# Patent

## Title
Quinoline derivatives as phosphodiesterase inhibitors

## Abstract

There are provided according to the invention novel compounds of formula (I)




or pharmaceutically acceptable salts thereof, wherein R1, R2, R19, R20, and R34 are as described in the specification, processes for preparing them, formulations containing them and their use in therapy for the treatment of inflammatory diseases.

## Background
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is filed pursuant to 35 U.S.C. § 371 as a United States National Phase Application of International Application No. PCT/EP2004/005494 filed May 19, 2004, which claims priority from GB 0311688.6 filed May 21, 2003 and GB 0326187.2 filed Nov. 10, 2003.
FIELD OF THE INVENTION
The present invention relates to quinoline compounds, processes for their preparation, intermediates usable in these processes, and pharmaceutical compositions containing the compounds. The invention also relates to the use of the quinoline compounds in therapy, for example as inhibitors of phosphodiesterases and/or for the treatment and/or prophylaxis of inflammatory and/or allergic diseases such as chronic obstructive pulmonary disease (COPD), asthma, rheumatoid arthritis or allergic rhinitis.
BACKGROUND OF THE INVENTION
WO 02/20489 A2 (Bristol-Myers-Squibb Company) discloses 4-aminoquinoline derivatives wherein the 4-amino group NR4R5 may represent an acyclic amino group wherein R4 and R5 may each independently represent hydrogen, alkyl, cycloalkyl, aryl, heteroaryl etc.; NR4R5 may alternatively represent an aliphatic heterocyclic group. The compounds are disclosed as inhibitors of cGMP phosphodiesterase, especially type 5 (PDE5).
EP 0 480 052 (Otsuka Pharmaceutical Co. Ltd.) discloses 4-aminoquinoline-3-carboxamides wherein the 4-amino group NHR4 may represent an amino group wherein R4 represents phenyl, tetrahydronaphthyl or naphthyl, optionally substituted with alkyl, halogen, alkoxy etc.; and the 3-carboxamide group CONR2R3 represents a primary, secondary or tertiary carboxamide group. The compounds are disclosed as inhibitors of gastric acid secretion, and as cytoprotective agents; inhibition of the ATPase activated by H+ and K+at the gastric wall cells is also disclosed.
It is desirable to find new compounds which bind to, and preferably inhibit, phosphodiesterase type IV (PDE4).
SUMMARY OF THE INVENTION
According to the invention there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof:




wherein:

R1 is
C1-6 alkyl;
C3-7cycloalkyl or C3-7cycloalkyl(C1-4alkyl)- wherein the C3-7cycloalkyl is optionally substituted by one or more substituents selected from ═O and OH;
C4-7cycloalkyl fused to an aryl ring;
Aryl or aryl(C1-6alkyl)- wherein the aryl is optionally substituted by one or more substituents selected from C1-6alkyl, C1-6alkylCONR6—, C1-6alkylCO—, halogen, —CF3, —(CH2)mOH, —OCF3, C1-6alkoxy-, C1-6alkoxy(C1-4alkyl)-, C1-6alkoxyC2-6alkoxy-, C1-6alkoxycarbonyl, —CN, R4R5NCO, R7R6N—, R9R10NCONR11—, HO(CH2)2-6O—, R12R13NSO2(CH2)m-, (4-morpholinyl)C2-8alkoxy, —NR14SO2C1-6alkyl, aryloxy, heteroaryl (optionally substituted by C1-6alkyl), CO2H, R21R22N(C1-4alkyl)-, C1-6alkoxyCONR23(CH2)m—, aryl(optionally substituted by C1-6alkyl);
Aryl fused to a C4-7cycloalkyl ring, wherein the cycloalkyl ring is optionally substituted by one or more ═O;
Aryl fused to a heterocyclyl ring, wherein the heterocyclyl ring is optionally substituted by one or more substituents selected from ═O, —COC1-4alkyl, C1-4alkyl;
Heteroaryl or heteroaryl(C1-6alkyl)- wherein the heteroaryl is optionally substituted by one or more substituents selected from: C1-6alkyl, aryl(C1-4alkyl), C1-6alkoxy, halogen, C1-6alkoxyCO; or
Heterocyclyl optionally fused to an aryl or heteroaryl ring;
R2 is hydrogen or C1-6alkyl;
R34 is hydrogen or a group of formula:




wherein R3 is

C1-6alkyl optionally substituted by one or more substituents selected from —OH, —NR16COR15, —NR17R18, —CO2R24, C1-6alkoxyCONR25—, —CONR26R27, C1-6alkoxy-, C1-6alkylSO2NR33-, or a group having one of the following formulae;




C3-7cycloalkyl;

Aryl or aryl(C1-6alkyl)- wherein the aryl is optionally substituted by one or more substituents selected from C1-6alkyl-, halogen-, C1-6alkoxy-, —CO2R28, —CH2CO2H, —OH, aryl(optionally substituted by a C1-6 alkoxy group), heteroaryl, —CONR29R30, C3-7cycloalkoxy, C3-7cycloalkyl(C1-6alkoxy)-, —CF3;
Heteroaryl or heteroaryl(C1-6alkyl)- wherein the heteroaryl is optionally substituted by one or more C1-6alkyl or —CONR29R30 groups; or
Heterocyclyl which is optionally substituted by one of more substituents selected from C1-6alkyl-, C1-6alkylCO—, C3-7cycloalkylCO—, heteroarylCO- (optionally substituted by one or more C1-4alkyl- groups), C1-6alkoxyCO—, arylCO—, R31R32NCO—, C1-6alkylSO2—, arylSO2, -heteroarylSO2 (optionally substituted by one or more C1-4alkyl or C1-4alkylCONH— groups) The heterocyclyl is linked to the S(═O)n moiety through a carbon atom.
m is 0-6
n is 0, 1 or 2;
R19 is hydrogen, C1-6alkyl or a group of formula:




R20 is hydrogen, C1-6alkyl, halogen or C1-6alkoxy;
R4-18, R21-25, R28 and R31-33 all independently represent H, C1-6 alkyl;
R26 and R27 independently represent H, C1-6 alkyl, C3-7cycloalkyl or heterocyclyl;
R29 and R30 independently represent H, C1-6alkyl optionally substituted by OH;
R7 and R8 together with the nitrogen atom to which they are attached may form a heterocyclyl ring;
R9 and R10 together with the nitrogen atom to which they are attached may form a heterocyclyl ring;
R17 and R18 together with the nitrogen atom to which they are attached may form a heterocyclyl ring such as morpholine;
R21 and R22 together with the nitrogen atom to which they are attached may form a heterocyclyl ring;
R26 and R27 together with the nitrogen atom to which they are attached may form a heterocyclyl ring;
R29 and R30 together with the nitrogen atom to which they are attached may form a heterocyclyl ring such as morpholine;
R31 and R32 together with the nitrogen atom to which they are attached may form a heterocyclyl ring;
with the proviso that R34 and R19 cannot both represent R3S(═O)n—.


DETAILED DESCRIPTION
As used herein, the term “alkyl” refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms. For example, C1-6alkyl means a straight or branched alkyl chain containing at least 1, and at most 6, carbon atoms. Examples of “alkyl” as used herein include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, t-butyl, n-pentyl and n-hexyl. A C1-4alkyl group is preferred, for example methyl, ethyl or isopropyl. The said alkyl groups may be optionally substituted with one or more fluorine atoms, for example, trifluoromethyl.
As used herein, the term “alkoxy” refers to a straight or branched chain alkoxy group, for example, methoxy, ethoxy, prop-1-oxy, prop-2-oxy, but-1-oxy, but-2-oxy, 2-methylprop-1-oxy, 2-methylprop-2-oxy, pentoxy or hexyloxy. A C1-4alkoxy group is preferred, for example methoxy or ethoxy. The said alkoxy groups may be optionally substituted with one or more fluorine atoms, for example, trifluoromethoxy.
As used herein, the term “cycloalkyl” refers to a non-aromatic hydrocarbon ring containing the specified number of carbon atoms. For example, C3-7cycloalkyl means a non-aromatic ring containing at least three, and at most seven, ring carbon atoms. Examples of “cycloalkyl” as used herein include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. A C3-6-cycloalkyl group is preferred, for example cyclopentyl or cyclohexyl.
When used herein, the term “aryl” refers to, unless otherwise defined, a mono- or bicyclic carbocyclic aromatic ring system containing up to 10 carbon atoms in the ring system, for instance phenyl or naphthyl, optionally fused to a C4-7cycloalkyl or heterocyclyl ring.
As used herein, the terms “heteroaryl ring” and “heteroaryl” refer to, unless otherwise defined, a monocyclic five- to seven-membered heterocyclic aromatic ring containing one or more heteroatoms selected from oxygen, nitrogen and sulfur. In a particular aspect such a ring contains 1-3 heteroatoms. Preferably, the heteroaryl ring has five or six ring atoms. Examples of heteroaryl rings include, but are not limited to, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl. The terms “heteroaryl ring” and “heteroaryl” also refer to fused bicyclic heterocyclic aromatic ring systems containing at least one heteroatom selected from oxygen, nitrogen and sulfur, preferably from 1-4 heteroatoms, more preferably from 1 to 3 heteroatoms. Preferably, the fused rings each independently have five or six ring atoms. Examples of fused aromatic rings include, but are not limited to, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, indolyl, indazolyl, pyrrolopyridinyj, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl and benzothiadiazolyl. The heteroaryl may attach to the rest of the molecule through any atom with a free valence.
As used herein, the term “heterocyclyl” refers to a monocyclic three- to seven-membered saturated or non-aromatic, unsaturated ring containing at least one heteroatom selected from oxygen, nitrogen and sulfur. In a particular aspect such a ring contains 1 or 2 heteroatoms. Preferably, the heterocyclyl ring has five or six ring atoms. Examples of heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, imidazolidinyl, pyrazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, diazepinyl, azepinyl, tetrahydrofuranyl, tetrahydropyranyl, and 1,4-dioxanyl.
As used herein, the terms “halogen” or “halo” refer to fluorine, chlorine, bromine and iodine. Preferred halogens are fluorine, chlorine and bromine. Particularly preferred halogens are fluorine and chlorine.
As used herein, the term “optionally” means that the subsequently described event(s) may or may not occur, and includes both event(s) which occur and events that do not occur.
As used herein, the term “substituted” refers to substitution with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated. Where one or more substituents are referred to, this will refer for instance to 1 to 4 substituents, and preferably to 1 or 2 substituents.
In one embodiment, R1 is selected from:
C3-7 cycloalkyl, in particular cyclohexyl;
Aryl optionally substituted by one or more substituents selected from: C1-6alkyl, halogen, C1-6alkoxy, C1-6alkoxy(C1-4alkyl)-, —CN, —(CH2)mOH, —CF3, C1-6alkoxyC2-6alkoxy-, R4R5NCO, C1-6alkylCONR8—, R7R8N—, C1-6-alkoxycarbonyl, HO(CH2)2-6O—, C1-6alkylCO—, heteroaryl (optionally substituted by C1-6alkyl) particularly oxazolyl, pyrazolyl or 1,2,4oxadiazolyl;
Aryl(C1-2alkyl) wherein the aryl is optionally substituted by —OH;
Aryl fused to a C5-8 cycloalkyl ring wherein the cycloalkyl is optionally substituted by (═O);
Aryl fused to a heterocyclyl ring, wherein the heterocyclyl ring is optionally substituted by one or more substituents selected from ═O, C1-4alkyl;
Heteroaryl optionally substituted by one or more C1-6alkyl, halogen (in particular chlorine or fluorine) or C1-6alkoxy groups in particular wherein heteroaryl represents benzothiazolyl, benzisoxazolyl, benzimidazolyl, indazolyl, pyridyl and pyrazolyl;
Heteroaryl(C1-2alkyl) wherein the heteroaryl is optionally substituted by one or more C1-6alkyl groups, in particular wherein heteroaryl represents pyridyl, pyrazolyl; or
Heterocyclyl, in particular tetrahydropyranyl.
Examples of suitable aryl fused to a C5-6 cycloalkyl ring include:




Examples of suitable aryl fused to heterocyclyl rings include:




The following aryl fused to heterocyclyl rings are further embodiments:




In a further embodiment, R1 is selected from:
Aryl optionally substituted by one or more substituents selected from: methyl, ethyl, fluorine, chlorine, —CN, —CH2OH, —OMe, —OH, —NMe2, —O(CH2)2OH, —CF3, —COMe, 1,2,4-oxadiazolyl substituted by methyl; particular substitued aryl groups include; 3-(methyloxy)phenyl, 3-methylphenyl, 3-cyanophenyl, 3-fluorophenyl, 3-chlorophenyl, 4-fluoro-3-(methyloxy)phenyl, 3-acetylphenyl, 4-hydroxy-3-(methyloxy)phenyl, 2-fluoro-3-chlorophenyl, 2,3-difluorophenyl, 3,5-difluorophenyl;
Aryl fused to a cyclohexane or cyclopentane ring, wherein the cyclopentane ring is optionally substituted by (═O); in particular the following fused systems:




Aryl fused to a heterocyclyl ring, optionally substituted by methyl; in particular the following heterocyclyl ring fused aryl systems:




Heteroaryl optionally substituted by one or more methyl, ethyl, flourine, chlorine or methoxy groups; in particular a pyridyl, benzimidazolyl, pyrazolyl or indazolyl group optionally substituted by one or more methyl, ethyl, flourine, chlorine, or methoxy groups;preferably 1-methyl-1H-benzimidazolyl-6-yl, 1-methyl-1H-indazol-6-yl, 5-(methyloxy)-3-pyridinyl, 3-pyridinyl, 1-ethyl-1H-pyrazol-5-yl, 5-methyl-3-pyridinyl, 1,3-benzothiazol-6-yl, 5-fluoro-3-pyridinyl, or 5-chloro-3-pyridinyl.
In one embodiment, R2 is hydrogen.
In one embodiment R3 is selected from:
C1-6 alkyl which is optionally substituted by one or more substituents selected from —NR16COR15; OH—, C1-6alkoxyCONR25—, —CONR28R27, —NH2, —NR17R18, —CO2R24, C1-6alkoxy; or a group having one of the following formulae:




C3-7cycloalkyl;
Aryl optionally substituted by one or more substituents selected from C1-6alkyl-, halogen-, C1-6alkoxy-, —CO2R28, —OH, —CONR29R30, C3-7cycloalkoxy, C3-7cycloalkyl(C1-6alkoxy);
Aryl(C1alkyl) wherein the aryl is optionally substituted by one or more C1-6alkoxy groups;
Heteroaryl or heteroaryl(C1-6alkyl) which is optionally substituted by one or more C1-6alkyl or —CONR29R30 groups; or
Heterocyclyl which is optionally substituted by one or more substituents selected from C1-6alkyl-, C1-6alkylCO—, C3-7cycloalkylCO—, heteroarylCO— (optionally substituted by one or more C1-4alkyl- groups), C1-6alkoxyCO—, arylCO—, C1-6alkylSO2—.
In an alternative embodiment R3 is selected from:
methyl, ethyl, n-propyl, tert-butyl, isopropyl, MeCONH(CH2)2—, Me2NCO(CH2)2—;
Cyclopentyl;
Aryl optionally substituted by one or more methoxy, methyl, —CONH2 or —CONMe2 groups; in particular: 4-(methyloxy)phenyl, phenyl, 3-[(dimethylamino)carbonyl]phenyl, 4-methylphenyl, 3-[(methyloxy)carbonyl]phenyl, 3,4-bis(methyloxy)phenyl, 3,4,5-tris(methyloxy)phenyl, 3-(ethyloxy)phenyl;
Heterocyclyl which is optionally substituted by one of more substituents selected from MeCO—, cyclopropylCO, 2-furylCO—, or MeSO2—; in particular wherein the heterocyclyl group is tetrahydropyran-4-yl; a tetrahydrofuran-3-yl; or piperidinyl substituted by one or more substituents selected from MeCO—, cyclopropylCO, 2-furylCO—, or MeSO2—, especially 1-acetyl-4-piperidinyl, 1-(2-furanylcarbonyl)-4-piperidinyl, 1-(cyclopropylcarbonyl)-4-piperidinyl;
Heteroaryl wherein the heteroaryl represents 3-pyridyl which is optionally substituted by CONMe2, especially 5-[(dimethylamino)carbonyl]-3-pyridinyl.
In one embodiment R9 and R10 together with the nitrogen to which they are attached represent 4-morpholinyl.
In one embodiment R4, R5, R6, R7, R8, R11-16, and R21-25 and R28-33 are independently selected from hydrogen and methyl.
In one embodiment R26 and R27 are independently selected from hydrogen, methyl, cyclopropyl, or 4-tetrahydropyranyl; or R26 and R27 together with the nitrogen to which they are attached form a heterocyclyl ring, in particular pyrrolidinyl or morpholinyl.
In one embodiment R19 is hydrogen, C1-6alkyl or MeSO2—. In a further embodiment R19 is hydrogen or methyl, especially hydrogen.
In one embodiment R20 is hydrogen, halogen or C1-6alkyl. Alternatively R20 is hydrogen, chlorine, fluorine, methyl or ethyl. In a further embodiment R20 is methyl, ethyl or chlorine.
In one embodiment m is 0 or 1.
In one embodiment n is 1 or 2, especially 2.
In one embodiment R34 represents a group of formula:




It is to be understood that the present invention covers all combinations of substituent groups referred to herein above.
It is to be understood that the present invention covers all combinations of particular and preferred groups described herein above.
Particular compounds according to the invention include those mentioned in the examples and their pharmaceutically acceptable salts. Specific examples which may be mentioned include:
Example 7: 4-[(3-methylphenyl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide,
Example 8: 4-[(3-cyanophenyl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide,
Example 20: 4-(2,3-dihydro-1-benzofuran-4-ylamino)-6-(methylsulfonyl)-3-quinolinecarboxamide,
Example 27: 4-{[3-(methyloxy)phenyl]amino}-6-(methylsulfonyl)-3-quinolinecarboxamide,
Example 32: 4-{[4-fluoro-3-(methyloxy)phenyl]amino}-6-(methylsulfonyl)-3-quinolinecarboxamide,
Example 35: 4-[(3-chlorophenyl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide,
Example 43: 4-(1,3-benzothiazol-6-ylamino)-6-(phenylsulfonyl)-3-quinolinecarboxamide,
Example 45: 4-[(1-methyl-1H-benzimidazol-6-yl)amino]-6-(phenylsulfonyl)-3-quinolinecarboxamide,
Example 52: 4-[(3-cyanophenyl)amino]-6-(phenylsulfonyl)-3-quinolinecarboxamide,
Example 66: 4-(2,3-dihydro-1-benzofuran-4-ylamino)-6-(phenylsulfonyl)-3-quinolinecarboxamide,
Example 74: 4-{[3-(methyloxy)phenyl]amino}-6-(phenylsulfonyl)-3-quinolinecarboxamide,
Example 89: 6-(cyclopentylsulfonyl)-4-[(3-fluorophenyl)amino]-3-quinolinecarboxamide,
Example 128: 4-{[3-(methyloxy)phenyl]amino}-6-{[4-(methyloxy)phenyl]sulfonyl}-3-quinolinecarboxamide,
Example 129: 6-[(1,1-dimethylethyl)sulfonyl]-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide,
Example 130: 6-{[2-(acetylamino)ethyl]sulfonyl}-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide.
Example 133: 6-[(1,1-dimethylethyl)thio]-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide,
Example 135: 6-{[2-(acetylamino)ethyl]thio}-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide,
Example 163: 4-[(1-methyl-1H-indazol-6-yl)amino]-6-(phenylsulfonyl)-3-quinolinecarboxamide,
Example 167: 4-{[4-hydroxy-3-(methyloxy)phenyl]amino}-6-(phenylsulfonyl)-3-quinolinecarboxamide,
Example 174: 4-[(3-acetylphenyl)amino]-6-(phenylsulfonyl)-3-quinolinecarboxamide,
Example 184: 8-methyl-4-{[3-(methyloxy)phenyl]amino}-6-(phenylsulfonyl)-3-quinolinecarboxamide,
Example 185: 4-{[4-fluoro-3-(methyloxy)phenyl]amino}-8-methyl-6-(phenylsulfonyl)-3-quinolinecarboxamide,
Example 186: 7-methyl-4-{[3-(methyloxy)phenyl]amino}-6-(methylsulfonyl)-3-quinolinecarboxamide,
Example 265: 8-methyl-4-{[3-(methyloxy)phenyl]amino}-6-{[4-(methyloxy)phenyl]sulfonyl}-3-quinolinecarboxamide,
Example 266: 4-(2,3-dihydro-1-benzofuran-4-ylamino)-8-methyl-6-{[4-(methyloxy)phenyl]sulfonyl}-3-quinolinecarboxamide,
Example 267: 4-[(3-acetylphenyl)amino]-8-methyl-6-{[4-(methyloxy)phenyl]sulfonyl}-3-quinolinecarboxamide
Example 268: 8-methyl-4-[(1-methyl-1H-indazol-6-yl)amino]-6-{[4-(methyloxy)phenyl]sulfonyl}-3-quinolinecarboxamide
Example 269: 4-(2,3-dihydro-1,4-benzodioxin-5-ylamino)-8-methyl-6-{[4-(methyloxy)phenyl]sulfonyl}-3-quinolinecarboxamide
Example 270: 4-[(3-chlorophenyl)amino]-8-methyl-6-{[4-(methyloxy)phenyl]sulfonyl}-3-quinolinecarboxamide
Example 271: 4-[(3-cyanophenyl)amino]-8-methyl-6-{[4-(methyloxy)phenyl]sulfonyl}-3-quinolinecarboxamide
Example 272: 4-(1,3-benzothiazol-6-ylamino)-8-methyl-6-{[4-(methyloxy)phenyl]sulfonyl}-3-quinolinecarboxamide
Example 273: 4-[(3-fluorophenyl)amino]-8-methyl-6-{[4-(methyloxy)phenyl]sulfonyl}-3-quinolinecarboxamide
Example 285: 4-(2,3-dihydro-1-benzofuran-4-ylamino)-8-methyl-6-[(4-methylphenyl)sulfonyl]-3-quinolinecarboxamide
Example 287: 8-methyl-4-[(1-methyl-1H-indazol-6-yl)amino]-6-[(4-methylphenyl)sulfonyl]-3-quinolinecarboxamide
Example 292: 8-methyl-4-{[3-(methyloxy)phenyl]amino}-6-[(4-methylphenyl)sulfonyl]-3-quinolinecarboxamide
Example 294: 4-{[4-fluoro-3-(methyloxy)phenyl]amino}-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide
Example 303: 8-methyl-4-[(1-methyl-1H-indazol-6-yl)amino]-6-(phenylsulfonyl)-3-quinolinecarboxamide
Example 307: 4-(2,3-dihydro-1-benzofuran-4-ylamino)-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide
Example 308: 8-methyl-6-(methylsulfonyl)-4-(3-pyridinylamino)-3-quinolinecarboxamide
Example 309: 8-methyl-4-[(1-methyl-1H-indazol-6-yl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide
Example 311: 4-[(3-fluorophenyl)amino]-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide
Example 312: 4-[(3-cyanophenyl)amino]-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide
Example 315: 4-[(1-ethyl-1H-pyrazol-5-yl)amino]-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide
Example 316: 8-methyl-4-{[5-(methyloxy)-3-pyridinyl]amino}-6-(methylsulfonyl)-3-quinolinecarboxamide
Example 317: 8-methyl-4-[(5-methyl-3-pyridinyl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide
Example 369: 8-chloro-4-[(3-methylphenyl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide
Example 370: 8-chloro-4-{[4-fluoro-3-(methyloxy)phenyl]amino}-6-(methylsulfonyl)-3-quinolinecarboxamide
Example 371: 8-chloro-4-(2,3-dihydro-1-benzofuran-4-ylamino)-6-(methylsulfonyl)-3-quinolinecarboxamide
Example 372: 8-chloro-4-[(3-cyanophenyl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide
Example 373: 8-chloro-4-[(3-fluorophenyl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide
Example 374: 8-chloro-4-[(1-methyl-1H-indazol-6-yl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide
Example 379: methyl 3-[(3-(aminocarbonyl)-8-methyl-4-{[3-(methyloxy)phenyl]amino}-6-quinolinyl)sulfonyl]benzoate
Example 380: 6-{[3,4-bis(methyloxy)phenyl]sulfonyl}-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide
Example 381: 8-methyl-4-{[3-(methyloxy)phenyl]amino}-6-{[3,4,5-tris(methyloxy)phenyl]sulfonyl}-3-quinolinecarboxamide hydrochloride
Example 382: 6-{[3,4-bis(methyloxy)phenyl]sulfonyl}-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide
Example 383: 6-{[3-(ethyloxy)phenyl]sulfonyl}-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide
Example 392: 6-{[2-(acetylamino)ethyl]sulfonyl}-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide,
Example 399: 6-({3-[(dimethylamino)carbonyl]phenyl}sulfonyl)-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide,
Example 400: 6-({3-[(dimethylamino)carbonyl]phenyl}sulfonyl)-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide,
Example 408: 4-[(3-cyanophenyl)amino]-6-({3-[(dimethylamino)carbonyl]phenyl}sulfonyl)-8-methyl-3-quinolinecarboxamide,
Example 409: 6-({3-[(dimethylamino)carbonyl]phenyl}sulfonyl)-8-methyl-4-[(1-methyl-1H-benzimidazol-6-yl)amino]-3-quinolinecarboxamide
Example 414: 4-(2,3-dihydro-1-benzofuran-4-ylamino)-6-({3-[(dimethylamino)carbonyl]phenyl}sulfonyl)-8-methyl-3-quinolinecarboxamide
Example 426: 6-[(1-acetyl-4-piperidinyl)sulfonyl]-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide
Example 442: 6-{[1-(2-furanylcarbonyl)-4-piperidinyl]sulfonyl}-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide
Example 443: 4-[(3-cyanophenyl)amino]-6-{[1-(2-furanylcarbonyl)-4-piperidinyl]sulfonyl}-8-methyl-3-quinolinecarboxamide
Example 445: 6-{[1-(cyclopropylcarbonyl)-4-piperidinyl]sulfonyl}-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide
Example 446: 4-(2,3-dihydro-1-benzofuran-4-ylamino)-6-{[1-(2-furanylcarbonyl)-4-piperidinyl]sulfonyl}-8-methyl-3-quinolinecarboxamide
Example 447: 6-{[1-(cyclopropylcarbonyl)-4-piperidinyl]sulfonyl}-4-(2,3-dihydro-1-benzofuran-4-ylamino)-8-methyl-3-quinolinecarboxamide
Example 451: 6-[1-acetyl-4-piperidinyl)sulfonyl]-4-{[4-fluoro-3-(methyloxy)phenyl]amino}-8-methyl-3-quinolinecarboxamide
Example 457: 4-(2,3-dihydro-1-benzofuran-4-ylamino)-8-methyl-6-({2-[(methylsulfonyl)amino]ethyl}sulfonyl)-3-quinolinecarboxamide
Example 459: 6-{[1-(2-furanylcarbonyl)-4-piperidinyl]sulfonyl}-8-methyl-4-[(1-methyl-1H-benzimidazol-6-yl)amino]-3-quinolinecarboxamide
Example 475: 6-{[3-(dimethylamino)-3-oxopropyl]sulfonyl}-4-{[4-fluoro-3-(methyloxy)phenyl]amino}-8-methyl-3-quinolinecarboxamide
Example 500: 4-[(2,3-difluorophenyl)amino]-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide
Example 501: 4-[(3-chloro-2-fluorophenyl)amino]-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide
Example 502: 4-[(3,5-difluorophenyl)amino]-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide
Example 539: 4-[(5-fluoro-3-pyridinyl)amino]-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide
Example 540: 4-[(5-chloro-3-pyridinyl)amino]-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide
Example 546: 6-({5-[(dimethylamino)carbonyl]-3-pyridinyl}sulfonyl)-8-methyl-4-{[3-(methyloxy)phenyl]amino}3-quinolinecarboxamide hydrochloride
Example 579: 8-methyl-6-[(1-methylethyl)sulfonyl]-4-(3-pyridinylamino)-3-quinolinecarboxamide
Example 580; 6-[(1,1-dimethylethyl)sulfonyl]-8-methyl-4-(3-pyridinylamino)-3-quinolinecarboxamide
Example 584: 4-[(1-ethyl-1H-pyrazol-5-yl)amino]-8-methyl-6-[(1-methylethyl)sulfonyl]-3-quinolinecarboxamide
Example 585: 6-[(1,1-dimethylethyl)sulfonyl]-4-[(1-ethyl-1H-pyrazol-5-yl)amino]-8-methyl-3-quinolinecarboxamide
Example 588: 4-(2,3-dihydro-1-benzofuran-4-ylamino)-8-methyl-6-(methylsulfinyl)-3-quinolinecarboxamide
Example 590: 4-[(5-chloro-3-pyridinyl)amino]-6-[(1,1-dimethylethyl)sulfonyl]-3-quinolinecarboxamide
Example 591: 8-ethyl-4-{[4-fluoro-3-(methyloxy)phenyl]amino}-6-(methylsulfonyl)-3-quinolinecarboxamide
Example 592: 8-ethyl-4-[(3-fluorophenyl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide
Example 593: 4-[(3-cyanophenyl)amino]-8-ethyl-6-(methylsulfonyl)-3-quinolinecarboxamide
Example 598: 8-ethyl-4-[(1-methyl-1H-indazol-6-yl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide
Example 599: 4-(2,3-dihydro-1-benzofuran-4-ylamino)-8-ethyl-6-(methylsulfonyl)-3-quinolinecarboxamide
Example 600: 8-ethyl-6-(methylsulfonyl)-4-(3-pyridinylamino)-3-quinolinecarboxamide
Example 624: 4-(2,3-dihydro-1-benzofuran-4-ylamino)-8-fluoro-6-(methylsulfonyl)-3-quinolinecarboxamide
Example 666: 8-chloro-4-[(5-chloro-3-pyridinyl)amino]-6-(ethylsulfonyl)-3-quinolinecarboxamide
Example 667: 8-chloro-4-[(5-chloro-3-pyridinyl)amino]-6-(propylsulfonyl)-3-quinolinecarboxamide
Example 668: 8-chloro-4-[(5-chloro-3-pyridinyl)amino]-6-[(1-methylethyl)sulfonyl]-3-quinolinecarboxamide
Example 669: 8-chloro-4-[(5-chloro-3-pyridinyl)amino]-6-[(1,1-dimethylethyl)sulfonyl]-3-quinolinecarboxamide
Example 670: 4-[(5-chloro-3-pyridinyl)amino]-8-methyl-6-[(1-methylethyl)sulfonyl]-3-quinolinecarboxamide
Example 671: 6-(ethylsulfonyl)-4-[(5-fluoro-3-pyridinyl)amino]-8-methyl-3-quinolinecarboxamide
Example 674: 6-[(1,1-dimethylethyl)sulfonyl]-4-[(5-fluoro-3-pyridinyl)amino]-8-methyl-3-quinolinecarboxamide
Example 676: 8-chloro-4-[(5-fluoro-3-pyridinyl)amino]-6-[(1-methylethyl)sulfonyl]-3-quinolinecarboxamide
Example 677: 8-chloro-6-[(1,1-dimethylethyl)sulfonyl]-4-[(5-fluoro-3-pyridinyl)amino]-3-quinolinecarboxamide
Example 678: 4-[(5-chloro-3-pyridinyl)amino]-6-(ethylsulfonyl)-8-methyl-3-quinolinecarboxamide
Example 679: 4-[(5-chloro-3-pyridinyl)amino]-8-methyl-6-(propylsulfonyl)-3-quinolinecarboxamide
Example 680: 4-[(5-chloro-3-pyridinyl)amino]-6-[(1,1-dimethylethyl)sulfonyl]-8-methyl-3-quinolinecarboxamide
and pharmaceutically acceptable salts thereof.
Preferred compounds include:
8-methyl-4-{[3-(methyloxy)phenyl]amino}-6-{[4-(methyloxy)phenyl]sulfonyl}-3-quinolinecarboxamide,
4-(2,3-dihydro-1-benzofuran-4-ylamino)-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide
8-methyl-4-[(1-methyl-1H-indazol-6-yl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide,
4-[(3-cyanophenyl)amino]-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide,
8-methyl-4-[(5-methyl-3-pyridinyl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide
6-({3-[(dimethylamino)carbonyl]phenyl}sulfonyl)-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide hydrochloride
6-({3-[(dimethylamino)carbonyl]phenyl}sulfonyl)-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide,
4-[(3-cyanophenyl)amino]-6-({3-[(dimethylamino)carbonyl]phenyl}sulfonyl)-8-methyl-3-quinolinecarboxamide,
4(2,3-dihydro-1-benzofuran-4-ylamino)-6-{[1-(2-furanylcarbonyl)-4-piperidinyl]sulfonyl}-8-methyl-3-quinolinecarboxamide
4-(2,3-dihydro-1-benzofuran-4-ylamino)-8-methyl-6-({2-[(methylsulfonyl) amino]ethyl}sulfonyl)-3-quinolinecarboxamide
4-[(3,5-difluorophenyl)amino]-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide
6-({5-[(dimethylamino)carbonyl]-3-pyridinyl}sulfonyl)-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide hydrochloride
4-[(1-ethyl-1H-pyrazol-5-yl)amino]-8-methyl-6-[(1-methylethyl)sulfonyl]-3-quinolinecarboxamide
6-[(1,1-dimethylethyl)sulfonyl]-4-[(5-fluoro-3-pyridinyl)amino]-8-methyl-3-quinolinecarboxamide
8-chloro-6-[(1,1-dimethylethyl)sulfonyl]-4-[(5-fluoro-3-pyridinyl)amino]-3-quinolinecarboxamide
and pharmaceutically acceptable salts thereof.
Salts of the compounds of the present invention are also encompassed within the scope of the invention. Because of their potential use in medicine, the salts of the compounds of formula (I) are preferably pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts can include acid or base addition salts. A pharmaceutically acceptable acid addition salt can be formed by reaction of a compound of formula (I) with a suitable inorganic or organic acid (such as hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, ρ-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid), optionally in a suitable solvent such as an organic solvent, to give the salt which is usually isolated for example by crystallisation and filtration. A pharmaceutically acceptable acid addition salt of a compound of formula (I) can be for example a hydrobromide, hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, acetate, fumarate, citrate, tartrate, benzoate, ρ-toluenesulfonate, methanesulfonate or naphthalenesulfonate salt. A pharmaceutically acceptable base addition salt can be formed by reaction of a compound of formula (I) with a suitable inorganic or organic base, optionally in a suitable solvent such as an organic solvent, to give the base addition salt which is usually isolated for example by crystallisation and filtration. Other non-pharmaceutically acceptable salts, eg. oxalates or trifluoroacetates, may be used, for example in the isolation of compounds of the invention, and are included within the scope of this invention. The invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the salts of the compounds of formula (I).
Also included within the scope of the invention are all solvates, hydrates and complexes of compounds and salts of the invention.
Certain compounds of formula (I) may exist in stereoisomeric forms (e.g. they may contain one or more asymmetric carbon atoms or may exhibit cis-trans isomerism). The individual stereoisomers (enantiomers and diastereomers) and mixtures of these are included within the scope of the present invention. The present invention also covers the individual isomers of the compounds represented by formula (I) as mixtures with isomers thereof in which one or more chiral centres are inverted. Likewise, it is understood that compounds of formula (I) may exist in tautomeric forms other than that shown in the formula and these are also included within the scope of the present invention.
The compounds of this invention may be made by a variety of methods, including standard chemistry. Any previously defined variable will continue to have the previously defined meaning unless otherwise indicated. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the working Examples.
Process a
Compounds of formula (I), wherein R34, R19, R20, R1 and R2 are as defined above, may be prepared from compounds of formula II;




wherein R34, R19, and R20 are as defined above, and X represents a halogen atom, by treatment with an amine of formula R1R2NH, wherein R1 and R2 are as defined above.

