Patent Application
20090227566
This invention relates to aromatic ethers which demonstrate activity as inhibitors of thrombin and/or factor Xa and, accordingly, which are useful antithrombotics in mammals. In particular it relates to aromatic ethers having high anticoagulant activity, good oral exposure and antithrombotic activity. Thus, this invention relates to new aromatic ethers which are inhibitors of thrombin and/or factor Xa, pharmaceutical compositions containing the aromatic ethers as active ingredients, and the use of the aromatic ethers as anticoagulants for prophylaxis and treatment of thromboembolic disorders such as venous thrombosis, pulmonary embolism, arterial thrombosis, in particular myocardial ischemia, myocardial infarction and cerebral thrombosis, general hypercoagulable states and local hypercoagulable states, such as following angioplasty and coronary bypass operations, and generalized tissue injury as it relates to the inflammatory process. In addition, the aromatic ethers are useful as anticoagulants in in vitro applications.
The process of blood coagulation, thrombosis, is triggered by a complex proteolytic cascade leading to the formation of thrombin. Thrombin proteolytically removes activation peptides from the Aα-chains and the Bβ-chains of fibrinogen, which is soluble in blood plasma, initiating insoluble fibrin formation. The formation of thrombin from prothrombin is catalyzed by factor Xa.
Anticoagulation currently is achieved by the administration of heparins and coumarins. Parenteral pharmacological control of coagulation and thrombosis is based on inhibition of thrombin through the use of heparins. Heparins act indirectly on thrombin by accelerating the inhibitory effect of endogenous antithrombin III (the main physiological inhibitor of thrombin). Because antithrombin III levels vary in plasma and because clot-bound thrombin seems resistant to this indirect mechanism, heparins can be an ineffective treatment. Because coagulation assays are believed to be associated with efficacy and with safety, heparin levels must be monitored with coagulation assays (particularly the activated partial thromboplastin time (APTT) assay). Coumarins impede the generation of thrombin by blocking the posttranslational gamma-carboxylation in the synthesis of prothrombin and other proteins of this type. Because of their mechanism of action, the effect of coumarins can only develop slowly, 6-24 hours after administration. Further, they are not selective anticoagulants. Coumarins also require monitoring with coagulation assays (particularly the prothrombin time (PT) assay).
Recently, interest has grown in small synthetic molecules which demonstrate potent direct inhibition of thrombin and factor Xa. See, for example, B. Y. Zhu and R. M. Scarborough, Annual Reports in Medicinal Chemistry, (2000), 35, 83-102, Factor Xa Inhibitors: Recent Advances in Anticoagulant Agents.
Although the heparins and coumarins are effective anticoagulants, there still exists a need for anticoagulants which act selectively on factor Xa and/or thrombin, and which, independent of antithrombin III, exert inhibitory action shortly after administration, preferably by an oral route, and do not interfere with lysis of blood clots, as required to maintain hemostasis.
The present invention is directed to the discovery that the aromatic ethers of the present invention, as defined below, are potent inhibitors of thrombin and/or factor Xa which may have high bioavailability following oral administration.
According to the invention there is provided a compound of formula I,
or a pharmaceutically acceptable salt thereof, wherein:
A3, A4, A5 and A6, together with the two carbons to which they are attached, complete a substituted benzene in which A3 is CR3, A4 is CR4, A5 is CR5, and A6 is CR6; wherein
R3 is hydrogen, methyl, fluoro, chloro or carboxy;
one of R4 and R5 is hydrogen, (1-4C)alkyl, halo, cyano, trifluoromethyl, trifluoro-methoxy, RfO—, RfO2CCH2O—, HO(CH2)aO— (in which a is 2, 3 or 4), RfO2C—, RfO2 CCH2—, nitro or RgNH—;
the other of R4 and R5 is hydrogen; and
R6 is hydrogen, methyl, fluoro, chloro or methoxy;
in which Rf is hydrogen, (1-4C)alkyl or benzyl; Rg is hydrogen or RhSO2—; and Rh is (1-4C)alkyl or dimethylamino;
L1 is —CO—NH— or —SO2—NH— such that -L1-Q1 is —CO—NH-Q1 or —SO2—NH-Q1;
Q1 is Q1A, Q1B, or Q1C wherein
Q1A is phenyl (in which the phenyl may bear one, two or three substituents at the 3-, 4- or 5-position(s) independently selected from halo, trifluoromethyl, cyano, carbamoyl, aminomethyl, methyl, methoxy, difluoromethoxy, hydroxymethyl, methylthio, formyl, acetyl, vinyl, nitro, amino, hydroxy and 3,4-methylenedioxy; and in addition the phenyl may bear a chloro, fluoro, methyl, methoxy, or nitro substituent at the 2- and/or 6-position),
Q1B is 5-membered ring heteroaryl (which 5-membered ring heteroaryl is a 5-membered aromatic ring which includes one to three heteroatoms selected from sulfur, oxygen and nitrogen and which is attached to L1 at a carbon atom and further which may bear one or more methyl substituents on carbon or nitrogen and may bear one or more halo substituents on carbon which is not bonded to a ring nitrogen), and
Q1C is 6-membered ring heteroaryl (which 6-membered ring heteroaryl is a 6-membered aromatic ring which includes one or two nitrogens and further which may bear one or more amino, nitro, methoxy, methylthio, trifluoromethyl or methyl substituents and may bear one or more halo substituents on carbon which is not bonded to a ring nitrogen); or
-L1-Q1 is piperazinocarbonyl (in which the piperazino may bear a 4-methyl substituent);
L2 is carbonyl or methylene;
R1 is —(CH2)i-Q-(CH2)j—NRaRb wherein:
a) Q is a single bond; the sum of i and j is 2, 3 or 4;
b) Q is oxy; i is 2; and j is 2;
d) Q is cyclohexane-1,4-diyl; i is 0; and j is 0;
f) Q is —CHRc; i is 0 or 1; j is 1; and Rb and Rc together are —(CH2)k— wherein k is 2 or 3;
g) Q is —CHRc; i is 1 or 2; j is 0; and Rb and Rc together are —(CH2)4—;
h) Q is —CHRc; i is 0; j is 2; and Rb and Rc together are —(CH2)2— or —C(CH3)2—CH2— (wherein the CH2 carbon is bonded to the nitrogen); or
i) Q is —CHRc; i is 1; j is 2; and Rb and Rc together are —(CH2)2—;
wherein, unless defined above,
Ra is hydrogen or Rd; and Rb is hydrogen or (1-3C) normal alkyl;
or NRaRb is a cyclic amino group selected from azetidin-1-yl, pyrrolidin-1-yl, 3,4-didehydropyrrolidin-1-yl, thiazolidin-3-yl, piperidin-1-yl, 3,4-didehydropiperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, hexahydroazepin-1-yl, hexahydro-1,4-diazepin-1-yl and octahydroazocin-1-yl (which cyclic group may bear one or more {for example, one to three} methyl substituents on carbon, or may bear a carbamoyl, hydroxymethyl, methoxymethyl, 2-hydroxyethyl, pyrrolidin-1-ylmethyl or 2-(pyrrolidin-1-yl)ethyl substituent on carbon, or may bear a hydroxy, amino, methylamino, dimethylamino, pyrrolidin-1-yl, piperidin-1-yl, {(1-2C)acyl}amino, or {(1-4C)alkoxy}carbonylamino substituent on a carbon which is not attached to a ring nitrogen, oxygen or sulfur nor double bonded to another carbon, or may bear a (1-3C)alkyl, cyclopentyl, pyrrolidin-1-ylcarbonylmethyl, 2-hydroxyethyl, acetyl, furanylcarbonyl, phenyl {which phenyl may bear a chloro, methyl or methoxy substituent}, pyridinyl, pyrimidinyl or pyrazinyl substituent on a ring nitrogen at the 4-position); or NRaRb is 1,3,3-trimethyl-6-azabicyclo[3.2.1]octan-6-yl or N(CH2Rw)2;
Rd is (1-7C)alkyl (which alkyl may bear one or more {for example, one or two} substituents Re on a carbon which is not otherwise directly bonded to a nitrogen or oxygen wherein each Re is independently hydroxy, (1-3C)alkoxy, (1-3C)alkylthio, amino {which amino may bear an acetyl or one or two (1-3C)alkyl groups which may be the same or different} or cyclic amino {which cyclic amino is selected from azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl and piperazin-1-yl}), or Rd is (3-8C)cycloalkyl (which cycloalkyl may bear one or more {for example, one to three} methyl substituents and/or may bear one or more {for example, one or two} hydroxy substituents on a carbon, including a methyl carbon, which is not otherwise directly bonded to a nitrogen or oxygen), or Rd is 3-phenylpropyl, hexahydro-2-oxo-azepin-3-yl, —CH2Rw, —CH(CH3)Rw, —CH2 CH(OH)Rw, —CH2 CH═CHRw, —(CH2)2Rw, —CH2 CH(CH3)Rw, α-(hydroxymethyl)benzyl, {(1-4C)alkoxy}carbonyl, trifluoroacetyl, —COCH2RX, —COYRy (in which Y is a single bond, carbonyl or 1,2-ethenediyl) or —CZNH—(CH2)zRz (in which z is 0, 1, 2 or 3; and Z is O or S); and in which
Rw is (1-4C)alkyl, ethynyl, trifluoromethyl, (3-7C)cycloalkyl (which cycloalkyl may bear one or more {for example, one to three} methyl substituents and/or may bear one or more {for example, one or two} hydroxy substituents on a carbon, including a methyl carbon, which is not otherwise directly bonded to a nitrogen or oxygen), tetrahydrofuran-2-yl, phenyl (which is unsubstituted or bears one to three substituents independently selected from halo, methyl, trifluoromethyl, methoxy, ethoxy, hydroxy, methylenedioxy, nitro, carboxy, methoxycarbonyl and cyano), or heteroaryl (which heteroaryl is a 5-membered aromatic ring which includes one to three heteroatoms selected from sulfur, oxygen and nitrogen or is a 6-membered aromatic ring which includes one to three nitrogen atoms, wherein the heteroaryl is attached at carbon and may bear one or more methyl substituents on carbon or nitrogen);
Rx is carboxymethyl, dimethylamino, thienyl, pyridinyl or 1-tetrazolyl;
Ry is methyl, phenyl (which may bear a fluoro or methyl substituent), or heteroaryl (which heteroaryl is a 5-membered aromatic ring which includes one to three heteroatoms selected from sulfur, oxygen and nitrogen or is a 6-membered aromatic ring which includes one to three nitrogen atoms, wherein the heteroaryl is attached at carbon and may bear one or more methyl substituents on carbon or nitrogen); and
Rz is phenyl (which may bear a fluoro or methyl substituent), thienyl or pyridinyl or (provided z is 2 or 3) Rz is (1-2C)alkoxy, di(1-2C)alkylamino or cyclic amino (which cyclic amino is selected from pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl and thiomorpholin-4-yl); or R1 is 4-oxocyclohexyl; and
R2 is fluoro, chloro, aminomethyl, 1-aminoethyl, 1-amino-1-methylethyl, —S(O)n—Rn (wherein n is 0, 1 or 2), (1-6C)alkyl, phenyl (which may bear a chloro or methoxy substituent at the 4-position), thienyl, —O—Rq or —NRSRt wherein
Rn is (1-2C)alkyl;
Rq is (1-6C)alkyl (which alkyl may bear a fluoro or methoxy substituent on a carbon not bound to oxygen), (3-7C)cycloalkyl or —CH2—Rr (in which Rr is ethynyl, cyano, carbamoyl, {(1-2C)alkoxy}carbonyl, phenyl or 1,2,4-triazol-3-yl); and wherein
Rs is hydrogen or (1-6C)alkyl and Rt is hydrogen or methyl, or —NRsRt is a cyclic amino group selected from azetidin-1-yl, pyrrolidin-1-yl, 3,4-didehydropyrrolidin-1-yl, piperidin-1-yl, 3,4-didehydropiperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, and hexahydro-1,4-diazepin-1-yl (which cyclic group may bear one or more methyl substituents on carbon, or may bear a carbamoyl, hydroxymethyl, methoxymethyl, or 2-hydroxyethyl substituent on carbon, or may bear a hydroxy, amino, methylamino, dimethylamino, (1-2C)acylamino, or {(1-4C)alkoxy}carbonylamino substituent on a carbon which is not attached to a ring nitrogen, oxygen or sulfur nor double bonded to another carbon, or may bear a (1-3C)alkyl, acetyl, hydroxyacetyl or acetoxyacetyl substituent on a ring nitrogen at the 4-position);
or —OR1 represents 1-(4-pyridyl)piperidin-4-ylcarbonylamino and R2 is hydrogen.
As used herein, the expression a compound of formula I or the expression a compound of the invention includes the compound and any conventional prodrug thereof, as well as a pharmaceutically acceptable salt of said compound or prodrug.
In this specification, the following definitions are used, unless otherwise described: Halo is fluoro, chloro, bromo or iodo. Alkyl, alkoxy, etc. denote both straight and branched groups; but reference to an individual radical such as “propyl” embraces only the straight chain (“normal”) radical, a branched chain isomer such as “isopropyl” being specifically denoted.
Particular values for the groups and ranges defined herein include the following: halo is fluoro, chloro, bromo or iodo; (1-2C)acyl is formyl or acetyl; for an alkyl group or the alkyl portion of an alkoxy or alkylthio group: (1-2C)alkyl is methyl or ethyl; (1-3C) normal alkyl is methyl, ethyl or propyl; (1-3C)alkyl is methyl, ethyl, propyl or isopropyl; (1-4C)alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or t-butyl; (1-6C)alkyl is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl or hexyl; (1-7C)alkyl is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, 1-methylpropyl, 2-methylpropyl, pentyl, 2-methyl-butyl, 3-methylbutyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 3,3-dimethylbutyl, 1,3-dimethylbutyl, 1,2,2-trimethylpropyl, 1-(1-methylethyl)-2-methylpropyl or heptyl; (3-6C)cycloalkyl is cyclopropyl, cyclobutyl, cyclopenylyl or cyclohexyl; (3-7C)cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; (3-8C)cycloalkyl is cyclopropyl, cyclobutyl, cyclopenylyl, cyclohexyl, cycloheptyl or cyclooctyl.
It will be appreciated that certain compounds of formula I (or salts or prodrugs, etc.) may exist in, and be isolated in, isomeric forms, including tautomeric forms, cis- or trans-isomers, as well as optically active, racemic, or diastereomeric forms. It is to be understood that the present invention encompasses a compound of formula I in any of the tautomeric forms or as an a mixture thereof; or as a mixture of diastereomers, as well as in the form of an individual diastereomer, and that the present invention encompasses a compound of formula I as a mixture of enantiomers, as well as in the form of an individual enantiomer, any of which mixtures or form possesses inhibitory properties against thrombin and/or factor Xa, it being well known in the art how to prepare or isolate particular forms and how to determine inhibitory properties against thrombin and/or factor Xa by standard tests including those described below.
In addition, a compound of formula I (or salt or prodrug, etc.) may exhibit polymorphism or may form a solvate with water or an organic solvent. The present invention also encompasses any such polymorphic form, any solvate or any mixture thereof.
A prodrug of a compound of formula I may be one formed in a conventional manner with a functional group of the compound, such as with an amino, hydroxy or carboxy group.
One particular compound of formula I is one wherein
R3 is hydrogen;
R4 is fluoro, chloro, methoxycarbonyl, carboxy, nitro or amino, and R5 is hydrogen; or
R4 is hydrogen, and R5 is hydrogen, fluoro, chloro, iodo or cyano; and
R6 is hydrogen.
Another particular compound, or salt thereof, as described above is one wherein
L1 is —CO—NH— such that -L1-Q1 is —CO—NH-Q1;
Q1A is 2-fluorophenyl, 2-methoxyphenyl, 4-acetylphenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-methylthiophenyl, 4-nitrophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 4-bromo-2-chlorophenyl, 4-chloro-2-methylphenyl, 2-chloro-4-nitrophenyl, 4-methoxy-2-nitrophenyl or 2,4,6-trichlorophenyl;
Q1B is 2-thiazolyl, 4-methylthiazol-2-yl, 5-methylisoxazol-3-yl or 1-methylpyrazol-4-yl; and
Q1C is 2-pyridinyl, 5-fluoropyridin-2-yl, 5-chloropyridin-2-yl, 5-methylpyridin-2-yl, 5-trifluoromethylpyridin-2-yl, 3-methylpyridin-2-yl, 3-nitropyridin-2-yl, 3,5-dichloropyridin-2-yl, 4,6-dimethylpyridin-2-yl or 5-chloropyrimidin-2-yl.
