Patent Application
20240327393
The present disclosure relates to compounds that modulate ferroptosis, compositions comprising the compounds, methods of preparing the compounds, and methods of using the compounds to treat various diseases or conditions, e.g., those involving ferroptosis.
Ferroptosis is a type of programmed cell death dependent on iron and characterized by the accumulation of lipid peroxides, and is genetically and biochemically distinct from other forms of regulated cell death such as apoptosis, autophagy, and necrosis. (Dixon et al., Cell 149, 1060-1072 (2012).) Certain mechanisms of ferroptosis and key contributors to ferroptotic cell death is reviewed and illustrated by Conrad et al., Nature Chemical Biology, vol. 15, Dec. 2019, 1137-1147.
Ferroptosis has been implicated in a number of diseases or conditions, including neuropathy, stroke, neurodegenerative disease (e.g., Alzheimer's disease), Parkinson's Disease, amyotrophic lateral sclerosis (AML), multiple sclerosis, Huntington's Disease, dementia with Lewy bodies, Friedreich's ataxia, hair follicle morphogenesis, diabetes, sepsis, transplant rejection, periventricular leukomalacia, ischemia reperfusion injury, blood coagulation, myocardial infarction, and kidney dysfunction such as acute kidney failure. For example, inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. (Angeli, et al., Nature Cell Biology, published online Nov. 17, 2014; DOI: 10.1038/ncb3064.) Ferroptosis has been considered to be implicated in several pathophysiological contexts such as tumor suppression, antiviral immunity, neurodegeneration, and ischemia/reperfusion injury (IRI). (Angeli et al., Trends in Pharmacological Sciences, May 2017, Vol. 38, No. 5, 489-498 (2017).)
Certain compounds that modulate ferroptosis are disclosed by Skouta et al., J. Am. Chem. Soc., dx.doi.org/10.1021/ja411006a; and in WO2013152039A1, WO2015084749A1, WO2019154795A1, WO2016075137A1, WO2020185738A1, and PCT/CN2021/078601.
One aspect of this disclosure provides a compound selected from compounds of the Formulae disclosed herein, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, which can be employed in the treatment of various diseases or conditions, such as diseases or conditions involving ferroptosis. For example, disclosed herein is a compound of the following structural Formula I:
a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein:
In one aspect of the disclosure, the compounds of the Formulae disclosed herein are selected from Compounds 1 to 659 shown below, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing.
In some embodiments, the disclosure provides pharmaceutical compositions comprising a compound of the Formulae disclosed herein, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical compositions may comprise a compound selected from Compounds 1 to 659 shown below, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, and a pharmaceutically acceptable carrier. These compositions may further comprise an additional active pharmaceutical agent.
Another aspect of the disclosure provides methods of treating a disease or condition, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of the Formulae disclosed herein, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing, wherein the disease or condition is selected from neuropathy, stroke, neurodegenerative disease (e.g., Alzheimer's disease), Parkinson's Disease, amyotrophic lateral sclerosis (AML), multiple sclerosis, Huntington's Disease, dementia with Lewy bodies, Friedreich's ataxia, hair follicle morphogenesis, diabetes, sepsis, transplant rejection, periventricular leukomalacia, ischemia reperfusion injury, blood coagulation, myocardial infarction, and kidney dysfunction such as acute kidney failure.
A further aspect of the disclosure provides methods of treating a disease or condition involving ferroptosis, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of the Formulae disclosed herein, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing.
In some embodiments, the methods of treatment comprise administering to a subject in need thereof, a compound selected from Compounds 1 to 659 shown below, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing.
In some embodiments, the methods of treatment comprise administration of an additional active pharmaceutical agent to the subject in need thereof, either in the same pharmaceutical composition as a compound of the Formulae disclosed herein, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, or in a separate composition. In some embodiments, the methods of treatment comprise administering a compound selected from Compounds 1 to 659 shown below, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing with an additional active pharmaceutical agent either in the same pharmaceutical composition or in a separate composition. When administered as a separate composition, the additional therapeutic agent may be administered prior to, at the same time as, or following administration of the compound, tautomer, solvate, stereoisomer, or a pharmaceutically acceptable salt disclosed herein.
Also disclosed herein are methods of modulating, e.g., inhibiting, ferroptosis in a subject in need thereof, comprising contacting the subject with a compound of the Formulae disclosed herein, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing. In some embodiments, the methods of modulating, e.g., inhibiting, ferroptosis in a subject in need thereof comprise contacting the subject with a compound selected from Compounds 1 to 659 shown below, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing.
The term “a” or “an” when referring to a noun as used herein encompasses the expression “at least one” and therefore encompasses both singular and plural units of the noun. For example, “an additional pharmaceutical agent” means a single or two or more additional pharmaceutical agents.
The term “alkyl” refers to a hydrocarbon group selected from linear and branched saturated hydrocarbon groups, containing 1-20, e.g., 1-18, 1-12, 1-10, 1-8, 1-6, 1-4, or 1-3, carbon atoms. Examples of the alkyl group include methyl, ethyl, 1-propyl or n-propyl (“n-Pr”), 2-propyl or isopropyl (“i-Pr”), 1-butyl or n-butyl (“n-Bu”), 2-methyl-1-propyl or isobutyl (“i-Bu”), 1-methylpropyl or s-butyl (“s-Bu”), and 1,1-dimethylethyl or t-butyl (“t-Bu”). Other examples of an alkyl group include 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl groups. Lower alkyl contains 1-8, preferably 1-6, more preferably 1-4 carbon atoms, and more preferably 1-3 carbon atoms.
The term “alkenyl” refers to a hydrocarbon group selected from linear and branched hydrocarbon groups, comprising at least one C═C double bond and 2-20, e.g., 2-18, 2-12, 2-10, 2-8, 2-6, or 2-4, carbon atoms. Examples of the alkenyl group may be selected from ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-diene, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hexa-1,3-dienyl groups. Lower alkenyl contains 2-8, preferably 2-6, and more preferably 2-4 carbon atoms.
The term “alkynyl” refers to a hydrocarbon group selected from linear and branched hydrocarbon groups, comprising at least one C≡C triple bond and 2-20, e.g., 2-18, 2-12, 2-10, 2-8, 2-6, or 2-4, carbon atoms. Examples of the alkynyl group include ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl groups. Lower alkynyl contains 2-8, preferably 2-6, and more preferably 2-4 carbon atoms.
The term “heteroalkyl” refers to an alkyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by a heteroatom, e.g., nitrogen, oxygen, or sulfur, e.g., CH3CH2OH, CH3CH2OC2H5, CH3CH2SH, CH3CH2SC2H5, CH3CH2NH2, CH3CH2NHC2H5, etc. In some embodiments, in addition to the replacement of one or more of the constituent carbon atoms by nitrogen, oxygen, or sulfur, a heteroalkyl group is further optionally substituted as defined herein.
The term “cycloalkyl” refers to a hydrocarbon group selected from saturated and partially unsaturated cyclic hydrocarbon groups, e.g., monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups. For example, the cycloalkyl group may be of 3-12, or 3-8, or 3-6, or 3-4, or 5-6 carbon atoms. Even further for example, the cycloalkyl group may be a monocyclic group of 3-12, or 3-8, or 3-6, or 3-4, or 5-6 carbon atoms. Examples of the monocyclic cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups. Examples of the bicyclic cycloalkyl groups include those having 7-12 ring atoms arranged as a bicycle ring selected from [4,4], [4,5], [5,5], [5,6] and [6,6] ring systems, or as a bridged bicyclic ring selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. The ring may be saturated or have at least one double bond (i.e., partially unsaturated), but is not fully conjugated, and is not aromatic, as aromatic is defined herein.
The term “heterocyclic” or “heterocycle” or “heterocyclyl” refers to a ring selected from 4- to 12-membered, e.g., 3- to 6-membered, 3- to 5-membered, 4- to 5-membered, or 5- to 6-membered, monocyclic, bicyclic, and tricyclic, saturated and partially unsaturated rings comprising at least one carbon atom in addition to 1, 2, 3, or 4 heteroatoms, selected from oxygen, sulfur, and nitrogen. “Heterocycle” also refers to a 5- to 7-membered heterocyclic ring comprising at least one heteroatom selected from N, O, and S fused with 5-, 6-, and/or 7-membered cycloalkyl, carbocyclic aromatic, or heteroaromatic ring, provided that the point of attachment is at the heterocyclic ring when the heterocyclic ring is fused with a carbocyclic aromatic or a heteroaromatic ring, and that the point of attachment can be at the cycloalkyl or heterocyclic ring when the heterocyclic ring is fused with cycloalkyl.
“Heterocycle” also refers to an aliphatic spirocyclic ring comprising at least one heteroatom selected from N, O, and S, provided that the point of attachment is at the heterocyclic ring. The rings may be saturated or have at least one double bond (i.e., partially unsaturated). A heterocycle may be substituted with oxo. The point of the attachment may be carbon or heteroatom in the heterocyclic ring. A heterocycle is not a heteroaryl as defined herein.
Examples of heterocycles include, but are not limited to, (as numbered from the linkage position assigned priority 1) 1-pyrrolidinyl, 2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2,5-piperazinyl, pyranyl, 2-morpholinyl, 3-morpholinyl, oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, 1,4-oxathianyl, 1,4-dioxepanyl, 1,4-oxathiepanyl, 1,4-oxaazepanyl, 1,4-dithiepanyl, 1,4-thiazepanyl, 1,4-diazepanyl, 1,4-dithianyl, 1,4-azathianyl, oxazepinyl, diazepinyl, thiazepinyl, dihydrothienyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, 1,4-dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinyl, imidazolinyl, pyrimidinonyl, 1,1-dioxo-thiomorpholinyl, 3-azabicyco[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl and azabicyclo[2.2.2]hexanyl. Substituted heterocycle also includes ring systems substituted with one or more oxo moieties, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl, and 1,1-dioxo-1-thiomorpholinyl.
The term “fused ring” herein refers to a polycyclic ring system, e.g., a bicyclic or tricyclic ring system, in which two rings share only two ring atoms and one bond in common. Examples of fused rings may comprise a fused bicyclic cycloalkyl ring such as those having from 7 to 12 ring atoms arranged as a bicyclic ring selected from [4,4], [4,5], [5,5], [5,6] and [6,6] ring systems as mentioned above; a fused bicyclic aryl ring such as 7 to 12 membered bicyclic aryl ring systems as mentioned above, a fused tricyclic aryl ring such as 10 to 15 membered tricyclic aryl ring systems mentioned above; a fused bicyclic heteroaryl ring such as 8- to 12-membered bicyclic heteroaryl rings as mentioned above, a fused tricyclic heteroaryl ring such as 11- to 14-membered tricyclic heteroaryl rings as mentioned above; and a fused bicyclic or tricyclic heterocyclyl ring as mentioned above.
The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, and phosphorus, including, any oxidized form of nitrogen or sulfur; the quaternized form of any basic nitrogen or a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+ (wherein R is, e.g., an optionally substituted alkyl group) (as in N-substituted pyrrolidinyl).
The term “unsaturated”, as used herein, means that a moiety has one or more units or degrees of unsaturation. Unsaturation is the state in which not all of the available valence bonds in a compound are satisfied by substituents and thus the compound contains one or more double or triple bonds.
The term “alkoxy” as used herein, refers to an alkyl group, as defined above, wherein one carbon of the alkyl group is replaced by an oxygen atom, provided that the oxygen atom is linked between two carbon atoms.
The term “halogen” includes F, Cl, Br, and I, i.e., fluoro, chloro, bromo, and iodo, respectively.
As used herein, a “CN”, “cyano” or “nitrile” group refers to —C≡N.
As used herein, an “aromatic ring” refers to a carbocyclic or heterocyclic ring that contains conjugated, planar ring systems with delocalized pi electron orbitals comprised of [4n+2] p orbital electrons, wherein n is an integer of 0 to 6. A “non-aromatic” ring refers to a carbocyclic or heterocyclic that does not meet the requirements set forth above for an aromatic ring, and can be either completely or partially saturated. Non-limiting examples of aromatic rings include aryl and heteroaryl rings that are further defined as follows. An “aromatic ring” may be depicted as a cycle with conjugated double bonds, such as
or as a cycle with an inside circle such as
or as otherwise indicated, such as
wherein Ar1 is indicated as aromatic or non-aromatic.
The term “aryl” herein refers to a group selected from: monocyclic carbocyclic aromatic rings, for example, phenyl; bicyclic ring systems such as 7-12 membered bicyclic ring systems wherein at least one ring is carbocyclic and aromatic, selected, for example, from naphthalene, indane, and 1,2,3,4-tetrahydroquinoline; and tricyclic ring systems such as 10-15 membered tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, fluorene.
For example, the aryl group may be a 6-membered carbocyclic aromatic ring fused to a 5- to 7-membered cycloalkyl or heterocyclic ring optionally comprising at least one heteroatom selected from N, O, and S, provided that the point of attachment is at the carbocyclic aromatic ring when the carbocyclic aromatic ring is fused with a heterocyclic ring, and the point of attachment can be at the carbocyclic aromatic ring or at the cycloalkyl group when the carbocyclic aromatic ring is fused with a cycloalkyl group. Bivalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals. Bivalent radicals derived from univalent polycyclic hydrocarbon radicals whose names end in “-yl” by removal of one hydrogen atom from the carbon atom with the free valence are named by adding “-idene” to the name of the corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene.
The term “heteroaryl” refers to a group selected from: 5- to 7-membered, e.g., 5- to 6-membered, aromatic, monocyclic rings comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon; 8- to 12-membered bicyclic rings comprising 1, 2, 3, or 4 heteroatoms, selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and 11- to 14-membered tricyclic rings comprising 1, 2, 3, or 4 heteroatoms, selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one ring is aromatic and at least one heteroatom is present in an aromatic ring.
For example, the heteroaryl group may be a 5- to 7-membered heterocyclic aromatic ring fused to a 5- to 7-membered cycloalkyl ring. For such fused, bicyclic heteroaryl ring systems wherein only one of the rings comprises at least one heteroatom, the point of attachment may be at the heteroaromatic ring or at the cycloalkyl ring.
When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is not more than 1.
Examples of the heteroaryl group include, but are not limited to, (as numbered from the linkage position assigned priority 1) pyridyl (such as 2-pyridyl, 3-pyridyl, or 4-pyridyl), cinnolinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl, thienyl, triazinyl, benzothienyl, furyl, benzofuryl, benzoimidazolyl, indolyl, isoindolyl, indolinyl, phthalazinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl, quinolinyl, isoquinolinyl, pyrazolyl, pyrrolopyridinyl (such as 1H-pyrrolo[2,3-b]pyridin-5-yl), pyrazolopyridinyl (such as 1H-pyrazolo[3,4-b]pyridin-5-yl), benzoxazolyl (such as benzo[d]oxazol-6-yl), pteridinyl, purinyl, 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, 1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl, 1-thia-3,4-diazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, benzothiazolyl (such as benzo[d]thiazol-6-yl), indazolyl (such as 1H-indazol-5-yl) and 5,6,7,8-tetrahydroisoquinolinyl.
The term “acyl” refers to a substituent group where a point of attachment in the substituent group is a carbonyl. Exemplary acyl groups include, but are not limited to, —C(═O)R′, —C(═O)NR′R″, or —C(═O)OR′, wherein R′ and R″ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, any of which may be further substituted by one or more substituents.
Some of the compounds may exist with different points of attachment of hydrogen, referred to as “tautomers.” For example, compounds including carbonyl —CH2C(O)— groups (keto forms) may undergo tautomerism to form hydroxyl —CH═C(OH)— groups (enol forms). Both keto and enol forms, individually as well as mixtures thereof, are also intended to be included where applicable.
The compounds, tautomers, solvates, or pharmaceutically acceptable salts of the disclosure may contain an asymmetric center and may thus exist as enantiomers. For example, where the compounds possess two or more asymmetric centers, they may additionally exist as diastereoisomers. Enantiomers and diastereoisomers fall within the broader class of stereoisomers. All such possible stereoisomers as substantially pure resolved enantiomers, racemic mixtures thereof, as well as mixtures of diastereoisomers are intended to be included in this disclosure. All stereoisomers of the compounds, tautomers, solvates, and pharmaceutically acceptable salts thereof are intended to be included. Unless specifically mentioned otherwise, reference to one isomer applies to any of the possible isomers. Whenever the isomeric composition is unspecified, all possible isomers are included.
Diastereoisomeric mixtures can be separated into their individual diastereoisomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereoisomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereoisomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers. Enantiomers can also be separated by use of a chiral HPLC column.
A single stereoisomer, e.g., a substantially pure enantiomer, may be obtained by resolution of the racemic mixture using a method such as formation of diastereoisomers using optically active resolving agents. Racemic mixtures of chiral compounds of the disclosure can be separated and isolated by any suitable method, including: (1) formation of ionic, diastereoisomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereoisomeric compounds with chiral derivatizing reagents, separation of the diastereoisomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions.
The term “substantially pure” in the context of stereoisomers means that the target stereoisomer contains no more than 35%, such as no more than 30%, further such as no more than 25%, even further such as no more than 20%, by weight of any other stereoisomer(s). In some embodiments, the term “substantially pure” means that the target stereoisomer contains no more than 10%, for example, no more than 5%, such as no more than 1%, by weight of any other stereoisomer(s).
Unless otherwise indicated, structures depicted herein are meant to include all isomeric forms of the structure, e.g., racemic mixtures, cis/trans isomers, geometric (or conformational) isomers, such as (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, geometric and conformational mixtures of the compounds disclosed herein are within the scope of the disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure.
The disclosure provides pharmaceutically acceptable salts of the disclosed compounds, tautomers, solvates, and stereoisomers. A salt of a compound is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group.
The term “pharmaceutically acceptable,” as used herein, refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A “pharmaceutically acceptable salt” means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this disclosure.
“Pharmaceutically acceptable salts” include, but are not limited to salts with inorganic acids, selected, for example, from hydrochlorates, phosphates, diphosphates, hydrobromates, sulfates, sulfinates, and nitrates; as well as salts with organic acids, selected, for example, from malates, maleates, fumarates, tartrates, succinates, citrates, lactates, methanesulfonates, p-toluenesulfonates, 2-hydroxyethylsulfonates, benzoates, salicylates, stearates, alkanoates such as acetate, and salts with HOOC—(CH2)n—COOH, wherein n is selected from 0 to 4. Similarly, examples of pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, magnesium, aluminum, lithium, and ammonium. Suitable pharmaceutically acceptable salts are, for example, those disclosed in S. M. Berge, et al. J. Pharmaceutical Sciences, 1977, 66, pp. 1 to 19.
Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, benzenesulfonic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate (i.e., caprate), caprylate, acrylate, formate, isobutyrate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, P-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and other salts. In some embodiments, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid.
Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(C1-4alkyl)4 salts. This disclosure also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium salts. Further non-limiting examples of pharmaceutically acceptable salts include salts of ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. Other suitable, non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.
If a compound is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid addition salt. Conversely, if the product is a free base, an addition salt, such as a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used without undue experimentation to prepare non-toxic pharmaceutically acceptable addition salts.
The compounds, tautomers, solvates, stereoisomers, and pharmaceutically acceptable salts of the disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, —CD3, —CD2H or —CDH2 contains one or more deuteriums in place of hydrogen. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I) or carbon-14 (14C). All isotopic variations of the compounds of the disclosure, whether radioactive or not, are intended to be encompassed within the scope of the disclosure.
As used herein, “optionally substituted” is interchangeable with the phrase “substituted or unsubstituted.” In general, the term “substituted,” refers to the replacement of a hydrogen radical in a given structure with the radical of a specified substituent. Unless otherwise indicated, an “optionally substituted” group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent chosen from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this disclosure are those that result in the formation of stable or chemically feasible compounds.
In some embodiments, substituents are independently selected from optionally substituted heteroatom and optionally substituted, optionally hetero-, optionally cyclic C1-C18 hydrocarbyl, particularly wherein the optionally substituted, optionally hetero-, optionally cyclic C1-C18 hydrocarbyl is optionally-substituted, optionally hetero-, optionally cyclic alkyl, alkenyl or alkynyl, or optionally-substituted, optionally hetero-, aryl; and/or the optionally substituted heteroatom is halogen, optionally substituted hydroxyl (such as alkoxy, aryloxy), optionally substituted acyl (such as formyl, alkanoyl, carbamoyl, carboxyl, amido), optionally substituted amino (such as amino, alkylamino, dialkylamino, amido, sulfamidyl), optionally substituted thiol (such as mercapto, alkylthiol, aryl thiol), optionally substituted sulfinyl or sulfonyl (such as alkylsulfinyl, arylsulfinyl, alkyl sulfonyl, arylsulfonyl), nitro, or cyano.
In some embodiments, substituents are independently selected from: halogen, —R′, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, —SiR′R″R′, —OC(═O)R′, —C(═O)R′, —CO2R′, —C(═O)NR′R″, —OC(═O)NR′R″, —NR″C(═O)R′, —NR′—C(═O)NR″R′″, —NR′—SO2NR″R″′, —NR″CO2R′, —NH—C(NH2)═NH, —NR′C(NH2)═NH, —NH—C(NH2)═NR′, —S(O)R′, —SO2R′, —SO2NR′R″, —NR″SO2R, —CN, —NO2, —N3, —CH(Ph)2, perfluoro(C1-C4)alkoxy, and perfluoro(C1-C4)alkyl, in a number ranging from zero to three, with those groups having zero, one, or two substituents being particularly preferred. R′, R″ and R″′ each independently refer to hydrogen, unsubstituted C1-C8 alkyl and heteroalkyl, C1-C8 alkyl and heteroalkyl substituted with one to three halogens, unsubstituted aryl, aryl substituted with one to three halogens, unsubstituted alkyl, alkoxy, or thioalkoxy groups, or aryl-(C1-C4) alkyl groups. When R′ and R″ are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6- or 7-membered ring. Hence, —NR′R″ includes, e.g., 1-pyrrolidinyl and 4-morpholinyl. When the aryl group is 1,2,3,4-tetrahydronaphthalenyl, it may be substituted with a substituted or unsubstituted C3-C7 spirocycloalkyl group. The C3-C7 spirocycloalkyl group may be substituted in the same manner as defined herein for “cycloalkyl.”
In some embodiments, substituents are selected from: halogen, —R′, —OR′, ═O, —NR′R″, —SR′, —SiR′R″R″′, —OC(═O)R′, —C(═O)R′, —CO2R′, —C(═O)NR′R″, —OC(═O)NR′R″, —NR″C(═O)R′, —NR″CO2R′, —NR′—SO2NR″R″′, —S(═O)R′, —SO2R′, —SO2NR′R″, —NR″SO2R, —CN, —NO2, perfluoro C1-C4 alkoxy and perfluoro C1-C4 alkyl, where R′ and R″ are as defined above.
In some embodiments, substituents are independently selected from substituted or unsubstituted heteroatom, substituted or unsubstituted, 0-3 heteroatom-containing C1-C6 alkyl (e.g., C1-C3 alkyl or C1-C2 alkyl), substituted or unsubstituted, 0-3 heteroatom-containing C2-C6 alkenyl (e.g., C2-C4 alkenyl), substituted or unsubstituted, 0-3 heteroatom-containing C2-C6 alkynyl (e.g., C2-C4 alkynyl), or substituted or unsubstituted, 0-3 heteroatom-containing C6-C14 aryl (e.g., C5-C6 aryl), wherein each heteroatom is independently oxygen, phosphorus, sulfur, or nitrogen.
In some embodiments, substituents are independently selected from aldehyde, aldimine, alkanoyloxy, alkoxy, alkoxycarbonyl, alkyloxy, alkyl, alkenyl, alkynyl, amine, azo, halogen, carbamoyl, carbonyl, carboxamido, carboxyl, cyanyl, ester, haloformyl, hydroperoxyl, hydroxyl, imine, isocyanide, iscyante, N-tert-butoxycarbonyl, nitrate, nitrile, nitrite, nitro, nitroso, phosphate, phosphono, sulfide, sulfonyl, sulfo, sulfhydryl, thiol, thiocyanyl, trifluoromethyl, and trifluromethyl ether (OCF3) groups.
Preferred substituents are disclosed herein and exemplified in the tables, structures, examples, and claims, and may be applied across different compounds of this disclosure. For example, substituents of a given compound may be combinatorically used with other compounds.
It may be advantageous to separate reaction products from one another and/or from starting materials. The desired products of each step or series of steps is separated and/or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art. Typically such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods including, for example, reverse-phase and normal phase; size exclusion; ion exchange; high, medium and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed (“SMB”) and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography. One skilled in the art may apply such techniques to achieve a desired separation.
Non-limiting examples of suitable solvents that may be used in this disclosure include water, methanol (MeOH), ethanol (EtOH), dichloromethane or methylene chloride (CH2Cl2), toluene, acetonitrile (MeCN), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), heptanes, isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropyl alcohol (IPA), tetrahydrofuran (THF), 2-methyl tetrahydrofuran (2-Me THF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (Et2O), methyl-tert-butyl ether (MTBE), 1,4-dioxane, and N-methyl pyrrolidone (NMP).
Non-limiting examples of suitable bases that may be used in this disclosure include 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), potassium tert-butoxide (KOtBu), potassium carbonate (K2CO3), N-methylmorpholine (NMM), triethylamine (Et3N; TEA), diisopropyl-ethyl amine (i-Pr2EtN; DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), and sodium methoxide (NaOMe; NaOCH3).
The term “subject” refers to an animal including a human.
The term “therapeutically effective amount” refers to the amount of a compound that produces a desired effect for which it is administered (e.g., improvement in a disease or condition, lessening the severity of a disease or condition, and/or reducing progression of a disease or condition, e.g., a disease or condition selected from neuropathy, stroke, neurodegenerative disease (e.g., Alzheimer's disease), Parkinson's Disease, amyotrophic lateral sclerosis (AML), multiple sclerosis, Huntington's Disease, dementia with Lewy bodies, Friedreich's ataxia, hair follicle morphogenesis, diabetes, sepsis, transplant rejection, periventricular leukomalacia, ischemia reperfusion injury, blood coagulation, myocardial infarction, and kidney dysfunction such as acute kidney failure. The disease or condition may be involved with dysregulated, e.g., abnormal, ferroptosis. The exact amount of a therapeutically effective amount will depend on the purpose of the treatment and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lloyd (1999), The Art, Science and Technology of Pharmaceutical Compounding).
As used herein, the term “treatment” and its cognates refer to slowing or stopping disease progression. “Treatment” and its cognates as used herein include, but are not limited to the following: complete or partial remission, curing a disease or condition or a symptom thereof, lower risk of a disease or condition, e.g., neuropathy, stroke, neurodegenerative disease (e.g., Alzheimer's disease), Parkinson's Disease, amyotrophic lateral sclerosis (AML), multiple sclerosis, Huntington's Disease, dementia with Lewy bodies, Friedreich's ataxia, hair follicle morphogenesis, diabetes, sepsis, transplant rejection, periventricular leukomalacia, ischemia reperfusion injury, blood coagulation, myocardial infarction, and kidney dysfunction such as acute kidney failure. The disease or condition may be involved with dysregulated, e.g., abnormal, ferroptosis. Improvements in or lessening the severity of any of these symptoms can be assessed according to methods and techniques known in the art.
The terms “about” and “approximately,” when used in connection with a number such as a percentage include the number as specified, and a range of the number (e.g., a range of percentages, for example, a range of ±10% with respect to a specific point value) that is recognized by one of ordinary skill in the art.
In a first embodiment, a compound of this disclosure is a compound of the following structural Formula I:
a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein:
Combinations of substituents as disclosed herein are those that result in the formation of stable or chemically feasible compounds. For abbreviation or according to common practice, certain hydrogen atoms attached to a certain atom (e.g., a carbon atom C or a nitrogen atom N) are not specifically spelled out in a chemical structure, formula, or notation; hydrogen atoms are deemed to be present to the extent the valences of the certain atom (e.g., C or N) are completed.
In a second embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, Ar1 is 5- to 6-membered heteroaryl or 5- to 7-membered heterocyclyl; and all other variables not specifically defined herein are as defined in the preceding embodiment.
In a third embodiment, a compound of the disclosure is a compound of the following structural Formula IIa:
a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.
In a fourth embodiment, a compound of the disclosure is a compound of the following structural Formula IIb:
a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.
In a fifth embodiment, a compound of the disclosure is a compound of the following structural Formula IIIa:
a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.
In a sixth embodiment, a compound of the disclosure is a compound of the following structural Formula IIIb:
a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.
In a seventh embodiment, a compound of the disclosure is a compound of the following structural Formula IIIc:
a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.
In an eighth embodiment, a compound of the disclosure is a compound of the following structural Formula IIId:
a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.
In a ninth embodiment, a compound of the disclosure is a compound of the following structural Formula IVa:
a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing; wherein X1 and X3 are each independently C or N; and Z1 and Z2 are each independently N or O; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.
In a tenth embodiment, a compound of the disclosure is a compound of the following structural Formula IVb:
a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing; wherein X1 and X3 are each independently C or N; Ar1 is aromatic or non-aromatic; and Z1, Z2, and Z3 are each independently N or C; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.
In an eleventh embodiment, a compound of the disclosure is a compound of the following structural Formula IVc:
a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing; wherein X1 and X3 are each independently C or N; and Z1 and Z2 are each independently O or N; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.
In a twelfth embodiment, a compound of the disclosure is a compound of the following structural Formula IVd:
a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing; wherein X1 and X3 are each independently C or N; and Z1 and Z2 are each independently O or N; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.
In a thirteenth embodiment, a compound of the disclosure is a compound of the following structural Formula Va:
a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing; wherein X1 and X3 are each independently N or C; T1 is C or O; T2 is C or N; Rg, for each occurrence, is selected from CF3, —CH3, —OCH3, and —CH2CH3; q is 0, 1, or 2; Rb is selected from H, halogen, C1 to C3 alkoxy, and C1 to C3 alkyl; and Rc is selected from halogen, C1 to C3 alkoxy, and C1 to C3 alkyl; wherein the C1 to C3 alkoxy and C1 to C3 alkyl of Rb and Rc, for each occurrence, are each optionally substituted with 1 to 3 groups of halogen; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.
In a fourteenth embodiment, a compound of the disclosure is a compound of the following structural Formula Vb:
a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing; wherein X1 and X3 are each independently N or C; Ra is selected from C1 to C3 alkoxy and C1 to C3 alkyl; Rb is selected from H, halogen, C1 to C3 alkoxy, and C1 to C3 alkyl; and Rc is selected from halogen, C1 to C3 alkoxy, and C1 to C3 alkyl; wherein the C1 to C3 alkoxy and C1 to C3 alkyl of Ra, Rb, and Rc, for each occurrence, are each optionally substituted with 1 to 3 groups of halogen; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.
In a fifteenth embodiment, a compound of the disclosure is a compound of the following structural Formula VIa:
a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing; wherein X1 and X3 are each independently N or C; T1 is C or O; T2 is C or N; Rg, for each occurrence, is independently selected from CF3, —CH3, —OCH3, and —CH2CH3; q is 0, 1, or 2; Rb is selected from H, halogen, C1 to C3 alkoxy, and C1 to C3 alkyl; and Rc is selected from halogen, C1 to C3 alkoxy, and C1 to C3 alkyl; the C1 to C3 alkoxy and C1 to C3 alkyl of Rb and Rc, for each occurrence, are each optionally substituted with 1 to 3 groups of halogen; Z1 and Z2 are each independently N or O; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.
In a sixteenth embodiment, a compound of the disclosure is a compound of the following structural Formula VIb:
a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing; wherein X1 and X3 are each independently N or C; T1 is C or O; T2 is C or N; Rg, for each occurrence, is independently selected from CF3, —CH3, —OCH3, and —CH2CH3; q is 0, 1, or 2; Rb is selected from H, halogen, C1 to C3 alkoxy, and C1 to C3 alkyl; and Rc is selected from halogen, C1 to C3 alkoxy, and C1 to C3 alkyl; the C1 to C3 alkoxy and C1 to C3 alkyl of Rb and Rc, for each occurrence, are each optionally substituted with 1 to 3 groups of halogen; Ar1 is aromatic or non-aromatic; and Z1, Z2, and Z3 are each independently N or C; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.
In a seventeenth embodiment, a compound of the disclosure is a compound of the following structural Formula VIc:
a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing; wherein X1 and X3 are each independently N or C; T1 is C or O; T2 is C or N; Rg, for each occurrence, is independently selected from CF3, —CH3, —OCH3, and —CH2CH3; q is 0, 1, or 2; Rb is selected from H, halogen, C1 to C3 alkoxy, and C1 to C3 alkyl; and Rc is selected from halogen, C1 to C3 alkoxy, and C1 to C3 alkyl; the C1 to C3 alkoxy and C1 to C3 alkyl of Rb and Rc, for each occurrence, are each optionally substituted with 1 to 3 groups of halogen; and Z1 and Z2 are each independently O or N; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.
In an eighteenth embodiment, a compound of the disclosure is a compound of the following structural Formula VId:
a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing; wherein X1 and X3 are each independently N or C; T1 is C or O; T2 is C or N; Rg, for each occurrence, is independently selected from CF3, —CH3, —OCH3, and —CH2CH3; q is 0, 1, or 2; Rb is selected from H, halogen, C1 to C3 alkoxy, and C1 to C3 alkyl; and Rc is selected from halogen, C1 to C3 alkoxy, and C1 to C3 alkyl; the C1 to C3 alkoxy and C1 to C3 alkyl of Rb and Rc, for each occurrence, are each optionally substituted with 1 to 3 groups of halogen; and Z1 and Z2 are each independently O or N; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.
In a nineteenth embodiment, a compound of the disclosure is a compound of the following structural Formula VIIa:
a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing; wherein Z1 and Z2 are each independently N or O; Ra is selected from C1 to C3 alkoxy and C1 to C3 alkyl; Rb is selected from H, halogen, C1 to C3 alkoxy, and C1 to C3 alkyl; and Rc is selected from halogen, C1 to C3 alkoxy, and C1 to C3 alkyl; wherein the C1 to C3 alkoxy and C1 to C3 alkyl of Ra, Rb, and Rc, for each occurrence, are each optionally substituted with 1 to 3 groups of halogen; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.
In a twentieth embodiment, a compound of the disclosure is a compound of the following structural Formula VIIb:
a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing; wherein Ar1 is aromatic or non-aromatic; Z1, Z2, and Z3 are each independently N or C; Ra is selected from C1 to C3 alkoxy and C1 to C3 alkyl; Rb is selected from H, halogen, C1 to C3 alkoxy, and C1 to C3 alkyl; and Rc is selected from halogen, C1 to C3 alkoxy, and C, to C3 alkyl; wherein the C1 to C3 alkoxy and C, to C3 alkyl of Ra, Rb, and Rc, for each occurrence, are each optionally substituted with 1 to 3 groups of halogen; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.
In a twenty-first embodiment, a compound of the disclosure is a compound of the following structural Formula VIIc:
a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein Z1 and Z2 are each independently O or N; Ra is selected from C1 to C3 alkoxy and C1 to C3 alkyl; Rb is selected from H, halogen, C1 to C3 alkoxy, and C, to C3 alkyl; and Rc is selected from halogen, C1 to C3 alkoxy, and C1 to C3 alkyl; wherein the C1 to C3 alkoxy and C, to C3 alkyl of Ra, Rb, and Rc, for each occurrence, are each optionally substituted with 1 to 3 groups of halogen; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.
In a twenty-second embodiment, a compound of the disclosure is a compound of the following structural Formula VIId:
a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein Z1 and Z2 are each independently O or N; Ra is selected from C1 to C3 alkoxy and C1 to C3 alkyl; Rb is selected from H, halogen, C1 to C3 alkoxy, and C1 to C3 alkyl; and Rc is selected from halogen, C1 to C3 alkoxy, and C1 to C3 alkyl; wherein the C1 to C3 alkoxy and C1 to C3 alkyl of Ra, Rb, and Rc, for each occurrence, are each optionally substituted with 1 to 3 groups of halogen; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.
In a twenty-third embodiment, a compound of the disclosure is a compound of the following structural Formulae VIIIa-VIIII:
a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein: X1 and X3 are each independently C or N;
In a twenty-fourth embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, Ra is selected from hydrogen, halogen, cyano, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3- to 10-membered heterocyclyl, phenyl, 5- to 7-membered heteroaryl, —C(═O)Rs, —C(═O)ORs, —NRpRq, —ORs, wherein the C3-C10 cycloalkyl, 3- to 10-membered heterocyclyl, phenyl, and 5- to 7-membered heteroaryl of Ra are each optionally substituted with 1-3 groups selected from halogen, ORs, and C1-C10 alkyl optionally substituted with 1 to 3 groups of halogen;
In a twenty-fifth embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, Ra is selected from H, F methyl,
—O(CH2)3CH3, —(CH2)4CH3,
—O(CH2)2CH2F,
—N(CH2CH3)2,
—N(CH2CH3)(CH2)4CH3, —N(CH2CH3)(CH2)3OCH3, —O(CH2)4CH3,
—C(CH3)2CH2CH3, —C(CH3)3,
—N(CH3)CH2CF3,
—N(CH3)2,
—O(CH2)2OCH3,
—C(═O)CF3, —N(CH2CH3)(CH2)4CH3, —N(CH2CH3)(CH2)3OCH3,
—O(CH2)4CH3, —OCH2CH3,
—C(═O)OCH2CH3, —OCH3,
—N(CH3)(CH2CH2OCH2OCH2CH3); all other variables not specifically defined herein are as defined in any one of the preceding embodiments.
In a twenty-sixth embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, Ra is selected from
—ORx, and —CH2Rx, wherein Rx, for each occurrence, is independently selected from C1 to C2 alkyl optionally substituted with 1 to 3 groups of halogen; all other variables not specifically defined herein are as defined in any one of the preceding embodiments.
In a twenty-seventh embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, Ra is selected from
—ORx, and —CH2Rx, wherein Rx, for each occurrence, is independently selected from CF3, —CH3, and —CH2CH3; all other variables not specifically defined herein are as defined in any one of the preceding embodiments.
In a twenty-eighth embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, Rb is selected from is H, halogen, C1 to C6 alkyl, —NRpRq, CN, C1-C6 alkoxy, and 5- to 6-membered heterocyclyl optionally substituted with C1-C3 alkyl optionally substituted with 1 to 3 groups selected from halogen, wherein Rp and Rq are each selected from C1 to C6 alkyl, and wherein the C1-C6 alkyl and C1-C6 alkoxy of Rb and the C1-C6 alkyl of Rp and Rq are each optionally substituted with 1 to 3 groups selected from halogen; all other variables not specifically defined herein are as defined in any one of the preceding embodiments.
In a twenty-ninth embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, Rb is H, methyl, —NHCH3, —N(CH3)2, —O(CH2)2CH3, F, —OCH3, —CF3, Cl, —N(CH3)2, and
all other variables not specifically defined herein are as defined in any one of the preceding embodiments.
In a thirtieth embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, Rb is selected from halogen, C1-C2 alkyl, and C1-C2 alkoxy; all other variables not specifically defined herein are as defined in any one of the preceding embodiments.
In a thirty-first embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, Rb is selected from F, methyl, and —OCH3; all other variables not specifically defined herein are as defined in any one of the preceding embodiments.
In a thirty-second embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, Rc, for each occurrence, is independently selected from is halogen, C1-C6 alkyl, —NRpRq, CN, and C1-C6 alkoxy, wherein Rp and Rq are each selected from C1 to C6 alkyl, and wherein the C1-C6 alkyl and C1-C6 alkoxy of Rc and the C1-C6 alkyl of Rp and Rq are each optionally substituted with 1 to 3 groups selected from halogen; all other variables not specifically defined herein are as defined in any one of the preceding embodiments.
In a thirty-third embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, Rc is selected from methyl, F, —OCH3, Cl, —N(CH3)2, and CN; all other variables not specifically defined herein are as defined in any one of the preceding embodiments.
In a thirty-fourth embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, Rc is selected from halogen, C1-C2 alkyl, and C1-C2 alkoxy; all other variables not specifically defined herein are as defined in any one of the preceding embodiments.
In a thirty-fifth embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, Rc is selected from F, methyl, and —OCH3; all other variables not specifically defined herein are as defined in any one of the preceding embodiments.
In a thirty-sixth embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, Rd, for each occurrence, is independently selected from halogen, C1-C6 alkyl, NO2, CN, and C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy of Rd are each optionally substituted with 1 to 3 groups selected from halogen; all other variables not specifically defined herein are as defined in any one of the preceding embodiments.
In a thirty-seventh embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, Rd is selected from F, methyl, Cl, NO2, and —OCH3; all other variables not specifically defined herein are as defined in any one of the preceding embodiments.
In a thirty-eighth embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, Rd is selected from halogen, C1-C2 alkyl, and C1-C2 alkoxy; all other variables not specifically defined herein are as defined in any one of the preceding embodiments.
In a thirty-nineth embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, Rd is selected from F, methyl, and —OCH3; all other variables not specifically defined herein are as defined in any one of the preceding embodiments.
In a fortieth embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, Re, for each occurrence, is independently selected from halogen, cyano, C1-C10 alkyl, phenyl, 5- to 7-membered heteroaryl, 3- to 10-membered heterocyclyl, C3-C10 cycloalkyl, —C(═O)Rs, C2-C10 alkenyl, ═O, ═NRp; —C(═O)ORs, —C(═O)NRpRq, —NRpRq, and —NRpC(═O)Rs, wherein
In a forty-first embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, Re, for each occurrence, is selected from methyl, ethyl, ═O, —(CH2)3OCH3, —(CH2)2OCH3, —CH2C(═O)NH2, —(CH2)2C(═O)NH2, —C(═O)C(CH3)3, —C(═O)NHC(CH3)3, —(CH2)2NHC(═O)NH2, —(CH2)3NHCH3, —(CH2)2NHCH3, —(CH2)3C(═O)NH2, —(CH2)2N(CH3)2, —(CH2)2OH,
—C(═O)CH3, —(CH2)2NH2,
—C(═O)OC(CH3)3,
—C(CH3)3, —(CH2)2O(CH2)2OCH3, Bn (benzyl), —(CH2)3N(CH3)2,
—CH(CH3)2,
═NH, ═NCH3, —C(═O)OH, —C(═O)CF3, —C(═O)NHCH2CH3, —NHC(═O)CH3,
—N(CH3)(CH2)2OCH2OCH2CH3, —NH2, —C(═O)N2,
—N(CH3)2, —NHCH2CH3, and
all other variables not specifically defined herein are as defined in any one of the preceding embodiments.
In a forty-second embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, Re is selected from ═O, —C(═O)NRpRq, and C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with 1 to 3 groups selected from C1-C3 alkoxy, —C(═O)NRpRq, and —NRpRq, wherein Rp and Rq are each selected from H and C1-C3 alkyl; all other variables not specifically defined herein are as defined in any one of the preceding embodiments.
In a forty-third embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, Re is selected from C1-C2 alkyl, ═O, and —C(═O)NH2; all other variables not specifically defined herein are as defined in any one of the preceding embodiments.
In a forty-fourth embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, Ra and Rb join to form a 5- to 6-membered carbocyclic, heterocyclic, aromatic, or heteroaromatic ring optionally substituted with 1 to 3 groups selected from ═O, C1-C6 alkyl, and 5- to 7-membered heterocyclyl, wherein the C1-C6 alkyl is optionally substituted with 1 to 3 groups of halogen, and the 5- to 7-membered heterocyclyl is optionally substituted with 1 to 3 groups of C1-C3 alkyl optionally substituted with 1 to 3 groups of halogen; all other variables not specifically defined herein are as defined in any one of the preceding embodiments.
In a forty-fifth embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, Ra and Rb join to form a structure selected from:
all other variables not specifically defined herein are as defined in any one of the preceding embodiments.
In a forty-sixth embodiment, a compound of the disclosure is a compound of the following structural formulae VIIIa-1, VIIId-1, and VIIIf-1:
a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein:
—ORx, and —CH2Rx, wherein Rx, for each occurrence, is independently selected from CF3 and C1 to C2 alkyl;
In certain embodiments, the at least one compound of the disclosure is selected from Compounds 1 to 659 depicted in Table 1, a tautomer thereof, a solvate or stereoisomer of the compound depicted in Table 1 or the tautomer, or a pharmaceutically acceptable salt of the foregoing.
Another aspect of the disclosure provides a pharmaceutical composition comprising at least one compound selected from a compound of the Formulae disclosed herein, Compounds 1 to 659, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, and at least one pharmaceutically acceptable carrier.
In some embodiments, the pharmaceutically acceptable carrier is selected from pharmaceutically acceptable vehicles and pharmaceutically acceptable adjuvants. In some embodiments, the pharmaceutically acceptable carrier is chosen from pharmaceutically acceptable fillers, disintegrants, surfactants, binders, and lubricants.
It will also be appreciated that a pharmaceutical composition of this disclosure can be employed in combination therapies; that is, the pharmaceutical compositions described herein can further include an additional active pharmaceutical agent. Alternatively, a pharmaceutical composition comprising a compound selected from a compound of the Formulae disclosed herein, Compounds 1 to 659, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing can be administered as a separate composition concurrently with, prior to, or subsequent to, a composition comprising an additional active pharmaceutical agent.
In some embodiments, the pharmaceutically acceptable carrier may be chosen from adjuvants and vehicles. The pharmaceutically acceptable carrier, as used herein, can be chosen, for example, from any and all solvents, diluents, other liquid vehicles, dispersion aids, suspension aids, surface active agents, isotonic agents, thickening agents, emulsifying agents, preservatives, solid binders, and lubricants, which are suited to the particular dosage form desired. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D. B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988 to 1999, Marcel Dekker, New York discloses various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier is incompatible with the compounds of this disclosure, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this disclosure. Non-limiting examples of suitable pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates, glycine, sorbic acid, and potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts, and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars (such as lactose, glucose and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository waxes), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil), glycols (such as propylene glycol and polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffering agents (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer solutions, non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), coloring agents, releasing agents, coating agents, sweetening agents, flavoring agents, perfuming agents, preservatives, and antioxidants.
A compound selected from a compound of the Formulae disclosed herein, Compounds 1 to 659, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition disclosed herein can be administered orally in solid dosage forms, such as capsules, tablets, troches, dragées, granules and powders, or in liquid dosage forms, such as elixirs, syrups, emulsions, dispersions, and suspensions. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described herein can also be administered parenterally, in sterile liquid dosage forms, such as dispersions, suspensions or solutions. Other dosages forms that can also be used to administer the compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described herein as an ointment, cream, drops, transdermal patch or powder for topical administration, as an ophthalmic solution or suspension formation, e.g., eye drops, for ocular administration, as an aerosol spray or powder composition for inhalation or intranasal administration, or as a cream, ointment, spray or suppository for rectal or vaginal administration.
Gelatin capsules containing a compound, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, and/or a pharmaceutically acceptable salt of the foregoing disclosed herein and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like, can also be used. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of time. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
Liquid dosage forms for oral administration can further comprise at least one agent selected from coloring and flavoring agents to increase patient acceptance.
In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols can be examples of suitable carriers for parenteral solutions. Solutions for parenteral administration may comprise a water soluble salt of the at least one compound describe herein, at least one suitable stabilizing agent, and if necessary, at least one buffer substance. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, can be examples of suitable stabilizing agents. Citric acid and its salts and sodium EDTA can also be used as examples of suitable stabilizing agents. In addition, parenteral solutions can further comprise at least one preservative, selected, for example, from benzalkonium chloride, methyl- and propylparaben, and chlorobutanol.
A pharmaceutically acceptable carrier is, for example, selected from carriers that are compatible with active ingredients of the composition (and in some embodiments, capable of stabilizing the active ingredients) and not deleterious to the subject to be treated. For example, solubilizing agents, such as cyclodextrins (which can form specific, more soluble complexes with the at least one compound and/or at least one pharmaceutically acceptable salt disclosed herein), can be utilized as pharmaceutical excipients for delivery of the active ingredients. Examples of other carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and pigments such as D&C Yellow #10. Suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences, A. Osol.
For administration by inhalation, the compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described herein may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or nebulisers. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described herein may also be delivered as powders, which may be formulated, and the powder composition may be inhaled with the aid of an insufflation powder inhaler device. One exemplary delivery system for inhalation can be metered dose inhalation (MDI) aerosol, which may be formulated as a suspension or solution of a compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described herein in at least one suitable propellant, selected, for example, from fluorocarbons and hydrocarbons.
For ocular administration, an ophthalmic preparation may be formulated with an appropriate weight percentage of a solution or suspension of the compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described herein in an appropriate ophthalmic vehicle, such that the compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described herein is maintained in contact with the ocular surface for a sufficient time period to allow the compound to penetrate the corneal and internal regions of the eye.
Useful pharmaceutical dosage-forms for administration of the compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described herein include, but are not limited to, hard and soft gelatin capsules, tablets, parenteral injectables, and oral suspensions. In some embodiments, the pharmaceutical compositions disclosed herein may be in the form of controlled release or sustained release compositions as known in the art.
The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules, lozenges or the like in the case of solid compositions. In such compositions, the active material is usually a component ranging from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form. Unit dosage formulations are preferably about of 5, 10, 25, 50, 100, 250, 500, or 1,000 mg per unit. In a particular embodiment, unit dosage forms are packaged in a multipack adapted for sequential use, such as blisterpack comprising sheets of at least 6, 9 or 12 unit dosage forms.
In some embodiments, unit capsules can be prepared by filling standard two-piece hard gelatin capsules each with, for example, 100 milligrams of the compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described herein in powder, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.
In some embodiments, a mixture of the compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described herein and a digestible oil such as soybean oil, cottonseed oil or olive oil can be prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient. The capsules are washed and dried.
In some embodiments, tablets can be prepared by conventional procedures so that the dosage unit comprises, for example, 100 milligrams of the compound, stereoisomers thereof, or pharmaceutically acceptable salts thereof, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.
In some embodiments, a parenteral composition suitable for administration by injection can be prepared by stirring 1.5% by weight of the compound and/or at least an enantiomer, a diastereoisomer, or pharmaceutically acceptable salt thereof disclosed herein in 10% by volume propylene glycol. The solution is made to the expected volume with water for injection and sterilized.
In some embodiment, an aqueous suspension can be prepared for oral administration. For example, each 5 milliliters of an aqueous suspension comprising 100 milligrams of finely divided compound, stereoisomers thereof, or pharmaceutically acceptable salts thereof, 100 milligrams of sodium carboxymethyl cellulose, 5 milligrams of sodium benzoate, 1.0 grams of sorbitol solution, U.S.P., and 0.025 milliliters of vanillin can be used.
The same dosage forms can generally be used when the compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described herein is administered stepwise or in conjunction with at least one other therapeutic agent. When drugs are administered in physical combination, the dosage form and administration route should be selected depending on the compatibility of the combined drugs. Thus, the term “coadministration” is understood to include the administration of at least two agents concomitantly or sequentially, or alternatively as a fixed dose combination of the at least two active components.
The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt disclosed herein can be administered as the sole active ingredient or in combination with at least one second active ingredient.
The compound, tautomer, solvate, or stereoisomer described herein may be used per se, or in the form of their pharmaceutically acceptable salts, such as hydrochlorides, hydrobromides, acetates, sulfates, citrates, carbonates, trifluoroacetates and the like. When the compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described herein contain relatively acidic functionalities, salts can be obtained by addition of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or the like. When the compound, tautomer, solvate, or stereoisomer described herein contain relatively basic functionalities, salts can be obtained by addition of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic acids, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galacturonic acids and the like (see, for example, Berge et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 1977, 66, 1-19).
Neutral forms of the pharmaceutically acceptable salt described herein may be regenerated by contacting the salt with a base or acid, and isolating the parent compound in the conventional manner.
This disclosure provides prodrugs. Prodrugs of the compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described herein that readily undergo chemical changes under physiological conditions to provide the compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of the present disclosure. Additionally, prodrugs can be converted to the compound, tautomer, solvate, stereoisomer, or a pharmaceutically acceptable salt of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of the present disclosure when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be more bioavailable by oral administration than the parent drug. The prodrug may also have improved solubility in pharmacological compositions over the parent drug. A wide variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. An example, without limitation, of a prodrug would be a compound of the present disclosure which is administered as an ester (the “prodrug”), but then is metabolically hydrolyzed to the carboxylic acid, i.e. the active entity.
Certain compound, tautomer, stereoisomer, or pharmaceutically acceptable salt of the disclosure can exist in unsolvated forms as well as solvated forms, including hydrate forms. Certain compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of the disclosure may exist in multiple crystalline or amorphous forms.
Certain compound, tautomer, solvate, or pharmaceutically acceptable salt in this disclosure possesses asymmetric carbon atoms (optical centers) or double bonds; the racemates, enantiomers, diastereoisomers, geometric isomers and individual isomers are all intended to be encompassed within the scope of the present disclosure.
Another aspect of the disclosure provides a method of treating a disease or condition, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of Formulae disclosed herein, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing, wherein the disease or condition is selected from neuropathy, stroke, neurodegenerative disease (e.g., Alzheimer's disease), Parkinson's Disease, amyotrophic lateral sclerosis (AML), multiple sclerosis, Huntington's Disease, dementia with Lewy bodies, Friedreich's ataxia, hair follicle morphogenesis, diabetes, sepsis, transplant rejection, periventricular leukomalacia, ischemia reperfusion injury, blood coagulation, myocardial infarction, and kidney dysfunction such as acute kidney failure. In some embodiments, the disease or condition is involved with dysregulated ferroptosis, e.g., abnormal ferroptosis.
In another aspect, disclosed herein is a compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt as described herein, including a compound of the Formulae disclosed herein, Compounds 1 to 659, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof, for use as a medicament.
In another aspect, disclosed herein is use of a compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt as described herein, including a compound of the Formulae disclosed herein, Compounds 1 to 659, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof, for the manufacture of a medicament for treating a disease or condition selected from neuropathy, stroke, neurodegenerative disease (e.g., Alzheimer's disease), Parkinson's Disease, amyotrophic lateral sclerosis (AML), multiple sclerosis, Huntington's Disease, dementia with Lewy bodies, Friedreich's ataxia, hair follicle morphogenesis, diabetes, sepsis, transplant rejection, periventricular leukomalacia, ischemia reperfusion injury, blood coagulation, myocardial infarction, and kidney dysfunction such as acute kidney failure. In some embodiments, the disease or condition is involved with dysregulated ferroptosis, e.g., abnormal ferroptosis.
In a further aspect of this disclosure, a compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt as described herein, including a compound of the Formulae disclosed herein, Compounds 1 to 659, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof, is for use in treating a disease or condition selected from neuropathy, stroke, neurodegenerative disease (e.g., Alzheimer's disease), Parkinson's Disease, amyotrophic lateral sclerosis (AML), multiple sclerosis, Huntington's Disease, dementia with Lewy bodies, Friedreich's ataxia, hair follicle morphogenesis, diabetes, sepsis, transplant rejection, periventricular leukomalacia, ischemia reperfusion injury, blood coagulation, myocardial infarction, and kidney dysfunction such as acute kidney failure. In some embodiments, the disease or condition is involved with dysregulated ferroptosis, e.g., abnormal ferroptosis.
Another aspect of the disclosure provides a method of modulating, e.g., inhibiting, ferroptosis in a subject in need thereof, comprising administering to the subject, a therapeutically effective amount of a compound of Formulae disclosed herein, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing.
In another aspect, disclosed herein is use of a compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt as described herein, including a compound of the Formulae disclosed herein, Compounds 1 to 659, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof, for modulating, e.g., inhibiting, ferroptosis in a subject in need thereof.
In another aspect of this disclosure, a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt as described herein, including a compound of the Formulae disclosed herein, Compounds 1 to 659, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof, is for use in modulating, e.g., inhibiting, ferroptosis in a subject in need thereof by contacting the subject with the compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, pharmaceutically acceptable salt, or pharmaceutical composition.
A compound of the Formulae disclosed herein, Compounds 1 to 659, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof may be administered once daily, twice daily, or three times daily, for example, for the treatment of a disease or condition, selected from neuropathy, stroke, neurodegenerative disease (e.g., Alzheimer's disease), Parkinson's Disease, amyotrophic lateral sclerosis (AML), multiple sclerosis, Huntington's Disease, dementia with Lewy bodies, Friedreich's ataxia, hair follicle morphogenesis, diabetes, sepsis, transplant rejection, periventricular leukomalacia, ischemia reperfusion injury, blood coagulation, myocardial infarction, and kidney dysfunction such as acute kidney failure. In some embodiments, the disease or condition is involved with dysregulated ferroptosis, e.g., abnormal ferroptosis.
A compound of the Formulae disclosed herein, Compounds 1 to 659, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof may be administered, for example, various manners, such as orally, topically, rectally, parenterally, by inhalation spray, or via an implanted reservoir, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The term “parenteral” as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. The compositions disclosed herein may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art. Parenteral administration can be by continuous infusion over a selected period of time. Other forms of administration contemplated in this disclosure are as described in International Patent Application Nos. WO 2013/075083, WO 2013/075084, WO 2013/078320, WO 2013/120104, WO 2014/124418, WO 2014/151142, and WO 2015/023915.
The contacting is generally effected by administering to the subject an effective amount of one or more compounds, tautomers, solvates, stereoisomers, and pharmaceutically acceptable salt disclosed herein. Generally, administration is adjusted to achieve a therapeutic dosage of about 0.1 to 50, preferably 0.5 to 10, more preferably 1 to 10 mg/kg, though optimal dosages are compound specific, and generally empirically determined for each compound.
The dosage administered will be dependent on factors, such as the age, health and weight of the recipient, the extent of disease, type of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired. In general, a daily dosage of the active ingredient can vary, for example, from 0.1 to 2000 milligrams per day. For example, 10-500 milligrams once or multiple times per day may be effective to obtain the desired results.
In some embodiments, 2 mg to 1500 mg or 5 mg to 1000 mg of a compound of the Formulae disclosed herein, Compounds 1 to 659, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof are administered once daily, twice daily, or three times daily. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described herein is administered for morning/daytime dosing, with off period at night.
In order that the disclosure described herein may be more fully understood, the following examples are disclosed herein. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this disclosure in any way.
The compounds of the disclosure, selected from a compound of the Formulae depicted herein, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, can be made according to standard chemical practices or as illustrated herein, including the following synthetic schemes for Compounds 1 to 659 as representative examples of Formula I.
To a solution of 4-methylpiperidine (252 mg, 2.55 mmol) and 1-fluoro-4-nitrobenzene (300 mg, 2.13 mmol) in DMSO (5 mL) was added K2CO3 (440 mg, 3.20 mmol). Then the reaction was stirred overnight at 80° C. The mixture was extracted by ethyl acetate (EA) (25 mL×3). The combined organic layers were washed with brine (15 mL×3), dried over Na2SO4 and concentrated to give the crude product, which was purified by silica gel chromatography (EA/petroleum ether (PE)=1:3) to give the desired product as a yellow solid (445 mg, 95%). Mass (m/z): 221.2 [M+H]+.
To a solution of 4-methyl-1-(4-nitrophenyl)piperidine (445 mg, 2.02 mmol) in MeOH (10 mL) was added Pd/C (50 mg). The solution was stirred for 3 hours at room temperature (r.t.) under H2. The reaction mixture was filtered and concentrated under vacuum to afford the desired product as a purple solid. (326 mg, 85%). Mass (m/z): 190.3 [M+H]+.
To a solution of 4-(4-methylpiperidin-1-yl)aniline (49.4 mg, 0.26 mmol) and 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (48.4 mg, 0.2 mmol) in 1,4-dioxane (5 mL) was added Pd2(dba)3 (9.2 mg, 0.01 mmol), X-Phos (23.8 mg, 0.05 mmol) and Cs2CO3 (98.4 mg, 0.3 mmol) respectively under an argon atmosphere. The resulting mixture was heated to 110° C. and stirred for overnight at the same temperature. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (5 mL) 3 times. The organic layer was combined and washed with water, saturated NaHCO3 (aq) and brine respectively, and then dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/AcOEt, 1/4) to give 46.0 mg of compound 1 in a yield of 65.3% as a dark khaki powder. 1H NMR (400 MHz, DMSO-d6) δ 7.02-6.85 (m, 5H), 6.66-6.54 (m, 2H), 4.57 (s, 2H), 3.70-3.57 (m, 2H), 3.22 (s, 3H), 2.71-2.55 (m, 2H), 1.81-1.62 (m, 2H), 1.46 (m, 1H), 1.37-1.10 (m, 2H), 0.94 (d, J=6.4 Hz, 3H). Mass (m/z): 352.3 [M+H]+.
The title compound 2 (910 mg) was prepared in a total yield of 74.6% as a yellow solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (878 mg, 3.6 mmol), 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (726 mg, 3.0 mmol), Pd2(dba)3 (27.5 mg, 0.03 mmol), X-Phos (71.55 mg, 0.15 mmol), and Cs2CO3 (1.47 g, 4.5 mmol) in 1,4-dioxane (30 mL) according to the procedure for compound 1. 1H NMR (300 MHz, DMSO-d6) δ 7.01-6.83 (m, 5H), 6.67-6.52 (m, 2H), 4.56 (s, 2H), 3.68-3.57 (m, 2H), 3.22 (s, 3H), 2.68-2.56 (m, 2H), 2.45-2.34 (m, 1H), 1.94-1.81 (m, 2H), 1.65-1.47 (m, 2H). Mass (m/z): 406.2 [M+H]+.
The title compound 3 (9.4 mg) was prepared in a total yield of 44.9% as a sky blue solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (15.9 mg, 0.065 mmol), 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (12.8 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.14 (d, J=8.8 Hz, 1H), 7.00 (d, J=8.4 Hz, 2H), 6.91 (d, J=8.4 Hz, 2H), 6.74 (dd, J=8.8, 2.4 Hz, 1H), 6.62 (d, J=2.4 Hz, 1H), 4.40 (t, J=6.4 Hz, 2H), 3.68-3.59 (m, 2H), 3.15 (s, 3H), 2.69-2.57 (m, 2H), 2.55-2.52 (m, 2H), 2.42 (m, 1H), 1.96-1.79 (m, 2H), 1.64-1.50 (m, 2H). Mass (m/z): 420.2 [M+H]+.
The title compound 4 (17 mg) was prepared in a total yield of 21.10% as brown oil from N1-(4-methoxybutyl)-N1-pentylbenzene-1,4-diamine (50 mg, 0.19 mmol), 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (46 mg, 0.19 mmol), tris(dibenzylidenacetone)palladium (0) (4.5 mg, 0.009 mmol), dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphane (1.73 mg, 0.019 mmol, 0.08 equivs) and sodium tert-butoxide (27 mg, 0.28 mmol, 1.5 equivs) in dry 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.57 (s, 1H), 6.99-6.85 (m, 3H), 6.64 (dd, J=22.2, 5.5 Hz, 2H), 6.52 (s, 1H), 6.44 (s, 1H), 4.54 (s, 2H), 3.21 (d, J=3.6 Hz, 1H), 1.51 (s, 7H), 1.40-1.17 (m, 3H), 0.87 (t, J=7.0 Hz, 4H). Mass (m/z): 426.7 [M+H]+.
The title compound 5 (26.0 mg) was prepared in a total yield of 38.3% as a grey solid from 4-butoxyaniline (41 mg, 0.250 mmol), 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (50 mg, 0.208 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-Phos (6 mg, 0.01 mmol) and Cs2CO3 (102 mg, 0.318 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.84 (s, 1H), 6.98 (dd, J=8.4, 5.6 Hz, 3H), 6.85 (d, J=8.8 Hz, 2H), 6.62 (dd, J=8.8, 2.4 Hz, 1H), 6.54 (d, J=2.4 Hz, 1H), 4.57 (s, 2H), 3.90 (t, J=6.4 Hz, 2H), 3.22 (s, 3H), 1.72-1.63 (m, 2H), 1.43 (h, J=7.6 Hz, 2H), 0.93 (t, J=7.6 Hz, 3H). Mass (m/z): 327.3 [M+H]+.
The title compound 6 (29.7 mg) was prepared in a total yield of 44.1% as an off-white solid from 4-pentylaniline (41 mg, 0.250 mmol), 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (50 mg, 0.208 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-Phos (6 mg, 0.01 mmol) and Cs2CO3 (102 mg, 0.318 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.05 (d, J=8.4 Hz, 2H), 7.01 (d, J=8.8 Hz, 1H), 6.95 (d, J=8.4 Hz, 2H), 6.73 (dd, J=8.8, 2.4 Hz, 1H), 6.64 (d, J=2.4 Hz, 1H), 4.58 (s, 2H), 3.23 (s, 3H), 2.47 (d, J=7.6 Hz, 1H), 1.53 (p, J=7.6 Hz, 2H), 1.28 (tq, J=8.8, 5.2, 4.0 Hz, 5H), 0.86 (t, J=6.8 Hz, 3H). Mass (m/z): 325.3 [M+H]+.
The title compound 7 (31.5 mg) was prepared in a total yield of 43.0% as a brown solid from 4-(cyclohexyloxy)aniline (48 mg, 0.250 mmol), 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (50 mg, 0.208 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (106 mg, 0.312 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.85 (s, 1H), 6.98 (d, J=8.8 Hz, 3H), 6.85 (d, J=8.8 Hz, 2H), 6.63 (dd, J=8.8, 2.4 Hz, 1H), 6.55 (d, J=2.4 Hz, 1H), 4.57 (s, 2H), 4.19 (td, J=8.4, 4.0 Hz, 1H), 3.22 (s, 3H), 1.95-1.86 (m, 2H), 1.75-1.66 (m, 2H), 1.53 (dd, J=11.2, 5.6 Hz, 1H), 1.45-1.21 (m, 6H). Mass (m/z): 353.3 [M+H]+.
The title compound 8 (28.1 mg) was prepared in a total yield of 29.3% as a brown solid from 3-propoxy-4-(4-(trifluoromethyl)piperidin-1-yl)aniline (75 mg, 0.248 mmol), 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (50 mg, 0.208 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (106 mg, 0.312 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (300 MHz, DMSO-d6) δ 7.91 (s, 1H), 6.98 (d, J=8.7 Hz, 1H), 6.78 (d, J=8.1 Hz, 1H), 6.69 (dd, J=8.7, 2.4 Hz, 1H), 6.61-6.54 (m, 3H), 4.57 (s, 2H), 3.85 (t, J=6.3 Hz, 2H), 3.22 (s, 3H), 2.54 (s, 1H), 2.39 (ddd, J=19.2, 9.6, 5.1 Hz, 2H), 1.87 (d, J=11.4 Hz, 2H), 1.75 (q, J=6.6 Hz, 2H), 1.58 (qd, J=12.3, 3.9 Hz, 3H), 1.02 (t, J=7.2 Hz, 3H). Mass (m/z): 464.3 [M+H]+.
The title compound 9 (50.7 mg) was prepared in a total yield of 56.3% as a green solid from 4-(4-methoxy-4-(trifluoromethyl)piperidin-1-yl)aniline (68 mg, 0.248 mmol), 7-bromo-4-methyl-2H-benzo[b][1,4] oxazin-3(4H)-one (50 mg, 0.208 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol) and Cs2CO3 (106 mg, 0.312 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.27-6.83 (m, 5H), 6.65 (d, J=34.0 Hz, 2H), 4.58 (s, 2H), 3.50 (s, 2H), 3.41 (d, J=1.6 Hz, 3H), 3.23 (s, 3H), 2.99 (s, 2H), 2.16-1.91 (m, 4H). Mass (m/z): 436.3 [M+H]+.
The title compound 10 (30.4 mg) was prepared in a total yield of 39.3% as a brown solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (49 mg, 0.200 mmol), 7-bromo-4-(3-methoxypropyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (50 mg, 0.167 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-Phos (6 mg, 0.01 mmol) and Cs2CO3 (82 mg, 0.251 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.02-6.94 (m, 3H), 6.92-6.87 (m, 2H), 6.63 (dd, J=8.8, 2.4 Hz, 1H), 6.56 (d, J=2.4 Hz, 1H), 4.54 (s, 2H), 3.91-3.83 (m, 2H), 3.62 (d, J=12.0 Hz, 2H), 3.34 (d, J=6.0 Hz, 2H), 3.23 (s, 3H), 2.62 (td, J=12.4, 2.4 Hz, 2H), 2.42 (ddt, J=16.0, 7.6, 4.0 Hz, 1H), 1.88 (d, J=12.4 Hz, 2H), 1.82-1.71 (m, 2H), 1.61-1.50 (m, 2H). Mass (m/z): 464.3 [M+H]+.
The title compound 11 (53.7 mg) was prepared in a total yield of 68.3% as a brown solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (51 mg, 0.210 mmol), 7-bromo-4-(2-methoxyethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (50 mg, 0.175 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-Phos (6 mg, 0.01 mmol) and Cs2CO3 (86 mg, 0.262 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.07 (d, J=8.8 Hz, 1H), 7.00-6.95 (m, 2H), 6.92-6.87 (m, 2H), 6.63 (dd, J=8.8, 2.4 Hz, 1H), 6.57 (d, J=2.4 Hz, 1H), 4.55 (s, 2H), 4.02 (t, J=5.6 Hz, 2H), 3.67-3.57 (m, 2H), 3.50 (t, J=5.6 Hz, 2H), 3.24 (s, 3H), 2.62 (td, J=12.4, 2.4 Hz, 2H), 2.42 (tp, J=12.4, 4.0 Hz, 1H), 1.92-1.83 (m, 2H), 1.57 (qd, J=12.4, 4.0 Hz, 2H). Mass (m/z): 450.3 [M+H]+.
The title compound 12 (9.6 mg) was prepared in a yield of 14.2% as a pale yellow powder from 6-butoxypyridin-3-amine (50 mg, 0.21 mmol) and 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (38 mg, 0.24 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.90 (d, J=2.8 Hz, 1H), 7.46 (dd, J=8.8, 2.9 Hz, 1H), 6.99 (d, J=8.7 Hz, 1H), 6.74 (d, J=8.8 Hz, 1H), 6.60 (dd, J=8.7, 2.5 Hz, 1H), 6.51 (d, J=2.5 Hz, 1H), 4.57 (s, 2H), 4.18 (t, J=6.6 Hz, 2H), 3.22 (s, 3H), 1.67 (dq, J=8.6, 6.7 Hz, 2H), 1.51-1.32 (m, 2H), 0.92 (t, J=7.4 Hz, 3H). Mass (m/z): 328.5 [M+H]+.
The title compound 13 (57.2 mg) was prepared in a yield of 48.83% as a brown oil from 4-(3-fluoropropoxy)aniline (60 mg, 0.35 mmol) and 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (86 mg, 0.35 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.85 (s, 1H), 6.98 (t, J=8.5 Hz, 3H), 6.91-6.83 (m, 2H), 6.64-6.60 (m, 1H), 6.54 (d, J=2.4 Hz, 1H), 4.65 (q, J=5.8 Hz, 1H), 4.56 (d, J=2.2 Hz, 2H), 4.52 (dd, J=11.5, 5.9 Hz, 1H), 4.00 (t, J=6.3 Hz, 2H), 3.22 (s, 3H), 2.14-2.01 (m, 2H). Mass (m/z): 331.2 [M+H]+.
The title compound 14 (12.6 mg) was prepared in a total yield of 56.10% as a light gray solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (15.9 mg, 0.065 mmol), 2-(7-bromo-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)acetamide (14.3 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.00-6.72 (m, 5H), 6.63-6.51 (m, 2H), 4.61 (s, 2H), 4.38 (s, 2H), 3.66-3.57 (m, 2H), 2.68-2.56 (m, 2H), 2.41 (m, 1H), 1.92-1.82 (m, 2H), 1.63-1.50 (m, 2H). Mass (m/z): 449.2 [M+H]+.
The title compound 15 (20.1 mg) was prepared in a total yield of 87.0% as a rosy brown solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (15.9 mg, 0.065 mmol), 3-(7-bromo-3-oxo-2,3-dihydro-4H-benzo[b][1,4] oxazin-4-yl)propanamide (14.9 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.04-6.86 (m, 5H), 6.65-6.53 (m, 2H), 4.54 (s, 2H), 4.05 (t, J=7.6 Hz, 2H), 3.66-3.58 (m, 2H), 2.67-2.55 (m, 2H), 2.45-2.30 (m, 3H), 1.95-1.79 (m, 2H), 1.63-1.50 (m, 2H). Mass (m/z): 463.3 [M+H]+.
The title compound 16 (71.5 mg) was prepared in a total yield of 73.0% as a white solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (57 mg, 0.234 mmol), 7-bromo-4-ethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (50 mg, 0.195 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol) and Cs2CO3 (96 mg, 0.292 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.83 (s, 1H), 7.01 (d, J=8.8 Hz, 1H), 6.99-6.94 (m, 2H), 6.92-6.88 (m, 2H), 6.63 (dd, J=8.8, 2.4 Hz, 1H), 6.55 (d, J=2.4 Hz, 1H), 4.54 (s, 2H), 3.86 (q, J=7.2 Hz, 2H), 3.62 (d, J=12.0 Hz, 2H), 2.62 (td, J=12.4, 2.4 Hz, 2H), 2.42 (qd, J=10.4, 8.8, 6.0 Hz, 1H), 1.88 (dt, J=10.4, 3.2 Hz, 2H), 1.57 (qd, J=12.4, 4.0 Hz, 2H), 1.13 (t, J=7.2 Hz, 3H). Mass (m/z): 420.3 [M+H]+.
The title compound 17 (17.1 mg) was prepared in a total yield of 84.0% as a light orange solid from 6-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-amine (15.9 mg, 0.065 mmol), 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (12.1 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.76 (s, 1H), 7.40-7.33 (m, 1H), 6.95 (d, J=8.8 Hz, 1H), 6.85 (d, J=8.8 Hz, 1H), 6.53 (dd, J=8.8, 2.4 Hz, 1H), 6.45 (d, J=2.4 Hz, 1H), 4.55 (s, 2H), 4.36-4.18 (m, 2H), 3.21 (s, 3H), 2.81-2.72 (m, 2H), 2.54 (m, 1H), 1.90-1.78 (m, 2H), 1.51-1.38 (m, 2H). Mass (m/z): 407.2 [M+H]+.
The title compound 18 (18.7 mg) was prepared in a total yield of 81.1% as a light gray solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (15.9 mg, 0.065 mmol), 1-(7-bromo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2,2-dimethylpropan-1-one (14.9 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.35 (d, J=8.8 Hz, 1H), 7.02-6.83 (m, 4H), 6.48-6.33 (m, 2H), 4.21 (t, J=4.4 Hz, 2H), 3.92 (t, J=4.4 Hz, 2H), 3.67-3,55 (m, 2H), 2.69-2.54 (m, 2H), 2.41 (m, 1H), 1.93-1.82 (m, 2H), 1.63-1.50 (m, 2H), 1.27 (s, 9H). Mass (m/z): 462.2 [M+H]+.
The title compound 19 (9.3 mg) was prepared in a total yield of 46.9% as a yellow solid from 6-(2,6-dimethylmorpholino)-N1-methylbenzene-1,3-diamine (15.3 mg, 0.065 mmol), 1-(7-bromo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2,2-dimethylpropan-1-one (14.9 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 6.98 (d, J=8.8 Hz, 1H), 6.82-6.59 (m, 3H), 6.35-6.15 (m, 2H), 4.57 (s, 2H), 3.83-3.72 (m, 2H), 3.22 (s, 3H), 2.81-2.74 (m, 2H), 2.69 (d, J=5.2 Hz, 3H), 2.30-2.15 (m, 2H), 1.08 (d, J=6.4 Hz, 6H). Mass (m/z): 397.2 [M+H]+.
The title compound 20 (14.3 mg) was prepared in a total yield of 69.5% as a yellow solid from 6-(2,6-dimethylmorpholino)-N1,N1-dimethylbenzene-1,3-diamine (16.2 mg, 0.065 mmol), 1-(7-bromo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2,2-dimethylpropan-1-one (14.9 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 6.98 (d, J=8.8 Hz, 1H), 6.81-6.66 (m, 2H), 6.64-6.56 (m, 3H), 4.57 (s, 2H), 3.85-3.65 (m, 2H), 3.34-3.29 (m, 2H), 3.22 (s, 3H), 2.76 (s, 6H), 2.18-2.09 (m, 2H), 1.10 (d, J=6.4 Hz, 6H). Mass (m/z): 411.3 [M+H]+.
The title compound 21 (73.8 mg) was prepared in a total yield of 64.0% as a yellow solid from 4-(2-azaspiro[3.3]heptan-2-yl)aniline (81 mg, 0.43 mmol), 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (80 mg, 0.33 mmol), Pd2(dba)3 (3.0 mg, 3.3 umol), X-Phos (7.9 mg, 16.5 umol) and Cs2CO3 (163 mg, 0.50 mmol) in 1,4-dioxane (3.0 mL) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.07-6.88 (m, 2H), 6.61-6.47 (m, 2H), 4.54 (s, 2H), 3.34 (s, 3H), 2.24 (t, J=7.6 Hz, 4H), 1.96-1.88 (m, 2H), 1.41-1.19 (m, 4H). Mass (m/z): 350.2[M+H]+.
The title compound 22 (43.0 mg) was prepared in a total yield of 40.2% as a dark yellow solid from a mixture of N1,N1-diethylbenzene-1,4-diamine (70.5 mg, 0.43 mmol), 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (80 mg, 0.33 mmol), Pd2(dba)3 (3.0 mg, 3.3 umol), X-Phos (7.9 mg, 16.5 umol) and Cs2CO3 (163 mg, 0.50 mmol) in 1,4-dioxane (3.0 mL) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 8.26-5.99 (m, 5H), 4.51 (s, 2H), 3.92-3.63 (m, 4H), 3.34 (s, 3H), 1.10 (t, J=7.0 Hz, 6H). Mass (m/z): 326.2 [M+H]+.