Suitable conditions for process a) include stirring in a suitable solvent such as acetonitrile, N,N-dimethylformamide or ethanol, at a suitable temperature, such as between room temperature and the reflux temperature of the solvent, for example at 80° C., optionally in the presence of a suitable base such as N,N-diisopropylethylamine, or in the presence of an acid catalyst such as the salt of an amine base, such as pyridine hydrochloride. Alternatively, process a) may be carried out under microwave irradiation, at a suitable power such as 100-30 W, for example at 150 W, in a suitable solvent such as N-methyl-2-pyrrolidinone or N,N-dimethylformamide, at a suitable temperature such as 60-200° C., for example at 150° C.
Compounds of formula (II), wherein R34, R19, R20 and X are as defined above, may be prepared from compounds of formula (IV);




wherein R34, R19, and R20 are as defined above, by treatment with a suitable chlorinating agent, such as thionyl chloride, in the presence of a suitable catalyst such as N,N-dimethylformamide, followed by treatment with ammonia under suitable conditions, such as 880 ammonia at room temperature.

Compounds of formula (IV), wherein R34, R19, and R20 are as defined above, may be prepared from compounds of formula (V);




wherein R34, R19, and R20 are as defined above, by hydrolysis with a suitable base, such as aqueous sodium hydroxide, in a suitable solvent, such as ethanol, at a suitable temperature such as room temperature.

Compounds of formula (V), wherein R34, R19, and R20 are as defined above, may be prepared from compounds of formula (VI);




wherein R34, R19, and R20 are as defined above, by heating in a suitable solvent, such as diphenyl ether, at a suitable temperature such as 200-300° C., for example at 250° C. The preparation of compounds of formulae (IV), (V), and (VI) wherein R34 represents MeSO2—, R19 represents H and R20 represents H have been previously described in patent application WO 02/068394 A1 (Glaxo Group Limited).

Compounds of formula (VI), wherein R34, R19, and R20 are as defined above, may be prepared from compounds of formula (VII), wherein R34, R19, and R20 are as defined above, and the compound of formula (VIII);




Suitable conditions include heating together compounds of formulae (VII) and (VIII) in a suitable solvent such as ethanol or in the absence of solvent, at a suitable temperature, such as 60-100° C., for example at 80° C.
Compounds of formula (VII) wherein R34, R19, and R20 are as defined above may be prepared by reduction of compounds of formula (XIV), wherein R34, R19, and R20 are as defined above;




suitable conditions where n=1 or 2 include catalytic hydrogenation with hydrogen and a suitable catalyst, such as palladium on carbon, in a suitable solvent such as acetic acid. Suitable conditions where n=0 include reduction with a reducing agent such as iron in dilute acetic acid, at a suitable temperature such as 85-90° C.

Compounds of formula (XIV), wherein R34 represents R3S(═O)n—, R19 represents hydrogen or C1-6alkyl, n is 0 or 2, and R20 is as defined above, may be prepared from compounds of formula (XV), wherein R19 represents hydrogen or C1-6alkyl and R20 is as defined above and compounds of formula (XVI) wherein R3 is defined above and n=0 or 2;




Suitable conditions where n=0 include treatment of the compound of formula (XV) with a thiol of formula (XVI) (n=0) in the presence of a suitable base such as potassium carbonate, in a suitable solvent such as acetonitrile, at a suitable temperature such as room temperature. Where n=2, suitable conditions include treatment of the compound of formula (XV) with the sodium salt of a sulphinic acid of formula (XVI) (n=2), in a suitable solvent such as dimethylacetamide, at a suitable temperature such as 30-100° C., for example at 50° C.
Alternatively, compounds of formula (XIV) where n represents 2 may be prepared from compounds of formula (XIV) where n represents 0 by oxidation with a suitable oxidising agent, such as oxone, in a suitable solvent such as a mixture of methanol and water, at a suitable temperature such as room temperature. Compounds of formula (XIV) where n represents 1 may be prepared from compounds of formula (XIV) where n represents 0 by oxidation with a suitable oxidising agent, such as ceric ammonium nitrate, in the presence of a suitable solid support such as hydrated silica gel, in a suitable solvent such as methylene chloride, at a suitable temperature such as 20-40° C., for example at room temperature.
Compounds of formula R1R2NH may contain amine or acid groups which are suitably protected. Examples of suitable protecting groups and the means for their removal are well known in the art, see for instance T. W. Greene and P. G. M. Wuts ‘Protective Groups in Organic Synthesis’ (3rd Ed., J. Wiley and Sons, 1999). Addition or removal of such protecting groups may be accomplished at any suitable stage in the synthesis of compounds of formula (I).
Compounds of formula (II) wherein R34 represents R3S(═O)n—, n represents 0, R19 represents hydrogen or C1-6alkyl, X represents chlorine and R20 is as defined above may alternatively be prepared from compounds of formula (IX), wherein X represents chlorine, Y represents iodine, Z represents hydrogen or C1-6alkyl, and R20 is as defined above, by treatment with a trialkylstannane of formula R3SSnW3, wherein W represents a C1-6alkyl group such as an n-butyl group. Suitable conditions include heating in the presence of a suitable catalyst, such as a palladium catalyst, for example tetrakistriphenylphosphine palladium (0), in a suitable solvent such as toluene, at a suitable temperature such as between 80° C. and 150° C., for example at 110° C.
Process b
Compounds of formula (I), wherein R1, R2, R34, R19, and R20 are as defined above, and n=0, may alternatively be prepared from compounds of formula (III);




wherein R1, R2 and R20 are as defined above, and Z represents hydrogen, C1-6alkyl or halogen for example chlorine and Y represents hydrogen, chlorine, bromine or iodine, by treatment with a thiol of formula R3SH, or the sodium salt thereof, R3SNa, wherein R3 is as defined above, with the proviso that at least one of Y and Z represent halogen.

Suitable conditions for process b) include heating in a suitable solvent such as toluene or N,N-dimethylformamide, at a suitable temperature such as 60-150° C., for example at 110° C., in the presence of a suitable catalyst, such as a palladium catalyst, for example tris(dibenzylideneacetone) palladium (II), and a suitable ligand, such as a phosphine ligand, for example (oxydi-2,1-phenylene)bis(diphenylphosphine), and in the presence of a suitable base such as potassium tert-butoxide.
Alternatively, conditions for process b) include heating in a suitable solvent such as 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone or dimethoxyethane, at a suitable temperature such as 60-150° C., for example at 85° C., optionally in the presence of a suitable catalyst, such as a copper catalyst, for example copper (I) iodide, and in the presence of a suitable base such as potassium phosphate or potassium carbonate and optionally in the presence of a suitable ligand for example N,N-diethylsalicylamide.
Compounds of formula (III), wherein R1, R2, R20, Y and Z are as defined above, may be prepared from compounds of formula (IX), wherein R20, X, Y and Z are as defined above, by treatment with an amine of formula R1R2NH, wherein R1 and R2 are as defined above;




suitable conditions include stirring in a suitable solvent such as acetonitrile, at a suitable temperature, such as between room temperature and the reflux temperature of the solvent, for example at 80° C., optionally in the presence of a base such a N,N-diisopropylethylamine, or in the presence of an acid catalyst such as pyridine hydrochloride. Alternatively, preparation of compounds of formula (III) from compounds of formula (IX) may be carried out under microwave irradiation, at a suitable power such as 100-300 W, for example at 150 W, in a suitable solvent such as N-methyl-2-pyrrolidinone, at a suitable temperature such as 60-200° C. for example at 150° C.

The compounds of formula (IX) may be prepared according to the following synthetic scheme, Scheme 1, wherein R19, R20, Y and Z are as defined above:




Suitable conditions for the reactions of Scheme 1 are: (A) heating together compounds of formulae (X) and (VIII) in the absence of solvent, at a suitable temperature, such as 60-100° C., for example at 80° C.; (B) heating compounds of formula (XI) in a suitable solvent, such as diphenyl ether, at a suitable temperature such as 200-300° C., for example at 250° C.; (C) hydrolysis of compounds of formula (XII) with a suitable base, such as aqueous sodium hydroxide, in a suitable solvent, such as ethanol, at a suitable temperature such as room temperature; (D) treatment of compounds of formula (XIII) with a suitable halogenating agent, such as a chlorinating agent, for example thionyl chloride, in the presence of a suitable catalyst such as N,N-dimethylformamide, followed by treatment with ammonia under suitable conditions, such as 880 ammonia at room temperature.
Preparation of the compounds of formulae (XI) and (XII) wherein Y represents iodine and Z and R20 both represent hydrogen have been previously described in: Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 2002, 41B(3), 650-652. Preparation of the compound of formula (XIII) wherein Y represents iodine and Z and R20 both represent hydrogen has been previously described in: PCT Int. Appl. (1999), WO9932450 A1.
Compounds of formula (X) are either known compounds (for example available from commercial suppliers such as Aldrich) or may be prepared by conventional means.
Compounds of formula (V), wherein R34 represents R3S(═O)n—, R19 represents hydrogen or C1-6alkyl, R20 is as defined above and n=0, may be prepared by treatment of compounds of formula (XII), wherein Y and R20 are as defined above and Z represents hydrogen or C1-6alkyl with a thiol of formula R3SH, wherein R3 is as defined above, according to the following scheme:




Suitable conditions for preparation of compounds of formula (V) from compounds of formula (XII) and a thiol of formula R3SH include heating in a suitable solvent such as toluene, at a suitable temperature such as 60-120° C., for example at 110° C., in the presence of a suitable catalyst, such as a palladium catalyst, for example tris(dibenzylideneacetone) palladium (II), and a suitable ligand, such as a phosphine ligand, for example (oxydi-2,1-phenylene)bis(diphenylphosphine), and in the presence of a suitable base such as potassium tert-butoxide.
Compounds of formulae R1R2NH and R3SH are either known compounds (for example available from commercial suppliers such as Aldrich) or may be prepared by conventional means.
Certain compounds of formula R3SH may be prepared from compounds of formula R3SSR3. Suitable conditions include treatment with a suitable reducing agent such as a phosphine, for example triphenylphosphine, in the presence of an acid such as concentrated hydrochloric acid, in a suitable solvent such as a mixture of water and 1,4-dioxane, at a suitable temperature such as between 20° C. and 100° C., for example at 40° C. Alternatively certain compounds of formula R3SH may be prepared from compounds of formula R3SO2Cl. Suitable conditions include treatment with a suitable reducing agent such as a phosphine, for example triphenylphosphine, in a suitable solvent such as 1,4-dioxane, at a suitable temperature such as between 0° C. and 50° C., for example at 20° C.
Compounds of formula R1R2NH may be used in the free base form, or in the form of a suitable salt, such as a hydrochloride salt. Where the free base form is commercially available, suitable salt forms may be prepared by conventional means. Similarly, where a salt form is commercially available, the free base form may be prepared by conventional means.
Compounds of formula R3SH may contain amine or acid groups which are suitably protected. Examples of suitable protecting groups and the means for their removal are well known in the art,see for instance T. W. Greene and P. G. M. Wuts ‘Protective Groups in Organic Synthesis’ (3rd Ed., J. Wiley and Sons, 1999). Addition or removal of such protecting groups may be accomplished at any suitable stage in the synthesis of compounds of formula (I).
Process c
Compounds of formula (I) may also be prepared by a process of interconversion between compounds of formula (I). For example, compounds of formula (I) where n=2 may be prepared from compounds of formula (i) wherein n=0 or 1, by treatment with a suitable oxidising agent, such as oxone, in a suitable solvent such N,N-dimethylformamide or a mixture of N,N-dimethylformamide and anisole, at a suitable temperature such as room temperature. Compounds of formula (I) where n=1 may be prepared from compounds of formula (I) where n=0 by oxidation with a suitable oxidising agent, such as oxone or ceric ammonium nitrate, in the presence of a suitable solid support such as hydrated silica gel, in a suitable solvent such as methylene chloride, at a suitable temperature such as 20-40° C., for example at room temperature.
Alternative processes of interconversion between compounds of formula (I) may include, for example oxidation, reduction, hydrolysis, alkylation, dealkylation, amide bond formation, protection, deprotection, sulphonamide formation or substitution, using methods for functional group interconversion well known to those skilled in the art.
Process d
As a particular example of a process of interconversion, compounds of formula (I), wherein R34 represents R3S(═O)n—, R3 represents an aryl group substituted by —CONR29R30, R19 represents hydrogen or C1-6alkyl, and wherein R1, R2, R20, R29, R30 and n are as defined above, may alternatively be prepared from corresponding compounds of formula (I) in which R3 represents an aryl group substituted by —COOH, namely compounds of formula (XVII);




wherein R19 represents hydrogen or C1-6alkyl, and R1, R2, R20 and n are as defined above, by coupling with a primary or secondary amine, in a suitable solvent, such as N,N-dimethylformamide, in the presence of a suitable amide coupling reagent, such as O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate, optionally in the presence of a suitable base, such as N,N-diisopropylethylamine, at a suitable temperature, such as room temperature. (Step (I))

Compounds of formula (XVII), wherein R19 represents hydrogen or C1-6alkyl, and R1, R2, R20 and n are as defined above, may be prepared from compounds of formula XVIII;




wherein R19 represents hydrogen or C1-6alkyl, and R1, R2, R20 and n are as defined above, by hydrolysis with a suitable base, such as aqueous sodium hydroxide, in a suitable solvent, such as ethanol, at a suitable temperature such as 75° C.( Step (II))

Compounds of formula (XVIII) wherein n=2 may be prepared from compounds of formula (XVIII) wherein n=0, by treatment with a suitable oxidising agent, such as oxone, in a suitable solvent such as N,N-dimethylformamide, at a suitable temperature such as room temperature. (Step (III))
Compounds of formula (XVIII), wherein R19 represents hydrogen or C1-6alkyl, R1, R2 and R20 are as defined above, and n=0, may be prepared from compounds of formula (III) wherein Z represents hydrogen or C1-6alkyl by treatment with a suitable thiol such as methyl 3-mercaptobenzoate or methyl 4-mercaptobenzoate (both commercially available from Toronto). Suitable conditions for this include heating in a suitable solvent such as 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, at a suitable temperature such as 60-150° C., for example at 85° C., in the presence of a suitable catalyst, such as a copper catalyst, for example copper (I) iodide, and in the presence of a suitable base such as potassium phosphate or potassium carbonate, optionally in the presence of a suitable ligand for example N,N-diethylsalicylamide. (Step (IV))
The order of the steps comprising this process may be arranged in a number of different ways. For example the order of steps (II) and (III) may be reversed so that compounds of formula (I) may be prepared by step (IV) followed by step (II) followed by step (III) followed by step (I).
By a similar process, compounds of formula (I), wherein R34 represents R3S(═O)n— and R3 represents a C1-6 alkyl group substituted by —CONR26R27 and wherein R19 represents hydrogen or C1-6alkyl, and R1, R2, R20, R26, R27 and n are as defined above, may alternatively be prepared from compounds of formula (III) where Z represents hydrogen or C1-6alkyl and a suitable thiol such as ethyl 3-mercaptopropionate (commercially available from Aldrich) as shown in the scheme below:
Steps (I) to (IV) of Scheme 2 use conditions as described in process d above.
The order of the steps comprising this process may be arranged in a number of different ways. For example the order of steps may be changed so that compounds of formula (I) may be prepared from compounds of formula (III) by step (IV) followed by step (II) followed by step (III) followed by step (I).
Alternatively the order of steps may be changed so that compounds of formula (I) may be prepared by step (IV) followed by step (II) followed by step (I) followed by step (III).




wherein R3 is R28R27NCO(CH2)2—.

Process e

As a particular example of a process of interconversion, compounds of formula (I), wherein R34 represents R3S(═O)n— and R3 represents a piperidinyl group which is substituted by a substituent selected from C1-6alkyl-, C1-6alkylCO—, C3-7cycloalkylCO—, heteroarylCO— (optionally substituted by one or more C1-4alkyl- groups), C1-6alkoxyCO—, arylCO—, R31R32NCO—, C1-6alkylSO2—, arylSO2— or heteroarylSO2— (optionally substituted by one or more C1-4alkyl or C1-4alkylCONH— groups) and wherein R1, R2, R20, R31, R32 and n are as defined above and R19 represents hydrogen or C1-6alkyl, may alternatively be prepared from compounds of formula (XIX);




wherein R1, R2, R20 and n are as defined above and R19 represents hydrogen or C1-6alkyl, by treatment with an electrophile, such as an acylating agent, such as an acid chloride, in a suitable solvent, such as 1,4-dioxane, in the presence of a suitable base, such as an amine base, for example triethylamine, at a suitable temperature, such as room temperature. Alternative electrophiles that may be used for this process include sulphonyl chlorides, alkyl chloroformates, alkyl halides and acid anhydrides.

Alternatively, compounds of formula (I), wherein R34 represents R3S(═O)n— and R3 represents a piperidinyl which is substituted by a substituent selected from C1-6alkylCO—, C3-7cycloalkylCO—, heteroarylCO— (optionally substituted by one or more C1-4alkyl- groups), or arylCO—, and wherein R1, R2, R20 and n are as defined above and R19 represents hydrogen or C1-6alkyl, may alternatively be prepared from compounds of formula (XIX), by coupling with a carboxylic acid, in a suitable solvent, such as N,N-dimethylformamide, in the presence of a suitable amide coupling reagent, such as O-(7-azabenzotriazol-1-yl)-N,N,N′, N′-tetramethyluronium hexafluorophosphate, optionally in the presence of a suitable base, such as N,N-diisopropylethylamine, at a suitable temperature, such as room temperature. (Step (I))
Compounds of formula (XIX), wherein R1, R2, R20 and n are as defined above and R19 represents hydrogen or C1-6alkyl, may be prepared from compounds of formula (XX);




wherein R1, R2, R20 and n are as defined above and R19 represents hydrogen or C1-6alkyl, by treatment with a suitable reagent, such as a strong acid, for example trifluoroacetic acid, at a suitable temperature, such as room temperature (Step (II)).

Compounds of formula (XX) wherein R1, R2, and R20 are as defined above, R19 represents hydrogen or C1-6alkyl, and n=2, may be prepared from compounds of formula (XX) wherein n=0, by treatment with a suitable oxidising agent, such as oxone, in a suitable solvent such as N,N-dimethylformamide, at a suitable temperature such as room temperature (Step (III)).
Compounds of formula (XX) wherein R1, R2, and R20 are as defined above, R19 represents hydrogen or C1-6alkyl, and n=0, may be prepared from compounds of formula (III) wherein R1, R2, Y and R20 are as defined above and Z represents hydrogen or C1-6alkyl, by treatment with 1,1-dimethylethyl 4-mercapto-1-piperidinecarboxylate (prepared as described in U.S. Pat. No. 5,317,025A) (Step (IV)).
Suitable conditions for this process include heating in a suitable solvent such as dimethylformamide, at a suitable temperature such as 60-150° C., for example at 110° C., in the presence of a suitable catalyst, such as a palladium catalyst, for example tris(dibenzylideneacetone) palladium (II), and a suitable ligand, such as a phosphine ligand, for example (oxydi-2,1-phenylene)bis(diphenylphosphine), and in the presence of a suitable base such as potassium tert-butoxide.
The order of the steps comprising this process may be arranged in a number of different ways. For example the order of steps may be changed so that compounds of formula (I) may be prepared by step (IV) followed by step (II) followed by step (I) followed by step (III).
Similarly, compounds of formula (I) wherein R34 represents R3S(═O)n— and R3 represents a C1-6alkyl which is substituted by —NR17R18, —NR16COR15, C1-6alkoxyCONR25— or C1-6alkylSO2NR33— and wherein R1, R2, R20 , R15, R17, R18 and n are as defined above, R19 represents hydrogen or C1-6alkyl, and R16, R25 and R33 represent hydrogen may alternatively be prepared from compounds of formula (III), wherein R1, R2, Y and R20 are as defined above and Z represents hydrogen or C1-6alkyl, and a thiol such as tert-butyl-N-(2-mercaptoethyl)carbamate (Aldrich), as is illustrated in the following Scheme (Scheme 3):
Steps (I) to (IV) of Scheme 3 use conditions as described in process e above.




wherein R34 represents C1-6alky)SO2-, wherein the C1-6alkyl group is substituted by R15CONR16—, C1-6alkoxyCONR25—, C1-6alkylSO2NR33— or R17R18N—.

Process f

As a particular example of a process of interconversion compounds of formula (I), wherein R34 represents R3S(═O)n— and R3 represents an aryl group substituted by a C1-6alkoxy-, C3-7cycloalkoxy- or C3-7cycloalkyl(C1-6alkoxy)- group, R1, R2, R20 and n are as defined above, and R19 represents hydrogen or C1-6alkyl, may alternatively be prepared from compounds of formula (XXI);




wherein R1, R2, R20 and n are as defined above and R19 represents hydrogen or C1-6alkyl, by coupling with a suitable alkylating agent, in a suitable solvent, such as acetonitrile, in the presence of a suitable base, such as potassium carbonate, at a suitable temperature, such as 0 to 100° C., for example the reflux temperature of the solvent.

Alternatively compounds of formula (I) wherein R34 represents R3S(═O)n— and R3 represents an aryl group substituted by a C1-6alkoxy-, C3-7cycloalkoxy- or C3-7cycloalkyl(C1-6alkoxy)- group, R1, R2, R20 and n are as defined above, and R19 represents hydrogen or C1-6alkyl, may be prepared from compounds of formula (XXI) by coupling with a suitable alcohol in a suitable solvent such as tetrahydrofuran, at a suitable temperature such as room temperature in the presence of a suitable coupling agent such as di-tert butylazodicarboxylate.
Compounds of formula (XXI) wherein n=2 may be prepared from compounds of formula (XXI) wherein n=0, by treatment with a suitable oxidising agent, such as oxone, in a suitable solvent such as N,N-dimethylformamide, at a suitable temperature such as room temperature.
Compounds of formula (XXI) wherein R1, R2, and R20 are as defined above, R19 represents hydrogen or C1-6alkyl, and n=0, may be prepared from compounds of formula (III) wherein R1, R2, R20 and Y are as defined above, and wherein Z represents hydrogen or C1-6alkyl, by treatment with 4{[tert-butyl(dimethyl)silyl]oxy}benzenethiol (prepared according to EP 465802 A1). Suitable conditions for this process include heating in a suitable solvent such as dimethylformamide, at a suitable temperature such as 60-150° C., for example at 110° C., in the presence of a suitable catalyst, such as a palladium catalyst, for example tris(dibenzylideneacetone) palladium (II), and a suitable ligand, such as a phosphine ligand, for example (oxydi-2,1-phenylene)bis(diphenylphosphine), and in the presence of a suitable base such as potassium tert-butoxide, followed by deprotection with a suitable fluoride source such as tetrabutylammonium fluoride in a suitable solvent such as tetrahydrofuran at a suitable temperature such as room temperature.
The order of the steps comprising this process may be arranged in a number of different ways.
Process g
Compounds of formula (I) may also be prepared by a process of deprotection of protected derivatives of compounds of formula (I). Examples of suitable protecting groups and the means for their removal are well known in the art, see for instance T. W. Greene and P. G. M. Wuts ‘Protective Groups in Organic Synthesis’ (3rd Ed., J. Wiley and Sons, 1999).
As an example of this, compounds of formula (I) containing a primary or secondary amine group may be prepared from compounds of formula (I) where that amine group is protected, such as a carbamate group, for example as a tert-butyl carbamate, by deprotecting under appropriate conditions, such as treating with a strong acid, for example trifluoroacetic acid.
Process h
As a particular example of a process of interconversion, compounds of formula (I), wherein R34 represents R3S(═O)n— and R3 represents C1-6alkoxyethyl-, R1, R2, R20 and n are as defined above, and R19 represents hydrogen or C1-6alkyl may be prepared from compounds of formula (XXVIII);




wherein R1, R2, R20 and n are as defined above and R19 represents hydrogen or C1-6alkyl, by alkylation with a suitable alkylating agent, in a suitable solvent, such as N,N-dimethylformamide, in the presence of a suitable base, such as sodium hydride, at a suitable temperature, such as 0 to 30° C., for example at room temperature.

Alternatively compounds of formula (I) wherein R34 represents R3S(═O)n— and R3 represents C1-6alkoxyethyl-, R1, R2, R20 and n are as defined above, and R19 represents hydrogen or C1-6alkyl may be prepared from compounds of formula (XXVIII) wherein R1, R2, R20 and n are as defined above and R19 represents hydrogen or C1-6alkyl, by coupling with a suitable alcohol in a suitable solvent such as tetrahydrofuran, at a suitable temperature such as room temperature in the presence of a suitable coupling agent such as di-tert butylazodicarboxylate.
Compounds of formula (XXVIII) wherein R1, R2, and R20 are as defined above, R19 represents hydrogen or C1-6alkyl, and n=2 may be prepared from compounds of formula (XXVIII) wherein n=0, by treatment with a suitable oxidising agent, such as oxone, in a suitable solvent such as N,N-dimethylformamide, at a suitable temperature such as room temperature.
Compounds of formula (XXVIII) wherein R1, R2 and R20 are as defined above, R19 represents hydrogen or C1-6alkyl, and n is 0, may be prepared from compounds of formula (III) wherein R1, R2, R20 and Y are as defined above and Z represents hydrogen or C1-6alkyl, by treatment with 2-mercaptoethanol (available from Aldrich). Suitable conditions for this process include heating in a suitable solvent such as N,N-dimethylformamide, at a suitable temperature such as 60-150° C., for example at 110° C., in the presence of a suitable catalyst, such as a palladium catalyst, for example tris(dibenzylideneacetone) palladium (II), and a suitable ligand, such as a phosphine ligand, for example (oxydi-2,1-phenylene)bis(diphenylphosphine), and in the presence of a suitable base such as potassium tert-butoxide.
The order of the steps comprising this process may be arranged in a number of different ways.
Process i
Compounds of formula (I) wherein R34 represents hydrogen, R19 represents R3S(═O)n—, and R1, R2, R20 and n are as defined above, may be prepared from compounds of formula (XXIX) wherein Y represents chlorine, bromine or iodine, in particular iodine, n=1 or 2, and R1, R2, R3 and R20 are as defined above, by hydrogenation using a suitable hydrogenation process such as palladium on carbon in a suitable solvent such as ethanol.




Compounds of formula (XXIX) wherein Y represents chlorine, bromine or iodine, in particular iodine, n=1 or 2, and R1, R2, R3 and R20 are as defined above, may be prepared from compounds of formula (XXIX) wherein n=0 by treatment with a suitable oxidising agent such as oxone in a suitable solvent such as N,N-dimethylformamide of a mixture of N,N-dimethylformamide and anisole at a suitable temperature such as room temperature.
Compounds of formula (XXIX) wherein Y represents chlorine, bromine or iodine, in particular iodine, R1, R2, R3 and R20 are as defined above, and n=0 may be prepared from compounds of formula (III) wherein R1, R2 and R20 are as defined above, Y represents chlorine, bromine or iodine, especially iodine, and Z represents chlorine, bromine or iodine, especially chlorine, and a thiol of formula R3SH by heating in a suitable solvent such as 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, at a suitable temperature such as 60-150° C. for example at 100° C. in the presence of a suitable base such as potassium carbonate.
Process j
As a particular example of a process of interconversion, compounds of formula (I), wherein R34 represents R3S(═O)n— and wherein R3 represents:




and wherein R1, R2, R20, and n are as defined above, and R19 represents hydrogen or C1-6alkyl, may be prepared from compounds of formula (XXVII) in scheme 3, wherein R1, R2, and R20 are as defined above and Z represents hydrogen or C1-6alkyl, by treatment with a suitable alkylating agent such as ethyl 4-bromobutyrate in a suitable solvent such as 1,4-dioxane at a suitable temperature such as 120° C.

