Quinoline compounds and their preparation and use as antimalarial agents

Abstract

Disclosed are compounds of Formula (I): # imgabs0 # wherein R1, R2, R3, A and B are as defined herein, as well as methods of making such compounds. Also disclosed are pharmaceutical compositions comprising the compounds of Formula (I), methods of blocking the transmission of Plasmodium parasites, and methods of treating or preventing malaria by killing or blocking the growth of a Plasmodium organism in a mammal, where the Plasmodium organism is in the hepatic phase, asexual phase or is a gametoblastic cell, the methods comprise administering to the animal an effective amount of a compound of formula (I).

Description

[0001] This application is a divisional application of Chinese patent application No. 201980042521.4, filed on May 13, 2019, entitled “Quinoline compounds, their preparation and use as antimalarial agents”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This patent application claims the benefit of U.S. Provisional Patent Application No. 62 / 670,351, filed May 11, 2018, the disclosure of which is incorporated herein by reference in its entirety for all purposes. Background Art

[0004] Thanks to the combined effects of long-lasting insecticidal bed nets, indoor residual spraying, and artemisinin-based combination therapy (ACT), malaria cases and deaths have fallen by 50% in 29 countries since 2000 [Kilama W. et al., Lancet, 2009, 374:1480-1482]. This success has raised hopes for malaria eradication and has stimulated interest in developing new agents that block gametocyte transmission, such as new and safe gametocytocidal drugs [Buchholz K. et al., The Journal of Infectious Diseases, 2011, 203:1445-1453]. Previous drug development efforts have focused on asexual parasites that cause symptoms but do not transmit malaria. In order to be transmitted from person to person by mosquitoes, the parasite must switch from asexual development to sexual development and produce male and female gametocytes. Once the gametocyte is taken up by the mosquito into a blood meal, fertilization is initiated and the resulting zygote differentiates into a motile kinetochore that migrates across the mosquito's midgut epithelium and forms a cyst. Over the next two weeks, tens of thousands of infectious sporozoites are produced and sequestered in the mosquito's salivary glands until released into a vertebrate host for transmission during the next blood meal.

[0005] Sexual-stage P. falciparum gametocytes have a lifespan exceeding three weeks and are not effectively eliminated by current antimalarial agents, with the exception of primaquine (PQ) [Sweeney AW et al., American Journal of Tropical Medicine and Hygiene, 2004, 71:187-189; Peatey CL et al., Journal of Infectious Diseases, 2009, 200:1518-1521]. Primaquine (PQ) is not widely used because it can cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency [Baird JK et al., Trends in Parasitology, 2011, 27:11-16]. Consequently, treatment with current antimalarial drugs often results in asymptomatic carriers who remain infectious for weeks after clearance of asexual parasites. Despite the risks associated with PQ, its efficacy has recently been demonstrated in field trials alongside artemisinin combination therapy (ACT) to reduce malaria transmission in PQ-tolerant patients. Besides PQ, the only other gametocytic candidate drug tested was methylene blue.

[0006] Therefore, a new generation of antimalarial agents with potent activity against both sexual and asexual parasites is urgently needed to achieve better therapeutic efficacy and eliminate malaria infection worldwide. Summary of the Invention

[0007] The present invention provides a compound of formula (I):

[0008]

[0009] Where A is CR 5 or N,

[0010] B is CR 8 =CR 9 or NR 2 ,

[0011] R 8 and R 9 Independently selected from hydrogen, hydroxy, OR 10 , halogen, optionally substituted C 6-10 Aryl and optionally substituted C 1-6 alkyl,

[0012] R 10 It is hydrogen, C 1-12 Alkyl, C 3-8 Cycloalkyl, CH2COOR 13 or H2N(CH2) n -, wherein n is an integer from 2 to 6,

[0013] R 1 is a C1-C6 alkyl radical optionally substituted by at least one substituent selected from -CN, halogen, -CF3, -CONH2, -OCF3, C1-C6 alkyl, C1-C6 alkylcarbonyl, -OH, C1-C6 alkylaminocarbonyl, C3-C8 cycloalkylaminocarbonyl, C1-C6 alkylaminoalkyl, cyanomethyl, piperazinylmethyl, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonylamino, dialkylaminoalkylamino, optionally substituted piperazinylcarbonyl and C1-C6 alkoxy. 6-10 aryl or heteroaryl, a heterocyclyl selected from piperazin-1-yl, 4-(C1-C6 alkylcarbonyl)piperazin-1-yl, morpholinyl optionally substituted by C1-C6 alkyl, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, octahydropyrrolo[3,4-b]pyrrolyl and 2-oxa-6-azaspiro[3.3]heptyl, each of which is a C3-C8 cycloalkyl or C3-C8 azacycloalkyl optionally substituted by morpholino, optionally substituted piperidinyl or optionally substituted piperazinyl,

[0014] R 2 is C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkylsulfonyl or optionally substituted benzyl,

[0015] R 3 is H, -CN, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, phenylsulfonyl, 4-methylphenylsulfonyl, C1-C6 alkylsulfonyl, aminocarbonyl, aminosulfonyl, optionally substituted benzyl, -OH, -OR, -SR, -(S=O)R (R=C1-C6 alkyl), guanidinyl or pyrimidin-5-yl,

[0016] R 4 is phenyl, heteroaryl, 1-phenyl-2-ethynyl or heterocyclyl, wherein the phenyl group of phenyl, heteroaryl, heterocyclyl or 1-phenyl-2-ethynyl is selected from halogen, C1-C6 alkyl, amino, oxo, dialkylaminoalkyl, dialkylaminoalkoxy, -CN, aminocarbonyl, -OR 6 , CF3 and one or more substituents of C1-C6 alkylsulfonyl are optionally substituted,

[0017] R 6 is H or C1-C6 alkyl,

[0018] R 5 is hydrogen, C1-C6 alkyl, C6-C 10 Aryl, halogen, hydroxyl or OR 7 ,

[0019] R 7is C1-C6 alkyl, formyl, C1-C6 acyl or C6-C 10 Aryl,

[0020] or a pharmaceutically acceptable salt thereof.

[0021] The present invention also provides a pharmaceutical composition comprising a compound or salt of formula (I) and a pharmaceutically acceptable carrier.

[0022] The present invention further provides a method of blocking the transmission of Plasmodium parasites comprising administering to a mammal in need of such treatment a therapeutically effective amount of a first compound of formula (I).

[0023] The present invention also provides a method for treating malaria by killing or arresting the growth of Plasmodium organisms in a mammal, wherein the Plasmodium organisms are in the liver stage or the asexual stage, the method comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or formula (II).

[0024] Advantageously, compounds and methods according to embodiments of the present invention kill all stages of the malaria parasite. Specific implementation plan

[0025] In one embodiment, the present invention provides a compound of formula (I):

[0026]

[0027] Where A is CR 5 or N,

[0028] B is CR 8 =CR 9 or NR 2 ,

[0029] R 8 and R 9 Independently selected from hydrogen, hydroxy, OR 10 , halogen, optionally substituted C 6-10 Aryl and optionally substituted C 1-6 alkyl,

[0030] R 10 It is hydrogen, C 1-12 Alkyl, C 3-8 Cycloalkyl, CH2COOR 13 or H2N(CH2) n -, wherein n is an integer from 2 to 6,

[0031] R 1is a C1-C6 alkyl radical optionally substituted by at least one substituent selected from -CN, halogen, -CF3, -CONH2, -OCF3, C1-C6 alkyl, C1-C6 alkylcarbonyl, -OH, C1-C6 alkylaminocarbonyl, C3-C8 cycloalkylaminocarbonyl, C1-C6 alkylaminoalkyl, cyanomethyl, piperazinylmethyl, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonylamino, dialkylaminoalkylamino, optionally substituted piperazinylcarbonyl and C1-C6 alkoxy. 6-10 aryl or heteroaryl, a heterocyclyl selected from piperazin-1-yl, 4-(C1-C6 alkylcarbonyl)piperazin-1-yl, morpholinyl optionally substituted by C1-C6 alkyl, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, octahydropyrrolo[3,4-b]pyrrolyl and 2-oxa-6-azaspiro[3.3]heptyl, each of which is a C3-C8 cycloalkyl or C3-C8 azacycloalkyl optionally substituted by morpholino, optionally substituted piperidinyl or optionally substituted piperazinyl,

[0032] R 2 is C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkylsulfonyl or optionally substituted benzyl,

[0033] R 3 is H, -CN, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, phenylsulfonyl, 4-methylphenylsulfonyl, C1-C6 alkylsulfonyl, aminocarbonyl, aminosulfonyl, optionally substituted benzyl, -OH, -OR, -SR, -(S=O)R (R=C1-C6 alkyl), guanidinyl or pyrimidin-5-yl,

[0034] R 4 is phenyl, heteroaryl, 1-phenyl-2-ethynyl or heterocyclyl, wherein the phenyl group of phenyl, heteroaryl, heterocyclyl or 1-phenyl-2-ethynyl is selected from halogen, C1-C6 alkyl, amino, oxo, dialkylaminoalkyl, dialkylaminoalkoxy, -CN, aminocarbonyl, -OR 6 , CF3 and one or more substituents of C1-C6 alkylsulfonyl are optionally substituted,

[0035] R 6 is H or C1-C6 alkyl,

[0036] R 5 is hydrogen, C1-C6 alkyl, C6-C 10 Aryl, halogen, hydroxyl or OR 7 ,

[0037] R 7 is C1-C6 alkyl, formyl, C1-C6 acyl or C6-C 10 Aryl,

[0038] or a pharmaceutically acceptable salt thereof.

[0039] Referring now to the terminology generally used herein, the term "alkyl" means a straight or branched chain alkyl substituent containing, for example, 1 to about 12 carbon atoms, preferably 1 to about 6 carbon atoms, and more preferably 1 to about 4 carbon atoms. Examples of such substituents include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, and the like.

[0040] The term "aryl" refers to an unsubstituted or substituted aromatic carbocyclic substituent as generally understood in the art. 10 "Aryl" includes phenyl and naphthyl. It will be understood that the term "aryl" applies to cyclic substituents that are planar and contain 4n + 2π electrons according to Hückel's rule. Aryl is optionally substituted with 1, 2, 3, 4 or 5 substituents as described herein, for example, alkyl such as methyl, ethyl, etc., halogen, dihaloalkyl, trihaloalkyl, nitro, hydroxy, alkoxy, aryloxy, amino, alkylamino, dialkylamino, acylamino, acylalkylamino, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, cyanomethyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, thio, alkylthio, arylthio and the like, wherein the optional substituents may be present at any open position on the aryl.

[0041] The term "heteroaryl" refers to a monocyclic or bicyclic 5-10 membered ring system as described herein, wherein the heteroaryl is unsaturated and satisfies Hückel's rule, and wherein the heteroaryl contains 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. Non-limiting examples of suitable heteroaryl groups include furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazole, 3-methyl-1,2,4-oxadiazole, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, indolyl, indazolyl, imidazolyl, quinolyl, isoquinolyl, benzimidazolyl, benzoxazolinyl, benzothiazolinyl and quinazolinyl. The term "pyridinyl" is synonymous with the term "pyridyl", and both terms refer to an optionally substituted pyridine group. The heteroaryl group may be attached at any open position on the heteroaryl group. The term "heterocycle" or "heterocyclyl" refers to a 4- to 12-membered heterocyclic ring system as described herein, wherein the heterocycle contains 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein the heterocycle is saturated or monounsaturated. The heterocyclyl or heteroaryl group is optionally substituted with 1, 2, 3, 4, or 5 substituents as described herein, for example, with alkyl groups such as methyl, ethyl, hydroxyalkyl groups such as hydroxyethyl, or with aryl groups such as phenyl, naphthyl, and the like, wherein the aryl group can be further substituted with, for example, halogen, dihaloalkyl, trihaloalkyl, nitro, hydroxy, alkoxy, aryloxy, amino, alkylamino, dialkylamino, acylamino, acylalkylamino, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, cyanomethyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, thio, alkylthio, arylthio, and the like, wherein the optional substituents can be present at any open position on the heterocyclyl or heteroaryl group.

[0042] The term "acyl" refers to an alkylcarbonyl (RC(=O)-) substituent. The term "aminosulfonyl" refers to a group of the structure: H2NSO2-. The term "alkylsulfonyl" refers to a group of the structure: alkyl-SO2-. The term "aminocarbonyl" refers to a group of the structure: R 1 R 2 NC(=O)- group, wherein R 1 and R 2are independently hydrogen, alkyl or aryl. The term "alkylsulfonylamino" refers to a group of the structure: alkyl-SO2-NH-. The term "guanidino" refers to a group of the structure: -C(=NH)NH2. The term "azacycloalkyl" refers to a cycloalkyl ring in which one or more ring carbon atoms are replaced by nitrogen. Non-limiting examples of suitable azacycloalkyls include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, and the like.

[0043] In certain embodiments, R 1 is a C1-C6 alkyl substituted with at least one substituent selected from -CN, halogen, -CF3, -CONH2, -OCF3, C1-C6 alkyl, C1-C6 alkylcarbonyl, -OH, C1-C6 alkylaminocarbonyl, C3-C8 cycloalkylaminocarbonyl, C1-C6 alkylaminoalkyl, cyanomethyl, piperazinylmethyl, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonylamino, dialkylaminoalkylamino, optionally substituted piperazinylcarbonyl and C1-C6 alkoxy. 6-10 aryl or heteroaryl, a heterocyclyl selected from morpholinyl, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, octahydropyrrolo[3,4-b]pyrrolyl and 2-oxa-6-azaspiro[3.3]heptyl optionally substituted by C1-C6 alkyl, a C3-C8 cycloalkyl or C3-C8 azacycloalkyl substituted by morpholino, optionally substituted piperidinyl or optionally substituted piperazinyl,

[0044] R 3 is H, -CN, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, phenylsulfonyl, 4-methylphenylsulfonyl, C1-C6 alkylsulfonyl, aminocarbonyl, aminosulfonyl, optionally substituted benzyl, -OH, -OR, -SR, -(S=O)R (R=C1-C6 alkyl) or guanidino, and

[0045] R 4 is phenyl, heteroaryl, 1-phenyl-2-ethynyl or heterocyclyl, wherein phenyl, heteroaryl or heterocyclyl is selected from halogen, C1-C6 alkyl, amino, oxo, dialkylaminoalkyl, dialkylaminoalkoxy, -CN, aminocarbonyl and -OR 6 is optionally substituted with one or more substituents.

[0046] In certain embodiments, B is NR 2 And R 1 Selected from

[0047]

[0048]

[0049]

[0050] In certain embodiments, A is CH, R 2 is a methyl group, and R 3 It’s H.

[0051] In certain embodiments, R 2 is methyl, R 3 is H, and R 4 It is 4-chlorophenyl.

[0052] In certain of these embodiments, R 2 is methyl, R 3 It's H, R 1 yes And R 4 yes

[0053] In certain embodiments, R 2 is methyl, R 3 It's H, R 1 yes And R 4 is 4-fluorophenyl, 3-dimethylaminomethylphenyl, 3-cyanophenyl, 3-cyano-4-chlorophenyl, 3-methoxy-4-chlorophenyl, 3-chlorophenyl, 3-fluorophenyl, phenyl, 3-methylphenyl, 3-hydroxyphenyl, 3-aminophenyl, 3-hydroxy-4-fluorophenyl, 3,4-dimethoxyphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 2-methylphenyl, 2-chlorophenyl or 2-hydroxyphenyl.

[0054] In certain embodiments, R 2 is methyl, R 3 It's H, R 4 is 4-chlorophenyl, and R 1 yes

[0055]

[0056] In certain embodiments, R 2 is methyl, R 1 yes R 4 is 4-chlorophenyl, and R 3 is –CN, ethylcarbonyl, 4-methylphenylsulfonyl, methyl, n-butyl, methylsulfonyl, guanidine, methoxycarbonyl, tert-butoxycarbonyl, n-butoxycarbonyl, or aminosulfonyl.

[0057] In certain specific embodiments, R 1 yes And R2 is methyl, R 4 is 4-fluorophenyl, and R 3 Yes – CN; R 2 is methyl, R 4 is 4-fluorophenyl and R 3 is or guanidine; R 2 is methyl, R 3 is aminosulfonyl, and R 4 is 4-chlorophenyl; R 2 is ethyl, R 3 is H, and R 4 is 4-chlorophenyl; R 2 is benzyl or 2-hydroxyethyl, R 3 is H, and R 4 is 4-chlorophenyl; R 2 is 2-hydroxyethyl, R 3 is H, and R 4 is 4-chlorophenyl, R 2 is methyl, R 3 is a methoxycarbonyl group, and R 4 is 2-methylpyridin-5-yl, or R 2 is methyl, R 3 is a methoxycarbonyl group, and R 4 It is 4-chlorophenyl.

[0058] In certain specific embodiments, R 2 is methyl, R 3 is aminosulfonyl or methoxycarbonyl, R 4 is 2-amino-5-pyridyl, and R 1 yes

[0059] In a specific embodiment, R 2 is methyl, R 3 It's H, R 4 is 4-chlorophenyl, and R 1 yes

[0060] In certain specific embodiments, R 2 is methyl, R 3 It's H, R 4 is 3-fluorophenyl, and R 1 yes

[0061] In certain specific embodiments, R 2 is methoxycarbonyl, R 3 It's H, R 4 is 3-fluorophenyl or 4-methylphenyl, and R 1 yes

[0062] In certain embodiments, B is CR 8 =CR 9 , A is CH, and R 8 and R 9 All are H.

[0063] In certain embodiments, R 1 yes

[0064] In certain embodiments, R 4 It is 4-chlorophenyl or 2-amino-5-pyridyl.

[0065] In certain specific embodiments, R 3 It's H, R 4 is 4-chlorophenyl, and R 1 is 3-trifluorophenyl, 3-chlorophenyl or

[0066] In a specific embodiment, R 3 Yes-CN, R 4 is 4-chlorophenyl, and R 1 yes

[0067] In a specific embodiment, R 3 is 4-methylphenylsulfonyl, R 4 is 4-chlorophenyl, and R 1 yes

[0068] In certain specific embodiments, R 3 is propionyl or methyl, R 4 is 4-chlorophenyl, and R 1 yes

[0069] In certain embodiments, A is CH and B is NR 2 , and R 1 Selected from

[0070] In certain embodiments, R 1 yes R 2 is methyl, R 3 is H, and R 4 It is 4-chlorophenyl, 4-fluorophenyl, 2-aminopyridin-5-yl, 4-methylphenyl, 3-fluorophenyl, 3,4-dimethoxyphenyl, 3-cyano-4-chlorophenyl, 3-trifluoromethoxy-4-chlorophenyl, 2-trifluoromethylpyridin-5-yl, 2-methylpyridin-5-yl or 2-methoxypyridin-5-yl.

[0071] In certain embodiments, R 1 yes R 2 is methyl, R 3 is H, and R 4 are 4-chlorophenyl, 4-fluorophenyl, 2-aminopyridin-5-yl, 4-methylphenyl, 3-fluorophenyl, 3-methoxy-4-chlorophenyl, 3-fluoro-4-methoxyphenyl, 3-methoxy-4-fluorophenyl, 3-trifluoromethyl-4-chlorophenyl, 3-trifluoromethoxy-4-chlorophenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4-dimethoxy-5-fluorophenyl, 3,4-dimethoxy-5-chlorophenyl and 3,4,5-trimethoxyphenyl.

[0072] In certain specific embodiments, R 2 is methyl, R 3 is H, and where:

[0073] R 1 yes And R 4 It is 4-chlorophenyl,

[0074] R 1 yes And R 4 is 3-fluorophenyl,

[0075] R 1 yes And R 4 is 4-chlorophenyl or 3-fluorophenyl,

[0076] R 1 yes And R 4 is 4-chlorophenyl or 3-fluorophenyl,

[0077] R 1 yes And R 4 is 4-chlorophenyl or 3-fluorophenyl,

[0078] R 1 yes And R 4 is 4-chlorophenyl or 3-fluoro, or

[0079] R 1 yes And R 4 It is 3,4-dimethoxyphenyl.

[0080] In certain embodiments, R 1 yes R 2 is methyl, R 3 yes And R 4 is 3-fluorophenyl, or

[0081] R 1 yes R 2 It's H, R 3 is H, and R 4 It is 3,4-dimethoxyphenyl.

[0082] Chemical

[0083] The compounds of the present invention may be synthesized using any suitable route. In one embodiment, wherein A is CH and B is NR 2 The compounds of formula (I) can be synthesized by the route shown in Scheme 1.

[0084] Solution 1

[0085]

[0086] Compound 1 can be reacted with amine 2 in the presence of HCl / dioxane in DMF at an elevated temperature, such as 100°C, to provide compound 3. Compound 3 can be reacted with Fe and NHCl in EtOH and H0 at a temperature, such as 85°C, to provide compound 4. Cyanation of compound 4 can be achieved by reaction with cyanogen bromide (BrCN) in a solvent, such as EtOH, at a temperature, such as 80°C to 90°C, to provide compound 5. Alkylation of compound 5 with compound 6 can be accomplished in DMF at a temperature, such as 20°C to 25°C, to provide compound 7. Suzuki coupling of compound 7 with boronic acid / ester 8 in the presence of a base, such as NaCO, and a catalyst, such as Pd(dppf)Cl, in a solvent, such as a mixture of dioxane and H0, at a temperature, such as 100°C, provides compound 9, which can be reacted with reagent 10 to form compound 11.

[0087] In one embodiment, wherein A is CH and B is CR 8 =CR 9 Compounds of formula (I) can be synthesized via the route shown in Scheme 2.

[0088] Option 2

[0089]

[0090] Compound 12 can be reacted with amine 2 in the presence of HCl / dioxane in a solvent such as DMF at a temperature such as 100°C to provide compound 13. Suzuki coupling of compound 13 with boronic acid / ester 8 in the presence of a base such as Na2CO3 and a catalyst such as Pd(dppf)Cl2 in a mixture of dioxane and H2O at a temperature such as 100°C provides compound 14. Reduction of compound 14 with a reagent such as NaBH4 in a mixture of EtOH and THF at a temperature such as 20°C to 25°C provides compound 15. Oxidation of compound 15 with an oxidizing agent such as MnO2 in a solvent such as DCM at a temperature such as 20°C to 25°C provides compound 16. Compound 16 is olefinated with 2-diethoxyphosphorylacetonitrile and a base such as K 2 CO 3 in a solvent such as DMF at a temperature such as 100° C. to provide compound 17, which can react with reagent 10 to form compound 18.

[0091] In another embodiment, wherein A is CH and B is NR 2 Compounds of formula (I) can be synthesized via a one-pot two-step synthesis via the route shown in Scheme 3.

[0092] Option 3

[0093]

[0094] Compound 1 is reduced with Fe and NH4Cl in EtOH and H2O to give compound 19. Compound 19 is Boc protected and then cyanated to give compound 21. Compound 21 is deprotected and then alkylated to give common intermediate 23. A mixture of compound 23 and amine 2 in NMP can be heated under microwave irradiation at, for example, 180°C (R 1 = alkyl) or at 150°C (R 1 =aryl) to form compound 24. Suzuki coupling of compound 24 is carried out at a temperature such as 150° C. by adding a solvent such as DMF and a base / buffer such as 1 M K 3 PO 4, followed by the addition of boronic acid / ester 8 and a catalyst such as Pd(dppf)Cl 2 to provide compound 9.

[0095] In one embodiment, the present invention provides a method for synthesizing a compound of formula 102, comprising the steps of:

[0096] (a) providing a compound of formula 100:

[0097]

[0098] where R 101is substituted by at least one substituent selected from -CN, halogen, -CF3, -CONH2, -OCF3, C1-C6 alkyl, C1-C6 alkylcarbonyl, -OH, C1-C6 alkylaminocarbonyl, C3-C8 cycloalkylaminocarbonyl, C1-C6 alkylaminoalkyl, cyanomethyl, piperazinylmethyl, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonylamino, dialkylaminoalkylamino, optionally substituted piperazinylcarbonyl and C1-C6 alkoxy, which is optionally further substituted with halogen, C 1-12 One or more substituents of the alkyl group substituted in combination with C 6-10 Aryl or heteroaryl, a heterocyclyl selected from optionally substituted piperazinyl, morpholinyl optionally substituted by C1-C6 alkyl, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, octahydropyrrolo[3,4-b]pyrrolyl, 2-oxa-6-azaspiro[3.3]heptyl, or a C3-C8 cycloalkyl or C3-C8 azacycloalkyl substituted by morpholino, optionally substituted piperidinyl or optionally substituted piperazinyl,

[0099] V is CR 103 or N,

[0100] W is CR 104 or N,

[0101] Y is CR 105 or N,

[0102] Z is CR 106 or N,

[0103] where R 103 -R 106 is independently hydrogen, optionally substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl, or when Y is CR 106 and Z is CR 107 When R 106 and R 106 together with the carbon to which they are bound, form an optionally substituted fused 5- to 8-membered carbocyclic, aryl, heterocyclyl or heteroaryl ring, wherein the heterocyclyl group contains one or more atoms selected from N, O and S,

[0104] wherein at least one of V, W, Y and Z is N,

[0105] (b) reacting a compound of Formula 100 with a cyanating agent to provide a compound of Formula 101:

[0106] as well as

[0107] (c) reacting a compound of formula 101 with a compound of formula: 102 -LG is reacted with an alkylating agent to obtain a compound of formula 102,

[0108] where R 102 is C1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkylsulfonyl or optionally substituted benzyl, and LG is a leaving group selected from halogen, alkylsulfonate and arylsulfonate:

[0109]

[0110] In another embodiment, the present invention provides a method for synthesizing a compound of formula 102, comprising the steps of:

[0111] (a) providing a compound of formula 103:

[0112]

[0113] Where V is CR 103 or N,

[0114] W is CR 104 or N,

[0115] Y is CR 105 or N,

[0116] Z is CR 106 or N,

[0117] where R 103 -R 106 is independently hydrogen, optionally substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl, or when Y is CR 106 and Z is CR 107 When R 106 and R 106 together with the carbon to which they are bound, form an optionally substituted fused 5- to 8-membered carbocyclic, aryl, heterocyclyl or heteroaryl ring, wherein the heterocyclyl group contains one or more atoms selected from N, O and S,

[0118] wherein at least one of V, W, Y and Z is N,

[0119] (b) reacting a compound of formula 103 with a compound of formula: 102 -LG is reacted with an alkylating agent to obtain a compound of formula 104,

[0120] where R 102 is C1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkylsulfonyl or optionally substituted benzyl, and LG is a leaving group selected from halogen, alkylsulfonate and arylsulfonate:

[0121] as well as

[0122] (c) making the compound of formula 104 and the compound of formula R 101 -NH2 to give a compound of formula 102:

[0123]

[0124] where R 101 is substituted by at least one substituent selected from -CN, halogen, -CF3, -CONH2, -OCF3, C1-C6 alkyl, C1-C6 alkylcarbonyl, -OH, C1-C6 alkylaminocarbonyl, C3-C8 cycloalkylaminocarbonyl, C1-C6 alkylaminoalkyl, cyanomethyl, piperazinylmethyl, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonylamino, dialkylaminoalkylamino, optionally substituted piperazinylcarbonyl and C1-C6 alkoxy, which is optionally further substituted with halogen, C 1-12 One or more substituents of the alkyl group substituted in combination with C 6-10 Aryl or heteroaryl, a heterocyclyl selected from optionally substituted piperazinyl, morpholinyl optionally substituted by C1-C6 alkyl, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, octahydropyrrolo[3,4-b]pyrrolyl, 2-oxa-6-azaspiro[3.3]heptyl, or a C3-C8 cycloalkyl or C3-C8 azacycloalkyl substituted by morpholino, optionally substituted piperidinyl or optionally substituted piperazinyl.

