QUINOLINE AND QUINOXALINE DERIVATIVES AS KINASE INHIBITORS

专利摘要:
quinoline and quinoxaline derivatives as kinase inhibitors. a series of quinoline and quinoxaline derivatives comprising a fluorinated ethyl side chain, which are selective inhibitors of p13 kinase enzymes, therefore not of benefit in medicine, for example in the treatment of inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic conditions, oncological, nociceptive or ophthalmic.
公开号:BR112013004750B1
申请号:R112013004750-0
申请日:2011-09-02
公开日:2021-06-15
发明作者:Andrew Harry Parton；Mezher Hussein Ali；Daniel Christopher Brookings；Julien Alistair Brown；Daniel James Ford；Richard Jeremy Franklin；Barry John Langham；Judi Charlotte Neuss；Joanna Rachel Quincey
申请人:Ucb Biopharma Sprl；
IPC主号:

专利说明:

[0001] The present invention concerns a class of quinoline and quinoxaline derivatives, and their use in therapy. More particularly, the present invention provides quinoline and quinoxaline derivatives which comprise a fluorinated ethyl side chain. These compounds are selective inhibitors of the phosphoinositide 3-kinase (PI3K) enzymes, and are therefore of benefit as pharmaceutical agents, especially in the treatment of inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive, and ophthalmic adverse conditions.
[0002] The PI3K pathway is implicated in a variety of physiological and pathological functions that are believed to be operative in a range of human diseases. Thus, PI3Ks provide a critical signal for cell proliferation, cell survival, membrane trafficking, glucose transport, neurite outgrowth, membrane undulation, superoxide production, actin reorganization, and chemotaxis (as per S. Ward et al., Chemistry & Biology, 2003, 10, 207213; and SG Ward & P. Finan, Current Opinion in Pharmacology, 2003, 3, 426-434); and are known to be involved in cancer pathology, and metabolic, inflammatory, and cardiovascular diseases (cf. M.P. Wymann et al., Trends in Pharmacol. Sci., 2003, 24, 366-376). Aberrant upregulation of the PI3K pathway is implicated in a wide variety of human cancers (cf. S. Brader & S. A. Eccles, Tumori, 2004, 90, 2-8).
[0003] The compounds according to the present invention, which are potent and selective inhibitors of PI3K, are therefore beneficial in the treatment and/or prevention of various human diseases. These include autoimmune and inflammatory disorders such as rheumatoid arthritis, multiple sclerosis, asthma, inflammatory bowel disease, psoriasis and transplant rejection; cardiovascular disorders including thrombosis, cardiac hypertrophy, hypertension, and irregular contractility of the heart (eg during heart failure); neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke, amyotrophic lateral sclerosis, spinal cord injury, head trauma and seizures; metabolic disorders such as obesity and type 2 diabetes; oncologic conditions including leukemia, glioblastoma, lymphoma, melanoma, and human cancers of the liver, bone, skin, brain, pancreas, lung, breast, stomach, colon, rectum, prostate, ovary, and cervix; pain and nociceptive disorders; and ophthalmic disorders including age-related macular degeneration (ARMD).
[0004] In addition, the compounds according to the present invention may be beneficial as pharmacological standards for use in the development of new biological tests and in research for new pharmacological agents. Thus, the compounds of this invention may be useful as radioligands in assays to detect compounds capable of binding to human PI3K enzymes.
[0005] WO 2008/118454, WO 2008/118455 and WO 2008/118468 describe several series of quinoline and quinoxaline derivatives which are structurally related to each other and are stated to be useful for inhibiting the biological activity of human PI3K6 and to be of use in the treatment of PI3K-mediated conditions or disorders.
WO 2009/081105, WO 2010/046639 and WO 2011/058108 co-pending (priority claim of UK patent applications 0919829.2 and 1012102.8), published May 19, 2011, describe separate classes of heteroaryl derivatives fused bicyclics as selective inhibitors of PI3K enzymes that are of benefit in the treatment of adverse inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, ontological, nociceptive, and ophthalmic conditions.
[0007] Nothing in the prior art available so far, however, discloses or suggests the precise structural class of quinoline and quinoxaline derivatives that comprise a fluorinated ethyl side chain as provided by the present invention.
[0008] The compounds of the present invention are potent and selective PI3K inhibitors having a binding affinity (IC50) for PI3Ka and/or PI3KI3 and/or human PI3Ky and/or PI3K6 isoforms of 50 µM or less, in general 20 µM or less, usually 5 µM or less, typically 1 µM or less, suitably 500 nM or less, ideally 100 nM or less, and preferably 20 nM or less (the skilled person will assess that an IC50 figure plus low indicates a more active compound). Compounds of the invention may possess at least a 10-fold selective activity, typically at least a 20-fold selective activity, suitably at least a 50-fold selective activity, and ideally at least a 100-fold selective activity, for PI3K isoforms and/or human PI3K and/or PI3K and/or PI3K relative to other human kinases.
[0009] The compounds of the invention possess notable advantages in terms of their high potency and selectivity, demonstrable efficacy, and valuable pharmacokinetic properties (which include clearance and bioavailability).
[0010] The present invention provides a compound of formula (I) or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof:
wherein U represents -CF3, -CHF2 or -CH2F; Q represents oxygen, sulfur, N-R4 or a covalent bond; Z represents an optionally substituted bicyclic heteroaryl moiety consisting of two fused six-membered aromatic rings, the heteroaryl moiety Z containing at least one nitrogen atom and being linked to the rest of the molecule through a carbon atom; M represents aryl or heteroaryl, each of the groups may optionally be substituted by one or more substituents; W represents C-R5 or N;R1 , R2 and R3 independently represent hydrogen, halogen, cyano, nitro, C1-6 alkyl, trifluoromethyl, C3-7 cycloalkyl (C1-6) alkyl, heterocycloalkyl C3-7 alkyl (C1-6), arylalkyl (C1-6), heteroaryl(1-6C)alkyl, hydroxy, C1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C1-6 alkylthio, C1-6 alkyl sulfinyl, C1-6 alkyl sulfonyl, amino, C1-6 alkyl amino, di(1-6C)alkyl amino, C 2-6 alkyl carbonylamino, C 2-6 alkoxy carbonylamino, C 1-6 alkyl sulfonylamino, fo rmyl, C2-6 alkyl carbonyl, carboxy, C2-6 alkoxy carbonyl, amino carbonyl, C1-6 alkyl aminocarbonyl, di(1-6C)alkyl aminocarbonyl, aminosulfonyl, C1-6 alkyl aminosulfonyl or di(1-6C alkyl)aminosulfonyl; represents hydrogen or C1-6 alkyl; and R5 represents hydrogen, halogen, C1-6 alkyla or C1-6 alkoxy.
[0011] Where any of the groups in the compounds of formula (I) above is set forth to be optionally substituted, this group may be unsubstituted, or substituted by one or more substituents. Typically, such groups will be unsubstituted, or substituted by one or two substituents.
[0012] For use in medicine, the salts of the compounds of formula (I) will be pharmaceutically acceptable salts. Other salts, however, may be useful in preparing the compounds of the invention or their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which, for example, can be formed by mixing a solution of the compound of the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, methanesulfonic acid , fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid or phosphoric acid. Furthermore, where the compounds of the invention bear an acidic moiety, for example carboxy, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, for example sodium or potassium salts; alkaline earth metal salts, for example calcium or magnesium salts; and salts formed with suitable organic ligands, for example quaternary ammonium salts.
[0013] The present invention includes within its scope solvates of the compounds of formula (I) above. Such solvates can be formed with common organic solvents, for example hydrocarbon solvents such as benzene or toluene; chlorinated solvents such as chloroform or dichloromethane; alcoholic solvents such as methanol, ethanol or isopropanol; etheric solvents such as diethyl ether or tetrahydrofuran; or ester solvents such as ethyl acetate. Alternatively, solvates of the compounds of formula (I) can be formed with water, in which case they will be hydrated.
Suitable alkyl groups which may be present in the compounds of the invention include straight and branched chain C 1-6 alkyl groups, for example C 1-4 alkyl groups. Typical examples include methyl and ethyl groups, and straight or branched chain propyl, butyl and pentyl groups. Particular alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2,2-dimethylpropyl and 3-methylbutyl. Derived expressions such as "C1-6 alkoxy", "C1-6 alkylthio", "C1-6 alkyl sulfonyl" and "C1-6 alkylamino" are to be interpreted accordingly.
The specific C3-7 cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
Suitable aryl groups include phenyl and naphthyl, preferably phenyl.
Suitable aryl(1-6C)alkyl groups include benzyl, phenylethyl, phenylpropyl and naphthylmethyl.
Suitable heterocycloalkyl groups, which may comprise benzo-fused analogues thereof, include azetidinyl, tetrahydrofuranoyl, dihydrobenzofuranyl, pyrrolidinyl, indolinyl, thiazolidinyl, imidazolidinyl, tetrahydropyranyl, chromanyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, 1, 2,3,4-tetrahydroisoquinolinyl, piperazinyl, 1,2,3,4-tetrahydroquinoxalinyl, homopiperazinyl, morpholinyl, benzoxazinyl and thiomorpholinyl.
Suitable heteroaryl groups include furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, dibenzothienyl, pyrrolyl, indolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolyl, pyrazolo[1] groups ,5-c]pyridinyl, pyrazolo[3,4-d]pyrimidinyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, imidazo[1,2-c]pyridinyl, imidazo[4,5 - b]pyridinyl, purinyl, imidazo[1,2-c]pyrimidinyl, imidazo-[1,2-c]pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl, benzotriazolyl, tetrazolyl, pyridinyl, quinolinyl, isoquinolinyl, naphthyridinyl, pyridazinyl, cinolinyl, phthalazinyl, pyrimidinyl, quinazolinyl, pyrazinyl, quinoxalinyl, pteridinyl, triazinyl and cromenyl.
The term "halogen" as used herein is intended to include atoms of fluorine, chlorine, bromine and iodine, typically fluorine, chlorine or bromine.
[0021] Where the compounds of formula (I) have one or more asymmetric centers, they consequently can exist as enantiomers. Where the compounds of the invention possess two or more asymmetric centers, they may additionally exist as diastereomers. The invention is to be understood to extend to all such enantiomers and diastereomers, and to mixtures thereof in any proportion, which include racemates. Formula (I) and formulas depicted below are intended to represent all individual stereoisomers and all possible mixtures thereof, unless otherwise stated or shown. Furthermore, the compounds of formula (I) can exist as tautomers, for example keto (CH2C=O)enol tautomers (CH=CHOH) or amide (NHC=O)hydroxyimine (N=COH) tautomers. Formula (I) and the formulas depicted below are intended to represent all individual tautomers and all possible mixtures thereof, unless otherwise stated or shown.
[0022] Advantageously, the absolute stereochemical configuration of the compounds of formula (I) above will be as represented in formula (I-1):
wherein U, Q, Z, M, W, R1, R2 and R3 are as defined above.
[0023] In a selected embodiment, where U represents -CF3, particular compounds of formula (I) as defined above include those wherein the carbon atom to which the -QZ and -CF3 moieties are directly attached is in the configuration (R).
[0024] It should be understood that each individual atom present in formula (I), or in the formulas depicted below, may in fact be present in the form of any of its naturally occurring isotopes, with the isotope(s) more abundant being preferred. Thus, by way of example, each individual hydrogen atom present in formula (I), or in the formulas shown below, may be present as a 1H, 2H (deuterium) or 3H (tritium) atom, preferably 1H. Similarly, by way of example, each individual carbon atom present in formula (I), or in the formulas shown below, may be present as a 12C, 13C or 14C, preferably 12C, atom.
[0025] In a particular embodiment, U represents -CF3. In another embodiment, U represents -CHF2. In another embodiment, U represents -CH2F.
[0026] In one embodiment, W represents C-R5. In another embodiment, W represents N.
[0027] Specific subclasses of compounds according to the present invention are represented by the compounds of formula (IA) and (IB), especially (IA):
wherein U, Q, Z, M, R1, R2, R3 and R5 are as defined above.
[0028] Advantageously, the absolute stereochemical configuration of the compounds of formula (IA) above will be as represented in formula (IA-1):
wherein U, Q, Z, M, R', R2, R3 and R5 are as defined above.
[0029] Advantageously, the absolute stereochemical configuration of the compounds of formula (IB) above will be as represented in formula (IB-1):
wherein U, Q, Z, M, R', R2 and R3 are as defined above.
[0030] In a selected embodiment, where U represents -CF3, particular compounds of formula (IA) and (IB) as defined above include those in which the carbon atom to which the -QZ and -CF3 moieties are directly connected is in the (R) configuration.
[0031] In one aspect of the invention, Q represents oxygen, sulfur or N-R4.
[0032] Suitable values of Q include oxygen and N-R4.
[0033] In one embodiment, Q represents oxygen. In another embodiment, Q represents sulfur. In a particular embodiment, Q represents N-R4. In another embodiment, Q represents a covalent bond.
[0034] In general, the bicyclic portion of heteroaryl Z contains one, two, three or four nitrogen atoms and none of the other heteroatoms. Typically, Z contains two, three or four nitrogen atoms. Suitably, Z contains two or three nitrogen atoms.
[0035] In one embodiment, Z contains a nitrogen atom. In another embodiment, Z contains two nitrogen atoms. In a particular embodiment, Z contains three nitrogen atoms. In another embodiment, Z contains four nitrogen atoms.
Typical values for the heteroaryl Z portion include quinolinyl, isoquinolinyl, cinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, pyridopyrimidinyl and pteridinyl, any such groups may optionally be substituted by one or more substituents.
[0037] In one embodiment, Z represents optionally substituted pyrido-pyrimidinyl. In one aspect of this embodiment, Z represents optionally substituted pyridopyrimidin-4-yl. In another aspect of this embodiment, Z represents optionally substituted pyrido[3,2-d]pyrimidinyl. In a more precise aspect of this embodiment, Z represents optionally substituted pyrido[3,2-c]pyrimidin-4-yl.
[0038] In a particular embodiment, the heteroaryl Z portion is unsubstituted. In another embodiment, Z is replaced by one or more substituents. In a subset of this embodiment, Z is monosubstituted. In another subset of this embodiment, Z is disubstituted.
Typical examples of optional substituents on the heteroaryl portion Z include one or more substituents independently selected from halogen, cyano, nitro, C1-6 alkyl, trifluoromethyl, hydroxy, oxo, C1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C1 alkyl -6 thio, C1-6 alkyl sulfinyl, C1-6 alkyl sulfonyl, amino, C1-6 alkyl amino, di(C1-6) alkylamino, arylamino, C1-6 alkoxy aryl(C1-6)alkylamino, C2-6 alkyl carbonylamino, C1-6 alkyl sulfonylamino, formyl, C2-6 alkyl carbonyl, C3-6 cycloalkylcarbonyl, C3-6 heterocycloalkylcarbonyl, carboxy, C2-6 alkoxy carbonyl, aminocarbonyl, C1-6 alkyl aminocarbonyl, di(1-6C)alkyl aminocarbonyl, aminosulfonyl, C1-6 alkyl aminosulfonyl and di(1-6C)alkyl aminosulfonyl. Additional examples include C2-6 alkoxy carbonylamino and (C1-6) alkyl (C3-6) heterocycloalkyl carbonyl.
Typical examples of specific substituents on Z include fluorine, chlorine, bromine, cyano, nitro, methyl, isopropyl, trifluoromethyl, hydroxy, oxo, methoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfinyl, methylsulfonyl, amino, methylamino, tert- butylamino, dimethylamino, phenylamino, methoxybenzylamino, acetylamino, methoxycarbonylamino, methylsulfonylamino, formyl, acetyl, cyclopropylcarbonyl, azetidinylcarbonyl, N-methylazetidinylcarbonyl, pyrrolidinylcarbonyl, N-methyl-pyrrolidinylcarbonyl, piperidinylcarbonyl, N-methylpiperidinylcarbonylcarbonyl, N-methylpiperidinylcarbonylcarbonyl, N-methylpiperidinylcarbonyl carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl and dimethylaminosulfonyl.
[0041] A specific value of Z is pyrido[3,2-d]pyrimidin-4-yl.
Suitably, the M portion represents a monocyclic aryl or heteroaryl group, each such group may optionally be substituted by one or more substituents.
[0043] In a particular embodiment, the aryl or heteroaryl M portion is unsubstituted. In another embodiment, M is replaced by one or more substituents. In a subset of this embodiment, M is monosubstituted. In another subset of this embodiment, M is disubstituted. In another subset of this embodiment, M is trisubstituted.
Typical values for the M portion include phenyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazinyl, and any trizolyl one of such groups may optionally be substituted by one or more substituents.
Selected values of M include phenyl, pyridinyl and pyrazinyl, any of such groups may optionally be substituted by one or more substituents.
Typical examples of optional substituents on the M portion of aryl or heteroaryl include one or more substituents independently selected from halogen, cyano, nitro, C1-6 alkyl, trifluoromethyl, hydroxy, C1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C1 alkyl -6 thio, C1-6 alkyl sulfinyl, C1-6 alkyl sulfonyl, amino, C1-6 alkyl amino, di(C1-6) alkylamino, C2-6 alkyl carbonylamino, C1-6 alkyl sulfonylamino, formyl, C2-6 alkyl carbonyl, carboxy, C2-6 alkoxy carbonyl, aminocarbonyl, C1-6 alkyl aminocarbonyl, di(1-6C)alkyl aminocarbonyl, aminosulfonyl, C1-6 alkyl aminosulfonyl, di(1-6C)alkyl aminosulfonyl, C3-7a cycloalkyl, C3- 6 heterocycloalkyl, monocyclic aryl and monocyclic heteroaryl. Additional examples include C2-6 alkoxy carbonylamino and (C1-6 alkyl) heterocycloalkyl (C3-6).
Selected examples of optional substituents on M include one or more substituents independently selected from halogen, C1-6 alkyl and C1-6 alkoxy.
Typical examples of specific substituents on M include one or more substituents independently selected from fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, isopropyl, trifluoromethyl, hydroxy, methoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfinyl , methylsulfonyl, amino, methylamino, dimethylamino, acetylamino, methoxycarbonylamino, methylsulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl, tetrahydromethylidinyl, pyrazolidinyl, azeopropylethyl , N-methylpyrrolidinyl, imidazolidinyl, N-methyl-imidazolidinyl, tetrahydropyranyl, piperidinyl, N-methylpiperidinyl, piperazinyl, N-methylpiperazinyl, morpholinyl, thiomorpholinyl, phenyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl , triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidi nil, pyridazinyl, pyrazinyl, tetrazolyl and triazinyl.
Selected examples of specific substituents on M include one or more substituents independently selected from chloro, methyl and methoxy.
Individual values of M include phenyl, pyridinyl, chloropyridinyl, methylpyridinyl, pyrazinyl and methoxypyrazinyl.
[0051] In a particular embodiment, M represents pyridinyl. In a particular aspect of this embodiment, M represents pyridin-3-yl.
[0052] In another embodiment, M represents methylpyridinyl. In a particular aspect of this embodiment, M represents 2-methylpyridin-3-yl.
Suitable values of R1, R2 and/or R3 include hydrogen, halogen, C1-6 alkyl, trifluoromethyl, aryl(C1-6)alkyl, C1-6 alkoxy and C1-6 alkyl sulfonyl.
Typical values of R1, R2 and/or R3 include hydrogen, halogen, C1-6 alkyl, aryl(C1-6) alkyl and C1-6 alkoxy.
Selected values of R1, R2 and/or R3 include hydrogen, halogen, C1-6 alkyla, trifluoromethyl and C1-6 alkyl sulfonyl.
Suitably, R1, R2 and R3 independently represent hydrogen, fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, trifluoromethyl, benzyl, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfinyl, methylsulfonyl, amino, methylamino, dimethylamino, acetylamino, methoxycarbonylamino, methylsulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl or dimethylaminosulfonyl.
Suitably, R1 represents hydrogen, halogen, C1-6 alkyl, trifluoromethyl, aryl(C1-6)alkyl, C1-6 alkoxy or C1-6 alkyl sulfonyl.
Typically, R1 represents hydrogen, halogen, C1-6 alkyl, aryl(C16)alkyl or C1-6 alkoxy.
Selected values of R1 include hydrogen, halogen, C1-6 alkyl, trifluoromethyl and C1-6 alkyl sulfonyl.
[0060] Illustrative values of R1 include hydrogen, halogen and C1-6 alkyl.
[0061] In one embodiment, R1 represents hydrogen. In another embodiment, R1 represents halogen, particularly fluorine or chlorine. In one aspect of this embodiment, R1 represents fluorine. In another aspect of this embodiment, R1 represents chlorine. In another embodiment, R 1 represents C 1-6 alkyl, particularly methyl or ethyl. In one aspect of this embodiment, R1 represents methyl. In another aspect of this embodiment, R1 represents ethyl. In another embodiment, R1 represents trifluoromethyl. In yet another embodiment, R1 represents aryl(1-6C)alkyl, especially benzyl. In a further embodiment, R1 represents C1-6 alkoxy, especially methoxy. In another embodiment, R 1 represents C 1-6 alkyl sulfonyl. In one aspect of this embodiment, R1 represents methylsulfonyl.
[0062] Suitably, R2 represents hydrogen, halogen or C1-6 alkyl.
[0063] Typically, R2 represents hydrogen or halogen.
[0064] In one embodiment, R2 represents hydrogen. In another embodiment, R2 represents halogen, particularly fluorine or chlorine. In one aspect of this embodiment, R2 represents fluorine. In another aspect of this embodiment, R2 represents chlorine. In another embodiment, R2 represents C1-6 alkyl. In one aspect of this embodiment, R2 represents methyl.
[0065] Suitably, R3 represents hydrogen or halogen.
[0066] Typically, R3 represents hydrogen.
[0067] In one embodiment, R3 represents hydrogen. In another embodiment, R3 represents halogen. In one aspect of this embodiment, R3 represents fluorine. In a particular embodiment, R2 and R3 both represent hydrogen.
[0068] In one embodiment, R4 represents hydrogen. In another embodiment, R4 represents C1-6 alkyl, especially methyl.
[0069] Suitable values for the R4 group include hydrogen and methyl.
[0070] Typically, R5 represents hydrogen or C1-6 alkyl.
[0071] In one embodiment, R5 represents hydrogen. In another embodiment, R5 represents halogen, particularly fluorine or chlorine. In one aspect of this embodiment, R5 represents fluorine. In another aspect of this embodiment, R5 represents chlorine. In another embodiment, R5 represents C1-6 alkyl, especially methyl. In a further embodiment, R5 represents C1-6 alkoxy, especially methoxy.
[0072] Suitable values for the R5 group include hydrogen, fluorine, chlorine, bromine, methyl and methoxy. Suitably R5 represents hydrogen or methyl. Typically, R5 represents hydrogen.
[0073] In a selected embodiment, the present invention provides an N-oxide derivative of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt or solvate thereof.
[0074] A subclass of compounds according to the invention is represented by the compounds of formula (IIA), and pharmaceutically acceptable salts and solvates thereof:
wherein R 1 and R 2 are as defined above; X represents N or CH; R 16 and R 17 independently represent hydrogen, halogen, cyano, C 1-6 alkyl, trifluoromethyl, amino, C 1-6 alkylamino or di(C 1-6 )alkylamino; and R18 and R19 independently represent hydrogen, halogen, cyano, C1-6 alkyl, trifluoromethyl or aminocarbonyl.
[0075] In one embodiment, X is N. In another embodiment, X is CH.
Typical values of R16 include hydrogen, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, amino, methylamino, ethylamino, tert-butylamino and dimethylamino.
[0077] A particular value of R16 is hydrogen.
Typical values of R17 include hydrogen, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, amino, methylamino, ethylamino, tert-butylamino and dimethylamino.
[0079] A particular value of R17 is hydrogen.
[0080] Suitable values of R18 include hydrogen and C1-6 alkyl.
Typical values of R18 include hydrogen, fluorine, chlorine, cyano, methyl, trifluoromethyl and amino carbonyl.
[0082] Selected values of R18 include hydrogen and methyl.
[0083] In one embodiment, R18 represents hydrogen. In another embodiment, R18 represents halogen. In one aspect of this embodiment, R18 represents fluorine. In another aspect of this embodiment, R18 represents chlorine. In another embodiment, R18 represents cyano. In another embodiment, R18 represents C1-6 alkyl. In one aspect of this embodiment, R18 represents methyl. In another embodiment, R18 represents trifluoromethyl. In a further embodiment, R18 represents aminocarbonyl.
[0084] Typical values of R19 include hydrogen, halogen, C1-6 alkyl and trifluoromethyl.
[0085] A particular value of R19 is hydrogen.
[0086] A particular subset of the compounds of formula (IIA) above is represented by compounds of formula (IIB), and pharmaceutically acceptable salts and solvates thereof:
wherein R1, R2, X, R16, R17 and R18 are as defined above.
Specific novel compounds according to the present invention include each of the compounds whose preparation is described in the accompanying Examples, and pharmaceutically acceptable salts and solvates thereof.
[0088] The present invention also provides a pharmaceutical composition comprising a compound according to the invention as described above, or a pharmaceutically acceptable salt or solvate thereof, in association with one or more pharmaceutically acceptable carriers.
The pharmaceutical compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical, ophthalmic or rectal administration, or a form suitable for administration by inhalation or insufflation.
[0090] For oral administration, pharmaceutical compositions may take the form, for example, of tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (for example pregelatinized corn starch, polyvinylpyrrolidine or hydroxypropyl methyl cellulose); fillers (for example lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (for example magnesium stearate, talc or silica); disintegrants (for example potato starch or sodium glycolate); or wetting agents (for example sodium lauryl sulphate). Tablets can be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles or preservatives. The preparations may also contain buffer salts, flavoring agents, coloring agents or sweetening agents, as appropriate.
[0091] Preparations for oral administration can be suitably formulated to give controlled release of the active compound.
[0092] For oral administration, the compositions may take the form of tablets or lozenges formulated in the conventional manner.
The compounds of formula (I) may be formulated for parenteral administration by injection, for example by bolus injection or infusion. Formulations for injection may be presented in unit dosage form, for example in glass ampoules or in multiple dose containers, for example a glass vial. Compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing, preserving and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, for example sterile pyrogen-free water, before use.
[0094] In addition to the formulations described above, the compounds of formula (I) can also be formulated as a depot preparation. Such long-acting formulations can be administered by implantation or by intramuscular injection.
[0095] For nasal administration or administration by inhalation, the compounds according to the present invention can be conveniently delivered in the form of an aerosol spray presentation to pressurized packs or a nebulizer, with the use of a suitable propellant, by example dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or gas mixture.
