Patent Grant
8518980
The present invention relates to a method of treatment of Duchenne muscular dystrophy.
Duchenne muscular dystrophy (DMD) is a common, genetic neuromuscular disease associated with the progressive deterioration of muscle function, first described over 150 years ago by the French neurologist, Duchenne de Boulogne, after whom the disease is named. DMD has been characterized as an X-linked recessive disorder that affects 1 in 3,500 males caused by mutations in the dystrophin gene. The gene is the largest in the human genome, encompassing 2.6 million base pairs of DNA and containing 79 exons. Approximately 60% of dystrophin mutations are large insertion or deletions that lead to frameshift errors downstream, whereas approximately 40% are point mutations or small frameshift rearrangements. The vast majority of DMD patients lack the dystrophin protein. Becker muscular dystrophy is a much milder form of DMD caused by reduction in the amount, or alteration in the size, of the dystrophin protein. The high incidence of DMD (1 in 10,000 sperm or eggs) means that genetic screening will never eliminate the disease, so an effective therapy is highly desirable.
A number of natural and engineered animal models of DMD exist, and provide a mainstay for preclinical studies (Allamand, V. & Campbell, K. P. Animal models for muscular dystrophy: valuable tools for the development of therapies. Hum. Mol. Genet. 9, 2459-2467 (2000).) Although the mouse, cat and dog models all have mutations in the DMD gene and exhibit a biochemical dystrophinopathy similar to that seen in humans, they show surprising and considerable variation in terms of their phenotype. Like humans, the canine (Golden retriever muscular dystrophy and German short-haired pointer) models have a severe phenotype; these dogs typically die of cardiac failure. Dogs offer the best phenocopy for human disease, and are considered a high benchmark for preclinical studies. Unfortunately, breeding these animals is expensive and difficult, and the clinical time course can be variable among litters.
The mdx mouse is the most widely used model due to availability, short gestation time, time to mature and relatively low cost (Bulfield, G., Siller, W. G., Wight, P. A. & Moore, K. J. X chromosome-linked muscular dystrophy (mdx) in the mouse. Proc. Natl. Acad. Sci. USA 81, 1189-1192 (1984)).
Since the discovery of the DMD gene about 20 years ago, varying degrees of success in the treatment of DMD have been achieved in preclinical animal studies, some of which are being followed up in humans. Present therapeutic strategies can be broadly divided into three groups: first, gene therapy approaches; second, cell therapy; and last, pharmacological therapy. Gene- and cell-based therapies offer the fundamental advantage of obviating the need to separately correct secondary defects/pathology (for example, contractures), especially if initiated early in the course of the disease. Unfortunately, these approaches face a number of technical hurdles. Immunological responses against viral vectors, myoblasts and newly synthesized dystrophin have been reported, in addition to toxicity, lack of stable expression and difficulty in delivery.
Pharmacological approaches for the treatment of muscular dystrophy differ from gene- and cell-based approaches in not being designed to deliver either the missing gene and/or protein. In general, the pharmacological strategies use drugs/molecules in an attempt to improve the phenotype by means such as decreasing inflammation, improving calcium homeostasis and increasing muscle progenitor proliferation or commitment. These strategies offer the advantage that they are easy to deliver systemically and can circumvent many of the immunological and/or toxicity issues that are related to vectors and cell-based therapies. Although investigations with corticosteroids and sodium cromoglycate, to reduce inflammation, dantrolene to maintain calcium homeostasis and clenbuterol to increase muscle strength, have produced promising results none of these potential therapies has yet been shown to be effective in treating DMD.
An alternative pharmacological approach is upregulation therapy. Upregulation therapy is based on increasing the expression of alternative genes to replace a defective gene and is particularly beneficial when an immune response is mounted against a previously absent protein. Upregulation of utrophin, an autosomal paralogue of dystrophin has been proposed as a potential therapy for DMD (Perkins & Davies, Neuromuscul Disord, S1: S78-S89 (2002), Khurana & Davies, Nat Rev Drug Discov 2:379-390 (2003)). When utrophin is overexpressed in transgenic mdx mice it localizes to the sarcolemma of muscle cells and restores the components of the dystrophin-associated protein complex (DAPC), which prevents the dystrophic development and in turn leads to functional improvement of skeletal muscle. Adenoviral delivery of utrophin in the dog has been shown to prevent pathology. Commencement of increased utrophin expression shortly after birth in the mouse model can be effective and no toxicity is observed when utrophin is ubiquitously expressed, which is promising for the translation of this therapy to humans. Upregulation of endogenous utrophin to sufficient levels to decrease pathology might be achieved by the delivery of small diffusible compounds.
We have now found a group of compounds which upregulate endogenous utrophin in predictive screens and, thus, may be useful in the treatment of DMD.
According to the invention, we provide use of a compound of Formula (I)
in which
A1, A2, A3 and A4, which may be the same or different, represent N or CR1,
X is a divalent group selected from O, S(O)n, C═W, NR4, NC(═O)R5 and CR6R7,
W is O, S, NR20,
Y is N or CR8,
one of R4, R5, R6, R8, R9 and NR20 represents -L-R3, in which L is a single bond or a linker group,
additionally, R3-R9, which may be the same or different, independently represent hydrogen or a substituent and
R20 represents hydrogen, hydroxyl, alkyl optionally substituted by aryl, alkoxy optionally substituted by aryl, aryl, CN, optionally substituted alkoxy, optionally substituted aryloxy, optionally substitute alkanoyl, optionally substituted aroyl, NO2, NR30R31, in which R30 and R31, which may be the same or different, represent hydrogen, optionally substituted alkyl or optionally substituted aryl; additionally, one of R30 and R31 may represent optionally substituted alkanoyl or optionally substituted aroyl,
n represents an integer from 0 to 2,
in addition,
when an adjacent pair of A1-A4 each represent CR1, then the adjacent carbon atoms, together with their substituents may form a ring B,
when X is CR6R7, R6 and R7, together with the carbon atom to which they are attached may form a ring C,
when one of A1-A4 is CR1, and R1 represents COR16, R16 is preferably alkoxy or NR10R11,
or a pharmaceutically acceptable salt thereof,
in the manufacture of a medicament for the therapeutic and/or prophylactic treatment of Duchenne muscular dystrophy, Becker muscular dystrophy or cachexia.
Compounds of formula I may exist in tautomeric, enantiomeric and diastereomeric forms, all of which are included within the scope of the invention.
Certain compounds of formula I are novel. According to the invention, we also provide those compounds of formula I which are novel, together with processes for their preparation, compositions containing them, as well as their use as pharmaceuticals.
Some of the compounds falling within the scope of formula I are known, as such, but not as pharmaceuticals. According to the invention, we claim compounds known in the art as such, but not previously described for use as pharmaceuticals, as pharmaceuticals.
All of the compounds of formula I may be made by conventional methods. Methods of making heteroaromatic ring systems are well known in the art. In particular, methods of synthesis are discussed in Comprehensive Heterocyclic Chemistry, Vol. 1 (Eds.: A R Katritzky, C W Rees), Pergamon Press, Oxford, 1984 and Comprehensive Heterocyclic Chemistry II: A Review of the Literature 1982-1995 The Structure, Reactions, Synthesis, and Uses of Heterocyclic Compounds, Alan R. Katritzky (Editor), Charles W. Rees (Editor), E. F. V. Scriven (Editor), Pergamon Pr, June 1996. Other general resources which would aid synthesis of the compounds of interest include March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Wiley-Interscience; 5th edition (Jan. 15, 2001). Of particular relevance are the synthetic methods discussed in WO 2006/044503.
Some general methods of synthesis are as follows.
Benzoxazoles of formula I or pharmaceutically acceptable salts thereof may be prepared from compounds of formula II.
Reaction Conditions:
Formation of the benzoxazole I can be carried out in a variety of ways, as illustrated above.
For example, reaction of the compound of formula II with an acyl derivative, such as the acid or the acid chloride, and heating in an appropriate solvent and an appropriate temperature in the presence of an acid catalyst, for example polyphosphoric acid. This is illustrated above as step (i).
The reaction may be carried out in an aprotic solvent, preferably a polar, aprotic solvent, for example tetrahydrofuran, and a temperature of from −10° C. to +150° C. Generally the reaction may be carried on at the reflux temperature of the solvent at normal pressure.
Alternatively, the compound of formula II may first be reacted with an excess of an acyl derivative R9COX (where X is for example Cl), such that acylation takes place on both oxygen and nitrogen. This can be brought about by, for example, reaction in pyridine at room temperature (step ii). Ring closure to form the compound of formula II can then occur in a subsequent ring closure step in which, for example, the doubly acylated product is heated in xylenes in the presence of an acid catalyst such as a sulphonic acid (step iii).
Another illustrative example of formation of a compound of formula I is shown by steps iv and v. First the amine is coupled to an acid using a peptide coupling reagent. Available coupling reagents are well known to those skilled in the art, and include HBTU, TBTU and HATU. Amide formation in the presence of an appropriate coupling reagent occurs, for example, in DMF in the presence of a nucleophilic catalyst such as pyridine.
When R1═CO2H, this acid may be coupled with an amine as shown by step (vi). Suitable coupling conditions include use of HATU in DMF in the presence of iPr2NEt, R16NH2 at room temperature.
Compounds in which the six membered ring is substituted with an amide derivative are of particular interest. These may be produced from an intermediate amine derivative III.
Reaction Conditions:
Intermediate amine III may be synthesised either by using the method outlined in scheme 1, step (i) wherein R1═NH2, or alternatively, in a two step process as defined by steps (iii) and (iv) of scheme 2. Nitro substituted benzoxazole derivative V is produced from nitro substituted phenyl derivative W, also in a method analogous to that illustrated by scheme 1, step 1, and then the nitro-benzoxazole derivative V is reduced in a subsequent step to give intermediate amine III. The skilled person is well aware of suitable methods to reduce a nitro group to give an amine. Selective methods for reducing NO2 to NH2 include Sn/HCl, or H2/Pd/C in a suitable solvent, e.g. ethanol at a temperature of from 0° to 80° C. or heating in the presence of iron, NH4Cl in industrial methylated spirits/water.
Intermediate amine III can then be coupled as required.
Amide derivatives of formula VI can be produced by coupling amine III with an acyl derivative. This can be achieved by, for example, reaction of an appropriate acid chloride in either pyridine, or in CH2Cl2 (step ii).
Sulfonamide derivatives VII can be produced by reaction of amine III with an appropriate sulfonyl chloride in, for example, CH2Cl2 in the presence of pyridine at room temperature.
Amine derivatives VIII can be produced by use of an appropriate reductive amination strategy. Methods of reductive amination are well known in the art. They include, for example, reaction of the amine with an appropriate aldehyde and sodium triacetoxyborohydride in 1,2-dichloroethane.
Urea derivatives of formula IX can be produced, for example, by reaction of amine III with the appropriate isocyanate, for example, at room temperature in CH2Cl2.
Benzothiazoles of formula X or pharmaceutically acceptable salts thereof may be prepared from compounds of formula XI.
Reaction Conditions:
The compounds of formula XI can be converted to the corresponding amide by, for example, reaction with the appropriate acid chloride in pyridine (step (i)), or by using an appropriate peptide coupling reagent. Such methods are well known to the person skilled in the art as discussed hereinabove.
The amide can then be converted to the nitro-benzothiazole of formula XII in a one-pot procedure involving reaction with Na2S, S8 at elevated temperature in industrial methylated spirit. Nitro derivative XII can be reduced as discussed previously and the resulting primary amine manipulated in an analogous manner to the primary amine in scheme 2 steps (ii), (v), (vi) and (vii).
Reaction Conditions:
Benzimidazoles of formula XII can be produced according to scheme 4. Reaction of a diaminophenyl derivative of formula XIII with an acyl derivative, such as an acid or an acid chloride in an appropriate solvent and at an appropriate temperature in the presence of an acid catalyst, for example polyphosphoric acid, produces a benzimidazole derivative of formula XII. This is illustrated above as step (i). The nitro group may then be reduced and manipulated to produce other functionality as discussed hereinabove.
Alternatively, benzimidazoles may be produced by reacting a di-nitro compound of formula XIV, wherein X represents a leaving group, preferably a halogen such as chlorine or fluorine, with an amine, for example, in DMSO at elevated temperature in the presence of a base. Subsequent selective reduction of one nitro group using sodium dithionite in THF/water can then take place to give a diamine of formula XV. Ring closure to form a benzimidazoles, and manipulation of the nitro group can then proceed as illustrated and discussed previously.
Reaction Conditions:
Benzoxazoles of formula XVI can be made by methods analogous to those discussed previously. For example the method illustrated above (ix) involves heating a compound of formula XVII in an appropriate solvent in the presence of acid catalyst and an appropriate acyl derivative eg a carboxylic acid.
Benzoxazoles of formula XVIII and XIX can be synthesised from the appropriate nitro compound of formula XX. Reduction of the nitro compound XX gives the corresponding amino alcohol XXI (for example using Sn/HCl, or any of the other appropriate methods well known to the person skilled in the art). Benzoxazole formation via reaction of the amino alcohol with an appropriate acyl derivative can then be achieved using any of the methods disclosed hereinabove.
For oxazoles of formula XXIII in which X═Br, a Suzuki coupling reaction can then be used to give further derivatives. An example of appropriate conditions are R1B(OH)2, Pd(PPh3)4, K2CO3, dioxane/water, μwave, in which a benzoxazole of formula XIX results. The person skilled in the art is familiar with Suzuki coupling reactions and could easily manipulate the conditions to produce a wide variety of compounds.
For oxazoles produced by step (ii) in which X═NO2, the nitro group can be reduced to the corresponding amine, using any of the methods well known to the person skilled in the art discussed hereinabove. The amine may then be manipulated using, for example, any of the methods discussed in scheme 2 above, to give, for example, a compound of formula XVIII.
Alternatively, benzoxazoles of formula XVIII can be made, also from a compound of formula XX, via thiocarbamate XXII, which is produced by heating a compound of formula XX with EtOC(S)SK in pyridine. The compound of formula XXII can be converted to the chloride of formula XXIII for example by use of well known reagents such as SOCl2 or POCl3. A Suzuki coupling using, for example, conditions illustrated by step viii above gives a benzoxazole of formula XVIII.
In the above processes it may be necessary for any functional groups, e.g. hydroxy or amino groups, present in the starting materials to be protected, thus it may be necessary to remove one or more protective groups to generate the compound of formula I.
Suitable protecting groups and methods for their removal are, for example, those described in “Protective Groups in Organic Synthesis” by T. Greene and P. G. M. Wutts, John Wiley and Sons Inc., 1991. Hydroxy groups may, for example, be protected by arylmethyl groups such as phenylmethyl, diphenylmethyl or triphenylmethyl; acyl groups such as acetyl, trichloroacetyl or trifluoroacetyl; or as tetrahydropyranyl derivatives. Suitable amino protecting groups include arylmethyl groups such as benzyl, (R,S)-α-phenylethyl, diphenylmethyl or triphenylmethyl, and acyl groups such as acetyl, trichloroacetyl or trifluoroacetyl. Conventional methods of deprotection may be used including hydrogenolysis, acid or base hydrolysis, or photolysis. Arylmethyl groups may, for example, be removed by hydrogenolysis in the presence of a metal catalyst e.g. palladium on charcoal. Tetrahydropyranyl groups may be cleaved by hydrolysis under acidic conditions. Acyl groups may be removed by hydrolysis with a base such as sodium hydroxide or potassium carbonate, or a group such as trichloroacetyl may be removed by reduction with, for example, zinc and acetic acid.
The compounds of formula I, and salts thereof, may be isolated from their reaction mixtures using conventional techniques.
Salts of the compounds of formula I may be formed by reacting the free acid, or a salt thereof, or the free base, or a salt or derivative thereof, with one or more equivalents of the appropriate base or acid. The reaction may be carried out in a solvent or medium in which the salt is insoluble or in a solvent in which the salt is soluble, e.g. ethanol, tetrahydrofuran or diethyl ether, which may be removed in vacuo, or by freeze drying. The reaction may also be a metathetical process or it may be carried out on an ion exchange resin.
Pharmaceutically acceptable salts of the compounds of formula I include alkali metal salts, e.g. sodium and potassium salts; alkaline earth metal salts, e.g. calcium and magnesium salts; salts of the Group III elements, e.g. aluminium salts; and ammonium salts. Salts with suitable organic bases, for example, salts with hydroxylamine; lower alkylamines, e.g. methylamine or ethylamine; with substituted lower alkylamines, e.g. hydroxy substituted alkylamines; or with monocyclic nitrogen heterocyclic compounds, e.g. piperidine or morpholine; and salts with amino acids, e.g. with arginine, lysine etc, or an N-alkyl derivative thereof; or with an aminosugar, e.g. N-methyl-D-glucamine or glucosamine. The non-toxic physiologically acceptable salts are preferred, although other salts are also useful, e.g. in isolating or purifying the product.
Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various optical isomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation.
Substituents that alkyl may represent include methyl, ethyl, butyl, eg sec butyl.
Halogen may represent F, Cl, Br and I, especially Cl.
Examples of substituents that R3 in the compound of formula I may represent include alkyl, alkoxy or aryl, each optionally substituted by one or more, preferably one to three substituents, R2, which may be the same or different.
In addition, when L is single bond, R3 may represent thioalkyl optionally substituted by alkyl or optionally substituted aryl,
thioaryl, in which the aryl is optionally substituted,
optionally substituted aryl,
hydroxyl,
NO2,
CN,
NR10R11,
halogen,
SO2R12,
NR13SO2R14,
C(═W)R16,
OC(═W)NR10R11
NR15C(═W)R17,
P(═O)OR40R41,
R10, R11, R12, R13, R14, R15, R16, R17, R40 and R41, which may be the same or which may be the same or different, represent hydrogen, alkyl optionally substituted by optionally substituted aryl, optionally substituted aryl,
in addition,
NR10R11 together with the nitrogen to which they are attached may form a ring,
R12 may have the same meaning as NR10R11,
when R17 represents NR10R11, that R10 and R11, which may be the same or different, may represent hydrogen, COalkyl and CO optionally substituted aryl,
R16 and R17, which may be the same or different, may each represent
alkyl substituted by one or more of halogen, alkoxy optionally substituted aryl or optionally substituted aryl,
optionally substituted aryloxy,
aryl or NR10R11,
and when R16 or R17 represents NR10R11, one of R10 and R11, may additionally represent CO alkyl optionally substituted or COaryl optionally substituted,
and in addition to the definitions shared with R17, R16 may represent hydroxy.
Examples of substituents that R1 and R2, which may be the same or different, may represent include:
alkyl optionally substituted by one or more halogen, alkoxy or optionally substituted aryl, thioaryl or aryloxy,
alkoxy optionally substituted by optionally by alkyl or optionally substituted aryl,
hydroxyl,
OC(═W)NR10R11
optionally substituted aryl,
thioalkyl optionally substituted by alkyl or optionally substituted aryl,
thioaryl, in which the aryl is optionally substituted,
NO2,
CN,
NR10R11,
halogen,
SO2R12,
NR13SO2R14,
C(═W)R16,
NR15C(═W)R17,
R10, R11, R12, R13, R14, R15, R16 and R17, which may be the same or different, represent hydrogen, alkyl optionally substituted by optionally substituted aryl, optionally substituted aryl,
in addition,
NR10R11 together with the nitrogen to which they are attached may form a ring,
R12 may have the same meaning as NR10R11,
when R17 represents NR10R11, that R10 and R11, which may be the same of different, may represent hydrogen, COalkyl and CO optionally substituted aryl,
R16 may represent hydroxy, alkoxy, or NR10R11,
R17 may represent alkyl substituted by one or more of halogen, alkoxy, optionally substituted aryl or NR10R11,
and when R17 represents NR10R11, that NR10R11 may represent hydrogen, COalkyl and CO optionally substituted aryl.
When L represents a linker group, examples of linker groups that L may represent include:
O, S, (CO)nNR18,
alkylene, alkenylene, alkynylene, each of which may be optionally interrupted by one or more of O, S, NR18, or one or more C—C single, double or triple bonds,
a —N—N— single or double bond,
R18 represents hydrogen, alkyl, COR16.
When L is (CO)nNR18, n may represent 0, 1 or 2, when n is 1 or 2, R18 preferably represents hydrogen.
Although the scope for variation of R4, R5, R6, R7 and R8 is large, preferably R4, R5, R6, R7 and R8, represent hydrogen, alkyl or optionally substituted aryl.
Preferably Y represents N and X represents O, S or NR4. That is preferably the compound according to formula I is a benzoxazole, a benzthiazole or a benzimidazole.
Although any one of R4, R6, R8 or R9 may represent -L-R3—, in preferred compounds R9 represents -L-R3.
Alkyl may represent any alkyl chain. Alkyl includes straight and branched, saturated and unsaturated alkyl, as well as cyclic alkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. However, preferably, when any of the substituents represents alkyl, alkyl is saturated, linear or branched and has from 1 to 10 carbon atoms, preferably from 1 to 8 carbon atoms and more preferably from 1 to 6 carbon atoms. When any of the substituents represents alkyl, a particularly preferred group is cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
Aryl may represent any aromatic system. Preferably, in the compounds of formula I, aryl is an aromatic hydrocarbon or a 5 to 10 membered aromatic heterocycle containing 1 to 4 hetero atoms selected from an oxygen atom, a sulphur atom and a nitrogen atom as a ring constituent besides carbon. We prefer heterocycles which contain one or two heteroatoms. Aromatic heterocycles that may be mentioned include furan, thiophene, pyrrole, pyridine.
Particularly preferably, when aryl is an aromatic hydrocarbon, aryl represents a 6 to 10 membered monocyclic or bicyclic system, for example phenyl or naphthalene.
Saturated and unsaturated heterocycles that may be mentioned include those containing 4 to 7 ring atoms, preferably 5 or 6 ring atoms, preferably containing one to two heteroatoms selected from N, S and O. Heterocycles that may be mentioned include pyrrolidine, piperidine, tetrahydrofuran, piperazine and morpholine. N-containing heterocycles are particularly preferred, eg when NR10R11 forms a heterocyclic ring.
As detailed above, when an adjacent pair of A1-A4 each represent CR1, the adjacent carbon atoms, together with their substituents may form a ring B. Also, when X is CR6R7, R6 and R7, together with the carbon to which they are attached may form a ring C. Preferably ring B and/or ring C is a saturated or unsaturated 3 to 10 membered carbocylic or heterocyclic ring.
Particularly preferably ring B is benzene ring.
Particularly preferably ring C is a 3-10 membered saturated or unsaturated carbocylic ring.
We particularly prefer compounds in which at least one R1 represents NR15C(═W)R17, more particularly the group NR15COR17.
We also prefer compounds in which at least one R1 represents CONR10R11.
For one group of particularly preferred compounds at least one R1 represents an amide group NHCOR17, wherein R17 is selected from:
alkyl C1-C6,
alkyl C1-C6 substituted by phenyl
alkyl C1-C6 substituted by alkoxy C1-C6,
haloalkyl C1-C6,
perfluoroalkyl C1-C6,
phenyl optionally substituted by one or more of halogen, alkyl C1-C6, alkoxy C1-C6, amino, (alkyl C1-C6)amino, di(alkyl C1-C6) amino or phenyl,
CH:CH phenyl,
naphthyl, pyridinyl, thiophenyl and furanyl.
We prefer compounds in which one or both of R1 and R2 are other than —COOH.
For another group of particularly preferred compounds at least one R1 represents a group NR15CONR10R11, then in which R10 and R11, which may be the same or different, are selected from optionally substituted aryl, alkyl and COaryl optionally substituted. A particularly preferred group which at least one of R1 may represent is NHCONHR15 and R15 is selected from phenyl, alkyl C1 to C6 and COphenyl optionally substituted by one or more halogen.
For another group of particularly preferred compounds at least one R1 represents alkyl C1 to C6, optionally substituted by phenyl or a 5 or 6-membered saturated or unsaturated heterocycle containing one to two heteroatoms selected from N, S and O.
For another group of particularly preferred compounds at least one R1 represents COR16 and R16 is alkoxy C1-C6, amino, (alkyl C1-C6)amino or di(alkyl C1-C6) amino.
For another group of particularly preferred compounds at least one R1 represents:
NO2,
halogen,
amino or (alkyl C1-C6)amino or di(alkyl C1-C6) amino in which the alkyl C1 to C6 is optionally substituted by phenyl or a 5 or 6 membered saturated or unsaturated heterocycle,
NHSO2alkyl C1-C6, NHSO2phenyl,
SO2alkyl C1-C6,
phenyl optionally substituted by C1 to C6 alkoxy C1-C6,
a 5-10 membered, saturated or unsaturated, mono- or bi-cyclic heterocycle containing from 1-3 heteroatoms selected from N, S and O.
There is also wide scope for variation of the group R3. Preferably R3 represents aryl and is optionally substituted by one to three substituents, R2, which may be the same or different.
Particularly preferably, R3 is a 5-10 membered aromatic mono- or bi-cyclic system, especially a hydrocarbon 5-10 membered aromatic mono- or bi-cyclic system, for example benzene or naphthalene.
Alternatively, the 5-10 membered aromatic mono- or bi-cyclic system, may be a heterocyclic system containing up to three heteroatoms selected from N, O and S, for example a thiophene, furan, pyridine or pyrrole.
Preferably the substituent(s) R2 is/are selected from:
alkyl C1-C6, optionally substituted by thiophenyl or phenoxy, each optionally substituted by halogen,
alkoxy C1-C6
phenyl,
thioalkyl C1-C6
thiophenyl, optionally substituted by halogen,
NO2,
CN
NR10R11, in which R10 and R11, which may be the same or different represent hydrogen, alkyl C1-C6, or together with the nitrogen to which they are attached form a 5 to 7 membered ring which may contain one or more additional heteroatoms selected from N, O and S,
halogen
SO2R12, in which R12 represents a 5 to 7 membered ring which may contain one or more additional heteroatoms selected from N, O and S
NHCOR17, in which R17 represents
Particularly preferably when R2 represents NR10R11, NR10R11 represents N-pyrrole, N-piperidine, N′(C1-C6) alkyl N piperazine or N-morpholine.
Preferably the linker group L represents:
A1-A4 may represent N or CR1. Consequently, the benzoxazole six membered ring may contain 1, 2, 3 or 4 nitrogen atoms. Embodiments of the invention exist in which two of A1-A4 represent nitrogen, one of A1-A4 represents nitrogen and in which all of A1-A4 represents CR1.
In a particularly preferred group of compounds:
A1, A2, A3 and A4, which may be the same or different, represent N or CR1,
X is a divalent group selected from O, S(O)n, C═W, NR4, NC(═O)R5 and CR6R7,
W is O, S, NR20,
Y is N or CR8,
one of R4, R5, R6, R8, R9 and NR20 represents -L-R3, in which L is a single bond or a linker group,
additionally, R4-R9, which may be the same or different, independently represent hydrogen or a substituent and
R20 represents hydrogen, hydroxyl, alkyl optionally substituted by aryl, alkoxy optionally substituted by aryl, aryl, CN, optionally substituted alkoxy, optionally substituted aryloxy, optionally substitute alkanoyl, optionally substituted aroyl, NO2, NR30R31, in which R30 and R31, which may be the same or different, represent hydrogen, optionally substituted alkyl or optionally substituted aryl; additionally, one of R30 and R31 may represent optionally substituted alkanoyl or optionally substituted aroyl,
n represents an integer from 0 to 2,
R3 represents alkyl, alkoxy or aryl, each optionally substituted by one to three substitutents, R2, which may be the same or different
R1 and R2, which may be the same or different, represent:
alkyl optionally substituted by one or more halogen, alkoxy or optionally substituted aryl, thioaryl or aryloxy,
alkoxy optionally substituted by optionally by alkyl or optionally substituted aryl,
hydroxyl,
OC(═W)NR10R11
optionally substituted aryl,
thioalkyl optionally substituted by alkyl or optionally substituted aryl,
thioaryl, in which the aryl is optionally substituted,
NO2,
CN,
NR10R11,
halogen,
SO2R12,
NR13SO2R14,
C(═W)R16,
NR15C(═W)R17,
R10, R11, R12, R13, R14, R15, R16 and R17, which may be the same or different, represent hydrogen, alkyl optionally substituted by optionally substituted aryl, optionally substituted aryl,
in addition,
NR10R11 together with the nitrogen to which they are attached may form a ring,
R12 may have the same meaning as NR10R11,
when R17 represents NR10R11, that NR10R11 may represent hydrogen, COalkyl and CO optionally substituted aryl,
R16 may represent hydroxy, alkoxy, or NR10R11,
R17 may represent alkyl substituted by one or more of halogen, alkoxy, optionally substituted aryl or NR10R11,
and when R17 represents NR10R11, that NR10R11 may represent hydrogen, COalkyl and CO optionally substituted aryl,
and in addition,
when an adjacent pair of A1-A4 each represent CR1, then the adjacent carbon atoms, together with their substituents may form a ring B,
when X is CR6R7, R6 and R7, together with the carbon atom to which they are attached may form a ring C,
or a pharmaceutically acceptable salt thereof,
in the manufacture of a medicament for the therapeutic and/or prophylactic treatment of Duchenne muscular dystrophy, Becker muscular dystrophy or cachexia.
We also provide a method for the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy or cachexia in a patient in need thereof, comprising administering to the patient an effective amount of a compound of formula (I) or a pharmaceutical acceptable salt.
The compounds of formula I for use in the treatment of DMD will generally be administered in the form of a pharmaceutical composition.
Thus, according to a further aspect of the invention there is provided a pharmaceutical composition including preferably less than 80% w/w, more preferably less than 50% w/w, e.g. 0.1 to 20%, of a compound of formula I, or a pharmaceutically acceptable salt thereof, as defined above, in admixture with a pharmaceutically acceptable diluent or carrier.
We also provide a process for the production of such a pharmaceutical composition which comprises mixing the ingredients. Examples of pharmaceutical formulations which may be used, and suitable diluents or carriers, are as follows:
for intravenous injection or infusion—purified water or saline solution;
for inhalation compositions—coarse lactose;
for tablets, capsules and dragees—microcrystalline cellulose, calcium phosphate, diatomaceous earth, a sugar such as lactose, dextrose or mannitol, talc, stearic acid, starch, sodium bicarbonate and/or gelatin;
for suppositories—natural or hardened oils or waxes.
When the compound is to be used in aqueous solution, e.g. for infusion, it may be necessary to incorporate other excipients. In particular there may be mentioned chelating or sequestering agents, antioxidants, tonicity adjusting agents, pH-modifying agents and buffering agents.
Solutions containing a compound of formula I may, if desired, be evaporated, e.g. by freeze drying or spray drying, to give a solid composition, which may be reconstituted prior to use.
When not in solution, the compound of formula I preferably is in a form having a mass median diameter of from 0.01 to 10 μm. The compositions may also contain suitable preserving, stabilising and wetting agents, solubilisers, e.g. a water-soluble cellulose polymer such as hydroxypropyl methylcellulose, or a water-soluble glycol such as propylene glycol, sweetening and colouring agents and flavourings. Where appropriate, the compositions may be formulated in sustained release form.
The content of compound formula I in a pharmaceutical composition is generally about 0.01-about 99.9 wt %, preferably about 0.1-about 50 wt %, relative to the entire preparation.
The dose of the compound of formula I is determined in consideration of age, body weight, general health condition, diet, administration time, administration method, clearance rate, combination of drugs, the level of disease for which the patient is under treatment then, and other factors.
While the dose varies depending on the target disease, condition, subject of administration, administration method and the like, for oral administration as a therapeutic agent for the treatment of Duchenne muscular dystrophy in a patient suffering from such a disease is from 0.01 mg-10 g, preferably 0.1-100 mg, is preferably administered in a single dose or in 2 or 3 portions per day.
The potential activity of the compounds of formula I for use in the treatment of DMD may be demonstrated in the following predictive assay and screens.
1. Luciferase Reporter Assay (Murine H2K Cells)
The cell line used for the screen is an immortalized mdx mouse H2K cell line that has been stably transfected with a plasmid containing ≈5 kb fragment of the Utrophin A promoter including the first untranslated exon linked to a luciferase reporter gene (see
Under conditions of low temperature and interferon containing media, the cells remain as myoblasts. These are plated into 96 well plates and cultured in the presence of compound for three days. The level of luciferase is then determined by cell lysis and reading of the light output from the expressed luciferase gene utilising a plate luminometer.
Example of pharmacological dose response of compounds in the assay is shown in
2. Mdx Mouse
Data obtained from the ADMET data was prioritised and the compounds with the best in vitro luciferase activity and reasonable ADMET data were prioritised for testing in the mdx proof of concept study where the outcome was to identify whether any of the compounds had the ability to increase the levels of utrophin protein in dystrophin deficient muscle when compared to vehicle only dosed control animals.
There were two animals injected with 10 mg/kg of compound administered ip daily for 28 days plus age matched controls. Muscle samples were taken and processed for sectioning (to identify increases in sarcolemmal staining of utrophin) and Western blotting (to identify overall increases in utrophin levels).
Muscles from the above treated mice were also excised and processed for Western blotting and stained with specific antibodies (see
Positive upregulation data from the first 28 day study were then repeated in a further two mouse 28 day study. A total of three different compounds have shown in duplicate the ability to increase the level of utrophin expression in the mdx mouse when delivered daily by ip for 28 days. This data demonstrates the ability of the compound when delivered ip causes a significant increase in the levels of utrophin found in the mdx muscle and therefore gives us the confidence that this approach will ameliorate the disease as all the published data to date demonstrates that any increase of utrophin levels over three fold has significant functional effects on dystrophin deficient muscle.
The H2K/mdx/Utro A reporter cell line maintenance
The H2K/mdx/Utro A reporter cell line was passaged twice a week until ≦30% confluent. The cells were grown at 33° C. in the presence of 10% CO2
To remove the myoblasts for platting, they were incubated with Trypsin/EDTA until the monolayer started to detach.
Growth Medium
DMEM Gibco 41966
20% FCS
1% Pen/Strep
1% glutamine
10 mls Chick embryo extract
Interferon (1276 905 Roche) Add fresh 10 μl/50 mls medium
Luciferase Assay for 96 Well Plates
The H2K/mdx/Utro A reporter cell line cells were plated out into 96 well plates (Falcon 353296, white opaque) at a density of approximately 5000 cells/well in 190 μl normal growth medium. The plates were then incubated at 33° C. in the presence of 10% CO2 for 24 hrs.
Compounds were dosed by adding 10 μl of diluted compound to each well giving a final concentration of 10 μM. The plates were then incubated for a further 48 hrs
Cells were then lysed in situ following the manufacture's protocols (Promega Steady-Glo Luciferase Assay System (E2520). Then counted for 10 seconds using a plate luminometer (Victor1420).
Compound Storage
Compounds for screening were stored at −20° C. as 10 mM stocks in 100% DMSO until required.
Injection of Mdx Mice with Compounds
Mdx from a breeding colony were selected for testing. Mice were injected daily with either vehicle or 10 mg/kg of compound using the intreperitoneal route (ip). Mice were weighed and compounds diluted in 5% DMSO, 0.1% tween in PBS.
Mice were sacrificed by cervical dislocation at desired time points, and muscles excised for analysis
Muscle Analysis
Immunohistochemistry
Tissues for sectioning were dissected, immersed in OCT (Bright Cryo-M-Bed) and frozen on liquid nitrogen cooled isopentane. Unfixed 8 μM cryosections were cut on a Bright Cryostat, and stored at −80° C.