The title compound 23 (63.3 mg) was prepared in a total yield of 82.9% as a brown solid from 4-(4-(fluoromethyl)piperidin-1-yl)aniline (52 mg, 0.248 mmol), 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (50 mg, 0.207 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-Phos (6 mg, 0.01 mmol) and Cs2CO3 (102 mg, 0.310 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J=7.6 Hz, 1H), 6.96 (dd, J=8.8, 2.4 Hz, 3H), 6.91-6.86 (m, 2H), 6.62 (dd, J=8.8, 2.4 Hz, 1H), 6.54 (d, J=2.4 Hz, 1H), 4.56 (s, 2H), 4.39 (d, J=6.0 Hz, 1H), 4.27 (d, J=5.6 Hz, 1H), 3.56 (dt, J=12.8, 3.2 Hz, 2H), 3.22 (s, 3H), 2.58 (td, J=12.0, 2.4 Hz, 2H), 1.80-1.69 (m, 3H), 1.35 (qd, J=12.0, 4.0 Hz, 2H). Mass (m/z): 370.3 [M+H]+.
The title compound 24 (12.6 mg) was prepared in a total yield of 60.0% as a wheat solid from 6-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-amine (15.9 mg, 0.065 mmol), 7-bromo-4-ethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (12.8 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.96 (d, J=2.8 Hz, 1H), 7.37 (dd, J=8.8, 2.8 Hz, 1H), 6.99 (d, J=8.8 Hz, 1H), 6.84 (d, J=8.8 Hz, 1H), 6.54 (dd, J=8.8, 2.8 Hz, 1H), 6.46 (d, J=2.8 Hz, 1H), 4.53 (s, 2H), 4.24-4.32 (m, 2H), 3.85 (q, J=7.2 Hz, 2H), 2.80-2.71 (m, 2H), 2.54 (m, 1H), 1.90-1.89 (m, 2H), 1.51-1.38 (m, 2H), 1.12 (t, J=7.2 Hz, 3H). Mass (m/z): 421.2 [M+H]+.
The title compound 25 (15.4 mg) was prepared in a total yield of 64.6% as a yellow solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (15.9 mg, 0.065 mmol), 7-bromo-N-(tert-butyl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxamide (15.7 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.20 (d, J=8.8 Hz, 1H), 7.03-6.80 (m, 4H), 6.53-6.36 (m, 2H), 4.08 (t, J=4.4 Hz, 2H), 3.66-3.57 (m, 4H), 2.68-2.55 (m, 2H), 2.41 (m, 1H), 1.92-1.81 (m, 2H), 1.64-1.51 (m, 2H), 1.28 (s, 9H). Mass (m/z): 477.3 [M+H]+.
The title Compound 26 (93.1 mg) was prepared in a total yield of 66.5% as a light yellow solid from 2-methyl-6-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-amine (111 mg, 0.43 mmol), 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (80 mg, 0.33 mmol), Pd2(dba)3 (3.0 mg, 3.3 umol), X-Phos (7.9 mg, 16.5 umol), and Cs2CO3 (163 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.31 (d, J=8.6 Hz, 1H), 7.26 (s, 1H), 6.92 (d, J=8.6 Hz, 1H), 6.71 (d, J=8.8 Hz, 1H), 6.27 (dd, J=8.6, 2.4 Hz, 1H), 6.22 (d, J=2.6 Hz, 1H), 4.54 (s, 2H), 4.40-4.32 (m, 2H), 3.21 (s, 3H), 2.83-2.73 (m, 2H), 2.60-2.53 (m, 1H), 2.23 (s, 3H), 1.91-1.84 (m, 1H), 1.44 (qd, J=12.6, 4.2 Hz, 2H). Mass (m/z): 421.3 [M+H]+.
The title Compound 27 (62.2 mg) was prepared in a total yield of 44.4% as a Light yellow powder from 5-fluoro-6-(4-(trifluoromethyl)piperidin-1-yl) pyridin-3-amine (113 mg, 0.43 mmol), 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (80 mg, 0.33 mmol), Pd2(dba)3 (3.0 mg, 3.3 umol), X-Phos (7.9 mg, 16.5 umol), and Cs2CO3 (163 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.85 (dd, J=2.4, 1.0 Hz, 1H), 7.28 (dd, J=14.2, 2.3 Hz, 1H), 7.03 (d, J=8.8 Hz, 1H), 6.71 (dd, J=8.8, 2.5 Hz, 1H), 6.61 (d, J=2.5 Hz, 1H), 4.60 (s, 2H), 3.83-3.75 (m, 2H), 3.24 (s, 3H), 2.81 (td, J=12.7, 2.4 Hz, 2H), 2.53 (d, J=10.3 Hz, 1H), 1.92-1.84 (m, 2H), 1.57 (qd, J=12.6, 4.1 Hz, 2H). Mass (m/z): 425.2 [M+H]+.
The title compound 28 (39.4 mg) was prepared in a total yield of 47.0% as a brown solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (60 mg, 0.248 mmol), 6-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (50 mg, 0.207 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-Phos (6 mg, 0.01 mmol) and Cs2CO3 (122 mg, 0.372 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.75 (s, 1H), 6.90 (d, J=8.8 Hz, 2H), 6.83-6.77 (m, 3H), 6.66 (d, J=2.4 Hz, 1H), 6.52 (dd, J=8.4, 2.4 Hz, 1H), 4.47 (s, 2H), 3.53 (d, J=12.0 Hz, 2H), 3.14 (s, 3H), 2.55 (t, J=11.6 Hz, 2H), 2.40-2.34 (m, 1H), 1.81 (d, J=12.4 Hz, 2H), 1.56-1.43 (m, 3H). Mass (m/z): 406.3 [M+H]+.
The title compound 29 (64.9 mg) was prepared in a total yield of 93.0% as a brown solid from 4-(piperidin-1-yl)aniline (43 mg, 0.248 mmol), 6-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (50 mg, 0.207 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-Phos (6 mg, 0.01 mmol) and Cs2CO3 (122 mg, 0.372 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.80 (s, 1H), 6.96 (dd, J=8.8, 6.4 Hz, 3H), 6.89-6.84 (m, 2H), 6.61 (dd, J=8.6, 2.5 Hz, 1H), 6.53 (d, J=2.5 Hz, 1H), 4.56 (s, 2H), 3.22 (s, 3H), 3.04-2.98 (m, 4H), 1.62 (q, J=4.1, 2.4 Hz, 4H), 1.51 (q, J=6.8, 6.4 Hz, 2H). Mass (m/z): 338.3 [M+H]+.
The title compound 30 (33.1 mg) was prepared in a total yield of 43.5% as a white solid from N1-ethyl-N1-pentylbenzene-1,4-diamine (51 mg, 0.248 mmol), 6-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (50 mg, 0.207 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-Phos (6 mg, 0.01 mmol) and Cs2CO3 (122 mg, 0.372 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.64 (s, 1H), 6.93 (d, J=8.4 Hz, 3H), 6.62 (d, J=8.4 Hz, 2H), 6.53 (d, J=8.8 Hz, 1H), 6.45 (d, J=2.4 Hz, 1H), 4.54 (s, 2H), 3.28 (d, J=7.2 Hz, 2H), 3.21 (s, 3H), 3.16 (d, J=7.6 Hz, 2H), 1.54-1.46 (m, 2H), 1.29 (td, J=12.0, 10.0, 5.6 Hz, 4H), 1.05 (t, J=6.8 Hz, 3H), 0.88 (t, J=6.8 Hz, 3H). Mass (m/z): 368.3 [M+H]+.
The title compound 31 (53.6 mg) was prepared in a total yield of 70.2% as a black oil from N‘-ethyl-N’-(3-methoxypropyl)benzene-1,4-diamine (51 mg, 0.248 mmol), 6-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (50 mg, 0.207 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-Phos (6 mg, 0.01 mmol) and Cs2CO3 (122 mg, 0.372 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.66 (s, 1H), 6.93 (d, J=8.4 Hz, 3H), 6.67-6.62 (m, 2H), 6.54 (dd, J=8.8, 2.4 Hz, 1H), 6.46 (d, J=2.4 Hz, 1H), 4.54 (s, 2H), 3.37 (s, 1H), 3.36-3.34 (m, 2H), 3.31-3.25 (m, 3H), 3.24 (s, 3H), 3.21 (s, 3H), 1.77-1.66 (m, 2H), 1.05 (t, J=6.8 Hz, 3H). Mass (m/z): 370.3 [M+H]+.
The title compound 32 (38.8 mg) was prepared in a total yield of 50.7% as a pink solid from 3-methoxy-4-(pentyloxy)aniline (52 mg, 0.248 mmol), 6-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (50 mg, 0.207 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-Phos (6 mg, 0.01 mmol) and Cs2CO3 (122 mg, 0.372 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.93 (s, 1H), 6.99 (d, J=8.8 Hz, 1H), 6.84 (d, J=8.8 Hz, 1H), 6.71-6.64 (m, 2H), 6.61-6.54 (m, 2H), 4.57 (s, 2H), 3.87 (t, J=6.4 Hz, 2H), 3.71 (s, 3H), 3.23 (s, 3H), 1.68 (p, J=6.8 Hz, 2H), 1.43-1.28 (m, 4H), 0.90 (t, J=7.2 Hz, 3H). Mass (m/z): 371.3 [M+H]+.
The title compound 33 (16.9 mg) was prepared in a total yield of 15.9% as a light pink solid from 4-fluoro-3-(4-(trifluoromethyl) piperidin-1-yl) aniline (86 mg, 0.33 mmol), 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (60 mg, 0.25 mmol), Pd2(dba)3 (2.3 mg, 2.5 umol), X-Phos (6.0 mg, 12.5 umol), and Cs2CO3 (122 mg, 0.75 mmol) according to the procedure for compound 1. 1H NMR (300 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.03-6.95 (m, 2H), 6.72 (dd, J=8.6, 2.5 Hz, 1H), 6.68-6.58 (m, 3H), 4.59 (s, 2H), 3.36-3.29 (m, 4H), 3.24 (s, 3H), 2.70-2.62 (m, 2H), 2.48-2.41 (m, 1H), 1.94-1.86 (m, 2H), 1.61 (qd, J=12.4, 4.1 Hz, 2H). Mass (m/z): 424.2 [M+H]+.
The title compound 34 (38.1 mg) as prepared in a total yield of 28.2% as a light gray solid from 2-fluoro-4-(4-(trifluoromethyl)piperidin-1-yl)aniline (100 mg, 0.38 mmol), 7-bromo-4-methyl-2H-benzo[b][1,4] oxazin-3(4H)-one (76 mg, 0.32 mmol), Pd2(dba)3 (2.9 mg, 3.2 umol), X-Phos (7.6 mg, 16 umol), and Cs2CO3 (156 mg, 0.48 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.54 (s, 1H), 7.14-7.07 (m, 1H), 6.95 (d, J=8.7 Hz, 1H), 6.87 (dd, J=14.3, 2.7 Hz, 1H), 6.74 (dd, J=8.7, 2.7 Hz, 1H), 6.46 (dd, J=8.6, 2.5 Hz, 1H), 6.37 (d, J=2.5 Hz, 1H), 4.55 (s, 2H), 3.78-3.68 (m, 2H), 3.21 (s, 3H), 2.69 (td, J=12.5, 2.6 Hz, 2H), 2.49-2.40 (m, 1H), 1.90-1.83 (m, 2H), 1.54 (qd, J=12.6, 4.1 Hz, 2H). Mass (m/z): 424.3 [M+H]+.
The title compound 35 (15.9 mg) was prepared in a total yield of 87.10% as a yellow powder from 4-(4,4-dimethylcyclohexyl)aniline (13.2 mg, 0.065 mmol), 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (12.1 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (300 MHz, DMSO-d6) δ 7.14-7.03 (m, 2H), 7.02-6.90 (m, 3H), 6.72 (dd, J=8.8, 2.4 Hz, 1H), 6.63 (d, J=2.4 Hz, 1H), 4.57 (s, 2H), 3.23 (s, 3H), 2.31 (m, 1H), 1.63-1.49 (m, 4H), 1.49-1.37 (m, 2H), 1.35-1.22 (m, 2H), 0.95 (s, 3H), 0.93 (s, 3H). Mass (m/z): 365.2 [M+H]+.
The title compound 36 (62.1 mg) was prepared in a total yield of 78.6% as a yellow solid from 2-(4-isopropylpiperidin-1-yl)pyrimidin-5-amine (55 mg, 0.248 mmol), 6-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (50 mg, 0.207 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-Phos (6 mg, 0.01 mmol), Cs2CO3 (122 mg, 0.372 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 2H), 7.67 (d, J=4.4 Hz, 1H), 6.91 (d, J=8.8 Hz, 1H), 6.42 (dd, J=8.8, 2.4 Hz, 1H), 6.35 (d, J=2.4 Hz, 1H), 4.60 (dt, J=12.8, 2.4 Hz, 2H), 4.52 (s, 2H), 3.17 (s, 3H), 2.71 (td, J=12.8, 2.4 Hz, 2H), 1.65 (dd, J=12.4, 2.8 Hz, 2H), 1.39 (dq, J=13.2, 6.8 Hz, 1H), 1.29-1.00 (m, 4H), 0.83 (d, J=6.8 Hz, 6H). Mass (m/z): 382.3 [M+H]+.
The title compound 37 (125.0 mg) was prepared in a total yield of 88.1% as a yellow solid from 6-bromo-1,1-dimethyl-1,2,3,4-tetrahydronaphthalene (0.1 g, 0.42 mmol), 7-amino-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (0.09 g, 0.5 mmol), Ruphos (39 mg, 0.08 mmol), Pd2(dba)3 (38 mg, 0.04 mmol) and Cs2CO3 (0.41 g, 1.26 mmol) in 1,4-dioxane (10 mL) according to the procedure for compound 1. 1H NMR (400 MHz, CDCl3) δ 7.23 (d, J=8.4 Hz, 1H), 6.88-6.83 (m, 2H), 6.73 (d, J=13.6 Hz, 3H), 4.59 (s, 2H), 3.49 (s, 1H), 3.34 (s, 3H), 2.71 (t, J=6.4 Hz, 2H), 1.81-1.76 (m, 2H), 1.66-1.64 (m, 2H), 1.27 (s, 6H). Mass (m/z): 337.2 [M+H]+.
The title compound 38 (60.0 mg) was prepared in a total yield of 33.2% as a white solid from 4-(tert-pentyl)aniline (100 mg, 0.613 mmol), 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (134 mg, 0.558 mmol), Pd2(dba)3 (25.5 mg, 0.028 mmol), X-Phos (26.6 mg, 0.056 mmol) and Cs2CO3 (364 mg, 1.12 mmol) in dioxane (15 mL) according to the procedure for compound 1. 1H NMR (400 MHz, CDCl3) δ 7.41-7.27 (m, 4H), 7.12 (t, J=10.6 Hz, 2H), 6.59 (t, J=8.6 Hz, 2H), 4.36-4.23 (m, 2H), 3.85 (d, J=15.9 Hz, 2H), 1.64-1.54 (m, 3H), 1.24 (d, J=10.9 Hz, 7H), 0.68 (t, J=7.4 Hz, 3H). Mass (m/z): 325.4 [M+H]+.
The title compound 39 (8 mg) was prepared as a yellow solid from 5-bromo-1,1,3,3-tetramethyl-2,3-dihydro-1H-indene (300 mg, 1.19 mmol), 7-amino-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (211 mg, 1.19 mmol), Cs2CO3 (772 mg, 2.38 mmol), Pd2(dba)3 (108 mg, 0.12 mmol) and Ruphos (110 mg, 0.24 mmol) in 1,4-dioxane (15 mL) according to the procedure for compound 1. 1H NMR (400 MHz, CD3OD) δ 6.97 (dd, J=8.4, 3.2 Hz, 2H), 6.88 (dd, J=8.2, 2.2 Hz, 1H), 6.79 (d, J=2.0 Hz, 1H), 6.70 (dd, J=8.6, 2.6 Hz, 1H), 6.64 (d, J=2.6 Hz, 1H), 4.53 (s, 2H), 3.30 (s, 3H), 1.89 (s, 2H), 1.26 (d, J=1.8 Hz, 12H). Mass (m/z): 351.3 [M+H]+.
A mixture of 7-bromo-2H-1,4-benzoxazine-3(4H)-one (454 mg, 2.0 mmol), tert-Butyl N-(2-bromoethyl)carbamate (892 mg, 4.0 mmol), KI (33.2 mg, 0.2 mmol) and K2CO3 (828 mg, 6.0 mmol) in DMF (10.0 mL) was stirred for 18 hours at 80° C. After cooling to r.t., 10 mL of water was added. The resulting solution was extracted with 3×10 mL of ethyl acetate. The organic layers were combined, washed with water (3×15 mL), dried and concentrated under vacuum. The residue was purified by a silica gel column (EA/PE=0-1/2) to afford the desired product as a yellow solid (250 mg, 33.8%). Mass (m/z): 3 71.2 [M+H]+.
The title compound (220 mg) as prepared in a total yield of 60.6% as a light yellow solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (214 mg, 0.89 mmol), tert-butyl (2-(7-bromo-3-oxo-2,3-dihydro-4H-benzo[b][1,4] oxazin-4-yl)ethyl)carbamate (250 mg, 0.68 mmol), Pd2(dba)3 (5.0 mg, 6.8 umol), X-Phos (16.3 mg, 34 umol), and Cs2CO3 (333 mg, 1.02 mmol) according to the procedure for compound 1. Mass (m/z): 535.2 [M+H]+.
To a solution of tert-butyl (2-(3-oxo-7-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethyl)carba mate (220 mg, 0.41 mmol) in DCM (5 mL) was added TFA (5 mL). Then the solution was stirred for 30 mins at r.t. and concentrated. 10 ml water was added. The pH of the filtration was adjusted to 8-9 with sodium carbonate solution. Then the mixture was extracted by DCM (15 mL×3). The combined organic layers were washed with water (10 mL), dried over Na2SO4 and concentrated. The residue was purified by perp-TLC (MeOH/DCM=1/5) to afford the desired product as a yellow solid. Mass (m/z): 435.1 [M+H]+.
To a solution of 4-(2-aminoethyl)-7-((4′-(trifluoromethyl)-3′,4′-dihydro-[1,1′-biphenyl]-4-yl)amino)-2H-benzo[b][1,4]oxazin-3(4H)-one (160 mg, 0.37 mmol) and TEA (112 mg, 1.11 mmol) in DMSO (3.0 mL) was added phenyl carbamate (60.6 mg, 0.44 mmol). Then the mixture was stirred overnight at 60° C. After cooling to rt., 10 mL of water was added. The resulting solution was extracted with 3×10 mL of ethyl acetate. The organic layers were combined, washed with water (3×15 mL), dried and concentrated under vacuum. The residue was purified by prep-TLC (MeOH/DCM=1/10) to afford the desired product (compound 40) as a yellow solid (17.5 mg, 9.9%). 1H NMR (400 MHz, DMSO-d6) δ 7.81 (s, 1H), 7.18 (d, J=8.8 Hz, 1H), 6.99-6.94 (m, 2H), 6.93-6.87 (m, 2H), 6.60 (dd, J=8.7, 2.5 Hz, 1H), 6.54 (d, J=2.4 Hz, 1H), 6.14 (t, J=5.9 Hz, 1H), 5.52 (s, 2H), 4.54 (s, 2H), 3.81 (t, J=7.0 Hz, 2H), 3.67-3.57 (m, 2H), 3.15 (q, J=6.5 Hz, 2H), 2.66-2.58 (m, 2H), 2.46-2.36 (m, 1H), 1.94-1.84 (m, 2H), 1.57 (qd, J=12.5, 4.1 Hz, 2H). Mass (m/z): 478.2 [M+H]+.
To a solution of tert-butyl (3-bromopropyl)carbamate (1.00 g, 4.20 mmol) in THF (10 mL) was added NaH (60%, 252 mg, 6.30 mmol) in portions at 0° C. The mixture was stirred at r.t. for 1 h. CH3I was then added to the above mixture and stirred at 35° C. for 12 h. The reaction mixture was quenched by the addition of water (20 mL) and extracted with ethyl acetate (3×50 mL). The combined organic phase was dried and concentrated to give the titled compound (1.06 g, theoretical yield) as a light yellow oil. LC-MS (m/z) 252.2 [M+H]+.
To a solution of 7-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (200 mg, 0.88 mmol) in DMF (3 mL) was added NaH (60%, 52.6 mg, 1.31 mmol) in portions at 0° C. The mixture was stirred at r.t. for 1 h. Tert-butyl (3-bromopropyl)(methyl)carbamate (221.13 mg, 0.877 mmol) was then added to the above mixture and stirred at room temperature for 12 h. The reaction mixture was quenched by the addition of water (20 mL) and extracted with ethyl acetate (3×50 mL). The combined organic phase was dried and concentrated. The residue was purified by TLC (Petroleum ether:Ethyl acetate=3:1) to give the titled compound (340 mg, 97% yield) as a light yellow oil. LC-MS (m/z) 399.2 [M+H]+.
The title compound (60 mg) as prepared in a total yield of 42.6% as light yellow oil from tert-butyl (3-(7-bromo-3-oxo-2,3-dihydro-4H-benzo[b][1,4] oxazin-4-yl)propyl)(methyl)carbamate (100 mg, 0.25 mmol) and 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (67.3 mg, 0.27 mmol), Pd2(dba)3 (11.5 mg, 0.013 mmol), X-phos (11 mg, 0.025 mmol) and Cs2CO3 (163 mg, 0.5 mmol) according to the procedure for compound 1. LC-MS (m/z) 563.2 [M+H]+.
To a solution of 4-(3-(methylamino)propyl)-7-((4-(4-(trifluoromethyl) piperidin-1-yl)phenyl)amino)-2H-benzo[b][1,4]oxazin-3(4H)-one (60 mg, 0.11 mmol) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at r.t. for 1 h. The reaction mixture was concentrated under vacuum. The residue was quenched by the addition of a saturated solution of NaHCO3 (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic phase was dried and concentrated. The residue was purified by Prep TLC (Dichloromethane:Methanol:Ammonia=5:1:0.1) to give the titled compound 41 (18.7 mg, 37.9% yield) as a light green solid. 1H NMR (400 MHz, DMSO-d6): δ 8.82 (s, 2H), 7.88 (s, 111), 7.09 (d, J=8.7 Hz, 111), 6.97 (d, J=8.2 Hz, 2H), 6.91 (s, 2H), 6.63 (d, J=8.7 Hz, 111), 6.57 (s, 111), 4.58 (s, 2H), 3.94-3.90 (t, J=7.2 Hz, 2H), 3.62 (d, J=12.1 Hz, 2H), 2.93 (d, J=8.5 Hz, 2H), 2.68-2.58 (m, 2H), 2.47-2.39 (m, 2H), 2.53 (s, 1H), 1.94-1.84 (m, 4H), 1.58 (s, 2H). LC-MS (m/z) 463.2 [M+H]+.
The title compound (16 mg) was prepared in a total yield of 8% as a yellow solid from 1,1-dimethyl-2,3-dihydro-1H-inden-5-amine (0.1 g, 0.6 mmol), 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (0.15 g, 0.6 mmol), Xantphos (69 mg, 0.12 mmol), Cs2CO3 (0.39 g, 1.2 mmol), Pd2(dba)3 (50 mg, 0.06 mmol) and toluene (10 mL) according to the procedure for compound 1. MS (ESI) m/z 322.8 [M+H]. 1H NMR (300 MHz, CD3OD) δ 7.11-6.80 (m, 4H), 6.72-6.62 (m, 2H), 4.55 (s, 2H), 3.32-3.27 (m, 3H), 2.80 (q, J=6 Hz, 2H), 1.91 (q, J=6 Hz, 2H), 1.23 (s, 6H).
To a solution of 7-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (150 mg, 0.66 mmol) in DMF (10 mL) was added NaH (60%, 162 mg, 0.72 mmol) in portions at 0° C. The mixture was stirred at r.t. for 1 h. Tert-butyl (2-bromoethyl)carbamate (31.6 mg, 0.79 mmol) was then added to the above mixture and stirred at room temperature for 12 h. The reaction mixture was quenched by the addition of water (20 mL) and extracted with ethyl acetate (3×50 mL). The combined organic phase was dried and concentrated. The residue was purified by Prep-TLC (petroleum ether:ethyl acetate=1:1) to afford the titled compound (236 mg, 96.6% yield) as a light yellow oil. LC-MS (m/z) 371.2 [M+H]+.
To a solution of tert-butyl (2-(7-bromo-3-oxo-2,3-dihydro-4H-benzo[b][1,4] oxazin-4-yl)ethyl)carbamate (236 mg, 0.64 mmol) in THE (3 mL) was added NaH (60%, 30.5 mg, 0.76 mmol) in portions at 0° C. The mixture was stirred at r.t. for 1 h. CH3I (108.33 mg, 0.76 mmol) was then added to the above mixture and stirred at room temperature for 2 h. The reaction mixture was quenched by the addition of water (20 mL) and extracted with ethyl acetate (3×50 mL). The combined organic phase was dried and concentrated to give the titled compound (228 mg, 93.1% yield) as brown oil. LC-MS (m/z) 385.2 [M+H]+.
The title compound (70 mg) was prepared in a total yield of 42.7% as light yellow oil from tert-butyl (2-(7-bromo-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethyl)(methyl)carbamate (115 mg, 0.30 mmol), 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (80.2 mg, 0.33 mmol), Pd2(dba)3 (13.7 mg, 0.015 mmol), X-phos (14.2 mg, 0.03 mmol) and Cs2CO3 (195 mg, 0.60 mmol) in 1,4-dioxane (5 mL) according to the procedure for compound 1. LC-MS (m/z) 549.2 [M+H]+.
The title compound 43 (20.1 mg) was prepared in a total yield of 35.1% as a khaki solid from methyl(2-(3-oxo-7-((4-(4-(trifluoromethyl) piperidin-1-yl)phenyl)amino)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)e thyl)carbamate (70 mg, 0.13 mmol), TFA (1 mL) and DCM (3 mL) according to the procedure for compound 41. 1H NMR (400 MHz, DMSO-d6): δ 7.82 (s, 1H), 7.05 (d, J=8.8 Hz, 1H), 6.96-6.89 (m, 2H), 6.91-6.83 (m, 2H), 6.61-6.49 (m, 2H), 4.55 (s, 2H), 4.05 (t, J=6.4 Hz, 2H), 3.59 (d, J=12.3 Hz, 2H), 3.26 (s, 3H), 2.96 (t, J=6.4 Hz, 2H), 2.59 (td, J=12.3, 2.5 Hz, 2H), 2.45-2.35 (m, 2H), 1.90-1.81 (m, 2H), 1.53 (qd, J=12.4, 4.1 Hz, 2H). LC-MS (m/z) 449.2 [M+H]+.
The title compound 44 (68.5 mg) was prepared in a total yield of 34.7% as a khaki solid from 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (130 mg, 0.54 mmol), 4-(2,6-dimethylmorpholino)aniline (122 mg, 0.59 mmol), Pd2(dba)3 (24.6 mg, 0.03 mmol), X-Phos (25.6 mg, 0.054 mmol) and Cs2CO3 (350 mg, 1.07 mmol) in 1,4-dioxane (5 mL) according to the procedure for compound 1. LC-MS (m/z) 368.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 7.75 (s, 1H), 6.96-6.87 (m, 3H), 6.87-6.80 (m, 2H), 6.58 (dd, J=8.7, 2.5 Hz, 1H), 6.49 (d, J=2.5 Hz, 1H), 4.53 (s, 2H), 3.69-3.61 (m, 2H), 3.40 (dt, J=11.1, 2.3 Hz, 2H), 3.18 (s, 3H), 2.15 (t, J=11.2 Hz, 2H), 1.10 (d, J=6.2 Hz, 6H).
To a solution of tert-butyl (3-(7-bromo-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propyl)(methyl)carbamate (120 mg, 0.30 mmol) and 4-(2,6-dimethylmorpholino)aniline (68.2 mg, 0.33 mmol) in 1,4-dioxane (5 mL) was added Pd2(dba)3 (13.8 mg, 0.015 mmol), X-Phos (14.3 mg, 0.03 mmol) and Cs2CO3 (196 mg, 0.60 mmol) under nitrogen atmosphere. The mixture was stirred at 100° C. for 12 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×50 mL). The combined organic phase was dried and concentrated. The residue was purified by Prep-TLC (Petroleum ether:Ethyl acetate=1:5) to give the titled compound (75 mg, 47.6%) as a brown oil. LC-MS (m/z) 525.3 [M+H]+.
To a solution of tert-butyl (3-(7-((4-(2,6-dimethylmorpholino) phenyl)amino)-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propyl)(m ethyl)carbamate (75 mg, 0.14 mmol) in dichloromethane (5 mL) was added TFA (1.0 mL). The mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated and adjusted PH to 7-8 with sat. NaHCO3 and extracted with dichloromethane (3×50 mL). The combined organic phase was dried and concentrated. The residue was purified by Prep-TLC (Dichloromethane:Methanol:Ammonia=5:1:0.1) to give the titled compound 45 (27 mg, 44.5%) as a khaki solid. 1H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 7.80 (s, 1H), 7.02 (d, J=8.8 Hz, 1H), 6.96-6.90 (m, 2H), 6.88-6.82 (m, 2H), 6.57 (dd, J=8.7, 2.5 Hz, 1H), 6.51 (d, J=2.5 Hz, 1H), 4.55 (s, 2H), 3.88 (t, J=7.0 Hz, 2H), 3.65 (ddd, J=10.3, 6.3, 2.3 Hz, 2H), 3.45-3.37 (m, 2H), 2.93-2.85 (m, 2H), 2.51 (s, 3H), 2.15 (dd, J=11.8, 10.3 Hz, 2H), 1.83 (q, J=7.5 Hz, 2H), 1.11 (d, J=6.2 Hz, 6H). LC-MS (m/z) 425.2 [M+H]+.
To a solution of 7-bromo-2H-1,4-benzoxazine-3(4H)-one (227 mg, 1 mmol) in DMF (10 mL) stirred at 0° C. under nitrogen atmosphere was added NaH (60%, 60 mg, 1.5 mmol). Then the mixture was stirred for 1 hour at 0° C. 4-Bromobutyronitrile (194 mg, 2 mmol) was added, the mixture was stirred overnight at r.t. 20 mL of water was added dropwise at 0° C. The precipitate was collected by filtration and washed with 10 mL of water. Target product was obtained as a yellow solid. (238 mg, 81.0%). Mass (m/z): 295.0 [M+H]+.
The title compound (161 mg) as prepared in a total yield of 43.4% as a yellow solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (198 mg, 0.81 mmol), 4-(7-bromo-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl) butanenitrile (238 mg, 0.81 mmol), Pd2(dba)3 (11.8 mg, 16 umol), X-Phos (18.5 mg, 32 umol), and Cs2CO3 (396 mg, 1.22 mmol) according to the procedure for compound 1. Mass (m/z): 459.2 [M+H]+.
To a solution of 4-(3-oxo-7-((4-(4-(trifluoromethyl)piperidin-1-yl) phenyl)amino)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)butanenitrile in MeOH (3 mL) was added 1 mL of 10% NaOH solution at 0° C. Followed by the addition of 0.3 mL of 30% H202 solution then the mixture was stirred for 3 hours at r.t. 10 mL of water was added. The resulting solution was extracted with 3×10 mL of ethyl acetate. The organic layers were combined, washed with water (3×15 mL), dried and concentrated under vacuum. The residue was purified by prep-TLC (MeOH/DCM=1/10) to afford the desired product as a yellow solid (9.6 mg, 15.5%). 1H NMR (400 MHz, DMSO-d6) δ 7.78 (s, 1H), 7.27 (s, 1H), 7.04 (d, J=8.8 Hz, 1H), 6.95-6.91 (m, 2H), 6.89-6.83 (m, 2H), 6.74 (s, 1H), 6.58 (dd, J=8.9, 2.2 Hz, 1H), 6.51 (d, J=2.4 Hz, 1H), 4.51 (s, 2H), 3.77 (t, J=7.5 Hz, 2H), 3.62-3.55 (m, 2H), 2.60-2.53 (m, 2H), 2.43-2.37 (m, 1H), 2.08 (t, J=7.4 Hz, 2H), 1.88-1.82 (m, 2H), 1.74-1.66 (m, 2H), 1.60-1.44 (m, 2H). Mass (m/z): 477.2 [M+H]+.
The title compound 47 (26.0 mg) was prepared in a yield of 20.0% as a light blue solid from 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (100 mg, 0.42 mmol), 4-(tert-butyl)aniline (68 mg, 0.46 mmol), 1,4-dioxane (2 mL), Pd2(dba)3 (38 mg, 0.04 mmol), Xphos (39 mg, 0.08 mmol) and Cs2CO3 (277 mg, 0.83 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.26-7.16 (m, 2H), 7.00-6.89 (m, 3H), 6.70 (dd, J=8.7, 2.5 Hz, 1H), 6.61 (d, J=2.4 Hz, 1H), 4.55 (s, 2H), 3.20 (s, 3H), 1.22 (s, 9H). Mass (m/z): 310.2 [M+H]+.
To a solution of tert-butyl (2-(7-bromo-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethyl)(methyl)carbamate (120 mg, 0.31 mmol) and 4-(tert-butyl)aniline (61 mg, 0.34 mmol) in 1,4-dioxane (2 mL) was added Pd2(dba)3 (28 mg, 0.03 mmol), Xphos (29 mg, 0.06 mmol) and Cs2CO3 (203 mg, 0.63 mmol) under nitrogen atmosphere. The mixture was stirred at 100° C. for 12 h, the mixture was purified by prep TLC to give tert-butyl (2-(7-((4-(tert-butyl)phenyl)amino)-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethyl)(methyl)carbamate (50 mg, 35%) as a brown solid. Mass (m/z): 454.2 [M+H]+.
To a solution of tert-butyl (2-(7-((4-(tert-butyl)phenyl)amino)-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethyl)(methyl)carbamate (50 mg, 0.11 mmol) in DCM (3 mL) was added 2,2,2-trifluoroacetic acid (1 mL). The mixture was stirred at r.t. for 1 h, the mixture was concentrated and purified by prep TLC to give 7-((4-(tert-butyl)phenyl)amino)-4-(2-(methylamino) ethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (16.9 mg, 43%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.63 (s, 1H), 8.20 (s, 1H), 7.32 (d, J=8.6 Hz, 1H), 7.07-6.99 (m, 2H), 6.94-6.86 (m, 2H), 6.57 (dd, J=8.6, 1.9 Hz, 1H), 6.46 (d, J=1.8 Hz, 1H), 3.72-3.60 (m, 2H), 3.51-3.43 (m, 2H), 3.18 (s, 3H), 2.23-2.13 (m, 2H), 1.12 (d, J=6.2 Hz, 6H). Mass (m/z): 354.2 [M+H]+.
To a stirred solution of compound 5-bromo-2,2-dimethyl-2,3-dihydro-1H-indene (80 mg, 0.355 mmol) and 7-amino-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (69.66 mg, 0.391 mmol) in dioxane under N2 was added NaOtBu (68.31 mg, 0.711 mmol), Pd2(dba)3 (32.54 mg, 0.036) and BINAP (44.26 mg, 0.071 mmol). The reaction mixture was stirred at 90° C. for 16 hrs. Then the mixture was filtered and concentrated. To the residue was added water (10 mL), extracted with EA (10 mL×3). The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was purified by prep-HPLC (column-Xbridge-C18, 150×21.2 mm, 5 um; Mobile phase: ACN-H2O (0.1% trifluoroacetic acid (TFA)), 60%-80%) to afford compound 49 as a yellow solid (12.6 mg). 1H NMR (400 MHz, CD3OD) δ 6.99 (dd, J=13.4, 8.3 Hz, 2H), 6.88 (s, 1H), 6.82 (d, J=8.0 Hz, 1H), 6.71 (dd, J=8.7, 2.5 Hz, 1H), 6.65 (d, J=2.4 Hz, 1H), 4.54 (s, 2H), 3.32 (s, 3H), 2.65 (d, J=6.3 Hz, 4H), 1.14 (s, 6H). MS (m/z): 322.17 [M+H]+.
The titled compound 50 (4.2 mg, 12.3%) as a white solid was prepared according to the procedure outlined for compound 48. 1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.22 (s, 1H), 6.96 (t, J=8.9 Hz, 2H), 6.81 (d, J=2.9 Hz, 1H), 6.72 (dd, J=8.7, 2.8 Hz, 1H), 6.31 (dd, J=8.7, 2.5 Hz, 1H), 6.23 (d, J=2.5 Hz, 1H), 4.52 (s, 2H), 3.86 (t, J=7.1 Hz, 1H), 3.70-3.65 (m, 1H), 3.65-3.53 (m, 1H), 3.51-3.43 (m, 2H), 2.93-2.80 (m, 2H), 2.50 (s, 3H), 2.27-2.10 (m, 2H), 2.09 (s, 3H), 1.89-1.76 (m, 1H), 1.21 (s, 2H), 1.11 (d, J=6.3 Hz, 6H). LC-MS (m/z) 439.2 [M+H]+.
The title compound 51 (95 mg) was prepared in a yield of 24.1% as a white solid from 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (250 mg, 1.03 mmol), 4-(2,6-dimethylmorpholino)-2-methylaniline (250.3 mg, 1.14 mmol), 1,4-dioxane (5 mL), Pd2(dba)3 (47.3 mg, 0.05 mmol), X-phos (49.2 mg, 0.103 mmol) and Cs2CO3 (674 mg, 2.06 mmol) according to the procedure of compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.17 (s, 1H), 6.95 (d, J=8.6 Hz, 1H), 6.87 (d, J=8.7 Hz, 1H), 6.80 (d, J=2.9 Hz, 1H), 6.71 (dd, J=8.6, 2.9 Hz, 1H), 6.30 (dd, J=8.7, 2.5 Hz, 1H), 6.22 (d, J=2.4 Hz, 1H), 4.50 (s, 2H), 3.68-3.61 (m, 2H), 3.47 (dt, J=10.7, 2.1 Hz, 2H), 3.16 (s, 3H), 2.17 (t, J=10.3 Hz, 2H), 2.08 (s, 3H), 1.11 (d, J=6.3 Hz, 6H). LC-MS (m/z) 382.2 [M+H]+.
The title compound 52 (37.4 mg) was prepared from in a yield of 23% as an off-white solid from 4-(2,6-dimethylmorpholino)-3-methylaniline (100 mg, 0.45 mmol), 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (120 mg, 0.50 mmol), 1,4-dioxane (2 mL), Pd2(dba)3 (41 mg, 0.05 mmol), Xphos (43 mg, 0.09 mmol) and Cs2CO3 (296 mg, 0.91 mmol) according to the procedure of compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.89 (s, 1H), 6.99 (d, J=8.7 Hz, 1H), 6.92 (d, J=8.3 Hz, 1H), 6.86 (s, 1H), 6.92-6.81 (m, 1H), 6.69 (dd, J=8.7, 2.5 Hz, 1H), 6.60 (d, J=2.5 Hz, 1H), 4.58 (s, 2H), 3.77-3.65 (m, 2H), 3.33 (s, 2H), 3.23 (s, 3H), 2.88-2.80 (m, 2H), 2.33-2.23 (m, 2H), 2.21 (s, 3H), 1.10 (d, J=6.2 Hz, 6H). Mass (m/z): 382.2 [M+H]+.
To a solution of tert-butyl (2-(7-bromo-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethyl)(methyl)carbamate (120 mg, 0.31 mmol) and 4-(2,6-dimethylmorpholino)aniline (71.0 mg, 0.34 mmol) in 1,4-dioxane (5 mL) was added Pd2(dba)3 (14.3 mg, 0.016 mmol), X-phos (14.8 mg, 0.031 mmol) and Cs2CO3 (203 mg, 0.623 mmol) under nitrogen atmosphere. The mixture was stirred at 100° C. for 12 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×50 mL). The combined organic phase was dried and concentrated to give the titled compound (150 mg, crude) as a brown oil. LC-MS (m/z) 511.2 [M+H]+.
To a solution of tert-butyl (2-(7-((4-(2,6-dimethylmorpholino) phenyl)amino)-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethyl)(met hyl)carbamate (140 mg, 0.27 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (TFA, 1.0 mL). The mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated and adjusted PH to 7-8 with sat. NaHCO3 and extracted with dichloromethane (3×50 mL). The combined organic phase was dried and concentrated. The residue was purified by Prep-TLC (Petroleum ether:Ethyl acetate=1:5) and further purified by Prep-HPLC with the following conditions: Column: Spherical C18 40-60 um, 40 g; Mobile phase A: water (0.5% NH4HCO3); Mobile phase B: acetonitrile or ACN; Flow rate: 50 mL/min; Gradient: 30% B-65% B in 20 min; Detector: 254 nm. The fractions containing desired product were collected at 60% B and concentrated under reduce pressure to give the titled compound 53 (33.3 mg, 29.6%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.78 (s, 1H), 7.04 (d, J=8.8 Hz, 1H), 7.01-6.92 (m, 2H), 6.92-6.84 (m, 2H), 6.60 (dd, J=8.7, 2.5 Hz, 1H), 6.52 (d, J=2.5 Hz, 1H), 4.54 (s, 2H), 3.89 (t, J=6.9 Hz, 2H), 3.72-3.64 (m, 2H), 3.44 (dt, J=10.8, 2.1 Hz, 2H), 2.63 (t, J=6.9 Hz, 2H), 2.28 (s, 3H), 2.19 (dd, J=11.8, 10.2 Hz, 2H), 1.14 (d, J=6.3 Hz, 6H). LC-MS (m/z) 411.2 [M+H]+.
The titled compound 54 (30.9 mg, 35%) as a white solid was prepared according to the procedure outlined for compound 53. 1H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.09 (d, J=8.4 Hz, 3H), 7.03-6.93 (m, 2H), 6.72 (dd, J=8.7, 2.5 Hz, 1H), 6.64 (d, J=2.5 Hz, 1H), 4.56 (s, 2H), 3.90 (t, J=6.9 Hz, 2H), 3.59-3.46 (m, 2H), 2.76-2.61 (m, 3H), 2.28 (s, 3H), 1.75-1.66 (m, 2H), 1.25-1.04 (m, 8H). LC-MS (m/z) 410.2 [M+H]+.
To a solution of tert-butyl (2-(7-bromo-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethyl)(methyl)carbamate (120 mg, 0.31 mmol) and 4-(2,6-dimethylmorpholino)-2-methylaniline (75.5 mg, 0.34 mmol) in 1,4-dioxane (5 mL) was added Pd2(dba)3 (14.3 mg, 0.016 mmol), X-phos (14.8 mg, 0.031 mmol) and Cs2CO3 (203 mg, 0.623 mmol) under nitrogen atmosphere. The mixture was stirred at 100° C. for 12 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×50 mL). The combined organic phase was dried and concentrated to give the titled compound (120 mg, crude) as a brown oil. LC-MS (m/z) 525.3 [M+H]+.
To a solution of tert-butyl (2-(7-((4-(2,6-dimethylmorpholino)-2-methylphenyl)amino)-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl) ethyl)(methyl)carbamate (120 mg, 0.23 mmol) in dichloromethane (5 mL) was added TFA (1.0 mL) The mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated and adjusted pH to 7-8 with sat. NaHCO3 and extracted with dichloromethane (3×50 mL). The combined organic phase was dried and concentrated. The residue was purified by Prep-HPLC with the following conditions: Column: Spherical C18 40-60 um, 40 g; Mobile phase A: water (0.5% NH4HCO3); Mobile phase B: acetonitrile or ACN; Flow rate: 50 mL/min; Gradient: 30% B-65% B in 20 min; Detector: 254 nm. The fractions containing desired product were collected at 57% B and concentrated under reduce pressure to give the titled compound 55 (25 mg, 25.7%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.19 (s, 1H), 6.99 (d, J=8.7 Hz, 2H), 6.83 (d, J=2.8 Hz, 1H), 6.75 (dd, J=8.7, 2.9 Hz, 1H), 6.34 (dd, J=8.7, 2.5 Hz, 1H), 6.25 (d, J=2.5 Hz, 1H), 4.51 (s, 2H), 3.88 (t, J=6.9 Hz, 2H), 3.68 (dtt, J=12.4, 6.2, 3.7 Hz, 2H), 3.54-3.46 (m, 2H), 2.65 (t, J=7.0 Hz, 2H), 2.29 (s, 3H), 2.20 (dd, J=11.9, 10.2 Hz, 2H), 2.12 (s, 3H), 1.15 (d, J=6.2 Hz, 6H). LC-MS (m/z) 425.2 [M+H]+.
To a solution of tert-butyl (3-(7-bromo-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)propyl)(methyl)carbamate (150 mg, 0.37 mmol) and 4-(2,6-dimethylmorpholino)-3-methylaniline (75 mg, 0.34 mmol) in 1,4-dioxane (2 mL) was added Pd2(dba)3 (31 mg, 0.03 mmol), Xphos (29 mg, 0.07 mmol) and Cs2CO3 (222 mg, 0.68 mmol) under nitrogen atmosphere. The mixture was stirred at 100° C. for 12 h, the mixture was purified by prep TLC to give tert-butyl (3-(7-((4-(2,6-dimethylmorpholino)-3-methylphenyl)amino)-3-oxo-2H-benzo[b][1,4]oxa zin-4(3H)-yl)propyl)(methyl)carbamate (50 mg, 27%) as a brown solid. Mass (m/z): 539.3 [M+H]+.
To a solution of tert-butyl (3-(7-((4-(2,6-dimethylmorpholino)-3-methylphenyl)amino)-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)propyl)(methyl)carbamate (50 mg, 0.09 mmol) in DCM (3 mL) was added 2,2,2-trifluoroacetic acid (1 mL). The mixture was stirred at r.t. for 1 h, the mixture was concentrated and purified by prep HPLC to give 7-((4-(2,6-dimethylmorpholino)-3-methylphenyl)amino)-4-(3-(methylamin o)propyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (16.8 mg, 41%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.03 (d, J=8.8 Hz, 1H), 6.89 (d, J=8.3 Hz, 1H), 6.86-6.77 (m, 2H), 6.68-6.61 (m, 1H), 6.56 (d, J=2.5 Hz, 1H), 4.53 (s, 2H), 3.85 (t, J=7.2 Hz, 2H), 3.74-3.62 (m, 2H), 2.85-2.74 (m, 2H), 2.54-2.48 (m, 2H), 2.26 (s, 3H), 2.29-2.19 (m, 2H), 2.17 (s, 3H), 1.66 (p, J=7.1 Hz, 2H), 1.07 (d, J=6.3 Hz, 6H). Mass (m/z): 439.3 [M+H]+.
The title compound 57 (108.7 mg) was prepared in a yield of 34.0% as an off-white solid from 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (190 mg, 0.79 mmol), 3,5-difluoro-4-(4-(trifluoromethyl) piperidin-1-yl)aniline (202 mg, 0.72 mmol), 1,4-dioxane (2 mL), Pd2(dba)3 (66 mg, 0.07 mmol), Xphos (68 mg, 0.14 mmol) and Cs2CO3 (470 mg, 1.44 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 7.04 (d, J=8.7 Hz, 1H), 6.77 (dd, J=8.7, 2.5 Hz, 1H), 6.67 (d, J=2.4 Hz, 1H), 6.60-6.47 (m, 2H), 4.59 (s, 2H), 3.22 (s, 3H), 3.09-2.91 (m, 4H), 2.45-2.32 (m, 1H), 1.84-1.75 (m, 2H), 1.50 (qd, J=12.2, 4.9 Hz, 2H). Mass (m/z): 442.4 [M+H]+.
The title compound 58 (56.6 mg) was prepared in a yield of 30.6% as a white solid from 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (110 mg, 0.45 mmol), 2-(4-(trifluoromethyl) piperidin-1-yl) pyrimidin-5-amine (112 mg, 0.45 mmol), 1,4-dioxane (5 mL), Pd2(dba)3 (20.8 mg, 0.023 mmol), X-phos (21.6 mg, 0.045 mmol) and Cs2CO3 (296.3 mg, 0.91 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 2H), 7.70 (s, 1H), 6.96 (d, J=8.7 Hz, 1H), 6.49 (dd, J=8.6, 2.5 Hz, 1H), 6.41 (d, J=2.5 Hz, 1H), 4.69 (d, J=13.3 Hz, 2H), 4.56 (s, 2H), 3.21 (s, 3H), 2.89 (td, J=13.0, 2.6 Hz, 2H), 2.63 (dq, J=7.8, 4.2, 3.6 Hz, 1H), 1.87 (dd, J=13.6, 3.6 Hz, 2H), 1.38 (qd, J=12.5, 4.3 Hz, 2H). LC-MS (m/z) 408.2 [M+H]+.
The title compound 59 (67.5 mg) was prepared in a yield of 30.6% as a light yellow solid from 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (110 mg, 0.45 mmol), 2-(4-(trifluoromethyl)piperidin-1-yl) pyrimidin-5-amine (125.5 mg, 0.45 mmol), 1,4-dioxane (5 mL), Pd2(dba)3 (20.8 mg, 0.023 mmol), X-phos (21.6 mg, 0.045 mmol) and Cs2CO3 (296.3 mg, 0.91 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.35 (s, 1H), 6.99 (d, J=8.7 Hz, 1H), 6.91-6.81 (m, 2H), 6.53 (dd, J=8.7, 2.5 Hz, 1H), 6.46 (d, J=2.4 Hz, 1H), 4.57 (s, 2H), 3.35 (s, 1H), 3.32 (s, 1H), 3.22 (s, 3H), 2.67 (td, J=12.1, 2.4 Hz, 2H), 2.47-2.38 (m, 1H), 2.12 (s, 3H), 1.90 (dd, J=12.1, 3.2 Hz, 2H), 1.60 (qd, J=12.4, 4.0 Hz, 2H). LC-MS (m/z) 438.2 [M+H]+.
The title compound 60 (18 mg) was prepared in a yield of 5% as a grey solid from 7-bromo-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (121 mg, 0.53 mmol), 4-(2,6-dimethylmorpholino)aniline (100 mg, 0.48 mmol), 1,4-dioxane (2 mL), Pd2(dba)3 (44 mg, 0.05 mmol), Xphos (46 mg, 0.10 mmol) and Cs2CO3 (316 mg, 0.97 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Pyr) δ 8.16 (s, 1H), 7.40-7.32 (m, 2H), 7.06 (d, J=2.5 Hz, 1H), 7.06-6.99 (m, 2H), 6.97 (dd, J=8.6, 2.5 Hz, 1H), 6.78 (d, J=8.5 Hz, 1H), 4.27-4.21 (m, 2H), 3.86-3.74 (m, 2H), 3.45-3.37 (m, 2H), 3.03 (t, J=4.4 Hz, 2H), 2.71 (s, 3H), 2.35 (t, J=10.9 Hz, 2H), 1.21 (d, J=6.2 Hz, 6H). Mass (m/z): 354.4 [M+H]+.
The title compound 61 (77 mg) was prepared in a yield of 45% as a white solid from 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (121 mg, 0.50 mmol), 4-(2,6-dimethylmorpholino)-5-fluoro-2-methylaniline (100 mg, 0.42 mmol), 1,4-dioxane (2 mL), Pd2(dba)3 (38 mg, 0.04 mmol), Xphos (40 mg, 0.08 mmol) and Cs2CO3 (274 mg, 0.84 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO) δ 7.34 (s, 1H), 6.98 (d, J=8.7 Hz, 1H), 6.91-6.81 (m, 2H), 6.52 (dd, J=8.7, 2.5 Hz, 1H), 6.44 (d, J=2.4 Hz, 1H), 4.57 (s, 2H), 3.79-3.67 (m, 2H), 3.22 (s, 3H), 3.19-3.11 (m, 2H), 2.37-2.27 (m, 2H), 2.12 (s, 3H), 1.11 (d, J=6.2 Hz, 6H). Mass (m/z): 400.4 [M+H]+.
To a solution of tert-butyl (2-(7-bromo-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethyl)(methyl)carbamate (146 mg, 0.38 mmol) and 4-(2,6-dimethylmorpholino)-3-methylaniline (70 mg, 0.32 mmol) in 1,4-dioxane (2 mL) was added Pd2(dba)3 (29 mg, 0.03 mmol), Xphos (30 mg, 0.06 mmol) and Cs2CO3 (207 mg, 0.63 mmol) under nitrogen atmosphere. The mixture was stirred at 100° C. for 12 h, the mixture was purified by prep TLC to give tert-butyl (2-(7-((4-(2,6-dimethylmorpholino)-3-methylphenyl)amino)-3-oxo-2H-benzo[b][1,4]oxa zin-4(3H)-yl)ethyl)(methyl)carbamate (50 mg, 30%) as a brown solid. Mass (m/z): 525.3 [M+H]+.
To a solution of tert-butyl (2-(7-((4-(2,6-dimethylmorpholino)-3-methylphenyl)amino)-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethyl)(methyl)carbamate (50 mg, 0.09 mmol) in DCM (3 mL) was added 2,2,2-trifluoroacetic acid (1 mL). The mixture was stirred at r.t. for 1 h, the mixture was concentrated and purified by prep HPLC to give 7-((4-(2,6-dimethylmorpholino)-3-methylphenyl)amino)-4-(2-(methylami no)ethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (20 mg, 49%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.86 (s, 1H), 7.03 (d, J=8.8 Hz, 1H), 6.92-6.77 (m, 3H), 6.64 (dd, J=8.7, 2.5 Hz, 1H), 6.56 (d, J=2.4 Hz, 1H), 4.52 (s, 2H), 3.86 (t, J=6.9 Hz, 2H), 3.74-3.62 (m, 2H), 2.85-2.74 (m, 2H), 2.60 (d, J=6.9 Hz, 2H), 2.29-2.15 (m, 8H), 1.07 (d, J=6.2 Hz, 6H). Mass (m/z): 425.3 [M+H]+.
The title compound 63 (127.7 mg) was prepared in a yield of 40% as a pink solid from 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (191 mg, 0.80 mmol), 3-fluoro-2-methyl-4-(4-(trifluoromethyl)piperidin-1-yl)aniline (200 mg, 0.72 mmol), 1,4-dioxane (2 mL), Pd2(dba)3 (66 mg, 0.07 mmol), Xphos (68 mg, 0.14 mmol) and Cs2CO3 (472 mg, 1.45 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.40 (s, 1H), 6.92 (d, J=8.7 Hz, 1H), 6.85 (d, J=8.8 Hz, 1H), 6.85-6.76 (m, 1H), 6.44 (dd, J=8.6, 2.5 Hz, 1H), 6.37 (d, J=2.4 Hz, 1H), 4.52 (s, 2H), 3.34-3.31 (m, 1H), 3.29-3.26 (m, 1H), 3.18 (s, 3H), 2.68-2.57 (m, 2H), 2.45-2.34 (m, 1H), 2.02 (d, J=2.5 Hz, 3H), 1.91-1.82 (m, 2H), 1.65-1.50 (m, 2H). Mass (m/z): 438.2 [M+H]+.
The title compound 64 (56 mg) was prepared in a yield of 44% as a light yellow solid from 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (90 mg, 0.38 mmol), 4-(2,6-dimethyltetrahydro-2H-pyran-4-yl)aniline (70 mg, 0.34 mmol), 1,4-dioxane (2 mL), Pd2(dba)3 (31 mg, 0.03 mmol), Xphos (31 mg, 0.07 mmol) and Cs2CO3 (223 mg, 0.68 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-D6) δ 8.00 (s, 1H), 7.10-7.02 (m, 2H), 6.97 (d, J=8.7 Hz, 1H), 6.97-6.89 (m, 2H), 6.70 (dd, J=8.7, 2.5 Hz, 1H), 6.61 (d, J=2.4 Hz, 1H), 4.55 (s, 2H), 3.55-3.43 (m, 2H), 3.20 (s, 3H), 2.73-2.62 (m, 1H), 1.71-1.62 (m, 2H), 1.22-1.12 (m, 2H), 1.09 (d, J=6.1 Hz, 6H). Mass (m/z): 367.4 [M+H]+.
The title compound 65 (66.5 mg) was prepared in a yield of 27% as a yellow solid from 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (154 mg, 0.64 mmol), 2-(2,6-dimethylmorpholino)quinolin-6-amine (150 mg, 0.58 mmol), 1,4-dioxane (2 mL), Pd2(dba)3 (53 mg, 0.06 mmol), Xphos (55 mg, 0.12 mmol) and Cs2CO3 (381 mg, 1.17 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H), 7.93 (d, J=9.1 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.34-7.25 (m, 2H), 7.18 (d, J=9.2 Hz, 1H), 7.05 (d, J=8.7 Hz, 1H), 6.82 (dd, J=8.7, 2.5 Hz, 1H), 6.73 (d, J=2.4 Hz, 1H), 4.61 (s, 2H), 4.33-4.24 (m, 2H), 3.69-3.59 (m, 2H), 3.25 (s, 3H), 2.48-2.40 (m, 2H), 1.18 (d, J=6.2 Hz, 6H). Mass (m/z): 419.4 [M+H]+.
The title compound 66 (61.5 mg) was prepared in a yield of 43.4% as a green solid from 2-(2,6-dimethylmorpholino)pyrimidin-5-amine (80 mg, 0.385 mmol), 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (92.7 mg, 0.385 mmol), dioxane (15 mL), Pd2(dba)3 (17.6 mg, 0.0193 mmol), X-phos (18.4 mg, 0.0385 mmol) and Cs2CO3 (188 mg, 0.578 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO) δ 8.25 (d, J=5.0 Hz, 2H), 7.69 (d, J=10.3 Hz, 1H), 6.96 (d, J=8.7 Hz, 1H), 6.48 (dd, J=8.7, 2.5 Hz, 1H), 6.41 (d, J=2.5 Hz, 1H), 4.56 (s, 2H), 4.40 (dd, J=13.0, 1.7 Hz, 2H), 3.64-3.46 (m, 2H), 3.21 (s, 3H), 2.46 (s, 1H), 2.08 (s, 1H), 1.15 (d, J=6.2 Hz, 6H). Mass (m/z): 370.4 [M+H]+
The title compound 67 (69 mg) was prepared in a yield of 41.6% as a yellow solid from 4-(2,6-dimethylmorpholino)-3,5-difluoroaniline (100 mg, 0.413 mmol), 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (99.6 mg, 0.413 mmol), dioxane (15 mL), Pd2(dba)3 (18.9 mg, 0.021 mmol), X-phos (19.7 mg, 0.0413 mmol) and Cs2CO3 (202 mg, 0.619 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO) δ 8.41 (s, 1H), 7.08 (d, J=8.7 Hz, 1H), 6.81 (dd, J=8.6, 2.4 Hz, 1H), 6.71 (d, J=2.4 Hz, 1H), 6.64-6.51 (m, 2H), 4.63 (s, 2H), 3.65 (dd, J=11.4, 4.6 Hz, 2H), 3.25 (s, 3H), 2.86 (d, J=10.0 Hz, 2H), 2.68 (t, J=10.7 Hz, 2H), 1.06 (d, J=6.3 Hz, 6H). Mass (m/z): 404.4 [M+H]+
To a solution of compound 2-amino-5-bromophenol (200 mg, 1.06 mmol) in DMF (5 mL) was added K2CO3 (367.53 mg, 2.659 mmol) and methyl 2-bromobutanoate (231 g, 1.28 mmol) at r.t. Then the mixture was stirred at 90° C. for 16 hrs. After cooling to rt, the reaction solution was diluted with water (20 mL), extracted with ethyl acetate (20 mL*3). The organic layers were combined, washed with brine (20 mL), concentrated under vacuum and the residue was purified by silica gel chromatography (PE:EA=5:1) to give the title compound as a white solid (220 mg, 80.8%). Mass (m/z): 255.7 [M+H]+.
To a solution of 7-bromo-2-ethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (220 mg, 0.86 mmol) in DMF (5 mL) was added K2CO3 (118.7 mg, 0.859 mmol) and Mel (365.82 mg, 2.57 mmol) at 25° C. Then the mixture was stirred at 25° C. for 2 hrs, diluted with water (20 mL), extracted with ethyl acetate (20 mL*3), the organic layers were combined, washed with brine (20 mL), concentrated under vacuum to give the title compound as a white solid (220 mg, 74.49%). Mass (m/z): 269.7 [M+H]+.
To a solution of compound 7-bromo-2-ethyl-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one
To a solution of 7-bromo-2-ethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (100 mg, 0.37 mmol), compound 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (108 mg, 0.444 mmol), Cs2CO3 (241 mg, 0.74 mmol) and Ruphos (17 mg, 0.037 mmol) in 1,4-dioxane (15 mL) was added Pd2(dba)3 (68 mg, 0.074 mmol). The mixture was stirred at 90° C. for 3 hours under N2 atmosphere. After cooling to ambient temperature, ethyl acetate (20 mL) was added to the reaction mixture and the mixture was filtered through celite. The filtrate was washed with water and saturated brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure.
The residue was purified by silica gel column to provide 8 mg of compound 68 as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.82 (s, 1H), 6.96 (m, 5H), 6.59 (d, J=25.6 Hz, 2H), 4.47 (dd, J=8.0, 4.5 Hz, 10H), 3.62 (s, 2H), 3.22 (s, 3H), 2.65 (d, J=14.9 Hz, 2H), 2.47-2.35 (m, 1H), 1.97-1.82 (m, 2H), 1.80-1.67 (m, 2H), 1.58 (brs, 2H), 0.96 (t, J=7.4 Hz, 3H). Mass (m/z): 434.2 [M+H]+.
The title compound 69 (19.1 mg) was prepared in a yield of 9% as a light yellow solid from 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (143 mg, 0.60 mmol), 6-(2,6-dimethylmorpholino)-2-methylpyridin-3-amine (120 mg, 0.54 mmol), 1,4-dioxane (2 mL), Pd2(dba)3 (50 mg, 0.05 mmol), Xphos (51 mg, 0.11 mmol) and Cs2CO3 (354 mg, 1.09 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, MeOD) δ 7.35 (d, J=8.7 Hz, 1H), 6.92 (d, J=8.7 Hz, 1H), 6.63 (d, J=8.8 Hz, 1H), 6.32 (dd, J=8.6, 2.5 Hz, 1H), 6.24 (d, J=2.5 Hz, 1H), 4.51 (s, 2H), 4.05 (dt, J=11.5, 2.0 Hz, 2H), 3.79-3.66 (m, 2H), 3.30 (s, 3H), 2.46-2.35 (m, 2H), 2.28 (s, 3H), 1.23 (d, J=6.2 Hz, 6H). Mass (m/z): 383.4 [M+H]+.
The title compound 70 (20.8 mg) was prepared in a yield of 15.5% as a pink solid from 4-(2,6-dimethylmorpholino)-3-methoxyaniline (80 mg, 0.339 mmol), 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (81.7 mg, 0.339 mmol), dioxane (15 mL), Pd2(dba)3 (15.5 mg, 0.017 mmol), X-phos (16.2 mg, 0.034 mmol) and Cs2CO3 (166 mg, 0.509 mmol) according to the procedure for compound 1.1H NMR (400 MHz, DMSO) δ 7.95 (s, 1H), 7.00 (d, J=8.7 Hz, 1H), 6.78 (d, J=8.4 Hz, 1H), 6.71 (dd, J=8.7, 2.4 Hz, 1H), 6.64-6.55 (m, 3H), 4.58 (s, 2H), 3.73 (s, 3H), 3.72-3.65 (m, 2H), 3.23 (s, 3H), 3.13 (d, J=10.6 Hz, 2H), 2.20 (t, J=10.8 Hz, 2H), 1.09 (d, J=6.2 Hz, 6H). Mass (m/z): 398.5 [M+H]+.
The title compound 71 (45.8 mg) was prepared in a yield of 28% as a grey solid from 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (112 mg, 0.47 mmol), 6-(2,6-dimethylmorpholino)naphthalen-2-amine (100 mg, 0.39 mmol), 1,4-dioxane (2 mL), Pd2(dba)3 (36 mg, 0.04 mmol), Xphos (37 mg, 0.08 mmol) and Cs2CO3 (255 mg, 0.78 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO) δ 8.20 (s, 1H), 7.61 (dd, J=19.6, 9.0 Hz, 2H), 7.34 (d, J=2.2 Hz, 1H), 7.29 (dd, J=9.1, 2.5 Hz, 1H), 7.17 (dd, J=8.8, 2.3 Hz, 1H), 7.10-7.02 (m, 2H), 6.83 (dd, J=8.7, 2.5 Hz, 1H), 6.74 (d, J=2.4 Hz, 1H), 4.61 (s, 2H), 3.81-3.69 (m, 2H), 3.67-3.59 (m, 2H), 3.25 (s, 3H), 2.33-2.23 (m, 2H), 1.18 (d, J=6.2 Hz, 6H). Mass (m/z): 418.4 [M+H]+.
The title compound 72 (44.7 mg) was prepared in a yield of 29.5% as an off-white solid from 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (97 mg, 0.41 mmol), 6-(2,6-dimethylmorpholino) naphthalen-2-amine (100 mg, 0.34 mmol), 1,4-dioxane (2 mL), Pd2(dba)3 (31 mg, 0.03 mmol), Xphos (32 mg, 0.07 mmol) and Cs2CO3 (221 mg, 0.68 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.58 (d, J=9.1 Hz, 1H), 7.34 (d, J=2.2 Hz, 1H), 7.27 (dd, J=9.1, 2.5 Hz, 1H), 7.17 (dd, J=8.8, 2.3 Hz, 1H), 7.12 (d, J=2.5 Hz, 1H), 7.06 (d, J=8.7 Hz, 1H), 6.83 (dd, J=8.7, 2.4 Hz, 1H), 6.74 (d, J=2.4 Hz, 1H), 4.61 (s, 2H), 3.83 (d, J=12.4 Hz, 2H), 3.26 (s, 3H), 2.79-2.68 (m, 2H), 2.54-2.51 (m, 1H), 1.97-1.88 (m, 2H), 1.69-1.54 (m, 2H). Mass (m/z): 446.4 [M+H]+.
The title compound 73 (66.1 mg) was prepared in a yield of 32% as a brown solid from 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (154 mg, 0.64 mmol), 4-(2,6-dimethylmorpholino)-3-fluoroaniline (120 mg, 0.54 mmol), 1,4-dioxane (2 mL), Pd2(dba)3 (49 mg, 0.05 mmol), Xphos (51 mg, 0.11 mmol) and Cs2CO3 (349 mg, 1.07 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO) δ 8.10 (s, 1H), 7.03 (d, J=8.7 Hz, 1H), 6.93 (dd, J=9.9, 8.4 Hz, 1H), 6.83-6.75 (m, 2H), 6.73 (dd, J=8.6, 2.5 Hz, 1H), 6.63 (d, J=2.4 Hz, 1H), 4.60 (s, 2H), 3.79-3.66 (m, 2H), 3.24 (s, 3H), 3.13-3.05 (m, 2H), 2.35-2.25 (m, 2H), 1.11 (d, J=6.2 Hz, 6H). Mass (m/z): 386.4 [M+H]+.
The title compound 74 (97.2 mg) was prepared in a yield of 43% as an off-white solid from 7-bromo-4-methyl-2H-benzo[b][1,4] oxazin-3(4H)-one (139 mg, 0.58 mmol), 6-(2,6-dimethylmorpholino) naphthalen-2-amine (130 mg, 0.58 mmol), 1,4-dioxane (2 mL), Pd2(dba)3 (53 mg, 0.06 mmol), Xphos (55 mg, 0.12 mmol) and Cs2CO3 (378 mg, 1.16 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO) δ 7.53 (s, 1H), 7.11 (t, J=9.3 Hz, 1H), 6.94 (d, J=8.7 Hz, 1H), 6.85 (dd, J=14.3, 2.7 Hz, 1H), 6.72 (dd, J=9.0, 2.7 Hz, 1H), 6.44 (dd, J=8.6, 2.5 Hz, 1H), 6.36 (d, J=2.4 Hz, 1H), 4.55 (s, 2H), 3.73-3.61 (m, 2H), 3.59-3.50 (m, 2H), 3.21 (s, 3H), 2.28-2.18 (m, 2H), 1.15 (d, J=6.2 Hz, 6H). Mass (m/z): 386.4 [M+H]+.
The title compound 75 (50.3 mg) was prepared in a yield of 20.1% as a white solid from 7-bromo-4-methyl-2H-pyrido[3,2-b][1,4] oxazin-3(4H)-one (150 mg, 0.62 mmol), 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (166 mg, 0.68 mmol) in 1,4-dioxane (5 mL), Pd2(dba)3 (28 mg, 0.03 mmol), X-phos (29.4 mg, 0.06 mmol) and Cs2CO3 (402 mg, 1.23 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.71 (d, J=2.3 Hz, 1H), 7.01-6.95 (m, 2H), 6.95-6.87 (m, 3H), 4.69 (s, 2H), 3.63 (d, J=12.3 Hz, 2H), 3.28 (s, 3H), 2.63 (td, J=12.2, 2.4 Hz, 2H), 2.42 (td, J=8.6, 4.1 Hz, 1H), 1.93-1.83 (m, 2H), 1.57 (qd, J=12.5, 4.1 Hz, 2H). LC-MS (m/z) 407.2 [M+H]+.
The title compound 76 (100 mg) was prepared in a yield of 44% as a light yellow solid from 7-bromo-4-methyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (150 mg, 0.62 mmol), 4-(2,6-dimethylmorpholino) aniline (140 mg, 0.68 mmol), 1,4-dioxane (5 mL), Pd2(dba)3 (28 mg, 0.03 mmol), X-phos (29.4 mg, 0.06 mmol) and Cs2CO3 (402 mg, 1.23 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.70 (d, J=2.4 Hz, 1H), 6.99 (d, J=2.2 Hz, 1H), 6.98-6.84 (m, 4H), 4.69 (s, 2H), 3.69 (dqd, J=12.4, 6.1, 2.1 Hz, 2H), 3.45 (dt, J=10.9, 2.1 Hz, 2H), 3.34 (s, 3H), 2.19 (dd, J=11.8, 10.2 Hz, 2H), 1.24-1.11 (m, 6H). LC-MS (m/z) 369.2 [M+H]+.
The title compound 77 (13 mg) was prepared in a yield of 44% as a white solid from 7-bromo-4-methyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (120 mg, 0.49 mmol), 3-fluoro-4-(4-(trifluoromethyl)piperidin-1-yl) aniline (130 mg, 0.49 mmol), 1,4-dioxane (5 mL), Pd2(dba)3 (22.7 mg, 0.025 mmol), X-phos (23.6 mg, 0.049 mmol) and Cs2CO3 (323.2 mg, 0.991 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.03 (d, J=8.7 Hz, 1H), 6.97 (dd, J=10.0, 8.4 Hz, 1H), 6.79 (s, 1H), 6.77 (t, J=2.7 Hz, 1H), 6.73 (dd, J=8.6, 2.5 Hz, 1H), 6.64 (d, J=2.5 Hz, 1H), 4.60 (s, 2H), 3.28 (d, J=11.7 Hz, 2H), 3.24 (s, 3H), 2.65 (dd, J=12.6, 10.2 Hz, 2H), 2.46-2.36 (m, 1H), 1.93-1.84 (m, 2H), 1.60 (qd, J=12.4, 4.0 Hz, 2H). LC-MS (m/z) 424.2 [M+H]+.
The title compound 78 (32 mg) was prepared in a yield of 15.4% as a white solid from 7-bromo-4-methyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (120 mg, 0.49 mmol), 2-methyl-4-(4-(trifluoromethyl) piperidin-1-yl)aniline (130 mg, 0.49 mmol), 1,4-dioxane (5 mL), Pd2(dba)3 (22.7 mg, 0.025 mmol), X-phos (23.6 mg, 0.049 mmol) and Cs2CO3 (323.2 mg, 0.991 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.20 (s, 1H), 6.98 (d, J=8.6 Hz, 1H), 6.91 (d, J=8.7 Hz, 1H), 6.85 (d, J=2.8 Hz, 1H), 6.76 (dd, J=8.7, 2.9 Hz, 1H), 6.35 (dd, J=8.7, 2.5 Hz, 1H), 6.27 (d, J=2.4 Hz, 1H), 4.53 (s, 2H), 3.70 (d, J=12.1 Hz, 2H), 3.20 (s, 3H), 2.65 (td, J=12.3, 2.5 Hz, 2H), 2.48-2.41 (m, 1H), 2.12 (s, 3H), 1.92-1.83 (m, 2H), 1.56 (qd, J=12.5, 4.1 Hz, 2H). LC-MS (m/z) 420.2 [M+H]+.
The title compound 79 (38 mg) was prepared in a yield of 16.3% as a white solid from 7-bromo-4-methyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (130 mg, 0.54 mmol), 2,6-dimethyl-4-(4-(trifluoromethyl) piperidin-1-yl)aniline (146 mg, 0.54 mmol), 1,4-dioxane (5 mL), Pd2(dba)3 (24.6 mg, 0.027 mmol), X-phos (25.6 mg, 0.054 mmol) and Cs2CO3 (350 mg, 1.07 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.06 (s, 1H), 6.86 (d, J=8.7 Hz, 1H), 6.72 (s, 2H), 6.05 (dd, J=8.6, 2.5 Hz, 1H), 5.98 (d, J=2.4 Hz, 1H), 4.51 (s, 2H), 3.75 (d, J=12.3 Hz, 2H), 3.18 (s, 3H), 2.67 (td, J=12.0, 2.4 Hz, 2H), 2.47-2.39 (m, 1H), 2.07 (d, J=2.8 Hz, 6H), 1.92-1.83 (m, 2H), 1.55 (qd, J=12.6, 4.1 Hz, 2H). LC-MS (m/z) 434.2 [M+H]+.
The title compound 80 (35.2 mg) was prepared in a yield of 24.4% as a pink solid from 4-(2,6-dimethylmorpholino)aniline (70 mg, 0.339 mmol), 7-bromo-4-(2-(dimethylamino)ethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (101 mg, 0.339 mmol), dioxane (5 mL), Pd2(dba)3 (15.6 mg, 0.017 mmol), X-phos (16.2 mg, 0.034 mmol) and Cs2CO3 (166 mg, 0.509 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO) δ 7.81 (s, 1H), 6.99 (dd, J=15.6, 8.9 Hz, 3H), 6.88 (d, J=9.0 Hz, 2H), 6.61 (dd, J=8.7, 2.4 Hz, 1H), 6.53 (d, J=2.4 Hz, 1H), 4.54 (s, 2H), 3.93 (t, J=6.9 Hz, 2H), 3.68 (dd, J=11.5, 5.0 Hz, 2H), 3.44 (d, J=10.6 Hz, 2H), 2.39 (t, J=6.9 Hz, 2H), 2.29 (dd, J=19.8, 10.7 Hz, 1H), 2.23-2.13 (m, 7H), 1.15 (t, J=5.7 Hz, 6H). Mass (m/z): 425.6 [M+H]+
The title compound 81 (12.5 mg) was prepared in a yield of 17% as a pink solid from 4-(2,6-dimethylmorpholino)aniline (38.3 mg, 0.186 mmol), 7-bromo-2-ethyl-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (50 mg, 0.186 mmol), dioxane (5 mL), Pd2(dba)3 (8.52 mg, 0.0093 mmol), X-phos (8.9 mg, 0.0186 mmol) and Cs2CO3 (91 mg, 0.279 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.79 (s, 1H), 7.00-6.85 (m, 4H), 6.63-6.49 (m, 2H), 4.46 (dd, J=8.0, 4.6 Hz, 1H), 3.76-3.61 (m, 2H), 3.45 (d, J=10.8 Hz, 2H), 3.22 (s, 3H), 2.25-2.13 (m, 2H), 1.15 (t, J=5.7 Hz, 5H), 1.02-0.85 (m, 3H). Mass (m/z): 396.5 [M+H]+
To a solution of 7-((4-(tert-butyl)phenyl)amino)-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (100 mg, 0.24 mmol) in methanol (3 mL) was added 4-methylbenzenesulfonic acid (44 mg, 0.26 mmol). The mixture was stirred at r.t. for 1 h, the mixture was concentrated and purified by prep HPLC to give 7-((4-(tert-butyl)phenyl)amino)-4-(2-hydroxyethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (16.9 mg, 43%) as a light yellow solid. Mass (m/z): 341.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.98 (s, 1H), 7.26-7.17 (m, 2H), 7.08 (d, J=8.8 Hz, 1H), 6.98-6.89 (m, 2H), 6.68 (dd, J=8.7, 2.5 Hz, 1H), 6.60 (d, J=2.5 Hz, 1H), 4.83 (t, J=5.7 Hz, 1H), 4.53 (s, 2H), 3.87 (t, J=6.3 Hz, 2H), 3.53 (q, J=6.1 Hz, 2H), 1.22 (s, 9H).
To a solution of 4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-7-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)-2H-benzo[b][1,4]oxazin-3(4H)-one (100 mg, 0.19 mmol) in methanol (3 mL) was added 4-methylbenzenesulfonic acid (36 mg, 0.21 mmol). The mixture was stirred at r.t. for 1 h, concentrated and purified by prep HPLC to give 4-(2-hydroxyethyl)-7-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)-2H-benzo[b][1,4]oxazin-3(4H)-one (16.9 mg, 43%) as a grey solid. 1H NMR (400 MHz, DMSO) δ 7.81 (s, 1H), 7.08 (d, J=8.8 Hz, 1H), 6.96 (d, J=9.0 Hz, 2H), 6.96-6.86 (m, 2H), 6.60 (dd, J=8.7, 2.5 Hz, 1H), 6.53 (d, J=2.5 Hz, 1H), 4.86 (t, J=5.7 Hz, 1H), 4.54 (s, 2H), 3.89 (t, J=6.3 Hz, 2H), 3.64 (s, 1H), 3.62-3.51 (m, 3H), 2.68-2.57 (m, 2H), 2.47-2.36 (m, 1H), 1.93-1.83 (m, 2H), 1.64-1.49 (m, 2H). Mass (m/z): 436.4 [M+H]+.