[0125] In yet another embodiment, the present invention provides a method for synthesizing a compound of formula 106, comprising the steps of:

[0126] (a) providing a compound of formula 105:

[0127]

[0128] where R 101 is substituted by at least one group selected from -CN, halogen, -CF3, -CONH2, -OCF3, C1-C6 alkyl, C1-C6 alkylcarbonyl, -OH, C1-C6 alkylaminocarbonyl, C3-C8 cycloalkylaminocarbonyl, C1-C6 alkylaminoalkyl, cyanomethyl, piperazinylmethyl, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonylamino, dialkylaminoalkylamino, optionally substituted piperazinylcarbonyl and C1-C6 alkoxy, which is optionally further substituted with halogen, C 1-12 One or more substituents of the alkyl group substituted in combination with C 6-10aryl or heteroaryl, a heterocyclyl selected from optionally substituted piperazinyl, morpholinyl optionally substituted by C1-C6 alkyl, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, octahydropyrrolo[3,4-b]pyrrolyl, 2-oxa-6-azaspiro[3.3]heptyl, or a C3-C8 cycloalkyl or C3-C8 azacycloalkyl substituted by morpholino, optionally substituted piperidinyl or optionally substituted piperazinyl, and

[0129] (b) reacting the compound of formula 105 with di(C1-C6)alkyl cyanomethylphosphonate to obtain

[0130] Compound of formula 106:

[0131]

[0132] According to one embodiment of the present invention, any compound or salt thereof can be administered in the form of a pharmaceutical composition comprising the compound or salt and a pharmaceutically acceptable carrier.

[0133] The pharmaceutically acceptable carriers described herein, such as solvents, adjuvants, excipients or diluents, are well known to those skilled in the art and are readily available to the public. Preferably, a pharmaceutically acceptable carrier is a carrier that is chemically inert to the active compound and does not have harmful side effects or toxicity under the conditions of use.

[0134] The choice of carrier will be determined in part by the specific active agent as well as by the specific method used to administer the composition. Thus, there are a variety of suitable formulations of the pharmaceutical compositions of the present invention. The following formulations for oral, aerosol, parenteral, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, intrathecal, rectal, and vaginal administration are exemplary only and are in no way limiting.

[0135] Formulations suitable for oral administration may include (a) liquid solutions, such as an effective amount of the compound dissolved in a diluent such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and lozenges, each containing a predetermined amount of the active ingredient such as a solid or granules; (c) powders; (d) suspensions in appropriate liquids; and (e) suitable emulsions. Liquid formulations may contain diluents such as water and alcohols (e.g., ethanol, benzyl alcohol, and polyvinyl alcohol), with or without the addition of pharmaceutically acceptable surfactants, suspending agents, or emulsifiers. Capsule forms may be conventional hard or soft shell gelatin types containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch. Tablet forms may contain one or more of the following: lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, gum arabic, gelatin, guar gum, colloidal silicon dioxide, cross-linked sodium carboxymethyl cellulose, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid and other excipients, colorants, diluents, buffers, disintegrants, wetting agents, preservatives, flavorings and pharmacologically compatible carriers. Lozenge forms may contain the active ingredient in a flavoring (usually sucrose and gum arabic or tragacanth), as well as candy lozenges containing the active ingredient in an inert matrix (such as gelatin and glycerin, or sucrose and gum arabic, emulsions, gels, etc.), in addition to the active ingredient, also containing such carriers as are known in the art.

[0136] The compounds of the present invention can be prepared into aerosol formulations, alone or in combination with other suitable ingredients, for administration by inhalation. These aerosol formulations can be placed in pressurized acceptable propellants such as dichlorodifluoromethane, propane, nitrogen, etc. They can also be formulated into medicaments for non-pressurized formulations, for example, in a nebulizer or atomizer.

[0137] Suitable formulations for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions which may contain suspending agents, solubilizers, thickening agents, stabilizers and preservatives. The compounds can be administered in a physiologically acceptable diluent in a pharmaceutical carrier such as a sterile liquid or mixture of liquids, including water, saline, aqueous solutions of dextrose and related sugars, alcohols (such as ethanol, isopropyl alcohol or hexadecanol), glycols (such as propylene glycol or polyethylene glycol), glycerol ketals (such as 2,2-dimethyl-1,3-dioxolane-4-methanol), ethers (such as poly(ethylene glycol) 400), oils, fatty acids, fatty acid esters or glycerides, or acetylated fatty acid glycerides, with or without the addition of pharmaceutically acceptable surfactants (such as soaps or detergents), suspending agents (such as pectin, carbomer, methylcellulose, hydroxypropyl methylcellulose or carboxymethylcellulose), or emulsifiers and other pharmaceutical excipients.

[0138] The oil that can be used for parenteral preparation comprises petroleum, animal oil, vegetable oil or synthetic oil.The concrete example of oil comprises peanut, soybean, sesame, cottonseed, corn, olive, petrolatum and mineral matter.The suitable fatty acid that is used for parenteral preparation comprises oleic acid, stearic acid and isostearic acid.Ethyl oleate and isopropyl myristate are the examples of suitable fatty acid esters. Suitable soaps for parenteral formulations include fatty alkali metal salts, ammonium salts and triethanolamine salts, and suitable detergents include (a) cationic detergents such as dimethyldialkylammonium halides and alkylpyridinium halides; (b) anionic detergents such as alkyl, aryl and olefin sulfonates, alkyl, olefin, ether and monoglyceride sulfates and sulfosuccinates, (c) nonionic detergents such as fatty amine oxides, fatty acid alkanolamides and polyoxyethylene-polypropylene copolymers, (d) amphoteric detergents such as alkyl-β-aminopropionates and 2-alkyl-imidazoline quaternary ammonium salts, and (3) mixtures thereof.

[0139] Parenteral formulations typically contain about 0.5% to about 25% by weight of active ingredient in solution. Suitable preservatives and buffers can be used in such formulations. In order to minimize or eliminate irritation at the injection site, such compositions may include one or more nonionic surfactants having a hydrophilic-lipophilic balance (HLB) of about 12 to about 17. The amount of surfactant in such formulations is about 5% to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adduct of ethylene oxide and a hydrophobic base, which is formed by the condensation of propylene oxide and propylene glycol. Parenteral formulations can be present in unit dose or multi-dose sealed containers such as ampoules and vials, and can be stored under freeze-dried (lyophilized) conditions, requiring only the addition of a sterile liquid carrier such as water for injection just before use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the aforementioned types.

[0140] The compounds of the present invention can be prepared into injectable formulations. The requirements for effective pharmaceutical carriers for injectable compositions are well known to those of ordinary skill in the art. See Pharmaceutics and Pharmacy Practice, JB Lippincott Co., Philadelphia, Pa., Banker and Chalmers, eds., pp. 238-250 (1982), and ASHP Handbook on Injectable Drugs, Toissel, 4th edition, pp. 622-630 (1986).

[0141] In addition, the compounds of the present invention can be made into suppositories by mixing with various bases such as emulsified bases or water-soluble bases. Formulations suitable for vaginal administration can be in the form of vaginal suppositories, tampons, creams, gels, pastes, foams or sprays, which contain, in addition to the active ingredient, such appropriate carriers known in the art.

[0142] Suitable carriers and their formulations are further described in AR Gennaro, ed., Remington: The Science and Practice of Pharmacy (19th ed.), Mack Publishing Company, Easton, PA (1995).

[0143] The compounds of the present invention or their compositions can be administered as pharmaceutically acceptable acid addition salts, base neutralized salts, or base addition salts, which are formed by reacting with inorganic acids (such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid) and organic acids (such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, and fumaric acid), or by reacting with inorganic bases (such as sodium hydroxide, ammonium hydroxide, potassium hydroxide) and organic bases (such as monoalkylamines, dialkylamines, trialkylamines, and arylamines, as well as substituted ethanolamines). The conversion to a salt is accomplished by treating the base compound with at least a stoichiometric amount of an appropriate acid. Typically, the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol, methanol, and the acid is added to a similar solvent. The mixture is maintained at a suitable temperature (e.g., 0°C to 50°C). The resulting salt precipitates spontaneously or can be brought out of solution with a less polar solvent.

[0144] The neutral form of the compound can be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties (such as solubility in polar solvents), but otherwise, for the purposes of the present invention, the salts are equivalent to the parent form of the compound.

[0145] It will be recognized that the particular counterion forming part of any salt of this invention is generally not a critical property so long as the salt as a whole is pharmacologically acceptable and so long as the counterion does not contribute to undesirable qualities of the salt as a whole.

[0146] It should also be understood that the above compounds and salts may form solvates or exist in a substantially uncomplexed form (e.g., anhydrous form). As used herein, the term "solvate" refers to a molecular complex in which solvent molecules (e.g., a crystallization solvent) are incorporated into the crystal lattice. When the solvent incorporated into the solvate is water, the molecular complex is referred to as a hydrate. Pharmaceutically acceptable solvates include hydrates, alcoholates such as methanolates and ethanolates, acetonitrile, and the like. These compounds may also exist in polymorphic forms.

[0147] In one embodiment, the present invention provides a method of blocking the transmission of Plasmodium parasites, the method comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of the present invention. In another embodiment, the present invention provides a method of treating malaria by killing or arresting the growth of Plasmodium organisms in a mammal, wherein the Plasmodium organisms are in the liver stage or the asexual stage, the method comprising administering to the mammal a therapeutically effective amount of a compound of the present invention.

[0148] The Plasmodium parasite can be any suitable Plasmodium parasite. Non-limiting examples of suitable Plasmodium parasites include Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale, and Plasmodium knowlesi. In a preferred embodiment, the Plasmodium parasite is Plasmodium falciparum.

[0149] In one embodiment, the Plasmodium parasite is a Plasmodium gametocyte.

[0150] In an embodiment, the Plasmodium gametocyte is a II-V mature stage gametocyte. In a preferred embodiment, the Plasmodium gametocyte is a III-V stage gametocyte, for example, a III-V mature stage gametocyte. In another preferred embodiment, the Plasmodium gametocyte is a V mature stage gametocyte.

[0151] In certain preferred embodiments, the compounds are effective in killing Plasmodium gametocytes.

[0152] In an embodiment, the Plasmodium parasite is a drug-resistant strain. Examples of drug-resistant strains of Plasmodium are described in Kun, JFJ et al., Antimicrob Agents Chemother., 1999 September; 43(9): 2205-2208 and references cited therein.

[0153] In an embodiment, the Plasmodium parasite is in an asexual stage. For example, the Plasmodium parasite can be a sporozoite, a hepatic stage parasite, a merozoite, an asexual erythrocytic stage parasite, a zygote, a kinetozoon, or an oocyst.

[0154] The amount or dosage of the compound of the present invention or its salt or its composition should be sufficient to produce a therapeutic or preventive reaction in a mammal. Appropriate dosage will depend on several factors. For example, dosage will also be determined by the presence, nature and degree of any adverse side effects that may accompany the administration of a particular compound or salt. Ultimately, the attending physician will consider various factors, such as age, body weight, general health, diet, sex, compound or salt to be administered, route of administration and the severity of the condition being treated, to determine the dosage of the compound of the present invention for treating each individual patient. By way of example and without intending to limit the present invention, the dosage of the compound described herein can be from about 0.1 mg to about 1 g per day, for example, from about 5 mg to about 500 mg per day. Additional examples of dosages include, but are not limited to, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.5 mg, 0.6 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 12 mg, 15 mg, 17 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 70 mg , 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 125 mg, 140 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg or 1000 mg / kg body weight / day.

[0155] In certain embodiments, the method further comprises administering to the mammal at least one other antimalarial compound. Any suitable antimalarial compound can be used, many of which are well known in the art. Non-limiting examples of suitable antimalarial compounds include primaquine, bravaquine, artemisinin and derivatives thereof, chloroquine, mefloquine, amodiaquine, piperaquine, pyronaridine, atovaquone, tafenoquine, methylene blue, trioxaquine, endoperoxides such as OZ 439 and OZ 277, decoquinate, 9-anilinoacridine, HIV protease inhibitors and natural products such as neem, epoxomicin, harmonine and riboflavin. In certain preferred embodiments, the compounds of the present invention are administered in combination with ilisimol, NSC174938, NVP-AUY922, maduramicin, naramycin, aspiramycin, omacetaxine, thiram, zinc pyrithione, ubiquinone, bortezomib, salinomycin sodium, monensin sodium, pyridoxine dithiothreitol, dicyclopentamethylene-thiuram disulfide, YM155, withaferin A, doxorubicin, romidepsin, AZD-1152-HQPA, CAY10581, plicamycin, CUDC-101, auranofin, trametinib, GSK-458, afatinib, panobinostat, or any combination thereof.

[0156] Illustrative Examples of Implementation

[0157] The present invention includes at least the following embodiments:

[0158] 1. Compounds of formula (I):

[0159]

[0160] Where A is CR 5 or N,

[0161] B is CR 8 =CR 9 or NR 2 ,

[0162] R 8 and R 9 Independently selected from hydrogen, hydroxy, OR 10 , halogen, optionally substituted C 6-10 Aryl and optionally substituted C 1-6 alkyl,

[0163] R 10 It is hydrogen, C 1-12 Alkyl, C 3-8 Cycloalkyl, CH2COOR 13 or H2N(CH2) n-, wherein n is an integer from 2 to 6,

[0164] R 1 is a C1-C6 alkyl radical optionally substituted by at least one substituent selected from -CN, halogen, -CF3, -CONH2, -OCF3, C1-C6 alkyl, C1-C6 alkylcarbonyl, -OH, C1-C6 alkylaminocarbonyl, C3-C8 cycloalkylaminocarbonyl, C1-C6 alkylaminoalkyl, cyanomethyl, piperazinylmethyl, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonylamino, dialkylaminoalkylamino, optionally substituted piperazinylcarbonyl and C1-C6 alkoxy. 6-10 aryl or heteroaryl, a heterocyclyl selected from 4-(C1-C6 alkylcarbonyl)piperazin-1-yl, morpholinyl optionally substituted by C1-C6 alkyl, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, octahydropyrrolo[3,4-b]pyrrolyl and 2-oxa-6-azaspiro[3.3]heptyl, C3-C8 cycloalkyl or C3-C8 azacycloalkyl each substituted by morpholino, optionally substituted piperidinyl or optionally substituted piperazinyl,

[0165] R 2 is C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkylsulfonyl or optionally substituted benzyl,

[0166] R 3 is H, -CN, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, phenylsulfonyl, 4-methylphenylsulfonyl, C1-C6 alkylsulfonyl, aminocarbonyl, aminosulfonyl, optionally substituted benzyl, -OH, -OR, -SR, -(S=O)R (R=C1-C6 alkyl), guanidinyl or pyrimidin-5-yl,

[0167] R 4 is phenyl, heteroaryl, 1-phenyl-2-ethynyl or heterocyclyl, wherein the phenyl group of phenyl, heteroaryl, heterocyclyl or 1-phenyl-2-ethynyl is selected from halogen, C1-C6 alkyl, amino, oxo, dialkylaminoalkyl, dialkylaminoalkoxy, -CN, aminocarbonyl, -OR 6 , CF3 and one or more substituents of C1-C6 alkylsulfonyl are optionally substituted,

[0168] R 6 is H or C1-C6 alkyl,

[0169] R 5 is hydrogen, C1-C6 alkyl, C6-C 10 Aryl, halogen, hydroxyl or OR 7 ,

[0170] R 7is C1-C6 alkyl, formyl, C1-C6 acyl or C6-C 10 Aryl,

[0171] or a pharmaceutically acceptable salt thereof.

[0172] 2. The compound or salt of embodiment 1, wherein:

[0173] R 1 is a C1-C6 alkyl substituted with at least one substituent selected from -CN, halogen, -CF3, -CONH2, -OCF3, C1-C6 alkyl, C1-C6 alkylcarbonyl, -OH, C1-C6 alkylaminocarbonyl, C3-C8 cycloalkylaminocarbonyl, C1-C6 alkylaminoalkyl, cyanomethyl, piperazinylmethyl, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonylamino, dialkylaminoalkylamino, optionally substituted piperazinylcarbonyl and C1-C6 alkoxy. 6-10 aryl or heteroaryl, a heterocyclic group selected from piperazin-1-yl, 4-(C1-C6 alkylcarbonyl)piperazin-1-yl, morpholinyl optionally substituted by C1-C6 alkyl, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, octahydropyrrolo[3,4-b]pyrrolyl and 2-oxa-6-azaspiro[3.3]heptyl, a C3-C8 cycloalkyl or C3-C8 azacycloalkyl substituted by morpholino, optionally substituted piperidinyl or optionally substituted piperazinyl,

[0174] R 3 is H, -CN, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, phenylsulfonyl, 4-methylphenylsulfonyl, C1-C6 alkylsulfonyl, aminocarbonyl, aminosulfonyl, optionally substituted benzyl, -OH, -OR, -SR, -(S=O)R (R=C1-C6 alkyl) or guanidino, and

[0175] R 4 is phenyl, heteroaryl, 1-phenyl-2-ethynyl or heterocyclyl, wherein the phenyl group of phenyl, heteroaryl, heterocyclyl or 1-phenyl-2-ethynyl is selected from halogen, C1-C6 alkyl, amino, oxo, dialkylaminoalkyl, dialkylaminoalkoxy, -CN, aminocarbonyl and -OR 6 One or more substituents are optionally substituted,

[0176] 3. The compound or salt of embodiment 1 or 2, wherein B is NR 2 .

[0177] 4. The compound or salt of embodiment 3, wherein R 1 Selected from

[0178]

[0179]

[0180]

[0181] 5. The compound or salt of embodiment 4, wherein A is CH.

[0182] 6. The compound or salt of embodiment 4 or 5, wherein R 2 It's methyl.

[0183] 7. The compound or salt of any one of embodiments 4 to 6, wherein R 3 It’s H.

[0184] 8. The compound or salt of any one of embodiments 4 to 7, wherein R 2 is methyl, R 3 is H, and R 4 It is 4-chlorophenyl.

[0185] 9. The compound or salt of any one of embodiments 4 to 8, wherein R 2 is methyl, R 3 It's H, R 1 yes And R 4 yes

[0186] 10. The compound or salt of any one of embodiments 4 to 7, wherein R 2 is methyl, R 3 It's H, R 1 yes And R 4 is 4-fluorophenyl, 3-dimethylaminomethylphenyl, 3-cyanophenyl, 3-cyano-4-chlorophenyl, 3-methoxy-4-chlorophenyl, 3-chlorophenyl, 3-fluorophenyl, phenyl, 3-methylphenyl, 3-hydroxyphenyl, 3-aminophenyl, 3-hydroxy-4-fluorophenyl, 3,4-dimethoxyphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 2-methylphenyl, 2-chlorophenyl or 2-hydroxyphenyl.

[0187] 11. The compound or salt of any one of embodiments 4 to 7, wherein R 2 is methyl, R 3 It's H, R 4 is 4-chlorophenyl, and R 1 yes

[0188]

[0189] 12. The compound or salt of any one of embodiments 4 to 6, wherein R 2 is methyl, R 1 yes R 4 is 4-chlorophenyl, and R 3 is –CN, ethylcarbonyl, 4-methylphenylsulfonyl, methyl, n-butyl, methylsulfonyl, guanidine, methoxycarbonyl, tert-butoxycarbonyl, n-butoxycarbonyl, or aminosulfonyl.

[0190] 13. The compound or salt of any one of embodiments 4 to 6, wherein R 2 is methyl, R 1 yes R 4 is 4-fluorophenyl, and R 3 It is –CN or guanidino.

[0191] 14. The compound or salt of any one of embodiments 4 to 6, wherein R 2 is methyl, R 1 yes R 3 is aminosulfonyl, and R 4 It is 4-chlorophenyl.

[0192] 15. The compound or salt of any one of embodiments 4 to 7, wherein R 1 yes R 3 It's H, R 4 is 4-chlorophenyl, and R 2 It is ethyl, benzyl or 2-hydroxyethyl.

[0193] 16. The compound or salt of any one of embodiments 4 to 6, wherein R 2 is methyl, R 1 yes R 3 is a methoxycarbonyl group, and R 4 It is 2-methylpyridin-5-yl or 4-chlorophenyl.

[0194] 17. The compound or salt of any one of embodiments 4 to 6, wherein R 3 is methyl, R 3 is aminosulfonyl or methoxycarbonyl, R 4 is 2-amino-5-pyridyl, and R 1 yes

[0195] 18. The compound or salt of any one of embodiments 4 to 6, wherein R 2 is methyl, R 3 It's H, R 4 is 4-chlorophenyl, and R1 yes

[0196] 19. The compound or salt of any one of embodiments 4 to 6, wherein R 2 is methyl, R 3 It's H, R 4 is 3-fluorophenyl, and R 1 yes

[0197] 20. The compound or salt of any one of embodiments 4 to 6, wherein R 2 is methoxycarbonyl, R 3 It's H, R 4 is 3-fluorophenyl or 4-methylphenyl, and R 1 yes

[0198] 21. The compound or salt of embodiment 1 or 2, wherein B is CR 8 =CR 9 And A is CH.

[0199] 22. The compound or salt of embodiment 21, wherein R 8 and R 9 All are H.

[0200] 23. The compound or salt of embodiment 21 or 22, wherein R 1 yes

[0201] 24. The compound or salt of any one of embodiments 21 to 23, wherein R 4 It is 4-chlorophenyl or 2-amino-5-pyridyl.

[0202] 25. The compound or salt of any one of embodiments 21 to 24, wherein R 3 It's H, R 4 is 4-chlorophenyl, and R 1 is 3-trifluorophenyl, 3-chlorophenyl or

[0203] 26. The compound or salt of any one of embodiments 21 to 24, wherein R 3 Yes-CN, R 4 is 4-chlorophenyl, and R 1 yes

[0204] 27. The compound or salt of any one of embodiments 21 to 24, wherein R 3 is 4-methylphenylsulfonyl, R 4is 4-chlorophenyl, and R 1 yes

[0205] 28. The compound or salt of any one of embodiments 21 to 24, wherein R 3 is propionyl or methyl, R 4 is 4-chlorophenyl, and R 1 yes

[0206] 29. The compound or salt of embodiment 1, wherein A is CH, B is NR 2 , and R 1 Selected from

[0207] 30. The compound or salt of embodiment 29, wherein R 1 yes R 2 is methyl, R 3 is H, and R 4 It is 4-chlorophenyl, 4-fluorophenyl, 2-aminopyridin-5-yl, 4-methylphenyl, 3-fluorophenyl, 3,4-dimethoxyphenyl, 3-cyano-4-chlorophenyl, 3-trifluoromethoxy-4-chlorophenyl, 2-trifluoromethylpyridin-5-yl, 2-methylpyridin-5-yl or 2-methoxypyridin-5-yl.

[0208] 31. The compound or salt of embodiment 29, wherein R 1 yes R 2 is methyl, R 3 is H, and R 4 are 4-chlorophenyl, 4-fluorophenyl, 2-aminopyridin-5-yl, 4-methylphenyl, 3-fluorophenyl, 3-methoxy-4-chlorophenyl, 3-fluoro-4-methoxyphenyl, 3-methoxy-4-fluorophenyl, 3-trifluoromethyl-4-chlorophenyl, 3-trifluoromethoxy-4-chlorophenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4-dimethoxy-5-fluorophenyl, 3,4-dimethoxy-5-chlorophenyl and 3,4,5-trimethoxyphenyl.

[0209] 32. The compound or salt of embodiment 29, wherein:

[0210] R 2 is methyl, R 3 is H, and where:

[0211] R 1 yes And R 4 It is 4-chlorophenyl,

[0212] R 1 yes And R 4 is 3-fluorophenyl,

[0213] R 1 yes And R 4 is 4-chlorophenyl or 3-fluorophenyl,

[0214] R 1 yes And R 4 is 4-chlorophenyl or 3-fluorophenyl,

[0215] R 1 yes And R 4 is 4-chlorophenyl or 3-fluorophenyl,

[0216] R 1 yes And R 4 is 4-chlorophenyl or 3-fluoro, or

[0217] R 1 yes And R 4 It is 3,4-dimethoxyphenyl.

[0218] 33. The compound or salt of embodiment 29, wherein:

[0219] R 1 yes R 2 is methyl, R 3 yes And R 4 is 3-fluorophenyl, or

[0220] R 1 yes R 2 It's H, R 3 is H, and R 4 It is 3,4-dimethoxyphenyl.

[0221] 34. A pharmaceutical composition comprising a compound or salt according to any one of embodiments 1 to 33 and a pharmaceutically acceptable carrier.

[0222] 35. A method of blocking the transmission of Plasmodium parasites, the method comprising administering to a mammal in need of such treatment a therapeutically effective amount of a first compound according to any one of embodiments 1 to 33.

[0223] 36. A method of treating or preventing malaria by killing or arresting the growth of Plasmodium organisms in a mammal, wherein the Plasmodium organisms are in the liver stage or the asexual stage, the method comprising administering to the mammal a therapeutically effective amount of a first compound according to any one of embodiments 1 to 33.

[0224] 37. A compound or salt according to any one of embodiments 1 to 33 for use in blocking the transmission of Plasmodium parasites in a mammal in need thereof.

[0225] 38. A compound or salt according to any one of embodiments 1 to 33 for use in killing or arresting the growth of a Plasmodium organism in a mammal, wherein the Plasmodium organism is in the liver stage or the asexual stage.

[0226] Example

[0227] The following examples further illustrate the invention but, of course, should not be construed as limiting the scope of the invention in any way.

[0228] Materials and methods

[0229] Cell culture. As previously described [Trager W et al., Journal of Parasitology 2005, 91: 484-486], asexual parasites of Plasmodium falciparum (P.falciparum) strain 3D7 were cultured. Stage III-V gametocytes were selected and treated with 50mM N-acetylglucosamine (NAG) for 3 days and then enriched by Percoll density gradient centrifugation after gametocyte production [Tanaka TQ et al., Molecular and Biochemical Parasitology, 2011, 177: 160-163]. Gametocytes of HB3 and Dd2 strains were generated and then measured with a similar process. HepG2 cells (ATCC, catalog number 77400) were grown in a 175 cm flask with 30 ml of growth medium. 2 The cells were cultured in tissue culture flasks at 37°C in a humidified atmosphere with 5% CO2. The growth medium was Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum (FBS). The growth medium was changed every other day and the cells were passaged at 75% confluence.

[0230] Compound library and gametocyte assay screening. The approved drug library contains 4,265 compounds from traditional chemical suppliers, specialty collections, pharmacies, and custom syntheses [Huang R et al., Science Translational Medicine, 2011, 3:80ps16], including 49% of drugs approved by the US Food and Drug Administration (FDA) for use in humans or animals, 23% of drugs approved in Canada / UK / EU / Japan, and the remaining 28% of drugs in clinical trials or research tool compounds. The malaria box contains 400 drugs or tool compounds with confirmed activity against blood-stage Plasmodium falciparum and evaluated cytotoxicity in mammalian cells [Gamo FJ et al., Nature, 2010 465:305-11356; Guiguemde WA et al., Nature, 2010, 465:311-315]. The MIPE library is an internal collection of 550 kinase inhibitors, including approved drugs and preclinical and clinical stage drug candidates [Mathews LA et al., Journal of Biomolecular Screening, 2012, 17: 1231-1242]. Except for several hundred from the approved drug library that were prepared as 4.47 mM stock solutions due to solubility limitations, compounds from all libraries were obtained as powder samples and dissolved in DMSO as 10 mM stock solutions.