In readiness for staining, sections were blocked in 5% foetal calf serum in PBS for 30 mins. The primary antibodies were diluted in blocking reagent and incubated on sections for 1.5 hrs in a humid chamber then washed three times for 5 mins in PBS. Secondary antibodies also diluted in blocking reagent, were incubated for 1 hr in the dark in a humid chamber. Finally sections were washed three times 5 mins in PBS and coverslip Mounted with hydromount. Slides were analysed using a Leica fluorescent microscope.
Results
Biological activity as assessed using the luciferase reporter assay in murine H2K cells, and is classified as follows:
+ Up to 200% relative to control
++ Between 201% and 300% relative to control
+++ Between 301% and 400% relative to control
++++ Above 401% relative to control
HPLC-UV-MS was performed on a Gilson 321 HPLC with detection performed by a Gilson 170 DAD and a Finnigan AQA mass spectrometer operating in electrospray ionisation mode. The HPLC column used is a Phenomenex Gemini C18 150×4.6 mm. Preparative HPLC was performed on a Gilson 321 with detection performed by a Gilson 170 DAD. Fractions were collected using a Gilson 215 fraction collector. The preparative HPLC column used is a Phenomenex Gemini C18 150×10 mm and the mobile phase is acetonitrile/water.
1H NMR spectra were recorded on a Bruker instrument operating at 300 MHz. NMR spectra were obtained as CDCl3 solutions (reported in ppm), using chloroform as the reference standard (7.25 ppm) or DMSO-D6 (2.50 ppm). When peak multiplicities are reported, the following abbreviations are used s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets), td (triplet of doublets). Coupling constants, when given, are reported in Hertz (Hz).
Column chromatography was performed either by flash chromatography (40-65 μm silica gel) or using an automated purification system (SP1™ Purification System from Biotage®). Reactions in the microwave were done in an Initiator 8™ (Biotage).
The abbreviations used are DMSO (dimethylsulfoxide), HATU (O-(7-azabenzotriazol-1yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate), HCl (hydrochloric acid), MgSO4 (magnesium sulfate), NaOH (sodium hydroxide), Na2CO3 (sodium carbonate), NaHCO3 (sodium bicarbonate), STAB (sodium triacetoxyborohydride), THF (tetrahydrofuran).
Method 1A (Compounds I)
To polyphosphoric acid at 110° C. were added simultaneously 2,4-diaminophenol dihydrochloride (7.88 g, 40 mmol) and benzoic acid (4.88 g, 40 mmol). The resulting mixture was then heated to 180° C. for 3 h. The solution was then poured into water. The resulting precipitate was collected by filtration and washed with saturated sodium bicarbonate solution. The crude product was recrystallised from ethanol/water to afford 8.15 g (97%) of the title compound (LCMS RT=5.17 min, MH+ 211.1)
1H NMR (DMSO): 8.15-8.12 (2H, m), 7.60-7.56 (3H, m), 7.42 (1H, d, J=8.7 Hz), 6.89 (1H, d, J=2.1 Hz), 6.68 (1H, dd, J 8.6 2.2 Hz), 5.12 (2H, s)
All compounds below were prepared following the same general method and purified either by trituration, recrystallisation or column chromatography.
LCMS RT=8.98 min, MH+ 279.0; 1H NMR (DMSO): 8.26 (2H, d, J 8.2 Hz), 7.88 (2H, d, J 8.3 Hz), 7.40 (1H, d, J 8.7 Hz), 6.84 (1H, d, J 2.1 Hz), 6.66 (1H, dd, J 8.8 2.2 Hz), 5.13 (2H, s)
LCMS RT=8.98 min, MH+ 282.2; 1H NMR (DMSO): 7.89 (2H, d, J 9.1 Hz), 7.30 (1H, d, J 8.5 Hz), 6.80-6.76 (3H, m), 6.54 (1H, dd, J 8.8 2.2 Hz), 4.99 (2H, s), 3.42 (2H, q, J 7.1 Hz), 1.14 (3H, q, J 7.1 Hz)
LCMS RT=6.42 min, MH+ 212.2; 1H NMR (DMSO): 9.29 (1H, d, J 1.9 Hz), 8.77 (1H, dd, J 4.8 1.4 Hz), 8.48-8.44 (1H, m), 7.62 (1H, dd, J 9.0 4.8 Hz), 7.46 (1H, d, J 8.8 Hz), 6.91 (1H, d, J 2.0 Hz), 6.71 (1H, dd, J 8.7 2.1 Hz), 5.18 (2H, s)
LCMS RT=6.94 min; 1H NMR (DMSO): 10.91 (1H, s), 8.74 (1H, d, J 2.3 Hz), 8.37 (1H, dd, J 9.0 2.4 Hz), 8.11-8.04 (2H, m), 7.60-7.55 (1H, m), 7.18-7.08 (2H, m)
LCMS RT=6.08 min, MH+ 227.2; 1H NMR (DMSO): 11.46 (1H, s), 8.02 (1H, dd, J 7.8 1.6 Hz), 7.58-7.53 (2H, m), 7.18-7.10 (2H, m), 6.96 (1H, d, J 2.1 Hz), 6.77 (1H, dd, J 8.7 2.2 Hz), 5.29 (2H, s)
LCMS RT=4.58 min, MH+ 282.1; 1H NMR (DMSO): 13.44 (1H, s), 8.78 (1H, s), 8.47 (1H, d, J=8.0 Hz), 8.22 (1H, d, J=8.4 Hz), 7.84-7.74 (2H, m), 7.70 (1H, s), 7.35 (1H, d, J=9.0 Hz), 2.78-2.73 (2H, m), 1.71 (2H, q, J=7.6 Hz), 0.98 (3H, d, J=7.2 Hz)
LCMS RT=5.24 min, MH+ 242.2; 1H NMR (DMSO): 11.40 (1H, s), 7.63 (1H, d, J 8.6 Hz), 7.40 (1H, d, J 8.7 Hz), 6.83 (1H, d, J 2.1 Hz), 6.63 (1H, dd, J 8.6 2.3 Hz), 6.31 (1H, d, J 8.4 2.2 Hz), 6.22 (1H, d, J 1.9 Hz), 6.05 (2H, s), 5.15 (2H, s)
LCMS RT=5.94 min, MH+ 288.1; 1H NMR (DMSO): 8.32 (1H, d, J 1.3 Hz), 8.26 (2H, dd, J 6.4 1.6 Hz), 8.10 (1H, d, J 8.5 Hz), 7.97 (1H, dd, J 8.5 1.7 Hz), 7.72-7.64 (3H, m), 3.43-3.38 (2H, m), 1.14 (3H, t, J 7.4 Hz)
LCMS RT=9.41 min, MH+ 271.9; 1H NMR (DMSO): 8.26-8.23 (2H, m), 8.08 (1H, d, J 1.3 Hz), 7.89 (1H, d, J 8.5 Hz), 7.77-7.72 (3H, m), 7.68-7.61 (3H, m), 7.51 (2H, t, J 7.7 Hz), 7.43-7.38 (1H, m)
LCMS RT=8.75 min, MH+ 246.2; 1H NMR (DMSO): 8.48 (1H, d, J=8.1 Hz), 8.32-8.27 (2H, m), 8.14 (1H, d, J 8.1 Hz), 8.01 (2H, s), 7.78-7.72 (1H, m), 7.68-7.60 (4H, m)
LCMS RT=4.41 min, MH+ 240.1; 1H NMR (DMSO): 13.00 (1H, br), 8.33 (1H, dd, J 1.6 0.5 Hz), 8.26-8.23 (2H, m), 8.06 (1H, dd, J 8.6 1.7 Hz), 7.91 (1H, dd, J 8.5 0.5 Hz), 7.72-7.62 (3H, m)
1H NMR (DMSO): 13.10 (1H, br), 8.30 (1H, dd, J 1.5 0.4 Hz), 8.15 (2H, d, J 8.3 Hz), 8.04 (1H, dd, J 8.6 1.7 Hz), 7.88 (1H, d, J 8.5 Hz), 7.47 (2H, d, J 8.4 Hz), 2.68 (2H, t, J 8.0 Hz), 1.70-1.62 (2H, m), 0.93 (3H, t, J 7.5 Hz)
1H NMR (DMSO): 13.10 (1H, br), 8.27 (1H, dd, J 1.5 0.5 Hz), 8.16 (2H, d, J 8.3 Hz), 8.02 (1H, dd, J 8.3 1.5 Hz), 7.88 (1H, dd, J 8.3 0.5 Hz), 7.48 (2H, d, J 8.4 Hz), 2.68 (2H, t, J 8.0 Hz), 1.72-1.58 (2H, m), 0.93 (3H, t, J 7.5 Hz)
LCMS RT=8.61 min, MH+ 230.1; 1H NMR (DMSO): 8.21 (2H, dd, J 7.6 1.4 Hz), 7.94 (1H, d, J 2.1 Hz), 7.86 (1H, d, J 8.7 Hz), 7.72-7.60 (3H, m), 7.49 (1H, dd, J 8.7 2.1 Hz)
LCMS RT=9.00 min, MH+ 230.1; 1H NMR (DMSO): 8.22-8.18 (2H, m), 8.02 (1H, d, J 1.9 Hz), 7.84 (1H, d, J 8.5 Hz), 7.70-7.60 (3H, m), 7.48 (1H, dd, J 8.5 2.0 Hz)
LCMS RT=9.82 min, MH+ 252.0; 1H NMR (DMSO): 7.72-7.70 (4H, m), 7.59 (2H, dt, J 7.6 1.0 Hz), 7.46-7.40 (2H, m), 1.38 (9H, s)
LCMS RT=7.30 min; 1H NMR (DMSO): 8.77-8.76 (1H, m), 8.34 (1H, d, J 8.8 Hz), 8.27 (2H, d, J 7.7 Hz), 8.05 (1H, d, J 8.8 Hz), 7.80-7.65 (3H, m)
LCMS RT=10.17 min, MH+ 301.1; 1H NMR (DMSO): 8.03 (2H, d, J 8.9 Hz), 7.82-7.76 (2H, m), 7.40 (1H, dd, J 8.6 2.0 Hz), 6.89 (2H, d, J 8.9 Hz)
LCMS RT=10.28 min, MH+ 301.0; 1H NMR (DMSO): 7.95 (2H, d, J 9.1 Hz), 7.87 (1H, d, J 1.7 Hz), 7.67 (1H, d, J 8.4 Hz), 7.38 (1H, dd, J 8.4 2.1 Hz), 6.83 (2H, d, J 9.1 Hz), 3.45 (4H, q, J 7.2 Hz), 1.15 (6H, t, J 7.1 Hz)
LCMS RT=13.81 min, MH+ 323.2; 1H NMR (DMSO): 7.94 (2H, d, J 9.3 Hz), 7.66 (1H, d, J 1.5 Hz), 7.58 (1H, d, J 8.6 Hz), 7.36 (1H, dd, J 8.6 1.9 Hz), 6.82 (2H, d, J 9.2 Hz), 3.44 (4H, q, J 7.0 Hz), 1.35 (9H, s), 1.15 (6H, t, J 7.1 Hz)
LCMS RT=10.50 min, MH+ 267.0; 1H NMR (DMSO): 7.97 (2H, d, J 9.1 Hz), 7.71-7.64 (2H, m), 7.36-7.30 (2H, m), 6.82 (2H, d, J 9.2 Hz), 3.44 (4H, q, J 7.0 Hz), 1.15 (6H, t, J 7.1 Hz)
LCMS RT=7.45 min, MH+ 358.9; 1H NMR (DMSO): 8.13 (1H, dd, J 1.3 0.4 Hz), 8.00 (2H, d, J 9.1 Hz), 7.95 (1H, dd, J 8.1 0.4 Hz), 7.83 (1H, dd, J 8.4 1.8 Hz), 6.85 (2H, d, J=9.2 Hz), 3.50-3.39 (6H, m), 1.23-1.04 (9H, m)
LCMS RT=15.22 min, MH+ 343.1; 1H NMR (DMSO): 7.99 (2H, d, J 8.9 Hz), 7.93 (1H, s), 7.77-7.71 (3H, m), 7.60 (1H, d, J 8.3 Hz), 7.52-7.46 (2H, m), 7.40-7.35 (1H, m), 6.84 (2H, d, J 9.0 Hz), 3.44 (4H, q, J 7.0 Hz), 1.15 (6H, t, J 7.1 Hz)
LCMS RT=11.21 min, MH+ 317.1; 1H NMR (DMSO): 8.41 (1H, d, J 8.3 Hz), 8.12-8.02 (3H, m), 7.94-7.86 (2H, m), 7.72-7.66 (1H, m), 7.60-7.55 (1H, m), 6.85 (2H, d, J 9.0 Hz), 3.44 (4H, q, J 7.0 Hz), 1.15 (6H, t, J 7.1 Hz)
LCMS RT=5.68 min, MH+ 197.0; 1H NMR (DMSO): 8.87 (1H, d, J 4.4 Hz), 8.41 (1H, d, J 8.0 Hz), 8.14 (1H, dt, J 7.8 1.5 Hz), 7.93 (2H, t, J 7.4 Hz), 7.73-7.69 (1H, m), 7.60-7.50 (2H, m)
LCMS RT=6.95 min, MH+ 206.1; 1H NMR (DMSO): 7.92 (2H, d, J 9.0 Hz), 7.32 (1H, d, J 9.0 Hz), 7.05 (2H, d, J 9.0 Hz), 6.80 (1H, d, J 2.1 Hz), 6.58 (1H, dd, J 8.0 2.0 Hz), 5.01 (2H, s), 1.60 (6H, m)
LCMS RT=5.34 min, MH+ 309.1; 1H NMR (DMSO): 7.94 (2H, d, J 9.0 Hz), 7.33 (1H, d, J 9.0 Hz), 7.08 (2H, d, J 9.0 Hz), 6.80 (1H, d, J 2.1 Hz), 6.58 (1H, dd, J 8.0 2.0 Hz), 5.03 (2H, s), 2.60-2.57 (4H, m), 2.45-2.42 (4H, m), 2.23 (3H, s)
1H NMR (DMSO): 13.00 (1H, br), 8.17 (1H, d, J 1.5 Hz), 7.99 (2H, d, J 9.0 Hz), 7.94 (1H, dd, J 8.5 1.7 Hz), 7.77 (1H, d, J 8.4 Hz), 6.84 (2H, d, J 9.1 Hz), 3.45 (4H, q, J 7.0 Hz), 1.15 (6H, t, J 7.0 Hz)
LCMS RT=6.81 min, MH+ 177.2; 1H NMR (DMSO): 7.26 (1H, d, J 8.6 Hz), 6.76 (1H, d, J 2.2 Hz), 6.57 (1H, dd, J 8.6 2.2 Hz), 4.98 (2H, s), 2.80 (2H, t, J 7.3 Hz), 1.81-1.70 (2H, m), 0.96 (3H, t, J 7.4 Hz)
LCMS RT=6.72 min, MH+ 211.1; 1H NMR (DMSO): 8.38 (1H, dd, J 5.0 1.5 Hz), 8.26 (1H, dd, J 7.9 1.6 Hz), 8.14 (2H, d, J 8.2 Hz), 7.53-7.45 (3H, m), 2.44 (3H, s)
LCMS RT=6.12 min, MH+ 211.1; 1H NMR (DMSO): 8.54 (1H, dd, J 4.9 1.4 Hz), 8.23 (1H, dd, J 8.2 1.4 Hz), 8.16 (2H, d, J 8.2 Hz), 7.59-7.44 (3H, m), 2.44 (3H, s)
LCMS RT=5.52 min, MH+ 295.8; 1H NMR (DMSO): 7.97 (2H, d, J 9.0 Hz), 7.33 (1H, d, J 9.0 Hz), 7.09 (2H, d, J 9.0 Hz), 6.81 (1H, d, J 2.1 Hz), 6.59 (1H, dd, J 8.0 2.0 Hz), 5.04 (2H, s), 3.77-3.74 (4H, m), 3.29-3.24 (4H, m)
LCMS RT=10.00 min, MH+ 286.1; 1H NMR (DMSO): 8.12 (2H, d, J 8.5 Hz), 8.06 (1H, d, J 1.8 Hz), 7.86 (1H, d, J 8.6 Hz), 7.77-7.70 (3H, m), 7.53-7.37 (5H, m), 2.43 (3H, s)
LCMS RT=10.54 min, MH+ 306.0; 1H NMR (DMSO): 8.24 (2H, d, J 8.6 Hz), 8.09 (1H, d, J 1.8 Hz), 7.89 (1H, d, J 8.6 Hz), 7.77-7.70 (5H, m), 7.53-7.34 (3H, m)
LCMS RT=7.90 min, MH+ 247.3; 1H NMR (CDCl3): 8.62 (1H, d, J 2.2 Hz), 8.33 (1H, dd, J 8.9 2.3 Hz), 7.63 (1H, d, J 8.9 Hz), 3.11-3.01 (1H, m), 2.27-2.21 (2H, m), 1.98-1.92 (2H, m), 1.84-1.71 (3H, m), 1.57-1.37 (3H, m)
LCMS RT=10.53 min, MH+ 266.1; 1H NMR (DMSO): 8.08 (2H, d, J 8.2 Hz), 7.78 (1H, d, J 1.6 Hz), 7.68 (1H, d, J 8.6 Hz), 7.48 (1H, dd, J 8.7 2.0 Hz), 7.43 (2H, d, J 8.0 Hz), 2.42 (3H, s), 1.37 (9H, s)
LCMS RT=7.82 min, MH+ 210.1; 1H NMR (DMSO): 8.11 (2H, d, J 8.2 Hz), 7.81-7.76 (2H, m), 7.46-7.40 (4H, m), 2.42 (3H, s)
LCMS RT=6.39 min, MH+ 279.0; 1H NMR (DMSO): 8.41 (1H, d, J 8.0 Hz), 8.37 (1H, s), 7.98 (1H, d, J 8.0 Hz), 7.84 (1H, t, J 8.0 Hz), 7.46 (1H, d, J 8.9 Hz), 6.91 (1H, d, J 1.9 Hz), 6.72 (1H, d, J 8.6 2.0 Hz), 5.18 (2H, s)
LCMS RT=6.46 min, MH+ 302.0; 1H NMR (DMSO): 8.28 (1H, d, J 1.6 Hz), 8.14 (2H, d, J 8.2 Hz), 8.06 (1H, d, J 8.6 Hz), 7.94 (1H, dd, J 8.6 1.7 Hz), 7.47 (2H, d, J 8.1 Hz), 3.42-3.34 (2H, m), 2.44 (3H, s), 1.12 (3H, t, J 7.3 Hz)
LCMS RT=6.63 min, MH+ 322.1; 1H NMR (CDCl3): 8.39 (1H, d, J 1.7 Hz), 8.27 (2H, d, J 8.7 Hz), 8.00 (1H, dd, J 8.5 1.8 Hz), 7.80 (1H, d, J 8.5 Hz), 7.60 (2H, d, J 8.6 Hz), 3.23 (2H, q, J 7.6 Hz), 1.36 (3H, t, J 7.4 Hz)
LCMS RT=6.97 min, MH+ 255.0; 1H NMR (DMSO): 8.27 (1H, dd, J 8.1 0.8 Hz), 8.23 (1H, dd, J 8.2 0.8 Hz), 8.18 (2H, d, J 8.2 Hz), 7.65 (1H, t, J 8.2 Hz), 7.49 (2H, d, J 8.0 Hz), 2.45 (3H, s)
LCMS RT=7.83 min, MH+ 255.0; 1H NMR (DMSO): 8.74 (1H, d, J 2.2 Hz), 8.33 (1H, dd, J 8.7 2.2 Hz), 8.17 (2H, d, J 8.2 Hz), 8.02 (1H, d, J 8.8 Hz), 7.49 (2H, d, J 7.9 Hz), 2.45 (3H, s)
LCMS RT=7.76 min; 1H NMR (DMSO): 8.77 (1H, d, J 2.2 Hz), 8.35 (1H, dd, J 8.7 2.2 Hz), 8.27 (2H, d, J 8.2 Hz), 8.06 (1H, d, J 8.8 Hz), 7.76 (2H, d, J 7.9 Hz)
LCMS RT=6.24 min, MH+ 211.0; 1H NMR (DMSO): 9.11 (1H, d, J 0.9 Hz), 8.59 (1H, d, J 5.6 Hz), 8.14 (2H, d, J 8.2 Hz), 7.90 (1H, dd, J 5.6 1.0 Hz), 7.47 (2H, d, J 8.0 Hz), 2.44 (3H, s)
LCMS RT=6.18 min, MH+ 225.0; 1H NMR (DMSO): 7.97-7.91 (2H, m), 7.50-7.39 (3H, m), 6.87 (1H, d, J 2.0 Hz), 6.67 (1H, dd, J 8.7 2.2 Hz), 5.11 (2H, s), 2.42 (3H, s)
LCMS RT=6.12 min, MH+ 254.0; 1H NMR (DMSO): 7.48-7.31 (4H, m), 6.96-6.92 (1H, m), 6.87 (1H, d, J 2.2 Hz), 6.66 (1H, dd, J 8.6 2.2 Hz), 5.09 (2H, s), 3.00 (6H, s)
LCMS RT=9.41 min, MH+ 289.8; 1H NMR (DMSO): 8.10 (2H, d, J 8.2 Hz), 8.04 (1H, d, J 1.9 Hz), 7.78 (1H, d, J 8.6 Hz), 7.58 (1H, dd, J 8.7 2.0 Hz), 7.45 (2H, d, J 8.0 Hz), 2.43 (3H, s)
LCMS RT=6.16 min, MH+ 225.0; 1H NMR (DMSO): 8.05 (1H, d, J 7.7 Hz), 7.53-7.37 (4H, m), 6.90 (1H, d, J 2.2 Hz), 6.68 (1H, dd, J 8.7 2.2 Hz), 5.10 (2H, s), 2.71 (3H, s)
LCMS RT=4.31 min, MH+ 245.0; 1H NMR (DMSO): 8.10 (1H, d, J 7.3 Hz), 7.75-7.52 (3H, m), 7.45 (1H, d, J 8.6 Hz), 6.92 (1H, d, J 1.6 Hz), 6.73 (1H, dd, J 8.8 2.1 Hz), 5.16 (2H, s)
LCMS RT=8.40 min, MH+ 288.8; 1H NMR (DMSO): 8.59 (1H, d, J 2.1 Hz), 8.50 (1H, d, J 2.2 Hz), 8.13 (2H, d, J 8.2 Hz), 7.48 (2H, d, J 8.0 Hz)
LCMS RT=8.76 min, MH+ 238.0; 1H NMR (DMSO): 8.06 (2H, d, J 8.2 Hz), 7.56 (2H, s), 7.41 (2H, d, J 8.2 Hz), 2.41 (3H, s), 2.35 (3H, s), 2.33 (3H, s)
LCMS RT=9.07 min, MH+ 258.0; 1H NMR (DMSO): 8.19 (2H, d, J 8.6 Hz), 7.69 (2H, d, J 8.6 Hz), 7.60 (2H, s), 2.38 (3H, s), 2.36 (3H, s)
LCMS RT=9.68 min, MH+ 291.9; 1H NMR (DMSO): 8.16 (1H, d, J 8.5 Hz), 7.90 (1H, d, J 2.1 Hz), 7.69-7.61 (3H, m), 2.38 (3H, s), 2.36 (3H, s)
LCMS RT=9.45 min, MH+ 229.1; 1H NMR (DMSO): 7.98 (1H, d, J 8.0 Hz), 7.89-7.84 (1H, m), 7.68-7.60 (1H, m), 7.48-7.42 (2H, m), 6.89 (1H, d, J 2.1 Hz), 6.71 (1H, dd, J 8.7 2.2 Hz), 5.15 (2H, s)
LCMS RT=7.34 min, MH+ 298.0; 1H NMR (DMSO): 8.81 (1H, d, J 2.1 Hz), 8.71 (1H, d, J 1.5 Hz), 8.37-8.32 (2H, m), 8.08 (1H, d, J 8.8 Hz), 7.95 (1H, dd, J 8.1 2.1 Hz), 2.75 (2H, t, J 7.6 Hz), 1.70-1.59 (2H, m), 1.41-1.29 (2H, m), 0.93 (3H, t, J 7.3 Hz)
LCMS RT=6.98 min; 1H NMR (DMSO): 8.29-8.24 (3H, m), 8.09 (1H, d, J 8.6 Hz), 7.94 (1H, dd, J 8.6 1.7 Hz), 7.74 (2H, d, J 8.6 Hz), 3.56-3.50 (1H, m), 1.19 (6H, d, J 6.8 Hz)
LCMS RT=9.09 min, MH+ 307.9; 1H NMR (DMSO): 8.21 (2H, d, J 8.7 Hz), 8.08 (1H, d, J 1.9 Hz), 7.80 (1H, d, J 8.7 Hz), 7.71 (2H, d, J 8.7 Hz), 7.62 (1H, dd, J 8.7 2.0 Hz)
LCMS RT=6.48 min, MH+ 244.9; 1H NMR (DMSO): 7.86 (2H, d, J 8.5 Hz), 7.74 (1H, d, J 2.1 Hz), 7.70 (1H, d, J 8.6 Hz), 7.34 (1H, dd, J 8.8 2.1 Hz), 6.70 (2H, d, J 8.7 Hz), 6.06 (2H, s)
LCMS RT=6.57 min, MH+ 245.0; 1H NMR (DMSO): 7.87-7.82 (3H, m), 7.66 (1H, d, J 8.5 Hz), 7.37 (1H, dd, J 8.7 2.0 Hz), 6.70 (2H, d, J 8.8 Hz), 6.04 (2H, s)
LCMS RT=6.78 min; 1H NMR (DMSO): 8.34 (1H, d, J 1.3 Hz), 8.23-8.20 (2H, m), 8.10 (1H, d, J 8.6 Hz), 7.99 (1H, dd, J 8.6 1.8 Hz), 7.80-7.76 (1H, m), 7.72-7.67 (1H, m), 3.40 (2H, q, J 7.3 Hz), 1.13 (3H, t, J 7.3 Hz)
LCMS RT=6.37 min; 1H NMR (DMSO): 8.39 (1H, d, J 1.6 Hz), 8.20 (1H, dd, J 7.6 1.7 Hz), 8.12 (1H, d, J 8.6 Hz), 8.01 (1H, dd, J 8.6 1.8 Hz), 7.78-7.60 (3H, m), 1.14 (3H, t, J=7.3 Hz)
LCMS RT=7.25 min; 1H NMR (DMSO): 8.39 (1H, d, J 2.0 Hz), 8.35 (1H, d, J 1.4 Hz), 8.19 (1H, dd, J 8.4 2.0 Hz), 8.10 (1H, d, J 8.6 Hz), 7.99 (1H, dd, J 8.6 1.8 Hz), 7.94 (1H, d, J 8.4 Hz), 3.41 (2H, q, J 7.3 Hz), 1.13 (3H, t, J 7.3 Hz)
LCMS RT=6.80 min; 1H NMR (DMSO): 8.42 (1H, d, J 1.8 0.6 Hz), 8.17-8.13 (2H, m), 8.05-7.96 (2H, m), 7.65 (1H, t, J 8.0 Hz), 3.41 (2H, q, J 7.3 Hz), 1.14 (3H, t, J 7.3 Hz)
LCMS RT=5.80 min, MH+ 239.0; 1H NMR (DMSO): 7.35-7.23 (6H, m), 6.80 (1H, d, J 2.1 Hz), 6.57 (1H, dd, J 8.6 2.2 Hz), 5.02 (2H, s), 4.42 (1H, q, J 7.1 Hz), 1.66 (3H, d, J 7.2 Hz)
LCMS RT=4.44 min, MH+ 309.9; 1H NMR (DMSO): 8.28 (2H, d, J 8.7 Hz), 8.03 (1H, s), 7.83-7.73 (4H, m)
LCMS RT=6.51 min, MH+ 231.0; 1H NMR (DMSO): 8.87 (2H, d, J 8.6 Hz), 8.11 (2H, d, J 6.1 Hz), 8.04 (1H, d, J 1.8 Hz), 7.92 (1H, d, J 8.8 Hz), 7.57 (1H, dd, J 8.7 2.1 Hz)
LCMS RT=6.49 min, MH+ 231.0; 1H NMR (DMSO): 8.87 (2H, d, J 6.1 Hz), 8.10-8.08 (3H, m), 7.93 (1H, d, J 8.6 Hz), 7.54 (1H, dd, J 8.6 2.0 Hz)
LCMS RT=6.70 min, MH+ 289.2; 1H NMR (DMSO): 7.88-7.83 (3H, m), 7.66 (1H, d, J 8.6 Hz), 7.46 (1H, dd, J 8.6 2.1 Hz), 6.69 (2H, d, J 8.8 Hz), 6.09 (2H, s)
LCMS RT=6.43 min, MH+ 308.2; 1H NMR (CDCl3): 8.43 (1H, dd, J 1.8 0.3 Hz), 8.28 (2H, d, J 8.7 Hz), 8.05 (1H, dd, J 8.6 1.9 Hz), 7.81 (1H, dd, J 8.5 0.4 Hz), 7.61 (2H, d, J 8.8 Hz), 3.18 (3H, s)
LCMS RT=7.09 min, MH+ 335.9; 1H NMR (CDCl3): 8.38 (1H, dd, J 1.7 0.4 Hz), 8.27 (2H, d, J 8.8 Hz), 8.00 (1H, dd, J 8.5 1.8 Hz), 7.80 (1H, dd, J 8.5 0.4 Hz), 7.60 (2H, d, J 8.8 Hz), 3.21-3.15 (2H, m), 1.89-1.76 (2H, m), 1.05 (3H, t, J 7.4 Hz)
LCMS RT=6.59 min, MH+ 261.1; 1H NMR (DMSO): 9.41 (1H, d, J 8.6 Hz), 8.38 (1H, dd, J 7.3 1.0 Hz), 8.19 (1H, d, J 8.2 Hz), 8.09 (1H, dd, J 7.8 0.9 Hz), 7.79-7.64 (3H, m), 7.49 (1H, d, J 8.7 Hz), 6.99 (1H, d, J 2.1 Hz), 6.74 (1H, d, J 8.7 2.2 Hz), 5.17 (2H, s)
LCMS RT=6.92 min, MH+ 287.1; 1H NMR (DMSO): 8.22 (2H, d, J 8.2 Hz), 7.90 (2H, d, J 8.3 Hz), 7.81-7.76 (2H, m), 7.53 (2H, t, J 7.8 Hz), 7.47-7.41 (2H, m), 6.90 (1H, d, J 2.2 Hz), 6.69 (1H, d, J 8.6 2.2 Hz), 5.14 (2H, s)
LCMS RT=5.78 min, MH+ 262.1; 1H NMR (DMSO): 8.60 (1H, d, J 8.7 Hz), 8.39 (1H, d, J 8.6 Hz), 8.19 (1H, dd, J 8.3 0.5 Hz), 8.10 (1H, dd, J 8.4 0.8 Hz), 7.92-7.86 (1H, m), 7.76-7.70 (1H, m), 7.56 (1H, d, J 8.7 Hz), 6.97 (1H, d, J 2.1 Hz), 6.79 (1H, dd, J 8.7 2.2 Hz), 5.22 (2H, s)
LCMS RT=5.76 min, MH+ 262.1; 1H NMR (DMSO): 9.58 (1H, d, J 2.1 Hz), 8.14 (1H, d, J 2.0 Hz), 8.24 (1H, dd, J 7.8 0.8 Hz), 8.13 (1H, d, J 8.3 Hz), 7.93-7.88 (1H, m), 7.74 (1H, td, J 8.0 0.9 Hz), 7.49 (1H, d, J 8.6 Hz), 6.95 (1H, d, J 2.1 Hz), 6.74 (1H, dd, J 8.7 2.2 Hz), 5.20 (2H, s)
LCMS RT=6.56 min, MH+ 291.1; 1H NMR (DMSO): 8.67 (1H, d, J 1.3 Hz), 8.16 (1H, dd, J 8.6 1.7 Hz), 8.07 (1H, d, J 9.1 Hz), 7.99 (1H, d, J 8.8 Hz), 7.45-7.42 (2H, m), 7.27 (1H, dd, J 8.7 2.5 Hz), 6.90 (1H, d, J 2.0 Hz), 6.68 (1H, dd, J 8.6 2.2 Hz), 5.12 (2H, s), 3.92 (3H, s)
LCMS RT=7.59 min, MH+ 339.3; 1H NMR (DMSO): 8.78 (1H, s), 8.34 (1H, d, J 1.7 Hz), 8.26 (1H, d, J 8.6 1.6 Hz), 8.14 (1H, d, J 8.9 Hz), 8.09 (1H, d, J 8.7 Hz), 7.76 (1H, dd, J 8.9 2.0 Hz), 7.46 (1H, d, J 8.7 Hz), 6.92 (1H, d, J 2.2 Hz), 6.72 (1H, dd, J 8.6 2.2 Hz), 5.16 (2H, s)
LCMS RT=9.55 min, MH+ 280.1; 1H NMR (DMSO): 8.47 (1H, dd, J 8.2 0.6 Hz), 8.29 (2H, d, J 8.7 Hz), 8.17-8.13 (1H, m), 8.02 (2H, s), 7.78-7.70 (3H, m), 7.67-7.61 (1H, m)
LCMS RT=7.92 min, MH+ 286.1; 1H NMR (DMSO): 8.44 (1H, dd, J 1.7 0.4 Hz), 8.24 (2H, d, J 8.7 Hz), 8.09 (1H, dd, J 8.6 1.7 Hz), 7.93 (1H, dd, J 8.6 0.4 Hz), 7.73 (2H, d, J 8.8 Hz), 3.17 (2H, q, J 7.2 Hz), 1.13 (3H, t, J 7.1 Hz)
LCMS RT=7.27 min, MH+ 271.7; 1H NMR (DMSO): 8.44 (1H, dd, J 1.7 0.4 Hz), 8.24 (2H, d, J 8.8 Hz), 8.08 (1H, dd, J 8.6 1.7 Hz), 7.93 (1H, dd, J 8.5 0.5 Hz), 7.73 (2H, d, J 8.8 Hz), 2.69 (3H, s)
LCMS RT=8.15 min, MH+ 293.1; 1H NMR (DMSO): 8.05 (2H, d, J 8.4 Hz), 7.45-7.38 (3H, m), 6.86 (1H, d, J 2.0 Hz), 6.65 (1H, dd, J 8.8 2.2 Hz), 5.10 (2H, s), 2.64-2.56 (1H, m), 1.83-1.70 (5H, m), 1.51-1.23 (5H, m)
LCMS RT=6.14 min, MH+ 339.1; 1H NMR (DMSO): 8.69 (1H, dd, J 8.5 2.2 Hz), 8.52-8.43 (2H, m), 8.28-8.21 (2H, m), 8.16 (1H, d, J 8.1 Hz), 8.09-8.04 (1H, m), 7.97-7.90 (1H, m), 7.82-7.76 (1H, m), 3.48-3.38 (2H, m), 1.15 (3H, td, J 7.3 1.3 Hz)
LCMS RT=6.05 min, MH+ 339.1; 1H NMR (DMSO): 9.65 (1H, d, J 2.1 Hz), 9.31 (1H, d, J 2.1 Hz), 8.40 (1H, d, J 1.8 Hz), 8.31 (1H, d, J 8.1 Hz), 8.17 (2H, dd, J 8.3 2.2 Hz), 8.02 (1H, dd, J 8.7 1.8 Hz), 8.00-7.93 (1H, m), 7.82-7.76 (1H, m), 3.43 (2H, q, J 7.3 Hz), 1.15 (3H, t, J 7.5 Hz)
LCMS RT=7.86 min, MH+ 418.0; 1H NMR (DMSO): 8.95 (1H, m), 8.39-8.33 (3H, m), 8.21 (1H, d, J 9.0 Hz), 8.17 (1H, d, J 8.9 Hz), 8.13 (1H, dd, J 8.5 0.5 Hz), 7.99 (1H, dd, J 8.6 1.8 Hz), 7.81 (1H, dd, J 8.7 1.9 Hz), 3.41 (2H, q, J 7.3 Hz), 1.15 (3H, t, J 7.5 Hz)
LCMS RT=8.56 min; 1H NMR (DMSO): 8.29 (1H, dd, J 1.8 0.4 Hz), 8.17 (2H, d, J 8.3 Hz), 8.07 (1H, dd, J 8.6 0.5 Hz), 7.94 (1H, dd, J 8.5 1.8 Hz), 7.51 (2H, d, J 8.4 Hz), 3.39 (2H, q, J 7.3 Hz), 2.74-2.60 (1H, m), 1.84-1.71 (5H, m), 1.53-1.24 (5H, m), 1.13 (3H, t, J 7.5 Hz)
LCMS RT=7.31 min, MH+ 364.1; 1H NMR (DMSO): 8.36-8.32 (3H, m), 8.11 (1H, dd, J 8.6 0.5 Hz), 8.00-7.95 (3H, m), 7.84-7.79 (2H, m), 7.57-7.43 (3H, m), 3.41 (2H, q, J 7.3 Hz), 1.14 (3H, t, J 7.5 Hz)
LCMS RT=7.03 min, MH+ 338.1; 1H NMR (DMSO): 9.41 (1H, d, J 8.8 Hz), 8.52 (1H, dd, J 7.2 1.2 Hz), 8.44 (1H, d, J 1.7 Hz), 8.30 (1H, d, J 8.3 Hz), 8.17-8.12 (2H, m), 8.02 (1H, dd, J 8.6 1.8 Hz), 7.84-7.68 (3H, m), 3.43 (2H, q, J 7.3 Hz), 1.15 (3H, t, J 7.5 Hz)
LCMS RT=7.29 min, MH+ 356.1; 1H NMR (DMSO): 8.97 (1H, m), 8.37-8.32 (3H, m), 8.17 (1H, d, J 8.9 Hz), 8.12 (1H, d, J 8.6 Hz), 7.99 (1H, dd, J 8.6 1.6 Hz), 7.89 (1H, dd, J 10.0 2.0 Hz), 7.61 (1H, td, J 8.7 2.0 Hz), 3.41 (2H, q, J 7.3 Hz), 1.14 (3H, t, J 7.5 Hz)
LCMS RT=6.77 min, MH+ 344.1; 1H NMR (CDCl3): 8.70 (1H, d, J 1.2 Hz), 8.27 (1H, dd, J 1.8 0.4 Hz), 8.18 (1H, dd, J 8.5 1.5 Hz), 7.99 (1H, d, J 8.6 Hz), 7.88 (1H, dd, J 8.5 1.8 Hz), 7.70 (1H, dd, J 8.5 0.4 Hz), 7.52 (1H, d, J 5.5 Hz), 7.43 (1H, dd, J 5.5 0.6 Hz), 3.12 (2H, q, J 7.4 Hz), 1.25 (3H, t, J 7.4 Hz)
LCMS RT=7.83 min, MH+ 295.1; 1H NMR (DMSO): 10.88 (1H, s), 8.19 (1H, s), 8.06 (1H, s), 7.69 (1H, d, J 8.7 Hz), 6.35 (1H, dd, J 8.7 2.1 Hz), 6.29 (2H, br), 6.24 (1H, d, J 2.1 Hz)
LCMS RT=7.68 min; 1H NMR (DMSO): 8.41 (1H, d, J 2.0 Hz), 8.31 (1H, dd, J 1.8 0.4 Hz), 8.21 (1H, dd, J 8.4 2.0 Hz), 8.11 (1H, dd, J 8.6 0.5 Hz), 7.98-7.93 (2H, m), 3.59-3.50 (1H, m), 1.19 (6H, d, J 6.8 Hz)
LCMS RT=6.70 min, MH+ 263.1; 1H NMR (DMSO): 10.83 (1H, s), 8.02 (1H, dd, J 9.9 6.9 Hz), 7.85 (1H, dd, J 10.4 7.5 Hz), 7.62 (1H, d, J 8.6 Hz), 6.29 (1H, dd, J 8.7 2.1 Hz), 6.18 (1H, d, J 2.0 Hz), 6.15 (2H, br)
LCMS RT=7.27 min, MH+ 279.0; 1H NMR (DMSO): 8.10 (1H, s), 7.97 (1H, s), 7.85 (2H, d, J 8.7 Hz), 6.70 (2H, d, J 8.8 Hz), 6.14 (2H, s)
LCMS RT=7.71 min, MH+ 342.2; 1H NMR (CDCl3): 8.03 (1H, dd, J 1.8 0.5 Hz), 7.93-7.87 (2H, m), 7.85 (1H, dd, J 8.5 1.8 Hz), 7.65 (1H, dd, J 8.5 0.5 Hz), 7.23-7.15 (1H, m), 3.11 (2H, q, J 7.4 Hz), 2.85-2.76 (4H, m), 1.81-1.76 (4H, m), 1.24 (3H, t, J 7.3 Hz)
LCMS RT=5.99 min, MH+ 319.2; 1H NMR (DMSO): 10.88 (1H, s), 8.16 (1H, dd, J 1.8 0.5 Hz), 7.97 (1H, dd, J 8.5 0.5 Hz), 7.84 (1H, dd, J 8.4 1.9 Hz), 7.69 (1H, d, J 8.6 Hz), 6.31 (1H, dd, J 8.7 2.1 Hz), 6.24 (2H, s), 6.20 (1H, d, J 2.1 Hz), 3.37 (2H, q, J 7.5 Hz), 1.12 (3H, t, J 7.3 Hz)
Method 1A (Compounds Ic)
LCMS RT=4.64 min, MH+ 317.1; 1H NMR (DMSO): 10.67 (1H, s), 9.37 (1H, d, J 1.5 Hz), 9.16 (1H, d, J 1.6 Hz), 8.84-8.78 (2H, m), 8.56 (1H, dt, J 8.0 1.7 Hz), 8.36-8.32 (2H, m), 7.86 (1H, d, J 8.8 Hz), 7.80 (1H, dd, J 8.9 2.0 Hz), 7.70-7.58 (2H, m)
1H NMR (DMSO): 10.25 (1H, s), 8.23 (1H, s), 8.16 (2H, d, J 8.9 Hz), 8.00 (2H, d, J 8.9 Hz), 7.72 (2H, s), 7.17 (2H, d, J 9.0 Hz), 7.09 (2H, d, J 8.8 Hz), 3.88 (3H, s), 3.85 (3H, s)
LCMS RT=6.22 min, MH+ 343.1; 1H NMR (CDCl3): 7.70 (1H, s), 7.42 (1H, s), 7.30-7.15 (12H, m), 4.14 (2H, s), 3.63 (2H, s)
LCMS RT=8.09 min, MH+ 450.9; 1H NMR (DMSO): 10.84 (1H, s), 8.32 (1H, d, J 1.7 Hz), 8.14 (1H, dd, J 8.9 1.5 Hz), 7.95 (1H, dd, J 8.1 1.6 Hz), 7.85 (1H, d, J 8.8 Hz), 7.81 (1H, dd, J 8.0 1.6 Hz), 7.73 (1H, dd, J 8.8 2.1 Hz), 7.65-7.50 (3H, m)
Method 1A (Compounds Id)
1H NMR (DMSO): 13.20 (1H, br), 8.58 (1H, dd, J 1.5 0.4 Hz), 8.33-8.30 (2H, m), 8.19 (2H, d, J 8.2 Hz), 8.06-0.802 (2H, m), 7.93 (1H, d, J 8.3 Hz), 7.50 (2H, d, J 8.4 Hz), 2.69 (2H, t, J 7.8 Hz), 1.73-1.61 (2H, m), 0.94 (3H, t, J 7.4 Hz)
Method 1A (Compounds Ie)
LCMS RT=6.87 min, MH+ 408.0; 1H NMR (DMSO): 10.14 (1H, s), 8.16 (2H, d, J 8.9 Hz), 8.07-8.01 (3H, m), 7.79-7.74 (3H, m), 7.57 (1H, dd, J 8.6 2.0 Hz), 6.62 (2H, d, J 8.7 Hz), 5.86 (2H, s)
Method 1B (Compounds I)
To 2-amino-4-nitrophenol (300 mg, 1.95 mmol) in dioxane (2.5 mL) was added 2-phenylacetyl chloride (290 μL, 2.15 mmol) at room temperature. The reaction vessel was heated in the microwave at 210° C. for 15 min. After cooling, the mixture was slowly poured into 1M aqueous sodium hydroxide (50 mL), and the resulting precipitate filtered and washed with water. The resulting solid was purified by column chromatography eluting using a gradient (ethyl acetate/hexanes 1:7 v/v to ethyl acetate/hexanes 1:5 v/v) to afford 165 mg (33%) of the title compound (LCMS RT=6.47 min, MH+ 255.2)
1H NMR (DMSO): 8.60 (1H, d, J 2.4 Hz), 8.30 (1H, dd, J 9.0 2.4 Hz), 7.95 (1H, d, J 9.0 Hz), 7.43-7.27 (5H, m), 4.44 (2H, s)
All compounds below were prepared following the same general method. The acid chloride used was either a commercially available compound or synthesized from the corresponding carboxylic acid using standard conditions.
