WO2024078513A1 - Condensed azines for treating cancer - Google Patents
Condensed azines for treating cancer Download PDFInfo
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- WO2024078513A1 WO2024078513A1 PCT/CN2023/123870 CN2023123870W WO2024078513A1 WO 2024078513 A1 WO2024078513 A1 WO 2024078513A1 CN 2023123870 W CN2023123870 W CN 2023123870W WO 2024078513 A1 WO2024078513 A1 WO 2024078513A1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
- C07D215/44—Nitrogen atoms attached in position 4 with aryl radicals attached to said nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D233/61—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms not forming part of a nitro radical, attached to ring nitrogen atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The present disclose includes, among other things, compounds that treat or lessen the severity of a disorder, pharmaceutical compositions and methods of making and using the same.
Description
Cancer is a term used for diseases in which abnormal cells divide without control and may invade other tissues. Cancer cells may also spread to other parts of the body through the blood and lymph systems.
There are more than 100 different types of cancer, with most cancers named for the organ or type of cell in which they start. For example, cancer that begins in the colon may be referred to as colon cancer; cancer that begins in basal cells of the skin may be referred to as basal cell carcinoma. Common types of cancer include breast cancer and lung cancer.
Cancer types can also be grouped into broader categories. The main categories of cancer include: carcinoma-cancer that begins in the skin or in tissues that line or cover internal organs; sarcoma-cancer that begins in bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue; leukemia-cancer that starts in blood-forming tissue such as the bone marrow and causes large numbers of abnormal blood cells to be produced and enter the blood; lymphoma and myeloma-cancers that begin in the cells of the immune system; central nervous system cancers-cancers that begin in the tissues of the brain and spinal cord.
Several techniques for treating cancer are known in the art. Such techniques include chemotherapy, radiation therapy, surgery, and transplantation. Each of these techniques, however, have undesirable side effects and varying success rates. Therefore, a need exists to develop new methods for treating cancer and/or diseases associated with cellular proliferation.
The present disclosure provides for compounds of Formula (I) :
or a pharmaceutically acceptable salt or N-oxide thereof. Additionally, the present disclosure
includes, among other things, pharmaceutical compositions, methods of using a compound of Formula (I) .
The present disclosure provides for compounds of Formula (II) :
or a pharmaceutically acceptable salt or N-oxide thereof. Additionally, the present disclosure includes, among other things, pharmaceutical compositions, methods of using a compound of Formula (II) .
The present disclosure provides for compounds of Formula (III) :
or a pharmaceutically acceptable or N-oxide salt thereof. Additionally, the present disclosure includes, among other things, pharmaceutical compositions, methods of using a compound of Formula (III) .
The present disclosure includes, among other things, a compound of Formula (I) :
or a pharmaceutically acceptable salt or N-oxide thereof,
wherein
A1 is -C (H) = or -N=;
A2 is -C (H) = or -N=;
R1 is selected from the group consisting of halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 haloalkoxy, -C (O) Ra, and -C (O) ORa;
R2 is selected from the group consisting of hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 haloaliphatic, -C (O) Ra, and -C (O) ORa;
R2’ is selected from the group consisting of optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 haloaliphatic, -C (O) Ra, and -C (O) ORa, ;
optionally, R2 and R2’ are taken together with the nitrogen on which they are attached to form optionally substituted 3-7-membered heterocyclyl or optionally substituted 5-9-membered heteroaryl;
each R3 is independently selected from the group consisting of halogen, -CN, -ORa, -N (Ra) 2, -NO2, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 haloaliphatic, -C (O) Ra, -C (O) ORa, and -C (O) N (Ra) 2;
each R4 is independently selected from the group consisting of halogen, -CN, -ORa, -N (Ra) 2, -NO2, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 haloaliphatic, -C (O) Ra, -C (O) ORa, -C (O) N (Ra) 2, optionally substituted phenyl, optionally substituted 3-7-membered heterocyclyl and optionally substituted 5-9-membered heteroaryl;
each R5 is independently selected from the group consisting of deuterium and halogen;
each Ra is independently is selected from the group consisting of hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 haloaliphatic, optionally substituted 3-7-membered heterocyclyl, optionally substituted 5-9-membered heteroaryl, -C (O) Rb, and -
C (O) ORb;
optionally, two instances of Ra are taken together with the nitrogen on which they are attached to form optionally substituted 3-7-membered heterocyclyl or optionally substituted 5-9-membered heteroaryl;
each Rb is independently optionally substituted C1-C6 aliphatic;
n is 0, 1, 2, or 3;
m is 0, 1, 2, 3, or 4; and
p is 0, 1, 2, or 3.
In some embodiments, present disclosure includes a compound of formula (I-a) :
or a pharmaceutically acceptable salt or N-oxide thereof, wherein R1, R4, A2, and m are defined above and described in classes and subclasses herein.
In some embodiments, present disclosure includes a compound of Formula (II) :
or a pharmaceutically acceptable salt or N-oxide thereof,
wherein
A1 is -C (H) = or -N=;
A2 is -C (H) = or -N=;
R2 is selected from the group consisting of -NH2, -NO2 -ORa, -O (CH2) 1-3Ra, -C (O) ORa, -C (O) N (Ra) 2, optionally substituted C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 3-10 membered heterocyclyl, and optionally substituted 5-9-membered heteroaryl;
each R3 is independently selected from the group consisting of halogen, -CN, -ORa, -N (Ra) 2, -NO2, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 haloaliphatic, -C (O) Ra, -C (O) ORa, and -C (O) N (Ra) 2;
each R4 is independently selected from the group consisting of halogen, -CN, -ORa, -N (Ra) 2, -NO2, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 haloaliphatic, -C (O) Ra, -C (O) ORa, -C (O) N (Ra) 2, optionally substituted phenyl, optionally substituted 3-7-membered heterocyclyl and optionally substituted 5-9-membered heteroaryl;
each R5 is independently selected from the group consisting of deuterium and halogen;
each Ra is independently is selected from the group consisting of hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 haloaliphatic, optionally substituted 3-7-membered heterocyclyl, optionally substituted 5-9-membered heteroaryl, -C (O) Rb, and -C (O) ORb;
optionally, two instances of Ra are taken together with the nitrogen on which they are attached to form optionally substituted 3-7-membered heterocyclyl or optionally substituted 5-9-membered heteroaryl;
each Rb is independently is selected from the group consisting of optionally substituted C1-C6 aliphatic and optionally substituted C1-C6 haloaliphatic;
n is 0, 1, 2, or 3;
m is 0, 1, 2, 3, or 4; and
p is 0, 1, 2, or 3.
In some embodiments, present disclosure includes a compound of formula (II-a) :
or a pharmaceutically acceptable salt or N-oxide thereof, wherein A1, A2, R2, R4, and m are defined above and described in classes and subclasses herein.
In some embodiments, present disclosure includes a compound of formula (II-b) :
or a pharmaceutically acceptable salt or N-oxide thereof, wherein A1, A2, R4, and m are defined above and described in classes and subclasses herein.
In some embodiments, present disclosure includes a compound of formula (II-c) :
or a pharmaceutically acceptable salt or N-oxide thereof, wherein A1, A2, R4, and m are defined above and described in classes and subclasses herein.
In some embodiments, present disclosure includes a compound of formula (II-d) :
or a pharmaceutically acceptable salt or N-oxide thereof, wherein A1, A2, R4, and m are defined above and described in classes and subclasses herein.
In some embodiments, present disclosure includes a compound of formula (II-e) :
or a pharmaceutically acceptable salt or N-oxide thereof, wherein A1, A2, R4, and m are defined above and described in classes and subclasses herein.
In some embodiments, the present disclosure includes a compound of Formula (III) :
or a pharmaceutically acceptable salt or N-oxide thereof,
wherein
A is -C (H) = or -N=;
one of Q1 and Q2 is -N (Ra) -or -S-and the other is -C (H) =;
R2 is selected from the group consisting of -C (O) ORa, -C (O) N (Ra) 2, optionally substituted C1-C6 haloaliphatic, and optionally substituted 5-9-membered heteroaryl;
each R3 is independently selected from the group consisting of halogen, -CN, -ORa, -N (Ra) 2, -NO2, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 haloaliphatic, -C (O) Ra, -C (O) ORa, and -C (O) N (Ra) 2;
each R4 is independently selected from the group consisting of halogen, -CN, -ORa, -N (Ra) 2, -NO2, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 haloaliphatic, -C (O) Ra, -C (O) ORa, -C (O) N (Ra) 2, optionally substituted phenyl, optionally substituted 3-7-membered heterocyclyl and optionally substituted 5-9-membered heteroaryl;
each Ra is independently is selected from the group consisting of hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 haloaliphatic, -C (O) Rb, and -C (O) ORb;
optionally, two instances of Ra are taken together with the nitrogen on which they are attached to form optionally substituted 3-7-membered heterocyclyl or optionally substituted 5-9-membered heteroaryl;
each Rb is independently is selected from the group consisting of optionally substituted C1-C6 aliphatic and optionally substituted C1-C6 haloaliphatic;
n is 0, 1, 2, or 3;
m is 0, 1, 2, 3, or 4.
R1
In some embodiments, R1 is selected from the group consisting of halogen optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 haloalkoxy, -C (O) Ra, and -C (O) ORa. In some embodiments, R1 is selected from the group consisting of optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 haloalkoxy, -C (O) Ra, and -C (O) ORa. In some embodiments, R1 is optionally substituted C1-C6 alkoxy. In some embodiments, R1 is -OMe. In some embodiments, R1 is -C (O) ORa. In some embodiments, R1 is -C (O) OMe.
R2 and R2’
In some embodiments, R2 is selected from the group consisting of hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 haloaliphatic, -C (O) Ra, and -C (O) ORa. In some embodiments, R2 is selected from the group consisting of -C (O) ORa, -C (O) N (Ra) 2, optionally substituted C1-C6 aliphatic, and optionally substituted 5-9-membered heteroaryl. In some embodiments, R2 is selected from the group consisting of -C (O) ORa, -C (O) N (Ra) 2, optionally substituted C1-C6 haloaliphatic, and optionally substituted 5-9-membered heteroaryl.
In some embodiments, R2 is selected from the group consisting of -NH2, -NO2 -ORa, -O (CH2) 1-3Ra, -C (O) ORa, -C (O) N (Ra) 2, optionally substituted C1-C6 aliphatic, and optionally substituted 5-9-membered heteroaryl. In some embodiments, R2 is optionally substituted 5-9-membered heteroaryl. In some embodiments, R2 is optionally substituted 5-membered heteroaryl. In some embodiments, R2 is optionally substituted 6-membered heteroaryl. In some embodiments, R2 is optionally substituted 5-9-membered heterocyclyl. In some embodiments, R2 is optionally substituted 5-membered heterocyclyl. In some embodiments, R2 is optionally substituted 6-membered heterocyclyl. In some embodiments, R2 is optionally substituted phenyl.
In some embodiments, R2’ is selected from the group consisting of optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 haloaliphatic, -C (O) Ra, and -C (O) ORa.
In some embodiments, R2 and R2’ are taken together with the nitrogen on which they are attached to form optionally substituted 3-7-membered heterocyclyl or optionally substituted 5-9-membered heteroaryl.
In some embodiments, R2 and R2’ are taken together with the nitrogen on which they are attached to form o optionally substituted 5-9-membered heteroaryl.
In some embodiments, R2 is -C (O) ORa. In some embodiments, R2 is -C (O) ORa, and Ra of R2 is C1-C6 aliphatic. In some embodiments, R2 is -C (O) ORa, and Ra of R2 is C1-C3 alkyl. In some embodiments, R2 is -C (O) OMe.
In some embodiments, R2 is -C (O) NHRa, In some embodiments, R2 is -C (O) NHRa, and Ra of R2 is C1-C6 aliphatic. In some embodiments, R2 is -C (O) NHRa, and Ra of R2 is C1-C3 alkyl. In some embodiments, R2 is -C (O) NHMe.
In some embodiments, R2 is optionally substituted 5-membered heteroaryl. In some embodiments, R2 is optionally substituted 5-membered heteroaryl comprising 1-3 heteroatoms
selected from the group consisting of O, N, and S. In some embodiments, R2 is optionally substituted 5-membered heteroaryl comprising 1-3 nitrogen atoms. In some embodiments, R2 is optionally substituted oxazolyl or optionally substituted pyrazolyl.
In some embodiments, R2 is optionally substituted C1-C6 aliphatic. In some embodiments, R2 is C1-C6 substituted with 1-7 instances of fluoro. In some embodiments, R2 is -CF3.
R3
In some embodiments, each each R3 is independently selected from the group consisting of halogen, -CN, -ORa, -N (Ra) 2, -NO2, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 haloaliphatic, -C (O) Ra, -C (O) ORa, and -C (O) N (Ra) 2.
R4
In some embodiments, each R4 is independently selected from the group consisting of halogen, -CN, -ORa, -N (Ra) 2, -NO2, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 haloaliphatic, -C (O) Ra, -C (O) ORa, -C (O) N (Ra) 2, optionally substituted phenyl, optionally substituted 3-7-membered heterocyclyl and optionally substituted 5-9-membered heteroaryl.
Ra
In some embodiments, each Ra is independently is selected from the group consisting of hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 haloaliphatic, optionally substituted 3-7-membered heterocyclyl, optionally substituted 5-9-membered heteroaryl, -C (O) Rb, and -C (O) ORb; optionally, two instances of Ra are taken together with the nitrogen on which they are attached to form optionally substituted 3-7-membered heterocyclyl or optionally substituted 5-9-membered heteroaryl. In some embodiments, each Ra is independently is selected from the group consisting of hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 haloaliphatic, -C (O) Rb, and -C (O) ORb; optionally, two instances of Ra are taken together with the nitrogen on which they are attached to form optionally substituted 3-7-membered heterocyclyl or optionally substituted 5-9-membered heteroaryl. In some embodiments, Ra is optionally substituted C1-C6 aliphatic. In some embodiments, Ra is optionally substituted C1-C3 alkyl. In some embodiments, Ra is optionally substituted methyl.
Rb
In some embodiments, each Rb is independently optionally substituted C1-C6 aliphatic. In
some embodiments, each Rb is independently optionally substituted C1-C3 alkyl. In some embodiments, Rb is independently optionally substituted methyl.
m, and n
In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 1, 2, or 3. In some embodiments, m is 0, 1, 2, 3, or 4. In some embodiments, m is 1, 2, 3, or 4.
Compounds
In some embodiments, compounds of the present disclosure includes those from Table 1.
Table 1
or a pharmaceutically acceptable salt thereof.
Definitions
The term "aliphatic" or "aliphatic group" , as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle" "cycloaliphatic" or "cycloalkyl" ) , that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic
carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" (or "carbocycle" or “carbocyclyl” or "cycloalkyl" ) refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl) alkyl, (cycloalkenyl) alkyl or (cycloalkyl) alkenyl.
The term "alkyl" refers to a straight or branched alkyl group. Exemplary alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
The term "halogen" means F, Cl, Br, or I.
The term "aryl" used alone or as part of a larger moiety as in "aralkyl" , "aralkoxy" , or "aryloxyalkyl" , refers to monocyclic and bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. The term "aryl" may be used interchangeably with the term "aryl ring" . In certain embodiments of the present disclosure, "aryl" refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term "aryl" , as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
The terms "heteroaryl" and "heteroar-" , used alone or as part of a larger moiety, e.g., "heteroaralkyl" , or "heteroaralkoxy" , refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroar-" , as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl,
isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido [2, 3-b] -l, 4-oxazin-3 (4Η) -one. A heteroaryl group may be mono-or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring" , "heteroaryl group" , or "heteroaromatic" , any of which terms include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.
As used herein, the terms "heterocycle" , "heterocyclyl" , "heterocyclic radical" , and "heterocyclic ring" are used interchangeably and refer to a stable 5-to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3, 4-dihydro-2H-pyrrolyl) , NH (as in pyrrolidinyl) , or +NR (as in TV-substituted pyrrolidinyl) . A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle" , "heterocyclyl" , "heterocyclyl ring" , "heterocyclic group" , "heterocyclic moiety" , and "heterocyclic radical" , are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring. A heterocyclyl group may be mono-or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having
multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted” , whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable” , as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; -SF5, - (CH2) 0-4R○; - (CH2) 0-4OR○; -O (CH2) 0-
4R○, -O- (CH2) 0-4C (O) OR○; - (CH2) 0-4CH (OR○) 2; - (CH2) 0-4SR○; - (CH2) 0-4Ph, which may be substituted with R○; - (CH2) 0-4O (CH2) 0-1Ph which may be substituted with R○; -CH═CHPh, which may be substituted with R○; - (CH2) 0-4O (CH2) 0-1-pyridyl which may be substituted with R○; -NO2; -CN; -N3; - (CH2) 0-4N (R○) 2; - (CH2) 0-4N (R○) C (O) R○; -N (R○) C (S) R○; - (CH2) 0-
4N (R○) C (O) NR○ 2; -N (R○) C (S) NR○ 2; - (CH2) 0-4N (R○) C (O) OR○; -N (R○) N (R○) C (O) R○; -N (R○) N (R○) C (O) NR○ 2; -N (R○) N (R○) C (O) OR○; - (CH2) 0-4C (O) R○; -C (S) R○; - (CH2) 0-
4C (O) OR○; - (CH2) 0-4C (O) SR○; - (CH2) 0-4C (O) OSiR○ 3; - (CH2) 0-4OC (O) R○; -OC (O) (CH2) 0-
4SR○, SC (S) SR○; - (CH2) 0-4SC (O) R○; - (CH2) 0-4C (O) NR○ 2; -C (S) NR○ 2; -C (S) SR○; -SC (S) SR○, - (CH2) 0-4OC (O) NR○ 2; -C (O) N (OR○) R○; -C (O) C (O) R○; -C (O) CH2C (O) R○; -C (NOR○) R○; - (CH2) 0-4SSR○; - (CH2) 0-4S (O) 2R○; - (CH2) 0-4S (O) 2OR○; - (CH2) 0-4OS (O) 2R○; -S (O) 2NR○ 2; - (CH2) 0-4S (O) R○; -S (O) (NR○) R○, -N (R○) S (O) 2NR○ 2; -N (R○) S (O) 2R○; -N (OR○) R○; -C (NH) NR○ 2; -P (O) 2R○; -P (O) R○ 2; -OP (O) R○ 2; -OP (O) (OR○) 2; SiR○ 3; - (C1-4 straight or branched alkylene) O-N (R○) 2; or - (C1-4 straight or branched alkylene) C (O) O-N (R○) 2, wherein each R○ may be substituted as defined below and is independently hydrogen, C1-
6 aliphatic, -CH2Ph, -O (CH2) 0-1Ph, -CH2- (5-6 membered heteroaryl ring) , or a 5-6-
membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R○, taken together with their intervening atom (s) , form a 3-12-membered saturated, partially unsaturated, or aryl mono-or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.
Suitable monovalent substituents on R○ (or the ring formed by taking two independent occurrences of R○ together with their intervening atoms) , are independently halogen, -SF5, - (CH2) 0-2R●, - (haloR●) , - (CH2) 0-2OH, - (CH2) 0-2OR●, - (CH2) 0-2CH (OR●) 2; -O (haloR●) , -CN, -N3, - (CH2) 0-2C (O) R●, - (CH2) 0-2C (O) OH, - (CH2) 0-2C (O) OR●, - (CH2) 0-2SR●, - (CH2) 0-2SH, - (CH2) 0-2NH2, - (CH2) 0-2NHR●, - (CH2) 0-2NR● 2, -NO2, -SiR● 3, -OSiR● 3, -C (O) SR●, - (C1-4 straight or branched alkylene) C (O) OR●, or -SSR● wherein each R● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1-4 aliphatic, -CH2Ph, -O (CH2) 0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R○ include ═O and ═S.
Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: ═O, ═S, ═NNR*
2, ═NNHC (O) R*, ═NNHC (O) OR*, ═NNHS (O) 2R*, ═NR*, ═NOR*, -O (C (R*
2) ) 2-3O-, or -S (C (R*
2) ) 2-3S-, wherein each independent occurrence of R*is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O (CR*
2) 2-3O-, wherein each independent occurrence of R*is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
Suitable substituents on the aliphatic group of R* include halogen, -SF5, -R●, - (haloR●) , -OH, -OR●, -O (haloR●) , -CN, -C (O) OH, -C (O) OR●, -NH2, -NHR●, -NR● 2, or -NO2, wherein each R● is unsubstituted or where preceded by “halo” is substituted
only with one or more halogens, and is independently C1-4 aliphatic, -CH2Ph, -O (CH2) 0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include
wherein each is independently hydrogen, C1-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences oftaken together with their intervening atom (s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono-or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
Suitable substituents on the aliphatic group ofare independently halogen, -SF5, -R●, - (haloR●) , -OH, -OR●, -O (haloR●) , -CN, -C (O) OH, -C (O) OR●, -NH2, -NHR●, -NR● 2, or -NO2, wherein each R● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, -CH2Ph, -O (CH2) 0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable
salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.
Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N (C1-4alkyl) 4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
As used herein, "N-oxide" refers to the oxide of the nitrogen atom of a nitrogen-containing heteroaryl or heterocycle. N-oxide can be formed in the presence of an oxidizing agent such as m-chloroperbenzoic acid or hydrogen peroxide. N-oxide refers to an amine oxide, also known as amine-N-oxide, and is a chemical compound that contains N-O bond.
Combinations of substituents and variables envisioned by this disclosure are only those that result in the formation of stable compounds. The term "stable" , as used herein, refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject) .
The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.
The compounds of the disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers. The term “stereoisomers” when used herein consist of all enantiomers or diastereomers. These compounds may be designated by the symbols “ (+) , ” “ (-) , ” “R” or “S, ” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled
artisan will recognize that a structure may denote a chiral center implicitly. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated “ (±) ” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.
The compounds of the disclosure may contain one or more double bonds and, therefore, exist as geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond. The symboldenotes a bond that may be a single, double or triple bond as described herein. Substituents around a carbon-carbon double bond are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the “E” and “Z” isomers. Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans, ” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond.
Compounds of the disclosure may contain a carbocyclic or heterocyclic ring and therefore, exist as geometric isomers resulting from the arrangement of substituents around the ring. Substituents around a carbocyclic or heterocyclic ring may also be referred to as “cis” or “trans” , where the term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis/trans. ”
Individual enantiomers and diasteriomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers on chiral liquid chromatographic columns or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their component enantiomers by well known methods, such as chiral-phase liquid chromatography or crystallizing the compound in a chiral solvent. Stereoselective syntheses,
a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre-existing one, are well known in the art. Stereoselective syntheses encompass both enantio-and diastereoselective transformations, and may involve the use of chiral auxiliaries. For examples, see Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.
Additionally, the present disclosure contemplates tautomers of the compounds as drawn herein.
The term "biological sample" , as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, biological specimen storage, and biological assays.
As used herein, a "therapeutically effective amount" means an amount of a substance (e.g., a therapeutic agent, composition, and/or formulation) that elicits a desired biological response. In some embodiments, a therapeutically effective amount of a substance is an amount that is sufficient, when administered as part of a dosing regimen to a subject suffering from or susceptible to a disease, disorder, and/or condition, to treat, diagnose, prevent, and/or delay the onset of the disease, disorder, and/or condition. As will be appreciated by those of ordinary skill in this art, the effective amount of a substance may vary depending on such factors as the desired biological endpoint, the substance to be delivered, the target cell or tissue, etc. For example, the effective amount of a provided compound in a formulation to treat a disease, disorder, and/or condition is the amount that alleviates, ameliorates, relieves, inhibits, prevents, delays onset of, reduces severity of and/or reduces incidence of one or more symptoms or features of the disease, disorder, and/or condition. I
As used herein, the terms "treatment, " "treat, " and "treating" refer to partially or completely alleviating, inhibiting, delaying onset of, ameliorating and/or relieving a disorder or condition, or one or more symptoms of the disorder or condition, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In some embodiments, the term "treating" includes halting the progression of a disease or disorder. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history
of symptoms and/or in light of genetic or other susceptibility factors) . Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence. Thus, in some embodiments, the term "treating" includes preventing relapse or recurrence of a disease or disorder.
The term “patient” , as used herein, means an animal, preferably a mammal, and most preferably a human.
The term “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound (s) with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of the compounds disclosed herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
A “pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this disclosure that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this disclosure or an inhibitorily active metabolite or residue thereof.
The expression “dosage unit form” as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that total daily usage of compounds and compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment. Specific effective dose level for any particular patient or organism will depend upon a variety of factors including disorder being treated and severity of the disorder; activity of specific compound employed; specific composition employed; age, body weight, general health, sex and diet of the patient; time of administration, route of administration, and rate of excretion of a specific compound employed; duration of treatment; drugs used in combination or coincidental with a specific compound employed, and like factors well known in the medical arts.
Alternative Embodiments
In an alternative embodiment, compounds described herein may also comprise one or more isotopic substitutions. For example, hydrogen may be 2H (D or deuterium) or 3H (T or tritium) ; carbon may be, for example, 13C or 14C; oxygen may be, for example, 18O; nitrogen may be, for example, 15N, and the like. In other embodiments, a particular isotope (e.g., 3H, 13C, 14C, 18O, or 15N) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9%of the total isotopic abundance of an element that occupies a specific site of the compound.
Pharmaceutical Compositions
In some embodiments, the present disclosure provides a composition comprising a compound of Formula (I) and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the amount of compound in compositions contemplated herein is such that is effective to measurably treat a disease or disorder in a biological sample or in a patient. In certain embodiments, the amount of compound in compositions of this disclosure is such that is effective to measurably treat a disease or disorder in a biological sample or in a patient. In certain embodiments, a composition contemplated by this disclosure is formulated for administration to a patient in need of such composition. In some embodiments, a composition contemplated by this disclosure is formulated for oral administration to a patient.
In some embodiments, compositions of the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. In some preferred embodiments, compositions are administered orally, intraperitoneally or intravenously. In some embodiments, sterile injectable forms of the compositions comprising one or more compounds of Formula (I) may be aqueous or oleaginous suspension. In some embodiments, suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. In some embodiments, sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic
parenterally acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. In some embodiments, among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In some embodiments, additional examples include, but are not limited to, sterile, fixed oils are conventionally employed as a solvent or suspending medium.
The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
Pharmaceutically acceptable compositions comprising one or more compounds of Formula (I) may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In some embodiments, carriers used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. In some embodiments, useful diluents include lactose and dried cornstarch. In some embodiments, when aqueous suspensions are required for oral use, an active ingredient is combined with emulsifying and suspending agents. In some embodiments, certain sweetening, flavoring or coloring agents may also be added.
Alternatively, pharmaceutically acceptable compositions comprising a compound of Formula (I) may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
Pharmaceutically acceptable compositions comprising a compound of Formula (I) may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. In some embodiments, pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components
suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
Pharmaceutically acceptable compositions comprising a compound of Formula (I) may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
In some embodiments, an amount of a compound of the present disclosure that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of between 0.01-100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.
Methods of Using Compounds of the Present Disclosure
In some embodiments, the present disclosure provides a method for treating or lessening the severity of a disease or condition associated with cell proliferation in a patient comprising the step of administering to said patient a composition according to the present disclosure.
The term “disease or condition associated with cell proliferation” , as used herein means any disease or other deleterious condition in which cell proliferation is known to play a role. Accordingly, another embodiment of the present disclosure relates to treating or lessening the severity of one or more diseases in which cell proliferation is known to play a role. In some embodiments, a disease or condition associated with cell proliferation is cancer.
In some embodiments, administration of a compound of the present disclosure results in arrest of mitosis or change in DNA content.
In some embodiments, administration of a compound of the present disclosure results in arrest of mitosis. In some embodiments, mitotic arrest is defined as a 10-100%reduction in mitosis. In some embodiments, mitotic arrest is defined as a 20-100%reduction in mitosis. In some embodiments, mitotic arrest is defined as a 30-100%reduction in mitosis. In some embodiments, mitotic arrest is defined as a 40-100%reduction in mitosis. In some embodiments, mitotic arrest
is defined as a 50-100%reduction in mitosis. In some embodiments, mitotic arrest is defined as a 60-100%reduction in mitosis. In some embodiments, mitotic arrest is defined as a 70-100%reduction in mitosis. In some embodiments, mitotic arrest is defined as a 80-100%reduction in mitosis. In some embodiments, mitotic arrest is defined as a 90-100%reduction in mitosis. In some embodiments, mitotic arrest is defined as a 100%reduction in mitosis.
In some embodiments, administration of a compound of the present disclosure results in change in DNA content. In some embodiments, change of DNA content is induction of polyploidy.
In some embodiments, compounds and compositions, according to a method of the present disclosure, may be administered using any amount and any route of administration effective for treating or lessening the severity of cancer. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, severity of the infection, particular agent, its mode of administration, and the like. Compounds of the present disclosure are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
In some embodiments, cancer is selected from the group consisting of lung cancer and breast cancer. In some embodiments, cancer is lung cancer. In some embodiments, lung cancer is non-small cell lung cancer. In some embodiments, non-small cell lung cancer is lung adenocarcinoma. In some embodiments, cancer is breast cancer. In some embodiments, breast cancer is mammary cancer. In some embodiments, breast cancer is breast adenocarcinoma.
In some embodiments, pharmaceutically acceptable compositions of comprising compounds of the present disclosure can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops) , buccally, as an oral or nasal spray, or the like, depending on the severity of infection being treated. In certain embodiments, compounds of the present disclose may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain desired therapeutic effect.
In some embodiments, one or more additional therapeutic agents, may also be administered in combination with compounds of the present disclosure. In some embodiments, a compound of the present disclosure and one or more additional therapeutic agents may be administered as part of a multiple dosage regime. In some embodiments, a compound of the present disclosure and one
or more additional therapeutic agents may be administered may be administered simultaneously, sequentially or within a period of time. In some embodiments, a compound of the present disclosure and one or more additional therapeutic agents may be administered within five hours of one another. In some embodiments, a compound of the present disclosure and one or more additional therapeutic agents may be administered within 24 hours of one another. In some embodiments, a compound of the present disclosure and one or more additional therapeutic agents may be administered within one week of one another.
In some embodiments, a compound of the present disclosure and one or more additional therapeutic agents may be formulated into a single dosage form.
Exemplification
General Methods
Unless stated otherwise, all the chemicals required for synthesis were purchased from commercially available suppliers and used without further purification. 1H NMR spectra was determined with a Bruker Avance III-400 at 400 MHz. LC-MS analysis was performed on a platform equipped with Agilent LC-MS 1260-6110 or Agilent LC-MS 1260-6120, using a Waters X Bridge C18: 50mm x 4.6 mm x 3.5 um column. Flash column chromatography was conducted with silica gel (200-300 mesh, Qingdao Haiyang Chemical Co. Ltd., China) . Analytical and preparative TLC analysis were performed on GF254 silica gel plates (Yantai Jiangyou Inc., China) . Unless otherwise noted, reagents and all solvents are analytically pure grade and were obtained commercially from vendors such as Chron Chemical or Energy-Chemical.
Abbreviations: TLC: Thin Layer Chromatography, EA: Ethyl Acetate, PE: Petroleum Ether, DMF: N, N-dimethylformamide, THF: Eetrahydrofuran, DCM: Dichloromethane, DIPEA: N, N-diisopropylethylamine,
DMAP: 4-dimethylaminopyridine
Example 1.
Compound 1: N- (3-Methoxy-5- (1H-pyrazol-1-yl) phenyl) quinolin-4-amine: To an oven
dried two neck round bottom flask 4-chloroquinoline (104 mg, 0.63 mmol, 1.5 equiv) , 3-methoxy-5- (1H-pyrazol-1-yl) aniline (80 mg, 0.42 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as pale brown solid (100 mg, yield = 74 %) .
TLC Rf = 0.2 (70%EA/PE)
1H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H) , 8.54 (s, 1H) , 8.54 (s, 1H) , 8.38 (d, J = 8.5 Hz, 1H) , 7.91 (d, J = 8.5 Hz, 1H) , 7.76 –7.73 (m, 1H) , 7.71 (d, J = 7.4 Hz, 1H) , 7.56 (t, J = 7.6 Hz, 1H) , 7.48 (brs, 1H) , 7.17 (s, 1H) , 7.15 (d, J = 5.2 Hz, 1H) , 6.86 (s, 1H) , 6.57 –6.52 (m, 1H) , 3.85 (s, 3H) .
Example 2.
Compound 2: N- (3-Methoxy-5- (1H-pyrazol-1-yl) phenyl) -2-methylquinolin-4-amine: To an oven dried two neck round bottom flask, 4-chloro-2-methylquinoline (103 mg, 0.58 mmol, 1.1 equiv) , 3-methoxy-5- (1H-pyrazol-1-yl) aniline (100 mg, 0.53 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as brown solid (35 mg, yield = 20 %) .
TLC Rf = 0.2 (5 %MeOH/DCM)
1H NMR (400 MHz, CDCl3) δ 8.08 –7.98 (m, 1H) , 7.98 –7.92 (m, 2H) , 7.73 (s, 1H) , 7.63 (t, J
= 7.2 Hz, 1H) , 7.45 (t, J = 7.4 Hz, 1H) , 7.27 (s, 1H) , 7.14 (s, 1H) , 6.81 (brs, 2H) , 6.49 (s, 1H) , 3.90 (s, 3H) , 2.58 (s, 3H) .
Example 3.
Compound 3: 6-Fluoro-N- (3-Methoxy-5- (1H-pyrazol-1-yl) phenyl) quinolin-4-amine: To an oven dried two neck round bottom flask, 4-chloro-6-fluoroquinoline (106 mg, 0.58 mmol, 1 equiv) , 3-methoxy-5- (1H-pyrazol-1-yl) aniline (100 mg, 0.53 mmol, 1.1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as pale brown solid (76 mg, yield = 43 %) .
TLC Rf = 0.2 (60 %EA/PE)
1H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H) , 8.69 (d, J = 10.3 Hz, 1H) , 8.62 (d, J = 2.3 Hz, 1H) , 8.59 (d, J = 6.8 Hz, 1H) , 8.18 (dd, J = 8.4, 4.6 Hz, 1H) , 8.05 –7.97 (m, 1H) , 7.78 (d, J = 1.2 Hz, 1H) , 7.61 (s, 1H) , 7.49 (s, 1H) , 7.06 (d, J = 6.8 Hz, 1H) , 7.01 (brs, 1H) , 6.59 (brs, 1H) , 3.89 (s, 3H) .
Example 4.
Compound 4: 6-Chloro-N- (3-Methoxy-5- (1H-pyrazol-1-yl) phenyl) quinolin-4-amine: To an oven dried two neck round bottom flask, 4, 6-dichloroquinoline (151 mg, 0.76 mmol, 1.2 equiv) , 3-methoxy-5- (1H-pyrazol-1-yl) aniline (120 mg, 0.63 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to
100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as brown solid (56 mg, yield = 25 %) .
TLC Rf = 0.2 (60 %EA/PE)
1H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H) , 8.55 (brs, 2H) , 8.52 (d, J = 1.7 Hz, 1H) , 7.92 (d, J = 9.0 Hz, 1H) , 7.75 (s, 1H) , 7.72 (d, J = 1.9 Hz, 1H) , 7.48 (s, 1H) , 7.19 (brs, 1H) , 7.18 (brs, 1H) , 6.86 (s, 1H) , 6.55 (brs, 1H) , 3.85 (s, 3H) .
Example 5.
Compound 5: 6-Bromo-N- (3-Methoxy-5- (1H-pyrazol-1-yl) phenyl) quinolin-4-amine: To an oven dried two neck round bottom flask, 6-bromo-4-chloroquinoline (108 mg, 0.44 mmol, 1.05 equiv) , 3-methoxy-5- (1H-pyrazol-1-yl) aniline (80 mg, 0.42 mmol, 1 equiv) and NMP (2 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (20 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as pale yellow solid (100 mg, yield = 34 %) .
TLC Rf = 0.2 (50 %EA/PE)
1H NMR (400 MHz, DMSO-d6) δ 9.83 (s, 1H) , 8.81 (s, 1H) , 8.57 (brs, 2H) , 7.97 (d, J = 9.0 Hz, 1H) , 7.89 (d, J = 8.9 Hz, 1H) , 7.76 (s, 1H) , 7.52 (s, 1H) , 7.30 (s, 1H) , 7.14 (d, J = 5.7 Hz, 1H) , 6.91 (s, 1H) , 6.56 (s, 1H) , 3.87 (s, 3H) .
Example 6.
Compound 6: 6-Methoxy-N- (3-Methoxy-5- (1H-pyrazol-1-yl) phenyl) quinolin-4-amine: To an oven dried two neck round bottom flask, 4-chloro-6-methoxyquinoline (82 mg, 0.42 mmol, 1.05 equiv) , 3-methoxy-5- (1H-pyrazol-1-yl) aniline (80 mg, 0.42 mmol, 1 equiv) and NMP (2 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (20 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as brown solid (50 mg, yield = 34 %) .
TLC Rf = 0.2 (100 %EA)
1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H) , 8.55 (d, J = 2.5 Hz, 1H) , 8.41 (d, J = 5.2 Hz, 1H) , 7.83 (d, J = 9.1 Hz, 1H) , 7.74 (d, J = 1.4 Hz, 1H) , 7.72 (d, J = 2.6 Hz, 1H) , 7.47 (d, J = 1.6 Hz, 1H) , 7.37 (dd, J = 10.9, 4.4 Hz, 1H) , 7.16 (t, J = 2.0 Hz, 1H) , 7.15 –7.09 (m, 1H) , 6.84 (brs, 1H) , 6.57 –6.52 (m, 1H) , 3.94 (s, 3H) , 3.85 (s, 3H) .
Example 7.
Compound 7: N- (3-Methoxy-5- (1H-pyrazol-1-yl) phenyl) -6- (trifluoromethyl) quinolin-4-amine: To an oven dried two neck round bottom flask, 4-chloro-6- (trifluoromethyl) quinoline (135 mg, 0.58 mmol, 1.1 equiv) , 3-methoxy-5- (1H-pyrazol-1-yl) aniline (100 mg, 0.53 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was
filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as brown solid (120 mg, yield = 59 %) .
TLC Rf = 0.2 (100 %EtOAc)
1H NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1H) , 9.30 (s, 1H) , 8.65 (d, J = 7.0 Hz, 1H) , 8.63 (d, J = 2.4 Hz, 1H) , 8.33 (d, J = 9.0 Hz, 1H) , 8.27 (d, J = 8.9 Hz, 1H) , 7.79 (d, J = 1.4 Hz, 1H) , 7.62 (brs, 1H) , 7.51 (brs, 1H) , 7.10 (d, J = 7.0 Hz, 1H) , 7.03 (brs, 1H) , 6.62 –6.57 (m, 1H) , 3.90 (s, 3H) .
Example 8.
Compound 8: Methyl 4- ( (3-Methoxy-5- (1H-pyrazol-1-yl) phenyl) amino) quinoline-6-carboxylate: To an oven dried two neck round bottom flask, methyl 4-chloroquinoline-6-carboxylate (129 mg, 0.58 mmol, 1.1 equiv) , 3-methoxy-5- (1H-pyrazol-1-yl) aniline (100 mg, 0.53 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as yellow solid (110 mg, yield = 55 %) .
TLC Rf = 0.2 (100 %EA)
1H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H) , 8.63 –8.58 (m, 2H) , 8.46 (d, J = 8.8 Hz, 1H) , 8.11 (d, J = 8.9 Hz, 1H) , 7.79 (d, J = 1.5 Hz, 1H) , 7.61 (d, J = 1.5 Hz, 1H) , 7.49 (s, 1H) , 7.08 (d, J = 6.9 Hz, 1H) , 7.01 (d, J = 1.7 Hz, 1H) , 6.61 –6.57 (m, 1H) , 3.98 (s, 3H) , 3.90 (s, 3H) .
Example 9.
Compound 9: 7-Fluoro-N- (3-Methoxy-5- (1H-pyrazol-1-yl) phenyl) quinolin-4-amine: To an oven dried two neck round bottom flask, 4-chloro-7-fluoroquinoline (139 mg, 0.76 mmol, 1.2 equiv) , 3-methoxy-5- (1H-pyrazol-1-yl) aniline (120 mg, 0.63 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as pale brown solid (56 mg, yield = 25 %) .
TLC Rf = 0.2 (60 %EA/PE)
1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H) , 8.88 (dd, J = 9.1, 5.5 Hz, 1H) , 8.62 (d, J = 2.3 Hz, 1H) , 8.57 (d, J = 7.0 Hz, 1H) , 7.81 –7.86 (m, 2H) , 7.79 (brs, 1H) , 7.61 (s, 1H) , 7.50 (s, 1H) , 7.02 (s, 1H) , 6.99 (d, J = 7.0 Hz, 1H) , 6.61 –6.56 (m, 1H) , 3.89 (s, 3H) .
Example 10.
Compound 10: 7-Chloro-N- (3-Methoxy-5- (1H-pyrazol-1-yl) phenyl) quinolin-4-amine: To an oven dried two neck round bottom flask, 4, 7-dichloroquinoline (115 mg, 0.58 mmol, 1.1 equiv) , 3-methoxy-5- (1H-pyrazol-1-yl) aniline (100 mg, 0.53 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to
afford the desired product as pale brown solid (75 mg, yield = 40 %) .
TLC Rf = 0.2 (60 %EA/PE)
1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H) , 8.77 (d, J = 9.1 Hz, 1H) , 8.62 (d, J = 2.4 Hz, 1H) , 8.58 (d, J = 6.9 Hz, 1H) , 8.11 (d, J = 1.7 Hz, 1H) , 7.92 (dd, J = 9.1, 1.7 Hz, 1H) , 7.78 (s, 1H) , 7.60 (s, 1H) , 7.50 (s, 1H) , 7.04 –6.98 (m, 2H) , 6.61 –6.57 (m, 1H) , 3.89 (s, 3H) .
Example 11.
Compound 11: 7-Bromo-N- (3-Methoxy-5- (1H-pyrazol-1-yl) phenyl) quinolin-4-amine: To an oven dried two neck round bottom flask, 7-bromo-4-chloroquinoline (141 mg, 0.58 mmol, 1.1 equiv) , 3-methoxy-5- (1H-pyrazol-1-yl) aniline (100 mg, 0.53 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as off white solid (165 mg, yield = 79 %) .
TLC Rf = 0.2 (5 %MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H) , 8.76 (t, J = 8.5 Hz, 1H) , 8.62 (d, J = 2.4 Hz, 1H) , 8.56 (d, J = 6.9 Hz, 1H) , 8.33 (d, J = 4.5 Hz, 1H) , 8.02 (d, J = 9.0 Hz, 1H) , 7.78 (d, J = 1.2 Hz, 1H) , 7.60 (s, 1H) , 7.49 (s, 1H) , 7.01 (brs, 2H) , 6.58 (brs, 1H) , 3.89 (s, 3H) .
Example 12.
Compound 12: 7-Methoxy-N- (3-Methoxy-5- (1H-pyrazol-1-yl) phenyl) quinolin-4-amine: To an oven dried two neck round bottom flask, 4, 7-dichloroquinoline (112 mg, 0.58 mmol,
1.1 equiv) , 3-methoxy-5- (1H-pyrazol-1-yl) aniline (100 mg, 0.53 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as brown solid (60 mg, yield = 32 %) .
TLC Rf = 0.2 (60 %EA/PE)
1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H) , 8.72 (d, J = 10.1 Hz, 1H) , 8.62 (d, J = 2.3 Hz, 1H) , 8.45 (d, J = 7.0 Hz, 1H) , 7.78 (d, J = 1.3 Hz, 1H) , 7.59 (s, 1H) , 7.47 (brs, 1H) , 7.46 (brs, 1H) , 7.42 –7.46 (m, 1H) , 7.00 (s, 1H) , 6.89 (d, J = 7.0 Hz, 1H) , 6.60 –6.56 (m, 1H) , 3.98 (s, 3H) , 3.89 (s, 3H) .
Example 13.
Compound 13: N- (3-Methoxy-5- (1H-pyrazol-1-yl) phenyl) -7- (trifluoromethyl) quinolin-4-amine: To an oven dried two neck round bottom flask, 4-chloro-7- (trifluoromethyl) quinoline (135 mg, 0.58 mmol, 1.1 equiv) , 3-methoxy-5- (1H-pyrazol-1-yl) aniline (100 mg, 0.53 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as off white solid (63 mg, yield = 31 %) .
TLC Rf = 0.2 (50 %EA/PE)
1H NMR (400 MHz, DMSO-d6) δ 11.27 (s, 1H) , 9.03 (d, J = 8.8 Hz, 1H) , 8.69 (d, J = 6.9 Hz, 1H) , 8.62 (d, J = 2.3 Hz, 1H) , 8.48 (s, 1H) , 8.17 (d, J = 9.0 Hz, 1H) , 7.78 (brs, 1H) , 7.62 (s, 1H) , 7.50 (s, 1H) , 7.12 (d, J = 6.9 Hz, 1H) , 7.03 (s, 1H) , 6.61 –6.57 (m, 1H) , 3.90 (s, 3H) .
Example 14.
Compound 14: N- (3-Methoxy-5- (1H-pyrazol-1-yl) phenyl) -8- (trifluoromethyl) quinolin-4-amine: To an oven dried two neck round bottom flask, 4-chloro-8- (trifluoromethyl) quinoline (135 mg, 0.58 mmol, 1.1 equiv) , 3-methoxy-5- (1H-pyrazol-1-yl) aniline (100 mg, 0.53 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as off white solid (70 mg, yield = 34 %) .
TLC Rf = 0.2 (60 %EA/PE)
1H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H) , 8.69 (d, J = 8.4 Hz, 1H) , 8.64 (d, J = 5.3 Hz, 1H) , 8.55 (d, J = 2.3 Hz, 1H) , 8.14 (d, J = 7.2 Hz, 1H) , 7.75 (d, J = 1.3 Hz, 1H) , 7.68 (t, J = 7.9 Hz, 1H) , 7.49 (s, 1H) , 7.25 –7.19 (m, 2H) , 6.88 (brs, 1H) , 6.57 –6.52 (m, 1H) , 3.86 (s, 3H) .
Example 15.
Compound 15: 6, 7-Dimethoxy-N- (3-Methoxy-5- (1H-pyrazol-1-yl) phenyl) quinolin-4-amine: To an oven dried two neck round bottom flask, 4-chloro-6, 7-dimethoxyquinoline (131 mg, 0.76 mmol, 1.2 equiv) , 3-methoxy-5- (1H-pyrazol-1-yl) aniline (120 mg, 0.63 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate
(25 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as pale brown solid (50 mg, yield = 21 %) .