The compositions, if desired, may be presented in a pack or dispensing device which may contain one or more unit dosage forms containing the active ingredient. The pack or dispensing device may be accompanied by instructions for administration.
[0097] For topical administration the compounds for use in the present invention may be conveniently formulated in a suitable ointment containing the active compound suspended or dissolved in one or more pharmaceutically acceptable carriers. Particular carriers include, for example, mineral oil, liquid petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax and water. Alternatively, compounds for use in the present invention may be formulated in a suitable lotion containing the active compound suspended or dissolved in one or more pharmaceutically acceptable carriers. Particular carriers include, for example, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester waxes, cetearyl alcohol, benzyl alcohol, 2-octyldodecanol and water.
[0098] For ophthalmic administration the compounds for use in the present invention may be conveniently formulated as micronized suspensions in sterile, isotonic saline, pH adjusted, with or without a preservative such as a bactericidal or fungicidal agent, for example phenylmercuric nitrate , benzylalkonium chloride or chlorhexidine acetate. Alternatively, for ophthalmic administration, the compounds may be formulated in an ointment such as petroleum jelly.
[0099] For rectal administration the compounds for use in the present invention may be conveniently formulated as suppositories. These can be prepared by mixing the active compound with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and so will melt in the rectum to release the active compound. Such materials include, for example, cocoa butter, beeswax and polyethylene glycols.
The amount of a compound of use in the invention required for the prophylaxis or treatment of a particular condition will vary depending on the compound chosen and the condition of the patient to be treated. In general, however, daily dosages can range from approximately 10 ng/kg to 1000 mg/kg, typically from 100 ng/kg to 100 mg/kg, for example from approximately 0.01 mg/kg to 40 mg/kg of body weight, for oral or buccal administration, from approximately 10 ng/kg to 50 mg/kg of body weight for parenteral administration, and from approximately 0.05 mg to approximately 1000 mg, for example from approximately 0.5 mg to approximately 1000 mg, for nasal administration or administration by inhalation or insufflation.
[00101] Compounds of formula (I) above wherein Q represents oxygen, sulfur or N-R4 may be prepared by a process comprising reacting a compound of formula L1-Z with a compound of formula (III):
wherein Q1 represents oxygen, sulfur or N-R4, L1 represents a suitable leaving group, and U, Z, M, W, R1, R2, R3 and R4 are as defined above.
[00102] The leaving group L1 is typically a halogen atom, eg chlorine. Alternatively, the leaving group L1 can be 2,5-dioxopyrrolidin-1-yloxy.
[00103] The reaction is conveniently carried out at an elevated temperature in a suitable solvent, for example a chlorinated solvent such as dichloromethane or chloroform, or a nitrile solvent such as acetonitrile. Optionally, the reaction can be carried out in the presence of a reaction promoter such as 4-(dimethylamino)pyridine or p-toluenesulfonic acid.
[00104] Alternatively, the reaction can be carried out at an elevated temperature in a suitable solvent, for example tetrahydrofuran, n-butanol, 1-methyl-2-pyrrolidinium (NMP) or 1,4-dioxane, typically in the presence of a base suitable, for example an organic base such as N,N-diisopropylethylamine.
[00105] Intermediates of formula (III) wherein Q1 represents NH and U represents -CF3 can be prepared by a three-step procedure comprising: (i) treating a suitable compound of formula (IV):
wherein M, W, R1, R2 and R3 are as defined above; with 2-methyl-2-propanesulfinamide in the presence of titanium(IV) isopropoxide or potassium phosphate; (ii) reaction of the resulting compound with (trifluoromethyl)trimethylsilane in the presence of tetrabutylammonium difluorotriphenylsilicate or tetrabutylammonium acetate; and (iii) treating the resulting compound with a mineral acid for example hydrochloric acid.
[00106] Intermediates of formula (IV) can be prepared by reacting a compound of formula M-T1 with a compound of formula (V):
wherein L2 represents a suitable leaving group, T1 represents a boronic acid moiety -B(OH)2 or a cyclic ester thereof formed with an organic diol, for example pinacol, 1,3-propanediol or neopentyl glycol, or T1 represents - Sn(Alk1)3 wherein Alk1 represents a C1-6 alkyl group, typically n-butyl, or T1 represents -B(Alk2)2 wherein Alk2 represents a C1-6 alkyl group, typically ethyl, and M, W, R1, R2 and R3 are as defined above; in the presence of a transition metal catalyst.
[00107] The leaving group L2 is typically a halogen atom, eg chlorine.
[00108] The transition metal catalyst is suitably tetracis(triphenylphosphine)palladium(0), in which case the reaction is conveniently carried out at an elevated temperature in a suitable solvent, for example an etheric solvent such as ethylene glycol dimethyl ether or 1,4-dioxane, typically in the presence of sodium carbonate or sodium bicarbonate.
[00109] Alternatively, intermediates of formula (IV) may be prepared by treating a compound of formula (VI):
wherein Ra represents C1-6 alkyl, for example ethyl, and M, W, R1, R2 and R3 are as defined above; with a reducing agent, for example diisobutylaluminum hydride (DIBAL-H); followed by treating the compound thus obtained with an oxidizing agent such as manganese dioxide.
[00110] The intermediates of the formula (VI) wherein W represents CH can be prepared by the reaction of a formula (VIII):
wherein M, R1, R2, R3 and Ra are as defined above, and Hal represents halogen, for example bromine or iodine; in the presence of a transition metal catalyst, for example palladium(II) acetate; followed by treating the compound thus obtained with an oxidizing agent such as manganese dioxide.
[00111] Intermediates of formula (VIII) can be prepared by reacting a compound of formula M-CHO with a compound of formula (IX):
where M and Ra are as defined above.
[00112] The reaction is conveniently carried out in the presence of a base, ideally an organic base such as 1,4-diazabicyclo[2,2,2]-octane (DABCO).
[00113] In another procedure, the intermediates of the formula (IV) wherein W represents CH can be prepared by reacting a compound of the formula M-CH=CH-CHO with a compound of the formula (X):
wherein M, R1, R2 and R3 are as defined above; in the presence of a base, for example 2,5-dimethylpyrrolidine; followed by treating the compound thus obtained with an oxidizing agent such as manganese dioxide.
[00114] In a variant method, intermediates of formula (III) wherein Q' represents NH and U represents -CF3 may be prepared by a four step procedure comprising: (i) treating a suitable compound of formula (V) as defined above with 2-methyl-2-propanesulfinamide in the presence of titanium(IV) isopropoxide or potassium phosphate; (ii) reacting the resulting compound with a compound of the formula M-T' under conditions analogous to those described above for the reaction between M-T' and the compound (V); (iii) reaction of the resulting compound with (trifluoromethyl)trimethylsilane in the presence of tetrabutylammonium difluorotriphenylsilicate or tetrabutylammonium acetate; and (iv) treating the resulting compound with a mineral acid, for example hydrochloric acid.
[00115] Where they are not commercially available, the starting materials of formulas (V), (VII), (IX) and (IX) can be prepared by methods analogous to those described in the accompanying Examples, or by the well-known standard methods in technique.
[00116] It will be understood that any compound of formula (I) initially obtained from any of the above processes, where appropriate, may subsequently be elaborated into another compound of formula (I) by techniques known in the art. By way of illustration, a compound of formula (I) wherein M represents pyridinyl may be converted to the corresponding compound wherein M is a pyridine-N-oxide moiety by treatment with a suitable oxidizing agent, for example 3-acid. chlorperoxybenzoic acid. Similarly, a compound of formula (I) wherein Z represents pyridopyrimidinyl can be converted to the corresponding compound wherein Z is a pyridopyrimidine-N-oxide moiety by treatment with a suitable oxidizing agent, for example 3-chloroperoxybenzoic acid. A compound of formula (I) wherein R4 represents hydrogen may be converted to the corresponding compound wherein R4 represents C1-6 alkyl, for example methyl, by treatment with a suitable alkylating agent, for example a methylating agent such as iodomethane, typically in the presence of a base such as sodium hydride.
[00117] Where a mixture of products is obtained from any of the processes described above for the preparation of compounds according to the invention, the desired product can be separated from it at an appropriate stage by conventional methods such as preparative HPLC; or column chromatography using, for example, silica and/or alumina in conjunction with an appropriate solvent system.
[00118] Where the processes described above for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, these isomers can be separated by conventional techniques. In particular, where it is desired to obtain a particular enantiomer of a compound of formula (I) this can be produced from a corresponding mixture of enantiomers using any conventional procedure suitable for resolving enantiomers. Thus, for example, diastereomeric derivatives, for example salts, can be produced by reacting a mixture of enantiomers of the formula (I), for example a racemate, and an appropriate chiral compound, for example a chiral base. The diastereomers can then be separated by any convenient means, for example by crystallization, and the desired enantiomer recovered, for example by treatment with an acid in the case where the diastereomer is a salt. In another resolution process, a racemate of formula (I) can be separated using chiral HPLC. Furthermore, if desired, a particular enantiomer can be obtained by using an appropriate chiral intermediate in one of the processes described above. Alternatively, a particular enantiomer can be obtained by carrying out an enantiomer-specific enzymatic biotransformation, for example an ester hydrolysis using an esterase, and then purifying only the enantiomerically pure hydrolyzed acid from the unreacted ester antipode. Chromatography, recrystallization and other conventional separation procedures can also be used with intermediates or final products where it is desired to obtain a particular geometric isomer of the invention.
[00119] During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules of interest. This can be accomplished by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 3rd edition, 1999. Protective groups can be removed at any convenient subsequent stage using methods known in the art.
The Examples which follow illustrate the preparation of compounds according to the invention.
The compounds according to this invention potentially inhibit the activity of human PI3K and/or PI3K and/or PI3K and/or PI3K.
[00122] Enzyme Inhibition Assays
[00123] Measurement of the ability of compounds to inhibit the lipid kinase activity of the four PI3 kinase class 1 isoforms (, , and ) was performed using a commercially available homogeneous time-resolved fluorescence assay as described by Gray et al. , Anal. Biochem., 2003, 313, 234-245, according to the manufacturer's instructions (Upstate). All assays were performed at 2 μM ATP and a concentration of purified class 1 PI3 kinase known to generate product within the linear range of the assay. Inhibitor dilutions in DMSO were added to the assay and compared to assays conducted in the presence of 2% (v/v) DMSO alum (100% activity). The concentration of inhibitor required to inhibit enzyme activity by 50% is quoted as the IC50.
[00124] When tested in the above assay, the compounds of the attached Examples were all found to have IC50 values for inhibition of human PI3Kα and/or PI3Kβ and/or PI3Ky and/or PI3Kδ activity of 50 μM or better.
[00125] EXAMPLES abbreviationsDCM: dichloromethane DMAP: 4-(dimethylamino)pyridineEtOAc: ethyl acetate MeOH: methanolTHF: tetrahydrofuran DME: ethylene glycol dimethyl ether DMSO: dimethyl sulfoxide MCPBA: 3-chloroperoxy-benzoic acid DABCO: 1,4-diazabicyclo[2 ,2,2]-octane DIBAL-H: diisobutylaluminum hydride Rochelle's Salt: DBU tartrate: 1,8-diazabicyclo[5.4.0]-undec-potassium sodiumAcOH: acetic acid 7-eneDMF: N, N-dimethylformamidar.t.: room temperatureSiO2: silica RT: retention time h: hourbr: broad M: massPd(PPh3)4: tetracis(triphenylphosphine)palladium(0)PyBOP: (benzotriazol-1-yloxy)tripyrrolidine-hexafluorophosphate phosphonium brine: saturated aqueous sodium chloride solutionLCMS: Liquid Chromatography Mass Spectrometry ES+: Electrospray Positive Ionization
[00126] INTERMEDIATE 1
[00127] 8-Chloro-2-(pyridin-3-yl)quinoline-3-carbaldehyde
[00128] A mixture of 2,8-dichloroquinoline-3-carbaldehyde (5.0 g, 22.2 mmol), Na2CO3 (3.51 g, 33.2 mmol) and 3-pyridylboronic acid (2.72 g, 22.2 mmol) in DME (60 ml) and water (30 ml) was degassed by bubbling N2 through it for 5 minutes. Pd(PPh3)4 (1.28 g, 1.11 mmol) was added and the mixture heated at 90°C for 7 h. The mixture was allowed to cool to room temperature. The resulting precipitate was filtered off and washed with water (5 x 50 ml) and diethyl ether (5 x 50 ml) to give the title compound (5.4 g, 91%) as a brown solid. H (DMSO-d6) 10.15 (s, 1H), 9.15 (s, 1H), 8.94 (dd, J 2.3, 0.8 Hz, 1H), 8.77 (dd, J4 0.9, 1.7 Hz, 1H), 8.31 (dd, J 8.3, 1.3 Hz, 1H), 8.20 - 8.19 (m, 1H), 8.18 - 8.16 (m, 1H), 7.75 (dd, J 7.9, 7.5 Hz, 1H), 7.62 (ddd, J 7.7, 4.9, 0.8 Hz, 1H). LCMS (ES+) 269 (M + H)+, RT 1.82 min.
[00129] Alternative procedure
[00130] To a solution of nicotinaldehyde (10.0 g, 93.4 mmol) in ethyl acrylate (20 ml, ~200 mmol) at room temperature was added DABCO (0.5 g, 4.5 mmol) and the mixture was stirred overnight. Excess ethyl acrylate was removed in vacuo to give a crude solid. This was washed with hexane to give 2-[(hydroxy)(pyridin-3-yl)methyl]acrylic acid ethyl ester (18.5 g, 95%) as a yellowish white solid. H (CDCl 3 ) 8.62 (d, J 1.7 Hz, 1H), 8.53 (dd, J 4.8, 1.3 Hz, 1H), 7.81 (d, J 7.9 Hz, 1H), 7.28 (s, 1H), 6.42 (s, 1H), 5.93 (s, 1H), 5.63 (s, 1H), 4.18 (m, 2H), 3. 20 (br, 1H), 1.27 (t, J 7.1 Hz, 3H). LCMS (ES+) 208.2 (M + H)+.
[00131] A degassed mixture of 2-[(hydroxy)(pyridin-3-yl)methyl]acrylic acid ethyl ester (8.2 g, 39.6 mmol), 6-chloro-2-iodoaniline (10.0 g, 39.5 mmol), triethylamine (9 ml, 122 mmol) and palladium(II) acetate (300 mg) in acetonitrile (80 ml) was heated at 70°C overnight. The mixture was cooled to room temperature and partitioned between ethyl acetate (200 ml) and water (100 ml). The aqueous layer was separated and the organic layer was washed with brine (50 ml), filtered, dried (phase separator) and concentrated in vacuo to give a crude solid. This was washed with a minimum of ice-cold diethyl ether to give 8-chloro-2-(pyridin-3-yl)-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (10.8 g, 87%) as a white solid. 6H (CDCl 3 ) 8.73 (m, 2H), 8.04 (m, 1H), 7.66 (dd, J 7.9, 5.5 Hz, 1H), 7.18 (m, 1H), 7.05 (m, 1H), 6.94 (m, 1H), 6.29 (s, 1H), 3.99 (m, 4H), 1.04 (t, J 7.1 Hz, 3H) . LCMS (ES+) 315.0 (M + H)+.
[00132] A suspension of 8-chloro-2-(pyridin-3-yl)-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (10.7 g, 34 mmol) in chlorobenzene (60 ml) was treated with MnO2 (10 g) and the mixture was heated at 60°C for 3 h. The mixture was filtered through a pad of celite and concentrated in vacuo. The residue was washed with diethyl ether to give 8-chloro-2-(pyridin-3-yl)quinoline-3-carboxylic acid ethyl ester (8.4 g, 79%) as a white solid. H (CDCl 3 ) 8.96 (d, J 1.7 Hz, 1H), 8.83 (s, 1H), 8.75 (dd, J 5.0, 1.1 Hz, 1H), 8.27 (dt, J 7.9, 1.7 Hz, 1H), 8.00 (dd, J 7.5, 1.0 Hz, 1H), 7.92 (dd, J 8.2, 1.0 Hz , 1H), 7.60 (m, 2H), 4.32 (q, J 7.1 Hz, 2H), 1.24 (t, J 7.1 Hz, 3H). LCMS (ES+) 313.2 (M + H)+.
To a suspension of 8-chloro-2-(pyridin-3-yl)quinoline-3-carboxylic acid ethyl ester (1.0 g, 3.2 mmol) in toluene at -78°C was added a DIBAL-H solution (10 ml, 1 M in DCM) dropwise in 10 minutes. The mixture was stirred at this temperature for 2 h, then quenched by the addition of a saturated aqueous Rochelle salt solution (5 ml). After warming to room temperature, extra Rochelle's salt solution (5 ml) was added. The resulting solid was filtered, washed over the sinter with aqueous NaOH solution (2N) and water, and dried to give [8-chloro-2-(pyridin-3-yl)quinolin-3-yl]methanol (860 mg, quantitative) as a beige solid. H (DMSO-d6) 8.92 (d, J 1.7 Hz, 1H), 8.73 (dd, J4.8, 1.6 Hz, 1H), 8.61 (s, 1H), 8. 17 (dt, J 7.9, 1.9 Hz, 1H), 8.09 (dd, J 8.2, 1.1 Hz, 1H), 7.97 (dd, J 7.5, 1.2 Hz, 1H), 7.63 (m, 1H), 7.58 (ddd, J 7.8, 4.8, 0.6 Hz, 1H), 5.76 (s, 1H), 5.62 ( t, J 5.2 Hz, 1H), 4.68 (d, J 4.9 Hz, 2H). LCMS (ES+) 271.0 (M + H)+.
[00134] A mixture of [8-chloro-2-(pyridin-3-yl)quinolin-3-yl]-methanol (0.6 g, 2.2 mmol) and MnO2 (1.0 g) in chlorobenzene ( 30 ml) was heated at 70°C overnight, filtered through a pad of celite, concentrated in vacuo and washed with DCM to give the title compound (510 mg, 86%) as a white solid.
[00135] INTERMEDIATE 2
[00136] 2-Methylpropane-2(S)-sulfinic acid N-[8-chloro-2-(pyridin-3-yl)quinolin-3-yl]meth-(E)-ylideneamide
[00137] Titanium(IV) isopropoxide (3.17 g, 11.2 mmol) was added to a suspension of Intermediate 1 (1.5 g, 5.58 mmol) in anhydrous THF (30 ml). The mixture was stirred at room temperature for 10 minutes. (S)-2-Methyl-2-propanesulfinamide (0.74 g, 6.14 mmol) was added and the mixture stirred at 50°C for 3 h. The reaction mixture was allowed to cool to room temperature then poured into brine (50 ml) and filtered through Celite, washing with EtOAc. The filtrate was washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography (SiO 2 , 40 to 100% EtOAc in hexane) gave the title compound (1.88 g, 91%) as a brown solid. H (DMSO-d6) 9.20 (s, 1H), 8.85 (d, J 1.7 Hz, 1H), 8.77 (dd, J 4.9, 1.7 Hz, 1H), 8 .61 (s, 1H), 8.29 (dd, J 8.3, 1.1 Hz, 1H), 8.13 (dd, J 7.5, 1.3 Hz, 1H), 8.12 - 8.08 (m, 1H), 7.72 (dd, J 8.1, 7.7 Hz, 1H), 7.64 (ddd, J 7.7, 4.9, 0.8 Hz, 1H) , 1.21 (s, 9H). LCMS (ES+) 372 (M + H)+, RT 2.37 min.
[00138] INTERMEDIATE 3
[00139] 2-methylpropane-2(S) acid {(R)-1-[8-chloro-2-(pyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl}amide -sulfinic
[00140] A mixture of Intermediate 2 (2.24 g, 6.03 mmol) and tetrabutylammonium difluorotriphenylsilicate (3.58 g, 6.64 mmol) in anhydrous THF (40 ml) was cooled to -40°C. Trifluoromethyl)trimethylsilane (1.03 g, 7.24 mmol) was added and the mixture stirred at -40°C for 1 h. Saturated aqueous ammonium chloride solution (5 ml) was added and the reaction mixture allowed to warm to room temperature. The solvent was removed in vacuo and the residue was partitioned between EtOAc and water. The aqueous phase was extracted with more EtOAc and the combined organic fractions were washed with brine, then dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography (SiO 2 , 40 to 100% EtOAc in hexane) to give the title compound (1.78 g, 67%) as a yellow gum. H (DMSO-d6) 9.02 (s, 1H), 8.80 (dd, J 4.9, 1.7 Hz, 1H), 8.78 (dd, J 2.3, 0.6 Hz, 1H), 8.15 - 8.09 (m, 2H), 8.04 - 7.99 (m, 1H), 7.77 - 7.71 (m, 1H), 7.67 (ddd, J 7 9.9, 4.9, 0.8 Hz, 1H), 6.65 (d, J 8.5 Hz, 1H), 5.12 - 5.00 (m, 1H), 1.15 (s, 9H) ). LCMS (ES+) 442 (M + H)+, RT 2.39 min.
[00141] INTERMEDIATE 4
[00142] (R)-1-[8-Chloro-2-(pyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethylamine
To a solution of Intermediate 3 (1.78g, 4.04mmol) in methanol (20ml) was added a 4N solution of HCl in 1,4-dioxane (4ml, 16.0mmol). The mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo and the residue triturated with diethyl ether (x 2). The residue was then partitioned between DCM and saturated aqueous NaHCO3 solution. The aqueous phase was extracted with more DCM and the combined organic fractions were washed with brine, then dried (Na 2 SO 4 ) and evaporated in vacuo to give the title compound (1.28 g, 94%) as a yellow gum. H (DMSO-d6) 8.92 (s, 1H), 8.82 (d, J2.1 Hz, 1H), 8.76 (dd, J 4.9, 1.5 Hz, 1H), 8. 13 - 8.09 (m, 1H), 8.07 - 8.03 (m, 2H), 7.72 - 7.60 (m, 2H), 4.72 - 4.65 (m, 1H), 2.88 - 2.83 (m, 2H). LCMS (ES+) 338 (M + H)+, RT 2.01 min.
[00144] INTERMEDIATE 5
[00145] 8-Chloro-2-phenylquinoline-3-carbaldehyde
[00146] A mixture of 2,8-dichloroquinoline-3-carbaldehyde (2.0 g, 8.85 mmol), 2 M aqueous solution of Na2CO3 (8 ml), phenylboronic acid (1.5 g, 12.3 mmol) ) and tetrakis(triphenylphosphine)palladium(0) (0.25 g, 0.216 mmol) in DME (30 ml) was degassed and the mixture heated at 110°C for 4 h. The mixture was allowed to cool to room temperature, diluted with EtOAc and washed with brine. The organic layer was dried (MgSO4 ) and the solvent removed under reduced pressure. The resulting solid was triturated in ether, filtered, washed with a small amount of ether, then petroleum ether, and dried to give the title compound (2.3 g, 97%) as a yellowish white solid. H(CDCl 3 ) 10.25 (s, 1H), 8.86 (s, 1H), 7.95 - 8.02 (m, 2H), 7.78 - 7.14 (m, 2H), 7. 54 - 7.62 (m, 4H). LCMS (ES+) 268 (M + H)+, RT 1.98 min.
[00147] INTERMEDIATE 6
[00148] 2-Methyl-propane-2(S)-sulfinic acid N-(8-chloro-2-phenylquinolin-3-yl)meth-(E)-ylideneamide
[00149] Titanium(IV) isopropoxide (5.1 ml, 17.24 mmol) was added to a stirred solution of Intermediate 5 (2.3 g, 8.6 mmol) in anhydrous THF (35 ml). The mixture was stirred at room temperature for 10 minutes, then (S)-2-methyl-2-propanesulfinamide (1.15 g, 9.5 mmol) was added and the mixture was stirred at 50°C for 5.5 h . Heating was turned off and the reaction mixture was allowed to stir at room temperature overnight. Ice water was added and the mixture was stirred for 10 minutes, diluted with EtOAc and filtered through Celite, washing with EtOAc. The filtrate was then washed with brine, dried (MgSO4 ) and concentrated in vacuo. The crude solid was triturated with ether, then filtered, washed with ether and dried to give the title compound (2.45 g, 77%) as a white solid. H (DMSO-d6) 9.14 (s, 1H), 8.61 (s, 1H), 8.27 (dd, J 4.9, 1.7 Hz, 1H), 8.10 (dd, J 8.3, 1.1 Hz, 1H), 7.59 - 7.69 (m, 6H), 1.24 (s, 9H). LCMS (ES+) 371 (M + H)+, RT 2.1 min.
[00150] INTERMEDIATE 7
[00151] [(R)-1-(8-chloro-2-phenylquinolin-3-yl)-2,2,2-trifluoroethyl]amide 2-methylpropane-2(S)-sulfinic acid
[00152] A mixture of Intermediate 6 (2.45 g, 6.61 mmol) and tetrabutylammonium difluorotriphenylsilicate (3.93 g, 7.28 mmol) in anhydrous THF (30 ml) was cooled to -70°C. ( Trifluoromethyl)trimethylsilane (1.2 ml, 8.13 mmol) was added dropwise and the mixture was stirred for 2 h, allowing the temperature to rise slowly. LCMS showed some unreacted starting material so the mixture was cooled once more to -70°C and more (trifluoromethyl)trimethylsilane (0.5ml, 3.39mmol) was added. The mixture was stirred for a further 2 h, allowing the temperature to slowly rise to 0°C. Saturated aqueous ammonium chloride solution (0.5 ml) was added and the reaction mixture was allowed to warm to room temperature. The reaction mixture was extracted twice using EtOAc, then dried (MgSO4), and the solvent evaporated in vacuo. The residue was purified by column chromatography (SiO 2 , 10 to 60% EtOAc in hexane) to give the title compound (1.7 g, 58%) as a pale yellow gum. H (DMSO-d6) 8.98 (s, 1H), 8.04 - 8.11 (m, 2H), 7.56 - 7.73 (m, 6H), 6.59 (d, J 8, 63Hz, 1H), 5.09 - 5.75 (m, 1H), 1.16 (s, 9H). LCMS (ES+) 441 (M + H)+, RT 2.06 min.
[00153] INTERMEDIATE 8
[00154] (R)-1-(8-Chloro-2-phenylquinolin-3-yl)-2,2,2-trifluoroethylamine
To a solution of Intermediate 7 (0.75 g, 1.7 mmol) in DCM (2 ml) was added a 4 H solution of HCl in 1,4-dioxane (10 ml). The mixture was stirred at room temperature for 20 minutes. The solvent was removed in vacuo and the residue was then partitioned between DCM and a saturated aqueous NaHCO3 solution. The aqueous phase was extracted with more DCM and the combined organic fractions were dried (MgSO4 ) and evaporated in vacuo to give the title compound (0.55 g, 96%) as a yellow foam which was used without further purification. LCMS (ES+) 337 (M + H)+, RT 1.99 minutes.
[00156] INTERMEDIATE 9
[00157] 2-Methylpropane-2(S)-sulfinic acid N-(2,8-dichloroquinolin-3-yl)meth-(E)-ylideneamide
Potassium phosphate (16 g, 75.47 mmol) was dissolved in water (50 ml) and (5)-2-methyl-2-propanesulfinamide (10.5 g, 86.78 mmol) was added. The mixture was stirred for 10 minutes, then a solution of 2,8-dichloroquinoline-3-carbaldehyde (17.0 g, 75.22 mmol) in 2-propanol (50 ml) was added and the reaction mixture was stirred for 10 minutes. two days. The solid was filtered, washed with water and dried in vacuo. The resulting solid was dissolved in DCM, washed with brine and dried (MgSO4 ) and the solvent removed under reduced pressure. The resulting solid was triturated in ether, filtered, washed with ether and dried to give the title compound (23.6 g, 95%) as a bright yellow solid. H (CDCl 3 ) 9.12 (s, 1H), 8.83 (s, 1H), 7.90 (d, J 1.9 Hz, 1H), 7.87 (d, J 8.2 Hz, 1H), 7.55 (t, J 7.9 Hz, 1H), 1.33 (s, 9H). LCMS (ES+) 330 (M + H)+, RT 1.94 min.
[00159] INTERMEDIATE 10
[00160] 2-Methylpropane-2(S)-sulfinic acid N-[8-chloro-2-(4-methylpyridin-3-yl)quinolin-3-yl]-meth-(E)-ylideneamide
[00161] A mixture of Intermediate 9 (5.0 g, 15.2 mmol), 4-methylpyridin-3-ylboronic acid (3.15 g, 21.43 mmol), tetracis(triphenylphosphine)-palladium (0) ( 0.17 g, 0.147 mmol) and a 2 M aqueous solution of sodium bicarbonate (20 ml) in 1,4-dioxane (80 ml) was degassed and heated under reflux in a nitrogen atmosphere for 1 hour. The reaction mixture was cooled to room temperature, then partitioned between EtOAc and brine, and the aqueous layer was extracted once more using EtOAc. The combined organic extracts were dried (MgSO4 ) and the solvent removed under reduced pressure. To a solution of the resulting material in 2-propanol (10 ml) was added a solution prepared by stirring potassium phosphate (2.8 g, 13.21 mmol) and (S)-2-methyl-2-propanesulfinamide (1.85 g, 15.3 mmol) in water (10 ml) for 15 minutes. The reaction mixture was allowed to stir over a weekend. Ice water was added, and the resulting solid was collected by filtration, washed thoroughly with water and air-dried to give the title compound (5.84 g, 99%) as a brown solid. H (CDCl 3 ) 8.91 (s, 1H), 8.58 (d, J 5.1Hz, 1H), 8.52 (s, 1H), 8.50 (s, 1H), 7 .96 (m, 2H), 7.58 (t, J 7.9 Hz, 1H), 7.29 (d, J 5.1Hz, 1H), 2.29 (s, 3H), 1 .24 (s, 9H). LCMS (ES+) 386 (M + H)+, RT 1.88 minutes.
[00162] INTERMEDIATE 11
[00163] 2-methylpropane-2 acid {(R)-1-[8-chloro-2-(4-methylpyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl}-amide (S)-sulfinic
[00164] A solution of Intermediate 10 (5 g, 12.96 mmol) and tetrabutylammonium difluorotriphenylsilicate (7.7 g, 14.26 mmol) in anhydrous THF (100 ml) was cooled to -70°C. (Trifluoromethyl) trimethylsilane (2.3 ml, 15.58 mmol) was added dropwise and the mixture was stirred for 2 hours, allowing the temperature to rise slowly. LCMS showed some unreacted starting material so the mixture was cooled once more to -70°C and more (trifluoromethyl)trimethylsilane (2.3ml, 15.58mmol) was added. The mixture was stirred for a further 2.5 hours, allowing the temperature to slowly rise to 0°C. A saturated aqueous solution of ammonium chloride (0.5 ml) was added and the reaction mixture was allowed to warm to room temperature. The resulting material was extracted twice using EtOAc, then dried (MgSO4 ), and the solvent evaporated in vacuo. The residue was purified by column chromatography (SiO 2 , 60% EtOAc in hexane). Fractions containing the pure required isomer were pooled and the solvent removed under reduced pressure to give the title compound (3.79 g, 32%) as a pale yellow gum. H (DMSO-d6 at 90°C) 9.03 (s, 1H), 8.62 (d, J 5.0Hz, 1H), 8.49 (br s, 1H), 8.06 - 8.11 (m, 2H), 7.73 (t, J 7.9 Hz, 1 H), 7.49 (d, J 5.0 Hz, 1 H), 6.29 (br s, 1 H), 4.83 (br s, 1H), 2.18 (s, 3H), 1.18 (s, 9H). LCMS (ES+) 456 (M + H)+, RT 1.93 min.
