WO 2006/124692 PCT/US2006/018582
3-CYANOQUINOLINE INHIBITORS OF TPL2 KINASE AND METHODS OF MAKING AND USING THE SAME
FIELD OF THE INVENTION
The invention relates to substituted 3~cyanoquinolines that are capable of modulating Tpl-2 kinase and to methods for the preparation of the substituted 3-cyanoquinolines. The cyanoquinolines of the present invention are useful for the treatment of inflammatory diseases, such as rheumatoid arthritis.
BACKGROUND
Protein kinases are a class of enzymes that catalyze the transfer of a phosphate group from ATP to a tyrosine, serine, threonine, or histidine residue located on a protein substrate, many of which play a role in normal cell growth. Protein tyrosine kinases (PTKs) play a key role in signal transduction pathways that regulate cell division and differentiation. Certain growth factor receptor kinases have been identified as markers for a poor prognosis in many human cancers if they are overexpressed. See Hickey e al. J. Cancer, 1994, 74:1693.
Similar to PTKs, serine/threonine kinases are also involved in the regulation of cell growth. The MEK kinase Tpl-2 (also known as Cot and MAP3K8) is a serine/threonine kinase that has been shown to be a protooncogene when it is cleaved at its C-terminus. See beinke et al., Mol. Cell Biol., 2003, 23:4739-4752.
Tpl-2 is known to be upstream in the MEK-ERK pathway and is essential for LPS induced tumor necrosis factor-a (TNF-a) production, as demonstrated by the Tpl2 knockout mouse (Tsichlis et. al. EMBO J,, 1996,15, 817). Tpl-2 is also required for TNF-α signaling (i.e. the cellular response to ligation of the TNF-α receptor). TNF-α is a pro-inflammatory cytokine that is involved in inflammation in a number of disease states, most notably in the autoimmune disease rheumatoid arthritis (RA). A protein therapeutic ENBREL/etanercept (sTNRRa) is currently available to patients with RA. However, an orally available small molecule that inhibits TNF-α synthesis and/or signaling is desirable. Tpl2 is not inhibited by staurosporine and it is the only human kinase that contains a proline instead of a conserved glycine in the glycine-rich ATP binding loop. These unique features of Tpl2 may increase the potential for discovering a selective inhibitor of the enzyme.
Heretofore, there have not been described cyanoquinolines that bind to and inhibit serine/threonine protein kinases and inhibit TNF-α synthesis and/or signaling

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that are useful -in the treatment ot inflammatory diseases. The present invention provides 4,6-diamino-3-cyanoquinolines that are inhibitors of the serinefthreonine kinase Tpl-2 and can be used to treat inflammatory diseases, such as RA. This invention also provides methods of making the 4,6-diamino-3-cyanoquinolines. Not wishing to be bound by any theory, it is believed that the compounds of the present invention are useful in the treatment of inflammatory disease states, such as RA, because they have a double benefit of blocking both TNF-α production and signaling.
SUMMARY OF THE INVENTION
The present invention provides compounds of formula (I):

and pharmaceutically acceptable salts thereof, wherein R\ R2, R3, R4, R5, R6, R7, R8, m and n are defined as described herein. The invention also provides methods of making the compounds of formula (I), and methods of treating inflammatory diseases, such as rheumatoid arthritis, comprising administering a therapeutically effective amount of a compound of formula (I) to a mammal.
DETAILED DESCRIPTION
The invention provides compounds of formula (I):

2
wherein:

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R1 is selected from the group consisting of C3-10 cycloalkyl, aryl, 3-10 membered cycloheteroalkyl, and heteroaryl, each optionally substituted with 1-4 moieties selected from the group consisting of:
a) halogen, b) CN, c) NO2, d) N3, e) OR9, f) NR10R1\ g) oxo, h) thioxo, i) S(O)PR9, j) SO2NR10R11, k) C(O)R9,1) C(O)OR9, m) C(O)NR10R11, n) Si(C1-6 alkyl)3,O) C1-6 alkyl, p) C2^ alkenyl, q) C2-6 alkynyl, r) C1-6 alkoxy, s) C1-6 alkylthio, t) C1-6 haloalkyl, u) C3-10 cycloalkyl, v) aryl, w) 3-10 membered cycloheteroalkyl, and x) heteroaryl,
wherein any of o) - x) optionally is substituted with 1-4 R12 groups;
alternatively, R1 is selected from the group consisting of halogen, C1-6 alkyl optionally substituted with 1-4 R12 groups, C1-6 haloalkyl, OR9, NR10R11, C(O)OR9, C(O)NR10R11, S(O)PR9, and N3;
R2 is selected from the group consisting of:
a) H, b) halogen, c) CN, d) NO2, e) OR9, f) NR10R11, g) S(O)PR9, h) SO2NR10R11, i) C(O)R9, j) C(O)OR9, k) C(O)NR10R11,1) C1-6 alkyl, m) C2-e alkenyl, n) C2^ alkynyl, o) C1-6 alkoxy, p) C1-6 alkylthio, q) C3.10 cycloalkyl, r) aryl, s) 3-10 membered cycloheteroalkyl, and t) heteroaryl,
wherein any of I) -1) optionally is substituted with 1-4 R12 groups;
R3 is selected from the group consisting of:
a) H, b) halogen, c) CN, d) NO2, e) OR9, f) NR10R11, g) S(O)PR9, h) SO2NR10R11, i) C(O)R9, j) C(O)OR9, k) C(O)NR10R11,1) d-e alkyl, m) C2^ alkenyl, n) C2^ alkynyl, o) C1-6 alkoxy, p) C1-6 alkylthio, q) C1-6 haloalkyl, r) C3-10 cycloalkyl, s) aryl, t) 3-10 membered cycloheteroalkyl, and u) heteroaryl,
wherein any of I) - u) optionally is substituted with 1-4 R12 groups;
R4 is selected from the group consisting of C3-10 cycloalkyl, aryl, C3-10 cycloheteroalkyl, and heteroaryl, each optionally substituted with 1-4 moieties selected from the group consisting of:
a) halogen, b) CN, c) NO2, d) OR9, e) NR10R1\ f) oxo, g) thioxo, h) S(O)PR9,
i) SO2NR10R11, j) C(O)R9, k) C(O)OR9,1) C(O)NR10R11, m) Si(d.6 alkyl)3,
n) C1-6 alkyl, o) CM alkenyl, p) C2-6 alkynyl, q) C1-6 alkoxy, r) C1-6 alkylthio,
s) C1-6 haloalkyl, t) C3-10 cycloalkyl, u) aryl, v) 3-10 membered
cycloheteroalkyl, and w) heteroaryl,
wherein any of n) - w) optionally is substituted with 1-4 R12 groups;
alternatively, R4 is selected from the group consisting of C1-6 alkyl optionally substituted with 1-4 R12 groups, C1-6 haloalkyl, C(O)OR9, C(O)NR10R11, S(O)PR9, and
N3;
R5 and R6 at each occurrence independently are selected from the group consisting of:
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a) H, b) C(O)R9, c) C(O)OR9, d) C(O)NR10R11, e) C1-6 alkyl, f) C2-6 alkenyl, g) C2-6 alkynyl, h) C1-6 haloalkyl, i) C3-10 cycloalkyl, j) aryl, k) 3-10 membered cycloheteroalkyl, and I) heteroaryl,
wherein any of e) -1) optionally is substituted with 1-4 R12 groups;
R7 and R8 at each occurrence independently are selected from the group consisting of:
a) H, b) halogen, c) OR9, d) NR10R1\ e) CM alkyl, f) C2^ alkenyl, g) C2^ alkynyl, h) C1-6 haloalkyl, and i) aryl;
alternatively, any two R7 or R8 groups and the carbon to which they are bonded may form a carbonyl group;
R9 at each occurrence is selected from the group consisting of: a) H, b) C(O)R13, c) C(O)OR13, d) C(O)NR13R14, e) C« alkyl, f) C2J6 alkenyl, g) C2* alkynyl, h) C1-6 haloalkyl, i) C^o cycloalkyl, j) aryl, k) 3-10 membered cycloheteroalkyl, and I) heteroaryl;
wherein any of e) -1) optionally is substituted with 1-4 R15 groups;
R10 and R11 at each occurrence independently are selected from the group consisting of:
a) H, b) OR13, c) SO2R13, d) C(O)R13, e) C(O)OR13, f) C(O)NR13R14, g) C1-6 alkyl, h) C2-6 alkenyl, i) C2-6 alkynyl, k) C1-6 haloalkyl, I) C3-10 cycloalkyl, m) aryl, n) 3-10 membered cycloheteroalkyl, and o) heteroaryl;
wherein any of g) - o) optionally is substituted with 1-4 R15 groups;
R12 at each occurrence independently is selected from the group consisting of:
a) halogen, b) CN, c) NO2, d) N3, e) OR9, f) NR10R11, g) oxo, h) thioxo, i) S(O)PR9, j) SO2NR10R1\ k) C(O)R9,1) C(O)OR9, m) C(O)NR10R11, n) Si(C^ alkyl)3l o) d-e alkyl, p) C2_e alkenyl, q) CM alkynyl, r) C14 alkoxy, s) CLB alkylthio, t) C14 haloalkyl, u) C3.10 cycloalkyl, v) aryl, w) 3-10 membered cycloheteroalkyl, and x) heteroaryl;
wherein any of o) - x) optionally is substituted with 1-4 R15 groups;
R13 and R14 at each occurrence independently are selected from the group consisting of:
a) H, b) C1-6 alkyl, c) C2-6 alkenyl, d) C2-6 alkynyl, e) C1-6 haloalkyl, f) C3-10 cycloalkyl, g) aryl, h) 3-10 membered cycloheteroalkyl, and i) heteroaryl,
wherein any of b) - j) optionally is substituted with 1-4 R15 groups;
R16 at each occurrence independently is selected from the group consisting of:
a) halogen, b) CN, c) NO2, d) N3, e) OH, f) O-d-e alkyl, g) NH2, h) NH(C1-6 alkyl), i) N(C1-6 alkyl)2, j) NH(aryl), k) NH(cycloalkyl), I) NH(heteroaryl),
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m) NH(cycloheteroalkyl), n) oxo, o) thioxo, p) SH, q) S(O)p-C1-6 alkyl, r) C(O)-Calkyl, s) C(O)OH, t) C(O)O-Calkyl, u) C(O)NH2, v) CfOJNHCn alkyl. w) C(O)N(C alkyl)2, x) C1-6 alkyl, y) C2.e alkenyl, z) C2-6 alkynyl, aa) C1-6 alkoxy, bb) C1-6 alkylthio, cc) Ce haloalkyl, dd) Co cycloalkyl, ee) aryl, ff) 3-10 membered cycloheteroalkyl, and gg) heteroaryl,
wherein any CM alkyl, C2-e alkenyl, C2.8 alkynyl, C3.10 cycloalkyl, aryl, 3-10 membered cycloheteroalkyl, or heteroaryl, alone as a part of another moiety, optionally is substituted with one or more moieties selected from the group consisting of halogen, CN, NO2l OH, O-Cealkyl, NH2, NH(C alkyl), H(C alkyl)2> NH(aryl), NH(cycloalkyl), NH(heteroaryl), NH(cycloheteroalkyl), oxo, thioxo, SH, S(O)P-C alkyl, C(O)-C alkyl, C(O)OH, C(O)O-C alkyl, C(O)NH2, C(O)NHC alkyl, C(O)N(Ci.6 alkyl)2, C1-6 alkyl, C2 alkenyl, C2.6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C3.10 cycloalkyl, aryl, 3-10 membered cycloheteroalkyl, and heteroaryl;
m is 0, 1,2, 3, or 4;
n is 0 or 1; and
p is 0, 1, or 2;
or a pharmaceutically acceptable salt thereof, provided that the compound of formula (I) does not comprise:

4-(3-Chloro-4-fluoro-phenylamino)-7-methoxy-6-(4-morpholin-4-yl-butylamino)-
5
quinoline-3-carbonitrile, or


WO 2006/124692 PCT/US2006/018582
4-(3-Bromo-phenylamino)-6-(3-pyrrolidin-1-yl-propylamino)-quinoline-3-carbonitrile.
R1 may be a 5 or 6 membered heteroaryl, such as imidazole, triazole (e.g., 1,2,3- triazole), tetrazole, pyridine, or N-oxypyridine.
In certain embodiments, R2 is H or alkylthio optionally substituted with NR10R11 (e.g., SCH2CH2N(CH3)2).
In some embodiments, R3 is H or a halogen, such as Cl or Br.
R4 may be phenyl optionally substituted with 1-2 halogens, such as Cl or F. In some embodiments, R4 is phenyl substituted with Cl and F, such as 3-chloro-4-fluorophenyl.
R5 may be, for instance, H or C1-6 alkyl.
Examples of R6 include H and C1-6 alkyl.
In certain embodiments, m is 1.
In some embodiments, n is 0.
In some embodiments, when m is 2, 3, or 4, R1 is not morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S,S-dioxide, piperidine, pyrrolidine, aziridine, pyridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, thiazole, thiazolidine, tetrazole, piperazine, furan, thiophene, tetrahydrothiophene, tetrahydrofuran, dioxane, 1,3-dioxolane, tetrahydropyran or

wherein q is 1-4.
In other embodiments, when R1 is a saturated 3-8 membered cycloheteroalkyl, R1 is not substituted with-(CR82)r-Het1 or -(CR82)s-Y-(CR82)t-Het1, wherein
Het1 is selected from the group consisting of morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S,S-dioxide, piperidine, pyrrolidine, aziridine, pyridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, thiazole, thiazolidine, tetrazole, piperazine, furan, thiophene, tetrahydrothiophene, tetrahydrofuran, dioxane, 1,3-dioxolane, pyrrole, and tetrahydropyran;
Y is selected from the group consisting of O, S, NR10C(O), C(O)NR10, and NR10;
r is 0-8;
s is 0-4; and
t is 0-4.
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The invention also includes intermediates of the compounds described herein having the formula (II):

wherein Z is halogen, C1-6 alkyl optionally substituted with 1-4 R12 groups, Ci.6 haloalkyl, OR9, NR10R1\ S(O)PR9, SO2NR10R11, C(O)R9, C(O)OR9, C(O)NR10R11, or N3, and R2, R3, R4, R6, R8, R9, R10, R1t, R12, n and p are defined as described above.
The invention also includes pharmaceutical compositions that include one or more compounds according to the invention, or pharmaceutically salts thereof, and one or more pharmaceutically acceptable carriers.
The compounds of the present invention are useful for the treatment of disease conditions mediated by Tpl2, such as rheumatoid arthritis (RA), juvenile RA, psoriatic arthritis, ankylosing spondylitis, and osteoarthritis and for the alleviation of symptoms thereof. Accordingly, the present invention further provides methods of treating these diseases and disorders using the compounds described herein. In some embodiments, the methods include identifying a mammal having a disease or disorder mediated by Tpl2, and providing to the mammal an effective amount of a compound as described herein.
In further embodiments, the methods are provided for alleviating a symptom of a disease or disorder mediated by Tpl2. In some embodiments, the methods include identifying a mammal having a symptom of a disease or disorder mediated by Tpl2, and providing to the mammal an amount of a compound as described herein effective to ameliorate (i.e., lessen the severity of) the symptom.
Pharmaceutically acceptable salts of the compounds of Formula (I) having an acidic moiety can be formed from organic and inorganic bases. Suitable salts with bases are, for example, metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, or magnesium salts; or salts with ammonia or an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine, for example ethyl-tert-butyl-, diethyl-, diisopropyl-, triethyl-,
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tributyl- or dimethylpropylamine, or a mono-, di-, or trihydroxy lower alkylamine, for example mono-, di- ortriethanolamine. Internal salts may furthermore be formed. Similarly, when a compound of the present invention contains a basic moiety, salts can be formed from organic and inorganic acids. For example, salts can be formed from acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, or camphorsulfonic acid, or other known pharmaceutically acceptable acids.
The present invention also includes prodrugs of the compounds described herein. As used herein, "prodrug" refers to a moiety that releases a compound of the invention when administered to a mammalian subject. Prodrugs can be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either by routine manipulation or in vivo, to the parent compounds. Examples of prodrugs include compounds of the invention as described herein that contain one or more molecular moieties appended to a hydroxyl, amino, sulfhydryl, or carboxyl group of the compound, and that when administered to a mammalian subject, cleaves in vivo to form the free hydroxyl, amino, sulfhydryl, or carboxyl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the invention. Preparation and use of prodrugs is discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference in their entirety.
The present invention provides pharmaceutical compositions comprising at least one compound according to the invention and one or more pharmaceutically acceptable carriers, excipients, or diluents. Examples of such carriers are well known to those skilled in the art and are prepared in accordance with acceptable pharmaceutical procedures, such as, for example, those described in Remington's Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, PA (1985), which is incorporated herein by reference in its entirety. Pharmaceutically acceptable carriers are those that are compatible with the other ingredients in the formulation and biologically acceptable. Supplementary active ingredients can also be incorporated into the compositions.
The compounds of the invention may be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers. Applicable solid carriers can include one or more substances which may also act as flavoring agents,
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lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents or encapsulating materials. They are formulated in conventional manner, for example, in a manner similar to that used for known antiinflammatory agents. Oral formulations containing the active compounds of this invention may comprise any conventionally used oral form, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions. In powders, the carrier is a finely divided solid, which is an admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets may contain up to 99% of the active ingredient.
Capsules may contain mixtures of the active compound(s) with inert fillers and/or diluents such as the pharmaceutically acceptable starches (e.g. corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses, such as crystalline and microcrystalline celluloses, flours, gelatins, gums, etc.
Useful tablet formulations may be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, surface modifying agents (including surfactants), suspending or stabilizing agents, including, but not limited to, magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidine, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, low melting waxes and ion exchange resins. Preferred surface modifying agents include nonionic and anionic surface modifying agents. Representative examples of surface modifying agents include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colliodol silicon dioxide, phosphates, sodium dodecylsulfate, magnesium aluminum silicate, and triethanolamine. Oral formulations herein may utilize standard delay or time release formulations to alter the absorption of the active compound(s). The oral formulation may also consist of administering the active ingredient in water or fruit juice, containing appropriate solubilizers or emulisifiers as needed.
Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs. The active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic
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solvent, or a mixture of both, or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as described above, e.g. cellulose derivatives, such as a sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.
Liquid pharmaceutical compositions, which are sterile solutions or suspensions, can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Compositions for oral administration may be in either liquid or solid form.
Preferably the pharmaceutical composition is in unit dosage form, e.g. as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form. Such unit dosage form may contain from about 1 mg/kg to about 250 mg/kg, and may given in a single dose or in two or more divided doses. Such doses may be administered in any manner useful in directing the active compounds herein to the recipient's bloodstream, including orally, via implants, parenterally (including intravenous, intraperitoneal and subcutaneous injections), rectally, vaginally, and transdermally. Such administrations may be carried out using the present compounds, or pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).
When administered for the treatment or inhibition of a particular disease state or disorder, it is understood that the effective dosage, may vary depending upon the particular compound utilized, the mode of administration, the condition, and severity thereof, of the condition being treated, as well as the various physical factors related to the individual being treated. In therapeutic application, compounds of the present
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invention are provided to a patient already suffering from a disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications. An amount adequate to accomplish this is defined as a "therapeutically effective amounf. The dosage to be used in the treatment of a specific case must be subjectively determined by the attending physician. The variables involved include the specific condition and the size, age and response pattern of the patient.
In some cases it may be desirable to administer the compounds directly to the airways in the form of an aerosol. For administration by intranasal or intrabrochial inhalation, the compounds of this invention may be formulated into an aqueous or partially aqueous solution.
The compounds of this invention may be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmaceutically acceptable salt may be prepared in water suitably mixed with a surfactant such as hydroxyl-propylcellulose. Dispersions may also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to inhibit the growth of microorganisms. •
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form should be sterile and should be fluid to the extent that easy syringability exists. It should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
The compounds of this invention can be administered transdermally, i.e., administered across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues. Such administrations may be carried out using the present compounds or pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal). Topical formaulations that deliver the compounds of the invention through the epidermis may be useful for localized treatment of inflammation and arthritis.
Transdermal administration may be accomplished through the use of a transdermal patch containing the active compound and a carrier that is inert to the
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active compound, is non-toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin. The carrier may take any number of forms such as cream? and ointments, pastes, gels and occlusive devices. The creams and ointments may be viscous liquid or semisoiid emulsions of either the oil-in-water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable. A variety of occlusive devices may be used to release the active ingredient into the blood stream, such as a semi-permeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature.
The compounds of this invention may be administered rectally or vaginally in the form of a conventional suppository. Suppository formulations may be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository's melting point, and glycerin. Water-soluble suppository bases, such as polyethylene glycols of various molecular weights, may also be used.
Lipid formulations or nanocapsules may be used to introduce the compounds of the present invention into host cells either in vitro or in vivo. Lipid formulations and nanocapsules may be prepared by methods known in the art.
In order to increase the effectiveness of the compounds of the present invention, it may be desirable to combine these compositions with other agents effective in the treatment of the target disease. For inflammatory diseases, other agents effective in their treatment, and particularly in the treatment of rheumatoid arthritis, may be administered with the compounds of the present invention. For cancer, additional anti-cancer agents may be administered. The other agents may be administered at the same time or at different times than the compounds of the present invention.
As used herein, "halo" or "halogen" includes fluoro, chloro, bromo, and iodo.
As used herein, "oxo" refers to a double-bonded oxygen (i.e., =0).
As used herein, the term "aikyl" refers to a straight-chain or branched saturated hydrocarbon group. AlkyI groups can contain from 1 to about 20,1 to about 10,1 to about 8,1 to about 6,1 to about 4, or 1 to about 3 carbon atoms. AlkyI groups preferably contain 1 to 6 carbon atoms. Example alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl) and the like. AlkyI groups can be substituted with up to four independently selected R12 groups, as described herein.
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As used herein, "alkenyl" refers to a straight-chain or branched alkyl group as defined above having one or more double carbon-carbon bonds. Alkenyl groups preferably contain 2 to 6 carbon atoms. Examples of alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, and the like. Alkenyl groups can be substituted with up to four independently selected R12 groups, as described herein.
As used herein, "alkynyl" refers to a straight-chain or branched alkyl group as defined above having one or more triple carbon-carbon bonds. Alkynyl groups preferably contain 2 to 6 carbon atoms. Examples of alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, and the like. Alkynyl groups can be substituted with up to four independently selected R12 groups, as described herein.
As used herein, "alkoxy" refers to an -O-alkyl group, wherein alkyl is as defined above. Alkoxy groups preferably contain 1 to 6 carbon atoms. Examples of alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like. Alkoxy groups can be substituted with up to four independently selected R12 groups, as described herein.
As used herein, "alkylthio" refers to an -S-alkyl group, wherein alkyl is as defined above. Alkylthio groups preferably contain 1 to 6 carbon atoms. Alkylthio groups can be substituted with up to four independently selected R12 groups, as described herein.
As used herein, "haloalkyl" refers to an alkyl group, as defined above, having one or more halogen substituents. Haloalkyl groups preferably contain 1 to 6 carbon atoms. Examples of haloalkyl groups include CF3, C2F5, CHF2, CCI3, CHCI2, C2CI5, and the like. Perhaloalkyl groups, i.e., alkyl groups wherein all of the hydrogen atoms are replaced with halogen atoms (e.g., CF3 and C2Fs), are included within the definition of "haloalkyl."
As used herein, "cycloalkyl" refers to non-aromatic carbocyclic groups including cyclized alkyl, alkenyl, and alkynyl groups. Cycloalkyl groups can be monocyclic (e.g., cyclohexyl) or poly-cyclic (e.g. fused, bridged, or spiro ring systems), wherein the carbon atoms are located inside or outside of the ring system. Cycloalkyl groups preferably contain 3 to 10 carbon atoms. Any suitable ring position of the cycloalkyl moiety may be covalently linked to the defined chemical structure. Examples of cycloalkyl groups include cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, cyclohexylethyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, spiro[4.5]deanyl, homologs, isomers, and the like. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e.,
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having a bond in common with) to the cycloalkyl ring, for example, benzo derivatives of cyclopentane (indanyl), cyclohexane (tetrahydronaphthyl), and the like. Cycloalkyl groups can be substituted with up to four independently selected R12 groups, as described herein.
As used herein, "aryl" refers to C6-20 aromatic monocyclic or polycyclic hydrocarbons such as, for example, phenyl, 1-naphthyl, 2-naphthyl, anthracenyl, phenanthrenyl, and the like. Aryl groups preferably contain 6 to 14 carbon atoms. Any suitable ring position of the aryl moiety may be covalently linked to the defined chemical structure. Aryl groups can be substituted with up to four independently selected R12 groups, as described herein.
As used herein, "heteroaryl" refers to monocyclic or polycyclic aromatic ring systems having from 5 to 20 ring atoms and containing 1-3 ring heteroatoms selected from oxygen (O), nitrogen (N) and sulfur (S). Generally, heteroaryl rings do not contain O-O, S-S, or S-0 bonds. Heteroaryl groups include monocyclic heteroaryl rings fused to a phenyl ring. The heteroaryl group may be attached to the defined chemical structure at any heteroatom or carbon atom that results in a stable structure. Examples of heteroaryl groups include, for example:

wherein K is defined as O, S, N or NR10. One or more N or S in a heteroaryl ring may be oxidized (e.g., pyridine N-oxide). Examples of heteroaryl rings include pyrrole, furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine, triazole, pyrazole, imidazole, isothiazole, thiazole, isoxazole, oxazole, indole, isoindole, benzofuran, benzothiophene, quinoline, isoquinoline, quinoxaline, quinazoline, benzotriazole, indazole, benzimidazole, benzothiazole, benzisoxazole, 2-methylquinoline-4-yl, 1-H-1,2,3-benzotriazoM-yl, 1-H-benzimidazoI-5-yl, 2,1,3-benzoxadiazol-5-yl, benzoxazole, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzo[c]isoxazolyl, benzo[d]isoxazolyl,
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benzo[c]isothiazolyl, benzo[d]isothiazolyl, cinnolinyl, 1H-indazolyl, 2H-indazolyl, indolizinyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolinyl, naphthyridinyl, phthalazinyl, pteridinyl, purinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyridinyl, furopyridinyl, thienopyridinyl, pyridopyrimidine, pyridopyrazine, pyridopyridazine, quinazolinyl, quinolinyl, quinoxalinyl, thienothiazolyl, thienoxazolyl, and thienoimidazolyl. Heteroaryl groups can be substituted with up to four independently selected R12 groups as described herein.
As used herein, "cycloheteroalkyl" refers to a non-aromatic cycloalkyl group that contains at least one ring heteroatom selected from 0, N and S, and optionally contains one or more double or triple bonds. Cycloheteroalkyl groups preferably contain 3 to 10 ring atoms, 1-3 of which are heteroatoms selected from O, S, and N. One or more N or S in a cycloheteroalkyl ring may be oxidized (e.g., thiomorpholine S-oxide, thiomorpholine S,S-dioxide). Examples of cycloheteroalkyl groups include morpholine, thiomorpholine, pyran, imidazolidine, imidazoline, oxazolidine, pyrazolidine, pyrazoline, pyrrolidine, pyrroline, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, and the like. Cycloheteroalkyl groups can be optionally substituted with up to four independently selected R12 groups as described herein. Nitrogen atoms of cycloheteroalkyl groups can bear a substituent, for example an R5 group, as described herein. Also included in the definition of cycloheteroalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloheteroalkyl ring, for example, benzimidazolinyl, chromanyl, chromenyl, indolinetetrahydorquinolinyl, and the like. Cycloheteroalkyl groups can also contain one or more oxo groups, such as phthalimide, piperidone, oxazolidinone, pyrimidine-2,4(1H,3H)-dione, and pyridin-2(1H)-one, and the like.
At various places in the present specification substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges. For example, the term "d aikyl" is specifically intended to individually disclose C1-6 C2t C3, C4, C5, C6, Ci-Ce, C1-C5, CrC4, CrC3, CrC2l C2-C6, CrCs, C2-C4> C2-C3, C3-C6, C3-Cs, C3-C4, C4-C6, C4-C5, and C5-C6 alkyl.
The compounds of the present invention can contain an asymmetric atom (also referred as a chiral center), and some of the compounds can contain one or more asymmetric atoms or centers, which can thus give rise to optical isomers (enantiomers) and diastereomers. The present invention includes such optical isomers (enantiomers) and diastereomers (geometric isomers); as well as the racemic and resolved, enantiomerically pure R and S stereoisomers, as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts
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thereof. Optical isomers can be obtained in pure form by standard procedures known to those skilled in the art, and include, but are not limited to, diastereomeric salt formation, kinetic resolution, and asymmetric synthesis. The present invention also encompasses cis and trans isomers of compounds containing alkenyl moieties. It is also understood that this invention encompasses all possible regioisomers, and mixtures thereof, which can be obtained in pure form by standard separation procedures known to those skilled in the art, and include, but are not limited to, column chromatography, thin-layer chromatography, and high-performance liquid chromatography.
The novel compounds of the present invention can be prepared in a variety of ways known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods as hereinafter described below, together with synthetic methods known in the art of synthetic organic chemistry or variations thereon as appreciated by those skilled in the art.
The compounds of present invention can be conveniently prepared in accordance with the procedures outlined in the schemes below, from commercially available starting materials, compounds known in the literature, or readily prepared intermediates, by employing standard synthetic methods and procedures known to those skilled in the art. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be readily obtained from the relevant scientific literature or from standard textbooks in the field. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. Those skilled in the art of organic synthesis will recognize that the nature and order of the synthetic steps presented may be varied for the purpose of optimizing the formation of the compounds of the invention.
The processes described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1H or 13C) infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatograpy (HPLC) or thin layer chromatography.
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Preparation of compounds can involve the protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Greene, et al., Protective Groups in Organic Synthesis, 2d. Ed., Wiley & Sons, 1991, which is incorporated herein by reference in its entirety.
The reactions of the processes described herein can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially nonreactive with the reactants, intermediates, and/or products at the temperatures at which the reactions are carried out, i.e., temperatures that can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected.
Compounds of the invention may be synthesized, for example, according to Scheme I below.
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Scheme I

As shown in Scheme 1, an unsubstituted or substituted 4-nitroaniline derivative a is reacted with ethoxy ethylenecyanoacetate, preferably in a solvent such as benzene, toluene or DMF to give a cyano-3-4-nitrophenylaminoacrylic acid ethyl ester intermediate b. The intermediate b is heated in a solvent such as Dowtherm A (Dow Chemical Company, Midland, Ml) to give a quinolone c. The quinolone c is converted to a chlorocyanoquinoline d by heating with a chlorinating agent such as POCI3 or SOCI2 either as a neat solution or in a solvent such as toluene. The chlorocyanoquinoline d is heated with an amine having the formula HNR6(CR82)nR4 to give the intermediate e. The nitro group of the intermediate e can be reduced to the amine using a reducing agent (e.g., tin (II) chloride dihydrate or ferrous chloride and ammonium chloride) to provide the 6-amino intermediate f. The intermediate f can be alkylated by treatment with an aldehyde or ketone (e.g., R1(CR72)mC(O)H or R1(CR72)mC(O)(CR72)4) and a reducing agent (e.g., sodium cyanoborohydride or sodium triacetoxyborohydride) to give a 4,6-diamino-3-cyanoquinoline of formula (I). Alternatively, intermediate f may be alkylated, for
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example, with a compound having the formula R1(CR72)mX (wherein X is a suitable leaving group, e.g., Cl, Br, mesylate, tosylate, etc.) in the presence of a base to give a 4,6-diamino-3-cyanoquinoline of formula (I). The C-6 amine may be further functionalized to add an R5 group.
Functionalization at the C-7 and/or C-8 positions of the quinoline ring may be carried out prior to the formation of intermediate b. For example, 4-nitroaniline may be treated with a brominating agent (e.g., Br2 in acetic acid) to form 2-bromo-4-nitroaniline, which can then be used to synthesize compounds of formula (I) wherein R3 is Br according to Scheme I above. Further functionalization at C-7 and/or C-8 may be carried out, for example, by treating compounds of formula (I) wherein R2 and/or R3 is a halogen with an organozinc, organotin, organoboronic acid or organocopper reagent and a catalyst (e.g.,palladium (bistriphenylphosphine) dichloride) to give C-7 and/or C-8 subsituted 3-cyanoquinolines.
Scheme II depicts another exemplary method for synthesizing compounds of the invention.
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Scheme II


