Mitogen-Activated Protein Kinase (MEK) Inhibitor

Abstract

The present invention relates to a compound of structure (F) as a mitogen-activated protein kinase (MEK) inhibitor. JPEG2025521928000294.jpg54114(I) The variables are described herein.

Description

Technical Field

[0001] Related Applications This application claims the benefit of U.S. Provisional Application No. 63 / 359,537, filed Jul. 8, 2022, the entire teachings of which are incorporated herein by reference.

Background Art

[0002] Cancer is one of the most common causes of death in the United States. Approximately one in four deaths in the United States is due to cancer. The 5-year relative survival rate of cancer patients diagnosed between 1996 and 2003 has increased from about half that between 1975 and 1977 to about two-thirds (Cancer Facts & Figures, American Cancer Society: Atlanta, Ga. (2008)). From 2000 to 2009, the annual incidence of new cancer cases decreased by an average of 0.6% in men, but there was no change in women. From 2000 to 2009, the overall mortality rate due to all cancers decreased by an average of 1.8% per year in men and 1.4% per year in women. This improvement in survival reflects progress in early-stage diagnosis and treatment, but the need for these remains. Discovering anti-cancer agents with low toxicity and high efficacy is a major goal of cancer research.

[0003] MEK is an important signaling intermediate in the MAPK / ERK pathway and is inappropriately activated across a wide range of human tumors, including those derived from the lung, pancreas, ovary, skin, and colon. Several MEK inhibitors have been approved by regulatory authorities to date, but these MEK inhibitors have not yet achieved the expected clinical efficacy, and a combination of these MEK inhibitors and RAF inhibitors is required to achieve a more sustained response. By identifying a new class of MEK inhibitors that can achieve dual inhibition of MEK / RAF and MEK / KSR, more complete suppression of the MAPK / ERK pathway can maximize pathological recovery, prevent reactivation of paradoxical pathways while limiting drug-related toxicity, which has a significant impact on the morbidity and mortality of cancer patients.

Summary of the Invention

[0004] Novel inhibitors of mitogen-activated protein kinase (MEK) and extracellular signal-regulated kinase (ERK) are disclosed herein (see Example 105) and may therefore be useful in the treatment of cancer. The disclosed inhibitors increase central nervous system penetration (CNS) and are thus expected to be useful in the treatment of CNS metastases and CNS cancers.

[0005] In one embodiment, a compound represented by Structural Formula (I):

Chemical formula

[0006] Pharmaceutical compositions of the compounds of the present invention are also disclosed herein. Certain embodiments include a pharmaceutically acceptable carrier or diluent, and one or more compounds of the present invention, or a pharmaceutically acceptable salt thereof.

[0007] Another embodiment of the present invention is a method of inhibiting mitogen-activated protein kinase (MEK) or extracellular signal-regulated kinase (ERK) in a subject in need thereof. This method includes administering to the subject an effective amount of a compound disclosed herein or a pharmaceutical composition disclosed herein. In one example, the "subject in need thereof" is a subject suffering from cancer.

Modes for Carrying Out the Invention

[0008] Compounds of the Invention In a first embodiment, the present invention provides a compound represented by Structural Formula (I'):

Chemical formula

Chemical formula

[0009] In a second embodiment, the present invention is a compound represented by the structural formula (I):

Chemical formula

Chemical formula

[0010] In a third embodiment, the present invention provides a compound represented by the structural formula (I’) or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1-4 alkyl, C 2=4 alkenyl, C 2-4 alkynyl,

Chemical formula

Chemical formula

[0011] In a fourth embodiment, the present invention provides a compound represented by the structural formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 is

Chemical formula

[0012] In the fifth embodiment, the present invention provides a compound selected from (II), (IIa), (IIb), and (IIc):

Chemical formula

[0013] In the sixth embodiment, the present invention provides a compound represented by the structural formula (II):

Chemical formula

[0014] In the seventh embodiment, the present invention provides a compound represented by the structural formula (I’), (I), (II), (IIa), (IIb), or (IIc) or a pharmaceutically acceptable salt thereof, wherein R 1 is methyl, allyl, propargyl,

Chemical formula

Chemical formula

[0015] In the eighth embodiment, the present invention is a compound represented by structural formula (I), (II), (IIa), (IIb), or (IIc) or a pharmaceutically acceptable salt thereof, wherein R 1 is

Chemical formula

[0016] In the ninth embodiment, the present invention is a compound represented by structural formula (I’), (I), (II), (IIa), (IIb), or (IIc) or a pharmaceutically acceptable salt thereof, wherein Ar-(CH2) x -R 3 is represented by the following structural formula,

Chemical formula

[0017] In the tenth embodiment, the present invention is a compound represented by structural formula (III):

Chemical formula

[0018] In the 11th embodiment, the present invention provides a compound represented by structural formula (IV):

Chemical formula

[0019] In the 12th embodiment, the present invention provides a compound represented by structural formula (V):

Chemical formula

[0020] In the 13th embodiment, the present invention provides a compound represented by structural formula (VI):

Chemical formula

[0021] In the 14th embodiment, the present invention provides a compound represented by structural formula (I’), (I), (II), (IIa), (IIb), or (IIc) or a pharmaceutically acceptable salt thereof, wherein Ar-(CH2) x -R 3 is represented by a structural formula selected from the following,

Chemical formula

[0022] In the 15th embodiment, the present invention is a compound represented by structural formula (I’), (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), or (VI) or a pharmaceutically acceptable salt thereof, wherein R 1 is

Chemical formula

[0023] In the 16th embodiment, the present invention is a compound represented by structural formula (I’), (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), or (VI) or a pharmaceutically acceptable salt thereof, wherein R 1 is

Chemical formula

[0024] In the 17th embodiment, the present invention is a compound represented by structural formula (I’), (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), or (VI) or a pharmaceutically acceptable salt thereof, wherein R 1 is

Chemical formula

[0025] In the 18th embodiment, the present invention is a compound represented by the structural formula (I’), (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), or (VI) or a pharmaceutically acceptable salt thereof, wherein R 1 is

Chemical formula

[0026] In the 19th embodiment, the present invention is a compound represented by the structural formula (I’), (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), or (VI) or a pharmaceutically acceptable salt thereof, wherein R 1 is C(O)N(R 6 )2, R 6 is H or C 1-6 alkyl, preferably H or methyl, and the remaining variables are as defined in the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, or 14th embodiment, to provide a compound or a pharmaceutically acceptable salt thereof.

[0027] In the 20th embodiment, the present invention is a compound represented by the structural formula (I’), (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), or (VI) or a pharmaceutically acceptable salt thereof, wherein x is 0, R 3 is

Chemical formula

[0028] In the 21st embodiment, the present invention is a compound represented by structural formula (I'), (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), or (VI) or a pharmaceutically acceptable salt thereof, wherein x is 0, and R 3 is

Chemical formula

[0029] In the 22nd embodiment, the present invention is a compound represented by structural formula (I'), (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), or (VI) or a pharmaceutically acceptable salt thereof, wherein x is 0, and R 3 is

Chemical formula

[0030] In the 23rd embodiment, the present invention is a compound represented by structural formula (I'), (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), or (VI) or a pharmaceutically acceptable salt thereof, wherein x is 0, and R 3 is

Chemical formula

[0031] In the 24th embodiment, the present invention is a compound represented by structural formula (I'), (I), (II), (IIa), (IIb), (IIc), (III), (IV)(V), or (VI) or a pharmaceutically acceptable salt thereof, wherein x is 0, R 3 is

Chemical formula

[0032] In the 25th embodiment, the present invention is a compound represented by structural formula (I), (II), (IIa), (IIb), (IIc), (III), (IV)(V), or (VI) or a pharmaceutically acceptable salt thereof, wherein Y is O, and the remaining variables are as defined in the 2nd, 4th, 6th, 8th, 10th, 11th, 12th, or 13th embodiment, to provide a compound or a pharmaceutically acceptable salt thereof.

[0033] In the 26th embodiment, the present invention is a compound represented by structural formula (I), (II), (IIa), (IIb), (IIc), (III), (IV)(V), or (VI) or a pharmaceutically acceptable salt thereof, wherein Y is NH, and the remaining variables are as defined in the 2nd, 4th, 6th, 8th, 10th, 11th, 12th, or 13th embodiment, to provide a compound or a pharmaceutically acceptable salt thereof.

[0034] In the 27th embodiment, the present invention is a compound represented by structural formula (I’), (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), or (VI) or a pharmaceutically acceptable salt thereof, wherein Y is O, NH, ^CH2O, N(CH3), or S or Y and R 2b together form NHCH=CH or NHCH2CH2CH2, and “^” indicates the attachment point to R 1 and provides a compound or a pharmaceutically acceptable salt thereof. Alternatively, Y is O, NH, N(CH3), or S. The remaining variables in both alternatives are as defined in the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, or 24th embodiment, and provides a compound or a pharmaceutically acceptable salt thereof.

[0035] In the 28th embodiment, the present invention is a compound represented by structural formula (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), or (VI) or a pharmaceutically acceptable salt thereof, wherein R 8 is H, R 9 is C 1-6 alkoxy, C 1-6 alkyl, or N(R 11 )2, R 10 is C1-C6 alkyl, and the remaining variables are as defined in the 2nd, 4th, 6th, 8th, 10th, 11th, 12th, 13th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, or 24th embodiment, and provides a compound or a pharmaceutically acceptable salt thereof.

[0036] In the 29th embodiment, the present invention is a compound represented by structural formula (I’), (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), or (VI) or a pharmaceutically acceptable salt thereof, wherein R 2b is H, C 1-6 alkyl, halo, C 1-6 alkoxy, (CH2)n OR 7 or a 4- to 6-membered heterocyclic ring, and R 4 is H, C 1-6 alkoxy, or halo, and R 5 is H, C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkynyl, cyano, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, SO2C 1-6 alkyl, SC 1-6 alkyl, halo, or C 3-8 cycloalkyl, and the remaining variables are as defined in the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th, or 28th embodiment, to provide a compound or a pharmaceutically acceptable salt thereof.

[0037] In the 30th embodiment, the present invention is a compound represented by the structural formula (I'), (I), (II), (IIa), (IIb), (IIc), (III), (IV)(V), or (VI) or a pharmaceutically acceptable salt thereof, wherein R 2b is C 1-6 alkyl, halo, C 1-6 alkoxy, (CH2) n OR 7 or a 4- to 6-membered heterocyclic ring, and R 4 is H or halo, and R 5 is H, C 1-6 alkyl, cyano, C 1-6 haloalkyl, halo, or C 3-8 cycloalkyl, and the remaining variables are as defined in the 2nd, 4th, 6th, 8th, 10th, 11th, 12th, 13th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, or 28th embodiment, to provide a compound or a pharmaceutically acceptable salt thereof.

[0038] In the 31st embodiment, the present invention is a compound represented by structural formula (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), or (VI) or a pharmaceutically acceptable salt thereof, wherein R 2b is H, methyl, ethyl, chloro, OCH3, CH2OCH3, or oxetane, and R 4 is H, OCH3, or fluoro, and R 5 is H, fluoro, chloro, bromo, iodo, cyano, OCH3, SCH3, SO2CH3, CHF2, CF3, methyl, ethyl, isopropyl, isobutyl, CD3, C≡CH, OCF3, OCHF2, or cyclopropyl, or two R 5 groups on adjacent phenyl ring atoms form OCH2CH2O, and R 6 is H or methyl, and the remaining variables are as defined in the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th, 28th, 29th, or 30th embodiment, and provides a compound or a pharmaceutically acceptable salt thereof.

[0039] In the 32nd embodiment, the present invention is a compound represented by structural formula (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), or (VI) or a pharmaceutically acceptable salt thereof, wherein R 2b is methyl, chloro, OMe, CH2OCH3, or oxetane, and R 4 is H or fluoro, and R 5 is H, fluoro, chloro, bromo, cyano, CF3, methyl, ethyl, or cyclopropyl, and R 6is H or methyl, and the remaining variables are as defined in the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th, 28th, 29th, 30th, or 31st embodiment, a compound or a pharmaceutically acceptable salt thereof is provided.

[0040] In a 33rd embodiment, the present invention is a compound represented by structural formula (I’), (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), or (VI) or a pharmaceutically acceptable salt thereof, wherein R 9 is OCH3, methyl, or NHCH3, and R 10 is H, methyl, ethyl, or propyl, and the remaining variables are as defined in the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th, 28th, 29th, 30th, 31st, or 32nd embodiment, a compound or a pharmaceutically acceptable salt thereof is provided.

[0041] In a 34th embodiment, the present invention is a compound represented by structural formula (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), or (VI) or a pharmaceutically acceptable salt thereof, wherein R 7 is H or methyl, and R 9 is OCH3, methyl, or NHCH3, and R 10 is methyl, and the remaining variables are as defined in the 2nd, 4th, 6th, 8th, 10th, 11th, 12th, 13th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 28th, 30th, or 32nd embodiment, a compound or a pharmaceutically acceptable salt thereof is provided.

[0042] In some embodiments, the present disclosure provides any one of the compounds of structural formula (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), or (VI), or the compounds (including intermediates) disclosed in the examples, in either neutral form or both its pharmaceutically acceptable salts.

[0043] In some embodiments, the present disclosure provides any one of the compounds of structural formula (I), (II), (IIa), (IIb), (IIc), (III), (IV), (V), or (VI), or the compounds (including intermediates) disclosed in the examples, or a pharmaceutically acceptable salt thereof, wherein one or more hydrogens are replaced by deuterium.

[0044] In the compounds disclosed herein, any position specifically designated as "D" or "deuterium" is understood to have a deuterium enrichment of 50, 80, 90, 95, 98, or 99%. "Deuterium enrichment" is in mole percent and is determined by dividing the number of compounds having deuterium at the indicated position by the total number of all compounds. When a position is designated as "H" or "hydrogen", hydrogen is present at that position at natural abundance. When it is unclear whether hydrogen or deuterium is present at a position, hydrogen is present at that position at natural abundance. One particular alternative embodiment relates to the compounds disclosed herein having deuterium enrichment, e.g., at least 50, 80, 90, 95, 98, or 99% deuterium enrichment, at one or more positions.

[0045] Definitions The term "pharmaceutically acceptable salt" refers to salts that are suitable for use in contact with the tissues of humans or lower animals within the scope of sound medical judgment, without undue toxicity, irritation, and allergic response, and 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 J. Pharm. Sci., 1977, 66, 1-19.

[0046] The present disclosure includes pharmaceutically acceptable salts of the compounds disclosed herein. Compounds having a basic group can form pharmaceutically acceptable salts with pharmaceutically acceptable acid(s). Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, and sulfuric acid), and salts of organic acids (such as acetic acid, benzenesulfonic acid, benzoic acid, ethanesulfonic acid, methanesulfonic acid, and succinic acid). Compounds of the present disclosure having an acidic group such as a carboxylic acid can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable basic salts include ammonium salts, alkali metal salts (such as sodium and potassium salts), and alkaline earth metal salts (such as magnesium salts and calcium salts).

[0047] The term "halo", as used herein, means halogen and includes chloro, fluoro, bromo, and iodo.

[0048] The term "alkyl", used alone or as part of a larger moiety such as "alkoxy" or "haloalkyl", means a saturated aliphatic straight or branched chain monovalent hydrocarbon group. Unless otherwise specified, the alkyl group has 1 to 6 carbon atoms, i.e., (C1-C6)alkyl. Examples include methyl, ethyl, n-propyl, isopropyl, isobutyl, etc.

[0049] The term "alkenyl" refers to an unsaturated hydrocarbon group that may be straight or branched chain and has at least one carbon-carbon double bond. Unless otherwise specified, the alkenyl group has 2 to 6 carbon atoms. Examples of alkenyl groups include ethenyl, n-propenyl, isopropenyl, n-but-2-enyl, n-pentenyl, n-hexa-3-enyl, etc.

[0050] The term "alkynyl" refers to an unsaturated hydrocarbon group that may be linear or branched and has at least one carbon-carbon triple bond. Unless otherwise specified, an alkynyl group has 2 to 6 carbon atoms. Examples of alkynyl groups include ethynyl, n-propynyl, n-but-2-ynyl, n-hexa-3-ynyl, and the like.

[0051] The term "alkoxy" means an alkyl group bonded through an oxygen linking atom and is represented by -O-alkyl. For example, "(C1-C6) alkoxy" includes methoxy, ethoxy, propoxy, and butoxy.

[0052] The term "haloalkyl" means an alkyl substituted with one or more halogen atoms.

[0053] The term "cycloalkyl" refers to a monocyclic saturated hydrocarbon ring system. Unless otherwise specified, cycloalkyl has 3 to 8 carbon atoms. For example, C3-C8 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0054] The term "heteroaryl" refers to a monocyclic aromatic ring group having 5 or 6 ring atoms (i.e., "5- to 6-membered") selected from carbon and at least one (typically 1 to 4, more typically 1 or 2) heteroatom (e.g., oxygen, nitrogen, nitric oxide, sulfur, sulfur oxide, or sulfur dioxide). Alternatively, the term "heteroaryl" refers to a bicyclic aromatic ring group having 8 to 10 ring atoms (i.e., "8- to 10-membered") selected from carbon and at least one (typically 1 to 4, more typically 1 or 2) heteroatom (e.g., oxygen, nitrogen, nitric oxide, sulfur, sulfur oxide, or sulfur dioxide).

[0055] Examples of the monocyclic heteroaryl group include furanyl (e.g., 2-furanyl, 3-furanyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 2-oxadiazolyl, 5-oxadiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), triazolyl (e.g., 2-triazolyl, 5-triazolyl), thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), tetrazolyl (e.g., tetrazolyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyrimidinyl, pyridinyl, and pyridazinyl.

[0056] Examples of the 8- to 10-membered bicyclic heteroaryl include, but are not limited to, pyrazolopyridyl, indolyl, indazolyl, azaindolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl, etc.

[0057] The term "heterocyclyl" or "heterocyclic" refers to a monocyclic non-aromatic ring radical containing 3 to 7 ring atoms (i.e., "3- to 7-membered") selected from carbon atoms and 1 or 2 heteroatoms. Each heteroatom is independently selected from nitrogen, quaternary nitrogen, nitrogen oxide (e.g., NO), oxygen, and sulfur including sulfoxide and sulfone. Representative heterocyclyl groups include morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.

[0058] The number of carbon atoms in a group is herein designated by the prefix "C" x-xx ", where x and xx are integers. For example, "C 1-6 alkyl" is an alkyl group having 1 to 6 carbon atoms.

[0059] A particular moiety (e.g., alkyl or cycloalkyl) is herein referred to as "substituted" or "optionally substituted". When a moiety is modified by either of these terms, unless otherwise noted, it means that any part of the moiety known to those skilled in the art as being substitutable can be substituted. If two or more substituents are present, each substituent can be independently selected. Such substitution means are well known in the art and / or taught by the present disclosure.

[0060] Pharmaceutical composition The compounds disclosed herein are mitogen-activated protein kinase (MEK) inhibitors. The pharmaceutical compositions of the present invention comprise one or more MEK inhibitors, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier or diluent.

[0061] "Pharmaceutically acceptable carriers" and "pharmaceutically acceptable diluents" refer to substances that assist in the formulation and / or administration of the active agent to a subject and / or absorption by the subject, and that can be included in the compositions of the present disclosure without causing significant adverse toxic effects to the subject. Non-limiting examples of pharmaceutically acceptable carriers and / or diluents include water, NaCl, normal saline, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavoring agents, salt solutions (such as Ringer's solution), alcohol, oils, gelatin, carbohydrates such as lactose, amylose or starch, hydroxymethylcellulose, fatty acid esters, polyvinylpyrrolidine, and coloring agents. Such preparations can be sterilized and, if desired, mixed with adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifying agents, salts for influencing osmotic pressure, buffers, coloring agents, and / or aromatic substances that do not react detrimentally with or inhibit the activity of the compounds provided herein. Those skilled in the art will recognize that other pharmaceutical excipients are suitable for use with the disclosed compounds.

[0062] The pharmaceutical composition of the present invention optionally comprises one or more pharmaceutically acceptable carriers and / or diluents thereof, such as lactose, starch, cellulose, and dextrose. Other excipients can also be included, such as flavors, sweeteners, and preservatives such as methyl, ethyl, propyl, and butyl parabens. A more complete list of suitable excipients is described in the Handbook of Pharmaceutical Excipients (5th Edition, Pharmaceutical Press (2005)). Those skilled in the art will know how to prepare formulations suitable for various types of administration routes. Conventional procedures and components for the selection and preparation of suitable formulations are described, for example, in Remington’s Pharmaceutical Sciences (2003 - 20th edition) and The United States Pharmacopeia: The National Formulary (USP 24 NF19) issued in 1999. The carrier, diluent, and / or excipient is "acceptable" in the sense that it is compatible with the other components of the pharmaceutical composition and is not harmful to its recipient.

[0063] Method of treatment In certain embodiments, the present invention provides a method of inhibiting mitogen-activated protein kinase (MEK) or extracellular signal-regulated kinase (ERK) in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition thereof.

[0064] "Subject" refers to a mammal in need of treatment. The mammal can be a veterinary animal (such as a dog or a cat), a farm animal (such as a horse, a cow, a sheep, or a goat), or a laboratory animal (such as a mouse, a rat, or a guinea pig). Most commonly, the subject is a human.

[0065] The "subject in need of treatment" is a subject suffering from a disease for which medical treatment is desirable. In some embodiments, the disease is cancer. In some embodiments, the cancer is selected from the group consisting of breast cancer, prostate cancer, esophageal cancer, colon cancer, endometrial cancer, blood cancer, brain tumor, glioma, head and neck cancer, thyroid cancer, gallbladder cancer, bladder cancer, skin cancer, malignant melanoma, uterine cancer, ovarian cancer, lung cancer, pancreatic cancer, liver cancer, kidney cancer, testicular cancer, kidney pelvic and ureteral cancer, prostate cancer, gastric cancer, stomach cancer, and blood cancer.

[0066] In some embodiments, the lung cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, and lung carcinoid tumor.

[0067] In some embodiments, the head and neck cancer is selected from the group consisting of pharyngeal cancer, laryngeal cancer, tongue cancer, and the like.

[0068] In some embodiments, the blood cancer is selected from the group consisting of leukemia, lymphoma, and multiple myeloma.

[0069] In some embodiments, the blood cancer is acute myeloblastic leukemia, chronic myelogenous leukemia, B-cell lymphoma, chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma, hairy cell leukemia, mantle cell lymphoma, Burkitt lymphoma, small lymphocyte lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, activated B-cell-like (ABC) diffuse large B-cell lymphoma, or germinal center B-cell (GCB) diffuse large B-cell lymphoma.

[0070] In some embodiments, the leukemia is selected from the group consisting of acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia (CML), chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy cell leukemia, T-cell prolymphocytic leukemia, juvenile myelomonocytic leukemia, myelodysplastic syndrome, and follicular lymphoma.

[0071] In some embodiments, the lymphoma is Hodgkin lymphoma or non-Hodgkin lymphoma (NHL).

[0072] In some embodiments, the non-Hodgkin lymphoma (NHL) is selected from relapsed NHL, refractory NHL, and relapsed follicular NHL.

[0073] In some embodiments, the method comprises administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of an anti-cancer agent, wherein the amounts of the combination and the chemotherapeutic agent together are effective for the treatment of a subject suffering from cancer. Currently, many chemotherapeutic agents are known in the art and can be used in combination. In some embodiments, the chemotherapeutic agent is selected from the group consisting of a mitotic inhibitor, an alkylating agent, an antimetabolite, an intercalating antibiotic, a growth factor inhibitor, a cell cycle inhibitor, an enzyme, a topoisomerase inhibitor, a biological response modifier, an antihormone, an angiogenesis inhibitor, and an antiandrogen agent. Also described is a method of treating a subject having cancer, comprising administering to a mammal a combination of radiation therapy and an amount of a MEK protein kinase inhibitor and / or a Raf protein kinase inhibitor, wherein the combination of the amount of the MEK protein kinase inhibitor and / or the Raf protein kinase inhibitor and radiation therapy is effective for the treatment of a patient having cancer. Techniques for administering radiation therapy are known in the art and these techniques can be used in the combination therapies described herein.

[0074] In some embodiments, the present disclosure also relates to a method of inhibiting abnormal cell growth in a mammal, which may comprise a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and an amount of one or more substances selected from an anti-angiogenic agent, a signal transduction inhibitor, and an anti-proliferative agent. Anti-angiogenic agents, such as MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors, and COX-11 (cyclooxygenase 11) inhibitors, can be used in combination with the compounds of the present invention and the pharmaceutical compositions described herein. Examples of useful COX-II inhibitors include CELEBREXTM (celecoxib), valdecoxib, and rofecoxib. Examples of useful matrix metalloprotease inhibitors are described in WO96 / 33172 (published October 24, 1996), WO96 / 27583 (published March 7, 1996), European Patent Application No. 97304971.1 (filed July 8, 1997), European Patent Application No. 99308617.2 (filed October 29, 1999), WO98 / 07697 (published February 26, 1998), WO98 / 03516 (published January 29, 1998), WO98 / 34918 (published August 13, 1998), WO98 / 34915 (published August 13, 1998), WO98 / 33768 (published August 6, 1998), WO98 / 30566 (published July 16, 1998), European Patent Publication No. 606,046 (published July 13, 1994), European Patent Publication No. 931,788 (published July 28, 1999), WO90 / 05719 (published May 31, 1990), WO99 / 52910 (published October 21, 1999), WO99 / 52889 (published October 21, 1999), WO99 / 29667 (published June 17, 1999), PCT International Patent Application No. PCT / IB98 / 01113 (filed July 21, 1991), European Patent Application No. 99302232.1 (filed March 25, 1999), United Kingdom Patent Application No. 9912961.1 (filed June 3, 1999), U.S. Provisional Application No. 60 / 148,464 (filed August 12, 1999), U.S. Patent No. 5,863,949 (issued January 26, 1999), U.S. Patent No. 5,861,510 (issued January 19, 1999), and European Patent Publication No. 780,386 (published June 25, 1997).Some MMP-2 and MMP-9 inhibitors have little or no activity to inhibit MMP-1, but some selectively inhibit MMP-2 and / or MMP-9 compared to other matrix metalloproteases (e.g., MAP-1, NEMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, and MMP-13). Some specific examples of MMP inhibitors useful in the present invention are AG-3340, RU32-3555, and RS13-0830.

[0075] In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are administered with at least one additional therapeutic agent. In some embodiments, the therapeutic agent is taxol, bortezomib, or both. In further or additional embodiments, the therapeutic agent is selected from the group consisting of cytotoxic agents, anti-angiogenic agents, and anti-tumor agents. In further or additional embodiments, the anti-tumor agent is selected from the group consisting of alkylating agents, antimetabolites, epichlorophyllotoxin, anti-tumor enzymes, topoisomerase inhibitors, procarbazine, mitoxantrone, platinum coordination complexes, biological response modifiers and growth inhibitors, hormone / anti-hormone therapeutic agents, and hematopoietic growth factors.

[0076] Currently, many chemotherapeutic agents are known in the art and can be used in combination with the compounds and compositions of the present disclosure. In some embodiments, the chemotherapeutic agent is selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and anti-androgen agents.

[0077] In some embodiments, the combination is administered in combination with an additional therapy. In further or additional embodiments, the additional therapy is radiation therapy, chemotherapy, surgery, or any combination thereof. In further or additional embodiments, the combination is administered in combination with at least one additional therapeutic agent. In further or additional embodiments, the therapeutic agent is selected from the group consisting of cytotoxic agents, anti-angiogenic agents, and anti-tumor agents. In further or additional embodiments, the anti-tumor agent is selected from the group consisting of alkylating agents, antimetabolites, epipodophyllotoxins, anti-tumor enzymes, topoisomerase inhibitors, procarbazine, mitoxantrone, platinum coordination complexes, biological response modifiers and growth inhibitors, hormone / anti-hormone therapeutic agents, and hematopoietic growth factors.

[0078] In some embodiments, the second therapeutic agent is an agent for co-regulating the MEK or RAF pathway. In some embodiments, the second therapeutic agent is a MEK or RAF inhibitor. In some embodiments, the RAF inhibitor is vemurafenib, dabrafenib 1b, XL-281, LGX-818, CEP-32496. ARQ-736, MEK-162, sotorasib, refametinib, E-620L pimasertib, WX-554, GDC-0973, or LXH254.

[0079] In some embodiments, the second therapeutic agent is an agent for co-regulating the MAPK pathway. In some embodiments, the agents for co-regulating the MAPK pathway include, but are not limited to, sotorasib·adagrasib, ARS-1620, ARS-3248, LY3499446, AMG-510, and MRTX849, KRAS G12C variant-selective inhibitors; KRAS G12D variant-selective inhibitors; son of sevenless 1 (SOS1) inhibitors (e.g., BI1701963, BI-3406, and RMC-023); SHP2 inhibitors (e.g., TNO155, BBP-398, and ICP-189); gefitinib, erlotinib, afatinib, lapatinib, aumolertinib (former almonertinib), ormutinib, dacomitinib, nazartinib, and osimertinib, EGFR inhibitors including, but not limited to, these.

[0080] In some embodiments, the second therapeutic agent is an agent against mutant p53 reactivators (PC14586, APR-246, and COTI-2).

[0081] In some embodiments, the second therapeutic agent is selected from aspirin, diflunisal, salsalate, acetaminophen, ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, aceclofenac, nabumetone, enolic acid, piroxicam, meloxicam, tenoxicam, droxicam, lomoxicam, isoxicam, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, sulfonanilide, clonixin, licofelone, dexamethasone, and prednisone.

[0082] In some embodiments, the second therapeutic agent is selected from mechlorethamine, cyclophosphamide, melphalan, chlorambucil, ifosfamide, busulfan, N-nitroso-N-methylurea (MNU), carmustine (BCNU), lomustine (CCNU), semustine (MeCCNU), fotemustine, streptozotocin, dacarbazine, mitozolomide, temozolomide, thiotepa, mitomycin, diaziquone (AZQ), cisplatin, carboplatin, and oxaliplatin.

[0083] In some embodiments, the second therapeutic agent is selected from vincristine, vinblastine, vinorelbine, vindesine, vinflunine, paclitaxel, docetaxel, etoposide, teniposide, tofacitinib, ixabepilone, irinotecan, topotecan, camptothecin, doxorubicin, mitoxantrone, and teniposide.

[0084] In some embodiments, the second therapeutic agent is selected from actinomycin, bleomycin, plicamycin, mitomycin, daunorubicin, epirubicin, idarubicin, pirarubicin, aclarubicin, mitoxantrone, cyclophosphamide, methotrexate, 5-fluorouracil, prednisone, folic acid, methotrexate, melphalan, capecitabine, mechlorethamine, uramustine, melphalan, chlorambucil, ifosfamide, bendamustine, 6-mercaptopurine, and procarbazine.

[0085] In some embodiments, the second therapeutic agent is selected from cladribine, pemetrexed, fludarabine, gemcitabine, hydroxyurea, nelarabine, cladribine, clofarabine, cytarabine, decitabine, cytarabine, liposomal cytarabine, pralatrexate, floxuridine, fludarabine, colchicine, thioguanine, cabazitaxel, larotaxel, ortataxel, tesetaxel, aminopterin, pemetrexed, pralatrexate, raltitrexed, pemetrexed, carmofur, and floxuridine.

[0086] In some embodiments, the second therapeutic agent is selected from azacitidine, decitabine, hydroxycarbamide, topotecan, irinotecan, belotecan, teniposide, aclarubicin, epirubicin, idarubicin, amrubicin, pirarubicin, valrubicin, zorbicin, mitoxantrone, pixantrone, mechlorethamine, chlorambucil, prednimustine, uramustine, estramustine, carmustine, lomustine, fotemustine, nimustine, ranimustine, carbocon, thiotepa, triaziquone, and triethylenemelamine.

[0087] In some embodiments, the second therapeutic agent is selected from nedaplatin, satraplatin, procarbazine, dacarbazine, temozolomide, altretamine, mitobronitol, pipobroman, actinomycin, bleomycin, plicamycin, aminolevulinic acid, methylaminolevulinic acid, efaproxiral, talaporfin, temoporfin, verteporfin, albosidib, seliciclib, palbociclib, bortezomib, carfilzomib, anagrelide, masoprocol, olaparib, belinostat, panobinostat, romidepsin, vorinostat, idelalisib, atrasentan, bexarotene, testolactone, amsacrine, trabectedin,alitretinoin, tretinoin, dexamethasone, elsamitrucin, etoglucid, lonidamine, lucanthone, mitotane, oblimersen, omacetaxine mepesuccinate, and eribulin.

[0088] In some embodiments, the second therapeutic agent is selected from azathioprine, mycophenolic acid, leflunomide, teriflunomide, tacrolimus, cyclosporine, pimecrolimus, abetimus, gusperimus, lenalidomide, pomalidomide, thalidomide, anakinra, sirolimus, everolimus, ridafolimus, temsirolimus, umirolimus, zotarolimus, eculizumab, adalimumab, afelimomab, certolizumab pegol, golimumab, infliximab, nerelimomab, mepolizumab, omalizumab, faralimumab, elsilimomab, lebrikizumab, ustekinumab, etanercept, oterixizumab, teplyzumab, bisilizumab, clenoliximab, keliximab, dianolinomab, efalizumab, epratuzumab, obinutuzumab, rituximab, and ocrelizumab.

[0089] In some embodiments, the second therapeutic agent is selected from pascolizumab, gomiliximab, lumiliximab, teneliximab, tralizumab, aselizumab, galiximab, gavrilimomab, ruplyzumab, belimumab, brisibimod, ipilimumab, tremelimumab, bervatimomab, lerdelimumab, metelimumab, natalizumab, tocilizumab, odelimumab, basiliximab, daclizumab, inolimomab, zolimomab, atorlimomab, cedelizumab, fontolizumab, maslimomab, mololizumab, pexelizumab, reslizumab, rovelizumab, siprilizumab, talizumab, terimalizumab, bapaliximab, bepalimumab, abatacept, veratascept, pegsunercept, afutacept, alefacept, and rilonacept.