[00165] INTERMEDIATE 12
[00166] (R)-1-[8-chloro-2-(4-methylpyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethylamine
To a solution of Intermediate 11 (1.8 g, 3.95 mmol) in 1,4-dioxane (2.5 ml) was added a 4 H solution of HCl in 1,4-dioxane (15 ml) . The mixture was stirred at room temperature for 20 minutes. The solvent was removed in vacuo and the residue was then partitioned between DCM and a saturated aqueous NaHCO3 solution. The aqueous phase was extracted with more DCM and the combined organic fractions were dried (MgSO4), evaporated in vacuo and purified by column chromatography (SiO2, 60% EtOAc in hexane) to give the title compound (1.25 g, 90%) as a light yellow foam. H (CDCl 3 ) 8.42 - 8.65 (m, 3H), 7.95 (d, J 7.1 Hz, 1H), 7.86 (d, J 8.2 Hz, 1H), 7 .55 (t, J 7.8 Hz, 1H), 7.24 - 7.40 (m, 2H), 2.15 - 2.32 (br s, 2H), 1.50 - 1.80 ( br s, 3H). LCMS (ES+) 352 (M + H)+, RT 1.81 min.
[00168] INTERMEDIATE 13
2-Methylpropane-2(S)-sulfinic acid N-[8-chloro-2-(2-methylpyridin-3-yl)quinolin-3-yl]-meth-(E)-ylideneamide
[00170] A mixture of Intermediate 9 (5.0 g, 15.2 mmol), 2-methylpyridin-3-ylboronic acid pinacolic ester (5 g, 22.43 mmol), tetracis-(triphenylphosphine)palladium (0) (0.2 g, 0.17 mmol) and a 2 M aqueous solution of sodium bicarbonate (20 ml) in 1,4-dioxane (80 ml) was degassed and heated under reflux in a nitrogen atmosphere for 3 hours. The reaction mixture was cooled to room temperature, partitioned between EtOAc and brine, and the aqueous layer was extracted once more using EtOAc. The combined organic extracts were dried (MgSO4 ) and the solvent removed under reduced pressure. To a solution of the resulting material in 2-propanol (10 ml) was added a solution prepared by stirring potassium phosphate (2.8 g, 13.21 mmol) and (S)-2-methyl-2-propanesulfinamide (1. .85 g, 15.3 mmol) in water (10 ml) for 15 minutes. The reaction mixture was stirred for 1 hour. Ice water was added and the resulting material was extracted using DCM. The organic extract was dried (MgSO4 ) and the solvent removed in vacuo. Column chromatography (SiO 2 , 50 to 60% EtOAc in hexane) gave the title compound (4.3 g, 73 %) as a pale yellow foam. H (CDCl 3 ) 8.91 (s, 1H), 8.66 (dd, J 5.0, 1.7Hz, 1H), 8.55 (s, 1H), 7.97 (m, 2H), 7.67 (dd, J 7.7, 1.6 Hz, 1 H), 7.60 (m, 1 H), 7.33 (dd, J 7.6, 5.0 Hz, 1 H), 2.30 (s, 3H), 1.24 (s, 9H). LCMS (ES+) 386 (M + H)+, RT 1.49 min.
[00171] INTERMEDIATE 14
[00172] 2-methylpropane-2 acid {(R)-1-[8-chloro-2-(2-methylpyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl}-amide (S)-sulfinic
[00173] A solution of Intermediate 13 (4.3 g, 11.17 mmol) and tetrabutylammonium difluorotriphenylsilicate (7.5 g, 13.9 mmol) in anhydrous THF (60 ml) was cooled to -50°C under nitrogen and (trifluoromethyl)-trimethylsilane (4.5 ml, 30.5 mmol) was added dropwise. The mixture was stirred for 2 hours, allowing the temperature to slowly rise to room temperature. The mixture was cooled once more to -20°C, the saturated aqueous ammonium chloride solution was added and the reaction mixture was allowed to warm to room temperature. The reaction mixture was extracted twice using DCM, then the organic extracts were dried (MgSO4 ) and filtered, and the solvent was evaporated in vacuo. The residue was purified by column chromatography (SiO 2 , 60% EtOAc in hexane). Fractions containing the pure required isomer were pooled and the solvent removed under reduced pressure to give the title compound (3.2 g, 63%) as a pale yellow syrup.H (DMSO-d6) 8.98 (d, J 17.8 Hz, 1 H), 8.59 (dd, J 4.9, 1.7 Hz, 1 H), 8.04 (m, 2H), 7.66 (t, J 7.9 Hz , 1H), 7.47 (m, 2H), 6.52 (m, 1H), 4.55 - 4.78 (m, 1H), 2.43 (br s, 3H), 1, 10 (br s, 9H). LCMS (ES+) 456 (M + H)+, RT 1.5 minutes.
[00174] INTERMEDIATE 15
[00175] (R)-1-[8-chloro-2-(2-methylpyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethylamine
To a solution of Intermediate 14 (3.5 g, 7.03 mmol) in 1,4-dioxane (8 ml) was added a 4 H solution of HCl in 1,4-dioxane (15 ml). The mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the residue was then partitioned between DCM and a saturated aqueous NaHCO3 solution. The organic extract was dried (MgSO4). The solvent was removed under reduced pressure to give the title compound as a pale yellow gum. LCMS (ES+) 352 (M + H)+, RT 1.36 min.
[00177] INTERMEDIATE 16
2-Methylpropane-2(S)-sulfinic acid N-[8-chloro-2-(5-methylpyridin-3-yl)quinolin-3-yl]-meth-(E)-ylideneamide
[00179] A mixture of Intermediate 9 (2.0 g, 6.08 mmol), 5-methylpyridin-3-ylboronic acid pinacolic ester (1.6 g, 7.31 mmol), tetracis(triphenylphosphine)palladium (0 ) (0.35 g, 0.31 mmol) and a 2 M aqueous solution of sodium bicarbonate (5 ml) in 1,4-dioxane (25 ml) was degassed and heated under reflux in a nitrogen atmosphere for 2 hours . The reaction mixture was cooled to room temperature, partitioned between DCM and brine, and the aqueous layer was extracted once more using EtOAc. The combined organic extracts were dried (MgSO4 ) and the solvent removed under reduced pressure. To a solution of the resulting material in 2-propanol (10 ml) was added a solution prepared by stirring potassium phosphate (1.2 g, 5.66 mmol) and (S)-2-methyl-2-propanesulfinamide (0 .75 g, 6.2 mmol) in water (10 ml) for 15 minutes. The reaction mixture was stirred overnight, then incubated at 60°C for a further 24 hours. DCM was added and washed with brine, the organic extract was dried (MgSO4 ) and the solvent removed in vacuo. Column chromatography (SiO 2 , 50 to 60% EtOAc in hexane) gave the title compound (2.28 g, 97%) as a light yellow foam. H (CDCl 3 ) 8.93 (s, 1H), 8.81 (s, 1H), 8.63 (m, 1H), 7.98 (m, 2H), 7.69 (m, 1 H), 7.61 (m, 1H), 7.50 (m, 1H), 2.54 (s, 3H), 1.31 (s, 9H). LCMS (ES+) 386 (M + H)+, RT 1.56 min.
[00180] INTERMEDIATE 17
[00181] {(R)-1-[8-chloro-2-(5-methylpyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl} 2-methylpropane-2(acid amide) S)-sulfinic
[00182] A solution of Intermediate 16 (2.28 g, 5.91 mmol) and tetrabutylammonium difluorotriphenylsilicate (3.83 g, 7.09 mmol) in anhydrous THF (60 ml) was cooled to -50°C under nitrogen and (trifluoromethyl)-trimethylsilane (2.1 ml, 14.23 mmol) was added dropwise. The mixture was stirred for 2 hours, allowing the temperature to slowly rise to 0°C. The reaction mixture was cooled once more to -10°C, the saturated aqueous solution of ammonium chloride was added and the reaction mixture was added. allowed to warm to room temperature. The reaction mixture was extracted twice using DCM, then the organic extracts were dried (MgSO4 ) and the solvent evaporated in vacuo. The residue was purified by column chromatography (SiO2, 50 to 60% EtOAc in hexane). Crystallization from ether/hexane gave the title compound (1.2 g, 40%) as a white crystalline solid.H (DMSO-d6) 9.00 (s, 1H), 8.65 (d, J 1.5 Hz, 1 H), 8.59 (d, J 2.0 Hz, 1 H), 8.12 (m, 2H), 7.84 (m, 1 H), 7.73 (m , 1H), 6.66 (d, J 8.3 Hz, 1H), 5.04 (m, 1H), 2.45 (s, 3H), 1.16 (s, 9H). LCMS (ES+) 456 (M + H)+, RT 1.55 minutes.
[00183] INTERMEDIATE 18
[00184] (R)-1-[8-chloro-2-(5-methylpyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethylamine
To a solution of Intermediate 17 (1.2 g, 2.63 mmol) in DCM (3 ml) was added a 4 H solution of HCl in 1,4-dioxane (10 ml). The mixture was stirred at room temperature for 20 minutes. The solvent was removed in vacuo and the residue was then partitioned between DCM and a saturated aqueous NaHCO3 solution. The aqueous phase was extracted once more using DCM and the combined organic extracts were dried (MgSO4 ) and evaporated in vacuo to give the title compound (0.9 g, 97%) as a pale yellow gum. LCMS (ES+) 352 (M + H)+, RT 1.41 min.
[00186] INTERMEDIATE 19
[00187] 8-Chloro-2-(pyrazin-2-yl)quinoline-3-carbaldehyde
[00188] A mixture of 2,8-dichloroquinoline-3-carbaldehyde (2.3 g, 10.18 mmol), 2-(tributylstannanyl)pyrazine (4.5 g, 12.2 mmol) and tetrakis-(triphenylphosphine) -palladium (0) (0.4 g, 0.35 mmol) in 1,4-dioxane (25 ml) was degassed and the mixture was heated under nitrogen at 110°C for 5 hours. The mixture was allowed to cool to room temperature overnight and the solidified product was collected by filtration and washed repeatedly with ether. The filtrate was concentrated and left in a refrigerator for 2 hours to give a second crop, which was filtered, washed with ether and combined with the bulk material to give the title compound (2.74 g, 99%) as a crystalline solid. yellow. LCMS (ES+) 270 (M + H)+, RT 1.41 min.
[00189] INTERMEDIATE 20
[00190] 2-methylpropane-2(S)-sulfinic acid N-[8-chloro-2-(pyrazin-2-yl)quinolin-3-yl]meth-(E)-ylideneamide
Titanium(IV) isopropoxide (6.1 ml, 20.62 mmol) was added to a stirred suspension of Intermediate 19 (2.74 g, 10.2 mmol) in anhydrous THF (30 ml). The mixture was stirred at room temperature for 10 minutes, then (S)-2-methyl-2-propanesulfinamide (1.35 g, 11.16 mmol) was added and the mixture was stirred at 50°C for 2 hours. Ice water was added and the mixture was stirred for 10 minutes. The resulting solid was filtered, washed with water and air dried. The solid was placed in a sintered funnel and extracted three times using hot DCM. The DCM extracts were concentrated under reduced pressure to give the title compound (1.1 g, 29%) as a brown gum. H (DMSO-d6) 9.18 (s, 1H), 8.91 (m, 1H), 8.28 (m, 2H), 8.13 (m, 2H), 7.74 (m, 2H), 1.26 (s, 9H).
[00192] LCMS (ES+) 373 (M + H)+, RT 1.58 min.
[00193] INTERMEDIATE 21
[00194] 2-methylpropane-2(S) acid {(R)-1-[8-chloro-2-(pyrazin-2-yl)quinolin-3-yl]-2,2,2-trifluoroethyl}amide -sulfinic
[00195] A mixture of Intermediate 20 (1.1 g, 2.95 mmol) and tetrabutylammonium difluorotriphenylsilicate (1.9 g, 3.52 mmol) in anhydrous THF (25 ml) was stirred at -50°C. ( Trifluoromethyl)trimethylsilane (1.1 ml, 7.45 mmol) was added dropwise and the mixture was stirred for 2 hours, allowing the temperature to rise slowly. The reaction mixture was cooled once more to -20°C, brine was added and the reaction mixture was allowed to warm up within 30 minutes. The reaction mixture was extracted twice using DCM, then the organic extracts were dried (MgSO4 ) and the solvent evaporated in vacuo. The residue was purified by column chromatography (SiO 2 , 50 to 60% EtOAc in hexane) to give the title compound (0.36 g, 28%) as a brown gum. H (DMSO-d6) 9.39 (s, 1H), 8.95 (s, 1H), 8.77 (m, 2H), 8.04 (m, 2H), 7.69 (m, 1H), 6.83 (m, 1H), 6.65 (d, J 9.5Hz, 1H), 1.04 (s, 9H). LCMS (ES+) 403 (M + H)+, RT 1.55 minutes.
[00196] INTERMEDIATE 22
[00197] (R)-1-[8-chloro-2-(pyrazin-2-yl)quinolin-3-yl]-2,2,2-trifluoroethylamine
To a solution of Intermediate 21 (0.36 g, 0.8 mmol) in DCM (2 ml) was added a 4 H solution of HCl in 1,4-dioxane (5 ml). The mixture was stirred at room temperature for 20 minutes. The solvent was removed in vacuo and the residue was then partitioned between DCM and a saturated aqueous NaHCO3 solution. The aqueous phase was extracted with more DCM and the combined organic fractions were dried (MgSO4 ) and evaporated. The residue was purified by column chromatography (SiO 2 , 50% EtOAc in hexane) to give the title compound (0.15 g, 28%) as a brown gum. H (DMSO-d6) 9.36 (d, J 1.4 Hz, 1H), 9.00 (s, 1H), 8.82 (m, 2H), 8.10 (m, 2H), 7.73 (m, 1H), 5.96 (q, J 7.8Hz, 1H), 2.86 (br s, 2H). LCMS (ES+) 339 (M + H)+, RT 1.41 min.
[00199] INTERMEDIATE 23
[00200] 8-Chloro-2-(6-methoxypyrazin-2-yl)quinoline-3-carbaldehyde
[00201] A mixture of 2,8-dichloroquinoline-3-carbaldehyde (0.5 g, 2.21 mmol), 2-methoxy-6-(tributylstannanyl)pyrazine (1.0 g, 2.51 mmol) and tetrakis (triphenylphosphine)palladium (0) (0.2 g, 0.173 mmol) in 1,4-dioxane (10 ml) was degassed and heated at 110°C overnight. The mixture was allowed to cool to room temperature and diluted with EtOAc. The resulting solid was collected by filtration, washed with EtOAc, then ether, and dried to give the title compound (0.42 g, 63%) as a yellow solid.H (DMSO-d6) 10.58 (s, 1 H), 9.24 (s, 1H), 8.93 (s, 1H), 8.53 (s, 1H), 8.27 (dd, J 8.3, 1.2 Hz, 1 H), 8.17 (dd, J 7.5, 1.2 Hz, 1H), 7.75 (m, 1H), 3.96 (s, 3H). LCMS (ES+) 300 (M + H)+, RT 1.51 minutes.
[00202] INTERMEDIATE 24
[00203] 2-Methylpropane-2(S)-sulfinic acid N-[8-chloro-2-(6-methoxypyrazin-2-yl)quinolin-3-yl]-meth-(E)-ylideneamide
Titanium (IV) isopropoxide (0.85 ml, 2.87 mmol) was added to a stirred suspension of Intermediate 23 (0.42 g, 1.4 mmol) in anhydrous THF (10 ml). The mixture was stirred at room temperature for 10 minutes, then (S)-2-methyl-2-propanesulfinamide (0.2 g, 1.65 mmol) was added and the mixture was stirred at 50°C for 8 hours. Ice water was added and the mixture was stirred for 10 minutes, then filtered through Celite. The resulting solid was repeatedly washed with EtOAc. The filtrate was washed with brine, dried (MgSO4 ) and concentrated in vacuo. The crude material was purified by column chromatography (SiO 2 , 25% EtOAc in hexane) to give the title compound (0.5 g, 49%) as a yellowish white solid. H (DMSO-d6) 9.35 (s, 1H), 9.17 (d, J 0.3Hz, 1H), 9.13 (s, 1H), 8.50 (m, 1H) ), 8.29 (dd, J 8.3, 1.2 Hz, 1 H), 8.13 (dd, J 7.5, 1.2 Hz, 1 H), 7.73 (m, 1 H ), 4.00 (s, 3H), 1.26 (s, 9H). LCMS (ES+) 403 (M + H)+, RT 1.69 min.
[00205] INTERMEDIATE 25
[00206] {(R)-1-[8-chloro-2-(6-methoxypyrazin-2-yl)quinolin-3-yl]-2,2,2-trifluoroethyl} 2-methylpropane-2(acid amide) S)-sulfinic
[00207] A solution of Intermediate 24 (0.5 g, 1.24 mmol) and tetrabutylammonium acetate (0.45 g, 1.5 mmol) in anhydrous THF (15 ml) was stirred at -50°C under nitrogen and (trifluoromethyl)trimethylsilane (0.4 ml, 2.71 mmol) was added dropwise. The mixture was stirred for 2 hours, allowing the temperature to slowly rise to room temperature. The reaction mixture was cooled once more to -10°C and quenched with brine. The reaction mixture was allowed to warm to room temperature and extracted twice using EtOAc. The combined organic extracts were dried (MgSO4 ) and the solvent evaporated in vacuo. The residue was purified by column chromatography (SiO 2 , 30 to 50% EtOAc in hexane) to give the title compound (120 mg, 20%) as a pale yellow foam. H (DMSO-d6) 9.07 (d, J 0.2 Hz, 1H), 9.01 (s, 1H), 8.53 (s, 1H), 8.11 (m, 2H) , 7.75 (dd, J 8.1, 7.6 Hz, 1H), 7.07 (m, 1H), 6.80 (d, J 9.3Hz, 1H), 4.06 (s, 3H), 1.08 (s, 9H). LCMS (ES+) 473 (M + H)+, RT 1.62 min.
[00208] INTERMEDIATE 26
2-Methylpropane-2(S)-sulfinic acid N-[8-chloro-2-(6-methylpyridin-3-yl)quinolin-3-yl]-meth-(E)-ylideneamide
[00210] A mixture of Intermediate 9 (3.0 g, 9.1 mmol), 2-methylpyridin-5-ylboronic acid (1.24 g, 9.1 mmol) and tetracis(triphenylphosphine)-palladium (0) ( 0.10 g, 0.1 mmol) in DME (60 ml) was treated with the 2 M aqueous solution of Na 2 CO 3 (11 ml). The reaction mixture was degassed and flushed three times with nitrogen gas, then heated at 90°C for 20 hours. The mixture was allowed to cool to room temperature, and diluted with EtOAc (50 ml). The organic solution was washed with water (50 ml) and brine (50 ml), then dried (MgSO4 ), and evaporated in vacuo. The resulting crude material was then treated with a mixture of titanium (IV) isopropoxide (5.4 ml, 18.0 mmol) and (S)-2-methyl-2-propanesulfinamide (1.21 g, 10.0 mmol) ) in anhydrous THF (50 ml) according to the procedure described for Intermediate 2. The title compound (1.46 g, 41%) was obtained as a yellow gum. H (DMSO-d6) 9.17 (s, 1H), 8.70 (d, J 1.9 Hz, 1H), 8.61 (s, 1H), 8.28 (dd, J 8 .3, 1.1 Hz, 1 H), 8.11 (dd, J 7.5, 1.3 Hz, 1 H), 8.00 (dd, J 7.9, 2.3 Hz, 1 H ), 7.71 (dd, J 8.1, 7.7 Hz, 1H), 7.50 (d, J 8.1 Hz, 1H), 2.60 (s, 3H), 1.22 (s, 9H). LCMS (ES+) 386 (M + H)+, RT 1.65 minutes.
[00211] INTERMEDIATE 27
[00212] {(R)-1-[8-chloro-2-(6-methylpyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl} 2-methylpropane-2(acid amide) S)-sulfinic
[00213] Prepared according to the procedure described for Intermediate 3, using Intermediate 26 (1.46 g, 3.79 mmol), tetrabutylammonium difluorotriphenylsilicate (2.25 g, 4.17 mmol), (trifluoromethyl)trimethylsilane (1.4 ml, 9.47 mmol) and anhydrous THF (40 ml). The title compound (0.94 g, 55%) was obtained as a yellow gum. H (DMSOd6) 9.00 (s, 1H), 8.65 (d, J 1.7Hz, 1H), 8.13 - 8.08 (m, 2H), 7.90 (dd, J 7.9, 2.3 Hz, 1H), 7.72 (dd, J 7.9, 7.9 Hz, 1H), 7.52 (d, J 8.1 Hz, 1H), 6 .64 (d, J 8.5Hz, 1H), 5.14 - 5.03 (m, 1H), 2.62 (s, 3H), 1.15 (s, 9H). LCMS (ES+) 456 (M + H)+, RT 1.70 minutes.
[00214] INTERMEDIATE 28
[00215] (R)-1-[8-Chloro-2-(6-methylpyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl-amine
Prepared according to the procedure described for Intermediate 4, using Intermediate 27 (0.94 g, 2.07 mmol), a 4 H solution of HCl in 1,4-dioxane (3 ml, 12.0 mmol) and methanol (18 ml). The title compound (1.28 g, 84%) was obtained as a colorless gum. H (DMSO-d6) 8.89 (s, 1 H), 8.68 (d, J 1.9 Hz, 1 H), 8.10 (dd, J 8.3, 1.3 Hz, 1 H ), 8.04 (dd, J 7.5, 1.3 Hz, 1 H), 7.93 (dd, J 7.9, 2.4 Hz, 1 H), 7.67 (dd, J 8 .1, 8.1 Hz, 1 H), 7.47 (d, J 7.9 Hz, 1 H), 4.70 (tq, J 7.2, 7.2 Hz, 1 H), 2, 84 (d, J 7.0 Hz, 2H), 2.60 (s, 3H). LCMS (ES+) 352 (M + H)+, RT 1.51 minutes.
[00217] INTERMEDIATE 29
[00218] 4-(Benzotriazol-1-yloxy)pyrido [3,2-d]pyrimidine
[00219] In a reactor, under nitrogen charge, ethylene glycol (2.7 liters) was heated to 45°C. 3-aminopyridine-2-carboxylic acid (1.37 kg) and formamidine acetate (1.37 kg) were added. The mixture was heated to 50°C to facilitate stirring. The mixture was progressively heated to 125 °C (about 1 hour) until the reaction was complete (2 to 3 hours). After cooling the mixture to 50°C, water (7 litres) was added slowly. The suspension was cooled to 20°C and stirred overnight, then cooled to -5°C and stirred for 1 hour. The resulting solid was isolated by filtration. The cake was washed with cold water (1.5 liter) and acetic acid solution (1.5 liter), and dried under vacuum at 55°C, to give a solid (985 g, 67.5%; HPLC purity of 99.25%). A mixture of this material (10 g, 68.0 mmol) and PyBOP (38.9 g, 74.8 mmol) in acetonitrile (250 ml) was treated with DBU (12.2 ml, 81.6 mmol) and stirred by 2.5 hours. The reaction mixture was filtered, and the precipitate was washed with diethyl ether (3 x 50 ml) and dried under vacuum. The title compound (13.51 g, 75%) was obtained as a creamy colorless solid. H (DMSO-d6) 9.28 (dd, J 4.2, 1.6 Hz, 1H), 8.82 (s, 1H), 8.59 (dd, J 8.6, 1.5 Hz, 1H), 8.24 - 8.18 (m, 2H), 7.88 - 7.85 (m, 1H), 7.69 - 7.64 (m, 1H), 7.60 - 7.54 (m, 1H). LCMS (ES+) 265 (M + H)+, RT 1.23 min.
[00220] INTERMEDIATE 30
[00221] 1-(Pyrido[3,2-d]pyrimidin-4-yloxy)pyrrolidine-2,5-dio
A mixture of Intermediate 29 (13.51 g, 51.0 mmol) and N-hydroxysuccimide (8.83 g, 77 mmol) in dichloromethane (350 ml) was stirred for 20 hours. The reaction mixture was filtered, and the filtrate was washed with water, then brine, dried (MgSO4 ), and evaporated in vacuo. The residue was triturated with diethyl ether and the precipitate was dried under vacuum. The title compound (10.9 g, 87%) was obtained as a pale yellow solid. H (DMSO-d6) 9.18 (dd, J 4.1, 1.5 Hz, 1H), 8.94 (s, 1H), 8.52 (dd, J 8.7, 1.7 Hz, 1H), 8.13 (dd, J 8.7, 4.3 Hz, 1H), 2.97 (s, 4H). LCMS (ES+) 245 (M + H)+, RT 0.51 min.
[00223] INTERMEDIATE 31
[00224] N-(o-Tolyl)acetamide
Acetic anhydride (33.0 ml, 350 mmol) was added to a stirred solution of o-toluidine (30.0 g, 280 mmol) in dichloromethane (500 ml) at 0°C. allowed to warm to room temperature and stirred for 20 hours. The reaction mixture was partitioned between DCM and water. The organic phase was washed with brine, then dried (MgSO4 ) and evaporated in vacuo. The residue was stirred in isohexane at 0°C for 2 hours, then filtered. The precipitate was washed with isohexane and dried under vacuum. The title compound (39.87 g, 95%) was obtained as a light pink solid. H(CDCl3) 7.80 - 7.78 (m, 1H), 7.26 - 7.20 (m, 2H), 7.13 - 7.08 (m, 1H), 6.92 (br s, 1H), 2.29 (s, 3H), 2.23 (s, 3H). LCMS (ES+) 150 (M + H)+, RT 0.85 minutes.
[00226] INTERMEDIATE 32
[00227] 2-Chloro-8-methylquinoline-3-carbaldehyde
[00228] N,N-Dimethylformamide (51.8 ml, 668 mmol) was added portionwise in 15 minutes, with stirring, to phosphorus oxychloride (175 ml, 1.87 mol) at 0°C. was allowed to warm to room temperature and treated with Intermediate 31 (39.8 g, 267 mmol), then heated to 80°C and stirred for 72 hours. The reaction mixture was cooled to room temperature, then carefully poured in portions into a vigorously stirred mixture of ice water. The ice water mixture was allowed to warm to room temperature over 30 minutes, then filtered. The precipitate was washed with water and dried under vacuum. The title compound (37.3 g, 68%) was obtained as a creamy colorless solid. H (CDCl 3 ) 10.50 (s, 1H), 8.73 (s, 1H), 7.83 (d, J 8.1 Hz, 1H), 7.76 - 7.72 (m, 1H), 7.55 (dd, J 7.9, 7.3 Hz, 1H), 2.81 (s, 3H). LCMS (ES+) 206 (M + H)+, RT 1.54 minutes.
[00229] INTERMEDIATE 33
[00230] 8-Methyl-2-(pyridin-3-yl)quinoline-3-carbaldehyde
[00231] Prepared according to the procedure described for Intermediate 1, using Intermediate 32 (10 g, 48.7 mmol), Na2CO3 (7.74 g, 73 mmol), 3-pyridylboronic acid (5.98 g, 48.7 mmol) and tetrakis(triphenylphosphine)palladium (0) (2.81 g, 2.43 mmol) in DME (150 ml) and water (40 ml). The title compound (11.36 g, 94%) was obtained as a brown solid. H(CDCl3) 10.20 (s, 1H), 9.02 (dd, J 2.3, 0.8Hz, 1H), 8.86 (s, 1H), 8.80 (dd, J 4.9, 1.7 Hz, 1 H), 8.10 (ddd, J 7.9, 2.3, 1.7 Hz, 1 H), 7.90 (d, J 8.3 Hz, 1H), 7.78 - 7.75 (m, 1H), 7.58 (dd, J 8.1, 7.2 Hz, 1H), 7.53 (ddd, J 7.9, 4 0.9, 0.8 Hz, 1H), 2.88 (s, 3H). LCMS (ES+) 249 (M + H)+, RT 1.41 min.
[00232] INTERMEDIATE 34
2-Methylpropane-2(S)-sulfinic acid N-[8-methyl-2-(pyridin-3-yl)quinolin-3-yl]meth-(E)-ylideneamide
[00234] Prepared according to the procedure described for Intermediate 2, using Intermediate 33 (5 g, 20.2 mmol), titanium (IV) isopropoxide (11.9 ml, 40.3 mmol), (S )-2-methyl-2-propanesulfinamide (2.69 g, 22.0 mmol) and anhydrous THF (60 ml). The title compound (7.8 g, >99 %) was obtained as a brown gum. H (DMSO-d6) 9.08 (s, 1H), 8.85 (dd, J 2.3, 0.8 Hz, 1H), 8.75 (dd, J 4.9, 1.7 Hz, 1H), 8.62 (s, 1H), 8.11 - 8.07 (m, 2H), 7.82 - 7.78 (m, 1H), 7.65 - 7.59 (m, 2H), 2.76 (s, 3H), 1.20 (s, 9H). LCMS (ES+) 352 (M + H)+, RT 1.58 min.
[00235] INTERMEDIATE 35
[00236] 2-Methylpropane-2(S)-sulfinic acid {(R)-1-[8-methyl-2-(pyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethylamide
[00237] Prepared according to the procedure described for Intermediate 3, using Intermediate 34 (7.8 g, 22.2 mmol), tetrabutylammonium difluoro-triphenylsilicate (13.2 g, 24.4 mmol), (trifluoromethyl) )-trimethylsilane (3.9 ml, 26.7 mmol) and anhydrous THF (150 ml). The title compound (5.34 g, 57%) was obtained as a yellow gum. H (DMSOd6) 8.89 (s, 1H), 8.80 - 8.77 (m, 2H), 8.03 (ddd, J 7.7, 1.9, 1.9 Hz, 1H) , 7.94 (d, J 7.7Hz, 1H), 7.78 - 7.75 (m, 1H), 7.68 - 7.61 (m, 2H), 6.62 (d, J 8.5 Hz, 1H), 5.05 (dq, J 7.9, 7.9 Hz, 1H), 3.17 (s, 3H), 1.15 (s, 9H). LCMS (ES+) 422 (M + H)+, RT 1.56 minutes.
[00238] INTERMEDIATE 36
[00239] (R)-1-[8-Methyl-2-(pyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethylamine
[00240] Prepared according to the procedure described for Intermediate 4, using Intermediate 35 (1.0 g, 2.4 mmol), a 4 H solution of HCl in 1,4-dioxane (3.5 ml, 14 0.0mmol) and methanol (18 ml). The title compound (611 g, 81%) was obtained as a yellow gum. H (DMSO-d6) 8.83 - 8.82 (m, 1H), 8.77 (s, 1H), 8.73 (dd, J 4.7, 1.5Hz, 1H), 8.04 (ddd, J 7.7, 2.1, 2.1 Hz, 1 H), 7.92 (d, J 7.9 Hz, 1 H), 7.72 - 7.69 (m, 1H), 7.62 - 7.56 (m, 2H), 4.74 - 4.61 (m, 1H), 2.82 (d, J 7.0 Hz, 2H), 2.70 ( s, 3H). LCMS (ES+) 318 (M + H)+, RT 1.41 min.
[00241] INTERMEDIATE 37
[00242] 7-Fluoro-8-methyl-2-(pyridin-3-yl)quinoline-3-carbaldehyde
[00243] Prepared according to the procedure described for Intermediate 1, using 2-chloro-7-fluoro-8-methylquinoline-3-carbaldehyde (5.0 g, 22.36 mmol), 3-pyridylboronic acid (3 .02 g, 24.6 mmol), tetrakis(triphenylphosphine)palladium (0) (127 mg, 0.11 mmol) and Na2CO3 (3.55 g, 33.54 mmol) in water (30 ml) and DME (60 ml). The title compound (5.52 g, 93%) was obtained as a beige solid. H (DMSO-d6) 10.13 (s, 1 H), 9.08 (s, 1 H), 8.95 (dd, J 2.3, 0.8 Hz, 1 H), 8.75 ( dd, J 4.9, 1.7 Hz, 1H), 8.24 (dd, J 9.0, 6.4Hz, 1H), 8.16 - 8.21 (m, 1H), 7.68 (t, J 9.2 Hz, 1 H), 7.61 (ddd, J 7.9, 4.0, 0.8 Hz, 1 H), 2.66 (d, J 2.4 Hz, 3H). LCMS (ES+) 267 (M + H)+, RT 2.16 min.
[00244] INTERMEDIATE 38
[00245] 2-Methylpropane-2(S)-sulfinic acid N-[7-fluoro-8-methyl-2-(pyridin-3-yl)quinolin-3-yl]-meth-(E)-ylideneamide
[00246] Prepared according to the procedure described for Intermediate 2, using Intermediate 37 (4.52 g, 16.99 mmol), titanium(IV) isopropoxide (9.66 g, 33.98 mmol), (S)-2-methyl-2-propanesulfinamide (2.27 g, 18.69 mmol) and anhydrous THF (90 ml). The crude material was triturated in diethyl ether (20 ml), and the solid was filtered off and dried in vacuo to give the title compound (4.37 g, 70%) as a beige solid. H (DMSO-d6) 9.14 (s, 1H), 8.85 (d, J 1.7Hz, 1H), 8.76 (dd, J4.9, 1.5Hz, 1H ), 8.60 (s, 1H), 8.23 (dd, J 9.4, 7.0Hz, 1H), 8.10 (dt, J7.9, 1.9Hz, 1H ), 7.59 - 7.71 (m, 2H), 2.65 (d, J 2.3 Hz, 3H), 1.21 (s, 9H). LCMS (ES+) 370 (M + H)+, RT 1.62 min.
[00247] INTERMEDIATE 39
[00248] {(R)-1-[7-fluoro-8-methyl-2-(pyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl} 2-methylpropane- acid amide 2(S)-sulfinic
[00249] A mixture of Intermediate 38 (4.37 g, 11.83 mmol) and tetrabutylammonium difluorotriphenylsilicate (7.02 g, 13.01 mmol) in anhydrous THF (100 ml) was cooled to -50°C. (trifluoromethyl)trimethylsilane (2.02 g, 14.2 mmol) was added and the mixture was stirred at -50°C for 2.5 hours. Saturated aqueous ammonium chloride solution (15 ml) was added and the reaction mixture was allowed to warm to room temperature. The solvent was removed in vacuo and the residue was partitioned between DCM (100 ml) and water (100 ml). The organic phase was washed with brine (100 ml), dried (phase separator) and evaporated in vacuo. The residue was purified by column chromatography (SiO 2 , 35100% EtOAc in hexane) to give the title compound (3.14 g, 60%) as a white foam. H (DMSO-d6) 8.94 (s, 1H), 8.77 - 8.81 (m, 2H), 8.00 - 8.09 (m, 2H), 7.62 - 7.70 ( m, 2H), 6.62 (d, J 8.5 Hz, 1H), 5.05 (quint, J 8.1 Hz, 1H), 2.60 (d, J 2.3 Hz, 3H ), 1.15 (s, 9H). LCMS (ES+) 400 (M + H)+, RT 2.56 minutes.
[00250] INTERMEDIATE 40
[00251] (R)-1-[7-Fluoro-8-methyl-2-(pyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl-amine
[00252] Prepared according to the procedure described for Intermediate 4, using Intermediate 39 (3.14 g, 7.15 mmol), a 4 H solution of HCl in 1,4-dioxane (6 ml, 24.0 mmol) and methanol (30 ml). The title compound (2.40 g, quantitative) was obtained as a yellow oil. H (DMSO-d6) 8.82 - 8.85 (m, 2H), 8.74 (dd, J 4.9, 1.7 Hz, 1H), 8.00 - 8.08 (m, 2H) ), 7.57 - 7.64 (m, 2H), 4.69 (q, J 7.7 Hz, 1H), 2.79 - 2.97 (m, 2H), 2.60 (d, J 2.4 Hz, 3H). LCMS (ES+) 336 (M + H)+, RT 2.20 minutes.
[00253] INTERMEDIATE 41
[00254] 7-Fluoro-8-methyl-2-(2-methylpyridin-3-yl)quinoline-3-carbaldehyde
A mixture of 2-chloro-7-fluoro-8-methylquinoline-3-carbaldehyde pinacolic ester (8.0 g, 35.77 mmol), 2-methylpyridin-3-yl-boronic acid (9.58) g, 39.35 mmol), tetrakis(triphenylphosphine)palladium (0) (207 mg, 18 mmol) and Na 2 CO 3 (5.69 g, 53.66 mmol) in water (50 ml) and DME (100 ml) was degassed and flushed three times with nitrogen gas, then heated to 90°C for 24 hours. The mixture was allowed to cool to room temperature. The reaction mixture was diluted with DCM (150 ml) and washed with water (150 ml). The aqueous phase was extracted with DCM (2 x 100 ml) and the combined organic fractions were washed with brine (150 ml), then dried (phase separator) and evaporated in vacuo. The crude material was triturated in hexane (50ml), then the solid was filtered off and dried in vacuo to give the title compound (9.07g, 90%) as a pale yellow solid. H (DMSO-d6) 9.94 (s, 1 H), 9.09 (1 H, s), 8.61 (dd, J 4.9, 1.7 Hz, 1 H), 8.26 ( dd, J 8.9, 6.4 Hz, 1 H), 7.78 (dd, J 7.7, 1.7 Hz, 1 H), 7.69 (t, J 9.2 Hz, 1 H ), 7.40 (dd, J 7.7, 4.9 Hz, 1H), 2.61 (d, J 2.4 Hz, 3H), 2.34 (s, 3H). LCMS (ES+) 281 (M + H)+, RT 2.26 min.