A further particular compound, or salt thereof, as described above is one wherein
R1 is —(CH2)2—NRaRb, —(CH2)3—NRaRb, —(CH2)4—NRaRb, —(CH2)2—O—(CH2)2—NRaRb, —CH2—CH(CH3)—CH2—NRaRb, —CH2—C(CH3)2—CH2—NRaRb, —CH2—CH(OH)—CH2—NRaRb, 1,4-cyclohexyl-NRaRb, —CH2—CH{(CH2)2—SCH3}CH2—NRaRb, 3-pyrrolidinyl bearing Ra on the nitrogen, 3-pyrrolidinylmethyl bearing Ra on the nitrogen, 3-piperidinyl bearing a group Ra on the nitrogen, 3-piperidinylmethyl bearing Ra on the nitrogen, 2-piperidinylmethyl bearing Ra on the nitrogen, 2-(2-piperidinyl)ethyl bearing Ra group on the nitrogen, 4-piperidinyl bearing Ra on the nitrogen, 3,3-dimethylpiperidin-4-yl bearing Ra on the nitrogen, or 4-piperidinylmethyl bearing Ra on the nitrogen;
Ra is hydrogen or Rd; and Rb is hydrogen, methyl, ethyl or propyl;
or NRaRb is azetidin-1-yl, pyrrolidin-1-yl, 2-methylpyrrolidin-1-yl, 2-(hydroxymethyl)pyrrolidin-1-yl, 2-(methoxymethyl)pyrrolidin-1-yl, 2-(2-hydroxyethyl)pyrrolidin-1-yl, 2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl, 3-hydroxypyrrolidin-1-yl, 2-(dimethylamino)pyrrolidin-1-yl, 3-(acetylamino)pyrrolidin-1-yl, thiazolidin-3-yl, piperidin-1-yl, 2-methylpiperidin-1-yl, 4-methylpiperidin-1-yl, 2,6-dimethylpiperidin-1-yl, 3,5-dimethylpiperidin-1-yl, 3-carbamoylpiperidin-1-yl, 4-carbamoylpiperidin-1-yl, 2-(hydroxymethyl)piperidin-1-yl, 3-(hydroxymethyl)-piperidin-1-yl, 4-(hydroxymethyl)piperidin-1-yl, 2-(2-hydroxyethyl)piperidin-1-yl, 4-(2-hydroxyethyl)piperidin-1-yl, 2-(2-pyrrolidin-1-ylethyl)piperidin-1-yl, 4-hydroxypiperidin-1-yl, 4-(pyrrolidin-1-yl)piperidin-1-yl, 4-(piperidin-1-yl)piperidin-1-yl, 3,4-didehydropiperidin-1-yl, morpholin-4-yl, 3,5-dimethylmorpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, 4-methylpiperazin-1-yl, 4-cyclopentylpiperazin-1-yl, 4-(pyrrolidin-1-ylcarbonylmethyl)piperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 4-acetylpiperazin-1-yl, 4-(furan-1-ylcarbonyl)piperazin-1-yl, 4-phenylpiperazin-1-yl, 4-(2-chlorophenyl)piperazin-1-yl, 4-(3-chlorophenyl)piperazin-1-yl, 4-(3-methylphenyl)-piperazin-1-yl, 4-(2-methoxyphenyl)piperazin-1-yl, 4-(pyridin-2-yl)piperazin-1-yl, 4-(pyridin-2-yl)piperazin-1-yl, 4-(pyrimidin-2-yl)piperazin-1-yl, 4-(pyrazin-2-yl)-piperazin-1-yl, hexahydroazepin-1-yl, 2,2,5-trimethylhexahydroazepin-1-yl, 3,3,5-trimethylhexahydroazepin-1-yl, 4-methylhexahydro-1,4-diazepin-1-yl, octahydroazocin-1-yl, 1,3,3-trimethyl-6-azabicyclo[3.2.1]octan-6-yl, di(thiophen-2-ylmethyl)amino, di(2-methylbenzyl)amino or di(cyclopropylmethyl)amino; and
Rd is methyl, propyl, isopropyl, butyl, t-butyl, pentyl, 2-methylbutyl, 3-methyl-butyl, hexyl, 3,3-dimethylbutyl, 1-(1-methylethyl)-2-methylpropyl, 2-hydroxyethyl, 2-hydroxy-1-methylethyl, 2-hydroxy-1,1-dimethylethyl, 1-hydroxymethyl-2-hydroxyethyl, 3-hydroxypropyl, 3-hydroxy-2-methylpropyl, 4-hydroxybutyl, 1-hydroxymethylpropyl, 3-hydroxy-2,2-dimethylpropyl, 1-hydroxymethyl-2-methylpropyl, 1-hydroxymethyl-2,2-dimethylpropyl, 1-hydroxymethyl-3-methylthiopropyl, 1-hydroxymethyl-3-methylbutyl, 2-methoxyethyl, 2-methylthioethyl, 2-(dimethylamino)ethyl, 1-methyl-2-(dimethylamino)ethyl, 2,2-dimethyl-3-(dimethylamino)propyl, 2-(acetylamino)ethyl, 2-(pyrrolidin-1-yl)ethyl, 2-(piperidin-1-yl)ethyl, cyclopropyl, cyclobutyl, cyclopenylyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-methylcyclohexyl, 4-methylcyclohexyl, trans-4-hydroxycyclohexyl, 1-(hydroxymethyl)cyclopenylyl, 3-phenylpropyl or hexahydro-2-oxoazepin-3-yl, or Rd is —CH2Rw, in which Rw is ethynyl, cyclopropyl, tetrahydrofuran-2-yl, phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-dimethoxyphenyl, 2,6-dimethoxyphenyl, 2-ethoxyphenyl, 2-hydroxyphenyl, 2-hydroxy-3-methoxyphenyl, 2,3-methylenedioxyphenyl, 2-nitrophenyl, 2-carboxyphenyl, 2-methoxycarbonylphenyl, 2-cyanophenyl, 2-furanyl, 2-thienyl, 3-methylthien-2-yl, 3-thienyl, 2-imidazolyl, 5-methylimidazol-4-yl, 2-thiazolyl, 2-pyridinyl, 3-pyridinyl or 4-pyridinyl, or Rd is —CH(CH3)Rw, in which Rw is phenyl or 2-pyridinyl, or Rd is —CH2 CH(OH)Rw, in which Rw is methyl, t-butyl or trifluoromethyl, or Rd is —CH2 CH═CHRw, in which Rw is phenyl or 2-furanyl, or Rd is —(CH2)2Rw, in which Rw is phenyl or 2-thienyl, or Rd is —CH2 CH(CH3)Rw, in which RW is phenyl, or Rd is α-(hydroxymethyl)benzyl, t-butoxycarbonyl, trifluoroacetyl, or Rd is —COCH2Rx, in which Rx is carboxymethyl, dimethylamino, 2-thienyl, 3-thienyl, 2-pyridinyl or 1-tetrazolyl, or Rd is —CORy in which Ry is methyl, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-thienyl, 3-methylthien-2-yl, 3-thienyl, 1-methylpyrrol-2-yl or 1-methylpyrazol-5-yl, or Rd is —CO—CO—Ry in which Ry is methyl, 2-furanyl or 2-thienyl, or Rd is —CONHRz in which Rz is 2-fluorophenyl or 4-fluoro-phenyl, or Rd is —CONH—(CH2)2Rz in which Rz is 2-thienyl, or Rd is —CSNHRz in which Rz is 2-fluorophenyl, or Rd is —CSNH—CH2—Rz in which Rz is 3-pyridinyl, or Rd is —CSNH—(CH2)2Rz in which Rz is methoxy, or Rd is —CSNH—(CH2)3Rz in which Rz is methoxy, dimethylamino, diethylamino or morpholin-4-yl;
or R1 is 4-oxocyclohexyl.
A more particular compound according to the above definitions is a one wherein
R2 is fluoro, chloro, 1-aminoethyl, 1-amino-1-methylethyl, methylthio, methylsulfinyl, methylsulfonyl, ethylsulfonyl, isopropyl, t-butyl, 4-chlorophenyl, 4-methoxyphenyl, 3-thienyl, methoxy, 2-fluoroethoxy, 2-methoxyethoxy, isopropoxy, 1-ethylpropoxy, 3-methylbutoxy, cyclopentyloxy, cycloheptyloxy, propargyloxy, 2-amino-2-oxoethoxy, 2-ethoxy-2-oxoethoxy, benzyloxy, 1,2,4-oxadiazol-3-ylmethoxy, dimethylamino, azetidin-1-yl, pyrrolidin-1-yl, (R)-2-carbamoylpyrrolidin-1-yl, (S)-2-(methoxymethyl)pyrrolidin-1-yl, 3-hydroxypyrrolidin-1-yl, 3-aminopyrrolidin-1-yl, (S)-3-aminopyrrolidin-1-yl, (S)-3-(dimethylamino)pyrrolidin-1-yl, 3-(t-butoxycarbonyl-amino)pyrrolidin-1-yl, (S)-3-(acetylamino)pyrrolidin-1-yl, piperidin-1-yl, 3-methylpiperidin-1-yl, 3-carbamoylpiperidin-1-yl, 4-carbamoylpiperidin-1-yl, 4-(2-hydroxyethyl)piperidin-1-yl, 3-hydroxypiperidin-1-yl, 4-hydroxypiperidin-1-yl, 3,4-didehydropiperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, 4-methylpiperazin-1-yl, 4-acetylpiperazin-1-yl, hexahydro-1,4-diazepin-1-yl or 4-methylhexahydro-1,4-diazepin-1-yl.
A further more particular compound according to the above definition is one wherein:
each of R3, R5 and R6 is hydrogen and R4 is methoxycarbonyl; or
each of R3, R4 and R6 is hydrogen and R5 is hydrogen, fluoro or chloro;
L1 is —CO—NH— such that -L1-Q1 is —CO—NH-Q1; and
Q1 is 5-chloropyridin-2-yl, 5-fluoropyridin-2-yl, or 6-chloropyridazin-3-yl; and, more particularly, wherein:
each of R3, R4 and R6 is hydrogen and R5 is hydrogen or fluoro; and
Q1 is 5-chloropyridin-2-yl.
One aromatic ether according to the above definitions is one wherein Ra is hydrogen or methyl, and Rb is hydrogen or methyl; or Ra is hydrogen or methyl, and Rb and Rc together are —(CH2)2—, —(CH2)3—, —(CH2)4— or —C(CH3)2—CH2—; particularly wherein R1 is 2-aminoethyl, 3-aminopropyl, 4-piperidinyl, 1-methylpiperidin-4-yl or 1-isopropylpiperidin-4-yl; and more particularly, wherein R1 is 3-aminopropyl or 4-piperidinyl.
Another aromatic ether according to the above definitions is one wherein R2 is 1-amino-1-methylethyl.
A further aromatic ether according to the above definitions is one wherein R2 is methylthio, methylsulfinyl, methylsulfonyl or ethylsulfonyl; particularly, wherein R2 is methylsulfinyl or methylsulfonyl.
Another aromatic ether according to the above definitions is one wherein R2 is methoxy, 2-fluoroethoxy, 2-methoxyethoxy, isopropoxy or propargyloxy; particularly, wherein R2 is 2-fluoroethoxy.
Another particular compound or salt according to the above definitions is one wherein R2 is dimethylamino, azetidin-1-yl, pyrrolidin-1-yl, 3-carbamoylpiperidin-1-yl, 4-hydroxypiperidin-1-yl, morpholin-4-yl or 4-methylhexahydro-1,4-diazepin-1-yl; particularly wherein R2 is dimethylamino, pyrrolidin-1-yl or 4-methylhexahydro-1,4-diazepin-1-yl.
Another particular compound or salt according to the above definitions is one wherein R1 is 4-oxocyclohexyl and R2 is 1-amino-1-methylethyl or 4-methylhexahydro-1,4-diazepin-1-yl.
A specific compound, or pharmaceutically acceptable salt thereof, is any one of those provided in the Examples, particularly the compound provided in one of Examples 2, 5, 89, 107, 109 and 1509, or a pharmaceutically acceptable salt thereof.
A pharmaceutically acceptable salt of a compound of formula I of the instant invention is an acid-addition salt made from a basic compound of formula I and an acid which provides a pharmaceutically acceptable anion or a salt which is made from an acidic compound of formula I and a base which provides a pharmaceutically acceptable cation.
As an additional aspect of the invention there is provided a pharmaceutical composition comprising in association with a pharmaceutically acceptable carrier, diluent or excipient, a compound of formula I, or a pharmaceutically acceptable salt thereof, as provided in any of the descriptions herein.
Further, there is provided a pharmaceutical composition for treating a thromboembolic disorder containing as an active ingredient a compound of formula I, or a pharmaceutically acceptable salt thereof, as provided in any of the descriptions herein.
In addition, there is provided the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, as described herein as an active ingredient in the manufacture of a medicament for use in producing an anticoagulant or antithrombotic effect.
The present invention also provides a method of inhibiting coagulation in a mammal, particularly a human, comprising administering to a mammal in need of treatment, a coagulation inhibiting dose of a compound of formula I, or a pharmaceutically acceptable salt thereof, having any of the definitions herein.
The present invention further provides a method of inhibiting thrombin and/or factor Xa comprising administering to a mammal, particularly a human, in need of treatment, a thrombin and/or factor Xa inhibiting dose of compound of formula I having any of the definitions herein.
Further, the present invention provides a method of treating a thromboembolic disorder comprising administering to a mammal, particularly a human, in need of treatment, an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, having any of the definitions herein.
Also, there is provided a compound of formula I, or a pharmaceutically acceptable salt thereof, having any of the definitions herein for use as an antithrombotic agent.
In addition, there is provided the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, having any of the definitions herein for the manufacture of a medicament for treatment of a thromboembolic disorder.
A compound of formula I may be prepared by processes which include processes known in the chemical art for the production of structurally analogous compounds or by a novel process described herein. A novel process described herein provides another aspect of the invention. A process for the preparation of a compound of formula I (or a pharmaceutically acceptable salt thereof) and novel intermediates for the manufacture of a compound of formula I provide further features of the invention and are illustrated by the following procedures in which the meanings of the generic radicals are as defined above, unless otherwise specified. It will be recognized that it may be preferred or necessary to prepare a compound of formula I in which a functional group is protected using a conventional protecting group, then to remove the protecting group to provide the compound of formula I.
Thus, there is provided a process for preparing a compound of formula I, or a pharmaceutically acceptable salt thereof, as provided in any of the above descriptions, comprising the step selected from
(A) for a compound in which L2 is carbonyl, acylating an amine of formula II,
using an acid of formula III,
or an activated derivative thereof;
(B) for a compound in which L1 is —CO—NH—, acylating an amine of formula Q1-NH2 using an acid of formula IV,
or an activated derivative thereof;
(C) for a compound of formula I in which L2 is methylene, substituting the group Ya of a compound of formula VI
in which Ya is a leaving group for nucleophilic aromatic substitution with an amine of formula VII; or
alkylating an amine of formula II directly, using a compound of formula VIII,
in which Yb is a leaving group for nucleophilic substitution, or indirectly, by reductive alkylation using an aldehyde of formula IX;
(D) for a compound of formula I in which each of Ra and Rb is (1-3C) normal alkyl, or NRaRb is 1-pyrrolidinyl or 4-morpholinyl, or NRaRb is N(CH2Rw)2, alkylating a corresponding compound of formula I in which each of Ra and Rb is hydrogen;
(E) for a compound of formula I in which Ra is Rd and Rd is (1-7C)alkyl, (3-8C)cycloalkyl, 3-phenylpropyl, —CH2Rw, —CH(CH3)Rw, —CH2 CH(OH)Rw, —CH2 CH═CHRw, —(CH2)2Rw, —CH2 CH(CH3)Rw or α-(hydroxymethyl)benzyl, alkylating a corresponding compound of formula I in which Ra is hydrogen;
(F) for a compound of formula I in which Ra is Rd and Rd is {(1-4C)alkoxy}-carbonyl, trifluoroacetyl, —COCH2Rx, —COYRy or —CZNH—(CH2)zRz, acylating a corresponding compound of formula I in which Ra is hydrogen;
(G) alkylating the phenolic oxygen of a compound of formula X,
using a corresponding compound of formula Y—R1, wherein Y is a conventional leaving group for nucleophilic substitution and wherein, for a compound of formula I in which i is 0, the stereochemistry of the carbon to which Y is attached is inverted from that of the product;
(H) for a compound of formula I in which L2 is carbonyl and R2 is —NRSRt, —ORf or —SRn, substitution of the group Yc of a compound of formula XI,
wherein Yc is a leaving group for nucleophilic aromatic substitution, using H—NRsRt, H—ORf or H—SRn, or the deprotonated form thereof;
(I) for a compound of formula I in which R2 is —ORf, alkylating the phenolic oxygen of a compound of formula XII,
using a corresponding compound of formula Y—Rf in which Y is a conventional leaving group for nucleophilic substitution;
(J) for a compound of formula I in which R2 is —S(O)n—Rn and n is 1, oxidizing the corresponding compound of formula I in which n is 0;
(K) for a compound of formula I in which R2 is —S(O)n—Rn and n is 2, oxidizing the corresponding compound of formula I in which n is 0 or 1;
(L) for a compound of formula I in which NRaRb is a basic moiety, other than one in which Rb and Rc together are —(CH2)2—, —(CH2)3—, —(CH2)4— or —C(CH3)2—CH2—, alkylation of a compound of formula H—NRaRb;
(M) for a compound of formula I in which R4 or R5 is amino, reducing the nitro group of a compound corresponding to a compound of formula I in which R4 or R5 is nitro;
(N) for a compound of formula I in which R4 or R5 is RgNH— and Rg is RhSO2—, substituting the amino group of a corresponding compound of formula I in which R4 or R5 is amino using an activated derivative of the sulfonic acid RhSO2—OH;
(O) for a compound of formula I in which R4 or R5 is RfO2 CCH2O—, RfO2C— or RfO2 CCH2— and Rf is H, decomposing the ester of a corresponding compound in which Rf is (1-4C)alkyl or benzyl;
(P) for a compound of formula I in which R4 or R5 is cyano, substituting the iodo or bromo group of a compound corresponding to a compound of formula I in which R4 or R5 is iodo or bromo;
wherein, for any of the above procedures, a functional group which is present and not involved in the indicated procedure may be protected using a protecting group, including a nitrogen protecting group Rp in place of an amino hydrogen or an ethylene ketal in place of an oxo group;
whereafter, for any of the above procedures, when a functional group is protected using a protecting group, removing the protecting group;
whereafter, for any of the above procedures, when a pharmaceutically acceptable salt of a compound of formula I is required, it is obtained by reacting the basic form of a basic compound of formula I with an acid affording a physiologically acceptable counterion or by any other conventional procedure; and wherein, unless otherwise specified above in this claim, A3-A6, L1, L2, R1, R2, and Q1, and the values therein have any of the values defined hereinabove.