LCMS RT=6.74 min, MH+ 284.9; 1H NMR (DMSO): 8.60 (1H, d, J 2.3 Hz), 8.31 (1H, dd, J 8.9 2.3 Hz), 7.99 (1H, d, J 9.0 Hz), 7.82 (1H, dd, J 8.2 1.7 Hz), 7.66 (1H, d, J 1.6 Hz), 7.18 (1H, d, J 8.4 Hz), 6.20 (2H, s)
LCMS RT=7.54 min, MH+ 274.0; 1H NMR (DMSO): 8.11 (2H, d, J 8.8 Hz), 7.66 (2H, d, J 8.7 Hz), 7.49 (1H, s), 7.36 (1H, s), 6.13 (2H, s)
LCMS RT=10.20 min, MH+ 286.0; 1H NMR (DMSO): 8.20 (2H, d, J 8.6 Hz), 7.80 (1H, d, J 1.9 Hz), 7.72-7.68 (3H, m), 7.52 (1H, dd, J 8.7 2.0 Hz), 1.37 (9H, s)
LCMS RT=8.40 min; 1H NMR (DMSO): 8.77 (1H, d, J 2.1 Hz), 8.40 (1H, d, J 2.0 Hz), 8.36 (1H, dd, J 8.8 2.2 Hz), 8.21 (1H, dd, J 8.5 2.1 Hz), 8.07 (1H, d, J 8.8 Hz), 7.96 (1H, d, J 8.4 Hz)
LCMS RT=6.04 min; 1H NMR (DMSO): 8.27-8.22 (3H, m), 8.02 (1H, d, J 8.6 Hz), 7.95-7.91 (1H, m), 7.74-7.71 (2H, m), 7.50 (2H, s)
LCMS RT=8.10 min; 1H NMR (DMSO): 8.73 (1H, s), 8.31 (1H, s), 8.24 (2H, d, J 8.7 Hz), 7.76 (2H, d, J 8.7 Hz)
LCMS RT=7.66 min; 1H NMR (DMSO): 8.72 (1H, d, J 2.3 Hz), 8.38 (3H, m), 8.09 (1H, d, J 8.8 Hz), 7.66 (2H, d, J 8.2 Hz)
LCMS RT=8.70 min, MH+ 307.9; 1H NMR (CDCl3): 8.18 (1H, d, J 2.0 Hz), 7.91 (1H, dd, J 8.4 2.0 Hz), 7.50 (1H, d, J 8.4 Hz), 7.09 (1H, s), 6.99 (1H, s), 5.99 (2H, s)
LCMS RT=6.24 min; 1H NMR (DMSO): 8.66 (1H, d, J 2.3 Hz), 8.35 (1H, dd, J 9.0 2.4 Hz), 8.18 (1H, d, J 1.0 Hz), 8.05 (1H, d, J 9.0 Hz), 7.62 (1H, d, J 3.5 Hz), 6.90-6.88 (1H, m)
LCMS RT=7.21 min; 1H NMR (DMSO): 8.68 (1H, s), 8.23 (1H, s), 7.83 (1H, dd, J 8.2 1.6 Hz), 7.66 (1H, d, J 1.7 Hz), 7.20 (1H, d, J 8.4 Hz), 6.22 (2H, s)
LCMS RT=6.94 min, MH+ 338.1; 1H NMR (DMSO): 8.90 (1H, br), 8.34 (1H, d, J 1.4 Hz), 8.30 (1H, dd, J 8.6 1.7 Hz), 8.24-8.05 (4H, m), 7.99 (1H, dd, J 8.5 1.8 Hz), 7.73-7.64 (2H, m), 3.41 (2H, q, J 7.3 Hz), 1.15 (3H, t, J 7.3 Hz)
LCMS RT=6.48 min, MH+ 338.8; 1H NMR (DMSO): 8.40 (1H, dd, J 1.7 0.5 Hz), 8.27-8.21 (1H, m), 8.14 (1H, dd, J 8.6 0.4 Hz), 8.01 (1H, dd, J 8.6 1.8 Hz), 7.97-7.92 (1H, m), 7.51 (1H, td, J 8.0 1.0 Hz), 3.41 (2H, q, J 7.3 Hz), 1.13 (3H, t, J 7.3 Hz)
LCMS RT=6.57 min, MH+ 293.9; 1H NMR (DMSO): 8.20 (1H, d, J 1.5 Hz), 7.97 (1H, dd, J 8.5 Hz), 7.88 (1H, dd, J 8.6 1.8 Hz), 3.35 (2H, q, J 7.4 Hz), 3.13-3.04 (1H, m), 2.14-2.09 (2H, m), 1.82-1.58 (5H, m), 1.50-1.18 (3H, m), 1.10 (3H, t, J 7.4 Hz)
LCMS RT=5.92 min, MH+ 323.1; 1H NMR (DMSO): 8.91 (1H, d, J 2.4 Hz), 8.42-8.39 (2H, m), 8.25 (1H, dd, J 8.5 2.4 Hz), 8.16 (1H, d, J 8.6 Hz), 8.03 (1H, dd, J 8.6 1.8 Hz), 3.41 (2H, q, J 7.2 Hz), 1.13 (3H, t, J 7.3 Hz)
LCMS RT=6.09 min, MH+ 332.0; 1H NMR (DMSO): 8.26 (1H, dd, J 1.8 0.5 Hz), 8.03 (1H, dd, J 8.5 0.5 Hz), 7.92 (1H, dd, J 8.5 1.8 Hz), 7.83 (1H, dd, J 8.2 1.7 Hz), 7.68 (1H, d, J 1.6 Hz), 7.19 (1H, d, J 8.2 Hz), 6.20 (2H, s), 3.39 (2H, q, J 7.3 Hz), 1.12 (3H, t, J 7.3 Hz)
LCMS RT=6.43 min; 1H NMR (DMSO): 8.45 (2H, d, J 8.4 Hz), 8.18 (2H, d, J 8.5 Hz), 8.02 (1H, d, J 1.9 Hz), 7.92 (1H, d, J 8.7 Hz), 7.56 (1H, dd, J 8.7 2.1 Hz)
LCMS RT=6.70 min; 1H NMR (DMSO): 8.32 (1H, dd, J 1.8 0.5 Hz), 8.24 (1H, d, J 1.6 Hz), 8.16 (1H, dd, J 8.5 1.7 Hz), 8.09 (1H, dd, J 8.6 0.5 Hz), 7.97 (1H, dd, J 8.5 1.8 Hz), 7.71 (1H, d, J 8.5 Hz), 3.40 (2H, q, J 7.3 Hz), 1.13 (3H, t, J 7.4 Hz)
LCMS RT=6.42 min, MH+ 246.0; 1H NMR (DMSO): 9.94 (1H, s), 8.13 (2H, d, J 8.6 Hz), 7.66 (2H, d, J 8.6 Hz), 7.60 (1H, d, J 8.6 Hz), 7.10 (1H, d, J 2.2 Hz), 6.87 (1H, dd, J 8.7 2.3 Hz)
LCMS RT=7.77 min, MH+ 353.9; 1H NMR (DMSO): 12.24 (1H, s), 8.44-8.39 (2H, m), 8.19-7.98 (4H, m), 7.77-7.63 (3H, m), 3.42 (2H, q, J 7.3 Hz), 1.15 (3H, t, J 7.3 Hz)
LCMS RT=6.47 min, MH+ 328.2; 1H NMR (DMSO): 8.61 (1H, d, J 1.7 Hz), 8.31 (1H, d, J 1.7 Hz), 8.22 (1H, dd, J 8.5 1.7 Hz), 8.19 (1H, d, J 2.2 Hz), 8.09 (1H, d, J 8.5 Hz), 7.95 (1H, dd, J 8.5 1.9 Hz), 7.88 (1H, d, J 8.7 Hz), 7.19-7.17 (1H, m), 3.40 (2H, q, J 7.4 Hz), 1.15 (3H, t, J 7.3 Hz)
LCMS RT=7.75 min, MH+ 364.9; 1H NMR (DMSO): 8.26-8.21 (3H, m), 8.03 (1H, d, J 8.6 Hz), 7.89 (1H, dd, J 8.6 1.8 Hz), 7.74 (2H, d, J 8.6 Hz), 3.22 (4H, q, J 7.2 Hz), 1.06 (6H, t, J 7.2 Hz)
LCMS RT=9.10 min, MH+ 330.1; 1H NMR (DMSO): 8.88 (1H, br), 8.27 (1H, dd, J 8.5 1.7 Hz), 8.23-8.19 (1H, m), 8.16 (1H, d, J 8.7 Hz), 8.08-8.04 (1H, m), 7.97 (1H, d, J 8.9 Hz), 7.95-7.93 (1H, m), 7.73-7.64 (2H, m), 7.52-7.47 (1H, m)
LCMS RT=4.83 min, MH+ 289.0; 1H NMR (DMSO): 13.20 (1H, br), 8.89 (1H, br), 8.36 (1H, dd, J 1.6 0.5 Hz), 8.30 (1H, dd, J 8.6 1.8 Hz), 8.24-8.20 (1H, m), 8.17 (1H, d, J 8.8 Hz), 8.10-8.04 (2H, m), 7.94 (1H, dd, J 8.5 0.5 Hz), 7.73-7.63 (2H, m)
LCMS RT=8.19 min, MH+ 246.1; 1H NMR (DMSO): 8.86 (1H, br), 8.29 (1H, dd, J 8.6 1.8 Hz), 8.22-8.18 (1H, m), 8.15 (1H, d, J 8.7 Hz), 8.07-8.03 (1H, m), 7.88-7.83 (2H, m), 7.71-7.62 (2H, m), 7.51-7.42 (2H, m)
LCMS RT=10.50 min, MH+ 302.2; 1H NMR (CDCl3): 8.70 (1H, s), 8.25 (1H, dd, J 8.6 1.5 Hz), 7.94-7.89 (2H, m), 7.85-7.81 (1H, m), 7.77 (1H, d, J 1.6 Hz), 7.54-7.45 (3H, m), 7.37 (1H, dd, J 8.5 1.8 Hz), 1.35 (9H, s)
LCMS RT=8.57 min, MH+ 282.1; 1H NMR (DMSO): 8.82 (1H, br), 8.24 (1H, dd, J 8.6 1.8 Hz), 8.21-8.12 (3H, m), 8.07-8.00 (2H, m), 7.72-7.63 (2H, m)
LCMS RT=8.19 min, MH+ 305.9; 1H NMR (DMSO): 8.45 (1H, dd, J 1.7 0.5 Hz), 8.38 (1H, d, J 2.0 Hz), 8.18 (1H, dd, J 8.5 2.1 Hz), 8.09 (1H, dd, J 8.6 1.8 Hz), 7.96-7.91 (2H, m), 2.69 (3H, s)
LCMS RT=8.41 min, MH+ 244.1; 1H NMR (DMSO): 8.18 (2H, d, J 8.7 Hz), 7.72-7.61 (4H, m), 7.27-7.23 (1H, m), 2.48 (3H, s)
LCMS RT=8.82 min, MH+ 260.2; 1H NMR (DMSO): 8.83 (1H, d, J 1.1 Hz), 8.26 (1H, dd, J 8.6 1.7 Hz), 8.21-8.16 (1H, m), 8.13 (1H, d, J 8.7 Hz), 8.06-8.02 (1H, m), 7.72-7.64 (4H, m), 7.30-7.26 (1H, m), 2.47 (3H, s)
Method 1C (Compounds I)
To polyphosphoric acid at 165° C. was added N-(5-nitro-2-oxo-1,2-dihydropyridin-3-yl)benzamide (300 mg, 1.16 mmol). The resulting mixture was then heated to 165° C. for 30 min. The solution was then poured into water. The resulting precipitate was collected by filtration, dissolved in diethyl ether, filtered through alumina and evaporated to afford 9 mg (3%) of the title compound.
1H NMR (DMSO): 9.31 (1H, d, J 2.5 Hz), 9.12 (1H, d, J 2.5 Hz), 8.32-8.27 (2H, m), 7.79-7.67 (3H, m)
All compounds below were prepared following the same general method.
LCMS RT=5.83 min, MH+ 241.9; 1H NMR (DMSO): 8.87-8.84 (1H, m), 8.78 (1H, d, J=2.3 Hz), 8.44-8.40 (2H, m), 8.16-8.10 (2H, m), 7.74-7.69 (1H, m)
LCMS RT=5.84 min, MH+ 242.0; 1H NMR (DMSO): 8.79-8.76 (2H, m), 8.34 (1H, dt, J 7.9 1.0 Hz), 8.29 (1H, dd, J 8.8 2.0 Hz), 8.07-8.02 (2H, m), 7.64 (1H, ddd, J 7.7 4.8 1.2 Hz)
LCMS RT=7.32 min, MH+ 298.1; 1H NMR (DMSO): 8.68 (1H, dd, J 2.3 0.3 Hz), 8.64 (1H, dd, J 2.1 0.5 Hz), 8.33 (1H, dd, J 9.0 2.4 Hz), 8.26 (1H, dd, J 8.0 0.6 Hz), 8.05 (1H, dd, J 9.0 0.3 Hz), 7.88 (1H, dd, J 8.1 2.1 Hz), 2.70-2.66 (2H, m), 1.62-1.52 (2H, m), 1.34-1.22 (2H, m), 0.86 (3H, t, J 7.4 Hz)
Method 1D (Compounds I)
A suspension of 2-(2,4-difluorobenzamido)-4,5-dimethylphenyl 2,4-difluorobenzoate (90 mg, 0.22 mmol) and 4-methylbenzenesulfonic acid (82 mg, 0.43 mmol) in xylene (2 mL) was heated at reflux for 16 h. After cooling, the solution was diluted with ethyl acetate and washed with aqueous sodium bicarbonate solution followed by brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 1:15 v/v to afford 36 mg (64%) of the title compound (LCMS RT=7.81 min, MH+ 260.0)
1H NMR (DMSO): 8.30-8.22 (1H, m), 7.63-7.52 (3H, m), 7.39-7.30 (1H, m), 2.37 (3H, s), 2.35 (3H, s)
Method 2A (Compounds Ib)
To 5-nitro-2-p-tolylbenzo[d]oxazole (4.8 g, 18.90 mmol) in ethyl acetate/acetic acid (250 mL/1 mL) was added palladium on carbon (480 mg). The reaction vessel was purged three times with nitrogen, followed by hydrogen three times, and then left stirring under hydrogen for 16 h. The reaction vessel was finally purged three times with nitrogen, before filtration on a pad of Celite®, which was washed with ethyl acetate. The organic solution was washed with saturated aqueous Na2CO3, followed by brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated to afford 2.5 g (60%) of the title compound.
1H NMR (DMSO): 8.02 (2H, d, J 8.2 Hz), 7.39 (3H, d, J 8.5 Hz), 6.86 (1H, d, J 2.0 Hz), 6.65 (1H, dd, J 8.7 2.2 Hz), 5.09 (2H, s), 2.40 (3H, s)
Method 2B (Compounds Ib)
As Method 2A, except ethanol was used instead of ethyl acetate/acetic acid. After evaporation of the solvents, the material was taken up in 2M HCl, the resulting precipitate was discarded, and the solution was basified with 2N NaOH to afford the title compound as a precipitate.
LCMS RT=5.93 min, MH+ 211.1; 1H NMR (DMSO): 8.10-8.07 (2H, m), 7.58-7.54 (3H, m), 7.42 (1H, d, J 8.4 Hz), 6.83 (1H, d, J 1.9 Hz), 6.65 (1H, dd, J 8.5 2.0 Hz), 5.46 (2H, s)
Method 2C (Compounds Ib)
To 5-nitro-2-(4-(trifluoromethoxy)phenyl)benzo[d]oxazole (850 mg, 2.62 mmol) in ethanol (20 mL) was added ammonium formate (827 mg, 13.1 mmol) and palladium on carbon (85 mg). The mixture was stirred at room temperature for 20 min, then filtrated through a pad of Celite®, and washed with ethyl acetate. The organic solution was washed with water, followed by brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated to afford 434 mg (56%) of the title compound (LCMS RT=6.51 min, MH+ 294.9)
1H NMR (DMSO): 8.25 (2H, d, J 8.9 Hz), 7.62-7.56 (2H, m), 7.44 (1H, d, J 8.7 Hz), 6.89 (1H, d, J 2.0 Hz), 6.70 (1H, dd, J 8.7 2.3 Hz), 5.16 (2H, s)
Method 2D (Compounds Ib)
To 4-nitro-2-p-tolylbenzo[d]oxazole (330 mg, 1.30 mmol) in ethanol (20 mL) was added tin (II) chloride (1.23 g, 6.5 mmol). The suspension was stirred at 70° C. for 16 h. After cooling, the solution was poured into ice/water and neutralize with saturated aqueous NaHCO3. The aqueous layer was then extracted twice with ethyl acetate (500 mL). The combined organic layers were dried over anhydrous MgSO4 and evaporated to afford 188 mg (65%) of the title compound (LCMS RT=6.76 min, MH+ 225.1)
1H NMR (DMSO): 8.04 (2H, d, J 8.2 Hz), 7.41 (2H, d, J 8.0 Hz), 7.07 (1H, t, J 8.0 Hz), 6.85 (1H, dd, J 8.0 0.8 Hz), 6.55 (1H, dd, J 8.0 0.8 Hz), 5.67 (2H, s), 2.41 (3H, s)
The compound below was prepared following the same general method.
LCMS RT=5.41 min, MH+ 212.1; 1H NMR (DMSO): 8.19-8.15 (2H, m), 7.73 (1H, d, J 2.4 Hz), 7.63-7.58 (3H, m), 7.32 (1H, d, J 2.4 Hz), 5.38 (2H, s)
Method 2E (Compounds Ib)
To 6-nitro-2-p-tolylbenzo[d]oxazole (2.1 g, 8.27 mmol) in ethanol:water 2:1 v/v (60 mL) at 70° C. was added iron powder (2.14 g, 38.3 mmol) and ammonium chloride (819 mg, 15.3 mmol). The suspension was stirred at reflux for 16 h. After cooling, the solution was filtered through a pad of Celite® and washed with ethanol. After evaporation of the solvent, the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate:hexanes 1:3 v/v to afford 70 mg (4%) of the title compound (LCMS RT=6.12 min, MH+ 223.1)
1H NMR (DMSO): 7.97 (2H, d, J 8.1 Hz), 7.40-7.36 (3H, m), 6.82 (1H, d, J 1.9 Hz), 6.64 (1H, dd, J 8.5 2.0 Hz), 5.41 (2H, s), 2.39 (3H, s)
All compounds below were prepared following the same general method.
LCMS RT=5.82 min, MH+ 238.9; 1H NMR (DMSO): 7.29-7.16 (6H, m), 6.76 (1H, d, J 1.9 Hz), 6.57 (1H, dd, J 8.6 2.2 Hz), 4.98 (2H, s), 3.19-3.06 (4H, m)
LCMS RT=5.77 min, MH+ 254.9; 1H NMR (DMSO): 7.69 (1H, dd, J 8.2 1.7 Hz), 7.58 (1H, d, J 1.7 Hz), 7.37 (1H, d, J 8.6 Hz), 7.11 (1H, d, J 8.2 Hz), 6.84 (1H, d, J 2.0 Hz), 6.64 (1H, dd, J 8.8 2.2 Hz), 6.16 (2H, s), 5.07 (2H, s)
LCMS RT=6.52 min, MH+ 289.1; 1H NMR (DMSO): 7.72 (1H, dd, J 8.2 1.8 Hz), 7.69 (1H, s), 7.61 (1H, d, J 1.6 Hz), 7.17 (1H, d, J 8.2 Hz), 7.13 (1H, s), 6.21 (2H, s), 5.66 (2H, s)
Method 2F (Compounds Ib)
As Method 2E, except THF:water (2:1 v/v) was used instead of ethanol:water (2:1 v/v).
LCMS RT=7.12 min, MH+ 278.1; 1H NMR (DMSO): 8.22 (1H, d, J 1.8 Hz), 8.03 (1H, dd, J 8.4 2.0 Hz), 7.83 (1H, d, J 8.4 Hz), 7.44 (1H, d, J 8.4 Hz), 6.82 (1H, d, J 2.0 Hz), 6.68 (1H, dd, J 8.6 2.0 Hz), 5.57 (2H, s)
Method 3A (Compounds II)
To a solution of 2-phenylbenzo[d]oxazol-5-amine (50 mg, 0.24 mmol) in dichloromethane (2 mL) at room temperature was added 3-phenylpropanoyl chloride (44.1 mg, 0.26 mmol) followed immediately by diisopropylethylamine (82 μL, 0.48 mmol). The resulting mixture was stirred at room temperature for 16 h. Dichloromethane was added and the organic layer was washed with saturated aqueous Na2CO3. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was dissolved in methanol, passed through an acidic scavenger column (silica-based quaternary amine SPE-AX from Biotage®) and then evaporated to afford 61.1 mg (75%) of the title compound (LCMS RT=6.45 min, MH+ 343.2)
1H NMR (DMSO): 10.11 (1H, s), 8.22-8.15 (3H, m), 7.71 (1H, d, J 8.8 Hz), 7.66-7.59 (3H, m), 7.51 (1H, dd, J 8.9 2.1 Hz), 7.33-7.17 (5H, m), 2.96 (2H, t, J 7.2 Hz), 2.67 (2H, t, J 7.1 Hz)
All compounds below were prepared following the same general method.
LCMS RT=5.16 min, MH+ 253.1; 1H NMR (DMSO): 10.14 (1H, s), 8.21-8.14 (3H, m), 7.71 (1H, d, J 8.8 Hz), 7.65-7.60 (3H, m), 7.51 (1H, dd, J 9.0 2.1 Hz), 2.09 (3H, s)
LCMS RT=5.49 min, MH+ 267.1; 1H NMR (DMSO): 10.09 (1H, s), 8.21-8.16 (3H, m), 7.71 (1H, d, J 8.8 Hz), 7.66-7.61 (3H, m), 7.54 (1H, dd, J 9.0 2.1 Hz), 2.37 (2H, q, J 7.6 Hz), 1.12 (3H, t, J 7.6 Hz)
LCMS RT=5.78 min, MH+ 281.1; 1H NMR (DMSO): 10.09 (1H, s), 8.21-8.16 (3H, m), 7.71 (1H, d, J 8.8 Hz), 7.64-7.60 (3H, m), 7.54 (1H, dd, J 9.0 2.1 Hz), 2.33 (2H, q, J 7.6 Hz), 1.69-1.61 (2H, m), 0.94 (3H, t, J 7.6 Hz)
LCMS RT=6.21 min, MH+ 295.1; 1H NMR (DMSO): 10.09 (1H, s), 8.21-8.16 (3H, m), 7.71 (1H, d, J 8.8 Hz), 7.65-7.60 (3H, m), 7.54 (1H, dd, J 9.0 2.1 Hz), 2.35 (2H, q, J 7.6 Hz), 1.66-1.58 (2H, m), 1.39-1.31 (2H, m), 0.92 (3H, t, J 7.6 Hz)
LCMS RT=5.79 min, MH+ 281.1; 1H NMR (DMSO): 10.02 (1H, s), 8.22-8.18 (3H, m), 7.71 (1H, d, J 8.8 Hz), 7.66-7.60 (3H, m), 7.55 (1H, dd, J 9.0 2.1 Hz), 2.67-2.58 (1H, m), 1.14 (6H, s)
LCMS RT=5.82 min, MH+ 305.1; 1H NMR (DMSO): 10.42 (1H, s), 8.26-8.20 (3H, m), 7.97 (1H, dd, J 1.7 0.8 Hz), 7.77 (2H, d, J 1.3 Hz), 7.66-7.62 (3H, m), 7.38 (1H, d, J 3.4 Hz), 6.73 (1H, dd, J 3.4 1.7 Hz)
LCMS RT=7.23 min, MH+ 363.1; 1H NMR (DMSO): 10.55 (1H, s), 8.32-8.31 (1H, m), 8.17 (2H, d, J 8.1 Hz), 8.08 (2H, d, J 8.6 Hz), 7.84-7.77 (2H, m), 7.70 (2H, d, J 8.6 Hz), 7.50 (2H, d, J 8.1 Hz), 2.49 (3H, s)
LCMS RT=6.41 min, MH+ 359.1; 1H NMR (DMSO): 10.35 (1H, s), 8.33 (1H, s), 8.17 (2H, d, J 8.1 Hz), 8.07 (2H, d, J 8.7 Hz), 7.81 (2H, s), 7.51 (2H, d, J 8.3 Hz), 7.16 (2H, d, J 8.8 Hz), 3.17 (3H, s), 2.49 (3H, s)
Method 3B (Compounds II)
As Method 3A, except instead of diisopropylamine, triethylamine was used as a base.