To a solution of 4-(2-hydroxyethyl)-7-((4-(4-(trifluoromethyl) piperidin-1-yl)phenyl)amino)-2H-benzo[b][1,4]oxazin-3(4H)-one (100 mg, 0.21 mmol) in methanol (3 mL) was added 4-methylbenzenesulfonic acid (39 mg, 0.23 mmol). The mixture was stirred at r.t. for 1 h, the mixture was concentrated and purified by prep HPLC to give 7-((4-(2,6-dimethylmorpholino)phenyl)amino)-4-(2-hydroxyethyl)-2H-ben zo[b][1,4]oxazin-3(4H)-one (16.9 mg, 43%) as a grey solid. 1H NMR (400 MHz, DMSO) δ 7.75 (s, 1H), 7.05 (d, J=8.8 Hz, 1H), 6.94 (d, J=8.9 Hz, 2H), 6.90-6.82 (m, 2H), 6.57 (dd, J=8.7, 2.5 Hz, 1H), 6.50 (d, J=2.4 Hz, 1H), 4.82 (s, 1H), 4.51 (s, 2H), 3.87 (t, J=6.3 Hz, 2H), 3.73-3.61 (m, 2H), 3.53 (t, J=6.4 Hz, 2H), 3.46-3.38 (m, 2H), 2.17 (t, J=11.0 Hz, 2H), 1.12 (d, J=6.2 Hz, 6H). Mass (m/z): 398.4 [M+H]+.
The title compound 85 (8.6 mg) was prepared in a total yield of 10.0% as a yellow solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (59 mg, 0.241 mmol), 7-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (50 mg, 0.219 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol) and Cs2CO3 (108 mg, 0.329 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 7.71 (s, 1H), 6.96-6.84 (m, 4H), 6.71 (d, J=8.4 Hz, 1H), 6.57-6.49 (m, 2H), 4.48 (s, 2H), 3.61 (d, J=12.4 Hz, 2H), 2.61 (td, J=12.4, 2.4 Hz, 2H), 2.42 (ddt, J=12.4, 8.8, 4.0 Hz, 1H), 1.91-1.82 (m, 2H), 1.57 (qd, J=12.4, 4.0 Hz, 2H). Mass (m/z): 392.3 [M+H]+.
The title compound 86 (156 mg) was prepared in a yield of 60% as a light yellow solid from 7-bromo-4-methyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (150 mg, 0.62 mmol), 3-methyl-4-(4-(trifluoromethyl) piperidin-1-yl)aniline (160 mg, 0.62 mmol), 1,4-dioxane (5 mL), Pd2(dba)3 (28.3 mg, 0.03 mmol), X-phos (29.5 mg, 0.06 mmol) and Cs2CO3 (404 mg, 1.24 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.89 (s, 1H), 6.99 (d, J=8.7 Hz, 1H), 6.94 (d, J=8.3 Hz, 1H), 6.89-6.81 (m, 2H), 6.69 (dd, J=8.7, 2.5 Hz, 1H), 6.60 (d, J=2.4 Hz, 1H), 4.58 (s, 2H), 3.23 (s, 3H), 3.04 (d, J=11.4 Hz, 2H), 2.61 (td, J=12.0, 2.3 Hz, 2H), 2.45-2.36 (m, 1H), 2.19 (s, 3H), 1.93-1.84 (m, 2H), 1.60 (qd, J=12.3, 4.0 Hz, 2H). LC-MS (m/z) 420.2 [M+H]+.
The title compound 87 (39.4 mg) was prepared in a yield of 22.2% as a white solid from 7-bromo-5-fluoro-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (120 mg, 0.46 mmol), 4-(2,6-dimethylmorpholino) aniline (95 mg, 0.46 mmol), 1,4-dioxane (5 mL), Pd2(dba)3 (21 mg, 0.023 mmol), X-phos (22 mg, 0.046 mmol) and Cs2CO3 (301 mg, 0.92 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.04-6.96 (m, 2H), 6.96-6.87 (m, 2H), 6.44-6.32 (m, 2H), 4.54 (s, 2H), 3.72-3.64 (m, 2H), 3.48 (dt, J=11.0, 2.1 Hz, 2H), 3.29 (d, J=5.5 Hz, 3H), 2.20 (dd, J=11.8, 10.2 Hz, 2H), 1.14 (d, J=6.2 Hz, 6H). LC-MS (m/z) 386.2 [M+H]+.
The titled compound 88 (46.5 mg, 23.8%) as an off-white solid was prepared according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.00 (d, J=6.5 Hz, 1H), 6.98-6.90 (m, 3H), 6.41 (dd, J=15.1, 2.5 Hz, 1H), 6.36 (dd, J=2.5, 1.2 Hz, 1H), 4.54 (s, 2H), 3.67 (d, J=12.3 Hz, 2H), 3.29 (d, J=5.5 Hz, 3H), 2.63 (dd, J=12.3, 2.5 Hz, 2H), 2.46-2.36 (m, 1H), 1.93-1.84 (m, 2H), 1.56 (qd, J=12.5, 4.1 Hz, 2H). LC-MS (m/z) 424.2 [M+H]+.
The title compound 89 (51.1 mg) was prepared in a yield of 26.9% as a light yellow solid from 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (120 mg, 0.49 mmol), 4-(2,6-dimethylmorpholino) aniline (110 mg, 0.49 mmol), 1,4-dioxane (5 mL), Pd2(dba)3 (22.7 mg, 0.025 mmol), X-phos (23.6 mg, 0.049 mmol) and Cs2CO3 (323 mg, 0.99 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.02 (d, J=8.7 Hz, 1H), 6.88 (dd, J=10.0, 8.4 Hz, 1H), 6.82-6.66 (m, 3H), 6.62 (d, J=2.5 Hz, 1H), 4.59 (s, 2H), 4.32 (dt, J=4.4, 2.2 Hz, 2H), 3.23 (s, 3H), 2.94 (dd, J=10.6, 1.5 Hz, 2H), 2.86 (dd, J=11.4, 2.0 Hz, 2H), 1.95 (q, J=6.2, 5.6 Hz, 2H), 1.81 (dd, J=7.8, 4.2 Hz, 2H). LC-MS (m/z) 384.2 [M+H]+.
The title compound 90 (48 mg) was prepared in a yield of 37.8% as a gray solid from 2-methoxy-4-(4-(trifluoromethyl)piperidin-1-yl)aniline (80 mg, 0.292 mmol), 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (70.4 mg, 0.292 mmol), dioxane (15 mL), Pd2(dba)3 (13.4 mg, 0.015 mmol), X-phos (14 mg, 0.0292 mmol) and Cs2CO3 (143 mg, 0.438 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO) δ 7.10 (s, 1H), 7.01 (d, J=8.6 Hz, 1H), 6.91 (d, J=8.7 Hz, 1H), 6.65 (d, J=2.5 Hz, 1H), 6.55-6.39 (m, 3H), 4.53 (s, 2H), 3.78 (d, J=13.8 Hz, 3H), 3.72 (d, J=12.4 Hz, 2H), 3.21 (s, 3H), 2.67 (dd, J=12.2, 10.5 Hz, 2H), 2.44 (dd, J=11.7, 8.3 Hz, 1H), 1.89 (d, J=13.4 Hz, 2H), 1.58 (qd, J=12.5, 3.9 Hz, 2H). Mass (m/z): 436.5 [M+H]+
The title compound 91 (27.8 mg) was prepared in a yield of 21.9% as a gray solid from 3-methoxy-4-(4-(trifluoromethyl)piperidin-1-yl)aniline (80 mg, 0.292 mmol), 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (70.4 mg, 0.292 mmol), dioxane (15 mL), Pd2(dba)3 (13.4 mg, 0.015 mmol), X-phos (14 mg, 0.0292 mmol) and Cs2CO3 (143 mg, 0.438 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.93 (s, 1H), 6.96 (d, J=8.8 Hz, 1H), 6.77 (d, J=8.4 Hz, 1H), 6.68 (dd, J=8.7, 2.4 Hz, 1H), 6.62-6.47 (m, 3H), 4.54 (s, 2H), 3.73 (d, J=20.5 Hz, 3H), 3.26 (s, 2H), 3.19 (s, 3H), 2.51-2.48 (m, 2H), 1.82 (d, J=11.7 Hz, 2H), 1.55 (dt, J=13.1, 8.7 Hz, 2H). Mass (m/z): 436.5 [M+H]+
The title compound 92 (23 mg) was prepared in a yield of 11% as a white solid from 4-(2,6-dimethyltetrahydro-2H-pyran-4-yl)aniline (100 mg, 0.488 mmol), 7-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (122 mg, 0.536 mmol), t-BuOH (5 mL), Pd2(dba)3 (22.4 mg, 0.0244 mmol), Brettphos (26.2 mg, 0.0488 mmol) and Cs2CO3 (239 mg, 0.732 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H), 7.93 (s, 1H), 7.07 (d, J=8.5 Hz, 2H), 6.94 (t, J=10.7 Hz, 2H), 6.75 (d, J=8.4 Hz, 1H), 6.66-6.55 (m, 2H), 4.50 (s, 2H), 3.52 (dq, J=12.2, 6.1 Hz, 2H), 2.73-2.61 (m, 1H), 1.70 (d, J=15.8 Hz, 2H), 1.25-1.14 (m, 2H), 1.11 (t, J=12.2 Hz, 6H). Mass (m/z): 353.4 [M+H]+
The title compound 93 (32 mg) was prepared in a yield of 31% as an olive solid from 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (68 mg, 0.28 mmol), 4-(2,2,6,6-tetramethylmorpholino)aniline (60 mg, 0.26 mmol), 1,4-dioxane (2 mL), Pd2(dba)3 (23 mg, 0.03 mmol), Xphos (24 mg, 0.05 mmol) and Cs2CO3 (167 mg, 0.51 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.81 (s, 1H), 7.02-6.92 (m, 3H), 6.91-6.82 (m, 2H), 6.62 (dd, J=8.7, 2.5 Hz, 1H), 6.53 (d, J=2.4 Hz, 1H), 4.56 (s, 2H), 3.22 (s, 3H), 2.84 (s, 4H), 1.22 (s, 12H). Mass (m/z): 396.4 [M+H]+.
The title compound 94 (36 mg) was prepared in a yield of 31% as a light pink solid from 7-bromo-4-(2-(dimethylamino)ethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (100 mg, 0.36 mmol), 4-(4-(trifluoromethyl) piperidin-1-yl)aniline (80 mg, 0.32 mmol), 1,4-dioxane (2 mL), Pd2(dba)3 (30 mg, 0.03 mmol), Xphos (31 mg, 0.07 mmol) and Cs2CO3 (213 mg, 0.66 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.83 (s, 1H), 7.01 (d, J=8.8 Hz, 1H), 7.00-6.93 (m, 2H), 6.93-6.86 (m, 2H), 6.62 (dd, J=8.7, 2.5 Hz, 1H), 6.54 (d, J=2.5 Hz, 1H), 4.54 (s, 2H), 3.93 (t, J=7.0 Hz, 2H), 3.66-3.59 (m, 2H), 2.68-2.57 (m, 2H), 2.46-2.35 (m, 3H), 2.18 (s, 6H), 1.92-1.83 (m, 2H), 1.64-1.49 (m, 2H).
The title compound 95 (56 mg) was prepared in a yield of 25% as a grey solid from 7-bromo-4-(2-methoxyethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (150 mg, 0.59 mmol), 4-(2,6-dimethylmorpholino)aniline (110 mg, 0.53 mmol), 1,4-dioxane (2 mL), Pd2(dba)3 (49 mg, 0.05 mmol), Xphos (51 mg, 0.11 mmol) and Cs2CO3 (348 mg, 1.06 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.77 (s, 1H), 7.03 (d, J=8.8 Hz, 1H), 6.97-6.89 (m, 2H), 6.89-6.80 (m, 2H), 6.55 (dd, J=8.7, 2.5 Hz, 1H), 6.49 (d, J=2.5 Hz, 1H), 4.51 (s, 2H), 3.98 (t, J=5.8 Hz, 2H), 3.71-3.59 (m, 2H), 3.46 (t, J=5.8 Hz, 2H), 3.44-3.37 (m, 2H), 3.20 (s, 3H), 2.20-2.10 (m, 2H), 1.10 (d, J=6.2 Hz, 6H).
The title compound 96 (20 mg) was prepared in a yield of 8% as a grey solid from 7-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (154 mg, 0.68 mmol), 4-(2,6-dimethylmorpholino)-2-methylaniline (150 mg, 0.68 mmol), 1,4-dioxane (2 mL), Brettphos Pd G3 (62 mg, 0.14 mmol), Brettphos (73 mg, 0.13 mmol) and Cs2CO3 (444 mg, 1.36 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 7.08 (s, 1H), 6.96 (d, J=8.6 Hz, 1H), 6.82 (d, J=2.8 Hz, 1H), 6.73 (dd, J=8.6, 2.8 Hz, 1H), 6.65 (d, J=8.4 Hz, 1H), 6.26 (dd, J=8.4, 2.4 Hz, 1H), 6.23 (d, J=2.3 Hz, 1H), 4.45 (s, 2H), 3.74-3.62 (m, 2H), 3.53-3.45 (m, 2H), 2.29-2.14 (m, 2H), 2.11 (s, 3H), 1.14 (d, J=6.2 Hz, 6H). Mass (m/z): 368.4 [M+H]+.
The title compound 97 (47.5 mg) was prepared in a yield of 26% as a light yellow solid from 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (120 mg, 0.49 mmol), 4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptan-5-yl)-3-fluoroaniline (103.2 mg, 0.49 mmol), 1,4-dioxane (5 mL), Pd2(dba)3 (22.7 mg, 0.025 mmol), X-phos (23.6 mg, 0.049 mmol) and Cs2CO3 (323 mg, 0.99 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.91 (s, 1H), 6.99 (d, J=8.7 Hz, 1H), 6.85-6.76 (m, 1H), 6.76-6.68 (m, 2H), 6.65 (dd, J=8.7, 2.5 Hz, 1H), 6.56 (d, J=2.4 Hz, 1H), 4.58 (s, 2H), 4.53 (t, J=1.9 Hz, 1H), 4.37 (s, 1H), 3.81 (d, J=7.6 Hz, 1H), 3.72 (dd, J=7.7, 1.6 Hz, 1H), 3.56 (ddd, J=9.7, 4.0, 1.7 Hz, 1H), 3.23 (s, 3H), 2.99 (dd, J=9.8, 3.5 Hz, 1H), 1.88 (dd, J=9.6, 2.3 Hz, 1H), 1.83-1.75 (m, 1H). LC-MS (m/z) 370.2 [M+H]+.
The title compound 98 (34.5 mg) was prepared in a yield of 16.7% as an off-white solid from 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (120 mg, 0.49 mmol), 4-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)-3-fluoroaniline (110 mg, 0.49 mmol), 1,4-dioxane (5 mL), Pd2(dba)3 (22.7 mg, 0.025 mmol), X-phos (23.6 mg, 0.049 mmol) and Cs2CO3 (323 mg, 0.99 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.00 (d, J=8.7 Hz, 1H), 6.89-6.84 (m, 1H), 6.84-6.81 (m, 1H), 6.80-6.73 (m, 1H), 6.66 (dd, J=8.7, 2.5 Hz, 1H), 6.57 (d, J=2.5 Hz, 1H), 4.58 (s, 2H), 4.09 (dt, J=8.9, 2.4 Hz, 1H), 3.92-3.84 (m, 2H), 3.69 (dq, J=10.5, 2.8 Hz, 1H), 3.54 (d, J=3.0 Hz, 1H), 3.32 (d, J=2.5 Hz, 1H), 3.23 (s, 3H), 2.08 (s, 1H), 2.02-1.93 (m, 1H), 1.88-1.67 (m, 2H). LC-MS (m/z) 384.2 [M+H]+.
The titled compound 99 (21.7 mg, 14.2%) as an off-white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.01 (d, J=8.7 Hz, 1H), 6.97 (dd, J=10.4, 8.6 Hz, 1H), 6.86-6.77 (m, 2H), 6.69 (dd, J=8.7, 2.5 Hz, 1H), 6.60 (d, J=2.4 Hz, 1H), 4.58 (d, J=3.7 Hz, 4H), 3.55 (d, J=11.3 Hz, 2H), 3.23 (s, 3H), 3.43 (d, J=11.4 Hz, 2H), 3.04 (dt, J=8.1, 6.3 Hz, 1H), 2.17 (d, J=8.2 Hz, 1H). LC-MS (m/z) 370.2 [M+H]+.
The title compound 100 (32 mg) was prepared in a yield of 9.0% as a white solid from 7-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (200 mg, 0.88 mmol), 2-methyl-4-(4-(trifluoromethyl)piperidin-1-yl)aniline (226 mg, 0.88 mmol), t-BuOH (5 mL), Pd2(dba)3 (40 mg, 0.045 mmol), Brettphos (47.1 mg, 0.088 mmol) and Cs2CO3 (572 mg, 1.75 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 7.08 (s, 1H), 6.96 (d, J=8.6 Hz, 1H), 6.84 (d, J=2.8 Hz, 1H), 6.75 (dd, J=8.7, 2.8 Hz, 1H), 6.65 (d, J=8.4 Hz, 1H), 6.28 (dd, J=8.4, 2.4 Hz, 1H), 6.24 (d, J=2.3 Hz, 1H), 4.45 (s, 2H), 3.68 (d, J=12.3 Hz, 2H), 2.62 (dd, J=12.4, 2.5 Hz, 2H), 2.47-2.38 (m, 1H), 2.11 (s, 3H), 1.92-1.83 (m, 2H), 1.56 (qd, J=12.5, 4.1 Hz, 2H). LC-MS (m/z) 406.2 [M+H]+.
The titled compound 101 (113 mg, 31.8%) as a white solid was prepared according to the procedure outlined for compound 1. LC-MS (m/z) 406.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 7.79 (s, 1H), 6.91 (d, J=8.3 Hz, 1H), 6.82 (d, J=8.8 Hz, 2H), 6.73 (d, J=8.4 Hz, 1H), 6.60 (dd, J=8.4, 2.3 Hz, 1H), 6.56 (d, J=2.3 Hz, 1H), 4.49 (s, 2H), 3.02 (d, J=11.5 Hz, 2H), 2.60 (td, J=11.9, 2.3 Hz, 2H), 2.43-2.32 (m, 1H), 2.18 (s, 3H), 1.92-1.84 (m, 2H), 1.60 (qd, J=12.3, 4.0 Hz, 2H).
The title compound 102 (8.5 mg) was prepared in a total yield of 11.9% as a purple solid from 4-(4-methylpiperidin-1-yl)aniline (48 mg, 0.256 mmol) and 6-bromo-1,4-dimethyl-3,4-dihydroquinoxalin-2(1H)-one (50 mg, 0.197 mmol) in 1,4-dioxane (5 mL), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (97 mg, 0.295 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.07 (d, J=8.4 Hz, 2H), 7.00 (d, J=8.4 Hz, 3H), 6.62 (d, J=8.4 Hz, 1H), 6.54 (s, 1H), 3.63 (d, J=7.2 Hz, 2H), 3.42 (s, 3H), 3.37 (s, 2H), 3.10 (s, 3H), 2.69 (s, 2H), 2.29 (dq, J=8.4, 4.8, 4.4 Hz, 1H), 2.01 (s, 1H), 1.98 (s, 1H), 1.76 (d, J=4.0 Hz, 1H), 1.73 (d, J=4.0 Hz, 1H), 1.73 (d, J=4.0 Hz, 1H). Mass (m/z): 365.3 [M+H]+.
To a solution of 6-bromo-1,2,3,4-tetrahydroisoquinoline (212 mg, 1.0 mmol) and 2-(4-methylpiperazin-1-yl)acetic acid (205 mg, 1.3 mmol) in DMF (5 mL) was added DIEA (0.33 mL, 2.0 mmol). Followed by the addition of HATU (501 mg, 1.3 mmol) then the reaction mixture was stirred for 3 hours at r.t. Then 40 ml of water was added. Then the mixture was extracted by DCM (20 mL×3). The combined organic layers were washed with water (20 mL×3), dried over Na2SO4 and concentrated under vacuum. The residue was purified by prep-TLC to give the desired product as yellow solid (301 mg, 85.2%). Mass (m/z): 352.1 [M+H]+.
The title compound 103 (18.5 mg) was prepared in a total yield of 82.6% as a yellow solid from 4-(piperidin-1-yl)aniline (11.4 mg, 0.065 mmol), 1-(6-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-2-(4-methylpiperazin-1-yl)e than-1-one (17.6 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.40-6.73 (m, 7H), 4.72 (s, 2H), 3.83 (s, 2H), 3.51-3.39 (m, 4H), 3.06-2.87 (m, 4H), 2.85-2.63 (m, 8H), 2.50 (s, 3H), 1.90-1.76 (m, 4H), 1.71-1.60 (m, 2H). Mass (m/z): 448.3 [M+H]+.
The title compound 104 (8.6 mg) was prepared in a total yield of 76.4% as an orange solid from 6-bromo-1,2,3,4-tetrahydroisoquinoline (10.6 mg, 0.05 mmol), aniline (6.1 mg, 0.065 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.29-7.18 (m, 2H), 7.09-6.79 (m, 6H), 4.10 (s, 2H), 3.29 (t, J=6.4 Hz, 2H), 2.93 (t, J=6.4 Hz, 2H). Mass (m/z): 225.3 [M+H]+.
The title compound 105 (9.8 mg) was prepared in a total yield of 77.8% as a orange solid from 6-bromo-2-ethyl-1,2,3,4-tetrahydroisoquinoline (12.0 mg, 0.05 mmol), aniline (6.1 mg, 0.065 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.24-7.17 (m, 2H), 7.08-7.02 (m, 2H), 7.00-6.80 (m, 4H), 3.89 (s, 2H), 3.08 (t, J=6.4 Hz, 2H), 2.97 (t, J=6.4 Hz, 2H), 2.91 (q, J=7.2 Hz, 2H), 1.29 (t, J=7.2 Hz, 3H). Mass (m/z): 253.2 [M+H]+.
The title compound 106 (9.2 mg) was prepared in a total yield of 68.9% as a orange solid from 1-(6-bromo-3,4-dihydroisoquinolin-2(1H)-yl) ethan-1-one (12.7 mg, 0.05 mmol), aniline (6.1 mg, 0.065 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.23-7.16 (m, 2H), 7.07-6.78 (m, 6H), 4.57 (s, 2H), 3.66 (t, J=6.4 Hz, 2H), 2.79 (t, J=6.4 Hz, 2H), 2.15 (s, 3H). Mass (m/z): 267.2 [M+H]+.
The title compound 107 (15.3 mg) was prepared in a total yield of 83.8% as an orange solid from 1-(6-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-2-(4-methylpiperazin-1-yl)ethan-1-one (17.6 mg, 0.05 mmol), aniline (6.1 mg, 0.065 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.25-7.14 (m, 2H), 7.08-6.78 (m, 6H), 4.62 (s, 2H), 3.72 (s, 2H), 3.36 (t, J=6.0 Hz, 2H), 2.84 (t, J=6.0 Hz, 2H), 2.80-2.58 (m, 8H), 2.44 (s, 3H). Mass (m/z): 365.2 [M+H]+
The title compound 108 (20.1 mg) was prepared in a total yield of 75.3% as a yellow solid from 3-fluoro-4-(4-(trifluoromethyl)piperidin-1-yl) aniline (17.1 mg, 0.065 mmol), 1-(6-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-2-(4-methylpiperazin-1-yl)ethan-1-one (17.6 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.14-6.72 (m, 6H), 4.63 (s, 2H), 3.76 (s, 2H), 3.41-3.33 (m, 4H), 2.96-2.75 (m, 4H), 2.73-2.55 (m, 8H), 2.41 (s, 3H), 2.25 (m, 1H), 1.98-1.90 (m, 2H), 1.79-1.68 (m, 2H). Mass (m/z): 534.3 [M+H]+
The title compound 109 (29.5 mg) was prepared in a total yield of 35.8% as a purple solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (62 mg, 0.256 mmol), 6-bromo-1,4-dimethyl-3,4-dihydroquinoxalin-2(1H)-one (50 mg, 0.197 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (97 mg, 0.295 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.07 (d, J=8.4 Hz, 2H), 7.00 (d, J=8.4 Hz, 3H), 6.62 (d, J=8.4 Hz, 1H), 6.54 (s, 1H), 3.63 (d, J=7.2 Hz, 2H), 3.42 (s, 3H), 3.37 (s, 2H), 3.10 (s, 3H), 2.69 (s, 2H), 2.29 (dq, J=8.4, 4.8, 4.4 Hz, 1H), 2.01 (s, 1H), 1.98 (s, 1H), 1.76 (d, J=4.0 Hz, 1H), 1.73 (d, J=4.0 Hz, 1H). Mass (m/z): 419.3 [M+H]+.
The title compound 110 (8.8 mg) as prepared in a total yield of 43.4% as a yellow powder from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (80 mg, 0.33 mmol), 6-bromo-1,4-dimethyl-1,4-dihydroquinoxaline-2,3-dione (67 mg, 0.25 mmol), Pd2(dba)3 (2.3 mg, 2.5 umol), X-Phos (6.0 mg, 12.5 umol), t-BuOK (36 mg, 0.38 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.30 (d, J=8.8 Hz, 1H), 7.16-7.08 (m, 2H), 7.04-6.94 (m, 4H), 3.72-3.66 (m, 2H), 3.65 (s, 3H), 3.60 (s, 3H), 2.76-2.65 (m, 2H), 2.35-2.25 (m, 1H), 2.03-1.96 (m, 1H), 1.75 (qd, J=12.5, 4.1 Hz, 2H). Mass (m/z): 433.3 [M+H]+.
The title compound 111 (37.9 mg) was prepared in a total yield of 22.6% as a yellow solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (122 mg, 0.502 mmol), 6-bromo-1-methylquinoxalin-2(1H)-one (100 mg, 0.418 mmol), Pd2(dba)3 (4 mg, 0.004 mmol), X-phos (10 mg, 0.02 mmol) and Cs2CO3 (206 mg, 0.628 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 8.06 (s, 1H), 7.48-7.42 (m, 1H), 7.28 (d, J=7.6 Hz, 2H), 7.06-7.03 (m, 2H), 6.97-6.92 (m, 2H), 3.66 (d, J=12.0 Hz, 2H), 3.57 (s, 3H), 2.65 (td, J=12.0, 2.4 Hz, 2H), 2.43 (ddd, J=12.4, 8.4, 3.6 Hz, 1H), 1.93-1.85 (m, 2H), 1.58 (qd, J=12.4, 4.0 Hz, 2H). Mass (m/z): 403.3 [M+H]+.
The title compound 112 (11.3 mg) was prepared in a total yield of 6.9% as a purple solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (115 mg, 0.470 mmol), 6-bromo-1,3-dimethyl-3,4-dihydroquinazolin-2(1H)-one (100 mg, 0.392 mmol), Pd2(dba)3 (4 mg, 0.004 mmol), X-phos (10 mg, 0.02 mmol) and Cs2CO3 (193 mg, 0.588 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.07 (d, J=8.4 Hz, 2H), 7.00 (d, J=8.4 Hz, 3H), 6.62 (d, J=8.4 Hz, 1H), 6.54 (s, 1H), 3.63 (d, J=7.2 Hz, 2H), 3.42 (s, 3H), 3.37 (s, 2H), 3.10 (s, 3H), 2.69 (s, 2H), 2.29 (dq, J=8.4, 4.8, 4.4 Hz, 1H), 2.01 (s, 1H), 1.98 (s, 1H), 1.76 (d, J=4.0 Hz, 1H), 1.73 (d, J=4.0 Hz, 1H). Mass (m/z): 419.3 [M+H]+.
The title compound 113 (33.4 mg) was prepared in a total yield of 20.3% as a pink solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (116 mg, 0.474 mmol), 6-bromo-1,4-dimethylquinazolin-2(1H)-one (100 mg, 0.395 mmol), Pd2(dba)3 (4 mg, 0.004 mmol), X-phos (10 mg, 0.02 mmol), Cs2CO3 (194 mg, 0.592 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.72 (s, 1H), 7.85 (s, 2H), 7.50 (s, 1H), 7.11 (s, 5H), 3.88-3.65 (m, 6H), 2.92 (d, J=44.4 Hz, 4H), 1.94 (s, 3H), 1.65 (s, 2H). Mass (m/z): 417.3 [M+H]+.
The title compound 114 (46.7 mg) was prepared in a total yield of 54.6% as a green solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (64 mg, 0.263 mmol), 7-bromo-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (50 mg, 0.219 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (108 mg, 0.328 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.82 (s, 1H), 6.97 (dt, J=10.0, 3.2 Hz, 3H), 6.94-6.87 (m, 2H), 6.63 (dd, J=8.8, 2.4 Hz, 1H), 6.55 (d, J=2.4 Hz, 1H), 4.57 (s, 2H), 3.77 (d, J=12.0, 2H), 0.63 (d, J=11.6 Hz, 2H), 3.23 (s, 3H), 2.63 (td, J=12.4, 2.4 Hz, 2H), 2.43 (dp, J=12.4, 4.0 Hz, 1H), 1.88 (d, J=12.0 Hz, 2H), 1.57 (qd, J=12.4, 4.0 Hz, 2H). Mass (m/z): 392.3 [M+H]+.
The title compound 115 (101.2 mg) was prepared in a total yield of 69.5% as a yellow solid from 4-(4-methylpiperidin-1-yl)aniline (95 mg, 0.502 mmol), 6-bromo-1-methylquinoxalin-2(1H)-one (100 mg, 0.418 mmol), Pd2(dba)3 (4 mg, 0.004 mmol), X-phos (12 mg, 0.02 mmol), Cs2CO3 (206 mg, 0.627 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.22 (s, 1H), 7.63-7.40 (m, 5H), 7.19 (d, J=8.5 Hz, 2H), 4.71 (s, 4H), 3.60 (s, 3H), 1.90 (d, J=13.8 Hz, 2H), 1.77 (d, J=7.8 Hz, 1H), 1.59 (d, J=12.6 Hz, 2H), 0.99 (d, J=6.3 Hz, 3H). Mass (m/z): 349.3 [M+H]+.
The title compound 116 (31.6 mg) was prepared in a total yield of 38.10% as a yellow solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (58 mg, 0.239 mmol), 6-bromo-1-ethylquinoxalin-2(1H)-one (50 mg, 0.199 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (98 mg, 0.299 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 7.69-6.81 (m, 7H), 4.22 (q, J=7.2 Hz, 4H), 3.07 (s, 2H), 2.62 (d, J=10.0 Hz, 1H), 2.10-1.92 (m, 2H), 1.80 (d, J=36.0 Hz, 2H), 1.23 (t, J=7.2 Hz, 3H). Mass (m/z): 417.3 [M+H]+.
The title compound 117 (40.2 mg) was prepared in a total yield of 55.8% as a yellow solid from 4-(4-methylpiperidin-1-yl)aniline (45 mg, 0.239 mmol), 6-bromo-1-ethylquinoxalin-2(1H)-one (50 mg, 0.199 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (98 mg, 0.299 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.81-8.54 (m, 1H), 8.20 (s, 1H), 7.72-7.03 (m, 7H), 4.23 (q, J=7.2 Hz, 2H), 3.71-3.60 (m, 4H), 2.00-1.46 (m, 5H), 1.24 (t, J=7.2 Hz, 3H), 0.98 (d, J=6.0 Hz, 3H). Mass (m/z): 363.3 [M+H]+.
To a solution of 7-hydroxy-4-methyl-2H-chromen-2-one (500 mg, 2.84 mmol) in pyridine (10 mL) was added trifluoromethanesulfonic anhydride (881 mg, 3.13 mmol) at 0° C. Then the mixture was stirred at room temperature for 1 hour. The mixture was diluted with water and extracted by EA (25 mL×3). The combined organic layers were washed with brine (15 mL×3), dried over Na2SO4 and concentrated to give the crude product which was purified by Column chromatography to give the desired product 600 mg as a yellow solid. Mass (m/z): 309.3 [M+H]+
To a solution of 4-methyl-2-oxo-2H-chromen-7-yl trifluoromethanesulfonate (100 mg, 0.324 mmol) and 4-(tert-butyl)aniline (53.2 mg, 0.356 mmol) in dioxane (5 mL) was added Pd2(dba)3 (14.8 mg, 0.016 mmol), Brettphos (17.4 mg, 0.0324 mmol) and Cs2CO3 (212 mg, 0.648 mmol) under nitrogen atmosphere. Then the mixture was stirred at 100° C. overnight. The mixture was extracted by EA (25 mL×3). The combined organic layers were washed with brine (15 mL×3), dried over Na2SO4 and concentrated to give the crude product, which was purified by pre-HPLC to give the desired product as yellow solid (48.8 mg, 49.0%). 1H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 7.53 (d, J=8.8 Hz, 1H), 7.37-7.29 (m, 2H), 7.15-7.07 (m, 2H), 6.92 (dd, J=8.8, 2.3 Hz, 1H), 6.78 (d, J=2.3 Hz, 1H), 6.01 (d, J=1.3 Hz, 1H), 2.31 (d, J=1.2 Hz, 3H), 1.25 (s, 9H). Mass (m/z): 308.4 [M+H]+.
The title compound 119 was prepared according to the procedure for compound 118. To a solution of 4-methyl-2-oxo-2H-chromen-7-yl trifluoromethanesulfonate (100 mg, 0.325 mmol) and 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (79.2 mg, 0.325 mmol) in dioxane (5 mL) was added Pd2(dba)3 (14.9 mg, 0.0163 mmol), Brettphos (17.5 mg, 0.0325 mmol) and Cs2CO3 (212 mg, 0.65 mmol) under nitrogen atmosphere. Then the mixture was stirred at 100° C. overnight. The mixture was extracted by EA (25 mL×3). The combined organic layers were washed with brine (15 mL×3), dried over Na2SO4 and concentrated to give the crude product, which was purified by pre-HPLC to give the desired product as yellow solid (34.1 mg, 26.1%). 1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 7.49 (d, J=8.8 Hz, 1H), 7.10-7.02 (m, 2H), 6.99-6.90 (m, 2H), 6.80 (dd, J=8.8, 2.3 Hz, 1H), 6.64 (d, J=2.2 Hz, 1H), 5.96 (d, J=1.3 Hz, 1H), 3.68 (d, J=12.3 Hz, 2H), 2.65 (td, J=12.4, 2.5 Hz, 2H), 2.30 (d, J=1.2 Hz, 3H), 1.90-1.81 (m, 2H), 1.54 (qd, J=12.5, 4.1 Hz, 2H). Mass (m/z): 403.4 [M+H]+.
The title compound 120 (40.2 mg) was prepared according to the procedure for compound 118. To a solution of 2-oxo-2H-chromen-6-yl trifluoromethanesulfonate (100 mg, 0.34 mmol) and 4-(tert-butyl)aniline (55.8 mg, 0.374 mmol) in dioxane (5 mL) was added Pd2(dba)3 (15.6 mg, 0.017 mmol), Brettphos (18.3 mg, 0.034 mmol) and Cs2CO3 (222 mg, 0.68 mmol) under nitrogen atmosphere. Then the mixture was stirred at 100° C. overnight. The mixture was extracted by EA (25 mL×3). The combined organic layers were washed with brine (15 mL×3), dried over Na2SO4 and concentrated to give the crude product, which was purified by pre-HPLC to give the desired product as yellow solid (80 mg, 80%). 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J=9.5 Hz, 1H), 7.33 (d, J=8.5 Hz, 2H), 7.21 (dd, J=11.1, 8.9 Hz, 2H), 7.13 (s, 1H), 7.02 (t, J=9.7 Hz, 2H), 6.40 (d, J=9.5 Hz, 1H), 1.32 (s, 9H). Mass (m/z): 294.3 [M+H]+.
Step 1. Preparation of 3-(((allyloxy)carbonyl)amino)propanoic acid (121-2)
To a solution of 3-aminopropanoic acid (3.0 g, 33.7 mmol) in THF (60 mL)/H2O (30 mL) was added NaOH (2N) (33.7 mL, 67.4 mmol), allyl carbonochloridate (5.9 mL, 33.7 mmol). Then the mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted by DCM (25 mL×3). The combined organic layers were washed with brine (15 mL×3), dried over Na2SO4 and concentrated to give the crude product which was purified by Column chromatography to give the desired product 3.2 g as colorless oil. Mass (m/z): 174.2 [M+H]+.
To a solution of 3-(((allyloxy)carbonyl)amino)propanoic acid (2.0 g, 11.6 mmol) in THF (50 mL) was added CDI (2.26 g, 13.9 mmol) under argon atmosphere, the mixture was stirred at room temperature for 2 hours. Then a mixture of MgCl2 (1.1 g, 11.6 mmol) and potassium 3-methoxy-3-oxopropanoate (2.71 g, 17.3 mmol) was added. The mixture was stirred at room temperature overnight. Then it was diluted with water and extracted by EA (25 mL×3). The combined organic layers were washed with brine (15 mL×3), dried over Na2SO4 and concentrated to give the crude product which was purified by Column chromatography to give the desired product 1.86 g as colorless oil. Mass (m/z): 230.2 [M+H]+.
To a solution of methyl 5-(((allyloxy)carbonyl)amino)-3-oxopentanoate (1.86 g, 8.12 mmol) in MsOH (20 mL) was added resorcinol (893 g, 8.12 mmol) under argon atmosphere at 0° C., the mixture was stirred at 0° C. for 3 hours. Then saturated NaHSO4 solution was added. The mixture was stirred from turbidity to clarification. Then it was diluted with water and extracted by EA (25 mL×3). The combined organic layers were washed with brine (15 mL×3), dried over Na2SO4 and concentrated to give the crude product which was purified by Column chromatography to give the desired product 1.0 g as yellow solid. Mass (m/z): 290.3 [M+H]+.
To a solution of allyl (2-(7-hydroxy-2-oxo-2H-chromen-4-yl)ethyl) carbamate (1.0 g, 3.46 mmol) in DCM (20 mL) was added trifluoromethanesulfonic anhydride (1.07 g, 3.8 mmol), TEA (700 mg, 6.92 mmol) at 0° C. Then the mixture was stirred at room temperature for 3 hours. The mixture was diluted with water and extracted by DCM (25 mL×3). The combined organic layers were washed with brine (15 mL×3), dried over Na2SO4 and concentrated to give the crude product which was purified by Column chromatography to give the desired product 600 mg as yellow solid. Mass (m/z): 422.4 [M+H]+.
To a solution of 4-(2-(((allyloxy)carbonyl)amino)ethyl)-2-oxo-2H-chromen-7-yl trifluoromethanesulfonate (100 mg, 0.238 mmol) and 4-(tert-butyl)aniline (35.4 mg, 0.238 mmol) in dioxane (5 mL) was added Pd2(dba)3 (10.9 mg, 0.012 mmol), Brettphos (12.8 mg, 0.0238 mmol) and Cs2CO3 (117 mg, 0.357 mmol) under nitrogen atmosphere. Then the mixture was stirred at 100° C. for 2 hours. The mixture was extracted by EA (25 mL×3). The combined organic layers were washed with brine (15 mL×3), dried over Na2SO4 and concentrated to give the crude product, which was purified by pre-HPLC to give the desired product as yellow solid (4.7 mg, 5.9%). 1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.32 (s, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.38-7.29 (m, 2H), 7.15-7.07 (m, 2H), 6.91 (dd, J=8.8, 2.3 Hz, 1H), 6.80 (d, J=2.3 Hz, 1H), 6.00 (s, 1H), 2.94-2.79 (m, 4H), 1.25 (s, 9H). Mass (m/z): 337.4 [M+H]+.
To a solution of 4-(2-(((allyloxy)carbonyl)amino)ethyl)-2-oxo-2H-chromen-7-yl trifluoromethanesulfonate (150 mg, 0.356 mmol) and 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (130 mg, 0.534 mmol) in dioxane (5 mL) was added Pd2(dba)3 (16.3 mg, 0.018 mmol), Brettphos (19.1 mg, 0.0356 mmol) and Cs2CO3 (174 mg, 0.534 mmol) under nitrogen atmosphere. Then the mixture was stirred at 100° C. for 2 hours. The mixture was extracted by EA (25 mL×3). The combined organic layers were washed with brine (15 mL×3), dried over Na2SO4 and concentrated to give the crude product, which was purified by pre-HPLC to give the desired product as yellow solid (21.0 mg, 13.7%). 1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.06 (d, J=8.9 Hz, 2H), 6.98-6.91 (m, 2H), 6.80 (dd, J=8.8, 2.4 Hz, 1H), 6.64 (d, J=2.3 Hz, 1H), 5.93 (s, 1H), 3.69 (d, J=12.1 Hz, 2H), 2.81 (dd, J=21.2, 6.4 Hz, 4H), 2.70-2.59 (m, 4H), 1.86 (d, J=12.6 Hz, 2H), 1.61-1.46 (m, 2H). Mass (m/z): 432.4 [M+H]+.
To a solution of 2-oxo-2H-chromen-6-yl trifluoromethanesulfonate (100 mg, 0.34 mmol) and 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (91.2 mg, 0.374 mmol) in dioxane (5 mL) was added Pd2(dba)3 (15.6 mg, 0.017 mmol), Brettphos (18.3 mg, 0.034 mmol) and Cs2CO3 (222 mg, 0.68 mmol) under nitrogen atmosphere. Then the mixture was stirred at 100° C. overnight. The mixture was extracted by EA (25 mL×3). The combined organic layers were washed with brine (15 mL×3), dried over Na2SO4 and concentrated to give the crude product, which was purified by pre-HPLC to give the desired product as yellow solid (22.0 mg, 15.2%). 1H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J=9.9 Hz, 2H), 7.21 (d, J=8.8 Hz, 1H), 7.16-7.07 (m, 2H), 7.03-6.95 (m, 2H), 6.93-6.85 (m, 2H), 6.37 (d, J=9.5 Hz, 1H), 3.61 (d, J=12.3 Hz, 2H), 2.59 (dd, J=12.3, 2.5 Hz, 2H), 2.43-2.39 (m, 1H), 1.85 (d, J=12.7 Hz, 2H), 1.54 (qd, J=12.5, 4.1 Hz, 2H). Mass (m/z): 389.3 [M+H]+.
To a solution of 4-bromo-2-hydroxybenzaldehyde (3.5 g, 17.4 mmol) in DCM (50 mL) was added 4-((tert-butoxycarbonyl)amino)butanoic acid (4.24 g, 20.9 mmol), DIC (2.85 g, 22.6 mmol) and DMAP (637 mg, 5.22 mmol). Then the mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted by DCM (25 mL×3). The combined organic layers were washed with brine (15 mL×3), dried over Na2SO4 and concentrated to give the crude product which was purified by Column chromatography to give the desired product 2.1 g as yellow solid. Mass (m/z): 386.3 [M+H]+.
To a solution of 5-bromo-2-formylphenyl 4-((tert-butoxycarbonyl) amino)butanoate (2.1 g, 5.44 mmol) in DCE (20 mL) was added TEA (1.1 g, 10.9 mmol), the mixture was reflux for 3 hours. Then it was diluted with water and extracted by EA (25 mL×3). The combined organic layers were washed with brine (15 mL×3), dried over Na2SO4 and concentrated to give the crude product which was purified by Column chromatography to give the desired product 300 mg as white solid. Mass (m/z): 369.3[M+H]+.
To a solution of tert-butyl (2-(7-bromo-2-oxo-2H-chromen-3-yl) ethyl)carbamate (100 mg, 0.272 mmol) and 4-(tert-butyl)aniline (57 mg, 0.326 mmol) in dioxane (5 mL) was added Pd2(dba)3 (2.5 mg, 0.00272 mmol), X-phos (6.5 mg, 0.0136 mmol) and Cs2CO3 (133 mg, 0.408 mmol) under nitrogen atmosphere. Then the mixture was stirred at 100° C. overnight. The mixture was extracted by EA (25 mL×3). The combined organic layers were washed with brine (15 mL×3), dried over Na2SO4 and concentrated to give the crude product, which was purified by TLC to give the desired product as yellow solid 50 mg. Mass (m/z): 437.6 [M+H]+.
To a solution of tert-butyl(2-(7-((4-(tert-butyl)phenyl)amino)-2-oxo-2H-chromen-3-yl)ethyl)carbamate (50 mg, 0.114 mmol) in DCM (9 mL) was added 2,2,2-trifluoroacetic acid (3 mL). Then the mixture was concentrated to give the crude product, which was purified by pre-HPLC to give the desired product as yellow solid (12.5 mg, 32.9%). 1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.32 (s, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.38-7.29 (m, 2H), 7.15-7.07 (m, 2H), 6.91 (dd, J=8.8, 2.3 Hz, 1H), 6.80 (d, J=2.3 Hz, 1H), 6.00 (s, 1H), 2.94-2.79 (m, 4H), 1.25 (s, 9H). Mass (m/z): 337.2 [M+H]+.
To a solution of tert-butyl (2-(7-bromo-2-oxo-2H-chromen-3-yl)ethyl)carbamate (85 mg, 0.231 mmol) and 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (67.6 mg, 0.277 mmol) in DMF (5 mL) was added Pd2(dba)3 (2.5 mg, 0.00272 mmol), X-phos (6.6 mg, 0.0139 mmol) and Cs2CO3 (135 mg, 0.416 mmol) under nitrogen atmosphere. Then the mixture was stirred at 100° C. overnight. The mixture was extracted by EA (25 mL×3). The combined organic layers were washed with brine (15 mL×3), dried over Na2SO4 and concentrated to give the crude product, which was purified by TLC to give the desired product as yellow solid (40 mg). Mass (m/z): 532.6 [M+H]+.
To a solution of tert-butyl(2-(2-oxo-7-((4-(4-(trifluoromethyl) piperidin-1-yl)phenyl)amino)-2H-chromen-3-yl)ethyl)carbamate (40 mg, 0.0752 mmol) in DCM (9 mL) was added 2,2,2-trifluoroacetic acid (3 mL). Then the mixture was concentrated to give the crude product, which was purified by pre-HPLC to give the desired product as yellow solid (5 mg, 15.6%). H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.34 (s, 1H), 7.65 (s, 1H), 7.36 (d, J=8.7 Hz, 1H), 7.05 (d, J=9.0 Hz, 2H), 6.94 (d, J=9.0 Hz, 2H), 6.78 (dd, J=8.6, 2.2 Hz, 1H), 6.65 (d, J=2.2 Hz, 1H), 3.68 (dd, J=12.1, 3.1 Hz, 3H), 2.86 (t, J=7.0 Hz, 2H), 2.77-2.51 (m, 7H), 1.86 (d, J=13.0 Hz, 3H), 1.55 (td, J=12.5, 4.1 Hz, 2H). Mass (m/z): 432.2 [M+H]+.
To a solution of 4-methylbenzene-1,3-diol (2.0 g, 16.1 mmol) in ethyl 3-oxobutanoate (3 mL) was added con·H2SO4 (5 mL) at 0° C. Then the mixture was stirred at 0° C. for 5 hours. The mixture was filtered and washed with water till PH to 7-8 and dried to give the desired product 1.1 g as grey solid. Mass (m/z): 191.2 [M+H]+.
To a solution of 7-hydroxy-4,6-dimethyl-2H-chromen-2-one (200 mg, 1.05 mmol) in DCM (10 mL) was added trifluoromethanesulfonic anhydride (356 mg, 1.26 mmol) and TEA (159 mg, 1.58 mmol) at 0° C. Then the mixture was stirred at room temperature for 3 hours. The mixture was diluted with water and extracted by DCM (25 mL×3). The combined organic layers were washed with brine (15 mL×3), dried over Na2SO4 and concentrated to give the crude product which was purified by Column chromatography to give the desired product 200 mg as yellow solid. Mass (m/z): 323.3 [M+H]+.
To a solution of 4,6-dimethyl-2-oxo-2H-chromen-7-yl trifluoromethanesulfonate (87 mg, 0.270 mmol) and 4-(4-(trifluoromethyl) piperidin-1-yl)aniline (60 mg, 0.246 mmol) in dioxane (3 mL) was added Pd2(dba)3 (11.3 mg, 0.0123 mmol), Brettphos (13.2 mg, 0.0246 mmol) and Cs2CO3 (120 mg, 0.369 mmol) under nitrogen atmosphere. Then the mixture was stirred at 100° C. overnight. The mixture was extracted by EA (25 mL×3). The combined organic layers were washed with brine (15 mL×3), dried over Na2SO4 and concentrated to give the crude product, which was purified by pre-HPLC to give the desired product as yellow solid (34.5 mg, 33.8%). 1H NMR (400 MHz, DMSO-d6) δ 7.62 (s, 1H), 7.45 (s, 1H), 7.17-7.08 (m, 2H), 7.06-6.92 (m, 2H), 6.57 (s, 1H), 5.98 (d, J=1.3 Hz, 1H), 3.75 (d, J=12.4 Hz, 2H), 2.72 (dd, J=12.3, 2.5 Hz, 2H), 2.35 (d, J=1.2 Hz, 3H), 2.29 (s, 3H), 1.96-1.83 (m, 2H), 1.58 (qd, J=12.5, 4.0 Hz, 2H). Mass (m/z): 417.4 [M+H]+.
To a solution of 6-bromo-3,4-dihydroquinolin-2(1H)-one 127-1 (500 mg, 2.21 mmol) and t-BuOK (496 mg, 4.42 mmol) in DMF (10 mL) was added Mel (408 mg, 2.88 mmol). Then the mixture was stirred at room temperature for overnight. The mixture was poured into H2O and extracted with EA (30 mL*3). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated, the residue was purified by silica gel chromatography with EA/PE (20:1 to 5:1) to give 6-bromo-1-methyl-3,4-dihydroquinolin-2(1H)-one 127-2 (493 mg, 93% yield) as a yellow solid. MS (ESI) m/z 239.8, 241.8 [M+H]+.
A mixture solution of 4-(4-(trifluoromethyl)piperidin-1-yl)aniline 127-3 (300 mg, 1.23 mmol), 6-bromo-1-methyl-3,4-dihydroquinolin-2(1H)-one 127-2 (295 mg, 1.23 mmol), Ruphos (115 mg, 0.25 mmol), Pd2(dba)3 (112 mg, 0.12 mmol) and Cs2CO3 (600 mg, 1.84 mmol) in 1,4-dioxane (10 mL) was stirred at 100° C. under N2 atmosphere for 12 hrs. The mixture was concentrated and the residue was purified by pre-HPLC to give compound 127 as a yellow solid (25.3 mg, 5%). Mass (m/z): 404.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 6.98 (d, J=9.0 Hz, 2H), 6.92 (dd, J=8.8, 4.2 Hz, 3H), 6.89-6.84 (m, 1H), 6.81 (d, J=2.5 Hz, 1H), 3.57 (dd, J=13.1, 0.6 Hz, 2H), 3.28 (s, 3H), 2.78 (dd, J=8.5, 6.2 Hz, 2H), 2.63 (td, J=12.2, 1.7 Hz, 2H), 2.54 (dd, J=8.5, 6.2 Hz, 2H), 2.33-2.15 (m, 1H), 1.99-1.89 (m, 2H), 1.77-1.64 (m, 2H).
To a solution of compound 411-1 (300 mg, 1.316 mmol) in DMF (10 mL) was added K2CO3 (363.63 mg, 2.631 mmol) and Mel (280 mg, 1.973 mmol) at 50° C. Then the mixture was stirred at 50° C. for 16 hrs. After cooling to rt, the reaction solution was washed with water, extracted with ethyl acetate (20 mL*3). The organic layers were combined and concentrated under vacuum, the residue was purified through silica gel chromatography (PE:EA=5:1) to give 6-bromo-1-methyl-1,4-dihydro-2H-benzo[d][1,3] oxazin-2-one as white solid (150 mg, 37.68%). Mass (m/z): 377.3 [M+H]+.
A mixture of 6-bromo-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one (150 mg, 0.6197 mmol), 4-(4-(trifluoromethyl)piperidin-1-yl) aniline (151.37 mg, 0.6197 mmol), NaOtBu (119.11 mg, 1.2394 mmol), Brettphos (33.26 mg, 0.062 mmol), Brettphos-Pd-G1 (49.44 mg, 0.062 mmol) in toluene (10 mL) was stirred 10 hrs at 100° C. under N2 atmosphere. After cooling to rt, the reaction solution was washed with water, extracted with ethyl acetate (20 mL*3), the organic layers were combined and concentrated under vacuum, the residue was purified by prep-HPLC(column-Xbridge-C18 150×21.2 mm, 5 um; Mobile phase: ACN-H2O (0.1% FA), 30%-35%) to afford compound 128 as yellow solid. (12.2 mg, 4.71%). Mass (m/z): 406 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 7.07-6.93 (m, 6H), 6.86 (d, J=2.1 Hz, 1H), 5.17 (s, 2H), 3.63 (d, J=12.2 Hz, 2H), 3.34 (s, 3H), 2.68 (td, J=12.3, 2.2 Hz, 2H), 2.34-2.25 (m, 1H), 1.99 (d, J=13.3 Hz, 2H), 1.79-1.69 (m, 2H).
To a solution of 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (138 mg, 0.57 mmol) and 4-(4-methoxy-4-(trifluoromethyl) piperidin-1-yl)-2-methylaniline (150 mg, 0.52 mmol) in 1,4-dioxane (2 mL) was added Pd2(dba)3 (47 mg, 0.05 mmol), Xphos (49 mg, 0.10 mmol) and Cs2CO3 (339 mg, 1.04 mmol) under nitrogen atmosphere. The mixture was stirred at 100° C. for 12 h, the mixture was purified by prep TLC then purified by prep HPLC to give 7-((4-(4-methoxy-4-(trifluoromethyl)piperidin-1-yl)-2-methylphenyl)amino)-4-methyl-2H-be nzo[b][1,4]oxazin-3(4H)-one (57.9 mg, 29.1%) as a red solid. Mass (m/z): 450.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.21 (s, 1H), 7.07-6.86 (m, 4H), 6.83-6.75 (m, 1H), 6.39-6.32 (m, 1H), 6.27 (d, J=2.5 Hz, 1H), 4.54 (s, 2H), 3.58-3.50 (m, 2H), 3.40 (s, 3H), 3.20 (s, 3H), 2.92-2.73 (m, 2H), 2.49-2.44 (m, 1H), 2.12 (s, 3H), 2.06-1.95 (m, 2H), 1.88-1.76 (m, 2H).
To a solution of 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (48 mg, 0.20 mmol) and 1-(4-amino-3-methylphenyl)-4-(trifluoromethyl)piperidin-4-ol (50 mg, 0.18 mmol) in 1,4-dioxane (1 mL) was added Pd2(dba)3 (17 mg, 0.02 mmol), Xphos (17 mg, 0.04 mmol) and Cs2CO3 (119 mg, 0.36 mmol) under nitrogen atmosphere. The mixture was stirred at 100° C. for 12 h, the mixture was purified by prep TLC then purified by prep HPLC to give 7-((4-(4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)-2-methylphenyl)amino)-4-methyl-2H-be nzo[b][1,4]oxazin-3(4H)-one (20.5 mg, 29.4%) as a pink solid. Mass (m/z): 436.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.20 (s, 1H), 6.98 (d, J=8.6 Hz, 1H), 6.91 (d, J=8.7 Hz, 1H), 6.87 (d, J=2.8 Hz, 1H), 6.82-6.74 (m, 1H), 6.39-6.31 (m, 1H), 6.27 (d, J=2.4 Hz, 1H), 5.95 (s, 1H), 4.53 (s, 2H), 3.57-3.50 (m, 2H), 3.20 (s, 3H), 3.01-2.81 (m, 2H), 2.12 (s, 3H), 1.85-1.68 (m, 4H).
To a solution of 7-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (66 mg, 0.291 mmol) and 5-methoxy-6-(4-(trifluoromethyl) piperidin-1-yl) pyridin-3-amine (80 mg, 0.291 mmol) in t-BuOH (5 mL) was added Pd2(dba)3 (13.3 mg, 0.0146 mmol), Brettphos (15.6 mg, 0.0291 mmol) and Cs2CO3 (142 mg, 0.437 mmol) under nitrogen atmosphere. Then the mixture was stirred at 100° C. overnight. The mixture was extracted by EA (25 mL×3). The combined organic layers were washed with brine (15 mL×3), dried over Na2SO4 and concentrated to give the crude product, which was purified by pre-HPLC to give the desired product as pink solid (51.9 mg, 42.3%). 1H NMR (400 MHz, DMSO) δ 10.50 (s, 1H), 7.87 (s, 1H), 7.59 (d, J=2.2 Hz, 1H), 6.95 (t, J=9.7 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 6.62-6.57 (m, 1H), 6.55 (d, J=2.3 Hz, 1H), 4.50 (s, 2H), 3.85-3.68 (m, 5H), 2.73-2.56 (m, 2H), 2.43 (s, 1H), 1.84 (d, J=11.0 Hz, 2H), 1.56 (qd, J=12.5, 3.9 Hz, 2H). Mass (m/z): 423.2 [M+H]+.
To a solution of 7-bromo-5-fluoro-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (70.7 mg, 0.273 mmol) and 4-(2,6-dimethylmorpholino)-3-methylaniline (60 mg, 0.273 mmol) in t-BuOH (5 mL) was added Pd2(dba)3 (12.5 mg, 0.0136 mmol), X-phos (13 mg, 0.0273 mmol) and Cs2CO3 (133 mg, 0.41 mmol) under a nitrogen atmosphere. Then the mixture was stirred at 100° C. overnight. The mixture was extracted by EA (25 mL×3). The combined organic layers were washed with brine (15 mL×3), dried over Na2SO4 and concentrated to give the crude product, which was purified by pre-HPLC to give the desired product as a pink solid (12.6 mg, 11.6%). 1H NMR (400 MHz, DMSO) δ 8.17 (s, 1H), 6.96 (d, J=9.4 Hz, 1H), 6.89 (d, J=7.0 Hz, 2H), 6.55-6.37 (m, 2H), 4.56 (s, 2H), 3.77-3.66 (m, 2H), 3.30 (d, J=5.5 Hz, 2H), 2.87 (d, J=10.8 Hz, 2H), 2.37-2.24 (m, 3H), 2.22 (s, 3H), 1.12 (dd, J=14.3, 10.1 Hz, 6H). Mass (m/z): 400.2 [M+H]+.
To a solution of 4-(2,6-dimethylmorpholin-4-yl) aniline (107 mg, 0.52 mmol), 6-bromo-1-methyl-1,2,3-benzotriazole (121 mg, 0.57 mmol) and t-BuONa (100 mg, 1.1 mmol) in toluene (2 mL) was added BrettPhos Pd G3 (47 mg, 0.052 mmol). The mixture was heated to 100° C. and stirred under nitrogen for 18 h. The resulting mixture was concentrated and the residue was purified by column chromatography (EA:PE=1:1) to give the product (27.5 mg, 15.56%) as a white solid. MS (ESI) m/z: 338 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.72 (d, J=9.2 Hz, 1H), 7.14 (d, J=9.2 Hz, 2H), 6.98-6.94 (m, 4H), 4.09 (s, 2H), 3.72-3.68 (m, 2H), 3.51 (d, J=10.4 Hz, 2H), 2.25-2.20 (m, 2H), 1.15 (d, J=6.4 Hz, 6H).
A mixture solution of N-methyl-4-nitroaniline (1 g, 6.58 mmol), Trifluoroacetic anhydride (TFAA, 1.52 g, 7.24 mmol), TEA (1.33 g, 13.16 mmol) in DCM (20 mL) was stirred at 25° C. for 12 hrs. The mixture was concentrated and the residue was purified by flash chromatography, eluting with PE:EA=10:1 to 1:1 to give 2,2,2-trifluoro-N-methyl-N-(4-nitrophenyl)acetamide as a yellow oil (1.5 g, 91.2%). Mass (m/z): 249.1 [M+H]+.
A mixture solution of 2,2,2-trifluoro-N-methyl-N-(4-nitrophenyl) acetamide 134-2 (1.5 g, 6.05 mmol), Pd/C (0.4 g) in THF (20 mL) was stirred under 1 atm of H2 atmosphere at 25° C. for 2 hrs. After filtration, the filtrate was removed under vacuum and the residue was purified by flash, eluting with PE:EA=10:1 to 1:1 to give N-(4-aminophenyl)-2,2,2-trifluoro-N-methylacetamide 134-3 as yellow solid. (1.2 g, 91.7%). Mass (m/z): 218.07 [M+H]+.
A solution of N-(4-aminophenyl)-2,2,2-trifluoro-N-methylacetamide 134-3 (0.5 g, 2.29 mmol) in BH3-THF (5 mL, 1.0 mol/L) and THF (2 mL) was stirred at 80° C. for 12 hrs. Quenched with MeOH (30 mL), concentrated, to the residue was added H2O (30 mL), extracted with EA (20 mL*3), the organic phase was concentrated under vacuum, the residue was purified by flash, eluting with PE:EA=10:1 to 1:1 to give N1-methyl-N1-(2,2,2-trifluoroethyl)benzene-1,4-diamine 134-4 as yellow solid. (0.16 g, 34.1%). Mass (m/z): 205.0 [M+H]+.
A mixture solution of N1-methyl-N1-(2,2,2-trifluoroethyl)benzene-1,4-diamine 134-4 (0.16 g, 0.78 mmol), 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (134-5) (0.2 g, 0.83 mmol), Ruphos (73 mg, 0.16 mmol), Pd2(dba)3 (72 mg, 0.08 mmol) and Cs2CO3 (0.76 g, 2.34 mmol) in 1,4-dioxane (10 mL) was stirred at 100° C. under N2 atmosphere for 12 hrs. The mixture was concentrated and the residue was purified by prep-HPLC to give compound 134 as a yellow solid (0.134 g, 47.1%). Mass (m/z): 365.7 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.72 (s, 1H), 6.96 (t, J=8.6 Hz, 3H), 6.81 (d, J=8.0 Hz, 2H), 6.57 (dd, J=8.8, 2.4 Hz, 1H), 6.49 (d, J=2.4 Hz, 1H), 4.55 (s, 2H), 4.13 (q, J=9.6 Hz, 2H), 3.22 (s, 3H), 2.96 (s, 3H).
To a solution of 7-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (333 mg, 1.48 mmol) and 4-(tert-butyl)aniline (60 mg, 0.26 mmol) in 1,4-dioxane (2 mL) was added Pd2(dba)3 (122 mg, 0.13 mmol), Brettphos (144 mg, 0.26 mmol) and Cs2CO3 (875 mg, 2.68 mmol) under nitrogen atmosphere. The mixture was stirred at 100° C. for 12 h, the mixture was purified by prep TLC then purified by prep HPLC to give 7-((4-(tert-butyl)phenyl)amino)-2H-benzo[b][1,4]oxazin-3(4H)-one (32 mg, 31%) as a yellow solid. Mass (m/z): 297.3 [M+H]+. 1H NMR (400 MHz, DMSO) δ 10.50 (s, 1H), 7.93 (s, 1H), 7.27-7.19 (m, 2H), 6.98-6.90 (m, 2H), 6.75 (d, J=8.4 Hz, 1H), 6.65 (dd, J=8.4, 2.4 Hz, 1H), 6.60 (d, J=2.3 Hz, 1H), 4.50 (s, 2H), 1.24 (s, 9H).
To a solution of 7-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (151 mg, 0.67 mmol) and 3,5-difluoro-4-(4-(trifluoromethyl)piperidin-1-yl)aniline (170 mg, 0.61 mmol) in 1,4-dioxane (2 mL) was added Pd2(dba)3 (55 mg, 0.06 mmol), Brettphos (65 mg, 0.12 mmol) and Cs2CO3 (396 mg, 1.21 mmol) under nitrogen atmosphere. The mixture was stirred at 100° C. for 12 h, the mixture was purified by prep TLC then purified by prep HPLC to give 7-((3,5-difluoro-4-(4-(trifluoromethyl)piperidin-1-yl)phenyl) amino)-2H-benzo[b][1,4]oxazin-3(4H)-one (28 mg, 10.8%) as a white solid. Mass (m/z): 428.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.31 (s, 1H), 6.82 (d, J=8.4 Hz, 1H), 6.71 (dd, J=8.4, 2.3 Hz, 1H), 6.66 (d, J=2.4 Hz, 1H), 6.58-6.46 (m, 2H), 4.54 (s, 2H), 3.11-2.92 (m, 4H), 2.49-2.35 (m, 1H), 1.88-1.79 (m, 2H), 1.61-1.46 (m, 2H).
A mixture solution of 5-bromo-2-fluorobenzonitrile (5 g, 25 mmol) in MeNH2 in MeOH (1 mol/L, 50 mL) was stirred at r.t. 2 hrs. Then the solvent was removed under reduced pressure, the residue was diluted with EA (50 mL), washed with water (50 mL×3), dried with Na2SO4, filtered and evaporated. The residue was purified by column chromatography to give 5-bromo-2-(methylamino)benzonitrile 137-2 (5 g, 94.76%).
A mixture solution of 5-bromo-2-(methylamino)benzonitrile (200 mg, 0.95 mmol), 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (255 mg, 1.04 mmol), Cs2CO3 (926 mg, 2.84 mmol), Ruphos (88 mg, 0.19 mmol) and Pd2(dba)3 (87 mg, 0.09 mmol) in dioxane was stirred at 100° C. for 16 hrs. Then the solvent was removed under vacuo, the residue was purified by silica gel column with PE:EA (3:1) to give 2-(methylamino)-5-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)benzonitrile 137-4 (300 mg, 84.56%). Mass (m/z): 374.7 [M+H]+.
A solution of 2-(methylamino)-5-((4-(4-(trifluoromethyl)piperidin-1-yl) phenyl)amino)benzonitrile (300 mg, 0.80 mmol) in BH3 in THF (1M, 20 mL) was stirred at r.t. for 16 hrs. Then the solvent was removed under vacuo, the residue was diluted with EA (20 mL), washed with water (20 mL×3), dried with Na2SO4, filtered and evaporated. The residue was purified by column chromatography to give 137-5 (300 mg, 98.93%). Mass (m/z): 378.8 [M+H]+.
A solution of 2-(aminomethyl)-N1-methyl-N4-(4-(4-(trifluoromethyl) piperidin-1-yl)phenyl)benzene-1,4-diamine (300 mg, 0.79 mmol) and CDI (141 mg, 0.87 mmol) in THE was stirred at r.t. for 16 hrs. Then the solvent was removed under vacuo, the residue was purified by prep-HPLC to give 1-methyl-6-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)-3,4-dihy droquinazolin-2(1H)-one compound 137 (90 mg, 28.07%). Mass (m/z): 404.7 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 6.89-6.76 (m, 7H), 4.29 (s, 2H), 3.57 (s, 2H), 3.23 (s, 3H), 2.65 (s, 2H), 2.37-2.17 (m, 1H), 1.96 (d, J=12.1 Hz, 2H), 1.72 (dd, J=12.6, 3.5 Hz, 2H).
To a solution of 7-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (114 mg, 0.500 mmol) and 4-(2,6-dimethylmorpholino)-3-methylaniline (100 mg, 0.455 mmol) in t-BuOH (5 mL) was added Pd2(dba)3 (20.8 mg, 0.0228 mmol), Brettphos (24.4 mg, 0.0455 mmol) and Cs2CO3 (223 mg, 0.683 mmol) under nitrogen atmosphere. Then the mixture was stirred at 100° C. for 2 hours. The mixture was extracted by EA (25 mL×3). The combined organic layers were washed with brine (15 mL×3), dried over Na2SO4 and concentrated to give the crude product, which was purified by pre-HPLC to give the desired product as white solid (37.2 mg, 22.3%). 1H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 7.79 (s, 1H), 6.90 (d, J=8.2 Hz, 1H), 6.85-6.76 (m, 2H), 6.73 (d, J=8.4 Hz, 1H), 6.62-6.50 (m, 2H), 4.49 (s, 2H), 3.78-3.60 (m, 2H), 2.81 (t, J=16.9 Hz, 2H), 2.37-2.22 (m, 2H), 2.20 (s, 3H), 1.10 (d, J=6.3 Hz, 6H). Mass (m/z): 368.2 [M+H]+.
To a solution of 2-amino-5-bromophenol (5.0 g, 26.6 mmol) in DMF (30 mL) was added K2CO3(7.34 g, 53.2 mmol), 2-chloropropanoyl chloride (3.72 g, 29.3 mmol) was added at 0° C. Then the mixture was stirred at r.t. for 0.5 hour then heated at 90° C. for 2 hours. The mixture was filtered and washed with water, dried over Na2SO4 and concentrated to give the desired product 4.1 g as grey solid. Mass (m/z): 242.1 [M+H]+.
To a solution of 7-bromo-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (129 mg, 0.534 mmol) and 4-(2,6-dimethylmorpholino)aniline (100 mg, 0.485 mmol) in t-BuOH (5 mL) was added Pd2(dba)3 (22.2 mg, 0.0243 mmol), Brettphos (26 mg, 0.0485 mmol) and Cs2CO3 (237 mg, 0.728 mmol) under nitrogen atmosphere. Then the mixture was stirred at 100° C. overnight. The mixture was extracted by EA (25 mL×3). The combined organic layers were washed with brine (15 mL×3), dried over Na2SO4 and concentrated to give the crude product, which was purified by pre-HPLC to give the desired product as gray solid (41.7 mg, 23.4%). 1H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 7.69 (s, 1H), 6.90 (dd, J=29.6, 9.0 Hz, 4H), 6.71 (d, J=8.4 Hz, 1H), 6.58-6.42 (m, 2H), 4.93-4.87 (m, 1H), 3.67 (tdd, J=25.5, 14.8, 10.7 Hz, 2H), 3.43 (d, J=10.6 Hz, 2H), 2.27-2.10 (m, 2H), 1.58-1.55 (m, 3H), 1.14 (d, J=6.2 Hz, 6H). Mass (m/z): 368.2 [M+H]+.
To a solution of 7-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (110.2 mg, 0.485 mmol) and 4-(2,6-dimethylmorpholino)aniline (100 mg, 0.485 mmol) in t-BuOH (5 mL) was added Pd2(dba)3 (22.2 mg, 0.0243 mmol), Brettphos (26 mg, 0.0485 mmol) and Cs2CO3 (237 mg, 0.728 mmol) under nitrogen atmosphere. Then the mixture was stirred at 100° C. overnight. The mixture was extracted by EA (25 mL×3). The combined organic layers were washed with brine (15 mL×3), dried over Na2SO4 and concentrated to give the crude product, which was purified by pre-HPLC to give the desired product as white solid (50 mg, 29.2%). 1H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 7.69 (s, 1H), 6.90 (dd, J=29.6, 9.0 Hz, 4H), 6.71 (d, J=8.4 Hz, 1H), 6.58-6.42 (m, 2H), 4.48 (s, 2H), 3.67 (tdd, J=25.5, 14.8, 10.7 Hz, 2H), 3.43 (d, J=10.6 Hz, 2H), 2.27-2.10 (m, 2H), 1.14 (d, J=6.2 Hz, 6H). Mass (m/z): 354.2 [M+H]+.
To a solution of 7-bromo-5-fluoro-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (90 mg, 0.347 mmol) and 4-(2,6-dimethylmorpholino)-2-methylaniline (77 mg, 0.347 mmol) in dioxane (5 mL) was added Pd2(dba)3 (16 mg, 0.0174 mmol), X-phos (16.6 mg, 0.0347 mmol) and Cs2CO3 (170 mg, 0.520 mmol) under nitrogen atmosphere. Then the mixture was stirred at 100° C. overnight. The mixture was extracted by EA (25 mL×3). The combined organic layers were washed with brine (15 mL×3), dried over Na2SO4 and concentrated to give the crude product, which was purified by pre-HPLC to give the desired product as pink solid (45 mg, 32.6%). 1H NMR (400 MHz, DMSO-d6) δ 7.55 (s, 1H), 6.99 (d, J=8.6 Hz, 1H), 6.89-6.72 (m, 2H), 6.16-6.03 (m, 2H), 4.52 (s, 2H), 3.74-3.63 (m, 2H), 3.53 (d, J=10.6 Hz, 2H), 3.27 (d, J=5.5 Hz, 3H), 2.23 (dd, J=21.8, 10.8 Hz, 2H), 2.10 (d, J=15.7 Hz, 3H), 1.15 (d, J=6.2 Hz, 6H). Mass (m/z): 400.2 [M+H]+.
To a solution of 5-methyl-6-(4-(trifluoromethyl)piperidin-1-yl) pyridin-3-amine (100 mg, 0.39 mmol), 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (112 mg, 0.46 mmol) in toluene (2 mL) was added tBuONa (74 mg, 0.77 mmol) and BrettPhos-Pd-G3 (35 mg, 0.038 mmol). The mixture was heated to 100° C. and stirred under nitrogen overnight. The resulting mixture was concentrated and the residue was purified by prep-HPLC to give compound 425 as a light yellow solid (14 mg, 8.22%). MS (ESI) m/z 421.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J=2.4 Hz, 1H), 7.29 (s, 1H), 6.84 (d, J=8.4 Hz, 1H), 6.64 (d, J=2.4 Hz, 1H), 6.62 (s, 1H), 4.59 (s, 2H), 3.45-3.39 (m, 1H), 3.34 (s, 3H), 2.80 (t, J=12.0 Hz, 2H), 2.26 (s, 2H), 2.23-2.16 (m, 1H), 1.99-1.96 (m, 4H), 1.80-1.70 (m, 2H).
To a solution of 6-(2,6-dimethylmorpholino)-5-methylpyridin-3-amine (90 mg, 0.41 mmol), 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (118 mg, 0.49 mmol) in toluene (2 mL) was added t-BuONa (78 mg, 0.81 mmol) and BrettPhos-Pd-G3 (36.7 mg, 0.041 mmol). The mixture was heated to 100° C. and stirred under nitrogen overnight. The resulting mixture was concentrated and the residue was purified by prep-HPLC to give 143 (14.6 mg, 8.80%) as a light yellow solid. MS (ESI) m/z 421.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J=2.4 Hz, 1H), 7.25 (d, J=2.4 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 6.64-6.58 (m, 2H), 4.58 (s, 2H), 3.88-3.80 (m, 2H), 3.33 (s, 3H), 3.17 (d, J=12.0 Hz, 2H), 2.60 (t, J=10.2 Hz, 2H), 2.27 (s, 3H), 1.23 (d, J=6.4 Hz, 6H).
To a solution of 4-(2,6-dimethylmorpholin-4-yl)aniline (100 mg, 0.485 mmol), 7-bromo-2-methyl-2,4-dihydro-1,4-benzoxazin-3-one (129 mg, 0.533 mmol), and t-BuONa (93.2 mg, 0.970 mmol) in toluene (2 mL) was added BrettPhos-Pd-G3 (44.0 mg, 0.0484 mmol). The resulting solution was stirred for 16 h at 100° C. under nitrogen atmosphere. The solution was diluted with water (20 mL) and EA (20 ml), then filtered through celite. The aqueous layer was extracted with EA (3×20 mL). The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by pre-TLC (PE/EA=2/1) to provide compound 426 (28.2 mg, 15.43% yield) as a light yellow solid. MS (ESI) m/z 368.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 7.68 (s, 1H), 6.98-6.83 (m, 4H), 6.70 (d, J=8.4 Hz, 1H), 6.57-6.45 (m, 2H), 4.56 (q, J=6.8 Hz, 1H), 3.73-3.64 (m, 2H), 3.43 (d, J=11.1 Hz, 2H), 2.18 (t, J=10.9 Hz, 2H), 1.38 (d, J=6.8 Hz, 3H), 1.14 (d, J=6.2 Hz, 6H).
To a solution of 7-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (154 mg, 0.57 mmol) and 4-(2,6-dimethylmorpholino)-3-methylaniline (115 mg, 0.52 mmol) in 1,4-dioxane (2 mL) was added Pd2(dba)3 (48 mg, 0.05 mmol), Brettphos (56 mg, 0.10 mmol) and Cs2CO3 (341 mg, 1.04 mmol) under nitrogen atmosphere. The mixture was stirred at 100° C. for 12 h, the mixture was purified by prep TLC then purified by prep HPLC to give 7-((4-(2,6-dimethylmorpholino)-3-methylphenyl)amino)-2H-benzo[b][1,4]oxazin-3(4H)-one (54 mg, 28%) as an off-white solid. Mass (m/z): 368.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 7.79 (s, 1H), 6.90 (d, J=8.3 Hz, 1H), 6.85-6.77 (m, 2H), 6.73 (d, J=8.3 Hz, 1H), 6.63-6.53 (m, 2H), 4.49 (s, 2H), 3.77-3.65 (m, 2H), 2.87-2.79 (m, 2H), 2.32-2.22 (m, 2H), 2.20 (s, 3H), 1.10 (d, J=6.2 Hz, 6H).
To a solution of 7-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (115 mg, 0.50 mmol) and 4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-methylaniline (100 mg, 0.46 mmol) in 1,4-dioxane (2 mL) was added Pd2(dba)3 (42 mg, 0.05 mmol), Brettphos (49 mg, 0.09 mmol) and Cs2CO3 (299 mg, 0.92 mmol) under nitrogen atmosphere. The mixture was stirred at 100° C. for 12 h, the mixture was purified by prep TLC then purified by prep HPLC to give 7-((4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-methylphenyl)amino)-2H-benzo[b][1,4]oxazin-3(4H)-one (23.5 mg, 14%) as a white solid. Mass (m/z): 366.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 7.79 (s, 1H), 6.99-6.92 (m, 1H), 6.84-6.78 (m, 2H), 6.73 (d, J=8.4 Hz, 1H), 6.63-6.54 (m, 2H), 4.49 (s, 2H), 4.30 (dt, J=4.7, 2.2 Hz, 2H), 2.88-2.77 (m, 2H), 2.67-2.59 (m, 2H), 2.22 (s, 3H), 2.10-1.99 (m, 2H), 1.85-1.73 (m, 2H).
To a solution of 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (121 mg, 0.50 mmol) and 4-(2-ethylmorpholino)-2-methylaniline (100 mg, 0.45 mmol) in 1,4-dioxane (2 mL) was added Pd2(dba)3 (42 mg, 0.05 mmol), Xphos (43 mg, 0.09 mmol) and Cs2CO3 (296 mg, 0.91 mmol) under nitrogen atmosphere. The mixture was stirred at 100° C. for 12 h, the mixture was purified by prep TLC then purified by prep HPLC to give 7-((4-(2-ethylmorpholino)-2-methylphenyl)amino)-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (62 mg, 35.7%) as a grey solid. Mass (m/z): 382.4 [M+H]+. 1H NMR (400 MHz, DMSO) δ 7.21 (s, 1H), 6.99 (d, J=8.6 Hz, 1H), 6.91 (d, J=8.7 Hz, 1H), 6.85 (d, J=2.8 Hz, 1H), 6.76 (dd, J=8.7, 2.9 Hz, 1H), 6.34 (dd, J=8.7, 2.5 Hz, 1H), 6.26 (d, J=2.5 Hz, 1H), 4.53 (s, 2H), 3.97-3.88 (m, 1H), 3.66-3.55 (m, 1H), 3.54-3.46 (m, 1H), 3.46-3.36 (m, 2H), 3.20 (s, 3H), 2.61 (td, J=11.8, 3.4 Hz, 1H), 2.36-2.26 (m, 1H), 2.12 (s, 3H), 1.55-1.42 (m, 2H), 0.95 (t, J=7.5 Hz, 3H).