The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance in a mammal such as a human. The compound or salt can be for use in the treatment and/or prophylaxis of any of the conditions described herein and/or for use as a phosphodiesterase inhibitor, for example for use as a phosphodiesterase 4 (PDE4) inhibitor. “Therapy” may include treatment and/or prophylaxis.
Also provided is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament (e.g. pharmaceutical composition) for the treatment and/or prophylaxis of an inflammatory and/or allergic disease in a mammal such as a human.
Also provided is a method of treatment and/or prophylaxis of an inflammatory and/or allergic disease in a mammal (e.g. human) in need thereof, which comprises administering to the mammal (e.g. human) a therapeutically effective amount of a compound of formula (I) as herein defined or a pharmaceutically acceptable salt thereof.
Phosphodiesterase 4 inhibitors are believed to be useful in the treatment and/or prophylaxis of a variety of diseases, especially inflammatory and/or allergic diseases, in mammals such as humans, for example: asthma, chronic bronchitis, emphysema, atopic dermatitis, urticaria, allergic rhinitis (seasonal or perennial), vasomotor rhinitis, nasal polyps, allergic conjunctivitis, vernal conjunctivitis, occupational conjunctivitis, infective conjunctivitis, eosinophilic syndromes, eosinophilic granuloma, psoriasis, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD) including chronic bronchitis and emphysema, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock, adult respiratory distress syndrome, multiple sclerosis or memory impairment (including Alzheimer's disease).
In the treatment and/or prophylaxis, the inflammatory and/or allergic disease is preferably chronic obstructive pulmonary disease (COPD) including chronic bronchitis and emphysema, asthma, rheumatoid arthritis, psoriasis or allergic rhinitis in a mammal (e.g. human). More preferably, the treatment and/or prophylaxis is of COPD including chronic bronchitis and emphysema or asthma in a mammal (e.g. human). PDE4 inhibitors are thought to be effective in the treatment of asthma (e.g. see M. A. Giembycz, Drugs, February 2000, 59(2), 193-212; Z. Huang et al., Current Opinion in Chemical Biology, 2001, 5, 432-438; and refs cited therein) and COPD (e.g. see S. L. Wolda, Emerging Drugs, 2000, 5(3), 309-319; Z. Huang et al., Current Opinion in Chemical Biology, 2001, 5, 432-438; and refs cited therein). COPD is often characterised by the presence of airflow obstruction due to chronic bronchitis and/or emphysema (S. L. Wolda, Emerging Drugs, 2000, 5(3), 309-319).
For use in medicine, the compounds of the present invention are usually administered as a pharmaceutical composition.
The present invention therefore provides in a further aspect a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers and/or excipients.
The pharmaceutical composition can be for use in the treatment and/or prophylaxis of any of the conditions described herein.
The compounds of formula (I) and/or the pharmaceutical composition may be administered, for example, by oral, parenteral (e.g. intravenous, subcutaneous, or intramuscular), inhaled, nasal, transdermal or rectal administration, or as topical treatments (e.g. ointments or gels). Accordingly, the pharmaceutical composition is preferably suitable for oral, parenteral (e.g. intravenous, subcutaneous or intramuscular), inhaled or nasal administration. More preferably, the pharmaceutical composition is suitable for inhaled or oral administration, e.g. to a mammal such as a human. Inhaled administration involves topical administration to the lung, e.g. by aerosol or dry powder composition.
A pharmaceutical composition suitable for oral administration can be liquid or solid; for example it can be a solution, a syrup, a suspension or emulsion, a tablet, a capsule or a lozenge.
A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable pharmaceutically acceptable liquid carrier(s), for example an aqueous solvent such as water, ethanol or glycerine, or an oil, or a non-aqueous solvent, such as a surfactant, such as polyethylene glycol. The formulation may also contain a suspending agent, preservative, flavouring and/or colouring agent.
A pharmaceutical composition suitable for oral administration being a tablet can comprise one or more pharmaceutically acceptable carriers and/or excipients suitable for preparing tablet formulations. Examples of such carriers include lactose and cellulose. The tablet can also or instead contain one or more pharmaceutically acceptable excipients, for example binding agents, lubricants such as magnesium stearate, and/or tablet disintegrants.
A pharmaceutical composition suitable for oral administration being a capsule can be prepared using encapsulation procedures. For example, pellets containing the active ingredient can be prepared using a suitable pharmaceutically acceptable carrier and then filled into a hard gelatin capsule. Alternatively, a dispersion, suspension or solution can be prepared using any suitable pharmaceutically acceptable carrier, for example an aqueous solution, aqueous gum or an oil and the dispersion, suspension or solution then filled into a hard or soft gelatin capsule.
The compounds of formula (I) and/or the pharmaceutical composition may be administered by a controlled or sustained release formulation as described in WO 00/50011.
A parenteral composition can comprise a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil. Alternatively, the solution can be lyophilised; the lyophilised parenteral pharmaceutical composition can be reconstituted with a suitable solvent just prior to administration.
Compositions for nasal or inhaled administration may conveniently be formulated as aerosols, solutions, suspensions, drops, gels or dry powders.
For compositions suitable and/or adapted for inhaled administration, it is preferred that the compound or salt of formula (I) is in a particle-size-reduced form, and more preferably the size-reduced form is obtained or obtainable by micronisation. The preferable particle size of the size-reduced (e.g. micronised) compound or salt is defined by a D50 value of about 0.5 to about 10 microns (for example as measured using laser diffraction).
Aerosol formulations, e.g. for inhaled administration, can comprise a solution or fine suspension of the active substance in a pharmaceutically acceptable aqueous or non-aqueous solvent. Aerosol formulations can be presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device or inhaler. Alternatively the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve (metered dose inhaler) which is intended for disposal once the contents of the container have been exhausted.
Where the dosage form comprises an aerosol dispenser, it preferably contains a suitable propellant under pressure such as compressed air, carbon dioxide or an organic propellant such as a chlorofluorocarbon (CFC) or hydrofluorocarbon (HFC). Suitable CFC propellants include dichlorodifluoromethane, trichlorofluoromethane and dichlorotetrafluoroethane. Suitable HFC propellants include 1,1,1,2,3,3,3-heptafluoropropane and 1,1,1,2-tetrafluoroethane. The aerosol dosage forms can also take the form of a pump-atomiser.
Optionally, in particular for dry powder inhalable compositions, a pharmaceutical composition for inhaled administration can be incorporated into a plurality of sealed dose containers (e.g. containing the dry powder composition) mounted longitudinally in a strip or ribbon inside a suitable inhalation device. The container is rupturable or peel-openable on demand and the dose of e.g. the dry powder composition can be administered by inhalation via the device such as the DISKUSTM device, marketed by GlaxoSmithKline. The DISKUSTM inhalation device is for example described in GB 2242134 A, and in such a device at least one container for the pharmaceutical composition in powder form (the container or containers preferably being a plurality of sealed dose containers mounted longitudinally in a strip or ribbon) is defined between two members peelably secured to one another; the device comprises: a means of defining an opening station for the said container or containers; a means for peeling the members apart at the opening station to open the container; and an outlet, communicating with the opened container, through which a user can inhale the pharmaceutical composition in powder form from the opened container.
In the pharmaceutical composition, each dosage unit for oral or parenteral administration preferably contains from 0.01 to 3000 mg, more preferably 0.5 to 1000 mg, of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base. Each dosage unit for nasal or inhaled administration preferably contains from 0.001 to 50 mg, more preferably 0.01 to 5 mg, of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base.
The pharmaceutically acceptable compounds or salts of the invention can be administered in a daily dose (for an adult patient) of, for example, an oral or parenteral dose of 0.01 mg to 3000 mg per day or 0.5 to 1000 mg per day, or a nasal or inhaled dose of 0.001 to 50 mg per day or 0.01 to 5 mg per day, of the compound of the formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base.
The compounds, salts and/or pharmaceutical compositions according to the invention may also be used in combination with one or more other therapeutically active agents, for example, a β2 adrenoreceptor agonist, an anti-histamine, an anti-allergic agent, an anti-inflammatory agent (including a steroid), an anticholinergic agent or an antiinfective agent (e.g. antibiotics or antivirals).
The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof with one or more other therapeutically active agents, for example, a β2-adrenoreceptor agonist, an anti-histamine, an anti-allergic agent, an anti-inflammatory agent (including a steroid), an anticholinergic agent or an antiinfective agent (e.g. antibiotics or antivirals).
Examples of β2-adrenoreceptor agonists include salmeterol (e.g. as racemate or a single enantiomer such as the R-enantiomer), salbutamol, formoterol, salmefamol, fenoterol or terbutaline and salts thereof, for example the xinafoate salt of salmeterol, the sulphate salt or free base of salbutamol or the fumarate salt of formoterol. Long-acting β2-adrenoreceptor agonists are preferred, especially those having a therapeutic effect over a 24 hour period, such as salmeterol or formoterol.
Examples of anti-histamines include methapyrilene or loratadine.
Examples of anti-inflammatory steroids include fluticasone propionate and budesonide.
Examples of anticholinergic compounds which may be used in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof are described in WO 03/011274 A2 and WO 02/069945 A2/US 2002/0193393 A1 and US 2002/052312 A1. For example, anticholinergic agents include muscarinic M3 antagonists, such as ipratropium bromide, oxitropium bromide or tiotropium bromide.
Other suitable combinations include, for example, combinations comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with other anti-inflammatory agents such as an anti-inflammatory corticosteroid; or a non-steroidal anti-inflammatory drug (NSAID) such as a leukotriene antagonist (e.g. montelukast), an iNOS inhibitor, a tryptase inhibitor, an elastase inhibitor, a beta-2 integrin antagonist, an adenosine a2a agonist, a chemokine antagonist such as a CCR3 antagonist, or a 5-lipoxygenase inhibitor; or an antiinfective agent (e.g. an antibiotic or an antiviral). An iNOS inhibitor is preferably for oral administration. Suitable iNOS inhibitors (inducible nitric oxide synthase inhibitors) incluse those disclosed in WO 93/13055, WO 98/30537, WO 02/50021, WO 95/34534 and WO 99/62875. Suitable CCR3 inhibitors include those disclosed in WO 02/26722.
The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical composition and thus a pharmaceutical composition comprising a combination as defined above together with one or more pharmaceutically acceptable carriers and/or excipients represent a further aspect of the invention.
The individual compounds of such combinations may be administered either sequentially or simultaneously in separate or in combined pharmaceutical compositions.
All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.
The various aspects of the invention will now be described by reference to the following Biological Test Methods and Examples. These Examples are merely illustrative and are not to be construed as a limitation of the scope of the present invention.
Biological Test Methods
PDE3, PDE4B, PDE4D, PDE5 and PDE6 Primary Assay Methods
The activity of the compounds can be measured as described below. Preferred compounds of the invention are selective PDE4 inhibitors, i.e. they inhibit PDE4 (e.g. PDE4B and/or PDE4D) more strongly than they inhibit other PDE's such as PDE3 and/or PDE5.
1. PDE Enzyme Sources and Literature References.
Human recombinant PDE4B, in particular the 2B splice variant thereof (HSPDE4B2B), is disclosed in WO 94/20079 and also in M. M. McLaughlin et al., “A low Km, rolipram-sensitive, cAMP-specific phosphodiesterase from human brain: cloning and expression of cDNA, biochemical characterisation of recombinant protein, and tissue distribution of mRNA”, J. Biol. Chem., 1993, 268, 6470-6476. For example, in Example 1 of WO 94/20079, human recombinant PDE4B is described as being expressed in the PDE-deficient yeast Saccharomyces cerevisiae strain GL62, e.g. after induction by addition of 150 μM CuSO4, and 100,000×g supernatant fractions of yeast cell lysates are described for use in the harvesting of PDE4B enzyme.
Human recombinant PDE4D (HSPDE4D3A) is disclosed in P. A. Baecker et al., “Isolation of a cDNA encoding a human rolipram-sensitive cyclic AMP phoshodiesterase (PDE IVD)”, Gene, 1994,138, 253-256.
Human recombinant PDE5 is disclosed in K. Loughney et al., “Isolation and characterisation of cDNAs encoding PDE5A, a human cGMP-binding, cGMP-specific 3′,5′-cyclic nucleotide phosphodiesterase”, Gene, 1998, 216, 139-147.
PDE3 was purified from bovine aorta. Its presence in the tissue was reported by H. Coste and P. Grondin in “Characterisation of a novel potent and specific inhibitor of type V phosphodiesterase”, Biochem. Pharmacol., 1995, 50,1577-1585.
PDE6 was purified from bovine retina. Its presence in this tissue was reported by: P. Catty and P. Deterre in “Activation and solubilization of the retinal cGMP-specific phosphodiesterase by limited proteolysis”, Eur. J. Biochem., 1991, 199, 263-269; A. Tar et al. in “Purification of bovine retinal cGMP phosphodiesterase”, Methods in Enzymology, 1994, 238, 3-12; and/or D. Srivastava et al. in “Effects of magnesium on cyclic GMP hydrolysis by the bovine retinal rod cyclic GMP phosphodiesterase”, Biochem. J., 1995, 308, 653-658.
2. Inhibition of PDE3, PDE4B, PDE4D, PDE5 or PDE6 Activity: Radioactive Scintillation Proximity Assay (SPA)
The ability of compounds to inhibit catalytic activity at PDE4B or 4D (human recombinant), PDE3 (from bovine aorta), PDE5 (human recombinant) or PDE 6 (from bovine retina) was determined by Scintillation Proximity Assay (SPA) in 96-well format. Test compounds (preferably as a solution in DMSO, e.g. 2 microlitre (μl) volume) were preincubated at ambient temperature in Wallac Isoplates (code 1450-514) with PDE enzyme in 50 mM Tris-HCl buffer pH 7.5, 8.3 mM MgCl2, 1.7 mM EGTA, 0.05% (w/v) bovine serum albumin for 10-30 minutes. The enzyme concentration was adjusted so that no more than 20% hydrolysis of the substrate occurred in control wells without compound, during the incubation. For the PDE3, PDE4B and PDE4D assays [5′,8-3H]adenosine 3′,5′-cyclic phosphate (Amersham Pharmacia Biotech, code TRK.559 or Amersham Biosciences UK Ltd, Pollards Wood, Chalfont St Giles, Buckinghamshire HP8 4SP, UK) was added to give 0.05 μCi per well and  ̃10 nM final concentration. For the PDE5 and PDE6 assays [8-3H]guanosine 3′,5′-cyclic phosphate (Amersham Pharmacia Biotech , code TRK.392) was added to give 0.05 μCi per well and  ̃36 nM final concentration. Plates e.g. containing approx. 100 μl volume of assay mixture were mixed on an orbital shaker for 5 minutes and incubated at ambient temperature for 1 hour. Phosphodiesterase SPA beads (Amersham Pharmacia Biotech, code RPNQ 0150) suspended in buffer were added ( ̃1 mg per well) to terminate the assay. Plates were sealed and shaken and allowed to stand at ambient temperature for 35 minutes to 1 hour to allow the beads to settle. Bound radioactive product was measured using a WALLAC TRILUX 1450 Microbeta scintillation counter. For inhibition curves, 10 concentrations (e.g. 1.5 nM-30 μM) of each compound were assayed; more potent compounds were assayed over lower concentration ranges (assay concentrations were generally between 30 μM and 50 fM). Curves were analysed using
ActivityBase and XLfit (ID Business Solutions Limited, 2 Ocean Court, Surrey Research Park, Guildford, Surrey GU2 7QB, United Kingdom). Results were expressed as pIC50 values.
Alternatively, the activity of the compounds can be measured in the following Fluorescence Polarisation (FP) assay:
3. Inhibition of PDE4B or PDE4D Activity: Fluorescence Polarisation (FP) Assay
The ability of compounds to inhibit catalytic activity at PDE4B (human recombinant) and PDE4D (human recombinant) was determined by IMAP Fluorescence Polarisation (FP) assay (Molecular Devices code: R8062) in 384-well format. Test compounds (small volume, e.g. 0.5 μl, of solution in DMSO) were preincubated at ambient temperature in black 384-well microtitre plates (supplier: NUNC, code 262260) with PDE enzyme in 10 mM Tris-HCl buffer pH 7.2, 10 mM MgCl2, 0.1% (w/v) bovine serum albumin. 0.05% NaN3 for 10-30 minutes. The enzyme level was set so that reaction was linear throughout the incubation.
Fluorescein adenosine 3′,5′-cyclic phosphate (Molecular Devices code: R7091) was added to give  ̃40 nM final concentration. Plates were mixed on an orbital shaker for 10 seconds and incubated at ambient temperature for 40 minutes. IMAP binding reagent (Molecular Devices code: R7207) was added (60 μl of a 1 in 400 dilution in binding buffer of the kit stock suspension) to terminate the assay. Plates were allowed to stand at ambient temperature for 1 hour. The FP ratio of parallel to perpendicular light was measured using an AnalystTM plate reader (from Molecular Devices Ltd). For inhibition curves, 11 concentrations (0.5 nM-30 μM) of each compound were assayed; more potent compounds were assayed over lower concentration ranges (assay concentrations were generally between 30 μM and 50 fM). Curves were analysed using ActivityBase and XLfit (ID Business Solutions Limited). Results were expressed as pIC50 values. For a given PDE4 inhibitor, the PDE4B (or PDE4D) inhibition values measured using the SPA and FP assays can differ slightly. However, in a regression analysis of 100 test compounds, the pIC50 inhibition values measured using SPA and FP assays have been found generally to agree within 0.5 log units for PDE4B and PDE4D (linear regression coefficient 0.966 for PDE4B and 0.971 for PDE4D; David R. Mobbs et al, “Comparison of the IMAP Fluorescence Polarisation Assay with the Scintillation Proximity Assay for Phosphodiesterase Activity”, poster presented at 2003 Molecular Devices UK & Europe User Meeting, 2nd Oct. 2003, Down Hall, Harlow, Essex, United Kingdom).
Examples of compounds of the invention described above inhibit the catalytic activity at the PDE4B (human recombinant) enzyme with pIC50 values in the range 6.0-11.7. Biological Data obtained for some of the Examples (PDE4B and PDE5 inhibitory activity) is as follows:













PDE4B
PDE5


Example
mean
mean


No.
pIC50
pIC50

















27
8.4
4.8


70
7.3
5.0


92
7.7
<4.5


125
6.6
5.5


265
11.3
5.2


307
10.5
<4.6


309
10.1
<4.9


312
9.4
<4.5


369
9.5
5.1


380
11.4
<7.0


399
>11.6
5.6


400
11.0
<5.0


408
11.4
4.9


446
11.3
<4.5


457
11.0
<5.5


502
8.9
<5


546
10.7
4.7









4. Emesis:

Many known PDE4 inhibitors cause emesis and/or nausea to greater or lesser extents (e.g. see Z. Huang et al., Current Opinion in Chemical Biology, 2001, 5, 432-438, see especially pages 433-434 and references cited therein). Therefore, it would be preferable but not essential that a PDE4 inhibitory compound of the invention causes only limited or manageable emetic side-effects. Emetic side-effects can for example be measured by the emetogenic potential of the compound when administered to ferrets; for example one can measure the time to onset, extent, frequency and/or duration of vomiting and/or writhing in ferrets after oral or parenteral administration of the compound. See for example A. Robichaud et al., “Emesis induced by inhibitors of PDE IV in the ferret” Neuropharmacology, 1999, 38, 289-297, erratum Neuropharmacology, 2001, 40, 465465.
EXAMPLES
In this section, “intermediates” represent syntheses of intermediate compounds intended for use in the synthesis of the “Examples”.

    
    
        Abbreviations used herein:
        HPLC high performance liquid chromatography
        NMR nuclear magnetic resonance
        LC/MS liquid chromatography/mass spectroscopy
        TLC thin layer chromatography
        SPE solid phase extraction column. Unless otherwise specified the solid phase will be silica gel. C18 SPE refers to reverse phase SPE columns (eg Varian Bond Elut C18 columns). Aminopropyl SPE refers to a silica SPE column with aminopropyl residues immobilised on the solid phase (eg. IST IsoluteTM columns). It is thought that compounds isolated by SPE are free bases.
        SCX solid phase extraction (SPE) column with benzene sulfonic acid residues immobilised on the solid phase (eg. IST lsoluteTM columns). When eluting with ammonia/methanol, it is thought that compounds isolated by SCX are free bases.

General Experimental Details

LC/MS (Liquid Chromatography/Mass Spectroscopy)

        Waters ZQ mass spectrometer operating in positive ion electrospray mode, mass range 100-1000 amu.
        UV wavelength: 215-330 nm
        Column: 3.3 cm×4.6 mm ID, 3 μm ABZ+PLUS
        Flow Rate: 3 ml/min
        Injection Volume: 5 μl
        Solvent A: 95% acetonitrile+0.05% formic acid
        Solvent B: 0.1% formic acid+10 mM ammonium acetate
        Gradient: Mixtures of Solvent A and Solvent B are used according to the following gradient profiles (expressed as % Solvent A in the mixture): 0% A/0.7 min, 0-100% A/3.5 min, 100% A/1.1 min, 100-0% A/0.2 min

Mass Directed Automated Preparative HPLC Column, Conditions and Eluent

Method A

        The preparative column used was a Supelcosil ABZplus (10 cm×2.12 cm internal diameter; particle size 5 μm)
        UV detection wavelength : 200-320 nm
        Flow rate: 20 ml/min
        Injection Volume: 0.5 ml
        Solvent A: 0.1 % formic acid
        Solvent B: 95% acetonitrile+0.05% formic acid
        Gradient systems: mixtures of Solvent A and Solvent B are used according to a choice of 5 generic gradient profiles (expressed as % Solvent B in the mixture), ranging from a start of 0 to 50% Solvent B, with all finishing at 100% Solvent B to ensure total elution. It is thought that compounds isolated by this method are free bases, unless the R1 or R3 groups contain basic moieties, in which case formate salts may be formed.

Mass Directed Automated Preparative HPLC Column, Conditions and Eluent

Method B

        The preparative column used was a Supelcosil ABZplus (10 cm×2.12 cm internal diameter; particle size 5 μm)
        UV detection wavelength: 200-320 nm
        Flow rate: 20 ml/min
        Injection Volume: 0.5 ml
        Solvent A: water+0.1% trifluoroacetic acid
        Solvent B: acetonitrile+0.1% trifluoroacetic acid
        Gradient systems: mixtures of Solvent A and Solvent B are used according to a choice of 5 generic gradient profiles (expressed as % Solvent B in the mixture), ranging from a start of 0 to 50% Solvent B, with all finishing at 100% Solvent B to ensure total elution. It is thought that compounds isolated by this method are trifluoroacetate salts.

Mass Directed Automated Preparative HPLC Column, Conditions and Eluent

Method C

    
    


This is identical to method A. After purification but before solvent removal an excess (between a few drops and 0.5 ml) of dilute hydrochloric acid is added to the product containing fractions.
It is thought that compounds isolated by this method are hydrochloride salts.
Product Isolation by Filtration Directly from the Reaction Mixture
It is thought that compounds isolated by this method from reactions involving displacement of a 4-chloroquinoline intermediate with an amine of formula R1R2NH are hydrochloride salts.
‘Hydrophobic Frit’
This refers to a Whatman PTFE filter medium (frit), pore size 5.0 μm, housed in a polypropylene tube.
Oasis Cartridge
This refers to a Waters OasisTM HLB Liquid Phase Extraction Cartridge
Evaporation of Product Fractions After Purification
Reference to column chromatography, SPE and preparative HPLC purification includes evaporation of the product containing fractions to dryness by an appropriate method.
Aqueous Ammonia Solutions
‘880 Ammonia’ or ‘0.880 ammonia’ refers to concentrated aqueous ammonia (specific gravity 0.880).
INTERMEDIATES AND EXAMPLES
All reagents not detailed in the text below are commercially available from established suppliers such as Sigma-Aldrich.
Intermediate 1. 1-(Cyclopentylthio)-4-nitrobenzene




Cyclopentanethiol (1.0 g) (available from Aldrich) was dissolved in acetonitrile (10 ml) and potassium carbonate (1.35 g) was added. After 5 min, 1-fluoro-4-nitrobenzene (1.38 g) (available from Aldrich) was added and the mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with ether. The organic layer was washed with 1M aqueous sodium hydroxide (20 ml), water (20 ml), and 1M aqueous hydrochoric acid (20 ml). The organic layer was separated and the solvent evaporated in vacuo to give the title compound as a yellow liquid (0.7 g).
1HNMR (CDCl3) δ 8.12 (2H,m), 7.33 (2H,m), 3.75 (1H,m), 2.19 (2H,m), 1.87-162 (6H,m).
Intermediate 2. 1-(Cyclopentylsulfonyl)-4-nitrobenzene




Intermediate 1 (0.7 g) was dissolved in methanol (20 ml) and the solution cooled to 0° C. A solution of oxone (1.93 g) in water (20 ml) was added and the mixture was stirred under nitrogen for 2 h at room temperature. The mixture was extracted with dichloromethane, the layers were separated (hydrophobic frit), and the organic layer evaporated to give the title compound as a yellow oil which crystallised on standing (0.79 g).
LC/MS Rt 3.05 min, m/z 273 [MNH4+]
Intermediate 3. 4-(Cyclopentylsulfonyl)aniline




Intermediate 2 (13.1 g) was dissolved in acetic acid (150 ml) and hydrogenated over palladium on activated carbon (1.6 g) with stirring overnight. The mixture was filtered through Celite filter aid, and the filtrate was evaporated to give a yellow/green oil. The oil was taken up in methanol and an insoluble precipitate filtered off; the filtrate was evaporated in vacuo to give a yellow solid. Trituration with ether and filtration gave the title compound as a pale yellow solid (8.1 g).
LC/MS Rt 2.5 min, m/z 243 [MNH4+]
Intermediate 4. Diethyl ({[4-cyclopentylsulfonyl)phenyl]amino}methylidene)propanedioate




Intermediate 3 (10.8 g) (Helvetica Chimica Acta 1983, 66(4), 1046-52) and diethyl (ethoxymethylene)malonate (11.4 g) (available from Aldrich) were heated at 130° C. for 2 h. After cooling, the brown oil was scratched around the edge of the flask which caused the oil to solidify. Trituration with methanol gave a beige solid, which was filtered off to give the title compound (12.3 g). The filtrate was evaporated in vacuo to give a brown oil. Purification by chromatography on silica gel, eluting with 5% ethyl acetate/cyclohexane followed by 10% ethyl acetate/cyclohexane, gave an orange solid; trituration with methanol and filtration gave the title compound as a yellow solid (2.5 g; total yield 14.8 g).
LC/MS Rt 3.27 min m/z 396 [MH+]
Intermediate 5. Ethyl 6-(cyclopentylsulfonyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylate




Intermediate 4 (14.7 g) was dissolved in diphenyl ether (150 ml) and the solution heated at 250° C. for 30 min. After cooling, the mixture was diluted with cyclohexane and the resulting precipitate filtered off and washed with further cyclohexane to give the title compound as a beige solid (10.9 g).
LC/MS Rt 2.46 min m/z 350 [MH30 ]
Intermediate 6. 6-(Cyclopentylsulfonyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid




Intermediate 5 (10.9 g) was dissolved in ethanol (100 ml) and 2M sodium hydroxide (100 ml), and the mixture was heated under reflux for 3 h. After cooling, the solvent was evaporated in vacuo and the residue was dissolved in water and washed with ethyl acetate. The aqueous layer was acidified with 2M hydrochloric acid to between pH 5 and pH 6 which caused a precipitate to form. The precipitate was filtered off, washed with water, and dried in vacuo overnight to give the title compound as a beige solid (9.47 g).
LC/MS Rt 2.65 min m/z 322 [MH+]
Intermediate 7. 4-Chloro-6-(cyclopentylsulfonyl)-3-quinolinecarboxamide




Intermediate 6 (1.43 g) was suspended in thionyl chloride (20 ml) and N,N-dimethylformamide (5 drops) was added. The mixture was heated under reflux for 2 h. After cooling, the thionyl chloride was evaporated in vacuo and the resulting residue was azeotroped with toluene. 0.880 Ammonia (25 ml) was added dropwise to the yellow solid (caution: exotherm), and the suspension was stirred at room temperature for 16 h. The resulting precipitate was filtered off, washed with water, and dried in vacuo to give the title compound (0.71 g).
LC/MS Rt 2.47 min m/z 339 [MH+]
Similarly prepared were the following:
















 













Intermediate




LCMS
LCMS


No.
R3—
R19—
R20—
Starting material/source
MH+
Rt (min)





Intermediate 8
Ph—
H—
H—
4-(phenylsulfonyl)aniline/
347
2.58






Maybridge


Intermediate 9
Me—
H—
H—
4-(methylsulphonyl)aniline/
285
2.00






Salor


Intermediate 16
Ph—
H—
Me—
Intermediate 15
361
2.78


Intermediate 17
Me—
Me—
H—
1-fluoro-2-methyl-4-
299
2.19






nitrobenzene/






Aldrich


Intermediate 95
tBu—
H—
H—
4-[(1,1-
327
2.40






dimethylethyl)sulphonyl]aniline/






Helvetica Chimica Ada






(1983), 66(4), 1046-52









Intermediate 30. 4-Chloro-6-[(1-methylethyl)sulfonyl]-3-quinolinecarboxamide




This was made in the same manner as Intermediate 7 starting from 4-[(1-methylethyl)sulfonyl]aniline (Helvetica Chimica Acta (1983), 66(4), 1046-52).
LC/MS Rt 2.27 min n/z 313 [MH+]
The following were also made in the same manner as Intermediate 7, with the proviso that the intermediates of formula




were prepared from the appropriate 4-fluoronitrobenzene in a similar manner to Intermediate 15:

















 
















Starting








Nitroaryl


LCMS


Intermediate


Compound/
Starting Sulfinic
LCMS
Rt


Number
R3SO2—
R20—
Supplier
Acid/Supplier
MH+
(min)





Intermediate 31




H—
4- fluoro nitrobenzene/ Aldrich
Sodium 4- (methyloxy) benzenesulfinate/ WO 9830566 A1
379
2.72


 


Intermediate 32




Me—
5-fluoro-2- nitrotoluene/ Aldrich
Sodium 4- (methyloxy) benzenesulfinate/ WO 9830566 A1
391
2.91


 


Intermediate 34




Me—
5-fluoro-2- nitrotoluene/ Aldrich
Sodium 4- methylbenzene sulfinate/Aldrich
375
2.93


 


Intermediate 33
MeSO2—
Me—
5-fluoro-2-
Methanesulfinic
299
2.12





nitrotoluene/
acid sodium salt/





Aldrich
Lancaster


Intermediate 50
MeSO2—
MeO—
4-fluoro-2-
Methanesulfinic
315
1.99





(methyloxy)-1-
acid sodium salt/





nitrobenzene/
Lancaster





Maybridge









Intermediate 10. Diethyl {[(4-iodophenyl)amino]methylidene}propanedioate




A mixture of 4-iodoaniline (208 g) (available from Aldrich) and diethyl (ethoxymethylene)malonate (210 ml) (available from Aldrich) was heated to ca. 60° C., whereupon the mixture set solid. Heating was continued to 100° C., and then the mixture was removed from heating and broken up. Heating was continued at 100° C. for 1 h, and the solid was collected, washed with cyclohexane (1 L) and ethanol (2×500 ml), and dried in vacuo at 40° C. overnight to give the title compound as a white solid (356 g).
LC/MS Rt 3.57 min m/z 390 [MH+]
Intermediate 11. Ethyl 6-iodo-4-oxo-1,4-dihydro-3-quinolinecarboxylate




Diphenyl ether (175 ml) was heated to reflux temperature, and Intermediate 10 was gradually added down an air condenser. Once all the reagent had been added the mixture was heated under reflux for a further 30 min. The mixture was then cooled and 2-methylpentane (200 ml) was added. The solid formed was collected by filtration to give the title compound (24.6 g).
1HNMR (DMSO) δ 8.58 (1H,s), 8.42(1H,d), 7.99 (1H,dd), 7.44(1H,d), 4.21(2H,q), 1.28 (3H,t)
Intermediate 12. 6-Iodo-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid




Sodium hydroxide (9.8 g) was dissolved in water (61 ml) and ethanol (30 ml) was added. The resultant solution was added to Intermediate 11, and the mixture was heated under reflux for 60 min with stirring under nitrogen. Concentrated hydrochloric acid was added, giving a white precipitate. After stirring for 16 h, the precipitate was filtered off, washed with water and dried in vacuo to give the title compound as a white solid (8.15 g).
LC/MS Rt 3.01min m/z 316 [MH+]
Intermediate 13. 4-Chloro-6-iodo-3-quinolinecarboxamide




Intermediate 12 (8.1 g) was added portionwise to stirred thionyl chloride (60 ml). N,N-dimethylformamide (3 drops) was added and the mixture was heated under reflux with stirring under nitrogen for 1.75 h. The excess thionyl chloride was evaporated in vacuo and the residue was azeotroped with toluene (2×50 ml). The resulting pale yellow solid was added portionwise to stirred 0.880 ammonia (250 ml), and the mixture stirred at room temperature for 1.5 h. The solid was filtered off, washed with water and dried in vacuo at 60° C. for 16 h to give the title compound as a white solid (7.94 g).
LC/MS Rt 2.72min m/z 332 [MH+]
The following were made in the same manner as Intermediate 13:
















 












Intermediate


Starting
LCMS
LCMS


Number
R19—
R20—
Material
MH+
Rt (min)





Intermediate 48
H—
Me—
4-iodo-2-
347
3.06





methylaniline/





Aldrich


Intermediate 49
H—
Cl—
2-chloro-4-
367
2.99





iodoaniline/





Avocado


Intermediate 72
H—
Et—
Intermediate 73
361
3.22


Intermediate 87
H—
F—
2-Fluoro-4-iodo
352
2.65





aniline/Aldrich


Intermediate 67
Cl—
H—
from 3-chloro-4-
367
3.07





iodoaniline/





Aldrich









Intermediate 68. 4.7-Dichloro-8-methyl-3-quinolinecarboxamide




Intermediate 68 was prepared from 2-methyl-3-chloroaniline (Aldrich) in a similar manner to Intermediate 13.
LC/MS Rt 3.00 min m/z 255 [MH+]
Intermediate 14. 6-Iodo-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide hydrochloride




Intermediate 13 (5.0 g) was dissolved in ethanol (60 ml), 3-methoxyaniline (3.37 ml) (available from Aldrich) was added, and the mixture was heated under reflux for 2.5 h. The resulting precipitate was filtered off and washed with ether to give the title compound.
LC/MS Rt 2.59 min m/z 420 [MH+]
The following were made in the same manner as Intermediate 14, using acetonitrile as solvent:
















 













Intermediate








Number


Starting

LCMS
LCMS


(a)
R1NH—
R20—
Material
Amine/Source
MH+
Rt (min)





Intermediate 38 HCl




Cl—
Intermediate 49
3-methylaniline/ Aldrich
438
3.56


 


Intermediate 35 HCl




Me—
Intermediate 48
4-fluoro-3- methoxyaniline/ Apollo-Chem
452
2.78


 


Intermediate 36 HCl




Me—
Intermediate 48
2,3-dihydro-1- benzofuran-4- amine hydrobromide/ Journal of Heterocyclic Chemistry, (1980), 17(6), 1333-5.
446
2.81


 


Intermediate 39 HCl




Cl—
Intermediate 49
4-fluoro-3- methoxyaniline/ Apollo-Chem
472
3.29


 


Intermediate 40 HCl




Cl—
Intermediate 49
2,3-dihydro-1- benzofuran-4- amine hydrobromide/ Journal of Heterocyclic Chemistry (1980), 17(6), 1333-5.
466
3.35


 


Intermediate 41 HCl




Cl—
Intermediate 49
3- aminobenzonitrile/ Aldrich
449
3.19


 


Intermediate 42 HCl




Cl—
Intermediate 49
3-fluoroaniline/ Aldrich
442
3.40


 


Intermediate 43 HCl




Cl—
Intermediate 49
1-methyl-1H- indazol-6-amine hydrochloride/ Synthetic Communications (1996), 26(13), 2443-2447.
477
3.05


 


Intermediate 44 HCl




Me—
Intermediate 48
1-methyl-1H- benzimidazol-6- amine/ Heterocycles (1991), 32(5), 1003-12.
458
2.03


 


Intermediate 45 HCl




Me—
Intermediate 48
3-methoxyaniline/ Aldrich
434
2.75


 


Intermediate 46 HCl




Me—
Intermediate 48
3- aminobenzonitrile/ Aldrich
429
2.93


 


Intermediate 61 HCl




Me—
Intermediate 48
3-fluoroaniline/ Aldrich
422
3.02


 


Intermediate 74 HCl




Et—
Intermediate 72
4-fluoro-3- methoxyaniline/ Apollo-Chem
466
2.92


 


Intermediate 75 HCl




Et—
Intermediate 72
3-fluoroaniline/ Aldrich
436
3.24


 


Intermediate 76 HCl




Et—
Intermediate 72
3-chloroaniline/ Aldrich
452
3.44


 


Intermediate 77 HCl




Et—
Intermediate 72
3- aminobenzonitrile/ Aldrich
443
3.12


 


Intermediate 78 HCl




Et—
Intermediate 72
3-methylaniline/ Aldrich
432
3.15


 


Intermediate 79 HCl




Et—
Intermediate 72
1-methyl-1H- indazol-6-amine hydrochloride/ Synthetic Communications (1996), 26(13). 2443-2447
472
2.8


 


Intermediate 80 HCl




Et—
Intermediate 72
2,3-dihydro-1- benzofuran-4- amine hydrobromide/ Joumal of Heterocyclic Chemistry (1980), 17(6), 1333-5.
460
2.97


 


Intermediate 88 HCl




F—
Intermediate 87
2,3-dihydro-1- benzofuran-4- amine hydrobromide/ Journal of Heterocyclic Chemistry (1980), 17(6), 1333-5.
450
3.06


 


Intermediate 89 HCl




F—
Intermediate 87
3-fluoroaniline/ Aldrich
426
3.11


 


Intermediate 90 HCl




F—
Intermediate 87
3-chloroaniline/ Aldrich
442
3.19


 


Intermediate 91 HCl




F—
Intermediate 87
3-methylaniline/ Aldrich
422
3.15


 


Intermediate 92 HCl




F—
Intermediate 87
3- aminobenzonitrile/ Aldrich
433
2.88


 


Intermediate 93 HCl




F—
Intermediate 87
1-methyl-1H- indazol-6-amine hydrochloride/ Synthetic Communications (1996), 26(13), 2443-2447
462
2.87


 


Intermediate 94 HCl




F—
Intermediate 87
4-fluoro-3- methoxyaniline/ Apollo-Chem
456
3.11





(a) Salt form: HCl = hydrochloride






Intermediate 63. 7-Chloro-6-iodo-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide hydrochloride




Intermediate 63 was prepared from Intermediate 67 in a similar manner to Intermediate 14, using acetonitrile as solvent.
LC/MS Rt 3.15 min m/z 452 [MH+]
Intermediate 66. 7-Chloro-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide hydrochloride




Intermediate 66 was prepared from Intermediate 68 using 3-methoxyaniline in a similar manner to Intermediate 14.
LC/MS Rt 2.80 min m/z 342 [MH+]
Intermediate 104. 7-Chloro-4-(2,3-dihydro-1-benzofuran-4-ylamino)-8-methyl-3-quinolinecarboxamide hydrochloride




Intermediate 104 was prepared from Intermediate 68 using 2,3-dihydro-1-benzofuran-4-amine in a similar manner to Intermediate 14, using acetonitrile as solvent.
LC/MS Rt 2.80 min m/z 354 [MH+]
Intermediate 15. 3-Methyl-4-nitrophenyl phenyl sulphone




4-Fluoro-2-methyl-1-nitrobenzene (2.6 g) (available from Aldrich) and sodium benzenesulfinate (3.0 g) (available from Aldrich) were heated in N,N-dimethylacetamide (40 ml) at 50° C. for 16 h. After cooling the mixture was filtered, the filtrate collected and the solvent removed in vacuo. The residue was triturated with cyclohexane and the resultant precipitate collected by filtration to give the title compound as a white solid (3.5 g).
LC/MS Rt 3.22 min m/z 295 [MNH4+]
Intermediate 18. 3-Amino-N-hydroxybenzenecarboximidamide




To a stirred solution of 3-aminobenzonitrile (4.0 g) (available from Aldrich) in ethanol (100 ml) was added hydroxylamine hydrochloride (4.7 g) and potassium carbonate (14.0 g) and the mixture heated under reflux for 22 h. After cooling to room temperature the mixture was filtered through ‘hyflo’ filter aid, the residue washed with ethanol, and the filtrates concentrated in vacuo to give the title compound as a viscous oil (5.3 g).
TLC SiO2 (ethyl acetate) Rf=0.34
Intermediate 19. 3-(5-Methyl-1,2,4-oxadiazol-3-yl)aniline




To a stirred solution of Intermediate 18 (5.3 g) in dry tetrahydrofuran (50 ml) was added 4 Å molecular sieves, followed by sodium hydride (60% dispersion in mineral oil; 1.5 g) and the mixture heated at 65° C. for 30 min. After cooling to room temperature methyl acetate (2.8 ml) was added and the mixture heated under reflux for 16 h. After cooling to 20° C. the mixture was added to water (100 ml) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulphate and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with dichloromethane to give the title compound as a white solid (4.0 g).
TLC SiO2 (30% ethyl acetate in cyclohexane) Rf=0.22
Intermediate 20. 1-[2-Amino-3-chloro-6-(methyloxy)phenyl]-2-chloroethanone




Boron trichloride (25 g) was added to dry dichloromethane (250 ml) at 0° C. and the resulting solution stirred for 10 min. A solution of 2-chloro-5-(methyloxy)aniline (30.6 g) (available from Pfaltz Bauer) in dichloromethane (100 ml) was added dropwise over 15 min to give a dark red/black mixture which was stirred for 20 min at 0° C. Chloroacetonitrile (29.5 ml) was added, followed by the portionwise addition of aluminum chloride (28.4 g). The mixture was stirred at room temperature for 1 h and then heated under reflux for 3 h. The mixture was cooled in an ice/water bath and 2M hydrochloric acid added, followed by 5M hydrochloric acid (200 ml). The resulting biphasic mixture was stirred at room temperature for 15 h and then heated at 80° C. for 30 min. After cooling to room temperature the organic layer was collected and the aqueous layer extracted with dichloromethane. The combined organic layers were washed with water, dried over sodium sulphate and concentrated in vacuo to give the title compound as a dark khaki solid (57.8 g).
TLC SiO2 (30% ethyl acetate in cyclohexane) Rf=0.52
Intermediate 21. 4-Amino-5-chloro-1-benzofuran-3(2H)-one




To a stirred suspension of aluminum chloride (77.6 g) in dry dichloromethane (300 ml) was added dropwise a solution of Intermediate 20 (45 g) in dichloromethane (250 ml). The mixture was heated under reflux for 6 h and then cooled to room temperature. The mixture was decomposed by the dropwise addition of 2M hydrochloric acid, then methanol and dichloromethane were added and the organic layer collected. The aqueous layer was extracted with dichloromethane and the combined organic layers dried over sodium sulphate and concentrated in vacuo. The residue was dissolved in boiling methanol and an excess of triethylamine added. The solvent was removed in vacuo and the residue absorbed onto silica gel. Purification by chromatography on silica gel eluting with a gradient of 20% to 50% ethyl acetate in cyclohexane gave the title compound as an orange/brown solid (46.9 g).
TLC SiO2 (30% ethyl acetate in cyclohexane) Rf=0.66
Intermediate 22. N-(5-Chloro-3-oxo-2,3-dihydro-1-benzofuran-4-yl)-2,2,2-trifluoroacetamide




To a stirred solution of Intermediate 21 (2 g) in dichloromethane (35 ml) at 0° C. was added triethylamine (2.1 ml) and trifluoroacetic anhydride (2.1 ml) and the mixture stirred at 0° C. for 30 min, then at room temperature for 30 min. The mixture was quenched by the dropwise addition of water, the organic layer washed with water and the combined aqueous layers re-extracted with dichloromethane. The combined organic layers were dried over sodium sulphate and concentrated in vacuo. Purification by chromatography on silica gel, eluting with 10% ethyl acetate in cyclohexane, gave the title compound as a bright yellow/orange solid (1.0 g).
TLC SiO2 (30% ethyl acetate in cyclohexane) Rf=0.69
Intermediate 23. N-(5-Chloro-3-methylidene-2,3-dihydro-1-benzofuran-4-yl)-2,2,2-trifluoroacetamide