LCMS RT=5.48 min, MH+ 316.1; 1H NMR (DMSO): 10.70 (1H, s), 9.21 (1H, d, J 2.1 Hz), 8.85 (1H, dd, J 4.8 1.6 Hz), 8.40 (1H, dt, J 8.0 2.0 Hz), 8.37 (1H, d, J 1.8 Hz), 8.30-8.27 (2H, m), 7.89-7.80 (2H, m), 7.72-7.64 (4H, m)
LCMS RT=5.46 min, MH+ 316.1; 1H NMR (DMSO): 10.76 (1H, s), 8.88 (2H, d, J 5.9 Hz), 8.36 (1H, d, J 1.7 Hz), 8.31-8.27 (2H, m), 7.97 (2H, d, J 6.1 Hz), 7.90-7.80 (2H, m), 7.73-7.68 (3H, m)
LCMS RT=7.07 min, MH+ 349.1; 1H NMR (DMSO): 10.57 (1H, s), 8.35-8.34 (1H, m), 8.30-8.27 (2H, m), 8.09 (2H, d, J 8.6 Hz), 7.88-7.80 (2H, m), 7.72-7.67 (5H, m)
LCMS RT=6.80 min, MH+ 329.2; 1H NMR (DMSO): 10.41 (1H, s), 8.37-8.35 (1H, m), 8.30-8.26 (2H, m), 7.98 (2H, d, J 8.1 Hz), 7.84 (2H, s), 7.72-7.67 (3H, m), 7.43 (2H, d, J 8.0 Hz), 2.47 (3H, s)
LCMS RT=6.37 min, MH+ 345.1; 1H NMR (DMSO): 10.33 (1H, s), 8.35 (1H, s), 8.30-8.26 (2H, m), 8.06 (2H, d, J 8.7 Hz), 7.83 (2H, s), 7.71-7.67 (3H, m), 7.14 (2H, d, J 8.8 Hz), 3.92 (3H, s)
LCMS RT=7.06 min, MH+ 345.1; 1H NMR (DMSO): 10.37 (1H, s), 8.38-8.36 (1H, m), 8.30-8.26 (2H, m), 7.84-7.56 (7H, m), 7.27 (1H, d, J 8.4 Hz), 7.14 (1H, t, J 7.3 Hz), 3.99 (3H, s)
LCMS RT=6.63 min, MH+ 358.2; 1H NMR (DMSO): 10.10 (1H, s), 8.35-8.34 (1H, m), 8.30-8.26 (2H, m), 7.96 (2H, d, J 8.9 Hz), 7.82-7.80 (2H, m), 7.71-7.68 (3H, m), 6.84 (2H, d, J 8.9 Hz), 3.08 (6H, s)
LCMS RT=7.95 min, MH+ 382.8; 1H NMR (DMSO): 10.63 (1H, s), 8.37-8.26 (4H, m), 8.04 (1H, dd, J 8.4 2.1 Hz), 7.92-7.78 (3H, m), 7.73-7.65 (3H, m)
LCMS RT=7.19 min, MH+ 383.1; 1H NMR (DMSO): 10.72 (1H, s), 8.37-8.24 (5H, m), 8.00 (2H, d, J 8.4 Hz), 7.89-7.82 (2H, m), 7.74-7.67 (3H, m)
LCMS RT=8.30 min, MH+ 382.9; 1H NMR (DMSO): 10.67 (1H, s), 8.33-8.26 (3H, m), 8.09 (2H, d, J 2.1 Hz), 7.96 (1H, t, J 2.0 Hz), 7.89-7.78 (2H, m), 7.72-7.67 (3H, m)
LCMS RT=6.53 min, MH+ 333.2; 1H NMR (DMSO): 10.50 (1H, s), 8.34-8.33 (1H, m), 8.39-8.26 (2H, m), 8.16-8.11 (2H, m), 7.86-7.79 (2H, m), 7.71-7.65 (3H, m), 7.45 (2H, t, J 8.8 Hz)
LCMS RT=7.74 min, MH+ 391.1; 1H NMR (DMSO): 10.55 (1H, s), 8.39-8.38 (1H, m), 8.31-8.27 (2H, m), 8.17 (2H, d, J 8.5 Hz), 7.93 (2H, d, J 8.4 Hz), 7.86-7.83 (4H, m), 7.72-7.69 (3H, m), 7.62-7.50 (3H, m)
LCMS RT=6.32 min, MH+ 329.2; 1H NMR (DMSO): 10.42 (1H, s), 8.27-8.21 (3H, m), 7.78 (1H, d, J 8.9 Hz), 7.71-7.65 (3H, m), 7.61 (1H, dd, J 8.9 2.1 Hz), 7.45-7.30 (5H, m), 3.75 (2H, s)
LCMS RT=6.86 min, MH+ 341.1; 1H NMR (DMSO): 10.48 (1H, s), 8.37 (1H, d, J 1.9 Hz), 8.29-8.26 (2H, m), 7.83 (1H, d, J 8.9 Hz), 7.73-7.67 (7H, m), 7.56-7.48 (3H, m), 6.93 (1H, d, J 15.6 Hz)
LCMS RT=7.07 min, MH+ 365.0; 1H NMR (DMSO): 10.82 (1H, s), 8.44 (1H, s), 8.31-8.28 (3H, m), 8.18-8.10 (2H, m), 7.88-7.83 (3H, m), 7.73-7.65 (6H, m)
LCMS RT=7.37 min, MH+ 365.1; 1H NMR (DMSO): 10.69 (1H, s), 8.69 (1H, s), 8.42 (1H, s), 8.31-8.28 (2H, m), 8.20-8.08 (4H, m), 7.90-7.88 (2H, m), 7.75-7.68 (5H, m)
LCMS RT=6.31 min, MH+ 321.1; 1H NMR (DMSO): 10.47 (1H, s), 8.30-8.26 (3H, m), 8.12 (1H, dd, J 3.8 1.1 Hz), 7.94 (1H, dd, J 5.0 1.1 Hz), 7.85 (1H, d, J 8.8 Hz), 7.77 (1H, dd, J 8.9 2.0 Hz), 7.73-7.65 (3H, m), 7.33-7.30 (1H, m)
LCMS RT=5.63 min, MH+ 315.8; 1H NMR (DMSO): 10.53 (1H, s), 9.45-9.42 (1H, m), 8.88 (1H, dd, J 4.9 1.6 Hz), 8.62 (1H, dt, J 8.0 1.8 Hz), 8.42-8.40 (1H, m), 8.06 (2H, dd, J 6.6 1.2 Hz), 7.88 (2H, s), 7.75-7.59 (4H, m)
LCMS RT=6.12 min, MH+ 349.9; 1H NMR (DMSO): 10.58 (1H, s), 9.43-9.42 (1H, m), 8.89-8.87 (1H, m), 8.64-8.59 (1H, m), 8.40-8.38 (1H, m), 8.09 (2H, d, J 8.5 Hz), 7.91-7.83 (2H, m), 7.76-7.69 (3H, m)
LCMS RT=5.91 min, MH+ 330.2; 1H NMR (DMSO): 10.43 (1H, s), 9.43 (1H, dd, J 2.1 0.9 Hz), 8.88 (1H, dd, J 4.8 1.6 Hz), 8.61 (1H, dt, J 8.0 1.9 Hz), 8.40 (1H, t, J 1.2 Hz), 7.98 (2H, d, J 8.2 Hz), 7.87 (2H, d, J 1.2 Hz), 7.75-7.70 (1H, m), 7.43 (2H, d, J 8.0 Hz), 2.47 (3H, s)
LCMS RT=5.64 min, MH+ 345.9; 1H NMR (DMSO): 10.37 (1H, s), 9.45 (1H, dd, J 1.6 0.8 Hz), 8.90 (1H, dd, J 4.9 1.7 Hz), 8.63 (1H, dt, J 8.0 1.9 Hz), 8.41 (1H, t, J 1.2 Hz), 8.08 (2H, d, J 8.5 Hz), 7.88 (2H, d, J 1.2 Hz), 7.77-7.72 (1H, m), 7.17 (2H, d, J 8.7 Hz), 3.94 (3H, s)
LCMS RT=6.02 min, MH+ 345.9; 1H NMR (DMSO): 10.33 (1H, s), 9.38-9.36 (1H, m), 8.82 (1H, dd, J 4.9 1.7 Hz), 8.55 (1H, dt, J 8.0 1.8 Hz), 8.36-8.34 (1H, m), 7.82-7.73 (2H, m), 7.69-7.65 (2H, m), 7.57-7.50 (1H, m), 7.21 (1H, d, J 8.4 Hz), 7.09 (1H, t, J 7.6 Hz), 3.93 (3H, s)
LCMS RT=5.82 min, MH+ 358.9; 1H NMR (DMSO): 10.13 (1H, s), 9.45 (1H, dd, J 2.3 0.9 Hz), 8.88 (1H, dd, J 4.8 1.6 Hz), 8.64-8.59 (1H, m), 8.40-8.39 (1H, m), 7.97 (2H, d, J 9.1 Hz), 7.86-7.85 (2H, m), 7.75-7.70 (1H, m), 6.86 (2H, d, J 9.1 Hz), 3.08 (6H, s)
LCMS RT=6.78 min, MH+ 383.5; 1H NMR (DMSO): 10.66 (1H, s), 9.43 (1H, d, J 2.1 0.6 Hz), 8.88 (1H, dd, J 4.8 1.6 Hz), 8.61 (1H, dt, J 8.0 2.0 Hz), 8.37 (1H, d, J 2.0 Hz), 8.32 (1H, d, J 2.1 Hz), 8.04 (1H, dd, J 8.4 2.1 Hz), 7.92-7.82 (3H, m), 7.75-7.71 (1H, m)
LCMS RT=6.32 min, MH+ 383.6; 1H NMR (DMSO): 10.68 (1H, s), 9.37 (1H, d, J 2.1 Hz), 8.82 (1H, dd, J 4.9 1.5 Hz), 8.56 (1H, dt, J 8.0 2.0 Hz), 8.34 (1H, d, J 1.7 Hz), 8.20 (2H, d, J 8.1 Hz), 7.95 (2H, d, J 8.4 Hz), 7.88-7.79 (2H, m), 7.69-7.65 (1H, m)
LCMS RT=7.06 min, MH+ 383.7; 1H NMR (DMSO): 10.69 (1H, s), 9.43-9.41 (1H, m), 8.88 (1H, dd, J 4.9 1.7 Hz), 8.61 (1H, dt, J 8.0 2.0 Hz), 8.37 (1H, d, J 1.9 Hz), 8.09 (2H, d, J 1.9 Hz), 7.96-7.82 (3H, m), 7.75-7.71 (1H, m)
LCMS RT=5.70 min, MH+ 334.0; 1H NMR (DMSO): 10.47 (1H, s), 9.38-9.36 (1H, m), 8.82 (1H, dd, J 4.9 1.7 Hz), 8.56 (1H, dt, J 8.0 2.0 Hz), 8.33-8.32 (1H, m), 8.11-8.06 (2H, m), 7.85-7.80 (2H, m), 7.69-7.65 (1H, m), 7.40 (2H, t, J 8.9 Hz)
LCMS RT=6.78 min, MH+ 391.6;
LCMS RT=5.63 min, MH+ 329.7; 1H NMR (DMSO): 10.46 (1H, s), 9.41-9.39 (1H, m), 8.87 (1H, dd, J 4.9 1.7 Hz), 8.59 (1H, dt, J 8.0 2.0 Hz), 8.26 (1H, d, J 2.0 Hz), 7.82 (1H, d, J 8.8 Hz), 7.73-7.69 (1H, m), 7.64 (1H, dd, J 8.8 2.0 Hz), 7.44-7.30 (5H, m), 3.75 (2H, s)
LCMS RT=5.84 min, MH+ 343.8; 1H NMR (DMSO): 10.14 (1H, s), 9.35-9.34 (1H, m), 8.81 (1H, dd, J 4.9 1.7 Hz), 8.53 (1H, dt, J 8.0 2.0 Hz), 8.19 (1H, d, J 2.0 Hz), 7.76 (1H, d, J 8.8 Hz), 7.69-7.63 (1H, m), 7.54 (1H, dd, J 8.8 2.0 Hz), 7.33-7.17 (5H, m), 2.95 (2H, t, J 7.6 Hz), 2.67 (2H, t, J 8.0 Hz)
LCMS RT=6.03 min, MH+ 342.0; 1H NMR (DMSO): 10.46 (1H, s), 9.37-9.35 (1H, m), 8.82 (1H, dd, J 4.9 1.7 Hz), 8.55 (1H, dt, J 8.0 2.0 Hz), 8.35 (1H, d, J 1.9 Hz), 7.82 (1H, d, J 8.9 Hz), 7.69-7.63 (5H, m), 7.49-7.41 (3H, m), 6.87 (1H, d, J 15.8 Hz)
LCMS RT=4.97 min, MH+ 267.9; 1H NMR (DMSO): 10.08 (1H, s), 9.34 (1H, dd, J 2.2 0.7 Hz), 8.81 (1H, dd, J 4.9 1.7 Hz), 8.53 (1H, dt, J 8.0 2.0 Hz), 8.21 (1H, d, J 2.0 Hz), 7.76 (1H, d, J 8.9 Hz), 7.68-7.63 (1H, m), 7.57 (1H, dd, J 9.0 2.1 Hz), 2.37 (2H, q, J 7.6 Hz), 1.12 (3H, t, J 7.6 Hz)
LCMS RT=5.26 min, MH+ 281.9; 1H NMR (DMSO): 10.17 (1H, s), 9.43 (1H, dd, J 2.2 0.7 Hz), 8.89 (1H, dd, J 4.9 1.7 Hz), 8.62 (1H, dt, J 8.0 2.0 Hz), 8.29 (1H, d, J 2.0 Hz), 7.84 (1H, d, J 8.9 Hz), 7.76-7.72 (1H, m), 7.65 (1H, dd, J 9.0 2.1 Hz), 2.42 (2H, q, J 7.6 Hz), 1.80-1.67 (2H, m), 1.03 (3H, t, J 7.6 Hz)
LCMS RT=5.60 min, MH+ 296.0; 1H NMR (DMSO): 10.09 (1H, s), 9.36-9.33 (1H, m), 8.81 (1H, dd, J 4.9 1.7 Hz), 8.53 (1H, dt, J 8.0 2.0 Hz), 8.20 (1H, d, J 2.0 Hz), 7.75 (1H, d, J 8.9 Hz), 7.648-7.64 (1H, m), 7.57 (1H, dd, J 9.0 2.1 Hz), 2.35 (2H, q, J 7.6 Hz), 1.66-1.56 (2H, m), 1.42-1.29 (2H, m), 0.92 (3H, t, J 7.6 Hz)
LCMS RT=5.22 min, MH+ 282.0; 1H NMR (DMSO): 10.11 (1H, s), 9.41 (1H, dd, J 2.2 0.7 Hz), 8.87 (1H, dd, J 4.9 1.7 Hz), 8.60 (1H, dt, J 8.0 2.0 Hz), 8.29 (1H, d, J 2.0 Hz), 7.83 (1H, d, J 8.9 Hz), 7.74-7.69 (1H, m), 7.65 (1H, dd, J 9.0 2.1 Hz), 2.70 (1H, t, J 6.8 Hz), 1.20 (6H, d, J 6.8 Hz)
LCMS RT=5.23 min, MH+ 305.7; 1H NMR (DMSO): 10.41 (1H, s), 9.37 (1H, dd, J 2.2 0.8 Hz), 8.82 (1H, dd, J 4.9 1.7 Hz), 8.55 (1H, dt, J 8.0 2.0 Hz), 8.30 (1H, t, J 1.3 Hz), 7.97 (1H, dd, J 1.7 0.8 Hz), 7.82-7.81 (2H, m), 7.69-7.64 (1H, m), 7.37 (1H, dd, J 3.5 0.8 Hz), 6.74 (1H, dd, J 3.5 1.7 Hz)
LCMS RT=5.55 min, MH+ 322.0; 1H NMR (DMSO): 10.44 (1H, s), 9.37 (1H, dd, J 2.2 0.8 Hz), 8.82 (1H, dd, J 4.9 1.7 Hz), 8.56 (1H, dt, J 8.0 2.0 Hz), 8.28 (1H, t, J 1.3 Hz), 8.06 (1H, dd, J 1.7 0.8 Hz), 7.89 (1H, dd, J 5.0 1.0 Hz), 7.83 (1H, d, J 9.0 Hz), 7.77-7.73 (1H, m), 7.70-7.65 (1H, m), 7.26 (1H, dd, J 5.0 1.2 Hz)
LCMS RT=6.82 min, MH+ 314.9; 1H NMR (DMSO): 10.43 (1H, s), 8.31-8.30 (1H, m), 8.25-8.20 (2H, m), 8.02-7.98 (2H, m), 7.79 (2H, d, J 1.2 Hz), 7.65-7.53 (6H, m)
LCMS RT=6.55 min, MH+ 386.8; 1H NMR (DMSO): 10.57 (1H, s), 9.14 (1H, d, J 2.1 Hz), 8.78 (1H, dd, J 4.8 1.6 Hz), 8.33 (1H, dt, J 8.0 2.0 Hz), 8.14 (1H, d, J 1.8 Hz), 7.96 (2H, d, J 9.0 Hz), 7.70-7.52 (3H, m), 6.82 (2H, d, J 9.1 Hz), 3.50-3.41 (4H, m), 1.15 (6H, t, J 7.0 Hz)
LCMS RT=6.63 min, MH+ 386.8; 1H NMR (DMSO): 10.69 (1H, s), 8.87 (2H, d, J 6.1 Hz), 8.20 (1H, d, J 1.5 Hz), 8.04 (2H, d, J 9.1 Hz), 7.96 (2H, d, J 6.0 Hz), 7.77-7.69 (2H, m), 6.89 (2H, d, J 9.1 Hz), 3.50-3.46 (4H, m), 1.21 (6H, t, J 7.0 Hz)
LCMS RT=7.84 min, MH+ 386.1; 1H NMR (DMSO): 10.43 (1H, s), 8.22-8.20 (1H, m), 8.06-8.01 (4H, m), 7.72 (2H, d, J 1.2 Hz), 7.68-7.58 (3H, m), 6.89 (2H, d, J 9.1 Hz), 3.51 (4H, q, J 7.0 Hz), 1.21 (6H, t, J 7.0 Hz)
LCMS RT=8.60 min, MH+ 419.9; 1H NMR (DMSO): 10.44 (1H, s), 8.13 (1H, s), 8.00-7.95 (4H, m), 7.66-7.62 (4H, m), 6.82 (2H, d, J 9.1 Hz), 3.45 (4H, q, J 7.0 Hz), 1.15 (6H, t, J 7.0 Hz)
LCMS RT=8.28 min, MH+ 400.2; 1H NMR (DMSO): 10.28 (1H, s), 8.14 (1H, s), 7.97 (2H, d, J 8.9 Hz), 8.03 (2H, d, J 8.1 Hz), 7.65 (2H, d, J 1.2 Hz), 7.36 (2H, d, J 8.1 Hz), 6.82 (2H, d, J 9.1 Hz), 3.44 (4H, q, J 7.0 Hz), 2.40 (3H, s), 1.15 (6H, t, J 7.0 Hz)
LCMS RT=7.86 min, MH+ 416.2; 1H NMR (DMSO): 10.20 (1H, s), 8.13-8.12 (1H, m), 8.00-7.95 (4H, m), 7.64 (2H, d, J 1.3 Hz), 7.07 (2H, d, J 8.9 Hz), 6.82 (2H, d, J 9.1 Hz), 3.85 (3H, s), 3.44 (4H, q, J 7.0 Hz), 1.15 (6H, t, J 7.0 Hz)
LCMS RT=8.69 min, MH+ 416.0; 1H NMR (DMSO): 10.24 (1H, s), 8.15 (1H, d, J 1.5 Hz), 7.96 (2H, d, J 8.9 Hz), 7.68-7.49 (4H, m), 7.19 (1H, d, J 8.4 Hz), 7.08 (1H, t, J 7.5 Hz), 6.83 (2H, d, J 9.1 Hz), 3.92 (3H, s), 3.44 (4H, q, J 7.0 Hz), 1.15 (6H, t, J 7.0 Hz)
LCMS RT=8.08 min, MH+ 429.0; 1H NMR (DMSO): 9.98 (1H, s), 8.13 (1H, s), 7.96 (2H, d, J 8.9 Hz), 7.90 (2H, d, J 8.9 Hz), 7.64-7.61 (2H, m), 6.84-6.76 (4H, m), 3.44 (4H, q, J 7.0 Hz), 3.01 (6H, s), 1.15 (6H, t, J 7.0 Hz)
LCMS RT=9.66 min, MH+ 453.9; 1H NMR (DMSO): 10.52 (1H, s), 8.25 (1H, d, J 2.0 Hz), 8.12 (1H, d, J 1.8 Hz), 7.98-7.94 (3H, m), 7.85 (1H, d, J 8.4 Hz), 7.70-7.60 (2H, m), 6.82 (2H, d, J 9.2 Hz), 3.45 (4H, q, J 7.0 Hz), 1.15 (6H, t, J 7.0 Hz)
LCMS RT=8.87 min, MH+ 454.4; 1H NMR (DMSO): 10.60 (1H, s), 8.20-8.15 (3H, m), 7.99-7.93 (4H, m), 7.70-7.63 (2H, m), 6.83 (2H, d, J 9.2 Hz), 3.45 (4H, q, J 7.0 Hz), 1.15 (6H, t, J 7.0 Hz)
LCMS RT=10.25 min, MH+ 453.8; 1H NMR (DMSO): 10.63 (1H, s), 8.21-8.19 (1H, m), 8.09 (2H, d, J 1.9 Hz), 8.05 (2H, d, J 9.1 Hz), 7.97 (1H, t, J 1.9 Hz), 7.78-7.69 (2H, m), 6.91 (2H, d, J 9.1 Hz), 3.50 (4H, q, J 7.0 Hz), 1.23 (6H, t, J 7.0 Hz)
LCMS RT=7.95 min, MH+ 404.1; 1H NMR (DMSO): 10.38 (1H, s), 8.13-8.12 (1H, m), 8.09-8.04 (2H, m), 7.96 (2H, d, J 9.1 Hz), 7.68-7.61 (2H, m), 7.39 (2H, t, J 8.9 Hz), 6.82 (2H, d, J 9.2 Hz), 3.45 (4H, q, J 7.0 Hz), 1.15 (6H, t, J 7.0 Hz)
LCMS RT=9.67 min, MH+ 461.9; 1H NMR (DMSO): 10.42 (1H, s), 8.18-8.17 (1H, m), 8.09 (2H, d, J 8.5 Hz), 7.98 (2H, d, J 9.0 Hz), 7.87 (2H, d, J 8.6 Hz), 7.78 (2H, d, J 7.1 Hz), 7.71-7.65 (2H, m), 7.45-7.41 (3H, m), 6.82 (2H, d, J 9.2 Hz), 3.45 (4H, q, J 7.0 Hz), 1.15 (6H, t, J 7.0 Hz)
LCMS RT=7.70 min, MH+ 400.1; 1H NMR (DMSO): 10.29 (1H, s), 8.00 (1H, d, J 1.8 Hz), 7.94 (2H, d, J 9.1 Hz), 7.59 (1H, d, J 8.7 Hz), 7.45-7.23 (6H, m), 6.81 (2H, d, J 9.2 Hz), 3.67 (2H, s), 3.43 (4H, q, J 7.0 Hz), 1.14 (6H, t, J 7.0 Hz)
LCMS RT=8.10 min, MH+ 413.9; 1H NMR (DMSO): 10.03 (1H, s), 7.99 (1H, d, J 1.9 Hz), 7.94 (2H, d, J 9.1 Hz), 7.58 (1H, d, J 8.7 Hz), 7.40 (1H, dd, J 8.7 2.0 Hz), 7.36-7.17 (5H, m), 6.82 (2H, d, J 9.2 Hz), 3.44 (4H, q, J 7.0 Hz), 2.94 (2H, d, J 8.1 Hz), 2.65 (1H, d, J 8.3 Hz), 1.15 (6H, t, J 7.0 Hz)
LCMS RT=6.79 min, MH+ 338.2; 1H NMR (DMSO): 10.11 (1H, s), 8.07 (1H, d, J 1.9 Hz), 7.99 (2H, d, J 9.0 Hz), 7.65 (1H, d, J 8.7 Hz), 7.48 (1H, dd, J 8.8 2.0 Hz), 6.87 (2H, d, J 9.1 Hz), 3.49 (4H, q, J 7.0 Hz), 2.41 (2H, q, J 7.5 Hz), 1.24-1.14 (9H, m)
LCMS RT=7.24 min, MH+ 352.2; 1H NMR (DMSO): 9.97 (1H, s), 8.00 (1H, d, J 1.9 Hz), 7.95 (2H, d, J 9.0 Hz), 7.58 (1H, d, J 8.7 Hz), 7.43 (1H, dd, J 8.8 2.0 Hz), 6.81 (2H, d, J 9.1 Hz), 3.44 (4H, q, J 7.0 Hz), 2.31 (2H, t, J 7.4 Hz), 1.68-1.58 (2H, m), 1.15 (6H, t, J 7.0 Hz), 0.94 (3H, t, J 7.4 Hz)
LCMS RT=7.84 min, MH+ 366.0; 1H NMR (DMSO): 9.98 (1H, s), 8.00 (1H, d, J 1.9 Hz), 7.95 (2H, d, J 9.0 Hz), 7.58 (1H, d, J 8.7 Hz), 7.42 (1H, dd, J 8.8 2.0 Hz), 6.81 (2H, d, J 9.1 Hz), 3.44 (4H, q, J 7.0 Hz), 2.33 (2H, t, J 7.5 Hz), 1.65-1.55 (2H, m), 1.41-1.28 (2H, m), 1.15 (6H, t, J 7.0 Hz), 0.91 (3H, t, J 7.4 Hz)
LCMS RT=7.25 min, MH+ 352.2; 1H NMR (DMSO): 9.99 (1H, s), 8.08 (1H, d, J 1.9 Hz), 8.01 (2H, d, J 9.0 Hz), 7.65 (1H, d, J 8.7 Hz), 7.51 (1H, dd, J 8.8 2.0 Hz), 6.88 (2H, d, J 9.1 Hz), 3.50 (4H, q, J 7.0 Hz), 2.70-2.64 (1H, m), 1.24-1.17 (12H, m)
LCMS RT=7.77 min, MH+ 392.1; 1H NMR (DMSO): 10.41 (1H, s), 8.14 (1H, d, J 1.8 Hz), 8.12 (1H, dd, J 3.8 1.0 Hz), 8.04 (2H, d, J 9.1 Hz), 7.95 (1H, dd, J 4.9 1.0 Hz), 7.73 (1H, d, J 8.6 Hz), 7.66 (1H, dd, J 8.7 1.9 Hz), 7.34-7.30 (1H, m), 6.90 (2H, d, J 9.2 Hz), 3.51 (4H, q, J 7.0 Hz), 1.22 (6H, t, J 7.0 Hz)
LCMS RT=6.36 min, MH+ 350.0; 1H NMR (DMSO): 10.71 (1H, s), 8.82 (2H, d, J 9.0 Hz), 8.32-8.30 (1H, m), 8.22 (2H, d, J 8.6 Hz), 7.90 (2H, d, J 6.0 Hz), 7.85-7.79 (2H, m), 7.71 (2H, d, J 8.6 Hz)
LCMS RT=7.67 min, MH+ 349.0; 1H NMR (DMSO): 10.46 (1H, s), 8.32 (1H, s), 8.22 (2H, d, J 8.5 Hz), 8.01-7.98 (2H, m), 7.79 (2H, d, J 1.1 Hz), 7.71 (2H, d, J 8.6 Hz), 7.65-7.50 (3H, m)
LCMS RT=8.51 min, MH+ 383.2; 1H NMR (DMSO): 10.52 (1H, s), 8.30 (1H, s), 8.22 (2H, d, J 8.8 Hz), 8.03 (2H, d, J 8.8 Hz), 7.82-7.77 (2H, m), 7.71 (2H, d, J 8.4 Hz), 7.64 (2H, d, J 8.4 Hz)
LCMS RT=8.21 min, MH+ 362.8; 1H NMR (DMSO): 10.36 (1H, s), 8.31 (1H, s), 8.22 (2H, d, J 8.7 Hz), 7.92 (2H, d, J 8.2 Hz), 7.78 (2H, d, J 1.3 Hz), 7.71 (2H, d, J 8.7 Hz), 7.37 (2H, d, J 8.0 Hz), 2.41 (3H, s)
LCMS RT=7.62 min, MH+ 378.7; 1H NMR (DMSO): 10.28 (1H, s), 8.30 (1H, s), 8.22 (2H, d, J 8.9 Hz), 7.99 (2H, d, J 8.9 Hz), 7.77 (2H, s), 7.70 (2H, d, J 8.3 Hz), 7.08 (2H, d, J 8.9 Hz), 3.86 (3H, s)
LCMS RT=8.55 min, MH+ 379.0; 1H NMR (DMSO): 10.29 (1H, s), 8.29 (1H, d, J 1.5 Hz), 8.18 (2H, d, J 8.6 Hz), 7.77-7.62 (5H, m), 7.52-7.46 (1H, m), 7.17 (1H, d, J 8.3 Hz), 7.05 (1H, t, J 7.5 Hz), 3.89 (3H, s)
LCMS RT=7.96 min, MH+ 392.3; 1H NMR (DMSO): 10.12 (1H, s), 8.36 (1H, s), 8.27 (2H, d, J 8.6 Hz), 7.96 (2H, d, J 8.8 Hz), 7.83-7.81 (2H, m), 7.76 (2H, d, J 8.5 Hz), 6.84 (2H, d, J 9.0 Hz), 3.07 (6H, s)
LCMS RT=8.65 min, MH+ 416.7; 1H NMR (DMSO): 10.67 (1H, s), 8.32 (1H, s), 8.24-8.18 (4H, m), 7.95 (2H, d, J 8.6 Hz), 7.84-7.77 (2H, m), 7.71 (2H, d, J 8.6 Hz)
LCMS RT=10.09 min, MH+ 417.1; 1H NMR (DMSO): 10.68 (1H, s), 8.34 (1H, d, J 1.8 Hz), 8.28 (2H, d, J 8.6 Hz), 8.08 (2H, d, J 1.9 Hz), 7.96 (1H, t, J 1.9 Hz), 7.89-7.78 (2H, m), 7.76 (2H, d, J 8.7 Hz)
LCMS RT=7.78 min, MH+ 367.3; 1H NMR (DMSO): 10.58 (1H, s), 8.35 (1H, s), 8.28 (2H, d, J 8.9 Hz), 8.16-8.11 (2H, m), 7.90-7.82 (2H, m), 7.77 (2H, d, J 8.4 Hz), 7.52-7.42 (2H, m)
LCMS RT=7.48 min, MH+ 362.8; 1H NMR (DMSO): 10.38 (1H, s), 8.22-8.17 (3H, m), 7.75-7.65 (3H, m), 7.55 (1H, dd, J 9.0 2.1 Hz), 7.38-7.24 (5H, m), 3.69 (2H, s)
LCMS RT=7.92 min, MH+ 377.3; 1H NMR (DMSO): 10.12 (1H, s), 8.19 (2H, d, J 8.8 Hz), 8.16 (1H, d, J 1.8 Hz), 7.74-7.68 (3H, m), 7.51 (1H, dd, J 8.8 2.0 Hz), 7.33-7.17 (5H, m), 2.95 (2H, t, J 7.3 Hz), 2.67 (2H, t, J 7.3 Hz),
LCMS RT=7.04 min, MH+ 315.1; 1H NMR (DMSO): 10.07 (1H, s), 8.21-8.18 (3H, m), 7.73-7.67 (3H, m), 7.54 (1H, dd, J 8.8 1.9 Hz), 2.32 (2H, t, J 7.4 Hz), 1.72-1.58 (2H, m), 0.94 (3H, t, J 7.4 Hz)
LCMS RT=7.66 min, MH+ 329.1; 1H NMR (DMSO): 10.07 (1H, s), 8.22-8.16 (3H, m), 7.73-7.68 (3H, m), 7.56-7.51 (1H, m), 2.34 (2H, t, J 7.5 Hz), 1.66-1.56 (2H, m), 1.42-1.30 (2H, m), 0.92 (3H, t, J 7.2 Hz)
LCMS RT=7.04 min, MH+ 315.1; 1H NMR (DMSO): 10.03 (1H, s), 8.22-8.18 (3H, m), 7.74-7.67 (3H, m), 7.56 (1H, dd, J 8.9 2.1 Hz), 2.67-2.59 (1H, m), 1.14 (6H, d, J 6.8 Hz)
LCMS RT=7.01 min, MH+ 338.9; 1H NMR (DMSO): 10.40 (1H, s), 8.27 (1H, d, J 1.1 Hz), 8.22 (2H, d, J 8.5 Hz), 7.97 (1H, s), 7.78 (2H, s), 7.70 (2H, d, J 8.5 Hz), 7.36 (1H, d, J 3.4 Hz), 6.74-6.73 (1H, m)
LCMS RT=7.54 min, MH+ 355.0; 1H NMR (DMSO): 10.42 (1H, s), 8.25-8.21 (3H, m), 8.06 (1H, dd, J 3.9 1.2 Hz), 7.89 (1H, dd, J 5.0 1.0 Hz), 7.80 (1H, d, J 8.8 Hz), 7.74-7.69 (3H, m), 7.26 (1H, dd, J 5.0 3.8 Hz)
LCMS RT=6.12 min, MH+ 330.1; 1H NMR (DMSO): 10.62 (1H, s), 9.15 (1H, dd, J 2.1 0.7 Hz), 8.79 (1H, dd, J 4.8 1.7 Hz), 8.34 (1H, dt, J 7.9 1.8 Hz), 8.27 (1H, d, J 1.6 Hz), 8.11 (2H, d, J 8.2 Hz), 7.82-7.72 (2H, m), 7.63-7.58 (1H, m), 7.44 (2H, d, J 8.0 Hz), 2.43 (3H, s)
LCMS RT=6.17 min, MH+ 330.1; 1H NMR (DMSO): 10.68 (1H, s), 8.82 (2H, d, J 6.0 Hz), 8.27 (1H, d, J 1.5 Hz), 8.22 (2H, d, J 8.2 Hz), 7.90 (2H, d, J 6.0 Hz), 7.81-7.72 (2H, m), 7.45 (2H, d, J 8.0 Hz), 2.43 (3H, s)
LCMS RT=6.34 min, MH+ 281.0; 1H NMR (DMSO): 10.03 (1H, s), 8.14 (1H, d, J 1.8 Hz), 8.08 (2H, d, J 8.2 Hz), 7.69 (1H, d, J 8.8 Hz), 7.51 (1H, dd, J 8.8 2.0 Hz), 7.44 (2H, d, J 8.0 Hz), 2.42 (3H, s), 2.36 (2H, q, J 7.5 Hz), 1.12 (3H, t, J 7.6 Hz)
LCMS RT=6.73 min, MH+ 295.1; 1H NMR (DMSO): 10.04 (1H, s), 8.13 (1H, d, J 1.8 Hz), 8.08 (2H, d, J 8.2 Hz), 7.69 (1H, d, J 8.8 Hz), 7.51 (1H, dd, J 8.8 2.0 Hz), 7.43 (2H, d, J 8.0 Hz), 2.42 (3H, s), 2.32 (2H, t, J 7.4 Hz), 1.71-1.58 (2H, m), 0.94 (3H, t, J 7.4 Hz)
LCMS RT=7.20 min, MH+ 309.1; 1H NMR (DMSO): 10.04 (1H, s), 8.13 (1H, d, J 1.8 Hz), 8.08 (2H, d, J 8.2 Hz), 7.68 (1H, d, J 8.8 Hz), 7.51 (1H, dd, J 8.8 2.0 Hz), 7.43 (2H, d, J 8.0 Hz), 2.42 (3H, s), 2.34 (2H, t, J 7.4 Hz), 1.67-1.56 (2H, m), 1.41-1.29 (2H, m), 0.92 (3H, t, J 7.4 Hz)
LCMS RT=6.74 min, MH+ 295.1; 1H NMR (DMSO): 10.00 (1H, s), 8.15 (1H, d, J 1.8 Hz), 8.09 (2H, d, J 8.2 Hz), 7.69 (1H, d, J 8.8 Hz), 7.53 (1H, dd, J 8.8 2.0 Hz), 7.43 (2H, d, J 8.0 Hz), 2.66-2.60 (1H, m), 2.42 (3H, s), 1.13 (6H, d, J 6.8 Hz)