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According to Scheme II, an unsubstituted or substituted 4-nitroaniline derivative g is alkylated (e.g., using the reductive animation or alkylation conditions described above) to form the alkylated intermediate h. The nitro group of intermediate h is then reduced to the amine to form diamine intermediate i, which can then be converted to the 4,6-diamino-3-cyanoquinolines of formula (I) according to the procedures described in Scheme I above.
Examples
The following describes the preparation of representative compounds of this invention in greater detail. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of parameters that can be changed or modified to yield essentially the same results.
Mass spectral data is reported as the mass-to-charge ratio, m/z, and for high resolution mass spectral data, the calculated and experimentally found masses, [M+H]+, for the neutral formulae M are reported. Nuclear magnetic resonance data is reported as 8 in parts per million (ppm) downfield from the standard (tetramethylsilane), along with the solvent, nucleus, and field strength parameters. The spin-spin homonuclear coupling constants are reported as J values in hertz; and the multiplicities are reported as a: s, singlet; d, doublet; t, triplet; q, quartet; quintet; or br, broadened.
Example 1: N-[4-(3-Chloro-4-fluoro-phenylamino)-3-cyano-quinolin-6-yl]-benzamide Step 1:6-bromo-4-chloro-quinoline-3-carbonitrile (2.5g, 9.4mmol) was taken up in 2-ethoxyethanol (110mL) and 3-chloro-4-fluoroniline (1.43g, 9.8mmol) was added and heated at reflux (135°C) for 2.5 hours or until complete by TLC. The reaction was cooled to room temperature and solid precipitated out. The solution was filtered to obtain 6-bromo-4- (3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile. Yield: 56%: 1H NMR (400 MHz, DMSO-D6) 5 ppm 7.47 (dq, J=6.63, 4.36, 2.53, 2.15 Hz, 1 H) 7.56 (t, J=8.97 Hz, 1 H) 7.75 (dd, J6.69, 2.65 Hz, 1 H) 7.98 (d, J=8.84 Hz, 1 H) 8.16 (dd, J=8.97,1.89 Hz, 1 H) 8.97 (s, 1 H) 9.01 (d, .7=2.02 Hz, 1 H)11.08(s, 1 H).
Step 2: A mixture of 6-bromo-4- (3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (100mg, 0.27mmol), benzamide (77mg, 0.64mmol), K3PO4 (113mg, 0.53mmol), Cul (20mg, 20 wt % eq), and fra/?s-1,2-diaminocyclohexane (20uL, 20 wt % eq) was suspended in 4mL of dioxane, flushed with N2 and heated at 150°C for 1 hour in the microwave. After the desired product formation was confirmed by
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LC/MS, the solution was filtered and solvent removed. The resulting crude material was purified via prep-HPLC to give N- [4-(3-Chloro-4-fluoro-phenylamino)-3-cyano-quinolin-6-yl]-benzamide (37mg, 33% yield): 1H NMR (400 MHz, DMSO-D6) 8 ppm 7.42 (none, 1 H) 7.49 (s, 1 H) 7.54 - 7.66 (m, 3 H) 8.00 - 8.05 (m, 2 H) 8.08 (dd, J=8.97, 2.40 Hz, 1 H) 8.56 (s, 1 H) 8.92 (s, 1 H) 10.65 (s, 1 H).
Example 2: N-[4-(3-Chloro-4-fluoro-phenylamino)-3-cyano-quinolin-6-yl]-nicotinamide
Coupling of 6-Bromo-4- (3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (100mg, 0.27mmol) with nicotinamide (78mg, 0.64mmol) was carried out according to Example 1, step 2, to obtain N- [4-(3-Chloro-4-fluoro-phenylamino)-3-cyano-quinolin-6-yl]-nicotinamide (39mg, 35% yield): 1H NMR (400 MHz, DMSO-D6) 8 ppm 7.29 (s, 1 H) 7.44 (t, J=9.09 Hz, 2 H) 7.51 (d, J=6.57 Hz, 1 H) 7.57 - 7.66 (m, 1 H) 7.98 (s, 1 H) 8.03 - 8.12 (m, 1 H) 8.36 (d, J=8.59 Hz, 1 H) 8.59 (s, 1 H) 8.80 (d, J=4.55 Hz, 1 H) 8.91 (s, 1 H) 9.17 (s, 1 H) 9.86 (s, 2 H) 10.84 (s, 1 H); HRMS (ESI+) calcd for C22H13CIFN.5O (MH+) 418.08654, found 418.0869.
Example 3: 4-(3-Chloro-4-fluoro-phenylamino)-6-[(furan-2-ylmethyl)-amino]-quinoline-3-carbonitrile
Step 1: 2-Cyano-3-(4-nitro-phenylamino)-acrylic acid ethyl ester (25g, 95.8mmol) was suspended in Dowtherm A (1L) and heated at 260°C for 18 hours. The reaction was cooled to room temperature (RT), then poured into 1.5L of hexanes and stirred for 1 hour. The dark brown solid was collected via suction filtration, triturated in refluxing ethanol (200mL) for 15 min then cooled to RT and stirred for 12 hours. The solid was collected by suction filtration to obtain 6-nitro-4-oxo-1,4-dihydro-quinoline-3-carbonitrile (15.4g) in 75% yield: 1H NMR (400 MHz, DMSO-D6) 8 ppm 7.82 (d, J=9.09 Hz, 1 H) 8.53 (dd, =9.09, 2.53 Hz, 1 H) 8.81 (d, J=2.53 Hz, 1 H) 8.90 (s, 1 H) 13.27 (s, 1 H).
Step 2: The product from Step 1 (6g, 27.9mmol) was suspended in POCI3 (45mL) and heated at reflux for 6 hours then cooled to RT. The solution became very thick and was slurried with ethyl acetate and stripped to dryness. Residue was scraped out and poured over ice. As the ice melted, the pH was adjusted to ~8 using solid NaHCO3. The solid was collected via suction filtration, washed with water and hexanes and dried under high vacuum for 24 hours to obtain 4-Chloro-6-nitro-quinoline-3-carbonitrile (6.15g) in 95% yield: 1H NMR (400 MHz, DMSO-D6) 8 ppm 8.43 (d, J=9.35 Hz, 1 H) 8.72 (dd, J=9.09, 2.53 Hz, 1 H) 9.06 (d, J=2.53 Hz, 1 H) 9.43 (s, 1 H).
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Step 3: The product from Step 2 (2.33g, 10mmol) and 3-chloro-4-fluoroaniline (1 J4g, 12mmol) were suspended in ethanol (60mL) and heated at reflux for 3 hours or until completed by TLC. After cooling, the solvent was removed in vacuum and the residue was triturated in ether / saf d aqueous NaHCO3 (100mL/75mL) for 2.5 hours. The solid was collected by suction filtration and dried under high vacuum for 24 hours to obtain 4-(3-chloro-4-fluoro-phenylamino)-6-nitro-quinoline-3-carbonitriIe (2.75g) in 80% yield: 1H NMR (400 MHz, DMSO-D6) 8 ppm 7.28 - 7.35 (m, 1 H) 7.47 (t, J=8.97 Hz, 1 H) 7.56 (dd, J=6.69, 2.65 Hz, 1 H) 7.99 (d, J=9.09 Hz, 1 H) 8.49 (dd, J=9.35, 2.53 Hz, 1 H) 8.64 (s, 1 H) 9.47 (d, J=2.27 Hz, 1 H) 10.72 (s, 1 H).
Step 4: The product from Step 3 (2.5g, 7.29mmol) was suspended in ethanol (85mL), then tin chloride dihydrate (8.3g, 36.5mmol) was added and the reaction was heated at reflux for 2.5 hours or until complete by TLC. The reaction was diluted with 10OmL of water, and then solid NaHCO3 was added until the pH was basic (~11g). The solution was extracted with chloroform, washed with brine, treated with activated carbon, dried over Mg2SO4, and stripped to obtain 6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (2.04g) in 90% yield: 1H NMR (400 MHz, DMSO-D6) 5 ppm 5.78 (s, 2 H) 7.12 - 7.19 (m, 2 H) 7.25 (dd, J=8.84, 2.27 Hz, 1 H) 7.34 - 7.42 (m, 2 H) 7.70 (d, J=9.09 Hz, 1 H) 8.34 (s, 1 H) 9.36 (s, 1 H).
Step 5: The product from Step 4 (150mg, 0.48mmol) and 2-furaldehyde (95uL, 1.15mmol) were taken up in ethanol (8mL), then acetic acid (700uL) and NaCNBH3 (36mg, 0.58mmol) were added and the reaction warmed at 30°C for 2.5 hours or until completed by TLC. The reaction was stripped to dryness and the residue was purified by flash chromatography eluting with 0-10% MeOH in CH2CI2 to obtain 4-(3-Chloro-4-fluoro-phenylamino)-6-[(furan-2-ylmethyl)-amino]-quinoline-3-carbonitrile (193mg) in 95 % yield: 1H NMR (400 MHz, DMSO-D6) 8 ppm 6.35 (dd, J=3.28, 0.76 Hz, 1 H) 6.39 (dd, J=3.28,1.77 Hz, 1 H) 6.79 (t, J=5.56 Hz, 1 H) 7.21 - 7.27 (m, 3 H) 7.35 (dd, J=9.09, 2.53 Hz, 1 H) 7.43 (t, J=8.97 Hz, 1 H) 7.48 (dd, J=6.69, 2.65 Hz, 1 H) 7.60 (dd, J=1.77, 0.76 Hz, 1 H) 7.70 (d, J=9.09 Hz, 1 H) 8.33 (s, 1 H); HRMS (ESI+) calcd for C2iH14CIFN4O (MH+) 393.09129, found 393.0917.
Example 4: 4-(3-Chloro-4-fluoro-phenylamino)-6-[(3H-imidazol-4-ylmethyl)-amino]-quinoline-3-carbonitrile
In a 50 mL round-bottomed flask 6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (0.2g, 0.64mmol), ethanol (10mL) and 4(5)-
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imidazole carboxaldehyde (0.147g , 1.53mmol) were added. Then, acetic acid was added to bring the pH of the solution to 4, and the mixture was stirred for 15 minutes. NaCNBH3 (48mg, 0.77mmol) was then added and the reaction warmed at 30 °C for 2.5h or until complete by TLC. The reaction was stripped to dryness and the residue was purified via preparative HPLC, and lyophilized to give the product as a yellow solid (0.166 g, 66%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 4.26 (d, J=4.80 Hz, 2 H) 6.53 (t, J=5.43 Hz, 1 H) 7.05 (s, 1 H) 7.20 (d, J=2.53 Hz, 1 H) 7.22 - 7.28 (m, 1 H) 7.38 (dd, J=8.97, 2.40 Hz, 1 H) 7.43 (t, J=9.09 Hz, 1 H) 7.48 (dd, J=6.57, 2.78 Hz, 1 H) 7.62 - 7.70 (m, 2 H) 8.15 (s, 2 H) 9.36 (s, 1 H); HRMS (ESI+) calcd for C2oH14CIFN6 (MH+) 393.10252, found 393.1019.
Example 5: 4-(3-Chloro-4-fluoro-phenylamino)-6-[(furan-3-ylmethyl)-amino]-quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (150mg, 048mmol) was reacted with 3-furaldehyde (95uL, 1.15mmol) and NaCIMBH3 (36mg, 0.58mmol) in 8mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (158mg, 85%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.20 (d, J=5.31 Hz, 2 H) 6.53 (dd, J=1.77, 0.76 Hz, 1 H) 6.61 (t, J=5.68 Hz, 1 H) 7.18 (d, J=2.27 Hz, 1 H) 7.22 - 7.27 (m, 1 H) 7.34 (dd, J=9.09, 2.53 Hz, 1 H) 7.43 (t, J=8.97 Hz, 1 H) 7.47 (dd, J=6.57, 2.53 Hz, 1 H) 7.63 (t, J=1.64 Hz, 1 H) 7.66 - 7.71 (m, 2 H) 8.30 - 8.34 (tn, 1 H) 9.34 (s, 1 H); HRMS (ESI+) calcd for C21H14CIFN4O (MH+) 393.09129, found 393.0915.
Example 6: 4-(3-Chloro-4-fluoro-phenylamino)-6-(3-nitro-benzylamino)-quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (300mg, 0.96mmol) was reacted with 3-nitrobenzaldehyde (348mg, 2.3mmol) and NaCNBH3 (73mg, 1.15mmol) in 16mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (275mg, 64%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 4.55 (d, J=6.32 Hz, 2 H) 7.07 - 7.12 (m, 2 H) 7.13 - 7.19 (m, 1 H) 7.33 - 7.40 (m, 3 H) 7.62 (t, J=7.96 Hz, 1 H) 7.73 (d, J=9.09 Hz, 1 H) 7.81 (d, J=8.34 Hz, 1 H) 8.08 - 8.13 (m, 1 H) 8.23 - 8.26 (m, 1 H) 8.34 (s, 1 H) 9.28 (s, 1 H); HRMS (ESI+) calcd for C23H15CIFN5O2 (MH+) 448.09711, found 448.0973.
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Example 7: 4-(3-Chloro-4-fluoro-phenylamino)-6-[(1-methyl-1 H-benzoimidazol-2-ylmethyl)-amino]-quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (150mg, 0.48mmol) was reacted with 1-methyl-2-formylbenzimidazole (184mg, 1.15mmol) and NaCNBH3 (36mg, 0.58mmol) in 8mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (17mg, 8%): 1H NMR (400 MHz, acetic acid-D4) 5 ppm 3.96 (s, 3 H) 5.18 (s, 2 H) 7.15 - 7.25 (m, 2 H) 7.37 -7.49 (m, 3 H) 7.52 - 7.67 (m, 4 H) 7.92 (d, J=10.11 Hz, 1 H) 8.47 (s, 1 H); HRMS (ESI+) calcd for C32H33N3O5 (MH+) 540.24930, found 540.2501.
Example 8: 4-(3-Chloro-4-fluoro-phenylamino)-6-[(thiazol-2-ylmethyl)-amino]-quinoline-3-carbonitrile
6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile(150mg, 0.48mmol, prepared according to Example 3 above), and 2-thiazolecarboxaldehyde (84uL, 0.96mmol) were taken up in dioxane (8mL) and heated at reflux for 12 hours. The reaction was cooled to RT, NaCNBH3 (90mg, 1.44mmol) in methanol (3mL) was added, and the mixture was stirred at RT for 4 hours. The reaction was stripped to dryness and residue was purified via flash chromatography eluting with 0-10% MeOH in CH2CI2 to obtain 4-(3-chloro-4-fluoro-phenylamino)-6-[(thiazol-2-ylmethyl)-amino]-quinoline-3-carbonitrile (86mg) in 45% yield: 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.77 (d, J=6.32 Hz, 2 H) 7.18 - 7.24 (m, 2 H) 7.26 (d, J=2.53 Hz, 1 H) 7.35 - 7.47 (m, 3 H) 7.58 (d, J=3.28 Hz, 1 H) 7.72 - 7.77 (m, 2 H) 8.34 (s, 1 H) 9.35 (s, 1 H); HRMS: calcd for C2oH13CIFN5S + H+, 410.06370; found (ESI-FTMS, [M+H]1+), 410.0646.
Example 9: 4-(3-Chloro-4-fluoro-phenylamino)-6-[(5-hydroxymethyl-furan-2-ylmethyl)-amino]-quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (150mg, 0.48mmol) was reacted with 5-(hydroxymethyl)furfural (145mg , 1.15mmol) and NaCNBH3 (36mg, 0.58mmol) in 8mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (183mg, 90%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.33 - 4.39 (m, 4 H) 5.76 (s, 1 H) 6.23 (dd, J=36.38, 3.03 Hz, 2 H) 6.76 (t, J=5.81 Hz, 1 H) 7.20 - 7.25 (m, 1 H) 7.29 - 7.36 (m, 2 H) 7.40 (t, J=9.09 Hz, 1 H) 7.45 (dd, J=6.57, 2.53 Hz, 1 H) 7.67 (d, .7=8.84 Hz, 1 H) 8.28 (s, 1 H); HRMS (ESI+) calcd for C22H16CIFN4O2 (MH+) 423.10186, found 423.1021.
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Example 10: 4-(3-Chloro-4-fluoro-phenylamino)-6-(3-cyano-benzylamino)-quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (150mg, 0.48mmol) was reacted with 3-cyanobenzaldehyde (125mg, 0.96mmol) and NaCNBH3 (36mg, 0.58mmol) in 8mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (100mg, 49%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 4.45 (d, J=5.81 Hz, 2 H) 6.97 (t, J=6.19 Hz, 1 H) 7.10 (d, J=1.52 Hz, 1 H) 7.15 - 7.22 (m, 1 H) 7.33 - 7.43 (m, 3 H) 7.54 (t, .7=7.71 Hz, 1 H) 7.71 (t, J=8.34 Hz, 3 H) 7.81 (s, 1 H) 8.34 (s, 1 H) 9.30 (s, 1 H); HRMS (ESI+) calcd for C24H15CIFN5 (MH+) 428.10728, found 428.1077.
Example 11: 4-(3-Chloro-4-fluoro-phenylamino)-6-[(5-nitro-furan-2-ylmethyl)-amino]-quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (150mg, 0.48mmol) was reacted with 5-nitro-2-furaldehyde (162mg, 1.15mmol) and NaCNBH3 (36mg, 0.58mmol) in 8mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (81 mg, 39%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 4.57 (d, J=6.06 Hz, 2 H) 6.72 (d, J=3.79 Hz, 1 H) 7.02 - 7.08 (m, 1 H) 7.20 - 7.28 (m, 2 H) 7.37 (dd, J=9.09, 2.53 Hz, 1 H) 7.42 (t, J=8.97 Hz, 1 H) 7.48 (dd, J=6.57, 2.78 Hz, 1 H) 7.63 (d, J=3.79 Hz, 1 H) 7.74 (d, J=8.84 Hz, 1 H) 8.34 (s, 1 H) 9.32 (s, 1 H); HRMS (ESI+) calcd for C2iH13CIFN5O3 (MH+) 438.07637, found 438.0763.
Example 12: 4-(3-Chloro-4-fluoro-phenylamino)-6-(4-imidazol-1 -yl-benzylamino)-quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (200mg, 0.64mmol) was reacted with 4-(1H-imidazol-1-yl)benzaldehyde (263mg , 1.53mmol)and NaCNBH3 (48mg, 0.76mmol) in 10mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (196mg, 66%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.43 (d, J=6.06 Hz, 2 H) 6.93 (t, J=5.68 Hz, 1 H) 7.09 (s, 1 H) 7.15 (d, J=2.02 Hz, 1 H) 7.18 - 7.23 (m, 1 H) 7.34 - 7.44 (m, 3 H) 7.50 (d, J=8.59 Hz, 2 H) 7.58 - 7.63 (m, 2 H) 7.69 - 7.74 (m, 2 H) 8.22 (s, 1 H) 8.33 (s, 1 H) 9.31 (s, 1 H); HRMS (ESI+) calcd for C26H18CIFN6 (MH+) 469.13382, found 469.1327.
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Example 13: 4-(3-Chloro-4-fluoro-phenylamino)-6-[(1 H-imidazol-2-ylmethyl)-amino]-quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (150mg, 0.48mmol) was reacted with 2-imidazole carboxaldehyde (110mg , 1.15mmol) and NaCNBH3 (36mg, 0.58mmol) in 10mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (103mg, 55%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 4.38 (d, J=5.31 Hz, 2 H) 6.69 (t, J=5.05 Hz, 1 H) 6.96 (s, 2 H) 7.21 - 7.29 (m, 2 H) 7.36 - 7.51 (m, 3 H) 7.70 (d, J=9.35 Hz, 1 H) 8.16 (s, 1 H) 8.33 (s, 1 H) 9.37 (s, 1 H); HRMS (ESI+) calcd for C2oH14CIFN6 (MH+) 393.10252, found 393.1024.
Example 14: 6-(3-Amino-benzylamino)-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile
4-(3-chloro-4-fiuoro-phenylamino)-6-(3-nitro-benzylamino)-quinoline-3-carbonitrile (200mg, 0.45mmol) was suspended in ethanol (1 OmL) and tin chloride dihydrate (505mg, 2.23mmol) was added and heated at reflux for 12 hours or until complete by TLC. It was diluted with water and NaHCO3 was added until basic then extracted with CHCI3, washed with brine, dried over Mg2SO4. The residue was purified via flash column chromatography eluting with 0-7.5% MeOH in CH2CI2 to obtain 6-(3-amino-benzylamino)-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (136mg) in 73% yield: 1H NMR (400 MHz, DMSO-D6) 5 ppm 4.21 (d, J=5.56 Hz, 2 H) 5.04 (s, 2 H) 6.42 - 6.46 (m, 1 H) 6.50 (dd, J=7.71, 1.14 Hz, 1 H) 6.57 (t, J=1.64 Hz, 1 H) 6.73 (t, .7=5.56 Hz, 1 H) 6.96 (t, J=7.71 Hz, 1 H) 7.12 (d, J=2.53 Hz, 1 H) 7.18 - 7.24 (m, 1 H) 7.35 (dd, J=9.09, 2.27 Hz, 1 H) 7.39 - 7.45 (m, 2 H) 7.68 (d, J=9.09 Hz, 1 H) 8.31 (s, 1 H) 9.32 (s, 1 H); HRMS (ESI+) calcd for C23H17CIFN5 (MH+) 418.12293, found 418.1227.
Example 15: 4-(3-Chloro-4-fluoro-phenylamino)-6-[(5-methyl-3H-imidazol-4-ylmethyl)-amino]-quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (200mg, 0.64mmol) was reacted with 4-methyl-5-imidazole carboxaldehyde (168 mg , 1.53 mmol) and NaCNBH3 (48mg, 0.77mmol) in 10mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (197mg, 76%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 2.16 (s, 3 H) 4.15 (d, J=4.29 Hz, 2 H) 6.39 (t,
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J=4.55 Hz, 1 H) 7.18 (s, 1 H) 7.21 - 7.27 (m, 1 H) 7.35 - 7.49 (m, 3 H) 7.50 (s, 1 H) 7.67 (d, J=9.35 Hz, 1 H) 8.16 (s, 1 H) 8.32 (s, 1 H) 9.35 (s, 1 H); HRMS (ESI+) calcd for C2iH16CIFN6 (MH+) 407.11818, found 407.118.
Example 16: N-(4-{[4-(3-Chloro-4-fluoro-phenylamino)-3-cyano-quinolin-6-ylamiho]-methyl}-phenyl)-acetamide
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (200mg, 0.64mmol) was reacted with 4-acetimidobenzaldehyde (208mg, 1.28mmol) and NaCNBH3 (48mg, 0.77mmol) in 8mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (70mg, 24%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 2.02 (s, 3 H) 4.30 (d, J=5.31 Hz, 2 H) 6.79 (t, J=5.68 Hz, 1 H) 7.13 (d, J=2.02 Hz, 1 H) 7.18 - 7.24 (m, 1 H) 7.29 (d, J=8.59 Hz, 2 H) 7.35 (dd, J=8.84, 2.27 Hz, 1 H) 7.38 - 7.46 (m, 2 H) 7.52 (d, J=8.59 Hz, 2 H) 7.67 - 7.71 (m, .7=9.09 Hz, 1 H) 8.32 (s, 1 H) 9.32 (s, 1 H) 9.91 (s, 1 H); HRMS (ESI+) calcd for C25H19CIFN5O (MH+) 460.13349, found 460.1337.
Example 17: 4-(3-Chloro-4-fluoro-phenylamino)-6-(4-nitro-benzylamino)-quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (200mg, 0.64mmol) was reacted with 4-nitrobenzaldehyde (231 mg , 1.53mmol) and NaCNBH3 (48mg, 0.77mmol) in 8mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (161 mg, 56%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 4.55 (d, J=6.06 Hz, 2 H) 7.04 (d, J=2.53 Hz, 1 H) 7.07 - 7.17 (m, 2 H) 7.32 - 7.39 (m, 3 H) 7.60 (d, J=8.84 Hz, 2 H) 7.73 (d, J=9.09 Hz, 1 H) 8.16 -8.23 (m, 2 H) 8.35 (s, 1 H) 9.27 (s, 1 H); HRMS (ESI+) calcd for C23H15CIFN5O2 (MH+) 448.09711, found 448.0969.
Example 18: N-(3-{[4-(3-Chloro-4-fluoro-phenylamino)-3-cyano-quinolin-6-ylamino]-methyl}-phenyl)-rnethanesulfonamide
6-(3-amino-benzylamino)-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (100mg, 0.24mmol, prepared according to the procedure described in Example 14) was taken up in NMP (3mL), and triethylamine (38uL, 0.28mmol) was added. The reaction was cooled using and ice-EtOH bath, and MeSO2CI (20uL, 0.26mmol) was added. After 12 hours, the solvent was evaporated and the solid was purified via prep-HPLC to obtain N-(3-{[4-(3-Chloro-4-fluoro-phenylamino)-3-
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cyano-quinolin-6-ylamino]-methyf}-phenyl)-methanesulfonamide (25mg) in 21% yield: 1H NMR (400 MHz, DMS0-D6) 8 ppm 2.92 (s, 3 H) 4.37 (d, J=5.81 Hz, 1 H) 6.88 (t, J=5.68 Hz, 1 H) 7.06 - 7.13 (m, 2 H) 7.15 (d, J=2.27 Hz, 1 H) 7.18 - 7.23 (m, 1 H) 7.25 (t, J=1.77 Hz, 1 H) 7.28 (t, J=7.83 Hz, 1 H) 7.35 (dd, .7=9.09, 2.53 Hz, 1 H) 7.38 - 7.45 (m, 2 H) 7.70 (d, J=9.09 Hz, 1 H) 8.31 (s, 1 H) 9.30 (s, 1 H) 9.73 (s, 1 H); HRMS (ESI+) calcd for C24H19CIFN5O2S (MH+) 496.10048, found 496.1001.
Example 19: 4-{3-Chloro-4-fluoro-phenylamino)-6-(4-cyano-benzylamino)-quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (200mg, 0.64mmol) was reacted with 4-cyanobenzaldehyde (72mg, 0.64mmol) and NaCNBH3 (48mg, 0.77mmol) in 8mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (195mg, 71%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 4.49 (d, J=6.06 Hz, 2 H) 7.00 - 7.08 (m, 2 H) 7.13 - 7.19 (m, 1 H) 7.33 - 7.41 (m, 3 H) 7.54 (d, J=8.34 Hz, 2 H) 7.72 (d, J=9.09 Hz, 1 H) 7.76 - 7.82 (m, 2 H) 8.34 (s, 1 H) 9.27 (s, 1 H); HRMS (ESI+) calcd for C24H15CIFNS (MH+) 428.10728, found 428.1074.
Example 20: 4-(3-Chloro-4-fluoro-phenylamino)-6-(3-cyano-4-dimethylamino-2-fluoro-benzylamino)-quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (200mg, 0.64mmol) was reacted with 3-cyano-4-dimethylamino-2-fluorobenzaldehyde (123mg, 0.64mmol) and NaCNBH3 (48mg, 0.77mmol) in 8mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (166mg, 53%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 3.02 (s, 6 H) 4.32 (d, J=5.56 Hz, 2 H) 6.75 -6.79 (m, 2 H) 7.12 (d, J=2.53 Hz, 1 H) 7.18 - 7.24 (m, 1 H) 7.34 (dd, J=8.97, 2.40 Hz, 1 H) 7.38 - 7.45 (m, 2 H) 7.49 (t, J=8.97 Hz, 1 H) 7.72 (d, J=9.09 Hz, 1 H) 8.34 (s, 1 H) 9.32 (s, 1 H).
Example 21: 4-(3-Chloro-4-fluoro-phenylamino)-6-(2-cyano-benzylamino)-quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (200mg, 0.64mmol) was reacted with 2-cyanobenzaldehyde (84mg, 0.64mmol) and NaCNBH3 (48mg, 0.77mmol) in 8mL EtOH. The crude product was purified by preparative HPLC, and
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lyophilized to give the product as a solid (75mg, 27%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 4.56 (d, J=5.56 Hz, 2 H) 6.95 (t, J=5.81 Hz, 1 H) 7.12 (d, J=2.27 Hz, 1 H) 7.15 - 7.21 (m, 1 H) 7.34 - 7.44 (m, 3 H) 7.46 - 7.51 (m, 1 H) 7.56 (d, J=7.07 Hz, 1 H) 7.64 - 7.70 (m, 1 H) 7.74 (d, J=8.84 Hz, 1 H) 7.86 (dd, J=7.45,1.14 Hz, 1 H) 8.36 (s, 1 H) 9.33 (s, 1 H).
Example 22: 4-(3-Chloro-4-fluoro-phenylamino)-6-{[1-(2-morpholin-4-yl-ethyl)-1 H-imidazol-2-ylmethyl]-amino}-quinoline-3-carbonitrile
Step 1:2-lmidazolecarboxaldehyde (750mg, 7.81 mmol), sodium carbonate (827mg, 7.81 mmol), N-(2-chloroethyl)morpholine hydrochloride (726mg, 3.9mmol), and sodium iodide (585mg, 3.9mmol) were taken up in DMF in a sealed tube and heated at 100°C for 18 hours. The reaction was filtered and diluted with ethyl acetate, washed with brine, dried over Mg2SO4 and stripped. 400mg of 3:1 (by LC/MS) mixture of 1-(2-Morpholin-4-yl-ethyl)-1H-imidazole-2-carbaldehyde and 2-Imidazolecarboxaldehyde was obtained and carried on crude to the reductive amination.
Step 2: Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (300mg, 0.96mmol) was reacted with 1-(2-morpholin-4-yl-ethyl)-1H-imidazole-2-carbaldehyde (crude mixture) (187mg, 0.96mmol)and NaCNBH3 (73mg, 1.15mmol)in 8mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (285mg, 59%): 1H NMR (400 MHz, H2O+D20) 8 ppm 3.12 (s, 2 H) 3.43 (t, J=10.36 Hz, 4 H) 3.72 - 3.80 (m, 4 H) 4.48 - 4.55 (m, 2 H) 4.80 (s, 2 H) 7.20 (d, J=2.27 Hz, 1 H) 7.22 - 7.29 (m, 3 H) 7.41 - 7.50 (m, 3 H) 7.71 (d, J=9.09 Hz, 1 H) 8.47 (s, 1 H).
Example 23: 4-(3-Chloro-4-fluoro-phenylamino)-6-[(2-ethyl-5-methyl-3H-imidazol-4-ylmethyl)-amino]-quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (200mg, 0.64mmol) was reacted with 2-ethyl-4-methyl-1H-imidazole-5-carboxaldehyde (88mg , 0.64mmol) and NaCNBH3 (50mg, 0.77mmol) in 8mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (189mg, 68%): 1H NMR (400 MHz, DMSO-D6) 6 ppm 1.17 (t, J=7.58 Hz, 3 H) 2.11 (s, 3 H) 2.55 (q, J=7.58 Hz, 2 H) 4.09 (d, J=4.29 Hz, 2 H) 6.36 (t, J=4.80 Hz, 1 H) 7.16 (d, J=2.27 Hz, 1 H) 7.21 - 7.26 (m, 1 H) 7.36 - 7.48 (m, 3 H) 7.67 (d, J=9.09 Hz, 1 H) 8.17 (s, 1
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H) 8.32 (s, 1 H) 9.34 (s, 1 H); HKM3 (ESI+) calcd for C23H20CIFN6 (MH+) 435.14947, found 435.1504.
Example 24: 6-[3-Bromo-4-(2-methoxy-ethoxy)-benzylamino]-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile
Step 1: 3-bromo-4-hydroxybenzaldehyde (1g, 4.97mmol) was taken up in DMF (20mL), then sodium hydride 60% (200mg, 4.97mmol) was added followed by 2-bromoethylmethylether (514uL, 5.47mmol) and heated at 50°C for 24 hours. Then the mixture was diluted with ethyl acetate, washed with brine, dried over Mg2SO4. The residue was purified via flash column chromatography to obtain 3-bromo-4-(2-methoxy-ethoxy)-benzaldehyde (900mg) in a 70% yield: 1H NMR (400 MHz, DMSO-D6) 5 ppm 3.35 (s, 3 H) 3.71 - 3.75 (m, 2 H) 4.30 - 4.34 (m, 2 H) 7.33 (d, J=8.59 Hz, 1 H) 7.92 (dd, J=8.34, 2.02 Hz, 1 H) 8.11 (d, J=2.02 Hz, 1 H) 9.86 (s, 1 H).
Step 2: Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (200mg, 0.64mmol) was reacted with 3-bromo-4-(2-methoxy-ethoxy)-benzaldehyde (166mg , 0.64mmol) and NaCNBH3 (50mg, 0.77mmol) in 8mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (330mg, 93%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 3.32 (s, 3 H) 3.65 - 3.69 (m, 2 H) 4.11-4.16 (m, 2 H) 4.31 (d, J=5.81 Hz, 2 H) 6.86 (t, J=6.19 Hz, 1 H) 7.07 (d, J=8.34 Hz, 1 H) 7.12 (d, J=2.02 Hz, 1 H) 7.18 - 7.23 (m, 1 H) 7.30 - 7.36 (m, 2 H) 7.38 - 7.45 (m, 2 H) 7.60 (d, J=2.02 Hz, 1 H) 7.70 (d, J=9.09 Hz, 1 H) 8.32 (s, 1 H) 9.30 (s, 1 H); HRMS (ESI+) calcd for C26H21BrCIFN4O2 (MH+) 555.05932, found 555.0606.
Example 25: 4-(3-Chloro-4-fluoro-phenylamino)-6-[3-cyano-4-(2-methoxy-ethoxy)-benzylamino]-quinoline~3-carbonitrile
6-[3-bromo-4-(2-methoxy-ethoxy)-benzylamino]-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (150mg, 0.27mmol, prepared according to the procedures described in Example 24 above), zinc(ll) cyanide (127mg, 1.08mmol), palladium tetrakis (93mg, 0.08mmol) were taken up in DMF (2mL) and heated 150oC in the microwave for 60 minutes. The mixture was then diluted with ethyl acetate, washed with brine, dried over Mg2SO4 and purified via flash column chromatography to obtain 4-(3-chloro-4-fluoro-phenylamino)-6-[3-cyano-4-(2-methoxy-ethoxy)-benzylamino]-quinoline-3-carbonitrile (108mg) in 80 % yield: 1H NMR (400 MHz, DMSO-D6) 8 ppm 3.32 (s, 3 H) 3.67 - 3.70 (m, 2 H) 4.22 - 4.26 (m, 2 H) 4.34 (d, J=5.56 Hz, 2 H) 6.88 (t, J=6.19 Hz, 1 H) 7.11 (d, J=2.53 Hz, 1 H) 7.18
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- 7.24 (m, 2 H) 7.34 (dd, J=9.09,2.53 Hz, 1 H) 7.38 - 7.44 (m, 2 H) 7.63 (dd, J=8.72, 2.15 Hz, 1 H) 7.69 - 7.73 (m, 2 H) 8.33 (s, 1 H) 9.31 (s, 1 H); HRMS (ESI+) calcd for C27H21CIFN5O2 (MH+) 502.14406, found 502.145.
Example 26: (2-Bromo-4-{[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-quinolin-6-ylamino]-methyl}-phenoxy)-acetic acid tert-butyl ester
Step 1: 3-bromo-4-hydroxybenzaldehyde (1g, 4.97mmol) was reacted with tert-butylbromoacetate (734uL, 4.97mmol) according to the procedure described above in Example 25, step 1, to obtain (2-bromo-4-formyl-phenoxy)-acetic acid tert-butyl ester (1.16g) in 74% yield: 1H NMR (400 MHz, DMSO-D6) 8 ppm 1.43 (s, 9 H) 4.95 (s, 2 H) 7.20 (d, J=8.59 Hz, 1 H) 7.89 (dd, J=8.34, 2.02 Hz, 1 H) 8.12 (d, J=1.77Hz, 1 H) 9.86 (s, 1 H).
Step 2: Following the procedure described above in Example 4,6-aminc-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (250mg, 0.80mmol) was reacted with (2-bromo-4-formyl-phenoxy)-acetic acid tert-butyl ester (251 mg, 0.80mmol) and NaCNBH3 (60mg, 0.96mmol) in 5mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (279mg, 57%): 1H NMR (400 MH DMSO-D6) 8 ppm 1.39 (s, 9 H) 4.32 (d, J=5.81 Hz, 2 H) 4.74 (s, 2 H) 6.86 (t, J=5.94 Hz, 1 H) 6.92 (d, J=8.59 Hz, 1 H) 7.13 (d, J=2.02 Hz, 1 H) 7.18 - 7.24 (m, 1 H) 7.28 - 7.36 (m, 2 H) 7.38 - 7.46 (m, 2 H) 7.61 (d, J=1.77 Hz, 1 H) 7.70 (d, J=9.09 Hz, 1 H) 8.32 (s, 1 H) 9.31 (s, 1 H).
Example 27: 4-(3-Chloro-4-fluoro-phenylamino)-6-[(1 H-pyrazol-3-ylmethyl)-amino]-quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (179mg, 0.57mmol) was reacted with 1 H-pyrazole-3-carbaldehyde (CL-201667) (55mg , 0.57mmol) and NaCNBH3 (43mg, 0.69mmol) in 8mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (105mg, 47%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.35 (d, J=5.05 Hz, 2 H) 6.25 (d, J=1.77 Hz, 1 H) 6.62 (t, J=5.18 Hz, 1 H) 7.20 - 7.28 (m, 2 H) 7.35 - 7.50 (m, 3 H) 7.62 (s, 1 H) 7.69 (d, J=9.09 Hz, 1 H) 8.32 (s, 1 H) 9.36 (s, 1 H) 12.64 (s, 1 H).
Example 28: 4-(3-Chloro-4-fluoro-phenylamino)-8-methoxy-6-[(pyridin-3-ylmethyl)-amino]-quinoline-3-carbonitrile
Step 1: 2-methoxy-4-nitroaniline (25g, 149mmol) and ethyl(ethoxymethylene) cyanoacetate (26.4g, 156mmol) was dissolved in DMF
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(125mL), then cesium carbonate (97g, 297mmol) was added, the reaction turned red and was left to stir at RT for 18 hours or until complete by LC/MS. The reaction was poured into 20X volume of water and a yellow solid precipitated out. The solid was collected by suction filtration, rinsed with water and hexanes then triturated for 18 hours in terf-butylmethylether (500mL), the filtered to obtain 2-cyano-3-(2-methoxy-4-nitro-phenylamino)-acrylic acid ethyl ester (31.2g) in 72% yield: 1H NMR (400 MHz, DMSO-D6) 8 ppm 1.28 (t, J=7.20 Hz, 3 H) 4.05 (s, 3 H) 4.27 (q, J=7.16 Hz, 2 H) 7.87 - 7.97 (m, 3 H) 8.80 (d, J=13.39 Hz, 1 H) 11.12 (d, J=13.39 Hz, 1 H).
Step 2: 2-Cyano-3-(2-methoxy-4-nitro-phenylamino)-acrylic acid ethyl ester (6.25g, 21mmol) was suspended in Dowtherm A (25mL) and heated at 260°C for 18 hours. The reaction is cooled to RT, the poured into 1.5L of hexanes and stirred for 1 hour. The dark brown solid is collected via suction filtration to obtain 8-methoxy-6-nitro-4-oxo-1,4-dihydro-quinoline-3-carbonitrile (4.62g, crude 66% desired product by LC/MS) in 88% yield: 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.13 (s, 3 H) 8.01 (d, J=2.53 Hz, 1 H) 8.42 (d, J=2.27 Hz, 1 H) 8.64 (s, 1 H).
Step 3: 8-methoxy-6-nitro-4-oxo-1,4-dihydro-quinoline-3-carbonitrile (2g, 8.2mmol) was suspended in POCI3 (15mL) and the reaction was carried out according to Example 4, step 2. The residue was purified via flash column chromatography to obtain 4-Chloro-8-methoxy-6-nitro-quinoline-3-carbonitrile (400mg) in 19% yield: 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.16 (s, 3 H) 8.06 (d, J=2.27 Hz, 1 H) 8.59 (d, J=2.27 Hz, 1 H) 9.34 (s, 1 H).
Step 4:4-chloro-8-methoxy-6-nitro-quinoline-3-carbonitrile (250mg, 1.02mmol) and 3-chloro-4-fluoroaniline (17 g, 1.2mmol) were suspended in ethanol (10mL) and the reaction carried out according to Example 4, step 3. The residue was purified via flash column chromatography to obtain 4-(3-chloro-4-fluoro-phenylamino)-8-methoxy-6-nitro-quinoline-3-carbonitrile (200mg) in 53% yield: 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.09 (s, 3 H) 7.40 (s, 1 H) 7.50 (s, 1 H) 7.66 (s, 1 H) 7.95 (d, J=2.27 Hz, 1 H) 8.70 (s, 1 H) 9.10 (s, 1 H) 10.46 (s, 1 H).
Step 5: 4-(3-Chloro-4-fluoro-phenylamino)-8-methoxy-6-nitro-quinoline-3-carbonitrile (390mg, 1.05mmol) was suspended in ethanol (4mL), then tin chloride dihydrate (948mg, 4.19 mmol, 4 eq) was added and the reaction heated in the microwave at 110°C for 5 minutes. The reaction was diluted with water, then NaHCO3 is added until the pH was basic. The solution was extracted with chloroform, washed with brine, treated with activated carbon, dried over Mg2SO4, and stripped to obtain 6-amino-4-(3-chloro-4-fluoro-phenylamino)-8-methoxy-quinoline-3-carbonitrile (332mg) in 93% yield: 1H NMR (400 MHz, DMSO-D6) 8
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ppm 3.88 (s, 3 H) 5.76 (s, 2 H) 6.72 (d, J=20.46 Hz, 2 H) 7.06 - 7.15 (m, 1 H) 7.31 (d, J=4.55 Hz, 1 H) 7.36 (t, J=9.09 Hz, 1 H) 8.27 (s, 1 H) 9.22 (s, 1 H).
Step 6: Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluoro-phenylamino)-8-methoxy-quinoline-3-carbonitrile (90mg, 0.26mmol) was reacted with pyridine-3-carbaldehyde (25uL, 0.26mmol) and NaCNBH3 (20mg, 0.32mmol) in 3mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (24mg, 21%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 3.87 (s, 3 H) 4.41 (d, J=5.56 Hz, 2 H) 6.73 (d, J=2.02 Hz, 1 H) 6.80 - 6.85 (m, 2 H) 7.14 - 7.20 (m, 1 H) 7.33 - 7.42 (m, 3 H) 7.74 -7.79 (m, 1 H) 8.26 (s, 1 H) 8.46 (dd, J=4.80,1.52 Hz, 1 H) 8.60 (d, J=2.02 Hz, 1 H) 9.18 (s, 1 H).
Example 29: 4-(3-Chloro-4-fluoro-phenylamino)-8-methoxy-6-(2-morpholin-4-yl-ethylamino)-quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluoro-phenylamino)-8-methoxy-quinoline-3-carbonitrile (200mg, 0.58mmol), was reacted with NaCNBH3 (44mg, 0.69mmol) and morpholin-4-yl-acetaldehyde (prepared by heating the corresponding dimethyl acetal (256mg, 1.45mmol) in 2.0mL concentrated HCI for 5 minutes in a microwave reactor at 110 °C, then neutralizing the mixture with solid K2CO3 until pH=6). The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (35mg, 13%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 2.40 - 2.45 (m, 4 H) 2.54 (t, J=6.69 Hz, 2 H) 3.20 - 3.26 (m, 2 H) 3.57 - 3.61 (m, 4 H) 3.87 (s, 3 H) 6.11 (t, J=5.56 Hz, 1 H) 6.61 (d, J=2.02 Hz, 1 H) 6.83 (d, J=2.02 Hz, 1 H) 7.16 - 7.22 (m, 1 H) 7.37 - 7.44 (m, 2 H) 8.25 (s, 1 H) 9.19 (s, 1 H).
Example 30: 4-(3-Chloro-4-fluoro-phenylamino)-6-[(1 -oxy-pyridin-3-ylmethyl)-amino]-quinoline-3-carbonitrile
Step 1: 3-Pyridylcarbinol-N-oxide (500mg, 4mmol) and manganese(IV) oxide (2.1g, 24mmol) was taken up in CHCI3 (15mL) and stirred at RT for 120 hours, then filtered and stripped to obtain 1-oxy-pyridine-3-carbaldehyde (80mg) in 16% yield: 1H NMR (400 MHz, DMSO-D6) 5 ppm 7.59 - 7.63 (m, 1 H) 7.76 (dt, J=7.83,1.14 Hz, 1 H) 8.45 - 8.49 (m, 1 H) 8.66 - 8.68 (m, 1 H) 9.97 (s, 1 H).
Step 2: Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (177mg, 0.57mmol) was reacted with 1-oxy-pyridine-3-carbaldehyde (80mg , 0.65mmol) and NaCNBH3 (49mg, 0.78mmol) in 5mL EtOH. The crude product was purified by preparative
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HPLC, and lyophilized to give the product in quantitative yield: 1H NMR (400 MHz, DMSO-D6) 5 ppm 4.40 (d, J6.57 Hz, 2 H) 6.95 (t, J=6.19 Hz, 1 H) 7.13 (d, J=2.27 Hz, 1 H) 7.20 - 7.25 (m, 1 H) 7.29 - 7.48 (m, 5 H) 7.73 (d, J=9.09 Hz, 1 H) 8.08 -8.12 (m, 1 H) 8.21 (s, 1 H) 8.33 (s, 1 H) 9.30 (s, 1 H).
Example 31: 4-(3-Chloro-4-fluoro-phenylamino)-6-[(5-methyl-1 H-pyrazol-3-ylmethyl)-amino]-quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (150mg, 0.48mmol) was reacted with 5-methyl-1H-pyrazole-3-carbaldehyde (CL-83045) (53mg , 0.48mmol) and NaCNBH3 (36mg, 0.58mmol) in 5mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (58mg, 30%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 2.18 (s, 3 H) 4.26 (d, J=5.31 Hz, 2 H) 5.98 (s, 1 H) 6.57 (t, J=5.18 Hz, 1 H) 7.20 (d, J=2.27 Hz, 1 H) 7.22 - 7.27 (m, 1 H) 7.37 (dd, J=9.09, 2.27 Hz, 1 H) 7.40 - 7.48 (m, 2 H) 7.68 (d, J=9.09 Hz, 1 H) 8.32 (s, 1 H) 9.35 (s, 1 H).
Example 32: 4-(3-Hydroxy-4-i nethyl-phenylamino)-8-rnethoxy-6-[(pyridin-3-ylmethyl)-amino]-quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-(3-hydroxy-4-methyl-phenylamino)-8-methoxy-quinoline-3-carbonitrile(67mg, 0.21 mmol) was reacted with pyridine-3-carbaldehyde (20uL, 0.21 mmol) and NaCNBH3(16mg, 0.25mmol) in 5mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (44mg, 51%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 2.11 (s, 3 H) 3.85 (s, 3 H) 4.40 (d, J=6.32 Hz, 2 H) 6.52 (s, 1 H) 6.58 (s, 1 H) 6.71 (s, 1 H) 6.81 (d, J=15.16 Hz, 2 H) 7.01 (d, J8.84 Hz, 1 H) 7.36 (dd, J=7.71, 4.67 Hz, 1 H) 7.77 (d, J=9.09 Hz, 1 H) 8.16 (s, 1 H) 8.46 (d, J=5.05 Hz, 1 H) 8.61 (s, 1 H) 8.98 (s, 1 H).
Example 33: 4-(3-Chloro-4-fluoro-phenylamino)-6-[(2,5-dimethyl-2H-pyrazol-3-ylmethyl)-amino]-quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (150mg, 0.48mmol) was reacted with 1,3-dimethyl-1H-pyrazole-5-carbaldehyde (60mg , 0.48mmol) and NaCNBH3 (36mg, 0.58mmol) in 15mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (128mg, 63%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 2.07 (s, 3 H) 3.72 (s, 3 H) 4.33 (d, J=5.31 Hz, 2
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H) 6.01 (s, 1 H) 6.72 (t, J=5.43 Hz, 1 H) 7.18 - 7.26 (m, 2 H) 7.35 (dd, J=9.09, 2.27 Hz, 1 H) 7.39 - 7.48 (m, 2 H) 7.71 (d, J=9.09 Hz, 1 H) 8.34 (s, 1 H) 9.34 (s, 1 H).
Example 34: (4-{[4-(3-Chloro-4-fluoro-phenylamino)-3-cyano-quinolin-6-ylamino]-methyl}-2-cyano-phenoxy)-aceticacid
Step 1: (2-bromo-4-{[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-quinolin-6-ylamino]-methyl}-phenoxy)-acetic acid tert-butyl ester (260mg, 0.44mmol, prepared according to the procedure described in Example 26) was converted to (4-{[4-(3-Chloro-4-fluoro-phenylamino)-3-cyano-quinolin-6-ylamino]-methyl}-2-cyano-phenoxy)-acetic acid tert-butyl ester according to the procedure described in Example 26 to obtain desired product in 90% yield.
Step 2: (4-{[4-(3-Chloro-4-fluoro-phenylamino)-3-cyano-quinolin-6-ylamino]-methyl}-2-cyano-phenoxy)-acetic acid tert-butyl ester (100mg, 0.18mmol), cerium chloride heptahydrate (134mg, 0.36mmol) and potassium iodide (40mg, 0.23mmol) were taken up in acetonitrile (1 OmL) and heated in the microwave at 150GC for 30 min, then filtered and purified via prep-HPLC to obtain (4-{[4-(3-Chloro-4-fluoro-phenylamino)-3-cyano-quinolin-6-ylamino]-methyl}-2-cyano-phenoxy)-acetic acid (30mg) in 33% yield: 1H NMR (400 MHz, DMSO-D6) 5 ppm 4.33 (d, J=5.56 Hz, 2 H) 4.83 (s, 2 H) 6.84 (t, J=6.19 Hz, 1 H) 7.08 - 7.15 (m, 2 H) 7.19 - 7.24 (m, 1 H) 7.33 (dd, J=8.97, 2.15 Hz, 1 H) 7.37 - 7.46 (m, 2 H) 7.61 (dd, J=8.59, 2.27 Hz, 1 H) 7.68 - 7.74 (m, 2 H) 8.32 (s, 1 H) 9.31 (s, 1 H) 13.20 (s, 1 H).
Example 35: 4-(3-Chloro-4-fluoro-phenylamino)-6-[(3-thiophen-2-yl-1 H-pyrazol-4-ylmethyl)-amino]-quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (200mg, 0.64mmol) was reacted with thiophen-2-yl-1H-pyrazo!e-4-carbaldehyde (iMmg , 0.64mmol) and NaCNBH3 (48mg, 0.78mmol) in 15mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (108mg, 36%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.27 (d, J=5.05 Hz, 2 H) 6.53 (t, J=5.05 Hz, 1 H) 7.07 (s, 1 H) 7.19 (d, J=2.53 Hz, 1 H) 7.22 - 7.28 (m, 1 H) 7.35 - 7.49 (m, 3 H) 7.65 - 7.73 (m, 2 H) 8.13 (s, 1 H) 8.31 (s, 1 H) 9.35 (s, 1 H) 12.51 (s, 1 H).
Example 36: 6-Benzylamino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (200mg, 0.64mmol) was
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reacted with benzaldehyde (65uL, 0.64mmol) and NaCNBH3 (48mg, 0.78mmol) in 10mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (202mg, 76%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 4.46 (s, 2 H) 7.21 (s, 1 H) 7.23 - 7.29 (m, 1 H) 7.34 (t, J=7.33 Hz, 2 H) 7.38 - 7.54 (m, 6 H) 7.68 (dd, J=6.57, 2.53 Hz, 1 H) 7.80 (d, J=9.09 Hz, 1 H) 8.66 (s, 1 H) 10.52 (s, 1 H).
Example 37: 4-(3-Chloro-4-fluoro-phenylamino)-6-[(pyridin-3-ylmethyl)-amino]-quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (200mg, 0.64mmol) was reacted with pyridine-3-carbaldehyde (60uL, 0.64mmol) and NaCNBH3 (48mg, 0.78mmol) in 10mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (93mg, 36%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.42 (d, J=5.56 Hz, 2 H) 6.90 (t, J=5.81 Hz, 1 H) 7.17 (d, J=2.27 Hz, 1 H) 7.18 - 7.24 (m, 1 H) 7.33 - 7.46 (m, 4 H) 7.71 (d, J=9.09 Hz, 1 H) 7.75 -7.80 (m, 1 H) 8.33 (s, 1 H) 8.47 (dd, J=4.80,1.52 Hz, 1 H) 8.61 (d, .7=2.02 Hz, 1 H)
9.31 (s, 1 H).
Example 38: 4-(3-Chloro-4-fluoro-phenylamino)-6-[(1,3-dimethyl-5-morpholin-4-yl-1 H-pyrazo!-4-ylmethyl)-amino]-q uinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (200mg, 0.64mmol) was reacted with 1,3-dimethyl-5-morpholin-4-yl-1H-pyrazole-4-carbaldehyde (134mg, 0.64mmol) and NaCNBH3 (48mg, 0.78mmol) in 15mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (96mg, 30%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 2.07 (s, 3 H) 3.00 - 3.05 (m, 4 H) 3.60 (s, 3 H) 3.63 - 3.69 (m, 4 H) 4.05 (d, J=4.04 Hz, 2 H) 6.30 (t, J=4A7 Hz, 1 H) 7.15 (d, J=2.02 Hz, 1 H) 7.23 - 7.29 (m, 1 H) 7.34 (dd, J=9.22,1.89 Hz, 1 H) 7.43 (t, J=8.97 Hz, 1 H) 7.48 (dd, J=6.06, 2.27 Hz, 1 H) 7.67 (d, J=9.09 Hz, 1 H)
8.32 (s, 1 H) 9.35 (s, 1 H).
Example 39: 4-(3-Chloro-4-fluoro-phenylamino)-6-[(1 -oxy-pyridin-2-ylmethyl)-amino]-quinoline-3-carbonitrile
Step 1: 2-pyridylcarbinol-N-oxide was converted to 1-Oxy-pyridine-2-carbaldehyde according to the procedure described in Example 30, and the crude product was used directly in the next step.
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Step 2: Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (200mg, 0.64mmol) was reacted with 1-oxy-pyridine-2-carbaldehyde (80mg (crude), 0.64mmol) and NaCNBH3 (48mg, 0.78mmol) in 15mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (198mg, 74%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 4.58 (s, 2 H) 7.03 (s, 1 H) 7.16 (d, J=2.27 Hz, 1 H) 7.21 - 7.27 (m, 1 H) 7.28 - 7.38 (m, 3 H) 7.37 - 7.51 (m, 3 H) 7.76 (d, J=9.09 Hz, 1 H) 8.32 (d, J=6.06 Hz, 1 H) 8.39 (s, 1 H) 9.58 (s, 1 H).
Example 40: 2-{[4-(3-Chloro-4-fluoro-phenylamino)-3-cyano-quinolin-6-ylamino]-methyl}-L-pyrrolidine-1-carboxylic acid tert-butyl ester
Following the procedure described above in Example 4, 6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (300mg, 0.96mmol) was reacted with N-(terf-butoxycarbonyl)-L-prolinal (180uL, 0.96mmol) and NaCNBH3 (73mg, 1.15mmol) in 10mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (165mg, 35%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 1.35 (s, 9 H) 1.76 -1.94 (m, 4 H) 3.04 (s, 1 H) 3.20 - 3.36 (m, 2 H) 3.92 - 4.06 (m, 1 H) 6.53 (s, 1 H) 7.04 - 7.46 (m, 5 H) 7.50 (d, J=6.06 Hz, 1 H) 7.68 (d, J=9.35 Hz, 1 H) 8.30 (s, 1 H) 9.04 (s, 1 H).
Example 41: 4-(3-Chloro-4-fluoro-phenylamino)-6-[(tetrahydro-furan-2-ylmethyl)-amino]-quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (200mg, 0.64mmol) was reacted with tetrahydrofuran-3-carboxaldehyde (50% wt in water) (130uL, 0.64mmol) and NaCNBH3 (50mg, 0.76mmol) in 10mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (156mg, 61%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 1.56 -1.66 (m, 1 H) 1.98 -2.08 (m, 1 H) 2.52 - 2.57 (m, 1 H) 3.06 - 3.12 (m, 2 H) 3.47 (dd, J=8.59, 5.56 Hz, 1 H) 3.61 - 3.68 (m, 1 H) 3.74 - 3.81 (m, 2 H) 6.45 (t, J=5.81 Hz, 1 H) 7.02 (d, J=2.27 Hz, 1 H) 7.22 - 7.27 (m, 1 H) 7.29 (dd, J=9.09, 2.53 Hz, 1 H) 7.39 - 7.48 (m, 2 H) 7.68 (d, J=9.09 Hz, 1 H) 8.30 (s, 1 H) 9.31 (s, 1 H).
Example 42: (4-Bromo-2-{[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-quinolin-6-ylamino]-methyl}-phenoxy)-acetic acid tert-butyl ester
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Step 1: 5-bromosalicylaldehyde (1g, 5mmol) was converted to (4-bromo-2-formyl-phenoxy)-acetic acid tert-butyl ester according to the procedure described above in Example 26 to obtain the desired product (1.2g) in 78% yield.
Step 2: Following the procedure described above in Example 4, 6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (200mg, 0.64mmol) was reacted with (4-bromo-2-formyl-phenoxy)-acetic acid tert-butyl ester (201 mg, 0.64mmol) and NaCNBH3 (50mg, 0.76mmol) in 10mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (150mg, 38%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 1.41 (s, 9 H) 4.40 (d, J=5.56 Hz, 2 H) 4.74 (s, 2 H) 6.71 (t, J=6.06 Hz, 1 H) 6.89 (d, J=8.84 Hz, 1 H) 7.11 - 7.14 (m, J=1.77 Hz, 1 H) 7.16 - 7.21 (m, 1 H) 7.34 - 7.44 (m, 5 H) 7.72 (d, J=8.84 Hz, 1 H) 8.33 (s, 1 H) 9.33 (s, 1 H).
Example 43: 4-(3-Chloro-4-fluoro-phenylamino)-6-[(L-pyrrolidin-2-ylmethyl)-amino]-quinoline-3-carbonitrile
2-{[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-quinolin-6-ylamino]-methyl}-L-pyrrolidine-1-carboxylic acid tert-butyl ester (80mg, 0.161mmol, prepared according to the procedure described in Example 40) was dissolved in dichloroethane (3mL) and trifluoroacetic acid (500uL) was added. The reaction mixture was stirred 18 hours at RT and stripped to obtain 4-(3-Chloro-4-fluoro-phenylamino)-6-[(L-pyrrolidin-2-ylmethyl)-amino]-quinoline-3-carbonitrile(98mg)in quantitative yield: 1H NMR (400 MHz, DMSO-D6) 8 ppm 1.62 -1.74 (m, 1 H) 1.85 -2.02 (m, 3 H) 2.10 - 2.21 (m, 1 H) 3.15 - 3.28 (m, 2 H) 3.42 - 3.49 (m, 2 H) 3.74 -3.83 (m, 1 H) 6.71 - 6.79 (m, 1 H) 7.29 (d, J=1.26 Hz, 1 H) 7.36 - 7.44 (m, 2 H) 7.52 (t, J=8.97 Hz, 1 H) 7.65 (d, J=5.81 Hz, 1 H) 7.79 (d, J=9.09 Hz, 1 H) 8.57 (dd, .7=7.71, 3.66 Hz, 1 H) 8.62 (s, 1 H) 9.00 - 9.10 (m, 1 H).
Example 44: (2-{[4-(3-Chloro-4-fluoro-phenylamino)-3-cyano-quinolin-6-ylamino]-methyl}-4-cyano-phenoxy)-aceticacid
(4-bromo-2-{[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-quinolin-6-ylamino]-methyl}-phenoxy)-acetic acid tert-butyl ester (250mg, 0.41 mmol, prepared according to Example 42) was converted to (2-{[4-(3-Chloro-4-fluoro-phenylamino)-3-cyano-quinolin-6-ylamino]-methyl}-4-cyano-phenoxy)-acetic acid according to the procedure described above in Example 26 to obtain the desired product (15mg) in 7% yield: 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.46 (s, 2 H) 4.78 (s, 2 H) 6.88 (s, 1 H) 7.14 (d, J=8.59 Hz, 1 H) 7.21 - 7.28 (m, 2 H) 7.30 - 7.39 (m, 2 H) 7.43 - 7.54 (m, 2 H) 7.62 - 7.73 (m, 3 H) 7.78 - 7.84 (m, 1 H) 8.31 (s, 1 H).
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Example 45: (2-{[4-(3-Chloro-4-fluoro-phenylamino)-3-cyano-quinolin-6-ylamino]-methyl}-4-cyano-phenoxy)-acetic acid tert-butyl ester
(4-bromo-2-{[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-quinolin-6-ylamino]-methyl}-phenoxy)-acetic acid tert-butyl ester (250mg, 0.41 mmol, prepared according to Example 42) was converted (2-{[4-(3-Chloro-4-fluoro-phenylamino)-3-cyano-quinolin-6-ylamino]-methyl}-4-cyano-phenoxy)-acetic acid tert-butyl ester according to the procedure described above in Example 26 to obtain desired product (15mg) in 7% yield: 1H NMR (400 MHz, DMSO-D6) 5 ppm 1.41 (s, 9 H) 4.41 (d, J=5.31 Hz, 2 H) 4.88 (s, 2 H) 6.72 (t, J=5.68 Hz, 1 H) 7.08 - 7.12 (m, 2 H) 7.15 - 7.20 (m, 1 H) 7.34 - 7.43 (m, 3 H) 7.67 (d, J=2.02 Hz, 1 H) 7.71 - 7.76 (m, 2 H) 8.34 (s, 1 H) 9.32 (s, 1 H).
Example 46: 4-(3-Chloro-4-fluoro-phenylamino)-6-[(D-pyrrolidin-2-ylmethyl)-amino]-quinoline-3-carbonitrile
4-(3-chloro-4-fluoro-phenylamino)-6-[(D-pyrrolidin-2-ylmethyl)-amino]-quinoline-3-carbonitrile was prepared according to the procedures described in Examples 40 and 43 above, yielding 77mg of the desired product in 20% yield: 1H NMR (400 MHz, DMSO-D6) 8 ppm 1.38 -1.48 (m, 1 H) 1.62 - 1.79 (m, 2 H) 1.83 -1.94 (m, 1 H) 2.81 - 2.94 (m, 2 H) 3.09 - 3.18 (m, 2 H) 3.26 - 3.32 (m, 1 H) 3.33 -3.41 (m, 1 H) 6.41 (t, J=4.80 Hz, 1 H) 7.09 (d, J=2.27 Hz, 1 H) 7.21 - 7.27 (m, 1 H) 7.32 (dd, J=9.09, 2.27 Hz, 1 H) 7.39 - 7.48 (m, 2 H) 7.67 (d, J=9.09 Hz, 1 H) 8.30 (s, 1 H).
Example 47: 4-(3-Chloro-4-fluoro-phenylamino)-6-[(3H-imidazol-4-ylmethyl)-amino]-8-methoxy-quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-4-(3-chloro-4-fluoro-phenylamino)-8-methoxy-quinoline-3-carbonitrile(190mg, 0.55mmol) was reacted with 4(5)-imidazole carboxaldehyde (53mg , 0.55mmol) and NaCNBH3 (24mg, 0.39mmol) in 8mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (33mg, 14%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 3.85 (s, 3 H) 4.22 - 4.27 (m, J=4.29 Hz, 2 H) 6.34 - 6.41 (m, 1 H) 6.77 (d, J=1.77 Hz, 1 H) 6.92 (s, 1 H) 7.05 (s, 1 H) 7.18 - 7.24 (m, 1 H) 7.38 - 7.45 (m, 2 H) 7.61 (d, J=1.01 Hz, 1 H) 8.24 (s, 1 H) 9.21 (s, 1 H).
Example 48: 6-[5-Bromo-2-(2-methoxy-ethoxy)-benzylamino]-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile
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Step 1: 5-Bromosalicylaldehyde (1g, 5mmol) was converted to 5-bromo-2-(2-methoxy-ethoxy)-benzaIdehyde according to the procedure described above in Example 26 to obtain the desired product (657mg) in 50% yield.
Step 2: Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (300mg, 0.96mmol) was reacted with 5-bromo-2-(2-methoxy-ethoxy)-benzaldehyde (248mg , 0.96mmol) and NaCNBH3 (42mg, 0.67mmol) in 10mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (247mg, 50%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 3.29 (s, 3 H) 3.64 - 3.69 (m, 2 H) 4.12 - 4.16 (m, 2 H) 4.36 (d, J=5.81 Hz, 2 H) 6.67 (t, .7=5.94 Hz, 1 H) 6.98 - 7.01 (m, 1 H) 7.09 (d, J=2.53 Hz, 1 H) 7.14 - 7.19 (m, 1 H) 7.32 - 7.43 (m, 5 H) 7.72 (d, J=9.0Q Hz, 1 H) 8.34 (s, 1 H) 9.31 (s, 1 H).
Example 49: 4-(3-Chloro-4-fIuoro-phenylamino)-6-[(4,5,6,7-tetrafluoro-1 H-indol-3-ylmethyl)-amino]-quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (80mg, 0.26mmol) was reacted with 4,5,6,7-Tetrafluoro-1H-indole-3-carbaldehyde (56mg , 0.26mmol) and NaCNBH3 (12mg, 0.18mmol) in 5 mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (76mg, 57%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 4.50 (d, J=4.55 Hz, 2 H) 6.64 (t, J=5.18 Hz, 1 H) 7.16 - 7.24 (m, 2 H) 7.34 - 7.42 (m, 2 H) 7.44 (dd, J-6.06, 2.78 Hz, 1 H) 7.56 (d, J=1.77 Hz, 1 H) 7.69 (d, J=9.09 Hz, 1 H) 8.33 (s, 1 H) 9.34 (s, 1 H).
Example 50: 4-(3-Chioro-4-fluoro-phenylamino)-6-(4-methanesulfonyl-benzylamino)-quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-4~(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (80mg, 0.26mmol) was reacted with 4-methylsulfonyl benzaldehyde (47mg , 0.26mmol) and NaCNBH3 (12mg, 0.18mmol) in 5 mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (33mg, 26%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 3.18 (s, 3 H) 4.52 (d, J=5.56 Hz, 2 H) 7.01 (t, J=5.43 Hz, 1 H) 7.13 - 7.15 (m, 1 H) 7.18 - 7.23 (m, 1 H) 7.33 - 7.45 (m, 3 H) 7.62 (d, J=8.34 Hz, 2 H) 7.72 (d, J=9.35 Hz, 1 H) 7.89 (d, J=8.34 Hz, 2 H) 8.32 (s, 1 H) 9.29 (s, 1 H).
Example 51: 4-(3-Chloro-4-fluoro-phenylamino)-6-[(2-methoxy-pyridin-3-ylmethyl)-amino]-quinoline-3-carbonitrile
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Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (200mg, 0.64mmol) was reacted with 2-methoxy-pyridine-3-carbaldehyde (88mg , 0.64mmol) and NaCNBH3 (28mg, 0.45mmol) in 5 mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (108mg, 55%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 3.91 (s, 3 H) 4.33 (d, J=5.81 Hz, 2 H) 6.74 (t, J=5.81 Hz, 1 H) 6.94 (dd, J=7.20, 5.18 Hz, 1 H) 7.06 (d, J=2.02 Hz, 1 H) 7.14 - 7.20 (m, 1 H) 7.33 - 7.43 (m, 3 H) 7.59 (d, J=6.S2 Hz, 1 H) 7.72 (d, J=8.84 Hz, 1 H) 8.06 (d, J=5.05 Hz, 1 H) 8.33 (s, 1 H) 9.29 (s, 1 H).
Example 52: 3-{[4-(3-ChIoro-4-fluoro-phenylamino)-3-cyano-quinolin-6-ylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester
Following the procedure described above in Example 4, 6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (200mg, 0.64mmol) was reacted with 3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (128mg , 0.64mmol) and NaCNBH3 (28mg, 0.45mmol) in 5 mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (168mg, 75%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 1.39 (s, 9 H) 1.58 -1.72 (m, 1 H) 1,94 - 2.06 (m, 1 H) 2.42 - 2.48 (m, 1 H) 3.00 (d, J=10.48, 7.20 Hz, 1 H) 3.09 -3.15 (m, 2 H) 3.18 - 3.29 (m, 1 H) 3.31 - 3.39 (m, 1 H) 3.45 - 3.52 (m, 1 H) 6.47 (t, J=5.43 Hz, 1 H) 7.01 (s, 1 H) 7.21 - 7.27 (m, 1 H) 7.30 (dd, J=9.09, 2.27 Hz, 1 H) 7.39 - 7.48 (m, 2 H) 7.68 (d, J=9.09 Hz, 1 H) 8.30 (s, 1 H) 9.31 (s, 1 H).
Example 53: 4-(3-Chloro-4-fluoro-phenylamino)-6-(3-hydroxy-benzylamino)-quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (80mg, 0.26mmol) was reacted with 3-hydroxy-benzaldehyde (31 mg, 0.26mmol) and NaCNBH3 (12 mg, 0.18mmol) in 5 mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (40mg, 37%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.30 (d, J=5.81 Hz, 2 H) 6.61 - 6.66 (m, 1 H) 6.75 - 6.83 (m, 3 H) 7.08 - 7.15 (m, 2 H) 7.17 - 7.23 (m, 1 H) 7.33 - 7.45 (m, 3 H) 7.69 (d, J=8.84 Hz, 1 H) 8.31 (s, 1 H) 9.29 - 9.39 (m, 2 H).
Example 54: 4-(3-Chloro-4-fluoro-phenylamino)-6-(3-methyl-benzylamino)-quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (80mg, 0.26mmol) was reacted with m-tolualdehyde (31 mg , 0.26mmol) and NaCNBH3 (12mg, 0.18mmol)
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in 5 mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (48mg, 45%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 2.27 (s, 3 H) 4.32 (d, J=5.81 Hz, 2 H) 6.82 (t, J=5.94 Hz, 1 H) 7.06 (d, J=7.07 Hz, 1 H) 7.09 - 7.23 (m, 5 H) 7.33 - 7.43 (m, 3 H) 7.69 (d, J=9.Q9 Hz, 1 H) 8.32 (s, 1 H) 9.30 (s, 1 H).
Example 55: 4-(3-Chloro-4-fluoro-phenylamino)-6-(2-hydroxy-benzylamino)-quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (80mg, 0.26mmol) was reacted with 2-hydroxy-benzaldehyde (S-265-2) (31 mg , 0.26mmol) and NaCNBH3 (12mg, 0.18mmol) in 5 mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (46mg, 43%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 4.31 (d, J=5.56 Hz, 2 H) 6.54 (t, J=5.05 Hz, 1 H) 6.74 (t, J=7.33 Hz, 1 H) 6.84 (d, J=8.34 Hz, 1 H) 7.08 (t, J=8.21 Hz, 1 H) 7.15 (d, J=2.02 Hz, 1 H) 7.21 (d, J=6.57 Hz, 2 H) 7.35 - 7.45 (m, 3 H) 7.68 (d, J=8.84 Hz, 1 H) 8.30 (s, 1 H) 9.34 (s, 1 H) 9.58 (s, 1 H).
Example 56: 6-(2-Bromo-4-dimethylamino-benzylamino)-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (200mg, 0.64mmol) was reacted with 2-bromo-4-dimethylamino-benzaldehyde (CL-242839-0) (146mg , 0.64mmol) and NaCNBH3 (28mg, 0.45mmol) in 5mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (139mg, 40%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 2.88 (s, 6 H) 4.26 (d, J=5.05 Hz, 2 H) 6.62 (t, J=5.05 Hz, 1 H) 6.69 (dd, J=8.59, 2.02 Hz, 1 H) 6.89 (d, J=2.78 Hz, 1 H) 7.08 (d, J=1.01 Hz, 1 H) 7.14 - 7.21 (m, 1 H) 7.24 (d, J=8.59 Hz, 1 H) 7.33 -7.44 (m, 3 H) 7.70 (d, J=9.09 Hz, 1 H) 8.34 (s, 1 H) 9.31 (s, 1 H).
Example 57: 4-(3-Chloro-4-fluoro-phenylamino)-6-[5-cyano-2-(2-methoxy-ethoxy)-benzylamino]-quinoline-3-carbonitrile
6-[5-bromo-2-(2-methoxy-ethoxy)-benzylamino]-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (150mg, 0.27mmol, prepared according to Example 48) was converted to 4-(3-Chloro-4-fluoro-phenylamino)-6-[5-cyano-2-(2-methoxy-ethoxy)-benzylamino]-quinoline-3-carbonitrile according to the procedure described above in Example 25 to obtain the desired compound (20mg) in 15%
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yield. NMR: 1H NMR (400 MHz, DMS0-D6) 5 ppm 3.29 (s, 3 H) 3.67 - 3.71 (m, 2 H) 4.23 - 4.28 (m, 2 H) 4.37 (d, J=5.81 Hz, 2 H) 6.69 (t, J=5.68 Hz, 1 H) 7.05 (d, J=2.53 Hz, 1 H) 7.13 - 7.18 (m, 1 H) 7.21 (d, J=8.59 Hz, 1 H) 7.32 - 7.40 (m, 3 H) 7.61 (d, J=2.02 Hz, 1 H) 7.71 - 7.76 (m, 2 H) 8.35 (s, 1 H) 9.30 (s, 1 H).
Example 58: 6-[2-Bromo-5-(2-ethoxy-ethoxy)-benzylamino]-4-(3-chloro4-fluoro-phenylamino)-quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (200mg, 0.64mmol) was reacted with 2-bromo-5-(2-ethoxy-ethoxy)-benzaldehyde (WY-15245-1) (175mg, 0.64mmol) and NaCNBH3 (28 mg, 0.45 mmol) in 5mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (145mg, 40%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 1.06 (q, J=6.95 Hz, 3 H) 3.42 (q, J=7.07 Hz, 2 H) 3.57 - 3.62 (m, 2 H) 3.97 - 4.02 (m, 2 H) 4.35 (d, J=5.81 Hz, 2 H) 6.80 - 6.86 (m, 2 H) 7.02 (d, J=3.03 Hz, 1 H) 7.06 (d, J=2.02 Hz, 1 H) 7.12 - 7.18 (m, 1 H) 7.32 - 7.42 (m, 3 H) 7.50 (d, J=8.59 Hz, 1 H) 7.73 (d, J=9.09 Hz, 1 H) 8.35 (s, 1 H) 9.32 (s, 1 H).
Example 59: 4-(3-Chloro-4-fluoro-phenylamino)-6-(2-cyano-4-dimethylamino-benzylamino)-quinoline-3-carbonitrile
6-(2-bromo-4-dimethylamino-benzylamino)-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (100mg, 0.19mmol, prepared according to the procedure described in Example 56) was converted to 4-(3-Chloro-4-fluoro-phenylamino)-6-(2-cyano-4-dimethylamino-benzylamino)-quinoIine-3-carbonitrile according to the procedure described above in Example 25 to obtain the desired compound (20mg) in 21 % yield: 1H NMR (400 MHz, DMSO-D6) 8 ppm 2.99 (s, 6 H) 5.08 (s, 2 H) 7.07 (dd, J=8.59, 2.53 Hz, 1 H) 7.30 - 7.37 (m, 1 H) 7.44 - 7.50 (m, 3 H) 7.57 (dd, J=6.69, 2.65 Hz, 1 H) 8.01 (d, J=9.35 Hz, 1 H) 8.20 (s, 1 H) 8.43 (d, J=2.27 Hz, 1 H) 8.57 (s, 1 H) 9.03 (dd, J=9.60,4.29 Hz, 1 H).
Example 60: 4-(3-Chloro-4-fluoro-phenylamino)-6-[2-cyano-5-(2-ethoxy-ethoxy)-benzylamino]-quinoline-3-carbonitrile
6-[2-bromo-5-(2-ethoxy-ethoxy)-benzylamino]-4-(3-ch!oro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (100mg, 0.18mmol, prepared according to the procedure described in Example 56) was converted to 4-(3-Chloro-4-fluoro-phenylamino)-6-[2-cyano-5-(2-ethoxy-ethoxy)-benzylamino]-quinoline-3-carbonitrile according to the procedure described above in Example 25 to obtain the desired
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compound (16mg) in 17 % yield: 1H NMR (400 MHz, DMSO-D6) 8 ppm 1.14 (t, J=6.95 Hz, 3 H) 3.52 (q, J=7.07 Hz, 2 H) 3.71 - 3.76 (m, 2 H) 4.17 - 4.23 (m, 2 H) 5.10 (s, 2 H) 7.13 (dd, J=8.34, 2.27 Hz, 1 H) 7.17 (d, J=2.27 Hz, 1 H) 7.28 - 7.36 (m, 1 H) 7.47 (t, J=8.97 Hz, 1 H) 7.56 (dd, J=6.44, 2.40 Hz, 1 H) 7.97 (d, J=9.35 Hz, 1 H) 8.01 (d, J=8.34 Hz, 1 H) 8.27 (s, 1 H) 8.35 (d, J=2.27 Hz, 1 H) 8.52 (s, 1 H) 9.20 (d, J=11.62Hz, 1 H).
Example 61: 4-(3-Chloro-4-fluoro-phenylamino)-6-[(tetrahydro-pyran-4-ylmethyl)-amino]-quino1ine-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (150mg, 0.48mmol) was reacted with tetrahydro-pyran-4-carbaldehyde (56mg , 0.48mmol) and NaCIMBH3 (21 mg, 0.34mmol) in 10mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (144mg, 73%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 1.18-1.32 (m, 2 H) 1.70 (d, J=13.14 Hz, 2 H) 1.75 -1.88 (m, 1 H) 2.96 - 3.05 (m, 2 H) 3.24 - 3.30 (m, 2 H) 3.87 (dd, J=11.49, 2.91 Hz, 2 H) 6.40 (t, J=5.43 Hz, 1 H) 6.97 (d, J=2.02 Hz, 1 H) 7.19 - 7.27 (m, 1 H) 7.31 (dd, J=9.09, 2.27 Hz, 1 H) 7.39 - 7.48 (m, 2 H) 7.67 (d, J=9.09 Hz, 1 H) 8.33 (s, 1 H) 9.36 (s, 1 H).
Example 62: 4-(3-Chloro-4-fluoro-phenylamino)-6-[(pyrrolidin-3-ylmethyl)-amino]-quinoline-3-carbonitrile
3-{[4-(3-Chloro-4-fluoro-phenylamino)-3-cyano-quinolin-6-ylamino]-methyl}-pyrrolidine-1-carboxyiic acid tert-butyl ester (80mg, 0.16mmol, prepared according to Example 52) was converted to 4-(3-Chloro-4-fluoro-phenylamino)-6-[(pyrrolidin-3-ylmethyl)-amino]-quinoline-3-carbonitrile following the procedure described in Example 43 to obtain desired product (84mg) in quantitative yield: 1H NMR (400 MHz, DMSO-D6) 8 ppm 1.60 -1.74 (m, 1 H) 2.05 - 2.22 (m, 1 H) 2.58 - 2.68 (m, 1 H) 2.83 - 2.95 (m, 1 H) 3.10 - 3.33 (m, 4 H) 3.34 - 3.45 (m, 1 H) 6.87 (s, 1 H) 7.25 (s, 1 H) 7.39 - 7.48 (m, 2 H) 7.54 (t, J=9.09 Hz, 1 H) 7.71 (dd, J=6.19, 2.15 Hz, 1 H) 7.76 (d, J=9.09 Hz, 1 H) 8.67 (s, 1 H) 8.84 (s, 2 H).
Example 63: 3-{[4-(3-Chloro-4-fluoro-phenylamino)-3-cyano-quinolin-6-ylamino]-methyi}-piperidine-1-carboxylic acid tert-butyl ester
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (200mg, 0.64mmol) was reacted with 3-formyl-piperidine-1-carboxylic acid tert-butyl ester (136mg,
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0.64mmol) and NaCNBH3 «mg, 0.45mmoi) in 5mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (51 mg, 16%): 1H NMR (500 MHz, DMSO-D6) 5 ppm 1.17 -1.28 (m, 2 H) 1.30 -1.44 (m, 10 H) 1.60 -1.68 (m, 1 H) 1.70 - 1.80 (m, 1 H) 1.85 (d, J=13.12 Hz, 1 H) 2.62 - 2.71 (m, 1 H) 2.79 - 2.89 (m, 1 H) 3.76 (d, J=12.82 Hz, 1 H) 3.93 (d, J=14.65 Hz, 1 H) 6.21 - 6.39 (m, 2 H) 6.98 (s, 1 H) 7.15 - 7.23 (m, 1 H) 7.30 - 7.35 (m, 1 H) 7.38 (t, J=8.85 Hz, 2 H) 7.70 (d, J=8.85 Hz, 1 H) 8.33 (s, 1 H) 9.18 (s, 1 H).
Example 64: 4-(3-Chloro-4-fluoro-phenylamino)-6-[(piperidin-3-ylmethyl)-amino]-quinoline-3-carbonitrile
3-{[4-(3-chIoro-4-fluoro-phenylamino)-3-cyano-quinolin-6-ylamino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (70mg, prepared according to the procedure described in Example 63) was converted to 4-(3-chloro-4-fluoro-phenylamino)-6-[(piperidin-3-ylmethyl)-amino]-quinoline-3-carbonitrile following the procedure described in Example 43 to obtain desired product (70mg) in quantitative yield: 1H NMR (400 MHz, DMSO-D6) 8 ppm 1.21 -1.32 (m, 1 H) 1.53 -1.67 (m, 1 H) 1.87 (dd, J=32.21,13.77 Hz, 2 H) 1.98 - 2.13 (m, J=14.15 Hz, 1 H) 2.61 - 2.74 (m, 1 H) 2.74 - 2.86 (m, 1 H) 3.05 - 3.20 (m, 2 H) 3.26 (d, J=12.38 Hz, 1 H) 3.36 (d, J=12.88 Hz, 1 H) 6.79 (s, 1 H) 7.21 (d, J=2.02 Hz, 1 H) 7.42 (dd, J=9.09, 2.02 Hz, 2 H) 7.54 (t, J=8.97 Hz, 1 H) 7.69 (dd, J=6.57, 2.27 Hz, 1 H) 7.75 (d, J=9.09 Hz, 1 H) 8.44 (d, J=11.12 Hz, 1 H) 8.65 (s, 1 H) 8.72 (d, J=11.12 Hz, 1 H).
Example 65: Methyl 2-(2-cyano-3-ethoxy-3-oxoprop-1-enylamino)-5-nitrobenzoate
Step 1: Following the procedure reported by J. Kerrigan and L. Vagnoni (Tetrahedron IQM, 57, 8227-8235) 5-nitroanthranilic acid (1.00g, 5.49mmol) was taken up in 10mL MeOH and 5mL benzene in a 100mL 2-necked round-bottomed flask fitted with a condenser and Dean-Stark trap, and 0.7mL concentrated sulfuric acid was added. The mixture was heated at reflex overnight, during which time most of the solvent distilled out of the flask. TLC analysis (100% EtOAc) indicated that the acid starting material had been completely consumed. The cooled reaction mixture was diluted with 10mL MeOH and 40mL EtOAc, washed 3 times with saturated NaHCO3 and once with brine, dried over anhydrous MgSO4, filtered, and evaporated to give pure product methyl 2-amino-5-nitrobenzoate as a yellow solid (0.89 g, 82% yield): 1H NMR (400 MHz, DMSO-D6) 8 3.86 (s, 3 H) 6.90 (d, J=9.4 Hz, 1 H) 7.84 (s, 2 H) 8.09 (dd, J=9.2,2.9 Hz, 1 H) 8.59 (d, J=2.8 Hz, 1 H).
Step 2: In a 1L round-bottomed flask, the product from the previous step (28.0g, 0.143 mol) was taken up in 140mL DMF, and ethyl
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(ethoxymethylene)cyanoacetate (26.6g, 0.157mol) was added. The mixture was stirred vigorously until both reagents went into solution, and Cs2CO3 (93g, 0.29mol) was added. The flask was capped with a rubber septum and shaken by hand until the reaction mixture solidified after 5 minutes, turning a deep reddish-orange color. TLC analysis (40% EtOAc in hexanes) showed complete consumption of the aniline starting material. The slurry was poured into 1600mL 1:1 EtOAc/water and stirred vigorously, and the pale yellow precipitate collected by suction filtration, washed 3 times with water, and dried under vacuum for 2 days. Pure product was obtained as a yellow solid (39g, 87% yield): 1H NMR (400 MHz, DMSO-D6) 5 1.28 (t, J=7.1 Hz, 3 H) 3.96 (s, 3 H) 4.28 (q, J=7.2 Hz, 2 H) 8.11 (d, J=9.4 Hz, 1 H) 8.45 (dd, J=9.4, 2.8 Hz, 1 H) 8.70 (d, J=2.8 Hz, 1 H) 8.79 (d, J=13.1 Hz, 1 H) 12.80 (d, J=12.9 Hz, 1 H); HRMS (ESI+) calcd for C14H16N4O6 (M[+NHa]+) 337.1142, found 337.1144.
Example 66: 6-(benzylamino)-4-(4-morpholinophenylamino)quinoline-3-carbonitrile
Step 1: In a 100mL round-bottomed flask fitted with a condenser, 6-iodo-4-oxo-1,4-dihydroquinoline-3-carbonitrile (1.00g, 3.38mmol) was taken up in 12mL POCI3 and heated at reflux for 1 hour. The reaction mixture was then allowed to cool to RT, and the POCI3 removed under reduced pressure. The residue was partitioned between 60mL each of CH2CI2 and 5% Na2CO3; a scoopful of solid Na2CO3 was added, and the mixture stirred for 30 minutes, checking the pH periodically to ensure that it remained at or above 8. The layers were then separated, and the aqueous layer extracted with additional CH2CI2. The combined organic layers were filtered through Celite and evaporated to give pure product 4-chloro-6-iodoquinoline-3-carbonitrile (0.93g, 88% yield): 1H NMR (400 MHz, DMSO-De) 5 7.94 (d, J=8.8 Hz, 1 H) 8.32 (dd, J=8.4,1.8 Hz, 1 H) 8.59 - 8.68 (m, 1 H) 9.21 (s, 1 H).
Step 2: In a 300mL round-bottomed flask equipped with a condenser, the product from the previous step (0.93g, 3.0mmol) was taken up in 40mL 2-ethoxyethanol, and 4-morpholinoaniline (0.58g, 3.3mmol) in 40mL 2-ethoxyethanol was added in one portion. The reaction mixture was heated at reflux for 1 hour, until TLC analysis (20% EtOAc in hexanes) showed complete disappearance of the 4-chloro-6-iodoquinoline-3-carbonitrile. The reaction mixture was then allowed to cool to RT, 80mL each EtOAc and 5% Na2CO3 were added, and the suspension allowed to stir for 30 minutes. The bright yellow precipitate was collected by suction filtration, washed with water, and dried under vacuum to give pure product 6-iodo-4-(4-morpholinophenylamino)quinoline-3-carbonitrile (1.09g, 81% yield): 1H NMR (400
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MHz, DMSO-D6) 8 3.03 - 3.22 (m, 4 H) 3.69 - 3.83 (m, 4 H) 6.97 (d, J=9.1 Hz, 2 H) 7.19 (d, J=9.1 Hz, 2 H) 7.64 (d, .7=8.6 Hz, 1 H) 8.06 (dd, J=8.7,1.9 Hz, 1 H) 8.47 (s, 1 H) 8.92 (d, J=1.8 Hz, 1 H) 9.75 (s, 1 H).
Step 3: Following the procedure reported by F. Kwong, A. Klapars and S. Buchwald (Org. Lett. 2002, 4(4), 581-584), the product from step 2 (0.20g, 0.438mmol), Cul (16.8mg, 0.088mmol) and freshly ground K3PO4 (186mg, 0.88mmol) were placed in a test tube fitted with an aluminum crimp seal. The tube was sealed, and a solution of benzylamine (0.114mL, 112mg, 1.0 mmol) and ethylene glycol (0.048mL, 54mg, 0.876mmol) in isopropanol was added via syringe. The tube was heated in an oil bath at 90 °C for 2 days, until TLC analysis showed significant conversion of 6-iodoquinoline to product. The reaction mixture was then cooled to RT and partitioned between EtOAc and brine. The aqueous layer was extracted 3 times with additional EtOAc, and the combined organic layers washed with brine, dried over anhydrous MgSO4, filtered, and evaporated. The crude product was purified by flash chromatography over silica gel (40% EtOAc in CH2CI2) and lyophilized to give the product as a fluffy, bright yellow solid (9.3mg, 2.1% yield): 1H NMR (400 MHz, DMSO-D6) 8 3.06 - 3.15 (m, 4 H) 3.70 - 3.78 (m, 4 H) 4.38 (d, J=5.8 Hz, 2 H) 6.71 (t, J=6.1 Hz, 1 H) 6.96 (d, J=9.1 Hz, 2 H) 7.12 (d, v/=9.1 Hz, 2 H) 7.22 - 7.41 (m, 7 H) 7.61 (d, J=8.8 Hz, 1 H) 8.16 (s, 1 H) 9.15 (s, 1 H); HRMS (ESI+) calcd for CNsO (MH+) 436.2132, found 436.2130.
Example 67: 6-bromo-4-(4-methoxyphenylamino)quinoline-3-carbonitrile
Step 1: Following the procedure described above in Example 66, 6-bromo-4-oxo-1,4-dihydroquinoline-3-carbonitrile (1.00g, 4.02mmol) was converted to 6-bromo-4-chloroquinoline-3-carbonitrile in quantitative yield (1.07g, 100% yield): 1H NMR (400 MHz, DMSO-D6) 5 8.09 - 8.14 (m, 1 H) 8.16 - 8.21 (m, 1 H) 8.46 (dd, J=2.0, 0.5 Hz, 1 H) 9.23 (s, 1 H).
Step 2: Following the procedure described above in Example 66, 6-bromo-4-chloroquinoline-3-carbonitrile (1.08g, 4.04mmol) was reacted with p-anisidine (0.547g, 4.44mmol) in 55mL 2-ethoxyethanol. Work-up of the cooled reaction mixture gave a brown oil which solidified under vacuum. This was washed twice with hexanes and dried under vacuum to give a beige-colored crystalline material (1:1 complex with 2-ethoxyethanol, 1.8 g, 53% yield): 1H NMR (400 MHz, DMSO-D6) 5 1.09 (t, J=7.0 Hz, 3 H) 3.36 (t, J=5.2 Hz, 2 H) 3.41 (q, J=7.0 Hz, 2 H) 3.47 (q, J=5.4 Hz, 2 H) 3.78 (s, 3 H) 4.55 (t, J=5.6 Hz, 1 H) 6.98 (d, J=8.8 Hz, 2 H) 7.27 (d, J=8.8 Hz, 2 H) 7.82 (d, J=9.1 Hz, 1 H) 7.95 (dd, J=9.0, 2.2 Hz, 1 H) 8.50 (s, 1 H)
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8.79 (d, J=2.0 Hz, 1 H) 9.81 (s, 1 H); HRMS (ESI+) calcd for C17H13BrN3O (MH+) 354.0237, found 354.0238.
Example 68: 4-{3-chlorophenylamino)-3-cyano-/V,A/-dimethyl-6-(2-morpholinoethylamino)quinoline-8-carboxamide
Step 1: In a 2L round-bottomed flask, 5-nitroanthranilic acid (100g, 0.55mol) and dimethylamine hydrochloride (50g, 0.60mol) were taken up in 500mL DMF. Once both reagents had dissolved, benzotriazol-1-
yloxytris(dimethylamino)phosphonium hexafluorophosphate (268g, 0.604mol) was added, followed by 4-methylmorpholine (134mL, 122g, 1.21mol). The mixture was stirred at RT overnight, then poured into 5L water and stirred vigorously until the suspension was evenly mixed. The precipitate was collected by suction filtration, washed with water three times, and dried under vacuum to give pure product 2-amino-A/,A/-dirnethyl-5-nitrobenzamide as a yellow powder (103 g, 89% yield): 1H NMR (400 MHz, DMSO-D6) 5 2.93 (br s, 6 H) 6.69 (s, 2 H)6.75 (d, J=9.4 Hz, 1 H) 7.88 (d, J=2.8 Hz, 1 H) 7.98 (dd, J=9.1, 2.8 Hz, 1 H).
Step 2: In a 2L round-bottomed flask, the product from the previous step (116g, 0.554mol) and ethyl (ethoxymethylene)cyanoacetate (188g, 1.11mol) were dissolved in 580mL DMF, and Cs2CO3 (362g, 1.11mol) was added. The mixture was heated to 45 °C for 2 hours, then cooled to RT, stirred overnight, and poured into 5L water. The yellow precipitate was collected by suction filtration, washed three times with water, and dried under vacuum to give pure product ethyl 2-cyano-3-(2-(dimethylcarbamoyl)-4-nitrophenylamino)acrylate (174g, 94% yield): 1H NMR (400 MHz, DMSO-D6) 8 1.28 (t, J=7.1 Hz, 3 H) 2.94 (s, 3 H) 3.06 (s, 3 H) 4.26 (q, J=7.2 Hz, 2 H) 8.00 (d, J=9A Hz, 1 H) 8.27 (d, J=2.5 Hz, 1 H) 8.30 - 8.37 (m, 1 H) 8.72 (d, J=12.9 Hz, 1 H) 11.34 (d, J=13.4 Hz, 1 H).
Step 3: In each of two 3L 3-necked round-bottomed flasks fitted with stir bars, ethylene glycol / water cooled condensers, heating mantles, inert gas inlets/outlets and an internal device to monitor reaction temperature, the product from step 2 (26.9g, 80.9mmol) was suspended in 1.5L Dowtherm A. Argon or nitrogen was bubbled through each suspension by means of a long needle for 40 minutes. The two flasks were then heated to 260 °C overnight, with inert gas being continually passed through. They were then allowed to cool to RT. The contents of each flask were poured into 2.4L hexanes, stirred vigorously and filtered, and the brown precipitate was washed twice with hexanes and once with EtOH and dried under vacuum overnight. This gave a brown powder of sufficient purity to be used in the next step (28 g, 61% yield): 1H NMR (400 MHz, DMSO-D6) 5 2.86 (s, 3 H)
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3.09 (s, 3 H) 8.48 (d, J=2.5 Hz, 1 H) 8.70 (s, 1 H) 8.85 (d, J=2.5 Hz, 1 H) 12.61 (br s, 1 H).
Step 4: In a 1L round-bottomed flask fitted with an addition funnel, 3-cyano-N,N-dimethyl-6-nitro-4-oxo-1,4-dihydroquinoline-8-carboxamide (28g, 98mmol) was suspended in 200mL DCE, and 1mL DMF was added. Oxalyl chloride (17mL, 25g, 0.20mol) was then added dropwise via the addition funnel. After the addition was complete, the addition funnel was replaced with a reflux condenser, and the mixture was refluxed for 2 hours. It was then allowed to cool to RT, and the solvent and excess oxalyl chloride removed under reduced pressure. The residue was taken up in CHCI3 and passed over a short column of silica gel in a BQchner funnel, eluting with additional CHCI3. Evaporation of the solvent gave product 4-chloro-3-cyano-/V,N-dimethyl-6-nitroquinoline-8-carboxamide as a brown powder (13.8g, 46% yield): 1H NMR (400 MHz, DMSO-D6) 8 2.69 (s, 3 H) 3.11 (s, 3 H) 8.64 (d, J=2.3 Hz, 1 H) 9.06 (d, J=2.5 Hz, 1 H) 9.43 (s, 1 H).
Step 5: In a microwave vial, 4-chloro-3-cyano-N,N-dimethyl-6-nitroquinoline-8-carboxamide (1.33g, 4.37mmol) and 3-chloroaniline (0.50mL, 0.61 g, 4.8mmol) were taken up in 5mL DME. The vial was crimp-sealed and heated in a microwave reactor at 140 °C for 10 minutes. The contents of the vial were transferred to a separatory funnel and partitioned between EtOAc and 5% Na2CO3, and the aqueous layer extracted two additional times with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous MgSO4, filtered and evaporated to give a solid. The crude product was purified by flash chromatography over silica gel (30-50% EtOAc in CH2CI2) to give product 4-(3-chlorophenylamino)-3-cyano-N,/V-dimethyl-6-nitroquinoline-8-carboxamide as a yellow solid (0.74g, 43% yield): 1H NMR (400 MHz, DMSO-D6) 8 2.71 (s, 3 H) 3.09 (s, 3 H) 7.33 - 7.40 (m, 2 H) 7.47 (d, J=7.8 Hz, 1 H) 7.49 - 7.51 (m, 1 H) 8.44 (d, J=2.3 Hz, 1 H) 8.83 (s, 1 H) 9.58 (d, J=2.5 Hz, 1 H) 10.62 (s, 1 H).
Step 6: In a 250mL 2-necked round-bottomed flask fitted with a condenser, the product from step 5 (0.74g, 1.9mmol) was taken up in 30mL EtOH and tin chloride dihydrate (2.11g, 9.35mmol) was added. The reaction mixture was heated at reflux for 2 hours, until TLC analysis showed complete disappearance of the nitroquinoline. The reaction mixture was then cooled to RT and poured into ice water. The orange suspension was neutralized with saturated NaHCO3 and extracted into CHCI3 (3 times), and the combined organic layers washed with brine, dried over anhydrous MgSO4, filtered and evaporated. Evaporation of the CHCI3 extracts gave 6-amino-4-(3-chlorophenylamino)-3-cyano-W,N-dimethylquinoline-8-carboxamide as a yellow powder, 0.35g, 51% yield): 1H NMR (400 MHz, DMSO-D6)
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8 2.69 (s, 3 H) 3.05 (s, 3 H) 5.91 (s, 2 H) 7.03 - 7.08 (m, 1 H) 7.08 - 7.12 (m, 1 H) 7.11 (d, J=2.3 Hz, 1 H) 7.17 (t, J=2.0 Hz, 2 H) 7.33 (t, J=8.0 Hz, 1 H) 8.41 (s, 1 H) 9.44 (s, 1 H); HRMS (ESI+) calcd for C19H17CIN5O (MH+) 366.1116, found 366.1118.
Step 7: Following the procedure described above in Example 4,6-amino-4-(3-chlorophenylamino)-3-cyano-N,N-dimethylquinoline-8-carboxamide (0.29 g, 0.79 mmol) was reacted with morpholin-4-yl-acetaldehyde (prepared by heating the corresponding dimethyl acetal (1.037g, 5.98mmol) in 2.0mL concentrated HCI and 1.5 mL water for 6 hours in a microwave reactor at 70 °C, then carefully neutralizing with solid NaHCO3 until pH=6) and NaCNBH3 (110mg, 1.76mmol) in 12mL EtOH. The crude product was purified by flash chromatography over silica gel (6% MeOH in CH2CI2) and lyophilized, giving pure product as a fluffy, bright yellow solid (48 mg, 13% yield): 1H NMR (400 MHz, DMSO-D6) 8 2.42 (br s, 4 H) 2.54 (t, J=6.7 Hz, 2 H) 2.68 (s, 3 H) 3.04 (s, 3 H) 3.25 (q, J=6.3 Hz, 2 H) 3.33 (s, 4 H) 3.48 - 3.64 (m, 4 H) 6.31 (t, J=5.3 Hz, 1 H) 7.07 (d, J=2.3 Hz, 1 H) 7.10 - 7.22 (m, 3 H) 7.25 (t, J=2.0 Hz, 1 H) 7.38 (t, J=8.0 Hz, 1 H) 8.38 (s, 1 H) 9.41 (s, 1 H); HRMS (ESI+) calcd for C2sH28CIN6O2 (MH+) 479.1957, found 479.1975.
Example 69: 8-bromo-4-(3-chlorophenylamino)-6-(2-morphoIinoethylamino)quinoline-3-carbonitrile
Step 1: According to the procedure described by M. Kothare et al. (Tetrahedron, 2000, 56, 9833-9841), 4-nitroaniline (50g, 0.36mol) was suspended in 465mL glacial acetic acid in a 2L Erlenmeyer flask. A solution of bromine (19mL, 58g, 0.36mol) in 280mL acetic acid was added from an addition funnel, with stirring. After addition was complete, the reaction mixture was allowed to stir for 1 hour, then warmed to 60 °C and poured into 1.1L ice water. The precipitate, a slightly dirty bright yellow color, was collected by suction filtration. It was then taken up in 1L Et2O, washed twice with saturated NaHCO3, dried over anhydrous MgSO4, filtered and evaporated to give pure product 2-bromo-4-nitroaniline as a bright yellow powder (64g, 82% yield): 1H NMR (400 MHz, DMSO-D6) 8 6.82 (m, 3 H) 7.97 (dd, J=9.1,2.5 Hz, 1 H) 8.22 (d, J=2.8 Hz, 1 H).
Step 2: A 2L round-bottomed flask was charged with 2-bromo-4-nitroaniline (71 g, 0.33mol), ethyl (ethoxymethylene)cyanoacetate (111g, 0.654mol) and 355mL DMF. The mixture was stirred vigorously to dissolve both reagents, Cs2CO3 (213g, 0.654mol) was added, and the reaction mixture was allowed to stir overnight. To work up, the contents of the flask were poured into 2.5L water and the precipitate collected by suction filtration. The filter cake was then re-suspended in water,
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stirred, and collected again. This was done three times, and the product was then allowed to dry on the BQchner funnel overnight under suction. It was then washed three times with Et2O and three times with hexanes, each time suspending the filter cake in the solvent of choice, stirring vigorously for 5-20 minutes, and re-filtering. Finally, the product ethyl 3-(2-bromo-4-nitrophenylamino)-2-cyanoacrylate was dried overnight under vacuum to give pure material as a free-flowing, pale yellow powder (WAY-191748, 99g, 90% yield): 1H NMR (400 MHz, DMSO-D6) 5 1.29 (t, J=7.1 Hz, 3 H) 4.30 (q, J=7.1 Hz, 2 H) 8.02 (d, J=9.4 Hz, 1 H) 8.31 (dd, J=9.1, 2.5 Hz, 1 H) 8.56 (d, J=2.5 Hz, 1 H) 8.86 (d, J=12.6 Hz, 1 H) 11.31 (d, J=13.1 Hz, 1 H); HRMS (ESI+) calcd for C12H10N3NaO4 (MNa+) 361.9747, found 361.9742.
Step 3: Following the procedure described above in Example 68, two batches of ethyl 3-(2-bromo-4-nitrophenylamino)-2-cyanoacrylate (30.3g each, 89.1 mmol) were cyclized. The product 8-bromo-6-nitro-4-oxo-1,4-dihydroquinoline-3-carbonitrile was obtained as a brown powder of sufficient purity to be used directly in the next step (WAY-191772,42g, 79% yield): 1H NMR (400 MHz, DMSO-D6) 8 8.69 (s, 1 H) 8.82 (dd, J=12.9, 2.5 Hz, 2 H) 12.55 (brs, 1 H); HRMS (ESI+) calcd for C10H5BrN3O3 (MH+) 293.9510, found 293.9509.
Step 4: Following the procedure described above in Example 68, 8-bromo-6-nitro-4-oxo-1,4-dihydroquinoline-3-carbonitrile (18g, 59mmol) was reacted with oxalyl chloride (10mL, 15g, 0.12mol) in 120mL DCE, with 1mL DMF. The product 8-bromo-4-chloro-6-nitroquinoline-3-carbonitrile was isolated as a brown powder (13.4g, 72% yield): 1H NMR (400 MHz, DMSO-De) 5 9.02 - 9.06 (m, 2 H) 9.52 (s, 1 H). Anal. Calcd for CoHgBrCINaO;,: C, 38.43; H, 0.97; N, 13.45. Found: C, 38.11; H, 0.92; N, 13.05.
Step 5: According to the procedure described above in Example 68, 8-bromo-4-chloro-6-nitroquinoline-3-carbonitrile (1.00g, 3.20mmol) was reacted with 3-chloroaniline (0.37mL, 0.45g, 3.5mmol) in 5mL DME. The crude product was purified by flash chromatography over silica gel (5% EtOAc in CH2CI2), to give pure product 8-bromo-4-(3-chlorophenylamino)-6-nitroquinoline-3-carbonitrile as a yellow solid (0.90g, 70% yield): 1H NMR (400 MHz, DMSO-D6) 5 7.33 - 7.41 (m, 2 H) 7.45 -7.51 (m, 2 H) 8.88 (d, J=2.3 Hz, 1 H) 8.91 (s, 1 H) 9.57 (d, J=2.5 Hz, 1 H) 10.65 (s, 1 H); HRMS (ESI+) calcd for C16H9BrCIN4O2 (MH+) 402.9592, found 402.9587. Anal. Calcd for C16H8BrCIN4O2: C, 47.61; H, 2.00; N, 13.88. Found: C, 47.79; H, 1.85; N, 13.66.
Step 6: In a microwave vial, the product from step 5 (0.500g, 1.24mmol) was taken up in 5mL EtOH and tin chloride dihydrate (1.40g, 6.19mmol) was added. The vial was sealed and heated in a microwave reactor at 110 °C for 5 minutes,
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until TLC analysis showed complete disappearance of the nitroquinoline. The contents of the vial were then emptied into ice water, and the reaction worked up as described above in Example 69 Step 5. Purification of the crude product by flash chromatography over silica gel (10-40% EtOAc in CH2CI2) gave pure product 6-amino-8-bromo-4-(3-chlorophenylamino)quinoline-3-carbonitrile as a brownish-yellow solid 0.195g, 42% yield): 1H NMR (400 MHz, DMSO-D6) 6 5.98 (s, 2 H) 7.03 - 7.08 (m, 1 H) 7.08 - 7.13 (m, 1 H) 7.17 (t, J=2.2 Hz, 2 H) 7.33 (t, J=8.1 Hz, 1 H) 7.66 (d, J=2.3 Hz, 1 H) 8.48 (s, 1 H) 9.48 (s, 1 H); HRMS (ESI+) calcd for C16H10BrCIN4 (MH+) 372.9850, found 372.9856.
Step 7: In a 1L round-bottomed flask, 6-amino-8-bromo-4-(3-chlorophenylamino)quinoline-3-carbonitrile (3.31 g, 8.86mmol) was taken up in 270mL EtOH. 2-morpholinoacetaldehyde (prepared by heating the corresponding dimethyl acetal overnight in 21 mL concentrated HCI and 34 mL water, at 70 °C, then neutralizing the solution with saturated NaHCO3) was added and the mixture was stirred at RT for 2 hours, then refluxed for 1 hour. After cooling to RT, the solution was acidified to pH 4 with acetic acid, and NaCNBH3 (0.61g, 9.8mmol) was added. The mixture was allowed to stir at RT overnight. Most of the solvent was then removed under reduced pressure, and the residue partitioned between EtOAc and enough 5% Na2CO3 to bring the aqueous layer to a neutral pH. The aqueous layer was extracted twice more with EtOAc, and the combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and evaporated. The crude product was purified twice by flash chromatography over silica gel (5% MeOH in CH2CI2, then 3% MeOH in CH2CI2), and lyophilized. Pure product was obtained as a fluffy golden-brown solid (0.506g, 12% yield): 1H NMR (400 MHz, DMSO-D6) 5 2.41 (s, 4 H) 2.51 - 2.59 (m, 2 H) 3.14 - 3.27 (m, 2 H) 3.48 - 3.65 (m, 4 H) 6.38 (t, J=5.6 Hz, 1 H) 7.07 (d, J=2.3 Hz, 1 H) 7.11 - 7.16 (m, 1 H) 7.17 - 7.22 (m, 1 H) 7.25 (t, J=2.0 Hz, 1 H) 7.38 (t, J=8.1 Hz, 1 H) 7.77 (d, J=2.3 Hz, 1 H) 8.44 (s, 1 H) 9.44 (s, 1 H); HRMS (ESI+) calcd for C22H22BrCIN5O (MH+) 486.0691, found 486.0696.
Example 70: 8-bromo-4-(3-chlorophenylamino)-6-(pyridin-3-ylmethylamino)quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-8-bromo-4-(3-chlorophenylamino)quinoline-3-carbonitrile (4.42g, 11.8mmol) was reacted with 3-pyridinecarboxaldehyde (1.1mL, 1.2g, 11mmol) and NaCNBH3(0.48g, 7.6mmol) in 1800mL EtOH. Ethanol was removed under reduced pressure, the residue partitioned between EtOAc and 5% Na2CO3, and the aqueous layer extracted with 4 additional portions of EtOAc. The combined organic layers were then washed with
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brine, evaporated, and purified by trituration with 150mL boiling EtOH to give pure product as a yellowish-brown powder (2.51 g, 46% yield): 1H NMR (400 MHz, DMSO-D6) 5 4.41 (d, J=5.8 Hz, 2 H) 7.03 (t, J=5J Hz, 1 H) 7.14 (dd, .7=7.7,1.6 Hz,
1 H) 7.18 - 7.23 (m, 2 H) 7.25 (t, J=2.0 Hz, 1 H) 7.34 - 7.41 (m, 2 H) 7.73 - 7.80 (m,
2 H) 8.46 (s, 1 H) 8.48 (dd, J=4.8,1.8 Hz, 1 H) 8.60 (d, J=2.3 Hz, 1 H) 9.45 (s, 1 H); HRMS (ESI+) calcd for C22H16BrCIN5 (MH+) 464.0274, found 464.0272.
Example 71: 4-(3-chlorophenylamino)-3-cyano-/V,N-dimethyl-6-(pyridin-3-ylmethylamino)quinoline-8-carboxamide
Following the procedure described above in Example 4, 6-amino-4-(3-chlorophenylamino)-3-cyano-N,N-dimethylquinoline-8-carboxamide (21.5mg, 0.0588mmol) was reacted with 3-pyridinecarboxaldehyde (6.1 uL, 6.9mg, 0.065mmol) and NaCNBH3 (4.1mg, 0.065mmol) in 1mL EtOH. The crude product was purified by flash chromatography over silica gel (6% MeOH in CH2CI2) and lyophilized to give a yellow solid (8.6mg, 32% yield): 1H NMR (400 MHz, DMSO-D6) 8 2.67 (s, 3 H) 3.04 (s, 3 H) 4.42 (d, J=5.8 Hz, 2 H) 6.99 (t, J=5.8 Hz, 1 H) 7.13 (dd, J=8.0,1.6 Hz, 1 H) 7.17 - 7.21 (m, 1 H) 7.20 (s, 2 H) 7.25 (t, J=2.0 Hz, 1 H) 7.33 -7.40 (m, 2 H) 7.77 (d, J=7.8 Hz, 1 H) 8.39 (s, 1 H) 8.47 (d, J=4.3 Hz, 1 H) 8.61 (s, 1 H) 9.42 (s, 1 H).
Example 72: 4-(3-chlorophenylamino)-6-(pyridin-3-ylmethylamino)quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-4-(3-chlorophenylamino)quinoline-3-carbonitrile (0.1 OOg, 0.339mmol) was reacted with 3-pyridinecarboxaldehyde (32uL, 36mg, 0.34mmol) and NaCNBH3 (23mg, 0.37mmol) in 40mL EtOH. Purification of the crude product by flash chromatography over silica gel (5% MeOH in CH2CI2), followed by lyophilization, gave a fluffy pale yellow solid (52mg, 40% yield): 1H NMR (400 MHz, DMSO-D6) 5 4.39 (d, J=5.8 Hz, 2 H) 6.94 (t, J=5.9 Hz, 1 H) 7.05 - 7.21 (m, 4 H) 7.31 - 7.40 (m, 3 H) 7.71 - 7.78 (m, 2 H) 8.39 (s, 1 H) 8.46 (dd, J=4.7,1.6 Hz, 1 H) 8.59 (d, J=1.5 Hz, 1 H) 9.33 (s, 1 H); HRMS (ESI+) calcd for CzCINgO (MH+) 386.1167, found 386.1169.
Example 73: /V-(4-(3-chlorophenylamino)-3-cyano-6-(pyridin-3-ylmethylamino)quinolin-8-yl)benzamide
A microwave vial was charged with 8-bromo-4-(3-chlorophenylamino)-6-(pyridin-3-ylmethylamino)quinoline-3-carbonitrile (0.1 OOg, 0.215mmol, prepared as
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described in Example 70 above), benzamide (63mg, 0.52mmol), Cul (20mg, 0.105mmol) and K3PO4 (91 mg, 0.43mmol), and crimp-sealed. The vial was evacuated and backfilled with an inert gas, and a solution of frans-1,2-diaminocyclohexane (20uL) in 4mL dioxane was added. The vial was then heated in a microwave reactor at 150 °C for 30 minutes, until LC-MS analysis showed complete disappearance of the bromide starting material. The vial contents were then partitioned between EtOAc and brine, the aqueous layer extracted twice with additional EtOAc, and the combined organic layers washed with brine, dried over anhydrous MgSO4, filtered, and evaporated. The crude product was purified first by flash chromatography over silica gel (3% MeOH in CH2CI2), then by preparative HPLC, and lyophilized to give a fluffy, pale yellow solid (13mg, 12% yield): 1H NMR (400 MHz, DMSO-D6) 8 4.43 (d, J=5.8 Hz, 2 H) 6.93 (d, J=2.5 Hz, 1 H) 7.10 - 7.27 (m, 4 H) 7.32 - 7.42 (m, 2 H) 7.59 - 7.71 (m, 3 H) 7.77 (d, J=8.1 Hz, 1 H) 7.99 (d, J=6.6 Hz, 2 H) 8.36 - 8.55 (m, 3 H) 8.61 (d, J=2.0 Hz, 1 H) 9.43 (s, 1 H) 10.50 (s, 1 H); HRMS (ESI+) calcd for CasCINeO (MH+) 505.1538, found 505.1537.
Example 74: 4-(3-chlorophenylamino)-6-(pyridin-3-ylmethylamino)quinoline-3,8-dicarbonitrile
In a microwave vial, under an inert atmosphere, 8-bromo-4-(3-chlorophenylamino)-6-(pyridin-3-ylmethylamino)quinoline-3-carbonitrile(0.100g, 0.215mmol), zinc cyanide (0.101g, 0.860mmol) and Pd(PPh3)4 (75mg, 0.065mmol) were taken up in 2mL anhydrous DMF. The sealed vial was heated in a microwave reactor at 150 °C for 15 minutes, until LC-MS analysis showed complete consumption of the bromoquinoline. The vial contents were partitioned between EtOAc and brine and the aqueous layer extracted twice more with EtOAc. The combined organic layers were then washed with brine, dried over anhydrous MgSO4, filtered and evaporated. The crude product was purified by preparative HPLC and lyophilized to give a fluffy yellow solid (6.9mg, 7.8% yield): • H NMR (400 MHz, DMSO-D6) 5 4.42 (d, J=6.1 Hz, 2 H) 7.03 (br s, 1 H) 7.09 (br s, 1 H) 7.31 (br s, 1 H) 7.37 (dd, J=7.5, 4.9 Hz, 1 H) 7.52 - 7.67 (m, 6 H) 7.78 (d, J=8.3 Hz, 1 H) 8.47 (d, J=5.3 Hz, 1 H) 8.61 (s, 1 H); HRMS (ESI+) calcd for C23H16CIN6 (MH+) 411.1120, found 411.1131.
Example 75: N-(4-(3-chlorophenyIamino)-3-cyano-6-(pyridin-3-ylmethylamino)quinolin-8-yl)formamide
Following the procedure described above in Example 73, 8-bromo-4-(3-chlorophenylamino)-6-(pyridin-3-ylmethylamino)quinoline-3-carbonitrile(0.100g,
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0.215mmol, prepared as described in Example 71 above) was reacted with formamide (0.020mL, 23mg, 0.52mmol), and the crude product was purified by preparative HPLC to give a glassy, brown solid (2.4mg, 2.6% yield): 1H NMR (400 MHz, DMSO-D6) 8 4.38 (d, J=5.8 Hz, 2 H) 6.86 (d, J=1.8 Hz, 1 H) 7.05 - 7.24 (m, 4 H) 7.30 - 7.44 (m, 2 H) 7.74 (d, J=7.8 Hz, 1 H) 8.37 - 8.46 (m, 3 H) 8.55 (d, J=17.7 Hz, 2 H) 9.36 (s, 1 H) 10.56 (s, 1 H); HRMS (ESI+) calcd for C23HiaCIN6O (MH+) 429.1225, found 429.1223.
Example 76: 6-((1 H-imidazol-5-yl)methylamino)-8-bromo-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile
Step 1: In a microwave vial, 8-bromo-4-chloro-6-nitroquinoline-3-carbonitrile (4.00g, 12.8mmol) and 3-chloro-4-fluoroaniline (2.05g, 14.1mmol) were taken up in 20mL EtOH. The vial was crimp-sealed and heated in a microwave reactor at 140 CC for 10 minutes. The cap was then removed, tin chloride dihydrate (16g, 71mmol) was added, and the vial was re-sealed and heated at 110 °C for 5 minutes. To work up the reaction, the contents of the vial were rinsed with EtOH into 300mL ice water and neutralized with saturated NaHCO3. The orange suspension was extracted with 4 aliquots of EtOAc, each equal to the volume of the aqueous layer. The combined organic layers were dried over anhydrous MgSO4, filtered and evaporated, and the crude product was purified by flash chromatography over silica gel (3-5% MeOH in CH2CI2) to give a brown solid 6-amino-8-bromo-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile(2.50g, 50% yield): 1H NMR (400 MHz, DMSO-D6) 5 6.05 (s, 2 H) 7.29 - 7.34 (m, 2 H) 7.49 -7.55 (m, 2 H) 7.77 (d, J=2.3 Hz, 1 H) 8.53 (s, 1 H) 9.60 (s, 1 H); HRMS (ESI+) calcd for Ci6H10BrCIFN4 (MH+) 390.9756, found 390.9754.
Step 2: In a 1L round-bottomed flask, the product from the previous step (5.40g, 13.8mmol) and 4(5)-imidazolecarboxaldehyde (1.33g, 13.8mmol) were taken up in 160mL THF and 55mL MeOH and stirred overnight. The solution was then acidified to pH 4 with acetic acid, NaCNBH3 (0.58g, 9.3mmol) was added, and the mixture was allowed to stir overnight again. Solvent was then removed under reduced pressure, and the crude product purified by flash chromatography over silica gel (6-9% MeOH in CH2CI2) and trituration with 165mL boiling EtOH, to give a bright yellow powder (2.93g, 45% yield): 1H NMR (400 MHz, DMSO-D6) 5 4.26 (d, J=5.1 Hz, 2 H) 6.67 (t, J=5.2 Hz, 1 H) 7.05 (s, 1 H) 7.25 (d, J=2.3 Hz, 1 H) 7.26 -7.32 (m, 1 H) 7.45 (t, J=9.0 Hz, 1 H) 7.53 (dd, J=6.6,2.5 Hz, 1 H) 7.62 (s, 1 H) 7.79 (d, J=2.0 Hz, 1 H) 8.38 (s, 1 H) 9.47 (s, 1 H) 11.96 (br s, 1 H); HRMS (ESI+) calcd for C20H14BrCIFN6 (MH+) 471.0131, found 471.0140.
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Example 77: 8-bromo-4-(3-chloro-4-fluorophenylamino)-6-(pyridin-3-ylmethylamino) quinoline-3-carbonitrile
In a 250mL round-bottomed flask, 6-amino-8-bromo-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (1.00g, 2.55mmol) was dissolved in 10mL DMF. After the addition of 3-pyridinecarboxaldehyde (0.24mL, 0.27g, 2.6mmol), the solution was allowed to stir for 5 hours. It was then acidified with acetic acid to pH 4, NaCNBH3 (0.108g, 1.71mmol) was added, and the mixture was stirred overnight. To work up the reaction, 5mL water was added, then the solution was poured into 50 mL 5% Na2CO3 and stirred vigorously for 30 minutes. The precipitate was collected by suction filtration, washing three times with water, and dried under vacuum overnight. The solid was extracted with 11mL boiling EtOH, and the evaporated extract purified by flash chromatography over silica gel (5-65% EtOAc in CH2CI2) and lyophilized to give a yellowish-brown powder (0.147g, 12% yield): 1H NMR (400 MHz, DMSO-D6) 8 4.44 (d, J=5.6 Hz, 2 H) 7.00 (t, J=5.8 Hz, 1 H) 7.21 - 7.30 (m, 2 H) 7.37 (dd, J=7.7,4.7 Hz, 1 H) 7.43 (t, J=9.0 Hz, 1 H) 7.50 (dd, J=6.4, 2.7 Hz, 1 H) 7.75 (d, J=1.8 Hz, 1 H) 7.79 (d, J=7.8 Hz, 1 H) 8.40 (s, 1 H) 8.48 (d, J=4.8 Hz, 1 H) 8.62 (d. J=2.0 Hz, 1 H) 9.44 (s, 1 H); HRMS (ESI+) calcd for C22H15BrCIFN5 (MH+) 482.0178, found 482.0179.
Example 78: 8-bromo-4-(3-chloro-4-fluorophenylamino)-6-(pyridin-2-ylmethylamino) quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-8~bromo-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (0.500g, 1.28mmol) was reacted with 2-pyridinecarboxaldehyde (0.12mL, 0.14g, 1.3mmol) in 15mLTHF and 5mL MeOH; first for 3.5 hours to form the imine, then, after acidification with NaCNBH3 (54mg, 0.86mmol) overnight. Solvent was removed under reduced pressure, and the crude product purified by preparative HPLC and lyophilized to give a fluffy yellow solid (0.13g, 21% yield): 1H NMR (400 MHz, DMSO-D6) 8 4.53 (d, J=5.6 Hz, 2 H) 7.07 (t, J=6.2 Hz, 1 H) 7.20 - 7.32 (m,3 H) 7.33 - 7.44 (m, 2 H) 7.47 (dd, J=6.6, 2.8 Hz, 1 H) 7.76 (t, J=7.7 Hz, 1 H) 7.83 (s, 1 H) 8.39 (s, 1 H) 8.54 (d, J=4.8 Hz, 1 H) 9.38 (br s, 1 H); HRMS (ESI+) calcd for CzaHigBrCIFNs (MH+) 482.0178, found 482.0188.
Example 79: 4-(3-chlorophenylamino)-8-iodo-6-(pyridin-3-ylmethylamino)quinoline-3-carbonitrile
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A modification of the procedure described by J. Zanon, A. Klapars and S. Buchwald (J. Am. Chem. Soc. 2002,124,14844-14845) was followed. A microwave vial was charged with 8-bromo-4-(3-chlorophenylamino)-6-(pyridin-3-ylmethylamino)quinoline-3-carbonitrile (0.1 OOg, 0.215mmol, prepared as described in Example 70 above), Cul (20mg, 0.105mmol) and Nal (64mg, 0.43mmol). The vial was crimp-sealed, evacuated, and back-filled with an inert gas. A solution of N,N'-dimethylethylenediamine (0.020mL, 17mg, 0.19mmol) in 4mL dioxane was added via syringe, and the vial heated in a microwave reactor at 150 °C for 30 minutes, until LC-MS analysis showed complete consumption of the bromide starting material. The reaction mixture was then worked up as described above in Example 73, and purified by flash chromatography over silica gel (3% MeOH in CH2CI2), to give a yellow powder (32mg, 29% yield): 1H NMR (400 MHz, DMSO-D6) 8 4.40 (d, J=5.8 Hz, 2 H) 6.97 (t, J=5.8 Hz, 1 H) 7.11 (ddd, J=8.1, 2.0, 0.8 Hz, 1 H) 7.16 - 7.24 (m, 3 H) 7.33 - 7.39 (m, 2 H) 7.75 (dt, J=8.0,1.9 Hz, 1 H) 8.02 (d, J=2.3 Hz, 1 H) 8.43 (a, 1 H) 8.47 (dd, J=4.8,1.5 Hz, 1 H) 8.59 (d, J=1.8 Hz, 1 H) 9.41 (s, 1 H); HRMS (ESI+) calcd for C22H16CIIN5 (MH+) 512.0134, found 512.0142.
Example 80: N-benzyl-4-(3-chlorophenylamino)-3-cyano-6-(pyridin-3-ylmethylamino) quinoline-8-carboxamide
A modification of the procedure described by A Schoenberg and R. Heck (J. Org. Chem. 1974, 39(23), 3327-3331) was followed. A 100mL 2-necked round-bottomed flask fitted with a condenser was charged with 8-bromo-4-(3-chloropheny)amino)-6-(pyridin-3-ylmethylamino)quinoline-3-carbonitrile(0.300g, 0.646mmol, prepared as described in Example 70 above), Pd(PPh3)2CI2 (68mg, 0.097mmol) and tri-n-butylamine (0.17mL, 0.13g, 0.71mmol). The reaction apparatus was purged with CO gas, and kept under an atmosphere of CO over the course of the reaction by means of a balloon. Benzylamine (15mL) was then added, and the mixture heated at 140 °C for 1.5 hours, until LC-MS analysis showed complete disappearance of the bromide starting material. The reaction was then cooled to RT and partitioned between EtOAc and brine. The aqueous layer was extracted twice more with EtOAc, and the combined organic layers washed successively with brine, 2M HOAc, brine, 5% Na2CO3 (2 *), and brine. The EtOAc solution was then dried over anhydrous MgSO4, filtered and evaporated, and purified by trituration with methanol to give a yellow solid (50mg, 12% yield): 1H NMR (400 MHz, DMSO-D6) 5 4.45 (d, J=5.8 Hz, 2 H) 4.65 (d, J=6.1 Hz, 2 H) 7.14 -7.41 (m, 12 H) 7.77 (d, J=8.1 Hz, 1 H) 8.21 (d, J=2.3 Hz, 1 H) 8.46 (dd, J=4.8,1.3
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Hz, 1 H) 8.48 (s, 1 H) 8.60 (d, J=2.0 Hz, 1 H) 9.54 (s, 1 H) 11.10 (t, .7=6.2 Hz, 1 H); HRMS (ESI+) calcd for CgoHzgCINeO (MH+) 519.1695, found 519.1717.
Example 81: N-(4-(3-chlorophenylamino)-3-cyano-6-(pyridin-3-ylmethylamino)quinolin-8-yl)isobutyramide
Following the procedure described above in Example 73, 8-bromo-4-(3-chlorophenylamino)-6-(pyridin-3-ylmethylamino)quinoline-3-carbonitrile(0.280g, 0.602mmol, prepared as described in Example 70 above) was reacted with isobutyramide (0.126g, 1.44mmol) in the presence of Cul (56mg, 0.29mmol), K3PO4 (0.256g, 1.20mmol) and N.N'-dimethylethylenedtamine (0.056mL, 46mg, 0.526mmol), in 7mL dioxane. The crude product was purified by preparative HPLC and lyophilized to give a fluffy yellow solid (16mg, 5.6% yield): 1H NMR (400 MHz, DMSO-D6) 8 1.16 (s, 6 H) 2.88 (s, 1 H) 4.39 (s, 2 H) 6.83 (s, 1 H) 7.09 (d, J=19.2 Hz, 2 H) 7.21 (s, 2 H) 7.34 (s, 2 H) 7.73 (s, 1 H) 8.39 (s, 2 H) 8.44 (s, 1 H) 8.57 (s, 1 H) 9.34 (s, 1 H) 9.85 (s, 1 H); HRMS (ESI+) calcd for C26H24CIN6O (MH+) 471.1695, found 471.1693.
Example 82: 4-(3-chloro-4-fluorophenylamino)-3-cyano-6-(cyclohexylmethylamino)-/V,/V-dirnethylquinoline-8-carboxamide
Step 1: In a 250mL round-bottomed flask fitted with a condenser, 4-chloro-3-cyano-tyN-dimethyl-e-nitroquinoline-S-carboxamide (4.97g, 16.3mmol) and 3-chloro-4-fluoroaniline (2.61g, 17.9mmol) were taken up in 60mL EtOH and refluxed for 30 minutes. The mixture was allowed to cool for 30 minutes, and tin chloride dihydrate (18.4g, 81.5mmol) was added. The mixture was then refluxed for an additional 30 minutes, cooled to RT, and poured into 300mL ice water. After neutralization with saturated NaHCO3, the orange suspension was extracted 5 times with 700mL portions of CHCI3. The organic extracts were dried over anhydrous MgSO4, filtered, combined and evaporated, and the crude product purified by flash chromatography over silica gel (5-9% MeOH in CH2CI2), to give a brown powder 6-amino-4-(3-ch!oro-4-fluorophenylamino)-3-cyano-N,/V-dimethylquinoline-8 carboxamide (5.09g, 81% yield): 1H NMR (400 MHz, DMSO-D6) 5 2.68 (s, 3 H) 3.04 (s, 3 H) 5.86 (s, 2 H) 7.09 (d, J=2.0 Hz, 1 H) 7.16 - 7.23 (m, 2 H) 7.35 - 7.44 (m, 2 H) 8.34 (s, 1 H) 9.44 (s, 1 H); HRMS (ESI+) calcd for C19H16CIFN5O (MH+) 384.1022, found 384.1029.
Step 2: In an 18 x150mm test tube, 6-amino-4-(3-chloro-4-fIuorophenylamino)-3-cyano-N,N-dimethylquinoline-8-carboxamide(0.300g, 0.782mmol) and cyclohexanecarboxaldehyde (0.094mL, 88mg, 0.782mmol) were
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taken up in 9mL THF and 3mL MeOH and stirred overnight. The mixture was then acidified to pH 4 with acetic acid, NaCNBH3 (33mg, 0.52mmol) was added, and it was allowed to stir overnight again. The yellow precipitate was then collected by suction filtration, washed with MeOH, and dried under vacuum, giving pure product as a bright yellow powder (71 mg, 20% yield): 1H NMR (400 MHz, DMSO-D6) 8 0.90 -1.04 (m, 2 H) 1.12 -1.29 (m, 3 H) 1.50 -1.86 (m, 6 H) 2.67 (s, 3 H) 2.93 - 2.99 (m, 2 H) 3.04 (s, 3 H) 6.38 (t, J=5.4 Hz, 1 H) 6.98 (d, J=2.3 Hz, 1 H) 7.15 (d, J=2.5 Hz,
1 H) 7.25 (ddd, J=8.8,4.1, 2.8 Hz, 1 H) 7.43 (t, J=9.0 Hz, 1 H) 7.48 (dd, J=6.6, 2.8
Hz, 1 H) 8.31 (s, 1 H) 9.38 (s, 1 H); HRMS (ESI+) calcd for QBHZBCIFNBO (MH+)
480.1961, found 480.1960.
Example 83: 4-(3-chloro-4-fluorophenylamino)-3-cyano-N,N-dimethyl-6-((1-methyl-1H-benzo[cflimidazol-2-yl)methylamino)quinoline-8-carboxamide
The procedure described above in Example 82 was followed. Because the product did not precipitate out of the reaction mixture, solvent was removed under reduced pressure, and the crude product taken up in 6mL MeOH, stirred vigorously, and filtered. The precipitate was washed with MeOH and dried under vacuum to give a pale yellow powder (83mg, 20% yield): 1H NMR (400 MHz, DMSO-D6) 5 2.67 (s, 3 H) 3.04 (s, 3 H) 3.83 (s, 3 H) 4.69 (dd, J=4.9, 2.4 Hz, 2 H) 6.95 (t, .7=5.3 Hz, 1 H) 7.16 - 7.21 (m, 1 H) 7.22 - 7.34 (m, 3 H) 7.39 (d, J=2.5 Hz, 1 H) 7.44 (t, J=9.0 Hz, 1 H) 7.51 - 7.62 (m, 3 H) 8.36 (s, 1 H) 9.45 (s, 1 H); HRMS (ESI+) calcd for C28H24CIFN7O (MH+) 528.1710, found 528.1716.
Example 84: 4-(3-chloro-4-fluorophenylamino)-3-cyano-6-(furan-2-ylmethylamino)-N,N-dimethylquinoline-8-carboxamide
Following the procedure described above in Example 4, 6-amino-4-(3-chloro-4-fluorophenylamino)-3-cyano-N,/\/-dimethylquinoline-8-carboxamide (0.300g, 0.782mmol) was reacted with 2-furaldehyde (0.065mL, 75mg, 0.78mmol) and NaCNBH3 (33mg, 0.52mmol). The crude product was purified by trituration with 6mL MeOH, to give a bright yellow powder (0.136g, 38% yield): 1H NMR (400 MHz, DMSO-D6) 5 2.67 (s, 3 H) 3.04 (s, 3 H) 4.41 (d, J=5.8 Hz, 2 H) 6.34 - 6.43 (m,
2 H) 6.85 (t, J=6.2 Hz, 1 H) 7.19 (d, =2.3 Hz, 1 H) 7.25 - 7.33 (m, 2 H) 7.44 (t,
J=9.1 Hz, 1 H) 7.53 (dd, J=6.6, 2.3 Hz, 1 H) 7.58 - 7.63 (m, 1 H) 8.33 (s, 1 H) 9.42
(s, 1 H); HRMS (ESI+) calcd for C24H20CIFN5O2 (MH+) 464.1284, found 464.1288.
Example 85: 4-(3-chloro-4-fluorophenylamino)-3-cyano-6-(3-cyanobenzylamino)-N,N-dimethylquinoline-8-carboxamide
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Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluorophenylamino)-3-cyano-N,N-dimethylquinoline-8-carboxamide (0.300g, 0.782mmol) was reacted with 3-cyanobenzaldehyde (103mg, 0.782mmol) and NaCNBH3 (33mg, 0.52mmol). The crude product was purified by preparative HPLC and lyophilized to give a fluffy, bright yellow solid (0.131 g, 34% yield): 1H NMR (400 MHz, DMSO-D6) 8 2.67 (s, 3 H) 3.04 (s, 3 H) 4.48 (d, J=6.1 Hz, 2 H) 7.01 (t, J=5.8 Hz, 1 H) 7.19 (s, 2 H) 7.24 (ddd, J=8.8,4.2, 2.7 Hz, 1 H) 7.41 (t, J=9.0 Hz, 1 H) 7.47 (dd, J=6.4, 2.7 Hz, 1 H) 7.56 (t, J=7.7 Hz, 1 H) 7.73 (t, J=7.5 Hz, 2 H) 7.84 (s, 1 H) 8.34 (s, 1 H) 9.41 (brs, 1 H); HRMS (ESI+) calcd for C27H21CIFNBO (MH+) 499.1444, found 499.1443.
Example 86: 4-(3-chloro-4-fluorophenylamino)-3-cyano-6-(4-cyanobenzylamino)-N,N-dimethylquinoline-8-carboxamide
Following the procedure described above in Example 4, 6-amino-4-(3-chloro-4-fluorophenylamino)-3-cyano-N,W-dimethylquinoline-8-carboxamide (0.300g, 0.782mmol) was reacted with 4-cyanobenzaIdehyde (103mg, 0.782mmol) and NaCNBH3 (33mg, 0.52mmol). The crude product was purified by preparative HPLC and lyophilized to give a fluffy, bright yellow solid (0.107g, 28% yield): 1H NMR (400 MHz, DMSO-D6) 5 2.67 (s, 3 H) 3.04 (s, 3 H) 4.52 (d, J=6.3 Hz, 2 H) 7.07 (t, J=6.2 Hz, 1 H) 7.14 - 7.24 (m, 3 H) 7.40 (t, J=9.0 Hz, 1 H) 7.45 (dd, J=6.6, 2.5 Hz, 1 H) 7.55 (d, J=8.3 Hz, 2 H) 7.80 (d, J=8.6 Hz, 2 H) 8.34 (s, 1 H) 9.39 (br s,
1 H); HRMS (ESI+) calcd for C27H21CIFN6O (MH+) 499.1444, found 499.1442.
Example 87: 6-((1 H-imidazol-5-yl)methylamino)-4-(3-chloro-4-fluorophenylamino)-3-cyano-N,N-dimethylquinoline-8-carboxamide
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluorophenylamino)-3-cyano-N,N-dimethylquinoline-8-carboxamide (0.300g, 0.782mmol) was reacted with 4(5)-imidazolecarboxaldehyde (75mg, 0.78mmol) and NaCNBH3 (33mg, 0.52mmol). The crude product was purified by preparative HPLC and lyophilized to give a fluffy, bright yellow solid (96mg, 26% yield): 1H NMR (400 MHz, DMSO-D6) 8 2.67 (s, 3 H) 3.03 (s, 3 H) 4.28 (d, J=5.1 Hz,
2 H) 6.62 (t, J=5.3 Hz, 1 H) 7.05 (s, 1 H) 7.19 - 7.33 (m, 3 H) 7.44 (t, J=9A Hz, 1 H)
7.53 (dd, J=6.6, 2.8 Hz, 1 H)7.62 (s, 1 H) 8.31 (s, 1 H) 9.47 (brs, 1 H); HRMS
(ESI+) calcd for C23H2oCIFN70 (MH+) 464.1397, found 464.1401.
Example 88: 4-(3-chloro-4-fluorophenylamino)-3-cyano-6-((5-(hydroxymethyl)furan-2-yl)methylamino)-N,N-dimethylquinoline-8-carboxamide
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Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluorophenylamino)-3-cyano-N,W-dimethylquinoline-8-carboxamide (0.300g, 0.782mmol) was reacted with 5-(hydroxymethyl)furfural (99mg, 0.78mmol) and NaCNBH3 (33mg, 0.52mmol). The crude product was purified by preparative HPLC and lyophilized to give a fluffy, bright yellow solid (47mg, 12% yield): 1H NMR (400 MHz, DMSO-D6) 5 2.67 (s, 3 H) 3.04 (s, 3 H) 4.34 (s, 2 H) 4.39 (d, J=5.6 Hz, 2 H) 5.17 (br s, 1 H) 6.19 (d, .7=3.0 Hz, 1 H) 6.29 (d, J=3.0 Hz, 1 H) 6.86 (t, J=5.8 Hz, 1 H) 7.19 (d, J=2.5 Hz, 1 H) 7.24 - 7.34 (m, 2 H) 7.44 (t, .7=9.0 Hz, 1 H) 7.53 (dd, J=6.7, 2.7 Hz, 1 H) 8.32 (s, 1 H) 9.46 (br s, 1 H); HRMS (ESI+) calcd for CzgHCIFNgOa (MH+) 494.1390, found 494.1392.
Example 89: 6-((1H-pyrazol-5-yl)methylamino)-4-(3-chloro-4-fluorophenylamino)-3-cyano-/v,/V-dimethylquinoline-8-carboxamide
Following the procedure described above in Example 4, 6-amino-4-(3-chloro-4-fluorophenylamino)-3-cyano-N,N-dimethylquinoline-8-carboxamide (0.300g, 0.782mmol) was reacted with pyrazol-3-carbaldehyde (75mg, 0.78mmol) and NaCNBH3 (33mg, 0.52mmol). The crude product was purified by preparative HPLC and lyophilized to give a yellow powder (41 mg, 11% yield): 1H NMR (400 MHz, DMSO-D6) 8 2.67 (s, 3 H) 3.04 (s, 3 H) 4.37 (d, J=5.1 Hz, 2 H) 6.26 (d, J=1.8 Hz, 1 H) 6.71 (br s, 1 H) 7.22 (d, .7=2.0 Hz, 1 H) 7.25 - 7.34 (m, 2 H) 7.44 (t, .7=9.0 Hz, 1 H) 7.52 (dd, J=6.6, 2.5 Hz, 1 H) 7.63 (br s, 1 H) 8.32 (s, 1 H) 9.47 (br s, 1 H) 12.68 (br s, 1 H); HRMS (ESI+) calcd for C23H20CIFN7O (MH+) 464.1397, found 464.1402.
Example 90: 4-(3-chloro-4-fluorophenylamino)-3-cyano-6-((1,3-dimethyl-1-H-pyrazol-5-yl)methylamino)-/V,/V-dimethylquinoline-8-cait>oxamide
Following the procedure described above in Example 4, 6-amino-4-(3-chloro-4-fluorophenylamino)-3-cyano-N,N-dimethylquinoline-8-carboxamide (0.300g, 0.782mmol) was reacted with 1,3-dimethyl-1H-pyrazole-5-carbaldehyde (97mg, 0.78mmol) and NaCNBH3 (33mg, 0.52mmol). The crude product was purified by preparative HPLC and lyophilized to give a fluffy yellow solid (69mg, 18% yield): *H NMR (400 MHz, DMSO-D6) 5 2.07 (s, 3 H) 2.67 (s, 3 H) 3.04 (s, 3 H) 3.72 (s, 3 H) 4.36 (d, .7=5.3 Hz, 2 H) 6.03 (s, 1 H) 6.78 (t, .7=5.1 Hz, 1 H) 7.19 (d, .7=2.5 Hz, 1 H) 7.25 - 7.34 (m, 2 H) 7.44 (t, .7=9.0 Hz, 1 H) 7.52 (dd, J=6.6,2.8 Hz, 1 H) 8.35 (s, 1 H) 9.49 (br s, 1 H); HRMS (ESI+) calcd for CzsHzaCIFNyO (MH+) 492.1710, found 492.1709.
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Example 91: 4-(3-chloro-4-fluorophenylamino)-3-cyano-W,/\/-climethyl-6-(pyriclin-2-ylmethylamino)quinoline-8-carboxamide
Following the procedure described above in Example 4, 6-amino-4-(3-chloro-4-fluorophenylamino)-3-cyano-N,N-dimethy!quinoline-8-carboxamide (0.300g, 0.782mmol) was reacted with 2-pyridinecarboxaldehyde (74uL, 84mg, 0.78mmol) and NaCNBH3 (33mg, 0.52mmol). The crude product was purified twice by preparative HPLC to give a yellowish-brown solid (4.5mg, 1.2% yield): 1H NMR (400 MHz, DMSO-De) 8 2.66 (s, 3 H) 3.03 (s, 3 H) 4.53 (d, J=5.8 Hz, 2 H) 7.01 (t, J=6.1 Hz, 1 H) 7.18 - 7.30 (m, 4 H) 7.35 - 7.42 (m, 2 H) 7.46 (dd, J=6.6, 2.5 Hz, 1 H) 7.74 (dt, J=7.7,1.8 Hz, 1 H) 8.31 (s, 1 H) 8.53 (d, J=4.0 Hz, 1 H) 9.45 (br s, 1 H); HRMS (ESI+) calcd for C25H21CIFN6O (MHf) 475.1444, found 475.1436.
Example 92: 4-(3-chloro-4-fluorophenylamino)-3-cyano-N,N-dimethyl-6-(3-methylbenzylamino)quinoline-8-carboxamide
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluorophenylamino)-3-cyano-W,/V-dimethylquinoline-8-carboxamide (0.300g, 0.782mmol) was reacted with m-tolualdehyde (92uL, 94mg, 0.78mmol) and NaCNBH3 (33mg, 0.52mmol). The crude product was purified by trituration with 7mL boiling MeOH, to give a bright yellow powder (0.151g, 40% yield): 1H NMR (400 MHz, DMSO-D6) 6 2.27 (s, 3 H) 2.66 (s, 3 H) 3.02 (s, 3 H) 4.34 (d, J=5.6 Hz, 2 H) 6.88 (t, J=5.7 Hz, 1 H) 7.06 (d, J=7.1 Hz, 1 H) 7.13 - 7.25 (m, 6 H) 7.41 (t, J=9.0 Hz, 1 H) 7.47 (dd, J=6.6, 2.8 Hz, 1 H) 8.32 (s, 1 H) 9.39 (s, 1 H); HRMS (ESI+) calcd for C27H24CIFN5O (MH+) 488.1648, found 488.1643.
Example 93: 4-(3-chloro-4-fluorophenylamino)-3-cyano-N-isopropyl-6-(pyridin-3-ylmethylamino)quinoline-8-carboxamide
The procedure used was a modification of those described by A. Schoenberg and R. Heck (J. Org. Chem. 1974, 39(23), 3327-3331), and M. Larhed et al. (J. Comb. Chem. 2002, 4,109-111). A microwave vial was charged with 8-bromo-4-(3-chloro-4-fluorophenylamino)-6-(pyridin-3-ylmethylamino)quinoline-3-carbonitrile as prepared in Example 77 (0.100g, 0.207mmol), Mo(CO)6 (27mg, O.IOmmol) and Pd(PPh3)2Cl2 (29mg, 0.041 mmol), and crimp-sealed. The vial was then purged with CO gas, and isopropylamine (5mL), tri-n-butylamine (0.055mL, 43mg, 0.23mmol) and toluene (1mL) were added. The vial was then heated in a microwave reactor at 150 °C for 15 minutes, until LC-MS analysis showed complete disappearance of 8-bromo-4-(3-chloro-4-fluorophenylamino)-6-(pyridin-3-ylmethylamino)quinoline-3-carbonitrile. This was repeated on the same scale with
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3 additional vials, and the contents of the 4 vials then worked up together by partitioning between EtOAc and brine, extracting the aqueous layer twice more with EtOAc, washing the combined organic layers with brine, drying over anhydrous MgSO4, filtering, and evaporating. The crude product was purified by preparative HPLC and lyophilized to give a yellow solid (50mg, 12% yield): 1H NMR (400 MHz, DMSO-D6) 5 1.22 (d, J=Q.6 Hz, 6 H) 4.45 (d, J=5.6 Hz, 2 H) 7.10 - 7.51 (m, 6 H) 7.77 (d, J=7.6 Hz, 1 H) 8.15 (d, J=2.0 Hz, 1 H) 8.39 (s, 1 H) 8.45 (d, J=3.3 Hz, 1 H) 8.60 (s, 1 H) 9.61 (br s, 1 H) 1C.68 (d, J=6.6 Hz, 1 H); HRMS (ESI+) calcd for C26H23CIFN6O (MH+) 489.1601, found 489.1595.
Example 94: 4-(3-chloro-4-fluorophenylamino)-3-cyano-N,/V-dimethyl-6-(pyridin-3-ylmethylamino)quinoline-8-carboxamide
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluorophenylamino)-3-cyano-N,N-dimethylquinoline-8-carboxamide (0.27g, 0.70mmol) was reacted with 3-pyridinecarboxaIdehyde (0.066mL, 75 mg, 0.70mmol) and NaCNBH3 (30mg, 0.47mmot) in 9mL THF and 3mL MeOH. The crude product was purified first by trituration with 5mL MeOH, then by preparative HPLC, and lyophilized to give a yellow solid (24mg, 7.2% yield): 1H NMR (400 MHz, DMSO-De) 5 2.65 (s, 3 H) 3.02 (s, 3 H) 4.43 (d, J=5.6 Hz, 2 H) 6.94 (t, J=5.7 Hz, 1 H) 7.18 (s, 1 H) 7.22 - 7.28 (m, 2 H) 7.33 - 7.44 (m, 2 H) 7.48 (dd, J=6.3, 2.5 Hz, 1 H) 7.78 (d, J=8.1 Hz, 1 H) 8.31 (s, 1 H) 8.46 (d, J=4.0 Hz, 1 H) 8.62 (s, 1 H) 9.45 (br s, 1 H); HRMS (ESI+) calcd for CzsHCIFNeO (MH+) 475.1444, found 475.1437.
Example 95: 4-(3-chloro-4-fluorophenylamino)-6-(phenylamino)quinoline-3-carbonitrile
A modification of the procedure described by J. Wolfe and S. Buchwald (Org. Synth. 2002, 78,23-25) was followed. A microwave vial was charged with 6-bromo-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (0.1 OOg, 0.266mmol), Pd(OAc)2 (20mg, 0.089mmol), (±)-BINAP (20mg, 0.032mmol) and CS2CO3, and crimp-sealed. The vial was purged and backfilled with an inert gas, and a solution of aniline (0.30mL, 0.31 g, 3.3mmol) in 5mL anhydrous THF was added. The vial was then heated in a microwave reactor at 180 °C for 2 hours, until LC-MS analysis showed complete consumption of starting material. The vial contents were partitioned between EtOAc and brine, the aqueous layer extracted twice more with EtOAc, and the combined organic layers washed with brine, dried over anhydrous MgSO4, filtered, and evaporated. The crude product was purified by preparative HPLC and lyophilized to give a yellow solid (9.2mg, 8.9% yield): 1H
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NMR (400 MHz, DMSO-D6) 8 6.90 (t, J=7.5 Hz, 1 H) 7.14 (d, J=8.1 Hz, 3 H) 7.24 (t, J=7.6 Hz, 2 H) 7.33 - 7.41 (m, 2 H) 7.54 (d, J=9.4 Hz, 1 H) 7.77 (s, 1 H) 7.83 (d, J=9.1 Hz, 1 H) 8.44 (s, 1 H) 8.69 (s, 1 H) 9.56 (s, 1 H); HRMS (ESI+) calcd for C22H15CIFN4 (MH+) 389.0964, found 389.0959.
Example 96: 6-((1H-imidazol-5-yl)methylamino)-8-bromo-4-(cyclopentylamino)quinoline-3-carbonitrile
Step 1: Following the procedure described above in Example 68,8-bromo-4-chloro-6-nitroquinoline-3-carbonitrile (1.00g, 3.20mmol) was reacted with cyclopentylamine (0.63mL, 0.54g, 6.4mrhol). The crude product was purified by flash chromatography over silica gel (5% EtOAc in CH2CI2) to give a fluffy, bright yellow solid 8-bromo-4-(cyclopentylamino)-6-nitroquinoline-3-carbonitrile (0.405g, 35% yield): 1H NMR (400 MHz, DMSO-D6) 8 1.54 -1.69 (m, 2 H) 1.72 -1.93 (m, 4 H) 2.03 - 2.15 (m, 2 H) 4.69 -4.82 (m, 1 H) 8.50 (d, J=7.6 Hz, 1 H) 8.75 (d, J=1.5 Hz, 2 H) 9.54 (d, J=2.5 Hz, 1 H); HRMS (ESI+) calcd for dsHBrNz (MH+) 361.0295, found 361.0293.
Step 2: Following the procedure described above in Example 69, 8-bromo-4-(cyclopentylamino)-6-nitroquinoline-3-carbonitrile (0.354g, 0.980mmol) was reacted with tin chloride dihydrate (1.11g, 4.90mmol). Work up was also as described, except that the neutralized aqueous suspension was extracted with EtOAc (4 x) instead of CHCI3. Evaporation of the EtOAc gave pure product 6-amino-8-bromo-4-(cyclopentylamino)quinoline-3-carbonitrile as a brown powder (0.252g, 78% yield): 1H NMR (400 MHz, DMSO-De) 8 1.51 -1.66 (m, 2 H) 1.69 -1.84 (m, 4 H) 1.97 - 2.11 (m, 2 H) 4.56 - 4.69 (m, 1 H) 5.65 (s, 2 H) 7.21 (d, J=7.3 Hz, 1 H) 7.27 (d, J=2.3 Hz, 1 H) 7.52 (d, J=2.0 Hz, 1 H) 8.22 (s, 1 H); HRMS (ESI+) calcd for C15H16BrN4 (MH+) 331.0553, found 331.0557.
Step 3: Following the procedure described above in Example 4,6-amino-8-bromo-4-(cyclopentylamino)quinoline-3-carbonitrile (0.224g, 0.676mmol) was reacted with 4(5)-imidazolecarboxaldehyde (65mg, 0.68mmol) and NaCNBH3 (29mg, 0.45mmol) in 4.5mL THF and 1.5mL MeOH. The crude product was taken up in MeOH, and a tan powder precipitated. This powder was collected, washed with MeOH, and dried under vacuum to give pure product (62mg, 22% yield): 1H NMR (400 MHz, DMSO-D6) 8 1.61 (br. s, 2 H) 1.70 -1.86 (m, 4 H) 2.01 - 2.14 (m, 2 H) 4.29 (d, J=5.3 Hz, 2 H) 4.59 - 4.74 (m, 1 H) 6.45 (t, J=5.2 Hz, 1 H) 7.05 (s, 1 H) 7.13 - 7.22 (m, 2 H) 7.61 (d, J=1.0 Hz, 1 H) 7.66 (d, J=2.3 Hz, 1 H) 8.24 (s, 1 H) 11.95 (br s, 1 H); HRMS (ESI+) calcd for C19H20BrN6 (MH+) 411.0928, found 411.0939.
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Example 97: 6-((1 H-imidazol-5-yl)methylarnino)-8-bromo-4-(cycloheptylamino) quinoline-3-carbonitrile
Step 1: Following the procedure described above in Example 68,8-bromo-4-chloro-6-nitroquinoline-3-carbonitrile (1.00g, 3.20mmol) was reacted with cycloheptylamine (0.82mL, 0.72g, 6.4mmol). The crude product was purified by flash chromatography over silica gel (gradient elution, 5-50% EtOAc in CH2CI2) to give a fluffy, bright yellow solid 8-brorno-4-(cycloheptylamino)-6-nitroquinoline-3-carbonitrile (WAY-199056, 0.293g, 23% yield): 1H NMR (400 MHz, DMSO-D6) 8 1.46 -1.67 (m, 6 H) 1.68 -1.88 (m, 4 H) 2.00 - 2.11 (m, 2 H) 4.47 - 4.64 (m, 1 H) 8.50 (d, J=8.6 Hz, 1 H) 8.73 (s, 1 H) 8.74 (d, J=2.3 Hz, 1 H) 9.53 (d, J=2.3 Hz, 1 H); HRMS (ESI+) calcd for C17Hi8BrN4O2 (MH+) 389.0608, found 389.0606.
Step 2: Following the procedure described above in Example 69, 8-bromo-4-(cycloheptylamino)-6-nitroquinoline-3-carbonitrile (0.234g, 0.601 mmol) was reacted with tin chloride dihydrate (0.68g, 3.01 mmol). Workup was also as described, except that the neutralized aqueous suspension was extracted with EtOAc (4 *) instead of CHCI3. Evaporation of the EtOAc gave pure product 6-amino-8-bromo-4-(cycloheptylamino)quinoline-3-carbonitrile as a purplish-brown powder (0.164g, 76% yield): 1H NMR (400 MHz, DMSO-D6) 5 1.46 -1.80 (m, 10 H) 1.94 - 2.05 (m, 2 H) 4.33 - 4.51 (m, 1 H) 5.64 (s, 2 H) 7.14 (d, J=8.8 Hz, 1 H) 7.27 (d, J=2.3 Hz, 1 H) 7.52 (d, J=2.3 Hz, 1 H) 8.21 (s, 1 H); HRMS (ESI+) calcd for C17H20BrN4O (MH+) 359.0866, found 359.0873.
Step 3: Following the procedure described above in Example 4, 6-amino-8-bromo-4-(cycloheptylamino)quinoline-3-carbonitrile (0.137g, 0.381mmol) was reacted with 4(5)-imidazolecarboxaldehyde (37mg, 0.38mmol) and NaCNBH3 (16mg, 0.26mmol) in 4.5mL THF and 1.5mL MeOH. The crude product was taken up in MeOH, and a beige powder precipitated. This powder was collected, washed with MeOH, and dried under vacuum to give pure product (37mg, 22% yield): 1H NMR (400 MHz, DMSO-D6) D 1.44 -1.86 (m, 10 H) 1.96 - 2.13 (m, 2 H) 4.29 (d, J=4.8 Hz, 2 H) 4.38 - 4.54 (m, 1 H) 6.44 (t, J=4.2 Hz, 1 H) 7.05 (s, 1 H) 7.10 - 7.24 (m, 2 H) 7.63 (d, J=17.4 Hz, 2 H) 8.23 (s, 1 H) 11.97 (br s, 1 H); HRMS (ESI+) calcd for C2iHZ4BrN6 (MH+) 439.1241, found 439.1253.
Example 98: 6-((1H-imidazol-5-yl)methylamino)-8-bromo-4-(te/f-butylamino)quinoline-3-carbonitrile
Step 1: Following the procedure described above in Example 68,8-bromo-4-chloro-6-nitroquinoline-3-carbonitrile (1.00g, 3.20mmol) was reacted with tert-
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butylamine (0.68mL, 0.46g, 13mmol). The crude product was purified by flash chromatography over silica gel (gradient elution, 1-20% EtOAc in CH2CI2) to give pure product 8-bromo-4-(terf-butylamino)-6-nitroquinoline-3-carbonitrile (0.518g, 46% yield): 1H NMR (400 MHz, DMSO-D6) 5 1.62 (s, 9 H) 7.83 (s, 1 H) 8.79 (d, J=2.5 Hz, 1 H) 8.87 (s, 1 H) 9.26 (d, J=2.3 Hz, 1 H); HRMS (ESI+) calcd for C14Hi4BrN4O2 (MH+) 349.0295, found 349.0297.
Step 2: In a 25mL round-bottomed flask fitted with a condenser, 8-bromo-4-fert-butylamino-6-nitroquinoline-3~carbonitrile (0.257g, 0.736mmol) was taken up in 4mL MeOH and 2mL water, and iron powder (0.370g, 6.62mmol) and NH4CI (0.591 g, 11 .Ommol) were added. The mixture was heated at reflux for 1 hour, until LC-MS analysis showed complete conversion of nitroquinoline to aniline. After cooling to RT, the reaction mixture was diluted with EtOAc, basified with saturated NaHCO3, dried by addition of anhydrous MgSO4, filtered, and evaporated to give the product 6-amino-8-bromo-4-(terf~butylamino)quinoline-3-carbonitrile as a golden-yellow powder (0.213g, 90% yield): 1H NMR (400 MHz, DMSO-D6) 5 1.51 (s, 9 H) 5.83 (s, 2 H) 6.18 (s, 1 H) 7.13 (d, J=2.3 Hz, 1 H) 7.56 (d, J=2.3 Hz, 1 H) 8.35 (s, 1 H); HRMS (ESI+) calcd for C14H16BrN4 (MH+) 319.0553, found 319.0557.
Step 3: Following the procedure described above in Example 4, 6-amino-8-bromo-4-terf-butylaminoquinoline-3-carbonitrile (137mg, 0.429mmol) was reacted with 4(5)-imidazolecarboxaldehyde (41 mg, 0.43mmol) and NaCNBH3 (18mg, 0.29mmol) in 4.5mL THF and 1.5mL MeOH. The crude product was purified by preparative HPLC and lyophilized to give a beige solid (68mg, 40% yield): 1H NMR (400 MHz, DMSO-D6) 8 1.49 (s, 9 H) 4.28 (d, J=4.3 Hz, 2 H) 6.18 (s, 1 H) 6.68 (t, J=4.9 Hz, 1 H) 7.03 (s, 1 H) 7.10 (s, 1 H) 7.60 (s, 1 H) 7.69 (s, 1 H) 8.39 (s, 1 H); HRMS (ESI+) calcd for C18H2oBrN6 (MH+) 399.0928, found 399.0912.
Example 99: 4-(3-cyano-6-(pyridin-3-ylmethylamino)quinolin-4-ylamino)benzamide
Step 1 Following the procedure described above in Example 69, 6-nitro-4-oxo-1,4-dihydroquinoline-3-carbonitrile (5.00g, 23.2mmol) was reacted with oxalyl chloride (4.0mL, 5.9g, 46mmol) in 50mL DCE, with 0.42mL DMF. Pure product 4-chloro-6-nitroquinoline-3-carbonitrile was obtained as a brown solid (5.00g, 92% yield): 1H NMR (400 MHz, DMSO-D6) 8 8.41 (d, J=9.1 Hz, 1 H) 8.70 (dd, J=9.1, 2.5 Hz, 1 H) 9.04 (d, J=2.5 Hz, 1 H) 9.41 (s, 1 H).
Step 2: Following the procedure described above in Example 76,4-chloro-6-nitroquinoline-3-carbonitrile (0.500g, 2.14mmol) was reacted first with 4-aminobenzamide (0.320g, 2.35mmol), then with tin chloride dihydrate (2.41 g, 10.7mmol), in 5mL EtOH. The crude product was purified by trituration with 17mL
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boiling EtOH, to give a pumpkin-orange colored powder 4-(6-amino-3-cyanoquinolin-4-ylamino)benzamide (0.210g, 32% yield): 1H NMR (400 MHz, DMSO-D6) 8 7.38 - 7.52 (m, 5 H) 7.87 (d, J=9.1 Hz, 1 H) 7.97 (d, J=8.6 Hz, 2 H) 8.05 (s, 1 H) 8.83 (s, 1 H) 10.90 (s, 1 H); HRMS (ESI+) calcd for C17H14N5O (MH+) 304.1193, found 304.1195.
Step 3: Following the procedure described above in Example 4,4-(6-amino-3-cyanoquinolin-4-ylamino)benzamide (0.145g, 0.478mmol) was reacted with 3-pyridinecarboxaldehyde (0.045mL, 51 mg, 0.48mmol) and NaCNBH3 (20mg, 0.32mmol) in 5mL THF and 14mL MeOH. The crude product was purified by preparative HPLC and lyophilized to give a yellowish-brown solid (29mg, 15% yield): 1H NMR (400 MHz, DMSO-D6) 8 4.32 (d, J=5.6 Hz, 2 H) 6.90 (t, J=5.7 Hz, 1 H) 7.04 - 7.09 (m, 3 H) 7.18 (s, 1 H) 7.25 - 7.35 (m, 2 H) 7.65 - 7.72 (m, 2 H) 7.78 -7.86 (m, 3 H) 8.37 (s, 1 H) 8.39 (dd, J=4.7,1.39 Hz, 1 H) 8.52 (d, J=1.8 Hz, 1 H) 9.36 (s, 1 H); HRMS (ESI+) calcd for C23H19Ne (MH+) 395.1615, found 395.1615.
Example 100: 4-(3-chlorophenylamino)-6-(pyridin-3-ylmethylamino)-8-(thiophen-3-yl)quinoline-3-carbonitrile
A microwave vial was charged with 8-bromo-4-(3-chlorophenylamino)-6-(pyridin-3-ylmethylamino)quinoline-3-carbonitrile as prepared in Example 70 above (80mg, 0.17mmol), 3-thiopheneboronic acid (26mg, 0.21mmol), Pd(PPh3)2Cl2 (12mg, 0.017mmol), Na2CO3 (22mg, 0.21 mmol), and 1.5mL each DME, EtOH and water. The vial was crimp-sealed and heated in a microwave reactor at 140 °C for 30 minutes, until LC-MS analysis showed complete consumption of 8-bromo-4-(3-chlorophenylamino)-6-(pyridin-3-ylmethylamino)quinoline-3-carbonitrile. The contents of the vial were then partitioned between EtOAc and brine, the aqueous layer extracted twice more with EtOAc, and the combined organic layers washed with brine, dried over anhydrous MgSO4, filtered and evaporated. Crude product was purified by preparative HPLC and lyophilized to give a light brown solid (11mg, 14% yield): 1H NMR (400 MHz, DMSO-D6) 8 4.44 (d, J=5.6 Hz, 2 H) 6.94 (t, J=5.9 Hz, 1 H) 7.08 (dd, J=7.7,1.6 Hz, 1 H) 7.11 - 7.17 (m, 2 H) 7.18 (t, J=2.0 Hz, 1 H) 7.35 (t, J=8.1 Hz, 2 H) 7.49 - 7.56 (m, 2 H) 7.60 (dd, J=4.8, 3.0 Hz, 1 H) 7.77 (d, J=7.8 Hz, 1 H) 7.92 (dd, J=3.0,1.3 Hz, 1 H) 8.43 (s, 1 H) 8.46 (d, J=4.6 Hz, 1 H) 8.61 (s, 1 H) 9.38 (s, 1 H); HRMS (ESI+) calcd for C26H19CIN5S (MH+) 468.1044, found 468.1046.
Example 101: 8-bromo-4-(3-chloro-4-fluorophenylamino)-6-(1 -oxypyridin-2-ylrnethylamino)quinoline-3-carbonitrile