To a mixture of potassium tert-butoxide (2.0) and methyltriphenylphosphonium iodide (7.1 g) was added dry toluene (70 ml) and the mixture stirred at room temperature for 30 min, then heated under reflux for 30 min. The mixture was cooled to room temperature, a solution of Intermediate 22 (1.0 g) in toluene (30 ml) added dropwise and the mixture heated under reflux for 30 min. The mixture was cooled and quenched by the dropwise addition of saturated ammonium chloride solution. The mixture was partitioned between ethyl acetate and water and the organic phase washed with water. The combined aqueous layers were re-extracted with ethyl acetate and the combined organic layers dried over sodium sulphate and concentrated in vacuo to give a dark brown oil. Purification by column chromatography on silica gel, eluting with 10% ethyl acetate in cyclohexane, gave the title compound as a rose coloured solid (0.5 g).
TLC SiO2 (30% ethyl acetate in cyclohexane) Rf=0.50
Intermediate 24. 2,2,2-Trifluoro-N-(3-methyl-2,3-dihydro-1-benzofuran-4-yl)acetamide




A solution of Intermediate 23 (0.10 g) in ethanol (20 ml) was added to 10% palladium on carbon (0.20 g) and the mixture stirred under an atmosphere of hydrogen for 20 h. The mixture was filtered through ‘hyflo’ filter aid, washed with ethanol and the solvent removed in vacuo to give the title compound as a white solid (0.092 g).
TLC SiO2 (30% ethyl acetate in cyclohexane) Rf=0.53
Intermediate 25. 3-Methyl-2,3-dihydro-1-benzofuran-4-amine




To a stirred solution of Intermediate 24 (0.087 g) in 2:2:1 tetrahydrofuran:methanol:water (5 ml) was added lithium hyroxide (0.149 g) and the mixture stirred at room temperature for 47 h, then at 60° C. for 2.5 h. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The aqueous layer was re-extracted with dichloromethane and the combined organic layers dried over sodium sulphate and concentrated in vacuo to give the title compound as a colourless oil (0.049 g).
TLC SiO2 (30% ethyl acetate in cyclohexane) Rf=0.69
Intermediate 26. 3-(1-Methyl-1H-pyrazol-3-yl)aniline




A solution of 3-(4-bromo-1-methyl-1H-pyrazol-3-yl)aniline (1.0 g) (available from Maybridge) in ethanol (20 ml) was added to a pre-hydrogenated suspension of 5% palladium on charcoal (0.5 g) in ethanol (40 ml). The resulting suspension was stirred under an atmosphere of hydrogen for 3 h. The mixture was filtered through ‘hyflo’ filter aid and the filter pad washed with ethanol (50 ml). The combined filtrate was evaporated in vacuo to give a brown gum. This gum was treated with 2M sodium carbonate solution (100 ml) and extracted with ethyl acetate (2×100 ml); the organic layer was dried over magnesium sulphate and the solvent removed in vacuo. Purification by chromatography on silica gel, eluting with diethyl ether, gave the title compound as a white crystalline solid (0.5 g).
TLC SiO2 (diethyl ether) Rf=0.28
Intermediate 27. 1.2-Dimethyl-1H-benzimidazol-6-amine




To a stirred solution of tin (II) chloride dihydrate (4.7 g) in concentrated hydrochloric acid (15 ml) was added 1,2-dimethyl-6-nitro-1H-benzimidazole (1 g) (J. Chem. Soc.,1931, 1143-1153), and the mixture was stirred at room temperature for 6 h. The mixture was poured onto ice and chloroform, and basified to pH 10 by the addition of 10M sodium hydroxide solution. The mixture was extracted several times with chloroform and the combined organic extracts dried and concentrated in vacuo to give a brown solid. This was crystallised from ethanol to give the title compound.
TLC SiO2 (dichloromethane:methanol:880 ammonia 90:10:1) Rf 0.75.
Intermediate 28. 3-Mercapto-N,N-dimethylbenzamide




Iodine (1 g) was added to a stirred solution of 3-[(dimethylamino)carbonylbenzenesulfonyl chloride (2 g) (Borthwick et al, J. Med. Chem 2002, 45(1), 1-18) and triphenylphosphine (8.4 g) in 1,4-dioxane at 0° C. The mixture was stirred for 0.5 h at ambient temperature. The mixture was poured into a sodium sulphite solution (50 ml), extracted into ethyl acetate (2×30 ml) and washed with 2N sodium hydroxide solution (2×40 ml). The alkaline extracts were acidified and re-extracted into dichloromethane (3×50 ml). The extracts were washed with water (100 ml), dried (Na2SO4) and evaporated to give the title compound as a colourless solid (1.1 g).
LC/MS Rt 2.32 min, m/z 182 [MH+]
Intermediate 28. 3-Mercapto-N,N-dimethylbenzamide (alternative synthesis)




A solution of 3,3′-dithiobis(N,N-dimethylbenzamide) (Ger. Offen. (1978), DE 2821410) (54.2 g) in 1,4-dioxane (400 ml) and water (100 ml) was warmed to 35° C. and concentrated hydrochloric acid (3 ml) was added. Triphenylphosphine (55 g) was added portionwise over 25 min maintaining the temperature below 42° C., then the mixture was stirred at 40° C. for 2.5 h. After cooling to ambient temperature the mixture was concentrated to ca. 200 ml, and partitioned between 2N aqueous sodium hydroxide solution (250 ml) and ethyl acetate (500 ml). The aqueous phase was separated and washed with ethyl acetate (2×300 ml). The aqueous phase was acidified with 5N hydrochloric acid and extracted with ethyl acetate (3×400 ml). The organic extracts of the acidic aqueous phase were combined, dried over sodium sulphate, and the solvent evaporated to leave a solid. The solid was dissolved in hot ethyl acetate (100 ml) and 40-60 petrol (160 ml) was added to the hot solution. The solution was left to cool and the resulting solid filtered off, washed and dried to give the title compound (28.4 g)
LC/MS Rt 2.24min m/z 182 [MH+].
Intermediate 29. 6-({3-[(Dimethylamino)carbonyl]phenyl}thio)-4-[(3-methoxyphenyl)amino]-8-methylquinoline-3-carboxamide




A stirred mixture of Intermediate 45 (0.5 g), Intermediate 28 (0.392 g), cuprous iodide (0.03 g) and potassium carbonate (0.38 g) in 1,3-dimethyltetrahydropyrimidin-2(1H)-one (7 ml) was heated at 100° C. for 16 h. The mixture was cooled, poured into water (100 ml) and extracted into ethyl acetate (3×40 ml). The extracts were washed with water (100 ml), dried (Na2SO4) and evaporated. The residual oil was triturated with ethyl acetate (10 ml) to give the title compound as a fawn coloured solid (0.263 g).
LC/MS Rt 2.67 min, m/z 487 [MH+]
Intermediate 37. 1,1-Dimethylethyl [(6-iodo-4-{[3-(methyloxy)phenyl]amino}-3-quinolinyl)carbonyl]carbamate




To a stirred suspension of Intermediate 14 (6.93 g) in dichloromethane (170 ml) was added N,N-dimethyl-4-aminopyridine (2.42 g) followed by di-tert-butyldicarbonate (18 g) (Aldrich). The solution was stirred at room temperature for 25 min, then quenched by addition of aqueous citric acid (200 ml) and stirred vigorously for 30 min. The organic layer was separated and the aqueous layer washed with dichloromethane (50 ml). The combined organic extracts were washed with brine (100 ml), dried over magnesium sulphate and concentrated in vacuo. The residue was trituated in diethyl ether to give a yellow solid which was collected by filtration, washed with diethyl ether (3×15 ml) and dried in vacuo to give the title compound as a yellow solid (6.6 g).
LC/MS Rt 3.59 min m/z 520 [MH+]
Intermediate 47. 6-[(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)thio]-4-[(3-methoxyphenyl)amino]quinoline-3-carboxamide




A stirred mixture of Intermediate 37 (0.8 g) and 4-{[tert-butyl(dimethyl)silyl]oxy} benzenethiol (0.74 g, EP465802A1), with (oxydi-2,1-phenylene)bis(diphenylphosphine) (0.05 g), potassium tert-butoxide (0.26 g) and tris(dibenzylideneacetone) dipalladium(0) (0.08 g) in toluene (30 ml) was heated at 106° C. for 18 h. The mixture was cooled, diluted with ethyl acetate (25 ml) and washed with a sodium carbonate solution (30 ml). The organic extracts were washed with water (30 ml) , dried (Na2SO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel using ethyl acetate/diethyl ether (7:3) as the eluent. The appropriate fractions were concentrated in vacuo to give the title compound as a yellow foam (0.38 g).
LC/MS Rt 3.9 min, m/z 532 [MH+]
Intermediate 51. 1.1-Dimethylethyl-4-amino-1H-indazole-1-carboxylate




To a solution of 4-nitro-1H-indazole (1.57 g, Journal of Heterocyclic Chemistry 1979, 16(8), 1599-603) and di-tert-butyidicarbonate (2.33 g) in acetonitrile (30 ml) was added N,N-dimethyl-4-aminopyridine (0.059 g). The reaction mixture was stirred at room temperature for 30 min, then concentrated in vacuo to leave a brown solid which was purified by silica SPE, eluting sequentially with dichloromethane and diethyl ether to give 1,1-dimethylethyl 4-nitro-1H-indazole-1-carboxylate as a yellow solid (1.9 g).
LC/MS Rt 3.26 min, m/z 263 [MH+]
1,1-Dimethylethyl 4-nitro-1H-indazole-1-carboxylate (1.2 g) was dissolved in ethanol (150 ml) and stirred with 10% palladium on carbon (0.24 g) under an atmosphere of hydrogen (1 atmosphere pressure) for 18 h. The solution was filtered through a pad of celite and the filtrate concentrated in vacuo to give the title compound as a yellow-orange solid (1.03 g).
LC/MS Rt 2.36 min, m/z 234 [MH+]
Intermediate 52: Ethyl 3-[(3-(aminocarbonyl)-4-{[4-fluoro-3-(methyloxy)phenyl]amino}-8-methyl-6-quinolinyl)thio]propanoate




A mixture containing Intermediate 35 (1.4 g), ethyl 3-mercaptopropionate (0.74 g, available from Aldrich), potassium tert-butoxide (0.64 g), tris(dibenzylideneacetone)dipalladium(0) (0.26 g) and (oxydi-2,1-phenylene)bis(diphenylphosphine) (0.15 g) was dissolved in N,N-dimethylformamide (20 ml) and stirred under an atmosphere of nitrogen at 100° C. for 18 h. The solvents were concentrated in vacuo and the residue dissolved in methanol. This was purified by chromatography on an SPE column eluting with methanol and a solution of ammonia in methanol, to give the title compound as a brown foam (1.06 g).
LC/MS Rt 2.69 min, m/z458 [MH+]
Similarly prepared were the following:
















 











Intermediate

Starting
LCMS
LCMS


Number
R1NH—
Material
MH+
Rt (min)





Intermediate 57




Intermediate 36
452
2.67


 


Intermediate 58




Intermediate 62
411
2.36


 


Intermediate 103




Intermediate 61
428
2.86









Intermediate 53: 3-[(3-(Aminocarbonyl)-4-{[4-fluoro-3-(methyloxy)phenyl]amino}-8-methyl-6-quinolinyl)thio]propanoic acid




A solution of Intermediate 52 (0.95 g) in ethanol (10 ml) was treated with 2M sodium hydroxide (10 ml) and the resulting solution was left standing at room temperature overnight. The solvent was evaporated in vacuo. The residue was dissolved in water and acidified with 2M hydrochloric acid to pH 4. The resulting precipitate was filtered off, washed with water and dried in vacuo to give the title compound as an orange solid (0.8 g).
LC/MS Rt 2.3 min, m/z 430 [MH+]
Similarly prepared were the following:
















 











Intermediate

Starting
LCMS
LCMS


Number
R1NH—
Material
MH+
Rt (min)





Intermediate 59




Intermediate 103
400
2.39


 


Intermediate 60




Intermediate 58
383
2.10









Intermediate 54. 4-{[3-(Methyloxy)phenyl]amino}6-(4-piperidinylsulfonyl)-3-quinolinecarboxamide trifluoroacetate




To a mixture containing Example 377 (0.64 g) in anisole (9 ml) was added a solution of 95% trifluoroacetic acid in water (16 ml). The mixture was stirred for 1.5 h at room temperature and was then concentrated in vacuo. The residue was co-evaporated with toluene (2×20 ml), triturated with ethyl acetate and filtered to give a yellow solid. This residue was again triturated with ethyl acetate and filtered to give the title compound as a yellow solid (0.570 g).
LC/MS Rt 1.94 min, m/z 455 [MH+]
Intermediate 55. 1,1-Dimethylethyl 4-[(3-(aminocarbonyl)-4-{[4-fluoro-3-(methyloxy)phenyl]amino}8-methyl-6-quinolinyl)sulfonyl]-1-piperidinecarboxylate




To a solution of Intermediate 35 (1.0 g) in N,N-dimethylformamide (30 ml) under an atmosphere of nitrogen was added 1,1-dimethylethyl 4-mercapto-1-piperidinecarboxylate (0.89 g, U.S. Pat. No. 5,317,025A), potassium tert-butoxide (0.46 g), tris(dibenzylideneacetone) dipalladium(0) (0.19 g) and (oxydi-2,1-phenylene)bis(diphenylphosphine) (0.11 g). The mixture was heated to 100° C. for 3 h, cooled and the solvent removed under reduced pressure. The residue was partitioned between ethyl acetate (100 ml) and water (100 ml) then dried over magnesium sulphate, filtered and concentrated in vacuo. The residue was purified by SPE (eluting with a gradient of 0 to 5% methanol in chloroform) to give intermediate 1,1-dimethylethyl 4-[(3-(aminocarbonyl)-4-{[4-fluoro-3-(methyloxy)phenyl]amino}-8-methyl-6-quinolinyl)thio]-1-piperidinecarboxylate as a yellow solid (1.1 g). This sulphide was dissolved in N,N-dimethylformamide (50 ml) and oxone (5.15 g) was added portionwise. The mixture was stirred at room temperature for 3 h, then quenched by addition of 1M sodium sulphite solution (500 ml). The mixture was extracted with chloroform (2×200 ml), and the organic layers were washed with 10% lithium chloride solution, dried over magnesium sulphate, filtered and concentrated to give the title compound as a pale yellow solid (0.71 g) after trituration with ether.
LC/MS Rt 3.04 min, m/z 573 [MH+]
Similarly prepared from Intermediate 35 and 1,1-dimethylethyl (2-mercaptoethyl) carbamate (available from Aldrich) was:
Intermediate 56. 1,1-Dimethylethyl {2-[(3-(aminocarbonyl)-4-{[4-fluoro-3-(methyloxy)phenyl]amino}-8-methyl-6-quinolinyl)sulfonyl]ethyl}carbamate




LC/MS Rt 2.79 min, m/z 533 [MH+]
Intermediate 62. 6-Iodo-8-methyl-4-(3-pyridinylamino)-3-quinolinecarboxamide hydrochloride




To a solution of Intermediate 48 (1.1 g) in N,N-dimethylformamide (20 ml) was added 3-aminopyridine (0.8 g, available from Aldrich) and pyridine hydrochloride (0.7 g, available from Aldrich). The mixture was heated at 80° C. under nitrogen for 2 days. The solvent was evaporated in vacuo. The residue was triturated with methanol and the precipitate filtered off to give the title compound as a brown solid (0.9 g).
LC/MS Rt 2.32 min m/z 405 [MH+].
Similarly prepared were the following:
















 













Intermediate








Number


Starting
Amine/
LCMS
LCMS


(a) (b)
R1NH—
R20—
Material
Supplier
MH+
Rt (min)





Intermediate 81 HCl




Et—
Intermediate 72
3-pyridinamine/ Aldrich
419
2.52


 


Intermediate 82 HCl




Et—
Intermediate 72
5-chloro-3- pyridinamine/ Synchem OHG
453
3.19


 


Intermediate 83 HCl




Et—
Intermediate 72
5-fluoro-3- pyridinamine/ Synchem OHG
437
2.93


 


Intermediate 84 HCl




F—
Intermediate 87
5-fluoro-3- pyridinamine/ Synchem OHG
427
2.6


 


Intermediate 85 HCl




F—
Intermediate 87
5-chloro-3- pyridinamine/ Synchem OHG
443
2.88


 


Intermediate 86 HCl




F—
Intermediate 87
3-pyridinamine/ Aldrich
409
2.27


 


96 HCl




Cl—
Intermediate 49
3-pyridinamine/ Aldrich
425
2.52


 


97 HCl




Me—
Intermediate 48
5-chloro-3- pyridinamine/ Synchem OHG
439
2.95


 


98 HCl




Me—
Intermediate 48
5-fluoro-3- pyridinamine/ Synchem OHG
423
2.65


 


99 HCl




Cl—
Intermediate 49
5-fluoro-3- pyridinamine/ Synchem OHG
443
2.91


 


100 HCl




Cl—
Intermediate 49
5-chloro-3- pyridinamine/ Synchem OHG
459
2.94


 


101 HCl




Me—
Intermediate 48
1-ethyl-1H- pyrazol-5-amine/ Aldrich
422
2.58


 


102 HCl




Cl—
Intermediate 49
1-ethyl-1H- pyrazol-5-amine/ Aldrich
442
2.86





(a) Salt form HCl = hydrochloride


(b) All products isolated by trituration with acetonitrile and filtration.






Intermediate 73. 2-Ethyl-4-iodoaniline




To a stirred solution of 2-ethylaniline (1.88 g, available from Aldrich) and sodium acetate (1.27 g) in acetic acid (20 ml) was added iodine monochloride (1 ml, available from Aldrich). The mixture was stirred at 20° C. for 90 min and then the solvent was removed in vacuo. The residue was partitioned between ethyl acetate (25 ml) and saturated aqueous sodium carbonate solution (25 ml). The organic layer was dried using a hydrophobic frit and the solvent was removed in vacuo. Purification by C18 SPE eluting with 20% acetonitrile in water gave the title compound as a purple solid (0.402 g).
LC/MS Rt 3.23 min, m/z 248 [MH+]
Intermediate 64. 7-({3-[(Dimethylamino)carbonyl]phenyl}thio)-6-iodo-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide




A stirred mixture of Intermediate 63 (0.4 g), Intermediate 28 (0.16 g) and potassium carbonate (0.38 g) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (10 ml) was heated at 100° C. under nitrogen for 3 h. A further portion of Intermediate 28 (0.07 g) was added and the mixture stirred at 60° C. for 23 h. The cooled mixture was diluted with water (100 ml) and extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with water (2×70 ml) and brine (70 ml), dried over magnesium sulphate and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with methanol followed by mass directed preparative HPLC (Method A) to give the title compound as a yellow foam (0.12 g).
LC/MS Rt 2.94 min, m/z 599 [MH+]
Intermediate 65. 7-({3-[(Dimethylamino)carbonyl]phenyl}sulfinyl)-6-iodo-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide




Oxone (0.5 g) was added portionwise to a stirred solution of Intermediate 64 (0.12 g) in N,N-dimethylformamide (5 ml). The solution was stirred at room temperature under nitrogen for 21 h. More oxone (0.5 g) was added and the mixture was stirred for a further 3 h, quenched with a solution of sodium sulphite (1.5 g) in water (15 ml), diluted with water (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organic extracts were dried over magnesium sulphate and concentrated in vacuo to give the title compound as a yellow solid (0.15 g).
LC/MS Rt 2.70 min, m/z 615 [MH+]
Intermediate 69. 5-Mercapto-N,N-dimethyl-3-pyridinecarboxamide




Sodium thiomethoxide (3 g) was added to a stirred solution of 5-bromo-N,N-dimethyl-3-pyridinecarboxamide (2.5g, WO2000055168) in N,N-dimethylformamide (40 ml) and the suspension stirred at 100° C. for 4 h. The solvent was concentrated in vacuo, the residue dissolved in 2M sodium hydroxide (35 ml) and water (50 ml), and the solution washed with chloroform (4×75 ml). The aqueous layer was acidified with 2M hydrochloric acid to pH 4 and extracted with chloroform (5×80 ml), and the combined organic layers were washed with brine (20 ml), dried over magnesium sulphate and concentrated in vacuo to give the title compound as an orange oil (1.8 g).
LC/MS Rt 0.96 min, m/z 183 [MH+]
Intermediate 70. 1-Methyl-4-nitro-2,3-dihydro-1H-indole




To a stirred solution of 1-methyl-4-nitro-1H-indole (3.8 g, Organic Process Research and Development 2001 5 (6) 604) and borane-tetrahydrofuran complex (1M in tetrahydrofuran, 86.3 ml) at 0° C. under an atmosphere of nitrogen was added, dropwise, trifluoroacetic acid (88 ml). The resulting mixture was allowed to warm to room temperature and stirred at room temperature for 90 min. The mixture was cautiously added to 2M sodium carbonate solution (750 ml) over 20 min and then stirred for 30 min. The mixture was extracted with ethyl acetate (2×300 ml), the combined organic extracts were dried over sodium sulphate and the solvent was removed in vacuo. Purification by column chromatography on silica gel, eluting with hexane : ethyl acetate (9:1) gave the title compound as a red solid (1.97 g).
TLC SiO2 (hexane:ethyl acetate (4:1)) Rf=0.61
Intermediate 71. 1-Methyl-2,3-dihydro-1H-indol-4-amine




A solution of Intermediate 70 (0.50 g) in ethanol (30 ml) was added to 10% palladium on carbon (0.050 g) and the mixture was stirred under an atmosphere of hydrogen for 20 min. The mixture was filtered through ‘hyflo’ filter aid and the solvent removed in vacuo to give the title compound as a brown oil (0.405 g).
TLC SiO2 (hexane:ethyl acetate (4:1)) Rf=0.25
EXAMPLES
Experimental details for the preparation of representative Examples are given in full below. Summary details for further Examples prepared by analagous methods are give in the accompanying tables,
Example 10
4-[(3-Fluorophenyl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide




Intermediate 9 (0.014 g) was suspended in acetonitrile (3 ml), 3-fluoroaniline (0.0056 g, available from Aldrich) was added, and the mixture was heated under reflux for 16 h. After cooling to room temperature, the mixture was cooled in a refrigerator for 2 h, filtered, and the residue purified by mass directed preparative HPLC (Method A) to give the title compound (0.011 g).
LC/MS Rt 1.95 min m/z 359 [MH+]
Similarly prepared were the following:
















 














Ex.




Isolation

LCMS


No.


Starting
Amine/Reagent
Method
LCMS
Rt


(a)
R1NH—
R3SO2—
Material
Source
(b)
MH+
(min)

















1 HCl




MeSO2—
Intermediate 9
6-aminobenzo thiazole/ Lancaster
(I)
399
1.9


 


2 HCl




MeSO2—
Intermediate 9
3-amino-N- methyl acetanilide/ Merlin synthesis
(I)
413
1.89


 


3 HCl




MeSO2—
Intermediate 9
N,N-dimethyl benzene-1,3- diamine hydrochloride/ Aldrich
(I)
385
1.83


 


4 HCl




MeSO2—
Intermediate 9
3,5- dimethoxyaniline/ Aldrich
(I)
402
2.05


 


5 HCl




MeSO2—
Intermediate 9
1,2- benzoisoxazol- 5-amine/ Key organics Ltd (8W-0024)
(I)
383
1.84


 


6 HCl




MeSO2—
Intermediate 9
methyl 3- amino benzoate hydrochloride/ Fluka
(I)
400
1.99


 


7 HCl




MeSO2—
Intermediate 9
3-methylaniline hydrochloride/ TCI-JP
(I)
356
2


 


8 HCl




MeSO2—
Intermediate 9
3-aminobenzo nitrile/ Aldrich
(I)
367
2.26


 


9




MeSO2—
Intermediate 9
3-aminobenzyl alcohol/ Aldrich
(II)
372
1.82


 


11




MeSO2—
Intermediate 9
1-methyl-1H- benzimidazol- 6-amine/ Heterocycles, 1991, 32(5), 1003-12.
(II)
396
1.65


 


12




MeSO2—
Intermediate 9
3-chloro-4- fluoroaniline/ ABCR
(II)
394
2.37


 


13 HCl




MeSO2—
Intermediate 9
aniline/ Aldrich
(I)
342
2.07


 


15 HCl




MeSO2—
Intermediate 9
6- aminobenzoxa- zolinone/ WO 9845268 A1
(I)
399
1.99


 


16 HCl




MeSO2—
Intermediate 9
2,3-dihydro- 1H-inden-5- ylamine hydrochloride/ Aldrich
(I)
382
2.48


 


17 HCl




MeSO2—
Intermediate 9
2,3-dihydro- benzodioxin-6- amine hydrochloride/ Aldrich
(I)
400
2.18


 


18 HCl




MeSO2—
Intermediate 9
2,3-dihydro- 1,4- benzodioxin-5- amine hydrochloride/ WO 9703067 A1
(I)
400
2.2


 


19 HCl




MeSO2—
Intermediate 9
1-amino- 5,6,7,8- tetrahydro napthalene/ Aldrich
(I)
396
2.57


 


20 HCl




MeSO2—
Intermediate 9
2,3-dihydro-1- benzofuran-4- amine hydrobromide/ Journal of Heterocyclic Chemistry, 1980, 17(6), 1333-5.
(I)
384
2.23


 


21




MeSO2—
Intermediate 9
7-amino-1,3- benzoxazol- 2(3H)-one/ Annales Universitatis Mariae Curie- Sklodowska, Sectio D: Medicine, 1980, Volume Date 1979, 35 121-8.
(II)
399
1.93


 


22 HCl




MeSO2—
Intermediate 9
3-ethylaniline/ Aldrich
(I)
370
2.33


 


23 HCl




MeSO2—
Intermediate 9
3- isopropylaniline/ APIN
(I)
384
2.5


 


24 HCl




MeSO2—
Intermediate 9
3-chloro-4- methoxyaniline/ Aldrich
(I)
406/408
2.2


 


25




MeSO2—
Intermediate 9
3- (methoxymethyl) aniline/ WO 0018721 A1
(II)
386
2.01


 


26 HCl




MeSO2—
Intermediate 9
2,5-dimethoxy aniline/ Aldrich
(I)
402
2.37


 


27 HCl




MeSO2—
Intermediate 9
3- methoxyaniline/ Aldrich
(I)
372
2.33


 


28 HCl




MeSO2—
Intermediate 9
3-hydroxy-4- methoxyaniline/ Aldrich
(I)
388
2.0


 


29 HCl




MeSO2—
Intermediate 9
3- phenoxyaniline/ Aldrich
(I)
434
2.97


 


30 HCl




MeSO2—
Intermediate 9
3-amino-2- methylphenol/ Aldrich
(I)
372
2.2


 


31 HCl




MeSO2—
Intermediate 9
3-aminophenol hydrochloride/ TCI-US
(I)
358
2.04


 


32 HCl




MeSO2—
Intermediate 9
4-fluoro-3- methoxyaniline/ Apollo-Chem
(I)
390
1.92


 


33 HCl




MeSO2—
Intermediate 9
2-(3-amino phenoxy) ethanol hydrochloride/ J. Amer. Chem. Soc.; 1937, 59; 1716
(I)
402
1.8


 


34 HCl




MeSO2—
Intermediate 9
3- ethoxyaniline/ Aldrich
(I)
386
2.04


 


35 HCl




MeSO2—
Intermediate 9
3- chloroaniline/ Aldrich
(I)
376
2.09


 


36 HCl




MeSO2—
Intermediate 9
[3-(2-methoxy ethoxy)phenyl] amine hydrochloride/ EP 388165 A2
(I)
416
1.94


 


37 HCl




MeSO2—
Intermediate 9
4- methoxyaniline/ Aldrich
(I)
372
1.88


 


38 HCl




MeSO2—
Intermediate 9
3,4-dimethoxy aniline/ Aldrich
(I)
402
1.84


 


39




PhSO2—
Intermediate 8
3- ethoxyaniline/ Aldrich
(II)
448
2.55


 


40




PhSO2—
Intermediate 8
[3-(2-methoxy ethoxy)phenyl] amine hydrochloride/ EP 388165 A2
(II)
478
1.42


 


41




PhSO2—
Intermediate 8
3-amino-N- methyl benzamide/ TCI-US
(II)
461
2.37


 


42




PhSO2—
Intermediate 8
4-aminophenol hydrochloride/ Aldrich
(II)
420
2.46


 


43 HCl




PhSO2—
Intermediate 8
6- aminobenzothia- zole/ Lancaster
(I)
461
2.67


 


44 HCl




PhSO2—
Intermediate 8
N-(3- aminophenyl)- N-methyl acetamide/ Merlin Synthesis
(I)
475
2.58


 


45 HCl




PhSO2—
Intermediate 8
1-methyl-1H- benzimidazol- 6-amine/ Gwyn Ellis Heterocycles, 1991, 32(5), 1003- 12.
(I)
458
2.24


 


46 HCl




PhSO2—
Intermediate 8
3,5-dimethoxy aniline/ Aldrich
(I)
464
2.89


 


47 HCl




PhSO2—
Intermediate 8
methyl 3- amino benzoate hydrochloride/ Fluka
(I)
462
2.86


 


48 HCl




PhSO2—
Intermediate 8
4-(2- morphalin-4- ylethoxy) aniline EP 410358 A1
(I)
533
2.1


 


49 HCl




PhSO2—
Intermediate 8
3-fluoroaniline/ Aldrich
(I)
422
2.96


 


50 HCl




PhSO2—
Intermediate 8
3-chloro-4- fluoroaniline/ Aldrich
(I)
456
3.12


 


51 HCl




PhSO2—
Intermediate 8
3-methylaniline hydrochloride/ TCI-US
(I)
418
2.87


 


52 HCl




PhSO2—
Intermediate 8
3-amino benzonitrile/ Aldrich
(I)
429
2.91


 


53




PhSO2—
Intermediate 8
N-(4- aminophenyl) morpholine-4- carboxamide/ Peakdale Molecular Ltd
(II)
532
2.34


 


54




PhSO2—
Intermediate 8
N,N-dimethyl benzene-1,3- diamine hydrochloride/ Aldrich
(II)
447
2.75


 


55




PhSO2—
Intermediate 8
N-(3- aminophenyl) acetamide hydrochloride/ Acros Chimica
(II)
461
2.4


 


56




PhSO2—
Intermediate 8
3-aminobenzyl alcohol/ Aldrich
(II)
434
2.34


 


57 HCl




PhSO2—
Intermediate 8
aniline/ Aldrich
(I)
404
2.73


 


58 HCl




PhSO2—
Intermediate 8
1-acetylindolin- 5-amine/ Maybridge
(I)
487
2.52


 


59 HCl




PhSO2—
Intermediate 8
6-amino-1,3- benzoxazol- 2(3H)-one/ WO 9845268 A1
(I)
461
2.48


 


60 HCl




PhSO2—
Intermediate 8
1-acetyl-6- aminoindoline/ SIGMA
(I)
487
2.55


 


61 HCl




PhSO2—
Intermediate 8
6-amino-2,3- dihydro-1H inden-1-one/ J. Med. Chem. 2003, 46(3), 399-408.
(I)
458
2.67


 


62 HCl




PhSO2—
Intermediate 8
6-amino- 1,2,3,4- tetrahydro naphthalen-1- one/ Maybridge
(I)
472
2.93


 


63 HCl




PhSO2—
Intermediate 8
2,3-dihydro- 1,4- benzodioxin-6- amine hydrochloride/ Aldrich
(I)
462
2.69


 


64 HCl




PhSO2—
Intermediate 8
1-amino- 5,6,7,8- tetrahydro napthalene/ Aldrich
(I)
458
3.07


 


65 HCl




PhSO2—
Intermediate 8
7-amino-1,3- benzoxazol- 2(3H)-one/ Medicine 1980, Volume Date 1979, 35, 121-8.
(I)
461
2.64


 


66 HCl




PhSO2—
Intermediate 8
2,3-dihydro-1- benzofuran-4- amine hydrobromide/ Journal of Heterocyclic Chemistry 1980, 17(6), 1333-5.
(I)
446
2.84


 


67




PhSO2—
Intermediate 8
2,3-dihydro- 1H-inden-5- amine hydrochloride/ Aldrich
(II)
444
2.95


 


68




PhSO2—
Intermediate 8
2,3-dihydro- 1,4- benzodioxin-5- amine hydrochloride/ WO 9703067 A1
(II)
462
2.69


 


69 HCl




PhSO2—
Intermediate 8
3-ethylaniline/ Aldrich
(I)
432
2.92


 


70 HCl




PhSO2—
Intermediate 8
3-isopropyl aniline/ APIN
(I)
446
3.04


 


71 HCl




PhSO2—
Intermediate 8
3-chloro-4- methoxyaniline/ Aldrich
(I)
468
2.76


 


72 HCl




PhSO2—
Intermediate 8
8-amino-3,4- dihydro-1(2H)- naphthalenone/ WO 0160826 A2
(I)
472
2.86


 


73




PhSO2—
Intermediate 8
3- [(methyloxy) methyl]aniline/ WO 0018721 A1
(II)
448
2.60


 


74 HCl




PhSO2—
Intermediate 8
3-(methyloxy) aniline/ Aldrich
(I)
434
2.77


 


75 HCl




PhSO2—
Intermediate 8
2-[(3- aminophenyl) oxy]ethanol hydrochloride/ J. Amer. Chem. Soc.; 1937, 59, 1716
(I)
464
2.21


 


76 HCl




PhSO2—
Intermediate 8
4-amino-N- methyl benzamide/ Buttpark
(I)
461
2.2


 


77




PhSO2—
Intermediate 8
3-amino-2- methylphenol/ Aldrich
(II)
434
2.57


 


78 HCl




PhSO2—
Intermediate 8
4- methoxyaniline hydrochloride/ Acros
(I)
434
2.32


 


79 HCl




PhSO2—
Intermediate 8
3-[(trifluoro methyl)oxy] aniline/ Aldrich
(I)
487
2.8


 


80




PhSO2—
Intermediate 8
3-(4- morpholinyl) aniline/ Journal of Organic Chemistry 2002, 67(9), 3029-3036.
(II)
489
2.72


 


81




PhSO2—
Intermediate 8
3-aminophenol hydrochloride/ TCI-US
(II)
420
2.6


 


82




PhSO2—
Intermediate 8
[3,4- bis(methyloxy) phenyl]amine hydrochloride/ Aldrich
(II)
463
2.58


 


83 HCl








Intermediate 7
6-aminobenzo thiazole/ Lancaster
(I)
453
2.3


 


84 HCl








Intermediate 7
N-(3- aminophenyl)- N-methyl acetamide/ Merlin synthesis
(I)
467
2.29


 


85 HCl








Intermediate 7
N-(4- aminophenyl)- 4-morpholine carboxamide/ Peakdale molecular Ltd
(I)
524
2.21


 


86 HCl








Intermediate 7
3,5-dimethoxy aniline/ Aldrich
(I)
456
2.51


 


87 HCl








Intermediate 7
methyl 3- amino benzoate hydrochloride/ Fluka
(I)
454
2.48


 


88 HCl








Intermediate 7
3-amino-N- methyl benzamide/ TCI-US
(I)
453
2.17


 


89 HCl








Intermediate 7
3-fluoroanillne/ Aldrich
(I)
414
2.53


 


90 HCl








Intermediate 7
3-chloro-4- fluoroaniline/ Aldrich
(I)
448
2.72


 


91 HCl








Intermediate 7
(3- methylphenyl) amine hydrochloride/ TCI-US
(I)
410
2.49


 


92








Intermediate 7
N,N-dimethyl- 1,3-benzene diamine hydrochloride/ Aldrich
(II)
439
2.62


 


93








Intermediate 7
N-(3- aminophenyl) acetamide hydrochloride/ Acros
(II)
453
2.25


 


94








Intermediate 7
2- chloroaniline/ Aldrich
(II)
430
2.69


 


95 HCl








Intermediate 7
aniline/Aldrich
(I)
396
2.58


 


96 HCl








Intermediate 7
1-methyl-1H- benzlmidazol- 6-amine/ Heterocycles 1991, 32(5), 1003- 12.
(I)
450
2.04