To a solution of 7-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (129 mg, 0.57 mmol) and 4-(2-methylmorpholino)aniline (100 mg, 0.52 mmol) in 1,4-dioxane (2 mL) was added Pd2(dba)3 (47 mg, 0.05 mmol), Brettphos (56 mg, 0.10 mmol) and Cs2CO3 (339 mg, 1.04 mmol) under nitrogen atmosphere. The mixture was stirred at 100° C. for 12 h, the mixture was purified by prep TLC then purified by flash chromatography to give 7-((4-(2-methylmorpholino)phenyl)amino)-2H-benzo[b][1,4]oxazin-3(4H)-one (62 mg, 35%) as a light blue solid. Mass (m/z): 340.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 7.69 (s, 1H), 6.98-6.90 (m, 2H), 6.90-6.82 (m, 2H), 6.71 (d, J=8.4 Hz, 1H), 6.56-6.47 (m, 2H), 4.48 (s, 2H), 3.93-3.84 (m, 1H), 3.69-3.57 (m, 2H), 3.48-3.39 (m, 1H), 3.38-3.30 (m, 1H), 2.62-2.51 (m, 1H), 2.25 (dd, J=11.7, 10.1 Hz, 1H), 1.14 (d, J=6.2 Hz, 3H).
To a solution of 7-bromo-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (138 mg, 0.57 mmol) and 4-(2-methylmorpholino)aniline (100 mg, 0.52 mmol) in 1,4-dioxane (2 mL) was added Pd2(dba)3 (47 mg, 0.05 mmol), Xphos (49 mg, 0.10 mmol) and Cs2CO3 (339 mg, 1.04 mmol) under nitrogen atmosphere. The mixture was stirred at 100° C. for 12 h, the mixture was purified by prep TLC then purified by flash chromatography to give 4-methyl-7-((4-(2-methylmorpholino)phenyl)amino)-2H-benzo[b][1,4]oxazin-3(4H)-one (117 mg, 63%) as a light yellow solid. Mass (m/z): 354.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.80 (s, 1H), 7.01-6.93 (m, 3H), 6.92-6.84 (m, 2H), 6.61 (dd, J=8.7, 2.5 Hz, 1H), 6.53 (d, J=2.4 Hz, 1H), 4.56 (s, 2H), 3.93-3.85 (m, 1H), 3.70-3.57 (m, 2H), 3.49-3.41 (m, 1H), 3.36 (d, J=11.1 Hz, 1H), 3.22 (s, 3H), 2.63-2.52 (m, 1H), 2.31-2.21 (m, 1H), 1.14 (d, J=6.2 Hz, 3H).
To a solution of 5-methyl-6-(4-(trifluoromethyl)piperidin-1-yl) pyridin-3-amine (100 mg, 0.39 mmol) and 7-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (105 mg, 0.46 mmol) in toluene (2 mL) was added t-BuONa (74 mg, 0.77 mmol) and BrettPhos-Pd-G3 (35 mg, 0.039 mmol). The mixture was heated to 100° C. and stirred under nitrogen overnight. The resulting mixture was concentrated and the residue was purified by prep-HPLC to give compound 150 as a light yellow solid (12.2 mg, 7.74%). MS (ESI) m/z 407.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 8.26 (s, 1H), 7.76 (s, 1H), 7.53 (s, 1H), 6.84-6.61 (m, 3H), 4.53 (s, 2H), 3.90-3.70 (m, 1H), 3.50-3.35 (m, 2H), 2.90-2.82 (m, 2H), 2.27 (s, 3H), 1.97-1.86 (m, 2H), 1.70-1.55 (m, 2H)
To a solution of cis-6-(2,6-dimethylmorpholino)-5-methylpyridin-3-amine (90 mg, 0.41 mmol) and 7-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (112 mg, 0.49 mmol) in toluene (2 mL) was added tBuONa (78 mg, 0.81 mmol) and BrettPhos-Pd-G3 (37 mg, 0.041 mmol). The mixture was heated to 100° C. and stirred under nitrogen overnight. The resulting mixture was concentrated and the residue was purified by prep-HPLC to give 151 as a light yellow solid (8.6 mg, 5.54%). 1H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 7.88 (s, 1H), 7.86 (d, J=2.8 Hz, 1H), 7.23 (d, J=2.8 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 6.61-6.52 (m, 2H), 4.49 (s, 2H), 3.76-3.66 (m, 2H), 3.08 (d, J=11.6 Hz, 2H), 2.40-2.34 (m, 2H), 2.20 (s, 3H), 1.09 (d, J=2.4 Hz, 6H). MS (ESI) m/z 369.0 [M+H]+.
To a solution of trans-6-(2,6-dimethylmorpholino)-5-methylpyridin-3-amine (40 mg, 0.18 mmol) and 7-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (49 mg, 0.22 mmol) in toluene (2 mL) was added tBuONa (35 mg, 0.36 mmol) and BrettPhos-Pd-G3 (16 mg, 0.018 mmol). The mixture was heated to 100° C. and stirred under nitrogen overnight. The resulting mixture was concentrated and the residue was purified by prep-HPLC to give compound 152 as a light yellow solid (5.0 mg, 3.32%). 1H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 7.88 (s, 1H), 7.86 (d, J=2.8 Hz, 1H), 7.23 (d, J=2.8 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 6.61-6.52 (m, 2H), 4.49 (s, 2H), 3.76-3.66 (m, 2H), 3.08 (d, J=11.6 Hz, 2H), 2.40-2.34 (m, 2H), 2.20 (s, 3H), 1.09 (d, J=2.4 Hz, 6H). MS (ESI) m/z 369.0 [M+H]+.
A solution of 7-bromo-4,5-dimethyl-2H-1,4-benzoxazin-3-one (100 mg, 0.35 mmol), 4-[4-(trifluoromethyl)piperidin-1-yl]aniline (86 mg, 0.35 mmol), t-BuONa (75 mg, 0.78 mmol) and BrettPhos-Pd-G3 (35.4 mg, 0.039 mmol) in toluene (2 mL) was heated to 100° C. and stirred under nitrogen for 18 hrs. The resulting mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC (0.05% NH3) to give compound 153 as a light yellow solid (9.0 mg, 10.93% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.13-7.08 (m, 3H), 7.14-7.06 (m, 3H), 6.96 (d, J=8.4 Hz, 2H), 6.71 (dd, J=8.4, 2.0 Hz, 1H), 6.63 (d, J=2.4 Hz, 1H), 4.88 (t, J=5.6 Hz, 1H), 4.56 (s, 2H), 3.90 (t, J=6.0 Hz, 2H), 3.59-3.49 (m, 4H), 2.74-2.67 (m, 1H), 1.74-1.66 (m, 2H), 1.23-1.17 (m, 2H), 1.12 (d, J=6.4 Hz, 6H). MS (ESI) m/z 397.0 [M+H]+.
To a solution of 4-(2,6-dimethylmorpholin-4-yl)aniline (100 mg, 0.485 mmol), 7-bromo-2-methyl-2,4-dihydro-1,4-benzoxazin-3-one (137 mg, 0.533 mmol), and t-BuONa (93.2 mg, 0.970 mmol) in toluene (2 mL) was added BrettPhos-Pd-G3 (44.0 mg, 0.0484 mmol). The resulting solution was stirred for 16 hrs at 100° C. under nitrogen atmosphere. The solution was diluted with water (20 mL) and EA (20 mL), then filtered through celite. The aqueous layer was extracted with EA (3×20 mL). The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by pre-TLC (PE/EA=2/1) to provide compound 436 (31.1 mg, 15.64% yield) as a light pink solid. MS (ESI) m/z 382.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 7.68 (s, 1H), 6.94 (d, J=9.0 Hz, 2H), 6.87 (d, J=9.0 Hz, 2H), 6.69 (d, J=8.5 Hz, 1H), 6.54-6.48 (m, 2H), 4.40 (dd, J=7.9, 4.5 Hz, 1H), 3.72-3.65 (m, 2H), 3.43 (d, J=10.5 Hz, 2H), 2.18 (t, J=10.2 Hz, 2H), 1.80-1.68 (m, 2H), 1.14 (d, J=6.2 Hz, 6H), 0.96 (t, J=7.4 Hz, 3H).
To a solution of 3,5-dimethyl-4-[4-(trifluoromethyl)piperidin-1-yl]aniline (100 mg, 0.367 mmol), 7-bromo-4-methyl-2H-1,4-benzoxazin-3-one (97.8 mg, 0.404 mmol), and t-BuONa (70.58 mg, 0.734 mmol) in toluene (2 mL) was added BrettPhos-Pd-G3 (33.3 mg, 0.0367 mmol). The resulting solution was stirred for 16 h at 100° C. under nitrogen atmosphere. The solution was diluted with water (20 mL) and EA (20 mL), then filtered through celite. The aqueous layer was extracted with EA (3×20 mL). The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC with CH3CN/H2O (0.05% NH3) to provide compound 155 (8.7 mg, 5.42% yield) as a light pink solid. MS (ESI) m/z 434.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.00 (d, J=8.7 Hz, 1H), 6.72 (dd, J=8.8, 2.4 Hz, 2H), 6.61 (dd, J=8.8, 2.4 Hz, 2H), 4.58 (s, 2H), 3.23 (s, 3H), 3.15 (t, J=10.8 Hz, 2H), 2.94-2.86 (m, 2H), 2.41-2.32 (m, 1H), 2.19 (d, J=10.5 Hz, 6H), 1.84-1.77 (m, 2H), 1.60-1.49 (m, 2H).
The mixture of 7-bromo-6-fluoro-4-methyl-2H-1,4-benzoxazin-3-one (100 mg, 0.384 mmol), 4-[4-(trifluoromethyl)piperidin-1-yl]aniline (85 mg, 0.346 mmol), t-BuONa (74 mg, 0.769 mmol) and BrettPhos Pd G3 (35.4 mg, 0.039 mmol) in toluene (2 mL) was heated to 100° C. and stirred for 18 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EA:PE=1:1) to give compound 156 (45.5 mg, 26.84% yield) as a white solid. Mass (m/z): 424 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.55 (s, 1H), 7.12 (d, J=12.4 Hz, 1H), 6.94-6.88 (m, 4H), 6.67 (d, J=8.0 Hz, 1H), 4.56 (s, 2H), 3.62 (d, J=12.4 Hz, 2H), 3.23 (s, 3H), 2.65-2.62 (m, 2H), 2.45-2.39 (m, 1H), 1.92-1.83 (m, 2H), 1.63-1.50 (m, 2H).
The mixture of 7-bromo-4,6-dimethyl-2H-1,4-benzoxazin-3-one (100 mg, 0.35 mmol), 4-[4-(trifluoromethyl)piperidin-1-yl]aniline (86 mg, 0.35 mmol), t-BuONa (75 mg, 0.78 mmol) and BrettPhos-Pd-G3 (35.4 mg, 0.039 mmol) in toluene (2 mL) was heated to 100° C. and stirred under nitrogen for 18 hrs. The resulting mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EA:PE=1:1) to give compound 157 (30 mg, 16.85% yield) as a white solid. Mass (m/z): 420 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 6.93 (d, J=10.8 Hz, 2H), 6.86-6.81 (m, 4H), 6.52 (s, 1H), 4.49 (s, 2H), 3.57 (d, J=12 Hz, 2H), 3.17 (s, 3H), 2.65-2.52 (m, 2H), 2.41-2.35 (m, 1H), 2.13 (s, 3H), 1.84 (d, J=12 Hz, 2H), 1.58-1.45 (m, 2H).
The mixture of compound 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (200 mg, 0.82 mmol), 6-bromo-3,4-dihydroquinolin-2(1H)-one (200 mg, 0.88 mmol), t-BuONa (250 mg, 2.60 mmol), and Brettphos-Pd-G3 (75 mg, 0.083 mmol) in toluene (10 mL) was heated to 100° C. and stirred for six hours at N2 atmosphere. TLC showed the reaction was completed. The resulting mixture was concentrated and the residue was purified through pre-TLC to give compound 158 (60 mg, 18.8% yield) as a white solid. MS (ESI) m/z 389.9 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 9.85 (s, 1H), 7.58 (s, 1H), 7.00-6.65 (m, 7H), 3.57 (d, J=10.4 Hz, 2H), 3.16 (d, J=5.2 Hz, 1H), 2.82-2.72 (m, 2H), 2.70-2.54 (m, 2H), 2.42-2.35 (m, 2H), 1.92-1.82 (m, 2H), 1.65-1.50 (m, 2H).
The titled compound 159 (60 mg, 29.3%) as a white solid was prepared according to the procedure outlined for compound 1. LC-MS (m/z) 390.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.31 (s, 1H), 6.82 (d, J=8.3 Hz, 1H), 6.71 (dd, J=8.4, 2.3 Hz, 1H), 6.66 (d, J=2.3 Hz, 1H), 6.58-6.46 (m, 2H), 4.54 (s, 2H), 3.65 (dtt, J=8.7, 6.3, 3.7 Hz, 2H), 2.89-2.81 (m, 2H), 2.72-2.62 (m, 2H), 1.06 (d, J=6.3 Hz, 6H).
The titled compound 160 (16.3 mg, 36%) as a white solid was prepared according to the procedure outlined for compound 1. LC-MS (m/z) 458.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.08 (d, J=8.7 Hz, 1H), 6.81 (dd, J=8.7, 2.5 Hz, 1H), 6.71 (d, J=2.4 Hz, 1H), 6.62-6.51 (m, 2H), 5.91 (s, 1H), 4.63 (s, 2H), 3.29 (d, J=12.8 Hz, 2H), 3.25 (s, 3H), 2.90-2.82 (m, 2H), 1.73 (dt, J=22.4, 8.5 Hz, 4H).
The titled compound 161 (80.6 mg, 30.2%) as a white solid was prepared according to the procedure outlined for compound 1. LC-MS (m/z) 472.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.08 (d, J=8.7 Hz, 1H), 6.81 (dd, J=8.7, 2.4 Hz, 1H), 6.71 (d, J=2.4 Hz, 1H), 6.63-6.51 (m, 2H), 4.63 (s, 2H), 3.43 (s, 3H), 3.25 (s, 3H), 3.16 (t, J=11.7 Hz, 2H), 2.95-2.87 (m, 2H), 1.97 (dt, J=14.0, 2.4 Hz, 2H), 1.79 (td, J=13.0, 4.7 Hz, 2H).
The titled compound 162 (6 mg, 2.2%) as a saddle brown solid was prepared according to the procedure outlined for compound 1. LC-MS (m/z) 422.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 7.71 (s, 1H), 6.97-6.87 (m, 4H), 6.71 (d, J=8.4 Hz, 1H), 6.58-6.48 (m, 2H), 4.48 (s, 2H), 3.45 (d, J=12.3 Hz, 2H), 3.41-3.36 (m, 3H), 2.74 (td, J=12.4, 2.4 Hz, 2H), 1.99 (dd, J=14.2, 2.6 Hz, 2H), 1.83 (td, J=13.1, 4.5 Hz, 2H).
The title compound 163 (16.8 mg) was prepared in a total yield of 78.0% as an orange solid from 4-(piperidin-1-yl)aniline (11.4 mg, 0.065 mmol), 1-(5-bromoisoindolin-2-yl)-2-(4-methylpiperazin-1-yl)ethan-1-one (16.9 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.08-6.96 (m, 3H), 6.94-6.83 (m, 4H), 4.70 (s, 2H), 4.56 (s, 2H), 3.24 (s, 2H), 3.08-2.86 (m, 4H), 2.76-2.54 (m, 8H), 2.34 (s, 3H), 1.73-1.64 (m, 4H), 1.57-1.48 (m, 2H). Mass (m/z): 434.3 [M+H]+.
The title compound 164 (17.2 mg) was prepared in a total yield of 66.3% as an orange solid from 3-fluoro-4-(4-(trifluoromethyl)piperidin-1-yl) aniline (17.1 mg, 0.065 mmol), 1-(5-bromoisoindolin-2-yl)-2-(4-methylpiperazin-1-yl)ethan-1-one (16.9 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.18-7.10 (m, 1H), 7.00-6.91 (m, 3H), 6.84-6.75 (m, 2H), 4.81 (s, 2H), 4.65 (s, 2H), 3.39-3.32 (m, 4H), 2.86-2.58 (m, 10H), 2.25 (m, 1H), 1.98-1.89 (m, 2H), 1.79-1.66 (m, 2H). Mass (m/z): 520.3 [M+H]+.
The title compound 165 (11.8 mg) was prepared in a total yield of 71.7% as a yellow solid from 4-(4,4-difluoropiperidin-1-yl)aniline (13.8 mg, 0.065 mmol), 5-bromoisoindoline (9.9 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.17-6.89 (m, 7H), 4.48 (s, 2H), 4.43 (s, 2H), 3.27-3.21 (m, 4H), 2.14-2.01 (m, 4H). Mass (m/z): 330.2 [M+H]+.
The title compound 166 (15.2 mg) was prepared in a total yield of 81.9% as a yellow solid from 4-(4,4-difluoropiperidin-1-yl)aniline (13.8 mg, 0.065 mmol), 1-(5-bromoisoindolin-2-yl)ethan-1-one (12.0 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.15-6.78 (m, 7H), 4.75 (s, 2H), 4.61 (s, 2H), 3.26-3.18 (m, 4H), 2.15 (s, 3H), 2.12-1.97 (m, 4H). Mass (m/z): 372.2 [M+H]+.
The title compound 167 (12.8 mg) was prepared in a total yield of 71.7% as a yellow solid from 4-(4,4-difluoropiperidin-1-yl)aniline (13.8 mg, 0.065 mmol), 5-bromo-2-ethylisoindoline (11.3 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.22-6.61 (m, 7H), 4.68 (s, 2H), 4.55 (s, 2H), 3.47 (q, J=7.2 Hz, 2H), 3.27-3.15 (m, 4H), 2.37-2.16 (m, 4H), 1.42 (t, J=7.2 Hz, 3H). Mass (m/z): 358.2 [M+H]+.
The title compound 168 (3.3 mg) was prepared in a total yield of 3.9% as a pale yellow solid from 4-(4,4-difluoropiperidin-1-yl)aniline (50 mg, 0.23 mmol), 6-bromo-2-methylisoindolin-1-one (53 mg, 0.23 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (10.91 mg, 0.019 mmol, 0.08 equivs), [1,1′-Bis(diphenylphosphino) ferrocene]dichloropalladium (II) (6.9 mg, 0.009 mmol, 0.04 equivs) and cesium carbonate (153.5 mg, 0.47 mmol, 2.0 equivs) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.36 (dd, J=5.2, 2.9 Hz, 1H), 7.32-7.28 (m, 1H), 7.17-7.13 (m, 1H), 7.08 (d, J=8.7 Hz, 2H), 7.03-6.97 (m, 2H), 4.38 (s, 2H), 3.25 (s 3H), 3.17 (d, J=3.0 Hz, 4H), 2.16-2.00 (m, 4H). 19F NMR (376 MHz, Methanol-d4) δ −99.32. LC-MS (m/z) 358.6 [M+H]+.
The title compound 169 (4.5 mg) was prepared in a total yield of 5.0% as a pale yellow solid from 3-fluoro-4-(4-(trifluoromethyl)piperidin-1-yl) aniline (50 mg, 0.24 mmol, 1.0 equivs), 6-bromo-2-methylisoindolin-1-one (53 mg, 0.24 mmol, 1.0 equivs), (9,9-dimethyl-9H-xanthene-4,5-diyl) bis(diphenylphosphane) (10.91 mg, 0.019 mmol, 0.08 equivs), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (6.9 mg, 0.009 mmol, 0.04 equivs) and cesium carbonate (92 mg, 0.28 mmol, 1.2 equivs) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.74 (dt, J=7.5, 1.0 Hz, 1H), 7.71 (dd, J=5.7, 3.3 Hz, 1H), 7.64-7.58 (m, 2H), 7.55 (ddd, J=7.6, 5.7, 1.0 Hz, 2H), 7.48 (ddd, J=8.3, 7.1, 1.5 Hz, 1H), 4.48 (s, 2H), 3.22 (d, J=2.3 Hz, 1H), 3.19 (s, 3H), 3.17 (d, J=5.1 Hz, 1H), 1.78-1.65 (m, 2H), 1.50-1.40 (m, 2H), 1.01-0.94 (m, 3H). 19F NMR (376 MHz, Methanol-d4) δ −75.43 (d, J=8.3 Hz), −76.95, −123.72, −123.75. Mass (m/z): 408.3 [M+H]+.
The title compound 170 (21.4 mg) was prepared in a yield of 24.38% as a pale yellow solid from 6-bromo-2-methylisoindolin-1-one (50 mg, 0.22 mmol) and 4-(4-methylpiperidin-1-yl)aniline (42 mg, 0.22 mmol), according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.75-7.46 (m, 2H), 7.36 (d, J=8.9 Hz, 2H), 7.28-6.95 (m, 3H), 4.40 (s, 2H), 3.67-3.45 (m, 2H), 3.16 (s, 3H), 3.04-2.96 (m, 1H), 1.86 (d, J=11.7 Hz, 2H), 1.64 (q, J=13.2, 11.6 Hz, 2H), 1.56-1.42 (m, 2H), 1.03 (d, J=6.4 Hz, 3H). LC-MS (m/z) 336.2 [M+H]+.
The title compound 171 (12.2 mg) was prepared in a yield of 14.17% as a pale yellow solid from 6-bromo-2-methylisoindolin-1-one (50 mg, 0.22 mmol) and 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (54 mg, 0.22 mmol), according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.67-7.46 (m, 2H), 7.42-7.28 (m, 2H), 7.24-7.04 (m, 2H), 6.99 (d, J=7.9 Hz, 1H), 4.36 (d, J=7.9 Hz, 2H), 3.65 (d, J=12.3 Hz, 1H), 3.16 (s, 3H), 2.68 (t, J=11.8 Hz, 1H), 2.28 (s, 1H), 1.80-1.65 (m, 2H), 1.46 (h, J=7.3 Hz, 1H), 1.39-1.18 (m, 3H). LC-MS (m/z) 390.3 [M+H]+.
The title compound 172 (93.8 mg) was prepared in a yield of 59.33% as a pale yellow powder from 5-bromo-2-methylisoindolin-1-one (100 mg, 0.44 mmol) and 4-(4,4-difluoropiperidin-1-yl)aniline (94 mg, 0.44 mmol), according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.50 (d, J=8.5 Hz, 1H), 7.14-6.96 (m, 6H), 4.32 (s, 2H), 3.27 (s, 3H), 3.12 (s, 4H), 2.09 (m, 4H). LC-MS (m/z) 358.2 [M+H]+.
To a solution of 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (108 mg, 0.44 mmol, 1.0 equivs) and 5-bromo-2-methylisoindolin-1-one (100 mg, 0.44 mmol, 1.0 equivs) in 1,4-dioxane (5 mL) was added (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (20.48 mg, 0.035 mmol, 0.08 equivs), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (12.95 mg, 0.018 mmol, 0.04 equivs) and cesium carbonate (216.18 mg, 0.66 mmol, 2.0 equivs) respectively under argon atmosphere. The resulting mixture was heated to 110° C. and stirred for overnight at the same temperature. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (5 mL) 3 times. The organic layer was combined and washed with water, sat·NaHCO3 (aq), and brine respectively. Then dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/AcOEt, 1/4) to give 58.4 mg of compound 1 in a yield of 33.90% as a blue powder. 1H NMR (400 MHz, Methanol-d4) δ 7.50 (d, J=8.4 Hz, 1H), 7.11 (d, J=8.5 Hz, 2H), 7.04-6.96 (m, 3H), 6.95-6.90 (m, 1H), 4.33 (s, 2H), 3.68 (d, J=12.4 Hz, 2H), 3.11 (s, 3H), 2.69 (s, 2H), 2.34-2.21 (m, 1H), 2.05-1.89 (m, 2H), 1.79-1.64 (m, 2H). LC-MS (m/z) 390.2 [M+H]+.
The title compound 174 (37.9 mg) was prepared in a yield of 25.54% as a pale yellow powder from 5-bromo-2-methylisoindolin-1-one (100 mg, 0.44 mmol) and 4-(4-methylpiperidin-1-yl)aniline (84 mg, 0.44 mmol), according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.49 (d, J=8.4 Hz, 1H), 7.14-7.05 (m, 2H), 7.02-6.95 (m, 3H), 6.92 (dd, J=8.4, 2.1 Hz, 1H), 4.30 (s, 2H), 3.54 (d, J=11.8 Hz, 2H), 3.10 (s, 3H), 2.64 (t, J=12.1 Hz, 2H), 1.82-1.68 (m, 2H), 1.57-1.42 (m, 1H), 1.41-1.30 (m, 2H), 0.99 (d, J=6.3 Hz, 3H). LC-MS (m/z) 336.3 [M+H]+.
The title compound 175 (14.7 mg) was prepared in a total yield of 75.6% as a yellow solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (15.9 mg, 0.065 mmol), 5-bromo-2-ethylisoindoline (11.3 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.07 (d, J=8.0 Hz, 1H), 7.04-7.00 (m, 2H), 6.97-6.93 (m, 2H), 6.90-6.83 (m, 2H), 4.05 (s, 4H), 3.65-3.55 (m, 2H), 2.97 (q, J=7.2 Hz, 2H), 2.70-2.61 (m, 2H), 2.26 (m, 1H), 2.00-1.89 (m, 2H), 1.79-1.64 (m, 2H), 1.25 (t, J=7.2 Hz, 3H). Mass (m/z): 390.3 [M+H]+.
The title compound 176 (13.9 mg) was prepared in a total yield of 82.9% as a yellow solid from 4-(4-methylpiperidin-1-yl)aniline (12.4 mg, 0.065 mmol), 5-bromo-2-ethylisoindoline (11.3 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.10-6.81 (m, 7H), 4.03 (s, 4H), 3.55-3.43 (m, 2H), 2.96 (q, J=7.2 Hz, 2H), 2.71-2.54 (m, 2H), 1.79-1.71 (m, 2H), 1.56-1.43 (m, 1H), 1.42-1.29 (m, 2H), 1.25 (t, J=7.2 Hz, 3H), 0.99 (d, J=6.4 Hz, 3H). Mass (m/z): 336.2 [M+H]+.
The title compound 177 (17.3 mg) was prepared in a total yield of 88.7% as a yellow solid from 4-(piperidin-1-yl)-3-(trifluoromethyl)aniline (15.9 mg, 0.065 mmol), 5-bromo-2-ethylisoindoline (11.3 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.37-7.23 (m, 3H), 7.19 (d, J=8.0 Hz, 1H), 7.07-6.98 (m, 2H), 4.38 (s, 2H), 4.36 (s, 2H), 3.25 (q, J=7.2 Hz, 2H), 2.85-2.70 (m, 4H), 1.71-1.62 (m, 4H), 1.58-1.50 (m, 2H), 1.35 (t, J=7.2 Hz, 3H). Mass (m/z): 390.3 [M+H]+.
The title compound 178 (58.4 mg) was prepared in a yield of 25.72% as a white powder from 5-bromo-2-methylisoindolin-1-one (100 mg, 0.44 mmol) and 4-(piperidin-1-yl)-3-(trifluoromethyl)aniline (108 mg, 0.44 mmol), according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.58 (d, J=8.4 Hz, 1H), 7.44-7.39 (m, 2H), 7.37 (t, J=1.5 Hz, 1H), 7.16-7.12 (m, 1H), 7.06 (dd, J=8.4, 2.1 Hz, 1H), 4.40 (s, 2H), 3.14 (s, 3H), 2.87-2.78 (m, 4H), 1.69 (p, J=5.7 Hz, 4H), 1.58 (d, J=6.0 Hz, 2H). LC-MS (m/z) 387.9 [M−H]−.
The title compound 179 (17.2 mg) was prepared in a yield of 9.78% as a pale yellow powder from 5-bromo-2-(cyclopropylmethyl)isoindolin-1-one (100 mg, 0.41 mmol) and 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (120 mg, 0.41 mmol), according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.41 (d, J=8.3 Hz, 1H), 7.07 (d, J=8.9 Hz, 2H), 6.99 (d, J=2.1 Hz, 1H), 6.98-6.92 (m, 2H), 6.90 (dt, J=8.4, 2.0 Hz, 1H), 4.40 (s, 2H), 3.69 (d, J=12.3 Hz, 2H), 2.71-2.61 (m, 2H), 1.89 (d, J=13.6 Hz, 2H), 1.57 (qd, J=12.4, 4.0 Hz, 2H), 1.24 (s, 2H), 1.04-0.94 (m, 1H), 0.89-0.82 (d, J=7.2 Hz, 1H), 0.51-0.44 (m, 2H), 0.30-0.22 (m, 2H). LC-MS (m/z) 430.3 [M+H]+.
The title compound 180 (73.1 mg) was prepared in a yield of 44.26% as a pale yellow powder from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (100 mg, 0.41 mmol) and 5-bromo-2-ethylisoindolin-1-one (98 mg, 0.41 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Chloroform-d) δ 7.58 (d, J=8.4 Hz, 1H), 7.49-7.35 (m, 1H), 7.15 (s, 2H), 6.98 (d, J=10.0 Hz, 4H), 4.32 (d, J=4.1 Hz, 2H), 3.69 (d, J=12.3 Hz, 2H), 3.61 (qd, J=7.3, 2.8 Hz, 2H), 3.42-3.33 (m, 1H), 2.71 (t, J=12.3 Hz, 2H), 2.19 (ddt, J=12.6, 8.3, 4.0 Hz, 1H), 2.00 (d, J=13.1 Hz, 2H), 1.87-1.70 (m, 2H), 1.25 (td, J=7.2, 3.1 Hz, 2H). Mass (m/z): 404.2 [M+H]+.
The title compound 181 (17.0 mg) was prepared in a total yield of 76.4% as a yellow solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (15.9 mg, 0.065 mmol), 1-(5-bromoisoindolin-2-yl)-2,2-dimethylpropan-1-one (14.1 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.27-6.75 (m, 7H), 4.96 (s, 2H), 4.67 (s, 2H), 3.83-3.41 (m, 2H), 2.71-2.57 (m, 2H), 2.27 (m, 1H), 2.07-1.89 (m, 2H), 1.81-1.62 (m, 2H), 1.32 (s, 9H). Mass (m/z): 446.3 [M+H]+.
The title compound 182 (1.1 mg) was prepared in a yield of 1.4% as a pale yellow powder from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (50 mg, 0.20 mmol) and 5-bromoisoindolin-1-one (43 mg, 0.20 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.53 (d, J=8.4 Hz, 1H), 7.15-7.09 (m, 2H), 7.03-6.98 (m, 3H), 6.95 (dd, J=8.3, 2.1 Hz, 1H), 4.32 (s, 2H), 3.69 (d, J=12.4 Hz, 2H), 2.70 (td, J=12.5, 2.4 Hz, 2H), 1.98 (d, J=13.4 Hz, 2H), 1.72 (qd, J=12.4, 4.5 Hz, 3H). Mass (m/z): 376.2 [M+H]+.
The title compound 183 (24.6 mg) was prepared in a yield of 28.22% as a pale yellow powder from 5-fluoro-6-(piperidin-1-yl)pyridin-3-amine (50 mg, 0.26 mmol) and 5-bromo-2-methylisoindolin-1-one (58 mg, 0.26 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 7.94 (dt, J=2.3, 1.2 Hz, 1H), 7.44 (d, J=8.3 Hz, 1H), 7.42-7.36 (m, 1H), 7.04 (d, J=2.2 Hz, 1H), 6.93 (dt, J=8.3, 1.9 Hz, 1H), 4.31 (s, 2H), 2.99 (s, 3H), 1.66-1.52 (m, 6H). Mass (m/z): 341.7 [M+H]+.
The title compound 184 (46.3 mg) was prepared in a yield of 46.92% as a pale yellow powder from 4-(4-methylpiperidin-1-yl)aniline (50 mg, 0.26 mmol) and 5-bromo-2-(cyclopropylmethyl)isoindolin-1-one (58 mg, 0.26 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.41 (d, J=8.3 Hz, 1H), 7.09-7.02 (m, 2H), 6.97 (d, J=2.1 Hz, 1H), 6.94 (s, 1H), 6.92-6.87 (m, 2H), 4.40 (s, 2H), 3.65-3.50 (m, 2H), 3.29 (d, J=7.1 Hz, 2H), 2.60 (t, J=11.9 Hz, 2H), 1.74-1.65 (m, 2H), 1.47 (dq, J=11.0, 6.6, 5.3 Hz, 1H), 1.26 (dd, J=12.7, 9.0 Hz, 3H), 0.95 (d, J=6.5 Hz, 3H), 0.53-0.45 (m, 2H), 0.31-0.22 (m, 2H). Mass (m/z): 376.3 [M+H]+.
The title compound 185 (72.1 mg) was prepared in a yield of 70.31% as a pale yellow powder from 4-(piperidin-1-yl)aniline (50 mg, 0.28 mmol) and 5-bromo-2-(cyclopropylmethyl)isoindolin-1-one (83 mg, 0.31 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.41 (d, J=8.3 Hz, 1H), 7.09-7.02 (m, 2H), 6.97 (t, J=2.3 Hz, 1H), 6.95-6.86 (m, 3H), 4.39 (s, 2H), 3.29 (d, J=7.1 Hz, 2H), 3.05 (d, J=10.9 Hz, 4H), 1.71-1.57 (m, 4H), 1.56-1.45 (m, 2H), 1.04-0.93 (m, 1H), 0.52-0.42 (m, 2H), 0.29-0.21 (m, 2H). Mass (m/z): 362.1 [M+H]+.
The title compound 186 (16.7 mg) was prepared in a total yield of 82.6% as a yellow solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (15.9 mg, 0.065 mmol), 1-(5-bromoisoindolin-2-yl)ethan-1-one (12.0 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Chloroform-d) δ 7.18-6.68 (m, 7H), 4.70 (s, 4H), 3.75-3.58 (m, 2H), 2.79-2.68 (m, 2H), 2.18 (m, 1H), 2.15 (s, 3H), 2.04-1.93 (m, 2H), 1.85-1.70 (m, 2H). Mass (m/z): 404.2 [M+H]+.
The title compound 187 (16.4 mg) was prepared in a total yield of 83.9% as a yellow solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (15.9 mg, 0.065 mmol), 6-bromo-2-methylbenzo[d]isoxazol-3(2H)-one (11.4 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Chloroform-d) δ 7.56 (d, J=8.8 Hz, 1H), 7.13 (d, J=8.8 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 6.66 (d, J=8.8 Hz, 1H), 6.55-6.49 (m, 1H), 3.77-3.69 (m, 2H), 3.54 (s, 3H), 2.77-2.67 (m, 2H), 2.17 (m, 1H), 2.05-1.95 (m, 2H), 1.88-1.70 (m, 2H). Mass (m/z): 392.2 [M+H]+.
The title compound 188 (26.4 mg) was prepared in a total yield of 53.8% as a yellow solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (31.8 mg, 0.13 mmol), tert-butyl 6-bromo-2-methyl-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate (32.8 mg, 0.1 mmol), Pd2(dba)3 (1.84 mg, 0.002 mmol), X-Phos (4.76 mg, 0.01 mmol) and Cs2CO3 (48.8 mg, 0.15 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Chloroform-d) δ 7.62 (d, J=8.4 Hz, 1H), 7.21 (s, 1H), 7.16-7.12 (m, 2H), 6.95 (d, J=8.4 Hz, 2H), 6.72 (m, 1H), 3.75-3.68 (m, 2H), 3.53 (s, 3H), 2.77-2.62 (m, 2H), 2.17 (m, 1H), 2.03-1.95 (m, 2H), 1.84-1.74 (m, 2H), 1.53 (s, 9H). Mass (m/z): 491.3 [M+H]+.
The title compound 189 (17.7 mg) was prepared in a total yield of 77.3% as a yellow solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (15.9 mg, 0.065 mmol), (5-bromo-1,1-dimethylisoindolin-2-yl) (cyclopropyl) methanone (14.7 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Chloroform-d) δ 7.12-7.00 (m, 3H), 6.96-6.88 (m, 2H), 6.89-6.83 (m, 1H), 6.73 (s, 1H), 4.92 (s, 2H), 3.72-3.62 (m, 2H), 2.73-2.59 (m, 2H), 2.14 (m, 1H), 2.03-1.91 (m, 2H), 1.83-1.75 (m, 3H), 1.70 (s, 6H), 1.06-0.97 (m, 2H), 0.83-0.72 (m, 2H). Mass (m/z): 458.1 [M+H]+.
The title compound 190 (16.5 mg) was prepared in a total yield of 76.7% as a yellow solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (15.9 mg, 0.065 mmol), (5-bromoisoindolin-2-yl)(cyclopropyl)methanone (13.3 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Chloroform-d) δ 7.19-6.72 (m, 7H), 4.91 (s, 2H), 4.72 (s, 2H), 3.73-3.62 (m, 2H), 2.78-2.57 (m, 2H), 2.14 (m, 1H), 2.04-1.93 (m, 2H), 1.86-1.64 (m, 3H), 1.09-1.03 (m, 2H), 0.86-0.80 (m, 2H). Mass (m/z): 430.2 [M+H]+.
A solution of tert-butyl 2-methyl-3-oxo-6-((4-(4-(trifluoromethyl) piperidin-1-yl) phenyl)amino)-2,3-dihydro-1H-indazole-1-carboxylate (12.3 mg, 0.025 mmol) in 1 mL of a solution of HCl in 1,4-dioxane was stirred for 30 mins at r.t. and concentrated. 5 ml water was added. The pH of the filtrate was adjusted to 8-9 with sodium carbonate solution. Then the mixture was extracted by DCM (3 mL×3). The combined organic layers were washed with water (5 mL), dried over Na2SO4 and concentrated. The residue was purified by perp-TLC (MeOH/DCM=1/10) to afford the desired product as a yellow solid (8.3 mg, 85.2%). 1H NMR (400 MHz, DMSO-d6) δ 7.36 (d, J=8.8 Hz, 1H), 7.06 (d, J=8.8 Hz, 2H), 6.96 (d, J=8.8 Hz, 2H), 6.62 (d, J=8.8 Hz, 1H), 6.52 (s, 1H), 3.73-3.65 (m, 2H), 3.22 (s, 3H), 2.73-2.61 (m, 2H), 2.11 (m, 1H), 1.93-1.85 (m, 2H), 1.65-1.51 (m, 2H). Mass (m/z): 391.2 [M+H]+.
The title compound 192 (37.3 mg) was prepared in a total yield of 45.4% as a white solid from 3,5-difluoro-4-(4-methylpiperidin-1-yl)aniline (65 mg, 0.288 mmol), 5-bromo-2-methylisoindolin-1-one (50 mg, 0.221 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol) and Cs2CO3 (109 mg, 0.332 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.61-7.50 (m, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.22 (d, J=2.0 Hz, 1H), 7.09 (dd, J=8.4, 2.0 Hz, 1H), 6.82-6.69 (m, 2H), 2.98 (s, 3H), 2.96-2.86 (m, 4H), 1.56 (dd, J=12.8, 3.2 Hz, 2H), 1.37 (dqd, J=13.2, 8.0, 6.8, 2.8 Hz, 1H), 1.18 (tq, J=11.6, 4.8 Hz, 2H), 0.88 (d, J=6.4 Hz, 3H). Mass (m/z): 372.3 [M+H]+.
The title compound 193 (27.1 mg) was prepared in a total yield of 33.8% as a white solid from 3,5-difluoro-4-(4-methylpiperidin-1-yl)aniline (61 mg, 0.271 mmol), 5-bromo-2-ethylisoindolin-1-one (50 mg, 0.208 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (102 mg, 0.312 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 7.49 (dd, J=8.0, 1.2 Hz, 1H), 7.21 (d, J=1.6 Hz, 1H), 7.05 (dt, J=8.0, 1.6 Hz, 1H), 6.76-6.66 (m, 2H), 4.36 (s, 2H), 3.54-3.40 (m, 2H), 3.02-2.88 (m, 4H), 1.68-1.55 (m, 2H), 1.48-1.34 (m, 1H), 1.21 (qd, J=11.6, 4.4 Hz, 2H), 1.12 (td, J=7.2, 1.2 Hz, 3H), 0.91 (dd, J=6.4, 1.2 Hz, 3H). Mass (m/z): 386.3 [M+H]+.
The title compound 194 (13.2 mg) was prepared in a total yield of 67.7% as a yellow solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (15.9 mg, 0.065 mmol), 3-bromo-6-methyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (11.3 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.17 (s, 1H), 7.12 (d, J=8.8 Hz, 2H), 6.96 (d, J=8.8 Hz, 2H), 4.24 (s, 2H), 3.76-3.69 (m, 2H), 3.19 (s, 3H), 2.77-2.67 (m, 2H), 2.19 (m, 1H), 2.04-1.95 (m, 2H), 1.85-1.70 (m, 2H). Mass (m/z): 391.2 [M+H]+.
The title compound 195 (15.0 mg) was prepared in a total yield of 88.2% as a yellow solid from 5-fluoro-6-(piperidin-1-yl)pyridin-3-amine (12.7 mg, 0.065 mmol), 5-bromo-2-ethylisoindoline (11.3 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Chloroform-d) δ 7.84 (d, J=2.0 Hz, 1H), 7.10-6.99 (m, 2H), 6.79 (d, J=8.4 Hz, 1H), 6.74 (s, 1H), 4.06 (s, 2H), 4.02 (s, 2H), 3.33-3.23 (m, 4H), 2.93 (q, J=7.2 Hz, 2H), 1.75-1.65 (m, 4H), 1.65-1.56 (m, 2H), 1.28 (t, J=7.2 Hz, 3H). Mass (m/z): 341.2 [M+H]+.
The title compound 196 (15.3 mg) was prepared in a total yield of 83.4% as a yellow solid from 5-fluoro-6-(piperidin-1-yl)pyridin-3-amine (12.7 mg, 0.065 mmol), 5-bromo-2-(cyclopropylmethyl)isoindoline (12.6 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Chloroform-d) δ 7.83 (d, J=2.0 Hz, 1H), 7.09-6.94 (m, 2H), 6.80 (d, J=8.4 Hz, 1H), 6.71 (s, 1H), 4.18 (s, 2H), 4.12 (s, 2H), 3.30-3.21 (m, 4H), 2.82 (d, J=6.8 Hz, 2H), 1.71-1.63 (m, 4H), 1.63-1.55 (m, 2H), 1.11 (m, 1H), 0.67-0.58 (m, 2H), 0.33-0.27 (m, 2H). Mass (m/z): 367.3 [M+H]+.
The title compound 197 (32.6 mg) was prepared in a yield of 18.45% as a pale yellow powder from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (100 mg, 0.41 mmol) and 5-bromo-2-(tert-butyl)isoindolin-1-one (121 mg, 0.45 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.66-7.58 (m, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.34-7.25 (m, 2H), 7.11 (d, J=8.4 Hz, 2H), 6.95-6.89 (m, 1H), 4.44 (d, J=0.9 Hz, 2H), 3.67 (d, J=12.5 Hz, 2H), 2.76-2.60 (m, 2H), 2.29 (dtq, J=16.7, 8.4, 4.3 Hz, 1H), 2.01-1.93 (m, 2H), 1.74 (td, J=12.6, 4.1 Hz, 2H), 1.53 (s, 9H). Mass (m/z): 432.5 [M+H]+.
The title compound 198 (41.6 mg) was prepared in a yield of 21.28% as a white powder from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (100 mg, 0.41 mmol) and 5-bromo-2-(2-(2-methoxyethoxy)ethyl)isoindolin-1-one (141 mg, 0.45 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.53 (d, J=8.4 Hz, 1H), 7.16-7.08 (m, 2H), 7.03-6.89 (m, 4H), 4.44 (s, 2H), 3.73-3.69 (m, 4H), 3.69-3.63 (m, 2H), 3.62-3.59 (m, 2H), 3.53-3.49 (m, 2H), 2.68 (s, 2H), 2.27 (tdt, J=12.3, 7.8, 3.9 Hz, 1H), 2.00-1.92 (m, 2H), 1.71 (qd, J=12.6, 4.1 Hz, 2H). Mass (m/z): 478.3 [M+H]+.
The title compound 199 (75.2 mg) was prepared in a yield of 39.37% as a white powder from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (100 mg, 0.41 mmol) and 2-benzyl-5-bromoisoindolin-1-one (123 mg, 0.45 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.57 (d, J=9.0 Hz, 1H), 7.39-7.31 (m, 3H), 7.31-7.25 (m, 3H), 7.14-7.08 (m, 2H), 7.03-6.98 (m, 2H), 6.96 (dq, J=4.6, 2.1 Hz, 2H), 4.74 (s, 2H), 4.23 (s, 2H), 3.72-3.65 (m, 2H), 2.69 (td, J=12.4, 2.5 Hz, 2H), 2.29 (dtd, J=16.1, 8.1, 3.9 Hz, 1H), 1.97 (dt, J=12.9, 3.0 Hz, 2H), 1.72 (qd, J=12.6, 4.2 Hz, 2H). Mass (m/z): 466.3 [M+H]+.
The title compound 200 (52.9 mg) was prepared in a yield of 28.06% as a white powder from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (100 mg, 0.41 mmol) and 5-bromo-2-(3-(dimethylamino)propyl)isoindolin-1-one (121 mg, 0.41 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.51 (dd, J=8.4, 0.5 Hz, 1H), 7.14-7.09 (m, 2H), 7.00 (dt, J=4.3, 1.5 Hz, 2H), 6.98 (d, J=2.2 Hz, 1H), 6.95 (dd, J=8.4, 2.0 Hz, 1H), 4.39 (s, 2H), 3.73-3.58 (m, 4H), 2.96-2.86 (m, 2H), 2.71 (s, 8H), 2.27 (dtq, J=17.0, 8.5, 4.2 Hz, 1H), 2.08-1.91 (m, 4H), 1.77-1.63 (m, 2H). Mass (m/z): 461.8 [M+H]+.
The title compound 201 (16.3 mg) was prepared in a total yield of 80.9% as a yellow solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (15.9 mg, 0.065 mmol), 5-bromo-2-methylisoindoline-1,3-dione (12.0 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Chloroform-d) δ 7.45 (m, 1H), 7.15-6.88 (m, 3H), 6.87-6.70 (m, 3H), 3.67-3.43 (m, 2H), 2.94 (s, 3H), 2.65-2.45 (m, 2H), 2.01 (m, 1H), 1.87-1.77 (m, 2H), 1.67-1.52 (m, 2H). Mass (m/z): 404.2 [M+H]+.
The title compound 202 (17.7 mg) was prepared in a total yield of 86.8% as a yellow solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (15.9 mg, 0.065 mmol), 5-bromo-7-fluoro-2-methylisoindolin-1-one (12.2 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Chloroform-d) δ 7.10 (d, J=8.4 Hz, 2H), 6.94 (d, J=8.4 Hz, 2H), 6.82-6.76 (m, 2H), 4.22 (s, 2H), 3.77-3.66 (m, 2H), 3.09 (s, 3H), 2.78-2.62 (m, 2H), 2.17 (m, 1H), 2.04-1.95 (m, 2H), 1.83-1.71 (m, 2H). Mass (m/z): 408.2 [M+H]+.
The title compound 203 (18.6 mg) was prepared in a total yield of 87.9% as a yellow solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (15.9 mg, 0.065 mmol), 5-bromo-7-chloro-2-methylisoindolin-1-one (13.0 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Chloroform-d) δ 7.13-7.07 (m, 2H), 6.99-6.92 (m, 2H), 6.84-6.77 (m, 2H), 4.23 (s, 2H), 3.72-3.64 (m, 2H), 3.08 (s, 3H), 2.75-2.63 (m, 2H), 2.19 (m, 1H), 2.01-1.93 (d, J=3.8 Hz, 2H), 1.80-1.66 (m, 2H). Mass (m/z): 424.1 [M+H]+.
The title compound 204 (16.2 mg) was prepared in a total yield of 79.4% as a yellow solid from 3-fluoro-4-(4-(trifluoromethyl)piperidin-1-yl)aniline (17.0 mg, 0.065 mmol), 5-bromo-2-methylisoindolin-1-one (11.3 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Chloroform-d) δ 7.62 (d, J=8.4 Hz, 1H), 7.02-6.85 (m, 4H), 6.51 (s, 1H), 4.25 (s, 2H), 3.54-3.41 (m, 2H), 3.13 (s, 3H), 2.71-2.62 (m, 2H), 2.14 (m, 1H), 2.01-1.92 (m, 2H), 1.89-1.76 (m, 2H). Mass (m/z): 408.2 [M+H]+.
The title compound 205 (19.0 mg) was prepared in a total yield of 82.6% as a yellow solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (15.9 mg, 0.065 mmol), 5-bromo-N-(tert-butyl)isoindoline-2-carboxamide (14.9 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.14-6.81 (m, 7H), 4.54 (s, 4H), 3.69-3.57 (m, 2H), 2.74-2.62 (m, 2H), 2.27 (m, 1H), 2.02-1.93 (m, 2H), 1.79-1.67 (m, 2H), 1.39 (s, 9H). Mass (m/z): 461.3 [M+H]+.
The title compound 206 (7.1 mg) was prepared in a yield of 7.61% as a yellow powder from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (50 mg, 0.20 mmol) and 5-bromo-2-(1-methyl-1H-imidazol-4-yl)isoindolin-1-one (60 mg, 0.20 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Chloroform-d) δ 7.75-7.68 (m, 1H), 7.52 (s, 1H), 7.40 (tdd, J=8.6, 6.4, 1.7 Hz, 4H), 7.29 (d, J=3.4 Hz, 1H), 7.04 (td, J=7.7, 2.6 Hz, 1H), 7.00-6.95 (m, 1H), 6.69 (ddd, J=15.6, 7.6, 1.6 Hz, 1H), 4.83 (s, 2H), 2.12 (d, J=37.6 Hz, 2H), 2.04 (s, 1H), 1.99 (s, 2H), 1.78 (s, 2H), 1.73 (s, 3H), 1.56 (s, 1H), 1.25 (t, J=7.1 Hz, 1H). Mass (m/z): 456.2 [M+H]+.
To a solution of 4-(2,6-dimethylmorpholin-4-yl)aniline (107 mg, 0.518 mmol), 5-bromo-1-methyl-1,2,3-benzotriazole (109 mg, 0.518 mmol) in toluene (2 mL) was added Cs2CO3 (338 mg, 1.04 mmol), Pd2(dba)3 (48 mg, 0.052 mmol) and Ru-Phos (48 mg, 0.104 mmol). The reaction mixture was stirred at 100° C. for 18 h under N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography (EA:PE=1:3) to give the target compound (61.8 mg, 34.55%) as a green solid. MS (ESI) m/z: 338 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.28 (s, 1H), 7.19 (dd, J=2.0, 8.8 Hz, 1H), 7.06 (d, J=8.8 Hz, 2H), 6.92 (d, J=8.8 Hz, 2H), 4.22 (s, 3H), 3.70-3.68 (m, 2H), 3.47 (d, J=10.4 Hz, 2H), 2.24-2.18 (m, 2H), 1.16 (d, J=6.0 Hz, 6H).
The title compound 208 (66.5 mg) was prepared in a yield of 34.37% as a white powder from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (100 mg, 0.41 mmol) and 5-bromo-2-(1-methylpiperidin-4-yl)isoindolin-1-one (127 mg, 0.41 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.50 (d, J=8.4 Hz, 1H), 7.10 (d, J=8.4 Hz, 2H), 7.04-6.86 (m, 4H), 4.39-4.28 (m, 3H), 3.75-3.59 (m, 2H), 3.59-3.47 (m, 2H), 3.13 (td, J=12.9, 2.9 Hz, 2H), 2.85 (s, 3H), 2.64 (s, 2H), 2.34-2.11 (m, 3H), 2.10-1.87 (m, 4H), 1.67 (qd, J=12.6, 4.1 Hz, 2H). Mass (m/z): 473.2 [M+H]+.
The title compound 209 (67.2 mg) was prepared in a yield of 39.51% as a pale yellow powder from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (100 mg, 0.41 mmol) and 5-bromo-2-cyclopropylisoindolin-1-one (103 mg, 0.41 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.44-7.34 (m, 1H), 7.08-7.03 (m, 2H), 6.98-6.93 (m, 2H), 6.92 (q, J=1.4, 0.8 Hz, 1H), 6.88 (dt, J=8.3, 2.0 Hz, 1H), 4.22 (s, 2H), 3.69 (d, J=12.5 Hz, 2H), 2.83 (tt, J=6.8, 4.3 Hz, 1H), 2.73-2.60 (m, 2H), 2.46 (d, J=3.2 Hz, 1H), 1.93-1.82 (m, 2H), 1.57 (qd, J=12.5, 4.1 Hz, 2H), 0.79-0.65 (m, 4H). Mass (m/z): 473.2 [M+H]+.
The title compound 210 (32.4 mg) was prepared in a yield of 18.96% as a pale yellow powder from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (100 mg, 0.41 mmol) and 5-bromo-2-isopropylisoindolin-1-one (104 mg, 0.41 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.51 (dd, J=8.4, 0.9 Hz, 1H), 7.29 (dt, J=15.2, 7.2 Hz, 2H), 7.14-7.10 (m, 2H), 7.04-6.99 (m, 3H), 4.33 (s, 2H), 3.74-3.63 (m, 2H), 2.74-2.66 (m, 2H), 2.30 (dtt, J=15.8, 7.6, 3.9 Hz, 1H), 1.98 (d, J=12.6 Hz, 2H), 1.74 (td, J=12.5, 4.3 Hz, 3H), 1.28 (dd, J=6.8, 1.1 Hz, 6H). Mass (m/z): 418.7 [M+H]+.
The title compound 211 (35.6 mg) was prepared in a yield of 20.3% as a yellow powder from 4-(4,4-dimethylpiperidin-1-yl)aniline (107 mg, 0.5 mmol), 5-bromo-2-methylisoindolin-1-one (87 mg, 0.38 mmol), Pd(dppf)Cl2 (5.6 mg, 7.6 umol), Xantphos (8.8 mg, 15.2 umol), Cs2CO3 (245 mg, 0.75 mmol) and 1,4-dioxane (3.0 mL) according to the procedure for compound 1. (35.6 mg, 20.3%). 1H NMR (400 MHz, Methanol-d4) δ 7.49 (d, J=8.4 Hz, 1H), 7.13-7.08 (m, 2H), 7.02-6.96 (m, 3H), 6.92 (dd, J=8.4, 2.1 Hz, 1H), 4.33 (s, 2H), 3.15-3.05 (m, 7H), 1.57-1.52 (m, 4H), 1.00 (s, 6H). Mass (m/z): 350.3 [M+H]+.
The title compound 212(17.7 mg) was prepared in a total yield of 86.8% as a yellow solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (15.9 mg, 0.065 mmol), 5-bromo-7-fluoro-2-methylisoindolin-1-one (12.2 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Chloroform-d) δ 7.10 (d, J=8.4 Hz, 2H), 6.94 (d, J=8.4 Hz, 2H), 6.82-6.76 (m, 2H), 4.22 (s, 2H), 3.77-3.66 (m, 2H), 3.09 (s, 3H), 2.78-2.62 (m, 2H), 2.17 (m, 1H), 2.04-1.95 (m, 2H), 1.83-1.71 (m, 2H). Mass (m/z): 408.2 [M+H]+.
The title compound 213 (18.6 mg) was prepared in a total yield of 87.9% as a yellow solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (15.9 mg, 0.065 mmol), 5-bromo-7-chloro-2-methylisoindolin-1-one (13.0 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Chloroform-d) δ 7.13-7.07 (m, 2H), 6.99-6.92 (m, 2H), 6.84-6.77 (m, 2H), 4.23 (s, 2H), 3.72-3.64 (m, 2H), 3.08 (s, 3H), 2.75-2.63 (m, 2H), 2.19 (m, 1H), 2.01-1.93 (d, J=3.8 Hz, 2H), 1.80-1.66 (m, 2H). Mass (m/z): 424.1 [M+H]+.
The title compound 214 (16.2 mg) was prepared in a total yield of 79.4% as a yellow solid from 3-fluoro-4-(4-(trifluoromethyl)piperidin-1-yl)aniline (17.0 mg, 0.065 mmol), 5-bromo-2-methylisoindolin-1-one (11.3 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Chloroform-d) δ 7.62 (d, J=8.4 Hz, 1H), 7.02-6.85 (m, 4H), 6.51 (s, 1H), 4.25 (s, 2H), 3.54-3.41 (m, 2H), 3.13 (s, 3H), 2.71-2.62 (m, 2H), 2.14 (m, 1H), 2.01-1.92 (m, 2H), 1.89-1.76 (m, 2H). Mass (m/z): 408.2 [M+H]+.
The title compound 215 (23.5 mg) was prepared in a yield of 12.72% as a pale yellow powder from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (100 mg, 0.41 mmol) and 5-bromo-2-(3,3-difluoroallyl)isoindolin-1-one (118 mg, 0.41 mmol) according to the procedure for compound 1. 1H NMR (DMSO-d6) δ: 8.35 (s, 1H), 7.42 (d, J=8.3 Hz, 1H), 7.12-7.02 (m, 2H), 7.01-6.93 (m, 3H), 6.90 (dd, J=8.4, 2.1 Hz, 1H), 4.76 (dtd, J=26.2, 7.7, 2.3 Hz, 1H), 4.30 (s, 2H), 4.07 (dt, J=7.7, 1.9 Hz, 2H), 3.69 (d, J=12.1 Hz, 2H), 2.66 (td, J=12.5, 2.5 Hz, 2H), 2.45 (td, J=12.4, 10.5, 6.3 Hz, 1H), 1.88 (d, J=12.3 Hz, 2H), 1.57 (qd, J=12.5, 4.1 Hz, 2H). 19F NMR (DMSO-d6) δ : −72.49 (d, J=8.8 Hz), −86.58 (d, J=2.2 Hz), −86.69 (d, J=2.2 Hz), −88.75, −88.84 (d, J=15.8 Hz), −88.93. Mass (m/z): 452.3 [M+H]+.
The title compound 216 (18.4 mg) was prepared in a total yield of 72.3% as a yellow solid from 3-fluoro-4-(4-(trifluoromethyl)piperidin-1-yl)aniline (17.0 mg, 0.065 mmol), tert-butyl 6-bromo-2-methyl-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate (16.4 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.57 (d, J=8.4 Hz, 1H), 7.38 (s, 1H), 7.07-6.95 (m, 3H), 6.85 (d, J=8.4 Hz, 1H), 3.53 (s, 3H), 3.48-3.42 (m, 2H), 2.76-2.66 (m, 2H), 2.24 (m, 1H), 2.02-1.93 (m, 2H), 1.83-1.72 (m, 2H), 1.56 (s, 9H). Mass (m/z): 509.3 [M+H]+.
The title compound 217 (13.6 mg) was prepared in a total yield of 85.0% as a yellow solid from 4-(piperidin-1-yl)aniline (11.4 mg, 0.065 mmol), 5-bromo-2-methylisoindolin-1-one (11.3 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Chloroform-d) δ 7.53 (d, J=8.4 Hz, 1H), 7.04 (d, J=8.8 Hz, 2H), 6.94-6.76 (m, 4H), 4.15 (s, 2H), 3.67-3.61 (m, 2H), 3.13-3.02 (m, 5H), 1.74-1.65 (m, 4H), 1.59-1.46 (m, 2H). Mass (m/z): 322.2 [M+H]+.
The title compound 218 (17.8 mg) was prepared in a total yield of 85.2% as a yellow solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (15.9 mg, 0.065 mmol), 6-bromo-1-ethyl-2-methyl-1,2-dihydro-3H-indazol-3-one (12.8 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.45 (d, J=8.8 Hz, 1H), 7.06 (d, J=8.8 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H), 6.67 (d, J=8.8 Hz, 1H), 6.59 (s, 1H), 3.72 (q, J=6.8 Hz, 2H), 3.63-3.55 (m, 2H), 3.26 (s, 3H), 2.67-2.46 (m, 2H), 2.17 (m, 1H), 1.94-1.81 (m, 2H), 1.69-1.56 (m, 2H), 0.75 (t, J=6.8 Hz, 3H). Mass (m/z): 419.2 [M+H]+.
The title compound 219 (8.9 mg) was prepared in a total yield of 87.0% as a yellow solid from tert-butyl 6-((3-fluoro-4-(4-(trifluoromethyl) piperidin-1-yl) phenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate (12.7 mg, 0.025 mmol) and HCl in 1,4-dioxane according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.52 (d, J=8.8 Hz, 1H), 7.05-6.88 (m, 3H), 6.79-6.72 (m, 2H), 3.46-3.35 (m, 5H), 2.73-2.64 (m, 2H), 2.26 (m, 1H), 2.01-1.89 (m, 2H), 1.81-1.68 (m, 2H). Mass (m/z): 409.2 [M+H]+.
The title compound 220 (32.9 mg) was prepared in a yield of 19.87% as a pale blue powder from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (100 mg, 0.41 mmol) and 5-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (99 mg, 0.41 mmol) according to the procedure for compound 1. 1H NMR (Methanol-d4) δ 7.13-6.85 (m, 8H), 3.61 (dddd, J=24.5, 12.6, 5.5, 3.1 Hz, 4H), 3.15 (pd, J=6.7, 4.3 Hz, 1H), 2.74-2.60 (m, 3H), 2.32-2.14 (m, 2H), 1.82-1.65 (m, 2H), 1.16-1.05 (m, 2H), 0.96 (t, J=7.3 Hz, 1H). Mass (m/z): 405.4 [M+H]+.
The title compound 221 (14.6 mg) was prepared in a yield of 7.56% as a pale yellow powder from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (100 mg, 0.41 mmol) and 5-bromo-2-(4-methylcyclohexyl)isoindolin-1-one (126 mg, 0.41 mmol) according to the procedure for compound 1. 1H NMR (Methanol-d4) δ 7.86-6.26 (m, 7H), 4.07 (s, 2H), 1.97 (d, J=17.1 Hz, 3H), 1.87-1.65 (m, 8H), 1.64-1.47 (m, 5H), 1.13 (q, J=13.9, 13.1 Hz, 1H), 1.02 (dd, J=7.2, 2.4 Hz, 2H), 0.98-0.77 (m, 2H). Mass (m/z): 472.3 [M+H]+.
The title compound 222 (17.6 mg) was prepared in a total yield of 21.2% as a white solid from 4-(3-(trifluoromethyl)pyrrolidin-1-yl)aniline (66 mg, 0.288 mmol), 5-bromo-2-ethylisoindolin-1-one (50 mg, 0.221 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (109 mg, 0.332 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.34 (d, J=8.4 Hz, 1H), 7.03 (d, J=8.4 Hz, 2H), 6.88-6.75 (m, 2H), 6.61 (d, J=8.4 Hz, 2H), 4.24 (s, 2H), 3.47 (t, J=8.8 Hz, 1H), 3.39-3.33 (m, 1H), 3.32-3.23 (m, 3H), 2.95 (s, 3H), 2.25 (dtd, J=12.8, 7.6, 5.0 Hz, 1H), 2.11-1.99 (m, 1H). Mass (m/z): 376.3 [M+H]+.
The title compound 223 (21.9 mg) was prepared in a total yield of 31.0% as a white solid from 4-(3,3-dimethylazetidin-1-yl)aniline (51 mg, 0.288 mmol), 5-bromo-2-ethylisoindolin-1-one (50 mg, 0.221 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (109 mg, 0.332 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H), 7.34 (d, J=8.4 Hz, 1H), 6.98 (d, J=8.4 Hz, 2H), 6.84-6.76 (m, 2H), 6.41-6.34 (m, 2H), 4.24 (s, 2H), 3.46 (s, 3H), 3.32 (s, 1H), 2.95 (s, 3H), 1.25 (s, 6H). Mass (m/z): 322.3 [M+H]+.
The title compound 224 (13.4 mg) was prepared in a total yield of 66.3% as a yellow solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (15.9 mg, 0.065 mmol), 6-bromo-1,2-dimethyl-1,2-dihydro-3H-indazol-3-one (12.1 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.52 (d, J=8.8 Hz, 1H), 7.24-6.53 (m, 6H), 3.75-3.62 (m, 2H), 3.35 (s, 3H), 3.16 (s, 3H), 2.78-2.63 (s, 2H), 2.18 (m, 1H), 2.03-1.93 (m, 2H), 1.83-1.66 (m, 2H). Mass (m/z): 405.2 [M+H]+.
The title compound 225(12.5 mg) was prepared in a total yield of 70.4% as a yellow solid from 3-chloro-4-(piperidin-1-yl)aniline (13.7 mg, 0.065 mmol), 5-bromo-2-methylisoindolin-1-one (11.3 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.54 (d, J=8.4 Hz, 1H), 7.17 (s 1H), 7.09-6.93 (m, 4H), 4.30 (s, 2H), 3.11 (s, 3H), 2.95-2.87 (m, 4H), 1.77-1.67 (m, 4H), 1.60-1.51 (m, 2H). Mass (m/z): 356.1 [M+H]+.
The title compound 226 (33.5 mg) was prepared in a total yield of 37.8% as a yellow solid from 3,5-dimethylaniline (52.2 mg, 0.43 mmol), 5-bromo-2-methylisoindolin-1-one (75 mg, 0.33 mmol), Pd(dppf)Cl2 (4.8 mg, 6.6 umol), Xantphos (7.6 mg, 13.2 umol), and Cs2CO3 (163 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.53 (dd, J=8.4, 1.4 Hz, 1H), 7.11 (s, 1H), 7.02 (dt, J=8.4, 1.8 Hz, 1H), 6.80 (s, 2H), 6.64 (s, 1H), 4.37 (s, 2H), 3.13 (d, J=1.4 Hz, 3H), 2.26 (d, J=1.3 Hz, 6H). Mass (m/z): 267.2 [M+H]+.
The title compound 227 (41.1 mg) was prepared in a total yield of 43.9% as a yellow solid from N,N-dimethyl-p-phenylenediamine (58.0 mg, 0.43 mmol), 5-bromo-2-methylisoindolin-1-one (75 mg, 0.33 mmol), Pd(dppf)Cl2 (4.8 mg, 6.6 umol), Xantphos (7.6 mg, 13.2 umol), and Cs2CO3 (161 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.48 (d, J=8.3 Hz, 1H), 7.11-7.05 (m, 2H), 6.93-6.76 (m, 5H), 4.32 (s, 2H), 3.11 (s, 3H), 2.90 (s, 6H). Mass (m/z): 282.2 [M+H]+.
The title compound 228 (33.6 mg) was prepared in a total yield of 32.0% as a yellow solid from 4-aminobiphenyl (73.0 mg, 0.43 mmol), 5-bromo-2-methylisoindolin-1-one (75 mg, 0.33 mmol), Pd(dppf)Cl2 (4.8 mg, 6.6 umol), Xantphos (7.6 mg, 13.2 umol), and Cs2CO3 (161 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.62-7.54 (m, 5H), 7.44-7.37 (m, 2H), 7.31-7.21 (m, 4H), 7.12 (dd, J=8.3, 2.0 Hz, 1H), 4.40 (s, 2H), 3.15 (s, 3H). Mass (m/z): 315.3 [M+H]+.
The title compound 229 (47.4 mg) was prepared in a total yield of 32.0% as a yellow solid from 1,4-benzodioxan-6-amine (65.0 mg, 0.43 mmol), 5-bromo-2-methylisoindolin-1-one (75 mg, 0.33 mmol), Pd(dppf)Cl2 (4.8 mg, 6.6 umol), Xantphos (7.6 mg, 13.2 umol), and Cs2CO3 (161 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.50 (dd, J=8.3, 0.6 Hz, 1H), 7.00-6.97 (m, 1H), 6.92 (dd, J=8.4, 2.0 Hz, 1H), 6.78 (d, J=8.4 Hz, 1H), 6.69-6.62 (m, 2H), 4.34 (s, 2H), 4.26-4.16 (m, 4H), 3.12 (s, 3H). Mass (m/z): 297.2 [M+H]+.
The title compound 230 (38.6 mg) was prepared in a total yield of 41.1% as a yellow solid from 2-Chloro-5-methylaniline (61.0 mg, 0.43 mmol), 5-bromo-2-methylisoindolin-1-one (75 mg, 0.33 mmol), Pd(dppf)Cl2 (4.8 mg, 6.6 umol), Xantphos (7.6 mg, 13.2 umol), and Cs2CO3 (161 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.59-7.55 (m, 1H), 7.32-7.26 (m, 1H), 7.22 (s, 1H), 7.07-7.00 (m, 1H), 6.89-6.83 (m, 1H), 4.38 (s, 2H), 3.14 (s, 3H), 2.29 (s, 3H). Mass (m/z): 287.1 [M+H]+.
The title compound 231 (30.6 mg) was prepared in a total yield of 32.9% as a yellow solid from 2-Methoxy-5-methylaniline (59.0 mg, 0.43 mmol), 5-bromo-2-methylisoindolin-1-one (75 mg, 0.33 mmol), Pd(dppf)2Cl2 (4.8 mg, 6.6 umol), Xantphos (7.6 mg, 13.2 umol), and Cs2CO3 (161 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.52 (dd, J=7.9, 1.0 Hz, 1H), 7.13 (d, J=2.1 Hz, 1H), 7.05-6.98 (m, 2H), 6.89 (d, J=8.2 Hz, 1H), 6.83-6.79 (m, 1H), 4.34 (s, 2H), 3.81 (s, 3H), 3.12 (s, 3H), 2.26 (s, 3H). Mass (m/z): 283.2 [M+H]+.
The title compound 232 (26.5 mg) was prepared in a total yield of 21.9% as a yellow solid from 4-(4-Chlorophenoxy)aniline (94.0 mg, 0.43 mmol), 5-bromo-2-methylisoindolin-1-one (75 mg, 0.33 mmol), Pd(dppf)2Cl2 (4.8 mg, 6.6 umol), Xantphos (7.6 mg, 13.2 umol), and Cs2CO3 (161 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.55 (d, J=8.4 Hz, 1H), 7.36-7.28 (m, 2H), 7.24-7.19 (m, 2H), 7.12-7.09 (m, 2H), 7.04-6.92 (m, 5H), 4.37 (s, 2H), 3.13 (s, 3H). Mass (m/z): 365.1 [M+H]+.
The title compound 233 (31.7 mg) was prepared in a total yield of 34.2% as a yellow solid from imidazo[1,2-a]pyridin-6-amine (94.0 mg, 0.43 mmol), 5-bromo-2-methylisoindolin-1-one (75 mg, 0.33 mmol), Pd(dppf)2Cl2 (4.8 mg, 6.6 umol), Xantphos (7.6 mg, 13.2 umol), and Cs2CO3 (161 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 8.43-8.40 (m, 1H), 7.84 (d, J=1.4 Hz, 1H), 7.64-7.55 (m, 3H), 7.34 (dt, J=9.6, 1.9 Hz, 1H), 7.13-7.08 (m, 1H), 7.07-7.01 (m, 1H), 4.39 (s, 2H), 3.14 (s, 3H). Mass (m/z): 279.2 [M+H]+.
The title compound 234 (34.6 mg) was prepared in a total yield of 36.9% as a yellow solid from N,N-dimethyl-m-phenylenediamine (58 mg, 0.43 mmol), 5-bromo-2-methylisoindolin-1-one (75 mg, 0.33 mmol), Pd(dppf)Cl2 (4.8 mg, 6.6 umol), Xantphos (7.6 mg, 13.2 umol), and Cs2CO3 (163 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.54-7.50 (m, 1H), 7.15-7.09 (m, 2H), 7.05 (dd, J=8.5, 1.9 Hz, 1H), 6.60-6.56 (m, 1H), 6.55 (t, J=2.3 Hz, 1H), 6.47-6.41 (m, 1H), 4.36 (s, 2H), 3.13 (s, 3H), 2.91 (d, J=0.8 Hz, 6H). Mass (m/z): 282.2 [M+H]+.
The title compound 235 (29.8 mg) was prepared in a total yield of 31.7% as a yellow solid from N2,N2-dimethylpyridine-2,5-diamine (59 mg, 0.43 mmol), 5-bromo-2-methylisoindolin-1-one (75 mg, 0.33 mmol), Pd(dppf)Cl2 (4.8 mg, 6.6 umol), Xantphos (7.6 mg, 13.2 umol), and Cs2CO3 (163 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.94 (dt, J=2.7, 0.7 Hz, 1H), 7.51-7.42 (m, 2H), 6.84-6.79 (m, 2H), 6.71 (dt, J=9.0, 0.7 Hz, 1H), 4.32 (s, 2H), 3.11 (s, 3H), 3.07 (s, 6H). Mass (m/z): 283.2 [M+H]+.
The title compound 236 (21.7 mg) was prepared in a total yield of 24.4% as a yellow solid from 4,6-dimethylpyridin-3-amine (52 mg, 0.43 mmol), 5-bromo-2-methylisoindolin-1-one (75 mg, 0.33 mmol), Pd(dppf)2Cl2 (4.8 mg, 6.6 umol), Xantphos (7.6 mg, 13.2 umol), and Cs2CO3 (163 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.94 (dt, J=2.7, 0.7 Hz, 1H), 7.51-7.42 (m, 2H), 6.84-6.79 (m, 2H), 6.71 (dt, J=9.0, 0.7 Hz, 1H), 4.32 (s, 2H), 3.11 (s, 3H), 3.07 (s, 6H). Mass (m/z): 268.2 [M+H]+.
The title compound 237 (51.0 mg) was prepared in a total yield of 49.0% as a yellow solid from 4-(2-methoxyethoxy)aniline (72 mg, 0.43 mmol), 5-bromo-2-methylisoindolin-1-one (75 mg, 0.33 mmol), Pd(dppf)Cl2 (4.8 mg, 6.6 umol), Xantphos (7.6 mg, 13.2 umol), and Cs2CO3 (163 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.49 (d, J=8.4 Hz, 1H), 7.15-7.06 (m, 2H), 6.98-6.85 (m, 5H), 4.32 (s, 2H), 4.14-4.04 (m, 2H), 3.76-3.72 (m, 2H), 3.42 (s, 3H), 3.11 (s, 3H). Mass (m/z): 313.3 [M+H]+.
The title compound 238 (24.6 mg) was prepared in a total yield of 23.0% as a yellow solid from 4-(Pyrrolidin-1-ylmethyl)aniline (76 mg, 0.43 mmol), 5-bromo-2-methylisoindolin-1-one (75 mg, 0.33 mmol), Pd(dppf)2Cl2 (4.8 mg, 6.6 umol), Xantphos (7.6 mg, 13.2 umol), and Cs2CO3 (163 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.59 (d, J=8.3 Hz, 1H), 7.46-7.41 (m, 2H), 7.27-7.23 (m, 3H), 7.15 (dd, J=8.4, 2.0 Hz, 1H), 4.40 (s, 2H), 4.30 (s, 2H), 3.37-3.31 (m, 4H), 3.14 (s, 3H), 2.15-2.01 (m, 4H). Mass (m/z): 322.3 [M+H]+.
The title compound 239 (22.7 mg) was prepared in a total yield of 28.7% as a white solid from 4-(4,4-difluoropiperidin-1-yl)aniline (61 mg, 0.288 mmol), 5-bromo-2-ethylisoindolin-1-one (50 mg, 0.221 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol) and Cs2CO3 (109 mg, 0.332 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.63 (d, J=8.4 Hz, 1H), 7.49 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 7.28 (d, J=2.0 Hz, 1H), 7.19 (dd, J=8.4, 2.0 Hz, 1H), 4.43 (s, 2H), 3.77 (s, 1H), 3.61 (d, J=6.4 Hz, 2H), 3.16 (s, 3H), 2.09-1.91 (m, 3H), 1.80 (q, J=11.2, 10.0 Hz, 2H). Mass (m/z): 358.3 [M+H]+.
The title compound 240 (46.4 mg) was prepared in a total yield of 62.7% as a white solid from 4-(2-methylpiperidin-1-yl)aniline (55 mg, 0.288 mmol), 5-bromo-2-ethylisoindolin-1-one (50 mg, 0.221 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (109 mg, 0.332 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.63 (d, J=8.4 Hz, 1H), 7.49 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 7.28 (d, J=2.0 Hz, 1H), 7.19 (dd, J=8.4, 2.0 Hz, 1H), 4.43 (s, 2H), 3.77 (s, 1H), 3.61 (d, J=6.4 Hz, 2H), 3.16 (s, 3H), 2.16 (d, J=10.0 Hz, 1H), 2.09-1.91 (m, 3H), 1.80 (q, J=11.2, 10.0 Hz, 2H), 1.11 (d, J=6.4 Hz, 3H). Mass (m/z): 336.3 [M+H]+.
The title compound 241 (32.5 mg) was prepared in a total yield of 43.9% as a white solid from 4-(3-methylpiperidin-1-yl)aniline (55 mg, 0.288 mmol), 5-bromo-2-ethylisoindolin-1-one (50 mg, 0.221 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (109 mg, 0.332 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.63 (d, J=8.4 Hz, 1H), 7.49 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 7.28 (d, J=2.0 Hz, 1H), 7.19 (dd, J=8.4, 2.0 Hz, 1H), 4.43 (s, 2H), 3.77 (s, 1H), 3.61 (d, J=6.4 Hz, 2H), 3.16 (s, 3H), 2.16 (d, J=10.0 Hz, 1H), 2.09-1.91 (m, 3H), 1.80 (q, J=11.2, 10.0 Hz, 2H), 1.11 (d, J=6.4 Hz, 3H). Mass (m/z): 336.3 [M+H]+.