[0090] In some embodiments, the second therapeutic agent is an immune checkpoint inhibitor such as a PD-1 inhibitor or a PD-L1 inhibitor. In some embodiments, the immune checkpoint inhibitor is balstilimab, camrelizumab, semaprilimab, dostarlimab, gepotidacin, nivolumab, pembrolizumab, penpulimab, pidilizumab, prolegozumab, retifanlimab, sasunlimab, serplulimab, sintilimab, spartalizumab, surituzumab, tebotelimab, telisotuzumab, tislelizumab, toripalimab, tremelimumab, zimberelimab, AMP-224 (manufactured by MedImmune), AMP-514 (manufactured by MedImmune), AT-16201 (manufactured by AIMM Therapeutics BV), AVI-102 (manufactured by Ab Vision Inc.), BAT-1308 (manufactured by Biosera Solutions Co., Ltd.), BH-2950 (manufactured by Beijing Hanmi Pharmaceutical Co., Ltd.), BSI-050K01 (manufactured by Biosion Co., Ltd.), CB-201 (manufactured by Crescent BioLogix), CYTO-101 (manufactured by Cytocom, Inc.), DB-004 (manufactured by DotBio, Inc.), EX-105 (manufactured by Excellmab Co., Ltd.), EX-108 (manufactured by Excellmab Co., Ltd.), GNR-051 (manufactured by Genellium), HAB-21 (manufactured by Suzhou Stoneway Biotechnology Co., Ltd.), IBI-319 (manufactured by Innovent Biologics, Inc.), IBI-321 (manufactured by Innovent Biologics, Inc.), IKT-202 (manufactured by Aisel Kirex Therapeutics LLC), IMU-201 (manufactured by Immugene Co., Ltd.), JS-201 (manufactured by Shanghai Junshi Biosciences Co., Ltd.), LBL-006 (manufactured by Lead Biolab Co., Ltd.), LBL-024 (manufactured by Lead Biolab Co., Ltd.), LD-01 (manufactured by Raidos Holdings LLC), LQ-005 (manufactured by Shanghai Novamab Biopharmaceutical Co., Ltd.), LQ-008 (manufactured by Shanghai Novamab Biopharmaceutical Co., Ltd.), MD-402 (manufactured by MD Bioscience GmbH), OT-2 (manufactured by Oncotrap Co., Ltd.), PE-0105 (manufactured by Shanghai Yunyi Health Technology Development Co., Ltd.), PF-07209960 (manufactured by Pfizer Inc.), PH-762 (manufactured by Fyopharmaceuticals Co., Ltd.), REGN-PD-1 / XX (manufactured by Regeneron), R07121661 (manufactured by Genentech),It is an anti-PD-1 antibody selected from the group consisting of SAUG-1 (manufactured by Juvenescence UK Limited), SCT-IIOA (manufactured by Sinocelltech), SG-001 (manufactured by CSPC Pharmaceutical Group Limited), SI-B003 (manufactured by Cistoimmune), SL-279137 (manufactured by Shattuck Labs), SSI-361 (manufactured by Revigen Biopharma Inc.), STI-A1110 (manufactured by Servier), STM-418 (manufactured by Scube), Sym-021 (manufactured by Symphony GenA / S), TSR-075 (manufactured by GlaxoSmithKline), TY101 (manufactured by Dayou Huaxia Biotechnology), Twist-PD-1 (manufactured by Twist Bioscience), XmAb-TGFpR2 (manufactured by Zencore), XmAb-YYCD28 (manufactured by Zencore), XmAb20717 (manufactured by Zencore), XmAb23104 (manufactured by Zencore), YBL-006 (manufactured by Y Biologics), YBL-019 (manufactured by Y Biologics), and mDX-400 (manufactured by Merck).

[0091] In one embodiment, the anti-cancer agent and the compound represented by formula (I) are administered simultaneously. When administered simultaneously, the anti-cancer agent and the compound can be administered in the same formulation or in different formulations. Alternatively, the compound and the additional anti-cancer agent are administered separately. Alternatively, the compound and the additional anti-cancer agent can be administered continuously as separate compositions within an appropriate time frame determined by a skilled clinician (e.g., cancer treatment session / interval (e.g., about 1.5 to about 5 hours, to about 10 hours, to about 15 hours, to about 20 hours; about 1 day to about 2 days, to about 5 days, to about 10 days, to about 14 days)) (e.g., a time sufficient to allow overlap of the pharmaceutical effects of the treatment). The compound and the additional anti-cancer agent can be administered in single or multiple doses in an order and schedule suitable to achieve the desired therapeutic effect (e.g., inhibition of tumor growth).

[0092] Accordingly, the present invention provides a method of treatment comprising administering to a subject a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, for treating at least one of the diseases or conditions recited above.

[0093] As used herein, the terms "treating" or "treatment" refer to obtaining a desired pharmacological and / or physiological effect. This effect can be a therapeutic effect, including, but not limited to, partially or substantially achieving one or more of the following results: reducing, in whole or in part, the severity of a disease, disorder, or syndrome; alleviating or improving clinical symptoms or markers associated with the disorder; or delaying, inhibiting, or reducing the likelihood of progression of a disease, disorder, or syndrome.

[0094] Route of Administration and Dosage Form The exact amount of a compound administered to provide an "effective amount" to a subject will vary depending on the mode of administration, the type and severity of the disease or condition, and characteristics of the subject such as general health, age, sex, weight, and tolerance to the drug. One of ordinary skill in the art will be able to determine appropriate dosages depending on these and other factors. When administered in combination with other therapeutic agents, for example, in combination with an anti-cancer agent, the "effective amount" of any additional therapeutic agent(s) will depend on the type of agent used. Suitable dosages of approved therapeutic agents are known, and one of ordinary skill in the art can adjust the dosages according to the condition of the subject, the type of condition(s) being treated, and the amount of the compound of the invention being used, for example, as reported in the literature and recommended in the Physician's Desk Reference (57th Edition, 2003).

[0095] The term "effective amount" means an amount that, when administered to a subject, produces a beneficial or desired result, including clinical results such as inhibiting, suppressing, or alleviating the symptoms of the condition being treated in the subject as compared to a control. For example, a therapeutically effective amount can be administered in unit dosage forms (e.g., 0.1 mg to about 50 g per day).

[0096] As used herein, the terms “administer,” “administering,” “administration,” etc. refer to methods that can be used to effect delivery of a composition to a desired site of a biological action. Such methods include, but are not limited to, intra-articular (into a joint), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, oral, topical, intrathecal, inhalation, transdermal, rectal, etc. Administration techniques that can be used with the agents and methods described herein are described, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington’s, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

[0097] Specific modes of administration and dosing regimens are selected by the attending clinician taking into account the details of the case (e.g., the subject, the disease, the medical condition involved, the particular therapy). Treatment may involve daily or several times a day, or less than daily (such as weekly or monthly) dosages over a period of days to months, or even years. However, one of ordinary skill in the art will immediately recognize appropriate dosages and / or equivalent dosages upon considering the dosages of approved compositions for treating a disease using the disclosed MEK inhibitors as a guide.

[0098] The compounds or corresponding pharmaceutical compositions taught herein can be administered to a patient in various forms depending on the selected route of administration, as will be understood by one of ordinary skill in the art. The compounds of the present teachings can be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump, or transdermal administration, and the pharmaceutical compositions are formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, trans-epithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration can be effected by continuous infusion over a selected period.

[0099] The pharmaceutical composition of the present invention is formulated to be compatible with its intended route of administration. In one embodiment, the composition is formulated according to ordinary procedures as a pharmaceutical composition suitable for intravenous, subcutaneous, intramuscular, oral, intranasal, or topical administration to humans. In a preferred embodiment, the pharmaceutical composition is formulated for intravenous administration.

[0100] Typically, for oral therapeutic administration, the compounds according to the present teachings are incorporated with excipients and can be used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.

[0101] Typically, for parenteral administration, solutions of the compounds of the present teachings can generally be prepared in water suitably admixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, DMSO, and mixtures thereof, with or without alcohol, and in oils. Under normal storage and use conditions, these preparations contain preservatives to prevent the growth of microorganisms.

[0102] Typically, for injection, sterile aqueous solutions or dispersions of the compounds described herein for immediate preparation of sterile injectable solutions or dispersions, and sterile powders are appropriate.

[0103] The following examples are provided to illustrate exemplary embodiments of the present invention and are not intended to limit or restrict its scope. Exemplification

[0104] The abbreviations used throughout this specification can be summarized below together with their specific meanings: ACN, MeCN - Acetonitrile, AcOK - Potassium acetate, AIBN - Azobisisobutyronitrile, BOC - tert-Butyloxycarbonyl, Boc2O - Di-tert-butyl dicarbonate, ℃ - Celsius temperature, CaCl2 - Calcium chloride, CBr4 - Carbon tetrabromide, CDCl3 or chloroform - d - Deuterated chloroform, Cs2CO3 - Cesium carbonate, d - Doublet, δ - Delta, DCM, CH2Cl2 - Dichloromethane, DMA - N,N - Dimethylacetamide, DMAP - 4 - Dimethylaminopyridine, DMF - N,N - Dimethylformamide, DMSO - Dimethyl sulfoxide, DMSO - d6 - Deuterated dimethyl sulfoxide, ESI - Electrospray ionization, EtOAc, EA - Ethyl acetate, Et3N - Triethylamine, FA - Formic acid, 19 F NMR - Fluorine - 19 nuclear magnetic resonance, g - Gram, h - Hour, 1 H - Proton, 1 H NMR - Proton nuclear magnetic resonance, H2O - Water, HCl - Hydrochloric acid, HP - High performance, Hz - Hertz, J - Coupling constant, K2CO3 - Potassium carbonate, LCMS - Liquid chromatography - mass spectrometry, M + - Molecular ion, m - Multiplet, MeOH - Methanol, Methanol - d4 - Deuterated methanol, mg - Milligram, min - Minute, MHz - Megahertz (frequency), mL - Milliliter, mmol - Millimole, MnO2 - Manganese dioxide, NaBH4 - Sodium borohydride, NaHCO3 - Sodium hydrogen carbonate, Na2SO4 - Sodium sulfate, NBS - N - Bromosuccinimide, NH3H2O - Ammonia aqueous solution, NH4Cl - Ammonium chloride, NH4HCO3 - Ammonium hydrogen carbonate Pd(dppf)Cl2 - [1,1’ - Bis(diphenylphosphino)ferrocene]dichloropalladium(II), Pd2(dba)3 - Tris(dibenzylideneacetone)dipalladium(0), PE - Petroleum ether, % - Percentage, pH - Hydrogen ion exponent, PPh3 - Triphenylphosphine, ppm - Parts per million, q - Quartet, RuPhos - 2 - Dicyclohexylphosphino - 2’,6’ - diisopropoxybiphenyl, RuPhos Pd G3 - (2 - Dicyclohexylphosphino - 2’,6’ - diisopropoxy - 1,1’ - biphenyl)[2 - (2’ - amino - 1,1’ - biphenyl)]palladium(II) methanesulfonate, s - Singlet, t - Triplet, TBAF - Tetrabutylammonium fluoride, TFA - Trifluoroacetic acid, THF - Tetrahydrofuran, TMSCHN2 - (Trimethylsilyl)diazomethane, XantPhos - 4,5 - Bis(diphenylphosphino) - 9,9 - dimethylxanthene.

[0105] Intermediate 1:

Chem.

[0106] Synthesis of Intermediate 1: Step 2 [Chemistry] To a stirred mixture of methyl 5-bromo-4-methylpyridine-3-carboxylate (5 g, 21.7 mmol, 1 equiv) and 2-fluoroaniline (4.8 g, 43.5 mmol, 2.0 equiv) in dioxane (50 mL), Cs2CO3 (21.24 g, 65.19 mmol, 3.0 equiv), RuPhos (1.01 g, 2.2 mmol, 0.1 equiv), and RuPhos Pd G3 (1.8 g, 2.2 mmol, 0.1 equiv) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:1) to afford methyl 5-[(2-fluorophenyl)amino]-4-methylpyridine-3-carboxylate (4.5 g, 79%) as a yellow solid. LCMS: (ESI, m / z): [M+1] + =261.0; 1 H NMR (400 MHz, chloroform-d) δ 8.77 (s, 1H), 8.56 (s, 1H), 7.12 (m, 1H), 7.01 (m, 1H), 6.89 (m, 2H), 5.54 (s, 1H), 3.95 (s, 3H), 2.52 (s, 3H).

[0107] Synthesis of Intermediate 1: Step 3

Chemical Structure

[0108] Synthesis of Intermediate 1: Step 4

Chemical Structure

[0109] Synthesis of Intermediate 1: Step 5

Chem.

[0110] Synthesis of Intermediate 1: Step 6

Chem.

[0111] Synthesis step 1 of boronate

Chem.

[0112] Synthesis step 2 of boronate

Chem.

[0113] Synthesis of Intermediate 1: Step 7

Chemical Structure

[0114] Synthesis of Intermediate 1: Step 8

Chemical Structure

[0115] Intermediate 2:

Chemical Structure

[0116] Intermediate 3:

Chemical Structure

Chemical Structure

[0117] Synthesis of Intermediate 3: Step 2

Chemical Structure

[0118] Intermediate 4:

Chemical formula

Chemical formula

[0119] Synthesis of Intermediate 4: Step 2 To a stirred solution of tert-butyl N-(3-fluoro-4-methylpyridin-2-yl)carbamate (2.3 g, 10.2 mmol, 1 equiv) in THF (20 mL), Et3N (2.1 g, 20.3 mmol, 2.0 equiv) was added at room temperature, then (Boc)2O (2.66 g, 12.19 mmol, 1.2 equiv) and DMAP (0.12 g, 1.01 mmol, 0.1 equiv) were added at 0 °C. After the addition was complete, the mixture was warmed to 25 °C and stirred at room temperature for 16 h. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:1) to give tert-butyl N-(tert-butoxycarbonyl)-N-(3-fluoro-4-methylpyridin-2-yl)carbamate (2.6 g, 65%) as a white solid. LCMS: (ESI, m / z): [M+1] + =327.20; 1 H NMR (300 MHz, chloroform-d) δ 8.14 (d, J = 4.9 Hz, 1H), 7.16 - 7.10 (m, 1H), 2.34 (m, 3H), 1.42 (s, 18H).; 19 F NMR (282 MHz, CDCl3) δ -131.69.

[0120] Synthesis of Intermediate 4: Step 3

Chemical Structure

[0121] Synthesis of Intermediate 4: Step 4 To a stirred mixture of tert-butyl N-[4-(bromomethyl)-3-fluoropyridin-2-yl]-N-(tert-butoxycarbonyl)carbamate (200 mg, 0.49 mmol, 1 equiv) and 4-methyl-5-nitropyridin-3-ylboronic acid (Intermediate 6: 107.75 mg, 0.59 mmol, 1.2 equiv) in dioxane (5 mL), K2CO3 (206.11 mg, 1.48 mmol, 3.0 equiv) and Pd(dppf)Cl2 (40.20 mg, 0.049 mmol, 0.1 equiv) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 16 h under a nitrogen atmosphere. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient from 45% to 65% in 20 min; detector, UV 254 / 220 nm to give tert-butyl N-(tert-butoxycarbonyl)-N-{3-fluoro-4-[(4-methyl-5-nitropyridin-3-yl)methyl]pyridin-2-yl}carbamate (110 mg, 48%) as a white solid. LCMS: (ESI, m / z): [M+1] + =463.2; 1 H NMR (400 MHz, chloroform-d) δ 8.98 (s, 1H), 8.56 (s, 1H), 8.24 (d, 1H), 6.96 - 6.77 (m, 1H), 4.18 (s, 2H), 2.41 (m, 3H), 1.40 (s, 18H); LCMS: (ESI, m / z): [M+1]+ = 183.1; 1H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.80 (s, 1H), 2.62 (s, 3H).

[0122] Synthesis of Intermediate 4: Step 5 A stirred mixture of tert-butyl N-(tert-butoxycarbonyl)-N-{3-fluoro-4-[(4-methyl-5-nitropyridin-3-yl)methyl]pyridin-2-yl}carbamate (100 mg, 0.22 mmol, 1 equiv), iron (60.38 mg, 1.08 mmol, 5 equiv) in water (1 mL) and methanol (5 mL) was added with NH4Cl (115.66 mg, 2.16 mmol, 10.0 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C for 1 h under a nitrogen atmosphere. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (10:1) to give tert-butyl N-{4-[(5-amino-4-methylpyridin-3-yl)methyl]-3-fluoropyridin-2-yl}-N-(tert-butoxycarbonyl)carbamate (55 mg, 58%) as a white solid. LCMS: (ESI, m / z): [M+1] + =433.3; 1 H NMR (400 MHz, chloroform-d) δ 8.15 (m, 1H), 8.07 (s, 1H), 7.86 (s, 1H), 6.85 (m, 1H), 4.03 (s, 2H), 1.99 (s, 3H), 1.42 (s, 18H).

[0123] Intermediate 5:

Chemical Structure

Chemical Structure

[0124] Example 1:

Chemical formula

Chemical formula

[0125] Example 2:

Chemical formula

Chemical formula

[0126] Step 2 A stirred solution of N-[4-({5-[(4-bromo-2-fluorophenyl)amino]-4-methylpyridin-3-yl}methyl)-3-fluoropyridin-2-yl]-N-methanesulfonylmethanesulfonamide (100 mg, crude) in MeOH (2 mL) was added dropwise with NaOH (2 mL, 1 M in water) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. The mixture was acidified to about pH 6 with HCl (2 M in water). The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (1 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (15:1) to give N-[4-({5-[(4-bromo-2-fluorophenyl)amino]-4-methylpyridin-3-yl}methyl)-3-fluoropyridin-2-yl]methanesulfonamide (12 mg, purity 92%) as a white solid. The residue was further purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient of 5% to 75% over 20 minutes, detector, UV 254 nm. Thereby, N-[4-({5-[(4-bromo-2-fluorophenyl)amino]-4-methylpyridin-3-yl}methyl)-3-fluoropyridin-2-yl]methanesulfonamide (6.1 mg, purity 99%) was obtained as a white solid. LCMS: [M+1] + =483.10; 1 H NMR (400 MHz, methanol-d4) δ 8.11 (m, 2H), 7.99 (m, 1H), 7.31 (m, 2.2 Hz, 1H), 7.15 (m, 1H), 6.76 (m, 1H), 6.63 m, 1H), 4.16 (s, 2H), 3.38 (s, 3H), 2.16 (s, 3H).; 19 F NMR (377 MHz, methanol-d4) δ -128.266, -140.621.

[0127] Example 3:

Chemical formula

[0128] Example 4: [Chemistry] Synthetic route: [Chemistry] To a stirred mixture of 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-N-(4-bromo-2-fluorophenyl)-4-methylpyridin-3-amine (Intermediate 1: 10 mg, 0.025 mmol, 1 equiv) and pyridine (5.86 mg, 0.075 mmol, 3.0 equiv) in DCM (1 mL) was added methyl chloroformate (2.33 mg, 0.025 mmol, 1.0 equiv) in DCM (0.1 mL) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under a nitrogen atmosphere. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient of 30% - 50% over 20 min; detector, UV254 / 220 nm to give methyl N-[4-({5-[(4-bromo-2-fluorophenyl)amino]-4-methylpyridin-3-yl}methyl)-3-fluoropyridin-2-yl]carbamate (2.0 mg, 17%) as a white solid. LCMS: (ESI, m / z): [M+1] + = 462.8. 1 H NMR (400 MHz, methanol-d4) δ 8.09 (m, 3H), 7.31 (m, 1H), 7.15 (m, 1H), 6.90 (m, 1H), 6.64 (m, 1H), 4.19 (s, 2H), 3.77 (s, 3H), 2.16 (s, 3H); 19 F NMR (377 MHz, methanol-d4) δ -128.274, -135.542.

[0129] Example 5:

Chemical Structure

Chemical Structure

[0130] Step 2: To a stirred mixture of 5-[(3-aminophenyl)methyl]-N-(4-bromo-2-fluorophenyl)-4-methylpyridin-3-amine (15 mg, 0.039 mmol, 1 equiv) and pyridine (30.72 mg, 0.39 mmol, 10.0 equiv) in DMA (1 mL) was added N-methylsulfamoyl chloride (25.16 mg, 0.2 mmol, 5 equiv) in DMA (0.2 mL) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under a nitrogen atmosphere. The desired product could be detected by LCMS. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient of 30% - 50% in 20 min; detector UV254 / 220 nm to give N-(4-bromo-2-fluorophenyl)-4-methyl-5-({4-[(methylsulfamoyl)amino]phenyl}methyl)pyridin-3-amine (4.3 mg, 23%) as a white solid. LCMS: (ESI, m / z): [M+1] + =478.90; 1 H NMR (400 MHz, methanol-d4) δ 8.10 (m, 2H), 7.32 - 7.20 (m, 2H), 7.15 - 7.03 (m, 2H), 7.00 (s, 1H), 6.87 (m, 1H), 6.56 (m, 1H), 4.07 (s, 2H), 2.55 (m, 3H), 2.13 (s, 3H); 19 F NMR (377 MHz, methanol-d4) δ -129.167.

[0131] Example 6:

Chemical formula

Chemical formula

[0132] Step 2: To a stirred solution of tert-butyl N-(tert-butoxycarbonyl)-N-[4-({5-[(4-chloro-2-fluorophenyl)amino]-4-methylpyridin-3-yl}methyl)-3-fluoropyridin-2-yl]carbamate (18 mg, 0.032 mmol, 1 equiv) in DCM (2 mL), TFA (0.60 mL, 8.06 mmol, 251.77 equiv) was added dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under a nitrogen atmosphere. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient of 40% - 80% in 20 min; detector, UV254 / 220 nm to give 4-({5-[(4-chloro-2-fluorophenyl)amino]-4-methylpyridin-3-yl}methyl)-3-fluoropyridin-2-amine (10 mg, 86%) as a white solid. LCMS: (ESI, m / z): [M+1] + =361.1

[0133] Step 3: To a stirred mixture of 4-({5-[(4-chloro-2-fluorophenyl)amino]-4-methylpyridin-3-yl}methyl)-3-fluoropyridin-2-amine (10 mg, 0.028 mmol, 1 equiv) and pyridine (21.92 mg, 0.280 mmol, 10 equiv) in DMA (2 mL), N-methylsulfamoyl chloride (17.96 mg, 0.140 mmol, 5 equiv) in 0.5 mL of DMA was added dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under a nitrogen atmosphere. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient of 10% - 50% in 20 min; detector UV254 / 220 nm to give N-(4-chloro-2-fluorophenyl)-5-({3-fluoro-2-[(methylsulfamoyl)amino]pyridin-4-yl}methyl)-4-methylpyridin-3-amine (5.1 mg, 40%) as a white solid. LCMS: (ESI, m / z): [M+1]+ =454.2; 1 1H NMR (400 MHz, methanol-d4) δ 8.09 (m, 2H), 7.97 (m, 1H), 7.19 (m, 1H), 7.02 (m, 1H), 6.75 - 6.64 (m, 2H), 4.15 (s, 2H), 2.63 (s, 3H), 2.16 (s, 3H).; 19 19F NMR (377 MHz, methanol-d4) δ -128.109, -142.314.

[0134] Example 7:

Chemical Structure

Chemical Structure

[0135] Step 2: To a stirred solution of tert-butyl N-(tert-butoxycarbonyl)-N-[4-({5-[(2,4-difluorophenyl)amino]-4-methylpyridin-3-yl}methyl)-3-fluoropyridin-2-yl]carbamate (15 mg, 0.028 mmol, 1.0 equiv) in DCM (1 mL) was added TFA (0.2 mL) at 0 °C, and then the mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The desired product was detected by LCMS. The residue was neutralized to pH 10 with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (1 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (10:1) to afford 4-({5-[(2,4-difluorophenyl)amino]-4-methylpyridin-3-yl}methyl)-3-fluoropyridin-2-amine (8 mg, 84%) as a white solid. LCMS: (ESI, m / z): [M + 1] + = 345.00; 1 1H NMR (300 MHz, chloroform-d) δ 8.30 (s, 1H), 8.14 (s, 1H), 7.73 (d, J = 5.2 Hz, 1H), 6.95 - 6.72 (m, 3H), 6.28 - 6.25 (m, 1H), 4.64 (s, 2H), 3.99 (s, 2H), 2.14 (s, 3H); 19 19F NMR (282 MHz, chloroform-d) δ -119.100, -126.990, -145.330.

[0136] Step 3: To a stirred solution of 4-({5-[(2,4-difluorophenyl)amino]-4-methylpyridin-3-yl}methyl)-3-fluoropyridin-2-amine (5 mg, 0.015 mmol, 1.0 equiv) and pyridine (11.49 mg, 0.15 mmol, 10 equiv) in DMA (0.5 mL) was added N-methylsulfamoyl chloride (9.41 mg, 0.075 mmol, 5 equiv) in DMA (0.2 mL) dropwise at 0 °C under an air atmosphere. Then, stirring was continued at room temperature for 1 h. The desired product could be detected by LCMS. The reaction mixture was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient of 5% - 60% in 40 min, detector, UV254 nm. N-(2,4-Difluorophenyl)-5-({3-fluoro-2-[(methylsulfamoyl)amino]pyridin-4-yl}methyl)-4-methylpyridin-3-amine (2.2 mg, 34%) was obtained as a white solid. LCMS: (ESI, m / z): [M+1] + =438.05; 1 H NMR (400 MHz, methanol-d4) δ 8.01 - 7.94 (m, 2H), 7.94 - 7.90 (m, 1H), 7.04 - 6.98 (m, 1H), 6.97 - 6.81 (m, 2H), 6.70 - 6.67 (m, 1H), 4.14 (s, 2H), 2.63 (s, 3H), 2.17 (s, 3H).; 19 F NMR (377 MHz, methanol-d4) δ -120.464, -123.894, -142.404.

[0137] Example 8:

Chemical formula

Chemical formula

[0138] Step 2: To a stirred solution of tert-butyl N-(tert-butoxycarbonyl)-N-{3-fluoro-4-[(5-{[2-fluoro-4-(trifluoromethyl)phenyl]amino}-4-methylpyridin-3-yl)methyl]pyridin-2-yl}carbamate (40 mg, 0.067 mmol, 1.0 equiv) in DCM (0.5 mL), TFA (0.1 mL) was added dropwise at 0 °C under an air atmosphere. The resulting mixture was stirred at room temperature for an additional 1 hour. The desired product could be detected by LCMS. The residue was neutralized to pH 10 with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (1 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with MeOH / DCM (1:10) to afford 3-fluoro-4-[(5-{[2-fluoro-4-(trifluoromethyl)phenyl]amino}-4-methylpyridin-3-yl)methyl]pyridin-2-amine (20 mg, 75%) as a yellow solid. LCMS: [M+1] + =395.10; 1 H NMR (300 MHz, chloroform-d) δ 8.50 (s, 1H), 8.32 (s, 1H), 7.75 (d, J = 5.4 Hz, 1H), 7.37 (d, J = 11.3 Hz, 1H), 7.24 (s, 1H), 6.73 (t, J = 8.4 Hz, 1H), 6.32 (t, J = 5.2 Hz, 1H), 5.76 (s, 1H), 5.00 (s, 2H), 4.06 (s, 2H), 2.19 (s, 3H).

[0139] Step 3: To a stirred solution of 3-fluoro-4-[(5-{[2-fluoro-4-(trifluoromethyl)phenyl]amino}-4-methylpyridin-3-yl)methyl]pyridin-2-amine (10 mg, 0.025 mmol, 1.0 equiv) and pyridine (20.06 mg, 0.250 mmol, 10 equiv) in DMA (1.00 mL) was added N-methylsulfamoyl chloride (16.43 mg, 0.13 mmol, 5 equiv) in DMA (0.2 mL) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for an additional 1 h. The desired product could be detected by LCMS. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient 30% - 70% in 30 min; detector, UV 254 nm. 5-({3-Fluoro-2-[(methylsulfamoyl)amino]pyridin-4-yl}methyl)-N-[2-fluoro-4-(trifluoromethyl)phenyl]-4-methylpyridin-3-amine (2.2 mg, 17%) was obtained as a white solid. LCMS: [M+1] + =488.05; 1 H NMR (300 MHz, methanol-d4) δ 8.30 - 8.25 (m, 2H), 8.02 - 8.00 (m, 1H), 7.43 - 7.39 (m, 1H), 7.33 - 7.30 - 7.25 (m, 1H), 6.77 - 6.74 (m, 1H), 6.66 - 6.60 (m, 1H), 4.21 (s, 2H), 2.65 (s, 3H), 2.19 (s, 3H).; 19 F NMR (282 MHz, methanol-d4) δ -62.898, -132.660, -142.345.

[0140] Example 9:

Chemical formula

Chemical formula

[0141] Step 2: To a stirred solution of 4-{[(tert-butyldimethylsilyl)oxy]methyl}-3-fluoro-2-(methylsulfanyl)pyridine (100 mg, 0.35 mmol, 1 equiv) in THF (0.5 mL), TBAF (90.95 mg, 0.35 mmol, 1 equiv) in THF (0.5 mL) was added dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h under a nitrogen atmosphere. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (10 × 3 mL). The combined organic layers were washed with brine (10 mL × 3) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1) to give [3-fluoro-2-(methylsulfanyl)pyridin-4-yl]methanol (50 mg, 83%) as a white solid. LCMS: (ESI, m / z): [M+1] + =174.0: 1 H NMR (400 MHz, chloroform-d) δ 8.27 (m, 1H), 7.16 (m, 1H), 4.78 (s, 2H), 2.58 (s, 3H): 1919F NMR (377 MHz, chloroform-d) δ -128.70, -128.96, -129.01, -129.17, -129.38.

[0142] Step 3: To a stirred solution of [3-fluoro-2-(methylsulfanyl)pyridin-4-yl]methanol (93 mg, 0.54 mmol, 1 equiv) and PPh3 (211.24 mg, 0.81 mmol, 1.50 equiv) in DCM (1 mL) was added CBr4 (267.09 mg, 0.81 mmol, 1.5 equiv) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1) to afford 4-(bromomethyl)-3-fluoro-2-(methylsulfanyl)pyridine (20 mg, 16%) as a white solid. LCMS: (ESI, m / z): [M+1] + = 235.0; 1 1H NMR (300 MHz, chloroform-d) δ 8.24 (d, J = 5.0 Hz, 1H), 7.04 (t, J = 5.2 Hz, 1H), 4.41 (d, J = 1.0 Hz, 2H), 2.58 (s, 3H); 19 19F NMR (282 MHz, chloroform-d) δ -127.40.

[0143] Step 4: To a stirred solution of 4-(bromomethyl)-3-fluoro-2-(methylsulfanyl)pyridine (20 mg, 0.085 mmol, 1 equiv) in dioxane (5 mL), Pd(dppf)Cl2·CH2Cl2 (6.90 mg, 0.009 mmol, 0.1 equiv), and K2CO3 (35.12 mg, 0.26 mmol, 3 equiv) was added 4-methyl-5-nitropyridin-3-ylboronic acid (18.49 mg, 0.102 mmol, 1.2 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 16 h under a nitrogen atmosphere. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (10:1) to afford 3-fluoro-4-[(4-methyl-5-nitropyridin-3-yl)methyl]-2-(methylsulfanyl)pyridine (6 mg, 24%) as a white solid. LCMS: (ESI, m / z): [M+1] + =294.3; 1 H NMR (400 MHz, chloroform-d) δ 8.97 (s, 1H), 8.58 (s, 1H), 8.19 (d, J = 5.0 Hz, 1H), 6.59 (t, J = 5.2 Hz, 1H), 4.10 (s, 2H), 2.59 (s, 3H), 2.43 (s, 3H); 19 F NMR (377 MHz, CDCl3) δ -126.41, -126.67.

[0144] Step 5: To a stirred solution of 3-fluoro-4-[(4-methyl-5-nitropyridin-3-yl)methyl]-2-(methylsulfanyl)pyridine (82 mg, 0.28 mmol, 1 equiv) in MeOH (1.6 mL) and H2O (0.4 mL) was added Fe (78.06 mg, 1.40 mmol, 5 equiv) and NH4Cl (149.54 mg, 2.80 mmol, 10 equiv) at room temperature. The resulting mixture was stirred at 60 °C for 2 h. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (10:1) to afford 5-{[3-fluoro-2-(methylsulfanyl)pyridin-4-yl]methyl}-4-methylpyridin-3-amine (54 mg, 73%) as a white solid. LCMS: (ESI, m / z): [M+1]+ =264.10; 1 1H NMR (300 MHz, chloroform-d) δ 8.28 - 7.70 (m, 3H), 6.55 (t, J = 5.2 Hz, 1H), 3.95 (s, 2H), 3.69 (d, J = 25.6 Hz, 2H), 2.58 (s, 3H), 1.99 (s, 3H); 19 19F NMR (282 MHz, chloroform-d) δ -127.34.

[0145] Step 6: To a stirred solution of 5-{[3-fluoro-2-(methylsulfanyl)pyridin-4-yl]methyl}-4-methylpyridin-3-amine (20 mg, 0.076 mmol, 1 equiv) in toluene (1 mL), Pd2(dba)3 (6.95 mg, 0.008 mmol, 0.1 equiv), Cs2CO3 (49.49 mg, 0.15 mmol, 2 equiv) and XantPhos (4.39 mg, 0.008 mmol, 0.1 equiv) were added 4-bromo-2-fluoro-1-iodobenzene (34.28 mg, 0.11 mmol, 1.5 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 2 h under a nitrogen atmosphere. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, MeCN in water (0.1% NH3·H2O), gradient from 10% to 60% in 30 min, detector, UV 254 nm. Thereby, N-(4-bromo-2-fluorophenyl)-5-{[3-fluoro-2-(methylsulfanyl)pyridin-4-yl]methyl}-4-methylpyridin-3-amine (14 mg, 42%) was obtained as a white solid. LCMS: (ESI, m / z): [M+1] + =436.0 1 1H NMR (400 MHz, chloroform-d) δ 8.36 (s, 1H), 8.17 (d, J = 5.4 Hz, 2H), 7.31 -; 7.27 (m, 1H), 7.14 (d, J = 8.5 Hz, 1H), 6.73 (t, J = 8.7 Hz, 1H), 6.61 (t, J = 5.2 Hz, 1H), 5.46 (s, 1H), 4.04 (s, 2H), 2.59 (s, 3H), 2.16 (s, 3H); 1919F NMR (377 MHz, chloroform-d) δ -126.97, -129.52.