As used herein, a nitrogen protecting group RP includes any conventional nitrogen protecting group which is appropriate for the relevant transformation(s) and compounds in terms of stability and removal. It may be preferred to introduce or change the nitrogen protecting group RP during the preparation of a compound. A typical value for RP is one which forms a urethane, such as for example a t-butoxycarbonyl or benzyloxycarbonyl group; however, RP will be other than a urethane when the intramolecular formation of a (cyclic) urethane is favorable, for example, RP may be a trifluoroacetyl or a phenylsulfonyl group. In addition, RP includes resin based protecting groups, such as the urethane formed with Wang-p-nitrophenyl carbonate (Wang-PNP) resin, as described in the examples, for example at Example 113-H, at General Procedure H at Example 1301 and at General Procedure K at Example 1602.
For a carboxylic acid herein, a typical activated derivative includes an ester (particularly a lower alkyl ester such as the methyl or ethyl ester), an acid halide (particularly the acid chloride), and an activated ester or anhydride (including the 4-nitrophenyl ester and an activated ester or mixed anhydride derived from a coupling reagent).
As used herein, a leaving group “Ya” or “Yc” is a moiety which is displaced in an aromatic nucleophilic substitution reaction, for example a halo group (such as fluoro or chloro) or a sulfonate ester group (such as methylsulfonyloxy, p-toluoylsulfonyloxy or trifluoromethylsulfonyloxy). The substitution may be carried out by heating a mixture of the reagents, optionally in a polar solvent, and optionally in the presence of a base, for example as described at Examples 4-F, 35-C, 168-D and 1401-B.
As used herein, a leaving group “Yb” is a moiety which is displaced in a nucleophilic substitution reaction, for example a halo group (such as chloro, bromo or iodo), a sulfonate ester group (such as methylsulfonyloxy, p-toluoyl-sulfonyloxy or trifluoromethylsulfonyloxy), or the reactive species derived from treating an alcohol with triphenyl-phospine, diethyl azodicarboxylate and triethyl amine (in a Mitsunobu reaction).
Reductive alkylations are described, for example, at Examples 3, 56-C, 92, 94-E and 147, as well as in General Procedure A prior to Example 202 and in General Procedure G prior to Example 313.
As used herein, a leaving group “Y” is a moiety which is displaced in a nucleophilic substitution reaction, for example a halo group (such as bromo or iodo), a sulfonate ester group (such as methylsulfonyloxy, p-toluoylsulfonyloxy or trifluoromethylsulfonyloxy), or the reactive species derived from treating an alcohol with triphenylphospine, diethyl azodicarboxylate and triethyl amine (in a Mitsunobu reaction). In addition, an epoxy group may provide the leaving group for the preparation of a compound in which the —CH(OH)— group is adjacent to the substituted carbon. Direct alkylation at nitrogen with an alkyl halide is described, for example, at General Procedure E prior to Example 402; and direct alkylation at nitrogen using an epoxide is described, for example, at Example 36, as well as at General Procedure D prior to Example 231 and GeneralProcedure F prior to Example 601. Direct alkylation at oxygen is described, for example, at Example 113-I, as well as in General Procedure H at Example 1301-B and at General Procedure K prior to Example 1602.
Acylating the amino nitrogen of a compound of formula I in which Ra is hydrogen is conveniently carried out using an activated derivative of the corresponding acid, for example the acyl chloride, an anhydride or an activated ester or mixed anhydride derived from a coupling reagent, optionally in the presense of a base. When Rd is —CZNH—(CH2)zRz, the acylating agent is conveniently the corresponding isocyanate or isothiocyanate of formula ZCN—(CH2)zRz. Acylations are described, for example, at Example 58, Example 139-A, General Procedure B prior to Example 206, General Procedure C prior to Example 228, and at Example 244.
Oxidizing a compound in which n is 0 to afford a compound in which n is 1 is conveniently carried out in a manner as described in Example 23 or by using one equivalent of meta-choloroperbenzoic acid. Oxidizing a compound in which n is 1 to afford a compound in which n is 2 is conveniently carried out using at least one equivalent of meta-choloroperbenzoic acid. When a compound in which n is 2 is required, it is conveniently obtained from the compound in which n is 0 as described in Example 25, in which the intermediate compound in which n is 1 is not isolated but oxidized directly in situ into the compound in which n is 2.
If not commercially available, a necessary starting material for the preparation of a compound of formula I may be prepared by a novel process described herein or one analogous thereto or by a procedure which is selected from standard techniques of organic chemistry, including aromatic substitution and transformation, from techniques which are analogous to the syntheses of known, structurally similar compounds, and techniques which are analogous to the above described procedures or procedures described in the Examples. It will be clear to one skilled in the art that a variety of sequences is available for the preparation of the starting materials. A novel intermediate or starting material compound provides a further aspect of the invention.
Selective methods of substitution, protection and deprotection are well known in the art for preparation of a compound such as one of formulae II-XIII.
Thus, one particular intermediate is an acid of formula III, or a salt thereof, or an activated derivative thereof,
wherein R1 and R2 have any of the values defined herein above (and in which Ra as hydrogen may be replaced by a nitrogen protecting group RP and/or an amino group in R2 may bear a nitrogen protecting group RP). Conveniently, the salt of a carboxylic acid herein may be the lithium, sodium or potassium salt. A particular acid of formula III is one in which R1 has any of the values defined herein above and R2 is aminomethyl, 1-aminoethyl or 1-amino-1-methylethyl, (and in which Ra as hydrogen may be replaced by a nitrogen protecting group RP and/or the amino group in R2 may bear a nitrogen protecting group RP).
Another aspect is an acid of formula IV
(in which Ra as hydrogen may be replaced by a nitrogen protecting group RP and/or an amino group in R2 may bear a nitrogen protecting group RP), or an activated derivative thereof, wherein A3-A6, L2, R1 and R2 have any of the values defined herein. In addition, for an acid of formula IV, in which L2 is carbonyl, a particular activated derivative is a compound of formula V,
or a salt of the active derivative, in which A3-A6, R1 and R2 have any of the values defined herein, or a derivative thereof in which a functional group other than the activated derivative of the carboxy group is protected using a protecting group. Further, for an acid of formula IV, in which L2 is methylene, a particular activated derivative is a compound of formula Va,
or a salt of the active derivative, in which A3-A6, R1 and R2 have any of the values defined herein, or a derivative thereof in which a functional group other than the activated derivative of the carboxy group is protected using a protecting group.
A compound of formula X or a salt thereof,
in which R2 is aminomethyl, 1-aminoethyl, 1-amino-1-methylethyl (in which the amino group in R2 may bear a nitrogen protecting group RP), wherein A3-A6, L1, L2 and Q1 have any of the values defined herein is another particular intermediate.
An additional intermediate, beyond a compound of formula I in which R2 is chloro or fluoro, is a compound of formula XI
(in which Ra as hydrogen may be replaced by a nitrogen protecting group RP or an oxo group may be replaced by a ketal) wherein Yc is a leaving group for nucleophilic aromatic substitution other than fluoro or chloro and A3-A6, -L1-Q1 and R1 have any of the values defined hereinabove.
A further intermediate is a compound of formula XII
(in which Ra as hydrogen may be replaced by a nitrogen protecting group RP or an oxo group may be replaced by a ketal) wherein A3-A6, -L1-Q1 and R1 have any of the values defined hereinabove.
As an another aspect of the invention there is provided compound of formula I as disclosed herein, but in which Ra as hydrogen is replaced by a nitrogen protecting group RP and/or an amino group in R2 bears a nitrogen protecting group RP and/or an oxo group is replaced by a ketal, wherein A3-A6, L1, L2, Q1, R1 and R2, otherwise, have any of the values defined herein.
As mentioned above, the invention includes a pharmaceutically acceptable salt of the thrombin and/or factor Xa inhibiting compound defined by the above formula I. A basic compound of this invention possesses one or more functional groups sufficiently basic to react with any of a number of inorganic and organic acids affording a physiologically acceptable counterion to form a pharmaceutically acceptable salt.
Generally, a basic compound of the invention is isolated best in the form of an acid addition salt. A salt of a compound of formula I formed with an acid such as mentioned above is useful as a pharmaceutically acceptable salt for administration of the antithrombotic agent and for preparation of a pharmaceutical composition of the agent. Other acid addition salts may be prepared and used in the isolation and purification of the compounds.
As noted above, the optically active isomers and diastereomers of the compounds of formula I are also considered part of this invention. Such optically active isomers may be prepared from their respective optically active precursors by the procedures described above, or by resolving the racemic mixtures. This resolution can be carried out by derivatization with a chiral reagent followed by chromatography or by repeated crystallization. Removal of the chiral auxiliary by standard methods affords substantially optically pure isomers of the compounds of the present invention or their precursors.
The compounds of the invention are believed to selectively inhibit thrombin and/or factor Xa over other proteinases and nonenzyme proteins involved in blood coagulation without appreciable interference with the body's natural clot lysing ability (the compounds have a low inhibitory effect on fibrinolysis). Further, such selectivity is believed to permit use with thrombolytic agents without substantial interference with thrombolysis and fibrinolysis.
The invention in one of its aspects provides a method of inhibiting thrombin and/or factor Xa in a mammal comprising administering to a mammal in need of treatment an effective (thrombin and/or factor Xa inhibiting) dose of a compound of formula I.
In another of its aspects, the invention provides a method of treating a thromboembolic disorder comprising administering to a mammal in need of treatment an effective (thromboembolic disorder therapeutic and/or prophylactic amount) dose of a compound of formula I.
The invention in another of its aspects provides a method of inhibiting coagulation in a mammal comprising administering to a mammal in need of treatment an effective (coagulation inhibiting) dose of a compound of formula I.
The thrombin and/or factor Xa inhibition, coagulation inhibition and thromboembolic disorder treatment contemplated by the present method includes both medical therapeutic and/or prophylactic treatment as appropriate.
In a further embodiment, the invention relates to treatment, in a human or animal, of a condition where inhibition of thrombin and/or factor Xa is required. The compounds of the invention are expected to be useful in mammals, including man, in treatment or prophylaxis of thrombosis and hypercoagulability in blood and tissues. Disorders in which the compounds have a potential utility are in treatment or prophylaxis of thrombosis and hypercoagulability in blood and tissues. Disorders in which the compounds have a potential utility, in treatment and/or prophylaxis, include venous thrombosis and pulmonary embolism, arterial thrombosis, such as in myocardial ischemia, myocardial infarction, unstable angina, thrombosis-based stroke and peripheral arterial thrombosis. Further, the compounds have expected utility in the treatment or prophylaxis of atherosclerotic disorders (diseases) such as coronary arterial disease, cerebral arterial disease and peripheral arterial disease. Further, the compounds are expected to be useful together with thrombolytics in myocardial infarction. Further, the compounds have expected utility in prophylaxis for reocclusion after thrombolysis, percutaneous transluminal angioplasty (PTCA) and coronary bypass operations. Further, the compounds have expected utility in prevention of rethrombosis after microsurgery. Further, the compounds are expected to be useful in anticoagulant treatment in connection with artificial organs, including joint replacement, and cardiac valves. Further, the compounds have expected utility in anticoagulant treatment in hemodialysis and disseminated intravascular coagulation. Further, the compounds may be useful in reducing the increased thrombin generation which occurs in the airways of patients with asthma; see, E. C. Gabazza, et al., Lung, (1999), 177(4), 253-262. A further expected utility is in rinsing or coating of catheters and mechanical devices used in patients in vivo, and as an anticoagulant for preservation of blood, plasma and other blood products in vitro. Still further, the compounds have expected utility in other diseases where blood coagulation could be a fundamental contributing process or a source of secondary pathology, such as cancer, including metastasis, inflammatory diseases, including arthritis, and diabetes. The anti-coagulant compound is administered orally or parenterally, e.g. by intravenous infusion (iv), intramuscular injection (im) or subcutaneously (sc).
The specific dose of a compound administered according to this invention to obtain therapeutic and/or prophylactic effects will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the rate of administration, the route of administration, and the condition being treated.
A typical daily dose for each of the above utilities is between about 0.01 mg/kg and about 1000 mg/kg. The dose regimen may vary e.g. for prophylactic use a single daily dose may be administered or multiple doses such as 3 or 5 times daily may be appropriate. In critical care situations a compound of the invention is administered by iv infusion at a rate between about 0.01 mg/kg/h and about 20 mg/kg/h and preferably between about 0.1 mg/kg/h and about 5 mg/kg/h.
The method of this invention also is practiced in conjunction with a clot lysing agent e.g. tissue plasminogen activator (t-PA), modified t-PA, streptokinase or urokinase. In cases when clot formation has occurred and an artery or vein is blocked, either partially or totally, a clot lysing agent is usually employed. A compound of the invention can be administered prior to or along with the lysing agent or subsequent to its use, and preferably further is administered along with aspirin to prevent the reoccurrence of clot formation.
The method of this invention is also practiced in conjunction with a platelet glycoprotein receptor (IIb/IIIa) antagonist, that inhibits platelet aggregation. A compound of the invention can be administered prior to or along with the IIb/IIIa antagonist or subsequent to its use to prevent the occurrence or reoccurrence of clot formation.
The method of this invention is also practiced in conjunction with aspirin. A compound of the invention can be administered prior to or along with aspirin or subsequent to its use to prevent the occurrence or reoccurrence of clot formation. As stated above, preferably a compound of the present invention is administered in conjunction with a clot lysing agent and aspirin.
This invention also provides a pharmaceutical composition for use in the above described therapeutic method. A pharmaceutical composition of the invention comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier, diluent or excipient.
The active ingredient in such formulations comprises from 0.1 percent to 99.9 percent by weight of the formulation. By “pharmaceutically acceptable” it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The present pharmaceutical compositions are prepared by known procedures using well known and readily available ingredients. The compositions of this invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
The ability of a compound of the present invention to be an effective and orally active thrombin and/or factor Xa inhibitor may be evaluated in one or more of the following assays or in other standard assays known to those in the art.
The inhibition by a compound of the invention of a serine protease of the human blood coagulation system or of the fibrinolytic system, as well as of trypsin, is determined in vitro for the particular enzyme by measuring its inhibitor binding affinity in an assay in which the enzyme hydrolyzes a particular chromogenic substrate, for example as described in Smith, G. F.; Gifford-Moore, D.; Craft, T. J.; Chirgadze, N.; Ruterbories, K. J.; Lindstrom, T. D.; Satterwhite, J. H. Efegatran: A New Cardiovascular Anticoagulant. New Anticoagulants for the Cardiovascular Patient; Pifarre, R., Ed.; Hanley & Belfus, Inc.: Philadelphia, 1997; pp. 265-300. The inhibitor binding affinity is measured as apparent association constant Kass which is the hypothetical equilibrium constant for the reaction between enzyme and the test inhibitor compound (I).
Conveniently, enzyme inhibition kinetics are performed in a high-volume protocol using automated dilutions of inhibitors (n=3 for each of four to eight inhibitor concentrations) into 96-well polystyrene plates and reaction rates are determined from the rate of hydrolysis of appropriate p-nitroanilide substrates at 405 nm using a Thermomax plate reader from Molecular Devices (San Francisco, Calif.). The same general protocol is followed for all enzymes studied: In each well is placed 50 μL buffer (0.06 M Tris, 0.3 M NaCl, pH 7.4), followed by 25 μL of inhibitor solution (in 100% methanol) and 25 μL enzyme solution (e.g., human factor Xa, 32 nM in 0.03 M Tris, 0.15 M NaCl, 1 mg/mL HAS); finally, within two minutes, 150 L aqueous solution of chromogenic substrate (e.g., 0.3 mM BzIle-Glu-Gly-Arg-pNA) is added to start the enzymatic reaction. Final factor Xa concentration is 3.2 nM. The rates of chromogenic substrate hydrolysis reactions provide a linear relationship with the enzymes studied such that free enzyme can be quantitated in reaction mixtures. Data is analyzed directly as rates by the Softmax program to produce [free enzyme] calculations for tight-binding Kass determinations.
For apparent Kass determinations, human factor Xa is used to hydrolyze Bzlle-Glu-Gly-Arg-pNA; 5.9 nM human thrombin is used to hydrolyze 0.2 mM BzPhe-Val-Arg-pNA; 3.4 nM human plasmin is used with 0.5 mM HD-Val-Leu-Lys-pNA; 1.2 nM human nt-PA is used with 0.8 mM HD-Ile-Pro-Arg-pNA; and 0.4 nM urokinase is used with 0.4 mM pyro-Glu-Gly-Arg-pNA.
Kass is calculated for a range of concentrations of test compounds which produce hydrolysis inhibition of between 20% and 80% of control and the mean value reported in units of liter per mole. In general, a compound of formula I of the instant invention, as exemplified hereinbelow in the working examples, exhibits a Kass for factor Xa of 0.1-1,000×106 L/mole or greater. Most of the examples also exhibit a Kass for thrombin (factor IIa) of 0.3-100×106 L/mole or greater. For example, the respective Kass values as to factor Xa/thrombin for Examples 41, 60, 106, 115, 1403 and 1414 are 407/16.9, 430/4.2, 3630/308, 3013/40 and 3630/308×106 L/mole.