[0231] As previously described [Tanaka TQ et al., Molecular and Biochemical Parasitology, 2013, 3188: 20-25], compound screening experiments were performed. In brief, 2.5 μl / well of incomplete culture medium was distributed to each well of a 1,536-well plate using Multidrop Combi, followed by transfer of 23 nl of compound using NX-TR Pintool (WAKO Scientific Solutions, San Diego, CA). 2.5 μl / well of gametocytes were distributed using Multidrop Combi at a seeding density of 20,000 cells / well. The assay plate was incubated at 37°C and 5% CO2 for 72 hours. After adding 5 μl / well of 2X AlamarBlue dye (Life Technologies, catalog number (Cat. No.) DAL1100), the plate was incubated at 37°C and 5% CO2 for 24 hours, and read on a ViewLux plate reader (PerkinElmer) in fluorescence detection mode (Ex = 525 nm, Em = 598 nm).

[0232] Small molecule pull-down. Affinity matrix: To prepare a bead-linked affinity probe for Torin 2, a tetraethylene glycol linker was attached to 1-(piperazin-1-yl)propan-1-one of HWW030 and then coupled to Affi-Gel 10 resin (Bio-Rad Laboratories, catalog number 153-6046) under mild alkaline conditions to obtain Torin 2 matrix (T2M). Torin 1 was also immobilized on the resin and used as a negative control (T1M). The resulting affinity probe was incubated with gametocyte lysate and the bound protein was eluted from the resin by boiling in SDS-PAGE sample loading buffer. The eluted fractions were separated by SDS-PAGE and visualized by silver staining. RBCs infected with gametocytes (3D7 strain: stage III-V) were washed three times with PBS and then lysed by treatment with 0.05% saponin in PBS for 5 minutes at room temperature. Prepared gametocytes were washed three times with PBS and frozen at -80°C. Affinity precipitation experiments were performed as previously described [Zhang Q et al., Proceedings of the National Academy of Sciences of the United States of America, 2007, 104:7444-7448; Arastu-Kapur S et al., Nature Chemical Biology, 2008, 4:203-213]. Frozen samples were lysed with homogenization buffer (60 mM glycerophosphate, 15 mM p-nitrophenyl phosphate, 25 mM MOPS (pH 7.2), 15 mM EGTA, 15 mM MgCl2, 1 mM DTT, protease inhibitors (Roche Diagnostics, catalog number 11836170001), and 0.5% Nonidet P-40). Cell lysates were centrifuged at 16,000 × g for 20 minutes at 4°C, and the supernatant was collected. The protein concentration in the supernatant was determined by using a BCA protein assay kit (Pierce Chemical, catalog number (Cat. No.) 23225). Lysate (0.5 mg) was then added to the affinity matrix filled, and a bead buffer (50 mM Tris HCl (pH 7.4), 5 mM NaF, 250 mM NaCl, 5 mM EDTA, 5 mM EGTA, protease inhibitors, and 0.1% Nonidet P-40) was added to a final volume of 1 ml. After rotating for 2 hours at 4 ° C, the mixture was centrifuged at 4 ° C for 2 minutes at 16,000 × g, and the supernatant was removed. The affinity matrix was then washed with cold bead buffer (six times) and eluted by boiling for 5 minutes at 95 ° C with SDS-PAGE sample loading buffer.The supernatant was separated on a 10% Bis-Tris gel (Life Technologies, catalog number NP0315BOX) and visualized by silver staining using the Pierce Silver Staining Kit for Mass Spectrometry (Pierce Chemical, catalog number 24600).

[0233] DARTS (Drug Affinity Response Target Stability). 3D7 gametocytes were lysed with M-PER supplemented with protease and phosphatase inhibitors as previously described [Lomenick B et al., Proceedings of the National Academy of Sciences of the United States of America, 2009, 106: 21984-21989]. After centrifugation at 16,000 × g for 20 minutes, the protein concentration in the supernatant was quantified and 2 μg / μl of protein was treated with 600 nM Torin 2 or 600 nM Torin 1 for 2 hours at room temperature. The samples were treated with 46 μg / ml pronase (Sigma-Aldrich, catalog number P6911) for 30 minutes at room temperature. The digestion was terminated by adding SDS-PAGE sample loading buffer and boiling at 70°C for 10 minutes. The samples were separated on 10% Bis-Tris gels and visualized by silver staining.

[0234] Malaria Mouse Model. Plasmodium berghei ANKA (Pb) parasites are serially passaged in outbred mice by intraperitoneal (ip) injection. Two days prior to feeding, female mice are infected intraperitoneally with 200-400 μl of whole blood from Pb-infected mice with >10% parasitemia. On the day of feeding, mice are examined for microgametogenesis and injected intravenously (iv) with either the drug vehicle alone (10% N-methylpyrrolidone, 40% PEG 400 in water), or (a) 2 mg / kg to 4 mg / kg Torin 2 (one or two doses), (b) 8 mg / kg NVP-AUY922 (two doses), or (c) 8 mg / kg aspiramycin (two doses). Two hours after treatment, mice were anesthetized and Anopheles stephensimosquito were allowed to feed on infected mice for 15 minutes. Parasitemia, gametocytes, and the presence of microgametogenesis were examined as previously described [Blagborough AM et al., Nature Communications, 2013, 4:1812]. Mosquitoes were maintained on 5% (w / v) glucose at 19°C and 80% relative humidity. On the 10th day after feeding, mosquito midguts were dissected and transmission was measured by staining the midguts with 0.2% mercurochrome and counting the number of oocysts per midgut.

[0235] Data analysis. The initial screening data were analyzed using custom software developed in-house [Wang Y et al., Current Chemical Genomics 2010, 4:57-66]. IC was calculated using Prism software (Graphpad Software, Inc. San Diego, CA). 50 Data are presented as mean ± SEM with n = 3 independent experiments.

[0236] General experimental details. All commercially available reagents, compounds and solvents were purchased and used without further purification. Silica gel column chromatography was performed on a RediSep column using a Teledyne ISCO combiflash Rf system. Preparative purification was performed on a Waters semi-preparative HPLC. The column used was a Phenomenex Luna C18 (5 microns, 30×75 mm) with a flow rate of 45 mL / min. The mobile phase consisted of acetonitrile and water (each containing 0.1% trifluoroacetic acid). During purification, a gradient of 10% to 50% acetonitrile over 8 minutes was used. Fraction collection was triggered by UV detection (220 nm).

[0237] 1 H spectra were recorded using a 400 MHz spectrometer (Varian & Bruker). Samples were analyzed on a Shimadzu 20 series LC / MS using an Xtimate C18 (2.1*30 mm, 3 μm) column and a flow rate of 0.8 mL / min. The mobile phase was a mixture of acetonitrile (mobile phase B, comprising 0.01875% trifluoroacetic acid) and H2O (mobile phase A, comprising 0.0375% trifluoroacetic acid). During the analysis, an acetonitrile gradient of 10% to 80% was used over a 6-minute period, with a 0.5-minute hold at 80%.

[0238] Example 1

[0239] This example illustrates a method for determining in vitro drug activity on gametocytes.

[0240] As before 1 As described above, III-V stage gametocytes (blood stage Plasmodium falciparum parasites) were enriched using 50mM N-acetylglucosamine (NAG) and Percoll density gradient centrifugation. Briefly, 2.5 μl / well of complete medium was dispensed into each well of a 1,536-well plate using a Multidrop Combi, followed by 23 nl compound transfer using an NX-TR Pintool (WAKO Scientific Solutions, San Diego, CA). 2.5 μl / well of gametocytes were then dispensed using a Multidrop Combi at a seeding density of 20,000 cells / well. The assay plate was incubated at 37°C and 5% CO2 for 72 hours. After adding 5 μl / well of 2X AlamarBlue dye (Life Technologies, catalog number DAL1100), the plates were incubated at 37° C. and 5% CO 2 for 24 hours and then read on a ViewLux plate reader (PerkinElmer) in fluorescence detection mode (Ex=525 nm, Em=598 nm).

[0241] Example 2

[0242] This example illustrates a method for determining in vitro drug activity against asexual parasites according to an embodiment of the present invention.

[0243] Asexual parasites of Plasmodium falciparum strain 3D7 were cultured as previously described (Trager, W. et al., J. Parasitol. 2005, 91(3):484-486). Drug activity against asexual stage parasites was tested using the SYBR Green assay as previously described (Eastman, RT et al., Antimicrob. Agents Chemother. 2013, 57(1):425-435; Smilkstein, M. et al., Antimicrob. Agents Chemother. 2004, 48(5):1803-1806). Briefly, parasites were diluted to 0.5% parasitemia in complete medium with 2% hematocrit and drug diluted in DMSO (≤0.5%) and then loaded into 96-well plates (200 μl / well). Wells without drug and wells with RBC alone served as positive and background controls, respectively, and each test condition was tested in duplicate. After incubation for 72 hours under standard culture conditions and freeze-thaw lysis steps at -80°C and room temperature, 100 μl / well of lysis buffer containing SYBR Green I was added to the parasite culture and incubated at room temperature for 30 minutes. The FLUOstar Optima TM The fluorescence of each well was measured at 520 nm after excitation at 490 nm using a microplate reader (BMG Labtech).

[0244] Example 3

[0245] This example illustrates the synthesis of compounds according to embodiments of the present invention.

[0246] General Procedure A (Scheme 1). A mixture of compound 1, amine 2, and HCl / dioxane in DMF is stirred at 100°C to give compound 3. Compound 3 is then mixed with Fe and NH4Cl in EtOH and H2O and stirred at 85°C to give compound 4. Compound 4 is cyanated with cyanogen bromide in EtOH at 80°C to 90°C to give compound 5. Compound 5 is alkylated with 6 in DMF at 20°C to 25°C to give compound 7. Suzuki coupling of compound 7 and boronic acid / ester 8 in dioxane and H2O at 100°C in the presence of Na2CO3 and Pd(dppf)Cl2 gives compound 9, which reacts with reagent 10 to form compound 11.

[0247] General Procedure B (Scheme 2). A mixture of compound 12, amine 2, and HCl / dioxane in DMF was stirred at 100°C to provide compound 13. Suzuki coupling of compound 13 and boronic acid / ester 8 in dioxane and H2O at 100°C in the presence of Na2CO3 and Pd(dppf)Cl2 afforded compound 14. Compound 14 was reduced with NaBH4 in EtOH and THF at 20°C to 25°C to provide compound 15. Compound 15 was oxidized with MnO2 in DCM at 20°C to 25°C to provide compound 16. Compound 16 was olefinated with 2-diethoxyphosphorylacetonitrile and K2CO3 in DMF at 100°C to provide compound 17, which was reacted with reagent 10 to form compound 18.

[0248] General Scheme C (Scheme 3). A mixture of compound 23 and amine 2 in NMP was heated under microwave irradiation at 180°C (R 1 = alkyl) or at 150°C (R 1 =aryl) to form compound 24. DMF and 1M K3PO4 were then added, followed by the addition of boronic acid / ester 8 and Pd(dppf)Cl2. Suzuki coupling of compound 24 at 150°C gave compound 9.

[0249] 5-(1-(5-cyano-2-methylphenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl)thiophene-2-carboxamide (1)

[0250]

[0251] LCMS: in 0-60AB_7min_220&254 (Xtimate 3um, C18, 2.1*30mm) R =2.733min, MS(ESI)m / z 439.1[M+H] + .

[0252] 1H NMR (400MHz, DMSO-d6) δ = 9.35 (s, 1H), 9.10 (s, 2H), 8.36 (d, J = 1.5Hz, 1H), 8.29 (dd, J = 1.7, 8.0Hz, 1H ),8.20(d,J=9.0Hz,1H),8.07(dd,J=2.0,8.8Hz,1H),8.04-7.97(m,2H),7.72-7.66(m,1H),7.48(br s, 1H), 7.34 (d, J = 3.7Hz, 1H), 6.90 (d, J = 1.8Hz, 1H), 3.93 (s, 3H), 2.22 (s, 3H).

[0253] 3-(8-(6-aminopyridin-3-yl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile (2)

[0254]

[0255] LCMS: in 10-80CD_7MIN_220&254 (XBridge Shield RP182.1*50mm, 5um) R =2.423min, MS(ESI)m / z 406.2[M+H] + .

[0256] 1 H NMR (400MHz, DMSO-d6) δ = 9.35 (s, 1H), 9.06 (br s,2H),8.37-8.30(m,1H),8.26-8.18(m,2H),7.98(dd,J=1.9,8.9Hz,1H),7.95-7.89(m,2H),7.66-7.60(m,1H),6.84(br d,J=8.4Hz,1H),6.74(d,J=1.8Hz,1H),3.92(s,3H),2.19(s,3H).

[0257] 3-(2-Imino-3-methyl-8-(2-oxoindole-5-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile (3)

[0258]

[0259] LCMS: in 0-60AB_7min_220&254 (Xtimate 3um, C18, 2.1*30mm) R=2.870min,MS(ESI)m / z 445.1[M+H] + .

[0260] 1 H NMR (400MHz, DMSO-d6) δ = 10.54 (s, 1H), 9.31 (s, 1H), 9.03 (s, 2H), 8.38 (d, J = 1 .5Hz,1H),8.31(dd,J=1.7,8.0Hz,1H),8.18(d,J=8.8Hz,1H),7.97(dd,J=2.1 ,8.9Hz,1H),7.94(d,J=8.4Hz,1H),7.13(d,J=7.9Hz,1H),7.10(s,1H),6.82( d,J=8.2Hz,1H),6.74(d,J=2.2Hz,1H),3.91(s,3H),3.51(s,2H),2.19(s,3H).

[0261] (E)-N-(8-(6-aminopyridin-3-yl)-1-(5-cyano-2-methylphenyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-ylidene)cyanamide (4)

[0262]

[0263] LCMS: in 0-60AB_7min_220&254 (Xtimate 3um, C18, 2.1*30mm) R =2.627min, MS(ESI)m / z 431.0[M+Na] + .

[0264] 1 H NMR (400MHz, DMSO-d6) δ = 9.16 (s, 1H), 8.39 (d, J = 1.1Hz, 1H), 8.19 (dd, J = 1.5, 7.9Hz, 1H), 8.10 (d, J = 8.8Hz, 1H), 7.88 (dd, J = 1.8, 8.8Hz, 1H), 7.85 (d, J=8.2Hz,1H),7.81(d,J=2.4Hz,1H),7.35(dd,J=2.5,8.7Hz,1H),6.72(d,J =1.5Hz,1H),6.44(d,J=8.6Hz,1H),6.24(s,2H),3.84(s,3H),2.20(s,3H).

[0265] 3-(2-Imino-3-methyl-8-(1-methyl-1H-pyrazol-5-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile (5)

[0266]

[0267] LCMS: in 0-60AB_7min_220&254 (Xtimate 3um, C18, 2.1*30mm) R =2.738min, MS(ESI)m / z 394.1[M+H] + .

[0268] 1 H NMR (400MHz, METHANOL-d4) δ = 9.32 (s, 1H), 8.31 (d, J = 8.8Hz, 1H), 8.21 (d, J = 1.5Hz, 1H), 8.12 (dd, J = 1.7, 8.0Hz, 1H), 7.95 -7.82(m,2H),7.47(d,J=2.0Hz,1H),6.95(d,J=2.0Hz,1H),6.28(d,J=2.0Hz,1H),4.02(s,3H),3.65(s,3H),2.28(s,3H).

[0269] (E)-3-(8-(4-chlorophenyl)-3-methyl-2-(methylimino)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile (6)

[0270]

[0271] LCMS: in 0-60AB_7min_220&254 (Xtimate 3um, C18, 2.1*30mm) R =4.136min, MS(ESI)m / z 438.1[M+H] + .

[0272] 1H NMR (400MHz, DMSO-d6) δ = 9.41 (s, 1H), 8.88 (br d,J=4.6Hz,1H),8.43(d,J=1.5Hz,1H),8.33-8.17(m,2H),8.02(dd,J=2.0,8.8Hz,1H),7.93(d,J=8.2Hz,1H), 7.55-7.43(m,2H),7.36-7.25(m,2H),6.73(d,J=1.8Hz,1H),4.04(s,3H),2.83(d,J=4.9Hz,3H),2.26(s,3H).

[0273] 3-(8-(4-Chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-ethylbenzonitrile (7)

[0274]

[0275] LCMS: in 0-60AB_7min chromatography (Xtimate 3um, C18, 2.1*30mm) R =5.880min,MS(ESI)m / z 438.1[M+H] + .

[0276] (E)-N-(8-(4-chlorophenyl)-1-(5-cyano-2-methylphenyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-ylidene)cyanamide (8)

[0277]

[0278] LCMS: in 0-60AB_7min_220&254 (Xtimate 3um, C18, 2.1*30mm) R =5.027min, MS(ESI)m / z 449.1[M+H] + .

[0279] 1 H NMR (400MHz, DMSO-d6) δ = 9.24 (s, 1H), 8.38 (d, J = 1.3Hz, 1H), 8.22-8.13 (m, 2H), 7.96 (dd, J = 2.0, 8.8Hz, 1H), 7.84(d,J=8.2Hz,1H),7.51-7.43(m,2H),7.34-7.25(m,2H),6.82(d,J=1.8Hz,1H),3.85(s,3H),2.21(s,3H).

[0280] (E)-N-(8-(4-chlorophenyl)-1-(5-cyano-2-methylphenyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-ylidene)propanamide (9)

[0281]

[0282] LCMS: in 10-80AB_7min_220&254 chromatography (Xtimate 3um, C18, 2.1*30mm) R =3.361min, MS(ESI)m / z 480.0[M+H] + .

[0283] 1 H NMR (400MHz, DMSO-d6) δ = 9.24 (s, 1H), 8.25-8.13 (m, 2H), 8.08 (dd, J = 1.5, 7.9Hz, 1H), 7.95 (dd, J = 2.1, 8.9Hz, 1H), 7.80 (d, J = 8.2Hz, 1H), 7 .47(d,J=8.6Hz,2H),7.32(d,J=8.6Hz,2H),6.95(d,J=1.8Hz,1H),3.69(s,3H),2.16(s,3H),2.08(q,J=7.6Hz,2H),0.84(t,J=7.5Hz,3H).

[0284] 3-(8-(4-Chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-fluorobenzonitrile (10)

[0285]

[0286] LCMS: in 0-60AB_7.0min chromatography (Xtimate 3um, C18, 2.1*30mm) R =4.008min, MS(ESI)m / z 428.0[M+H] + .

[0287] 1H NMR:(DMSO-d6 400MHz): δ9.44-9.26(m,3H),8.69(dd,J=2.0,6.8Hz,1H),8.53(dd,J=2.4,8.9Hz,1H),8.29(d,J= 8.8Hz,1H),8.15-8.06(m,2H),7.59-7.50(m,2H),7.43(d,J=8.5Hz,2H),7.07(s,1H),3.97(s,3H).

[0288] 3-(8-(4-Chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)benzonitrile (11)

[0289]

[0290] LCMS: in 0-60AB_7.0min chromatography (Xtimate 3um, C18, 2.1*30mm) R =4.048min, MS(ESI)m / z 410.0[M+H] + .

[0291] 1 H NMR (400MHz, DMSO-d6) δ = 9.38 (s, 1H), 9.01 (s, 2H), 8.50 (s, 1H), 8.39 (d, J = 7.7Hz, 1H), 8.26 (d, J = 8.8Hz, 2H),8.10-8.02(m,2H),7.51(d,J=8.6Hz,2H),7.37(d,J=8.6Hz,2H),6.96(d,J=1.8Hz,1H),3.95(s,3H).

[0292] 3-(8-(4-Fluorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile (12)

[0293]

[0294] LCMS: in 0-60AB_7min_220&254 (Xtimate 3um, C18, 2.1*30mm) R =3.811min, MS(ESI)m / z 408.1[M+H] + .

[0295] 1H NMR (400MHz, METHANOL-d4) δ = 9.25 (s, 1H), 8.26 (d, J = 9.0Hz, 1H), 8.23 (d, J = 1.8Hz, 1H), 8.15 (dd, J = 1.7, 8.0Hz, 1H), 8.01 (dd, J =2.1,8.9Hz,1H),7.91(d,J=8.2Hz,1H),7.42-7.27(m,2H),7.19-7.10(m,2H),6.96(d,J=1.8Hz,1H),4.01(s,3H),2.29(s,3H).

[0296] 8-(4-Chlorophenyl)-3-methyl-1-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imide (13)

[0297]

[0298] LCMS: in 0-60AB_7min_220&254 (Xtimate 3um, C18, 2.1*30mm) R =3.552min, MS(ESI)m / z 389.0[M+H] + .

[0299] 1 H NMR (400MHz, METHANOL-d4) δ = 9.19 (s, 1H), 8.29 (s, 1H), 8.23 (d, J = 9.0Hz, 1H), 8.02 (br d,J=9.3Hz,1H),7.96(s,1H),7.55(s,1H),7.46(s,4H),4.11(s,3H),3.95(s,3H).

[0300] 5-(8-(4-Chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methyl-2-(piperazin-1-yl)benzonitrile (14)

[0301]

[0302] LCMS: in 0-60AB_7.0min chromatography (Xtimate 3um, C18, 2.1*30mm) R =3.105min, MS(ESI)m / z 508.2[M+H] + .

[0303] 1H NMR (400MHz, DMSO-d6) δ=9.38(s,1H),9.11-8.93(m,4H),8.30-8.23(m,2H),8.08(br d,J=8.6Hz,1H),7.59(s,1H),7.53(br d,J=7.3Hz,2H),7.41(br d,J=7.5Hz,2H),6.99(s,1H),3.95(s,3H),3.63(br d,J=12.8Hz,2H),3.48(br s,6H),2.17(s,3H).

[0304] tert-Butyl 4-(4-(8-(4-chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-2-cyano-5-methylphenyl)piperazine-1-carboxylate (15)

[0305]

[0306] LCMS: in 0-60AB_7.0min chromatography (Xtimate 3um, C18, 2.1*30mm) R =5.034min, MS(ESI)m / z 608.2[M+H] + .

[0307] 1 H NMR(400MHz,DMSO-d6)δ=8.82(br s,1H),8.03(d,J=9.3Hz,2H),7.81(dd,J=2.0,9.0Hz,1H),7.46(d,J=8.6Hz,2H),7.40(s,1H),7.34(d,J=8.8Hz,2H),6.92(s,1H),3.58(br s,4H),3.54(s,3H),3.31(s,2H),3.27-3.18(m,2H),2.09(br s,3H),1.46(s,9H).

[0308] (E)-N-(8-(4-chlorophenyl)-1-(5-cyano-2-methylphenyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-ylidene)-4-methylbenzenesulfonamide (16)

[0309]

[0310] LCMS: in 10-80AB_7min_220&254 (Xtimate 3um, C18, 2.1*30mm) R=4.347min, MS(ESI)m / z 578.1[M+H] + .

[0311] 1 H NMR (400MHz, DMSO-d6) δ = 9.31 (s, 1H), 8.21 (d, J = 8.8Hz, 1H), 8.08-8.03 (m, 2H), 7.99 (dd, J = 2.1, 8.9Hz, 1H), 7.73 (d, J = 8.6Hz, 1H), 7.46 (d, J=8.6Hz,2H),7.41(d,J=8.2Hz,2H),7.32-7.27(m,2H),7.16(d,J=8.2Hz,2H),6.85(d,J=1.8Hz,1H),4.04(s,3H),2.32(s,3H),2.08(s,3H).

[0312] (E)-3-(2-(butylimino)-8-(4-chlorophenyl)-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile (17)

[0313]

[0314] LCMS: in 0-60AB_7min_220&254 (Xtimate 3um, C18, 2.1*30mm) R =4.661min, MS(ESI)m / z 480.1[M+H] + .

[0315] 1 H NMR (400MHz, DMSO-d6) δ = 9.41 (s, 1H), 8.74 (br t,J=5.8Hz,1H),8.48(s,1H),8.30(d,J=8.2Hz,1H),8.24(d,J=8.8Hz,1H),8 .03(dd,J=1.9,8.9Hz,1H),7.95(d,J=7.9Hz,1H),7.49(d,J=8.6Hz,2H),7.31 (d,J=8.6Hz,2H),6.72(d,J=1.8Hz,1H),4.02(s,3H),3.24-3.03(m,2H),2.2 5(s,3H),1.42(quin,J=7.1Hz,2H),1.23-1.00(m,2H),0.76(t,J=7.4Hz,3H).

[0316] (E)-N-(8-(4-chlorophenyl)-1-(5-cyano-2-(methylthio)phenyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-ylidene)cyanamide (18)

[0317]

[0318] LCMS: in 0-60AB_7min chromatography (Xtimate 3um, C18, 2.1*30mm) R =4.955min, MS(ESI)m / z 481.0[M+H] + .

[0319] 1 H NMR:(DMSO-d6 400MHz): δ=9.25(s,1H),8.42(d,J=1.8Hz,1H),8.23(dd,J=1.8,8.4Hz,1H),8.18(d,J=8.8Hz,1H),7.98(dd,J=1.9,8.9Hz ,1H),7.77(d,J=8.6Hz,1H),7.48(d,J=8.6Hz,2H),7.32(d,J=8.4Hz,2H),6.95(d,J=1.5Hz,1H),3.83(s,3H),2.49(s,3H).

[0320] 3-(8-(4-Chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-ethoxybenzonitrile (19)

[0321]

[0322] (E)-N-(8-(4-chlorophenyl)-1-(5-cyano-2-methylphenyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-ylidene)methanesulfonamide (20)

[0323]

[0324] LCMS: in 10-80AB_7min_220&254 (Xtimate 3um, C18, 2.1*30mm) R =3.554min, MS(ESI)m / z 502.0[M+H] + .

[0325] 1H NMR (400MHz, DMSO-d6) δ=9.32(s,1H),8.32(d,J=1.0Hz,1H),8.23(d,J=9.0Hz,1H),8.16(dd,J=1.3,8.0Hz,1H),8.03(dd,J=1.9,8.9Hz ,1H),7.85(d,J=8.0Hz,1H),7.51(d,J=8.5Hz,2H),7.34(d,J=8.5Hz,2H),6.89(d,J=1.5Hz,1H),4.04(s,3H),2.85(s,3H),2.18(s,3H).

[0326] 5-(8-(4-Chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-6-methyl-2-morpholinonitrile (21)

[0327]

[0328] LCMS: in 0-60AB_7min chromatography (Xtimate 3um, C18, 2.1*30mm) R =4.214min, MS(ESI)m / z 510.1[M+H] + .

[0329] 1 H NMR:(DMSO-d6 400MHz): δ=9.37(s,1H),9.20(s,2H),8.50(s,1H),8.26(d,J=9.0Hz,1H),8.06(dd,J=2.0,8.8Hz,1H),7.55 -7.51(m,2H),7.49-7.46(m,2H),7.18(d,J=1.8Hz,1H),3.95-3.90(m,7H),3.89-3.75(m,4H),2.24(s,3H).

[0330] 5-(8-(4-Chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-6-methylnicotinonitrile (22)

[0331]

[0332] LCMS: in 0-60AB_7min_220&254 (Xtimate 3um, C18, 2.1*30mm) R =3.740min, MS(ESI)m / z 424.9[M+H] + .

[0333] 1 H NMR (400MHz, DMSO-d6) δ = 9.45-9.39 (m, 2H), 9.35 (s, 2H), 8.87 (d, J = 1.8Hz, 1H), 8.29 (d, J = 9.0Hz, 1H), 8.07 (dd, J=2.0,9.0Hz,1H),7.54(d,J=8.5Hz,2H),7.40(d,J=8.5Hz,2H),6.90(d,J=1.8Hz,1H),4.00(s,3H),2.48(s,3H).