TLC Rf = 0.2 (60 %EA/PE)
1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H) , 8.56 (d, J = 2.3 Hz, 1H) , 8.36 (d, J = 5.0 Hz, 1H) , 7.75 (d, J = 1.5 Hz, 1H) , 7.70 (s, 1H) , 7.46 (t, J = 1.7 Hz, 1H) , 7.29 (s, 1H) , 7.18 (t, J = 1.9 Hz, 1H) , 7.03 (d, J = 5.4 Hz, 1H) , 6.83 (t, J = 1.9 Hz, 1H) , 6.57 –6.52 (m, 1H) , 3.95 (s, 3H) , 3.93 (s, 3H) , 3.86 (s, 3H) .
Example 16.
Compound 16: Methyl 7-Methoxy-4- ( (3-Methoxy-5- (1H-pyrazol-1-yl) phenyl) amino) quinoline-6-carboxylate: To an oven dried two neck round bottom flask, methyl 4-chloro-7-methoxyquinoline-6-carboxylate (146 mg, 0.58 mmol, 1.1 equiv) , 3-methoxy-5- (1H-pyrazol-1-yl) aniline (100 mg, 0.53 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as yellow solid (90 mg, yield = 42 %) .
TLC Rf = 0.2 (80 %EA/PE)
1H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H) , 9.09 (s, 1H) , 8.62 (d, J = 2.4 Hz, 1H) , 8.50 (d, J = 7.1 Hz, 1H) , 7.78 (d, J = 1.4 Hz, 1H) , 7.59 (s, 1H) , 7.52 (s, 1H) , 7.48 (s, 1H) , 6.99 (s, 1H) , 6.94 (d, J = 7.1 Hz, 1H) , 6.61 –6.57 (m, 1H) , 4.02 (s, 3H) , 3.91 (s, 3H) , 3.89 (s, 3H) .
Example 17.
Compound 17: 7-Methoxy-4- ( (3-Methoxy-5- (1H-pyrazol-1-yl) phenyl) amino) quinoline-6-carboxamide: To an oven dried two neck round bottom flask, 4-chloro-7-methoxyquinoline-6-carboxamide (137 mg, 0.58 mmol, 1.1 equiv) , 3-methoxy-5- (1H-pyrazol-1-yl) aniline (100 mg, 0.52 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as yellow solid (95 mg, yield = 46 %) .
TLC Rf = 0.2 (10 %MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H) , 8.84 (s, 1H) , 8.54 (d, J = 2.0 Hz, 1H) , 8.49 (d, J = 5.0 Hz, 1H) , 7.81 (s, 1H) , 7.74 (s, 1H) , 7.71 (s, 1H) , 7.49 (s, 1H) , 7.38 (s, 1H) , 7.18 (s, 1H) , 7.05 (d, J = 5.3 Hz, 1H) , 6.87 (s, 1H) , 6.55 (s, 1H) , 4.01 (s, 3H) , 3.85 (s, 3H) .
Example 18.
Compound 18: N- (3-Methoxy-5- (1H-pyrazol-1-yl) phenyl) -1H-pyrrolo [3, 2-b] pyridin-7-amine: To an oven dried two neck round bottom flask, 7-chloro-3a, 7a-dihydro-1H-pyrrolo [3, 2-b] pyridine (147 mg, 0.95 mmol, 1.2 equiv) , 3-methoxy-5- (1H-pyrazol-1-yl) aniline (150 mg, 0.79 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered
and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as brown solid (45 mg, yield = 14 %) .
TLC Rf = 0.2 (5 %MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) δ 12.25 (s, 1H) , 10.46 (s, 1H) , 8.60 (d, J = 2.2 Hz, 1H) , 8.22 (d, J = 6.8 Hz, 1H) , 7.92 (d, J = 2.2 Hz, 1H) , 7.77 (d, J = 1.2 Hz, 1H) , 7.52 (s, 1H) , 7.36 (s, 1H) , 7.05 (d, J = 6.8 Hz, 1H) , 6.91 (s, 1H) , 6.65 (d, J = 1.2 Hz, 1H) , 6.59 –6.55 (m, 1H) , 3.88 (s, 3H) .
Example 19.
Compound 19: N- (3- (1H-Imidazol-1-yl) -5-Methoxyphenyl) quinolin-4-amine: To an oven dried two neck round bottom flask, 4-chloroquinoline (95 mg, 0.58 mmol, 1.1 equiv) , 3-methoxy-5- (1H-pyrazol-1-yl) aniline (100 mg, 0.52 mmol, 1 equiv) and NMP (2 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (20 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as brown thick liquid (70 mg, yield = 42 %) .
TLC Rf = 0.2 (10 %MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H) , 8.54 (d, J = 4.7 Hz, 1H) , 8.46 (d, J = 8.3 Hz, 1H) , 8.33 (s, 1H) , 7.94 (d, J = 8.3 Hz, 1H) , 7.85 –7.79 (m, 2H) , 7.64 (t, J = 7.6 Hz, 1H) , 7.27 (s, 1H) , 7.14 (s, 1H) , 7.12 (s, 1H) , 7.08 (s, 1H) , 6.95 (s, 1H) , 3.86 (s, 3H) .
Example 20.
Compound 20 : N- (3- (1H-Imidazol-1-yl) -5-Methoxyphenyl) -2-methylquinolin-4-amine: To an oven dried two neck round bottom flask, 4-chloro-2-methylquinoline (169 mg, 0.95 mmol, 1.2 equiv) , 3- (1H-imidazol-1-yl) -5-methoxyaniline (150 mg, 0.79 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as brown solid (35 mg, yield = 13 %) .
TLC Rf = 0.2 (3 %MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J = 8.4 Hz, 1H) , 8.33 (s, 1H) , 7.86 (t, J = 8.1 Hz, 2H) , 7.81 (s, 1H) , 7.68 –7.58 (m, 1H) , 7.28 (s, 1H) , 7.13 –7.15 (m, 1H) , 7.12 (s, 1H) , 6.97 (s, 1H) , 6.95 (s, 1H) , 3.87 (s, 3H) , 2.56 (s, 3H) .
Example 21.
Compound 21 : N- (3- (1H-Imidazol-1-yl) -5-Methoxyphenyl) -6-fluoroquinolin-4-amine: To an oven dried two neck round bottom flask, 4-chloro-6-fluoroquinoline (158 mg, 0.87 mmol, 1.1 equiv) , 3- (1H-imidazol-1-yl) -5-methoxyaniline (150 mg, 0.79 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 105 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as pale brown solid (45 mg, yield = 16 %) .
TLC Rf = 0.2 (5%MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) δ 9.23 (s, 1H) , 8.53 (d, J = 4.8 Hz, 1H) , 8.45 (dd, J = 9.4, 6.2 Hz, 1H) , 8.30 (s, 1H) , 7.78 (s, 1H) , 7.61 (dd, J = 10.5, 2.1 Hz, 1H) , 7.51 (td, J = 9.0, 2.0 Hz, 1H) , 7.21
(brs, 1H) , 7.12 (d, J = 5.0 Hz, 1H) , 7.10 (s, 1H) , 7.01 (brs, 1H) , 6.90 (brs, 1H) , 3.85 (s, 3H) .
Example 22.
Compound 22: N- (3- (1H-Imidazol-1-yl) -5-Methoxyphenyl) -6-chloroquinolin-4-amine: To an oven dried two neck round bottom flask, 4, 6-dichloroquinoline (172 mg, 0.87 mmol, 1.1 equiv) , 3- (1H-imidazol-1-yl) -5-methoxyaniline (150 mg, 0.79 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 105 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as pale yellow solid (45 mg, yield = 16 %) .
TLC Rf = 0.2 (5%MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1H) , 8.55 (d, J = 5.2 Hz, 1H) , 8.51 (d, J = 2.0 Hz, 1H) , 8.30 (s, 1H) , 7.93 (d, J = 9.0 Hz, 1H) , 7.78 (s, 1H) , 7.74 (dd, J = 9.0, 2.1 Hz, 1H) , 7.22 (brs, 1H) , 7.21 (brs, 1H) , 7.10 (s, 1H) , 7.00 (brs, 1H) , 6.90 (brs, 1H) , 3.86 (s, 3H) .
Example 23.
Compound 23: N- (3- (1H-Imidazol-1-yl) -5-Methoxyphenyl) -6-bromoquinolin-4-amine: To an oven dried two neck round bottom flask, 6-bromo-4-chloroquinoline (102 mg, 0.42 mmol, 1. equiv) , 3- (1H-imidazol-1-yl) -5-methoxyaniline (80 mg, 0.42 mmol, 1 equiv) and NMP (2 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate
(20 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as pale brown solid (55 mg, yield = 34 %) .
TLC Rf = 0.2 (100 %EA)
1H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 1H) , 8.66 (s, 1H) , 8.55 (d, J = 5.1 Hz, 1H) , 8.30 (s, 1H) , 7.84 (brs, 2H) , 7.78 (s, 1H) , 7.23 –7.16 (m, 2H) , 7.10 (s, 1H) , 7.00 (brs, 1H) , 6.90 (s, 1H) , 3.86 (s, 3H) .
Example 24.
Compound 24 : N- (3- (1H-Imidazol-1-yl) -5-Methoxyphenyl) -6-methoxyquinolin-4-amine: To an oven dried two neck round bottom flask, 4-chloro-6-methoxyquinoline (168.5 mg, 0.87 mmol, 1.1 equiv) , 3- (1H-imidazol-1-yl) -5-methoxyaniline (150 mg, 0.79 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 105 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as pale yellow solid (50 mg, yield = 18 %) .
TLC Rf = 0.2 (5 %MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H) , 8.41 (d, J = 5.2 Hz, 1H) , 8.30 (s, 1H) , 7.83 (d, J = 9.2 Hz, 1H) , 7.78 (s, 1H) , 7.72 (d, J = 2.5 Hz, 1H) , 7.38 (dd, J = 9.2, 2.6 Hz, 1H) , 7.19 (brs, 1H) , 7.14 (d, J = 5.2 Hz, 1H) , 7.10 (s, 1H) , 6.99 (t, J = 1.8 Hz, 1H) , 6.89 (brs, 1H) , 3.94 (s, 3H) , 3.86 (s, 3H) .
Example 25.
Compound 25: N- (3- (1H-Imidazol-1-yl) -5-Methoxyphenyl) -6- (trifluoromethyl) quinolin-4-amine: To an oven dried two neck round bottom flask, 4-chloro-6- (trifluoromethyl) quinoline (135 mg, 0.58 mmol, 1.1 equiv) ., 3-methoxy-5- (1H-imidazol-1-yl) benzenamine (100 mg, 0.53 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 105 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as brown solid (18 mg, yield = 9 %) .
TLC Rf = 0.2 (5%MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H) , 8.88 (s, 1H) , 8.64 (d, J = 5.3 Hz, 1H) , 8.31 (s, 1H) , 8.08 (d, J = 8.7 Hz, 1H) , 7.96 (d, J = 9.9 Hz, 1H) , 7.80 (s, 1H) , 7.24 (brs, 1H) , 7.23 (brs, 1H) , 7.11 (s, 1H) , 7.05 (brs, 1H) , 6.93 (brs, 1H) , 3.87 (s, 3H) .
Example 26.
Compound 26: N- (3- (1H-Imidazol-1-yl) -5-Methoxyphenyl) -6- (trifluoromethoxy) quinolin-4-amine: To an oven dried two neck round bottom flask, 4-chloro-2-methylquinoline (131 mg, 0.52 mmol, 1 equiv) , 3- (1H-imidazol-1-yl) -5-methoxyaniline (100 mg, 0.52 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered
and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as pale brown solid (55 mg, yield = 26 %) .
TLC Rf = 0.2 (5 %MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H) , 8.58 (d, J = 5.2 Hz, 1H) , 8.41 (s, 1H) , 8.30 (s, 1H) , 8.03 (d, J = 9.2 Hz, 1H) , 7.79 (s, 1H) , 7.72 (dd, J = 9.1, 0.5 Hz, 1H) , 7.22 (brs, 1H) , 7.21 (d, J = 5.6 Hz, 1H) , 7.10 (s, 1H) , 7.02 (s, 1H) , 6.90 (s, 1H) , 3.86 (s, 3H) .
Example 27.
Compound 27: Methyl 4- ( (3- (1H-Imidazol-1-yl) -5-Methoxyphenyl) amino) quinoline-6-carboxylate: To an oven dried two neck round bottom flask, methyl 4-chloroquinoline-6-carboxylate (193 mg, 0.87 mmol, 1.1 equiv) , 3- (1H-imidazol-1-yl) -5-methoxyaniline (150 mg, 0.79 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as pale yellow solid (90 mg, yield = 34%) .
TLC Rf = 0.2 (7 %MeOH/DCM )
1H NMR (400 MHz, DMSO-d6) δ 9.60 (brs, 1H) , 9.14 (s, 1H) , 8.60 (brs, 1H) , 8.31 (s, 1H) , 8.19 (d, J = 8.7 Hz, 1H) , 7.97 (d, J = 8.2 Hz, 1H) , 7.79 (s, 1H) , 7.25 (s, 1H) , 7.20 (brs, 1H) , 7.11 (s, 1H) , 7.03 (s, 1H) , 6.94 (s, 1H) , 3.95 (s, 3H) , 3.86 (s, 3H)
Example 28.
Compound 28: N- (3- (1H-Imidazol-1-yl) -5-Methoxyphenyl) -6- (methylsulfonyl) quinolin-4-amine: To an oven dried two neck round bottom flask, 4-chloro-6- (methylsulfonyl) quinoline (140 mg, 0.58 mmol, 1.1 equiv) , 3- (1H-imidazol-1-yl) -5-methoxyaniline (100 mg, 0.52 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as yellow solid (30 mg, yield = 14%) .
TLC Rf = 0.2 (5 %MeOH/DCM )
1H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H) , 9.06 (s, 1H) , 8.65 (brs, 1H) , 8.31 (s, 1H) , 8.14 (d, J = 8.5 Hz, 1H) , 8.09 (d, J = 8.0 Hz, 1H) , 7.79 (s, 1H) , 7.24 (brs, 2H) , 7.10 (s, 1H) , 7.04 (s, 1H) , 6.93 (s, 1H) , 3.86 (s, 3H) , 3.33 (s, 3H) .
Example 29.
Compound 29 : N- (3- (1H-Imidazol-1-yl) -5-Methoxyphenyl) -7-fluoroquinolin-4-amine: To an oven dried two neck round bottom flask, 4-chloro-7-fluoroquinoline (158 mg, 0.87 mmol, 1.1 equiv) , 3-methoxy-5- (1H-imidazol-1-yl) benzenamine (150 mg, 0.79 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 105 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2
× 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as pale yellow solid (60 mg, yield = 22 %) .
TLC Rf = 0.2 (5 %MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) δ 9.23 (s, 1H) , 8.53 (d, J = 4.8 Hz, 1H) , 8.45 (dd, J = 9.3, 6.2 Hz, 1H) , 8.30 (s, 1H) , 7.78 (s, 1H) , 7.61 (dd, J = 10.6, 2.4 Hz, 1H) , 7.51 (td, J = 9.1, 2.5 Hz, 1H) , 7.21 (brs, 1H) , 7.12 (d, J = 4.9 Hz, 1H) , 7.10 (s, 1H) , 7.01 (t, J = 1.8 Hz, 1H) , 6.90 (brs, 1H) , 3.85 (s, 3H) .
Example 30.
Compound 30: N- (3- (1H-Imidazol-1-yl) -5-Methoxyphenyl) -7-chloroquinolin-4-amine: To an oven dried two neck round bottom flask, 4, 7-dichloroquinoline (172 mg, 0.87 mmol, 1.1 equiv) , 3-methoxy-5- (1H-imidazol-1-yl) benzenamine (150 mg, 0.79 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 105 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as brown solid (40 mg, yield = 14 %) .
TLC Rf = 0.2 (1%MeOH/EtOAc)
1H NMR (400 MHz, DMSO-d6) δ 9.23 (s, 1H) , 8.54 (d, J = 5.3 Hz, 1H) , 8.41 (d, J = 9.1 Hz, 1H) , 8.30 (s, 1H) , 7.93 (d, J = 2.0 Hz, 1H) , 7.78 (s, 1H) , 7.62 (dd, J = 9.0, 2.0 Hz, 1H) , 7.22 (brs, 1H) , 7.16 (d, J = 5.3 Hz, 1H) , 7.10 (s, 1H) , 7.01 (brs, 1H) , 6.90 (brs, 1H) , 3.85 (s, 3H) .
Example 31.
Compound 31 : N- (3- (1H-Imidazol-1-yl) -5-Methoxyphenyl) -7-bromoquinolin-4-amine: To an oven dried two neck round bottom flask, 7-bromo-4-chloroquinoline (211 mg, 0.87 mmol, 1.1 equiv) , 3-methoxy-5- (1H-imidazol-1-yl) benzenamine (150 mg, 0.79 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 105 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as pale yellow solid (70 mg, yield = 22 %) .
TLC Rf = 0.2 (1%MeOH/EtOAc)
1H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H) , 8.53 (d, J = 5.0 Hz, 1H) , 8.34 (d, J = 9.0 Hz, 1H) , 8.30 (s, 1H) , 8.09 (d, J = 1.4 Hz, 1H) , 7.78 (s, 1H) , 7.73 (dd, J = 9.1, 1.8 Hz, 1H) , 7.22 (s, 1H) , 7.17 (d, J = 5.2 Hz, 1H) , 7.10 (s, 1H) , 7.01 (s, 1H) , 6.90 (s, 1H) , 3.85 (s, 3H) .
Example 32.
Compound 32 : N- (3- (1H-Imidazol-1-yl) -5-Methoxyphenyl) -7-methoxyquinolin-4-amine: To an oven dried two neck round bottom flask, 4-chloro-7-methoxyquinoline (122 mg, 0.63 mmol, 1.2 equiv) , 3-methoxy-5- (1H-imidazol-1-yl) benzenamine (100 mg, 0.53 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 105 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash
column chromatography to afford the desired product as brown solid (10 mg, yield = 6 %) .
TLC Rf = 0.2 (100 %EtOAc)
1H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H) , 8.45 (d, J = 5.4 Hz, 1H) , 8.32 –8.26 (m, 2H) , 7.77 (s, 1H) , 7.29 (d, J = 2.4 Hz, 1H) , 7.23 (dd, J = 9.2, 2.5 Hz, 1H) , 7.20 (brs, 1H) , 7.10 (s, 1H) , 7.03 (d, J = 5.4 Hz, 1H) , 7.00 (brs, 1H) , 6.89 (brs, 1H) , 3.92 (s, 3H) , 3.85 (s, 3H) .
Example 33.
Compound 33 : N- (3- (1H-Imidazol-1-yl) -5-Methoxyphenyl) -7- (trifluoromethyl) quinolin-4-amine) : To an oven dried two neck round bottom flask, 4-chloro-7- (trifluoromethyl) quinoline (135 mg, 0.58 mmol, 1.1 equiv) , 3-methoxy-5- (1H-imidazol-1-yl) benzenamine (100 mg, 0.53 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 105 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as brown solid (15 mg, yield = 7 %) .
TLC Rf = 0.2 (5%MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H) , 8.65 (d, J = 5.2 Hz, 1H) , 8.62 (d, J = 9.0 Hz, 1H) , 8.30 (s, 1H) , 8.22 (s, 1H) , 7.86 (dd, J = 8.9, 1.3 Hz, 1H) , 7.79 (s, 1H) , 7.28 (d, J = 5.3 Hz, 1H) , 7.25 (brs, 1H) , 7.10 (s, 1H) , 7.03 (t, J = 1.9 Hz, 1H) , 6.93 (brs, 1H) , 3.86 (s, 3H) .
Example 34.
Compound 34: N- (3- (1H-Imidazol-1-yl) -5-Methoxyphenyl) -8-methoxyquinolin-4-
amine: To an oven dried two neck round bottom flask, methyl 4-chloro-8-methoxyquinoline (169 mg, 0.87 mmol, 1.1 equiv) , 3-methoxy-5- (1H-imidazol-1-yl) benzenamine (150 mg, 0.79 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 105 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as pale yellow solid (60 mg, yield = 22 %) .
TLC Rf = 0.2 (5 %MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H) , 8.38 (d, J = 6.9 Hz, 1H) , 8.27 (d, J = 8.6 Hz, 1H) , 7.86 (s, 1H) , 7.76 (t, J = 8.3 Hz, 1H) , 7.60 (d, J = 8.0 Hz, 1H) , 7.43 (s, 1H) , 7.32 (s, 1H) , 7.14 (s, 1H) , 7.06 (brs, 2H) , 7.04 (brs, 1H) , 4.11 (s, 3H) , 3.89 (s, 3H) .
Example 35.
Compound 35: N- (3- (1H-Imidazol-1-yl) -5-Methoxyphenyl) -8- (trifluoromethyl) quinolin-4-amine: To an oven dried two neck round bottom flask, 4-chloro-8- (trifluoromethyl) quinoline (220 mg, 0.95 mmol, 1.2 equiv) , 3- (1H-imidazol-1-yl) -5-methoxyaniline (150 mg, 0.79 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as off white solid (65 mg, yield = 21 %) .
TLC Rf = 0.2 (3 %MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H) , 8.67 (d, J = 8.5 Hz, 1H) , 8.64 (d, J = 5.3 Hz, 1H) , 8.30 (s, 1H) , 8.14 (d, J = 7.2 Hz, 1H) , 7.78 (s, 1H) , 7.69 (t, J = 7.9 Hz, 1H) , 7.26 (d, J = 5.3 Hz,
1H) , 7.24 (brs, 1H) , 7.10 (s, 1H) , 7.03 (t, J = 1.8 Hz, 1H) , 6.92 (brs, 1H) , 3.86 (s, 3H) .
Example 36.
Compound 36: N- (3- (1H-Imidazol-1-yl) -5-Methoxyphenyl) -6, 7-dimethoxyquinolin-4-amine: To an oven dried two neck round bottom flask, 4-chloro-6, 7-dimethoxyquinoline (195 mg, 0.87 mmol, 1.1 equiv) , 3- (1H-imidazol-1-yl) -5-methoxyaniline (150 mg, 0.79 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as brown solid (45 mg, yield = 15 %) .
TLC Rf = 0.2 (100 %EA)
1H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H) , 8.36 (d, J = 5.7 Hz, 1H) , 8.31 (s, 1H) , 7.80 (s, 1H) , 7.75 (s, 1H) , 7.30 (s, 1H) , 7.22 (s, 1H) , 7.10 (s, 1H) , 7.05 (brs, 1H) , 7.03 (d, J = 5.7 Hz, 1H) , 6.90 (brs, 1H) , 3.96 (s, 3H) , 3.93 (s, 3H) , 3.86 (s, 3H) .
Example 37.
Compound 37: Methyl 4- ( (3- (1H-Imidazol-1-yl) -5-Methoxyphenyl) amino) -7-methoxyquinoline-6-carboxylate: To an oven dried two neck round bottom flask, methyl 4-chloro-7-methoxyquinoline-6-carboxylate (219 mg, 0.87 mmol, 1.1 equiv) , 3-methoxy-5- (1H-imidazol-1-yl) benzenamine (150 mg, 0.79 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 105 ℃ and stirred at same
temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as pale yellow solid (58 mg, yield = 18 %) .
TLC Rf = 0.2 (7 %MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H) , 8.74 (s, 1H) , 8.49 (d, J = 4.7 Hz, 1H) , 8.29 (s, 1H) , 7.78 (s, 1H) , 7.38 (s, 1H) , 7.20 (s, 1H) , 7.10 (s, 1H) , 7.07 –7.03 (m, 1H) , 7.01 (brs, 1H) , 6.90 (brs, 1H) , 3.95 (s, 3H) , 3.88 (s, 3H) , 3.85 (s, 3H) .
Example 38.
Compound 38: 4- ( (3- (1H-Imidazol-1-yl) -5-Methoxyphenyl) amino) -7-methoxyquinoline-6-carboxamide : To an oven dried two neck round bottom flask, methyl 4-chloro-7-methoxyquinoline-6-carboxamide (206 mg, 0.87 mmol, 1.1 equiv) , 3-methoxy-5- (1H-imidazol -1-yl) benzenamine (150 mg, 0.79 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 105 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as pale yellow solid (55 mg, yield = 18 %) .
TLC Rf = 0.2 (10 %MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H) , 8.83 (s, 1H) , 8.48 (d, J = 5.3 Hz, 1H) , 8.28 (s, 1H) , 7.81 (s, 1H) , 7.76 (s, 1H) , 7.71 (s, 1H) , 7.38 (s, 1H) , 7.20 (brs, 1H) , 7.10 (s, 1H) , 7.07 (d, J =5.3 Hz, 1H) , 6.98 (t, J = 1.8 Hz, 1H) , 6.92 (brs, 1H) , 4.00 (s, 3H) , 3.85 (s, 3H) .
Example 39.
Compound 39: N- (3-Methoxy-5- (4-Methyl-1H-imidazol-1-yl) phenyl) quinolin-4-amine: To an oven dried two neck round bottom flask, 4-chloroquinoline (89 mg, 0.54 mmol, 1.1 equiv) , 3-methoxy-5- (4-methyl-1H-imidazol-1-yl) ) aniline (100 mg, 0.49 mmol, 1 equiv) and NMP (2 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (20 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as brown thick liquid (50 mg, yield = 31 %) .
TLC Rf = 0.2 (100 %EA)
1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H) , 8.53 (d, J = 5.1 Hz, 1H) , 8.36 (d, J = 8.2 Hz, 1H) , 8.15 (brs, 1H) , 7.90 (d, J = 8.3 Hz, 1H) , 7.72 (t, J = 7.5 Hz, 1H) , 7.56 (t, J = 7.7 Hz, 1H) , 7.45 (s, 1H) , 7.19 –7.11 (m, 2H) , 6.92 (s, 1H) , 6.87 (s, 1H) , 3.84 (s, 3H) , 2.15 (s, 3H) .
Example 40.
Compound 40: N- (3-Methoxy-5- (4-Methyl-1H-imidazol-1-yl) phenyl) -2-methylquinolin-4-amine: To an oven dried two neck round bottom flask, 4-chloro-2-methylquinoline (114 mg, 0.64 mmol, 1.3 equiv) , 3-methoxy-5- (4-methyl-1H-imidazol-1-yl) aniline (100 mg, 0.49 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 105 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude
compound was purified by flash column chromatography to afford the desired product as pale yellow solid (56 mg, yield = 33 %) .
TLC Rf = 0.2 (5 %MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J = 8.1 Hz, 1H) , 8.18 (s, 1H) , 7.86 (d, J = 8.3 Hz, 1H) , 7.77 (dd, J = 11.5, 3.7 Hz, 1H) , 7.58 (dd, J = 11.1, 4.0 Hz, 1H) , 7.48 (s, 1H) , 7.20 (s, 1H) , 7.03 (s, 1H) , 6.97 (s, 1H) , 6.90 (s, 1H) , 3.85 (s, 3H) , 2.54 (s, 3H) , 2.16 (s, 3H) .
Example 41.
Compound 41 : 6-Fluoro-N- (3-Methoxy-5- (4-Methyl-1H-imidazol-1-yl) phenyl) quinolin-4-amine: To an oven dried two neck round bottom flask, 4-chloro-6-fluoroquinoline (134 mg, 0.74 mmol, 1.5 equiv) , 3-methoxy-5- (4-methyl-1H-imidazol-1-yl) aniline (100 mg, 0.49 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 105 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as pale yellow solid (36 mg, yield = 20 %) .
TLC Rf = 0.2 (3 %MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H) , 8.53 (d, J = 5.1 Hz, 1H) , 8.22 –8.11 (m, 2H) , 7.97 (dd, J = 9.0, 5.8 Hz, 1H) , 7.64 (td, J = 9.0, 2.5 Hz, 1H) , 7.46 (s, 1H) , 7.19 (d, J = 5.0 Hz, 1H) , 7.15 (brs, 1H) , 6.93 (d, J = 1.6 Hz, 1H) , 6.86 (brs, 1H) , 3.84 (s, 3H) , 2.15 (s, 3H) .
Example 42.
Compound 42: 6-Chloro-N- (3-Methoxy-5- (4-Methyl-1H-imidazol-1-yl) phenyl) quinolin-4-amine: To an oven dried two neck round bottom flask, 4, 6-dichloroquinoline (107 mg, 0.54 mmol, 1.1 equiv) , 3-methoxy-5- (4-methyl-1H-imidazol-1-yl) aniline (100 mg, 0.49 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as brown solid (80 mg, yield = 44 %) .
TLC Rf = 0.2 (5 %MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) 9.17 –9.08 (m, 1H) , 8.98 (d, J = 8.3 Hz, 1H) , 8.59 (d, J = 6.8 Hz, 1H) , 8.15 –8.12 (m, 1H) , 8.08 (dd, J = 9.0, 1.7 Hz, 1H) , 7.87 (brs, 1H) , 7.47 (s, 1H) , 7.36 (s, 1H) , 7.17 –7.10 (m, 2H) , 3.90 (s, 3H) , 2.28 (s, 3H) .
Example 43.
Compound 43: 6-Bromo-N- (3-Methoxy-5- (4-Methyl-1H-imidazol-1-yl) phenyl) quinolin-4-amine: To an oven dried two neck round bottom flask, 6-bromo-4-chloroquinoline (95 mg, 0.42 mmol, 1. equiv) , 3-methoxy-5- (4-methyl-1H-imidazol-1-yl) aniline (80 mg, 0.42 mmol, 1 equiv) and NMP (2 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (20 mL) was added to obtain the solid. The residue was
filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as brown solid (50 mg, yield = 31 %) .
TLC Rf = 0.2 (100 %EA)
1H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H) , 8.65 (s, 1H) , 8.55 (d, J = 5.3 Hz, 1H) , 8.16 (d, J = 0.9 Hz, 1H) , 7.84 (s, 2H) , 7.46 (s, 1H) , 7.20 (d, J = 5.3 Hz, 1H) , 7.15 (brs, 1H) , 6.94 (t, J = 1.9 Hz, 1H) , 6.86 (t, J = 1.8 Hz, 1H) , 3.84 (s, 3H) , 2.15 (s, 3H) .
Example 44.
Compound 44: 6-Methoxy-N- (3-Methoxy-5- (4-Methyl-1H-imidazol-1-yl) phenyl) quinolin-4-amine: To an oven dried two neck round bottom flask, 4-chloro-6-methoxyquinoline (157 mg, 0.81 mmol, 1.1 equiv) , 3-methoxy-5- (4-methyl-1H-imidazol-1-yl) aniline (150 mg, 0.73 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as off white solid (75 mg, yield = 29 %) .
TLC Rf = 0.2 (3 %MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H) , 8.42 (d, J = 5.5 Hz, 1H) , 8.19 (s, 1H) , 7.86 (d, J = 9.2 Hz, 1H) , 7.79 (d, J = 2.2 Hz, 1H) , 7.49 (s, 1H) , 7.44 (dd, J = 9.2, 2.4 Hz, 1H) , 7.18 (s, 1H) , 7.11 (d, J = 5.5 Hz, 1H) , 6.99 (s, 1H) , 6.88 (s, 1H) , 3.95 (s, 3H) , 3.85 (s, 3H) , 2.15 (s, 3H) .
Example 45.
Compound 45: N- (3-Methoxy-5- (4-Methyl-1H-imidazol-1-yl) phenyl) -6- (trifluoromethyl) quinolin-4-amine: To an oven dried two neck round bottom flask, 4-chloro-6- (trifluoromethyl) quinoline (148 mg, 0.64 mmol, 1.3 equiv) , 3-methoxy-5- (4-methyl-1H-imidazol-1-yl) aniline (100 mg, 0.49 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 105 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as pale yellow solid (25 mg, yield = 13 %) .
TLC Rf = 0.2 (5 %MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H) , 8.90 (s, 1H) , 8.63 (s, 1H) , 8.23 (s, 1H) , 8.08 (d, J = 9.3 Hz, 1H) , 7.99 (d, J = 8.7 Hz, 1H) , 7.51 (s, 1H) , 7.20 (brs, 2H) , 7.01 (s, 1H) , 6.90 (s, 1H) , 3.86 (s, 3H) , 2.16 (s, 3H) .
Example 46.
Compound 46: Methyl 4- ( (3-Methoxy-5- (4-Methyl-1H-imidazol-1-yl) phenyl) amino) quinoline-6-carboxylate: To an oven dried two neck round bottom flask, methyl 4-chloroquinoline-6-carboxylate (120 mg, 0.54 mmol, 1.1 equiv) , 3-methoxy-5- (4-methyl-1H-imidazol-1-yl) aniline (100 mg, 0.49 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the
solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as yellow solid (60 mg, yield = 31 %) .
TLC Rf = 0.2 (10 %MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H) , 8.90 –8.74 (m, 1H) , 8.61 (d, J = 6.7 Hz, 1H) , 8.49 –8.40 (m, 1H) , 8.16 (d, J = 8.8 Hz, 1H) , 7.81 –7.70 (m, 1H) , 7.43 (brs, 1H) , 7.32 (brs 1H) , 7.13 –7.07 (m, 2H) , 3.98 (s, 3H) , 3.90 (s, 3H) , 2.24 (s, 3H)
Example 47.
Compound 47: 7-Fluoro-N- (3-Methoxy-5- (4-Methyl-1H-imidazol-1-yl) phenyl) quinolin-4-amine: To an oven dried two neck round bottom flask, 4-chloro-7-fluoroquinoline (147 mg, 0.81 mmol, 1.1 equiv) , 3-methoxy-5- (4-methyl-1H-imidazol-1-yl) aniline (150 mg, 0.73 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as off white solid (40 mg, yield = 15 %) .
TLC Rf = 0.2 (5 %MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H) , 8.53 (d, J = 5.3 Hz, 1H) , 8.47 (dd, J = 9.2, 6.2 Hz, 1H) , 8.18 (s, 1H) , 7.62 (dd, J = 10.5, 2.5 Hz, 1H) , 7.53 (td, J = 9.2, 2.6 Hz, 1H) , 7.47 (s, 1H) , 7.17 (s, 1H) , 7.10 (d, J = 5.5 Hz, 1H) , 6.97 (s, 1H) , 6.87 (s, 1H) , 3.84 (s, 3H) , 2.15 (s, 3H) .
Example 48.
Compound 48 : 7-Chloro-N- (3-Methoxy-5- (4-Methyl-1H-imidazol-1-yl) phenyl) quinolin-4-amine: To an oven dried two neck round bottom flask, 4, 7-dichloroquinoline (126 mg, 0.64 mmol, 1.3 equiv) , 3-methoxy-5- (4-methyl-1H-imidazol-1-yl) aniline (100 mg, 0.49 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 105 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as pale yellow solid (60 mg, yield = 33 %) .
TLC Rf = 0.2 (5 %MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) δ 9.27 (s, 1H) , 8.54 (d, J = 5.0 Hz, 1H) , 8.42 (d, J = 9.1 Hz, 1H) , 8.18 (s, 1H) , 7.93 (d, J = 1.8 Hz, 1H) , 7.62 (dd, J = 9.0, 2.0 Hz, 1H) , 7.47 (s, 1H) , 7.17 (brs, 1H) , 7.14 (d, J = 5.1 Hz, 1H) , 6.96 (brs, 1H) , 6.87 (s, 1H) , 3.84 (s, 3H) , 2.15 (s, 3H) .
Example 49.
Compound 49 : 7-Bromo-N- (3-Methoxy-5- (4-Methyl-1H-imidazol-1-yl) phenyl) quinolin-4-amine: To an oven dried two neck round bottom flask, methyl 7-bromo-4-chloroquinoline (131 mg, 0.54 mmol, 1.1 equiv) , 3-methoxy-5- (4-methyl-1H-imidazol-1-yl) aniline (100 mg, 0.49 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 105 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue
was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as pale yellow solid (97 mg, yield = 48 %) .
TLC Rf = 0.2 (5 %MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H) , 9.03 (s, 1H) , 8.73 (d, J = 9.1 Hz, 1H) , 8.57 (d, J = 6.8 Hz, 1H) , 8.31 (d, J = 1.7 Hz, 1H) , 8.01 (dd, J = 9.0, 1.7 Hz, 1H) , 7.83 (s, 1H) , 7.45 (brs, 1H) , 7.34 (brs, 1H) , 7.13 (brs, 1H) , 7.08 (d, J = 6.8 Hz, 1H) , 3.89 (s, 3H) , 2.27 (s, 3H) .
Example 50.
Compound 50: 7-Methoxy-N- (3-Methoxy-5- (4-Methyl-1H-imidazol-1-yl) phenyl) quinolin-4-amine: To an oven dried two neck round bottom flask, methyl 4-chloro-7-methoxyquinoline (105 mg, 0.54 mmol, 1.1 equiv) , 3-methoxy-5- (4-methyl-1H-imidazol-1-yl) aniline (100 mg, 0.49 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 110 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as pale yellow solid (73 mg, yield = 41 %) .
TLC Rf = 0.2 (7 %MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H) , 8.45 (d, J = 5.6 Hz, 1H) , 8.31 (d, J = 9.2 Hz, 1H) , 8.16 (s, 1H) , 7.46 (s, 1H) , 7.29 (d, J = 2.4 Hz, 1H) , 7.24 (dd, J = 9.2, 2.5 Hz, 1H) , 7.16 (s, 1H) , 7.01 (d, J = 5.6 Hz, 1H) , 6.96 (t, J = 1.8 Hz, 1H) , 6.87 (t, J = 1.7 Hz, 1H) , 3.92 (s, 3H) , 3.84 (s, 3H) , 2.15 (s, 3H) .
Example 51.
Compound 51 : N- (3-Methoxy-5- (4-Methyl-1H-imidazol-1-yl) phenyl) -7- (trifluoromethyl) quinolin-4-amine: To an oven dried two neck round bottom flask, 4-chloro-7- (trifluoromethyl) quinoline (148 mg, 0.64 mmol, 1.3 equiv) , 3-methoxy-5- (4-methyl-1H-imidazol-1-yl) aniline (100 mg, 0.49 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 105 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as pale yellow solid (40 mg, yield = 20.4 %) .
TLC Rf = 0.2 (3 %MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H) , 8.65 (d, J = 5.1 Hz, 1H) , 8.61 (d, J = 8.8 Hz, 1H) , 8.22 (s, 1H) , 8.18 (s, 1H) , 7.85 (d, J = 8.7 Hz, 1H) , 7.48 (s, 1H) , 7.26 (d, J = 5.2 Hz, 1H) , 7.19 (s, 1H) , 6.98 (brs, 1H) , 6.89 (brs, 1H) , 3.85 (s, 3H) , 2.15 (s, 3H) .
Example 52.
Compound 52: 6, 7-Dimethoxy-N- (3-Methoxy-5- (4-Methyl-1H-imidazol-1-yl) phenyl) quinolin-4-amine: To an oven dried two neck round bottom flask, 4-chloro-6, 7-dimethoxyquinoline (143 mg, 0.64 mmol, 1.3 equiv) , 3-methoxy-5- (4-methyl-1H-imidazol-1-yl) aniline (100 mg, 0.49 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 105 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue
was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as pale yellow solid (40 mg, yield = 21 %) .
TLC Rf = 0.2 (5 %MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H) , 8.36 (d, J = 5.1 Hz, 1H) , 8.18 (s, 1H) , 7.73 (s, 1H) , 7.49 (s, 1H) , 7.30 (s, 1H) , 7.16 (s, 1H) , 7.02 (d, J = 5.6 Hz, 1H) , 6.98 (brs, 1H) , 6.86 (brs, 1H) , 3.95 (s, 3H) , 3.93 (s, 3H) , 3.85 (s, 3H) , 2.15 (s, 3H) .
Example 53.
Compound 53: Methyl 7-Methoxy-4- ( (3-Methoxy-5- (4-methyl-1H-imidazol-1-yl) phenyl) amino) quinoline-6-carboxylate: To an oven dried two neck round bottom flask, methyl 4-chloro-7-methoxyquinoline-6-carboxylate (161 mg, 0.64 mmol, 1.3 equiv) , 3-methoxy-5- (4-methyl-1H-imidazol-1-yl) aniline (100 mg, 0.49 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 105 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as pale yellow solid (26 mg, yield = 13 %) .
TLC Rf = 0.2 (7 %MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H) , 8.74 (s, 1H) , 8.49 (brs, 1H) , 8.16 (s, 1H) , 7.46 (s, 1H) , 7.38 (s, 1H) , 7.15 (s, 1H) , 7.04 (brs, 1H) , 6.95 (brs, 1H) , 6.86 (s, 1H) , 3.95 (s, 3H) , 3.88 (s, 3H) , 3.84 (s, 3H) , 2.15 (s, 3H) .
Example 54.
Compound 54: N- (3-Methoxy-5- (4-Methylthiophen-2-yl) phenyl) quinolin-4-amine: To an oven dried two neck round bottom flask, 4-chloroquinoline (82 mg, 0.50 mmol, 1.1 equiv) , 3-methoxy-5- (4-methylthiophen-2-yl) aniline (100 mg, 0.45 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added. The resulting mixture was washed with water (2×20 mL) and brine (2×20 mL, ) . The organic phase was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude compound was purified by flash column chromatography to afford the desired product as off white solid (110 mg, yield = 69 %) .
TLC Rf = 0.2 (70 %EA/PE)
1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H) , 8.76 (d, J = 8.6 Hz, 1H) , 8.55 (d, J = 7.0 Hz, 1H) , 8.06 (s, 1H) , 8.06 –8.01 (m, 1H) , 7.81 –7.85 (m, 1H) , 7.48 (brs, 1H) , 7.30 (s, 1H) , 7.23 (s, 1H) , 7.19 (s, 1H) , 7.02 (s, 1H) , 6.95 (d, J = 7.0 Hz, 1H) , 3.87 (s, 3H) , 2.24 (s, 3H)
Example 55.
Compound 55 N- (3-Methoxy-5- (4-Methylthiophen-2-yl) phenyl) -2-methylquinolin-4-amine: To an oven dried two neck round bottom flask, 4-chloro-2-methylquinoline (89 mg, 0.50 mmol, 1.1 equiv) , 3-methoxy-5- (4-methylthiophen-2-yl) aniline (100 mg, 0.45 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added. The resulting mixture was washed with water (2×20 mL) and brine (2×20
mL,) . The organic phase was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude compound was purified by flash column chromatography to afford the desired product as off white solid (65 mg, yield = 40 %) .
TLC Rf = 0.2 (50 %EA/PE)
1H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H) , 8.71 –8.63 (m, 1H) , 8.00 –7.94 (m, 2H) , 7.80 –7.73 (m, 1H) , 7.47 (s, 1H) , 7.26 (s, 1H) , 7.22 (s, 1H) , 7.19 (s, 1H) , 6.99 (s, 1H) , 6.83 (s, 1H) , 3.87 (s, 3H) , 2.63 (s, 3H) , 2.24 (s, 3H) .
Example 56.
Compound 56: 6-Fluoro-N- (3-Methoxy-5- (4-Methylthiophen-2-yl) phenyl) quinolin-4-amine: To an oven dried two neck round bottom flask, 4-chloro-6-fluoroquinoline (92 mg, 0.50 mmol, 1.1 equiv) , 3-methoxy-5- (4-methylthiophen-2-yl) aniline (100 mg, 0.45 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added. The resulting mixture was washed with water (2×20 mL) and brine (2×20 mL,) . The organic phase was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude compound was purified by flash column chromatography to afford the desired product as white solid (85 mg, yield = 51 %) .
TLC Rf = 0.2 (50 %EA/PE)
1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H) , 8.64 (dd, J = 10.3, 2.3 Hz, 1H) , 8.57 (d, J = 6.9 Hz, 1H) , 8.15 (dd, J = 9.3, 5.1 Hz, 1H) , 8.04 –7.97 (m, 1H) , 7.48 (brs, 1H) , 7.29 (s, 1H) , 7.23 (s, 1H) , 7.19 (s, 1H) , 7.01 –6.97 (m, 2H) , 3.87 (s, 3H) , 2.24 (s, 3H) .
Example 57.
Compound 57 : 6-Chloro-N- (3-Methoxy-5- (4-Methylthiophen-2-yl) phenyl) quinolin-4-amine: To an oven dried two neck round bottom flask, 4, 6-dichloroquinoline (99 mg, 0.50 mmol, 1.1 equiv) , 3-methoxy-5- (4-methylthiophen-2-yl) aniline (100 mg, 0.45 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added. The resulting mixture was washed with water (2×20 mL) and brine (2×20 mL,) . The organic phase was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude compound was purified by flash column chromatography to afford the desired product as pale brown solid (110 mg, yield = 63 %) .
TLC Rf = 0.2 (70 %EA/PE)
1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H) , 8.92 (s, 1H) , 8.57 (d, J = 7.0 Hz, 1H) , 8.09 (s, 2H) , 7.48 (s, 1H) , 7.29 (s, 1H) , 7.23 (s, 1H) , 7.19 (s, 1H) , 7.01 (brs, 1H) , 7.00 (brs, 1H) , 3.87 (s, 3H) , 2.24 (s, 3H) .
Example 58.
Compound 58: 6-Bromo-N- (3-Methoxy-5- (4-Methylthiophen-2-yl) phenyl) quinolin-4-amine: To an oven dried two neck round bottom flask, 6-bromo-4-chloroquinoline (146 mg, 0.60 mmol, 1.1 equiv) , 3-methoxy-5- (4-methylthiophen-2-yl) aniline (120 mg, 0.54 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added. The resulting mixture was washed with water (2×20 mL) and brine (2×20
mL,) . The organic phase was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude compound was purified by flash column chromatography to afford the desired product as off white solid (54 mg, yield = 23 %) .
TLC Rf = 0.2 (50 %EA/PE)
1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H) , 9.10 (s, 1H) , 8.55 (d, J = 7.0 Hz, 1H) , 8.19 (dd, J = 9.0, 1.7 Hz, 1H) , 8.05 (d, J = 9.0 Hz, 1H) , 7.47 (s, 1H) , 7.29 (s, 1H) , 7.22 (s, 1H) , 7.19 (s, 1H) , 6.99 –7.03 (m, 2H) , 3.87 (s, 3H) , 2.24 (s, 3H) .
Example 59.