[00256] INTERMEDIATE 42
[00257] N-[7-fluoro-8-methyl-2-(2-methylpyridin-3-yl)-quinolin-3-yl]-met-(E)-ylidene-amidated 2-methylpropane-2(S) acid )-sulfinic
[00258] Prepared according to the procedure described for Intermediate 2, using Intermediate 41 (5.0 g, 17.84 mmol), titanium (IV) isopropoxide (10.14 g, 35.68 mmol), (S)-2-methyl-2-propanesulfinamide (2.38 g, 19.63 mmol) and anhydrous THF (100 ml). The crude material was triturated in diethyl ether (20 ml), and the solid was filtered off and dried in vacuo to give the title compound (5.14 g, 75%) as a pale yellow solid. H (DMSO-d6) 9.16 (s, 1H), 8.61 (dd, J 4.9, 1.7 Hz, 1H), 8.37 (s, 1H), 8.22 ( dd, J 8.9, 6.4 Hz, 1 H), 7.74 (dd, J 7.7, 1.7 Hz, 1 H), 7.67 (t, J 9.0 Hz, 1 H ), 7.40 (dd, J 7.5, 4.9 Hz, 1H), 2.60 (d, J 2.4 Hz, 3H), 2.29 (s, 3H), 1.11 ( s, 9H). LCMS (ES+) 384 (M + H)+, RT 2.59 min.
[00259] INTERMEDIATE 43
[00260] {(R)-1-[7-fluoro-8-methyl-2-(2-methylpyridin-3-yl)-quinolin-3-yl]-2,2,2-tri-fluoroethyl}amide 2-methylpropane-2(S)-sulfinic acid
[00261] Prepared according to the procedure described for Intermediate 39, using Intermediate 42 (5.13 g, 13.38 mmol), tetrabutylammonium difluorotriphenylsilicate (7.95 g, 14.72 mmol), (trifluoro-methyl) )trimethylsilane (4.56 g, 32.12 mmol) and anhydrous THF (100 ml). The title compound (2.64 g, 43%) was obtained as a yellowish white foam. H (DMSO-d6, 400 MHz, 110°C) 8.90 (s, 1 H), 8.63 (dd, J 4.8, 1.5 Hz, 1 H), 8.00 (dd, J 9.1, 6.3 Hz, 1 H), 7.65 - 7.76 (m, 1 H), 7.58 (t, J 9.3 Hz, 1 H), 7.40 (dd, J 7.6, 5.1 Hz, 1H), 6.00 - 6.11 (m, 1H), 4.74 - 4.87 (m, 1H), 2.59 (d, J 2, 5Hz, 3H), 2.32 (s, 3H), 1.18 (s, 9H). LCMS (ES+) 454 (M + H)+, RT 2.55 minutes.
[00262] INTERMEDIATE 40
[00263] (R)-1-[7-Fluoro-8-methyl-2-(2-methylpyridin-3-yl)quinolin-3-yl]-2,2,2-tri-fluoroethyl-amine
To a solution of Intermediate 43 (2.64 g, 5.82 mmol) in methanol (25 ml) was added a 4 H solution of HCl in 1,4-dioxane (5.0 ml, 20.0 mmol) ). The mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue dissolved in water (10 ml) and washed with DCM (3 x 10 ml). The aqueous phase was then basified with 10% aqueous NaOH solution (10 ml) and extracted with DCM (4 x 25 ml). The combined organic fractions were then dried (phase separator) and evaporated in vacuo to give the title compound (1.76 g, 87%) as a pale yellow solid. H (DMSO-d6, 400 MHz, 110°C) 8.75 (s, 1H), 8.60 (dd, J 4.8, 1.8 Hz, 1H), 7.99 (dd, J 8.8, 6.1Hz, 1H), 7.67 - 7.71 (m, 1H), 7.53 (t, J 9.3Hz, 1H), 7.34 - 7.39 (m, 1H), 4.34 - 4.46 (m, 1H), 2.60 (d, J 2.5Hz, 3H), 2.31 (s, 3H). LCMS (ES+) 350 (M + H)+, RT 2.22 minutes.
[00265] INTERMEDIATE 45
[00266] 7-Fluoro-8-methyl-2-(5-methylpyridin-3-yl)quinoline-3-carbaldehyde
[00267] Prepared according to the procedure described for Intermediate 41, using 2-chloro-7-fluoro-8-methylquinoline-3-carbaldehyde (5.0 g, 22.36 mmol), 5-methylpyridin-3-ylboronic acid (6.95 g, 50.75 mmol), tetrakis(triphenylphosphine)palladium (0) (258 mg, 0.22 mmol) and Na2CO3 (3.55 g, 33.54 mmol) in water (30 ml) and DME (60 ml). The crude material was triturated in diethyl ether (75 ml), and the solid was filtered off and dried in vacuo to give the title compound (5.0 g, 80%) as a brown solid. H (DMSO-d6) 10.12 (s, 1 H), 9.06 (s, 1 H), 8.72 (d, J 1.9 Hz, 1 H), 8.60 (d, J 1 .5Hz, 1H), 8.24 (dd, J 9.0, 6.4Hz, 1H), 7.99 (d, J 0.6Hz, 1H), 7.68 (t, J 9.2 Hz, 1H), 2.66 (d, J 2.4 Hz, 3H), 2.40 (s, 3H). LCMS (ES+) 281 (M + H)+, RT 1.66 min.
[00268] INTERMEDIATE 46
[00269] 2-Methylpropane-2(S acid) N-[7-fluoro-8-methyl-2-(5-methylpyridin-3-yl)-quinolin-3-yl]meth-(E)-ylidene-amide )-sulfinic
[00270] Prepared according to the procedure described for Intermediate 2, using Intermediate 45 (4.99 g, 17.80 mmol), titanium (IV) isopropoxide (10.12 g, 35.60 mmol), (S)-2-methyl-2-propanesulfinamide (2.38 g, 19.6 mmol) and anhydrous THF (100 ml). The title compound (5.63 g, 82%) was obtained as a dark brown solid. H (DMSO-d6) 9.13 (s, 1H), 8.62 (dd, J 7.7, 1.9 Hz, 2H), 8.59 (s, 1H), 8.22 (dd , J 9.0, 6.4 Hz, 1 H), 7.88 - 7.91 (m, 1 H), 7.65 (t, J 9.2 Hz, 1 H), 2.65 (d , J 2.4Hz, 3H), 2.42 (s, 3H), 1.21 (s, 9H). LCMS (ES+) 384 (M + H)+, RT 2.76 min.
[00271] INTERMEDIATE 47
[00272] {(R)-1-[7-fluoro-8-methyl-2-(5-methylpyridin-3-yl)-quinolin-3-yl]-2,2,2-tri-fluoroethyl} amide 2-methylpropane-2(S)-sulfinic acid
[00273] Prepared according to the procedure described for Intermediate 39, using Intermediate 46 (5.63 g, 14.68 mmol), tetrabutylammonium difluorotriphenylsilicate (8.72 g, 16.15 mmol), (trifluoro-methyl) )trimethylsilane (10.04 g, 70.60 mmol) and anhydrous THF (100 ml). The title compound (3.48 g, 52%) was obtained as a beige solid. H (DMSO-d6) 8.91 (s, 1H), 8.58 - 8.68 (m, 2H), 8.05 (dd, J 9.0, 6.4Hz, 1H), 7 .83 - 7.87 (m, 1 H), 7.65 (t, J 9.2 Hz, 1 H), 6.62 (d, J 8.3 Hz, 1 H), 4.97 - 5 .10 (m, 1H), 2.60 (d, J 2.4Hz, 3H), 2.40 (s, 3H), 1.17 (s, 9H). LCMS (ES+) 454 (M + H)+, RT 2.66 minutes.
[00274] INTERMEDIATE 48
[00275] (R)-1-[7-fluoro-8-methyl-2-(5-methylpyridin-3-yl)quinolin-3-yl]-2,2,2-tri-fluoroethyl-amine
[00276] Prepared according to the procedure described for Intermediate 40, using Intermediate 47 (3.42 g, 7.54 mmol), a 4 H solution of HCl in 1,4-dioxane (5.0 ml, 20 0.0mmol) and methanol (25ml). The title compound (2.41 g, 92%) was obtained as a pale yellow solid. H (DMSO-d6) 8.82 (s, 1 H), 8.60 (d, J 1.9 Hz, 1 H), 8.57 (dd, J 2.1, 0.6 Hz, 1 H ), 8.02 (dd, J 8.9, 6.2 Hz, 1 H), 7.85 (td, J 2.1, 0.6 Hz, 1 H), 7.59 (t, J 9 .2Hz, 1H), 4.60 - 4.75 (m, 1H), 2.80 (d, J 7.0Hz, 2H), 2.59 (d, J 2.4Hz, 3H ), 2.43 (s, 3H). LCMS (ES+) 350 (M + H)+, RT 2.39 min.
[00277] INTERMEDIATE 49
[00278] 2-Amino-3-(trifluoromethyl)benzaldehyde
[00279] Manganese dioxide (27 g, 0.32 mol) was added to a solution of the [2-amino-3-(trifluoromethyl)phenyl]methanol (12.0 g, 0.063 mol) in DCM (150 ml) and the mixture was stirred for 18 hours at room temperature. After this time, more manganese dioxide (27 g, 0.32 mol) was added, and the reaction mixture was left for a further 18 hours. The reaction mixture was filtered through Celite, then the solvent was removed in vacuo to yield the title compound (9.5 g, 80%) as an orange oil. H (DMSO-d6) 9.93 (s, 1H), 7.68 (m, 2H), 6.82 (m, 3H).
[00280] INTERMEDIATE 50
[00281] 2-(Pyridin-3-yl)-8-(trifluoromethyl)-1,2-dihydroquinoline-3-carbaldehyde
2,5-Dimethylpyrrolidine hydrochloride (100 mg) was added to a solution of Intermediate 49 (4.1 g, 0.022 mol) and 3-(pyridin-3-yl)-acrolein (2.9 g, 0.022 mol) in chloroform (100 ml). The reaction mixture was heated to reflux, with stirring, for 7 days. The reaction mixture was concentrated in vacuo before purification by column chromatography (SiO 2 , 10 to 100% EtOAc/DCM) to yield the title compound (3.4 g, 51%) as a pale brown oil. . LCMS (ES+) 301.2 (M + H)+, RT 1.29 minutes.
[00283] INTERMEDIATE 51
[00284] 2-(Pyridin-3-yl)-8-(trifluoromethyl)quinoline-3-carbaldehyde
[00285] Manganese dioxide (4.8 g, 0.056 mol) was added to a solution of Intermediate 50 (3.4 g, 0.011 mol) in chloroform (100 ml) and the reaction mixture was stirred for 18 hours. More manganese dioxide (2.0 g) was added, and the mixture was stirred for a further 2 hours. The reaction mixture was then filtered through Celite, washed with THF. The filtrate was dried (Na 2 SO 4 ) and concentrated in vacuo, and was then purified by column chromatography (SiO 2 , diethyl ether) to yield the title compound (505 mg, 15%) as an organic solid. LCMS (ES+) 303.2 (M + H)+, RT 1.29 minutes.
[00286] INTERMEDIATE 52
[00287] 2-Methylpropane-2(S)-sulfinic acid N-[2-(pyridin-3-yl)-8-(trifluoromethyl)quinolin-3-yl]-meth-(E)-ylideneamide
[00288] Titanium(IV) isopropoxide (909 mg, 3.2 mmol) was added to a solution of Intermediate 51 (485 mg, 1.60 mmol) in anhydrous THF (30 ml). The mixture was stirred at room temperature for 10 minutes. (S)-2-Methyl-2-propanesulfinamide (213 mg, 1.76 mmol) was added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then poured into brine (50 ml) and filtered through Celite, washed with EtOAc. The filtrate was washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography (SiO 2 , 40 to 100% EtOAc in hexane) gave the title compound (395 mg, 61 %). LCMS (ES+) 406 (M + H)+, RT 1.64 min.
[00289] INTERMEDIATE 53
[00290] {(R)-1-[2-(pyridin-3-yl)-8-(trifluoromethyl)quinolin3-yl]-2,2,2-trifluoroethyl} 2-methylpropane-2(S) acid amide -sulfinic
[00291] A mixture of Intermediate 52 (320 mg, 0.79 mmol) and tetrabutylammonium difluorotriphenylsilicate (405 mg, 0.75 mmol) in anhydrous THF (20 ml) was cooled to -78°C. (Trifluoromethyl)trimethylsilane ( 123 mg, 0.87 mmol) was added, and the mixture was allowed to warm to -35°C and stirred for 30 minutes at this temperature. More (trifluoromethyl)trimethylsilane (123 mg, 0.87 mmol) was added and the mixture was stirred for a further 2 hours with the temperature kept below -35°C. A saturated aqueous solution of ammonium chloride (5 ml) was then added and the reaction mixture was allowed to warm to room temperature. The solvent was removed in vacuo and the residue was partitioned between EtOAc and water. The aqueous phase was extracted with more EtOAc and the combined organic fractions were washed with brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography (SiO 2 , 10100% EtOAc in DCM) to give the title compound (270 mg, 72%) as a yellow gum. LCMS (ES+) 476 (M + H)+, RT 1.70 minutes.
[00292] INTERMEDIATE 54
[00293] (R)-1-[2-(pyridin-3-yl)-8-(trifluoromethyl)quinolin-3-yl]-2,2,2-trifluoroethyl-amine
[00294] To a solution of Intermediate 53 (243 mg, 0.51 mmol) in methanol (20 ml) was added a 4 H solution of HCl in 1,4-dioxane (4 ml, 16.0 mmol). The mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the residue was then partitioned between DCM and saturated aqueous NaHCO3 solution and evaporated in vacuo to give the title compound (180mg, 95%) as a pale yellow gum. LCMS (ES+) 372.2 (M + H)+, RT 1.56 min.
[00295] INTERMEDIATE 55
2-[(hydroxy-6-methylpyridin-3-yl)acrylic acid ethyl ester
[00297] To a solution of the 6-methylpyridine-3-carbaldehyde (5.0 g, 41 mmol) in ethyl acrylate (10 ml) at room temperature was added DABCO (1.0 g, 9 mmol), and the mixture was stirred overnight. The reaction mixture was concentrated in vacuo and the residue purified by column chromatography (SiO 2 , 40% hexane, ethyl acetate) to give the title compound (5.6 g, 62%) as a yellow oil. LCMS (ES+) 222.2 (M + H)+, RT 0.98 min.
[00298] INTERMEDIATE 56
[00299] 2-(6-Methylpyridin-3-yl)-5,6,8-trifluoro-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester
To a solution of Intermediate 55 (4.2 g, 19.09 mmol), 2,4,5-trifluoro-6-bromoaniline (4.3 g, 19.09 mmol) and tri(o-tolyl) phosphine (590 mg, 10 mol%) in propionitrile (50 ml) was added triethylamine (9.6 ml, 60 mmol). The reaction mixture was degassed and purged with nitrogen gas before addition of palladium(II) acetate (215 mg, 5 mol%). The reaction mixture was heated at 100°C overnight. The reaction mixture was diluted with ethyl acetate and the organic phase was washed twice with water. The organic phase was passed through a phase separator and concentrated. the resulting brown gum was purified using column chromatography (SiO 2 , EtOAc/hexane gradient, 40 to 80% EtOAc) to give the title compound (3 g, 45%) as an orange oil. LCMS pH 10 (ES+) 349 (M + H)+, RT 1.40 minutes.
[00301] INTERMEDIATE 57
[00302] 2-(6-Methylpyridin-3-yl)-5,6,8-trifluoroquinoline-3-carboxylic acid ethyl ester
To a solution of Intermediate 56 (2.8 g, 8.02 mmol) in DCM was added manganese dioxide (2.8 g, 28.73 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated to give the title compound (2.8 g, 100%) as a yellow solid. LCMS pH 10 (ES+) 347 (M + H)+, RT 1.38 minutes.
[00304] INTERMEDIATE 58
[00305] [2-(6-Methylpyridin-3-yl)-5,6,8-trifluoroquinolin-3-yl]methanol
To a solution of Intermediate 57 (2.8 g, 8.1 mmol) in toluene at -78°C was added DIBAL-H in 20 minutes. The resulting solution was stirred at -78°C for 60 minutes. The reaction was quenched with 2M NaOH and the resulting solid was removed by filtration. The filtrate was partitioned between EtOAc and water and the aqueous phase was extracted with EtOAc. The combined organic phases were dried, filtered and evaporated to give the title compound (2.5 g, 97%) as a yellowish white solid. LCMS (ES+) 305 (M + H)+.
[00307] INTERMEDIATE 59
[00308] 2-(6-Methylpyridin-3-yl)-5,6,8-trifluoroquinoline-3-carbaldehyde
A mixture of Intermediate 58 (2.5 g, 8.2 mmol) and manganese dioxide (3.5 g, 41 mmol) in dichloromethane was stirred at room temperature for 20 hours. The reaction mixture was filtered through celite and the resulting yellow solution was concentrated to give the title compound (1.1 g, 40%) as a yellow solid. LCMS (ES+) 303 (M + H)+.
[00310] INTERMEDIATE 60
[00311] 2-methylpropane-2(S)-sulfinic acid N-[2-(6-methylpyridin-3-yl)-5,6,8-trifluoroquinolin3-yl]meth-(E)-ylideneamide
Titanium(IV) isopropoxide (2.1 g, 7.2 mmol) was added to a suspension of Intermediate 59 (1.1 g, 3.6 mmol) in anhydrous THF (30 ml). The mixture was stirred at room temperature for 10 minutes. (S)-2-Methyl-2-propanesulfinamide (480 mg, 3.9 mmol) was added and the mixture was stirred at 60°C for 1 hour. The reaction mixture was concentrated and the residue was purified by column chromatography (SiO 2 , 40 to 80% EtOAc in hexane) to give the title compound (1.1 g) as a brown solid. LCMS (ES+) 406 (M + H)+, RT 1.526 minutes.
[00313] INTERMEDIATE 61
[00314] {(R)-1-[2-(6-methylpyridin-3-yl)-5,6,8-trifluoroquinolin-3-yl]-2,2,2-trifluoro-ethyl} acid 2 amide -methylpropane-2(S)-sulfinic
A mixture of Intermediate 60 (2.24 g, 6.03 mmol) and tetrabutylammonium difluorotriphenylsilicate (3.58 g, 6.64 mmol) in anhydrous THF (40 ml) was cooled to -40°C. (trifluoromethyl)trimethylsilane (1.03 g, 7.24 mmol) was added and the mixture was stirred at -40°C for 1 hour. Saturated aqueous ammonium chloride solution (5 ml) was added and the reaction mixture was allowed to warm to room temperature. The solvent was removed in vacuo and the residue was partitioned between EtOAc and water. The aqueous phase was extracted with more EtOAc and the combined organic fractions were washed with brine, then dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography (SiO 2 , 40 to 100% EtOAc in hexane) to give the title compound (1.78 g, 67%) as a yellow gum. LCMS (ES+) 476 (M + H)+, RT 1.509 minutes.
[00316] INTERMEDIATE 62
[00317] (R)-1-[2-(6-Methylpyridin-3-yl)-5,6,8-trifluoroquinolin-3-yl]-2,2,2-trifluoro-ethylamine
To a solution of Intermediate 61 (400mg, 0.84mmol) in methanol (10ml) was added a 4H solution of HCl in 1,4-dioxane (10ml). The mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the residue was then partitioned between DCM and a saturated aqueous NaHCO3 solution. The aqueous phase was extracted with DCM then dried (Na 2 SO 4 ) and evaporated in vacuo to give the title compound (160 mg) as a yellow solid. LCMS (ES+) 372 (M + H)+, RT 1.394 minutes.
[00319] INTERMEDIATE 63
[00320] 2-Acid N-[8-chloro-2-(pyridin-3-yl)-quinolin-3-yl]meth-(E)-ylideneamide Methylpropane-2(R)-sulfinic
Titanium(IV) isopropoxide (3.6 g, 12.6 mmol) was added to a suspension of Intermediate 1 (1.7 g, 6.33 mmol) in anhydrous THF (20 ml). The mixture was stirred at room temperature for 10 minutes. (R)-2-Methyl-2-propanesulfinamide (0.84 g, 6.96 mmol) was added and the mixture was stirred at 50°C for 3 hours. The reaction mixture was allowed to cool to room temperature then poured into brine (50ml) and filtered through Celite, washed with EtOAc. The filtrate was washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography (SiO 2 from 30 to 100% EtOAc in hexane) gave the title compound (1.88 g, 91%) as a brown solid. H (DMSO-d6) 9.20 (s, 1H), 8.85 (d, J 1.7Hz, 1H), 8.77 (dd, J4.9, 1.7Hz, 1H ), 8.61 (s, 1H), 8.29 (dd, J 8.3, 1.1Hz, 1H), 8.13 (dd, J7.5, 1.3Hz, 1H ), 8.12 - 8.08 (m, 1H), 7.72 (dd, J 8.1, 7.7 Hz, 1H), 7.64 (ddd, J 7.7, 4.9 , 0.8 Hz, 1H), 1.21 (s, 9H). LCMS (ES+) 372 (M + H)+, RT 2.30 minutes.
[00322] INTERMEDIATE 64
[00323] 2-Methylpropane-2(R) acid {(S)-1-[8-chloro-2-(pyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl}amide -sulfinic
A mixture of Intermediate 63 (0.69 g, 1.86 mmol) and tetrabutylammonium difluorotriphenylsilicate (1.1 g, 2.04 mmol) in anhydrous THF (20 ml) was cooled to -78°C. Trifluoromethyl)trimethylsilane (0.32 g, 2.23 mmol) was added and the mixture stirred at -78°C at room temperature for 4 hours. A saturated aqueous solution of ammonium chloride (5 ml) was added. The mixture was partitioned between EtOAc and water. The aqueous phase was extracted with more EtOAc and the combined organic fractions were washed with brine, then dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography (SiO 2 , 65 to 90% EtOAc in hexane) and then a second column (SiO 2 , 20 to 80% EtOAc in hexane) to give the title compound (0.42 g, 51 %) as a light brown gum.
[00325] H (DMSO-d6) 9.02 (s, 1H), 8.80 (dd, J 4.9, 1.7 Hz, 1H), 8.78 (dd, J 2.3, 0.6Hz, 1H), 8.15 - 8.09 (m, 2H), 8.04 - 7.99 (m, 1H), 7.77 - 7.71 (m, 1H), 7.67 (ddd, J 7.9, 4.9, 0.8 Hz, 1 H), 6.65 (d, J 8.5 Hz, 1 H), 5.12 - 5.00 (m, 1H), 1.15(s, 9H). LCMS (ES+) 402 (M + H)+, RT 2.37 minutes.
[00326] INTERMEDIATE 65
[00327] (5)-1-[8-chloro-2-(pyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethylamine
To a solution of Intermediate 64 (0.42 g, 0.952 mmol) in methanol (10 ml) was added a 4 H solution of HCl in 1,4-dioxane (1 ml, 4.0 mmol). The mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the residue triturated with diethyl ether (x 2). The residue was then partitioned between DCM and a saturated aqueous NaHCO3 solution. The aqueous phase was extracted with more DCM and the combined organic fractions were washed with brine, then dried (Na 2 SO 4 ) and evaporated in vacuo to give the title compound (0.184 g, 57%) as a yellow gum. LCMS (ES+) 338 (M + H)+, RT 1.52 min.
[00329] INTERMEDIATE 66
[00330] N-{(S)-1-[8-Chloro-2-(pyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl} acetamide
A solution of Intermediate 65 (0.50 g, 1.48 mmol) in acetic acid (10 ml) was heated at 60°C for 16 hours. The solvent was removed in vacuo and the residue partitioned between DCM and saturated aqueous NaHCO3 solution. The aqueous phase was extracted with more DCM and the combined organic fractions were washed with brine, then dried (Na 2 SO 4 ) and evaporated in vacuo to give the title compound (0.55 g, 98%) as a yellow gum. LCMS (ES+) 380.2 (M + H)+, RT 1.27 minutes.
[00332] INTERMEDIATE 67
[00333] N-{(S)-1-[8-Chloro-2-(1-oxypyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl}acetamide
A stirred solution of Intermediate 66 (550mg, 1.45mmol) in DCM (30ml) was cooled to 0°C MCPBA (650mg, 2.90mmol) was added and the mixture was allowed to warm slowly into room temperature in 3 hours. The reaction mixture was partitioned between DCM and a saturated aqueous NaHCO3 solution. The aqueous phase was extracted with more DCM and the combined organic fractions were washed with brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography (SiO 2 0 to 15% MeOH in EtOAc) to give the title compound (506 mg, 88%) as a colorless gum. LCMS (ES+) 396 (M + H)+, RT 1.75 minutes.
[00335] INTERMEDIATE 68
[00336] (S)-1-[8-Chloro-2-(1-oxypyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethylamine
[00337] A mixture of Intermediate 67 (0.506 g, 1.28 mmol), and conc. (5 ml) in water (5 ml) and ethanol (10 ml) was heated at 70°C for 40 hours. The solvent was removed in vacuo and the residue was partitioned between DCM and saturated aqueous NaHCO3 solution. The aqueous phase was extracted with more DCM and the combined organic fractions were washed with brine, then dried (Na 2 SO 4 ) and evaporated in vacuo to give the title compound (0.340 g, 76%) as a brown solid. LCMS (ES+) 354.0 (M + H)+, RT 1.41 min.
[00338] INTERMEDIATE 69
[00339] 2-(Pyridin-3-yl)quinoline-3-carbaldehyde
A mixture of 2-chloroquinoline-3-carbaldehyde (5.0 g, 26.1 mmol), Na2CO3 (4.15 g, 39.1 mmol) and diethyl(3-pyridyl)borane (4.22 g , 28.7 mmol) in DME (100 ml) and the water (30 ml) was degassed by bubbling nitrogen gas through it for 5 minutes. Tetracis(triphenylphosphine)palladium (0) (0.30 g, 0.261 mmol) was added and the mixture was heated at 90°C for 5 hours. The mixture was allowed to cool to room temperature. The resulting precipitate was filtered off and washed with water (5 x 50 ml) and diethyl ether (5 x 50 ml) to give the title compound (4.3 g, 70%) as a pale green solid. LCMS (ES+) 235 (M + H)+, RT 1.53 min.
[00341] INTERMEDIATE 70
2-Methyl-propane-2(S)-sulfinic acid N-[2-(pyridin-3-yl)quinolin-3-yl]meth-(E)-ylideneamide
Titanium (IV) isopropoxide (6.07 g, 21.4 mmol) was added to a suspension of Intermediate 69 (2.5 g, 10.7 mmol) in anhydrous THF (80 ml). The mixture was stirred at room temperature for 10 minutes. (S)-2-Methyl-2-propanesulfinamide (1.42 g, 11.7 mmol) was added and the mixture was stirred at 50°C for 3 hours. The reaction mixture was allowed to cool to room temperature then poured into brine (50ml) and filtered through Celite, washed with EtOAc. The filtrate was washed with brine, dried (Na 2 SO 4 ) and concentrated in vacuo to give the title compound (3.6 g, 99%) as a brown solid. LCMS (ES+) 338 (M + H)+, RT 2.01 min.
[00344] INTERMEDIATE 71
[00345] {(R)-1-[2-(pyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl} 2-methylpropane-2(S)-sulfinic acid amide
[00346] A mixture of Intermediate 70 (3.6 g, 10.7 mmol) and tetrabutylammonium difluorotriphenylsilicate (6.35 g, 11.8 mmol) in anhydrous THF (60 ml) was cooled to -40°C. ( Trifluoromethyl)trimethylsilane (2.28 g, 16.1 mmol) was added and the mixture was stirred at -40°C for 1 hour. Saturated aqueous ammonium chloride solution (5 ml) was added and the reaction mixture was allowed to warm to room temperature. The solvent was removed in vacuo and the residue was partitioned between EtOAc and water. The aqueous phase was extracted with more EtOAc and the combined organic fractions were washed with brine, then dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (SiO 2 , 60 to 100% EtOAc in hexane) to give the title compound (1.9 g, 40%) as a yellow gum. LCMS (ES+) 408 (M + H)+, RT 1.80 minutes.
[00347] INTERMEDIATE 72
[00348] (R)-1[2-(Pyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethylamine
To a solution of Intermediate 71 (0.90 g, 2.21 mmol) in methanol (10 ml) was added a 4 H solution of HCl in 1,4-dioxane (2 ml, 8.0 mmol). The mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue was triturated with diethyl ether (x 2). The residue was then partitioned between DCM and saturated aqueous NaHCO3 solution. The aqueous phase was extracted with more DCM and the combined organic fractions were washed with brine, then dried (Na 2 SO 4 ) and evaporated in vacuo to give the title compound (0.86 g, quantitative) as a yellow gum. LCMS (ES+) 304 (M + H)+, RT 1.57 minutes.
[00350] INTERMEDIATE 73
[00351] 8-Chloro-2-(6-chloropyridin-3-yl)quinoline-3-carbaldehyde
[00352] A mixture of 2,8-dichloroquinoline-3-carbaldehyde (2.6 g, 11.5 mmol), Na2CO3 (1.83 g, 17.3 mmol) and 2-chloropyridin-5-ylboronic acid (1 .81 g, 11.5 mmol) in 1,4-dioxane (40 ml) and water (20 ml) was degassed by bubbling nitrogen gas through it for 5 minutes. Tetracis(triphenylphosphine)palladium (0) (0.13 g, 0.115 mmol) was added and the mixture was heated at 90°C for 16 hours. The mixture was allowed to cool to room temperature. The resulting precipitate was filtered off and washed with water (5 x 50 ml) and diethyl ether (5 x 50 ml) to give the title compound (4.3 g, 70%) as a brown solid. LCMS (ES+) 305 (M + H)+, RT 1.54 minutes.
[00353] INTERMEDIATE 74
[00354] 2-Methylpropane-2(S)-sulfinic acid N-[8-chloro-2-(6-chloropyridin-3-yl)quinolin-3-yl]meth(E)-ylideneamide
Titanium(IV) isopropoxide (5.04 g, 17.8 mmol) was added to a suspension of Intermediate 73 (2.69 g, 8.88 mmol) in anhydrous THF (80 ml). The mixture was stirred at room temperature for 10 minutes. (S)-2-Methyl-2-propanesulfinamide (1.18 g, 9.77 mmol) was added and the mixture was stirred at 50°C for 3 hours. The reaction mixture was allowed to cool to room temperature then poured into brine (50ml) and filtered through Celite, washed with EtOAc. The filtrate was washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (SiO 2 , 25 to 80% EtOAc in hexane) to give the title compound (1.98 g, 55%) as a pale yellow solid. LCMS (ES+) 406.2 (M + H)+, RT 1.68 min.
[00356] INTERMEDIATE 75
[00357] {(R)-1-[8-chloro-2-(6-chloropyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl} 2-methylpropane-2(acid amide) S)-sulfinic
[00358] A mixture of Intermediate 74 (1.97 g, 4.85 mmol) and tetrabutylammonium acetate (1.61 g, 5.34 mmol) in anhydrous THF (50 ml) was cooled to -40°C. Trifluoromethyl)trimethylsilane (1.38 g, 9.70 mmol) was added and the mixture was stirred at -40°C for 2 hours. Saturated aqueous ammonium chloride solution (5 ml) was added and the reaction mixture was allowed to warm to room temperature. The solvent was removed in vacuo and the residue was partitioned between EtOAc and water. The aqueous phase was extracted with more EtOAc and the combined organic fractions were washed with brine, then dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography (SiO 2 , 15 to 65% EtOAc in hexane) to give the title compound (0.50 g, 22%) as a yellow gum. LCMS (ES+) 476 (M + H)+, RT 2.67 minutes.
[00359] INTERMEDIATE 76
[00360] (R)-1-[8-chloro-2-(6-chloropyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethylamine
To a solution of Intermediate 75 (0.50 g, 1.05 mmol) in methanol (20 ml) was added a 4 H solution of HCl in 1,4-dioxane (5 ml, 20.0 mmol). The mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue partitioned between DCM and saturated aqueous NaHCO3 solution. The aqueous phase was extracted with more DCM and the combined organic fractions were washed with brine, then dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography (SiO 2 , 30 to 70% EtOAc in hexane) to give the title compound (0.37 g, 95%) as a yellow gum. LCMS (ES+) 372.2 (M + H)+, RT 1.56 min.
[00362] INTERMEDIATE 77
[00363] 2-[(Hydroxy)(2-methylpyridin-3-yl)methyl]acrylic acid ethyl ester
To 2-methylpyridine-3-carbaldehyde (5 g, 0.04 mol) in ethyl acrylate (10 ml) were added DABCO (1 g, 0.01 mol) and methanol (1 ml). The reaction mixture was stirred at 45°C for 3 days. The reaction mixture was then concentrated and purified by column chromatography (SiO 2 , 60 to 100% EtOAc/DCM) to give the title compound (62%) as a colorless oil. H (DMSO-d6) 8.32 (dd, J 4.8, 1.7 Hz, 1 H), 7.51 (dd, J 7.7, 1.7 Hz, 1 H), 7.17 ( dd, J 7.7, 4.8 Hz, 1 H), 6.28 (t, J 1.3 Hz, 1 H), 5.91 (t, J 1.6 Hz, 1 H), 5. 78 (d, J 5.0Hz, 1H), 5.62 (d, J 5.0Hz, 1H), 4.10 - 4.00 (m, 2H), 3.29 (s, 3H ), 1.10 (t, J 7.0 Hz, 3H). LCMS (ES+) 222 (M + H)+, RT 1.11 min.
[00365] INTERMEDIATE 78
[00366] 2-(2-Methylpyridin-3-yl)-8-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester
To a degassed mixture of 2-amino-3-bromobenzotrifluoride (3.2 g, 17 mmol), Intermediate 77 (3.3 g, 15 mmol), tri(o-tolyl)phosphine (256 mg) and triethylamine (4 ml) in propionitrile (40 ml) at room temperature was added palladium(II) acetate (120 mg, 5 mol%). The mixture was again degassed and heated at 110°C for 2 hours, then diluted with water (20 ml) and EtOAc (100 ml). The aqueous layer was separated and extracted into EtOAc (100 ml). The combined organic fractions were washed with brine (10 ml), dried (Na2SO4), filtered and concentrated in vacuo to give a yellow oil. The resulting crude material was dissolved in chlorobenzene (30 ml), treated with MnO2 (6 g) and heated to 60°C for 2 hours, then at 100°C for 4 hours. The mixture was filtered through a pad of celite (at 70°C), washed with DCM and concentrated in vacuo. The resulting dark oil was purified by column chromatography (SiO 2 , 40% hexane EtOAc) to give the title compound (3.3 g, 66%) as a brown oil. H (DMSO-d6) 8.87 (s, 1H), 8.59 (dd, J 4.9, 1.7 Hz, 1H), 8.18 (m, 2H), 7.70 (t , J 7.7Hz, 1H), 7.59 (dd, J7.7, 1.7Hz, 1H), 7.23 (dd, J7.6, 4.9Hz, 1H) , 4.18 (q, J 7.1 Hz, 2H), 2.48 (s, 3H), 1.06 (t, J 7.1 Hz, 3H). LCMS (ES+) 361.2 (M + H)+.