[0334] 5-(8-(4-Chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methyl-2-morpholinobenzonitrile (23)

[0335]

[0336] LCMS: in 0-60AB_7.0min chromatography (Xtimate 3um, C18, 2.1*30mm) R =4.195min, MS(ESI)m / z 509.1[M+H] + .

[0337] 1 H NMR (400MHz, DMSO-d6) δ = 9.41 (s, 1H), 9.25 (s, 2H), 8.28 (d, J = 8.8Hz, 1H), 8.20 (s, 1H), 8.08 (dd, J = 2.1, 8.9Hz, 1H), 7.53-7.45 (m, 3H), 7. 43-7.36(m,2H),6.98(d,J=1.5Hz,1H),3.97(s,3H),3.83(t,J=4.6Hz,4H),3.49-3.38(m,2H),3.29(td,J=4.7,12.5Hz,2H),2.14(s,3H).

[0338] 3-(8-(3-((dimethylamino)methyl)phenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile (24)

[0339]

[0340] LCMS: in 0-60AB_7.0min chromatography (Xtimate 3um, C18, 2.1*30mm) R=2.332min, MS(ESI)m / z 447.1[M+H] + .

[0341] 1 H NMR (400MHz, DMSO-d6) δ = 10.45 (br s, 1H), 9.41 (s, 1H), 9.23 (br s,2H),8.41(d,J=1.5Hz,1H),8.37-8.22(m,2H),8.07(dd,J=1.9,8.9Hz,1H),8.01-7.91(m,1H),7.60(s,1H),7.57 -7.51(m,2H),7.36-7.28(m,1H),6.93(d,J=1.8Hz,1H),4.39-4.25(m,2H),3.99(s,3H),2.78(s,6H),2.25(s,3H).

[0342] 3-(8-(3-cyanophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile (25)

[0343]

[0344] LCMS: in 0-60AB_7.0min chromatography (Xtimate 3um, C18, 2.1*30mm) R =3.438min, MS(ESI)m / z 415.1[M+H] + .

[0345] 1 H NMR (400MHz, DMSO-d6) δ = 9.41 (s, 1H), 9.18 (br s,2H),8.40(d,J=0.9Hz,1H),8.32-8.22(m,2H),8.13(dd,J=1.8,8.8Hz,1H),7.96(d,J=8.2Hz,1H), 7.91-7.83(m,1H),7.77(s,1H),7.70-7.62(m,2H),6.89(d,J=1.5Hz,1H),3.97(s,3H),2.24(s,3H).

[0346] 8-(4-Chlorophenyl)-3-methyl-1-(3-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imide (26)

[0347]

[0348] LCMS: ES7316-92-P1D in 0-60AB_7min_220&254 (Xtimate 3um, C18, 2.1*30mm) R =4.491min, MS(ESI)m / z 453.0[M+H] + .

[0349] 1 H NMR (ES7316-92-P1A, 400MHz, DMSO-d6) δ = 9.38 (s, 1H), 9.05 (s, 2H), 8.46 (s, 1H), 8.30 (br d,J=7.9Hz,1H),8.28-8.20(m,2H),8.13-8.07(m,1H),8.04(dd,J=1.9,8.9Hz,1H) ,7.47(d,J=8.4Hz,2H),7.31(d,J=8.6Hz,2H),6.86(d,J=1.8Hz,1H),3.96(s,3H).

[0350] 8-(4-Chlorophenyl)-3-methyl-1-(2-methyl-5-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imide (27)

[0351]

[0352] LCMS: in 0-60AB_7min chromatography (Xtimate 3um, C18, 2.1*30mm) R =4.538min, MS(ESI)m / z 467.0[M+H] + .

[0353] 1 H NMR (400MHz, DMSO-d6) δ = 9.39 (s, 1H), 9.17 (s, 2H), 8.35 (s, 1H), 8.26 (d, J = 9.04Hz, 1H), 8.19 (d, J = 8.16Hz, 1H), 8.03 (dd, J = 8.82, 1. 10Hz, 1H), 7.97 (d, J = 8.16Hz, 1H), 7.46 (d, J = 8.38Hz, 2H), 7.29 (d, J = 8.60Hz, 2H), 6.78 (d, J = 1.76Hz, 1H), 3.97 (s, 3H), 2.24 (s, 3H).

[0354] 1-(3-Chlorophenyl)-8-(4-chlorophenyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imide (28)

[0355]

[0356] LCMS: in 0-60AB_7min chromatography (Xtimate 3um, C18, 2.1*30mm) R =4.174min, MS(ESI)m / z 419.0[M+H] +。 .

[0357] 1 H NMR:(DMSO-d6 400MHz): δ=9.23(s,1H),8.18(d,J=8.8Hz,1H),8.05(s,1H),7.99-7.91(m,2H),7.85- 7.81(m,2H),7.50-7.46(m,2H),7.38-7.34(m,2H),7.00(d,J=1.8Hz,1H),3.84(s,3H).

[0358] 1-(5-chloro-2-methylphenyl)-8-(4-chlorophenyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imide (29)

[0359]

[0360] LCMS: in 0-60AB_7.0min chromatography (Xtimate 3um, C18, 2.1*30mm) R =4.377min, MS(ESI)m / z 433.0[M+H] + .

[0361] 1 H NMR (400MHz, DMSO-d6) δ = 9.36 (s, 1H), 9.01 (s, 2H), 8.24 (d, J = 8.8Hz, 1H), 8.06-7.97 (m, 2H), 7.91-7.84 (m, 1H) ,7.76(d,J=8.6Hz,1H),7.53-7.46(m,2H),7.38-7.32(m,2H),6.90(d,J=1.8Hz,1H),3.93(s,3H),2.11(s,3H).

[0362] 2-Chloro-5-(1-(5-cyano-2-methylphenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl)benzonitrile (30)

[0363]

[0364] LCMS: in 0-60AB_7MIN_220&254 chromatography (Xtimate 3um, C18, 2.1*30mm) R =3.823min, MS(ESI)m / z 449.0[M+H] + .

[0365] 1 H NMR: (400MHz, DMSO-d6) δ = 9.42 (s, 1H), 9.20 (br s,2H),8.39(d,J=1.5Hz,1H),8.31-8.22(m,2H),8.11(dd,J=2.0,8.8Hz,1H),7.95(d,J=8.2Hz,1H),7.91(d,J= 2.4Hz, 1H), 7.82 (d, J = 8.6Hz, 1H), 7.61 (dd, J = 2.3, 8.5Hz, 1H), 6.87 (d, J = 1.8Hz, 1H), 3.97 (s, 3H), 2.23 (s, 3H).

[0366] 3-(8-(4-chloro-3-methoxyphenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile (31)

[0367]

[0368] LCMS: in 0-60AB_7MIN_220&254 chromatography (Xtimate 3um, C18, 2.1*30mm) R =4.016min, MS(ESI)m / z 454.1[M+H] + .

[0369] 1 H NMR: (400MHz, DMSO-d6) δ = 9.38 (s, 1H), 9.08 (s, 2H), 8.38 (d, J = 1.5Hz, 1H), 8.30-8.22 (m, 2H), 8.07 (dd, J = 2.0, 9.0Hz, 1H), 7.93 (d, J =7.9Hz,1H),7.47(d,J=8.2Hz,1H),6.98(dd,J=2.0,8.2Hz,1H),6.91(dd,J=1.9,10.5Hz,2H),3.94(s,3H),3.87(s,3H),2.21(s,3H).

[0370] 3-(2-Imino-8-(3-methoxyphenyl)-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile (32)

[0371]

[0372] LCMS: in 0-60AB_7MIN_220&254 chromatography (Xtimate 3um, C18, 2.1*30mm) R =3.648min, MS(ESI)m / z 420.1[M+H] + .

[0373] 1 H NMR: (400MHz, DMSO-d6) δ = 9.39 (s, 1H), 9.07 (br s,2H),8.41(d,J=1.3Hz,1H),8.31-8.24(m,2H),8.07(dd,J=1.9,8.9Hz,1H),7.96(d,J=8.2Hz,1 H),7.35(t,J=7.9Hz,1H),6.97-6.92(m,3H),6.82(s,1H),3.96(s,3H),3.79(s,3H),2.23(s,3H).

[0374] 3-(8-(3-chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile (33)

[0375]

[0376] LCMS: in 0-60AB_7MIN_220&254 chromatography (Xtimate 3um, C18, 2.1*30mm) R =3.922min, MS(ESI)m / z 424.1[M+H] + .

[0377] 1H NMR: (400MHz, DMSO-d6) δ = 9.41 (s, 1H), 9.14 (s, 2H), 8.43 (d, J = 1.5Hz, 1H), 8.32-8.25 (m, 2H), 8.11 (dd, J = 2.1, 8.9Hz, 1H), 7. 98(d,J=8.2Hz,1H),7.50-7.45(m,2H),7.40-7.37(m,1H),7.30-7.28(m,1H),6.88(d,J=1.8Hz,1H),3.97(s,3H),2.24(s,3H).

[0378] 3-(8-(3-Fluorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile (34)

[0379]

[0380] LCMS: in 0-60AB_7MIN_220&254 chromatography (Xtimate 3um, C18, 2.1*30mm) R =3.722min, MS(ESI)m / z 408.1[M+H] + .

[0381] 1 H NMR: (400MHz, DMSO-d6) δ = 9.40 (s, 1H), 9.07 (s, 2H), 8.40 (s, 1H), 8.31-8.25 (m, 2H), 8.09 (dd, J = 2.1, 8.7Hz, 1H), 7.97 (d ,J=8.2Hz,1H),7.52-7.45(m,1H),7.27-7.21(m,1H),7.19-7.13(m,2H),6.90(d,J=2.0Hz,1H),3.96(s,3H),2.23(s,3H).

[0382] 3-(2-Imino-3-methyl-8-phenyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile (35)

[0383]

[0384] LCMS: in 0-60AB_7MIN_220&254 chromatography (Xtimate 3um, C18, 2.1*30mm) R =3.592min, MS(ESI)m / z 390.0[M+H] + .

[0385] 1 H NMR: (400MHz, DMSO-d6) δ = 9.36 (s, 1H), 9.02 (br s,2H),8.38(s,1H),8.26(dd,J=1.8,8.2Hz,1H),8.23(d,J=9.0Hz,1H),8.03(dd,J=1.9,8.9Hz,1H),7.94(br d,J=8.2Hz,1H),7.44-7.35(m,3H),7.31(br d,J=6.6Hz,2H),6.87(br d,J=1.8Hz,1H),3.93(s,3H),2.21(s,3H).

[0386] 3-(2-Imino-3-methyl-8-(m-tolyl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile (36)

[0387]

[0388] LCMS: in 0-60AB_7MIN_220&254 chromatography (Xtimate 3um, C18, 2.1*30mm) R =3.863min, MS(ESI)m / z 449.1[M+H] + .

[0389] 1 H NMR: (400MHz, DMSO-d6) δ = 9.38 (s, 1H), 9.11 (s, 2H), 8.44 (d, J = 1.1Hz, 1H), 8.32 (dd, J = 1.4, 8.0Hz, 1H), 8.24 (d, J = 8.8Hz, 1H), 8.06 (dd, J = 1.9, 8. 9Hz,1H),7.98(d,J=8.2Hz,1H),7.36-7.30(m,1H),7.26-7.19(m,2H),7. 04(s,1H),6.88(d,J=1.5Hz,1H),3.96(s,3H),2.35(s,3H),2.23(s,3H).

[0390] 3-(8-(3-Hydroxyphenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile (37)

[0391]

[0392] LCMS: in 0-60AB_7min chromatography (Xtimate 3um, C18, 2.1*30mm) R =2.979min, MS(ESI)m / z 406.1[M+H] + .

[0393] 1 H NMR: (400MHz, DMSO-d6)δ=9.54(br s,1H),8.81(s,1H),8.18(s,1H),8.06(brd,J=7.9Hz,1H),7.99(d,J=8.8Hz,1H),7.81(d,J=7.9Hz,1H),7.71(dd,J=2.0,9.0Hz,1H), 7.15(t,J=7.8Hz,1H),6.83(d,J=1.8Hz,1H),6.75-6.66(m,2H),6.62(d,J=7.9Hz,1H),5.88-5.62(m,1H),3.53(s,3H),2.16(s,3H).

[0394] 3-(8-(3-Aminophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile (38)

[0395]

[0396] LCMS: in 0-60AB_7min chromatography (Xtimate 3um, C18, 2.1*30mm) R =2.391min, MS(ESI)m / z 405.0[M+H] + .

[0397] 1 H NMR: (400MHz, DMSO-d6) δ=8.81(s,1H),8.19(s,1H),8.09(dd,J=1.5,7.9Hz,1H),7.99(d,J=8.8Hz,1H),7.84(d,J=8.2Hz,1H),7.68(dd,J=2.0,9.0H z,1H),7.00(t,J=7.7Hz,1H),6.82(d,J=1.8Hz,1H),6.58-6.49(m,2H),6. 33(d,J=7.7Hz,1H),5.75(brs,1H),5.12(s,2H),3.54(s,3H),2.17(s,3H).

[0398] 3-(8-(4-Fluoro-3-hydroxyphenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile (39)

[0399]

[0400] LCMS: in 0-60AB_7min chromatography (Xtimate 3um, C18, 2.1*30mm) R =3.081min, MS(ESI)m / z 424.1[M+H] + .

[0401] 1 H NMR: (400MHz, DMSO-d6)δ=10.02(br s,1H),8.80(s,1H),8.15(s,1H),8.07-8.01(m,1H),7.98(d,J=9.0Hz,1H),7.79(d,J=7.9Hz,1H),7.66(dd,J=2.0,8.8Hz,1H) ,7.11(dd,J=8.5,11.1Hz,1H),6.85(dd,J=2.2,8.4Hz,1H),6.75(d,J=1.8Hz,1H),6.59(ddd,J=2.3,4.0,8.4Hz,1H),5.80(br s,1H),3.51(s,3H),2.14(s,3H).

[0402] 3-(8-(3-amino-4-chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile (40)

[0403]

[0404] LCMS: in 0-60AB_7min_220&254 (Xtimate 3um, C18, 2.1*30mm) R =3.600min,MS(ESI)m / z 439.1[M+H] + .

[0405] 1H NMR (400MHz, DMSO-d6) δ = 9.37 (s, 1H), 9.02 (s, 2H), 8.36 (d, J = 1.8Hz, 1H), 8.29-8.21 (m, 2H), 7.98 (d, J = 8.2Hz, 1H), 7.89 ( dd,J=2.0,9.0Hz,1H),7.21(d,J=8.2Hz,1H),6.82(t,J=2.3Hz,2H),6.34(dd,J=2.3,8.3Hz,1H),3.94(s,3H),2.23(s,3H).

[0406] 3-(8-(3,4-Dimethoxyphenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile (41)

[0407]

[0408] LCMS: in 0-60AB_7MIN_220&254 chromatography (Xtimate 3um, C18, 2.1*30mm) R =3.333min, MS(ESI)m / z 450.1[M+H] + .

[0409] 1 H NMR: (400MHz, DMSO-d6) δ = 9.36 (s, 1H), 9.04 (br s,2H),8.41(d,J=1.5Hz,1H),8.30(dd,J=1.7,8.0Hz,1H),8.23(d,J=8.8Hz,1H),8.06(dd,J=2.0,8.8Hz,1H),7.96 (d,J=8.2Hz,1H),7.02(s,2H),6.89(d,J=1.8Hz,1H),6.75(s,1H),3.96(s,3H),3.79(d,J=4.4Hz,6H),2.23(s,3H).

[0410] 3-(8-(3,4-Dichlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile (42)

[0411]

[0412] LCMS: in 0-60AB_7MIN_220&254 chromatography (Xtimate 3um, C18, 2.1*30mm) R=4.328min, MS(ESI)m / z 458.0[M+H] + .

[0413] 1 H NMR: (400MHz, DMSO-d6) δ=9.41(s,1H),9.08(br s,2H),8.40(s,1H),8.31-8.25(m,2H),8.11(br d,J=9.0Hz,1H),7.96(br d,J=7.9Hz,1H),7.72(br d,J=8.2Hz,1H),7.48(br d,J=2.2Hz,1H),7.39(br dd,J=2.3,8.5Hz,1H),6.85(s,1H),3.95(s,3H),2.22(s,3H).

[0414] 3-(8-(3,4-Difluorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile (43)

[0415]

[0416] LCMS: in 0-60AB_7MIN_220&254 chromatography (Xtimate 3um, C18, 2.1*30mm) R =3.837min, MS(ESI)m / z 426.0[M+H] + .

[0417] 1 H NMR: (400MHz, DMSO-d6)δ=9.41(s,1H),9.09(s,2H),8.39(s,1H),8.31-8.24(m,2H),8.06( dd,J=1.9,8.9Hz,1H),7.96(d,J=8.2Hz,1H),7.57-7.49(m,1H),7.46-7.38(m,1H),7.16(br d,J=8.6Hz,1H),6.85(d,J=1.5Hz,1H),3.96(s,3H),2.23(s,3H).

[0418] 3-(8-(5-chloropyridin-2-yl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile (44)

[0419]

[0420] LCMS: in 0-60AB_7.0min chromatography (Xtimate, 2.1*30mm, 3um) R =3.610min,MS(ESI)m / z 425.0[M+H] + .

[0421] 1 H NMR: (400MHz, DMSO-d6): δ=9.91(s,2H),9.74(s,1H),8.55(s,1H),8.50-8.48(m,2H),8.42(s,1H),8.30(d,J=8.0H z,1H),8.01(d,J=7.2Hz,1H),7.94(d,J=8.0Hz,1H),7.76(d,J=8.4Hz,1H),7.58(s,1H),4.08(s,3H),2.22(s,3H).

[0422] 5-(8-(4-Chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)nicotinonitrile (45)

[0423]

[0424] LCMS: in 0-60AB_7min chromatography (Xtimate 3um, C18, 2.1*30mm) R =3.662min, MS(ESI)m / z 411.0[M+H] + .

[0425] 1 H NMR: (400MHz, DMSO-d6)δ=9.55(br s,2H),9.49(d,J=1.3Hz,1H),9.44(s,1H),9.37(d,J=2.0Hz,1H),9.00(s,1H),8.30(d,J=9.0Hz,1H) ,8.07(dd,J=1.5,9.0Hz,1H),7.50(d,J=8.6Hz,2H),7.39(d,J=8.4Hz,2H),6.97(s,1H),4.01(s,3H).

[0426] 5-(8-(4-Chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)nicotinamide (46)

[0427]

[0428] LCMS: in 0-60AB_7min chromatography (Xtimate 3um, C18, 2.1*30mm) R =3.181min, MS(ESI)m / z 429.0[M+H] + .

[0429] 1 H NMR: (400MHz, DMSO-d6) δ = 9.25 (s, 1H), 9.00 (d, J = 2.2Hz, 1H), 8.84 (s, 1H), 8.51 (s, 1H), 8.34 ( s,1H),8.03(d,J=9.0Hz,1H),7.85-7.76(m,2H),7.46-7.38(m,2H),7.36-7.28(m,2H),6.98(br s,1H),3.54(s,3H).

[0430] 5-(8-(4-Chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-6-methyl-2-(piperazin-1-yl)nicotinonitrile (47)

[0431]

[0432] LCMS: in 0-30AB_7.0min chromatography (Xtimate, 2.1*30mm, 3um) R =4.896min, MS(ESI)m / z 509.1[M+H] + .

[0433] 1 H NMR: (400MHz, DMSO-d6): δ = 9.78 (s, 2H), 9.52 (s, 2H), 9.44 (s, 1H), 8.61 (s, 1H), 8.32 (d, J = 9.2Hz, 1H), 8.13-8.10 (m, 1 H),7.58-7.56(m,2H),7.48-7.46(m,2H),7.22(s,1H),4.07-4.04(m,4H),3.99(s,3H),3.32-3.29(m,4H),2.28(s,3H).

[0434] 5-(8-(4-Chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-2-(piperazin-1-yl)nicotinonitrile (48)

[0435]

[0436] LCMS: in 0-60AB_7min chromatography (Xtimate 3um, C18, 2.1*30mm) R =3.867min, MS(ESI)m / z 495.2[M+H] + .

[0437] 5-(8-(4-Chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-2-(piperazin-1-yl)benzonitrile (49)

[0438]

[0439] LCMS: in 0-60AB_7min_220&254 (Xtimate 3um, C18, 2.1*30mm) R =3.044min, MS(ESI)m / z 494.2[M+H] + .

[0440] 1 H NMR (400MHz, DMSO-d6) δ=9.33(s,1H),9.14-8.94(m,4H),8.34(d,J=2.4Hz,1H),8.23(d,J=9.0Hz,1H),8.06(ddd,J=2.2,8.8,18.3H z,2H),7.64(d,J=9.0Hz,1H),7.53-7.46(m,2H),7.44-7.36(m,2H),7.04(d,J=2.0Hz,1H),3.91(s,3H),3.49-3.43(m,4H),3.38(br s,4H).

[0441] 5-(8-(4-Chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-2-morpholinonitrile (50)

[0442]

[0443] LCMS: in 0-60AB_7min chromatography (Xtimate 3um, C18, 2.1*30mm) R =3.865min, MS(ESI)m / z 496.0[M+H] + .

[0444] 1HNMR: (DMSO-d6 400MHz): δ=9.38(s,1H),9.23(s,1H),9.27-9.18(m,1H),8.84(d,J=2.5Hz,1H),8.67(d,J=2.8Hz,1H),8.29(d,J=8.8Hz,1H),8.10(br d,J=2.0Hz,1H),8.08(d,J=1.8Hz,1H),7.57-7.50(m,4H),7.30(d,J=1.8Hz,1H),3.97(s,3H),3.96-3.71(m,8H).

[0445] 5-(8-(4-Chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-2-morpholinobenzonitrile (51)

[0446]

[0447] LCMS: in 0-60AB_7min_220&254 (Xtimate 3um, C18, 2.1*30mm) R =4.089min, MS(ESI)m / z 495.1[M+H] + .

[0448] 1 H NMR (400MHz, DMSO-d6) δ=8.78(s,1H),8.10(br s,1H),7.99(d,J=9.0Hz,1H),7.87-7.82(m,1H),7.77(br d,J=8.6Hz,1H),7.43(br d,J=8.4Hz,3H),7.34(br d,J=8.4Hz,2H),7.02(br s,1H),3.82(br s,4H),3.49(s,3H),3.27-3.16(m,4H).

[0449] 3-(8-(5-chloropyrimidin-2-yl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile (52)

[0450]

[0451] LCMS: in 0-60AB_7.0min chromatography (Xtimate, 2.1*30mm, 3um) R =3.486min, MS(ESI)m / z 426.0[M+H] + .

[0452] 1 H NMR: (400MHz, DMSO-d6): δ = 9.43 (s, 1H), 9.22 (s, 2H), 8.91 (s, 2H), 8.56-8.54 (m, 1H), 8.35 (s,1H),8.29-8.26(m,2H),7.94-7.92(m,1H),7.90-7.89(m,1H),3.97(s,3H),2.18(s,3H).

[0453] 3-(8-(4-Chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methoxybenzonitrile (53)

[0454]

[0455] LCMS: in 0-60AB_7.0min chromatography (Xtimate, 2.1*30mm, 3um) R =3.982min, MS(ESI)m / z 440.0[M+H] + .

[0456] 1 H NMR: (400MHz, DMSO-d6): δ=8.78-8.76(m,1H),8.24-8.13(m,1H),7.99(d,J=9.2Hz,1H),7.77-7.74(m,1H),7 .56-7.54(m,1H),7.45(d,J=8.8Hz,2H),7.31(d,J=8.4Hz,2H),6.99-6.97(m,1H),3.73(s,3H),3.49(s,3H).

[0457] 3-(8-(4-Chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-(trifluoromethoxy)benzonitrile (54)

[0458]

[0459] LCMS: In 10-60AB_7.0min chromatography (Xtimate, 2.1*30mm, 3um) R =4.535min, MS(ESI)m / z 493.9[M+H] + .

[0460] 1H NMR: (400MHz, DMSO-d6): δ = 8.82 (s, 1H), 8.56 (s, 1H), 8.31 (s, 1H), 8.03-7.99 (m, 2H), 7. 80-7.77(m,1H),7.45(d,J=8.8Hz,2H),7.31(d,J=8.8Hz,2H),6.92(s,1H),3.51(s,3H).

[0461] (E)-1-(1-(5-cyano-2-methylphenyl)-8-(4-fluorophenyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-ylidene)urea(55)

[0462]

[0463] LCMS: in 10-80CD_7MIN_220&254 (XBrige Shield RP182.1*50mm, 5um) R =3.323min, MS(ESI)m / z 451.1[M+H] + .

[0464] 1 H NMR (400MHz, DMSO-d6) δ = 9.09 (s, 1H), 8.21 (s, 1H), 8.11 (d, J = 9.3Hz, 1H), 8.05 (d, J = 8.2Hz, 1H), 7.88 (d, J = 8.8Hz, 1H), 7.77(d,J=7.9Hz,1H),7.38-7.29(m,2H),7.28-7.19(m,2H),6.86(s,1H),6.50-5.54(m,2H),3.67(s,3H),2.17(s,3H).

[0465] (E)-1-(1-(5-cyano-2-methylphenyl)-8-(4-fluorophenyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-ylidene)guanidine (56)

[0466]

[0467] LCMS: in 10-80AB_7min_220&254 (Xtimate C18 2.1*30mm, 3um) R =2.564min, MS(ESI)m / z 450.0[M+H] + .

[0468] 1H NMR (400MHz, METHANOL-d4) δ = 9.22 (s, 1H), 8.24 (d, J = 9.0Hz, 1H), 8.10-8.07 (m, 1H), 8.06 (dd, J = 1.4, 7.8Hz, 1H), 8.01 (dd, J = 1. 9,8.7Hz,1H),7.82(d,J=8.2Hz,1H),7.39-7.32(m,2H),7.15(t,J=8.7Hz,2H),7.09(d,J=2.0Hz,1H),3.90(s,3H),2.27(s,3H).

[0469] 8-(4-Chlorophenyl)-3-methyl-1-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imine (57)

[0470]

[0471] LCMS: in 0-30AB_7min_220&254 (Xtimate 3um, C18, 2.1*30mm) R =4.299min, MS(ESI)m / z 476.0[M+H] + .

[0472] 1 H NMR (400MHz, DMSO-d6) δ=11.08(br s,1H),9.35(br d,J=15.1Hz,3H),8.50(s,1H),8.36(d,J=8.8Hz,1H),8.17(br d,J=8.8Hz,1H),8.00(d,J=8.5Hz,2H),7.64(d,J=8.5Hz,2H),5.79(br d,J=5.3Hz,1H),4.00-3.75(m,9H),3.62(br s,1H),3.51-3.18(m,6H),2.10(br d,J=10.8Hz,2H),1.86-1.71(m,2H).

[0473] 8-(4-Chlorophenyl)-3-methyl-1-(3-morpholinocyclobutyl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imine (58)

[0474]

[0475] LCMS: in 0-30AB_7min_220&254 (Xtimate 3um, C18, 2.1*30mm)R =4.483min, MS(ESI)m / z 448.0[M+H] + .