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Following the procedure described above in Example 4,6-amino-8-bromo-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (0.600g, 1.53mmol) was reacted with methoxy-(1-oxypyridin-2-yl)methanol (0.238g, 1.53mmol) and NaCNBH3 (64mg, 1 .Ommol) in 18mL THF and 6mL MeOH. After the reaction mixture had stirred overnight, the bright yellow precipitate was collected by suction filtration, washed with methanol and dried under vacuum to give pure product as a bright yellow powder (0.352g, 46% yield): 1H NMR (400 MHz, DMSO-D6) 5 4.58 (d, J=6.1 Hz, 2 H) 7.04 (t, J=6.3 Hz, 1 H) 7.17 (s, 1 H) 7.20 - 7.44 (m, 5 H) 7.49 (dd, J=6.6, 2.5 Hz, 1 H) 7.82 (d, J=1.8 Hz, 1 H) 8.31 (d, J=6.1 Hz, 1 H) 8.37 (s, 1 H) 9.46 (s, 1 H); HRMS (ESI+) calcd for C22H15BrCIFN5O (MH+) 498.0127, found 498.0108.
Example 102: 4-(3-chloro-4-fluorophenylamino)-8-(furan-3-yl)-6-(pyridin-3-ylmethylamino)quinoline-3-carbonitrile
Following the procedure described above in Example 100, 8-bromo-4-(3-chloro-4-fluorophenylamino)-6-(pyridin-3-ylmethylamino)quinoline-3-carbonitrile (0.200g, 0.414mmol, prepared as described in Example 77 above) was reacted with with furan-3-boronic acid (56mg, 0.50mmol), Pd(PPh3)2CI2 (15mg, 0.021 mmol) and Na2CO3 (53 mg, 0.50mmol) for 15 minutes at 130 °C. The crude product was purified by preparative HPLC and lyophilized to give a golden-brown solid (41 mg, 21% yield): 1H NMR (400 MHz, DMSO-D6) 8 4.45 (d, J=5.8 Hz, 2 H) 6.85 (t, J=6.2 Hz, 1 H) 6.96 (s, 1 H) 7.15 (d, J=2.3 Hz, 1 H) 7.18 - 7.24 (m, 1 H) 7.32 - 7.45 (m, 3 H) 7.60 (d, J=2.0 Hz, 1 H) 7.74 - 7.82 (m, 2 H) 8.41 (s, 1 H) 8.46 (d, J=4.3 Hz, 1 H) 8.54 (s, 1 H) 8.63 (s, 1 H) 9.36 (s, 1 H); HRMS (ES1+) calcd for C26H18CIFN5O (MH+) 470.1179, found 470.1186.
Example 103; 2-(4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino)-N, N-di methylacetamide
Step 1: Following the procedure described above in Example 76,4-chloro-6-nitroquinoline-3-carbonitrile (2.50g, 5.35mmol) was reacted with 3-chloro-4-fluoroaniline (1.71g, 11.8mmol), in 2 batches, each in 5mL EtOH, except that CHCI3 was used instead of EtOAc for the work-up. The 2 batches were worked up together, and the crude product 6-amino-4-(3-chloro-4-fluorophenylamino)quinoIine-3-carbonitrile purified by flash chromatography over silica gel (gradient elution, 4-6% MeOH in CH2CI2) to give a brown solid (1.36g, 81% yield): 1H NMR (400 MHz, DMSO-De) 8 5.76 (s, 2 H) 7.11-7.16 (m, 2 H) 7.24 (dd, J=9.0, 2.4 Hz, 1 H) 7.32 -7.40 (m, 2 H) 7.69 (d, J=8.8 Hz, 1 H) 8.32 (s, 1 H) 9.34 (s, 1 H).
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Step 2: Following the procedure described above in Example 4,6-amino-4-(3-criloro-4-fluorophenylamino)quinoline-3-carbonitrile (1.26g, 4.03mmol) was reacted with a 50 wt% solution of glyoxylic acid in water (0.44mL, 0.30g, 4.0mmol) and NaCNBH3 (0.170 g, 2.70 mmol), in 40 mL THF and 15 mL MeOH. The yellow precipitate was collected out of the reaction mixture by suction filtration, washing with MeOH, and dried under vacuum to give the product 2-(4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino)acetic acid as a yellow-orange powder (0.420g, 28% yield): 1H NMR (400 MHz, DMSO-De) 5 3.95 (s, 2 H) 6.50 (br s, 1 H) 7.09 (d, J=2.0 Hz, 1 H) 7.21 - 7.31 (m, 1 H) 7.35 - 7.46 (m, 2 H) 7.49 (dd, J=6.3, 2.5 Hz, 1 H) 7.68 (d, J=8.8 Hz, 1 H) 8.29 (s, 1 H) 9.34 (s, 1 H).
Step 3: Following the procedure described above in Example 68,2-(4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino)aceticacid(0.100g, 0.270mmol) was reacted with dimethylamine hydrochloride (24mg, 0.30mmol), BOP reagent (0.131g, 0.297mmol) and 4-methylmorpholine (0.065mL, 60mg, 0.59mmol) in 3 mL DMF. Product was obtained as a brownish-yellow powder (62mg, 58% yield): 1H NMR (400 MHz, DMSO-D6) 8 2.89 (s, 3 H) 3.02 (s, 3 H) 3.97 (s, 2 H) 6.26 (s, 1 H) 7.04 (s, 1 H) 7.24 - 7.32 (m, 1 H) 7.40 - 7.56 (m, 3 H) 7.69 (d, J=9A Hz, 1 H) 8.34 (s, 1 H) 9.34 (s, 1 H); HRMS (ESI+) calcd for C20H18ClFN5O (MH+) 398.1179, found 398.1173.
Example 104: 8-bromo-4-(ferf-butylamino)-6-(1 -oxypyridin-2-ylmethylamino) quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-8-bromo-4-(terf-butylamino)quinoline-3-carbonitrile (0.213g, 0.667mmol) was reacted with methoxy-(1-oxypyridin-2-yl)rnethano! (0.104g, 0.667mmol) and NaCNBH3 (28mg, 0.45mmol) in 6mL THF and 2mL MeOH. The crude product was purified twice by preparative HPLC and once by flash chromatography over silica gel (gradient elution, 1-10% MeOH in CH2CI2), then lyophilized, to give a beige solid (26mg, 9.2% yield): 1H NMR (400 MHz, DMSO-D6) 5 1.33 (s, 9 H) 4.62 (d, J=6A Hz, 2 H) 6.12 (s, 1 H) 6.99 (d, J=2.0 Hz, 1 H) 7.09 (t, J=6.1 Hz, 1 H) 7.24 - 7.39 (m, 3 H) 7.73 (s, 1 H) 8.33 (d, J=6.6 Hz, 1 H) 8.43 (s, 1 H); HRMS (ESI+) calcd for C2oH21BrN50 (MH+) 426.0924, found 426.0929.
Example 105: 8-bromo-4-(3-chloro-4-fluorophenylamino)-6-((2-methyl-1 H-imidazol-5-yl)methylamino)quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-8-bromo-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile(0.300g, 0.766mmol,
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prepared as described in Example 78 above) was reacted with 2-methyl-1tf-imidazole-5-carbaldehyde (84mg, 0.77mmol) and NaCNBH3 (32mg, 0.51 mmol) in 9mL THF and 3mL MeOH. The aude product was purified by preparative HPLC and lyophilized to give a bright yellow solid (0.238g, 64% yield): 1H NMR (400 MHz, DMSO-D6) 5 2.23 (s, 3 H) 4.16 (d, J=5.1 Hz, 2 H) 6.64 (t, J=4.8 Hz, 1 H) 6.87 (s, 1 H) 7.21 (d, J=1.8 Hz, 1 H) 7.25 - 7.32 (m, 1 H) 7.44 (t, J=9.1 Hz, 1 H) 7.52 (dd, J=6.6, 2.5 Hz, 1 H) 7.78 (d, J=1.5 Hz, 1 H) 8.36 (s, 1 H) 9.47 (s, 1 H) 11.84 (br s, 1 H); HRMS (ESI+) calcd for C21H16BrCIFN6O (MH+) 485.0287, found 485.0290.
Example 106: 8-bromo-4-(3-chloro-4-fluorophenylamino)-6-((2-phenyl-1 H-imidazol-5-yl)methylamino)quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-8-bromo-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (0.300g, 0.766mmol, prepared as described in Example 78 above) was reacted with 2-phenyl-1H-imidazole-5-carbaldehyde (0.132g, 0.766mmol) and NaCNBH3 (32mg, 0.51mmol) in 9 mL THF and 3mL MeOH. The crude product was purified by trituration with boiling EtOH, and a second crop of crystals collected from the filtrate, to give a yellow solid (0.206g, 49% yield): 1H NMR (400 MHz, DMSO-D6) 5 4.30 (d, J=5.8 Hz, 2 H) 6.77 (t, J=5.3 Hz, 1 H) 7.20 (s, 1 H) 7.26 - 7.35 (m, 3 H) 7.37 - 7.47 (m, 3 H) 7.53 (dd, J=6.6, 2.8 Hz, 1 H) 7.81 (s, 1 H) 7.90 (d, J=7.3 Hz, 2 H) 8.37 (s, 1 H) 9.49 (s, 1 H) 11.94 (s, 0.5 H) 12.40 (s, 0.5 H); HRMS (ESI+) calcd for CzeHBrCIFNe (MH+) 547.0444, found 547.0457.
Example 107: 8-bromo-6-((2-butyl-1 W-imidazol-5-yl)methylamino)-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile
Step 1: The procedure described by R. Paul and J. Menschik (J. Heterocyclic Chem. 1979, 16, 277-282) was followed. In a 50mL round-bottomed flask, (2-butyl-1H-imidazol-5-yl)methanol (5.00g, 32.4mmol) was taken up in 5mL concentrated nitric acid. The open flask was heated in an oil bath at 100 °C until brown fumes issued from its mouth, lifted out of the oil bath briefly to ensure that the reaction did not become too vigorous, and then, upon calming, returned to the oil bath and heated until the evolution of brown fumes ceased. The reaction mixture was then cooled to RT and neutralized with saturated Na2CO3, and the off-white precipitate collected, rinsed with water, and dried under vacuum to give pure product 2-butyl-1H-imidazole-5-carbaldehyde (2.64g, 53% yield): 1H NMR (400 MHz, DMSO-D6) 8 0.87 (t, J=7.5 Hz, 3 H) 1.28 (br s, 2 H) 1.63 (quint, 2 H) 7.73 (s,
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0.5 H) 7.90 (s, 0.5 H) 9.56 (s, 0.5 H) 9.64 (s, 0.5 H) 12.50 (s, 0.5 H) 12.89 (s, 0.5
H).
Step 2: Following the procedure described above in Example 76, 6-amino-8-bromo-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (0.300 g, 0.766 mmol) was reacted with 2-butyl-1H-imidazole-5-carbaldehyde (0.117 g, 0.766 mmol) and NaCNBH3 (32 mg, 0.51 mmol) in 9 mL THF and 3 mL MeOH. The crude product was recrystallized from MeCN to give a yellow solid (0.193 g, 48% yield): 1H NMR (400 MHz, DMSO-D6) 8 0.87 (t, J=7.3 Hz, 3 H) 1.30 (sext, 2 H) 1.60 (quint, 2 H) 2.53 - 2.61 (m, 2 H) 4.19 (d, J=4.8 Hz, 2 H) 6.64 (t, J=5.2 Hz, 1 H) 6.88 (s, 1 H) 7.24 (d, J=2.0 Hz, 1 H) 7.28 (ddd, J=8.9,4.1, 2.7 Hz, 1 H) 7.44 (t, J=9.1 Hz, 1 H) 7.52 (dd, J=6.6, 2.8 Hz, 1 H) 7.79 (d, J=2.0 Hz, 1 H) 8.37 (s, 1 H) 9.48 (s, 1 H) 11.59 (s, 1 H); HRMS (ESI+) calcd for C24H22BrCIFN6 (MH+) 527.0757, found 527.0761.
Example 108: 2-(4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino)-/V-methylacetamide
Following the procedure described above in Example 103, 2-(4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino)acetic acid (0.150g, 0.405mmol) was reacted with methylamine hydrochloride (30mg, 0.45mmol) in the presence of BOP reagent (0.197g, 0.445mmol) and 4-methylmorpholine (0.098mL, 90mg, 0.89mmol), in 3mL DMF. Product was isolated as a bright yellow powder (0.113g, 73% yield): 1H NMR (400 MHz, DMSO-D6) 5 2.60 (d, J=4.3 Hz, 3 H) 3.80 (d, >5.6 Hz, 2 H) 6.56 (s, 1 H) 7.08 (s, 1 H) 7.18 - 7.49 (m, 4 H) 7.71 (d, J=8.6 Hz, 1 H) 7.83 (s, 1 H) 8.33 (s, 1 H) 9.37 (s, 1 H); HRMS (ESI+) calcd for C19H16CIFN5O (MH+) 384.1022, found 384.1019.
Example 109: (£)-4-(3-chloro-4-fluorophenylamino)-8-(prop-1-enyl)-6-(pyridin-3-ylmethylamino)quinoline-3-carbonitrile
In a flame-dried, crimp-sealed microwave vial, under an inert atmosphere, 8-bromo-4-(3-chloro-4-fluorbphenylamino)-6-(pyridin-3-ylmethylamino)quinoline-3-carbonitrile (0.1 OOg, 0.207mmol, prepared as described in Example 77) and Pd(PPh3)4 (24mg, 0.021 mmol) were taken up in 4mL anhydrous THF. A flame-dried 25mL round-bottomed flask, under an inert atmosphere, was charged with a 0.5M THF solution of 1-propenylmagnesium bromide (1.2mL, 0.62mmol). A 0.5M THF solution of zinc chloride (1.2mL, 0.62mmol) was then added, and the mixture stirred for 5 minutes at RT. It was then transferred by syringe to the microwave tube. The yellow suspension immediately became a clear, dark red solution. The
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vial and its contents were heated in a microwave reactor at 110 °C for 5 minutes, until LC-MS analysis showed that most of the bromide starting material had been consumed. The contents of the vial were then partitioned between EtOAc and saturated NH4CI, the aqueous layer extracted twice more with EtOAc, and the combined organic layers washed with brine, dried over anhydrous MgSO4, filtered, and evaporated. The crude product was purified by preparative HPLC and lyophilized to give a golden yellow powder (16mg, 18% yield): 1H NMR (400 MHz, DMSO-De) 8 1.94 (dd, J=6.6,1.8 Hz, 3 H) 4.44 (d, J=5.6 Hz, 2 H) 6.24 - 6.41 (m, 1 H) 6.81 (t, J=5.9 Hz, 1 H) 7.11 (d, J=2.3 Hz, 1 H) 7.19 (ddd, J=8.7, 4.2, 2.8 Hz, 1 H) 7.31 - 7.53 (m, 5 H) 7.77 (d, J=7.8 Hz, 1 H) 8.36 (s, 1 H) 8.46 (d, J=4.3 Hz, 1 H) 8.61 (s, 1 H) 9.28 (s, 1 H); HRMS (ESI+) calcd for CzsHzoCIFNg (MH+) 444.1386, found 444.1379.
Example 110: Methyl 5-((8-bromo-4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino)methyl)-1 H-imidazole-4-carboxylate
Step 1: In a microwave vial, methyl 5-hydroxymethyl-1W-imidazole-4-carboxylate (0.200g, 1.28mmol) was taken up in 2.5mL each CH2CI2 and 1,4-dioxane, and activated MnO2 (0.95g, 11mmol) was added. The vial was crimp-sealed and heated in a microwave reactor at 140°C for 5 minutes, until LC-MS analysis showed complete disappearance of starting material. The contents of the vial were then rinsed into a 1 L Erlenmeyer flask and stirred with 400mL MeOH for 30 minutes. The suspension was then filtered to remove MnO2, and the filtrate dried over anhydrous MgSO4, filtered a second time, and evaporated to give product methyl 5-formyl-1H-imidazole-4-carboxylate of sufficient purity to be used in the next step (0.163g, 83% yield): 1H NMR (400 MHz, DMSO-D6) 5 3.88 (s, 3 H) 8.06 (s, 1 H) 10.22 (s, 1 H) 13.76 (s, 1 H); HRMS (ESI+) calcd for Q5H7N2O3 (MH+) 155.0451, found 155.0450.
Step 2: Following the procedure described above in Example 76, 6-amino-8-bromo-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (0.400 g, 1.02 mmol, prepared as described abovie in Example 78) was reacted with with methyl 5-formyl-1tf-imidazole-4-carboxylate (157 mg, 1.02 mmol) and NaCNBH3 (43 mg, 0.68 mmol) in 12 mL THF and 4 mL MeOH. The crude product was purified by preparative HPLC and lyophilized to give a bright yellow powder (0.18 g, 33% yield): 1H NMR (400 MHz, DMSO-D6) 5 3.76 (br s, 3 H) 4.50 (br s, 1 H) 4.62 (br s, 1 H) 6.65 (br s, 0.5 H) 6.74 (br s, 0.5 H) 7.20 - 7.31 (m, 2 H) 7.43 (t, J=9.0 Hz, 1 H) 7.50 (dd, J=6.4, 2.7 Hz, 1 H) 7.63 - 7.88 (m, 2 H) 8.39 (s, 1 H) 9.45 (br s, 1 H) 12.70
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(br s, 0.5 H) 13.09 (br s, 0.5 H); HRMS (ESI+) calcd for QsHieBrCIFNsOz (MH+) 529.0185, found 529.0186.
Example 111: 8-bromo-4-(3-chloro-4-fluorophenylamino)-6-((4-phenyl-1 H-imidazol-5-yl)methylamino)quinoline-3-carbonitrile
Step 1: The procedure described by Y. Hayashi etal.(J. Org. Chem. 2000, 65, 8402-8405) was followed. In a 250mL round-bottomed flask fitted with an addition funnel, ethyl benzoylacetate (9.0mL, 10 g, 52mmol) was dissolved in 40 mL CHCI3 and cooled to 0 °C in an ice bath. Sulfuryl chloride (4.4mL, 7.4g, 55mmol) was then added dropwise via the addition funnel. After the addition was complete, the ice bath was removed and the solution allowed to stir for 1 hour at RT. It was then heated at reflux for 2 hours. Upon cooling to RT, the cloudy yellow solution was washed successively with water, saturated NaHCO3, water and brine, dried over anhydrous MgSO* filtered, and evaporated to give the product ethyl 2-chloro-3-oxo-3-phenylpropanoate as a golden-yellow oil of sufficient purity to be used in the next step (12.7g, 108% yield): 1H NMR (400 MHz, CDCI3) 5 1.24 (t, J=7.2 Hz, 3 H) 4.28 (q, J=7.2 Hz, 2 H) 5.59 (s, 1 H) 7.50 (t, J=7.7 Hz, 2 H) 7.63 (t, J=7.5 Hz, 1 H) 7.99 (d, J=7.3 Hz, 2 H).
Step 2: A modification of the procedures described by Y. Hayashi et al. (J. Org. Chem. 2000, 65, 8402-8405) and G. Durant et al. (US 4024271) was followed. A 250mL round-bottomed flask fitted with a condenser was charged with ethyl 2-chloro-3-oxo-3-phenylpropanoate (6.7g, 30mmol), formamide (12mL, 13g, 0.30mol) and water (1.1mL, 1.1g, 59mmol), and heated at 195 °C until LC-MS analysis showed desired product as the major component. The reaction mixture was then cooled to RT and partitioned between CHCI3 and saturated Na2CO3. The aqueous layer was extracted twice more with CHCI3, and the combined organic layers washed twice with saturated Na2CO3 and twice with brine, then dried over anhydrous MgSO4, filtered and evaporated. The crude product was purified by flash chromatography over silica gel (5% MeOH in CH2CI2) to give the product ethyl 4-phenyl-1H-imidazole-5-carboxylate as an off-white solid (0.833g, 13% yield): 1H NMR (400 MHz, DMSO-D6) 5 1.17 (t, J=7.1 Hz, 1.2 H) 1.25 (t, J=7.1 Hz, 1.8 H) 4.14 (q, J=7.1 Hz, 0.8 H) 4.24 (q, J=7.2 Hz, 1.2 H) 7.28 - 7.47 (m, 3.6 H) 7.61 (d, J=7.1 Hz, 1 H) 7.79 (s, 0.4 H) 7.83 - 7.92 (m, 2 H) 12.86 (br s, 0.4 H) 13.02 (br s, 0.6 H).
Step 3: In a flame-dried 100mL round-bottomed flask under an inert atmosphere, ethyl 4-phenyl-1H-imidazole-5-carboxylate (1.14g, 5.26mmol) was taken up in 25mL anhydrous THF and cooled to 0 °C in an ice bath. A1.0 M solution of lithium aluminum hydride in THF (5.3mL, 5.3mmol) was then added
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slowly via syringe. After the addition was complete, the ice bath was removed, and the reaction mixture allowed to warm to RT over 30 minutes. The reaction was then cooled back to 0 °C and quenched by addition of 5mL saturated Na2SO4. This was followed by addition of enough 1M HCI to bring the pH of the solution down to 8. The white precipitate was then filtered off, washing with copious amounts of EtOAc. The filtrate was dried over anhydrous MgSO4) filtered and evaporated to give the product (4-phenyl-1H-imidazol-5-yl)methanol as a waxy yellow solid of sufficient purity to be used in the next step (0.765g, 83% yield): 1H NMR (400 MHz, DMSO-De) 5 4.54 (d, J=4.3 Hz, 2 H) 5.19 (br s, 1 H) 7.24 (t, J=7.3 Hz, 1 H) 7.39 (t, J=7.7 Hz, 2 H) 7.62 (s, 1 H) 7.68 (d, J=7.1 Hz, 2 H) 12.24 (br s, 1 H).
Step 4: Following the procedure described above in Example 110, (4-phenyl-1 W-imidazol-5-yl)methanol (0.400g, 2.30mmol) was reacted with activated manganese dioxide (0.400g, 4.60mmol). The crude product 4-phenyl-1 tf-imidazole-5-carbaldehyde obtained was of sufficient purity to be used directly in the next step (0.538g, 136% yield): 'H NMR (400 MHz, DMSO-D6) 8 7.40 - 7.53 (m, 3 H) 7.83 (d, J=7.1 Hz, 2 H) 8.03 (s, 1 H) 9.86 (s, 1 H) 13.29 (s, 1 H).
Step 5: Following the procedure described above in Example 4, 6-amino-8-bromo-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile(0.300g, 0.766mmol, prepared as described above in Example 78) was reacted with 4-phenyl-1H-imidazole-5-carbaldehyde (132mg, 0.766mmol) and NaCNBH3 (32mg, 0.51 mmol) in 9mL THF and 3mL MeOH. The reaction mixture was allowed to stir overnight after addition of NaCNBH3, but LC-MS analysis showed that more 6-aminoquinoline than product was present. Additional aldehyde (132mg) and NaCNBH3 were added, and the reaction was stirred for an additional day. Solvent was then removed under reduced pressure, and the crude product purified by preparative HPLC and lyophilized, to give a bright yellow solid (62mg, 15% yield): 1H NMR (400 MHz, DMSO-D6) 5 m 4.33 (dd, J=49.4, 3.9 Hz, 2 H) 6.75 (s, 0.5 H) 6.95 (s, 0.5 H) 7.18 - 7.90 (m, 11 H) 8.41 (d, J=8.3 Hz, 1 H) 9.45 (s, 1 H) 12.43 (s, 0.5 H) 12.53 (s, 0.5 H); HRMS (ESI+) calcd for C26H18BrCIFNe (MH+) 547.0444, found 547.0451.
Example 112: 8-bromo-4-(3-chloro-4-fluorophenylamino)-6-((4-ethyl-1 H-imidazoI-5-yl)methylamino)quinoline-3-carbonitrile
Step 1: Following the procedure described above in Example 111, ethyl propionylacetate (9.9mL, 10g, 69mmol) was reacted with sulfuryl chloride (5.9mL, 9.8g, 73mmol) in 50mL CHCI3, to give pure product ethyl 2-chloro-3-oxopentanoate as a colorless oil (9.90 g, 80% yield): 1H NMR (400 MHz, CDCI3) 6 1.11 (t, J=7.2
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Hz, 3 H) 1.30 (t, J=7.1 Hz, 3 H) 2.73 (dq, J=7.2, 2.5 Hz, 2 H) 4.27 (q, J=7.2 Hz, 2 H) 4.78 (s, 1 H).
Step 2: Following the procedure described above in Example 111, ethyl 2-chloro-3-oxopentanoate (8.90g, 49.8mmol) with formamide (20mL, 22g, 0.50mol) and water (1.8mL, 1.8g, lOOmmol). To work up the reaction, 50mL 1M HCI was added to the cooled, dark brown solution, and it was then heated to its boiling point, treated with activated charcoal, and filtered while hot. The clear reddish-golden brown solution was then acidified with additional 1M HCI to ph 1, then basified with concentrated NH4OH and extracted with 3 portions of CHCI3. The combined organic extracts were dried over anhydrous MgSO4, filtered, and evaporated to give an oily yellow solid. This was purified by flash chromatography over silica gel (gradient elution, 1-10% MeOH in CH2CI2) to give the product ethyl 4-ethyl-1H-imidazole-5-carboxylate as a white crystalline solid (0.641g, 7.6% yield): 1H NMR (400 MHz, DMSO-D6) 5 1.15 (t, J=7.5 Hz, 3 H) 1.21 - 1.33 (m, 3 H) 2.78 (q, J=7.6 Hz, 0.68 H) 2.88 (q, J=7.6 Hz, 1.32 H) 4.19 (q, J=7.1 Hz, 1.32 H) 4.25 (q, J=7.2 Hz, 0.68 H) 7.58 (s, 0.66 H) 7.68 (s, 0.34 H) 12.42 (br s, 0.66 H) 12.72 (br s, 0.34 H).
Step 3: Following the procedure described above in Example 111, ethyl 4-ethyl-1H-imidazole-5-carboxylate (0.641 g, 3.81 mmol) was reacted with a 1.0M THF solution of lithium aluminum hydride (3.8mL, 3.8mmol) in 20mL THF. After quenching the reaction mixture with saturated Na2SO4l the white precipitate was filtered off, washing with copious amounts of EtOAc, and the filtrate dried over anhydrous MgSO4, filtered and evaporated to give a product (4-ethyl-1H-imidazol-5-yl)methanol of sufficient purity to be used directly in the next step (0.471 g, 98% yield): 1H NMR (400 MHz, DMSO-D6) 8 1.11 (t, J=7.6 Hz, 3 H) 2.46 - 2.53 (m, 2 H) 4.32 (s, 2 H) 4.66 (s, 1 H) 7.39 (s, 1 H) 11.67 (s, 1 H).
Step 4: Following the procedure described above in Example 110, (4-ethyl-1H-imidazol-5-yl)methanol (0.471 g, 3.73mmol) was reacted with activated manganese dioxide (0.973g, 11.2mmol) to give the product 4-ethyl-1 H-imidazole-5-carbaldehyde as an oily brown solid of sufficient purity to be used directly in the next step (0.386g, 83% yield): 1H NMR (400 MHz, DMSO-D6) 5 1.19 (br s, 3 H) 2.86 (br s, 2 H) 7.73 (br s, 1 H) 9.78 (br s, 1 H).
Step 5: Following the procedure described above in Example 4, 6-amino-8-bromo-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile(0.300g, 0.766mmol, prepared as described above in Example 78) was reacted with 4-ethyl-1H-imidazole-5-carbaldehyde (95mg, 0.77mmol) and NaCNBH3 (32mg, 0.51 mmol) in 9mL THF and 3mL MeOH. The crude product was purified by preparative HPLC, and lyophilized to give a fluffy bright yellow solid (111 mg, 29% yield): 1H NMR (400
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MHz, DMSO-De) 5 1.11 (t, J=7.5 Hz, 3 H) 2.57 (br s, 2 H) 4.14 (br s, 2 H) 6.51 (br s, 1 H) 7.23 (s, 1 H) 7.25 - 7.35 (m, 1 H) 7.44 (t, J=9.1 Hz, 1 H) 7.48 - 7.57 (m, 2 H) 7.81 (s, 1 H) 8.39 (s, 1 H) 9.46 (s, 1 H) 11.82 (brs, 1 H); HRMS (ESI+) calcd for C22H18BrCIFN6 (MH+) 499.0444, found 499.0453.
Example 113: 8-bromo-4-(3-chioro-4-fluorophenylamino)-6-((1,5-dimethyl-1 H-irnidazol-4-yl)methylamino)quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-8-bromo-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (88mg, 0.226mmol, prepared as described in Example 78) was reacted with 1,5-dimethyl-1H-imidazole-4-carbaldehyde (28mg, 0.27mmol) and NaCNBH3 (10mg, 0.15mmol) in 3mL THF and 1mL MeOH. The crude product was purified by preparative HPLC and lyophilized to give a fluffy bright yellow solid (36mg, 32% yield): 1H NMR (400 MHz, DMSO-D6) 8 2.16 (s, 3 H) 3.51 (s, 3 H) 4.12 (d, J=4.6 Hz, 2 H) 6.50 (t, J=4.7 Hz, 1 H) 7.23 (d, J=1.8 Hz, 1 H) 7.25 - 7.31 (m, 1 H) 7.44 (t, J=9.0 Hz, 1 H) 7.48 - 7.54 (m, 2 H) 7.80 (d, J=2.0 Hz, 1 H) 8.38 (s, 1 H) 9.46 (s, 1 H); HRMS (ESI+) calcd for C22H18BrCIFN6 (MH+) 499.0444, found 499.0455.
Example 114: 8-bromo-4-(3-chloro-4-fluorophenylamino)-6-((4-(trifluoromethyl)-1H-imidazol-5-yl)methylamino)quino!ine-3-carbonitrile
Step 1: Following the procedure described above in Example 111, ethyl 2-chloro-4,4,4-trifluoroacetoacetate (50g, 0.23mol) was reacted with formamide (91.0mL, 103g, 2.29mol) and water (8.3mL, 8.3g, 0.46mol). The reaction mixture, which turned into a brown sludge, was worked up by pouring into ice water, diluting to 300 mL, and collecting the precipitate by suction filtration, washing with water and drying under vacuum. Pure product ethyl 4-(trifluoromethyl)-1H-imidazole-5-carboxylate was obtained as a dark brown powder (9.90g, 21% yield): 1H NMR (400 MHz, DMSO-De) 5 1.30 (t, J=7.1 Hz, 3 H) 4.33 (q, J=7A Hz, 2 H) 8.01 (s, 1 H) 13.89 (s, 1 H); HRMS (ESI+) calcd for C7HBF3N2O2 (MH+) 209.0533, found 209.0533.
Step 2: Following the procedure described above in Example 111, ethyl 4-(trifluoromethyl)-1H-imidazole-5-carboxylate (1.00g, 4.80mmol) with a 1.0M THF solution of lithium aluminum hydride (4.8mL, 4.8mmol) in 20mL THF. After filtering off the precipitate during the work-up, the filtrate was diluted with an equal volume of MeOH to dissolve the dark oil clinging to the bottom of the flask, dried over anhydrous MgSO4, filtered, and evaporated to give the product (4-(trifluoromethyl)-1H-imidazol-5-yl)methanol as an oily, light orange solid of sufficient purity to be
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used directly in the next step (0.745g, 94% yield): 1H NMR (400 MHz, DMSO-D6) 8 4.53 (d, J=1.5 Hz, 2 H) 7.70 (s, 1 H) 13.07 (s, 1 H).
Step 3: Following the procedure described above in Example 110, (4-(trifluoromethyl)-1H-imidazol-5-yl)methanol (0.500g, 3.01 mmol) was reacted with activated manganese dioxide (0.79g, 9.0mmol) to give a product 4-(trifluoromethyl)-1H-imidazole-5-carbaldehyde of sufficient purity to be used directly in the next step (0.573 g, 116% yield): 1H NMR (400 MHz, DMSO-D6) 8 7.88 (br s, 1 H) 9.83 (br s, 1 H).
Step 4: Following the procedure described above in Example 4, 6-amino-8-bromo-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile(0.300g, 0.766mmol prepared as described above in Example 78) was reacted with 4-(trifluoromethyl)-1H-imidazole-5-carbaldehyde (126mg, 0.766mmol) and NaCNBH3 (32mg, 0.51 mmol) in 9mL THF and 3mL MeOH. After 1 day, LC-MS analysis showed that very little product was present, so additional aldehyde (126mg) and NaCNBH3 (32mg) were added. After another day, there was still more 6-aminoquinoline than desired product, so additional aldehyde (126mg) and NaCNBH3 (32mg) were once again added, and the reaction was allowed to stir for 3 days. Solvent was then removed under reduced pressure, and the crude product purified twice by preparative HPLC, and lyophilized to give a brownish-yellow powder (22 mg, 5.2% yield): 1H NMR (400 MHz, DMSO-D6) 8 4.41 (d, J=4.0 Hz, 2 H) 6.76 - 6.86 (m, 1 H) 7.23 - 7.33 (m, 2 H) 7.45 (t, J=9.0 Hz, 1 H) 7.53 (dd, J=6.8, 2.5 Hz, 1 H) 7.73 (d, J=2.0 Hz, 1 H) 7.83 (s, 1 H) 8.42 (s, 1 H) 9.47 (br s, 1 H) 12.92 (br s, 1 H); HRMS (ESI+) calcd for C21H13BrCIF4N6 (MH+) 539.0004, found 539.0014.
Example 115: 8-bromo-4-(3-chloro-4-fluorophenylamino)-6-((4-isopropyl-1H-imidazol-5-yl)methylamino)quinoline-3-carbonitrile
Step 1: Following the procedure described above in Example 111, ethyl isobutyrylacetate (10.2mL, 10.0g, 63.2mmol) was reacted with sulfuryl chloride (5.3mL, 9.0g, 66mmol) in 50mL CHCI3, to give product ethyl 2-chloro-4-methyl-3-oxopentanoate of sufficient purity to be used directly in the next step (12.2g, 94% yield): 1H NMR (400 MHz, CDCI3) 8 1.17 (dd, J=9.1, 6.8 Hz, 6 H) 1.30 (t, J=6.8 Hz, 3 H) 2.99 - 3.16 (m, 1 H) 4.24 - 4.33 (m, 2 H) 4.92 (s, 1 H).
Step 2: Following the procedure described above in Example 111, ethyl 2-chloro-4-methyl-3-oxo-pentanoate (12.2g, 63.3mol) was reacted with formamide (25mL, 29g, 0.63mol) and water (2.3mL, 2.3g, 0.13mol). The crude product was purified by flash chromatography over silica gel (4-6% MeOH in CH2CI2) to give product ethyl 4-isopropyl-1H-imidazole-5-carboxylate of sufficient purity to be used
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in the next step (0.558g, 4.8% yield): 1H NMR (400 MHz, DMSO-D6) 8 1.20 (d, J=7.1 Hz, 6 H) 1.23 -1.33 (m, 3 H) 3.44 - 3.57 (m, 0.35 H) 3.65 - 3.79 (m, 0.65 H) 4.12 - 4.33 (m, 2 H) 7.58 (s, 0.65 H) 7.66 (s, 0.35 H) 12.39 (br s, 0.65 H) 12.67 (br s, 0.35 H).
Step 3: Following the procedure described above in Example 112, ethyl 4-isopropyl-1tf-imidazole-5-carboxylate (0.558g, 3.06mmol) was reacted with a 1.0M THF solution of lithium aluminum hydride (3.1mL, 3.1mmol) in 20mL THF. Work-up gave product (4-isopropyl-1H-imidazol-5-yl)methanol of sufficient purity to be used directly in the next step (0.397g, 92% yield): 1H NMR (400 MHz, DMSO-D6) 81.15 (d, J=6.8 Hz, 6 H) 2.78 - 3.12 (m, 1 H) 4.33 (s, 2 H) 4.66 (br s, 1 H) 7.38 (s, 1 H) 11.66 (brs,1H).
Step 4: Following the procedure described above in Example 110, (4-isopropyl-1H-imidazol-5-yl)methanol (0.217g, 1.55mmol) with activated manganese dioxide (0.404g, 4.64mmol) in 5mL acetone. The crude product was purified by flash chromatography over silica gel (gradient elution, 5-100% EtOAc in CH2CI2) to give pure product 4-isopropyl-1 H-imidazole-5-carbaldehyde as a pale pink solid (0.278g, 37% yield): 1H NMR (400 MHz, DMSO-D6) 8 1.23 (d, J=6.8 Hz, 6 H) 3.41 (br s, 0.35 H) 3.53 - 3.68 (m, 0.65 H) 7.71 (s, 0.65 H) 7.85 (s, 0.35 H) 9.82 (s, 1 H) 12.66 (br s, 0.65 H) 12.91 (br s, 0.35 H).
Step 5: Following the procedure described above in Example 4, 6-amino-8-bromo-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile(0.300g, 0.766mmol, prepared as described in Example 78) was reacted with 4-isopropyl-1H-imidazole-5-carbaldehyde (106mg, 0.766mmol) and NaCNBH3 (32mg, 0.51 mmol) in 9mL THF and 3mL MeOH. The crude product was purified by preparative HPLC, and lyophilized to give a fluffy bright yellow solid (162mg, 41% yield): 1H NMR (400 MHz, DMSO-D6) 8 1.16 (d, J=6.8 Hz, 6 H) 3.09 (br s, 1 H) 4.13 (s, 2 H) 6.49 (s, 1 H) 7.21 (s, 1 H) 7.24 - 7.33 (m, 1 H) 7.44 (t, J=9.0 Hz, 1 H) 7.48 -7.55 (m, 2 H) 7.83 (s, 1 H) 8.39 (s, 1 H) 9.45 (s, 1 H) 11.82 (s, 1 H); HRMS (ESI+) calcd for CzsHaoBrCIFNe (MH+) 513.0600, found 513.0594.
Example 116: 8-bromo-4-(3-chloro-4-fluorophenylamino)-6-((1 -methyl-1 H-imidazol-4-yl)methylamino)quinoline-3-carbonitrile
Step 1: Following the procedure described above in Example 112, ethyl 1-methyl-1H-imidazole-4-carboxylate (1.00g, 7.14mmol) was reacted with a 1.0M THF solution of lithium aluminum hydride (7.1 mL, 7.1 mmol) in 20mL THF. Work-up gave product (1 -methyl-1 H-imidazol-4-yl)methanol of sufficient purity to be used
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directly in the next step (0.806g, 101% yield): 1H NMR (400 MHz, DMSO-D6) 8 3.60 (s, 3 H) 4.30 (s, 2 H) 4.79 (br s, 1 H) 6.92 (s, 1 H) 7.45 (s, 1 H).
Step 2: Following the procedure described above in Example 110, (1-methyl-1H-imidazol-4-yl)methanol (0.806g, 7.19mmol) was reacted with activated manganese dioxide (1.87g, 21.6mmol) in 15mL acetone. The crude product 1-methyl-1H-imidazole-4-carbaldehyde was purified by flash chromatography over silica gel (gradient elution, 10-100% EtOAc in CH2CI2) to give pure product as a waxy, yellowish solid (0.234g, 30% yield): 1H NMR (400 MHz, DMSO-D6) 5 3.73 (s, 3 H) 7.81 (s, 1 H) 8.00 (s, 1 H) 9.70 (s, 1 H).
Step 3: Following the procedure described above in Example 4, 6-amino-8-bromo-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile(0.200g, 0.511mmol, prepared as described in Example 78) was reacted with 1-methyl-1H-imidazole-4-carbaldehyde (56mg, 0.51 mmol) and NaCNBH3 (22mg, 0.34mmol) in 6mL THF and 2mL MeOH. The yellow precipitate that appeared was collected by suction filtration, washed with MeOH, and dried under vacuum to give pure product as a bright yellow powder (155mg, 63% yield): 1H NMR (400 MHz, DMSO-D6) 8 3.60 (s, 3 H) 4.21 (d, J=5.3 Hz, 2 H) 6.67 (t, J=5.2 Hz, 1 H) 7.05 (s, 1 H) 7.23 (d, J=2.3 Hz, 1 H) 7.28 (ddd, J=8.7, 4.2, 2.8 Hz, 1 H) 7.45 (t, J=9.0 Hz, 1 H) 7.52 (dd, J=6.7, 2.7 Hz, 1 H) 7.54 (s, 1 H) 7.79 (d, J=2.3 Hz, 1 H) 8.38 (s, 1 H) 9.47 (s, 1 H); HRMS (ESI+) calcd for C21H16BrCIFN6 (MH+) 485.0287, found 485.0278.
Example 117: N-(8-bromo-4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-yl)-2-(1 H-imidazol-5-yl)acetamide
Following the procedure described above in Example 103,6-amino-8-bromo-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (0.500g, 1.28mmol, prepared as described in Example 76) was reacted with imidazoleacetic acid hydrochloride (0.228g, 1.40mmol) overnight, in the presence of BOP reagent (0.619g, 1.40mmol) and 4-methylmorpholine (0.31 mL, 0.29g, 2.8mmol), in 10mL DMF. LC-MS analysis showed very little product, so the reaction mixture was heated at 60 °C overnight. No additional product was generated, so additional acid (0.228g), BOP (0.619g) and 4-methylmorpholine (0.31 mL) were added, and stirring continued at RT overnight. LC-MS analysis showed very little change, so acid (0.684g), BOP (1.86g) and 4-methylmorpholine (0.93mL) were added again, and stirring continued for 3 days at RT. At this point, there finally seemed to be enough product to isolate. The reaction mixture was poured into 100mL water, and the dark brown precipitate collected by suction filtration, washed with water, and dried under vacuum. This crude product was then purified twice by preparative HPLC and
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lyophilized to give a pale yellow powder (76mg, 12% yield): 'H NMR (400 MHz, DMSO-D6) 8 3.64 (s, 2 H) 6.98 (s, 1 H) 7.28 (ddd, J=8.8, 4.2, 2.9 Hz, 1 H) 7.44 (t, J=9.0 Hz, 1 H) 7.52 (dd, J=6.6, 2.8 Hz, 1 H) 7.60 (s, 1 H) 8.38 (d, J=2.0 Hz, 1 H) 8.61 - 8.70 (m, 2 H) 9.95 (s, 1 H) 10.54 (s, 1 H) 12.21 (s, 1 H); HRMS (ESI+) calcd for C2iH14BrCIFN6O (MH+) 499.0080, found 499.0071. •
Example 118: 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-({[5-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile
In a 15mL round-bottom flask were added 6-amino-4-(4-bromo-3-fluoro-phenylamino)-quinoline-3-carbonitrile (30mg, 0.076mmol), ethanol (1mL) and 5-(2-fluorophenyl)-1H-1,2,3-triazole-4-carbaldehyde (16mg, 0.08mmol). Acetic acid was added to bring the pH of the solution to 4, and the mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (32mg, 0.153mmol) was then added and the reaction was stirred at RT overnight. The reaction mixture was stripped to dryness and the residue was purified via preparative HPLC and lyophilized to give the product as a yellow solid (8.6mg, 20%). 1H NMR (400 MHz, MeOD) 5 ppm
4.56 (s, 2 H) 7.08 (d, J=2.53 Hz, 1 H) 7.15 - 7.29 (m, 4 H) 7.34 (dd, J=6.44, 2.65
Hz, 1 H) 7.40 - 7.49 (m, 1 H) 7.50 - 7.61 (m, 2 H) 7.75 (s, 1 H) 8.32 (s, 1 H).
Example 119: 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-({[5-(3-fluorophenyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile
In a 15mL round-bottom flask were added 6-amino-4-(4-bromo-3-fluoro-phenylamino)-quinoline-3-carbonitrile (30mg, 0.076mmol), ethanol (1mL) and 5-(3-fluorophenyl)-1H-1,2,3-triazole-4-carbaldehyde (16mg, 0.08mmol). Acetic acid was added to bring the pH of the solution to 4, and the mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (32mg, 0.153mmol) was then added and the reaction was stirred at RT overnight. The reaction mixture was stripped to dryness and the residue was purified via preparative HPLC and lyophilized to give the product as a yellow solid (6mg, 14%). 1H NMR (400 MHz, DMSO-D6) 8 ppm
4.57 (s, 2 H) 7.18 - 7.24 (m, 1 H) 7.26 - 7.31 (m, 1 H) 7.34 (d, J=2.27 Hz, 1 H) 7.41
(t, J=8.97 Hz, 2 H) 7.47 - 7.62 (m, 4 H) 7.78 (d, J=2.02 Hz, 1 H) 8.43 (s, 1 H).
Example 120: 6-(4-(moroholinosulfonyl)benzylamino)-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-(3-chIoro-4-fluorophenylamino)quinoline-3-carbonitrile (0.137g, 0.44mmol) was reacted with 4-(morpholinosulfonyl)benzaldehyde (261.9mg, 1.03mmol) and
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NaCNBH3 (33mg, 0.53mmol) in 8mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (156mg, 53%): 1H NMR (400 MHz, acetonitrile-D3) 8 ppm 2.84 - 2.91 (m, 4 H) 3.61 - 3.66 (m, 4 H) 4.51 (d, J=6.32 Hz, 2 H) 5.60 - 5.66 (m, 1 H) 6.76 (d, J=2.53 Hz, 1 H) 7.07 - 7.13 (m, 1 H) 7.22 (t, J=8.97 Hz, 1 H) 7.28 (dd, J=6.57, 2.53 Hz, 1 H) 7.32 (dd, J=9.09, 2.78 Hz, 1 H) 7.56 (d, J=8.59 Hz, 2 H) 7.60 - 7.64 (m, 1 H) 7.66 - 7.71 (m, 2 H) 7.78 (d, J=9.09 Hz, 1 H) 8.38 (s, 1 H); HRMS (ESI+) calcd for CzrHzsCIFNsOaS (MH+) 552.12669, found 552.1262.
Example 121: 4-((4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino)methyl)benzenesulfonamide
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (0.3g, 0.96mmol) was reacted with 4-formylbenzenesulfonamide (178mg, 0.96mmol) and NaCNBH3 (33mg, 1.46 mmol) in 7mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (33mg, 7%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.48 (d, J=5.81 Hz, 2 H) 6.97 (t, J=5.94 Hz, 1 H) 7.15 (d, J=2.27 Hz, 1 H) 7.19 - 7.26 (m, 1 H) 7.30 (s, 2 H) 7.35 (dd, J=8.97, 2.40 Hz, 1 H) 7.41 (t, J=8.97 Hz, 1 H) 7.46 (dd, J=6.57, 2.53 Hz, 1 H) 7.55 (d, J=8.59 Hz, 2 H) 7.71 (d, J=9.09 Hz, 1 H) 7.76 - 7.80 (m, 2 H) 8.32 (s, 1 H) 9.31 (s, 1 H); HRMS (ESI+) calcd for CzsHCIFNsOaS (MH+) 482.08483, found 482.0845.
Example 122: 6-(4-(4-methylpiperazin-1 -ylsulfonyl)benzylamino)-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (0.3g, 0.96mmol) was reacted with 4-(4-methylpiperazin-1-ylsulfonyl)benzaldehyde (407mg, 1.52mmol) and NaCNBH3 (72mg, 1.15mmol) in 15mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (103mg, 19%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 2.11 (s, 3 H) 2.33 (t, J=4.93 Hz, 4 H) 2.82 - 2.88 (m, 4 H) 4.52 (d, J=5.81 Hz, 2 H) 7.00 (t, J=5.94 Hz, 1 H) 7.16 (d, J=2.27 Hz, 1 H) 7.18 - 7.24 (m, 1 H) 7.35 (dd, J=9.47,1.89 Hz, 1 H) 7.38 - 7.45 (m, 2 H) 7.61 - 7.65 (m, 2 H) 7.68 - 7.74 (m, 3 H) 8.15 (s, 1 H) 8.32 (s, 1 H) 9.30 (s, 1 H); HRMS (ESI+) calcd for C2BH26CIFN6O2S (MH+) 565.15832, found 565.1581.
Example 123: 4-((4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino)methyl)-N-(2-(dimethylamino)ethyl)benzenesulfonamide
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Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (0.253g, 0.81 mmol) was reacted with N-(2-(dimethylamino)ethyl)-4-formylbenzenesulfonamide (208mg, 0.81 mmol) and NaCNBH3 (73mg, 1.15mmol) in 15mL EtOH. The crude product was purified by combiflash (10%Methanol in dichloromethane), and lyophilized to give the product as a solid (207mg, 46%): 1H NMR (400 MHz, MeOD) 8 ppm 2.15 (s, 6 H) 2.38 (t, J=6.82 Hz, 2 H) 2.89 - 2.94 (m, 2 H) 4.52 (s, 2 H) 6.99 (d, J=2.53 Hz, 1 H) 7.11-7.16 (m, 1 H) 7.24 (t, J=8.84 Hz, 1 H) 7.30 - 7.36 (m, 2 H) 7.54 (d, J=8.59 Hz, 2 H) 7.71 (d, J=9.09 Hz, 1 H) 7.78 - 7.82 (m, J=8.53, 2.15,1.96 Hz, 2 H) 8.27 (s, 1 H); HRMS (ESI+) calcd for C14H16Br2O7S (MNa+) 508.88756, found 508.8881.
Example 124: 4-(3-bromophenylamino)-8-((dimethylamino)methyl)-6-(pyridin-3-ylmethylamino)quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-4-(3-bromophenylamino)-8-((dimethylamino)methyl)quinoline-3-carbonitrile(0.1g, 0.25mmol) was reacted with nicotinaldehyde (0.06mL, 0.64mmol) and NaCNBH3 (21 mg, 0.33 mmol) in 8mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (92mg, 75%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 2.25 (s, 6 H) 3.95 (s, 2 H) 4.39 (d, J=5.81 Hz, 2 H) 6.97 (t, J=6.06 Hz, 1 H) 7.02 (d, J=2.53 Hz, 1 H) 7.08 - 7.12 (m, 1 H) 7.24 - 7.29 (m, 2 H) 7.29 - 7.31 (m, 1 H) 7.34 (ddd, J=7.83, 4.80,0.76 Hz, 1 H) 7.49 (d, J=2.53 Hz, 1 H) 7.73 (dt, J=7.83, 2.02 Hz, 1 H) 8.18 (s, 1 H) 8.45 (dd, J=4.80,1.77 Hz, 1 H) 8.58 (d, J=2.27 Hz, 1 H) 9.27 (s, 1 H); HRMS (ESI+) calcd for C25H23BrN6 (MH+) 487.12403, found 487.1238.
Example 125: 6-amino-4-(3-bromophenylamino)-8-methylquinoline-3-carbonitrile
To a 50mL round-bottomed flask was added 4-(3-bromophenylamino)-8-methyl-6-nitroquinoline~3-carbonitrile (229mg, 0.6mmol), SnCI2.2H2O (742mg, 3.28mmol), and ethyl alcohol (10mL). The mixture was heated to reflux for 12 hr. After cooling down to RT, water (10mL) was added followed by sodium bicarbonate (585mg) and the mixture stirred for 30min. Workup (ethyl acetate/brine) of the reaction gave a solid as product (204mg, 97%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 2.58 (s, 3 H) 5.73 (s, 2 H) 6.95 (d, .7=2.53 Hz, 1 H) 6.97 - 7.02 (m, 1 H) 7.13 -7.18 (m, 2 H) 7.19 - 7.26 (m, 2 H) 8.46 (s, 1 H) 9.25 (s, 1 H); HRMS (ESI+) calcd for C17H13BrN4 (MH+) 353.03963, found 353.0398.
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Example 126: 4-(3-bromophenylamino)-8-methyl-6-(pyridin-3-ylmethylamino)quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-(3-bromophenylamino)-8-methylquinoline-3-carbonitrile (0.1g, 0.28mmol) was reacted with nicotinaldehyde (0.067mL, 0.71 mmol) and NaCNBH3 (28mg, 0.45mmol) in 10mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (102mg, 81%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 2.57 (s, 3 H) 4.37 (d, J=5.81 Hz, 2 H) 6.85 (t, J=6.06 Hz, 1 H) 6.95 (d, J=2.53 Hz, 1 H) 7.06 - 7.09 (m, 1 H) 7.23 - 7.30 (m, 4 H) 7.34 (ddd, J=7.83, 4.80,1.01 Hz, 1 H) 7.73 (dt, J=7.83, 1.89 Hz, 1 H) 5.43 (s, 1 H) 8.45 (dd, J=4.80,1.77 Hz, 1 H) 8.57 (d, J=2.27 Hz, 1 H) 9.23 (s, 1 H); HRMS (ESI+) calcd for CHBrNg (MH+) 444.08183, found 444.0837.
Example 127: 4-(3-chloro-4-fluorophenylamino)-6-(1-(pyridin-2-yl)ethylamino)quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (0.108g, 0.35mmol) was reacted with 1-(pyridin-2-yl)ethanone (0.42g, 3.47mmol) and NaCNBH3 (38mg, 0.6mmol) in 5mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (61mg, 42%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 1.50 (d, J=6.57 Hz, 3 H) 4.76 - 4.82 (m, 1 H) 6.87 (d, J=8.59 Hz, 1 H) 7.00 (d, J=2.53 Hz, 1 H) 7.09 - 7.14 (m, 1 H) 7.21 (ddd, J=7.45,4.80,1.14 Hz, 1 H) 7.32 - 7.41 (m, 4 H) 7.67 - 7.72 (m, 2 H) 8.16 (s, 1 H) 8.50 (dq, J=4.89, 0.89 Hz, 1 H) 9.25 (s, 1 H); HRMS (ESI+) calcd for C23H17CIFN5 (MH+) 418.12293, found 418.124.
Example 128: 4-(3-chloro-4-fluorophenylamino)-6-((1,5-dimethyl-1 H-imidazol-4-yl)methylamino)quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (0.102g, 0.33mmol) was reacted with 1,5-dimethyl-1H-imidazole-4-carbaldehyde (0.091 g, 0.73mmol) and NaCNBH3 (29mg, 0.46mmol) in 8mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (120mg, 88%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 2.16 (s, 3 H) 3.51 (s, 3 H) 4.12 (d, J=4.80 Hz, 2 H) 6.32 (t, J=4.42 Hz, 1 H) 7.17 (d, J=2.02 Hz, 1 H) 7.21 - 7.27 (m, 1 H) 7.36 - 7.48 (m, 3 H) 7.49 (s, 1 H) 7.66 (d, J=9.09 Hz, 1 H) 8.31 (s, 1 H) 9.33 (s, 1 H); HRMS (ESI+) calcd for CaHCIFNe (MH+) 421.13382, found 421.1343.
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Example 129: 4-(3-chloro-4-fluorophenylamino)-6-((5-methyl-1 -(2-morpholinoethyl)-1H-imidazol-4-yl)methylamino)quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (0.107g, 0.34mmol) was reacted with 5-methyl-1-(2-moipholinoethyl)-1H-imidazole-4-carbaldehyde (0.165g, 0.74mmol) and NaCNBH3 (30mg, 0.48mmol) in 10mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (130mg, 73%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 2.19 (s, 3 H) 2.36 - 2.43 (m, J=4.55 Hz, 4 H) 2.52 - 2.56 (m, 2 H) 3.51 - 3.56 (m, 4 H) 3.96 (t, J=6.57 Hz, 2 H) 4.12 (d, J=4.80 Hz, 2 H) 6.35 (t, J=4.80 Hz, 1 H) 7.16 (d, J=2.53 Hz, 1 H) 7.21 -7.27 (m, 1 H) 7.37 - 7.48 (m, 3 H) 7.57 (s, 1 H) 7.67 (d, J=9.09 Hz, 1 H) 8.32 (s, 1 H) 9.31 - 9.35 (m, 1 H); HRMS (ESI+) calcd for C27H27CIFN7O (MH+) 520.20224, found 520.203.
Example 130: 4-(3-chloro-4-fluorophenylamino)-6-((4-methyl-1 -(2-morpholinoethyl)-1H-imidazol-5-yl)methylamino)quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (0.111g, 0.35mmol) was reacted with 4-methyl-1-(2-morpholinoethyl)-1H-imidazole-5-carbaldehyde (0.328g, 1.47mmol) and NaCNBH3 (35mg, 0.56mmol) in 10mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (88mg, 48%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 2.13 (s, 3 H) 2.30 - 2.35 (m, 4 H) 2.57 (t, J=6.69 Hz, 2 H) 3.46 - 3.51 (m, 4 H) 3.98 (t, J=6.44 Hz, 2 H) 4.24 (d, J=4.80 Hz, 2 H) 6.49 (t, J=4.55 Hz, 1 H) 7.21 - 7.27 (m, 2 H) 7.33 (dd, J=8.97, 2.15 Hz, 1 H) 7.41 - 7.48 (m, 2 H) 7.60 (s, 1 H) 7.70 (d, J=9.09 Hz, 1 H) 8.35 (s, 1 H) 9.35 (s, 1 H); HRMS (ESI+) caicd for Cz/HzrCIFNyO (MH+) 520.20224, found 520.2026.
Example 131: 4-(3-bromophenylamino)-8-methyl-6-(2-morpholinoethylamino)quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-(3-bromophenylamino)-8-methylquinoline-3-carbonitrile (0.070g, 0.20mmol) was reacted with crude morpholin-4-yl-acetaldehyde (0.3g, 1.71mmol, made from 4-(2,2-dimethoxyethyl)morpholine) and NaCNBH3 (20mg, 0.32mmol) in 4mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (49mg, 53%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 2.38 - 2.42
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(m, 4 H) 2.57 (s, 3 H) 3.1B - 3.?.3 (m, 2 H) 3.55 - 3.59 (m, 4 H) 6.11 (t, J=5.31 Hz, 1 H) 6.84 (d, J=2.53 Hz, 1 H) 7.06 - 7.10 (m, 1 H) 7.20 - 7.30 (m, 4 H) 8.43 (s, 1 H) 9.24 (s, 1 H); HRMS (ESI+) calcd for C23H24BrN5O (MH+) 466.12370, found 466.1241.
Example 132: 6-((5-chloro-1,3-dimethyM H-pyrazol-4-yl)methylamino)-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (0.105g, 0.34mmol) was reacted with 5-chloro-1,3-dimethyl-1 H-pyrazole-4-carbaldehyde (0.140g, 0.88mmol) and NaCNBH3 (33mg, 0.53mmol) in 5mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (96mg, 63%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 2.16 (s, 3 H) 3.73 (s, 3 H) 4.05 (d, J=4.55 Hz, 2 H) 6.41 (t, J=4.55 Hz, 1 H) 7.18 (d, J=2.27 Hz, 1 H) 7.21 - 7.27 (m, 1 H) 7.32 (dd, J=9.09, 2.53 Hz, 1 H) 7.40 - 7.48 (m, 2 H) 7.69 (d, J=8.84 Hz, 1 H) 8.34 (s, 1 H) 9.35 (s, 1 H); HRMS (ESI+) calcd for CasHCIzFNe (MH+) 455.09485, found 455.0957.
Example 133: 4-(3-chloro-4-fluorophenylamino)-6-((1,4-dimethyl-1 H-imidazol-5-yl)methylamino)quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (0.162g, 0.52mmol) was reacted with 1,4-dimethyl-1H-imidazole-5-carbaldehyde (0.080g, 0.65mmol) and NaCNBH3 (46mg, 0.73mmol) in 10mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (32mg, 15%): 1H NMR (400 MHz, DMSO-D6) 6 ppm 2.11 (s, 3 H) 3.56 (s, 3 H) 4.22 (d, J=4.55 Hz, 2 H) 6.46 - 6.51 (m, 1 H) 7.20 - 7.27 (m, J=2.27 Hz, 2 H) 7.33 (dd, J=9.09, 2.27 Hz, 1 H) 7.39 - 7.48 (m, 2 H) 7.51 (s, 1 H) 7.69 (d, J=8.84 Hz, 1 H) 8.34 (s, 1 H) 9.37 (s, 1 H); HRMS (ESI+) calcd for C22H18CIFN6 (MH+) 421.13382, found 421.1337.
Example 134: 4-(3-bromophenylamino)-8-((dimethylamino)methyl)-6-(2-morpholinoethylamino)quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-4-(3-bromophenylamino)-8-((dimethylamino)methyl)quinoline-3-carbonitrile(0.090g, 0.23mmol) was reacted with crude morpholin-4-yl-acetaldehyde (0.31 g, 1.77mmol, made from 4-(2,2-dimethoxyethyl)morpholine) and NaCNBH3 (23mg, 0.37mmol) in 10mL EtOH. The crude product was purified by preparative HPLC, and lyophilized
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to give the product as a solid (44mg, 38%): 1H NMR (400 MHz, MeOD) 8 ppm 2.70 (s, 6 H) 2.75 - 2.82 (m, 4 H) 2.90 (t, J=6.69 Hz, 1 H) 3.59 - 3.62 (m, 2 H) 3.95 - 4.02 (m, 4 H) 4.39 (s, 2 H) 7.24 (d, J=2.53 Hz, 1 H) 7.36 - 7.41 (m, 1 H) 7.51 - 7.56 (m, 2 H) 7.60 (dd, J=8.34, 2.02 Hz, 2 H) 8.67 - 8.69 (m, 1 H) 8.83 (s, 1 H); HRMS (ESI+) calcd for C25H29BrN6O (MH+) 509.16590, found 509.1658.
Example 135: 6-((4-chloro-1-methyl-1H-pyrazol-3-yl)methylamino)-4-(3-chloro-4-fluorophenylamino)quinoIine-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (0.129g, 0.41 mmol) was reacted with 4-chloro-1-methyl-1H-pyrazole-3-carbaldehyde (0.086g, 0.59mmol) and NaCNBH3 (56mg, 0.89mmol) in 4mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (37mg, 20%): 1H NMR (400 MHz, DMSO-D6) 6 ppm 3.79 (s, 3 H) 4.25 (d, J=5.05 Hz, 2 H) 6.53 -6.59 (m, 1 H) 7.19 - 7.26 (m, 2 H) 7.36 - 7.48 (m, 3 H) 7.69 (d, J=9.09 Hz, 1 H) 7.93 (s, 1 H) 8.34 (s, 1 H) 9.34 (s, 1 H); HRMS (ESI+) calcd for C21H15CI2FN6 (MH+) 441.07920, found 441.0797.
Example 136: 2-(2-((4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino) methyl)-1 H-imidazol-1-yl)acetic acid
To methyl 2-(2-((4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino)methyl)-1H-imidazol-1-yl)acetate (264mg, 0.57mmol) in tetrahydrofuran (6mL) and methanol (8mL) was added lithium hydroxide (1N, 4.5mL). After the reaction was complete by TLC, the crude product was purified by preparative HPLC, and lyophilized to give the product as a solid in quantitative yield: 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.63 4.74 (m, J=2.78 Hz, 2 H) 5.06 (s, 2 H) 6.99 (s, 1 H) 7.26 - 7.33 (m, 2 H) 7.34 - 7.44 (m, 2 H) 7.46 (s, 1 H) 7.50 - 7.56 (m, 2 H) 7.72 (d, J=9.09 Hz, 1 H) 8.34 (s, 1 H); HRMS (ESI+) calcd for C22H16CIFN6O2 (MH+) 451.10800, found 451.1086.
Example 137: Methyl 2-(2-((4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino)methyl)-1 H-imidazol-1 yi)acetate
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (0.86g, 2.75mmol) was reacted with methyl 2-(2-formyl-1 H-imidazol-1 -yl)acetate (0.659g, 3.92mmol) and NaCNBH3 (230mg, 3.66mmol) in 10mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (544mg, 45%): 1H NMR (400
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MHz, DMS0-D6) 5 ppm 3.60 (s, 3 H) 4.36 (d, J=5.56 Hz, 2 H) 4.97 (s, 2 H) 6.60 (t, J=5.31 Hz, 1 H) 6.85 (d, J=1.26 Hz, 1 H) 7.15 (d, J=1.26 Hz, 1 H) 7.20 - 7.27 (m, 2 H) 7.33 - 7.50 (m, 3 H) 7.71 (d, J=9.35 Hz, 1 H) 8.34 (s, 1 H) 9.31 (s, 1 H); HRMS (ESI+) calcd for C23H18CIFN6O2 (MH+) 465.12365, found 465.1253.
Example 138: 4-(3-chloro-4-fluorophenylamino)-6-((1 -(2-morpholino-2-oxoethyl)-1 H-imidazol-2-yl)methylamino)quinoline-3-carbonitrile
To a 50mL round-bottomed flask under nitrogen was added 2-(2-((4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino)methyl)-1H-imidazol-1-yl)acetic acid (74mg, 0.16mmol), morpholine (0.027mL, 0.31mmol), benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (77mg, 0.17mmol), diisopropylethyl amine (0.06mL, 0.34mmol) and N,N-dimethylformamide (3mL). After 12 hr of reaction at RT, the crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (16mg, 20%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 3.34 - 3.39 (m, 4 H) 3.49 (q, J=5.22 Hz, 4 H) 4.33 (d, J=5.56 Hz, 2 H) 5.02 (s, 2 H) 6.57 - 6.62 (m, 1 H) 6.83 (s, 1 H) 7.06 (s, 1 H) 7.20 - 7.26 (m, 2 H) 7.36 (dd, J=9.10, 2.27 Hz, 1 H) 7.40 - 7.48 (m, 2 H) 7.70 (d, J=9.09 Hz, 1 H) 8.33 (s, 1 H) 9.29 (s, 1 H); HRMS (ESI+) calcd for CaeHaaCIFNyOa (MH+) 520.16585, found 520.1651.
Example 139: 2-(2-((4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino) methyl)-1 H-imidazol-1 -yl)acetamide
Following the procedure described above in Example 138, the desired product was obtained in 31 % yield (22mg from 70 mg of starting acid): 1H NMR (400 MHz, DMSO-D6) 5 ppm 4.32 (d, J=5.05 Hz, 2 H) 4.69 (s, 2 H) 6.62 (t, J=4.80 Hz, 1 H) 6.82 (d, J=1.26 Hz, 1 H) 7.12 (d, J=1.01 Hz, 1 H) 7.21 (d, J=2.53 Hz, 1 H) 7.23 - 7.29 (m, 1 H) 7.30 (s, 1 H) 7.37 (dd, J=8.97, 2.40 Hz, 1 H) 7.43 (t, J=8.97 Hz, 1 H) 7.49 (dd, J=6.57, 2.53 Hz, 1 H) 7.62 (s, 1 H) 7.70 (d, .7=8.84 Hz, 1 H) 8.33 (s, 1 H) 9.36 (s, 1 H); HRMS (ESI+) calcd for C22H17CIFN7O (MH+) 450.12399, found 450.1233.
Example 140: 2-(2-((4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino) methyl)-1 H-imidazol-1 -yl)-N,N-dimethylacetamide
Following the procedure described above in Example 138, the desired product was obtained in 23% yield (17mg from 70 mg of starting acid): 1H NMR (400 MHz, DMSO-D6) 5 ppm 2.77 (s, 3 H) 2.93 (s, 3 H) 4.32 (d, J=5.05 Hz, 2 H) 5.00 (s, 2 H) 6.61 (t, J=4.93 Hz, 1 H) 6.82 (s, 1 H) 7.05 (s, 1 H) 7.18 (d, J=2.02 Hz,
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1 H) 7.21 - 7.28 (m, 1 H) 7.36 (dd, J=8.97, 2.40 Hz, 1 H) 7.42 (t, J=9.09 Hz, 1 H) 7.47 (dd, J=6.44,2.40 Hz, 1 H) 7.70 (d, J=9.09 Hz, 1 H) 8.32 (s, 1 H) 9.29 (s, 1 H); HRMS (ESI+) calcd for C24H21CIFN7O (MH+) 478.15529, found 478.1546.
Example 141: 4-(3-chloro-4-fluorophenylamino)-6-((1-(2-{4-methylpiperazin-1-yl)-2-oxoethyl)-1H-imidazol-2-yl)methylamino)quinoline-3-carbonitrile
Following the procedure described above in Example 138, the desired product was obtained in 29% yield (24mg from 70 mg of starting acid): 1H NMR (400 MHz, DMSO-D6) 5 ppm 2.03 (s, 3 H) 2.10 - 2.15 (m, 4 H) 3.28 - 3.36 (m, 4 H) 4.31 (d, J=5.05 Hz, 2 H) 5.01 (s, 2 H) 6.58 (t, J=4.93 Hz, 1 H) 6.80 (d, J=1.26 Hz, 1 H) 7.05 (d, J=1.26 Hz, 1 H) 7.20 - 7.26 (m, 2 H) 7.35 (dd, J=9.09, 2.27 Hz, 1 H) 7.41 - 7.47 (m, 2 H) 7.69 (d, J=9.09 Hz, 1 H) 8.32 (s, 1 H) 9.33 (s, 1 H); HRMS (ESI+) calcd for CZTHCIFNSO (MH+) 533.19749, found 533.1962.
Example 142: tert-butyl 4-(2-(2-((4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino)methyl)-1 H-imidazol-1 -yl)acetamido)piperidine-1 -carboxylate
Following the procedure described above in Example 4, the desired product was obtained in 51% yield (50mg from 70 mg of starting acid): 1H NMR (400 MHz, DMSO-D6)8 ppm 1.12-1.23 (m, 2 H) 1.37 (s, 9 H) 1.60 -1.66 (m, 2 H) 2.71 - 2.81 (m, 2 H) 3.62 - 3.77 (m, 3 H) 4.33 (d, J=5.05 Hz, 2 H) 4.69 (s, 2 H) 6.64 (t, J=5.05 Hz, 1 H) 6.81 (d, J=1.26 Hz, 1 H) 7.11 (d, J=1.26 Hz, 1 H) 7.18 (d, J=2.27 Hz, 1 H) 7.22 - 7.28 (m, 1 H) 7.34 - 7.38 (m, 1 H) 7.41 - 7.49 (m, 2 H) 7.70 (d, J=8.84 Hz, 1 H) 8.21 (d, J=7.58 Hz, 1 H) 8.32 (s, 1 H) 9.30 (s, 1 H).
Example 143: 2-(2-((4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino) methyl)-1 H-imidazol-1 -yl)-N-(piperidin-4-yl)acetamide
To a 50 mL round-bottomed flask was added tert-butyl 4-(2-(2-((4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino)methyl)-1H-imidazol-1-yl)acetamido)piperidine-1 -carboxylate (10 mg), trifluoroacetic acid (1.5 mL), and dichloroethane (10 mL). After 30 min of reaction, the reaction mixture was stripped to dryness and the residue was purified via preparative HPLC, and lyophilized to give the product as a yellow solid in quantitative yield: 1H NMR (500 MHz, DMSO-D6) 5 ppm 1.17 -1.37 (m, 4 H) 1.56 - 1.84 (m, 4 H) 3.55 - 3.72 (m, 1 H) 4.34 (d, J=4.58 Hz, 2 H) 4.70 (s, 2 H) 6.63 - 6.71 (m, 1 H) 6.82 (d, J=7.32 Hz, 1 H) 7.09 -7.14 (m, 1 H) 7.19 (d, J=7.63 Hz, 1 H) 7.26 (d, J=6.10 Hz, 1 H) 7.37 (d, J=8.85 Hz, 1 H) 7.42 - 7.50 (m, 2 H) 7.71 (d, J=9.16 Hz, 1 H) 8.18 - 8.36 (m, 2 H) 9.31 (s, 1 H); HRMS (ESI+) calcd for C27H26G!FN8O (MH+) 533.19749, found 533.1972.
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The compounds shown in Examples 144-152 were made using the following parallel synthesis strategy:
To a mixture of 6-amino-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (50 mg, 0.16mmol), the corresponding aldehyde (0.32mmol) and N,N-dimethylformamide (2mL) was added acetic acid (0.05mL) and MP-BH4 (150mg, 3.0mmol/g, 0.45mmol). After 12hr of reaction, the mixture was filtered and the filtrate was quenched with PS-isocyanate (500mg, 1.5mmol/g, 0.75mmol). The filtrate was then passed through a cartridge of MP-TsOH (200mg, 4mmol/g) and washed with tetrahedron (3x) to remove impurities. The crude product was washed out of the cartridge with 2% NH4OH in methanol. After preparative HPLC and solvent removal, product was obtained as yellowish solid.
Example 144: 6-(2-fluorobenzylamino)-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile
13.1 mg, 20%: 1H NMR (400 MHz, DMSO-D6) 5 ppm 4.43 (d, J=5.31 Hz, 2 H) 6.80 (t, J=5.94 Hz, 1 H) 7.12 - 7.23 (m, 4 H) 7.29 - 7.35 (m, 1 H) 7.35 - 7.45 (m, 4 H) 7.72 (d, J=9.09 Hz, 1 H) 8.33 (s, 1 H) 9.31 (s, 1 H).
Example 145: 6-(3-fluorobenzylamino)-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile
15mg, 22%: 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.41 (d, J=6.06 Hz, 2 H) 6.91 (t, J=6.44 Hz, 1 H) 7.03 - 7.12 (m, 2 H) 7.15 - 7.23 (m, 3 H) 7.33 - 7.43 (m, 4 H) 7.71 (d, J=9.09 Hz, 1 H) 8.33 (s, 1 H) 9.28 (s, 1 H).
Example 146: 6-(4-fluorobenzylamino)-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile
7mg, 10%: 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.36 (d, J=5.56 Hz, 2 H) 6.86 (s, 1 H) 7.10 - 7.21 (m, 4 H) 7.32 - 7.44 (m, 5 H) 7.70 (d, J=8.34 Hz, 1 H) 8.33 (s, 1 H) 9.29 (s, 1 H).
Example 147: 6-(3-bromobenzylamino)-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile
20mg, 26%: 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.40 (d, J=6.06 Hz, 2 H) 6.93 (t, J=5.94 Hz, 1 H) 7.11 (d, J=2.53 Hz, 1 H) 7.16 - 7.21 (m, 1 H) 7.28 (t, J=7.83 Hz, 1 H) 7.33 - 7.46 (m, 5 H) 7.58 (t, J=1.52 Hz, 1 H) 7.71 (d, J=9.09 Hz, 1 H) 8.33 (s, 1 H) 9.29 (s, 1 H)
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Example 148: 6-(3-(trifluoromethoxy)benzylamino)-4-(3-chloro-4-fluorophenylamino) quinoline-3-carbonitrile
18mg, 23%: 1H NMR (400 MHz, DMS0-D6) 8 ppm 4.45 (d, J=6.06 Hz, 2 H) 6.97 (t, J=6.19 Hz, 1 H) 7.13 (d, J=2.53 Hz, 1 H) 7.15 - 7.20 (m, 1 H) 7.21 - 7.25 (m, 1 H) 7.33 - 7.43 (m, 5 H) 7.46 (t, J=7.83 Hz, 1 H) 7.71 (d, J=9.09 Hz, 1 H) 8.33 (s, 1 H) 9.28 (s, 1 H).
Example 149: 6-(3-(trifluoromethyl)benzylamino)-4-(3-chloro-4-fluorophenylamino) quinoline-3-carbonitrile
18mg, 24%: 1H NMR (400 MHz, DMS0-D6) 5 ppm 4.49 (d, J=5.81 Hz, 2 H) 6.99 (t, J=6.06 Hz, 1 H) 7.13 (d, J=2.27 Hz, 1 H.) 7.15 - 7.21 (m, 1 H) 7.33 - 7.42 (m, 3 H) 7.53 - 7.62 (m, 2 H) 7.65 - 7.69 (m, 1 H) 7.72 (d, J=8.84 Hz, 1 H) 7.76 (s, 1 H) 8.33 (s, 1 H) 9.28 (s, 1 H).
Example 150: 6-(3-phenoxybenzylamino)-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile
5mg, 19%: 1H NMR (400 MHz, DMS0-D6) 8 ppm 4.38 (d, J=5.81 Hz, 2 H) 6.84 - 6.91 (m, 2 H) 6.91 - 6.97 (m, 2 H) 7.02 - 7.22 (m, 5 H) 7.28 - 7.49 (m, 6 H) 7.65 - 7.72 (m, 1 H) 8.32 (s, 1 H) 9.28 (s, 1 H).
Example 151: 6-(3-chloro-4-hydroxybenzylamino)-4-(3-chloro-fluorophenylamino) quinoline-3-carbonitrile
15mg, 21%: 1H NMR (400 MHz, DMS0-D6) 8 ppm 4.25 (d, J=6.06 Hz, 2 H) 6.78 (t, J=5.56 Hz, 1 H) 6.91 (d, J=8.34 Hz, 1 H) 7.10 - 7.16 (m, 2 H) 7.16 - 7.23 (m, 1 H) 7.31 - 7.35 (m, 2 H) 7.38 - 7.46 (m, 2 H) 7.69 (d, J=8.84 Hz, 1 H) 8.32 (s, 1 H) 9.30 (s, 1 H).
Example 152: 6-(3-chlorobenzylamino)-4-(3-chloro-4-fluorophenylarnino)quinoline-3-carbonitrile
16mg, 23%: 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.40 (d, J=5.81 Hz, 2 H) 6.93 (t, J=6.82 Hz, 1 H) 7.11 (d, J=2.27 Hz, 1 H) 7.15 - 7.22 (m, 1 H) 7.28 - 7.45 (m, 7 H) 7.71 (d, J=9.09 Hz, 1 H) 8.33 (s, 1 H) 9.29 (s, 1 H).
Example 153: 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({5-[2-(trifluoromethyl) phenyl]-1H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile
In a 15mL round-bottom flask were added 6-amino-4-(4-bromo-3-fIuoro-phenylamino)-quinoline-3-carbonitrile (30mg, 0.076mmol), ethanol (1mL) and 5-(2-
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(trifluoromethyl)phenyl)-1H-1,2,3-triazole-4-carbaldehyde (20mg, 0.08mmol). Acetic acid was added to bring the pH of the solution to 4, and the mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (32mg, 0.153mmol) was then added and the reaction was stirred at RT overnight. The reaction mixture was stripped to dryness and the residue was purified via preparative HPLC and lyophilized to give the product as a yellow solid (16.8mg, 34%). 1H NMR (400 MHz, MeOD) 8 ppm 4.42 (s, 2 H) 6.99 (d, J=2.27 Hz, 1 H) 7.16 - 7.30 (m, 2 H) 7.33 - 7.42 (m, 2 H) 7.45 (d, J=2.27 Hz, 1 H) 7.53 - 7.62 (m, 2 H) 7.71 - 7.80 (m, 1 H) 8.25 (s, 1 H).
Example 154: 4-(3-chloro-4-fluorophenylamino)-6-((6-((dimethylamino)methyl)-1 H-indol-2-yl)methylamino)quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (0.100g, 0.32mmol) was reacted with 6-((dimethylamino)methyl)-1H-indole-2-carbaldehyde (0.094g, 0.46mmol) and NaCNBH3 (20mg, 0.32mmol) in 5mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (103mg, 65%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 2.20 (s, 6 H) 3.53 (s, 2 H) 4.49 (d, J=5.05 Hz, 2 H) 6.34 (s, 1 H) 6.76 (t, J=5.81 Hz, 1 H) 6.91 (dd, J=8.08,1.26 Hz, 1 H) 7.20 - 7.28 (m, 3 H) 7.36 - 7.43 (m, 3 H) 7.43 - 7.49 (m, 1 H) 7.71 (d, J=9.09 Hz, 1 H) 8.33 (s, 1 H) 9.36 (s, 1 H) 11.10 (d, J=1.52 Hz, 1 H); HRMS (ESI+)calcd for C28H24CIFN6 (MH+) 499.18077, found 499.1838.
Example 155: 2-((4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino)methyl)-N,N-dimethyl-1H-indole-6-carboxamide
Following the procedure described above in Example 4, 6-amino-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (0.100g, 0.32mmol) was reacted with 2-formyl-N,N-dimethyl~1H-indole-6-carboxarnide (0.098g, 0.45mmol) and NaCNBH3 (20mg, 0.32mmol) in 5mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (36mg, 22%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 2.96 (s, 6 H) 4.53 (d, J=5.05 Hz, 2 H) 6.41 (d, J=1.26 Hz, 1 H) 6.80 (t, J=5.43 Hz, 1 H) 7.00 (dd, J=8.08, 1.52 Hz, 1 H) 7.21 - 7.26 (m, 1 H) 7.27 (d, J=2.53 Hz, 1 H) 7.37 - 7.49 (m, 5 H) 7.72 (d, J=8.84 Hz, 1 H) 8.33 (s, 1 H) 9.35 (s, 1 H) 11.32 (d, J=1.52 Hz, 1 H); HRMS (ESI+) calcd for C28H22CIFN6O (MH+) 513.16004, found 513.1618.
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Example 156: 2-((4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino)methyl)-N, N, 1-trimethyl-1 H-indole-6-carboxamide
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (0.1 OOg, 0.32mmol) was reacted with 2-formyl-N,N,1-trirnethyl-1 H-indole-6-carboxamide (0.097g, 0.42mmol) and NaCNBH3 (20mg, 0.32mmol) in 5mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (128mg, 76%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 2.98 (s, 6 H) 3.78 (s, 3 H) 4.57 (d, J=5.05 Hz, 2 H) 6.50 (s, 1 H) 6.84 (t, J=5A3 Hz, 1 H) 7.04 (dd, J=8.08,1.52 Hz, 1 H) 7.21 - 7.29 (m, 2 H) 7.37 - 7.54 (m, 5 H) 7.72 (d, J=9.09 Hz, 1 H) 8.34 (s, 1 H) 9.34 (s, 1 H); HRMS (ESI+) calcd for C29H24CIFN6O (MH+) 527.17569, found 527.1762.
Example 157: 6-((1 H-indol-2-yl)methylamino)-4-(3-chloro-4-fluorophenylamino) quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (0.100g, 0.32mmol) was reacted with 1 H-indole-2-carbaldehyde (0.1 OOg, 0.67mmol) and NaCNBH3 (20mg, 0.32mmol) in 5mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (76mg, 54%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.50 (d, J=5.31 Hz, 2 H) 6.36 (d, J=1.01 Hz, 1 H) 6.76 (t, J=5.18 Hz, 1 H) 6.94 (td, J=7.45,1.01 Hz, 1 H) 7.03 (td, .7=7.52,1.14 Hz, 1 H) 7.21 - 7.28 (m, 2 H) 7.31 - 7.35 (m, 1 H) 7.38 - 7.49 (m, 4 H) 8.33 (s, 1 H) 9.36 (s, 1 H) 11.12 (s, 1 H); HRMS (ESI+) calcd for C25H17CIFN5 (MH+) 442.12293, found 442.1237.
Example 158: 6-((1 H-imidazol-5-yl)methylamino)-4-(3-chloro-4-fluorophenylamino)-7-isopropoxyquinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluorophenylamino)-7-isopropoxyquinoline-3-carbonitrile(0.050g, 0.13mmol) was reacted with 4(5)-imidazole carboxaldehyde (0.027g, 0.28mmol) and NaCNBH3 (15mg, 0.24mmol) in 6mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (55mg, 91%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 1.38 (d, J=5.81 Hz, 6 H) 3.36 - 3.41 (m, 1 H) 4.27 - 4.33 (m, 1 H) 4.88 - 4.95 (m, 1 H) 5.54 (s, 1 H) 7.03 (s, 1 H) 7.17 - 7.26 (m, 3 H) 7.38 - 7.44 (m, 2 H) 7.62 (d, J=1.77 Hz, 1 H) 8.35 (s, 1 H) 9.24 (s, 1 H) 11.96 (s, 1 H); HRMS (ESI+) calcd for CzaHzoCIFNaO (MH+) 451.14439; found 451.1456.
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Example 159: 6-((1 H-imidazol-5-yl)methylamino)-4-(3-chloro-4-fluorophenylamino)-7-(3-morpholinopropoxy)quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluorophenylamino)-7-(3-morpholinopropoxy)quinoline-3-carbonitrile (0.050g, O.Hmmol) was reacted with 4(5)-imidazole carboxaldehyde (0.018g, 0.19mmol) and NaCNBH3 (11mg, 0.18mmol) in 6mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (28mg, 48%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 1.94 - 2.03 (m, 2 H) 2.35 - 2.41 (m, 4 H) 2.46 - 2.49 (m, 2 H) 3.55 - 3.61 (m, 4 H) 4.26 (t, J=6.32 Hz, 2 H) 4.32 (d, J=5.05 Hz, 2 H) 5.64 (t, J=5.81 Hz, 1 H) 7.00 (s, 1 H) 7.17 - 7.26 (m, 3 H) 7.38 - 7.43 (m, 2 H) 7.60 (s, 1 H) 8.17 (s, 2 H) 9.25 (s, 1 H); HRMS (ESI+) calcd for C27H27CIFN7O2 (MH+) 536.19715, found 536.1973.
Example 160: 6-((1 H-imidazoi-5-yl)methylamino)-4-(3-chloro-4-fluorophenylamino)-7-morpholinoquinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-4-(3-chloro-4-fluorophenylamino)-7-morpholinoquinoline-3-carbonitrile (0.028g, 0.07mmol) was reacted with 4(5)-imidazole carboxaldehyde (0.024g, 0.25mmol) and NaCNBH3 (11mg, 0.18mmol) in 6mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (12mg, 36%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 2.96 - 3.03 (m, 4 H) 3.78 - 3.84 (m, 4 H) 4.33 (d, J=5.56 Hz, 2 H) 5.68 (t, J=5.43 Hz, 1 H) 7.01 (s, 1 H) 7.19 - 7.25 (m, 1 H) 7.29 (s, 1 H) 7.38 - 7.47 (m, 3 H) 7.63 (d, J=1.01 Hz, 1 H) 8.20 (s, 1 H) 8.35 (s, 1 H) 9.33 (s, 1 H); HRMS (ESI+) calcd for C24H21CIFN7O (MH+) 478.15529, found 478.1552.
Example 161: 6-((1 H-imidazol-5-yl)methylamino)-4-(3-chloro-4-fluorophenylamino)-7-(4-methylpiperazin-1-yl)quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-4-(3-chloro-4-fluorophenylamino)-7-(4-methylpiperazin-1-yl)quinoline-3-carbonitrile (0.043g, O.IOmmol) was reacted with 4(5)-imidazole carboxaldehyde (0.024g, 0.25mmol) and NaCNBH3 (20mg, 0.32mmol) in 6mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (33mg, 64%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 2.44 (s, 3 H) 2.80 (s, 4 H) 3.06 (s, 4 H) 4.33 (d, J=5.05 Hz, 2 H) 5.56 (t, J=5.43 Hz, 1 H) 6.51 (s, 1 H) 7.04 (s, 1 H) 7.20 -7.26 (m, 1 H) 7.29 (s, 1 H) 7.39 - 7.47 (m, 3 H) 7.67 (d, J=1.01 Hz, 1 H) 8.35 (s, 1 H) 9.33 (s, 1 H); HRMS (ESI+) calcd for CzsHCIFNs (MH+) 491.18692, found 491.1867.
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Example 162: 6-((1 H-imidazol-5-yl)methylamino)-4-(3-chloro4-fluoropheny!amino)-7-(trifluoromethoxy)quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-4-(3-chloro-4-fluorophenylamino)-7-(trifluoromethoxy)quinoline-3-carbonitrile(0.049g, 0.12mmol) was reacted with 4(5)-imidazole carboxaldehyde (0.018g, 0.19mmol) and NaCNBH3 (11mg, 0.18mmol) in 6mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (19mg, 32%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 4.40 (d, J=6.06 Hz, 2 H) 6.35 - 6.41 (m, 1 H) 6.96 (s, 1 H) 7.27 - 7.33 (m, 1 H) 7.45 (t, J=8.97 Hz, 1 H) 7.52 (s, 1 H) 7.55 (dd, J=6.95, 2.91 Hz, 1 H) 7.59 (s, 1 H) 7.69 (d, J=1.77 Hz, 1 H) 8.16 (s, 1 H) 8.37 (s, 1 H) 9.54 (s, 1 H); HRMS (ESI+) calcd for C2iH13CIF4N6O (MH+) 477.08482, found 477.0845.
Example 163: 6-((1 H-imidazol-5-yl)methylamino)-4-(3-chloro-4-fluorophenylamino)-7-(2-(dimethylamino)ethylthio)quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluorophenylamino)-7-(2-(dimethylamino)ethylthio)quinoline-3-carbonitrile (0.032g, 0.08mmol) was reacted with 4(5)-imidazole carboxaldehyde (0.020g, 0.21 mmol) and NaCNBH3 (15mg, 0.24mmol) in 6mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (25mg, 66%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 2.20 (s, 6 H) 2.54 - 2.59 (m, 2 H) 3.19 (t, J=6.95 Hz, 2 H) 4.35 (d, J=3.03 Hz, 2 H) 5.68 - 5.74 (m, 1 H) 6.52 (s, 1 H) 7.04 (s, 1 H) 7.25 - 7.31 (m, 1 H) 7.33 (s, 1 H) 7.44 (t, J=8.97 Hz, 1 H) 7.49 - 7.53 (m, 1 H) 7.83 (s, 1 H) 8.14 (s, 2 H) 8.35 (s, 1 H) 9.46 (s, 1 H); HRMS (ESI+) calcd for C24H23CIFN7S (MH+) 496.14809, found 496.1492.
Example 164: 6-((1 H-imidazol-5-yl)methylamino)-4-(3-chloro-4-fluorophenylamino)-7-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-4-(3-chloro-4-fluorophenylamino)-7-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)quinoline-3-carbonitrile (0.038g, 0.08mmol) was reacted with 4(5)-imidazole carboxaldehyde (0.020g, 0.21 mmol) and NaCNBH3 (20mg, 0.32mmol) in 6mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (25mg, 56%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 2.31 (s, 6 H) 2.55 - 2.70 (m, 8 H) 3.00 (s, 4 H) 4.31 (d, J=5.81 Hz, 2 H) 5.50 (t, J=5.68 Hz, 1 H) 7.03 (s, 1 H) 7.19 - 7.25 (m, 1 H) 7.28 (s, 1 H) 7.38 (s, 1 H) 7.39 - 7.46 (m, 2 H) 7.65 (d, J=1.26
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Hz, 1 H) 8.16 (s, 3 H) 8.34 (s, 1 H) 9.33 (d, J=1.01 Hz, 1 H); HRMS (ESI+) calcd for C28H31CIFN9 (MH+) 548.24477, found 548.2456.
Example 165: 6-((1 H-imidazol-5-yl)methylamino)-4-(3-chloro-4-fluorophenyIamino)-7-ethoxyquinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluorophenylamino)-7-ethoxyquinoline-3-carbonitrile(0.050g, 0.14mmol) was reacted with 4(5)-imidazole carboxaldehyde (0.023g, 0.24mmol) and NaCNBH3 (11mg, 0.18mmol) in 6mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (19mg, 31%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 1.44 (t, J=6.95 Hz, 3 H) 4.28 (t, 4 H) 5.59 (t, J=5.31 Hz, 1 H) 7.01 (s, 1 H) 7.16 - 7.26 (m, 3 H) 7.37 - 7.44 (m, 2 H) 7.61 (d, J=1.26 Hz, 1 H) 8.15 (s, 1 H) 8.35 (s, 1 H) 9.25 (s, 1 H); HRMS (ESI+) calcd for C22H18CIFN6O (MH+) 437.12874, found 437.1295.
Example 166: 6-((1 H-imidazol-5-yl)methylamino)-7-(2-bromoethoxy)-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-7-(2-bromoethoxy)-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile(0.049g, 0.11mmol) was reacted with 4(5)-imidazole carboxaldehyde (0.025g, 0.26mmol) and NaCNBH3 (16mg, 0.25mmol) in 6mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (11mg, 19%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 3.90 - 3.95 (m, 2 H) 4.34 (d, J=4.55 Hz, 2 H) 4.54 - 4.59 (m, 2 H) 5.57 (t, J=5.56 Hz, 1 H) 7.05 (s, 1 H) 7.22 (ddd, J=8.84, 4.04, 2.78 Hz, 1 H) 7.29 (d, J=6.32 Hz, 2 H) 7.38 - 7.45 (m, 2 H) 7.68 (s, 1 H) 8.13 (s, 1 H) 8.36 (s, 1 H) 9.29 (s, 1 H); HRMS (ESI+) calcd for C22H17BrCIFN6O (MH+) 515.03925, found 515.0405.
Example 167: 6-(3-(methylsulfonyl)benzylamino)-4-(3-chloro-4-fluorophenylamino) quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (0.164g, 0.52mmol) was reacted with 3-(methylsulfonyl)benzaldehyde (0.110g, 0.60mmol) and NaCNBH3 (38mg, 0.60mmol) in 5mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (136mg, 54%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 3.14 (s, 3 H) 4.52 (d, J=6.06 Hz, 2 H) 7.03 (t, J=6.19 Hz, 1 H) 7.15 (d, J1.77 Hz, 1 H) 7.18 - 7.24 (m, 1 H) 7.34 - 7.46 (m, 3 H) 7.61 (t, J=7.71
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Hz, 1 H) 7.69 - 7.74 (m, 2 H) 7.79 - 7.83 (m, 1 H) 7.99 (t, J=1.64 Hz, 1 H) 8.32 (s, 1 H) 9.29 (s, 1 H); HRMS (ESI+) calcd for C24H18CIFN4O2S (MH+) 481.08958, found 481.0907.
Example 168: 3-((4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino)methyl)benzenesulfonamide
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (0.124g, 0.40mmol) was reacted with 3-formylbenzenesulfonamide (0.095g, 0.52mmol) and NaCNBH3 (33mg, 0.53mmol) in 6mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (61 mg, 32%): 1H NMR (400 MHz, DMSO-D6) 6 ppm 4.48 (d, J=6.06 Hz, 2 H) 6.98 (t, J=5.81 Hz, 1 H) 7.17 (d, J=2.53 Hz, 1 H) 7.18 - 7.24 (m, 1 H) 7.32 - 7.46 (m, 5 H) 7.52 (t, J=7.83 Hz, 1 H) 7.56 - 7.60 (m, 1 H) 7.69 - 7.74 (m, 2 H) 7.86 (t, J=1.52 Hz, 1 H) 8.32 (s, 1 H) 9.30 (s, 1 H); HRMS (ESI+) calcd for C23H17CIFN5O2S (MH+) 482.08483, found 482.0855.
Example 169: 6-((1 H-imidazol-5-yl)methylamino)-4-(3-bromophenylamino)quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-4-(3-bromophenylamino)quinoline-3-carbonitrile (0.103g, 0.30mmol) was reacted with 4(5)-imidazole carboxaldehyde (0.034g, 0.35mmol) and NaCNBH3 (25mg, 0.40mmol) in 5mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (88mg, 69%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 4.29 (d, J=4.80 Hz, 1 H) 6.62 (t, J=5.43 Hz, 1 H) 7.13 - 7.19 (m, 3 H) 7.28 - 7.32 (m, 2 H) 7.35 (dd, 1 H) 7.38 (dd, J=9.09, 2.27 Hz, 1 H) 7.72 (d, J=9.09 Hz, 1 H) 8.02 (s, 1 H) 8.13 (s, 1 H) 8.39 (s, 1 H) 9.34 (s, 1 H) 12.90 (s, 1 H); HRMS (ESI+) calcd for C20H15BrN6 (MH+) 419.06143, found 419.0617.
Example 170: 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-({[5-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile
In a 15mL round-bottom flask were added 6-amino-4-(4-bromo-3-fluoro-phenylamino)-quinoline-3-carbonitrile (30mg, 0.076mmol), ethanol (1mL) and 5-(4-fluorophenyl)-1 W-1,2,3-triazole-4-carbaldehyde (16mg, 0.08mmol). Acetic acid was added to bring the pH of the solution to 4, and the mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (32mg, 0.153mmol) was then added and the reaction was stirred at RT overnight. The reaction mixture was stripped to
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dryness and the residue was purified via preparative HPLC and lyophilized to give the product as a yellow solid (3.3mg, 7.68%). 1H NMR (400 MHz, MeOD) 5 ppm 4.58 (s, 2 H) 7.13 - 7.28 (m. 4 H) 7.39 (d, J=4.55 Hz, 1 H) 7.68 - 7.74 (m, 2 H) 7.84 (s, 1 H) 8.33 (s,1H) 8.56 (s,1!H).
Example 171: 4-(3-chloro-4-fluorophenylamino)-6-((1-methyl-1 H-imidazol-2-yl) methylamino)quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (0.158g, 0.51 mmol) was reacted with 1~methyl-1H-imidazole-2-carbaldehyde (0.067g, OJOmmol) and NaCNBH3 (32mg, 0.51mmol) in 6mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (39mg, 19%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 3.64 (s, 3 H) 4.38 (d, J=5.31 Hz, 2 H) 6.66 (t, J=4.42 Hz, 1 H) 6.82 (d, J=1.26 Hz, 1 H) 7.13 (d, J=1.26 Hz, 1 H) 7.22 - 7.28 (m, 2 H) 7.39 - 7.50 (m, 3 H) 7.71 (d, ,7=9.35 Hz, 1 H) 8.34 (s, 1 H) 9.35 (s, 1 H); HRMS (ESI+) calcd for C2iH16CIFN6 (MH+) 407.11818, found 407.1189.
Example 172: (R)-4-(3-chloro-4-fluorophenylamino)-6-(1 -(pyridin-2-yl)ethylamino) quinoline-3-carbonitrile
4-(3-chloro-4-fluorophenylamino)-6-(1-(pyridin-2-yl)ethylamino)quinoline-3-carbonitrile (prepared as described in Example 127) was subjected to SFC chiral column chromatography to give the desired product: 1H NMR (400 MHz, DMSO-D6) 8 ppm 1.50 (d, J=6.57 Hz, 3 H) 4.75 - 4.84 (m, 1 H) 6.86 (d, J=8.08 Hz, 1 H) 7.00 (d, J=2.53 Hz, 1 H) 7.11 (ddd, J=8.91,4.23,2.78 Hz, 1 H) 7.21 (ddd, J=7.58, 4.80,1.01 Hz, 1 H) 7.31 - 7.41 (m, 4 H) 7.66 - 7.72 (m, 2 H) 8.32 (s, 1 H) 8.48 -8.51 (m, J=4.83,1.01, 0.87, 0.87 Hz, 1 H) 9.24 (s, 1 H); HRMS (ESI+) calcd for C23H17CIFN.5 (MH+) 418.12293, found 418.1236.
Example 173: (S)-4-(3-chloro-4-fluorophenylamino)-6-(1 -(pyridin-2-yl)ethylamino) quinoline-3-carbonitrile
4-(3-chloro-4-fluorophenylamino)-6-(1-(pyridin-2-yl)ethylamino)quinoline-3-carbonitrile (prepared as described in Example 127) was subjected to SFC chiral column chromatography to give the desired product: 1H NMR (400 MHz, DMSO-D6) 5 ppm 150 (d, J=6.57 Hz, 3 H) 4.75 - 4.84 (m, 1 H) 6.86 (d, J=8.34 Hz, 1 H) 7.00 (d, J=2.53 Hz, 1 H) 7.11 (ddd, J=8.84, 4.29,2.78 Hz, 1 H) 7.21 (ddd, J=7.45, 4.80,1.14 Hz, 1 H) 7.31 - 7.42 (m, 4 H) 7.66 - 7.72 (m, 2 H) 8.32 (s, 1 H) 8.47 -
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8.52 (m, 1 H) 9.24 (s, 1 H); HRMS (ESI+) calcd for CaHirCIFNg (MH+) 418.12293, found 418.1236.
Example 174: Ethyl 2-(4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino) acetate
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (0.313g, lOOmmol) was reacted with ethyl 2-oxoacetate (1mL, 50% in toluene) and NaCNBH3 (72mg, 1.15mmol) in 10mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (334mg, 84%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 1.18 (t, J=7.07 Hz, 3 H) 4.06 (d, J=6.06 Hz, 2 H) 4.13 (q, J=7.07 Hz, 2 H) 6.59 - 6.69 (m. 1 H) 7.08 (d, J=2.27 Hz, 1 H) 7.21 - 7.27 (m, 1 H) 7.36 -7.51 (m, 3 H) 7.71 (d, J=9.09 Hz, 1 H) 8.33 (s, 1 H) 9.33 (s, 1 H); HRMS (ESI+) calcd for CaoHCIFNz (MH+) 399.10186, found 399.1023.
Example 175: 2-(4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino)acetic acid
Hydrolysis of ethyl 2-(4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino)acetate (334 mg, 0.84mmol) in THF (10mL) and MeOH (7.5mL) using lithium hydroxide (1N, 3mL) gave the desired product in quantitative yield: 1H NMR (400 MHz, DMSO-D6) 5 ppm 3.90 (s, 2 H) 6.42 (s, 1 H) 7.09 (s, 1 H) 7.23 - 7.31 (m, 1 H) 7.36 - 7.52 (m, 3 H) 7.65 - 7.72 (m, 1 H) 8.30 (s, 1 H) 9.36 (s, 1 H); HRMS (ESI+) calcd for C18H12CIFN4O2 (MH+) 371.07056, found 371.0711.
Example 176: 2-(4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino) acetamide
2-(4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino)aceticacid (90mg, 0.24mmoi), ammonium chloride (34mg, 0.64mmol), benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (135mg, 0.31 mmol), diisopropylethyl amine (0.14mL, 0.80mmol) and N,N-dirnethylformamide (12mL) were mixed together under nitrogen. After 12 hr of reaction at RT, the crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (39mg, 43%):1H NMR (400 MHz, DMSO-D6) 5 ppm 3.78 (d, J=5.81 Hz, 2 H) 6.49 (t, J=5.81 Hz, 1 H) 7.08 - 7.15 (m, 2 H) 7.20 - 7.27 (m, 1 H) 7.34 - 7.48 (m, 3 H) 7.70 (d, J=8.84 Hz, 1 H) 8.25 - 8.37 (m, 2 H) 9.45 (s, 1 H); HRMS (ESI+) calcd for C18H13CIFN5O (MH+) 370.08654, found 370.0853.
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Example 177: 6-((1 H-imidazol-5-yl)methylamino)-8-chloro-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile
Step 1: A suspension of (Z)-ethyl 3-(2-chloro-4-nitrophenylamino)-2-cyanoacrylate (3.6g) in Dowtherm (125mL) under an argon atmosphere was heated to 260°C for 6hr. After cooling down to RT, hexane (100mL) was added and precipitate was collected, washed to hexane and dried under vaccum to give solid 8-chloro-4-hydroxy-6-nitroquinoline-3-carbonitrile (2.73g, 90%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 8.73 - 8.75 (m, 2 H) 8.76 - 8.78 (m, 1 H) 12.87 (s, 1 H); HRMS (ESI+) calcd for doCINgOg (MH+) 250.00140, found 250.0015.
Step 2: A suspension of 8-chloro-4-hydroxy-6-nitroquinoline-3-carbonitrile (2.75g, 11.02mmol) in phosphoryl trichloride (20mL) was heated to reflux for 12hr. Then solvent was removed and the residue was poured into a beaker containing ice. Sodium bicarbonate was added until pH =7. The precipitate was filtered, washed with water and dried under vacuum to give solid 4,8-dichloro-6-nitroquinoline-3-carbonitrile (2.75g, 93%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 8.92 (d, J=2.27 Hz, 1 H) 9.01 (d, J=2.27 Hz, 1 H) 9.53 (s, 1 H); HRMS (ESI+) calcd for C10H3CI2N3O2 (MH+) 267.96751, found 267.9673.
Step 3: 4,8-dichloro-6-nitroquinoline-3-carbonitrile (645mg, 2.41 mmol) and 3-chloro-4-fluorobenzenamine (417mg, 2.88mmol) were suspended in EtOH (12mL) under nitrogen atmosphere. The mixture was heated to reflux for 12hr. The reaction was stripped to dryness and the residue was washed with saturated sodium bicarbonate solution and diethyl ether and dried to give a solid 8-chloro-4-(3-chloro-4-fluorophenylamino)-6-nitroquinoline-3-carbonitrile (605mg, 67%): 1H NMR (400 MHz, DMSO-D6) 6 ppm 7.38 - 7.46 (m, 1 H) 7.52 (t, J=9.09 Hz, 1 H) 7.68 (d, J=4.04 Hz, 1 H) 8.71 (d, J=2.02 Hz, 1 H) 8.80 - 8.87 (m, 1 H) 9.51 (d, J=1.52 Hz, 1 H) 10.67 (s, 1 H); HRMS (ESI+) calcd for deHyCfeFN (MH+) 377.00028, found 377.001.
Step 4: To a 50 mL round-bottomed flask was added 8-chloro-4-(3-chloro-4-fluorophenylamino)-6-nitroquinoline-3-carbonitrile (850mg, 2.26mmol), SnCI2.2H2O (3100mg, 13.72mmol), and ethyl alcohol (30mL). The mixture was heated to reflux for 3 hr. After cooling down to RT, water (20mL) was added followed by sodium carbonate to adjust pH to around 7. Workup (ethyl acetate/brine) of the reaction gave solid 6-amino-8-chloro-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (636mg, 81%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 5.21 (s, 2 H) 5.93 (s, 1 H) 6.45 - 6.52 (m, 1 H) 6.65 (dd, J=6.44, 2.65 Hz, 1 H) 7.02 (t, 1 H) 7.14 - 7.23 (m, 1 H) 7.35 - 7.47 (m, 2 H); HRMS (ESI+) calcd for C16H9CI2FN4 (MH+) 347.02610, found 347.0255.
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Step 5: Following the procedure described above in Example 4,6-amino-8-chloro-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (0.089g, 0.26mmol) was reacted with 4(5)-imidazole carboxaldehyde (0.028g, 0.29mmol) and NaCNBH3 (22mg, 0.35mmol) in 6mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (65mg, 60%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 4.26 (d, J=5.05 Hz, 2 H) 6.67 (t, =5.43 Hz, 1 H) 7.05 (s, 1 H) 7.22 (d, J=2.02 Hz, 1 H) 7.27 - 7.32 (m, 1 H) 7.45 (t, J=8.97 Hz, 1 H) 7.53 (dd, J=6.57, 2.78 Hz, 1 H) 7.57 - 7.63 (m, 2 H) 8.16 (s, 1 H) 8.38 (s, 1 H) 9.47 (s, 1 H); HRMS (ESI+) calcd for C2oH13CI2FN6 (MH+) 427.06355, found 427.062.
Example 178: 8-chloro-4-(3-chloro-4-fluorophenylamino)-6-(pyridin-3-ylmethylamino) quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-8-chloro-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (0.087g, 0.25mmol) was reacted with nicotinaldehyde (0.026mL, 0.28mmol) and NaCNBH3 (22mg, 0.35mmol) in 9mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (52mg, 47%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.44 (d, J=5.81 Hz, 2 H) 6.51 (d, 1 H) 7.01 (t, J=5.94 Hz, 1 H) 7.21 (d, J=2.27 Hz, 1 H) 7.24 - 7.29 (m, 1 H) 7.37 (dd, J=8.21,5.18 Hz, 1 H) 7.43 (t, J=9.09 Hz, 1 H) 7.51 (dd, J=6.57, 2.78 Hz, 1 H) 7.55 (d, J=2.27 Hz, 1 H) 7.77 - 7.80 (m, 1 H) 8.13 (s, 1 H) 8.40 (s, 1 H) 8.48 (dd, J=4.67, 1.64 Hz, 1 H) 8.62 (d, J=1.77 Hz, 1 H) 9.44 (s, 1 H); HRMS (ESI+) calcd for C22Hi4CI2FN5 (MH+) 438.06830, found 438.0675.
Example 179: 6-(1-(1H-imidazol-5-yl)ethylamino)-4-(3-chloro-4-fluorophenylamino) quinoline-3-carbonitrile
A 25 mL round-bottomed flask under nitrogen atmosphere containing 1-trityl-1H-imidazole-4-carbaldehyde (493mg, 1.46mmol) in THF (8mL) was cooled to -78°C followed by dropwise addition of methylmagnesium bromide (1.2mL, 1.4M in THF, 1.68mmol). The mixture was allowed to warm to RT. The reaction mixture was quenched with water (10 mL) 2hr later. The white precipitate was collected by filtration and dried to give 1-(1-trityl-1H-imidazol-4-yl)ethanol (439mg, 85%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 1.30 (d, J=6.32 Hz, 3 H) 4.56 - 4.63 (m, 1 H) 4.86 (d, J=4.80 Hz, 1 H) 6.65 - 6.67 (m, 1 H) 7.06 - 7.11 (m, J=6.32,1.77,1.52 Hz, 6 H) 7.25 (d, J=1.52 Hz, 1 H) 7.35 - 7.45 (m, 9 H); HRMS (ESI+) calcd for 2 C24H22N2O (MNa+) 731.33564, found 731.337.
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To a solution of 1-(1-trityl-1H-imidazol-4-yl)ethanol (300mg, 0.85mmol) in dichloromethane under nitrogen atmosphere was added diisopropylethylamine (0.177mL, 1.02mmol) followed by methylsulfonyl chloride (0.077mL, 1mmol) at 0°C. The mixture was allowed to warm up to RT. After 1h of reaction, the reaction was worked-up (EtOAc/brine) to give 1-(1-trityl-1H-imidazol-4-yl)ethyl methanesulfonate as a crude solid product which was used for further reaction without purification. To a mixture of 6-amino-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (106mg, 0.34mmol) and the previously made mesylate (136mg, 0.31 mmol) was added acetonitrile (15mL) followed by triethylamine (0.055mL, 0.39mmol). The mixture was heated to reflux for 12hr. The solvent was removed. Reagent grade acetone (100mL) was added followed by HCI (1N, 11mL). The mixture was heated to 60°C for 2h. The reaction was stripped to dryness and the residue was purified via preparative HPLC, and lyophilized to give the product as a yellow solid (0.011 g, 5%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 1.47 (d, J=6.57 Hz, 3 H) 4.71 - 4.86 (m, 1 H) 6.39 - 6.49 (m, J=8.34 Hz, 1 H) 6.90 (s, 1 H) 7.16 - 7.25 (m, 2 H) 7.33 - 7.47 (m, 3 H) 7.54 (d, J=1.01 Hz, 1 H) 7.66 (d, J=9.09 Hz, 1 H) 8.28 (s, 2 H) 9.30 (s, 1 H); HRMS (ESI+) calcd for C2iH16CIFN6 (MH+) 407.11818, found 407.1184.
Example 180: N-(6-((1 H-imidazol-5-yl)methylamino)-3-cyanoquinolin-4-yl)-2-methylpropane-2-sulfonamide
2-Methylpropane-2-sulfonamide (450mg, 3.28mmol) and sodium (139mg, 60% in mineral oil, 3.48mmol) in DMF (10mL) in microwave reactor was allowed to stirred at RT for 10min. Then 4-chloro-6-nitroquinoline-3-carbonitrile (764mg, 3.27mmol) in DMF (2mL) was added and the mixture was heated to 180°C for 2h. Workup (EtOAc/brine) gave a crude N-(3-cyano-6-nitroquinolin-4-yl)-2-methylpropane-2-sulfonamide. SnCI2.2H2O (2.23g, 9.87mmol) was added to the crude product in ethanol (15mL). The mixture was heated to reflux for 2.5h. After cooling down to RT, water (10mL) was added followed by sodium carbonate to adjust pH to around 7. Workup (ethyl acetate/brine) of the reaction gave crude N-(6-amino-3-cyanoquinolin-4-yl)-2-methylpropane-2-sulfonamide.
Following the procedure described above in Example 4, crude N-(6~aminc~ 3-cyanoquinolin-4-yl)-2-methylpropane-2-sulfonamide was reacted with 4(5)-imidazole carboxaldehyde (0.071g, 0.74mmol) and NaCNBH3 (40mg, 0.64mmol) in 10mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (6mg, 5% overall yield): 1H NMR (400 MHz, DMSO-D6) 5 ppm 1.41 (s, 9 H) 4.25 (d, J=1.52 Hz, 2 H) 6.20 (s, 1 H) 7.05 (s, 1 H) 7.19 (dd,
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J=8.97, 2.65 Hz, 1 H) 7.50 (d, J=8.B4 Hz, 1 H) 7.59 - 7.67 (m, 2 H) 8.18 (s, 1 H) 8.23 (s, 1 H); HRMS (ESI+)calcd for C18H20N6O2S (MH+) 385.14412, found 385.1444.
Example 181: 6-((1H-imidazol-5-yl)methylamino)-4-(3-chloro-4-fluorophenylamino) 8-hydroxyquinoline-3-carbonitrile
Step 1: 4-chloro-8-methoxy-6-nitroquinoline-3-carbonitrile (400mg, 1.51mmol) and 3-chloro-4-fluorobenzenamine (220mg, 1.51mmol) were suspended in EtOH (3.5mL) in microwave reactor. The mixture was heated to 140°C for 15min. The reaction was stripped to dryness and the residue was washed with saturated sodium bicarbonate solution and diethyl ether and dried to give solid 4-(3-chloro-4-fluorophenylamino)-8-methoxy-6-nitroquinoline-3-carbonitrile (491 mg, 87%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 4.06 - 4.20 (m, 3 H) 7.38 - 7.45 (m, 1 H) 7.52 (t, J=8.97 Hz, 1 H) 7.67 (d, J=5.56 Hz, 1 H) 8.00 (d, J=2.27 Hz, 1 H) 8.74 (s, 1 H) 9.15 (d, .7=1.01 Hz, 1 H); HRMS (ESI+) calcd for C17H10CIFN4O3 (MH+) 373.04982, found 373.04977.
Step 2: 4-(3-chloro-4-fluorophenylamino)-8-methoxy-6-nitroquinoline-3-carbonitrile (323mg, 0.87mmol) and pyridine hydrochloride (130mg, 1.12mmol) in 6mL of DMF in microwave reactor was heated to 200°C for 35min. The crude product was purified by preparative HPLC, and lyophilized to give solid 4-(3-chloro-4-fluorophenylamino)-8-hydroxy-6-nitroquinoline-3-carbonitrile (222mg, 71%): 1H NMR (400 MHz, DMSO-D6) S ppm 7.43 (dd, J=6.82, 2.27 Hz, 1 H) 7.51 (t, J=8.84 Hz, 1 H) 7.69 (d, J=4.80 Hz, 1 H) 7.83 (s, 1 H) 8.73 (s, 1 H) 8.98 (s, 1 H) 10.40 (s, 1 H) 10.89 (s, 1 H); HRMS (ESI+) calcd for Ci6H8CIFN4O3 (MH+) 359.03417, found 359.034.
Step 3: 4-(3-chloro-4-fluorophenylamino)-8-hydroxy-6-nitroquinoline-3-carbonitrile (176mg, 0.49mmol), SnCI2.2H2O (547mg, 2.42mmol) in ethyl alcohol (5mL) in microwave reactor was heated to 110°C for 10min. After cooling down to RT, water (20mL) was added followed by sodium carbonate to adjust pH to around 7. Workup (ethyl acetate/brine) of the reaction gave a solid as product (160mg, 99%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 5.64 (s, 2 H) 6.59 - 6.67 (m, 2 H) 7.09 - 7.17 (m, 1 H) 7.32 - 7.43 (m, 2 H) 8.26 (s, 1 H) 9.24 (s, 1 H) 9.56 (s, 1 H); HRMS (ESI+) calcd for C16H10CIFN4O (MH+) 329.05999, found 329.0601.
Step 4: Following the procedure described above in Example 4, 6-amino-4-(3-chloro-4-fluorophenylamino)-8-hydroxyquinoline-3-carbonitrile(122mg, 0.37mmol) was reacted with 4(5)-imidazole carboxaldehyde (0.054g, 0.56mmol) and NaCNBH3 (30mg, 0.48mmol) in 10mL EtOH. The crude product was purified
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by preparative HPLC, and lyophilized to give the product as a solid (59mg, 39%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.16 (d, J=4.80 Hz, 2 H) 6.25 - 6.33 (m, 1 H) 6.65 - 6.71 (m, 1 H) 6.94 (s, 1 H) 7.13 - 7.22 (m, 1 H) 7.33 - 7.42 (m, 2 H) 7.53 (d, J=1.26 Hz, 1 H) 8.11 (s, 1 H) 8.18 (s, 1 H) 9.20 (s, 1 H) 9.42 (s, 1 H); HRMS (ESI+) calcd for C20HCIFNeO (MH+) 409.09744, found 409.0975.
Example 182: 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-oxidopyridin-2- yl) methyl]amino}quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-8-chloro-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (97mg, 0.28mmol) was reacted with pyridine-2-carbaldehyde 1-oxide (0.071 g, 0.58mmol) and NaCNBH3 (35mg, 0.56mmol) in 10mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (64mg, 50%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 4.52 (d, J=6.06 Hz, 2 H) 6.98 (t, J=5.94 Hz, 1 H) 7.08 (d, J=2.02 Hz, 1 H) 7.14 - 7.37 (m, 5 H) 7.42 (d, J=5.56 Hz, 1 H) 7.55 (s, 1 H) 8.24 -8.27 (m, 1 H) 8.30 (s, 1 H) 9.41 (s, 1 H); HRMS (ESI+) calcd for C22H14CI2FN5O (MH+) 454.06322, found 454.0628.
Example 183: 8-chloro-4-(3-chloro-4-fluorophenylamino)-6-((1,5-dimethyl-1H-imidazol-4-yl)methylamino)quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-8-chloro-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (79mg, 0.23mmol) was reacted with 1,5-dimethyl-1 H-imidazole-4-carbaldehyde (0.036g, 0.29mmol) and NaCNBH3 (18mg, 0.29mmol) in 6mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (39mg, 38%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 2.30 (s, 3 H) 3.64 (s, 3 H) 4.26 (d, J=4.80 Hz, 2 H) 6.59 - 6.68 (m, 1 H) 7.32 (d, J=2.27 Hz, 1 H) 7.39 - 7.45 (m, 1 H) 7.58 (t, J=8.97 Hz, 1 H) 7.63 - 7.68 (m, 2 H) 7.74 (d, J=2.27 Hz, 1 H) 8.52 (s, 1 H) 9.59 (s, 1 H); HRMS (ESI+) calcd for CHCfcFNe (MH+) 455.09485, found 455.0946.
Example 184: 6-(4-(methylsulfonyl)benzylamino)-8-chloro-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-8-chloro-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (100mg, 0.29mmol) was reacted with 4-(methylsulfonyl)benzaldehyde (0.067g, 0.36mmol) and NaCNBH3 (22mg, 0.35mmol) in 6mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (38mg, 26%): 1H NMR (400
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MHz, DMS0-D6) 5 ppm 3.12 (s, 3 H) 4.47 (d, J=6.06 Hz, 2 H) 7.05 (t, J=5.94 Hz, 1 H) 7.12 (d, J=2.27 Hz, 1 H) 7.16 - 7.22 (m, 1 H) 7.36 (t, J=9.09 Hz, 1 H) 7.41 - 7.46 (m, 1 H) 7.49 (d, .7=2.02 Hz, 1 H) 7.57 (d, J=8.34 Hz, 1 H) 7.81 - 7.87 (m, 2 H) 8.32 (s, 1 H) 9.37 (s, 1 H); HRMS (ESI+) calcd for C24H17CI2FN4O2S (MH+) 515.05060, found 515.0521.
Example 185: 6-(3-(methylsulfonyl)benzylamino)-8-chloro-4-(3-chloro-4-fluorophenyIamino)quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-8-chloro-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (75mg, 0.22mmol) was reacted with 3-(methylsulfonyl)benzaldehyde (0.040g, 0.22mmol) and NaCNBH3 (16mg, 0.25mmol) in 10mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (13mg, 12%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 3.09 (s, 3 H) 4.47 (d, .7=5.81 Hz, 2 H) 7.08 (t, J=6.06 Hz, 1 H) 7.12 (d, .7=2.27 Hz, 1 H) 7.17 - 7.22 (m, 1 H) 7.36 (t, .7=8.97 Hz, 1 H) 7.44 (dd, .7=6.69, 2.65 Hz, 1 H) 7.56 (t, .7=7.71 Hz, 1 H) 7.66 (d, J=7.58 Hz, 1 H) 7.75 (dd, .7=7.58, 1.77 Hz, 1 H) 7.93 (s, 1 H) 8.15 (s, 1 H) 8.32 (s, 1 H) 9.37 (s, 1 H); HRMS (ESI+) calcd for CHCIzFNS (MH+) 515.05060, found 515.0519.
Example 186: 4-((8-chloro-4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino)methyl)benzenesulfonamide
Following the procedure described above in Example 4,6-amino-8-chloro-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (114mg, 0.33mmol) was reacted with 4-formylbenzenesulfonamide (0.080g, 0.43mmol) and NaCNBH3 (27mg, 0.43mmol) in 6mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (95mg, 56%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.42 (d, J=5.56 Hz, 2 H) 7.00 (t, 1 H) 7.13 (d, J=2.02 Hz, 1 H) 7.17 - 7.22 (m, 1 H) 7.24 (s, 2 H) 7.36 (t, .7=8.97 Hz, 1 H) 7.42 - 7.50 (m, 4 H) 7.72 (d, .7=8.59 Hz, 2 H) 8.30 (s, 1 H) 9.38 (s, 1 H); HRMS (ESI+) calcd for C23H1BCI2FN5O2S (MH+) 516.04585, found 516.0469.
Example 187: 6-((H-imidazo[1,2-a]pyridin-2-yl)methylamino)-8-chloro-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-8-chloro-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (94mg, 0.27mmol) was reacted with H-imidazo[1,2-a]pyridine-2-carbaldehyde (0.051g, 0.35mmol) and NaCNBH3 (24mg, 0.38mmol) in 4mL EtOH. The crude product was purified by
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preparative HPLC, and lyophilized to give the product as a solid (69mg, 53%): 1H NMR (400 MHz, DMSO-D6) D ppm 4.75 (d, J=5.31 Hz, 2 H) 6.53 (d, 1 H) 6.98 (t, J=5.18 Hz, 1 H) 7.05 (t, J=6.82 Hz, 1 H) 7.29 - 7.33 (m, 1 H) 7.36 (d, .7=2.27 Hz, 1 H) 7.46 (t, .7=9.09 Hz, 1 H) 7.52 (d, J=2.27 Hz, 1 H) 7.55 (dd, J=6.69, 2.65 Hz, 1 H) 7.65 (d, J=9.35 Hz, 1 H) 7.75 (s, 1 H) 8.13 (s, 1 H) 8.40 - 8.47 (m, 2 H) 9.52 (s, 1 H); HRMS (ESI+) calcd for QCNe (MH+) 477.07920, found 477.0794.
Example 188: 8-chloro-4-(3-chloro-4-fluorophenylamino)-6-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methylamino)quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-8-chloro-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (85mg, 0.24mmol) was reacted with 2,3-dihydropyrazolo[5,1-b]oxazole-6-carbaldehyde (0.034g, 0.25mmol) and NaCNBH3 (24mg, 0.38mmol) in 6mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (36mg, 31%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 4.14 - 4.30 (m, 4 H) 4.97 - 5.09 (m, 2 H) 5.42 (s, 1 H) 6.74 (t, J=5.18 Hz, 1 H) 7.22 (d, .7=2.27 Hz, 1 H) 7.24 - 7.32 (m, 1 H) 7.44 (t, .7=8.97 Hz, 1 H) 7.50 - 7.54 (m, 1 H) 7.57 (d, J=2.02 Hz, 1 H) 8.38 (s, 1 H) 9.48 (s, 1 H); HRMS (ESI+) calcd for CsClaFNeO (MH+) 469.07412, found 469.0737.
Example 189: 8-chloro-4-(3-chloro-4-fluorophenylamino)-6-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)methylamino)quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-8-chloro-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (80mg, 0.23mmol) was reacted with 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carbaldehyde (0.041 g, 0.30mmol) and NaCNBH3 (24mg, 0.38mmol) in 6mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (36mg, 34%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 2.45 - 2.55 (m, 2 H) 2.73 - 2.86 (m, 2 H) 3.95 - 4.07 (m, 2 H) 4.27 (d, .7=5.31 Hz, 2 H) 5.97 (s, 1 H) 6.74 (s, 1 H) 7.22 (d, .7=2.02 Hz, 1 H) 7.24 - 7.31 (m, 1 H) 7.45 (t, .7=9.09 Hz, 1 H) 7.52 (d, J=6.82 Hz, 1 H) 7.58 (d, .7=2.02 Hz, 1 H) 8.38 (s, 1 H) 9.48 (s, 1 H); HRMS (ESI+) calcd for C23H17Cl2FN6 (MH+) 467.09485, found 467.0945.
Example 190: 8-chloro-4-(3-chloro-4-fluorophenylamino)-6-((2-ethyl-5-methyl-1 H-imidazol-4-yl)methylamino)quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-8-chloro-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (80mg, 0.23mmol) was reacted with 2-ethyl-5-methyl-1H-imidazole-4-carbaldehyde (0.067g, 0.49mmol)
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and NaCNBH3 (24mg, 0.38mmol) in 6mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (52mg, 48%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 1.17 (t, J=7.58 Hz, 3 H) 2.06 - 2.17 (m, 3 H) 2.51 - 2.60 (m, 2 H) 4.09 (d, J=4.55 Hz, 2 H) 6.53 (t, J=4.80 Hz, 1 H) 7.18 (t, J=2.27 Hz, 1 H) 7.25 - 7.32 (m, 1 H) 7.45 (t, J=8.97 Hz, 1 H) 7.52 (dd, J=6.57, 2.78 Hz, 1 H) 7.60 (d, J=2.27 Hz, 1 H) 8.16 (s, 1 H) 8.39 (s, 1 H) 9.47 (s, 1 H); HRMS (ESI+) calcd for CgClzFNe (MH+) 469.11050, found 469.1102.
Example 191: 2-(4-((8-chloro-4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino)methyl)-2-methyl-1 H-imidazol-1 -yl)acetamide
Following the procedure described above in Example 4, 6-amino-8-chloro-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (86mg, 0.25mmol) was reacted with 2-(4-formyl-2-methyl-1 H-imidazol-1 -yl)acetamide (0.043g, 0.24mmol) and NaCNBH3 (24mg, 0.38mmol) in 6mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (15mg, 12%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 2.19 (s, 3 H) 4.16 (d, J=5.05 Hz, 2 H) 4.50 (s, 2 H) 6.65 (t, J=5.18 Hz, 1 H) 6.94 (s, 1 H) 7.19 (d, J=2.27 Hz, 1 H) 7.24 (s, 1 H) 7.26 -7.32 (m, 1 H) 7.45 (t, J=9.09 Hz, 1 H) 7.50 - 7.55 (m, 1 H) 7.61 (d, J=2.27 Hz, 1 H) 8.19 (s, 1 H) 8.37 (s, 1 H) 9.47 (s, 1 H); HRMS (ESI+) calcd for C23H18Cl2FN7O (MH+) 496.08611, found 496.0878.
Example 192: 8-chloro-4-(3-chloro-4-fluorophenylamino)-6-((6-methylpyridin-2-yl) methylamino)quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-8-chloro-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (80mg, 0.23mmol) was reacted with 6-methylpicolinaldehyde (0.120g, 0.99mmol) and NaCNBH3 (24mg, 0.38mmol) in 6mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (62mg, 59%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 2.46 (s, 3 H) 4.49 (d, J=6.06 Hz, 2 H) 7.06 (t, J=5.94 Hz, 1 H) 7.14 (dd, J=9.85, 7.83 Hz, 2 H) 7.19 (d, J=2.27 Hz, 1 H) 7.21 - 7.26 (m, 1 H) 7.41 (t, J=8.97 Hz, 1 H) 7.47 (dd, J=6.57, 2.53 Hz, 1 H) 7.60 - 7.67 (m, 2 H) 8.39 (s, 1 H) 9.45 (s, 1 H); HRMS (ESI+) calcd for QsHCIaFNg (MH+) 452.08395, found 452.0834.
Example 193: 2-(4-((8-chloro-4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino)methyl)-2-ethyl-1 H-imidazol-1 -yl)acetamide
Following the procedure described above in Example 4, 6-amino-8-chloro-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (86mg, 0.25mmol) was
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reacted with 2-(2-ethyl-4-fonnyl-1H-imidazol-1-yl)acetamide (0.043g, 0.24mmol) and NaCNBH3 (24mg, 0.38mmol) in 6mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (13mg, 10%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 1.17 (t, J=7.45 Hz, 3 H) 2.52 - 2.56 (m, 2 H) 4.20 (d, J=5.56 Hz, 2 H) 4.50 (s, 2 H) 6.67 (t, J=5.43 Hz, 1 H) 6.93 (s, 1 H) 7.21 (d, J=2.27 Hz, 1 H) 7.24 (s, 1 H) 7.26 - 7.32 (m, 1 H) 7.45 (t, J=9.09 Hz, 1 H) 7.51 -7.55 (m, 2 H) 7.61 (d, J=2.27 Hz, 1 H) 8.37 (s, 1 H) 9.47 (s, 1 H); HRMS (ESI+) calcd for C24H2oCI2FN70 (MH+) 512.11632, found 512.115.
Example 194: tert-butyl 4-((8-chloro-4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino)methyl)-2-ethyl-5-methyl-1H-imidazole-1-carboxylate
Following the procedure described above in Example 4,6-amino-8-chloro-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (98mg, 0.28mmol) was reacted with tert-butyl 2-ethyl-4-foimyl-5-methyl-1H-imidazole-1-carboxylate (0.066g, 0.28mmol) and NaCNBH3 (24mg, 0.38mmol) in 6mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (88mg, 55%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 1.17 (t, J=7.45 Hz, 3 H) 1.55 (s, 9 H) 2.30 (s, 3 H) 2.84 (q, J=7.33 Hz, 2 H) 4.13 (d, J=4.80 Hz, 2 H) 6.63 (t, J=5.05 Hz, 1 H) 7.20 (d, J=2.27 Hz, 1 H) 7.24 - 7.30 (m, 1 H) 7.44 (t, J=8.97 Hz, 1 H) 7.50 (dd, J=6.57, 2.53 Hz, 1 H) 7.58 (d, J=2.27 Hz, 1 H) 8.41 (s, 1 H) 9.46 (s, 1 H); HRMS (ESI+) calcd for C28H27CI2FN6O2 (MH+) 569.16293, found 569.1617.
Example 195: 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(6-methyl-1 -oxidopyridin-2-yl)methyl]amino}quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-8-chloro-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (116mg, 0.33mmol) was reacted with 6-methylpyridine-2-carbaldehyde 1-oxide (0.152g, 1.11mmol) and NaCNBH3 (31 mg, 0.49mmol) in 12mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (7mg, 4%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 1.75 (s, 1 H) 2.40 (s, 3 H) 4.61 (s, 2 H) 7.13 -7.17 (m, .£=2.27 Hz, 1 H) 7.20 - 7.27 (m, 2 H) 7.37 - 7.44 (m, 2 H) 7.50 (dd, J=6.57, 2.53 Hz, 1 H) 7.64 (d, J=2.27 Hz, 1 H) 8.39 (s, 1 H) 9.53 (s, 1 H); HRMS (ESI+) calcd for CzgHCIzFNsO (MH+) 468.07887, found 468.0787.
Example 196: 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(3-methyl-1 -oxidopyridin-2-yl)methyl]amino}quinoline-3-cart3onitrile
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Following the procedure described above in Example 4,6-amino-8-chloro-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (130mg, 0.37mmol) was reacted with 3-methylpyridine-2-carbaldehyde 1-oxide (0.90g, 0.66mmol) and NaCNBH3 (31 mg, 0.49mmol) in 8mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (29mg, 17%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 2.40 (s, 3 H) 4.63 (d, J=5.05 Hz, 2 H) 6.74 (d, J=5.81 Hz, 1 H) 7.22 - 7.34 (m, 2 H) 7.41 - 7.49 (m, 2 H) 7.53 - 7.57 (m, 1 H) 7.59 (d, J=2.53 Hz, 1 H) 8.22 (d, J=7.33 Hz, 1 H) 8.41 (s, 1 H) 9.45 (s, 1 H); HRMS (ESI+) calcd for C23H16CI2FN5O (MH+) 468.07887, found 468.0785.
Example 197: 4-[(3-chloro-4-fluorophenyl)amino]-8-iodo-6-nitroquinoline-3-carbonitrile
4-chloro-8-iodo-6-nitroquinoline-3-carbonitrile (4.64g, 12.92mmol) and 3-chloro-4-fluorobenzenamine (2.3g, 15.80mmol) were suspended in EtOH (70mL) under nitrogen atmosphere. The mixture was heated to reflux for 12hr. The reaction was stripped to dryness and the residue was washed with saturated sodium bicarbonate solution and diethyl ether and dried to give a solid product in quantitative yield: 1H NMR (400 MHz, DMSO-D6) 5 ppm 6.71 - 6.80 (m, 1 H) 6.89 (d, J=6.57 Hz, 1 H) 7.18 (t, J=9.09 Hz, 1 H) 7.98 (s, 1 H) 8.63 (d, J=2.53 Hz, 1 H) 9.14 (d, J=2.53 Hz, 1 H); HRMS (ESI+) calcd for C16H7CIFIN4O2 (MH+) 468.93590, found 468.9362.
Example 198: 6-({[1-[(benzyloxy)methyl]-4-(3-hydroxypropyl)-1 H-imidazol-5-yl] methyl}amino)-8-chloro-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile
To a mixture of 1-(benzyloxymethyl)-4-iodo-1H-imidazole-5-carbaldehyde (715mg, 2.09mmol) and PdCI2(PPh3)2 (85mg, 0.12mmol) in DMF (5mL) under nitrogen atmosphere was added Et3N (1.1 mL) followed by prop-2-yn-1-ol (0.245mL, 4.21 mmol). The mixture was heated to 90°C for 4hr. The reaction was purified via preparative HPLC to give a liquid product 1-(benzyloxymethyl)-4-(3-hydroxyprop-1-ynyl)-1 H-imidazole-5-carbaldehyde (405mg, 72%).
Following the procedure described above in Example 4,6-amino-8-chloro-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (209mg, 0.60mmol) was reacted with 1 -(benzyloxymethyl)-4-(3-hydroxyprop-1 -ynyl)-1 H-imidazole-5-carbaldehyde (0.187g, 0.69mmol) and NaCNBH3 (42mg, 0.67mmol) in 10mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give 6-((1-(benzyloxymethyl)-4-(3-hydroxyprop-1-ynyl)-1H-imidazol-5-yl)methylamino)-8-chloro-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile as a solid (80mg,
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22%). Hydrogenation of the solid was carried out according to procedure described in Example 119 to give the desired product as a solid (18mg, 22%): 1H NMR (400 MHz, acetonitrile-D3) 8 ppm 1.66 -1.72 (m, 2 H) 2.55 (t, J=7.20 Hz, 2 H) 3.42 (t, J=5.94 Hz, 2 H) 4.25 (d, J=4.80 Hz, 2 H) 4.38 (s, 2 H) 5.08 (s, 1 H) 5.28 (s, 2 H) 6.87 (d, .7=2.02 Hz, 1 H) 7.11 - 7.21 (m, 8 H) 7.30 (dd, J=6.32, 2.27 Hz, 1 H) 7.51 (s, 1 H) 7.81 (s, 1 H) 8.00 (s, 1 H) 8.35 (s, 1 H); HRMS (ESI+) calcd for C31H27CI2FN6O2 (MH+) 605.16293, found 605.1645.
Example 199: 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-(ethylamino)quinoline-3-carbonitrile
The product was isolated from the synthesis of 6-((1-(benzyloxymethyl)-4-(3-hydroxyprop-1-ynyl)-1H-imidazol-5-yl)methylamino)-8-chloro-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile in Example 209:1 H NMR (400 MHz, DMSO-D6) 5 ppm 1.22 (t, J=7.07 Hz, 3 H) 3.10 - 3.23 (m, 2 H) 6.41 - 6.49 (m, 1 H) 7.06 (d, J=2.27 Hz, 1 H) 7.22 - 7.32 (m, 2 H) 7.42 - 7.47 (m, 2 H) 7.51 (dd, J=6.57, 2.78 Hz, 1 H) 8.37 (s, 1 H) 9.46 (s, 1 H); HRMS (ESI+) calcd for C18H13CI2FN4 (MH+) 375.05740, found 375.0574.
Example 200: 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[2-(1 H-tetrazol-5-yl)ethyl] amino}quinoline-3-carbonitrile
A mixture of 3,3-diethoxypropanenitrile (1mL, 6.66mmol) and azidotributylstannane (2.38mL, 8.69mmol) in ethyleneglycol diethylether (18mL) under nitrogen atmosphere was heated to reflux for 24hr. The reaction was stripped to dryness. Hydrochloric acid (-1.25N in methanol, 50mL) was added followed by water (0.5mL). The mixture was heated to reflux for 5h. The reaction was stripped to dryness and the crude material was used for reaction without purification.
Following the procedure described above in Example 4,6-amino-8-chloro-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (102mg, 0.29mmol) was reacted with the crude material obtained above and NaCNBH3 (42mg, 0.67mmol) in 15mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (60mg, 46%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 3.17 (t, J=6.95 Hz, 2 H) 3.54 - 3.62 (m, 2 H) 6.58 - 6.67 (m, 1 H) 7.18 (d, J=2.02 Hz, 1 H) 7.29 - 7.35 (m, 1 H) 7.42 - 7.49 (m, 2 H) 7.56 (dd, J=6.44, 2.65 Hz, 1 H) 8.38 (s, 1 H) 9.55 (s, 1 H); HRMS (ESI+) calcd for CgHCIzFNs (MH+) 443.06970, found 443.0702.
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Example 201: 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-methyl-1 H-imidazol-4-yl)methyl]amino}quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-8-chloro-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (80mg, 0.23mmol) was reacted with 1-methyl-1H-imidazole-4-carbaldehyde (28mg, 0.25mmol) and NaCNBH3 (22mg, 0.35mmol) in 5mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (50mg, 49%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 3.61 (s, 3 H) 4.21 (d, J=5.31 Hz, 2 H) 6.68 (d, 1 H) 7.06 (s, 1 H) 7.20 (s, 1 H) 7.25 - 7.33 (m, 1 H) 7.45 (t, J=8.72 Hz, 1 H) 7.51 -7.62 (m, 2 H) 8.37 (s, 1 H) 9.48 (s, 1 H); HRMS (ESI+) calcd for C2iH15CI2FN6 (MH+) 441.07920, found 441.0809.
Example 202: 8-(allyloxy)-4-[(3-chloro-4-fluorophenyl)amino]-6-nitroquinoline-3-carbonitrile
To a mixture of 4-(3-chloro-4-fluorophenylamino)-8-hydroxy-6-nitroquinoline-3-carbonitrile (274mg, 0.77mmol)and potassium carbonate (218mg, 1.58mmol) in DMF (7mL) under nitrogen atmosphere was added ally! bromide (0.073mL, 0.84mmol) at RT. After 12hr of reaction, the reaction was purified via preparative HPLC to give the desired product as a solid (229mg, 75%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 4.92 (d, J=5.31 Hz, 2 H) 5.36 (dd, J=10.48,1.64 Hz, 1 H) 5.49 -5.57 (m, 1 H) 6.11 - 6.23 (m, 1 H) 7.36 (s, 1 H) 7.49 (t, J=8.97 Hz, 1 H) 7.62 (s, 1 H) 7.95 (d, J=2.27 Hz, 1 H) 8.68 (s, 1 H) 9.08 (s, 1 H) 10.45 (s, 1 H).
Example 203: 4-[allyl(3-chloro-4-fluorophenyl)amino]-8-(allyloxy)-6-nitroquinoline-3-carbonitrile
The product was isolated from the synthesis of 8-(allyloxy)-4-[(3-chloro-4-fluorophenyl)amino]-6-nitroquinoline-3-carbonitrile in Example 202:1H NMR (400 MHz, DMSO-D6) 5 ppm 4.89 (d, ,7=5.81 Hz, 2 H) 5.05 (d, J=4.80 Hz, 2 H) 5.11 -5.22 (m, 2 H) 5.39 (d, J=10.61 Hz, 1 H) 5.50 (dd, J=17.31, 1.64 Hz, 1 H) 6.00 - 6.18 (m, 2 H) 6.85 - 6.88 (m, 1 H) 7.09 (dd, J=6.57, 2.53 Hz, 1 H) 7.31 (t, J=9.09 Hz, 1 H) 7.99 (d, J=2.53 Hz, 1 H) 8.30 (s, 1 H) 8.82 (d, J=2.53 Hz, 1 H).
Example 204: 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[(4,5-dihydro-1 H-imidazol-2-ylmethyl)amino]quinoline-3-carbonitrile
A mixture of 6-amino-8-chloro-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (90mg, 0.26mmol) and 2-(chloromethyl)-4,5-dihydro-1 H-imidazole hydrochloride (20mg, 0.13mmol) in ethanol (5mL) in microwave reactor was heated
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to 180°C for 2h. The reaction was stripped to dryness and purified via preparative HPLC to give the desired product as a solid (12mg, 11%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 3.60 (s, 4 H) 4.12 (d, J=3.79 Hz, 2 H) 6.86 (t, J=4.04 Hz, 1 H) 7.25 (d, J=1.01 Hz, 1 H) 7.27 - 7.32 (m, 1 H) 7.45 (t, J=8.97 Hz, 1 H) 7.54 (dd, J=6.57, 2.53 Hz, 1 H) 7.60 (d, J=2.27 Hz, 1 H) 8.32 (s, 1 H) 8.39 - 8.43 (m, 1 H); HRMS (ESI+) calcd for CajHCfeFNe (MH+) 429.07920, found 429.079.
Example 205: 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[4-(3-hydroxypropyl)-1H- imidazol-5-yl]methyl}amino)quinoline-3-carbonitrile
Hydrogenation of 1-(benzyloxymethyl)-4-(3-hydroxyprop-1-ynyl)-1H-imidazole-5-carbaldehyde (120mg, 0.44mmol) was carried out using parr shaker to give 1 -(benzyloxymethyl)-4-(3-hydroxypropyl)-1 H-imidazole-5-carbaldehyde in quantitative yield. The mixture of 1-(benzyloxymethyl)-4-(3-hydroxypropyl)-1H-imidazole-5-carbaldehyde (88mg, 0.32mmol), HCI (6N, 10mL) and methanol (10mL) was heated to reflux for 12h. The reaction was stripped to dryness to give a crude material for further reaction without purification.
Following the procedure described in Example 4,6-amino-8-chloro-4-(3-chloro-4-fluorophenylamino) quinoline-3-carbonitrile (100mg, 0.29mmol) was reacted with the crude material obtained above and NaCNBH3 (22mg, 0.35mmol) in 15mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (25mg, 18%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 1.64-1.75 (m, 2 H) 2.53 - 2.61 (m, 2 H) 3.33 - 3.41 (m, 2 H) 4.15 (d, J=4.04 Hz, 2 H) 6.52 (s, 1 H) 7.20 (s, 1 H) 7.25 - 7.35 (m, 1 H) 7.45 (t, J=8.97 Hz, 1 H) 7.50 - 7.56 (m, 2 H) 7.60 (d, J=2.02 Hz, 1 H) 8.24 (s, 2 H) 8.38 (s, 1 H); HRMS (ESI+) calcd for C23H19CI2FN6O (MH+) 485.10542, found 485.1053.
Example 206: N'-{8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}-N,N- dimethylimidoformarnide
The product was isolated from the reaction mixture of 6-amino-8-chloro-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrilewith2-iodo-2-methylpropane in DMF in the presence of silver carbonate (180°C): 1H NMR (400 MHz, acetonitrile-D3) 8 ppm 2.92 (s, 3 H) 2.98 (s, 3 H) 7.16 - 7.24 (m, 2 H) 7.35 (dd, J=6.44, 2.40 Hz, 1 H) 7.42 (d, J=2.02 Hz, 1 H) 7.59 (d, J=2.27 Hz, 1 H) 7.76 (s, 1 H) 7.96 (s, 1 H) 8.43 (s, 1 H); HRMS (ESI+) calcd for CHuCFNg (MH+) 402.06830, found 402.0682.
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Example 207: 4-[(3-chloro-4-fluorophenyl)amino]-8-(2,3-dihydroxypropoxy)-6-nitroquinoline-3-carbonitrile
To a mixture of 8-(allyloxy)-4-(3-chloro-4-fluorophenylamino)-6-nitroquinoline-3-carbonitrile (138mg, 0.35mmol), reagent grade acetone (16mL) and water (6mL) was added 4-methylmorpholine N-oxide (235mg, 2.01 mmol) followed by OsO4 (0.5mL, 2.5% in tBuOH). After 12hr of reaction and workup (EtOAc/brine), the reaction was purified via preparative HPLC to give a solid product (71 mg, 47%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 2.07 (s, 1 H) 4.33 (d, J=5.56 Hz, 2 H) 5.03 (s, 2 H) 6.60 (s, 1 H) 6.83 (s, 1 H) 7.06 (s, 1 H) 7.19 - 7.26 (m, 2 H) 7.33 - 7.50 (m, 2 H) 7.70 (d, J=9.09 Hz, 1 H) 8.33 (s, 1 H) 9.29 (s, 1 H); HRMS (ESI+) calcd for C19H14CIFN4O5 (MH+) 433.07095, found 433.0705.
Example 208: 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-(2,3-dihydroxypropoxy) quinoline-3- carbonitrile
To a 25 mL round-bottomed flask was added 4-(3-chloro-4-fluorophenylamino)-8-(2,3-dihydroxypropoxy)-6-nitroquinoline-3-carbonitrile (33mg, 0.076mmol), SnCI2.2H2O (104mg, 0.48mmol), and ethyl alcohol (8mL). The mixture was heated to reflux for 12 hr. After cooling to RT, water (20mL) was added followed by sodium carbonate to adjust pH to around 7. Workup (ethyl acetate/brine) of the reaction gave a solid as product in quantitative yield: 1H NMR (400 MHz, DMSO-D6) 8 ppm 1.17 (t, J=7.07 Hz, 2 H) 3.50-3.53 (m, 1 H) 4.03 (q, J=6.91 Hz, 2 H) 4.72 (t, J=5.68 Hz, 1 H) 5.08 (d, J=4.80 Hz, 1 H) 5.73 (s, 2 H) 6.67
- 6.73 (m, J=2.02 Hz, 1 H) 6.78 (s, 1 H) 7.11 (dd, J=7.33, 3.79 Hz, 1 H) 7.27 - 7.33
(m, 1 H) 7.37 (t, J=9.09 Hz, 1 H) 8.30 (s, 1 H) 9.22 (s, 1 H); HRMS (ESI+) calcd for
C19H16CIFN4O3 (MH+) 403.09677, found 403.0958.
Example 209: 4-[(3-chloro-4-fluorophenyl)amino]-8-(2,3-dihydroxypropoxy)-6-[(1 H-imidazol-5-ylmethyl)amino]quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-4-(3-chloro-4-fluorophenylamino)-8-(2,3-dihydroxypropoxy)quinoline-3-carbonitrile (33mg, 0.08mmol) was reacted with 4(5)-imidazole carboxaldehyde (0.014g, 0.15mmol) and NaCNBH3 (7mg, 0.11 mmol) in EtOHATHF (2mL/7mL). The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (10mg, 25%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 2.65 - 2.69 (m, 1 H) 3.49
- 3.55 (m, 2 H) 3.98 (dd, J=9.09, 6.32 Hz, 2 H) 4.08 - 4.13 (m, 1 H) 4.22 - 4.27 (m, 2
H) 4.72 - 4.77 (m, 1 H) 6.32 - 6.42 (m, 1 H) 6.82 (s, 1 H) 6.97 (s, 1 H) 7.03 (s, 1 H)
7.22 (d, J=9.09 Hz, 1 H) 7.41 (d, J=9.09 Hz, 2 H) 7.61 (s, 1 H) 8.25 - 8.34 (m, 2 H)
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9.25 (s, 1 H); HRMS (ESI+) calcd for CzaHzoCIFNeOa (MH+) 483.13422, found 483.1328.
Example 210: 6-[(2-azidoethyl)amino]-8-chloro-4-[(3-chloro-4-fluorophenyl)amino] quinoline-3- carbonitrile
Following the procedure described above in Example 4,6-amino-8-chloro-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (0.258g, 0.74mmol) was reacted with 2-azidoacetaldehyde and NaCNBH3 (22mg, 0.35mmol) in 20mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (13mg, 4%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.91 (d, J=5.56 Hz, 2 H) 5.42 (t, J=5.68 Hz, 2 H) 7.32 - 7.49 (m, 3 H) 7.56 - 7.63 (m, 1 H) 7.73 - 7.78 (m, 1 H) 7.83 (dd, J=7.96,1.14 Hz, 1 H); HRMS (ESI+) calcd for C18H12CI2FN7 (MH+) 416.05880, found 416.0581.
Example 211: 8-chloro-4-t(3-chloro-4-fluorophenyl)amino]-6-{[2-(1 H-1,2,3-triazol-1 -yl)ethyl]amino}quinoline-3-carbonitrile
To6-(2-azidoethylamino)-8-chloro-4-(3-chloro-4-fluorophenylamino) quinoline-3-carbonitrile (65mg, 0.16mmol) in DMF (1.5mL) under nitrogen was added trimethylsilylacetylene (2mL), followed by CuSO4.5H2O (10mg, 0.04mmol) and sodium ascorbate (8mg, 0.04mmol) were added. After 12 hr, the reaction was worked-up (EtOAc extraction, wash with 1N HCI 3x, brine 2x). The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (12mg, 17%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 3.64 - 3.76 (m, 2 H) 4.63 (t, J=5.94 Hz, 2 H) 6.59 - 6.66 (m, 1 H) 7.17 (d, J=2.02 Hz, 1 H) 7.28 - 7.36 (m, 1 H) 7.44 - 7.50 (m, 2 H) 7.56 (dd, J=6.69, 2.65 Hz, 2 H) 7.73 (d, J=1.01 Hz, 1 H) 8.13 (s, 1 H) 8.39 (s, 1 H); HRMS (ESI+) calcd for CzoHuClzFNy (MH+) 440.05990, found 440.0609.
Example 212: 8-chloro-4-[(3-chlorc-4-fluorophenyl)amino]-6-{[2-(1 H-imidazol-1-yl)ethyl] amino}quinoline-3-carbonitrile
Step 1: A mixture of 2-bromo-1,1-diethoxyethane (1.0mL, 6.65mmol) and imidazole sodium salt (480mg, 5.33mmol) in DMF (4.5mL) under nitrogen atmosphere was heated to 115°C for 12hr. Workup with EtOAc/brine gave 1-(2,2-diethoxyethyl)-1H-imidazole as liquid (423mg, 43%).
Step 2: A mixture of 1-(2,2-diethoxyethyl)-1H-imidazole (222mg, 1.21mmol), HCI (-1.25N in MeOH, 15mL) and H2O (0.5mL) was taken to reflux temperature.
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The reaction was stripped to dryness after 3 hr of reaction. The crude material obtained was used for further reaction without purification.
Step 3: Following the procedure described above in Example 4, 6-amino-8-chloro-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile(98mg, 0.28mmol) was reacted with the crude material obtained above and NaCNBH3 (22mg, 0.35mmol) in 25mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (43mg, 35%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 3.52 (q, J=6.40 Hz, 2 H) 4.20 (t, J=6.06 Hz, 2 H) 6.63 (t, J=5.68 Hz, 1 H) 6.88 (s, 1 H) 7.12 (d, J=2.27 Hz, 1 H) 7.21 (s, 1 H) 7.28 - 7.34 (m, 1 H) 7.43 - 7.51 (m, 2 H) 7.54 (dd, J=6.44, 2.40 Hz, 1 H) 7.63 (s, 1 H) 8.17 (s, 1 H) 8.39 (s, 1 H); HRMS (ESI+) calcd for C2iH15CI2FN6 (MH-) 439.06465,found 439.0661.
Example 213: 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({2-[4-(2-hydroxyethyl)-1H-1,2,3- triazol-1-yl]ethyl}amino)quinoline-3-carbonitrile
Step 1: A mixture of 2-bromo-1,1-diethoxyethane (1.35mL, 8.97mmol) and sodium azide (885mg, 13.6mmol) in DMF (10mL) under nitrogen was heated to 115°C for 24hr. After workup (EtOAc/brine), 2-azido-1,1 -diethoxyethane (1.15g, 81%) was obtained as a viscous liquid.
Step 2: To a mixture of 2-azido-1,1 -diethoxyethane (96mg, 0.60mmol), CuSO4.5H2O (20mg, 0.08mmol) and sodium ascorbate (60mg, 0.30mmol) in water (4.5mL) was added but-3-yn-1-ol (0.050mL, 0.66mmol) followed by tert-butanol (3mL). After 4 hr of reaction and workup, 2-(1-{2,2-diethoxyethyl)-1 H-1,2,3-triazol-4-yl)ethanol was obtained as a liquid (65mg, 47%).
Step 3: A mixture of 2-(1-(2,2-diethoxyethyl)-1 H-1,2,3-triazol-4-yl)ethanol (65mg, 0.28mmol), HCI (-1.25N in MeOH, 15mL) and H2O (0.5mL) was taken to reflux temperature. The reaction was stripped to dryness after 3 hr of reaction. The crude material obtained was used for further reaction without purification.
Step 4: Following the procedure described above in Example 4,6-amino-8-chloro-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (59mg, 0.17mmol) was reacted with the crude material obtained in Step 3 and NaCNBH3 (22mg, 0.35mmol) in 8mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (7mg, 8%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 2.74 (t, J=7.V7 Hz, 2 H) 3.59 (t, J=6.95 Hz, 2 H) 3.66 (q, J=6.32 Hz, 2 H) 4.55 (t, J=6.06 Hz, 2 H) 4.70 (s, 1 H) 6.62 (s, 1 H) 7.19 (d, J=2.27 Hz, 1 H) 7.30 (d, J=6.06 Hz, 1 H) 7.42 - 7.50 (m, 2 H) 7.55 (s, 1 H) 7.89 (s, 1 H) 8.37 (s, 1 H); HRMS (ESI+) calcd for C22H18CI2FN7O (MH+) 486.10067, found 486.0996.
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Example 214: 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(4-isopropyl-1 H-imidazol-5-yl)methyl]amino}quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-8-chloro-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (76mg, 0.22mmol) was reacted with 4-isopropyl-1H-imidazole-5-carbaldehyde (36mg, 0.26mmol) and NaCNBH3 (22mg, 0.35mmol) in 9mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (74mg, 72%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 1.16 (d, J=7.07 Hz, 6 H) 4.16 (d, J=4.55 Hz, 2 H) 6.54 (d, J=4.42 Hz, 1 H) 7.19 (d, J=2.02 Hz, 1 H) 7.26 - 7.34 (m, 1 H) 7.45 (t, J=8.97 Hz, 1 H) 7.49 - 7.56 (m, 2 H) 7.61 (d, J=2.27 Hz, 1 H) 8.16 (s, 1 H) 8.39 (s, 1 H) 9.47 (s, 1 H); HRMS (ESI+) calcd for C23H19CI2FN6 (MH+) 469.11050, found 469.1096.
Example 215: 6-{[(1 -benzyl-1 H-1,2,3-triazol-4-yl)methyl]amino}-8-chloro-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-8-chloro-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (55mg, 0.16mmol) was reacted with 1 -benzyl-1 H-1,2,3-triazo!e-4-carbaldehyde (61 mg, 0.33mmol) and NaCNBH3 (22mg, 0.35mmol) in 6mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (30mg, 36%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.45 (d, .7=5.81 Hz, 2 H) 5.57 (s, 2 H) 6.89 (d, J=2.02 Hz, 1 H) 7.23 - 7.36 (m. 6 H) 7.41 - 7.56 (m, 3 H) 8.09 (s, 1 H) 8.38 (s, 1 H) 9.48 (s, 1 H); HRMS (ESI+) calcd for C26H18CI2FN7 (MH+) 518.10575, found 518.1065.
Example 216: 6-([1,2,3]triazolo[1,5-a]pyridin-3-ylmethylamino)-8-chloro-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-8-chloro-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (51mg, 0.15mmol) was reacted with [1,2,3]triazolo[1,5-a]pyridine-3-carbaldehyde (25mg, 0.17mmol) and NaCNBH3 (22mg, 0.35mmol) in 6mL EtOH. The crude product was purified by preparative HPL.C, and lyophilized to give the product as a solid (6mg, 9%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.79 (d, J=5.31 Hz, 2 H) 7.02 (s, 1 H) 7.15 (t, J=6.69 Hz, 1 H) 7.25 (d, J=8.59 Hz, 1 H) 7.29 - 7.37 (m, 1 H) 7.37 - 7.52 (m, 3 H) 7.55 (d, J=1.52 Hz, 1 H) 8.02 (d, J=9.09 Hz, 1 H) 8.36 - 8.49 (m, 2 H) 9.03 (d, J=6.82 Hz, 1 H); HRMS (ESI+) calcd for C23H14Cl2FN7 (MH+) 478.07445, found 478.0757.
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Example 217: 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-methyI-1 H-1,2,3-triazol-4-yl)methyl]amino}quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-8-chloro-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (101 mg, 0.29mmol) was reacted with 1-methyl-1H-1,2,3-triazole-4-carbaldehyde (40mg, 0.36mmol) and NaCNBH3 (22mg, 0.35mmol) in 7mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (23mg, 18%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.02 (s, 3 H) 4.44 (d, J=5.56 Hz, 2 H) 6.88 (t, J=5.68 Hz, 1 H) 7.23 - 7.35 (m, 2 H) 7.46 (t, J=Q.O9 Hz, 1 H) 7.51 - 7.59 (m, 2 H) 7.99 (s, 1 H) 8.39 (s, 1 H) 9.50 (s, 1 H); HRMS (ESI+) calcd for CzoHCIzFNy (MH+) 442.07445, found 442.074.
Example 218: N-(2-(4-((8-bromo-4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino)methyl)-1 H-1,2,3-triazoM -yl)ethyl)-2-methoxyacetamide
Step 1: A mixture of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5g, 26.08mmol), 4-dimethylaminopyridine (1.76g, 14.41mmol), 2-chloroethanamine hydrochloride (1.41g, 12.16mmol),2-methoxyaceticacid (1mL, 13.03mmol) in DMF (10mL) was allowed to react for 12hr. After workup, N-(2-chloroethyl)-2-methoxyacetamide (0.711g, 39%) was obtained as a viscous liquid: 1H NMR (400 MHz, DMSO-D6) 5 ppm 3.31 (s, 3 H) 3.42 (q, J=6.23 Hz, 2 H) 3.63 (t, J=6.44 Hz, 2 H) 3.82 (s, 2 H) 8.01 (s, 1 H).
Step 2: A mixture of N-(2-chloroethyl)-2-methoxyacetamide (315mg, 2.09mmol) and sodium azide (237mg, 3.65mmol) in DMF (5mL) in microwave reactor was heated to 100°Cfor 1h. After workup (EtOAc/brine), N-(2-azidoethyl)-2-methoxyacetamide was obtained in quantitative yield: 1H NMR (400 MHz, DMSO-D6) 8 ppm 3.27 - 3.33 (m, 5 H) 3.35 - 3.41 (m, 2 H) 3.80 (s, 2 H) 8.01 (s, 1 H).
Step 3: To a mixture of N-(2-azidoethyl)-2-methoxyacetamide (201 mg, 1.27mmol), CuSO45H2O (45mg, 0.18mmol) and sodium ascorbate (100mg, 0.51 mmol) in water (10mL) was added 3,3-diethoxyprop-1-yne (0.2mL, 1.40mmol) followed by tert-butanol (1 OmL). After 4 hr of reaction and workup, N-(2-(4-(diethoxymethyl)-1H-1,2,3-triazol-1-yl)ethyl)-2-methoxyacetamide was obtained as asolid(118mg, 32%).
Step 4: A mixture of N-(2-(4-(diethoxymethyl)-1 H-1,2,3-triazol-1-yl)ethyl)-2-methoxyacetamide (118mg, 0.41mmol), HCI (-1.25N in MeOH, 15mL) and H2O (0.5mL) was taken to reflux temperature. The reaction was stripped to dryness