Compound 59: 6-Methoxy-N- (3-Methoxy-5- (4-Methylthiophen-2-yl) phenyl) quinolin-4-amine: To an oven dried two neck round bottom flask, 4-chloro-6-methoxyquinoline (97 mg, 0.50 mmol, 1.1 equiv) , 3-methoxy-5- (4-methylthiophen-2-yl) aniline (100 mg, 0.45 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added. The resulting mixture was washed with water (2×20 mL) and brine (2×20 mL,) . The organic phase was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude compound was purified by flash column chromatography to afford the desired product as brown solid (80 mg, yield = 47 %) .
TLC Rf = 0.2 (70 %EA/PE)
1H NMR (400 MHz, DMSO-d6) δ 8.83 (s, 1H) , 8.39 (d, J = 4.8 Hz, 1H) , 7.81 (d, J = 9.2 Hz, 1H) , 7.70 (d, J = 2.4 Hz, 1H) , 7.39 (brs, 1H) , 7.36 (dd, J = 9.2, 2.6 Hz, 1H) , 7.15 (s, 1H) , 7.13 (s, 1H) , 7.07 (d, J = 5.1 Hz, 1H) , 6.93 (brs, 1H) , 6.85 (brs, 1H) , 3.94 (s, 3H) , 3.83 (s, 3H) , 2.24 (s, 3H) .
Example 60.
Compound 60: N- (3-Methoxy-5- (4-Methylthiophen-2-yl) phenyl) -6- (trifluoromethyl) quinolin-4-amine: To an oven dried two neck round bottom flask, 4-chloro-6- (trifluoromethyl) quinoline (116 mg, 0.50 mmol, 1.1 equiv) , 3-methoxy-5- (4-methylthiophen-2-yl) aniline (100 mg, 0.45 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added. The resulting mixture was washed with water (2×20 mL) and brine (2×20 mL, ) . The organic phase was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude compound was purified by flash column chromatography to afford the desired product as brown solid (60 mg, yield = 32 %) .
TLC Rf = 0.2 (60 %EA/PE)
1H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 1H) , 8.89 (s, 1H) , 8.62 (d, J = 5.2 Hz, 1H) , 8.06 (d, J = 8.8 Hz, 1H) , 7.95 (d, J = 8.5 Hz, 1H) , 7.41 (s, 1H) , 7.19 (s, 1H) , 7.17 –7.12 (m, 2H) , 7.00 (s, 1H) , 6.89 (s, 1H) , 3.84 (s, 3H) , 2.24 (s, 3H) .
Example 61.
Compound 61 : Methyl 4- ( (3-Methoxy-5- (4-Methylthiophen-2-yl) phenyl) amino) quinoline-6-carboxylate: To an oven dried two neck round bottom flask, methyl 4-chloroquinoline-6-carboxylate (112 mg, 0.50 mmol, 1.1 equiv) , 3-methoxy-5- (4-methylthiophen-2-yl) aniline (100 mg, 0.45 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added. The resulting mixture was washed with water (2×20 mL) and brine (2×20 mL, ) . The organic phase was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude compound was purified by flash column chromatography to afford the desired product as yellow solid (55 mg, yield = 29 %) .
TLC Rf = 0.2 (40 %EA/PE)
1H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H) , 9.13 (s, 1H) , 8.59 (d, J = 5.3 Hz, 1H) , 8.17 (d, J = 8.9 Hz, 1H) , 7.96 (d, J = 8.8 Hz, 1H) , 7.40 (s, 1H) , 7.21 (s, 1H) , 7.16 –7.11 (m, 2H) , 6.97 (s, 1H) , 6.90 (s, 1H) , 3.95 (s, 3H) , 3.83 (s, 3H) , 2.24 (s, 3H)
Example 62.
Compound 62: 7-Fluoro-N- (3-Methoxy-5- (4-Methylthiophen-2-yl) phenyl) quinolin-4-amine: To an oven dried two neck round bottom flask, 4-chloro-7-fluoroquinoline (91 mg, 0.50 mmol, 1.1 equiv) , 3-methoxy-5- (4-methylthiophen-2-yl) aniline (100 mg, 0.45 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added. The resulting mixture was washed with water (2×20 mL) and brine (2×20 mL,) . The organic phase was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude compound was purified by flash column chromatography to afford the desired product as off white solid (75 mg, yield = 45 %) .
TLC Rf = 0.2 (50 %EA/PE)
1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H) , 8.87 –8.77 (m, 1H) , 8.55 (d, J = 7.0 Hz, 1H) , 7.84 –7.76 (m, 2H) , 7.48 (brs, 1H) , 7.29 (s, 1H) , 7.24 (s, 1H) , 7.19 (s, 1H) , 7.01 (t, J = 1.7 Hz, 1H) , 6.93 (d, J = 7.0 Hz, 1H) , 3.87 (s, 3H) , 2.24 (s, 3H) .
Example 63.
Compound 63: 7-Chloro-N- (3-Methoxy-5- (4-Methylthiophen-2-yl) phenyl) quinolin-4-amine: To an oven dried two neck round bottom flask, 4, 7-dichloroquinoline (99 mg, 0.50 mmol,
1.1 equiv) , 3-methoxy-5- (4-methylthiophen-2-yl) aniline (100 mg, 0.45 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added. The resulting mixture was washed with water (2×20 mL) and brine (2×20 mL,) . The organic phase was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude compound was purified by flash column chromatography to afford the desired product as off white solid (100 mg, yield = 57 %) .
TLC Rf = 0.2 (70 %EA/PE)
1H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H) , 8.79 (dd, J = 9.0, 3.3 Hz, 1H) , 8.55 (d, J = 7.0 Hz, 1H) , 8.13 (brs, 1H) , 7.91 (dd, J = 9.1, 1.8 Hz, 1H) , 7.47 (brs, 1H) , 7.29 (s, 1H) , 7.23 (brs, 1H) , 7.19 (s, 1H) , 7.01 (t, J = 1.7 Hz, 1H) , 6.95 (d, J = 7.0 Hz, 1H) , 3.86 (s, 3H) , 2.24 (s, 3H) .
Example 64.
Compound 64: 7-Bromo-N- (3-Methoxy-5- (4-Methylthiophen-2-yl) phenyl) quinolin-4-amine: To an oven dried two neck round bottom flask, 7-bromo-4-chloroquinoline (122 mg, 0.50 mmol, 1.1 equiv) , 3-methoxy-5- (4-methylthiophen-2-yl) aniline (100 mg, 0.45 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added. The resulting mixture was washed with water (2×20 mL) and brine (2×20 mL,) . The organic phase was separated , dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude compound was purified by flash column chromatography to afford the desired product as off white solid (125 mg, yield = 64 %) .
TLC Rf = 0.2 (70 %EA/PE)
1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H) , 8.66 (d, J = 9.1 Hz, 1H) , 8.55 (d, J = 7.0 Hz, 1H) , 8.23 (d, J = 1.4 Hz, 1H) , 8.03 (dd, J = 9.1, 1.7 Hz, 1H) , 7.48 (s, 1H) , 7.28 (s, 1H) , 7.23 (s, 1H) , 7.19 (s, 1H) , 7.02 –6.98 (m, 1H) , 6.97 (d, J = 7.0 Hz, 1H) , 3.86 (s, 3H) , 2.24 (s, 3H) .
Example 65.
Compound 65: 7-Methoxy-N- (3-Methoxy-5- (4-Methylthiophen-2-yl) phenyl) quinolin-4-amine: To an oven dried two neck round bottom flask, 4-chloro-7-methoxyquinoline (97 mg, 0.50 mmol, 1.1 equiv) , 3-methoxy-5- (4-methylthiophen-2-yl) aniline (100 mg, 0.45 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added. The resulting mixture was washed with water (2×20 mL) and brine (2×20 mL,) . The organic phase was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude compound was purified by flash column chromatography to afford the desired product as off white (80 mg, yield = 46 %) .
TLC Rf = 0.2 (60 %EA/PE)
1H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H) , 8.43 (d, J = 4.7 Hz, 1H) , 8.26 (d, J = 9.3 Hz, 1H) , 7.38 (s, 1H) , 7.27 (d, J = 2.1 Hz, 1H) , 7.19 (dd, J = 9.2, 2.4 Hz, 1H) , 7.15 (s, 1H) , 7.13 (s, 1H) , 6.97 (d, J = 5.2 Hz, 1H) , 6.92 (brs, 1H) , 6.84 (brs, 1H) , 3.91 (s, 3H) , 3.82 (s, 3H) , 2.23 (s, 3H) .
Example 66.
Compound 66: N- (3-Methoxy-5- (4-Methylthiophen-2-yl) phenyl) -7- (trifluoromethyl) quinolin-4-amine: To an oven dried two neck round bottom flask, 4-chloro-7- (trifluoromethyl) quinoline (116 mg, 0.50 mmol, 1.1 equiv) , 3-methoxy-5- (4-methylthiophen-2-yl) aniline (100 mg, 0.45 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled
down to room temperature and ethyl acetate (25 mL) was added. The resulting mixture was washed with water (2×20 mL) and brine (2×20 mL, ) . The organic phase was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude compound was purified by flash column chromatography to afford the desired product as off white solid (90 mg, yield = 47 %) .
TLC Rf = 0.2 (40 %EA/PE)
1H NMR (400 MHz, DMSO-d6) 8.96 (d, J = 8.8 Hz, 1H) , 8.67 (d, J = 6.9 Hz, 1H) , 8.41 (s, 1H) , 8.17 (d, J = 8.9 Hz, 1H) , 7.48 (brs, 1H) , 7.30 (brs, 1H) , 7.24 (s, 1H) , 7.20 (s, 1H) , 7.07 (d, J = 6.9 Hz, 1H) , 7.02 (t, J = 1.9 Hz, 1H) , 3.87 (s, 3H) , 2.25 (s, 3H) .
Example 67.
Compound 67: 8-Methoxy-N- (3-Methoxy-5- (4-Methylthiophen-2-yl) phenyl) quinolin-4-amine: To an oven dried two neck round bottom flask, 4-chloro-8-methoxyquinoline (97 mg, 0.50 mmol, 1.1 equiv) , 3-methoxy-5- (4-methylthiophen-2-yl) aniline (100 mg, 0.45 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added. The resulting mixture was washed with water (2×20 mL) and brine (2×20 mL,) . The organic phase was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude compound was purified by flash column chromatography to afford the desired product as pale brown solid (80 mg, yield = 46 %) .
TLC Rf = 0.2 (70 %EA/PE)
1H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 1H) , 8.44 (d, J = 4.8 Hz, 1H) , 7.91 (d, J = 8.4 Hz, 1H) , 7.48 (t, J = 8.1 Hz, 1H) , 7.39 (s, 1H) , 7.20 (d, J = 7.7 Hz, 1H) , 7.17 (s, 1H) , 7.13 (s, 1H) , 7.09 (d, J = 5.0 Hz, 1H) , 6.95 (s, 1H) , 6.86 (s, 1H) , 3.95 (s, 3H) , 3.82 (s, 3H) , 2.23 (s, 3H) .
Example 68.
Compound 68: N- (3-Methoxy-5- (4-Methylthiophen-2-yl) phenyl) -8- (trifluoromethyl) quinolin-4-amine: To an oven dried two neck round bottom flask, 4-chloro-8- (trifluoromethyl) quinoline (116 mg, 0.50 mmol, 1.1 equiv) , 3-methoxy-5- (4-methylthiophen-2-yl) aniline (100 mg, 0.45 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added. The resulting mixture was washed with water (2×20 mL) and brine (2×20 mL, ) . The organic phase was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude compound was purified byflash column chromatography to afford the desired product as white solid (95 mg, yield = 50 %) .
TLC Rf = 0.2 (40 %EA/PE)
1H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H) , 8.68 (d, J = 8.4 Hz, 1H) , 8.61 (d, J = 5.3 Hz, 1H) , 8.13 (d, J = 7.2 Hz, 1H) , 7.67 (t, J = 7.9 Hz, 1H) , 7.40 (s, 1H) , 7.19 (s, 1H) , 7.17 (d, J = 5.3 Hz, 1H) , 7.14 (s, 1H) , 6.98 (brs, 1H) , 6.89 (brs, 1H) , 3.83 (s, 3H) , 2.24 (s, 3H) .
Example 69.
Compound 69: 6, 7-Dimethoxy-N- (3-Methoxy-5- (4-Methylthiophen-2-yl) phenyl) quinolin-4-amine: To an oven dried two neck round bottom flask, 4-chloro-6, 7-dimethoxyquinoline (135 mg, 0.60 mmol, 1.1 equiv) , 3-methoxy-5- (4-methylthiophen-2-yl) aniline (120 mg, 0.54 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled
down to room temperature and ethyl acetate (25 mL) was added. The resulting mixture was washed with water (2×20 mL) and brine (2×20 mL, ) . The organic phase was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude compound was purified by flash column chromatography to afford the desired product as brown solid (86 mg, yield = 39 %) .
TLC Rf = 0.2 (100 %EA)
1H NMR (400 MHz, DMSO-d6) δ 10.66 (brs, 1H) , 8.37 (d, J = 6.9 Hz, 1H) , 8.13 (s, 1H) , 7.47 (s, 1H) , 7.45 (s, 1H) , 7.26 (s, 1H) , 7.22 –7.14 (m, 2H) , 6.99 (s, 1H) , 6.88 (d, J = 6.9 Hz, 1H) , 4.01 (s, 3H) , 3.98 (s, 3H) , 3.87 (s, 3H) , 2.22 (brs, 3H) .
Example 70.
Compound 70: Methyl 7-methoxy-4- ( (3-methoxy-5- (4-methylthiophen-2-yl) phenyl) amino) quinoline-6-carboxylate: To an oven dried two neck round bottom flask, methyl 4-chloro-7-methoxyquinoline-6-carboxylate (126 mg, 0.50 mmol, 1.1 equiv) , 3-methoxy-5- (4-methylthiophen-2-yl) aniline (100 mg, 0.45 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added. The resulting mixture was washed with water (2×20 mL) and brine (2×20 mL, ) . The organic phase was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude compound was purified by flash column chromatography to afford the desired product as yellow solid (90 mg, yield = 45 %) .
TLC Rf = 0.2 (50 %EA/PE)
1H NMR (400 MHz, DMSO-d6) δ 9.27 (s, 1H) , 8.73 (s, 1H) , 8.49 (d, J = 4.8 Hz, 1H) , 7.39 (s, 1H) , 7.37 (s, 1H) , 7.17 (s, 1H) , 7.14 (s, 1H) , 6.99 (d, J = 5.1 Hz, 1H) , 6.95 (brs, 1H) , 6.86 (brs, 1H) , 3.94 (s, 3H) , 3.87 (s, 3H) , 3.82 (s, 3H) , 2.24 (s, 3H) .
Example 71.
Compound 71: N- (3-Bromo-5-methoxyphenyl) -6, 7-dimethoxyquinolin-4-amine: To an oven dried two neck round bottom flask, 4-chloro-6, 7-dimethoxyquinoline (608 mg, 2.72 mmol, 1.1 equiv) , 3-bromo-5-methoxyaniline (500 mg, 2.5 mmol, 1 equiv) and NMP (6 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as off white solid (600 mg, yield = 62 %) .
TLC Rf = 0.2 (70 %EA/PE)
1H NMR (400 MHz, DMSO-d6) δ 10.62 (s, 1H) , 8.40 (d, J = 6.9 Hz, 1H) , 8.09 (s, 1H) , 7.43 (s, 1H) , 7.28 (s, 1H) , 7.21 –7.17 (m, 1H) , 7.09 (t, J = 1.7 Hz, 1H) , 6.90 (d, J = 6.9 Hz, 1H) , 4.00 (s, 3H) , 3.98 (s, 3H) , 3.83 (s, 3H) .
Example 72.
Compound 72: 6, 7-Dimethoxy-N- (5-Methoxy- [1, 1'-biphenyl] -3-yl) quinolin-4-amine: To an oven dried seal tube with a magnetic bar was filled with 1, 4-dioaxne : H2O (4: 1) mixture. The solvent mixture was purged with argon at room temperature. To this purged solution, N- (3-bromo-5-methoxyphenyl) -6, 7-dimethoxyquinolin-4-amine (150 mg, 0.38 mmol, 1 equiv) , phenylboronic acid (61 mg, 0.50 mmol, 1.3 equiv) , Pd (dppf) Cl2 (17 mg, 6 mol%) and K2CO3 (160 mg, 1.15 mmol, 3 equiv) were added. The reaction mixture was degassed with argon (the sequence was carried out 2 times) and reaction tube was sealed with Teflon screw cap. The reaction mixture was subsequently stirred in a preheated oil bath at 100 ℃ for 16 h. The reaction mixture was cooled
down to room temperature, diluted with ethyl acetate (50 mL) and washed with water (3×20 mL) &brine (3×20 mL, ) . The organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude residue was purified by flash column chromatography to afford the product as as pale yellow solid (76 mg, yield = 50 %) .
TLC Rf = 0.2 (2 %MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H) , 8.33 (d, J = 5.4 Hz, 1H) , 7.70 (brs, 3H) , 7.68 (s, 1H) , 7.47 (t, J = 7.5 Hz, 2H) , 7.39 (t, J = 7.3 Hz, 1H) , 7.27 (s, 1H) , 7.20 (s, 1H) , 7.00 (d, J = 5.5 Hz, 1H) , 6.97 (brs, 1H) , 6.91 (brs, 1H) , 3.95 (s, 3H) , 3.92 (s, 3H) , 3.86 (s, 3H) .
Example 73.
Compound 73: 6, 7-Dimethoxy-N- (3-Methoxy-5- (pyridin-4-yl) phenyl) quinolin-4-amine: To an oven dried seal tube with a magnetic bar was filled with 1, 4-dioaxne : H2O (4: 1) mixture. The solvent mixture was purged with argon at room temperature. To this purged solution, N- (3-bromo-5-methoxyphenyl) -6, 7-dimethoxyquinolin-4-amine (150 mg, 0.38 mmol, 1 equiv) , pyridin-4-ylboronic acid (57 mg, 0.46 mmol, 1.2 equiv) , Pd (dppf) Cl2 (17 mg, 6 mol%) and K2CO3 (160 mg, 1.15 mmol, 3 equiv) were added. The reaction mixture was degassed with argon (the sequence was carried out 2 times) and reaction tube was sealed with Teflon screw cap. The reaction mixture was subsequently stirred in a preheated oil bath at 110 ℃ for 14 h. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate (50 mL) and washed with water (3×20 mL) &brine (3×20 mL, ) . The organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude residue was purified by flash column chromatography to afford the product as as pale yellow solid (123 mg, yield = 82 %) .
TLC Rf = 0.2 (7 %MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H) , 8.65 (d, J = 5.6 Hz, 2H) , 8.35 (d, J = 5.7 Hz, 1H) , 7.76 (s, 1H) , 7.74 (d, J = 6.0 Hz, 2H) , 7.35 (s, 1H) , 7.30 (s, 1H) , 7.16 (s, 1H) , 7.04 (brs, 1H) , 7.00 (d, J = 5.7 Hz, 1H) , 3.96 (s, 3H) , 3.94 (s, 3H) , 3.88 (s, 3H) .
Example 74.
Compound 74: 6, 7-Dimethoxy-N- (3-Methoxy-5- (pyridin-3-yl) phenyl) quinolin-4-amine: To an oven dried seal tube with a magnetic bar was filled with 1, 4-dioaxne : H2O (4: 1) mixture. The solvent mixture was purged with argon at room temperature. To this purged solution, N- (3-bromo-5-methoxyphenyl) -6, 7-dimethoxyquinolin-4-amine (150 mg, 0.38 mmol, 1 equiv) , pyridin-3-ylboronic acid (62 mg, 0.5 mmol, 1.3 equiv) , Pd (dppf) Cl2 (17 mg, 6 mol%) and K2CO3 (160 mg, 1.15 mmol, 3 equiv) were added. The reaction mixture was degassed with argon (the sequence was carried out 2 times) and reaction tube was sealed with Teflon screw cap. The reaction mixture was subsequently stirred in a preheated oil bath at 105 ℃ for 14 h. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate (50 mL) and washed with water (3×20 mL) &brine (3×20 mL, ) . The organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude residue was purified by flash column chromatography to afford the product as off white solid (90 mg, yield = 60 %) .
TLC Rf = 0.2 (7 %MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) δ 9.22 (s, 1H) , 8.93 (s, 1H) , 8.59 (d, J = 3.9 Hz, 1H) , 8.35 (d, J = 5.5 Hz, 1H) , 8.11 (d, J = 7.8 Hz, 1H) , 7.75 (s, 1H) , 7.50 (dd, J = 7.6, 4.9 Hz, 1H) , 7.29 (s, 1H) , 7.27 (s, 1H) , 7.09 (s, 1H) , 7.02 (d, J = 5.6 Hz, 1H) , 6.98 (s, 1H) , 3.96 (s, 3H) , 3.93 (s, 3H) , 3.87 (s, 3H) .
Example 75.
Compound 75: 6, 7-Dimethoxy-N- (3-Methoxy-5- (thiophen-2-yl) phenyl) quinolin-4-amine: To an oven dried seal tube with a magnetic bar was filled with 1, 4-dioaxne : H2O (4: 1) mixture. The solvent mixture was purged with argon at room temperature. To this purged solution, N- (3-bromo-5-methoxyphenyl) -6, 7-dimethoxyquinolin-4-amine (150 mg, 0.38 mmol, 1 equiv) ,
thiophen-2-ylboronic acid (59 mg, 0.46 mmol, 1.2 equiv) , Pd (dppf) Cl2 (17 mg, 6 mol%) and K2CO3 (160 mg, 1.15 mmol, 3 equiv) were added. The reaction mixture was degassed with argon (the sequence was carried out 2 times) and reaction tube was sealed with Teflon screw cap. The reaction mixture was subsequently stirred in a preheated oil bath at 105 ℃ for 14 h. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate (50 mL) and washed with water (3×20 mL) &brine (3×20 mL, ) . The organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude residue was purified by flash column chromatography to afford the product as as pale yellow solid (68 mg, yield = 45 %) .
TLC Rf = 0.2 (100 %EtOAc)
1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H) , 8.34 (d, J = 5.5 Hz, 1H) , 7.71 (s, 1H) , 7.58 (s, 1H) , 7.57 (s, 1H) , 7.28 (s, 1H) , 7.19 (brs, 1H) , 7.17 –7.12 (m, 1H) , 7.01 (brs, 1H) , 6.97 (d, J = 5.5 Hz, 1H) , 6.87 (brs, 1H) , 3.95 (s, 3H) , 3.93 (s, 3H) , 3.84 (s, 3H) .
Example 76.
Compound 76: 6, 7-Dimethoxy-N- (3-Methoxy-5- (thiophen-3-yl) phenyl) quinolin-4-amine: To an oven dried seal tube with a magnetic bar was filled with 1, 4-dioaxne : H2O (4: 1) mixture. The solvent mixture was purged with argon at room temperature. To this purged solution, N- (3-bromo-5-methoxyphenyl) -6, 7-dimethoxyquinolin-4-amine (120 mg, 0.31 mmol, 1 equiv) , thiophen-3-ylboronic acid (48 mg, 0.37 mmol, 1.2 equiv) , Pd (dppf) Cl2 (11 mg, 6 mol%) and K2CO3 (128 mg, 0.93 mmol, 3 equiv) were added. The reaction mixture was degassed with argon (the sequence was carried out 2 times) and reaction tube was sealed with Teflon screw cap. The reaction mixture was subsequently stirred in a preheated oil bath at 105 ℃ for 12 h. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate (50 mL) and washed with water (3×20 mL) &brine (3×20 mL, ) . The organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude residue was purified by flash column chromatography to afford the product as as pale yellow solid (26 mg, yield = 13 %) .
TLC Rf = 0.2 (100 %EtOAc)
1H NMR (400 MHz, DMSO-d6) δ 8.34 (d, J = 6.0 Hz, 1H) , 7.98 –7.95 (m, 1H) , 7.82 (s, 1H) , 7.65 (dd, J = 4.9, 2.9 Hz, 1H) , 7.60 (dd, J = 5.1, 1.1 Hz, 1H) , 7.31 (s, 1H) , 7.30 (s, 1H) , 7.17 (brs, 1H) , 6.91 (d, J = 6.0 Hz, 1H) , 6.89 (brs, 1H) , 3.97 (s, 3H) , 3.95 (s, 3H) , 3.85 (s, 3H) .
Example 77.
Compound 77: N- (3- (Furan-2-yl) -5-Methoxyphenyl) -6, 7-Dimethoxyquinolin-4-amine: To an oven dried seal tube with a magnetic bar was filled with 1, 4-dioaxne : H2O (4: 1) mixture. The solvent mixture was purged with argon at room temperature. To this purged solution, N- (3-bromo-5-methoxyphenyl) -6, 7-dimethoxyquinolin-4-amine (150 mg, 0.38 mmol, 1 equiv) , furan-2-ylboronic acid (56 mg, 0.5 mmol, 1.3 equiv) , Pd (dppf) Cl2 (17 mg, 6 mol%) and K2CO3 (160 mg, 1.15 mmol, 3 equiv) were added. The reaction mixture was degassed with argon (the sequence was carried out 2 times) and reaction tube was sealed with Teflon screw cap. The reaction mixture was subsequently stirred in a preheated oil bath at 105 ℃ for 14 h. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate (50 mL) and washed with water (3×20 mL) &brine (3×20 mL, ) . The organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude residue was purified by flash column chromatography to afford the product as brown solid (95 mg, yield = 65 %) .
TLC Rf = 0.2 (100 %EtOAc)
1H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H) , 8.32 (d, J = 5.7 Hz, 1H) , 8.25 (s, 1H) , 7.76 (brs, 1H) , 7.75 (brs, 1H) , 7.28 (s, 1H) , 7.19 (s, 1H) , 7.03 (s, 1H) , 6.99 (brs, 1H) , 6.88 (d, J = 5.7 Hz, 1H) , 6.83 (s, 1H) , 3.95 (s, 3H) , 3.93 (s, 3H) , 3.83 (s, 3H) .
Example 78.
Compound 78: N- (3- (Furan-3-yl) -5-Methoxyphenyl) -6, 7-Dimethoxyquinolin-4-
amine: To an oven dried seal tube with a magnetic bar was filled with 1, 4-dioaxne : H2O (4: 1) mixture. The solvent mixture was purged with argon at room temperature. To this purged solution, N- (3-bromo-5-methoxyphenyl) -6, 7-dimethoxyquinolin-4-amine (120 mg, 0.31 mmol, 1 equiv) , furan-3-ylboronic acid (41 mg, 0.37 mmol, 1.2 equiv, Pd (dppf) Cl2 (11 mg, 6 mol%) and K2CO3 (128 mg, 0.93 mmol, 3 equiv) were added. The reaction mixture was degassed with argon (the sequence was carried out 2 times) and reaction tube was sealed with Teflon screw cap. The reaction mixture was subsequently stirred in a preheated oil bath at 105 ℃ for 12 h. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate (50 mL) and washed with water (3×20 mL) &brine (3×20 mL, ) . The organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude residue was purified by flash column chromatography to afford the product as brown solid (60 mg, yield = 52 %) .
TLC Rf = 0.2 (100 %EtOAc)
1H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H) , 8.34 (d, J = 5.6 Hz, 1H) , 7.77 (d, J = 1.0 Hz, 1H) , 7.73 (s, 1H) , 7.28 (s, 2H) , 7.07 (s, 1H) , 7.02 (d, J = 3.0 Hz, 1H) , 6.94 (d, J = 5.6 Hz, 1H) , 6.85 (s, 1H) , 6.63 –6.59 (m, 1H) , 3.95 (s, 3H) , 3.93 (s, 3H) , 3.84 (s, 3H) .
Example 79.
Compound 79: 6, 7-Dimethoxy-N- (3-Methoxy-5- (1H-pyrazol-4-yl) phenyl) quinolin-4-amine: To an oven dried seal tube with a magnetic bar was filled with 1, 4-dioaxne : H2O (4: 1) mixture. The solvent mixture was purged with argon at room temperature. To this purged solution, N- (3-bromo-5-methoxyphenyl) -6, 7-dimethoxyquinolin-4-amine (150 mg, 0.38 mmol, 1 equiv) , 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (90 mg, 0.46 mmol, 1.2 equiv) , Pd(dppf) Cl2 (17 mg, 6 mol%) and K2CO3 (160 mg, 1.15 mmol, 3 equiv) were added. The reaction mixture was degassed with argon (the sequence was carried out 2 times) and reaction tube was sealed with Teflon screw cap. The reaction mixture was subsequently stirred in a preheated oil bath at 100 ℃ for 14 h. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate (50 mL) and washed with water (3×20 mL) &brine (3×20 mL, ) . The organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The
crude residue was purified by flash column chromatography to afford the product as as pale yellow solid (24 mg, yield = 17 %) .
TLC Rf = 0.2 (10 %MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) δ 9.65 (s, 1H) , 8.33 (d, J = 6.0 Hz, 1H) , 8.22 (brs, 1H) , 8.08 –7.91 (m, 1H) , 7.86 (s, 1H) , 7.30 (s, 1H) , 7.22 (s, 1H) , 7.12 (s, 1H) , 6.86 (d, J = 6.2 Hz, 1H) , 6.79 (s, 1H) , 3.97 (s, 3H) , 3.95 (s, 3H) , 3.83 (s, 3H) .
Example 80.
Compound 80: 6, 7-Dimethoxy-N- (3-Methoxy-5- (1-Methyl-1H-pyrazol-4-yl) phenyl) quinolin-4-amine: To an oven dried seal tube with a magnetic bar was filled with 1, 4-dioaxne : H2O (4: 1) mixture. The solvent mixture was purged with argon at room temperature. To this purged solution, N- (3-bromo-5-methoxyphenyl) -6, 7-dimethoxyquinolin-4-amine (150 mg, 0.38 mmol, 1 equiv) , 1-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (96 mg, 0.46 mmol, 1.2 equiv) , Pd (dppf) Cl2 (17 mg, 6 mol%) and K2CO3 (160 mg, 1.15 mmol, 3 equiv) were added. The reaction mixture was degassed with argon (the sequence was carried out 2 times) and reaction tube was sealed with Teflon screw cap. The reaction mixture was subsequently stirred in a preheated oil bath at 100 ℃ for 14 h. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate (50 mL) and washed with water (3×20 mL) &brine (3×20 mL,) . The organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude residue was purified by flash column chromatography to afford the product as as pale yellow solid (24 mg, yield = 17 %) .
TLC Rf = 0.2 (7 %MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H) , 8.32 (d, J = 5.7 Hz, 1H) , 8.18 (s, 1H) , 7.89 (s, 1H) , 7.75 (s, 1H) , 7.27 (s, 1H) , 7.13 (s, 1H) , 6.97 (s, 1H) , 6.89 (d, J = 5.7 Hz, 1H) , 6.75 (brs, 1H) , 3.95 (s, 3H) , 3.93 (s, 3H) , 3.85 (s, 3H) , 3.82 (s, 3H) .
Example 81.
Compound 81: N- (3- (1-Isobutyl-1H-pyrazol-4-yl) -5-methoxyphenyl) -6, 7-dimethoxyquinolin-4-amine: To an oven dried seal tube with a magnetic bar was filled with 1, 4-dioaxne : H2O (4: 1) mixture. The solvent mixture was purged with argon at room temperature. To this purged solution, N- (3-bromo-5-methoxyphenyl) -6, 7-dimethoxyquinolin-4-amine (150 mg, 0.38 mmol, 1 equiv) , 1-isobutyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (125 mg, 0.5 mmol, 1.3 equiv) , Pd (dppf) Cl2 (17 mg, 6 mol%) and K2CO3 (160 mg, 1.15 mmol, 3 equiv) were added. The reaction mixture was degassed with argon (the sequence was carried out 2 times) and reaction tube was sealed with Teflon screw cap. The reaction mixture was subsequently stirred in a preheated oil bath at 105 ℃ for 14 h. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate (50 mL) and washed with water (3×20 mL) &brine (3×20 mL, ) . The organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude residue was purified by flash column chromatography to afford the product as pale brown solid (65 mg, yield = 39 %) .
TLC Rf = 0.2 (7 %MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) δ 9.27 (s, -1H) , 8.33 (d, J = 6.0 Hz, 1H) , 8.23 (s, 1H) , 7.92 (s, 1H) , 7.81 (s, 1H) , 7.29 (s, 1H) , 7.17 (s, 1H) , 7.05 (s, 1H) , 6.87 (d, J = 6.0 Hz, 1H) , 6.77 (s, 1H) , 3.96 (s, 3H) , 3.94 (s, 3H) , 3.93 (s, 1H) , 3.91 (s, 1H) , 3.83 (s, 3H) , 2.21 –2.05 (m, 1H) .
Example 82.
Compound 82: 6, 7-Dimethoxy-N- (3-Methoxy-5- (1H-pyrazol-5-yl) phenyl) quinolin-4-amine: To an oven dried seal tube with a magnetic bar was filled with 1, 4-dioaxne : H2O (4: 1) mixture. The solvent mixture was purged with argon at room temperature. To this purged solution, N- (3-bromo-5-methoxyphenyl) -6, 7-dimethoxyquinolin-4-amine (150 mg, 0.38 mmol, 1 equiv) , 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (89 mg, 0.46 mmol, 1.2 equiv) ,
Pd(dppf) Cl2 (17 mg, 6 mol%) and K2CO3 (160 mg, 1.15 mmol, 3 equiv) were added. The reaction mixture was degassed with argon (the sequence was carried out 2 times) and reaction tube was sealed with Teflon screw cap. The reaction mixture was subsequently stirred in a preheated oil bath at 100 ℃ for 16 h. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate (50 mL) and washed with water (3×20 mL) &brine (3×20 mL, ) . The organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude residue was purified by flash column chromatography to afford the product as pale yellow solid (60 mg, yield = 41 %) .
TLC Rf = 0.2 (10 %MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H) , 8.34 (d, J = 5.9 Hz, 1H) , 7.80 (brs, 2H) , 7.44 (brs, 1H) , 7.29 (s, 1H) , 7.23 (s, 1H) , 6.92 (d, J = 5.9 Hz, 1H) , 6.88 (s, 1H) , 6.76 (s, 1H) , 3.96 (s, 3H) , 3.94 (s, 3H) , 3.84 (s, 3H) .
Example 83.
Compound 83: 6, 7-Dimethoxy-N- (3-Methoxy-5- (1-methyl-1H-pyrazol-5-yl) phenyl) quinolin-4-amine: To an oven dried seal tube with a magnetic bar was filled with 1, 4-dioaxne : H2O (4: 1) mixture. The solvent mixture was purged with argon at room temperature. To this purged solution, N- (3-bromo-5-methoxyphenyl) -6, 7-dimethoxyquinolin-4-amine (150 mg, 0.38 mmol, 1 equiv) , 1-methyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (48 mg, 0.46 mmol, 1.2 equiv) , Pd (dppf) Cl2 (17 mg, 6 mol%) and K2CO3 (160 mg, 1.15 mmol, 3 equiv) were added. The reaction mixture was degassed with argon (the sequence was carried out 2 times) and reaction tube was sealed with Teflon screw cap. The reaction mixture was subsequently stirred in a preheated oil bath at 105 ℃ for 12 h. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate (50 mL) and washed with water (3×20 mL) &brine (3×20 mL,) . The organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude residue was purified by flash column chromatography to afford the product as pale yellow solid (98 mg, yield = 65 %) .
TLC Rf = 0.2 (5 %MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H) , 8.35 (d, J = 5.6 Hz, 1H) , 7.71 (s, 1H) , 7.47 (d, J = 1.8 Hz, 1H) , 7.29 (s, 1H) , 7.05 (s, 1H) , 7.01 –6.95 (m, 2H) , 6.87 (s, 1H) , 6.46 (d, J = 1.8 Hz, 1H) , 3.95 (s, 3H) , 3.93 (s, 3H) , 3.90 (s, 3H) , 3.84 (s, 3H) .
Example 84.
Compound 84: 4- ( (3-Bromo-5-methoxyphenyl) amino) -7-Methoxyquinoline-6-carboxamide: To an oven dried two neck round bottom flask, 4-chloro-7-methoxyquinoline-6-carboxamide (2.58 g, 10.9 mmol, 1.1 equiv) , 3-bromo-5-methoxyaniline (2 g, 9.9 mmol, 1 equiv) and NMP (20 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added to obtain the solid. The residue was filtered and washed with ethyl acetate (2 × 10 mL) to obtain crude material. The crude compound was purified by flash column chromatography to afford the desired product as yellow solid (3 g, yield = 75 %) .
TLC Rf = 0.2 (50 %EA/PE)
1H NMR (400 MHz, DMSO-d6) δ 11.17 (s, 1H) , 9.70 (s, 1H) , 8.61 (s, 1H) , 8.45 (d, J = 7.0 Hz, 1H) , 8.31 (s, 1H) , 7.33 (s, 1H) , 7.30 (s, 1H) , 7.21 (s, 1H) , 7.11 (s, 1H) , 6.86 (d, J = 7.0 Hz, 1H) , 3.83 (s, 3H) .
Example 85.
Compound 85: 7-Methoxy-4- ( (5-Methoxy- [1, 1'-biphenyl] -3-yl) amino) quinoline-6-carboxamide: To an oven dried seal tube with a magnetic bar was filled with 1, 4-dioaxne : H2O (4: 1) mixture. The solvent mixture was purged with argon at room temperature. To this purged solution, 4- ( (3-bromo-5-methoxyphenyl) amino) -7-methoxyquinoline-6-carboxamide (150 mg,
0.37 mmol, 1 equiv) , phenylboronic acid (61 mg, 0.48 mmol, 1.3 equiv) , Pd (dppf) Cl2 (17 mg, 6 mol%) and K2CO3 (160 mg, 1.15 mmol, 3 equiv) were added. The reaction mixture was degassed with argon (the sequence was carried out 2 times) and reaction tube was sealed with Teflon screw cap. The reaction mixture was subsequently stirred in a preheated oil bath at 100 ℃ for 16 h. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate (50 mL) and washed with water (3×20 mL) &brine (3×20 mL, ) . The organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude residue was purified by flash column chromatography to afford the product as as pale yellow solid (25 mg, yield = 17 %) .
TLC Rf = 0.2 (10 %MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) δ 9.42-9.36 (m, 1H) , 8.84 (s, 1H) , 8.46 (d, J = 5.1 Hz, 1H) , 7.81 (s, 1H) , 7.69 (s, 2H) , 7.67 (s, 1H) , 7.47 (t, J = 7.5 Hz, 2H) , 7.39 (d, J = 7.3 Hz, 1H) , 7.36 (s, 1H) , 7.23 (s, 1H) , 7.03 (d, J = 5.3 Hz, 1H) , 6.96 (s, 1H) , 6.94 (s, 1H) , 4.00 (s, 3H) , 3.84 (s, 3H) .
Example 86.
Compound 86: 7-Methoxy-4- ( (3-Methoxy-5- (pyridin-3-yl) phenyl) amino) quinoline-6-carboxamide: To an oven dried seal tube with a magnetic bar was filled with 1, 4-dioaxne : H2O (4: 1) mixture. The solvent mixture was purged with argon at room temperature. To this purged solution, 4- ( (3-bromo-5-methoxyphenyl) amino) -7-methoxyquinoline-6-carboxamide (150 mg, 0.37 mmol, 1 equiv) , pyridin-3-ylboronic acid (50 mg, 0.41 mmol, 1.1 equiv) , Pd (P (C6H5) 3) 4 (11 mg, 2.5 mol%) and K2CO3 (129 mg, 0.93 mmol, 2.5 equiv) were added. The reaction mixture was degassed with argon (the sequence was carried out 2 times) and reaction tube was sealed with Teflon screw cap. The reaction mixture was subsequently stirred in a preheated oil bath at 110 ℃for 16 h. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate (50 mL) and washed with water (3×20 mL) &brine (3×20 mL, ) . The organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude residue was purified by flash column chromatography to afford the product as yellow solid (55 mg, yield = 37 %) .
TLC Rf = 0.2 (100 %EtOAc)
1H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H) , 8.91 (s, 1H) , 8.83 (s, 1H) , 8.59 (d, J = 3.5 Hz, 1H) , 8.47 (d, J = 5.0 Hz, 1H) , 8.09 (d, J = 8.3 Hz, 1H) , 7.80 (s, 1H) , 7.70 (s, 1H) , 7.49 (dd, J = 7.5, 4.8 Hz, 1H) , 7.37 (s, 1H) , 7.27 (s, 1H) , 7.06 (d, J = 5.2 Hz, 1H) , 7.02 (s, 1H) , 6.99 (s, 1H) , 4.00 (s, 3H) , 3.85 (s, 3H) .
Example 87.
Compound 87: 7-Methoxy-4- ( (3-Methoxy-5- (pyridin-4-yl) phenyl) amino) quinoline-6-carboxamide: To an oven dried seal tube with a magnetic bar was filled with 1, 4-dioaxne : H2O (4: 1) mixture. The solvent mixture was purged with argon at room temperature. To this purged solution, 4- ( (3-bromo-5-methoxyphenyl) amino) -7-methoxyquinoline-6-carboxamide (100 mg, 0.24 mmol, 1 equiv) , pyridin-3-ylboronic acid (46 mg, 0.37 mmol, 1.5 equiv) , Pd (dppf) Cl2 (11 mg, 6 mol%) and K2CO3 (103 mg, 0.74 mmol, 3 equiv) were added. The reaction mixture was degassed with argon (the sequence was carried out 2 times) and reaction tube was sealed with Teflon screw cap. The reaction mixture was subsequently stirred in a preheated oil bath at 105 ℃ for 14 h. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate (30 mL) and washed with water (3×20 mL) &brine (3×20 mL, ) . The organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude residue was purified by flash column chromatography to afford the product as yellow solid (45 mg, yield =45 %) .
TLC Rf = 0.2 (10 %MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H) , 8.84 (s, 1H) , 8.64 (d, J = 4.7 Hz, 2H) , 8.47 (d, J = 4.4 Hz, 1H) , 7.80 (s, 1H) , 7.72 (s, 1H) , 7.71 (brs, 2H) , 7.37 (s, 1H) , 7.35 (s, 1H) , 7.08 (s, 1H) , 7.04 (brs, 2H) , 4.01 (s, 3H) , 3.86 (s, 3H) .
Example 88.
Compound 88: 7-Methoxy-4- ( (3-Methoxy-5- (thiophen-2-yl) phenyl) amino) quinoline-6-carboxamide: To an oven dried seal tube with a magnetic bar was filled with 1, 4-dioaxne : H2O (4: 1) mixture. The solvent mixture was purged with argon at room temperature. To this purged solution, 4- ( (3-bromo-5-methoxyphenyl) amino) -7-methoxyquinoline-6-carboxamide (150 mg, 0.37 mmol, 1 equiv) , thiophen-2-ylboronic acid (52 mg, 0.41 mmol, 1.1 equiv) , Pd (P (C6H5) 3) 4 (11 mg, 2.5 mol%) and K2CO3 (129 mg, 0.93 mmol, 2.5 equiv) were added. The reaction mixture was degassed with argon (the sequence was carried out 2 times) and reaction tube was sealed with Teflon screw cap. The reaction mixture was subsequently stirred in a preheated oil bath at 110 ℃for 16 h. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate (50 mL) and washed with water (3×20 mL) &brine (3×20 mL, ) . The organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude residue was purified by flash column chromatography to afford the product as yellow solid (58 mg, yield = 38 %) .
TLC Rf = 0.2 (100 %EtOAc)
1H NMR (400 MHz, DMSO-d6) δ 9.36 (brs, 1H) , 8.83 (s, 1H) , 8.47 (d, J = 5.2 Hz, 1H) , 7.80 (s, 1H) , 7.70 (s, 1H) , 7.59 –7.54 (m, 2H) , 7.37 (s, 1H) , 7.23 (s, 1H) , 7.17 –7.12 (m, 1H) , 7.01 (d, J = 5.3 Hz, 1H) , 6.97 (s, 1H) , 6.89 (s, 1H) , 4.00 (s, 3H) , 3.83 (s, 3H) .
Example 89.
Compound 89: 7-Methoxy-4- ( (3-Methoxy-5- (thiophen-3-yl) phenyl) amino) quinoline-6-carboxamide: To an oven dried seal tube with a magnetic bar was filled with 1, 4-dioaxne : H2O (4: 1) mixture. The solvent mixture was purged with argon at room temperature. To this purged
solution, 4- ( (3-bromo-5-methoxyphenyl) amino) -7-methoxyquinoline-6-carboxamide (150 mg, 0.37 mmol, 1 equiv) , thiophen-3-ylboronic acid (52 mg, 0.41 mmol, 1.1 equiv) , Pd (P (C6H5) 3) 4 (11 mg, 2.5 mol%) and K2CO3 (129 mg, 0.93 mmol, 2.5 equiv) were added. The reaction mixture was degassed with argon (the sequence was carried out 2 times) and reaction tube was sealed with Teflon screw cap. The reaction mixture was subsequently stirred in a preheated oil bath at 110 ℃for 16 h. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate (50 mL) and washed with water (3×20 mL) &brine (3×20 mL, ) . The organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude residue was purified by flash column chromatography to afford the product as brown solid (60 mg, yield = 40 %) .
TLC Rf = 0.2 (100 %EtOAc)
1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H) , 8.84 (s, 1H) , 8.45 (d, J = 5.4 Hz, 1H) , 7.90 (brs, 1H) , 7.80 (s, 1H) , 7.70 (s, 1H) , 7.64 (dd, J = 4.9, 2.9 Hz, 1H) , 7.55 (dd, J = 4.9, 0.8 Hz, 1H) , 7.36 (s, 1H) , 7.29 (s, 1H) , 7.04 (s, 1H) , 6.98 (d, J = 5.4 Hz, 1H) , 6.87 (s, 1H) , 4.00 (s, 3H) , 3.83 (s, 3H) .
Example 90.