[0476] 1 H NMR (400MHz, DMSO-d6) δ = 11.90 (br s, 1H), 9.36 (s, 1H), 9.29 (br s,2H),8.38(d,J=1.5Hz,1H),8.32(d,J=8.8Hz,1H),8.15(dd,J=1.8,8.8Hz,1H),7.98(d,J=8.5Hz,2H),7.63(d,J=8.5 Hz,2H),5.55(quin,J=8.2Hz,1H),3.99-3.85(m,5H),3.78-3.60(m,3H),3.36-3.30(m,2H),3.26-3.11(m,4H),2.95(br d,J=10.8Hz,2H).

[0477] 8-(4-Chlorophenyl)-3-methyl-1-((1s,4s)-4-morpholinocyclohexyl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imine (59)

[0478]

[0479] LCMS: in 0-60AB_7min chromatography (Xtimate 3um, C18, 2.1*30mm) R =3.900min,MS(ESI)m / z 476.2[M+H] + .

[0480] 3-(2-Imino-3-methyl-8-(1-methyl-2,5-dihydro-1H-pyrrol-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile (60)

[0481]

[0482] LCMS: in 0-60AB_7.0min chromatography (Xtimate 3um, C18, 2.1*30mm) R =1.572min, MS(ESI)m / z 395.2[M+H] + .

[0483] 1H NMR (400MHz, DMSO-d6) δ = 10.81-10.58 (m, 1H), 9.39 (s, 1H), 9.12 (s, 2H), 8.34 (s, 1H), 8 .30-8.24(m,1H),8.21(d,J=9.0Hz,1H),8.02-7.92(m,2H),6.48-6.36(m,2H),4.46(br d,J=14.3Hz,1H),4.22-4.01(m,3H),3.95(s,3H),2.96(s,3H),2.22(s,3H).

[0484] 3-(2-Imino-3-methyl-8-(o-tolyl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile (61)

[0485]

[0486] LCMS: in 0-60AB_7MIN_220&254 chromatography (Xtimate 3um, C18, 2.1*30mm) R =3.678min, MS(ESI)m / z 404.1[M+H] + .

[0487] 1 H NMR: (400MHz, DMSO-d6) δ = 9.42 (s, 1H), 9.01 (br s,2H),8.36(d,J=1.5Hz,1H),8.26(d,J=8.6Hz,1H),8.20(dd,J=1.7,8.0Hz,1H),7.89(d,J=8.4Hz,1H),7.75(dd,J=2.0,8.8Hz, 1H),7.30-7.26(m,2H),7.26-7.21(m,1H),7.09(d,J=7.1Hz,1H),6.69(d,J=1.5Hz,1H),3.96(s,3H),2.22(s,3H),2.04(s,3H).

[0488] 3-(8-(2-chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile (62)

[0489]

[0490] LCMS: in 0-60AB_7.0min chromatography (Xtimate 3um, C18, 2.1*30mm) R=3.723min, MS(ESI)m / z 424.0[M+H] + .

[0491] 1 H NMR (400MHz, DMSO-d6) δ=9.69(s,1H),8.40(d,J=9.0Hz,1H),8.25(d,J=1.8Hz,1H),8.08(ddd,J=1.8,8.5,16.4Hz,2H),7.88 (d,J=8.2Hz,1H),7.54-7.47(m,1H),7.45-7.38(m,2H),7.37-7.31(m,1H),7.14(d,J=1.5Hz,1H),4.08(s,3H),2.34(s,3H).

[0492] 8-(4-Chlorophenyl)-3-methyl-1-phenyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imide (63)

[0493]

[0494] LCMS: in 0-60AB_7min_220&254 (Xtimate 3um, C18, 2.1*30mm) R =4.500min, MS(ESI)m / z 385.0[M+H] + .

[0495] 1 H NMR (400MHz, DMSO-d6) δ = 9.33 (s, 1H), 8.87 (s, 2H), 8.21 (d, J = 9.0Hz, 1H), 7.99 (dd, J = 2.1, 8.9Hz, 1H),7.89-7.82(m,4H),7.49-7.44(m,2H),7.32-7.28(m,2H),6.90(d,J=1.8Hz,1H),3.91(s,3H).

[0496] 8-(4-Chlorophenyl)-1-(3-methoxyphenyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imide (64)

[0497]

[0498] LCMS: in 0-60AB_7MIN_220&254 chromatography (Xtimate 3um, C18, 2.1*30mm) R =4.489min, MS(ESI)m / z 415.0[M+H]+ .

[0499] 1 H NMR: (400MHz, DMSO-d6) δ = 9.35 (s, 1H), 8.92 (s, 2H), 8.24 (d, J = 8.8Hz, 1H), 8.03 (dd, J = 2.1, 8.9Hz, 1H), 7.77 (t, J = 8 .2Hz,1H),7.53-7.49(m,3H),7.49-7.42(m,2H),7.39-7.35(m,2H),7.08(d,J=1.8Hz,1H),3.94(s,3H),3.86(s,3H).

[0500] 4-(8-(4-Chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-N-cyclopropylbenzamide (65)

[0501]

[0502] LCMS: in 0-60AB_7.0min chromatography (Xtimate, 2.1*30mm, 3um) R =3.792min, MS(ESI)m / z 468.1[M+H] + .

[0503] 1 H NMR: (400MHz, DMSO-d6): δ=8.79(s,1H),8.68(s,1H),8.10(d,J=8.4Hz,2H),7.97(s,1H),7.76-7.69(m,3H),7.33(d,J =8.4Hz,2H),7.24(d,J=8.8Hz,2H),6.84(s,1H),3.50(s,3H),2.93-2.92(m,1H),0.75-0.72(m,2H),0.62-0.60(m,2H).

[0504] 8-(4-Chlorophenyl)-3-methyl-1-(m-tolyl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imide (66)

[0505]

[0506] LCMS: in 0-60AB_7min_220&254 (Xtimate 3um, C18, 2.1*30mm) R =4.154min, MS(ESI)m / z 399.0[M+H]+ .

[0507] 1 H NMR (400MHz, DMSO-d6) δ = 9.32 (s, 1H), 8.89 (s, 2H), 8.20 (d, J = 9.0Hz, 1H), 8.00 (dd, J = 2.1, 8.9Hz, 1H), 7.74-7.67 (m,3H),7.66-7.59(m,1H),7.52-7.44(m,2H),7.36-7.28(m,2H),6.98(d,J=1.8Hz,1H),3.91(s,3H),2.49(s,3H).

[0508] 1-(3-(8-(4-chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-N-methylmethanamine (67)

[0509]

[0510] LCMS: in 0-60AB_7min_220&254 (Xtimate C18 2.1*30mm, 3um) R =2.861min, MS(ESI)m / z 427.9[M+H] + .

[0511] 1 H NMR (400MHz, DMSO-d6) δ = 9.37 (s, 1H), 9.32-9.15 (m, 2H), 9.02 (br s,2H),8.25(d,J=9.0Hz,1H),8.03(dd,J=1.6,8.9Hz,1H),8.00-7.88(m,4H),7.51(d,J=8.5Hz,2H ),7.35(d,J=8.5Hz,2H),6.99(d,J=1.3Hz,1H),4.40-4.25(m,2H),3.96(s,3H),2.58-2.53(m,3H).

[0512] 2-(8-(4-Chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)benzonitrile (68)

[0513]

[0514] LCMS: in 0-60AB_7min_220&254 chromatography (Xtimate, 2.1*30mm, 3um) R=3.965min, MS(ESI)m / z 409.9[M+H] + .

[0515] 1 H NMR: (400MHz, DMSO-d6) δ=10.15(br s,1H),9.91(br s,1H),9.61(s,1H),8.79(br d,J=7.8Hz,1H),8.58(br d,J=5.3Hz,1H),8.50(br s,1H),8.35(br d,J=8.8Hz,1H),8.21(br t,J=7.7Hz,1H),8.12(br d,J=8.3Hz,1H),7.90(br t,J=7.5Hz,1H),7.77(br s,2H),7.57(br d,J=7.8Hz,2H),4.08(s,3H).

[0516] 3-(8-(4-Chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylbenzonitrile (69)

[0517]

[0518] LCMS: in 0-60AB_7.0min chromatography (Xtimate, 2.1*30mm, 3um) R =4.062min, MS(ESI)m / z 424.0[M+H] + .

[0519] 1 H NMR: (400MHz, DMSO-d6): δ = 8.82 (s, 1H), 8.11 (s, 1H), 8.01 (s, 1H), 7.90-7.89 (m, 1H), 7.78-7.75 (m, 1H) ,7.74-7.68(m,1H),7.43(d,J=8.4Hz,2H),7.27(d,J=8.8Hz,2H),6.79(s,1H),3.52(s,3H),2.28(s,3H).

[0520] 5-(8-(4-Chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylbenzonitrile (70)

[0521]

[0522] LCMS: in 0-60AB_7min chromatography (Xtimate 3um, C18, 2.1*30mm) R =4.081min, MS(ESI)m / z 424.1[M+H] + .

[0523] 1 H NMR (400MHz, DMSO-d6) δ = 9.36 (s, 1H), 9.00 (s, 2H), 8.42 (d, J = 2.21Hz, 1H), 8.26 (d, J = 9.04Hz, 1H), 8.13 (dd, J = 8.16, 2.21Hz, 1H), 8.06 ( dd,J=8.93,2.09Hz,1H),7.97(d,J=8.16Hz,1H),7.51-7.55(m,2H),7.35-7.39(m,2H),6.99(d,J=1.98Hz,1H),3.94(s,3H),2.75(s,3H).

[0524] 3-(8-(4-Chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-5-methylbenzonitrile (71)

[0525]

[0526] LCMS: in 0-60AB_7min chromatography (Xtimate 3um, C18, 2.1*30mm) R =4.664min, MS(ESI)m / z 424.0[M+H] + .

[0527] 1 H NMR (400MHz, DMSO) δ = 9.52 (s, 1H), 8.34 (d, J = 9.2Hz, 1H), 8.29 (s, 1H), 8.23 (s, 1H), 8.13-8.09 (m, 2H),7.51(d,J=8.8Hz,2H),7.36(d,J=8.8Hz,2H),7.04(d,J=2.0Hz,1H),4.03(s,3H),2.54(s,3H).

[0528] 8-(4-Chlorophenyl)-3-methyl-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imide (72)

[0529]

[0530] LCMS: in 0-60AB_7min_220&254 (Xtimate 3um, C18, 2.1*30mm) R =3.819min, MS(ESI)m / z 537.0[M+H] + .

[0531] 1 H NMR (400MHz, DMSO-d6) δ = 9.36 (s, 1H), 9.03 (s, 2H), 8.98-8.26 (m, 4H), 8.21 (d, J = 8.8Hz, 1H), 8.05 (dd, J = 2.0, 8.8Hz, 1H), 7.97 (d, J =8.6Hz,1H),7.48(d,J=8.6Hz,2H),7.35(d,J=8.4Hz,2H),6.92(d,J=2.0Hz,1H),3.94(s,3H),3.35-3.30(m,4H),3.23-3.20(m,4H).

[0532] 2-(3-(8-(4-chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)acetonitrile (73)

[0533]

[0534] LCMS: in 0-60AB_7min_220&254 (Xtimate C18 2.1*30mm, 3um) R =4.025min, MS(ESI)m / z 424.0[M+H] + .

[0535] 1 H NMR (400MHz, DMSO-d6) δ = 9.33 (s, 1H), 8.90 (s, 2H), 8.22 (d, J = 8.8Hz, 1H), 8.01 (dd, J = 2.0, 8.8Hz, 1H), 7 .92-7.77(m,4H),7.51-7.46(m,2H),7.37-7.32(m,2H),6.91(d,J=1.8Hz,1H),4.30(s,2H),3.91(s,3H).

[0536] 1-(3-(8-(4-chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)ethan-1-one (74)

[0537]

[0538] LCMS: in 0-60AB_7min_220&254 (Xtimate C18 2.1*30mm, 3um) R =3.727min, MS(ESI)m / z 426.9[M+H] + .

[0539] 1 H NMR (400MHz, DMSO-d6) δ = 9.34 (s, 1H), 8.96 (s, 2H), 8.47-8.40 (m, 2H), 8.22 (d, J = 9.0Hz, 1H), 8.16-8.10 (m, 1 H),8.03-7.95(m,2H),7.48-7.41(m,2H),7.32-7.24(m,2H),6.93(d,J=1.8Hz,1H),3.92(s,3H),2.67(s,3H).

[0540] 8-(4-Chlorophenyl)-3-methyl-1-(3-(methylsulfonyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imide (75)

[0541]

[0542] LCMS: in 0-60AB_7min_220&254 (Xtimate 3um, C18, 2.1*30mm) R =3.563min, MS(ESI)m / z 462.9[M+H] + .

[0543] 1 H NMR (400MHz, DMSO-d6) δ = 9.39 (s, 1H), 9.21 (s, 2H), 8.52 (t, J = 1.8Hz, 1H), 8.42 (td, J = 1.2, 8.2Hz, 1H), 8.25 (d, J = 9.0Hz, 1H), 8.23-8.20 (m, 1H),8.11-8.06(m,1H),8.03(dd,J=2.1,8.9Hz,1H),7.46-7.42(m,2H),7.33-7.29(m,2H),6.85(d,J=1.8Hz,1H),3.95(s,3H),3.31(s,3H).

[0544] 8-(4-Chlorophenyl)-3-methyl-1-(3-(piperazin-1-yl)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imide (76)

[0545]

[0546] LCMS: in 0-60AB_7min chromatography (Xtimate 3um, C18, 2.1*30mm) R =3.965min, MS(ESI)m / z 469.0[M+H] + .

[0547] 1 H NMR: (400MHz, DMSO-d6) δ = 9.31 (s, 1H), 9.08-8.97 (m, 2H), 8.93 (s, 2H), 8.20 (d, J = 8.8Hz, 1H), 8.00 (dd, J = 2.1, 8.9Hz, 1H), 7.70-7.63(m,1H),7.52-7.43(m,3H),7.35(d,J=8.6Hz,2H),7.28-7.22(m,1H),7.04(d,J=1.8Hz,1H),3.91(s,3H),3.44(br t,J=5.0Hz,4H),3.24(br s,4H).

[0548] 3-(8-(4-Chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)benzenesulfonamide (77)

[0549]

[0550] LCMS: in 0-60AB_7min_220&254 (Xtimate 3um, C18, 2.1*30mm) R =3.416min, MS(ESI)m / z 463.9[M+H] + .

[0551] 1 H NMR (400MHz, DMSO-d6) δ=9.32(s,1H),8.96(s,2H),8.34(s,1H),8.23(dd,J=8.4,17.4Hz ,2H),8.08-8.04(m,1H),8.03-7.96(m,2H),7.80(s,2H),7.45(d,J=8.6Hz,2H),7.35(br d,J=8.4Hz,2H),6.85(s,1H),3.89(s,3H).

[0552] 8-(4-Chlorophenyl)-1-(3-fluorophenyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imide (78)

[0553]

[0554] LCMS: in 0-60AB_7min_220&254 (Xtimate 3um, C18, 2.1*30mm) R =4.048min, MS(ESI)m / z 403.0[M+H] + .

[0555] 1 H NMR (400MHz, DMSO-d6) δ = 9.32 (s, 1H), 8.95 (s, 2H), 8.22 (d, J = 8.8Hz, 1H), 8.00 (dd, J = 2.0, 8.8Hz, 1H), 7.92 -7.83(m,2H),7.78-7.70(m,2H),7.52-7.44(m,2H),7.37-7.29(m,2H),6.98(d,J=1.8Hz,1H),3.90(s,3H).

[0556] 3-(8-(4-Chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenol(79)

[0557]

[0558] LCMS: in 5-95AB_1.5MIN_220&254 chromatography (RP-18e, 25-2 mm) R =0.717min,MS(ESI)m / z 399.0[M+H] + .

[0559] 1 H NMR: (400MHz, DMSO-d6)δ=10.42(br s,1H),9.33(s,1H),8.90(br s,2H),8.23(d,J=8.8Hz,1H),8.02(dd,J=2.1,8.9Hz,1H),7.65(t,J=8.0Hz,1H),7.53-7.48(m,2 H),7.42-7.37(m,2H),7.29-7.24(m,2H),7.23-7.21(m,1H),7.12(d,J=1.8Hz,1H),3.92(s,3H).

[0560] 8-(4-Chlorophenyl)-1-(2-fluorophenyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imide (80)

[0561]

[0562] LCMS: in 0-60AB_7MIN_220&254 chromatography (Xtimate 3um, C18, 2.1*30mm) R =3.975min, MS(ESI)m / z 403.0[M+H] + .

[0563] 1 H NMR: (400MHz, DMSO-d6) δ=8.83(br s,1H),8.03(br d,J=9.0Hz,1H),7.80(brd,J=8.6Hz,3H),7.65(br d,J=9.5Hz,1H),7.56(br d,J=7.1Hz,1H),7.46(br d,J=8.4Hz,2H),7.32(br d,J=8.4Hz,2H),7.04(br s,1H),3.55(s,3H).

[0564] 8-(4-Chlorophenyl)-3-methyl-1-(o-tolyl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imide (81)

[0565]

[0566] LCMS: in 0-60AB_7min_220&254 (Xtimate 3um, C18, 2.1*30mm) R =3.944min, MS(ESI)m / z 398.9[M+H] + .

[0567] 1 H NMR (400MHz, DMSO-d6) δ = 9.34 (s, 1H), 8.96 (s, 2H), 8.21 (d, J = 8.8Hz, 1H), 7.99 (dd, J = 2.1, 8.9Hz, 1H), 7.79-7.69 (m,3H),7.65-7.59(m,1H),7.48-7.42(m,2H),7.31-7.25(m,2H),6.81(d,J=1.8Hz,1H),3.92(s,3H),2.11(s,3H).

[0568] 8-(4-Chlorophenyl)-1-(2-methoxyphenyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imide (82)

[0569]

[0570] LCMS: in 0-60AB_7min_220&254 (Xtimate 3um, C18, 2.1*30mm) R =4.626min, MS(ESI)m / z 414.9[M+H] + .

[0571] 1 H NMR (400MHz, DMSO-d6) δ = 9.30 (s, 1H), 8.96 (s, 2H), 8.20 (d, J = 9.0Hz, 1H), 8.00 (dd, J = 2.1, 8.9Hz, 1H), 7.87-7.82 (m, 1H), 7.78 (dd ,J=1.5,7.7Hz,1H),7.51(d,J=7.7Hz,1H),7.49-7.45(m,2H),7.37-7.30(m,3H),7.01(d,J=1.8Hz,1H),3.92(s,3H),3.73(s,3H).

[0572] 2-(8-(4-Chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenol (83)

[0573]

[0574] LCMS: in 0-60AB_7min_220&254 (Xtimate 3um, C18, 2.1*30mm) R =3.838min, MS(ESI)m / z 401.9[M+H] + .

[0575] 1 H NMR(400MHz,DMSO-d6)δ=10.37(br s,2H),9.26(s,1H),8.23-8.17(m,1H),8.11(dd,J=1.8,9.0Hz,1H),7.61-7.47(m,4 H),7.40-7.35(m,3H),7.23-7.18(m,1H),7.12(dt,J=1.1,7.6Hz,1H),3.65(s,3H).

[0576] 5-(8-(4-Chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-2-methoxybenzonitrile (84)

[0577]

[0578] LCMS: in 5-95AB_1.5MIN_220&254 chromatography (RP-18e, 25-2 mm) R =0.682min,MS(ESI)m / z 400.0[M+H] + .

[0579] 1 H NMR: (400MHz, DMSO-d6) δ = 9.36 (s, 1H), 8.98 (s, 2H), 8.38 (d, J = 2.6Hz, 1H), 8.26 (d, J = 9.0Hz, 1H), 8.21 (dd, J = 2.6, 9.0Hz, 1H), 8.05 ( dd,J=2.1,8.9Hz,1H),7.74(d,J=9.0Hz,1H),7.54-7.50(m,2H),7.45-7.40(m,2H),7.09(d,J=1.8Hz,1H),4.13(s,3H),3.93(s,3H).

[0580] 8-(4-Chlorophenyl)-3-methyl-1-(3-(piperazin-1-ylmethyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imide (85)

[0581]

[0582] LCMS: in 0-60AB_7min_220&254 (Xtimate C18 2.1*30mm, 3um) R =2.995min, MS(ESI)m / z 483.0[M+H] + .

[0583] 1H NMR (400MHz, DMSO-d6) δ=9.33(s,1H),9.27-8.86(m,4H),8.22(d,J=8.8Hz,1H),7.99(dd,J=2.1,8.9Hz,1H),7.92-7.81(m,4H),7 .53-7.43(m,2H),7.31-7.25(m,2H),6.89(d,J=1.8Hz,1H),4.06-4.03(m,2H),3.93(s,3H),3.14-3.02(m,4H),2.95-2.82(m,4H).

[0584] 3-(8-(2-Hydroxyphenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile (86)

[0585]

[0586] LCMS: in 0-60AB_7.0min chromatography (Xtimate 3um, C18, 2.1*30mm) R =3.101min, MS(ESI)m / z 406.1[M+H] + .

[0587] 1 H NMR (400MHz, DMSO-d6) δ = 9.61 (s, 1H), 9.36 (s, 1H), 8.95 (s, 2H), 8.33 (d, J = 1.5Hz, 1H), 8.19 (d, J = 8.8Hz, 2H), 7.95 (dd, J = 1.9, 8.9Hz, 1 H),7.88(d,J=8.2Hz,1H),7.21-7.13(m,1H),7.11-7.04(m,2H),6.92(d,J=7.3Hz,1H),6.84(t,J=7.4Hz,1H),3.95(s,3H),2.23(s,3H).

[0588] Methyl (E)-(8-(4-chlorophenyl)-1-(5-cyano-2-methylphenyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-ylidene)carbamate (87)

[0589]

[0590] LCMS: in 5-95AB_1.5min chromatography (RP-18e, 25-2mm) R =0.691min,MS(ESI)m / z482.1[M+H]+ .

[0591] 1 H NMR (400 MHz, CHLOROFORM-d) δ = 8.98 (s, 1H), 8.25 (d, J = 9.04 Hz, 1H), 7.82-7.87 (m, 2H), 7.80 (s, 1H), 7.64 (br d, J = 7.94 Hz, 1H), 7.35-7.41 (m, 2H), 7.17-7.22 (m, 2H), 6.98 (d, J = 1.76 Hz, 1H), 3.83 (s, 3H), 3.56 (s, 3H), 2.27 (s, 3H).

[0592] Tert-butyl (E)-(8-(4-chlorophenyl)-1-(5-cyano-2-methylphenyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-ylidene)carbamate (88)

[0593]

[0594] LCMS: in 0-60AB_2min chromatography (XBridge Shield 2.1*50mm) R =1.586min, MS(ESI)m / z 524.3[M+H] + .

[0595] 1 H NMR (400 MHz, CHLOROFORM-d) δ = 8.93 (s, 1H), 8.23 (d, J = 8.8 Hz, 1H), 7.84-7.82 (m, 2H), 7.81-7.79 (m, 1H), 7.62 (d, J = 7.5 Hz, 1H), 7.40-7.36 (m, 2H), 7.22-7.19 (m, 2H), 7.01 (d, J = 1.5 Hz, 1H), 3.80 (s, 3H), 2.31 (s, 3H), 1.29 (s, 9H).

[0596] Butyl (E)-(8-(4-chlorophenyl)-1-(5-cyano-2-methylphenyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-ylidene)carbamate (89)

[0597]

[0598] LCMS: in 0-60AB_7min chromatography (Xtimate 3um, C18, 2.1*30mm) R =5.934min, MS(ESI)m / z 524.1[M+H] +.

[0599] 1 H NMR (400MHz, chloroform-d) δ = 8.96 (s, 1H), 8.24 (d, J = 8.8Hz, 1H), 7.85-7.83 (m, 1H) ,7.83-7.82(m,1H),7.81-7.80(m,1H),7.63(d,J=7.9Hz,1H),7.39-7.36(m, 2H),7.22-7.19(m,2H),7.00(d,J=2.0Hz,1H),3.93-3.83(m,2H),3.82(s,3H ), 2.29 (s, 3H), 1.54-1.48 (m, 2H), 1.36-1.29 (m, 2H), 0.90 (t, J = 7.3Hz, 3H).

[0600] 4-(8-(4-Chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)picolinonitrile (90)

[0601]

[0602] LCMS: in 0-60AB_7min_220&254 (Xtimate 3um, C18, 2.1*30mm) R =3.708min, MS(ESI)m / z 410.9[M+H] + .

[0603] 1 H NMR (400MHz, DMSO-d6) δ = 9.40 (s, 1H), 9.25 (d, J = 5.3Hz, 1H), 9.15 (br s,2H),8.72(d,J=1.5Hz,1H),8.37(dd,J=1.8,5.3Hz,1H),8.29(d,J=8.8Hz,1H),8.06( dd,J=1.6,8.9Hz,1H),7.56-7.49(m,2H),7.49-7.44(m,2H),7.13(s,1H),3.95(s,3H).

[0604] 3-(2-Imino-3-methyl-8-(pyridin-2-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile (91)

[0605]

[0606] LCMS: in 0-60AB_7.0min chromatography (Xtimate, 2.1*30mm, 3um) R =2.970min, MS(ESI)m / z 390.9[M+H] + .

[0607] 1 H NMR: (400MHz, DMSO-d6): δ = 8.82 (s, 1H), 8.53-8.52 (m, 1H), 8.15-8.13 (m, 3H), 8.02-8. 00(m,1H),7.81-7.79(m,2H),7.47-7.44(m,2H),7.29(s,1H),3.53(s,3H),2.13(s,3H).

[0608] 3-(8-(4-Chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzamide (92)

[0609]

[0610] LCMS: in 0-60AB_7.0min chromatography (Xtimate, 2.1*30mm, 3um) R =3.497min, MS(ESI)m / z 441.9[M+H] + .

[0611] 1 H NMR: (400MHz, DMSO-d6): δ = 8.81 (s, 1H), 8.10-8.08 (m, 2H), 8.02-7.98 (m, 2H), 7.76-7.73 (m, 1H), 7.67-7.6 5(m,1H),7.48(s,1H),7.38(d,J=8.8Hz,2H),7.22(d,J=8.4Hz,2H),6.82(s,1H),3.53(s,3H),2.10(s,3H).

[0612] 3-(8-(4-Chlorophenyl)-3-ethyl-2-imino-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile (93)

[0613]

[0614] LCMS: in 0-60AB_7min chromatography (Xtimate 3um, C18, 2.1*30mm) R=4.087min, MS(ESI)m / z 438.0[M+H] + .

[0615] 1 H NMR: (400MHz, DMSO-d6) δ = 9.47 (s, 1H), 9.36-9.25 (m, 2H), 8.43 (d, J = 1.5Hz, 1H), 8.31-8.21 (m, 2H), 8.06 (dd, J = 2.0, 9.0Hz, 1H), 7.92 (d, J =8.2Hz,1H),7.48(d,J=8.4Hz,2H),7.32(d,J=8.6Hz,2H),6.84(d,J=2.0Hz,1H),4.54(q,J=7.1Hz,2H),2.19(s,3H),1.45(t,J=7.2Hz,3H).

[0616] 3-(3-Benzyl-8-(4-chlorophenyl)-2-imino-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile (94)

[0617]

[0618] LCMS: in 0-60AB_7min chromatography (Xtimate 3um, C18, 2.1*30mm) R =4.593min, MS(ESI)m / z 500.0[M+H] + .