The title compound 242 (16.9 mg) was prepared in a total yield of 19.7% as a white solid from 4-(3-(trifluoromethyl)piperidin-1-yl)aniline (70 mg, 0.288 mmol), 5-bromo-2-ethylisoindolin-1-one (50 mg, 0.221 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (109 mg, 0.332 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.63 (d, J=8.4 Hz, 1H), 7.49 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 7.28 (d, J=2.0 Hz, 1H), 7.19 (dd, J=8.4, 2.0 Hz, 1H), 4.43 (s, 2H), 3.77 (s, 1H), 3.61 (d, J=6.4 Hz, 2H), 3.16 (s, 3H), 2.16 (d, J=10.0 Hz, 1H), 2.09-1.91 (m, 3H), 1.80 (q, J=11.2, 10.0 Hz, 2H). Mass (m/z): 390.3 [M+H]+.
The title compound 243 (49.0 mg) was prepared in a total yield of 52.9% as a white solid from 3-methoxy-4-(4-(trifluoromethyl)piperidin-1-yl)aniline (79 mg, 0.288 mmol), 5-bromo-2-ethylisoindolin-1-one (50 mg, 0.221 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (109 mg, 0.332 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, Chloroform-d) δ 7.55 (d, J=8.0 Hz, 1H), 6.90-6.79 (m, 3H), 6.68 (dd, J=8.4, 2.4 Hz, 1H), 6.62 (d, J=2.4 Hz, 1H), 4.16 (s, 2H), 3.74 (s, 3H), 3.45 (d, J=11.2 Hz, 2H), 3.05 (s, 3H), 2.56-2.42 (m, 2H), 2.07 (tdt, J=11.6, 7.6, 3.6 Hz, 1H), 1.92-1.75 (m, 4H). Mass (m/z): 420.3 [M+H]+.
The title compound 244 (35.5 mg) was prepared in a total yield of 48.2% as a white solid from 4-(2-azaspiro[3.3]heptan-2-yl)aniline (54 mg, 0.288 mmol), 5-bromo-2-ethylisoindolin-1-one (50 mg, 0.221 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (109 mg, 0.332 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, Chloroform-d) δ 7.57 (d, J=8.4 Hz, 1H), 7.03 (s, 2H), 6.83-6.68 (m, 2H), 6.43 (s, 2H), 5.90 (s, 1H), 4.18 (s, 2H), 3.46 (s, 1H), 3.10 (s, 3H), 2.20 (t, J=7.6 Hz, 4H), 1.93-1.83 (m, 2H). Mass (m/z): 334.3 [M+H]+.
The title compound 245 (32.9 mg) was prepared in a total yield of 44.6% as a white solid from 4-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)aniline (54 mg, 0.288 mmol), 5-bromo-2-ethylisoindolin-1-one (50 mg, 0.221 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (109 mg, 0.332 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, Chloroform-d) δ 7.62-7.52 (m, 1H), 7.03 (s, 2H), 6.73 (s, 3H), 6.52 (s, 1H), 4.17 (s, 3H), 3.47 (s, 1H), 3.10 (s, 3H), 2.59 (s, 1H), 1.85-1.64 (m, 4H), 1.50 (s, 1H), 1.41-1.31 (m, 1H). Mass (m/z): 334.3 [M+H]+.
The title compound 246 (35.5 mg) was prepared in a total yield of 43.7% as a purple solid from 4-(2-azaspiro[3.4]octan-2-yl)aniline (56 mg, 0.288 mmol), 5-bromo-2-ethylisoindolin-1-one (50 mg, 0.221 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (109 mg, 0.332 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, Chloroform-d) δ 7.57 (d, J=8.4 Hz, 1H), 7.03 (s, 2H), 6.83-6.68 (m, 2H), 6.43 (s, 2H), 5.90 (s, 1H), 4.18 (s, 2H), 3.46 (s, 1H), 3.10 (s, 3H), 2.56-2.42 (m, 2H), 2.20 (t, J=7.6 Hz, 4H), 1.93-1.83 (m, 2H). Mass (m/z): 348.3 [M+H]+.
The title compound 247 (24.8 mg) was prepared in a yield of 35.45% as a pale yellow powder from 4-(4,4-dimethylpiperidin-1-yl)aniline (32 mg, 0.16 mmol) and 5-bromo-2-(1-methylpiperidin-4-yl)isoindolin-1-one (50 mg, 0.16 mmol) according to the procedure for compound 1. 1H NMR (Methanol-d4) δ 7.51 (d, J=8.4 Hz, 1H), 7.11 (s, 2H), 6.97 (d, J=29.5 Hz, 4H), 4.37 (s, 2H), 4.30 (ddt, J=11.9, 8.1, 4.2 Hz, 2H), 3.52 (dt, J=12.4, 2.5 Hz, 2H), 3.22-3.00 (m, 5H), 2.82 (s, 3H), 2.16 (qd, J=13.1, 4.0 Hz, 2H), 2.08-1.96 (m, 2H), 1.55 (t, J=5.7 Hz, 4H), 1.00 (s, 6H). Mass (m/z): 433.5 [M+H]+.
The title compound 248 (24.5 mg) was prepared in a yield of 25.49% as a pale yellow powder from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (50 mg, 0.20 mmol) and 5-bromo-2-((1-methyl-1H-imidazol-5-yl) methyl)isoindolin-1-one (63 mg, 0.20 mmol) according to the procedure for compound 1. 1H NMR (Methanol-d4) δ 7.94 (s, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.18-7.09 (m, 3H), 7.05-6.94 (m, 4H), 4.83 (s, 2H), 4.26 (s, 2H), 3.74 (s, 5H), 2.71 (t, J=12.0 Hz, 2H), 2.35 (dtd, J=12.3, 8.4, 3.8 Hz, 1H), 1.98 (d, J=13.1 Hz, 2H), 1.71 (qd, J=12.5, 4.1 Hz, 2H). Mass (m/z): 470.3 [M+H]+.
The title compound 249 (19.6 mg) was prepared in a yield of 28.96% as a pale yellow powder from 4-(4-methylpiperidin-1-yl)aniline (30 mg, 0.16 mmol) and 5-bromo-2-(1-methylpiperidin-4-yl)isoindolin-1-one (50 mg, 0.16 mmol) according to the procedure for compound 1. 1H NMR (Methanol-d4) δ: 7.51 (d, J=8.4 Hz, 1H), 7.14-7.08 (m, 2H), 7.05-6.97 (m, 3H), 6.94 (dd, J=8.5, 2.0 Hz, 1H), 4.37 (s, 2H), 4.28 (ddt, J=11.9, 8.3, 4.0 Hz, 1H), 3.55 (d, J=12.0 Hz, 2H), 3.45 (d, J=12.6 Hz, 2H), 2.96 (td, J=12.6, 2.9 Hz, 2H), 2.76 (s, 3H), 2.65 (s, 2H), 2.13 (qd, J=12.8, 3.7 Hz, 2H), 2.05-1.94 (m, 2H), 1.76 (dd, J=13.0, 3.0 Hz, 2H), 1.61-1.42 (m, 1H), 1.44-1.25 (m, 3H), 0.99 (d, J=6.4 Hz, 3H). Mass (m/z): 419.3 [M+H]+.
The title compound 250 (15.6 mg) was prepared in a total yield of 89.1% as a yellow solid from 4-(4-methylpiperidin-1-yl)aniline (12.4 mg, 0.065 mmol), 6-bromo-1,2-dimethyl-1,2-dihydro-3H-indazol-3-one (12.1 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (300 MHz, Chloroform-d) δ 7.46 (m, 1H), 7.15-6.45 (m, 6H), 3.83 (s, 3H), 3.63-3.45 (m, 2H), 3.05 (s, 3H), 2.76-2.48 (m, 2H), 1.76-1.28 (m, 5H), 0.90 (d, J=5.7 Hz, 3H). Mass (m/z): 351.2 [M+H]+.
The title compound 251 (30.7 mg) was prepared in a total yield of 91.1% as a yellow solid from tert-butyl 2-methyl-6-((4-(4-methylpiperidin-1-yl)phenyl)amino)-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate (43.6 mg, 0.1 mmol) and HCl in 1,4-dioxane according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.71-7.59 (m, 3H), 7.41-7.33 (m, 2H), 7.01-6.94 (m, 2H), 3.72-3.61 (m, 7H), 2.13-2.01 (m, 2H), 1.91 (m, 1H), 1.83-1.72 (m, 2H), 1.10 (d, J=6.4 Hz, 3H). Mass (m/z): 337.2 [M+H]+.
The title compound 252 (18.3 mg) was prepared in a total yield of 90.6% as a yellow solid from tert-butyl 2-ethyl-3-oxo-6-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)-2,3-dihydro-1H-indazole-1-carboxylate (25.2 mg, 0.05 mmol) and HCl in 1,4-dioxane according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.68-7.60 (m, 3H), 7.38-7.33 (m, 2H), 7.00-6.90 (m, 2H), 3.98 (q, J=7.2 Hz, 2H), 3.85-3.65 (m, 4H), 2.80 (m, 1H), 2.34-2.26 (m, 2H), 2.23-2.11 (m, 2H), 1.37 (t, J=7.2 Hz, 3H). Mass (m/z): 405.2 [M+H]+.
The title compound 253 (19.1 mg) was prepared in a total yield of 87.4% as a red solid from 4-(4-methylpiperidin-1-yl)aniline (12.4 mg, 0.065 mmol), 1-(6-bromo-4-chloroisoindolin-2-yl)-2,2,2-trifluoroethan-1-one (16.4 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Chloroform-d) δ 7.33-6.78 (m, 6H), 4.90 (s, 2H), 4.78 (s, 2H), 3.74-3.65 (m, 2H), 2.79-2.67 (m, 2H), 1.91-1.70 (m, 2H), 1.55 (m, 1H), 1.47-1.36 (m, 2H), 1.02 (d, J=6.4 Hz, 3H). Mass (m/z): 438.1 [M+H]+.
The title compound 254 (13.4 mg) was prepared in a total yield of 76.4% as a white solid from 4-(2,5-dimethylpyrrolidin-1-yl)aniline (12.4 mg, 0.065 mmol), 5-bromo-2-methylisoindoline-1,3-dione (12.0 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.61-6.57 (m, 7H), 3.55-3.51 (m, 2H), 3.45 (s, 3H), 3.37 (s, 3H), 2.16-1.67 (m, 4H), 1.15 (d, J=6.4 Hz, 6H). Mass (m/z): 351.2 [M+H]+.
The title compound 255 (18.7 mg) was prepared in a total yield of 83.5% as a red solid from 4-(4-methylpiperidin-1-yl)aniline (12.4 mg, 0.065 mmol), 1-(6-bromo-4-nitroisoindolin-2-yl)-2,2,2-trifluoroethan-1-one (16.9 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.65-6.81 (m, 6H), 4.94 (s, 2H), 4.79 (s, 2H), 3.51-3.40 (m, 2H), 2.72-2.66 (m, 2H), 1.79-1.68 (m, 2H), 1.48 (m, 1H), 1.43-1.31 (m, 2H), 0.99 (d, J=6.4 Hz, 3H). Mass (m/z): 449.3 [M+H]+.
The title compound 256 (11.3 mg) was prepared in a total yield of 66.7% as a white solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (15.9 mg, 0.065 mmol), 6-bromo-3-methylbenzo[d]oxazol-2(3H)-one (11.4 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.21-6.78 (m, 7H), 3.68-3.57 (m, 2H), 3.35 (s, 3H), 2.75-2.57 (m, 2H), 2.27 (m, 1H), 2.03-1.93 (m, 2H), 1.83-1.67 (m, 2H). Mass (m/z): 392.1 [M+H]+.
The title compound 257 (28.7 mg) was prepared in a total yield of 88.9% as a white solid from tert-butyl 2-methyl-3-oxo-6-((4-(piperidin-1-yl) phenyl)amino)-2,3-dihydro-1H-indazole-1-carboxylate (42.2 mg, 0.1 mmol) and HCl according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.61-6.81 (m, 7H), 3.26 (s, 3H), 2.96-2.85 (m, 4H), 1.93-1.74 (m, 4H), 1.68-1.57 (m, 2H). Mass (m/z): 323.2 [M+H]+.
The title compound 258 (10.4 mg) was prepared in a yield of 11.06% as a pale yellow powder from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (50 mg, 0.20 mmol) and 5-bromo-2-(tetrahydro-2H-pyran-4-yl)isoindolin-1-one (60 mg, 0.20 mmol) according to the procedure for compound 1. 1H NMR (DMSO-d6) δ 8.30 (s, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.05 (d, J=8.9 Hz, 2H), 6.95 (dd, J=9.0, 2.5 Hz, 3H), 6.89 (dd, J=8.3, 2.0 Hz, 1H), 4.30 (s, 2H), 4.24-4.12 (m, 2H), 3.95-3.87 (m, 2H), 3.68 (d, J=12.3 Hz, 2H), 3.42 (t, J=11.6 Hz, 2H), 2.62 (s, 2H), 1.88 (d, J=13.2 Hz, 2H), 1.82-1.68 (m, 2H), 1.64-1.51 (m, 4H). Mass (m/z): 460.3 [M+H]+.
The title compound 259 (30.7 mg) was prepared in a total yield of 91.1% as a white solid from tert-butyl 6-((4-(2,5-dimethylpyrrolidin-1-yl) phenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate (43.6 mg, 0.1 mmol) and HCl according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.77-7.18 (m, 5H), 6.89-6.78 (m, 2H), 4.04-3.83 (m, 2H), 3.37 (s, 3H), 2.37-2.31 (m, 2H), 1.98-1.89 (m, 2H), 1.25 (d, J=6.4 Hz, 6H). Mass (m/z): 337.2 [M+H]+.
The title compound 260 (11.3 mg) was prepared in a total yield of 12.3% as a yellow solid from N1-ethyl-N1-pentylbenzene-1,4-diamine (67 mg, 0.33 mmol), 5-bromo-1,3-dimethyl-2,3-dihydro-1H-1,3-benzodiazol-2-one (60 mg, 0.25 mmol), Pd(dppf)Cl2 (3.7 mg, 5 umol), Xantphos (5.8 mg, 10.0 umol), and Cs2CO3 (122 mg, 0.38 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.72-6.81 (m, 8H), 3.65-3.29 (m, 10H), 1.49-1.15 (m, 4H), 1.07-0.99 (m, 2H), 0.93-0.77 (m, 6H). Mass (m/z): 367.3 [M+H]+.
The title compound 261 (39.9 mg) was prepared in a total yield of 31.0% as a white solid from 4-(tert-butyl)aniline (80 mg, 0.542 mmol), 5-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (100 mg, 0.417 mmol), Pd2(dba)3 (4 mg, 0.004 mmol), X-phos (12 mg, 0.02 mmol), Cs2CO3 (205 mg, 0.625 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.20 (d, J=8.4 Hz, 2H), 7.00 (d, J=8.4 Hz, 1H), 6.94 (d, J=8.4 Hz, 2H), 6.87 (d, J=2.0 Hz, 1H), 6.78 (dd, J=8.4, 2.0 Hz, 1H), 3.28 (d, J=7.6 Hz, 6H), 1.24 (s, 9H). Mass (m/z): 310.3 [M+H]+.
The title compound 262 (8.3 mg) was prepared in a total yield of 6.8% as a gray powder from N1-ethyl-N1-(3-methoxypropyl)benzene-1,4-diamine (89 mg, 0.43 mmol), 5-bromo-1,3-dimethyl-2,3-dihydro-1H-1,3-benzodiazol-2-one (80 mg, 0.33 mmol), Pd(dppf)Cl2 (4.8 mg, 6.6 umol), Xantphos (7.6 mg, 13.2 umol), and Cs2CO3 (163 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.75-6.69 (m, 8H), 3.65-3.29 (m, 15H), 1.10-1.02 (m, 2H), 0.93-0.77 (m, 3H). Mass (m/z): 369.2 [M+H]+.
The title compound 263 (21.4 mg) was prepared in a total yield of 16.9% as a pink powder from 2-fluoro-3-methyl-4-(4-methylpiperidin-1-yl)aniline (95 mg, 0.43 mmol), 5-bromo-1,3-dimethyl-2,3-dihydro-1H-1,3-benzodiazol-2-one (80 mg, 0.33 mmol), Pd(dppf)Cl2 (4.8 mg, 6.6 umol), Xantphos (7.6 mg, 13.2 umol), and Cs2CO3 (163 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (301 MHz, Methanol-d4) δ 7.27-6.91 (m, 5H), 3.69-3.49 (m, 4H), 3.42 (s, 3H), 3.39 (s, 3H), 2.43 (s, 3H), 2.10-1.97 (m, 2H), 1.89-1.71 (m, 3H), 1.09 (d, J=5.9 Hz, 3H). Mass (m/z): 383.3 [M+H]+.
The title compound 264 (12.1 mg) was prepared in a total yield of 10.0% as a light pink powder from 5-fluoro-2-methyl-4-(4-methylpiperidin-1-yl)aniline (95 mg, 0.43 mmol), 5-bromo-1,3-dimethyl-2,3-dihydro-1H-1,3-benzodiazol-2-one (80 mg, 0.33 mmol), Pd(dppf)Cl2 (4.8 mg, 6.6 umol), Xantphos (7.6 mg, 13.2 umol), and Cs2CO3 (163 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (300 MHz, Methanol-d4) δ 6.99 (d, J=8.2 Hz, 1H), 6.89 (d, J=9.6 Hz, 1H), 6.79-6.67 (m, 3H), 3.39 (s, 3H), 3.35 (s, 3H), 3.27 (s, 2H), 2.65 (t, J=11.3 Hz, 2H), 2.19 (s, 3H), 1.79-1.71 (m, 2H), 1.50-1.37 (m, 3H), 1.00 (d, J=6.0 Hz, 3H). Mass (m/z): 383.3 [M+H]+.
The title compound 265 (28.9 mg) was prepared in a total yield of 21.8% as a white powder from 5-chloro-2-methyl-4-(4-methylpiperidin-1-yl) aniline (102 mg, 0.43 mmol), 5-bromo-1,3-dimethyl-2,3-dihydro-1H-1,3-benzodiazol-2-one (80 mg, 0.33 mmol), Pd(dppf)Cl2 (4.8 mg, 6.6 umol), Xantphos (7.6 mg, 13.2 umol), and Cs2CO3 (163 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (300 MHz, Methanol-d4) δ 7.14-6.94 (m, 3H), 6.72-6.65 (m, 2H), 3.39 (s, 3H), 3.34 (s, 3H), 3.24 (d, J=11.4 Hz, 2H), 2.62 (t, J=11.4 Hz, 2H), 2.20 (s, 3H), 1.77-1.70 (m, 2H), 1.49-1.37 (m, 3H), 1.01 (d, J=5.9 Hz, 4H). Mass (m/z): 399.3 [M+H]+.
The title compound 266 (28.9 mg) was prepared in a total yield of 21.8% as a white powder from 1-methyl-1H-indol-5-amine (63 mg, 0.43 mmol), 5-bromo-1,3-dimethyl-2,3-dihydro-1H-1,3-benzodiazol-2-one (80 mg, 0.33 mmol), Pd(dppf)Cl2 (4.8 mg, 6.6 umol), Xantphos (7.6 mg, 13.2 umol), and Cs2CO3 (163 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.31 (d, J=7.0 Hz, 1H), 7.30 (s, 1H), 7.12 (d, J=3.0 Hz, 1H), 7.02 (dd, J=8.6, 2.2 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H), 6.80 (dd, J=8.3, 2.1 Hz, 1H), 6.76 (d, J=2.1 Hz, 1H), 6.33 (dd, J=3.0, 0.8 Hz, 1H), 3.80 (s, 3H), 3.39 (s, 3H), 3.34 (s, 3H). Mass (m/z): 307.3 [M+H]+.
The title compound 267 (12.6 mg) was prepared in a total yield of 70.8% as a dim gray powder from 4-(4-methylpiperidin-1-yl)aniline (12.4 mg, 0.065 mmol), 6-bromo-4-chloro-2-methylisoindoline (12.3 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.29 (s, 1H), 7.14-6.86 (m, 5H), 4.30 (s, 2H), 4.24 (s, 2H), 3.65-3.53 (m, 2H), 2.88 (s, 3H), 2.73-2.59 (m, 2H), 1.85-1.73 (m, 2H), 1.52 (m, 1H), 1.44-1.27 (m, 2H), 1.00 (d, J=6.4 Hz, 3H). Mass (m/z): 356.2 [M+H]+.
The title compound 268 (14.1 mg) was prepared in a yield of 14.28% as a pale yellow powder from N1,N1-diethylbenzene-1,4-diamine (50 mg, 0.30 mmol) and 5-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (73 mg, 0.30 mmol) according to the procedure for compound 1. 1H NMR (DMSO-d6) δ 8.41 (s, 1H), 7.61 (s, 1H), 7.40 (s, 1H), 7.06 (s, 2H), 6.97 (s, 1H), 6.52 (s, 1H), 3.53 (m, 4H), 1.24 (s, 6H), 1.17 (d, J=12.0 Hz, 6H). Mass (m/z): 325.6 [M+H]+.
The title compound 269 (27.1 mg) was prepared in a total yield of 15.0% as a white solid from 3-methoxy-4-(4-(trifluoromethyl)piperidin-1-yl)aniline (148 mg, 0.542 mmol), 5-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (100 mg, 0.417 mmol), Pd2(dba)3 (4 mg, 0.004 mmol), X-phos (12 mg, 0.02 mmol), Cs2CO3 (205 mg, 0.625 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, Chloroform-d) δ 7.55 (d, J=8.0 Hz, 1H), 6.90-6.79 (m, 3H), 6.68 (dd, J=8.4, 2.4 Hz, 1H), 6.62 (d, J=2.4 Hz, 1H), 3.89 (d, J=7.6 Hz, 6H), 3.74 (s, 3H), 3.45 (d, J=11.2 Hz, 2H), 2.56-2.42 (m, 2H), 2.07 (tdt, J=11.6, 7.6, 3.6 Hz, 1H), 1.92-1.75 (m, 4H). Mass (m/z): 435.3 [M+H]+.
The title compound 270 (19.4 mg) was prepared in a total yield of 12.1% as a gray solid from 4-(4-methylpiperidin-1-yl)aniline (124 mg, 0.65 mmol), 6-bromo-1-methyl-1H-1,3-benzodiazole (105 mg, 0.50 mmol), Pd(dppf)Cl2 (7.3 mg, 10 umol), Xantphos (11.6 mg, 20 umol), and Cs2CO3 (245 mg, 0.75 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H), 7.89 (s, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.08-7.00 (m, 3H), 6.98-6.82 (m, 3H), 3.77 (s, 3H), 3.55-3.48 (m, 2H), 2.61-2.52 (m, 2H), 1.73-1.65 (m, 2H), 1.53-1.38 (m, 1H), 1.31-1.20 (m, 2H), 0.95 (d, J=6.5 Hz, 3H). Mass (m/z): 321.3 [M+H]+.
The title compound 271 (19.4 mg) was prepared in a total yield of 12.1% as a gray solid from 4-(pyrrolidin-1-yl)aniline (73 mg, 0.45 mmol), 5-bromo-1,3-dimethyl-2,3-dihydro-1H-1,3-benzodiazol-2-one (80 mg, 0.33 mmol), Pd(dppf)2Cl2 (4.8 mg, 6.6 umol), Xantphos (7.6 mg, 13.2 umol), and Cs2CO3 (163 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.86-6.01 (m, 8H), 3.56-3.33 (m, 8H), 3.30-3.14 (m, 2H), 2.11-1.89 (m, 4H). Mass (m/z): 323.2 [M+H]+.
The title compound 272 (2.4 mg) was prepared in a total yield of 2.1% as a gray solid from 2-fluoro-6-methoxy-4-(4-methylpiperidin-1-yl)aniline (90 mg, 0.38 mmol), 5-bromo-1,3-dimethyl-2,3-dihydro-1H-1,3-benzodiazol-2-one (70 mg, 0.29 mmol), Pd(dppf)Cl2 (4.2 mg, 5.8 umol), Xantphos (6.7 mg, 11.6 umol), and Cs2CO3 (142 mg, 0.44 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.18-6.84 (m, 3H), 6.73-6.45 (m, 2H), 4.00-3.89 (m, 2H), 3.49-3.36 (m, 5H), 3.35 (s, 3H), 3.34 (s, 3H), 2.13-1.98 (m, 2H), 1.88-1.76 (m, 1H), 1.68-1.57 (m, 2H), 1.10 (d, J=6.3 Hz, 3H). Mass (m/z): 399.3 [M+H]+.
The title compound 273 (12.6 mg) was prepared in a total yield of 70.8% as a dim gray powder from 4-(4-methylpiperidin-1-yl)aniline (12.4 mg, 0.065 mmol), 6-bromo-3-methylbenzo[d]oxazol-2(3H)-one (11.4 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.58-6.64 (m, 7H), 3.53-3.37 (m, 2H), 3.26 (s, 3H), 2.77-2.63 (m, 2H), 1.87-1.72 (m, 2H), 1.55 (m, 1H), 1.46-1.29 (m, 2H), 1.01 (d, J=6.4 Hz, 3H). Mass (m/z): 338.3 [M+H]+.
The title compound 274 (15.2 mg) was prepared in a total yield of 78.6% as a violet solid from 3,5-difluoro-4-(4-methylpiperidin-1-yl)aniline (14.7 mg, 0.065 mmol), 5-bromo-2-methylisoindoline-1,3-dione (12.0 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.01-6.65 (m, 5H), 3.65-3.56 (m, 2H), 3.39 (s, 3H), 3.35 (s, 3H), 2.76-2.61 (m, 2H), 1.81-1.73 (m, 2H), 1.54 (m, 1H), 1.48-1.35 (m, 3H), 1.01 (d, J=6.4 Hz, 3H). Mass (m/z): 387.2 [M+H]+.
The title compound 275 (15.2 mg) was prepared in a total yield of 78.6% as a violet solid from 3-fluoro-2-methyl-4-(4-methylpiperidin-1-yl)aniline (14.4 mg, 0.065 mmol), 5-bromo-2-methylisoindoline-1,3-dione (12.0 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 6.97 (d, J=8.4 Hz, 1H), 6.87-6.82 (m, 2H), 6.69-6.64 (m, 2H), 3.67-3.55 (m, 2H), 3.38 (s, 3H), 3.33 (s, 3H), 2.70-2.59 (m, 2H), 2.14 (s, 3H), 1.80-1.72 (m, 2H), 1.58-1.35 (m, 3H), 1.01 (d, J=6.4 Hz, 3H). Mass (m/z): 383.2 [M+H]+.
The title compound 276 (14.3 mg) was prepared in a total yield of 81.3% as a white solid from 6-(4-methylpiperidin-1-yl)pyridin-3-amine (12.4 mg, 0.065 mmol), 5-bromo-2-methylisoindoline-1,3-dione (12.0 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.51 (d, J=2.0 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 6.94-6.58 (m, 4H), 4.14-4.05 (m, 2H), 3.31 (s, 3H), 3.26 (s, 3H), 2.72-2.64 (m, 2H), 1.71-1.64 (m, 2H), 1.58 (m, 1H), 1.52-1.43 (m, 2H), 1.11 (d, J=6.4 Hz, 3H). Mass (m/z): 352.2 [M+H]+.
The title compound 277 (13.3 mg) was prepared in a total yield of 78.5% as a gray solid from N1,N1,N3,N3-tetramethylbenzene-1,3,5-triamine (11.6 mg, 0.065 mmol), 5-bromo-2-methylisoindoline-1,3-dione (12.0 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.44-6.57 (m, 6H), 3.39 (s, 3H), 3.36 (s, 3H), 3.22 (s, 12H). Mass (m/z): 340.2 [M+H]+.
The title compound 278 (12.4 mg) was prepared in a total yield of 65.6% as a gray solid from 2,6-dimethyl-4-(4-methylpiperidin-1-yl)aniline (14.2 mg, 0.065 mmol), 5-bromo-2-methylisoindoline-1,3-dione (12.0 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.33-7.05 (m, 2H), 6.83 (s, 1H), 6.26 (s, 1H), 6.05 (s, 1H), 3.66-3.54 (m, 4H), 3.23 (s, 3H), 3.19 (s, 3H), 2.14 (s, 6H), 1.97-1.86 (m, 2H), 1.70 (m, 1H), 1.49-1.39 (m, 2H), 0.98 (d, J=6.4 Hz, 3H). Mass (m/z): 379.3 [M+H]+.
The title compound 279 (9.8 mg) was prepared in a total yield of 12.9% as a blue solid from 4-(2,6-dimethylmorpholino)aniline (56 mg, 0.271 mmol), 5-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (50 mg, 0.208 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (102 mg, 0.312 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.07-6.76 (m, 7H), 3.82 (ddt, J=12.8, 6.4, 3.2 Hz, 2H), 3.44 (s, 2H), 3.40 (s, 3H), 3.36 (s, 3H), 2.38-2.21 (m, 2H), 1.24 (d, J=6.4 Hz, 6H). Mass (m/z): 367.3 [M+H]+.
The title compound 280 (9.2 mg) was prepared in a total yield of 12.1% as a blue solid from 2-methyl-4-(4-methylpiperidin-1-yl)aniline (55 mg, 0.271 mmol), 5-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (50 mg, 0.208 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (102 mg, 0.312 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.00-6.88 (m, 3H), 6.59-6.49 (m, 2H), 3.38 (s, 3H), 3.34 (s, 3H), 3.03 (d, J=11.8 Hz, 2H), 2.79 (t, J=12.4 Hz, 1H), 2.63 (t, J=11.6 Hz, 2H), 2.29 (s, 3H), 1.01 (dd, J=14.8, 6.4 Hz, 4H), 1.02 (d, J=6.0 Hz, 3H). Mass (m/z): 365.3 [M+H]+.
The title compound 281 (5.0 mg) was prepared in a total yield of 6.4% as a yellow solid from 2,3-dimethyl-4-(4-methylpiperidin-1-yl)aniline (59 mg, 0.271 mmol), 5-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (50 mg, 0.208 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (102 mg, 0.312 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.00-6.88 (m, 3H), 6.59-6.49 (m, 2H), 3.38 (s, 3H), 3.34 (s, 3H), 3.03 (d, J=11.8 Hz, 2H), 2.79 (t, J=12.4 Hz, 1H), 2.63 (t, J=11.6 Hz, 2H), 2.29 (s, 3H), 2.16 (S, 3H), 1.01 (dd, J=14.8, 6.4 Hz, 4H), 1.02 (d, J=6.0 Hz, 3H). Mass (m/z): 379.3 [M+H]+.
The title compound 282 (8.7 mg) was prepared in a total yield of 11.5% as a yellow solid from 3-methyl-4-(4-methylpiperidin-1-yl)aniline (55 mg, 0.271 mmol), 5-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (50 mg, 0.208 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (102 mg, 0.312 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.00-6.88 (m, 3H), 6.59-6.49 (m, 2H), 3.38 (s, 3H), 3.34 (s, 3H), 3.03 (d, J=11.8 Hz, 2H), 2.79 (t, J=12.4 Hz, 1H), 2.63 (t, J=11.6 Hz, 2H), 2.16 (S, 3H), 1.01 (dd, J=14.8, 6.4 Hz, 4H), 1.02 (d, J=6.0 Hz, 3H). Mass (m/z): 365.3 [M+H]+.
The title compound 283 (3.9 mg) was prepared in a total yield of 5.1% as a yellow solid from 3-fluoro-4-(4-methylpiperidin-1-yl)aniline (56 mg, 0.271 mmol), 5-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (50 mg, 0.208 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (102 mg, 0.312 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.07-7.03 (m, 1H), 6.98 (t, J=9.3 Hz, 1H), 6.90 (dd, J=6.4, 2.4 Hz, 2H), 6.79-6.72 (m, 2H), 3.42 (s, 3H), 3.39 (s, 3H), 2.66 (t, J=11.2 Hz, 2H), 2.21 (t, J=7.6 Hz, 1H), 2.05 (d, J=6.0 Hz, 1H), 1.76 (d, J=12.4 Hz, 2H), 1.48-1.39 (m, 3H), 1.02 (d, J=6.0 Hz, 3H). Mass (m/z): 369.3 [M+H]+.
The title compound 284 (12.1 mg) was prepared in a yield of 11.12% as a gray powder from N1,N1-dimethylbenzene-1,4-diamine (50 mg, 0.37 mmol) and 5-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (88 mg, 0.37 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.42 (s, 1H), 6.93 (s, 3H), 6.66 (s, 5H), 3.22 (s, 6H), 2.81 (s, 6H). Mass (m/z): 297.5 [M+H]+.
The title compound 285 (14.0 mg) was prepared in a yield of 16.63% as a violet powder from 4-(4-methylpiperidin-1-yl)aniline (50 mg, 0.26 mmol) and 5-bromo-1-methyl-1H-benzo[d]imidazole (55 mg, 0.26 mmol) according to the procedure for compound 1. 1H NMR (DMSO-d6) δ 8.08 (s, 1H), 7.84 (s, 1H), 7.51 (s, 1H), 6.95 (d, J=58.4 Hz, 6H), 3.74 (s, 3H), 3.50 (s, 2H), 2.56 (s, 1H), 1.69 (s, 2H), 1.45 (s, 1H), 1.24 (s, 3H), 0.94 (d, J=6.4 Hz, 3H). Mass (m/z): 321.6 [M+H]+.
The title compound 286 (5.1 mg) was prepared in a yield of 5.75% as a wheat powder from 4-(4-methylpiperidin-1-yl)aniline (50 mg, 0.26 mmol) and 5-bromo-3-methylbenzo[d]oxazol-2(3H)-one (60 mg, 0.26 mmol) according to the procedure for compound 1. 1H NMR (DMSO-d6) δ 7.80 (s, 1H), 7.11 (d, J=8.7 Hz, 1H), 7.04-6.80 (m, 4H), 6.73 (s, 1H), 6.61 (d, J=8.5 Hz, 1H), 3.51 (d, J=11.8 Hz, 2H), 3.26 (s, 3H), 2.59 (s, 1H), 1.69 (d, J=12.6 Hz, 2H), 1.45 (s, 1H), 1.25 (d, J=9.0 Hz, 3H), 0.94 (d, J=6.5 Hz, 3H). Mass (m/z): 338.3 [M+H]+.
The title compound 287 (13.9 mg) was prepared in a total yield of 79.2% as a yellow solid from 4-(4-methylpiperidin-1-yl)aniline (12.4 mg, 0.065 mmol), 5-bromo-2-methylisoindoline-1,3-dione (12.0 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.46 (d, J=8.4 Hz, 2H), 7.08 (d, J=8.4 Hz, 1H), 7.01 (d, J=8.4 Hz, 2H), 6.93 (s, 1H), 6.84 (d, J=8.4 Hz, 1H), 3.60-3.42 (m, 4H), 3.32 (s, 3H), 3.29 (s, 3H), 1.96-1.84 (m, 2H), 1.76 (m, 1H), 1.65-1.48 (m, 2H), 0.98 (d, J=6.4 Hz, 3H). Mass (m/z): 351.3 [M+H]+.
The title compound 288 (30.5 mg) was prepared in a total yield of 37.7% as a gray solid from 5-amino-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (89 mg, 0.50 mmol), 7-bromo-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (57 mg, 0.25 mmol), Pd2(dba)3 (2.3 mg, 2.5 umol), X-Phos (6.0 mg, 12.5 umol), and t-BuONa (36 mg, 0.38 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.50 (s, 1H), 7.01-6.90 (m, 1H), 6.77-6.59 (m, 3H), 6.54 (s, 1H), 6.42 (s, 1H), 4.28-4.15 (m, 2H), 3.27 (s, 3H), 3.25 (s, 3H), 3.17-3.04 (m, 2H), 2.75 (s, 3H). Mass (m/z): 325.2 [M+H]+.
To a solution of 1,3-dimethyl-5-((1-methyl-1H-indol-5-yl)amino)-1,3-dihydro-2H-benzo[d]imidazol-2-one (70 mg, 0.23 mmol) in AcOH (2.0 mL) was added NaBH3CN (29 mg, 0.46 mmol). Then the mixture was stirred overnight at r.t. 5 mL of water was added. The PH of the filtration was adjusted to 8-9 with sodium carbonate solution. Then the mixture was extracted by DCM (15 mL×3). The combined organic layers were washed with water (10 mL), dried over Na2SO4 and concentrated. The residue was purified by perp-HPLC to afford the desired product as a blue solid. 1H NMR (400 MHz, DMSO-d6) δ 7.49 (s, 1H), 7.06-6.98 (m, 1H), 6.77-6.59 (m, 3H), 6.54 (s, 1H), 4.28-4.15 (m, 2H), 3.34 (s, 3H), 3.27 (s, 3H), 3.25 (s, 3H), 3.17-3.04 (m, 2H). Mass (m/z): 309.2 [M+H]+.
The title compound 290(6.6 mg) was prepared in a total yield of 7.2% as a gray solid from 4-ethynylaniline (90 mg, 0.38 mmol), 5-bromo-1,3-dimethyl-2,3-dihydro-1H-1,3-benzodiazol-2-one (70 mg, 0.29 mmol), Pd2(dba)3 (3.0 mg, 3.3 umol), X-Phos (7.8 mg, 16.5 umol), and t-BuONa (48 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.29-7.21 (m, 4H), 7.12 (d, J=8.0 Hz, 1H), 6.71-6.65 (m, 2H), 3.43 (d, J=1.4 Hz, 6H). Mass (m/z): 278.2 [M+H]+.
The title compound 291 (3.3 mg) was prepared in a total yield of 3.4% as a gray solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (122 mg, 0.50 mmol), 5-bromo-2-methylisoindolin-1-imine (56 mg, 0.25 mmol), Pd2(dba)3 (2.3 mg, 2.5 umol), X-Phos (5.9 mg, 12.5 umol), and t-BuONa (36 mg, 0.38 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.69-7.59 (m, 1H), 7.12-6.82 (m, 6H), 4.60 (s, 2H), 3.74-3.56 (m, 2H), 3.24 (s, 3H), 2.74-2.59 (m, 2H), 2.30-2.20 (m, 1H), 1.94-1.85 (m, 2H), 1.67-1.57 (m, 2H). Mass (m/z): 389.3 [M+H]+.
The title compound 292 (14.5 mg) was prepared in a total yield of 20.7% as a light green solid from 5-amino-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (71 mg, 0.40 mmol), (4-bromophenyl) (pyrrolidin-1-yl)methanone (63 mg, 0.25 mmol), Pd2(dba)3 (1.8 mg, 2 umol), X-Phos (4.8 mg, 10.0 umol), and t-BuONa (29 mg, 0.30 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.36-7.27 (m, 2H), 6.98 (d, J=8.8 Hz, 1H), 6.89 (dt, J=6.9, 2.2 Hz, 4H), 3.52-3.44 (m, 4H), 3.31 (s, 3H), 3.29 (s, 3H), 1.94-1.74 (m, 4H). Mass (m/z): 351.2 [M+H]+.
The title compound 293 (11.1 mg) was prepared in a total yield of 9.0% as a light gray powder from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (122 mg, 0.50 mmol), 5-bromo-1,3,3-trimethylindolin-2-one (84 mg, 0.33 mmol), Pd2(dba)3 (3.0 mg, 3.3 umol), X-Phos (7.8 mg, 16.5 umol), and t-BuONa (48 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 6.94-6.82 (m, 6H), 6.76 (d, J=8.2 Hz, 1H), 3.56-3.44 (m, 2H), 3.09 (s, 3H), 2.63-2.49 (m, 2H), 2.25-2.10 (m, 1H), 1.95-1.83 (m, 2H), 1.63 (qd, J=12.5, 4.1 Hz, 3H), 1.22 (s, 6H). Mass (m/z): 418.2 [M+H]+.
The title compound 294 (11.1 mg) was prepared in a total yield of 10.0% as a yellow powder from 4-(4-methylpiperidin-1-yl)aniline (95 mg, 0.50 mmol), 5-bromo-2-methylisoindolin-1-imine (75 mg, 0.33 mmol), Pd2(dba)3 (3.0 mg, 3.3 umol), X-Phos (7.8 mg, 16.5 umol), and t-BuONa (48 mg, 0.5 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.62 (d, J=8.6 Hz, 1H), 7.05-7.00 (m, 2H), 6.95-6.85 (m, 4H), 4.59 (s, 2H), 3.50 (dt, J=12.7, 3.3 Hz, 2H), 2.58 (td, J=12.1, 2.6 Hz, 2H), 1.73-1.64 (m, 2H), 1.48-1.38 (m, 1H), 1.26 (qd, J=12.1, 3.9 Hz, 2H), 0.90 (d, J=6.5 Hz, 3H). Mass (m/z): 335.3 [M+H]+
The title compound 295 (31.3 mg) was prepared in a total yield of 37.2% as a Rosy Brown green solid from 1-(4-bromobenzyl)pyrrolidine (71 mg, 0.40 mmol), 5-amino-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (60 mg, 0.25 mmol), Pd2(dba)3 (1.8 mg, 2 umol), X-Phos (4.8 mg, 10.0 umol), and t-BuONa (29 mg, 0.30 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.17-7.11 (m, 2H), 6.98-6.88 (m, 3H), 6.86-6.81 (m, 2H), 3.86 (s, 2H), 3.30 (s, 3H), 3.27 (s, 3H), 2.95-2.85 (m, 4H), 1.91-1.83 (m, 4H). Mass (m/z): 337.2 [M+H]+.
The title compound 296 (7.4 mg) was prepared in a total yield of 9.6% as a yellow solid from 3-methoxy-4-(pentyloxy)aniline (56 mg, 0.271 mmol), 5-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (50 mg, 0.208 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol) and Cs2CO3 (102 mg, 0.312 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.71 (s, 1H), 6.99 (d, J=8.3 Hz, 1H), 6.81 (dd, J=5.3, 3.3 Hz, 2H), 6.73 (dd, J=8.3, 2.1 Hz, 1H), 6.66 (d, J=2.6 Hz, 1H), 6.53 (dd, J=8.5, 2.5 Hz, 1H), 3.85 (t, J=6.6 Hz, 2H), 3.70 (s, 2H), 3.32 (s, 3H), 3.28 (s, 3H), 3.26 (s, 3H), 1.67 (p, J=6.8 Hz, 2H), 1.42-1.31 (m, 4H), 0.90 (t, J=7.0 Hz, 3H). Mass (m/z): 370.3 [M+H]+.
The title compound 297 (10.4 mg) was prepared in a total yield of 13.4% as a blue solid from 4-(4,4-difluoropiperidin-1-yl)aniline (58 mg, 0.271 mmol), 5-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (50 mg, 0.208 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (102 mg, 0.312 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 6.89-6.79 (m, 5H), 6.68 (d, J=2.0 Hz, 1H), 6.62 (dd, J=8.4, 2.0 Hz, 1H), 3.21 (s, 3H), 3.18 (s, 3H), 3.12 (d, J=10.0 Hz, 2H), 2.85-2.93 (m, 2H), 1.92 (dd, J=10.4, 5.2 Hz, 2H), 1.75 (d, J=10.4 Hz, 2H). Mass (m/z): 373.3 [M+H]+.
The title compound 298 (15.2 mg) was prepared in a total yield of 19.0% as a white solid from 3-chloro-4-(4-methylpiperidin-1-yl)aniline (60 mg, 0.271 mmol), 5-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (50 mg, 0.208 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (102 mg, 0.312 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 6.96 (t, J=8.8 Hz, 2H), 6.90 (d, J=2.4 Hz, 1H), 6.84 (dd, J=8.8, 2.6 Hz, 1H), 6.78 (d, J=2.0 Hz, 1H), 6.71 (dd, J=8.4, 2.0 Hz, 1H), 3.26 (s, 1H), 3.23 (s, 3H), 3.21 (s, 3H), 3.01 (d, J=11.6 Hz, 2H), 2.48 (d, J=2.4 Hz, 1H), 1.66-1.56 (m, 2H), 1.42-1.32 (m, 1H), 1.22 (dd, J=12.0, 3.6 Hz, 2H), 0.88 (d, J=6.4 Hz, 3H). Mass (m/z): 386.3 [M+H]+.
The title compound 299 (10.3 mg) was prepared in a total yield of 14.1% as a white solid from 4-(4-fluoropiperidin-1-yl)aniline (49 mg, 0.271 mmol), 5-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (50 mg, 0.208 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (102 mg, 0.312 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 6.89-6.79 (m, 5H), 6.68 (d, J=2.0 Hz, 1H), 6.62 (dd, J=8.4, 2.0 Hz, 1H), 3.21 (s, 3H), 3.18 (s, 3H), 3.12 (d, J=10.0 Hz, 2H), 2.91 (td, J=8.4, 7.6, 4.0 Hz, 3H), 1.92 (dd, J=10.4, 5.2 Hz, 2H), 1.75 (d, J=10.4 Hz, 2H). Mass (m/z): 355.3 [M+H]+.
The title compound 300 (19.7 mg) was prepared in a total yield of 22.2% as a white solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (69 mg, 0.283 mmol), 5-bromo-1-methyl-1H-benzo[d][1,2,3]triazole (50 mg, 0.236 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (116 mg, 0.354 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.23 (d, J=2.0 Hz, 1H), 7.15 (dd, J=8.8, 2.0 Hz, 1H), 7.03-6.97 (m, 2H), 6.90-6.84 (m, 2H), 4.15 (s, 3H), 3.59 (d, J=12.0 Hz, 2H), 2.58 (td, J=12.4, 2.6 Hz, 2H), 1.82 (d, J=12.4 Hz, 2H), 1.52 (qd, J=12.4, 4.0 Hz, 2H). Mass (m/z): 376.3 [M+H]+.
The title compound 301 (44.6 mg) was prepared in a total yield of 54.5% as a white solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (57 mg, 0.234 mmol), 5-bromo-4-methoxy-2-methylisoindolin-1-one (50 mg, 0.195 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (96 mg, 0.293 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.50 (s, 1H), 7.10 (d, J=8.0 Hz, 1H), 7.04-7.00 (m, 2H), 6.93-6.85 (m, 3H), 4.49 (s, 2H), 3.81 (s, 3H), 3.62 (d, J=12.4 Hz, 2H), 2.95 (s, 3H), 2.60 (td, J=12.4, 2.4 Hz, 2H), 1.86-1.76 (m, 2H), 1.50 (qd, J=12.4, 4.0 Hz, 2H). Mass (m/z): 420.3 [M+H]+.
The title compound 302 (16.2 mg) was prepared in a total yield of 80.2% as a yellow solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (15.9 mg, 0.065 mmol), 5-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-imine (12.0 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.35-6.71 (m, 7H), 3.76-3.66 (m, 2H), 3.59 (s, 3H), 3.56 (s, 3H), 2.79-2.61 (m, 2H), 2.11 (m, 1H), 1.99-1.86 (m, 2H), 1.75-1.69 (m, 2H). Mass (m/z): 404.2 [M+H]+.
The title compound 303 (14.5 mg) was prepared in a total yield of 79.7% as a white solid from N1,N1-dimethyl-6-(piperidin-1-yl) benzene-1,3-diamine (14.2 mg, 0.065 mmol), 5-bromo-2-methylisoindolin-1-one (11.3 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.67-7.57 (m, 2H), 7.41 (d, J=2.4 Hz, 1H), 7.31-7.23 (m, 2H), 7.18 (dd, J=8.4, 2.4 Hz, 1H), 4.44 (s, 2H), 3.25-3.18 (m, 4H), 3.16 (s, 3H), 3.03 (s, 6H), 1.74-1.63 (m, 4H), 1.59-1.51 (m, 2H). Mass (m/z): 365.2 [M+H]+.
The title compound 304 (15.3 mg) was prepared in a total yield of 83.8% as a light pink solid from tert-butyl 6-((3-(dimethylamino)-4-(piperidin-1-yl)phenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate (23.3 mg, 0.05 mmol) and 3 ml HCl (4.0 M) in 1,4-dioxane according to the procedure for compound 203. 1H NMR (400 MHz, Methanol-d4) δ 7.80-7.26 (m, 5H), 6.97 (s, 1H), 3.25 (s, 3H), 3.20-3.09 (m, 4H), 3.02 (s, 6H), 1.86-1.68 (m, 4H), 1.56-1.34 (m, 2H). Mass (m/z): 366.2 [M+H]+.
The title compound 305 (42.0 mg) was prepared in a total yield of 39.3% as a light blue powder from 4-(1H-Imidazol-1-yl)aniline (67 mg, 0.43 mmol), 5-bromo-1,3-dimethyl-2,3-dihydro-1H-1,3-benzodiazol-2-one (80 mg, 0.33 mmol), Pd2(dba)3 (3.0 mg, 3.3 umol), X-Phos (7.8 mg, 16.5 umol), and t-BuONa (48 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 9.20 (s, 1H), 7.84 (t, J=1.8 Hz, 1H), 7.62 (t, J=1.7 Hz, 1H), 7.42-7.32 (m, 2H), 7.06-6.98 (m, 3H), 6.94-6.86 (m, 2H), 3.32 (s, 3H), 3.29 (s, 3H). Mass (m/z): 320.3 [M+H]+.
The title compound 306 (32.7 mg) was prepared in a total yield of 30.0% as a light yellow powder from 4-(ethoxycarbonyl)phenylamine (71 mg, 0.43 mmol), 5-bromo-1,3-dimethyl-2,3-dihydro-1H-1,3-benzodiazol-2-one (80 mg, 0.33 mmol), Pd2(dba)3 (3.0 mg, 3.3 umol), X-Phos (7.8 mg, 16.5 umol), and t-BuONa (48 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.85-7.79 (m, 2H), 7.16-7.07 (m, 1H), 7.03-6.90 (m, 4H), 3.43 (s, 3H), 3.40 (s, 3H), 1.37 (t, J=7.1 Hz, 3H). Mass (m/z): 326.2 [M+H]+.
The title compound 307 (34.9 mg) was prepared in a total yield of 33.7% as a light yellow powder from 1,4-benzodioxan-6-amine (85 mg, 0.43 mmol), 5-bromo-1,3-dimethyl-2,3-dihydro-1H-1,3-benzodiazol-2-one (80 mg, 0.33 mmol), Pd2(dba)3 (3.0 mg, 3.3 umol), X-Phos (7.8 mg, 16.5 umol), and t-BuONa (48 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.00 (d, J=8.6 Hz, 1H), 6.84-6.77 (m, 2H), 6.72 (d, J=8.5 Hz, 1H), 6.60-6.51 (m, 2H), 4.24-4.16 (m, 4H), 3.40 (s, 3H), 3.37 (s, 3H). Mass (m/z): 312.2 [M+H]+.
The title compound 308 (12.6 mg) was prepared in a total yield of 12.8% as a light yellow powder from N,N-dimethyl-m-phenylenediamine (59 mg, 0.43 mmol), 5-bromo-1,3-dimethyl-2,3-dihydro-1H-1,3-benzodiazol-2-one (80 mg, 0.33 mmol), Pd2(dba)3 (3.0 mg, 3.3 umol), X-Phos (7.8 mg, 16.5 umol), and t-BuONa (48 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 6.98-6.87 (m, 2H), 6.84-6.77 (m, 2H), 6.40-6.30 (m, 2H), 6.24-6.17 (m, 1H), 3.29 (s, 3H), 3.25 (s, 3H), 2.77 (s, 6H). Mass (m/z): 297.3 [M+H]+.
The title compound 309 (36.5 mg) was prepared in a total yield of 36.9% as a light blue powder from 4-ethoxybenzenamine (59 mg, 0.43 mmol), 5-bromo-1,3-dimethyl-2,3-dihydro-1H-1,3-benzodiazol-2-one (80 mg, 0.33 mmol), Pd2(dba)3 (3.0 mg, 3.3 umol), X-Phos (7.8 mg, 16.5 umol), and t-BuONa (48 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 6.96-6.82 (m, 3H), 6.76-6.58 (m, 4H), 3.89 (q, J=7.0 Hz, 2H), 3.27 (s, 3H), 3.23 (s, 3H), 1.27 (t, J=7.0 Hz, 3H). Mass (m/z): 298.2 [M+H]+.
The title compound 310 (33.9 mg) was prepared in a total yield of 34.7% as a yellow powder from H-imidazo[1,2-a]pyridin-6-amine (57 mg, 0.43 mmol), 5-bromo-1,3-dimethyl-2,3-dihydro-1H-1,3-benzodiazol-2-one (80 mg, 0.33 mmol), Pd2(dba)3 (3.0 mg, 3.3 umol), X-Phos (7.8 mg, 16.5 umol), and t-BuONa (48 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 8.16 (dd, J=2.2, 0.9 Hz, 1H), 7.84 (d, J=1.9 Hz, 1H), 7.67 (d, J=1.9 Hz, 1H), 7.59 (d, J=9.6 Hz, 1H), 7.49 (dd, J=9.7, 2.2 Hz, 1H), 7.04 (d, J=8.3 Hz, 1H), 6.94 (d, J=2.0 Hz, 1H), 6.91 (dd, J=8.3, 2.1 Hz, 1H), 3.33 (s, 3H), 3.32 (s, 3H). Mass (m/z): 294.2 [M+H]+.
The title compound 311 (28.1 mg) was prepared in a total yield of 24.1% as a light green powder from 4-(4-methylpiperidin-1-yl)aniline (82 mg, 0.43 mmol), 5-bromo-1,3,3-trimethylindoline (80 mg, 0.33 mmol), Pd2(dba)3 (3.0 mg, 3.3 umol), X-Phos (7.8 mg, 16.5 umol), and t-BuONa (48 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 8.15-5.87 (m, 7H), 3.73-3.28 (m, 2H), 3.34 (s, 3H), 2.82-2.43 (m, 2H), 1.70-1.63 (m, 2H), 1.31-1.07 (m, 8H), 0.90 (d, J=6.1 Hz, 6H), 0.83-0.74 (m, 2H). Mass (m/z): 350.4 [M+H]+.
The title compound 312 (34.4 mg) was prepared in a total yield of 30.2% as a white powder from 3,4,5-trimethoxyaniline (79 mg, 0.43 mmol), 5-bromo-1,3-dimethyl-2,3-dihydro-1H-1,3-benzodiazol-2-one (80 mg, 0.33 mmol), Pd2(dba)3 (3.0 mg, 3.3 umol), X-Phos (7.8 mg, 16.5 umol), and t-BuONa (48 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 6.97-6.90 (m, 1H), 6.83-6.78 (m, 2H), 6.22 (s, 2H), 3.66 (s, 6H), 3.60 (s, 3H), 3.29 (s, 3H), 3.26 (s, 3H). Mass (m/z): 344.2 [M+H]+.
The title compound 313 (9.4 mg) was prepared in a total yield of 11.2% as a white solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (61 mg, 0.251 mmol), 5-bromo-N,2-dimethylisoindolin-1-imine (50 mg, 0.209 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (103 mg, 0.314 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.59 (s, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.14-7.05 (m, 4H), 6.99 (d, J=8.8 Hz, 2H), 3.73 (d, J=12.4 Hz, 2H), 3.08 (s, 3H), 2.73-2.66 (m, 2H), 1.90 (d, J=12.8 Hz, 2H), 1.58 (qd, J=12.4, 4.0 Hz, 3H), 1.24 (s, 2H). Mass (m/z): 403.3 [M+H]+.
The title compound 314 (8.5 mg) was prepared in a total yield of 9.6% as a white solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (69 mg, 0.283 mmol), 6-bromo-1-methyl-1H-benzo[d][1,2,3]triazole (50 mg, 0.236 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (116 mg, 0.354 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.77 (d, J=9.6 Hz, 1H), 7.18-7.13 (m, 2H), 7.03-6.90 (m, 4H), 4.10 (s, 3H), 3.70 (d, J=12.4 Hz, 2H), 2.68 (d, J=23.6 Hz, 2H), 1.90 (d, J=12.4 Hz, 2H), 1.59 (qd, J=12.4, 4.0 Hz, 2H). Mass (m/z): 376.3 [M+H]+.
The title compound 315 (26.0 mg) was prepared in a total yield of 35.4% as a white solid from 4-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)aniline (50 mg, 0.263 mmol), 6-bromo-3-methylbenzo[d]oxazol-2(3H)-one (50 mg, 0.219 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (108 mg, 0.329 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.63 (s, 1H), 7.00 (d, J=8.4 Hz, 1H), 6.93 (d, J=8.0 Hz, 2H), 6.76 (s, 1H), 6.67 (d, J=8.4 Hz, 1H), 6.48 (d, J=8.4 Hz, 2H), 4.09 (s, 1H), 2.62 (d, J=8.0 Hz, 1H), 2.54 (s, 1H), 1.69 (d, J=9.2 Hz, 1H), 1.61 (s, 2H), 1.46 (d, J=9.2 Hz, 1H), 1.25 (d, J=12.0 Hz, 2H). Mass (m/z): 336.3 [M+H]+.
The title compound 316 (8.3 mg) was prepared in a total yield of 10.8% as a white solid from 4-(2-azaspiro[3.4]octan-2-yl)aniline (53 mg, 0.263 mmol), 6-bromo-3-methylbenzo[d]oxazol-2(3H)-one (50 mg, 0.219 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (108 mg, 0.329 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.63 (s, 1H), 6.95 (d, J=8.4 Hz, 1H), 6.89-6.84 (m, 2H), 6.72 (d, J=2.0 Hz, 1H), 6.63 (dd, J=8.4, 2.1 Hz, 1H), 6.32 (d, J=8.8 Hz, 2H), 3.54 (s, 3H), 3.21 (s, 2H), 1.71 (q, J=6.0, 4.4 Hz, 4H), 1.55-1.48 (m, 4H). Mass (m/z): 350.3 [M+H]+.
The title compound 317 (19.4 mg) was prepared in a total yield of 25.1% as a white solid from 4-(2,6-dimethylmorpholino)aniline (54 mg, 0.263 mmol), 6-bromo-3-methylbenzo[d]oxazol-2(3H)-one (50 mg, 0.219 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (108 mg, 0.329 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.85 (s, 1H), 7.06 (d, J=8.4 Hz, 1H), 6.99-6.94 (m, 2H), 6.91-6.86 (m, 3H), 6.79 (dd, J=8.4, 2.0 Hz, 1H), 3.69 (ddt, J=12.4, 6.4, 3.2 Hz, 2H), 3.44 (d, J=11.2 Hz, 2H), 2.23-2.15 (m, 2H), 1.14 (d, J=6.4 Hz, 6H). Mass (m/z): 354.3 [M+H]+.
The title compound 318 (18.4 mg) was prepared in a total yield of 27.0% as a white solid from 4-(2-methoxyethoxy)aniline (42 mg, 0.250 mmol), 5-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (50 mg, 0.208 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (102 mg, 0.312 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.69 (s, 1H), 6.97 (dd, J=8.8, 2.4 Hz, 3H), 6.86-6.81 (m, 2H), 6.75 (d, J=2.0 Hz, 1H), 6.70 (dd, J=8.4, 2.1 Hz, 1H), 4.04-3.99 (m, 2H), 3.66-3.60 (m, 2H), 3.31 (s, 3H), 3.28 (s, 3H), 3.25 (s, 3H). Mass (m/z): 328.3 [M+H]+.
The title compound 319 (9.9 mg) was prepared in a total yield of 16.7% as a white solid from 2-methoxypyrimidin-5-amine (31 mg, 0.250 mmol), 5-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (50 mg, 0.208 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (102 mg, 0.312 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 2H), 7.95 (s, 1H), 7.02 (d, J=8.4 Hz, 1H), 6.83 (d, J=2.0 Hz, 1H), 6.72 (dd, J=8.4, 2.0 Hz, 1H), 3.86 (s, 3H), 3.29 (d, J=4.4 Hz, 6H). Mass (m/z): 286.3 [M+H]+.
The title compound 320 (34.5 mg) was prepared in a total yield of 58.4% as a white solid from 6-methoxypyridin-3-amine (31 mg, 0.250 mmol), 5-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (50 mg, 0.208 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), Xphos (6 mg, 0.01 mmol), Cs2CO3 (102 mg, 0.312 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.93 (d, J=2.8 Hz, 1H), 7.82 (s, 1H), 7.45 (dd, J=8.8, 2.8 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 6.78-6.72 (m, 2H), 6.69 (dd, J=8.4, 2.0 Hz, 1H), 3.79 (s, 3H), 3.27 (d, J=7.6 Hz, 6H). Mass (m/z): 285.3 [M+H]+.
The title compound 321 (55.1 mg) was prepared in a total yield of 72.6% as a white solid from 4-(4-methylpiperidin-1-yl)aniline (54 mg, 0.283 mmol), 6-bromo-1-methyl-1H-benzo[d][1,2,3]triazole (50 mg, 0.236 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (116 mg, 0.354 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.36-8.29 (m, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.15-7.10 (m, 2H), 7.01-6.97 (m, 1H), 6.97-6.91 (m, 3H), 4.09 (s, 3H), 3.57 (dt, J=12.4, 3.6 Hz, 2H), 2.60 (td, J=12.0, 2.6 Hz, 2H), 1.74-1.65 (m, 2H), 1.53-1.41 (m, 1H), 1.31-1.18 (m, 2H), 0.95 (d, J=6.4 Hz, 3H). Mass (m/z): 322.3 [M+H]+.
The title compound 322 (24.8 mg) was prepared in a total yield of 32.7% as a white solid from 4-(4-methylpiperidin-1-yl)aniline (54 mg, 0.283 mmol), 5-bromo-1-methyl-1H-benzo[d][1,2,3]triazole (50 mg, 0.236 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (116 mg, 0.354 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.36-7.31 (m, 1H), 7.28 (d, J=2.0 Hz, 1H), 7.09-7.02 (m, 2H), 6.94-6.89 (m, 2H), 4.22 (s, 3H), 3.53 (dt, J=12.4, 3.2 Hz, 2H), 2.57 (td, J=12.0, 2.4 Hz, 2H), 1.69 (d, J=13.6 Hz, 2H), 1.45 (ddt, J=10.4, 7.2, 3.6 Hz, 1H), 1.25 (dd, J=12.4, 3.6 Hz, 2H), 0.94 (d, J=6.4 Hz, 3H). Mass (m/z): 322.3 [M+H]+.
The title compound 323 (61.6 mg) was prepared in a total yield of 64.1% as a white solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (69 mg, 0.283 mmol), 6-bromo-2-methylbenzo[d]oxazole (50 mg, 0.256 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol) and Cs2CO3 (126 mg, 0.384 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.03 (dt, J=6.8, 2.8 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 7.03 (d, J=2.0 Hz, 1H), 7.00-6.94 (m, 2H), 6.88-6.80 (m, 3H), 3.57 (d, J=12.4 Hz, 2H), 2.56 (td, J=12.4, 2.4 Hz, 2H), 2.45 (s, 3H), 2.36 (ddq, J=12.4, 8.8, 3.6 Hz, 1H), 1.86-1.76 (m, 2H), 1.51 (qd, J=12.4, 4.0 Hz, 2H). Mass (m/z): 376.3 [M+H]+.
The title compound 324 (13.1 mg) was prepared in a total yield of 80.9% as a yellow solid from 4-(3,3-dimethylazetidin-1-yl)aniline (11.4 mg, 0.065 mmol), 6-bromo-3-methylbenzo[d]oxazol-2(3H)-one (11.4 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.14-6.58 (m, 7H), 3.64 (s, 4H), 3.37 (s, 3H), 1.25 (s, 6H). Mass (m/z): 324.1 [M+H]+.
The title compound 325 (11.3 mg) was prepared in a total yield of 66.7% as a white solid from 4-(2,5-dimethylpyrrolidin-1-yl)aniline (12.4 mg, 0.065 mmol), 6-bromo-3-methylbenzo[d]oxazol-2(3H)-one (11.4 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.05-6.87 (m, 3H), 6.78-6.63 (m, 2H), 6.54-6.43 (m, 2H), 3.53-3.46 (m, 2H), 3.34 (s, 3H), 2.11-1.65 (m, 4H), 1.14 (d, J=6.4 Hz, 6H). Mass (m/z): 338.2 [M+H]+.
The title compound 326 (16.7 mg) was prepared in a total yield of 82.6% as a light yellow solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (15.9 mg, 0.065 mmol), 5-bromo-2,7-dimethylisoindolin-1-one (12.0 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Chloroform-d) δ 7.34-6.75 (m, 6H), 4.29 (s, 2H), 3.76-3.61 (m, 2H), 3.11 (s, 3H), 2.79-2.66 (m, 2H), 2.53 (s, 3H), 2.15 (m, 1H), 2.06-1.93 (m, 2H), 1.79-1.66 (m, 2H). Mass (m/z): 404.2 [M+H]+.
The title compound 327 (15.8 mg) was prepared in a total yield of 78.2% as a wheat solid from 4-(2-azaspiro[3.3]heptan-2-yl)aniline (12.2 mg, 0.065 mmol), 6-bromo-3-methylbenzo[d]oxazol-2(3H)-one (11.4 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Chloroform-d) δ 7.41-6.74 (m, 6H), 3.71 (s, 4H), 3.15 (s, 3H), 2.19-2.11 (m, 4H), 1.89-1.77 (m, 2H). Mass (m/z): 404.2 [M+H]+.
The title compound 328 (1.2 mg) was prepared in a yield of 1.21% as a grey solid from 4-(4-methylpiperidin-1-yl)aniline (50 mg, 0.26 mmol) and 5-bromo-1,3-diethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (70 mg, 0.26 mmol) according to the procedure for compound 1. 1H NMR (DMSO-d6) δ 7.61 (s, 1H), 7.21 (s, 1H), 7.01-6.72 (m, 4H), 6.65 (s, 1H), 3.79 (s, 2H), 1.99 (q, J=6.9, 6.2 Hz, 5H), 1.65 (m, 1H), 1.45 (s, 3H), 1.19-1.13 (m, 5H), 0.94 (d, J=6.4 Hz, 2H), 0.84 (d, J=7.2 Hz, 4H). Mass (m/z): 379.3 [M+H]+.
The title compound 329 (1.5 mg) was prepared in a yield of 1.79% as a grey solid from 4-(4-methylpiperidin-1-yl)aniline (50 mg, 0.26 mmol) and 5-bromo-1-methyl-1H-indole (55 mg, 0.26 mmol) according to the procedure for compound 1. 1H NMR (DMSO-d6) δ 7.20 (s, 5H), 7.02-6.82(m, 3), 6.64 (s, 2H), 2.10-1.80 (m, 5H), 1.44 (s, 3H), 1.14 (s, 3H), 0.83 (d, J=6.8 Hz, 4H). Mass (m/z): 320.4 [M+H]+.
The title compound 330 (2.4 mg) was prepared in a yield of 2.86% as a grey powder from 4-(4-methylpiperidin-1-yl)aniline (50 mg, 0.26 mmol) and 6-bromo-1-methyl-1H-indole (55 mg, 0.26 mmol) according to the procedure for compound 1. 1H NMR (DMSO-d6) δ 7.62-7.34 (m, 4H), 7.21-6.86 (m, 3H), 6.65 (s, 2H), 2.67 (s, 4H), 1.99 (q, J=7.0, 6.4 Hz, 3H), 1.66 (s, 2H), 1.45 (s, 2H), 1.14 (s, 1H), 0.84 (d, J=7.1 Hz, 3H). Mass (m/z): 320.6 [M+H]+.
The title compound 331 (8.3 mg) was prepared in a yield of 11.4% as a white powder from 5-amino-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (50 mg, 0.24 mmol) and 5-bromo-1-methyl-1H-benzo[d]imidazole (42 mg, 0.24 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.81 (s, 1H), 7.42 (d, J=8.6 Hz, 1H), 7.27 (s, 1H), 7.07-6.96 (m, 2H), 6.81 (d, J=1.9 Hz, 1H), 6.76 (d, J=8.3 Hz, 1H), 3.79 (s, 3H), 3.29 (s, 3H), 3.25 (s, 3H). Mass (m/z): 308.4 [M+H]+.
The title compound 332 (5.6 mg) was prepared in a yield of 6.42% as a grey powder from 1-(4-aminophenyl)-4-(trifluoromethyl)piperidin-4-ol (50 mg, 0.19 mmol) and 5-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (54 mg, 0.21 mmol) according to the procedure for compound 1. 1H NMR (301 MHz, DMSO-d6) δ 7.64 (s, 1H), 7.01-6.83 (m, 5H), 6.75 (d, J=2.0 Hz, 1H), 6.72-6.64 (m, 1H), 5.92 (s, 1H), 3.26 (dd, J=7.2, 1.5 Hz, 6H), 2.85 (t, J=11.5 Hz, 3H), 1.88-1.61 (m, 5H). Mass (m/z): 421.6 [M+H]+.
The title compound 333 (2.4 mg) was prepared in a yield of 3.07% as a pale yellow powder from 1-(4-aminophenyl)-4-(trifluoromethyl)piperidin-4-ol (50 mg, 0.19 mmol) and 6-bromo-3-methylbenzo[d]oxazol-2(3H)-one (48 mg, 0.21 mmol) according to the procedure for compound 1. 1H NMR (DMSO-d6) δ 7.81 (s, 1H), 7.21 (s, 1H), 7.05 (d, J=8.4 Hz, 1H), 7.00-6.86 (m, 3H), 6.78 (d, J=9.0 Hz, 1H), 6.66 (s, 1H), 5.93 (s, 1H), 2.88 (d, J=11.3 Hz, 2H), 2.00 (q, J=7.0, 6.3 Hz, 3H), 1.73 (s, 2H), 1.45 (s, 2H), 0.84 (d, J=7.0 Hz, 2H). Mass (m/z): 408.6 [M+H]+.
The title compound 334 (44.0 mg) was prepared in a total yield of 29.5% as a dark gray powder from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (79.3 mg, 0.33 mmol), 5-bromo-3-(2-methoxyethyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (71 mg, 0.25 mmol), Pd2(dba)3 (2.3 mg, 2.5 umol), X-Phos (6.0 mg, 12.5 umol), and t-BuONa (36.8 mg, 0.38 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.06-6.91 (m, 6H), 6.84-6.78 (m, 1H), 4.01 (t, J=5.3 Hz, 2H), 3.66 (t, J=5.3 Hz, 3H), 3.63-3.55 (m, 2H), 3.39 (s, 3H), 3.33 (s, 3H), 2.83-2.53 (m, 2H), 2.36-2.22 (m, 2H), 2.01-1.92 (m, 2H), 1.74 (qd, J=12.5, 4.1 Hz, 3H). Mass (m/z): 449.3 [M+H]+.
The title compound 335 (51.1 mg) was prepared in a total yield of 36.8% as a light gray powder from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (122 mg, 0.50 mmol), 6-bromo-1,3,3-trimethylindolin-2-one (84 mg, 0.33 mmol), Pd2(dba)3 (3.0 mg, 3.3 umol), X-Phos (7.8 mg, 16.5 umol), and t-BuONa (48 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 8.09-5.93 (m, 7H), 3.16 (s, 3H), 2.53-2.31 (m, 1H), 2.21-1.66 (m, 4H), 1.31 (s, 6H). Mass (m/z): 418.3 [M+H]+.
The title compound 336 (35.1 mg) was prepared in a total yield of 28.1% as a yellow powder from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (105 mg, 0.43 mmol), 5-bromo-1-methyl-1H-benzo[d]imidazole (70 mg, 0.33 mmol), Pd2(dba)3 (3.0 mg, 3.3 umol), X-Phos (7.8 mg, 16.5 umol), and t-BuONa (48 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 8.02 (s, 1H), 7.40 (d, J=8.7 Hz, 1H), 7.32-7.20 (m, 1H), 7.13-6.75 (m, 5H), 3.85 (s, 3H), 3.69-3.49 (m, 2H), 2.79-2.48 (m, 2H), 2.35-2.16 (m, 2H), 2.01-1.87 (m, 2H), 1.80-1.65 (m, 2H). Mass (m/z): 375.3 [M+H]+.
The title compound 337 (54.6 mg) was prepared in a total yield of 45.5% as a yellow powder from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (105 mg, 0.43 mmol), 5-bromobenzofuran (66 mg, 0.33 mmol), Pd2(dba)3 (3.0 mg, 3.3 umol), X-Phos (7.8 mg, 16.5 umol), and t-BuONa (48 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.64 (d, J=2.2 Hz, 1H), 7.47-6.75 (m, 7H), 6.68 (d, J=1.6 Hz, 1H), 3.86-3.40 (m, 2H), 3.04-2.16 (m, 3H), 2.04-1.91 (m, 2H), 1.81-1.61 (m, 2H). Mass (m/z): 361.2 [M+H]+.
The title compound 338 (43.2 mg) was prepared in a total yield of 45.5% as a yellow powder from 4-(4-methylpiperidin-1-yl)aniline (82 mg, 0.43 mmol), 6-bromo-1,3,3-trimethylindoline (80 mg, 0.33 mmol), Pd2(dba)3 (3.0 mg, 3.3 umol), X-Phos (7.8 mg, 16.5 umol), and t-BuONa (48 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 6.92-6.86 (m, 2H), 6.85-6.80 (m, 2H), 6.69 (s, 1H), 6.09 (s, 1H), 3.38-3.31 (m, 2H), 2.90 (s, 2H), 2.56 (s, 3H), 2.54-2.44 (m, 2H), 1.70-1.59 (m, 2H), 1.42-1.21 (m, 3H), 1.14 (s, 6H), 0.88 (d, J=6.3 Hz, 3H). Mass (m/z): 350.3 [M+H]+.
The title compound 339 (69.4 mg) was prepared in a total yield of 84.3% as a white solid from 4-(4-methylpiperidin-1-yl)aniline (54 mg, 0.283 mmol), 6-bromo-2-methylbenzo[d]oxazole (50 mg, 0.256 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (126 mg, 0.384 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.11-6.83 (m, 6H), 3.52 (s, 2H), 3.36 (s, 3H), 2.55 (s, 2H), 1.68 (s, 2H), 1.46 (s, 1H), 1.24 (d, J=9.2 Hz, 2H), 0.94 (d, J=6.4 Hz, 3H). Mass (m/z): 322.3 [M+H]+.
The title compound 340 (2.2 mg) was prepared in a total yield of 2.7% as a white solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (57 mg, 0.236 mmol), 5-bromo-N,1,3-trimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-imine (50 mg, 0.197 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (97 mg, 0.296 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 6.89-6.79 (m, 5H), 6.68 (d, J=2.0 Hz, 1H), 6.62 (dd, J=8.4, 2.0 Hz, 1H), 3.21 (s, 3H), 3.18 (s, 3H), 3.12 (d, J=10.0 Hz, 2H), 2.91 (td, J=8.4, 7.6, 4.0 Hz, 3H), 1.92 (dd, J=10.4, 5.2 Hz, 2H), 1.75 (d, J=10.4 Hz, 2H), 1.02 (d, J=6.0 Hz, 3H). Mass (m/z): 418.3 [M+H]+.
The title compound 341 (12.1 mg) was prepared in a total yield of 15.9% as a green solid from 1-(4-aminophenyl)-4-methylpiperidin-4-ol (51 mg, 0.250 mmol), 5-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (50 mg, 0.208 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (102 mg, 0.312 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.65-7.59 (m, 1H), 6.98-6.91 (m, 3H), 6.87-6.82 (m, 2H), 6.73 (d, J=2.0 Hz, 1H), 6.68 (dd, J=8.4, 2.0 Hz, 1H), 4.27 (q, J=1.6 Hz, 1H), 3.26 (d, J=10.4 Hz, 6H), 3.10 (dt, J=12.0, 4.4 Hz, 2H), 3.01 (dt, J=12.4, 6.4 Hz, 2H), 1.57 (dd, J=6.4, 4.4 Hz, 4H), 1.15 (s, 3H). Mass (m/z): 367.3 [M+H]+.
The title compound 342 (6.4 mg) was prepared in a total yield of 11.9% as a brown solid from thiophen-3-amine (34 mg, 0.250 mmol), 5-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (50 mg, 0.208 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (102 mg, 0.312 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.93 (d, J=2.8 Hz, 1H), 7.82 (s, 1H), 7.45 (dd, J=8.8, 2.8 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 6.78-6.72 (m, 2H), 6.69 (dd, J=8.4, 2.0 Hz, 1H), 3.27 (d, J=7.6 Hz, 6H). Mass (m/z): 260.3 [M+H]+.
The title compound 343 (7.0 mg) was prepared in a total yield of 8.3% as a green solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (60 mg, 0.248 mmol), 5-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (50 mg, 0.207 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (102 mg, 0.310 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.72 (s, 2H), 7.25-6.80 (m, 5H), 3.47 (s, 3H), 3.30 (s, 6H), 2.73 (s, 1H), 1.91 (s, 2H), 1.63 (s, 2H). Mass (m/z): 406.3 [M+H]+.
The title compound 344 (11.3 mg) was prepared in a total yield of 16.8% as a white solid from 6-amino-3-methylbenzo[d]oxazol-2(3H)-one (41 mg, 0.250 mmol), 5-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (50 mg, 0.208 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (102 mg, 0.312 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.01 (d, J=8.4 Hz, 1H), 6.96 (d, J=8.4 Hz, 1H), 6.90 (d, J=2.0 Hz, 1H), 6.78 (dd, J=8.0, 2.1 Hz, 2H), 6.70 (dd, J=8.0, 2.0 Hz, 1H), 3.25-3.22 (m, 6H), 3.20 (s, 3H). Mass (m/z): 325.3 [M+H]+.
The title compound 345 (13.9 mg) was prepared in a total yield of 79.2% as a light blue solid from 4-(4-methylpiperidin-1-yl)aniline (12.4 mg, 0.065 mmol), 5-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-imine (12.0 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.47-6.79 (m, 7H), 3.78-3.67 (m, 2H), 3.64 (s, 3H), 3.59 (s, 3H), 2.83-2.54 (m, 2H), 1.97-1.68 (m, 2H), 1.53 (m, 1H), 1.47-1.36 (m, 2H), 1.01 (d, J=6.4 Hz, 3H). Mass (m/z): 350.2 [M+H]+.