[0146] Step 7: To an 8 mL round-bottom flask were added N-(4-bromo-2-fluorophenyl)-5-{[3-fluoro-2-(methylsulfanyl)pyridin-4-yl]methyl}-4-methylpyridin-3-amine (12 mg, 0.028 mmol, 1 equiv) and acetone (1 mL) / H2O (1 mL) / MeOH (0.1 mL) at room temperature. To the above mixture was added oxone (18.50 mg, 0.112 mmol, 4 equiv) portionwise at room temperature over 30 minutes. The resulting mixture was stirred at room temperature for an additional 16 hours. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, MeCN (0.1% FA) in water, gradient of 10% - 65% in 30 minutes, detector, UV 254 nm. This gave N-(4-bromo-2-fluorophenyl)-5-[(3-fluoro-2-methanesulfonylpyridin-4-yl)methyl]-4-methylpyridin-3-amine (4.3 mg, 33%) as a white solid. LCMS: (ESI, m / z): [M+1] + = 467.85; 1 1H NMR (400 MHz, chloroform-d) δ 8.42 (s, 1H), 8.36 (m, 1H), 8.19 (s, 1H), 7.34 - 7.26 (m, 1H), 7.19 - 7.12 (m, 2H), 6.79 - 6.77 (m, 1H), 5.48 (s, 1H), 4.17 (s, 2H), 3.38 (s, 3H), 2.16 (m, 3H); 19 19F NMR (377 MHz, chloroform-d) δ -124.114, -129.373.

[0147] Example 10:

Chemical formula

Chemical formula

[0148] Step 2: To a stirred solution of tert-butyl N-(tert-butoxycarbonyl)-N-[4-({5-[(4-ethyl-2-fluorophenyl)amino]-4-methylpyridin-3-yl}methyl)-3-fluoropyridin-2-yl]carbamate (30 mg, 0.054 mmol, 1 equiv) in DCM (2 mL), TFA (0.5 mL) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (1 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (10:1) to afford 4-({5-[(4-ethyl-2-fluorophenyl)amino]-4-methylpyridin-3-yl}methyl)-3-fluoropyridin-2-amine (17 mg, 89%) as a white solid. LCMS: (ESI, m / z): [M+1] + =355.4; 1 H NMR (400 MHz, chloroform-d) δ 8.22 (d, J = 88.8 Hz, 2H), 7.74 (d, J = 5.2 Hz, 1H), 7.00 - 6.94 (m, 1H), 6.91 - 6.83 (m, 2H), 6.27 (t, J = 5.1 Hz, 1H), 5.35 (s, 1H), 4.67 (s, 2H), 4.00 (s, 2H), 2.61 (q, J = 7.6 Hz, 2H), 2.17 (s, 3H), 1.23 (t, J = 7.6 Hz, 3H); 19 F NMR (377 MHz, chloroform-d) δ -131.45, -145.22.

[0149] Step 3: To a stirred solution of 4-({5-[(4-ethyl-2-fluorophenyl)amino]-4-methylpyridin-3-yl}methyl)-3-fluoropyridin-2-amine (14 mg, 0.04 mmol, 1 equiv) in DMA (0.5 mL) was added dropwise pyridine (31.25 mg, 0.40 mmol, 10 equiv) and N-methylsulfamoyl chloride (25.59 mg, 0.20 mmol, 5 equiv) in DMA (0.5 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The desired product was detected by LCMS. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient 10% - 80% in 30 min; detector, UV 254 nm. This gave N-(4-ethyl-2-fluorophenyl)-5-({3-fluoro-2-[(methylsulfamoyl)amino]pyridin-4-yl}methyl)-4-methylpyridin-3-amine (4.6 mg, 26%) as a white solid. LCMS: (ESI, m / z): [M+1] + =448.05; 1 H NMR (400 MHz, chloroform-d) δ 8.33 (s, 1H), 8.08 (s, 1H), 7.96 (d, J = 5.2 Hz, 1H), 7.28 - 7.26 (m, 1H), 7.03 - 6.83 (m, 3H), 6.61 - 6.59 (m, 1H), 5.48 (s, 1H), 5.37 (s, 1H), 4.06 (s, 2H), 2.78 (d, J = 3.2 Hz, 3H), 2.64 - 2.59 (m, 2H), 2.17 (s, 3H), 1.23 (t, J = 7.6 Hz, 3H); 19 F NMR (377 MHz, chloroform-d) δ -130.867, -142.765.

[0150] Example 11:

Chemical Structure

Chemical Structure

[0151] Step 2: To a stirred solution of tert-butyl N-(tert-butoxycarbonyl)-N-[4-({5-[(4-cyano-2-fluorophenyl)amino]-4-methylpyridin-3-yl}methyl)-3-fluoropyridin-2-yl]carbamate (50 mg, 0.091 mmol, 1 equiv) in DCM (5 mL), TFA (1 mL, 13.46 mmol, 148.52 equiv) was added dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The mixture was basified to pH 10 with NaHCO3. The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (1 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (8:1) to afford 4-({5-[(2-amino-3-fluoropyridin-4-yl)methyl]-4-methylpyridin-3-yl}amino)-3-fluorobenzonitrile (20 mg, 63%) as a brown solid. LCMS: (ESI, m / z): [M+1] + =352.4; 1 H NMR (400 MHz, chloroform-d) δ 8.41 (m,; 2H), 7.73 (m, 1H), 7.37 (m, 1H), 7.28 (m, 1H), 6.61 (m, 1H), 6.29 (m, 1H), 5.91 (m, 1H), 4.89 (s, 2H), 4.03 (s, 2H), 2.16 (s, 3H); 19 F NMR (377 MHz, 400 MHz, chloroform-d) δ -133.33, -144.70.

[0152] Step 3: To a stirred solution of 4-({5-[(2-amino-3-fluoropyridin-4-yl)methyl]-4-methylpyridin-3-yl}amino)-3-fluorobenzonitrile (20 mg, 0.057 mmol, 1 eq) in DMA (0.5 mL) was added dropwise pyridine (45.02 mg, 0.570 mmol, 10 eq) and N-methylsulfamoyl chloride (36.87 mg, 0.285 mmol, 5 eq) in DMA (0.5 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, MeCN (0.1% FA) in water, gradient 10% - 50% in 30 min, detector, UV 254 nm. This gave 3-fluoro-4-{[5-({3-fluoro-2-[(methylsulfamoyl)amino]pyridin-4-yl}methyl)-4-methylpyridin-3-yl]amino}benzonitrile (2.4 mg, 10%) as a white solid. LCMS: (ESI, m / z): [M+1] + = 445.1; 1 H NMR (400 MHz, methanol-d4) δ 8.33 - 8.28 (m, 2H), 8.01 - 7.98 (m, 1H), 7.52 - 7.49 (m, 1H), 7.37 - 7.30 (m, 1H), 6.76 - 6.73 (m, 1H), 6.62 - 6.58 (m, 1H), 4.21 (s, 2H), 2.63 (s, 3H), 2.20 (s, 3H); 19 F NMR (377 MHz, methanol-d4) δ -131.916, -142.205.12

[0153] Example 12:

Chemical formula

Chemical formula

[0154] Example 13: 1-[4-({5-[(4-bromo-2-fluorophenyl)amino]-4-methylpyridin-3-yl}methyl)-3-fluoropyridin-2-yl]-3-methylurea

Chem.

[0155] Example 14: 3-[(4-chloro-2-fluorophenyl)amino]-5-({3-fluoro-2-[(methylsulfamoyl)amino]pyridin-4-yl}methyl)-4-methylpyridin-1-ium-1-oleate [Chem.] Synthetic route: [Chem.] To a stirred solution of N-(4-chloro-2-fluorophenyl)-5-({3-fluoro-2-[(methylsulfamoyl)amino]pyridin-4-yl}methyl)-4-methylpyridin-3-amine (10 mg, 0.022 mmol) in DCM (1 mL), m-CPBA (4.18 mg, 0.024 mmol, 1.1 eq) was added at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 2 h. The desired product could be detected by LCMS. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, ACN in water (10 mmol / L NH4HCO3), gradient of 5% - 60% in 30 min, detector, UV 254 nm. This gave 3-[(4-chloro-2-fluorophenyl)amino]-5-({3-fluoro-2-[(methylsulfamoyl)amino]pyridin-4-yl}methyl)-4-methylpyridin-1-ium-1-olate (2.4 mg). LCMS: (ESI, m / z): [M+1] + = 470.1. 1 H NMR (400 MHz, methanol-d4) δ 8.01 (d, J = 5.1 Hz, 1H), 7.80 (d, J = 1.9 Hz, 1H), 7.62 (t, J = 2.0 Hz, 1H), 7.31 (m, 1H), 7.25 - 7.16 (m, 1H), 7.13 (t, J = 8.6 Hz, 1H), 6.78 (t, J = 5.1 Hz, 1H), 4.13 (s, 2H), 2.63 (s, 3H), 2.20 (s, 3H). 19 F NMR (377 MHz, methanol-d4) δ -122.495, -142.050.

[0156] Example 15: N-(4-chloro-2-fluorophenyl)-5-({3-fluoro-2-[(methylsulfamoyl)amino]pyridin-4-yl}oxy)-4-methylpyridin-3-amine [Chem.] Synthetic route: [Chem.] Step 1: A solution of 4-methyl-5-nitropyridin-3-ylboronic acid (1 g, 5.4 mmol, Example 6) in THF (10 mL) was treated with NaOH (659.51 mg, 16.488 mmol) in H2O (2.5 mL, 27.755 mmol) at 0 °C, followed by dropwise addition of H2O2 (30%) (2.56 mL, 32.976 mmol 30%) at 0 °C. The resulting mixture was stirred at 0 °C for 1 h under an air atmosphere. The reaction was quenched with sodium bisulfite (aqueous solution) at 0 °C. The resulting mixture was extracted with EtOAc (5 × 10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (20:1) to give 4-methyl-5-nitropyridin-3-ol (400 mg) as a white solid. LCMS: (ESI, m / z): [M+1] + = 155.1; 1 H NMR (400 MHz, chloroform-d) δ 8.67 (s, 1H), 8.37 (s, 1H), 2.53 (s, 3H).

[0157] Step 2: To a solution of 4-methyl-5-nitropyridin-3-ol (100 mg, 0.649 mmol) in 5 mL of MeOH in a 10 mL two-necked round-bottom flask was added 10% Pd / C (10 mg) under a nitrogen atmosphere. The mixture was hydrogenated at room temperature for 1 h under a hydrogen atmosphere using a hydrogen balloon, filtered through a Celite pad, and concentrated under reduced pressure. This gave 5-amino-4-methylpyridin-3-ol (82 mg, crude) as a yellow oil. LCMS: (ESI, m / z): [M+1] + = 125.1; 1 H NMR (400 MHz, methanol-d4) δ 7.49 (s, 1H), 7.40 (s, 1H), 2.03 (s, 3H).

[0158] Step 3: To a solution of 5-amino-4-methylpyridin-3-ol (240 mg, 1.933 mmol, Example 1) and N-[(2,4-dimethoxyphenyl)methyl]-3-fluoro-4-iodopyridin-2-amine (900.54 mg, 2.320 mmol, 1.2 eq) in DMSO (4 mL), K3PO4 (820.72 mg, 3.866 mmol), pyridine-2-carboxylic acid (23.80 mg, 0.193 mmol, 0.1 eq) and CuI (18.41 mg, 0.097 mmol, 0.05 eq) were added. After stirring at 80 °C for 16 h under a nitrogen atmosphere, the desired product could be detected by LCMS. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (1 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (10:1) to give 5-[(2-{[(2,4-dimethoxyphenyl)methyl]amino}-3-fluoropyridin-4-yl)oxy]-4-methylpyridin-3-amine (60 mg, 8%) as a pale yellow solid. LCMS: (ESI, m / z): [M+1] + = 385.2; 1 H NMR (300 MHz, DMSO-d6) δ 7.85 (s, 1H), 7.60 (m, 1H), 7.53 (s, 1H), 7.07 (m, 1H), 6.93 (m, 1H), 6.54 (m, 1H), 6.44 (m, 1H), 5.86 (m, 1H), 5.44 (s, 2H), 4.45 (d, J = 5.9 Hz, 2H), 3.80 (s, 3H), 3.72 (s, 3H), 1.92 (s, 3H); 19 F NMR (282 MHz, DMSO-d6) δ -165.61.

[0159] Step 4: To a solution of 5-[(2-{[(2,4-dimethoxyphenyl)methyl]amino}-3-fluoropyridin-4-yl)oxy]-4-methylpyridin-3-amine (60 mg, 0.156 mmol) and 4-chloro-2-fluoro-1-iodobenzene (48.03 mg, 0.187 mmol, 1.2 equiv) in dioxane (2 mL) were added Cs2CO3 (101.71 mg, 0.312 mmol), XantPhos (9.03 mg, 0.016 mmol) and Pd2(dba)3 (14.29 mg, 0.016 mmol). After stirring at 80 °C for 4 h under a nitrogen atmosphere, the desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (4:1) to give N-(4-chloro-2-fluorophenyl)-5-[(2-{[(2,4-dimethoxyphenyl)methyl]amino}-3-fluoropyridin-4-yl)oxy]-4-methylpyridin-3-amine (56 mg) as a yellow solid. LCMS: (ESI, m / z): [M+1] + = 513.0; 1H NMR (400 MHz, chloroform-d) δ 8.32 (s, 1H), 8.05 (s, 1H), 7.79 (m, 1H), 7.29 (m, 1H), 7.16 (m, 1H), 7.04 (m, 1H), 6.93 m, 1H), 6.49 m, 1H), 6.45 (m, 1H), 6.02 (m, 1H), 5.47 (s, 1H), 5.15 (s, 1H), 4.64 (m, 2H), 3.86 (s, 3H), 3.81 (s, 3H), 2.18 (s, 3H); 19F NMR (376 MHz, chloroform-d) δ -129.08, -165.21.

[0160] Step 5: To a mixture of N-(4-chloro-2-fluorophenyl)-5-[(2-{[(2,4-dimethoxyphenyl)methyl]amino}-3-fluoropyridin-4-yl)oxy]-4-methylpyridin-3-amine (56 mg, 0.109 mmol) in DCM (2 mL), TFA (0.5 mL) was added dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 1 h under a nitrogen atmosphere. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was basified to pH 10 with NaHCO3 (aqueous solution). The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (1 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (10:1) to give 5-[(2-amino-3-fluoropyridin-4-yl)oxy]-N-(4-chloro-2-fluorophenyl)-4-methylpyridin-3-amine (30 mg). LCMS: (ESI, m / z): [M+1] + = 362.9; 1 H NMR (400 MHz, chloroform-d) δ 8.36 (s, 1H), 8.08 (s, 1H), 7.74 - 7.68 (m, 1H), 7.17 (m, 1H), 7.05 (m, 1H), 6.95 (m, 1H), 6.10 (m, 1H), 5.53 - 5.44 (m, 1H), 4.88 (s, 2H), 2.18 (s, 3H); 19 F NMR (377 MHz, chloroform-d) δ -128.90, -162.99.

[0161] Step 6: To a stirred solution of 5-[(2-amino-3-fluoropyridin-4-yl)oxy]-N-(4-chloro-2-fluorophenyl)-4-methylpyridine-3-amine (45 mg, 0.124 mmol) and pyridine (98.12 mg, 1.240 mmol) in DMA (1 mL) was added N-methylsulfamoyl chloride (80.36 mg, 0.620 mmol) in DMA (1 mL) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under a nitrogen atmosphere. The desired product could be detected by LCMS. The reaction mixture was purified by preparative HPLC under the following conditions (column: YMC-Actus Triart C18 ExRS, 30 * 150 mm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN, flow rate: 60 mL / min, gradient: 12% B - 32% B in 9 min, 32% B, wavelength: 254 / 220 nm, RT1 (min): 15.03, number of runs: 0) to give N-(4-chloro-2-fluorophenyl)-5-({3-fluoro-2-[(methylsulfamoyl)amino]pyridin-4-yl}oxy)-4-methylpyridine-3-amine (11.2 mg). LCMS: (ESI, m / z): [M + 1] + = 455.90; 1H NMR (400 MHz, methanol-d4) δ 8.02 (m, 1H), 7.95 (s, 1H), 7.90 (m, 1H), 7.24 (m, 1H), 7.11 (m, 1H), 6.97 m, 1H), 6.40 (m, 1H), 2.63 (s, 3H), 2.16 (s, 3H). 19 F NMR (377 MHz, methanol-d4) δ -125.667, -160.051.

[0162] Example 16: N-(4-chloro-2-fluorophenyl)-5-({3-fluoro-2-[(methylsulfamoyl)amino]pyridin-4-yl}methyl)-N,4-dimethylpyridine-3-amine

Chemical formula

Chemical formula

[0163] Step 2: To a stirred solution of tert-butyl N-(tert-butoxycarbonyl)-N-[4-(1-{5-[(4-chloro-2-fluorophenyl)amino]-4-methylpyridin-3-yl}ethyl)-3-fluoropyridin-2-yl]carbamate (50 mg, 0.087 mmol) in DCM (2 mL), TFA (0.5 mL) was added dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum. The residue was basified to pH 10 with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with EA (3 × 10 mL). The combined organic layers were washed with brine (1 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, ACN in water (10 mmol / L NH4HCO3), gradient of 5% - 70% in 20 minutes, detector, UV 254 nm. Thereby, 4-(1-{5-[(4-chloro-2-fluorophenyl)amino]-4-methylpyridin-3-yl}ethyl)-3-fluoropyridin-2-amine (27 mg) was obtained. LCMS: (ESI, m / z): [M+1] + =375.3 1 H NMR (400 MHz, chloroform-d) δ 8.33 (m, 2H), 7.76 (d, J = 5.3 Hz, 1H), 7.13 (dd, J = 10.8, 2.3 Hz, 1H), 7.01 - 6.93 (m, 1H), 6.69 (t, J = 8.9 Hz, 1H), 6.39 (t, J = 5.1 Hz, 1H), 5.42 (s, 1H), 4.73 (s, 2H), 4.61 (q, J = 7.2 Hz, 1H), 2.15 (s, 3H), 1.67 (d, J = 7.2 Hz, 3H). 19 F NMR (377 MHz, chloroform-d) δ -130.27, -145.86

[0164] Step 3: To a stirred solution of 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-N-(4-chloro-2-fluorophenyl)-N,4-dimethylpyridin-3-amine (10 mg, 0.027 mmol) and pyridine (21.10 mg, 0.270 mmol, 10 equiv) in DMA (0.5 mL) was added N-methylsulfamoyl chloride (17.28 mg, 0.135 mmol, 5 equiv) in DMA (0.2 mL) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The desired product could be detected by LCMS. The reaction mixture was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN in water (10 mmol / L NH4HCO3), gradient of 5% - 60% in 30 min; detector, UV254 nm. This gave N-(4-chloro-2-fluorophenyl)-5-({3-fluoro-2-[(methylsulfamoyl)amino]pyridin-4-yl}methyl)-N,4-dimethylpyridin-3-amine (4.6 mg). LCMS: (ESI, m / z): [M+1] + =467.90 1 H NMR (400 MHz, methanol-d4) δ 8.15 (s, 1H), 8.09 (s, 1H), 7.97 (d, J = 5.2 Hz, 1H), 7.17 (dd, J = 11.1, 2.3 Hz, 1H), 7.00 (m, 1H), 6.78 (s, 1H), 6.62 (t, J = 8.9 Hz, 1H), 4.73 (q, J = 7.2 Hz, 1H), 2.59 (s, 3H), 2.17 (s, 3H), 1.68 (d, J = 7.1 Hz, 3H). 19 F NMR (377 MHz, methanol-d4) δ -128.52, -142.44.

[0165] Example 17: N-(2,4-Difluorophenyl)-5-[(3-fluoropyridin-4-yl)methyl]-4-methylpyridin-3-amine

Chemical formula

Chemical formula

[0166] Step 2: Oxone (89.58 mg, 0.532 mmol) was added portionwise to a stirred solution of N-(2,4-difluorophenyl)-5-{[3-fluoro-2-(methylsulfanyl)pyridin-4-yl]methyl}-4-methylpyridin-3-amine (50 mg, 0.133 mmol) in acetone (2 mL), H2O (2 mL), and MeOH (0.2 mL) at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN, flow rate: 60 mL / min, gradient: 25% B - 45% B in 9 min, 45% B, wavelength: 254 / 220 nm, RT1 (min): 11.25, number of runs: 3. Thereby, N-(2,4-difluorophenyl)-5-[(3-fluoro-2-methanesulfonylpyridin-4-yl)methyl]-4-methylpyridin-3-amine (13.6 mg) was obtained. LCMS: (ESI, m / z): [M+1] + =408.10. 1 H NMR (400 MHz, methanol-d4) δ 8.39 (d, J = 4.8 Hz, 1H), 8.01 (s, 1H), 7.94 (s, 1H), 7.38 (t, J = 5.1 Hz, 1H), 7.06 - 6.85 (m, 3H), 4.28 (s, 2H), 3.37 (s, 3H), 2.17 (s, 3H). 19F NMR (377 MHz, methanol-d4) δ -120.10, -123.51, -125.85.

[0167] Example 18: 4-[[5-(4-chloro-2-fluoro-anilino)-3-pyridyl]methyl]-3-fluoro-N-(methylsulfamoyl)pyridin-2-amine

Chemical Structure

Chemical Structure

[0168] Step 2: To a solution of 3-fluoro-4-methyl-pyridin-2-amine (10 g, 79.28 mmol) in DCM (100 mL), Boc2O (38.07 g, 174.42 mmol, 40.07 mL), DMAP (968.58 mg, 7.93 mmol), and TEA (24.07 g, 237.85 mmol, 33.11 mL) were added. The mixture was stirred at 25 °C for 12 h. Water (80 mL) was added and the mixture was extracted with EtOAc (50 mL × 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash column chromatography on silica gel (EtOAc in petroleum ether = 0 - 30%) to give tert-butyl N-tert-butoxycarbonyl-N-(3-fluoro-4-methyl-2-pyridyl)carbamate (19 g, 58.22 mmol) as a yellow oil. 11H NMR (400 MHz, CDCl3) δ = 8.14 (d, J = 4.8 Hz, 1H), 7.13 (t, J = 4.8 Hz, 1H), 2.33 (s, 3H), 1.42 (s, 18H). 19 19F NMR (376.5 MHz, CDCl3) δ = -131.767 ppm.

[0169] Step 3: To a solution of tert-butyl N-tert-butoxycarbonyl-N-(3-fluoro-4-methyl-2-pyridyl)carbamate (17 g, 52.09 mmol) in DCE (170 mL) were added AIBN (1.71 g, 10.42 mmol) and NBS (27.81 g, 156.27 mmol). The mixture was stirred at 85 °C for 4 h. The reaction was concentrated. Water (100 mL) was added and the aqueous layer was extracted with DCM (2 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated.

[0170] To a solution of the crude in MeCN (200 mL) were added DIPEA (13.46 g, 104.18 mmol, 18.15 mL) and 1-ethoxyphosphonoyloxyethane (719.38 mg, 5.21 mmol, 672.31 μL). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated. The residue was poured into water (200 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel (ethyl acetate in petroleum ether = 0 - 27%) to afford tert-butyl N-[4-(bromomethyl)-3-fluoro-2-pyridyl]-N-tert-butoxycarbonyl-carbamate (17.6 g, 23.89 mmol).

[0171] The product tert-butyl N-[4-(bromomethyl)-3-fluoro-2-pyridyl]-N-tert-butoxycarbonyl-carbamate (7 g, 9.50 mmol, purity 55%) was purified by preparative HPLC (column: Xtimate C18 150×40 mm×10 um, mobile phase: [water (NH3H2O + NH4HCO3)-ACN], B%: 49% - 79%, 8 minutes) to give tert-butyl N-[4-(bromomethyl)-3-fluoro-2-pyridyl]-N-tert-butoxycarbonyl-carbamate (3 g, 7.40 mmol). 1 H NMR (400 MHz, CDCl3) δ = 8.27 (d, J = 5.2 Hz, 1H), 7.32 (t, J = 5.2 Hz, 1H), 4.45 (s, 2H), 1.42 (s, 18H). 19 F NMR (376.5 MHz, CDCl3) δ = -130.835 ppm.

[0172] Target: Step 1: To a solution of 5-bromopyridin-3-amine (4.8 g, 27.74 mmol) in 1,4-dioxane (50 mL) were added Pd(OAc)2 (622.87 mg, 2.77 mmol), 4-chloro-2-fluoro-1-iodo-benzene (7.11 g, 27.74 mmol), Cs2CO3 (18.08 g, 55.49 mmol), and Xantphos (3.21 g, 5.55 mmol). The mixture was stirred at 80 °C for 2 hours. The mixture was poured into H2O (50 mL) and EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (ethyl acetate in petroleum ether = 0 - 20%) to give 5-bromo-N-(4-chloro-2-fluoro-phenyl)pyridin-3-amine (7.6 g, 25.20 mmol). 1 H NMR (400 MHz, CDCl3) δ = 8.29 (d, J = 2.8 Hz, 1H), 8.25 (d, J = 1.6 Hz, 1H), 7.49 (t, J = 2.0 Hz, 1H), 7.24 - 7.16 (m, 2H), 7.13 - 7.06 (m, 1H), 5.81 (br s, 1H). 1919F NMR (376.5 MHz, CDCl3) δ = -126.453 ppm.

[0173] Step 2: To a solution of 5-bromo-N-(4-chloro-2-fluoro-phenyl)pyridin-3-amine (1 g, 3.32 mmol) in dioxane (10 mL) were added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.68 g, 6.63 mmol), Pd(dppf)Cl2 (121.33 mg, 165.81 μmol), and KOAc (976.40 mg, 9.95 mmol). The mixture was stirred at 100 °C for 4 h. The mixture was concentrated. [5-(4-Chloro-2-fluoro-anilino)-3-pyridyl]boronic acid (883.67 mg, 3.32 mmol) was used as a solid in the next step without purification. LCMS Rt = 0.679 min, chromatography for 1.5 min, 5 - 95 CD, C 11 H 10 BClFN2O2 [M+H] + ESI calculated value 267.0, measured value 266.9.

[0174] Step 3: To a solution of [5-(4-chloro-2-fluoro-anilino)-3-pyridyl]boronic acid (883.67 mg, 3.32 mmol) and tert-butyl N-[4-(bromomethyl)-3-fluoro-2-pyridyl]-N-tert-butoxycarbonyl-carbamate (2.44 g, 3.32 mmol) in dioxane (10 mL) and H2O (1 mL), Pd(dppf)Cl2 (121.33 mg, 165.81 μmol) and K2CO3 (1.37 g, 9.95 mmol) were added. The mixture was stirred at 100 °C for 2 h. The reaction mixture was concentrated. The residue was poured into water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (ethyl acetate in petroleum ether = 0 - 27%) to afford tert-butyl N-tert-butoxycarbonyl-N-[4-[[5-(4-chloro-2-fluoro-anilino)-3-pyridyl]methyl]-3-fluoro-2-pyridyl]carbamate (490 mg, 895.81 μmol). LCMS Rt = 0.869 min, chromatography for 1.5 min, 5 - 95 CD, C 27 H 30 ClF2N4O4[M+H] + The ESI calculated value for 547.2, measured value 547.0.

[0175] Step 4: To a solution of tert-butyl N-tert-butoxycarbonyl-N-[4-[[5-(4-chloro-2-fluoro-anilino)-3-pyridyl]methyl]-3-fluoro-2-pyridyl]carbamate (490 mg, 895.81 μmol) in MeOH (5 mL) was added HCl / MeOH (4 M, 5.00 mL). The mixture was stirred at 25 °C for 2 h. The residue was poured into water (10 mL) and extracted with DCM (10 mL × 3). Saturated NaHCO3 solution was added dropwise to adjust the pH to 7 at 0 °C. The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (ethyl acetate in petroleum ether = 0 - 27%) to afford 4-[[5-(4-chloro-2-fluoro-anilino)-3-pyridyl]methyl]-3-fluoro-pyridin-2-amine (150 mg, 432.57 μmol). 1 1H NMR (400 MHz, CDCl3) δ = 8.34 (d, J = 2.4 Hz, 1H), 8.15 (d, J = 1.4 Hz, 1H), 7.77 (d, J = 5.2 Hz, 1H), 7.22 - 7.15 (m, 3H), 7.11 - 7.04 (m, 1H), 6.47 (t, J = 5.2 Hz, 1H), 5.89 (br s, 1H), 4.92 (br s, 2H), 3.95 (s, 2H). 19 19F NMR (376.5 MHz, CDCl3) δ = -127.266, -145.251 ppm.

[0176] Step 5: To a solution of 4-[[5-(4-chloro-2-fluoro-anilino)-3-pyridyl]methyl]-3-fluoro-pyridin-2-amine (30 mg, 86.51 μmol) in MeCN (1 mL) and DMA (1 mL) were added Py (68.43 mg, 865.15 μmol, 69.83 μL) and N-methylsulfamoyl chloride (112.09 mg, 865.15 μmol). The mixture was stirred at 25 °C for 2 h. The mixture was concentrated. The crude product was subjected to preparative HPLC (column: Xtimate C 18 150×40 mm×10um, mobile phase: [column: Welch Xtimate C 18Purified by [water (NH3H2O + ACN)] as the mobile phase, B%: 22% - 52%, for 7 minutes to obtain 4-[[5-(4-chloro-2-fluoro-anilino)-3-pyridyl]methyl]-3-fluoro-N-(methylsulfamoyl)pyridine-2-amine (9 mg, 20.46 μmol). 1 H NMR (400 MHz, DMSO-d6) δ = 8.31 (br s, 1H), 8.15 (d, J = 2.4 Hz, 1H), 8.02 - 7.95 (m, 2H), 7.43 (dd, J = 2.4, 11.2 Hz, 1H), 7.26 (t, J = 8.8 Hz, 1H), 7.20 - 7.15 (m, 2H), 7.03 - 6.86 (m, 1H), 3.97 (s, 2H), 2.49 (s, 3H). 19 F NMR (376.5 MHz, DMSO-d6) δ = -122.147, -139.025 ppm. LCMS R t = 0.667 min, by chromatography for 1.5 minutes, with 5 - 95 AB, C 18 H 17 ClF2N5O2S [M + H] + The ESI calculated value for it is 440.1, and the measured value is 440.0.

[0177] Example 19: 3-Fluoro-4-({5-[(3-fluoropyridin-2-yl)oxy]-4-methylpyridin-3-yl}methyl)pyridin-2-amine

Chemical Structure

Chemical Structure

[0178] Step 2: To a stirred solution of 3-bromo-5-methoxy-4-methylpyridine (10 g, 49.49 mmol) in DCM (100 mL) was added BBr3 (1 M in DCM, 99 mL, 99 mmol) dropwise at -78 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h under a nitrogen atmosphere. The desired product could be detected by LCMS. The reaction was quenched with MeOH at -78 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, ACN in water (10 mmol / L NH4HCO3), gradient from 5% to 60% in 30 min, detector, UV254 nm. This gave 5-bromo-4-methylpyridin-3-ol (6.2 g). LCMS: (ESI, m / z): [M+1] + =187.8. 1 H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.27 (s, 1H), 2.38 (s, 3H).

[0179] Step 3: To a stirred mixture of 5-bromo-4-methylpyridin-3-ol (2.1 g, 11.16 mmol) and 2,3-difluoropyridine (2.57 g, 22.33 mmol) in DMSO (21 mL), Cs2CO3 (14.56 g, 44.67 mmol) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C for 16 h under a nitrogen atmosphere. The desired product could be detected by LCMS. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN in water (10 mmol / L NH4HCO3), 5% - 50% gradient over 20 min, detector, UV254 nm. This gave 3-bromo-5-[(3-fluoropyridin-2-yl)oxy]-4-methylpyridine (1.8 g). LCMS: (ESI, m / z): [M + 1] + = 283.0. 1 H NMR (400 MHz, chloroform-d) δ 8.57 (s, 1H), 8.33 (s, 1H), 7.86 (m, 1H), 7.55 - 7.49 (m, 1H), 7.07 - 7.01 (m, 1H), 2.31 (s, 3H).

[0180] Step 4: To a stirred mixture of 3-bromo-5-[(3-fluoropyridin-2-yl)oxy]-4-methylpyridine (400 mg, 1.41 mmol) and bis(pinacolato)diboron (430.56 mg, 1.696 mmol, 1.2 equiv) in dioxane (10 mL), AcOK (277.34 mg, 2.86 mmol) and Pd(PPh3)2Cl2 (99.17 mg, 0.141 mmol, 0.1 equiv) were added. The resulting mixture was stirred at 80 °C for 16 h under a nitrogen atmosphere. The desired product could be detected by LCMS. The reaction mixture was concentrated under reduced pressure. This gave 3-[(3-fluoropyridin-2-yl)oxy]-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (400 mg). LCM.S: (ESI, m / z): [M + 1] + = 331.2

[0181] Step 5: To a stirred mixture of 3-[(3-fluoropyridin-2-yl)oxy]-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (488.82 mg, 1.480 mmol) and tert-butyl N-[4-(bromomethyl)-3-fluoropyridin-2-yl]-N-(tert-butoxycarbonyl)carbamate (300 mg, 0.740 mmol, 0.5 eq) in dioxane (6 mL) and H2O (0.6 mL) were added K2CO3 (614 mg, 4.44 mmol, 3 eq) and Pd(dppf)Cl2 (108.2 mg, 0.148 mmol, 0.1 eq). The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN (0.1% FA) in water, gradient of 10% to 95% in 20 min; detector, UV254 nm. This gave tert-butyl N-(tert-butoxycarbonyl)-N-[3-fluoro-4-({5-[(3-fluoropyridin-2-yl)oxy]-4-methylpyridin-3-yl}methyl)pyridin-2-yl]carbamate (170 mg). LCMS: (ESI, m / z): [M+1] + =529.2. 1 H NMR (400 MHz, chloroform-d) δ 8.44 (s, 1H), 8.30 (s, 1H), 8.22 (d, J = 4.7 Hz, 1H), 7.87 (dd, J = 4.9, 1.5 Hz, 1H), 7.53 (ddd, J = 9.5, 7.8, 1.5 Hz, 1H), 7.06 (ddd, J = 8.0, 4.8, 3.2 Hz, 1H), 6.93 (t, J = 4.9 Hz, 1H), 4.15 (s, 2H), 2.16 (s, 3H), 1.42 (s, 18H).

[0182] Step 6: To a stirred solution of tert-butyl N-(tert-butoxycarbonyl)-N-[3-fluoro-4-({5-[(3-fluoropyridin-2-yl)oxy]-4-methylpyridin-3-yl}methyl)pyridin-2-yl]carbamate (170 mg, 0.322 mmol) in DCM (4 mL) was added dropwise TFA (1 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, ACN in water (10 mmol / L NH4HCO3), gradient of 5% to 60% in 30 min, detector, UV 254 nm. Thereby, 3-fluoro-4-({5-[(3-fluoropyridin-2-yl)oxy]-4-methylpyridin-3-yl}methyl)pyridin-2-amine (60 mg) was obtained. LCMS: (ESI, m / z): [M+1] + = 328.9. 1 H NMR (400 MHz, chloroform-d) δ 8.36 (m, 2H), 7.86 (m, 1H), 7.78 (s, 1H), 7.50 (m, 1H), 7.01 (m, 1H), 6.31 (t, J = 5.1 Hz, 1H), 4.67 (s, 2H), 4.02 (s, 2H), 2.11 (s, 3H). 19 F NMR (376 MHz, chloroform-d) -137.69, -145.09.