Compound 90: 4- ( (3- (Furan-2-yl) -5-Methoxyphenyl) amino) -7-methoxyquinoline-6-carboxamide: To an oven dried seal tube with a magnetic bar was filled with 1, 4-dioaxne : H2O (4: 1) mixture. The solvent mixture was purged with argon at room temperature. To this purged solution, 4- ( (3-bromo-5-methoxyphenyl) amino) -7-methoxyquinoline-6-carboxamide (150 mg, 0.37 mmol, 1 equiv) , furan-2-ylboronic acid (46 mg, 0.41 mmol, 1.1 equiv) , Pd (P (C6H5) 3) 4 (11 mg, 2.5 mol%) and K2CO3 (129 mg, 0.93 mmol, 2.5 equiv) were added. The reaction mixture was degassed with argon (the sequence was carried out 2 times) and reaction tube was sealed with Teflon screw cap. The reaction mixture was subsequently stirred in a preheated oil bath at 110 ℃for 16 h. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate (50 mL) and washed with water (3×20 mL) &brine (3×20 mL, ) . The organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude residue was purified by flash column chromatography to afford the product as yellow solid (62 mg, yield
= 43 %) .
TLC Rf = 0.2 (100 %EtOAc)
1H NMR (400 MHz, DMSO-d6) δ 9.32 (brs, 1H) , 8.82 (s, 1H) , 8.46 (brs, 1H) , 7.80 (s, 1H) , 7.76 (s, 1H) , 7.69 (s, 1H) , 7.36 (s, 1H) , 7.30 (s, 1H) , 7.01 (s, 1H) , 6.99 (brs, 2H) , 6.86 (s, 1H) , 6.60 (s, 1H) , 4.00 (s, 3H) , 3.82 (s, 3H) .
Example 91.
Compound 91: 4- ( (3- (Furan-3-yl) -5-Methoxyphenyl) amino) -7-methoxyquinoline-6-carboxamide: To an oven dried seal tube with a magnetic bar was filled with 1, 4-dioaxne : H2O (4: 1) mixture. The solvent mixture was purged with argon at room temperature. To this purged solution, 4- ( (3-bromo-5-methoxyphenyl) amino) -7-methoxyquinoline-6-carboxamide (150 mg, 0.37 mmol, 1 equiv) , furan-3-ylboronic acid (46 mg, 0.41 mmol, 1.1 equiv) , Pd (P (C6H5) 3) 4 (11 mg, 2.5 mol%) and K2CO3 (129 mg, 0.93 mmol, 2.5 equiv) were added. The reaction mixture was degassed with argon (the sequence was carried out 2 times) and reaction tube was sealed with Teflon screw cap. The reaction mixture was subsequently stirred in a preheated oil bath at 110 ℃for 16 h. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate (50 mL) and washed with water (3×20 mL) &brine (3×20 mL, ) . The organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude residue was purified by flash column chromatography to afford the product as yellow solid (55 mg, yield = 38 %) .
TLC Rf = 0.2 (100 %EtOAc)
Example 92.
Compound 92: 7-Methoxy-4- ( (3-Methoxy-5- (4-methylthiophen-2-
yl) phenyl) amino) quinoline-6-carboxamide: To an oven dried two neck round bottom flask, 4-chloro-7-methoxyquinoline-6-carboxamide (119 mg, 0.50 mmol, 1.1 equiv) , 3-methoxy-5- (4-methylthiophen-2-yl) aniline (100 mg, 0.45 mmol, 1 equiv) and NMP (3 mL) . were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature and ethyl acetate (25 mL) was added. The resulting mixture was washed with water (2×20 mL) and brine (2×20 mL, ) . The organic phase was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude compound was purified by flash column chromatography to afford the desired product as yellow solid (40 mg, yield = 21 %) .
TLC Rf = 0.2 (100 %EA)
1H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H) , 8.81 (s, 1H) , 8.47 (d, J = 5.1 Hz, 1H) , 7.80 (s, 1H) , 7.69 (s, 1H) , 7.37 (s, 1H) , 7.36 (s, 1H) , 7.18 (s, 1H) , 7.13 (s, 1H) , 7.00 (d, J = 5.4 Hz, 1H) , 6.92 (s, 1H) , 6.87 (s, 1H) , 4.00 (s, 3H) , 3.82 (s, 3H) , 2.23 (s, 3H) .
Example 93.
Compound 93 : 7-Methoxy-4- ( (3-Methoxy-5- (1H-pyrazol-4-yl) phenyl) amino) quinoline-6-carboxamide: To an oven dried seal tube with a magnetic bar was filled with 1, 4-dioaxne : H2O (4: 1) mixture. The solvent mixture was purged with argon at room temperature. To this purged solution, 4- ( (3-bromo-5-methoxyphenyl) amino) -7-methoxyquinoline-6-carboxamide (150 mg, 0.37 mmol, 1 equiv) , 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (79 mg, 0.41 mmol, 1.1 equiv) , Pd (P (C6H5) 3) 4 (11 mg, 2.5 mol%) and K2CO3 (129 mg, 0.93 mmol, 2.5 equiv) were added. The reaction mixture was degassed with argon (the sequence was carried out 2 times) and reaction tube was sealed with Teflon screw cap. The reaction mixture was subsequently stirred in a preheated oil bath at 110 ℃ for 16 h. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate (50 mL) and washed with water (3×20 mL) &brine (3×20 mL, ) . The organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude residue was purified by flash
column chromatography to afford the product as yellow solid (50 mg, yield = 33 %) .
TLC Rf = 0.2 (7 %MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H) , 8.85 (s, 1H) , 8.43 (d, J = 5.4 Hz, 1H) , 8.25 (s, 1H) , 7.80 (brs, 1H) , 7.70 (brs, 1H) , 7.64 –7.53 (m, 1H) , 7.35 (s, 1H) , 7.19 (s, 1H) , 7.09 (s, 1H) , 6.98 (s, 1H) , 6.92 (d, J = 5.4 Hz, 1H) , 6.76 (s, 1H) , 4.00 (s, 3H) , 3.81 (s, 3H) .
Example 94.
Compound 94: 4- ( (3- (1-Isobutyl-1H-pyrazol-4-yl) -5-Methoxyphenyl) amino) -7-methoxyquinoline-6-carboxamide: To an oven dried seal tube with a magnetic bar was filled with 1, 4-dioaxne : H2O (4: 1) mixture. The solvent mixture was purged with argon at room temperature. To this purged solution, 4- ( (3-bromo-5-methoxyphenyl) amino) -7-methoxyquinoline-6-carboxamide (150 mg, 0.37 mmol, 1 equiv) , 1-isobutyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (103 mg, 0.41 mmol, 1.1 equiv) , Pd (P (C6H5) 3) 4 (11 mg, 2.5 mol%) and K2CO3 (129 mg, 0.93 mmol, 2.5 equiv) were added. The reaction mixture was degassed with argon (the sequence was carried out 2 times) and reaction tube was sealed with Teflon screw cap. The reaction mixture was subsequently stirred in a preheated oil bath at 110 ℃ for 16 h. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate (50 mL) and washed with water (3×20 mL) &brine (3×20 mL, ) . The organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude residue was purified by flash column chromatography to afford the product as pale yellow solid (35 mg, yield = 21 %) .
TLC Rf = 0.2 (5 %MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) δ 9.22 (s, 1H) , 8.83 (s, 1H) , 8.44 (d, J = 5.3 Hz, 1H) , 8.18 (s, 1H) , 7.87 (s, 1H) , 7.79 (s, 1H) , 7.68 (s, 1H) , 7.66 –7.49 (m, 1H) , 7.15 (s, 1H) , 6.97 –6.88 (m, 2H) , 6.75 (s, 1H) , 4.00 (s, 3H) , 3.92 (s, 1H) , 3.91 (s, 1H) , 3.80 (s, 3H) , 2.16 –2.08 (m, 1H) , 0.86 (d, J = 6.7 Hz, 6H) .
Example 95.
Compound 95: 7-Methoxy-4- ( (3-Methoxy-5- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) quinoline-6-carboxamide: To an oven dried seal tube with a magnetic bar was filled with 1, 4-dioaxne : H2O (4: 1) mixture. The solvent mixture was purged with argon at room temperature. To this purged solution, 4- ( (3-bromo-5-methoxyphenyl) amino) -7-methoxyquinoline-6-carboxamide (150 mg, 0.37 mmol, 1 equiv) , 1-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (85 mg, 0.41 mmol, 1.1 equiv) , Pd (P (C6H5) 3) 4 (11 mg, 2.5 mol%) and K2CO3 (129 mg, 0.93 mmol, 2.5 equiv) were added. The reaction mixture was degassed with argon (the sequence was carried out 2 times) and reaction tube was sealed with Teflon screw cap. The reaction mixture was subsequently stirred in a preheated oil bath at 110 ℃ for 16 h. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate (50 mL) and washed with water (3×20 mL) &brine (3×20 mL, ) . The organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude residue was purified by flash column chromatography to afford the product as yellow solid (62 mg, yield =41 %) .
TLC Rf = 0.2 (6 %MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) δ 9.23 (s, 1H) , 8.83 (s, 1H) , 8.43 (d, J = 5.3 Hz, 1H) , 8.15 (s, 1H) , 7.85 (s, 1H) , 7.79 (s, 1H) , 7.68 (brs, 1H) , 7.35 (s, 1H) , 7.14 (s, 1H) , 6.94 (d, J = 5.3 Hz, 1H) , 6.90 (s, 1H) , 6.76 (brs, 1H) , 4.00 (s, 3H) , 3.85 (s, 3H) , 3.80 (s, 3H) .
Example 96.
Compound 96: 7-Methoxy-4- ( (3-Methoxy-5- (1-methyl-1H-pyrazol-5-yl) phenyl) amino) quinoline-6-carboxamide: To an oven dried seal tube with a magnetic bar was filled with 1, 4-dioaxne : H2O (4: 1) mixture. The solvent mixture was purged with argon at room
temperature. To this purged solution, 4- ( (3-bromo-5-methoxyphenyl) amino) -7-methoxyquinoline-6-carboxamide (100 mg, 0.24 mmol, 1 equiv) , 1-methyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (46 mg, 0.37 mmol, 1.5 equiv) , Pd (dppf) Cl2 (11 mg, 6 mol%) and K2CO3 (103 mg, 0.74 mmol, 3 equiv) were added. The reaction mixture was degassed with argon (the sequence was carried out 2 times) and reaction tube was sealed with Teflon screw cap. The reaction mixture was subsequently stirred in a preheated oil bath at 105 ℃ for 14 h. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate (30 mL) and washed with water (3×20 mL) &brine (3×20 mL, ) . The organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude residue was purified by flash column chromatography to afford the product as yellow solid (45 mg, yield = 45 %) .
TLC Rf = 0.2 (10 %MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H) , 8.80 (s, 1H) , 8.47 (d, J = 5.0 Hz, 1H) , 7.80 (s, 1H) , 7.69 (s, 1H) , 7.46 (s, 1H) , 7.37 (s, 1H) , 7.07 (s, 1H) , 7.04 (d, J = 5.1 Hz, 1H) , 6.99 (s, 1H) , 6.81 (s, 1H) , 6.44 (s, 1H) , 4.00 (s, 3H) , 3.90 (s, 3H) , 3.83 (s, 3H) .
Example 97.
Compound 97: 7-Methoxy-4- ( (3-Methoxy-5- (1H-pyrazol-3-yl) phenyl) amino) quinoline-6-carboxamide: To an oven dried seal tube with a magnetic bar was filled with 1, 4-dioaxne : H2O (4: 1) mixture. The solvent mixture was purged with argon at room temperature. To this purged solution, 4- ( (3-bromo-5-methoxyphenyl) amino) -7-methoxyquinoline-6-carboxamide (150 mg, 0.37 mmol, 1 equiv) , 3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (80 mg, 0.41 mmol, 1.1 equiv) , Pd (P (C6H5) 3) 4 (11 mg, 2.5 mol%) and K2CO3 (129 mg, 0.93 mmol, 2.5 equiv) were added. The reaction mixture was degassed with argon (the sequence was carried out 2 times) and reaction tube was sealed with Teflon screw cap. The reaction mixture was subsequently stirred in a preheated oil bath at 110 ℃ for 16 h. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate (50 mL) and washed with water (3×20 mL) &brine (3×20 mL, ) . The organic phase was dried over anhydrous Na2SO4, and
concentrated under reduced pressure to obtain the crude. The crude residue was purified by flash column chromatography to afford the product as yellow solid (42 mg, yield = 29 %) .
TLC Rf = 0.2 (7 %MeOH/DCM)
1H NMR (400 MHz, DMSO-d6) δ 9.28 (s, 1H) , 8.83 (s, 1H) , 8.45 (d, J = 5.0 Hz, 1H) , 7.79 (s, 1H) , 7.68 (s, 1H) , 7.64 –7.58 (m, 1H) , 7.57 –7.49 (m, 1H) , 7.43 (brs, 1H) , 7.36 (s, 1H) , 7.13 (s, 1H) , 6.97 (d, J = 5.2 Hz, 1H) , 6.86 (brs, 1H) , 6.72 (brs, 1H) , 4.00 (s, 3H) , 3.82 (s, 3H) .
Example 98.
N- (3-Methyl-5- (1H-pyrazol-1-yl) phenyl) quinolin-4-amine: 4-Chloroquinoline (79 mg, 0.48 mmol, 1.0 equiv) , 3-methyl-5- (1H-pyrazol-1-yl) aniline (83 mg, 0.48 mmol, 1.0 equiv) and PPTS (36 mg, 0.14 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (143 mg, yield = 99%) , purity = 98.13%) .
TLC Rf = 0.4 (DCM/MeOH=20/1) ;
MS (ESI+) : m/z = 301.60 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.04 (s, 1H) , 8.45 (d, J = 5.3 Hz, 1H) , 8.42 (dd, J = 2.5, 0.6 Hz, 1H) , 8.38 –8.31 (m, 1H) , 7.84 (dd, J = 8.5, 1.3 Hz, 1H) , 7.67 (dd, J = 1.7, 0.5 Hz, 1H) , 7.65 –7.61 (m, 2H) , 7.48 (ddd, J = 8.3, 6.8, 1.3 Hz, 1H) , 7.37 (ddd, J = 2.1, 1.4, 0.8 Hz, 1H) , 7.07 (ddd, J = 2.1, 1.4, 0.8 Hz, 1H) , 7.01 (d, J = 5.3 Hz, 1H) , 6.47 (dd, J = 2.5, 1.7 Hz, 1H) , 2.35 –2.31 (m, 3H) .
Example 99.
6-Chloro-N- (3-methyl-5- (1H-pyrazol-1-yl) phenyl) quinolin-4-amine 4, 6-Dichloroquinoline (95 mg, 0.48 mmol, 1.2 equiv) , 3-methyl-5- (1H-pyrazol-1-yl) aniline (69 mg, 0.40 mmol, 1.0 equiv) and PPTS (30 mg, 0.12 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (132 mg, yield = 99%) , purity = 100%) .
TLC Rf = 0.45 (DCM/MeOH=20/1) ;
MS (ESI+) : m/z =335.50 (M+H) ;
1H NMR (600 MHz, DMSO-d6) : δ 9.14 (s, 1H) , 8.55 (d, J = 2.3 Hz, 1H) , 8.53 (d, J = 5.3 Hz, 1H) , 8.50 (d, J = 2.5 Hz, 1H) , 7.92 (d, J = 9.0 Hz, 1H) , 7.75 (d, J = 1.7 Hz, 1H) , 7.72 (dd, J = 9.0, 2.3 Hz, 1H) , 7.68 (d, J = 2.1 Hz, 1H) , 7.46 (d, J = 2.0 Hz, 1H) , 7.14 (s, 1H) , 7.12 (d, J = 5.3 Hz, 1H) , 6.57 –6.53 (m, 1H) , 2.41 (s, 3H) .
Example 100.
6-Bromo-N- (3-methyl-5- (1H-pyrazol-1-yl) phenyl) quinolin-4-amine: 6-Bromo-4-chloroquinoline (116.4 mg, 0.48 mmol, 1.2 equiv) , 3-methyl-5- (1H-pyrazol-1-yl) aniline (69 mg, 0.40 mmol, 1.0 equiv) and PPTS (30 mg, 0.12 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction
mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (143 mg, yield = 94.3%, purity = 100%) .
TLC Rf = 0.45 (DCM/MeOH=20/1) ;
MS (ESI+) : m/z = 381.00 (M+H) ;
1H NMR (600 MHz, DMSO-d6) : δ 9.16 (s, 1H) , 8.82 –8.64 (m, 1H) , 8.54 (d, J = 5.3 Hz, 1H) , 8.50 (d, J = 2.5 Hz, 1H) , 7.87 –7.81 (m, 2H) , 7.75 (d, J = 1.7 Hz, 1H) , 7.68 (t, J = 2.1 Hz, 1H) , 7.46 (t, J = 1.4 Hz, 1H) , 7.14 (s, 1H) , 7.12 (d, J = 5.3 Hz, 1H) , 6.55 (dd, J = 2.5, 1.7 Hz, 1H) , 2.41 (s, 3H) .
Example 101.
6-Iodo-N- (3-methyl-5- (1H-pyrazol-1-yl) phenyl) quinolin-4-amine: 4-Chloro-6-iodoquinoline (139 mg, 0.48 mmol, 1.2 equiv) , 3-methyl-5- (1H-pyrazol-1-yl) aniline (69 mg, 0.40 mmol, 1.0 equiv) and PPTS (30 mg, 0.12 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (168 mg, yield = 99%) , purity = 100%) .
TLC Rf = 0.45 (DCM/MeOH=20/1) ;
MS (ESI+) : m/z = 427.60 (M+H) ;
1H NMR (600 MHz, DMSO-d6) : δ 9.16 (s, 1H) , 8.85 (d, J = 1.9 Hz, 1H) , 8.52 (d, J = 5.3 Hz, 1H) , 8.51 –8.47 (m, 1H) , 7.96 (dd, J = 8.8, 1.9 Hz, 1H) , 7.75 (d, J = 1.9 Hz, 1H) , 7.69 –7.65 (m, 2H) , 7.48 –7.41 (m, 1H) , 7.13 (s, 1H) , 7.10 (d, J = 5.3 Hz, 1H) , 6.55 (dd, J = 2.5, 1.7 Hz, 1H) , 2.41 (s, 3H) .
Example 102.
N- (3-Methyl-5- (1H-pyrazol-1-yl) phenyl) -6- (trifluoromethyl) quinolin-4-amine: 4-Chloro-6- (trifluoromethyl) quinoline (92.64 mg, 0.40 mmol, 1.0 equiv) , 3-methyl-5- (1H-pyrazol-1-yl) aniline (83 mg, 0.48 mmol, 1.0 equiv) and PPTS (30 mg, 0.12 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (112 mg, yield = 76%, purity = 100%) .
TLC Rf = 0.4 (DCM/MeOH=20/1) ;
MS (ESI+) : m/z = 369.60 (M+H) ;
1H NMR (600 MHz, DMSO-d6) : δ 9.44 (s, 1H) , 8.92 (s, 1H) , 8.63 (d, J = 5.4 Hz, 1H) , 8.52 (d, J = 2.5 Hz, 1H) , 8.07 (d, J = 8.9 Hz, 1H) , 7.95 (dd, J = 8.8, 2.0 Hz, 1H) , 7.75 (d, J = 1.7 Hz, 1H) , 7.71 (s, 1H) , 7.50 (s, 1H) , 7.17 (s, 1H) , 7.15 (d, J = 5.4 Hz, 1H) , 6.55 (t, J = 2.1 Hz, 1H) , 2.42 (s, 3H) .
Example 103.
6-Methoxy-N- (3-methyl-5- (1H-pyrazol-1-yl) phenyl) quinolin-4-amine: 4-chloro-6-methoxyquinoline (93 mg, 0.48 mmol, 1.0 equiv) , 3-methyl-5- (1H-pyrazol-1-yl) aniline (83 mg, 0.48 mmol, 1.0 equiv) and PPTS (36 mg, 0.14 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was
evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (157 mg, yield = 99%) , purity = 98.13%) .
TLC Rf = 0.4 (DCM/MeOH=20/1) ;
MS (ESI+) : m/z = 331.70 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 8.90 (s, 1H) , 8.51 (dd, J = 2.6, 0.6 Hz, 1H) , 8.40 (d, J = 5.2 Hz, 1H) , 7.83 (d, J = 9.1 Hz, 1H) , 7.75 (dt, J = 1.7, 0.9 Hz, 2H) , 7.68 (t, J = 2.3 Hz, 1H) , 7.43 (tt, J = 1.5, 0.8 Hz, 1H) , 7.37 (dd, J = 9.1, 2.6 Hz, 1H) , 7.13 (ddd, J = 2.2, 1.4, 0.8 Hz, 1H) , 7.07 (d, J = 5.2 Hz, 1H) , 6.55 (dd, J = 2.5, 1.7 Hz, 1H) , 3.95 (s, 3H) , 2.41 (s, 3H) .
Example 104.
6, 7-Dimethoxy-N- (3-methyl-5- (1H-pyrazol-1-yl) phenyl) quinolin-4-amine: 4-Chloro-6, 7-dimethoxyquinoline (107 mg, 0.48 mmol, 1.0 equiv) , 3-methyl-5- (1H-pyrazol-1-yl) aniline (83 mg, 0.48 mmol, 1.0 equiv) and PPTS (36 mg, 0.14 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (98 mg, yield = 56.8%, purity = 100%) .
TLC Rf = 0.4 (DCM/MeOH=20/1) ;
MS (ESI+) : m/z = 361.60 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 8.94 (s, 1H) , 8.50 (dd, J = 2.6, 0.6 Hz, 1H) , 8.35 (d, J = 5.4 Hz, 1H) , 7.75 (d, J = 1.7 Hz, 1H) , 7.71 (s, 1H) , 7.66 (t, J = 2.1 Hz, 1H) , 7.45 –7.41 (m, 1H) , 7.29 (s, 1H) , 7.14 –7.09 (m, 1H) , 6.98 (d, J = 5.4 Hz, 1H) , 6.55 (dd, J = 2.5, 1.7 Hz, 1H) , 3.96 (s, 3H) ,
3.93 (s, 3H) , 2.41 (s, 3H) .
Example 105.
7-Methoxy-4- ( (3-methyl-5- (1H-pyrazol-1-yl) phenyl) amino) quinoline-6-carboxamide: 4-Chloro-7-methoxyquinoline-6-carboxamide (95 mg, 0.40 mmol, 1.0 equiv ) , 3-methyl-5- (1H-pyrazol-1-yl) aniline (83 mg, 0.48 mmol, 1.2 equiv) and PPTS (30 mg, 0.12 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (143 mg, yield = 95.4%, purity = 100%) .
TLC Rf = 0.2 (DCM/MeOH=10/1) ;
MS (ESI+) : m/z = 374.70 (M+H) ;
1H NMR (600 MHz, DMSO-d6) : δ 9.38 (s, 1H) , 8.49 –8.44 (m, 1H) , , 8.48 (s, 1H) , 7.88 –7.77 (m, 1H) , 7.74 (d, J = 1.7 Hz, 1H) , 7.65 –7.70 (m, , 2H) , 7.44 –7.41 (m, 1H) , 7.37 (s, 1H) , 7.14 (d, J = 2.1 Hz, 1H) , 6.98 (d, J = 5.4 Hz, 1H) , 6.54 (dd, J = 2.5, 1.7 Hz, 1H) , 4.01 (s, 3H) , 2.40 (s, 3H) .
Example 106.
6-Bromo-7-methoxy-N- (3-methyl-5- (1H-pyrazol-1-yl) phenyl) quinolin-4-amine: 6-Bromo-4-chloro-7-methoxyquinoline (131 mg, 0.48 mmol, 1.0 equiv) , 3-methyl-5- (1H-pyrazol-1-yl) aniline (83 mg, 0.48 mmol, 1.0 equiv) and PPTS (36 mg, 0.14 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction
vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (187 mg, yield = 95.1%, purity = 97.22%) .
TLC Rf = 0.4 (DCM/MeOH=20/1) ;
MS (ESI+) : m/z = 411.30 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.13 (s, 1H) , 8.73 (s, 1H) , 8.49 (dd, J = 2.6, 0.6 Hz, 1H) , 8.47 (d, J = 5.4 Hz, 1H) , 7.75 (dd, J = 1.7, 0.6 Hz, 1H) , 7.68 –7.63 (m, 1H) , 7.44 (ddd, J = 2.0, 1.4, 0.8 Hz, 1H) , 7.40 (s, 1H) , 7.12 (ddd, J = 2.1, 1.4, 0.8 Hz, 1H) , 7.00 (d, J = 5.4 Hz, 1H) , 6.55 (dd, J =2.5, 1.8 Hz, 1H) , 4.00 (s, 3H) , 2.43 –2.38 (m, 3H) .
Example 107.
N- (3- (1H-Imidazol-1-yl) -5-methylphenyl) quinolin-4-amine: 4-Chloroquinoline (78.5 mg, 0.48 mmol, 1.2 equiv) , 3- (1H-imidazol-1-yl) -5-methylaniline (69 mg, 0.40 mmol, 1.0 equiv) and PPTS (30 mg, 0.12 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (113mg, yield = 94.2%, purity = 82.02%) .
TLC Rf = 0.35 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z = 301.40 (M+H)
Example 108.
N- (3- (1H-Imidazol-1-yl) -5-methylphenyl) -6-chloroquinolin-4-amine: 4, 6-Dichloroquinoline (95 mg, 0.48 mmol, 1.2 equiv) , 3- (1H-imidazol-1-yl) -5-methylaniline (69 mg, 0.4 mmol, 1.0 equiv) and PPTS (30 mg, 0.12 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (72 mg, yield = 53.8%, purity = 93.44%) .
TLC Rf = 0.3 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z = 335.50 (M+H) ;
1H NMR (600 MHz, DMSO-d6) : δ 9.14 (d, J = 11.8 Hz, 1H) , 8.67 (d, J = 1.8 Hz, 1H) , 8.56 –8.49 (m, 1H) , 8.25 (d, J = 1.2 Hz, 1H) , 7.84 (d, J = 1.8 Hz, 1H) , 7.74 (t, J = 1.3 Hz, 1H) , 7.41 (s, 1H) , 7.26 (s, 1H) , 7.19 (s, 1H) , 7.14 (d, J = 5.2 Hz, 1H) , 7.11 (t, J = 1.2 Hz, 1H) , 4.14 (q, J = 5.3 Hz, 1H) , 2.40 (s, 3H) .
Example 109.
N- (3- (1H-Imidazol-1-yl) -5-methylphenyl) -6-bromoquinolin-4-amine: 6-Bromo-4-chloroquinoline (116.4 mg, 0.48 mmol, 1.2 equiv) , 3- (1H-imidazol-1-yl) -5-methylaniline (69 mg, 0.4 mmol, 1.0 equiv) and PPTS (30 mg, 0.12 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was
heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (147 mg, yield = 93.5%, purity = 79.3%) .
TLC Rf = 0.5 (DCM/MeOH=20/1) ;
MS (ESI+) : m/z = 379.40 (M+H) .
Example 110.
N- (3- (1H-Imidazol-1-yl) -5-methylphenyl) -6-iodoquinolin-4-amine: 4-Chloro-6-iodoquinoline (139 mg, 0.48 mmol, 1.2 equiv) , 3- (1H-imidazol-1-yl) -5-methylaniline (69 mg, 0.4 mmol, 1.0 equiv) and PPTS (30 mg, 0.12 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (28 mg, yield = 16.4%, purity = 83.5%) .
TLC Rf = 0.2 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z = 427.40 (M+H) .
Example 111.
N- (3- (1H-Imidazol-1-yl) -5-methylphenyl) -6-methoxyquinolin-4-amine: 4-Chloro-6-methoxyquinoline (92.9 mg, 0.48 mmol, 1.2 equiv) , 3- (1H-imidazol-1-yl) -5-methylaniline (69 mg,
0.40 mmol, 1.0 equiv) and PPTS (30 mg, 0.12 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (121 mg, yield = 83.73%, purity = 83.73%) .
TLC Rf = 0.35 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z = 331.70 (M+H) .
Example 112.
N- (3- (1H-Imidazol-1-yl) -5-methylphenyl) -6- (trifluoromethyl) quinolin-4-amine: 4-Chloro-6- (trifluoromethyl) quinoline (111 mg, 0.48 mmol, 1.2 equiv) , 3- (1H-imidazol-1-yl) -5-methylaniline (69 mg, 0.40 mmol, 1.0 equiv) and PPTS (30 mg, 0.12 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (105 mg, yield = 71.2%, purity = 92.33%) .
TLC Rf = 0.4 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z = 369.50 (M+H) ;
1H NMR (600 MHz, DMSO-d6) : δ 9.51 (s, 1H) , 8.97 (d, J = 2.1 Hz, 1H) , 8.67 (d, J = 5.4 Hz, 1H) , 8.37 –8.31 (m, 1H) , 8.12 (d, J = 8.8 Hz, 1H) , 8.01 (dd, J = 8.8, 2.0 Hz, 1H) , 7.82 (t, J = 1.4 Hz, 1H) , 7.52 (t, J = 2.0 Hz, 1H) , 7.37 (t, J = 1.4 Hz, 1H) , 7.26 (s, 1H) , 7.21 (d, J = 5.4 Hz, 1H) , 7.17 (t, J = 1.2 Hz, 1H) , 2.47 (s, 3H) .
Example 113.
N- (3- (1H-Imidazol-1-yl) -5-methylphenyl) -6, 7-dimethoxyquinolin-4-amine: 4-Chloro-6,7-dimethoxyquinoline (107 mg, 0.48 mmol, 1.2 equiv) , 3- (1H-imidazol-1-yl) -5-methylaniline (69 mg, 0.40 mmol, 1.0 equiv) and PPTS (30 mg, 0.12 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (77 mg, yield = 53.4%, purity = 100%) .
TLC Rf = 0.35 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z = 361.60 (M+H) ;
1H NMR (600 MHz, DMSO-d6) : δ 9.04 (s, 1H) , 8.35 (d, J = 5.4 Hz, 1H) , 8.26 (t, J = 1.2 Hz, 1H) , 7.75 (t, J = 1.4 Hz, 1H) , 7.72 (s, 1H) , 7.41 (d, J = 2.1 Hz, 1H) , 7.29 (s, 1H) , 7.25 (t, J = 1.5 Hz, 1H) , 7.17 (d, J = 1.9 Hz, 1H) , 7.11 (t, J = 1.1 Hz, 1H) , 6.98 (d, J = 5.4 Hz, 1H) , 3.95 (s, 3H) , 3.93 (s, 3H) , 2.40 (s, 3H) .
Example 114.
4- ( (3- (1H-Imidazol-1-yl) -5-methylphenyl) amino) -7-methoxyquinoline-6-carboxamide: 4-Chloro-7-methoxyquinoline-6-carboxamide (95 mg, 0.40 mmol, 1.0 equiv) , 3-(1H-imidazol-1-yl) -5-methylaniline (83.4 mg, 0.48 mmol, 1.2 equiv) and PPTS (30 mg, 0.12 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected
with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (63 mg, yield = 42.7%, purity = 99.21%) .
TLC Rf = 0.2 (DCM/MeOH = 10/1) ;
MS (ESI+) : m/z = 374.70 (M+H) ;
1H NMR (600 MHz, DMSO-d6) : δ 9.30 (s, 1H) , 8.77 (s, 1H) , 8.40 (d, J = 5.4 Hz, 1H) , 8.17 (t, J = 1.2 Hz, 1H) , 7.78 –7.70 (m, 1H) , 7.65 (t, J = 1.4 Hz, 1H) , 7.63 –7.57 (m, 1H) , 7.33 (d, J = 2.1 Hz, 1H) , 7.30 (s, 1H) , 7.16 (d, J = 1.8 Hz, 1H) , 7.12 (d, J = 2.0 Hz, 1H) , 7.03 (d, J = 1.2 Hz, 1H) , 6.93 (d, J = 5.4 Hz, 1H) , 3.94 (s, 3H) , 2.32 (s, 3H) .
Example 115.
N- (3- (1H-Imidazol-1-yl) -5-methylphenyl) -6-bromo-7-methoxyquinolin-4-amine: 6-Bromo-4-chloro-7-methoxyquinoline (130.8 mg, 0.48 mmol, 1.2 equiv) , 3- (1H-imidazol-1-yl) -5-methylaniline (69 mg, 0.4 mmol, 1.0 equiv) and PPTS (30 mg, 0.12 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (91 mg, yield = 55.6%, purity = 92.5%) .
TLC Rf = 0.3 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z = 411.30 (M+H) ;
1H NMR (600 MHz, DMSO-d6) : δ 9.20 (s, 1H) , 8.73 (s, 1H) , 8.47 (d, J = 5.4 Hz, 1H) , 8.25 (t, J = 1.1 Hz, 1H) , 7.74 (t, J = 1.4 Hz, 1H) , 7.41 (s, 1H) , 7.40 (s, 1H) , 7.26 (t, J = 1.4 Hz, 1H) , 7.17 (d,
J = 2.0 Hz, 1H) , 7.11 (d, J = 1.1 Hz, 1H) , 7.01 (d, J = 5.4 Hz, 1H) , 4.00 (s, 3H) , 2.40 (s, 3H) .
Example 116.
N- (3-Methyl-5- (1H-1, 2, 4-triazol-1-yl) phenyl) quinolin-4-amine: 4-Chloroquinoline (65 mg, 0.4 mmol, 1.0 equiv) , 3-methyl-5- (1H-1, 2, 4-triazol-1-yl) aniline (69.6 mg, 0.4 mmol, 1.0 equiv) and PPTS (30 mg, 0.012 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (118 mg, yield = 99%) , purity = 98.37%) .
TLC Rf = 0.3 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z = 302.40 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.35 (s, 1H) , 9.22 (s, 1H) , 8.59 (d, J = 5.3 Hz, 1H) , 8.45 (dd, J = 8.5, 1.3 Hz, 1H) , 8.29 (s, 1H) , 7.97 (dd, J = 8.4, 1.3 Hz, 1H) , 7.78 (ddd, J = 8.3, 6.8, 1.3 Hz, 1H) , 7.75 –7.71 (m, 1H) , 7.62 (ddd, J = 8.3, 6.8, 1.3 Hz, 1H) , 7.56 –7.49 (m, 1H) , 7.33 –7.27 (m, 1H) , 7.17 (d, J = 5.3 Hz, 1H) , 2.47 (s, 3H) .
Example 117.
6-Methoxy-N- (3-methyl-5- (1H-1, 2, 4-triazol-1-yl) phenyl) quinolin-4-amine: 4-Chloro-6-methoxyquinoline (77.6 mg, 0.4 mmol, 1.0 equiv) , 3-methyl-5- (1H-1, 2, 4-triazol-1-yl) aniline (69.6 mg, 0.4 mmol, 1.0 equiv) and PPTS (30 mg, 0.012 mmol, 0.3 equiv) were added to a round-
bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (120.7 mg, yield = 91.2%, purity = 99.23%) .
TLC Rf = 0.4 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z = 332.60 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.31 (s, 1H) , 9.04 (s, 1H) , 8.42 (d, J = 5.3 Hz, 1H) , 8.24 (s, 1H) , 7.84 (d, J = 9.1 Hz, 1H) , 7.76 (d, J = 2.7 Hz, 1H) , 7.68 (t, J = 2.1 Hz, 1H) , 7.52 –7.45 (m, 1H) , 7.39 (dd, J = 9.2, 2.7 Hz, 1H) , 7.26 –7.22 (m, 1H) , 7.11 (d, J = 5.3 Hz, 1H) , 3.95 (s, 3H) , 2.43 (s, 3H) .
Example 118.
6-Iodo-N- (3-methyl-5- (1H-1, 2, 4-triazol-1-yl) phenyl) quinolin-4-amine: 4-Chloro-6-iodoquinoline (115 mg, 0.4 mmol, 1.0 equiv) , 3-methyl-5- (1H-1, 2, 4-triazol-1-yl) aniline (69.6 mg, 0.4 mmol, 1.0 equiv) and PPTS (30 mg, 0.012 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (160 mg, yield = 95%) , purity = 94.75%) .
TLC Rf = 0.40 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z = 428.30 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.36 (s, 1H) , 9.31 (s, 1H) , 8.90 (d, J = 1.9 Hz, 1H) , 8.59 (d, J = 5.3 Hz, 1H) , 8.30 (s, 1H) , 8.03 (dd, J = 8.9, 1.9 Hz, 1H) , 7.79 –7.69 (m, 2H) , 7.58 –7.51 (m,
1H) , 7.33 –7.27 (m, 1H) , 7.19 (d, J = 5.4 Hz, 1H) , 2.48 (s, 3H) .
Example 119.
6, 7-Dimethoxy-N- (3-methyl-5- (1H-1, 2, 4-triazol-1-yl) phenyl) quinolin-4-amine: 4-Chloro-6, 7-dimethoxyquinoline (89 mg, 0.4 mmol, 1.0 equiv) , 3-methyl-5- (1H-1, 2, 4-triazol-1-yl) aniline (69.6 mg, 0.4 mmol, 1.0 equiv) and PPTS (30 mg, 0.12 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (105.4 mg, yield = 73%, purity = 98.46%) .
TLC Rf = 0.3 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z =362.50 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.31 (s, 1H) , 9.13 (s, 1H) , 8.37 (d, J = 5.5 Hz, 1H) , 8.24 (s, 1H) , 7.73 (s, 1H) , 7.67 (t, J = 2.1 Hz, 1H) , 7.54 –7.45 (m, 1H) , 7.30 (s, 1H) , 7.25 –7.21 (m, 1H) , 7.01 (d, J = 5.5 Hz, 1H) , 3.96 (s, 3H) , 3.93 (s, 3H) , 2.42 (s, 3H) .
Example 120.
7-Methoxy-4- ( (3-methyl-5- (1H-1, 2, 4-triazol-1-yl) phenyl) amino) quinoline-6-carboxamide: 4-Chloro-7-methoxyquinoline-6-carboxamide (94 mg, 0.4 mmol, 1.0 equiv) , 3-methyl-5- (1H-1, 2, 4-triazol-1-yl) aniline (69.6 mg, 0.4 mmol, 1.0 equiv) and PPTS (30 mg, 0.012 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was
added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (143 mg, yield =96.12%, purity = 94.39%) .
TLC Rf = 0.50 (DCM/MeOH = 10/1) ;
MS (ESI+) : m/z = 375.40 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.42 (s, 1H) , 9.29 (s, 1H) , 8.84 (s, 1H) , 8.49 (d, J = 5.4 Hz, 1H) , 8.24 (s, 1H) , 7.86 –7.77 (m, 1H) , 7.69 (d, J = 2.2 Hz, 1H) , 7.68 (t, J = 2.1 Hz, 1H) , 7.47 –7.43 (m, 1H) , 7.38 (s, 1H) , 7.24 (d, J = 2.0 Hz, 1H) , 7.02 (d, J = 5.4 Hz, 1H) , 4.01 (s, 3H) , 2.41 (s, 3H) .
Example 121.
6-Bromo-7-methoxy-N- (3-methyl-5- (1H-1, 2, 4-triazol-1-yl) phenyl) quinolin-4-amine: 6-Bromo-4-chloro-7-methoxyquinoline (109 mg, 0.4 mmol, 1.0 equiv) , 3-methyl-5- (1H-1, 2, 4-triazol-1-yl) aniline (69.6 mg, 0.4 mmol, 1.0 equiv) and PPTS (30 mg, 0.012 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (162 mg, yield = 99%) , purity = 92.67%) .
TLC Rf = 0.15 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z = 412.20 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.35 (s, 1H) , 9.25 (s, 1H) , 8.78 (s, 1H) , 8.54 (d, J = 5.4 Hz, 1H) , 8.29 (s, 1H) , 7.71 (d, J = 2.1 Hz, 1H) , 7.57 –7.50 (m, 1H) , 7.47 (s, 1H) , 7.32 –7.25 (m, 1H) ,
7.09 (d, J = 5.4 Hz, 1H) , 4.06 (s, 3H) , 2.47 (s, 3H) .
Example 122.
N- (3, 5-Dimethoxyphenyl) quinolin-4-amine: 4-Chloroquinoline (81.8 mg, 0.5 mmol, 1.0 equiv) , 3, 5-dimethoxyaniline (76.5 mg, 0.5 mmol, 1.0 equiv) and PPTS (37.7 mg, 0.15 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (93 mg, yield = 66.4%, purity =88.98%) .
TLC Rf = 0.25 (PE/EA=2/1) ;
MS (ESI+) : m/z = 281.4 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 8.94 (s, 1H) , 8.50 (d, J = 5.3 Hz, 1H) , 8.36 (dd, J = 8.5, 1.4 Hz, 1H) , 7.89 (d, J = 8.4 Hz, 1H) , 7.70 (ddd, J = 8.3, 6.7, 1.3 Hz, 1H) , 7.57 –7.53 (m, 1H) , 7.08 (d, J = 5.3 Hz, 1H) , 6.55 (d, J = 2.2 Hz, 2H) , 6.29 (t, J = 2.2 Hz, 1H) , 3.76 (s, 6H) .
Example 123.
N- (3, 5-Dimethoxyphenyl) -6- (trifluoromethyl) quinolin-4-amine: 4, 6-Dichloroquinoline (118 mg, 0.6 mmol, 1.2 equiv) , 3, 5-dimethoxyaniline (76 mg, 0.5 mmol, 1.0 equiv) and PPTS (37.7 mg, 0.15 mmol, 0.3 equiv) were added to a round-bottom flask with a
magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (97 mg, yield = 61.6%, purity = 99.35%) .
TLC Rf = 0.25 (PE/EA= 4/1) ;
MS (ESI+) : m/z = 315.40 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 8.98 (s, 1H) , 8.51 (d, J = 5.3 Hz, 1H) , 8.49 (d, J = 2.4 Hz, 1H) , 7.90 (d, J = 8.9 Hz, 1H) , 7.71 (dd, J = 9.0, 2.3 Hz, 1H) , 7.12 (d, J = 5.3 Hz, 1H) , 6.54 (d, J = 2.2 Hz, 2H) , 6.31 (t, J = 2.2 Hz, 1H) , 3.76 (s, 6H) .
Example 124.
6-Bromo-N- (3, 5-dimethoxyphenyl) quinolin-4-amine: 6-Bromo-4-chloroquinoline (121 mg, 0.5 mmol, 1.0 equiv) , 3, 5-dimethoxyaniline (76.5 mg, 0.5 mmol, 1.0 equiv) and PPTS (37.7 mg, 0.15 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (25.8 mg, yield = 14.4%, purity = 96.52%) .
TLC Rf = 0.30 (PE/EA=2/1) ;
MS (ESI+) : m/z = 359.70 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.05 (s, 1H) , 8.69 (t, J = 1.4 Hz, 1H) , 8.56 (d, J = 5.3 Hz, 1H) , 7.87 (d, J = 1.3 Hz, 2H) , 7.16 (d, J = 5.3 Hz, 1H) , 6.58 (d, J = 2.2 Hz, 2H) , 6.35 (t, J = 2.2 Hz, 1H) , 3.81 (s, 6H) .
Example 125.
N- (3, 5-Dimethoxyphenyl) -6-iodoquinolin-4-amine: 4-Chloro-6-iodoquinoline (144.5 mg, 0.5 mmol, 1.0 equiv) , 3, 5-dimethoxyaniline (76.5 mg, 0.5 mmol, 1.0 equiv) and PPTS (37.7 mg, 0.15 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (184.4 mg, yield = 90.8%, purity = 97.82%) .
TLC Rf = 0.20 (PE/EA=2/1) ;
MS (ESI+) : m/z = 407.40 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 8.99 (s, 1H) , 8.79 (d, J = 1.9 Hz, 1H) , 8.50 (d, J = 5.3 Hz, 1H) , 7.95 (dd, J = 8.9, 1.9 Hz, 1H) , 7.66 (d, J = 8.8 Hz, 1H) , 7.10 (d, J = 5.3 Hz, 1H) , 6.53 (d, J = 2.3 Hz, 2H) , 6.30 (t, J = 2.2 Hz, 1H) , 3.76 (s, 6H) .
Example 126.
N- (3, 5-Dimethoxyphenyl) -6- (trifluoromethyl) quinolin-4-amine: 4-Chloro-6- (trifluoromethyl) quinoline (139 mg, 0.6 mmol, 1.2 equiv) , 3, 5-dimethoxyaniline (76 mg, 0.5 mmol, 1.0 equiv) and PPTS (37.7 mg, 0.15 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and
backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (145 mg, yield = 83.3%, purity = 98.49%) .
TLC Rf = 0.25 (PE/EA= 4/1) ;
MS (ESI+) : m/z = 349.50 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.28 (s, 1H) , 8.87 (s, 1H) , 8.60 (d, J = 5.4 Hz, 1H) , 8.05 (d, J = 8.8 Hz, 1H) , 7.93 (dd, J = 8.8, 1.9 Hz, 1H) , 7.14 (d, J = 5.4 Hz, 1H) , 6.56 (d, J = 2.2 Hz, 2H) , 6.35 (t, J = 2.2 Hz, 1H) , 3.77 (s, 6H) .
Example 127.
N- (3, 5-Dimethoxyphenyl) -6, 7-dimethoxyquinolin-4-amine: 4-Chloro-6, 7-dimethoxyquinoline (112 mg, 0.5 mmol, 1.0 equiv) , 3, 5-dimethoxyaniline (77 mg, 0.5 mmol, 1.0 equiv) and PPTS (37.7 mg, 0.15 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (170 mg, yield = 99%, purity = 97.76%) .
TLC Rf = 0.25 (DCM/MeOH = 40/1) ;
MS (ESI+) : m/z = 341.60 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.23 (s, 1H) , 8.33 (d, J = 5.8 Hz, 1H) , 7.78 (s, 1H) , 7.31 (s, 1H) , 6.94 (d, J = 5.8 Hz, 1H) , 6.54 (d, J = 2.2 Hz, 2H) , 6.35 (t, J = 2.2 Hz, 1H) , 3.96 (s, 3H) , 3.93 (s, 3H) , 3.77 (s, 6H) .
Example 128.
N- (2, 5-dimethoxyphenyl) -6-bromoquinolin-4-amine: 6-Bromo-4-chloroquinoline (145.5 mg, 0.6 mmol, 1.2 equiv) , 2, 5-dimethoxyaniline (76.5 mg, 0.5 mmol, 1.0 equiv) and PPTS (37.7 mg, 0.15 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (178 mg, yield = 99%, purity = 99.27%) .
TLC Rf = 0.2 (PE/EA=1/1) ;
MS (ESI+) : m/z = 359.50 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 8.75 (d, J = 1.8 Hz, 2H) , 8.45 (d, J = 5.3 Hz, 1H) , 7.86 –7.81 (m, 2H) , 7.15 (d, J = 8.9 Hz, 1H) , 6.97 –6.88 (m, 2H) , 6.36 (d, J = 5.3 Hz, 1H) , 3.78 (s, 3H) , 3.75 (s, 3H) .