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without purification.
Step 5: Following the procedure described above in Example 4,6-amino-8-bromo-4-(3-chloro-4-fIuorophenylamino)quinoline-3-carbonitrile (50mg, 0.13mmol, prepared as deacribed in Example 78) was reacted with the crude material obtained in Step 2 and NaCNBH3 (11mg, 0.18mmol) in 5mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (17mg, 23%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 3.21 (s, 3 H) 3.53 (q, J=5.89 Hz, 2 H) 3.69 (s, 2 H) 4.40 - 4.49 (m, 4 H) 6.88 (t, ,7=5.56, 5.56 Hz, 1 H) 7.27 - 7.33 (m, 2 H) 7.46 (t, J=8.97 Hz, 1 H) 7.54 (dd, J=6.57, 2.53 Hz, 1 H) 7.76 (d, J=2.53 Hz, 1 H) 7.94 (t, J=5.56 Hz, 1 H) 7.99 (s, 1 H) 8.39 (s, 1 H); HRMS (ESI+) calcd for C24H2iBrCIFN8O2 (MH+) 587.07161, found 587.0725.
Example 219: N-(2-(4-((8-chloro-4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino)methyl)-1 H-1,2,3-triazol-1 -yl)ethyl)-2-methoxyacetamide
Following the procedure described above in Example 4,6-amino-8-chloro-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (50mg, 0.14mmol) was reacted with the crude material obtained in step 4 of Example 218 and NaCNBH3 (11mg, 0.18mmol) in 5mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (10mg, 13%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 3.21 (s, 3 H) 3.53 (q, J=5.81 Hz, 2 H) 3.69 (s, 2 H) 4.44 (t, J=5.68 Hz, 4 H) 6.54 (t, 1 H) 6.88 (t, J=5.94 Hz, 1 H) 7.26 (d, J=2.53 Hz, 1 H) 7.27 -7.34 (m, 1 H) 7.46 (t, J=8.97 Hz, 1 H) 7.53 - 7.57 (m, 2 H) 7.94 (t, J=5.56 Hz, 1 H) 8.00 (s, 1 H) 8.39 (s, 1 H); HRMS (ESI+) calcd for C24H21CI2FN8O2 (MH+) 543.12213, found 543.1222.
Example 220: 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1 -methyl-1 H-imidazol-2-yl)methyl]amino}quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-8-bromo-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (134mg, 0.34mmol, prepared as described in Example 78) was reacted with 1 -methyl-1 H-imidazole-2-carbaldehyde (70mg, 0.64mmol) and NaCNBH3 (22mg, 0.35mmol) in 6mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (26mg, 16%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 3.64 (s, 3 H) 4.40 (d, J=5.05 Hz, 2 H) 6.78 - 6.88 (m, 1H) 7.15 (d, J=1.01 Hz, 1 H) 7.24 - 7.34 (m, 2 H) 7.45 (t, J=9.09 Hz, 1 H) 7.53 (dd, .1=6.57, 2.53 Hz. 1 H) 7.83 (d, J=2.27 Hz,
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1 H) 8.14 (s, 1 H) 8.41 (s, 1 H) 9.49 (s, 1 H); HRMS (ESI+) calcd for C21H15BrCIFN6 (MH+) 485.02869, found 485.0306.
Example 221: 8-bromo-4-(3-chloro-4-fluorophenylamino)-6-((1 -methyl-1 H-1,2,3-triazol-4-yl)methylamino)quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-8-bromo-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (58mg, 0.15mmol, prepared as described in Example 78) was reacted with 1 -methyl-1 H-1,2,3-triazole-4-carbaldehyde (54mg, 0.49mmol) and NaCNBH3 (22mg, 0.35mmol) in 7mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (15mg, 21%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 4.01 (s, 3 H) 4.44 (d, J=5.31 Hz, 2 H) 6.87 (s, 1 H) 7.31 (d, J=2.27 Hz, 2 H) 7.45 (t, J=9.09 Hz, 1 H) 7.53 (t, J=6.32 Hz, 1 H) 7.74 (d, J=1.77 Hz, 1 H) 7.98 (s, 1 H) 8.38 (s, 1 H) 9.49 (s, 1 H); HRMS (ESI+) calcd for C20H14BrCIFN7 (M H+) 486.02394, found 486.0244.
Example 222: 8-chloro-4-(3-chloro-4-fluorophenylamino)-6-((1 -(2-(2-oxooxazolidin-3-yl)ethyl)-1H-1,2,3-triazol-4-yl)methylamino)quinoline-3-carbonitrile
Step 1: To a mixture of 3-(2-azidoethyl)oxazolidin-2-one (492mg, 3.15mmol), CuSO4.5H2O (55mg, 0.22mmol) and sodium ascorbate (77mg, 0.39mmol) in DMF (10mL) was added 3,3-diethoxyprop-1-yne (0.675mL, 4.74mmol) followed by tert-butanol (3mL). After 12 hr of reaction and workup, 3-(2-(4-(diethoxymethyl)-1H-1,2,3-triazol-1-yl)ethyl)oxazolidin-2-one was obtained as a solid.
Step 2: A mixture of 3-(2-(4-(diethoxymethyl)-1H-1,2,3-triazol-1-yl)ethyl)oxazolidin-2-one obtained in Step 1, HCI (-1.25N in MeOH, 8mL) and H2O (0.5mL) was taken to reflux temperature. The reaction was stripped to dryness after 3 hr of reaction. The crude material obtained was used for further reaction without purification.
Step 3: Following the procedure described above in Example 4, 6-amino-8-chloro-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitriie (64mg, 0.18mmol) was reacted with the crude material obtained in Step 2 and NaCNBH3 (11mg, 0.18mmol) in 5mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (6mg, 6%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 3.35 - 3.41 (m, 2 H) 3.54 - 3.60 (m, 2 H) 4.08 - 4.14 (m, 2 H) 4.46 (d, J=5.56 Hz, 2 H) 4.50 - 4.55 (m, 2 H) 6.61 (s, 1 H) 6.91 (t, J=6.19 Hz, 1 H) 7.24 - 7.32 (m, 2
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H) 7.45 (t, J=8.97 Hz, 1 H) 7.51 - 7.57 (m, 2 H) 8.06 (s, 1 H) 8.39 (s, 1 H) 9.48 (s, 1 H); HRMS (ESI+) calcd for C24H19CI2FN8O2 (MH+) 541.10648, found 541.1068.
Example 223: 8-bromo-4-(3-ch!oro-4-fluorophenylamino)-6-((1-(2-(2-oxooxazolidin-3-yl)ethyl)-1H-1,2,3-triazol-4-yl)methylamino)quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-8-bromo-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (53mg, 0.14mmol, prepared as described in Example 78) was reacted with the crude material obtained in Example 235, Step 2, and NaCNBH3 (11mg, 0.18mmol) in 5mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a solid (8mg, 10%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 3.34 - 3.40 (m, 2 H) 3.53 -3.59 (m, 2 H) 4.10 (dd, J=8.72, 7.20 Hz, 2 H) 4.46 (d, J=5.81 Hz, 2 H) 4.50 - 4.55 (m, 2 H) 6.90 (s, 1 H) 7.30 (d, J=2.02 Hz, 2 H) 7.44 (t, J=8.97 Hz, 1 H) 7.51 (s, 1 H) 7.74 (s, 1 H) 8.06 (s, 1 H) 8.37 (s, 1 H) 8.45 (s, 1 H); HRMS (ESI+) calcd for C24H18BrCIFN8O2 (MH+) 585.05596, found 585.0571.
Example 224: 8-chloro-4-(3-chloro-4-fluorophenylamino)-6-((1-(morpholinosulfonylmethyl)-1H-1,2,3-triazol-4-yl)methylamino)quinoline-3-carbonitrile
Step 1: A mixture of 4-(chloromethylsulfonyl)rnorpholine (505mg, 2.54mmol) and sodium azide (400mg, 6.15mmol) in DMF (10mL) was heated to 120°C for 24h. After workup (EtOAc/brine), 4-(azidomethylsulfonyl)morpholine was obtained a white solid (419mg, 80%).
Step 2: To a mixture of 4-(azidomethylsulfonyl)morpholine (370mg, 1.80mmol), CuSO4.5H2O (40mg, 0.16mmol) and sodium ascorbate (55mg, 0.28mmol) in water (10mL) was added 3,3-diethoxyprop-1-yne (0.39mL, 2.74mmol) followed by tert-butanol (3mL). After 12h of reaction and workup, 4-((4-(diethoxymethyl)-1H-1,2,3-triazol-1-yl)methylsulfonyl)morpholine was obtained as a solid.
Step 3: A mixture of 4-((4-(diethoxymethyl)-1H-1,2,3-triazol-1-yl)methylsulfonyl) morpholine obtained above, HCI (~1.25N in MeOH, 15mL) and H2O (0.5mL) was taken to reflux temperature. The reaction was stripped to dryness after 3 hr of reaction. The crude material obtained was used for further reaction without purification.
Step 4: Following the procedure described above in Example 4, 6-amino-8-chloro-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile(55mg, 0.16mmol) was reacted with the crude material obtained in Step 3 and NaCNBH3 (11mg, 0.18mmol) in 8mL EtOH. The crude product was purified by preparative HPLC, and
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lyophilized to give the product as a solid (27mg, 29%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 2.84 - 2.95 (m, 4 H) 3.35 - 3.43 (m, 4 H) 4.54 (d, J=6.06 Hz, 2 H) 6.09 (s, 2 H) 7.02 (t, J=6.32 Hz, 1 H) 7.27 - 7.34 (m, 2 H) 7.48 (t, J=9.09 Hz, 1 H) 7.51 -
7.58 (m, 2 H) 8.14 (s, 1 H) 8.37 (s, 1 H) 9.50 (s, 1 H); HRMS (ESI+) calcd for
C24H21Cl2FN8O3S (MH+) 591.08912, found 591.0899.
Example 225: 4-[(3-Chloro-4-nuorophenyl)amino]-7-methyl-6-[(pyridin-3-ylmethyl)amino]quinoline-3-carbonitrile
Step 1: A 300mL round-bottomed flask was charged with 3-methyl-4-nitro-phenylamine (8.0g, 52.6mmol), ethyl (ethoxymethylene)cyanoacetate (9.8g, 57.8mmol) and 40 mL DMF. The mixture was stirred vigorously to dissolve both reagents, Cs2CO3 (34.3g, 105.2mmol) was added, and the reaction mixture was stirred at RT for 2 hours. To work up, the contents of the flask were poured into 600mL water and the precipitate collected by suction filtration, washed three times with water, then washed twice with ether, and dried under vacuum to give ethyl-2-cyano-3-[(3-methyl-4-nitrophenyl)amino] acrylate as a yellow solid (14.4g, 99% yield): 1H NMR (400 MHz, DMSO-D6) 8 ppm (66%) 1.20 -1.35 (m, 3 H) 2.53 - 2.61 (m, 3 H) 4.14 - 4.33 (m, 2 H) 7.41 - 7.49 (m, J=9.09, 2.53 Hz, 1 H) 7.53 (d, J=2.53 Hz, 1 H) 8.05 (s, 1H) 8.45 (s, 1 H) 11.01 (s, 1 H); (34%) 1.17 -1.36 (m, 3 H) 2.53 -
2.59 (m, 3 H) 4.16 - 4.32 (m, 2 H) 7.54 - 7.58 (m, 1 H) 7.66 (d, =2.27 Hz, 1 H) 8.07
(s, 1 H) 8.60 (d, J=12.88 Hz, 1 H) 10.82 (d, J=13.39 Hz, 1 H); HRMS (ESI+) calcd
for C13H13N3O4 276.09788, found (MH+), 276.0978.
Step 2: In a 2L 3-necked round-bottomed flasks equipped with a stir bar, ethylene glycol/water cooled condenser, heating mantle, inert gas inlet/outlet and an internal temperature monitor, ethyl-2-cyano-3-[(3-methyl-4-nitrophenyl)amino] acrylate (14.0g, 51.0mmol) was suspended in 570mL Dowtherm A. Argon or nitrogen was bubbled through suspension for 30 min. The flask was then heated to 260 °C for 4.5 hours under inert gas. The reaction was then stirred at RT overnight. The contents of the flask were poured into 800mL hexane, stirred vigorously and filtered. The resulting brown precipitate was washed twice with hexanes and twice with dichloromethane and dried under vacuum. The product was isolated as brown powder (a mixture of two regioisomers (7-methyl-6-nitro-4-oxo-1,4-dihydro-quinoline-3-carbonitrile and 5-methyl-6-nitro-4-oxo-1,4-dihydro-quinoline-3-carbonitrile) and was used in the next step without further separation (6.7g, 57% yield).
Step 3: In a 100mL round-bottomed flask equipped with a condenser, the products from the previous step (3.5g, 15.3mmol) were taken up in 25mL POCI3
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and heated at reflux for 4 hours. The reaction mixture was then allowed to cool to RT, and the POCI3 was removed under reduced pressure. Ice chips were added to the residue and then saturated NaHCO3 solution was added carefully, the mixture was stirred for 30 minutes, checking the pH periodically to ensure that it remained at or above 8. The mixture was filtered and dried under high vacuum overnight to give a dark brown solid as a mixture of two regioisomers (4-chloro-7-methyl-6-nitro-quinoline-3-carbonitrile and 4-chloro-5-methyl-6-nitro-quinoline-3-carbonitrile), used in the next step without further separation (3.02g, 80% yield).
Step 4: In a 100mL round-bottomed flask equipped with a condenser, the product from step 3 (0.8g, 3.2mmol) was taken up in 25mL of EtOH, and 3-chloro-4-fluoroaniline (0.56g, 3.9mmol) was added in one portion. The reaction mixture was heated at reflux for 3.5 hours. The reaction mixture was then allowed to cool to RT and the EtOH was removed under reduced pressure. The residue was then partitioned between 30mL ether and 25mL saturated NaHCO3, and stirred for 10 minutes, then filtered and dried under high vacuum overnight to give a brown-yellow solid as a mixture of two regioisomers (4-(3-Chloro-4-fluoro-phenylamino)-7-methyl-6-nitro-quinoline-3-carbonitrileand4-(3-Chloro-4-fluoro-phenylamino)-5-methyl-6-nitro-quinoline-3-carbonitrile), and was used in the next step without further separation (0.42g, 37% yield).
Step 5: In a 100mL round-bottomed flask equipped with a condenser, the product from step 4 (0.42g, 1.2mmol) was taken up in 17mL EtOH and tin chloride dihydrate (1.33g, 5.89mmol) was added. The reaction mixture was heated at reflux for 2.5 hours, until TLC analysis showed complete disappearance of the nitroquinoline. The reaction mixture was then cooled to RT and poured into ice water. The orange suspension was neutralized with saturated NaHCO3 and extracted into CHCI3 (3 x100mL), and the combined organic layers washed with brine, dried over anhydrous Na2SO4) filtered and evaporated. Evaporation of the CHCI3 extracts gave a brown-yellow powder as a mixture of two regioisomers (6-amino-4-(3-chloro-4-fluoro-phenylamino)-7-methyl-quinoline-3-carbonitrile(HRIVIS (ESI+) calcd for C17Hi2CIFN4 (MH+) 327.08073, found 327.081) and 6-amino-4-(3-chloro-4-fluoro-phenylamino)-5-methyl-quinoline-3-carbonitrile), and was used in the next step without further separation (0.24g, 62% yield).
Step 6: Following the procedure described above in Example 4, (6-amino-4-(3-chloro-4-fluoro-phenylamino)-7 and 5-methyl-quinoline-3-carbonitrile (0.19g, 0.58mmol) was reacted with 3-pyridine carboxyaldehyde (0.19g, 1.76mmol) and NaCNBH3(71.4mg, 1.13mmol) in 4mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (35.0mg,
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14%). The 1H-NMR-NOE verified the identity of product as 4-[(3-chloro-4-fluorophenyl)amino]-7-methyl-6-[(pyridin-3-ylmethyl)amino]quinoline-3-carbonitrile: 1H NMR (400 MHz, DMSO-D6) 8 ppm 2.38 (s, 3 H) 4.49 (d, J=5.56 Hz, 2 H) 6.30 (s, 1 H) 7.06 (s, 1 H) 7.10 - 7.20 (m, 1 H) 7.24 - 7.47 (m, 3 H) 7.59 - 7.80 (m, 2 H) 8.33 (s, 1 H) 8.38 - 8.46 (m, 1 H) 8.57 (s, 1 H) 9.25 (s, 1 H); HRMS (ESI+) calcd for C23H17CIFN5 (MH+) 418.12293, found 418.1235.
Example 226: 4-[(3-chloro-4-fluorophenyl)amino]-6-[(1 H-imidazol-5-ylmethyl)amino]-7-methylquinoline-3-carbonitrile
Following the procedure described above in Example 4, (6-amino-4-(3-chloro-4-fluoro-phenylamino)-7 and 5-methyl-quinoline-3-carbonitrile (0.18g, 0.55mmol) were reacted with 4{5)-imidazolecarboxyaldehyde (0.11g, Hmmol) and NaCNBH3 (51.9mg, 0.83mmol) in 5mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (21.0mg, 9%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 2.34 (s, 3 H) 4.35 (d, J=5.31 Hz, 2 H) 5.65 (t, J=5.68 Hz, 1 H) 7.05 (s, 1 H) 7.17 - 7.30 (m, 2 H) 7.36 - 7.51 (m, 2 H) 7.63 (d, J=10.61 Hz, 2 H) 8.32 (s, 1 H) 9.35 (br, s, 1 H) 11.98 (br, s, 1 H); HRMS (ESI+) calcd for C2iH16CIFN6 (MH+) 407.11818, found 407.1185.
Example 227: 4-[(3-chloro-4-fluorophenyl)amino]-7-methyl-6-[(2-morpholin-4-ylethyl) amino]quinoline-3-carbonitrile
Following the procedure described above in Example 4, (6-amino-4-(3-chloro-4-fluoro-phenylamino)-7 and 5-methyl-quinoline-3-carbonitrile (0.20g, 0.55mmol), were reacted with NaCNBH3 (57.5mg, 0.83mmol) and morpholin-4-yl-acetaldehyde (prepared by heating the corresponding dimethyl acetal (0.322g, 1.84mmol) in 2.0mL concentrated HCI for 5 minutes in a microwave reactor at 110 °C, then neutralizing with solid NaHCO3 until pH=6) in 5mL EtOH and 1.5mLTHF. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (38.0mg, 14%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 2.31 (s, 3 H) 2.38 - 2.47 (m, 4 H) 2.62 (t, J=6.69 Hz, 2 H) 3.14 - 3.20 (m, J=2.27 Hz, 2 H) 3.54 - 3.64 (m, 4 H) 5.38 (t, J=5.18 Hz, 1 H) 7.04 - 7.11 (m, 1 H) 7.15 - 7.26 (m, 1 H) 7.37 - 7.46 (m, 2 H) 7.64 (s, 1 H) 8.33 (s, 1 H) 9.34 (s, 1 H); HRMS (ESI+) calcd for C23H23CIFN5O (MH+) 440.16479, found 440.1654.
Example 228: 4-[(3-chloro-4-fluorophenyl)amino]-6-{[(2I4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)methyl]amino}quinoline-3-carbonitrile
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Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (0.15g, 0.48mmol) was reacted with 5-formyluracil (0.13g, 0.96mmol) and NaCNBH3 (45.2mg, 0.72mmol) in 5mL EtOH and 2.5mL THF. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (58.5mg, 28%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 3.98 (d, J=5.05 Hz, 2 H) 6.43 (d, J=11.12 Hz, 1 H) 7.12 (d, J=2.27 Hz, 1 H) 7.23 - 7.29 (m, 1 H) 7.32 (dd, J=8.97, 2.40 Hz, 1 H) 7.36 - 7.51 (m, 3 H) 7.69 (d, J=9.09 Hz, 1 H) 8.30 (s, 1 H) 9.35 (s, 1 H) 10.77 (d, J=7.58 Hz, 1 H) 11.18 (s, 1 H); HRMS (ESI+) calcd for C21H14CIFN6O2 (MH+) 437.09235, found 437.0922.
Example 229: 4-[(3-chloro-4-fluorophenyl)amino]-6-[(1 H-imidazol-5-ylmethyl)amino]-8-(trifluoromethyl)quinoline-3-carbonitrile
Step 1: In a 100mL round-bottomed flask, 4-nitro-3-trifluoromethyl-phenylamine (3.0g, 14.6mmol) and ethyl (ethoxymethylene)cyanoacetate (2.71 g, 16mmol) were dissolved in 15mL DMF, and Cs2CO3 (9.5g, 29.2mmol) was added. The mixture was stirred at RT for 1.5 hours, and poured into 500mL water. The yellow precipitate was collected by suction filtration, washed three times with water, and dried under vacuum to give ethyl-2-cyano-3-{[4-nitro-3-(trifluoromethyl)phenyl]amino}acrylate as a yellow solid (4.26g, 89% yield): 1H NMR (400 MHz, DMSO-D6) 8 ppm (68%) 1.16 -1.37 (m, 3 H) 4.07 - 4.42 (m, 2 H) 7.93 (dd, J=8.97,2.15 Hz, 1 H) 8.06 (d, J=2.27 Hz, 1 H) 8.21 (s, 1 H) 8.55 (s, 1 H) 11.16 (s, 1 H); (32%) 1.17 -1.39 (m, 3 H) 4.15 - 4.34 (m, 2 H) 7.99 - 8.05 (m, 1 H) 8.19 (s, 1 H) 8.26 (d, J=1.77 Hz, 1 H) 8.68 (d, «/=13.39 Hz, 1 H) 10.99 (d, J=13.90 Hz, 1 H); HRMS (ESI+) calcd for CHNaC 330.06962, found (MH+) 330.0698.
Step 2: In a 1L 3-necked round-bottomed flasks equipped with a stir bar, ethylene glycol / water cooled condenser, heating mantle, inert gas inlet/outlet and an internal temperature monitor, 2-cyano-3-(4-nitro-2-trifluoromethyl-phenylamino)-acrylic acid ethyl ester (8.5 g, 25.7mmol) was suspended in 300mL Dowtherm A. Argon was bubbled through suspension for 30 min. The flask was then heated to 260 °C for 8 hours under inert gas. They were then allowed to cool to RT and the contents of flask were poured into 500mL hexane, stirred vigorously and filtered. The resulting brown precipitate was washed twice with hexanes and once with dichloromethane and dried under vacuum. The product 6-nitro-4-oxo-8-(trifluoromethyl)-i ,4-dihydroquinoline-3-carbonitrile was isolated as a brown-yellow solid (6.0g, 82%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 8.69 (s, 1 H) 8.73 (d,
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J=2.53 Hz, 1 H) 9.06 (d, J=2.78 Hz, 1 H); HRMS (ESI+) calcd for C11H4F3N3O3 (MH+) 284.02775, found 284.0276.
Step 3: In a 100mL round-bottomed flask equipped with a condenser, the product from the previous step (3.5g, 12.4mmol) was taken up in 25mL POCI3 and heated at reflux for 5 hours. The reaction mixture was then stirred at RT overnight, and the POCI3 was removed under reduced pressure. Ice chips were added to the residue and then saturated NaHCO3 solution was added carefully, the mixture was stirred for 30 minutes, checking the pH periodically to ensure that it remained at or above 8. The mixture was filtered and dried under high vacuum to give a brown solid as 4-chforo-6-nitro-8-trifluoromethyl-quinoline-3-carbonitrile (3.5g, 93% yield): 1H NMR (400 MHz, DMSO-D6) 5 ppm 8.92 - 9.00 (m, J=1.77 Hz, 1 H) 9.26 - 9.34 (m, J=2.02 Hz, 1 H) 9.57 (s, 1 H).
Step 4: In a 100mL round-bottomed flask equipped with a condenser, the product from step 3 (2.44g, 8.1mmol) was taken up in 35mL EtOH, and 3-chloro-4-fluoroaniline (1.41 g, 9.7mmol) was added in one portion. The reaction mixture was heated at reflux for 1 hour and was stirred at RT overnight. The EtOH was removed under reduced pressure, the residue was then partitioned between 50mL ether and 25mL saturated NaHCO3, and stirred for 15 minutes, then evaporated some ether by rotovamp until precipitate formed. The mixture was filtered and dried under high vacuum overnight to give a brown-yellow solid as 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-8-(trifluoromethyl)quinoline-3-carbonitrile (3.3g, 99% yield): 1H NMR (400 MHz, DMSO-D6) 5 ppm 7.37 - 7.48 (m, 1 H) 7.53 (t, J=8.97 Hz, 1 H) 7.71 (dd, J=6.44, 2.40 Hz, 1 H) 8.79 (d, J=2.27 Hz, 1 H) 8.87 (s, 1 H) 9.80 (d, J=2.27 Hz, 1 H) 10.77 (s, 1 H); HRMS (ESI+) calcd for C17H7CIF4N4O2 (MH+) 411.02664, found 411.026.
Step 5: In a 100mL round-bottomed flask equipped with a condenser, the product from step 4 (1.65g, 4.0 mmol) was taken up in 50mL EtOH and tin chloride dihydrate (4.53g, 20.1 mmol) was added. The reaction mixture was heated at reflux for 1 hour, until LC/MS. analysis showed complete disappearance of the nitroquinoline. The reaction mixture was then cooled to RT and poured into ice water. The orange suspension was neutralized with saturated NaHCO3 and extracted with CHCI3 (3 x150mL) first, and then extracted with EtOAc (2 xi50mL). The combined organic layers washed with brine, dried over anhydrous Na2SO4, filtered and evaporated. Evaporation of the organic extracts gave a yellow solid as 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-(trifluoromethyl)quinoline-3-carbonitrile (1.5g, 98% yield): 1H NMR (400 MHz, DMSO-D6) 8 ppm 3.92 - 4.12 (m, 1 H) 6.09 (s, 2 H) 7.15 - 7.31 (m, 1 H) 7.33 - 7.53 (m, 2 H) 7.70 (d, J=2.27 Hz, 1 H)
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8.44 (s, 1 H) 9.57 (s, 1 H); HRMS (ESI+) calcd for C17H9CIF4N4 (MH+) 381.05246, found 381.053.
Step 6: Following the procedure described above in Example 4, 6-amino-4-[(3-chloro-4-f luorophenyl)amino]-8-(trifluoromethyl)quinoline-3-carbonitrile (0.15g, 0.39mmol) was reacted with 4(5)-imidazolecarboxyaldehyde (75.7mg, 0.79mmol) and NaCNBH3 (37.1 mg, 0.72mmol) in 5mL EtOH. The crude product was purified by preparative HPLC, arftl lyophilized to give the product as a yellow solid (137.2 mg, 76%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.31 (d, J=5.31 Hz, 2 H) 6.82 -6.91 (m, J=5.31, 5.31 Hz, 1 H) 7.08 (s, 1 H) 7.28 - 7.37 (m, 1 H) 7.41 - 7.50 (m, 2 H) 7.57 (dd, J=6.69, 2.65 Hz, 1 H) 7.66 (d, J=1.01 Hz, 1 H) 7.86 (d, J=2.27 Hz, 1 H) 8.41 (s, 1 H) 9.55 (s, 1 H) 12.18 (s, 1 H); HRMS (ESI+) calcd for C2iH13CIF4N6 (MH+) 461.08991, found 461.0903.
Example 230: 4-[(3-chloro-4-fluorophenyl)amino]-6-[(pyridin-3-ylmethyl)amino]-8-(trifluoromethyl)quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-(trifluoromethyl)quinoline-3-carbonitrile (0.10g, 0.26mmol) was reacted with pyridine-3-carbaldehyde (36.6mg, 0.34mmol) and NaCNBH3 (11.6mg, 0.18mmol) in 4mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (58.0mg, 47%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 4.47 (d, J=5.56 Hz, 2 H) 7.15 - 7.24 (m, 1 H) 7.25 - 7.33 (m, 1 H) 7.38 (dd, J=7.58, 4.80 Hz, 1 H) 7.41 - 7.49 (m, 2 H) 7.55 (dd, J=6.57, 2.53 Hz, 1 H) 7.81 (d, J=2.27 Hz, 2 H) 8.24 (s, 1 H) 8.43 (s, 1 H) 8.49 (d, J=4.55 Hz, 1 H) 8.64 (s, 1 H); HRMS (ESI+) calcd for C23H14CIF4N5 (MH+) 472.09466, found 472.0946.
Example 231: 4-[(3-chloro-4-fluorophenyl)amino]-6-[(pyridin-2-ylmethyl)amino]-8-(trifluoromethyl)quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-(trifluoromethyl)quinoline-3-carbonitrile(0.10g, 0.26mmol) was reacted with pyridine-2-carbaldehyde (36.6mg, 0.34mmol) and NaCNBH3 (11.6mg, 0.18mmol) in 4mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (43.1 mg, 35%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.57 (d, J=6.06 Hz, 2 H) 7.22 - 7.32 (m, 3 H) 7.36 - 7.48 (m, 3 H) 7.52 (dd, J=6.57, 2.53 Hz, 1 H) 7.73 - 7.81 (m, 1 H) 7.90 (d, J=2.27 Hz, 1 H) 8.43 (s, 1 H) 8.55 (dd, J=4.42,1.39 Hz, 1 H) 9.53 (s, 1 H); HRMS (ESI+) calcd for C23HCNs (MH+) 472.09466, found 472.0948.
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Example 232: 4-[(3-chloro-4-fluorophenyl)amino]-6-[(3-cyanobenzyl)amino]-8-(trifluoromethyl)quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-(trifluoromethyl)quinoline-3-carbonitrile (0.10g, 0.26mmol) was reacted with 3-formyl-benzonitrile (44.9mg, 0.34mmol) and NaCNBH3 (11.6 mg, 0.18mmol) in 4mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (53.7mg, 41%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 4.50 (d, J=5.81 Hz, 2 H) 7.20 - 7.31 (m, 2 H) 7.38 (d, J=2.27 Hz, 1 H) 7.43 (t, J=8.97 Hz, 1 H) 7.52 (dd, J=6.57, 2.53 Hz, 1 H) 7.57 (t, J=7.83 Hz, 1 H) 7.70 - 7.77 (m, 2 H) 7.81 (d, J=2.27 Hz, 1 H) 7.86 (s, 1 H) 8.44 (s, 1 H) 9.50 (s, 1 H); HRMS (ESI+) calcd for C25H14CIF4N5 (MH+) 496.09466, found 496.0943.
Example 233: 4-[(3-chloro-4-fluorophenyl)amino]-6-[(2-cyanobenzyl)amino]-8-(trifluoromethyl)quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-(trifluoromethyl)quinoline-3-carbonitrile (0.1 Og, 0.26mmol) was reacted with 2-formyl-benzonitrile (67.9mg, 0.52mmol) and NaCNBH3 (21.6 mg, 0.34mmol) in 4mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (37.9mg, 29%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 4.62 (d, .7=5.56 Hz, 2 H) 7.22 (m, 1 H) 7.24 - 7.31 (m, 1 H) 7.39-7.44(m, 2H) 7.48 - 7.55 (m, 2 H) 7.59 (d, J=8.08 Hz, 1 H) 7.66 - 7.73 (m, 1 H) 7.82 - 7.91 (m, 2 H) 8.46 (s, 1 H) 9.52 (s, 1 H); HRMS (ESI+) calcd for C25H14CIF4N5 (MH+) 496.09466, found 496.0943.
Example 234: 4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-cyanobenzyl)amino]-8-(trifluoromethyl)quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-(trifluoromethyl)quinoline-3-carbonitrile (0.1 Og, 0.26mmol) was reacted with 4-formyl-benzonitrile (44.9mg, 0.34mmol) and NaCNBH3 (11.6mg, 0.18mmol) in 4mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (69.7mg, 53%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.55 (d, J=5.81 Hz, 2 H) 7.23 - 7.28 (m, 1 H) 7.30 (t, J=6.06 Hz, 1 H) 7.35 (d, J=2.Q2 Hz, 1 H) 7.42 (t, J=8.97 Hz, 1 H) 7.50 (dd, J=6.57,2.53 Hz, 1 H) 7.56 (d, J=8.34 Hz, 2 H) 7.75 - 7.86 (m, 3 H) 8.44
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(s, 1 H) 9.47 (s, 1 H);HRMS (ESI+) calcd for C25H14CIF4N5 (MH+) 496.09466, found 496.0942.
Example 235: 4-[(3-chloro-4-fluorophenyl)amino]-6-[(2-fluorobenzyl)amino]-8-(trifluoromethyl)quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-(trifluoromethyl)quinoline-3-carbonitrile(0.10g, 0.26mmol) was reacted with 2-fluoro-benzaldehyde (42.5mg, 0.34mmol) and NaCNBH3 (11.6mg, 0.18mmol) in 4mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (22.5mg, 18%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 4.48 (d, J=5.56 Hz, 2 H) 7.10 (t, J=5.68 Hz, 1 H) 7.16 - 7.26 (m, 2 H) 7.25 - 7.31 (m, 1 H) 7.32 - 7.39 (m, 1 H) 7.40 -7.48 (m, 3 H) 7.54 (dd, J=6.57, 2.53 Hz, 1 H) 7.84 (d, J=2.27 Hz, 1 H) 8.44 (s, 1 H) 9.53 (s, 1 H); HRMS (ESI+) calcd for C24H14CIF5N4 (MH+) 489.08999, found 489.0897.
Example 236: 4-[(3-chloro-4-f!uorophenyl)amino]-6-{[(1 -methyl-1 H-imidazol-2-yl)methyl] amino}-8-(trifluoromethyl)quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-(trifluoromethyl)quinoline-3-carbonitrile (0.10g, 0.26mmol) was reacted with 1 -methyl-1 H-imidazole-2-carbaldehyde (37.7mg, 0.34mmol) and NaCNBH3 (11.6mg, 0.18mmol) in 4mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (54.6mg, 44%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 3.65 (s, 3 H) 4.43 (d, J=5.05 Hz, 2 H) 6.83 (d, J=1.26 Hz, 1 H) 7.01 (t, J=5.05 Hz, 1 H) 7.15 (d, J=1.26 Hz, 1 H) 7.29 - 7.36 (m, 1 H) 7.46 (t, J=8.97 Hz, 1 H) 7.52 (d, J=2.27 Hz, 1 H) 7.57 (dd, J=6.57, 2.78 Hz, 1 H) 7.89 (d, J=2.27 Hz, 1 H) 8.44 (s, 1 H) 9.57 (s, 1 H); HRMS (ESI+) calcd for C22H15CIF4N6 (MH+) 475.10556, found 475.106.
Example 237: 4-[(3-chloro-4-fluorophenyl)amino]-6-({[1 -(phenylsulfonyl)-i H-pyrrol-2-yl]methyl}amino)-8-(trifluoromethyl)quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-(trifluoromethyl)quinoline-3-carbonitrile (0.10g, 0.26mmol) was reacted with 1-benzenesulfonyl-1H-pyrrole-2-carbaldehyde (80.5 mg, 0.34mmol) and NaCNBH3 (11.6mg, 0.18mmol) in 4mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (87.1 mg, 55%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 4.56 (d, J=5.56
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Hz, 2 H) 6.24 - 6.42 (m, 2 H) 6.80 (t, J=5.56 Hz, 1 H) 7.24 - 7.36 (m, 1 H) 7.39 -7.50 (m, 3 H) 7.52 - 7.60 (m, 3 H) 7.64 (d, J=2.02 Hz, 1 H) 7.69 (t, J=7.45 Hz, 1 H) 7.86 - 7.94 (m, 2 H) 8.37 - 8.50 (m, 1 H) 9.59 (s, 1 H); HRMS (ESI+) calcd for C28H1aCIF4N5O2S (MH+) 600.08786, found 600.0885.
Example 238: 4-[(3-chloro-4-fluorophenyl)amino]-6-{[(4,5-dimethy1-2-furyl)methyl] amino}-8-(trifluoromethyl)quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-(trifluoromethyl)quinoline-3-carbonitrile(0.10g, 0.26mmol) was reacted with 4,5-dimethyl-furan-2-carbaldehyde (42.5mg, 0.34mmol) and NaCNBH3 (11.6mg, 0.18mmol) in 4mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (18.9mg, 15%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 1.85 (s, 3 H) 2.14 (s, 3 H) 4.32 (d, J=5.56 Hz, 2 H) 6.14 (s, 1 H) 7.02 (t, J=5.56 Hz, 1 H) 7.27 - 7.36 (m, 1 H) 7.41 - 7.49 (m, 2 H) 7.55 (dd, J=6.69, 2.65 Hz, 1 H) 7.79 (d, J=2.27 Hz, 1 H) 8.42 (s, 1 H) 9.56 (s, 1 H); HRMS (ESI+) calcd for C24H17CIF4N4O (MH+) 489.10998, found 489.1107.
Example 239: 4-[(3-chloro-4-fluorophenyl)amino]-6-[(1,3-thiazol-5-ylmethyl)amino]-8-(trifluoromethyl)quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-(trifluoromethyl)quinoline-3-carbonitrile (0.10g, 0.26mmol) was reacted with thiazole-5-carbaldehyde (38.7mg, 0.34mmol) and NaCNBH3 (11.6mg, 0.18mmol) in 4mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (43.9mg, 35%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 4.72 (d, J=6.06 Hz, 2 H) 7.23 (t, J=5.81 Hz, 1 H) 7.29 - 7.38 (m, 1 H) 7.46 (t, J=9.09 Hz, 1 H) 7.54 (d, J=2.27 Hz, 1 H) 7.58 (dd, J=6.69, 2.65 Hz, 1 H) 7.77 (d, J=2.27 Hz, 1 H) 7.93 (s, 1 H) 8.44 (s, 1 H) 9.00 (s, 1 H) 9.55 (s, 1 H);HRMS (ESI+) calcd for C21H12CIF4N5S (MH+) 478.05108, found 478.051.
Example 240: 4-[(3-chloro-4-fluorophenyl)amino]-6-[(pyrimidin-5-ylmethyl)amino]-8-(trifluoromethyl)quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-(trifluoromethyl)quinoline-3-carbonitrile (0.10g, 0.26mmol) was reacted with pyrimidine-5-carbaldehyde (57.0mg, 0.53mmol) and NaCNBH3 (21.6mg, 0.34mmol) in 4mL EtOH. The crude product was purified by
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preparative HPLC, and lyophilized to give the product as a yellow solid (68.2mg, 55%): 1H NMR (400 MHz, DMGO-D6) 8 ppm 4.50 (d, J=5.56 Hz, 2 H) 7.22 (t, J=11.12 Hz, 1 H) 7.27 - 7.35 (m, 1 H) 7.40 - 7.51 (m, 2 H) 7.56 (dd, J=6.57, 2.53 Hz, 1 H) 7.79 (d, J=2.02 Hz, 1 H) 8.44 (s, 1 H) 8.86 (s, 2 H) 9.12 (s, 1 H) 9.57 (br, s, 1 H); HRMS (ESI+) calcd for C22H13CIF4N6 (MH+) 473.08991, found 473.0896.
Example 241: 4-[(3-chloro-4-fluorophenyl)amino]-6-{[(4,6-dimethoxypyrimidin-5-yl)methyl]amino}-8-(trifluoromethyl)quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-(trifluoromethyl)quinoline-3-carbonitrile(0.10g, 0.26mmol) was reacted with 2,4-dimethoxy-pyrimidine-5-carbaldehyde (57.5mg, 0.34mmol) and NaCNBH3 (11.6mg, 0.18mmol) in 4mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (44.6mg, 32%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 3.88 (s, 3 H) 3.95 (s, 3 H) 4.27 (d, J=5.31 Hz, 2 H) 6.93 (t, J=5.43 Hz, 1 H) 7.29-7.32 (m, 1 H) 7.36 - 7.50 (m, 2 H) 7.55 (dd, J=6.69, 2.65 Mz, 1 H) 7.78 (d, J=1.77 Hz, 1 H) 8.30 (s, 1 H) 8.44 (s, 1 H) 9.55 (s, 1 H); HRMS (ESI+) calcd for C24H17CIF4N6O2 (MH+) 533.11104, found 533.1112.
Example 242: 4-[(3-chloro-4-fluoropheny!)amino]-6-({[2-(phenylsulfonyl)-1,3-thiazol-5-yl]methyl}amino)-8-(trifluoromethyl)quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-(trifluoromethyl)quinoline-3-carbonitrile (0.10g, 0.26mmol) was reacted with 2-benzenesulfonyl-thiazole-5-carbaldehyde (86.6mg, 0.34mmol) and NaCNBH3 (11.6mg, 0.18mmol) in 4mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (19.0mg, 12%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.79 (d, J=5.81 Hz, 2 H) 7.28 - 7.39 (m, 2 H) 7.46 (t, J=8.97 Hz, 1 H) 7.54 (s, 1 H) 7.56 - 7.63 (m, 1 H) 7.64 - 7.72 (m, .7=7.58 Hz, 2 H) 7.72 - 7.85 (m, 2 H) 8.01 (d, J=7.58 Hz, 2 H) 8.11 (s, 1 H) 8.45 (s, 1 H) 9.52 (s, 1 H); HRMS (ESI+) calcd for C27H16CN5O2S2 (MH+) 618.04428, found 618.0426.
Example 243: 4-[(3-chloro-4-fluorophenyl)amino]-6-{[(2-morpholin-4-yl-1,3-thiazol-5-yl)methyl]amino}quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (0.10g, 0.32mmol) was reacted with 2-morpholin-4-yl-thiazole-5-carbaldehyde (82.4 mg, 0.42 mmol) and
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NaCNBH3 (14.1 mg, 0.22mmol) in 4mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (66.5mg, 42%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 3.26 - 3.31 (m, 4 H) 3.63 - 3.70 (m, 4 H) 4.43 (d, J=5.81 Hz, 2 H) 6.77 (t, J=5.94 Hz, 1 H) 7.17 (s, 1 H) 7.20 - 7.27 (m, 2 H) 7.31 (dd, J=9.09, 2.53 Hz, 1 H) 7.39 - 7.49 (m, 2 H) 7.70 (d, J=8.84 Hz, 1 H) 8.33 (s, 1 H) 9.32 (s, 1 H); HRMS (ESI+) calcd for C24H2oCIFN6OS (MH+) 495.11646, found 495.1153.
Example 244: 4-[(3-chloro-4-fluorophenyl)amino]-6-{[(2-morpholin-4-yl-1,3-thiazol-5-yl)methyl]amino}-8-(trifluoromethyl)quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-(trifluoromethyl)quinoline-3-carbonitrile(0.10g, 0.26mmol) was reacted with 2-morpholin-4-yl-thiazole-5-carbaldehyde (67.8mg, 0.34mmol) and NaCNBH3 (11.6mg, 0.18mmol) in 4mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (58.1 mg, 39%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 3.20 - 3.36 (m, 4 H) 3.60 - 3.75 (m, 4 H) 4.48 (d, J=5.56 Hz, 2 H) 7.08 (t, 1 H) 7.21 (s, 1 H) 7.29 - 7.38 (m, 1 H) 7.42 - 7.51 (m, 2 H) 7.57 (dd, J=6.57, 2.53 Hz, 1 H) 7.75 (d, J=2.02 Hz, 1 H) 8.44 (s, 1 H) 9.54 (s, 1 H); HRMS (ESI+) calcd for C25H19CIF4N6OS (MH+) 563.10384, found 563.1025.
Example 245: 4-[(3-chloro-4-fluorophenyl)amino]-6-({[2-(phenylsulfonyl)-1,3-thiazol-5-yl]methyl}amino)quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (0.1 Og, 0.32mmol) was reacted with 2-benzenesulfonyl-thiazole-5-carbaldehyde (71.3mg, 0.28mmol) and NaCNBH3 (11.3mg, 0.18mmol) in 4mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (11 .Omg, 8%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.79 (d, J=6.06 Hz, 2 H) 7.10 (t, J=6.19 Hz, 1 H) 7.27 - 7.41 (m, 3 H) 7.49 (t, J=8.97 Hz, 1 H) 7.57 (dd, J=6.57, 2.78 Hz, 1 H) 7.70 - 7.89 (m, 4 H) 8.06 (dd, J=8.46,1.14 Hz, 2 H) 8.15 (s, 1 H) 8.40 (s, 1 H) 9.38 (s, 1 H); HRMS (ESI+) calcd for CzeHnCIFNsOaSz (MH+) 550.05690, found 550.0575.
Example 246: 4-(cycloheptylamino)-6-[(pyridin-3-ylmethyl)amino]quinoline-3-carbonitrile
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Step 1: In a 100mL round-bottomed flask equipped with a condenser, 6-nitro-4-oxo-1,4-dihydro-quinoline-3-carbonitrile (3.3g, 15.3mmol) was taken up in 40mL POCI3 and heated at reflux for 6 hours. The reaction mixture was then stirred at RT overnight, and then POCI3 was removed under reduced pressure. Ice chips were added to the residue and then saturated NaHCO3 solution was added carefully, the mixture was stirred for 30 minutes, checking the pH periodically to ensure that it remained at or above 8. The mixture was filtered and dried under high vacuum overnight to give a light brown solid as 4-chloro-6-nitro-quinoline-3-carbonitrile (3.2g, 90% yield).
Step 2: In a microwave vial, the product from step 1 (0.4g, 1.71mmol) was taken up in 2mL EtOH and cycloheptyl amine (0.23g, 2.05mmol) was added. The vial was crimp-sealed and heated in a microwave reactor at 150 °C for 45 minutes. This was repeated with a second batch of reagents, with 0.6g of 4-chloro-6-nitro-quinoline-3-carbonitrile. The contents of the two vials were combined and evaporated down the solvent to a yellow residue. The residue was partitioned between ether and H2O, the resulting suspension was filtered, washed with H2O, dried under high vacuum overnight to give a yellow solid as 4-cycloheptylamino-6-nitro-quinoline-3-carbonitrile (0.93g, 70% yield).
Step 3: In a microwave vial, the product from step 2 (0.30g, 0.97mmol) was taken up in 2mL EtOH and tin chloride dihydrate (1.09g, 4.83mmol) was added. The vial was sealed and heated in a microwave reactor at 110 °C for 10 minutes, until LC/MS analysis showed complete disappearance of the nitroquinoline. This was repeated with a second batch of reagents, with 0.63g of 4-cycloheptylamino-6-nitro-quinoline-3-carbonitrile. The contents of the two vials were combined and then poured into ice water, and the reaction worked up as described above in Example 229 for the synthesis of 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-(trifluoromethyl)quinoline-3-carbonitrile. 6-amino-4-cycloheptylamino-quinoline-3-carbonitrile was obtained as a yellow solid (0.70g, 83% yield).
Step 4: Following the procedure described above in Example 4,6-amino-4-cycloheptylamino-quinoline-3-carbonitrile (80.0mg, 0.29mmol) was reacted with pyridine-3-carbaldehyde (39.7mg, 0.37mmol) and NaCNBH3 (12.5mg, 0.20mmol) in 3mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (73.6mg, 70%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 1.37 -1.78 (m, 10 H) 1.89 - 2.05 (m, 2 H) 4.31 - 4.39 (m, 1 H) 4.41 (d, J=5.81 Hz, 2 H) 6.65 (t, J=5.94 Hz, 1 H) 6.88 (d, J=8.34 Hz, 1 H) 7.05 (d, J=2.27 Hz, 1 H) 7.15 (dd, J=8.97,2.40 Hz, 1 H) 7.29 (dd, J=7.33,4.29 Hz, 1 H) 7.49 (d, J=9.09 Hz, 1 H) 7.71 - 7.80 (m, 1 H) 8.10 (d, J=6.32 Hz, 1 H) 8.39 (dd, J=4.80,1.77 Hz, 1 H)
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8.60 (d, J=1.77 Hz, 1 H); HRMS (ESI+) calcd for C23H25N5 (MH+) 372.21827, found 372.2186.
Example 247: 6-[(3-Cyanobenzyl)amino]-4-(cycloheptylamino)quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-cycloheptylamino-quinoline-3-carbonitrile (80.0mg, 0.29mmol) was reacted with 3-formyl-benzonitrile (48.7mg, 0.37mmol) and NaCNBH3 (12.5mg, 0.20mmol) in 3mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (43.6mg, 39%): 1H NMR (400 MHz, DMSO-D6) 8 ppm
1.51 -1.93 (m, 10 H) 1.96 -2.17 (m, 2 H) 4.35 - 4.55 (m, J=9.09 Hz, 1 H) 4.60 (d,
J=5.81 Hz, 2 H) 6.88 - 7.01 (m, 2 H) 7.12 (d, J=2.27 Hz, 1 H) 7.30 (dd, J=8.84, 2.27
Hz, 1 H) 7.58 - 7.69 (m, 2 H) 7.83 (dd, J=20.34, 7.71 Hz, 2 H) 8.01 (s, 1 H) 8.21 -
8.30 (m, 1 H); HRMS (ESI+) calcd for C25H25N5 (MH+) 396.21827, found 396.218.
Example 248: 4-(cycloheptylamino)-6-P-(methylsulfonyl)benzyljamino}quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-cycloheptylamino-quinoline-3-carbonitrile (80.0mg, 0.29mmol) was reacted with 3-methanesulfonyl-benzaldehyde (68.3mg, 0.37mmol) and NaCNBH3 (12.5mg, 0.20mmol) in 3mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (58.2mg, 46%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 1.34 - 1.87 (m, 10 H) 1.90 - 2.07 (m, 2 H) 3.12 (s, 3 H) 4.53 (s, 3 H) 7.20 - 7.26 (m, J=2.27 Hz, 1 H) 7.28(br, s, 1 H) 7.34 (dd, J=9.09, 2.27 Hz, 1 H)
7.52 - 7.64 (m, 2 H) 7.74 (dd, J=24.63, 7.71 Hz, 2 H) 7.94 (s, 1 H) 8.31 (d, J=7.58
Hz, 1 H) 8.69 (s, 1 H); HRMS (ESI+) calcd for CasHOaS (MH+) 449.20057,
found 449.2007.
Example 249: 4-(cycloheptylamino)-6-{[(1-methyl-1 H-imidazol-2-yl)methyl]amino} quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-4-cycloheptylamino-quinoline-3-carbonitrile (80.0mg, 0.29mmol) was reacted with 1-methyl-1H-imidazole-2-carbaldehyde (40.9mg, 0.37mmol) and NaCNBH3 (12.5mg, 0.20mmol) in 3mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (62.0mg, 58%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 1.39 - 1.80 (m, 10 H) 1.93 - 2.11 (m, 2 H) 3.59 (s, 3 H) 4.27 -4.52 (m, J=5.31 Hz, 3 H) 6.48 (t, J=5.31 Hz, 1 H) 6.71 (d, J=8.59 Hz, 1 H) 6.76 (d, J=1.01 Hz, 1 H) 7.00 - 7.11 (m, J=1.26 Hz, 1 H) 7.16 - 7.23 (m, 2 H) 7.50 (d, J=9.60
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Hz, 1 H) 8.11 (s, 1 H); HRMS (ESI+) calcd for CeNe (MH+) 375.22917, found 375.2298.
Example 250: 4-(P-cyano-4-(cycloheptylamino)quinolin-6-yl]amino}rnethyl) benzenesulfonamide
Following the procedure described above in Example 4,6-amino-4-cycloheptyla.mino-quinoline-3-carbonitrile (70.0mg, 0.25mmol) was reacted with 4-formyl-benzenesulfonamide (60.2mg, 0.33mmol) and NaCNBH3 (11.0mg, 0.18mmol) in 4mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (72.1 mg, 64%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 1.34 -1.87 (m, 10 H) 1.91-2.05 (m, J=18.19 Hz, 2 H) 4.39 - 4.63 (m, 3 H) 7.18 - 7.24 (m, J=1.77 Hz, 1 H) 7.26 (s, 2 H) 7.32 (dd, J=8.97, 2.15 Hz, 1 H) 7.55 (dd, J=16.30, 8.72 Hz, 3 H) 7.69 - 7.75 (m, 2 H) 8.26(br, s, 1 H) 8.68 (s, 1 H); HRMS (ESI+) calcd for C24H27NSO2S (MH+) 450.19582, found 450.1956.
Example 251: 4-(cycloheptylamino)-6-[(1 H-pyrazol-5-ylmethyl)amino]quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-4-cycloheptylamino-quinoline-3-carbonitrile (50.0mg, 0.18mmol) was reacted with 2H-pyrazole-3-carbaldehyde (26.0mg, 0.27mmol) and NaCNBH3 (7.9mg, 0.13mmol) in 3mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (26.9mg, 42%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 1.37 -1.78 (m, 10 H) 1.95 (d, J=13.90 Hz, 2 H) 4.31 (d, J=5.31 Hz, 2 H) 4.34 -4.42 (m, 1 H) 6.18 (d, .7=2.27 Hz, 2 H) 6.29 (t, J=5.43 Hz, 1 H) 6.90 (d, J=8.84 Hz, 1 H) 7.07 (d, J=2.27 Hz, 1 H) 7.16 (dd, J=8.84, 2.27 Hz, 1 H) 7.45 (d, J=8.84 Hz, 1 H) 7.51 (d, J=1.52 Hz, 1 H) 8.04 - 8.12 (m, 1H); HRMS (ESI+) calcd for C21H24N6 (MH+) 361.21352, found 361.2141.
Example 252: 4-(cycloheptylamino)-6-[(2-morpholin-4-ylethyl)amino]quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-cycloheptylamino-quinoline-3-carbonitrile (70.0mg, 0.25mmol) was reacted with NaCNBH3 (11.0mg, 0.18mmol) and morpholin-4-yl-acetaldehyde (prepared by heating the corresponding dimethyl acetal (70.0mg, 0.40mmol) in 1.2mL concentrated HCI for 5 minutes in a microwave reactor at 110 °C, then neutralizing with solid NaHCO3 until pH=6) in 4 mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (27.6mg,
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28%): 1H NMR (400 MHz, DMS0-D6) 5 ppm 0.92 (t, J=7.07 Hz, 2 H) 1.40 -1.79 (m, 10 H) 1.91 - 2.05 (m, 2 H) 2.39 (s, 2 H) 2.46 - 2.58 (m, 4 H) 3.18 - 3.30 (m, 2 H) 4.28 - 4.50 (m, 2 H) 5.81 (s, 1 H) 6.89 - 7.06 (m, 2 H) 7.14 (dd, J=8.97, 2.15 Hz, 1 H) 7.47 (d, J=8.84 Hz, 1 H) 8.08 (s, 1 H) 8.25 (s, 1 H); HRMS (ESI+) calcd for C23H31N5O (MH+) 394.26014, found 394.26.
Example 253: 4-(cycloheptylamino)-6-{[(1 -oxidopyridin-2-yl)methyl]amino}quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-cycloheptylamino-quinoline-3-carbonitrile (80.0mg, 0.29mmol) was reacted with 1-oxy-pyridine-2-carbaldehyde (45.7mg, 0.37mmol) and NaCNBH3 (12.5 mg, 0.20 mmol) in 3mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (63.3mg, 57%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 1.40 -1.86 (m, 10 H) 1.92 - 2.06 (m, 2 H) 4.45 - 4.71 (m, 3 H) 7.21 - 7.43 (m, 4 H) 7.59 (dd, J-20.46, 9.09 Hz, 1 H) 8.26 - 8.42 (m, 2 H) 8.52 (d, J=8.59 Hz, 1 H) 8.71 (s, 1 H); HRMS (ESI+) calcd for C23H25N5O (MH+) 388.21319, found 388.2134.
Example 254: 4-[(3-chloro-4-fluorophenyl)amino]-6-[(1 H-imidazol-5-ylmethyl)amino]-2-methy!quinoline-3-carbonitrile
Step 1: In a 500mL round-bottomed flask equipped with a condenser, cyano-acetic acid methyl ester (15.7g, 158.2 mmol) and triethyl orthoacetate (25.7g, 158.2 mmol) were taken up in 200mL acetic anhydride and heated to 90°C for 7.5 hours under nitrogen. The reaction mixture was then stirred at RT overnight, and then the solvent was removed under reduced pressure. 10mL Ether and 20mL hexane were added to the dark yellow liquid residue, a crystal of the product was also added to this two-layer solution. The solution was put into the refrigerator. After sitting in the refrigerator overnight, lots of crystals formed, the mixture was filtered, washed with hexane first, then washed with small amount of ether, dried under vacuum overnight to give a white crystal solid as 2-cyano-3-ethoxy-but-2-enoic acid methyl ester (7.1g, 27% yield): 1H NMR (400 MHz, CHLOROFORM-D) 5 ppm 1.44 (t, J=7.07 Hz, 3 H) 2.62 (s, 3 H) 3.78 (s, 3 H) 4.29 (q, J=7.07 Hz, 2 H).
Step 2: The procedure described above in Example 229 was followed, reacting 4-nitro-phenylamine (5.53g, 40.0mmol) with the product from the previous step (7.1g, 42.0mmol) and Cs2CO3 (26.1mg, 80.0mmol) in 25mL DMF. An orange solid was obtained as product methyl-2-cyano-3-[(4-nitrophenyl)amino]but-2-enoate (WAY-199403, 7.8g, 74%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 2.64 (s, 3 H)
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3.89 (s, 3 H) 7.75 (d, J=8.34 Hz, 2 H) 8.42 (d, J=8.84 Hz, 2 H) 11.64 (s, 1 H); HRMS (ESI+) calcd for C12H11N3O4 (MH+) 262.08223, found 262.08234.
Step 3: Following the procedure described above in Example 229, the product from step 2 (6.23g, 23.9mmol) was taken up in 240mL dowtherm A and heated at reflux for 4 hours under argon. Part of the crude product (1.5g) was dissolved in 8mL DMSO and heated to 80°C for 5 minutes, then filtered, washed with small amount of DMSO. To the filtrate was added H2O (150mL), precipitate formed. The mixture was filtered, washed with H2O, dried under vacuum to give 2-methyl-6-nitro-4-oxo-1,4-dihydroquinoline-3-carbonitrile (0.4g, 21%) as a light brown solid: 1H NMR (400 MHz, DMSO-D6) 5 ppm 2.57 (s, 3 H) 7.72 (d, J=9.09 Hz, 1 H) 8.46 (dd, J=9.09, 2.53 Hz, 1 H) 8.71 (d, J=2.78 Hz, 1 H) 12.97 (s, 1 H); HRMS (ESI+) calcd for CnHyNgOs (MH+) 230.05602, found 230.0565.
Step 4: In a 100mL round-bottomed flask equipped with a condenser, the product from step 3 (0.35g, 1.5mmol) was taken up in 10mL POCI3 and heated at reflux for 8 hours. The reaction mixture was then stirred at RT overnight, and then POCI3 was removed under reduced pressure. Ice chips were added to the residue and then saturated NaHCO3 solution was added carefully, the mixture was stirred for 30 minutes, checking the pH periodically to ensure that it remained at or above 8. The mixture was filtered and dried under high vacuum overnight to give a black solid as 4-chloro-2-methyl-6-nitro-quinoline-3-carbonitrile (0.32g, 85% yield).
Step 5: Following the procedure described above in Example 229,4-chloro-2-methyl-6-nitro-quinoline-3-carbonitrile (0.32g, 1.29mmol) was reacted with 3-chloro-4-fluoroaniline (0.23g, 1.55mmol) in 4mL EtOH. After work up, 4-(3-chloro-4-fluoro-phenylamino)-2-methyl-6-nitro-quinoline-3-carbonitrile was obtained as a dark brown solid (0.19g, 40% yield).
Step 6: Following the procedure described above in Example 229,4-(3-chloro-4-fluoro-phenylamino)-2-methyl-6-nitro-quinoline-3-carbonitrile (0.19g, 0.52mmol) was reacted with tin chloride dihydrate (0.59g, 2.61 mmol) in 3mL EtOH. After work up, 6-amino-4-(3-chloro-4-fluoro-phenylamino)-2-methyl-quinoline-3-carbonitrile was obtained as a brown solid (0.14g, 81% yield).
Step 7: Following the procedure described above in Example 4,6~amino-4-(3-chloro-4-fluoro-phenylamino)-2-methyl-quinoline-3-carbonitrile (80.0mg, 0.25mmol) was reacted with 4(5)-imidazolecarboxyaldehyde (30.6mg, 0.32mmol) and NaCNBH3 (10.8mg, 0.17mmol) in 4mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (29.0mg, 29%): 1H NMR (400 MHz, DMSO-D6) 6 ppm 2.48 (s, 3 H) 4.15 (d, J=5.31 Hz, 2 H) 6.32 (s, 1 H) 6.94 (s, 1 H) 7.01 - 7.15 (m, 2 H) 7.22 - 7.38 (m, 3 H) 7.47 - 7.60 (m, 2
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H) 9.16 (s, 1 H); HRMS (ESI+) calcd for CHCIFNe (MH+) 407.11818, found 407.1178.
Example 255: 4-[(3-chloro-4-fluorophenyl)amino]-2-methyl-6-[(pyridin-3-ylmethyl) amino] quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluoro-phenylamino)-2-methyl-quinoline-3-carbonitrile (52.0mg, 0.16mmol) was reacted with pyridine-3-carbaldehyde (22.2mg, 0.21 mmol) and NaCNBH3 (7.0mg, 0.11 mmol) in 3mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (12.7mg, 19%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 2.49 (s, 3 H) 4.30 (d, J=5.81 Hz, 2 H) 6.73 (t, J=5.94 Hz, 1 H) 6.92 - 7.09 (m, 2 H) 7.22 - 7.33 (m, 4 H) 7.58 (d, J=8.84 Hz, 1 H) 7.68 (dd, J=7.83, 1.77 Hz, 1 H) 8.39 (dd, J=4.80,1.52 Hz, 1 H) 8.51 (d, J=1.52 Hz, 1 H) 9.13 (s, 1 H); HRMS (ESI+) calcd for CzsHnCIFNg (MH+) 418.12293, found 418.1233.
Example 256: 4-[(3-chloro-4-fluorophenyl)amino]-6-[(2-pyridin-2-ylcyclopentyl)amino] quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (100mg, 0.32mmol) was reacted with 2-pyridin-2-yl-cyclopentanone (97.0mg, 0.61 mmol) and NaCNBH3 (21.1mg, 0.33mmol) in 5mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (6.0mg, 4%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 1.24 -1.36 (m, 1 H) 1.61 -1.82 (m, 3 H) 1.89 - 2.00 (m, 1 H) 2.13 - 2.21 (m, 1 H) 2.97 - 3.10 (m, 1 H) 3.92 - 4.04 (m, 1 H) 6.37 (d, J=7.83 Hz, 1 H) 6.74 (d, J=2.27 Hz, 1 H) 6.93 - 6.99 (m, 1 H) 7.01 - 7.07 (m, 2 H) 7.11 (d, J=7.83 Hz, 1 H) 7.22 - 7.30 (m, 2 H) 7.41 - 7.48 (m, 2 H) 8.11 (s, 1 H) 8.29 (d, J=3.79 Hz, 1 H) 9.08 (s, 1 H); HRMS (ESI+) calcd for C26H21CIFN5 (MH+) 458.15423, found 458.1545.
Example 257: 4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1 -oxidopyridin-2-yl)methyl]amino}-8-(trifluoromethyl)quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-[(3~ chloro-4-fluorophenyl)amino]-8-(trifluoromethyl)quinoline-3-carbonitrile(80.0mg, 0.21 mmol) was reacted with 1-oxy-pyridine-2-carbaldehyde (53.6mg, 0.43mmol) and NaCNBH3 (18.4mg, 0.29mmol) in 4mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (21.5mg,
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21%): 1H NMR (400 MHz, DMS0-D6) 6 ppm 4.53 (d, J=6.32 Hz, 2 H) 7.11 - 7.28 (m, 6 H) 7.32 (t, J=8.97 Hz, 1 H) 7.44 (dd, J=6.57,2.53 Hz, 1 H) 7.79 (d, J=2.27 Hz, 1 H) 8.23 (d, J=6.57 Hz, 1 H) 8.31 (s, 1 H) 9.45 (s, 1 H); HRMS (ESI+) calcd for C23H14ClF4N5O (MH+) 488.08957, found 488.0894.
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (80mg, 0.26mmol) was reacted with 6-bromo-pyridine-2-carbaldehyde (71.4mg, 0.38mmol) and NaCNBH3 (11.4mg, 0.18mmol) in 4mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (62.0mg, 49%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.68 (d, J=6.06 Hz, 2 H) 7.17 (t, J=6.32 Hz, 1 H) 7.28 (d, J=2.27 Hz, 1 H) 7.30 - 7.39 (m, 1 H) 7.47 - 7.60 (m, 4 H) 7.66 (d, J=7.83 Hz, 1 H) 7.80 - 7.93 (m, 2 H) 8.48 (s, 1 H) 9.44 (s, 1 H); HRMS (ESI+) calcd for C22H14BrCIFN5 (MH+) 482.01779, found 482.0181.
Example 259: 6-{[(6-Bromopyridin-2-yl)methyl]amino}~4-[(3-chloro-4-fluorophenyl)amino]-8-(trifluoromethyl)quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-(trifluoromethyl)quinoline-3-carbonitrile (0.10g, 0.26mmol) was reacted with 6-bromo-pyridine-2-carbaldehyde (73.3mg, 0.39mmol) and NaCNBH3 (11.6mg, 0.18mmol) in 4mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (68.2mg, 47 %): 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.56 (d, J=6.06 Hz, 2 H) 7.24 - 7.33 (m, 2 H) 7.37 - 7.44 (m, 3 H) 7.48 - 7.54 (m, 2 H) 7.70 (t, J=7.71 Hz, 1 H) 7.86 (d, J=2.27 Hz, 1 H) 8.41 (s, 1 H) 9.45 - 9.52 (m, 1 H); HRMS (ESI+) calcd for C23H13BrCIF4N5 (MH+) 550.00517, found 550.0054.
Example 260: 4-[(3-chloro-4-fiuorophenyl)amino]-6-[(1-pyrazin-2-ylethyl)amino] quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (80mg, 0.26mmol) was reacted with 1-pyrazin-2-yl-ethanone (213.3mg, 1.98mmol) and NaCNBH3 (22.8mg, 0.36mmol) in 4mL EtOH. The crude product was purified by preparative HPLC under basic condition, and lyophilized to give a yellow solid as EtaN salt form (8.0mg, 6%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 1.48 (d, J=6.82 Hz, 3 H) 4.77 -
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4.87 (m, 1 H) 6.87 (d, J=8.59 Hz, 1 H) 6.98 (d, J=2.27 Hz, 1 H) 7.03 - 7.10 (m, 1 H) 7.26 - 7.36 (m, 3 H) 7.64 (d, J=9.35 Hz, 1 H) 8.26 (s, 1 H) 8.43 (d, J=2.53 Hz, 1 H) 8.51 (dd, J=2.53,1.52 Hz, 1 H) 8.61 (d, J=1.52 Hz, 1 H) 9.20 (s, 1 H); HRMS (ESI+) alcd for C22H16CIFN6 (MH+) 419.11818, found 419.1176.
Example 261: 4-[(3-fe/f-butyl-1 -methyl-1 H-pyrazol-5-yl)amino]-6-[(1 H-imidazol-5-ylmethyl)amino]quinoline-3-carbonitrile
Step 1: In a microwave vial, 4-chloro-6-nitro-quinoline-3-carbonitrile (0.3g, 1.28mmol) and 5-tert-butyl-2-methyl-2H-pyrazol-3-ylamine (0.37g, 2.43mmol) were taken up in 4mL DME. The vial was crimp-sealed and heated in a microwave reactor at 140 °C for 30 minutes. The content of the vial was evaporated down the solvent and the residue was partitioned between ether and saturated NaHCO3 until pH=7, and stirred for 15 minutes, then evaporated some ether by rotovamp until precipitate formed. The mixture was filtered and dried under high vacuum overnight to give 4-[(3-7e/f-butyl-1 -methyl-1 H-pyrazol-5-yl)amino]-6-nitroquinoline-3-carbonitrile as a yellow solid (0.33g, 74% yield): 1H NMR (400 MHz, DMSO-D6) 5 ppm 1.08 (s, 9 H) 3.16 (s, 3 H) 6.07 (s, 1 H) 7.96 (d, J=8.59 Hz, 1 H) 8.40 (d, J=7.33 Hz, 1 H) 8.61 (s, 1 H) 9.40 (s, 1 H) 10.17 (s, 1 H); HRMS (ESI+) calcd for C18H18N6O2 (MH+) 351.15640, found 351.1563.
Step 2: In a microwave vial, the product from the previous step (50mg, 0.14mmol) was taken up in 1.5mL EtOH and tin chloride dihydrate (161 .Omg, 0.71 mmol) was added. The vial was sealed and heated in a microwave reactor at 110 °C for 10 minutes, until LC/MS analysis showed complete disappearance of the nitroquinoline. This was repeated with a second batch of reagents, with 0.25g of 4-[(3-terf-butyl-1 -methyl-1 H-pyrazol-5-yl)amino]-6-nitroquinoline-3-carbonitrile. The contents of the two vials were combined and then poured into ice water, and the reaction worked up as described above in Example 229. A yellow solid was obtained as product 6-amino-4-[(3-ferf-butyl-1 -methyl-1 H-pyrazol-5-yl)amino]quinoline-3-carbonitrile (109.0mg, 40% yield): 1H NMR (400 MHz, DMSO-D6) 8 ppm 1.18 -1.35 (m, 9 H) 3.62 (s, 3 H) 5.75 (s, 2 H) 6.13 (s, 1 H) 7.21 - 7.36 (m, 2 H) 7.69 (d, J=9.35 Hz, 1 H) 8.25 (s, 1 H) 9.19 (s, 1 H); HRMS (ESI+) calcd for C18H2oN6 (MH+) 321.18222, found 321.182.
Step 3: Following the procedure described above in Example 4, 6-amino-4-[(3-terf-butyl-1 -methyl-1 H~pyrazol-5-yl)amino]quinoline-3-carbonitrile (80mg, 0.25mmol) was reacted with 4(5)-imidazolecarboxyaldehyde (31.2mg, 0.32mmol) and NaCNBH3 (11.0mg, 0.18mmol) in 5mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (31.6mg,
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32%): 1H NMR (400 MHz, DMS0-D6) 8 ppm 1.30 (s, 9 H) 3.65 (s, 3 H) 4.32 (s, 2 H) 6.22 (s, 1 H) 6.55 (s, 1 H) 7.16 (s, 1 H) 7.29 (s, 1 H) 7.43 (d, J=8.34 Hz, 1 H) 7.61 - 7.76 (m, 2 H) 8.29 (s, 1 H) 9.26 (s, 1 H) 11.95 (s, 1 H); HRMS (ESI+) calcd for 024 (MH+) 401.21967, found 401.2205.
Example 262: 4-[(3,4-dimethylisoxazol-5-yl)amino]-6-[(1 H-imidazol-5-ylmethyl)amino] q uinoline-3-carbonitrile
Step 1: Following the procedure described above in Example 229, 4-chloro-6-nitro-quinoline-3-carbonitrile (0.30g, 1.28mmol) was reacted with 3,4-dimethyl-isoxazol-5-ylamine (0.17g, 1.54mmol) in 4mL EtOH. After work up, 4-(3,4-dimethyl-isoxazol-5-ylamino)-6-nitro-q uinoline-3-carbonitrile was obtained as a red solid (0.26g, 52% purify by LC/MS, 34% yield), and was used in the next step without further purification.
Step 2: Following the procedure described above in Example 261, the product from the previous step (0.26g, 0.80mmol) was reacted with tin chloride dihydrate (0.95g, 4.2mmol) in 6mL EtOH. After work up, 6-amino-4-(3,4-dimethyl-isoxazol-5-ylamino)-quinoline-3-carbonitrile was obtained as a yellow solid(0.15g, 64% yield).
Step 3: Following the procedure described above in Example 4, 6-amino-4-(3,4-dimethyl-isoxazol-5-ylamino)-quinoline-3-carbonitrile (150mg, 0.54mmol) was reacted with 4(5)-imidazolecarboxyaldehyde (67.1 mg, OJOmmol) and NaCNBH3 (23.8mg, 0.38mmol) in 7mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (13.9mg, 7%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 1.78 (s, 3 H) 2.11 - 2.32 (m, 3 H) 4.29 (d, J=2.53 Hz, 2 H) 6.65 (s, 1 H) 7.09 (s, 1 H) 7.27 (s, 1 H) 7.43 (s, 1 H) 7.68 (s, 2 H) 8.40 (s, 1 H) 9.91 (br, s, 1 H) 12.02 (br, s, 1 H); HRMS (ESI+) calcd for C19Hi7N7O (MH+) 360.15673, found 360.1573.
Example 263: 6-[(1 H-imidazol-5-ylmethyl)amino]-4-(pyridin-3-ylamino)quinoline-3-carbonitrile
Following the procedure described above in Example 262, 6-amino-4-(pyridin-3-ylamino)-quinoline-3-carbonitrile (140mg, 0.54mmol) with 4(5)-imidazolecarboxyaldehyde (67.3mg, OJOmmol) and NaCNBH3 (23.8mg, 0.38mmol) in 5mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (26.0mg, 14%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.42 (d, J=5.05 Hz, 2 H) 6.73 (t, J=4.80 Hz, 1 H) 7.14 - 7.26 (m, 1 H) 7.38 (d, J=2.27 Hz, 1 H) 7.53 - 7.61 (m, 2 H) 7.79 (d, J=1.01 Hz, 2 H) 7.87 (d,
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J=9.09 Hz, 1 H) 8.46 - 8.58 (m, 2 H) 8.69 (d, J2.53 Hz, 1 H) 9.56 (s, 1 H) 12.14 (br, s, 1 H); HRMS (ESI+) calcd for C19H15N7 (MH+) 342.14617, found 342.1467.
Example 264: 6-[(1 H-imidazol-5-ylmethyI)amino]-4-(pyridin-4-ylamino)quinoline-3-carbonitrile
Following the procedure described above in Example 262, 6-amino-4-(pyridin-4-ylamino)-quinoline-3-carbonitrile (114mg, 0.44mmol) with 4(5)-imidazolecarboxyaldehyde (54.5mg, 0.57mmol)and NaCNBH3 (19.2mg, 0.31 mmol) in 5mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a dark yellow solid (13.8mg, 9%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 4.20 (d, J=5.05 Hz, 2 H) 6.75 (s, 1 H) 6.88 (s, 2 H) 6.94 - 7.01 (m, 2 H) 7.47 (dd, J=9.09, 2.27 Hz, 1 H) 7.60 (s, 1 H) 7.81 (d, J=9.09 Hz, 1 H) 8.31 (s, 2 H) 8.59 (s, 1 H) 9.61 (br, s, 1 H) 11.94 (br, s, 1 H); HRMS (ESI+) calcd for Ci9H15N7 (MH+) 342.14617, found 342.1467.
Example 265: 4-[(3-Chloro-4-fluorophenyl)aminoJ-8-fluoro-6-[(1 H-imidazol-5-ylmethyl) amino] quinoline-3-carbonitrile
Step 1: A 250mL round-bottomed flask was charged with 2-fluoro-4-nitro-phenylamine (5.0g, 32.0mmol), ethyl (ethoxymethylene)cyanoacetate (5.96g, 35.2mmol) and 60mL DMF. The mixture was stirred vigorously to dissolve both reagents, Cs2CO3 (20.86g, 64.0mmol) was added, and the reaction mixture was stirred at RT for 3.5 hours. To work up, the contents of the flask were poured into 500mL water and the precipitate collected by suction filtration, washed three times with water, then washed twice with ether, and dried under vacuum to give an orange solid as crude, and was purified by dissolving the crude in 60mL DMF, then 800mL EtOAc was added. The solution was then washed with brine twice (2 * 200mL), separated. The organic layer was dried over Na2SO4l filtered, concentrated down to a brown-red solid. Ether was added, the resulting suspension was filtered, washed with ether, dried under high vacuum overnight to give 2-cyano-3-(2-fluoro-4-nitro-phenylamino)-acrylic acid ethyl ester as a brown-red solid (6.6g, 74% yield): (50%) 1H NMR (400 MHz, DMSO-D6) 5 ppm 1.21 (t, .7=7.07 Hz, 3 H) 4.11 (q, J=7.07 Hz, 2 H) 7.35 (q, 1 H) 7.95 - 8.12 (m, 3 H); (50%) 1H NMR (400 MHz, DMSO-D6) D ppm 1.21 (t, J=7.07 Hz, 3 H) 4.28 (q, J=7.07 Hz, 2 H) 8.19 (q, J=8.84 Hz, 1 H) 8.32 (dd, J=10.99, 2.40 Hz, 1 H) 8.39 (s, 1 H) 8.82 (s, 1 H) 11.00 (s, 1 H).
Step 2: Following the procedure described above in Example 229, the product from the previous step (6.48g, 23.0mmol) was taken up in 300mL Dowtherm and heated at reflux for 3 hours under argon. After work up, 8-fluoro-6-
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nitro-4-oxo-1,4-dihydroquinoline-3-carbonitrile was obtained as a brown solid (2.17g, 40%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 8.49 (dd, J=10.48, 2.40 Hz, 1 H) 8.55 - 8.62 (m, 1 H) 8.76 (s, 1 H) 13.40 (br, s, 1 H); HRMS (ESI+) calcd for C10H4FN3O3 (MH+) 234.03095, found 234.0308.
Step 3: In a 100mL round-bottomed flask equipped with a condenser, the product from step 2 (2.1g, 8.9mmol) was taken up in 30mL POCI3 and heated at reflux for 7.5 hours. The reaction mixture was then stirred at RT overnight, and then POC!3 was removed under reduced pressure. Ice chips were added to the residue and then saturated NaHCO3 solution was added carefully, the mixture was stirred for 30 minutes, checking the pH periodically to ensure that it remained at or above 8. The mixture was filtered and dried under high vacuum overnight to give 4-chloro-8-fluoro-6-nitro-quinoline-3-carbonitrile as a brown solid (2.23g, 100% yield): 1H NMR (400 MHz, DMSO-D6) 8 ppm 8.71 (dd, J=9.85, 2.27 Hz, 1 H) 8.86 - 8.92 (m, 1 H) 9.46 (s, 1 H).
Step 4: Following the procedure described above in Example 229,4-chloro-8-fluoro-6-nitro-quinoline-3-carbonitrile (0.60g, 2.38mmol) was reacted with 3-chloro-4-fluoroaniline (0.42g, 2.86mmol) in 10mL EtOH. After work up, 4-[(3-chloro-4-fluorophenyl)amino]-8-fluoro-6-nitroquinoline-3-carbonitrile was obtained as a brown solid (0.7g, 82% yield): 1H NMR (400 MHz, DMSO-D6) 5 ppm 7.51 - 7.58 (m, 1 H) 7.62 (t, J=8.97 Hz, 1 H) 7.82 (dd, J=6.44, 2.15 Hz, 1 H) 8.59 (dd, J=10.11, 2.02 Hz, 1 H) 8.91 (s, 1 H) 9.52 (s, 1 H) 10.73 (s, 1 H); HRMS (ESI+) calcd for C16H7CIF2N4O2 (MH+) 361.02983, found 361.0294.
Step 5: Following the procedure described above in Example 229,4-[(3-chloro-4-fluorophenyl)amino]-8-fluoro-6-nitroquinoline-3-carbonitrile(1.55g, 4.30mmol) was reacted with tin chloride dihydrate (4.85g, 21.5mmol) in 60mL EtOH. After work up, 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-fluoroquinoline-3-carbonitrile was obtained as a light brown solid (1.42g, 100% yield): 1H NMR (400 MHz, DMSO-D6) 5 ppm 5.94 (s, 2 H) 6.98 - 7.10 (m, 2 H) 7.15 - 7.29 (m, 1 H) 7.35 - 7.48 (m, 2 H) 8.26 - 8.39 (m, 1 H) 9.45 (br, s, 1 H); HRMS (ESI+) calcd for C16H9CIF2N4 (MH+) 331.05566, found 331.0562.
Step 6: Following the procedure described above in Example 4, 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-fluoroquinoline-3-carbonitrile (70mg, 0.21 mmol) was reacted with 4(5)-imidazolecarboxyaldehyde (28.5mg, 0.30mmol) and NaCNBH3 (9.3 mg, 0.15 mmol) in 4mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a bright yellow solid (26.7mg, 31%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.19 (d, J=5.05 Hz, 2 H) 6.61 (t, J=5.05 Hz, 1 H) 6.95 - 7.07 (m, 2 H) 7.15 (d, J=12.88, 2.02 Hz, 1 H) 7.19 -
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7.28 (m, 1 H) 7.38 (t, J=9.Uy HZ, 1 H) 7.48 (dd, J=6.57, 2.53 Hz, 1 H) 7.56 (d, J=1.01 Hz, 1 H) 8.11 (s, 1 H) 8.23 (s, 1 H) 9.40 (s, 1 H); HRMS (ESI+) calcd for C20H13CIF2N6 (MH+) 411.09310, found 411.0925.
Example 266: 4-[(3-chloro-4-fluorophenyi)amino]-8-fluoro-6-{[(1-oxidopyridin-2-yl) methyl]amino}quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-fluoroquinoline-3-carbonitrile (70mg, 0.21 mmol) was reacted with 1-oxy-pyridine-2-carbaldehyde (54.6mg, 0.44mmol) and NaCNBH3 (9.3 mg, 0.15mmol) in 4mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (5.6mg, 6%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.52 (d, J=6.06 Hz, 2 H) 6.86 - 7.08 (m, 2 H) 7.12 - 7.41 (m, 6 H) 7.41 - 7.53 (m, 1 H) 8.17 - 8.35 (m, 2 H) 9.38 (s, 1 H); HRMS (ESI+) calcd for C22H14CIF2N5O (MH+) 438.09277, found 438.092.
Example 267: 4-[(3-chloro-4-fluorophenyl)amino]-8-fluoro-6-[(1H-pyrazol-5-ylmethyl) amino] quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-fluoroquinoline-3-carbonitrile (80mg, 0.24mmol) was reacted with 2H-pyrazole-3-carbaldehyde (34.6mg, 0.36mmol) and NaCNBH3 (10.6mg, 0.17mmol) in 4mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a bright yellow solid (10.3mg, 10%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.29 (d, J=5.05 Hz, 2 H) 6.13 - 6.24 (m, J=2.02 Hz, 1 H) 6.71 (d, J=6.57 Hz, 1 H) 7.05 (s, 1 H) 7.11 - 7.19 (m, 1 H) 7.19 -7.27 (m, 1 H) 7.30 - 7.42 (m, 1 H) 7.47 (dd, 7=6.69, 2.40 Hz, 2 H) 7.56 (s, 1 H) 8.24 (s, 1 H) 9.43 (s, 1 H); HRMS (ESI+) calcd for C2oH13CIF2N6 (MH+) 411.09310, found 411.0932.
Example 268: 4-[(3-Chloro-4-fluorophenyl)amino]-8-fluoro-6-{[(1 -methyl-1 H-imidazol-2-yl)methyl]amino}quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-fluoroquinoline-3-carbonitrile (80mg, 0.24mmol) was reacted with 1-methyl-1 H-imidazole-2-carbaldehyde (39.6mg, 0.36mmol) and NaCNBH3 (10.6mg, 0.17mmol) in 5mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a bright yellow solid (39.3mg, 39%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 3.58 (s, 3 H) 4.33 (d, J=4.80 Hz, 2 H) 6.69 - 6.83 (m, 2 H) 7.01 - 7.14 (m, 2 H) 7.19 - 7.26 (m, 2 H) 7.38 (t,
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J=9.09 Hz, 1 H) 7.47 (dd, J=6.57, 2.53 Hz, 1 H) 8.26 (s, 1 H) 9.41 (s, 1 H); HRMS (ESI+) calcd for C2iH15CIF2N6 (MH+) 425.10875, found 425.1094.
Example 269: 4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1,5-dimethyl-1 H-imidazol-4-yl) methyl] amino}-8-fluoroquinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-fluoroquinoline-3-carbonitrile (80mg, 0.24mmol) was reacted with 1-methyl-1H-imidazole-2-carbaldehyde (35.8mg, 0.29mmol) and NaCNBH3 (10.6mg, 0.17mmol) in 5mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a bright yellow solid (13.2 mg, 13%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 2.27 (s, 3 H) 3.62 (s, 3 H) 4.23 (d, J=4.55 Hz, 2 H) 6.59 (t, .7=4.04 Hz, 1 H) 7.16 (d, J=1.52 Hz, 1 H) 7.34 (d, J=13.14, 2.02 Hz, 1 H) 7.37 - 7.45 (m, 1 H) 7.56 (t, J=8.97 Hz, 1 H) 7.60 - 7.68 (m, 2 H) 8.41 (s, 1 H) 9.54 (s, 1 H); HRMS (ESI+) calcd for C22H17CIF2N6 (MH+) 439.12440, found 439.1248.
Example 270: 4-[(3-Chloro-4-fluorophenyl)amino]-8-fluoro-6-{[(1 -oxidopyridin-4-yl) methyl] amino}quinoline-3-carbonitrile
Step 1: In a microwave vial, (1-oxy-pyridin-4-yl)-methanol (0.45g, 3.60mmol) was taken up in 2mL each CH2CI2 and 1,4-dioxane, and activated MnO2 (1.09g, 12.6mmol) was added. The vial was crimp-sealed and heated in a microwave reactor at 140 °C for 5 minutes, until LC-MS analysis showed complete disappearance of the starting material. The contents of the vial were then rinsed into a 500mL Erlenmeyer flask and stirred with 200mL H2O for 30 minutes. The suspension was then filtered to remove MnO2, and evaporated to give product isonicotinaldehyde 1-oxide of sufficient purity to be used in the next step (0.44g, 99% yield): 1H NMR (400 MHz, DMSO-D6) 5 ppm 7.90 (d, J=5.56 Hz, 2 H) 8.41 (d, J=5.81 Hz, 2 H) 9.97 (s, 1 H).
Step 2: Following the procedure described above in Example 4, 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-fluoroquinoline-3-carbonitrile(80mg, 0.24mmol) was reacted with 1-oxy-pyridine-4-carbaldehyde (44.3mg, 0.36mmol) and NaCNBH3 (10.6mg, 0.17mmol) in 5mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (9.2mg, 9%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.49 (d, J=6.06 Hz, 2 H) 7.04 - 7.11 (m, 1 H) 7.16 (t, J=6.19 Hz, 1 H) 7.24 (dd, J=12.63, 2.02 Hz, 1 H) 7.31 - 7.39 (m, 1 H) 7.43 (d, J=6.82 Hz, 2 H) 7.51 (t, J=8.97 Hz, 1 H) 7.59 (dd, J=6.44,2.65 Hz, 1 H)
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8.24 (d, J=6.82 Hz, 2 H) 8.39 (s, 1 H) 9.47 (s, 1 H); HRMS (ESI+) calcd for C22H14CIF2N5O (MH+) 438.09277, found 438.0929.
Example 271: Preparation of 8-Chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1 -oxidopyridin-4-yl)methyl]amino}quinoline-3-carbonitrile
Step 1: Following the procedure described above in Example 229,4-chloro-8-chloro-6-nitro-quinoline-3-carbonitrile (2.0g, 7.46mmol) was reacted with 3-chloro-4-fluoroaniline (1.3g, 8.95mmol) in 30mL EtOH. After work up, 8-chloro-4-(3-chloro-4-fluoro-phenylamino)-6-nitro-quinoline-3-carbonitrile was obtained as a yellow solid (2.0g, 71% yield).
Step 2: Following the procedure described above in Example 229, 8-chloro-4-(3-chloro-4-fluoro-phenylamino)-6-nitro-quinoline-3-carbonitrile (1.73g, 4.59mmol) was reacted with tin chloride dihydrate (4.14g, 18.35mmol) in 70mL EtOH. After work up, 6-amino-8-chloro-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile was obtained as a brown solid (1.4g, 88% yield).
Step 3: Following the procedure described above in Example 4, 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-chloroquinoline-3-carbonitrile(80mg, 0.23mmol) was reacted with 1-oxy-pyridine-4-carbaldehyde (42.5mg, 0.35mmol) and NaCNBH3 (10.1mg, 0.16mmol) in 4mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (10.7mg, 10%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 4.36 (d, J=5.81 Hz, 2 H) 7.03 (t, J=6.06 Hz, 1 H) 7.08 (d, J=2.27 Hz, 1 H) 7.17 - 7.24 (m, 1 H) 7.30 (d, J=7.07 Hz, 2 H) 7.37 (t, J=8.97 Hz, 1 H) 7.45 (dd, J=6.57, 2.53 Hz, 1 H) 7.48 (d, J=2.27 Hz, 1 H) 8.10 (d, J=7.07 Hz, 2 H) 8.34 (s, 1 H) 9.35(s, 1 H); HRMS (ESI+) calcd for C22H14Cl2FN5O (MH+) 454.06322, found 454.0631.
Example 272: 8-Chloro-4-(3-chIoro-4-fluoro-phenylamino)-6-[(pyrimidin-5-ylmethyl)-amino]-quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-chloroquinoline-3-carbonitrile(80mg, 0.23mmol) was reacted with pyrimidine-5-carbaldehyde (52.3mg, 0.48mmol) and NaCNBH3 (10.1 mg, 0.16mmol) in 5mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (32.8mg, 33%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.47 (d, J=5.81 Hz, 2 H) 7.04 (t, J=5.81 Hz, 1 H) 7.22 (d, J=2.53 Hz, 1 H) 7.24 - 7.32 (m, 1 H) 7.43 (t, J=8.97 Hz, 1 H) 7.49 - 7.58 (m, 2 H) 8.41 (s, 1 H) 8.84 (s, 2 H) 9.11 (s, 1 H) 9.45 (s, 1 H); HRMS (ESI+) calcd for C2iH13CI2FN6 (MH+) 439.06355, found 439.0627.
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Example 273: 8-Chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-methoxy-3-(2-morpholin-4-ylethoxy)benzyl]amino}quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-chloroquinoline-3-carbonitrile(70mg, 0.20mmol) was reacted with 4-methoxy-3-(2-morpholin-4-yl-ethoxy)-benzaldehyde (79.6mg, 0.30mmol) and NaCNBH3 (8.8mg, 0.14mmol) in 4mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (53.5mg, 45%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 2.39 - 2.45 (m, 4 H) 2.62 (t, J=5.81 Hz, 2 H) 3.54 (t, 4 H) 3.72 (s, 3 H) 4.01 (t, .7=5.94 Hz, 2 H) 4.29 (d, .7=5.56 Hz, 2 H) 6.91 (d, 3 H) 7.07 (s, 1 H) 7.19 (d, J=2.27 Hz, 1 H) 7.22 - 7.30 (m, 1 H) 7.44 (t, J=8.97 Hz, 1 H) 7.50 (dd, .7=6.57, 2.78 Hz, 1 H) 7.54 (d, J=2.27 Hz, 1 H) 8.38 (s, 1 H) 9.44 (s, 1 H); HRMS (ESI+) calcd for C30H2aCI2FN5O3 (MH+) 596.16260, found 596.1622.
Example 274: 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(6-morpholin-4-ylpyridin-2-yl)methyl]amino}quinoline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-4-|"(3-chloro-4-fluorophenyl)amino]-8-chloroquinoline-3-carbonitrile (80mg, 0.23mmol) was reacted with 6-morpholin-4-yl-pyridine-2-carbaldehyde (49.0mg, 0.25mmol) and NaCNBH3 (10.1mg, 0.16mmol) in 4mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (55.3mg, 46%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 3.37 - 3.51 (m, 4 H) 3.61 - 3.73 (m, 4 H) 4.36 (d, .7=6.06 Hz, 2 H) 6.68 (t, J=7.83 Hz, 2 H) 6.92 (t, J=6.06 Hz, 1 H) 7.17 -7.31 (m, 2 H) 7.42 (t, J=8.97,1 H) 7.45 - 7.55 (m, 2 H) 7.65 (d, .7=2.27 Hz, 1 H) 8.39 (s, 1 H) 9.46 (s, 1 H); HRMS (ESI+) calcd for C26H2iCI2FN6O (MH+) 523.12107, found 523.1207.
Example 275: 8-Chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1 -oxido-6-(trifluoromethyl)pyridin-3-yl]methyl}amino)quinoline-3-carbonitrile
Step 1: In a 50mL round-bottomed flask, 6-trifluoromethyl-nicotinic acid (0.50g, 2.62mmol) was taken up in 6mL dry THF and cooled down to 0°C. Then solid LiAIH4 was added in 3 portions (3 * 33.1mg, 2.62mmol) at 0°C. The reaction mixture was then allowed to warm up to RT and stirred at RT for 2 days, until TLC analysis showed complete disappearance of starting material. And the reaction mixture was quenched with 1N NaOH solution at 0°C. Then extracted the mixture with EtOAc 3 times, the combined EtOAc layers were dried over Na2SO4, filtered
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and concentrated down to give the product (6-trifluoromethyl-pyridin-3-yl)-methanol as a yellow oil (0.33g, 70% yield): 1H NMR (400 MHz, DMSO-D6) 5 ppm 4.65 (s, 2 H) 5.53 (s, 1 H) 7.87 (d, J=8.08 Hz, 1 H) 8.00 (d, J=8.08 Hz, 1 H) 8.70 (s, 1 H).
Step 2: In a 50mL round-bottomed flask equipped with a condenser, the product from the previous step (0.33 g, 1.8 mmol) was taken up in 10mL CH2CI2/ MeOH (9:1, v/v). Then MMPP (magnesium monoperoxyphthalate hexahydrate) (2.96g, 6.0mmol) was added. The reaction mixture was heated at reflux for 2 days under nitrogen and then allowed it to cool to RT. The white suspension was filtered, washed with CH2CI2,the filtrate obtained was concentrated down to give a liquid as crude. The crude product was purified by preparative HPLC to give the product (1-oxy-6-trifluoromethyl-pyridin-3-yl)-methanol as a colorless liquid (30.0mg, 9% yield): 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.56 (d, J=5.56 Hz, 2 H) 5.63 (t, J=5.81 Hz, 1 H) 7.44 (d, J=8.34 Hz, 1 H) 7.91 (d, J=8.34 Hz, 1 H) 8.35 (s, 1 H).
Step 3: In a microwave vial, the product from step 2 (30.0mg, 0.16mmol) was taken up in 1mL each CH2CI2 and 1,4-dioxane, and activated MnO2 (47.3mg, 0.54mmol) was added. The vial was crimp-sealed and heated in a microwave reactor at 120 °C for 35 minutes, until LC-MS analysis showed complete disappearance of starting material. The contents of the vial were then rinsed into a 500mL Erlenmeyer flask and stirred with 50mL H2O for 30 minutes. The suspension was then filtered to remove MnO2, and evaporated to give product 1-oxy-6-trifluoromethyl-pyridine-3-carbaldehyde of sufficient purity to be used in the next step (30.0 mg, 100% yield).
Step 4: Following the procedure described above in Example 4, 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-chloroquinoline-3-carbonitrile(70mg, 0.20mmol) was reacted with 1-oxy-6-trifluoromethyl-pyridine-3-carbaldehyde (38.2mg, 0.20mmol) and NaCNBH3 (8.8mg, 0.14mmol) in 4mL EtOH. The crude product was purified by preparative HPLC under basic condition, and lyophilized to give a yellow solid as EtaN salt form (4.0mg, 1%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 4.50 (d, v/=6.06 Hz, 2 H) 7.02 - 7.11 (m, 1 H) 7.16 - 7.28 (m, 2 H) 7.40 (t, J=9.09 Hz, 1 H) 7.46 (s, 2 H) 7.52 (s, 1 H) 7.92 (d, J=8.34 Hz, 1 H) 8.36 (s, 1 H) 8.46 (s, 1 H) 9.39 (s, 1 H); HRMS (ESI+) calcd for CHCINsO (MH+) 522.05060, found 522.0502.
Example 276: 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]amino}quinoline-3-carbonitrile
Step 1: In a microwave vial, (4-methoxy-3,5-dimethyl-pyridin-2-yl)-methanol (0.20g, 1.2mmol) was taken up in 1mL each CH2CI2 and 1,4-dioxane, and activated
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MnO2 (0.36g, 4.2mmol) was added. The vial was crimp-sealed and heated in a microwave reactor at 140 °C for 7 minutes, until LC-MS analysis showed complete disappearance of starting material. The contents of the vial were then rinsed into a 500mL Erlenmeyer flask and stirred with 100mI_ H2O for 30 minutes. The suspension was then filtered to remove MnO2, and evaporated to give product 4-methoxy-3,5-dimethyl-pyridine-2-carbaldehyde of sufficient purity to be used in the next step (40.0 mg, 33% yield).
Step 2: Following the procedure described above in Example 4,6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-chloroquinoline-3-carbonitrile (70mg, 0.20mmol) was reacted with 4-methoxy-3,5-dimethyl-pyridine-2-carbaldehyde (105.0mg, 0.64mmol) and NaCNBH3 (8.8mg, 0.14mmol) in 4mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (42.0mg, 42%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 2.23 (d, J=5.81 Hz, 6 H) 3.74 (s, 3 H) 4.38 (d, J=4.04 Hz, 2 H) 6.85 (t, J=3.79 Hz, 1 H) 7.22 (d, J=2.53 Hz, 1 H) 7.27 - 7.33 (m, 1 H) 7.45 (t, J=9.09 Hz, 1 H) 7.50 - 7.57 (m, 1 H) 7.75 (d, J=2.27 Hz, 1 H) 8.22 (s, 1 H) 8.41 (s, 1 H) 9.46 (s, 1 H); HRMS (ESI+) calcd for C25H20Cl2FN5O (MH+) 496.11017, found 496.1095.
Example 277: 8-Chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(4-methoxy-3,5-dimethyl-1-oxidopyridin-2-yl)methyl]amino}quinoline-3-carbonitrile
Step 1: In a 100mL round-bottomed flask, (4-methoxy-3,5-dimethyl-pyridin-2-yl)-methanol (1.0g, 6.0mmol) was taken up in 50mL CH2CI2/ MeOH (9:1, v/v). Then MMPP (magnesium monoperoxyphthalate hexahydrate) (5.92g, 12.0mmol) was added. The reaction mixture was stirred at RT overnight under nitrogen, then filtered and washed with CH2CI2. The filtrate obtained was concentrated down to give a light yellow gum as crude. The crude product was purified by preparative HPLC to give the product (4-methoxy-3,5-dimethyl-1-oxy~pyridin-2-yl)-methanol as a colorless sticky oil (0.65g, 59% yield): 1H NMR (400 MHz, DMSO-D6) 5 ppm 2.16 (s, 3 H) 2.24 (s, 3 H) 3.70 (s, 3 H) 4.69 (s, 2 H) 8.11 (s, 1 H).
Step 2: In a microwave vial, the product from the previous step (0.16g, 0.86mmol) was taken up in 1 mL each CH2CI2 and 1,4-dioxane, and activated MnO2 (0.26g, 3.0mmol) was added. The vial was crimp-sealed and heated in a microwave reactor at 140 CC for 8 minutes, until LC-MS analysis showed complete disappearance of starting material. The contents of the vial were then rinsed into a 500mL Erlenmeyer flask and stirred with 100mL H2O for 30 minutes. The suspension was then filtered to remove MnO2, and evaporated to give product 4-methoxy-3,5-dimethyl-1-oxy-pyridine-2-carbaldehyde of sufficient purity to be used
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in the next step (0.15g, 99% yield): 1H NMR (400 MHz, DMS0-D6) 5 ppm 2.37 -2.89 (m, 6 H) 3.73 (s, 3 H) 8.24 (s, 1 H) 10.29 (s, 1 H).
Step 3: Following the procedure described above in Example 4,6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-chloroquinoline-3-carbonitrile(80mg, 0.23mmol) was reacted with 4-methoxy-3,5-dimethyl-1-oxy-pyridine-2-carbaldehyde (83.5mg, 0.46mmol) and NaCNBH3 (10.1mg, 0.16mmol) in 5mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (23.0mg, 20%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 2.18 (s, 3 H) 2.28 (s, 3 H) 3.70 (s, 3 H) 4.61 (d, J=5.05 Hz, 2 H) 6.52 (s, 1 H) 6.70 - 6.81 (m, 1 H) 7.31 (s, 1 H) 7.45 (t, .7=9.09 Hz, 1 H) 7.47 - 7.61 (m, 2 H) 8.19 (s, 1 H) 8.39 (s, 1 H) 9.43 (s, 1 H); HRMS (ESI+) calcd for C2sH2oCI2FN502 (MH+) 512.10508, found 512.1044.
Example 278: 8-Chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[(quinolin-4-ylmethyl) amino] quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-chloroquinoline-3-carbonitrile(80mg, 0.23mmol) was reacted with quinoline-4-carbaldehyde (108.4mg, 0.70mmol) and NaCNBH3 (10.1mg, 0.16mmol) in 4mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (13.8mg, 12%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.94 (d, J=5.81 Hz, 2 H) 7.14 (t, J=6.19 Hz, 1 H) 7.19 - 7.26 (m, 2 H) 7.36 (t, J=9.09 Hz, 1 H) 7.42 - 7.51 (m, 2 H) 7.63 (d, J=2.27 Hz, 1 H) 7.67 (t, J=7.71 Hz, 1 H) 7.80 (t, J=6.95 Hz, 1 H) 8.05 - 8.09 (m, 1 H) 8.18 (d, J=8.34 Hz, 1 H) 8.41 (s, 1 H) 8.84 (d, J=4.29 Hz, 1 H) 9.39 (s, 1 H); HRMS (ESI+) calcd for C26H16CI2FN5 (MH+) 488.08395, found 488.0832.
Example 279: 8-Chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[(1 H-tetrazol-5-ylmethyl)amino]quinoline-3-carbonitrile
Step 1: In a 100mL round-bottomed flask, diethoxy acetonnitrile (1.0g, 7.7mmol) was taken up in 35mL DEE. Then azidotributyltin (3.34g, 10.1mmol) was added. The reaction mixture was heated at reflux overnight under nitrogen, then evaporated the solvent in vacuo to a black residue. 20mL 1.25M HCI in MeOH was added to the residue, the mixture was heated at reflux for 3 hours, then allowed it cool down to RT and evaporated down solvent to give a black oil as crude, and was used in the next step directly without further purification.
Step 2: Following the procedure described above in Example 4,6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-chloroquinoline-3-carbonitrile(200mg, 0.58mmol) was reacted with 1 H-tetrazole-5-carbaldehyde (141.2mg, 1.44mmol)
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and NaCNBH3 (25.3mg, 0.40mmol) in 5mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (17.0mg, 7%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.45 (d, J=5.05 Hz, 2 H) 6.74 (t, J=4.93 Hz, 1 H) 7.26 (d, J=2.27 Hz, 1 H) 7.28 - 7.34 (m, 1 H) 7.45 (t, J=9.09 Hz, 1 H) 7.54 (dd, J=6.57, 2.78 Hz, 1 H) 7.68 (d, J=2.27 Hz, 1 H) 8.37 (s, 1 H) 9.54 (s, 1 H); HRMS (ESI+) calcd for CujHnCfeFNa (MH+) 429.05405, found 429.0539.
Example 280: 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[4-(methylamino)-2-(methylthio)pyrimidin-5-yl]methyl}amino)quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-[(3-chloro-4-fiuorophenyl)amino]-8-chloroquinoline-3-carbonitrile(80mg, 0.23mmol) was reacted with 4-methylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (59.0mg, 0.32mmol) and NaCNBH3 (10.1mg, 0.16mmol) in 4mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (34.1mg, 29%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 2.42 (s, 3 H) 2.86 (d, J=4.55 Hz, 3 H) 4.11 (d, J=4.55 Hz, 2 H) 6.65 (t, J=5.05 Hz, 1 H) 7.09 (t, J=4.80 Hz, 1 H) 7.18 (d, J=2.27 Hz, 1 H) 7.24 - 7.32 (m, 1 H) 7.44 (t, J=8.97 Hz, 1 H) 7.49 - 7.56 (m, 2 H) 7.92 (s, 1 H) 8.40 (s, 1 H) 9.50 (s, 1 H); HRMS (ESI+) calcd for C23H18CI2FN7S (MH+) 514.07782, found 514.0785.
Example 281: 8-Chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[2-(methylthio) pyrimidin-5-yl]methyl}amino)quinoline-3-carbonitrile
Following the procedure described above in Example 4,6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-chloroquinoline-3-carbonitrile (70mg, 0.20mmol) was reacted with 2-methylsulfanyl-pyrimidine-5-carbaldehyde (50.0mg, 0.32mmol) and NaCNBH3 (8.8mg, 0.14mmol) in 3mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (36.8mg, 38%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 2.50 - 2.54 (m, 3 H) 4.37 (d, J=5.56 Hz, 2 H) 6.98 (t, J=5.68 Hz, 1 H) 7.23 (d, J=2.27 Hz, 1 H) 7.26 - 7.33 (m, 1 H) 7.45 (t, J=8.97 Hz, 1 H) 7.49 - 7.58 (m, 2 H) 8.41 (s, 1 H) 8.68 (s, 2 H) 9.47 (s, 1 H); HRMS (ESI+) calcd for C22HCIzFNeS (MH+) 485.05127, found 485.0532.
Example 282: 8-Chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[2-(methylsulfonyl) pyrimidin-4-yl]methyl}amino)qu!iioline-3-carbonitrile
Following the procedure described above in Example 4, 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-chloroquinoline-3-carbonitrile (40mg, 0.12mmol) was reacted with 2-methanesulfonyl-pyrimidine-4-carbaldehyde (22.0mg,
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0.13mmol) and NaCNBH3 (b.3mg, 0.08mmol) in 3mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (2.3mg, 4%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 3.39 (s, 3 H) 4.73 (d, J=6.32 Hz, 2 H) 6.55 (s, 1 H) 7.20 - 7.30 (m, 3 H) 7.43 (t, J=8.97 Hz, 1 H) 7.51 (dd, J=6.57, 2.53 Hz, 1 H) 7.66 (d, J=2.53 Hz, 1 H) 7.72 (d, J=5.31 Hz, 1 H) 8.39 - 8.42 (m, 1 H) 8.99 (d, J=5:31 Hz, 1 H) 9.44 (s, 1 H); HRMS (ESI+) calcd for C22H15CI2FN6O2S (MH+) 517.04110, found 517.0427.
Example 283: 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[2-(1 H-imidazol-5-yl) ethyl]amino}quinoline-3-carbonitrile
Step 1: In a microwave vial, triphenyl phosphine (0.50g, 1.91mmol) was taken up in 4mL toluene, and bromo methoxy methane (0.29g, 2.29mmol) was added. The vial was crimp-sealed and heated in a microwave reactor at 140 °C for 5 minutes, until LC-MS analysis showed complete disappearance of starting material. The content of the vial was transferred to a round-bottomed flask and evaporated solvent in vacuo. The solid obtained was suspended in toluene, then filtered, washed with toluene to give the product methoxymethyl-triphenyl-phosphonium; bromide as a white solid (0.60g, 81% yield): 1H NMR (400 MHz, DMSO-D6) 8 ppm 3.48 (s, 3 H) 5.63 (d, J=5.05 Hz, 2 H) 7.70 - 7.86 (m, 15 H).
Step 2: In a microwave vial, the product from the previous step (300.0mg, 0.77mmol) was taken up in 4mL THF, and NaH (46.5g, 0.46mmol, 60% in mineral oil) was added to this suspension. The vial was crimp-sealed and heated in a microwave reactor at 80 °C for 5 minutes, then trityl imidazole aldehyde (104.9mg, 0.31 mmol) was added to the reaction mixture and stirred at RT for 3 hours, until LC-MS analysis showed complete disappearance of starting material. The solvent was evaporated and the crude product was purified by flash chromatography over silica gel (5% MeOH in CH2CI2) to give the product 5-(2-methoxy-vinyl)-1-trityl-1H-imidazole as a white solid (90.0mg, 79% yield).
Step 3: In a 50 mL round-bottomed flask equipped with a condenser, the product from step 3 (90mg, 0.25mmol) was taken up in 5mL 1N HCI and 3mLTHF and heated at 60°C for 2 hours under nitrogen, until LC-MS analysis showed complete disappearance of starting material. The reaction mixture was then allowed to cool to RT and evaporated solvent in vacuo to give a white solid as product (3H-imidazol-4-yl)-acetaldehyde of sufficient purity to be used in the next step (26mg, 96% yield).
Step 4: Following the procedure described above in Example 4,6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-chloroquinoline-3-carbonitrile (85mg, 0.24mmol)
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was reacted with (3H-imidazol-4-yl)-acetaldehyde (26.0mg, 0.24mmol) and NaCNBH3 (13.8mg, 0.22mmol) in 5mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (15.1mg, 14%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 2.83 (t, J=7.07 Hz, 2 H) 3.31 - 3.44 (m, 2 H) 6.56 (t, J=5.68 Hz, 1 H) 6.87 (s, 1 H) 7.12 (d, J=2.27 Hz, 1 H) 7.24 - 7.35 (m, 1 H) 7.45 (t, J=9.09 Hz, 1 H) 7.49 (d, J=2.27 Hz, 1 H) 7.51 - 7.60 (m, 2 H) 8.20 (s, 1 H) 8.37 (s, 1 H) 9.53 (s, 1 H); HRMS (ESI-) calcd for C21H15CI2FN6 (MH-) 439.06465, found 439.0661.
Example 284: 4-[(3-chloro-4-fluorophenyl)amino]-6-[(1 H-imidazol-5-ylmethyl)amino]-8-(methylsulfinyl)quinoline-3-carbonitrile
Step 1: In a 50mL round-bottomed flask, 8-fluoro-4-hydroxy-6-nit.ro-quinoline-3-carbonitrile (0.50g, 2.14mmol) was taken up in 9mL DMPU. MeSNa (0.57g, 8.1mmol) was added. The reaction mixture was stirred at RT overnight, and then the mixture was poured into ice-water, 1N HCI was added slowly until pH = 6. Lots of precipitate formed. The mixture was filtered, washed with water to give a black solid. The crude product was purified by preparative HPLC, and lyophilized to give the product 8-(methylthio)-6-nitro-4-oxo-1,4-dihydroquinoline-3-carbonitrile as a yellow solid (0.21 g, 38%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 2.72 (s, 3 H) 8.39 (d, J=2.27 Hz, 1 H) 8.54 - 8.76 (m, 2 H) 12.45 (s, 1 H).
Step 2: In a 100mL round-bottomed flask equipped with a condenser, 4-hydroxy-8-methylsulfanyl-6-nitro-quinoline-3-carbonitrile (0.19g, 0.71mmol) was taken up in 6mL POCI3 and heated at reflux for 5 hours. The reaction mixture was then stirred at RT overnight, and then POCI3 was removed under reduced pressure. Ice chips were added to the residue and then saturated NaHCO3 solution was added carefully, the mixture was stirred for 30 minutes, checking the pH periodically to ensure that it remained at or above 8. The mixture was filtered and dried under high vacuum overnight to give the product 4-chloro-8-methylsulfanyl-6-nit.ro-quinoline-3-carbonitrile as a brown solid (0.18g, 90% yield): 1H NMR (400 MHz, DMSO-D6) 5 ppm 2.68 (s, 3 H) 8.21 (s, 1 H) 8.71 (s, 1 H) 9.40 (s, 1 H).
Step 3: Following the procedure described above in Example 229,4-chloro-8-methylsulfanyl-6-nitro-quinoline-3-carbonitrile (0.18g, 0.64mmol) was reacted with 3-chloro-4-fluoroaniline (0.11g, 0.77mmol) in 4mL EtOH. After work up, 4-[(3-chloro-4-fluorophenyl)amino]-8-(methylthio)-6-nitroquinoline-3-carbonitrilewas obtained as a yellow solid (0.18g, 72% yield): 1H NMR (400 MHz, DMSO-D6) 5 ppm 2.60 (s, 3 H) 7.41 - 7.48 (m, 1 H) 7.53 (t, J=8.97 Hz, 1 H) 7.71 (dd, J=6.69,
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2.40 Hz, 1 H) 8.11 (d, J=2.02 Hz, 1 H) 8.78 (s, 1 H) 9.26 (d, J=2.27 Hz, 1 H) 10.52 (s, 1 H).
Step 4: To a solution of the product from step 3 (50.0mg, 0.13mmol) in 2mL CH2CI2 was added a solution of mcPBA (28.8mg, 0.13mmol) in 2mL CH2CI2 slowly through an additional funnel at -5°C. The reaction mixture was then stirred at -5°C-0°C for 1.5 hours, until TLC analysis showed complete disappearance of starting material. 5mL saturated NaHCO3 solution was added to the reaction mixture at 0°C and the layers were separated. The organic layer was washed with saturated NaHCO3 solution and brine, separated, and concentrated to yield 4-(3-chloro-4-fluoro-phenylamino)-8-methanesulfinyl-6-nitro-quinoline-3-carbonitrileasa yellow solid (56.0mg, 100 % yield), which was used in the next step directly without further purification: 1H NMR (400 MHz, DMSO-D6) 5 ppm 2.95 (s, 3 H) 7.38 (s, 1 H) 7.46 - 7.57 (m, 1 H) 7.65 (s, 1 H) 8.73 (d, J=2.27 Hz, 2 H) 9.65 (d, J=3.03 Hz, 1 H) 10.82(s, 1 H).
Step 5: Following the procedure described above in Example 229,4-(3-chloro-4-fluoro-phenylamino)-8-methanesulfinyl-6-nitro-quinoline-3-carbonitrile (56.0mg, 0.14mmol) was reacted with tin chloride dihydrate (0.13g, 0.55mmol) in 4mL EtOH. After work up, product 6-amino-4-(3-chloro-4-fluoro-phenylamino)-8-methanesulfinyl-quinoline-3-carbonitrile was obtained as a light brown solid (37.0mg, 71% yield): 1H NMR (400 MHz, DMSO-D6) 8 ppm 2.86 (s, 3 H) 6.16 (s, 2 H) 7.20 - 7.30 (m, 2 H) 7.40 - 7.50 (m, 2 H) 7.69 (d, J=2.27 Hz, 1 H) 8.35 (s, 1 H) 9.60 (s, 1 H).
Step 6: Following the procedure described above in Example 4, 6-amino-4-(3-chloro-4-fluoro-phenylamino)-8-methanesulfinyl-quinoline-3-carbonitrile(35.0mg, 0.09mmol) was reacted with 4(5)-imidazolecarboxyaldehyde (16.2mg, 0.17mmol) and NaCNBH3 (4.0mg, 0.06mmol) in 3mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (10.0mg, 24%). HRMS (ESI-) calcd for C21H16CIFN6OS (M-H+) 453.07061, found 453.0726: 1H NMR (400 MHz, DMSO-D6) 5 ppm 2.86 (s, 3 H) 4.32 (d, J=5.31 Hz, 2 H) 7.01 -7.10 (m, 2 H) 7.29 - 7.37 (m, 2 H) 7.42 - 7.51 (m, 1 H) 7.55 - 7.63 (m, 2 H) 7.81 (d, J=2.27 Hz, 1 H) 8.23 (s, 1 H) 8.32(s, 1 H) 9.60 (s, 1 H).
Example 285: 8-Chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1 -methyl-2H-tetrazol-5-yl)methyl]amino}quinoline-3-carbonitrileand8-Chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(2-methyl-2H-tetrazol-5-yl)methyl]amino}quinoline-3-carbonitrile
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Step 1: In a pressure tube, 5-diethoxymethyl-1H-tetrazole (0.4g, 2.32mmol) was taken up in 10mLTHF. Mei (0.66g, 465mmol) and K2CO3 (0.64g, 4.65mmol) were added. The tube was capped and heated at 50°C overnight. The reaction mixture was allowed to cool to RT, then it was filtered, washed with THF, and concentrated to a dark brown liquid. 10mL of 1.25M HCI in MeOH was added to the residue, the mixture was heated at reflux for 5 hours, then allowed to cool down to RT and evaporated down solvent to give a dark brown oil (-0.3 g). The crude product was used in the next step directly without further purification.
Step 2: Following the procedure described above in Example 4, 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-chloroquinoline-3-carbonitrile(100mg, 0.29mmol) was reacted with a mixture of 1-methyl-1H-tetrazole-5-carbaldehyde and 2-methyl-2H-tetrazole-5-carbaldehyde (260mg, 2.32mmol) and NaCNBH3 (12.8mg, 0.20mmol) in 5mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the 2-methyl product as a yellow solid (4.5mg, 7%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.33 (s, 3 H) 4.69 (d, J=6.06 Hz, 2 H) 7.05 (s, 1 H)' 7.25 (s, 1 H) 7.33 (s, 1 H) 7.43 (t, J=9.35 Hz, 1 H) 7.49 (s, 1 H) 7.57 (s, 1 H) 8.36 (s, 1 H) 8.44 (s, 1 H); and the 1-methyl product as a yellow solid (1.5 mg, 2.3%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.08 (s, 3 H) 4.77 (d, J=5.81 Hz, 2 H) 7.06 (s, 1 H) 7.21 - 7.28 (m, 1 H) 7.36 (d, J=2.02 Hz, 1 H) 7.42 (t, J=8.97 Hz, 1 H) 7.48 (d, J=4.55 Hz, 1 H) 7.56 (s, 1 H) 8.38 (s, 1 H) 8.44 (s, 1 H); HRMS (ESI+) calcd for C19H13Cl2FN8 (MH+) 443.06970, found 443.0697.
Example 286: 4-[(3-chloro-4-fluorophenyl)amino]-6-[(1 H-imidazol-5-ylmethyl)amino]-8-(methylsulfonyl)quinoline-3-carbonitrile
Step 1: To a solution of 4-(3-chloro-4-fluoro-phenylamino)-8-methylsulfanyl-6-nitro-quinoline-3-carbonitrile (70.0mg, 0.18mmol) in 2mL THF was added a solution of mcPBA (100.9mg, 0.45mmol) in 3mL THF slowly through an additional funnel at 0°C. The reaction mixture was then stirred at 0°C for 30 minutes, then it was allowed to warm to RT and stirred at RT for 2 days until TLC analysis showed complete disappearance of starting material. 5mL saturated NaHCO3 solution was added to the reaction mixture at 0°C, then 15mL of EtOAC was added. The layers were separated, the organic layer was washed with saturated NaHCO3 and brine, and concentrated to give 4-(3-chloro-4-fluoro-phenylamino)-8-methanesulfonyl-6-nitro-quinoline-3-carbonitrile as a light brown solid (70mg, 93% yield). The product was used in the next step directly without further purification: 1H NMR (400 MHz, DMSO-D6) 8 ppm 3.47 - 3.61 (m, 3 H) 7.45 - 7.53 (m, 2 H) 7.56 - 7.67 (m, 2 H) 7.86 -7.89(m,3H).
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Step 2: Following the procedure described above in Example 229,4-(3-chloro-4-fluoro-phenylamino)-8-mettianesulfonyl-6-nitro-quinoline-3-carbonitrile (70mg, 0.17mmol) was reacted with tin chloride dihydrate (0.23g, 1.04mmol) in 4mL EtOH. After work up, product 6-amino-4-(3-chloro-4-fluoro-phenylamino)-8-methanesulfonyl-quinoline-3-carbonitrile was isolated as a dark yellow solid (50.0mg, 77% yield).
Step 3: Following the procedure described above in Example 4, 6-amino-4-(3-chloro-4-fluoro-phenylamino)-8-methanesulfonyl-quinoline-3-carbonitrile (50.0mg, 0.12mmol) was reacted with 4(5)-imidazolecarboxyaldehyde (20.8mg, 0.22mmol) and NaCNBH3 (5.2mg, 0.08mmol) in 3mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (9.0mg, 15%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 3.52 (s, 3 H) 4.32 (d, J=5.05 Hz, 2 H) 7.04 - 7.08 (m, 1 H) 7.11 (t, J=5.81 Hz, 1 H) 7.31 - 7.37 (m, 1 H) 7.47 (t, J=8.97 Hz, 1 H) 7.51 (d, J=2.27 Hz, 1 H) 7.58 (dd, J=6.57, 2.53 Hz, 1 H) 7.61 (d, ,7=1.01 Hz, 1 H) 8.12 (d, J=2.27 Hz, 1 H) 8.28 (s, 1 H) 8.45 (s, 1 H); HRMS (ESI+) calcd for C2iHi6CIFNeO2S (MH+) 471.08007, found 471.0796.
Example 287: 4-[(3-chloro-4-fluorophenyl)amino]-6-[(1 H-imidazol-5-ylmethyl)amino]-8-(methylthio)quinoline-3-carbonitrile
Step 1: Following the procedure described above in Example 229, 4-(3-chloro-4-fluoro-phenylamino)-8-methylsulfanyl-6-nitro-quinoline-3-carbonitrile (54.0mg, 0.14mmol) was reacted with tin chloride dihydrate (0.13g, 0.56mmol) in 3mL EtOH. After work up, product 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-(methylthio) quinoline-3-carbonitrile was obtained as a dark yellow solid (45.8mg, 91% yield): 1H NMR (400 MHz, DMSO-D6) 5 ppm 2.42 (s, 3 H) 5.80 (s, 2 H) 6.88 (d, J=2.02 Hz, 1 H) 7.01 (d, J=2.02 Hz, 1 H) 7.13 - 7.16 (m, 1 H) 7.34-7.40 (m, 2 H) 8.33 (s, 1 H) 9.34 (s, 1 H).
Step 2: Following the procedure described above in Example 4, 6-amino-4-(3-chloro-4-fluoro-phenylamino)-8-methylsulfanyl-quinoline-3-carbonitrile(44.0mg, 0.12mmol) was reacted with 4(5)-imidazolecarboxyaldehyde (21.2mg, 0.22mmol) and NaCNBH3 (5.3mg, 0.08mmol) in 3mL EtOH. The crude product was purified by preparative HPLC, and lyophilized to give the product as a yellow solid (28.0mg, 53%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 2.39 (s, 3 H) 4.25 (d, .7=5.05 Hz, 2 H) 6.48 (d, 1 H) 6.95 (d, J=1.77 Hz, 1 H) 7.05 (s, 1 H) 7.18 (d, J=2.02 Hz, 1 H) 7.22 -7.28 (m, 1 H) 7.38 - 7.51 (m, 2 H) 7.62 (d, J=1.01 Hz, 1 H) 8.19 (s, 1 H) 8.30 (s, 1 H) 9.34 (s, 1 H); HRMS (ESI+) calcd for C2iH16CIFN6S (MH+) 439.09024, found 439.0898.
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Example 288: 8-Bromo-4-(3-chloro-4-fluoro-phenylamino)-6-[(1-phenyl-1 H-[1,2,3]triazol-4-ylmethyl)-amino]-quinoline-3-carbonitrile.
In a 15mL round-bottomed flask were added 6-amino-4-(4-bromo-3-fluoro-phenylamino)-quinoline-3-carbonitrile (0.06g, 0.15mmol), ethanol (4mL) and 1-Phenyl-1H-[1 ,2,3]triazole-4-carbaldehyde (0.4mmol). Acetic acid was added to bring the pH of the solution to 4, and the mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (0.5mmol) was then added and the reaction was stirred at RT for 24 h. The reaction mixture was stripped to dryness and the residue was purified via preparative HPLC, and lyophilized to give the product as a yellow solid (0.062g, 76%). 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.56 (s, 2 H) 7.26 - 7.34 (m, 2 H) 7.44 (t, J=9.22 Hz, 1 H) 7.51 (d, J=6.06 Hz, 2 H) 7.59 (t, J=7.58 Hz, 2 H) 7.76 - 7.85 (m,
3 H) 8.39 (s, 1 H) 8.67 (s, 1 H); HRMS (ESI+) calcd for C25H16BrCIFN7 (MH+)
548.03958, found 548.0406.
Example 289: 8-Bromo-4-(3-chloro-4-fluoro-phenylamino)-6-{[1 -(4-methoxy-phenyl)-1 H-[1,2,3]triazol-4-ylmethyl]-amino}-quinoline-3-carbonitrile
In a 15mL round-bottomed flask were added 6-amino-4-(4-bromo-3-fluoro-phenylamino)-quinoline-3-carbonitrile (0.06g, 0.15mmol), ethanol (4mL) and 1-(4-methoxy-phenyl)-1H-[1,2,3]triazole-4-carbaldehyde (0.4mmol). Acetic acid was added to bring the pH of the solution to 4, and the mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (0.5mmol) was then added and the reaction was stirred at RT overnight. The reaction mixture was stripped to dryness and the residue was purified via preparative HPLC, and lyophilized to give the product as a yellow solid (0.056g, 64%). 1H NMR (400 MHz, DMSO-D6) 8 ppm 3.72 (s, 3 H) 4.44 (s, 2 H) 5.46 (s, 2 H) 6.86 (d, J=8.59 Hz, 2 H) 7.25 (t, J=8.97 Hz,
4 H) 7.41 - 7.52 (m, 2 H) 7.73 (d, =1.52 Hz, 1 H) 8.01 (s, 1 H) 8.37 (s, 1 H).
Example 290: 8-Bromo-4-(3-chloro-4-fluoro-phenylamino)-6-[(5-phenyl-2H-[1,2,4]triazol-3-ylmethyl)-amino]-quinoline-3-carbonitrile
In a 15mL round-bottomed flask were added 6-amino-4-(4-bromo-3-fluoro-phenylamino)-quinoline-3-carbonitrile (0.06g, 0.15mmol), ethanol (4mL) and 5-Phenyl-2H-[1,2,4]triazole-3-carbaldehyde (0.4mmol). Acetic acid was added to bring the pH of the solution to 4, and the mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (0.5mmol) was then added and the reaction was stirred at RT for 0.5 h, then the reaction was proceeded at 50 °C overnight. The reaction mixture was stripped to dryness and the residue was purified via preparative HPLC, and
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lyophilized to give the product as a yellow solid (0.041 g, 51%). 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.56 (s, 2 H) 7.25 - 7.30 (m, 1 H) 7.34 (d, =2.27 Hz, 1 H) 7.40 -7.52 (m, 5 H) 7.81 (d, J=1.77 Hz, 1 H) 7.95 (dd, J=7.20, 2.15 Hz, 2 H) 8.40 (s, 1 H).
Example 291: (4-{[8-Bromo-4-(3-chloro-4-fluoro-phenylamino)-3-cyano-quinolin-6-ylamino]-methyl}-[1,2,3]triazol-1-yl)-acetic acid
In a 15mL round-bottomed flask were added 6-amino-4-(4-bromo-3-fluoro-phenylamino)-quinoline-3-carbonitrile (0.06g, 0.15mmol), ethanol (4mL) and (4-Formyl-[1,2,3]triazol-1-yl)-acetic acid ethyl ester (0.4mmol). Acetic acid was added to bring the pH of the solution to 4, and the mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (0.5mmol) was then added and the reaction was stirred at RT overnight. The reaction mixture was diluted with water and the precipitate was collected via filtration. The crude was treated with a solution of LiOH (1mmol) in THF-water (1:1,3mL) for 4 h. The reaction was acidified with dilute HCI to bring the pH to 4. The precipitate was collected through filtration to give pure product 40mg (yield 51 %). 1H NMR (400 MHz, DMSO-D6) 8 ppm 4.38 (d, J=4.04 Hz, 2 H) 4.55 (s, 2 H) 6.72 (s, 1 H) 7.19 (s, 1 H) 7.33 (s, 3 H) 7.68 (s, 1 H) 7.83 -7.90 (m, 1 H) 8.24 (s, 1 H).
Example 292: 4-(4-{[8-Bromo-4-(3-chloro-4-fluoro-phenylamino)-3-cyanc~quinolin-6-ylamino]-methyl}-[1,2,3]triazol-1-yl)-benzoic acid
In a 15mL round-bottomed flask were added 6-amino-4-(4-bromo-3-fluoro-phenylarnino)-quinoline-3-carbonitrile (0.06g, 0.15mmol), ethanol (4mL) and 4-(4-Formyl-[1,2,3]triazol-1-yl)-benzoic acid (0.4mmol). Acetic acid was added to bring the pH of the solution to 4, and the mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (0.5mmol) was then added and the reaction was stirred at RT overnight. The reaction mixture was stripped to dryness and the residue was purified via preparative HPLC, and lyophilized to give the product as a yellow solid (0.035g, 41%). 1H NMR (400 MHz, MeOD) 5 ppm 4.62 (s, 2 H) 7.23 - 7.27 (m, 2 H) 7.41 (s, 1 H) 7.74 (d, J=2.27 Hz, 1 H) 7.92 (d, J=8.84 Hz, 1 H) 8.17 (d, J=9.09 Hz, 2 H) 8.30 - 8.40 (m, 3 H) 8.56 (s, 1 H).
Example 293: 8-Bromo-4-(3-chloro-4-fluoro-phenylamino)-6-[(5-diethoxymethyl-1 H-[1,2,3]triazol-4-ylmethyl)-amino]-quinoline-3-carbonitrile
Step 1: 4,4-Diethoxy-but-2-ynal (0.78g, 5mmol) was added to a solution of sodium azide (10mmol) in DMSO (5mL) cooled with an ice bath. After 1 h, the reaction was diluted with ethyl acetate (25mL) and water (10mL) and pH was
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adjusted to 7 with dilute HCI. The two layers were separated and the aqueous layer was extracted with ethyl acetate (15mL) twice. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of the solvent provided 0.74 g of 5-diethoxymethyl-1H-[1,2,3]triazole-4-carbaldehyde (yield 74%). 1H NMR (400 MHz, chloroform-D) 5 ppm 1.16 -1.33 (m, 6 H) 3.63 - 3.83 (m, 4 H) 6.05 (s, 1 H) 10.27 (s, 1 H).
Step 2: In a 15mL round-bottomed flask were added 6~amino-4-(4-bromo-3-fluoro-phenylamino)-quinoline-3-carbonitrile (0.26g, 0.6mmol), ethanol (10mL) and 5-Diethoxymethyl-1H-[1,2,3]triazole-4-carbaldehyde (1.8mmol). Acetic acid was added to bring the pH of the solution to 4, and the mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (1.8mmol) was then added and the reaction was stirred at RT for 72 h. The reaction mixture was stripped to dryness and the residue was purified via preparative HPLC, and lyophilized to give the product as a yellow solid (0.15g, 44%). 1H NMR (400 MHz, MeOD) 5 ppm 1.18 (t, J=7.07 Hz, 6 H) 3.54 - 3.71 (m, 4 H) 4.56 (s, 2 H) 5.78 (s, 1 H) 7.19 - 7.31 (m, 3 H) 7.41 (dd, J=6.82, 2.53 Hz, 1 H) 7.70 (d, J=2.27 Hz, 1 H) 8.32 (s, 1 H).
Example 294: 8-Bromo-4-(3-chloro-4-fluoro-phenylamino)-6-[(5-hydroxymethyl-1 H-[1,2,3]triazol-4-ylmethyl)-amino]-quinoline-3-carbonitrile
8-Bromo-4-(3-chloro-4-fluoro-phenylamino)-6-[(5-diethoxymethyl-1H-[1,2,3]triazol-4-ylmethyl)-amino]-quinoline-3-carbonitrile (30mg) was dissolved into methanol (3mL). Hydrochloric acid (3 M, 1 mL) was added to the solution and the solution was heated to 60°C for 1 h. The solution was cooled with an ice bath and neutralized with sodium carbonate solution to pH = 5. The resulting precipitate was filtered and collected to give the crude aldehyde product. To the crude was added methanol (3mL), and sodium borohydride (20mg) and the mixture was stirred at RT for 5 h. The product was purified by HPLC to give product (26mg, 95%). 1H NMR (400 MHz, MeOD) 8 ppm 4.52 (s, 2 H) 4.75 (s, 2 H) 7.23 - 7.34 (m, 3 H) 7.44 (dd, J=6.44,1.89 Hz, 1 H) 7.68 (d, J=2.02 Hz, 1 H) 8.26 (s, 1 H).
Example 295: 8-Bromo-4-(3-chloro-4-fluoro-phenylamino)-6-({5-[(2-hydroxy-ethylamino)-methyl]-1H-[1,2,3]triazol-4-ylmethyl}-amino)-quinoline-3-carbonitrile
8-Bromo-4-(3-chloro-4-fluoro-phenylamino)-6-[(5-diethoxymethyl-1H-[1,2,3]triazol-4-ylmethyl)-amino]-quinoline-3-carbonitrile (30mg) was dissolved in methanol (3mL). Hydrochloric acid (3M, 1mL) was added to the solution and the solution was heated to 60°C for 1h. The solution was cooled with an ice bath and neutralized with sodium carbonate solution to pH = 5. The resulting precipitate was
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filtered and collected to give the crude aldehyde product. In a 15mL round-bottomed flask were added the crude product, ethanol (4mL) and 2-aminoethanol (O.immol). Acetic acid was added to bring the pH of the solution to 4, and the mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (0.5mmol) was then added and the reaction was stirred at RT for 4 h. The reaction mixture was stripped to dryness and the residue was purified via preparative HPLC and lyophilized to give the product as a yellow solid (0.026g, 92%). 1H NMR (400 MHz, MeOD) 5 ppm 2.81 - 2.90 (m, 2 H) 3.64 - 3.75 (m, 2 H) 4.06 (s, 2 H) 4.55 (s, 2 H) 7.21 - 7.31 (m, 3 H) 7.42 (dd, J=6.19, 2.40 Hz, 1 H) 7.71 (d, J=2.53 Hz, 1 H) 8.32 (s, 1 H).
Example 296: 8-Bromo-4-(3-chloro-4-fluoro-phenylamino)-6-{[1-(2-piperidin-1-yl-ethyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-quinoline-3-carbonitrile
In a 15mL round-bottomed flask were added 6-amino-4-(4-bromo-3-fluoro-phenylamino)-quinoline-3-carbonitrile (0.06g, 0.15mmol), ethanol (4mL) and 1-(2-piperidin-1-yl-ethyl)-1 H-[1,2,3]triazole-4-carbaldehyde (0.4mmol). Acetic acid was added to bring the pH of the solution to 4, and the mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (0.5mmol) was then added and the reaction was stirred at RT for 96 h. The reaction mixture was stripped to dryness and the residue was purified via preparative HPLC, and lyophilized to give the product as a yellow solid (0.04g, 46%). 1H NMR (400 MHz, MeOD) 6 ppm 1.30 -1.49 (m, 6 H) 2.37 (s, 4 H) 2.74 (t, J=6.44 Hz, 2 H) 4.48 (t, J=6.44 Hz, 2 H) 4.54 (s, 2 H) 7.17 (d, J=2.53 Hz, 1 H) 7.21 - 7.25 (m, 1 H) 7.28 (t, J=8.72 Hz, 1 H) 7.40 (dd, J=6.69, 2.40 Hz, 1 H) 7.69 (d, J=2.53 Hz, 1 H) 7.91 (s, 1 H) 8.30 (s, 1 H); HRMS (ESI+) calcd for C26H25BrCIFN8 (MH+) 583.11308, found 583.113.
Example 297: 8-Bromo-4-(3-chloro-4-fluoro-phenylamino)-6-{[1 -(2-morpholin-4-yl-ethyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-quinoline-3-carbonitrile
In a 50mL round-bottomed flask were added 6-amino-4-(4-bromo-3-fluoro-phenylamino)-quinoline-3-carbonitrile (0.90g, 2.30mmol), dichloroethane (15mL) and 1-(2-morpholin-4-yl-ethyl)-1H-[1,2,3]triazole-4-carbaldehyde (2.5mmol). Acetic acid was added to bring the pH of the solution to 4, and the mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (0.5mmol) was then added and the reaction was stirred at RT for 5 h. The reaction mixture was stripped to dryness and the residue was purified via preparative HPLC, and lyophilized to give the product as a yellow solid (0.72g, 71%). 1H NMR (400 MHz, MeOD) 8 ppm 2.80 -2.89 (m, 4 H) 3.17 - 3.23 (m, J=6.06, 6.06 Hz, 2 H) 3.89 - 3.95 (m, 4 H) 4.87 - 4.95
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(m, 4 H) 7.55 - 7.58 (m, J=2.27 Hz, 1 H) 7.60 - 7.64 (m, 1 H) 7.68 (t, J=8.84 Hz, 1 H) 7.80 (dd, J=6.57,2.53 Hz, 1 H) 8.08 (d, J=2.53 Hz, 1 H) 8.32 (s, 1 H) 8.48 (s, 1 H) 8.70 (s, 1 H); HRMS (ESI+) calcd for C25H23BrCIFN8O (MH+) 585.09235, found 585.0921.
Example 298: 8-Bromo-4-(3-chloro-4-fluoro-phenylamino)-6-{[1 -(2-morpholin-4-yl-2-oxo-ethyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-quinoline-3-carbonitrile
In a 15mL round-bottomed flask were added 6-amino-4-(4-bromo-3-fluoro-phenylamino)-quinoline-3-carbonitrile (0.06g, 0.15mmol), dichloroethane (2mL) and 1-(2-morpholin-4-yl-2-oxo-ethyl)-1 H-[1,2,3]triazole-4-carbaldehyde (0.22mmol). The mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (0.45mmol) was then added and the reaction was stirred at RT for 5 h. The reaction mixture was stripped to dryness and the residue was purified via preparative HPLC and lyophilized to give the product as a yellow solid (0.079g, 89%). 1H NMR (400 MHz, MeOD) 8 ppm 1.12 -1.23 (m, 2 H) 2.08 (d, J=1.52 Hz, 2 H) 2.70-2.71 (m, 2 H) 3.52 - 3.84 (m, 4 H) 4.57 (s, 2 H) 7.29 (s, 4 H) 7.43 (s, 1 H) 7.69 (s, 1 H) 8.30 (d, J=3.03 Hz, 1 H).
Example 299: 8-Bromo-4-(3-chloro-4-fluoro-phenylamino)-6-[(furan-3-ylmethyl)-amino]-quinoline-3-carbonitrile
In a 15mL round-bottomed flask were added 6-amino-4-(4-bromo-3-fluoro-phenylamino)-quinoline-3-carbonitrile (0.06g, 0.15mmol), ethanol (4mL) and furan-3-carbaldehyde (0.4mmol). Acetic acid was added to bring the pH of the solution to 4, and the mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (0.5mmol) was then added and the reaction was stirred at RT overnight. The reaction mixture was stripped to dryness and the residue was purified via preparative HPLC, and lyophilized to give the product as a yellow solid (0.035g, 50%). 1H NMR (400 MHz, MeOD) 5 ppm 4.24 (s, 2 H) 6.45 (s, 1 H) 7.12 (d, J=2.02 Hz, 1 H) 7.19 - 7.23 (m, 1 H) 7.27 (t, J=8.72 Hz, 1 H) 7.39 (dd, J=6.44, 2.40 Hz, 1 H) 7.44 - 7.50 (m, 2 H) 7.68 (d, J=2.02 Hz, 1 H) 8.29 (s, 1 H); HRMS (ESI+) calcd for C21H13BrCIFN4O (MH+) 471.00180, found 471.0004.
Example 300: 8-Chloro-4-(3-chloro-4-fluoro-phenylamino)-6-{[1 -(2-piperidin-1 -yl-ethyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-quinoline-3-carbonitrile
In a 15mL round-bottomed flask were added 6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (0.052g, 0.15mmol), dichloroethane (2mL) and 1-(2-Piperidin-1-yl-ethyl)-1H-[1,2,3]triazole-4-carbaldehyde (0.22mmol). The
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mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (0.45mmol) was then added and the reaction was stirred at RT for 5 h. The reaction mixture was stripped to dryness and the residue was purified via preparative HPLC, and lyophilized to give the product as a yellow solid (0.056g, 70%). 1H NMR (400 MHz, MeOD) 5 ppm 1.66 - 1.88 (m, 6 H) 2.96 (s, 4 H) 3.30 - 3.39 (m, 2 H) 4.77 (s, 2 H) 4.85 (t, J=6.44 Hz, 2 H) 7.40 (t, J=2.5Z Hz, 1 H) 7.42 - 7.47 (m, 1 H) 7.50 (t, J=8.84 Hz, 1 H) 7.62 (dd, J=6.57, 2.53 Hz, 1 H) 7.90 (d, J=2.27 Hz, 1 H) 8.16 (s, 1 H) 8.48 (s, 1 H) 8.52 (s, 1 H); HRMS (ESI+) calcd for C26H25CI2FN8 (MH+) 539.16360, found 539.1623.
Example 301: 8-Chloro-4-(3-chloro-4-fluoro-phenylamino)-6-{[1 -(2-morpholin-4-yl-ethyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-quinoline-3-carbonitrile
In a 15mL round-bottomed flask were added 6-amino-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (0.052g, 0.15mmol), dichloroethane (2mL) and 1-(2-Morpholin-4-yl-ethyl)-1H-[1,2,3]triazole-4-carbaldehyde (0.22mmol). The mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (0.45mmol) was then added and the reaction was stirred at RT for 5 h. The reaction mixture was stripped to dryness and the residue was purified via preparative HPLC, and lyophilized to give the product as a yellow solid (0.047g, 59%). 1H NMR (400 MHz, MeOD) 8 ppm 2.39 - 2.52 (m, 4 H) 2.83 (t, J=6.19 Hz, 2 H) 3.49 - 3.60 (m, 4 H) 4.44 - 4.58 (m, 4 H) 7.13 - 7.18 (m, J=2.53 Hz, 1 H) 7.23 - 7.33 (m. 2 H) 7.42 (dd, J=GM, 2.40 Hz, 1 H) 7.49 (d, J=2.27 Hz, 1 H) 7.94 (s, 1 H) 8.09 (s, 2 H) 8.31 (s, 1 H); HRMS (ES1+) calcd for C25H23CI2FN8O (MH+) 541.14287, found 541.1424.
Example 302: 8-Bromo-4-(3-chloro-4-fluoro-phenylamino)-6-[([1,2,3]thiadiazol-4-ylmethyl)-amino]-quinoline-3-carbonitrile
In a 15mL round-bottomed flask were added 6-amino-4-(4-bromo-3-fluoro-phenylamino)-quinoline-3-carbonitrile (0.06g, 0.15mmol), ethanol (4mL) and [1,2,3]Thiadiazole-4-carbaldehyde (0.4mmol). Acetic acid was added to bring the pH of the solution to 4, and the mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (0.5mmol) was then added and the reaction was stirred at RT overnight. The reaction mixture was stripped to dryness and the residue was purified via preparative HPLC, and lyophilized to give the product as a yellow solid (0.005g, 7%). 1H NMR (400 MHz, MeOD) 8 ppm 5.02 (s, 2 H) 7.25 - 7.28 (m, 1 H) 7.32 (t, J=8.72 Hz, 1 H) 7.44 (dd, J=6.57, 2.53 Hz, 1 H) 7.80 (d, J=2.53 Hz, 1 H) 8.38 (s, 1 H) 8.86 (s, 1 H).
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Example 303: 8-Bromo-4-(3-chloro-4-fluoro-phenylamino)-6-({1 -[2-(1,3-dioxo-1,3-
dihydro-isoindol-2-yl)-ethyl]-1H-[1,2,3]triazol-4-ylmethyamino)-quinoline-3-
carbonitrile
In a 15mL round-bottomed flask were added 6-amino-4-(4-bromo-3-fluoro-phenylamino)-quinoline-3-carbonitrile (0.18g, 0.45mmol), ethanol (15mL) and 1-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-1 H-[1,2,3]triazole-4-carbaldehyde (1.2mmol). Acetic acid was added to bring the pH of the solution to 4, and the mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (1.2mmol) was then added and the reaction was stirred at RT overnight. The reaction mixture was stripped to dryness and the residue was purified via preparative HPLC and lyophilized to give the product as a yellow solid (0.20g, 70%). 1H NMR (400 MHz, DMSO-D6) 8 ppm 3.92 - 4.04 (m, 2 H) 4.41 (d, J=5.56 Hz, 2 H) 4.56 - 4.68 (m, 2 H) 6.86 (t, J=6.32 Hz, 1 H) 7.27 (d, J=1.77 Hz, 2 H) 7.45 (t, J=8.97 Hz, 1 H) 7.52 (dd, J=6.57, 2.53 Hz, 1 H) 7.72 - 7.83 (m, 4 H) 8.09 (s, 1 H) 8.39 (s, 1 H) 9.46 (s, 1 H); HRMS (ESI+) calcd for C29H19BrCIFN8O2 (MH+) 645.05596, found 645.0559.
Example 304: 6-{[1 -(2-Amino-ethyl)-1 H-[1,2,3]triazol-4-ylmethyl]-amino}-8-bromo-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile
8-Bromo-4-(3-chloro-4-fluoro-phenylamino)-6-({1 -[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-1H-[1,2,3]triazol-4-ylmethyl}-amino)-quinoline-3-carbonitrile (0.20g, 0.32mmol) was added into a solution of hydrazine hydrate (1mmol) in ethanol (10mL). The mixture was heated to 60°C for 4 h, the reaction mixture was stripped to dryness. The residue was purified via preparative HPLC and lyophilized to give the product as a yellow solid (0.105g, 64%). 1H NMR (400 MHz, DMSO-D6) S ppm 2.36 (s, 1 H) 2.57 (s, 1 H) 2.70 (s, 1 H) 3.12 (t, J=6.32 Hz, 2 H) 4.43 -4.49 (m, 3 H) 7.26 - 7.32 (m, 2 H) 7.46 (t, J=8.97 Hz, 1 H) 7.52 (d, J=9.09 Hz, 1 H) 7.76 (d, J=2.27 Hz, 1 H) 8.04 (s, 1 H) 8.33 (s, 1 H) 8.39 (s, 1 H); HRMS (ESI+) calcd for C21H17BrCIFN8 (MH+) 515.05048, found 515.0511.
Example 305: 8-Bromo-4-(3-chloro-4-fluoro-phenylamino)-6-({1-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-1H-[1,2,3]triazol-4-ylmethyl}-amino)-quinoline-3-carbonitrile In a 15mL round-bottomed flask were added 6-amino-4-(4-bromo-3-fluoro-phenylamino)-quinoline-3-carbonitri!e (0.04g, O.IOmmol), dichloroethane (2mL) and 1 -[2-(1 -methyl-pyrrolidin-2-yl)-ethyl]-1 H-[1,2,3]triazole-4-carbaldehyde (0.12mmol). The mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (0.27mmol) was then added and the reaction was stirred at RT for 5 h. The reaction mixture was stripped to dryness and the residue was purified via preparative HPLC and
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lyophilized to give the product as a yellow solid (0.04g, 68%). 1H NMR (400 MHz, MeOD) 8 ppm 2.08 - 2.42 (m, 5 H) 2.67 - 2.84 (m, 2 H) 3.31 (dd, J=45.98,12.38 Hz, 2 H) 4.62 - 4.75 (m, 5 H) 7.34 - 7.48 (m, 3 H) 7.53 - 7.58 (m, 1 H) 7.84 (s, 1 H) 8.13 (s, 1 H) 8.44 - 8.52 (m, 3 H); HRMS (ESI+) calcd for C26H25BrCIFN8 (MH+) 583.11308, found 583.1147.
Example 306: 8-Bromo-4-(3-chloro-4-fluoro-phenylamino)-6-[(1 -pyridin-3-ylmethyl-1 H-[1,2,3]triazol-4-ylmethyl)-amino]-quinoline-3-carbonitrile
In a 15mL round-bottomed flask were added 6-amino-4-(4-bromo-3-fluoro-phenylamino)-quinoline-3-carbonitrile (0.04g, 0.10mmol), dichloroethane (2mL) and 1-pyridin-3-ylmethyl-1H-[1,2,3]1r:azole-4-carbaldehyde (0.12mmol). The mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (0.27mmol) was then added and the reaction was stirred at RT for 5 h. The reaction mixture was stripped to dryness and the residue was purified via preparative HPLC and lyophilized to give the product as a yellow solid (0.026g, 46%). 1H NMR (400 MHz, MeOD) 8 ppm 4.81 (s, 2 H) 5.94 (s, 2 H) 7.42 - 7.60 (m, 2 H) 7.68 (d, J=4.29 Hz, 1 H) 7.96 (s, 1 H) 8.05 (d, J=8.84 Hz, 1 H) 8.28 (s, 1 H) 8.59 (s, 1 H) 8.76 - 8.84 (m, 2 H); HRMS (ESI+) calcd for C25H17BrCIFN8 (MH+) 563.05048, found 563.0512.
Example 307: 6-{[1-(2-Azepan-1 -yl-ethyl)-1 H-[1,2,3]triazol-4-ylmethyl]-amino}-8-bromo-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile
In a 15mL round-bottomed flask were added 6-amino-4-(4-bromo-3-fluoro-phenylamino)-quinoline-3-carbonitrile (0.04g, O.IOmmol), dichloroethane (2mL) and 1 -(2-azepan-1 -yl-ethyl)-1 H-[1,2,3]triazole-4-carbaldehyde (0.12mmol). The mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (0.27mmol) was then added and the reaction was stirred at RT for 5 h. The reaction mixture was stripped to dryness and the residue was purified via preparative HPLC and lyophilized to give the product as a yellow solid (0.044g, 73%). 1H NMR (400 MHz, MeOD) 8 ppm 2.03 (d, J=54.32 Hz, 8 H) 3.45 (s, 4 H) 3.83 (d, J=3.79 Hz, 2 H) 4.92 (s, 2 H) 5.08 (d, .7=5.81 Hz, 2 H) 7.54 - 7.68 (m, 3 H) 7.76 (dd, J=6.44, 2.15 Hz, 1 H) 8.05 (s, 1 H) 8.35 (s, 1 H) 8.65 (s, 1 H); HRMS (ESI+) calcd for C27H27BrCIFN8 (MH+) 597.12873, found 597.1304.
Example 308: 8-Bromo-4-(3-chloro-4-fluoro-phenylamino)-6-{[1-(2-pyrrolidin-1-yl-ethyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-quinoline-3-carbonitrile
In a 15mL round-bottomed flask were added 6-amino-4-(4-bromo-3-fluoro-phenylamino)-quinoline-3-carbonitrile (0.04g, O.IOmmol), dichloroethane (2mL) and
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1-(2-pyrrolidin-1 -yl-ethyl)-1 H-[1,2,3]triazole-4-carbaldehyde (0.12mmol). The mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (0.27mmol) was then added and the reaction was stirred at RT for 5 h. The reaction mixture was stripped to dryness and the residue was purified via preparative HPLC, and lyophilized to give the product as a yellow solid (0.036g, 64%). 1H NMR (400 MHz, MeOD) 8 ppm 2.21 (s, 4 H) 2.86 (s, 2 H) 3.48 (m, 4 H) 3.92 (d, J=4.55 Hz, 2 H) 4.75 (s, 2 H) 7.38 - 7.51 (m, 3 H) 7.57 (d, J=2.02 Hz, 1 H) 7.88 (s, 1 H) 8.22 (s, 1 H) 8.48 (s, 2 H); HRMS (ESI+) calcd for C25H23BrCIFNe (MH+) 569.09743, found 569.0987.
Example 309: 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-(4-hydroxy-3-oxobutyl)quinoline-3-carbonitrile
In a 20mL microwave vial were added 6-amino-4-(4-bromo-3-fluoro-phenylamino)-quinoline-3-carbonitrile (500mg, 1.3mmol), DMF (15mL), but-3-ene-1,2-diol (114mg, 1.3mmol), palladium acetate (30mg, 0.13mmol), P(o-tol)3 (60mg, 0.26mmol) and triethylamine (530mg, 0.52mmol). The reaction mixture was heated under microwave radiation at 180°C for 20min. The reaction mixture was diluted with water. The aqueous reaction mixture was washed with ethyl acetate (3X). The pooled ethyl acetate extracts were dried over magnesium sulfate and concentrated in vacuo. The residue was purified via preparative HPLC, and lyophilized to give the product as a yellow solid (84mg, 16.2%). 1H NMR (400 MHz, DMSO-D6) 8 ppm 2.83 (t, J=7.58 Hz, 2 H) 3.21 (t, J=7.58 Hz, 2 H) 4.06 (d, J=5.81 Hz, 2 H) 5.12 (t, J=5.94 Hz, 1 H) 5.71 (s, 2 H) 7.01 (d, J=2.27 Hz, 1 H) 7.08 - 7.15 (m, 2 H) 7.29 -7.41 (m, 2 H) 8.38 (s, 1 H) 9.29 (s, 1 H).
Example 310: 4-[(3-chloro-4-fluorophenyl)amino]-8-(4-hydroxy-3-oxybutyl)-6-[(1 H-imidazol-5-ylmethyl)amino]quinoline-3-carbonitrile
6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-(4-hydroxy-3-oxybutyl)quinoline-3-carbonitrile (81 mg, 0.20mmol) was treated with sodium borohydride (16mg, 0.40mmol) in methanol (1mL). The heterogeneous mixture, which turned to homogeneous solution upon addition of the reducing agent was allowed to stir at RT for 2h. The solvent was rotavaped off and water was added to the crude reaction mixture. Dilute HCI was added to bring the pH of the aqueous solution to 4. The solid precipitated out which was filtered to give 4-[(3-chloro-4-fluorophenyl)amino]-8-(4-hydroxy-3-oxybutyl)-6-[(1H-imidazoI-5-ylmethyl)amino]quinoline-3-carbonitrile in quantitative yields. This was used directly in the next step.
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In a 15mL round-bottom flask were added 6-amino-4-(4-bromo-3-fluoro-phenylamino)-quinoline-3-carbonitrile (82mg, 0.20mmol), ethanol (2mL) and 1H-imidazole-5-carbaldehyde (20mg, 0.20mmol). Acetic acid was added to bring the pH of the solution to 4, and the mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (43mg, 0.40mmol) was then added and the reaction was stirred at RT overnight. The reaction mixture was stripped to dryness and the residue was purified via preparative HPLC and lyophilized to give the product as a yellow solid (43mg, 44.7%). 1H NMR (400 MHz, DMSO-D6) 8 ppm 1.58 (s, 1 H) 1.82 (d, J=7.07 Hz, 1 H) 3.00 - 3.10 (m, 1 H) 3.10 - 3.23 (m, 4 H) 3.26 - 3.38 (m, 2 H) 3.41 - 3.52 (m, 2 H) 4.26 (s, 2 H) 7.06 (s, 2 H) 7.19 - 7.31 (m, 2 H) 7.36 - 7.49 (m, 2 H) 7.62 (s, 1 H) 8.35 (s, 1 H).
Example 311: 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(4-phenyl-1 H-1,2,3-triazol-5-yl)methyl]amino}quinoline-3-carbonitrile