[0183] Example 20: N-(4-chloro-2-fluoro-phenyl)-5-[(2-fluoro-4-methylsulfonyl-phenyl)methyl]-4-methyl-pyridin-3-amine

Chemical formula

Chemical formula

[0184] Step 2: To a solution of 1-bromo-2-fluoro-4-methylsulfonyl-benzene (1 g, 3.95 mmol) in dioxane (10 mL), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (3.01 g, 11.85 mmol) and KOAc (1.16 g, 11.85 mmol) were added. The mixture was degassed and purged with N2 three times. Then Pd(dppf)Cl2 (289.11 mg, 395.12 μmol) was added to the mixture, which was degassed and purged with N2 three times. The mixture was stirred at 100 °C for 3 h under a N2 atmosphere. The reaction mixture was concentrated and purified by flash chromatography on silica gel (ethyl acetate in petroleum ether = 0 - 10%) to afford (2-fluoro-4-methylsulfonyl-phenyl)boronic acid (650 mg, 2.98 mmol).1 1H NMR (400 MHz, CDCl3) δ = 7.82 - 7.77 (m, 1H), 7.72 - 7.69 (m, 1H), 7.64 - 7.61 (m, 1H), 3.07 (s, 3H), 1.58 (s, 2H). 19 19F NMR (376.5 MHz, CDCl3) δ = -102.207 ppm.

[0185] Step 3: To a solution of (2-fluoro-4-methylsulfonyl-phenyl)boronic acid (148.82 mg, 682.65 μmol) and 5-(bromomethyl)-N-(4-chloro-2-fluoro-phenyl)-4-methyl-pyridin-3-amine (150 mg, 455.10 μmol) in toluene (3 mL) and EtOH (1.5 mL) was added Na2CO3 (192.94 mg, 1.82 mmol). The mixture was degassed and purged three times with N2. Then, Pd(PPh3)4 (52.59 mg, 45.51 μmol) was added to the mixture, which was degassed and purged three times with N2. The mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated and purified by flash chromatography on silica gel (ethyl acetate in petroleum ether = 0 - 50%) and preparative HPLC (column: YMC Triart C 18 70*250 mm * 7 μm, mobile phase: [water (NH4HCO3)-ACN], B%: 30% - 60%, 15 min) to give N-(4-chloro-2-fluoro-phenyl)-5-[(2-fluoro-4-methylsulfonyl-phenyl)methyl]-4-methyl-pyridin-3-amine (5 mg, 11.82 μmol). 1 1H NMR (400 MHz, CDCl3) δ = 8.41 (br s, 1H), 8.17 (br s, 1H), 7.67 (t, J = 8.8 Hz, 2H), 7.22 - 7.10 (m, 2H), 6.98 (d, J = 8.8 Hz, 1H), 6.75 (t, J = 8.4 Hz, 1H), 5.42 (s, 1H), 4.12 (s, 2H), 3.07 (s, 3H), 2.14 (s, 3H). 19 19F NMR (376.5 MHz, CDCl3) δ = -112.684, -130.327 ppm. LCMS R t = 0.735 min, chromatography for 1.5 min, with 5 - 95 AB, C 20H 18 ClF2N2O2S[M+H] + ESI calculated value: 423.1, measured value: 422.9.

[0186] Step 1 to the intermediate bromide: To a solution of 5-bromo-4-methyl-pyridin-3-amine (5 g, 26.73 mmol) in 1,4-dioxane (100 mL) were added 4-chloro-2-fluoro-1-iodo-benzene (6.86 g, 26.73 mmol), Pd(OAc)2 (600.17 mg, 2.67 mmol), Xantphos (3.09 g, 5.35 mmol), and Cs2CO3 (17.42 g, 53.47 mmol). The mixture was stirred at 100 °C for 12 h. Water (80 mL) was added and the mixture was extracted with EtOAc (50 mL × 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash column chromatography on silica gel (EtOAc in petroleum ether = 0 - 10%) to afford 5-bromo-N-(4-chloro-2-fluoro-phenyl)-4-methyl-pyridin-3-amine (6.4 g, 20.28 mmol). 1 H NMR (400 MHz, DMSO-d6) δ = 8.37 (s, 1H), 8.08 (s, 1H), 7.90 (s, 1H), 7.40 (dd, J = 2.0, 11.6 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 6.83 (t, J = 8.8 Hz, 1H), 2.27 (s, 3H). 19 F NMR (376.5 MHz, DMSO-d6) δ = -123.680.

[0187] Step 2: To 5-bromo-N-(4-chloro-2-fluoro-phenyl)-4-methyl-pyridin-3-amine (5 g, 15.84 mmol) in MeOH solution (70 mL) were added TEA (12.83 g, 126.76 mmol, 17.64 mL) and Pd(dppf)Cl2 (2.32 g, 3.17 mmol). The mixture was stirred at 60 °C for 12 h under CO (50 Psi). Water (50 mL) was added and the mixture was extracted with EtOAc (50 ml×2). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel (EtOAc in petroleum ether = 0~20%) to give methyl 5-(4-chloro-2-fluoro-anilino)-4-methyl-pyridine-3-carboxylate (2.8 g, 9.50 mmol). 1 H NMR (400 MHz, DMSO-d6) δ = 8.59 (s, 1H), 8.29 (s, 1H), 7.85 (s, 1H), 7.40 (dd, J = 2.4, 11.6 Hz, 1H), 6.74 (d, J = 8.8 Hz, 1H), 3.87 (s, 3H), 2.35 (s, 3H). 19 F NMR (376.5 MHz, DMSO-d6) δ = -124.380.

[0188] Step 3: To a solution of LiAlH4 (695.44 mg, 18.32 mmol) in THF (60 mL) in a three-necked bottle was added methyl 5-(4-chloro-2-fluoro-anilino)-4-methyl-pyridine-3-carboxylate (2.7 g, 9.16 mmol) at 0 °C under N2. The mixture was stirred at 25 °C for 3 h under N2. Water (3 mL), 15% NaOH (3 mL) and H2O (9 mL) were successively added to the mixture at 0 °C and the mixture was stirred at 25 °C for 30 min. Then THF (80 mL) was added. The resulting mixture was filtered and the filter cake was washed with EtOAc (30 mL×3). Then the filtrate was concentrated to give [5-(4-chloro-2-fluoro-anilino)-4-methyl-3-pyridyl]methanol (2.4 g, 9.00 mmol), which was used directly in the next step without purification. 11H NMR (400 MHz, DMSO-d6) δ = 8.24 (s, 1H), 8.13 (s, 1H), 7.68 (s, 1H), 7.36 (dd, J = 2.4, 11.2 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.56 (t, J = 9.2 Hz, 1H), 5.22 (t, J = 5.2 Hz, 1H), 4.55 (d, J = 5.2 Hz, 2H), 2.12 (s, 3H). 19 19F NMR (376.5 MHz, DMSO-d6) δ = -126.121.

[0189] Step 4: To a solution of [5-(4-chloro-2-fluoro-anilino)-4-methyl-3-pyridyl]methanol (2.3 g, 8.62 mmol) in DCM (25 mL) was added PBr3 (7.00 g, 25.87 mmol, 2.43 mL). The mixture was stirred at 25 °C for 2 h. Water (40 mL) was added and the mixture was extracted with DCM (30 mL × 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give 5-(bromomethyl)-N-(4-chloro-2-fluoro-phenyl)-4-methyl-pyridin-3-amine (2.6 g, 7.89 mmol, 91.47% yield) as a yellow solid, which was used directly in the next step without purification. 1 1H NMR (400 MHz, CDCl3) δ = 8.39 (s, 1H), 8.31 (s, 1H), 7.14 (dd, J = 2.0, 10.8 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 6.75 (d, J = 9.2 Hz, 1H), 5.46 (s, 1H), 4.53 (s, 2H), 2.31 (s, 3H). 19 19F NMR (376.5 MHz, CDCl3) δ = -130.065.

[0190] Example 21: N-(4-chloro-2-fluoro-phenyl)-6-[[3-fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]pyrazine-2-amine

Chemical Structure

Chemical Structure

[0191] Step 2: To a solution of 6-bromo-N-(4-chloro-2-fluoro-phenyl)pyrazine-2-amine (500 mg, 1.65 mmol) and trimethyl(trimethylstannyl)stannane (590 mg, 1.80 mmol, 373.42 μL) in dioxane (5 mL) was added Pd(PPh3)4 (190.98 mg, 165.27 μmol). The mixture was stirred at 90 °C for 2 h. The mixture was used directly in the next step. N-(4-Chloro-2-fluoro-phenyl)-6-trimethylstannyl-pyrazine-2-amine (638.68 mg, 1.65 mmol). LCMS R t = 1.036 min, chromatography for 1.5 min, with 5 - 95 AB, C 13 H 16 ClFN3Sn [M + H] + ESI calculated value for 386.0, measured value 385.7.

[0192] Step 3: To a solution of N-(4-chloro-2-fluoro-phenyl)-6-trimethylstannyl-pyrazine-2-amine (538 mg, 1.39 mmol) in dioxane (10 mL) were added tert-butyl N-[4-(bromomethyl)-3-fluoro-2-pyridyl]-N-tert-butoxycarbonyl-carbamate (846.30 mg, 2.09 mmol, from Example 18), DPPF (308.72 mg, 556.88 μmol) Pd(OAc)2 (62.51 mg, 278.44 μmol) and CsF (845.92 mg, 5.57 mmol, 205.32 μL). The mixture was stirred at 90 °C for 2 h. H2O (30 mL) was added. The residue was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in petroleum ether = 0 - 35%) to give tert-butyl N-tert-butoxycarbonyl-N-[4-[[6-(4-chloro-2-fluoro-anilino)pyrazin-2-yl]methyl]-3-fluoro-2-pyridyl]carbamate (400 mg, 729.95 μmol). 11H NMR (400 MHz, CDCl3) δ = 8.25 (d, J = 5.2 Hz, 1H), 8.11 - 8.05 (m, 2H), 7.99 (s, 1H), 7.17 - 7.06 (m, 2H), 7.00 - 6.66 (m, 1H), 4.13 (s, 2H), 1.38 (s, 18H). 19 19F NMR (376.5 MHz, CDCl3) δ = -131.407.

[0193] Step 4: To a solution of tert-butyl N-tert-butoxycarbonyl-N-[4-[[6-(4-chloro-2-fluoro-anilino)pyrazin-2-yl]methyl]-3-fluoro-2-pyridyl]carbamate (400 mg, 729.95 μmol) in MeOH (1 mL) was added HCl / MeOH (4 M, 6.96 mL, 27.83 mmol). The mixture was stirred at 25 °C for 12 h. NH3 / MeOH (10 mL × 3) was added. The mixture was concentrated. The crude product was purified by preparative HPLC (column: Boston Prime C18 150×30 mm×5um, mobile phase: [water (NH3H2O + NH4HCO3)-ACN], B%: 53% - 53%, 7 min) to give 6-[(2-amino-3-fluoro-4-pyridyl)methyl]-N-(4-chloro-2-fluoro-phenyl)pyrazine-2-amine (120 mg, 345.08 μmol). 1 1H NMR (400 MHz, CDCl3) δ = 8.14 - 7.93 (m, 3H), 7.80 (d, J = 5.2 Hz, 1H), 7.17 - 7.00 (m, 2H), 6.71 - 6.51 (m, 2H), 4.68 (s, 2H), 4.04 (s, 2H). 19 19F NMR (376.5 MHz, CDCl3) δ = -128.701, -145.392.

[0194] Step 5: Pyridine (47.77 mg, 603.88 μmol, 48.74 μL) was added to a solution of 6-[(2-amino-3-fluoro-4-pyridyl)methyl]-N-(4-chloro-2-fluoro-phenyl)pyrazine-2-amine (35 mg, 100.65 μmol) in DMA (0.6 mL). Then, N-methylsulfamoyl chloride (130.40 mg, 1.01 mmol) in CH3CN (0.6 mL) was added. The mixture was stirred at 28 °C for 1 hour. The mixture was concentrated. The crude product was purified by preparative HPLC (column: Welch Xtimate C18 150×30 mm×5 μm, mobile phase: [water (NH3H2O + NH4HCO3)-ACN], B%: 25% - 55%, 7 minutes) to give N-(4-chloro-2-fluoro-phenyl)-6-[[3-fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]pyrazine-2-amine (16.1 mg, 36.52 umol). 1 H NMR (400 MHz, DMSO-d6) δ = 10.39 (s, 1H), 9.30 (s, 1H), 8.29 (s, 1H), 8.05 - 7.99 (m, 3H), 7.41 (d, J = 14.0 Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H), 7.08 - 6.98 (m, 2H), 4.09 (s, 2H), 2.48 (s, 3H). 19 F NMR (376.5 MHz, DMSO-d6) δ = -123.604, -139.020 ppm. LCMS R t = 0.813 min, chromatography for 1.5 minutes, with 5 - 95 AB, C 17 H 16 ClF2N6O2S [M + H] + The ESI calculated value for is 441.1, the measured value is 441.0.

[0195] Example 22: 5-({3-Fluoro-2-[(methylsulfamoyl)amino]pyridin-4-yl}methyl)-N-(2-fluoro-4-methoxyphenyl)-4-methylpyridin-3-amine

Chemical Structure

Chemical Structure

[0196] Example 23:

Chemical formula

Chemical formula

[0197] Step 2: To a stirred solution of 3-fluoro-4-({5-[(2-fluoro-4-methoxyphenyl)amino]-4-methylpyridin-3-yl}methyl)pyridin-2-amine (18 mg, 0.051 mmol) and pyridine (39.95 mg, 0.510 mmol, 10 equiv) in DMA (0.3 mL) was added N-methylsulfamoyl chloride (32.72 mg, 0.255 mmol, 5 equiv) in DMA (0.3 mL) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The desired product could be detected by LCMS. The reaction mixture was purified by preparative HPLC under the following conditions: column: XBridge Shield RP18 OBD column, 30 * 150 mm, 5 μm, mobile phase: water (10 mmol / L NH4HCO3), mobile phase B: ACN, flow rate: 60 mL / min, gradient: 27% B - 42% B in 10 min, 42% B; wavelength: 254 / 220 nm, RT1 (min): 9.437, number of runs: 0). Thereby, (19.1 mg) was obtained. LCMS: (ESI, m / z): [M+1] + =450.15. 1 H NMR (400 MHz, methanol-d4) δ 7.95 (d, J = 5.2 Hz, 1H), 7.86 (s, 1H), 7.72 (d, J = 1.8 Hz, 1H), 7.02 (t, J = 9.0 Hz, 1H), 6.79 (dd, J = 12.5, 2.8 Hz, 1H), 6.75 - 6.71 (m, 1H), 6.65 (t, J = 5.0 Hz, 1H), 4.11 (s, 2H), 3.79 (s, 3H), 2.63 (s, 3H), 2.17 (s, 3H). 19 F NMR (377 MHz, methanol-d4) δ -123.53, -142.44.

[0198] Example 24 ({3-Fluoro-4-[(5-methoxy-4-methylpyridin-3-yl)methyl]pyridin-2-yl}sulfamoyl)(methyl)amine

Chemical formula

Chemical formula

[0199] Step 2: To a stirred solution of tert-butyl N-(tert-butoxycarbonyl)-N-{3-fluoro-4-[(5-methoxy-4-methylpyridin-3-yl)methyl]pyridin-2-yl}carbamate (92 mg, 0.206 mmol) in DCM (4 mL), TFA (1 mL) was added dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was basified to pH 10 with NaHCO3 (aqueous solution). The resulting mixture was extracted with EA (3 × 10 mL). The combined organic layers were washed with brine (1 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient of 40% - 70% over 20 minutes; detector, UV254 / 220 nm to give 3-fluoro-4-[(5-methoxy-4-methylpyridin-3-yl)methyl]pyridin-2-amine (60 mg) as a white solid. LCMS: (ESI, m / z): [M+1] + =248.1

[0200] Step 3: To a stirred mixture of 3-fluoro-4-[(5-methoxy-4-methylpyridin-3-yl)methyl]pyridin-2-amine (53 mg, 0.214 mmol) in DMA, pyridine (84.77 mg, 1.070 mmol, 5 equiv) and N-methylsulfamoyl chloride (27.77 mg, 0.214 mmol) were added dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The desired product could be detected by LCMS. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient of 30% - 60% over 20 minutes; detector, UV254 / 220 nm to give a white solid (20 mg). LCMS: (ESI, m / z): [M+1] + =341.; 11H NMR (400 MHz, methanol-d4) δ 8.30 - 7.68 (m, 3H), 6.65 (m, 1H), 4.11 (s, 2H), 3.94 (s, 3H), 2.62 (s, 3H), 2.15 (s, 3H); 19 19F NMR (377 MHz, methanol-d4) δ -142.455.

[0201] Example 25: N-(4-Chloro-2-fluoro-phenyl)-5-[[3-methoxy-4-(methylsulfamoylamino)phenyl]methyl]-4-methyl-pyridin-3-amine

Chemical Structure

Chemical Structure

[0202] Step 2: To a solution of 4-chloro-2-fluoro-1-iodo-benzene (6.86 g, 26.73 mmol) in dioxane (100 mL) were added 5-bromo-4-methyl-pyridin-3-amine (5 g, 26.73 mmol) and Cs2CO3 (17.42 g, 53.47 mmol) under N2, and then Pd(OAc)2 (600.17 mg, 2.67 mmol) and Xantphos (3.09 g, 5.35 mmol) were added. The mixture was stirred at 100 °C for 10 h under N2. The mixture was cooled to 25 °C. The mixture was filtered and the filtrate was concentrated under reduced pressure. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (ethyl acetate in petroleum ether = 0 - 25%) to give 5-bromo-N-(4-chloro-2-fluoro-phenyl)-4-methyl-pyridin-3-amine (6.2 g, 19.65 mmol). 1 1H NMR (400 MHz, CDCl3) δ = 8.43 (s, 1H), 8.31 (s, 1H), 7.14 (dd, J = 2.4, 10.8 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 6.77 (t, J = 8.8 Hz, 1H), 5.55 (s, 1H), 2.35 (s, 3H). 19 19F NMR (376.5 MHz, CDCl3) δ = -129.53 ppm.

[0203] Step 3: Toluene (30 mL) in a 100 mL three-necked flask was cooled to -60 °C. n-BuLi (2.5 M, 5.02 mL) was mixed with toluene. A solution of 5-bromo-N-(4-chloro-2-fluoro-phenyl)-4-methyl-pyridin-3-amine (1.8 g, 5.70 mmol) in toluene (10 mL) was added. The mixture was stirred at -60 °C for 30 minutes, then THF (10 mL) was slowly added. The mixture was aged for 15 minutes, then DMF (500.31 mg, 6.84 mmol, 526.64 μL) was added at -60 °C. The mixture was stirred at -60 °C for 30 minutes. Water (100 mL) was added, and the aqueous layer was extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The mixture was purified by flash chromatography on silica gel (EtOAc in petroleum ether = 0 - 30%) to give 5-(4-chloro-2-fluoro-anilino)-4-methyl-pyridine-3-carbaldehyde (1.4 g, 5.29 mmol). 1 H NMR (400 MHz, CDCl3) δ = 10.34 (s, 1H), 8.70 (s, 1H), 8.60 (s, 1H), 7.22 - 7.09 (m, 1H), 7.07 - 6.94 (m, 1H), 6.88 - 6.71 (m, 1H), 5.52 (br s, 1H), 2.59 (s, 3H).

[0204] Step 4: 4-Methylbenzenesulfonohydrazide (605.10 mg, 3.25 mmol) was added to a solution of 5-(4-chloro-2-fluoro-anilino)-4-methyl-pyridine-3-carbaldehyde (860 mg, 3.25 mmol) in MeOH (8 mL). The mixture was stirred at 60 °C for 2 hours. The mixture was concentrated. The crude product was triturated from MeOH (3 mL) to afford N-[(E)-[5-(4-chloro-2-fluoro-anilino)-4-methyl-3-pyridyl]methylenamino]-4-methyl-benzenesulfonamide (840 mg, 1.94 mmol). 11H NMR (400 MHz, CDCl3) δ = 8.51 (s, 1H), 8.39 (s, 1H), 8.33 - 8.09 (m, 1H), 8.01 (s, 1H), 7.88 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.14 (dd, J = 2.4, 10.8 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H), 6.67 (t, J = 8.8 Hz, 1H), 5.45 (s, 1H), 2.43 (s, 3H), 2.31 (s, 3H). 19 19F NMR (376.5 MHz, CDCl3) δ = -130.010 ppm.

[0205] Target pathway: Step 1: To a solution of tert-butoxycarbonyl tert-butyl carbonate (2.38 g, 10.89 mmol, 2.50 mL) in THF (20 mL) was added DIPEA (3.84 g, 29.70 mmol, 5.17 mL) and 4-bromo-2-methoxy-aniline (2 g, 9.90 mmol). The mixture was stirred at 25 °C for 4 h. The reaction mixture was concentrated. The residue was poured into water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (ethyl acetate in petroleum ether = 0 - 27%) to afford tert-butyl N-(4-bromo-2-methoxy-phenyl)carbamate (1.8 g, 5.96 mmol). 1 1H NMR (400 MHz, CDCl3) δ = 7.96 (d, J = 8.0 Hz, 1H), 7.06 (dd, J = 2.0, 8.4 Hz, 1H), 7.00 (br s, 1H), 6.95 (d, J = 2.0 Hz, 1H), 3.85 (s, 3H), 1.52 (s, 9H).

[0206] Step 2: To a solution of tert-butyl N-(4-bromo-2-methoxyphenyl)carbamate (500 mg, 1.65 mmol) in dioxane (5 mL) were added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (840.40 mg, 3.31 mmol), KOAc (487.20 mg, 4.96 mmol), and Pd(dppf)Cl2 (60.54 mg, 82.74 μmol). The mixture was stirred at 80 °C for 12 h. The mixture was filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (EtOAc in petroleum ether = 0 - 20%) to give tert-butyl N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (570 mg, 1.63 mmol). 1 H NMR (400 MHz, CDCl3) δ = 8.10 (d, J = 7.6 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.25 - 7.20 (m, 2H), 3.91 (s, 3H), 1.52 (s, 9H), 1.34 (s, 12H).

[0207] Step 3: To a solution of tert-butyl N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (570 mg, 1.63 mmol) in acetone (20 mL) were added NaIO4 (1.75 g, 8.16 mmol, 452.21 μL) and KOAc (1 M, 8.16 mL). The mixture was stirred at 20 °C for 16 h. The resulting solution was diluted with dilute water (20 mL) and quenched with saturated Na2SO3 solution until the KI test paper turned white. The mixture was extracted with ethyl acetate (20 mL × 3). The organic layers were combined and dried over sodium sulfate. The solid was filtered off and the solution was concentrated. The crude product was purified by flash column chromatography on silica gel (MeOH in DCM = 0 - 10%) to give [4-(tert-butoxycarbonylamino)-3-methoxyphenyl]boronic acid (330 mg, 1.24 mmol). 11H NMR (400 MHz, CDCl3) δ = 8.17 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.57 (br s, 1H), 7.22 - 7.19 (m, 1H), 3.94 (s, 3H), 1.49 (s, 9H).

[0208] Step 4: To a solution of N-[(E)-[5-(4-chloro-2-fluoro-anilino)-4-methyl-3-pyridyl]methyleneamino]-4-methyl-benzenesulfonamide (120 mg, 277.20 μmol) and [4-(tert-butoxycarbonylamino)-3-methoxy-phenyl]boronic acid (185.09 mg, 693.00 μmol) in dioxane (2 mL) was added K2CO3 (114.94 mg, 831.60 μmol). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated. The residue was poured into DCM (2 mL) and filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl N-[4-[[5-(4-chloro-2-fluoro-anilino)-4-methyl-3-pyridyl]methyl]-2-methoxy-phenyl]carbamate (130.83 mg, 277.21 μmol), which was used in the next step without purification. LCMS R t = 0.821 min, 1.5 min chromatography, 5 - 95 AB, C 25 H 28 ClFN3O3 [M + H] + The ESI calculated value for 472.2, measured value 472.1.

[0209] Step 5: To a solution of tert-butyl N-[4-[[5-(4-chloro-2-fluoro-anilino)-4-methyl-3-pyridyl]methyl]-2-methoxy-phenyl]carbamate (130.83 mg, 277.21 μmol) in MeOH (2 mL) was added HCl / MeOH (4 M, 2 mL). The mixture was stirred at 25 °C for 2 h. The residue was poured into water (10 mL) and extracted with DCM (10 mL×3). Saturated NaHCO3 (20 ml) was slowly added dropwise to the mixture to adjust the pH to 7. The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The crude product was purified by flash chromatography on silica gel (methanol in dichloromethane = 0 - 10%) to afford 5-[(4-amino-3-methoxy-phenyl)methyl]-N-(4-chloro-2-fluoro-phenyl)-4-methyl-pyridin-3-amine (90 mg, 242.04 μmol). LCMS R t = 0.683 min, 1.5 min chromatography, 5 - 95 AB, C 20 H 20 ClFN3O [M+H] + ESI calculated value for 372.1, measured value 372.0.

[0210] Step 6: To a solution of 5-[(4-amino-3-methoxyphenyl)methyl]-N-(4-chloro-2-fluorophenyl)-4-methylpyridin-3-amine (50 mg, 134.47 μmol) in DCM (1 mL) were added TEA (40.82 mg, 403.40 μmol, 56.15 μL) and N-methylsulfamoyl chloride (52.27 mg, 403.40 μmol). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated. The residue was purified by flash chromatography on silica gel (ethyl acetate in petroleum ether = 0 - 50%) and preparative HPLC (column: Welch Xtimate C18 150×30 mm×5 μm, mobile phase: [water (NH3H2O + NH4HCO3)-ACN], B%: 45% - 75%, 8 min) to give N-(4-chloro-2-fluorophenyl)-5-[[3-methoxy-4-(methylsulfamoylamino)phenyl]methyl]-4-methylpyridin-3-amine (19 mg, 40.87 μmol). 1 H NMR (400 MHz, CDCl3) δ = 8.6 (s, 1H), 8.16 (s, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.12 (dd, J = 2.4, 10.8 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 6.86 (br s, 1H), 6.78 - 6.61 (m, 3H), 5.44 (br s, 1H), 4.59 - 4.48 (m, 1H), 3.99 (s, 2H), 3.82 (s, 3H), 2.68 (d, J = 5.2 Hz, 3H), 2.13 (s, 3H). 19 F NMR (376.5 MHz, CDCl3) δ = -130.456 ppm. LCMS R t = 0.699 min 1.5

[0211] Example 26: 4-[[5-(4-chloro-2-fluoroanilino)-4-fluoro-3-pyridyl]methyl]-3-fluoro-N-(methylsulfamoyl)pyridin-2-amine

Chemical Structure

Chemical Structure

[0212] Step 2: 4-Chloro-2-fluoro-aniline (1.74 g, 11.93 mmol), Pd(OAc)₂ (267.73 mg, 1.19 mmol), Xantphos (1.38 g, 2.39 mmol), and Cs₂CO₃ (7.77 g, 23.85 mmol) were added to a solution of 3-bromo-4-fluoro-5-iodo-pyridine (3.6 g, 11.93 mmol) in 1,4-dioxane (70 mL). The mixture was stirred at 80 °C for 4 h. Water (30 mL) was added and the mixture was extracted with EtOAc (20 mL × 2). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by flash column chromatography on silica gel (EtOAc in PE = 0 - 7%) to afford 5-bromo-N-(4-chloro-2-fluoro-phenyl)-4-fluoro-pyridine-3-amine (2.3 g, 7.20 mmol). 11H NMR (400 MHz, DMSO-d6) δ = 8.42 (s, 1H), 8.40 (d, J = 8.4 Hz, 1H), 8.21 (dd, J = 1.2, 9.6 Hz, 1H), 7.46 (dd, J = 2.4, 11.2 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 7.12 - 7.07 (m, 1H). 19 19F NMR (376.5 MHz, DMSO-d6) δ = -112.378, -122.188.

[0213] Step 3: To a solution of 5-bromo-N-(4-chloro-2-fluoro-phenyl)-4-fluoro-pyridin-3-amine (0.78 g, 2.44 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL) were added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (451.15 mg, 2.93 mmol, 496.86 μL), K2CO3 (1.01 g, 7.32 mmol), and Pd(dppf)Cl2 (178.61 mg, 244.11 μmol). The mixture was stirred at 80 °C for 4 h. Water (40 mL) was added and the mixture was extracted with EtOAc (20 mL × 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (EtOAc in petroleum ether = 0 - 17%) to afford N-(4-chloro-2-fluoro-phenyl)-4-fluoro-5-vinyl-pyridin-3-amine (0.58 g, 2.17 mmol). 1 1H NMR (400 MHz, CDCl3) δ = 8.42 (d, J = 6.4 Hz, 1H), 8.18 (d, J = 9.2 Hz, 2H), 7.44 (dd, J = 2.0, 11.2 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.02 - 6.97 (m, 1H), 6.84 - 6.76 (m, 1H), 6.04 (d, J = 18.0 Hz, 1H), 5.56 (d, J = 11.6 Hz, 1H). 19 19F NMR (376.5 MHz, CDCl3) δ = -123.398, -123.413.

[0214] Step 4: To a solution of N-(4-chloro-2-fluoro-phenyl)-4-fluoro-5-vinyl-pyridin-3-amine (0.58 g, 2.17 mmol) in THF (32 mL) and H2O (8 mL) were added K2OsO4·2H2O (80.14 mg, 217.49 μmol) and NaIO4 (1.86 g, 8.70 mmol, 482.07 μL). The mixture was stirred at 25 °C for 1 h. Water (10 mL) was added and the mixture was extracted with EtOAc (10 mL×2). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel (EtOAc in petroleum ether = 0 - 25%) to afford 5-(4-chloro-2-fluoro-anilino)-4-fluoro-pyridine-3-carbaldehyde (0.34 g, 1.27 mmol). 1 1H NMR (400 MHz, CDCl3) δ = 10.39 (s, 1H), 8.64 (t, J = 9.6 Hz, 2H), 7.23 - 7.13 (m, 3H), 5.78 (s, 1H). 19 19F NMR (376.5 MHz, CDCl3) δ = -125.228, -131.315.

[0215] Step 5: To a solution of 5-(4-chloro-2-fluoro-anilino)-4-fluoro-pyridine-3-carbaldehyde (0.3 g, 1.12 mmol) in MeOH (3 mL) was added 4-methylbenzenesulfonohydrazide (207.97 mg, 1.12 mmol). The mixture was stirred at 60 °C for 1 h. The residue was filtered and the filter cake was washed with MeOH (5 mL). The filter cake was dried to afford N-[(E)-[5-(4-chloro-2-fluoro-anilino)-4-fluoro-3-pyridyl]methyleneamino]-4-methyl-benzenesulfonamide (0.34 g, 778.28 μmol). 1 1H NMR (400 MHz, CDCl3) δ = 11.79 (s, 1H), 8.38 (d, J = 8.4 Hz, 1H), 8.26 - 8.22 (m, 2H), 8.03 (s, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.45 - 7.41 (m, 3H), 7.14 (d, J = 8.4 Hz, 1H), 7.20 (t, J = 8.4 Hz, 1H), 2.37 (s, 3H).19 19F NMR (376.5 MHz, CDCl3) δ = -123.032, -123.973.

[0216] Step 6: To a solution of N-[(E)-[5-(4-chloro-2-fluoro-anilino)-4-fluoro-3-pyridyl]methyleneamino]-4-methyl-benzenesulfonamide (0.26 g, 595.15 μmol) in dioxane (5 mL) was added [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoro-4-pyridyl]boronic acid (728.70 mg, 1.19 mmol, Example 32) and K2CO3 (246.76 mg, 1.79 mmol). The mixture was stirred at 110 °C for 2 hours. Water (30 mL) was added and the mixture was extracted with EtOAc (20 ml × 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash column chromatography on silica gel (EtOAc in petroleum ether = 0 - 17%) to afford 4-[[5-(4-chloro-2-fluoro-anilino)-4-fluoro-3-pyridyl]methyl]-N-[(2,4-dimethoxyphenyl)methyl]-3-fluoro-pyridine-2-amine (0.12 g, 233.04 μmol). LCMS R t = 0.793 min, chromatography for 1.5 min, with 5 - 95 AB, C 26 H 23 ClF3N4O2 [M + H] + The ESI calculated value for 515.1, measured value 515.0.

[0217] Step 7: To a solution of 4-[[5-(4-chloro-2-fluoro-anilino)-4-fluoro-3-pyridyl]methyl]-N-[(2,4-dimethoxyphenyl)methyl]-3-fluoro-pyridine-2-amine (0.08 g, 155.36 μmol) in DCM (2 mL) was added TFA (513.72 mg, 4.51 mmol, 333.58 μL). The mixture was stirred at 25 °C for 2 h. Water (20 mL) was added and the mixture was extracted with EtOAc (10 mL × 2). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel (EtOAc in petroleum ether = 0 - 30%) to afford 4-[[5-(4-chloro-2-fluoro-anilino)-4-fluoro-3-pyridyl]methyl]-3-fluoro-pyridine-2-amine (0.05 g, 137.08 μmol). 1 H NMR (400 MHz, DMSO-d6) δ = 8.17 (t, J = 7.2 Hz, 3H), 7.65 (d, J = 5.2 Hz, 1H), 7.44 (dd, J = 2.0, 11.2 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 6.98 (t, J = 8.8 Hz, 1H), 6.37 (d, J = 4.8 Hz, 1H), 6.16 (s, 2H), 3.97 (s, 2H). 19 F NMR (376.5 MHz, DMSO-d6) δ = -121.716, -122.988, -145.462.