Example 129.
N- (2, 5-Dimethoxyphenyl) -6-iodoquinolin-4-amine: 4-Chloro-6-iodoquinoline (174 mg, 0.6 mmol, 1.2 equiv) , 2, 5-dimethoxyaniline (76.5 mg, 0.5 mmol, 1.0 equiv) and PPTS (37.7 mg, 0.15 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was
purified by silica gel flash chromatography to afford the product as yellow solid (97 mg, yield =47.68%, purity = 99.35%) .
TLC Rf = 0.2 (PE/EA= 1/1) ;
MS (ESI+) : m/z = 407.30 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 8.90 (d, J = 2.0 Hz, 1H) , 8.76 (s, 1H) , 8.43 (d, J = 5.4 Hz, 1H) , 7.96 (dd, J = 8.8, 1.9 Hz, 1H) , 7.67 (d, J = 8.8 Hz, 1H) , 7.14 (d, J = 8.9 Hz, 1H) , 6.94 (d, J = 3.0 Hz, 1H) , 6.91 (dd, J = 8.9, 3.1 Hz, 1H) , 6.34 (d, J = 5.3 Hz, 1H) , 3.78 (s, 3H) , 3.75 (s, 3H) .
Example 130.
N- (3, 5-Dimethoxyphenyl) -6- (1-methyl-1H-pyrazol-4-yl) quinolin-4-amine: 6-Bromo-N- (3, 5-dimethoxyphenyl) quinolin-4-amine (179 mg, 0.5 mmol, 1.0 equiv) , 1-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (156 mg, 0.75 mmol, 1.5 equiv) , Pd (dppf) Cl2 (18.23 mg, 0.025 mmol, 0.05 equiv) and K2CO3 (228 mg, 1.65 mmol, 3.3 equiv) were added to a round-bottom flask with a magnetic bar, then 4 mL dioxane and 0.5 mL water were added as solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 90 ℃ for 8 h with vigorous stirring. The cooled solution was diluted with 120 mL ethyl acetate and washed with brine. The organic phase was dried over anhydrous Na2SO4, and concentrated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (149 mg, yield = 82.78%, purity =98.67%) .
TLC Rf = 0.23 (DCM/MeOH=20/1) ;
MS (ESI+) : m/z = 361.60 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 8.98 (s, 1H) , 8.56 (d, J = 1.8 Hz, 1H) , 8.42 (d, J = 5.3 Hz, 1H) , 8.27 (s, 1H) , 8.06 (d, J = 0.8 Hz, 1H) , 7.94 (dd, J = 8.7, 1.8 Hz, 1H) , 7.86 (d, J = 8.7 Hz, 1H) , 7.04 (d, J = 5.4 Hz, 1H) , 6.57 (d, J = 2.2 Hz, 2H) , 6.33 (t, J = 2.2 Hz, 1H) , 3.92 (s, 3H) , 3.78 (s, 6H) .
Example 131.
2- (3- ( (6-Iodoquinolin-4-yl) amino) -5-methoxyphenoxy) -N-methylacetamide: 4-Chloroquinoline (82 mg, 0.5 mmol, 1.0 equiv) , 2- (3-amino-5-methoxyphenoxy) -N-methylacetamide (105 mg, 0.5 mmol, 1.0 equiv) and PPTS (37.7 mg, 0.15 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (157.9 mg, yield = 93.7%, purity = 96.52%) .
TLC Rf = 0.38 (DCM/MeOH=10/1) ;
MS (ESI+) : m/z = 338.70 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.02 (s, 1H) , 8.44 (d, J = 5.4 Hz, 1H) , 8.31 (dd, J = 8.6, 1.3 Hz, 1H) , 7.98 (q, J = 4.7 Hz, 1H) , 7.83 (dd, J = 8.5, 1.3 Hz, 1H) , 7.66 (ddd, J = 8.4, 6.8, 1.3 Hz, 1H) , 7.49 (ddd, J = 8.3, 6.8, 1.4 Hz, 1H) , 7.01 (d, J = 5.4 Hz, 1H) , 6.52 (t, J = 2.0 Hz, 1H) , 6.51 (t, J = 2.0 Hz, 1H) , 6.27 (t, J = 2.2 Hz, 1H) , 4.40 (s, 2H) , 3.69 (s, 3H) , 2.60 (d, J = 4.7 Hz, 3H) .
Example 132.
2- (3- ( (6-Bromoquinolin-4-yl) amino) -5-methoxyphenoxy) -N-methylacetamide: 6-Bromo-4-chloroquinoline (121 mg, 0.5 mmol, 1.0 equiv) , 2- (3-amino-5-methoxyphenoxy) -N-methylacetamide (105 mg, 0.5 mmol, 1.0 equiv) and PPTS (37.7 mg, 0.15 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The
reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (4.3mg, yield = 2%) .
TLC Rf = 0.20 (PE/EA=1/8) .
Example 133.
2- (3- ( (6-Iodoquinolin-4-yl) amino) -5-methoxyphenoxy) -N-methylacetamide: 4-Chloro-6-iodoquinoline (144 mg, 0.5 mmol, 1.0 equiv) , 2- (3-amino-5-methoxyphenoxy) -N-methylacetamide (105 mg, 0.5 mmol, 1.0 equiv) and PPTS (37.7 mg, 0.15 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (183.6 mg, yield = 79%, purity = 90.53%) .
TLC Rf = 0.30 (PE/EA=1/8) ;
MS (ESI+) : m/z = 464.50 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.03 (s, 1H) , 8.79 (d, J = 1.9 Hz, 1H) , 8.51 (d, J = 5.3 Hz, 1H) , 8.04 (q, J = 4.7 Hz, 1H) , 7.95 (dd, J = 8.8, 1.8 Hz, 1H) , 7.66 (d, J = 8.8 Hz, 1H) , 7.10 (d, J = 5.3 Hz, 1H) , 6.56 (dt, J = 9.7, 1.9 Hz, 2H) , 6.34 (t, J = 2.2 Hz, 1H) , 4.47 (s, 2H) , 3.76 (s, 3H) , 2.67 (d, J = 4.6 Hz, 3H) .
Example 134.
2- (3- ( (6, 7-Dimethoxyquinolin-4-yl) amino) -5-methoxyphenoxy) -N-methylacetamide: 4-Chloro-6, 7-dimethoxyquinoline (112 mg, 0.5 mmol, 1.0 equiv) , 2- (3-amino-5-methoxyphenoxy) -N-methylacetamide (105 mg, 0.5 mmol, 1.0 equiv) and PPTS (37.7 mg, 0.15 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (131.4 mg, yield = 66.2%, purity = 95.97%) .
TLC Rf = 0.35 (DCM/MeOH=10/1) ;
MS (ESI+) : m/z = 398.50 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 8.89 (s, 1H) , 8.33 (d, J = 5.5 Hz, 1H) , 8.05 (q, J = 4.7 Hz, 1H) , 7.67 (s, 1H) , 7.28 (s, 1H) , 6.96 (d, J = 5.5 Hz, 1H) , 6.56 (t, J = 2.0 Hz, 1H) , 6.53 (t, J = 2.0 Hz, 1H) , 6.34 (t, J = 2.2 Hz, 1H) , 4.47 (s, 2H) , 3.95 (s, 3H) , 3.92 (s, 3H) , 3.77 (s, 3H) , 2.67 (d, J = 4.7 Hz, 3H) .
Example 135.
3-Methoxy-5- (quinolin-4-ylamino) phenol: 4-Chloroquinoline (82 mg, 0.5 mmol, 1.0 equiv) , 3-amino-5-methoxyphenol (111 mg, 0.8 mmol, 1.6 equiv) and PPTS (37.7 mg, 0.15 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added
as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (46.4 mg, yield = 34.85%, purity = 94.05%) .
TLC Rf = 0.2 (PE/EA=1/4) ;
MS (ESI+) : m/z = 267.40 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.49 (s, 1H) , 8.75 (s, 1H) , 8.41 (d, J = 5.3 Hz, 1H) , 8.28 (dd, J = 8.6, 1.4 Hz, 1H) , 7.80 (dd, J = 8.5, 1.3 Hz, 1H) , 7.62 (ddd, J = 8.3, 6.8, 1.3 Hz, 1H) , 7.45 (ddd, J = 8.3, 6.8, 1.4 Hz, 1H) , 6.97 (d, J = 5.3 Hz, 1H) , 6.35 (t, J = 1.9 Hz, 1H) , 6.32 (t, J = 2.1 Hz, 1H) , 6.06 (t, J = 2.2 Hz, 1H) , 3.64 (s, 3H) .
Example 136.
3- ( (6-Chloroquinolin-4-yl) amino) -5-methoxyphenol: 6-Chloro-N- (3-methoxy-5- (2, 2, 2-trifluoroethoxy) phenyl) quinolin-4-amine (98 mg, 0.5 mmol, 1.0 equiv) , 3-amino-5-methoxyphenol (111 mg, 0.8 mmol, 1.6 equiv) and PPTS (37.7 mg, 0.15 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (54.8 mg, yield = 36.5%, purity = 97.7 %) .
TLC Rf = 0.2 (PE/EA=1/1) ;
MS (ESI+) : m/z = 301.40 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.62 (s, 1H) , 8.95 (s, 1H) , 8.55 (d, J = 3.1 Hz, 1H) , 8.54 (s,
1H) , 7.94 (d, J = 9.0 Hz, 1H) , 7.75 (dd, J = 9.0, 2.3 Hz, 1H) , 7.13 (d, J = 5.3 Hz, 1H) , 6.46 (t, J =2.0 Hz, 1H) , 6.43 (t, J = 2.1 Hz, 1H) , 6.20 (t, J = 2.1 Hz, 1H) , 3.77 (s, 3H) .
Example 137.
3- ( (6-Bromoquinolin-4-yl) amino) -5-methoxyphenol: 6-Bromo-4-chloroquinoline (121 mg, 0.5 mmol, 1.0 equiv) , 3-amino-5-methoxyphenol (111 mg, 0.8 mmol, 1.6 equiv) and PPTS (37.7 mg, 0.15 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (23.9 mg, yield = 13.8%, purity = 100%) .
TLC Rf = 0.2 (PE/EA=1/1) ;
MS (ESI+) : m/z = 345.50 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.50 (s, 1H) , 8.86 (s, 1H) , 8.57 (t, J = 1.4 Hz, 1H) , 8.44 (d, J = 5.3 Hz, 1H) , 7.74 (d, J = 1.2 Hz, 2H) , 7.00 (d, J = 5.3 Hz, 1H) , 6.34 (t, J = 2.0 Hz, 1H) , 6.31 (t, J = 2.1 Hz, 1H) , 6.08 (t, J = 2.2 Hz, 1H) , 3.65 (s, 3H) .
Example 138.
6-Bromo-N- (3-methoxy-5- ( (1-methylpyrrolidin-3-yl) oxy) phenyl) quinolin-4-amine: 6-Bromo-4-chloroquinoline (145.5 mg, 0.6 mmol, 1.2 equiv) , 3-methoxy-5- ( (1-methylpyrrolidin-3-
yl) oxy) aniline (113.7 mg, 0.5 mmol, 1.0 equiv) and PPTS (62.8 mg, 0.25 mmol, 0.5 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (164 mg, yield = 76.6%, purity = 97.36%) .
TLC Rf = 0.2 (DCM/MeOH = 10/1) ;
MS (ESI+) : m/z = 428.40 (M+H) ;
Example 139.
6-Chloro-N- (3-methoxy-5- ( (1-methylpyrrolidin-3-yl) oxy) phenyl) quinolin-4-amine: 4, 6-Dichloroquinoline (95 mg, 0.48 mmol, 1.2 equiv) , 3-methoxy-5- ( (1-methylpyrrolidin-3-yl) oxy) aniline (88.8 mg, 0.4 mmol, 1.0 equiv) and PPTS (30 mg, 0.12 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (104 mg, yield = 67.7%, purity = 92.99%) .
TLC Rf = 0.4 (DCM/MeOH = 10/1) ;
MS (ESI+) : m/z = 384.50 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 8.99 (s, 1H) , 8.52 (d, J = 5.3 Hz, 1H) , 8.49 (d, J = 2.3 Hz, 1H) , 7.90 (d, J = 9.0 Hz, 1H) , 7.71 (dd, J = 9.0, 2.3 Hz, 1H) , 7.11 (d, J = 5.3 Hz, 1H) , 6.53 (t, J = 2.0 Hz, 1H) , 6.48 (t, J = 2.0 Hz, 1H) , 6.24 (t, J = 2.2 Hz, 1H) , 4.90 (ddt, J = 8.1, 5.6, 2.7 Hz, 1H) , 3.75 (s, 3H) , 2.91 (dd, J = 10.8, 5.9 Hz, 1H) , 2.88 –2.72 (m, 2H) , 2.61 –2.51 (m, 1H) , 2.37 (s, 3H) ,
2.35 –2.24 (m, 1H) , 1.90 –1.79 (m, 1H) .
Example 140.
N- (3-Methoxy-5- ( (1-methylpyrrolidin-3-yl) oxy) phenyl) -6- (trifluoromethyl) quinolin-4-amine (LC44) : 4-Chloro-6- (trifluoromethyl) quinoline (111.2 mg, 0.48 mmol, 1.2 equiv) , 3-methoxy-5- ( (1-methylpyrrolidin-3-yl) oxy) aniline (88.8 mg, 0.4 mmol, 1.0 equiv) and PPTS (30 mg, 0.12 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (162 mg, yield = 97%, purity = 98.3%) .
TLC Rf = 0.4 (DCM/MeOH = 10/1) ;
MS (ESI+) : m/z = 418.60 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.20 (s, 1H) , 8.84 –8.74 (m, 1H) , 8.53 (d, J = 5.4 Hz, 1H) , 7.98 (d, J = 8.8 Hz, 1H) , 7.86 (dd, J = 8.9, 2.0 Hz, 1H) , 7.05 (d, J = 5.4 Hz, 1H) , 6.47 (t, J = 2.0 Hz, 1H) , 6.41 (t, J = 2.0 Hz, 1H) , 6.20 (t, J = 2.2 Hz, 1H) , 4.89 –4.74 (m, 1H) , 3.69 (s, 3H) , 2.75 (dd, J = 10.5, 6.0 Hz, 1H) , 2.71 –2.57 (m, 2H) , 2.35 (td, J = 8.8, 8.3, 6.4 Hz, 1H) , 2.28 –2.16 (m, 1H) , 2.24 (s, 3H) , 1.76 (dddd, J = 11.0, 7.5, 5.6, 3.0 Hz, 1H) .
Example 141.
N- (3-Methoxy-5- ( (tetrahydrofuran-3-yl) oxy) phenyl) quinolin-4-amine: 4-Chloroquinoline (78.5 mg, 0.48 mmol, 1.2 equiv) , 3-methoxy-5- ( (tetrahydrofuran-3-yl) oxy) aniline (84 mg, 0.4 mmol, 1.0 equiv) and PPTS (30 mg, 0.12 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (110 mg, yield = 81.8%, purity = 99.6%) .
TLC Rf = 0.15 (PE/EA= 1/10) ;
MS (ESI+) : m/z = 337.60 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 8.84 (s, 1H) , 8.43 (d, J = 5.3 Hz, 1H) , 8.27 (dd, J = 8.5, 1.4 Hz, 1H) , 7.82 (dd, J = 8.5, 1.3 Hz, 1H) , 7.63 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H) , 7.47 (ddd, J = 8.3, 6.8, 1.3 Hz, 1H) , 7.01 (d, J = 5.3 Hz, 1H) , 6.47 (t, J = 2.0 Hz, 1H) , 6.43 (t, J = 2.0 Hz, 1H) , 6.19 (t, J = 2.2 Hz, 1H) , 4.94 (ddt, J = 6.4, 4.3, 1.8 Hz, 1H) , 3.84 –3.71 (m, 3H) , 3.71 –3.64 (m, 1H) , 3.68 (s, 3H) , 2.14 (dtd, J = 13.3, 8.2, 6.2 Hz, 1H) , 1.97 –1.87 (m, 1H) .
Example 142.
6-Chloro-N- (3-methoxy-5- ( (tetrahydrofuran-3-yl) oxy) phenyl) quinolin-4-amine: 4, 6-Dichloroquinoline (95 mg, 0.48 mmol, 1.2 equiv) , 3-methoxy-5- ( (tetrahydrofuran-3-yl) oxy) aniline (84 mg, 0.4 mmol, 1.0 equiv) and PPTS (30 mg, 0.12 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (118 mg, yield = 79.6%, purity = 99.6%) .
TLC Rf = 0.25 (PE/EA= 1/2) ;
MS (ESI+) : m/z = 371.60 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.02 (s, 1H) , 8.56 (d, J = 5.3 Hz, 1H) , 8.53 (d, J = 2.3 Hz, 1H) , 7.95 (d, J = 9.0 Hz, 1H) , 7.76 (dd, J = 9.0, 2.3 Hz, 1H) , 7.15 (d, J = 5.3 Hz, 1H) , 6.58 (t, J = 2.0 Hz, 1H) , 6.54 (t, J = 2.0 Hz, 1H) , 6.32 (t, J = 2.2 Hz, 1H) , 5.06 (ddt, J = 6.3, 4.1, 1.8 Hz, 1H) , 3.96 –3.83 (m, 3H) , 3.83 –3.76 (m, 1H) , 3.80 (s, 3H) , 2.26 (dtd, J = 13.3, 8.2, 6.2 Hz, 1H) , 2.10 –2.00 (m, 1H) .
Example 143.
6-Bromo-N- (3-methoxy-5- ( (tetrahydrofuran-3-yl) oxy) phenyl) quinolin-4-amine: 6-Bromo-4-chloroquinoline (116.4 mg, 0.48 mmol, 1.2 equiv) , 3-methoxy-5- ( (tetrahydrofuran-3-yl) oxy) aniline (84 mg, 0.4 mmol, 1.0 equiv) and PPTS (30 mg, 0.12 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (137 mg, yield = 82.5%, purity = 98.72%) .
TLC Rf = 0.25 (PE/EA= 1/2) ;
MS (ESI+) : m/z = 415.70 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 8.92 (s, 1H) , 8.56 (t, J = 1.3 Hz, 1H) , 8.45 (d, J = 5.3 Hz, 1H) , 7.75 (d, J = 1.2 Hz, 2H) , 7.03 (d, J = 5.3 Hz, 1H) , 6.46 (t, J = 2.0 Hz, 1H) , 6.42 (t, J = 2.0 Hz, 1H) , 6.20 (t, J = 2.2 Hz, 1H) , 4.95 (ddt, J = 6.3, 4.1, 1.8 Hz, 1H) , 3.84 –3.72 (m, 3H) , 3.71 –3.65 (m, 1H) , 3.69 (s, 3H) , 2.14 (dtd, J = 13.4, 8.2, 6.2 Hz, 1H) , 1.97 –1.88 (m, 1H) .
Example 144.
6-Iodo-N- (3-methoxy-5- ( (tetrahydrofuran-3-yl) oxy) phenyl) quinolin-4-amine: 4-Chloro-6-iodoquinoline (139 mg, 0.48 mmol, 1.2 equiv) , 3-methoxy-5- ( (tetrahydrofuran-3-yl) oxy) aniline (84 mg, 0.4 mmol, 1.0 equiv) and PPTS (30 mg, 0.12 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (162 mg, yield = 87.7%, purity = 98.3%) .
TLC Rf = 0.35 (PE/EA= 1/4) ;
MS (ESI+) : m/z =463.40 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 8.99 (s, 1H) , 8.78 (d, J = 1.9 Hz, 1H) , 8.51 (d, J = 5.3 Hz, 1H) , 7.95 (dd, J = 8.8, 1.9 Hz, 1H) , 7.66 (d, J = 8.8 Hz, 1H) , 7.08 (d, J = 5.3 Hz, 1H) , 6.53 (t, J = 2.0 Hz, 1H) , 6.49 (t, J = 2.0 Hz, 1H) , 6.27 (t, J = 2.2 Hz, 1H) , 5.02 (ddt, J = 6.4, 4.3, 1.8 Hz, 1H) , 3.91 –3.79 (m, 3H) , 3.78 –3.72 (m, 1H) , 3.76 (s, 3H) , 2.22 (dtd, J = 13.3, 8.2, 6.2 Hz, 1H) , 2.04 –1.95 (m, 1H) .
Example 145.
6-Methoxy-N- (3-methoxy-5- ( (tetrahydrofuran-3-yl) oxy) phenyl) quinolin-4-amine: 4-Chloro-6-methoxyquinoline (92 mg, 0.48 mmol, 1.2 equiv) , 3-methoxy-5- ( (tetrahydrofuran-3-yl) oxy) aniline (84 mg, 0.4 mmol, 1.0 equiv) and PPTS (30 mg, 0.12 mmol, 0.3 equiv) were added
to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (93 mg, yield = 63.5%, purity = 100%) .
TLC Rf = 0.15 (PE/EA= 1/10) ;
MS (ESI+) : m/z = 367.70 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 8.75 (s, 1H) , 8.43 (d, J = 5.2 Hz, 1H) , 7.85 (d, J = 9.1 Hz, 1H) , 7.73 (d, J = 2.8 Hz, 1H) , 7.39 (dd, J = 9.1, 2.7 Hz, 1H) , 7.10 (d, J = 5.2 Hz, 1H) , 6.56 (t, J = 2.0 Hz, 1H) , 6.53 (t, J = 2.0 Hz, 1H) , 6.30 (t, J = 2.2 Hz, 1H) , 5.06 (td, J = 4.4, 2.1 Hz, 1H) , 3.98 (s, 3H) , 3.95 –3.83 (m, 3H) , 3.83 –3.76 (m, 1H) , 3.80 (s, 3H) , 2.25 (dtd, J = 13.3, 8.2, 6.2 Hz, 1H) , 2.09 –1.99 (m, 1H) .
Example 146.
N- (3-Methoxy-5- ( (tetrahydrofuran-3-yl) oxy) phenyl) -6- (trifluoromethyl) quinolin-4-amine: 4-Chloro-6- (trifluoromethyl) quinoline (111.2 mg, 0.48 mmol, 1.2 equiv) , 3-methoxy-5- ( (tetrahydrofuran-3-yl) oxy) aniline (84 mg, 0.4 mmol, 1.0 equiv) and PPTS (30 mg, 0.12 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (133 mg, yield = 82.2%, purity = 98.13%) .
TLC Rf = 0.25 (PE/EA= 1/2) ;
MS (ESI+) : m/z = 405.70 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.33 (s, 1H) , 8.91 (s, 1H) , 8.66 (d, J = 5.4 Hz, 1H) , 8.11 (d, J = 8.8 Hz, 1H) , 7.99 (dd, J = 8.9, 1.9 Hz, 1H) , 7.18 (d, J = 5.4 Hz, 1H) , 6.61 (t, J = 2.0 Hz, 1H) , 6.58 (t, J = 2.1 Hz, 1H) , 6.37 (t, J = 2.2 Hz, 1H) , 5.09 (ddt, J = 6.3, 4.2, 1.8 Hz, 1H) , 3.97 –3.84 (m, 3H) , 3.84 –3.78 (m, 1H) , 3.82 (s, 3H) , 2.37 –2.19 (m, 1H) , 2.11 –1.99 (m, 1H) .
Example 147.
6, 7-Dimethoxy-N- (3-methoxy-5- ( (tetrahydrofuran-3-yl) oxy) phenyl) quinolin-4-amine: 4-Chloro-6, 7-dimethoxyquinoline (107 mg, 0.48 mmol, 1.2 equiv) , 3-methoxy-5- ( (tetrahydrofuran-3-yl) oxy) aniline (84 mg, 0.4 mmol, 1.0 equiv) and PPTS (30 mg, 0.12 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (158 mg, yield = 99%, purity = 99.7%) .
TLC Rf = 0.4 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z =397.60 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.04 (s, 1H) , 8.33 (d, J = 5.6 Hz, 1H) , 7.72 (s, 1H) , 7.29 (s, 1H) , 6.94 (d, J = 5.6 Hz, 1H) , 6.53 (t, J = 2.0 Hz, 1H) , 6.50 (t, J = 2.0 Hz, 1H) , 6.29 (t, J = 2.2 Hz, 1H) , 5.03 (ddt, J = 6.4, 4.2, 1.9 Hz, 1H) , 3.95 (s, 3H) , 3.93 (s, 3H) , 3.91 –3.79 (m, 3H) , 3.78 –3.72 (m, 1H) , 3.76 (s, 3H) , 2.21 (dtd, J = 13.4, 8.2, 6.3 Hz, 1H) , 2.06 –1.94 (m, 1H) .
Example 148.
7-Methoxy-4- ( (3-methoxy-5- ( (tetrahydrofuran-3-yl) oxy) phenyl) amino) quinoline-6-carboxamide: 4-Chloro-7-methoxyquinoline-6-carboxamide (95 mg, 0.4 mmol, 1.0 equiv) , 3-methoxy-5- ( (tetrahydrofuran-3-yl) oxy) aniline (100 mg, 0.48 mmol, 1.2 equiv) and PPTS (30 mg, 0.12 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (157 mg, yield =96.0%, purity = 99.89%) .
TLC Rf = 0.3 (DCM/MeOH = 10/1) ;
MS (ESI+) : m/z = 410.80 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.19 (s, 1H) , 8.80 (s, 1H) , 8.46 (d, J = 5.4 Hz, 1H) , 7.92 –7.74 (m, 1H) , 7.69 (s, 1H) , 7.36 (s, 1H) , 6.99 (d, J = 5.5 Hz, 1H) , 6.55 (t, J = 2.0 Hz, 1H) , 6.51 (t, J =2.0 Hz, 1H) , 6.25 (t, J = 2.2 Hz, 1H) , 5.00 (td, J = 4.5, 2.2 Hz, 1H) , 4.00 (s, 3H) , 3.91 –3.79 (m, 3H) , 3.78 –3.72 (m, 1H) , 3.75 (s, 3H) , 2.21 (dtd, J = 13.3, 8.2, 6.2 Hz, 1H) , 2.05 –1.93 (m, 1H) .
Example 149.
6-Bromo-7-methoxy-N- (3-methoxy-5- ( (tetrahydrofuran-3-yl) oxy) phenyl) quinolin-4-amine: 6-Bromo-4-chloro-7-methoxyquinoline (130 mg, 0.48 mmol, 1.2 equiv) , 3-methoxy-5- ( (tetrahydrofuran-3-yl) oxy) aniline (84 mg, 0.4 mmol, 1.0 equiv) and PPTS (30 mg, 0.12 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by
silica gel flash chromatography to afford the product as yellow solid (110 mg, yield = 61.6%, purity = 91.23%) .
TLC Rf = 0.25 (PE/EA= 1/2) ;
MS (ESI+) : m/z = 447.50 (M+H) ;
1H NMR (600 MHz, DMSO-d6) : δ 8.95 (s, 1H) , 8.66 (s, 1H) , 8.46 (d, J = 5.4 Hz, 1H) , 7.39 (s, 1H) , 6.98 (d, J = 5.3 Hz, 1H) , 6.52 (t, J = 2.0 Hz, 1H) , 6.48 (t, J = 2.0 Hz, 1H) , 6.26 (t, J = 2.2 Hz, 1H) , 5.01 (ddt, J = 6.4, 4.1, 1.8 Hz, 1H) , 3.99 (s, 3H) , 3.87 (d, J = 4.5 Hz, 1H) , 3.84 (dd, J = 8.2, 7.0 Hz, 1H) , 3.81 (dt, J = 10.1, 1.3 Hz, 1H) , 3.78 –3.73 (m, 1H) , 3.75 (s, 3H) , 2.21 (dtd, J = 13.4, 8.2, 6.2 Hz, 1H) , 2.03 –1.96 (m, 1H) .
Example 150.
6-Chloro-N- (3-methoxy-5- ( (tetrahydrofuran-2-yl) methoxy) phenyl) quinolin-4-amine: 4, 6-Dichloroquinoline (98 mg, 0.5 mmol, 1.0 equiv) , 3-methoxy-5- ( (tetrahydrofuran-2-yl) methoxy) aniline (112 mg, 0.5 mmol, 1.0 equiv) and PPTS (37.7 mg, 0.15 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (193 mg, yield = 99%, purity = 98.65%) .
TLC Rf = 0.20 (PE/EA=1/1) ;
MS (ESI+) : m/z = 385.60 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 8.89 (s, 1H) , 8.44 (d, J = 5.3 Hz, 1H) , 8.42 (d, J = 2.3 Hz, 1H) , 7.83 (d, J = 9.0 Hz, 1H) , 7.63 (dd, J = 8.9, 2.3 Hz, 1H) , 7.04 (d, J = 5.3 Hz, 1H) , 6.49 –6.44 (m, 2H) , 6.24 (t, J = 2.2 Hz, 1H) , 4.08 (qd, J = 6.8, 4.0 Hz, 1H) , 3.87 (qd, J = 10.2, 5.1 Hz, 2H) , 3.76 –3.70 (m, 1H) , 3.69 (s, 3H) , 3.64 –3.57 (m, 1H) , 2.03 –1.85 (m, 1H) , 1.87 –1.68 (m, 2H) , 1.59
(ddt, J = 11.8, 8.5, 6.8 Hz, 1H) .
Example 151.
6-Bromo-N- (3-methoxy-5- ( (tetrahydrofuran-2-yl) methoxy) phenyl) quinolin-4-amine: 6-Bromo-4-chloroquinoline (121 mg, 0.5 mmol, 1.0 equiv) , 3-methoxy-5- ( (tetrahydrofuran-2-yl) methoxy) aniline (112 mg, 0.5 mmol, 1.0 equiv) and PPTS (37.7 mg, 0.15 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (209.4 mg, yield = 97.85%, purity = 98.96%) .
TLC Rf = 0.20 (PE/EA=1/1) ;
MS (ESI+) : m/z = 429.50 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.03 (s, 1H) , 8.68 (t, J = 1.3 Hz, 1H) , 8.57 (d, J = 5.3 Hz, 1H) , 7.86 (d, J = 1.4 Hz, 2H) , 7.15 (d, J = 5.3 Hz, 1H) , 6.57 (t, J = 2.2 Hz, 2H) , 6.36 (t, J = 2.2 Hz, 1H) , 4.20 (qd, J = 6.8, 4.0 Hz, 1H) , 3.98 (qd, J = 10.2, 5.2 Hz, 2H) , 3.84 (dd, J = 8.1, 6.6 Hz, 1H) , 3.81 (s, 3H) , 3.73 (td, J = 7.7, 6.2 Hz, 1H) , 2.10 –1.99 (m, 1H) , 1.99 –1.80 (m, 2H) , 1.71 (ddt, J = 11.8, 8.5, 6.9 Hz, 1H) .
Example 152.
6-Iodo-N- (3-methoxy-5- ( (tetrahydrofuran-2-yl) methoxy) phenyl) quinolin-4-amine: 4-Chloro-6-iodoquinoline (144 mg, 0.5 mmol, 1.0 equiv) , 3-methoxy-5- ( (tetrahydrofuran-2-yl) methoxy) aniline (112 mg, 0.5 mmol, 1.0 equiv) and PPTS (37.7 mg, 0.15 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (241 mg, yield = 99%, purity = 96.68%) .
TLC Rf = 0.20 (PE/EA=1/1) ;
MS (ESI+) : m/z = 477.60 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 8.98 (s, 1H) , 8.79 (d, J = 1.9 Hz, 1H) , 8.50 (d, J = 5.3 Hz, 1H) , 7.94 (dd, J = 8.8, 1.9 Hz, 1H) , 7.66 (d, J = 8.8 Hz, 1H) , 7.09 (d, J = 5.3 Hz, 1H) , 6.55 –6.50 (m, 2H) , 6.30 (t, J = 2.2 Hz, 1H) , 4.15 (qd, J = 6.8, 4.0 Hz, 1H) , 3.93 (qd, J = 10.2, 5.2 Hz, 2H) , 3.83 –3.77 (m, 1H) , 3.76 (s, 3H) , 3.68 (ddd, J = 8.2, 7.3, 6.1 Hz, 1H) , 2.10 –1.95 (m, 1H) , 1.94 –1.76 (m, 2H) , 1.66 (ddt, J = 11.8, 8.5, 6.8 Hz, 1H) .
Example 153.
N- (3-Methoxy-5- ( (tetrahydrofuran-2-yl) methoxy) phenyl) -6- (trifluoromethyl) quinolin-4-amine: 4-Chloro-6- (trifluoromethyl) quinoline (116 mg, 0.5 mmol, 1.0 equiv) , 3-methoxy-5- ( (tetrahydrofuran-2-yl) methoxy) aniline (112 mg, 0.5 mmol, 1.0 equiv) and PPTS (37.7 mg, 0.15 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in
vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (224.7 mg, yield = 99%, purity = 98.94%) .
TLC Rf = 0.20 (PE/EA=1/1) ;
MS (ESI+) : m/z = 419.70 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.26 (s, 1H) , 8.87 (s, 1H) , 8.61 (d, J = 5.4 Hz, 1H) , 8.05 (d, J = 8.8 Hz, 1H) , 7.94 (dd, J = 8.9, 1.9 Hz, 1H) , 7.14 (d, J = 5.4 Hz, 1H) , 6.62 –6.50 (m, 2H) , 6.35 (t, J = 2.2 Hz, 1H) , 4.16 (qd, J = 6.8, 4.0 Hz, 1H) , 3.95 (qd, J = 10.2, 5.2 Hz, 2H) , 3.83 –3.78 (m, 1H) , 3.77 (s, 3H) , 3.68 (td, J = 7.7, 6.2 Hz, 1H) , 2.05 –1.95 (m, 1H) , 1.95 –1.77 (m, 2H) , 1.67 (ddt, J = 11.8, 8.5, 6.8 Hz, 1H) .
Example 154.
7-Methoxy-4- ( (3-methoxy-5- ( (tetrahydrofuran-2-yl) methoxy) phenyl) amino) quinoline-6-carboxamide: 4-Chloro-7-methoxyquinoline-6-carboxamide (118 mg, 0.5 mmol, 1.0 equiv) , 3-methoxy-5- ( (tetrahydrofuran-2-yl) methoxy) aniline (112 mg, 0.5 mmol, 1.0 equiv) and PPTS (37.7 mg, 0.15 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (92.6 mg, yield = 43.78%, purity = 99.35%) .
TLC Rf = 0.20 (DCM/MeOH=20/1) ;
MS (ESI+) : m/z = 425.00 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.26 (s, 1H) , 8.81 (s, 1H) , 8.46 (d, J = 5.5 Hz, 1H) , 7.88 –7.75 (m, 1H) , 7.69 (s, 1H) , 7.36 (s, 1H) , 6.98 (d, J = 5.5 Hz, 1H) , 6.66 –6.47 (m, 2H) , 6.29 (t, J = 2.2 Hz, 1H) , 4.15 (qd, J = 6.8, 4.0 Hz, 1H) , 4.00 (s, 3H) , 3.93 (qd, J = 10.2, 5.2 Hz, 2H) , 3.83 –3.76
(m, 1H) , 3.75 (s, 3H) , 3.68 (td, J = 7.7, 6.2 Hz, 1H) , 2.06 –1.94 (m, 1H) , 1.94 –1.75 (m, 2H) , 1.66 (ddt, J = 11.8, 8.5, 6.8 Hz, 1H) .
Example 155.
N- (3-Methoxy-5- ( (tetrahydrofuran-3-yl) methoxy) phenyl) quinolin-4-amine: 4-Chloroquinoline (82 mg, 0.5 mmol, 1.0 equiv) , 3-methoxy-5- ( (tetrahydrofuran-3-yl) methoxy) aniline (112 mg, 0.5 mmol, 1.0 equiv) and PPTS (37.7 mg, 0.15 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (173 mg, yield = 99%) , purity = 97.5%) .
TLC Rf = 0.25 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z = 351.60 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 8.93 (s, 1H) , 8.50 (d, J = 5.3 Hz, 1H) , 8.36 (dd, J = 8.6, 1.4 Hz, 1H) , 7.89 (dd, J = 8.5, 1.3 Hz, 1H) , 7.71 (ddd, J = 8.4, 6.8, 1.3 Hz, 1H) , 7.54 (ddd, J = 8.3, 6.8, 1.4 Hz, 1H) , 7.08 (d, J = 5.3 Hz, 1H) , 6.55 (d, J = 2.2 Hz, 2H) , 6.31 (t, J = 2.2 Hz, 1H) , 3.98 –3.85 (m, 2H) , 3.83 –3.73 (m, 2H) , 3.76 (s, 3H) , 3.66 (td, J = 7.9, 6.8 Hz, 1H) , 3.54 (dd, J = 8.6, 5.5 Hz, 1H) , 2.72 –2.58 (m, 1H) , 2.02 (dtd, J = 14.0, 7.6, 5.6 Hz, 1H) , 1.65 (dddd, J = 12.4, 7.8, 6.7, 5.8 Hz, 1H) .
Example 156.
6-Chloro-N- (3-methoxy-5- ( (tetrahydrofuran-3-yl) methoxy) phenyl) quinolin-4-amine: 4, 6-Dichloroquinoline (99 mg, 0.5 mmol, 1.0 equiv) , 3-methoxy-5- ( (tetrahydrofuran-3-yl) methoxy) aniline (112 mg, 0.5 mmol, 1.0 equiv) and PPTS (37.7 mg, 0.15 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (120, yield = 62.5%, purity = 98.31%) .
TLC Rf = 0.15 (PE/EA= 1/1) ;
MS (ESI+) : m/z = 385.6 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 8.96 (s, 1H) , 8.52 (d, J = 5.3 Hz, 1H) , 8.50 (d, J = 2.3 Hz, 1H) , 7.91 (d, J = 8.9 Hz, 1H) , 7.71 (dd, J = 9.0, 2.3 Hz, 1H) , 7.12 (d, J = 5.3 Hz, 1H) , 6.54 (d, J = 2.2 Hz, 2H) , 6.32 (t, J = 2.2 Hz, 1H) , 4.01 –3.85 (m, 2H) , 3.83 –3.74 (m, 2H) , 3.77 (s, 3H) , 3.66 (td, J = 8.0, 6.9 Hz, 1H) , 3.55 (dd, J = 8.6, 5.5 Hz, 1H) , 2.73 –2.59 (m, 1H) , 2.03 (dddd, J = 12.5, 8.5, 7.6, 5.6 Hz, 1H) , 1.66 (dddd, J = 12.5, 7.8, 6.7, 5.8 Hz, 1H) .
Example 157.
6-Bromo-N- (3-methoxy-5- ( (tetrahydrofuran-3-yl) methoxy) phenyl) quinolin-4-amine: 6-Bromo-4-chloroquinoline (183 mg, 0.75 mmol, 1.0 equiv) , 3-methoxy-5- ( (tetrahydrofuran-3-yl) methoxy) aniline (168 mg, 0.75 mmol, 1.0 equiv) and PPTS (56.5 mg, 0.223 mmol, 0.3 equiv)
were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (30 mg, yield = 9.32%, purity = 97.34%) .
TLC Rf = 0.3 (PE/EA=1/2) ;
MS (ESI+) : m/z = 431.60 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 8.91 (s, 1H) , 8.56 (t, J = 1.4 Hz, 1H) , 8.45 (d, J = 5.3 Hz, 1H) , 7.74 (d, J = 1.7 Hz, 2H) , 7.03 (d, J = 5.3 Hz, 1H) , 6.46 (dt, J = 2.6, 1.2 Hz, 2H) , 6.24 (t, J = 2.2 Hz, 1H) , 3.90 –3.77 (m, 2H) , 3.77 –3.65 (m, 2H) , 3.69 (s, 3H) , 3.62 –3.55 (m, 1H) , 3.47 (dd, J = 8.6, 5.5 Hz, 1H) , 2.65 –2.52 (m, 1H) , 2.00 –1.89 (m, 1H) , 1.58 (dddd, J = 12.4, 7.9, 6.8, 5.8 Hz, 1H) .
Example 158.
6-Iodo-N- (3-methoxy-5- ( (tetrahydrofuran-3-yl) methoxy) phenyl) quinolin-4-amine: 4-Chloro-6-iodoquinoline (145 mg, 0.5 mmol, 1.0 equiv) , 3-methoxy-5- ( (tetrahydrofuran-3-yl) methoxy) aniline (112 mg, 0.5 mmol, 1.0 equiv) and PPTS (37.7 mg, 0.15 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (210 mg, yield = 88.18%, purity = 91.92%) .
TLC Rf = 0.15 (PE/EA= 1/1) ;
MS (ESI+) : m/z = 477.40 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 8.98 (s, 1H) , 8.79 (d, J = 1.9 Hz, 1H) , 8.50 (d, J = 5.3 Hz, 1H) , 7.95 (dd, J = 8.8, 1.9 Hz, 1H) , 7.65 (d, J = 8.8 Hz, 1H) , 7.09 (d, J = 5.3 Hz, 1H) , 6.53 (d, J = 2.2 Hz, 2H) , 6.31 (t, J = 2.2 Hz, 1H) , 3.98 –3.85 (m, 2H) , 3.82 –3.73 (m, 2H) , 3.76 (s, 3H) , 3.66 (td, J = 8.0, 6.8 Hz, 1H) , 3.54 (dd, J = 8.6, 5.5 Hz, 1H) , 2.65 (p, J = 6.5 Hz, 1H) , 2.07 –1.97 (m, 1H) , 1.73 –1.58 (m, 1H) .
Example 159.
N- (3-Methoxy-5- ( (tetrahydrofuran-3-yl) methoxy) phenyl) -6- (trifluoromethyl) quinolin-4-amine: 4-Chloro-6- (trifluoromethyl) quinoline (116 mg, 0.5 mmol, 1.0 equiv) , 3-methoxy-5- ( (tetrahydrofuran-3-yl) methoxy) aniline (112 mg, 0.5 mmol, 1.0 equiv) and PPTS (37.7 mg, 0.15 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (207 mg, yield = 99%) , purity = 98.12%) .
TLC Rf = 0.2 (PE/EA=1/1) ;
MS (ESI+) : m/z = 419.70 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.31 (s, 1H) , 8.91 (s, 1H) , 8.65 (d, J = 5.4 Hz, 1H) , 8.10 (d, J = 8.8 Hz, 1H) , 7.98 (dd, J = 8.9, 1.9 Hz, 1H) , 7.18 (d, J = 5.4 Hz, 1H) , 6.68 –6.54 (m, 2H) , 6.40 (t, J = 2.2 Hz, 1H) , 4.03 –3.90 (m, 2H) , 3.87 –3.78 (m, 2H) , 3.82 (s, 3H) , 3.70 (td, J = 8.0, 6.8 Hz, 1H) , 3.59 (dd, J = 8.6, 5.5 Hz, 1H) , 2.77 –2.64 (m, 1H) , 2.13 –2.01 (m, 1H) , 1.70 (dddd, J =12.5, 7.8, 6.7, 5.8 Hz, 1H) .
Example 160.
6-Methoxy-N- (3-methoxy-5- ( (tetrahydrofuran-3-yl) methoxy) phenyl) quinolin-4-amine: 4-Chloro-6-methoxyquinoline (97 mg, 0.5 mmol, 1.0 equiv) , 3-methoxy-5- ( (tetrahydrofuran-3-yl) methoxy) aniline (112 mg, 0.5 mmol, 1.0 equiv) and PPTS (37.7 mg, 0.15 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (280 mg, yield =99%, purity = 95.71%) .
TLC Rf = 0.2 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z = 381.70 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 8.76 (s, 1H) , 8.38 (d, J = 5.3 Hz, 1H) , 7.81 (d, J = 9.1 Hz, 1H) , 7.70 (d, J = 2.7 Hz, 1H) , 7.36 (dd, J = 9.1, 2.7 Hz, 1H) , 7.05 (d, J = 5.2 Hz, 1H) , 6.52 (d, J = 2.2 Hz, 2H) , 6.30 (t, J = 2.2 Hz, 1H) , 3.98 –3.85 (m, 2H) , 3.94 (s, 3H) , 3.83 –3.73 (m, 2H) , 3.76 (s, 3H) , 3.66 (td, J = 8.0, 6.7 Hz, 1H) , 3.54 (dd, J = 8.6, 5.5 Hz, 1H) , 2.75 –2.57 (m, 1H) , 2.02 (dddd, J = 14.0, 8.6, 7.5, 5.6 Hz, 1H) , 1.66 (dddd, J = 12.5, 7.9, 6.7, 5.8 Hz, 1H) .
Example 161.
6, 7-Dimethoxy-N- (3-methoxy-5- ( (tetrahydrofuran-3-yl) methoxy) phenyl) quinolin-4-amine: 4-Chloro-6, 7-dimethoxyquinoline (112 mg, 0.5 mmol, 1.0 equiv) , 3-methoxy-5-
( (tetrahydrofuran-3-yl) methoxy) aniline (112 mg, 0.5 mmol, 1.0 equiv) and PPTS (37.7 mg, 0.15 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (203 mg, yield =99%) , purity = 97.59%) .
TLC Rf = 0.5 (DCM/MeOH=20/1) ;
MS (ESI+) : m/z = 411.60 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 8.84 (s, 1H) , 8.33 (d, J = 5.4 Hz, 1H) , 7.67 (s, 1H) , 7.27 (s, 1H) , 6.96 (d, J = 5.5 Hz, 1H) , 6.51 (d, J = 2.1 Hz, 2H) , 6.30 (t, J = 2.2 Hz, 1H) , 3.98 –3.85 (m, 2H) , 3.95 (s, 3H) , 3.92 (s, 3H) , 3.82 –3.73 (m, 2H) , 3.76 (s, 3H) , 3.66 (td, J = 8.0, 6.8 Hz, 1H) , 3.54 (dd, J = 8.7, 5.5 Hz, 1H) , 2.74 –2.58 (m, 1H) , 2.11 –1.94 (m, 1H) , 1.65 (ddt, J = 12.5, 7.9, 6.8 Hz, 1H) .
Example 162.
7-Methoxy-4- ( (3-methoxy-5- ( (tetrahydrofuran-3-yl) methoxy) phenyl) amino) quinoline-6-carboxamide: 4-Chloro-7-methoxyquinoline-6-carboxamide (119 mg, 0.5 mmol, 1.0 equiv) , 3-methoxy-5- ( (tetrahydrofuran-3-yl) methoxy) aniline (112 mg, 0.5 mmol, 1.0 equiv) and PPTS (37.7 mg, 0.15 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (210 mg, yield = 99%) , purity = 97.64%) .