The thrombin and/or factor Xa inhibitor preferably should spare fibrinolysis induced by urokinase, tissue plasminogen activator (t-PA) and streptokinase. This would be important to the therapeutic use of such an agent as an adjunct to streptokinase, tp-PA or urokinase thrombolytic therapy and to the use of such an agent as an endogenous fibrinolysis-sparing (with respect to t-PA and urokinase) antithrombotic agent. In addition to the lack of interference with the amidase activity of the fibrinolytic proteases, such fibrinolytic system sparing can be studied by the use of human plasma clots and their lysis by the respective fibrinolytic plasminogen activators.
Dog plasma is obtained from conscious mixed-breed hounds (either sex Butler Farms, Clyde, N.Y., U.S.A.) by venipuncture into 3.8 percent citrate. Fibrinogen is prepared from fresh dog plasma and human fibrinogen is prepared from in-date ACD human blood at the fraction I-2 according to previous procedures and specification. Smith, Biochem. J., 185, 1-11 (1980; and Smith, et al., Biochemistry, 11, 2958-2967, (1972). Human fibrinogen (98 percent pure/plasmin free) is from American Diagnostica, Greenwich, Conn. Radiolabeling of fibrinogen I-2 preparations is performed as previously reported. Smith, et al., Biochemistry, 11, 2958-2967, (1972). Urokinase is purchased from Leo Pharmaceuticals, Denmark, as 2200 Ploug units/vial. Streptokinase is purchased from Hoechst-Roussel Pharmaceuticals, Somerville, N.J.
Dog plasma and rat plasma are obtained from conscious mixed-breed hounds (either sex, Butler Farms, Clyde, N.Y., U.S.A.) or from anesthetized male Sprague-Dawley rats (Harlan Sprague-Dawley, Inc., Indianapolis, Ind., U.S.A.) by venipuncture into 3.8 percent citrate. Fibrinogen is prepared from in-date ACD human blood as the fraction I-2 according to previous procedures and specifications. Smith, Biochem. J., 185, 1-11 (1980); and Smith, et al., Biochemistry, 11, 2958-2967 (1972). Human fibrinogen is also purchased as 98 percent pure/plasmin free from American Diagnostica, Greenwich, Connecticut. Coagulation reagents Actin, Thromboplastin, Innovin and Human plasma are from Baxter Healthcare Corp., Dade Division, Miami, Fla. Bovine thrombin from Parke-Davis (Detroit, Mich.) is used for coagulation assays in plasma.
Coagulation assay procedures are as previously described. Smith, et al., Thrombosis Research, 50, 163-174 (1988). A CoAScreener coagulation instrument (American LABor, Inc.) is used for all coagulation assay measurements. The prothrombin time (PT) is measured by adding 0.05 mL saline and 0.05 mL Thromboplastin-C reagent or recombinant human tissue factor reagent (Innovin) to 0.05 mL test plasma. The activated partial thromboplastin time (APTT) is measured by incubation of 0.05 mL test plasma with 0.05 mL Actin reagent for 120 seconds followed by 0.05 mL CaCl2 (0.02 M). The thrombin time (TT) is measured by adding 0.05 mL saline and 0.05 mL thrombin (10 NIH units/mL) to 0.05 mL test plasma. Thus, the plasma concentrations are three times the assay concentrations. The compounds of formula I are added to human or animal plasma over a wide range of concentrations to determine prolongation effects on the APTT, PT, and TT assays. Linear extrapolations are performed to estimate the concentrations required to double the clotting time for each assay. Compounds of the instant invention potently extended the prolongation times in the APTT and PT assays, for example in some cases, with assay concentrations necessary to double the APPT or PT of less than 1 μM.
Male Sprague Dawley rats (350-425 gm, Harlan Sprague Dawley Inc., Indianapolis, Ind.) are anesthetized with xylazine (20 mg/kg, s.c.) and ketamine (120 mg/kg, s.c.) or preferably are anesthetized using isoflurane anesthesia (2-3%, conveniently 2.5%, for surgery; 1.5-2.5%, conveniently 2.5%, for maintenance; flow rate kept at 0.5% throughout) and maintained on a heated water blanket (37° C.). The jugular vein(s) is cannulated to allow for infusions.
The left jugular vein and right carotid artery are cannulated with 20 cm lengths of polyethylene PE 60 tubing. A 6 cm center section of larger tubing (PE 190) with a cotton thread (5 cm) in the lumen, is friction fitted between the longer sections to complete the arterio-venous shunt circuit. Blood is circulated through the shunt for 15 min before the thread is carefully removed and weighed. The weight of a wet thread is subtracted from the total weight of the thread and thrombus (see J. R. Smith, Br J Pharmacol, 77:29, 1982).
The carotid arteries are isolated via a midline ventral cervical incision. A thermocouple is placed under each artery and vessel temperature is recorded continuously on a strip chart recorder. A cuff of tubing (0.058 ID×0.077 OD×4 mm, Baxter Med. Grade Silicone), cut longitudinally, is placed around each carotid directly above the thermocouple. FeCl3 hexahydrate is dissolved in water and the concentration (20 percent) is expressed in terms of the actual weight of FeCl3 only. To injure the artery and induce thrombosis, 2.85 μL is pipetted into the cuff to bathe the artery above the thermocouple probe. Arterial occlusion is indicated by a rapid drop in temperature. The time to occlusion is reported in minutes and represents the elapsed time between application of FeCl3 and the rapid drop in vessel temperature (see K. D. Kurz, Thromb. Res., 60:269, 1990).
Ex vivo plasma thrombin time (TT), prothrombin time (PT) and activated partial thromboplastin time (APTT) are measured with a fibrometer. Blood is sampled from a jugular catheter and collected in syringe containing sodium citrate (3.8 percent, 1 part to 9 parts blood). To measure TT, rat plasma (0.1 mL) is mixed with isotonic saline (0.1 mL) and bovine thrombin (0.1 mL, 30 U/mL in TRIS buffer; Parke Davis) at 37° C. For PT, to plasma (0.1 mL) mixed with isotonic saline (0.1 mL) is added PT reagent (0.1 mL, Dade, Thromboplastin-C); and the fibrometer started immediately after the addition of the final reagent. For APTT, plasma (0.1 mL) and APTT solution (0.1 mL, Organon Teknika) are incubated for 5 minutes (37° C.); and CaCl2 (0.1 mL, 0.025 M) is added to start coagulation. Assays are done in duplicate and averaged.
Bioavailability studies may be conducted as follows. Compounds are administered as aqueous solutions, or as solutions in 5% PEG 200, to male Fisher rats, intravenously (iv) at 5 mg/kg via tail vein injection and orally (po) as aqueous solutions, or as a suspension in 5% acacia, to fasted animals at 20 mg/kg by gavage. Serial blood samples are obtained at 5, 30, 120, and 240 minutes postdose following intravenous administration and at 1, 2, 4, and 6 hours after oral dosing. Plasma is analyzed for drug concentration using an HPLC procedure involving C8 Bond Elute (Varian) cartridges for sample preparation and a methanol/30 nM ammonium acetate buffer (pH 4) gradient optimized for each compound. % Oral bioavailability is calculated by the following equation:
where AUC is area under the curve calculated from the plasma level of compound over the time course of the experiment following oral (AUC po) and intravenous (AUC iv) dosing.
For oral determinations, the compound may be administered orally, by gavage, as a suspension in 5% acaia to conscious fasted rats. The pretreatment time before flow is established through the shunt is selected based upon the peak apparent plasma concentration recorded in preliminary time course experiments that track apparent drug concentration in plasma following oral administration to conscious fasted rats, and typically varies between 1 to 5 hours. Animals used in antithrombotic efficacy experiments are anesthetized as described 15 minutes before the predetermined pretreatment time to allow for surgical preparation of the animals. Compound solutions are prepared fresh daily in normal saline or in 5% PEG200 in water for iv determinations and are injected as a bolus or are infused starting 15 minutes before and continuing throughout the experimental perturbation which is 15 minutes in the arteriovenous shunt model and 60 minutes in the FeCl3 model of arterial injury and in the spontaneous thrombolysis model. Typically, bolus injection volume is 1 mL/kg for iv, and 5 mL/kg for po, and infusion volume is 3 mL/h. For a similar procedure run in the anesthesized rabbit, for example an infusion rate of 6.8 mL/h was used for one compound infused in 5% PEG200 in water.
Results are expressed as means+/−SEM. One-way analysis of variance is used to detect statistically significant differences and then Dunnett's test is applied to determine which means are different. Significance level for rejection of the null hypothesis of equal means is P<0.05.
Animals Male dogs (Beagles; 18 months-2 years; 12-13 kg, Marshall Farms, North Rose, New York 14516) are fasted overnight and fed Purina certified Prescription Diet (Purina Mills, St. Louis, Mo.) 240 minutes after dosing. Water is available ad libitum. The room temperature is maintained between 66-74° F.; 45-50 percent relative humidity; and lighted from 0600-1800 hours.
Test compound is formulated immediately prior to dosing by making a suspension in a “wet granulaion” (povidone, 0.85 mg/mL; lactose, 15.0 mg/mL; and polysorbate 80, 65 μL in 250 mL water). Dogs are given a single 20 mg/kg (in 25 mL of wet granulation) dose of test compound by oral gavage. Blood samples (4.5 mL) are taken from the cephalic vein at 0.25, 0.5, 0.75, 1, 2, 3, 4 and 6 hours after dosing. Samples are collected in citrated Vacutainer tubes and kept on ice prior to reduction to plasma by centrifugation. Plasma samples are analyzed by HPLC MS. Plasma concentration of test compound is recorded and used to calculate the pharmacokinetic parameters: elimination rate constant, Ke; total clearance, Clt; volume of distribution, VD; time of maximum plasma test compound concentration, Tmax; maximum concentration of test compound of Tmax, Cmax; plasma half-life, t0.5; and area under the curve, A.U.C.; fraction of test compound absorbed, F.
Male dogs (Beagles, as described above) are fasted overnight and dosed with test compound that is fomulated immediately prior to dosing by making a suspension in a “wet granulation” as described above. Dogs are given a single dose of 5, 10 or 20 mg/kg (in 25 mL of wet granulation) of test compound by oral gavage. Based on the pharmacokinetics of the test compound, dogs are dosed either 1 or 2 hours prior to anesthesia. Dogs are anesthetized with sodium pentobarbital (30 mg/kg intravenously, i.v.), intubated, and ventilated with room air. Tidal volume and respiratory rates are adjusted to maintain blood PO2, PCO2, and pH within normal limits. Subdermal needle electrodes are inserted for the recording of a lead II ECG.
The left jugular vein and common carotid artery are isolated through a left mediolateral neck incision. Arterial blood pressure (ABP) is measured continuously with a precalibrated Millar transducer (model MPC-500, Millar Instruments, Houston, Tex., U.S.A.) inserted into the carotid artery. The jugular vein is cannulated for blood sampling during the experiment. In addition, the femoral veins of both hindlegs are cannulated for administration of test compound.
A left thoracotomy is performed at the fifth intercostal space, and the heart is suspended in a pericardial cradle. A 1- to 2-cm segment of the left circumflex coronary artery (LCX) is isolated proximal to the first major diagonal ventricular branch. A 26-gauge needle-tipped wire anodal electrode (Teflon-coated, 30-gauge silverplated copper wire) 3-4 mm long is inserted into the LCX and placed in contact with the intimal surface of the artery (confirmed at the end of the experiment). The stimulating circuit is completed by placing the cathode in a subcutaneous (s.c.) site. An adjustable plastic occluder is placed around the LCX, over the region of the electrode. A precalibrated electromagnetic flow probe (Carolina Medical Electronics, King, N.C., U.S.A.) is placed around the LCX proximal to the anode for measurement of coronary blood flow (CBF). The occluder is adjusted to produce a 40-50 percent inhibition of the hyperemic blood flow response observed after 10-s mechanical occlusion of the LCX. All hemodynamic and ECG measurements are recorded and analyzed with a data acquisition system (Notochord HEM data analysis system, Croissy, France).
Electrolytic injury of the intima of the LCX is produced by applying 100-μA direct current (DC) to the anode. The current is maintained for 60 min and then discontinued whether the vessel has occluded or not. Thrombus formation proceeds spontaneously until the LCX is totally occluded (determined as zero CBF and an increase in the S-T segment for a minimum of 30 minutes). The preparation is followed for 4 hours at which time the animal is euthanized and the thrombus is dissected from the LCX and weighed.
Citrated blood (3 mL, 1 part 3.8% citrate:9 parts blood) is drawn before drug administration, at 60 min after administration, at 60 min after initiation of vessel injury and just prior to the end of the experiment. Whole blood cell counts, hemoglobin, and hematocrit values are determined on a 40-μL sample of the citrated whole blood with a hematology analyzer (Cell-Dyn 900, Sequoia-Turner, Mount View, Calif., U.S.A.). The remaining blood was cetrifuged at 3,000 g for 5 min to prepare cell-free plasma. Plasma clotting times, prothrombin time (PT) and activated partial thromoplastin times (APTT) were performed using standard Dade reagents and the Coa-Screener coagulation device (American Labor, Largo, Fla.). Gingival template bleeding times are determined with a Simplate II bleeding time device (Organon Teknika Durham, N.C., U.S.A.). The device is used to make 2 horizontal incisions in the gingiva of either the upper or lower left jaw of the dog. Each incision is 3 mm wide×2 mm deep. The incisions are made, and a stopwatch is used to determine how long bleeding occurs. A cotton swab is used to soak up the blood as it oozes from the incision. Template bleeding time is the time from incision to stoppage of bleeding. Bleeding times are taken just before administration of test compound (0 min), 60 min into infusion, at conclusion of administration of the test compound (120 min), and at the end of the experiment.
All data are analyzed by one-way analysis of variance (ANOVA) followed by Dunnet's post hoc t test to determine the level of significance. Repeated-measures ANOVA are used to determine significant differences between time points during the experiments. Values are determined to be statistically different at least at the level of p<0.05. All values are mean±SEM. All studies are conducted in accordance with the guiding principles of the American Physiological Society. Further details regarding the procedures are described in Jackson, et al., J. Cardiovasc. Pharmacol., (1993), 21, 587-599.
Compounds of the instant invention are potent anticoagulant and antithrombotic agents which exhibit particularly good plasma exposure following oral administration, as evidenced by standard pharmacokinetic/pharmcodynamic assays.
The following Examples are provided to further describe the invention and are not to be construed as limitations thereof. Resin based reagents used in the examples are commercially available or well described in the literature. The term “aldehyde resin” refers to a formylpolystyrene resin. See, for example, X. Beebe et at., J. Amer. Chem. Soc., 114, 10061 (1992); J. M. Frechet and C. Schuerch, J. Amer. Chem. Soc., 93, 492 (1971). Generally, see S. W. Kaldor and M. G. Siegel, Current Opinion in Chem. Biol., 1, 101-106 (1997).
The abbreviations, symbols and terms used in the examples have the following meanings.
IR=Infrared Spectrum
When indicated without data, 1NMR, IR or MS means a satisfactory spectrum was obtained.
To a solution of 2-hydroxy-4-(N,N-dimethylamino)benzoic acid (9.05 g, 50 mmol) and MeOH (100 mL) at 0° C. was added thionyl chloride (5.34 mL, 75 mmol) dropwise. The reaction was warmed to room temperature and refluxed for 14 hours. After cooling, ether was added to the mixture and the reaction was carefully quenched with satd NaHCO3. The mixture was diluted with ether (200 mL) and partitioned. The organic layer was dried over MgSO4 and the crude product was adsorbed onto silica gel. The crude product was chromatographed on silica gel (5% CH2Cl2/hexane to 25% CH2Cl2/hexane) and triturated with ether/hexane to give the desired product as a white solid (7.1 g, 73%).
1NMR (300 MHz, DMSO-d6): δ 10.90 (s, 1H), 7.65 (d, J=9.0 Hz, 1H), 6.23 (dd, J=2.3, 9.0 Hz, 1H), 6.15 (d, J=2.3 Hz, 1H), 3.88 (s, 3H), 3.02 (s, 6H).
IS-MS, m/e: 196.2 (m+1).
Analysis for C10H13NO3:
Calcd: C, 61.53; H, 6.71; N, 7.18;
Found: C, 61.31; H, 6.62; N, 7.30.
To a mixture of 4-hydroxypiperidine (60.69 g, 0.6 mol), 4-(dimethylamino)-pyridine (74 mg, 0.6 mmol), CH2Cl2 (150 mL), and THF (150 mL) was added di-tert-butyl dicarbonate (130.95 g, 0.6 mol). After stirring for 6 hours, the reaction was heated to 35° C. for 16 hours. More di-tert-butyl dicarbonate (13.09 g, 0.06 mol) in THF (20 mL) was added and the reaction was heated for 10 hours. After cooling, water and ether (1 L) were added and the mixture was stirred for 2 hours. The organic layer was partitioned, dried (MgSO4), and concentrated in vacuo. The residue was crystallized from ether to give the desired product as a white solid (105 g, 87%).
1NMR (300 MHz, DMSO-d6): δ 3.85 (m, 3H), 3.04 (m, 2H), 1.88 (m, 2H), 1.56 (m, 2H), 1.25 (s, 9H).
IS-MS, m/e: 202.0 (m+1).
To a mixture of methyl 2-hydroxy-4-(N,N-dimethylamino)benzoate (7.809 g, 40 mmol), 4-hydroxy-1-tert-butoxycarbonylpiperidine (8.048 g, 40 mmol), triphenylphosphine (11.02 g, 42 mmol), and THF (250 mL) at 0° C. was added diethyl azodicarboxylate (7.1 mL, 45.1 mmol), dropwise. The reaction was warmed to room temperature and stirred overnight. The reaction was concentrated, chromatographed (hexane to 30% EtOAc/hexane), and triturated with ether/hexane to give the desired product as a white solid (5.55 g, 37%).
