES-LCMS m / z:234.0[M+H] + .

[0323] Intermediate 6 :2-Ethoxyacetyl chloride

[0324]

[0325] Oxalyl chloride (1.83 g, 14.41 mmol, 1.26 mL, 1.5 equiv) was added to a solution of 2-ethoxyacetic acid (1.00 g, 9.61 mmol, 909.09 μL, 1.0 equiv) and a catalytic amount of DMF (10.00 mg, 136.82 μmol, 10.53 μL, 0.01 equiv) in DCM (30.00 mL) at 0°C. The resulting mixture was stirred for 2 h at 25°C. The reaction mixture was concentrated under reduced pressure to remove the solvent. 2-Ethoxyacetyl chloride (900.00 mg, 7.34 mmol, 76.42% yield) was obtained as a yellow oil.

[0326] Intermediate 7: 3-Methoxypropionyl chloride

[0327]

[0328] 3-Methoxypropanoyl chloride (yellow oil, 84.9% yield) was prepared by the same method as that for Intermediate 6 using the corresponding starting material 3-methoxypropionic acid.

[0329] Intermediate 8: (3-Hydroxy-3-methyl-butyl) 4-methylbenzenesulfonate

[0330]

[0331] At 0°C, a solution of TsCl (17.39 g, 91.22 mmol, 0.95 eq) in DCM (100 mL) was added dropwise to 3-methylbutane-1,3-diol (10.00 g, 96.02 mmol, 10.20 mL, 1.0 eq), Et 3 N (14.57 g, 144.03 mmol, 19.96 mL, 1.5 eq) and DMAP (14.08 g, 115.22 mmol, 1.2 eq) in DCM (200.00 mL). The resulting mixture was stirred at 0 °C for 1 h. The pH of the mixture was adjusted to 6 using citric acid. The organic layer was separated and washed with brine (100 mL) and then heated to 40 °C in anhydrous Na 2 SO 4 The mixture was dried over high temperature, filtered, and concentrated under vacuum to obtain (3-hydroxy-3-methyl-butyl) 4-methylbenzenesulfonate (19.80 g, 76.65 mmol, 79.83% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 )δppm:7.80-7.78(m,2H), 7.34(d,J=8.0Hz,2H), 4.22-4.19(m,2H), 2.45(s,3H), 1.87-1.84(m,2H), 1.21(d,J=1.2Hz,6H); ES-LCMS m / z:276.2[M+H 2 O] + .

[0332] Intermediate 9: Isoamyl-4-methylbenzenesulfonate

[0333]

[0334] Isoamyl-4-methylbenzenesulfonate was prepared using a method similar to that for intermediate 8 using the corresponding starting material, 3-methyl n-butanol, and purified by silica gel chromatography (PE / EA=20 / 1 to 10 / 1) to obtain isopentyl-4-methylbenzenesulfonate (isolated yield 72.76%, yellow oil). 1 H NMR (400 MHz, CDCl 3)δppm:7.81-7.79(m,2H), 7.35(d,J=8.0Hz,2H), 4.06(t,J=6.6Hz,2H), 2.4 6(s,3H), 1.70-1.67(m,1H), 1.57-1.51(m,2H), 0.88-0.84(m,6H); ES-LCMS m / z:264.9[M+Na] + .

[0335] Intermediate 10 :2-isopropoxyethyl 4-methylbenzenesulfonate

[0336]

[0337] 2-Isopropoxyethyl 4-methylbenzenesulfonate was prepared in a similar manner to that of Intermediate 8 using the corresponding starting material 2-isopropoxyethanol in a yield of 81.44% as a colorless oil. 1 H NMR (400 MHz, CDCl 3 )δppm:7.80(d,J=8.0Hz,2H), 7.33(d,J=8.4Hz,2H), 4.14-4.11(m,2H), 3.60 -3.58(m,2H), 3.55-3.54(m,1H), 2.44(s,3H), 1.08(d,J=6.0Hz,6H); ES-LCMS m / z:259.3[M+H] + .