[0619] 1 H NMR: (400MHz, DMSO-d6)δ=9.56(br s,2H),9.22(s,1H),8.57(d,J=1.5Hz,1H),8.28(dd,J=1.8,7.9Hz,1H),8.23(d,J=8.8Hz,1H),8.05(dd,J=2.0,8.8Hz,1H),7.95(d,J=8.2H z,1H),7.53-7.47(m,4H),7.46-7.40(m,2H),7.40-7.36(m,1H),7.35-7.31(m,2H),6.86(d,J=1.8Hz,1H),5.93-5.81(m,2H),2.23(s,3H).

[0620] 3-(8-(4-chlorophenyl)-3-(2-hydroxyethyl)-2-imino-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile (95)

[0621]

[0622] LCMS: in 0-60AB_7min chromatography (Xtimate 3um, C18, 2.1*30mm) R =4.707min, MS(ESI)m / z 454.1[M+H] + .

[0623] 8-(4-Chlorophenyl)-3-methyl-1-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imide (96)

[0624]

[0625] LCMS: in 0-60AB_7min chromatography (Xtimate 3um, C18, 2.1*30mm) R =4.703min, MS(ESI)m / z 475.2[M+H] + .

[0626] 1-([1,4'-Bipiperidinyl]-4-yl)-8-(4-chlorophenyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imide (97)

[0627]

[0628] LCMS: in 0-30AB_7min_220&254 (Xtimate 3um, C18, 2.1*30mm) R =3.555min, MS(ESI)m / z 475.1[M+H] + .

[0629] 1H NMR (400MHz, DMSO-d6) δ = 11.32 (br s, 1H), 9.41-9.24 (m, 4H), 9.16 (br d,J=9.0Hz,1H),8.50(s,1H),8.36(d,J=8.8Hz,1H),8.16(dd,J=1.5,8.8Hz,1H),8.00(d,J=8 .6Hz,2H),7.63(d,J=8.6Hz,1H),7.68-7.58(m,1H),5.85-5.68(m,1H),3.88(s,3H),3.71(br s,2H),3.53-3.42(m,6H),3.29(br d,J=11.9Hz,2H),2.97(br d, J=11.9 Hz, 2H), 2.39

[0630] -2.27(m,2H),2.18-1.94(m,2H).

[0631] 8-(4-Chlorophenyl)-3-methyl-1-(3-(piperazin-1-yl)cyclobutyl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imide (98)

[0632]

[0633] LCMS: in 0-30AB_7min_220&254 (Xtimate 3um, C18, 2.1*30mm) R =4.189min, MS(ESI)m / z 447.1[M+H] + .

[0634] 1 H NMR (400MHz, DMSO-d6) δ = 9.63 (br s, 2H), 9.33 (s, 1H), 9.25 (br s,2H),8.36(s,1H),8.30(d,J=8.8Hz,1H),8.14(dd,J=1.8,9.0Hz,1H),8.17-8.08(m,1H),7.98(d,J=8.5Hz,2H),7.63(d,J=8.5Hz,2H),5.50(br t,J=7.8Hz,1H),3.89(s,5H),3.69-3.34(m,4H),3.33-2.91(m,7H).

[0635] 8-(4-Chlorophenyl)-1-(2,6-dimethylphenyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imide (99)

[0636]

[0637] LCMS: in 0-60AB_7min_220&254 chromatography (Xtimate, 2.1*30mm, 3um) R =4.643min, MS(ESI)m / z 412.9[M+H] + .

[0638] 1 H NMR: (400MHz, DMSO-d6) δ = 9.37 (s, 1H), 9.07 (s, 2H), 8.23 (d, J = 9.0Hz, 1H), 8.02 (dd, J = 2.0, 9.0Hz, 1H), 7 .72-7.62(m,1H),7.55-7.42(m,4H),7.33-7.24(m,2H),6.81(d,J=1.8Hz,1H),3.96(s,3H),2.03(s,6H).

[0639] (8-(4-chlorophenyl)-1-(5-cyano-2-methylphenyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-ylidene)sulfonamide

[0640]

[0641] LCMS: in 0-60AB_7min chromatography (Xtimate 3um, C18, 2.1*30mm) R =4.374min, MS(ESI)m / z 502.9[M+H] + .

[0642] 1 H NMR (400MHz, DMSO-d6) δ = 9.21 (s, 1H), 8.27 (d, J = 1.8Hz, 1H), 8.19 (d, J = 8.8Hz, 1H), 8.13 (dd, J = 1.7, 8.0Hz, 1H), 7.98 (dd, J = 2.0, 8. 8Hz,1H),7.82(d,J=8.2Hz,1H),7.52-7.49(m,2H),7.34-7.31(m,2H),6.82(d,J=1.5Hz,1H),6.51(s,2H),4.08(s,3H),2.17(s,3H).

[0643] (8-(6-aminopyridin-3-yl)-1-(5-cyano-2-methylphenyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-ylidene)sulfonamide

[0644]

[0645] LCMS: in 10-80CD_7MIN_220&254 (XBrige Shield RP182.1*50mm) R =2.309min, MS(ESI)m / z 485.1[M+H] + .

[0646] 1 H NMR (400MHz, DMSO-d6) δ = 9.14 (s, 1H), 8.28 (d, J = 1.5Hz, 1H), 8.16-8.07 (m, 2H), 7.90 (dd, J = 1.9, 8.9Hz, 1H), 7.86-7.7 9(m,2H),7.38(dd,J=2.5,8.7Hz,1H),6.72(d,J=2.0Hz,1H),6.53-6.42(m,3H),6.25(s,2H),4.07(s,3H),2.17(s,3H).

[0647] 8-(4-Chlorophenyl)-1-cyclohexyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imide (102)

[0648]

[0649] LCMS: in 0-60AB_7min_220&254 chromatography (Xtimate, 2.1*30mm, 3um) R =4.231min, MS(ESI)m / z 391.0[M+H] + .

[0650] 1 H NMR (400MHz, DMSO-d6) δ = 9.26 (s, 1H), 9.00 (br s,2H),8.61-8.31(m,1H),8.27(d,J=8.8Hz,1H),8.06(dd,J=1.8,8.8Hz,1H),7.83(d,J=8.4Hz,2H),7.68-7.59(m,2H),4.94(br s,1H),3.85(s,3H),2.48-2.38(m,2H),2.13-1.91(m,4H),1.74(br d,J=11.0Hz,1H),1.56(q,J=12.8Hz,2H),1.46-1.33(m,1H).

[0651] 3-(2-Imino-8-(6-methoxypyridin-3-yl)-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile (103)

[0652]

[0653] LCMS: in 0-60AB_7min_220&254 (Xtimate 3um, C18, 2.1*30mm) R =3.078min, MS(ESI)m / z 421.0[M+H] + .

[0654] 1 H NMR (400MHz, DMSO-d6) δ = 8.84 (s, 1H), 8.19 (br s, 1H), 8.10 (br d,J=2.6Hz,2H),8.03(d,J=9.0Hz,1H),7.87-7.76(m,3H),7.61(dd,J=2.5,8.7Hz,1H),6.86(d,J=8.6Hz,1H),6.80(br d,J=1.5Hz,1H),3.88(s,3H),3.55(s,3H),2.18(s,3H).

[0655] 1-(4-(8-(4-chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)propan-1-one (104)

[0656]

[0657] LCMS: in 0-60AB_7min_220&254 (Xtimate 3um, C18, 2.1*30mm) R =3.816min, MS(ESI)m / z 448.0[M+H] + .

[0658] 1H NMR (400MHz, DMSO-d6) δ=8.74-8.66(m,1H),8.34(br s,1H),8.06(d,J=8.8Hz,1H),7.85(br d,J=9.0Hz,1H),7.78(br s,2H),7.62-7.50(m,2H),5.85(br s,1H),5.18(s,1H),4.79-4.60(m,1H),4.17-3.97(m,1H),3.49-3.42(m,3H),3.26(br s,1H),3.21(br d,J=11.5Hz,1H),2.83-2.64(m,2H),2.44-2.26(m,2H),1.95-1.80(m,2H),1.07-0.91(m,3H).

[0659] 3-(2-Imino-3-methyl-8-(quinolin-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile (105)

[0660]

[0661] LCMS: in 10-80AB_7min_220&254 (Xtimate 3um, C18, 2.1*30mm) R =2.312min, MS(ESI)m / z 441.0[M+H] + .

[0662] 1 H NMR (400MHz, DMSO-d6) δ = 9.41 (s, 1H), 9.05 (s, 2H), 8.78 (d, J = 2.4Hz, 1H), 8.40-8.39 (m, 2H), 8.34-8.30 (m, 2H), 8.27-8.24 (m, 1H) ,8.04(d,J=8.0Hz,1H),8.01-7.96(m,2H),7.82-7.78(m,1H),7.70-7.66(m,1H),7.05(d,J=2.0Hz,1H),3.94(s,3H),2.24(s,3H).

[0663] 3-(8-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile (106)

[0664]

[0665] LCMS: in 0-60AB_7min_220&254 chromatography (Xtimate C18 2.1*30mm, 3um) R =2.470min, MS(ESI)m / z 492.1[M+H] + .

[0666] 1 H NMR: (400MHz, DMSO-d6)δ=10.82(br s,1H),9.69-9.55(m,3H),8.43-8.35(m,2H),8.25(dd,J=1.5,7.9Hz,1H),8.16(dd, J=2.0,9.0Hz,1H),8.11(d,J=2.4Hz,1H),7.93(d,J=8.2Hz,1H),7.66(dd,J=2.6,8.6 Hz,1H),6.89(d,J=8.6Hz,1H),6.84(d,J=1.5Hz,1H),4.33(t,J=6.2Hz,2H),4.07-3. 95(m,3H),3.19-3.14(m,2H),2.73(d,J=4.9Hz,6H),2.22(s,3H),2.23-2.10(m,2H).

[0667] 3-(2-Imino-8-(1H-indazol-5-yl)-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile (107)

[0668]

[0669] LCMS: in 0-60AB_7min_220&254 (Xtimate 3um, C18, 2.1*30mm) R =2.881min, MS(ESI)m / z 430.0[M+H] + .

[0670] 1 H NMR (400MHz, DMSO-d6): δ = 13.16 (br s, 1H), 8.80 (br s, 1H), 8.25 (br s,1H),8.16-8.06(m,2H),8.01(d,J=9.0Hz,1H),7.87-7.78(m,2H),7.68(s,1H),7.53 (d,J=8.6Hz,1H),7.24(dd,J=1.7,8.7Hz,1H),6.86(s,1H),3.54(s,3H),2.16(s,3H).

[0671] 5-(8-(4-Chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methyl-2-(4-methylpiperazin-1-yl)benzonitrile (108)

[0672]

[0673] LCMS: in 0-60AB_7min chromatography (Xtimate 3um, C18, 2.1*30mm) R =3.099min, MS(ESI)m / z 522.1[M+H] + .

[0674] 1 H NMR:(DMSO-d6 400MHz): δ=9.39(s,1H),9.22(s,2H),8.28(s,1H),8.26(s,1H),8.08(dd,J=2.1,8.9Hz,1H),7.61(s,1H),7.54(d,J= 8.6Hz,2H),7.39(d,J=8.8Hz,2H),7.00(d,J=1.8Hz,1H),3.97(s,3H),3.77-3.65(m,2H),3.64-3.55(m,2H),3.36(br d,J=12.1Hz,2H),3.33-3.23(m,2H),2.88(d,J=4.2Hz,3H),2.16(s,3H).

[0675] 2-(4-Acetylpiperazin-1-yl)-5-(8-(4-chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile (109)

[0676]

[0677] LCMS: in 0-60AB_7min chromatography (Xtimate 3um, C18, 2.1*30mm) R =3.929min, MS(ESI)m / z 551.0[M+H] + .

[0678] 1H NMR:(DMSO-d6 400MHz): δ=9.04(s,1H),8.14(s,1H),8.12(s,1H),8.09(s,1H),7.92(dd,J=2.0,9.0Hz,1H),7.5 1-7.47(m,2H),7.41-7.38(m,3H),7.06(d,J=1.8Hz,1H),3.73-3.68(m,4H),3.63(s,3H),3.39(br s,4H),2.12(s,3H),2.11(s,3H).

[0679] 2-(Azetidin-1-yl)-5-(8-(4-chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile (110)

[0680]

[0681] LCMS: in 0-60AB_7min_220&254 (Xtimate C18 2.1*30mm, 3um) R =4.295min, MS(ESI)m / z 479.0[M+H] + .

[0682] 1 H NMR (400MHz, DMSO-d6) δ = 9.36 (s, 1H), 9.03 (s, 2H), 8.26 (d, J = 8.8Hz, 1H), 8.08 (dd, J = 2.0, 8.8Hz, 1H), 7.98 (s, 1H), 7.58 (d, J = 8.5Hz, 2H),7.48(d,J=7.9Hz,2H),7.10(d,J=2.0Hz,1H),6.85(s,1H),4.30(sxt,J=8.1Hz,4H),3.94(s,3H),2.55-2.52(m,2H),2.06(s,3H).

[0683] 5-(8-(4-Chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methyl-2-(pyrrolidin-1-yl)benzonitrile (111)

[0684]

[0685] LCMS: in 0-60AB_7min_220&254 (Xtimate C18 2.1*30mm, 3um) R=4.436min, MS(ESI)m / z 493.0[M+H] + .

[0686] 1 H NMR (400MHz, DMSO-d6) δ = 9.40 (s, 1H), 9.19 (s, 2H), 8.27 (d, J = 9.0Hz, 1H), 8.09 (d, J = 2.0Hz, 1H), 7.97 ( s,1H),7.50-7.46(m,2H),7.45-7.40(m,2H),7.10(d,J=2.0Hz,1H),7.05(s,1H),3.94(s,3H),3.65(br d,J=5.1Hz,4H),2.09-1.96(m,7H).

[0687] 5-(8-(4-Chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methyl-2-(piperidin-1-yl)benzonitrile (112)

[0688]

[0689] LCMS: in 0-60AB_7min_220&254 (Xtimate C18 2.1*30mm, 3um) R =4.721min, MS(ESI)m / z 507.0[M+H] + .

[0690] 1 H NMR (400MHz, DMSO-d6) δ = 9.34 (s, 1H), 9.01 (br s,2H),8.23(d,J=8.6Hz,1H),8.12(s,1H),8.03(d,J=9.3Hz,1H),7.48-7.44(m,2H), 7.42-7.37(m,3H),6.97(s,1H),3.91(s,3H),3.44-3.39(m,4H),2.11(s,3H),1.69(br d,J=19.2Hz,6H).

[0691] 5-(8-(4-Chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-2-((2-(dimethylamino)ethyl)amino)-4-methylbenzonitrile (113)

[0692]

[0693] LCMS: in 10-80CD_7MIN_220&254 (Xtimate 2.1*30mm, 3um) R =4.606min, MS (ESI) m / z 510.0[M+H]+.

[0694] 1 H NMR (400MHz, DMSO-d6) δ = 9.72 (br, 1H), 9.34 (s, 1H), 9.00 (s, 2H), 8.24 (d, J = 8.8Hz, 1H), 8.05 (d, J = 8.8Hz, 1H), 7.99 (s, 1H), 7.52 (d, J = 8. 4Hz,2H),7.43(d,J=8.4Hz,2H),7.16(s,1H),7.12(s,1H),6.99-6.94(m,1H),3.91(s,3H),3.73-3.66(m,2H),3.31-3.24(m,2H),2.89(br s,6H),2.08(s,3H).

[0695] 5-(8-(4-Chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-2-(4-hydroxypiperidin-1-yl)-4-methylbenzonitrile (114)

[0696]

[0697] LCMS: in 10-80 CD_7.0min chromatography (Xtimate 3um, C18, 2.1*30mm) R =3.841min, MS (ESI) m / z 523.0[M+H]+.

[0698] 1H NMR: (DMSO-d6 400MHz): δ = 9.46 (s, 1H), 9.30 (br s,2H),8.32(d,J=8.8Hz,1H),8.16(s,1H),8.12(dd,J=2.0,8.8Hz,1H),7.53-7.48(m,2H),7.47(s ,1H),7.44-7.40(m,2H),7.03(d,J=1.8Hz,1H),3.99(s,3H),3.81(dt,J=3.9,8.2Hz,1H),3.69(br s,1H),3.66-3.65(m,1H),3.67-3.64(m,1H),3.53-3.52(m,1H),3.48-3.40(m,1H),3.29-3.13(m,2H),2.14(s,3H),1.96(br d,J=8.5Hz,2H),1.71-1.56(m,2H).

[0699] 5-(8-(4-chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-2-(4-(2-hydroxyethyl)piperazin-1-yl)-4-methylbenzonitrile (115)

[0700]

[0701] LCMS: in 0-60AB_7.0min chromatography (Xtimate 3um, C18, 2.1*30mm) R =2.989, MS (ESI) m / z 552.1[M+H]+.

[0702] 1 H NMR: (DMSO-d6 400MHz):9.43(s,1H),9.29(br s,2H),8.33-8.27(m,2H),8.10(d,J=2.0Hz,1H),8.13(br d,J=2.0Hz,1H),7.62(s,1H),7.57(d,J=8.5Hz,2H),7.42(d,J=8.5Hz,2H),7.04(d,J=1.8Hz,1H),4.00(s,3H),3.97-3.73(m,8H),2.19(s,3H).

[0703] (1-(5-cyano-2-methylphenyl)-8-(3-fluorophenyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-ylidene)sulfonamide

[0704]

[0705] LCMS: in 0-60AB_7min chromatography (Xtimate 3um, C18, 2.1*30mm) R =3.969min, MS(ESI)m / z 487.0[M+H] + .

[0706] 1 H NMR:(DMSO-d6 400MHz): δ=9.46(s,1H),8.36(d,J=8.8Hz,1H),8.31(d,J=1.5Hz,1H),8.18(ddd,J=1.8,8.5,12.6Hz,2H),7.87(d,J= 8.0Hz,1H),7.54-7.47(m,1H),7.30-7.23(m,1H),7.19-7.13(m,2H),6.90(d,J=1.8Hz,1H),4.11(s,3H),2.22(s,3H).

[0707] 5-(8-(4-Chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-2-(2,6-dimethylmorpholino)-4-methylbenzonitrile (117)

[0708]

[0709] LCMS: in 10-80CD_7MIN_220&254 (Xtimate 2.1*30mm, 3um) R =4.794min, MS(ESI)m / z 537.2[M+H] + .

[0710] 1 H NMR (400MHz, METHANOL-d4) δ = 8.78 (s, 1H), 8.04 (d, J = 9.0Hz, 1H), 7.84 (s, 1H) ),7.79(dd,J=2.0,9.0Hz,1H),7.39-7.34(m,2H),7.34-7.25(m,3H),6.91(d ,J=1.5Hz,1H),3.98-3.86(m,2H),3.65(s,3H),3.64-3.54(m,2H),2.72(dd, J=10.6,11.2Hz,1H),2.63-2.56(m,1H),2.11(s,3H),1.28(t,J=6.4Hz,6H).

[0711] 5-(8-(4-chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methyl-2-(4-(methylsulfonyl)piperazin-1-yl)benzonitrile (118)

[0712]

[0713] LCMS: in 0-60AB_7min_220&254 (Xtimate C18 2.1*30mm, 3um) R =4.046min, MS(ESI)m / z 586.0[M+H] + .

[0714] 1 H NMR (400MHz, DMSO-d6) δ = 9.48 (s, 1H), 9.39 (br s,2H),8.34(d,J=9.0Hz,1H),8.26(s,1H),8.13(dd,J=2.0,9.0Hz,1H),7.58-7.52(m,3H),7.41(d,J=8.5H z, 2H), 7.02 (d, J = 1.8Hz, 1H), 4.01 (s, 3H), 3.55-3.50 (m, 2H), 3.46-3.38 (m, 6H), 3.02 (s, 3H), 2.18 (s, 3H).

[0715] 5-(8-(4-Chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methyl-2-(2-methylmorpholino)benzonitrile (119)

[0716]

[0717] LCMS: in 0-60AB_7min_220&254 (Xtimate C18 2.1*30mm, 3um) R =4.267min, MS(ESI)m / z 523.0[M+H] + .

[0718] 1H NMR (400MHz, DMSO-d6) δ = 9.39 (s, 1H), 9.21 (d, J = 7.2Hz, 2H), 8.27 (d, J = 8.8Hz, 1H), 8 .19(d,J=6.6Hz,1H),8.06(ddd,J=2.2,4.8,8.9Hz,1H),7.52-7.43(m,3H),7.40-7.3 6(m,2H),7.01-6.87(m,1H),4.06-3.93(m,4H),3.82-3.62(m,2H),3.49-3.41(m,2H) ,3.18-2.96(m,1H),2.88-2.66(m,1H),2.13(d,J=2.4Hz,3H),1.20(t,J=6.5Hz,3H).

[0719] 5-(8-(4-Chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methyl-2-((4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)benzonitrile (120)

[0720]

[0721] LCMS: in 0-60AB_7min chromatography (Xtimate 3um, C18, 2.1*30mm) R =3.271min, MS(ESI)m / z 548.1[M+H] + .

[0722] 1 H NMR: (DMSO-d6 400MHz): δ=9.37(s,1H),8.99(br d,J=16.3Hz,2H),8.66(brs,1H),8.27(d,J=8.8Hz,1H),8.12-8.01(m,2H),7.58-7.52(m,2H),7.50-7.42(m, 2H),7.24-7.10(m,2H),4.12-4.01(m,2H),3.94(d,J=2.5Hz,3H),3.90-3.71(m,4H),3.09(brs,1H),2.76(br s, 1H), 2.11 (d, J = 7.3Hz, 3H), 1.77 (br s, 4H).

[0723] 5-(8-(4-Chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methyl-2-(2-oxa-6-azaspiro[3.3]hept-6-yl)benzonitrile (121)

[0724]

[0725] LCMS: in 0-60AB_7.0min chromatography (Xtimate 3um, C18, 2.1*30mm) R =3.984min, MS(ESI)m / z 521.0[M+H] + .

[0726] 1 H NMR: (DMSO-d6 400MHz): δ=8.80(br s,1H),7.99(br s,1H),7.79(br s,2H),7.57-7.26(m,6H),7.01-6.91(m,1H),6.76(br s,1H),4.79(br s, 4H), 4.39 (br d, J = 9.3Hz, 4H), 3.51 (br s, 3H), 1.97 (br s, 3H).

[0727] 8-(4-Chlorophenyl)-3-methyl-1-(2-methyl-5-(methylsulfonyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imide (122)

[0728]

[0729] LCMS: in 0-60AB_7min chromatography (Xtimate 3um, C18, 2.1*30mm) R =3.672min, MS(ESI)m / z 476.9[M+H] + .

[0730] 1 H NMR (400MHz, DMSO-d6) δ = 9.36 (s, 1H), 9.11 (br s,2H),8.43(s,1H),8.33(brd,J=9.7Hz,1H),8.24(d,J=9.0Hz,1H),7.99(dd,J=8.7,12.9Hz,2H), 7.45(d,J=8.4Hz,2H),7.30(d,J=8.6Hz,2H),6.78(s,1H),3.93(s,3H),3.27(s,3H),2.22(s,3H).

[0731] N-(4-(8-(4-chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-2-cyano-5-methylphenyl)methanesulfonamide (123)

[0732]

[0733] LCMS: In 0-60AB_7.0MIN chromatography (Xtimate C18 2.1*30mm, 3um) R =3.930min, MS(ESI)m / z 516.9[M+H] + .

[0734] 1 H NMR (400MHz, DMSO-d6) δ = 9.31 (s, 1H), 8.96 (br s,2H),8.28-8.18(m,1H),8.09(dd,J=2.0,9.0Hz,1H),7.71(s,1H),7.56-7.45(m,5H),7.27(s,1H),3.91(s,3H),2.79(s,3H),1.97(s,3H).

[0735] 5-(8-(4-Chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methyl-2-(3-methylpiperazin-1-yl)benzonitrile (124)

[0736]

[0737] LCMS: in 10-80CD_7MIN_220&254 (Xtimate 2.1*30mm, 3um) R =4.204min, MS(ESI)m / z 522.2[M+H] + .

[0738] 1H NMR (400MHz, DMSO-d6) δ = 8.79 (s, 1H), 8.00 (d, J = 8.8Hz, 1H), 7.97 (br d,J=8.6Hz,1H),7.78(ddd,J=2.2,3.6,9.0Hz,1H),7.43-7.38(m,2H),7.34-7.30(m,3H),6.90(d,J=1.8Hz,1H),3.60-3.46(m ,4H),3.06-2.97(m,1H),2.93-2.81(m,3H),2.62-2.55(m,1H),2.46-2.39(m,1H),2.05(s,3H),1.05(dd,J=6.4,10.8Hz,3H).

[0739] (E)-(1-(5-cyano-2-methylphenyl)-3-methyl-8-(6-methylpyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-ylidene)carbamic acid methyl ester (125)

[0740]

[0741] LCMS: in 10-80CD_7MIN_220&25 (Xtimate 3um, C18, 2.1*30mm) R =2.838min, MS(ESI)m / z 463.2[M+H] + .

[0742] 1 H NMR (400MHz, METHANOL-d4) δ = 9.18 (s, 1H), 8.30 (d, J = 2.2Hz, 1H), 8.25 (d, J = 8.8Hz, 1H), 8.05 (s, 1H), 8.03-7.96 (m, 2H ),7.81-7.73(m,2H),7.36(d,J=8.2Hz,1H),7.11(d,J=1.8Hz,1H),3.84(s,3H),3.50(s,3H),2.55(s,3H),2.21(s,3H).

[0743] 4-(4-(8-(4-chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-2-cyano-5-methylphenyl)piperazine-1-carboxamide (126)

[0744]

[0745] LCMS: in 10-80CD_7MIN (Xtimate 2.1*30mm, 3um) R =3.478

[0746] min, MS (ESI) m / z 551.2 [M+H] + .

[0747] 1 H NMR (400MHz, DMSO-d6) δ = 8.80 (s, 1H), 8.00 (d, J = 8.8Hz, 2H), 7.79 (dd, J = 2.1, 8.9Hz, 1H), 7.44-7.40 ( m,2H),7.37(s,1H),7.34-7.30(m,2H),6.91(d,J=1.3Hz,1H),6.14(s,2H),3.54-3.50(m,7H),3.28(br d,J=5.1Hz,2H),3.24-3.19(m,2H),2.07(s,3H).

[0748] 1-(4-(8-(4-chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-[1,4'-bipiperidinyl]-1'-yl)ethan-1-one (127)

[0749]

[0750] LCMS: in 0-30AB_7min_220&254 (Xtimate 3um, C18, 2.1*30mm) R =4.513min, MS(ESI)m / z 517.1[M+H] + .

[0751] 1H NMR(400MHz,DMSO-d6)δ=11.11(br s,1H),9.40-9.24(m,3H),8.50(s,1H),8.36(d,J=9.0Hz,1H),8.17(d,J=10.0Hz,1H),7. 99(d,J=8.5Hz,2H),7.64(d,J=8.5Hz,2H),5.85-5.71(m,1H),5.85-5.71(m,1H),4.57(br d,J=13.6Hz,1H),4.02(br d,J=13.8Hz,1H),3.87(s,3H),3.77(br s,2H),3.46(br d,J=11.8Hz,2H),3.38-3.20(m,2H),3.16-3.03(m,1H),2.57-2.54(m,2H),2.48-2.39(m,2H),2.17(br t,J=13.1Hz,2H),2.04(s,3H),1.81-1.66(m,1H),1.66-1.48(m,1H).

[0752] 1-(4-(8-(4-chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-[1,4'-bipiperidinyl]-1'-yl)propan-1-one (128)

[0753]

[0754] LCMS: in 0-30AB_7min_220&254 (Xtimate 3um, C18, 2.1*30mm) R =4.853min, MS(ESI)m / z 531.1[M+H] + .