 


97 HCl








Intermediate 7
3-ethylaniline/ Aldrich
(I)
424
2.81


 


98 HCl








Intermediate 7
3-isopropyl aniline/ TCI-US
(I)
438
3.0


 


99 HCl








Intermediate 7
3-methoxy aniline/ Aldrich
(I)
426
2.58


 


100




PhSO2—
Intermediate 8
3- aminopyridine/ Aldrich
(II)
405
2.41


 


145 HCl




MeSO2—
Intermediate 9
4-fluoro-3- methylaniline/ Aldrich
(I)
396
1.77


 


146 TFA




MeSO2—
Intermediate 9
5-amino-2- methyl benzofuran hydrochloride/ Aldrich
(III)
396
2.43


 


147 TFA




MeSO2—
Intermediate 9
1-methyl-1H- indazol-6- amine hydrochloride/ Synthetic Communications, 1996, 26(13), 2443- 2447.
(III)
396
2.15


 


148 TFA




MeSO2—
Intermediate 9
1-methyl-1H- indazole-5- amine/ Bionet Research Ltd
(III)
396
2.06


 


149 TFA




MeSO2—
Intermediate 9
1- (phenylmethyl)- 1H-indazol-5- amine/ WO 0283654 A1
(III)
472
2.56


 


150 HCl




MeSO2—
Intermediate 9
3-(trifluoro methyl)aniline/ Aldrich
(I)
410
2.05


 


151 HCl




MeSO2—
Intermediate 9
1-(3- aminophenyl) ethanone/ Aldrich
(I)
384
1.71


 


152 HCl




MeSO2—
Intermediate 9
3-(5-methyl- 1,2,4- oxadiazol-3- yl)aniline/ Intermediate 19
(I)
424
1.88


 


153 HCl




MeSO2—
Intermediate 9
1-(3- aminophenyl)- N,N-dimethyl methane sulfonamide/ Peakdale molecular Ltd
(I)
463
1.78


 


154 HCl




MeSO2—
Intermediate 9
3-(3- thienyl)aniline/ U.S. Pat. No. 6,211,220 B1
(I)
424
2.15


 


155 HCl




MeSO2—
Intermediate 9
3-methyl-2,3- dihydro-1- benzofuran-4- amine/ Intermediate 25
(I)
398
1.91


 


156




MeSO2—
Intermediate 9
4-amino-2- methyl-1H- isoindole- 1,3(2H)-dione/ Archiv der Pharmazie (Weinheim, Germany) 1989, 322(7), 419-26.
(II)
425
2.35


 


157 TFA




PhSO2—
Intermediate 8
1,2- benzisoxazol- 5-amine/ Key organics Ltd
(III)
445
2.61


 


158 TFA




PhSO2—
Intermediate 8
1,2-dimethyl- 1H- benzimidazol- 6-amine/ Intermediate 27
(III)
472
2.15


 


159 TFA




PhSO2—
Intermediate 8
3,5- dichloroaniline/ Aldrich
(III)
472
3.35


 


160 TFA




PhSO2—
Intermediate 8
2-methyl-1,3- benzoxazol-5- amine/ Collection of Czechoslovak Chemical Communications 1996, 61(3), 371-380.
(III)
459
2.33


 


161 TFA




PhSO2—
Intermediate 8
4-chloro-3- methoxyaniline/ Wychem
(III)
468
3.08


 


162 TFA




PhSO2—
Intermediate 8
5-amino-2- methyl benzofuran hydrochloride/ Sigma Aldrich
(III)
458
2.92


 


163 TFA




PhSO2—
Intermediate 8
1-methyl-1H- indazol-6- amine hydrochloride/ Heterocycles, 1995, 41(3), 487-96.
(III)
458
2.67


 


164 TFA




PhSO2—
Intermediate 8
5-fluoro-2- methoxyaniline/ Wychem
(III)
452
2.92


 


165 TFA




PhSO2—
Intermediate 8
1-methyl-1H- indazol-5- amine/ Bionet Research Ltd
(III)
458
2.51


 


166 TFA




PhSO2—
Intermediate 8
1- (phenylmethyl)- 1H-indazol-5- amine/ WO 0283654 A1
(III)
534
2.97


 


167 TFA




PhSO2—
Intermediate 8
4-amino-2- (methyloxy) phenol hydrochloride/ Journal of Chemical Research, Synopses 1988, (9), 284-5.
(III)
450
2.42


 


168 TFA




PhSO2—
Intermediate 8
3-fluoro-4- methylaniline/ Aldrich
(III)
436
3.04


 


169 TFA




PhSO2—
Intermediate 8
2-methyl-1,3- benzothiazol- 6-amine/ AsInEx Compound Collection
(III)
475
2.73


 


170 TFA




PhSO2—
Intermediate 8
1H-indol-6- amine/ Lancaster Synthesis
(III)
443
2.7


 


171 TFA




PhSO2—
Intermediate 8
3-chloro-5- (methyloxy) aniline/ J. Chem. Soc. Perkin 2, 1977, 14.
(III)
468
3.17


 


172 HCl




PhSO2—
Intermediate 8
3-(2-methyl-4- pyrimidinyl) aniline/ Fluorochem
(I)
496
2.23


 


173 HCl




PhSO2—
Intermediate 8
3-(trifluoro methyl)aniline/ Aldrich
(I)
472
2.62


 


174 HCl




PhSO2—
Intermediate 8
1-(3- aminophenyl) ethanone/ Aldrich
(I)
446
2.2


 


175 HCl




PhSO2—
Intermediate 8
3-(1,3-oxazol- 5-yl)aniline/ Fluorochem
(I)
471
2.24


 


176 HCl




PhSO2—
Intermediate 8
3-(1-methyl- 1H-pyrazol-3- yl)aniline/ Intermediate 26
(I)
484
2.27


 


177 HCl




PhSO2—
Intermediate 8
3-(5-methyl- 1,2,4- oxadiazol-3- yl)aniline/ Intermediate 19
(I)
486
2.34


 


178 HCl




PhSO2—
Intermediate 8
1-(3- aminophenyl)- N,N-dimethyl methane sulfonamide/ Peakdale molecular Ltd
(I)
525
2.23


 


179 HCl




PhSO2—
Intermediate 8
3-(3- thienyl)aniline/ U.S. Pat. No. 6,211,220 B1
(I)
486
2.55


 


180 HCl




PhSO2—
Intermediate 8
3-methyl-2,3- dihydro-1- benzofuran-4- amine/ Intermediate 25
(I)
460
2.36


 


181 HCl




PhSO2—
Intermediate 8
2,2-dimethyl- 2,3-dihydro-1- benzofuran-7- amine/ DE 3526510 A1
(I)
474
2.34


 


182




PhSO2—
Intermediate 8
4-amino-2- methyl-1H- isoindole- 1,3(2H)-dione/ Archiv der Pharmazie (Weinheim, Germany) 1989, 322(7), 419-26.
(II)
487
2.85


 


183




PhSO2—
Intermediate 8
[4-(methyloxy)- 2- naphthalenyl] amine 4- methyl benzene sulfonate/ Sigma
(I)
484
3.19


 


590 HCl








Intermediate 95
5-chloro-3- pyridinamine/ Synchem OHG
(I)
419
2.44


 


589 HCl








Intermediate 95
3-pyridinamine Aldrich
(I)
385
1.96





(a) Salt forms: HCl = hydrochloride


TFA = trifluoroacetate


(b) Isolation Method:


(I) Filtered off directly from the reaction mixture.


(II) Mass Directed preparative HPLC Method A.


(III) Mass Directed preparative HPLC Method B.






The following compounds were prepared by a similar method to Example 10:
















 















Ex.





Isolation

LCMS


No.



Starting
Amine Reagent/
Method
LCMS
Rt


(a)
R1NH—
R3SO2—
R20—
Material
Source
(b)
MH+
(min)


















187 HCl




MeSO2—
H—
Intermediate 9
1,1-dimethylethyl (3-aminophenyl) carbamate/ J. Med. Chem. 2003, 46(9) 1661- 1669
(I)
457
2.47


 


188 HCl




MeSO2—
H—
Intermediate 9
1,1-dimethylethyl [(3-aminophenyl) methyl]carbamate/ J. Med. Chem. 2003, 46(9) 1661- 1669
(I)
471
2.39


 


189




MeSO2—
H—
Intermediate 9
1,3-benzodioxol- 5-amine/ Aldrich
(II)
386
1.98


 


190 HCl




MeSO2—
H—
Intermediate 9
3-(1,3-oxazol-5- yl)aniline/ Maybridge
(I)
409
1.82


 


191 HCl




MeSO2—
H—
Intermediate 9
3-(3- aminophenyl)-1- methyl-1H- pyrazole/ Buttpark
(I)
422
1.88


 


192 HCl




MeSO2—
H—
Intermediate 9
3-chloro-2- fluoroaniline/ Aldrich
(I)
394
2.46


 


193 HCl




MeSO2—
H—
Intermediate 9
2,3-difluoroaniline/ Aldrich
(I)
378
2.3


 


194 HCl




MeSO2—
H—
Intermediate 9
3- aminobenzonitrile/ Aldrich
(I)
367
2.07


 


195 HCl




MeSO2—
H—
Intermediate 9
5-amino-2- fluorobenzonitrile/ Maybridge
(I)
385
2.15


 


196 HCl




MeSO2—
H—
Intermediate 9
3- isopropoxyaniline/ Maybridge
(I)
400
2.35


 


197 HCl




MeSO2—
H—
Intermediate 9
2-amino-5- fluorotoluene/ Aldrich
(I)
374
2.2


 


198 HCl




MeSO2—
H—
Intermediate 9
3,4-difluoroaniline/ Aldrich
(I)
378
2.26


 


199 HCl




MeSO2—
H—
Intermediate 9
4-fluoro-3- (trifluoromethyl) aniline/Avocado
(I)
428
2.61


 


200 HCl




MeSO2—
H—
Intermediate 9
2-fluoroaniline/ Aldrich
(I)
360
2.04


 


201 HCl




MeSO2—
H—
Intermediate 9
2,4-difluoroaniline/ Aldrich
(I)
378
2.22


 


202 HCl




MeSO2—
H—
Intermediate 9
2-chloro-4- fluoroaniline/ Aldrich
(I)
394
2.43


 


203 HCl




MeSO2—
H—
Intermediate 9
3-aminopyridine/ Aldrich
(IV)
343
1.69


 


204 HCl




MeSO2—
H—
Intermediate 9
4-aminobenzoic acid/Aldrich
(I)
386
2


 


205 TFA




MeSO2—
H—
Intermediate 9
4-chloro-3- methoxyaniline/ Wychem
(III)
406
2.49


 


206 TFA




MeSO2—
H—
Intermediate 9
1-methyl-1H- benzimidazol-6- amine/ Heterocycles. 1991, 32(5), 1003-12.
(III)
396
1.77


 


207 TFA




MeSO2—
H—
Intermediate 9
6-(methyloxy)- 1,3-benzothiazol- 4-amine J. Am. Chem. Soc, 1939, 61(8), 2013-2017.
(III)
429
2.35


 


208 TFA




MeSO2—
H—
Intermediate 9
3-fluoro-5-(3- pyridinyl)aniline J. Med. Chem. 2000, 43(6), 1123-1134.
(III)
437
2.34


 


209 TFA




MeSO2—
H—
Intermediate 9
5-fluoro-2- methoxyaniline/ Wychem
(III)
390
2.3


 


210 TFA




MeSO2—
H—
Intermediate 9
1-methyl-1H- 1,2,3- benzotriazol-5- amine/US 2003060453 A1
(III)
397
1.98


 


211 TFA




MeSO2—
H—
Intermediate 9
3,5-dlfluoroaniline/ Aldrich
(III)
378
2.51


 


212 TFA




MeSO2—
H—
Intermediate 9
3-fluoro-4- methylaniline/ Aldrich
(III)
374
2.43


 


213 TFA




MeSO2—
H—
Intermediate 9
4-amino-2- fluorophenol/ Apollo
(III)
376
2.01


 


214 TFA




MeSO2—
H—
Intermediate 9
4-(methyloxy)-2- naphthalenamine/ Sigma
(III)
422
2.73


 


215 TFA




MeSO2—
H—
Intermediate 9
6-aminoindole/ Lancaster
(III)
381
2.25


 


216 TFA




MeSO2—
H—
Intermediate 9
methyl 4-amino- 2-methoxy benzoate/ Avocado
(III)
430
2.36


 


217 HCl




MeSO2—
H—
Intermediate 9
1,3-benzodioxol- 4-amine J. Med. Chem. 1979, 22(11), 1354-7.
(I)
386
2.06


 


218 HCl




PhSO2—
H—
Intermediate 8
3- aminobenzonitrile/ Aldrich
(I)
429
2.80


 


219




PhSO2—
H—
Intermediate 8
1,3-benzodioxol- 5-amine/Aldrich
(II)
448
2.63


 


220




PhSO2—
H—
Intermediate 8
3-amino-N,N- dimethylbenzene sulfonamide/WO 9737646 A1
(II)
511
2.94


 


221




PhSO2—
H—
Intermediate 8
3-aminobenzene sulfonamide/ Fluka
(II)
483
2.6


 


222




PhSO2—
H—
Intermediate 8
4-amino-N- methylbenzene- sulfonamide/ Zelinsky BB
(II)
497
2.51


 


223 TFA




PhSO2—
H—
Intermediate 8
6-(methyloxy)- 1,3-benzothiazol- 4-amine J. Am. Chem. Soc., 1939, 61(8), 2013- 2017.
(III)
491
2.92


 


224 TFA




PhSO2—
H—
Intermediate 8
3-fluoro-5-(3- pyridinyl)aniline/ J. Med. Chem., 2000, 43(6), 1123-1134.
(III)
499
2.89


 


225 TFA




PhSO2—
H—
Intermediate 8
Intermediate 51
(III)
444
3.21


 


226 TFA




PhSO2—
H—
Intermediate 8
3,5-difluoroaniline/ Aldrich
(III)
440
3.12


 


227 TFA




PhSO2—
H—
Intermediate 8
4-amino-2- fluorophenol/ Apollo
(III)
438
2.56


 


228 TFA




PhSO2—
H—
Intermediate 8
3,4-difluoroaniline/ Aldrich
(III)
440
3.03


 


229 TFA




PhSO2—
H—
Intermediate 8
methyl 4-amino- 2-methoxy benzoate/ Avocado
(III)
492
2.89


 


230 HCl




PhSO2—
Me—
Intermediate 16
2-(3- aminophenoxy) ethanol/Key Organics Ltd.
(I)
478
2.22


 


231 HCl




PhSO2—
Me—
Intermediate 16
3- aminothiophene- 2-carboxylic acid methyl ester/ Avocado
(I)
482
2.79


 


232 HCl




PhSO2—
Me—
Intermediate 16
5-amino-2- methoxyphenol/ Aldrich
(I)
464
2.1


 


233 HCl




PhSO2—
Me—
Intermediate 16
5-aminotetralin/ Aldrich
(I)
472
2.64


 


234 HCl




PhSO2—
Me—
Intermediate 16
ethyl 3- aminobenzoate/ Aldrich
(I)
490
2.66


 


235 HCl




PhSO2—
Me—
Intermediate 16
5-amino-2- methylphenol/ TCI America
(I)
448
2.31


 


236 HCl




PhSO2—
Me—
Intermediate 16
1-dimethylethyl [(3-aminophenyl) methyl]carbamate/ J. Med. Chem., 2003, 46(9), 1661-1669.
(I)
547
2.64


 


237 HCl




PhSO2—
Me—
Intermediate 16
4-amino-N- methylbenzamide/ Buttpark
(I)
475
2.27


 


238 HCl




PhSO2—
Me—
Intermediate 16
3-aminobenzyl alcohol/Aldrich
(I)
448
2.13


 


239 TFA




PhSO2—
Me—
Intermediate 16
3-aminobenzoyl methylamide/ Buttpark
(III)
475
2.55


 


240 TFA




PhSO2—
Me—
Intermediate 16
3-aminophenol/ Aldrich
(III)
434
2.64


 


241 TFA




PhSO2—
Me—
Intermediate 16
5-amino-1- ethylpyrazole/ Aldrich
(III)
436
2.75


 


242 TFA




PhSO2—
Me—
Intermediate 16
3-cyano-4- fluoroaniline hydrochloride/ Combiblocks
(III)
461
3.04


 


243 TFA




PhSO2—
Me—
Intermediate 16
1-acetyl-6- aminoindoline/ Sigma
(III)
501
2.59


 


244 HCl




iPrSO2—
H—
Intermediate 30
2,3-dihydro-1- benzofuran-4- amine hydrobromide/ J. Heterocyclic Chem., 1980, 17(6), 1333-5.
(I)
412
2.36


 


245 HCl




iPrSO2—
H—
Intermediate 30
3-amino- acetophenone/ Aldrich
(I)
412
2.33


 


246 HCl




iPrSO2—
H—
Intermediate 30
1-methyl-1H- indazol-6-amine hydrochloride/ Synth. Comm., 1996. 26(13), 2443-2447.
(I)
424
2.22


 


247 HCl




iPrSO2—
H—
Intermediate 30
4-fluoro-3- methoxyaniline/ Apollo-Chem
(I)
418
2.38


 


248 HCl




iPrSO2—
H—
Intermediate 30
2,3-dihydro-1,4- benzodioxin-5- amine hydrochloride/ WO 9703067 A1
(I)
428
2.30


 


249 HCl




iPrSO2—
H—
Intermediate 30
3-chloroaniline/ Aldrich
(I)
404
2.64


 


250 HCl




iPrSO2—
H—
Intermediate 30
3- aminobenzonitrile/ Aldrich
(I)
395
2.40


 


251 HCl




iPrSO2—
H—
Intermediate 30
3-methylaniline hydrochloride/ TCI-US
(I)
384
2.41


 


252 HCl




iPrSO2—
H—
Intermediate 30
3-aminopyridine/ Aldrich
(I)
371
1.92


 


253 HCl




iPrSO2—
H—
Intermediate 30
6-aminobenzo thiazole/ Lancaster
(I)
427
2.20


 


254 HCl








H—
Intermediate 31
3-iodoaniline/ Aldrich
(I)
560
3.06


 


255 HCl








H—
Intermediate 31
3-amino- acetophenone/ Aldrich
(I)
476
2.68


 


256 HCl








H—
Intermediate 31
1-methyl-1H- benzimidazol-6- amine/ Heterocycles, 1991, 32(5), 1003-12.
(I)
488
2.17


 


257 HCl








H—
Intermediate 31
2,3-dihydro-1- benzofuran-4- amine hydmbromide/ J. Heterocyclic Chem., 1980, 17(6), 1333-5.
(I)
476
2.76


 


258 HCl








H—
Intermediate 31
3-fluoroaniline/ Aldrich
(I)
452
2.89


 


259 HCl








H—
Intermediate 31
4-fluoro-3- methoxyaniline/ Apollo-Chem
(I)
482
2.78


 


260 HCl








H—
Intermediate 31
6-aminobenzo thiazole/ Lancaster
(I)
491
2.61


 


261 HCl








H—
Intermediate 31
1-methyl-1H- indazol-6-amine hydrochloride/ Synth. Comm., 1996, 26(13), 2443-2447.
(I)
488
2.62


 


262 HCl








H—
Intermediate 31
3- aminobenzonitrile/ Aldrich
(I)
459
2.86


 


263 HCl








H—
Intermediate 31
3-chloroaniline/ Aldrich
(I)
468
3.02


 


264 HCl








H—
Intermediate 31
3-methylaniline hydrochlorlde/ TCI-US
(I)
448
2.78


 


265








Me—
Intermediate 32
3-methoxyaniline/ Aldrich
(II)
478
3.04


 


266 TFA








Me—
Intermediate 32
2,3-dihydro-1- benzofuran-4- amine hydrobromide/ J. Heterocyclic Chem., 1980, 17(6). 1333-5.
(III)
490
2.45


 


267 TFA








Me—
Intermediate 32
3-amino- acetophenone/ Aldrich
(III)
490
2.41


 


268 TFA








Me—
Intermediate 32
1-methyl-1H- indazol-6-amine hydrochloride/ Synth. Comm., 1996, 26(13), 2443-2447.
(III)
502
2.36


 


269 TFA








Me—
Intermediate 32
2,3-dihydro-1,4- benzodioxin-5- amine hydrochloride/ WO 9703067 A1
(III)
506
2.36


 


270 TFA








Me—
Intermediate 32
3-chloroaniline/ Aldrich
(III)
482
2.72


 


271 TFA








Me—
Intermediate 32
3- aminobenzonitrile/ Aldrich
(III)
473
2.62


 


272 TFA








Me—
Intermediate 32
6-aminobenzo thiazole/ Lancaster
(III)
505
2.36


 


273 TFA








Me—
Intermediate 32
3-fluoroaniline/ Aldrich
(III)
466
2.6


 


274 HCl








H—
Intermediate 31
2-(3- aminophenoxy) ethanol hydrochloride/ J. Am. Chem. Soc., 1937, 59; 1716
(I)
494
2.15


 


275 HCl








H—
Intermediate 31
3-aminophenol/ Aldrich
(I)
450
2.15


 


276 HCl








H—
Intermediate 31
ethyl 3- aminobenzoate/ Aldrich
(I)
506
2.51


 


277 HCl








H—
Intermediate 31
5-amino-2- methylphenol/ TCI America
(I)
464
2.27


 


278 HCl








H—
Intermediate 31
4-amino-N- methylbenzamide/ Buttpark
(I)
491
2.16


 


279 HCl








H—
Intermediate 31
3-aminobenzyl- alcohol/Aldrich
(I)
464
2.07


 


280 TFA








H—
Intermediate 31
methyl 3- aminothiophene- 2-carboxylate/ Avocado
(III)
498
2.95


 


281 TFA








H—
Intermediate 31
5-amino-2- methoxyphenol/ Aldrich
(III)
480
2.37


 


282 TFA








H—
Intermediate 31
3-amino-N- methylbenzamide/ Buttpark
(III)
491
2.43


 


283 TFA








H—
Intermediate 31
1-amino-5,6,7,8- tetrahydro napthalene/ Aldrich
(III)
488
2.96


 


284 TFA








H—
Intermediate 31
4-amino-2- methoxyphenol/ WO 2003049702 A2
(III)
480
2.34


 


285 TFA








Me—
Intermediate 34
2,3-dihydro-1- benzofuran-4- amine hydrobromide/ J. Heterocyclic Chem., 1980, 17(6), 1333-5.
(III)
474
2.53


 


286 TFA








Me—
Intermediate 34
3-amino- acetophenone/ Aldrich
(III)
474
2.49


 


287 TFA








Me—
Intermediate 34
1-methyl-1H- indazol-6-amine hydrochloride/ Synth. Comm., 1996, 26(13), 2443-2447.
(III)
486
2.41


 


288 TFA








Me—
Intermediate 34
2,3-dihydro-1,4- benzodioxin-5- amine hydrochloride/ WO 9703067 A1
(III)
490
2.43


 


289 TFA








Me—
Intermediate 34
3-chloroaniline/ Aldrich
(III)
466
2.82


 


290 TFA








Me—
Intermediate 34
3-fluoroaniline/ Aldrich
(III)
450
2.70


 


291 TFA








Me—
Intermediate 34
3- aminobenzonitrile/ Aldrich
(III)
457
2.71


 


292 TFA








Me—
Intermediate 34
3-methoxyaniline/ Aldrich
(III)
462
2.51


 


293 HCl




MeSO2—
Me—
Intermediate 33
3-methoxyaniline/ Aldrich
(I)
386
2.20


 


294 HCl




MeSO2—
Me—
Intermediate 33
4-fluoro-3- methoxyaniline/ Apollo-Chem
(I)
404
2.23


 


295 HCl




MeSO2—
MeO—
Intermediate 50
3-methoxyaniline/ Aldrich
(I)
402
2.09


 


296 HCl




MeSO2—
MeO—
Intermediate 50
4-fluoro-3- methoxyaniline/ Apollo-Chem
(I)
420
2.12


 


297 HCl




PhSO2—
Me—
Intermediate 16
3-amino- acetophenone/ Aldrich
(I)
460
2.82


 


298 HCl




PhSO2—
Me—
Intermediate 16
1-methyl-1H- benzimidazol-6- amine/ Heterocycles, 1991, 32(5), 1003-12.
(I)
472
2.24


 


299 HCl




PhSO2—
Me—
Intermediate 16
2,3-dihydro-1- benzofuran-4- amine hydrobromide/ J. Heterocyclic Chem., 1980, 17(6), 1333-5.
(I)
460
2.90


 


300 HCl




PhSO2—
Me—
Intermediate 16
3-fluoroaniline/ Aldrich
(I)
436
3.07


 


301 TFA




PhSO2—
Me—
Intermediate 16
2,3-dihydro-1,4- benzodioxin-5- amine hydrochloride/ WO 9703067 A1
(III)
476
2.77


 


302 HCl




PhSO2—
Me—
Intermediate 16
6-aminobenzo thiazole/ Lancaster
(I)
475
2.75


 


303 HCl




PhSO2—
Me—
Intermediate 16
1-methyl-1H- indazol-6-amine hydrochloride/ Synth. Comm., 1996, 26(13), 2443-2447.
(I)
472
2.74


 


304 HCl




PhSO2—
Me—
Intermediate 16
3- aminobenzonitrile/ Aldrich
(I)
443
3.01


 


305 HCl




PhSO2—
Me—
Intermediate 16
3-chloroaniline/ Aldrich
(I)
452
3.21


 


306 HCl




PhSO2—
Me—
Intermediate 16
3-methylaniline/ Aldrich
(I)
432
2.93


 


307 HCl




MeSO2—
Me—
Intermediate 33
2,3-dihydro-1- benzofuran-4- amine hydrobromide/ J. Heterocyclic Chem., 1980, 17(6), 1333-5.
(I)
398
2.38


 


308 TFA




MeSO2—
Me—
Intermediate 33
3-aminopyridine/ Aldrich
(III)
357
1.95


 


309 HCl




MeSO2—
Me—
Intermediate 33
1-methyl-1H- indazol-6-amine hydrochloride/ Synth. Comm., 1996, 26(13), 2443-2447.
(I)
410
2.28


 


310 HCl




MeSO2—
Me—
Intermediate 33
3-chloroaniline/ Aldrich
(I)
390
2.68


 


311 HCl




MeSO2—
Me—
Intermediate 33
3-fluoroaniline/ Aldrich
(I)
374
2.49


 


312 HCl




MeSO2—
Me—
Intermediate 33
3- aminobenzonitrile/ Aldrich
(I)
381
2.44


 


313 HCl




MeSO2—
Me—
Intermediate 33
1-methyl-1H- benzimidazol-6- amine/ Heterocycles, 1991, 32(5), 1003-12.
(I)
410
1.87


 


314 HCl




MeSO2—
Me—
Intermediate 33
3-methylaniline/ Aldrich
(I)
370
2.40


 


315 HCl




MeSO2—
Me—
Intermediate 33
1-ethyl-1H- pyrazol-5-amine/ Aldrich
(I)
374
2.22


 


316 HCl




MeSO2—
Me—
Intermediate 33
5-(methyloxy)-3- pyridinamine/ Australian J. Chem., 1981, 34(4). 927-32
(I)
387
2.08


 


317 HCl




MeSO2—
Me—
Intermediate 33
5-methyl-3- pyridinamine/ Synchem
(I)
371
1.90


 


318 HCl




MeSO2—
Me—
Intermediate 33
5-amino-2- fluorobenzonitrile/ Matrix Scientific
(I)
399
2.38


 


329 HCl




PhSO2—
Me—
Intermediate 16
2-methoxybenzyl amine/Aldrich
(I)
462
2.26


 


479 HCl




MeSO2—
Me—
Intermediate 33
1-methyl-1H- pyrazol-5-amine/ Apollo Chem
(IV)
360
2.09


 


496 HCl




MeSO2—
Me—
Intermediate 33
1,3-benzodioxol- 4-amine/J. Med. Chem., 2002, 45(19), 4128- 4139
(I)
400
2.22


 


497 HCl




MeSO2—
Me—
Intermediate 33
4-fluoro-3- methylaniline/ Fluoro Chem
(I)
388
2.35


 


498 HCl




MeSO2—
Me—
Intermediate 33
3-chloro-4- fluoroaniline/ Aldrich
(IV)
408
2.59


 


499 HCl




MeSO2—
Me—
Intermediate 33
5,6,7,8- tetrahydro-1- naphthalenamine/ Fluka
(I)
410
2.57


 


500 HCl




MeSO2—
Me—
Intermediate 33
2,3-difluoroaniline/ Aldrich
(IV)
392
2.52


 


501 HCl




MeSO2—
Me—
Intermediate 33
3-chloro-2- fluoroaniline/ Aldrich
(I)
408
2.67


 


502 HCl




MeSO2—
Me—
Intermediate 33
3,5-difluoroaniline Aldrich
(I)
392
2.60


 


503 HCl




MeSO2—
Me—
Intermediate 33
1,3-benzothiazol- 6-amine/ Maybridge
(I)
413
2.13


 


504 HCl




MeSO2—
Me—
Intermediate 33
3,4-difluoroaniline/ Aldrich
(I)
392
2.43


 


505 HCl




MeSO2—
Me—
Intermediate 33
2,4-difluoroaniline/ Aldrich
(I)
392
2.33


 


508 HCl




MeSO2—
Me—
Intermediate 33
1-methyl-2,3- dihydro-1H-indol- 4-amine/ Intermediate 71
(IV)
411
2.2


 


509 HCl




MeSO2—
Me—
Intermediate 33
1-methyl-1H- indazol-4-amine/ J. Med. Chem., 2002, 45(3), 740-743
(I)
410
2.21


 


510 HCl




MeSO2—
Me—
Intermediate 33
2,3-dihydro-1- benzofuran-7- amine/ WO 9517401 A1
(I)
398
2.15


 


511 HCl




MeSO2—
Me—
Intermediate 33
2,3-dihydro-1H- inden-4-amine/ Aldrich
(I)
396
2.46


 


512 HCl




MeSO2—
Me—
Intermediate 33
4-amino-2,3- dihydro-1H-inden- 1-one/Davos
(IV)
410
2.13


 


520 HCl




MeSO2—
Me—
Intermediate 33
2-methyl-4- pyridinamine/ Asym Chem
(I)
371
1.7


 


542 HCl




MeSO2—
Me—
Intermediate 33
1,3-dihydro-2- benzofuran-4- amine/U.S. Pat. No. 4,521,241
(I)
398
2.16


 


587 HCl




MeSO2—
Me—
Intermediate 33
3,4-dihydro-2H- chromen-5- ylamine/J. Heterocyclic Chem., 1973, 10(4), 623-9
(I)
412
2.26





(a) Salt forms: HCl = hydrochloride


TFA = trifluoroacetate


(b) Isolation Method:


(I) Filtered off directly from the reaction mixture.


(II) Mass Directed preparative HPLC Method A.


(III) Mass Directed preparative HPLC Method B.


(IV) Mass Directed preparative HPLC Method C.






Example 14
4-[(3-Chlorophenyl)(methyl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide




Intermediate 9 (0.023 g) was dissolved in 1-methyl-2-pyrrolidinone (1 ml), and 3-chloro-N-methylaniline (available from Avocado) (0.012 ml) was added. The mixture was stirred under microwave irradiation (power 150 W) for 10 min at 180° C. and for a further 10 min (power 150 W) at 150° C. Purification by mass directed HPLC (Method A) gave the title compound (0.015 g).
LC/MS Rt 2.58 min m/z 390 [MH+]
Example 112
4-({[2-(Methyloxy)phenyl]methyl}amino)-6-(phenylsulfonyl)-3-quinolinecarboxamide




Intermediate 8 (0.017 g) was taken up in acetonitrile (1.5 ml) to give a slurry. 2-Methoxy benzylamine (available from Aldrich) (0.021 g) and N,N-diisopropylethylamine (0.050 ml) were added and the resultant mixture was heated under reflux for 16 h. The mixture was cooled, the solvent evaporated in vacuo and the residue purified by mass directed HPLC (Method A) to give the title compound (0.014 g).
LC/MS Rt 2.73 min m/z 448 [MH+]
Similarly prepared were the following:
















 














Ex.




Isolation

LCMS


No.


Starting
Amine reagent/
Method
LCMS
Rt


(a)
R1NH
R3SO2
Material
Source
(b)
MH+
(min)

















101 (c) HCl




MeSO2—
Intermediate 9
1- phenylmethanamine/ Aldrich
(I)
356
2.07


 


102




MeSO2—
Intermediate 9
tetrahydro-2H-pyran- 3-amine hydrochloride/ Anales de Quimica, Serie C: Quimica Organica y Bioquimica, 1988, 64(2), 148-55.
(II)
350
1.78


 


103




PhSO2—
Intermediate 8
2- (aminomethyl)phenol/ Buttpark
(I)
434
2.56


 


104




PhSO2—
Intermediate 8
2,3-dihydro-1H-inden- 2-amine hydrochloride/ Aldrich
(I)
444
2.85


 


105




PhSO2—
Intermediate 8
cyclopropylamine/ Aldrich
(I)
368
2.37


 


106




PhSO2—
Intermediate 8
[4-(aminomethyl) phenyl] dimethylamine hydrochloride/ Aldrich
(I)
461
2.69


 


107




PhSO2—
Intermediate 8
N-[3- (aminomethyl)phenyl] methanesulfonamide trifluoroacetate/ J. Med. Chem., 1999, 42(14), 2504-2526.
(I)
511
2.52


 


108




PhSO2—
Intermediate 8
2-aminocyclohexanol/ TCI-US
(I)
426
2.49


 


109




PhSO2—
Intermediate 8
[(1-methyl-1H- pyrazol-4-yl) methyl]amine/ Zelinsky-BB; CA 400877-05-6
(I)
422
2.28


 


110




PhSO2—
Intermediate 8
(2-pyridinylmethyl) amine hydrochloride/ Aldrich
(I)
419
2.35


 


111




PhSO2—
Intermediate 8
1,2,3,4-tetrahydro-1- naphthalenamine hydrochloride/ Aldrich
(I)
458
2.92


 


113




PhSO2—
Intermediate 8
(cyclohexylmethyl) amine/Aldrich
(I)
424
2.87


 


114




PhSO2—
Intermediate 8
{[4- (methyloxy)phenyl] methyl}amine hydrochloride/ Aldrich
(I)
448
2.69


 


115




PhSO2—
Intermediate 8
(phenylmethyl)amine hydrochloride/ Aldrich
(I)
418
2.67


 


116




PhSO2—
Intermediate 8
cyclohexylamine hydrochloride/ Acros
(II)
410
2.59


 


117




PhSO2—
Intermediate 8
2-methyl-1- propanamine trifluoroacetate/ Aldrich
(II)
384
2.43


 


118




PhSO2—
Intermediate 8
[2-(3-pyridinyl)ethyl] amine/Lancaster
(II)
433
2.08


 


119




PhSO2—
Intermediate 8
[2-(4-pyridinyl)ethyl] amine/Maybridge
(II)
433
2.01


 


120




PhSO2—
Intermediate 8
2-phenylethanamine/ Aldrich
(II)
432
2.68


 


121




PhSO2—
Intermediate 8
(3-pyridinylmethyl) amine/Aldrich
(II)
419
2.12


 


122




PhSO2—
Intermediate 8
{[3,5- bis(methyloxy)phenyl] methyl}amine hydrochloride/ Aldrich
(II)
478
2.68


 


123




PhSO2—
Intermediate 8
tetrahydro-2H-pyran- 3-amine hydrochloride/ Anales de Quimica, Serie C: Quimica Organica y Bioquimica, 1988, 84(2), 148-55.
(II)
412
2.20


 


124




PhSO2—
Intermediate 8
4-amino cyclohexanane/ Nouveau Journal de Chimie, 1984, 8(7), 459-67.
(II)
424
2.15


 


125 (c) HCl




PhSO2—
Intermediate 8
{[3-chloro-4- (methyloxy)phenyl] methyl}amine/ Apin Chemicals
(I)
482
2.56


 


126








Intermediate 7
cyclohexylamine/ Aldrich
(II)
402
2.49


 


127








Intermediate 7
2-methyl-1- propanamine/ Aldrich
(II)
376
2.34





(a) Salt forms: HCl = hydrochloride


(b) Isolation Method:


(I) Filtered off directly from the reaction mixture; it is thought that compounds isolated by this method are free bases, apart from Examples 101 and 125 which are thought to be hydrochloride salts.