The title compound 346 (18.3 mg) was prepared in a total yield of 87.1% as a wheat solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (15.9 mg, 0.065 mmol), 8-bromo-4-methyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (12.8 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Chloroform-d) δ 7.74 (d, J=8.4 Hz, 1H), 7.08 (d, J=8.4 Hz, 2H), 6.91 (d, J=8.4 Hz, 2H), 6.59 (dd, J=8.4, 2.4 Hz, 1H), 6.43 (d, J=2.4 Hz, 1H), 4.33 (t, J=4.8 Hz, 2H), 3.74-3.63 (m, 2H), 3.53 (t, J=4.8 Hz, 2H), 3.17 (s, 3H), 2.81-2.57 (m, 2H), 2.15 (m, 1H), 2.02-1.92 (m, 2H), 1.85-1.68 (m, 2H). Mass (m/z): 420.3 [M+H]+.
The title compound 347 (23.9 mg) was prepared in a yield of 31.27% as a pale gray powder from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (50 mg, 0.20 mmol) and 5-bromo-1-methyl-1H-indole (47 mg, 0.23 mmol) according to the procedure for compound 1. 1H NMR (DMSO-d6) δ 7.57-6.42 (br, 9H), 4.62-3.21 (br, 8H), 2.64-1.41 (br, 4H). Mass (m/z): 374.2 [M+H]+.
The title compound 348 (38.0 mg) was prepared in a yield of 49.71% as a white powder from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (50 mg, 0.20 mmol) and 6-bromo-1-methyl-1H-indole (47 mg, 0.22 mmol) according to the procedure for compound 1. 1H NMR (DMSO-d6) δ 7.86-6.63 (br, 9H), 4.51-3.04 (br, 8H), 2.36-1.52 (br, 4H). Mass (m/z): 374.1 [M+H]+.
The title compound 349 (8.8 mg) was prepared in a yield of 10.25% as a dim gray powder from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (50 mg, 0.22 mmol) and 5-bromo-3-methylbenzo[d]oxazol-2(3H)-one (59 mg, 0.22 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.84 (s, 1H), 7.12 (d, J=8.6 Hz, 1H), 7.03-6.95 (m, 2H), 6.94-6.87 (m, 2H), 6.75 (d, J=2.1 Hz, 1H), 6.63 (dt, J=8.6, 1.9 Hz, 1H), 3.62 (d, J=12.4 Hz, 2H), 3.26 (s, 3H), 2.63 (td, J=12.3, 2.5 Hz, 2H), 1.93-1.79 (m, 2H), 1.57 (qd, J=12.4, 4.2 Hz, 3H). Mass (m/z): 392.6 [M+H]+.
The title compound 350 (35.6 mg) was prepared in a total yield of 28.5% as a yellow powder from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (82 mg, 0.43 mmol), 6-bromo-1-methyl-1H-benzo[d]imidazole (70 mg, 0.33 mmol), Pd2(dba)3 (3.0 mg, 3.3 umol), X-Phos (7.8 mg, 16.5 umol), and t-BuONa (48 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 1H), 7.96 (s, 1H), 7.60 (d, J=8.7 Hz, 1H), 7.09-7.02 (m, 3H), 6.97-6.88 (m, 3H), 3.79 (d, J=1.6 Hz, 3H), 3.67-3.60 (m, 2H), 2.64 (td, J=12.4, 2.5 Hz, 2H), 2.47-2.40 (m, 1H), 1.93-1.84 (m, 2H), 1.58 (qd, J=12.5, 4.1 Hz, 2H). Mass (m/z): 375.3 [M+H]+.
The title compound 351 (10.3 mg) was prepared in a total yield of 8.6% as a yellow powder from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (105 mg, 0.43 mmol), 6-bromobenzofuran (66 mg, 0.33 mmol), Pd2(dba)3 (3.0 mg, 3.3 umol), X-Phos (7.8 mg, 16.5 umol), and t-BuONa (48 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.55 (d, J=2.2 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.09 (d, J=8.9 Hz, 3H), 6.99 (d, J=8.4 Hz, 2H), 6.91 (d, J=8.4 Hz, 1H), 6.70 (dd, J=2.2, 1.0 Hz, 1H), 3.67-3.54 (m, 2H), 2.78-2.59 (m, 2H), 2.38-2.23 (m, 2H), 2.03-1.91 (m, 2H), 1.75 (qd, J=12.6, 4.1 Hz, 2H). Mass (m/z): 361.2 [M+H]+.
The title compound 352 (9.9 mg) was prepared in a total yield of 8.9% as a yellow powder from 4-(4-methylpiperidin-1-yl)aniline (81.7 mg, 0.43 mmol), 5-bromo-1-methyl-1H-indazol-3-amine (75 mg, 0.33 mmol), Pd2(dba)3 (3.0 mg, 3.3 umol), X-Phos (7.8 mg, 16.5 umol), and t-BuONa (48 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.38-6.52 (m, 7H), 3.76 (s, 3H), 3.61-3.35 (m, 2H), 2.98-2.43 (m, 2H), 1.87-1.71 (m, 2H), 1.58-1.35 (m, 3H), 1.01 (d, J=6.2 Hz, 3H). Mass (m/z): 336.4 [M+H]+.
The title compound 353 (11.1 mg) was prepared in a total yield of 9.2% as a yellow powder from 4-(4-methylpiperidin-1-yl)aniline (81.7 mg, 0.43 mmol), 5-bromo-1-methyl-1H-indole-3-carboxylic acid (85 mg, 0.33 mmol), Pd2(dba)3 (3.0 mg, 3.3 umol), X-Phos (7.8 mg, 16.5 umol), and t-BuONa (48 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 8.18-6.47 (m, 8H), 4.17-3.61 (m, 7H), 1.75-1.45 (m, 5H), 1.02 (d, J=6.1 Hz, 3H). Mass (m/z): 364.3 [M+H]+.
The title compound 354 (59.1 mg) was prepared in a total yield of 40.0% as a gray powder from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (105 mg, 0.43 mmol), 5-bromo-1-(2-methoxyethyl)-3-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (94.7 mg, 0.33 mmol), Pd2(dba)3 (3.0 mg, 3.3 umol), X-Phos (7.8 mg, 16.5 umol), and t-BuONa (48 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 8.10-6.03 (m, 7H), 4.03 (t, J=5.4 Hz, 2H), 3.87-3.42 (m, 4H), 3.33-3.31 (m, 5H), 2.34-2.21 (m, 1H), 2.05-1.91 (m, 2H), 1.80-1.65 (m, 2H). Mass (m/z): 449.3 [M+H]+.
The title compound 355 (7.0 mg) was prepared in a total yield of 4.6% as a gray powder from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (80 mg, 0.43 mmol), 5-bromo-1-(2-(dimethylamino)ethyl)-3-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (74.5 mg, 0.25 mmol), Pd2(dba)3 (3.0 mg, 3.3 umol), X-Phos (7.8 mg, 16.5 umol), and t-BuONa (48 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.27-6.47 (m, 7H), 3.99 (t, J=6.5 Hz, 2H), 3.64-3.36 (m, 2H), 3.24 (s, 3H), 2.87 (t, J=6.5 Hz, 2H), 2.76-2.46 (m, 2H), 2.45 (s, 6H), 2.24-2.12 (m, 1H), 1.94-1.82 (m, 2H), 1.62 (q, J=12.5, 11.9 Hz, 2H). Mass (m/z): 462.4 [M+H]+.
The title compound 356 (4.0 mg) was prepared in a total yield of 3.2% as a gray powder from 4-(4-methylpiperidin-1-yl)aniline (82 mg, 0.43 mmol), N-(5-bromo-1-methyl-1H-indazol-3-yl)acetamide (74.5 mg, 0.25 mmol), Pd2(dba)3 (3.0 mg, 3.3 umol), X-Phos (7.8 mg, 16.5 umol), and t-BuONa (48 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.84-6.71 (m, 7H), 4.24-3.43 (m, 7H), 2.20 (s, 3H), 2.07-2.00 (m, 1H), 1.93-1.40 (m, 7H), 1.06 (d, J=6.0 Hz, 4H). Mass (m/z): 378.3 [M+H]+.
To a solution of tert-butyl 6-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl) amino)-1H-benzo[d]imidazole-1-carboxylate (153 mg, 0.33 mmol) in EtOH (5 mL) was added a solution of HCl in 1,4-dioxane (5 mL). Then the solution was stirred for 30 mins at r.t. and concentrated. 10 ml water was added. The PH of the filtration was adjusted to 8-9 with sodium carbonate solution. Then the mixture was extracted by DCM (15 mL×3). The combined organic layers were washed with water (10 mL), dried over Na2SO4 and concentrated. The residue was purified by perp-TLC (MeOH/DCM=1/10) to afford the desired product as a light gray solid. (6.1 mg, 5.0%). 1H NMR (400 MHz, Methanol-d4) δ 8.56 (s, 1H), 8.04-6.31 (m, 7H), 4.01-3.51 (m, 2H), 3.11-2.57 (m, 2H), 2.41-2.27 (m, 1H), 2.13-1.65 (m, 4H). Mass (m/z): 361.2 [M+H]+.
The title compound 358 (19.1 mg) was prepared in a total yield of 21.0% as a white solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (73 mg, 0.303 mmol), 6-bromobenzo[d]isoxazole (50 mg, 0.252 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (124 mg, 0.374 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.46 (s, 1H), 7.25 (d, J=8.4 Hz, 1H), 7.06-7.00 (m, 2H), 6.95 (d, J=8.8 Hz, 2H), 6.45 (d, J=2.0 Hz, 1H), 6.34 (dd, J=8.4, 2.1 Hz, 1H), 3.71 (d, J=12.0 Hz, 2H), 2.67 (td, J=12.4, 2.4 Hz, 2H), 2.44 (ddd, J=15.2, 7.6, 3.6 Hz, 1H), 1.94-1.84 (m, 2H), 1.57 (qd, J=12.4, 4.0 Hz, 2H). Mass (m/z): 362.3 [M+H]+.
The title compound 359 (9.3 mg) was prepared in a total yield of 10.2% as a white solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (73 mg, 0.303 mmol), 5-bromobenzo[d]oxazole (50 mg, 0.252 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (124 mg, 0.374 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 7.90 (s, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.23 (d, J=2.0 Hz, 1H), 7.04-6.99 (m, 3H), 6.96-6.90 (m, 2H), 3.63 (d, J=12.4 Hz, 2H), 2.63 (td, J=12.4, 2.4 Hz, 2H), 2.43 (dtd, J=12.4, 8.4, 3.6 Hz, 1H), 1.93-1.84 (m, 2H), 1.58 (qd, J=12.4, 4.0 Hz, 2H). Mass (m/z): 362.3 [M+H]+.
The title compound 360 (27.3 mg) was prepared in a total yield of 30.0% as a white solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (73 mg, 0.303 mmol), 6-bromobenzo[d]oxazole (50 mg, 0.252 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol) and Cs2CO3 (124 mg, 0.374 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 8.08 (s, 1H), 7.48 (d, J=8.8 Hz, 1H), 7.09 (d, J=2.0 Hz, 1H), 7.04-6.96 (m, 2H), 6.88 (td, J=8.8, 2.0 Hz, 3H), 3.59 (d, J=11.6 Hz, 2H), 2.57 (td, J=12.4, 2.4 Hz, 2H), 2.36 (dq, J=12.4, 3.6 Hz, 1H), 1.88-1.76 (m, 2H), 1.51 (qd, J=12.4, 4.0 Hz, 2H). Mass (m/z): 362.3 [M+H]+.
The title compound 361 (10.3 mg) was prepared in a total yield of 53.9% as a white solid from methyl 3-((4-aminophenyl)(ethyl)amino)propanoate (14.4 mg, 0.065 mmol), 5-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (12.0 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.35-6.70 (m, 7H), 3.67 (s, 3H), 3.62 (s, 3H), 3.41-3.32 (m, 4H), 3.29 (s, 3H), 2.58-2.46 (m, 2H), 1.08 (t, J=6.8 Hz, 3H). Mass (m/z): 383.2 [M+H]+.
The title compound 362 (13.7 mg) was prepared in a total yield of 67.6% as a yellow solid from 6-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-amine (15.9 mg, 0.065 mmol), 5-bromo-2-methylisoindoline-1,3-dione (12.0 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.96 (d, J=2.4 Hz, 1H), 7.43 (dd, J=8.8, 2.4 Hz, 1H), 6.97 (d, J=8.8 Hz, 1H), 6.84 (d, J=8.8 Hz, 1H), 6.77-6.70 (m, 2H), 4.25-4.17 (m, 2H), 3.37 (s, 3H), 3.34 (s, 3H), 2.86-2.73 (m, 2H), 2.38 (m, 1H), 1.99-1.88 (m, 2H), 1.67-1.53 (m, 2H). Mass (m/z): 406.2 [M+H]+.
The title compound 363 (16.5 mg) was prepared in a total yield of 84.4% as a yellow solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (15.9 mg, 0.065 mmol), 5-bromo-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (11.3 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.46-6.65 (m, 7H), 3.71-3.65 (m, 2H), 3.58 (s, 3H), 2.78-2.66 (m, 2H), 2.13 (m, 1H), 2.01-1.87 (m, 2H), 1.76-1.67 (m, 2H). Mass (m/z): 391.2 [M+H]+.
The title compound 364 (89.9 mg) was prepared in a total yield of 71.9% as a light yellow solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (105 mg, 0.43 mmol), 5-bromo-1-methyl-1H-indazole (70 mg, 0.33 mmol), Pd2(dba)3 (3.0 mg, 3.3 umol), X-Phos (7.8 mg, 16.5 umol), and Cs2CO3 (163 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.80 (s, 1H), 7.47-6.83 (m, 7H), 4.02 (s, 3H), 3.76-3.41 (m, 2H), 3.22-2.34 (m, 2H), 2.33-2.20 (m, 2H), 2.02-1.93 (m, 2H), 1.73 (qd, J=12.7, 3.9 Hz, 2H). Mass (m/z): 375.3 [M+H]+.
The title compound 365 (12.0 mg) was prepared in a total yield of 9.2% as a gray solid from 4-(4-methylpiperidin-1-yl)aniline (81.7 mg, 0.43 mmol), 5-bromo-N-ethyl-1-methyl-1H-indole-3-carboxamide (93.3 mg, 0.33 mmol), Pd2(dba)3 (3.0 mg, 3.3 umol), X-Phos (7.8 mg, 16.5 umol), and Cs2CO3 (163 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.71 (s, 1H), 7.55-6.6 (m, 7H), 4.00-3.75 (m, 4H), 3.39 (q, J=7.2 Hz, 2H), 3.33 (s, 3H), 1.88-1.34 (m, 5H), 1.22 (t, J=7.2 Hz, 3H), 1.02 (d, J=6.1 Hz, 3H). Mass (m/z): 391.3 [M+H]+.
To a solution of tert-butyl 6-((4-(4-(trifluoromethyl)piperidin-1-yl) phenyl)amino)-1H-indazole-1-carboxylate (45 mg, 0.10 mmol) in EtOH (5 mL) was added a solution of HCl in 1,4-dioxane (5 mL). Then the solution was stirred for 30 mins at r.t. and concentrated. 10 ml water was added. The pH of the filtration was adjusted to 8-9 with sodium carbonate solution. Then the mixture was extracted by DCM (15 mL×3). The combined organic layers were washed with water (10 mL), dried over Na2SO4 and concentrated. The residue was purified by perp-TLC (MeOH/DCM=1/10) to afford the desired product as a light gray solid. (23.0 mg, 63.8%). 1H NMR (400 MHz, Methanol-d4) δ 8.56 (s, 1H), 8.04-6.31 (m, 7H), 4.01-3.51 (m, 2H), 3.11-2.57 (m, 2H), 2.41-2.27 (m, 1H), 2.13-1.65 (m, 4H). 1H NMR (400 MHz, Methanol-d4) δ 8.56 (s, 1H), 7.87 (d, J=9.0 Hz, 1H), 7.78-7.70 (m, 2H), 7.50-7.41 (m, 2H), 7.23-7.14 (m, 1H), 3.85-3.77 (m, 4H), 2.91-2.78 (m, 1H), 2.36-2.20 (m, 4H). Mass (m/z): 361.2 [M+H]+.
The title compound 367 (22.1 mg) was prepared in a total yield of 87.9% as a yellow solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (15.9 mg, 0.065 mmol), 5-bromo-3-methyl-1-(2-(2-oxopyrrolidin-1-yl) ethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (16.9 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.35-6.54 (m, 7H), 4.07-3.96 (m, 2H), 3.59 (t, J=6.8 Hz, 2H), 3.43 (t, J=6.8 Hz, 2H), 3.33 (s, 3H), 2.81-2.65 (m, 2H), 2.21 (m, 1H), 2.19 (t, J=8.1 Hz, 2H), 2.05-1.86 (m, 4H), 1.82-1.62 (m, 2H). Mass (m/z): 502.3 [M+H]+
The title compound 368 (31.9 mg) was prepared in a total yield of 43.8% as a green solid from 4-(2-methylpiperidin-1-yl)aniline (48 mg, 0.250 mmol), 5-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (50 mg, 0.208 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (102 mg, 0.312 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.78 (s, 1H), 7.14-6.63 (m, 7H), 3.50 (s, 1H), 3.27 (s, 6H), 3.00 (s, 2H), 1.89-1.33 (m, 6H), 0.88 (s, 3H). Mass (m/z): 321.3 [M+H]+.
The title compound 369 (41.8 mg) was prepared in a total yield of 52.3% as a brown solid from N1-(2-(2-methoxyethoxy)ethyl)-N1-methylbenzene-1,4-diamine (56 mg, 0.250 mmol), 5-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (50 mg, 0.208 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (102 mg, 0.312 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.45 (s, 1H), 6.94 (t, J=9.2 Hz, 3H), 6.72-6.56 (m, 4H), 3.57-3.49 (m, 4H), 3.45-3.38 (m, 4H), 3.24 (d, J=3.2 Hz, 6H), 2.86 (s, 3H). Mass (m/z): 385.3 [M+H]+.
The title compound 370 (2.0 mg) was prepared in a total yield of 1.5% as a light pink solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (105 mg, 0.43 mmol), 5-bromo-1-methyl-1H-benzo[d]imidazol-2-amine (75 mg, 0.33 mmol), Pd2(dba)3 (3.0 mg, 3.3 umol), X-Phos (7.8 mg, 16.5 umol), and t-BuONa (48 mg, 0.50 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.13-6.52 (m, 7H), 3.73-3.44 (m, 5H), 2.85-2.49 (m, 2H), 2.34-2.21 (m, 1H), 2.02-1.91 (m, 2H), 1.80-1.67 (m, 2H). Mass (m/z): 390.3 [M+H]+.
The title compound 371 (33.4 mg) was prepared in a total yield of 31.9% as a light yellow powder from 5-methyl-6-(4-(trifluoromethyl) piperidin-1-yl)pyridin-3-amine (84 mg, 0.33 mmol), 5-bromo-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one (60 mg, 0.25 mmol), Pd2(dba)3 (2.0 mg, 2.5 umol), X-Phos (6.0 mg, 12.5 umol), and t-BuONa (36 mg, 0.38 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.88 (d, J=2.8 Hz, 1H), 7.31 (dd, J=2.8, 0.9 Hz, 1H), 7.08-7.02 (m, 1H), 6.89-6.83 (m, 2H), 3.41 (s, 3H), 3.38 (s, 3H), 3.37-3.34 (m, 2H), 2.79 (td, J=12.4, 2.3 Hz, 2H), 2.37-2.29 (m, 1H), 2.28 (s, 3H), 2.01-1.94 (m, 2H), 1.69-1.57 (m, 2H). Mass (m/z): 420.3 [M+H]+.
The title compound 372 (21.7 mg) was prepared in a total yield of 19.9% as a light gray powder from 5-methoxy-6-(4-(trifluoromethyl) piperidin-1-yl)pyridin-3-amine (84 mg, 0.33 mmol), 5-bromo-1,3-dimethyl-2,3-dihydro-1H-1,3-benzodiazol-2-one (60 mg, 0.25 mmol), Pd2(dba)3 (2.0 mg, 2.5 umol), X-Phos (6.0 mg, 12.5 umol), and t-BuONa (36 mg, 0.38 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.61 (d, J=2.3 Hz, 1H), 7.06 (d, J=5.7 Hz, 1H), 7.05 (s, 1H), 6.91-6.86 (m, 2H), 3.85 (s, 3H), 3.82-3.73 (m, 2H), 3.41 (s, 3H), 3.39 (s, 3H), 2.72 (td, J=12.5, 2.4 Hz, 2H), 2.36-2.25 (m, 1H), 1.98-1.89 (m, 2H), 1.69-1.57 (m, 2H). Mass (m/z): 436.3 [M+H]+.
The title compound 373 (54.4 mg) was prepared in a total yield of 51.8% as a light yellow powder from 2-methyl-6-(4-(trifluoromethyl) piperidin-1-yl)pyridin-3-amine (84 mg, 0.33 mmol), 5-bromo-1,3-dimethyl-2,3-dihydro-1H-1,3-benzodiazol-2-one (60 mg, 0.25 mmol), Pd2(dba)3 (2.3 mg, 2.5 umol), X-Phos (6.0 mg, 12.5 umol), and t-BuONa (36 mg, 0.38 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.39 (d, J=8.7 Hz, 1H), 6.94 (d, J=8.4 Hz, 1H), 6.68 (d, J=8.8 Hz, 1H), 6.52 (dd, J=8.4, 2.1 Hz, 1H), 6.47 (d, J=2.1 Hz, 1H), 4.35 (d, J=12.9 Hz, 2H), 3.38 (s, 3H), 2.81 (t, J=12.7 Hz, 2H), 2.47-2.35 (m, 1H), 2.33 (s, 3H), 2.00-1.89 (m, 1H), 1.69-1.57 (m, 2H). Mass (m/z): 420.3 [M+H]+.
The title compound 374 (45.4 mg) was prepared in a yield of 56.93% as a white powder from 2-amino-5-(4-(trifluoromethyl)piperidin-1-yl) benzonitrile (50 mg, 0.19 mmol) and 5-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (49 mg, 0.20 mmol) according to the procedure for compound 1. 1H NMR (Methanol-d4) δ 7.20 (dd, J=9.1, 2.9 Hz, 1H), 7.16-7.13 (m, 1H), 7.10 (d, J=9.1 Hz, 1H), 7.06 (d, J=8.9 Hz, 1H), 6.90-6.86 (m, 2H), 3.63 (d, J=11.9 Hz, 2H), 3.41 (s, 3H), 3.37 (s, 3H), 2.68 (td, J=12.3, 2.5 Hz, 2H), 2.29 (ddp, J=12.4, 7.9, 4.0 Hz, 1H), 1.98 (d, J=12.9 Hz, 2H), 1.78-1.62 (m, 2H). Mass (m/z): 430.5 [M+H]+.
The title compound 375 (36.7 mg) was prepared in a yield of 46.34% as a white powder from 2-methoxy-4-(4-(trifluoromethyl)piperidin-1-yl)aniline (50 mg, 0.18 mmol) and 5-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (48 mg, 0.20 mmol) according to the procedure for compound 1. 1H NMR (Methanol-d4) δ: 7.30-6.28 (m, 6H), 3.87 (s, 5H), 3.41-3.36 (m, 3H), 2.21 (s, 2H), 2.11-1.85 (m, 4H), 1.66 (d, J=48.8 Hz, 4H). Mass (m/z): 435.2 [M+H]+.
The title compound 376 (10.1 mg) was prepared in a total yield of 13.8% as a white solid from 2-(4-methylpiperidin-1-yl)pyrimidin-5-amine (48 mg, 0.250 mmol), 5-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (50 mg, 0.208 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (102 mg, 0.312 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 2H), 7.49 (s, 1H), 6.94 (d, J=8.4 Hz, 1H), 6.61 (d, J=2.0 Hz, 1H), 6.54 (dd, J=8.4, 2.0 Hz, 1H), 4.55 (dt, J=12.4, 3.2 Hz, 2H), 3.25 (d, J=7.2 Hz, 6H), 2.82 (td, J=12.8, 2.4 Hz, 2H), 1.70-1.60 (m, 3H), 1.12-1.00 (m, 2H), 0.93 (d, J=6.4 Hz, 3H). Mass (m/z): 353.3 [M+H]+.
The title compound 377 (40.6 mg) was prepared in a total yield of 37.3% as a purple powder from 2-methoxy-6-(4-(trifluoromethyl) piperidin-1-yl) pyridin-3-amine (79 mg, 0.29 mmol), 5-bromo-1,3-dimethyl-2,3-dihydro-1H-1,3-benzodiazol-2-one (60 mg, 0.25 mmol), Pd2(dba)3 (2.3 mg, 2.5 umol), X-Phos (6.0 mg, 12.5 umol), and t-BuONa (36 mg, 0.38 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.38 (d, J=8.3 Hz, 1H), 6.96 (d, J=8.4 Hz, 1H), 6.71 (d, J=8.4 Hz, 1H), 6.67 (d, J=2.1 Hz, 1H), 6.31 (d, J=8.3 Hz, 1H), 4.38-4.32 (m, 2H), 3.93 (s, 3H), 3.38 (s, 3H), 3.34 (s, 3H), 2.79 (t, J=12.8 Hz, 2H), 2.44-2.35 (m, 1H), 1.98-1.92 (m, 2H), 1.69-1.57 (m, 2H). Mass (m/z): 436.3 [M+H]+.
The title compound 378 (40.6 mg) was prepared in a total yield of 42.0% as a brown powder from 5-fluoro-6-(4-(trifluoromethyl)piperidin-1-yl) pyridin-3-amine (75.6 mg, 0.29 mmol), 5-bromo-1,3-dimethyl-2,3-dihydro-1H-1,3-benzodiazol-2-one (60 mg, 0.25 mmol), Pd2(dba)3 (2.3 mg, 2.5 umol), X-Phos (6.0 mg, 12.5 umol), and t-BuONa (36 mg, 0.38 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.80 (d, J=2.1 Hz, 1H), 7.18 (dd, J=13.9, 2.4 Hz, 1H), 7.06-7.01 (m, 1H), 6.89-6.83 (m, 2H), 3.85-3.77 (m, 2H), 3.40 (s, 3H), 3.38 (s, 3H), 2.83 (td, J=12.6, 2.4 Hz, 2H), 2.39-2.26 (m, 1H), 1.99-1.89 (m, 2H), 1.78-1.65 (m, 2H). Mass (m/z): 424.3 [M+H]+.
The title compound 379 (49.7 mg) was prepared in a total yield of 47.3% as a peach puff powder from 4-methyl-6-(4-(trifluoromethyl) piperidin-1-yl)pyridin-3-amine (75.0 mg, 0.29 mmol), 5-bromo-1,3-dimethyl-2,3-dihydro-1H-1,3-benzodiazol-2-one (60 mg, 0.25 mmol), Pd2(dba)3 (2.3 mg, 2.5 umol), X-Phos (6.0 mg, 12.5 umol), and t-BuONa (36 mg, 0.38 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.92 (s, 1H), 6.95 (d, J=8.4 Hz, 1H), 6.82 (s, 1H), 6.51 (dd, J=8.4, 2.1 Hz, 1H), 6.48 (d, J=2.1 Hz, 1H), 4.34-4.24 (m, 2H), 3.38 (s, 3H), 3.32 (s, 3H), 2.90-2.81 (m, 2H), 2.48-2.36 (m, 1H), 2.21 (s, 3H), 2.00-1.92 (m, 2H), 1.68-1.55 (m, 2H). Mass (m/z): 420.3 [M+H]+.
The title compound 380 (27.0 mg) was prepared in a total yield of 21.6% as a light yellow powder from 4-methoxy-6-(4-(trifluoromethyl) piperidin-1-yl)pyridin-3-amine (69.0 mg, 0.29 mmol), 5-bromo-1,3-dimethyl-2,3-dihydro-1H-1,3-benzodiazol-2-one (60 mg, 0.25 mmol), Pd2(dba)3 (2.3 mg, 2.5 umol), X-Phos (6.0 mg, 12.5 umol), and t-BuONa (36 mg, 0.38 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.85 (s, 1H), 6.98 (d, J=8.3 Hz, 1H), 6.71 (dd, J=8.3, 2.1 Hz, 1H), 6.68 (d, J=2.1 Hz, 1H), 6.52 (d, J=6.9 Hz, 1H), 4.32-4.24 (m, 2H), 3.92 (s, 3H), 3.39 (s, 3H), 3.35 (s, 3H), 2.92-2.85 (m, 2H), 2.48-2.40 (m, 1H), 2.02-1.99 (m, 2H), 1.67-1.61 (m, 2H). Mass (m/z): 436.3 [M+H]+.
The title compound 381 (37.8 mg) was prepared in a total yield of 41.8% as a yellow solid from 3-methoxy-4-(4-(trifluoromethyl)piperidin-1-yl)aniline (65 mg, 0.250 mmol), 5-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (50 mg, 0.208 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (102 mg, 0.312 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (300 MHz, DMSO-d6) δ 7.10-6.46 (m, 6H), 3.82 (s, 3H), 3.48 (s, 3H), 3.22 (s, 6H), 2.72 (s, 1H), 2.12-1.81 (m, 5H). Mass (m/z): 435.3 [M+H]+.
The title compound 382 (41.7 mg) was prepared in a total yield of 79.1% as a yellow solid from aniline (22 mg, 0.250 mmol), 5-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (50 mg, 0.208 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (102 mg, 0.312 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.20-7.14 (m, 2H), 7.03 (d, J=8.4 Hz, 1H), 7.00-6.95 (m, 2H), 6.89 (d, J=2.0 Hz, 1H), 6.81 (dd, J=8.4, 2.0 Hz, 1H), 6.72 (tt, J=7.2, 1.1 Hz, 1H), 3.29 (d, J=7.6 Hz, 6H). Mass (m/z): 254.3 [M+H]+.
The title compound 383 (3.7 mg) was prepared in a yield of 4.5% as a white powder from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (50 mg, 0.20 mmol) and 5-bromo-1-methyl-1H-indole-3-carboxamide (48 mg, 0.20 mmol) according to the procedure for compound 1. 1H NMR (DMSO-d6) δ 7.93 (s, 2H), 7.34 (s, 2H), 6.81 (d, J=119.4 Hz, 4H), 3.92 (s, 4H), 3.16 (s, 1H), 2.72-2.63 (m, 1H), 2.32 (p, J=1.9 Hz, 1H), 1.99 (q, J=6.9, 6.3 Hz, 3H), 1.42 (s, 1H), 0.90-0.79 (m, 1H). Mass (m/z): 417.4 [M+H]+.
The title compound 384 (30.2 mg) was prepared in a total yield of 33.4% as a yellow solid from 4-(4-methoxy-4-(trifluoromethyl)piperidin-1-yl) aniline (68 mg, 0.250 mmol), 5-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (50 mg, 0.208 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (102 mg, 0.312 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, Pyridine-d5) δ 8.90 (s, 2H), 8.60 (s, 3H), 8.46 (s, 1H), 8.37 (d, J=8.4 Hz, 1H), 4.95 (s, 2H), 4.86 (q, J=1.2 Hz, 3H), 4.78 (s, 3H), 4.72 (s, 3H), 4.40 (s, 2H), 3.54-3.37 (m, 4H). Mass (m/z): 435.3 [M+H]+.
The title compound 385 (19.4 mg) was prepared in a total yield of 25.3% as a blue solid from 4-(4-(fluoromethyl)piperidin-1-yl)aniline (52 mg, 0.250 mmol), 5-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (50 mg, 0.208 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (102 mg, 0.312 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.83 (s, 1H), 7.12 (d, J=8.4 Hz, 1H), 6.99 (d, J=8.4 Hz, 2H), 6.89 (d, J=8.4 Hz, 2H), 6.74 (s, 1H), 6.63 (d, J=8.8 Hz, 1H), 4.40 (d, J=6.0 Hz, 1H), 4.28 (d, J=5.6 Hz, 1H), 3.57 (d, J=12.0 Hz, 2H), 3.24 (d, J=3.2 Hz, 6H), 2.60 (t, J=12.0 Hz, 2H), 1.74 (d, J=13.2 Hz, 3H), 1.36 (d, J=12.4 Hz, 2H). Mass (m/z): 369.3 [M+H]+.
The title compound 386 (23.6 mg) was prepared in a total yield of 25.6% as a yellow solid from 4-(4-methoxy-4-(trifluoromethyl)piperidin-1-yl) aniline (72 mg, 0.263 mmol), 6-bromo-3-methylbenzo[d]oxazol-2(3H)-one (50 mg, 0.219 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (129 mg, 0.394 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.83 (s, 1H), 7.06 (d, J=8.4 Hz, 1H), 6.99-6.88 (m, 5H), 6.79 (dd, J=8.4, 2.0 Hz, 1H), 3.46 (d, J=12.4 Hz, 2H), 3.39 (d, J=1.2 Hz, 3H), 3.29 (s, 3H), 2.75 (td, J=12.4, 2.4 Hz, 2H), 2.03-1.95 (m, 2H), 1.83 (td, J=13.2, 4.4 Hz, 2H). Mass (m/z): 422.3 [M+H]+.
The title compound 387 (29.7 mg) was prepared in a total yield of 38.2% as a white solid from 4-(4-(fluoromethyl)piperidin-1-yl)aniline (55 mg, 0.263 mmol), 6-bromo-3-methylbenzo[d]oxazol-2(3H)-one (50 mg, 0.219 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (129 mg, 0.394 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.83 (s, 1H), 7.12 (d, J=8.4 Hz, 1H), 6.99 (d, J=8.4 Hz, 2H), 6.89 (d, J=8.4 Hz, 2H), 6.74 (s, 1H), 6.63 (d, J=8.8 Hz, 1H), 4.40 (d, J=6.0 Hz, 1H), 4.28 (d, J=5.6 Hz, 1H), 3.57 (d, J=11.6 Hz, 2H), 3.27 (s, 3H), 2.60 (t, J=12.0 Hz, 2H), 1.74 (d, J=13.2 Hz, 3H), 1.36 (d, J=12.4 Hz, 2H). Mass (m/z): 356.3 [M+H]+.
The title compound 388 (5.3 mg) was prepared in a total yield of 5.2% as a light yellow powder from 5-fluoro-6-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-amine (87.0 mg, 0.33 mmol), 5-bromo-3-methylbenzo[d]oxazol-2(3H)-one (57 mg, 0.25 mmol), Pd2(dba)3 (2.3 mg, 2.5 umol), X-Phos (6.0 mg, 12.5 umol), and Cs2CO3 (122 mg, 0.38 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.89 (dd, J=2.4, 1.0 Hz, 1H), 7.30 (dd, J=14.2, 2.4 Hz, 1H), 7.19 (d, J=8.6 Hz, 1H), 6.89 (d, J=2.3 Hz, 1H), 6.71 (dd, J=8.6, 2.3 Hz, 1H), 3.81-3.76 (m, 2H), 3.31 (s, 3H), 2.86-2.75 (m, 2H), 2.59-2.52 (m, 1H), 1.92-1.84 (m, 2H), 1.63-1.51 (m, 2H). Mass (m/z): 411.2 [M+H]+.
The title compound 389 (56.0 mg) was prepared in a total yield of 79.1% as a white solid from 4-(piperidin-1-yl)aniline (46 mg, 0.263 mmol), 5-bromo-3-methylbenzo[d]oxazol-2(3H)-one (50 mg, 0.219 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (129 mg, 0.394 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.77 (s, 1H), 7.04 (d, J=8.4 Hz, 1H), 6.96-6.88 (m, 2H), 6.80 (d, J=8.0 Hz, 2H), 6.67 (s, 1H), 6.55 (d, J=8.8 Hz, 1H), 3.19 (s, 3H), 2.94 (s, 4H), 1.55 (s, 4H), 1.43 (s, 2H). Mass (m/z): 324.3 [M+H]+.
The title compound 390 (52.0 mg) was prepared in a total yield of 56.3% as a white solid from 4-(4-methoxy-4-(trifluoromethyl)piperidin-1-yl)aniline (72 mg, 0.263 mmol), 5-bromo-3-methylbenzo[d]oxazol-2(3H)-one (50 mg, 0.219 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (129 mg, 0.394 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.13 (d, J=8.4 Hz, 1H), 7.04-6.89 (m, 4H), 6.76 (s, 1H), 6.64 (d, J=8.8 Hz, 1H), 3.47 (d, J=12.0 Hz, 2H), 3.40 (d, J=1.2 Hz, 3H), 3.27 (s, 3H), 2.78 (d, J=10.4 Hz, 2H), 2.01 (d, J=13.6 Hz, 2H), 1.86 (d, J=13.6 Hz, 2H). Mass (m/z): 422.3 [M+H]+.
The title compound 391 (25.9 mg) was prepared in a total yield of 33.3% as a white solid from 4-(4-(fluoromethyl)piperidin-1-yl)aniline (55 mg, 0.263 mmol), 5-bromo-3-methylbenzo[d]oxazol-2(3H)-one (50 mg, 0.219 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (129 mg, 0.394 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.83 (s, 1H), 7.12 (d, J=8.4 Hz, 1H), 6.99 (d, J=8.4 Hz, 2H), 6.89 (d, J=8.4 Hz, 2H), 6.74 (s, 1H), 6.63 (d, J=8.8 Hz, 1H), 4.40 (d, J=6.0 Hz, 1H), 4.28 (d, J=5.6 Hz, 1H), 3.57 (d, J=11.6 Hz, 2H), 3.27 (s, 3H), 2.60 (t, J=12.0 Hz, 2H), 1.74 (d, J=13.2 Hz, 3H), 1.36 (d, J=12.4 Hz, 2H). Mass (m/z): 356.3 [M+H]+.
The title compound 392 (75.1 mg) was prepared in a total yield of 89.4% as a white solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (60 mg, 0.248 mmol), 5-bromo-3-ethylbenzo[d]oxazol-2(3H)-one (50 mg, 0.207 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (122 mg, 0.372 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.92 (t, J=4.4 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 7.02-6.97 (m, 2H), 6.93-6.88 (m, 2H), 6.81 (d, J=2.0 Hz, 1H), 6.65 (dd, J=8.4, 2.0 Hz, 1H), 3.78 (q, J=7.2 Hz, 2H), 3.62 (d, J=12.0 Hz, 2H), 2.63 (td, J=12.4, 2.4 Hz, 2H), 2.43 (ddq, J=12.4, 8.8, 4.0 Hz, 1H), 1.93-1.84 (m, 2H), 1.57 (qd, J=12.4, 4.0 Hz, 2H), 1.22 (t, J=7.2 Hz, 3H). Mass (m/z): 406.3 [M+H]+.
The title compound 393 (58.0 mg) was prepared in a total yield of 72.5% as a white solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (54 mg, 0.221 mmol), 5-bromo-3-(2-methoxyethyl)benzo[d]oxazol-2(3H)-one (50 mg, 0.184 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (91 mg, 0.276 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.13 (d, J=8.4 Hz, 1H), 7.02-6.96 (m, 2H), 6.93-6.84 (m, 3H), 6.64 (dd, J=8.8, 2.0 Hz, 1H), 3.91 (t, J=5.2 Hz, 2H), 3.65-3.56 (m, 4H), 3.25 (s, 3H), 2.63 (t, J=12.0 Hz, 2H), 2.47-2.37 (m, 1H), 1.88 (d, J=12.4 Hz, 2H), 1.58 (d, J=12.8 Hz, 2H). Mass (m/z): 436.3 [M+H]+.
The title compound 394 (49.7 mg) was prepared in a total yield of 71.6% as a yellow solid from 4-cyclohexylaniline (44 mg, 0.248 mmol), 5-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (50 mg, 0.207 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (102 mg, 0.310 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.86 (s, 1H), 7.05-6.99 (m, 3H), 6.95-6.89 (m, 2H), 6.85 (d, J=2.1 Hz, 1H), 6.78 (dd, J=8.3, 2.1 Hz, 1H), 3.28 (d, J=7.9 Hz, 6H), 2.42-2.42 (m, 1H), 1.82-1.66 (m, 5H), 1.42-1.28 (m, 4H), 1.22 (s, 1H). Mass (m/z): 336.3 [M+H]+.
The title compound 395 (17.1 mg) was prepared in a total yield of 84.8% as a yellow solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (15.9 mg, 0.065 mmol), 6-bromo-4-methoxy-1-methyl-1H-indole (12.0 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.10-6.78 (m, 5H), 6.58 (s, 1H), 6.26 (d, J=2.8 Hz, 2H), 3.80 (s, 3H), 3.60 (s, 3H), 3.58-3.51 (m, 2H), 2.69-2.52 (m, 2H), 2.38 (m, 1H), 1.94-1.79 (m, 2H), 1.66-1.49 (m, 2H). Mass (m/z): 404.2 [M+H]+.
The title compound 396 (17.1 mg) was prepared in a total yield of 84.8% as a yellow solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (15.9 mg, 0.065 mmol), 6-bromo-N-(cyclopropylmethyl)-1-methyl-1H-indol-2-amine (13.9 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.43-6.58 (m, 7H), 3.75-3.45 (m, 5H), 3.40-3.22 (m, 2H), 2.80-2.54 (m, 2H), 2.41 (m, 1H), 1.98-1.82 (m, 2H), 1.69-1.47 (m, 2H), 1.29-1.14 (m, 1H), 0.57-0.46 (m, 2H), 0.43-0.24 (m, 2H). Mass (m/z): 443.2 [M+H]+
The title compound 397 (20.3 mg) was prepared in a total yield of 81.8% as a yellow solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (15.9 mg, 0.065 mmol), 6-bromo-N,N-bis(cyclopropylmethyl)-1-methyl-1H-indol-2-amine (16.7 mg, 0.05 mmol), Pd2(dba)3 (0.92 mg, 0.001 mmol), X-Phos (2.38 mg, 0.005 mmol) and Cs2CO3 (24.4 mg, 0.075 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.40-6.49 (m, 8H), 3.70-3.42 (m, 5H), 3.16 (d, J=6.8 Hz, 4H), 2.79-2.55 (m, 2H), 2.37 (m, 1H), 1.95-1.81 (m, 2H), 1.68-1.47 (m, 2H), 1.10-0.94 (m, 2H), 0.50-0.32 (m, 4H), 0.19-0.10 (m, 4H). Mass (m/z): 497.3 [M+H]+.
The title compound 398 (8.2 mg) was prepared in a yield of 9.9% as a white powder from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (50 mg, 0.20 mmol) and 5-bromo-1H-indazole-1-carboxamide (49 mg, 0.20 mmol) according to the procedure for compound 1. 1H NMR (DMSO-d6) δ 8.13 (d, J=0.8 Hz, 1H), 8.06 (d, J=9.0 Hz, 1H), 7.89 (s, 1H), 7.58 (d, J=45.8 Hz, 2H), 7.28-7.23 (m, 1H), 7.18 (dd, J=9.0, 2.2 Hz, 1H), 7.02 (d, J=8.9 Hz, 2H), 6.92 (d, J=8.5 Hz, 2H), 3.63 (d, J=12.2 Hz, 1H), 2.67 (q, J=1.9 Hz, 2H), 2.32 (d, J=1.9 Hz, 1H), 1.87 (s, 2H), 1.58 (dd, J=12.2, 4.0 Hz, 2H). Mass (m/z): 404.6 [M+H]+.
The title compound 399 (34.3 mg) was prepared in a total yield of 41.6% as a white solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (58 mg, 0.237 mmol), 4-bromo-N,N,1-trimethyl-1H-indol-3-amine (50 mg, 0.198 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (97 mg, 0.297 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.69 (s, 1H), 7.31-7.01 (m, 6H), 6.90 (s, 1H), 3.78 (s, 3H), 3.65 (d, J=12.0 Hz, 2H), 3.13 (s, 6H), 2.62 (s, 1H), 2.02 (d, J=13.6 Hz, 2H), 1.77 (d, J=12.4 Hz, 2H). Mass (m/z): 417.3 [M+H]+.
The title compound 400 (49.1 mg) was prepared in a total yield of 60.1% as a white solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (57 mg, 0.232 mmol), 5-bromo-7-methoxy-3-methylbenzo[d]oxazol-2(3H)-one (50 mg, 0.194 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (95 mg, 0.291 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.05-6.99 (m, 2H), 6.94-6.88 (m, 2H), 6.37 (s, 2H), 3.83 (s, 3H), 3.64 (d, J=12.4 Hz, 2H), 3.24 (s, 3H), 2.63 (dd, J=13.2, 10.7 Hz, 2H), 2.42 (td, J=8.8, 4.0 Hz, 1H), 1.93-1.82 (m, 2H), 1.57 (qd, J=12.4, 4.0 Hz, 2H). Mass (m/z): 422.3 [M+H]+.
The title compound 401 (23.6 mg) was prepared in a yield of 28.7% as a white powder from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (50 mg, 0.20 mmol) and 5-bromo-N-ethyl-1-methyl-1H-benzo[d]imidazol-2-amine (48 mg, 0.20 mmol) according to the procedure for compound 1. 1H NMR (DMSO-d6) δ 12.75 (s, 1H), 8.66 (s, 1H), 8.15 (s, 1H), 7.17 (d, J=87.5 Hz, 6H), 4.22 (s, 5H), 3.59 (d, J=40.2 Hz, 7H), 1.96 (s, 1H), 1.69 (s, 1H), 1.27 (t, J=7.2 Hz, 3H). Mass (m/z): 418.6 [M+H]+.
The title compound 402 (28.5 mg) was prepared in a total yield of 36.1% as a white solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (52 mg, 0.213 mmol), 6-bromo-N,N-diethyl-1-methyl-1H-benzo[d]imidazol-2-amine (50 mg, 0.177 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (87 mg, 0.265 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, Pyridine-d5) δ 7.76 (s, 1H), 7.05 (s, 2H), 3.56 (s, 2H), 3.36 (s, 3H), 3.33-3.20 (m, 4H), 2.52 (s, 2H), 2.12 (s, 1H), 1.78 (s, 2H), 1.66 (d, J=12.8 Hz, 2H), 1.24 (d, J=6.4 Hz, 1H), 1.09 (t, J=7.2 Hz, 6H). Mass (m/z): 446.3 [M+H]+.
The title compound 403 (9.6 mg) was prepared in a total yield of 11.5% as a light yellow powder from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (63 mg, 0.26 mmol, 6-bromo-1-methyl-1H-indole-3-carboxamide (50 mg, 0.20 mmol), Pd2(dba)3 (2.3 mg, 2.5 umol), X-Phos (6.0 mg, 12.5 umol), and Cs2CO3 (122 mg, 0.38 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.91 (d, J=8.5 Hz, 1H), 7.76 (d, J=7.3 Hz, 2H), 7.22 (s, 1H), 7.05-7.01 (m, 2H), 6.96 (d, J=1.9 Hz, 1H), 6.92-6.86 (m, 2H), 6.82 (dd, J=8.7, 2.0 Hz, 1H), 6.68 (s, 1H), 3.67 (s, 3H), 3.64-3.58 (m, 2H), 2.69-2.59 (m, 2H), 2.46-2.38 (m, 1H), 1.92-1.85 (m, 2H), 1.64-1.50 (m, 2H). Mass (m/z): 417.2 [M+H]+.
The title compound 404 (90.3 mg) was prepared in a total yield of 67.4% as a white solid from 4-(trifluoromethyl)aniline (80 mg, 0.450 mmol), 5-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (100 mg, 0.417 mmol), Pd2(dba)3 (4 mg, 0.004 mmol), X-phos (12 mg, 0.02 mmol), Cs2CO3 (200 mg, 0.625 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 1H), 7.46 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.0 Hz, 1H), 7.08-6.98 (m, 3H), 6.90 (dd, J=8.4, 2.0 Hz, 1H), 3.31 (d, J=6.8 Hz, 6H). Mass (m/z): 322.3 [M+H]+.
The title compound 405 (11.0 mg) was prepared in a total yield of 19.4% as a green solid from 4-(4,4-dimethylcyclohexyl)aniline (30 mg, 0.148 mmol), 5-bromo-1-(2-(dimethylamino)ethyl)-3-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (40 mg, 0.135 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (66 mg, 0.202 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 9.44 (s, 1H), 7.90 (s, 1H), 7.15 (d, J=8.4 Hz, 1H), 7.08 (d, J=8.4 Hz, 2H), 6.97-6.89 (m, 3H), 6.79 (dd, J=8.4, 2.0 Hz, 1H), 4.18 (t, J=6.0 Hz, 2H), 3.29 (s, 3H), 2.89 (s, 6H), 2.29 (dt, J=10.4, 5.2 Hz, 1H), 1.61-1.38 (m, 6H), 1.28 (ddd, J=23.2, 11.6, 4.4 Hz, 3H), 0.95 (d, J=9.6 Hz, 6H). Mass (m/z): 421.3 [M+H]+.
The title compound 406 (6.8 mg) was prepared in a total yield of 11.1% as a white solid from 4-(4,4-dimethylcyclohexyl)aniline (39 mg, 0.193 mmol), 6-bromo-3-methylbenzo[d]oxazol-2(3H)-one (40 mg, 0.175 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (84 mg, 0.262 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.10 (dd, J=8.4, 2.0 Hz, 3H), 7.00 (d, J=2.0 Hz, 1H), 6.96-6.92 (m, 2H), 6.89 (dd, J=8.4, 2.0 Hz, 1H), 3.30 (s, 3H), 2.31 (tt, J=10.4, 5.2 Hz, 1H), 1.60-1.54 (m, 3H), 1.48-1.41 (m, 2H), 1.35-1.21 (m, 3H), 0.95 (d, J=10.0 Hz, 6H). Mass (m/z): 351.3 [M+H]+.
The title compound 407 (4.4 mg) was prepared in a total yield of 7.2% as a green solid from 4-(4,4-dimethylcyclohexyl)aniline (37 mg, 0.183 mmol), 5-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (40 mg, 0.167 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (80 mg, 0.250 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.83 (s, 1H), 7.09-7.03 (m, 2H), 7.00 (d, J=8.4 Hz, 1H), 6.94-6.89 (m, 2H), 6.85 (d, J=2.0 Hz, 1H), 6.77 (dd, J=8.4, 2.0 Hz, 1H), 3.28 (d, J=8.0 Hz, 6H), 2.28 (dt, J=10.4, 5.2 Hz, 1H), 1.61-1.54 (m, 3H), 1.44 (d, J=12.8 Hz, 2H), 1.29 (td, J=12.8, 6.0 Hz, 3H), 0.94 (d, J=10.0 Hz, 6H). Mass (m/z): 364.3 [M+H]+.
A solution of 4-(4-(4,4-dimethylcyclohexyl)phenoxy)aniline (50 mg, 0.17 mmol), NaSCN (16.5 mg, 0.20 mmol) and Br2 (32 mg, 0.20 mmol) in HOAc (1 mL) was stirred at r.t. for 18 hours. After filtration, the filtrate was concentrated under vacuum. The residue was purified by prep-HPLC (column-Xbridge-C18 150×19 mm, 5 um; Mobile phase: ACN-H2O (0.1% FA), 25%-40%) to afford 408 (22.3 mg) as a white solid. Mass (m/z): 353.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.43 (d, J=2.6 Hz, 1H), 7.34 (d, J=8.8 Hz, 1H), 7.22-7.19 (m, 2H), 6.96 (dd, J=8.8, 2.5 Hz, 1H), 6.87-6.84 (m, 2H), 2.36 (td, J=10.6, 4.9 Hz, 1H), 1.54 (dt, J=16.4, 5.9 Hz, 4H), 1.41 (d, J=12.4 Hz, 2H), 1.31-1.24 (m, 2H), 0.91 (d, J=10.0 Hz, 6H).
A solution of N1-(4-(4,4-dimethylcyclohexyl)phenyl)benzene-1,4-diamine (60 mg, 0.20 mmol), NaSCN (20.0 mg, 0.24 mmol) and Br2 (39.0 mg, 0.24 mmol) in MeOH (2 mL) was stirred at r.t. for 18 hours. The solids were filtered, the filtrate was concentrated under vacuum. The residue was purified by prep-HPLC (column-Xbridge-C18 150×19 mm, 5 um; Mobile phase: ACN-H2O (0.1% FA), 25%-40%) to afford compound 409 (5.0 mg) as a white solid. Mass (m/z): 352.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 7.29 (d, J=2.2 Hz, 1H), 7.24 (d, J=8.6 Hz, 1H), 7.07 (d, J=8.4 Hz, 2H), 6.98 (dd, J=8.6, 2.4 Hz, 1H), 6.95 (d, J=8.6 Hz, 2H), 2.38-2.31 (m, 1H), 1.64 (d, J=3.0 Hz, 2H), 1.50 (d, J=12.0 Hz, 2H), 1.33 (dd, J=20.0, 6.8 Hz, 4H), 1.00 (s, 3H), 0.95 (s, 3H).
To a solution of 2-methyl-4-(4-(trifluoromethyl)piperidin-1-yl)aniline (72 mg, 0.278 mmol) and 5-bromoisoindoline (50 mg, 0.253 mmol) in 1,4-dioxane (5 mL) was added BrettPhos Pd G3 (23 mg, 0.025 mmol), BrettPhos (27 mg, 0.051 mmol) and Cs2CO3 (247 mg, 0.759 mmol), then the mixture was stirred at 110° C. for 16 h. The mixture was extracted by EA (25 mL×3). The combined organic layers were washed with brine (15 mL×3), dried over Na2SO4 and concentrated to give the crude product, which was purified by TLC (MeOH/DCM=1/5) to give the desired product as a yellow solid (14.2 mg, 14.9%). 1H NMR (400 MHz, DMSO-d6) δ 6.97 (t, J=8.0 Hz, 2H), 6.84 (s, 1H), 6.75 (d, J=9.2 Hz, 1H), 6.51 (d, J=6.4 Hz, 2H), 3.92 (d, J=6.0 Hz, 3H), 3.68 (d, J=12.4 Hz, 2H), 2.66 (q, J=12.4 Hz, 3H), 2.44 (d, J=10.0 Hz, 1H), 2.12 (s, 3H), 1.88 (d, J=12.4 Hz, 2H), 1.56 (q, J=12.4 Hz, 2H). Mass (m/z): 376.3 [M+H]+.
To a solution of 5-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (134 mg, 0.558 mmol) and 4-(tert-pentyl)aniline (100 mg, 0.613 mmol) in dioxane (5 mL) was added Pd2(dba)3 (25.5 mg, 0.028 mmol), X-phos (26.6 mg, 0.0558 mmol) and Cs2CO3 (364 mg, 1.12 mmol) under nitrogen atmosphere. Then the mixture was stirred at 100° C. overnight. The mixture was extracted by EA (25 mL×3). The combined organic layers were washed with brine (15 mL×3), dried over Na2SO4 and concentrated to give the crude product, which was purified by pre-HPLC to give the desired product as a white solid (20.3 mg, 24.0%). H NMR (300 MHz, DMSO-d6) δ 7.82 (s, 1H), 7.13 (d, J=8.6 Hz, 2H), 6.99 (d, J=8.3 Hz, 1H), 6.92 (d, J=8.6 Hz, 2H), 6.85 (d, J=2.0 Hz, 1H), 6.77 (dd, J=8.3, 2.0 Hz, 1H), 3.28 (d, J=4.9 Hz, 6H), 1.55 (t, J=7.4 Hz, 2H), 1.20 (s, 6H), 0.64 (t, J=7.4 Hz, 3H). Mass (m/z): 324.2 [M+H]+
The title compound 412 (37.7 mg) was prepared in a total yield of 36.5% as a purple powder from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (70 mg, 0.29 mmol), 3-(5-bromo-1H-indazol-1-yl)propanamide (63 mg, 0.24 mmol), Pd2(dba)3 (2.3 mg, 2.5 umol), X-Phos (6.0 mg, 12.5 umol), and Cs2CO3 (122 mg, 0.38 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.81 (s, 1H), 7.55 (s, 2H), 7.32-6.68 (m, 7H), 4.63 (t, J=6.8 Hz, 2H), 3.75-3.48 (m, 2H), 2.79 (t, J=6.8 Hz, 2H), 2.74-2.47 (m, 2H), 2.35-2.22 (m, 1H), 2.04-1.88 (m, 2H), 1.80-1.64 (m, 2H). Mass (m/z): 432.1 [M+H]+.
The title compound 413 (16.5 mg) was prepared in a total yield of 16.0% as a purple powder from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (70 mg, 0.29 mmol), 3-(5-bromo-2H-indazol-2-yl)propanamide (63 mg, 0.24 mmol), Pd2(dba)3 (2.3 mg, 2.5 umol), X-Phos (6.0 mg, 12.5 umol), and Cs2CO3 (122 mg, 0.38 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.91 (s, 2H), 7.46 (d, J=9.4 Hz, 1H), 7.30-6.71 (m, 7H), 4.63 (t, J=6.8 Hz, 2H), 3.75-3.48 (m, 2H), 2.89 (t, J=6.8 Hz, 2H), 2.80-2.61 (m, 2H), 2.35-2.22 (m, 1H), 2.04-1.88 (m, 2H), 1.80-1.64 (m, 2H). Mass (m/z): 432.1 [M+H]+.
To a solution of tert-butyl (3-(5-((4-(4-(trifluoromethyl)piperidin-1-yl) phenyl)amino)-1H-indazol-1-yl)propyl)carbamate (116 mg, 0.22 mol) in THF (10 mL) was added LiAlH4 (17 mg, 0.45 mol) at 0° C., and the mixture was refluxed for 2 h. After cooling to 0° C., water (17 μL), 10% NaOH (34 μL) and water (51 μL) were added, and the mixture was stirred for 3 min at room temperature. The solid was filtered and the filtered gray cake was washed with THF (10 mL×2); then the combined filtrates were dried over Na2SO4 and concentrated. The residue was purified by prep-TLC (MeOH/DCM=1/5) to give the desired products as a white solid. (28.5 mg, 29.5%). 1H NMR (400 MHz, DMSO-D6) δ 8.67 (s, 1H), 7.83 (s, 1H), 7.68 (s, 1H), 7.53 (d, J=8.9 Hz, 1H), 7.19 (s, 1H), 7.08 (dd, J=9.1, 2.0 Hz, 1H), 6.93 (d, J=8.7 Hz, 2H), 6.86 (d, J=8.6 Hz, 2H), 4.40 (t, J=6.7 Hz, 2H), 3.56 (d, J=11.7 Hz, 2H), 2.91-2.79 (m, 2H), 2.62-2.55 (m, 2H), 2.39 (s, 1H), 2.10 (p, J=6.9 Hz, 2H), 1.85 (d, J=12.5 Hz, 2H), 1.67-1.44 (m, 2H). Mass (m/z): 432.3 [M+H]+.
The title compound 415 (129 mg) was prepared in a total yield of 54.6% as a yellow powder from tert-butyl (3-(5-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)amino)-2H-indazol-2-yl)propyl)carbamate (176 mg, 0.5 mmol) and LiAlH4 (38 mg, 0.45 mol) according to the procedure for compound 414. 1H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 2H), 8.06 (s, 1H), 7.67 (s, 1H), 7.44 (d, J=9.2 Hz, 1H), 7.05-6.88 (m, 5H), 4.42 (t, J=6.7 Hz, 2H), 3.57 (d, J=12.0 Hz, 2H), 2.92-2.75 (m, 2H), 2.62-2.54 (m, 2H), 2.45-2.32 (m, 1H) 2.27-2.14 (m, 2H), 1.92-1.80 (m, 2H), 1.62-1.47 (m, 2H). Mass (m/z): 432.3 [M+H]+.
TFA (1 mL) was added to a solution of tert-butyl (3-(5-((4-(2,6-dimethylmorpholino)phenyl)amino)-2-oxobenzo[d]oxazol-3(2H)-yl)pr opyl)(methyl)carbamate (130 mg, 0.25 mmol) in dichloromethane (5 mL). The mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum. The residue was diluted with a saturated solution of NaHCO3 (30 mL) and extracted with dichloromethane (3×50 mL). The combined organic phases were dried and concentrated. The residue was purified by Prep-HPLC with the following conditions: Column: Spherical C18 40-60 um, 40 g; Mobile phase A: water (0.5% NH4HCO3); Mobile phase B: acetonitrile or ACN; Flow rate: 45 mL/min; Gradient: 30% B-65% B in 20 min; Detector: 254 nm. The fractions containing desired product were collected at 55% B and concentrated under reduced pressure to give the titled compound 416 (51 mg, 48.8%) as a grey solid. LC-MS (m/z) 411.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 7.87 (s, 1H), 7.15 (d, J=8.6 Hz, 1H), 7.03-6.97 (m, 2H), 6.93-6.84 (m, 3H), 6.64 (dd, J=8.6, 2.2 Hz, 1H), 3.84 (t, J=6.7 Hz, 2H), 3.69 (dtt, J=12.6, 6.4, 3.7 Hz, 2H), 3.48-3.40 (m, 2H), 3.31 (s, 3H), 2.95-2.86 (m, 2H), 2.19 (dd, J=11.8, 10.2 Hz, 2H), 1.99 (p, J=6.9 Hz, 2H), 1.14 (d, J=6.2 Hz, 6H).
To a solution of 3-(2-aminoethyl)-5-((4-(4-(trifluoromethyl) piperidin-1-yl)phenyl)amino)benzo[d]oxazol-2(3H)-one (crude) in DMSO (6 mL) was added phenyl carbamate (8 mg, 0.0577 mmol), TEA (7.5 mg, 0.0722 mmol). Then the mixture was stirred at 60° C. for 2 hours. The mixture was diluted with water and extracted by EA (25 mL×3). The combined organic layers were washed with brine (15 mL×3), dried over Na2SO4 and concentrated to give the crude product, which was purified by pre-HPLC to give the desired product as a blue solid (17.2 mg, 77%). 1H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J=11.5 Hz, 1H), 7.08 (d, J=8.6 Hz, 1H), 6.99-6.92 (m, 2H), 6.89-6.84 (m, 2H), 6.76 (t, J=9.0 Hz, 1H), 6.58 (dt, J=11.3, 5.7 Hz, 1H), 6.17-6.03 (m, 1H), 5.41 (d, J=35.3 Hz, 2H), 3.76-3.65 (m, 2H), 3.56 (t, J=15.9 Hz, 2H), 3.21 (dd, J=15.1, 9.1 Hz, 2H), 1.85 (d, J=12.1 Hz, 3H), 1.63-1.47 (m, 3H). Mass (m/z): 464.2 [M+H]+.
To a solution of tert-butyl methyl(3-(2-oxo-5-((4-(4-(trifluoromethyl) piperidin-1-yl)phenyl)amino)benzo[d]oxazol-3(2H)-yl)propyl)carbamate (crude) in DCM (6 mL) was added TFA (2 mL). The mixture was stirred at r.t. for 0.5 hour. Then the mixture was concentrated to give the crude product, which was purified by pre-HPLC to give the desired product as a purple solid (13.9 mg, 12.6%). 1H NMR (400 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.11 (d, J=8.6 Hz, 1H), 6.96 (d, J=9.0 Hz, 2H), 6.89-6.80 (m, 3H), 6.62 (dd, J=8.7, 2.2 Hz, 1H), 3.81 (t, J=6.8 Hz, 2H), 3.69-3.51 (m, 2H), 2.94-2.77 (m, 2H), 2.76-2.56 (m, 3H), 2.43 (s, 3H), 2.06-1.73 (m, 4H), 1.54 (qd, J=12.4, 4.0 Hz, 2H). Mass (m/z): 449.2 [M+H]+.
To a solution of 2-(2-aminoethyl)-N-(4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)-2H-indazol-5-amine (66 mg, 0.15 mmol) and TEA (45 mg, 0.45 mmol) in DMSO (1 mL) was added phenyl carbamate (21 mg, 0.15 mmol). Then the mixture was stirred for 1 hour at 60° C. After cooling to r.t., 10 mL of water was added. The resulting solution was extracted with 3×10 mL of ethyl acetate. The organic layers were combined, washed with water (3×15 mL), dried and concentrated under vacuum. The residue was purified by prep-TLC (MeOH/DCM=1/10) to afford the desired product as a yellow solid (10.0 mg, 15.0%). 1H NMR (400 MHz, DMSO-d6) δ 7.96 (d, J=1.0 Hz, 1H), 7.61 (s, 1H), 7.47-7.40 (m, 1H), 7.05-7.02 (m, 1H), 6.97-6.93 (m, 2H), 6.88-6.84 (m, 1H), 5.96 (t, J=5.9 Hz, 1H), 5.48 (s, 2H), 4.30 (t, J=6.0 Hz, 2H), 3.57 (d, J=12.3 Hz, 2H), 3.45 (q, J=6.0 Hz, 2H), 2.63-2.56 (m, 2H), 2.44-2.33 (m, 1H), 1.88-1.80 (m, 2H), 1.62-1.47 (m, 1H). Mass (m/z): 447.2 [M+H]+.
The titled compound 420 (62.3 mg, 30.9%) was obtained as an off-white solid according to the procedure outlined for compound 1. LC-MS (m/z) 354.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.83 (s, 1H), 7.12 (d, J=8.6 Hz, 1H), 7.04-6.96 (m, 2H), 6.94-6.84 (m, 2H), 6.74 (d, J=2.3 Hz, 1H), 6.62 (dd, J=8.6, 2.3 Hz, 1H), 3.69 (dqd, J=12.4, 6.2, 2.2 Hz, 2H), 3.45 (dt, J=10.8, 2.0 Hz, 2H), 3.26 (s, 3H), 2.19 (dd, J=11.8, 10.2 Hz, 2H), 1.14 (d, J=6.2 Hz, 6H).
The title compound 421 (19.9 mg) was prepared in a total yield of 29.9% as a light yellow powder from 1-(2-aminoethyl)-N-(4-(4-(trifluoromethyl) piperidin-1-yl)phenyl)-1H-indazol-5-amine (66 mg, 0.15 mmol), TEA (48 mg, 0.45 mmol) and phenyl carbamate (21 mg, 0.15 mmol) according to the procedure for compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.84 (s, 1H), 7.50-6.65 (m, 8H), 4.44 (t, J=6.0 Hz, 2H), 3.75-3.52 (m, 4H), 2.78-2.53 (m, 2H), 2.34-2.20 (m, 2H), 2.05-1.92 (m, 2H), 1.82-1.66 (m, 2H). Mass (m/z): 447.3 [M+H]+.
The titled compound 422 (89.6 mg, 30.9%) as a gray solid was prepared according to the procedure outlined for compound 1. LC-MS (m/z) 337.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 2H), 7.51 (s, 1H), 7.18 (s, 3H), 7.02 (s, 3H), 4.10 (s, 3H), 3.84 (s, 2H), 3.48 (s, 2H), 2.75-2.60 (m, 2H), 1.17 (d, J=6.2 Hz, 6H).
The titled compound 423 (68.1 mg, 30.9%) as a light yellow solid was prepared according to the procedure outlined for compound 1. LC-MS (m/z) 337.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 2H), 7.50 (s, 1H), 7.20 (s, 3H), 7.02 (s, 3H), 4.05 (s, 3H), 3.81 (s, 2H), 3.45 (s, 2H), 2.74-2.60 (m, 2H), 1.17 (d, J=6.2 Hz, 6H).
To a solution of 5-bromo-3-(2-(dimethylamino)ethyl)benzo[d]oxazol-2(3H)-one (96.5 mg, 0.339 mmol) and 4-(2,6-dimethylmorpholino)aniline (70 mg, 0.339 mmol) in dioxane (5 mL) was added Pd2(dba)3 (15.6 mg, 0.017 mmol), X-phos (16.2 mg, 0.0339 mmol) and Cs2CO3 (166.2 mg, 0.51 mmol) under nitrogen atmosphere. Then the mixture was stirred at 100° C. overnight. The mixture was extracted by EA (25 mL×3). The combined organic layers were washed with brine (15 mL×3), dried over Na2SO4 and concentrated to give the crude product, which was purified by pre-HPLC to give the desired product as a pink solid (35.2 mg, 25.3%). 1H NMR (400 MHz, DMSO-d6) δ 7.81 (s, 1H), 6.99 (dd, J=15.6, 8.9 Hz, 3H), 6.88 (d, J=9.0 Hz, 2H), 6.61 (dd, J=8.7, 2.4 Hz, 1H), 6.53 (d, J=2.4 Hz, 1H), 5.76 (s, 1H), 4.54 (s, 2H), 3.93 (t, J=6.9 Hz, 2H), 3.75-3.62 (m, 3H), 3.45 (d, J=10.6 Hz, 2H), 2.39 (t, J=6.9 Hz, 2H), 2.23-2.12 (m, 7H), 2.06 (s, 1H), 1.15 (t, J=5.7 Hz, 6H). Mass (m/z): 411.2 [M+H]+.
To a solution of 5-((4-(2,6-dimethylmorpholino)phenyl)amino)-1-methyl-1H-indole-3-carboxylic acid (120 mg, 0.317 mmol) in DMF (5 mL) was added HATU (301 mg, 0.793 mmol), NH4Cl (33.9 mg, 0.633 mmol) and TEA (128 mg, 1.27 mmol). The mixture was stirred at 80° C. for 2 hours. Then the mixture was diluted with water and extracted by EA (25 mL×3). The combined organic layers were washed with brine (15 mL×3), dried over Na2SO4 and concentrated to give the crude product, which was purified by pre-HPLC to give the desired product as green solid (9.2 mg, 7.7%). 1H NMR (400 MHz, DMSO-d6) δ 7.92-7.76 (m, 2H), 7.57 (s, 1H), 7.32 (d, J=8.8 Hz, 1H), 6.97-6.88 (m, 3H), 6.84 (d, J=9.0 Hz, 2H), 3.75 (s, 3H), 3.72-3.63 (m, 2H), 3.45-3.36 (m, 2H), 2.17 (t, J=11.0 Hz, 2H), 1.14 (d, J=6.2 Hz, 6H). Mass (m/z): 379.2 [M+H]+.
The titled compound 426 (16.7 mg, 8%) as a purple solid was prepared from 4-(2,6-dimethylmorpholino)aniline (100 mg, 0.50 mmol), 5-bromo-1-(2-(dimethylamino)ethyl)-3-methyl-1H-benzo[d]imidazol-2(3H )-one (150 mg, 0.51 mmol), 1,4-dioxane (2 mL), Pd2(dba)3 (46 mg, 0.05 mmol), Xphos (48 mg, 0.10 mmol) and Cs2CO3 (329 mg, 1.01 mmol) according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.61 (s, 2H), 7.00 (d, J=8.3 Hz, 2H), 6.98-6.92 (m, 4H), 6.89-6.81 (m, 4H), 6.73 (d, J=2.1 Hz, 2H), 6.66 (dd, J=8.4, 2.1 Hz, 2H), 3.85 (t, J=6.6 Hz, 4H), 3.75-3.63 (m, 4H), 3.45-3.37 (m, 4H), 3.24 (s, 6H), 2.48 (s, 1H), 2.20 (s, 1H), 2.17 (s, 14H), 2.15 (s, 1H), 1.14 (d, J=6.2 Hz, 12H). Mass (m/z): 424.4 [M+H]+.
To a solution of tert-butyl (2-(5-((4-(2,6-dimethylmorpholino)phenyl) amino)-2-oxobenzo[d]oxazol-3(2H)-yl)ethyl)(methyl)carbamate (crude) in DCM (6 mL) was added TFA (2 mL). The mixture was stirred at r.t. for 0.5 hour. Then the mixture was concentrated to give the crude product, which was purified by pre-HPLC to give the desired product as gray solid (7.4 mg, 4.8%). 1H NMR (400 MHz, DMSO-d6) δ 7.57 (s, 1H), 6.97-6.87 (m, 4H), 6.86-6.75 (m, 3H), 6.58 (s, 1H), 3.77-3.60 (m, 7H), 3.39 (dd, J=18.6, 9.6 Hz, 3H), 2.52 (d, J=2.8 Hz, 2H), 2.20-2.10 (m, 2H), 1.13 (d, J=6.2 Hz, 6H). Mass (m/z): 397.2 [M+H]+.
To a solution of 5-bromo-1,3,3-trimethylindolin-2-one (135 mg, 0.53 mmol) and 4-(2,6-dimethylmorpholino)aniline (100 mg, 0.49 mmol) in 1,4-dioxane (2 mL) was added Pd2(dba)3 (44 mg, 0.05 mmol), Xphos (46 mg, 0.09 mmol) and Cs2CO3 (317 mg, 0.97 mmol) under nitrogen atmosphere. The mixture was stirred at 100° C. for 12 h, the mixture was purified by prep HPLC to give 5-((4-(2,6-dimethylmorpholino) phenyl)amino)-1,3,3-trimethylindolin-2-one (71 mg, 38%) as a light purple solid. Mass (m/z): 380.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.57 (s, 1H), 6.95-6.91 (m, 1H), 6.89-6.85 (m, 2H), 6.83-6.79 (m, 4H), 3.65 (s, 2H), 3.41-3.34 (m, 2H), 2.16-2.11 (m, 2H), 1.20 (s, 6H), 1.10 (d, J=6.2 Hz, 6H).
To a solution of 5-bromo-3-(2-(dimethylamino)ethyl)benzo[d]oxazol-2(3H)-one (70 mg, 0.25 mmol) and 5-bromo-2-methylisoindoline (66 mg, 0.27 mmol) in 1,4-dioxane (2 mL) was added Pd2(dba)3 (22 mg, 0.02 mmol), Xphos (23 mg, 0.04 mmol) and Cs2CO3 (161 mg, 0.50 mmol) under nitrogen atmosphere. The mixture was stirred at 100° C. for 12 h and the mixture was purified by flash chromatography to give 3-(2-(dimethylamino)ethyl)-5-((4-(4-(trifluoromethyl)piperidin-1-yl)pheny 1)amino)benzo[d]oxazol-2(3H)-one (25 mg, 22%) as a grey solid. 1H NMR (400 MHz, DMSO) δ 7.85 (s, 1H), 7.12 (d, J=8.6 Hz, 1H), 7.02-6.94 (m, 2H), 6.94-6.86 (m, 2H), 6.83 (d, J=2.2 Hz, 1H), 6.63 (dd, J=8.6, 2.3 Hz, 1H), 3.83 (t, J=6.2 Hz, 2H), 3.62 (d, J=12.0 Hz, 2H), 2.68-2.57 (m, 2H), 2.55-2.52 (m, 2H), 2.47-2.43 (m, 1H), 2.17 (s, 6H), 1.93-1.83 (m, 2H), 1.64-1.50 (m, 2H). Mass (m/z): 449.4 [M+H]+.
To a solution of 4-(2,6-dimethylmorpholino)aniline (100 mg, 0.48 mmol) and 5-bromo-2-methylisoindoline (113 mg, 0.53 mmol) in 1,4-dioxane (2 mL) was added Pd2(dba)3 (44 mg, 0.05 mmol), Xphos (46 mg, 0.10 mmol) and Cs2CO3 (316 mg, 0.97 mmol) under nitrogen atmosphere. The mixture was stirred at 100° C. for 12 h and the mixture was purified by flash chromatography to give N-(4-(2,6-dimethylmorpholino)phenyl)-2-methylisoindolin-5-amine (32 mg, 19%) as a light blue solid. 1H NMR (400 MHz, DMSO) δ 8.04 (s, 1H), 7.26-7.09 (m, 1H), 7.09-6.98 (m, 2H), 6.98-6.75 (m, 3H), 4.65-4.61 (m, 2H), 4.35-4.26 (m, 2H), 3.74-3.69 (m, 2H), 2.98-2.93 (m, 3H), 2.24-2.20 (m, 2H), 1.15 (d, J=6.2 Hz, 6H). LC-MS (m/z): 338.2 [M+H]+.
To a solution of 5-bromoisoindoline (105 mg, 0.53 mmol) and 4-(2,6-dimethylmorpholino)aniline (100 mg, 0.48 mmol) in 1,4-dioxane (2 mL) was added Brettphos Pd G3 (44 mg, 0.04 mmol), Brettphos (52 mg, 0.10 mmol) and Cs2CO3 (316 mg, 0.97 mmol) under nitrogen atmosphere. The mixture was stirred at 100° C. for 12 h, the mixture was purified by prep TLC then purified by flash chromatography to give N-(4-(2,6-dimethylmorpholino)phenyl)isoindolin-5-amine (86 mg, 54%) as a light yellow solid. Mass (m/z): 324.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.70 (s, 1H), 7.08-6.99 (m, 1H), 6.98-6.90 (m, 2H), 6.88-6.81 (m, 2H), 6.81-6.70 (m, 2H), 4.43 (d, J=7.7 Hz, 1H), 4.01 (d, J=5.4 Hz, 3H), 3.71-3.59 (m, 2H), 3.44-3.35 (m, 2H), 2.19-2.09 (m, 2H), 1.10 (d, J=6.3 Hz, 6H).
To a solution of tert-butyl 6-((4-(2,6-dimethylmorpholino)phenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate (100 mg, 0.22 mmol) in DCM (3 mL) was added 2,2,2-trifluoroacetic acid (1 mL). The mixture was stirred at r.t. for 1 h, the mixture was concentrated and purified by flash chromatography to give 6-((4-(2,6-dimethylmorpholino) phenyl)amino)-2-methyl-1H-indazol-3(2H)-one (32 mg, 41%) as a white solid. Mass (m/z): 353.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.63 (s, 1H), 8.20 (s, 1H), 7.32 (d, J=8.6 Hz, 1H), 7.07-6.99 (m, 2H), 6.94-6.86 (m, 2H), 6.57 (dd, J=8.6, 1.9 Hz, 1H), 6.46 (d, J=1.8 Hz, 1H), 3.72-3.60 (m, 2H), 3.51-3.43 (m, 2H), 3.18 (s, 3H), 2.23-2.13 (m, 2H), 1.12 (d, J=6.2 Hz, 6H).
The title compound 433 (3.8 mg) was prepared in a total yield of 4.3% as a white solid from 4-(4-(trifluoromethyl)piperidin-1-yl)aniline (64 mg, 0.259 mmol), 5-bromobenzo[d]oxazol-2(3H)-one (50 mg, 0.236 mmol), Pd2(dba)3 (2 mg, 0.002 mmol), X-phos (6 mg, 0.01 mmol), Cs2CO3 (115 mg, 0.354 mmol) and 1,4-dioxane (5 mL) according to the procedure for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.24 (s, 1H), 6.88-6.78 (m, 3H), 6.65 (d, J=8.0 Hz, 1H), 6.45 (d, J=2.4 Hz, 1H), 6.25 (dd, J=8.0, 2.0 Hz, 1H), 3.53 (d, J=12.0 Hz, 2H), 2.61-2.54 (m, 2H), 2.38 (dt, J=8.8, 4.8 Hz, 1H), 1.87 (d, J=12.0 Hz, 2H), 1.62-1.54 (m, 2H). Mass (m/z): 378.3 [M+H]+.