[0755] 1H NMR(400MHz,DMSO-d6)δ=11.11(br s,1H),9.43-9.23(m,3H),8.50(s,1H),8.36(d,J=8.8Hz,1H),8.17(d,J=9.0Hz ,1H),8.00(d,J=8.5Hz,2H),7.64(d,J=8.5Hz,2H),5.86-5.65(m,1H),4.59(br d,J=12.8Hz,1H),4.07(br d,J=14.1Hz,1H),3.87(s,3H),3.64-3.57(m,2H),3.46(br d,J=9.0Hz,2H),3.35-3.21(m,2H),3.05(br t,J=12.5Hz,1H),2.63-2.53(m,2H),2.46(br s,2H),2.37(q,J=7.7Hz,2H),2.17(br t,J=9.8Hz,2H),1.82-1.47(m,2H),1.00(t,J=7.3Hz,3H).

[0756] 1-(4-((1r,3r)-3-(8-(4-chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)cyclobutyl)piperazin-1-yl)ethan-1-one (129)

[0757]

[0758] LCMS: in 0-30AB_7min_220&254 chromatography (Xtimate C18 2.1*30mm, 3um) R =4.466min, MS(ESI)m / z 489.0[M+H] + .

[0759] 1H NMR (400MHz, DMSO-d6) δ = 11.99 (br s, 1H), 12.05-11.91 (m, 1H), 9.44-9.23 (m, 3H), 8.38 (s, 1H), 8.33 (d, J = 9.0Hz, 1H), 8.16 (br d,J=8.8Hz,1H),7.98(d,J=8.5Hz,2H),7.63(d,J=8.5Hz,2H),5.60-5.48(m,1H),4.42(br d,J=12.5Hz,1H),3.95(br d,J=15.1Hz,1H),3.89(s,3H),3.45-3.33(m,3H),3.18(br dd,J=8.3,17.6Hz,4H),2.87(br d,J=13.6Hz,2H),2.78(br d,J=9.5Hz,1H),2.43(br s,1H),2.02(s,3H).

[0760] 2-(4-Acetylpiperazin-1-yl)-5-(8-(4-chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-6-methylnicotinonitrile (130)

[0761]

[0762] LCMS: in 0-60AB_7.0min chromatography (Xtimate, 2.1*30mm, 3um) R =4.005min, MS(ESI)m / z 551.1[M+H] + .

[0763] 1 H NMR: (400MHz, DMSO-d6): δ = 9.43 (s, 1H), 9.36 (s, 2H), 8.55 (s, 1H), 8.31 (d, J = 8.8Hz, 1H), 8.10 (dd, J = 2.0, 8.8Hz, 1H), 7.54-7.48(m,4H),7.23(d,J=2.0Hz,1H),3.99(s,3H),3.97-3.95(m,4H),3.68-3.65(m,4H),2.28(s,3H),2.12(s,3H).

[0764] N-(1-(4-(8-(4-chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-2-cyano-5-methylphenyl)piperidin-4-yl)methanesulfonamide (131)

[0765]

[0766] LCMS: In 0-60AB_7.0MIN chromatography (Xtimate C18 2.1*30mm, 3um) R =4.150min,MS(ESI)m / z 600.1[M+H] + .

[0767] 1 H NMR (400MHz, DMSO-d6) δ = 9.34 (s, 1H), 9.00 (br s,2H),8.23(d,J=8.8Hz,1H),8.14(s,1H),8.04(dd,J=2.1,8.9Hz,1H),7.50- 7.45(m,2H),7.43(s,1H),7.38(d,J=8.4Hz,2H),7.26(d,J=7.5Hz,1H),6.98(d ,J=1.8Hz,1H),3.91(s,3H),3.79-3.59(m,2H),3.30-3.26(m,1H),3.18-3.08( m,2H),2.98(s,3H),2.10(s,3H),2.09-2.00(m,2H),1.66(brd,J=18.3Hz,2H).

[0768] N-(1-(4-(8-(4-chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-2-cyano-5-methylphenyl)piperidin-4-yl)acetamide (132)

[0769]

[0770] LCMS: In 0-60AB_7.0MIN chromatography (Xtimate C18 2.1*30mm, 3um) R =3.838min, MS(ESI)m / z 564.1[M+H] + .

[0771] 1H NMR (400MHz, DMSO-d6) δ = 9.35 (s, 1H), 9.02 (s, 2H), 8.24 (d, J = 9.0Hz, 1H), 8.15 (s, 1H), 8.05 (dd, J = 2.0, 8.8Hz, 1H), 7.95 (d, J = 7.5Hz, 1H), 7.52-7. 43(m,3H),7.39(d,J=8.6Hz,2H),6.98(d,J=1.8Hz,1H),3.92(s,3H),3.84 -3.81(m,1H),3.79-3.60(m,2H),3.20-3.04(m,2H),2.11(s,3H),1.96(br d,J=8.2Hz,2H),1.83(s,3H),1.71-1.48(m,2H).

[0772] 5-(8-(4-Chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methyl-2-(3-oxopiperazin-1-yl)benzonitrile (133)

[0773]

[0774] LCMS: In 0-60AB_7.0MIN chromatography (Xtimate C18 2.1*30mm, 3um) R =3.689min, MS(ESI)m / z 522.0[M+H] + .

[0775] 1 H NMR (400MHz, DMSO-d6) δ = 9.37 (s, 1H), 9.06 (s, 2H), 8.30-8.24 (m, 2H), 8.22 (s, 1H), 8.07 (dd, J = 2.1, 8.9Hz, 1H), 7.54-7.49 (m, 3H), 7.44-7.4 0(m,2H),7.02(d,J=2.2Hz,1H),4.10-4.06(m,1H),3.96-3.92(m,4H), 3.86-3.73(m,1H),3.70-3.61(m,1H),3.46-3.45(m,2H),2.15(s,3H).

[0776] 5-(8-(4-Chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-2-fluoro-4-methylbenzonitrile (134)

[0777]

[0778] LCMS: in 0-60AB_7min chromatography (Xtimate 3um, C18, 2.1*30mm) R =4.302min, MS(ESI)m / z 441.9[M+H] + .

[0779] 1 H NMR: DMSO-d6 400MHz): δ = 9.41 (s, 1H), 9.11 (br s,2H),8.52(d,J=6.0Hz,1H),8.29(d,J=8.8Hz,1H),8.11-8.00(m,2H),7.57-7.5 1(m,2H),7.44(d,J=8.5Hz,2H),7.01(d,J=1.5Hz,1H),3.96(s,3H),2.25(s,3H).

[0780] 4-(8-(4-Chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-5-methylphthalonitrile (135)

[0781]

[0782] LCMS: in 0-60AB_7min chromatography (Xtimate 3um, C18, 2.1*30mm) R =4.941min, MS(ESI)m / z 449.1[M+H] + .

[0783] 3-(2-Imino-3-methyl-8-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile (136)

[0784]

[0785] LCMS: in 0-60AB_7min_220&254 chromatography (Xtimate 3um, C18, 2.1*30mm) R =2.502min, MS(ESI)m / z 394.0[M+H] + .

[0786] 1H NMR (400MHz, DMSO-d6) δ = 9.27 (s, 1H), 9.04 (s, 2H), 8.39-8.30 (m, 2H), 8.12 (d, J = 8.8Hz, 1H), 7.98 (d, J = 7.9Hz, 1H), 7.94(s,1H),7.88(dd,J=2.0,8.8Hz,1H),7.17(s,1H),6.68(d,J=1.5Hz,1H),3.91(s,3H),3.82(s,3H),2.20(s,3H).

[0787] 3-(8-(4-Chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile (137)

[0788]

[0789] LCMS: in 0-60AB_7min_220&254 chromatography (Xtimate 3um, C18, 2.1*30mm) R =3.841min, MS(ESI)m / z 424.0[M+H] + .

[0790] 1 H NMR (400MHz, DMSO-d6) δ=9.37(s,1H),9.08(s,2H),8.36(d,J=1.3Hz,1H),8.31-8.20(m,2H),8.02(dd,J=2.0,8.8Hz,1H ),7.93(d,J=7.9Hz,1H),7.48(d,J=8.6Hz,2H),7.32(d,J=8.6Hz,2H),6.83(d,J=1.8Hz,1H),3.93(s,3H),2.20(s,3H).

[0791] (Z)-N-(9-(4-chlorophenyl)-1-(4-(4-(2-(dimethylamino)ethyl)piperazine-1-carbonyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-ylidene)cyanamide (138)

[0792]

[0793] LCMS: in 0-60AB_7min_220&254 (Xtimate 3um, C18, 2.1*30mm) R =3.794min, MS(ESI)m / z 612.1[M+Na] + .

[0794] 1 H NMR (400MHz, DMSO-d6) δ = 9.31 (s, 1H), 8.56 (d, J = 9.3Hz, 1H), 8.20-8.16 (m, 1H), 8.10-8.05 (m, 1H), 7.76-7.69 (m, 4H), 7.66 (d, J = 9.3Hz, 1H) ,7.53(d,J=8.5Hz,2H),7.30(d,J=1.0Hz,1H),7.21(d,J=8.3Hz,2H),3.75-3.62(m,2H),3.25-3.13(m,2H),2.45-2.25(m,8H),2.16(s,6H).

[0795] 3-(9-(4-Chlorophenyl)-2-iminobenzo[h][1,6]naphthyridin-1(2H)-yl)benzonitrile(139)

[0796]

[0797] LCMS: in 0-60AB_7MIN_220&254 chromatography (Xtimate 3um, C18, 2.1*30mm) R =4.299min, MS(ESI)m / z 406.9[M+H] + .

[0798] 1 H NMR: (400MHz, DMSO-d6) δ = 10.05 (s, 2H), 8.79 (s, 1H), 7.98 (br d, J = 8.8Hz, 1H), 7.75 (br dd, J = 2.0, 8.8Hz, 1H), 7.50 (br t, J = 7.8Hz, 1H), 7.36 (br dd,J=5.5,8.8Hz,2H),7.21(br t,J=8.8Hz,2H),7.13(br d,J=1.5Hz,1H),7.06(br d,J=7.9Hz,1H),7.01(br d,J=6.6Hz,1H),6.93(br s,1H),3.50(s,3H).

[0799] 9-(4-Chlorophenyl)-1-(3-(trifluoromethyl)phenyl)benzo[h][1,6]naphthyridine-2(1H)-imine (140)

[0800]

[0801] LCMS: in 0-60AB_7min chromatography (Xtimate 3um, C18, 2.1*30mm)R =4.930min,MS(ESI)m / z 449.9[M+H] + .

[0802] 1 H NMR: (400MHz, DMSO-d6) δ=8.82(br s,1H),8.02(br s,1H),7.96(br d,J=8.6Hz,2H),7.86(br d,J=8.2Hz,1H),7.78(br s,1H),7.67(br d, J=6.4Hz, 1H), 7.54 (brd, J=9.0Hz, 1H), 7.37 (br d, J=7.7Hz, 2H), 7.05 (br d, J=8.2Hz, 2H), 6.96 (br s, 1H), 6.85 (br d, J=9.3Hz, 1H).

[0803] 1-(3-Chlorophenyl)-9-(4-chlorophenyl)benzo[h][1,6]naphthyridine-2(1H)-imine (141)

[0804]

[0805] LCMS: in 0-60AB_7min_220&254 chromatography (Xtimate, 2.1*30mm, 3um) R =4.729min, MS(ESI)m / z 415.9[M+H] + .

[0806] 1 H NMR (400MHz, DMSO-d6) δ=8.82(s,1H),8.00-7.93(m,1H),7.92-7.84(m,1H),7.76-7.67(m,2H),7.62(br t,J=7.9Hz,1H),7.55(br d,J=9.3Hz,1H),7.46-7.35(m,3H),7.20-7.05(m,3H),6.84(d,J=9.5Hz,1H).

[0807] 5-(8-(3-Fluorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-6-methyl-2-morpholinonitrile (142)

[0808]

[0809] LCMS: in 0-60AB_7min chromatography (Xtimate 3um, C18, 2.1*30mm)R =4.262min, MS(ESI)m / z 494.0[M+H] + .

[0810] 1 HNMR: (DMSO-d6 400MHz): δ = 9.43 (s, 1H), 9.36 (br s,2H),8.55(s,1H),8.31(d,J=8.8Hz,1H),8.16(dd,J=2.0,9.0Hz,1H),7.58-7.49(m ,1H),7.38-7.23(m,4H),7.22(brs,1H),3.99(s,3H),3.95-3.77(m,8H),2.28(s,3H).

[0811] 5-(8-(3-Fluorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-6-methyl-2-(4-methylpiperazin-1-yl)nicotinonitrile (143)

[0812]

[0813] LCMS: in 0-30AB_7.0min chromatography (Xtimate, 2.1*30mm, 3um) R =4.380min,MS(ESI)m / z 507.1[M+H] + .

[0814] 1 H NMR: (400MHz, DMSO-d6): δ = 11.79 (s, 1H), 9.61 (s, 2H), 9.48 (s, 1H), 8.68 (s, 1H), 8.34 (d, J = 8.0Hz, 1H), 8.18 (d, J = 8.8Hz, 2H), 7.6 1-7.59(m,1H),7.35-7.26(m,4H),4.54-4.49(m,2H),4.02(s,3H),3.67-3.60(m,4H),3.33-3.21(m,2H),2.85(s,3H),2.32(s,3H).

[0815] 5-(8-(3-Fluorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methyl-2-(4-methylpiperazin-1-yl)benzonitrile (144)

[0816]

[0817] LCMS: in 0-60AB_7min chromatography (Xtimate 3um, C18, 2.1*30mm) R =2.824min, MS(ESI)m / z 506.1[M+H] + .

[0818] 1 H NMR: (DMSO-d6 400MHz): δ=11.70(br s,1H),9.41(s,1H),9.31(br s,2H),8.30-8.26(m,2H),8.12(dd,J=1.9,8.9Hz,1H),7.63(s,1H),7.60-7.54(m,1H),7.27-7.16(m,2H),7.21-7.15(m,1H ),7.01(d,J=1.8Hz,1H),3.99(s,3H),3.81-3.70(m,2H),3.64-3.61(m,2H),3.51-3.43(m,2H),3.33-3.20(m,2H),2.86(br d,J=4.2Hz,3H),2.31(s,1H),2.16(s,3H).

[0819] 5-(2-Imino-3-methyl-8-(p-tolyl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methyl-2-morpholinobenzonitrile (145)

[0820]

[0821] LCMS: in 0-60AB_7.0min chromatography (Xtimate 3um, C18, 2.1*30mm) R =4.133min, MS(ESI)m / z 489.1[M+H] + .

[0822] 1 H NMR (400MHz, DMSO-d6) δ = 9.34 (s, 1H), 9.04 (s, 2H), 8.23 (t, J = 4.4Hz, 2H), 8.06 (dd, J = 1.8, 9.0Hz, 1H), 7.51 (s, 1H) ,7.33-7.21(m,4H),6.99(s,1H),3.94(s,3H),3.87(t,J=4.5Hz,4H),3.36-3.29(m,4H),2.35(s,3H),2.16(s,3H).

[0823] (E)-(1-(5-cyano-2-methyl-4-(4-methylpiperazin-1-yl)phenyl)-8-(3-fluorophenyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-ylidene)carbamic acid methyl ester (146)

[0824]

[0825] LCMS: in 0-60AB_7.0min chromatography (Xtimate 3um, C18, 2.1*30mm) R =3.133min, MS(ESI)m / z 564.1[M+H] + .

[0826] 1 H NMR (400MHz, DMSO-d6) δ = 9.23 (s, 1H), 8.19 (d, J = 8.8Hz, 1H), 8.08-7.99 (m, 2H), 7.52-7.43 (m, 1H), 7.39 (s, 1H), 7.29-7.21 (m, 2H), 7.16 (br d,J=10.8Hz,1H),7.09(d,J=2.0Hz,1H),3.73(s,3H),3.39(s,3H),3.32-3.28(m,4H),2.56(br s,4H),2.28(s,3H),2.09(s,3H).

[0827] (E)-(1-(5-cyano-2-methyl-4-(4-methylpiperazin-1-yl)phenyl)-3-methyl-8-(p-tolyl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-ylidene)carbamic acid methyl ester (147)

[0828]

[0829] LCMS: in 0-60AB_7min_220&254 (Xtimate 3um, C18, 2.1*30mm) R =3.241min, MS(ESI)m / z 560.1[M+H] + .

[0830] 1H NMR (400MHz, DMSO-d6) δ=9.16(s,1H),8.13(d,J=8.8Hz,1H),8.03(s,1H),7.94(dd,J=2.0,9.0Hz,1H),7.35(s,1H),7.27-7.22(m,2H),7.21 -7.16(m,2H),7.03(d,J=1.8Hz,1H),3.69(s,3H),3.36(s,3H),3.31-3 .25(m,4H),2.57-2.52(m,4H),2.31(s,3H),2.26(s,3H),2.05(s,3H).

[0831] (E)-(1-(5-cyano-2-methyl-4-morpholinophenyl)-8-(3-fluorophenyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-ylidene)carbamic acid methyl ester (148)

[0832]

[0833] LCMS: In 0-60AB_7.0MIN chromatography (Xtimate C18 2.1*30mm, 3um) R =4.216min, MS(ESI)m / z 551.1[M+H] + .

[0834] 1 H NMR (400MHz, DMSO-d6) δ = 9.21 (s, 1H), 8.17 (d, J = 9.0Hz, 1H), 8.08 (s, 1H), 8.01 (dd, J = 2.1, 8.9Hz, 1H), 7.50-7.42 (m, 1H), 7.40 (s, 1H), 7.26-7 .19(m,2H),7.14(brd,J=10.1Hz,1H),7.06(d,J=1.8Hz,1H),3.81(t,J=4.6Hz,4H),3.71(s,3H),3.37(s,3H),3.29-3.22(m,4H),2.09(s,3H).

[0835] (E)-4-(9-(4-Chlorophenyl)-2-(tosylimino)benzo[h][1,6]naphthyridin-1(2H)-yl)-N-cyclopropylbenzamide (149)

[0836]

[0837] LCMS: in 0-60AB_7MIN_220&254 (Xtimate, 2.1*30mm, 3um)R =5.485min, MS(ESI)m / z 619.0[M+H] + .

[0838] 1 H NMR (400MHz, DMSO-d6) δ = 9.23 (s, 1H), 8.75 (d, J = 4.0Hz, 1H), 8.53 (d, J = 9.7Hz, 1H), 8.17- 8.10(m,3H),8.03(dd,J=2.0,8.6Hz,1H),7.89(d,J=9.5Hz,1H),7.69(d,J=8.6Hz,2H),7.4 3(d,J=8.4Hz,2H),7.32(d,J=8.6Hz,2H),7.21(d,J=8.2Hz,2H),7.06(d,J=8.4Hz,2H),6. 89(d,J=1.8Hz,1H),3.02-2.90(m,1H),2.30(s,3H),0.83-0.75(m,2H),0.67-0.60(m,2H).

[0839] (Z)-4-(9-(4-chlorophenyl)-2-(propionylimino)benzo[h][1,6]naphthyridin-1(2H)-yl)-N-cyclopropylbenzamide (150)

[0840]

[0841] LCMS: in 10-80CD_7MIN_220&254 (XBridge Shield RP182.1*50mm, 5um) R =4.104min, MS(ESI)m / z 521.2[M+H] + .

[0842] 1 H NMR (400MHz, DMSO-d6) δ = 9.06 (s, 1H), 8.71 (d, J = 4.0Hz, 1H), 8.13-8.02 (m, 4H) ,7.95(dd,J=1.9,8.7Hz,1H),7.62(d,J=8.6Hz,2H),7.35(d,J=9.5Hz,1H),7.33 -7.28(m,2H),7.06-7.01(m,2H),6.89(d,J=1.5Hz,1H),2.99-2.87(m,1H),2.1 7(q,J=7.5Hz,2H),0.88(t,J=7.4Hz,3H),0.81-0.73(m,2H),0.65-0.59(m,2H).

[0843] (E)-4-(9-(4-Chlorophenyl)-2-(methylimino)benzo[h][1,6]naphthyridin-1(2H)-yl)-N-cyclopropylbenzamide (151)

[0844]

[0845] LCMS: in 0-60AB_7.0min chromatography (Xtimate, 2.1*30mm, 3um) R =3.973min, MS(ESI)m / z 479.1[M+H] + .

[0846] 1 H NMR: (400MHz, DMSO-d6): δ=8.34(d,J=4.0Hz,1H),8.12(s,1H),7.90-7.89(m,1H),7.88-7.87(m,2H),7.83-7.81(m,1H),7.63-7.61(m,1H),7.2 8-7.26(m,3H),7.14-7.12(m,2H),6.77(d,J=8.4Hz,2H),6.63(brs,1H) ,3.76(s,3H),2.89-2.86(m,1H),0.73-0.69(m,2H),0.59-0.56(m,2H).

[0847] 5-(2-Imino-1-(3-(trifluoromethyl)phenyl)-1,2-dihydrobenzo[h][1,6]naphthyridin-9-yl)pyridin-2-amine (152)

[0848]

[0849] LCMS: in 0-60AB_7min chromatography (Xtimate 3um, C18, 2.1*30mm) R =2.230min, MS(ESI)m / z 432.0[M+H] + .

[0850] 1H NMR:(DMSO-d6 400MHz): δ10.13(s,1H),9.41(s,1H),8.75(d,J=9.3Hz,1H),8.51(s,1H),8.35-8.08(m,7H),7.84(d,J=2. 0Hz, 1H), 7.58 (d, J = 9.3Hz, 1H), 7.38 (dd, J = 2.1, 9.2Hz, 1H), 6.90 (d, J = 9.3Hz, 1H), 6.58 (d, J = 1.3Hz, 1H).

[0851] 4-(9-(4-Chlorophenyl)-2-iminobenzo[h][1,6]naphthyridin-1(2H)-yl)-N-cyclopropylbenzamide (153)

[0852]

[0853] LCMS: in 10-80AB_7min_220&254 chromatography (Xtimate 3um, C18, 2.1*30mm) R =2.803min, MS(ESI)m / z 465.1[M+H] + .

[0854] 1 H NMR (400MHz, DMSO-d6) δ=9.29(s,1H),8.93(br d,J=3.7Hz,1H),8.56(br d,J=9.3Hz,1H),8.35(br d,J=8.4Hz,2H),8.17(d,J=8.6Hz,1H),8.06(br d,J=8.6Hz,1H),7.91(br d,J=8.4Hz,2H),7.55(br d,J=9.3Hz,1H),7.33(br d,J=8.4Hz,2H),7.09(br d,J=8.4Hz,2H),6.74(s,1H),3.03-2.92(m,1H),0.85-0.64(m,4H).

[0855] 3-(2-Imino-3-methyl-8-(phenylethynyl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile (154)

[0856]

[0857] LCMS: in 0-60AB_7MIN_220&254 chromatography (Xtimate 3um, C18, 2.1*30mm) R=4.677min, MS(ESI)m / z 414.1[M+H] + .

[0858] 1 H NMR: (400MHz, DMSO-d6) δ=8.86(br s,1H),8.13(br s,3H),7.97(br d,J=9.3Hz,1H),7.85(br s,1H),7.56(br d,J=9.0Hz,1H),7.44(s,4H),6.77(br s,1H),3.55(s,3H),2.16(br s,3H).

[0859] 3-(8-((4-Chlorophenyl)ethynyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylbenzonitrile (155)

[0860]

[0861] LCMS: in 0-60AB_7MIN_220&254 chromatography (Xtimate 3um, C18, 2.1*30mm) R =4.919min, MS(ESI)m / z 448.0[M+H] + .

[0862] 1 H NMR: (400MHz, DMSO-d6) δ=8.87(s,1H),8.19(br s,1H),8.11(br d,J=7.9Hz,1H),7.98(d,J=8.8Hz,1H),7.84(br d,J=7.7Hz,1H),7.65(br d,J=8.6Hz,1H),7.56(dd,J=1.8,8.8Hz,1H),7.52-7.45(m,4H),6.77(s,1H),3.54(s,3H),2.15(s,3H).

[0863] 8-(4-Chlorophenyl)-3-methyl-1-(pyrimidin-5-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imine

[0864]

[0865] LCMS: In 0-60AB_7.0MIN chromatography (Xtimate C18 2.1*30mm, 3um) R=3.411min, MS(ESI)m / z 387.1[M+H] + .

[0866] 1 H NMR (400MHz, DMSO-d6) δ=9.66(s,1H),9.41(d,J=6.4Hz,5H),8.29(d,J=8.8Hz,1H),8.04(dd,J= 2.0,8.8Hz,1H),7.51(d,J=8.6Hz,2H),7.37(d,J=8.6Hz,2H),6.93(d,J=1.7Hz,1H),3.99(s,3H)

[0867] 8-(4-Fluorophenyl)-3-methyl-1-(pyrimidin-5-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imine

[0868]

[0869] LCMS: In 0-60AB_7.0MIN chromatography (Xtimate C18 2.1*30mm, 3um) R =3.010min,MS(ESI)m / z 371.1[M+H] + .

[0870] 1 H NMR (400MHz, DMSO-d6) δ = 9.68 (s, 1H), 9.49-9.33 (m, 5H), 8.30 (d, J = 8.8Hz, 1H), 8 .06(dd,J=2.0,9.0Hz,1H),7.49-7.21(m,4H),6.93(d,J=1.7Hz,1H),4.01(s,3H)

[0871] 5-(2-Imino-3-methyl-1-(pyrimidin-5-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl)pyridin-2-amine

[0872]

[0873] LCMS: In 0-60AB_7MIN chromatography (Xtimate C18 2.1*30mm, 3um) R =1.507min, MS(ESI)m / z 369.1[M+H] + .

[0874] 1H NMR (400MHz, DMSO-d6) δ = 9.67 (s, 1H), 9.48-9.33 (m, 5H), 8.30 (d, J = 8.8Hz, 2H), 8.13-7.95 ( m,2H),7.86(dd,J=2.3,9.3Hz,1H),7.07(d,J=9.3Hz,1H),6.92(d,J=1.8Hz,1H),4.01(s,3H)

[0875] 3-Methyl-1-(pyrimidin-5-yl)-8-(p-tolyl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imide

[0876]

[0877] LCMS: In 0-60AB_7MIN chromatography (Xtimate C18 2.1*30mm, 3um) R =3.269min, MS(ESI)m / z 367.1[M+H] + .

[0878] 1 H NMR (400MHz, DMSO-d6) δ = 9.70 (s, 1H), 9.49-9.29 (m, 5H), 8.39-8.19 (m, 1H), 8 .11-7.95(m,1H),7.26(s,3H),6.94(d,J=1.8Hz,1H),4.00(s,3H),2.33(s,3H)

[0879] 8-(3-Fluorophenyl)-3-methyl-1-(pyrimidin-5-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imine

[0880]

[0881] LCMS: In 0-60AB_7MIN chromatography (Xtimate C18 2.1*30mm, 3um) R =3.027min, MS(ESI)m / z 371.1[M+H] + .

[0882] 1H NMR (400MHz, DMSO-d6) δ = 9.70 (s, 1H), 9.49-9.31 (m, 5H), 8.30 (d, J = 9.0Hz, 1H), 8.10 (dd, J = 2.0,9.0Hz,1H),7.51(q,J=7.5Hz,1H),7.33-7.17(m,3H),6.99(d,J=1.8Hz,1H),4.00(s,3H)

[0883] 8-(4-chlorophenyl)-3-methyl-1-(4-methylpyrimidin-5-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imine

[0884]

[0885] LCMS: In 0-60AB_7.0MIN chromatography (Xtimate C18 2.1*30mm, 3um) R =3.482min, MS(ESI)m / z 401.1[M+H] + .