[0218] Step 8: To a solution of 4-[[5-(4-chloro-2-fluoro-anilino)-4-fluoro-3-pyridyl]methyl]-3-fluoro-pyridine-2-amine (0.03 g, 82.25 μmol) in DMA (1.5 mL) and MeCN (1.5 mL) was added N-methylsulfamoyl chloride (53.28 mg, 411.24 μmol) and Py (65.06 mg, 822.48 μmol, 66.39 uL). The mixture was stirred at 40 °C for 1 h. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Boston Prime C18 150×30 mm×5 μm, mobile phase: [water (NH3H2O + NH4HCO3)-ACN], B%: 27% - 57%, 7 min) to afford 4-[[5-(4-chloro-2-fluoro-anilino)-4-fluoro-3-pyridyl]methyl]-3-fluoro-N-(methylsulfamoyl)pyridine-2-amine (9 mg, 19.66 μmol). 1 1H NMR (400 MHz, DMSO-d6) δ = 8.17 - 8.12 (m, 3H), 7.99 (d, J = 4.0 Hz, 1H), 7.39 (dd, J = 2.0, 11.2 Hz, 1H), 7.16 - 7.15 (m, 1H), 7.15 - 7.13 (m, 1H), 6.97 - 6.91 (m, 1H), 4.05 (s, 2H), 2.33 (s, 3H). 19 19F NMR (376.5 MHz, DMSO-d6) δ = -121.548, -122.913, -138.740. LCMS R t = 0.702 min, 1.5 min chromatography, 5 - 95 AB, C 18 H 16 ClF3N5O2S [M + H] + The ESI calculated value of 458.1, measured value 458.0.

[0219] Example 27: {[4-({5-[(5-chloropyridin-2-yl)oxy]-4-methylpyridin-3-yl}methyl)-3-fluoropyridin-2-yl]sulfamoyl}(methyl)amine

Chemical formula

Chemical formula

[0220] Step 2: A mixture of 3-bromo-5-[(5-chloropyridin-2-yl)oxy]-4-methylpyridine (500 mg, 1.669 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (508.64 mg, 2.003 mmol, 1.2 equiv), AcOK (327.63 mg, 3.338 mmol, 2.0 equiv) and Pd(PPh3)2Cl2 (117.16 mg, 0.167 mmol, 0.1 equiv) in dioxane (5 mL) was stirred at 80 °C for 16 h under a nitrogen atmosphere. The desired product could be detected by LCMS. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Thereby, 3-[(5-chloropyridin-2-yl)oxy]-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine was obtained, LCMS: (ESI, m / z): [M+1] + = 347.2.

[0221] Step 3: A mixture of 3-[(5-chloropyridin-2-yl)oxy]-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (153.95 mg, 0.444 mmol), tert-butyl N-[4-(bromomethyl)-3-fluoropyridin-2-yl]-N-(tert-butoxycarbonyl)carbamate (90 mg, 0.222 mmol, 0.5 equiv), K2CO3 (92.08 mg, 0.666 mmol, 1.5 equiv), and Pd(dppf)Cl2 (16.25 mg, 0.022 mmol, 0.05 equiv) in dioxane (3 mL) and H2O (0.3 mL) was stirred at 80 °C for 1 h under a nitrogen atmosphere. The desired product could be detected by LCMS. The reaction mixture was diluted with water (20 mL). The resulting mixture was extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1) to give tert-butyl N-(tert-butoxycarbonyl)-N-[4-({5-[(5-chloropyridin-2-yl)oxy]-4-methylpyridin-3-yl}methyl)-3-fluoropyridin-2-yl]carbamate (120 mg). LCMS: (ESI, m / z): [M+1] + =545.3. 1 H NMR (400 MHz, chloroform-d) δ 8.30 (s, 1H), 8.20 (d, J = 4.9 Hz, 1H), 8.07 - 7.99 (m, 2H), 7.69 (dd, J = 8.7, 2.6 Hz, 1H), 7.01 - 6.88 (m, 2H), 4.13 (s, 2H), 2.05 (s, 3H), 1.41 (s, 18H). 19 F NMR (376 MHz, chloroform-d) δ -130.99.

[0222] Step 4: To a stirred solution of tert-butyl N-(tert-butoxycarbonyl)-N-[4-({5-[(5-chloropyridin-2-yl)oxy]-4-methylpyridin-3-yl}methyl)-3-fluoropyridin-2-yl]carbamate (240 mg, 0.440 mmol) in DCM (4 mL) was added dropwise TFA (1 mL) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The desired product could be detected by LCMS. The resulting mixture was basified to pH 8 with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with EA (3 × 10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, ACN in water (10 mmol / L NH4HCO3), gradient 5% - 60% in 20 min, detector, UV 254 nm. Thereby, 4-({5-[(5-chloropyridin-2-yl)oxy]-4-methylpyridin-3-yl}methyl)-3-fluoropyridin-2-amine (114 mg) was obtained. LCMS: (ESI, m / z): [M + 1] + = 345.1. 1 H NMR (400 MHz, chloroform-d) δ 8.28 (d, J = 1.4 Hz, 2H), 8.05 (dd, J = 2.6, 0.7 Hz, 1H), 7.73 (d, J = 5.3 Hz, 1H), 7.68 (dd, J = 8.7, 2.7 Hz, 1H), 6.96 (dd, J = 8.7, 0.7 Hz, 1H), 6.30 (t, J = 5.1 Hz, 1H), 4.79 - 4.70 (m, 2H), 4.01 (s, 2H), 2.07 (s, 3H). 19 F NMR (376 MHz, chloroform-d) -144.99.

[0223] Step 5: To a stirred solution of 4-({5-[(5-chloropyridin-2-yl)oxy]-4-methylpyridin-3-yl}methyl)-3-fluoropyridin-2-amine (50 mg, 0.145 mmol) and pyridine (114.71 mg, 1.450 mmol, 10 equiv) in DMA (0.5 mL) was added N-methylsulfamoyl chloride (22.55 mg, 0.174 mmol, 1.2 equiv) in DMA (0.5 mL) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The desired product could be detected by LCMS. The reaction mixture was purified by preparative HPLC under the following conditions: Column: XBridge Prep Phenyl OBD column, 19*250 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: MeOH--HPLC, Flow rate: 50 mL / min, Gradient: 53%B - 68%B in 8 min, Wavelength: 254 / 220 nm, RT1 (min): 9.22. Thereby, {[4-({5-[(5-chloropyridin-2-yl)oxy]-4-methylpyridin-3-yl}methyl)-3-fluoropyridin-2-yl]sulfamoyl}(methyl)amine (36 mg) was obtained. LCMS: (ESI, m / z): [M+1] + =438.10. 1 H NMR (400 MHz, methanol-d4) δ 8.23 (m, 2H), 8.01 (m, 2H), 7.87 (dd, J = 8.7, 2.6 Hz, 1H), 7.12 (d, J = 8.7 Hz, 1H), 6.72 (t, J = 5.1 Hz, 1H), 4.18 (s, 2H), 2.63 (s, 3H), 2.11 (s, 3H). 19 F NMR (376 MHz, methanol-d4) δ -142.128.

[0224] Example 28: N-(4-chloro-2-fluorophenyl)-5-[(3-fluoro-2-methanesulfonylpyridin-4-yl)methyl]-4-methylpyridin-3-amine

Chemical formula

Chemical formula

[0225] Step 2: Oxone (17.17 mg, 0.104 mmol, 4 eq) was added portionwise to a stirred solution of N-(4-chloro-2-fluorophenyl)-5-{[3-fluoro-2-(methylsulfanyl)pyridin-4-yl]methyl}-4-methylpyridin-3-amine (10 mg, 0.026 mmol) in acetone (1 mL), MeOH (1 mL), and H2O (0.1 mL) at 0 °C under an air atmosphere. The resulting mixture was stirred at room temperature for 24 h under an air atmosphere. The desired product could be detected by LCMS. The reaction was quenched with saturated Na2S2O3 (aqueous solution) at 0 °C. The resulting mixture was extracted with EA (3 × 10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, ACN in water (10 mmol / L NH4HCO3), 5% - 80% gradient over 25 min, detector, UV254 nm. This gave N-(4-chloro-2-fluorophenyl)-5-[(3-fluoro-2-methanesulfonylpyridin-4-yl)methyl]-4-methylpyridin-3-amine (5.9 mg). LCMS: (ESI, m / z): [M+1] + =424.20. 1 H NMR (400 MHz, methanol-d4) δ 8.40 (d, J = 4.8 Hz, 1H), 8.15 - 8.09 (m, 2H), 7.40 (t, J = 5.1 Hz, 1H), 7.24 - 7.15 (m, 1H), 7.08 - 7.00 (m, 1H), 6.75 (t, J = 8.9 Hz, 1H), 4.29 (s, 2H), 3.37 (s, 3H), 2.16 (s, 3H). 19 F NMR (377 MHz, methanol-d4) δ -125.80, -127.80.

[0226] Example 29: {[4-({5-[(5-chloro-3-fluoropyridin-2-yl)oxy]-4-methylpyridin-3-yl}methyl)-3-fluoropyridin-2-yl]sulfamoyl}(methyl)amine

Chemical Structure

Chemical formula

[0227] Step 2: To a stirred mixture of 2-[(5-bromo-4-methylpyridin-3-yl)oxy]-5-chloro-3-fluoropyridine (200 mg, 0.630 mmol, 1 equiv) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (191.93 mg, 0.756 mmol) in dioxane (5 mL) were added KOAc (123.63 mg, 1.26 mmol) and Pd(PPh3)2Cl2 (44.21 mg, 0.063 mmol). The resulting mixture was stirred at 80 °C for 16 h under a nitrogen atmosphere and then concentrated under reduced pressure. This gave 5-chloro-3-fluoro-2-((4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)oxy)pyridine.

[0228] Step 3: To a stirred mixture of 3-[(5-chloro-3-fluoropyridin-2-yl)oxy]-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (200 mg, 0.549 mmol, 1 equiv) and Pd(dppf)Cl2 (40.14 mg, 0.055 mmol) in dioxane (5 mL) were added tert-butyl N-[4-(bromomethyl)-3-fluoropyridin-2-yl]-N-(tert-butoxycarbonyl)carbamate (111.15 mg, 0.275 mmol, 0.5 equiv) and H2O (0.1 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The desired product could be detected by LCMS. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1), to give tert-butyl N-(tert-butoxycarbonyl)-N-[4-({5-[(5-chloro-3-fluoropyridin-2-yl)oxy]-4-methylpyridin-3-yl}methyl)-3-fluoropyridin-2-yl]carbamate (150 mg). LCMS: (ESI, m / z): [M+1] + = 563.3. 11H NMR (300 MHz, chloroform-d) δ 8.35 (m, 2H), 8.21 (d, J = 4.9 Hz, 1H), 7.85 (dd, J = 12.2, 2.2 Hz, 1H), 7.61 - 7.53 (m, 1H), 6.93 (t, J = 5.0 Hz, 1H), 4.12 (d, J = 7.6 Hz, 2H), 2.11 (s, 3H), 1.42 (s, 18H). 19 19F NMR (282 MHz, chloroform-d) δ -130.93, -134.13.

[0229] Step 4: To a stirred solution of tert-butyl N-(tert-butoxycarbonyl)-N-[4-({5-[(5-chloro-3-fluoropyridin-2-yl)oxy]-4-methylpyridin-3-yl}methyl)-3-fluoropyridin-2-yl]carbamate (215 mg, 0.382 mmol) in DCM (4 mL) was added dropwise TFA (1 mL) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 4 h under a nitrogen atmosphere. The desired product could be detected by LCMS. The reaction mixture was concentrated under reduced pressure. The residue was basified to pH 10 with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10:1) to give 4-({5-[(5-chloro-3-fluoropyridin-2-yl)oxy]-4-methylpyridin-3-yl}methyl)-3-fluoropyridin-2-amine (65 mg). LCMS: (ESI, m / z): [M + 1] + = 362.9. 1 1H NMR (400 MHz, chloroform-d) δ 8.41 (s, 1H), 8.32 (s, 1H), 7.83 (d, J = 2.2 Hz, 1H), 7.62 - 7.51 (m, 2H), 6.45 (t, J = 6.0 Hz, 1H), 4.14 (d, J = 1.4 Hz, 2H), 2.12 (s, 3H). 19 19F NMR (377 MHz, chloroform-d)) δ -134.01, -139.89.

[0230] Step 5: To a stirred solution of 4-({5-[(5-chloro-3-fluoropyridin-2-yl)oxy]-4-methylpyridin-3-yl}methyl)-3-fluoropyridine-2-amine (30 mg, 0.083 mmol) and pyridine (65.42 mg, 0.830 mmol) in DMA (0.2 mL) was added dropwise N-methylsulfamoyl chloride (21.3 mg, 0.16 mmol) in DMA (0.2 mL) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under a nitrogen atmosphere. The desired product could be detected by LCMS. The reaction mixture was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, ACN in water (10 mmol / L NH4HCO3), gradient of 5% - 60% in 40 min, detector, UV254 nm. This gave {[4-({5-[(5-chloro-3-fluoropyridin-2-yl)oxy]-4-methylpyridin-3-yl}methyl)-3-fluoropyridin-2-yl]sulfamoyl}(methyl)amine (12.4 mg) LCMS: (ESI, m / z): [M+1] + =456.05. 1 H NMR (400 MHz, methanol-d4) δ 8.26 (s, 2H), 7.88 (d, J = 7.0 Hz, 3H), 6.55 (t, J = 5.2 Hz, 1H), 4.14 (s, 2H), 2.59 (s, 3H), 2.13 (s, 3H). 19 F NMR (377 MHz, methanol-d4) δ -136.569, -141.502.

[0231] Example 30: 4-[(5-Allyloxy-4-methyl-3-pyridyl)methyl]-3-fluoro-N-(methylsulfamoyl)pyridin-2-amine

Chemical Structure

Chemical Structure

[0232] Step 2: A mixture of 3-benzyloxy-5-bromo-4-methyl-pyridine (4 g, 14.38 mmol), Pd(dppf)Cl2 (1.05 g, 1.44 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (5.48 g, 21.57 mmol) and KOAc (4.23 g, 43.14 mmol) in dioxane (45 mL) was stirred at 110 °C for 4 h. After cooling to room temperature, the mixture was filtered and the filter cake was washed with EtOAc (30 mL×2). The filtrate was concentrated. The residue was purified by flash chromatography on silica gel (ethyl acetate in petroleum ether = 0~80%) to afford 3-benzyloxy-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.3 g, 4.00 mmol). 1 H NMR (400 MHz, DMSO-d6) δ = 8.36 (s, 1H), 8.31 (s, 1H), 7.48 - 7.32 (m, 5H), 5.24 (s, 2H), 2.38 (s, 3H), 1.31 (s, 12H).

[0233] Step 3: To a solution of 3-benzyloxy-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.3 g, 4.00 mmol), tert-butyl N-[4-(bromomethyl)-3-fluoro-2-pyridyl]-N-tert-butoxycarbonyl-carbamate (2.11 g, 5.20 mmol), and Cs2CO3 (2.60 g, 7.99 mmol) in a mixed solvent of toluene (20 mL) and H2O (4 mL), Pd(dppf)Cl2·CH2Cl2 (326.45 mg, 399.74 μmol) was added under N2. The mixture was stirred at 100 °C for 2 h. After cooling to room temperature, the mixture was filtered, the filter cake was washed with EtOAc (20 mL × 2), and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (ethyl acetate in petroleum ether = 0 - 60%) to afford tert-butyl N-[4-[(5-benzyloxy-4-methyl-3-pyridyl)methyl]-3-fluoro-2-pyridyl]-N-tert-butoxycarbonyl-carbamate (800 mg, 1.53 mmol). 1 1H NMR (400 MHz, CDCl3) δ = 8.24 (s, 1H), 8.18 (d, J = 5.2 Hz, 1H), 8.10 (s, 1H), 7.42 - 7.35 (m, 5H), 6.86 (t, J = 5.2 Hz, 1H), 5.18 (s, 2H), 4.09 (s, 2H), 2.18 (s, 3H), 1.41 (s, 18H). 19 19F NMR (376.5 MHz, CDCl3) δ = -130.974.

[0234] Step 4: Wet Pd / C (800 mg, 751.74 μmol, purity 10%) was added to a solution of tert-butyl N-[4-[(5-benzyloxy-4-methyl-3-pyridyl)methyl]-3-fluoro-2-pyridyl]-N-tert-butoxycarbonyl-carbamate (800 mg, 1.53 mmol) in MeOH (15 mL) under N2. The suspension was degassed under vacuum and purged several times with H2. The mixture was stirred at 50 °C for 16 h under H2 (50 psi). The reaction mixture was filtered, the filter cake was washed with MeOH (20 mL × 3), and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (ethyl acetate in petroleum ether = 0 - 60%) to afford tert-butyl N-tert-butoxycarbonyl-N-[3-fluoro-4-[(5-hydroxy-4-methyl-3-pyridyl)methyl]-2-pyridyl]carbamate (300 mg, 692.09 μmol). 1 H NMR (400 MHz, CDCl3) δ = 8.41 - 8.31 (m, 1H), 8.23 - 8.16 (m, 1H), 7.88 (s, 1H), 6.90 (t, J = 4.8 Hz, 1H), 4.09 (s, 2H), 3.49 (s, 1H), 2.21 (s, 3H), 1.42 (s, 18H). 19 F NMR (376.5 MHz, CDCl3) δ = -130.881.

[0235] Step 5: To a solution of tert-butyl N-[4-[(5-benzyloxy-4-methyl-3-pyridyl)methyl]-3-fluoro-2-pyridyl]-N-tert-butoxycarbonyl-carbamate (800 mg, 1.53 mmol) in MeOH (15 mL) was added moistened Pd / C (800 mg, 751.74 μmol, purity 10%) under N2. The suspension was degassed under vacuum and purged several times with H2. The mixture was stirred at 50 °C for 16 h under H2 (50 psi). The reaction mixture was filtered, the filter cake was washed with MeOH (20 mL × 3), and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (ethyl acetate in petroleum ether = 0 - 60%) to afford tert-butyl N-tert-butoxycarbonyl-N-[3-fluoro-4-[(5-hydroxy-4-methyl-3-pyridyl)methyl]-2-pyridyl]carbamate (300 mg, 692.09 μmol). 1 H NMR (400 MHz, CDCl3) δ = 8.41 - 8.31 (m, 1H), 8.23 - 8.16 (m, 1H), 7.88 (s, 1H), 6.90 (t, J = 4.8 Hz, 1H), 4.09 (s, 2H), 3.49 (s, 1H), 2.21 (s, 3H), 1.42 (s, 18H). 19 F NMR (376.5 MHz, CDCl3) δ = -130.881.

[0236] Step 6: A solution of tert-butyl N-[4-[(5-allyloxy-4-methyl-3-pyridyl)methyl]-3-fluoro-2-pyridyl]-N-tert-butoxycarbonyl-carbamate (150 mg, 316.77 μmol) in HCl / MeOH (4 M, 2 mL) was stirred at 25 °C for 5 h. The mixture was concentrated to afford 4-[(5-allyloxy-4-methyl-3-pyridyl)methyl]-3-fluoro-pyridin-2-amine (86.57 mg, 316.75 μmol). 11H NMR (400 MHz, DMSO-d6) δ = 8.53 (d, J = 17.2 Hz, 2H), 8.47 - 8.05 (m, 2H), 7.77 (d, J = 6.4 Hz, 1H), 6.61 (t, J = 6.4 Hz, 1H), 6.18 - 5.97 (m, 1H), 5.46 (dd, J = 1.2, 17.2 Hz, 1H), 5.34 (dd, J = 1.2, 10.4 Hz, 1H), 4.84 (d, J = 5.2 Hz, 2H), 4.32 (s, 2H), 2.31 (s, 3H). 19 19F NMR (376.5 MHz, DMSO-d6) δ = -137.046.

[0237] Step 7: To a solution of 4-[(5-allyloxy-4-methyl-3-pyridyl)methyl]-3-fluoro-pyridine-2-amine (75 mg, 274.42 μmol) and Py (217.07 mg, 2.74 mmol, 221.49 μL) in MeCN (5 mL) was added N-methylsulfamoyl chloride (71.11 mg, 548.84 μmol) under N2. The mixture was stirred at 25 °C for 2 h. The mixture was concentrated. The residue was purified by flash chromatography on silica gel (MeOH in DCM = 0 - 10%) and then by SFC (column: DAICEL CHIRALCEL OJ (250 mm * 30 mm, 10 μm), mobile phase: [CO2 - EtOH (0.1% NH3H2O)], B%: 20%, isocratic elution mode) to afford 4-[(5-allyloxy-4-methyl-3-pyridyl)methyl]-3-fluoro-N-(methylsulfamoyl)pyridine-2-amine (35.1 mg, 95.79 μmol). 1 1H NMR (400 MHz, CDCl3) δ = 8.39 - 8.06 (m, 2H), 7.96 (br s, 1H), 6.60 (br s, 1H), 6.27 - 5.91 (m, 1H), 5.55 - 5.42 (m, 2H), 5.37 (d, J = 10.4 Hz, 1H), 4.68 (s, 2H), 4.06 (s, 2H), 2.77 (s, 3H), 2.26 (s, 3H). 19 19F NMR (376.5 MHz, CDCl3) δ = -142.189. LCMS R t = 1.348 min, 3 min chromatography, 0 - 60 CD, C 16H 20 FN4O3S[M+H] + The calculated ESI value is 367.1 and the measured value is 367.2.

[0238] Example 31: 3-Fluoro-4-[[5-(3-fluoro-2-pyridyl)-4-methyl-3-pyridyl]methyl]-N-(methylsulfamoyl)pyridin-2-amine

Chemical Structure

Chemical Structure

[0239] Step 3: To a solution of 3-bromo-5-(3-fluoro-2-pyridyl)-4-methyl-pyridine (500 mg, 1.87 mmol) in dioxane (6 mL) and H2O (1.2 mL) were added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (634.28 mg, 4.12 mmol, 698.55 mL), K2CO3 (776.16 mg, 5.62 mmol), and Pd(dppf)Cl2 (273.95 mg, 374.40 mmol). The mixture was stirred at 90 °C for 12 h. Water (20 mL) was added. The mixture was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0~50%) to afford 3-(3-fluoro-2-pyridyl)-4-methyl-5-vinyl-pyridine (390 mg, 1.82 mmol). 1 1H NMR (400 MHz, CDCl3) δ = 8.67 (s, 1H), 8.58 - 8.50 (m, 1H), 8.47 (s, 1H), 7.58 - 7.50 (m, 1H), 7.42 - 7.35 (m, 1H), 6.92 (dd, J = 10.8, 17.6 Hz, 1H), 5.74 (d, J = 17.6 Hz, 1H), 5.47 (d, J = 11.2 Hz, 1H), 2.23 (s, 3H). 19 19F NMR (376.5 MHz, CDCl3) δ = -120.931.

[0240] Step 4: To a solution of 3-(3-fluoro-2-pyridyl)-4-methyl-5-vinylpyridine (390 mg, 1.82 mmol) in THF (16 mL) and H2O (4 mL) were added potassium dichromate (dioxo) osmium dihydrate (67.07 mg, 182.04 mmol) and NaIO4 (1.95 g, 9.10 mmol, 504.36 mL). The mixture was stirred at 25 °C for 0.5 h. Water (20 mL) was added. The mixture was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0 - 55%) to afford 5-(3-fluoro-2-pyridyl)-4-methyl-pyridine-3-carbaldehyde (240 mg, 1.11 mmol). 1 H NMR (400 MHz, CDCl3) δ = 10.40 (s, 1H), 9.02 (s, 1H), 8.76 (s, 1H), 8.61 - 8.58 (m, 1H), 7.66 - 7.55 (m, 1H), 7.48 - 7.42 (m, 1H), 2.59 (s, 3H). 19 F NMR (376.5 MHz, CDCl3) δ = -120.720.

[0241] Step 5: To a solution of 5-(3-fluoro-2-pyridyl)-4-methyl-pyridine-3-carbaldehyde (310 mg, 1.43 mmol) in MeOH (4 mL) was added 4-methylbenzenesulfonohydrazide (267.02 mg, 1.43 mmol). The mixture was stirred at 60 °C for 1 h. The mixture was concentrated. N-[(E)-[5-(3-fluoro-2-pyridyl)-4-methyl-3-pyridyl]methyleneamino]-4-methyl-benzenesulfonamide (551.19 mg, 1.43 mmol). 1 H NMR (400 MHz, CDCl3) δ = 8.76 (s, 1H), 8.59 - 8.56 (m, 1H), 8.49 (s, 1H), 8.04 (s, 1H), 7.86 (d, J = 8.4 Hz, 2H), 7.58 - 7.52 (m, 1H), 7.45 - 7.40 (m, 1H), 7.32 (d, J = 8.0 Hz, 2H), 2.41 (s, 3H), 2.27 (s, 3H).19 19F NMR (376.5 MHz, CDCl3) δ = -120.699.

[0242] Step 6: To a solution of N-[(E)-[5-(3-fluoro-2-pyridyl)-4-methyl-3-pyridyl]methyleneamino]-4-methyl-benzenesulfonamide (551.19 mg, 1.43 mmol) in dioxane (6 mL) was added [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoro-4-pyridyl]boronic acid (877.76 mg, 2.87 mmol, Example 30) and K2CO3 (594.48 mg, 4.30 mmol). The mixture was stirred at 100 °C for 2 h. Then the mixture was stirred at 110 °C for 2 h. Water (20 mL) was added. The mixture was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0 - 57%) to afford N-[(2,4-dimethoxyphenyl)methyl]-3-fluoro-4-[[5-(3-fluoro-2-pyridyl)-4-methyl-3-pyridyl]methyl]pyridin-2-amine (200 mg, 432.44 mmol). LCMS R t = 4.098 min, chromatography for 8 min, 10 - 80 CD, C 26 H 25 F2N4O2 [M + H] + The ESI calculated value of 463.2, measured value 463.2.

[0243] Step 7: To a solution of N-[(2,4-dimethoxyphenyl)methyl]-3-fluoro-4-[[5-(3-fluoro-2-pyridyl)-4-methyl-3-pyridyl]methyl]pyridin-2-amine (200 mg, 432.44 mmol) in DCM (1 mL) was added TFA (1.54 g, 13.51 mmol, 1 mL). The mixture was stirred at 25 °C for 2 h. Anhydrous NaHCO3 (20 mL) was added. The mixture was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0 - 100%) and preparative TLC (EA = 100%).

[0244] Example 32: 4-[[5-(5-chloro-3-fluoro-2-pyridyl)-4-methyl-3-pyridyl]methyl]-3-fluoro-N-(methylsulfamoyl)pyridin-2-amine

Chemical formula

Chemical formula

[0245] Step 2: To a solution of 2-(5-bromo-4-methyl-3-pyridinyl)-5-chloro-3-fluoro-pyridine (400 mg, 1.33 mmol) in dioxane (6 mL) and H2O (1.2 mL), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (449.46 mg, 2.92 mmol, 495.00 mL), K2CO3 (550.00 mg, 3.98 mmol), and Pd(dppf)Cl2 (194.12 mg, 265.30 mmol) were added. The mixture was stirred at 80 °C for 2 h. Water (20 ml) was added and the mixture was extracted with EtOAc (20 ml × 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in petroleum ether = 0 - 30%) to afford 3-(5-chloro-3-fluoro-2-pyridyl)-4-methyl-5-vinyl-pyridine (290 mg, 1.17 mmol). 1 1H NMR (400 MHz, CDCl3) δ = 8.69 (s, 1H), 8.55 (s, 1H), 8.46 (s, 1H), 7.63 - 7.58 (m, 1H), 6.91 (dd, J = 11.2, 17.6, Hz, 1H), 5.76 (d, J = 17.2 Hz, 1H), 5.51 (d, J = 11.2 Hz, 1H), 2.25 (s, 3H).

[0246] Step 3: To a solution of 3-(5-chloro-3-fluoro-2-pyridyl)-4-methyl-5-vinyl-pyridine (290 mg, 1.17 mmol) in THF (4 mL) and H2O (0.8 mL) was added K2OsO4·2H2O (42.97 mg, 116.61 mmol) and NaIO4 (997.71 mg, 4.66 mmol, 258.47 mL). The mixture was stirred at 25 °C for 1 h. The resulting solution was diluted with water (20 mL) and quenched with saturated Na2SO3 solution until the KI test paper turned white. The mixture was filtered. Water (20 mL) was added and the mixture was extracted with EtOAc (20 mL×2). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel (EtOAc in petroleum ether = 0~30%) to give 5-(5-chloro-3-fluoro-2-pyridyl)-4-methyl-pyridine-3-carbaldehyde (110 mg, 438.85 mmol). 1 1H NMR (400 MHz, CDCl3) δ = 10.39 (s, 1H), 9.03 (s, 1H), 8.73 (s, 1H), 8.58 (d, J = 1.2 Hz, 1H), 7.64 (dd, J = 2.0, 8.8 Hz, 1H), 2.59 - 2.56 (m, 3H).

[0247] Step 4: To a solution of 5-(5-chloro-3-fluoro-2-pyridyl)-4-methyl-pyridine-3-carbaldehyde (110 mg, 438.85 mmol) in MeOH (2 mL) was added 4-methylbenzenesulfonohydrazide (81.73 mg, 438.85 mmol). The mixture was stirred at 60 °C for 1 h. Water (20 mL) was added and the mixture was extracted with EtOAc (20 mL×2). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give N-[(E)-[5-(5-chloro-3-fluoro-2-pyridyl)-4-methyl-3-pyridyl]methylenamino]-4-methyl-benzenesulfonamide (183 mg, 436.89 mmol). 11H NMR (400 MHz, CDCl3) δ = 8.85 (s, 1H), 8.58 - 8.51 (m, 3H), 8.11 (s, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.63 (dd, J = 2.4, 8.8 Hz, 1H), 7.35 (d, J = 8.0 Hz, 2H), 2.44 (s, 3H), 2.32 (s, 3H).

[0248] Step 5: To a solution of N-[(E)-[5-(5-chloro-3-fluoro-2-pyridyl)-4-methyl-3-pyridyl]methyleneamino]-4-methyl-benzenesulfonamide (183 mg, 436.89 mmol) in dioxane (2 mL) was added [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoro-4-pyridyl]boronic acid (534.92 mg, 873.78 mmol, purity 50%) and K2CO3 (181.14 mg, 1.31 mmol). The mixture was stirred at 110 °C for 2 h. Water (20 mL) was added and the mixture was extracted with EtOAc (20 mL × 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash column chromatography on silica gel (EtOAc in petroleum ether = 0 - 40%) to afford 4-[[5-(5-chloro-3-fluoro-2-pyridyl)-4-methyl-3-pyridyl]methyl]-N-[(2,4-dimethoxyphenyl)methyl]-3-fluoro-pyridine-2-amine (340 mg, 232.63 mmol, yield 53.25%). LCMS Rt = 0.747 min, chromatography for 1.5 min, with 5 - 95 AB, C 26 H 24 ClN4F2O2 [M + H] + The ESI calculated value for 497.1, measured value 497.0.

[0249] Step 6: To a solution of 4-[[5-(5-chloro-3-fluoro-2-pyridyl)-4-methyl-3-pyridyl]methyl]-N-[(2,4-dimethoxyphenyl)methyl]-3-fluoro-pyridine-2-amine (340 mg, 0.23263 mmol, purity 34%) in DCM (2 mL) was added TFA (2.26 g, 0.01984 mmol, 1.47 mL). The mixture was stirred at 25 °C for 2 h. The mixture was adjusted to pH > 7 with NH3-MeOH (7 M, 10 mL) and the mixture was concentrated. Water (20 mL) was added and the mixture was extracted with DCM (20 mL × 2). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by flash column chromatography on silica gel (EtOAc in petroleum ether = 0 - 100%) and triturated with DCM (20 mL) to afford 4-[[5-(5-chloro-3-fluoro-2-pyridyl)-4-methyl-3-pyridyl]methyl]-3-fluoro-pyridine-2-amine (30 mg, 0.08651 mmol). LCMS Rt = 1.453 min, chromatography for 1.5 min, 5 - 95 AB, C 17 H 14 ClN4F2[M+H] + The ESI calculated value of 347.1, measured value 347.1.

[0250] Step 7: To a solution of 4-[[5-(5-chloro-3-fluoro-2-pyridyl)-4-methyl-3-pyridyl]methyl]-3-fluoro-pyridine-2-amine (12 mg, 0.03461 mmol) in DMA (1 mL) and MeCN (1 mL) were added N-methylsulfamoyl chloride (44.84 mg, 0.34606 mmol) and Py (27.37 mg, 0.34606 mmol, 27.93 mL). The mixture was stirred at 20 °C for 2 h. The mixture was concentrated. The crude was purified by preparative HPLC (column: Phenomenex C18 80×40 mm×3 mm, mobile phase: [water (NH3H2O + NH4HCO3)-ACN], B%: 20% - 50%, 7 min) to afford 4-[[5-(5-chloro-3-fluoro-2-pyridyl)-4-methyl-3-pyridyl]methyl]-3-fluoro-N-(methylsulfamoyl)pyridine-2-amine (2.1 mg, 4.77 μmol).1 1H NMR (400 MHz, CD3CN) δ = 8.78 - 8.19 (m, 3H), 7.94 - 7.92 (s, 1H), 7.84 (dd, J = 9.2, 2.0 Hz, 1H), 6.77 - 6.64 (m, 1H), 4.14 (s, 2H), 2.62 - 2.50 (m, 3H), 2.07 (s, 3H). 19 19F NMR (376.5 MHz, CD3CN) δ = -120.53, -141.74 ppm. LCMS R t = 0.712 minutes, chromatography for 1.5 minutes, with 5 - 95 AB, C 18 H 17 C11H11ClN5F2O2S [M + H] + ESI calculated value 440.1, measured value 439.9.

[0251] Example 33: 3 - Fluoro - 4 - ({5 - [(2 - Fluoro - 4 - methylphenyl)amino] - 4 - methylpyridin - 3 - yl}methyl)pyridin - 2 - amine

Chemical Structure

Chemical Structure

[0252] Step 2: TFA (0.5 mL) was added dropwise to a stirred solution of tert-butyl N-(tert-butoxycarbonyl)-N-[3-fluoro-4-({5-[(2-fluorophenyl)amino]-4-methylpyridin-3-yl}methyl)pyridin-2-yl]carbamate (109 mg, 0.202 mmol) in DCM (2 mL) at 0 °C. The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The reaction mixture was basified to pH 10 with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with EA (3 × 10 mL). The combined organic layers were washed with brine (1 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, ACN in water (10 mmol / L NH4HCO3), gradient from 5% to 70% in 25 min, detector, UV 254 nm. Thereby, 3-fluoro-4-({5-[(2-fluorophenyl)amino]-4-methylpyridin-3-yl}methyl)pyridin-2-amine (60 mg) was obtained. LCMS: (ESI, m / z): [M+1] + = 341.05. 1 H NMR (400 MHz, chloroform-d) δ 8.35 (s, 1H), 8.12 (s, 1H), 7.73 (d, J = 5.2 Hz, 1H), 6.93 (d, J = 12.0 Hz, 1H), 6.86 - 6.79 (m, 2H), 6.26 (t, J = 5.1 Hz, 1H), 5.32 (s, 1H), 4.62 (s, 2H), 3.99 (s, 2H), 2.30 (s, 3H), 2.14 (s, 3H). 19 F NMR (377 MHz, chloroform-d) δ -132.30, -145.41.