5-phenyl-1H-1,2,3-triazole-4-carbaldehyde was prepared by mixing 3-phenylpropiolaldehyde (250mg, 1.92mmol) and sodium azide (250mg, 3.84mmol) in 12mL of DMF at RT for 4-5h. In a 15mL round-bottom flask were added 6-amino-4-(4-bromo-3-fluoro-phenylamino)-quinoline-3-carbonitrile (1 OOmg, 0.26mmol), ethanol (1mL) and 5-phenyl-1H-1,2,3-triazole-4-carbaldehyde (334mg, 1.92mmol). Acetic acid was added to bring the pH of the solution to 4, and the mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (108mg, 0.51 mmol) was then added and the reaction was stirred at RT overnight. The reaction mixture was stripped to dryness and the residue was purified via preparative HPLC and lyophilized to give the product as a yellow solid (12.7mg, 8.9%). 1H NMR (400 MHz, DMSO-D6) 6 ppm 4.54 (s, 2 H) 6.91 (d, J=4.04 Hz, 1 H) 7.25 - 7.57 (m, 8 H) 7.70 - 7.85 (m, 3 H) 8.42 (s, 1 H).
Example 312: Ethyl (2E)-3-{4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-6-[(1H-imidazol-5-ylmethyl)amino]quinolin-8-yl}acrylate
In a 20mL microwave vial were added 6-amino-4-(4-bromo-3-fluoro-phenylamino)-quinoline-3-carbonitrile (500mg, 1.3mmol), DMF (15mL), ethyl acrylate (128mg, 1.3mmol), palladium acetate (30mg, 0.13mmol), P(o-tol)3 (60mg,
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0.26mmol) and triethylamine (530mg, 0.52mmol). The reaction mixture was heated under microwave radiation at 180°C for 20min. The reaction mixture was diluted with water. The aqueous reaction mixture was washed with ethyl acetate (3X). The pooled ethyl acetate extracts were dried over magnesium sulfate and concentrated in vacuo. The residue was purified via combiflash, and lyophilized to give the product as a yellow solid (162mg, 30%).
In a 15mL round-bottom flask were added E-ethyl-(6-amino-4-(3-chloro-4-fluorophenyl)amino)-3-cyanoquinolin-8-yl)acrylate (162mg, 0.39mmol), ethanol (2mL) and 1 H-imidazole-5-carbaldehyde (38mg, 0.39mmol). Acetic acid was added to bring the pH of the solution to 4, and the mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (166mg, 0.78mmol) was then added and the reaction was stirred at RT overnight. The reaction mixture was stripped to dryness and the residue was purified via preparative HPLC and lyophilized to give the product as a yellow solid (1.8mg, 0.94%). 1H NMR (400 MHz, DMSO-D6) 8 ppm 1.29 (t, J=7.07 Hz, 3 H) 4.23 (q, J=7.07 Hz, 2 H) 4.31 (d, J=1.77 Hz, 2 H) 6.47 (d, 1 H) 6.63 (d, J=16.42 Hz, 1 H) 7.06 (d, J=4.55 Hz, 1 H) 7.26 - 7.31 (m, 1 H) 7.35 - 7.39 (m, 1 H) 7.45 (t, J=8.97 Hz, 1 H) 7.52 (dd, J=6.57, 2.78 Hz, 1 H) 7.63 (s, 1 H) 7.87 (s, 1 H) 8.42 (s, 1 H) 8.70 (d, J=16.42 Hz, 1 H) 9.48 (s, 1 H).
Example 313: 1-[(3-chloro-4-fluorophenyl)amino]-5-[(1£)-3-hydroxyprop-1-en-1-yl]-7-[(1H-imidazol-5-ylmethyl)amino]-2-naphthonitrile
In a 15mL round-bottom flask were added E-ethyl-(6-amino-4-(3-chloro~4-fluorophenyl)amino)-3-cyanoquinolin-8-yl)acrylate (65mg, 0.16mmol), THF (1mL) and two equivalents of DIBAL-H (1M solution in touluene). The reaction mixture was allowed to stir for 2 hours. The solvent was then evaporated to get the crude product, (£}-6-amino-4-(3-chloro-4-fluorophenylamino)-8-(3-hydroxyprop-1-enyl)quinoline-3-carbonitrile, which was used directly in the next step.
In a 15mL round-bottom flask were added (E)-6-amino-4-(3-chloro-4-fluorophenylamino)-8-(3-hydroxyprop-1-enyl)quinoline-3-carbonitrile (0.16mmol), ethanol (2mL) and 1H-imidazole-5-carbaldehyde (38mg, 0.39mmol). Acetic acid was added to bring the pH of the solution to 4, and the mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (166mg, 0.78mmol) was then added and the reaction was stirred at RT overnight. The reaction mixture was stripped to dryness and the residue was purified via preparative HPLC and lyophilized to give the product as a yellow solid (4.2mg, 5.86%). 1H NMR (400 MHz, MeOD) 5 ppm 2.12 - 2.17 (m, 2 H) 4.31 (dd, J=5.68,1.64 Hz, 2 H) 4.44 (s, 1 H) 6.41 - 6.49 (m, 1 H) 7.07 (d, J=2.27 Hz, 1 H) 7.13 - 7.20 (m, 2 H) 7.24 (t, J=8.97 Hz, 1 H) 7.33 (dd,
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J=6.44, 2.65 Hz, 1 H) 7.51 (d, J=2.27 Hz, 1 H) 7.61 (d, J=15.92 Hz, 1 H) 8.07 (s, 1 H) 8.21 (s, 2 H) 8.30 - 8.35 (m, 1 H).
Example 314: 4-[(3-chloro-4-fluorophenyl)amino]-8-(2,3-dihydroxypropyl)-6-[(1 H-imidazol-5-ylmethyl)amino]quinoline-3-carbonitrile
In a 20mL microwave vial were added 6-amino-4-(4-bromo-3-fluoro-phenylamino)-quinoline-3-carbonitrile (500mg, 1.3mmol), DMF (15mL), allyltributylstannane (630mg, 1.9mmol) and PdCI2(PPh3)2 (100mg, 0.13mmol). The reaction mixture was heated under microwave radiation at 180°C for 30min. The reaction mixture was diluted with water. The aqueous reaction mixture was washed with ethyl acetate (3X). The pooled ethyl acetate extracts were dried over magnesium sulfate and concentrated in vacuo. The residue was purified via preparative HPLC, and lyophilized to give the product as a yellow solid (214mg, 48%).
In a 15mL round-bottom flask were added 8-allyl-6-amino-4-(3-chloro-4-fluorophenylamino) quinoline-3-carbonitrile (214mg, 0.6mmol), dichloromethane (3mL), pyridine (119mg, 1.5mmol) and trifluoroacetic anhydride (265mg, 1.3mmol). The reaction was stirred at RT for 3-4h. The reaction mixture was diluted with water and extracted with ethyl acetate (3X). The pooled ethyl acetate extracts were dried over magnesium sulfate and concentrated in vacuo. The crude product (258mg, 0.48mmol) was dissolved in 1:1 mixture of acetone and water (2mL). To this were added osmiumtetraoxide (2.5wt% in t-BuOH, 293mg, 0.03mmol) and NMO (112mg, 0.96mmol). The reaction mixture was stirred at RT for 4h. To this was added 1mL of 5M LiOH solution and stirred for another 3h. The heterogeneous mixture was filtered through a pad of celite and washed with acetone and water. The filtrate was diluted with ethyl acetate and the two layers were separated. The aqueous reaction mixture was washed with ethyl acetate (2X). The pooled ethyl acetate extracts were dried over magnesium sulfate and concentrated in vacuo to give crude 6-aminc~4-(3-chloro-4-fluorophenylamino)-8-(2,3-dihydroxypropyl)quinoline-3-carbonitrile, which was used directly for the next step.
In a 15mL round-bottom flask were added 6-amino-4-(3-chloro-4-fluorophenylamino)-8-(2,3-dihydroxypropyl)quinoline-3-carbonitrile(186mg, 0.48mmol), ethanol (2mL) and 1H-imidazole-5-carbaldehyde (51 mg, 0.53mmol). Acetic acid was added to bring the pH of the solution to 4, and the mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (204mg, 0.96mmol) was then added and the reaction was stirred at RT overnight. The reaction mixture was stripped to dryness and the residue was purified via preparative HPLC and
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lyophilized to give the product as a yellow solid (30.2mg, 13.5%). 1H NMR (400 MHz, MeOD) 8 ppm 2.02 - 2.04 (m, 1 H) 2.66 (s, 1 H) 3.14 (dd, J=13.77, 7.71 Hz, 1 H) 3.35 (s, 1 H) 3.52 (d, J=5.31 Hz, 2 H) 3.94 - 4.02 (m, 1 H) 4.58 (s, 2 H) 7.13 (s, 1 H) 7.21 - 7.35 (m, 3 H) 7.38 - 7.47 (m, 2 H) 8.41 (s, 1 H) 8.81 (s, 1 H).
Example 315: 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[(2H-1,2,3-triazol-4-ylmethyl)amino]quinoline-3-carbonitrile
In a microwave vial were added 3,3-diethoxy-prop-1-yne (1000mg, 7.5mmol), DEE (15mL) and tributyltin azide (3240mg, 9.76mmol). The reaction mixture was heated under microwave radiation at 180°C for 3h. The solvent was evaporated under vacuo and the residue was treated with 2M HCI in MeOH for 16h. The solvent was stripped down and the residue was dissolved in methanol and dichloroethane (20mL). To this was added 6-amino-4-(4-bromo-3-fluoro-phenylamino)-quinoline-3-carbonitrile (500mg, 1.3mmol). Acetic acid was added to bring the pH of the solution to 4, and the mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (542mg, 2.55mmol) was then added and the reaction was stirred at RT overnight. The reaction mixture was stripped to dryness and the residue was purified via preparative HPLC and lyophilized to give the product as a yellow solid (151.4mg, 24%). 1H NMR (400 MHz, MeOD) 8 ppm 4.54 (s, 2 H) 7.18 (d, J=2.53 Hz, 1 H) 7.21 - 7.31 (m, 2 H) 7.41 (dd, J=6.44, 2.40 Hz, 1 H) 7.69 (d, J=2.27 Hz, 2 H) 8.30 (s, 1 H).
Example 316: 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-piperidin-4-yl-1 H-1,2,3-triazol-4-yl)methyl]amino}quinoline-3-carbonitrile
In a 15mL round-bottom flask were added 6-amino-4-(4-bromo-3-fluoro-phenylamino)-quinoline-3-carbonitrile (450mg, 0.1.15mmol), dichloroethane (4mL) and fert-butyl 4-(4-formyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (323mg, 1.15mmol). Acetic acid was added to bring the pH of the solution to 4, and the mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (490mg, 2.3mmol) was then added and the reaction was stirred at RT overnight. The reaction mixture was stripped to dryness and the residue was purified via preparative HPLC and lyophilized to give the product, te/f-butyl 4-(4-((8-bromo-4-(3-chloro-4-fluorophenylamino)-3-cyanoquinoline-6-ylamino)methyl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate as a yellow solid (516mg, 64%).
tert-butyl4-(4-((8-bromo-4-(3-chloro-4-fluorophenylamino)-3-cyanoquinoline-6-ylamino)methyl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (511mg, 0.73mmol) was dissolved in 50%TFA solution in DCM. The reaction was allowed to stir for 2h.
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The solvent was stripped down and the residue was diluted with ethyl acetate and sodium bicarbonate. The ethyl acetate layer was separated, dried over magnesium sulfate and concentrated in vacuo to give final product as a free base (318mg, 78.5%). 1H NMR (400 MHz, MeOD) 5 ppm 2.27 - 2.47 (m, 4 H) 3.19 - 3.29 (m, 2 H) 3.56 (d, J= 13.39 Hz, 2 H) 4.56 (s, 2 H) 4.86 (d, J=4.04 Hz, 1 H) 7.32 - 7.46 (m, 3 H) 7.59 (dd, J=6.57, 2.27 Hz, 1 H) 7.75 (d, J=2.27 Hz, 1 H) 8.07 (s, 1 H) 8.43 (s, 1 H).
Example 317: 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(1-methylpiperidin-4-yl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile
In a 15mL round-bottom flask were added 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1 -piperidin-4-yM H-1,2,3-triazol-4-yl)methyl]amino} quinoline-3-carbonitrile (90mg, 0.16mmol), dichloroethane (1mL) and formaldehyde (14mg, 0.17mmol, 13uL). Acetic acid was added to bring the pH of the solution to 4, and the mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (68mg, 0.32mmol) was then added and the reaction was stirred at RT overnight. The reaction mixture was stripped to dryness and the residue was purified via preparative HPLC and lyophilized to give the product as a yellow solid (59.4mg, 60.3%). 1H NMR (400 MHz, MeOD) 6 ppm 2.26 - 2.37 (m, 4 H) 2.71 (s, 3 H) 2.86 -2.96 (m, 2 H) 3.35 - 3.44 (m, 2 H) 4.52 (s, 2 H) 4.71 (s, 1 H) 7.16 - 7.35 (m, 3 H) 7.41 (dd, J=6.32, 2.27 Hz, 1 H) 7.67 (s, 1 H) 8.01 (s, 1 H) 8.27 - 8.46 (m, 2 H).
Example 318: 8-bromo-4-(3-chloro-4-fluorophenylamino)-6-((5-(2-hydroxypropyl)-3H-1,2,3-triazoW-yl)methylamino)quinoline-3-carbonitrile
3,3-diethoxy-prop-1-yne (1000mg, 7.6mmol) was dissolved in ether (20mL) in a 50mL round bottom flask. p-BuLi (2.5M in hexanes; 7.6mmol) was slowly added to the above solution. The reaction mixture was stirred and heated to reflux for 1h. 2-methoxyoxirane (880mg, 15.2mmol) was then added to the above mixture. The stirring was continued at reflux temperatures for another 16h. The reaction was cooled to RT and ether layer washed with water until neutral (3x). The ether layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was then subjected to 2M HCI solution for 3h. The solvent was removed in vacuo. The crude product was then dissolved in DMSO (10mL) and treated with excess sodium azide. The reaction mixture was diluted with water. The aqueous reaction mixture was washed with ethyl acetate (3X). The pooled ethyl acetate extracts were dried over magnesium sulfate and concentrated in vacuo to give crude 5-(2-hydroxypropyl)-3tf-1,2,3-triazole-4-carbaldehyde. The crude
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product was then taken up in ethanol (5mL) and 6-amino-4-(4-bromo-3-fluoro-phenylamino)-quinoline-3-carbonitrile (200mg, 0.5mmol) was added. Acetic acid was added to bring the pH of the solution to 4, and the mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (212mg, 1mmol) was then added and the reaction was stirred at RT overnight. The reaction mixture was stripped to dryness and the residue was purified via preparative HPLC and lyophilized to give the product as a yellow solid (14.3mg, 5.3%). 1H NMR (400 MHz, MeOD) 8 ppm 1.18 (d, .7=6.06 Hz, 3 H) 2.75 - 2.95 (m, 2 H) 3.96 - 4.10 (m, 1 H) 4.49 (s, 2 H) 7.18 (s, 1 H) 7.21 - 7.31 (m, 2 H) 7.43 (dd, J=6.32, 1.77 Hz, 1 H) 7.65 (d, J=2.02 Hz, 1 H) 8.17(8,1 H) 8.27 (s, 1 H).
Example 319: 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1 -(2-hydroxy-3-morpholin-4-ylpropyl)-1H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile
In a 50mL round-bottom flask were added 4-(oxiran-2-ylmethyl)morpholine (500mg, 3.5mmol), cerium(lll) chloride (432mg, 1.75mmol), acetonitrile-water(9:1; 30mL) and sodium azide (250mg, 3.85mmol). The mixture was heated to reflux for 5h. The reaction mixture was diluted with water and extracted with ethyl acetate (3X). The pooled ethyl acetate extracts were dried over magnesium sulfate and concentrated in vacuo. The crude product was used directly in the next step.
The crude product of the above reaction was dissolved in water (10mL) and 3,3-diethoxy-prop-1-yne (463mg, 3.5mmol), copper sulfate pentahydrate (5mg, 0.09mmol)) and ascorbic acid (18mg, 0.18mmol) were added. The heterogeneous mixture was allowed to stir overnight at RT. The mixture was cooled to 0°C and cone. HCI was (1mL) was added. After 5h, the solvent was removed in vacuo.
The crude product of the above reaction was dissolved in dichloroethane (5mL)and6-amino-4-(4-bromo-3-fluoro-phenylamino)-quinoline-3-carbonitrile (100mg, 0.26mmol) was added. Acetic acid was added to bring the pH of the solution to 4, and the mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (108mg, 0.51mmol) was then added and the reaction was stirred at RT overnight. The reaction mixture was stripped to dryness and the residue was purified via preparative HPLC and lyophilized to give the product as a yellow solid (2.3mg, 1.5%). 1H NMR (400 MHz, MeOD) 5 ppm 1.51 -1.72 (m, 6 H) 2.38 - 2.51 (m, 2 H) 2.53 - 2.62 (m, 2 H) 3.47 - 3.58 (m, 2 H) 4.19 (s, 1 H) 4.38 (s, 1 H) 4.53 (s, 2 H) 7.42 (s, 1 H) 7.64 - 7.82 (m, 3 H) 7.95 (s, 1 H) 8.29 (s, 1 H).
Example 320: 2-(4-((8-chloro-4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino)methyl)-1 H-1,2,3-triazoM -yl)-N-(pyridin-2-ylmethyl)acetamide
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To a dry 15 mL round-bottomed flask was added with 2-(4-((8-chloro-4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino)methyl)-1 H-1,2,3-triazol-1 -yl)acetic acid (73 mg, 0.15 mmo!), BOP (100 mg, 0.225 mmol), DMF (2 mL). After stirring for 15 min, the mixture was added to pyridin-2-ylmethanamine (6 mmol) and stirred at room temperaturet for 4 h. The mixture was purified by HPLC to give 22 mg product. 1H NMR (400 MHz, DMSO-d6) 5 ppm 4.41 (d, 2 H) 4.48 (s, 2 H) 5.19 (s, 2 H) 7.25 - 7.34 (m, 4 H) 7.45 (t, J=8.84 Hz, 1 H) 7.54 (dd, J=6.44, 2.15 Hz, 1 H) 7.57 (s, 1 H) 7.76 (t, J=8.08 Hz, 1 H) 8.03 (s, 1 H) 8.38 (s, 1 H) 8.50 (d, J=6.32 Hz, 1 H)
Example 321: 8-chloro-4-(3-chloro-4-fluorophenylamino)-6-(methyl((1 -(2-(1 -methylpyrrolidin-2-yl)ethyl)-1H-1,2,3-triazol-4-yl)methyl)amino)quinoline-3-carbonitrile In a test tube were added 8-chloro-4-(3-chloro-4-fluorophenylamino)-6-((1-(2-(1 -methylpyrrolidin-2-yl)ethyl)-1 H-1,2,3-triazol-4-yl)methylamino)quinoline-3-carbonitrile (0.020 g), dichloroethane (1mL) and paraformaldehyde (excess). The mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (excess) was then added and the reaction was stirred at room temperature overnight. The reaction mixture was stripped to dryness and the residue was purified via preparative HPLC, and lyophilized to give 0.011 g product. 1H NMR (400 MHz, MeOD) 5 ppm 1.66 -1.85 (m, 1 H) 1.99 - 2.41 (m, 3 H) 2.61 - 2.76 (m, 1 H) 2.96 (s, 3 H) 3.12 - 3.24 (m, 1 H) 3.64 - 3.77 (m, 1 H) 4.67 (s, 2 H) 7.34 - 7.62 (m, 3 H) 8.06 (s, 1 H) 8.12 (s, 1 H) 8.48 (s, 1 H) 8.59 (s, 1 H)
Example 322: tert-butyl 4-((8-chloro-4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-y!amino)methyl)piperidine-1-carboxylate
In a 25mL round-bottomed flask were added 6-amino-8-chloro-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (0.35 g, 1 mmol), dichloroethane (5 mL) and tert-butyl 4-formylpiperidine-1-carboxylate (2.5 mmol). The mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (3 mmol) was then added and the reaction was stirred at rt for 24 h. The reaction mixture was stripped to dryness and the residue was purified via preparative HPLC, and lyophilized to give 0.5 g product as a yellow solid. 1H NMR (400 MHz, DMSO-d6) 8 ppm 0.97 -1.13 (m, 2 H) 1.39 (s, 9 H) 1.64 - 1.81 (m, 2 H) 2.63 - 2.78 (m, 1 H) 3.03 (d, J=6.57 Hz, 2 H) 4.07 - 4.10 (m, 4 H) 6.98 (d, J=2.02 Hz, 1 H) 7.27 (d, J=3.03 Hz, 1 H) 7.41 - 7.49 (m, 2 H) 7.51 (d, J=2.27 Hz, 1 H) 8.35 (s, 1 H)
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Example 323: s-chloro-4--cnioro-4-Tiuorophenylamino)-6-((1-(pyridin-3-ylmethyl)piperidin-4-yl)methylamino)quinoline-3-carbonitrile
To a 15 mL round-bottomed flask was added tert-butyl 4-((8-chloro-4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino)methyl)piperidine-1-carboxylate(0.05 g), methylene chloride (2 mL) and TFA (0.5 mL). The reaction was stirred at room temperature for 2h, and the solvent was removed in vacuo. The residue was dissolved in dichloroethane and nicotinaldehyde (1.5 equiv.) was added. After 15 min, sodium borotriacetoxyhydride (excess) was added and stirred at room temperature for 5 h. The reaction mixture was stripped to dryness and the residue was purified via preparative HPLC, and lyophilized to give 0.033 g product as a yellow solid. 1H NMR (400 MHz, MeOD) 5 ppm 1.74 -1.93 (m, 2 H) 2.18 - 2.30 (m, 1 H) 2.32 - 2.42 (m, 2 H) 3.17 (s, 2 H) 3.48 (d, J=6.57 Hz, 2 H) 3.75 (s, 2 H) 4.54 (s, 2 H) 7.32 (d, J=2.02 Hz, 1 H) 7.52 - 7.59 (m, 1 H) 7.63 (t, J=8.84 Hz, 1 H) 7.70 - 7.78 (m, 2 H) 7.87 (dd, J=7.96, 4.93 Hz, 1 H) 8.31 (dd, J=7.96, 1.64 Hz, 1 H) 8.64 (s, 1 H) 8.91 - 9.06 (m, 2 H)
Example 324: (S)-8-bromo-4-(3-chloro-4-fluorophenylamino)-6-((1-(2-(1-methylpyrrolidin-2-yl)ethyl)-1H-1,2,3-triazol-4-yl)methyiamino)quinoline-3-carbonitrile In a 15mL round-bottomed flask were added 6-amino-8-bromo-4-(3-chloro-4-fluoro-phenylamino)-quinoline-3-carbonitrile (0.34g, 1 mmol), dichloroethane (6 mL) and 1 -[2-(1 -Methyl-pyrrolidin-2-yl)-ethyl]-1 H-[1,2,3]triazole-4-carbaldehyde (1.2mmol). The mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (2.4 mmol) was then added and the reaction was stirred at room temperature for 24 h. The reaction mixture was stripped to dryness and the residue was purified via preparative HPLC, and lyophilized to give 8-Bromo-4-(3-chloro-4-fluoro-phenylamino)-6-({1 -[2-(1 -methyl-pyrrolidin-2-yl)-ethyl]-1 H-[1,2,3]triazol-4-ylmethyl}-amino)-quinoline-3-carbonitrile as a yellow solid (0.3 g). The product was then separated by chiral HPLC to give (R)-8-Bromo-4-(3-chloro-4-fluoro-phenylamino)-6-({1-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-1H-[1,2,3]triazol-4-ylmethyl}-amino)-quinoline-3-carbonitrile (75 mg) and (S)-8-bromo-4-(3-chloro-4-fluorophenylamino)-6-((1-(2-(1-methylpyrrolidin-2-yl)ethyl)-1H-1,2,3-triazol-4-yl)methylamino)quinoline-3-carbonitrile (88 mg). 1H NMR (400 MHz, MeOD) 8 ppm 1.48 -1.68 (m, 2 H) 1.84 - 2.21 (m, 4 H) 2.25 - 2.60 (m, 6 H) 3.21 - 3.29 (m, 1 H) 4.58 - 4.73 (m, 2 H) 4.75 (s, 2 H) 7.35 - 7.40 (m, 1 H) 7.42 - 7.47 (m, 1 H) 7.50 (t, J=8.72 Hz, 1 H) 7.59 - 7.67 (m, 1 H) 7.89 (d, J=2.53 Hz, 1 H) 8.15 (s, 1 H) 8.51 (s, 1 H); 1H NMR (400 MHz, MeOD) 8 ppm 1.47 -1.56 (m, 5 H) 1.65 -1.81 (m, 1 H) 1.96 - 2.11 (m, 3 H) 2.22 - 2.36 (m, 1 H) 2.73 (s, 3
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H) 3.19 - 3.33 (m, 3 H) 4.75 (s, 2 H) 7.39 (d, J=2.27 Hz, 1 H) 7.42 - 7.48 (m, 1 H)
7.50 (t, J=8.72 Hz, 1 H) 7.59 - 7.67 (m, 1 H) 7.89 (d, J=2.27 Hz, 1 H) 8.18 (s, 1 H)
8.50 (s, 1 H)
Example 325: 8-chloro-4-(3-chloro-4-fluorophenylamino)-6-((1-(1-cyclobutylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)methylamino)quinoline-3-carbonitrile In a test tube were added 8-chloro-4-(3-chloro-4-fluorophenylamino)~6-((1-(piperidin-4-yl)-1 H-1,2,3-triazol-4-yl)methylamino)quinoline-3-carbonitrile (50 mg), dichloroethane (2 mL) and cyclobutanone(1.2 equiv.). The mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (2 equiv.) was then added and the reaction was stirred at room temperature overnight. The reaction mixture was stripped to dryness and the residue was purified via preparative HPLC, and lyophilized to give 8-ch!oro-4-(3-chloro-4-fluorophenylamino)-6-((1 -(1-cyclobutylpiperidin-4-yl)-1 H-1,2,3-triazol-4-yl)methylamino)quinoline-3-carbonitrile (0.047 g). 1H NMR (400 MHz, MeOD) 8 ppm 2.00 - 2.14 (m, 2 H) 2.32 - 2.42 (m, 2 H) 2.46 - 2.61 (m, 5 H) 2.95 -3.09 (m, 2 H) 3.59 - 3.75 (m, 3 H) 4.76 (s, 2 H) 4.90 - 5.01 (m, 1 H) 7.37 (d, J=2.27 Hz, 1 H) 7.43 - 7.49 (m, 1 H) 7.51 (t, J=8.72 Hz, 1 H) 7.64 (dd, J=6.44, 2.40 Hz, 1 H) 7.70 (d, J=2.53 Hz, 1 H) 8.21 (s, 1 H) 8.53 (s, 1 H)
Example 326: N-[2-({8-chloro-4-[(3-ch!oro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)ethyl]methanesulfonamide
Step 1. In a microwave tube, 2,2-dimethoxyethylamine (0.15 g, 1.44 mmol) was taken up in 5 mL DCM, and Hunig's base (0.50 mL, 2.88 mmol) was added. Methane sulfonylchloride (165.0 mg, 1.44 mmol) was then added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC. The pH was adjusted to 1-2 by adding HCI (1.25 M in MeOH), then 7-8 drops of H2O was added. The reaction mixture was heated to 80°C for 10 min in a microwave. Solvent was reduced to minimum volume. This mixture containing crude aldehyde N-(2-Oxo-ethyl)-methanesulfonamide was used for next step synthesis without purification.
Step 2. The procedure described above for the synthesis of 6-((1 H-imidazol-4-yl)methylamino)-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile was followed, reacting 6-amino-8-chloro-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile (100 mg, 0.29 mmol) with the crude aldehyde, HOAc (200 uL), and NaCNBH3 (12.7 mg, 0.20 mmol) in 3 mL EtOH. Purification using preparative-HPLC gave a yellow solid as product (2.5 mg, 1.9% yield). 1H NMR (400 MHz, MeOD) S
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ppm 1.94 (s, 2 H) 2.85 (s, 3 H) 3.25 - 3.37 (m, 2 H) 6.99 - 7.04 (m, J=2.27 Hz, 1 H) 7.14 - 7.23 (m, 2 H) 7.30 - 7.39 (m, 2 H) 8.21 (s, 1 H); HRMS (ESI+) calcd for Ci9H16CI2FN5O2S (MH+) 468.04585, found 468.0462.
Example 327: 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(1-ethylpiperidin-4-yl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile
In a 15mL round-bottom flask were added 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1 -piperidin-4-yl-1 H-1,2,3-triazol-4-yl)methyl]amino}quinoline-3-carbonitrile (75mg, 0.15mmol), dichloroethane (1mL) and acetaldehyde (7mg, 0.15mmol). Acetic acid was added to bring the pH of the solution to 4, and the mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (64mg, 0.3mmol) was then added and the reaction was stirred at room temperature overnight. The reaction mixture was stripped to dryness and the residue was purified via preparative HPLC, and lyophilized to give the product as a yellow solid (9.4mg, 10.7%). 1H NMR (400 MHz, CHLOROFORM-D) 8 ppm 1.31 (t, J=7.20 Hz, 3 H) 2.29 - 2.41 (m, 3 H) 2.78 - 2.92 (m, 2 H) 2.93 - 3.03 (m, 2 H) 3.39 - 3.51 (m, 2 H) 4.54 (s, 2 H) 7.08 - 7.16 (m, 1 H) 7.20 - 7.29 (m, 2 H) 7.34 - 7.41 (m, 1 H) 7.43 - 7.49 (m, 1 H) 7.65 - 7.68 (m, 1 H) 8.29 - 8.38 (m, 2 H). HRMS: calcd for CaHaCfeFNa + H+, 539.16360; found (ESI-FTMS, [M+H]1+), 539.162
Example 328: 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1 -(1 -propylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile
In a 15mL round-bottom flask were added 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1 -piperidin-4-yl-1 H-1,2,3-triazol-4-yl)methyl]amino}quinoline-3-carbonitrile (100mg, 0.2mmo!), dichloroethane (1mL) and propanal (12mg, 0.2mmol). Acetic acid was added to bring the pH of the solution to 4, and the mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (85mg, 0.4mmol) was then added and the reaction was stirred at room temperature overnight. The reaction mixture was stripped to dryness and the residue was purified via preparative HPLC, and lyophilized to give the product as a yellow solid (68.8mg, 57.5%). 1H NMR (400 MHz, MeOD) 8 ppm 1.02 (t, J=7.33 Hz, 3 H) 1.69 -1.84 (m, 2 H) 2.33 - 2.51 (m, 4 H) 2.98 - 3.08 (m, 2 H) 3.09 - 3.20 (m, 2 H) 3.61 (d, J=12.38 Hz, 2 H) 4.52 (s, 2 H) 4.75 -4.87 (m, 1 H) 7.08 - 7.16 (m, 1 H) 7.19 - 7.30 (m, 2 H) 7.35 - 7.47 (m, 2 H) 8.03 (s, 1 H) 8.26 (s, 1 H) 8.34 (s, 4 H). HRMS: calcd for C27H27CI2FNa + H+, 553.17925; found (ESI-FTMS, [M+H]1+), 553.1817
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Example 329: 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1 -(1 -methylazepan-4-yl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile
In a 15mL round-bottom flask were added 6-{[(1-azepan-4-yl-1H-1,2,3-triazol-4-yl)methyl]amino}-8-chloro-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile (90mg, 0.17mmol), dichloroethane (1mL) and formaldehyde (14mg, 0.17mmol). Acetic acid was added to bring the pH of the solution to 4, and the mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (72mg, 0.34mmol) was then added and the reaction was stirred at room temperature overnight. The reaction mixture was stripped to dryness and the residue was purified via preparative HPLC, and lyophilized to give the product as a yellow solid (23.5mg, 23.6%). 1H NMR (400 MHz, MeOD) 6 ppm 1.91 - 2.05 (m, 1 H) 2.05 - 2.27 (m, 2 H) 2.28 - 2.61 (m, 3 H) 2.89 (s, 3 H) 3.33 - 3.45 (m, 3 H) 3.47 - 3.59 (m, 1 H) 4.51 (s, 2 H) 7.07 - 7.16 (m, 1 H) 7.19 - 7.30 (m, 2 H) 7.34 - 7.45 (m, 2 H) 7.99 (s, 1 H) 8.24 (s, 1 H) 8.47 (s, 1 H). HRMS: calcd for C26H25CI2FN8 + H+, 539.16360; found (ESI-FTMS, [M+H]1+), 539.166
Example 330: 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1 -(1 -ethylazepan-4-yl)-1H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile
In a 15mL round-bottom flask were added 6-{[(1-azepan-4-yl-1H-1,2,3-triazol-4-yl)methyl]amino}-8-chloro-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile (90mg, 0.17mmol), dichloroethane (1mL) and acetaldehyde (8mg, 0.17mmol). Acetic acid was added to bring the pH of the solution to 4, and the mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (72mg, 0.34mmol) was then added and the reaction was stirred at room temperature overnight. The reaction mixture was stripped to dryness and the residue was purified via preparative HPLC, and lyophilized to give the product as a yellow solid (25.4mg, 25%). 1H NMR (400 MHz, MeOD) 5 ppm 1.27 - 1.39 (m, 4 H) 1.89 - 2.04 (m, 1 H) 2.05 - 2.25 (m, 2 H) 2.27 -2.62 (m, 3 H) 3.15 - 3.26 (m, 2 H) 3.32 - 3.46 (m, 3 H) 3.47 - 3.57 (m, 1 H) 4.52 (s, 2 H) 7.10 - 7.16 (m, 1 H) 7.19 - 7.30 (m, 2 H) 7.36 - 7.47 (m, 2 H) 7.98 (s, 1 H) 8.28 (s, 1 H) 8.49 (s, 1 H). HRMS: calcd for C27H27CI2FN8 + H+, 553.17925; found (ESI-FTMS, [M+H]1+), 553.1816
Example 331: 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(1-isopropylazepan-4-yl)-1H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile
In a 15mL round-bottom flask were added 6-{[(1-azepan-4-yl-1H-1,2,3-triazol-4-yl)methyl]amino}-8-chloro-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile
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(90mg, 0.17mmol), dichloroethane (1mL) and acetone (excess). Acetic acid was added to bring the pH of the sclution to 4, and the mixture was stirred for 15 minutes. Sodium triacetoxyborohydride (72mg, 0.34mmol) was then added and the reaction was stirred at room temperature overnight. The reaction mixture was stripped to dryness and the residue was purified via preparative HPLC, and lyophilized to give the product as a yellow solid (67.2mg, 64.4%). 1H NMR (400 MHz, MeOD) 5 ppm 1.35 (d, J=6.57 Hz, 6 H) 1.91 - 2.06 (m, 1 H) 2.08 - 2.39 (m, 3 H) 2.41 - 2.61 (m, 2 H) 3.33 - 3.42 (m, 3 H) 3.43 - 3.53 (m, 1 H) 3.54 - 3.67 (m, 1 H) 4.51 (s, 2 H) 7.08 - 7.16 (m, 1 H) 7.18 - 7.30 (m, 2 H) 7.34 - 7.45 (m, 2 H) 8.25 (s, 1 H) 8.52 (s, 1 H). HRMS: calcd for CaHaCfeFNa + H+, 567.19490; found (ESI-FTMS, [M+H]1+), 567.1962
Example 332: 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1 -(1,4-dioxaspiro[4.5]dec-8-yl)-1H-1,2,3-triazol-4-yQmethyl}amino)quinoline-3-carbonitrile
Step 1: In a round bottom flask was added 1,4-Dioxaspiro{4,5]decan-5-ol (5 g, 31.6 mmol), 20 ml Dichloromethane, and DIEA (7.1ml, 37.9mmol), then the mixture was cooled to 0°C and mesyl chioride (2.9 ml, 34.8 mmol) was added dropwise. The reaction was then warmed to room temperature. After five hours of stirring, the reaction was diluted with dichloromethane and extracted three times with saturated sodium bicarbonate. The organic phase was dried with MgSO4, filtered and evaporated under reduced pressure to give the product as an oil (7.53 g, 93.53%).
Step 2: To the crude from Step 1 was added sodium azide (5.13 g, 78.9 mmol), and 35 ml DMF and the mixture was stirred at 120°C overnight. The reaction was extracted with chloroform/sat. NaHCO3. The organic layer was dried with MgSCU, filtered and the solvent was removed under reduced pressure (4.6 g, 79.3%).
Step 3: To the crude from Step 2 was added 25 ml DMF, 20 ml water, propiolaldehyde diethylacetal (5.4ml, 38mmol), Na L-Ascorbate (250 mg, 1.3 mmol) and CuSO4 (316 mg, 1.3 mmol). The mixture was stirred at 40°C for two hours and then at room temperature overnight. The reaction mixture was extracted with chloroform/ saturated NaHCO3. The organic layer was dried with MgSO4, filtered and the solvent was removed under reduced pressure.
Step 4: The procedure described above for the synthesis of 4-[(3-chloro-4-fluorophenyl)amino]-6-[(1W-imidazol-5-ylmethyl)amino]quinoline-3-carbonitrilewas followed, reacting 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-(chloro)quinoline-3-carbonitrile (2 g, 5.76 mmol) with the crude from Step 3 (254 mg, 13.5 mmol) and NaCNBH3 (362.0 mg, 5.76 mmol) in 40mL DMF. The reaction was filtered and purified via preparative HPLC, and lyophilized to give the product as a yellow solid
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(0.8g, 36.7%): 1H NMR (400 MHz, DMS0-D6) 8 ppm 1.64 -1.79 (m, 4 H) 1.93 - 2.03 (m, 4 H) 3.89 (s, 4 H) 4.42 (d, J=5.31 Hz, 2 H) 4.53 - 4.64 (m, 1 H) 6.88 (t, J=5.31 Hz, 1 H) 7.24 (d, J=2.27 Hz, 1 H) 7.26 - 7.32 (m, 1 H) 7.46 (t, J=8.97 Hz, 1 H) 7.53 (dd, J=6.44, 2.65 Hz, 1 H) 7.56 (d, J=2.27 Hz, 1 H) 8.13 (s, 1 H) 8.40 (s, 1 H) 9.48 (s, 1 H); HRMS: calcd for C27H24C!2FN7O2 + H+, 568.14253; found (ESI-FTMS, [M+H]1+), 568.14101.
Example 333: 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1 -(4-oxocyclohexyl)-1H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile
In a round bottom flask was added 8-chloro-4-[(3-chloro-4-fluorophenyl) amino]-6-({[1-(1,4-dioxaspiro[4.5]dec-8-yl)-1 H-1,2,3-triazol-4-yl]methyl}amino) quinoline-3-carbonitrile (400 mg, 0.7 mmol), 8ml TFA, 1 ml Acetone and 1 ml water, and the mixture was stirred overnight. The reaction was filtered and purified via preparative HPLC, and lyophilized to give the product as a yellow solid (234 mg, 63.4%): 1H NMR (400 MHz, DMSO-D6) 8 ppm 1.01 - 1.11 (m, 3 H) 1.21 - 1.36 (m, 1 H) 1.57 -1.84 (m, 5 H) 1.97 - 2.08 (m, 2 H) 2.08 - 2.21 (m, 1 H) 2.54 - 2.64 (m, 1 H) 2.67 - 2.73 (m, 1 H) 4.37 - 4.55 (m, 3 H) 6.68 (s, 1 H) 6.90 (t, J=5.81 Hz, 1 H) 7.22 -7.33 (m, 2 H) 7.45 (t, J=9.09 Hz, 1 H) 7.50 - 7.55 (m, 1 H) 7.56 (t, J=2.40 Hz, 1 H) 8.11 (d, J=19.20 Hz, 1 H) 8.40 (d, J=2.27 Hz, 1 H) 9.50 (s, 1 H): HRMS: calcd for C25H2oCI2FN70 + H+, 524.11632; found (ESI-FTMS, [M+H]1+), 524.11386.
Example 334: 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-phenyl-1 H-1,2,3-trjazol-4-yl)methyl]amino}quinoline-3-carbonitrile
Step 1: The procedure described above for the synthesis of 6-{[(1 -fe/t-butyl-1H-1,2,3-triazol-4-yl)methyl]amino}-8-chloro-4-[(3-chloro-4-fluorophenyl)amino] quinoline-3-carbonitrile was followed, reacting (1-phenyl-1H-1,2,3-triazol-4-yl)methanol (576mg, 3.31 mmol), 4mL methylene chloride , 4mL DME and 576mg MnO2. Purification by flash chromatography (1 to 1.5% MeOH/DCM) gave the product (400 mg, 70.2%).
Step 2: In a 50ml round bottom flask was added 10 ml anhydrous MeOH, 1ml DIEA, 630mg 2,2,2-Trifluoroethylamine HCI and the product from Stepi and the mixture was stirred at room temperature overnight under nitrogen flow. MeOH was removed under reduced pressure. The salts were washed with water/EtOAc and then with brine. The EtOAc phase was dried with MgSC>4 and filtered. The solvent was removed under reduced pressure to give the product as a yellow solid (~440mg, -74.8%).
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Step 3: In a Microwave tube was added crude from step 2 in ~3g of DMSO. Replacement reaction was done in a microwave reactor at 140 °C for 15min. After extraction with brine/EtOAc, the organic layer was dried over MgSO4 and filtered and then the solvent was removed under reduced pressure. The crude product was used in the next step.
Step 4: In a 50 ml round bottom flask was added the crude from step 3 in 15 ml MeOH, 4.0 ml formic acid (96%) and 11 ml water and refluxed overnight at 80 °C. The reaction was then cooled to room temperature and 50 ml water was added. The product was extracted three times with chloroform, and the chloroform extracts were washed with water and dried over MgSO4. The solvent was removed under reduced pressure and the crude was used in the next step.
Step 5: The procedure described above for the synthesis of 4-[(3-chloro-4-fluorophenyl)amino]-6-[(1H-imidazol-5-ylmethyl)amino]quinoline-3-carbonitrilewas followed, reacting 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-(chloro)quinoline-3-carbonitrile (50.0 mg, 0.14 mmol) with the crude from Step 4 and NaCNBH3 (17.4 mg, 0.28 mmol) in 10 mL EtOH. The reaction was stripped to dryness and the residue was purified via preparative HPLC, and lyophilized to give the product as a yellow solid (28.1 mg, 38.7%): 1H NMR (400 MHz, DMSO-D6) 5 ppm 4.55 (d, J=5.56 Hz, 2 H) 6.98 (t, J=5.18 Hz, 1 H) 7.25 - 7.33 (m, 2 H) 7.45 (t, J=8.97 Hz, 1 H) 7.48 -7.52 (m, 1 H) 7.54 (dd, J=6.32, 2.27 Hz, 1 H) 7.56 - 7.62 (m, 3 H) 7.84 - 7.89 (m, 2 H) 8.40 (s, 1 H) 8.76 (s, 1 H) 9.51 (s, 1 H); HRMS (ESI+) calcd for C25H16CI2FN7 (MH+) 504.09010, found 504.09.
Example 335: 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1 -(4-hydroxy-4-pyridin-2-ylcyclohexyl)-1H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile
Step 1: 25]nL 2-Bromopyridine was mixed into 5ml THF, cooled to -78°C and 105JJ1 solution of Butyl lithium (2.5M in Hexanes) was added dropwise. The reaction was stirred for 15 minutes, then a solution of 4-[4-(diethoxymethyl)-1H-1,2,3-triazol-1-yl]cyclohexanone (70.4mg in 3 ml THF) was added over five minutes under nitrogen flow. The reaction was stirred 1h at-78°C and 1h at room temperature. The solvent was removed under reduced pressure to yield brown oil.
Step 2: To the crude from Step 1 was added 6ml of a 1.25M solution of hydrochloric acid in methanol and 2ml water. The mixture was then refluxed for an hour and the solvents were removed under reduced pressure to yield brown oil.
Step 3: The procedure described above for the synthesis of 4-[(3-chloro-4-fluorophenyl)amino]-6-[(1H-imidazol-5-ylmethyl)amino]quinoline-3-carbonitrilewas
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followed, reacting 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-(chloro)quinoline-3-carbonitrile (49.5mg, 0.142mmol) with the crude from Step 2 and NaCNBH3 (25mg, 0.4mmol) in 4mL DMF. The reaction was filtered and purified via preparative HPLC, and lyophilized to give the product as a yellow solid (3.0mg, 3.49%). 1H NMR (400 MHz, DMSO-d6) 8 ppm 1.52 -1.62 (m, 1 H) 1.67 -1.75 (m, 1 H) 1.92 - 2.01 (m, 2 H) 2.04 - 2.31 (m, 4 H) 4.45 (d, J=4.80 Hz, 2 H) 4.60 - 4.70 (m, 1 H) 5.26 (d, .7=16.42 Hz, 1 H) 6.88 (s, 1 H) 7.18 - 7.36 (m, 3 H) 7.37 - 7.61 (m, 3 H) 7.61 - 7.73 (m, 1 H) 7.74 - 7.85 (m, 1 H) 8.14 (d, J=9.09 Hz, 1 H) 8.34 - 8.44 (m, 1 H) 8.45 - 8.55 (m, 1 H) 9.51 (s, 1 H); HRMS: calcd for C3oH25CI2FN80 + H+, 603.15852; found (ESI-FTMS, [M+H]1+), 603.15706.
BIOLOGICAL TESTING
To determine whether Tpl2 inhibitors may be efficacious in the treatment of rheumatoid arthritis, as well as other inflammatory disease states, an N-terminal 6His-tagged human Cot/Tpl2 kinase construct encoding residues 30-398 was expressed in a baculovirus system (BD Biosciences, San Jose, CA). Sf9 cells expressing the kinase were lysed in 50 mM NaPhosphate pH = 8; 300 mM NaCI; 5 mM imidazole; 0.1 mM EGTA; 25 mM beta-glycerophosphate; 1%TX-100,1% giycerol; 6 mM beta-mercaptoethanol and protease inhibitors. The lysate was clarified by centrifugation and was loaded onto a Ni-Sepharose column. The column was washed with 50 mM NaPhosphate pH = 8; 300 mM NaCI; 15 mM imidazole; 1% giycerol; and 6 mM beta-mercaptoethanol. His-Tpl2 was eluted with 50 mM NaPhosphate pH = 8; 300 mM NaCI; 250 mM imidazole; 1% giycerol; and 6 mM beta-mercaptoethanol. The eluted protein was further purified by size exclusion chromatography. Fractions corresponding to monomeric Tpl2 were then used in the assay.
Tpl2/Cot activity was directly assayed using GST-MEK1 as a substrate. GST-MEK1 phosphorylation on serine residues 217 and 221 was detected by ELISA. 0.4 nM Tpl2 was incubated with 35 nM GST-MEK1 in a kinase reaction buffer containing 20 mM MOPS pH = 7.2; 50 uM ATP; 20 mM MgCI2; 1 mM DTT; 25 mM p-glycerophosphate; 5 mM EGTA; and 1 mM sodium orthovanadate for 1 h at 30°C. The compounds of the inventions solubilized in 100% DMSO were pre-diluted in assay buffer so that the final concentration of DMSO in the reaction was 1%. The kinase reaction was carried out in 100 ul volume on 96 well plates. The kinase reaction was then stopped with the addition of 100 mM EDTA. The entire reaction mix was then transferred to the detection plate, a 96 well Immunosorb
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plate that had been pre-coated with anti-GST antibody (Amersham). After a 1 hour incubation at room temperature, the detection plate was washed 4 times with TBST (TBS+0.05% Tween 20) and then incubated for another hour at room temperature with anti phospho-MEK1 antibody (Gell Signaling) 1:1000 in 10 mM MOPS 7.5; 150 mM NaCI; 0.05% Tween 20; 0.1% Gelatin; 0.02% NaN3; and 1% BSA. The detection plate was washed again and incubated for 30 min with DELFIA Europium (Eu) labeled goat anti-rabbit IgG (Perkin-Elmer), 1:4000 in the same buffer used for the primary incubation. After a final wash, Eu detection solution was added to each well and the Eu signal was measured in a Wallac Victor2 Multilabel Counter. IC50 calculations were performed using the XLfit software package (IDBS, Guildford, UK). IC50 values for representative compounds according to the invention are listed in Table 1 below.
Table 1