[0338] Intermediate 11 :3-Hydroxybutyl 4-methylbenzenesulfonate

[0339]

[0340] 3-Hydroxybutyl 4-methylbenzenesulfonate was prepared in a similar manner to that of Intermediate 8 using the corresponding starting material butane-1,3-diol in a yield of 59.04% as a colorless oil. 1 H NMR (400 MHz, CDCl 3 )δppm:7.83-7.79(m,2H),7.37-7.34(m,2H),4.26-4.22(m,1H),4.15-4.12(m,1H),3.9 8-3.93(m,1H),2.46(s,3H),1.85-1.81(m,1H),1.74-1.68(m,1H),1.20(m,3H); ES-LCMS m / z:245.2[M+H] + .

[0341] Intermediate 12:Acetylmethyl 4-methylbenzenesulfonate

[0342]

[0343] Acetylmethyl 4-methylbenzenesulfonate was prepared in a similar manner to that of Intermediate 8 using the corresponding starting material 1-hydroxy-2-propanone in a yield of 25.31% as a colorless oil. 1 H NMR (400 MHz, CDCl 3 )δppm:7.82(d,J=8.4Hz,2H),7.37(d,J=8.4Hz,2H),4.48(s,2H),2.46(s,3H),2.22(s,3H); ES-LCMS m / z:229.2[M+H] + .

[0344] Other 2-amino-quinoline derivatives were prepared using methods similar to those described in Examples 1-7 and are listed in Table 1. These compounds were prepared in the form of hydrochloride salts and / or neutral amines. It will be clearly understood and appreciated by those skilled in the art that other analogs may be prepared using methods identical or similar to those described in Examples 1-7. These examples are not intended to limit in any way the analogs prepared using methods identical or similar to those described herein.

[0345]

[0346]

[0347]

[0348] Some of the prepared compounds were tested for compound functionality by stimulating and measuring cytokine production in PBMCs.

[0349] Human PBMCs were prepared from buffy coats from healthy voluntary donors by Ficoll centrifugation and the final cell concentration was adjusted to 1×10 6 cells / mL.

[0350] For evaluating compound activity, 1x10 5PBMCs were seeded in 96-well plates in 100 μl of RPMI1640 complete medium (Lot No. 31800-022, manufactured by Life Technologies, GIBCO, Grand Island, New York, USA) supplemented with 10% fetal bovine serum. The tested compounds were first dissolved in DMSO and further diluted in PBS and RPMI 1640 medium to a final concentration of 20 μM (corresponding to 6.28 μg / mL), followed by three-fold serial dilutions in 96-well round-bottom plates. 100 μl of the diluted compounds were added to the same volume of 1×10 5 PBMC plates were cultured and incubated at 37°C with an atmospheric humidity of 5% CO 2 The cells were cultured for 20-22 hours under the conditions of 4% paraformaldehyde and 1% paraformaldehyde. The supernatants were collected and analyzed for human IFN-α, IL 12 (p70) and IL-6 by ELISA according to the manufacturer's instructions (Mabtech AB, Sweden). Resiquimod was used as a positive control.

[0351] Table 2 below lists the test results for the evaluation of cytokine production for most of the compounds prepared.

[0352] Table 2*

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359] *Note 1: All compounds were tested at a concentration of 10 μM.

[0360] * Note 2: “+” means IFNa or IL-6 production on PBMCs, while “-” means no IFNa or IL-6 production on PBMCs was detected.

Claims

1. A compound represented by the following formula or a salt thereof:

2. A compound represented by the following formula or a salt thereof:

3. Use of the compound according to claim 1 or 2 in the manufacture of a medicament for treating HCV infection.

4. A dosage form suitable for administration to a mammal, comprising the compound of claim 1 or 2.

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