A mixture solution of 4-(2,6-dimethylmorpholino)aniline (0.2 g, 0.97 mmol), 5-bromo-1-methyl-1H-benzo[d]imidazole (0.22 g, 1.07 mmol), Pd2(dba)3 (88 mg, 0.1 mmol), Ruphos (89 mg, 0.2 mmol), Cs2CO3 (0.95 g, 0.3 mmol) and 1,4-dioxane (10 mL) was stirred at 100° C. under N2 atmosphere for 12 hrs. The mixture was concentrated and the residue was purified by prep-HPLC to give 434 as a yellow solid (0.11 g, 34.0%). Mass (m/z): 336.8 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.98 (s, 1H), 7.60 (s, 1H), 7.34 (d, J=8.4 Hz, 1H), 7.15 (d, J=2.0 Hz, 1H), 6.94-6.90 (m, 3H), 6.86-6.78 (m, 2H), 3.73 (s, 3H), 3.69-3.62 (m, 2H), 3.37 (d, J=10.4 Hz, 2H), 2.14 (dd, J=11.6, 10.4 Hz, 2H), 1.10 (d, J=6.0 Hz, 6H).
A mixture solution of tert-butyl (5-bromo-1-methyl-1H-benzo[d]imidazol-2-yl)(tert-butoxycarbonyl)carbamate (0.26 g, 0.61 mmol), 4-(2,6-dimethylmorpholino)aniline (0.25 g, 1.22 mmol), Pd2(dba)3 (56 mg, 0.06 mmol), Ruphos (57 mg, 0.12 mmol), Cs2CO3 (0.6 g, 1.83 mmol) and dioxane (10 mL) was stirred at 100° C. under N2 atmosphere for 12 hrs. The mixture was concentrated and the residue was purified by prep-HPLC to give compound 435 as a yellow solid (18.3 mg, 8.5%). Mass (m/z): 351.8 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.33 (s, 1H), 7.06-6.72 (m, 6H), 6.59 (s, 1H), 6.26 (s, 2H), 3.69 (s, 2H), 3.44 (s, 5H), 2.17 (d, J=10.4 Hz, 2H), 1.14 (s, 6H).
To a solution of tert-butyl (2-(5-((4-(2,6-dimethylmorpholino) phenyl) amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl) (methyl)carbamate (100 mg, 0.19 mmol) in DCM (3 mL) was added 2,2,2-trifluoroacetic acid (1 mL). The mixture was stirred at r.t. for 1 h, the mixture was concentrated and purified by prep HPLC to give 5-((4-(2,6-dimethylmorpholino)phenyl)amino)-3-methyl-1-(2-(methylamin o)ethyl)-1H-benzo[d]imidazol-2(3H)-one (23 mg, 28%) as a purple solid. Mass (m/z): 410.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.61 (s, 1H), 7.01 (d, J=8.3 Hz, 1H), 6.98-6.91 (m, 2H), 6.89-6.81 (m, 2H), 6.73 (d, J=2.1 Hz, 1H), 6.66 (dd, J=8.3, 2.1 Hz, 1H), 3.84 (t, J=6.4 Hz, 2H), 3.75-3.63 (m, 2H), 3.45-3.37 (m, 2H), 3.24 (s, 3H), 2.75 (t, J=6.5 Hz, 2H), 2.29 (s, 3H), 2.22-2.12 (m, 2H), 1.14 (d, J=6.2 Hz, 6H).
To a solution of 5-bromo-1-methyl-1H-indazole (105 mg, 0.5 mmol) and 4-(2,6-dimethylmorpholino)-2-methylaniline (100 mg, 0.45 mmol) in 1,4-dioxane (2 mL) was added Pd2(dba)3 (41 mg, 0.04 mmol), Xphos (43 mg, 0.09 mmol) and Cs2CO3 (296 mg, 0.91 mmol) under nitrogen atmosphere. The mixture was stirred at 100° C. for 12 h, the mixture was purified by flash chromatography to give N-(4-(2,6-dimethylmorpholino)-2-methylphenyl)-1-methyl-1H-indazol-5-amine (15 mg, 9%) as a light brown solid. Mass (m/z): 351.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J=1.0 Hz, 1H), 7.44 (d, J=8.9 Hz, 1H), 7.05-6.98 (m, 2H), 6.97 (d, J=8.7 Hz, 1H), 6.84 (d, J=2.8 Hz, 1H), 6.77-6.70 (m, 2H), 3.96 (s, 3H), 3.75-3.63 (m, 2H), 3.52-3.44 (m, 2H), 2.25-2.16 (m, 2H), 2.14 (s, 3H), 1.15 (d, J=6.2 Hz, 6H).
To a solution of 5-bromo-1,3,3-trimethylindolin-2-one (126 mg, 0.5 mmol) and 4-(2,6-dimethylmorpholino)-2-methylaniline (100 mg, 0.45 mmol) in 1,4-dioxane (2 mL) was added Pd2(dba)3 (41 mg, 0.04 mmol), Xphos (43 mg, 0.09 mmol) and Cs2CO3 (296 mg, 0.91 mmol) under nitrogen atmosphere. The mixture was stirred at 100° C. for 12 h, the mixture was purified by flash chromatography to give 5-((4-(2,6-dimethylmorpholino)-2-methylphenyl)amino)-1,3,3-trimethylindolin-2-one (48 mg, 26.8%) as a light pink solid. Mass (m/z): 395.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 6.99-6.92 (m, 2H), 6.84-6.75 (m, 3H), 6.71 (dd, J=8.6, 2.9 Hz, 1H), 6.56 (dd, J=8.3, 2.2 Hz, 1H), 3.74-3.62 (m, 2H), 3.52-3.43 (m, 2H), 3.07 (s, 3H), 2.24-2.15 (m, 2H), 2.13 (s, 3H), 1.21 (s, 6H), 1.14 (d, J=6.2 Hz, 6H).
To a solution of 4-(2,6-dimethylmorpholino)-2-methylaniline (100 mg, 0.45 mmol) and 5-bromo-2-methylisoindoline (86 mg, 0.40 mmol) in 1,4-dioxane (2 mL) was added Pd2(dba)3 (41 mg, 0.05 mmol), Xphos (43 mg, 0.09 mmol) and Cs2CO3 (296 mg, 0.91 mmol) under nitrogen atmosphere. The mixture was stirred at 100° C. for 12 h, the mixture was purified by flash chromatography to give N-(4-(2,6-dimethylmorpholino)-2-methylphenyl)-2-methylisoindolin-5-amine (15 mg, 9%) as a grey solid. 1H NMR (400 MHz, DMSO-d6) δ 7.50 (s, 1H), 7.09 (d, J=8.3 Hz, 1H), 6.98 (d, J=8.5 Hz, 1H), 6.90 (s, 1H), 6.81 (s, 1H), 6.64-6.58 (m, 1H), 6.53 (s, 1H), 4.63-4.55 (m, 2H), 4.31-4.21 (m, 2H), 3.73-3.66 (m, 2H), 3.54-3.46 (m, 2H), 2.93 (d, J=4.8 Hz, 3H), 2.28-2.24 (m, 2H), 2.10 (s, 3H), 1.14 (d, J=6.2 Hz, 6H).
To a solution of 5-bromoisoindoline (99 mg, 0.50 mmol) and 4-(2,6-dimethylmorpholino)-2-methylaniline (100 mg, 0.45 mmol) in 1,4-dioxane (2 mL) was added Brettphos Pd G3 (41 mg, 0.05 mmol), Brettphos (49 mg, 0.09 mmol) and Cs2CO3 (296 mg, 0.91 mmol) under a nitrogen atmosphere. The mixture was stirred at 100° C. for 12 h, the mixture was purified by prep TLC then purified by flash chromatography to give N-(4-(2,6-dimethylmorpholino)-2-methylphenyl)isoindolin-5-amine (71 mg, 48%) as a grey solid. Mass (m/z): 338.4 [M+H]+. 1H NMR (400 MHz, DMSO) δ 9.64 (s, 1H), 7.45 (s, 1H), 7.08 (d, J=8.3 Hz, 1H), 6.97 (d, J=8.5 Hz, 1H), 6.86 (s, 1H), 6.77 (s, 1H), 6.61 (d, J=8.3 Hz, 1H), 6.51 (s, 1H), 4.31 (d, J=5.6 Hz, 4H), 3.70-3.66 (m, 2H), 3.50 (d, J=11.6 Hz, 2H), 2.24-2.19 (m, 2H), 2.08 (d, J=14.6 Hz, 3H), 1.13 (d, J=6.2 Hz, 6H).
To a solution of 5-bromobenzo[d]oxazol-2(3H)-one (200 mg, 0.93 mmol) and 4-(2,6-dimethylmorpholino)aniline (193 mg, 0.93 mmol) in t-BuOH (5 mL) was added Pd2(dba)3 (42 mg, 0.05 mmol), Brettphos (50.1 mg, 0.09 mmol) and Cs2CO3 (609 mg, 1.87 mmol) under nitrogen atmosphere. The mixture was stirred at 100° C. for overnight. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×50 mL). The combined organic phases were dried and concentrated. The residue was purified by Prep-TLC (Petroleum ether:Ethyl acetate=1:5) and further purified by Prep-HPLC with the following conditions: Column: Spherical C18 40-60 um, 40 g; Mobile phase A: water (0.5% NH4HCO3); Mobile phase B: acetonitrile or ACN; Flow rate: 50 mL/min; Gradient: 20% B-65% B in 20 min; Detector: 254 nm. The fractions containing desired product were collected at 60% B and concentrated under reduced pressure to give the titled compound 441 (34.2 mg, 10.8%) as a white solid. LC-MS (m/z) 340.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 7.74 (s, 1H), 7.06 (d, J=8.5 Hz, 1H), 7.01-6.93 (m, 2H), 6.92-6.84 (m, 2H), 6.63-6.53 (m, 2H), 3.69 (dqd, J=12.5, 6.1, 2.2 Hz, 2H), 3.44 (dt, J=10.7, 2.0 Hz, 2H), 2.19 (dd, J=11.8, 10.2 Hz, 2H), 1.14 (d, J=6.2 Hz, 6H).
To a suspension of NH4Cl in toluene at 0° C. was treated with AlMe3, and the mixture was stirred at room temperature for 10 min. Methyl 6-((4-(2,6-dimethylmorpholino)phenyl)amino)-1-methyl-1H-indole-3-carb oxylate (85 mg, 0.22 mmol) in toluene (5 mL) was added to the above mixture. The mixture was heated to 80° C. and stirred for 6 h. The reaction mixture was cooled and quenched with water (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic phases were dried and concentrated. The residue was purified by Prep-TLC (Petroleum ether:Ethyl acetate=1:10) to give the titled compound 442 (44.4 mg, 54.3%) as a white solid. LC-MS (m/z) 379.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.04-7.6 (m, 3H), 7.75-6.52 (m, 8H), 3.74 (s, 3H), 3.69 (dqd, J=12.5, 6.1, 2.2 Hz, 2H), 3.44 (dt, J=10.7, 2.0 Hz, 2H), 2.19 (dd, J=11.8, 10.2 Hz, 2H), 1.14 (d, J=6.2 Hz, 6H).
A mixture of tert-butyl 5-((4-(2,6-dimethylmorpholino)-2-methylphenyl) amino)-1H-indazole-1-carboxylate (110 mg, 0.25 mmol) in HCl (4M in dioxane, 5 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum. The residue was diluted with a saturated solution of NaHCO3 (30 mL) and extracted with dichloromethane (3×50 mL). The combined organic phases were dried and concentrated. The residue was purified by Prep-HPLC with the following conditions: Column: Spherical C18 40-60 um, 40 g; Mobile phase A: water (0.5% NH4HCO3); Mobile phase B: acetonitrile or ACN; Flow rate: 45 mL/min; Gradient: 20% B-65% B in 20 min; Detector: 254 nm. The fractions containing desired product were collected at 45% B and concentrated under reduced pressure to give the titled compound 443 (11.7 mg, 13.8%) as a white solid. LC-MS (m/z) 337.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 7.74 (s, 1H), 7.06 (d, J=8.5 Hz, 1H), 7.01-6.93 (m, 2H), 6.92-6.84 (m, 2H), 6.63-6.53 (m, 2H), 3.83-3.61 (m, 2H), 3.44 (dt, J=10.7, 2.0 Hz, 2H), 3.33-3.29 (m, 2H), 2.19 (s, 3H), 1.14 (d, J=6.2 Hz, 6H).
To a solution of 5-((4-(2,6-dimethylmorpholino)-2-methylphenyl) amino)-1-methyl-1H-indole-3-carboxylic acid (50 mg, 0.127 mmol) in DMF (5 mL) was added HATU (58 mg, 0.152 mmol), NH4Cl (8.1 mg, 0.152 mmol) and TEA (19.2 mg, 0.191 mmol). The mixture was stirred at 80° C. for 2 hours. Then the mixture was diluted with water and extracted by EA (25 mL×3). The combined organic layers were washed with brine (15 mL×3), dried over Na2SO4 and concentrated to give the crude product, which was purified by pre-HPLC to give the desired product as pink solid (3 mg, 6.1%). 1H NMR (400 MHz, DMSO-d6) δ 7.83 (s, 1H), 7.54 (d, J=2.0 Hz, 1H), 7.26 (d, J=8.8 Hz, 1H), 6.96 (d, J=8.6 Hz, 1H), 6.89-6.64 (m, 4H), 3.83-3.60 (m, 5H), 3.46 (d, J=10.6 Hz, 2H), 2.25-2.08 (m, 4H), 1.14 (d, J=6.2 Hz, 6H). Mass (m/z): 393.2 [M+H]+.
To a solution of 5-bromo-2-methyl-2H-indazole (105 mg, 0.5 mmol) and 4-(2,6-dimethylmorpholino)-2-methylaniline (100 mg, 0.45 mmol) in 1,4-dioxane (2 mL) was added Pd2(dba)3 (41 mg, 0.04 mmol), Xphos (43 mg, 0.09 mmol) and Cs2CO3 (296 mg, 0.91 mmol) under nitrogen atmosphere. The mixture was stirred at 100° C. for 12 h, the mixture was purified by flash chromatography to give N-(4-(2,6-dimethylmorpholino)-2-methylphenyl)-2-methyl-2H-indazol-5-amine (24.5 mg, 15%) as a grey solid. Mass (m/z): 351.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.90 (d, J=0.9 Hz, 1H), 7.41 (d, J=9.1 Hz, 1H), 7.02-6.96 (m, 2H), 6.93 (dd, J=9.2, 2.2 Hz, 1H), 6.84 (d, J=2.8 Hz, 1H), 6.74 (dd, J=8.6, 2.9 Hz, 1H), 6.50 (d, J=2.0 Hz, 1H), 4.04 (s, 3H), 3.75-3.63 (m, 2H), 3.53-3.45 (m, 2H), 2.26-2.16 (m, 2H), 2.14 (s, 3H), 1.15 (d, J=6.2 Hz, 6H).
To a solution of 4-(2,6-dimethylmorpholino)-2-methylaniline (100 mg, 0.45 mmol) and 5-bromo-3-methylbenzo[d]oxazol-2(3H)-one (113 mg, 0.5 mmol) in 1,4-dioxane (2 mL) was added Pd2(dba)3 (41 mg, 0.05 mmol), Xphos (43 mg, 0.09 mmol) and Cs2CO3 (296 mg, 0.91 mmol) under nitrogen atmosphere. The mixture was stirred at 100° C. for 12 h, the mixture was purified by prep TLC to give 5-((4-(2,6-dimethylmorpholino)-2-methylphenyl)amino)-3-methylbenzo[d]oxazol-2(3H)-one (69 mg, 41%) as a light blue solid. Mass (m/z): 368.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.26 (s, 1H), 7.03 (dd, J=16.8, 8.6 Hz, 2H), 6.85 (d, J=2.8 Hz, 1H), 6.75 (dd, J=8.6, 2.9 Hz, 1H), 6.44 (d, J=2.2 Hz, 1H), 6.35 (dd, J=8.6, 2.3 Hz, 1H), 3.74-3.62 (m, 2H), 3.55-3.47 (m, 2H), 3.22 (s, 3H), 2.26-2.16 (m, 2H), 2.14 (s, 3H), 1.15 (d, J=6.2 Hz, 6H).
To a solution of 5-bromo-1-methyl-1H-benzo[d]imidazole (105 mg, 0.5 mmol) and 4-(2,6-dimethylmorpholino)-2-methylaniline (100 mg, 0.45 mmol) in 1,4-dioxane (2 mL) was added Pd2(dba)3 (41 mg, 0.04 mmol), Xphos (43 mg, 0.09 mmol) and Cs2CO3 (296 mg, 0.91 mmol) under nitrogen atmosphere. The mixture was stirred at 100° C. for 12 h, the mixture was purified by flash chromatography to give N-(4-(2,6-dimethylmorpholino)-2-methylphenyl)-1-methyl-1H-benzo[d]imidazol-5-a mine (45 mg, 28%) as a pink solid. Mass (m/z): 351.4 [M+H]+. 1H NMR (400 MHz, DMSO) δ 7.96 (s, 1H), 7.32 (d, J=9.1 Hz, 1H), 6.98 (d, J=8.6 Hz, 1H), 6.94 (s, 1H), 6.86-6.78 (m, 3H), 6.72 (dd, J=8.7, 2.9 Hz, 1H), 3.75 (s, 3H), 3.73-3.63 (m, 2H), 3.52-3.44 (m, 2H), 2.25-2.16 (m, 2H), 2.15 (s, 3H), 1.15 (d, J=6.2 Hz, 6H).
The titled compound 448 (6.8 mg, 4.38%) as a light-yellow solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 7.34-7.27 (m, 1H), 7.26-7.00 (m, 2H), 6.91 (s, 1H), 6.69 (s, 1H), 6.41 (s, 2H), 4.47 (s, 2H), 3.80-3.66 (m, 2H), 3.51 (br, 1H), 2.76-2.62 (m, 2H), 1.86 (s, 2H), 1.56 (s, 2H). Mass (m/z): 425.9 [M+H]+.
The titled compound 449 (3.8 mg, 2.06%) as a light-brown solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.86 (s, 1H), 7.06 (d, J=8.0 Hz, 1H), 7.01 (d, J=8.8 Hz, 2H), 6.88 (d, J=9.2 Hz, 2H), 6.56-6.49 (m, 2H), 3.72-3.64 (m, 2H), 3.45 (d, J=10.4 Hz, 2H), 3.05 (s, 3H), 2.22-2.15 (m, 2H), 1.22 (s, 6H), 1.14 (d, J=6.4 Hz, 6H). Mass (m/z): 380.0 [M+H]+.
The titled compound 450 (3.5 mg, 2.15%) as a light-purple solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.85 (s, 1H), 7.59 (d, J=2.4 Hz, 1H), 7.00-6.87 (m, 5H), 4.57 (s, 2H), 3.62 (d, J=12.4 Hz, 2H), 2.62 (t, J=11.2 Hz, 2H), 2.45-2.39 (m, 1H), 1.88 (d, J=12.8 Hz, 2H), 1.61-1.53 (m, 2H). Mass (m/z): 392.9 [M+H]+.
The titled compound 451 (19.4 mg, 12.1%) as a light-purple solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.45 (s, 1H), 7.14 (d, J=8.8 Hz, 1H), 7.04 (d, J=2.8 Hz, 1H), 6.97-6.89 (m, 2H), 6.48 (dd, J=8.8, 2.4 Hz, 1H), 6.42 (d, J=2.4 Hz, 1H), 4.56 (s, 2H), 3.73 (d, J=12.0 Hz, 2H), 3.22 (s, 3H), 2.69 (dd, J=12.4, 10.4 Hz, 2H), 1.88 (d, J=12.4 Hz, 2H), 1.54 (dt, J=12.4, 8.8 Hz, 2H). Mass (m/z): 439.9 [M+H]+.
The titled compound 452 (54.9 mg, 32.20%) as a white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.29 (s, 1H), 6.91 (d, J=8.8 Hz, 1H), 6.82 (s, 1H), 6.24 (dd, J=8.8, 2.4 Hz, 1H), 6.18 (d, J=2.4 Hz, 1H), 4.54 (s, 2H), 4.35 (d, J=13.2 Hz, 2H), 3.20 (s, 3H), 2.80 (t, J=12.0 Hz, 2H), 2.66-2.54 (m, 1H), 2.09 (s, 3H), 1.85 (d, J=11.2 Hz, 2H), 1.46-1.21 (m, 2H). Mass (m/z): 421.0 [M+H]+.
The titled compound 453 (23.5 mg, 14.23%) as a white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 7.85 (s, 1H), 7.16 (s, 1H), 6.80 (s, 1H), 6.65 (d, J=8.0 Hz, 1H), 6.16 (d, J=8.4 Hz, 2H), 4.45 (s, 2H), 4.34 (d, J=12.4 Hz, 2H), 2.79 (t, J=12.4 Hz, 2H), 2.53 (s, 1H), 2.08 (s, 3H), 1.85 (d, J=11.6 Hz, 2H), 1.43 (d, J=11.6 Hz, 2H). Mass (m/z): 407.0 [M+H]+.
The titled compound 454 (21.4 mg, 13.95%) as a white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 7.31 (s, 1H), 6.91-6.78 (m, 2H), 6.70 (d, J=8.0 Hz, 1H), 6.43-6.36 (m, 2H), 4.48 (s, 2H), 3.31 (s, 1H), 2.65 (t, J=11.2 Hz, 2H), 2.49-2.35 (m, 2H), 2.06 (t, J=6.0 Hz, 3H), 1.89 (d, J=11.6 Hz, 2H), 1.65-1.52 (m, 2H). Mass (m/z): 424.0 [M+H]+.
The titled compound 455 (12.1 mg, 29.63%) as a light-purple solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.10 (d, J=8.8 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.87-6.82 (m, 2H), 6.67 (dd, J=8.8, 2.4 Hz, 1H), 6.59 (d, J=2.4 Hz, 1H), 4.87 (t, J=5.6 Hz, 1H), 4.55 (s, 2H), 3.90 (t, J=6.4 Hz, 2H), 3.75-3.68 (m, 2H), 3.56 (q, J=6.4 Hz, 2H), 2.84 (d, J=10.8 Hz, 2H), 2.28 (dd, J=11.6, 10.0 Hz, 2H), 2.21 (s, 3H), 1.10 (d, J=6.4 Hz, 6H). Mass (m/z): 412.0 [M+H]+.
The titled compound 456 (36.0 mg, 57.33%) as a light-purple solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.17 (s, 1H), 6.96 (dd, J=13.6, 8.8 Hz, 2H), 6.80 (d, J=2.8 Hz, 1H), 6.71 (dd, J=8.8, 2.8 Hz, 1H), 6.30 (dd, J=8.8, 2.4 Hz, 1H), 6.21 (d, J=2.4 Hz, 1H), 6.04 (s, 1H), 4.47 (s, 2H), 3.83 (t, J=6.4 Hz, 2H), 3.67-3.60 (m, 2H), 3.53-3.45 (m, 4H), 2.20-2.14 (m, 2H), 2.08 (s, 3H), 1.11 (d, J=6.4 Hz, 6H). Mass (m/z): 412.0 [M+H]+.
The titled compound 457 (126 mg, 48.6%) as a yellow solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.47 (d, J=2.4 Hz, 1H), 7.38 (s, 1H), 6.99 (d, J=8.8 Hz, 1H), 6.85 (d, J=2.8 Hz, 1H), 6.76 (dd, J=8.8, 2.8 Hz, 1H), 6.60 (d, J=2.4 Hz, 1H), 4.66 (s, 2H), 3.69-3.65 (m, 2H), 3.51 (d, J=10.4 Hz, 2H), 3.26 (s, 3H), 2.23-2.20 (m, 2H), 2.14 (s, 3H), 1.15 (d, J=6.4 Hz, 6H). Mass (m/z): 383.0 [M+H]+.
The titled compound 458 (61.8 mg, 34.55%) as a green solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.66-7.64 (m, 1H), 7.28 (s, 2H), 7.20-7.18 (m, 1H), 7.08-7.05 (d, J=12 Hz, 2H), 6.94-6.91 (m, 2H), 4.22 (s, 3H), 3.70-3.68 (m, 2H), 3.48-3.46 (m, 2H), 2.24-2.21 (m, 2H), 1.16-1.14 (m, 6H). Mass (m/z): 338.0 [M+H]+.
The titled compound 459 (70.6 mg, 45.31%) as a yellow solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H), 8.06 (s, 1H), 7.81 (d, J=1.6 Hz, 1H), 7.23 (dd, J=14.4, 2.4 Hz, 1H), 6.77 (d, J=8.4 Hz, 1H), 6.62 (dd, J=8.4, 2.4 Hz, 1H), 6.57 (d, J=2.4 Hz, 1H), 4.51 (s, 2H), 3.76 (d, J=12.8 Hz, 2H), 3.34-3.33 (m, 1H), 2.80 (t, J=11.6 Hz, 2H), 1.87 (d, J=11.6 Hz, 2H), 1.56 (dd, J=12.8, 3.6 Hz, 2H). Mass (m/z): 411.0 [M+H]+.
The titled compound 460 (24.7 mg, 14.51%) as a light-purple solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.37 (d, J=2.4 Hz, 1H), 7.26 (s, 1H), 6.98 (d, J=8.8 Hz, 1H), 6.86 (d, J=2.8 Hz, 1H), 6.77 (dd, J=8.8, 2.8 Hz, 1H), 6.60 (d, J=2.4 Hz, 1H), 4.54 (s, 2H), 3.70 (d, J=12.4 Hz, 2H), 2.65 (dd, J=12.4, 10.4 Hz, 2H), 2.48-2.39 (m, 1H), 2.13 (s, 3H), 1.88 (d, J=12.0 Hz, 2H), 1.62-1.52 (m, 2H). Mass (m/z): 407.0 [M+H]+.
The titled compound 461 (3.3 mg, 10.02% yield) as a grey solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 6.99-6.94 (m, 2H), 6.85-6.80 (m, 2H), 6.75-6.69 (m, 2H), 6.57 (dd, J=8.8, 2.8 Hz, 1H), 6.50 (d, J=2.4 Hz, 1H), 4.14 (s, 2H), 3.72-3.65 (m, 2H), 3.48 (d, J=10.4 Hz, 2H), 3.09 (s, 3H), 2.22-2.16 (m, 2H), 2.12 (s, 3H), 1.14 (d, J=6.4 Hz, 6H). Mass (m/z): 412.0 [M+H]+.
The titled compound 462 (26.0 mg, 15.33%) as a light purple solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.37 (d, J=2.4 Hz, 1H), 7.26 (s, 1H), 6.98 (d, J=8.8 Hz, 1H), 6.86 (d, J=2.8 Hz, 1H), 6.77 (dd, J=8.8, 2.8 Hz, 1H), 6.60 (d, J=2.4 Hz, 1H), 4.54 (s, 2H), 3.70 (d, J=12.4 Hz, 2H), 2.65 (dd, J=12.4, 10.4 Hz, 2H), 2.48-2.39 (m, 1H), 2.13 (s, 3H), 1.88 (d, J=12.0 Hz, 2H), 1.62-1.52 (m, 2H). Mass (m/z): 369.0 [M+H]+.
The titled compound 463 (4.0 mg, 1.82%) as a light-yellow solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.79 (s, 1H), 6.93 (dd, J=34.4, 8.8 Hz, 4H), 6.43 (d, J=16.8 Hz, 2H), 4.40 (s, 2H), 3.76-3.61 (m, 2H), 3.45 (d, J=11.2 Hz, 2H), 3.26 (s, 3H), 2.29 (s, 3H), 2.19 (t, J=11.2 Hz, 2H), 1.14 (d, J=6.4 Hz, 6H). Mass (m/z): 382.0 [M+H]+.
The titled compound 464 (12.5 mg, 7.73%) as a light-yellow solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.78 (d, J=2.4 Hz, 1H), 7.02 (d, J=2.4 Hz, 1H), 6.82 (d, J=8.4 Hz, 1H), 6.65-6.56 (m, 2H), 4.70 (s, 2H), 3.75 (s, 3H), 3.29 (s, 4H), 2.59-2.51 (m, 3H), 2.43-2.32 (m, 1H), 1.86 (d, J=11.2 Hz, 2H), 1.59 (dd, J=12.4, 3.6 Hz, 2H).Mass (m/z): 437.0 [M+H]+.
The titled compound 465 (7.8 mg, 4.94%) as a light-brown solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 11.20-10.78 (m, 1H), 7.99 (s, 1H), 7.67 (d, J=2.4 Hz, 1H), 6.99 (d, J=2.4 Hz, 1H), 6.81 (d, J=8.4 Hz, 1H), 6.65-6.49 (m, 2H), 4.58 (s, 2H), 3.74 (s, 3H), 3.30 (s, 2H), 2.54 (d, J=12.0 Hz, 2H), 2.37 (dd, J=12.4, 8.8 Hz, 1H), 1.86 (d, J=11.2 Hz, 2H), 1.59 (qd, J=12.4, 3.6 Hz, 2H). Mass (m/z): 422.9 [M+H]+.
The titled compound 466 ((4.7 mg, 3.02%) as a white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, CDCl3) δ 7.71 (s, 1H), 7.16 (s, 1H), 6.73 (s, 1H), 6.67 (d, J=8.4 Hz, 1H), 6.61 (s, 1H), 6.56 (s, 1H), 4.58 (s, 2H), 3.67 (d, J=10.0 Hz, 2H), 2.74 (s, 2H), 2.19 (s, 1H), 2.01 (s, 2H), 1.82 (s, 2H). Mass (m/z): 410.0 [M+H]+.
The titled compound 467 (12.0 mg, 7.9%) as a yellow solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, CD3OD) δ 7.02 (d, J=8.8 Hz, 1H), 6.94 (d, J=8.8 Hz, 1H), 6.88 (d, J=2.4 Hz, 1H), 6.78-6.80 (m, 1H), 6.50-6.32 (m, 2H), 3.66 (d, J=12.0 Hz, 2H), 2.65-2.68 (m, 2H), 2.25-2.27 (m, 1H), 2.17 (d, J=10.0 Hz, 3H), 1.97-2.00 (m, 2H), 1.75-1.64 (m, 2H). Mass (m/z): 391.7 [M+H]+.
The titled compound 468 (12.0 mg, 7.9%) as a yellow solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 7.55 (s, 1H), 6.99 (d, J=8.8 Hz, 1H), 6.89 (d, J=2.8 Hz, 1H), 6.80 (dd, J=8.8, 2.8 Hz, 1H), 6.53 (d, J=2.4 Hz, 1H), 6.42 (d, J=2.4 Hz, 1H), 4.54 (s, 2H), 3.74 (d, J=12.8 Hz, 2H), 2.67 (dd, J=12.4, 10.4 Hz, 2H), 2.45 (dd, J=12.4, 8.8 Hz, 1H), 2.10 (s, 3H), 1.91-1.85 (m, 2H), 1.60-1.50 (m, 2H). Mass (m/z): 431.0 [M+H]+.
The titled compound 468 (6 mg, 3.6%) as a yellow solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 6.92-6.78 (m, 3H), 6.71 (d, J=6.8 Hz, 2H), 6.56 (s, 2H), 4.47 (s, 2H), 3.60-3.50 (m, 2H), 3.21 (s, 3H), 2.79-2.58 (m, 2H), 2.48-2.34 (m, 1H), 1.88 (d, J=12.4 Hz, 2H), 1.67-1.48 (m, 2H). Mass (m/z): 420.9 [M+H]+.
The titled compound 470 (32.9 mg, 20.1%) as a blue solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 12.57 (s, 1H), 10.38 (s, 1H), 7.08-6.90 (m, 2H), 6.85-6.57 (m, 3H), 6.32-6.20 (m, 1H), 4.46 (s, 2H), 2.12 (s, 3H), 1.61 (s, 4H), 1.28-1.21 (m, 4H), 0.85 (t, J=6.4 Hz, 2H). Mass (m/z): 338.3 [M+H]+.
The titled compound 471 (35.0 mg, 48.2%) as a light-yellow solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.33 (d, J=8.8 Hz, 1H), 6.68 (d, J=8.4 Hz, 1H), 6.60 (d, J=8.8 Hz, 1H), 6.28-6.18 (m, 2H), 4.47 (s, 2H), 4.09-4.01 (m, 1H), 3.87-3.75 (m, 1H), 3.70-3.61 (m, 1H), 3.53-3.44 (m, 1H), 3.39-3.33 (m, 1H), 3.14-3.04 (m, 1H), 2.28 (s, 3H), 1.81-1.69 (m, 1H), 1.63-1.52 (m, 1H), 1.25 (d, J=6.4 Hz, 3H), 0.98 (t, J=7.2 Hz, 3H). Mass (m/z): 383.2 [M+H]+.
The titled compound 472 (46.0 mg, 34%) as a white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, CD3OD) δ 7.13 (d, J=8.0 Hz, 2H), 7.02 (d, J=8.0 Hz, 2H), 6.97 (d, J=8.4 Hz, 1H), 6.74 (dd, J=8.4, 2.0 Hz, 1H), 6.68 (d, J=2.4 Hz, 1H), 4.49-4.39 (m, 1H), 4.03 (d, J=11.2 Hz, 2H), 3.61-3.50 (m, 2H), 2.82-2.66 (m, 1H), 1.91-1.71 (m, 6H), 1.05 (t, J=7.2 Hz, 3H). Mass (m/z): 367.5 [M+H]+.
The titled compound 473 (50.8 mg, 34%) as a purple solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 7.00 (s, 1H), 6.96 (d, J=8.8 Hz, 1H), 6.83 (d, J=2.8 Hz, 1H), 6.75 (dd, J=8.8, 2.8 Hz, 1H), 6.15 (s, 1H), 6.10 (s, 1H), 4.39 (s, 2H), 3.68 (d, J=12.0 Hz, 2H), 2.65 (t, J=11.6 Hz, 2H), 2.46-2.38 (m, 1H), 2.10 (s, 6H), 1.88 (d, J=11.6 Hz, 2H), 1.63-1.48 (m, 2H). Mass (m/z): 420.5[M+H]+.
The titled compound 474 (70.3 mg, 43%) as an off-white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 7.93 (d, J=2.8 Hz, 1H), 7.61 (s, 1H), 7.34 (dd, J=9.2, 2.8 Hz, 1H), 6.84 (d, J=9.2 Hz, 1H), 6.70 (d, J=8.4 Hz, 1H), 6.49-6.39 (m, 2H), 4.47 (s, 2H), 4.27 (d, J=13.2 Hz, 2H), 2.76 (t, J=12.4 Hz, 2H), 2.61-2.54 (m, 1H), 1.85 (d, J=12.8 Hz, 2H), 1.52-1.37 (m, 2H). Mass (m/z): 393.4 [M+H]+.
The titled compound 475 (58.5 mg, 36%) as an off-white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.22 (s, 2H), 7.57 (s, 1H), 6.70 (d, J=8.4 Hz, 1H), 6.44-6.35 (m, 2H), 4.72-4.64 (m, 2H), 4.47 (s, 2H), 2.94-2.82 (m, 2H), 2.59-2.55 (m, 1H), 1.87 (d, J=12.0 Hz, 2H), 1.46-1.31 (m, 2H). Mass (m/z): 394.4 [M+H]+.
The titled compound 476 (10.5 mg, 6%) as an off-white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.22 (s, 2H), 7.57 (s, 1H), 6.70 (d, J=8.4 Hz, 1H), 6.44-6.35 (m, 2H), 4.72-4.64 (m, 2H), 4.47 (s, 2H), 2.94-2.82 (m, 2H), 2.59-2.55 (m, 1H), 1.87 (d, J=12.0 Hz, 2H), 1.46-1.31 (m, 2H). Mass (m/z): 393.4 [M+H]+.
The titled compound 477 (67.7 mg, 44.7%) as an off-white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 6.92-6.84 (m, 2H), 6.84-6.72 (m, 2H), 6.44 (s, 1H), 5.93 (s, 1H), 4.46 (s, 2H), 3.70 (d, J=12.4 Hz, 2H), 3.22 (s, 3H), 2.66 (t, J=12.0 Hz, 2H), 2.47-2.38 (m, 2H) 2.17 (s, 3H), 2.08 (s, 3H), 1.88 (d, J=13.2 Hz, 2H), 1.64-1.49 (m, 2H). Mass (m/z): 434.5 [M+H]+.
The titled compound 478 (23.3 mg, 14.7%) as a gray solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.97 (s, 1H), 7.62 (d, J=2.3 Hz, 1H), 7.04-6.95 (m, 2H), 6.69 (dd, J=8.8, 2.4 Hz, 1H), 6.58 (d, J=2.4 Hz, 1H), 4.58 (s, 2H), 3.85-3.78 (m, 2H), 3.77 (s, 3H), 3.23 (s, 3H), 2.66 (d, J=24.0 Hz, 2H), 1.85 (d, J=12.0 Hz, 2H), 1.57 (qd, J=12.4, 3.6 Hz, 2H). Mass (m/z): 436.2 [M+H]+.
The titled compound 479 (26.2 mg, 11.4%) as a white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 7.94 (s, 1H), 7.13-7.05 (m, 2H), 7.03-6.88 (m, 2H), 6.75 (d, J=8.4 Hz, 1H), 6.69-6.55 (m, 2H), 4.50 (s, 2H), 4.03-3.85 (m, 1H), 3.54-3.41 (m, 2H), 2.66 (dd, J=24.0, 3.6 Hz, 1H), 1.82-1.45 (m, 31H), 1.25 (td, J=12.4, 10.8 Hz, 1H), 1.12 (d, J=6.0 Hz, 3H). Mass (m/z): 339.2 [M+H]+.
The titled compound 480 (25 mg, 5.9%) as a white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 7.34 (s, 1H), 6.98 (d, J=8.4 Hz, 1H), 6.86 (d, J=2.8 Hz, 1H), 6.78 (dd, J=8.8, 2.8 Hz, 1H), 6.06 (d, J=11.2 Hz, 2H), 4.48 (s, 2H), 3.72 (d, J=12.4 Hz, 2H), 2.67 (t, J=12.0 Hz, 3H), 2.51-2.49 (m, 1H), 2.10 (s, 3H), 1.88 (d, J=12.0 Hz, 2H), 1.56 (qd, J=12.4, 4.0 Hz, 2H). Mass (m/z): 424.2 [M+H]+.
The titled compound 481 (34.7 mg, 8.2%) as a white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 7.98 (s, 1H), 6.95 (d, J=8.8 Hz, 1H), 6.86 (d, J=7.2 Hz, 2H), 6.44 (d, J=12.4 Hz, 1H), 6.38 (s, 1H), 4.53 (s, 2H), 3.05 (d, J=11.6 Hz, 2H), 2.63 (d, J=11.6 Hz, 2H), 2.51-2.49 (m, 1H), 2.20 (s, 3H), 1.97-1.80 (m, 2H), 1.60 (qd, J=12.4, 4.0 Hz, 2H). Mass (m/z): 424.2 [M+H]+.
The titled compound 482 (27.2 mg, 13.1%) as a white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 7.05 (s, 1H), 6.96 (d, J=8.8 Hz, 1H), 6.84 (d, J=2.8 Hz, 1H), 6.75 (dd, J=8.0, 2.8 Hz, 1H), 6.65 (d, J=8.4 Hz, 1H), 6.29 (d, J=8.4 Hz, 1H), 6.23 (s, 1H), 4.52 (q, J=6.8 Hz, 1H), 3.68 (d, J=12.0 Hz, 2H), 2.65 (t, J=12.0 Hz, 2H), 2.47-2.37 (m, 1H), 2.11 (s, 3H), 1.88 (d, J=12.4 Hz, 2H), 1.61-1.51 (m, 2H), 1.36 (d, J=6.8 Hz, 3H). Mass (m/z): 420.2 [M+H]+.
The titled compound 483 (12 mg, 5.9%) as a white solid was prepared according to the procedure outlined for 1. 1H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 7.05 (s, 1H), 6.97 (d, J=8.8 Hz, 1H), 6.85 (d, J=2.8 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 6.66 (d, J=8.4 Hz, 1H), 6.29 (d, J=8.4 Hz, 1H), 6.23 (s, 1H), 4.36 (q, J=8.0 Hz, 1H), 3.68 (d, J=12.0 Hz, 2H), 2.63 (t, J=12.4 Hz, 2H), 2.47-2.37 (m, 1H), 2.11 (s, 3H), 1.88 (d, J=12.8 Hz, 2H), 1.78-1.67 (m, 2H), 1.61-1.50 (m, 2H), 0.95 (t, J=7.2 Hz, 3H). Mass (m/z): 434.2 [M+H]+.
The titled compound 484 (26.2 mg, 11.4%) as a white solid was prepared according to the procedure outlined for 1. 1H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 7.94 (s, 1H), 7.13-7.05 (m, 2H), 7.03-6.88 (m, 2H), 6.75 (d, J=8.4 Hz, 1H), 6.69-6.55 (m, 2H), 4.50 (s, 2H), 4.03-3.85 (m, 1H), 3.54-3.41 (m, 2H), 2.66 (dd, J=24.0, 3.6 Hz, 1H), 1.82-1.45 (m, 3H), 1.25 (td, J=12.8, 10.8 Hz, 1H), 1.12 (d, J=6.0 Hz, 3H). Mass (m/z): 339.2 [M+H]+.
The titled compound 485 (32 mg, 20.7%) as a white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 7.81 (s, 1H), 6.76 (dd, J=19.6, 8.4 Hz, 2H), 6.66-6.49 (m, 4H), 4.49 (s, 2H), 3.73 (s, 3H), 3.28 (s, 2H), 2.55-2.53 (m, 2H), 2.51-2.49 (m, 1H), 1.85 (d, J=12.8 Hz, 2H), 1.59 (qd, J=12.0, 40 Hz, 2H). Mass (m/z): 424.4 [M+H]+.
The titled compound 486 (18.1 mg, 11.6%) as a pink solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.52 (s, 1H), 8.00 (s, 1H), 6.94 (t, J=9.2 Hz, 1H), 6.82-6.70 (m, 3H), 6.68-6.55 (m, 2H), 4.51 (s, 2H), 3.27 (d, J=12.0 Hz, 2H), 2.71-2.60 (m, 2H), 2.44-2.36 (m, 1H), 1.88 (d, J=12.4 Hz, 2H), 1.70-1.51 (m, 2H). Mass (m/z): 410.4 [M+H]+.
The titled compound 487 (10 mg, 6.5%) as a pink solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 7.21 (s, 1H), 6.98-6.81 (m, 2H), 6.66 (d, J=8.4 Hz, 1H), 6.33-6.16 (m, 2H), 4.44 (s, 2H), 3.03 (d, J=11.6 Hz, 2H), 2.63 (d, J=11.6 Hz, 3H), 2.19 (s, 3H), 2.05 (s, 3H), 1.89 (d, J=12.4 Hz, 2H), 1.64 (tt, J=14.8, 8.0 Hz, 2H). Mass (m/z): 420.2 [M+H]+.
The titled compound 488 (24 mg, 15.7%) as a pink solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 7.22 (s, 1H), 6.94-6.68 (m, 3H), 6.53-6.35 (m, 2H), 4.49 (s, 2H), 3.29 (d, J=11.6 Hz, 2H), 2.74-2.59 (m, 2H), 2.42-2.39 (m, 1H), 2.11 (s, 3H), 1.89 (d, J=12.4 Hz, 2H), 1.60 (q, J=12.4, 11.6 Hz, 2H). Mass (m/z): 424.2 [M+H]+.
The titled compound 489 (26.7 mg, 17%) as a yellow solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 7.28 (d, J=8.8 Hz, 1H), 7.13 (s, 1H), 6.67 (t, J=9.6 Hz, 2H), 6.19 (d, J=9.6 Hz, 2H), 4.45 (s, 2H), 4.34 (d, J=13.2 Hz, 2H), 2.76 (t, J=12.8 Hz, 2H), 2.42-2.39 (m, 1H), 2.21 (s, 3H), 1.86 (d, J=12.8 Hz, 2H), 1.43 (qd, J=12.4, 3.6 Hz, 2H). Mass (m/z): 407.2 [M+H]+.
The titled compound 490 (32.9 mg, 18.35%) as a white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.18 (s, 1H), 6.96 (d, J=8.8 Hz, 1H), 6.90 (d, J=8.8 Hz, 1H), 6.82 (d, J=2.8 Hz, 1H), 6.73 (dd, J=8.8, 2.4 Hz, 1H), 6.33 (dd, J=8.8, 2.4 Hz, 1H), 6.25 (d, J=2.4 Hz, 1H), 4.53 (s, 2H), 3.57 (d, J=12.4 Hz, 2H), 3.20 (s, 3H), 2.58 (t, J=11.2 Hz, 2H), 2.09 (d, J=11.2 Hz, 3H), 1.68 (d, J=11.6 Hz, 2H), 1.53-1.37 (m, 1H), 1.23 (qd, J=12.4, 4.0 Hz, 2H), 0.94 (d, J=6.8 Hz, 3H). Mass (m/z): 365.9 [M+H]+.
The titled compound 491 (7.8 mg, 4.52%) as a white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.05 (d, J=8.0 Hz, 1H), 6.81 (d, J=20.0 Hz, 2H), 6.61 (d, J=8.0 Hz, 1H), 6.36 (s, 2H), 5.12 (s, 1H), 4.55 (s, 2H), 3.60 (d, J=11.2 Hz, 2H), 2.67 (s, 2H), 2.19 (s, 3H), 1.75 (d, J=12.4 Hz, 2H), 1.58 (s, 1H), 1.36 (d, J=11.2 Hz, 2H), 0.99 (d, J=6.4 Hz, 3H). Mass (m/z): 352.1 [M+H]+.
The titled compound 492 (74.9 mg, 59.73%) as a white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, CDCl3) δ 7.31-7.26 (m, 1H), 6.94-6.86 (m, 1H), 6.83 (d, J=8.6 Hz, 1H), 6.46 (dd, J=11.8, 2.9 Hz, 2H), 4.57 (s, 2H), 3.55 (d, J=11.8 Hz, 2H), 3.32 (s, 3H), 2.75 (d, J=11.4 Hz, 2H), 2.42 (s, 3H), 2.23-2.09 (m, 1H), 2.04-1.86 (m, 4H). Mass (m/z): 444.8 [M+H]+.
The titled compound 493 (35.6 mg, 56%) as a grey solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 7.94 (s, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.06-6.99 (m, 2H), 6.84 (d, J=2.4 Hz, 1H), 6.77-6.70 (m, 2H), 6.67 (s, 1H), 3.69 (m, 2H), 3.49 (d, J=10.4 Hz, 2H), 2.25-2.17 (m, 2H), 2.15 (s, 3H), 1.15 (d, J=6.4 Hz, 6H). Mass (m/z): 337 [M+H]+.
The titled compound 494 (4.2 mg, 1.72%) as a light-yellow solid was prepared according to the procedure outlined for compound 461. 1H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 6.92 (d, J=8.8 Hz, 1H), 6.84 (s, 1H), 6.79 (d, J=2.8 Hz, 1H), 6.70 (dd, J=8.8, 2.8 Hz, 1H), 6.57 (d, J=8.4 Hz, 2H), 6.50 (dd, J=8.4, 2.4 Hz, 1H), 6.44 (s, 1H), 4.18 (s, 2H), 3.71-3.64 (m, 2H), 3.46 (d, J=10.4 Hz, 2H), 2.21-2.15 (m, 2H), 2.11 (s, 3H), 1.14 (d, J=6.2 Hz, 6H). Mass (m/z): 366.9 [M+H]+.
The titled compound 495 (15 mg, 7.6%) as a yellow solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 9.44 (s, 1H), 7.72 (s, 1H), 7.39 (s, 2H), 6.93 (d, J=7.6 Hz, 2H), 6.73 (d, J=33.2 Hz, 2H), 4.55 (s, 2H), 3.63 (s, 4H), 3.23 (s, 3H), 2.76 (d, J=23.6 Hz, 1H), 2.12 (s, 2H), 1.94 (d, J=18.0 Hz, 2H). Mass (m/z): 421.8[M+H]+.
The titled compound 496 (15 mg, 4.9%) as a yellow solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, CD3OD) δ 7.03 (d, J=8.8 Hz, 1H), 6.91 (d, J=2.4 Hz, 1H), 6.82-6.84 (m, 2H), 6.60-6.52 (m, 2H), 3.68 (d, J=12.4 Hz, 2H), 2.67-2.69 (m, 2H), 2.34-2.23 (m, 1H), 2.17 (d, J=5.2 Hz, 3H), 2.03-1.94 (m, 2H), 1.77-1.66 (m, 2H). Mass (m/z): 392.2 [M+H]+.
The titled compound 497 (41.8 mg, 46.22%) as a yellow solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, CD3OD) δ 7.79 (s, 1H), 7.40 (d, J=8.9 Hz, 1H), 7.10 (dd, J=8.8, 2.0 Hz, 1H), 7.05 (d, J=8.8 Hz, 1H), 6.93 (s, 2H), 6.83 (s, 1H), 3.67 (d, J=12.4 Hz, 2H), 2.74-2.63 (m, 2H), 2.38-2.24 (m, 1H), 2.23 (s, 3H), 1.99 (d, J=12.8 Hz, 2H), 1.75 (qd, J=12.8, 4.0 Hz, 2H). Mass (m/z): 374.7 [M+H]+.
The titled compound 498 (36.9 mg, 51.3%) as a light-yellow solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.13 (s, 1H), 6.65 (d, J=8.4 Hz, 2H), 6.26-6.11 (m, 2H), 4.45 (s, 2H), 4.04 (d, J=12.4 Hz, 1H), 3.99-3.89 (m, 2H), 3.60-3.47 (m, 1H), 3.42-3.33 (m, 1H), 2.80-2.66 (m, 1H), 2.43 (t, J=11.6 Hz, 1H), 2.22 (s, 3H), 1.56-1.46 (m, 2H), 0.94 (t, J=8.4, 6.4 Hz, 3H). Mass (m/z): 369.2 [M+H]+.
The titled compound 499 (34.5 mg, 50.6%) as a white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 7.28 (d, J=8.8 Hz, 1H), 7.12 (s, 1H), 6.66 (d, J=8.0 Hz, 2H), 6.23-6.11 (m, 2H), 4.44 (s, 2H), 4.06 (d, J=12.4 Hz, 2H), 3.43-3.34 (m, 2H), 2.34 (t, J=11.2 Hz, 2H), 2.21 (s, 3H), 1.58-1.45 (m, 4H), 0.96 (t, J=6.4 Hz, 6H). Mass (m/z): 397.3 [M+H]+.
The titled compound 500 (5.9 mg, 3.54%) as a yellow solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 7.23 (d, J=8.8 Hz, 1H), 7.07 (s, 1H), 6.60 (d, J=8.4 Hz, 2H), 6.13 (d, J=8.8 Hz, 2H), 4.39 (s, 2H), 3.66 (t, J=5.2 Hz, 2H), 3.18 (s, 2H), 2.15 (s, 3H), 1.15 (s, 6H). Mass (m/z): 369.6 [M+H]+.
The titled compound 501 (33.4 mg, 22.04%) as a white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 6.96 (s, 1H), 6.89 (d, J=8.8 Hz, 1H), 6.62 (d, J=8.8 Hz, 1H), 6.54 (d, J=3.2 Hz, 1H), 6.48 (dd, J=8.8, 2.8 Hz, 1H), 6.18 (dd, J=8.4, 2.4 Hz, 1H), 6.14 (d, J=2.4 Hz, 1H), 4.42 (d, J=2.0 Hz, 2H), 3.27 (t, J=7.2 Hz, 4H), 2.08 (s, 3H), 1.07 (t, J=7.2 Hz, 6H). Mass (m/z): 326.3 [M+H]+.
The titled compound 502 (3.9 mg, 4.35%) as a white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 7.03 (s, 1H), 6.93 (d, J=8.4 Hz, 1H), 6.62 (d, J=8.5 Hz, 1H), 6.52 (s, 1H), 6.44 (d, J=8.3 Hz, 1H), 6.18 (d, J=8.5 Hz, 1H), 6.14 (s, 1H), 4.43 (s, 2H), 3.49 (t, J=8.5 Hz, 1H), 3.26 (d, J=8.0 Hz, 4H), 2.25 (d, J=6.3 Hz, 1H), 2.10 (s, 4H). Mass (m/z): 437.7 [M+H]+. Mass (m/z): 392.7 [M+H]+.
The titled compound 503 (10.7 mg, 12.78%) as a white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 7.29 (d, J=8.7 Hz, 1H), 7.13 (s, 1H), 6.70 (d, J=8.7 Hz, 1H), 6.66 (d, J=8.2 Hz, 1H), 6.19 (d, J=10.7 Hz, 2H), 4.45 (s, 2H), 4.18 (d, J=13.1 Hz, 2H), 3.41 (s, 3H), 2.89 (t, J=12.8 Hz, 2H), 2.22 (s, 3H), 1.98 (d, J=13.7 Hz, 2H), 1.70 (td, J=13.3, 4.5 Hz, 2H). Mass (m/z): 437.7 [M+H]+.
The titled compound 504 (18.9 mg, 15.5%) as a yellow solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 7.27 (d, J=8.8 Hz, 1H), 7.12 (s, 1H), 6.65 (t, J=8.0 Hz, 2H), 6.18 (d, J=10.0 Hz, 2H), 4.44 (s, 2H), 2.20 (s, 3H), 1.19 (s, 12H). Mass (m/z): 397.3 [M+H]+.
The titled compound 505 (9.2 mg, 9.4%) as a yellow solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 7.09 (s, 1H), 6.94 (d, J=8.4 Hz, 1H), 6.81 (s, 1H), 6.75-6.63 m, 3H), 6.29-6.21 (m, 2H), 4.44 (s, 2H), 3.56 (t, J=5.2 Hz, 2H), 3.44 (t, J=4.8 Hz, 4H), 3.40 (s, 1H), 3.25 (s, 3H), 2.79 (t, J=11.2 Hz, 2H), 2.10 (s, 3H), 1.94-1.89 (m, 2H), 1.45-1.53 (q, J=6.6, 3.6 Hz, 2H). Mass (m/z): 412.2 [M+H]+.
The titled compound 506 (46.7 mg, 31.5%) as a yellow solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, CD3OD) δ 7.03 (d, J=8.8 Hz, 1H), 6.94-6.87 (m, 2H), 6.82 (d, J=8.8 Hz, 1H), 6.40 (d, J=8.8 Hz, 1H), 6.30 (s, 1H), 4.50 (s, 2H), 3.30 (s, 3H), 3.11-3.04 (m, 4H), 2.16 (s, 3H), 1.78-1.68 (m, 4H), 1.63-1.54 (m, 3H). Mass (m/z): 352.5 [M+H]+.
The titled compound 507 (34.1 mg, 19.5%) as a purple solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 7.65 (s, 1H), 6.95-6.81 (m, 4H), 6.70 (dd, J=8.4, 2.4 Hz, 1H), 6.55-6.46 (m, 2H), 4.47 (s, 2H), 3.53-3.45 (m, 2H), 2.59-2.52 (m, 2H), 1.68 (d, J=12.8 Hz, 2H), 1.49-1.39 (m, 1H), 1.32-1.17 (m, 2H), 0.97-0.90 (m, 3H). Mass (m/z): 337.5 [M+H]+.
The titled compound 508 (42.5 mg, 24%) as a grey solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, CD3OD) δ 7.02-6.91 (m, 4H), 6.75-6.68 (m, 1H), 6.60-6.53 (m, 2H), 4.83-4.60 (m, 1H), 4.49 (s, 2H), 3.27-3.20 (m, 2H), 3.06-3.01 (m, 2H), 2.08-1.96 (m, 2H), 1.96-1.89 (m, 2H). Mass (m/z): 342.5 [M+H]+.
The titled compound 509 (38 mg, 23.5%) as an off-white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, CD3OD) δ 7.03 (d, J=8.8 Hz, 1H), 6.91 (s, 1H), 6.83 (d, J=8.8 Hz, 1H), 6.67 (d, J=8.4 Hz, 1H), 6.33 (d, J=8.8 Hz, 1H), 6.29 (s, 1H), 4.47 (s, 2H), 3.49 (d, J=12.0 Hz, 2H), 2.98 (t, J=12.4 Hz, 2H), 2.17 (s, 3H), 2.02-1.90 (m, 2H), 1.81 (d, J=13.2 Hz, 2H). Mass (m/z): 422.5 [M+H]+.
The titled compound 510 (56.7 mg, 36%) as an off-white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, CD3OD) δ 7.00-6.96 (m, 4H), 6.75-6.69 (m, 1H), 6.60-6.56 (m, 2H), 4.49 (s, 2H), 3.45-3.38 (m, 2H), 2.98-2.94 (m, 2H), 2.05-1.91 (m, 2H), 1.86-1.78 (m, 2H). Mass (m/z): 408.5 [M+H]+.
The titled compound 511 (50.4 mg, 30%) as a purple solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 7.01 (s, 1H), 6.96 (d, J=8.0 Hz, 1H), 6.85 (s, 1H), 6.76 (d, J=8.8 Hz, 1H), 6.15 (s, 1H), 6.09 (s, 1H), 5.94 (s, 1H), 4.40 (s, 2H), 3.52 (d, J=12.0 Hz, 2H), 2.89 (t, J=12.0 Hz, 2H), 2.10 (s, 6H), 1.88-1.63 (m, 4H). Mass (m/z): 437.5 [M+H]+.
The titled compound 512 (4.6 mg, 2.8%) as a grey solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, CDCl3) δ 7.01-6.64 (m, 3H), 6.53 (s, 1H), 6.17 (s, 1H), 4.36 (s, 2H), 3.64-3.51 (m, 2H), 3.29-3.21 (m, 1H), 2.71-2.49 (m, 2H), 2.08 (s, 6H), 1.99-1.85 (m, 2H), 1.81-1.62 (m, 2H). Mass (m/z): 420.5 [M+H]+.
The titled compound 513 (3.6 mg, 0.48%) as a purple solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 2H), 6.94 (d, J=8.8 Hz, 1H), 6.83 (d, J=3.6 Hz, 2H), 6.75-6.67 (m, 2H), 6.36 (dd, J=8.4, 2.0 Hz, 1H), 6.31 (d, J=2.0 Hz, 1H), 3.65 (d, J=12.0 Hz, 2H), 2.63 (dd, J=12.0, 10.4 Hz, 2H), 2.44 (dd, J=8.8, 3.6 Hz, 1H), 2.12 (s, 3H), 1.88 (d, J=12.4 Hz, 2H), 1.56 (m, J=12.4, 8.4 Hz, 2H). Mass (m/z): 390.8 [M+H]+.
The titled compound 514 (4.8 mg, 0.99%) as a purple solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 6.92 (d, J=8.8 Hz, 1H), 6.87 (s, 1H), 6.82 (d, J=2.8 Hz, 1H), 6.76-6.69 (m, 2H), 6.64 (d, J=8.0 Hz, 1H), 6.52 (dd, J=8.4, 2.0 Hz, 1H), 3.64 (d, J=12.4 Hz, 2H), 2.62 (dd, J=12.0, 10.0 Hz, 2H), 2.43 (d, J=8.8 Hz, 1H), 2.12 (s, 3H), 1.88 (d, J=12.8 Hz, 2H), 1.61-1.51 (m, 2H), 1.20 (s, 6H). Mass (m/z): 417.8 [M+H]+.
The titled compound 515 (14.4 mg, 9.2%) as a blue solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 7.11-6.91 (m, 2H), 6.87-6.64 (m, 3H), 6.36-6.15 (m, 2H), 4.41 (d, J=2.4 Hz, 2H), 3.68 (d, J=12.0 Hz, 2H), 2.64 (s, 2H), 2.42-2.39 (m, 1H), 2.11 (s, 3H), 1.88 (d, J=12.4 Hz, 2H), 1.56 (q, J=12.8 Hz, 2H). Mass (m/z): 406.2 [M+H]+.
The titled compound 516 (26.3 mg, 17%) as a white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 7.05-6.89 (m, 2H), 6.65 (d, J=9.2 Hz, 2H), 6.44 (dd, J=15.2, 6.4 Hz, 3H), 4.45 (d, J=2.4 Hz, 2H), 3.76 (d, J=2.4 Hz, 3H), 3.70 (d, J=12.4 Hz, 2H), 2.67 (d, J=9.2 Hz, 2H), 2.51-2.49 (m, 1H), 1.89 (d, J=12.4 Hz, 2H), 1.58 (q, J=11.6, 11.2 Hz, 2H). Mass (m/z): 424.4 [M+H]+.
The titled compound 517 (48.5 mg, 22.8%) as a white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 6.93-6.91 (m, 2H), 6.86-6.84 (m, 2H), 6.71 (d, J=8.0 Hz, 1H), 6.53-6.49 (m, 2H), 4.74 (s, 2H), 3.02-2.96 (m, 4H), 1.65-1.58 (m, 4H), 1.53-1.45 (m, 2H). Mass (m/z): 324.1 [M+H]+.
The titled compound 518 (55.4 mg, 23.7%) as a yellow solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 6.97 (d, J=8.8 Hz, 1H), 6.84 (s, 1H), 6.76 (d, J=8.8 Hz, 1H), 6.66 (d, J=8.4 Hz, 1H), 6.28-6.24 (m, 2H), 4.91-4.71 (m, 1H), 4.44 (s, 2H), 3.31-3.22 (m, 2H), 3.08-2.98 (m, 2H), 2.11 (s, 3H), 2.04-1.89 (m, 2H), 1.85-1.72 (m, 2H). Mass (m/z): 356.1 [M+H]+.
The titled compound 519 (12.4 mg, 10.5%) as a yellow solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 7.07 (s, 1H), 6.95 (d, J=8.8 Hz, 1H), 6.81 (s, 1H), 6.73 (d, J=8.8 Hz, 1H), 6.65 (d, J=8.4 Hz, 1H), 6.31-6.17 (m, 2H), 4.44 (s, 2H), 3.47 (d, J=11.6 Hz, 2H), 3.38 (t, J=10.4 Hz, 2H), 2.82 (t, J=8.4 Hz, 2H), 2.33 (t, J=11.2 Hz, 2H), 2.11 (s, 3H), 1.10 (d, J=6.4 Hz, 6H). Mass (m/z): 449.2 [M+H]+.
The titled compound 520 (12.4 mg, 10.5%) as a grey solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 7.27 (d, J=8.8 Hz, 1H), 7.11 (s, 1H), 6.66 (d, J=2.0 Hz, 1H), 6.65-6.62 (m, 1H), 6.20-6.14 (m, 2H), 4.44 (s, 2H), 4.13 (d, J=12.0 Hz, 1H), 3.93 (d, J=12.4 Hz, 1H), 3.89-3.80 (m, 1H), 2.48-2.43 (m, 1H), 2.32-2.23 (m, 1H), 2.20 (s, 3H), 1.21 (s, 3H), 1.18 (s, 3H), 1.09 (d, J=6.0 Hz, 3H). Mass (m/z): 383.1 [M+H]+.
The titled compound 521 (28.1 mg, 18.3%) as a white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 7.28 (d, J=8.8 Hz, 1H), 7.13 (s, 1H), 6.65 (dd, J=8.4, 5.6 Hz, 2H), 6.24-6.11 (m, 2H), 4.44 (s, 2H), 3.43 (t, J=5.2 Hz, 4H), 3.22 (q, J=10.4 Hz, 2H), 2.70 (t, J=5.2 Hz, 4H), 2.21 (s, 3H). Mass (m/z): 422.3[M+H]+.
The titled compound 522 (35.3 mg, 45.6%) as a white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 7.28 (dd, J=8.8, 2.4 Hz, 1H), 7.10 (s, 1H), 6.70-6.57 (m, 2H), 6.21-6.09 (m, 2H), 4.49-4.40 (m, 2H), 4.08 (d, J=12.4 Hz, 2H), 3.68-3.51 (m, 2H), 2.61-2.53 (m, 2H), 2.33 (t, J=11.6 Hz, 2H), 1.20-1.07 (m, 9H). Mass (m/z): 383.3 [M+H]+.
The titled compound 523 (29 mg, 18.1%) as a yellow solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H), 7.66 (s, 1H), 7.00-6.84 (m, 4H), 6.77 (d, J=8.8 Hz, 1H), 6.58 (d, J=3.6 Hz, 1H), 6.48 (d, J=8.8 Hz, 1H), 4.45 (d, J=2.4 Hz, 2H), 3.60 (d, J=12.0 Hz, 2H), 2.61 (s, 3H), 1.88 (d, J=12.4 Hz, 2H), 1.57 (q, J=12.8 Hz, 2H). Mass (m/z): 392.2 [M+H]+.
The titled compound 524 (11.7 mg, 6.9%) as a pink solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 7.73 (s, 1H), 6.93 (s, 3H), 6.71 (d, J=8.4 Hz, 1H), 6.54 (d, J=16.0 Hz, 2H), 4.48 (d, J=2.4 Hz, 2H), 3.18 (d, J=6.0 Hz, 4H), 2.06 (p, J=8.8 Hz, 4H). Mass (m/z): 360.1 [M+H]+.
The titled compound 525 (14.4 mg, 8.7%) as pink oil was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 7.09 (s, 1H), 6.97 (dd, J=8.8, 2.4 Hz, 1H), 6.88 (s, 1H), 6.78 (d, J=8.8 Hz, 1H), 6.66 (dd, J=8.4, 2.4 Hz, 1H), 6.36-6.19 (m, 2H), 4.45 (d, J=2.4 Hz, 2H), 3.26-3.24 (m, 4H), 2.11 (d, J=2.4 Hz, 3H), 2.04 (dq, J=12.8, 6.8, 5.2 Hz, 4H). Mass (m/z): 374.2 [M+H]+
The titled compound 526 (21.1 mg 91.8%) as a black solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.52 (s, 1H), 6.91-6.89 (m, 2H), 6.80 (d, J=2.4, 1H), 6.69-6.67 (m, 1H), 6.58 (d, J=1.6, 2H), 6.44 (s, 1H), 5.92 (s, 2H), 3.60 (d, J=12.0, 2H), 2.60 (t, J=12.0, 2H), 2.42-2.37 (m, 1H), 2.15 (d, J=4.4, 3H), 1.87 (d, J=12.0, 2H), 1.62-1.51 (m, 2H). Mass (m/z): 389.7 [M+H]+.
The titled compound 527 (15.3 mg, 4.73%) as a purple solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 7.19 (s, 1H), 6.98 (dd, J=23.6, 8.4 Hz, 2H), 6.86 (d, J=2.8 Hz, 1H), 6.77 (dd, J=8.8, 2.8 Hz, 1H), 6.24 (dd, J=8.0, 2.0 Hz, 1H), 6.16 (d, J=2.0 Hz, 1H), 3.70 (d, J=12.4 Hz, 2H), 2.65 (dd, J=12.0, 10.4 Hz, 2H), 2.47-2.40 (m, 1H), 2.13 (s, 3H), 1.89 (d, J=12.0 Hz, 2H), 1.56 (m, J=12.4, 8.8 Hz, 2H), 1.18 (s, 6H). Mass (m/z): 417.7 [M+H]+.
The titled compound 528 (25.1 mg, 15.7%) as a yellow solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.00-6.91 (m, 2H), 6.81 (s, 1H), 6.72 (d, J=8.4 Hz, 2H), 6.43 (d, J=8.4 Hz, 1H), 6.33 (s, 1H), 3.72-3.62 (m, 4H), 3.48 (d, J=11.6 Hz, 2H), 3.33-3.32 (m, 2H), 2.86 (s, 2H), 2.19 (t, J=11.2 Hz, 2H), 2.11 (s, 3H), 1.17-1.11 (m, 6H). Mass (m/z): 352.5 [M+H]+.
The titled compound 529 (15 mg, 9.7%) as a yellow solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 6.99-6.92 (m, 2H), 6.81 (s, 1H), 6.73 (d, J=8.4 Hz, 2H), 6.44 (d, J=8.4 Hz, 1H), 6.34 (s, 1H), 3.89 (d, J=11.2 Hz, 1H), 3.70 (s, 2H), 3.68-3.56 (m, 2H), 3.49 (d, J=11.6 Hz, 1H), 3.39 (d, J=12.0 Hz, 1H), 2.90-2.83 (m, 2H), 2.70-2.58 (m, 2H), 2.35-2.23 (m, 2H), 2.11 (s, 3H), 1.14 (d, J=6.4 Hz, 3H). Mass (m/z): 338.5 [M+H]+.
The titled compound 530 (26.7 mg, 17%) as an off-white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 7.96-7.89 (m, 1H), 7.67 (d, J=8.8 Hz, 1H), 7.07-7.00 (m, 2H), 6.98-6.91 (m, 2H), 6.57 (d, J=8.8 Hz, 1H), 6.35 (s, 1H), 4.21 (d, J=4.8 Hz, 2H), 3.69 (d, J=12.0 Hz, 2H), 3.33 (d, J=2.0 Hz, 2H), 2.66 (t, J=12.0 Hz, 2H), 2.47-2.36 (m, 1H), 1.88 (d, J=12.4 Hz, 2H), 1.64-1.49 (m, 2H). Mass (m/z): 406.5 [M+H]+.
The titled compound 531 (18 mg, 10%) as a grey solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.86 (s, 1H), 7.76 (s, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 6.88 (s, 1H), 6.80 (d, J=8.8 Hz, 1H), 6.34 (d, J=8.8 Hz, 1H), 6.00 (s, 1H), 4.18 (d, J=5.2 Hz, 2H), 3.75 (d, J=12.0 Hz, 2H), 3.28 (s, 2H), 2.73-2.62 (m, 2H), 2.41-2.37 (m, 1H), 2.11 (s, 3H), 1.88 (d, J=12.4 Hz, 2H), 1.63-1.49 (m, 2H). Mass (m/z): 420.5 [M+H]+.
To a solution of 4-methyl-7-((4-(4-(trifluoromethyl)piperidin-1-yl)phenyl) amino)-2H-benzo[b][1,4]oxazin-3(4H)-one (100 mg, 0.24 mmol) in DCM (2 mL) was added formaldehyde (15 mg, 0.49 mmol) and sodium triacetoxyhydroborate (104 mg, 0.49 mmol). The mixture was stirred for 2 hs and concentrated under vacuum. The residue was purified by C18 column to give 4-methyl-7-(methyl(4-(4-(trifluoromethyl)piperidin-1-yl) phenyl)amino)-2H-benzo[b][1,4]oxazin-3(4H)-one (22.5 mg, 21.7%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.03-6.92 (m, 5H), 6.43 (d, J=8.8 Hz, 1H), 6.37 (s, 1H), 4.56 (s, 2H), 3.73 (d, J=12.4 Hz, 2H), 3.22 (s, 3H), 3.15 (s, 3H), 2.74-2.63 (m, 2H), 2.45-2.40 (m, 1H), 1.89 (d, J=12.8 Hz, 2H), 1.63-1.49 (m, 2H). Mass (m/z): 420.5 [M+H]+.
The titled compound 533 (7.5 mg, 19%) as a grey solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 7.17 (s, 1H), 6.98 (d, J=9.2 Hz, 1H), 6.85 (s, 1H), 6.82-6.72 (m, 2H), 6.36 (d, J=8.8 Hz, 1H), 6.26 (s, 1H), 4.35-4.28 (m, 2H), 3.69 (d, J=12.4 Hz, 2H), 2.67-2.63 (m, 2H), 2.44-2.37 (m, 1H), 2.11 (s, 3H), 1.88 (d, J=12.8 Hz, 2H), 1.63-1.49 (m, 2H). Mass (m/z): 420.5 [M+H]+.
The titled compound 534 (8.8 mg, 22%) as a grey solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 7.78 (s, 1H), 6.96 (d, J=8.4 Hz, 2H), 6.90 (d, J=8.4 Hz, 2H), 6.84 (d, J=8.6 Hz, 1H), 6.60 (d, J=8.7 Hz, 1H), 6.55 (s, 1H), 4.34 (t, J=6.2 Hz, 2H), 3.62 (d, J=12.1 Hz, 2H), 2.68-2.58 (m, 4H), 2.43-2.36 (m, 1H), 1.88 (d, J=12.7 Hz, 2H), 1.66-1.49 (m, 2H). Mass (m/z): 406.5 [M+H]+.
The titled compound 535 (22.0 mg, 15.28%) as a white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 6.92 (d, J=8.8 Hz, 1H), 6.86-6.77 (m, 2H), 6.71 (dd, J=8.8, 2.8 Hz, 1H), 6.58 (d, J=8.4 Hz, 2H), 6.52 (dd, J=8.4, 2.4 Hz, 1H), 6.46 (d, J=2.0 Hz, 1H), 4.19 (s, 2H), 3.64 (d, J=12.4 Hz, 2H), 2.68-2.57 (m, 2H), 2.45-2.36 (m, 1H), 2.11 (s, 3H), 1.87 (d, J=12.0 Hz, 2H), 1.61-1.50 (m, 2H). Mass (m/z): 404.8 [M+H]+.
The titled compound 536 (2.6 mg, 0.66%) as a yellow solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 6.91 (d, J=8.4 Hz, 2H), 6.79 (d, J=2.4 Hz, 1H), 6.71-6.60 (m, 2H), 6.56 (d, J=1.2 Hz, 1H), 6.44 (dd, J=8.4, 1.6 Hz, 1H), 6.36 (s, 2H), 3.73-3.63 (m, 2H), 3.43 (d, J=10.0 Hz, 5H), 2.22-2.10 (m, 5H), 1.14 (d, J=6.4 Hz, 6H). Mass (m/z): 366.0 [M+H]+.
The titled compound 537 (29.3 mg, 17.03%) as a white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 6.90 (d, J=8.8 Hz, 1H), 6.68 (d, J=8.4 Hz, 1H), 6.42 (dd, J=11.6, 3.2 Hz, 2H), 4.57 (s, 2H), 3.54 (d, J=12.0 Hz, 2H), 2.78 (t, J=11.2 Hz, 2H), 2.41 (s, 3H), 2.15 (ddd, J=12.0, 8.0, 4.0 Hz, 1H), 2.04-1.86 (m, 4H). Mass (m/z): 430.8 [M+H]+.
The titled compound 538 (10.0 mg, 12.34%) as a pink solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, CDCl3) δ 7.17 (s, 1H), 6.94 (d, J=8.8 Hz, 1H), 6.87 (d, J=8.8 Hz, 1H), 6.80 (d, J=2.8 Hz, 1H), 6.70 (dd, J=8.8, 2.8 Hz, 1H), 6.31 (dd, J=8.8, 2.4 Hz, 1H), 6.23 (d, J=2.4 Hz, 1H), 4.49 (s, 2H), 3.25-3.18 (m, 2H), 3.16 (s, 3H), 3.08-3.01 (m, 4H), 2.75-2.68 (m, 4H), 2.08 (s, 3H). Mass (m/z): 434.9 [M+H]+.
The titled compound 539 (5 mg, 3.2%) as a white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 9.78 (s, 1H), 7.03 (s, 1H), 6.91 (d, J=8.8 Hz, 1H), 6.80 (d, J=2.8 Hz, 1H), 6.70 (dd, J=8.8, 2.8 Hz, 1H), 6.64 (d, J=8.8 Hz, 1H), 6.56 (dd, J=8.8, 2.4 Hz, 1H), 6.46 (d, J=2.4 Hz, 1H), 5.10 (s, 2H), 3.64 (d, J=12.4 Hz, 2H), 2.60 (td, J=12.4, 2.0 Hz, 2H), 2.08 (s, 3H), 1.84 (d, J=11.6 Hz, 2H), 1.52 (dd, J=12.4, 3.6 Hz, 2H), 1.20 (s, 1H). Mass (m/z): 405.9 [M+H]+.
The titled compound 540 (46.8 mg, 30.2%) as a grey solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 7.66 (s, 1H), 7.11-6.31 (m, 7H), 4.47 (d, J=2.4 Hz, 2H), 4.26 (s, 1H), 3.28-2.75 (m, 4H), 1.57 (s, 4H), 1.15 (s, 3H). Mass (m/z): 354.1 [M+H]+.
The titled compound 541 (17.6 mg, 10.9%) as a grey solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 7.26-6.46 (m, 5H), 6.43-5.99 (m, 2H), 4.44 (s, 2H), 4.26 (s, 1H), 3.12 (m, 4H), 2.10 (s, 3H), 1.56 (s, 4H), 1.15 (s, 3H). Mass (m/z): 368.1 [M+H]+.
The titled compound 542 (23.8 mg, 15.0%) as a grey solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 7.06 (s, 1H), 6.94 (d, J=8.4 Hz, 1H), 6.81 (s, 1H), 6.72 (d, J=8.8 Hz, 1H), 6.65 (d, J=8.4 Hz, 1H), 6.29-6.20 (m, 2H), 4.44 (s, 2H), 4.13 (s, 1H), 3.66 (d, J=11.6 Hz, 2H), 2.53 (m, 2H), 2.10 (s, 3H), 1.77 (d, J=11.2 Hz, 2H), 1.44-1.21 (m, 3H), 1.06 (s, 6H). Mass (m/z): 396.2 [M+H]+.
The titled compound 543 (43.5 mg, 26.8%) as a grey solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 7.92-7.43 (m, 1H), 7.18-6.18 (m, 7H), 4.48 (s, 2H), 4.13 (s, 1H), 3.59 (s, 2H), 2.45-2.22 (m, 2H), 1.95-1.56 (m, 2H), 1.43-1.22 (m, 3H), 1.06 (s, 6H). Mass (m/z): 382.2 [M+H]+.
The titled compound 544 (14.2 mg, 13.2%) as a yellow solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 6.97 (t, J=8.0 Hz, 2H), 6.84 (s, 1H), 6.75 (d, J=9.2 Hz, 1H), 6.51 (d, J=6.4 Hz, 2H), 3.92 (d, J=6.0 Hz, 3H), 3.68 (d, J=12.4 Hz, 2H), 2.66 (q, J=12.4 Hz, 3H), 2.44 (d, J=10.0 Hz, 1H), 2.12 (s, 3H), 1.88 (d, J=12.4 Hz, 2H), 1.56 (q, J=12.4 Hz, 2H). Mass (m/z): 376.3 [M+H]+.