Example ICso (MM)
1 11
2 23.9
3 0.24
4 0.03
5 0.37
6 0.2
7 0.018
8 0.031
g 0.211
10 0.2
11 0.123
12 1.3
13 0.03
14 0.14
15 0.015
16 0.227
17 0.19
18 0.28
19 0.59
20 0.61
21 0.13
22 0.068
23 0.64
24 0.38
25 0.082
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26 >40
27 0.074
28 1.1
29 5.2
30 0.13
31 0.11
32 >40
33 0.2
34 0.26
35 1.8
36 0.63
37 0.41
38 2.6
39 0.011
40 2.4
41 2.2
2 26.8
43 15.3
44 3.3
45 14.7
46 30
47 0.013
48 1.5
49 >40
50 0.2
51 0.11
52 1.5
53 0.54
54 1.3
55 1.8
56 3.4
57 0.65
58 1.1
59 3.8
60 >40
61 0.81
62 >40
63 >40
64 >40
66 >40
68 11
69 0.42
70 0.036
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71 0.4
72 0.024
73 >40
74 0.14
75 2.6
76 0.0068
77 0.11
78 0.075
79 0.57
80 >40
81 >40
82 3.9
83 0.063
84 >40
85 0.67
86 1.1
87 0.13
88 0.25
89 0.29
90 1.7
91 0.36
92 >40
93 >40
94 0.53
95 >40
96 n 0.44
97 0.23
98 1.5
99 24.1
100 >40
101 0.0041
102 1.3
103 0.51
104 1.5
105 0.17
106 5.9
107 0.9
108 0.55
109 2.2
110 0.087
111 0.033
112 0.0035
113 0.01
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114 0.31
115 0.13
116 0.016
117 >40 '
118 0.11
119 0.35
120 0.024
121 0.114
122 0.58
123 0.54
124 >10
125 11
126 3.3
127 0.064
128 0.0032
129 0.014
130 0.26
131 16
132 17.3
133 0.2
134 >40
135 >40
135 0.064
137 0.028
138 0.027
139 0.099
140 0.02
141 0.12
142 1.8
143 0.75
144 0.92
145 2.1
146 5.3
147 1.6
148 2.2
149 1.5
150 6.4
151 0.61
152 1.3
153 0.22
154 2.5
155 1.5
156 0.42
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157 8.5
158 >40
159 9.2
160 >40
161 >40
162 >40
163 0.15
164 >40
165 >40
166 >40
167 0.028
168 0.15
169 0.021
170 0.68
171 0.014
172 0.084
173 >40
174 3.5
175 0.31
176 4.3
177 0.01
178 0.016
179 3.9
180 >40
181 11.3
182 0.018
183 0.022
184 0.11
185 0.047
186 0.045
187 0.13
188 0.059
189 0.1
190 0.32
191 0.064
192 0.17
193 0.41
194 9.7
195 0.032
196 0.066
198 0.87
199 1.4
200 0.068
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201 0.0091
204 2.6
205 0.0032
206 7.4
210 1.9
211 0.35
212 0.4
213 1.5
214 0.016
215 0.14
216 0.0059
217 0.0072
218 0.032
219 0.065
220 0.026
221 0.028
222 0.01
223 0.037
224 0.28
225 >40
226 >40
227 >40
228 0.48
229 0.19
230 >40
231 19.7
232 24
233 >40
234 15.1
235 >40
236 0.2
237 24.8
238 8.4
239 0.78
240 0.19
241 >40
242 >40
243 >40
244 >40
245 0.91
246 2.4
247 2.5
248 2.5
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249 0.38
250 6.8
251 0.65
252 6.1
253 1.4
254 19.9
255 >40
256 0.31
257 0.37
258 0.27
259 >40
260 0.83
261 >40
262 2.2
263 1.6
264 2.5
265 0.021
266 0.013
267 0.1
268 0.012
269 0.016
270 0.1
271 0.054
272 0.047
273 0.083
274 .035
275 0.37
276 4.7
277 0.066
278 0.46
279 0.0026
280 >40
281 0.042
282 0.023
283 0.13
284 0.02
286 0.19
287 0.34
288 >40
289 0.203
290 >40
291 0.0072
292 0.0035
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293 0.013
294 0.5
295 0.067
296 0.015
297 0.029
298 0.038
299 0.48
300 0.022
301 0.008
302 0.021
303 >40
304 0.017
305 0.025
306 0.017
307 0.061
308 0.028
309 7.1
310 0.15
311 0.012
312 9.7
313 0.23
314 0.91
315 0.018
316 0.01
317 0.019
318 0.0057
319 0.21
320 0.0056
321 0.49
322 2.12
323 1.36
324 0.05
325 0.01
326 0.07
327 0.0016
328 0.0082
329 0.0044
330 0.0085
331 0.0082
332 0.039
333 0.0011
334 0.12
335 0.02
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Additional representative compounds of the invention made according to the methods described herein and their corresponding IC50 values are listed in Table 2 below.
Table 2