[00368] INTERMEDIATE 79
[00369] 2-(2-Methylpyridin-3-yl)-8-(trifluoromethyl)quinoline-3-carbaldehyde
To a cooled (-50°C) solution of Intermediate 79 (3.3 ml, 9.3 mmol) in toluene (50 ml) was added DIBAL-H (27.6 ml of a 1 M solution in DCM ) in drops. The mixture was allowed to warm to room temperature in 2 hours, stirred at this temperature for a further 30 minutes, then cooled to -78°C, before dropwise addition of 1 M aqueous NaOH solution (45 ml), during which time the temperature was allowed to rise to room temperature. The organic phase was separated and the aqueous phase extracted into EtOAc (30 ml). The combined organic fractions were washed with 2M aqueous NaOH solution (3 x 50ml), water (50ml) and brine (50ml), then dried (Na2SO4), filtered and concentrated in vacuo to give a light brown solid ( 3.1 g). The mixture was treated with MnO2 (1.7 g), heated at 70°C for 4 hours, filtered through a pad of celite, washed with DCM and concentrated in vacuo. the resulting crude solid material was washed with diethyl ether to yield the title compound (2.3 g, 78%) as a white powder. H (DMSO-d6) 9.97 (s, 1H), 9.23 (s, 1H), 8.63 (m, 2H), 8.41 (d, J 7.0Hz, 1H) , 7.92 (t, J 7.8 Hz, 1H), 7.82 (dd, J 7.7, 1.7 Hz, 1H), 7.41 (dd, J 7.5, 5, 0Hz, 1H), 2.39(s, 3H). LCMS (ES+) 317.2 (M + H)+.
[00371] INTERMEDIATE 80
[00372] N-[2-(2-methylpyridin-3-yl)-8-(trifluoromethyl)-quinolin-3-yl]meth-(E)-ylidene-amidated 2-methylpropane-2(S)-sulfinic acid
To a solution of Intermediate 79 (2.0 g, 6.3 mmol) in THF (15 ml) at room temperature was added titanium(IV) isopropoxide (3.5 ml). The mixture was stirred for 15 minutes before adding (S)-2-methyl-2-propanesulfinamide (0.91 g, 7.5 mmol) and then heated at 50°C for 2 hours. After cooling to room temperature, water (10 ml) was added and the resulting precipitate filtered through a pad of celite. The filtrate was concentrated in vacuo to give the title compound (2.2 g, 83%) as a pale yellow oil. H (CDCl 3 ) 8.96 (s, 1H), 8.66 (dd, J 4.9, 1.7 Hz, 1H), 8.58 (s, 1H), 8.22 (d, J 7.9 Hz, 2H), 7.73 (t, J 7.8 Hz, 1 H), 7.59 (dd, J 7.7, 1.6 Hz, 1 H), 7.30 (m , 1H), 2.06 (s, 3H), 1.26 (s, 9H). LCMS (ES+) 420 (M + H)+.
[00374] INTERMEDIATE 81
[00375] 2-acid {(R)-1-[2-(2-methylpyridin-3-yl)-8-(trifluoromethyl)quinolin-3-yl]-2,2,2-trifluoroethyl}amide methylpropane-2-(S)-sulfinic
[00376] To a solution of Intermediate 80 (2.2 g, 5.2 mmol) in THF (25 ml) was added tetrabutylammonium acetate (1.9 g) and the mixture was cooled to -30°C before addition to the drops of (trifluoromethyl)trimethylsilane (1.7 ml). After stirring for 1.5 hours, brine (25 ml) was added, the mixture was allowed to warm to room temperature and stirred was continued for a further 15 minutes. EtOAc (50 ml) was added, then the organic fraction was separated, washed with brine (20 ml), water (20 ml) and brine (20 ml), dried (Na2SO4), filtered and concentrated in vacuo. The resulting pale yellow solid was subjected to column chromatography (SiO 2 , 40% hexane EtOAc) to give the title compound (0.90 g, 35%) as a pale yellow oil. H (CDCl 3 ) 8.52 (dd, J 4.9, 1.6 Hz, 1H), 8.35 (s, 1H), 8.01 (m, 1H), 7.96 (d, J 8.3 Hz, 1 H), 7.77 (dd, J 7.6, 1.4 Hz, 1 H), 7.54 (t, J 7.6 Hz, 1 H), 7.23 ( dd, J 7.6, 5.0 Hz, 1 H), 4.85 (t, J 7.4 Hz, 1 H), 3.83 (d, J 7.7 Hz, 1 H), 2, 28 (s, 3H), 1.13 (s, 9H). LCMS (ES+) 490.2 (M + H)+.
[00377] INTERMEDIATE 82
[00378] (R)-1-[2-(2-Methylpyridin-3-yl)-8-(trifluoromethyl)quinolin-3-yl]-2,2,2-trifluoroethyl-amine
To a solution of Intermediate 81 (0.86 g, 1.8 mmol) in DCM (10 ml) was added HCl (1.25 ml of a solution in 1,4-dioxane). To the resulting solid suspension, MeOH (10 ml) was added and stirring was continued for 10 minutes. The mixture was partitioned between DCM (20 ml) and saturated aqueous NaHCO3 solution (20 ml). The organic phase was separated and the aqueous phase extracted into DCM (10 ml). The combined organic phases were dried (Na 2 SO 4 ), filtered and concentrated in vacuo to give the title compound (664 mg, > 95%) as a pale yellow oil. H (CDCl 3 ) 8.68 (d, J 4.7 Hz , 1H), 8.62 (s, 1H), 8.16 (m, 2H), 7.71 (t, J 7.9Hz, 2H), 7.34 (m, 1H), 4 .50 (m, 1H), 3.82 (s, 2H), 2.45 (d, J 26.8 Hz, 3H). LCMS (ES+) 386.2 (M + H)+.
[00380] INTERMEDIATE 83
[00381] N-{(R)-1-[2-(2-methylpyridin-3-yl)-8-(trifluoromethyl)quinolin-3-yl]-2,2,2-trifluoroethyl} acetamide
Intermediate 82 (660 mg, 1.7 mmol) was dissolved in AcOH (8 ml) and heated at 60°C overnight and then at 70°C for 2 hours. The mixture was concentrated in vacuo and the residue was purified by column chromatography (SiO 2 , 100% hexane EtOAc) to give the title compound (550 mg, 76%) as a white foam. H (CDCl3) 8.69 (m, 1H), 8.49 (m, 1H), 8.19 (m, 2H), 8.14 (m, 1H), 7.73 (t, J 7.7Hz, 1H), 7.47 (m, 1H), 6.65 (m, 1H), 5.85 (m, 1H), 2.53 (s, 3H), 2, 17 (s, 3H). LCMS (ES+) 428.2 (M + H)+.
[00383] INTERMEDIATE 84
[00384] (R)-1-[2-(2-Methyl-1-oxypyridin-3-yl)-8-(trifluoromethyl)quinolin-3-yl]-2,2,2-trifluoroethylamine
To a solution of Intermediate 83 (0.50 g, 1.2 mmol) in DCM (10 ml) at room temperature was added MCPBA (0.46 g) in one portion. After 1.5 hours the mixture was partitioned between DCM (50 ml) and 1N aqueous NaOH solution (30 ml). The aqueous layer was acidified with citric acid (10% aqueous) and extracted into DCM (2 x 20 ml), dried (phase separator) and concentrated in vacuo. The resulting white powder was treated with EtOH (5 ml) and conc. (5 ml) and heated at 55°C overnight. The mixture was cooled and concentrated in vacuo, and the residue was partitioned between water (10 ml) and DCM (10 ml). The saturated aqueous NaHCO3 solution was added until the aqueous layer was pH 5 and this was extracted into DCM (4 x 10 ml). The combined organic layers were dried (phase separator) and concentrated in vacuo. The resulting yellow oil was purified by column chromatography (SiO 2 , 23 : 2 EtOAc : MeOH) to give the title compound (365 mg, 76%) as a clear oil. H (CDCl 3 ) 8.57 (s, 1H), 8.43 (d, J 6.1 Hz, 1H), 8.06 (m, 2H), 7.62 (td, J 7.8, 3.6Hz, 1H), 7.29 (m, 2H), 4.48 (m, 1H), 2.30 (d, J 5.9Hz, 3H). LCMS (ES+) 402.2 (M + H)+.
[00386] INTERMEDIATE 85
[00387] 2-Bromo-6-(methanesulfonyl)phenylamine
2-Bromo-6-(methylsulfanyl)phenylamine (2 g, 10.7 mmol) in DCM (100 ml) was treated with MCPBA (4 g, 23.2 mmol) at room temperature and stirred for 30 minutes. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution, dried over sodium sulfide, filtered and concentrated in vacuo to give the title compound. H (DMSO-d6) 7.77 (dd, J 7.8, 1.4 Hz, 1 H), 7.63 (dd, J 8.0, 1.4 Hz, 1 H), 6.73 ( t, J 7.9 Hz, 1H), 6.03 (s, 2H), 3.18 (s, 3H). LCMS (ES+) 250 (M + H)+, RT 1.175 minutes.
[00389] INTERMEDIATE 86
8-(Methanesulfonyl)-2-(2-methylpyridin-3-yl)-1,4-dihydroquinoline-3-carboxylic acid ethyl ester
Intermediate 85 (1.2 g, 4.9 mmol), Intermediate 77 (1.2 g, 5.4 mmol), palladium(II) acetate (54.0 mg, 0.05 mmol) , tri(o-tolyl)phosphine (149.0 mg, 0.1 mmol) and triethylamine (1.33 ml, 2.0 mmol) in acetonitrile (10 ml) were degassed and heated at 100°C for 16 hours. The reaction mixture was then concentrated in vacuo and purified by column chromatography (SiO 2 , 60% ethyl acetate/hexanes) to give the title compound (57%) as a clear solid. H (DMSO-d6) 8.50 (dd, J 4.9, 1.7 Hz, 1H), 8.19 (s, 1H), 7.67 - 7.60 (dt, J 7.6 , 1.7 Hz, 2H), 7.53 (d, J 7.6 Hz, 1H), 7.29 (dd, J 7.6, 4.9 Hz, 1H), 7.16 (t , J 7.7Hz, 1H), 3.89 (s, 2H), 3.85 - 3.77 (m, 2H), 3.24 (s, 3H), 2.42 (s, 3H) , 0.81 (t, J 7.1 Hz, 3H). LCMS (ES+) 373 (M + H)+, RT 1.49 min.
[00392] INTERMEDIATE 87
8-(Methanesulfonyl)-2-(2-methylpyridin-3-yl)quinoline-3-carboxylic acid ethyl ester
Intermediate 86 (880 mg, 2.46 mmol) in DCM (40 ml) was treated portionwise with manganese dioxide (1.0 g) and stirred at 45°C for 4 hours. The reaction mixture was filtered and concentrated in vacuo to give the title compound (79%) as a pale solid. H (DMSO-d6) 9.24 (s, 1H), 8.63 (dd, J 8.3, 1.4 Hz, 1H), 8.58 - 8.54 (m, 2H), 7 .96 (dd, J 8.1, 7.5 Hz, 1H), 7.68 (dd, J 7.7, 1.7 Hz, 1H), 7.36 (dd, J 7.6, 4.9 Hz, 1H), 4.18 - 4.11 (q, J 7.1 Hz, 2H), 3.51 (s, 3H), 2.33 (s, 3H), 1.02 ( t, J 7.1 Hz, 3H). LCMS (ES+) 371 (M + H)+, RT 1.35 minutes.
[00395] INTERMEDIATE 88
[00396] [8-(Methanesulfonyl)-2-(2-methylpyridin-3-yl)quinolin-3-yl]methanol
Intermediate 87 (1.9g, 5.3mmol) in toluene (20ml) was cooled to -78°C and treated with DIBAL-H (1M in DCM, 16ml, 16mmol). After stirring for 1 hour the reaction mixture was quenched with 1 M aqueous NaOH solution, extracted into ethyl acetate, dried over sodium sulphide and concentrated in vacuo. The crude material was purified by column chromatography (SiO 2 , 2% methanol/EtOAc) to give the title compound (59%) as a pale solid. H (DMSO-d6) 8.71 (s, 1H), 8.59 (dd, J 4.9, 1.7 Hz, 1H), 8.49 (dd, J 8.1, 1.3 Hz, 1H), 8.40 (dd, J 7.4, 1.4 Hz, 1H), 7.85 (dd, J 8.1, 7.4 Hz, 1H), 7.77 ( dd, J 7.7, 1.7 Hz, 1 H), 7.38 (m, 1 H), 5.53 (t, J 5.1 Hz, 1 H), 4.52 - 4.43 ( br s, 1H), 4.36 (d, J 4.4Hz, 1H), 3.49 (s, 3H), 2.26 (s, 3H). LCMS (ES+) 329 (M + H)+, RT 1.10 minutes.
[00398] INTERMEDIATE 89
[00399] 8-(Methanesulfonyl)-2-(2-methylpyridin-3-yl)quinoline-3-carbaldehyde
Intermediate 88 (1.8 g, 5.3 mmol) in DCM (80 ml) was treated portionwise with manganese dioxide (2.0 g) and stirred at room temperature for 4 hours. The reaction mixture was filtered, concentrated in vacuo and purified by column chromatography (SiO 2 , EtOAc) to give the title compound (83%) as a pale solid. H (DMSO-d6) 9.98 (s, 1H), 9.27 (s, 1H), 8.70 - 8.60 (m, 3H), 7.98 (dd, J 8.1, 7.5 Hz, 1 H), 7.82 (dd, J 7.7, 1.7 Hz, 1 H), 7.42 (dd, J 7.7, 4.9 Hz, 1 H), 3 .52 (s, 3H), 2.39 (s, 3H). LCMS (ES+) 327 (M + H)+, RT 1.18 minutes.
[00401] INTERMEDIATE 90
[00402] 2-Methylpropane-2(S)-sulfinic acid N-[8-(methanesulfonyl)-2-(2-methylpyridin-3-yl)-quinolin-3-yl]meth-(E)-ylideneamide
Intermediate 89 (1.1 g, 3.3 mmol) and (S)-2-methyl-2-propane-sulfinamide (436 mg, 6.6 mmol) were mixed and stirred for 10 minutes in anhydrous THF . Titanium(IV) isopropoxide (1.95 ml, 6.6 mmol) was added and the reaction mixture was heated to 45°C for 12 hours. The reaction mixture was poured into water, extracted into ethyl acetate, dried over sodium sulfide and concentrated to give the title compound (94%) as a pale solid. LCMS (ES+) 430.0 (M + H)+, RT 1.33 minutes.
[00404] INTERMEDIATE 91
[00405] [(R)-1-(8-methanesulfonyl)-2-(2-methylpyridin-3-yl)quinolin-3-yl)-2,2,2-trifluoroethyl]amide 2-methylpropane-2 acid (S)-sulfinic
Intermediate 90 (1.4 g, 3.3 mmol) in anhydrous THF was cooled to -40°C. Tetrabutylammonium acetate (1.0 g, 3.6 mmol) was added and the reaction mixture was stirred for 10 minutes. (Trifluoromethyl)trimethylsilane (0.94 g, 6.6 mmol) was then added and the reaction mixture was stirred for 1 hour. Saturated aqueous ammonium chloride solution (15 ml) was added and the reaction mixture was allowed to warm to room temperature. The solvent was removed in vacuo and the residue was partitioned between DCM and water. The organic phase was washed with brine (30 ml), dried (phase separator) and evaporated in vacuo. The residue was purified by column chromatography (SiO 2 , 60100% EtOAc in hexane) to give the title compound (53%) as a white foam. H (DMSOd6; 1 : 1 mixture of Rotamers) 9.08 (m, 1H), 8.58 (m, 1H), 8.45 (m, 2H), 7.85 (m, 1H), 7.87 (m, 0.5H), 7.57 (m, 0.5H), 7.34 (m, 1H), 6.53 (m, 1H), 4.64 (m, 1H) ), 3.40 (s, 3H), 2.29 (s, 1.5H), 2.20 (s, 1.5H), 1.10 (s, 4.5H), 1.04 (s, 4.5H).
[00407] INTERMEDIATE 92
[00408] (R)-1-[8-(Methanesulfonyl)-2-(2-methylpyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl-amine
Intermediate 91 (1.2 g, 2.5 mmol) in DCM (5 ml) was treated with 4M HCl in 1,4-dioxane (20 ml) and stirred at room temperature for 30 minutes. Methanol (5 ml) was added and the reaction mixture was stirred for a further 30 minutes. The reaction mixture was concentrated and partitioned between DCM and saturated sodium hydrogen carbonate solution. The organic phase was dried and concentrated to give the title compound (96%) as a pale solid. LCMS (ES+) 396.0 (M + H)+, RT 1.25 minutes.
[00410] INTERMEDIATE 93
[00411] [(2-hydroxy)(pyridin-3-yl)methyl]acrylic acid ethyl ester
[00412] To a solution of the nicotinaldehyde (10.0 g, 93.4 mmol) in ethyl acrylate (20 ml, -200 mmol) at room temperature was added DABCO (0.5 g, 4.5 mmol) and the mixture was stirred overnight. Excess ethyl acrylate was removed in vacuo. The resulting crude solid was washed with hexane to give the title compound (18.5 g, 95%) as a yellowish white solid. H (CDCl 3 ) 8.62 (d, J 1.7 Hz, 1 H), 8.53 (dd, J 4.8, 1.3 Hz, 1 H), 7.81 (d, J 7.9 Hz, 1H), 7.28 (s, 1H), 6.42 (s, 1H), 5.93 (s, 1H), 5.63 (s, 1H), 4.18 ( m, 2H), 3.20 (br s, 1H), 1.27 (t, J 7.1 Hz, 3H). LCMS (ES+) 208.2 (M + H)+.
[00413] INTERMEDIATE 94
[00414] 8-(Methanesulfonyl)-2-(pyridin-3-yl)-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester
[00415] Intermediate 85 (500 mg, 2.0 mmol), Intermediate 93 (455 mg, 2.2 mmol), palladium(II) acetate (22.5 mg, 0.01 mmol), tri(o) -tolyl)phosphine (60 mg, 0.02 mmol) and triethylamine (0.56 ml, 4.0 mmol) in acetonitrile (5 ml) were degassed and heated at 120°C for 3 hours. The reaction mixture was concentrated in vacuo and chromatographed (SiO 2 , 0 to 100% DCM-ethyl acetate) to give the title compound (400 mg). H (DMSO-d6) 9.18 (s, 1H), 8.88 (d, J 1.9Hz, 1H), 8.73 (dd, J 4.8, 1.6Hz, 1H ), 8.61 (dd, J 8.2, 1.3 Hz, 1 H), 8.55 (dd, J 7.4, 1.4 Hz, 1 H), 8.10 (m, 1 H ), 7.95 (m, 1H), 7.60 (ddd, J 7.8, 4.8, 0.5 Hz, 1H), 4.27 (q, J 7.1 Hz, 2H) , 3.60 (s, 3H), 1.15 (t, J 7.1 Hz, 3H). LCMS (ES+) 359 (M + H)+, RT 1.331 min.
[00416] INTERMEDIATE 95
[00417] 8-(Methanesulfonyl)-2-(pyridin-3-yl)quinoline-3-carboxylic acid ethyl ester
Intermediate 94 (400 mg, 1.23 mmol) in DCM (20 ml) was treated portionwise with manganese dioxide (500 mg) and stirred at room temperature for 2 hours. The reaction mixture was filtered and concentrated in vacuo to give the title compound (355 mg, 80%). H (DMSO-d6) 9.18 (s, 1H), 8.88 (d, J 1.9Hz, 1H), 8.73 (dd, J 4.8, 1.6Hz, 1H ), 8.61 (dd, J 8.2, 1.3 Hz, 1 H), 8.55 (dd, J 7.4, 1.4 Hz, 1 H), 8.10 (m, 1 H ), 7.95 (m, 1H), 7.60 (m, 1H), 4.27 (q, J 7.1Hz, 2H), 3.60 (s, 3H), 1.15 ( t, J 7.1 Hz, 3H). LCMS (ES+) 357 (M + H)+, RT 1.237 min.
[00419] INTERMEDIATE 96
[00420] 8-(Methanesulfonyl)-2-(pyridin-3-yl)quinoline-3-carbaldehyde
Intermediate 95 (1.9 g, 5.3 mmol) in toluene (20 ml) was cooled to -78°C and treated with 1 M DIBAL-H (16 ml, 16 mmol) in DCM. After stirring for 1 hour, the reaction mixture was quenched with Rochelle's salt, extracted into ethyl acetate, dried over sodium sulphide and concentrated in vacuo. The resulting material (1.67 g, 5.3 mmol) was suspended in DCM and treated with manganese dioxide (2 g). After stirring at room temperature for 90 minutes, the reaction mixture was filtered and the resulting solid washed with methanol-DCM 1:1. The filtrate was concentrated in vacuo, then purified by column chromatography (SiO2, DCM-ethyl acetate) to give the title compound (1.0 g). H (DMSO-d6) 10.19 (s, 1 H), 9.25 (s, 1 H), 9.01 (dd, J 2.2, 0.6 Hz, 1 H), 8.79 ( dd, J 4.8, 1.7 Hz, 1 H), 8.68 (dd, J 8.2, 1.3 Hz, 1 H), 8.59 (dd, J 7.4, 1.4 Hz, 1H), 8.25 (m, 1H), 7.97 (dd, J 8.1, 7.5 Hz, 1H), 7.66 (ddd, J 7.9, 4.8 , 0.7 Hz, 1H), 3.62 (s, 3H). LCMS (ES+) 313 (M + H)+, RT 1.084 minutes.
[00422] INTERMEDIATE 97
[00423] 2-Methylpropane-2(S)-sulfinic acid N-[8-(methanesulfonyl)-2-(pyridin-3-yl)quinolin-3-yl]meth-(E)-ylideneamide
Intermediate 96 (1 g, 3.3 mmol) and (S)-2-methyl-2-propane-sulfinamide (436 mg, 6.6 mmol) were mixed and stirred for 10 minutes in THF. Titanium(IV) isopropoxide (1.95 ml, 6.6 mmol) was added and the reaction mixture was heated to 50°C for 3 hours. The reaction mixture was poured into water, extracted into ethyl acetate, dried over sodium sulfide, concentrated and chromatographed (SiO 2 , hexane-DCM) to give the title compound (1.4 g). H (DMSO-d6) 9.32 (s, 1H), 8.92 (d, J 2.0Hz, 1H), 8.80 (dd, J 4.8, 1.5Hz, 1H ), 8.67 (m, 2H), 8.55 (dd, J 7.3, 1.2 Hz, 1 H), 8.16 (dt, J 7.9, 1.9 Hz, 1 H) , 7.95 (t, J 7.8 Hz, 1H), 7.68 (dd, J 7.7, 4.8 Hz, 1H), 3.62 (s, 3H), 1.25 ( s, 9H). LCMS (ES+) 416 (M + H)+, RT 1.311 minutes.
[00425] INTERMEDIATE 98
[00426] {(R)-1-[8-(methanesulfonyl)-2-(pyridin-3-yl)-quinolin-3-yl]-2,2,2-trifluoro-ethyl} 2-methylpropane acid amide -2(S)-sulfinic
Intermediate 97 (1.37 g, 3.3 mmol) in THF was cooled to -40°C. Tetrabutylammonium difluorotriphenylsilicate (1.96 g, 3.63 mmol) was added and the reaction mixture was added stirred for 10 minutes. (Trifluoromethyl)trimethylsilane (0.94 g, 6.6 mmol) was added and the reaction mixture was stirred for 1 hour. The reaction mixture was poured into a saturated aqueous Rochelle salt solution, then extracted into DCM, dried over sodium sulphide and concentrated in vacuo. Chromatography (60% water; 40% methanol) on reverse phase silica gave the title compound (1.2 g). H (DMSO-d6) 9.14 (s, 1H), 8.84 (m, 2H), 8.53 (m, 2H), 8.08 (m, 1H), 7.96 (dd, J 8.1, 7.5 Hz, 1 H), 7.70 (ddd, J 7.8, 4.9, 0.6 Hz, 1 H), 6.68 (d, J 8.4 Hz, 1H), 5.16 (t, J 8.0Hz, 1H), 3.57 (s, 3H), 1.17 (s, 9H). LCMS (ES+) 486 (M + H)+, RT 1.341 min.
[00428] INTERMEDIATE 99
[00429] (R)-1-[8-(Methanesulfonyl)-2-(pyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoro-ethylamine
Intermediate 98 (1.2 g, 2.47 mmol) in DCM (5 ml) was treated with 4M HCl in 1,4-dioxane (20 ml) and stirred at room temperature for 30 minutes. Methanol (5 ml) was added and the reaction mixture was stirred for a further 30 minutes. The reaction mixture was concentrated and partitioned between DCM and saturated aqueous sodium hydrogen carbonate solution, dried and concentrated to give the title compound (870 mg). H (DMSO-d6) 9.05 (s, 1H), 8.89 (d, J 1.8Hz, 1H), 8.78 (dd, J 4.8, 1.6Hz, 1H ), 8.50 (m, 2H), 8.12 (m, 1H), 7.92 (m, 1H), 7.66 (m, 1H), 4.79 (m, 1H) , 3.61 (s, 3H). LCMS (ES+) 382 (M + H)+, RT 1.171 min.
[00431] INTERMEDIATE 100
[00432] N-{(R)-1-[8-chloro-2-(pyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl} acetamide
Acetic anhydride (4.40 ml, 46.9 mmol) was added to a solution of Intermediate 4 (15.08 g, 40.7 mmol) in THF (150 ml). The reaction mixture was stirred at room temperature for 2 hours, then concentrated to a volume of approximately 50 ml. The mixture was diluted with EtOAc (200 ml), and the organic solution was washed with saturated aqueous NaHCO3 (3 x 200 ml) and brine (200 ml), then dried (MgSO4 ) and evaporated in vacuo to give the title compound ( 17.0 g, >99 %) as a yellow/orange foamy gum. H (DMSO-d6) 9.40 (d, J 8.9 Hz, 1 H), 8.85 (s, 1 H), 8.79 (dd, J 2.3, 0.6 Hz, 1 H ), 8.77 (dd, J 4.9, 1.7 Hz, 1 H), 8.12 (dd, J 4.5, 1.1 Hz, 1 H), 8.09 (dd, J 3 9.9, 1.1 Hz, 1H), 8.03 (ddd, J 7.8, 1.9, 1.9 Hz, 1H), 7.73 (dd, J 7.9, 7.9 Hz, 1H), 7.62 (ddd, J 7.8, 4.8, 0.7 Hz, 1H), 6.01 (dq, J 8.1, 8.1 Hz, 1H), 1.95 (s, 3H). LCMS (pH 3) (ES+) 380 (M + H)+, RT 1.58 min.
[00434] INTERMEDIATE 101
[00435] N-{(R)-1-[8-Chloro-2-(1-oxypyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl} acetamide
3-Chloroperoxybenzoic acid (13.5 g, 60.4 mmol) was added to a solution of Intermediate 100 (17.0 g, 40.7 mmol) in DCM (250 ml) at 0°C. Reaction mixture was allowed to warm slowly to room temperature in 20 hours. The mixture was treated with saturated aqueous NaHCO3 solution (200 ml) and stirred for 3 hours. It was then acidified to pH 8 with 10% aqueous HCl, and the organic layer was separated. The aqueous layer was extracted with DCM (2 x 100 ml), and the combined organic phases were washed with saturated aqueous NaHCO 3 (200 ml) and brine (100 ml), then dried (MgSO 4 ) and evaporated in vacuo to give the compound. titer (17.7 g, >99 %) as an orange foamy gum. H (DMSO-d6) 9.36 (d, J 8.7 Hz, 1H), 8.82 (s, 1H), 8.40 - 8.43 (s, 1H), 8.40 ( ddd, J 6.4, 1.7, 0.9 Hz, 1H), 8.15 - 8.09 (m, 2H), 7.75 (dd, J 7.9, 7.9 Hz, 1 H), 7.64 - 7.59 (m, 1H), 7.54 - 7.50 (m, 1H), 5.97 (qd, J 8.3, 8.3 Hz, 1H) , 1.93 (s, 3H). LCMS (ES+) 396 (M + H)+, RT 1.12 minutes.
[00437] INTERMEDIATE 102
[00438] (R)-1-[8-Chloro-2-(1-oxypyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethylamine
[00439] A mixture of concentrated HCl (100 ml) and water (65 ml) was added to a solution of Intermediate 101 (17.7 g, 40.7 mmol) in ethanol (165 ml). The reaction mixture was heated to 80°C and stirred for 3 days. The mixture was cooled to room temperature and concentrated in vacuo to a volume of approximately 100 ml, and basified to pH 8 with saturated aqueous NaHCO3 solution. The aqueous solution was extracted with 10% methanol/DCM (5 x 100 ml) and the combined organic layers were passed through a phase separator cartridge, then evaporated. The residue was purified by column chromatography [SiO2, 2 to 20% (9:1:28% NH4OH methanol) in DCM], followed by a second column (aminopropyl-SiO2, EtOAc) to give the title compound (13.2 g, 83%) as a foamy brown gum. H (DMSO-d6) 8.93 (s, 1H), 8.48 - 8.47 (m, 1H), 8.41 - 8.38 (m, 1H), 8.13 (dd, J 8.3, 1.2 Hz, 1 H), 8.07 (dd, J 7.5, 1.2 Hz, 1 H), 7.71 (dd, J 7.8, 7.8 Hz, 1H), 7.62 (dd, J 7.7, 6.8 Hz, 1H), 7.56 (ddd, J 7.8, 1.3, 1.3 Hz, 1H), 4, 72 (tq, J 7.4, 7.4 Hz, 1H), 2.84 (d, J 6.9 Hz, 2H). LCMS (ES+) 354 (M + H)+, RT 1.31 min.
[00440] EXAMPLE 1
[00441] N-{(R)-1-[8-Chloro-2-(pyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl}pyrido[3,2-d]- pyrimidin-4-ylamine
A mixture of Intermediate 4 (0.62 g, 1.85 mmol), 4-chloropyrido[3,2-d]-pyrimidine (0.37 g, 2.22 mmol) and DMAP (0.32 g , 2.59 mmol) in DCM (15 ml) was heated under microwave irradiation at 140°C for 1 hour. The reaction mixture was partitioned between DCM and water. The aqueous phase was extracted with more DCM and the combined organic fractions were washed with brine, then dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography (SiO 2 , 020% MeOH in EtOAc) to give the title compound (232 mg, 27%) as a brown gum. H (DMSO-d6) 9.50 (br s, 1H), 9.35 (s, 1H), 8.92 (dd, J 4.3, 1.5Hz, 1H), 8.77 (d, J 1.8 Hz, 1H), 8.68 (dd, J 4.8, 1.5Hz, 1H), 8.48 (s, 1H), 8.21 (dd, J 8.3, 1.5 Hz, 1 H), 8.13 (dd, J 8.3, 1.0 Hz, 1 H), 8.08 (dd, J 7.6, 1.3 Hz, 1 H), 8.07 - 8.04 (m, 1H), 7.92 (dd, J 8.3, 4.0 Hz, 1H), 7.74 - 7.70 (m, 1H) , 7.52 (ddd, J 7.8, 5.1, 0.8 Hz, 1H), 6.81 - 6.74 (m, 1H). LCMS (ES+) 467 (M + H)+, RT 2.39 min.
[00443] EXAMPLE 2
[00444] N-{(R)-1-[8-Chloro-2-(1-oxypyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl}-pyrido[3,2- d]-pyrimidin-4-ylamine
A stirred solution of Example 1 (140 mg, 0.308 mmol) in DCM (10 ml) was cooled to -10° C. MCPBA (56 mg, 0.325 mmol) was added and the mixture was allowed to warm slowly to room temperature in 3 hours. The reaction mixture was partitioned between DCM and a saturated aqueous NaHCO3 solution. The aqueous phase was extracted with more DCM and the combined organic fractions were washed with brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography (SiO 2 , 5 to 35% MeOH in EtOAc) to give the title compound (54 mg, 36%) as a yellow solid. H (DMSOd6) 9.55 (d, J 9.0 Hz, 1 H), 9.27 (s, 1 H), 8.90 (dd, J 4.1, 1.5 Hz, 1 H), 8.54 (s, 1 H), 8.49 (t, J 1.5 Hz, 1 H), 8.26 (ddd, J 6.4, 1.5, 0.9 Hz, 1 H), 8.21 (dd, J 8.5, 1.5 Hz, 1H), 8.17 - 8.07 (m, 2H), 7.91 (dd, J 8.5, 4.1 Hz, 1 H), 7.76 - 7.70 (m, 1H), 7.47 - 7.51 (m, 1H), 7.37 - 7.43 (m, 1H), 6.73 - 6 .87 (m, 1H). LCMS (ES+) 483 (M + H)+, RT 2.08 min.
[00446] Alternative procedure
[00447] A mixture of Intermediate 102 (13.1 g, 37 mmol), Intermediate 30 (10.8 g, 40 mmol) and p-toluenesulfonic acid monohydrate (0.70 g, 3.7 mmol) in chloroform (200 ml) was heated at 0°C under nitrogen for 20 hours. The solution was cooled to room temperature, diluted with DCM (200 ml), washed with saturated aqueous NaHCO3 solution (3 x 200 ml) and brine (200 ml), then dried (MgSO4 ) and evaporated in vacuo. The residue was dissolved in DCM (30 ml) and filtered to remove an insoluble solid. The filtrate was purified by column chromatography (SiO 2 , 2 to 20% MeOH in EtOAc), followed by a second column (aminopropyl-SiO 2 , EtOAc) to give the title compound (13.45 g, 62%) like a cream colored powder.
[00448] EXAMPLE 3
[00449] N-[(R)-1-(8-Chloro-2-phenylquinolin-3-yl)-2,2,2-trifluoroethyl}pyrido[3,2-d]-pyrimidin-4-ylamine
A mixture of Intermediate 8 (0.55 g, 1.63 mmol) and 4-chloropyrido[3,2-d]-pyrimidine (0.31 g, 1.87 mmol) in acetonitrile (5 ml) was stirred at 80°C for 2.5 hours. The reaction mixture was partitioned between DCM and brine. The aqueous phase was extracted with more DCM and the combined organic fractions were washed with brine, then dried (MgSO4 ) and evaporated in vacuo. The residue was purified by column chromatography (SiO 2 , 30% EtOAc in hexane) and the product was freeze-dried to give the title compound (35 mg, 2.3%) as a white lyophilized solid. H (DMSO-d6) 9.40 (d, J 9.3 Hz, 1 H), 9.37 (s, 1 H), 8.93 (dd, J 4.2, 1.5 Hz, 1 H ), 8.51 (s, 1H), 8.21 (dd, J 8.5, 1.5 Hz, 1H), 8.04 - 8.11 (m, 2H), 7.92 (dd , J 8.5, 4.2 Hz, 1H), 7.69 (t, J 8.9 Hz, 1H), 7.47 - 7.61 (m, 5H), 6.88 (m, 1H). LCMS (ES+) 466 (M + H)+, RT 2.78 min.
[00451] EXAMPLE 4
[00452] N-{(R)-1-[8-Chloro-2-(4-methylpyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl}pyrido[3.2 -dtpyrimidin-4-ylamine
A mixture of Intermediate 12 (216 mg, 0.615 mmol) and Intermediate 30 (180 mg, 0.738 mmol) in DCM (15 ml) was heated under microwave irradiation at 140°C for 1 hour. The reaction mixture was diluted with DCM and washed with brine, then dried (MgSO4 ) and evaporated in vacuo. The residue was purified by column chromatography (SiO 2 , 0 to 6% MeOH in EtOAc) to give the title compound (90 mg, 30%) as a brown gum. H (DMSO-d6) 9.54 (br s, 1H), 9.27 (br s, 1H), 8.90 (m, J 4.3, 1H), 8.62 (m, 1 H), 8.47 (m, 1H), 8.31 (m, 1H), 8.18 - 8.24 (m, 3H), 8.08 (m, 1H), 7.91 ( m, 1H), 7.20 (m, 1H), 6.57 (m, 1H), 3.35 - 3.55 (br s, 3H). LCMS (ES+) 481 (M + H)+, RT 1.93 min.
[00454] EXAMPLE 5
[00455] N-{(R)-1-[8-Chloro-2-(4-methyl-1-oxypyridin-3-yl)quinolin-3-yl]-2,2,2-tri-fluoroethyl}- pyrido[3,2-dipyrimidin-4-ylamine
[00456] A solution of Example 4 (90 mg, 0.187 mmol) in DCM (5 ml) was stirred in an ice bath under nitrogen, MCPBA (42 mg, 0.187 mmol) was added, and the mixture was allowed to warm slowly to temperature environment in 3 hours. The reaction mixture was diluted with DCM, then washed with saturated aqueous NaHCO3 solution, dried (MgSO4 ) and evaporated in vacuo. The residue was purified by column chromatography (SiO 2 6 to 20% MeOH in EtOAc) then freeze dried to give the title compound (33 mg, 35%) as a white lyophilized solid. H (DMSO-d6) 9.51 - 9.60 (m, 1H), 9.02 - 9.36 (m, 1H), 8.82 - 8.95 (m, 1H), 8. 52 - 8.56 (m, 1H), 8.05 - 8.28 (m, 4H), 7.86 - 7.96 (m, 2H), 7.70 - 7.78 (m, 1H) ), 6.52 - 6.80 (m, 2H), 1.60 (br s, 3H). LCMS (ES+) 497 (M + H)+, RT 1.77 min.
[00457] EXAMPLE 6
[00458] N-{(R)-1-[8-Chloro-2-(2-methylpyridin-3-yl)quinolin-3-yl]-2,2,2trifluoroethyl}pyrido[3,2-d]pyrimidin -4-ilamine
A mixture of Intermediate 15 (1.38 g, 3.93 mmol), and Intermediate 30 (1.1 g, 4.51 mmol) in DCM (15 ml) was heated under microwave irradiation at 140° C for 1 hour. The reaction mixture was diluted with DCM and washed with brine, then dried (MgSO4 ) and evaporated in vacuo. The residue was purified by column chromatography (SiO 2 , 05% MeOH in EtOAc) to give the title compound (1.1 g, 58%) as brown syrup. H (DMSO-d6) 9.51 (m, 1H), 9.29 (m, 1H), 8.91 (m, 1H), 8.51 (m, 1.5H), 8.20 (m, 2.5H), 8.09 (m, 1H), 7.88 (m, 1.5H), 7.72 (m, 1H), 7.61 (m, 0.5H), 7.42 (m, 0.5H), 7.10 (m, 0.5H), 6.57 (m, 1H), 2.22 (s, 1H), 1.99 (s, 2H) . LCMS (ES+) 481 (M + H)+, RT 1.47 min.
[00460] EXAMPLE 7
[00461] N-{(R)-1-[8-chloro-2-(2-methyl-1-oxypyridin-3-yl)quinolin-3-yl]-2,2,2-tri-fluoroethyl}- pyrido[3,2-dipyrimidin-4-ylamine