1NMR (300 MHz, DMSO-d6): δ 8.60 (d, J=8.7 Hz, 1H), 6.85 (br s, 1H), 6.60 (d, J=8.7 Hz, 1H), 4.63 (m, 1H), 3.85 (s, 3H), 3.70-3.43 (m, 4H), 3.07 (s, 6H), 1.90 (m, 4H), 1.46 (s, 9H).
IS-MS, m/e: 379 (m+1).
Potassium hydroxide (3.79 g, 67.5 mmol) in water (135 mL) was added to a mixture of methyl 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(N,N-dimethylamino)-benzoate (5.11 g, 13.5 mmol) and ethanol. The reaction was heated to 70° C. for 14 hours. The ethanol was removed in vacuo. The resulting aqueous mixture was cooled to 5° C., acidified with satd citric acid, filtered with water wash, and vacuum dried to give the desired product as a white solid (4.65 g, 95%).
1NMR (300 MHz, DMSO-d6): δ 7.60 (d, J=6.6 Hz, 1H), 6.29 (dd, J=1.6, 6.6 Hz, 1H), 6.24 (s, 1H), 4.68 (br s, 1H), 3.48 (m, 4H), 2.93 (s, 6H), 1.76 (m, 2H), 1.63 (m, 2H), 1.37 (s, 9H).
IS-MS, m/e: 365 (m+1).
A mixture of 20 g (123 mmol) isatoic anhydride (formed by treating anthranilic acid with phosgene) and 15.64 g (123 mmol) 4-chloroaniline was heated at 120° C. for 2 hours. The reaction was cooled to room temperature, mixed with CH2Cl2 and filtered.
The filtrate was purified by silica gel chromatography using 30% hexanes in CHCl3 to recover 18.38 g (65%) of a white solid. This was recrystallized from EtOAc to give 11.16 g of a white solid.
1NMR
The 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(N,N-dimethylamino)benzoic acid (950 mg, 2.61 mmol) was dissolved in methylene chloride (15 mL). Pyridine (0.27 mL, 3.39 mmol) and DMF (1 drop) were added, followed by oxalyl chloride (0.27 mL, 3.13 mmol). Vigorous bubbling occurred. After 45 minutes, more pyridine (0.27 mL, 3.39 mmol) was added, followed by the N-(4-chlorophenyl)-2-amino-benzamide (645 mg, 2.61 mmol). The reaction was stirred for 2 hours and then diluted with methylene chloride and washed with 50% saturated aqueous sodium bicarbonate.
The organic layer was concentrated and purified by flash column chromatography (about 120 g silica, 100% CH2Cl2 to 10% EtOAc/CH2Cl2) to give the desired product (207 mg, 0.35 mmol, 13%).
1NMR (300 MHz, CDCl3): δ 8.48 (br s, 1H), 8.27 (d, J=8.4 Hz, 1H), 8.07 (d, J=9.0 Hz, 1H), 7.57 (m, 4H), 7.42 (m, 1H), 7.33 (m, 2H), 7.11 (m, 1H), 6.56 (m, 2H), 4.66 (m, 1H), 3.75 (m, 1H), 3.20 (m, 1H), 3.05 (m, 6H), 2.1 (m, 2H), 1.60 (m, 4H), 1.43 (s, 9H).
IS-MS, m/e: 593 (m+1).
The 2-[4-(N,N-dimethylamino)-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-benzoylamino]-N-(4-chlorophenyl)benzamide (178 mg, 0.30 mmol) was dissolved in methylene chloride (2 mL) and TFA (1 mL). After 1 hour, the reaction was concentrated, diluted with methylene chloride, and washed with saturated aqueous sodium carbonate.
The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by flash column chromatography (about 10 g silica, 10% EtOAc/CH2Cl2 to 3:2:20:75 MeOHIEt3 N/EtOAc/CH2Cl2) to give the desired product (122 mg, 0.25 mmol, 82%) as a white solid.
1NMR (300 MHz, DMSO-d6): 10.80 (br s, 1H), 10.60 (br s, 1H), 8.40 (d, J=8.3 Hz, 1H), 7.80-7.67 (m, 4H), 7.50 (t, J=4.9 Hz, 1H), 7.40 (d, J=9.0 Hz, 2H), 7.20 (t, J=7.1 Hz, 1H), 6.40 (dd, J=2.3, 9.0 Hz, 1H), 6.30 (m, 1H), 4.63 (m, 1H), 3.00 (s, 6H), 2.77 (m, 2H), 2.52 (m, 2H), 1.85 (m, 2H), 1.65 (m, 2H).
IS-MS, m/e: 493.3 (m+1).
Analysis for C27H29ClN4O3.0.5H2O:
Calcd: C, 64.60; H, 6.02; N, 11.16;
Found: C, 64.57; H, 5.91; N, 11.17.
To a stirring solution of 2-amino-5-chloropyridine (3.7 g, 29 mmol) and pyridine (7.3 mL, 90 mmol) in dichloromethane (200 mL) was added 2-nitrobenzoyl chloride (5.7 g, 30 mmol). After stirring for 4 h, the solvents were removed in vacuo and the residue was partitioned between ethyl acetate and water. The layers were separated and the organic phase was washed again with water and once with brine, then dried with MgSO4, filtered and partially concentrated in vacuo. The precipitate was filtered, washed with diethyl ether and dried in vacuo to give 6.4 g (79%) of an off-white solid.
1NMR
FD-MS, m/e 276.9 (m)
Analysis for C12H8ClN3O3:
Calcd: C, 51.91; H, 2.90; N, 15.13;
Found: C, 52.61; H, 2.89; N, 15.29.
To a solution of N-(5-chloropyridin-2-yl)-2-nitrobenzamide (2 g, 7.2 mmol) in THF (50 mL) and ethyl acetate (50 mL) was added Raney Ni (0.2 g) and the mixture was placed under hydrogen (4.1 bar) in a high pressure apparatus. After shaking overnight, the mixture was filtered and concentrated in vacuo and purified by flash chromatography to give 1.5 g (83%) of an off-white solid.
1NMR
To a mixture of 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(N,N-dimethyl-amino)benzoic acid (950 mg, 2.61 mmol), pyridine (0.23 mL, 2.86 mmol), DMF (1 drop) and methylene chloride (15 mL) was added oxalyl chloride (0.24 mL, 2.73 mmol) dropwise. After 15 minutes, more pyridine (0.23 mL, 2.86 mmol) was added, followed by the N-(4-chlorophenyl)-2-aminobenzamide (645 mg, 2.61 mmol). The reaction was stirred for 1 hour, diluted with methylene chloride, washed with 50% saturated aqueous sodium bicarbonate, and dried over Na2 SO4. The organic solution was concentrated, chromatographed (2000 g silica, 5% EtOAc/CH2Cl2 to 15% EtOAc/CH2Cl2), and triturated with ether to give the desired product (1.32 g, 83%).
1NMR (300 MHz, CDCl3): δ 8.57 (s, 1H), 8.51 (d, J=8.7 Hz, 1H), 8.24 (m, 2H), 8.04 (d, J=8.7 Hz, 1H), 7.76 (dd, J=2.4, 8.7 Hz, 1H), 7.64 (d, J=8.7 Hz, 1H), 7.55 (m, 1H), 7.20 (m, 1H), 6.47 (d, 8.7 Hz, 1H), 6.43 (br s, 1H), 4.65 (m, 1H), 3.86 (m, 1H), 3.17 (m, 1H), 3.05 (s, 6H), 2.06 (m, 2H), 1.60 (m, 4H), 1.45 (s, 9H).
IS-MS, m/e: 594.5 (m+1).
Analysis for C31H36ClN5O5. 0.5H2O:
Calcd: C, 61.74; H, 6.18; N, 11.61;
Found: C, 61.68; H, 6.15; N, 11.47.
Using a procedure similar to Example 1-G, 2-[4-(N,N-dimethylamino)-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide gave the desired product (638 mg, 60%) as a white solid after chromatography and CH2Cl2/ether trituration.
1NMR
IS-MS, m/e: 494.2 (m+1).
Purification by HPLC (Vydac, 5% CH3 CN in 0.1% TFA/H2O to 70% CH3 CN in 0.1% TFA/H2O, t=31.2 m) of N-(5-chloropyridin-2-yl)-2-[4-(N,N-dimethylamino)-2-(piperidin-4-yloxy)benzoylamino]benzamide followed by treatment with HCl gave the desired salt as a white solid (118 mg, 44%).
1NMR
IS-MS, m/e: 494.0 (m+1).
To a mixture of N-(5-chloropyridin-2-yl)-2-[4-(N,N-dimethylamino)-2-(piperidin-4-yloxy)benzoylamino]benzamide (250 mg, 0.51 mmol), acetone (0.07 mL, 1.0 mmol) and 20% AcOH/MeOH (2 mL) was added a solution of 0.25 M NaCNBH3/MeOH (2 mL, 0.5 mmol). The reaction was stirred for 24 hours and then it was diluted with water and CH2Cl2. After partitioning, the organic layer was washed with 50% satd Na2 CO3, dried over Na2 SO4, and concentrated. The residue was HPLC chromatographed (Vydac, 5% CH3 CN in 0.1% TFA/H2O to 70% CH3 CN in 0.1% TFA/H2O, t=28.8 m) and then treated with HCl to give the desired product as a white solid (66 mg, 23%).
1NMR
IS-MS, m/e: 536.1 (m+1).
Potassium carbonate (51.6 g, 373 mmol) was dried by heating at 200° C. for 12 hours. This was treated with 3-fluorophenol (16.5 g, 147 mmol) in a sealed container which was then pressurized with carbon monoxide at 61.2 bar. The reaction was heated to 175° C. for 5 hours. Subsequently, the reaction mixture was dissolved in water, acidified with concentrated hydrochloric acid, and filtered. The solid was washed with water, then hexanes. The solid was then dissolved in EtOAc, dried over magnesium sulfate, and concentrated to give 12 g of solid. This crude solid was purified by flash chromatrography using CHCl3/MeOH/HOAc 98:1:1 to give 11 g of a white solid which was recrystallized from toluene to give 9.5 g of the product as needles.
1NMR
FD-MS, m/e 155 (m−1)
Analysis for C7H5FO3.0.1C7H8.0.3H2O:
Calcd: C, 54.17; H, 3.78;
Found: C, 54.12; H, 3.39.
A solution of 4-fluoro-2-hydroxybenzoic acid (9.8 g, 62.3 mmol) in benzene (100 mL) and MeOH (20 mL) was cooled in an ice bath and a 2 M hexane solution of trimethylsilyldiazomethane (50 mL) was added dropwise. The reaction was stirred overnight at ambient temperature, diluted with benzene (348 mL) and MeOH (39 mL), and treated with more of the trimethylsilyldiazomethane solution (15 mL). The mixture was concentrated in vacuo to dryness to give 10.4 g of an oil which crystallized.
1NMR
FD-MS, m/e 170 (m+)
Analysis for C8H7FO3:
Calcd: C, 56.48; H, 4.15;
Found: C, 56.17; H, 4.28.
Using a procedure analogous to Example 1-C, methyl 2-hydroxy-4-fluorobenzoate gave the desired product as a white solid (17.8 g, 67%).
1NMR (300 MHz, CDCl3) 5 ppm: 7.85 (dd, J=6.9, 8.7 Hz, 1H), 6.68 (m, 2H), 4.58 (m, 1H), 3.87 (s, 3H), 3.57 (m, 4H), 1.86 (m, 4H), 1.47 (s, 9H).
IS-MS, m/e: 354.3 (m+1).
Analysis for C18H24 FNO5:
Calcd: C, 61.18; H, 6.85; N, 3.96;
Found: C, 61.14; H, 6.74; N, 4.01.
A mixture of methyl-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-fluorobenzoate (3.05 g, 8.64 mmol), 1 M aq LiOH (15 mL, 15 mmol), MeOH (15 mL), and THF (45 mL) was stirred overnight. The reaction was diluted with EtOAc, washed with satd citric acid, dried over MgSO4, concentrated, and triturated with ether to give the desired product as a white solid (2.23 g, 76%).
1NMR (300 MHz, CDCl3): δ 7.68 (m, 1H), 7.10 (d, J=8.7 Hz, 1H), 6.79 (m, 1H), 4.72 (m, 1H), 3.48 (m, 4H), 1.65 (m, 2H), 1.60 (m, 2H), 1.37 (s, 9H).
IS-MS, m/e: 340 (m+1).
The 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-fluorobenzoic acid (507 mg, 2.05 mmol) was diluted with methylene chloride (20 mL). DMF (4 drops) and pyridine (0.2 mL, 2.47 mmol) were added, followed by oxalyl chloride (0.2 mL, 2.29 mmol). Vigorous bubbling occurred. After 1.5 hours, the reaction was concentrated in vacuo. The residue was diluted with methylene chloride (20 mL). N-(5-Chloropyridin-2-yl)-2-aminobenzamide (507 mg, 2.05 mmol) was added, followed by pyridine (0.2 mL, 2.47 mmol). After stirring overnight, the reaction was diluted with methylene chloride (100 mL) and washed with water (2×10 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by flash column chromatography (100% CH2Cl2 to 10% EtOAc/CH2Cl2) to give the desired product (992 mg, 1.74 mmol, 85%) as a white solid.
IR(CHCl3): 1675, 1503, 1375, 1296 cm−1.
1NMR (400 MHz, DMSO-d6): δ 11.23 (s, 1H); 11.04 (s, 1H); 8.40 (d, J=2.8 Hz, 1H); 8.35 (d, J=8.4 Hz, 1H); 8.12 (d, J=9.2 Hz, 1H); 7.93-7.89 (m, 2H); 7.79 (d, J=8.0 Hz, 1H); 7.23 (m, 2H); 6.89 (t, J=8.4 Hz, 1H); 4.79 (m, 1H); 3.70 (m, 2H); 3.01 (m, 2H); 1.84 (m, 4H); 1.32 (s, 9H).
IS-MS, m/e 569.4 (m+1).
The 2-[4-fluoro-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (203 mg, 0.35 mmol) was diluted with morpholine (4 mL, 45.9 mmol). The mixture was heated to 129° C. for 2 days. The reaction was diluted with methylene chloride (100 mL) and washed with water (2×10 mL). The aqueous layers were combined and extracted with ethyl acetate (100 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by flash column chromatography (about 25 g silica, 10% EtOAc/CH2Cl2 to 20% EtOAc/CH2Cl2) to give the desired product (125 mg, 0.20 mmol, 56%) as a white solid.
1NMR (300 MHz, DMSO-d6): δ 11.19 (s, 1H); 10.89 (s, 1H); 8.39 (s, 1H); 8.32 (d, J=8.1 Hz, 1H); 8.13 (d, J=8.7 Hz, 1H); 7.90 (d, J=9.0 Hz, 1H); 7.74 (t, J=8.3 Hz, 1H); 7.50 (t, J=7.7 Hz, 1H); 7.15 (t, J=7.5 Hz, 1H); 6.59 (s, 2H); 4.80 (m, 1H); 3.70 (m, 4H); 3.29 (m, 4H); 3.22 (m, 2H); 3.00 (m, 2H); 1.91-1.75 (m, 4H); 1.31 (s, 9H).
IS-MS, m/e 636.2 (m+1).
The 2-[4-(morpholin-4-yl)-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (164 mg, 0.26 mmol) was dissolved in TFA (3 mL). After 5 minutes, the reaction was concentrated in vacuo. The residue was diluted with methylene chloride (100 mL) and washed with saturated aqueous sodium carbonate. The organic layer was dried over sodium sulfate, filtered, and concentrated to give the desired product (138 mg, 0.26 mmol, 100%).
1NMR (300 MHz, DMSO-d6): δ 11.16 (s, 1H); 10.89 (s, 1H); 8.41 (d, J=2.4 Hz, 1H); 8.29 (d, J=8.4 Hz, 1H); 8.11 (d, J=9.0 Hz, 1H); 7.93 (dd, J=9.0, 2.7 Hz, 1H); 7.77 (d, J=8.1 Hz, 1H); 7.71 (d, J=8.7 Hz, 1H); 7.53 (t, J=7.8 Hz, 1H); 7.17 (t, J=7.5 Hz, 1H); 6.63 (d, J=11.7, 1H); 6.61 (s, 1H); 4.90 (m, 1H); 3.70 (m, 4H); 3.24-2.99 (m, 8H); 2.02 (m, 4H).
IS-MS, m/e 536.3 (m+1).
Analysis for C28H30ClN5O4.H2O:
Calcd: C, 60.70; H, 5.82; N, 12.64;
Found: C, 60.83; H, 5.83; N, 12.25.
Using methods substantially equivalent to those described in example 4-F except that the reaction was heated to 80° C., 2-[4-(pyrrolidin-1-yl)-2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (101 mg, 0.16 mmol, 90%) was prepared from 2-[4-fluoro-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-benzoylamino]-N-(5-chloropyridin-2-yl)benzamide and pyrrolidine.
1NMR (400 MHz, DMSO-d6): δ 11.18 (s, 1H); 10.83 (s, 1H); 8.39 (d, J=2.8 Hz, 1H); 8.31 (d, J=8.4 Hz, 1H); 8.15 (d, J=8.8 Hz, 1H); 7.90 (dd, J=8.8, 2.8 Hz, 1H); 7.73 (m, 2H); 7.49 (t, J=7.6 Hz, 1H); 7.13 (t, J=7.4 Hz, 1H); 6.22 (d, J=8.8, 1H); 6.15 (s, 1H); 4.78 (m, 1H); 3.69 (m, 2H); 3.27 (m, 4H); 3.00 (m, 2H); 1.93-1.82 (m, 8H); 1.32 (s, 9H).
IS-MS, m/e 620.1 (m+1).