Example Compound IC50 (μM)
336 6-bromo-4-[(4-phenoxyphenyl)amino]quinoline-3-carbonitrile 1
337 4-[(3-chloro-4-fiuorophenyl)amino]-6-[(2-morpholin-4-ylethyl)amino]quinoline-3-carbonitrile 1
338 6-[(2-morpholin-4-ylethyl)amino]-4-[(4-phenoxyphenyl)amino]quinoline-3-carbonitrile 0.15
339 6-bromo-4-[(4-methoxyphenyl)arnino]quinoline-3-carbonitrile 40
340 4-[(3,4-difluorophenyl)amino]-6-{[(6-methoxypyridin-3-yl)methyl]amino}quinoline-3-carbonitrile 0.44
341 4-[(3,4-difluorophenyl)amino]-6-{[(6-oxo-1,6-dihydropyridin-3-yl)methyl]amino}quinoline-3-carbonitrile 0.4
342 6-[(2-morpholin-4-ylethyl)amino]-4-{[3-(trifluoromethyl)phenyl]amino}quinoline-3-carbonitrile >10
343 4-[(3,4-difluorophenyl)amino]-6-{[(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl] amino}quinoline-3-carbonitrile 1.04
344 4-[(3,4-difluorophenyl)amino]-6-({[6-(2-morpholin-4-ylethoxy)pyridin-3-yl]methyl}amino)quinoline-3-carbonitrile 1.48
345 4-[(3,4-difluorophenyl)amino]-6-({[1-(2-morpholin-4-ylethyl)-6-oxo-1,6-dihydropyridin-3-yl]methyl}amino)quinoline-3-carbonitrile 1.7
346 6-[(1,3-benzodioxol-5-ylmethyl)amino]-4-[(3-chlorophenyl)amino]quinoline-3-carbonitrile 0.6
347 4-[(3-chlorophenyl)amino]-6-({4-[3-(dimethylamino) propoxy]benzyl}amino)quinoline-3-carbonitrile 0.6
348 4-[(3-chlorophenyl)amino]-6-[(pyridin-3-ylmethyl)amino] quinoline-3-carbonitrile 0.09
349 4-[(3-chlorophenyl)amino]-6-{[4-(methylsulfonyl) benryl]amino}quinoline-3-carbonitrile 0.37
350 4-[(3-chlorophenyl)amino]-6-[(2-morpholin-4-ylethyl)amino]quinoline-3-carbonitrile 0.69
351 4-[(3-fluorophenyl)amino]-6-[(2-morpholin-4-ylethyl)amino]quinoline-3-carbonitrile 1.9
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352 4-[(3-isopropylphenyl)amino]-6-[(2-morpholin-4-ylethyl)amino]quinoline-3-carbonitrile >10
353 4-{[3-chloro-4-(phenylthio)phenyl]amino}-6-[(2-morpholin-4-ylethyl)amino]quinoline-3-carbonitrile 0.47
354 4-{[3-(dimethylamino)phenyl]annino}-6-[(2-morpholin-4-ylethyl)amino]quinoline-3-carbonitrile >10
355 4-[(4-bromophenyl)amino]-6-[(2-morpholin-4-ylethyl)amino]quinoline-3-carbonitrile >10
356 4-(1H-indol-5-ylamino)-6-[(2-morpholin-4-ylethyl)amino]quinoline-3-carbonitrile >10
357 4-[(3-ethynylphenyl)amino]-6-[(2-morpholin-4-ylethyl)amino]quinoline-3-carbonitrile 1.3
358 4-[(3-chloro-4-fluorophenyl)thio]-6-[(2-morpholin-4-ylethyl)amino]quinoline-3-carbonitrile >40
359 e-aminop-chlorophenyOaminol-S-cyano-N.N-dimethylquinoline-8-carboxamide 8.4
360 4-(cyclohexylamino)-6-[(pyridin-2-ylmethyl)amino]quinoline-3-carbonitrile 0.21
361 4-anilino-6-[(pyridin-2-ylmethyl)amino]quinolihe-3-carbonitrile 0.25
362 8-bromo-4-[(3-chlorophenyl)amino]-6-nitroquinoline-3-carbonitrile >10
363 6-amino-4-[(1-benzylpiperidin-4-yl)amino]quinoline-3-carbonitrile >40
364 4-[(3-chloro-4-fIuorophenyl)amino]-6-[(1-methylpiperidin-4-yl)amino]quinoline-3-carbonitrile >10
365 6-amino-8-bromo-4-[(3-chlorophenyl)amino]quinoline-3-carbonitrile 0.39
366 4-[(3-chloro-4-fluorophenyl)amino]-6-[(1-isopropylpiperidin-4-yl)amino]quinoline-3-carbonitrile 25.5
367 4-[(1-benzylpiperidin-4-yl)amino]-6-[(2-morpholin-4-ylethyl)amino]quinoline-3-carbonitrile >40
368 4-(3-chloro-4-fluorophenoxy)-6-[(2-morpholin-4-ylethyl)amino]quinoline-3-carbonitrile >40
369 4-[(3-chloro-4-fluorophenyl)amino]-6-{[(2-ethyl-4-methyl-1H-imidazol-5-yl)methyl]amino}quinoline-3-carbonitrile 0.64
370 4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1,5-dimethyl-1 H-imidazol-4-yl)methyl]amino}quinoline-3-carbonitrile 0.0032
371 6-{[3-bromo-4-(2-methoxyethoxy)benzyl]amino}-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 0.38
372 8-bromo-4-[(3-chlorophenyl)amino]-6-[(2-morpholin-4-ylethyl)amino]quinoline-3-carbonitrile 0.42
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373 4-[(3-chloro-4-fluorophenyl)amino]-6-({[5-methyl-1-(2-morpholin-4-ylethyl)-1H-imidazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.014
374 8-bromo-4-[(3-chlorophenyl)amino]-6-[(pyridin-3-ylmethyl)amino]quinoline-3-carbonitrile 0.036
375 4-[(3-chloro-4-fluorophenyl)amino]-6-{[3-cyano-4-(2-methoxyethoxy)benzyl]amino}quinoline-3-carbonitrile 0.082
376 4-[(3-chlorophenyl)amino]-3-cyano-N,N-dimethyl-6-[(pyridin-3-ylmethyl)amino]quinoline-8-carboxamide 0.4
377 4-[(3-chloro-4-fluorophenyl)amino]-6-[( 1 -ethyl-3-methylpiperidin-4-yl)amino]quinoline-3-carbonitrile >40
378 6-[(1-benzylpiperidin-4-yl)amino]-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 1.7
379 tert-butyl4-({4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)piperidine-1-carboxylate >40
380 4-[(3-chloro-4-fluorophenyl)amino]-8-methoxy-6-[(pyridin-3-ylmethyl)amino]quinoline-3-carbonitrile 1.1
381 tert-butyl{2-bromo-4-[({4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]phenoxy}acetate >40
382 4-[(3-chloro-4-fluorophenyl)amino]-6-[(1H-pyrazol-3-ylmethyl)amino]quinoline-3-carbonitrile 0.074
383 4-[(3-chloro-4-f!uorophenyl)amino]-8-methoxy-6-[(2-morpholin-4-ylethyl)amino]quinoline-3-carbonitrile 5.2
384 4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-oxidopyridin-3-yl)methyl]amino}quinoline-3-carbonitrile 0.13
385 4-t(3-chloro-4-fluorophenyl)amino]-6-{[(5-methyl-1H-pyrazol-3-yl)methyl]annino}quinoline-3-carbonitrile 0.11
386 4-[(3-hydroxy-4-methylphenyl)amino]-8-methoxy-6-[(pyridin-3-ylmethyl)amino]quinoline-3-carbonitrile >40
387 4-[(3-bromophenyl)amino]-8-[(dimethylamino)methyl]-6-[(2-morpholin-4-ylethyl)amino]quinoline-3-carbonitrile >40
388 4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1,4-dimethyl-1 H-imidazol-5-yl)methyl]amino}quinoline-3-carbonitrile 0.2
389 4-[(3-chloro-4-fIuorophenyl)amino]-6-{[(4-chloro-1-methyl-1H-pyrazol-3-yl)methyl]amino}quinoline-3-carbonitrile >40
390 6-amino-4-[(4-benzylphenyl)amino]quinoline-3-carbonitrile 0.043
391 4-[(4-benzylphenyl)amino]-6-[(2-morpholin-4-ylethyl)amino]quinoline-3-carbonitrile 0.026
392 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-7-methy!quinoline-3-carbonitrile >40
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393 6-amino-8-bromo-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 0.52
394 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-(trifluoromethyl)quinoline-3-carbonitrile 5.8
395 4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-N,N-dimethyl-6-nitroquinoIine-8-carboxamide >40
396 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-N,N-dimethylquinoline-8-carboxamide 6
397 methyl 3-[({4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]benzoate 0.32
398 3-[({4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]benzoic acid 0.18
399 3-[({4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]benzamide 0.46
400 4-(cycloheptylamino)-6-[(1H-imidazol-5-ylmethyl)amino]quinoline-3-carbonitrile 0.49
401 4-(tert-butylamino)-6-[(1H-imidazol-5-ylmethyl)amino]quinoline-3-carbonitrile 3.1
402 6-amino-4-(cyclopentylamino)quinoline-3-carbonitrile >40
403 4-(tert-butylamino)-6-[(3-cyanobenzyl)amino]quinoline-3-carbonitrile 11.5
404 4-(tert-butylamino)-6-{[3-(methylsulfonyl)benzyl]amino} quinoline-3-carbonitrile 4.8
405 4-(tert-butylamino)-6-[(1H-pyrazol-5-ylmethyl)amino]quinoline-3-carbonitrile >40
406 4-(tert-butylamino)-6-{[( 1-oxidopyridin-2-yl)methyl]amino} quinoline-3-carbonitrile 5.4
407 4-(tert-butylamino)-6-{[(1 -methyl-1 H-imidazol-2-yl)methyl]amino}quinoline-3-carbonitrile 5.1
408 4-({[4-(tert-butylamino)-3-cyanoquinolin-6-yl]amino}methyl)benzenesulfonamide 21.9
409 6-amino-8-chloro-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 0.92
410 4-(cyclopentylamino)-6-{[(1-oxidopyridin-2-yl)methyl]amino} quinoline-3-carbonitrile 1.3
411 4-({[3-cyano-4-(cyclopentylamino)quinolin-6-yl]amino}methyl)benzenesulfonamide 7.3
412 4-(cyclopentylamino)-6-{[(1 -methyl-1 H-imidazol-2-yl)methy0amino}quinoline-3-carbonitrile 3
413 4-(cyclopentylamino)-6-[(1H-pyrazol-5-ylmethyl)amino] quinoline-3-carbonitrile 1.6
414 4-(cyclopentylamino)-6-{[3~ (methylsulfonyl)benzyl]amino} quinoline-3-carbonitrile 2.9
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415 6-(benzylamino)-4-(cyclopentylamino)quinoline-3-carbonitrile 21.3
416 6-[(2-cyanobenzyl)amino]-4-(cyclopentylamino)quinoline-3-carbonitrile 1.7
417 4-(cyclopentylamino)-6-[(1H-imidazol-5-ylmethyl)amino] quinoline-3-carbonitrile 0.3
418 4-(cyclopentylamino)-6-[(pyridin-3-ylmethyI)amino]quinoline-3-carbonitrile 2.6
419 4-(cyclopentylamino)-6-[(2-morpholin-4-ylethyl)amino]quinoline-3-carbonitrile 19.7
420 6-[(3-cyanobenzyl)amino]-4-(cyclopentylamino)quinoline-3-carbonitrile 2.2
421 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-8-hydroxyquinoline-3-carbonitrile 10.6
422 4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-oxidopyridin-2-yI)methyl]amino}-2-oxo-1,2-dihydroquinoline-3-carbonitrile >40
423 4-[(3-chloro-4-fluorophenyl)amino]-6-[(1H-imidazol-5-ylmethyl)amino]-2-oxo-1,2-dihydroquinoline-3-carbonitrile >40
424 8-bromo-4-[(3-chloro-4-fIuorophenyl)amino]-6-{[4-(1,112,2-tetrafluoroethoxy)benzyl]amino}quinoline-3-carbonitrile >40
425 6-amino-4-[(3-tert-butyl-1 -methyl-1 H-pyrazol-5-yl)amino] quinoline-3-carbonitrile >40
426 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-methyl-1H-imidazol-2-yl)methyl]amino}quinoline-3-carbonitrile 0.0032
427 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[(1H-pyrazol-3-ylmethyl)amino]quinoline-3-carbonitrile 0.047
428 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[2,2,2-trifluoro-1 -hydroxy-1 -(trifluoromethyl)ethyl]benzyl}amino) quinoline-3-carbonitrile >40
429 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(5-methyl-1H-pyrazol-3-yl)methyl]amino}quinoline-3-carbonitrile 0.1
430 S-chloroKS-chlorofluorophenyOaminol-e-IKI.S-dimethyl-1H-pyrazol-5-yl)methyl]amino}quinoline-3-carbonitrile 0.12
431 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(2,5-dimethyl-1H-imidazol-4-yl)methyl]amino}quinoline-3-carbonitrile 0.22
432 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[2-(methoxymethyl)-i H-imidazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.26
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433 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-pheny!-1H-pyrazol-5-yl)methyl]amino}quinoline-3-carbonitrile 0.25
434 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-{l(2-phenyl-2H-1,2,3-triazol-4-yl)methyl]amino}quinoline-3-carbonitrile >40
435 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-({[5-(trimethylsilyl)-2H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.021
436 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-hydroxy-1H-imidazol-5-yl)methyl]amino}quinoline-3-carbonitrile 0.15
437 4-[(3-chloro-4-fluorophenyl)amino]-8-fluoro-6-{[(''-hydroxy-1H-imidazol-5-yl)methyl]amino}quinoline-3-carbonitrile 0.2
438 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-hydroxy-1H-imidazol-5-yl)methyl]amino}quinoline-3-carbonitrile 0.11
439 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-methyl-1H-imidazol-5-yl)methyl]amino}quinoline-3-carbonitrile 0.22
440 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[(1,2,3-thiadiazol-4-ylmethyl)amino]quinoline-3-carbonitrile 0.049
441 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(2-cyclopentyl-5-methyl-1H-imidazol-4-yl)methyl]amino}quinoline-3-carbonitrile 1.9
442 methyl 2-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 -methyl-1 H-imidazole-5-carboxylate 3.4
443 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(5-propyl-1H-imidazol-4-yl)methyl]amino}quinoline-3-carbonitrile 0.025
444 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(5-methyl-2-pyridin-3-yl-1H-imidazol-4-yl)methyl]amino}quinoline-3-carbonitrile 20.6
445 8-chloro-4-[(3-chloro-4-fIuorophenyl)amino]-6-{[(3-methoxy-2-thienyl)methyl]amino}quinoline-3-carbonitrile 1.1
446 8-bromo-4-(3-chloro-4-fluorophenylamino)-6-((1-methyl-1H-pyrazol-5-yl)methylamino)quinoline-3-carbonitrile 0.098
447 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[(2-oxo-2-phenylethyl)amino]quinoline-3-carbonitrile 0.87
448 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[(4,516,7-tetrahydro-1H-indazol-3-ylmethyl)amino]quinoline-3-carbonitrile 0.37
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449 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-{l(1,5-dimethyl-1H-pyrazol-3-yl)methyl]amino}quinoline-3-carbonitrile 5.5
450 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[(2-methyl-2-morpholin-4-ylpropyl)amino]quinoline-3-carbonitrile 2.4
451 8-chloro-4-[(3-chloro-4-fIuorophenyl)amffro]-&-[(2H-1,2,3-tria2ol-4-y!methyl)amino]quinoline-3-carbonitrile 0.031
452 4-[(3-chloro-4-fluorophenyl)amino]-6-[(1H-imidazol-5-ylmethyl)amino]-8-iodoquinoline-3-carbonitrile 0.051
453 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-methyl-5-phenyM H-pyrazol-3-yl)methyl]amino}quinoline-3-carbonitrile >40
454 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(5-phenyl-1H-pyrazol-3-yl)methyl]amino}quinoline-3-carbonitrile 0.33
455 8-bromo-4-[(3-chloro-4-fIuorophenyl)amino]-6-{[(5-pyridin-4-yl-1H-pyrazol-3-yl)methyl]amino}quinoline-3-carbonitrile 13.5
456 8-bromo-6-{[(4-bromo-1 -methyl-1 H-pyrazol-5-yl)methyl]amino}-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 1
457 4-[(3-chloro-4-fIuorophenyl)amino]-6-[(1H-imidazol-5-ylmethyl)amino]-8-vinylquinoline-3-carbonitrile 0.17
458 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[(2,3-dihydroxybenzyl)amino]quinoline-3-carbonitrile 1.3
459 8-acetyl-4-t(3-chloro-4-fluorophenyl)amino]-6-[(1H-imidazol-5-ylmethyl)amino]quinoline-3-carbonitrile 0.023
460 6-[({1 -[(benzyloxy)methyl]-4-[3-(dimethylamino)prop-1 -yn-1-yl]-1H-imidazol-5-yl}methyl)amino]-8-chloro-4-[(3-chloro-4-fluoraphenyl)amino]quinoline-3-carbonitrile 2
461 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({4-[3-(dimethylamino)propyl]-1H-imidazol-5-yl}methyl)amino]quinoline-3-carbonitrile 0.13
462 4-[(3-chloro-4-fluorophenyl)amino]-8-(2-hydroxyethyl)-6-[(1H-imidazol-5-ylmethyl)amino]quinoline-3-carbonitrile 1.2
463 4-[(3-chloro-4-fluorophenyl)amino]-8-(1-hydroxyethyl)-6-[(1H-imidazol-5-ylmethyl)amino]quinoline-3-carbonitrile 0.26
464 4-[(3-chloro-4-fluorophenyl)amino]-8-(hydroxymethyl)-6-[(1H-imidazol-5-yltnethyl)amino]quinoline-3-carbonitrile 0.57
465 N-{8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}glycine 0.051
466 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(2-methyl-2H-tetrazol-5-yl)methyI]amino}quinoline-3-carbonitrile 0.23
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467 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[2-(2-methyl-2H-tetrazol-5-yl)ethyl]amino}quinoline-3-carbonitrile 1.2
468 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[2-(4-methylpiperazin-1-yl)-2-oxoethyl]amino}quinoline-3-carbonitrile 0.36
469 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[2-(1-methyl-1H-tetrazol-5-yl)ethyl]amino}quinoIine-3-carbonitrile 0.17
470 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[(2-oxo-2-piperazin-1-ylethyl)amino]quinoline-3-carbonitrile 0.42
471 2-(8-chloro-4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino)-N-methoxy-N-methylacetamide >40
472 2-(8-chloro-4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino)-N-methoxyacetamide 0.16
473 2-(8-chloro-4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino)-N-methylacetamide 0.47
474 2-(8-chloro-4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino)-N,N-dimethylacetamide 1.7
475 ethyl N-{8-chloro-4-[(3-chloro-4-fluorophenyI)amino]-3-cyanoquinolin-6-yl}glycinate 1.4
476 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(5-ethyl-1H-imidazol-4-yl)methyl]amino}quinoline-3-carbonitrile 0.016
477 6-(bis{[1-(2-morpholin-4-ylethyl)-1 H-1,2,3-triazoM-yl]methyl}amino)-8-bromo-4-[(3-chloro-4-fluoropheny!)amino]quinoline-3-carbonitrlle >40
478 8-chloro-4-l(3-chloro-4-fluorophenyl)amino]-6-{[(1-methyl-1 H-1,2,4-triazol-3-yl)methyl]annino}quinoline-3-carbonitrile 0.53
479 6-({[1 -(1 -adamantyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)-8-bromo-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 1.7
480 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[3-(dimethylamino)propyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.02
481 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[2-(dimethylamino)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.024
482 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(2-morpholin-4-ylethyl)-1H-imidazol-5-yl]methyl}amino)quinoline-3-carbonitrile 0.16
483 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[(1 H-1,2,4-triazol-3-ylmethyl)amino]quinoline-3-carbonitrile 0.1
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484 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[(1 H-1,2,4-triazol-3-ylmethyl)amino]quinoline-3-carbonitrile 0.11
485 6-{[(1 -tert-butyl-1 H-1,2,3-triazol-4-yl)methyl]amino}-8-chloro-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 0.029
486 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-methyl-1 H-112,4-triazol-3-yl)methyl]amino}quinoline-3-carbonitrile 0.2
487 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(2-hydroxypropyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.011
488 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(2-morpholin-4-ylethyl)-1H-imidazol-4-yl]msihyl}amino)quinoline-3-carbonitrile 0.041
489 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(2-morpholin-4-ylethyl)-1H-imidazol-5-yl]methyl}amino)quinoline-3-carbonitrile 0.062
490 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(2-morpholin-4-ylethyl)-1H-imidazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.033
491 8-chloro-4-[(3-chloro-4-fIuorophenyl)amino]-6-({];i-(2,2,2-trifluoroethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.023
492 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-phenyl-1 H-1,2,3-triazol-4-yl)methyl]amino}quinoline-3-carbonitrile 0.12
493 tert-butyl4-{4-[({8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1 -yl}piperidine-1 -carboxylate 0.25
494 tert-butyl4-({4-[({8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triszoM -yl}methyl) piperidine-1 -carboxylate 0.17
495 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(pyridin-4-ylmethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.0048
496 8-bromo-4-[(3-chloro-4-fIuorophenyl)amino]-6-({[1-(piperidin-4-ylmethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.047
497 8-bromo-6-{[(1 -tert-butyl-1 H-1,2,3-triazol-4-yl)methyl]amino}-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 0.061
498 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(2,2)2-trifluoroethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.1
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499 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1 -[(1 -methylpiperidin-4-yl)methyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.012
500 tert-butyl(2-{4-[({8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1-yl}ethyl)methylcarbamate 0.067
501 di-tert-butyl[({8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}imino)bis(methylene-1 H-1,2,3-triazole-4,1 -diylethane-2,1 -diyl)]bis(methylcarbamate) 4.7
502 tert-butyl(2-{4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazoM -yl}ethyl)methylcarbamate 0.048
503 tert-butyl4-(2-{4-[({8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazoM -yl}ethyl)piperidine-1 -carboxylate 0.13
504 tert-butyl4-(2-{4-t({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1-yl}ethyl)piperidine-1-carboxylate 0.075
505 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[methyl({1-[(1-methylpiperidin-4-yl)methyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.29
506 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-(methyl{[1-(1-methylpiperidin-4-yl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.022
507 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-({[4-(3-methoxypropyl)-1 H-imidazol-5-yl]methyl}amino)quinoline-3-carbonitrile 0.0621
508 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[2-(methylthio)ethyl]-1 H-1,2,3-triazol-4-yl}methy!)amino]quinoline-3-carbonitrile 0.082
509 di-tert-butyl4,4'-[({8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}imino)bis(methylene-1 H-1,2,3-triazole-4,1-diylethane-2,1-diyl)]dipiperidine-1-carboxylate >3
510 8-bromo-4-[(3-chloro-4-fIuorophenyl)amino]-6-({[1-(2-hydroxyethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.028
511 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[2-(methylsulfonyl)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.091
512 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[2-(methylamino)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.038
513 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[2-(methylamino)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.029
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514 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[3-(dimethylamino)propyO-i H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.039
515 8-chloro-4-[(3-chloro-4=fluorophenyl)amino]-6-({[1-(2-pyrralidin-1-ylethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.04
516 8-chloro-4-[(3-chloro-4-f luorophenyl)amino]-6-[({1 -[2-(1 -methylpyrrolidin-2-yl)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.029
517 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(2-piperidin-4-ylethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.09
518 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(2-piperidin-4-ylethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.045
519 8-chloro-4-[(3-chIoro-4-fluorophenyl)amino]-6-({[1-(pyridin-3-ylmethyl)-1 H-1,2,3-triazol-4-y[]methyl}amino)quinoline-3-carbonitrile 0.01
520 8-bromo-4-[(3-chloro-4-fluoropheny!)amino]-6-[({1-[2-(1-methylpiperidin-4-yl)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.044
521 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1 -[2-(1 -methylpiperidin-4-yl)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.038
522 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(2-methoxyethyl)-1H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.018
523 8-bromo-4-[{3-chloro-4-fluorophenyl)amino]-6-({[1-(3-hydroxypropyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.018
524 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[2-(cydopentylsulfonyl)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]qulnoline-3-carbonitrile 0.053
525 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1 -[1 -(methylsulfonyl)piperidin-4-yr|-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.0011
526 8-bromo-4-[(3-chloro-4-fiuorophenyl)amino]-6-[(imidazo[1,2-a]pyridin-3-ylmethyl)amino]quinoline-3-carbonitrile 0.28
527 N-(3-chloro-4-fluorophenyl)-5-{4-[(1H-imidazol-5-ylmethyl)amino]phenyl}pyrimidin-4-amine >3
528 8-bromo-4-[(3-chloro-4-fiuorophenyl)amino]-6-[(imidazo[1,2-a]pyrazin-3-ylmethyl)amino]quinoline-3-carbonitrile 0.11
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529 8-bromo-4-[(3-ch!oro-4-fluorophenyl)amino]-6-[({1-[2-(methylsulfonyl)ethyl]-1 H-imidazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.043
530 8-bromo-4-[(3-chloro-4-fluorophenyI)amino]-6-[({1-[(methy[thio)methyl]-1 H-1,2,3-triazol-4-yl}mslhyl)amino]quinoline-3-carbonitrile 0.012
531 8-bromo-4-[(3-chloro-4-fIuorophenyl)amino]-6-[({1-[(methylsulfonyl)methyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.033
532 8-bromo-4-[(3-chloro-4-fIuorophenyl)amino]-6-[({1-[(methylsulfinyl)methyl]-1 H-1,2,3-tiiazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.12
533 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(pyridin-3-ylmethyl)-1H-imidazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.0031
534 4-[(3-chloro-4-fluorophenyl)amino]-5-{2-[(1H-irnidazol-5-ylmethyl)amino]phenyl}nicotinonitrile >3
535 N-(3-chloro-4-fluorophenyl)-5-{3-[(1H-imidazol-5-ylmethyl)amino]phenyl}pyrimidin-4-amine >3
536 N-(3-chloro-4-fluorophenyl)-5-{2-[(1H-imidazol-5-ylmethyl)amino]phenyl}pyrimidin-4-amine >3
537 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(3-piperidin-4-yl-1H-pyrazol-5-yl)methyl]amino}quinoline-3-carbonitrile 0.8
538 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(3-piperidin-1 -ylpropyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.0034
539 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(3-piperidin-1-ylpropyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.0011
540 tert-buty!3-({4-[({8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyf|-1 H-1,2,3-triazol-1-yl}methyl)piperidine-1-carboxylate 0.12
541 tert-butyl3-({4-[({8-chloro-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazoM -yl}methyl)piperidine-1-carboxylate 0.25
542 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1 -[1 -(2,2-dimethylpropyl)piperidin-4-yl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.19
543 tert-butyl2-({4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-tr!azol-1-yl}methyl)pyrrolidine-1-carboxylate 0.32
544 tert-bu{yl2-({4-[({8-bromo-4-I(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1-yl}methyl)pyiTolidine-1-carboxylate 0.27
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545 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(piperidin-3-ylmethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoIine-3-carbonitrile 0.033
546 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(piperidin-3-ylmethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.048
547 6-({[1 -(1 -acetylpiperidin-4-yl)-1 H-1,2,3-triazol-4-yl]methyl}amino)-8-bromo-4-[(3-chloro-4-fluorophenyl)amino]quinoIine-3-carbonitrile 0.0061
548 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1 -[2-(1 -methylpyrrolidin-2-yl)ethyl]-1H-imidazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.034
54 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(pyrrolidin-2-ylmethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.0091
550 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(pyrrolidin-2-ylmethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.0092
551 6-{[(1 -allyl-1 H-imidazol-4-yl)methyl]amino}-8-bromo-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 0.0048
552 6-({I1-(2-azepan-1-ylethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)-8-chloro-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 0.0028
553 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(pyridin-3-ylmethyl)-1H-imidazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.0007
554 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-pyridin-4-yl-1H-imidazol-4-yl)methyl]amino}quinoline-3-carbonitrile 0.023
555 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({3-[(2S)-pyrrolidin-2-yO-1H-pyrazol-5-yl}methyl)amino]quinoline-3-carbonitrile 0.33
556 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[2-(dimethyiamino)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.013
557 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(pyridin-4-ylmethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.0041
558 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(2-pyridin-2-ylethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.0034
559 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-{I(1-pyridin-4-yl-1 H-1,2,3-triazol-4-yl)methyl]amino}quinoline-3-carbonitrile 0.0055
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560 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{|;(1-pyridin-4-yl-1 H-1,2,3-triazol-4-yl)methyl]amino}quinoline-3-carbonitrile 0.0032
561 6-{[(1-allyl-1 H-1,2>triazol-4-yl)methyl]amino}-8-bromo-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 0.02
562 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(2-methoxyethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.02
563 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(2-pyridin-2-ylethyl)-1 H-1,2,3-triazol-4-yl]m8thyl}amino)quinoline-3-carbonitrile 0.025
564 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[2-(2-methoxyethoxy)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.021
565 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[2-(2-methoxyethoxy)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.1
566 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[(1-ethylpiperidin-4-yl)methyll-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.04
567 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1 -[(1 -isopropylpiperidin-4-yl)methyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.029
568 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[2-(1-ethylpiperidin-4-yl)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.064
569 8-bromo-4-t(3-chloro-4-fluorophenyl)amino]-6-[({1-[2-(1-isopropylpiperidin-4-yl)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.057
570 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(tetrahydro-2H-pyran-4-yl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.014
571 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({4-[2-(dimethylamino)ethyl]-1H-imidazol-5-yl}methyl)amino]quinoline-3-carbonitrile 0.24
572 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-{2-[2-(2-hydroxyethoxy)ethoxy]ethyl}-1 H-1,2,3-triazol-4-yl)methyl]amino}quinoline-3-carbonitrile 0.091
573 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-{[( 1 -{2-[2-(2-hydroxyethoxy)ethoxy]ethyl}-1 H-1,2,3-triazol-4-yl)methyl]amino}quinoline-3-carbonitrile 0.14
574 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[2-(dimethylamino)-1-phenylethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.07
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575 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[2-(dimethylamino)-1-phenylethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.093
576 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(1-oxidopyridin-4-yl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.016
577 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(1-oxidopyridin-4-yl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.015
578 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(2-piperidin-1 -ylpyrimidin-4-yl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.32
579 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(pyridin-2-ylmethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitri!e 0.033
580 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(pyridin-2-ylmethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.0021
581 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(3-hydroxypropyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.0036
582 3-{4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1-yl}propyl dimethylcarbamate 0.016
583 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[4-(trif luoromethyl)benzyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile >3
584 3-{4-[({8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1 -yl}propyl dimethylcarbamate 0.0035
585 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(cyclohexylmethyl)-i H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.79
586 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1 -(1 -phenylethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.096
587 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[3-(dimethylamino)-1-pyridin-3-ylpropyi]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.0067
588 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[3-(dimethylamino)-1-pyridin-3-ylpropyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.036
589 tert-butyl4-(3-{4-[({8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1 -yl}propyl)-1,4-diazepane-1 -carboxylate 0.52
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590 tert-butyl 4-(3-{4-[({8-chloro-4-[(3-chloro-4-fIuorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1H-1,2,3-triazol-1-yl}propyl)-1,4-diazepane-1-carboxylate 0.12
591 tert-butyl 4-(3-{4-[({8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1-yl}propyl)piperazine-1-carboxylate 1.3
592 tert-butyl 4-(3-{4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazoM -yl}propyl)piperazine-1 -carboxylate 0.23
593 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-pyridin-3-yl-1 H-1,2,3-triazol-4-yl)methyr|amino}quinoline-3-carbonitrile 0.0076
594 8-bromo-4-[(3-chloro-4-fIuorophenyl)amino]-6-[({1-[3-(1,4-diazepan-1 -yl)propyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.043
595 8-chloro-4-[(3-chloro-4-fiuorophenyl)amino]-6-[({1 -[3-(1,4-diazepan-1 -yl)propyl]-1 H-1,2,3-triazol-4-yl}methy!)amino] quinoline-3-carbonitrile 0.074
596 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(3-piperazin-1 -ylpropyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.11
597 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(3-piperazin-1-ylpropyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.16
598 2-(8-chloro-4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino)-N-(pyridin-3-ylmethyl)acetamide 0.2
599 2-{4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1-yl}ethyl carbamate 0.0059
600 2-(8-chloro-4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino)-N-(pyridin-4-ylmethyl)acetamide 0.048
601 2-(8-chloro-4-(3-chloro-4-fIuorophenylamino)-3-cyanoquinolin-6-ylamino)-N-(pyridin-3-yl)acetamide 0.11
602 2-(8-chloro-4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino)-N-(pyridin-4-yl)acetamide 2.4
603 2-(8-chloro-4-(3-chloro-4-fIuorophenylamino)-3-cyanoquinolin-6-ylamino)-N-(3-(dimethylamino)propyl)acetamide >3
604 2-(8-chloro-4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino)-N-(3-morpholinopropyl)acetamide >3
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605 2-(8-chloro-4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino)-N-(2-(dimethylamino)ethyl)acetamide 1.6
606 2-(8-chloro-4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino)-N-(3-methoxypropyl)acetamide 0.23
607 2-(8-chloro-4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino)-N-(pyridin-2-ylmethyl)acetamide 0.33
608 2-(8-chloro-4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino)-N-(2-morpholinoethyl)acetamide 0.53
609 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-{3-[cyclohexyl(methyl)amino]propyl}-1 H-1,2,3-triazol-4-yl)methyl]amino}quinoline-3-carbonitrile 0.0018
610 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[3-(3,5-dimethylpiperidin-1-yl)propyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.15
611 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-{methyl[(1 -methyl-1 H-imidazol-4-yl)methyl]amino}quinoline-3-carbonitrile >3
612 2-(8-chloro-4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino)-N-(2-(1-methylpyrrolidin-2-yl)ethyl)acetamide >3
613 2-{4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazoM -yl}-N(N-dimethylacetamide 0.00054
614 3-{4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1-yl}-N,N-dimethylpropanamide 0.01
615 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[2-(1,3-dimethyl-2-oxoimidazolidin~4-yl)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.0061
616 8-chloro-4-[(3-chloro-4-f luorophenyl)amino]-6-[({1 -[2-(1 -ethyl-2-oxo-3-phenylimidazolidin-4-yl)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.025
617 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1 -[2-(1 -ethyl-3-phenyl-2-thioxoimidazolidin-4-yl)ethyl]-1 H-1,2,3-triazo!-4-yl}methyl)amino]quinoline-3-carbonitrile 0.13
618 tert-butyl(2S)-2-[({8-chloro-4-[(3-chloro-4-fIuorophenyl)amino]-3-(yanoquinolin-6-yl}amino)methyl]pyrrolidine-1-carboxylate >3
619 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(2S)-pyrrolidin-2-ylmethyl]amino}quinoline-3-carbonitrile >3
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620 8-bromo-4-[(3-chloro-4-fIuorophenyl)amino]-6-({[1-(pyridin-2-ylmethyl)-1H-imidazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.034
621 8-chloro-4-[(3-chloro-4-f luorophenyl)amino]-6-({[1 -(pyridin-2-ylmethyl)-1H-imidazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.041
622 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(pyridin-4-ylmethyl)-1 H-imidazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.0053
623 tert-butyl (2S)-2-{[{8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}(ethyl)amino]methyl}pyrrolidine-1-carboxylate >3
624 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[3-(4-methyl-1,4-diazepan-1-yl)propyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.07
625 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[3-(4-methyl-1,4-diazepan-1 -yl)propyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.048
626 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[3-(4-methylpiperazin-1-yl)propyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.029
627 8-chIoro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[3-(4-methylpiperazin-1-yl)propyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.039
628 8-chloro-6-[(2-chlorocyclopentyl)amino]-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile >3
629 6-(2-azidocyclopentylamino)-8-chloro-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile 0.42
630 N-{8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}glycine 0.14
631 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[(2,3-dihydroxypropyl)amino]quinoline-3-carbonitrile 0.59
632 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-cyclopentyl-1H-imidazol-4-yl)methyl]amino}quinoiine-3-carbonitrile 0.23
633 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-isopropyl-1H-imidazol-4-yl)methyl]amino}quinoline-3-carbonitrile >3
634 N-(4-{4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-iI-yl}phenyl)acetamide 0.035
635 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({2-[4-(2-hydroxyethyl)-1 H-1,2,3-triazol-1 -yl]cyclopentyl}amino)quinoline-3-carbonitrile 0.067
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636 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[(2-{4-[(dimethylamino)methyl]-1 H-1,2,3-triazoM -yl}cyclopentyl)amino]quinoline-3-carbonitrile >3
637 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[(3-hydroxy-2-pyridin-4-ylpropyl)amino]quinoline-3-carbonitrile >3
638 6-[({1 -[(benzyloxy)methyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]-8-bromo-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile >3
639 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[(2-pyridin-4-ylpropyl)amino]quinoline-3-carbonitrile 0.2
640 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{ethyl[(2S)-pyrrolidin-2-ylmethyl]amino}quinoline-3-carbonitrile >3
641 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[(2S)-1-ethylpyrrolidin-2-yl]methyl}amino)quinoline-3-carbonitrile 0.33
642 6-({[(2S)-1-acetylpyrrolidin-2-yl]methyl}amino)-8-chloro-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 0.054
643 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-(ethyl{[(2S)-1-ethylpyrrolidin-2-yl]methyl}amino)quinoline-3-carbonitrile 1.2
644 6-[{[(2S)-1-acetylpyrrolidin-2-yl]methyl}(ethyl)amino]-8-chloro-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile >3
645 6-[({1 -[(benzyloxy)methyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]-8-chloro-4-[(3-chloro-4-fIuorophenyl)amino]quinoline-3-carbonitrile >3
646 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({2-[(dimethylamino)methyl]cyclohexyl}amino)quinoline-3-carbonitrile >3
647 2-{4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1-yl}-N-isopropylacetamide 0.0035
648 6-({[1 -(2-azepan-1 -yl-2-oxoethyl)-1 H-1,2,3-triazo!-4-yl]methyl}amino)-8-chloro-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 0.0046
649 6-({[1 -(2-azocan-1 -yl-2-oxoethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)-8-chloro-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 0.0053
650 2-{4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazoM-yl}-N-(2-methoxyethyl)acetamide 0.015
651 2-{4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinoIin-6-yl}amino)methyI]-1 H-1,2,3-triazoM-yl}-N-[2-(1-methylpyrrolidin-2-yl)ethyl]acetamide 0.0069
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652 2-{4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1 -yl}-N-[2-(dimethylamino)ethyl]acetamide 0.0068
653 2-{4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazoM-yl}-N-(pyridin-3-ylmethyl)acetamide 0.0008
654 2-{4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazoM -yl}-N-(2-morpholin-4-ylethyl)acetamide 0.014
655 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}amino)quinoline-3-carbonitrile 0.2
656 tert-butyl4-(4-(3-chloro-4-fluorophenylamino)-3-cyanoquinolin-6-ylamino)piperidine-1-carboxylate >40
657 6-(1-benzylpiperidin-4-ylamino)-4-(3-chloro-4-fluorophenylamino)quinoline-3-carbonitrile 1.7
658 4-(3-chloro-4-fluorophenylamino)-6-(1-isopropylpiperidin-4-ylamino)quinoline-3-carbonitrile 25.5
659 4-(3-chloro-4-fluorophenylamino)-6-( 1 -ethyl-3-methylpiperidin-4-ylamino)quinoline-3-carbonitrile >40
660 N-(8-bromo-4-(3-chloro-4-fIuorophenylamino)-3-cyanoquinolin-6-yl)acetamide 4.7
661 6-({[1 -(1 -adamantyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)-8-bromo-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 1.7
662 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[3-(dimethylamino)propyl]-1 H-1,2,3-triazol-4-y!}methyl)amino]quinoline-3-carbonitrile 0.02
663 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[2-(dimethylamino)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.024
664 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-methyl-1 H-1,2,4-triazol-3-yl)methyl]amino}quinoline-3-carbonitrile 0.2
665 6-{[(1 -tert-butyl-1 H-1,2,3-triazol-4-yl)methyl]amino}-8-chloro-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 0/029
666 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[(1 H-1,2,4-triazol-3-ylmethyl)amino]quinoline-3-carbonitrile 0.1
667 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[(1H-1,2,4-triazol-3-ylmethyl)amino]quinoline-3-carbonitrile 0.11
668 8-bromo-4-t(3-chloro-4-fluorophenyl)amino]-6-({[1-(2-morpholin-4-ylethyl)-1H-imidazol-5-yl]methyl}amino)quinoline-3-carbonitrile 0.16
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669 8-bromo-4-[(3-chforo-4-fluorophenyl)amino]-6-({[1-(2-morpholin-4-ylethyl)-1H-imidazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.041
670 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(2-morpholin-4-ylethyl)-1H-imidazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.033
671 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(2-morpholin-4-ylethyl)-1H~imidazol-5-yl]methyl}amino)quinoline-3-carbonitrile 0.062
672 8-bromo-6-{[(1 -tert-butyl-1 H-1,2,3-triazol-4-yl)methyl]amino}-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 0.061
673 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(2,2,2-trifluoroethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.1
674 tert-butyl4-(2-{4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1-yl}ethyl)piperidine-1-carboxylate 0.075
675 tert-butyl4-(2-{4-[({8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1-yl}ethyl)piperidine-1-carboxylate 0.13
676 tert-butyl(2-{4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1-yl}ethyl)methylcarbamate 0.048
677 di-tert-butyl[({8-bromo-4-[(3-chloro-4-fIuorophenyl)amino]-3-cyanoquinolin-6-yl}imino)bis(methyiene-1 H-1,2,3-triazole-4,1 -diylethane-2,1 -diyl)]bis(methylcarbamate) 4.7
678 tert-butyl(2-{4-[({8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1-yl}ethyl)methylcarbamate 0.067
679 8-bromo-4-[(3-chloro-4-fiuorophenyl)amino]-6-[methyl({1-[(1-methylpiperidin-4-yl)methyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.29
680 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1 -[(1 -methylp;peridin-4-yl)methyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.012
681 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-(methyl{[1-(1-methylpiperidin-4-yl)-1H-1,2,3-trjazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.022
682 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[2-(methylthio)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.082
683 8-bromo-4-[(3-chloro-4-f!uorophenyl)amino]-6-({[4-(3-methoxypropyl)-1 H-imidazol-5-yl]methyl}amino)quinoline-3-carbonitrile 0.062
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684 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[2-(methylamino)ethyl]-1 H-1,2,3-triazoI-4-yi}methyl)amino]quinoline-3-carbonitrile 0.038
685 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[2-(methylamino)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitriIe 0.029
686 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(2-hydroxyethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.028
867 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[3-(dimethylamino)propyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.002
688 8-chloro-4-[(3-chloro-4-f luorophenyl)amino]-6-({[1 -(2-pyrrolidin-1 -ylethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.04
689 8-chloro-4-[(3-chloro-4-f luorophenyl)amino]-6-[({1 -[2-(1 -methylpyrrolidin-2-yl)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.015
690 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(pyridin-3-ylmethyl)-1 H-1,2,3-triazol-4-yl]msihyl}amino)quinoline-3-carbonitrile 0.01
691 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-({t1-(2-piperidin-4-ylethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.09
692 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(2-piperidin-4-ylethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.13
693 di-tert-butyl4,41-[({8-bromo-4-[(3-chloro-4-f!uorophenyl)amino]-3-cyanoquinolin-6-yl}imino)bis(methylene-1 H-1,2,3-triazole-4,1 -diylethane-2,1 -diyl)]dipiperidine-1 -carboxylate >3
694 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[2-(methylsulfonyl)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.091
695 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[2-(1-methylpiperidin-4-yl)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.044
696 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1 -[2-(1 -methylptperidin-4-yl)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.0017
697 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(3-hydroxypropyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.018
698 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(2-methoxyethyl)-1 H-1,2,3-triazol-4-yl]methy!}amino)quinoline-3-carbonitrile 0.018
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699 8-bromo-4-[(3-chloro-4-fIuorophenyl)amino]-6-[({1-[2-(cyclopentylsulfonyl)ethylj-i H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.053
700 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[(imidazo[1,2-a]pyrazin-3-ylmethyl)amino]quinoline-3-carbonitrile 0.11
701 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[(imidazo[1,2-a]pyridin-3-ylmethyl)amino]quinoline-3-carbonitrile 0.28
702 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[2-(methylsulfonyl)ethyl]-1H-imidazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.043
703 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[(methylsulfinyl)methyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.12
704 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[(methylsulfonyl)methyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.033
705 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[(methylthio)methyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.012
706 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(pyridin-3-ylmethyl)-1H-imidazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.0031
707 8-bromo-4-[(3-chloro-4-fIuorophenyl)amino]-6-{[(3-piperidin-4-yl-1H-pyrazol-5-yl)methyl]amino}quinoline-3-carbonitrile 0.8
708 8-bromo-4-[(3-chloro-4-fIuorophenyl)amino]-6-[({1 -[2-(1 -methylpyrrolidin-2-yl)ethyl]-1H-imidazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.034
709 6-{[(1 -allyl-1 H-imidazol-4-yl)methyl]amino}-8-bromo-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 0.0048
710 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1 -[1 -(methylsulfonyl)piperidin-4-yl]-1 H-1 .S-triazoM-yl}methyl)amino]quinoline-3-carbonitrile 0.0011
711 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(3-piperidin-1-ylpropyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.0034
712 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(3-piperidin-1 -ylpropyl)-1 H-1,2,3-triazol-4-yl]methy!}amino)quinoline-3-carbonitrile 0.0011
713 tert-butyl3-({4-[({8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1-yl}methyl)piperidine-1-carboxylate 0.12
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714 tert-butyl3-({4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1H-1,2,3-triazoM -yl}methyl)piperidine-1 -carboxylate 0.25
715 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1 -[1 -(2,2-dimethylpropyl)piperidin-4-yO-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.19
716 tert-butyl2-({4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazoM -yl}methyl)pyrrolidine-1 -carboxylate 0.32
717 tert-butyl2-({4-[({8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1-yl}methyl)pyrrolidine-1 -carboxylate 0.27
718 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(piperidin-3-ylmethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.033
719 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{{[1-(piperidin-3-ylmethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.048
720 6-({[1-(1-acetylpiperidin-4-yl)-1 H-1,2,3-triazol-4-yl]methyl}amino)-8-bromo-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 0.0061
721 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(pyrrolidin-2-ylmethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.0091
722 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(pyrrolidin-2-ylmethyl)-1 H-1,2,3-triazol-4- . yl]methyl}amino)quinoline-3-carbonitrile 0.0092
723 6-({[1-(2-azepan-1-ylethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)-8-chloro-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 0.0028
724 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({3-[(2S)-pyrrolidin-2-yl]-1H-pyrazol-5-yl}methyl)amino]quinoline-3-carbonitrile 0.33
725 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-pyridin-4-yl-1H-imidazol-4-yl)methyl]amino}quinoline-3-carbonitrile 0.023
726 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(pyridin-3-ylmethyl)-1H-imidazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.007
727 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(pyridin-4-ylmethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.0041
728 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(2-pyridin-2-ylethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.0034
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729 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-pyridin-4-yl-1 H-1,2,3-triazol-4-yl)methyl]amino}quinoline-3-carbonitrile 0.0055
730 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-pyridin-4-yl-1 H-1,2,3-triazol-4-yl)methyl]amino}quinoline-3-carbonitrile 0.0032
731 8-chloro-4-[(3-chloro-4-fluorophenyl)ami no]-6-[({1 -[2-(dimethylamino)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.013
732 6-{[(1 -allyl-1 H-1,2,3-triazol-4-yl)methyl]amino}-8-bromo-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 0.02
733 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(2-methoxyethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.02
734 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(tetrahydro-2H-pyran-4-yl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.014
735 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1 -[(1 -ethylpiperidin-4-yl)methyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.04
736 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1 -[(1 -isopropylpiperidin-4-yl)methyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.029
737 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1 -[2-(1 -ethylpiperidin-4-yl)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.064
738 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[2-(1-isopropylpiperidin-4-yl)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.057
739 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[2-(dimethylamino)-1-phenylethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.093
740 8-chloro-4-[(3-chloro-4-fluoraphenyl)amino]-6-[({1-[2-(dimethylamino)-1-phenylethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.07
741 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-{2-[2-(2-hydroxyethoxy)ethoxy]ethyl}-1 H-1 .S-triazoM-yl)methyl]amino}quinoline-3-carbonitrile 0.14
742 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-{2-[2-(2-hydroxyethoxy)ethoxy]ethyl}-1 H-1,2,3-triazol-4-yl)methyl]amino}quinoline-3-carbonitrile 0.091
743 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[2-(2-methoxyethoxy)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.1
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744 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[2-(2-methoxyethoxy)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.021
745 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({4-[2-(dimethylamino)ethyl]-1H-imidazol-5-yl}methyl)amino]quinoline-3-carbonitrile 0.24
746 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(2-pyridin-2-ylethyl)-1 H-1,2,3-triazol-4-yflmethyl}amino)quinoline-3-carbonitrile 0.025
747 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(2-piperidin-1 -ylpyrimidin-4-yl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.32
748 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1 -(1 -oxidopyridin-4-yl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitriie 0.015
749 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(1-oxidopyridin-4-yl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.016
750 3-{4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1-yl}propyl dimethylcarbamate 0.016
751 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(3-hydroxypropyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.0036
752 3-{4-[({8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1-yljpropyl dimethylcarbamate 0.0035
753 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(pyridin-2-ylmethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.033
754 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(pyridin-2-ylmethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.0021
755 8-chloro--[(3-chloro-4-fluorophenyl)amino]-6-({[1-(cyclohexylmethyl)-i H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.79
756 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[4-(trif luoromethyl)benzyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile >3
757 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[3-(dimethylamino)-1-pyridin-3-ylpropyf]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.0067
758 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-pyridin-3-yl-1 H-1,2,3-triazol-4-yl)methyl]amino}quinoline-3-carbonitrile 0.0076
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759 8-chloro-4-r(3-chloro-4-fluorophenyI)amino]-6-[({1-[3-(dimethylamino)-1-pyridin-3-ylpropyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.036
760 methyl 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinoline-6-carboxylate >3
761 8-chloro-4-[(3-chloro-4-f luorophenyl)amino]-6-({[1 -(1 -phenylethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitriIe 0.096
762 tert-butyl4-(3-{4-[({8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1 -yl}propyl)-1,4-diazepane-1 -carboxylate 0.52
763 tert-butyl4-(3-{4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1 -yl}propyl)-1,4-diazepane-1 -carboxylate 0.12
764 tert-butyl4-(3-{4-[({8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1H-1,2,3-triazol-1-yl}propyl)piperazine-1-carboxylate 1.3
765 tert-butyl4-(3-{4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1-yl}propyl)piperazine-1-carboxylate 0.23
766 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[3-(1,4-diazepan-1 -yl)propyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.043
767 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[3-(1,4-diazepan-1-yl)propyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.074
768 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(3-piperazin-1-ylpropyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.11
769 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(3-piperazin-1 -ylpropyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.16
770 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyaRoquinoline-6-carboxylic acid 2.4
771 N2-{8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}-N-(pyridin-3-ylmethyl)glycinamide 0.2
772 N2-{8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}-N-(pyridin-4-ylmethyl)glycinamide 0.048
773 N2-{8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}-N-pyridin-3-ylglycinamide 0.11
774 N2-{8-chloro-4-[(3-chloro-4-fIuorophenyl)amino]-3-cyanoquinolin-6-yl}-N-pyridin-4-ylglycinamide 2.4
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775 N2-{8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}-N-[3-(dimethylamino)propyl]glycinamide >3
776 N2-{8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}-N-(3-morpholin-4-ylpropyl)glycinamide >3
777 N2-{8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}-N-(2-morpholin-4-ylethyl)giycinamide 0.53
778 N2-{8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}-N-[2-(dimethylamino)ethyl]glycinamide 1.6
779 N2-{8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}-N-(3-methoxypropyl)glycinamide 0.23
780 N2-{8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}-N-(pyridin-2-ylmethyl)glycinamide 0.33
781 N2-{8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}-N-[2-(1-methylpyrrolidin-2-yl)ethyl]glycinamide >3
782 8-chloro-6-[(2-chlorocyclopentyl)amino]-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile >3
783 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[2-(2l5-triaz-1 -en-2-yn-1 -yl)cyclopentyl]amino}quinoline-3-carbonitrile 0.42
784 2-{4-[({8-chloro-4-[(3-chloro-4-fiuorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1 -yljethyl carbamate 0.0059
785 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(pyridin-2-ylmethyl)-1H-imidazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.034
786 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(pyridin-2-ylmethyl)-1H-imidazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.041
787 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(pyridin-4-ylmethyl)-1H-imidazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.0053
788 2-{4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-i-yl}-N,N-dimethylacetamide 0.005
789 3-{4-[({8-chloro-4-[(3-ch!oro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1-yl}-N,N-dimethylpropanamide 0.01
790 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[2-(1,3-dimethyl-2-oxoimidazolidin-4-yl)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.0061
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791 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1 -[2-(1 -ethyl-2-oxo-3-phenylimidazolidin-4-yl)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.025
792 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1 -[2-(1 -ethyl-3-phenyl-2-thioxoimidazolidin-4-yl)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.13
793 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[3-(4-methyl-1,4-diazepan-1 -yl)propyl]-1 H-1,2,3~triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.07
794 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[3-(4-methyl-1,4-diazepan-1 -yl)propyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.048
795 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[3-(4-methylpiperazin-1 -yl)propyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.029
796 8-ch!oro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[3-(4-methylpiperazin-1-yl)propyl]-1 H-1,2,3-triazol-4-yl}methyI)aminoJquinoline-3-carbonitrile 0.039
797 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[(2,3-dihydroxypropyl)amino]quinoline-3-carbonitrile 0.59
798 N-{8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}glycine 0.14
799 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-cyclopentyl-1H-imidazol-4-yl)methyl]amino}quinoline-3-carbonitrile 0.23
800 8-chloro-4-[(3-chloro4-fluorophenyl)amino]-6-[({1-[3-(3,5-dimethylpiperidin-1 -yl)propyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.15
801 8-chloro-4-f(3-chloro-4-fluorophenyl)amino]-6-{[(1-{3-[cyclohexyl(methyl)amino]propyl}-1 H-1,2,3-triazol-4-yl)methyl]amino}quinoline-3-carbonitrile 0.0018
802 N-(4-{4-[({8-chloro-4-[(3-chloro-4-fIuorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazoM -yl}phenyl)acetamide 0.035
803 8-chloro-4-[(3-chloro-4-fluorophenyl)aminoJ-6-({2-[4-(2-hydroxyethyl)-1 H-1,2,3-triazol-1 -yl]cydopentyl}amino)quinoline-3-carbonitrile 0.067
804 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-isopropyl-1H-imidazol-4-yl)methyl]amino}quinoline-3-carbonitrile 0.068
805 6-[({1-[(benzyloxy)methyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]-8-bromo-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile >3
806 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[(2-pyridin-4-ylpropyl)amino]quinoline-3-carbonitrile 0.2
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807 6-[({1 -[(benzyloxy)methyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]-8-chloro-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile >3
808 {4-[({8-chIoro-4-t(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1 -yl}acetic acid 0.0096
809 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[(2S)-1-ethylpyrrolidin-2-yl]methyl}amino)quinoline-3-carbonitrile 0.33
810 6-({[(2S)-1-acetylpyrrolidin-2-yl]methyl}amino)-8-chloro-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 0.054
811 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-. (ethyl{[(2S)-1-ethylpyrrolidin-2-yl]methyl}amino)quinoline-3-carbonitrile 1.2
812 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}amino)quinoline-3-carbonitrile 0.2
813 2-{4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1-yl}-N-isopropylacetamide 0.0035
814 6-({[1 -(2-azepan-1-yl-2-oxoethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)-8-chloro-4-[(3-chloro-4-fiuorophenyl)amino]quinoline-3-carbonitrile 0.0046
815 6-({[1 -(2-azocan-1 -yl-2-oxoethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)-8-chloro-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 0.0053
816 2-{4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1 -yl}-N-(2-methoxyethyl)acetamide 0.015
817 2-{4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazoM-yl}-N-[2-(1-methylpyrrolidin-2-yl)ethyl]acetamide 0.0069
818 2-{4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazoM -yl}-N-[2-(dimethylamino)ethyl]acetamide 0.0068
819 2-{4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazoM -yl}-N-(pyridin-3-ylmethyl)acetamide 0.0008
820 2-{4-[({8-chIoro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1-yl}-N-(2-morpholin-4-ylethyl)acetamide 0.014
821 2-{4-[({8-ch!oro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1-yl}-N-pyridin-3-ylacetamide 0.0027
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822 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[2-(4-methylpiperazin-1 -yl)-2-oxoethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitriIe 0.013
823 6-[bis({1-[2-(1-methylpyrrolidin-2-yl)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]-8-bromo-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 0.86
824 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[(piperidin-4-ylmethyl)amino]quinoline-3-carbonitrile 1.24
825 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1 -[(1 -methylpiperidin-4-yl)methyI]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.037
826 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-I({1 -[(1 -ethylpiperidin-4-yl)methyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.035
827 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1 -[(1 -isopropylpiperidin-4-yl)methyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.011
828 4-({4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1-yl}methyl)-N,N-dimethylpiperidine-1-carboxamide 0.0026
829 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1 -[2-(1 -ethylpiperidin-4-yl)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.0018
830 4-(2-{4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1 -ylJethyl)-N,N-dimethylpiperidine-1-carboxamide 0.019
831 4-(2-{4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-i-yl}ethyl)-N-ethylpiperidine-1-carboxamide 0.0093
832 6-[({1-[2-(1-acetylpiperidin-4-yl)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]-8-chloro-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 0.0012
833 2-{4-[({8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazoM -yljethyl carbamate 0.009
834 2-{4-[({8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazoM -yl}-N,N-dimethylacetamide 0.014
835 2-(4-{[{8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinoIin-6-yl}(ethyl)amino]methyl}-1 H-1,2,3-triazol-1 -yl)-N, N-dimethylacetamide 0.0091
836 2-(4-{[{8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}(ethyl)amino]methyl}-1 H-1,2,3-triazol-1-yl)-N,N-dimethylacetamide 0.19
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837 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[(2-methylpyridin-4-yl)methyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.011
838 6-({[1-(1-azabicyclo[2.2.2]oct-3-yl)-1 H-1,2,3-triazol-4-yl]methyl}amino)-8-bromo-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 0.01
839 6-({[1 -(1 -azabicyclo[2.2.2]oct-3-yl)-1 H-1,2,3-triazol-4-yl]methyl}amino)-8-chloro-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 0.0018
840 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[(2-methylpyridin-3-yl)methyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.01
841 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[3-(4,4-difluoropiperidin-1-yl)propyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.029
842 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[(2-methyl-1 -oxidopyridin-3-yl)methyl]-1 H-1,2,3-triazol-4-yl}m3ihyl)amino]quinoline-3-carbonitrile 0.0009
843 N-[2-({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)ethyl]-N-(pyridin-3-ylmethyl)acetamide 0.058
844 N-[2-({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)ethyl]-N-(pyridin-4-ylmethyl)acetamide 0.06
845 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[(pyridin-4-ylmethyl)amino]quinoline-3-carbonitrile 0.022
846 N-[2-({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)ethyl]-N-(pyridin-2-ylmethyl)acetamide 0.17
847 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{I(1-isobutyl-1 H-1,2,3-triazol-4-yl)methyl]amino}quinoline-3-carbonitrile 0.17
848 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-(ethyl{[1-(pyridin-3-ylcarbonyl)piperidin-4-yl]methyl}amino)quinoline-3-carbonitrile 0.38
849 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-methylpiperidin-4-yl)methyljamino}quinoline-3-carbonitrile 1.91
850 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(pyridin-3-ylcarbonyl)piperidin-4-yl]methyl}amino)quinoline-3-carbonitrile 0.13
851 2-(4-{[{8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}(methyl)amino]methyl}-1 H-1,2,3-triazol-1-yl)-N,N-dimethylacetamide 0.15
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852 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1 -[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.12
853 N-[2-({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)ethyl]methanesulfonamide 0.88
854 N-[2-({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)ethyl]benzenesulfonamide 1.96
855 N-[2-({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)ethyl]pyridine-3-sulfonamide >3
856 N-[2-({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)ethyl]pyridine-2-sulfonamide 0.82
857 N-[2-({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)ethyl]-1-pyridin-2-ylmethanesulfonamide 0.67
858 N-[2-({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)ethyl]-4-cyanobenzenesulfonamide 0.79.
859 N-[2-({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)ethyl]pyridine-2-carboxamide >3
860 N-[2-({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)ethyl]nicotinamide >3
861 N-[2-({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)ethyl]-2-pyridin-2-ylacetamide >3
862 N-[2-({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)ethyl]-2-pyridin-3-ylacetamide >3
863 N-[2-({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)ethyl]-2-pyridin-4-ylacetamide 1.04
864 N-[2-({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)ethyl]pyrimidine-5-carboxamide 0.65
865 N-[(1-acetylpiperidin-4-yl)methyl]-N-{8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}acetamide 0.38
866 6-{[(1-acetylpiperidin-4-yl)methyl]amino}-8-chloro-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 0.26
867 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[1-(pyridin-3-ylmethyl)pyrrolidin-3-yl]amino}quinoline-3-carbonitrile 1.01
868 8-chloro-4-[(3-chloro-4-fluorophenyI)amino]-6-[(1-ethylpiperidin-3-yl)amino]quinoline-3-carbonitrile 1.19
869 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[1-(pyridin-3-ylmethyl)piperidin-4-yl]amino}quinoline-3-carbonitrile 0.82
870 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-ethylpiperidin-2-yl)methyl]amino}quinoline-3-carbonitrile 1.97
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871 6-[(1-acetylpynrolidin-3-yl)amino]-8-chIoro-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 0.15
872 6-[(1-acetylpiperidin-3-yl)amino]-8-chloro-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 0.096
873 6-[(1-acetylpiperidin-4-yl)amino]-8-chloro-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 0.66
874 6-{[(1-acetylpiperidin-3-yl)methyl]amino}-8-chloro-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 0.61
875 6-{[(1-acetylpiperidin-2-yl)methyl]amino}-8-chloro-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 0.62
876 2-{4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1 -yl}-N-cyclopropylacetamide 0.0013
877 6-({[1 -(3-aminopropyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)-8-chloro-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 0.02
878 8-bromo-4-[(3-chloro-4-fIuorophenyl)amino]-6-[({1 -[(1 -isopropylpyrrolidin-2-yl)methyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.11
879 8-chloro-4-[(3-chlora-4-fluorophenyl)amino]-6-({[1-(pyrimidin-5-ylmethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.0011
880 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(pyrimidin-5-ylmethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.0025
881 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-{[6-(trifluoromethyl)pyridin-2-yl]methyl}-1 H-1,2,3-triazol-4-yl)methyl]amino}quinoline-3-carbonitrile 0.27
882 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-{[6-(trifIuoromethyl)pyridin-2-yl]methyl}-1 H-1,2,3-triazol-4-yl)methyl]amino}quinoline-3-carbonitrile 0.27
883 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-{[2-(trifluoromethyl)pyridin-4-yl]methyl}-1 H-1,2,3-triazol-4-yl)methyl]amino}quinoIine-3-carbonitrile 0.08
884 ethyl 2-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]cyclopropanecarboxylate 0.66
885 6-[(2-azepan-1-yl-2-oxoethyl)amino]-8-chloro-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 0.39
886 2-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]cyclopropanecarboxylic acid 0.22
887 tert-butyl(2R)-2-({4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1-yl}methyl)pyrrolidine-1-carboxylate 0.16
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888 tert-butyl(2S)-2-({4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1H-1,2,3-triazol-1 -yl}methyl)pyrrolidine-1 -carboxylate 0.2
889 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[(2R)-pyrrolidin-2-ylmethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.0084
890 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[(2S)-pyrrolidin-2-ylmethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.0076
891 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-{[(2R)-1 -methylpyrrolidin-2-yl]methyl}-1 H-1,2,3-triazol-4-yl)methyl]amino}quinoline-3-carbonitrile 0.033
892 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-{[(2R)-1 -ethylpyrrolidin-2-yl]methyl}-1 H-1,2,3~triazol-4-yl)methyl]amino}quinoline-3-carbonitrile 0.03
893 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-{[(2R)-1 -isopropylpyrrolidin-2-yl]methyl}-1 H-1,2,3-triazol-4-yl)methyl]amino}quinoline-3-carbonitrile 0.046
894 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{I(1-{[(2S)-1-methylpyrrolidin-2-yl]methyl}-1 H-1,2,3-triazol-4-yl)methyl]amino}quinoline-3-carbonitrile 0.0018
895 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-{[(2S)-1 -ethylpyrrolidin-2-yl]methyl}-1 H-1,2,3-triazol-4-yl)methyl]amino}quinoline-3-carbonitrile 0.01
896 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-{[(2S)-1 -isopropylpyrrolidin-2-yl]methyl}-1 H-1,2,3-triazol-4-yl)methyl]amino}quinoline-3-carbonitrile 0.034
897 (2R)-2-({4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1 -yl}methyl)-N ,N-dimethylpyrrolidine-1 -carboxamide 0.11
898 6-{[(1 -{[(2R)-1 -acetylpyrrolidin-2-yl]methy1 H-1,2,3-triazol-4-yl)methyi]amino}-8-chloro-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 0.0002
899 (2R)-2-({4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1 -yl}methyl)-N-ethylpyrrolidine-1-carboxamide 0.0006
900 (2S)-2-({4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1 -yl}methyl)-N,N-dimethylpyrrolidine-1-carboxamide 0.0005
901 6-{[(1 -{[(2S)-1 -acetylpyrrolidin-2-yl]methy1 H-1,2,3-triazol-4-yl)methyl]amino}-8-chloro-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 0.001
902 (2S)-2-({4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1 -yl}methyl)-N-ethylpyrrolidine-1-carboxamide 0.0005
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903 6-({[1 -(azepan-1 -ylacetyl)piperidin-3-yl]methyl}amino)-8-chloro-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 0.62
904 8-ch!oro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[N-(2-methoxyethyl)glycyl]piperidin-3-yl}methyl)amino]quinoline-3-carbonitrile 0.26
905 N-(3-{4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1 -yl}propyl)methanesulfonamide 0.0028
906 N-(3-{4-[({8-chloro-4-[(3-chloro-4-fIuorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazoM -yl}propyl)-1,1,1-trtfluoromethanesulfonamide 0.0013
907 N-(3-{4-[({8-i;hloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazoM -yl}propyl)propane-2-sulfonamide 0.0045
908 N-(3-{4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1 -yl}propyl)-N'-isopropylurea 0.001
909 N-(3-{4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyG-1 H-1,2,3-triazol-1-yl}propyl)-N'-methylurea 0.001
910 N-(3-{4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1 -yl}propyl)acetamide 0.0007
911 N-(3-{4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazoM -yl}propyl)-2-methylpropanamide 0.0024
912 N-(3-{4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazoH-yl}propyl)cyclopropanecarboxamide 0.0019
913 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[3-(diisobutylamino)propyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.045
914 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[3-(cyclopentylamino)propyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.052
915 N-{8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}-N-({1 -[3-(formylamino)propyl]-1 H-1,2,3-triazol-4-yl}methyl)formamide 0.17
916 N-[3-(4-{[{8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}(formyl)amino]methyl}-1 H-1,2,3-triazol-1-yl)propyl]methanesulfonamide 0.83
917 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(methoxymethyl)-i H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.076
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918 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(2-pyridin-4-ylethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.0009
919 8-bromo-4-[(3-chloro-4-fiuorophenyl)amino]-6-({[1-(2-pyridin-4-ylethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.0013
920 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[( 1 -{N-[2-(dimethylamino)ethyl]glycyl}piperidin-3-yl)methyl]amino}quinoline-3-carbonitrile 0.86
921 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[N-(pyridin-3-ylmethyl)glycyl]piperidin-3-yl}methyl)amino]quinoline-3-carbonitrile 0.54
922 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[N-(pyridin-2-ylmethyl)glycyl]piperidin-3-yl}methyl)amino]quinoline-3-carbonitrile 1.69
923 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(N-pyridin-3-ylglycyl)piperidin-3-yl]methyl}amino)quinoline-3-carbonitrile 0.56
924 8-chloro-6-({[1-(chloroacetyl)piperidin-3-yl]methyl}amino)-4-[(3-chloro-fluorophenyl)amino]quinoline-3-carbonitrile 1.32
925 tert-butyl4-{4-t({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2.3-triazol-1 -yl}piperidine-1-carboxylate 0.073
926 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-piperidin-4-yl-1 H-1,2,3-triazol-4-yl)methyl]amino}quinoline-3-carbonitrile 0.0053
927 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1 -(1 -methylpiperidin-4-yl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.0022
928 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1 -(1 -isopropylpiperidin-4-yl)-1 H-1,2,3-triazo!-4-yl]methyl}amino)quinoline-3-carbonitrile 0.0091
929 4-{4-[({8-chlcro-4-[(3-chloro-4-fIuorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1-yl}-N.N-dimethylpiperidine-i-carboxamide 0.007
930 6-({[1 -(1 -acetylpiperidin-4-yl)-1 H-1,2,3-triazol-4-yl]methyl}amino)-8-chloro-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 0.0033
931 4-{4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-3
936 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1 -{2-[1 -(cyclopropylmethyl)piperidin-4-yl]ethyl}-1 H-1,2,3-triazol-4-yl)methyl]amino}quinoline-3-carbonitrile 0.13
937 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1 -[2-(1 -cyclobutylpiperidin-4-yl)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.15
938 8-chloro-4-[(3-chloro-4-f luorophenyl)amino]-6-[({1 -[2-(1 -cyclopentylpiperidin-4-yl)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbpnitrile 0.2
939 2,5-anhydro-1-({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)-1,3-dideoxy-4-O-(pyridin-3-ylmethyl)-D-erythro-pentitol >3
940 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[(1-piperidin-4-yl-1 H-1,2,3-triazol-4-yl)methoxy]quinoline-3-carbonitrile 0.15
941 tert-butyl4-{4-[({8-ch!oro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}oxy)methyl]-1 H-1,2,3-triazol-1-yl}piperidine-1-carboxylate 0.52
942 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-{2-[(2S)-1 -isopropylpyrrolidin-2-yl]ethyl}-1 H-1,2,3-triazol-4-yl)methydamino}quinoline-3-carbonitrile 0.019
943 tert-butyl4-[4-({[8-chloro-3-cyano-4-(cyclopentylamino)quinolin-6-yl]amino}methyl)-1 H-1,2,3-triazol-1 -yi]prperidine-1 -carboxylate >3
944 8-chloro-4-(cyclopentylamino)-6-[({1-[2-(1-methylpyrrolidin-2-yl)ethyl]-1 H-1,2,3-triazol-4~ yl}methyl)amino]quinoline-3-carbonitrile >3
945 6-({[1 -(2-azepan-1 -ylethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)-8-chloro-4-(cyclopentylamino)quinoline-3-carbonitrile 0.63
946 8-chloro-4-(cyclopentylamino)-6-[({1-[2-(dimethylamino)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.59
947 8-chloro-4-(cycloheptylamino)-6-[({1 -[2-(1 -methylpyrrolidin-2-yl)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.70
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948 tert-butyl 4-[4-({[8-chloro-3-cyano-4-(cycloheptylamino)quinolin-6-yl]amino}methyl)-1 H-1,2,3-triazol-1 -yl]piperidine-1 -carboxylate 2.31
949 6-({[1-(2-azepan-1-ylethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)-8-chloro-4-(cycloheptylamino)quinoline-3-carbonitrile 0.46
950 8-chloro-4-(cycloheptylamino)-6-[({1-[2-(dimethylamino)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.62
951 8-chloro-4-(cyclobutylamino)-6-[({1 -[2-(1 -methylpyrrolidin-2-yl)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.46
952 8-chloro-6-[({1 -[2-(1 -methylpyrrolidin-2-yl)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]-4-(tetrahydro-2H-pyran-4-ylamino)quinoline-3-carbonitrile 1.13
953 tert-butyl 4-[4-({[8-chloro-3-cyano-4-(cyclobutylamino)quinolin-6-yl]amino}methyl)-1 H-1,2,3-triazol-1-yl]piperidine-1-carboxylate 0.81
954 8-chloro-4-(cyclobutylamino)-6-({[1-(2-piperidin-1-ylethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.52
955 6-({[1-(2-azepan-1-ylethyl)-1H-1,2,3-triazol-4-yl]methyl}amino)-8-chloro-4-(cyclobutylamino)quinoline-3-carbonitrile 0.44
956 8-chloro-4-(cyclobutylamino)-6-[({1-[2-(dimethylamino)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.73
957 tert-butyl 4-(2-{4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1-yl}ethyl)piperazine-1-carboxylate >3
958 8-chloro-4-[(3-chloro-4-fIuorophenyl)amino]-6-({[1-(2-piperazin-1-ylethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.31
959 6-[({1 -[2-(4-acetylpiperazin-1 -yl)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]-8-chloro-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 0.092
960 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-{2-[4-(3,3-dimethylbutanoyl)piperazin-1 -yl]ethyl}-1 H-1,2,3-triazol-4-yl)methyl]amino}quinoline-3-carbonitrile 0.13
961 4-(2-{4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1-yl}ethy!)-N,N-dimethylpiperazine-1-carboxamide 0.031
962 4-(2-{4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1 -yl}ethyl)-N-ethylpiperazine-1-carboxamide 0.023
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963 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[2-(4-methylpiperazin-1 -yl)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.65
964 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[2-(4-ethylpiperazin-1 -yl)ethyl]-1 H-1,2,3-triazoM-yl}methyl)amino]quinoline-3-carbonitrile 0.26
965 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[2-(4-isopropylpiperazin-1 -yl)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.43
966 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-{2-[4-(cyclopropylmethyl)piperazin-1-yl]ethyl}-1 H-1,2,3-triazol-4-yl)methyl]amino}quinoline-3-carbonitrile 0.15
967 4-(cyclohexylamino)-6-[({1 -[2-(1 -methylpyrrolidin-2-yl)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.46
968 tert-butyl4-[4-({[3-cyano-4-(cyclohexylamino)quinolin-6-yl]amino}methyl)-1 H-1,2,3-triazol-1-yl]piperidine-1-carboxylate 0.67
969 4-(cyclohexylamino)-6-[({1 -[2-(dimethylamino)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.38
970 6-({[1 -(2-azepan-1-ylethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)-4-(cyclohexylamino)quinoline-3-carbonitrile 0.51
971 8-chloro-6-[({1 -[2-(1 -methylpyrrolidin-2-yl)ethyG-1 H-1,2,3-triazol-4-yl}methyl)amino]-4-(spiro[5.5]undec-3-yl?jmino)quinoline-3-carbonitrile >3
972 8-chloro-6-[({1 -[2-(1 -methylpyrrolidin-2-yl)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]-4-(spiro[4.5]dec-7-ylamino)quinoline-3-carbonitrile >3
973 tert-butyl4-[4-({[8-chloro-3-(yano-4-(spiro[5.5]undec-3-ylamino)quinolin-6-yl]amino}methyl)-1 H-1,2,3-triazol-1 -yl]piperidine-1 -carboxylate >3
974 tert-butyl4-[4-({[8-chloro-3-cyano-4-(spiro[4.5]dec-7-ylamino)quinolin-6-yl]amino}methyl)-1 H-1,2,3-triazol-1-yl]piperidine-1-carboxylate >3
975 6-({[1-(2-azepan-1-ylethyl)-1H-1,2,3-triazol-4-yl]methyl}amino)-8-chloro-4-(spiro[5.5]undec-3-ylamino)quino!ine-3-carbonitrile >3
976 6-({[1-(2-azepan-1-ylethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)-8-chloro-4-(spiro[4.5]dec-7-ylamino)quinoline-3-carbonitrile >3
977 4-(cyclohexylamino)-6-{[(1 -piperidin-4-yl-1 H-1,2,3-triazol-4-yl)methyl]amino}quinoline-3-carbonitrile 0.13
978 8-chloro-6-{[(1-piperidin-4-yl-1 H-1,2,3-triazol-4-yl)methyl]amino}-4-(spiro[5.5]undec-3-ylamino)quinoline-3-carbonitrile >3
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979 8-chloro-6-{[(1-pipericlin-4-yl-1 H-1,2,3-triazoI-4-yl)methyl]amino>-4-(spiro[4.5]dec-7-ylamino)quinoline-3-carbonitrile 0.97
980 methyl 4-{4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazol-1-yl}piperidine-1-carbo)cylate 0.024
981 methyl 4-(4-{[{8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}(methoxycarbonyl)amino]methyl}-1 H-1,2,3-triazol-1 -yl)piperidine-1 -carboxylate 0.61
982 2-fluoroethyl4-{4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazoM -yl}piperidine-1 -carboxylate 0.031
983 2-fluoroethyl4-[4-({{8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}[(2-fluoroethoxy)carbonyl]amino}methyl)-1 H-1,2,3-triazol-1-yl]piperidine-1 -carboxylate >3
984 8-chloro-6-[({1-[2-(dimethylamino)ethyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]-4-[(2,2,2-trifluoroethyl)amino]quinoline-3-carbonitrile 1.09
985 8-chloro-6-({[1 -(2-piperidin-1 -ylethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)-4-[(2,2,2-trifluoroethyl)amino]quinoline-3-carbonitrile 1.41
986 8-chloro-4-(cyclobutylamino)-6-{[(1 -piperidin-4-yl-1 H-1,2,3-triazol-4-yl)methyl]amino}quinoline-3-carbonitrile 0.35
987 8-chloro-6-{[(1-piperidin-4-yl-1 H-1,2,3-triazol-4-yl)methyl]amino}-4-(tetrahydro-2H-pyran-4-ylamino)quino!ine-3-carbonitrile 1.1
988 6-({[1 -(2-azepan-1 -ylethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)-8-chloro-4-[(4-phenoxyphenyl)amino]quinoline-3-carbonitrile >3
989 tert-butyl4-{4-[({8-chloro-3-cyano-4-[(4-phenoxyphenyl)amino]quinolin-6-yl}amino)methyl]-1H-1,2,3-triazol-1 -yl}piperidine-1 -carboxylate 0.4
990 8-chloro-6-[({1-[2-(1-methylpyrrolidin-2-yl)ethyl]-1H-1,2,3-triazol-4-yl}methyl)amino]-4-[(4-phenoxyphenyl)amino]quinoline-3-carbonitrile 0.83
991 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1 -{1 -[(2R,3R)-2,3I4-trihydroxybutyl]piperidin-4-yl}-1 H-1,2,3-triazol-4-yl)methyl]amino}quinoline-3-carbonitrile 0.0082
992 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[1-(2-hydraxyethyl)piperidin-4-yl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.002
993 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(2-hydroxy-2-pyridin-2-ylethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.048
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994 8-chloro-4-[(3-chloro-4-f luorophenyl)amino]-6-[({1 -[1 -(2,3-dihydroxypropyl)piperidin-4-yl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.0068
995 6-{[(1-but-2-yn-1-yl-1 H-1,2,3-triazol-4-yl)methy!]amino}-8-chloro-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 0.24
996 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(5-methylisoxazol-3-yl)methyl]amino}qiiinoline-3-carbonitrile >3
997 6-({[1 -(8-azabicyclo[3.2.1]oct-3-yl)-1 H-1,2,3-triazoM-yl]methyl}amino)-8-chloro-4-[(3-chloro-4-fluorophenyl)amino)quinoline-3-carbonitrile 0.011
998 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1 -[1 -(cyanomethyl)piperidin-4-yl]-1 H-1,2,3-triazol-4-yl}msihyl)amino]quinoline-3-carbonitrile 0.022
999 8-chloro-4-(cyclobutylamino)-6-({[1-(1-isopropylpiperidin-4-yl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.13
1000 8-chloro-6-({[1-(1-isopropylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl]methyl}amino)-4-(tetrahydro-2H-pyran-4-ylamino)quinoline-3-carbonitrile 0.48
1001 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(2-hydroxy-2-pyridin-4-ylethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.019
1002 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[(2-thienylmethyl)amino]quinoline-3-carbonitrile >3
1003 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1 -(1 -cyciopropylpiperidin-4-yl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.017
1004 6-{[(4-bromo-2-thienyl)methyl]amino}-8-chloro-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile >3
1005 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(8-ethyl-8-azabicydo[3.2.1]oct-3-yl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.041
1006 tert-butyl4-{4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazoM -yl}azepane-1 -carboxylate 0.24
1007 6-{[(1 -azepan-4-yl-1 H-1,2,3-triazol-4-yl)methyi]annino}-8-chloro-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 0.016
1008 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1 -{1 -[3-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}-1 H-1,2,3-triazol-4-yl)methyl]amino}quinoline-3-carbonitrile 0.49
1009 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1 -[1 -(2,2,2-trifluoroethyl)azepan-4-yl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.27
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1010 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1 -[1 -(2,2-difluoroethyl)azepar»-4-yl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.31
1011 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1 -[1 -(2-fluoroethyl)azepan-4-yl]-1 H-1,2,3-triazol-4-yl}methyI)amino]quinoIine-3-carbonitrile 0.0091
1012 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1 -[1 -(2,2,3,3,3-pentafluoropropyl)azepan-4-yl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile >3
1013 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1 -[1 -(2,2,3,3-tetrafluoropropyl)azepan-4-yl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.43
1014 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1 -[1 -(2,2,2-trifluoroethyl)piperidin-4-yl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.28
1015 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1 -[1 -(2,2-difluoroethyl)piperidin-4-yl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.092
1016 8-chloro-4-[(3-chloro-4-fiuorophenyl)amino]-6-[({1 -[1 -(2-fluoroethyl)piperidin-4-yl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.015
1017 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1 -[1 -(2,2l3,3,3-pentafIuoropropyl)piperidin-4-yl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 1.04
1018 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1 -[1 -(2,2,3,3-tetrafluoropropyl)piperidin-4-yl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.40
1019 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({5-[2,2,2-trifluoro-1 -hydroxy-1 -(trifluoromethyl)ethyl]pyridin-3-yl}methyl)amino]quinoline-3-carbonitrile >3
1020 8-chloro-4-[(3-chloro-4-fIuorophenyl)amino]-6-({[1-(2-pyridin-3-ylethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.13
1021 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(cyanomethyl)-i H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.43
1022 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({4-[3-(dimethylamino)propyl]-2-thienyl}methyl)amino]quinoline-3-carbonitrile 0.98
1023 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({4-[3-(dimethylamino)prop-i-yn-1-yl]-2-thienyl}methyl)amino]quinoline-3-carbonitrile 1.16
1024 6-{[(4-bromo-2-furyl)methyl]amino}-8-chloro-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile >3
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1025 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-({5-p-trifluoro-i-hydroxy-i-CtrifluoromethyOethyllpyridin-3-yl}methyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.91
1026 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1-methyl-1H-pyrazol-4-yl)methyl]amino}quinoline-3-carbonitrile 0.29
1027 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1 -[1 -(cyclopropylmethyl)piperidin-4-yl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.0079
1028 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[(cyclopropylmethyl)({1 -[1 -(cyclopropylmethyl)piperidin-4-yl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.41
1029 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-(cyclobutyl{[1 -(1 -cyclobutylpiperidin-4-yl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.29
1030 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1 -(1 -cyclobutylazepan-4-yl)-1 H-1,2,3-triazol-4-yl]methyI}amino)quinoline-3-carbonitrile 0.012
1031 tert-butyl4-{5-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]pyridin-3-yl}-4-hydroxypiperidine-1-carboxylate 0.16
1032 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[5-(4-hydroxypiperidin-4-yl)pyridin-3-yl]methyl}amino)quinoline-3-carbonitrile >3
1033 8-chIoro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[5-(4-hydroxy-1-isopropylpiperidin-4-yl)pyridin-3-yl]methyl}amino)quinoline-3-carbonitrile 0.5
1034 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[5-(1-ethyl-4-hydroxypiperidin-4-yl)pyridin-3-yl]methyl}amino)quinoline-3-carbonitrile 0.4
1035 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[4-(ethylamino)cyclohexyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.036
1036 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[4-(methylamino)cyclohexyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.04
1037 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-{4-(isopropylamino)cyclohexyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.02
1038 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[4-(cyclopentylamino)cyclohexyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.017
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1039 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[4-(pyridin-2-ylamino)cyclohexyI]-1 H-1,2,3-triazol-4-yl}methyl)aminolquinoline-3-carbonitrile 0.1
1040 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[4-(cyclopropylamino)cyclohexyl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.017
1041 8-chloro-4-f(3-chloro-4-fluorophenyl)amino]-6-({[1-(4-hydroxycyclohexyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.0057
1042 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(2-{5-[2,2,2-trifluoro-1 -hydroxy-1 -(trifluoromethyl)ethyl]pyridin-3-yl}ethyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.13
1043 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(1,2,2,6,6-pentamethylpiperidin-4-yl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.052
1044 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-({[3-(1-isopropylpiperidin-4-yl)-1H-pyrazol-5-yl]methyi}amino)quinoline-3-carbonitrile 0.86
1045 8-bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-({[3-(1-ethylpiperidin-4-yl)-1H-pyrazol-5-yl]methyl}amino)quinoline-3-carbonitrile 0.61
1046 tert-butyl3-{4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-1 H-1,2,3-triazoM -yl}-8-azabicyclo[3.2.1 ]octane-8-carboxylate 0.3
1047 6-{[(5-bromopyridin-3-yl)methyl]amino}-8-chloro-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 0.47
1048 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[5-(4-hydroxytetrahydro-2H-pyran-4-yl)pyridin-3-yl]methyl}amino)quinoline-3-carbonitrile 0.45
1049 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(8-isopropyl-8-azabicyclo[3.2.1]oct-3-yl)-1 H-1,2,3-triazol-4-yI]methyl}amino)quinoline-3-carbonitrile 0.42
1050 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[8-(methylsulfonyl)-8-azabicyclo[3.2.1]oct-3-yl]-1 H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.046
1051 tert-butyl5-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyanoquinolin-6-yl}amino)methyl]-3',6'-dihydro-3,4l-bipyridine-1I(2IH)-carboxylate >3
1052 3-{4-[({8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-canoquinolin-6-yl}amino)methyll-1 H-1,2,3-triazoM -yl}-N-ethyl-8-azabicyclo[3.2.1 ]octane-8-carboxamide 0.023
1053 6-({[1-(8-acetyl-8-azabicyclo[3.2.1]oct-3-yl)-1 H-1,2,3-triazol-4-yl]methy!}amino)-8-chloro-4-[(3-chloro-4-fluorophenyl)amino]quinoline-3-carbonitrile 0.024
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1054 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(1'- • isopropyl-1\2\3\6I-tetrahydro-3,4I-bipyridin-5-yl)methyl]amino}quinoline-3-carbonitrile 1.3
1055 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.008
1056 B-chloro--KS-chloro-fluorophenyOaminoJ-e-KI''.S'.e1-tetrahydro-3 '-bipyridin-S-ylmethyOaminolq uinoline-3-carbonitrile 0.88
1057 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({1-[8-(cyclopropylmethyl)-8-azabicyclo[3.2.1]oct-3-yl]-1H-1,2,3-triazol-4-yl}methyl)amino]quinoline-3-carbonitrile 0.011
1058 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(8-isobutyl-8-azabicyclo[3.2.1]oct-3-yl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.07
1059 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(8-formyl-8-azabicyclo[3.2.1]oct-3-yl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.014
1060 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[1-(4-hydroxy-4-methylcyclohexyl)-1 H-1,2,3-triazol-4-yl]methyl}amino)quinoline-3-carbonitrile 0.045
1061 8-chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-({[5-(1-isopropylpiperidin-4-yl)pyridin-3-yl]methyl}amino)quinoline-3-carbonitrile 0.6
It is intended that each of the patents, applications, and printed publications including books mentioned in this patent document be hereby incorporated by reference in their entirety.
As those skilled in the art will appreciate, numerous changes and modifications may be made to the preferred embodiments of the invention without departing from the spirit of the invention. It is intended that all such variations fall within the scope of the invention.
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What is claimed is:
1. A compound of formula (I):