TLC Rf = 0.2 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z = 424.60 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.17 (s, 1H) , 8.73 (s, 1H) , 8.38 (d, J = 5.5 Hz, 1H) , 7.77 –7.67 (m, 1H) , 7.66 –7.55 (m, 1H) , 7.29 (s, 1H) , 6.91 (d, J = 5.4 Hz, 1H) , 6.50 –6.41 (m, 2H) , 6.22 (t, J = 2.2 Hz, 1H) , 3.93 (s, 3H) , 3.90 –3.76 (m, 2H) , 3.76 –3.64 (m, 2H) , 3.68 (s, 3H) , 3.58 (td, J =8.0, 6.9 Hz, 1H) , 3.46 (dd, J = 8.7, 5.5 Hz, 1H) , 2.58 (dt, J = 13.5, 6.5 Hz, 1H) , 1.95 (dtd, J = 12.6, 7.9, 5.6 Hz, 1H) , 1.58 (ddt, J = 12.5, 7.9, 6.7 Hz, 1H) .
Example 163.
N- (3-Methoxy-5- ( (tetrahydro-2H-pyran-4-yl) oxy) phenyl) quinolin-4-amine: 4-Chloro-quinoline (82 mg, 0.5 mmol, 1.0 equiv) , 3-methoxy-5- ( (tetrahydro-2H-pyran-4-yl) oxy) aniline (112 mg, 0.5 mmol, 1.0 equiv) and PPTS (37.7 mg, 0.15 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (140 mg, yield = 80%, purity = 96.55%) .
TLC Rf = 0.25 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z = 351.60 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 8.92 (s, 1H) , 8.50 (d, J = 5.3 Hz, 1H) , 8.35 (dd, J = 8.5, 1.4 Hz, 1H) , 7.89 (dd, J = 8.4, 1.3 Hz, 1H) , 7.70 (ddd, J = 8.3, 6.8, 1.3 Hz, 1H) , 7.54 (ddd, J = 8.3, 6.8, 1.3 Hz, 1H) , 7.05 (d, J = 5.3 Hz, 1H) , 6.57 (t, J = 2.0 Hz, 1H) , 6.54 (t, J = 2.0 Hz, 1H) , 6.33 (t, J = 2.2 Hz, 1H) , 4.56 (tt, J = 8.5, 4.0 Hz, 1H) , 3.85 (dt, J = 11.7, 4.4 Hz, 2H) , 3.75 (s, 3H) , 3.48 (ddd, J = 11.9, 9.4, 2.8 Hz, 2H) , 1.98 (ddt, J = 11.5, 5.3, 3.2 Hz, 2H) , 1.60 (dtd, J = 13.0, 9.1, 4.0 Hz, 2H) .
Example 164.
6-Chloro-N- (3-methoxy-5- ( (tetrahydro-2H-pyran-4-yl) oxy) phenyl) quinolin-4-amine: 4, 6-Dichloroquinoline (99 mg, 0.5 mmol, 1.0 equiv) , 3-methoxy-5- ( (tetrahydro-2H-pyran-4-yl) oxy) aniline (112 mg, 0.5 mmol, 1.0 equiv) and PPTS (37.7 mg, 0.15 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (97 mg, yield = 50.52%, purity = 92.39%) .
TLC Rf = 0.25 (PE/EA= 1/2) ;
MS (ESI+) : m/z = 385.60 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 8.95 (s, 1H) , 8.51 (d, J = 5.4 Hz, 1H) , 8.48 (d, J = 2.3 Hz, 1H) , 7.90 (d, J = 9.0 Hz, 1H) , 7.71 (dd, J = 9.0, 2.3 Hz, 1H) , 7.08 (d, J = 5.3 Hz, 1H) , 6.54 (dt, J = 13.1, 2.0 Hz, 2H) , 6.34 (t, J = 2.2 Hz, 1H) , 4.56 (tt, J = 8.4, 4.0 Hz, 1H) , 3.85 (dt, J = 11.7, 4.4 Hz, 2H) , 3.76 (s, 3H) , 3.48 (ddd, J = 11.8, 9.4, 2.8 Hz, 2H) , 1.98 (ddt, J = 11.1, 4.8, 2.8 Hz, 2H) , 1.60 (dtd, J = 13.0, 9.1, 4.0 Hz, 2H) .
Example 165.
6-Bromo-N- (3-methoxy-5- ( (tetrahydro-2H-pyran-4-yl) oxy) phenyl) quinolin-4-amine: 6-Bromo-4-chloroquinoline (122 mg, 0.5 mmol, 1.0 equiv) , 3-methoxy-5- ( (tetrahydro-2H-pyran-
4-yl) oxy) aniline (112 mg, 0.5 mmol, 1.0 equiv) and PPTS (37.7 mg, 0.15 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (170 mg, yield = 79.25%, purity = 94.91%) .
TLC Rf = 0.2 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z = 431.40 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.02 (s, 1H) , 8.67 (t, J = 1.3 Hz, 1H) , 8.56 (d, J = 5.3 Hz, 1H) , 7.86 (d, J = 1.3 Hz, 2H) , 7.12 (d, J = 5.3 Hz, 1H) , 6.60 (t, J = 2.0 Hz, 1H) , 6.57 (t, J = 2.0 Hz, 1H) , 6.39 (t, J = 2.2 Hz, 1H) , 4.61 (dt, J = 8.7, 4.4 Hz, 1H) , 3.90 (dt, J = 11.6, 4.4 Hz, 2H) , 3.80 (s, 3H) , 3.53 (ddd, J = 11.9, 9.4, 2.8 Hz, 2H) , 2.12 –1.98 (m, 2H) , 1.65 (dtd, J = 13.1, 9.1, 4.0 Hz, 2H) .
Example 166.
6-Iodo-N- (3-methoxy-5- ( (tetrahydro-2H-pyran-4-yl) oxy) phenyl) quinolin-4-amine: 4-Chloro-6-iodoquinoline (145 mg, 0.5 mmol, 1.0 equiv) , 3-methoxy-5- ( (tetrahydro-2H-pyran-4-yl) oxy) aniline (112 mg, 0.5 mmol, 1.0 equiv) and PPTS (37.7 mg, 0.15 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (180 mg, yield = 75.45%, purity = 96.69%) .
TLC Rf = 0.25 (PE/EA= 1/2) ;
MS (ESI+) : m/z = 477.40 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 8.97 (s, 1H) , 8.78 (d, J = 1.9 Hz, 1H) , 8.50 (d, J = 5.3 Hz, 1H) , 7.95 (dd, J = 8.8, 1.9 Hz, 1H) , 7.65 (d, J = 8.8 Hz, 1H) , 7.06 (d, J = 5.3 Hz, 1H) , 6.55 (t, J = 2.0 Hz, 1H) , 6.52 (t, J = 2.0 Hz, 1H) , 6.34 (t, J = 2.2 Hz, 1H) , 4.56 (tt, J = 8.4, 4.0 Hz, 1H) , 3.85 (dt, J = 11.6, 4.4 Hz, 2H) , 3.75 (s, 3H) , 3.48 (ddd, J = 11.8, 9.4, 2.8 Hz, 2H) , 1.98 (dqd, J = 12.4, 4.3, 2.6, 2.1 Hz, 2H) , 1.60 (dtd, J = 13.1, 9.1, 4.0 Hz, 2H) .
Example 167.
N- (3-Methoxy-5- ( (tetrahydro-2H-pyran-4-yl) oxy) phenyl) -6- (trifluoromethyl) quinolin-4-amine: 4-Chloro-6- (trifluoromethyl) quinoline (116 mg, 0.5 mmol, 1.0 equiv) , 3-methoxy-5- ( (tetrahydro-2H-pyran-4-yl) oxy) aniline (112 mg, 0.5 mmol, 1.0 equiv) and PPTS (37.7 mg, 0.15 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (150 mg, yield = 71.77%, purity = 49.67%) .
TLC Rf = 0.25 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z = 419.7 (M+H) ;
Example 168.
6-Methoxy-N- (3-methoxy-5- ( (tetrahydro-2H-pyran-4-yl) oxy) phenyl) quinolin-4-amine: 4-Chloro-6-methoxyquinoline (97 mg, 0.5 mmol, 1.0 equiv) , 3-methoxy-5- ( (tetrahydro-
2H-pyran-4-yl) oxy) aniline (112 mg, 0.5 mmol, 1.0 equiv) and PPTS (37.7 mg, 0.15 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (150 mg, yield = 78.95%, purity =97.4%) .
TLC Rf = 0.25 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z = 381.70 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 8.74 (s, 1H) , 8.38 (d, J = 5.2 Hz, 1H) , 7.81 (d, J = 9.1 Hz, 1H) , 7.69 (d, J = 2.8 Hz, 1H) , 7.36 (dd, J = 9.2, 2.7 Hz, 1H) , 7.03 (d, J = 5.2 Hz, 1H) , 6.54 (t, J = 2.0 Hz, 1H) , 6.51 (t, J = 2.0 Hz, 1H) , 6.33 (t, J = 2.2 Hz, 1H) , 4.57 (tt, J = 8.4, 4.0 Hz, 1H) , 3.93 (s, 3H) , 3.85 (dt, J = 11.6, 4.4 Hz, 2H) , 3.76 (s, 3H) , 3.48 (ddd, J = 11.8, 9.3, 2.8 Hz, 2H) , 2.05 –1.92 (m, 2H) , 1.60 (dtd, J = 13.0, 9.0, 4.0 Hz, 2H) .
Example 169.
6, 7-Dimethoxy-N- (3-methoxy-5- ( (tetrahydro-2H-pyran-4-yl) oxy) phenyl) quinolin-4-amine: 4-Chloro-6, 7-dimethoxyquinoline (112 mg, 0.5 mmol, 1.0 equiv) , 3-methoxy-5- ( (tetrahydro-2H-pyran-4-yl) oxy) aniline (112 mg, 0.5 mmol, 1.0 equiv) and PPTS (37.7 mg, 0.15 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (100 mg, yield =48.78%, purity = 98.96%) .
TLC Rf = 0.25 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z = 411.60 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 8.95 (s, 1H) , 8.33 (d, J = 5.5 Hz, 1H) , 7.70 (s, 1H) , 7.28 (s, 1H) , 6.92 (d, J = 5.6 Hz, 1H) , 6.55 (t, J = 2.0 Hz, 1H) , 6.51 (t, J = 2.0 Hz, 1H) , 6.35 (t, J = 2.2 Hz, 1H) , 4.57 (tt, J = 8.4, 4.0 Hz, 1H) , 3.95 (s, 3H) , 3.92 (s, 3H) , 3.85 (dt, J = 11.6, 4.4 Hz, 2H) , 3.76 (s, 3H) , 3.48 (ddd, J = 11.8, 9.3, 2.8 Hz, 2H) , 1.97 (ddd, J = 11.2, 4.7, 2.9 Hz, 2H) , 1.60 (dtd, J =13.0, 9.0, 4.0 Hz, 2H) .
Example 170.
7-Methoxy-4- ( (3-methoxy-5- ( (tetrahydro-2H-pyran-4-yl) oxy) phenyl) amino) quinoline-6-carboxamide: 4-Chloro-7-methoxyquinoline-6-carboxamide (119 mg, 0.5 mmol, 1.0 equiv) , 3-methoxy-5- ( (tetrahydro-2H-pyran-4-yl) oxy) aniline (112 mg, 0.5 mmol, 1.0 equiv) and PPTS (37.7 mg, 0.15 mmol, 0.3 equiv) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (160 mg, yield = 75.65%, purity = 99.77%) .
TLC Rf = 0.2 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z = 424.80 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.22 (s, 1H) , 8.80 (s, 1H) , 8.46 (d, J = 5.4 Hz, 1H) , 7.79 (s, 1H) , 7.69 (s, 1H) , , 7.36 (s, 1H) , 6.96 (d, J = 5.4 Hz, 1H) , 6.57 (t, J = 2.0 Hz, 1H) , 6.53 (t, J = 2.0 Hz, 1H) , 6.32 (t, J = 2.2 Hz, 1H) , 4.55 (tt, J = 8.5, 4.0 Hz, 1H) , 4.00 (s, 3H) , 3.85 (dt, J = 11.6, 4.4 Hz, 2H) , 3.75 (s, 3H) , 3.48 (ddd, J = 11.8, 9.4, 2.8 Hz, 2H) , 2.05 –1.92 (m, 2H) , 1.60 (dtd, J =13.0, 9.1, 4.0 Hz, 2H) .
Example 171.
7-Methoxy-4- ( (3-methoxy-5- (pyrrolidin-1-yl) phenyl) amino) quinoline-6-carboxamide: 4-chloro-7-methoxyquinoline-6-carboxamide (223 mg, 0.94 mmol, 1.0 eq) , 3-methoxy-5- (pyrrolidin-1-yl) aniline (181mg, 0.94 mmol, 1.0 eq) and PPTS (71 mg, 0.28 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as a solid (254.5 mg, yield = 68.89 %, purity = 93.44 %) .
TLC Rf = 0.35 (DCM/MeOH = 10/1) ;
MS (ESI+) : m/z = 392.60 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.06 (s, 1H) , 8.81 (s, 1H) , 8.40 (d, J = 5.4 Hz, 1H) , 7.80 –7.75 (m, 1H) , 7.68 –7.64 (m, 1H) , 7.33 (s, 1H) , 6.96 (d, J = 5.4 Hz, 1H) , 6.22 (t, J = 2.0 Hz, 1H) , 6.17 (t, J = 2.0 Hz, 1H) , 5.87 (t, J = 2.1 Hz, 1H) , 3.99 (s, 3H) , 3.72 (s, 3H) , 3.25 –3.17 (m, 4H) , 1.97 –1.89 (m, 4H) .
Example 172.
7-Methoxy-4- ( (3-methoxy-5- (piperidin-1-yl) phenyl) amino) quinoline-6-carboxamide: 4-chloro-7-methoxyquinoline-6-carboxamide (142 mg, 0.6 mmol, 1.0 eq) , 3-methoxy-5- (piperidin-1-yl) aniline (125 mg, 0.6 mmol, 1.0 eq) and PPTS (45 mg, 0.18 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution
was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as a solid (155 mg, yield = 63.63 %, purity = 93.92 %) .
TLC Rf = 0.20 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z = 407.10 (M+H)
Example 173.
7-methoxy-4- ( (3-methoxy-5-morpholinophenyl) amino) quinoline-6-carboxamide: To a nitrogen purged solution of 4-chloro-7-methoxyquinoline-6-carboxamide (30 mg, 0.07 mmol, 1 eq) , in t-BuOH (2 mL) at room temperature was added 3-methoxy-5-morpholinoaniline (31 mg, 0.36 mmol, 5.0 eq) , Palladium (II) acetate (0.8 mg, 0.003 mmol, 0.05 eq) , X-Phos (3.4 mg, 0.007 mmol, 0.1 eq) , and NaOt-Bu (21 g, 0.21 mmol, 3.0 eq) and the reaction mass was purged for 10 min. Reaction mixture was allowed to stir at 100 ℃, for 8 h. After completion of the reaction, the reaction mixture was quenched with water and portioned between EtOAc (80 mL) and water (30 mL) , followed by washing the organic layer with brine (20 mL) solution. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification using column chromatography afforded as a brown solid (9 mg, 17%) .
TLC Rf = 0.7 (0%EtOAc/DCM) .
MS (ESI+) : m/z = 420.20 (M+H)
Example 174.
4- ( (3- (2, 2-Difluoroethoxy) -5-methoxyphenyl) amino) -7-methoxyquinoline-6-carboxamide: 4-chloro-7-methoxyquinoline-6-carboxamide (119 mg, 0.5 mmol, 1.0 eq) , 3- (2, 2-difluoroethoxy) -5-methoxyaniline (153 mg, 0.75 mmol, 1.5 eq) and PPTS (38 mg, 0.15 mmol, 0.3
eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuo. The crude material was purified by silica gel flash chromatography to afford the product as a solid (166 mg, yield = 82.3 %, purity =100 %) .
TLC Rf = 0.45 (DCM/MeOH = 10/1) ;
MS (ESI+) : m/z = 403.5 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.20 (s, 1H) , 8.78 (s, 1H) , 8.46 (d, J = 5.4 Hz, 1H) , 7.79 (d, J = 2.5 Hz, 1H) , 7.70 –7.65 (m, 1H) , 7.36 (s, 1H) , 7.01 (d, J = 5.4 Hz, 1H) , 6.59 (d, J = 2.2 Hz, 2H) , 6.54 –6.23 (m, 2H) , 4.31 (td, J = 14.7, 3.6 Hz, 2H) , 4.00 (s, 3H) , 3.76 (s, 3H) .
Example 175.
7-Methoxy-4- ( (3-methoxy-5- ( (tetrahydro-2H-pyran-4-yl) methoxy) phenyl) amino) quinoline-6-carboxamide: 4-chloro-7-methoxyquinoline-6-carboxamide (133 mg, 0.5 mmol, 1.0 eq) , 3-methoxy-5- ( (tetrahydro-2H-pyran-4-yl) methoxy) aniline (142 mg, 0.6 mmol, 1.2 eq) and PPTS (38 mg, 0.15 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuo. The crude material was purified by silica gel flash chromatography to afford the product as a solid (133 mg, yield = 60.8 %, purity = 100 %) .
TLC Rf = 0.3 (DCM/MeOH = 10/1) ;
MS (ESI+) : m/z = 438.6 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.19 (s, 1H) , 8.79 (s, 1H) , 8.45 (d, J = 5.4 Hz, 1H) , 7.81 –7.76 (m, 1H) , 7.68 (s, 1H) , 7.35 (s, 1H) , 6.98 (d, J = 5.4 Hz, 1H) , 6.53 (d, J = 2.2 Hz, 2H) , 6.26 (t, J =
2.2 Hz, 1H) , 3.99 (s, 3H) , 3.87 (ddd, J = 11.5, 4.4, 1.8 Hz, 2H) , 3.81 (d, J = 6.4 Hz, 2H) , 3.74 (s, 3H) , 3.31 (dd, J = 11.7, 2.1 Hz, 2H) , 1.98 (ttd, J = 10.5, 6.5, 3.3 Hz, 1H) , 1.67 (ddd, J = 12.8, 4.0, 1.8 Hz, 2H) , 1.38 –1.26 (m, 2H) .
Example 176.
(S) -7-methoxy-4- ( (3-methoxy-5- ( (tetrahydrofuran-3-yl) methoxy) phenyl) amino) quinoline-6-carboxamide: To an oven dried two neck round bottom 4-chloro-7-methoxyquinoline-6-carboxamide (250 mg, 1.06 mmol, 1 eq) , (S) -3-methoxy-5- ( (tetrahydrofuran-3-yl) methoxy) aniline (235 mg, 1.06 mmol, 1 eq) and NMP (3 mL) were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 110 ℃ and stirred at same temperature for 16 h. After consumption of the starting material monitored by TLC, the reaction mixture was cooled down to room temperature. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 25 mL) . The combined organic phase was washed with brine solution, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude compound was purified by flash column chromatography to afford the product as a pale yellow liquid (108 mg, 24.14%) .
TLC Rf = 0.1 (30%EtOAc/PE) .
MS (ESI+) : m/z = 424.10 (M+H)
1H NMR (400 MHz, DMSO-d6) : δ 9.58 (s, 1H) , 8.84 (s, 1H) , 8.45 (d, J = 5.8 Hz, 1H) , 7.81 (s, 1H) , 7.73 (s, 1H) , 7.37 (s, 1H) , 6.95 (d, J = 5.8 Hz, 1H) , 6.62 –6.48 (m, 2H) , 6.34 (t, J = 2.2 Hz, 1H) , 4.00 (s, 3H) , 3.97 –3.91 (m, 1H) , 3.87 (dd, J = 9.4, 7.8 Hz, 1H) , 3.82 –3.72 (m, 5H) , 3.65 (q, J = 7.6 Hz, 1H) , 3.53 (dd, J = 8.6, 5.5 Hz, 1H) , 2.71 –2.59 (m, 1H) , 2.08 –1.95 (m, 1H) , 1.71 –1.58 (m, 1H) .
Example 177.
4- ( (3- (Furan-3-ylmethoxy) -5-methoxyphenyl) amino) -7-methoxyquinoline-6-carboxamide: 4-chloro-7-methoxyquinoline-6-carboxamide (118 mg, 0.5 mmol, 1.0 eq) , 3- (furan-3-ylmethoxy) -5-methoxyaniline (109.5 mg, 0.5 mmol, 1.0 eq) and PPTS (38 mg, 0.13 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 5 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as a solid (116.2 mg, yield = 55.44 %, purity = 100 %) .
TLC Rf = 0.25 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z = 420.0 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.23 (s, 1H) , 8.79 (s, 1H) , 8.44 (d, J = 5.4 Hz, 1H) , 7.81 –7.76 (m, 2H) , 7.68 (t, J = 2.0 Hz, 2H) , 7.35 (s, 1H) , 6.94 (d, J = 5.5 Hz, 1H) , 6.59 (dt, J = 4.4, 1.5 Hz, 2H) , 6.54 (t, J = 2.0 Hz, 1H) , 6.35 (t, J = 2.2 Hz, 1H) , 4.95 (s, 2H) , 4.00 (s, 3H) , 3.75 (s, 3H) .
Example 178.
3- ( (6-Iodoquinolin-4-yl) amino) -5-methoxyphenol 4-chloro-6-iodoquinoline (120 mg, 0.4 mmol, 1.0 eq) , 3-amino-5-methoxyphenol (56 mg, 0.4 mmol, 1.0 eq) and PPTS (30 mg, 0.12mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous
stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuo. The crude material was purified by silica gel flash chromatography to afford the product as a solid (116 mg, yield =74.0%, purity = 96.71%) .
TLC Rf = 0.25 (PE/EA = 1/1) ;
MS (ESI+) : m/z = 392.8 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.56 (s, 1H) , 8.93 (s, 1H) , 8.79 (d, J = 2.0 Hz, 1H) , 8.48 (d, J = 5.4 Hz, 1H) , 7.93 (dd, J = 8.8, 1.8 Hz, 1H) , 7.64 (d, J = 8.8 Hz, 1H) , 7.05 (d, J = 5.4 Hz, 1H) , 6.40 (t, J = 2.0 Hz, 1H) , 6.37 (t, J = 2.1 Hz, 1H) , 6.14 (t, J = 2.2 Hz, 1H) , 3.71 (s, 3H) .
Example 179.
1- (4- (3- ( (6-iodoquinolin-4-yl) amino) -5-methoxyphenyl) -1H-pyrazol-1-yl) -2-methylpropan-2-ol: 4-chloro-6-iodoquinoline (70 mg, 0.24 mmol, 1.0 eq) , 1- (4- (3-amino-5- methoxyphenyl) -1H-pyrazol-1-yl) -2-methylpropan-2-ol (66 mg, 0.25 mmol, 1.05 eq) and PPTS (18 mg, 0.07 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 3 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as brown solid (96 mg, yield = 77.1%, purity = 96.5%) .
TLC Rf = 0.3 (PE/EA=1/4) ;
MS (ESI+) : m/z = 515.3 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.05 (s, 1H) , 8.84 (d, J = 1.9 Hz, 1H) , 8.48 (d, J = 5.4 Hz, 1H) , 8.26 (s, 1H) , 7.95 (dd, J = 8.8, 1.8 Hz, 1H) , 7.88 (s, 1H) , 7.65 (d, J = 8.8 Hz, 1H) , 7.18 (t, J = 1.7 Hz, 1H) , 7.00 (q, J = 2.9, 2.0 Hz, 2H) , 6.73 (t, J = 2.1 Hz, 1H) , 4.98 (t, J = 5.6 Hz, 1H) , 3.82 (s,
3H) , 3.60 (d, J = 5.5 Hz, 2H) , 1.49 (s, 6H) .
Example 180.
5- (3- ( (6-iodoquinolin-4-yl) amino) -5-methoxyphenyl) -1-methylpyridin-2 (1H) -one: 4-chloro-6-iodoquinoline (70 mg, 0.24 mmol, 1.0 eq) , 5- (3-amino-5-methoxyphenyl) -1-methylpyridin-2 (1H) -one (58 mg, 0.25 mmol, 1.05 eq) and PPTS (18 mg, 0.07 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 3 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as off-white solid (71 mg, yield = 60.7%, purity = 93.95%) .
TLC Rf = 0.25 (PE/EA=1/4) ;
MS (ESI+) : m/z = 484.0 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.16 (s, 1H) , 8.84 (d, J = 1.9 Hz, 1H) , 8.50 (d, J = 5.4 Hz, 1H) , 8.17 (d, J = 2.7 Hz, 1H) , 7.96 (dd, J = 8.8, 1.8 Hz, 1H) , 7.83 (dd, J = 9.4, 2.7 Hz, 1H) , 7.66 (d, J =8.8 Hz, 1H) , 7.15 (t, J = 1.7 Hz, 1H) , 7.08 (d, J = 5.4 Hz, 1H) , 6.93 (t, J = 1.9 Hz, 1H) , 6.85 (t, J = 2.1 Hz, 1H) , 6.48 (d, J = 9.4 Hz, 1H) , 3.84 (s, 3H) , 3.50 (s, 3H) .
Example 181.
4- (3- ( (6-Iodoquinolin-4-yl) amino) -5-methoxyphenyl) -1-methylpyridin-2 (1H) -one: 4-chloro-6-iodoquinoline (80 mg, 0.27 mmol, 1.0 eq) , 4- (3-amino-5-methoxyphenyl) -1-methylpyridin-2 (1H) -one (67 mg, 0.29 mmol, 1.05 eq) and PPTS (21 mg, 0.08 mmol, 0.3 eq) were
added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 3 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as off-white solid (92 mg, yield = 68.8%, purity = 100%) .
TLC Rf = 0.25 (EA/PE=4/1) ;
MS (ESI+) : m/z = 483.9 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.12 (s, 1H) , 8.81 (d, J = 1.9 Hz, 1H) , 8.52 (d, J = 5.3 Hz, 1H) , 7.95 (dd, J = 8.8, 1.8 Hz, 1H) , 7.77 (d, J = 7.1 Hz, 1H) , 7.66 (d, J = 8.8 Hz, 1H) , 7.23 (t, J = 1.7 Hz, 1H) , 7.14 (d, J = 5.3 Hz, 1H) , 6.99 (dt, J = 6.1, 2.1 Hz, 2H) , 6.69 (d, J = 2.1 Hz, 1H) , 6.56 (dd, J = 7.1, 2.1 Hz, 1H) , 3.85 (s, 3H) , 3.45 (s, 3H) .
Example 182.
N- (3- (1H-imidazol-1-yl) -5-methoxyphenyl) -6-iodoquinolin-4-amine: 4-chloro-6-iodoquinoline (144.5 mg, 0.5 mmol, 1.0 eq) , 3- (1H-imidazol-1-yl) -5-methoxyaniline (113.4 mg, 0.3 mmol, 1.0 eq) , and PPTS (37 mg, 0.15 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as a solid (198 mg, yield = 89.59 %, purity = 92.01 %) .
TLC Rf = 0.50 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z = 442.90 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.17 (s, 1H) , 8.80 (d, J = 1.9 Hz, 1H) , 8.54 (d, J = 5.3 Hz, 1H) ,
8.29 (d, J = 1.2 Hz, 1H) , 7.96 (dd, J = 8.9, 1.9 Hz, 1H) , 7.77 (t, J = 1.4 Hz, 1H) , 7.68 (d, J = 8.8 Hz, 1H) , 7.19 (q, J = 3.3, 2.5 Hz, 2H) , 7.10 (d, J = 1.2 Hz, 1H) , 6.99 (t, J = 2.1 Hz, 1H) , 6.90 (t, J = 2.0 Hz, 1H) , 3.85 (s, 3H) .
Example 183.
6-Iodo-N- (3-methoxy-5- (1- (2-methoxyethyl) -1H-pyrazol-4-yl) phenyl) quinolin-4-amine: 4-chloro-6-iodoquinoline (116 mg, 0.4 mmol, 1.0 eq) , 3-methoxy-5- (1- (2-methoxyethyl) -1H-pyrazol-4-yl) aniline (99 mg, 0.4 mmol, 1.0 eq) , and PPTS (30 mg, 0.12 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as an oil (119.9 mg, yield = 59.95 %, purity = 96.49 %) .
TLC Rf = 0.40 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z = 501.20 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.06 (s, 1H) , 8.84 (d, J = 2.0 Hz, 1H) , 8.49 (d, J = 5.3 Hz, 1H) , 8.19 (d, J = 0.8 Hz, 1H) , 7.94 (dd, J = 8.8, 1.9 Hz, 1H) , 7.90 (d, J = 0.8 Hz, 1H) , 7.65 (d, J =8.8 Hz, 1H) , 7.15 (t, J = 1.6 Hz, 1H) , 7.04 (d, J = 5.3 Hz, 1H) , 6.95 (dd, J = 2.4, 1.4 Hz, 1H) , 6.75 (t, J = 2.1 Hz, 1H) , 4.27 (t, J = 5.3 Hz, 2H) , 3.82 (s, 3H) , 3.71 (t, J = 5.3 Hz, 2H) , 3.24 (s, 3H) .
Example 184.
4- (3- ( (6-Iodoquinolin-4-yl) amino) -5-methoxyphenyl) piperazin-2-one: 4-chloro-6-iodoquinoline (87 mg, 0.3 mmol, 1.5eq) , 4- (3-amino-5-methoxyphenyl) piperazin-2-one (47 mg, 0.2 mmol, 1.0 eq) and PPTS (50 mg, 0.2 mmol, 1.0 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuo. The crude material was purified by silica gel flash chromatography to afford the product as a black solid (14mg, yield =14.8 %, purity = 98.26 %) .
TLC Rf = 0.45 (DCM/MeOH= 20/1) ;
MS (ESI+) : m/z = 475.1 (M+H) ;
Example 185.
N- (3- (1-cyclopropyl-1H-pyrazol-4-yl) -5-methoxyphenyl) -6-iodoquinolin-4-amine: 4-chloro-6-iodoquinoline (116 mg, 0.4 mmol, 1.0 eq) , 3- (1-cyclopropyl-1H-pyrazol-4-yl) -5-methoxyaniline (92 mg, 0.4 mmol, 1.0 eq) , and PPTS (30 mg, 0.12 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as a solid (76.1 mg, yield = 39.47 %, purity = 99.66 %) .
TLC Rf = 0.50 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z = 483.30 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.03 (s, 1H) , 8.83 (d, J = 1.9 Hz, 1H) , 8.48 (d, J = 5.3 Hz, 1H) , 8.27 (s, 1H) , 7.94 (dd, J = 8.9, 1.8 Hz, 1H) , 7.86 (d, J = 0.7 Hz, 1H) , 7.65 (d, J = 8.8 Hz, 1H) , 7.16
(t, J = 1.7 Hz, 1H) , 7.02 (d, J = 5.3 Hz, 1H) , 6.96 (t, J = 1.8 Hz, 1H) , 6.74 (t, J = 2.1 Hz, 1H) , 3.81 (s, 3H) , 3.73 (tt, J = 7.4, 3.9 Hz, 1H) , 1.10 –1.03 (m, 2H) , 1.00 –0.94 (m, 2H) .
Example 186.
6-Iodo-N- (3- (isoxazol-4-yl) -5-methoxyphenyl) quinolin-4-amine: 4-chloro-6-iodoquinoline (70 mg, 0.24 mmol, 1.0 eq) , 3- (isoxazol-4-yl) -5-methoxyaniline (97 mg, 0.26 mmol, 1.05 eq) and PPTS (18 mg, 0.07 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃for 3 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as a yellow solid (76 mg, yield = 70.9%, purity = 87.5%) .
TLC Rf = 0.25 (EA/PA=4/1) ;
MS (ESI+) : m/z = 444.1 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.49 (s, 1H) , 9.19 (s, 1H) , 8.85 (d, J = 1.9 Hz, 1H) , 8.05 –7.92 (m, 2H) , 7.67 (d, J = 8.9 Hz, 1H) , 7.30 (t, J = 1.6 Hz, 1H) , 7.12 (dd, J = 2.4, 1.4 Hz, 1H) , 7.05 (d, J = 5.5 Hz, 1H) , 6.88 (t, J = 2.1 Hz, 1H) , 3.84 (s, 3H) .
Example 187.
6-Iodo-N- (3-methoxy-5- (1- (oxetan-3-yl) -1H-pyrazol-4-yl) phenyl) quinolin-4-amine: 4-chloro-6-iodoquinoline (80 mg, 0.27 mmol, 1.0 eq) , 3-methoxy-5- (1- (oxetan-3-yl) -1H-pyrazol-4-yl) aniline (75 mg, 0.3 mmol, 1.05 eq) and PPTS (21 mg, 0.08 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction
vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 3 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as a yellow solid (106 mg, yield = 76.9%, purity = 100%) .
TLC Rf = 0.3 (EA/PE=4/1) ;
MS (ESI+) : m/z = 499.2 (M+H) ;
Example 188.
6-Iodo-N- (3-methoxy-5- (1-methyl-1H-imidazol-5-yl) phenyl) quinolin-4-amine: 4-chloro-6-iodoquinoline (100 mg, 0.34 mmol, 1.0 eq) , 3-methoxy-5- (1-methyl-1H-imidazol-5-yl) aniline (74 mg, 0.36 mmol, 1.05 eq) and PPTS (26 mg, 0.1 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 3 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as a yellow solid (106 mg, yield = 67.2%, purity = 100%) .
TLC Rf = 0.3 (10%MeOH/DCM) ;
MS (ESI+) : m/z = 457.1 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.12 (s, 1H) , 8.80 (d, J = 1.9 Hz, 1H) , 8.51 (d, J = 5.3 Hz, 1H) , 7.95 (dd, J = 8.8, 1.8 Hz, 1H) , 7.73 –7.69 (m, 1H) , 7.66 (d, J = 8.8 Hz, 1H) , 7.15 –7.09 (m, 2H) , 7.04 (t, J = 1.7 Hz, 1H) , 6.92 (t, J = 2.1 Hz, 1H) , 6.81 (dd, J = 2.4, 1.4 Hz, 1H) , 3.82 (s, 3H) , 3.73 (s, 3H) .
Example 189.
6-Chloro-N- (3- (furan-3-yl) -5-methoxyphenyl) quinolin-4-amine: 4, 6-dichloroquinoline (99 mg, 0.5 mmol, 1.0 eq) , 3- (furan-3-yl) -5-methoxyaniline (95 mg, 0.5 mmol, 1.0 eq) and PPTS (38 mg, 0.15 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuo. The crude material was purified by silica gel flash chromatography to afford the product as a solid (120 mg, yield = 68.4 %, purity = 100 %) .
TLC Rf = 0.25 (PE/EA=2/1) ;
MS (ESI+) : m/z =351.2 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.04 (s, 1H) , 8.53 (d, J = 2.3 Hz, 1H) , 8.50 (d, J = 5.3 Hz, 1H) , 8.23 (t, J = 1.1 Hz, 1H) , 7.90 (d, J = 9.0 Hz, 1H) , 7.75 (t, J = 1.7 Hz, 1H) , 7.71 (dd, J = 9.0, 2.3 Hz, 1H) , 7.19 (t, J = 1.6 Hz, 1H) , 7.06 (d, J = 5.3 Hz, 1H) , 6.99 (t, J = 1.9 Hz, 1H) , 6.97 (d, J = 1.8 Hz, 1H) , 6.83 (t, J = 2.1 Hz, 1H) , 3.82 (s, 3H) .
Example 190.
1- (4- (3- ( (6-chloroquinolin-4-yl) amino) -5-methoxyphenyl) -1H-pyrazol-1-yl) -2-methylpropan-2-ol: 4, 6-dichloroquinoline (70 mg, 0.35 mmol, 1.0 eq) , 1- (4- (3-amino-5-methoxyphenyl) -1H-pyrazol-1-yl) -2-methylpropan-2-ol (97 mg, 0.37 mmol, 1.05 eq) and PPTS (27 mg, 0.1 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL
DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 3 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as brown solid (98 mg, yield = 65.5%, purity = 97.9%) .
TLC Rf = 0.3 (PE/EA=1/4) ;
MS (ESI+) : m/z = 423.1 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.02 (s, 1H) , 8.53 (d, J = 2.3 Hz, 1H) , 8.49 (d, J = 5.3 Hz, 1H) , 8.26 (s, 1H) , 7.93 –7.85 (m, 2H) , 7.71 (dd, J = 9.0, 2.3 Hz, 1H) , 7.20 (t, J = 1.7 Hz, 1H) , 7.07 –6.97 (m, 2H) , 6.74 (t, J = 2.1 Hz, 1H) , 4.99 (t, J = 5.6 Hz, 1H) , 3.82 (s, 3H) , 3.60 (d, J = 5.3 Hz, 2H) , 1.49 (s, 6H) .
Example 191.
5- (3- ( (6-chloroquinolin-4-yl) amino) -5-methoxyphenyl) -1-methylpyridin-2 (1H) -one: 4, 6-dichloroquinoline (70 mg, 0.35 mmol, 1.0 eq) , 5- (3-amino-5-methoxyphenyl) -1-methylpyridin-2 (1H) -one (85.4 mg, 0.37 mmol, 1.05 eq) and PPTS (26.6 mg, 0.1 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 3 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as off-white solid (123 mg, yield = 88.8%, purity = 96%) .
TLC Rf = 0.25 (PE/EA=1/4) ;
MS (ESI+) : m/z = 392.10 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 11.09 (s, 1H) , 9.02 (d, J = 2.1 Hz, 1H) , 8.54 (d, J = 7.0 Hz, 1H) , 8.26 (d, J = 2.7 Hz, 1H) , 8.14 (d, J = 9.0 Hz, 1H) , 8.08 (dd, J = 9.0, 2.1 Hz, 1H) , 7.88 (dd, J
= 9.4, 2.8 Hz, 1H) , 7.30 (t, J = 1.7 Hz, 1H) , 7.21 (t, J = 1.9 Hz, 1H) , 7.03 –6.94 (m, 2H) , 6.49 (d, J = 9.5 Hz, 1H) , 3.87 (s, 3H) , 3.51 (s, 3H) .
Example 192.
4- (3- ( (6-Chloroquinolin-4-yl) amino) -5-methoxyphenyl) -1-methylpyridin-2 (1H) -one: 4, 6-dichloroquinoline (80 mg, 0.4 mmol, 1.0 eq) , 4- (3-amino-5-methoxyphenyl) -1-methylpyridin-2 (1H) -one (98 mg, 0.42 mmol, 1.05 eq) and PPTS (30 mg, 0.12 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 3 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as off-white solid (106 mg, yield = 67%, purity = 100%) .
TLC Rf = 0.25 (EA/PE=4/1) ;
MS (ESI+) : m/z = 392.10 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.24 (s, 1H) , 8.56 –8.50 (m, 2H) , 7.92 (d, J = 9.0 Hz, 1H) , 7.77 (d, J = 7.1 Hz, 1H) , 7.74 (dd, J = 9.0, 2.3 Hz, 1H) , 7.25 (t, J = 1.7 Hz, 1H) , 7.15 (d, J = 5.4 Hz, 1H) , 7.01 (p, J = 2.1 Hz, 2H) , 6.70 (d, J = 2.1 Hz, 1H) , 6.57 (dd, J = 7.1, 2.1 Hz, 1H) , 3.85 (s, 3H) , 3.45 (s, 3H) .
Example 193.
6-Chloro-N- (3- (isoxazol-4-yl) -5-methoxyphenyl) quinolin-4-amine: 4, 6-
dichloroquinoline (80 mg, 0.4 mmol, 1.0 eq) , 3- (isoxazol-4-yl) -5-methoxyaniline (85 mg, 0.44 mmol, 1.1 eq) and PPTS (30 mg, 0.12 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 3 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as pale-yellow solid (115 mg, yield = 80.9 %, purity = 90.3%) .
TLC Rf = 0.25 (EA/PE=1/1) ;
MS (ESI+) : m/z = 352.1 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.50 (s, 1H) , 9.20 (s, 1H) , 8.62 –8.55 (m, 1H) , 8.51 (d, J =5.5 Hz, 1H) , 8.05 –7.68 (m, 3H) , 7.32 (s, 1H) , 7.15 (s, 1H) , 7.12 –7.03 (m, 1H) , 6.90 (s, 1H) , 3.84 (s, 4H) .
Example 194.
6-Chloro-N- (3-methoxy-5- (1- (oxetan-3-yl) -1H-pyrazol-4-yl) phenyl) quinolin-4-amine: 4, 6-dichloroquinoline (80 mg, 0.4 mmol, 1.0 eq) , 3-methoxy-5- (1- (oxetan-3-yl) -1H-pyrazol-4-yl) aniline (109 mg, 0.44 mmol, 1.1 eq) and PPTS (30 mg, 0.12 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 3 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (120 mg, yield = 73 %, purity = 100%) .
TLC Rf = 0.25 (100%EA) ;
MS (ESI+) : m/z = 407.2 (M+H) ;
Example 195.
6-Chloro-N- (3-methoxy-5- (1- (3-methoxypropyl) -1H-pyrazol-4-yl) phenyl) quinolin-4-amine: 4, 6-dichloroquinoline (79 mg, 0.4 mmol, 1.0 eq) , 3-methoxy-5- (1- (3-methoxypropyl) -1H-pyrazol-4-yl) aniline (105 mg, 0.4 mmol, 1.0 eq) , and PPTS (30 mg, 0.12 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as an oil (144.4 mg, yield = 85.54 %, purity = 99.34 %) .
TLC Rf = 0.50 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z =423.10 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.03 (s, 1H) , 8.53 (d, J = 2.3 Hz, 1H) , 8.49 (d, J = 5.3 Hz, 1H) , 8.21 (s, 1H) , 7.93 –7.86 (m, 2H) , 7.71 (dd, J = 9.0, 2.2 Hz, 1H) , 7.16 (t, J = 1.6 Hz, 1H) , 7.05 (d, J = 5.3 Hz, 1H) , 6.96 (dd, J = 2.3, 1.4 Hz, 1H) , 6.75 (t, J = 2.1 Hz, 1H) , 4.16 (t, J = 7.0 Hz, 2H) , 3.81 (s, 3H) , 3.30 (t, J = 6.2 Hz, 2H) , 3.23 (s, 3H) , 2.03 (p, J = 6.6 Hz, 2H) .
Example 196.
3- (4- (3- ( (6-Chloroquinolin-4-yl) amino) -5-methoxyphenyl) -1H-pyrazol-1-yl) propanenitrile: 4, 6-dichloroquinoline (79 mg, 0.4 mmol, 1.0 eq) , 3- (4- (3-amino-5-methoxyphenyl) -1H-pyrazol-1-yl) propanenitrile (97 mg, 0.4 mmol, 1.0 eq) , and PPTS (30 mg, 0.12 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO
was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as an oil (151.3 mg, yield =93.86 %, purity = 99.27 %) .
TLC Rf = 0.45 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z = 404.10 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.06 (s, 1H) , 8.53 (d, J = 2.3 Hz, 1H) , 8.50 (d, J = 5.3 Hz, 1H) , 8.30 (d, J = 0.8 Hz, 1H) , 7.99 (d, J = 0.8 Hz, 1H) , 7.90 (d, J = 8.9 Hz, 1H) , 7.71 (dd, J = 9.0, 2.3 Hz, 1H) , 7.17 (t, J = 1.7 Hz, 1H) , 7.06 (d, J = 5.4 Hz, 1H) , 6.97 (dd, J = 2.4, 1.4 Hz, 1H) , 6.78 (t, J = 2.1 Hz, 1H) , 4.41 (t, J = 6.4 Hz, 2H) , 3.82 (s, 3H) , 3.11 (t, J = 6.4 Hz, 2H) .
Example 197.
6-Chloro-N- (3-methoxy-5- (1- (2-methoxyethyl) -1H-pyrazol-4-yl) phenyl) quinolin-4-amine: 4, 6-dichloroquinoline (99 mg, 0.5 mmol, 1.0 eq) , 3-methoxy-5- (1- (2-methoxyethyl) -1H-pyrazol-4-yl) aniline (124 mg, 0.5 mmol, 1.0 eq) , and PPTS (38 mg, 0.15 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as an oil (110.4 mg, yield = 54.12 %, purity = 98.38 %) .
TLC Rf = 0.45 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z = 409.20 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.03 (s, 1H) , 8.53 (d, J = 2.3 Hz, 1H) , 8.50 (d, J = 5.3 Hz, 1H) , 8.19 (d, J = 0.8 Hz, 1H) , 7.93 –7.86 (m, 2H) , 7.71 (dd, J = 9.0, 2.3 Hz, 1H) , 7.15 (t, J = 1.6 Hz,
1H) , 7.05 (d, J = 5.3 Hz, 1H) , 6.96 (dd, J = 2.4, 1.4 Hz, 1H) , 6.75 (t, J = 2.1 Hz, 1H) , 4.26 (t, J =5.3 Hz, 2H) , 3.82 (s, 3H) , 3.75 –3.67 (m, 2H) , 3.24 (s, 3H) .
Example 198.
4- (3- ( (6-Chloroquinolin-4-yl) amino) -5-methoxyphenyl) piperazin-2-one: 4, 6-dichloroquinoline (89 mg, 0.45 mmol, 1.5 eq) , 4- (3-amino-5-methoxyphenyl) piperazin-2-one (66 mg, 0.3 mmol, 1.0 eq) and PPTS (75 mg, 0.3 mmol, 1.0 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuo. The crude material was purified by silica gel flash chromatography to afford the product as a black solid (50 mg, yield = 43.5%, purity = 94.29 %) .
TLC Rf = 0.25 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z = 383.10 (M+H) ;
Example 199.
6-Chloro-N- (3- (1-cyclopropyl-1H-pyrazol-4-yl) -5-methoxyphenyl) quinolin-4-amine: 4, 6-dichloroquinoline (79 mg, 0.4 mmol, 1.0 eq) , 3- (1-cyclopropyl-1H-pyrazol-4-yl) -5-methoxyaniline (92 mg, 0.4 mmol, 1.0 eq) , and PPTS (30 mg, 0.12 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured
into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as a solid (134.4 mg, yield = 86.15 %, purity = 95.32 %) .