[0253] Example 34: {[3-Fluoro-4-({5-[(3-fluoropyridin-2-yl)methoxy]-4-methylpyridin-3-yl}methyl)pyridin-2-yl]sulfamoyl}(methyl)amine

Chemical Structure

Chemical Structure

[0254] Step 2: A mixture of 2-(bromomethyl)-3-fluoropyridine (3.9 g, 20.525 mmol), 5-bromo-4-methylpyridin-3-ol (2 g, 10.637 mmol, 0.5 equiv) and K2CO3 (7.35 g, 53.185 mmol, 2.5 equiv) in DMF (20 mL) was stirred at 80 °C for 15 min under a nitrogen atmosphere. The desired product could be detected by LCMS. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (4:1) to give 3-bromo-5-[(3-fluoropyridin-2-yl)methoxy]-4-methylpyridine (1.2 g). LCMS: (ESI, m / z): [M+1] + = 297.05. 11H NMR (400 MHz, chloroform-d) δ 8.46 (m, 1H), 8.38 - 8.18 (m, 2H), 7.59 - 7.41 (m, 1H), 7.36 (m, 1H), 5.35 (m, 2H), 2.44 - 2.26 (m, 3H). 19 19F NMR (377 MHz, chloroform-d) δ -124.35.

[0255] Step 3: To a solution of 3-bromo-5-[(3-fluoropyridin-2-yl)methoxy]-4-methylpyridine (600 mg, 2.019 mmol) and bis(pinacolato)diboron (615.35 mg, 2.423 mmol, 1.2 equiv) in dioxane (3 mL) were added KOAc (396.36 mg, 4.038 mmol) and Pd(PPh3)2Cl2 (141.74 mg, 0.202 mmol, 0.1 equiv). After stirring at 80 °C for 16 h under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. Thereby, 3-((3-fluoropyridin-2-yl)methoxy)-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine was obtained as a crude product and used directly in the next step without further purification. LCMS: (ESI, m / z): [M+1] + = 345.2.

[0256] Step 4: To a stirred mixture of tert-butyl N-[4-(bromomethyl)-3-fluoropyridin-2-yl]-N-(tert-butoxycarbonyl)carbamate (300 mg, 0.740 mmol, 1.00 equiv) and 3-[(3-fluoropyridin-2-yl)methoxy]-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (509.58 mg, 1.480 mmol) in dioxane (10 mL) and H2O (1 mL) were added K2CO3 (306.92 mg, 2.220 mmol, 3 equiv) and Pd(dppf)Cl2 (54.17 mg, 0.074 mmol, 0.1 equiv). The resulting mixture was stirred at 80 °C for 1 h under a nitrogen atmosphere and then concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN in water (10 mmol / L NH4HCO3), gradient 5%–60% in 20 min; detector, UV 254 nm. This gave tert-butyl N-(tert-butoxycarbonyl)-N-[3-fluoro-4-({5-[(3-fluoropyridin-2-yl)methoxy]-4-methylpyridin-3-yl}methyl)pyridin-2-yl]carbamate (180 mg). LCMS: (ESI, m / z): [M+1] + = 543.3.

[0257] Step 5: TFA (1 mL) was added dropwise to a stirred solution of tert-butyl N-(tert-butoxycarbonyl)-N-[3-fluoro-4-({5-[(3-fluoropyridin-2-yl)methoxy]-4-methylpyridin-3-yl}methyl)pyridin-2-yl]carbamate (180 mg, 0.332 mmol) in DCM (4 mL) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The desired product could be detected by LCMS. The reaction mixture was concentrated under reduced pressure. The residue was basified to pH 10 with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, ACN in water (10 mmol / L NH4HCO3), gradient from 5% to 60% in 20 min, detector, UV 254 nm. Thereby, 3-fluoro-4-({5-[(3-fluoropyridin-2-yl)methoxy]-4-methylpyridin-3-yl}methyl)pyridin-2-amine (45 mg) was obtained. LCMS: (ESI, m / z): [M+1] + =342.3. 1 H NMR (400 MHz, chloroform-d) δ 8.46 (m, 1H), 8.31 (s, 1H), 8.09 (s, 1H), 7.69 (d, J = 5.2 Hz, 1H), 7.47 (m, 1H), 7.35 (m, 1H), 6.22 (t, J = 5.1 Hz, 1H), 5.34 (d, J = 1.9 Hz, 2H), 4.67 (s, 2H), 3.95 (s, 2H), 2.12 (s, 3H). 19 F NMR (376 MHz, chloroform-d) δ -124.42, -145.28.

[0258] Step 6: To a stirred solution of 3-fluoro-4-({5-[(3-fluoropyridin-2-yl)methoxy]-4-methylpyridin-3-yl}methyl)pyridin-2-amine (30 mg, 0.088 mmol) and pyridine (69.31 mg, 0.880 mmol, 10 equiv) in DMA (0.5 mL) was added N-methylsulfamoyl chloride (13.62 mg, 0.106 mmol, 1.2 equiv) in DMA (0.5 mL) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The desired product could be detected by LCMS. The reaction mixture was purified by preparative HPLC under the following conditions (column: XBridge Prep Phenyl OBD column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN, flow rate: 50 mL / min, gradient: 8%B - 25%B in 8 min, 25%B, wavelength: 254 / 220 nm, RT1 (min): 10.13, number of runs: 0. Thereby, {[3-fluoro-4-({5-[(3-fluoropyridin-2-yl)methoxy]-4-methylpyridin-3-yl}methyl)pyridin-2-yl]sulfamoyl}(methyl)amine (21 mg) was obtained. LCMS: (ESI, m / z): [M+1] + =436.10. 1 H NMR (400 MHz, methanol-d4) δ 8.41 (m, 1H), 8.29 (s, 1H), 8.03 (s, 1H), 7.93 (d, J = 5.1 Hz, 1H), 7.68 (m, 1H), 7.49 (m, 1H), 6.63 (t, J = 5.1 Hz, 1H), 5.37 (d, J = 1.9 Hz, 2H), 4.09 (s, 2H), 2.61 (s, 3H), 2.13 (s, 3H). 19 F NMR (376 MHz, methanol-d4) δ -126.17, -142.34.

[0259] Example 35: 4-[[5-(4-chloro-2-methoxy-anilino)-4-methyl-3-pyridyl]methyl]-3-fluoro-N-(methylsulfamoyl)pyridin-2-amine

Chemical Structure

[0260] Step 2: A mixture of tert-butyl N-tert-butoxycarbonyl-N-[4-[[5-(4-chloro-2-methoxy-anilino)-4-methyl-3-pyridyl]methyl]-3-fluoro-2-pyridyl]carbamate (200 mg, 349.01 μmol) in HCl / MeOH (4 mL, 4M) was stirred at 25 °C for 4 hours. The mixture was concentrated to afford 4-[[5-(4-chloro-2-methoxy-anilino)-4-methyl-3-pyridyl]methyl]-3-fluoro-pyridin-2-amine (142.8 mg, 348.90 μmol).

[0261] Step 3: To a solution of 4-[[5-(4-chloro-2-methoxy-anilino)-4-methyl-3-pyridyl]methyl]-3-fluoro-pyridine-2-amine (50 mg, 122.16 μmol, HCl) in MeCN (1 mL) was added Py (96.63 mg, 1.22 mmol, 98.60 μL) and methylsulfamoyl chloride (158.28 mg, 1.22 mmol). The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched with ice water (5 mL). The mixture was extracted with DCM (10 mL × 2), the combined organic layers were washed with brine (10 mL × 2), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Welch Xtimate C18 150×30 mm×5 μm, mobile phase: [water (NH3H2O + NH4HCO3)-ACN], B%: 20% - 50%, 7 min) to afford 4-[[5-(4-chloro-2-methoxy-anilino)-4-methyl-3-pyridyl]methyl]-3-fluoro-N-(methylsulfamoyl)pyridine-2-amine (18.2 mg, 39.06 μmol). 1 1H NMR (400 MHz, DMSO-d6) δ = 8.07 (s, 2H), 7.84 (d, J = 5.2 Hz, 1H), 7.14 - 6.96 (m, 2H), 6.80 (d, J = 6.4 Hz, 1H), 6.54 - 6.38 (m, 2H), 4.01 (s, 2H), 3.84 (s, 3H), 2.43 (s, 3H), 2.02 (s, 3H). 19 19F NMR (376.5 MHz, DMSO-d6) δ = -138.699 ppm. LCMS R t = 0.753 min, 1.5 min chromatography, 5 - 95 AB, C 20 H 22 ClFN5O3S [M + H] + The ESI calculated value for 468.1, measured value 467.8.

[0262] Example 36: N-(4-chloro-2-fluorophenyl)-5-({3-fluoro-2-[(methylsulfamoyl)amino]pyridin-4-yl}methyl)-N,4-dimethylpyridin-3-amine

Chemical formula

Chem.

[0263] Step 2: To a stirred solution of tert-butyl N-(tert-butoxycarbonyl)-N-[4-({5-[(4-chloro-2-fluorophenyl)(methyl)amino]-4-methylpyridin-3-yl}methyl)-3-fluoropyridin-2-yl]carbamate (113 mg, 0.197 mmol) in DCM (4 mL) was added dropwise TFA (1 mL) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The desired product could be detected by LCMS. The reaction mixture was concentrated under reduced pressure. The mixture was basified to pH 10 with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with EA (3 × 20 mL). The combined organic layers were washed with water (5 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, ACN in water (10 mmol / L NH4HCO3), gradient of 5% - 60% in 20 min, detector, UV 254 nm. Thereby, 4-({5-[(4-chloro-2-fluorophenyl)(methyl)amino]-4-methylpyridin-3-yl}methyl)-3-fluoropyridin-2-amine (14 mg) was obtained. LCMS: (ESI, m / z): [M+1] + = 375.2. 1 H NMR (400 MHz, chloroform-d) δ 8.24 (m, 2H), 7.72 (d, J = 5.2 Hz, 1H), 7.10 - 6.90 (m, 2H), 6.90 - 6.59 (m, 1H), 6.22 (t, J = 5.1 Hz, 1H), 4.84 - 4.52 (m, 2H), 3.97 (s, 2H), 3.21 (d, J = 0.7 Hz, 3H), 2.05 (s, 3H). 19 F NMR (376 MHz, chloroform-d) δ -120.04, -145.18.

[0264] Step 3: To a stirred solution of 4-({5-[(4-chloro-2-fluorophenyl)(methyl)amino]-4-methylpyridin-3-yl}methyl)-3-fluoropyridin-2-amine (10 mg, 0.027 mmol) and pyridine (21.10 mg, 0.270 mmol, 10 equiv) in DMA (0.3 mL) was added N-methylsulfamoyl chloride (4.15 mg, 0.032 mmol, 1.2 equiv) in DMA (0.2 mL) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The desired product could be detected by LCMS. The reaction mixture was purified by preparative HPLC under the following conditions: column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm, mobile phase: water (10 mmol / L NH4HCO3), mobile phase B: ACN, flow rate: 60 mL / min, gradient: 26% B - 46% B in 10 min, wavelength: 254 / 220 nm, RT1 (min): 11.03. Thereby, N-(4-chloro-2-fluorophenyl)-5-({3-fluoro-2-[(methylsulfamoyl)amino]pyridin-4-yl}methyl)-N,4-dimethylpyridin-3-amine (6.8 mg) was obtained. LCMS: (ESI, m / z): [M+1] + =468.1. 1 H NMR (400 MHz, methanol-d4) δ 8.17 (d, J = 6.5 Hz, 2H), 7.96 (d, J = 5.2 Hz, 1H), 7.14 - 7.07 (m, 2H), 7.00 (t, J = 8.9 Hz, 1H), 6.64 (s, 1H), 4.14 (s, 2H), 3.22 (s, 3H), 2.63 (s, 3H), 2.12 (s, 3H). 19 F NMR (376 MHz, methanol-d4) δ -122.070, -142.358.

[0265] Example 37: N-(4-chloro-2-fluorophenyl)-5-({3-fluoro-2-[(methylsulfamoyl)amino]pyridin-4-yl}methyl)-4-methoxypyridin-3-amine

Chemical Structure

[0266] Step 2: A mixture of N’-[(1E)-(5-bromo-4-methoxypyridin-3-yl)methylidene]-4-methylbenzenesulfonohydrazide (70 mg, 0.182 mmol), K2CO3 (30.21 mg, 0.218 mmol, 1.2 equiv), and 2-{[(2,4-dimethoxyphenyl)methyl]amino}-3-fluoropyridin-4-ylboronic acid (557.63 mg, 1.820 mmol, 10 equiv) in dioxane (5 mL) was stirred at 110 °C for 1 h under a nitrogen atmosphere. The desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN in water (0.1% FA), gradient of 5% - 70% in 30 min; detector, UV254 nm. This gave 4-[(5-bromo-4-methoxypyridin-3-yl)methyl]-N-[(2,4-dimethoxyphenyl)methyl]-3-fluoropyridin-2-amine (35 mg). LCMS: (ESI, m / z): [M+1]+ =461.95 . 1 1H NMR (400 MHz, chloroform-d) δ 8.59 (s, 1H), 8.31 (s, 1H), 7.80 (d, J = 5.6 Hz, 1H), 7.34 (d, J = 8.3 Hz, 1H), 6.56 - 6.38 (m, 3H), 6.34 (s, 1H), 4.71 (s, 2H), 3.94 (s, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 3.80 (s, 3H).

[0267] Step 3: To a solution of 4-[(5-bromo-4-methoxypyridin-3-yl)methyl]-N-[(2,4-dimethoxyphenyl)methyl]-3-fluoropyridine-2-amine (204 mg, 0.441 mmol) and 4-chloro-2-fluoroaniline (96.34 mg, 0.661 mmol, 1.5 eq) in dioxane (10 mL) were added Cs2CO3 (287.54 mg, 0.882 mmol), X-Phos (21.04 mg, 0.044 mmol, 0.1 eq) and Pd2(dba)3 (40.41 mg, 0.044 mmol, 0.1 eq). After stirring at 80 °C for 2 h under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1) to give N-(4-chloro-2-fluorophenyl)-5-[(2-{[(2,4-dimethoxyphenyl)methyl]amino}-3-fluoropyridin-4-yl)methyl]-4-methoxypyridin-3-amine (182 mg). LCMS: (ESI, m / z): [M+1] + =527.50. 1 1H NMR (400 MHz, chloroform-d) δ 8.37 (s, 1H), 8.08 (s, 1H), 7.81 (d, J = 5.3 Hz, 1H), 7.28 (m, 1H), 7.20 - 7.13 (m, 1H), 7.09 - 7.03 (m, 2H), 6.48 (d, J = 2.4 Hz, 1H), 6.43 (dd, J = 8.2, 2.4 Hz, 1H), 6.30 (t, J = 5.1 Hz, 1H), 5.81 (s, 1H), 5.06 (s, 1H), 4.60 (d, J = 5.7 Hz, 2H), 3.94 (s, 2H), 3.85 (s, 3H), 3.80 (s, 3H), 3.77 (s, 3H). 1919F NMR (376 MHz, chloroform-d) δ -128.20, -147.74.

[0268] Step 4: TFA (1 mL) was added to a stirred solution of N-(4-chloro-2-fluorophenyl)-5-[(2-{[(2,4-dimethoxyphenyl)methyl]amino}-3-fluoropyridin-4-yl)methyl]-4-methoxypyridin-3-amine (172 mg, 0.326 mmol) in DCM (4 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The desired product could be detected by LCMS. The reaction mixture was concentrated under reduced pressure. The residue was basified to pH 10 with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with EA (3 × 5 mL). The combined organic layers were washed with water (5 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, ACN in water (10 mmol / L NH4HCO3), gradient from 5% to 60% in 30 min, detector, UV 254 nm. Thereby, 4-({5-[(4-chloro-2-fluorophenyl)amino]-4-methoxypyridin-3-yl}methyl)-3-fluoropyridin-2-amine (60 mg) was obtained. LCMS: (ESI, m / z): [M+1] + = 376.90. 1 1H NMR (400 MHz, chloroform-d) δ 8.41 (s, 1H), 8.11 (s, 1H), 7.75 (d, J = 5.2 Hz, 1H), 7.18 - 7.13 (m, 1H), 7.10 - 7.05 (m, 2H), 6.43 (t, J = 5.0 Hz, 1H), 5.79 (s, 1H), 4.64 (s, 2H), 3.98 (s, 2H), 3.76 (d, J = 0.9 Hz, 3H). 19 19F NMR (376 MHz, chloroform-d) δ -128.73, -145.54.

[0269] Step 5: To a stirred solution of 4-({5-[(4-chloro-2-fluorophenyl)amino]-4-methoxypyridin-3-yl}methyl)-3-fluoropyridin-2-amine (30 mg, 0.080 mmol) and pyridine (62.98 mg, 0.800 mmol, 10 equiv) in DMA (0.8 mL) was added N-methylsulfamoyl chloride (11.35 mg, 0.088 mmol, 1.1 equiv) in DMA (0.2 mL) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under a nitrogen atmosphere. The desired product was detectable by LCMS. The crude product was purified by preparative HPLC under the following conditions: column: XBridge Shield RP18 OBD column, 30 * 150 mm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN, flow rate: 60 mL / min, gradient: 7% B - 27% B in 8 min, wavelength: 254 nm / 220 nm, RT1 (min): 10.08). Thereby, N-(4-chloro-2-fluorophenyl)-5-({3-fluoro-2-[(methylsulfamoyl)amino]pyridin-4-yl}methyl)-4-methoxypyridin-3-amine (16.5 mg) was obtained. LCMS: (ESI, m / z): [M + 1] + = 470.05. 1 H NMR (400 MHz, methanol-d4) δ 8.13 - 8.07 (m, 2H), 7.98 (s, 1H), 7.21 (m, 1H), 7.05 (m, 1H), 6.85 - 6.79 (m, 2H), 4.08 (s, 2H), 3.70 (s, 3H), 2.63 (s, 3H). 19 F NMR (377 MHz, methanol-d4) δ -127.75, -142.86.

[0270] Example 38: N-(4-chloro-2-fluorophenyl)-5-({3-fluoro-2-[(methylsulfamoyl)amino]pyridin-4-yl}methyl)-4-(trifluoromethyl)pyridin-3-amine

Chemical Structure

Chemical Structure

[0271] Step 2: To a stirred solution of 2,2,6,6 - tetramethylpiperidine (2.90 g, 20.495 mmol, 1.00 equiv) in THF (50 mL), n - BuLi in hexane (8.20 mL, 20.495 mmol) was added dropwise at - 78 °C under a nitrogen atmosphere. After stirring continuously at - 78 °C for 1 h, 3 - chloro - 4 - (trifluoromethyl)-2-(trimethylsilyl)pyridine (5.2 g, 20.495 mmol) was added to the solution. The resulting mixture was stirred at - 78 °C for 2 h. Then, dry ice (10 g) was added to the reaction mixture and it was warmed to room temperature. The resulting mixture was stirred at room temperature for 16 h. The resulting reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 1 M aqueous NaOH and refluxed at 50 °C for 1 h. The desired product could be detected by LCMS. The mixture was acidified to pH 1 with 1 M HCl (aqueous solution). The resulting mixture was extracted with EA (3×50 mL). The combined organic layers were washed with brine (1×50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 5 - chloro - 4 - (trifluoromethyl)pyridine - 3 - carboxylic acid (2.5 g). LCMS: (ESI, m / z): [M + 1] + =226.05. 1 H NMR(300MHz,DMSO - d6)δ 9.04(s,1H),8.88(d,J = 0.9Hz,1H).

[0272] Step 3: To a stirred solution of 5 - chloro - 4 - (trifluoromethyl)pyridine - 3 - carboxylic acid (2 g, 8.867 mmol) in DCM (10 mL) and MeOH (10 mL), TMSCH2N2 (2 M in n - hexane, 22.17 mL, 44.335 mmol, 5 equiv) was added dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure to give methyl 5 - chloro - 4 - (trifluoromethyl)pyridine - 3 - carboxylate (1.6 g). LCMS: (ESI, m / z): [M + 1] + =240.00. 1 H NMR(400MHz,chloroform - d)δ 8.84(s,1H),8.68 - 8.64(m,1H),3.97(s,3H).

[0273] Step 4: To a mixture of methyl 5-chloro-4-(trifluoromethyl)pyridine-3-carboxylate (1.5 g, 6.261 mmol), K3PO4 (2.65 g, 12.522 mmol), Pd2(dba)3 (573.33 mg, 0.625 mmol, 0.1 equiv), and X-Phos (298.48 mg, 0.625 mmol, 0.1 equiv) in toluene (20 mL) was added 4-chloro-2-fluoroaniline (1.09 g, 7.513 mmol, 1.2 equiv) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 80 °C for 4 h, and the desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EA (3 × 20 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1) to give methyl 5-[(4-chloro-2-fluorophenyl)amino]-4-(trifluoromethyl)pyridine-3-carboxylate (990 mg). LCMS: (ESI, m / z): [M+1] + = 349.10. 1 H NMR (400 MHz, chloroform-d) δ 8.57 (s, 1H), 8.31 (s, 1H), 7.25 - 7.12 (m, 3H), 6.04 (s, 1H), 3.96 (s, 3H).

[0274] Step 5: To a stirred solution of methyl 5-[(4-chloro-2-fluorophenyl)amino]-4-(trifluoromethyl)pyridine-3-carboxylate (990 mg, 2.839 mmol) in MeOH (6 mL) and H2O (6 mL), LiOH.H2O (238.24 mg, 5.678 mmol) was added portionwise at 0 °C. The reaction mixture was stirred at 60 °C for 1 h and the desired product could be detected by LCMS. The reaction mixture was concentrated under reduced pressure. The aqueous layer was acidified to pH 1 with 2 M HCl (aqueous solution). The aqueous layer was extracted with EA (3 × 30 mL), the combined organic layers were washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave 5-[(4-chloro-2-fluorophenyl)amino]-4-(trifluoromethyl)pyridine-3-carboxylic acid (580 mg). LCMS: (ESI, m / z): [M+1] + = 335.00. 1 H NMR (300 MHz, DMSO-d6) δ 8.39 - 8.30 (m, 2H), 8.12 (s, 1H), 7.55 - 7.47 (m, 1H), 7.31 - 7.18 (m, 2H).

[0275] Step 6: To a stirred solution of 5-[(4-chloro-2-fluorophenyl)amino]-4-(trifluoromethyl)pyridine-3-carboxylic acid (580 mg, 1.733 mmol) and 4-methylmorpholine (350.55 mg, 3.466 mmol) in 1,2-dimethoxyethane (5 mL), isobutyl chloroformate (286.94 mg, 2.079 mmol, 1.2 equiv) was added dropwise at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 h. Then, NaBH4 (135.17 mg, 3.466 mmol) was added at -15 °C and the resulting mixture was stirred at -15 °C for an additional 1 h. The desired product could be detected by LCMS. The reaction was quenched with MeOH at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient 5% - 60% in 30 min; detector, UV 254 nm. Thereby, {5-[(4-chloro-2-fluorophenyl)amino]-4-(trifluoromethyl)pyridin-3-yl}methanol (65 mg) was obtained. LCMS: (ESI, m / z): [M+1] + =320.90. 1 H NMR (300 MHz, chloroform-d) δ 8.53 (d, J = 10.2 Hz, 2H), 7.25 - 7.08 (m, 3H), 6.02 (s, 1H), 4.97 - 4.91 (m, 2H).

[0276] Step 7: To a stirred solution of {5-[(4-chloro-2-fluorophenyl)amino]-4-(trifluoromethyl)pyridin-3-yl}methanol (65 mg, 0.202 mmol) and PPh3 (79.73 mg, 0.304 mmol, 1.5 eq) in DCM (1 mL) was added CBr4 (100.81 mg, 0.304 mmol, 1.5 eq) at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 h. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 5:1) to give 5-(bromomethyl)-N-(4-chloro-2-fluorophenyl)-4-(trifluoromethyl)pyridin-3-amine (45 mg). LCMS: (ESI, m / z): [M+1] + = 383.1. 1 H NMR (400 MHz, chloroform-d) δ 8.39 (s, 1H), 8.22 (d, J = 1.0 Hz, 1H), 7.17 - 7.03 (m, 3H), 5.99 (s, 1H), 4.60 - 4.52 (m, 2H).

[0277] Step 8: To a mixture of 5-(bromomethyl)-N-(4-chloro-2-fluorophenyl)-4-(trifluoromethyl)pyridin-3-amine (40 mg, 0.104 mmol) and 2-{[(3,4-dimethylphenyl)methyl]amino}-3-fluoropyridin-4-ylboronic acid (42.88 mg, 0.156 mmol, 1.5 equiv) in dioxane (1 mL) were added K2CO3 (43.24 mg, 0.312 mmol, 3 equiv) and Pd(dppf)Cl2 (7.64 mg, 0.01 mmol, 0.1 equiv). The reaction mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The desired product could be detected by LCMS. The resulting mixture was filtered and the precipitated solid was washed with EA (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient from 20% to 95% in 10 min, detector, UV 254 nm. Thereby, N-(4-chloro-2-fluorophenyl)-5-[(2-{[(2,4-dimethoxyphenyl)methyl]amino}-3-fluoropyridin-4-yl)methyl]-4-(trifluoromethyl)pyridin-3-amine (33 mg) was obtained. LCMS: (ESI, m / z): [M+1] + =565.50. 1 H NMR (400 MHz, chloroform-d) δ 8.41 (s, 1H), 8.02 (s, 1H), 7.74 (d, J = 5.3 Hz, 1H), 7.22 (t, J = 4.1 Hz, 1H), 7.16 - 7.00 (m, 3H), 6.46 - 6.41 (m, 1H), 6.40 - 6.35 (m, 1H), 6.03 (t, J = 5.1 Hz, 1H), 5.95 (s, 1H), 4.56 (t, J = 5.9 Hz, 2H), 4.05 (s, 2H), 3.78 (d, J = 3.0 Hz, 3H), 3.73 (s, 3H).

[0278] Step 9: To a stirred solution of N-(4-chloro-2-fluorophenyl)-5-[(2-{[(2,4-dimethoxyphenyl)methyl]amino}-3-fluoropyridin-4-yl)methyl]-4-(trifluoromethyl)pyridin-3-amine (30 mg, 0.053 mmol) in DCM (0.8 mL) was added dropwise TFA (0.2 mL) at 0 °C under an air atmosphere. The reaction mixture was stirred at room temperature for 1 hour. The desired product could be detected by LCMS. The resulting mixture was basified to pH 8 with saturated NaHCO3 (aqueous solution). The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, ACN in water (10 mmol / L NH4HCO3), gradient of 20% to 80% in 25 minutes, detector, UV 254 nm. Thereby, 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-N-(4-chloro-2-fluorophenyl)-4-(trifluoromethyl)pyridin-3-amine (16 mg) was obtained. LCMS: (ESI, m / z): [M+1] + = 415.00. 1 H NMR (400 MHz, chloroform-d) δ 8.48 (s, 1H), 8.10 (s, 1H), 7.74 (d, J = 6.1 Hz, 1H), 7.23 - 7.02 (m, 3H), 6.20 (d, J = 6.7 Hz, 1H), 6.03 (s, 1H), 4.71 (s, 2H), 4.16 (s, 2H). 19 F NMR (377 MHz, chloroform-d) δ -55.91, -125.23, -145.28.

[0279] Step 10: To a stirred solution of 4-({5-[(4-chloro-2-fluorophenyl)amino]-4-(trifluoromethyl)pyridin-3-yl}methyl)-3-fluoropyridin-2-amine (16 mg, 0.038 mmol) and pyridine (30.2 mg, 0.38 mmol, 10 equiv) in DMA (1 mL) was added N-methylsulfamoyl chloride (24.6 mg, 0.19 mmol, 5 equiv) in DMA (1 mL) dropwise at 0 °C under an air atmosphere. The resulting mixture was stirred at room temperature for 2 h. The desired product could be detected by LCMS. The reaction mixture was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN in water (10 mmol / L NH4HCO3), gradient 5% - 60% in 30 min; detector, UV 254 nm. This gave N-(4-chloro-2-fluorophenyl)-5-({3-fluoro-2-[(methylsulfamoyl)amino]pyridin-4-yl}methyl)-4-(trifluoromethyl)pyridin-3-amine (6.3 mg). LCMS: (ESI, m / z): [M+1] + =507.85 1 1H NMR (300 MHz, methanol-d4) δ 8.18 (s, 1H), 8.10 (s, 1H), 7.96 (d, J = 5.2 Hz, 1H), 7.34 - 7.24 (m, 1H), 7.24 - 7.10 (m, 2H), 6.61 - 6.52 (m, 1H), 4.29 (s, 2H), 2.63 (s, 3H). 19 19F NMR (282 MHz, methanol-d4) δ -58.083, -123.496, -142.339.

[0280] Example 39: 3-Fluoro-4-[[5-[2-fluoro-3-(trifluoromethoxy)anilino]-4-methyl-3-pyridyl]methyl]-N-(methylsulfamoyl)pyridin-2-amine

Chemical Structure

Chemical Structure

[0281] Step 2: N-tert-Butoxycarbonyl-N-[3-fluoro-4-[[5-[2-fluoro-4-(trifluoromethoxy)anilino]-4-methyl-3-pyridyl]methyl]-2-pyridyl]carbamate (100 mg, 163.78 μmol) and HCl / MeOH (4 M, 2.20 mL) in MeOH (0.3 mL) were stirred at 25 °C for 24 h under N2. The mixture was added dropwise to NH3 / MeOH (7 M, 10 mL) and then concentrated. The residue was purified by flash chromatography on silica gel (MeOH in DCM = 0 - 10%) to afford 3-fluoro-4-[[5-[2-fluoro-4-(trifluoromethoxy)anilino]-4-methyl-3-pyridyl]methyl]pyridin-2-amine (60 mg, 146.22 μmol). 1 H NMR (400 MHz, CDCl3) δ = 8.40 (s, 1H), 8.21 (s, 1H), 7.73 (d, J = 5.2 Hz, 1H), 7.04 (d, J = 11.2 Hz, 1H), 6.90 (d, J = 9.2 Hz, 1H), 6.78 (t, J = 8.8 Hz, 1H), 6.28 (t, J = 4.8 Hz, 1H), 5.48 (s, 1H), 4.82 (s, 2H), 4.01 (s, 2H), 2.16 (s, 3H). 19 F NMR (376.5 MHz, CDCl3) δ = -58.526 ppm, -129.203 ppm, -144.864 ppm.

[0282] Step 3: To a solution of 3-fluoro-4-[[5-[2-fluoro-4-(trifluoromethoxy)anilino]-4-methyl-3-pyridyl]methyl]pyridin-2-amine (100 mg, 243.70 μmol) and Py (192.77 mg, 2.44 mmol, 196.70 μL) in MeCN (0.9 mL) was added N-methylsulfamoyl chloride (157.88 mg, 1.22 mmol) under N2. The mixture was stirred at 25 °C for 16 h. The mixture was concentrated. The residue was purified by preparative HPLC (column: Boston Prime C18 150*30 mm*5 μm, mobile phase: [water (NH3H2O + NH4HCO3)-ACN], B%: 28% - 58%, 7 min) to afford 3-fluoro-4-[[5-[2-fluoro-3-(trifluoromethoxy)anilino]-4-methyl-3-pyridyl]methyl]-N-(methylsulfamoyl)pyridin-2-amine (15.3 mg, 30.39 μmol). 1 H NMR (400 MHz, DMSO-d6) δ = 8.09 (d, J = 3.6 Hz, 2H), 7.94 (d, J = 5.2 Hz, 1H), 7.73 (s, 1H), 7.34 (dd, J = 1.6, 11.2 Hz, 1H), 7.04 (d, J = 9.6 Hz, 1H), 6.75 - 6.62 (m, 2H), 4.06 (s, 2H), 2.47 (s, 3H), 2.05 (s, 3H). 19 F NMR (376.5 MHz, DMSO-d6) δ = -57.451 ppm, -124.486 ppm, 138.407 ppm. LCMS R t = 1.198 min, chromatography for 3 min, 10 - 80 CD, C 20 H 19 F5N5O3S[M + H] + The ESI calculated value for is 504.1, the measured value is 504.2.

[0283] Example 40: 4-[[6-(4-chloro-2-fluorophenoxy)pyrazin-2-yl]methyl]-3-fluoro-N-(methylsulfamoyl)pyridin-2-amine

Chemical Structure

[0284] Step 2: To a solution of 2-chloro-6-(4-chloro-2-fluoro-phenoxy)pyrazine (2 g, 7.72 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.78 g, 11.58 mmol, 1.96 mL) in dioxane (25 mL) and H2O (5 mL) were added Pd(dppf)Cl2 (282.44 mg, 386.01 μmol) and Na2CO3 (2.45 g, 23.16 mmol). The mixture was stirred at 100 °C for 12 h. The mixture was poured into saturated NH4Cl (25 mL) and extracted with EtOAc (25 mL×3). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by flash chromatography on silica gel (dichloromethane in petroleum ether = 0~50%) to afford 2-(4-chloro-2-fluoro-phenoxy)-6-vinyl-pyrazine (1.6 g, 6.38 mmol). 1 1H NMR (400 MHz, CDCl3) δ = 8.33 (s, 1H), 8.24 (s, 1H), 7.26 - 7.16 (m, 3H), 6.64 (dd, J = 10.8, 17.2 Hz, 1H), 6.09 (d, J = 17.2 Hz, 1H), 5.49 (d, J = 10.8 Hz, 1H). 19 19F NMR (376.5 MHz, CDCl3) δ = -123.866 ppm.