wherein:
R1 is selected from the group consisting of C3-10 cycloalkyl, aryl, 3-10 membered cycloheteroalkyl, and heteroaryl, each optionally substituted with 1-4 moieties selected from the group consisting of:
a) halogen, b) CN, c) NO2, d) N3, e) OR9, f) NR10R11, g) oxo, h) thioxo,
i) S(O)PR9, j) SO2NR10R11, k) C(O)R9,1) C(O)OR9, m) C(O)NR10R11,
n) Si(C1-6 alkyl)3, o) C1-6 alkyl, p) C2-6 alkenyl, q) C2-6 alkynyl, r) C1-6 alkoxy,
s) C1-6 alkylthio, t) C1-6 haloalkyl, u) C3-10 cycloalkyl, v) aryl, w) 3-10 memberec
cycloheteroalkyl, and x) heteroaryl,
wherein any of 0) - x) optionally is substituted with 1-4 R12 groups;
R2 is selected from the group consisting of:
a) H, b) halogen, c) CN. d) NO2) e) OR9, f) NR10R1\ g) S(O)PR9, h) SO2NR10R11, i) C(O)R9, j) C(O)OR9, k) C(O)NR10R11,1) C1-6 alkyl, m) C2-6 alkenyl, n) C2-6 alkynyl, 0) C1-6 alkoxy, p) C1-6 alkylthio, q) C3-10 cycloalkyl, r) aryl, s) 3-10 membered cycloheteroalkyl, and t) heteroaryl, wherein any of I) -1) optionally is substituted with 1-4 R12 groups;
R3 is selected from the group consisting of:
a) H, b) halogen, c) CN, d) NO2, e) OR9, f) NR10R11, g) S(O)PR9,
h) SO2NR10R11, i) C(O)R9, j) C(O)OR9, k) C(O)NR10R11,1) C1-6 alkyl, m) C«
alkenyl, n) C2 alkynyl, o) C1-6 alkoxy, p) C1-6 alkylthio, q) d-e haloalkyl,
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r) C3-10 cycloalkyl, s) aryl, t) 3-10 membered cycloheteroalkyl, and
u) heteroaryl,
wherein any of I) - u) optionally is substituted with 1-4 R12 groups;
R4 is selected from the group consisting of C3-10 cycloalkyl, aryl, 3-10 membered cycloheteroalkyl, and heteroaryl, each optionally substituted with 1-4 moieties selected from the group consisting of:
a) halogen, b) CN, c) NO2) d) OR9, e) NR10R1\ f) oxo, g) thioxo, h) S(O)PR9, i) SO2NR10R1\ j) C(O)R9, k) C(O)OR9,1) C(O)NR10R11, m) Si(C alkyl)3, n) C-i-e alkyl, o) C2-e alkenyl, p) C2.e alkynyl, q) C1-6 alkoxy, r) d-e alkylthio, s) d-e haloalkyl, t) C3.10 cycloalkyl, u) aryl, v) 3-10 membered cycloheteroalkyl, and w) heteroaryl, wherein any of n) - w) optionally is substituted with 1-4 R12 groups;
alternatively, R4 is selected from the group consisting of Ci.8 alkyl optionally substituted with 1-4 R12 groups, CM haloalkyl, OR9, NR10R11,C(O)OR9, C(O)NR10R11, S(O)PR9, and N3;
R5 and R6 at each occurrence independently are selected from the group consisting of:
a) H, b) C(O)R9, c) C(O)OR9, d) C(O)NR10R1\ e) Ci-e alkyl, f) CM alkenyl, g)
C2-6 alkynyl, h) Ci haloalkyl, i) C3.10 cycloalkyl, j) aryl, k) 3-10 membered
cycloheteroalkyl, and I) heteroaryl,
wherein any of e) -1) optionally is substituted with 1-4 R12 groups;
R7 and R8 at each occurrence independently are selected from the group consisting of:
a) H, b) halogen, c) OR9, d) NR10R1\ e) CM alkyl, f) CM alkenyl, g) CM
alkynyl, h) Ci haloalkyl, and i) aryl;
alternatively, any two R7 or R8 groups and the carbon to which they are bonded may form a carbonyl group;
R9 at each occurrence is selected from the group consisting of.
a) H, b) C(O)R13, c) C(O)OR13, d) C(O)NR13R14, e) C1-6 alkyl, f) C1-6 alkenyl, g) C2 alkynyl, h) Ci haloalkyl, i) Ca.10 cycloalkyl, j) aryl, k) 3-10 membered cycloheteroalkyl, and I) heteroaryl,
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wherein any of e) -1) optionally is substituted with 1-4 R15 groups;
R10 and R11 at each occurrence independently are selected from the group consisting of:
a) H, b) OR13, c) SO2R13, d) C(O)R13, e) C(O)OR13, f) C(O)NR13R14, g) Ce
alkyl, h) O2-e alkenyl, i) C2-e alkynyl, k) Ci.6 haloalkyl, I) C3.10 cycloalkyl, m) aryl,
n) 3-10 membered cycloheteroalkyl, and o) heteroaryl;
wherein any of g) - o) optionally is substituted with 1-4 R15 groups;
R12 at each occurrence independently is selected from the group consisting of: a) halogen, b) CN, c) NO2, d) N3, e) OR9, f) NR10R11, g) oxo, h) thioxo, i) S(O)PR9, j) SO2NR10R1\ k) C(O)R9,1) C(O)OR9, m) C(O)NR10R11, n) Si(C alkyl)3, o) C1-6 alkyl, p) CM alkenyl, q) C2.6 alkynyl, r) C1-6 alkoxy, s) Ci.e alkylthio, t) C-t-e haloalkyl, u) C3.10 cycloalkyl, v) aryl, w) 3-10 membered cycloheteroalkyl, and x) heteroaryl; wherein any of o) - x) optionally is substituted with 1-4 R15 groups;
R13 and R14 at each occurrence independently are selected from the group consisting
of:
a) H, b) C1-6 alkyl, c) C2 alkenyl, d) CM alkynyl, e) C1-6 haloalkyl, f) C3.10 cycloalkyl, g) aryl, h) 3-10 membered cycloheteroalkyl, and i) heteroaryl, wherein any of b) - j) optionally is substituted with 1-4 R15 groups;
R15 at each occurrence independently is selected from the group consisting of: a) halogen, b) CN, c) NO2, d) N3, e) OH, f) O-C alkyl, g) NH2, h) NH(C alkyl), i) N(C,.8 alkyl)2, j) NH(aryl), k) NH(cycloalkyl), I) NH(heteroaryl), m) NH(cycloheteroalkyl), n) oxo, o) thioxo, p) SH, q) S(O)P-C alkyl, r) C(O)-C alkyl, s) C(O)OH, t)C(O)O-C alkyl, u) C(O)NH2, v) C(O)NHC alkyl, w) C(O)N(C alkyl)2, x) CM alkyl, y) CM alkenyl, z) C2 alkynyl, aa) Ce alkoxy, bb) C1-6 alkylthio, cc) C1-6 haloalkyl, dd) Co cycloalkyl, ee) aryl, ff) 3-10 membered cycloheteroalkyl, and gg) heteroaryl,
wherein any C1-6 alkyl, CM alkenyl, CM alkynyl, Co cycloalkyl, aryl, 3-10 membered cycloheteroalkyl, or heteroaryl, alone as a part of another moiety, optionally is substituted with one or more moieties selected from the group consisting of halogen, CN, NO2, OH, O-d.6 alkyl, NH2, NH(C alkyl), N(Calkyl)2, NH(aryl),
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NH(cycloalkyl), NH(heteroaryl), NH(cycloheteroalkyl), oxo, thioxo, SH, S(O)p-Calky[, C(O)-Calkyl, C(O)OH, cpp-d-e alkyl, C(O)NH2, C(O)NHC alkyl, C(O)N(C alkyl)2> CM alkyl, C2 alkenyl, C2-e alkynyl, C1-6 alkoxy, d.6 alkylthio, d-e haloalkyl, C3-10 cycloalkyl, aryl, 3-10 membered cycloheteroalkyl, and heteroaryl;
misO, 1,2, 3, or 4;
n is 0 or 1; and
pis 0,1, or 2;
or a pharmaceutically acceptable salt thereof,
provided that the compound of formula (I) does not comprise 4-(3-Chloro-4-fluoro-
phenylamino)-7-methoxy-6-(4-morpholin-4-yl-butylamino)-quinoline-3-carbonitrileor
4-(3-Bromo-phenylamino)-6-(3-pyrrolidin-1-yl-propylamino)-quinoline-3-carbonitrile.
2. The compound according to claim 1, wherein R2 is H.
3. The compound according to claim 1, wherein R2 is C1-6 alkylthio optionally substituted with NR10R11.
4. The compound according to claim 3, wherein R2 is SCH2CH2N(CHs)2.
5. The compound according to any one of claims 1 to 4, wherein R3 is H.
6. The compound according to any one of claims 1 to 4, wherein R3 is halogen.
7. The compound according to claim 6, wherein R3 is is Br.
8. The compound according to claim 6, wherein R3 is is Cl.
9. The compound according to any one of claims 1 to 8, wherein R4 is phenyl.
10. The compound according to claim 9, wherein R4 is phenyl substituted with 1-2 halogens.
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11. The compound according to claim 10, wherein R4 is phenyl substituted with Cl.
12. The compound according to claim 10, wherein R4 is phenyl substituted with F.
13. The compound according to claim 10, wherein R4 is phenyl substituted with Cl and F.
14. The compound according to claim 13, wherein R4 is 3-chloro-4-fIuorophenyl.
15. The compound according to any one of claims 1 to 14, wherein R1 is a 5 or 6 membered heteroaryl.
16. The compound according to claim 15, wherein R1 is imidazole.
17. The compound according to claim 15, wherein R1 is triazole.
18. The compound according to claim 17, wherein R1 is 1,2,3-triazole.
19. The compound according to claim 15, wherein R1 is tetrazole.
20. The compound according to claim 15, wherein R1 is pyridine.
21. The compound according to claim 15, wherein R1 is N-oxypyridine.
22. The compound according to any one of claims 1 to 21, wherein m is 1.
23. The compound according to any one of claims 1 to 22, wherein n is 0.
24. The compound according to any one of claims 1 to 23, wherein R5 is H.
25. The compound according to any one of claims 1 to 23, wherein R5 is C14 alkyl.
26. The compound according to any one of claims 1 to 25, wherein R6 is H.
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27. The compound according to any one of claims 1 to 25, wherein R6 is C1-6 alkyl.
28. A method of preventing or treating disease conditions mediated by TpI-2 kinase in a mammal, comprising administering to the mammal a pharmaceutically effective amount of a compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof.
29. A method of alleviating a symptom of a disease mediated by Tpl-2 kinase in a mammal, comprising administering to the mammal a pharmaceutically effective amount of a compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof.
30. A method of preventing or treating an inflammatory disease in a mammal, comprising administering to the mammal a pharmaceutically effective amount of a compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof.
31. A method of alleviating a symptom of an inflammatory disease in a mammal, comprising administering to the mammal a pharmaceutically effective amount of a compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof.
32. The method of claim 30 or 31, wherein the inflammatory disease is rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, or osteoarthritis.
33. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 27, or pharmaceutically salts thereof, and one or more pharmaceutically acceptable carriers.
34. A compound of formula (II):
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wherein:
Z is selected from the group consisting of halogen, Ci« alkyl optionally substituted with 1-4 R12 groups, C1-6 haloalkyl, OR9, NR10R1\ S(O)PR9, SO2NR10R1\ C(O)R9, C(O)OR9, C(O)NR10R11, and N3;
and wherein R2, R3, R4, Re, R8, R9, R10, R11, R12, n and p are as defined for any one of claims 1 to 27;
or a pharmaceutically acceptable salt thereof.
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The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof, whereinR1, R2, R3, R4, R5, R6, R7, R8, m and n are defined as described herein. The invention also provides methods of making the compounds of formula (I), and methods of treating inflammatory diseases, such as rheumatoid arthritis, in a mammal comprising administering a therapeutically effective amount of a compound of formula (I) to the mammal.