Using methods substantially equivalent to those described in example 4-G, N-(5-chloropyridin-2-yl)-2-[2-(piperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]-benzamide (39 mg, 0.07 mmol, 76%) was prepared from 2-[4-(pyrrolidin-1-yl)-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide.
IR(KBr): 1603, 1502, 1375, 1292 cm−1.
1NMR (400 MHz, DMSO-d6): δ 10.77 (s, 1H); 8.40 (d, J=2.0 Hz, 1H); 8.36 (d, J=8.4 Hz, 1H); 8.19 (d, J=9.2 Hz, 1H); 7.93 (dd, J=8.8, 2.8 Hz, 1H); 7.72 (m, 2H); 7.49 (t, J=8.0 Hz, 1H); 7.13 (t, J=7.6 Hz, 1H); 6.21 (d, J=9.2 Hz, 1H); 6.12 (s, 1H); 4.60 (m, 1H); 2.79 (m, 2H); 2.50 (m, 6H); 1.86 (m, 6H); 1.65 (m, 2H).
IS-MS, m/e 520.2 (m+1).
Analysis for C28H30ClN5O31.1H2O:
Calcd: C, 62.30; H, 6.01; N, 12.97;
Found: C, 62.14; H, 5.52; N, 12.59.
Using methods substantially equivalent to those described in example 4-F except that the reaction was heated to 106° C., 2-[4-(piperidin-1-yl)-2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (200 mg, 0.32 mmol, 44%) was prepared from 2-[4-fluoro-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-benzoylamino]-N-(5-chloropyridin-2-yl)benzamide and piperidine.
1NMR (300 MHz, DMSO-d6): δ 11.18 (s, 1H); 10.85 (s, 1H); 8.39 (d, J=2.4 Hz, 1H); 8.31 (d, J=8.4 Hz, 1H); 8.14 (d, J=9.0 Hz, 1H); 7.90 (dd, J=9.2, 2.6 Hz, 1H); 7.72 (d, J=8.7 Hz, 2H); 7.49 (t, J=7.7 Hz, 1H); 7.14 (t, J=7.8 Hz, 1H); 6.57 (d, J=9.9, 1H); 6.54 (s, 1H); 4.81 (m, 1H); 3.67 (m, 2H); 3.29 (m, 4H); 3.00 (m, 2H); 1.85 (m, 4H); 1.54 (m, 6H); 1.31 (s, 9H).
IS-MS, m/e 634.3 (m+1).
Analysis for C34H40ClN5O5:
Calcd: C, 64.39; H, 6.36; N, 11.04;
Found: C, 64.66; H, 6.37; N, 10.95.
Using methods substantially equivalent to those described in example 4-G, N-(5-chloropyridin-2-yl)-2-[4-(piperidin-1-yl)-2-(piperidin-4-yloxy)benzoylamino]-benzamide (144 mg, 0.27 mmol, 100%) was prepared from 2-[4-(piperidin-1-yl)-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)-benzamide. The hydrochloride salt was prepared by treating the free base with 1 N HCl in MeOH.
1NMR (300 MHz, DMSO-d6): δ 11.15 (s, 1H); 10.88 (s, 1H); 8.40 (d, J=2.4 Hz, 1H); 8.27 (d, J=8.1 Hz, 1H); 8.12 (d, J=9.0 Hz, 1H); 7.94 (dd, J=8.9, 2.3 Hz, 1H); 7.76 (m, 3H); 7.53 (d, J=7.5 Hz, 1H); 7.18 (t, J=7.5 Hz, 1H); 6.85 (m, 3H); 4.90 (m, 1H); 3.13 (m, 2H); 3.02 (m, 2H); 2.10-1.98 (m, 4H); 1.59 (m, 6H).
IS-MS, m/e 534.2 (m+1).
Calcd: C, 56.55; H, 5.73; N, 11.37;
Found: C, 56.67; H, 5.52; N, 11.20.
A dry reaction flask equipped with a magnetic stirring bar and a rubber septum was charged with 3-tert-butylphenol (15.02 g, 100 mmol), N,N-diisopropylethylamine (34.83 mL, 200 mmol) and CH2Cl2. The reaction mixture was cooled to 0° C. Methyl chloromethyl ether (8.96 mL, 118 mmol) was added under N2 to the reaction mixture over a period of 20 min. The reaction was stirred at 0° C. for 1 h and at room temperature for 2 h. The reaction was then quenched with H2O (1000 mL) and the organic layer was separated and washed with H2O (200 mL). The organic solution was dried (Na2 SO4) and concentrated. The residue was dissolved in CH2Cl2 (500 mL) and extracted with 2 N NaOH (500 mL). The organic layer was dried (Na2 SO4) and the solvent was removed under reduced pressure to obtain the desired product (10.44 g, 54%), TLC Rf: 0.75 (20% EtOAc/n-hexanes).
1NMR (400 MHz, CDCl3): δ 7.23 (m, 1H); 7.04 (bm, 2H); 6.87 (m, 1H); 5.17 (s, 2H); 3.48 (s, 3H); 1.30 (s, 9H).
A dry reaction flask equipped with a magnetic stirring bar and a addition funnel was charged with 3-(tert-butyl)methoxymethylphenyl ether (10.40 g, 53.60 mmol) and ethyl ether (200 mL) under N2. The reaction flask was cooled to 0° C. Then tert-BuLi (1.7 M, pentane, 34.68 mL, 58.96 mmol) was added over a period of 20 min using an addition funnel. The reaction was stirred at 0° C. for 2 h. Carbon dioxide (gas) was bubbled into this turbid solution until it became clear. The reaction was stirred for an additional 2 h at room temperature. The reaction was quenched with H2O (100 mL), stirred for 30 minutes, acidified with conc HCl (to pH 4-5), and extracted with ethyl ether (3×300 mL). The organic solution was dried (Na2 SO4) and the solvent was removed. The resulting residue containing the desired acid was dissolved in ethyl ether (300 mL) and extracted with 2 N NaOH (3×75 mL). The aqueous alkaline solution was acidified with cone HCl (to pH 6). The resulting colorless solid was filtered and dried to obtain 8.24 g (65%) of the requisite acid; mp: 72° C., TLC Rf: 0.08 (40% EtOAc/n-hexanes).
1NMR (400 MHz, CDCl3) δ 10.7 (bs, 1H); 7.86 (dd, 1H, J=4 and 8.4 Hz); 7.07 (bd, 1H); 6.99 (dd, 1H, J=2 and 6.4 Hz); 5.22 (s, 2H); 3.37 (s, 3H); 1.13 (s, 9H).
A dry reaction flask equipped with a stirring bar and a rubber septum was charged with 4-tert-butyl-2-(methoxymethoxy)benzoic acid (11.9 g, 50 mmol) and MeOH (166 mL). The solution was cooled to 0° C. and dry HCl gas was bubbled into the reaction. The reaction color changed from faint yellow to peach and again back to faint yellow. The reaction mixture was refluxed for 18 h, cooled to room temperature, and the solvent was removed. The resulting thick oil was diluted with CH2Cl2 (100 mL) and washed with H2O (100 mL) and 5% aqueous NaHCO3 solution (2×50 mL). The organic solution was dried (Na2 SO4) and the solvent was removed to obtain the requisite compound (9.10 g, 87%) as a colorless liquid, TLC Rf: 0.77 (10% EtOAc/n-hexanes).
1H NMR (400 MHz, CDCl3) δ 10.66 (s, 1H); 7.72 (d, 1H, J=8.4 Hz); 6.97 (d, 1H, J=2 Hz); 6.90 (dd, 1H, J=2 and 8.4 Hz); 3.91 (s, 3H); 1.29 (s, 9H).
To a stirring solution of 1-Boc-piperidin-4-one (10.28 g, 51.6 mmol) in THF (170 mL) at −78° C. was added via syringe a solution of lithium hexamethyldisilazide (1 M in hexanes, 54.2 mL, 54.2 mmol), followed 20 min later by methyl iodide (3.53 mL, 56.7 mmol). After an additional 2 h, the cooling bath was removed and the solution was allowed to warm to room temperature. After an additional 10 h, the solvent was removed in vacuo and the residue was flushed through a pad of silica gel with ethyl acetate and then concentrated in vacuo. The residue was then chromatographed, eluting with a gradient from 5% ethyl acetate in hexanes through 25% ethyl acetate in hexanes. The product containing fractions (clean only) were combined and concentrated in vacuo to give 0.54 g (5%) of the title compound.
1NMR
To a stirring solution of 1-Boc-3,3-dimethylpiperidin-4-one (0.48 g, 2.1 mmol) in methanol (20 mL) at 0° C., was added sodium borohydride (0.096 g, 2.5 mmol). After 1 h, satd aq ammonium chloride (1 mL) was added and the solution was concentrated in vacuo. The residue was flushed through a pad of silica gel, eluting with ethyl acetate and the filtrate was concentrated in vacuo to give 0.46 g (96%) of a clear colorless oil.
1NMR
IS-MS, m/e 230.1 (m+1)
By methods substantially equivalent to those described in Example 1-C, methyl 4-tert-butyl-2-(1-Boc-3,3-dimethylpiperidin-4-yloxy)benzoate (0.058 g, 6%) was prepared from methyl 4-tert-butyl-2-hydroxybenzoate and 1-Boc-3,3-dimethylpiperidin-4-ol.
1NMR
IS-MS, m/e 420.1 (m+1)
By methods substantially equivalent to those described in Example 1-D, 4-tert-butyl-2-(1-Boc-3,3-dimethylpiperidin-4-yloxy)benzoic acid (0.045 g, 85%) was prepared from methyl 4-tert-butyl-2-(1-Boc-3,3-dimethylpiperidin-4-yloxy)benzoate.
1NMR
IS-MS, m/e 406.1 (m+1)
By methods substantially equivalent to those described in Example 1-F and 1-G, 2-[4-(tert-butyl)-2-(3,3-dimethylpiperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide trifluoroacetate (3.5 mg, 5%) was prepared from 4-tert-butyl-2-(1-Boc-3,3-dimethylpiperidin-4-yloxy)benzoic acid and N-(5-chloropyridin-2-yl)-2-aminobenzamide.
1NMR
IS-MS, m/e 535.1 (m+1)
Using methods substantially equivalent to those described in example 4-F except that the workup used saturated aqueous citric acid instead of water, 2-[2-(1-tert-butoxy-carbonylpiperidin-4-yloxy)-4-(3-hydroxypyrrolidin-1-yl)benzoylamino]-N-(5-chhloro-pyridin-2-yl)benzamide (160 mg, 0.25 mmol, 47%) was prepared from 2-[4-fluoro-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)-benzamide and 3-hydroxypyrrolidine.
1NMR (300 MHz, DMSO-d6): δ 11.17 (s, 1H); 10.83 (s, 1H); 8.39 (d, J=2.1 Hz, 1H); 8.31 (d, J=8.7 Hz, 1H); 8.14 (d, J=9.0 Hz, 1H); 7.90 (dd, J=9.0, 2.4 Hz, 1H); 7.73 (m, 2H); 7.48 (t, J=7.7 Hz, 1H); 7.13 (t, J=7.4 Hz, 1H); 6.19 (d, J=9.0, 1H); 6.13 (s, 1H); 4.98 (d, J=3.6 Hz, 1H); 4.78 (m, 1H); 4.37 (br s, 1H); 3.69 (m, 2H); 3.45-3.11 (m, 4H); 3.00 (m, 2H); 1.89 (m, 6H); 1.32 (s, 9H).
IS-MS, m/e 636.2 (m+1).
Analysis for C33H38ClN5O6:
Calcd: C, 62.31; H, 6.02; N, 11.01;
Found: C, 62.07; H, 5.84; N, 11.02.
Using methods substantially equivalent to those described in example 4-G, N-(5-chloropyridin-2-yl)-2-[4-(3-hydroxypyrrolidin-1-yl)-2-(piperidin-4-yloxy)benzoylamino]-benzamide (72 mg, 0.13 mmol, 67%) was prepared from 2-[2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-4-(3-hydroxypyrrolidin-1-yl)benzoylamino]-N-(5-chloropyridin-2-yl)-benzamide.
1NMR (300 MHz, DMSO-d6): δ 11.15 (s, 1H); 10.84 (s, 1H); 8.41 (d, J=1.8 Hz, 1H); 8.28 (d, J=8.1 Hz, 1H); 8.11 (d, J=9.0 Hz, 1H); 7.93 (dd, J=8.7, 2.4 Hz, 1H); 7.75 (d, J=7.8 Hz, 1H); 7.70 (d, J=9.0 Hz, 1H); 7.51 (t, J=7.5 Hz, 1H); 7.15 (t, J=7.5 Hz, 1H); 6.23 (d, J=9.0, 1H); 6.15 (s, 1H); 4.89 (m, 1H); 4.38 (m, 1H); 3.58-3.01 (m, 8H); 2.06-1.90 (m, 6H).
IS-MS, m/e 536.2 (m+1).
Analysis for C28H30ClN5O4.TFA.1.5H2O:
Calcd: C, 53.22; H, 5.06; N, 10.34;
Found: C, 53.43; H, 4.74; N, 10.08.
Using methods substantially equivalent to those described in Example 4-F, 2-[4-(4-methylpiperazin-1-yl)-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (132 mg, 0.20 mmol, 60%) was prepared from 2-[4-fluoro-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoylamino]-N-(5-chloro-pyridin-2-yl)benzamide and 1-methylpiperazine.
1NMR (400 MHz, DMSO-d6): δ 11.19 (s, 1H); 10.88 (s, 1H); 8.39 (d, J=3.2 Hz, 1H); 8.32 (d, J=8.4 Hz, 1H); 8.14 (d, J=8.8 Hz, 1H); 7.90 (dd, J=9.0, 3.0 Hz, 1H); 7.74 (m, 2H); 7.50 (t, J=8.0 Hz, 1H); 7.15 (t, J=7.4 Hz, 1H); 6.59 (m, 2H); 4.81 (m, 1H); 3.67 (m, 2H); 3.27 (m, 2H); 3.00 (m, 4H); 2.47 (s, 3H); 2.22 (m, 4H); 1.86 (m, 4H); 1.32 (s, 9H).
IS-MS, m/e 649.5 (m+1).
Analysis for C34H41ClN6O5:
Calcd: C, 62.91; H, 6.37; N, 12.95;
Found: C, 62.62; H, 6.43; N, 12.93.
Using methods substantially equivalent to those described in example 4-G, N-(5-chloropyridin-2-yl)-2-[4-(4-methylpiperazin-1-yl)-2-(piperidin-4-yloxy)-benzoylamino]benzamide was prepared from 2-[4-(4-methylpiperazin-1-yl)-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide.
The impure product was purified by RPHPLC to give the dihydrochloride salt (66 mg, 0.11 mmol, 26%).
1NMR (300 MHz, DMSO-d6): δ 11.17 (s, 1H); 10.91 (s, 1H); 8.41 (d, J=2.4 Hz, 1H); 8.30 (d, J=8.4 Hz, 1H); 8.10 (d, J=9.0 Hz, 1H); 7.94 (dd, J=8.9, 2.6 Hz, 1H); 7.79 (d, J=7.5 Hz, 1H); 7.72 (d, J=8.7 Hz, 1H); 7.54 (t, J=8.0 Hz, 1H); 7.18 (t, J=7.8 Hz, 1H); 6.68 (m, 2H); 4.93 (m, 2H); 4.03 (m, 2H); 3.53-2.98 (m, 10H); 2.79 (d, J=3.6 Hz, 1H); 2.46 (s, 3H); 2.04 (m, 4H).
IS-MS, m/e 549.3 (m+1).
Analysis for C29H33ClN6O3.2HCl.0.5H2O:
Calcd: C, 55.20; H, 5.75; N, 13.32;
Found: C, 55.65; H, 5.34; N, 13.13.
Using methods substantially equivalent to those described in Example 4-F, except that the reaction was quenched with water and the resulting precipitate was collected, 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(3-hydroxypiperidin-1-yl)-benzoylamino]-N-(5-chloropyridin-2-yl)-benzamide (166 mg, 0.26 mmol, 34%) was prepared from 2-[4-fluoro-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide and 3-hydroxypiperidine.
1NMR (300 MHz, DMSO-d6): δ 11.18 (s, 1H); 10.85 (s, 1H); 8.39 (d, J=1.5 Hz, 1H); 8.31 (d, J=8.4 Hz, 1H); 8.14 (d, J=9.0 Hz, 1H); 7.90 (dd, J=9.2, 1.7 Hz, 1H); 7.72 (d, J=8.4 Hz, 2H); 7.49 (t, J=7.5 Hz, 1H); 7.17 (t, J=7.5 Hz, 1H); 6.53 (m, 2H); 4.81 (m, 2H); 3.72-2.68 (m, 8H); 1.90-1.69 (m, 8H); 1.31 (s, 9H).
IS-MS, m/e 650.4 (m+1).
Analysis for C34H40ClN5O6:
Calcd: C, 62.81; H, 6.20; N, 10.77;
Found: C, 62.58; H, 5.92; N, 11.07.
Using methods substantially equivalent to those described in example 4-G, N-(5-chloropyridin-2-yl)-2-[4-(3-hydroxypiperidin-1-yl)-2-(piperidin-4-yloxy)-benzoylamino]benzamide (67 mg, 0.12 mmol, 53%) was prepared from 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(3-hydroxypiperidin-1-yl)benzoylamino]-N-(5-chloropyridin-2-yl)-benzamide.