LCMS RT=6.71 min, MH+ 319.0; 1H NMR (DMSO): 10.37 (1H, s), 8.23 (1H, s), 8.10 (2H, d, J 8.2 Hz), 7.98-7.96 (1H, m), 7.75 (2H, d, J 1.0 Hz), 7.44 (2H, d, J 8.0 Hz), 7.36 (1H, d, J 3.6 Hz), 6.74-6.72 (1H, m), 2.43 (3H, s)
LCMS RT=7.15 min, MH+ 335.0; 1H NMR (DMSO): 10.40 (1H, s), 8.21 (1H, d, J 1.7 Hz), 8.11 (2H, d, J 8.2 Hz), 8.05 (1H, dd, J 3.8 1.0 Hz), 7.89 (1H, d, J 4.9 1.0 Hz), 7.76 (1H, d, J 8.8 Hz), 7.69 (1H, dd, J 8.9 2.0 Hz), 7.44 (2H, d, J 8.0 Hz), 7.26 (1H, dd, J 5.0 3.8 Hz), 2.43 (3H, s)
LCMS RT=6.49 min, MH+ 383.9; 1H NMR (DMSO): 10.70 (1H, s), 9.20-9.18 (1H, m), 8.82 (1H, dd, J 4.6 1.5 Hz), 8.46 (2H, d, J 8.1 Hz), 8.40-8.36 (2H, m), 8.04 (2H, d, J 8.0 Hz), 7.92-7.82 (2H, m), 7.66-7.61 (1H, m)
LCMS RT=6.52 min; 1H NMR (DMSO): 10.80 (1H, s), 8.90 (2H, d, J 6.0 Hz), 8.51 (2H, d, J 8.2 Hz), 8.44 (1H, d, J 1.6 Hz), 8.09 (2H, d, J 8.2 Hz), 8.01-7.93 (3H, m), 7.89 (1H, dd, J 8.9 1.9 Hz)
LCMS RT=6.30 min, MH+ 320.7; 1H NMR (DMSO): 10.17 (1H, s), 8.40 (2H, d, J 8.7 Hz), 8.22-8.19 (1H, m), 7.99 (2H, d, J 8.5 Hz), 7.77 (1H, d, J 8.7 Hz), 7.58-7.53 (1H, m), 2.09 (3H, s)
LCMS RT=6.73 min, MH+ 335.0; 1H NMR (DMSO): 10.09 (1H, s), 8.40 (2H, d, J 7.8 Hz), 8.23 (1H, d, J 1.9 Hz), 7.99 (2H, d, J 8.2 Hz), 7.77 (1H, d, J 8.7 Hz), 7.57 (1H, dd, J 8.8 2.0 Hz), 2.37 (2H, q, J 7.5 Hz), 1.12 (3H, t, J 7.5 Hz)
LCMS RT=7.18 min, MH+ 348.9; 1H NMR (DMSO): 10.10 (1H, s), 8.40 (2H, d, J 7.8 Hz), 8.23 (1H, d, J 1.9 Hz), 7.99 (2H, d, J 8.2 Hz), 7.77 (1H, d, J 8.7 Hz), 7.58 (1H, dd, J 8.8 2.0 Hz), 2.33 (2H, t, J 7.3 Hz), 1.69-1.59 (2H, m), 0.94 (3H, t, J 7.6 Hz)
LCMS RT=7.74 min, MH+ 363.1; 1H NMR (DMSO): 10.10 (1H, s), 8.40 (2H, d, J 7.8 Hz), 8.22 (1H, d, J 1.9 Hz), 7.99 (2H, d, J 8.2 Hz), 7.77 (1H, d, J 8.7 Hz), 7.57 (1H, dd, J 8.8 2.0 Hz), 2.36 (2H, t, J 7.3 Hz), 1.66-1.58 (2H, m), 1.42-1.29 (2H, m), 0.92 (3H, t, J 7.6 Hz)
LCMS RT=7.15 min, MH+ 349.1; 1H NMR (DMSO): 10.09 (1H, s), 8.43 (2H, d, J 7.8 Hz), 8.27 (1H, d, J 1.9 Hz), 8.02 (2H, d, J 8.2 Hz), 7.80 (1H, d, J 8.7 Hz), 7.63 (1H, dd, J 8.8 2.0 Hz), 2.72-2.63 (1H, m), 1.18 (6H, d, J 6.8 Hz)
LCMS RT=7.15 min, MH+ 373.0; 1H NMR (DMSO): 10.28 (1H, s), 8.27 (2H, d, J 8.0 Hz), 8.18-8.16 (1H, m), 7.86 (2H, d, J 8.2 Hz), 7.84-7.82 (1H, m), 7.69-7.67 (2H, m), 7.23 (1H, dd, J 3.5 0.8 Hz), 6.59 (1H, dd, J 3.5 1.7 Hz)
LCMS RT=5.76 min, MH+ 346.0; 1H NMR (DMSO): 10.66 (1H, s), 8.81 (2H, d, J 6.1 Hz), 8.24 (1H, d, J 1.7 Hz), 8.16 (2H, d, J 9.0 Hz), 7.90 (2H, d, J 6.1 Hz), 7.77 (1H, d, J 8.8 Hz), 7.72 (1H, dd, J 8.8 1.9 Hz), 7.18 (2H, d, J 8.9 Hz), 3.88 (3H, s)
LCMS RT=5.59 min, MH+ 283.0; 1H NMR (DMSO): 10.09 (1H, s), 8.13 (2H, d, J 8.9 Hz), 8.08 (1H, d, J 1.8 Hz), 7.67 (1H, d, J 8.9 Hz), 7.47 (1H, dd, J 8.8 2.0 Hz), 7.16 (2H, d, J 9.0 Hz), 3.87 (3H, s), 2.08 (3H, s)
LCMS RT=5.89 min, MH+ 297.1; 1H NMR (DMSO): 10.02 (1H, s), 8.15-8.10 (3H, m), 7.67 (1H, d, J 8.7 Hz), 7.49 (1H, dd, J 8.8 1.8 Hz), 7.16 (2H, d, J 8.8 Hz), 3.88 (3H, s), 2.36 (2H, q, J 7.7 Hz), 1.11 (3H, t, J 7.5 Hz)
LCMS RT=6.19 min, MH+ 311.1; 1H NMR (DMSO): 10.02 (1H, s), 8.13 (2H, d, J 9.0 Hz), 8.10 (1H, d, J 1.9 Hz), 7.66 (1H, d, J 8.9 Hz), 7.49 (1H, dd, J 8.8 1.8 Hz), 7.16 (2H, d, J 9.0 Hz), 3.87 (3H, s), 2.32 (2H, t, J 7.3 Hz), 1.70-1.58 (2H, m), 0.94 (3H, t, J 7.5 Hz)
LCMS RT=6.59 min, MH+ 325.1; 1H NMR (DMSO): 10.02 (1H, s), 8.13 (2H, d, J 9.0 Hz), 8.10 (1H, d, J 1.9 Hz), 7.66 (1H, d, J 8.9 Hz), 7.49 (1H, dd, J 8.8 1.8 Hz), 7.16 (2H, d, J 9.0 Hz), 3.87 (3H, s), 2.34 (2H, t, J 7.3 Hz), 1.66-1.56 (2H, m), 1.41-1.29 (2H, m), 0.92 (3H, t, J 7.5 Hz)
LCMS RT=6.19 min, MH+ 311.1; 1H NMR (DMSO): 9.98 (1H, s), 8.15-8.11 (3H, m), 7.66 (1H, d, J 8.9 Hz), 7.51 (1H, dd, J 8.8 1.8 Hz), 7.16 (2H, d, J 9.0 Hz), 3.88 (3H, s), 1.13 (6H, d, J 6.9 Hz)
LCMS RT=6.16 min, MH+ 335.1; 1H NMR (DMSO): 10.36 (1H, s), 8.20-8.13 (3H, m), 7.96 (1H, dd, J 1.8 0.8 Hz), 7.72 (2H, d, J 1.2 Hz), 7.36 (1H, dd, J 3.5 0.8 Hz), 7.17 (2H, d, J 9.0 Hz), 6.73 (1H, dd, J 3.5 1.7 Hz), 3.88 (3H, s)
LCMS RT=6.54 min, MH+ 351.0; 1H NMR (DMSO): 10.38 (1H, s), 8.19-8.14 (3H, m), 8.05 (1H, dd, J 3.7 1.0 Hz), 7.88 (1H, dd, J 4.1 1.0 Hz), 7.74 (1H, d, J 8.8 Hz), 7.67 (1H, dd, J 8.8 2.0 Hz), 7.27-7.23 (1H, m), 7.17 (2H, d, J 8.9 Hz), 3.88 (3H, s)
LCMS RT=6.67 min, MH+ 295.0;
LCMS RT=6.62 min, MH+ 324.1; 1H NMR (DMSO): 10.06 (1H, s), 8.13 (1H, d, J 1.8 Hz), 7.70 (1H, d, J 8.8 Hz), 7.53 (1H, dd, J 8.8 2.0 Hz), 7.49-7.37 (3H, m), 7.00-6.96 (1H, m), 3.00 (6H, s), 2.32 (2H, t, J 7.6 Hz), 1.71-1.55 (2H, m), 0.94 (3H, t, J 7.4 Hz)
LCMS RT=6.64 min, MH+ 295.0; 1H NMR (DMSO): 10.02 (1H, s), 8.17 (1H, d, J 1.9 Hz), 8.03-7.98 (2H, m), 7.71 (1H, d, J 8.8 Hz), 7.56-7.44 (3H, m), 2.60-2.58 (1H, m), 2.44 (3H, s), 1.14 (6H, d, J 6.8 Hz)
LCMS RT=6.88 min, MH+ 349.0; 1H NMR (DMSO): 10.06 (1H, s), 8.51-8.43 (2H, m), 8.23 (1H, s), 8.03 (1H, d, J 7.4 Hz), 7.91-7.85 (1H, m), 7.77 (1H, d, J 8.5 Hz), 7.62-7.57 (1H, m), 2.63 (1H, t, J 6.8 Hz), 1.14 (6H, d, J 6.8 Hz)
LCMS RT=6.59 min, MH+ 324.1; 1H NMR (DMSO): 10.01 (1H, s), 8.15 (1H, d, J 1.8 Hz), 7.70 (1H, d, J 8.8 Hz), 7.55 (1H, dd, J 8.8 2.0 Hz), 7.49-7.37 (3H, m), 7.00-6.96 (1H, m), 3.01 (6H, s), 2.65-2.58 (1H, m), 1.13 (6H, d, J 7.0 Hz)
LCMS RT=6.85 min, MH+ 349.0; 1H NMR (DMSO): 10.08 (1H, s), 8.48 (1H, d, J 7.8 Hz), 8.43 (1H, s), 8.21 (1H, d, J 1.9 Hz), 8.02 (1H, d, J 8.0 Hz), 7.88 (1H, d, J 7.7 Hz), 7.76 (1H, d, J 8.8 Hz), 7.58 (1H, dd, J 8.8 2.0 Hz), 2.33 (2H, t, J 7.4 Hz), 1.71-1.59 (2H, m), 0.95 (3H, t, J 7.4 Hz)
LCMS RT=6.62 min, MH+ 295.1; 1H NMR (DMSO): 10.00 (1H, s), 8.19 (1H, d, J 1.9 Hz), 8.12 (1H, dd, J 7.4 1.5 Hz), 7.71 (1H, d, J 8.8 Hz), 7.57-7.40 (4H, m), 2.75 (3H, s), 2.65-2.59 (1H, m), 1.14 (6H, d, J 6.7 Hz)
LCMS RT=6.42 min, MH+ 315.0; 1H NMR (DMSO): 10.08 (1H, s), 8.22 (1H, d, J 1.8 Hz), 8.15 (1H, dd, J 7.6 1.8 Hz), 7.76-7.55 (5H, m), 2.34 (2H, t, J 7.4 Hz), 1.71-1.59 (2H, m), 0.95 (3H, t, J 7.4 Hz)
LCMS RT=6.41 min, MH+ 315.0; 1H NMR (DMSO): 10.03 (1H, s), 8.23 (1H, d, J 1.8 Hz), 8.15 (1H, dd, J 7.6 1.7 Hz), 7.71-7.55 (5H, m), 2.68-2.58 (1H, m), 1.14 (6H, d, J 6.7 Hz)
LCMS RT=6.89 min, MH+ 315.0; 1H NMR (DMSO): 10.05 (1H, s), 8.21-8.15 (3H, m), 7.75-7.63 (3H, m), 7.57 (1H, d, J 8.8 2.0 Hz), 2.62-2.58 (1H, m), 1.14 (6H, d, J 6.8 Hz)
LCMS RT=6.89 min, MH+ 315.1; 1H NMR (DMSO): 10.07 (1H, s), 8.19-8.11 (3H, m), 7.75-7.63 (3H, m), 7.56 (1H, d, J 8.8 2.0 Hz), 2.33 (2H, t, J 7.4 Hz), 1.71-1.59 (2H, m), 0.94 (3H, t, J 7.4 Hz)
Method 3C (Compounds II)
As Method 3A, except instead of diisopropylamine in dichloromethane, pyridine was used both as solvent and base.
LCMS RT=5.95 min, MH+ 282.0; 1H NMR (DMSO): 10.31 (1H, s), 8.54 (1H, d, J 2.3 Hz), 8.48 (1H, d, J 2.3 Hz), 8.24-8.21 (2H, m), 7.72-7.62 (3H, m), 2.37 (2H, t, J 7.3 Hz), 1.72-1.60 (2H, m), 0.95 (3H, t, J 7.5 Hz)
LCMS RT=6.54 min, MH+ 301.0; 1H NMR (DMSO): 10.07 (1H, s), 8.21-8.18 (3H, m), 7.73-7.67 (3H, m), 7.53 (1H, dd, J 8.8 2.0 Hz), 2.36 (2H, q, J 7.6 Hz), 1.12 (3H, t, J 7.5 Hz)
LCMS RT=6.94 min, MH+ 309.1; 1H NMR (DMSO): 9.36 (1H, s), 8.13 (1H, d, J 1.8 Hz), 8.09 (2H, d, J 8.2 Hz), 7.69 (1H, d, J 8.8 Hz), 7.61 (1H, dd, J 8.8 2.0 Hz), 7.43 (2H, d, J 8.0 Hz), 2.42 (3H, s), 1.26 (9H, s)
LCMS RT=7.28 min, MH+ 329.1; 1H NMR (DMSO): 9.39 (1H, s), 8.20 (2H, d, J 8.6 Hz), 8.17 (1H, d, J 1.7 Hz), 7.74-7.62 (4H, m), 1.26 (9H, s)
LCMS RT=5.98 min, MH+ 295.1; 1H NMR (DMSO): 9.97 (1H, s), 8.03 (1H, d, J 1.8 Hz), 7.56 (1H, d, J 8.7 Hz), 7.44 (1H, dd, J 8.9 2.1 Hz), 7.38-7.35 (4H, m), 7.33-7.25 (1H, m), 4.31 (2H, s), 2.28 (2H, t, J 7.3 Hz), 1.69-1.53 (2H, m), 0.92 (3H, t, J 7.5 Hz)
LCMS RT=5.96 min, MH+ 295.1; 1H NMR (DMSO): 9.93 (1H, s), 8.04 (1H, d, J 2.1 Hz), 7.56 (1H, d, J 8.9 Hz), 7.47 (1H, dd, J 9.0 2.0 Hz), 7.38-7.35 (4H, m), 7.33-7.28 (1H, m), 4.31 (2H, s), 2.60-2.58 (1H, m), 1.11 (6H, d, J 6.8 Hz)
LCMS RT=7.54 min, MH+ 295.1; 1H NMR (DMSO): 10.03 (1H, s), 8.13 (2H, d, J 8.2 Hz), 8.03 (1H, d, J 8.2 Hz), 7.48-7.44 (3H, m), 7.34 (1H, t, J 8.2 Hz), 2.43 (3H, s), 1.72-1.60 (2H, m), 1.09 (3H, t, J 6.9 Hz)
LCMS RT=7.51 min, MH+ 295.1; 1H NMR (DMSO): 9.78 (1H, s), 7.93 (2H, d, J 8.4 Hz), 7.83 (1H, d, J 8.2 Hz), 7.28-7.23 (3H, m), 7.14 (1H, t, J 8.4 Hz), 2.22 (3H, s), 0.94 (6H, d, J 6.8 Hz)
LCMS RT=6.48 min, MH+ 287.1; 1H NMR (CDCl3): 7.82 (1H, d, J 1.7 Hz), 7.66-7.56 (1H, m), 7.46 (1H, d, J 8.8 Hz), 7.30-7.25 (1H, m), 3.07-2.97 (1H, m), 2.65-2.53 (1H, m), 2.26-2.16 (2H, m), 1.97-1.72 (5H, m), 1.56-1.37 (3H, m), 1.33 (6H, t, J 6.8 Hz)
LCMS RT=6.51 min, MH+ 287.2; 1H NMR (CDCl3): 7.69 (1H, s), 7.45 (1H, d, J 8.8 Hz), 7.33 (1H, d, J 8.8 Hz), 7.16 (1H, s), 2.93-2.83 (1H, m), 2.29 (2H, t, J 7.6 Hz), 2.11-2.06 (2H, m), 1.83-1.57 (6H, m), 1.43-1.18 (4H, m), 0.95 (3H, t, J 7.5 Hz)
LCMS RT=7.17 min, MH+ 348.9; 1H NMR (DMSO): 10.11 (1H, s), 8.23 (1H, d, J 1.7 Hz), 8.19 (1H, d, J 8.8 Hz), 7.92 (1H, d, J 2.1 Hz), 7.75 (1H, d, J 9.0 Hz), 7.68 (1H, dd, J 8.5 2.1 Hz), 7.60 (1H, dd, J 8.7 2.0 Hz), 2.64 (1H, t, J 6.8 Hz), 1.14 (6H, d, J 6.8 Hz)
LCMS RT=6.39 min, MH+ 299.0; 1H NMR (DMSO): 10.00 (1H, s), 8.27-8.23 (2H, m), 8.18-8.17 (1H, m), 7.70 (1H, d, J 8.6 Hz), 7.55 (1H, dd, J 8.7 2.0 Hz), 7.46 (2H, t, J 8.7 Hz), 2.64-2.59 (1H, m), 1.14 (6H, d, J 6.8 Hz)
LCMS RT=7.55 min, MH+ 349.5; 1H NMR (DMSO): 10.03 (1H, s), 8.35 (1H, d, J 1.9 Hz), 8.21 (1H, d, J 1.9 Hz), 8.15 (1H, d, J 8.4 2.0 Hz), 7.89 (1H, d, J 8.4 Hz), 7.74 (1H, d, J 8.9 Hz), 7.58 (1H, dd, J 8.9 2.0 Hz), 2.67-2.60 (1H, m), 1.14 (6H, d, J 6.8 Hz)
LCMS RT=5.95 min, MH+ 316.0; 1H NMR (DMSO): 10.05 (1H, s), 8.86 (1H, d, J 2.1 Hz), 8.35 (1H, d, J 8.5 Hz), 8.25 (1H, d, J 1.7 Hz), 8.19 (1H, dd, J 8.5 2.4 Hz), 7.77 (1H, d, J 8.8 Hz), 7.60 (1H, dd, J 8.8 2.0 Hz), 2.65-2.61 (1H, m), 1.14 (6H, d, J 6.7 Hz)
LCMS RT=7.83 min, MH+ 348.7; 1H NMR (DMSO): 10.05 (1H, s), 8.23 (1H, d, J 1.9 Hz), 8.15 (2H, d, J 2.0 Hz), 7.92 (1H, t, J 2.0 Hz), 7.75 (1H, d, J 8.8 Hz), 7.60 (1H, dd, J 8.9 2.0 Hz), 2.68-2.60 (1H, m), 1.14 (6H, d, J 6.8 Hz)
LCMS RT=6.80 min, MH+ 348.9; 1H NMR (DMSO): 10.04 (1H, s), 8.24 (1H, d, J 1.8 Hz), 8.11 (1H, dd, J 7.9 1.6 Hz), 7.93 (1H, dd, J 8.1 1.6 Hz), 7.76 (1H, d, J 8.8 Hz), 7.63-7.59 (2H, m), 2.70-2.58 (1H, m), 1.14 (6H, d, J 6.8 Hz)
LCMS RT=6.22 min, MH+ 309.1; 1H NMR (DMSO): 9.92 (1H, s), 8.03 (1H, d, J 1.8 Hz), 7.57 (1H, d, J 8.8 Hz), 7.46 (1H, dd, J 8.7 2.0 Hz), 7.29-7.27 (4H, m), 7.23-7.16 (1H, m), 3.21-3.10 (4H, m), 1.12 (6H, d, J 6.7 Hz)
LCMS RT=6.23 min, MH+ 309.1; 1H NMR (DMSO): 9.93 (1H, s), 8.06 (1H, d, J 1.9 Hz), 7.54 (1H, d, J 8.8 Hz), 7.47 (1H, dd, J 8.8 2.1 Hz), 7.36-7.32 (4H, m), 7.30-7.24 (1H, m), 4.51 (1H, q, J 7.1 Hz), 2.65-2.57 (1H, m), 1.71 (3H, d, J 7.2 Hz), 1.12 (6H, d, J 6.8 Hz)
LCMS RT=7.10 min, MH+ 349.0; 1H NMR (DMSO): 10.11 (1H, s), 8.31 (1H, d, J 1.8 Hz), 8.25 (1H, dd, J 2.4 0.5 Hz), 7.83 (2H, d, J 8.7 Hz), 7.80 (1H, dd, J 8.7 2.5 Hz), 7.67 (1H, dd, J 8.9 2.0 Hz), 2.74-2.64 (1H, m), 1.20 (6H, d, J 6.8 Hz)
LCMS RT=6.59 min, MH+ 333.0; 1H NMR (DMSO): 10.05 (1H, s), 8.30-8.20 (2H, m), 7.77-7.73 (2H, m), 7.59 (1H, dd, J 8.8 2.0 Hz), 7.51-7.45 (1H, m), 2.68-2.57 (1H, m), 1.14 (6H, d, J 6.8 Hz)
LCMS RT=6.29 min, MH+ 333.1; 1H NMR (DMSO): 10.08 (1H, s), 8.26 (1H, d, J 1.9 Hz), 7.80-7.71 (2H, m), 7.64-7.60 (2H, m), 7.57-7.50 (1H, m), 2.68-2.58 (1H, m), 1.14 (6H, d, J 6.9 Hz)
LCMS RT=6.65 min, MH+ 333.1; 1H NMR (DMSO): 10.06 (1H, s), 8.31-8.16 (2H, m), 7.88 (1H, dt, J 8.4 1.7 Hz), 7.77 (1H, d, J 8.8 Hz), 7.60 (1H, dd, J 8.9 2.0 Hz), 7.47 (1H, dt, J 8.0 1.0 Hz), 2.66-2.60 (1H, m), 1.14 (6H, d, J 6.7 Hz)
LCMS RT=6.69 min, MH+ 333.1; 1H NMR (DMSO): 10.05 (1H, s), 8.28-8.21 (2H, m), 7.79-7.73 (2H, m), 7.60-7.53 (2H, m), 2.67-2.58 (1H, m), 1.14 (6H, d, J 6.7 Hz)
LCMS RT=6.54 min, MH+ 333.1; 1H NMR (DMSO): 10.07 (1H, s), 8.25 (1H, d, J 1.9 Hz), 7.99 (1H, dd, J 9.2 3.2 Hz), 7.80-7.75 (2H, m), 7.63-7.52 (2H, m), 2.68-2.59 (1H, m), 1.14 (6H, d, J 6.7 Hz)
LCMS RT=7.52 min, MH+ 341.0; 1H NMR (DMSO): 10.08 (1H, s), 8.20-8.16 (3H, m), 7.73-7.66 (3H, m), 7.55 (1H, dd, J 8.8 2.0 Hz), 2.85-2.75 (1H, m), 1.93-1.57 (8H, m)
LCMS RT=8.10 min; 1H NMR (DMSO): 9.59 (1H, s), 8.20 (2H, d, J 8.8 Hz), 8.12 (1H, s), 8.02 (1H, s), 7.71 (2H, d, J 8.6 Hz), 2.84-2.73 (1H, m), 1.16 (6H, d, J 6.8 Hz)
LCMS RT=5.38 min, MH+ 289.0; 1H NMR (DMSO): 9.95 (1H, s), 8.04 (1H, d, J 1.9 Hz), 7.59 (1H, d, J 8.8 Hz), 7.48 (1H, dd, J 8.8 2.0 Hz), 3.95-3.88 (2H, m), 3.47-3.43 (3H, m), 2.64-2.55 (1H, m), 2.06-1.99 (2H, m), 1.89-1.75 (2H, m), 1.12 (6H, d, J 6.8 Hz)
LCMS RT=6.99 min, MH+ 348.8; 1H NMR (DMSO): 10.45 (1H, s), 8.30 (1H, dd, J 2.0 Hz), 8.15 (1H, d, J 1.9 Hz), 8.10 (1H, dd, J 8.4 2.0 Hz), 7.86 (1H, d, J 8.4 Hz), 7.71 (1H, d, J 8.9 Hz), 7.53 (1H, dd, J 8.9 2.0 Hz), 1.81-1.74 (1H, m), 0.82-0.76 (4H, m)
LCMS RT=6.93 min, MH+ 312.9; 1H NMR (DMSO): 10.53 (1H, s), 8.27 (1H, dd, J 1.7 Hz), 8.18 (2H, d, J 8.7 Hz), 7.74 (1H, d, J 8.7 Hz), 7.68 (2H, d, J 8.7 Hz), 7.44 (1H, dd, J 8.7 1.9 Hz), 1.86-1.78 (1H, m), 0.85-0.80 (4H, m)
LCMS RT=7.05 min; 1H NMR (DMSO): 10.21 (1H, s), 8.34 (1H, d, J 1.8 Hz), 8.11 (1H, dd, J 7.9 1.6 Hz), 7.92 (1H, dd, J 8.1 1.5 Hz), 7.81 (1H, d, J 8.7 Hz), 7.60 (1H, t, J 8.0 Hz), 7.48 (1H, dd, J 8.7 1.9 Hz), 2.67-2.61 (1H, m), 1.14 (6H, d, J 6.8 Hz)
LCMS RT=7.04 min; 1H NMR (DMSO): 10.05 (1H, s), 8.32 (2H, d, J 9.0 Hz), 8.20 (1H, d, J 1.9 Hz), 7.74 (1H, d, J 8.9 Hz), 7.63-7.55 (3H, m), 2.68-2.57 (1H, m), 1.14 (6H, d, J 6.8 Hz)
LCMS RT=5.23 min, MH+ 273.0; 1H NMR (DMSO): 9.93 (1H, s), 8.01 (1H, d, J 1.8 Hz), 7.57 (1H, d, J 8.7 Hz), 7.46 (1H, dd, J 8.8 1.8 Hz), 3.42-3.39 (1H, m), 2.61-2.57 (1H, m), 2.15-2.04 (2H, m), 1.95-1.87 (2H, m), 1.78-1.62 (4H, m), 1.12 (6H, d, J 6.8 Hz)
LCMS RT=5.08 min, MH+ 309.9; 1H NMR (DMSO): 10.31 (1H, s), 10.11 (1H, s), 8.13-8.08 (3H, m), 7.82 (2H, d, J 8.7 Hz), 7.68 (1H, d, J 8.7 Hz), 7.48 (1H, dd, J 8.8 2.0 Hz), 2.11 (3H, s), 2.08 (3H, s)
LCMS RT=6.78 min, MH+ 383.0; 1H NMR (DMSO): 10.07 (1H, s), 8.40 (1H, dd, J 8.1 1.3 Hz), 8.27 (1H, d, J 1.8 Hz), 8.14 (1H, dd, J 7.9 1.3 Hz), 7.82-7.77 (2H, m), 7.62 (1H, dd, J 8.8 2.1 Hz), 2.66-2.61 (1H, m), 1.14 (6H, d, J 6.8 Hz)
LCMS RT=7.82 min, MH+ 349.1; 1H NMR (DMSO): 10.20 (1H, s), 8.33 (1H, d, J 2.0 Hz), 8.31 (1H, d, J 1.7 Hz), 8.14 (1H, dd, J 8.4 2.0 Hz), 7.88 (1H, d, J 8.5 Hz), 7.75 (1H, d, J 8.8 Hz), 7.48 (1H, dd, J 8.7 1.9 Hz), 2.68-2.60 (1H, m), 1.14 (6H, d, J 6.8 Hz)
LCMS RT=6.45 min, MH+ 303.1; 1H NMR (DMSO): 10.15 (1H, s), 8.84 (1H, s), 8.27 (1H, dd, J 8.6 1.7 Hz), 8.20-8.13 (3H, m), 8.06-8.03 (1H, m), 7.76 (1H, d, J 8.6 Hz), 7.71-7.63 (2H, m), 7.54 (1H, dd, J 8.8 2.1 Hz), 2.17 (3H, s)
LCMS RT=5.52 min, MH+ 338.0; 1H NMR (DMSO): 10.46 (1H, s), 10.31 (1H, s), 8.15-8.11 (3H, m), 7.82 (2H, d, J 8.7 Hz), 7.67 (1H, d, J 8.7 Hz), 7.52 (1H, dd, J 8.8 1.9 Hz), 2.67-2.58 (1H, m), 2.11 (3H, s), 1.13 (6H, d, J 6.9 Hz)
LCMS RT=7.10 min, MH+ 331.1; 1H NMR (DMSO): 10.04 (1H, s), 8.84 (1H, s), 8.28-8.12 (4H, m), 8.07-8.03 (1H, m), 7.76 (1H, d, J 8.9 Hz), 7.77-7.62 (2H, m), 7.58 (1H, dd, J 8.8 2.1 Hz), 2.64 (1H, t, J 7.4 Hz), 1.15 (6H, d, J 6.9 Hz)
LCMS RT=7.47 min, MH+ 370.8; 1H NMR (DMSO): 10.44 (1H, s), 8.86 (1H, s), 8.30-8.14 (4H, m), 8.08-8.04 (2H, m), 7.89 (1H, dd, J 5.0 1.0 Hz), 7.83 (1H, d, J 8.8 Hz), 7.76-7.64 (3H, m), 7.28-7.25 (1H, m)
LCMS RT=7.25 min, MH+ 331.2; 1H NMR (DMSO): 10.07 (1H, s), 9.42 (1H, dd, J 8.2 0.7 Hz), 8.45 (1H, dd, J 7.4 1.2 Hz), 8.29 (1H, d, J 1.9 Hz), 8.26-8.21 (1H, m), 8.13-8.09 (1H, m), 7.81-7.66 (4H, m), 7.61 (1H, dd, J 8.8 2.1 Hz), 2.70-2.61 (1H, m), 1.16 (6H, d, J 6.8 Hz)
LCMS RT=7.56 min, MH+ 357.3; 1H NMR (DMSO): 10.03 (1H, s), 8.28 (2H, d, J 8.5 Hz), 8.20 (1H, d, J 2.0 Hz), 7.94 (2H, d, J 8.6 Hz), 7.82-7.78 (2H, m), 7.74 (1H, d, J 8.8 Hz), 7.58-7.41 (4H, m), 2.68-2.59 (1H, m), 1.15 (6H, d, J 6.8 Hz)
LCMS RT=7.02 min, MH+ 361.2; 1H NMR (DMSO): 10.03 (1H, s), 8.75 (1H, d, J 0.8 Hz), 8.21 (2H, dd, J 8.9 1.6 Hz), 8.10 (1H, d, J 9.0 Hz), 8.02 (1H, d, J 8.7 Hz), 7.73 (1H, d, J 8.7 Hz), 7.56 (1H, dd, J 8.8 2.0 Hz), 7.46 (1H, d, J 2.3 Hz), 7.29 (1H, dd, J 8.8 2.5 Hz), 3.93 (3H, s), 2.68-2.58 (1H, m), 1.15 (6H, d, J 6.8 Hz)
LCMS RT=8.13 min, MH+ 411.1; 1H NMR (DMSO): 10.06 (1H, s), 8.86 (1H, s), 8.36 (1H, d, J 1.7 Hz), 8.31 (1H, d, J 8.7 1.7 Hz), 8.23 (1H, d, J 1.9 Hz), 8.18 (1H, d, J 8.9 Hz), 8.13 (1H, d, J 8.7 Hz), 7.80-7.74 (2H, m), 7.58 (1H, dd, J 8.9 2.2 Hz), 2.68-2.59 (1H, m), 1.15 (6H, d, J 6.8 Hz)
LCMS RT=6.24 min, MH+ 332.2; 1H NMR (DMSO): 10.08 (1H, s), 9.62 (1H, d, J 2.1 Hz), 9.22 (1H, d, J 1.9 Hz), 8.29-8.24 (2H, m), 8.15 (1H, d, J 8.6 Hz), 7.95-7.90 (1H, m), 7.80-7.73 (2H, m), 7.61 (1H, dd, J 8.8 2.2 Hz), 2.69-2.60 (1H, m), 1.15 (6H, d, J 6.9 Hz)
LCMS RT=6.28 min, MH+ 332.2; 1H NMR (DMSO): 10.09 (1H, s), 8.64 (1H, d, J 8.4 Hz), 8.45 (1H, d, J 8.5 Hz), 8.32 (1H, d, J 1.8 Hz), 8.22 (1H, d, J 8.7 Hz), 8.13 (1H, dd, J 8.5 0.9 Hz), 7.94-7.84 (2H, m), 7.78-7.73 (1H, m), 7.63 (1H, dd, J 8.8 2.0 Hz), 2.69-2.60 (1H, m), 1.15 (6H, d, J 6.8 Hz)
LCMS RT=8.87 min, MH+ 363.3; 1H NMR (DMSO): 10.00 (1H, s), 8.15 (1H, d, J 1.9 Hz), 8.11 (2H, d, J 8.4 Hz), 7.69 (1H, d, J 8.7 Hz), 7.53 (1H, dd, J 8.8 2.1 Hz), 7.47 (2H, d, J 8.3 Hz), 2.67-2.58 (2H, m), 1.84-1.71 (5H, m), 1.52-1.23 (5H, m), 1.13 (6H, d, J 6.8 Hz)
1H NMR (DMSO): 9.56 (1H, s), 8.05 (1H, s), 7.94 (1H, s), 7.77 (1H, dd, J 8.1 1.7 Hz), 7.64 (1H, d, J 1.6 Hz), 7.16 (1H, d, J 8.2 Hz), 6.19 (2H, s), 2.83-2.72 (1H, m), 1.15 (6H, d, J 6.8 Hz)
LCMS RT=5.75 min, MH+ 271.1; 1H NMR (DMSO): 9.95 (1H, s), 8.08 (1H, d, J 1.8 Hz), 8.01 (1H, dd, J 1.7 0.7 Hz), 7.62 (1H, d, J 8.9 Hz), 7.47 (1H, dd, J 8.9 2.0 Hz), 7.39 (1H, dd, J 3.5 0.7 Hz), 6.75 (1H, dd, J 3.5 1.8 Hz), 2.60-2.50 (1H, m), 1.07 (6H, d, J 6.8 Hz)
LCMS RT=7.49 min, MH+ 331.1; 1H NMR (DMSO): 10.22 (1H, s), 8.45 (1H, d, J 8.1 Hz), 8.22 (2H, d, J 8.7 Hz), 8.13 (1H, d, J 8.5 Hz), 7.98 (2H, s), 7.89 (2H, d, J 8.9 Hz), 7.77-7.70 (1H, m), 7.65-7.59 (1H, m), 2.69-2.60 (1H, m), 1.14 (6H, d, J 6.7 Hz)
LCMS RT=6.48 min, MH+ 281.1; 1H NMR (DMSO): 10.23 (1H, s), 8.14 (2H, d, J 8.9 Hz), 7.86 (2H, d, J 8.8 Hz), 7.79-7.75 (2H, m), 7.42-7.38 (2H, m), 2.70-2.60 (1H, m), 1.13 (6H, d, J 6.8 Hz)
Method 3D (Compounds II)
As Method 3A, except instead of diisopropylethylamine in dichloromethane, pyridine in dichloromethane was used.