[0886] 1 H NMR (400MHz, METHANOL-d4) δ = 9.61 (s, 1H), 9.52 (s, 1H), 9.21 (s, 1H), 8.38 (d, J = 9.0Hz, 1H), 8.23 (dd, J =2.0,9.0Hz,1H),7.53-7.41(m,2H),7.40-7.31(m,2H),7.06(d,J=1.5Hz,1H),4.06(s,3H),2.55(s,3H)

[0887] 8-(4-Fluorophenyl)-3-methyl-1-(4-methylpyrimidin-5-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imine

[0888]

[0889] LCMS: In 0-60AB_7.0MIN chromatography (Xtimate C18 2.1*30mm, 3um) R =3.138min, MS(ESI)m / z 385.1[M+H] + .

[0890] 1H NMR (400MHz, METHANOL-d4) δ = 9.74 (s, 1H), 9.53 (s, 1H), 9.24 (s, 1H), 8.45-8.37 (m, 1H), 8.31 (dd, J = 1. 7,9.0Hz,1H),7.46-7.35(m,2H),7.21(t,J=8.8Hz,2H),7.08(d,J=1.7Hz,1H),4.08(s,3H),2.57(s,3H)

[0891] 5-(2-Imino-3-methyl-1-(4-methylpyrimidin-5-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl)pyridin-2-amine

[0892]

[0893] LCMS: In 0-60AB_7.0MIN chromatography (Xtimate C18 2.1*30mm, 3um) R =1.627min, MS(ESI)m / z 383.2[M+H] + .

[0894] 1 H NMR (400MHz, DMSO-d6)δ=9.59-9.34(m,4H),9.19(s,1H),8.59-8.15(m,3H),8.11-7.97(m,2H),7.81(br d,J=9.3Hz,1H),7.18-7.00(m,1H),6.82(s,1H),4.01(s,3H),2.45(s,3H)

[0895] 3-Methyl-1-(4-methylpyrimidin-5-yl)-8-(p-tolyl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imide

[0896]

[0897] LCMS: In 0-60AB_7.0MIN chromatography (Xtimate C18 2.1*30mm, 3um) R =3.358min, MS(ESI)m / z 381.2[M+H] + .

[0898] 1H NMR (400MHz, METHANOL-d4) δ = 9.63 (s, 1H), 9.57-9.51 (m, 1H), 9.23 (s, 1H), 8.42-8.33 (m, 1H), 8.28 (dd, J=1.7,9.0Hz,1H),7.32-7.24(m,4H),7.08(d,J=1.5Hz,1H),4.13-4.03(m,3H),2.57(s,3H),2.39(s,3H)

[0899] 8-(3-Fluorophenyl)-3-methyl-1-(4-methylpyrimidin-5-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imine

[0900]

[0901] LCMS: In 0-60AB_7.0MIN chromatography (Xtimate C18 2.1*30mm, 3um) R =3.178min, MS(ESI)m / z 385.1[M+H] + .

[0902] 1 H NMR(400MHz, METHANOL-d4)δ=9.90-9.73(m,1H),9.54(s,1H),9.31(s,1H),8.54- 8.29(m,2H),7.63-7.44(m,1H),7.29-7.04(m,4H),4.17-4.04(m,3H),2.60(s,3H)

[0903] 1-(4-(5-(8-(4-chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)pyrimidin-2-yl)piperazin-1-yl)ethan-1-one

[0904]

[0905] LCMS: In 0-60AB_7.0MIN chromatography (Xtimate C18 2.1*30mm, 3um) R =4.267min, MS(ESI)m / z 513.2[M+H] + .

[0906] (E)-8-(3-Fluorophenyl)-3-methyl-N,1-di(pyrimidin-5-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imine

[0907]

[0908] LCMS: In 0-60AB_7.0MIN chromatography (Xtimate C18 2.1*30mm, 3um) R =3.799min,MS(ESI)m / z 449.0[M+H] + .

[0909] 3-Methyl-8-(1-methyl-1H-pyrazol-5-yl)-1-(pyrimidin-5-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imine

[0910]

[0911] LCMS: In 0-60AB_7.0MIN chromatography (Xtimate C18 2.1*30mm, 3um) R =2.965min, MS(ESI)m / z 357.1[M+H] + .

[0912] 8-(4-chloro-3-methoxyphenyl)-3-methyl-1-(4-methylpyrimidin-5-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imide

[0913]

[0914] LCMS: in 0-60AB_7.0min chromatography (Xtimate, 2.1*30mm, 3um) R =4.151min, MS(ESI)m / z 431.2[M+H] + .

[0915] 1 H NMR: (400MHz, DMSO-d6): δ = 9.66 (brs, 2H), 9.51-9.45 (m, 2H), 9.22 (s, 1H), 8.34 (d, J = 9.2Hz, 1H), 8.15-8.12 (m, 1H), 7.4 9(d,J=8.0Hz,1H),7.01-7.00(m,1H),6.99-6.96(m,1H),6.91(td,J=1.6Hz,1H),4.02(s,3H),3.89(s,3H),2.44(s,3H).

[0916] 8-(3-Fluoro-4-methoxyphenyl)-3-methyl-1-(4-methylpyrimidin-5-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imide

[0917]

[0918] LCMS: in 0-60AB_7.0min chromatography (Xtimate, 2.1*30mm, 3um) R =3.783min, MS(ESI)m / z 415.2[M+H] + .

[0919] 1 H NMR: (400MHz, DMSO-d6): δ = 9.58 (brs, 2H), 9.51 (s, 1H), 9.45 (s, 1H), 9.23 (s, 1H), 8.29 (d, J = 8.8Hz, 1H), 8.10-8 .07(m,1H),7.28-7.23(m,2H),7.12-7.10(m,1H),6.84(d,J=1.6Hz,1H),4.02(s,3H),3.88(s,3H),2.45(s,3H).

[0920] 8-(4-Fluoro-3-methoxyphenyl)-3-methyl-1-(4-methylpyrimidin-5-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imide

[0921]

[0922] LCMS: in 0-60AB_7.0min chromatography (Xtimate, 2.1*30mm, 3um) R =3.847min, MS(ESI)m / z 415.2[M+H] + .

[0923] 1 H NMR: (400MHz, DMSO-d6): δ = 9.86 (brs, 2H), 9.59 (s, 1H), 9.48 (s, 1H), 9.24 (s, 1H), 8.39 (d, J = 8.8Hz, 1H), 8.18-8 .16(m,1H),7.32-7.27(m,2H),7.01-6.97(m,2H),6.89(d,J=2.0Hz,1H),4.04(s,3H),3.87(s,3H),2.45(s,3H).

[0924] 8-(3,4-Dimethoxyphenyl)-3-methyl-1-(pyrimidin-5-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imine

[0925]

[0926] LCMS: In 0-60AB_7.0MIN chromatography (Xtimate C18 2.1*30mm, 3um) R =3.495min, MS(ESI)m / z 413.0[M+H] + .

[0927] 8-(4-chloro-3-(trifluoromethyl)phenyl)-3-methyl-1-(4-methylpyrimidin-5-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imine

[0928]

[0929] LCMS: In 0-60AB_7.0MIN chromatography (Xtimate C18 2.1*30mm, 3um) R =4.560min,MS(ESI)m / z 469.0[M+H] + .

[0930] 2-Chloro-5-(2-imino-3-methyl-1-(pyrimidin-5-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl)benzonitrile

[0931]

[0932] LCMS: In 0-60AB_7.0MIN chromatography (Xtimate C18 2.1*30mm, 3um) R =4.019min, MS(ESI)m / z 412.1[M+H] + .

[0933] 8-(4-chloro-3-(trifluoromethoxy)phenyl)-3-methyl-1-(4-methylpyrimidin-5-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imide

[0934]

[0935] LCMS: In 0-60AB_7.0MIN chromatography (Xtimate C18 2.1*30mm, 3um) R =4.747min, MS(ESI)m / z 485.1[M+H] + .

[0936] 8-(4-chloro-3-(trifluoromethoxy)phenyl)-3-methyl-1-(pyrimidin-5-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imide

[0937]

[0938] LCMS: In 0-60AB_7.0MIN chromatography (Xtimate C18 2.1*30mm, 3um) R =4.702min, MS(ESI)m / z 471.1[M+H] + .

[0939] 8-(3,4-Dimethoxyphenyl)-3-methyl-1-(4-methylpyrimidin-5-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imide

[0940]

[0941] LCMS: In 0-60AB_7.0MIN chromatography (Xtimate C18 2.1*30mm, 3um) R =3.562min, MS(ESI)m / z 427.1[M+H] + .

[0942] 3-Methyl-1-(pyrimidin-5-yl)-8-(6-(trifluoromethyl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imine

[0943]

[0944] LCMS: In 0-60AB_7.0MIN chromatography (Xtimate C18 2.1*30mm, 3um) R =3.823min, MS(ESI)m / z 422.2[M+H] + .

[0945] 3-Methyl-8-(6-methylpyridin-3-yl)-1-(pyrimidin-5-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imine

[0946]

[0947] LCMS: In 0-60AB_7.0MIN chromatography (Xtimate C18 2.1*30mm, 3um) R =2.418min, MS(ESI)m / z 368.2[M+H]+ .

[0948] 8-(6-methoxypyridin-3-yl)-3-methyl-1-(pyrimidin-5-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imine

[0949]

[0950] LCMS: In 0-60AB_7.0MIN chromatography (Xtimate C18 2.1*30mm, 3um) R =3.503min, MS(ESI)m / z 384.2[M+H] + .

[0951] 4-(8-(4-chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)pyrimidin-2-amine

[0952]

[0953] LCMS: in 0-60AB_7min_220&254_Shimadzu chromatography (Xtimate C182.1*30mm) R =3.299min, MS(ESI)m / z 402.0[M+H] + .

[0954] 1 H NMR (400MHz, DMSO-d6) δ = 9.54 (br s, 2H), 9.48 (s, 1H), 8.76 (d, J = 4.8Hz, 1H), 8.35 (d, J = 8.9Hz, 1H), 8.14 (br d,J=9.0Hz,1H),7.65-7.52(m,6H),7,7.14(d,J=4.9Hz,1H),3.98(s,3H).

[0955] 4-(8-(3-Fluorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)pyrimidin-2-amine

[0956]

[0957] LCMS: in 0-60AB_7min_220&254_Shimadzu chromatography (Xtimate C182.1*30mm) R =3.024min, MS(ESI)m / z 386.0[M+H] + .

[0958] 1 H NMR (400MHz, DMSO-d6) δ = 9.96 (br s, 2H), 9.68 (s, 1H), 8.79 (br d, J = 4.6Hz, 1H), 8.46 (br d, J = 8.9Hz, 1H), 8.26 (br d,J=8.9Hz,1H),7.61(s,1H),7.53(q,J=7.3Hz,1H),7.38(br d,J=8.5Hz,2H),7.29(br t,J=8.4Hz,1H),7.19(br d,J=4.6Hz,1H),4.05(s,3H).

[0959] 8-(4-chlorophenyl)-3-methyl-1-(4-(trifluoromethyl)pyrimidin-2-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imide

[0960]

[0961] LCMS: in 0-60AB_7min_220&254_Shimadzu chromatography (Xtimate C182.1*30mm, 3um) R =4.207min, MS(ESI)m / z 455.2[M+H] + .

[0962] 1 H NMR (400MHz, DMSO-d6) δ = 9.63 (d, J = 5.1Hz, 1H), 9.54 (br s,2H),9.38(s,1H),8.50(d,J=5.1Hz,1H),8.26(d,J=8.8Hz,1H),8.06(dd ,J=2.0,8.8Hz,1H),7.63-7.55(m,3H),7.47(d,J=8.6Hz,2H),3.94(s,3H).

[0963] 8-(3-Fluorophenyl)-3-methyl-1-(4-(trifluoromethyl)pyrimidin-2-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imine

[0964]

[0965] LCMS: in 0-60AB_7min_220&254_Shimadzu chromatography (Xtimate C182.1*30mm, 3um) R=4.372min, MS(ESI)m / z 439.2[M+H] + .

[0966] 1 H NMR (400MHz, DMSO-d6) δ = 9.63 (d, J = 5.1Hz, 1H), 9.59 (br s,2H),9.40(s,1H),8.52(d,J=5.1Hz,1H),8.27(d,J=8.8Hz,1H),8.10(dd,J=2.0,9.0Hz,1H),7.67(d,J=1.7Hz,1H),7.51-7.36(m,3H),7.21(br t,J=8.2Hz,1H),3.95(s,3H).

[0967] 8-(4-chlorophenyl)-1-(4-methoxypyrimidin-2-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imine

[0968]

[0969] LCMS: in 0-60AB_7min_220&254_Shimadzu (Xtimate C182.1*30mm, 3um) R =4.031min, MS(ESI)m / z 417.2[M+H] + .

[0970] 1 H NMR: (400MHz, DMSO-d6)δ=9.58-9.44(m,1H),9.47(br s,1H),9.39(s,1H),8.96(d,J=5.8Hz,1H),8.29(d,J=8.8Hz,1H),8.14-8.07( m,1H),7.57(q,J=8.7Hz,5H),7.42(d,J=6.0Hz,1H),3.97(s,3H),3.95(s,3H)

[0971] 2-(8-(4-chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)pyrimidin-4-ol

[0972]

[0973] LCMS: in 0-60AB_7min_220&254_Shimadzu (Xtimate C182.1*30mm, 3um) R=3.692min, MS(ESI)m / z 403.2[M+H] + .

[0974] 1 H NMR: (400MHz, DMSO-d6) δ = 9.54-9.40 (m, 2H), 9.37 (s, 1H), 8.81 (d, J = 5.9Hz, 1H), 8.28 (d, J = 8.8Hz, 1H) ,8.08(dd,J=2.0,9.0Hz,1H),7.70-7.59(m,3H),7.58-7.53(m,2H),7.16(d,J=6.1Hz,1H),3.94(s,3H)

[0975] 8-(3-Fluorophenyl)-1-(4-methoxypyrimidin-2-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imine

[0976]

[0977] LCMS: in 0-60AB_7min_220&254_Shimadzu (Xtimate C182.1*30mm, 3um) R =5.051min, MS(ESI)m / z 401.2[M+H] + .

[0978] 1 H NMR: (400MHz, DMSO-d6)δ=9.41(br s,2H),9.40(s,1H),8.96(d,J=6.0Hz,1H),8.29(d,J=8.8Hz,1H),8.13(dd,J=2.0,9.0Hz,1H), 7.65(s,1H),7.56-7.50(m,1H),7.47-7.40(m,3H),7.30-7.24(m,1H),3.96(s,3H),3.95(s,3H)

[0979] 2-(8-(3-Fluorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)pyrimidin-4-ol

[0980]

[0981] LCMS: in 0-60AB_7.0min_220&254_Shimadzu (Xtimate C182.1*30mm, 3um) R=3.187min, MS(ESI)m / z 387.1[M+H] + .

[0982] 1 H NMR: (400MHz, DMSO-d6) δ = 9.31 (s, 2H), 8.24 (d, J = 9.0Hz, 1H), 8.17-7.97 (m, 4H), 7.57-7.47 (m, 3H), 7.25 (s, 1H), 3.90 (s, 3H)

[0983] 2-(8-(4-chlorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)pyrimidin-4-amine

[0984]

[0985] LCMS: in 0-60AB_7min_220&254_Shimadzu chromatography (Xtimate C182.1*30mm) R =3.400min, MS(ESI)m / z 402.0[M+H] + .

[0986] 1 H NMR (400MHz, DMSO-d6) δ=9.62(br s,2H),9.45(s,1H),8.39(br d,J=5.6Hz,1H),8.32(br d,J=8.8Hz,1H),8.12(br d,J=8.9Hz,1H),8.03(br s,1H),7.82(br s,1H),7.76(s,1H),7.67-7.61(m,2H),7.60-7.52(m,2H),6.82(br d,J=5.9Hz,1H),3.98(s,3H).

[0987] 2-(8-(3-Fluorophenyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)pyrimidin-4-amine

[0988]

[0989] LCMS: in 0-60AB_7min_220&254_Shimadzu chromatography (Xtimate C182.1*30mm) R =3.130min, MS(ESI)m / z 386.0[M+H] + .

[0990] 1 H NMR (400MHz, DMSO-d6) δ=9.34(br d,J=3.6Hz,3H),8.39(br d,J=5.6Hz,1H),8.24(br d,J=8.8Hz,1H),8.08(br d,J=8.8Hz,1H),7.96(br s,1H),7.77(s,2H),7.53(q,J=7.1Hz,1H),7.49-7.40(m,2H),7.35-7.22(m,1H),6.79(br d,J=5.8Hz,1H),3.92(s,3H).

[0991] 8-(3,4-Dimethoxyphenyl)-3-methyl-1-(3-methylpyrazin-2-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imide

[0992]

[0993] LCMS: in 0-60AB_7min_220&254_Shimadzu chromatography (Xtimate C182.1*30mm) R =3.768min, MS(ESI)m / z 427.1[M+H] + .

[0994] 3-Methyl-8-(6-methylpyridin-3-yl)-1-(4-(methylsulfonyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imide

[0995]

[0996] LCMS: in 0-60AB_7min_220&254_Shimadzu chromatography (Xtimate C182.1*30mm) R =2.739min, MS(ESI)m / z 444.2[M+H] + .

[0997] 8-(3,4-Dimethoxyphenyl)-1-(pyridazin-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imide

[0998]

[0999] LCMS: in 0-60AB_7min_220&254_Shimadzu chromatography (Xtimate C182.1*30mm)R =3.409min, MS(ESI)m / z 399.2[M+H] + .

[1000] 3-Methyl-1-(4-methylpyrimidin-5-yl)-8-(3-(methylsulfonyl)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imide

[1001]

[1002] LCMS: in 0-60AB_7min_220&254_Shimadzu chromatography (Xtimate C182.1*30mm) R =3.268min, MS(ESI)m / z 445.0[M+H] + .

[1003] 8-(3-Fluoro-4,5-dimethoxyphenyl)-3-methyl-1-(4-methylpyrimidin-5-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-imide

[1004]

[1005] LCMS: tR=4.074 min, MS (ESI) m / z 445.2 [M+H]+ in 0-60AB_7min_220&254_Shimadzu chromatography (Xtimate C18 2.1*30mm).

[1006] Example 4

[1007] This example demonstrates gametocytic activity and activity against asexual parasites according to embodiments of the present invention.

[1008] Compounds were screened against gametocytes and asexual parasites as described in Examples 1 and 2. The results are given in Tables 1-3.

[1009] Table 1

[1010]

[1011]

[1012]

[1013]

[1014]

[1015]

[1016]

[1017]

[1018]

[1019]

[1020]

[1021]

[1022]

[1023]

[1024]

[1025]

[1026]

[1027]

[1028]

[1029] Table 2

[1030]

[1031]

[1032] Table 3

[1033]

[1034]

[1035]

[1036]

[1037]

[1038] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

[1039] In the context of describing the present invention (especially in the context of the appended claims), unless otherwise stated herein or clearly contradicted by the context, the use of the terms "a" and "a kind of" and "the" and "at least one" and similar references will be interpreted as covering both singular and plural forms. Unless otherwise stated herein or clearly contradicted by the context, the use of the term "at least one" followed by a listing of one or more items (e.g., "at least one of A and B") will be interpreted as meaning any combination of two or more of the listed items (A or B) selected from the listed items (A or B), unless otherwise stated herein or clearly contradicted by the context. Unless otherwise stated, the terms "comprising," "having," "including," and "containing" should be interpreted as open terms (i.e., meaning "including but not limited to"). Unless otherwise stated herein, the enumeration of numerical ranges herein is intended only to be used as a shorthand method of referring to each individual value falling within the range, and each individual value is incorporated into the specification as if it were individually listed herein. Unless otherwise stated herein or clearly contradicted by the context, all methods described herein can be performed in any suitable order. The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended merely to better illuminate the invention and does not limit the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[1040] Preferred embodiments of the present invention are described herein, including the best mode known to the inventor for implementing the present invention. By reading the foregoing description, variations of those preferred embodiments will be apparent to those of ordinary skill in the art. The inventor expects that a skilled person will appropriately adopt such variations, and the inventor wishes to practice the present invention in a manner different from that specifically described herein. Therefore, the present invention includes all modifications and equivalents of the subject matter recited in the appended claims as permitted by applicable law. Moreover, unless otherwise noted herein or clearly contradicted by context, the present invention encompasses any combination of the above elements with all their possible variations.

Claims

1. Compounds of formula (I): Where A is CR 5 or N, B is CR 8 =CR 9 or NR 2 , R 8 and R 9 Independently selected from hydrogen, hydroxy, OR 10 , halogen, optionally substituted C 6-10 Aryl and optionally substituted C 1-6 alkyl, R 10 It is hydrogen, C 1-12 Alkyl, C 3-8 Cycloalkyl, CH2COOR 13 or H2N(CH2) n -, wherein n is an integer from 2 to 6, R 1 It is C 6-10 Aryl or heteroaryl, each of which is substituted by at least one selected from -CN, halogen, -CF3, -CONH2, -OCF3, C1-C6 alkyl, C1-C6 alkylcarbonyl, -OH, C1-C6 alkylaminocarbonyl, C3-C8 cycloalkylaminocarbonyl, C1-C6 alkylaminoalkyl, cyanomethyl, piperazinylmethyl, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonylamino, dialkylaminoalkylamino, optionally substituted piperazinylcarbonyl, C1-C6 alkoxy and heterocyclyl substituents are optionally substituted, wherein the heterocyclyl is selected from piperazin-1-yl, 4-(C1-C6 alkylcarbonyl)piperazin-1-yl, morpholinyl optionally substituted by C1-C6 alkyl, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, octahydropyrrolo[3,4-b]pyrrolyl and 2-oxa-6-azaspiro[3.3]heptyl, C3-C8 cycloalkyl or C3-C8 azacycloalkyl each optionally substituted by morpholino, optionally substituted piperidinyl or optionally substituted piperazinyl, R 2 is C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkylsulfonyl or optionally substituted benzyl, R 3 It's H. R 4 is phenyl, heteroaryl, 1-phenyl-2-ethynyl or heterocyclic, wherein the phenyl, heteroaryl, heterocyclic or phenyl of the 1-phenyl-2-ethynyl is selected from halogen, C1-C6 alkyl, amino, oxo, dialkylaminoalkyl, dialkylaminoalkoxy, -CN, aminocarbonyl, -OR 6 , CF3 and C1-C6 alkylsulfonyl are optionally substituted with one or more substituents, R 6 is H or C1-C6 alkyl, and R 5 is hydrogen, C1-C6 alkyl, C6-C 10 Aryl, halogen, hydroxyl or OR 7 , where R 7 is C1-C6 alkyl, formyl, C1-C6 acyl or C6-C 10 Aryl, or a pharmaceutically acceptable salt thereof.

2. The compound or salt of claim 1, wherein A is CH, B is NR 2 , and R 1 Selected from 3. The compound or salt of claim 2, wherein R 2 is methyl, R 1 yes And R 4 It is chlorophenyl, 4. The compound or salt of claim 2, wherein R 2 is methyl, R 1 yes And R 4 is 4-fluorophenyl, 3-dimethylaminomethylphenyl, 3-cyanophenyl, 3-cyano-4-chlorophenyl, 3-methoxy-4-chlorophenyl, 3-chlorophenyl, 3-fluorophenyl, phenyl, 3-methylphenyl, 3-hydroxyphenyl, 3-aminophenyl, 3-hydroxy-4-fluorophenyl, 3,4-dimethoxyphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 2-methylphenyl, 2-chlorophenyl or 2-hydroxyphenyl.

5. The compound or salt of claim 2, wherein R 2 is methyl, R 4 is 4-chlorophenyl, and R 1 yes 6. The compound or salt of claim 2, wherein R 1 yes R 2 is a methyl group, and R 4 is 4-chlorophenyl, or where R 1 yes as well as R 2 is a methyl group, and R 4 is 4-fluorophenyl, R 2 is ethyl, and R 4 It is 4-chlorophenyl, R 2 is benzyl or hydroxyethyl, and R 4 It is 4-chlorophenyl, R 2 is 2-hydroxyethyl, and R 4 is 4-chlorophenyl, or R 2 is a methyl group, and R 4 is 4-chlorophenyl, or where R 1 yes R 2 is a methyl group, and R 4 is 3-fluorophenyl, or wherein R 1 yes R 2 is a methoxycarbonyl group, and R 4 is 3-fluorophenyl or 4-methylphenyl, or where R 1 yes R 2 is a methoxycarbonyl group, and R 4 It is 3-fluorophenyl or 4-methylphenyl.

7. The compound or salt of claim 1, wherein B is CR 8 =CR 9 , A is CH, and R 8 and R 9 Both are H.

8. The compound or salt of claim 7, wherein R 1 yes And R 4 It is 4-chlorophenyl or 2-amino-5-pyridyl.

9. The compound or salt of claim 1, wherein A is CH, B is NR 2 , and R 1 Selected from 10. The compound or salt of claim 9, wherein R 1 yes R 2 is a methyl group, and R 4 It is 4-chlorophenyl, 4-fluorophenyl, 2-aminopyridin-5-yl, 4-methylphenyl, 3-fluorophenyl, 3,4-dimethoxyphenyl, 3-cyano-4-chlorophenyl, 3-trifluoromethoxy-4-chlorophenyl, 2-trifluoromethylpyridin-5-yl, 2-methylpyridin-5-yl or 2-methoxypyridin-5-yl.

11. The compound or salt of claim 9, wherein R 1 yes R 2 is a methyl group, and R 4 It is 4-chlorophenyl, 4-fluorophenyl, 2-aminopyridin-5-yl, 4-methylphenyl, 3-fluorophenyl, 3-methoxy-4-chlorophenyl, 3-fluoro-4-methoxyphenyl, 3-methoxy-4-fluorophenyl, 3-trifluoromethyl-4-chlorophenyl, 3-trifluoromethoxy-4-chlorophenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4-dimethoxy-5-fluorophenyl, 3,4-dimethoxy-5-chlorophenyl or 3,4,5-trimethoxyphenyl.

12. The compound or salt of claim 9, wherein: R 2 is methyl, and wherein: R 1 yes And R 4 It is 4-chlorophenyl, R 1 yes And R 4 is 3-fluorophenyl, R 1 yes And R 4 is 4-chlorophenyl or 3-fluorophenyl, R 1 yes And R 4 is 4-chlorophenyl or 3-fluorophenyl, R 1 yes And R 4 is 4-chlorophenyl or 3-fluorophenyl, R 1 yes And R 4 is 4-chlorophenyl or 3-fluorophenyl, R 1 yes And R 4 is 3,4-dimethoxyphenyl, or R 1 yes And R 4 It is 3,4-dimethoxyphenyl.

13. The compound or salt of claim 9, wherein: R 1 yes R 2 is a methyl group, and R 4 is 3-fluorophenyl, R 1 yes R 2 is H, and R 4 It is 3,4-dimethoxyphenyl.

14. A pharmaceutical composition comprising the compound or salt according to any one of claims 1 to 13 and a pharmaceutically acceptable carrier.

15. Use of a compound or salt as claimed in any one of claims 1 to 13 for the preparation of a pharmaceutical composition for blocking the transmission of Plasmodium parasites in a mammal or for killing or arresting the growth of Plasmodium organisms in a mammal, wherein the Plasmodium organisms are present in the hepatic stage or the asexual stage.

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