1NMR (300 MHz, DMSO-d6): δ 11.16 (s, 1H); 10.87 (s, 1H); 8.42 (d, J=2.1 Hz, 1H); 8.29 (d, J=8.1 Hz, 1H); 8.11 (d, J=9.0 Hz, 1H); 7.93 (dd, J=11.49, 2.4 Hz, 1H); 7.77 (d, J=7.2 Hz, 1H); 7.68 (d, J=9.0 Hz, 1H); 7.52 (t, J=8.1 Hz, 1H); 7.17 (t, J=8.1 Hz, 1H); 6.59 (d, J=9.0 Hz, 1H); 6.55 (s, 1H); 4.90 (m, 1H); 3.87 (m, 1H); 3.20-1.69 (m, 16H).
IS-MS, m/e 550.4 (m+1).
Using methods substantially equivalent to those described in Example 4-F except that the workup used saturated aqueous citric acid instead of water, 2-[2-(1-tert-butoxy-carbonylpiperidin-4-yloxy)-4-(4-hydroxypiperidin-1-yl)benzoylamino]-N-(5-chloro-pyridin-2-yl)benzamide (196 mg, 0.30 mmol, 39%) was prepared from 2-[4-fluoro-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)-benzamide and 4-hydroxypiperidine.
1NMR (300 MHz, DMSO-d6): δ 11.18 (s, 1H); 10.86 (s, 1H); 8.39 (d, J=2.4 Hz, 1H); 8.31 (d, J=8.4 Hz, 1H); 8.14 (d, J=9.0 Hz, 1H); 7.90 (dd, J=8.7, 2.4 Hz, 1H); 7.72 (d, J=8.4 Hz, 1H); 7.72 (d, J=8.4 Hz, 2H); 7.49 (t, J=8.3 Hz, 1H); 7.14 (t, J=7.7 Hz, 1H); 6.55 (m, 2H); 4.81 (m, 1H); 4.67 (m, 1H); 3.67 (m, 1H); 2.99 (m, 4H); 1.80 (m, 8H).
IS-MS, m/e 650.4 (m+1).
Analysis for C34H40ClN5O6:
Calcd: C, 62.81; H, 6.20; N, 10.77;
Found: C, 63.09; H, 6.18; N, 10.74.
Using methods substantially equivalent to those described in example 4-G, N-(5-chloropyridin-2-yl)-2-[4-(4-hydroxypiperidin-1-yl)-2-(piperidin-4-yloxy)-benzoylamino]benzamide (62 mg, 0.11 mmol, 45%) was prepared from 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(4-hydroxypiperidin-1-yl)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide.
1NMR (300 MHz, DMSO-d6): δ 11.51 (s, 1H); 10.87 (s, 1H); 8.41 (s, 1H); 8.29 (d, J=8.4 Hz, 1H); 8.11 (d, J=9.0 Hz, 1H); 7.94 (d, J=8.7 Hz, 1H); 7.77 (d, J=7.5 Hz, 1H); 7.68 (d, J=8.4 Hz, 1H); 7.52 (t, J=7.5 Hz, 1H); 7.17 (t, J=7.5 Hz, 1H); 6.61 (d, J=9.0 Hz, 1H); 6.57 (s, 1H); 4.89 (m, 1H); 4.30 (m, 4H); 3.68 (m, 2H); 3.15 (m, 1H); 2.99 (m, 2H); 2.02 (m, 4H); 1.76 (m, 2H); 1.38 (m, 2H).
IS-MS, m/e 550.4 (m+1).
To a stirring suspension of 2-nitro-4-chlorobenzoic acid (20 g, 99 mmol) in dichloromethane (500 mL) was added a few drops of DMF, followed by oxalyl chloride (15.1 g, 119 mmol). After 1 h, the solvent was removed in vacuo and the residue was dissolved in dichloromethane (500 mL). To this stirring solution was added pyridine (24 mL, 297 mmol) followed by 2-amino-5-chloropyridine (12.7 g, 99 mmol). After stirring overnight, the solvents were removed in vacuo and the residue was stirred vigorously with ethyl acetate and water for several hours. The mixture was filtered to give a white solid, which was washed with ethyl acetate and dried in vacuo to give 23 g (74%) of the title compound. The combined ethyl acetate washings and extract were then washed twice with 1 M citric acid, once with brine, twice with saturated aq sodium bicarbonate, and again with brine. The organic phase was then dried with MgSO4, filtered and concentrated in vacuo. The solid was suspended in diethyl ether, sonicated and filtered to give a second crop of the title compound as a white solid (5.79 g, 19%).
1NMR
IS-MS, m/e 312.0 (m+1)
Analysis for C12H7Cl2N3O3:
Calcd: C, 46.18; H, 2.26; N, 13.46;
Found: C, 46.24; H, 2.37; N, 13.43.
Using methods substantially equivalent to those described in example 2-B, N-(5-chloropyridin-2-yl)-2-amino-4-chlorobenzamide (7.85 g, 87%) was prepared from N-(5-chloropyridin-2-yl)-2-nitro-4-chlorobenzamide.
1NMR
IS-MS, m/e 280.2 (m−1)
Analysis for C12H9Cl2N3O:
Calcd: C, 51.09; H, 3.22; N, 14.89;
Found: C, 51.52; H, 3.56; N, 14.68.
To a stirring solution of methyl 4-tert-butyl-2-hydroxybenzoate (9.45 g, 45.4 mmol), 1-Boc-piperidine-4-ol (9.6 g, 47.7 mmol) and triphenylphosphine (12.5 g, 47.7 mmol) in THF (125 mL) was added, dropwise via an addition funnel, a solution of diisopropyl azodicarboxylate (9.4 mL, 47.7 mmol) in THF (25 mL). After 72 h, the solvent was removed in vacuo and the residue was dissolved in a minimal amount of chloroform and vacuum filtered through a pad of silica gel, eluting with a solution of 20% ethyl acetate in hexanes. The filtrate was then concentrated in vacuo and the residue was chromatographed over silica gel, eluting with a gradient of 5% ethyl acetate in hexanes through 20% ethyl acetate in hexanes. The product containing fractions were combined and concentrated in vacuo to give 12.9 g (73% of a thick colorless oil).
1NMR
ES-MS, m/e 392.3 (MH+)
To a stirring solution of methyl 4-(tert-Butyl)-2-(1-Boc-piperidin-4-yloxy)-benzoate (12.9 g, 33 mmol) in p-dioxane (150 mL) was added a solution of LiOH hydrate (2.8 g, 66 mmol) in water (75 mL). The next morning, the solvent was removed in vacuo and the residue was diluted with water (200 mL) and washed with diethyl ether. The aqueous phase was then adjusted to pH 3 with citric acid and extracted twice with diethyl ether. The combined ether extracts were then washed twice with brine, dried with MgSO4, filtered and concentrated in vacuo to give 11.3 g (91%) of a white foam.
1NMR
IS-MS, m/e 378.5 (m+1)
Analysis for C21H31NO5:
Calcd: C, 66.82; H, 8.28; N, 3.71;
Found: C, 67.06; H, 8.39; N, 3.71.
To a stirring solution of 4-(tert-butyl)-2-(1-Boc-piperidin-4-yloxy)benzoic acid (4.0 g, 10.6 mmol) in dichloromethane (20 mL) at 0° C., was added oxalyl chloride (13 mmol), followed by a small amount of DMF. After 30 min, the solvents were removed in vacuo and the residue was dissolved in dichloromethane to make a solution of the title compound, approximately 0.1 g/mL.
To a stirring solution of N-(5-chloropyridin-2-yl)-2-amino-4-chlorobenzamide (0.74 g, 26.5 mmol) in pyridine (1 mL) and dichloromethane (20 mL) at 0° C. was added a solution of 4-(tert-butyl)-2-(1-Boc-piperidin-4-yloxy)benzoyl chloride (1.05 g, 26.5 mmol) in dichloromethane (10.5 mL). The cold bath was then removed and after 72 h, the solvent was removed in vacuo and the residue was dissolved in ethyl acetate and washed with water, followed by satd aq NaHCO3 and then brine. The organic phase was then dried with MgSO4, filtered and concentrated in vacuo. The residue was chromatographed over silica gel, eluting with a solution of 20% ethyl acetate in hexanes.
The product containing fractions were combined and concentrated in vacuo to give 0.89 g (52%) of a white solid.
1NMR
IS-MS, m/e 641.2 (m+1)
Analysis for C33H38Cl2N4O5:
Calcd: C, 61.78; H, 5.97; N, 8.73;
Found: C, 62.15; H, 6.20; N, 8.43.
2-[4-(tert-Butyl)-2-(1-Boc-piperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)-4-chlorobenzamide (0.4 g, 0.64 mmol) was dissolved in 4 N HCl/p-dioxane (15 mL). After stirring for 30 min, the solution was concentrated in vacuo and the residue was purified by RPHPLC, eluting with a gradient of 20% through 60% acetonitrile in 0.05% aq HCl over 320 min. The clean product containing fractions were combined, partially concentrated and lypholyzed to give 0.0864 g (23%) of white solid.
1NMR
IS-MS, m/e 541.1 (m+1)
Analysis for C28H30Cl2 N4O3.1.3HCl.1.1H2O:
Calcd: C, 55.25; H, 5.55; N, 9.20; Cl, 19.22;
Found: C, 55.28; H, 5.32; N, 9.40; Cl, 19.16.
Using methods substantially equivalent to those described in Example 16-A, N-(5-chloropyridin-2-yl)-2-nitro-5-chlorobenzamide (26.4 g, 85%) was prepared from 2-amino-5-chloropyridine and 2-nitro-5-chlorobenzoic acid.
1NMR
IS-MS, m/e 312.0 (m+1)
Analysis for C12H7Cl2N3O3:
Calcd: C, 46.18; H, 2.26; N, 13.46;
Found: C, 46.37; H, 2.41; N, 13.43.
Using methods substantially equivalent to those described in example 2-B, N-(5-chloropyridin-2-yl)-2-amino-5-chlorobenzamide (7.79 g, 72%) was prepared from N-(5-chloropyridin-2-yl)-2-nitro-5-chlorobenzamide.
1NMR
IS-MS, m/e 282.1 (m+1)
Analysis for C12H9Cl2N3O:
Calcd: C, 51.09; H, 3.22; N, 14.89; Cl, 25.13;
Found: C, 51.29; H, 3.36; N, 14.89; Cl, 25.41.
By methods substantially equivalent to those described in Example 16-F, 2-[4-(tert-butyl)-2-(1-Boc-piperidin-4-yloxy)benzoylamino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide (0.81 g, 48%) was prepared from 4-(tert-butyl)-2-(1-Boc-piperidin-4-yloxy)benzoyl chloride and N-(5-chloropyridin-2-yl)-2-amino-5-chlorobenzamide.
1NMR
IS-MS, m/e 641.0 (m+1)
Analysis for C33H38Cl2N4O5:
Calcd: C, 61.78; H, 5.97; N, 8.73;
Found: C, 62.27; H, 6.18; N, 8.41.
By methods substantially equivalent to those described in Example 16-G, 2-[4-(tert-butyl)-2-(piperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)-5-chloro-benzamide hydrochloride (0.326 g, 88%) was prepared from 2-[4-(tert-butyl)-2-(1-Boc-piperidin-4-yloxy)benzoylamino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide.
1NMR
IS-MS, m/e 541.0 (m+1)
Using methods substantially equivalent to those described in example 16-A, N-(5-chloropyridin-2-yl)-2-nitro-5-fluorobenzamide (8.7 g, 70%) was prepared from 2-nitro-5-fluorobenzoic acid and 2-amino-5-chloropyridine.
1NMR
IS-MS, m/e 296.2 (m+1)
Analysis for C12H7ClFN3O3:
Calcd: C, 48.75; H, 2.39; N, 14.21;
Found: C, 48.96; H, 2.59; N, 14.02.
Using methods substantially equivalent to those described in example 2-B, N-(5-chloropyridin-2-yl)-2-amino-5-fluorobenzamide (11.6 g, 86%) was prepared from N-(5-chloropyridin-2-yl)-2-nitro-5-fluorobenzamide.
1NMR
IS-MS, m/e 264.1 (m−1)
Analysis for C12H9CFN30:
Calcd: C, 54.25; H, 3.42; N, 15.82;
Found: C, 54.46; H, 3.58; N, 15.84.
By methods substantially equivalent to those described in Example 16-F, 2-[4-(tert-butyl)-2-(1-Boc-piperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide (1.17 g, 70%) was prepared from 4-(tert-butyl)-2-(1-Boc-piperidin-4-yloxy)benzoyl chloride and N-(5-chloropyridin-2-yl)-2-amino-5-fluorobenzamide.
1NMR
IS-MS, m/e 625.0 (m+1)
Analysis for C33H38 ClFN4O5:
Calcd: C, 63.40; H, 6.13; N, 8.96;
Found: C, 64.25; H, 6.57; N, 8.63.
By methods substantially equivalent to those described in Example 16-G, 2-[4-(tert-butyl)-2-(piperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide hydrochloride (0.36 g, 99%) was prepared from 2-[4-(tert-butyl)-2-(1-Boc-piperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide.
1NMR
IS-MS, m/e 525.0 (m+1)
Analysis for C28H30 ClFN4O3F.2.0HCl.0.4H2O:
Calcd: C, 55.57; H, 5.46; N, 9.26; Cl, 17.58;
Found: C, 55.92; H, 5.36; N, 9.35; Cl, 17.54.
Using methods substantially equivalent to those described in Example 4-F except that saturated aqueous citric acid was used instead of water in the workup, 2-[4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (234 mg, 0.32 mmol, 44%) was prepared from 2-[4-fluoro-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide and 3-tert-butoxycarbonylaminopyrrolidine.
1NMR (300 MHz, DMSO-d6): δ 11.17 (s, 1H); 10.83 (s, 1H); 8.39 (d, J=2.4 Hz, 1H); 8.30 (d, J=8.1 Hz, 1H); 8.14 (d, J=9.0 Hz, 1H); 7.90 (dd, J=2.6, 8.9 Hz, 1H); 7.72 (m, 2H); 7.48 (t, J=7.8 Hz, 1H); 7.15 (m, 2H); 6.19 (d, J=9.0 Hz, 1H); 6.13 (s, 1H); 4.79 (m, 1H); 4.06 (m, 1H); 3.68 (m, 2H); 3.54-3.37 (m, 2H); 3.03 (m, 4H); 2.05 (m, 1H); 1.87 (m, 5H); 1.36 (s, 9H); 1.32 (s, 9H).
IS-MS, m/e 735.5 (m+1).
Analysis for C38H47ClN6O7:
Calcd: C, 62.07; H, 6.44; N, 11.43;
Found: C, 62.73; H, 6.53; N, 11.53.
Using methods substantially equivalent to those described in Example 4-G, 2-[4-(3-aminopyrrolidin-1-yl)-2-(piperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (98 mg, 0.18 mmol, 67%) was prepared from 2-[4-[3-(tert-butoxycarbonyl-amino)pyrrolidin-1-yl]-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide.
1NMR (300 MHz, DMSO-d6): δ 10.77 (s, 1H); 8.40 (d, J=2.1 Hz, 1H); 8.35 (d, J=8.4 Hz, 1H); 8.18 (d, J=9.3 Hz, 1H); 7.93 (dd, J=2.1, 9.0 Hz, 1H); 7.72 (m, 2H); 7.48 (t, J=7.8 Hz, 1H); 7.13 (t, J=7.5 Hz, 1H); 6.18 (d, J=8.7 Hz, 1H); 6.08 (s, 1H); 4.61 (m, 1H); 3.59-1.65 (m, 18H).
IS-MS, m/e 535.2 (m+1).
2-Methoxy-4-(methylthio)benzoic acid (1.002 g, 5.05 mmol) was dissolved in dichloromethane (18 mL). The solution was cooled to −65° C. in a dry ice/chloroform bath. A dichloromethane solution of boron tribromide (5.4 mL, 5.4 mmol) was then added slowly. After 3 hours, the reaction was quenched with water (5 mL) and 1 N HCl (10 mL). After stirring for 10 minutes, the reaction was extracted with dichloromethane (100 mL). The organic layer was washed with 1 N HCl (10 mL) and then dried over magnesium sulfate, filtered, and concentrated to give the pure product as a pale yellow solid (866 mg, 4.70 mmol, 93%).
IR(CHCl3): 1657, 1616, 1451, 1287, 1225, 918 cm−1.
1NMR (400 MHz, DMSO-d6): δ 7.63 (d, J=8.0 Hz, 1H); 6.75 (m, 2H); 2.46 (s, 3H).
IS-MS, m/e 185.2 (m+1).
Analysis for C8H8SO3:
Calcd: C, 52.16; H, 4.38;
Found: C, 52.26; H, 4.40.
The 2-hydroxy-4-(methyltho)benzoic acid (836 mg, 4.54 mmol) was dissolved in MeOH (45 mL). Thionyl chloride (0.35 mL, 4.80 mmol) was added and the solution was heated to 65° C. and left overnight. TLC indicated that there was still starting material present so more thionyl chloride (1.0 mL, 13.7 mmol) was added. After about 1.5 hour, TLC indicated formation of baseline material; so the reaction was concentrated in vacuo.
The crude residue was purified using flash column chromatography (CH2Cl2) to give the desired compound as an off-white solid (567 mg, 2.86 mmol, 63%).
IR(CHCl3): 1670, 1441, 1340, 1291, 1110, 910 cm−1.
1NMR (300 MHz, DMSO-d6): δ 10.62 (s, 1H); 7.63 (d, J=9.0 Hz, 1H); 6.77 (m, 2H); 3.83 (s, 3H); 2.46 (s, 3H).
IS-MS, m/e 199.1 (m+1).
Analysis for C9H10O3S:
Calcd: C, 54.53; H, 5.08;
Found: C, 54.47; H, 4.95.