[0285] Step 3: To a solution of 2-(4-chloro-2-fluoro-phenoxy)-6-vinylpyrazine (1.6 g, 6.38 mmol) in THF (20 mL) and H2O (2.5 mL) was added NaIO4 (5.46 g, 25.53 mmol, 1.41 mL) and K2OsO4·2H2O (235.19 mg, 638.33 μmol). The mixture was stirred at 25 °C for 2 h. The resulting solution was diluted with water (10 mL) and quenched with saturated Na2SO3 solution (20 mL) until the KI test paper turned white. The mixture was extracted with ethyl acetate (10 mL × 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (dichloromethane in petroleum ether = 0 - 50%) to afford 6-(4-chloro-2-fluoro-phenoxy)pyrazine-2-carbaldehyde (1.5 g, 5.94 mmol). 1 1H NMR (400 MHz, CDCl3) δ = 9.85 (s, 1H), 8.89 (s, 1H), 8.72 (s, 1H), 7.29 - 7.22 (m, 3H). 19 19F NMR (376.5 MHz, CDCl3) δ = -123.641 ppm.

[0286] Step 4: To a solution of 6-(4-chloro-2-fluoro-phenoxy)pyrazine-2-carbaldehyde (1.6 g, 6.33 mmol) in THF (15 mL) was added 4-methylbenzenesulfonohydrazide (1.30 g, 6.97 mmol). The mixture was stirred at 60 °C for 4 h. The mixture was concentrated. The crude product was triturated with MeOH (5 mL) and purified by preparative HPLC (column: Xtimate C18 150×40 mm×10 μm, mobile phase: [water (FA)-ACN], B%: 52% - 82%, 7 min) to give N-[(E)-[6-(4-chloro-2-fluoro-phenoxy)pyrazin-2-yl]methylideneamino]-4-methyl-benzenesulfonamide (1.9 g, 4.51 mmol). 11H NMR (400 MHz, CDCl3) δ = 11.84 (s, 1H), 8.56 (s, 1H), 8.35 (s, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.41 - 7.37 (m, 4H), 7.26 - 7.20 (m, 2H), 2.40 (s, 3H). 19 19F NMR (376.5 MHz, CDCl3) δ = -124.630 ppm.

[0287] Step 5: To a solution of N-[(E)-[6-(4-chloro-2-fluoro-phenoxy)pyrazin-2-yl]methyleneamino]-4-methyl-benzenesulfonamide (300 mg, 712.85 mmol) and [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoro-4-pyridyl]boronic acid (654.60 mg, 2.14 mmol, Example 30) in dioxane (2 mL) was added K2CO3 (295.56 mg, 2.14 mmol). The mixture was stirred at 110 °C for 4 h. The mixture was concentrated. The crude product was purified by flash chromatography on silica gel (ethyl acetate in petroleum ether = 0 - 50%) and flash chromatography on silica gel (ethyl acetate in petroleum ether = 0 - 50%) to give 4-[[6-(4-chloro-2-fluoro-phenoxy)pyrazin-2-yl]methyl]-N-[(2,4-dimethoxyphenyl)methyl]-3-fluoro-pyridin-2-amine (160 mg, 320.70 mmol). LCMS R t = 0.851 min, chromatography for 1.5 min, 5 - 95 AB, C 25 H 22 ClF2N4O3 [M + H] + The ESI calculated value for 499.1, measured value 499.1.

[0288] Step 6: TFA (1 mL) was added to a solution of [[6-(4-chloro-2-fluoro-phenoxy)pyrazin-2-yl]methyl]-N-[(2,4-dimethoxyphenyl)methyl]-3-fluoro-pyridin-2-amine (160 mg, 320.70 mmol). The mixture was stirred at 25 °C for 1 h. The mixture was added dropwise to H2O (3 mL) at 0 °C. The mixture was slowly adjusted to pH = 7 with saturated NaHCO3 solution at 0 °C, and the aqueous layer was extracted with EtOAc (5 mL × 2). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (ethyl acetate in petroleum ether = 0 - 50%) to give [[6-(4-chloro-2-fluoro-phenoxy)pyrazin-2-yl]methyl]-3-fluoro-pyridin-2-amine (50 mg, 143.38 umol). LCMS R t = 1.42 min, 3.0 min chromatography, 5 - 95 CD, C 16 H 12 ClF2N4O [M + H] + The ESI calculated value of 349.1, measured value 349.0.

[0289] Step 7: Py (90.73 mg, 1.15 mmol, 92.58 mL) was added to a solution of [[6-(4-chloro-2-fluoro-phenoxy)pyrazin-2-yl]methyl]-3-fluoro-pyridin-2-amine (40 mg, 114.70 mmol) and N-methylsulfamoyl chloride (74.31 mg, 573.50 mmol) in MeCN (1 mL). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated. The crude product was purified by preparative HPLC (column: Boston Prime C18 150×30 mm×5 um, mobile phase: [water (NH3H2O + NH4HCO3)-ACN], B%: 32% - 62%, 7 min) to give [[6-(4-chloro-2-fluoro-phenoxy)pyrazin-2-yl]methyl]-3-fluoro-N-(methylsulfamoyl)pyridin-2-amine (4.9 mg, 11.09 umol). 11H NMR (400 MHz, CDCl3) δ = 8.37 (s, 1H), 8.24 (s, 1H), 7.91 (d, J = 4.8 Hz, 1H), 7.21 - 7.09 (m, 4H), 6.71 (t, J = 5.2 Hz, 1H), 5.48 (br s, 1H), 3.99 (s, 2H), 2.72 (d, J = 5.2 Hz, 3H). 19 19F NMR (376.5 MHz, CDCl3) δ = -123.484, -143.314 ppm. LCMS R t = 0.881 min, chromatography for 1.5 minutes, with 5 - 95 AB, C 17 H 15 ClF2N5O3S [M + H] + The ESI calculated value is 442.1, the measured value is 441.9.

[0290] Example 41: 7 - Fluoro - N - [5 - [[3 - fluoro - 2 - (methylsulfamoyl amino) - 4 - pyridyl]methyl] - 4 - methyl - 3 - pyridyl] - 2,3 - dihydro - [1,4] dioxino [2,3 - b] pyridin - 6 - amine

Chemical Structure

Chemical Structure

[0291] Step 2: To a solution of 5-fluoro-2,6-diiodo-pyridin-3-ol (5 g, 13.70 mmol) in DMF (50 mL) was added Cs2CO3 (13.39 g, 41.11 mmol) and 2-bromoethoxy-tert-butyl-dimethyl-silane (3.61 g, 15.07 mmol). The mixture was stirred at 80 °C for 3 h. The resulting mixture was filtered and the filter cake was washed with DCM (50 mL×3). The filtrate was concentrated. The crude was purified by flash chromatography on silica gel (EtOAc in PE = 10%) to give tert-butyl-[2-[(5-fluoro-2,6-diiodo-3-pyridyl)oxy]ethoxy]-dimethyl-silane (4.7 g, 8.98 mmol). 1 H NMR(400MHz,CDCl3)δ=6.88(d,J=8.4Hz,1H),4.16-4.11(m,2H),4.04-3.99(m,2H),0.89(s,9H),0.13(s,6H).

[0292] Step 3: A solution of tert-butyl-[2-[(5-fluoro-2,6-diiodo-3-pyridyl)oxy]ethoxy]-dimethyl-silane (4.5 g, 8.60 mmol) in HCl / MeOH (4 M, 22.50 mL) was stirred at 25 °C for 2 h. The mixture was concentrated. The mixture was added to NH3 / MeOH (3 mL) and adjusted to pH = 7. The mixture was concentrated. The mixture was purified by flash chromatography on silica gel (EtOAc in petroleum ether = 0~10%) to give 2-[(5-fluoro-2,6-diiodo-3-pyridyl)oxy]ethanol (2.9 g, 7.09 mmol). 1 H NMR(400MHz,DMSO-d6)δ=7.50(d,J=9.6Hz,1H),4.94(t,J=5.2Hz,1H),4.14(t,J=5.2Hz,2H),3.74(q,J=5.2Hz,2H).

[0293] Step 4: To a solution of 2-[(5-fluoro-2,6-diiodo-3-pyridyl)oxy]ethanol (1.7 g, 4.16 mmol) in t-BuOH (24 mL) was added t-BuOK (559.78 mg, 4.99 mmol). The mixture was stirred at 90 °C for 3 h. The mixture was poured into water (20 mL). The aqueous layer was extracted with EtOAc (30 mL × 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The mixture was purified by flash chromatography on silica gel (DCM in petroleum ether = 0 - 100%) to give 7-fluoro-6-iodo-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (450 mg, 1.60 mmol). 1 H NMR (400 MHz, DMSO-d6) δ = 7.44 (d, J = 7.6 Hz, 1H), 4.46 - 4.36 (m, 2H), 4.31 - 4.23 (m, 2H).

[0294] Step 5: 7-Fluoro-6-iodo-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (228.29 mg, 812.34 μmol) and Pd2(dba)3 (24.80 mg, 27.08 μmol) were added under nitrogen to a solution of tert-butyl N-[4-[(5-amino-4-methyl-3-pyridyl)methyl]-3-fluoro-2-pyridyl]carbamate (180 mg, 541.56 μmol) in dioxane (5 mL). The medium was degassed under N2 for 5 min before adding Cs2CO3 (247.03 mg, 758.19 μmol) and Xantphos (31.34 mg, 54.16 μmol). The reaction medium was stirred at 80 °C for 2 h. The mixture was concentrated. The mixture was purified by flash chromatography on silica gel (DCM in petroleum ether = 0 - 100%) to give tert-butyl N-[3-fluoro-4-[[5-[(7-fluoro-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)amino]-4-methyl-3-pyridyl]methyl]-2-pyridyl]carbamate (200 mg, 411.96 μmol). 11H NMR (400 MHz, CDCl3) δ = 8.90 (s, 1H), 8.22 - 8.01 (m, 2H), 7.04 (d, J = 10.0 Hz, 1H), 6.93 (br s, 1H), 6.62 (t, J = 5.2 Hz, 1H), 5.96 (br s, 1H), 4.39 - 4.34 (m, 2H), 4.21 - 4.18 (m, 2H), 4.05 (s, 2H), 2.11 (s, 3H), 1.53 (s, 9H).

[0295] Step 6: A solution of tert-butyl N-[3-fluoro-4-[[5-[(7-fluoro-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)amino]-4-methyl-3-pyridyl]methyl]-2-pyridyl]carbamate (200 mg, 411.96 μmol) in HCl / MeOH (4 mL) was stirred at 25 °C for 3 h. The mixture was concentrated. The mixture was added to NH3 / MeOH (3 mL) and adjusted to pH = 7. The mixture was purified by flash chromatography on silica gel (MeOH in DCM = 0 - 10%) to give N-[5-[(2-amino-3-fluoro-4-pyridyl)methyl]-4-methyl-3-pyridyl]-7-fluoro-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-amine (110 mg, 285.44 μmol). LCMS Rt = 0.612 min, chromatography for 1.5 min, 5 - 95 AB, ESI calculated value for C19H18F2N5O2 [M + H]+ 386.1, measured value 386.1.

[0296] Step 7: To a solution of N-[5-[(2-amino-3-fluoro-4-pyridyl)methyl]-4-methyl-3-pyridyl]-7-fluoro-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-amine (60 mg, 155.70 μmol) in MeCN (1 mL) were added Py (123.16 mg, 1.56 mmol, 125.67 μL) and methylsulfamoyl chloride (100.86 mg, 778.48 μmol) at 25 °C. The mixture was stirred at 25 °C for 24 h. The mixture was concentrated. The mixture was purified by preparative HPLC (column: Phenomenex C18 75×30 mm×3 μm, mobile phase: [water (NH3H2O + NH4HCO3)-ACN], B%: 15% - 45%, 8 min) to give 7-fluoro-N-[5-[[3-fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]-4-methyl-3-pyridyl]-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-amine (36.2 mg, 75.66 μmol). 1 1H NMR (400 MHz, CDCl3) δ = 8.89 (br s, 1H), 8.15 (br s, 1H), 7.93 (d, J = 5.2 Hz, 1H), 7.05 (d, J = 10.0 Hz, 1H), 6.58 (t, J = 5.2 Hz, 1H), 5.97 (br s, 1H), 5.52 (br s, 1H), 4.46 - 4.27 (m, 2H), 4.25 - 4.10 (m, 2H), 4.04 (s, 2H), 2.76 (s, 3H), 2.04 (s, 3H) were obtained. 19 19F NMR (376.5 MHz, CDCl3) δ = -142.641, -145.030 ppm. LCMS Rt = 0.709 min, chromatography for 1.5 min, 5 - 95 AB, C 20 H 21 F2N6O4S [M + H] + The ESI calculated value for 479.1, measured value 479.2.

[0297] Example 42: 3-Fluoro-4-[[5-[(6-fluoro-2,3-dihydro-1,4-benzoxazin-7-yl)amino]-4-methyl-3-pyridyl]methyl]-N-(methylsulfamoyl)pyridin-2-amine

Chemical formula

Chem.

[0298] Step 2: To a solution of 6-fluoro-2,3-dihydro-1,4-benzodioxine (1.3 g, 8.43 mmol) in MeCN (20 mL) was added NBS (2.25 g, 12.65 mmol) and TFA (96.17 mg, 843.40 μmol, 62.45 mL). The mixture was stirred at 25 °C for 16 h. Water (50 mL) was added and the mixture was extracted with EtOAc (30 mL × 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give 6-bromo-7-fluoro-2,3-dihydro-1,4-benzodioxine (1.7 g, 7.30 mmol) 1 1H NMR (400 MHz, CDCl3) δ = 7.03 (d, J = 6.4 Hz, 1H), 6.68 (d, J = 9.2, Hz, 1H), 4.26~4.21 (m, 4H) was obtained. 19 19F NMR (376.5 MHz, CDCl3) δ = -116.066.

[0299] Step 3: To a solution of 6-bromo-7-fluoro-2,3-dihydro-1,4-benzodioxin (50 mg, 214.56 mmol) in dioxane (1 mL) were added tert-butyl N-[4-[(5-amino-4-methyl-3-pyridyl)methyl]-3-fluoro-2-pyridyl]-N-tert-butoxycarbonyl-carbamate (92.79 mg, 214.56 mmol, Example 6), Cs2CO3 (139.82 mg, 429.12 mmol), Pd2(dba)3 (9.82 mg, 10.73 umol), and Xantphos (12.41 mg, 21.46 mmol). The mixture was stirred at 100 °C for 4 h. Water (20 mL) was added and the mixture was extracted with EtOAc (20 mL × 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash column chromatography on silica gel (EtOAc in petroleum ether = 0 - 80%) to give tert-butyl N-tert-butoxycarbonyl-N-[3-fluoro-4-[[5-[(6-fluoro-2,3-dihydro-1,4-benzodioxin-7-yl)amino]-4-methyl-3-pyridyl]methyl]-2-pyridyl]carbamate (70 mg, 119.74 mmol). LCMS R t = 0.818 min, 1.5 min chromatography, 5 - 95 AB, C 30 H 35 F2N4O6[M + H] + The ESI calculated value of 585.2, measured value 585.3.

[0300] Step 4: HCl / MeOH (3 mL) was added to a solution of tert-butoxycarbonyl-N-[3-fluoro-4-[[5-[(6-fluoro-2,3-dihydro-1,4-benzoxazin-7-yl)amino]-4-methyl-3-pyridyl]methyl]-2-pyridyl]carbamate (70 mg, 119.74 mmol) in DCM (1 mL). The mixture was stirred at 25 °C for 1 h. The mixture was adjusted to pH = 9 with NH3.MeOH (7 M, 10 mL) and concentrated. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (EtOAc in petroleum ether = 0 - 30%) to give 3-fluoro-4-[[5-[(6-fluoro-2,3-dihydro-1,4-benzoxazin-7-yl)amino]-4-methyl-3-pyridyl]methyl]pyridin-2-amine (30 mg, 78.05 mmol). 1 H NMR (400 MHz, CDCl3) δ = 8.25 (s, 1H), 8.08 (s, 1H), 7.73 (d, J = 5.2 Hz, 1H), 6.69 (dd, J = 4.0, 11.6 Hz, 1H), 6.49 (d, J = 8.0 Hz, 1H), 6.26 (m, 1H), 4.23 - 4,21 (m, 4H), 3.98 (s, 2H), 2.14 (s, 3H). 19 F NMR (376.5 MHz, CDCl3) δ = -138.566, -145.341.

[0301] Step 5: To a solution of 3-fluoro-4-[[5-[(6-fluoro-2,3-dihydro-1,4-benzodioxin-7-yl)amino]-4-methyl-3-pyridyl]methyl]pyridin-2-amine (20 mg, 52.03 mmol) in MeCN (1 mL) was added N-methylsulfamoyl chloride (33.71 mg, 260.16 mmol) and Py (41.16 mg, 520.32 mmol, 42.00 mL). The mixture was stirred at 40 °C for 1 h. The mixture was concentrated and purified by preparative HPLC (column: Boston Prime C18 150*30 mm*5um, mobile phase: [water (NH3H2O + NH4HCO3)-ACN], B%: 22% - 52%, 7 min) to afford 3-fluoro-4-[[5-[(6-fluoro-2,3-dihydro-1,4-benzodioxin-7-yl)amino]-4-methyl-3-pyridyl]methyl]-N-(methylsulfamoyl)pyridin-2-amine (3.1 mg, 6.49 umol). 1 H NMR (400 MHz, DMSO-d6) δ = 10.38 (brs, 1H), 7.98 (d, J = 4.8 Hz, 1H), 7.92 (s, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.13 (s, 1H), 7.00 - 6.99 (m, 1H), 6.84 (brs, 1H), 6.72 (s, 1H), 6.45 (d, J = 8.0 Hz, 1H), 4.21 - 4.19 (m, 4H), 4.05 (s, 2H), 2.49 (s, 3H), 2.07 (s, 3H). 19 F NMR (376.5 MHz, DMSO-d6) δ = -131.509, -138.306. LCMS R t = 0.636 min, chromatography for 1.5 min, with 5 - 95 AB, C 21 H 22 F2N5O4S [M + H] + The ESI calculated value for is 478.1, the measured value is 478.1.

[0302] Example 43: 4-({5-[(4-chloro-2-fluorophenyl)amino]-4-methylpyridin-3-yl}methyl)-N-methyl-2H,3H-pyrrolo[2,3-b]pyridine-1-sulfonamide

Chemical Structure

Chem.

[0303] Step 2: To a stirred mixture of methyl 5-[(4-chloro-2-fluorophenyl)amino]-4-methylpyridine-3-carboxylate (473 mg, 1.605 mmol) and CaCl₂ (890.60 mg, 8.025 mmol, 5.0 equiv) in MeOH (5 mL) was added NaBH₄ (607.16 mg, 16.050 mmol, 10.0 equiv) portionwise at 0 °C. The resulting mixture was stirred at 0 °C for 1 h under a nitrogen atmosphere. The desired product could be detected by LCMS. The reaction was quenched with NH₄Cl(aq.) (50 mL) at 0 °C. The resulting mixture was extracted with EA (3 × 50 mL). The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH₂Cl₂ / MeOH (10:1) to give {5-[(4-chloro-2-fluorophenyl)amino]-4-methylpyridin-3-yl}methanol (470 mg). LCMS: (ESI, m / z): [M+1] + =267.00. 1 H NMR (400 MHz, chloroform-d) δ 8.39 (s, 1H), 8.32 (s, 1H), 7.19 - 7.12 (m, 1H), 7.03 - 6.95 (m, 1H), 6.74 (t, J = 8.8 Hz, 1H), 5.47 (s, 1H), 4.78 (s, 2H), 2.30 (s, 3H).

[0304] Step 3: To a stirred solution of {5-[(4-chloro-2-fluorophenyl)amino]-4-methylpyridin-3-yl}methanol (100 mg, 0.375 mmol) in DCM (2 mL) was added SOCl₂ (89.21 mg, 0.750 mmol) dropwise at 0 °C. The resulting mixture was stirred at 50 °C for 16 h under a nitrogen atmosphere. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. This gave N-(4-chloro-2-fluorophenyl)-5-(chloromethyl)-4-methylpyridin-3-amine (80 mg). LCMS: (ESI, m / z): [M+1] + =285.10. 11H NMR (400 MHz, chloroform-d) δ 8.42 (s, 1H), 8.31 (s, 1H), 7.17 - 7.13 (m, 1H), 7.02 - 6.97 (m, 1H), 6.82 - 6.73 (m, 1H), 5.47 (s, 1H), 4.65 (s, 2H), 2.35 (s, 3H).

[0305] Step 4: To a stirred solution of 4-bromo-1H,2H,3H-pyrrolo[2,3-b]pyridine (450 mg, 2.261 mmol) and TEA (686.31 mg, 6.783 mmol, 3 equiv) in DCM (5 mL) was added (Boc)2O (740.10 mg, 3.392 mmol, 1.5 equiv) and DMAP (27.62 mg, 0.226 mmol, 0.1 equiv) at 0 °C. After stirring at room temperature for 4 h under a nitrogen atmosphere, the desired product could be detected by LCMS. The resulting mixture was extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (1 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (3:1) to give tert-butyl 4-bromo-2H,3H-pyrrolo[2,3-b]pyridine-1-carboxylate (475 mg). LCMS: (ESI, m / z): [M+1] + = 299.10. 1 1H NMR (400 MHz, chloroform-d) δ 8.07 - 8.01 (m, 1H), 6.98 (d, J = 5.6 Hz, 1H), 4.08 - 3.99 (m, 2H), 3.09 - 2.99 (m, 2H), 1.56 (s, 9H).

[0306] Step 5: To a solution of tert-butyl 4-bromo-2H,3H-pyrrolo[2,3-b]pyridine-1-carboxylate (300 mg, 1.0 mmol) and 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (305.57 mg, 1.20 mmol) in dioxane (5 mL) were added AcOK (196.83 mg, 2.006 mmol) and Pd(PPh3)2Cl2 (70.39 mg, 0.100 mmol, 0.1 equiv). After stirring at 80 °C for 2 h under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was treated with formic acid (2 mL) at room temperature for 2 h under a nitrogen atmosphere. The desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN in water (0.1% FA), gradient of 5% to 50% in 25 min; detector, UV 254 nm. This gave 1-(tert-butoxycarbonyl)-2H,3H-pyrrolo[2,3-b]pyridin-4-ylboronic acid (55 mg). LCMS: (ESI, m / z): [M+1] + =265.00.

[0307] Step 6: To a solution of N-(4-chloro-2-fluorophenyl)-5-(chloromethyl)-4-methylpyridin-3-amine (10 mg, 0.035 mmol) and 1-(tert-butoxycarbonyl)-2H,3H-pyrrolo[2,3-b]pyridin-4-ylboronic acid (13.89 mg, 0.053 mmol, 1.5 equiv) in dioxane (1 mL) were added K3PO4 (14.89 mg, 0.070 mmol), PPh3 (1.84 mg, 0.007 mmol, 0.2 equiv) and Pd(OAc)2 (0.79 mg, 0.004 mmol, 0.1 equiv). The resulting mixture was stirred at 80 °C for 16 h under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to give the crude product (30 mg). LCMS: (ESI, m / z): [M+1] + =469.30.

[0308] Step 7: TFA (0.1 mL) was added to a stirred mixture of tert-butyl 4-({5-[(4-chloro-2-fluorophenyl)amino]-4-methylpyridin-3-yl}methyl)-2H,3H-pyrrolo[2,3-b]pyridine-1-carboxylate (30 mg, 0.064 mmol) in DCM (0.4 mL) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The desired product could be detected by LCMS. The reaction mixture was concentrated under vacuum. The residue was basified to pH 10 with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with EA (3 × 10 mL). The combined organic layers were washed with brine (1 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, ACN in water (10 mmol / L NH4HCO3), gradient 5% - 70% in 30 min, detector, UV 254 nm. Thereby, N-(4-chloro-2-fluorophenyl)-4-methyl-5-{1H,2H,3H-pyrrolo[2,3-b]pyridin-4-ylmethyl}pyridin-3-amine (10 mg) was obtained. LCMS: (ESI, m / z): [M + 1] + = 369.30. 1 H NMR (400 MHz, chloroform-d) δ 8.39 (s, 1H), 8.17 (s, 1H), 7.71 (d, J = 5.5 Hz, 1H), 7.12 (dd, J = 10.9, 2.3 Hz, 1H), 7.01 - 6.91 (m, 1H), 6.71 (t, J = 8.9 Hz, 1H), 6.15 (d, J = 5.5 Hz, 1H), 5.42 (s, 1H), 4.68 (s, 1H), 3.86 (s, 2H), 3.65 (t, J = 8.4 Hz, 2H), 2.98 (t, J = 8.4 Hz, 2H), 2.10 (s, 3H).

[0309] Step 8: To a stirred solution of N-(4-chloro-2-fluorophenyl)-4-methyl-5-{1H,2H,3H-pyrrolo[2,3-b]pyridin-4-ylmethyl}pyridin-3-amine (8 mg, 0.022 mmol) and pyridine (8.58 mg, 0.110 mmol, 5 eq) in DMA (0.5 mL) was added N-methylsulfamoyl chloride (5.62 mg, 0.044 mmol) in DMA (0.2 mL) dropwise at 0 °C under an atmosphere of air. The resulting mixture was stirred at room temperature for 2 h. The desired product could be detected by LCMS. The reaction mixture was diluted with water (10 mL) and extracted with EA (3 × 10 mL). The combined organic layers were washed with brine (1 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column: Aeris PEPTIDE 5um XB-C18 Axia, 21.2 mm × 250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN, flow rate: 60 mL / min, gradient: 33% B - 51% B in 10 min, wavelength: 220 / 254 nm; RT1 (min): 11.37. This gave 4-({5-[(4-chloro-2-fluorophenyl)amino]-4-methylpyridin-3-yl}methyl)-N-methyl-2H,3H-pyrrolo[2,3-b]pyridine-1-sulfonamide (5.6 mg). LCMS: (ESI, m / z): [M+1] + =462.10. 1 H NMR (400 MHz, methanol-d4) δ 8.11 (d, J = 1.0 Hz, 1H), 8.05 (s, 1H), 7.99 - 7.93 (m, 1H), 7.23 - 7.15 (m, 1H), 7.06 - 6.98 (m, 1H), 6.71 (t, J = 8.9 Hz, 1H), 6.54 (d, J = 5.4 Hz, 1H), 4.08 - 4.00 (m, 4H), 3.09 (t, J = 8.4 Hz, 2H), 2.65 (s, 3H), 2.12 (s, 3H). 19 F NMR (377 MHz, methanol-d4) δ -128.128.

[0310] Example 44: [(4-{[5-(4-chloro-2-fluorophenyl)-4-methylpyridin-3-yl]methyl}-3-fluoropyridin-2-yl)sulfamoyl](methyl)amine

Chemical formula

Chemical formula

[0311] Step 2: A mixture of 3-bromo-5-(4-chloro-2-fluorophenyl)-4-methylpyridine (400 mg, 1.331 mmol), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (405.55 mg, 1.597 mmol, 1.2 equiv), AcOK (261.22 mg, 2.662 mmol), and Pd(dppf)Cl2 (97.38 mg, 0.133 mmol, 0.1 equiv) in dioxane (5 mL) was stirred at 100 °C for 16 h under a nitrogen atmosphere. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. Thereby, 3-(4-chloro-2-fluorophenyl)-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine was obtained. LCMS: (ESI, m / z): [M+1] + = 348.25.

[0312] Step 3: A mixture of tert-butyl N-[4-(bromomethyl)-3-fluoropyridin-2-yl]-N-(tert-butoxycarbonyl)carbamate (200 mg, 0.494 mmol), 3-(4-chloro-2-fluorophenyl)-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (257.33 mg, 0.741 mmol, 1.5 equiv), K2CO3 (204.61 mg, 1.482 mmol, 3 equiv), and Pd(dppf)Cl2 (36.11 mg, 0.049 mmol, 0.1 equiv) in dioxane (5 mL) and H2O (0.5 mL) was stirred at 80 °C for 2 h under a nitrogen atmosphere. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (2:1), to give tert-butyl N-(tert-butoxycarbonyl)-N-(4-{[5-(4-chloro-2-fluorophenyl)-4-methylpyridin-3-yl]methyl}-3-fluoropyridin-2-yl)carbamate (83 mg). LCMS: (ESI, m / z): [M+1] + = 546.25. 11H NMR (300 MHz, chloroform-d) δ 8.40 (d, J = 10.1 Hz, 2H), 8.22 (d, J = 3.8 Hz, 1H), 7.27 - 7.16 (m, 3H), 6.95 (s, 1H), 4.14 (s, 2H), 2.09 (s, 3H), 1.41 (s, 18H). 19 19F NMR (282 MHz, chloroform-d) δ -111.27, -130.87.

[0313] Step 4: To a stirred solution of tert-butyl N-(tert-butoxycarbonyl)-N-(4-{[5-(4-chloro-2-fluorophenyl)-4-methylpyridin-3-yl]methyl}-3-fluoropyridin-2-yl)carbamate (73 mg, 0.134 mmol) in DCM (0.8 mL), TFA (0.2 mL) was added dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 hour. The desired product could be detected by LCMS. The reaction mixture was basified to pH 10 with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with EA (3 × 10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, ACN in water (10 mmol / L NH4HCO3), gradient from 5% to 70% in 30 minutes, detector, UV 254 nm. Thereby, 4-{[5-(4-chloro-2-fluorophenyl)-4-methylpyridin-3-yl]methyl}-3-fluoropyridin-2-amine (37 mg) was obtained. LCMS: (ESI, m / z): [M+1] + = 345.95. 1 1H NMR (400 MHz, chloroform-d) δ 8.38 (d, J = 24.3 Hz, 2H), 7.72 (d, J = 5.4 Hz, 1H), 7.26 - 7.16 (m, 3H), 6.32 (t, J = 5.2 Hz, 1H), 5.11 (s, 2H), 4.05 (s, 2H), 2.09 (d, J = 1.8 Hz, 3H). 19 19F NMR (376 MHz, chloroform-d) δ -111.28, -144.13.

[0314] Step 5: To a stirred solution of 4-{[5-(4-chloro-2-fluorophenyl)-4-methylpyridin-3-yl]methyl}-3-fluoropyridin-2-amine (30 mg, 0.087 mmol) in DMA (1 mL) was added dropwise pyridine (34.31 mg, 0.435 mmol, 5 equiv) and N-methylsulfamoyl chloride (13.49 mg, 0.104 mmol, 1.2 equiv) in DMA (0.2 mL) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The desired product could be detected by LCMS. The reaction mixture was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN in water (10 mmol / L NH4HCO3), gradient 5% to 60% in 30 min; detector, UV 254 nm. This gave [(4-{[5-(4-chloro-2-fluorophenyl)-4-methylpyridin-3-yl]methyl}-3-fluoropyridin-2-yl)sulfamoyl](methyl)amine (21 mg). LCMS: (ESI, m / z): [M+1] + =439.05. 1 H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.41 (s, 1H), 8.31 (s, 1H), 8.00 (d, J = 4.9 Hz, 1H), 7.63 - 7.57 (m, 1H), 7.48 - 7.40 (m, 2H), 7.00 (s, 1H), 6.77 (s, 1H), 4.15 (s, 2H), 3.36 (s, 3H), 2.04 (d, J = 1.5 Hz, 3H). 19 F NMR (377 MHz, DMSO-d6) δ -111.87, -138.03.

[0315] Example 45: 4-[[5-(4-chloro-2-fluoro-anilino)-4-methyl-3-pyridyl]methyl]-3-methoxy-N-(methylsulfamoyl)pyridin-2-amine

Chemical formula

Chemical formula

[0316] Step 2: Tribromophosphane (3.23 g, 11.92 mmol, 1.12 mL) was added dropwise to a solution of (2-bromo-3-methoxy-4-pyridyl)methanol (2 g, 9.17 mmol) in DCM (20 mL) at 0 °C under N2. The mixture was stirred at 25 °C for 1 hour. The mixture was added dropwise to H2O (50 mL) at 0 °C. The mixture was slowly adjusted to pH = 7 at 0 °C with saturated NaHCO3 solution. The aqueous layer was extracted with DCM (50 mL × 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain 2-bromo-4-(bromomethyl)-3-methoxypyridine (2.4 g, 8.54 mmol) 11H NMR (400 MHz, CDCl3) δ = 8.12 (d, J = 4.8 Hz, 1H), 7.274 (d, J = 4.8 Hz, 1H), 4.46 (s, 2H), 4.00 (s, 3H) was obtained.

[0317] Step 3: To a solution of 2-bromo-4-(bromomethyl)-3-methoxypyridine (2.4 g, 8.54 mmol) in toluene (16 mL) and EtOH (4 mL) were added 4-methyl-3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.88 g, 7.12 mmol), Pd(PPh3)4 (411.31 mg, 355.94 μmol), and Na2CO3 (1.51 g, 14.24 mmol) in H2O (2 mL). The mixture was stirred at 80 °C for 2 h. The reaction mixture was poured into water (20 mL) and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The mixture was purified by flash chromatography on silica gel (ethyl acetate in petroleum ether = 0 - 25%) to give 2-bromo-3-methoxy-4-[(4-methyl-5-nitro-3-pyridyl)methyl]pyridine (1.24 g, 3.67 mmol). 1 1H NMR (400 MHz, CDCl3) δ = 8.97 (s, 1H), 8.65 (d, J = 4.8 Hz, 1H), 7.77 (d, J = 4.8 Hz, 1H), 4.16 (s, 2H), 3.91 (s, 3H), 2.39 (s, 3H).

[0318] Step 4: SnCl2·2H2O (4.00 g, 17.74 mmol) was added to a solution of 2-bromo-3-methoxy-4-[(4-methyl-5-nitro-3-pyridyl)methyl]pyridine (1.2 g, 3.55 mmol) in EtOH (5 mL) and EtOAc (5 mL). The mixture was stirred at 90 °C for 2 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to remove EtOH. Saturated NaHCO3 solution was added to the reaction mixture until pH = 10. The mixture was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (ethyl acetate in petroleum ether = 0 - 25%) to give 5-[(2-bromo-3-methoxy-4-pyridyl)methyl]-4-methyl-pyridin-3-amine (1.04 g, 3.37 mmol). 1 H NMR (400 MHz, CDCl3) δ = 8.01 (s, 1H), 7.98 (d, J = 4.8 Hz, 1H), 7.84 (s, 1H), 6.73 (d, J = 4.8 Hz, 1H), 4.08 (s, 2H), 3.90 (s, 3H), 3.71 (br s, 2H), 1.94 (s, 3H).