LCMS RT=6.10 min, MH+ 299.0; 1H NMR (DMSO): 10.07 (1H, s), 8.25-8.19 (2H, m), 7.75 (1H, d, J 8.8 Hz), 7.72-7.66 (1H, m), 7.58-7.42 (3H, m), 2.33 (2H, t, J 7.5 Hz), 1.71-1.59 (2H, m), 0.94 (3H, t, J 7.4 Hz)
LCMS RT=6.09 min, MH+ 299.0; 1H NMR (DMSO): 10.09 (1H, s), 8.31-8.25 (2H, m), 7.81 (1H, d, J 8.8 Hz), 7.78-7.72 (1H, m), 7.64 (1H, d, J 8.7 1.8 Hz), 7.58-7.48 (2H, m), 2.74-2.65 (1H, m), 1.20 (6H, d, J 6.8 Hz)
LCMS RT=6.39 min, MH+ 299.0; 1H NMR (DMSO): 10.12 (1H, s), 8.24 (1H, d, J 1.9 Hz), 8.12-8.08 (1H, m), 8.02-7.97 (1H, m), 7.79 (1H, d, J 8.8 Hz), 7.75-7.70 (1H, m), 7.63-7.53 (2H, m), 2.38 (2H, t, J 7.4 Hz), 1.77-1.64 (2H, m), 1.00 (3H, t, J 7.4 Hz)
LCMS RT=6.37 min, MH+ 299.0; 1H NMR (DMSO): 10.08 (1H, s), 8.26 (1H, d, J 1.9 Hz), 8.12-8.08 (1H, m), 8.02-7.97 (1H, m), 7.79 (1H, d, J 9.0 Hz), 7.75-7.69 (1H, m), 7.63 (1H, dd, J 8.8 1.9 Hz), 7.59-7.52 (1H, m), 2.73-2.66 (1H, m), 1.19 (6H, d, J 6.9 Hz)
LCMS RT=6.14 min, MH+ 324.9; 1H NMR (DMSO): 10.04 (1H, s), 8.18 (1H, d, J 1.8 Hz), 7.82 (1H, dd, J 8.2 1.8 Hz), 7.73-7.69 (2H, m), 7.58 (1H, dd, J 8.7 2.0 Hz), 7.20 (1H, d, J 8.2 Hz), 6.24 (2H, s), 2.72-2.65 (1H, m), 1.19 (6H, d, J 6.9 Hz)
LCMS RT=7.14 min, MH+ 317.1; 1H NMR (DMSO): 9.80 (1H, s), 8.18 (2H, d, J 8.6 Hz), 7.96 (1H, d, J 1.7 Hz), 7.71-7.67 (3H, m), 7.45 (1H, dd, J 8.8 2.0 Hz), 4.16 (2H, q, J 7.2 Hz), 1.27 (3H, t, J 7.1 Hz)
Method 3E (Compounds II)
As Method 3C, except a flake of DMAP is added to the reaction
LCMS RT=7.07 min, MH+ 314.9; 1H NMR (DMSO): 10.15 (1H, s), 8.29 (1H, d, J 1.7 Hz), 8.18 (2H, d, J 8.8 Hz), 7.73 (1H, d, J 8.7 Hz), 7.68 (2H, d, J 8.7 Hz), 7.49 (1H, dd, J 8.7 1.9 Hz), 2.64 (1H, t, J 6.8 Hz), 1.14 (6H, d, J 6.8 Hz)
LCMS RT=7.07 min, MH+ 314.9; 1H NMR (DMSO): 10.20 (1H, s), 8.29 (1H, d, J 1.7 Hz), 8.18 (2H, d, J 8.8 Hz), 7.73 (1H, d, J 8.7 Hz), 7.68 (2H, d, J 8.7 Hz), 7.43 (1H, dd, J 8.7 1.9 Hz), 2.34 (2H, t, J 7.3 Hz), 1.71-1.59 (2H, m), 0.94 (3H, t, J 7.4 Hz)
LCMS RT=6.69 min, MH+ 313.1; 1H NMR (DMSO): 10.39 (1H, s), 8.20-8.15 (3H, m), 7.74-7.68 (3H, m), 7.54 (1H, d, J 8.9 2.1 Hz), 1.84-1.76 (1H, m), 0.81-0.78 (4H, m)
LCMS RT=7.07 min, MH+ 327.0; 1H NMR (DMSO): 9.91 (1H, s), 8.21-8.17 (3H, m), 7.73-7.67 (3H, m), 7.55 (1H, d, J 8.9 2.1 Hz), 2.33-1.81 (7H, m)
Method 3F (Compounds II)
To 4,4,4-trifluorobutanoic acid (128 mg, 0.90 mmol) in dry dimethylformamide (5 mL) was added HATU (397 mg, 1.05 mmol) and diisopropylethylamine (496 μL, 2.85 mmol). The mixture was then stirred at room temperature for 10 min. 2-p-Tolylbenzo[d]oxazol-5-amine (200 mg, 0.95 mmol) was then added and the resulting mixture was stirred at room temperature for 16 h. Ethyl acetate was added and the organic layer was washed once with saturated aqueous Na2CO3, followed by another wash with brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 40:60 v/v to afford 26.7 mg (8%) of the title compound (LCMS RT=6.77 min, MH+ 348.9)
1H NMR (DMSO): 10.28 (1H, s), 8.12 (1H, d, J 1.9 Hz), 8.08 (2H, d, J 8.2 Hz), 7.72 (1H, d, J 8.8 Hz), 7.50 (1H, dd, J 8.8 2.1 Hz), 7.43 (2H, d, J 8.1 Hz), 2.67-2.56 (4H, m), 2.42 (3H, s)
All compounds below were prepared following the same general method.
LCMS RT=6.03 min, MH+ 311.0; 1H NMR (DMSO): 10.13 (1H, s), 8.14 (1H, d, J 2.2 Hz), 8.08 (2H, d, J 8.4 Hz), 7.70 (1H, d, J 8.9 Hz), 7.52 (1H, dd, J 8.9 2.0 Hz), 7.43 (2H, d, J 8.3 Hz), 3.65 (2H, t, J 6.2 Hz), 3.26 (3H, s), 2.61-2.56 (2H, m), 2.42 (3H, s)
LCMS RT=6.22 min, MH+ 382.0; 1H NMR (CDCl3): 8.19-8.14 (2H, m), 7.89 (2H, s), 7.50-7.42 (5H, m), 5.15-5.05 (1H, br), 3.49-3.43 (2H, m), 2.59 (2H, t, J 7.6 Hz), 1.38 (9H, s)
LCMS RT=14.01 min, MH+ 335.0; 1H NMR (DMSO): 10.48 (1H, s), 8.11-8.08 (3H, m), 7.75 (1H, d, J 9.0 Hz), 7.49 (1H, dd, J 8.7 2.1 Hz), 7.44 (2H, d, J 8.0 Hz), 3.55 (2H, q, J 10.9 Hz)
LCMS RT=6.32 min, MH+ 331.1; 1H NMR (DMSO): 10.17 (1H, s), 8.22-8.17 (3H, m), 7.74-7.68 (3H, m), 7.54 (1H, dd, J 8.9 2.1 Hz), 3.65 (2H, t, J 6.1 Hz), 3.26 (3H, s), 2.59 (2H, t, J 6.1 Hz)
LCMS RT=6.72 min, MH+ 354.7; 1H NMR (DMSO): 10.52 (1H, s), 8.21 (2H, d, J 8.7 Hz), 8.14 (1H, d, J 2.0 Hz), 7.78 (1H, d, J 8.7 Hz), 7.70 (2H, d, J 8.7 Hz), 7.52 (1H, dd, J 8.8 2.1 Hz), 3.56 (2H, q, J 11.1 Hz)
LCMS RT=7.41 min, MH+ 388.8; 1H NMR (DMSO): 10.54 (1H, s), 8.36 (1H, d, J 2.0 Hz), 8.17-8.14 (2H, m), 7.90 (1H, d, J 8.4 Hz), 7.80 (1H, d, J 8.8 Hz), 7.54 (1H, dd, J 8.9 2.1 Hz), 3.56 (2H, q, J 11.1 Hz)
LCMS RT=6.76 min, MH+ 388.9; 1H NMR (DMSO): 10.55 (1H, s), 8.20 (1H, d, J 1.9 Hz), 8.12 (1H, dd, J 7.9 1.6 Hz), 7.94 (1H, dd, J 8.1 1.6 Hz), 7.83 (1H, d, J 8.8 Hz), 7.64-7.55 (2H, m), 3.58 (2H, q, J 11.1 Hz)
The compounds below were obtained by Method 3F, using the appropriate Boc-amino acid. Coupling was followed by deprotection of Boc group using 4M HCl in dioxane for 20 min at room temperature.
LCMS RT=4.54 min, MH+ 342.0; 1H NMR (DMSO): 10.15 (1H, s), 8.23 (1H, d, J 1.7 Hz), 8.19 (2H, d, J 8.7 Hz), 7.74-7.63 (4H, m), 3.75-3.69 (1H, m), 2.91 (2H, t, J 6.5 Hz), 2.12-2.00 (1H, m), 1.90-1.60 (3H, m)
LCMS RT=4.46 min, MH+ 330.1; 1H NMR (DMSO): 8.20-8.10 (3H, m), 7.67 (2H, d, J 8.8 Hz), 7.58-7.47 (2H, m), 3.00 (1H, q, J 6.8 Hz), 2.24 (3H, s), 1.16 (3H, d, J 6.8 Hz)
The compound below was obtained by Method 3F, using the appropriate Fmoc-amino acid. Coupling was followed by deprotection of the Fmoc group using piperidine/DMF 20:80 v/v.
LCMS RT=4.46 min, MH+ 316.1; 1H NMR (CDCl3): 9.56 (1H, s), 8.11 (2H, d, J 8.7 Hz), 7.98 (1H, d, J 1.9 Hz), 7.55 (1H, dd, J 8.8 2.1 Hz), 7.46-7.41 (3H, m), 3.60 (1H, q, J 7.0 Hz), 1.41 (3H, d, J 7.0 Hz)
Method 3G (Compounds II)
As Method 3C, except instead of the acid chloride, the corresponding anhydride was used
LCMS RT=6.93 min, MH+ 321.0; 1H NMR (DMSO): 11.46 (1H, br), 8.22 (2H, d, J 8.6 Hz), 8.15 (1H, d, J 1.9 Hz), 7.85 (1H, d, J 8.8 Hz), 7.73-7.68 (3H, m)
LCMS RT=7.12 min, MH+ 340.8; 1H NMR (DMSO): 11.43 (1H, br), 8.12-8.09 (3H, m), 7.82 (1H, d, J 8.8 Hz), 7.67 (1H, dd, J 8.9 2.1 Hz), 7.45 (2H, d, J 8.0 Hz)
Method 3H (Compounds II)
To 2-phenylbenzo[d]oxazol-5-amine (75 mg, 0.36 mmol) and methyl 3-morpholinopropanoate (63 μL, 0.39 mmol) in toluene (2.5 mL) was added a 2M solution of trimethylaluminum in toluene (0.22 mL, 0.43 mmol). The resulting solution was heated twice for 5 min at 160° C. in the microwave. After cooling, sodium bicarbonate solution was added and the aqueous layer was extracted with ethyl acetate. The organic layer was then washed with brine and the combined organic layers were dried over anhydrous MgSO4. After evaporation, the impurities were removed by filtering through on a plug of silica eluting with ethyl acetate/hexanes 50:50 v/v and the desired product was obtained by elution with methanol to afford 17.5 mg (14%) of the title compound (LCMS RT=5.54 min, MH+ 352.0)
1H NMR (DMSO): 10.25 (1H, s), 8.22-8.15 (3H, m), 7.73 (1H, d, J 8.8 Hz), 7.65-7.59 (3H, m), 7.52 (1H, dd, J 8.8 2.0 Hz), 3.60-3.57 (4H, m), 2.68-2.64 (2H, m), 2.44-2.41 (4H, m)
Method 4 (Compounds III)
To a solution of 2-phenylbenzo[d]oxazol-5-amine (100 mg, 0.48 mmol) in dichloromethane (2 mL) at room temperature was added pyridine (83 μL, 0.95 mmol) followed by propane-1-sulfonyl chloride (61 μL, 0.52 mmol). The resulting solution was then stirred at room temperature for 16 h. Dichloromethane was added and the organic layer was washed with saturated aqueous copper sulfate solution. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting insoluble solid was washed with saturated aqueous NaHCO3 to afford 37.2 mg (25%) of the title compound (LCMS RT=6.25 min, MH+ 317.0)
1H NMR (DMSO): 9.89 (1H, br), 8.21-8.18 (2H, m), 7.77 (1H, d, J 8.8 Hz), 7.66-7.59 (4H, m), 7.28 (1H, dd, J 8.8 2.1 Hz), 3.10-3.04 (2H, m), 1.77-1.64 (2H, m), 0.94 (3H, t, J 7.5 Hz)
The compounds below were prepared following the same general method, and purified by column chromatography eluting with ethyl acetate:hexanes 30:70 v/v.
LCMS RT=6.16 min, MH+ 317.0; 1H NMR (DMSO): 9.89 (1H, br), 8.21-8.18 (2H, m), 7.76 (1H, d, J 8.8 Hz), 7.69-7.59 (4H, m), 7.30 (1H, dd, J 8.8 2.2 Hz), 1.26 (6H, d, J 6.9 Hz)
LCMS RT=6.43 min, MH+ 350.8; 1H NMR (DMSO): 10.40 (1H, br), 8.15 (2H, dd, J 7.2 1.6 Hz), 7.77-7.74 (2H, m), 7.68-7.51 (7H, m), 7.46 (1H, d, J 2.1 Hz), 7.12 (1H, dd, J 8.8 2.1 Hz)
LCMS RT=6.53 min, MH+ 331.0; 1H NMR (DMSO): 9.85 (1H, br), 8.80 (2H, d, J 7.8 Hz), 7.74 (1H, d, J 9.0 Hz), 7.60 (1H, d, J 2.0 Hz), 7.44 (2H, d, J 8.1 Hz), 7.26 (1H, dd, J 8.7 2.2 Hz), 3.09-3.04 (2H, m), 2.42 (3H, s), 1.74-1.64 (2H, m), 0.94 (3H, t, J 7.6 Hz)
LCMS RT=6.58 min, MH+ 330.9; 1H NMR (DMSO): 9.85 (1H, br), 8.08 (2H, d, J 8.2 Hz), 7.72 (1H, d, J 8.6 Hz), 7.62 (1H, d, J 1.8 Hz), 7.43 (2H, d, J 8.2 Hz), 7.28 (1H, dd, J 8.8 2.2 Hz), 2.60-2.57 (1H, m), 2.42 (3H, s), 1.26 (6H, d, J 6.8 Hz)
LCMS RT=6.81 min, MH+ 350.9; 1H NMR (DMSO): 9.73 (1H, br), 8.20 (2H, d, J 8.7 Hz), 7.77 (1H, d, J 8.6 Hz), 7.71 (2H, d, J 8.7 Hz), 7.63 (1H, d, J 1.9 Hz), 7.29 (1H, dd, J 8.8 2.2 Hz), 3.10-3.05 (2H, m), 1.77-1.65 (2H, m), 0.94 (3H, t, J 7.6 Hz)
LCMS RT=6.68 min, MH+ 351.0; 1H NMR (DMSO): 9.88 (1H, br), 8.19 (2H, d, J 8.7 Hz), 7.76 (1H, d, J 8.8 Hz), 7.70 (2H, d, J 8.7 Hz), 7.65 (1H, d, J 2.0 Hz), 7.32 (1H, dd, J 8.8 2.2 Hz), 3.24 (1H, t, J 6.7 Hz), 1.26 (6H, d, J 6.7 Hz)
Method 5 (Compounds IV)
To 2-p-tolylbenzo[d]oxazol-5-amine (500 mg, 2.32 mmol) in 1,2-dichloroethane (20 mL) at room temperature was added acetic acid (142 μL, 2.32 mmol) and isonicotinaldehyde (222.5 μL, 2.29 mmol) and the mixture was stirred for 1 h. Sodium triacetoxyborohydride (707 mg, 3.35 mmol) was then added and the mixture was stirred at room temperature for 24 h. The mixture was then diluted with dichloromethane and the organic layer was washed with saturated aqueous NaHCO3. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate:hexanes 20:80 to afford 328 mg (47%) of the title compound (LCMS RT=6.27 min, MH+ 316.1)
1H NMR (DMSO): 8.50 (2H, d, J 6.0 Hz), 8.00 (2H, d, J 8.1 Hz), 7.48-7.37 (5H, m), 6.76-6.72 (2H, m), 6.51 (1H, t, J 6.2 Hz), 4.38 (2H, d, J 6.1 Hz), 2.39 (3H, s)
All compounds below were prepared following the same general method.
LCMS RT=7.90 min, MH+ 301.0; 1H NMR (DMSO): 9.14-8.10 (2H, m), 7.61-7.56 (3H, m), 7.48-7.21 (6H, m), 6.79-6.75 (2H, m), 6.39 (1H, t, J 6.0 Hz), 4.32 (2H, d, J 6.1 Hz)
LCMS RT=8.25 min, MH+ 267.0; 1H NMR (DMSO): 8.16-8.12 (2H, m), 7.61-7.58 (3H, m), 7.47 (1H, d, J 8.7 Hz), 6.81 (1H, d, J 2.1 Hz), 6.72 (1H, dd, J 8.8 2.3 Hz), 6.64 (1H, t, J 5.5 Hz), 3.08-3.00 (2H, m), 1.64-1.51 (2H, m), 1.49-1.35 (2H, m), 0.94 (3H, t, J 7.2 Hz)
LCMS RT=8.26 min, MH+ 267.0; 1H NMR (DMSO): 8.15-8.12 (2H, m), 7.62-7.51 (3H, m), 7.46 (1H, d, J 8.8 Hz), 6.81 (1H, d, J 2.1 Hz), 6.74 (1H, dd, J 8.8 2.3 Hz), 5.73 (1H, t, J 5.6 Hz), 2.87 (2H, t, J 6.1 Hz), 1.95-1.82 (1H, m), 0.97 (6H, d, J 6.6 Hz)
LCMS RT=9.58 min, MH+ 301.1; 1H NMR (DMSO): 8.14 (2H, d, J 8.7 Hz), 7.66 (2H, d, J 8.7 Hz), 7.47 (1H, d, J 8.7 Hz), 6.81 (1H, d, J 2.1 Hz), 6.73 (1H, dd, J 8.8 2.2 Hz), 6.67 (1H, t, J 5.7 Hz), 3.07-3.00 (2H, m), 1.62-1.53 (2H, m), 1.48-1.36 (2H, m), 0.94 (3H, t, J 7.2 Hz)
LCMS RT=8.85 min, MH+ 301.0; 1H NMR (DMSO): 8.14 (2H, d, J 8.7 Hz), 7.66 (2H, d, J 8.7 Hz), 7.47 (1H, d, J 8.8 Hz), 6.80 (1H, d, J 2.0 Hz), 6.75 (1H, dd, J 8.8 2.2 Hz), 5.75 (1H, t, J 5.7 Hz), 2.87 (2H, d, J 6.2 Hz), 1.93-1.82 (1H, m), 0.97 (6H, d, J 6.7 Hz)
LCMS RT=8.39 min, MH+ 335.0; 1H NMR (DMSO): 8.11 (2H, d, J 8.8 Hz), 7.65 (2H, d, J 8.7 Hz), 7.47 (1H, d, J 9.4 Hz), 7.42-7.21 (5H, m), 6.81-6.78 (2H, m), 6.42 (1H, t, J 5.8 Hz), 4.32 (2H, d, J 6.8 Hz)
LCMS RT=8.44 min, MH+ 281.0; 1H NMR (DMSO): 8.02 (2H, d, J 8.2 Hz), 7.46-7.38 (3H, m), 6.79 (1H, d, J 2.0 Hz), 6.69 (1H, dd, J 8.8 2.4 Hz), 5.62 (1H, t, J 5.7 Hz), 3.06-3.00 (2H, m), 2.40 (3H, s), 1.62-1.53 (2H, m), 1.48-1.36 (2H, m), 0.94 (3H, t, J 7.2 Hz)
LCMS RT=8.48 min, MH+ 281.0; 1H NMR (DMSO): 8.03 (2H, d, J 8.1 Hz), 7.45-7.38 (3H, m), 6.79 (1H, d, J 2.1 Hz), 6.71 (1H, dd, J 8.8 2.3 Hz), 5.70 (1H, t, J 5.7 Hz), 2.86 (2H, t, J 6.3 Hz), 2.40 (3H, s), 1.95-1.81 (1H, m), 0.97 (6H, d, J 6.7 Hz)
LCMS RT=7.95 min, MH+ 315.1; 1H NMR (DMSO): 8.00 (2H, d, J 8.1 Hz), 7.46-7.21 (8H, m), 6.77-6.73 (2H, m), 6.37 (1H, t, J 6.4 Hz), 4.32 (2H, d, J 6.0 Hz), 2.40 (3H, s)
LCMS RT=17.03 min, MH+ 357.1; 1H NMR (DMSO): 8.26 (2H, d, J 8.5 Hz), 7.80 (2H, d, J 8.6 Hz), 7.67 (1H, d, J 9.0 Hz), 7.09 (1H, d, J 2.3 Hz), 6.96 (1H, dd, J 9.1 2.4 Hz), 3.32 (4H, d, J 7.2 Hz), 2.20-2.10 (2H, m), 1.02 (12H, d, J 6.6 Hz)
Method 6 (Compounds V)
To 2-phenylbenzo[d]oxazol-5-amine (75 mg, 0.36 mmol) in dichloromethane (2 mL) at room temperature was added phenyl isocyanate (43 μL, 0.39 mmol). The solution was stirred at room temperature for 16 h. The resulting precipitate was filtered off and washed with dichloromethane to afford 99.9 mg (85%) of the title compound (LCMS RT=6.45 min, MH+ 330.1)
1H NMR (DMSO): 8.85 (1H, s), 8.71 (1H, s), 8.22-8.19 (2H, m), 8.00 (1H, d, J 2.0 Hz), 7.71 (1H, d, J 8.9 Hz), 7.65-7.60 (3H, m), 7.50-7.47 (2H, m), 7.40 (1H, dd, J 8.8 2.1 Hz), 7.30 (2H, t, J 8.4 Hz), 7.02-6.95 (1H, m)
The compound below was prepared following the same general method.
LCMS RT=5.94 min, MH+ 296.0; 1H NMR (DMSO): 8.47 (1H, s), 8.20-8.16 (2H, m), 7.93 (1H, d, J 1.9 Hz), 7.64-7.59 (4H, m), 7.30 (1H, dd, J 8.8 2.1 Hz), 6.03 (1H, d, J 7.5 Hz), 3.85-3.74 (1H, m), 1.12 (6H, d, J 6.5 Hz)
Method 7 (Compounds VI)
To sodium hydride (15 mg, 0.37 mmol) under nitrogen at 0° C. was slowly added a solution of N-(2-(4-chlorophenyl)benzo[d]oxazol-5-yl)propionamide (100 mg, 0.33 mmol) in dimethylformamide (10 mL). After 10 min at 0° C., methyl iodide (56 μL, 0.37 mmol) was added, and the solution was left warming up to room temperature for 16 h. The mixture was then diluted with ethyl acetate, and then washed three times with water. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 50:50 v/v to afford 36.4 mg (35%) of the title compound (LCMS RT=7.00 min, MH+ 315.0)
1H NMR (CDCl3): 8.13 (2H, d, J 8.6 Hz), 7.55-7.52 (2H, m), 7.46 (2H, d, J 8.6 Hz), 7.13 (1H, dd, J 8.3 2.0 Hz), 3.26 (3H, s), 2.04 (2H, q, J 7.6 Hz), 1.00 (3H, t, J 7.6 Hz)
Method 7 (Compounds VIb)
LCMS RT=7.44 min, MH+ 329.1; 1H NMR (DMSO): 8.22 (2H, d, J 8.7 Hz), 7.91-7.87 (2H, m), 7.72 (2H, d, J 8.6 Hz), 7.43 (1H, d, J 8.3 Hz), 3.20 (3H, s), 2.46-2.42 (1H, m), 0.93 (6H, d, J 6.6 Hz)
LCMS RT=10.59 min, MH+ 315.1; 1H NMR (DMSO): 8.15 (2H, d, J 8.6 Hz), 7.67 (2H, d, J 8.6 Hz), 7.56 (1H, d, J 9.0 Hz), 6.96 (1H, d, J 2.5 Hz), 6.84 (1H, dd, J 9.1 2.5 Hz), 3.17 (2H, d, J 7.3 Hz), 2.97 (3H, s), 2.13-1.97 (1H, m), 0.90 (6H, d, J 6.7 Hz)
Method 8 (Compounds VII)
To N-(2-(4-chlorophenyl)benzo[d]oxazol-5-yl)isobutyramide (50 mg, 0.16 mmol) in toluene (2 mL) at 110° C. was added Lawesson's reagent (35 mg, 0.09 mmol). The resulting solution was heated at 110° C. for 7 h. After cooling, the solution was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, then dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 20:80 v/v to afford 13.8 mg (26%) of the title compound (LCMS RT=7.36 min, MH+ 331.2)
1H NMR (DMSO): 11.59 (1H, s), 8.37 (1H, d, J 2.0 Hz), 8.22 (2H, d, J 8.8 Hz), 7.83 (1H, d, J 8.7 Hz), 7.73-7.65 (3H, m), 3.18-3.09 (1H, m), 1.25 (6H, d, J 6.7 Hz)
Method 9 (Compound VIII)
To a solution of 2-(4-chlorophenyl)benzo[d]oxazol-5-amine (500 mg, 2.04 mmol) in water (3 mL) and tetrafluoroboric acid (50% in water, 2 mL) at 0° C. was added a solution of sodium nitrite (140 mg, 2.04 mmol) in water (2 mL), dropwise over 5 min. The resulting mixture was stirred at 0° C. for 15 min, and then at room temperature for 1 h. The solid was then filtered off, washed with dilute aqueous tetrafluoroboric acid solution and methanol to afford 370 mg (53%) of the title compound, which was used directly without characterization.
Method 10 (Compound IX)
To a stirred solution of potassium thioacetate (130 mg, 1.13 mmol) in DMSO (2.8 mL) at room temperature was added dropwise a solution of 2-(4-chlorophenyl)benzo[d]oxazole-5-diazonium tetrafluoroboric acid salt (370 mg, 1.08 mmol) in DMSO (1.4 mL). After 15 min, the mixture was heated at 70° C. for 1 h. After cooling, the mixture was diluted with water, and then extracted several times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting using a gradient (ethyl acetate/hexanes 5:95 v/v to ethyl acetate/hexanes 15:85 v/v) and triturated with diethyl ether/hexanes to afford 11.3 mg (3%) of the title compound (LCMS RT=7.89 min, MH+ 304.2)
1H NMR (CDCl3): 8.24 (2H, d, J 8.7 Hz), 7.88 (1H, dd, J 1.7 0.4 Hz), 7.67 (1H, dd, J 8.7 0.4 Hz), 7.57 (2H, d, J 8.8 Hz), 7.46 (1H, dd, J 8.4 1.7 Hz), 2.51 (3H, s)
Method 11A (Compound X)
To a stirred solution of 2-amino-4-(ethylsulfonyl)phenol (452.7 mg, 2.25 mmol) in ethanol (17 mL) was added 5-methyl-2-thiophenecarboxaldehyde (242 μL, 2.25 mmol). The mixture was heated at 70° C. for 70 min. After cooling, a small amount of precipitate was formed. After filtration and evaporation of the filtrate, the resulting product was dissolved in acetonitrile (9.8 mL) and lead tetraacetate (887 mg, 2 mmol) was added. The resulting mixture was heated at 100° C. for 5 min. After cooling, the reaction mixture was filtered off, and the filtrate evaporated in vacuo. The resulting mixture was purified by column chromatography eluting with ethyl acetate/hexanes 20:80 v/v, and then purified by reverse phase HPLC to afford 2.2 mg (0.3%) of the title product (LCMS RT=6.41 min, MH+ 308.1)
1H NMR (DMSO): 8.22 (1H, dd, J 1.8 0.5 Hz), 8.02 (1H, dd, J 8.6 0.5 Hz), 7.92-7.88 (2H, m), 7.08 (1H, dd, J 3.7 1.0 Hz), 3.37 (2H, q, J 7.3 Hz), 2.60 (3H, d, J 0.6 Hz), 1.12 (3H, t, J 7.4 Hz)
Method 11B (Compounds X)
As for Method 11A, but iodosobenzene diacetate was used instead of lead tetraacetate
LCMS RT=6.08 min, MH+ 294.1; 1H NMR (DMSO): 8.26 (1H, d, J 1.7 Hz), 8.08-8.04 (3H, m), 7.93 (1H, dd, J 8.5 1.8 Hz), 7.36 (1H, dd, J 4.9 3.8 Hz), 3.38 (2H, q, J 7.3 Hz), 1.13 (3H, t, J 7.4 Hz)
LCMS RT=6.45 min, MH+ 308.1; 1H NMR (DMSO): 8.02 (1H, d, J 1.8 0.5 Hz), 7.81 (1H, dd, J 8.5 0.5 Hz), 7.69-7.66 (2H, m), 6.98 (1H, dd, J 5.0 0.4 Hz), 3.15 (2H, q, J 7.3 Hz), 2.47 (3H, s), 0.88 (3H, t, J 7.4 Hz)
LCMS RT=5.53 min, MH+ 292.1; 1H NMR (DMSO): 8.00 (1H, d, J 1.8 0.6 Hz), 7.81 (1H, d, J 6.6 Hz), 7.69 (1H, dd, J 8.6 1.9 Hz), 7.26 (1H, d, J 3.7 Hz), 6.31-6.27 (1H, m), 3.18-3.14 (2H, m), 2.24 (3H, s), 0.90 (3H, t, J 7.4 Hz)
LCMS RT=6.40 min, MH+ 616.9; 1H NMR (DMSO): 8.24 (1H, d, J 1.8 0.5 Hz), 8.03 (1H, dd, J 8.6 0.5 Hz), 7.94-7.89 (2H, m), 7.65 (1H, t, J 1.2 Hz), 3.42-3.36 (2H, m), 2.32 (3H, d, J 0.6 Hz), 1.12 (3H, t, J 7.5 Hz)
Method 12 (Compounds XI)
To 2-p-tolylbenzo[d]oxazole-5-carboxylic acid (100 mg, 0.39 mmol) in dry dimethylformamide (10 mL) was added HATU (165 mg, 0.44 mmol) and diisopropylethylamine (206 μL, 1.18 mmol). The mixture was then stirred at room temperature for 10 min. Butan-1-amine (43 μL, 0.44 mmol) was then added and the resulting mixture was stirred at room temperature for 16 h. Ethyl acetate was added and the organic layer was washed three times with water. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 40:60 v/v to afford 26 mg (11%) of the title compound (LCMS RT=6.81 min, MH+ 309.1)
1H NMR (CDCl3): 8.22-8.15 (3H, m), 7.89 (1H, dd, J 8.1 1.1 Hz), 7.67 (1H, d, J 8.3 Hz), 7.40 (2H, d, J 7.5 Hz), 6.17 (1H, br), 3.59-3.52 (2H, m), 2.51 (3H, s), 1.72-1.64 (2H, m), 1.54-1.46 (2H, m), 1.03 (3H, t, J 7.3 Hz)
All compounds below were prepared following the same general method.
LCMS RT=6.42 min, MH+ 295.1; 1H NMR (CDCl3): 8.08 (2H, d, J 8.2 Hz), 8.04 (1H, d, J 1.4 Hz), 7.77 (1H, dd, J 8.5 1.7 Hz), 7.54 (1H, d, J 8.6 Hz), 7.28 (2H, d, J 7.9 Hz), 6.07 (1H, br), 3.44-3.37 (2H, m), 2.39 (3H, s), 1.65-1.55 (2H, m), 0.95 (3H, t, J 7.5 Hz)
LCMS RT=6.38 min, MH+ 295.1; 1H NMR (CDCl3): 8.20 (2H, d, J 8.2 Hz), 8.15 (1H, d, J 1.4 Hz), 7.87 (1H, dd, J 8.5 1.8 Hz), 7.65 (1H, d, J 8.5 Hz), 7.40 (2H, d, J 8.0 Hz), 6.00 (1H, br), 4.43-4.31 (1H, m), 2.51 (3H, s), 1.35 (6H, d, J 6.6 Hz)
LCMS RT=5.61 min, MH+ 253.0; 1H NMR (DMSO): 8.30 (1H, d, J 1.2 Hz), 8.12 (2H, d, J 8.2 Hz), 7.98 (1H, dd, J 8.5 1.7 Hz), 7.81 (1H, d, J 8.5 Hz), 7.45 (2H, d, J 8.0 Hz), 2.44 (3H, s)
LCMS RT=6.68 min, MH+ 315.5; 1H NMR (DMSO): 8.36-8.31 (2H, m), 8.23 (2H, d, J=8.7 Hz), 7.98 (1H, dd, J 8.5 1.7 Hz), 7.87 (1H, d, J 8.5 Hz), 7.72 (2H, d, J 8.7 Hz), 4.19-4.08 (1H, m), 1.21 (6H, d, J 6.6 Hz)
LCMS RT=5.81 min, MH+ 273.2; 1H NMR (DMSO): 8.11 (1H, s), 8.01 (2H, d, J 8.3 Hz), 7.89 (1H, br), 7.78 (1H, d, J 8.6 Hz), 7.64 (1H, d, J 8.6 Hz), 7.49 (2H, d, J 8.3 Hz), 7.25 (1H, br)
Method 8 (Compounds iso-VI)
LCMS RT=6.09 min, MH+ 286.9; 1H NMR (DMSO): 8.57 (1H, br), 8.28 (1H, d, J 1.2 Hz), 8.23 (2H, d, J 8.7 Hz), 7.96 (1H, dd, J 8.6 1.7 Hz), 7.87 (1H, d, J 8.6 Hz), 7.72 (2H, d, J 8.6 Hz), 2.83 (3H, d, J 4.5 Hz)
LCMS RT=6.90 min, MH+ 329.0; 1H NMR (DMSO): 8.23 (2H, d, J 8.6 Hz), 7.88-7.81 (2H, m), 7.72 (2H, d, J 8.7 Hz), 7.44 (1H, d, J 8.2 Hz), 2.88-2.78 (3H, m), 1.18-1.12 (6H, m)
Method 7 (Compounds iso-VII)
LCMS RT=7.37 min, MH+ 331.0; 1H NMR (DMSO): 10.18 (1H, d, J 7.3 Hz), 8.23 (2H, d, J 8.8 Hz), 8.11 (1H, dd, J 1.7 0.5 Hz), 7.88 (1H, dd, J 8.6 1.8 Hz), 7.83 (1H, dd, J 8.8
Method 13 (Compounds XII)
To a solution of 5-bromo-2-p-tolylbenzo[d]oxazole (146.1 mg, 0.50 mmol) in dioxane (1.5 mL) was added water (0.5 mL), 4-methoxyphenylboronic acid (114 mg, 0.75 mmol), potassium carbonate (138 mg, 1.00 mmol) and tetrakis(triphenylphosphine)palladium(0) (3 mg). The resulting suspension was heated in the microwave at 150° C. for 15 min. After cooling, the reaction was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 1:99 v/v to afford 60 mg (38%) of the title compound (LCMS RT=9.18 min, MH+ 316.1)
1H NMR (DMSO): 8.12 (2H, d, J 8.2 Hz), 7.99 (1H, d, J 1.5 Hz), 7.82 (1H, d, J 8.5 Hz), 7.71-7.64 (3H, m), 7.45 (2H, d, J 8.0 Hz), 7.06 (2H, d, J 8.8 Hz), 3.82 (3H, s), 2.43 (3H, s)
All compounds below were prepared following the same general method.