A solution of Example 6 (0.55 g, 1.145 mmol) in DCM (8 ml) was stirred in an ice bath under nitrogen and 77% MCPBA (0.256 g, 1.143 mmol) was added and stirred overnight. . The reaction mixture was diluted with DCM, then washed with saturated aqueous NaHCO3 solution, dried (MgSO4 ) and evaporated in vacuo. The residue was purified by column chromatography (SiO 2 , 6 to 14% MeOH in EtOAc) to give the title compound (300 mg, 53%) as a white foam. H (DMSO-d6) 9.56 (m, 0.5H), 9.54 (m, 0.5H), 9.28 (m, 0.5H), 9.21 (m, 0.5H), 8.89 (m, 0.5H), 8.86 (m, 0.5H), 8.29 - 8.35 (m, 2H), 8.17 - 8.23 (m, 2H), 8. 10 (m, 1H), 7.90 (m, 1H), 7.76 (m, 1H), 7.47 (m, 1H), 7.15 (m, 0.5H), 7 .08 (m, 0.5H), 6.63 (m, 0.5H), 6.56 (m, 0.5H), 2.19 (s, 1H), 1.59 (s, 2H) . LCMS (ES+) 497 (M + H)+, RT 1.31 min.
[00463] EXAMPLE 8
[00464] N-{(R)-1-[8-Chloro-2-(5-methylpyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl}-pyrido[3,2- d]pyrimidin-4-ylamine
A mixture of Intermediate 18 (0.9 g, 2.56 mmol) and Intermediate 30 (0.75 g, 3.07 mmol) in DCM (15 ml) was heated under microwave irradiation at 140°C for 1 hour. The reaction mixture was diluted with DCM and washed with brine, then dried (MgSO4 ) and evaporated in vacuo. The residue was purified by column chromatography (SiO 2 , 05% MeOH in EtOAc) to give the title compound (0.48 g, 39%) as a yellow syrup. H (DMSO-d6) 9.53 (d, J 9.2 Hz, 1H), 9.30 (s, 1H), 8.79 - 8.94 (m, 1H), 8.42 - 8.56 (m, 2H), 8.23 (d, J 1.5 Hz, 1 H), 8.21 (d, J 1.5 Hz, 1 H), 8.06 - 8.16 (m , 2H), 7.90 - 7.94 (m, 1H), 7.70 - 7.83 (m, 2H), 6.74 - 6.79 (m, 1H), 2.22 (s , 3H). LCMS (ES+) 481 (M + H)+, RT 1.51 min.
[00466] EXAMPLE 9
[00467] N-{(R)-1-[8-Chloro-2-(5-methyl-1-oxypyridin-3-yl)quinolin-3-yl]-2,2,2-tri-fluoroethyl}- pyrido[3,2-d]pyrimidin-4-yl-amine
A solution of Example 8 (0.48 g, 1 mmol) in DCM (8 ml) was stirred in an ice bath under nitrogen and 77% MCPBA (0.22 g, 0.98 mmol) was added and stirred at night. The reaction mixture was diluted with DCM, then washed with saturated aqueous NaHCO3 solution, dried (MgSO4 ) and evaporated in vacuo. The residue was purified by column chromatography (SiO 2 , 6 to 10% MeOH in EtOAc), followed by crystallization from 2-propanol, to give the title compound (155 mg, 31%) as a white crystalline solid. . H (DMSO-d6) 9.53 (d, J 9.0 Hz, 1 H), 9.19 (s, 1 H), 8.90 (dd, J 4.2, 1.4 Hz, 1 H ), 8.55 (s, 1H), 8.33 (s, 1H), 8.22 (dd, J 8.5, 1.5 Hz, 1H), 8.17 (dd, J 8 .2, 0.9 Hz, 1H), 8.08 (m, 2H), 7.91 (dd, J 8.5, 4.2 Hz, 1H), 7.73 (m, 1H) , 7.20 (s, 1H), 6.79 (m, 1H), 2.00 (s, 3H). LCMS (ES+) 497 (M + H)+, RT 1.34 min.
[00469] EXAMPLE 10
[00470] N-{(R)-1-[8-Chloro-2-(pyrazin-2-yl)quinolin-3-yl]-2,2,2-trifluoroethyl}pyrido-[3,2-d] - pyrimidin-4-ylamine
A mixture of Intermediate 22 (150 mg, 0.403 mmol) and Intermediate 30 (130 mg, 0.53 mmol) in DCM (4 ml) was heated under microwave irradiation at 140°C for 1 hour. The reaction mixture was diluted with DCM and washed with brine, then dried (MgSO4 ) and evaporated in vacuo. The residue was purified by column chromatography (SiO 2 , 60 to 75% EtOAc in hexane) then freeze dried to give the title compound (135 mg, 65%) as a yellowish white lyophilized solid. H (DMSO-d6) 9.59 (d, J9.4 Hz, 1H), 9.36 (s, 1H), 9.27 (d, J 1.4Hz, 1H), 8.91 (dd, J4.2, 1.3 Hz, 1 H), 8.84 (dd, J 2.5, 1.6 Hz, 1 H), 8.81 (d, J 2.6 Hz, 1 H ), 8.41 (s, 1H), 8.15 (m, 3H), 7.90 (dd, J 8.5, 4.2 Hz, 1H), 7.75 (t, J 7, 9Hz, 2H). LCMS (ES+) 468 (M + H)+, RT 1.56 min.
[00472] EXAMPLE 11
[00473] N-{(R)-1-[8-Chloro-2-(6-methoxypyrazin-2-yl)quinolin-3-yl]-2,2,2-trifluoroethyl}pyrido[3.2 -dipyrimidin-4-ylamine
To a solution of Intermediate 25 (120 mg, 0.25 mmol) in DCM (2 ml) was added a 4 H solution of HCl in 1,4-dioxane (5 ml). The mixture was stirred at room temperature for 10 minutes. The solvent was removed in vacuo and the residue was then partitioned between DCM and a saturated aqueous NaHCO3 solution. The aqueous phase was extracted with more DCM and the combined organic fractions were dried (MgSO4 ) and evaporated. A mixture of the resulting material and Intermediate 30 (88 mg, 0.36 mmol) in DCM (4 ml) was heated under microwave irradiation at 140°C for 1 hour. The reaction mixture was diluted with DCM and washed with brine, then dried (MgSO4 ) and evaporated in vacuo. The residue was purified twice by column chromatography (SiO 2 , 50% EtOAc in hexane) then freeze-dried to give the title compound (30 mg, 24%) as a yellowish white lyophilized solid. H (DMSO-d6) 9.41 (m, 2H), 8.92 (dd, J 4.2, 1.5 Hz, 1H), 8.89 (s, 1H), 8.46 (s , 1H), 8.42 (s, 1H), 8.18 (m, 4H), 7.91 (m, 1H), 7.74 (m, 1H), 4.12 (s, 3H). LCMS (ES+) 498 (M + H)+, RT 1.63 min.
[00475] EXAMPLE 12
[00476] N-{(R)-1-[8-Chloro-2-(6-methylpyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl}-pyrido[3,2- d]pyrimidin-4-amine
A mixture of Intermediate 28 (614 mg, 1.75 mmol) and Intermediate 30 (469 mg, 1.92 mmol) in DCM (10 ml) was heated under microwave irradiation at 140°C for 4 hours. The reaction mixture was partitioned between DCM and water. The aqueous phase was extracted with more DCM and the combined organic fractions were washed with brine, then dried (MgSO4 ) and evaporated in vacuo. The residue was purified by column chromatography (SiO 2 , 0.5 to 10% MeOH in EtOAc) to give the title compound (679 mg, 81%) as a brown foamy gum. H (DMSO-d6) 9.51 (d, J 9.2 Hz, 1 H), 9.31 (s, 1 H), 8.92 (dd, J 4.1, 1.5 Hz, 1 H ), 8.63 (d, J 1.9 Hz, 1 H), 8.50 (s, 1 H), 8.22 (dd, J 8.5, 1.7 Hz, 1 H), 8. 12 (dd, J 8.3, 1.3 Hz, 1H), 8.06 (dd, J 7.5, 1.3 Hz, 1H), 7.93 - 7.89 (m, 2H) , 7.70 (dd, J 7.9, 7.9 Hz, 1H), 7.34 (d, J 7.9Hz, 1H), 6.85 - 6.73 (m, 1H) , 2.54 (s, 3H). LCMS (ES+) 481 (M + H)+, RT 2.36 min.
[00478] EXAMPLE 13
[00479] N-{(R)-1-[8-Chloro-2-(6-methyl-1-oxypyridin-3-yl)quinolin-3-yl]-2,2,2-tri-fluoroethyl}- pyrido[3,2-d]pyrimidin-4-amine
Prepared according to the procedure described for Example 2 using Example 12 (679mg, 1.41mmol), MCPBA (317mg, 1.41mmol) and DCM (30ml). The title compound (458 mg, 65%) was obtained as a creamy colorless solid. H (DMSO-d6) 9.51 (d, J 9.0 Hz, 1 H), 9.21 (s, 1 H), 8.89 (dd, J 4.3, 1.5 Hz, 1 H ), 8.51 (s, 2H), 8.21 (dd, J 8.5, 1.7 Hz, 1H), 8.15 (dd, J 8.3, 1.1 Hz, 1H) , 8.08 (dd, J 7.5, 1.1 Hz, 1 H), 7.90 (dd, J 8.5, 4.1 Hz, 1 H), 7.73 (dd, J 7, 9. 7.9 Hz, 1H), 7.41 - 7.34 (m, 2H), 6.88 - 6.77 (m, 1H), 2.35 (s, 3H). LCMS (ES+) 495 (M + H)+, RT 2.03 minutes.
[00481] EXAMPLE 14
[00482] N-{(R)-1-[8-Methyl-2-(pyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl}pyrido-3,2-c]- pyrimidin-4-amine
Prepared according to the procedure described for Example 1, using Intermediate 36 (0.61 g, 1.92 mmol), 4-chloropyrido[3,2-d]pyrimidine (0.38 g, 2, 31 mmol) and DMAP (0.59 g, 4.82 mmol) in DCM (15 ml). The title compound (93 mg, 10%) was obtained as a yellow gum. H (DMSO-d6) 9.52 (d, J 8.9 Hz, 1 H), 9.25 (s, 1 H), 8.93 (dd, J 4.1, 1.5 Hz, 1 H ), 8.79 (d, J 1.7 Hz, 1H), 8.69 (dd, J 4.7, 1.5 Hz, 1H), 8.50 (s, 1H), 8. 21 (dd, J 8.5, 1.3 Hz, 1 H), 8.07 (ddd, J 7.9, 1.9, 1.9 Hz, 1 H), 7.94 (d, J 8 .7 Hz, 1H), 7.92 (dd, J 8.5, 4.1 Hz, 1H), 7.74 (d, J 6.8 Hz, 1H), 7.62 (dd, J 8.1, 7.5 Hz, 1 H), 7.54 (ddd, J 7.9, 4.9, 0.8 Hz, 1 H), 6.78 (qd, J 7.7, 7 .7 Hz, 1H), 2.69 (s, 3H). LCMS (ES+) 407 (M + H)+, RT 2.42 minutes.
[00484] EXAMPLE 15
[00485] N-{(R)-1-[8-Methyl-2-(1-oxypyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl}-pyrido[3,2- capyrimidin-4-amine
Prepared according to the procedure described for Example 2 using Example 14 (93 mg, 0.21 mmol), MCPBA (47 mg, 0.21 mmol) and DCM (10 ml). The title compound (45 mg, 47%) was obtained as a colorless creamy solid. (DMSO-d6) 9.55 (d, J 9.0 Hz, 1H), 9.20 (s, 1H), 8.91 (dd, J 4.3, 1.5 Hz, 1H), 8.55 (s, 1H), 8.49 (m, 1H), 8.29 (ddd, J 6.4 , 1.7, 1.1 Hz, 1H), 8.21 (dd, J 8.5, 1.5 Hz, 1H), 7.95 (d, J 7.9 Hz, 1H), 7.91 (dd, J 8.5, 4.1 Hz, 1H), 7.76 - 7.73 (m, 1H), 7.64 (dd, J 8.1, 7.3 Hz, 1H), 7.56 - 7.52 (m, 1H), 7.46 (dd, J 7.7, 6.6 Hz, 1H), 6.79 (qd, J 8.1, 8 0.1Hz, 1H), 2.69 (s, 3H). LCMS (ES+) 463 (M + H)+, RT 2.02 minutes.
[00487] EXAMPLE 16
[00488] N-{(R)-1-[7-Fluoro-8-methyl-2-(pyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoro-ethyl}pyrido[3 ,2-d]pyrimidin-4-amine
To a suspension of 4-chloropyrido[3,2-d]pyrimidine (0.66 g, 3.98 mmol) and DMAP (0.49 g, 4.01 mmol) in DCM (14 ml) was added Intermediate 40 (1.12 g, 3.34 mmol). The mixture was heated under microwave irradiation at 140°C for 1 hour. The resulting material was purified by column chromatography (SiO 2 , 0 to 10% MeOH in EtOAc) to give the title compound (626 mg, 40%) as a brown gum. H (DMSO-d6) 9.50 (d, J 9.0 Hz, 1 H), 9.30 (s, 1 H), 8.92 (dd, J 4.3, 1.5 Hz, 1 H ), 8.78 - 8.81 (m, 1H), 8.69 (dd, J 4.9, 1.7 Hz, 1H), 8.50 (s, 1H), 8.21 ( dd, J 8.5, 1.3 Hz, 1H), 8.01 - 8.10 (m, 2H), 7.92 (dd, J 8.5, 4.1 Hz, 1H), 7 .63 (t, J 9.2 Hz, 1 H), 7.54 (dd, J 7.9, 4.9 Hz, 1 H), 6.70 - 6.84 (m, 1 H), 2 .58 (d, J 2.4 Hz, 3H). LCMS (ES+) 465 (M + H)+, RT 2.55 minutes.
[00490] EXAMPLE 17
[00491] N-{(R)-1-[7-Fluoro-8-methyl-2-(1-oxypyridin-3-yl)quinolin-3-yl]-2,2,2-tri-fluoroethyl}- pyrido[3,2-cflpyrimidin-4-amine
A stirred solution of Example 16 (351mg, 0.76mmol) in DCM (10ml) was cooled to 0° C. MCPBA (131mg, 0.76mmol) was added and the mixture was allowed to warm slowly into the mixture. room temperature in 4 hours. The reaction mixture was diluted with DCM (15 ml), washed with saturated aqueous NaHCO3 solution (25 ml) and brine (25 ml), dried (phase separator) and evaporated in vacuo. The residue was purified by column chromatography (SiO 2 , 0 to 20% MeOH in EtOAc), and the resulting material was freeze-dried from acetonitrile/water to give the title compound (152 mg, 43%) as a light yellow solid. H (DMSO-d6) 9.53 (d, J 8.9 Hz, 1 H), 9.24 (s, 1 H), 8.91 (dd, J 4.1, 1.5 Hz, 1 H ), 8.55 (s, 1H), 8.48 - 8.51 (m, 1H), 8.27 - 8.31 (m, 1H), 8.21 (dd, J 8.5 , 1.5Hz, 1H), 8.06 (dd, J9.2, 6.6Hz, 1H), 7.91 (dd, J8.5, 4.1Hz, 1H), 7 .66 (t, J 9.2 Hz, 1H), 7.51 - 7.56 (m, 1H), 7.42 - 7.48 (m, 1H), 6.71 - 6.85 (m, 1H), 2.59 (d, J 2.3Hz, 3H). LCMS (ES+) 481 (M + H)+, RT 2.07 minutes.
[00493] EXAMPLE 18
[00494] N-{(R)-1-[7-Fluoro-8-methyl-2-(2-methylpyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl}pyrido [3,2-d]pyrimidin-4-amine
Prepared according to the procedure described for Example 16, using Intermediate 40 (0.50 g, 1.43 mmol), 4-chloropyrido[3,2-d]pyrimidine (285 mg, 1.72 mmol) ) and DMAP (210mg, 1.72mmol) in DCM (10ml). The title compound (307 mg, 45%) was obtained as a yellow foam. H (DMSO-d6, 400 MHz, 110°C) 9.13 (s, 1H), 8.87 (dd, J 4.0, 1.5 Hz, 1H), 8.55 (dd, J 4.8, 1.5 Hz, 1 H), 8.42 (s, 1 H), 8.17 (dd, J 8.3, 1.5 Hz, 1 H), 8.05 (dd, J 9.1, 6.3 Hz, 1H), 7.87 (dd, J 8.6, 4.3 Hz, 1H), 7.69 (dd, J 7.6, 1.3 Hz, 1 H), 7.56 (t, J 9.1 Hz, 1 H), 7.20 - 7.32 (m, 1 H), 6.52 (q, J 8.1 Hz, 1 H), 2 .58 (d, J 2.5 Hz, 3H), 2.04 - 2.25 (m, 3H). LCMS (ES+) 479 (M + H)+, RT 2.94 min.
[00496] EXAMPLE 19
[00497] N-{(R)-1-[7-Fluoro-8-methyl-2-(2-methyl-1-oxypyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl }pyrido[3,2-d]pyrimidin-4-amine
Prepared according to the procedure described for Example 17 using Example 18 (304mg, 0.64mmol), MCPBA (110mg, 0.64mmol) and anhydrous DCM (10ml). The title compound (94 mg, 30%) was obtained as a white solid.H (DMSO-d6, 400 MHz, 110°C) 9.14 (s, 1H), 8.84 - 8.90 (m , 1H), 8.35 - 8.60 (m, 1H), 8.33 (d, J 7.6Hz, 1H), 8.18 (dd, J 8.6, 1.5Hz , 1H), 8.07 (dd, J 9.1, 6.3 Hz, 1H), 7.87 (dd, J 8.6, 4.3Hz, 1H), 7.60 (t , J 9.1 Hz, 1H), 7.10 - 7.50 (m, 2H), 6.58 (q, J 8.1 Hz, 1H), 2.58 (d, J 2.5 Hz, 3H), 1.64 - 2.34 (m, 3H). LCMS (ES+) 495 (M + H)+, RT 2.08 min.
[00499] EXAMPLE 20
[00500] N-{(R)-1-[7-Fluoro-8-methyl-2-(5-methylpyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl}pyrido [3,2-d]pyrimidin-4-amine
A mixture of Intermediate 48 (500 mg, 1.43 mmol) and Intermediate 30 (420 mg, 1.72 mmol) in DCM (10 ml) was heated under microwave irradiation at 160°C for 30 minutes. The reaction mixture was diluted with DCM (40 ml) and washed with water (2 x 50 ml). The aqueous phase was extracted with more DCM (50 ml) and the combined organic fractions were dried (phase separator) and evaporated in vacuo. The residue was purified by column chromatography (SiO 2 , 0 to 10% MeOH in EtOAc) to give the title compound (302 mg, 40%) as a dark blue solid.H (DMSO-d6) 9.48 (d, J 9.2 Hz, 1 H), 9.26 (s, 1 H), 8.92 (dd, J 4.3, 1.7 Hz, 1 H), 8.58 (d, J 2.1 Hz, 1 H), 8.52 (s, 1 H), 8.47 - 8.50 (m, 1 H), 8.22 (dd, J 8.5, 1.5 Hz, 1 H), 8.05 (dd, J 8.9, 6.2 Hz, 1H), 7.92 (dd, J 8.5, 4.3 Hz, 1H), 7.76 - 7.80 (m, 1H), 7.63 (t, J 9.0Hz, 1H), 6.69 - 6.83 (m, 1H), 2.58 (d, J 2.3Hz, 3H ), 2.26 (s, 3H). LCMS (ES+) 479 (M + H)+, RT 2.63 min.
[00502] EXAMPLE 21
[00503] N-{(R)-1-[7-Fluoro-8-methyl-2-(5-methyl-1-oxypyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl }pyrido[3,2-d]pyrimidin-4-amine
Prepared according to the procedure described for Example 17 using Example 20 (300mg, 0.63mmol), MCPBA (85mg, 0.49mmol) and anhydrous DCM (10ml). The title compound (101 mg, 32%) was obtained as a white solid. H (DMSO-d6) 9.50 (d, J 9.0 Hz, 1 H), 9.18 (s, 1 H), 8.91 (dd, J 4.1, 1.5 Hz, 1 H ), 8.56 (s, 1H), 8.32 (s, 1H), 8.22 (dd, J 8.7, 1.7 Hz, 1H), 8.05 - 8.14 ( m, 2H), 7.91 (dd, J 8.5, 4.1 Hz, 1H), 7.66 (t, J 9.2 Hz, 1H), 7.26 (s, 1H) , 6.71 - 6.84 (m, 1H), 2.58 (d, J 2.3 Hz, 3H), 2.08 (s, 3H). LCMS (ES+) 495 (M + H)+, RT 2.17 minutes.
[00505] EXAMPLE 22
[00506] N-{(R)-1-[2-(Pyridin-3-yl)-8-(trifluoromethyl)quinolin-3-yl]-2,2,2-trifluoroethyl}pyrido[3.2 -d]pyrimidin-4-amine
A mixture of Intermediate 54 (180 mg, 0.49 mmol) and Intermediate 30 (179 mg, 0.74 mmol) in DCM (5 ml) was heated under microwave irradiation at 140°C for 1 hour. The reaction mixture was purified by column chromatography (SiO 2 , EtOAc) to give the title compound (41 mg, 17%) as a brown gum. LCMS (ES+) 501.2 (M + H)+, RT 1.65 minutes.
[00508] EXAMPLE 23
[00509] N-{(R)-1-[2-(1-Oxypyridin-3-yl)-8-(trifluoromethyl)quinolin-3-yl]-2,2,2-trifluoroethyl}-pyrido[3, 2-d]pyrimidin-4-amine
A stirred solution of Example 22 (33mg, 0.07mmol) in DCM (5ml) was cooled (ice bath) and MCPBA (11mg, 0.05mmol) was added. The mixture was allowed to stir for 5 hours at below 5°C. After this time, the reaction mixture was partitioned between DCM and saturated aqueous Na2CO3 solution. The aqueous phase was extracted with more DCM and the combined organic fractions were dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography (SiO 2 , 0 to 20% MeOH in EtOAc) to give the title compound (21 mg, 58%) as a pale yellow powder. H (DMSO-d6) 8.81 (d, J 1.4 Hz, 1 H), 8.77 (dd, J 1.5, 4.2 Hz, 1 H), 8.63 (s, 1 H ), 8.53 (s, 1H), 8.30 (dd, J 6.5, 1.0 Hz, 1H), 8.14 - 8.01 (m, 3H), 7.86 (d , J 8.3 Hz, 1H), 7.76 (d, J 8.0Hz, 1H), 7.70 (dd, J 4.2, 8.5Hz, 1H), 7.61 (m, 1H), 7.40, (dd, J 6.7, 7.8 Hz, 1H), 6.56 - 6.47 (m, 1H). LCMS (ES+) 517.2 (M + H)+, RT 2.06 minutes.
[00511] EXAMPLE 24
[00512] N-{(R)-1-[2-(6-Methylpyridin-3-yl)-5,6,8-trifluoroquinolin-3-yl]-2,2,2-trifluoroethyl}-pyrido[3 ,2-d]pyrimidin-4-amine
A mixture of Intermediate 62 (160 mg, 0.43 mmol) and Intermediate 30 (124 mg, 0.51 mmol) in DCM (5 ml) was heated under microwave irradiation at 140°C for 3 hours. The reaction mixture was purified directly using column chromatography (SiO 2 , 0 to 5% MeOH in DCM) to give the title compound (210 mg, 93%) as a green solid. LCMS (ES+) 501 (M + H)+, RT 1.481 min.
[00514] EXAMPLE 25
[00515] N-{(R)-1-[2-(6-Methyl-1-oxypyridin-3-yl)-5,6,8-trifluoroquinolin-3-yl]-2,2,2-trifluoroethyl} pyrido[3,2-cflpyrimidin-4-amine
A stirred solution of Example 24 (210mg, 0.42mmol) in DCM (20ml) was cooled to 0° C. MCPBA (61mg, 0.3mmol) was added and the mixture was allowed to warm slowly into the room temperature in 3 hours. The reaction mixture was partitioned between DCM and a saturated aqueous NaHCO3 solution. The organic layer was extracted using DCM and passed through a phase separator. The resulting yellow solution was evaporated in vacuo. The residue was purified by column chromatography (SiO 2 , 0 to 10% MeOH in DCM) to give the title compound (54 mg) as a freeze-dried white solid. H (DMSO-d6) 9.89 (d, J 9.5 Hz, 1H), 9.48 (s, 1H), 8.92 (dd, J 4.0 Hz, 1H), 8. 55 (s, 1H), 8.53 (s, 1H), 8.23 - 8.13 (m, 2H) 7.93 - 7.89 (m, 1H), 7.49 (d, J 8.1 Hz, 1H), 7.42 (d, J 5.0Hz, 1H), 6.92 - 6.68 (m, 1H), 2.49 (s, 3H). LCMS pH 3 (ES+) 517 (M + H)+, RT 1.886 minutes; LCMS pH 10 (ES+) 517 (M + H)+, RT 1.982 minutes.
[00517] EXAMPLE 26
[00518] N-{(R)-1-[8-Chloro-2-(pyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl}-N-methyl-pyrido[3, 2-dipyrimidin-4-ylamine
A stirred solution of Example 1 (92 mg, 0.197 mmol) in DMF (10 ml) was cooled to 0°C. NaH (60%; 9 mg, 0.217 mmol) was added and the mixture was stirred at 0° C for 5 minutes. Methyl iodide (30 mg, 0.207 mmol) was added and the mixture was stirred at room temperature for 16 hours. Water (0.5 ml) was added and the mixture was evaporated in vacuo. The residue was partitioned between DCM and water. The aqueous phase was extracted with more DCM, the combined organic fractions were washed with brine and dried (Na2SO4), then the solvent was evaporated in vacuo. The residue was purified twice by column chromatography (SiO 2 , 0 to 35% MeOH in EtOAc) to give the title compound (16 mg, 17%) as a yellowish white solid. H (DMSO-d6) 9.00 (d, J 1.7 Hz, 1 H), 8.77 (dd, J 4.8, 1.6 Hz, 1 H), 8.73 - 8.70 ( m, 2H), 8.27 (dt, J 7.8, 1.8 Hz, 1H), 8.11 (dd, J 8.3, 1.2 Hz, 1H), 8.01 (s , 1H), 7.98 (dd, J 7.5, 1.2 Hz, 1H), 7.85 (dd, J 8.5, 1.2 Hz, 1H), 7.71 (dd , J 8.5, 4.4 Hz, 1H), 7.66 - 7.56 (m, 2H), 5.93 (q, J 7.7 Hz, 1H), 3.53 (s, 3H). LCMS (ES+) 481 (M + H)+, RT 2.31 min.
[00520] EXAMPLE 27
[00521] N-{(R)-1-[8-Chloro-2-(pyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl}-N-(1-oxypyrido-[ 3,2-dipyrimidin-4-yl)amine
A stirred solution of Example 1 (955mg, 2.05mmol) in DCM (40ml) was cooled to 0°C MCPBA (410mg, 1.84mmol) was added and the mixture was allowed to warm slowly into the mixture. room temperature in 3 hours. The reaction mixture was partitioned between DCM and a saturated aqueous NaHCO3 solution. The aqueous phase was extracted with more DCM and the combined organic fractions were washed with brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography (SiO 2 , 3 to 60% MeOH in EtOAc) to give the title compound (39 mg, 4%) as a yellow solid. H (DMSOd6) 9.64 - 9.52 (m, 1H), 9.30 (s, 1H), 9.06 (dd, J 4.2, 1.3Hz, 1H), 8, 78 - 8.71 (m, 2H), 8.67 (dd, J 4.9, 1.6 Hz, 1H), 8.64 (s, 1H), 8.16 - 8.01 (m , 4H), 7.75 - 7.69 (m, 1H), 7.52 (ddd, J 7.8, 4.9, 0.7 Hz, 1H), 6.65 - 6.52 ( m, 1H). LCMS (ES+) 483 (M + H)+, RT 1.87 min.
[00523] EXAMPLE 28
[00524] N-{(R)-1-[8-Chloro-2-(1-oxypyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl}-N-(1-oxy - pyrido[3,2-dipyrimidin-4-yl)amine
Prepared according to the procedure described for Example 27. The last fractions of the column gave the title compound (50 mg, 5%) as a yellow solid. H (DMSO-d6) 9.79 (br s, 1H), 9.18 (s, 1H), 8.97 (m, 1H), 8.69 - 8.52 (m, 2H), 8.49 (s, 1H), 8.32 - 8.27 (m, 1H), 8.14 (dd, J 8.3, 1.2 Hz, 1H), 8.07 (dd, 1H), J 7.5, 1.1 Hz, 1 H), 8.02 - 7.93 (m, 1 H), 7.71 (t, J 7.9 Hz, 1 H), 7.60 - 7, 53 (m, 1H), 7.52 - 7.45 (m, 1H), 6.56 - 6.40 (m, 1H). LCMS (ES+) 499 (M + H)+, RT 1.53 minutes.
[00526] EXAMPLE 29
[00527] N-{(5)-1[8-Chloro-2-(pyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl}pyrido-[3,2-d]- pyrimidin-4-ylamine
A mixture of Intermediate 65 (0.16 g, 0.46 mmol), 4-chloropyrido[3,2-d]-pyrimidine (0.076 g, 0.46 mmol) and DMAP (0.11 g, 0 .92 mmol) in DCM (10 ml) was heated under microwave irradiation at 140°C for 1 hour. The reaction mixture was partitioned between DCM and water. The aqueous phase was extracted with more DCM and the combined organic fractions were washed with brine, then dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography (SiO 2 , 020% MeOH in EtOAc) and then further purified by preparative HPLC to give the title compound (15 mg, 7%) as a yellowish white solid. H (DMSO-d6) 9.54 (br s, 1H), 9.34 (s, 1H), 8.92 (dd, J 4.2, 1.4Hz, 1H), 8.77 (d, J 1.7Hz, 1H), 8.68 (dd, J 4.8, 1.6Hz, 1H), 8.49 (s, 1H), 8.21 (dd, J 8.5, 1.5 Hz, 1H), 8.13 (dd, J 8.3, 1.0 Hz, 1H), 8.09 - 8.03 (m, 2H), 7.92 ( dd, J 8.5, 4.2 Hz, 1 H), 7.72 (t, J 7.9 Hz, 1 H), 7.52 (ddd, J 7.7, 4.8, 0.4 Hz, 1H), 6.77 (q, J 7.7Hz, 1H). LCMS (ES+) 467 (M + H)+, RT 2.28 minutes.
[00529] EXAMPLE 30
[00530] N-{(5)-1-[8-Chloro-2-(1-oxypyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl}-pyrido[3,2- d]-pyrimidin-4-ylamine
[00531] A mixture of Intermediate 68 (0.34 g, 0.98 mmol), Intermediate 30 (0.285 g, 1.17 mmol) and p-toluenesulfonic acid (0.019 g, 0.098 mmol) in chloroform (75 ml) was heated to reflux for 16 hours. The reaction mixture was partitioned between DCM and water. The aqueous phase was extracted with more DCM and the combined organic fractions were washed with saturated aqueous NaHCO3 solution and brine, then dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography (SiO 2 , 320% MeOH in EtOAc) to give the title compound (364 mg, 77%) as a yellowish white solid. H (DMSO-d6) 9.57 (d, J 9.0 Hz, 1 H), 9.27 (s, 1 H), 8.90 (dd, J 4.2, 1.5 Hz, 1 H ), 8.54 (s, 1H), 8.50 (t, J 1.3Hz, 1H), 8.28 - 8.07 (m, 4H), 7.91 (dd, J 8, 5, 4.2 Hz, 1H), 7.78 - 7.70 (m, 1H), 7.51 - 7.46 (m, 1H), 7.40 (dd, J 7.6, 6.5Hz, 1H), 6.86 - 6.74 (m, 1H). LCMS (ES+) 483 (M + H)+, RT 1.86 minutes.
[00532] EXAMPLE 31
[00533] N-{(R)-1-[2-(Pyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl}pyrido[3,2-d]-pyrimidin-4- the mine
A mixture of Intermediate 72 (0.67 g, 2.21 mmol) and Intermediate 30 (0.65 g, 2.65 mmol) in DCM (12 ml) was heated under microwave irradiation at 140°C for 1 hour. The reaction mixture was partitioned between DCM and water. The aqueous phase was extracted with more DCM and the combined organic fractions were washed with brine, then dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography (SiO 2 , 0 to 20% MeOH in EtOAc) to give the title compound (291 mg, 30%) as a dark blue solid. H (DMSO-d6) 9.52 (d, J 9.2 Hz, 1 H), 9.28 (s, 1 H), 8.92 (dd, J 4.2, 1.5 Hz, 1 H ), 8.74 (dd, J 2.2, 0.7 Hz, 1 H), 8.67 (dd, J 4.8, 1.6 Hz, 1 H), 8.48 (s, 1 H ), 8.21 (dd, J 8.5, 1.6 Hz, 1 H), 8.13 (dd, J 8.2, 0.7 Hz, 1 H), 8.08 (d, J 8 0.6Hz, 1H), 8.05 - 8.00 (m, 1H), 7.94 - 7.86 (m, 2H), 7.77 - 7.71 (m, 1H), 7 .51 (ddd, J 7.8, 4.9, 0.8 Hz, 1H), 6.74 (quint, J 8.3 Hz, 1H). LCMS (ES+) 433 (M + H)+, RT 1.99 minutes.
[00535] EXAMPLE 32
[00536] N-{(R)-1-[2-(1-Oxypyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl}pyrido-[3,2-d]pyrimidin -4-amine
A stirred solution of Example 31 (273mg, 0.632mmol) in DCM (10ml) was cooled to 0° C. MCPBA (98mg, 0.569mmol) was added and the mixture was allowed to warm slowly to room temperature in 3°C. hours. The reaction mixture was partitioned between DCM and a saturated aqueous NaHCO3 solution. The aqueous phase was extracted with more DCM and the combined organic fractions were washed with brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography (SiO 2 , 0 to 25% MeOH in EtOAc) to give the title compound (66 mg, 23%) as a yellowish white solid. H (DMSO-d6) 9.54 (d, J 9.1 Hz, 1 H), 9.21 (s, 1 H), 8.91 (dd, J 4.2, 1.6 Hz, 1 H ), 8.54 (s, 1H), 8.47 (t, J 1.3Hz, 1H), 8.26 - 8.07 (m, 4H), 7.94 - 7.87 (m , 2H), 7.79 - 7.72 (m, 1H), 7.50 - 7.38 (m, 2H), 6.76 (quint, J 8.1 Hz, 1H). LCMS (ES+) 409 (M + H)+, RT 1.71 min.
[00538] EXAMPLE 33
[00539] N-{(R)-1-[8-Chloro-2-(6-chloropyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl}-pyrido[3,2- d]pyrimidin-4-ylamine
[00540] A mixture of Intermediate 76 (0.37 g, 0.995 mmol) and Intermediate 30 (0.27 g, 1.09 mmol) in DCM (5 ml) was heated under microwave irradiation at 140°C for 30 minutes . The reaction mixture was partitioned between DCM and water. The aqueous phase was extracted with more DCM and the combined organic fractions were washed with brine, then dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography (SiO 2 , 40 to 100% EtOAc in hexane) to give the title compound (371 mg, 74%) as a yellow gum. H (DMSO-d6) 9.55 (d, J 9.0 Hz, 1 H), 9.29 (s, 1 H), 8.91 (dd, J4.2, 1.5 Hz, 1 H) , 8.62 (dd, J 2.4, 0.4 Hz, 1 H), 8.51 (s, 1 H), 8.22 (dd, J 8.5, 1.5 Hz, 1 H) , 8.16 - 8.06 (m, 3H), 7.92 (dd, J 8.5, 4.2 Hz, 1H), 7.76 - 7.69 (m, 1H), 7. 61 (dd, J 8.2, 0.5 Hz, 1H), 6.73 (quint, J 8.1 Hz, 1H). LCMS (ES+) 501 (M + H) RT 2.67 minutes.
[00541] EXAMPLE 34
[00542] N-{(R)-1-[2-(2-Methyl-1-oxypyridin-3-yl)-8-(trifluoromethyl)quinolin-3-yl]-2,2,2-trifluoroethyl}pyroxide [3,2-d]pyrimidin-4-amine
[00543] A mixture of Intermediate 84 (395 mg, 1.0 mmol), Intermediate 30 (270 mg, 1.1 mmol) and p-toluenesulfonic acid (25 mg) in chloroform (5 ml) was heated to 70° C overnight. The reaction mixture was cooled to room temperature, diluted with DCM (20 ml), washed with water (2 x 10 ml) and brine (10 ml), then dried (Na2SO4), filtered and concentrated in vacuo. The resulting yellowish white foam was purified by column chromatography (SiO 2 , 8% EtOAc in MeOH). The colorless glass thus obtained was freeze-dried from MeCN/H2O to give the title compound (255 mg, 48%) as a white solid.H (DMSO-d6; as a mixture of approximately 0.55:0 .45 of Rotamers) 9.61 (d, J 9.2 Hz, 0.45H), 9.52 (d, J 9.2 Hz, 0.55H), 9.41 (s, 0.45H), 9.21 (s, 0.55H), 8.93 (dd, J 4.2, 1.5 Hz, 0.45H), 8.84 (dd, J 4.1, 1.4 Hz, 0. 55H), 8.56 (m, 1H), 8.49 (d, J 7.9 Hz, 0.5H), 8.38 (d, J 6.3 Hz, 0.4H), 8.33 (m, 1.5H), 8.22 (m, 1.5H), 7.90 (m, 2H), 7.46 (m, 1.1H), 7.23 (m, 0.9H) , 6.65 (m, 1H), 2.19 (s, 1.4H), 1.61 (s, 1.6H). LCMS (ES+) 531.2 (M + H)+.
[00544] EXAMPLE 35
[00545] N-{(R)-1-[8-(Methanesulfonyl)-2-(2-methylpyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl}pyrido[3.2 -dipyrimidin-4-amine
Intermediate 92 (340 mg, 0.86 mmol) and Intermediate 30 (294 mg, 1.29 mmol) were suspended in DCM and heated under microwave irradiation at 140°C for 1 hour. The reaction mixture was cooled and partitioned between DCM and the sodium hydrogen sulfate solution, then dried over sodium sulfide and concentrated. The crude material was purified by column chromatography (SiO 2 , EtOAc/5% MeOH) to give the title compound (62%) as a pale solid. H (DMSO-d6; 1:1 mixture of Rotamers) 9.55 (m, 0.5H), 9.47 (s, 1H), 9.29 (s, 0.5H), 8.94 - 8 .84 (m, 1H), 8.60 (m, 1H), 8.49 - 8.41 (m, 2.5H), 8.29 - 8.14 (m, 1.5H), 7 .97 - 7.85 (m, 2.5H), 7.72 (m, 0.5H), 7.41 (m, 0.5H), 7.17 (m, 0.5H), 6.58 (m, 1H), 3.47 (s, 1.5H), 3.40 (s, 1.5H), 2.29 (s, 1.5H), 1.82 (s, 1.5H) . LCMS (ES+) 525.0 (M + H)+, RT 1.88 min.
[00547] EXAMPLE 36
[00548] N-{(R)-1-[8-(methanesulfonyl)-2-(2-methyl-1-oxypyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl}pyrido [3,2-dipyrimidin-4-amine
A stirred solution of Example 35 (500 mg, 0.95 mmol) in DCM (20 ml) was cooled to 0° C. MCPBA (150 mg, 0.76 mmol) was added and the mixture was allowed to warm slowly into the room temperature in 4 hours. The reaction mixture was diluted with DCM (15 ml) and washed with saturated aqueous NaHCO3 (25 ml) and brine (25 ml), dried (phase separator) and evaporated in vacuo. The residue was purified by preparative HPLC to give the title compound (36%) as a pale yellow solid. H (DMSO-d6; 1:1 mixture of Rotamers) 9.60 (d, J 9.1 Hz, 0.5H), 9.56 (d, J 9.5 Hz, 0.5H), 9.40 ( s, 0.5H), 9.27 (s, 0.5H), 8.92 - 8.84 (m, 1H), 8.64 - 8.56 (m, 1H), 8.54 ( s, 0.5H), 8.54 - 8.50 (m, 1H), 8.38 (m, 0.5H), 8.31 (s, 0.5H), 8.25 (m, 0 .5H), 8.24 - 8.17 (m, 1H), 7.99 - 7.95 (m, 1H), 7.95 - 7.86 (m, 1H), 7.53 - 7.46 (m, 1H), 7.28 (m, 0.5H), 7.17 (m, 0.5H), 6.72 - 6.59 (br m, 1H), 3.46 (s, 1.5H), 3.40 (s, 1.5H), 2.21 (s, 1.5H), 1.63 (s, 1.5H). LCMS (ES+) 541.0 (M + H)+, RT 1.62 and 1.66 minutes.
[00550] EXAMPLE 37
[00551] N-{(R)-1-[8-(Methanesulfonyl)-2-(pyridin-3-yl)quinolin-3-yl]-2,2,2-tri-fluoroethyl}-pyrido[3, 2-d]pyrimidin-4-amine
Intermediate 99 (870 mg, 2.28 mmol) and Intermediate 30 (669 mg, 2.74 mmol) in DCM were heated under microwave irradiation at 140°C for 1 hour. The reaction mixture was cooled and partitioned between DCM and the sodium hydrogen carbonate solution, then dried over sodium sulphide and concentrated. Chromatography (30 to 70% ethanol-water) on C-18 reverse phase silica gave the title compound (350 mg). H (DMSO-d6) 9.60 (d, J 9.1 Hz, 1 H), 9.46 (s, 1 H), 8.93 (dd, J 4.2, 1.4 Hz, 1 H ), 8.85 (d, J 1.9 Hz, 1H), 8.70 (dd, J 4.8, 1.6 Hz, 1H), 8.51 (m, 3H), 8.22 (dd, J 8.5, 1.5 Hz, 1H), 8.15 (dt, J 7.8, 1.9 Hz, 1H), 7.94 (m, 2H), 7.56 ( m, 1H), 6.85 (m, 1H), 3.54 (s, 3H). LCMS (ES+) 511 (M + H)+, RT 1.87 minutes.