[0319] Step 5: To a solution of 5-[(2-bromo-3-methoxy-4-pyridyl)methyl]-4-methyl-pyridin-3-amine (950 mg, 3.08 mmol) in dioxane (10 mL) were added 4-chloro-2-fluoro-1-iodo-benzene (1.58 g, 6.17 mmol), Pd(OAc)2 (69.21 mg, 308.27 μmol), Xantphos (356.74 mg, 616.54 μmol) and Cs2CO3 (2.01 g, 6.17 mmol). The mixture was stirred at 70 °C for 3 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The mixture was purified by flash chromatography on silica gel (ethyl acetate in petroleum ether = 0 - 25%) to afford 5-[(2-bromo-3-methoxy-4-pyridyl)methyl]-N-(4-chloro-2-fluoro-phenyl)-4-methyl-pyridin-3-amine (1 g, 2.29 mmol). 1 H NMR (400 MHz, CDCl3) δ = 8.37 (s, 1H), 8.16 (s, 1H), 8.03 (d, J = 4.8 Hz, 1H), 7.12 (dd, J = 10.8 Hz, 2.4 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.82 - 6.77 (m, 2H), 5.52 (br s, 1H), 4.10 (s, 2H), 3.91 (s, 3H, 2.11 (s, 3H).

[0320] Step 6: To a solution of 5-[(2-bromo-3-methoxy-4-pyridyl)methyl]-N-(4-chloro-2-fluoro-phenyl)-4-methyl-pyridin-3-amine (500 mg, 1.14 mmol) in toluene (5 mL) were added diphenylmethanimine (249.00 mg, 1.37 mmol, 230.56 μL), Pd2(dba)3 (209.69 mg, 228.99 μmol), Xantphos (264.99 mg, 457.98 μmol), and NaOtBu (264.08 mg, 2.75 mmol). The mixture was stirred at 110 °C for 4 h. The reaction mixture was quenched with water (50 mL). The mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (ethyl acetate in petroleum ether = 0 - 100%) to give 5-[[2-(benzylideneamino)-3-methoxy-4-pyridyl]methyl]-N-(4-chloro-2-fluoro-phenyl)-4-methyl-pyridin-3-amine (200 mg, 372.42 μmol). 1 H NMR (400 MHz, CDCl3) δ = 8.36 (s, 1H), 8.02 (s, 1H), 7.91 (d, J = 4.8 Hz, 1H), 7.80 (s, 2H), 7.55 - 7.35 (m, 4H), 7.25 - 7.15 (m, 5H), 6.95 (d, J = 8H, 1H), 6.65 (t, J = 8.8 Hz, 1H), 6.40 - 6.35 (m, 1H), 5.42 (br s, 1H), 3.91 (s, 2H), 3.78 (s, 3H), 1.80 (s, 3H). 19 F NMR (376.5 MHz, CDCl3) δ = -130.571.

[0321] Step 7: To a solution of 5-[[2-(benzylideneamino)-3-methoxy-4-pyridyl]methyl]-N-(4-chloro-2-fluoro-phenyl)-4-methyl-pyridine-3-amine (200 mg, 372.42 μmol) in MeOH (0.5 mL) was added HCl / MeOH (4 M, 2 mL). The mixture was stirred at 25 °C for 5 h. The mixture was added dropwise to H2O (20 mL). The mixture was slowly adjusted to pH = 7 with saturated NaHCO3 solution. The solution was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The mixture was purified by flash chromatography on silica gel (ethyl acetate in petroleum ether = 0 - 25%) to give 4-[[5-(4-chloro-2-fluoro-anilino)-4-methyl-3-pyridyl]methyl]-3-methoxy-pyridine-2-amine (100 mg, 268.22 μmol). 1 H NMR (400 MHz, CDCl3) δ = 8.37 (s, 1H), 8.18 (s, 1H), 7.69 (d, J = 5.2 Hz, 1H), 7.10 (dd, J = 2.0 Hz, J = 10.8 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 6.69 (t, J = 8.8 Hz, 1H), 6.19 (d, J = 5.2 Hz, 1H), 5.50 (s, 1H), 4.75 (br s, 2H), 3.99 (s, 2H), 3.77 (s, 3H), 2.09 (s, 3H). 19 F NMR (376.5 MHz, CDCl3) δ = -130.614.

[0322] Step 8: To a solution of 4-[[5-(4-chloro-2-fluoro-anilino)-4-methyl-3-pyridyl]methyl]-3-methoxy-pyridine-2-amine (20 mg, 53.64 μmol) in MeCN (1 mL) was added N-methylsulfamoyl chloride (34.75 mg, 268.22 μmol, 5 equiv) and Py (42.43 mg, 536.45 μmol, 43.30 μL). The mixture was stirred at 25 °C for 1.5 h. The reaction solution was concentrated. The solid was blended with another batch prepared from 14 mg of 4-[[5-(4-chloro-2-fluoro-anilino)-4-methyl-3-pyridyl]methyl]-3-methoxy-pyridine-2-amine. The crude product was purified by preparative HPLC (column: Boston Green ODS 150*30 mm*5um, mobile phase: [water (FA)-ACN], B%: 15% - 45%, 6 min) to give 4-[[5-(4-chloro-2-fluoro-anilino)-4-methyl-3-pyridyl]methyl]-3-methoxy-N-(methylsulfamoyl)pyridine-2-amine (6 mg, 12.88 μmol). 1 H NMR (400 MHz, CDCl3) δ = 8.41 (s, 1H), 8.18 (s, 1H), 7.97 - 7.83 (m, 1H), 7.54 - 7.33 (m, 1H), 7.14 (d, J = 10.8 Hz, 1H), 6.98 (d, J = 8.8 Hz, 1H), 6.75 (t, J = 8.8 Hz, 1H), 6.50 (d, J = 4.8 Hz, 1H), 5.57 (s, 1H), 5.42 (s, 1H), 4.05 (s, 2H), 3.85 (s, 3H), 2.75 (s, 3H), 2.08 (s, 3H). 19 F NMR (376.5 MHz, CDCl3) δ = -130.176. LCMS R t = 0.674 min, 1.5 min chromatography, 5 - 95 AB, C 20 H 22 ClFN5O3S [M + H] + The ESI calculated value for 466.1, measured value 466.1.

[0323] Example 46: 5-[[5-[(5-chloro-3-fluoro-2-pyridyl)oxy]-4-methyl-3-pyridyl]methyl]-N-(methylsulfamoyl)pyridine-2-amine

Chem.

Chem.

[0324] Step 2: To a solution of 5-bromo-4-methyl-pyridin-3-amine (10 g, 53.47 mmol) in H2SO4 (50 mL) was added NaNO2 (4.06 g, 58.81 mmol) in H2O (25 mL) at 0 °C for 0.25 h. A solution of Cu(NO3)2 (258.35 g, 1.07 mol) in H2O (400 mL) was added, followed by Cu2O (8.80 g, 61.49 mmol, 6.28 mL). The mixture was stirred at 25 °C for 11.75 h. NaOH solution (1.0 M) was added to the reaction mixture until pH = 7. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The solid was purified by flash chromatography on silica gel (ethyl acetate in petroleum ether = 0 - 30%) to afford 5-bromo-4-methyl-pyridin-3-ol (6.3 g, 33.51 mmol). 11H NMR (400 MHz, CDCl3) δ = 8.17 (s, 1H), 8.06 (s, 1H), 2.38 (s, 3H). LCMS R t = 0.463 min, chromatography for 1.5 min, with 5 - 95 AB, C6H7BrNO [M + H] + ESI calculated value for + is 190.0, measured value is 189.9.

[0325] Step 3: To a solution of 5 - bromo - 4 - methyl - pyridin - 3 - ol (2 g, 10.64 mmol) in DMAC (20 mL) was added 5 - chloro - 2,3 - difluoro - pyridine (3.18 g, 21.27 mmol), CsF (2.42 g, 15.96 mmol, 588.28 μL), and TEA (3.23 g, 31.91 mmol, 4.44 mL). The mixture was stirred at 80 °C for 5 h. H2O (30 mL) was added to the mixture. The aqueous phase was extracted with EtOAc (20 mL × 3), the combined organic phases were washed with brine (20 mL × 3), dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (ethyl acetate in petroleum ether = 0 - 10%) to give 2 - [(5 - bromo - 4 - methyl - 3 - pyridyl)oxy] - 5 - chloro - 3 - fluoro - pyridine (990 mg, 3.12 mmol). 1 1H NMR (400 MHz, CDCl3) δ = 8.59 (s, 1H), 8.30 (s, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.56 (dd, J = 2.0, 8.8 Hz, 1H), 2.29 (s, 3H). 19 19F NMR (376.5 MHz, CDCl3) δ = - 134.165. LCMS R t = 0.946 min, chromatography for 1.5 min, with 5 - 95 AB, C 11 H8BrClFN2O [M + H] + ESI calculated value for + is 318.9, measured value is 318.7.

[0326] Step 4: To a solution of 2-[(5-bromo-4-methyl-3-pyridyl)oxy]-5-chloro-3-fluoro-pyridine (400 mg, 1.26 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (232.81 mg, 1.51 mmol, 256.40 μL) in dioxane (4 mL) and H2O (0.4 mL), K2CO3 (522.29 mg, 3.78 mmol) was added. The mixture was degassed and purged three times with N2, then Pd(dppf)Cl2 (92.17 mg, 125.97 μmol) was added to the mixture, which was degassed and purged three times with N2. The mixture was stirred at 80 °C for 3 h. The mixture was blended with two batches (prepared from 400 mg and 50 mg of 2-[(5-bromo-4-methyl-3-pyridyl)oxy]-5-chloro-3-fluoro-pyridine). Water (20 mL) was added and the mixture was extracted with EtOAc (30 mL × 2). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by flash chromatography on silica gel (ethyl acetate in petroleum ether = 0 - 10%) to give 3-[(5-chloro-3-fluoro-2-pyridyl)oxy]-4-methyl-5-vinyl-pyridine (500 mg, 1.89 mmol). 1 H NMR (400 MHz, CDCl3) δ = 8.55 (s, 1H), 8.28 (s, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.54 (dd, J = 2.4, 9.2 Hz, 1H), 6.85 (dd, J = 10.8, 17.6 Hz, 1H), 5.76 (dd, J = 1.2, 17.6 Hz, 1H), 5.48 (dd, J = 1.2, 10.8 Hz, 1H), 2.19 (s, 3H). 19 F NMR (376.5 MHz, CDCl3) δ = -134.356. LCMS R t = 0.791 min, 1.5 min chromatography, 5 - 95 AB, C 13 H 11 ClFN2O [M + H] + The ESI calculated value for 265.1, measured value 264.9.

[0327] Step 5: To a solution of 3-[(5-chloro-3-fluoro-2-pyridyl)oxy]-4-methyl-5-vinylpyridine (450 mg, 1.70 mmol) in THF (13.5 mL) and H2O (2.7 mL) were added K2OsO4·2H2O (62.64 mg, 170.02 μmol) and NaIO4 (1.45 g, 6.80 mmol, 376.84 μL). The mixture was stirred at 25 °C for 1 h. The mixture was blended with another batch prepared from 50 mg of 3-[(5-chloro-3-fluoro-2-pyridyl)oxy]-4-methyl-5-vinyl-pyridine. The reaction was diluted with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel (ethyl acetate in petroleum ether = 0 - 20%) to give 5-[(5-chloro-3-fluoro-2-pyridyl)oxy]-4-methyl-pyridine-3-carbaldehyde (400 mg, 1.50 mmol). 1 H NMR (400 MHz, CDCl3) δ = 10.34 (s, 1H), 8.87 (s, 1H), 8.57 (s, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.58 (dd, J = 2.4, 9.2 Hz, 1H), 2.53 (s, 3H). 19 F NMR (376.5 MHz, CDCl3) δ = -134.181. LCMS R t = 0.811 min, 1.5 min chromatography, 5 - 95 AB, C 12 H9ClFN2O2 [M + H] + ESI calculated value for 267.0, measured value 266.9.

[0328] Step 6: To a solution of 5-[(5-chloro-3-fluoro-2-pyridyl)oxy]-4-methyl-pyridine-3-carbaldehyde (300 mg, 1.13 mmol) in MeOH (4 mL) was added 4-methylbenzenesulfonohydrazide (209.52 mg, 1.13 mmol). The mixture was stirred at 60 °C for 2 h. The mixture was blended with another batch prepared in the form of 100 mg of 5-[(5-chloro-3-fluoro-2-pyridyl)oxy]-4-methyl-pyridine-3-carbaldehyde. The mixture was concentrated directly. N-[(E)-[5-[(5-chloro-3-fluoro-2-pyridyl)oxy]-4-methyl-3-pyridyl]methyleneamino]-4-methyl-benzenesulfonamide (600 mg, 1.38 mmol). 1 H NMR (400 MHz, CDCl3) δ = 8.66 (s, 1H), 8.35 (s, 1H), 8.01 (s, 1H), 7.86 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 2.4 Hz, 1H), 7.55 (dd, J = 2.4, 9.2 Hz, 1H), 7.32 (d, J = 8.4 Hz, 2H), 2.42 (s, 3H), 2.25 (s, 3H). 19 F NMR (376.5 MHz, CDCl3) δ = -134.211. LCMS R t = 0.867 min, 1.5 min chromatography, 5 - 95 AB, C 19 H 17 ClFN4O3S [M + H] + The ESI calculated value for 435.1, measured value 434.9.

[0329] Step 7: To a solution of N-[(E)-[5-[(5-chloro-3-fluoro-2-pyridyl)oxy]-4-methyl-3-pyridyl]methyleneamino]-4-methyl-benzenesulfonamide (240 mg, 551.89 μmol) and [6-(tert-butoxycarbonylamino)-3-pyridyl]boronic acid (262.75 mg, 1.10 mmol) in dioxane (3 mL) was added K2CO3 (228.82 mg, 1.66 mmol). The mixture was stirred at 110 °C for 2 h. The mixture was blended with another batch in which 30 mg of N-[(E)-[5-[(5-chloro-3-fluoro-2-pyridyl)oxy]-4-methyl-3-pyridyl]methyleneamino]-4-methyl-benzenesulfonamide was prepared. H2O (30 mL) was added to the mixture. The aqueous phase was extracted with EtOAc (30 mL × 3). The combined organic phases were washed with brine (20 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (ethyl acetate in petroleum ether = 0 - 60%) to give tert-butyl N-[5-[[5-[(5-chloro-3-fluoro-2-pyridyl)oxy]-4-methyl-3-pyridyl]methyl]-2-pyridyl]carbamate (140 mg, 314.69 μmol). 1 H NMR (400 MHz, CDCl3) δ = 8.32 (s, 1H), 8.28 (s, 1H), 8.05 (d, J = 2.0 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.56 - 7.52 (m, 2H), 7.43 (dd, J = 2.0, 8.8 Hz, 1H), 3.99 (s, 2H), 2.07 (s, 3H), 1.52 (s, 9H). 19 F NMR (376.5 MHz, CDCl3) δ = -134.319. LCMS R t = 0.840 min, 1.5 min chromatography, 5 - 95 AB, C 22 H 23 ClFN4O3 [M + H] + The ESI calculated value for 445.1, measured value 445.1.

[0330] Step 8: To a solution of tert-butyl N-[5-[[5-[(5-chloro-3-fluoro-2-pyridyl)oxy]-4-methyl-3-pyridyl]methyl]-2-pyridyl]carbamate (120 mg, 269.73 μmol) in MeOH (2 mL) was added HCl / MeOH (4 M, 2.70 mL). The mixture was stirred at 25 °C for 2 h. The mixture was blended with another batch prepared from 20 mg of N-[5-[[5-[(5-chloro-3-fluoro-2-pyridyl)oxy]-4-methyl-3-pyridyl]methyl]-2-pyridyl]carbamate. Saturated NaHCO3 solution was added to the mixture until pH = 7. The reaction mixture was extracted with EtOAc (30 mL×3), and the combined organic phases were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The crude was purified by flash chromatography on silica gel (dichloromethane in methanol = 0 - 10%) to afford 5-[[5-[(5-chloro-3-fluoro-2-pyridyl)oxy]-4-methyl-3-pyridyl]methyl]pyridin-2-amine (100 mg, 290.05 μmol). 1 H NMR (400 MHz, CDCl3) δ = 8.28 (d, J = 6.4 Hz, 2H), 7.88 (s, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.53 (dd, J = 2.0, 9.2 Hz, 1H), 7.22 (dd, J = 2.4, 8.8 Hz, 1H), 6.49 (d, J = 8.8 Hz, 1H), 4.63 (br s, 2H), 3.90 (s, 2H), 2.08 (s, 3H). 19 F NMR (376.5 MHz, CDCl3) δ = -134.368. LCMS R t = 0.688 min, 1.5 min chromatography, 5 - 95 AB, C 17 H 15 ClFN4O [M + H] + The ESI calculated value for 345.1, measured value 345.1.

[0331] Step 9: To a solution of 5-[[5-[(5-chloro-3-fluoro-2-pyridyl)oxy]-4-methyl-3-pyridyl]methyl]pyridin-2-amine (80 mg, 232.04 μmol) in MeCN (1 mL) were added Py (220.25 mg, 2.78 mmol, 224.75 μL) and N-methylsulfamoyl chloride (60.13 mg, 464.08 μmol). The mixture was stirred at 25 °C for 2 h. The mixture was blended with another batch prepared from 20 mg of 5-[[5-[(5-chloro-3-fluoro-2-pyridyl)oxy]-4-methyl-3-pyridyl]methyl]pyridin-2-amine. The mixture was concentrated directly and purified by preparative HPLC (column: Boston Green ODS 150*30 mm*5um, mobile phase: [water (FA)-ACN], B%: 38% - 68%, 6 min) to give 5-[[5-[(5-chloro-3-fluoro-2-pyridyl)oxy]-4-methyl-3-pyridyl]methyl]-N-(methylsulfamoyl)pyridin-2-amine (23 mg, 52.53 umol). 1 H NMR (400 MHz, CDCl3) δ = 8.42 - 8.22 (m, 2H), 8.13 (d, J = 1.2 Hz, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.55 (dd, J = 2.4, 9.2 Hz, 1H), 7.43 (dd, J = 2.4, 8.8 Hz, 1H), 7.00 (d, J = 8.8 Hz, 1H), 5.03 (br s, 1H), 4.01 (s, 2H), 2.73 (s, 3H), 2.13 (s, 3H). 19 F NMR (376.5 MHz, CDCl3) δ = -134.174. LCMS R t = 0.769 min, 1.5 min chromatography, 5 - 95 AB, C 18 H 18 ClFN5O3S [M + H] + The ESI calculated value for 438.1, measured value 438.1. HPLC R t = 2.908 min, 8 min chromatography, 220 nm, purity 98.116%.

[0332] Example 47: 4-[[5-(4-Cyclopropyl-2-fluoro-anilino)-4-methyl-3-pyridyl]methyl]-3-fluoro-N-(methylsulfamoyl)pyridin-2-amine

Chemical formula

Chemical formula

[0333] Step 2: To a solution of tert-butyl N-[4-[[5-(4-bromo-2-fluoro-anilino)-4-methyl-3-pyridyl]methyl]-3-fluoro-2-pyridyl]-N-tert-butoxycarbonyl-carbamate (160 mg, 264.26 μmol) in dioxane (3 mL) were added K3PO4 (168.28 mg, 792.77 μmol), Pd(dppf)Cl2 (19.34 mg, 26.43 μmol), and CsF (20.07 mg, 132.13 μmol, 4.87 μL), and cyclopropylboronic acid (226.99 mg, 2.64 mmol). The mixture was stirred at 75 °C for 3 hours. The mixture was concentrated. The mixture was purified by flash chromatography on silica gel (MeOH in DCM = 0 - 4%) to afford tert-butyl N-tert-butoxycarbonyl-N-[4-[[5-(4-cyclopropyl-2-fluoro-anilino)-4-methyl-3-pyridyl]methyl]-3-fluoro-2-pyridyl]carbamate (149.7 mg, 264.19 μmol). LCMS Rt = 5.035 min, chromatography for 7 minutes, 10 - 80 CD, C 31 H 37 F2N4O4[M+H] + ESI calculated value for 567.3, measured value 567.3.

[0334] Step 3: To a solution of tert-butyl N-tert-butoxycarbonyl-N-[4-[[5-(4-cyclopropyl-2-fluoro-anilino)-4-methyl-3-pyridyl]methyl]-3-fluoro-2-pyridyl]carbamate (149.7 mg, 264.19 μmol) in MeOH (2 mL) was added HCl / MeOH (4 M, 7.25 mL). The mixture was stirred at 20 °C for 3 h. The mixture was concentrated. The mixture was added to NH3 / MeOH (3 mL) and adjusted to pH = 7. The mixture was concentrated. The mixture was purified by flash chromatography on silica gel (EtOAc in petroleum ether = 0 - 100%) to give 4-[[5-(4-cyclopropyl-2-fluoro-anilino)-4-methyl-3-pyridyl]methyl]-3-fluoro-pyridin-2-amine (70 mg, 191.04 μmol). nLCMS Rt = 1.47 min, chromatography for 3 min, 5 - 95 CD, C 21 H 21 F2N4[M+H] + Calculated value 367.3, measured value 367.2.

[0335] Step 4: To a solution of 4-[[5-(4-cyclopropyl-2-fluoro-anilino)-4-methyl-3-pyridyl]methyl]-3-fluoro-pyridin-2-amine (30 mg, 81.88 μmol) in MeCN (1 mL) were added Py (64.76 mg, 818.76 μmol, 66.09 μL) and ...

Claims

1. The compound represented by the following structural formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, in the formula, Y is a covalent bond, NH, NCH ３ , S, CH ２ , OCH ２ ^, or O, and "^" is R １ It shows the connection point to, W is CH ２ , CH (CH ３ ), or O, Z １ , Z ２ , and Z ３ are each independently selected from N, N-oxide, and CR ２ａ , provided that Z １ , Z ２ , and Z ３ are each one or less of N-oxide, Z ４ However, N or CR ２ｂ Selected from, Ar is phenyl, a six-membered heteroaryl, or 2-pyridinone, and each of the phenyl, the six-membered heteroaryl, and the 2-pyridinone is independently R ４ Substituted with 0, 1, or 2 groups represented by 【Chemistry 2】 However, on a base represented by Ar, they are 1, 3 or 1, 4 relative to each other. R １ However, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, pyridinonyl, C ３－６ Cycloalkyl, phenyl, 5-10 member heteroaryl, or C(O)N(R) ６ ) ２ And the above C ３－６ Cycloalkyl, phenyl, and the 5-10 member heteroaryl are each independently R ５ Substituted with 0, 1, 2, or 3 groups represented by R ２ａ However, H, F, or C １－３ It is alkyl, R ２ｂ But, H, Halo, (CH ２ ) ｎ OR ７ , C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C １－６ Alkoxy, C(O)N(C １－６－ Alkyl), C(O)NHO(C ２－６ (Hydroxyalkyl), (CH ２ ) ２－６ N(R) ７ ) ２ ,C(O)NHO(CH ２ ) ２－６ N(R) ７ ) ２ And each R ２０ However, H or C １－６ Alkyl, C ３－６ It is a cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-6 membered heterocycle, or R ２ｂ And Y, together with their intervening atoms, form a 5-6 member nitrogen-containing heterocycle or a 5-6 member nitrogen-containing heteroaryl compound. R ３ However, N(R １０ ) ２ , 【Transformation 3】 And, Each R ４ However, they became independent: H, Halo, C １－６ Alkoxy, or C １－６ It is alkyl, R ５ However, H, cyano, halo, SO ２ C １－６ Alkyl, C １－６ Alkyl, deuterated C １－６ Alkyl, C ２－６ Alkenyl, deuterized C １－６ Alkenil, C ２－６ Alkynyl, deuterized C １－６ Alkinyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, SC １－６ Alkyl, C ３－８ It is either cycloalkyl or has two R atoms on adjacent phenyl ring carbon atoms. ５ However, together with the ring carbon atoms to which they are bonded, they form an oxygen-containing heterocycle, or C ３－６ Two Rs on the same ring carbon atom of a cycloalkyl group ５ However, C is chosen at will. １－４ It forms an alkyl-substituted 4-6 member nitrogen-containing heterocycle, Each R ６ However, independently, H or C １－６ Alkyl (preferably H or C) １－６ Selected from alkyl, Each R ７ and each R ８ However, independently, H or C １－３ Selected from alkyl, or if x is 0, R ８ and W and R ３ R in the ortho position relative to ４ These, together with the intervening atoms, form a 5-6 member nitrogen-containing heterocycle. R ９ is H, C １－６ alkoxy, C １－６ alkyl, C ２－６ alkenyl, C １－６ haloalkyl, C ３－８ cycloalkyl (optionally substituted with methyl), or N(R １１ ), ２ wherein the C １－６ alkyl is optionally substituted with cyano, hydroxy, C １－６ alkoxy, or N(R １１ ), ２ and Each R １０ independently represents H, C １－６ alkyl, C ２－６ alkenyl, C ３－８ cycloalkyl (optionally substituted with methyl), or C １－６ haloalkyl, and wherein said C １－６ alkyl is optionally substituted with cyano, hydroxy, C １－６ alkoxy, or N(R １１ ) ２ or is unsubstituted Two R's １０ However, together with the nitrogen atoms to which they are bonded, they form a 3- to 7-membered heterocycle. Each R １１ However, independently, it is H or methyl, n is 0 or 1, A compound, or a pharmaceutically acceptable salt thereof, in which x is 0 or 1.

2. The compound according to claim 1, represented by the following structural formula: 【Chemistry 4】 or a pharmaceutically acceptable salt thereof, in the formula, Y is a covalent bond, NH, NCH ３ , S, CH ２ , OCH ２ ^, or O, and "^" is R １ It shows the connection point to, Z １ Z ２ , and Z ３ However, N and CR are independent of each other. ２ａ Selected from, Z ４ However, N or CR ２ｂ Selected from, Ar is phenyl, a six-membered heteroaryl, or 2-pyridinone, and each of the phenyl, the six-membered heteroaryl, and the 2-pyridinone is independently R ４ Substituted with 0, 1, or 2 groups represented by 【Transformation 5】 However, on a base represented by Ar, they are 1, 3 or 1, 4 relative to each other. R １ However, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, phenyl, 5-6 member heteroaryl, or C(O)N(R) ６ ) ２ The phenyl and the 5-6 member heteroaryl are each independently R ５ Substituted with 0, 1, or 2 groups represented by R ２ａ However, H, F, or C １－３ It is alkyl, R ２ｂ But, H, Halo, (CH ２ ) ｎ OR ７ , C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C １－６ Alkoxy, C ３－６ It is a cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-6 membered heterocycle. R ３ However, N(R １０ ) ２ , 【Transformation 6】 And, Each R ４ However, they became independent: H, Halo, C １－６ Alkoxy, or C １－６ It is alkyl, R ５ However, H, cyano, halo, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C １－６ Alkoxy, halomethoxy, or C ３－８ It is a cycloalkyl, Each R ６ However, independently, H or C １－６ Selected from alkyl groups, R ７ and R ８ However, independently, H or C １－３ Selected from alkyl groups, R ９ However, H, C １－６ Alkoxy, C １－６ Alkyl, C ２－６ Alkenil, C １－６ Haloalkyl, C ３－８ Cycloalkyl (optionally substituted with methyl), or N(R) １１ ) ２ And the above C １－６ Alkyl is optionally cyano, hydroxy, C １－６ Alkoxy, or N(R) １１ ) ２ Replaced by, Each R １０ However, independently, H and C １－６ Alkyl, C ２－６ Alkenil, C ３－８ Cycloalkyl (optionally substituted with methyl), or C １－６ It is a haloalkyl, and the C １－６ Alkyl is optionally cyano, hydroxy, C １－６ Alkoxy, or N(R) １１ ) ２ It will be replaced by, or Two R's １０ However, together with the nitrogen atoms to which they are bonded, they form a 3- to 7-membered heterocycle. Each R １１ However, independently, it is H or methyl, n is 0 or 1, The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein x is 0 or 1.

3. R １ However, C １－４ Alkyl, C ２＝４ Alkenil, C ２－４ Alkinil, 【Transformation 7】 Selectively choose one or two R's ５” C replaced by ４ -C ６ Cycloalkyl, or C(O)N(R) ６ ) ２ And R ５’ However, H or halo, and each R ５” However, C １－３ Alkyl or two R ５” However, together with the ring carbon atoms to which they are bonded, C ４－６ A nitrogen-containing heterocycline is formed, and the ring nitrogen atom is optionally N-(C) １－３ ) The compound according to claim 1, wherein m is alkylated and m is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

4. R １ but, 【Transformation 8】 or C(O)N(R) ６ ) ２ The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, or 2.

5. A compound according to any one of claims 1 to 4, represented by a structural formula selected from the following, or a pharmaceutically acceptable salt thereof. 【Chemistry 9】

6. The compound according to claim 2 or 4, represented by the following structural formula: 【Chemistry 10】 or a pharmaceutically acceptable salt thereof.

7. R １ However, methyl, allyl, propargyl, 【Chemistry 11】 Cyclohexyl or C(O)N(R) substituted with one or two methyl groups as optionally. ６ ) ２ The compound according to claim 1 or 3, or a pharmaceutically acceptable salt thereof.

8. R １ but, 【Chemistry 12】 or C(O)N(R) ６ ) ２ The compound according to claim 2 or 4, or a pharmaceutically acceptable salt thereof.

9. Ar-(CH ２ ) ｘ -R ３ However, it is represented by the following structural formula, 【Chemistry 13】 In the formula, X ４ However, N, CH, C (C １－４ Alkyl), or C (C １－４ It is an alkoxy, and X ５ However, N or CR ４ A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

10. It is represented by the following structural formula, 【Chemistry 14】 In the formula, X ４ The compound according to claim 2 or 4, or a pharmaceutically acceptable salt thereof, wherein the compound is N or CH.

11. A compound according to claim 2 or 4, represented by the following structural formula, or a pharmaceutically acceptable salt thereof. 【Chemistry 15】

12. A compound according to claim 2 or 4, represented by the following structural formula, or a pharmaceutically acceptable salt thereof. 【Chemistry 16】

13. A compound according to claim 2 or 4, represented by the following structural formula, or a pharmaceutically acceptable salt thereof. 【Chemistry 17】

14. -Ar-(CH ２ ) ｘ R ３ However, the compound according to any one of claims 1 to 4, represented by a structural formula selected from the following, or a pharmaceutically acceptable salt thereof. [Chemistry 18]

15. R １ but, 【Chemistry 19】 A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

16. R １ but, 【Chemistry 20】 A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

17. R １ but, 【Chemistry 21】 A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

18. R １ but, 【Chemistry 22】 A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

19. R １ However, C(O)N(R ６ ) ２ And R ６ However, H or C １－６ A compound according to any one of claims 1 to 4, wherein the compound is alkyl, preferably H or methyl, or a pharmaceutically acceptable salt thereof.

20. x is 0, R ３ but, 【Chemistry 23】 A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

21. x is 0, R ３ but, 【Chemistry 24】 A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

22. x is 0, R ３ but, 【Chemistry 25】 A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

23. x is 0, R ３ but, 【Chemistry 26】 A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

24. x is 0, R ３ but, 【Chemistry 27】 A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

25. A compound according to claim 2 or 4, or a pharmaceutically acceptable salt thereof, wherein Y is O.

26. A compound according to claim 2 or 4, or a pharmaceutically acceptable salt thereof, wherein Y is NH.

27. Y is O, NH, N(CH ３ A compound according to any one of claims 1 to 4, which is ), or S, or a pharmaceutically acceptable salt thereof.

28. R ８ However, H is R ９ However, C １－６ Alkoxy, C １－６ Alkyl, or N(R) １１ ) ２ And R １０ However, C １ -C ６ A compound according to claim 2 or 4, which is alkyl, or a pharmaceutically acceptable salt thereof.

29. R ２ｂ However, H, C １－６ Alkyl, Halo, C １－６ Alkoxy, (CH ２ ) ｎ OR ７ , or a 4- to 6-membered heterocyclic ring, R ４ However, H, C １－６ It is an alkoxy or halo, and R ５ However, H, C １－６ Alkyl, deuterated C １－６ Alkyl, C １－６ Alkinyl, Cyano, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, SO ２ C １－６ Alkyl, SC １－６ Alkyl, halo, or C ３－８ A compound according to any one of claims 1 to 4, which is a cycloalkyl compound, or a pharmaceutically acceptable salt thereof.

30. R ２ｂ However, C １－６ Alkyl, Halo, C １－６ Alkoxy, (CH ２ ) ｎ OR ７ , or a 4- to 6-membered heterocyclic ring, R ４ However, H or halo, R ５ However, H, C １－６ Alkyl, cyano, C １－６ Haloalkyl, halo, or C ３－８ A cycloalkyl compound according to claim 2 or 4, or a pharmaceutically acceptable salt thereof.

31. R ２ｂ However, H, methyl, ethyl, chloro, OCH ３ ,CH ２ OCH ３ , or oxetane, R ４ However, H, OCH ３ , or fluoro, R ５ However, H, fluoro, chloro, bromo, iod, cyano, OCH ３ SCH ３ SO ２ CH ３ CHF ２ CF ３ Methyl, ethyl, isopropyl, isobutyl, CD ３ C≡CH,OCF ３ , OCHF ２ , or cyclopropyl, or two R on adjacent phenyl ring atoms ５ The base is OCH ２ CH ２ Form O, R ６ The compound according to any one of claims 1 to 4, wherein the compound is H or methyl, or a pharmaceutically acceptable salt thereof.

32. R ２ｂ However, methyl, chloro, OMe, CH ２ OCH ３ , or oxetane, R ４ However, it is H or fluoro, and R ５ However, H, fluoro, chloro, bromo, cyano, CF ３ , methyl, ethyl, or cyclopropyl, R ６ The compound according to any one of claims 1 to 4, wherein the compound is H or methyl, or a pharmaceutically acceptable salt thereof.

33. R ７ However, it is H or methyl, and R ９ However, OCH ３ , methyl, or NHCH ３ And R １０ A compound according to any one of claims 1 to 4, wherein the compound is H, methyl, ethyl, or propyl, or a pharmaceutically acceptable salt thereof.

34. R ７ However, it is H or methyl, and R ９ However, OCH ３ , methyl, or NHCH ３ And R １０ The compound according to claim 2 or 4, or a pharmaceutically acceptable salt thereof, wherein the compound is methyl.

35. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent, and the compound described in claim 1, or a pharmaceutically acceptable salt thereof.

36. A pharmaceutical composition for use in a method for inhibiting mitogen-activated protein kinase (MEK) in a subject requiring such inhibition, comprising: i) a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof; or ii) an effective amount of the pharmaceutical composition according to claim 35.

37. A pharmaceutical composition for use in a method of treating a subject having cancer, comprising: i) a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof; or ii) an effective amount of the pharmaceutical composition according to claim 35.

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