(II) Mass Directed preparative HPLC Method A.


(c) No N,N-diisopropylethylamine was used in the preparation of Examples 101 and 125.






The following were made in a similar manner to Example 112:
















 















Ex.





Isolation

LCMS


No.



Starting
Amine Reagent/
Method
LCMS
Rt


(a)
R1R2N—
R3SO2—
R20—
Material
Source
(b)
MH+
(min)


















319




PhSO2—
H—
Intermediate 8
N,3-dimethylaniline/ Acros
(II)
432
2.97


 


320




PhSO2—
H—
Intermediate 8
3-chloro-N- methylaniline/ Maybridge
(II)
452
3.00


 


321 TFA




PhSO2—
H—
Intermediate 8
3-aminoquinuclidine dihydrochloride/ Aldrich
(III)
437
1.98


 


330 TFA




PhSO2—
Me—
Intermediate 16
(3-pyridinylmethyl) amine/ Aldrich
(III)
433
2.08


 


331 HCl








H—
Intermediate 31
2-(aminomethyl) phenol/Buttpark
(I*)
464
2.14


 


332 TFA








H—
Intermediate 31
(3-pyridinylmethyl) amine/ Aldrich
(III)
449
2.06


 


333 TFA








H—
Intermediate 31
[2-(4-pyridinyl)ethyl] amine/ Maybridge
(III)
463
1.93


 


334 HCl




MeSO2—
Me—
Intermediate 33
2-methyl-2- propanamine/Aldrich
(IV)
336
2.04





(a) Salt forms: HCl = hydrochloride


TFA = trifluoroacetate


(b) Isolation Method:


(I) Filtered off directly from the reaction mixture; it is thought that compounds isolated by this method are free bases.


(I*) No base is used in the reaction procedure. Filtered off directly from the reaction mixture; it is thought that compounds isolated by this method are hydrochloride salts.


(II) Mass Directed HPLC Method A; it is thought that compounds isolated by this method are free bases unless the R1 or R3 groups contain basic moieties, in which case formate salts may be formed.


(III) Mass Directed HPLC Method B; it is thought that compounds isolated by this method are trifluoroacetate salts.


(IV) Mass Directed HPLC Method C; it is thought that compounds isolated by this method are hydrochloride salts.






Example 133
6-[(1,1-Dimethylethyl)thio]-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide




Intermediate 14 (0.050 g), potassium tert-butoxide (0.015 g) and tert-butylmercaptan (0.0135 ml) were added to a stirred solution of tris(dibenzylidineacetone)dipalladium (0) (0.007 g) and (oxydi-2,1-phenylene)bis(diphenylphosphine) (0.005 g) in toluene (2 ml), and the mixture was heated at 100° C. for 3.5 h and left to cool. The solvent was evaporated in vacuo to leave a brown solid (0.072 g), which was purified by Mass Directed Preparative HPLC (Method A) to give the title compound (0.008 g).
LC/MS Rt 2.83 min m/z 382 [MH+].
Similarly prepared from Intermediate 14 were the following:
















 















Isolation




Ex.

Thiol reagent/
Method
LCMS
LCMS


No.
R3S—
Source
(b)
MH+
Rt (min)















132




cyclohexanethiol/ Aldrich
(II)
408
2.99


 


135




N-(2-mercaptoethyl) acetamide/Aldrich
(II)
411
2.11


 


136




2,6-dichlorobenzene thiol/Aldrich
(II)
471
2.77


 


137




2-methyl-1- propanethiol/ Aldrich
(II)
382
2.66


 


138




1,3-oxazole-2(3H)- thione/ Can. J. Chem., 1972, 50(18), 3082-3.
(II)
393
2.29


 


139




5-methyl-1,3,4- oxadiazole-2(3H)- thione/ U.S. Pat. No. 5,670,526 A
(II)
408
2.22


 


140




phenylmethane thiol/ Aldrich
(II)
416
2.86


 


141




4-fluorobenzene thiol/ Aldrich
(IV)
420
2.87


 


142




4-(methyloxy) benzenethiol/ Aldrich
(II)
432
2.90


 


143




cyclopentanethiol/ Aldrich
(I)
394
2.98


 


144




benzenethiol/ Aldrich
(I)
402
2.96





(b) Isolation Method:


(I) Filtered off directly from the reaction mixture; it is thought that compounds isolated by this method are free bases.


(II) Mass Directed preparative HPLC Method A.


(IV) Purified by chromatography on silica gel, eluting with dichloromethane followed by ethyl acetate. It is thought that compounds isolated by this method are free bases.






The following were prepared in a similar manner to Example 133, using N,N-dimethylformamide as the reaction solvent:
















 





















Isolation




Ex.



Starting
Thiol Reagent/
Method
LCMS
LCMS


No.
R1NH—
R3S—
R20—
Material
Source
(b)
MH+
Rt (min)


















337








Me—
Intermediate 35
2- mercaptoethanol/ Sigma
(I)
402
2.19


 


338








Me—
Intermediate 35
1,2,4-triazole-3- thiol/Aldrich
(I)
425
2.12


 


339








Me—
Intermediate 35
1-methyl-2- mercaptoimidazole/ Aldrich
(I)
438
2.15


 


340








Me—
Intermediate 35
2- mercaptoimidazole/ Aldrich
(I)
424
1.96


 


341








Me—
Intermediate 35
2- benzimidazolethiol/ Aldrich
(I)
474
2.54


 


342








Me—
Intermediate 35
4-methyl-1,3- oxazole-2(3H)- thione J. Org. Chem., 1967, 32(7), 2079-81.
(I)
439
2.67


 


343








Me—
Intermediate 35
2-furanyl methanethiol/ Aldrich
(I)
438
2.79


 


344








Me—
Intermediate 36
1,1-dimethylethyl (2-mercaptoethyl) carbamate/Aldrich
(V)
495
2.73


 


345








Me—
Intermediate 36
1,1-dimethylethyl 4-mercapto-1- piperidine- carboxylate/ U.S. Pat. No. 5,317,025 A
(V)
535
3.22


 


563








Me—
Intermediate 62
tetrahydro-3- furanthiol/Advan. Carbohydrate Chem. (1963), 18 123-99
(I)
381
2.17


 


564








Me—
Intermediate 61
tetrahydro-3- furanthiol/Advan. Carbohydrate Chem. (1963), 18 123-99
(I)
398
2.65


 


565








Me—
Intermediate 61
tetrahydro-2H- pyran-4-thiol/ WO98/05635
(I)
412
2.70


 


566








Me—
Intermediate 62
tetrahydro-2H- pyran-4-thiol/ WO98/05635
(I)
395
2.20


 


569








Me—
Intermediate 62
1,1-dimethylethyl 4-mercapto-1- piperidine carboxylate/U.S. Pat. No. 5,317,025 A
(I)
494
2.80


 


570








Me—
Intermediate 61
N-(2- mercaptoethyl) acetamide/Aldrich
(I)
413
2.20


 


572








Me—
Intermediate 62
N-(2- mercaptoethyl)- acetamide/ Aldrich
(V)
396
1.90


 


516








Me—
Intermediate 35
1,1-dimethylethyl 4-mercapto-1- piperidine carboxylate/ U.S. Pat. No. 5,317,025A
(V)
541
3.10


 


517








Me—
Intermediate 35
1,1-dimethylethyl (2-mercaptoethyl) carbamate/Aldrich
(V)
501
3.68


 


528








Me—
Intermediate 36
2-mercaptoethanol/ Aldrich
(I)
396
2.20


 


603








Me—
Intermediate 61
1,1-dimethylethyl (2-mercaptoethyl) carbamate
(I)
471
2.80


 


634








Me—
Intermediate 62
ethanethiol/ Aldrich
(I)
339
2.32


 


635








Me—
Intermediate 62
1-propanethiol/ Aldrich
(I)
353
2.71


 


636








Me—
Intermediate 62
2-propanethiol/ Aldrich
(I)
353
2.47


 


637








Me—
Intermediate 62
2-methyl-2- propanethiol/ Aldrich
(I)
367
2.58


 


638








Cl—
Intermediate 96
ethanethiol/ Aldrich
(I)
359
2.59


 


639








Cl—
Intermediate 96
1-propanethiol/ Aldrich
(I)
373
2.76


 


640








Cl—
Intermediate 96
2-propanethiol/ Aldrich
(I)
373
2.71


 


641








Cl—
Intermediate 96
2-methyl-2- propanethiol/ Aldrich
(I)
387
2.93


 


642








Me—
Intermediate 62
ethanethiol/ Aldrich
(I)
373
2.81


 


643








Me—
Intermediate 97
1-propanethiol/ Aldrich
(I)
387
3.06


 


644








Me—
Intermediate 97
2-propanethiol/ Aldrich
(I)
387
2.95


 


645








Me—
Intermediate 97
2-methyl-2- propanethiol/ Aldrich
(I)
401
3.16


 


646








Cl—
Intermediate 100
ethanethiol/ Aldrich
(I)
393
3.1


 


647








Cl—
Intermediate 100
1-propanethiol/ Aldrich
(I)
407
3.3


 


648








Cl—
Intermediate 100
2-propanethiol/ Aldrich
(I)
407
3.25


 


649








Cl—
Intermediate 100
2-methyl-2- propanethiol/ Aldrich
(I)
421
3.33


 


650








Me—
Intermediate 98
ethanethiol/ Aldrich
(I)
357
2.59


 


651








Me—
Intermediate 98
1-propanethiol/ Aldrich
(I)
371
2.84


 


652








Me—
Intermediate 98
2-propanethiol/ Aldrich
(I)
371
2.84


 


653








Me—
Intermediate 98
2-methyl-2- propanethiol/ Aldrich
(I)
385
2.94


 


654








Cl—
Intermediate 99
ethanethiol/ Aldrich
(I)
377
2.88


 


655








Cl—
Intermediate 99
1-propanethiol/ Aldrich
(I)
391
3.07


 


656








Cl—
Intermediate 99
2-propanethiol/ Aldrich
(I)
391
3.03


 


657








Cl—
Intermediate 99
2-methyl-2- propanethiol/ Aldrich
(I)
405
3.14


 


658








Cl—
Intermediate 102
ethanethiol/ Aldrich
(I)
376
2.94


 


659








Cl—
Intermediate 102
1-propanethiol/ Aldrich
(I)
390
3.08


 


660








Cl—
Intermediate 102
2-propanethiol/ Aldrich
(I)
390
3.02


 


661








Cl—
Intermediate 102
2-methyl-2- propanethiol/ Aldrich
(I)
404
3.21


 


662








Me—
Intermediate 101
ethanethiol/ Aldrich
(I)
356
2.5


 


663








Me—
Intermediate 101
1-propanethiol/ Aldrich
(I)
370
2.65


 


664








Me—
Intermediate 101
2-propanethiol/ Aldrich
(I)
370
2.61


 


665








Me—
Intermediate 101
2-methyl-2- propanethiol/ Aldrich
(I)
384
2.89


 


681








Me—
Intermediate 101
N-(2- mercaptoethyl)-N- methylacetamide/ Tetrahedron 1986, 42 (5), 1449
(I)
427
2.30





(b) Isolation Method:


(I) These were purified by SCX column, eluting with ammonia/methanol.


(V) These were purified by chromatography on silica gel (eluting with ethyl acetate/cyclohexane) followed by trituration with cyclohexane to give the pure product; it is thought that compounds isolated by this method are free bases.






Example 577
4-(2,3-Dihydro-1-benzofuran-4-ylamino)-8-methyl-6-(methylthio)-3-quinolinecarboxamide




A stirred mixture of Intermediate 36 (0.2 g), sodium thiomethoxide (0.058 g), tris(dibenzylideneacetone)dipalladium(0) (0.076 g), (oxidi-2,1-phenylene)-bis(diphenylphosphine) (0.045 g), and potassium tert-butoxide (0.047 g) in N,N-dimethylformamide (10 ml) was heated at 100° C. under nitrogen for 18 h. The cooled reaction mixture was applied directly to an SCX cartridge (10 g) and eluted with methanol (150 ml) followed by 2M ammonia in methanol (100 ml). Evaporation of the methanol/ammonia fraction gave the title compound as a yellow solid (0.13 g).
LC/MS Rt 2.48 min, m/z 366 [MH+]
The following were prepared in a similar manner to Example 577, but without adding potassium tert-butoxide to the reaction mixture:
















 












Ex.


Starting
LCMS
LCMS


No.
R1NH—
R20—
Material
MH+
Rt (min)





577




Me—
Intermediate 36
382
2.00


 


604




Et—
Intermediate 74
388
2.57


 


605




Et—
Intermediate 75
356
2.76


 


606




Et—
Intermediate 76
372
2.95


 


607




Et—
Intermediate 77
363
2.71


 


608




Et—
Intermediate 78
352
2.65


 


609




Et—
Intermediate 79
392
2.44


 


610




Et—
Intermediate 80
380
2.62


 


611




Et—
Intermediate 81
339
2.2


 


612




Et—
Intermediate 82
357
2.55


 


613




Et—
Intermediate 83
373
2.73


 


614




F—
Intermediate 85
363
2.69


 


615




F—
Intermediate 86
329
2.16


 


616




F—
Intermediate 84
347
2.53


 


617




F—
Intermediate 89
346
2.87


 


618




F—
Intermediate 90
363
3.06


 


619




F—
Intermediate 91
342
2.91


 


620




F—
Intermediate 92
353
2.77


 


621




F—
Intermediate 93
382
2.56


 


622




F—
Intermediate 94
376
2.88


 


623




F—
Intermediate 88
370
2.81


 


682




Cl—
Intermediate 38
358
3.27


 


683




Cl—
Intermediate 39
392
3.06


 


684




Cl—
Intermediate 40
386
3.10


 


685




Cl—
Intermediate 41
369
3.01


 


686




Cl—
Intermediate 42
362
3.20


 


687




Cl—
Intermediate 43
398
2.82









Example 134
4-{[3-(Methyloxy)phenyl]amino}-6-({[4-(methyloxy)phenyl]methyl}thio)-3-quinolinecarboxamide




Intermediate 14 (0.020 g), potassium tert-butoxide (0.0061 g) and [4-(methyloxy) phenyl]methanethiol (available from Aldrich) (0.007 ml) were added to a stirred solution of tris(dibenzylidineacetone)dipalladium(0) (0.002 g) and (oxydi-2,1-phenylene)bis (diphenylphosphine) (0.002 g) in N,N-dimethylformamide (1.5 ml), and the mixture was heated under microwave irradiation at 60° C. for 8 min. The solvent was evaporated in vacuo, and the residue purified by Mass Directed Preparative HPLC (Method A) to give the title compound (0.0048 g).
LC/MS Rt 2.93 min m/z 446 [MH+]
Example 129
6-[(1,1-Dimethylethyl)sulfonyl]-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide




Example 133 (0.010 g) was dissolved in N,N-dimethylformamide (2 ml) and anisole (0.013 ml) was added. Oxone (0.075 g) was added and the mixture stirred for 16 h at room temperature. After quenching with 1M aqueous sodium sulphite, the mixture was extracted with dichloromethane; the organic layer was dried over magnesium sulphate and evaporated in vacuo to give a yellow solid. Purification by mass directed HPLC (Method A) gave the title compound (0.005 g).
LC/MS Rt 2.48 min m/z 414 [MH+].
Similarly prepared were the following:
















 















Isolation




Ex.

Starting
Method
LCMS
LCMS


No.
R3SO2—
Material
(b)
MH+
Rt (min)















128




Example 142
(II)
464.09
2.83


 


130 (a)




Example 135
(II)
443.1
2.11





(a) No anisole was used in the reaction mixture in this Example.


(b) Isolation Method:


(II) Mass Directed preparative HPLC (Method A).






The following were prepared in a similar manner to Example 129, but without the addition of anisole to the reaction mixture:
















 














Ex.




Isolation




No.



Starting
Method
LCMS
LCMS


(a)
R1NH—
R3SO2—
R20—
Material
(b)
MH+
Rt (min)

















346 HCl








Me—
Example 337
(IV)
434
2.10


 


347 HCl








Me—
Example 338
(IV)
457
2.30


 


348 HCl








Me—
Example 339
(IV)
470
2.46


 


349 HCl








Me—
Example 340
(IV)
456
2.27


 


350 HCl








Me—
Example 341
(IV)
506
2.79


 


351 HCl








Me—
Example 343
(IV)
470
2.66


 


352








Me—
Example 345
(V)
567
3.08


 


353








Me—
Example 344
(VI)
527.5
2.76


 


369 HCl




MeSO2—
Cl—
Example 682
(IV)
390
2.77


 


370 HCl




MeSO2—
Cl—
Example 683
(IV)
424
2.63


 


371 HCl




MeSO2—
Cl—
Example 684
(IV)
418
2.77


 


372 HCl




MeSO2—
Cl—
Example 685
(IV)
401
2.57


 


373 HCl




MeSO2—
Cl—
Example 686
(IV)
394
2.70


 


374 HCl




MeSO2—
Cl—
Example 687
(IV)
430
2.51


 


478








Me—
Intermediate 29
(VI)
519
2.55


 


602








Me—
Example 603
(VII)
503
2.90


 


515








Me—
Example 562
(VI)
449
2.60





(a) Salt forms: HCl = hydrochloride.


(b) Isolation Method:


(IV) Mass Directed preparative HPLC (Method C).


(V) Column chromatography on silica gel.


(VI) Aqueous work-up.


(VII) Trituration from acetonitrile.






The following were prepared in a similar manner to Example 129 without the addition of anisole to the reaction mixture:
















 














Ex.




Isolation




No.



Starting
Method
LCMS
LCMS


(a)
R1NH—
R20—
R3SO2—
Material
(b)
MH+
Rt (min)

















522




Me—




Example 521
(II)
448
2.33


 


591 HCl




Et—
MeSO2—
Example 604
(IV)
418
2.39


 


592 HCl




Et—
MeSO2—
Example 605
(IV)
388
2.51


 


593 HCl




Et—
MeSO2—
Example 607
(IV)
395
2.46


 


594 HCl




Et—
MeSO2—
Example 612
(IV)
389
2.32


 


595 HCl




Et—
MeSO2—
Example 613
(IV)
405
2.47


 


596 HCl




Et—
MeSO2—
Example 608
(IV)
384
2.41


 


597 HCl




Et—
MeSO2—
Example 606
(IV)
404
2.70


 


598 HCl




Et—
MeSO2—
Example 609
(IV)
424
2.34


 


599 HCl




Et—
MeSO2—
Example 610
(IV)
412
2.44


 


600 HCl




Et—
MeSO2—
Example 611
(IV)
370
1.99


 


624




F—
MeSO2—
Example 623
(II)
402
2.52


 


625




F—
MeSO2—
Example 617
(II)
378
2.54


 


626




F—
MeSO2—
Example 618
(II)
395
2.70


 


627




F—
MeSO2—
Example 619
(II)
374
2.61


 


628




F—
MeSO2—
Example 620
(II)
385
2.42


 


629




F—
MeSO2—
Example 621
(II)
414
2.27


 


630




F—
MeSO2—
Example 622
(II)
408
2.45


 


631




F—
MeSO2—
Example 615
(II)
361
1.91


 


632




F—
MeSO2—
Example 614
(II)
395
2.32


 


633




F—
MeSO2—
Example 616
(II)
379
2.09





(a) Salt forms: HCl = hydrochoride.


(b) Isolation method:


(II) Mass Directed preparative HPLC (Method A).


(IV) Mass Directed preparative HPLC (Method C).






Example 184
8-Methyl-4-{[3-(methyloxy)phenyl]amino}-6-(phenylsulfonyl)-3-quinolinecarboxamide hydrochloride




Intermediate 16 (0.036 g) was suspended in acetonitrile (2 ml), 3-methoxyaniline (available from Aldrich) (0.012 g) was added, and the mixture was heated under reflux for 16 h. After cooling to room temperature the mixture was filtered and the residue dried to give the title compound as a beige solid (0.020 g).
LC/MS Rt 2.86 min m/z 448 [MH+]
Similarly prepared was:
















 














Ex.




Isolation




No.


Starting
Amine Reagent/
Method
LCMS
LCMS


(a)
R1NH—
R3SO2—
Material
Source
(b)
MH+
Rt (min)





185 HCl




PhSO2—
Intermediate 16
4-fluoro-3- methoxyaniline/ Apollo-Chem
(I)
466
2.89





(b) Isolation method:


(I) Filtered off from the reaction mixture.






Example 186
7-Methyl-4-{[3-(methyloxy)phenyl]amino}-6-(methylsulfonyl)-3-quinolinecarboxamide hydrochloride




Intermediate 17 (0.058 g) was suspended in acetonitrile (2 ml), 3-methoxyaniline (0.024 g) (available from Aldrich) was added, and the mixture was heated under reflux for 4 h. After cooling,to room temperature the mixture was filtered and the residue dried to give the title compound as a beige solid (0.042 g).
LC/MS Rt 2.21 min m/z 386 [MH+]
Example 335
4-[(3-Aminophenyl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide trifluoroacetate




To a stirred mixture of Example 187 (0.130 g) in dichloromethane (5 ml) was added trifluoroacetic acid (1 ml). The mixture was stirred at 20° C. for 1 h and then the solvent was removed in vacuo to give the title compound as a yellow gum (0.100 g).
LC/MS Rt 1.87 min m/z 357 [MH+]
Similarly prepared from example 188 was:
Example 336
4-{[3-(Aminomethyl)phenyl]amino}-6-(methylsulfonyl)-3-quinolinecarboxamide trifluoroacetate




Example 376
1,1-Dimethylethyl 4-({3-(aminocarbonyl)-8-methyl-4-[(1-methyl-1H-benzimidazol-6-yl)amino]-6-quinolinyl}sulfonyl)-1-piperidinecarboxylate




A mixture containing Intermediate 44 (0.500 g), 1,1-dimethylethyl 4-mercapto-1-piperidinecarboxylate (0.442 g, synthesised according to U.S. Pat. No. 5,317,025A), potassium tert-butoxide (0.248 g), tris(dibenzylideneacetone) dipalladium (0.093 g) and (oxydi-2,1-phenylene)bis(diphenylphosphine) (0.091 g) was dissolved in N,N-dimethylformamide (20 ml) and stirred under an atmosphere of nitrogen at 100° C. for 2 h. The solvents were concentrated in vacuo and the residue partitioned between ethyl acetate (100 ml) and water (100 ml). The organic extract was washed with sodium bicarbonate solution followed by brine, dried over magnesium sulfate and concentrated in vacuo to an orange solid. This was purified by flash chromatography on silica gel eluting with a gradient of ethanol (0% to 10%) in ethyl acetate, to give the intermediate sulphide 1,1-dimethylethyl 4-({3-(aminocarbonyl)-8-methyl-4-[(1-methyl-1H-benzimidazol-6-yl)amino]-6-quinolinyl}thio)-1-piperidinecarboxylate as a yellow solid (0.375 g).
LC/MS Rt 2.63 min, m/z 547 [MH+]
Oxone (1.6 g) was added to a solution of the sulphide (0.370 g) in N,N-dimethylformamide (10 ml). The mixture was stirred at room temperature for 1 h and was quenched with a solution of sodium sulphite (4 g) in water (150 ml). The mixture was extracted with ethyl acetate (2×100 ml) and the combined organic suspension washed with water (2×100 ml) and extracted in vacuo to a pale yellow solid. This was purified by recrystallisation from boiling methanol to give the title compound as a pale yellow powder (0.265 g).
LC/MS Rt 2.47 min, m/z 579 [MH+]
Similarly prepared were the following:


































Ex.







No.



Starting
Thiol Reagent/


(a)
R1NH—
R3SO2—
R20—
Material
Source





354








H—
Intermediate 37
Methyl 4- mercaptobenzoate/ Toronto Research Chemicals


 


355








H—
Intermediate 37
Methyl 3- mercaptobenzoate/ Toronto Research Chemicals


 


356








H—
Intermediate 37
3-methylbenzene thiol/ Aldrich


 


357 HCl








H—
Intermediate 14
3,4-dimethylthio phenol/Aldrich


 


358








H—
Intermediate 14
3-fluorobenzene thiol/Avocado


 


359 HCl








H—
Intermediate 14
4-(trifluoromethyl) thiophenol/ Fluorochem


 


361








H—
Intermediate 37
3-chlorothiophenol/ Adrich


 


362








H—
Intermediate 37
4-tert-butylthio phenol/ Lancaster


 


363








H—
Intermediate 37
3,5-dimethyl benzenethiol/ Aldrich


 


364








H—
Intermediate 37
1,1-dimethylethyl (2-mercaptoethyl) carbamate/Aldrich


 


365 HCl








H—
Intermediate 37
[4-(methyloxy) phenyl] methanethiol/ Aldrich


 


366








H—
Intermediate 37
4-bromothiophenol/ Aldrich


 


367 HCl








H—
Intermediate 37
2-mercaptoanisole/ Lancaster


 


368 HCl








H—
Intermediate 37
(4-chlorophenyl) methanethiol/ Aldrich


 


375 HCl








H—
Intermediate 37
3-methoxybenzene thiol/ Aldrich


 


377








H—
Intermediate 45
1,1-dimethylethyl 4-mercapto-1- piperidine carboxylate/ U.S. Pat. No. 5,317,025 A


 


378








H—
Intermediate 46
1,1-dimethylethyl 4-mercapto-1- piperidine carboxylate/ U.S. Pat. No. 5,317,025 A


 


472








H—
Intermediate 14
1,1-dimethylethyl 4-mercapto-1- piperidine carboxylate/ U.S. Pat. No. 5,317,025 A
















Ex.
Isolation






No.
Method

LCMS
LCMS



(a)
(b)
Solvent
MH+
Rt (min)







354
(II)
Toluene
492
2.76



355
(II)
Toluene
492
2.76



356
(VII)
Toluene
448
2.90



357
(IV)
Toluene
462
3.02



HCl



358
(V)
Toluene
452
2.83



359
(IV)
Toluene
502
3.16



HCl



361
(II)
Toluene
468
2.96



362
(II)
Toluene
490
3.26



363
(II)
Toluene
462
3.05



364
(V)
Toluene
469
2.59



365
(IV)
Toluene
478
2.63



HCl



366
(VI)
Toluene
513
3.02



367
(IV)
Toluene
464
2.52



HCl



368
(IV)
Toluene
482
2.91



HCl



375
(VIII)
N,N-dimethyl-
464
2.76



HCl

formamide



377
(V)
N,N-dimethyl-
555
2.97





formamide



378
(V)
N,N-dimethyl-
550
3.01





formamide



472
(V)
N,N-dimethyl-
541
2.89





formamide







(a) Salt forms: HCl = hydrochloride



(b) Isolation Method:



(II) Mass Directed preparative HPLC (Method A).



(IV) Mass Directed preparative HPLC (Method C).



(V) Column chromatography on silica gel. Compounds isolated by this method are free bases.



(VI) Aqueous workup only with no further chromatography. Compounds isolated by this method are free bases.



(VII) Recrystallised from methanol



(VIII) Mass Directed preparative HPLC (Method A), followed by treatment with 2M HCl in ethanol.






Example 360
6-[(4-Hydroxyphenyl)sulfonyl]-4-[(3-methoxyphenyl)amino]quinoline-3-carboxamide




Oxone (3.9 g) was added to a stirred solution of Intermediate 47 (1.1 g) in dry N,N-dimethylformamide (30 ml) at room temperature for 18 h. The mixture was poured into aqueous sodium sulphite solution (200 ml) and extracted with ethyl acetate (3×100 ml). The organic extracts were washed with water (2×100 ml), dried (Na2SO4) and concentrated. A solution of the residual oil in tetrahydrofuran (20 ml) was stirred with a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (4 ml) for 1 h. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (2×25 ml) and water (2×50 ml). The organic extracts were dried (Na2SO4) and concentrated to give the title compound as a yellow solid (0.67 g).
LC/MS Rt 2.58 min, m/z 450 [MH+]
Example 379
Methyl 3-[(3-(aminocarbonyl)-8-methyl-4-{[3-(methyloxy)phenyl]amino}-6-quinolinyl)sulfonyl]benzoate




To Intermediate 45 (0.47 g) in dimethoxyethane (10 ml) was added methyl 3-mercaptobenzoate (0.34 ml), potassium phosphate (0.42 g), copper (I) iodide (0.028 g) and N,N-diethylsalicylamide (0.39 g). The mixture was heated at 85° C. for 4 h before adding further methyl 3-mercaptobenzoate (0.34 ml) and copper (I) iodide (0.028 g). After a further 16 h the reaction mixture was concentrated in vacuo and partitioned between ethyl acetate (150 ml) and water (150 ml). The organic layers were washed with brine (100 ml), dried over sodium sulfate and concentrated in vacuo to yield a crude product which was triturated with diethyl ether (20 ml). The solid obtained was collected by filtration, washed with diethyl ether (2×10 ml) to give methyl 3-[(3-(aminocarbonyl)-8-methyl-4-{[3-(methyloxy)phenyl]amino}-6-quinolinyl)thio]benzoate as a beige solid (0.37 g).
LC/MS Rt 3.09 min m/z 474 [MH+]
To a solution of the methyl 3-[(3-(aminocarbonyl)-8-methyl-4-{[3-(methyloxy)phenyl]amino}-6-quinolinyl)thio]benzoate (0.367 g) in N,N-dimethylformamide (10 ml) was added oxone (1.91 g). The mixture was stirred at room temperature for 18 h before quenching with aqueous sodium sulphite solution and extracting with chloroform (3×200 ml). The organic layers were combined, washed with brine, dried over magnesium sulfate and concentrated in vacuo and purified by chromatography on silica gel, eluting with 2:1 ethyl acetate: cyclohexane, to give the title compound as a yellow solid (0.100 g).
LC/MS Rt 3.03 min m/z 506 [MH+]
The following were synthesised in the same manner as Example 379, however potassium carbonate was used as a base instead of potassium phosphate and no N′N-diethylsalicylamide was added.
















 














Ex.




Purification




No.


Starting
Thiol Reagent/
Method
LCMS
LCMS


(a)
R3SO2—
R20—
Material
Source
(b)
MH+
Rt (min)

















380




Me—
Intermediate 45
3,4- dimethoxythiophenol Aldrich
(V)
508
2.81


 


381 HCl




Me—
Intermediate 45
3,4,5-tris(methyloxy) benzenethiol J. Am. Chem. Soc., 2002, 124(17), 4642-4846
(IV)
538
2.92


 


382 HCl




H—
Intermediate 14
3,4- dimethoxythiophenol/ Avocado
(IV)
494
2.59


 


383 HCl




Me—
Intermediate 45
3-ethoxythiophenol/ Aldrich
(IV)
492
3.08





(a) Salt forms: HCl = hydrochloride


(b) Isolation Method:


(IV) Mass Directed preparative HPLC (Method C).


(V) Column chromatography on silica gel; it is thought that compounds isolated by this method are free bases.






Example 386
6-(Ethylsulfonyl)-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide hydrochloride




Intermediate 37 (0.100 g) was combined with (oxydi-2,1-phenylene)bis(diphenylphosphine) (0.011 g), potassium tert-butoxide (0.025 g) and tris(dibenzylideneacetone)dipalladium(o) (0.008 g) in 1,4-dioxane (1 ml). Ethanethiol (available from Aldrich, 0.023 ml) was added and the mixture was stirred under microwave irradiation (power 40 W) for 8 min at 90° C. The reaction was quenched by addition of 4M HCl in dioxane, then partitioned between ethyl acetate and sodium bicarbonate solution. The organic layer was concentrated in vacuo to give 0.090 g of crude 6-(ethylthio)-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide.
The crude sulphide was dissolved in N,N-dimethylformamide (5 ml) and treated with an excess of oxone (0.375 g) and stirred at room temperature for 4 h. The reaction was quenched by the addition of 1M aqueous sodium sulphite solution, then partitioned between dichloromethane and sodium bicarbonate solution. The solvent was removed in vacuo and the residue was purified by mass directed preparative HPLC (Method C). After evaporation of solvent the title compound was obtained as a yellow solid.
LC/MS Rt 2.30 min, m/z 386 [MH+]
The following were prepared in the same manner as Example 386:
















 













Ex.





LCMS


No.


Starting
Thiol Reagent/
LCMS
Rt


(a)
R3SO2—
R20—
Material
Source
MH+
(min)





384 (b)




H—
Intermediate 14
Isobutyl mercaptan/ Aldrich
414
2.56


 


387 HCl




H—
Intermediate 37
1-butanethiol/ Aldrich
414
2.67


 


388 HCl




H—
Intermediate 37
Methyl-3- mercaptopropionate/ Fluka
444
2.39


 


389 HCl




H—
Intermediate 37
Phenethyl mercaptan/Aldrich
462
2.88


 


390 HCl




H—
Intermediate 37
2- furanylmethanethiol/ Aldrich
438
2.46


 


391 HCl




H—
Intermediate 37
2,2,2- trifluoroethanethiol/ Aldrich
440
2.6


 


392 HCl




Me—
Intermediate 45
N-(2-mercaptoethyl) acetamide/Aldrich
457
2.25





(a) Salt forms: HCl = hydrochloride


(b) Isolation method: Mass Directed preparative HPLC (Method A).






Example 393
3-[(3-(Aminocarbonyl)-8-methyl-4-{[3-(methyloxy)phenyl]amino}-6-quinolinyl)sulfonyl]benzoic acid




Example 379 (0.1 g) was dissolved in methanol (5 ml) and 2M aqueous sodium hydroxide (1 ml). The mixture was heated to 75° C. for 4 h before cooling and standing at ambient temperature for 18 h. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (100 ml) and water (100 ml). The layers were separated and the aqueous layer was washed with diethyl ether (50 ml), acidifed to pH4 (2M hydrochloric acid) and extracted with ethyl acetate (2×150 ml). The combined ethyl acetate layers were washed with brine (100 ml), dried over magnesium sulfate and concentrated in vacuo to yield the title compound as a beige solid (0.082 g).
LC/MS Rt 2.82 min m/z 492 [MH+].
Similarly prepared were the following:
















 















Isolation




Example

Starting
Method
LCMS
LCMS


Number
R3SO2—
Material
(b)
MH+
Rt (min)





394




Example 354
(II)
478
2.67


 


395




Example 355
(II)
478
2.65





(b) Isolation Method: (II) Mass Directed HPLC Method A






The following were prepared from the intermediates shown in the table in a similar manner to the method by which Example 393 was prepared, via Example 379, from Intermediate 45.
















 












Example


Isolation




Number

Starting
Method
LCMS
LCMS


(a)
R1NH—
Material
(b)
MH+
Rt (min)















396 HCl




Intermediate 44
(IV)
516
2.25


 


397 HCl




Intermediate 46
(IV)
487
2.9


 


398




Intermediate 36
(I)
504
2.83





(a) Salt forms: HCl = hydrochloride


(b) Isolation Method:


(I) filtered off and used crude.


(IV) Mass Directed HPLC Method C; it is thought that compounds isolated by this method are hydrochloride salts.