权利要求:
Claims (10)
[0001]
1. Compound, characterized in that it is of the formula (IIA), or a pharmaceutically acceptable salt thereof:
[0002]
2. Compound according to claim 1, characterized in that it is represented by the formula (IIB), or a pharmaceutically acceptable salt thereof:
[0003]
3. Compound according to claim 1 or 2, characterized in that R18 represents hydrogen.
[0004]
4. Compound according to any one of claims 1 to 3, characterized in that R1 represents chlorine.
[0005]
5. Compound according to any one of claims 1 to 4, characterized in that R2 represents hydrogen.
[0006]
6. Pharmaceutical composition, characterized in that it comprises a compound of formula (IIA) as defined in claim 1 or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.
[0007]
7. Use of a compound of the formula (IIA) as defined in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that it is in the manufacture of a drug for the treatment and/or prevention of a disorder for which the administration of a selective PI3K inhibitor is indicated.
[0008]
8. Compound, characterized in that it is N-{(R)-1-[8-Chloro-2-(1-oxypyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl}- pyrido[3,2-d]pyrimidin-4-ylamine.
[0009]
9. Pharmaceutical composition, characterized in that it comprises N-{(R)-1-[8-chloro-2-(1-oxypyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethylIpyrido [3,2-d]pyrimidin-4-ylamine in association with a pharmaceutically acceptable carrier.
[0010]
10. Use of N-{(R)-1-[8-chloro-2-(1-oxypyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl}pyrido[3,2- d]pyrimidin-4-ylamine, characterized in that it is for the manufacture of a drug for the treatment and/or prevention of an inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncologic, nociceptive or ophthalmic condition.