LCMS RT=7.51 min, MH+ 362.8; 1H NMR (DMSO): 10.04 (1H, s), 8.23 (2H, d, J 8.5 Hz), 8.05 (1H, d, J 1.6 Hz), 7.86 (1H, d, J 8.5 Hz), 7.73-7.69 (7H, m), 2.09 (3H, s)
LCMS RT=8.31 min, MH+ 397.8; 1H NMR (DMSO): 8.27-8.23 (3H, m), 8.09-7.94 (5H, m), 7.85 (1H, dd, J 8.6 1.8 Hz), 7.73 (2H, d, J 8.7 Hz), 3.39-3.34 (2H, m), 1.16 (3H, t, J=7.5 Hz)
LCMS RT=9.34 min, MH+ 363.9; 1H NMR (DMSO): 8.25 (2H, d, J 8.7 Hz), 8.20 (1H, d, J 1.3 Hz), 8.08 (2H, d, J 8.6 Hz), 7.95-7.91 (3H, m), 7.83 (1H, dd, J 8.6 1.8 Hz), 7.73 (2H, d, J 8.7 Hz), 3.90 (3H, s)
LCMS RT=7.40 min, MH+ 363.0; 1H NMR (DMSO): 10.05 (1H, s), 8.25 (2H, d, J 8.7 Hz), 8.00 (1H, d, J 1.4 Hz), 7.98-7.95 (1H, m), 7.90 (1H, d, J 8.5 Hz), 7.72 (2H, d, J 8.8 Hz), 7.67 (1H, dd, J 8.5 1.8 Hz), 7.60-7.57 (1H, m), 7.42-7.40 (2H, m), 2.09 (3H, s)
LCMS RT=17.49 min, MH+ 391.0; 1H NMR (DMSO): 8.23 (2H, d, J 8.9 Hz), 8.00 (1H, d, J 1.4 Hz), 7.83 (1H, d, J 8.6 Hz), 7.74-7.67 (3H, m), 7.64 (2H, d, J 8.9 Hz), 7.06 (2H, d, J 8.9 Hz), 3.79-3.75 (4H, m), 3.19-3.15 (4H, m)
LCMS RT=10.82 min, MH+ 365.7; 1H NMR (DMSO): 8.25 (2H, d, J 8.7 Hz), 8.11 (1H, d, J 1.4 Hz), 7.89 (1H, d, J 8.6 Hz), 7.77-7.70 (3H, m), 7.62 (1H, t, J 1.7 Hz), 7.55 (1H, dt, J 7.6 1.2 Hz), 7.44 (1H, t, J 7.6 Hz), 7.35-7.32 (1H, m), 3.09 (2H, q, J 7.3 Hz), 1.29 (3H, t, J 7.4 Hz)
LCMS RT=6.84 min, MH+ 363.0; 1H NMR (DMSO): 9.29 (1H, s), 8.24 (2H, d, J 8.6 Hz), 7.86 (1H, d, J 8.4 Hz), 7.78-7.76 (1H, m), 7.72 (2H, d, J 8.5 Hz), 7.53-7.29 (5H, m), 1.87 (3H, s)
LCMS RT=7.46 min, MH+ 337.0; 1H NMR (DMSO): 8.49 (1H, d, J 5.8 Hz), 8.45 (1H, s), 8.24 (2H, d, J 8.9 Hz), 7.95 (1H, d, J 1.7 0.5 Hz), 7.87 (1H, dd, J 8.5 0.6 Hz), 7.72 (2H, d, J 8.8 Hz), 7.58 (1H, dd, J 8.5 1.7 Hz), 7.21 (1H, d, J 5.8 Hz), 3.89 (3H, s)
LCMS RT=8.83 min, MH+ 337.0; 1H NMR (DMSO): 8.57 (1H, dd, J 2.6 0.6 Hz), 8.24 (2H, d, J 8.8 Hz), 8.13-8.10 (2H, m), 7.89 (1H, dd, J 8.6 0.5 Hz), 7.75-7.70 (3H, m), 6.95 (1H, dd, J 8.6 0.6 Hz), 3.92 (3H, s)
LCMS RT=4.62 min, MH+ 350.1; 1H NMR (DMSO): 8.27-8.23 (3H, m), 8.12 (1H, d, J=1.4 Hz), 8.03-7.95 (2H, m), 7.91 (1H, d, J 8.7 Hz), 7.78 (1H, dd, J 8.5 1.8 Hz), 7.72 (2H, d, J 8.8 Hz), 7.64 (1H, t, J 7.7 Hz)
LCMS RT=8.59 min, MH+ 340.9; 1H NMR (DMSO): 8.33 (1H, d, J 2.2 Hz), 8.28-8.23 (4H, m), 7.95 (1H, d, J 8.6 Hz), 7.83 (1H, dd, J 8.5 1.8 Hz), 7.73 (2H, d, J 8.7 Hz), 7.65 (1H, d, J 8.4 Hz)
LCMS RT=8.05 min, MH+ 325.0; 1H NMR (DMSO): 8.65 (1H, d, J 2.7 Hz), 8.39 (1H, td, J 8.2 2.7 Hz), 8.25 (2H, d, J 8.7 Hz), 8.20 (1H, dd, J 1.8 0.5 Hz), 7.94 (1H, dd, J 8.6 0.6 Hz), 7.80 (1H, dd, J 8.6 1.9 Hz), 7.73 (2H, d, J 8.7 Hz), 7.33 (1H, dd, J 8.6 3.0 Hz)
LCMS RT=8.46 min, MH+ 391.8; 1H NMR (DMSO): 8.55 (1H, d, J 2.4 Hz), 8.23 (2H, d, J 8.7 Hz), 8.06 (1H, d, J 1.4 Hz), 7.98 (1H, dd, J 8.9 2.6 Hz), 7.86 (1H, d, J 8.8 Hz), 7.73-7.69 (3H, m), 6.96 (1H, d, J 8.9 Hz), 3.75-3.71 (4H, m), 3.53-3.49 (4H, m)
LCMS RT=9.84 min, MH+ 337.1; 1H NMR (DMSO): 8.54 (1H, d, J 1.6 Hz), 8.26-8.23 (3H, m), 7.91 (1H, d, J 8.7 Hz), 7.82 (1H, t, J 7.9 Hz), 7.74-7.68 (3H, m), 6.81 (1H, d, J=8.1 Hz), 4.00 (3H, s)
LCMS RT=7.78 min, MH+ 321.1; 1H NMR (DMSO): 8.24 (2H, d, J 8.7 Hz), 7.73 (1H, dd, J 1.8 0.4 Hz), 7.85 (1H, d, J 8.5 Hz), 7.72 (2H, d, J 8.8 Hz), 7.63 (1H, dd, J 8.6 1.8 Hz), 7.13 (1H, t, J 7.8 Hz), 6.90 (1H, t, J 1.9 Hz), 6.87-6.82 (1H, m), 6.62-6.57 (1H, m), 5.19 (2H, s)
LCMS RT=7.77 min, MH+ 321.1; 1H NMR (DMSO): 8.22 (2H, d, J 8.7 Hz), 7.91 (1H, d, J 1.5 Hz), 7.78 (1H, d, J 8.6 Hz), 7.71 (2H, d, J 8.6 Hz), 7.61 (1H, dd, J 8.6 1.8 Hz), 7.43 (2H, d, J 8.6 Hz), 6.67 (2H, d, J 8.6 Hz), 5.26 (2H, s)
LCMS RT=7.12 min, MH+ 322.1; 1H NMR (DMSO): 8.32 (1H, d, J 2.2 Hz), 8.23 (2H, d, J 8.7 Hz), 7.98 (1H, d, J 1.4 Hz), 7.84-7.77 (2H, m), 7.72 (2H, d, J 8.7 Hz), 7.64 (1H, dd, J 8.5 1.8 Hz), 6.56 (1H, d, J 8.6 Hz), 6.09 (2H, s)
LCMS RT=7.73 min, MH+ 320.9; 1H NMR (DMSO): 7.94 (1H, d, J 1.5 Hz), 7.89 (2H, d, J 8.6 Hz), 7.78-7.74 (3H, m), 7.60 (1H, dd, J 8.6 1.8 Hz), 7.53 (2H, d, J 8.6 Hz), 6.71 (2H, d, J 8.7 Hz), 6.04 (2H, s)
Method 13a (Compound XIIa)
To 5-(2-(4-chlorophenyl)benzo[d]oxazol-5-yl)pyridin-2-amine (96.5 mg, 0.30 mmol) in dry pyridine (3 mL) at room temperature was added acetyl chloride (26 μL, 0.36 mmol), and stirred at 80° C. for 40 h. After cooling, the mixture was poured into water to give a precipitate, which was filtered off. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 20:80 v/v to afford 45 mg (41%) of the title compound.
1H NMR (DMSO): 10.61 (1H, s), 8.73-8.71 (1H, m), 8.24 (2H, d, J 8.6 Hz), 8.18-8.16 (3H, m), 7.91 (1H, d, J 8.5 Hz), 7.79 (1H, dd, J 8.6 1.8 Hz), 7.73 (2H, d, J 8.6 Hz), 2.13 (3H, s)
Method 13b (Compound XIIb)
In accordance with well known procedures (see Xu, Y. et al., Synthesis, 1984, 778-780.), a solution of methanol (2.70 mL, 66.75 mmol) and triethylamine (4.23 mL, 30.35 mmol) in diethyl ether (1 5 mL) was added dropwise at 0° C. to a solution of ethyl dichlorophosphine (3.15 mL, 30.35 mmol) in diethyl ether (30 mL). After the addition was complete, the resulting slurry was refluxed for 1 h. After cooling at 0° C., the precipitated solid was filtered off and washed with diethyl ether. The filtrate was then concentrated to afford a colourless oil, which was used without any purification in the next step.
To 5-bromo-2-p-tolylbenzo[d]oxazole (519.7 mg, 1.68 mmol) and methyl ethylphosphinate (276.9 mg, 2.02 mmol) in anhydrous toluene (10 mL) was added tetrakis(triphenylphosphine)palladium(0) (101.6 mg) and triethylamine (7.5 mL, 5.4 mmol). The resulting suspension was refluxed under nitrogen for 18 h. After cooling, ethyl acetate was added, and the organic layer was washed with water. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting using a gradient (starting with hexanes to ethyl acetate and then methanol/ethyl acetate 5:95 v/v) and then purified by reverse phase HPLC to afford 10.4 mg (2%) of the title product (LCMS RT=6.32 min, MH+ 336.1)
1H NMR (DMSO): 8.24 (2H, d, J 8.7 Hz), 8.18-8.13 (1H, m), 8.00 (1H, ddd, J 8.5 2.4 0.6 Hz), 7.81 (1H, ddd, J 10.9 8.2 1.4 Hz), 7.73 (2H, d, J 8.7 Hz), 3.54 (3H, d, J 10.9 Hz), 2.09-1.94 (2H, m), 1.04-0.91 (3H, m)
Method 14 (Compounds XIII)
To a solution of 4-(5-chlorobenzo[d]oxazol-2-yl)aniline (122.3 mg, 0.50 mmol) in pyridine (3 mL) at room temperature was added acetyl chloride (39 μL, 0.55 mmol). The resulting mixture was stirred at room temperature for 16 h. The solution was then poured into water, and the resulting precipitate collected by filtration. The solid was washed with diluted hydrochloric acid solution, followed by diluted sodium hydroxide solution, and then by water to afford 120 mg (84%) of the title compound (LCMS RT=6.38 min, MH+ 287.0)
1H NMR (DMSO): 10.33 (1H, s), 8.14 (2H, d, J 8.7 Hz), 7.88-7.80 (4H, m), 7.45 (1H, dd, J 8.7 2.1 Hz), 2.11 (3H, s)
All compounds below were prepared following the same general method.
LCMS RT=7.03 min, MH+ 315.1; 1H NMR (DMSO): 10.22 (1H, s), 8.14 (2H, d, J 8.7 Hz), 7.88-7.79 (4H, m), 7.45 (1H, dd, J 8.7 2.1 Hz), 2.70-2.61 (1H, m), 1.13 (6H, d, J 6.8 Hz)
LCMS RT=7.44 min, MH+ 355.0; 1H NMR (DMSO): 10.57 (1H, s), 8.21 (2H, d, J 8.9 Hz), 8.09 (1H, dd, J 3.8 1.1 Hz), 8.02 (2H, d, J 8.9 Hz), 7.93-7.90 (2H, m), 7.82 (1H, d, J=8.6 Hz), 7.46 (1H, dd, J 8.6 2.1 Hz), 7.27 (1H, dd, J 4.9 3.8 Hz)
LCMS RT=6.37 min, MH+ 287.0; 1H NMR (DMSO): 10.32 (1H, s), 8.13 (2H, d, J 8.8 Hz), 7.96 (1H, d, J 1.8 Hz), 7.84-7.77 (3H, m), 7.45 (1H, dd, J 8.4 1.9 Hz), 2.11 (3H, s)
LCMS RT=7.18 min, MH+ 315.1; 1H NMR (DMSO): 10.22 (1H, s), 8.12 (2H, d, J 8.8 Hz), 7.96 (1H, d, J 1.8 Hz), 7.86 (2H, d, J 8.9 Hz), 7.79 (1H, d, J 8.5 Hz), 7.45 (1H, dd, J 8.5 2.0 Hz), 2.70-2.61 (1H, m), 1.13 (6H, d, J 6.9 Hz)
LCMS RT=7.61 min, MH+ 354.9; 1H NMR (DMSO): 10.57 (1H, s), 8.19 (2H, d, J 8.9 Hz), 8.09 (1H, dd, J 3.7 1.0 Hz), 8.01 (2H, d, J 8.9 Hz), 7.98 (1H, d, J 1.8 Hz), 7.92 (1H, dd, J 5.0 1.0 Hz), 7.81 (1H, d, J 8.5 Hz), 7.46 (1H, dd, J 8.5 2.0 Hz), 7.26 (1H, dd, J 5.0 3.8 Hz)
1H NMR (DMSO): 10.35 (1H, s), 8.14 (2H, d, J 8.8 Hz), 8.01 (1H, d, J 1.8 Hz), 7.83 (2H, d, J 8.7 Hz), 7.76 (1H, d, J 8.6 Hz), 7.57 (1H, dd, J 8.6 2.0 Hz), 2.11 (3H, s)
LCMS RT=7.53 min, MH+ 363.0; 1H NMR (DMSO): 10.34 (1H, s), 8.17 (2H, d, J 8.7 Hz), 8.06-8.04 (1H, m), 7.87-7.82 (3H, m), 7.78 (2H, d, J 8.5 Hz), 7.72-7.67 (1H, m), 7.55 (2H, d, J 8.6 Hz), 2.12 (3H, s)
LCMS RT=7.22 min, MH+ 297.2; 1H NMR (DMSO): 11.24 (1H, br), 10.24 (1H, s), 7.91 (1H, d, J 8.6 Hz), 7.59 (2H, d, J 6.4 Hz), 7.51 (1H, d, J 1.9 Hz), 7.22 (1H, dd, J 8.7 2.0 Hz), 2.37 (3H, s), 2.34 (3H, s), 2.09 (3H, s)
Method 15 (Compounds XIV)
To a solution of 1-(2-(4-chlorophenyl)benzo[d]oxazol-5-yl)ethanone (150 mg, 0.55 mmol) in tetrahydrofuran at 0° C. was added sodium borohydride (52 mg, 1.38 mmol). The resulting mixture was stirred at room temperature for 16 h. The reaction was then quenched at 0° C. with 1M hydrochloric acid solution and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting using a gradient (ethyl acetate/hexanes 1:3 v/v to ethyl acetate/hexanes 1:2 v/v) to afford 81.7 mg (54%) of the title compound. (LCMS RT=6.47 min, MH+ 274.0)
1H NMR (DMSO): 8.20 (2H, d, J 8.7 Hz), 7.76-7.68 (4H, m), 7.44 (1H, dd, J 8.6 1.6 Hz), 5.31 (1H, d, J 4.3 Hz), 4.92-4.83 (1H, m), 1.38 (3H, d, J 6.4 Hz)
LCMS RT=7.18 min, MH+ 308.1; 1H NMR (DMSO): 8.36 (1H, d, J 2.0 Hz), 8.16 (1H, dd, J 8.5 2.0 Hz), 7.90 (1H, d, J 8.4 Hz), 7.78-7.77 (1H, m), 7.74 (1H, d, J 8.4 Hz), 7.47 (1H, dd, J 8.6 1.7 Hz), 5.32 (1H, d, J 4.3 Hz), 4.93-4.84 (1H, m), 1.39 (3H, d, J 6.4 Hz)
In accordance with well known procedures, (see Batista-Parra, A. et al. Heterocycles, 2003, 60, 1367), a suspension of 2-amino-4-nitrophenol (1.54 g, 10 mmol) and potassium O-ethyl carbonodithioate (1.68 g, 10.5 mmol) in dry pyridine (10 mL) was stirred at 120° C. for 6 h, and then at room temperature for 16 h. The solution was poured into water and aqueous hydrochloric acid was added. The resulting precipitate was collected by filtration, washed with dilute aqueous hydrochloric acid, followed by water and then dried in the vacuum oven to afford 3.3 g (84%) of the title compound.
1H NMR (DMSO): 8.18 (1H, dd, J 8.9 2.4 Hz), 7.94 (1H, dd, J 2.4 0.4 Hz), 7.73 (1H, dd, J 8.9 0.4 Hz)
Method 16 (Compound XV)
5-nitrobenzo[d]oxazole-2(3H)-thione (98.1 mg, 0.5 mmol) and morpholine (66 μL, 0.75 mmol) in tetrahydrofuran (3 mL) were heated at 150° C. for 15 min in the microwave. After cooling, the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4 and absorbed on silica. Purification by column chromatography, eluting with ethyl acetate/hexanes 25:75 v/v affords 115 mg (92%) of the title compound.
1H NMR (DMSO): 8.10 (1H, d, J 2.3 Hz), 8.00 (1H, dd, J 8.8 2.4 Hz), 7.66 (1H, d, J 8.8 Hz), 3.76-3.72 (4H, m), 3.67-3.64 (4H, m)
Method 17a (Compound XVI)
A solution of 2-morpholino-5-nitrobenzo[d]oxazole (130 mg, 0.52 mmol) in ethanol/water 1:1 v/v (10 mL) was treated with sodium dithionite (182 mg, 1.04 mmol) at room temperature and then refluxed for 16 h. After cooling, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO4 and evaporated to afford 35 mg (30%) of the title compound.
1H NMR (DMSO): 7.03 (1H, d, J 8.5 Hz), 6.50 (1H, d, J 2.1 Hz), 6.25 (1H, dd, J 8.4 2.2 Hz), 4.80 (2H, s), 3.71-3.68 (4H, m), 3.53-3.50 (4H, m)
Method 17b (Compound XVI)
To a suspension of N-(4-chlorobenzyl)-5-nitrobenzo[d]oxazol-2-amine (150 mg, 0.50 mmol) in ethanol/water 1:1 v/v (10 mL) at 90° C. was added ammonium chloride (53 mg, 1.0 mmol), followed by iron powder (140 mg, 2.5 mmol). The resulting mixture was stirred for 4 h at 90° C. After cooling, ethyl acetate was added and the solution was passed through a pad of Celite®. The organic layer was then washed with brine, dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 50:50 v/v to afford 60 mg (44%) of the title compound (LCMS RT=5.60 min, MH+ 274.0)
1H NMR (DMSO): 8.20 (1H, t, J 6.2 Hz), 7.42-7.36 (4H, m), 6.97 (1H, d, J 8.4 Hz), 6.45 (1H, d, J 2.1 Hz), 6.20 (1H, dd, J 8.4 2.2 Hz), 4.72 (2H, s), 4.46 (2H, d, J 6.2 Hz)
Method 18 (Compound XVII)
To a suspension of 5-nitrobenzo[d]oxazole-2(3H)-thione (196.2 mg, 1.0 mmol) in chloroform (10 mL) was added triethylamine (278 μL, 2 mmol) followed by 1-(bromomethyl)-4-chlorobenzene (226 mg, 1.1 mmol). The reaction was stirred at 60° C. for 2 h. After cooling, the reaction was diluted with ethyl acetate, washed with dilute aqueous hydrochloric solution and brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 1:10 v/v to afford 250 mg (78%) of the title compound (LCMS RT=7.64 min)
1H NMR (DMSO): 8.52 (1H, d, J 2.3 Hz), 8.27 (1H, dd, J 8.9 2.3 Hz), 7.92 (1H, d, J 9.0 Hz), 7.58 (2H, d, J 8.5 Hz), 7.42 (2H, d, J 8.5 Hz), 4.67 (2H, s)
Method 19 (Compound XVIII)
To a suspension of 2-(4-chlorobenzylthio)-5-nitrobenzo[d]oxazole (220 mg, 0.70 mmol) in ethanol/water (5 mL/5 mL) at 90° C. was added ammonium chloride (75 mg, 1.4 mmol), followed by iron powder (192 mg, 3.44 mmol). The resulting mixture was stirred for 4 h at 90° C. After cooling, ethyl acetate was added and the solution was passed through a pad of Celite®. The organic layer was then washed with brine, dried over anhydrous MgSO4 and evaporated to afford 190 mg (94%) of the title compound (LCMS RT=6.54 min, MH+ 290.9)
1H NMR (DMSO): 7.52 (2H, d, J 8.7 Hz), 7.40 (2H, d, J 8.5 Hz), 7.26 (1H, d, J 8.7 Hz), 6.74 (1H, d, J 1.9 Hz), 6.54 (1H, dd, J 8.7 2.2 Hz), 5.06 (2H, s), 4.55 (2H, s)
Method 20 (Compounds XIX)
To a solution of 2-(4-chlorobenzylthio)benzo[d]oxazol-5-amine (87 mg, 0.30 mmol) in dry pyridine (3 mL) at room temperature was added acetyl chloride (21 μL, 0.30 mmol). The resulting solution was stirred at room temperature for 16 h. Water was then added, the precipitate was collected by filtration, washed with diluted aqueous hydrochloric acid and then with water. Trituration with diethyl ether afforded 40 mg (40%) of the title compound (LCMS RT=6.40 min, MH+ 333.1)
1H NMR (DMSO): 10.08 (1H, s), 8.01 (1H, d, J 1.8 Hz), 7.58-7.52 (3H, m), 7.43-7.35 (3H, m), 4.60 (2H, s), 2.06 (3H, s)
The compound below was prepared following the same general method.
LCMS RT=7.00 min, MH+ 361.1; 1H NMR (DMSO): 9.96 (1H, s), 8.04 (1H, d, J 1.8 Hz), 7.58-7.52 (3H, m), 7.43-7.39 (3H, m), 4.60 (2H, s), 2.65-2.60 (1H, m), 1.12 (6H, d, J 6.8 Hz)
Method 21 (Compound XX)
To a solution of 5-nitrobenzo[d]oxazole-2(3H)-thione (2.52 g, 12.86 mmol) in phosphorous oxychloride (21 mL) was added phosphorous pentachloride (2.68 g, 12.86 mmol) in one portion. The mixture was then heated to 100° C. for 2.5 h. After cooling, the excess of phosphorous oxychloride was removed in vacuo and the resulting mixture was used crude without characterisation.
Method 22 (Compound XXI)
A mixture of 2-chloro-5-nitrobenzo[d]oxazole (404 mg, 2.04 mmol), 2-(tributylstannyl)-thiophene (648 μL, 2.04 mmol) and tetrakis(triphenylphosphine)palladium (0) (40.8 mg) in dioxane (12.2 mL) was heated at 100° C. for 16 h under nitrogen. Ethyl acetate was added, the organic layer was washed with water, dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 10:90 v/v, and then purified by reverse phase HPLC to afford 3 mg (2%) of the title product (LCMS RT=6.95 min)
1H NMR (DMSO): 8.54 (1H, d, J 2.2 Hz), 8.27 (1H, dd, J 9.0 2.3 Hz), 8.04 (1H, dd, J 5.4 1.2 Hz), 7.93 (1H, d, J 9.0 Hz), 7.69 (1H, dd, J 3.7 1.2 Hz), 7.29 (1H, dd, J 5.4 3.7 Hz)
Method 23 (Compounds XXII)
To polyphosphoric acid at 130° C. were added 4,5-dimethylbenzene-1,2-diamine (500 mg, 3.67 mmol) and 4-amino-2-hydroxybenzoic acid (562 mg, 3.67 mmol), and the resulting mixture was then heated to 130° C. for 16 h. The solution was then poured into water and the resulting precipitate was dissolved in ethyl acetate and washed with Na2CO3. The aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 50:50 v/v to afford 260 mg (28%) of the title compound (LCMS RT=6.14 min, MH+ 254.1)
1H NMR (DMSO): 13.07 (1H, s), 12.40 (1H, s), 7.61 (1H, d, J 8.3 Hz), 7.35 (1H, s), 7.24 (1H, s), 6.19 (1H, dd, J 8.5 2.2 Hz), 6.12 (1H, d, J 2.1 Hz), 5.59 (2H, s), 2.32 (3H, s), 2.30 (3H, s)
All compounds below were prepared following the same general method.
LCMS RT=5.87 min, MH+ 254.1; 1H NMR (DMSO): 13.20 (1H, br), 9.31 (1H, s), 8.21-8.19 (2H, m), 7.67-7.64 (2H, m), 7.28-7.25 (2H, m), 2.65 (3H, s)
LCMS RT=6.48 min, MH+ 256.0; 1H NMR (DMSO): 13.50 (1H, br), 12.40 (1H, br), 8.56 (1H, s), 8.20-8.14 (2H, m), 7.84 (1H, d, J 8.8 Hz), 7.48-7.43 (1H, m), 7.12-7.04 (2H, m)
LCMS RT=6.24 min, MH+ 273.9; 1H NMR (DMSO): 13.80 (1H, br), 8.54 (1H, d, J 2.1 Hz), 8.29 (2H, d, J 8.6 Hz), 8.21 (1H, dd, J 8.9 2.2 Hz), 7.84 (1H, d, J 8.9 Hz), 7.75 (2H, d, J 8.5 Hz)
Method 24 (Compound XXIIb)
To 2-(5-nitro-1H-benzo[d]imidazol-2-yl)phenol (90 mg, 0.35 mmol) in ethyl acetate/water/acetic acid 1:1:0.01 v/v/v (10 mL) was added palladium on carbon (15 mg). The reaction vessel was purged three times with nitrogen, followed by three times with hydrogen, and then left stirring under hydrogen for 2 h. The reaction vessel was finally purged three times with nitrogen, before filtration on a pad of Celite®, which was washed with ethyl acetate. The organic layer was washed with saturated aqueous NaHCO3. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 2:1 v/v to afford 60 mg (76%) of the title compound (LCMS RT=5.39 min, MH+ 226.1)
1H NMR (DMSO): 13.28 (1H, br), 12.63 (1H, br), 7.72 (1H, d, J 8.4 Hz), 7.33-7.28 (2H, m), 6.99-6.94 (2H, m), 6.71-6.58 (2H, m), 5.12 (2H, s)
Method 25 (Compounds XXIII)
To a solution of 2-p-tolyl-1H-benzo[d]imidazol-5-amine (150 mg, 0.67 mmol) in pyridine (10 mL) at room temperature was added butyryl chloride (77 μL, 0.74 mmol). The resulting mixture was stirred at room temperature for 16 h. Ethyl acetate was added and the organic layer was washed twice with saturated aqueous copper sulfate, followed by sodium bicarbonate and brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 50:50 v/v to afford 56 mg (28%) of the title compound (LCMS RT=6.96 min, MH+ 294.0)
1H NMR (DMSO): 12.68 (1H, br), 9.87 (1H, s), 8.08-8.00 (3H, m), 7.52-7.20 (4H, m), 2.38 (3H, s), 2.31 (2H, t, J 7.3 Hz), 1.70-1.58 (2H, m), 0.94 (3H, t, J 7.4 Hz)
All compounds below were prepared following the same general method.
LCMS RT=5.43 min, MH+ 294.1; 1H NMR (DMSO): 12.67 (1H, br), 9.91 (1H, s), 8.08-8.01 (3H, m), 7.50-7.28 (4H, m), 4.03 (1H, q, J 7.2 Hz), 2.38 (3H, s), 1.13 (6H, d, J 6.8 Hz)
LCMS RT=5.54 min, MH+ 314.0; 1H NMR (DMSO): 12.85 (1H, br), 9.90 (1H, s), 8.14 (3H, d, J 8.6 Hz), 7.62 (2H, d, J 8.7 Hz), 7.53 (1H, br), 7.25 (1H, br), 2.32 (2H, t, J 7.1 Hz), 1.71-1.58 (2H, m), 0.94 (3H, t, J 7.5 Hz)
LCMS RT=5.32 min, MH+ 280.0; 1H NMR (DMSO): 12.80 (1H, br), 9.85 (1H, s), 8.16-8.09 (3H, m), 7.58-7.47 (4H, m), 7.28 (1H, d, J 8.1 Hz), 2.68-2.60 (1H, m), 1.13 (6H, d, J 6.9 Hz)
LCMS RT=5.32 min, MH+ 280.0; 1H NMR (DMSO): 12.77 (1H, br), 9.90 (1H, s), 8.15-8.12 (3H, m), 7.58-7.45 (4H, m), 7.26 (1H, br), 2.31 (2H, t, J 7.1 Hz), 1.71-1.58 (2H, m), 0.94 (3H, t, J 7.5 Hz)
LCMS RT=5.71 min, MH+ 314.0; 1H NMR (DMSO): 12.89 (1H, br), 9.86 (1H, s), 8.18-8.10 (3H, m), 7.62 (2H, d, J 8.8 Hz), 7.52 (1H, d, J 8.8 Hz), 7.29 (1H, d, J 8.3 Hz), 2.66-2.60 (1H, m), 1.13 (6H, d, J 6.9 Hz)
Method 26 (Compound XXIV)
2-Fluoro-5-nitroaniline (1 g, 6.41 mmol), sodium sulfide nonahydrate (1.7 g, 7.05 mmol), sodium bicarbonate (600 mg, 7.05 mmol) and water (15 mL) were combined and heated in the microwave at 125° C. for 5 min. After cooling, dichloromethane was added, and the organic layer was washed with 2M aqueous hydrochloric acid and then brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated to afford 1.1 g (33%) of the title compound.
1H NMR (DMSO): 7.61-7.55 (2H, m), 7.47 (1H, d, J 8.2 Hz), 7.31 (3H, s)
Method 27 (Compound XXV)
2-Amino-4-nitrobenzenethiol (315 mg, 1.85 mmol), 2-chlorobenzoic acid (290 mg, 1.85 mmol) and Eaton's reagent (5 mL) were combined and heated in the microwave at 130° C. for 10 min. After cooling, the mixture was poured into water and basified with 5M aqueous sodium hydroxide to give a precipitate, which was filtered off and dried to afford 530 mg (98%) of the title compound.
1H NMR (DMSO): 8.93 (1H, d, J 2.2 Hz), 8.53 (1H, d, J 8.9 Hz), 8.37 (1H, dd, J 8.9 2.2 Hz), 8.29 (1H, dd, J 7.4 1.9 Hz), 7.78-7.75 (1H, m), 7.70-7.60 (2H, m)
Method 28 (Compound XXVI)
To 2-chloro-5-nitroaniline (2 g, 11.59 mmol) in pyridine (5 mL) at room temperature was added 4-methylbenzoyl chloride (1.6 mL, 12.17 mmol), followed by pyridine (5 mL). The mixture was then stirred at room temperature for 16 h. Ethyl acetate was then added to the solution to give a precipitate, which was filtered off and washed twice with ethyl acetate, and then hexanes. The resulting solid was then washed with aqueous sodium bicarbonate, 1M aqueous sodium hydroxide, water and hexanes to afford (1.4 g, 42%) of the title compound.
1H NMR (DMSO): 10.26 (1H, s), 8.58 (1H, d, J 2.8 Hz), 8.11 (1H, dd, J 8.9 2.8 Hz), 7.93 (2H, d, J 8.2 Hz), 7.87 (1H, d, J 8.9 Hz), 7.38 (2H, d, J 8.0 Hz), 2.41 (3H, s)
Method 29 (Compound XXV)
Sodium sulfide nonahydrate (875 mg, 3.78 mmol) and sulfur (120 mg, 3.78 mmol) were heated until molten. The water was driven off with nitrogen to give a solid. The obtained solid was added in portions to N-(2-chloro-5-nitrophenyl)-4-methylbenzamide (1 g, 3.44 mmol) in ethanol (20 mL) at 85° C. The solution was stirred at 85° C. for 3 h. After cooling, 2M aqueous HCl was added, and the solution was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 10:90 v/v to afford 400 mg (43%) of the title compound.
1H NMR (DMSO): 8.81 (1H, d, J 2.2 Hz), 8.45 (1H, d, J 8.8 Hz), 8.29 (1H, dd, J 8.8 2.3 Hz), 8.06 (2H, d, J 8.2 Hz), 7.44 (2H, d, J 8.0 Hz), 2.42 (3H, s)
Method 30 (Compounds XXVII)
5-Nitro-2-p-tolylbenzo[d]thiazole (400 mg, 1.48 mmol) was suspended in ethanol/water (8 mL/4 mL) and heated at 80° C. Ammonium chloride (160 mg, 2.96 mmol) and iron powder (414 mg, 7.40 mmol) were added to the suspension, and the mixture was left stirring at 80° C. for 75 min. After cooling, the solution was filtrated through a pad of Celite® and the pad washed with ethanol. Water was added to the filtrate, ethanol was evaporated and the remaining aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4 and evaporated to afford 220 mg (62%) of the title compound (LCMS RT=6.51 min, MH+ 241.0)
1H NMR (DMSO): 7.91 (2H, d, J 8.1 Hz), 7.68 (1H, d, J 8.6 Hz), 7.35 (2H, d, J 8.0 Hz), 7.15 (1H, d, J 2.0 Hz), 6.77 (1H, dd, J 8.6 2.0 Hz), 5.32 (2H, s), 2.39 (3H, s)
All compounds below were prepared following the same general method.