Example 399
6-({3-[(Dimethylamino)carbonyl]phenyl}sulfonyl)-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide hydrochloride




To a solution of Example 393 (0.082 g) in N,N-dimethylformamide (3 ml) was added N,N-diisopropylethylamine (0.12 ml) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.071 g). The mixture was stirred for 20 min before adding a solution of dimethylamine in tetrahydrofuran (2M, 0.8 ml, Aldrich). After a further 1 h more dimethylamine in tetrahydrofuran (2M, 0.8 ml) was added. After 1 h the reaction mixture was concentrated in vacuo and partitioned between ethyl acetate (200 ml) and aqueous sodium bicarbonate (100 ml). The organic layers were washed with brine (100 ml), dried over magnesium sulfate and concentrated in vacuo. Purification by mass directed HPLC (Method C) gave the title compound as a yellow solid (0.022 g).
LC/MS Rt 2.61 min m/z 519 [MH+].
Similarly prepared were the following:
















 














Example




Amine




Number



Starting
Reagent/
LCMS
LCMS


(a)
R1NH—
R20—
R29R30N—
Material
Source
MH+
Rt (min)





400 HCl




H—
Me2N—
Example 395
dimethylamine 2M solution in tetrahydrofuran/ Aldrich
505
2.52


 


401 HCl




H—
H2N—
Example 395
Ammonia solution 880/Merck
477
2.42


 


402 HCl




H—
MeNH—
Example 395
methylamine 2M solution in tetrahydrofuran/ Aldrich
491
2.47


 


403 HCl




H—




Example 395
Pyrrolidine/ Lancaster
531
2.64


 


404 HCl




H—




Example 395
propylamine/ Aldrich
519
2.74


 


405 (b)




H—




Example 395
Isobutylamine/ Aldrich
533
2.76


 


406 HCl




H—




Example 395
Morpholine/ Lancaster
547
2.51


 


407 HCl




H—




Example 395
Ethanolamine/ Aldrich
521
2.38


 


408 HCl




Me—
Me2N—
Example 397
dimethylamine 2M solution in tetrahydrofuran/ Aldrich
514
2.71


 


409 HCl




Me—
Me2N—
Example 396
dimethylamine 2M solution in tetrahydrofuran/ Aldrich
543
2.19


 


410 HCl




Me—
H2N—
Example 396
Ammonia solution 880/Merck
515
2.13


 


411 HCl




Me—
MeNH—
Example 396
methylamine 2M solution in tetrahydrofuran/ Aldrich
529
2.17


 


412 HCl




Me—
H2N—
Example 397
dimethylamine 2M solution in tetrahydrofuran/ Aldrich
486
2.61


 


413 HCl




Me—
MeNH—
Example 397
methylamine 2M solution in tetrahydrofuran/ Aldrich
500
2.69


 


414 (c)




Me—
Me2N—
Example 398
dimethylamine 2M solution in tetrahydrofuran/ Aldrich
531
2.65





(a) Salt form: HCl = hydrochloride


(b) Example 405 was isolated by Mass Directed preparative HPLC (Method A).


(c) Example 414 was isolated by aqueous work up.






Similarly prepared from Example 394 were the following:
















 












Example


Isolation




Number

Amine Reagent/
method
LCMS
LCMS


(a)
R29R30N—
Source
(b)
MH+
Rt (min)















415
H2N—
Ammonia solution
(I)
477
2.45


HCl

880/Merck


416
MeHN—
methylamine 2M
(I)
491
2.51


HCl

solution in




tetrahydrofuran/




Aldrich


 


417 HCl




Pyrrolidine/Lancaster
(I)
531
2.66


 


418 HCl




propylamine/Aldrich
(I)
519
2.75


 


419
Me2N—
dimethylamine 2M
(I)
505
2.53


HCl

solution in




tetrahydrofuran/




Aldrich


 


420




Isobutylamine/Aldrich
(II)
533
2.8





(a) Salt form: HCl = hydrochloride


(b) Isolation Method:


(I) Mass Directed preparative HPLC (Method C).


(II) Mass Directed preparative HPLC (Method A).






Example 421
4-{[3-(Methyloxy)phenyl]amino}-6-(4-piperidinylsulfonyl)-3-quinolinecarboxamide




To a mixture containing Example 472 (1.3 g) in anisole (9 ml) was added a solution of 95% trifluoroacetic acid in water (45 ml). The mixture was stirred for 2 h at room temperature and was then concentrated in vacuo. The residue was co-evaporated with toluene (2×20 ml) and triturated with diethyl ether to give a yellow solid. The solid was partitioned between aqueous potassium carbonate (300 ml) and chloroform (300 ml) and the aqueous phase extracted with chloroform (3×200 ml). The combined organic extracts were washed with water (100 ml), dried and concentrated in vacuo to give the title compound as a yellow solid (1.1 g).
LC/MS Rt 1.94 min, m/z 441 [MH+]
Similarly prepared were the following:
















 














Ex.




Isolation

LCMS


No.



Starting
Method
LCMS
Rt


(a)
R1NH—
R20—
R3SO2—
Material
(b)
MH+
(min)

















422 TFA




Me—




Example 353
(I)
1.98
427


 


423




Me—




Example 352
(II)
467
1.97


 


470 TFA




Me—




Example 378
(III)
450
2.03


 


474 TFA




Me—




Example 376
(I)
479
1.77


 


476




Me—




Intermediate 55
(II)
473
2.10


 


477




Me—




Intermediate 56
(II)
433
2.03


 


561




Me—




Example 602
(IV)
403
1.93


 


567 HCl




Me—




Example 568
(V)
426
1.80





(a) Salt forms: TFA = trifluoroacetate


(b) Isolation Method:


(I) Filtered off directly from the reaction mixture; it is thought that compounds isolated by this method are trifluoroacetate salts.


(II) Aqueous workup of the crude reaction mixture without further purification; it is thought that compounds isolated by this method are free bases.


(III) Crude product was trituated to give the desired product and no further purification was carried out; it is thought that compounds isolated by this method are trifluoroacetate salts.


(IV) Product isolated by SCX ion exchange to give the free base


(V) Reaction mixture evaporated to dryness; it is assumed that this method gave the hydrochloride salt.






Example 424
4-{[3-(Methyloxy)phenyl]amino}-6-{[1-(phenylcarbonyl)-4-piperidinyl]sulfonyl}-3-quinolinecarboxamide




To a mixture containing Example 421 (0.050 g) and triethylamine (0.025 ml) in dioxane (2 ml) was added benzoyl chloride (0.020 ml). The mixture was stirred under nitrogen for 18 h at room temperature and was then diluted with methanol (5 ml). The solution was applied to an aminopropyl cartridge and eluted with methanol. The eluent was evaporated and the residual gum purified by chromatography on SPE eluting with a gradient of methanol in chloroform (0% to 10%) to give the title compound as a yellow solid (0.043 g).
LC/MS Rt 2.63 min, m/z 545 [MH+]
Similarly prepared were the following:
















 















Ex.





Isolation

LCMS


No.



Starting
Electrophile/
Method
LCMS
Rt


(a)
R1NH—
R20—
Rx—
Material
Source
(b)
MH+
(min)


















425




H—




Example 421
Methyl chloroformate/ Aldrich
(II)
499
2.48


 


426




H—




Example 421
Acetyl chloride/ Aldrich
(II)
483
2.27


 


427




H—




Example 421
Methane sulphonyl chloride/ Aldrich
(V)
519
2.43


 


428




H—




Example 421
3-methylbutanoyl chloride/Aldrich
(III)
525
2.61


 


429




H—




Example 421
Cyclopropane carbonyl chloride/ Aldrich
(III)
509
2.42


 


430




H—




Example 421
2-furancarbonyl chloride/Aldrich
(III)
535
2.5


 


431




H—




Example 421
5-methyl-3- isoxazolecarbonyl chloride/ Maybridge
(III)
550
2.55


 


432




H—




Example 421
Benzene sulphonyl chloride/ Aldrich
(IV)
581
2.9


 


433




H—




Example 421
3,5-dimethyl-4- isoxazolesulfonyl chloride/Avocado
(IV)
600
2.88


 


434




H—




Example 421
2-(acetylamino)-4- methyl-1,3- thiazole-5-sulfonyl chloride/Aldrich
(IV)
659
2.69


 


435




H—




Example 421
1-butanesulphonyl chloride/Aldrich
(IV)
561
2.75


 


436




H—




Example 421
1-methylimidazole 4-sulphonyl chloride/ Maybridge
(IV)
585
2.35


 


437




H—




Example 421
Isoxazole-5- carbonyl chloride/ Lancaster
(III)
536
2.37


 


438




H—




Example 421
2-furancarbonyl chloride/ Maybridge
(III)
535
2.42


 


439




H—




Example 421
isobutyryl chloride/ Aldrich
(III)
511
2.42


 


440




H—




Example 421
Propionyl chloride/ Aldrich
(III)
497
2.31


 


441




H—




Example 421
1- pyrrolidinecarbonyl chloride/Lancaster
(III)
538
2.44


 


442




Me—




Intermediate 54
2-furancarbonyl chloride/Aldrich
(I)
549
2.65


 


443




Me—




Example 470
2-furancarbonyl chloride/Aldrich
(I)
544
2.69


 


444




Me—




Example 470
Cyclopropane carbonyl chloride/ Aldrich
(I)
518
2.63


 


445




Me—




Intermediate 54
Cyclopropane carbonyl chloride/ Aldrich
(I)
523
2.57


 


446




Me—




Example 423
2-furancarbonyl chloride/Aldrich
(I)
561
2.66


 


447




Me—




Example 423
Cyclopropane carbonyl chloride/ Aldrich
(I)
535
2.58


 


448 HCl




Me—




Example 423
Methyl chloroformate/ Aldrich
(VI)
525
2.57





(a) Salt forms: HCl = hydrochloride


(b) Isolation Method:


(I) Purified by chromatography on an SPE column.


(II) Aqueous workup of the crude reaction mixture without further purification.


(III) Purified using an SPE cartridge (aminopropyl solid phase) followed by chromatography using a silica SPE column.


(IV) Purified using an SPE cartridge (aminopropyl solid phase) followed by trituration.


(V) Aqueous workup of the crude reaction followed by trituration of the crude product.


(VI) Aqueous workup of the crude reaction followed by addition of dilute HCl in dioxane and evaporation; it is thought that compounds isolated by this method are hydrochloride salts.






Example 449
4-(2,3-Dihydro-1-benzofuran-4-ylamino)-8-methyl-6-[(1-methyl-4-piperidinyl)sulfonyl]-3-quinolinecarboxamide hydrochloride




To a mixture containing Example 423 (0.050 g) and triethylamine (0.025 ml) in N,N-dimethylformamide (2 ml) was added methyl iodide (0.0075 ml). The mixture was stirred under nitrogen for 18 h at room temperature and was concentrated by blowing down under nitrogen. Purification by chromatography on silica gel, eluting with dichloromethane/methanol (95:5), gave a white solid which was dissolved in dioxane (10 ml) and treated with 4M hydrogen chloride in 1,4 dioxane (0.100 ml). After evaporation by blowing down under nitrogen the title compound was obtained as a yellow solid (0.028 g).
LC/MS Rt 1.99 min, m/z 481 [MH+]
Example 450
6-[(1-Acetyl-4-piperidinyl)sulfonyl]-4-(2,3-dihydro-1-benzofuran-4-ylamino)-8-methyl-3-quinolinecarboxamide hydrochloride




To a mixture containing Example 423 (0.050 g) in pyridine (2 ml) was added acetic anhydride (0.011 ml). The mixture was stirred under nitrogen for 18 h at room temperature, partitioned between chloroform (100 ml) and 10% sodium carbonate solution (100 ml), the layers separated by hydrophobic frit and the organic layer treated with 4M hydrogen chloride in 1,4-dioxane (0.100 ml). After evaporation by blowing down under nitrogen the title compound was obtained as a pale yellow solid (0.021 g).
LC/MS Rt 2.32 min, m/z 509 [MH+]
Similarly prepared were the following:
















 















Ex.





Isolation

LCMS


No.



Starting
Electrophile/
Method
LCMS
Rt


(a)
R1NH—
R20—
R3SO2—
Material
Source
(b)
MH+
(min)





451




Me—




Example 476
Acetic anhydride/ Aldrich
(II)
515
2.31


 


452 HCl




Me—




Example 422
Acetyl chloride/ Aldrich
(V)
469
2.14


 


453 HCl




Me—




Example 477
Acetic anhydride/ Aldrich
(I)
475
2.15


 


454 HCl




Me—




Example 477
Methane- sulphonyl chloride/ Aldrich
(IV)
511
2.23


 


455 HCl




Me—




Example 477
Methyl chloroformate/ Aldrich
(IV)
491
2.29


 


456




Me—




Example 422
Methyl chloroformate/ Aldrich
(VI)
485
2.36


 


457




Me—




Example 422
Methane- sulphonyl chloride/ Aldrich
(VI)
505
2.31


 


531




Me—




Example 567
Acetic anhydride/ Aldrich
(III)
468
2.00





(a) Salt forms: HCl = hydrochloride.


(c) Isolation Method:


(I) As for Example 450


(II) Mass Directed HPLC (Method A)


(III) Purified by silica SPE eluting with ethyl acetate/methanol


(IV) Mass Directed preparative HPLC (Method C).


(V) Aqueous work-up followed by addition of 4M HCl in 1,4-dioxane to a chloroform solution of the free base to give the hydrochloride salt.


(VI) Aminopropyl SPE column.






Example 473
4-{[3-(Methyloxy)phenyl]amino}-6-({2-[(2-methylpropanoyl)amino]ethyl}sulfonyl)-3-quinolinecarboxamide




A solution of Example 364 (0.052 g) in anisole (1 ml) was treated with a solution of 95% trifluoroacetic acid in water (5 ml). The mixture was stirred for 3 h at room temperature and was then concentrated in vacuo. The residue was trituated with ethyl acetate, and the resulting solid was collected by filtration, washed with ethyl acetate and ether and dried to give a yellow solid (0.031 g). The solid was treated with dioxane (2 ml) and the suspension treated with N,N-diisopropylethylamine (0.04 ml) followed by isobutyryl chloride (0.015 ml, Aldrich) and the resulting solution stirred at room temperature under nitrogen for 2 h. The solution was diluted with methanol (5 ml) and applied to an aminopropyl SPE cartridge. Elution with methanol gave a gum after evaporation of solvent. The gum was purified by chromatography on silica gel eluting with a gradient of 0% to 6% methanol in chloroform to give the title compound as a yellow solid (0.017 g).
LC/MS Rt 2.22 min, mlz 471 [MH+]
Example 458
6-{[1-(1H-Imidazol-4-ylcarbonyl)-4-piperidinyl]sulfonyl}-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide




To a solution containing Intermediate 54 (0.041 g) in N,N-dimethylformamide (3 ml) were added imidazole-4-carboxylic acid (0.012 g, Aldrich), (1H-1,2,3-benzotriazol-1-yloxy)(tri-1-pyrrolidinyl)phosphonium hexafluorophosphate (PyBop) (0.053 g) and N,N-diisopropylethylamine (0.03 ml). The solution was stirred under nitrogen at room temperature for 18 h and was then concentrated in vacuo. The residual gum was purified using an aminopropyl SPE cartridge eluting with methanol followed by chromatography on silica gel (SPE cartridge), eluting with a gradient of 0% to 8% methanol in chloroform, to give the title compound as a yellow solid (0.031 g).
LC/MS Rt 2.32 min, m/z 549 [MH+]
Similarly prepared were the following:
















 












Example







Number

Starting
Amine Reagent/
LCMS
LCMS


(a)
Rx—
Material
Source
MH+
Rt (min)





459




Example 474
2-furoic acid/Aldrich
573
2.15


 


460




Example 474
Cyclopropylmethanoic acid/Aldrich
547
2.12









Example 461
4-(2,3-Dihydro-1-benzofuran-4-ylamino)-8-methyl-6-{[1-(methylsulfonyl)-4-piperidinyl]sulfonyl}-3-quinolinecarboxamide hydrochloride




To a mixture containing Example 423 (0.050 g) in 1,4-dioxane (2 ml) was added methanesulphonyl chloride (0.009 ml). The mixture was stirred under nitrogen for 18h at room temperature, partitioned between ethyl acetate (100 ml) and 10% sodium bicarbonate solution (100 ml), separated and dried. The solid obtained was dissolved in 1,4-dioxane and treated with 4M hydrogen chloride in 1,4-dioxane (0.100 ml). After evaporation the title compound was obtained as a pale yellow solid (0.021 g).
LC/MS Rt 2.5 min, m/z 545 [MH+]
Example 462
6-{[4-(Cyclopropylmethoxy)phenyl]sulfonyl}-4-[(3-methoxyphenyl)amino]quinoline-3-carboxamide hydrochloride




Tributyl phosphine (0.05 ml) was added to a stirred mixture of Example 360 (0.052 g), cyclopropylmethanol (0.028 g) and di-tert-butylazodicarboxylate (0.06 g) in tetrahydrofuran (1.5 ml) at 20° under nitrogen, and stirring was continued at 20° for 3 h. The solvent was concentrated and the residue purified by mass directed preparative HPLC (Method C) to give the title compound as a yellow solid (0.09 g).
LC/MS Rt 3.4 min, m/z 504 [MH+]
Example 463
6-[(4-Ethoxyphenyl)sulfonyl]-4-[(3-methoxyphenyl)amino]quinoline-3-carboxamide hydrochloride




A stirred mixture of Example 360 (0.05 g), iodoethane (0.35 ml) and potassium carbonate (0.02 g) in acetonitrile (1.5 ml) was heated under reflux temperature for 1 h. The solvent was evaporated to dryness. The resulting solid was partitioned between dichloromethane (2×15 ml ) and water (30 ml). The extracts were dried (Na2SO4) and concentrated. The residual solid was purified by mass directed HPLC (Method C) to give the title compound as a pale yellow solid (0.033 g).
LC/MS Rt 2.87 min, m/z 478 [MH+]
The following examples were similarly prepared:
















 












Example


Alkylating




Number

Starting
Agent/
LCMS
LCMS


(a)
RxO—
Material
Source
MH+
Rt (min)





464 HCl




Example 360
1-iodopropane/ Aldrich
492
3.07


 


465 HCl




Example 360
2-iodopropane/ Aldrich
492
3.00


 


466 HCl




Example 360
Iodocyclopentane/ Aldrich
518
3.24





(a) Salt form: HCl = hydrochloride.






Example 467
4-{[3-(3-Furyl)phenyl]amino}-6-[(4methoxyphenyl)sulfonyl]quinoline-3-carboxamide hydrochloride




A stirred mixture of Example 254 (0.051 g), 3-furanboronic acid (0.017 g, Aldrich), tetrakis(triphenylphosphine)palladium(0) (0.059) and 2M sodium carbonate solution (1 ml) in dimethoxyethane (2 ml) was heated at 100° C. for 1 h. The mixture was cooled and poured into 2M sodium carbonate solution and extracted into dichloromethane (2×15 ml). The extracts were dried (Na2SO4) and concentrated. The residue was purified by mass directed HPLC (Method C) to give the title compound as a yellow solid (0.026 g).
LC/MS Rt 2.93min, m/z 500 [MH+]
Similarly prepared were the following:
















 



















LCMS


Ex.


Starting
Boronic Acid/
LCMS
Rt


No.
R1NH—
R3SO2—
Material
Source
MH+
(min)





468 (a)








Example 366
[4-(methyloxy)phenyl] boronic acid/Aldrich
540
3.18


 


469 (b)








Example 366
3-furanboronic acid/ Aldrich
500
3.02





(a) Example 468 was isolated as the free base by trituration with ether.


(b) Example 469 was isolated as the free base by chromatography on silica gel, eluting with ethyl acetate.






Example 475
6-{[3-(Dimethylamino)-3-oxypropyl]sulfonyl}-4-{[4-fluoro-3-(methyloxy)phenyl]amino}-8-methyl-3-quinolinecarboxamide hydrochloride




A solution of Intermediate 53 (0.04 g) in N,N-dimethylformamide (3 ml) was treated with oxone (0.22 g) and the resulting solution was stirred at room temperature overnight. The reaction was quenched by the addition on 1M sodium sulphite solution (1 ml) and extracted into dichloromethane. The combined organic layers were dried using a hydrophobic frit and evaporated in vacuo, and the product was dissolved in N,N-dimethylformamide (2 ml ) and treated with O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.016 g). After 5 min, dimethylamine hydrochloride (0.065 g) and N,N-diisopropylethylamine (0.015 ml) in N,N-dimethylformamide (2 ml) were added. The resulting solution was left standing at room temperature overnight. Chromatographic purification by SCX (IST lsoluteTM, 10 g), eluting with methanol and 2M ammonia/methanol gave a yellow oil. Further purification by mass-directed HPLC (Method C) gave the title compound as a yellow solid (0.009 g).
LC/MS Rt 2.34 min, m/z 489 [MH+]
Example 540
4-[(5-Chloro-3-pyridinyl)amino]-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide hydrochloride




To a solution of Intermediate 33 (0.050 g) in N1N-dimethylformamide was added 5-chloro-3-pyridinamine (0.032 g; Specs) and pyridine hydrochloride (0.029 g) and the mixture heated at 90° C. for 16 h. The solvent was blown off under a stream of nitrogen at 45° C. The residue was triturated with acetonitrile and the resultant precipitate collected by filtration to give the title compound as a brown solid.
LC/MS Rt 2.25 min m/z 391 [MH+]
Similarly prepared were the following:
















 














Ex.



Amine
Isolation

LCMS


No.


Starting
Reagent/
Method
LCMS
Rt


(a)
R1NH—
R3SO2—
Material
Source
(b)
MH+
(min)





539




MeSO2—
Intermediate 33
5-Fluoro-3- pyridinamine/ Synchem OHG
(I)
375
2.2


 


541 HCl




MeSO2—
Intermediate 33
6-Methyl-3- pyridinamine/ AsymChem
(IV)
371
1.79


 


543 HCl




MeSO2—
Intermediate 33
4-Amino-2- benzofuran- 1(3H)-one/ EP0529636A1
(II)
412
2.25


 


601




MeSO2—
Intermediate 33
2,6-dimethyl-3- pyridylamine/ Lancaster
(III)
385
1.76





(a) Salt form: HCl = hydrochoride


(b) Isolation method:


(I) Trituration with acetonitrile followed by elution through an aminopropyl SPE cartridge with methanol.


(II) Reaction was performed at 80° C. in acetonitrile and the product isolated by filtration of the reaction mixture.


(III) Mass Directed preparative HPLC (Method A) followed by chromatography on silica gel eluting with 3% methanol in dichloromethane.


(IV) Trituration with acetonitrile followed by isolation of the product by filtration.






Example 480
Ethyl 3-{[3-(aminocarbonyl)-4-(2,3-dihydro-1-benzofuran-4-ylamino)-8-methyl-6-quinolinyl]sulfonyl}propanoate




To a solution of Intermediate 57 (0.82 g) in N,N-dimethylformamide (25 ml) was added oxone (4.5 g). The mixture was stirred at room temperature for 2 h before quenching with aqueous sodium sulphite solution and extracting with dichloromethane (2×25 ml). The organic layers were combined, washed with water, dried using a hydrophobic frit, concentrated in vacuo and purified by chromatography on silica gel, eluting with an ethyl acetate: cyclohexane gradient, to give the title compound as a yellow solid (0.12 g).
LC/MS Rt 2.61 min m/z 484 [MH+].
Example 481
3-[(3-(Aminocarbonyl)-4-{[4-fluoro-3-(methyloxy)phenyl]amino}-8-methyl-6-quinolinyl)sulfonyl]propanoic acid hydrochloride




To a solution of Intermediate 53 (0.8 g) in N,N-dimethylformamide (10 ml) was added oxone (4.6 g). The mixture was stirred at room temperature for 48 h before quenching with aqueous sodium sulphite solution and extracting with dichloromethane (3×25 ml). The aqueous layers were combined and applied to an Oasis cartridge, eluting with water and methanol. The methanol fractions were combined and concentrated in vacuo. The residue was applied to an SPE cartridge (Isolute, aminopropyl solid phase), eluting with methanol and 2M ammonia/methanol; evaporation of the methanol/ammonia fraction gave an orange oil. Further purification by mass directed preparative HPLC (Method C) gave the title compound as a yellow oil (0.003 g).
LC/MS Rt 2.23 min m/z 462 [MH+].
Similarly prepared were the following:
















 











Example



LCMS


Number

Starting
LCMS
Rt


(a)
R1NH—
Material
MH+
(min)





549 HCl




Intermediate 59
432
2.38


 


550 HCl




Intermediate 60
415
1.92





(a) Salt forms: HCl = hydrochloride






Example 482
4-{[4-Fluoro-3-(methyloxy)phenyl]amino}-8-methyl-6-{[3-(4-morpholinyl) -3-oxopropyl]sulfonyl}-3-quinolinecarboxamide hydrochloride




To a solution of Example 481 (0.035 g) in N,N-dimethylformamide (2 ml) was added O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.029 g). After 5 min, morpholine (0.007 ml, available from Aldrich) and N,N-diisopropylethylamine (0.026 ml ) were added. The resulting solution was stirred at room temperature overnight, and applied directly to an SCX cartridge (IST IsoluteTM, 5 g). Elution with methanol and 2M ammonia/methanol gave an orange residue, which was further purified by mass directed preparative HPLC (Method C) to give the title compound as a yellow solid (0.006 g).
LC/MS Rt 2.37 min m/z 531 [MH+].
Similarly prepared were the following:
















 














Example



Amine
Isolation

LCMS


Number


Starting
reagent/
Method
LCMS
Rt


(a)
R3SO2—
R1NH—
Material
Source
(b)
MH+
(min)





483 HCl








Example 481
tetrahydro-2H- pyran-4-amine/ Aldrich
(II)
545
2.22


 


484 HCl








Example 481
1-methyl piperazine/ Aldrich
(II)
544
1.84


 


506 HCl








Example 550
1-methyl piperazine/ Aldrich
(II)
497
1.75


 


507 HCl








Example 549
1-methyl piperazine/ Aldrich
(II)
514
1.98





(a) Salt form HCl = hydrochloride


(b) Isolation Method:


(II) Mass Directed preparative HPLC (Method C).






Example 551
6-{[3-(Dimethylamino)-3-oxopropyl]thio}-4-[(3-fluorophenyl)amino]-8-methyl-3-quinolinecarboxamide




To a solution of Intermediate 59 (0.04 g) in N,N-dimethylformamide (1 ml) was added O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.038 g). After 5 min, dimethylamine hydrochloride (0.026 g) and N,N-diisopropylethylamine (0.07 ml) were added. The resulting solution was stirred at room temperature overnight, and applied directly to an SCX cartridge (IST IsoluteTM, 5 g), eluting with methanol followed by 2M ammonia in methanol to give the title compound as an orange oil (0.038 g).
LC/MS Rt 2.39 min m/z 427 [MH+].
Similarly prepared were the following:
















 



















LCMS


Example


Starting
Amine reagent/
LCMS
Rt


Number
R28R27N—
R1NH—
Material
Source
MH+
(min)





552








Intermediate 59
tetrahydro-2H- pyran-4-amine/ Aldrich
483
2.34


 


553








Intermediate 59
cyclopropyl(methyl) amine/Karl Industries
453
2.56


 


554








Intermediate 59
Morpholine/ Aldrich
469
2.36


 


555








Intermediate 59
Pyrrolidine/Aldrich
453
2.49


 


556








Intermediate 60
Dimethylamine/ Aldrich
410
2.03


 


557








Intermediate 60
tetrahydro-2H- pyran-4-amine/ Aldrich
466
2.01


 


558








Intermediate 60
cyclopropyl(methyl) amine/Karl Industries
436
2.20


 


559








Intermediate 60
Morpholine/ Aldrich
452
2.03


 


560








Intermediate 60
Pyrrolidine/Aldrich
436
2.13









Example 485
6-{[3-(Dimethylamino)-3-oxopropyl]sulfonyl}-4-[(3-fluorophenyl)amino]-8-methyl-3-quinolinecarboxamide hydrochloride




To a solution of the Example 551 (0.038 g) in N,N-dimethylformamide (2 ml) was added oxone (0.22 g). The mixture was stirred at room temperature for 2 h before quenching with aqueous sodium sulphite solution and extracting with dichloromethane. The organic layers were combined, dried by filtration through a hydrophobic frit and concentrated in vacuo. Purification by mass directed preparative HPLC (Method C) gave the title compound as a yellow solid (0.015 g).
LC/MS Rt 2.31 min m/z 459 [MH+].
Similarly prepared were the following:
















 














Example




Isolation

LCMS


Number

Starting


Method
LCMS
Rt


(a)
R3SO2—
Material
R28—
R1NH—
(b)
MH+
(min)

















486 HCl




Example 552
Me—




(II)
515
2.39


 


487 HCl




Example 553
Me—




(II)
485
2.62


 


488 HCl




Example 554
Me—




(II)
501
2.38


 


489 HCl




Example 555
Me—




(II)
485
2.49


 


490 HCl




Example 556
Me—




(II)
442
1.98


 


491 HCl




Example 557
Me—




(II)
498
1.95


 


492 HCl




Example 558
Me—




(II)
468
2.1


 


493 HCl




Example 559
Me—




(II)
484
1.96


 


494 HCl




Example 560
Me—




(II)
468
2.04


 


525 HCOOH




Example 563
Me—




(I)
413
2.00


 


526




Example 564
Me—




(I)
430
2.50


 


527




Example 681
Me—




(III)
459
2.30


 


529




Example 565
Me—




(IV)
444
2.5


 


530 HCl




Example 566
Me—




(II)
427
2.00


 


532




Example 570
Me—




(V)
445
2.20


 


533 HCl




Example 571
Me—




(II)
442
2.3


 


534 HCOOH




Example 572
Me—




(I)
428
1.8


 


535 HCOOH




Example 573
Me—




(I)
467
2.6


 


538 HCl




Example 574
Me—




(II)
520
2.83


 


568




Example 569
Me—




(VI)
526
2.60


 


578 HCl




Example 635
Me—




(II)
385
2.13


 


579 HCl




Example 636
Me—




(II)
385
2.08


 


580 HCl




Example 637
Me—




(II)
399
2.22


 


581 HCl




Example 634
Me—




(II)
371
1.95


 


582 HCl




Example 638
Cl—




(II)
391
2.07


 


583 HCl




Example 662
Me—




(II)
388
2.33


 


584 HCl




Example 664
Me—




(II)
402
2.4


 


585 HCl




Example 665
Me—




(II)
416
2.54


 


666 HCl




Example 646
Cl—




(II)
425
2.52


 


667 HCl




Example 647
Cl—




(II)
439
2.73


 


668 HCl




Example 648
Cl—




(II)
439
2.56


 


669 HCl




Example 649
Cl—




(II)
453
2.66


 


670 HCl




Example 644
Me—




(II)
419
2.47


 


671 HCl




Example 650
Me—




(II)
389
2.28


 


672 HCl




Example 651
Me—




(II)
403
2.49


 


673 HCl




Example 652
Me—




(II)
403
2.35


 


674 HCl




Example 653
Me—




(II)
417
2.47


 


675 HCl




Example 655
Cl—




(II)
423
2.49


 


676 HCl




Example 656
Cl—




(II)
423
2.43


 


677 HCl




Example 657
Cl—




(II)
437
2.54


 


678 HCl




Example 642
Me—




(II)
405
2.38


 


679 HCl




Example 643
Me—




(II)
419
2.53


 


680 HCl




Example 645
Me—




(II)
433
2.67





(a) Salt form HCl = hydrochloride


HCOOH = formate


(b) Isolation Method:


(I) Mass Directed Preparative HPLC (Method A)


(II) Mass Directed Preparative HPLC (Method C)


(III) Aqueous work-up


(IV) SCX ion exchange eluting with 2M ammonia in methanol


(V) Trituration with methanol and collection of the product by filtration


(VI) Chromatography on silica gel eluting with methanol/ethyl acetate mixtures






Example 495
4-{[4-Fluoro-3-(methyloxy)phenyl]amino}-8-methyl-6-{[2-(2-oxo-1-pyrrolidinyl)ethyl]sulfonyl}-3-quinolinecarboxamide hydrochloride




To a solution of Example 477 (0.03 g) in 1,4-dioxan (5 ml) was added ethyl 4-bromobutyrate (0.01 ml, available from Aldrich). The mixture was heated at 120° C. for 48h. The solvent was evaporated in vacuo. Purification by mass directed preparative HPLC (Method C) gave the title compound as a yellow solid (0.007 g).
LC/MS Rt 2.3 min m/z 501 [MH+].
Similarly prepared were the following:
















 











Example



LCMS


Number

Starting
LCMS
Rt


(a)
R1NH—
Material
MH+
(min)





514 HCl




Example 561
471
2.29





(a) Salt form HCl = hydrochloride






Example 518
6-{[2-(Dimethylamino)ethyl]sulfonyl}-4-{[4-fluoro-3-(methyloxy)phenyl]amino}8-methyl-3-quinolinecarboxamide formate salt




To a stirred mixture of Example 477 (0.05 g) in dry N,N-dimethylformamide (1 ml) was added methyl iodide (0.033 g) and triethylamine (0.032 ml), and the mixture was stirred under nitrogen for 18 h. The mixture was applied directly to an SPE cartridge (1 g) and eluted with 4% methanol in chloroform; the eluent was evaporated in vacuo and the residue purified using mass directed preparative HPLC (Method A) to give the title compound as a yellow solid (0.003 g).
LC/MS Rt 2.01 min, m/z 461 [MH+]
Example 519
4-(2,3-Dihydro-1-benzofuran-4-ylamino)-6-{[2-(dimethylamino)ethyl]sulfonyl}-8-methyl-3-quinolinecarboxamide formate salt
Example 519 was prepared by a similar method to Example 518 from Example 422 to give the title compound as a yellow solid (0.005 g)




LC/MS Rt 1.94 min, m/z 455 [MH+]
Example 521
4-{[4-Fluoro-3-(methyloxy)phenyl]amino}-8-methyl-6-{[2-(methyloxy)ethyl]thio}-3-quinolinecarboxamide.