TLC Rf = 0.50 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z = 391.10 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.01 (s, 1H) , 8.53 (d, J = 2.3 Hz, 1H) , 8.49 (d, J = 5.3 Hz, 1H) , 8.27 (s, 1H) , 7.93 –7.85 (m, 2H) , 7.70 (dd, J = 9.0, 2.3 Hz, 1H) , 7.17 (t, J = 1.7 Hz, 1H) , 7.04 (d, J = 5.3 Hz, 1H) , 6.99 –6.95 (m, 1H) , 6.75 (t, J = 2.1 Hz, 1H) , 3.81 (s, 3H) , 3.73 (tt, J = 7.5, 3.9 Hz, 1H) , 1.11 –1.04 (m, 2H) , 1.00 –0.93 (m, 2H) .
Example 200.
6-Chloro-N- (3-methoxy-5- (1-methyl-1H-imidazol-5-yl) phenyl) quinolin-4-amine: 4, 6-dichloroquinoline (100 mg, 0.5 mmol, 1.0 eq) , 3-methoxy-5- (1-methyl-1H-imidazol-5-yl) aniline (108 mg, 0.53 mmol, 1.05 eq) and PPTS (38 mg, 0.15 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 3 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (132 mg, yield = 71.6%, purity = 100%) .
TLC Rf = 0.3 (10%MeOH/DCM) ;
MS (ESI+) : m/z = 365.1 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.09 (s, 1H) , 8.51 (dd, J = 6.6, 3.8 Hz, 2H) , 7.90 (d, J = 9.0 Hz, 1H) , 7.75 –7.68 (m, 2H) , 7.15 (d, J = 5.4 Hz, 1H) , 7.12 (s, 1H) , 7.05 (t, J = 1.6 Hz, 1H) , 6.93 (t, J = 2.1 Hz, 1H) , 6.82 (dd, J = 2.4, 1.4 Hz, 1H) , 3.83 (s, 3H) , 3.73 (s, 3H) .
Example 201.
6-Chloro-N- (3-methoxy-5- (1-methyl-1H-pyrazol-5-yl) phenyl) quinolin-4-amine: 4, 6-dichloroquinoline (100 mg, 0.5 mmol, 1.0 eq) , 3-methoxy-5- (1-methyl-1H-pyrazol-5-yl) aniline (108 mg, 0.53 mmol, 1.05 eq) and PPTS (38 mg, 0.15 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 3 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (137 mg, yield = 74.3%, purity = 98.9%) .
TLC Rf = 0.2 (EA/PE=1/1) ;
MS (ESI+) : m/z = 365.1 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.11 (s, 1H) , 8.53 (d, J = 5.4 Hz, 1H) , 8.50 (d, J = 2.3 Hz, 1H) , 7.91 (d, J = 9.0 Hz, 1H) , 7.72 (dd, J = 8.9, 2.3 Hz, 1H) , 7.47 (d, J = 1.9 Hz, 1H) , 7.16 (d, J = 5.3 Hz, 1H) , 7.07 (t, J = 1.7 Hz, 1H) , 6.99 (t, J = 2.1 Hz, 1H) , 6.84 (dd, J = 2.4, 1.4 Hz, 1H) , 6.45 (d, J = 1.9 Hz, 1H) , 3.91 (s, 3H) , 3.84 (s, 3H) .
Example 202.
6-Bromo-N- (3-methoxy-5- (2-methoxypropoxy) phenyl) quinolin-4-amine: 6-bromo-4-chloroquinoline (73 mg, 0.3 mmol, 1.0 eq) , 3-methoxy-5- (2-methoxypropoxy) aniline (68 mg, 0.3 mmol, 1.0 eq) and PPTS (23 mg, 0.09 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then
washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuo. The crude material was purified by silica gel flash chromatography to afford the product as a solid (125 mg, yield = 99 %, purity = 100 %) .
TLC Rf = 0.25 (PE/EA = 4/1) ;
MS (ESI+) : m/z = 417.2 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.00 (s, 1H) , 8.63 (t, J = 1.4 Hz, 1H) , 8.51 (d, J = 5.3 Hz, 1H) , 7.81 (d, J = 1.3 Hz, 2H) , 7.10 (d, J = 5.3 Hz, 1H) , 6.52 (dt, J = 3.1, 1.5 Hz, 2H) , 6.31 (t, J = 2.2 Hz, 1H) , 3.92 (d, J = 5.1 Hz, 2H) , 3.76 (s, 3H) , 3.70 –3.61 (m, 1H) , 3.31 (s, 3H) , 1.16 (d, J = 6.3 Hz, 3H) .
Example 203.
6-Bromo-N- (3-methoxy-5- ( (1-methoxypropan-2-yl) oxy) phenyl) quinolin-4-amine: 6-bromo-4-chloroquinoline (122 mg, 0.5 mmol, 1.0 eq) , 3-methoxy-5- ( (1-methoxypropan-2-yl) oxy) aniline (106 mg, 0.5 mmol, 1.0 eq) and PPTS (38 mg, 0.15 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuo. The crude material was purified by silica gel flash chromatography to afford the product as a solid (145 mg, yield = 69.5 %, purity = 98.2 %) .
TLC Rf = 0.25 (PE/EA = 4/1) ;
MS (ESI+) : m/z = 418.3 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 8.96 (s, 1H) , 8.62 (t, J = 1.4 Hz, 1H) , 8.51 (d, J = 5.3 Hz, 1H) , 7.81 (d, J = 1.3 Hz, 2H) , 7.08 (d, J = 5.3 Hz, 1H) , 6.51 (dt, J = 6.9, 1.9 Hz, 2H) , 6.29 (t, J = 2.2 Hz, 1H) , 4.58 (pd, J = 6.1, 4.1 Hz, 1H) , 3.74 (s, 3H) , 3.54 –3.39 (m, 2H) , 3.29 (s, 3H) , 1.23 (d, J = 6.2 Hz, 3H) .
Example 204.
6-Bromo-N- (3- (2, 2-difluoroethoxy) -5-methoxyphenyl) quinolin-4-amine: 6-bromo-4-chloroquinoline (122 mg, 0.5 mmol, 1.0 eq) , 3- (2, 2-difluoroethoxy) -5-methoxyaniline (102 mg, 0.5 mmol, 1.0 eq) and PPTS (38 mg, 0.15 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuo. The crude material was purified by silica gel flash chromatography to afford the product as a solid (140 mg, yield = 68.4 %, purity = 100 %) .
TLC Rf = 0.25 (PE/EA = 1/1) ;
MS (ESI+) : m/z = 410.3 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.01 (s, 1H) , 8.63 (t, J = 1.3 Hz, 1H) , 8.52 (d, J = 5.3 Hz, 1H) , 7.82 (d, J = 1.6 Hz, 2H) , 7.13 (d, J = 5.3 Hz, 1H) , 6.58 (p, J = 1.9 Hz, 2H) , 6.42 –6.36 (m, 2H) , 4.32 (td, J = 14.7, 3.6 Hz, 2H) , 3.77 (s, 3H) .
Example 205.
6-Bromo-N- (3-methoxy-5- (tetrahydrofuran-3-yl) phenyl) quinolin-4-amine: 6-bromo-4-chloroquinoline (122 mg, 0.5 mmol, 1.0 eq) , 3-methoxy-5- (tetrahydrofuran-3-yl) aniline (97 mg, 0.5 mmol, 1.0 eq) and PPTS (38 mg, 0.15 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then
washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuo. The crude material was purified by silica gel flash chromatography to afford the product as a solid (175 mg, yield = 87.7 %, purity = 100 %) .
TLC Rf = 0.25 (PE/EA = 1/2) ;
MS (ESI+) : m/z = 400.2 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.01 (s, 1H) , 8.65 (t, J = 1.4 Hz, 1H) , 8.50 (d, J = 5.3 Hz, 1H) , 7.81 (d, J = 1.2 Hz, 2H) , 7.05 (d, J = 5.3 Hz, 1H) , 6.86 (t, J = 1.7 Hz, 1H) , 6.78 (t, J = 2.2 Hz, 1H) , 6.64 (t, J = 1.9 Hz, 1H) , 4.03 (dd, J = 8.2, 7.4 Hz, 1H) , 3.94 (td, J = 8.3, 4.6 Hz, 1H) , 3.84 –3.73 (m, 4H) , 3.60 (dd, J = 8.3, 7.3 Hz, 1H) , 3.37 (p, J = 8.0 Hz, 1H) , 2.37 –2.25 (m, 1H) , 1.94 (dq, J = 12.2, 8.0 Hz, 1H) .
Example 206.
6-Bromo-N- (3-methoxy-5- (pyrrolidin-1-yl) phenyl) quinolin-4-amine: 6-bromo-4-chloroquinoline (363 mg, 1.5 mmol, 1.0 eq) , 3-methoxy-5- (pyrrolidin-1-yl) aniline (288 mg, 1.5 mmol, 1.0 eq) and PPTS (113 mg, 0.45 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 5 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as a solid (516.4 mg, yield = 86.7 %, purity = 92.94 %) .
TLC Rf = 0.55 (DCM/MeOH = 10/1) ;
MS (ESI+) : m/z = 400.10 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 8.88 (s, 1H) , 8.66 (t, J = 1.4 Hz, 1H) , 8.46 (d, J = 5.4 Hz, 1H) , 7.79 (d, J = 1.2 Hz, 2H) , 7.06 (d, J = 5.3 Hz, 1H) , 6.20 (t, J = 1.9 Hz, 1H) , 6.14 (t, J = 1.9 Hz, 1H) , 5.89 (t, J = 2.1 Hz, 1H) , 3.73 (s, 3H) , 3.24 –3.18 (m, 4H) , 1.96 –1.92 (m, 4H) .
Example 207.
6-Bromo-N- (3-methoxy-5- (piperidin-1-yl) phenyl) quinolin-4-amine: 6-bromo-4-chloroquinoline (484 mg, 2 mmol, 1.0 eq) , 3-methoxy-5- (piperidin-1-yl) aniline (412 mg, 2 mmol, 1.0 eq) and PPTS (151 mg, 0.6 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 5 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as a solid (705.5 mg, yield = 85.82 %, purity = 94.30 %) .
TLC Rf = 0.50 (DCM/MeOH = 10/1) ;
MS (ESI+) : m/z = 412.20 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 8.89 (s, 1H) , 8.64 (t, J = 1.3 Hz, 1H) , 8.47 (d, J = 5.3 Hz, 1H) , 7.79 (d, J = 1.4 Hz, 2H) , 7.03 (d, J = 5.4 Hz, 1H) , 6.49 (t, J = 1.9 Hz, 1H) , 6.34 (t, J = 1.9 Hz, 1H) , 6.26 (t, J = 2.2 Hz, 1H) , 3.73 (s, 3H) , 3.15 (t, J = 5.3 Hz, 4H) , 1.67 –1.45 (m, 6H) .
Example 208.
6-Bromo-N- (3-methoxy-5-morpholinophenyl) quinolin-4-amine: 6-bromo-4-chloroquinoline (121 mg, 0.5 mmol, 1.0 eq) , 3-methoxy-5-morpholinoaniline (104 mg, 0.5 mmol, 1.0 eq) and PPTS (38 mg, 0.15 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed
with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as a solid (239.2 mg, yield = 99 %, purity = 99.02 %) .
TLC Rf = 0.40 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z = 415.20 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 8.94 (s, 1H) , 8.65 (t, J = 1.4 Hz, 1H) , 8.48 (d, J = 5.3 Hz, 1H) , 7.80 (d, J = 1.2 Hz, 2H) , 7.04 (d, J = 5.3 Hz, 1H) , 6.51 (t, J = 1.9 Hz, 1H) , 6.41 (t, J = 1.9 Hz, 1H) , 6.30 (t, J = 2.2 Hz, 1H) , 3.76 –3.70 (m, 7H) , 3.15 –3.08 (m, 4H) .
Example 209.
6-Bromo-N- (3- (furan-3-yl) -5-methoxyphenyl) quinolin-4-amine: 6-bromo-4-chloroquinoline (110 mg, 0.46 mmol, 1.0 eq) , 3- (furan-3-yl) -5-methoxyaniline (86 mg, 46 mmol, 1.0 eq) and PPTS (35 mg, 0.14 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuo. The crude material was purified by silica gel flash chromatography to afford the product as a solid (131 mg, yield = 72.1 %, purity =100 %) .
TLC Rf = 0.25 (PE/EA = 2/1) ;
MS (ESI+) : m/z = 396.2 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.06 (s, 1H) , 8.68 (t, J = 1.3 Hz, 1H) , 8.51 (d, J = 5.3 Hz, 1H) , 8.25 –8.20 (m, 1H) , 7.82 (d, J = 1.7 Hz, 2H) , 7.74 (t, J = 1.7 Hz, 1H) , 7.19 (t, J = 1.7 Hz, 1H) , 7.06 (d, J = 5.3 Hz, 1H) , 6.99 (dd, J = 2.4, 1.4 Hz, 1H) , 6.97 (dd, J = 1.9, 0.9 Hz, 1H) , 6.83 (t, J =2.1 Hz, 1H) , 3.82 (s, 3H) .
Example 210.
6-Bromo-N- (3-methoxy-5- (thiophen-3-yl) phenyl) quinolin-4-amine: 6-bromo-4-chloroquinoline (122 mg, 0.5 mmol, 1.0 eq) , 3-methoxy-5- (thiophen-3-yl) aniline (103 mg, 0.5 mmol, 1.0 eq) and PPTS (38 mg, 0.15 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuo. The crude material was purified by silica gel flash chromatography to afford the product as a solid (137 mg, yield = 66.7 %, purity = 100 %) .
TLC Rf = 0.25 (PE/EA = 2/1) ;
MS (ESI+) : m/z = 413.4 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.09 (s, 1H) , 8.68 (t, J = 1.4 Hz, 1H) , 8.51 (d, J = 5.3 Hz, 1H) , 7.92 (dd, J = 3.0, 1.4 Hz, 1H) , 7.82 (d, J = 1.6 Hz, 2H) , 7.64 (dd, J = 5.0, 2.9 Hz, 1H) , 7.56 (dd, J = 5.0, 1.4 Hz, 1H) , 7.29 (t, J = 1.7 Hz, 1H) , 7.10 (d, J = 5.4 Hz, 1H) , 7.07 (dd, J = 2.3, 1.4 Hz, 1H) , 6.87 (t, J = 2.1 Hz, 1H) , 3.84 (s, 3H) .
Example 211.
6-Bromo-N- (3-methoxy-5- (1H-pyrazol-4-yl) phenyl) quinolin-4-amine 6-bromo-4-chloroquinoline (134 mg, 0.55 mmol, 1.0e quiv) , tert-butyl 4- (3-amino-5-methoxyphenyl) -1H-pyrazole-1-carboxylate (158 mg, 0.55 mmol, 1.0 eq) and PPTS (43 mg, 0.17 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of
N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuo. The crude material was purified by silica gel flash chromatography to afford the product as a solid (67 mg, yield = 30.8 %, purity = 93 %) .
TLC Rf = 0.25 (PE/EA = 1/4) ;
MS (ESI+) : m/z = 395.8 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 12.96 (s, 1H) , 9.05 (s, 1H) , 8.69 (t, J = 1.4 Hz, 1H) , 8.50 (d, J = 5.3 Hz, 1H) , 8.21 (s, 1H) , 7.95 (dd, J = 7.4, 5.3 Hz, 1H) , 7.81 (d, J = 1.3 Hz, 2H) , 7.19 (t, J =1.6 Hz, 1H) , 7.05 (d, J = 5.3 Hz, 1H) , 7.00 (dd, J = 2.4, 1.4 Hz, 1H) , 6.76 (t, J = 2.1 Hz, 1H) , 3.82 (s, 3H) .
Example 212.
6-Bromo-N- (3-methoxy-5- (1- (2-methoxyethyl) -1H-pyrazol-4-yl) phenyl) quinolin-4-amine: 6-bromo-4-chloroquinoline (121 mg, 0.5 mmol, 1.0 eq) , 3-methoxy-5- (1- (2-methoxyethyl) -1H-pyrazol-4-yl) aniline (123 mg, 0.5 mmol, 1.0 eq) , and PPTS (38 mg, 0.15 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as an oil (153.4 mg, yield = 67.88 %, purity = 89.40 %) .
TLC Rf = 0.40 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z = 453.20 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.07 (s, 1H) , 8.68 (t, J = 1.4 Hz, 1H) , 8.50 (d, J = 5.4 Hz, 1H) , 8.19 (d, J = 0.8 Hz, 1H) , 7.90 (d, J = 0.8 Hz, 1H) , 7.89 –7.80 (m, 2H) , 7.15 (t, J = 1.7 Hz, 1H) , 7.05 (d, J = 5.3 Hz, 1H) , 6.96 (dd, J = 2.4, 1.4 Hz, 1H) , 6.76 (t, J = 2.1 Hz, 1H) , 4.26 (t, J = 5.3
Hz, 2H) , 3.82 (s, 3H) , 3.71 (t, J = 5.3 Hz, 2H) , 3.24 (s, 3H) .
Example 213.
2- (4- (3- ( (6-Bromoquinolin-4-yl) amino) -5-methoxyphenyl) -1H-pyrazol-1-yl) ethan-1-ol: 6-bromo-4-chloroquinoline (121 mg, 0.5 mmol, 1.0 eq) , 2- (4- (3-amino-5-methoxyphenyl) -1H-pyrazol-1-yl) ethan-1-ol (116 mg, 0.5 mmol, 1.0 eq) , and PPTS (38 mg, 0.15 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as an oil (195.9 mg, yield = 89.45%, purity = 93.99 %) .
TLC Rf = 0.20 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z = 438.10 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.09 (s, 1H) , 8.69 (t, J = 1.4 Hz, 1H) , 8.50 (d, J = 5.4 Hz, 1H) , 8.18 (d, J = 0.8 Hz, 1H) , 7.89 (d, J = 0.8 Hz, 1H) , 7.82 (d, J = 1.2 Hz, 2H) , 7.16 (t, J = 1.6 Hz, 1H) , 7.05 (d, J = 5.3 Hz, 1H) , 6.96 (dd, J = 2.4, 1.4 Hz, 1H) , 6.75 (t, J = 2.1 Hz, 1H) , 4.93 (d, J =5.7 Hz, 1H) , 4.15 (t, J = 5.6 Hz, 2H) , 3.82 (s, 3H) , 3.76 (q, J = 5.2 Hz, 2H) .
Example 214.
4- (3- ( (6-Bromoquinolin-4-yl) amino) -5-methoxyphenyl) -1-methylpyridin-2 (1H) -one: 6-bromo-4-chloroquinoline (80 mg, 0.32 mmol, 1.0 eq) , 4- (3-amino-5-methoxyphenyl) -1-methylpyridin-2 (1H) -one (80 mg, 0.34 mmol, 1.05 eq) and PPTS (25 mg, 0.09 mmol, 0.3 eq) were
added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 3 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as off-white solid (89 mg, yield = 61.8 %, purity = 98.76%) .
TLC Rf = 0.25 (EA/PE=4/1) ;
MS (ESI+) : m/z = 435.90 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.12 (s, 1H) , 8.65 (t, J = 1.3 Hz, 1H) , 8.54 (d, J = 5.3 Hz, 1H) , 7.83 (d, J = 1.4 Hz, 2H) , 7.24 (t, J = 1.7 Hz, 1H) , 7.16 (d, J = 5.3 Hz, 1H) , 7.00 (dt, J = 5.5, 2.1 Hz, 2H) , 6.69 (d, J = 2.1 Hz, 1H) , 6.56 (dd, J = 7.1, 2.1 Hz, 1H) , 3.85 (s, 3H) , 3.45 (s, 3H) .
Example 215.
6-Bromo-N- (3-methoxy-5- (1- (oxetan-3-yl) -1H-pyrazol-4-yl) phenyl) quinolin-4-amine: 6-bromo-4-chloroquinoline (80 mg, 0.32 mmol, 1.0 eq) , 3-methoxy-5- (1- (oxetan-3-yl) -1H-pyrazol-4-yl) aniline (89 mg, 0.36 mmol, 1.1 eq) and PPTS (25 mg, 0.09 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 3 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (131 mg, yield = 87.9 %, purity = 96.2%) .
TLC Rf = 0.25 (100%EA) ;
MS (ESI+) : m/z = 453.2 (M+2) ;
Example 216.
6-Bromo-N- (3-methoxy-5- (1- (3-methoxypropyl) -1H-pyrazol-4-yl) phenyl) quinolin-4-amine: 6-bromo-4-chloroquinoline (97 mg, 0.4 mmol, 1.0 eq) , 3-methoxy-5- (1- (3-methoxypropyl) -1H-pyrazol-4-yl) aniline (105 mg, 0.4 mmol, 1.0 eq) , and PPTS (30 mg, 0.12 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as an oil (106.1 mg, yield =56.92 %, purity = 99.51 %) .
TLC Rf = 0.45 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z = 468.80 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.05 (s, 1H) , 8.68 (t, J = 1.3 Hz, 1H) , 8.50 (d, J = 5.3 Hz, 1H) , 8.21 (d, J = 0.8 Hz, 1H) , 7.89 (d, J = 0.8 Hz, 1H) , 7.82 (d, J = 1.3 Hz, 2H) , 7.16 (t, J = 1.6 Hz, 1H) , 7.05 (d, J = 5.3 Hz, 1H) , 6.96 (dd, J = 2.4, 1.4 Hz, 1H) , 6.75 (t, J = 2.1 Hz, 1H) , 4.15 (t, J =7.0 Hz, 2H) , 3.81 (s, 3H) , 3.30 (t, J = 6.2 Hz, 2H) , 3.23 (s, 3H) , 2.08 –1.96 (m, 2H) .
Example 217.
3- (4- (3- ( (6-Bromoquinolin-4-yl) amino) -5-methoxyphenyl) -1H-pyrazol-1-yl) propanenitrile: 6-bromo-4-chloroquinoline (97 mg, 0.4 mmol, 1.0 eq) , 3- (4- (3-amino-5-methoxyphenyl) -1H-pyrazol-1-yl) propanenitrile (97mg, 0.4 mmol, 1.0 eq) , and PPTS (30 mg, 0.12 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO
was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as an oil (165.4 mg, yield =92.50 %, purity = 99.38 %) .
TLC Rf = 0.40 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z = 449.90 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.08 (s, 1H) , 8.68 (t, J = 1.4 Hz, 1H) , 8.51 (d, J = 5.3 Hz, 1H) , 8.30 (d, J = 0.8 Hz, 1H) , 7.99 (d, J = 0.8 Hz, 1H) , 7.82 (d, J = 1.2 Hz, 2H) , 7.17 (t, J = 1.6 Hz, 1H) , 7.06 (d, J = 5.3 Hz, 1H) , 6.97 (dd, J = 2.3, 1.4 Hz, 1H) , 6.78 (t, J = 2.1 Hz, 1H) , 4.41 (t, J =6.4 Hz, 2H) , 3.82 (s, 3H) , 3.11 (t, J = 6.4 Hz, 2H) .
Example 218.
6-Bromo-N- (3- (1-cyclopropyl-1H-pyrazol-4-yl) -5-methoxyphenyl) quinolin-4-amine: 6-bromo-4-chloroquinoline (97 mg, 0.4 mmol, 1.0 eq) , 3- (1-cyclopropyl-1H-pyrazol-4-yl) -5-methoxyaniline (92 mg, 0.4 mmol, 1.0 eq) , and PPTS (30 mg, 0.12 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as a solid (143.1 mg, yield = 82.43 %, purity = 99.49 %) .
TLC Rf = 0.50 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z = 436.90 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.04 (s, 1H) , 8.68 (t, J = 1.4 Hz, 1H) , 8.50 (d, J = 5.3 Hz, 1H) , 8.27 (d, J = 0.8 Hz, 1H) , 7.87 (d, J = 0.8 Hz, 1H) , 7.83 –7.80 (m, 2H) , 7.17 (t, J = 1.7 Hz, 1H) ,
7.04 (d, J = 5.3 Hz, 1H) , 6.97 (dd, J = 2.4, 1.4 Hz, 1H) , 6.75 (t, J = 2.1 Hz, 1H) , 3.81 (s, 3H) , 3.73 (tt, J = 7.5, 3.9 Hz, 1H) , 1.10 –1.04 (m, 2H) , 1.00 –0.94 (m, 2H) .
Example 219.
4- (3- ( (6-Bromoquinolin-4-yl) amino) -5-methoxyphenyl) piperazin-2-one: 6-bromo-4-chloroquinoline (110 mg, 0.45 mmol, 1.5 eq) , 4- (3-amino-5-methoxyphenyl) piperazin-2-one (66 mg, 0.3 mmol, 1.0 eq) and PPTS (75 mg, 0.3 mmol, 1.0 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuo. The crude material was purified by silica gel flash chromatography to afford the product as a black solid (41 mg, yield = 32.0 %, purity = 89.23 %) .
TLC Rf = 0.25 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z = 427.0 (M+H) ;
Example 220.
6-Bromo-N- (3-methoxy-5- (1-methyl-1H-imidazol-5-yl) phenyl) quinolin-4-amine: 6-bromo-4-chloroquinoline (100 mg, 0.41 mmol, 1.0 eq) , 3-methoxy-5- (1-methyl-1H-imidazol-5-yl) aniline (88 mg, 0.43 mmol, 1.05 eq) and PPTS (31 mg, 0.12 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 3 h with vigorous stirring. The cooled solution was poured
into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as brown solid (124 mg, yield = 73.4%, purity = 98.82%) .
TLC Rf = 0.3 (10%MeOH/DCM) ;
MS (ESI+) : m/z = 410.9 (M+2) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.11 (s, 1H) , 8.65 (t, J = 1.4 Hz, 1H) , 8.52 (d, J = 5.3 Hz, 1H) , 7.82 (d, J = 1.4 Hz, 2H) , 7.71 (s, 1H) , 7.17 –7.10 (m, 2H) , 7.04 (t, J = 1.7 Hz, 1H) , 6.93 (t, J = 2.1 Hz, 1H) , 6.84 –6.80 (m, 1H) , 3.83 (s, 3H) , 3.73 (s, 3H) .
Example 221.
6-Bromo-N- (3-methoxy-5- (1-methyl-1H-pyrazol-5-yl) phenyl) quinolin-4-amine: 6-bromo-4-chloroquinoline (100 mg, 0.41 mmol, 1.0 eq) , 3-methoxy-5- (1-methyl-1H-pyrazol-5-yl) aniline (88 mg, 0.43 mmol, 1.05 eq) and PPTS (31 mg, 0.12 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 3 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (120 mg, yield = 71.1%, purity = 99.01%) .
TLC Rf = 0.2 (EA/PE=1/1) ;
MS (ESI+) : m/z = 411.0 (M+2) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.13 (s, 1H) , 8.64 (t, J = 1.4 Hz, 1H) , 8.53 (d, J = 5.3 Hz, 1H) , 7.83 (d, J = 1.6 Hz, 2H) , 7.47 (d, J = 1.9 Hz, 1H) , 7.16 (d, J = 5.3 Hz, 1H) , 7.07 (t, J = 1.6 Hz, 1H) , 6.99 (t, J = 2.1 Hz, 1H) , 6.84 (dd, J = 2.4, 1.4 Hz, 1H) , 6.45 (d, J = 1.9 Hz, 1H) , 3.91 (s, 3H) , 3.84 (s, 3H) .
Example 222.
1- (4- (3- ( (6-bromoquinolin-4-yl) amino) -5-methoxyphenyl) -1H-pyrazol-1-yl) -2-methylpropan-2-ol: 6-bromo-4-chloroquinoline (70 mg, 0.28 mmol, 1.0 eq) , 1- (4- (3-amino-5-methoxyphenyl) -1H-pyrazol-1-yl) -2-methylpropan-2-ol (79 mg, 0.3 mmol, 1.05 eq) and PPTS (22 mg, 0.08 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 3 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as off-white solid (96 mg, yield = 71.1%, purity = 99.3%) .
TLC Rf = 0.3 (PE/EA=1/4) ;
MS (ESI+) : m/z = 469.1 (M+2) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.07 (s, 1H) , 8.69 (t, J = 1.3 Hz, 1H) , 8.50 (d, J = 5.4 Hz, 1H) , 8.26 (s, 1H) , 7.89 (s, 1H) , 7.85 –7.78 (m, 2H) , 7.19 (t, J = 1.7 Hz, 1H) , 7.08 –6.97 (m, 2H) , 6.74 (t, J = 2.1 Hz, 1H) , 4.99 (t, J = 5.7 Hz, 1H) , 3.82 (s, 3H) , 3.60 (d, J = 5.0 Hz, 2H) , 1.49 (s, 6H) .
Example 223.
6-bromo-N- (3- (isoxazol-4-yl) -5-methoxyphenyl) quinolin-4-amine: 6-bromo-4-chloroquinoline (70 mg, 0.28 mmol, 1.0 eq) , 3- (isoxazol-4-yl) -5-methoxyaniline (58 mg, 0.3 mmol, 1.05 eq) and PPTS (22 mg, 0.08 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and
backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 3 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as off-white solid (103 mg, yield = 90%, purity = 98.2%) .
TLC Rf = 0.4 (PE/EA=1/4) ;
1H NMR (400 MHz, DMSO-d6) : 9.50 (s, 1H) , 9.36 –8.93 (m, 2H) , 8.69 (d, J = 1.4 Hz, 1H) , 8.52 (d, J = 5.3 Hz, 1H) , 7.88 –7.80 (m, 2H) , 7.30 (t, J = 1.6 Hz, 1H) , 7.12 (t, J = 1.9 Hz, 1H) , 7.07 (d, J = 5.4 Hz, 1H) , 6.88 (t, J = 2.1 Hz, 1H) , 3.84 (s, 3H) .
Example 224.
6-Bromo-N- (3-methoxy-5- (1H-1, 2, 4-triazol-1-yl) phenyl) quinolin-4-amine: 6-bromo-4-chloroquinoline (121.5 mg, 0.5 mmol, 1.0 eq) , 3-methoxy-5- (1H-1, 2, 4-triazol-1-yl) aniline (95.1 mg, 0.5 mmol, 1.0 eq) and PPTS (38 mg, 0.0.13 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 5 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as a solid (94.9 mg, yield = 48.05 %, purity = 100 %) .
TLC Rf = 0.3 (DCM/MeOH = 10/1) ;
MS (ESI+) : m/z = 397.60 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.35 (s, 1H) , 9.24 (s, 1H) , 8.66 (t, J = 1.3 Hz, 1H) , 8.57 (d, J = 5.3 Hz, 1H) , 8.24 (s, 1H) , 7.84 (d, J = 1.9 Hz, 2H) , 7.47 (d, J = 2.0 Hz, 1H) , 7.25 –7.20 (m, 2H) , 6.96 (t, J = 2.1 Hz, 1H) , 3.87 (s, 3H) .
Example 225.
6-Bromo-N- (3-methoxy-5- (4-methyl-1H-1, 2, 3-triazol-1-yl) phenyl) quinolin-4-amine: 6-bromo-4-chloroquinoline (122 mg, 0.5 mmol, 1.0 eq) , 3-methoxy-5- (4-methyl-1H-1, 2, 3-triazol-1-yl) aniline (102 mg, 0.5 mmol, 1.0 eq) and PPTS (38 mg, 0.15 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuo. The crude material was purified by silica gel flash chromatography to afford the product as a solid (178 mg, yield = 86.8 %, purity = 100 %) .
TLC Rf = 0.25 (PE/EA = 1/2) ;
MS (ESI+) : m/z = 411.8 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.24 (s, 1H) , 8.67 –8.63 (m, 1H) , 8.60 –8.56 (m, 2H) , 7.89 –7.80 (m, 2H) , 7.49 (t, J = 1.9 Hz, 1H) , 7.24 (d, J = 5.3 Hz, 1H) , 7.18 (t, J = 2.1 Hz, 1H) , 6.99 (t, J = 2.0 Hz, 1H) , 3.87 (s, 3H) , 2.33 (d, J = 0.8 Hz, 3H) .
Example 226.
6-Bromo-N- (3-methoxy-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) phenyl) quinolin-4-amine: 6-bromo-4-chloroquinoline (29 mg, 0.12 mmol, 1.0 eq) , 3-methoxy-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) aniline (25 mg, 0.12 mmol, 1.0 eq) and PPTS (9 mg, 0.04 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 1 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured
into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuo. The crude material was purified by silica gel flash chromatography to afford the product as a solid (28 mg, yield = 56.8%, purity = 99.3%) .
TLC Rf = 0.25 (PE/EA = 2/1) ;
MS (ESI+) : m/z = 413.0 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.25 (s, 1H) , 8.65 (t, J = 1.3 Hz, 1H) , 8.58 (d, J = 5.3 Hz, 1H) , 7.85 (d, J = 1.8 Hz, 2H) , 7.56 (t, J = 1.7 Hz, 1H) , 7.24 –7.18 (m, 2H) , 7.15 (t, J = 2.2 Hz, 1H) , 3.87 (s, 3H) , 2.59 (s, 3H) .
Example 227.
5- (3- ( (6-bromoquinolin-4-yl) amino) -5-methoxyphenyl) -1-methylpyridin-2 (1H) -one: 6-bromo-4-chloroquinoline (70 mg, 0.28 mmol, 1.0 eq) , 5- (3-amino-5-methoxyphenyl) -1-methylpyridin-2 (1H) -one (70 mg, 0.3 mmol, 1.05 eq) and PPTS (22 mg, 0.08 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 3 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as off-white solid (116 mg, yield = 92.1%, purity = 98.78%) .
TLC Rf = 0.25 (PE/EA=1/4) ;
MS (ESI+) : m/z = 436.0 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 11.12 (s, 1H) , 9.17 (d, J = 2.0 Hz, 1H) , 8.53 (d, J = 7.0 Hz, 1H) , 8.26 (d, J = 2.7 Hz, 1H) , 8.18 (dd, J = 9.0, 1.9 Hz, 1H) , 8.07 (d, J = 8.9 Hz, 1H) , 7.87 (dd, J = 9.5, 2.7 Hz, 1H) , 7.29 (t, J = 1.7 Hz, 1H) , 7.20 (t, J = 1.9 Hz, 1H) , 7.02 –6.94 (m, 2H) , 6.48 (d, J = 9.5 Hz, 1H) , 3.87 (s, 3H) , 3.51 (s, 3H) .
Example 228.
N- (3- (1H-imidazol-1-yl) -5-methoxyphenyl) -6-bromoquinolin-2-d-4-amine: To an oven dried two neck round bottom 6-bromo-4-chloroquinoline-2-d (70 mg, 0.29 mmol, 1 eq) , 3- (1H-imidazol-1-yl) -5-methoxyaniline (54 mg, 0.29 mmol, 1 eq) and NMP (2 mL) were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 100 ℃ and stirred at same temperature for 16 h. After consumption of the starting material monitored by TLC, the reaction mixture was cooled down to room temperature. The reaction mixture was diluted with water (25 mL) and extracted with EtOAc (3 x 20 mL) . The combined organic phase was washed with brine solution, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude compound was purified by flash column chromatography to afford the product as a brown solid (35 mg, 30.7%) .
TLC Rf = 0.2 (100%EtOAc) .
MS (ESI+) : m/z = 398.30 (M+H)
1H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H) , 8.65 (s, 1H) , 8.30 (s, 1H) , 7.88 –7.82 (m, 2H) , 7.78 (s, 1H) , 7.29 –7.16 (m, 2H) , 7.10 (s, 1H) , 7.00 (s, 1H) , 6.90 (s, 1H) , 3.85 (s, 3H) .
Example 229.
N- (3- (furan-3-yl) -5-methoxyphenyl) -6- (trifluoromethyl) quinolin-4-amine 4-chloro-6-(trifluoromethyl) quinoline (116 mg, 0.5 mmol, 1.0 eq) , 3- (furan-3-yl) -5-methoxyaniline (95 mg, 0.5 mmol, 1.0 eq) and PPTS (38 mg, 0.15 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then
washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuo. The crude material was purified by silica gel flash chromatography to afford the product as a solid (154 mg, yield = 80.1 %, purity = 100 %) .
TLC Rf = 0.25 (PE/EA = 2/1) ;
MS (ESI+) : m/z = 385.2 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.35 (s, 1H) , 8.91 (s, 1H) , 8.59 (d, J = 5.4 Hz, 1H) , 8.24 (t, J = 1.2 Hz, 1H) , 8.05 (d, J = 8.8 Hz, 1H) , 7.93 (dd, J = 8.9, 1.9 Hz, 1H) , 7.75 (t, J = 1.8 Hz, 1H) , 7.22 (t, J = 1.7 Hz, 1H) , 7.08 (d, J = 5.4 Hz, 1H) , 7.04 (dd, J = 2.3, 1.4 Hz, 1H) , 6.99 (dd, J = 1.9, 0.9 Hz, 1H) , 6.86 (t, J = 2.1 Hz, 1H) , 3.83 (s, 3H) .
Example 230.
N- (3-Methoxy-5- (thiophen-2-yl) phenyl) -6- (trifluoromethoxy) quinolin-4-amine: To an oven dried seal tube with a magnetic bar was filled with 1, 4-dioaxne : H2O (4: 1) mixture. The solvent mixture was purged with argon at room temperature. To this purged solution, N- (3-bromo-5-methoxyphenyl) -6- (trifluoromethoxy) quinolin-4-amine (150 mg, 0.36 mmol, 1 eq) , thiophen-2-ylboronic acid (60.4 mg, 0.47 mmol, 1.3 eq) , Pd (dppf) Cl2 (13 mg, 5 mol%) and K2CO3 (100 mg, 0.72 mmol, 2 eq) were added. The reaction mixture was degassed with argon (the sequence was carried out 2 times) and reaction tube was sealed with Teflon screw cap. The reaction mixture was subsequently stirred in a preheated oil bath at 110 ℃ for 16 h. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate (50 mL) and washed with water (3×20 mL) &brine (3×20 mL) . The organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude residue was purified by flash column chromatography to afford the product as an off-white solid (50 mg, yield = 33%) .
TLC Rf = 0.2 (100%EA) .
1H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 1H) , 8.56 (d, J = 5.3 Hz, 1H) , 8.43 (s, 1H) , 8.02 (d, J = 9.2 Hz, 1H) , 7.77 (s, 1H) , 7.71 (d, J = 9.2 Hz, 1H) , 7.30 (s, 1H) , 7.11 (d, J = 5.3 Hz, 1H) , 7.06 (s, 1H) , 7.02 (s, 1H) , 6.87 (s, 1H) , 6.61 (s, 1H) , 3.83 (s, 3H) .
Example 231.
N- (3- (Furan-3-yl) -5-methoxyphenyl) -6- (trifluoromethoxy) quinolin-4-amine: To an oven dried seal tube with a magnetic bar was filled with 1, 4-dioaxne : H2O (4: 1) mixture. The solvent mixture was purged with argon at room temperature. To this purged solution, N- (3-bromo-5-methoxyphenyl) -6- (trifluoromethoxy) quinolin-4-amine (150 mg, 0.36 mmol, 1 eq) , furan-3-ylboronic acid (53 mg, 0.47 mmol, 1.3 eq) , Pd (dppf) Cl2 (13 mg, 5 mol%) and K2CO3 (100 mg, 0.72 mmol, 2 eq) were added. The reaction mixture was degassed with argon (the sequence was carried out 2 times) and reaction tube was sealed with Teflon screw cap. The reaction mixture was subsequently stirred in a preheated oil bath at 110 ℃ for 16 h. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate (50 mL) and washed with water (3×20 mL) &brine (3×20 mL) . The organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude residue was purified by flash column chromatography to afford the product as a pale-yellow solid (66 mg, yield = 45.4%) .
TLC Rf = 0.2 (100%EA) .
MS (ESI+) : m/z = 401.10 (M+H) .
1H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H) , 8.53 (d, J = 5.4 Hz, 1H) , 8.45 (s, 1H) , 8.24 (s, 1H) , 8.01 (d, J = 9.1 Hz, 1H) , 7.75 (s, 1H) , 7.71 (d, J = 9.4 Hz, 1H) , 7.20 (s, 1H) , 7.05 (d, J = 5.4 Hz, 1H) , 7.02 (s, 1H) , 6.98 (s, 1H) , 6.84 (d, J = 2.1 Hz, 1H) , 3.82 (s, 3H) .
Example 232.
N- (3-methoxy-5- (1H-pyrazol-1-yl) phenyl) -6- (trifluoromethoxy) quinolin-4-amine: To an oven dried two neck round bottom 4-chloro-6- (trifluoromethoxy) quinoline hydrochloride
(100.00 mg, 0.352 mmol, 1.00 eq) and 3-methoxy-5- (1H-pyrazol-1-yl) aniline (80.00 mg, 0.422 mmol, 1.2 eq) , K2CO3 (48.65 mg, 0.352 mmol, 1.0 eq) and NMP (3 mL) were added at room temperature under N2 atmosphere. The reaction mixture was warmed to 110 ℃ and stirred at same temperature for 16 h. After consumption of starting material monitored by TLC, the reaction mixture was cooled down to room temperature. The reaction mixture was diluted with water (25 mL) and extracted with EtOAc (3 x 20 mL) . The combined organic phase was washed with brine solution, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude compound was purified by flash column chromatography to afford the product as a pale brown solid (75 mg, 53.2%) .
TLC Rf = 0.4 (100%EtOAc) .
MS (ESI+) : m/z = 401.10 (M+H) .
1H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 1H) , 8.59 (d, J = 5.3 Hz, 1H) , 8.56 (d, J = 2.5 Hz, 1H) , 8.43 (s, 1H) , 8.03 (d, J = 9.2 Hz, 1H) , 7.79 –7.67 (m, 2H) , 7.49 (d, J = 2.0 Hz, 1H) , 7.25 –7.13 (m, 2H) , 6.87 (t, J = 2.1 Hz, 1H) , 6.55 (t, J = 2.2 Hz, 1H) , 3.86 (s, 3H) .
Example 233.
N- (3-Methoxy-5- (1H-pyrazol-3-yl) phenyl) -6- (trifluoromethoxy) quinolin-4-amine: To an oven dried seal tube with a magnetic bar was filled with 1, 4-dioaxne : H2O (4: 1) mixture. The solvent mixture was purged with argon at room temperature. To this purged solution, N- (3-bromo-5-methoxyphenyl) -6- (trifluoromethoxy) quinolin-4-amine (150 mg, 0.36 mmol, 1 eq) , 3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (91.6 mg, 0.47 mmol, 1.3 eq) , Pd (dppf) Cl2 (13 mg, 5 mol%) and K2CO3 (100 mg, 0.72 mmol, 2 eq) were added. The reaction mixture was degassed with argon (the sequence was carried out 2 times) and reaction tube was sealed with Teflon screw cap. The reaction mixture was subsequently stirred in a preheated oil bath at 110 ℃for 16 h. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate (50 mL) and washed with water (3×20 mL) &brine (3×20 mL) . The organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude residue
was purified by flash column chromatography to afford the product as a pale-yellow solid (75 mg, yield = 51.6%) .
TLC Rf = 0.1 (50% EA/DCM) .
MS (ESI+) : m/z = 400.90 (M+H) .
1H NMR (400 MHz, DMSO-d6) δ 12.94 (s, 1H) , 9.10 (s, 1H) , 8.53 (d, J = 5.2 Hz, 1H) , 8.46 (s, 1H) , 8.28 -7.90 (m, 3H) , 7.70 (d, J = 10.2 Hz, 1H) , 7.20 (s, 1H) , 7.07 –7.00 (m, 2H) , 6.76 (s, 1H) , 3.82 (s, 3H) .
Example 234.
N- (3-Methoxy-5- (1H-pyrazol-4-yl) phenyl) -6- (trifluoromethoxy) quinolin-4-amine: To an oven dried seal tube with a magnetic bar was filled with 1, 4-dioaxne : H2O (4: 1) mixture. The solvent mixture was purged with argon at room temperature. To this purged solution, N- (3-bromo-5-methoxyphenyl) -6- (trifluoromethoxy) quinolin-4-amine (150 mg, 0.36 mmol, 1 eq) , 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (91.6 mg, 0.47 mmol, 1.3 eq) , Pd (dppf) Cl2 (13 mg, 5 mol%) and K2CO3 (100 mg, 0.72 mmol, 2 eq) were added. The reaction mixture was degassed with argon (the sequence was carried out 2 times) and reaction tube was sealed with Teflon screw cap. The reaction mixture was subsequently stirred in a preheated oil bath at 110 ℃for 16 h. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate (50 mL) and washed with water (3×20 mL) &brine (3×20 mL) . The organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude residue was purified by flash column chromatography to afford the product as an off-white solid (40 mg, yield = 27.5%) .
TLC Rf = 0.1 (50%EA/DCM) .
MS (ESI+) : m/z = 401.10 (M+H) .
1H NMR (400 MHz, DMSO-d6) : δ 12.93 (s, 1H) , 9.12 (s, 1H) , 8.55 (d, J = 4.9 Hz, 1H) , 8.46 (s, 1H) , 8.01 (d, J = 9.1 Hz, 1H) , 7.80 (s, 1H) , 7.71 (d, J = 8.7 Hz, 1H) , 7.45 (s, 1H) , 7.19 (s, 1H) , 7.10 (d, J = 5.0 Hz, 1H) , 6.87 (s, 1H) , 6.75 (s, 1H) , 3.84 (s, 3H) .
Example 235.
N- (3-methoxy-5- (1-methyl-1H-pyrazol-5-yl) phenyl) -6- (trifluoromethoxy) quinolin-4-amine: N- (3-bromo-5-methoxyphenyl) -6- (trifluoromethoxy) quinolin-4-amine (130 mg, 0.31 mmol, 1. eq) , 1-methyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (78 mg, 0.37 mmol, 1.2 eq) , Pd (dppf) Cl2 (19 mg, 0.01 mmol, 0.06 eq) and K2CO3 (87 mg, 0.62 mmol, 2 eq) were added to a round-bottom flask with a magnetic bar, then 8 ml dioxane and 2 ml water were added as solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 90 ℃ for 3h with vigorous stirring. The cooled solution was diluted with ethyl acetate and washed with brine. The organic phase was dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica gel flash chromatography to afford the product as off-white solid (112 mg, yield = 85.9%, purity = 100%) .
TLC Rf = 0.25 (PE/EA=1/4) ;
MS (ESI+) : m/z = 415.1 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.15 (s, 1H) , 8.57 (d, J = 5.3 Hz, 1H) , 8.41 (d, J = 2.6 Hz, 1H) , 8.02 (d, J = 9.1 Hz, 1H) , 7.71 (ddd, J = 9.2, 2.6, 1.1 Hz, 1H) , 7.47 (d, J = 1.9 Hz, 1H) , 7.17 (d, J =5.3 Hz, 1H) , 7.08 (t, J = 1.6 Hz, 1H) , 7.00 (t, J = 2.1 Hz, 1H) , 6.86 (dd, J = 2.4, 1.4 Hz, 1H) , 6.46 (d, J = 1.9 Hz, 1H) , 3.91 (s, 3H) , 3.84 (s, 3H) .