The titled compound 545 (22.1 mg, 18.7%) as a white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.24 (s, 1H), 7.01 (t, J=8.0 Hz, 2H), 6.86 (s, 1H), 6.77 (d, J=8.8 Hz, 1H), 6.59 (d, J=8.4 Hz, 1H), 6.52 (s, 1H), 5.87 (s, 2H), 4.42 (s, 4H), 3.70 (d, J=12.4 Hz, 2H), 2.66 (t, J=12.0 Hz, 2H), 2.44 (s, 1H), 2.12 (s, 3H), 1.88 (d, J=12.8 Hz, 2H), 1.56 (q, J=12.4 Hz, 2H). Mass (m/z): 419.3 [M+H]+.
The titled compound 546 (25.6 mg, 21.2%) as a pink solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 7.18 (s, 1H), 6.70 (d, J=23.2 Hz, 3H), 6.42-6.29 (m, 2H), 4.46 (d, J=2.4 Hz, 2H), 3.68 (d, J=2.4 Hz, 3H), 3.38 (s, 2H), 2.60-2.55 (m, 3H), 2.06 (d, J=2.4 Hz, 3H), 1.87 (d, J=12.4 Hz, 2H), 1.61 (dd, J=14.0, 10.4 Hz, 2H). Mass (m/z): 436.2 [M+H]+.
The titled compound 547 (18.3 mg, 15.1%) as a pink solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.45 (s, 1H), 7.34 (s, 1H), 6.75 (s, 1H), 6.72-6.60 (m, 2H), 4.55 (d, J=2.4 Hz, 2H), 3.69 (d, J=2.4 Hz, 3H), 3.37 (d, J=13.6 Hz, 2H), 2.58-2.55 (m, 2H), 2.43-2.39 (m, 1H), 2.08 (d, J=2.4 Hz, 3H), 1.87 (d, J=12.4 Hz, 2H), 1.59 (q, J=12.4 Hz, 2H). Mass (m/z): 437.2 [M+H]+.
The titled compound 548 (24 mg, 19.2%) as a pink solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 7.13 (s, 1H), 6.70 (d, J=23.6 Hz, 2H), 6.20 (d, J=24.4 Hz, 2H), 4.41 (s, 2H), 3.68 (d, J=2.4 Hz, 3H), 3.37 (d, J=10.0 Hz, 2H), 2.58-2.55 (m, 2H), 2.43-2.39 (m, 1H), 2.12 (s, 3H), 2.05 (s, 3H), 1.87 (d, J=12.4 Hz, 2H), 1.59 (q, J=12.4 Hz, 2H). Mass (m/z): 450.2 [M+H]+.
The titled compound 549 (6.8 mg, 4.8%) as a pink solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 7.59 (s, 1H), 6.95-6.77 (m, 4H), 6.69 (d, J=8.4 Hz, 1H), 6.55-6.40 (m, 2H), 4.47 (d, J=2.8 Hz, 2H), 4.13 (s, 2H), 1.64 (d, J=7.6 Hz, 4H), 1.37 (d, J=7.6 Hz, 4H). Mass (m/z): 336.2 [M+H]+.
The titled compound 550 (17.3 mg, 19.4%) as a pink solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 7.03 (s, 1H), 7.00-6.90 (m, 1H), 6.85 (s, 1H), 6.80-6.65 (m, 2H), 6.34-6.18 (m, 2H), 5.94 (s, 1H), 4.41 (d, J=2.4 Hz, 2H), 3.51 (d, J=12.0 Hz, 2H), 2.88 (t, J=12.0 Hz, 2H), 2.11 (d, J=2.4 Hz, 3H), 1.89-1.63 (m, 4H). Mass (m/z): 408.2 [M+H]+.
The titled compound 551 (18 mg, 10.8%) as a black solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J=8.8 Hz, 1H), 7.71 (s, 1H), 7.10-7.05 (m, 2H), 6.86 (d, J=2.8 Hz, 1H), 6.77-6.74 (m, 1H), 6.71-6.68 (m, 1H), 6.60 (d, J=1.6 Hz, 1H), 3.69 (d, J=12.4 Hz, 2H), 3.61 (s, 3H), 3.31 (m, 1H), 2.63 (d, J=10.4 Hz, 2H), 2.16 (s, 3H), 1.89 (d, J=12.4 Hz, 2H), 1.57 (dd, J=12.4, 4.0 Hz, 2H). Mass (m/z): 430.8 [M+H]+.
The titled compound 552 (8 mg, 5%) as a pink solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 7.11 (s, 1H), 6.99 (d, J=8.8 Hz, 1H), 6.84 (s, 1H), 6.78-6.71 (m, 1H), 6.66 (d, J=8.4 Hz, 1H), 6.32-6.24 (m, 2H), 4.63-4.58 (m, 1H), 4.45 (s, 2H), 4.28-4.20 (m, 1H), 3.79 (d, J=13.6 Hz, 1H), 3.68-3.53 (m, 2H), 3.53-3.47 (m, 1H), 2.93-2.77 (m, 1H), 2.12 (s, 3H), 1.49-1.30 (m, 3H). Mass (m/z): 449.5 [M+H]+.
The titled compound 553 (24.4 mg, 16.9%) as a grey solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 7.75 (s, 1H), 6.98-6.92 (m, 2H), 6.88 (d, J=8.4 Hz, 2H), 6.71 (d, J=8.4 Hz, 1H), 6.58-6.49 (m, 2H), 4.63-4.58 (m, 1H), 4.48 (s, 2H), 4.28-4.20 (m, 1H), 3.82-3.75 (m, 1H), 3.67-3.40 (m, 3H), 2.84-2.77 (m, 1H), 1.53-1.30 (m, 3H). Mass (m/z): 435.5 [M+H]+.
The titled compound 554 (23.9 mg, 13.5%) as a purple solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 7.86 (s, 1H), 7.60 (s, 1H), 6.96-6.88 (m, 5H), 4.97-4.68 (m, 1H), 4.57 (s, 2H), 3.26-3.22 (m, 2H), 3.04-3.00 (m, 2H), 2.06-1.90 (m, 2H), 1.86-1.78 (m, 2H). Mass (m/z): 343.5 [M+H]+.
The titled compound 555 (16.6 mg, 42%) as an off-white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 7.17 (s, 1H), 6.98 (d, J=8.4 Hz, 1H), 6.86 (s, 1H), 6.79 (d, J=7.6 Hz, 2H), 6.36 (d, J=8.8 Hz, 1H), 6.26 (s, 1H), 5.94 (s, 1H), 4.32 (t, J=6.4 Hz, 2H), 3.53 (d, J=12.0 Hz, 2H), 2.89 (t, J=12.0 Hz, 2H), 2.11 (s, 3H), 1.84-1.68 (m, 4H). Mass (m/z): 436.5 [M+H]+.
The titled compound 556 (11.7 mg, 30%) as a grey solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 7.77 (s, 1H), 6.96 (d, J=8.4 Hz, 2H), 6.91 (d, J=8.4 Hz, 2H), 6.84 (d, J=8.4 Hz, 1H), 6.63-6.52 (m, 2H), 5.93 (s, 1H), 4.34 (t, J=6.4 Hz, 2H), 3.45 (d, J=12.0 Hz, 2H), 2.87 (t, J=12.0 Hz, 2H), 2.62-2.58 (m, 2H), 1.89-1.70 (m, 4H). Mass (m/z): 422.5 [M+H]+.
The titled compound 557 (10 mg, 24%) as a white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.25 (s, 1H), 6.79 (d, J=8.8 Hz, 1H), 6.67 (d, J=8.8 Hz, 1H), 6.29 (d, J=8.8 Hz, 1H), 6.18 (s, 1H), 4.32 (t, J=5.2 Hz, 2H), 4.05 (d, J=12.4 Hz, 1H), 3.95 (t, J=10.8 Hz, 2H), 3.54 (t, J=11.6 Hz, 1H), 2.76-2.72 (m, 1H), 2.62-2.58 (m, 1H), 2.48-2.37 (m, 3H), 2.22 (s, 3H), 1.50 (p, J=8.0 Hz, 2H), 0.95 (t, J=7.6 Hz, 3H). Mass (m/z): 383.5 [M+H]+.
The titled compound 558 (11 mg, 6.47%) as a yellow solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 7.37 (s, 1H), 7.26 (s, 1H), 6.97 (d, J=8.8 Hz, 1H), 6.87 (s, 1H), 6.77 (d, J=8.8 Hz, 1H), 6.60 (s, 1H), 4.95-4.78 (m, 1H), 4.54 (s, 2H), 3.29-3.27 (m, 2H), 3.11-2.98 (m, 2H), 2.13 (s, 3H), 2.05-1.88 (m, 2H), 1.85-1.70 (m, 2H). Mass (m/z): 357.1 [M+H]+.
The titled compound 559 (37.8 mg, 24.2%) as an off-white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 7.05 (s, 1H), 6.94 (d, J=8.8 Hz, 1H), 6.80 (s, 1H), 6.72 (d, J=8.8 Hz, 1H), 6.65 (d, J=8.4 Hz, 1H), 6.29-6.20 (m, 2H), 4.44 (s, 2H), 3.65 (d, J=11.6 Hz, 2H), 3.10 (s, 3H), 2.10 (s, 3H), 1.69 (d, J=12.4 Hz, 2H), 1.55-1.44 (m, 1H), 1.41-1.27 (m, 2H), 1.06 (s, 6H). Mass (m/z): 410.2 [M+H]+.
The titled compound 560 (13 mg, 8.2%) as a grey solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 7.66 (s, 1H), 6.95-6.88 (m, 2H), 6.85 (d, J=7.2 Hz, 2H), 6.73-6.67 (m, 1H), 6.55-6.47 (m, 2H), 4.47 (d, J=2.4 Hz, 2H), 3.58 (d, J=11.6 Hz, 2H), 3.09 (d, J=2.4 Hz, 3H), 2.48-2.42 (m, 2H), 1.69 (d, J=12.4 Hz, 2H), 1.54-1.44 (m, 1H), 1.35 (q, J=12.4 Hz, 2H), 1.10 (s, 6H). Mass (m/z): 396.2 [M+H]+.
The titled compound 561 (44 mg, 16.4%) as a white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 7.76 (s, 1H), 6.96-6.86 (m, 4H), 6.72 (d, J=8.4 Hz, 1H), 6.57-6.46 (m, 2H), 4.48 (s, 2H), 4.29 (d, J=68.4 Hz, 1H), 3.87 (s, 1H), 3.58-3.46 (m, 1H), 3.23-3.06 (m, 2H), 2.82-2.75 (m, 1H), 1.24 (dd, J=23.2, 6.4 Hz, 3H). Mass (m/z): 408.2 [M+H]+.
The titled compound 562 (40 mg, 14.4%) as a light-yellow solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 7.11 (s, 1H), 6.99 (d, J=8.0 Hz, 1H), 6.87 (d, J=19.6 Hz, 1H), 6.82-6.72 (m, 1H), 6.65 (d, J=8.0 Hz, 1H), 6.32-6.22 (m, 2H), 4.48 (s, 2H), 4.29 (d, J=68.4 Hz, 1H), 3.87 (s, 1H), 3.58-3.46 (m, 1H), 3.23-3.06 (m, 2H), 2.82-2.75 (m, 1H), 2.12 (s, 3H), 1.24 (dd, J=23.2, 6.4 Hz, 3H). Mass (m/z): 422.2 [M+H]+.
The titled compound 563 (14.8 mg, 13.7%) as a grey solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 6.98 (s, 1H), 6.90 (d, J=8.4 Hz, 1H), 6.61 (d, J=8.4 Hz, 1H), 6.42 (d, J=2.8 Hz, 1H), 6.36 (dd, J=8.4, 2.8 Hz, 1H), 6.15 (dd, J=8.4, 2.4 Hz, 1H), 6.11 (d, J=2.4 Hz, 1H), 4.42 (s, 2H), 3.19 (q, J=6.0, 4.8 Hz, 4H), 2.08 (s, 3H), 1.98-1.88 (m, 4H). Mass (m/z): 324.2 [M+H]+.
The titled compound 564 (10.2 mg, 5.99%) as a light purple solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 7.14 (s, 1H), 7.00 (d, J=8.8 Hz, 1H), 6.84 (d, J=2.8 Hz, 1H), 6.76 (dd, J=8.8, 2.8 Hz, 1H), 6.10 (d, J=2.0 Hz, 1H), 5.82 (d, J=2.0 Hz, 1H), 4.39 (s, 2H), 3.77-3.63 (m, 5H), 2.65 (dd, J=12.4, 10.0 Hz, 2H), 2.45 (dd, J=12.0, 3.6 Hz, 1H), 2.12 (s, 3H), 1.88 (d, J=12.4 Hz, 2H), 1.62-1.50 (m, 2H). Mass (m/z): 435.8 [M+H]+.
The titled compound 565 (3.7 mg, 2.04%) as a dark purple solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.33 (s, 1H), 7.02 (d, J=8.8 Hz, 1H), 6.86 (d, J=2.8 Hz, 1H), 6.77 (dd, J=8.8, 2.8 Hz, 1H), 6.17 (d, J=2.4 Hz, 1H), 5.85 (d, J=2.4 Hz, 1H), 4.38 (s, 2H), 3.71 (d, J=14.4 Hz, 5H), 3.25 (s, 3H), 2.70-2.60 (m, 2H), 2.47-2.40 (m, 1H), 2.13 (s, 3H), 1.88 (d, J=12.0 Hz, 2H), 1.60-1.50 (m, 2H). Mass (m/z): 449.8 [M+H]+.
The titled compound 566 (14.3 mg, 7%) as a light yellow solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 6.92 (d, J=8.8 Hz, 1H), 6.87 (s, 1H), 6.82 (d, J=2.4 Hz, 1H), 6.71 (dd, J=8.8, 2.8 Hz, 1H), 6.55 (dt, J=8.4, 5.2 Hz, 2H), 6.45 (s, 1H), 4.26 (s, 2H), 3.65 (d, J=12.4 Hz, 2H), 2.81 (s, 3H), 2.62 (t, J=11.2 Hz, 2H), 2.47-2.37 (m, 1H), 2.11 (s, 3H), 1.87 (d, J=11.6 Hz, 2H), 1.56 (tt, J=12.4, 6.4 Hz, 2H). Mass (m/z): 418.9 [M+H]+.
The titled compound 567 (32.1 mg, 40%) as a grey solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 7.44 (d, J=8.8 Hz, 1H), 7.28 (s, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.89 (s, 1H), 6.81 (dd, J=14.0, 9.2 Hz, 1H), 6.69 (s, 1H), 3.71 (d, J=11.6 Hz, 2H), 2.67 (t, J=11.6 Hz, 2H), 2.50-2.33 (m, 1H), 2.15 (s, 3H), 1.89 (d, J=12.0 Hz, 2H), 1.58 (dd, J=12.4, 2.8 Hz, 2H). Mass (m/z): 375 [M+H]+.
The titled compound 568 (38.9 mg, 22.66%) as a dark purple solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 6.99 (s, 1H), 6.74 (m, 6H), 4.54 (s, 2H), 3.55 (d, J=11.2 Hz, 2H), 2.60 (m, 2H), 2.40 (s, 1H), 2.05 (d, J=20.4 Hz, 3H), 1.87 (d, J=10.4 Hz, 2H), 1.57 (d, J=10.4 Hz, 2H). Mass (m/z): 406 [M+H]+.
The titled compound 569 (69.2 mg, 29%) as a purple solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 7.08 (s, 1H), 6.96 (d, J=8.8 Hz, 1H), 6.81 (d, J=2.4 Hz, 1H), 6.72 (dd, J=8.8, 2.4 Hz, 1H), 6.65 (d, J=8.4 Hz, 1H), 6.31-6.21 (m, 2H), 4.45 (s, 2H), 3.23 (q, J=10.0 Hz, 2H), 3.12-3.03 (m, 4H), 2.78-2.72 (m, 4H), 2.11 (s, 3H). Mass (m/z): 421 [M+H]+.
The titled compound 570 (2.1 mg, 3.44%) as a white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.16-7.13 (m, 1H), 6.97-6.94 (m, 1H), 6.84-6.81 (m, 2H), 6.75-6.71 (m, 1H), 6.31-6.27 (m, 1H), 6.23-6.22 (m, 1H), 5.01-4.93 (m, 1H), 4.53-4.50 (m, 1H), 3.72-3.63 (m, 4H), 3.15 (s, 3H), 2.65-2.58 (m, 2H), 2.44-2.37 (m, 1H), 2.08 (s, 3H), 1.84 (d, J=11.6 Hz, 2H), 1.57-1.48 (m, 2H). Mass (m/z): 449.8 [M+H]+.
The titled compound 571 (18 mg, 10.8%) as a black solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 11.20 (d, J=2.4 Hz, 1H), 7.85 (d, J=3.2 Hz, 1H), 7.53 (d, J=2.0 Hz, 1H), 7.17 (d, J=8.8 Hz, 1H), 6.91 (d, J=8.8 Hz, 1H), 6.80-6.76 (m, 2H), 6.71-6.64 (m, 2H), 3.60 (d, J=12.0 Hz, 2H), 2.65-2.54 (m, 2H), 2.38 (dd, J=8.0, 3.6 Hz, 1H), 2.12 (s, 3H), 1.84 (d, J=12.0 Hz, 2H), 1.54 (dd, J=12.4, 3.6 Hz, 2H). Mass (m/z): 416.7 [M+H]+.
The titled compound 572 (23.5 mg, 17.0%) as a white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 7.05 (s, 1H), 6.94 (d, J=8.4 Hz, 1H), 6.64 (d, J=8.4 Hz, 1H), 6.38 (s, 1H), 6.31 (d, J=8.8 Hz, 1H), 6.25-6.11 (m, 2H), 5.58-5.34 (m, 1H), 4.44 (s, 2H), 4.19-4.05 (m, 2H), 3.88-3.75 (m, 2H), 2.09 (s, 3H). Mass (m/z): 328.2 [M+H]+.
The titled compound 573 (26.6 mg, 5.05%) as a light-yellow solid was prepared according to the procedure outlined for compound 461. 1H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 7.27 (d, J=8.8 Hz, 1H), 6.93 (s, 1H), 6.63 (d, J=8.8 Hz, 1H), 6.58 (d, J=8.4 Hz, 2H), 6.44 (dd, J=8.4, 2.4 Hz, 1H), 6.35 (d, J=1.6 Hz, 1H), 4.18 (s, 2H), 4.02 (d, J=12.0 Hz, 1H), 3.93 (d, J=10.8 Hz, 2H), 3.54 (dd, J=11.6, 9.2 Hz, 1H), 3.37 (s, 1H), 2.76-2.67 (m, 1H), 2.40 (dd, J=12.4, 10.4 Hz, 1H), 2.22 (s, 3H), 1.49 (dd, J=14.4, 7.2 Hz, 2H), 0.95 (t, J=7.6 Hz, 3H). Mass (m/z): 367.9 [M+H]+.
The titled compound 574 (20.0 mg, 10.4%) as a yellow solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.16-7.13 (m, 1H), 6.97-6.94 (m, 1H), 6.84-6.81 (m, 2H), 6.75-6.71 (m, 1H), 6.31-6.27 (m, 1H), 6.23-6.22 (m, 1H), 5.01-4.93 (m, 1H), 4.53-4.50 (m, 1H), 3.72-3.63 (m, 4H), 3.15 (s, 3H), 2.63 (m, 2H), 2.44-2.37 (m, 1H), 2.08 (s, 3H), 1.84 (d, J=11.6 Hz, 2H), 1.57-1.48 (m, 2H). Mass (m/z): 420 [M+H]+.
The titled compound 575 (31.2 mg, 33.80%) as a grey solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 7.32 (d, J=2.4 Hz, 1H), 7.20 (s, 1H), 6.91 (d, J=8.8 Hz, 1H), 6.79 (d, J=2.8 Hz, 1H), 6.69 (dd, J=8.8, 2.8 Hz, 1H), 6.54 (d, J=2.4 Hz, 1H), 4.50 (s, 2H), 3.54 (d, J=12.4 Hz, 2H), 2.54 (d, J=2.4 Hz, 2H), 2.08 (s, 3H), 1.64 (d, J=12.4 Hz, 2H), 1.45-1.39 (m, 1H), 1.19 (dd, J=12.0, 3.6 Hz, 2H), 0.90 (d, J=6.4 Hz, 3H). Mass (m/z): 353 [M+H]+.
The titled compound 576 (4.6 mg, 1.45%) as an off-white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 7.10 (s, 1H), 6.98 (d, J=8.4 Hz, 1H), 6.65 (d, J=8.4 Hz, 1H), 6.46 (d, J=2.4 Hz, 1H), 6.38 (dd, J=8.4, 2.8 Hz, 1H), 6.26-6.18 (m, 2H), 4.44 (s, 2H), 4.21 (t, J=12.4 Hz, 4H), 2.10 (s, 3H). Mass (m/z): 345.8 [M+H]+.
The titled compound 577 (3.3 mg, 1.15%) as a white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 7.01 (s, 1H), 6.90 (d, J=8.4 Hz, 1H), 6.62 (d, J=8.4 Hz, 1H), 6.28 (d, J=2.4 Hz, 1H), 6.23-6.16 (m, 2H), 6.13 (d, J=2.4 Hz, 1H), 4.43 (s, 2H), 3.90 (t, J=7.2 Hz, 2H), 3.31 (d, J=6.8 Hz, 1H), 2.74 (dd, J=13.6, 6.4 Hz, 1H), 2.06 (s, 3H), 1.22 (d, J=6.8 Hz, 3H). Mass (m/z): 323.9 [M+H]+.
The titled compound 578 (2.1 mg, 1.07%) as a white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 7.03 (s, 1H), 6.91 (d, J=8.4 Hz, 1H), 6.63 (d, J=8.4 Hz, 1H), 6.33 (d, J=2.4 Hz, 1H), 6.26 (dd, J=8.4, 2.8 Hz, 1H), 6.21-6.12 (m, 2H), 4.43 (s, 2H), 4.31-4.26 (m, 1H), 4.05-3.96 (m, 2H), 3.53 (dd, J=8.4, 4.4 Hz, 2H), 3.23 (s, 3H), 2.07 (s, 3H). Mass (m/z): 339.8 [M+H]+.
The titled compound 579 (2.3 mg, 3.5%) as a white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.28 (s, 1H), 7.09 (d, J=7.6 Hz, 2H), 6.96 (t, J=9.2 Hz, 2H), 6.84 (s, 1H), 6.75 (d, J=8.8 Hz, 1H), 6.51 (d, J=5.6 Hz, 2H), 3.83 (s, 4H), 3.69 (d, J=12.4 Hz, 2H), 3.22 (s, 2H), 2.71-2.63 (m, 3H), 2.11 (s, 3H), 1.88 (d, J=12.4 Hz, 2H), 1.56 (d, J=12.4 Hz, 2H). Mass (m/z): 433.2 [M+H]+.
The titled compound 580 (23.7 mg, 15%) as a grey solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 7.07 (s, 1H), 6.95 (d, J=8.4 Hz, 1H), 6.81 (s, 1H), 6.72 (d, J=8.8 Hz, 1H), 6.65 (d, J=8.4 Hz, 1H), 6.30-6.21 (m, 2H), 4.44 (s, 2H), 3.49-3.34 (m, 2H), 3.20-3.06 (m, 1H), 3.03-2.95 (m, 1H), 2.80-2.68 (m, 3H), 2.48-2.42 (m, 2H), 2.11 (s, 3H), 1.12-1.06 (m, 3H). Mass (m/z): 435.5 [M+H]+.
The titled compound 581 (42.7 mg, 22.7%) as a light brown solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 7.68 (s, 1H), 6.93 (d, J=8.4 Hz, 2H), 6.85 (d, J=8.4 Hz, 2H), 6.70 (d, J=8.4 Hz, 1H), 6.56-6.47 (m, 2H), 4.47 (s, 2H), 3.50-3.37 (m, 1H), 3.31-3.21 (m, 2H), 3.17-3.06 (m, 1H), 3.02-2.95 (m, 1H), 2.77-2.71 (m, 3H), 2.48-2.41 (m, 2H), 1.11-1.05 (m, 3H). Mass (m/z): 421.5 [M+H]+.
The titled compound 582 (21.6 mg, 12.9%) as an off-white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 7.74 (s, 1H), 6.97-6.86 (m, 4H), 6.84-6.78 (m, 2H), 6.78-6.72 (m, 1H), 3.62 (d, J=12.0 Hz, 2H), 3.39 (s, 2H), 2.64-2.57 (m, 2H), 2.44-2.37 (m, 1H), 1.88 (d, J=12.8 Hz, 2H), 1.65-1.49 (m, 2H). Mass (m/z): 408.5 [M+H]+.
The titled compound 583 (19.1 mg, 11.6%) as a white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 7.06 (s, 1H), 6.95 (d, J=8.4 Hz, 1H), 6.63 (d, J=8.4 Hz, 1H), 6.38 (s, 1H), 6.31 (d, J=8.8 Hz, 1H), 6.24-6.14 (m, 2H), 4.44 (s, 2H), 4.00 (t, J=8.4 Hz, 2H), 3.80 (t, J=6.8 Hz, 2H), 3.70-3.66 (m, 1H), 2.09 (s, 3H). Mass (m/z): 378.5 [M+H]+.
The titled compound 584 (6.8 mg, 6.1%) as brown oil was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 7.07-6.89 (m, 2H), 6.69 (d, J=8.8 Hz, 1H), 6.52 (s, 1H), 6.44 (d, J=8.4 Hz, 1H), 6.25-6.08 (m, 2H), 4.39 (s, 2H), 3.47 (d, J=9.2 Hz, 1H), 3.26 (d, J=8.5 Hz, 2H), 2.15-2.0 (m, 4H), 1.23 (s, 2H). Mass (m/z): 392.4 [M+H]+.
The titled compound 585 (22.6 mg, 14.8%) as pink oil was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 7.01 (s, 1H), 6.90 (d, J=8.0 Hz, 1H), 6.63 (d, J=8.0 Hz, 1H), 6.29 (s, 1H), 6.26-6.06 (m, 3H), 4.43 (d, J=2.8 Hz, 2H), 3.75 (t, J=7.6 Hz, 4H), 2.27 (t, J=7.6 Hz, 2H), 2.07 (s, 3H). Mass (m/z): 310.2 [M+H]+.
The titled compound 586 (19.3 mg, 58.5%) as pink oil was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H), 7.11 (d, J=2.8 Hz, 1H), 6.92 (dd, J=8.4, 2.4 Hz, 1H), 6.76 (dd, J=8.8, 2.4 Hz, 1H), 6.35-6.19 (m, 3H), 6.16 (s, 1H), 4.31 (q, J=5.2 Hz, 2H), 3.83-3.67 (m, 4H), 2.56 (s, 2H), 2.27 (t, J=7.6 Hz, 2H), 2.07 (d, J=2.8 Hz, 3H). Mass (m/z): 324.2 [M+H]+.
The titled compound 587 (33.5 mg, 6.9%) as an off-white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 7.03 (s, 1H), 6.97-6.90 (m, 1H), 6.66-6.59 (m, 1H), 6.52 (s, 1H), 6.44 (d, J=8.8 Hz, 1H), 6.21-6.12 (m, 2H), 4.43 (s, 2H), 3.53-3.44 (m, 1H), 3.40-3.35 (m, 2H), 3.32-3.23 (m, 2H), 2.30-2.25 (m, 1H), 2.14-2.01 (m, 4H). Mass (m/z): 392.4 [M+H]+.
The titled compound 588 (24.4 mg, 5%) as a purple solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 7.03 (s, 1H), 6.97-6.90 (m, 1H), 6.66-6.59 (m, 1H), 6.52 (s, 1H), 6.44 (d, J=8.8 Hz, 1H), 6.21-6.12 (m, 2H), 4.43 (s, 2H), 3.53-3.44 (m, 1H), 3.40-3.35 (m, 2H), 3.32-3.23 (m, 1H), 2.28 (d, J=12.0 Hz, 1H), 2.16-2.01 (m, 4H). Mass (m/z): 392.4 [M+H]+.
The titled compound 589 (8.7 mg, 5.5%) as an off-white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 7.03 (s, 1H), 6.97-6.90 (m, 1H), 6.66-6.58 (m, 1H), 6.48 (s, 1H), 6.41 (d, J=8.8 Hz, 1H), 6.20-6.11 (m, 2H), 5.22 (s, 1H), 4.43 (s, 2H), 3.62-3.54 (m, 1H), 3.44-3.34 (m, 2H), 2.43-2.27 (m, 2H), 2.26-2.16 (m, 1H), 2.10 (s, 3H). Mass (m/z): 408.5 [M+H]+.
The titled compound 590 (11 mg, 28%) as a purple solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 7.15 (s, 1H), 7.00-6.93 (m, 1H), 6.80-6.73 (m, 1H), 6.39 (s, 1H), 6.35-6.26 (m, 2H), 6.18 (s, 1H), 4.35-4.27 (m, 2H), 4.05-3.96 (m, 2H), 3.86-3.75 (m, 2H), 3.71-3.66 (m, 1H), 2.62-2.54 (m, 2H), 2.09 (s, 3H). Mass (m/z): 392.5 [M+H]+.
The titled compound 591 (3.1 mg, 7.9%) as a light brown solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, CD3OD) δ 6.99 (d, J=8.4 Hz, 1H), 6.76 (d, J=8.4 Hz, 1H), 6.51 (s, 1H), 6.45 (d, J=8.4 Hz, 1H), 6.33 (d, J=8.4 Hz, 1H), 6.24 (s, 1H), 5.12 (s, 1H), 4.41 (s, 2H), 3.64-3.60 (m, 1H), 3.47-3.40 (m, 3H), 2.69-2.61 (m, 2H), 2.33-2.29 (m, 2H), 2.16 (s, 3H). Mass (m/z): 422.5 [M+H]+.
The titled compound 592 (10.9 mg, 26.8%) as a light brown solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 7.07 (s, 1H), 6.97 (d, J=8.8 Hz, 1H), 6.84 (s, 1H), 6.75 (d, J=8.8 Hz, 1H), 6.63 (d, J=8.4 Hz, 1H), 6.27 (d, J=11.2 Hz, 2H), 4.38-4.33 (m, 1H), 3.68 (d, J=12.0 Hz, 2H), 2.90 (s, 2H), 2.66-2.59 (m, 2H), 2.44-2.36 (m, 1H), 2.11 (s, 3H), 1.88 (d, J=12.8 Hz, 2H), 1.63-1.49 (m, 2H). Mass (m/z): 435.5 [M+H]+.
The titled compound 593 (28.7 mg, 15%) as a white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 7.14 (s, 1H), 6.99-6.92 (m, 1H), 6.85 (s, 1H), 6.79-6.71 (m, 2H), 6.55-6.47 (m, 2H), 3.69 (d, J=12.0 Hz, 2H), 3.37 (s, 2H), 2.63 (d, J=12.4 Hz, 2H), 2.48-2.36 (m, 1H), 2.11 (d, J=2.8 Hz, 3H), 1.88 (d, J=12.4 Hz, 2H), 1.63-1.49 (m, 2H). Mass (m/z): 422.5 [M+H]+.
The titled compound 594 (25.8 mg, 18%) as a white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.39 (s, 1H), 7.09 (d, J=8.4 Hz, 1H), 7.02 (d, J=8.4 Hz, 1H), 6.87 (s, 1H), 6.78 (d, J=8.4 Hz, 1H), 6.49 (d, J=8.4 Hz, 1H), 6.32 (s, 1H), 4.41-4.34 (m, 2H), 3.72 (d, J=12.0 Hz, 2H), 3.33 (s, 3H), 2.72-2.61 (m, 2H), 2.46-2.38 (m, 1H), 2.13 (s, 3H), 1.88 (d, J=12.8 Hz, 2H), 1.63-1.49 (m, 2H). Mass (m/z): 434.5 [M+H]+.
The titled compound 595 (37.7 mg, 13%) as a purple solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 7.05 (s, 1H), 6.94 (d, J=8.4 Hz, 1H), 6.63 (d, J=8.4 Hz, 1H), 6.37 (d, J=2.4 Hz, 1H), 6.30 (dd, J=8.4, 2.8 Hz, 1H), 6.21 (dd, J=8.4, 2.4 Hz, 1H), 6.16 (d, J=2.4 Hz, 1H), 4.44 (s, 2H), 3.86 (d, J=19.2 Hz, 4H), 2.08 (s, 3H), 1.62 (d, J=22.4 Hz, 3H). Mass (m/z): 342 [M+H]+.
The titled compound 596 (22.5 mg, 15.19%) as a green solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.77 (s, 1H), 7.54 (d, J=2.4 Hz, 1H), 6.90 (d, J=8.8 Hz, 2H), 6.86-6.83 (m, 3H), 4.53 (s, 2H), 3.47 (d, J=12.4 Hz, 2H), 2.58-2.48 (m, 2H), 1.65 (d, J=12.8 Hz, 2H), 1.45-1.38 (m, 1H), 1.20 (dd, J=11.6, 3.2 Hz, 2H), 0.90 (d, J=6.4 Hz, 3H). Mass (m/z): 339 [M+H]+.
The titled compound 597 (53.4 mg, 24.23%) as a grey solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 7.06 (s, 1H), 6.96 (d, J=8.4 Hz, 1H), 6.63 (d, J=8.4 Hz, 1H), 6.53 (d, J=2.4 Hz, 1H), 6.45 (dd, J=8.4, 2.8 Hz, 1H), 6.22-6.15 (m, 2H), 4.43 (s, 2H), 3.65 (t, J=13.6 Hz, 2H), 3.43 (t, J=7.2 Hz, 2H), 2.54 (d, J=7.6 Hz, 1H), 2.48 (s, 1H), 2.11 (s, 3H). Mass (m/z): 360 [M+H]+.
The titled compound 598 (4.3 mg, 8.56%) as a white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 6.99 (s, 1H), 6.92 (d, J=8.8 Hz, 1H), 6.80 (d, J=2.8 Hz, 1H), 6.70 (dd, J=8.8, 2.8 Hz, 1H), 6.63 (d, J=8.4 Hz, 1H), 6.53-6.47 (m, 2H), 5.96 (s, 1H), 3.73 (dd, J=13.6, 6.6 Hz, 1H), 3.64 (d, J=12.4 Hz, 2H), 2.88-2.72 (m, 2H), 2.64-2.57 (m, 2H), 2.45-2.35 (m, 1H), 2.08 (s, 3H), 1.84 (d, J=12.4 Hz, 2H), 1.60-1.45 (m, 2H). Mass (m/z): 418.8 [M+H]+.
The titled compound 599 (7 mg, 3.89%) as a white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 7.02 (s, 1H), 6.93 (d, J=8.4 Hz, 1H), 6.62 (d, J=8.4 Hz, 1H), 6.47 (d, J=2.4 Hz, 1H), 6.39 (dd, J=8.4, 2.4 Hz, 1H), 6.21-6.10 (m, 2H), 4.43 (s, 2H), 3.49 (m, 3H), 3.29 (d, J=9.2 Hz, 2H), 2.29-2.13 (m, 2H), 2.08 (d, J=8.0 Hz, 3H). Mass (m/z): 341.9 [M+H]+.
The titled compound 600 (9.6 mg, 4.3%) as a white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.19 (d, J=2.8 Hz, 1H), 7.83 (s, 1H), 6.96 (d, J=9.6 Hz, 2H), 6.89 (d, J=8.4 Hz, 2H), 6.71 (d, J=9.2 Hz, 1H), 6.63-6.52 (m, 2H), 4.77-4.65 (m, 2H), 3.62 (d, J=12.0 Hz, 2H), 2.62 (s, 2H), 2.46-2.38 (m, 1H), 1.88 (d, J=12.8 Hz, 2H), 1.57 (q, J=12.8 Hz, 2H), 1.23 (d, J=3.2 Hz, 9H). Mass (m/z): 491.2 [M+H]+.
The titled compound 601 (19.5 mg, 39.8%) as a yellow solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 9.48 (s, 1H), 7.24 (s, 1H), 6.99 (d, J=8.8, 1H), 6.85 (s, 1H), 6.82-6.73 (m, 2H), 6.39 (d, J=8.8 Hz, 1H), 6.31 (s, 1H), 4.24-4.15 (m, 1H), 3.92 (t, J=10.8 Hz, 1H), 3.70 (d, J=12.4 Hz, 2H), 3.58 (t, J=9.2 Hz, 1H), 2.65 (t, J=12.4 Hz, 3H), 2.48-2.39 (m, 2H), 2.11 (s, 3H), 1.88 (d, J=12.8 Hz, 2H), 1.72 (s, 2H), 1.64-1.48 (m, 2H). Mass (m/z): 435.2 [M+H]+.
The titled compound 602 (2.7 mg, 1.54%) as an off-white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 7.05 (s, 1H), 6.97 (d, J=8.8 Hz, 1H), 6.84 (d, J=2.4 Hz, 1H), 6.75 (dd, J=8.8, 2.8 Hz, 1H), 6.61 (d, J=8.4 Hz, 1H), 6.24 (dt, J=6.8, 2.4 Hz, 2H), 5.01 (t, J=5.6 Hz, 1H), 4.49 (dd, J=5.2, 3.2 Hz, 1H), 3.79-3.64 (m, 4H), 2.64 (td, J=12.0, 2.0 Hz, 2H), 2.47-2.40 (m, 1H), 2.11 (s, 3H), 1.88 (d, J=11.2 Hz, 2H), 1.61-1.50 (m, 2H). Mass (m/z): 435.8 [M+H]+.
The titled compound 603 (8.7 mg, 4.22%) as a light brown was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.42 (d, J=8.8 Hz, 1H), 7.35 (d, J=8.8 Hz, 1H), 7.25 (s, 1H), 6.82 (dd, J=8.8, 1.6 Hz, 1H), 6.68 (dd, J=5.2, 3.2 Hz, 2H), 4.05 (d, J=12.4 Hz, 1H), 4.00-3.91 (m, 2H), 3.81 (s, 3H), 3.55 (td, J=11.6, 2.4 Hz, 1H), 3.40-3.32 (m, 1H), 2.75 (d, J=3.2 Hz, 1H), 2.44 (dd, J=12.4, 10.4 Hz, 1H), 2.24 (s, 3H), 1.57-1.41 (m, 2H), 0.95 (t, J=7.6 Hz, 3H). Mass (m/z): 351.9 [M+H]+.
The titled compound 604 (19.0 mg, 10.35%) as a dark blue solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 6.94 (s, 1H), 6.89 (d, J=8.4 Hz, 1H), 6.67 (d, J=8.4 Hz, 1H), 6.39 (d, J=2.4 Hz, 1H), 6.33 (dd, J=8.4, 2.8 Hz, 1H), 6.15 (d, J=2.4 Hz, 1H), 6.11 (dd, J=8.8, 2.4 Hz, 1H), 4.38 (s, 2H), 3.38 (d, J=8.8 Hz, 2H), 3.28-3.20 (m, 2H), 2.80-2.73 (m, 1H), 2.38-2.30 (m, 1H), 2.08 (s, 3H), 1.57 (dd, J=12.0, 8.4 Hz, 1H), 1.08 (d, J=6.8 Hz, 3H). Mass (m/z): 338 [M+H]+.
The titled compound 605 (81.3 mg, 51.03%) as an off-white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.29 (d, J=8.6 Hz, 2H), 6.98 (s, 1H), 6.73-6.70 (m, 1H), 6.68 (d, J=1.8 Hz, 1H), 6.62 (d, J=8.8 Hz, 1H), 4.01 (dd, J=12.7, 1.9 Hz, 2H), 3.72 (s, 3H), 3.64-3.56 (m, 2H), 2.28 (dd, J=12.6, 10.5 Hz, 2H), 2.22 (s, 3H), 1.14 (s, 3H), 1.12 (s, 3H). Mass (m/z): 352 [M+H]+.
The titled compound 606 (13.4 mg, 110%) as a brown solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.22 (d, J=7.2 Hz, 1H), 7.67 (s, 1H), 7.56 (s, 1H), 7.19 (s, 1H), 7.06 (d, J=8.4 Hz, 1H), 6.92 (s, 1H), 6.83 (d, J=8.8 Hz, 1H), 6.52 (d, J=7.2 Hz, 1H), 6.09 (s, 1H), 3.76 (d, J=12.4 Hz, 2H), 2.72-2.68 (m, 1H), 2.47-2.38 (m, 1H), 2.14 (s, 3H), 1.89 (d, J=12.8 Hz, 2H), 1.64-1.50 (m, 2H). Mass (m/z): 375.5 [M+H]+.
The titled compound 607 (4.6 mg, 11%) as an off-white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.20 (s, 1H), 6.99 (d, J=9.2 Hz, 1H), 6.92-6.83 (m, 2H), 6.77 (d, J=8.8 Hz, 1H), 6.35 (d, J=8.8 Hz, 1H), 6.29 (s, 1H), 4.43-4.37 (m, 1H), 3.70 (d, J=12.0 Hz, 2H), 3.19 (s, 3H), 2.92-2.88 (m, 1H), 2.64-2.56 (m, 2H), 2.43-2.35 (m, 1H), 2.12 (s, 3H), 1.88 (d, J=12.8 Hz, 2H), 1.63-1.49 (m, 2H). Mass (m/z): 449.5 [M+H]+.
The titled compound 608 (12.5 mg, 32%) as an off-white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 1H), 7.35 (s, 1H), 7.03-6.92 (m, 2H), 6.86 (s, 1H), 6.77 (d, J=8.8 Hz, 1H), 6.30 (d, J=8.4 Hz, 1H), 6.23 (s, 1H), 4.44 (s, 2H), 4.11 (s, 2H), 3.71 (d, J=12.0 Hz, 2H), 2.71-2.61 (m, 2H), 2.47-2.38 (m, 1H), 2.11 (s, 3H), 1.88 (d, J=12.8 Hz, 2H), 1.63-1.48 (m, 2H). Mass (m/z): 420.5 [M+H]+.
The titled compound 609 (16 mg, 24%) as an off-white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J=7.6 Hz, 1H), 7.68-7.61 (m, 1H), 7.09-7.02 (m, 2H), 6.91 (s, 1H), 6.83 (d, J=8.8 Hz, 1H), 6.55 (d, J=7.2 Hz, 1H), 6.09 (s, 1H), 3.84 (s, 2H), 3.76 (d, J=12.4 Hz, 2H), 2.72-2.67 (m, 2H), 2.36-2.29 (m, 1H), 2.24 (s, 3H), 2.14 (s, 3H), 1.89 (d, J=12.4 Hz, 2H), 1.64-1.50 (m, 2H). Mass (m/z): 418.5 [M+H]+.
The titled compound 610 (3.3 mg, 10.6%) as an off-white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 7.15 (s, 1H), 6.96 (d, J=8.4 Hz, 1H), 6.77 (d, J=8.6 Hz, 1H), 6.43-6.25 (m, 3H), 6.18 (s, 1H), 5.64-5.33 (m, 1H), 4.34-4.27 (m, 2H), 4.20-4.05 (m, 2H), 3.88-3.75 (m, 2H), 2.74-2.53 (m, 2H), 2.09 (s, 3H). Mass (m/z): 342.1 [M+H]+.
The titled compound 611 (4.4 mg, 11.10%) as an off-white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 7.23 (s, 1H), 6.97 (d, J=8.4 Hz, 1H), 6.77 (d, J=8.8 Hz, 1H), 6.43-6.20 (m, 4H), 5.57-5.35 (m, 1H), 4.30-4.07 (m, 3H), 4.00-3.75 (m, 3H), 3.68-3.60 (m, 1H), 2.81-2.58 (m, 2H), 2.09 (s, 3H). Mass (m/z): 357.1 [M+H]+.
The titled compound 612 (14.5 mg, 12.5%) as a grey solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J=7.6 Hz, 1H), 7.68 (d, J=3.8 Hz, 2H), 7.12-7.02 (m, 1H), 6.91 (s, 1H), 6.82 (d, J=8.7 Hz, 1H), 6.48 (d, J=7.5 Hz, 1H), 6.19 (s, 1H), 6.04 (s, 1H), 3.76 (d, J=12.2 Hz, 2H), 2.71 (d, J=12.5 Hz, 2H), 2.44-2.42 (m, 1H), 2.14 (d, J=2.9 Hz, 3H), 1.89 (d, J=12.6 Hz, 2H), 1.57 (q, J=12.7 Hz, 2H). Mass (m/z): 375.2 [M+H]+.
The titled compound 613 (14.6 mg, 44.5%) as a yellow solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 9.44 (s, 1H), 7.20 (s, 1H), 6.96 (d, J=8.4 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.53 (s, 1H), 6.46 (d, J=8.8 Hz, 1H), 6.31 (d, J=8.8 Hz, 1H), 6.22 (s, 1H), 4.18 (t, J=8.8 Hz, 1H), 3.91 (t, J=10.8 Hz, 1H), 3.54 (dt, J=30.8, 8.4 Hz, 2H), 3.28 (t, J=6.8 Hz, 2H), 2.27 (s, 1H), 2.11 (s, 3H), 2.23-2.19 (m, 1H), 1.73 (s, 2H). Mass (m/z): 421.4 [M+H]+.
The titled compound 614 (3.0 mg, 9.7%) as a pink solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 7.16 (s, 1H), 6.96 (d, J=8.4 Hz, 1H), 6.77 (d, J=8.8 Hz, 1H), 6.40 (s, 1H), 6.32 (t, J=9.6 Hz, 2H), 6.19 (s, 1H), 5.27 (s, 1H), 4.30 (d, J=7.6 Hz, 2H), 4.18 (d, J=7.6 Hz, 2H), 3.84 (s, 2H), 2.09 (s, 3H). Mass (m/z): 408.2 [M+H]+.
To a solution of N-(2-methyl-4-(4-(trifluoromethyl)piperidin-1-yl)phenyl)-1H-indazol-5-amine (200 mg, 0.53 mmol) in DCM (5 mL) was added TEA (108 mg, 1.06 mmol), DMAP (65 mg, 0.53 mmol) and TMSNCO (61 mg, 0.53 mmol) at room temperature. The reaction mixture was heated to 25° C. for 8 h under nitrogen atmosphere. After the reaction was completed, the filtrate was concentrated. The residue was purified by silica gel flash column chromatography (PE/EtOAc=10/1) to afford 6-methyl-8-(4-(trifluoromethyl)piperidin-1-yl)pyrazolo[4,3-b]carbazole-1(5H)-carboxa mide (10.6 mg, 4.8% yield) as a yellow solid. 1H NMR (400 MHz, CD3OD) δ 8.12 (s, 1H), 7.53-7.48 (m, 3H), 7.23(d, J=7.6 Hz, 1H), 6.79 (s, 1H), 3.92-3.87 (m, 2H), 3.51-3.40 (m, 1H), 2.70-2.54 (m, 1H), 2.32-2.12 (m, 5H), 1.26-1.21 (m, 2H). Mass (m/z): 415.7 [M+H]+.
The titled compound 616 (5.2 mg, 2.51%) as a light purple solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 7.06 (s, 1H), 6.94 (d, J=8.4 Hz, 1H), 6.63 (d, J=8.4 Hz, 1H), 6.54 (d, J=2.8 Hz, 1H), 6.46 (dd, J=8.8, 2.8 Hz, 1H), 6.22-6.12 (m, 2H), 4.43 (s, 2H), 3.57 (d, J=11.6 Hz, 1H), 3.49 (d, J=11.2 Hz, 1H), 3.45-3.36 (m, 5H), 2.43-2.35 (m, 1H), 2.31 (dd, J=10.8, 5.2 Hz, 1H), 2.09 (d, J=9.6 Hz, 3H). Mass (m/z): 421.8 [M+H]+.
The titled compound 617 (44.5 mg, 18.05%) as a dark grey solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 7.04 (s, 1H), 6.94 (d, J=8.4 Hz, 1H), 6.62 (d, J=8.4 Hz, 1H), 6.48 (d, J=2.8 Hz, 1H), 6.44-6.37 (m, 2H), 6.20-6.12 (m, 2H), 4.43 (s, 2H), 3.59 (d, J=10.8 Hz, 1H), 3.48-3.36 (m, 2H), 3.29 (d, J=10.8 Hz, 1H), 2.29-2.22 (m, 1H), 2.13-2.06 (m, 4H). Mass (m/z): 407.8 [M+H]+.
The titled compound 618 (3.6 mg, 1.6%) as a light brown solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 7.01 (s, 1H), 6.91 (d, J=8.4 Hz, 1H), 6.61 (d, J=8.4 Hz, 1H), 6.43 (d, J=2.4 Hz, 1H), 6.36 (dd, J=8.4, 2.4 Hz, 1H), 6.20-6.08 (m, 2H), 4.42 (s, 2H), 3.39 (dd, J=10.8, 5.2 Hz, 2H), 3.26 (s, 3H), 3.22 (dd, J=16.0, 8.8 Hz, 3H), 2.09 (s, 3H), 2.05 (dd, J=10.0, 5.2 Hz, 2H). Mass (m/z): 353.9 [M+H]+.
The titled compound 619 (5.1 mg, 3.08%) as a light brown solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 7.92 (s, 1H), 6.94 (dd, J=21.2, 9.2 Hz, 4H), 6.43-6.23 (m, 2H), 4.51 (s, 2H), 3.65 (d, J=12.4 Hz, 2H), 2.63 (dd, J=12.4, 10.4 Hz, 2H), 2.47-2.38 (m, 1H), 1.88 (d, J=12.4 Hz, 2H), 1.64-1.49 (m, 2H). Mass (m/z): 409.9 [M+H]+.
The titled compound 620 (79.2 mg, 28.7%) as a light purple solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 6.97 (d, J=8.0 Hz, 1H), 6.91 (s, 1H), 6.86 (d, J=8.0 Hz, 1H), 6.53 (s, 1H), 6.48 (s, 1H), 6.44 (d, J=8.4 Hz, 1H), 6.35 (d, J=8.0 Hz, 1H), 3.84 (s, 2H), 3.55-3.44 (m, 3H), 3.33 (s, 2H), 3.29 (s, 2H), 3.24 (s, 3H), 3.20 (s, 3H), 2.26 (s, 1H), 2.13 (s, 3H), 2.07 (s, 1H). Mass (m/z): 449 [M+H]+.
The titled compound 621 (4.6 mg, 5.8%) as a grey solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 7.06 (s, 1H), 6.94 (d, J=8.4 Hz, 1H), 6.64 (d, J=8.4 Hz, 1H), 6.39 (s, 1H), 6.32 (d, J=8.4 Hz, 1H), 6.25-6.11 (m, 2H), 5.27 (s, 1H), 4.43 (d, J=3.2 Hz, 2H), 4.18 (t, J=7.6 Hz, 2H), 3.81 (d, J=8.4 Hz, 2H), 2.09 (d, J=3.2 Hz, 3H). Mass (m/z): 394.3 [M+H]+.
The titled compound 622 (10.1 mg, 26.8%) as a pink solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H), 7.16 (s, 1H), 6.98 (d, J=8.4 Hz, 1H), 6.77 (d, J=8.4 Hz, 1H), 6.53 (s, 1H), 6.46 (d, J=8.8 Hz, 1H), 6.29 (d, J=8.8 Hz, 1H), 6.18 (s, 1H), 4.30 (d, J=7.2 Hz, 2H), 3.65 (t, J=13.6 Hz, 2H), 3.43 (d, J=7.6 Hz, 2H), 2.61-2.56 (m, 4H), 2.11 (s, 3H). Mass (m/z): 374.4 [M+H]+.
The titled compound 623 (4.8 mg, 16.1%) as a red solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 7.14 (s, 1H), 6.95 (d, J=9.6 Hz, 1H), 6.83-6.71 (m, 1H), 6.38 (s, 1H), 6.31 (d, J=7.2 Hz, 2H), 6.18 (s, 1H), 4.31 (q, J=5.2 Hz, 2H), 3.87 (dd, J=19.2, 3.2 Hz, 4H), 2.09 (d, J=3.2 Hz, 3H), 1.72-1.52 (m, 3H). Mass (m/z): 356.4 [M+H]+.
The titled compound 624 (18.8 mg, 15%) as a grey solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.75 (s, 1H), 7.58 (d, J=2.0 Hz, 1H), 7.44-7.34 (m, 2H), 7.03 (s, 1H), 7.02-6.94 (m, 2H), 6.88 (d, J=2.8 Hz, 1H), 6.81-6.74 (m, 1H), 3.70 (d, J=12.4 Hz, 2H), 2.71-2.60 (m, 2H), 2.48-2.43 (m, 1H), 2.17 (s, 3H), 1.93-1.84 (m, 2H), 1.64-1.49 (m, 2H). Mass (m/z): 375.5 [M+H]+.
The titled compound 625 (16.1 mg, 34%) as an off-white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J=7.6 Hz, 1H), 8.24 (s, 1H), 8.04 (s, 1H), 7.32-7.28 (m, 1H), 7.08 (d, J=8.8 Hz, 1H), 6.94 (dd, J=11.2, 2.8 Hz, 2H), 6.84 (dd, J=8.8, 2.8 Hz, 1H), 6.67-6.62 (m, 1H), 6.56 (dd, J=7.6, 2.4 Hz, 1H), 3.79 (d, J=12.4 Hz, 2H), 2.77-2.66 (m, 2H), 2.45-2.38 (m, 1H), 2.14 (s, 3H), 1.89 (d, J=12.4 Hz, 2H), 1.65-1.50 (m, 2H). Mass (m/z): 420.5 [M+H]+.
The titled compound 626 (10.5 mg, 28.1%) as a red solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 7.19 (s, 1H), 7.00 (d, J=8.4 Hz, 1H), 6.78 (d, J=8.4 Hz, 1H), 6.47 (d, J=2.8 Hz, 1H), 6.39 (dd, J=8.4, 2.8 Hz, 1H), 6.33 (dd, J=8.4, 2.8 Hz, 1H), 6.21 (d, J=2.4 Hz, 1H), 4.31 (t, J=6.0 Hz, 2H), 4.22 (t, J=12.4 Hz, 4H), 2.57 (t, J=6.0 Hz, 2H), 2.11 (s, 3H). Mass (m/z): 360.4 [M+H]+.
The titled compound 627 (8.1 mg, 32.3%) as a yellow solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 7.26 (s, 1H), 7.01 (d, J=8.4 Hz, 1H), 6.77 (d, J=8.4 Hz, 1H), 6.48 (d, J=2.8 Hz, 1H), 6.38 (ddd, J=18.0, 8.4, 2.8 Hz, 2H), 6.27 (d, J=2.4 Hz, 1H), 4.32-4.16 (m, 4H), 3.92 (t, J=10.8 Hz, 1H), 3.58 (dd, J=11.2, 6.4 Hz, 1H), 2.11 (s, 3H), 1.79 (s, 1H). Mass (m/z): 375.2 [M+H]+.
The titled compound 628 (22.3 mg, 34.4%) as a grey solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H), 7.13 (s, 1H), 6.95 (d, J=8.4 Hz, 1H), 6.76 (d, J=8.8 Hz, 1H), 6.53 (d, J=2.8 Hz, 1H), 6.45 (dd, J=8.8, 2.8 Hz, 1H), 6.28 (dd, J=8.8, 2.6 Hz, 1H), 6.16 (d, J=2.4 Hz, 1H), 4.31 (t, J=6.0 Hz, 2H), 3.50 (t, J=8.8 Hz, 1H), 3.41-3.34 (m, 2H), 3.31-3.23 (m, 2H), 2.56 (t, J=6.0 Hz, 2H), 2.31-2.21 (m, 1H), 2.10 (s, 3H), 2.09-2.02 (m, 1H). Mass (m/z): 406.2 [M+H]+.
The titled compound 629 (17 mg, 20.6%) as a grey solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 7.19 (s, 1H), 6.99 (d, J=8.8 Hz, 1H), 6.89 (d, J=2.8 Hz, 1H), 6.80 (dd, J=8.8, 3.6 Hz, 2H), 6.37 (dd, J=8.8, 2.4 Hz, 1H), 6.27 (d, J=2.4 Hz, 1H), 4.32 (t, J=6.0 Hz, 2H), 3.29-3.19 (m, 4H), 2.57 (t, J=6.0 Hz, 2H), 2.12 (s, 3H), 2.10-2.00 (m, 4H). Mass (m/z): 388.2 [M+H]+.
The titled compound 630 (10 mg, 21%) as an grey solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.92 (d, J=2.0 Hz, 1H), 8.32 (s, 1H), 8.03-7.83 (m, 1H), 7.66 (d, J=9.6 Hz, 1H), 7.60 (s, 1H), 7.48-7.27 (m, 2H), 7.02 (d, J=8.8 Hz, 1H), 6.98-6.87 (m, 1H), 6.81 (dd, J=8.8, 2.8 Hz, 1H), 3.74 (d, J=12.4 Hz, 2H), 2.71 (t, J=11.6 Hz, 2H), 2.46-2.37 (m, 1H), 2.17 (s, 3H), 1.89 (d, J=11.6 Hz, 2H), 1.67-1.48 (m, 2H). Mass (m/z): 420.5 [M+H]+.
The titled compound 631 (56 mg, 33%) as an off-white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.33 (s, 1H), 7.01-6.90 (m, 2H), 6.86 (d, J=2.8 Hz, 1H), 6.77 (dd, J=8.8, 2.8 Hz, 1H), 6.25 (dd, J=8.2, 2.3 Hz, 1H), 6.13 (d, J=2.4 Hz, 1H), 4.61 (s, 2H), 4.45 (s, 2H), 3.71 (d, J=12.0 Hz, 2H), 2.95 (s, 3H), 2.72-2.60 (m, 2H), 2.47-2.43 (m, 1H), 2.10 (s, 3H), 1.88 (d, J=12.0 Hz, 2H), 1.63-1.48 (m, 2H). Mass (m/z): 434.5 [M+H]+.
The titled compound 632 (1.6 mg, 0.64%) as a light brown solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 7.25 (s, 1H), 7.07 (s, 1H), 6.95 (d, J=8.4 Hz, 1H), 6.64 (d, J=8.4 Hz, 1H), 6.41 (d, J=2.4 Hz, 1H), 6.33 (dd, J=8.4, 2.4 Hz, 1H), 6.21 (dd, J=8.4, 2.4 Hz, 1H), 6.17 (d, J=2.0 Hz, 1H), 4.44 (s, 2H), 4.10 (d, J=8.8 Hz, 2H), 3.76 (d, J=8.8 Hz, 2H), 2.09 (s, 3H). Mass (m/z): 393.8 [M+H]+.
The titled compound 633 (4.0 mg, 1.82%) as a light brown solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 7.08 (s, 1H), 6.96 (d, J=8.4 Hz, 1H), 6.64 (d, J=8.4 Hz, 1H), 6.43 (d, J=2.4 Hz, 1H), 6.36 (dd, J=8.4, 2.4 Hz, 1H), 6.24-6.16 (m, 2H), 4.44 (s, 2H), 4.05-3.98 (m, 4H), 3.47 (s, 3H), 2.10 (s, 3H). Mass (m/z): 407.8 [M+H]+.
The titled compound 634 (15.4 mg, 10.8%) as a grey solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 6.92 (s, 1H), 6.81 (d, J=8.4 Hz, 1H), 6.65-6.59 (m, 2H), 6.55 (dd, J=8.4, 2.8 Hz, 1H), 6.20 (dd, J=8.4, 2.4 Hz, 1H), 6.15 (d, J=2.4 Hz, 1H), 4.66 (s, 1H), 4.43 (s, 2H), 2.04 (s, 3H), 1.26 (s, 9H). Mass (m/z): 326.2 [M+H]+.
The titled compound 635 (20.4 mg, 15.6%) as a grey solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 6.90 (s, 1H), 6.82 (d, J=8.4 Hz, 1H), 6.61 (d, J=8.4 Hz, 1H), 6.44 (d, J=2.4 Hz, 1H), 6.37 (dd, J=8.4, 2.8 Hz, 1H), 6.20-6.04 (m, 2H), 5.24 (s, 1H), 4.42 (s, 2H), 3.00 (q, J=7.2 Hz, 2H), 2.03 (s, 3H), 1.15 (t, J=7.2 Hz, 3H). Mass (m/z): 298.2 [M+H]+.
The titled compound 636 (16.3 mg, 15.1%) as a grey solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 7.12 (s, 1H), 7.00 (d, J=8.8 Hz, 1H), 6.70-6.61 (m, 2H), 6.56-6.50 (m, 1H), 6.27-6.17 (m, 2H), 4.44 (s, 2H), 4.03-3.88 (m, 4H), 2.12 (s, 3H). Mass (m/z): 396.2 [M+H]+.
The titled compound 637 (78.8 mg, 50.0%) as a grey solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.43 (d, J=8.8 Hz, 1H), 7.18 (s, 1H), 7.04 (d, J=8.8 Hz, 1H), 6.86 (d, J=2.8 Hz, 1H), 6.79-6.75 (m, 1H), 6.72-6.68 (m, 1H), 6.36-6.31 (m, 1H), 3.99 (s, 3H), 3.74-3.64 (m, 2H), 3.55-3.50 (m, 2H), 2.27-2.19 (m, 2H), 2.15 (s, 3H), 1.15 (d, J=6.4 Hz, 6H). Mass (m/z): 351.1 [M+H]+.
The titled compound 638 (78.5 mg, 49.8%) as a grey solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.74 (s, 1H), 7.53-7.37 (m, 2H), 7.10 (d, J=8.8 Hz, 1H), 6.88 (d, J=2.8 Hz, 1H), 6.83-6.76 (m, 1H), 6.71-6.64 (m, 1H), 6.37 (s, 1H), 3.77 (s, 3H), 3.73-3.63 (m, 2H), 3.60-3.50 (m, 2H), 2.28-2.20 (m, 2H), 2.16 (s, 3H), 1.16 (d, J=6.4 Hz, 6H). Mass (m/z): 351.2 [M+H]+.
The titled compound 639 (10.2 mg, 5.65%) as a purple solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 7.03 (s, 1H), 6.93 (s, 1H), 6.64 (s, 1H), 6.26-6.28 (s, 1H), 6.19-6.20 (s, 1H), 6.17-6.18 (s, 1H), 6.14-6.15 (s, 1H), 4.43 (m, 2H), 3.62-3.65 (m, 4H), 3.18 (m, 3H), 2.07 (m, 3H), 1.47 (m, 3H). Mass (m/z): 354.2 [M+H]+.
The titled compound 640 (7.1 mg, 2.88%) as a yellow solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 7.02 (s, 1H), 6.91 (d, J=8.4 Hz, 1H), 6.63 (d, J=8.4 Hz, 1H), 6.33-6.32 (m, 1H), 6.27-6.24 (m, 1H), 6.20-6.17 (m, 1H), 6.15-6.14 (m, 1H), 4.52-4.37 (m, 3H), 4.06 (t, J=7.2 Hz, 2H), 3.66-3.60 (m, 1H), 3.48-3.45 (m, 2H), 2.07 (s, 3H), 1.10 (d, J=6.0 Hz, 6H). Mass (m/z): 368.2 [M+H]+.
The titled compound 641 (5 mg, 2%) as a white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 7.01 (s, 1H), 6.89 (d, J=8.4 Hz, 1H), 6.63 (d, J=8.4 Hz, 1H), 6.38 (s, 2H), 6.18-6.11 (m, 2H), 4.42 (s, 2H), 3.46 (d, J=9.2 Hz, 2H), 3.11 (d, J=8.4 Hz, 2H), 2.07 (s, 3H), 1.68-1.63 (m, 2H), 0.68 (td, J=7.6, 4.0 Hz, 1H), 0.27 (d, J=4.0 Hz, 1H). Mass (m/z): 336.2 [M+H]+.
The titled compound 642 (6.5 mg, 8.3%) as a purple solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 7.93 (s, 1H), 7.06-6.87 (m, 4H), 6.76 (d, J=8.4 Hz, 1H), 6.69-6.52 (m, 2H), 4.50 (s, 2H), 3.02 (d, J=11.6 Hz, 1H), 2.84 (t, J=7.6 Hz, 1H), 2.78-2.68 (m, 1H), 1.96-1.76 (m, 2H), 1.56 (tt, J=12.6, 6.4 Hz, 1H), 1.35-1.12 (m, 2H), 0.84 (d, J=6.0 Hz, 3H). Mass (m/z): 406.2 [M+H]+.
The titled compound 643 (2.5 mg, 12.3%) as a blue solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 6.90-6.77 (m, 2H), 6.67 (dd, J=8.8, 3.2 Hz, 1H), 6.61 (d, J=8.0 Hz, 2H), 6.56-6.44 (m, 2H), 4.87 (s, 2H), 3.65-3.53 (m, 3H), 2.97 (t, J=4.4 Hz, 2H), 2.61-2.59 (m, 2H), 2.12 (s, 3H), 1.87 (d, J=12.4 Hz, 2H), 1.61-1.51 (m, 2H). Mass (m/z): 419.2 [M+H]+.
The titled compound 644 (12.3 mg, 14.7%) as a yellow solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.48 (t, J=5.6 Hz, 1H), 7.40 (s, 2H), 7.27 (s, 2H), 7.15 (s, 2H), 6.97 (d, J=8.4 Hz, 1H), 3.65 (s, 2H), 3.56 (d, J=5.6 Hz, 4H), 2.21 (s, 3H), 2.00 (d, J=11.2 Hz, 2H). Mass (m/z): 433.2 [M+H]+.
The titled compound 645 (52 mg, 82%) as a light brown solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 7.17 (s, 1H), 6.98 (d, J=8.4 Hz, 1H), 6.78 (d, J=8.4 Hz, 1H), 6.44 (d, J=2.8 Hz, 1H), 6.37 (dd, J=8.4, 2.8 Hz, 1H), 6.31 (dd, J=8.8, 2.8 Hz, 1H), 6.20 (d, J=2.4 Hz, 1H), 4.31 (t, J=6.0 Hz, 2H), 4.07-3.97 (m, 4H), 3.48 (s, 3H), 2.60-2.53 (m, 2H), 2.10 (s, 3H). Mass (m/z): 422.4 [M+H]+.
The titled compound 646 (5.6 mg, 13.12%) as a grey solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 7.05 (s, 1H), 6.97 (d, J=8.8 Hz, 1H), 6.84 (d, J=2.8 Hz, 1H), 6.78-6.72 (m, 1H), 6.61 (d, J=8.4 Hz, 1H), 6.29-6.20 (m, 2H), 5.00 (t, J=5.6 Hz, 1H), 4.51-4.47 (m, 1H), 3.81-3.64 (m, 4H), 2.70-2.60 (m, 2H), 2.47-2.38 (m, 1H), 2.11 (s, 3H), 1.92-1.83 (m, 2H), 1.64-1.48 (m, 2H). Mass (m/z): 436.2 [M+H]+.
The titled compound 647 (20 mg, 35.52%) as a grey solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H), 7.14 (s, 1H), 6.96 (d, J=8.4 Hz, 1H), 6.76 (d, J=8.4 Hz, 1H), 6.55 (d, J=2.8 Hz, 1H), 6.50-6.44 (m, 1H), 6.31-6.26 (m, 1H), 6.17 (d, J=2.4 Hz, 1H), 4.31 (t, J=6.0 Hz, 2H), 3.58 (d, J=11.6 Hz, 1H), 3.50 (d, J=11.6 Hz, 1H), 3.46-3.38 (m, 3H), 3.33 (s, 3H), 2.56 (t, J=6.0 Hz, 2H), 2.46-2.36 (m, 1H), 2.35-2.24 (m, 1H), 2.11 (s, 3H). Mass (m/z): 436.1 [M+H]+.
The titled compound 648 (48.5 mg, 60.42%) as a grey solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H), 7.76 (s, 1H), 7.45 (d, J=8.8 Hz, 1H), 7.39 (s, 1H), 7.06 (d, J=8.8 Hz, 1H), 6.88 (d, J=2.8 Hz, 1H), 6.81-6.75 (m, 1H), 6.70-6.63 (m, 1H), 6.36-6.31 (m, 1H), 3.76-3.63 (m, 2H), 3.57-3.49 (m, 2H), 2.28-2.20 (m, 2H), 2.14 (s, 3H), 1.16 (d, J=6.4 Hz, 6H). Mass (m/z): 337.1 [M+H]+.
The titled compound 649 (3.9 mg, 9.80%) as a pink solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 7.23 (s, 1H), 7.15 (s, 1H), 6.97 (d, J=8.4 Hz, 1H), 6.77 (d, J=8.4 Hz, 1H), 6.41 (d, J=2.8 Hz, 1H), 6.38-6.26 (m, 2H), 6.18 (d, J=2.4 Hz, 1H), 4.35-4.27 (m, 2H), 4.10 (d, J=8.8 Hz, 2H), 3.77 (d, J=8.8 Hz, 2H), 2.60-2.52 (m, 2H), 2.09 (s, 3H). Mass (m/z): 408.4 [M+H]+.
The titled compound 650 (7.2 mg, 39%) as a brown solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 7.11 (s, 1H), 6.93 (dd, J=24.8, 8.4 Hz, 2H), 6.84 (d, J=2.8 Hz, 1H), 6.74 (dd, J=8.8, 2.8 Hz, 1H), 6.57 (dd, J=8.8, 2.8 Hz, 1H), 6.47 (d, J=2.8 Hz, 1H), 4.54 (s, 2H), 4.31 (s, 2H), 3.68 (d, J=12.0 Hz, 2H), 2.71-2.63 (m, 2H), 2.43-2.41 (m, 1H), 2.11 (s, 3H), 1.88 (d, J=12.0 Hz, 2H), 1.57 (tt, J=12.8, 6.4 Hz, 2H). Mass (m/z): 420.2 [M+H]+.
The titled compound 651 (51 mg, 32%) as a yellow solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.30 (d, J=8.8 Hz, 1H), 7.22 (s, 1H), 6.98 (d, J=8.4 Hz, 1H), 6.91 (s, 1H), 6.76 (dd, J=8.8, 2.0 Hz, 1H), 6.72 (d, J=2.0 Hz, 1H), 6.42 (d, J=2.8 Hz, 1H), 6.34 (dd, J=8.4, 2.8 Hz, 1H), 4.10 (d, J=8.8 Hz, 2H), 3.77 (d, J=8.8 Hz, 2H), 3.74 (s, 3H), 2.12 (s, 3H). Mass (m/z): 377.5 [M+H]+.
The titled compound 652 (23 mg, 14%) as a purple solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 7.04 (s, 1H), 6.93 (d, J=8.4 Hz, 1H), 6.77 (t, J=75.2 Hz, 1H), 6.63 (d, J=8.4 Hz, 1H), 6.37 (d, J=2.8 Hz, 1H), 6.29 (dd, J=8.4, 2.8 Hz, 1H), 6.20 (dd, J=8.4, 2.4 Hz, 1H), 6.16 (d, J=2.4 Hz, 1H), 5.09-4.99 (m, 1H), 4.43 (s, 2H), 4.17-4.09 (m, 2H), 3.74-3.66 (m, 2H), 2.08 (s, 3H). Mass (m/z): 376.4 [M+H]+.
The titled compound 653 (9.0 mg, 9%) as an off-white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 7.27 (s, 1H), 7.09 (d, J=2.0 Hz, 1H), 7.07 (t, J=76 Hz, 1H), 7.02 (d, J=2.8 Hz, 1H), 6.95-6.88 (m, 1H), 6.73 (d, J=8.4 Hz, 1H), 6.51-6.42 (m, 2H), 4.49 (s, 2H), 2.18 (s, 3H). Mass (m/z): 321.4 [M+H]+.
The titled compound 654 (25 mg, 18%) as a brown solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 7.05 (s, 1H), 6.95 (d, J=8.8 Hz, 1H), 6.82 (d, J=2.8 Hz, 1H), 6.74 (dd, J=8.8, 2.8 Hz, 1H), 6.65 (d, J=8.4 Hz, 1H), 6.27 (dd, J=8.4, 2.4 Hz, 1H), 6.23 (d, J=2.4 Hz, 1H), 5.95 (td, J=56.8, 4.4 Hz, 1H), 4.44 (s, 2H), 3.65 (d, J=12.0 Hz, 2H), 2.66-2.56 (m, 2H), 2.10 (s, 3H), 2.02-1.85 (m, 1H), 1.79-1.71 (m, 2H), 1.54-1.39 (m, 2H). Mass (m/z): 388.5 [M+H]+.
The titled compound 655 (21 mg, 14%) as an off-white solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 7.03 (s, 1H), 6.93 (d, J=8.4 Hz, 1H), 6.63 (d, J=8.4 Hz, 1H), 6.51-6.20 (m, 3H), 6.19 (dd, J=8.4, 2.4 Hz, 1H), 6.15 (d, J=2.4 Hz, 1H), 4.43 (s, 2H), 3.88 (t, J=8.0 Hz, 2H), 3.71 (dd, J=7.6, 5.6 Hz, 2H), 3.24-3.11 (m, 1H), 2.08 (s, 3H). Mass (m/z): 360.5 [M+H]+.
The titled compound 656 (15 mg, 9%) as a light yellow solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 7.34 (s, 1H), 7.02 (d, J=8.8 Hz, 1H), 6.91 (d, J=8.8 Hz, 1H), 6.88-6.84 (m, 2H), 6.81 (dd, J=8.8, 2.8 Hz, 1H), 6.77 (dd, J=8.8, 2.8 Hz, 1H), 3.83 (s, 2H), 3.70 (d, J=12.4 Hz, 2H), 2.71-2.60 (m, 2H), 2.47-2.40 (m, 1H), 2.27 (s, 3H), 2.14 (s, 3H), 1.93-1.84 (m, 2H), 1.64-1.49 (m, 2H). Mass (m/z): 431.5 [M+H]+.
The titled compound 657 (2.3 mg, 5%) as a light yellow solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 7.02 (s, 1H), 6.95 (d, J=8.4 Hz, 1H), 6.59 (d, J=8.4 Hz, 1H), 6.39 (d, J=2.8 Hz, 1H), 6.32 (dd, J=8.4, 2.8 Hz, 1H), 6.22-6.13 (m, 2H), 5.30-5.23 (m, 1H), 4.98 (t, J=5.6 Hz, 1H), 4.48 (dd, J=5.2, 3.2 Hz, 1H), 4.19 (dd, J=8.8, 6.4 Hz, 2H), 3.82 (dd, J=8.8, 4.0 Hz, 2H), 3.79-3.65 (m, 2H), 2.09 (s, 3H). Mass (m/z): 424.5 [M+H]+.
The titled compound 658 (6.8 mg, 10%) as a pink solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 7.01 (s, 1H), 6.94 (d, J=8.4 Hz, 1H), 6.78 (t, J=74.8 Hz, 1H), 6.61-6.57 (m, 1H), 6.37 (d, J=2.8 Hz, 1H), 6.30 (dd, J=8.4, 2.8 Hz, 1H), 6.18 (dd, J=8.4, 2.4 Hz, 1H), 6.15 (d, J=2.4 Hz, 1H), 5.09-4.95 (m, 2H), 4.51-4.44 (m, 1H), 4.17-4.09 (m, 2H), 3.80-3.65 (m, 4H), 2.09 (s, 3H). Mass (m/z): 406.5 [M+H]+.
The titled compound 659 (14 mg, 7%) as a light brown solid was prepared according to the procedure outlined for compound 1. 1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 6.93 (s, 1H), 6.80 (d, J=8.4 Hz, 1H), 6.66-6.57 (m, 2H), 6.53 (dd, J=8.4, 2.8 Hz, 1H), 6.19 (dd, J=8.4, 2.4 Hz, 1H), 6.14 (d, J=2.4 Hz, 1H), 4.66 (s, 1H), 4.43 (s, 2H), 2.03 (s, 3H), 1.60 (q, J=7.2 Hz, 2H), 1.20 (s, 6H), 0.82 (t, J=7.4 Hz, 3H). Mass (m/z): 340.5 [M+H]+.
HT-1080 (ATCC, CCL-121) cells (6000 in 100 μl) were seeded in 96-well plates (Corning) and cultured in a 37° C. incubator with a humidified atmosphere of 5% CO2 for overnight. Cells were then treated with ferroptosis inducer RSL3 (TargetMol) and a 3-fold, 10-point serial dilution series of compounds with 1.1 μM as the highest concentration, for hours. Cell viability was assessed using the Cell Titer-Glo Kit (Promega). The luminescence intensity was measured with a microplate reader (Envision, PerkinElmer), and cell viability was calculated by normalizing the data to untreated controls. The EC50 values of the compounds (e.g., Compounds 1-659) were calculated in GraphPad Prism (GraphPad Software, Inc., San Diego, CA, USA). The curves were fitted using a non-linear regression model with a sigmoidal dose response.
Ferroptosis inhibitory activity of compounds 1-447 is summarized in Table 2. In Table 2, activity is provided as follows: +++=0.1 nM≤EC50<100 nM; ++=100 nM≤EC50<1000 nM; +=1000 nM≤EC50<10000 nM.
Ferroptosis inhibitory activity of compounds 448-659 is summarized in Table 3. In Table 3, activity is provided as follows: +++=0.1 nM≤EC50<100 nM; ++=100 nM≤EC50<1000 nM; +=1000 nM≤EC50<10000 nM.
All publications, including but not limited to disclosures and disclosure applications, cited in this specification are herein incorporated by reference as though fully set forth. If certain content of a publication cited herein contradicts or is inconsistent with the present disclosure, the present disclosure controls.
One skilled in the art will readily recognize from the disclosure and claims that various changes, modifications, and variations can be made therein without departing from the spirit and scope of the disclosure as defined in the following claims.
| Number | Date | Country | Kind |
|---|---|---|---|
| PCT/CN2021/105449 | Jul 2021 | WO | international |
This application claims priority to International Application No. PCT/CN2021/105449, filed on Jul. 9, 2021, the content of which is incorporated by reference in its entirety.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/CN2022/104559 | 7/8/2022 | WO |