To a solution of Example 337 (0.05 g) in dry N,N-dimethylformamide (2 ml) under nitrogen was added sodium hydride (60% dispersion in mineral oil, 0.015 g). The mixture was stirred at room temperature for 10 min when methyl iodide (0.0078 ml) was added; the mixture was stirred at room temperature for 18 h and the solvent evaporated in vacuo. The residue was partitioned between chloroform and water, the layers separated by hydrophobic frit, and the organic layer evaporated. The crude product was purified using mass directed preparative HPLC (Method A) to give the title compound as a yellow solid (0.025 g).
LC/MS Rt 2.46 min, m/z 416 [MH+]
Similarly prepared from Example 528 was the following:
Example 571
4-(2,3-Dihydro-1-benzofuran-4-ylamino)-8-methyl-6-{[2-(methyloxy)ethyl]thio}-3-quinolinecarboxamide




LC/MS Rt 2.40 min, m/z 410 [MH+]
Example 523
4-(2,3-Dihydro-1-benzofuran-4-ylamino)-6-[(2-hydroxyethyl)sulfonyl]-8-methyl-3-quinolinecarboxamide




To a solution of Example 528 (0.05 g) in N,N-dimethylformamide (2 ml) was added oxone (0.311 g). The mixture was stirred at room temperature for 3 h before quenching with aqueous sodium sulphite solution and extracting with ethyl acetate (50 ml). The organic layer was dried (Na2SO4) and concentrated in vacuo, and the mixture purified by mass directed preparative HPLC (Method A) to give the title compound as a white solid (0.035 g).
LC/MS Rt 2.1 min m/z 428 [MH+].
Example 524
4-(2,3-Dihydro-1-benzofuran-4-ylamino)-8-methyl-6-{[2-(methyloxy)ethyl]sulfonyl}-3-quinolinecarboxamide




To a solution of Example 523 (0.018 g) in dry N,N-dimethylformamide (1 ml) under nitrogen was added sodium hydride (60% dispersion in mineral oil, 0.0017 g). The mixture was stirred at room temperature for 10 min when methyl iodide (0.0026 ml) was added, stirring was continued for 18 h at room temperature and the solvent evaporated in vacuo. The residue was partitioned between ethyl acetate and water and the organic layer dried (MgSO4) and evaporated. The crude product was purified using mass directed preparative HPLC (Method A) to give the title compound as a yellow solid (0.0024 g).
LC/MS Rt 2.3 min, m/z 442 [MH+]
Example 536
6-({3-[(Dimethylamino)carbonyl]phenyl}sulfinyl)-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide




To a mixture containing Example 544 (0.10 g) in N,N-dimethylformamide (10 ml) was added oxone (0.253 g). The mixture was stirred under nitrogen for 3 h at room temperature and was then quenched with a solution of sodium sulphite (0.25 g) in water (10 ml), diluted with water (30 ml) and extracted with ethyl acetate (2×30 ml). The combined organic extracts were evaporated to dryness and the residue purified by mass directed preparative HPLC (Method A) to give the title compound as a yellow solid (0.028 g).
LC/MS Rt 2.24 min, m/z 503 [MH+]
Example 537
6-({3-[(Dimethylamino)carbonyl]phenyl}sulfonyl)-4-[(3-hydroxyphenyl)amino]-8-methyl-3-quinolinecarboxamide




A solution of borontribromide in dichloromethane (1.0 M, 2.2 ml) was added dropwise to an ice-cooled mixture containing Example 478 (0.35 g) in dichloromethane (25 ml) under nitrogen. The mixture was stirred at room temperature for 20 h, and was then treated with a further portion of borontribromide in dichloromethane (1.0 M, 2.2 ml) and stirred for a further 5 h. The mixture was quenched with methanol (10 ml) and evaporated to dryness in vacuo. The residue was partitioned between ethyl acetate (30 ml) and saturated aqueous sodium bicarbonate (30 ml), the organic extract evaporated to dryness in vacuo, and the residue purified by mass directed preparative HPLC (Method A) to give the title compound as a yellow solid (0.075 g).
LC/MS Rt 2.46 min, m/z 505 [MH+]
Example 575
7-({3-[(Dimethylamino)carbonyl]phenyl}sulfinyl)-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide




A mixture containing Intermediate 65 (0.15 g), 10% palladium on activated carbon (0.04 g) and triethylamine (5 ml) in ethanol (25 ml) and N,N-dimethylformamide (10 ml) was hydrogenated at room temperature for 4 h. The suspension was filtered through celite, the residue washed with ethanol/N,N-dimethylformamide (3:1, 50 ml), and the filtrate concentrated in vacuo. The residue was purified by mass directed preparative HPLC (Method A) to give the title compound as a yellow solid (0.035 g).
LC/MS Rt 2.32 min, m/z 489 [MH+]
Example 545
7-({3-[(Dimethylamino)carbonyl]phenyl}sulfonyl)-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide




Oxone (0.22 g) was added portionwise to a stirred solution of Example 575 (0.035 g) in N,N-dimethylformamide (4 ml). The mixture was stirred at room temperature under nitrogen for 24 h, a further portion of oxone (0.17 g) was added, and the mixture stirred for a further 5 h. The reaction was quenched with a solution of sodium sulphite (1.2 g) in water (15 ml), diluted with water (10 ml) and extracted with ethyl acetate (3×30 ml). The combined organic extracts were dried over magnesium sulphate and concentrated in vacuo to give the title compound as a buff solid (0.035 g).
LC/MS Rt 2.66 min, m/z 505 [MH+]
Example 576
6-({5-[(Dimethylamino)carbonyl]-3-pyridinyl}thio)-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide, formate salt




A stirred mixture of Intermediate 45 (0.47 g), Intermediate 69 (0.37 g), copper iodide (0.06 g), and potassium carbonate (0.47 g) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (10 m) was heated at 100° C. under nitrogen for 4 h. The mixture was diluted with water (150 ml) and extracted with ethyl acetate (3×200 ml). The combined organic extracts were washed with water (2×200 ml) and brine (200 ml), and the organic layers dried over magnesium sulphate and concentrated in vacuo. The residue was purified by mass directed preparative HPLC (Method A) to give the title compound as a yellow solid (0.1 g).
LC/MS Rt 2.35 min, m/z 488 [MH+]
Example 547
6-({5-[(Dimethylamino)carbonyl]-3-pyridinyl}sulfinyl)-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide hydrochloride and
Example 546
6-({5-[(Dimethylamino)carbonyl]-3-pyridinyl}sulfonyl)-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide hydrochloride




Oxone (1.2 g) was added portionwise to a stirred solution of Example 576 (0.1 g) in N,N-dimethylformamide (6 ml). The solution was stirred at room temperature under nitrogen for 2 h and then quenched with a solution of sodium sulphite (3 g) in water (30 ml). The mixture was diluted with water (25 ml) and extracted with ethyl acetate (4×50 ml) and the combined organic layers were washed with water (2×50 ml) and brine (50 ml), dried over magnesium sulphate and concentrated in vacuo. The residue was purified using mass directed preparative HPLC (Method C) to give Example 546 as a yellow solid (0.010 g) and Example 547 as a yellow solid (0.041 g).
Example 546: LC/MS Rt 2.57 min, m/z 520 [MH+]
Example 547: LC/MS Rt 2.12 min, m/z 504 [MH+]
Example 586
8-Methyl-4-[(3-methyl-5-isoxazolyl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide hydrochloride




To a stirred suspension of sodium hydride (0.008 g; 60% dispersion in mineral oil) in dry N,N-dimethylformamide (1 ml) was added [(3-methyl-5-isoxazolyl)methyl]amine (available from Aldrich) (0.020 g) and the mixture heated at 80° C. for 30 min. A suspension of Intermediate 33 (0.020 g) in dry N,N-dimethylformamide (0.5 ml) was added and the mixture heated at 80° C. for 3 h. The mixture was quenched by the dropwise addition of ethanol (0.1 ml). The mixture was loaded onto a 2 g SCX cartridge, washed with methanol, and the product eluted with 10% ‘880’ ammonia in methanol. The solvent was removed in vacuo and the residue purified by mass directed preparative HPLC (Method C) to give the title compound as a pale yellow solid (0.009 g)
LC/MS Rt 2.23 min, m/z 361 [MH+]
Example 544
6-({3-[(Dimethylamino)carbonyl]phenyl}thio)-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide




A stirred mixture of Intermediate 45 (50 g), Intermediate 28 (40 g), and potassium carbonate (40 g) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (500 ml) was purged of air (by evacuation of the vessel and refilling with nitrogen three times) and left under nitrogen. Copper (I) iodide (5 g) was added and the mixture was warmed at 90° C. for 23 h. The mixture was cooled to 20° C. and poured into water (2.5 L). The precipitated solid was filtered off, washed with water and sucked partially dry. The damp solid was dissolved in chloroform (4 L) and washed with IN sodium hydroxide solution (1 L), followed by water (2×1 L) and brine (1 L). The organic phase was dried over sodium sulphate and the solvent evaporated to leave a sticky solid. The solid was crystallised from hot ethanol (650 ml) to give the title compound as a solid (45.1 g).
LC/MS Rt 2.60 min m/z 487 [MH+].
Similarly prepared were the following:
















 













Example



Isolation

LCMS


Number


Starting
Method
LCMS
Rt


(a)
R1NH—
R3S—
Material
(b)
MH+
(min)





562








Intermediate 45
(I)
417
2.27


 


573 HCl








Intermediate 35
(II)
435
2.56


 


574








Intermediate 36
(III)
487
2.86





(a) Salt form: HCl = hydrochoride


(b) Isolation method:


(I) Aqueous work-up followed by trituration with ether and filtration.


(II) Mass directed preparative HPLC (Method C).


(III) Trituration with ether and filtration.






Example 544
6-({3-[(Dimethylamino)carbonyl]phenyl}thio)-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide (alternative synthesis)




Intermediate 45 (5.0 g), Intermediate 28 (2.89 g), copper iodide (0.506 g) and potassium carbonate (2.94 g) were added to 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU, 25 ml) and the resulting stirred slurry was heated to 100° C. under nitrogen. The mixture was stirred at 100° C. for 7 h, allowed to cooled to room temperature and stirred overnight. DMPU (20 ml) and water (80 ml) containing pyridine (0.43 ml) were added and the slurry was heated to 100° C. The resulting solution was seeded with crystals of Example 544 and stirred for 1 h at 100° C. The suspension was cooled gradually over 6 h, allowing the product to crystallise. The product was isolated by filtration, washed with water (2×50 ml) and dried at 40° C. in vacuo to give the title compound as a pale yellow solid (3.9 g).
LC/MS Rt 2.58 min m/z 487 [MH+].
Example 478
6-({3-[(Dimethylamino)carbonyl]phenyl}sulfonyl)-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide (alternative synthesis)




To a solution of Example 544 (29 g) in N,N-dimethylformamide (290 ml) cooled in a water bath was added oxone (87 g) in portions over 10 min. The mixture was stirred for 2 h, then poured into a cold (5° C.) solution of sodium metabisulphite (45 g) in water (2 L). After stirring for 35 min the mixture was extracted with chloroform (2 L+3×800 ml). The combined chloroform extracts were washed with water (3×600 ml), and the aqueous washes were extracted with chloroform (600 ml). The combined organic phases were dried over sodium sulphate and the solvent evaporated to leave a solid which was dried in vacuo at 40° C. for 3 days providing the title compound (27.8 g).
LC/MS Rt 2.62 min m/z 519 [MH+].
The solid was crystallised from hot ethanol containing 20% water (5 L) to give the title compound (20.2 g).
LC/MS Rt 2.62 min m/z 519 [MH+].
Example 478
6-({3-[(Dimethylamino)carbonyl]phenyl}sulfonyl)-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide (alternative procedure)




To a solution of Example 544 (3.5 g) in glacial acetic acid (18 ml) and water (3.5 ml ) was added oxone (5.76 g) portionwise over 15 min. The mixture was stirred for 1.5 h at 20° C. and excess oxone quenched with a solution of sodium sulphite (0.545 g) in water (3.5 ml). The mixture was diluted with glacial acetic acid (11 ml) and water (21 ml), heated to 90°, treated dropwise over 30 min with 2M aqueous sodium hydroxide (20 ml), and cooled to 25° C. over 30 min. The resulting precipitate was collected by filtration, washed with water (25 ml×3) and dried in vacuo to give the title compound as a pale yellow solid (3.0 g).
LC/MS Rt 2.54 min m/z 519 [MH+].
Example 588
4-(2,3-Dihydro-1-benzofuran-4-ylamino)-8-methyl-6-(methylsulfinyl)-3-quinolinecarboxamide formate salt




To a suspension of Example 577 (0.04 g) in methanol (10 ml) was added sodium periodate (0.023 g) in water (0.2 ml). The mixture was stirred at room temperature for 4 days and the solvents evaporated in vacuo. The residue was purified using mass directed preparative HPLC (Method A) to give the title compound as a yellow solid (0.017 g).
LC/MS Rt 2.0 min, m/z 382 [MH+]
Example 307
4-(2,3-Dihydro-1-benzofuran-4-ylamino)-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide hydrochloride (alternative synthesis)




To a solution of Example 577 (0.04 g) in N,N-dimethylformamide (1 ml) was added oxone (0.337 g). The mixture was stirred at room temperature for 18 h, and quenched by addition of 10% sodium sulphite solution (15 ml). The mixture was extracted with ethyl acetate (50 ml), and the organic layer dried (Na2SO4) and evaporated in vacuo. The residue was purified using mass directed preparative HPLC (Method C) to give the title compound as a yellow solid (0.018 g).
LC/MS Rt 2.2 min, m/z 398 [MH+]
Example 688
4-(2,3-Dihydro-1-benzofuran-4-ylamino)-8-methyl-7-(methylthio)-3-quinolinecarboxamide




A stirred mixture of Intermediate 104 (0.50 g), sodium methanethiolate (0.35 g), potassium carbonate (0.43 g) and copper (I) iodide (0.025 g) in dry N,N-dimethylformamide (3 ml) was heated at 100° under nitrogen for 18 h. The mixture was cooled, poured into water (50 ml) and stirred for 15 min. The solid material was filtered off, dried in vacuo at 80° for 2 h, and boiled in ethanol:water 15:1 (50 ml) for 30 min. The insoluble material was filtered off, and the filtrate evaporated to dryness to give the title compound as a pale yellow solid (0.163 g).
LC/MS Rt 2.40 min m/z 366 [MH+]
Example 548
4-(2,3-Dihydro-1-benzofuran-4-ylamino)-8-methyl-7-(methylsulfonyl)-3-quinolinecarboxamide hydrochloride




Example 548 was prepared from Example 688 by a similar method to Example 129, but without the addition of anisole to the reaction mixture, using 10:1 N,N-dimethylformamide: water as solvent, and purifying by mass directed preparative HPLC (method C).
LC/MS Rt 2.50 min m/z 398 [MH+]

## Claims

1. A compound of formula (I)



or a pharmaceutically acceptable salt thereof,

wherein:
R1 is
C1-6 alkyl;
C3-7cycloalkyl or C3-7cycloalkyl(C1-4alkyl)- wherein the C3-7cycloalkyl is optionally substituted by one or more substituents selected from ═O and OH;
C4-7cycloalkyl fused to an aryl ring;
Aryl or aryl(C1-6alkyl)- wherein the aryl is optionally substituted by one or more substituents selected from C1-6alkyl, C1-6alkylCONR6—, C1-6alkylCO—, halogen, —CF3, —(CH2)mOH, —OCF3, C1-6alkoxy-, C1-6alkoxy(C1-4alkyl)-, C1-6alkoxyC2-6alkoxy-, C1-6alkoxycarbonyl, —CN, R4R5NCO, R7R8N—, R9R10NCONR11—, HO(CH2)2-6O—, R12R13NSO2(CH2)m—, (4-morpholinyl)C2-6alkoxy, —NR14SO2C1-6alkyl, aryloxy, heteroaryl(optionally substituted by C1-6alkyl), CO2H, R21R22N(C1-4alkyl)-, C1-6alkoxyCONR23(CH2)m—, aryl(optionally substituted by C1-6alkyl);
Aryl fused to a C4-7cycloalkyl ring, wherein the cycloalkyl ring is optionally substituted by one or more ═O;
Aryl fused to a heterocyclyl ring, wherein the heterocyclyl ring is optionally substituted by one or more substituents selected from ═O, —COC1-4alkyl, C1-4alkyl;
Heteroaryl or heteroaryl(C1-6alkyl)- wherein the heteroaryl is optionally substituted by one or more substituents selected from: C1-6alkyl, aryl(C1-4alkyl), C1-6alkoxy, halogen, C1-6alkoxyCO; or
Heterocyclyl optionally fused to an aryl or heteroaryl ring;
R2 is hydrogen or C1-6alkyl;
R34 is hydrogen or a group of formula:




R3 is
C1-6alkyl optionally substituted by one or more substituents selected from —OH,—NR16COR15, —NR17R18, —CO2R24, C1-6alkoxyCONR25—, —CONR26R27, C1-6alkoxy-, C1-6alkylSO2NR33—, or a group having one of the following formulae:




C1-7cycloalkyl;
Aryl or aryl(C1-6alkyl)- wherein the aryl is optionally substituted by one or more substituents selected from C1-6alkyl-, halogen-, C1-6alkoxy-, —CO2R28, —CH2CO2H, —OH, aryl(optionally substituted by a C1-6alkoxy group), heteroaryl, —CONR29R30, C3-7cycloalkoxy, C3-7cycloalkyl(C1-6alkoxy)-, —CF3;
Heteroaryl or heteroaryl(C1-6alkyl)- wherein the heteroaryl is optionally substituted by one or more C1-6alkyl or —CONR29R30 groups; or
Heterocyclyl linked to the S(═O)n moiety through a carbon atom which is optionally substituted by one of more substituents selected from C1-6alkyl-, C1-6alkylCO—, C3-7cycloalkylCO—, heteroarylCO—, optionally substituted by one or more C1-4alkyl-groups), C1-6alkoxyCO—, arylCO—, R31R32NCO—, C1-6alkylSO2—, arylSO2, -heteroarylSO2 (optionally substituted by one or more C1-4alkyl or C1-4alkylCONH— groups;
m is 0-6;
n is 0, 1 or2;
R19 is hydrogen, C1-6alkyl;
R20 is hydrogen, C1-6alkyl, halogen or C1-6alkoxy;
R4-18, R21-25, R28 and R31-33 all independently represent H, C1-6 alkyl;
R26 and R27 independently represent H, C1-6 alkyl, C3-7cycloalkyl or heterocyclyl;
R29 and R30 independently represent H, C1-6alkyl optionally substituted by OH;
R7 and R8 together with the nitrogen atom to which they are attached may form a heterocyclyl ring;
R9 and R10 together with the nitrogen atom to which they are attached may form a heterocyclyl ring;
R17 and R18 together with the nitrogen atom to which they are attached may form aheterocyclyl ring such as morpholine;
R21 and R22 together with the nitrogen atom to which they are attached may form a heterocyclyl ring;
R26 and R27 together with the nitrogen atom to which they are attached may form a heterocyclyl ring;
R29 and R30 together with the nitrogen atom to which they are attached may form a heterocyclyl ring such as morpholine;
R31 and R32 together with the nitrogen atom to which they are attached may form a heterocyclyl ring.

2. A compound according to claim 1 wherein R1 is selected from
Aryl optionally substituted by one or more substituents selected from C1-6alkyl, halogen, C1-6alkoxy-, —CN, —(CH2)m(OH), and C1-6alkylCO—;
Aryl fused to a heterocyclyl ring,and
Heteroaryl optionally substituted by one or more substituents selected from: C1-6alkyl, halogen, and C1-6alkoxy groups.

3. A compound according to claim 1 wherein R1 is selected from benzothiazolyl, benzimidazolyl, indazolyl, pyridyl and pyrazolyl.

4. A compound according to claim 1 wherein R1 is selectedfrom

5. A compound according to claim 1 wherein R1 is selected from
Aryl optionally substituted by one or more substituents selected from: methyl, fluorine, chlorine, —CN, —OMe, —OH, COMe; and
Heteroaryl optionally substituted by one or more methyl, ethyl, flourine, chlorine or methoxy groups.

6. A compound according to claim 1 wherein R1 is selected from 3-(methyloxy)phenyl, 3-methylphenyl, 3-cyanophenyl, 3-fluorophenyl, 3-chlorophenyl, 4-fluoro-3-(methyloxy)phenyl, 3-acetylphenyl, 4-hydroxy-3-(methyloxy)phenyl, 2-fluoro-3-chlorophenyl, 2,3-difluorophenyl, 3,5-difluorophenyl, 1-methyl-1H-benzimidazolyl-6-yl, 1-methyl-1H-indazol-6-yl, 5-(methyloxy)-3-pyridinyl, 3-pyridinyl, 1-ethyl-1H-pyrazol-5-yl, 5-methyl-3-pyridinyl, 1,3-benzothiazol-6-yl, 5-fluoro-3-pyridinyl, and 5-chloro-3-pyridinyl.

7. A compound according to claim 1 wherein R2 is hydrogen.

8. A compound according to claim 1 wherein R3 is selected from:
C1-6 alkyl which is optionally substituted by one or more substituents selected from —NR16COR15 and —CONR26R27;
C3-7cycloalkyl;
Aryl optionally substituted by one or more substituents selected from C1-6alkyl-, C1-6alkoxy-, and CONR29R30;and
Heterocyclyl which is optionally substituted by one or more substituents selected from C1-6alkylCO—, C3-7cycloalkylCO—, heteroarylCO—.

9. A compound according to claim 1 wherein R3 is selected from
methyl, ethyl, n-propyl, tert-butyl, isopropyl, MeCONH(CH2)2—, Me2NCO(CH2)2—;
Cyclopentyl;
Aryl optionally substituted by one or more methoxy, methyl, —CONMe2 groups; and
Heterocyclyl which is optionally substituted by one of more substituents selected from MeCO—, cyclopropylCO, 2-furylCO—.

10. A compound according to claim 8 wherein R3 is selected from 4-(methyloxy)phenyl, phenyl, 3-[(dimethylamino)carbonyl]phenyl, 4-methylphenyl, 3,4-bis(methyloxy)phenyl, 3,4,5-tris(methyloxy)phenyl, 3-(ethyloxy)phenyl.

11. A compound according to claim 1 wherein R3 is a piperidinyl group substituted by one or more substituents selected from MeCO—, cyclopropylCO, and 2-furylCO—.

12. A compound according to claim 1 wherein R3 is 1-acetyl-4-piperidinyl, 1-(2-furanylcarbonyl)-4-piperidinyl, or 1-(cyclopropylcarbonyl)-4-piperidinyl.

13. A compound according to claim 1 wherein R20 is hydrogen, methyl, ethyl, fluorine or chlorine.

14. A compound according to claim 1 wherein n is 2.

15. A compound selected from
4-[(3-methylphenyl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide,
4-[(3-cyanophenyl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide,
4-(2,3-dihydro-1-benzofuran-4-ylamino)-6-(methylsulfonyl)-3-quinolinecarboxamide,
4-{[3-(methyloxy)phenyl]amino}-6-(methylsulfonyl)-3-quinolinecarboxamide,
4-{[4-fluoro-3-(methyloxy)phenyl]amino}-6-(methylsulfonyl)-3-quinolinecarboxamide,
4-[(3-chlorophenyl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide,
4-(1,3-benzothiazol-6-ylamino)-6-(phenylsulfonyl-3-quinolinecarboxamide,
4-[(1-methyl-1H-benzimidazol-6-yl)amino]-6-(phenylsulfonyl)-3-quinolinecarboxamide,
4-[(3-cyanophenyl)amino]-6-(phenylsulfonyl)-3-quinolinecarboxamide,
4-(2,3-dihydro-1-benzofuran-4-ylamino)-6-(phenylsulfonyl)-3-quinolinecarboxamide,
4-{[3-(methyloxy)phenyl]amino}-6-(phenylsulfonyl)-3-quinolinecarboxamide,
6-(cyclopentylsulfonyl)-4-[(3-fluorophenyl)amino]-3-quinolinecarboxamide,
4-{[3-(methyloxy)phenyl]amino}-6-{[4-(methyloxy)phenyl]sulfonyl}-3-quinolinecarboxamide,
6-[(1,1-dimethylethyl)sulfonyl]-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide,
6-{[2-(acetylamino)ethyl]sulfonyl}-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide,
6-[(1,1-dimethylethyl)thio]-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide,
6-{[2-(acetylamino)ethyl]thio}-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide,
4-[(1-methyl-1H-indazol-6-yl)amino]-6-(phenylsulfonyl)-3-quinolinecarboxamide,
4-{[4-hydroxy-3-(methyloxy)phenyl]amino}-6-(phenylsulfonyl)-3-quinolinecarboxamide,
4-[(3-acetylphenyl)amino]-6-(phenylsulfonyl)-3-quinolinecarboxamide,
8-methyl-4-{[3-(methyloxy)phenyl]amino}-6-(phenylsulfonyl)-3-quinolinecarboxamide,
4-{[4-fluoro-3-(methyloxy)phenyl]amino}-8-methyl-6-(phenylsulfonyl)-3-quinolinecarboxamide,
7-methyl-4-{[3-(methyloxy)phenyl]amino}-6-(methylsulfonyl)-3-quinolinecarboxamide,
8-methyl-4-{[3-(methyloxy)phenyl]amino}-6-{[4-(methyloxy)phenyl]sulfonyl}-3-quinolinecarboxamide,
4-(2,3-dihydro-1-benzofuran-4-ylamino)-8-methyl-6-{[4-(methyloxy)phenyl]sulfonyl}-3-quinolinecarboxamide,
4-[(3-acetylphenyl)amino]-8-methyl-6-{[4-(methyloxy)phenyl]sulfonyl}-3-quinolinecarboxamide,
8-methyl-4-[(1-methyl-1H-indazol-6-yl)amino]-6-{[4-(methyloxy)phenyl]sulfonyl}-3-quinolinecarboxamide,
4-(2,3-dihydro-1,4-benzodioxin-5-ylamino)-8-methyl-6-{[4-(methyloxy)phenyl]sulfonyl}-3-quinolinecarboxamide,
4-[(3-chlorophenyl)amino]-8-methyl-6-{[4-(methyloxy)phenyl]sulfonyl}-3-quinolinecarboxamide,
4-[(3-cyanophenyl)amino]-8-methyl-6-{[4-(methyloxy)phenyl]sulfonyl}-3-quinolinecarboxamide,
4-(1,3-benzothiazol-6-ylamino)-8-methyl-6-{[4-(methyloxy)phenyl]sulfonyl}-3-quinolinecarboxamide,
4-[(3-fluorophenyl)amino]-8-methyl-6-{[4-(methyloxy)phenyl]sulfonyl}-3-quinolinecarboxamide,
4-(2,3-dihydro-1-benzofuran-4-ylamino)-8-methyl-6-[(4-methylphenyl)sulfonyl]-3-quinolinecarboxamide,
8-methyl-4-[(1-methyl-1H-indazol-6-yl)amino]-6-[(4-methylphenyl)sulfonyl]-3-quinolinecarboxamide,
8-methyl-4-{[3-(methyloxy)phenyl]amino}-6-[(4-methylphenyl)sulfonyl]-3-quinolinecarboxamide,
4-{[4-fluoro-3-(methyloxy)phenyl]amino}-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide,
8-methyl-4-[(1-methyl-1H-indazol-6-yl)amino]-6-(phenylsulfonyl)-3-quinolinecarboxamide,
4-(2,3-dihydro-1-benzofuran-4-ylamino)-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide,
8-methyl-6-(methylsulfonyl)-4-(3-pyridinylamino)-3-quinolinecarboxamide 8-methyl-4-[(1-methyl-1H-indazol-6-yl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide,
4-[(3-fluorophenyl)amino]-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide,
4-[(3-cyanophenyl)amino]-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide,
4-[(1-ethyl-1H-pyrazol-5-yl)amino]-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide,
8-methyl-4-{[5-(methyloxy)-3-pyridinyl]amino}-6-(methylsulfonyl)-3-quinolinecarboxamide,
8-methyl-4-[(5-methyl-3-pyridinyl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide,
8-chloro-4-[(3-methylphenyl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide,
8-chloro4-{[4-fluoro-3-(methyloxy)phenyl]amino}-6-(methylsulfonyl)-3-quinolinecarboxamide,
8-chloro-4-(2,3-dihydro-1-benzofuran-4-ylamino)-6-(methylsulfonyl)-3-quinolinecarboxamide,
8-chloro-4-[(3-cyanophenyl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide,
8-chloro-4-[(3-fluorophenyl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide,
8-chloro-4-[(1-methyl-1H-indazol-6-yl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide,
methyl 3-[(3-(aminocarbonyl)-8-methyl-4-{[3-(methyloxy)phenyl]amino}-6-quinolinyl)sulfonyl]benzoate,
6-{[3,4-bis(methyloxy)phenyl]sulfonyl}-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide,
8-methyl-4-{[3-(methyloxy)phenyl]amino}-6-{[3,4,5-tris(methyloxy)phenyl]sulfonyl}-3-quinolinecarboxamide hydrochloride,
6-{[3,4-bis(methyloxy)phenyl]sulfonyl}-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide,
6-{[3-(ethyloxy)phenyl]sulfonyl}-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide,
6-{[2-(acetylamino)ethyl]sulfonyl}-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide,
6-({3-[(dimethylamino)carbonyl]phenyl}sulfonyl)-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide,
6-({3-[(dimethylamino)carbonyl]phenyl}sulfonyl)-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide,
4-[(3-cyanophenyl)amino]-6-({3-[(dimethylamino)carbonyl]phenyl}sulfonyl)-8-methyl-3-quinolinecarboxamide,
6-({3-[(dimethylamino)carbonyl]phenyl}sulfonyl)-8-methyl-4-[(1-methyl-1H -benzimidazol-6-yl)amino]-3-quinolinecarboxamide,
4-(2,3-dihydro-1-benzofuran-4-ylamino)-6-({3-[(dimethylamino)carbonyl]phenyl}sulfonyl)-8-methyl-3-quinolinecarboxamide,
6-[(1-acetyl-4-piperidinyl)sulfonyl]-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide,
6-{[1-(2-furanylcarbonyl)-4-piperidinyl]sulfonyl}-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide,
4-[(3-cyanophenyl)amino]-6-{[1-(2-furanylcarbonyl)-4-piperidinyl]sulfonyl}-8-methyl-3-quinolinecarboxamide,
6-{[1-(cyclopropylcarbonyl)-4piperidinyl]sulfonyl}-8-methyl-4-{[3-(methyloxy) phenyl]amino}3-quinolinecarboxamide,
4-(2,3-dihydro-1-benzofuran-4-ylamino)-6-{[1-(2-furanylcarbonyl)-4-piperidinyl]sulfonyl}-8-methyl-3-quinolinecarboxamide,
6-{[1-(cyclopropylcarbonyl)-4-piperidinyl]sulfonyl}-4-(2,3-dihydro-1-benzofuran-4-ylamino)-8-methyl-3-quinolinecarboxamide,
6-[(1-acetyl-4-piperidinyl)sulfonyl]-4-{[4-fluoro-3-(methyloxy)phenyl]amino}-8-methyl-3-quinolinecarboxamide,
4-(2,3-dihydro-1-benzofuran-4-ylamino)-8-methyl-6-({2-[(methylsulfonyl) amino]ethyl}sulfonyl)-3-quinolinecarboxamide,
6-{[1-(2-furanylcarbonyl)-4-piperidinyl]sulfonyl}-8-methyl-4-[(1-methyl-1H -benzimidazol-6-yl)amino]-3-quinolinecarboxamide,
6-{[3-(dimethylamino)-3-oxopropyl]sulfonyl}-4-{[4-fluoro-3-(methyloxy)phenyl]amino}-8-methyl-3-quinolinecarboxamide,
4-[(2,3-difluorophenyl)amino]-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide,
4-[(3-chloro-2-fluorophenyl)amino]-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide,
4-[(3,5-difluorophenyl)amino]-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide,
4-[(5-fluoro-3-pyridinyl)amino]-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide,
4-[(5-chloro-3-pyridinyl)amino]-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide,
6-({5-[(dimethylamino)carbonyl]-3-pyridinyl}sulfonyl)-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide hydrochloride,
8-methyl-6-[(1-methylethyl)sulfonyl]-4-(3-pyridinylamino)-3-quinolinecarboxamide,
6-[(1,1-dimethylethyl)sulfonyl]-8-methyl-4-(3-pyridinylamino)-3-quinolinecarboxamide,
4-[(1-ethyl-1H-pyrazol-5-yl)amino]-8-methyl-6-[(1-methylethyl)sulfonyl]-3-quinolinecarboxamide,
6-[(1,1-dimethylethyl)sulfonyl]-4-[(1-ethyl-1H-pyrazol-5-yl)amino]-8-methyl-3-quinolinecarboxamide,
4-(3,4-dihydro-2H-chromen-5-ylamino)-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide,
4-(2,3-dihydro-1-benzofuran-4-ylamino)-8-methyl-6-(methylsulfinyl)-3-quinolinecarboxamide,
4-[(5-chloro-3-pyridinyl)amino]-6-[(1,1-dimethylethyl)sulfonyl]-3-quinolinecarboxamide,
8-ethyl-4-{[4-fluoro-3-(methyloxy)phenyl]amino}-6-(methylsulfonyl)-3-quinolinecarboxamide,
8-ethyl-4-[(3-fluorophenyl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide,
4-[(3-cyanophenyl)amino]-8-ethyl-6-(methylsulfonyl)-3-quinolinecarboxamide,
8-ethyl-4-[(1-methyl-1H-indazol-6-yl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide,
4-(2,3-dihydro-1-benzofuran-4-ylamino)-8-ethyl-6-(methylsulfonyl)-3-quinolinecarboxamide,
8-ethyl-6-(methylsulfonyl)-4-(3-pyridinylamino)-3-quinolinecarboxamide
4-(2,3-dihydro-1-benzofuran-4-ylamino)-8-fluoro-6-(methylsulfonyl)-3-quinolinecarboxamide,
8-chloro-4-[(5-chloro-3-pyridinyl)amino]-6-(ethylsulfonyl)-3-quinolinecarboxamide,
8-chloro-4-[(5-chloro-3-pyridinyl)amino]-6-(propylsulfonyl)-3-quinolinecarboxamide,
8-chloro-4-[(5-chloro-3-pyridinyl)amino]-6-[(1-methylethyl)sulfonyl]-3-quinolinecarboxamide,
8-chloro-4-[(5-chloro-3-pyridinyl)amino]-6-[(1,1-dimethylethyl)sulfonyl]-3-quinolinecarboxamide,
4-[(5-chloro-3-pyridinyl)amino]-8-methyl-6-[(1-methylethyl)sulfonyl]-3-quinolinecarboxamide,
6-(ethylsulfonyl)-4-[(5-fluoro-3-pyridinyl)amino]-8-methyl-3-quinolinecarboxamide,
6-[(1,1-dimethylethyl)sulfonyl]-4-[(5-fluoro-3-pyridinyl)amino]-8-methyl-3-quinolinecarboxamide,
8-chloro-4-[(5-fluoro-3-pyridinyl)amino]-6-[(1-methylethyl)sulfonyl]-3-quinolinecarboxamide,
8-chloro-6-[(1,1-dimethylethyl)sulfonyl]-4-[(5-fluoro-3-pyridinyl)amino]-3-quinolinecarboxamide,
4-[(5-chloro-3-pyridinyl)amino]-6-(ethylsulfonyl)-8-methyl-3-quinolinecarboxamide,
4-[(5-chloro-3-pyridinyl)amino]-8-methyl-6-(propylsulfonyl)-3-quinolinecarboxamide,
4-[(5-chloro-3-pyridinyl)amino]-6-[(1,1-dimethylethyl)sulfonyl]-8-methyl-3-quinolinecarboxamide,and
or a pharmaceutically acceptable salt thereof.

16. A compound according to claim 15 selected from
4-(2,3-dihydro-1-benzofuran-4-ylamino)-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide,
8-methyl-4-[(1-methyl-1H-indazol-6-yl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide,
4-[(3-cyanophenyl)amino]-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide,
8-methyl-4-[(5-methyl-3-pyridinyl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide,
4-[(3,5-difluorophenyl)amino]-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide,
4-[(1-ethyl-1H-pyrazol-5-yl)amino]-8-methyl-6-[(1-methylethyl)sulfonyl]-3-quinolinecarboxamide,
6-[(1,1-dimethylethyl)sulfonyl]-4-[(5-fluoro-3-pyridinyl)amino]-8-methyl-3-quinolinecarboxamide,
8-chloro-6-[(1,1-dimethylethyl)sulfonyl]-4-[(5-fluoro-3-pyridinyl)amino]-3-quinolinecarboxamide,and pharmaceutically acceptable salts therof.

17. A compound according to claim 15 selected from
8-methyl-4-{[3-(methyloxy)phenyl]amino}-6-{[4-(methyloxy)phenyl]sulfonyl}-3-quinolinecarboxamide,
6-({3-[(dimethylamino)carbonyl]phenyl}sulfonyl)-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide hydrochloride,
6-({3-[(dimethylamino)carbonyl]phenyl}sulfonyl)-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide,
4-[(3-cyanophenyl)amino]-6-({3-[(dimethylamino)carbonyl]phenyl}sulfonyl)-8-methyl-3-quinolinecarboxamide,
4-(2,3-dihydro-1-benzofuran-4-ylamino)-6-{[1-(2-furanylcarbonyl)-4-piperidinyl]sulfonyl}-8-methyl-3-quinolinecarboxamide,
4-(2,3-dihydro-1-benzofuran-4-ylamino)-8-methyl-6-({2-[(methylsulfonyl)amino]ethyl}sulfonyl)-3-quinolinecarboxamide,
6-({5-[(dimethylamino)carbonyl]-3-pyridinyl}sulfonyl)-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide hydrochloride, and
a pharmaceutically acceptable salt thereof.

18. A pharmaceutical formulation comprising a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient, and optionally one or more other therapeutic ingredients.

19. A combination comprising a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt and one or more other therapeutic ingredients.

20. A process for preparing a compound of formula (I) as claimed in claim 1 which process comprises:
(i) treating a compound of formula II:




wherein R34, R19, and R20 are as defined in claim 1, and X represents a halogen atom, with an amine of formula R1R2NH, wherein R1 and R2 are as defined in claim 1, to make a compound of formula (I).

21. The process of claim 20, further comprising the step of
deprotecting the compound of formula (I) to form another compound of formula (I).

22. The process of claim 20, further comprising the step of
converting the compound of formula (I) into a further compound of formula (I).

23. The process of claim 20, further comprising the step of
converting the compound of formula (I) into a salt thereof.