Example 236.
N- (3-methoxy-5- (1- (oxetan-3-yl) -1H-pyrazol-4-yl) phenyl) -6-
(trifluoromethoxy) quinolin-4-amine: N- (3-bromo-5-methoxyphenyl) -6- (trifluoromethoxy) quinolin-4-amine (130 mg, 0.31 mmol, 1.0 eq) , 1- (oxetan-3-yl) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (94 mg, 0.37 mmol, 1.2 eq) , Pd (dppf) Cl2 (19 mg, 0.01 mmol, 0.06 eq) and K2CO3 (87 mg, 0.62 mmol, 2 eq) were added to a round-bottom flask with a magnetic bar, then 8 ml dioxane and 2 ml water were added as solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 90 ℃ for 3h with vigorous stirring. The cooled solution was diluted with ethyl acetate and washed with brine. The organic phase was dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica gel flash chromatography to afford the product as off-white solid (92 mg, yield = 64 %, purity = 100%) .
TLC Rf = 0.3 (PE/EA=1/4) ;
MS (ESI+) : m/z = 457.3 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.08 (s, 1H) , 8.53 (d, J = 5.3 Hz, 1H) , 8.49 –8.39 (m, 2H) , 8.06 (s, 1H) , 8.01 (d, J = 9.2 Hz, 1H) , 7.70 (ddd, J = 9.2, 2.6, 1.2 Hz, 1H) , 7.21 (d, J = 1.7 Hz, 1H) , 7.05 (d, J = 5.3 Hz, 1H) , 7.02 (t, J = 1.8 Hz, 1H) , 6.78 (t, J = 2.1 Hz, 1H) , 5.64 –5.50 (m, 1H) , 4.99 –4.87 (m, 4H) , 3.83 (s, 3H) .
Example 237.
1- (4- (3-methoxy-5- ( (6- (trifluoromethoxy) quinolin-4-yl) amino) phenyl) -1H-pyrazol-1-yl) -2-methylpropan-2-ol: 4-chloro-6- (trifluoromethoxy) quinoline (70 mg, 0.28 mmol, 1.0 eq) , 1- (4- (3-amino-5-methoxyphenyl) -1H-pyrazol-1-yl) -2-methylpropan-2-ol (78 mg, 0.29 mmol, 1.05 eq) and PPTS (21 mg, 0.08 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 3 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum.
The residue was purified by silica gel flash chromatography to afford the product as brown solid (92 mg, yield = 68.8%, purity = 99.4%) .
TLC Rf = 0.3 (PE/EA=1/4) ;
MS (ESI+) : m/z = 473.2 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.09 (s, 1H) , 8.52 (d, J = 5.3 Hz, 1H) , 8.45 (d, J = 2.6 Hz, 1H) , 8.27 (s, 1H) , 8.00 (d, J = 9.2 Hz, 1H) , 7.90 (s, 1H) , 7.70 (ddd, J = 9.2, 2.7, 1.1 Hz, 1H) , 7.20 (t, J = 1.7 Hz, 1H) , 7.07 –6.98 (m, 2H) , 6.74 (t, J = 2.1 Hz, 1H) , 4.98 (t, J = 5.7 Hz, 1H) , 3.83 (s, 3H) , 3.60 (d, J = 5.3 Hz, 2H) , 1.49 (s, 6H) .
Example 238.
N- (5-methoxy- [1, 1'-biphenyl] -3-yl) -6- (trifluoromethoxy) quinolin-4-amine: To an oven dried seal tube with a magnetic bar was filled with 1, 4-dioaxne : H2O (4: 1) mixture. The solvent mixture was purged with argon at room temperature. To this purged solution, N- (3-bromo-5-methoxyphenyl) -6- (trifluoromethoxy) quinolin-4-amine (150 mg, 0.36 mmol, 1 eq) , phenylboronic acid (57.4 mg, 0.47 mmol, 1.3 eq) , Pd (dppf) Cl2 (13 mg, 5 mol%) and K2CO3 (100 mg, 0.72 mmol, 2 eq) were added. The reaction mixture was degassed with argon (the sequence was carried out 2 times) and reaction tube was sealed with Teflon screw cap. The reaction mixture was subsequently stirred in a preheated oil bath at 110 ℃ for 16 h. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate (50 mL) and washed with water (3×20 mL) &brine (3×20 mL) . The organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude residue was purified by flash column chromatography to afford the product as an ash color solid (30 mg, yield = 20.14%) .
TLC Rf = 0.3 (10% EA/DCM) .
MS (ESI+) : m/z = 411.20 (M+H) .
1H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1H) , 8.56 (s, 1H) , 8.45 (s, 1H) , 8.01 (s, 1H) , 7.84 -7.60 (m, 3H) , 7.55 -7.31 (m, 3H) , 7.30 -7.08 (m, 2H) , 7.05 -6.85 (m, 2H) , 3.86 (s, 3H) .
Example 239.
N- (3-Methoxy-5- (pyridin-3-yl) phenyl) -6- (trifluoromethoxy) quinolin-4-amine: To an oven dried seal tube with a magnetic bar was filled with 1, 4-dioaxne : H2O (4: 1) mixture. The solvent mixture was purged with argon at room temperature. To this purged solution, N- (3-bromo-5-methoxyphenyl) -6- (trifluoromethoxy) quinolin-4-amine (150 mg, 0.36 mmol, 1 eq) , pyridin-3-ylboronic acid (58 mg, 0.47 mmol, 1.3 eq) , Pd (dppf) Cl2 (13 mg, 5 mol%) and K2CO3 (100 mg, 0.72 mmol, 2 eq) were added. The reaction mixture was degassed with argon (the sequence was carried out 2 times) and reaction tube was sealed with Teflon screw cap. The reaction mixture was subsequently stirred in a preheated oil bath at 110 ℃ for 16 h. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate (50 mL) and washed with water (3×20 mL) &brine (3×20 mL) . The organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude residue was purified by flash column chromatography to afford the product as an off-white solid (35 mg, yield = 23.44%) .
TLC Rf = 0.3 (100%EA) .
MS (ESI+) : m/z = 412.10 (M+H)
1H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1H) , 8.93 (d, J = 2.4 Hz, 1H) , 8.59 (d, J = 4.7 Hz, 1H) , 8.57 (d, J = 5.3 Hz, 1H) , 8.46 –8.41 (m, 1H) , 8.15 –8.07 (m, 1H) , 8.02 (d, J = 9.2 Hz, 1H) , 7.71 (d, J = 9.2 Hz, 1H) , 7.50 (dd, J = 8.0, 4.8 Hz, 1H) , 7.28 (d, J = 2.1 Hz, 1H) , 7.19 (d, J = 5.3 Hz, 1H) , 7.07 (t, J = 1.9 Hz, 1H) , 6.99 (t, J = 2.1 Hz, 1H) , 3.87 (s, 3H) .
Example 240.
N- (3-Methoxy-5- (pyridin-4-yl) phenyl) -6- (trifluoromethoxy) quinolin-4-amine: To an oven dried seal tube with a magnetic bar was filled with 1, 4-dioaxne : H2O (4: 1) mixture. The solvent mixture was purged with argon at room temperature. To this purged solution, N- (3-bromo-
5-methoxyphenyl) -6- (trifluoromethoxy) quinolin-4-amine (150 mg, 0.36 mmol, 1 eq) , pyridin-4-ylboronic acid (58 mg, 0.47 mmol, 1.3 eq) , Pd (dppf) Cl2 (13 mg, 5 mol%) and K2CO3 (100 mg, 0.72 mmol, 2 eq) were added. The reaction mixture was degassed with argon (the sequence was carried out 2 times) and reaction tube was sealed with Teflon screw cap. The reaction mixture was subsequently stirred in a preheated oil bath at 110 ℃ for 16 h. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate (50 mL) and washed with water (3×20 mL) &brine (3×20 mL) . The organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude residue was purified by flash column chromatography to afford the product as ash color solid (30 mg, yield = 20 %) .
TLC Rf = 0.2 (100%EA) .
MS (ESI+) : m/z = 412.10 (M+H)
1H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H) , 8.65 (d, J = 5.0 Hz, 2H) , 8.56 (d, J = 5.4 Hz, 1H) , 8.47 (d, J = 2.6 Hz, 1H) , 8.03 (d, J = 9.1 Hz, 1H) , 7.84 –7.65 (m, 3H) , 7.37 (s, 1H) , 7.22 –7.10 (m, 2H) , 7.05 (d, J = 2.0 Hz, 1H) , 3.88 (s, 3H) .
Example 241.
N- (3’-Fluoro-5-methoxy- [1, 1'-biphenyl] -3-yl) -6- (trifluoromethoxy) quinolin-4-amine: To an oven dried seal tube with a magnetic bar was filled with 1, 4-dioaxne : H2O (4: 1) mixture. The solvent mixture was purged with argon at room temperature. To this purged solution, N- (3-bromo-5-methoxyphenyl) -6- (trifluoromethoxy) quinolin-4-amine (150 mg, 0.36 mmol, 1 eq) , (3-fluorophenyl) boronic acid (66 mg, 0.47 mmol, 1.3 eq) , Pd (dppf) Cl2 (13 mg, 5 mol%) and K2CO3 (100 mg, 0.72 mmol, 2 eq) were added. The reaction mixture was degassed with argon (the sequence was carried out 2 times) and reaction tube was sealed with Teflon screw cap. The reaction mixture was subsequently stirred in a preheated oil bath at 110 ℃ for 16 h. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate (50 mL) and washed with water (3×20 mL) &brine (3×20 mL) . The organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude residue was purified by flash
column chromatography to afford the product as an ash color solid (60 mg, yield = 38.58%) .
TLC Rf = 0.2 (10%EA/DCM) .
MS (ESI+) : m/z = 429.10 (M+H) .
1H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H) , 8.57 (s, 1H) , 8.44 (s, 1H) , 8.02 (s, 1H) , 7.72 (s, 1H) , 7.64 –7.43 (m, 3H) , 7.35 –6.78 (m, 5H) , 3.87 (s, 3H) .
Example 242.
3'-Methoxy-5'- ( (6- (trifluoromethoxy) quinolin-4-yl) amino) - [1, 1'-biphenyl] -3-ol: To an oven dried seal tube with a magnetic bar was filled with 1, 4-dioaxne : H2O (4: 1) mixture. The solvent mixture was purged with argon at room temperature. To this purged solution, N- (3-bromo-5-methoxyphenyl) -6- (trifluoromethoxy) quinolin-4-amine (100 mg, 0.24 mmol, 1 eq) , (3-hydroxyphenyl) boronic acid (40 mg, 0.29 mmol, 1.2 eq) , Pd (dppf) Cl2 (10.6 mg, 6 mol%) and K2CO3 (100 mg, 0.72 mmol, 3 eq) were added. The reaction mixture was degassed with argon (the sequence was carried out 2 times) and reaction tube was sealed with Teflon screw cap. The reaction mixture was subsequently stirred in a preheated oil bath at 110 ℃ for 16 h. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate (50 mL) and washed with water (3×20 mL) &brine (3×20 mL) . The organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude residue was purified by flash column chromatography to afford the product as a pale brown solid (70 mg, yield = 67.83%) .
TLC Rf = 0.4 (30% EA/DCM) .
MS (ESI+) : m/z = 427.00 (M+H) .
1H NMR (400 MHz, DMSO-d6) : δ 9.57 (s, 1H) , 9.21 (s, 1H) , 8.57 (d, J = 5.3 Hz, 1H) , 8.46 (s, 1H) , 8.03 (d, J = 9.2 Hz, 1H) , 7.73 (d, J = 8.9 Hz, 1H) , 7.26 (t, J = 7.8 Hz, 1H) , 7.18 –7.14 (m, 2H) , 7.10 (d, J = 7.7 Hz, 1H) , 7.05 (s, 1H) , 6.94 (s, 2H) , 6.80 -6.72 (m, 1H) , 3.85 (s, 3H) .
Example 243.
3'-Methoxy-5'- ( (6- (trifluoromethoxy) quinolin-4-yl) amino) - [1, 1'-biphenyl] -3-carbonitrile: To an oven dried seal tube with a magnetic bar was filled with 1, 4-dioaxne : H2O (4: 1) mixture. The solvent mixture was purged with argon at room temperature. To this purged solution, N- (3-bromo-5-methoxyphenyl) -6- (trifluoromethoxy) quinolin-4-amine (100 mg, 0.24 mmol, 1 eq) , (3-cyanophenyl) boronic acid (42.6 mg, 0.29 mmol, 1.2 eq) , Pd (dppf) Cl2 (10.6 mg, 6 mol%) and K2CO3 (100 mg, 0.72 mmol, 3 eq) were added. The reaction mixture was degassed with argon (the sequence was carried out 2 times) and reaction tube was sealed with Teflon screw cap. The reaction mixture was subsequently stirred in a preheated oil bath at 110 ℃ for 16 h. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate (50 mL) and washed with water (3×20 mL) &brine (3×20 mL) . The organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude residue was purified by flash column chromatography to afford the product as an off-white light solid (30 mg, yield = 28.5%) .
TLC Rf = 0.5 (30%EA/DCM) .
MS (ESI+) : m/z = 436.20 (M+H) .
Example 244.
N- (3-methoxy-5- (6-methoxypyridin-3-yl) phenyl) -6- (trifluoromethoxy) quinolin-4-amine: N- (3-bromo-5-methoxyphenyl) -6- (trifluoromethoxy) quinolin-4-amine (130 mg, 0.31 mmol, 1. eq) , 2-methoxy-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (89 mg, 0.37 mmol, 1.2 eq) , Pd (dppf) Cl2 (14 mg, 0.01 mmol, 0.06 eq) and K2CO3 (87 mg, 0.62 mmol, 2 eq) were added to a round-bottom flask with a magnetic bar, then 8 ml dioxane and 2 ml water were added as solvent. The reaction vessel was evacuated and backfilled with N2 three times and
protected with a balloon of N2. The reaction mixture was heated at 90 ℃ for 3h with vigorous stirring. The cooled solution was diluted with ethyl acetate and washed with brine. The organic phase was dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica gel flash chromatography to afford the product as pale-yellow solid (98 mg, yield = 70.5 %, purity = 99%) .
TLC Rf = 0.2 (PE/EA=1/4) ;
MS (ESI+) : m/z = 442.2 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.13 (s, 1H) , 8.56 (d, J = 5.3 Hz, 1H) , 8.52 (d, J = 2.6 Hz, 1H) , 8.44 (d, J = 2.7 Hz, 1H) , 8.10 –7.95 (m, 2H) , 7.77 –7.66 (m, 1H) , 7.22 (t, J = 1.7 Hz, 1H) , 7.17 (d, J = 5.3 Hz, 1H) , 7.00 (t, J = 1.8 Hz, 1H) , 6.93 (t, J = 2.1 Hz, 1H) , 6.91 (d, J = 8.6 Hz, 1H) , 3.90 (s, 3H) , 3.85 (s, 3H) .
Example 245.
5- (3-methoxy-5- ( (6- (trifluoromethoxy) quinolin-4-yl) amino) phenyl) -1-methylpyridin-2 (1H) -one: 4-chloro-6- (trifluoromethoxy) quinoline (70 mg, 0.28 mmol, 1.0 eq) , 5- (3-amino-5-methoxyphenyl) -1-methylpyridin-2 (1H) -one (68 mg, 0.29 mmol, 1.05 eq) and PPTS (21 mg, 0.08 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 3 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (86 mg, yield =68.9%, purity = 98.04%) .
TLC Rf = 0.25 (PE/EA=1/4) ;
MS (ESI+) : m/z = 442.2 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 11.12 (s, 1H) , 8.89 (s, 1H) , 8.58 (d, J = 7.0 Hz, 1H) , 8.27 (d, J = 2.7 Hz, 1H) , 8.23 (d, J = 9.2 Hz, 1H) , 8.09 (d, J = 9.1 Hz, 1H) , 7.89 (dd, J = 9.5, 2.7 Hz, 1H) ,
7.31 (s, 1H) , 7.24 (s, 1H) , 7.00 (s, 1H) , 6.97 (d, J = 6.9 Hz, 1H) , 6.50 (d, J = 9.5 Hz, 1H) , 3.88 (s, 3H) , 3.51 (s, 3H) .
Example 246.
N- (3-Methoxy-5- (quinolin-6-yl) phenyl) -6- (trifluoromethoxy) quinolin-4-amine: To an oven dried seal tube with a magnetic bar was filled with 1, 4-dioaxne : H2O (4: 1) mixture. The solvent mixture was purged with argon at room temperature. To this purged solution, N- (3-bromo-5-methoxyphenyl) -6- (trifluoromethoxy) quinolin-4-amine (100 mg, 0.24 mmol, 1 eq) , quinolin-6-ylboronic acid (50.2 mg, 0.29 mmol, 1.2 eq) , Pd (dppf) Cl2 (10.6 mg, 6 mol%) and K2CO3 (100 mg, 0.72 mmol, 3 eq) were added. The reaction mixture was degassed with argon (the sequence was carried out 2 times) and reaction tube was sealed with Teflon screw cap. The reaction mixture was subsequently stirred in a preheated oil bath at 110 ℃ for 16 h. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate (50 mL) and washed with water (3×20 mL) &brine (3×20 mL) . The organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude. The crude residue was purified by flash column chromatography to afford the product as a brown solid (34 mg, yield = 30.44%) .
TLC Rf = 0.2 (30%EA/DCM) .
MS (ESI+) : m/z = 462.20 (M+H) .
1H NMR (400 MHz, DMSO-d6) : δ 9.25 (s, 1H) , 8.92 (dd, J = 4.2, 1.7 Hz, 1H) , 8.57 (d, J = 5.4 Hz, 1H) , 8.47 (d, J = 2.6 Hz, 1H) , 8.44 (dd, J = 8.4, 1.8 Hz, 1H) , 8.35 (d, J = 2.0 Hz, 1H) , 8.14 (dd, J = 8.8, 2.0 Hz, 1H) , 8.10 (d, J = 8.9 Hz, 1H) , 8.03 (d, J = 9.1 Hz, 1H) , 7.80 –7.69 (m, 1H) , 7.58 (dd, J = 8.3, 4.2 Hz, 1H) , 7.42 (t, J = 1.8 Hz, 1H) , 7.28 –7.11 (m, 2H) , 7.01 (t, J = 2.1 Hz, 1H) , 3.90 (s, 3H) .
Example 247.
N- (3-methoxy-5- (1- (2-morpholinoethyl) -1H-pyrazol-4-yl) phenyl) -6- (trifluoromethoxy) quinolin-4-amine: N- (3-bromo-5-methoxyphenyl) -6- (trifluoromethoxy) quinolin-4-amine (100 mg, 0.24 mmol, 1. Eq) , 4- (2- (4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) ethyl) morpholine (89 mg, 0.29 mmol, 1.2 eq) , Pd(dppf) Cl2 (11 mg, 0.01 mmol, 0.06 eq) and K2CO3 (67 mg, 0.48 mmol, 2 eq) were added to a round-bottom flask with a magnetic bar, then 8 ml dioxane and 2 ml water were added as solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 90 ℃ for 3h with vigorous stirring. The cooled solution was diluted with ethyl acetate and washed with brine. The organic phase was dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica gel flash chromatography to afford the product as yellow solid (72 mg, yield = 57.9%, purity = 99.2%) .
TLC Rf = 0.25 (5%MeOH/DCM) ;
MS (ESI+) : m/z = 514.4 (M+H) ;
Example 248.
N- (3- (isoxazol-4-yl) -5-methoxyphenyl) -6- (trifluoromethoxy) quinolin-4-amine: N- (3-bromo-5-methoxyphenyl) -6- (trifluoromethoxy) quinolin-4-amine (100 mg, 0.24 mmol, 1. Eq) , 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoxazole (85 mg, 0.29 mmol, 1.2 eq) , Pd (dppf) Cl2 (11 mg, 0.01 mmol, 0.06 eq) and K2CO3 (67 mg, 0.48 mmol, 2 eq) were added to a round-bottom flask with a magnetic bar, then 8 ml dioxane and 2 ml water were added as solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The
reaction mixture was heated at 90 ℃ for 3h with vigorous stirring. The cooled solution was diluted with ethyl acetate and washed with brine. The organic phase was dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica gel flash chromatography to afford the product as pale-yellow solid (66 mg, yield = 57.9%, purity = 45.3%) .
TLC Rf = 0.2 (EA/PE=4/1) ;
MS (ESI+) : m/z = 402.0 (M+H) ;
Example 249.
4- (3-Methoxy-5- ( (6- (trifluoromethoxy) quinolin-4-yl) amino) phenyl) -1-methylpyridin-2 (1H) -one: 4-chloro-6- (trifluoromethoxy) quinoline (80 mg, 0.32mmol, 1.0 eq) , 4- (3-amino-5-methoxyphenyl) -1-methylpyridin-2 (1H) -one (78 mg, 0.33 mmol, 1.05 eq) and PPTS (24 mg, 0.09 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 3 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as brown solid (86 mg, yield = 60.3%, purity = 100%) .
TLC Rf = 0.25 (EA/PE=4/1) ;
MS (ESI+) : m/z = 442.20 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.14 (s, 1H) , 8.57 (d, J = 5.3 Hz, 1H) , 8.42 (d, J = 2.7 Hz, 1H) , 8.02 (d, J = 9.1 Hz, 1H) , 7.77 (d, J = 7.1 Hz, 1H) , 7.74 –7.66 (m, 1H) , 7.25 (d, J = 1.8 Hz, 1H) , 7.16 (d, J = 5.3 Hz, 1H) , 7.01 (d, J = 1.7 Hz, 2H) , 6.70 (d, J = 2.0 Hz, 1H) , 6.57 (dd, J = 7.0, 2.1 Hz, 1H) , 3.85 (s, 3H) , 3.45 (s, 3H) .
Example 250.
N- (3-methoxy-5- (1-methyl-1H-imidazol-5-yl) phenyl) -6- (trifluoromethoxy) quinolin-4-amine: N- (3-bromo-5-methoxyphenyl) -6- (trifluoromethoxy) quinolin-4-amine (150 mg, 0.36 mmol, 1. eq) , 1-methyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-imidazole (91 mg, 0.43 mmol, 1.2 eq) , Pd (dppf) Cl2 (16 mg, 0.02 mmol, 0.06 eq) and K2CO3 (100 mg, 0.72 mmol, 2 eq) were added to a round-bottom flask with a magnetic bar, then 8 ml dioxane and 2 ml water were added as solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 90 ℃ for 3h with vigorous stirring. The cooled solution was diluted with ethyl acetate and washed with brine. The organic phase was dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica gel flash chromatography to afford the product as off-white solid (116 mg, yield = 77.1%, purity = 96.64%) .
TLC Rf = 0.25 (5%MeOH/DCM) ;
MS (ESI+) : m/z = 415.0 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.13 (s, 1H) , 8.56 (d, J = 5.2 Hz, 1H) , 8.42 (d, J = 2.6 Hz, 1H) , 8.01 (d, J = 9.2 Hz, 1H) , 7.71 (d, J = 10.8 Hz, 2H) , 7.15 (d, J = 5.3 Hz, 2H) , 7.05 (s, 1H) , 6.93 (s, 1H) , 6.84 (s, 1H) , 3.83 (s, 3H) , 3.74 (s, 3H) .
Example 251.
N- (3-methoxy-5- (1- (2-methoxyethyl) -1H-pyrazol-4-yl) phenyl) -6- (trifluoromethoxy) quinolin-4-amine: 4-chloro-6- (trifluoromethoxy) quinoline (74 mg, 0.3 mmol, 1.0 eq) , 3-methoxy-5- (1- (2-methoxyethyl) -1H-pyrazol-4-yl) aniline (74 mg, 0.3 mmol, 1.0 eq) , and
PPTS (23 mg, 0.09 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as an oil (76.7 mg, yield = 55.82 %, purity = 98.03%) .
TLC Rf = 0.50 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z = 459.30 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.08 (s, 1H) , 8.53 (d, J = 5.3 Hz, 1H) , 8.45 (d, J = 2.6 Hz, 1H) , 8.20 (d, J = 0.8 Hz, 1H) , 8.00 (d, J = 9.2 Hz, 1H) , 7.91 (d, J = 0.8 Hz, 1H) , 7.70 (ddd, J = 9.2, 2.6, 1.1 Hz, 1H) , 7.16 (t, J = 1.7 Hz, 1H) , 7.05 (d, J = 5.3 Hz, 1H) , 6.98 (dd, J = 2.3, 1.4 Hz, 1H) , 6.76 (t, J = 2.1 Hz, 1H) , 4.26 (t, J = 5.3 Hz, 2H) , 3.82 (s, 3H) , 3.71 (t, J = 5.3 Hz, 2H) , 3.24 (s, 3H) .
Example 252.
N- (3-methoxy-5- (4-methylpiperazin-1-yl) phenyl) -6- (trifluoromethoxy) quinolin-4-amine: 4-chloro-6- (trifluoromethoxy) quinoline (186 mg, 0.75 mmol, 1.5 eq) , 3-methoxy-5- (4-methylpiperazin-1-yl) aniline (111 mg, 0.5 mmol, 1.0 eq) and PPTS (38 mg, 0.15 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuo. The crude material was purified by silica gel flash chromatography to afford the product as a black solid (154 mg, yield = 71.2 %, purity =100 %) .
TLC Rf = 0.25 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z = 433.2 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 8.93 (s, 1H) , 8.51 (d, J = 5.3 Hz, 1H) , 8.41 (d, J = 2.6 Hz, 1H) , 7.98 (d, J = 9.2 Hz, 1H) , 7.67 (ddt, J = 9.2, 2.1, 1.0 Hz, 1H) , 7.03 (d, J = 5.3 Hz, 1H) , 6.50 (t, J =2.0 Hz, 1H) , 6.38 (t, J = 1.9 Hz, 1H) , 6.30 (t, J = 2.1 Hz, 1H) , 3.74 (s, 3H) , 3.18 –3.11 (m, 4H) , 2.44 (t, J = 5.0 Hz, 4H) , 2.22 (s, 3H) .
Example 253.
3- (4- (3-Methoxy-5- ( (6- (trifluoromethoxy) quinolin-4-yl) amino) phenyl) -1H-pyrazol-1-yl) propanenitrile: 4-chloro-6- (trifluoromethoxy) quinoline (99 mg, 0.4 mmol, 1.0 eq) , 3- (4- (3-amino-5-methoxyphenyl) -1H-pyrazol-1-yl) propanenitrile (9 7mg, 0.4 mmol, 1.0 eq) , and PPTS (30 mg, 0.12 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as an oil (164.5 mg, yield =90.78 %, purity = 97.54 %) .
TLC Rf = 0.50 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z = 454.20 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.09 (s, 1H) , 8.54 (d, J = 5.3 Hz, 1H) , 8.45 (d, J = 2.6 Hz, 1H) , 8.31 (d, J = 0.8 Hz, 1H) , 8.04 –7.93 (m, 2H) , 7.70 (ddt, J = 9.1, 2.0, 1.0 Hz, 1H) , 7.17 (t, J = 1.6 Hz, 1H) , 7.06 (d, J = 5.3 Hz, 1H) , 6.99 (dd, J = 2.3, 1.4 Hz, 1H) , 6.78 (t, J = 2.1 Hz, 1H) , 4.40 (t, J = 6.4 Hz, 2H) , 3.83 (s, 3H) , 3.10 (t, J = 6.4 Hz, 2H) .
Example 254.
N- (3- (1-cyclopropyl-1H-pyrazol-4-yl) -5-methoxyphenyl) -6- (trifluoromethoxy) quinolin-4-amine: 4-chloro-6- (trifluoromethoxy) quinoline (99 mg, 0.4 mmol, 1.0 eq) , 3- (1-cyclopropyl-1H-pyrazol-4-yl) -5-methoxyaniline (92mg, 0.4 mmol, 1.0 eq) , and PPTS (30 mg, 0.12 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as a solid (132.6 mg, yield = 75.34 %, purity = 100 %) .
TLC Rf = 0.50 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z = 441.20 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.06 (s, 1H) , 8.53 (d, J = 5.3 Hz, 1H) , 8.45 (d, J = 2.6 Hz, 1H) , 8.28 (s, 1H) , 8.00 (d, J = 9.2 Hz, 1H) , 7.88 (s, 1H) , 7.69 (ddd, J = 9.2, 2.6, 1.1 Hz, 1H) , 7.17 (t, J = 1.7 Hz, 1H) , 7.03 (d, J = 5.3 Hz, 1H) , 6.99 (t, J = 1.8 Hz, 1H) , 6.75 (t, J = 2.1 Hz, 1H) , 3.82 (s, 3H) , 3.73 (tt, J = 7.4, 3.9 Hz, 1H) , 1.10 –1.04 (m, 2H) , 1.00 –0.94 (m, 2H) .
Example 255.
4- (3-Methoxy-5- ( (6- (trifluoromethoxy) quinolin-4-yl) amino) phenyl) piperazin-2-one: 4-chloro-6- (trifluoromethoxy) quinoline (74 mg, 0.3mmol, 1.5eq) , 4- (3-amino-5-methoxyphenyl) piperazin-2-one (47 mg, 0.2 mmol, 1.0 eq) and PPTS (50 mg, 0.2 mmol, 1.0 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent.
The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃ for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuo. The crude material was purified by silica gel flash chromatography to afford the product as a black solid (53 mg, yield = 61.3 %, purity =89.34 %) .
TLC Rf = 0.45 (DCM/MeOH= 20/1) ;
MS (ESI+) : m/z = 433.2 (M+H) ;
Example 256.
N- (3-Methoxy-5- (1- (3-methoxypropyl) -1H-pyrazol-4-yl) phenyl) -6- (trifluoromethoxy) quinolin-4-amine: 4-chloro-6- (trifluoromethoxy) quinoline (99 mg, 0.4 mmol, 1.0 eq) , 3-methoxy-5- (1- (3-methoxypropyl) -1H-pyrazol-4-yl) aniline (105 mg, 0.4 mmol, 1.0 eq) , and PPTS (30 mg, 0.12 mmol, 0.3 eq) were added to a round-bottom flask with a magnetic bar, then 3 mL DMSO was added as a solvent. The reaction vessel was evacuated and backfilled with N2 three times and protected with a balloon of N2. The reaction mixture was heated at 80 ℃for 8 h with vigorous stirring. The cooled solution was poured into EtOAc (20 mL) , then washed with Na2CO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to afford the product as an oil (188 mg, yield = 99 %, purity = 100 %) .
TLC Rf = 0.50 (DCM/MeOH = 20/1) ;
MS (ESI+) : m/z = 473.30 (M+H) ;
1H NMR (400 MHz, DMSO-d6) : δ 9.07 (s, 1H) , 8.53 (d, J = 5.3 Hz, 1H) , 8.45 (d, J = 2.7 Hz, 1H) , 8.22 (d, J = 0.8 Hz, 1H) , 8.00 (d, J = 9.1 Hz, 1H) , 7.91 (d, J = 0.9 Hz, 1H) , 7.69 (ddd, J = 9.3, 2.7, 1.1 Hz, 1H) , 7.17 (t, J = 1.7 Hz, 1H) , 7.05 (d, J = 5.3 Hz, 1H) , 6.98 (dd, J = 2.3, 1.4 Hz, 1H) , 6.76 (t, J = 2.1 Hz, 1H) , 4.16 (t, J = 7.0 Hz, 2H) , 3.82 (s, 3H) , 3.30 (t, J = 6.2 Hz, 2H) , 3.23 (s, 3H) , 2.03 (p, J = 6.6 Hz, 2H) .
Example 257. Cell culture and treatment
The human retinal pigment epithelial cell lines RPE-MYCH2B-GFP (Li et al., 2021; Zhang et al., 2021) and RPE-MYCBcl2 (Zhang et al., 2020) have been described in the published literature. Cell lines were cultured in DMEM (Gibco, Cat. No. 12100061) supplemented with 10%fetal bovine serum (Excell, Cat. No. FSP500 10099141) , penicillin (100 U/mL) -streptomycin (100 μg/mL) (Gibco, Cat. No. 15140-122) , 2 mM L-glutamine (Gibco, Cat. No. 25030081) , and 1 mM sodium pyruvate (Gibco, Cat. No. 11360070) . Cell culture was maintained at 37℃ with 5%CO2 in a humidified incubator. Mycoplasma contamination of cell lines was evaluated by using a Myco-LumiTM Luminescent Mycoplasma Detection Kit (Beyotime, Cat. No. C0298M) before experiments were initiated. Each cell line was then expanded and stored in aliquots at -80℃. Each aliquot was used only for 10-15 passages, after which we conducted additional assays to examine contamination.
Example 258. Mechanism-informed phenotypic screening assay to guide the identification and optimization of compounds
An live cell, image-based screening assay was conducted to identify compounds that phenocopy the genetic loss of the chromosomal passenger protein complex. This high-thoughput assay has been described previously (Li et al., 2021; Zhang et al., 2021) . Briefly, the screening cell line RPE-MYCH2B-GFP expresses the chimeric protein Histone 2B fused with a green fluorescent protein (H2B-GFP) in the RPE-MYC cell line to enable chromosome visualization. Screening cells were replated on to 96-well plates, 18-24 hours before exposure to test compounds at concentrations between 10 nM and 20 μM, with a 2-fold serial dilution. For any compound that was active at the lowest concentration of 10 nM, further dilution was conducted to determine the minimally effective concentration (MEC) . At 24, 48, or 72 hours after initiation of treatment, cells were analyzed by a high-content fluorescent cell imager (GE IN-Cell Analyzer 2000) Cells treated with 0.1%DMSO were used as the vehicle control for all assays. To be scored as positive for a phenotypic change, a threshold value was arbitrarily chosen to reflect no less than a two-fold change elicited by the test compound. Values were considered accurate when the difference in MEC values between independent experiments were no more than two-fold. Four independent phenotypes were assayed: a. mitotic arrest; b. induction of polyploidy; c. cell death; d. reduced cell number.
a. Mitotic arrest: Compounds were considered as inducing arrest if the percentage of
mitotic cells at 24 hours was ≥10%. Mitotic cells were identified as rounded-up cells with condensed chromosomes with DAPI staining. The basal mitotic index (MI) of the screening cell line is 4.7%. An approximately two-fold increase of the MI was arbitrarily chosen to define the mitotic arrest.
b. Induction of polyploidy: Compounds were considered positive for the induction of polyploidy when the percentage of polyploid cells in the interphase population, 72 hours after initiation of treatment, was ≥5% (with deduction of basal level of polyploid cells) . Polyploid cells were defined as those with multinucleated nuclei, visible upon DAPI staining. The basal level of spontaneous polyploid cells with the screening cell line was less than 1%.
c. Cell death: Compounds were considered positive for the induction of cell death with the presence of a substantial number of floating dead cells. Arbitrarily, this was determined substantial with more than one thousand dead cells per well in a 96-well plate, as determined by a follow-up trypan blue exclusion assay. The basal level of dead cells was less than ten per well.
d. Reduced cell number: Compounds were considered positive for the ability to reduce cell number when the cell number at 72 hours was two-fold less than that of the vehicle control group.
Example 259. Trypan Blue Exclusion Assays
Trypan blue exclusion assays were used to confirm non-viable cells after compound exposure. Cells were plated and allowed to adhere overnight at 37℃ before being incubated with a vehicle control or drug for indicated times. Cells were washed with PBS once, treated with a 0.25%trypsin-EDTA solution to free cells from the plate and then resuspended in DMEM. After staining with trypan blue (0.04%, 1: 1) , non-viable cells were quantified.
Table 1. List of the compounds, structures, and bioactivity
Assays were determined in the screening cell line RPEMYCH2BGFP. Subscripts denote
active concentrations for the following activities:
a. Mitotic arrest –the percentage of mitotic cells at 24 h ≥10%. The basal mitotic index (MI) of the screening cell line is 4.7%. A two-fold increase of the MI was arbitrarily chosen to define the mitotic arrest.
b. Polyploidy –the percentage of polyploid cells in the population ≥5%. The basal level of spontaneous polyploid cells of the screening cell line was less than 1%.
c. Cell death –the presence of more than one thousand floating dead cells per well in a 96-well plate was detected by the trypan blue exclusion assay. The basal level of dead cells was less than ten in this assay.
d. Decreased cell number –the cell number at 72 h in the presence of the indicated compound was at least twofold less than that of the control group. Cells treated with 0.1%of DMSO were used as a negative control for all four assays. Assays were carried out in duplicate (technical repeats) to confirm findings. The difference in MEC values between different independent experiments for a given compound was no more than two-fold.
MECP –the minimal effective concentration that elicited polyploidy. We defined the percentage of polyploid cells in the population ≥5%. The basal level of spontaneous polyploid cells of the screening cell line was less than 1%. MECP was determined in the screening cell line RPEMYCH2BGFP after 72 hours.
AUC0-6h: area under the plasma concentration-time curve from time zero to 6 h
AUC0-6h/Dose: AUC0-6h divided by dose
Cmax: the maximum plasma concentration after oral dose normalization at 10 mg/kg
Tmax: the time to maximum concentration
PEG300: 10%DMSO, 50%PEG300, 1%Tween 80, 39%ddH2O, pH 2.
PMC: 0.5%HPMC in ddH2O, pH 2.
ID: individual dosing, 50 mg/kg
CD: cassette dosing of 4 -5 compounds, 10 mg/kg/compound
ND: not determined
NA: not applicable
A: 1 nM<conc. ≤1 μM; B: 1 μM<conc. ≤20 μM; C: 20 μM<conc.; Cell: RPE MYCH2BGFP; Assay Time: 24~72 h.
References
Li J, Yan Z, Li H, Shi Q, Huang L, Nimishetti N, Allen TD, Yang D and Zhang J (2021) A high-content screen for anti-mitosis and polyploidy-induction identifies an unknown activity of two benzophenanthridine alkaloids from Corydalis longicalcarata. Phytochemistry Letters 41: 180-185. Zhang J, Zhang S, Shi Q, Allen TD, You F and Yang D (2020) The anti-apoptotic proteins Bcl-2 and Bcl-xL suppress Beclin 1/Atg6-mediated lethal autophagy in polyploid cells. Exp Cell Res 394 (1) : 112112.
Zhang J, Zhang S, Shi Q, Allen TD, You F and Yang D (2021) A high-content screen identifies the vulnerability of MYC-overexpressing cells to dimethylfasudil. PLoS One 16 (3) : e0248355.
Claims (21)
- A compound of Formula (I) :
or a pharmaceutically acceptable salt or N-oxide thereof,whereinA1 is -C (H) = or -N=;A2 is -C (H) = or -N=;R1 is selected from the group consisting of halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 haloalkoxy, -C (O) Ra , and -C (O) ORa;R2 is selected from the group consisting of hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 haloaliphatic, -C (O) Ra , and -C (O) ORa;R2’ is selected from the group consisting of optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 haloaliphatic, -C (O) Ra, and -C (O) ORa , ;optionally, R2 and R2’ are taken together with the nitrogen on which they are attached to form optionally substituted 3-7-membered heterocyclyl or optionally substituted 5-9-membered heteroaryl;each R3 is independently selected from the group consisting of halogen, -CN, -ORa, -N (Ra) 2, -NO2, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 haloaliphatic, -C (O) Ra, -C (O) ORa, and -C (O) N (Ra) 2;each R4 is independently selected from the group consisting of halogen, -CN, -ORa, -N (Ra) 2, -NO2, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 haloaliphatic, -C (O) Ra, -C (O) ORa, -C (O) N (Ra) 2, optionally substituted phenyl, optionally substituted 3-7-membered heterocyclyl and optionally substituted 5-9-membered heteroaryl;each R5 is independently selected from the group consisting of deuterium and halogen;each Ra is independently is selected from the group consisting of hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 haloaliphatic, optionally substituted 3-7-membered heterocyclyl, optionally substituted 5-9-membered heteroaryl, -C (O) Rb , and -C (O) ORb;optionally, two instances of Ra are taken together with the nitrogen on which they are attached to form optionally substituted 3-7-membered heterocyclyl or optionally substituted 5-9-membered heteroaryl;each Rb is independently optionally substituted C1-C6 aliphatic;n is 0, 1, 2, or 3;m is 0, 1, 2, 3, or 4; andp is 0, 1, 2, or 3. - The compound of claim 1, wherein R2 and R2’ are taken together with the nitrogen on which they are attached to form optionally substituted 3-7-membered heterocyclyl or optionally substituted 5-9-membered heteroaryl.
- The compound of claim 2, wherein R2 and R2’ are taken together with the nitrogen on which they are attached to form o optionally substituted 5-9-membered heteroaryl.
- The compound of claim 1, wherein the compound is a compound of Formula (I-a) :
or a pharmaceutically acceptable salt or N-oxide thereof. - The compound of claim 1, wherein the compound is a compound of Formula (I-b) :
or a pharmaceutically acceptable salt or N-oxide thereof. - The compound of any of claim 1-5, wherein R1 is optionally substituted C1-C6 alkoxy.
- The compound of claim 6, wherein R1 is -OMe.
- A compound of Formula (II) :
or a pharmaceutically acceptable salt or N-oxide thereof,whereinA1 is -C (H) = or -N=;A2 is -C (H) = or -N=;R2 is selected from the group consisting of -NH2, -NO2 -ORa, -O (CH2) 1-3Ra, -C (O) ORa, -C (O) N (Ra) 2, optionally substituted C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 3-10 membered heterocyclyl, and optionally substituted 5-9-membered heteroaryl;each R3 is independently selected from the group consisting of halogen, -CN, -ORa, -N (Ra) 2, -NO2, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 haloaliphatic, -C (O) Ra, -C (O) ORa, and -C (O) N (Ra) 2;each R4 is independently selected from the group consisting of halogen, -CN, -ORa, -N (Ra) 2, -NO2, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 haloaliphatic, -C (O) Ra, -C (O) ORa, -C (O) N (Ra) 2, optionally substituted phenyl, optionally substituted 3-7-membered heterocyclyl and optionally substituted 5-9-membered heteroaryl;each R5 is independently selected from the group consisting of deuterium and halogen;each Ra is independently is selected from the group consisting of hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 haloaliphatic, optionally substituted 3-7-membered heterocyclyl, optionally substituted 5-9-membered heteroaryl, -C (O) Rb, and -C (O) ORb;optionally, two instances of Ra are taken together with the nitrogen on which they are attached to form optionally substituted 3-7-membered heterocyclyl or optionally substituted 5-9-membered heteroaryl;each Rb is independently is selected from the group consisting of optionally substituted C1-C6 aliphatic and optionally substituted C1-C6 haloaliphatic;n is 0, 1, 2, or 3;m is 0, 1, 2, 3, or 4; andp is 0, 1, 2, or 3. - The compound of claim 8, wherein the compound is of Formula (II-a) :
or a pharmaceutically acceptable salt or N-oxide thereof. - The compound of any of claims 8-9, wherein R2 is -C (O) ORa, and Ra of R2 is C1-C6 aliphatic.
- The compound of any of claims 8-9, wherein R2 is -C (O) NHRa, and Ra of R2 is C1-C6 aliphatic.
- The compound of any of claims 8-9, wherein R2 is optionally substituted 5-membered heteroaryl.
- The compound of any of claims 8-9, wherein R2 is optionally substituted C1-C6 aliphatic.
- The compound of claim 13, wherein R2 is C1-C6 substituted with 1-7 instances of fluoro.
- The compound of claim 14, wherein R2 is -CF3.
- A compound of Formula (III) :
or a pharmaceutically acceptable salt or N-oxide thereof,whereinA is -C (H) = or -N=;one of Q1 and Q2 is -N (Ra) -or -S-and the other is -C (H) =;R2 is selected from the group consisting of -C (O) ORa, -C (O) N (Ra) 2, optionally substituted C1-C6 haloaliphatic, and optionally substituted 5-9-membered heteroaryl;each R3 is independently selected from the group consisting of halogen, -CN, -ORa, -N (Ra) 2, -NO2, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 haloaliphatic, -C (O) Ra, -C (O) ORa, and -C (O) N (Ra) 2;each R4 is independently selected from the group consisting of halogen, -CN, -ORa, -N (Ra) 2, -NO2, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 haloaliphatic, -C (O) Ra, -C (O) ORa, -C (O) N (Ra) 2, optionally substituted phenyl, optionally substituted 3-7-membered heterocyclyl and optionally substituted 5-9-membered heteroaryl;each Ra is independently is selected from the group consisting of hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 haloaliphatic, -C (O) Rb , and -C (O) ORb;optionally, two instances of Ra are taken together with the nitrogen on which they are attached to form optionally substituted 3-7-membered heterocyclyl or optionally substituted 5-9-membered heteroaryl;each Rb is independently is selected from the group consisting of optionally substituted C1-C6 aliphatic and optionally substituted C1-C6 haloaliphatic;n is 0, 1, 2, or 3;m is 0, 1, 2, 3, or 4. - The compound of claim 16, wherein R2 is -C (O) ORa or optionally substituted 5-9-membered heteroaryl.
- The compound of claim 17, wherein R2 is -C (O) OMe or pyrazole.
- A compound selected from the group consisting of:
or a pharmaceutically acceptable salt or N-oxide thereof. - A pharmaceutical composition comprising a compound of any of the previous claims and a pharmaceutically acceptable excipient.
- A method of treat cancer comprising administering to a patient in need thereof the compound of any of claims 1-19 or the pharmaceutical composition of claim 20.
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WO2021026101A1 (en) * | 2019-08-02 | 2021-02-11 | Amgen Inc. | Kif18a inhibitors |
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US20180086747A1 (en) * | 2016-09-23 | 2018-03-29 | Gilead Sciences, Inc. | Phosphatidylinositol 3-kinase inhibitors |
WO2021026101A1 (en) * | 2019-08-02 | 2021-02-11 | Amgen Inc. | Kif18a inhibitors |
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LI JYAN ZLI HSHI QHUANG LNIMISHETTI NALLEN TDYANG DZHANG J: "A high-content screen for anti-mitosis and polyploidy-induction identifies an unknown activity of two benzophenanthridine alkaloids from Corydalis longicalcarata", PHYTOCHEMISTRY LETTERS, vol. 41, 2021, pages 180 - 185 |
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