LCMS RT=6.1 min, MH+ 227.1; 1H NMR (DMSO): 8.04-8.01 (2H, m), 7.71 (1H, d, J 8.5 Hz), 7.56-7.53 (3H, m), 7.18 (1H, d, J 2.1 Hz), 6.79 (1H, dd, J 8.6 2.3 Hz), 5.33 (2H, s)
LCMS RT=6.72 min, MH+ 260.7; 1H NMR (DMSO): 8.04 (2H, d, J 8.7 Hz), 7.72 (1H, d, J 8.6 Hz), 7.61 (2H, d, J 8.7 Hz), 7.17 (1H, d, J 2.0 Hz), 6.80 (1H, dd, J 8.6 2.2 Hz), 5.35 (2H, s)
LCMS RT=6.49 min, MH+ 260.8; 1H NMR (DMSO): 8.19-8.16 (1H, m), 7.76 (1H, d, J 8.6 Hz), 7.69-7.66 (1H, m), 7.56-7.52 (2H, m), 7.22 (1H, d, J 2.0 Hz), 6.85 (1H, dd, J 8.6 2.1 Hz), 5.37 (2H, s)
LCMS RT=6.79 min, MH+ 260.8; 1H NMR (DMSO): 8.05-8.04 (1H, m), 7.96 (1H, dt, J 7.0 1.7 Hz), 7.74 (1H, d, J 8.6 Hz), 7.64-7.55 (2H, m), 7.19 (1H, d, J 1.7 Hz), 6.82 (1H, dd, J 8.6 2.2 Hz), 5.37 (2H, s)
LCMS RT=7.49 min, MH+ 294.9; 1H NMR (DMSO): 8.24 (1H, d, J 2.1 Hz), 8.00 (1H, dd, J 8.4 2.1 Hz), 7.82 (1H, d, J 8.4 Hz), 7.76 (1H, d, J 8.6 Hz), 7.20 (1H, d, J 1.9 Hz), 6.84 (1H, dd, J 8.6 2.2 Hz), 5.41 (2H, s)
LCMS RT=7.00 min, MH+ 294.9; 1H NMR (DMSO): 8.08 (1H, dd, J 7.9 1.6 Hz), 7.84 (1H, dd, J 8.0 1.6 Hz), 7.78 (1H, d, J 8.6 Hz), 7.55 (1H, t, J 8.0 Hz), 7.22 (1H, d, J 2.0 Hz), 6.87 (1H, dd, J 8.6 2.2 Hz), 5.38 (2H, s)
Method 31 (Compounds XXVIII)
To a solution of 2-p-tolylbenzo[d]thiazol-5-amine (110 mg, 0.46 mmol) in pyridine (3 mL) at room temperature was added butyryl chloride (53 μL, 0.50 mmol). The resulting mixture was stirred at room temperature for 2 days. Ethyl acetate was added and the organic layer was washed with saturated aqueous copper sulfate, followed by aqueous sodium bicarbonate and finally with brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 50:50 v/v to afford 25 mg (18%) of the title compound (LCMS RT=7.10 min, MH+ 311.0)
1H NMR (DMSO): 10.12 (1H, s), 8.43 (1H, d, J 1.8 Hz), 8.02-7.96 (3H, m), 7.58 (1H, dd, J 8.6 2.0 Hz), 7.38 (2H, d, J 8.0 Hz), 2.40 (3H, s), 2.35 (2H, t, J 7.5 Hz), 1.72-1.60 (2H, m), 0.95 (3H, t, J 7.4 Hz)
All compounds below were prepared following the same general method.
LCMS RT=7.06 min, MH+ 311.0; 1H NMR (DMSO): 10.08 (1H, s), 8.44 (1H, d, J 1.3 Hz), 8.03-7.96 (3H, m), 7.60 (1H, dd, J 8.7 1.6 Hz), 7.38 (2H, d, J 8.0 Hz), 2.69-2.60 (1H, m), 2.40 (3H, s), 1.15 (6H, d, J 6.8 Hz)
LCMS RT=6.56 min, MH+ 297.0; 1H NMR (DMSO): 10.07 (1H, s), 8.47 (1H, d, J 1.8 Hz), 8.11-8.07 (2H, m), 8.04 (1H, d, J 8.6 Hz), 7.64-7.56 (4H, m), 2.70-2.61 (1H, m), 1.15 (6H, d, J 6.8 Hz)
LCMS RT=7.42 min, MH+ 331.0; 1H NMR (DMSO): 10.08 (1H, s), 8.47 (1H, d, J 1.9 Hz), 8.10 (2H, d, J 8.6 Hz), 8.05 (1H, d, J 8.7 Hz), 7.67-7.61 (3H, m), 2.70-2.60 (1H, m), 1.15 (6H, d, J 6.8 Hz)
LCMS RT=6.99 min, MH+ 330.9; 1H NMR (DMSO): 10.12 (1H, s), 8.55 (1H, d, J 1.9 Hz), 8.25-8.22 (1H, m), 8.10 (1H, d, J 8.8 Hz), 7.74-7.55 (4H, m), 2.72-2.63 (1H, m), 1.17 (6H, d, J 6.8 Hz)
LCMS RT=7.34 min, MH+ 330.9; 1H NMR (DMSO): 10.11 (1H, s), 8.50 (1H, d, J 1.7 Hz), 8.13-8.03 (3H, m), 7.69-7.60 (3H, m), 2.71-2.62 (1H, m), 1.17 (6H, d, J 6.8 Hz)
LCMS RT=8.21 min, MH+ 364.7; 1H NMR (DMSO): 10.11 (1H, s), 8.52-8.50 (1H, m), 8.30 (1H, d, J 2.1 Hz), 8.10-8.04 (2H, m), 7.85 (1H, d, J 8.4 Hz), 7.69-7.64 (1H, m), 2.71-2.64 (1H, m), 1.17 (6H, d, J 6.8 Hz)
LCMS RT=7.62 min, MH+ 364.9; 1H NMR (DMSO): 10.12 (1H, s), 8.55 (1H, d, J 1.7 Hz), 8.14-8.10 (2H, m), 7.88 (1H, dd, J 8.0 1.4 Hz), 7.67 (1H, dd, J 8.8 2.0 Hz), 7.58 (1H, t, J 8.0 Hz), 2.70-2.61 (1H, m), 1.15 (6H, d, J 6.8 Hz)
Method 32 (Compound XXIX)
To 4-(methylthio)aniline (1 mL, 8.19 mmol) in dichloromethane (20 mL) was added pyridine (2 mL, 24.6 mmol). The resulting solution was cooled to 10-15° C. and 4-chlorobenzoyl chloride (1.14 mL, 9.00 mmol) was added over 5 min. The mixture was stirred at room temperature for 90 min. The precipitate was filtered off, washed with dichloromethane, 1M aqueous sodium hydroxide solution and 1M aqueous hydrochloric acid solution to afford 2.12 g (93%) of the title compound.
1H NMR (DMSO): 10.31 (1H, s), 7.98 (2H, d, J 8.7 Hz), 7.73 (2H, d, J 8.8 Hz), 7.61 (2H, d, J 8.8 Hz), 7.28 (2H, d, J 8.8 Hz), 2.47 (3H, s)
Method 33 (Compound XXX)
A suspension of 4-chloro-N-(4-(methylthio)phenyl)benzamide (1 g, 3.60 mmol) and Lawesson's reagent (875 mg, 2.16 mmol) in toluene (25 mL) was heated to 11 0° C. for 16 h. After cooling, toluene was removed in vacuo and the resulting solid was purified by column chromatography eluting using a gradient (hexanes to ethyl acetate/hexanes 30:70 v/v) to afford 503 mg (48%) of the title compound.
LCMS RT=6.98 min, MH+ 294.1; 1H NMR (DMSO): 11.80 (1H, s), 7.85 (2H, d, J 8.6 Hz), 7.78 (2H, d, J 8.7 Hz), 7.54 (2H, d, J 8.6 Hz), 7.33 (2H, d, J 8.7 Hz)
Method 34 (Compound XXXI)
To a solution of potassium hexacyanoferrate(III) (670 mg, 2.04 mmol) in water (5 mL) at 90° C. was added dropwise over 5 minutes a solution of 4-chloro-N-(4-(methylthio)phenyl)benzothioamide (150 mg, 0.51 mmol) in ethanol (2 mL) and 3M aqueous sodium hydroxide solution (1.4 mL, 4.08 mmol). The resulting mixture was heated at 90° C. for 30 minutes. After cooling, the precipitate formed was filtered off and washed with water to give a yellow solid. The yellow solid was purified by column chromatography eluting using a gradient (hexanes to ethyl acetate/hexanes 5:95 v/v) to afford 100 mg (67%) of the title compound (LCMS RT=9.37 min, MH+ 292.2)
1H NMR (DMSO): 8.11-8.06 (3H, m), 7.98 (1H, d, J 8.6 Hz), 7.65 (2H, d, J 8.7 Hz), 7.45 (1H, dd, J 8.6 1.9 Hz), 2.58 (3H, s)
Method 35 (Compound XXXII)
To a solution of 2-(4-chlorophenyl)-6-(methylthio)benzo[d]thiazole (240 mg, 0.82 mmol) in dichloromethane (20 mL) was added 3-chloroperoxybenzoic acid (77% in water, 710 mg, 4.11 mmol) over 5 min. The resulting mixture was stirred at room temperature for 3 h. 1M aqueous sodium hydroxide solution was added carefully, and the mixture was then stirred for 5 min. The organic layer was then washed with 1M aqueous sodium hydroxide solution, dried over anhydrous MgSO4 and evaporated. The resulting solid was recrystallised from hot ethyl acetate to afford 125 mg (47%) of the title compound (LCMS RT=6.81 min, MH+ 324.0)
1H NMR (CDCl3): 8.61 (1H, dd, J 1.8 0.4 Hz), 8.26 (1H, dd, J 8.6 0.5 Hz), 8.14-8.09 (3H, m), 7.57 (2H, d, J 8.6 Hz), 3.19 (3H, s)
Method 36 (Compounds XXXIII)
To a suspension of 5-bromo-2-(4-chlorophenyl)-1H-indole (200 mg, 0.65 mmol) in dioxane/water 4:1 v/v (5 mL) was added phenylboronic acid (87 mg, 0.72 mmol) and a few milligrams of tetrakis(triphenylphosphine)palladium(0). The resulting suspension was heated in the microwave at 160° C. for 15 min. After cooling, the reaction was poured into water to give a precipitate, which was filtered off and washed with water. The resulting solid was purified by column chromatography eluting using a gradient (hexanes to ethyl acetate/hexanes 30:70 v/v), followed by a recrystallisation from hot ethyl acetate to afford 21 mg (11%) of the title compound (LCMS RT=8.54 min, MH+ 304.1)
1H NMR (DMSO): 11.68 (1H, s), 7.91 (2H, d, J 8.6 Hz), 7.81 (1H, d, J 1.1 Hz), 7.70-7.66 (2H, m), 7.55 (2H, d, J 8.6 Hz), 7.50-7.41 (4H, m), 7.33-7.28 (1H, m), 7.01 (1H, d, J 1.2 Hz)
The compound below was prepared following the same general method.
LCMS RT=6.69 min, MH+ 361.0; 1H NMR (DMSO): 11.64 (1H, s), 9.98 (1H, s), 7.91 (2H, d, J 8.6 Hz), 7.77 (1H, d, J 1.0 Hz), 7.68-7.60 (4H, m), 7.54 (2H, d, J 8.6 Hz), 7.46 (1H, d, J 8.3 Hz), 7.41 (1H, dd, J 8.5 1.6 Hz), 6.99 (1H, d, J 1.5 Hz), 2.07 (3H, s)
Method 37 (Compound XXXIV)
To a solution of 6-nitro-1H-indole (100 mg, 0.62 mmol) and 18-Crown-6 (180 mg, 0.68 mmol) in anhydrous tetrahydrofuran (2 mL) at room temperature was slowly added potassium tert-butoxide (76 mg, 0.68 mmol) followed by methyl iodide (42 μL, 0.68 mmol). The solution was stirred at room temperature for 30 min. Tetrahydrofuran was removed in vacuo. Ethyl acetate was added, and the organic layer was washed with water and then brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated to afford 91 mg (84%) of the title compound.
1H NMR (CDCl3): 8.16 (1H, d, J 1.8 Hz), 7.85 (1H, dd, J 8.7 1.9 Hz), 7.49 (1H, d, J 8.7 Hz), 7.19 (1H, d, J 3.1 Hz), 6.43 (1H, dd, J 3.1 0.9 Hz), 3.74 (3H, s)
Method 38 (Compound XXXV)
1-methyl-6-nitro-1H-indole (90 mg, 0.51 mmol), ammonium chloride (55 mg, 1.02 mmol) and iron powder (143 mg, 2.55 mmol) were suspended in ethanol/water (2 mL/1 mL) and heated at 70° C. for 2 h. After cooling, the solution was filtrated through a pad of Celite®, which was washed with ethanol. Ethyl acetate was added to the filtrate and the organic layer was washed with water twice. The combined organic layers were dried over anhydrous MgSO4 and evaporated to afford 30 mg (37%) of the title compound
1H NMR (DMSO): 7.17 (1H, d, J 8.4 Hz), 6.93 (1H, d, J 3.1 Hz), 6.51-6.49 (1H, m), 6.41 (1H, dd, J 8.3 1.9 Hz), 6.16 (1H, d, J 3.1 Hz), 4.76 (2H, s), 3.60 (3H, s)
Method 39 (Compounds XXXVI)
To a solution of 1-methyl-1H-indol-6-amine (45 mg, 0.31 mmol) in pyridine (2 mL) at room temperature was added isobutyryl chloride (35 μL, 0.34 mmol). The resulting mixture was stirred at room temperature for 16 h. Ethyl acetate was added and the organic layer was washed three times with brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated to afford 24.3 mg (36%) of the title compound (LCMS RT=5.73 min, MH+ 217.2)
1H NMR (DMSO): 9.78 (1H, s), 7.96 (1H, m), 7.44 (1H, d, J 8.4 Hz), 7.24 (1H, d, J 3.1 Hz), 7.08 (1H, dd, J 8.4 1.7 Hz), 6.35 (1H, dd, J 3.0 0.7 Hz), 3.73 (3H, s), 2.68-2.61 (1H, m), 1.13 (6H, d, J 6.9 Hz)
The compound below was prepared following the same general method.
LCMS RT=6.36 min, MH+ 293.2; 1H NMR (DMSO): 9.73 (1H, s), 7.90 (1H, m), 7.45 (1H, d, J 8.5 Hz), 7.41 (1H, d, J 3.1 Hz), 7.34-7.24 (3H, m), 7.14-7.10 (3H, m), 6.42 (1H, d, J 3.2 Hz), 5.35 (2H, s), 1.08 (6H, d, J 6.8 Hz)
Method 40 (Compound XXXVII)
To a solution of 2-amino-4-nitrophenol (10 g, 64.9 mmol) in dichloromethane (250 mL) under nitrogen at 0° C. was added pyridine (10.5 mL, 129.9 mmol) followed by butyryl chloride (7.05 mL, 68.2 mmol) over a period of 5 min. After 30 min at 0° C., the solution was left warming up to room temperature for 2 days. The organic layer was washed with aqueous copper sulfate solution and brine. Insoluble material from the aqueous layer was filtered off and washed with water to afford 4.95 g (34%) of the title compound.
1H NMR (DMSO): 11.64 (1H, br), 9.37 (1H, s), 8.95 (1H, d, J 2.8 Hz), 7.89 (1H, dd, J 8.9 2.8 Hz), 7.02 (1H, d, J 8.9 Hz), 2.43 (2H, t, J 7.4 Hz), 1.67-1.55 (2H, m), 0.92 (3H, t, J 7.5 Hz)
Method 41 (Compound XXXVIII)
To a solution of sodium hydride (220 mg, 5.58 mmol) in dry acetonitrile (40 mL) at 0° C. under nitrogen was added a solution of N-(2-hydroxy-5-nitrophenyl)butyramide (1 g, 4.46 mmol) in dry acetonitrile (90 mL). The solution was then stirred at 0° C. for 30 min. Trifluoromethanesulfonic anhydride (825 μL, 4.90 mmol) was added dropwise at 0° C. over a period of 10 min. After 3 h at 0° C., the solution was stirred at room temperature for 3 h. Water was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was then washed with dilute aqueous hydrochloric acid, aqueous sodium bicarbonate and brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting oil was purified by column chromatography eluting using a gradient (hexanes to ethyl acetate/hexanes 25:75 v/v) to afford 860 mg (54%) of the title compound.
1H NMR (CDCl3): 9.37 (1H, d, J 2.8 Hz), 8.09 (1H, dd, J 9.1 2.8 Hz), 7.53 (2H, d, J 9.1 Hz), 2.50 (2H, t, J 7.6 Hz), 1.91-1.78 (2H, m), 1.09 (3H, t, J 7.5 Hz)
Method 42 (Compound XXXIX)
To a solution of 2-butyramido-4-nitrophenyl trifluoromethanesulfonate (860 mg, 2.42 mmol) in dry acetonitrile (30 mL) under nitrogen was added tetrabutylammonium iodide (1.34 g, 3.62 mmol), tetrakis(triphenylphosphine)palladium(0) (280 mg, 0.24 mmol) and copper iodide (140 mg, 0.72 mmol). Triethylamine (6 mL) was then added, followed by phenyl acetylene (530 μL, 4.83 mmol). The resulting solution was stirred at room temperature for 2 h. Ammonium chloride was then added to quench the reaction, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting using a gradient (hexanes to ethyl acetate) to afford 580 mg (78%) of the title compound.
1H NMR (DMSO): 9.81 (1H, s), 8.74 (1H, d, J 2.3 Hz), 8.01 (1H, dd, J 8.6 2.4 Hz), 7.83 (1H, d, J 8.6 Hz), 7.70-7.67 (2H, m), 7.52-7.49 (3H, m), 1.73-1.61 (2H, m), 0.96 (3H, t, J 7.5 Hz)
Method 43 (Compound XLa)
To a solution of N-(5-nitro-2-(phenylethynyl)phenyl)butyramide (580 mg, 1.88 mmol) in 1-Methyl-2-pyrrolidinone (20 mL) under nitrogen was added potassium tert-butoxide (243 mg, 2.16 mmol). The resulting solution was heated at 70° C. for 6 h, and then left at room temperature for 16 h. Water was added and the aqueous layer was extracted several times with ethyl acetate. The combined organic layers were washed 10 times with water, 3 times with brine, dried over anhydrous MgSO4 and evaporated. The resulting material was purified by column chromatography eluting with ethyl acetate/hexanes 15:85 v/v to afford 175 mg (39%) of the title compound.
1H NMR (DMSO): 12.35 (1H, s), 8.30 (1H, d, J 2.1 Hz), 7.97-7.90 (3H, m), 7.73 (1H, d, J 8.9 Hz), 7.57-7.52 (2H, m), 7.47-7.42 (1H, m), 7.17 (1H, dd, J 2.0 0.8 Hz)
Method 44 (Compound XLb)
To a solution of 6-nitro-2-phenyl-1H-indole (106 mg, 0.44 mmol) and 18-Crown-6 (130 mg, 0.49 mmol) in anhydrous tetrahydrofuran (2 mL) at room temperature was added potassium tert-butoxide (55 mg, 0.49 mmol) followed by methyl iodide (31 μL, 0.49 mmol). The solution was stirred at room temperature for 30 min. Tetrahydrofuran was removed in vacuo. Ethyl acetate was added, and the organic layer was washed with water and then brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated to afford 110 mg (98%) of the title compound.
1H NMR (DMSO): 8.60 (1H, d, J 2.1 Hz), 8.03 (1H, dd, J 8.8 2.1 Hz), 7.82 (1H, d, J 8.7 Hz), 7.74-7.71 (2H, m), 7.67-7.57 (3H, m), 6.87 (1H, d, J 0.8 Hz), 3.95 (3H, s)
Method 45 (Compound XLI)
6-Nitro-2-phenyl-1H-indole (175 mg, 0.73 mmol), ammonium chloride (80 mg, 1.47 mmol) and iron powder (205 mg, 3.68 mmol) were suspended in ethanol/water (4 mL/2 mL) and heated at 70° C. for 2 h. After cooling, the solution was filtrated through a pad of Celite®, which was washed with ethanol. The organic layer was evaporated into vacuo to obtain a solid, which was purified by column chromatography eluting using a gradient (ethyl acetate/hexanes 10:90 v/v to ethyl acetate/hexanes 50:50 v/v) to afford 54 mg (35%) of the title compound.
1H NMR (DMSO): 10.88 (1H, s), 7.76-7.72 (2H, m), 7.39 (2H, t, J 7.9 Hz), 7.23-7.16 (2H, m), 6.67 (1H, dd, J 2.0 0.7 Hz), 6.59-6.57 (1H, m), 6.39 (1H, dd, J 8.4 2.0 Hz), 4.82 (2H, s)
Method 46 (Compounds XLII)
To a solution of 2-phenyl-1H-indol-6-amine (54 mg, 0.26 mmol) in pyridine (2 mL) at room temperature was added isobutyryl chloride (30 μL, 0.29 mmol). The resulting mixture was stirred at room temperature for 2 days. When water was added, a precipitate was formed. This solid was recrystallised from hot ethyl acetate to afford 15 mg (21%) of the title compound (LCMS RT=6.27 min, MH+ 279.0)
1H NMR (DMSO): 11.40 (1H, s), 9.74 (1H, s), 8.02 (1H, s), 7.82 (2H, d, J 7.5 Hz), 7.47-7.40 (3H, m), 7.28 (1H, t, J 7.3 Hz), 7.07 (1H, dd, J 8.5 1.6 Hz), 6.83 (1H, d, J 1.1 Hz), 2.67-2.60 (1H, m), 1.13 (6H, d, J 6.7 Hz)
The compound below was prepared following the same general method.
LCMS RT=6.66 min, MH+ 293.2; 1H NMR (DMSO): 9.83 (1H, s), 8.02 (1H, s), 7.61-7.39 (6H, m), 7.13 (1H, dd, J 8.5 1.7 Hz), 6.50 (1H, d, J 0.5 Hz), 3.69 (3H, s), 2.69-2.60 (1H, m), 1.13 (6H, d, J 6.8 Hz)
Method 47 (Compound XLIIIa)
A solution of 2-iodo-4-nitrophenol (500 mg, 1.89 mmol), prolinol (573 mg, 5.66 mmol), palladium on carbon (60 mg, 0.06 mmol), triphenylphosphine (59.4 mg, 0.226 mmol) and copper iodide (22 mg, 0.113 mmol) in water (6 mL) was stirred for 1 h at room temperature. Ethynylbenzene (482 mg, 4.72 mmol) was slowly added, and the resulting mixture was heated at 80° C. for 3 h. After cooling, ethyl acetate was added, and the mixture was passed through a pad of Celite®. The filtrate was washed with water; the combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting material was purified by column chromatography eluting with ethyl acetate/hexanes 1:40 v/v to afford 134 mg (30%) of the title compound.
1H NMR (DMSO): 8.62 (1H, d, J 2.4 Hz), 8.23 (1H, dd, J 9.1 2.5 Hz), 8.00-7.96 (2H, m), 7.89 (1H, d, J 9.0 Hz), 7.66 (1H, d, J 0.4 Hz), 7.60-7.46 (3H, m)
Method 48 (Compound XLIIIb)
To 5-Nitro-2-phenylbenzofuran (250 mg, 1.04 mmol) in ethanol/water 2:1 v/v (12 mL) at 80° C. was added ammonium chloride (112 mg, 2.09 mmol) and iron powder (292 mg, 5.23 mmol). The resulting mixture was heated at 80° C. for 4 h. After cooling, the solution was filtrated through a pad of Celite®, which was washed with ethanol. The organic layer was evaporated into vacuo to obtain a solid, which was then taken up in ethyl acetate and washed with water. The combined organic layers were dried over anhydrous MgSO4 and evaporated to afford 211 mg (96%) of the title compound.
1H NMR (DMSO): 7.87-7.83 (2H, m), 7.50-7.44 (2H, m), 7.40-7.34 (1H, m), 7.28 (1H, d, J 8.7 Hz), 7.20 (1H, d, J 0.7 Hz), 6.74 (1H, d, J 2.2 Hz), 6.60 (1H, dd, J 8.7 2.3 Hz), 4.88 (2H, s)
Method 49 (Compounds XLIV)
To a solution of 2-phenylbenzofuran-5-amine (210 mg, 1.00 mmol) in pyridine (5 mL) at room temperature was added isobutyryl chloride (120 μL, 1.10 mmol). The resulting mixture was stirred at room temperature for 16 h. Ethyl acetate was added and the organic layer was washed with saturated aqueous copper sulfate solution followed by saturated aqueous potassium carbonate solution. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting material was purified by column chromatography eluting using a gradient (ethyl acetate/hexanes 1:3 v/v to ethyl acetate/hexanes 1:2 v/v) to afford 134 mg (48%) of the title compound (LCMS RT=6.81 min, MH+ 280.1)
1H NMR (DMSO): 9.87 (1H, s), 8.05 (1H, s), 7.91 (2H, d, J 7.4 Hz), 7.58-7.48 (3H, m), 7.45-7.38 (3H, m), 2.66-2.54 (1H, m), 1.13 (6H, d, J 6.8 Hz)
The compound below was prepared following the same general method.
LCMS RT=7.41 min, MH+ 314.2; 1H NMR (DMSO): 9.88 (1H, s), 8.06 (1H, d, J 1.9 Hz), 7.92 (2H, d, J 8.7 Hz), 7.59-7.53 (3H, m), 7.49 (1H, d, J 0.8 Hz), 7.43 (1H, dd, J 9.0 2.2 Hz), 2.66-2.56 (1H, m), 1.13 (6H, d, J 6.8 Hz)
Method 50 (Compound XLIV)
To 3,3,3-trifluoropropanoic acid (136 mg, 1.06 mmol) in dry dichloromethane (10 mL) was added HATU (468 mg, 1.23 mmol) and diisopropylethylamine (580 μL, 3.35 mmol). The mixture was then stirred at room temperature for 10 min. 2-phenylbenzofuran-5-amine (234 mg, 1.12 mmol) was then added and the resulting mixture was stirred at room temperature for 48 h. Ethyl acetate was added and the organic layer was washed once with saturated aqueous water. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting using a gradient (ethyl acetate/hexanes 1:3 v/v to ethyl acetate/hexanes 1:1 v/v) followed by trituration in ethyl acetate to afford 99.3 mg (28%) of the title compound (LCMS RT=6.62 min)
1H NMR (DMSO): 10.37 (1H, s), 8.01 (1H, d, J 2.0 Hz), 7.92 (2H, dd, J 7.5 1.5 Hz), 7.61 (1H, d, J 8.8 Hz), 7.55-7.41 (4H, m), 7.38 (1H, dd, J 8.9 2.2 Hz), 3.53 (2H, q, J 11.2 Hz)
The compounds listed in Table 2, can be prepared by analogues methods to those described above, or by literature methods known or adapted by the persons skilled in the art.
| Number | Date | Country | Kind |
|---|---|---|---|
| 0602768.4 | Feb 2006 | GB | national |
| 0614690.6 | Jul 2006 | GB | national |
| 0619281.9 | Sep 2006 | GB | national |
| 0623983.4 | Nov 2006 | GB | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/GB2007/050055 | 2/9/2007 | WO | 00 | 11/6/2008 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2007/091106 | 8/16/2007 | WO | A |
| Number | Name | Date | Kind |
|---|---|---|---|
| 3185698 | Koch et al. | May 1965 | A |
| 3993659 | Meyer | Nov 1976 | A |
| 4110246 | Frischkorn et al. | Aug 1978 | A |
| 4245007 | Guglielmetti | Jan 1981 | A |
| 4447350 | Martini et al. | May 1984 | A |
| 4791205 | Schinzel et al. | Dec 1988 | A |
| 4831152 | Itoh et al. | May 1989 | A |
| 5015565 | Wolff | May 1991 | A |
| 5302704 | Adam et al. | Apr 1994 | A |
| 5567843 | Lysenko | Oct 1996 | A |
| 5583178 | Oxman et al. | Dec 1996 | A |
| 5585091 | Pelzer et al. | Dec 1996 | A |
| 5596025 | Oxman et al. | Jan 1997 | A |
| 5645948 | Shi et al. | Jul 1997 | A |
| 5914213 | Grasshoff et al. | Jun 1999 | A |
| 5977101 | Ali et al. | Nov 1999 | A |
| 6004719 | Gaudiana et al. | Dec 1999 | A |
| 6110638 | Boggs et al. | Aug 2000 | A |
| 6177572 | Wang | Jan 2001 | B1 |
| 6222044 | Lysenko | Apr 2001 | B1 |
| 6248311 | Candau | Jun 2001 | B1 |
| 6251373 | Candau | Jun 2001 | B1 |
| 6296835 | Candau | Oct 2001 | B1 |
| 6312822 | Irick et al. | Nov 2001 | B1 |
| 6372736 | Kemp et al. | Apr 2002 | B1 |
| 6436558 | Sato et al. | Aug 2002 | B1 |
| 6541423 | Mayer et al. | Apr 2003 | B1 |
| 6565987 | Irick | May 2003 | B2 |
| 6589915 | Mayer et al. | Jul 2003 | B1 |
| 6716413 | Achilefu et al. | Apr 2004 | B1 |
| 7097888 | Shukla et al. | Aug 2006 | B2 |
| 7147935 | Kamatani et al. | Dec 2006 | B2 |
| 7361678 | Mjalli et al. | Apr 2008 | B2 |
| 8138351 | Wynne et al. | Mar 2012 | B2 |
| 20040082542 | Mjalli et al. | Apr 2004 | A1 |
| 20040214896 | Konno et al. | Oct 2004 | A1 |
| 20040242673 | Lockhart et al. | Dec 2004 | A1 |
| 20050026811 | Mjalli et al. | Feb 2005 | A1 |
| 20050107399 | Boman et al. | May 2005 | A1 |
| 20050113283 | Solow-Cordero et al. | May 2005 | A1 |
| 20050129874 | Shukla et al. | Jun 2005 | A1 |
| 20050260126 | Kudo et al. | Nov 2005 | A1 |
| 20050261298 | Solow-Cordero et al. | Nov 2005 | A1 |
| 20050267093 | Lehmann-Lintz et al. | Dec 2005 | A1 |
| 20060038484 | Noh et al. | Feb 2006 | A1 |
| 20060223849 | Mjalli et al. | Oct 2006 | A1 |
| 20060287344 | Albers et al. | Dec 2006 | A1 |
| 20070032564 | Callant et al. | Feb 2007 | A1 |
| 20070072113 | Taguchi et al. | Mar 2007 | A1 |
| 20070125712 | Little et al. | Jun 2007 | A1 |
| 20070176542 | Ragini et al. | Aug 2007 | A1 |
| 20070178332 | Ragini et al. | Aug 2007 | A1 |
| 20070185176 | Van Gelder et al. | Aug 2007 | A1 |
| 20070267959 | Ragini et al. | Nov 2007 | A1 |
| 20080114022 | Bala et al. | May 2008 | A1 |
| Number | Date | Country |
|---|---|---|
| 1018173 | Sep 1977 | CA |
| 616544 | Apr 1980 | CH |
| 2757389 | Jun 1998 | FR |
| 2818142 | Jun 2002 | FR |
| 2353038 | Feb 2001 | GB |
| 1265259 | Oct 1989 | JP |
| 08015917 | Jan 1996 | JP |
| 08175992 | Jul 1996 | JP |
| 8183771 | Jul 1996 | JP |
| 10002862 | Jan 1998 | JP |
| 11171881 | Jun 1999 | JP |
| 03069292 | May 2000 | JP |
| 2001039034 | Feb 2001 | JP |
| 2001261664 | Sep 2001 | JP |
| 2002047278 | Feb 2002 | JP |
| 2003005356 | Jan 2003 | JP |
| 2004034438 | Feb 2004 | JP |
| 2004250411 | Sep 2004 | JP |
| 2007238540 | Sep 2007 | JP |
| WO 9916761 | Apr 1999 | WO |
| WO0037501 | Jun 2000 | WO |
| WO0158896 | Aug 2001 | WO |
| WO0216333 | Feb 2002 | WO |
| WO03062392 | Jul 2003 | WO |
| WO2004041277 | May 2004 | WO |
| WO2004069394 | Aug 2004 | WO |
| WO2004098494 | Nov 2004 | WO |
| WO2006015959 | Feb 2006 | WO |
| WO2006042391 | Apr 2006 | WO |
| WO2006044503 | Apr 2006 | WO |
| WO2006051410 | May 2006 | WO |
| WO2006069155 | Jun 2006 | WO |
| WO2006091862 | Aug 2006 | WO |
| WO2006094235 | Sep 2006 | WO |
| WO 2006094236 | Sep 2006 | WO |
| WO2006124780 | Nov 2006 | WO |
| WO2007017602 | Feb 2007 | WO |
| WO2007019344 | Feb 2007 | WO |
| WO 2007019417 | Feb 2007 | WO |
| WO2007052985 | May 2007 | WO |
| WO2007058990 | May 2007 | WO |
| WO2007091106 | Aug 2007 | WO |
| WO2007096362 | Aug 2007 | WO |
| WO2007146712 | Dec 2007 | WO |
| Entry |
|---|
| Verma et al. A comparison between two polarizability parameters in chemical-biological interactions. Bioorg. Med. Chem. 13(7) 2355-72 (2005). |
| Paget et al. Heterocyclic substituted ureas. II. Immunosuppressive and antiviral activity of benzothiazolyl- and benzoxazolylureas. J. Med. Chem. 12(6), pp. 1016-1018 (1969). |
| Pinar et al. Some fused heterocyclic compounds as eukaryotic topoisomerase II inhibitors. Biochem. Biophys. Res. Comm. 317(2), 670-674 (2004). |
| Pottorf et al. Parallel synthesis of benzoxazoles via microwave-assisted dielectric heating. Tetrahedron Lett. 44(1), 175-178 (2003). |
| Allamand, et al., Human Molecular Genetics, 2000, 9(16), 2459-67. |
| Bulfield, et al., Proc. Natl. Acad. Sci. USA, 1984, 81, 1189-92. |
| Khurana, et al., Nature Reviews Drug Discovery, 2003, 2, 379-90. |
| Nicolaus, Decision Making in Drug Research, 1983, pp. 173-186, Raven Press, New York. |
| Perkins, et al., Neuromuscular Disorders, 2002, 12, S78-S89. |
| International Search Report, mailed Jan. 15, 2008, International Application No. PCT/GB2007/050055. |
| Written Opinion of the International Search Authority, mailed Jan. 15, 2008, International Application No. PCT/GB2007/050055. |
| International Preliminary Report on Patentability, issued Aug. 12, 2008, International Application No. PCT/GB2007/050055. |
| Caira, “Crystalline Polymorphism of Organic Compounds,” in, Topics in Current Chemistry, Springer Verlag, Berlin Heidelberg, vol. 198, pp. 163-208 (1998). |
| Deluca, et al., Tetrahedron, vol. 53, No. 2, pp. 457-464 (1997). |
| Kumar, et al., Synlett, No. 9, pp. 1401-1404 (2005). |
| Pottorf, et al., Tetrahedron Letters, vol. 44, No. 1, pp. 175-178 (2003). |
| Razavi, et al., Angew. Chem. Int. Ed., vol. 42, pp. 2758-2761 (2003). |
| Number | Date | Country | |
|---|---|---|---|
| 20090075938 A1 | Mar 2009 | US |