类似技术:

---

公开号 | 公开日 | 专利标题

---

KR101880280B1|2018-07-20|Quinoline and quinoxaline derivatives as kinase inhibitors

---

ES2737696T3|2020-01-15|Pyrazolopyridines and pyrazolopyrimidines

---

CN107072985B|2020-02-07|Therapeutic inhibiting compounds

---

EP2499126B1|2015-01-07|Fused bicyclic pyridine and pyrazine derivatives as kinase inhibitors

---

EP2240494B1|2016-03-30|Thieno-pyridine derivatives as mek inhibitors

---

US8653272B2|2014-02-18|Fused pyridine derivatives as kinase inhibitors

---

US20080269268A1|2008-10-30|Substituted Phenylamino-Pyrimidines

---

JP2007514759A|2007-06-07|Kinase inhibitor

---

CZ20023945A3|2003-10-15|Substituted pyrrolopyridine derivatives intended for use as phosphodiesterase inhibitors

---

WO2010061180A1|2010-06-03|Quinoline derivatives as p13 kinase inhibitors

---

JP5570981B2|2014-08-13|Condensed thiazole derivatives as kinase inhibitors

---

WO2015110092A1|2015-07-30|4-substituted pyrrolo[2,3-d]pyrimidine compound and use thereof

---

WO2011058112A1|2011-05-19|Fused bicyclic pyrazole derivatives as kinase inhibitors

---

JP2021533085A|2021-12-02|1,2,4-Triazole derivative as a tankylase inhibitor

---

EP2017277A1|2009-01-21|Thiophene-imidazopyridines

同族专利:

---

公开号 | 公开日

---

US9029392B2|2015-05-12|

---

MA34600B1|2013-10-02|

---

HK1181754A1|2013-11-15|

---

ES2544289T3|2015-08-28|

---

HUE025223T2|2016-02-29|

---

SI2614061T1|2015-08-31|

---

JP5820882B2|2015-11-24|

---

AR082799A1|2013-01-09|

---

TW201217371A|2012-05-01|

---

CL2013000603A1|2013-06-21|

---

HRP20150868T1|2015-09-25|

---

SMT201500195B|2015-09-07|

---

EA024162B1|2016-08-31|

---

EA201300317A1|2013-11-29|

---

WO2012032334A1|2012-03-15|

---

DK2614061T3|2015-08-10|

---

AU2011300521B2|2017-05-25|

---

CO6680717A2|2013-05-31|

---

CA2808959A1|2012-03-15|

---

RS54202B1|2015-12-31|

---

MY162396A|2017-06-15|

---

CN103153996B|2016-01-27|

---

NZ607966A|2014-07-25|

---

AU2011300521A1|2013-04-04|

---

BR112013004750A2|2016-08-02|

---

MX2013002529A|2013-10-28|

---

TWI510489B|2015-12-01|

---

PT2614061E|2015-10-01|

---

JP2013537183A|2013-09-30|

---

EP2614061A1|2013-07-17|

---

CY1116734T1|2017-03-15|

---

IL224841A|2017-03-30|

---

US20130296338A1|2013-11-07|

---

SG187924A1|2013-03-28|

---

ZA201301751B|2014-05-28|

---

CA2808959C|2018-07-17|

---

EP2614061B1|2015-05-20|

---

KR101880280B1|2018-07-20|

---

CN103153996A|2013-06-12|

---

PL2614061T3|2015-11-30|

---

ME02203B|2016-02-20|

---

KR20130139909A|2013-12-23|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

AU2008231385B2|2007-03-23|2012-02-02|Amgen Inc.|Delta3- substituted quinoline or quinoxaline derivatives and their use as phosphatidylinositol 3-kinase inhibitors|

---

KR101504773B1|2007-03-23|2015-03-20|암젠 인크|Heterocyclic compounds and their uses|

---

EP2132207A2|2007-03-23|2009-12-16|Amgen Inc.|Heterocyclic compounds and their uses|

---

US8399483B2|2007-12-21|2013-03-19|Ucb Pharma S.A.|Quinoxaline and quinoline derivatives as kinase inhibitors|

---

GB0819593D0|2008-10-24|2008-12-03|Ucb Pharma Sa|Therapeutic agents|

---

WO2011058108A1|2009-11-12|2011-05-19|Ucb Pharma S.A.|Quinoline and quinoxaline derivatives as kinase inhibitors|

---

AR082799A1|2010-09-08|2013-01-09|Ucb Pharma Sa|DERIVATIVES OF QUINOLINE AND QUINOXALINE AS QUINASE INHIBITORS|NZ587051A|2008-01-04|2012-12-21|Intellikine Llc|Isoquinolinone derivatives, compositions and methods of inhibiting phosphatidyl inositol-3 kinase |

---

US8193182B2|2008-01-04|2012-06-05|Intellikine, Inc.|Substituted isoquinolin-1-ones, and methods of use thereof|

---

US8703778B2|2008-09-26|2014-04-22|Intellikine Llc|Heterocyclic kinase inhibitors|

---

JP5789252B2|2009-05-07|2015-10-07|インテリカイン， エルエルシー|Heterocyclic compounds and uses thereof|

---

JP5951600B2|2010-05-21|2016-07-13|インフィニティー ファーマシューティカルズ， インコーポレイテッド|Compounds, compositions and methods for kinase regulation|

---

AR082799A1|2010-09-08|2013-01-09|Ucb Pharma Sa|DERIVATIVES OF QUINOLINE AND QUINOXALINE AS QUINASE INHIBITORS|

---

CN103298474B|2010-11-10|2016-06-29|无限药品股份有限公司|Heterocyclic compound and application thereof|

---

WO2012088266A2|2010-12-22|2012-06-28|Incyte Corporation|Substituted imidazopyridazines and benzimidazoles as inhibitors of fgfr3|

---

AU2012205669B2|2011-01-10|2015-08-20|Infinity Pharmaceuticals Inc.|Processes for preparing isoquinolinones and solid forms of isoquinolinones|

---

WO2013012915A1|2011-07-19|2013-01-24|Infinity Pharmaceuticals Inc.|Heterocyclic compounds and uses thereof|

---

CA2842190A1|2011-07-19|2013-01-24|Infinity Pharmaceuticals Inc.|Heterocyclic compounds and uses thereof|

---

AU2012302197B2|2011-08-29|2016-01-07|Infinity Pharmaceuticals Inc.|Heterocyclic compounds and uses thereof|

---

US8940742B2|2012-04-10|2015-01-27|Infinity Pharmaceuticals, Inc.|Heterocyclic compounds and uses thereof|

---

JP6301321B2|2012-06-13|2018-03-28|インサイト・ホールディングス・コーポレイションＩｎｃｙｔｅ Ｈｏｌｄｉｎｇｓ Ｃｏｒｐｏｒａｔｉｏｎ|Substituted tricyclic compounds as FGFR inhibitors|

---

US8828998B2|2012-06-25|2014-09-09|Infinity Pharmaceuticals, Inc.|Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using PI3 kinase inhibitors|

---

US9388185B2|2012-08-10|2016-07-12|Incyte Holdings Corporation|Substituted pyrrolo[2,3-b]pyrazines as FGFR inhibitors|

---

US9266892B2|2012-12-19|2016-02-23|Incyte Holdings Corporation|Fused pyrazoles as FGFR inhibitors|

---

US9481667B2|2013-03-15|2016-11-01|Infinity Pharmaceuticals, Inc.|Salts and solid forms of isoquinolinones and composition comprising and methods of using the same|

---

MY181497A|2013-04-19|2020-12-23|Incyte Holdings Corp|Bicyclic heterocycles as fgfr inhibitors|

---

US9751888B2|2013-10-04|2017-09-05|Infinity Pharmaceuticals, Inc.|Heterocyclic compounds and uses thereof|

---

PE20160685A1|2013-10-04|2016-07-23|Infinity Pharmaceuticals Inc|HETEROCYCLIC COMPOUNDS AND USES OF THEM|

---

CN104744435B|2013-12-25|2017-03-01|上海医药工业研究院|Quinolines, its salt, its intermediate, preparation method and application|

---

CA2943075A1|2014-03-19|2015-09-24|Infinity Pharmaceuticals, Inc.|Heterocyclic compounds for use in the treatment of pi3k-gamma mediated disorders|

---

WO2015160975A2|2014-04-16|2015-10-22|Infinity Pharmaceuticals, Inc.|Combination therapies|

---

US9708348B2|2014-10-03|2017-07-18|Infinity Pharmaceuticals, Inc.|Trisubstituted bicyclic heterocyclic compounds with kinase activities and uses thereof|

---

US10851105B2|2014-10-22|2020-12-01|Incyte Corporation|Bicyclic heterocycles as FGFR4 inhibitors|

---

MA41551A|2015-02-20|2017-12-26|Incyte Corp|BICYCLIC HETEROCYCLES USED AS FGFR4 INHIBITORS|

---

ES2895769T3|2015-02-20|2022-02-22|Incyte Corp|Bicyclic heterocycles as FGFR inhibitors|

---

US9580423B2|2015-02-20|2017-02-28|Incyte Corporation|Bicyclic heterocycles as FGFR4 inhibitors|

---

GB201506786D0|2015-04-21|2015-06-03|Ucb Biopharma Sprl|Therapeutic use|

---

MX2018003058A|2015-09-14|2018-08-01|Infinity Pharmaceuticals Inc|Solid forms of isoquinolinone derivatives, process of making, compositions comprising, and methods of using the same.|

---

WO2017161116A1|2016-03-17|2017-09-21|Infinity Pharmaceuticals, Inc.|Isotopologues of isoquinolinone and quinazolinone compounds and uses thereof as pi3k kinase inhibitors|

---

GB201604970D0|2016-03-23|2016-05-04|Syngenta Participations Ag|Improvements in or relating to organic compounds|

---

GB201608797D0|2016-05-19|2016-07-06|Ucb Biopharma Sprl|Therapeutic use|

---

US10919914B2|2016-06-08|2021-02-16|Infinity Pharmaceuticals, Inc.|Heterocyclic compounds and uses thereof|

---

US11147818B2|2016-06-24|2021-10-19|Infinity Pharmaceuticals, Inc.|Combination therapies|

---

CN108239076B|2016-12-26|2021-07-06|中国医学科学院药物研究所|Quinazoline compound, preparation method, application and pharmaceutical composition thereof|

---

AR111960A1|2017-05-26|2019-09-04|Incyte Corp|CRYSTALLINE FORMS OF A FGFR INHIBITOR AND PROCESSES FOR ITS PREPARATION|

---

GB201708856D0|2017-06-02|2017-07-19|Ucb Biopharma Sprl|Seletalisib crystalline forms|

---

WO2019213506A1|2018-05-04|2019-11-07|Incyte Corporation|Salts of an fgfr inhibitor|

法律状态:
2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

---

2018-04-03| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

---

2019-01-22| B25A| Requested transfer of rights approved|Owner name: UCB BIOPHARMA SPRL (BE) |

---

2019-07-02| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

---

2019-08-06| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

---

2021-05-25| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

---

2021-06-15| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 02/09/2011, OBSERVADAS AS CONDICOES LEGAIS. |

---

2021-10-26| B25D| Requested change of name of applicant approved|Owner name: UCB BIOPHARMA SRL (BE) |

优先权:

---

申请号 | 申请日 | 专利标题

---

GB1014963.1|2010-09-08|

---

GBGB1014963.1A|GB201014963D0|2010-09-08|2010-09-08|Therapeutic agents|

---

GB1101128.5|2011-01-21|

---

GBGB1101128.5A|GB201101128D0|2011-01-21|2011-01-21|Therapeutic agents|

---

PCT/GB2011/051647|WO2012032334A1|2010-09-08|2011-09-02|Quinoline and quinoxaline derivatives as kinase inhibitors|

---