The methyl 2-hydroxy-4-(methylthio)benzoate (4.00 g, 20.2 mmol) was dissolved in THF (300 mL). The solution was cooled to 0° C. and the N-Boc-4-hydroxypiperidine (4.07 g, 20.2 mmol) and triphenylphosphine (6.35 g, 24.2 mmol) were added, followed by diethyl azodicarboxylate (4.0 mL, 25.4 mmol). After 5 minutes, the reaction was allowed to warm to room temperature and left overnight. The reaction was concentrated in vacuo and the crude material was purified by flash column chromatography (about 500 g silica, 15% EtOAc/hexanes tthrough 20% EtOAc/hexanes) to give the desired product (7.185 g, 18.83 mmol, 93%).
IR(CHCl3): 1683, 1593, 1435, 1235 cm−1.
1NMR (400 MHz, DMSO-d6): δ 7.60 (d, J=8.0 Hz, 1H); 6.97 (s, 1H); 6.85 (d, J=8.0 Hz, 1H); 4.76 (m, 1H); 3.72 (s, 3H); 3.38 (m, 4H); 2.48 (s, 3H); 1.75 (m, 2H); 1.60 (m, 2H); 1.37 (s, 9H).
IS-MS, m/e 382.4 (m+1).
Analysis for C19H27NO5S:
Calcd: C, 59.82; H, 7.13; N, 3.67;
Found: C, 59.58; H, 7.00; N, 3.73.
The methyl 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(methylthio)benzoate (504 mg, 1.32 mmol) was dissolved in a mixture of 1 M LiOH (2 mL), MeOH (2 mL), and THF (6 mL) and left to stir overnight. The mixture was concentrated in vacuo to remove MeOH and THF. The residue was diluted with dichloromethane (50 mL), washed with saturated aqueous citric acid (2×5 mL) and water (2×5 mL), dried over sodium sulfate, filtered, and concentrated to give the desired product as a yellow solid (417 mg, 1.13 mmol, 86%).
1NMR (300 MHz, DMSO-d6): δ 7.58 (d, J=8.1 Hz, 1H); 6.95 (s, 1H); 6.83 (d, J=8.1 Hz, 1H); 4.73 (m, 1H); 3.48-3.32 (m, 4H); 1.87 (s, 3H); 1.74 (m, 2H); 1.58 (m, 2H); 1.36 (s, 9H).
IS-MS, m/e 368.1 (m+1).
Analysis for C18H25NO5S:
Calcd: C, 58.84; H, 6.86; N, 3.81;
Found: C, 58.80; H, 6.64; N, 4.00.
Using methods substantially equivalent to those described in Example 4-E, 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(methylthio)benzoylamino]-N-(5-chloro-pyridin-2-yl)benzamide (432 mg, 0.72 mmol, 75%) was prepared from N-(5-chloro-pyridin-2-yl)-2-aminobenzamide and 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(methylthio)benzoic acid.
IR(CHCl3): 1676, 1593, 1502, 1375, 1295 cm−1.
1NMR (300 MHz, DMSO-d6): δ 11.21 (s, 1H); 11.00 (s, 1H); 8.39 (d, J=2.1 Hz, 1H); 8.35 (d, J=8.1 Hz, 1H); 7.90 (dd, J=2.1, 9.0 Hz, 1H); 7.77 (m, 2H); 7.53 (t, J=7.8 Hz, 1H); 7.18 (t, J=7.6 Hz, 1H); 7.04 (s, 1H); 6.91 (d, J=8.4 Hz, 1H); 4.83 (m, 1H); 3.65 (m, 2H); 3.01 (m, 2H); 2.50 (s, 3H); 1.82 (m, 4H); 1.31 (s, 9H).
IS-MS, m/e 597.4 (m+1).
Analysis for C30H33ClN4O5S:
Calcd: C, 60.34; H, 5.57; N, 9.38;
Found: C, 60.34; H, 5.52; N, 9.19.
Using methods substantially equivalent to those described in Example 4-G, N-(5-chloropyridin-2-yl)-2-[4-(methylthio)-2-(piperidin-4-yloxy)benzoylamino]-benzamide (83 mg, 0.17 mmol, 100%) was prepared from 2-[2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-4-(methylthio)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide.
IR(CHCl3): 1662, 1593, 1502, 1375, 1296 cm−1.
1NMR (400 MHz, DMSO-d6): δ 8.42 (d, J=2.8 Hz, 1H); 8.32 (d, J=8.0 Hz, 1H); 8.11 (d, J=8.8 Hz, 1H); 7.93 (dd, J=2.4, 8.8 Hz, 1H); 7.80 (d, J=6.0 Hz, 1H); 7.73 (d, J=8.4 Hz, 1H); 7.55 (t, J=8.8 Hz, 1H); 7.21 (t, J=8.4 Hz, 1H); 7.05 (s, 1H); 6.95 (d, J=8.0 Hz, 1H); 4.88 (m, 1H); 3.19 (m, 2H); 2.94 (m, 2H); 2.50 (s, 3H); 1.96 (m, 4H).
IS-MS, m/e 497.2 (m+1).
Analysis for C25H25ClN4O3S:
Calcd: C, 60.42; H, 5.07; N, 11.27;
Found: C, 60.30; H, 5.11; N, 11.35.
The 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(methylthio)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (291 mg, 0.49 mmol) was dissolved in chloroform (2.5 mL). Camphorsulfonic acid (20 mg, 0.09 mmol) was added, followed by t-butyl hydroperoxide solution (0.1 mL, 1.00 mmol). The reaction was stirred overnight and then loaded directly onto a column for flash column chromatographic purification (about 30 g silica, 10% EtOAc/CH2Cl2 through 100% EtOAc). The pure material (75 mg, 0.12 mmol, 25%) was obtained as a white solid.
1NMR (300 MHz, DMSO-d6): δ 11.22 (s, 1H); 11.09 (s, 1H); 8.40 (d, J=2.4 Hz, 1H); 8.36 (d, J=8.4 Hz, 1H); 8.10 (d, J=8.7 Hz, 1H); 7.96 (d, J=8.1 Hz, 1H); 7.90 (dd, J=2.6, 8.9 Hz, 1H); 7.80 (d, J=7.5 Hz, 1H); 7.56 (t, J=8.0 Hz, 1H); 7.48 (s, 1H); 7.34 (d, J=8.1 Hz, 1H); 7.22 (t, J=7.4 Hz, 1H); 4.84 (m, 1H); 3.49 (m, 2H); 3.06 (m, 2H); 2.77 (s, 3H); 1.86 (m, 2H); 1.77 (m, 2H); 1.31 (s, 9H).
IS-MS, m/e 613.2 (m+1).
Using methods substantially equivalent to those described in example 4-G, N-(5-chloropyridin-2-yl)-2-[4-(methylsulfinyl)-2-(piperidin-4-yloxy)benzoylamino]-benzamide (55 mg, 0.11 mmol, 100%) was prepared from 2-[2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-4-(methylsulfinyl)-benzoylamino]-N-(5-chloropyridin-2-yl)-benzamide.
1NMR (300 MHz, DMSO-d6): δ 11.02 (br s, 1H); 8.41 (d, J=2.1 Hz, 1H); 8.29 (d, J=8.4 Hz, 1H); 8.10 (d, J=9.0 Hz, 1H); 7.89 (m, 2H); 7.81 (d, J=7.5 Hz, 1H); 7.57 (t, J=7.8 Hz, 1H); 7.47 (s, 1H); 7.35 (d, J=8.1 Hz, 1H); 7.23 (t, J=7.7 Hz, 1H); 4.86 (m, 1H); 3.04 (m, 2H); 2.90 (m, 2H); 2.77 (s, 9H); 2.00 (m, 2H); 1.86 (m, 2H).
IS-MS, m/e 513.4 (m+1).
The 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(methylthio)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (193 mg, 0.32 mmol) was dissolved in chloroform (5 mL). After the solution had been cooled to 0° C., 3-chloroperoxybenzoic acid (mCPBA) (259 mg, 0.87 mmol, 58% purity) was added in portions. After 30 minutes, the reaction was warmed to room temperature and calcium hydroxide (80 mg, 1.1 mmol) was added. After 5 minutes, the reaction was filtered and the filtrate was concentrated in vacuo. The crude material was purified by flash column chromatography (˜20 g silica, 10% EtOAc/CH2Cl2 through 100% EtOAc) to give the desired product (146 mg, 0.23 mmol, 73%) as a white solid.
1NMR (300 MHz, DMSO-d6): δ 11.21 (s, 1H); 11.10 (s, 1H); 8.40 (s, 1H); 8.33 (d, J=8.1 Hz, 1H); 8.09 (d, J=9.0 Hz, 1H); 7.96 (d, J=8.1 Hz, 1H); 7.90 (dd, J=2.4, 9.0 Hz, 1H); 7.81 (d, J=7.2 Hz, 1H); 7.66 (s, 1H); 7.57 (d, J=7.8 Hz, 1H); 7.24 (t, J=7.8 Hz, 1H); 4.91 (m, 1H); 3.61-3.55 (m, 2H); 3.26 (s, 3H); 3.20-3.07 (m, 2H); 1.94-1.70 (m, 4H); 1.31 (s, 9H).
IS-MS, m/e 629.3 (m+1).
Using methods substantially equivalent to those described in Example 4-G, N-(5-chloropyridin-2-yl)-2-[4-(methylsulfonyl)-2-(piperidin-4-yloxy)benzoylamino]-benzamide (81 mg, 0.15 mmol, 85%) was prepared from 2-[2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-4-(methylsulfonyl)benzoylamino]-N-(5-chloropyridin-2-yl)-benzamide.
1NMR (300 MHz, DMSO-d6): δ 8.41 (d, J=2.4 Hz, 1H); 8.37 (d, J=8.1 Hz, 1H); 8.13 (d, J=9.0 Hz, 1H); 7.96 (s, 1H); 7.92 (dd, J=2.9, 8.6 Hz, 1H); 7.81 (d, J=7.8 Hz, 1H); 7.62-7.54 (m, 3H); 7.23 (t, J=7.7 Hz, 1H); 4.74 (m, 1H); 3.29 (s, 2H); 2.77 (m, 2H); 2.51-2.46 (m, 2H); 1.85-1.82 (m, 2H); 1.61-1.55 (m, 2H).
IS-MS, m/e 529.1 (m+1).
Analysis for C25H25ClN4O5S:
Calcd: C, 56.76; H, 4.76; N, 10.59;
Found: C, 56.51; H, 4.83; N, 10.30.
To a solution of neopentanolamine (75 g, 728 mmol) and sodium carbonate (77.2 g, 728 mmol) in p-dioxane (1 L) and water (1 L) at 0° C. was added di-tert-butyl dicarbonate (175 g, 801 mmol). After stirring overnight, the solution was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was washed again with brine and then dried with MgSO4, filtered, and concentrated in vacuo to give 139 g (94%) of a thick, colorless syrup.
1NMR
Using methods substantially equivalent to those described in Example 21-C, methyl 2-(3-tert-butoxycarbonylamino-2,2-dimethylpropoxy)-4-fluorobenzoate (8.52 g, 24.0 mmol, 81%) was prepared from methyl 4-fluoro-2-hydroxybenzoate and 3-tert-butoxycarbonylamino-2,2-dimethylpropanol.
IR(CHCl3): 1716, 1501, 1251, 1165 cm−1.
1NMR (400 MHz, DMSO-d6): δ 7.75 (t, J=8.0 Hz, 1H); 6.94 (d, J=11.6 Hz, 1H); 6.80 (t, J=8.4 Hz, 2H); 3.77 (s, 3H); 3.69 (s, 2H); 2.95 (d, J=6.4 Hz, 2H); 1.33 (s, 9H); 0.90 (s, 6H).
IS-MS, m/e 356.3 (m+1).
Analysis for C18H26 FNO5.0.25CH2Cl2:
Calcd: C, 58.20; H, 7.09; N, 3.72;
Found: C, 58.42; H, 7.12; N, 3.81.
Using methods substantially equivalent to those described in Example 21-D, 2-(3-tert-butoxycarbonylamino-2,2-dimethylpropoxy)-4-fluorobenzoic acid (8.01 g, 23.5 mmol, 99%) was prepared from methyl 2-(3-tert-butoxycarbonylamino-2,2-dimethylpropoxy)-4-fluorobenzoate.
IR(CHCl3): 2979, 1698, 1611, 1515, 1164 cm−1.
1NMR (300 MHz, DMSO-d6): δ 7.71 (t, J=7.8 Hz, 1H); 6.90 (d, J=11.4 Hz, 1H); 6.81-6.74 (m, 1H); 3.66 (s, 2H); 2.93 (d, J=6.3 Hz, 2H); 1.32 (s, 9H); 0.89 (s, 6H).
IS-MS, m/e 342.1 (m+1).
Analysis for C17H24 FNO5:
Calcd: C, 59.81; H, 7.09; N, 4.10;
Found: C, 59.83; H, 7.01; N, 4.27.
Using methods substantially equivalent to those described in Example 4-E, 2-[2-(3-tert-butoxycarbonylamino-2,2-dimethylpropoxy)-4-fluorobenzoylamino]-N-(5-chloropyridin-2-yl)benzamide (10 g, 17.5 mmol, 82%) was prepared from 2-(3-tert-butoxycarbonylamino-2,2-dimethylpropoxy)-4-fluorobenzoic acid and N-(5-chloro-pyridin-2-yl)-2-aminobenzamide.
IR(KBr): 1711, 1665, 1504, 1375 cm−1.
1NMR (400 MHz, DMSO-d6): δ 11.03 (s, 1H); 10.66 (s, 1H); 8.38 (s, 1H); 8.11 (d, J=8.0 Hz, 1H); 8.07 (d, J=8.8 Hz, 1H); 7.88 (dd, J=2.4, 8.8 Hz, 1H); 7.79 (d, J=7.6 Hz, 1H); 7.66 (t, J=8.0 Hz, 1H); 7.55 (t, J=7.8 Hz, 1H); 7.22 (t, J=7.6 Hz, 1H); 7.05 (d, J=11.2 Hz, 1H); 6.87-6.82 (m, 1H); 3.79 (s, 2H); 2.84 (d, J=6.0 Hz, 2H); 1.28 (s, 9H); 0.80 (s, 6H).
IS-MS, m/e 571.3 (m+1).
Analysis for C29H32 FClN4O5:
Calcd: C, 61.00; H, 5.65; N, 9.81;
Found: C, 61.08; H, 5.74; N, 9.51.
Using methods substantially equivalent to those described in Example 4-F, except that the reaction was heated to 80° C., 2-[2-(3-tert-butoxycarbonylamino-2,2-dimethyl-propoxy)-4-(pyrrolidin-1-yl)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (453 mg, 0.73 mmol, 43%) was prepared from 2-[2-(3-tert-butoxycarbonylamino-2,2-dimethyl-propoxy)-4-fluorobenzoylamino]-N-(5-chloropyridin-2-yl)benzamide and pyrrolidine.
IR(CHCl3): 1710, 1603, 1504, 1375 cm−1.
1NMR (400 MHz, DMSO-d6): δ 11.01 (s, 1H); 10.49 (s, 1H); 8.37 (d, J=2.4 Hz, 1H); 8.14 (d, J=8.4 Hz, 1H); 8.08 (d, J=8.8 Hz, 1H); 7.89 (dd, J=2.8, 8.8 Hz, 1H); 7.75 (d, J=8.0 Hz, 1H); 7.59 (t, J=8.4 Hz, 1H); 7.50 (t, J=7.8 Hz, 1H); 7.16 (t, J=7.6 Hz, 1H); 6.83 (m, 1H); 6.18 (d, J=8.8 Hz, 1H); 6.12 (s, 1H); 3.85 (s, 2H); 3.30-3.27 (m, 4H); 2.85 (d, J=6.4 Hz, 2H); 1.95-1.92 (m, 4H); 1.30 (s, 9H); 0.81 (s, 6H).
IS-MS, m/e 622.5 (m+1).
Analysis for C33H40ClN5O5:
Calcd: C, 63.71; H, 6.48; N, 11.26;
Found: C, 63.53; H, 6.58; N, 11.07.
Using methods substantially equivalent to those described in Example 4-F except that saturated aqueous citric acid was used in the workup instead of water, 2-[2-(3-tert-butoxycarbonylamino-2,2-dimethylpropoxy)-4-(morpholin-4-yl)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (150 mg, 0.24 mmol, 36%) was prepared from 2-[2-(3-tert-butoxycarbonylamino-2,2-dimethylpropoxy)-4-fluorobenzoylamino]-N-(5-chloropyridin-2-yl)benzamide and morpholine.
1NMR (400 MHz, DMSO-d6): δ 11.02 (s, 1H); 10.53 (s, 1H); 8.37 (d, J=2.4 Hz, 1H); 8.14 (d, J=8.0 Hz, 1H); 8.07 (d, J=9.2 Hz, 1H); 7.88 (dd, J=2.6, 9.0 Hz, 1H); 7.77 (d, J=7.6 Hz, 1H); 7.58 (d, J=8.4 Hz, 1H); 7.52 (t, J=7.8 Hz, 1H); 7.18 (t, J=7.6 Hz, 1H); 6.80 (m, 1H); 6.57 (d, J=8.0 Hz, 1H); 6.56 (s, 1H); 3.83 (s, 2H); 3.71 (m, 4H); 3.21 (m, 4H); 2.85 (d, J=6.0 Hz, 2H); 1.29 (s, 9H); 0.80 (s, 6H).
IS-MS, m/e 638.2 (m+1).
Analysis for C33H40ClN5O6:
Calc: C, 62.11; H, 6.32; N, 10.97;
Found: C, 62.11; H, 6.30; N, 10.76.
To a solution of 2-tert-butoxycarbonylaminoethanol (4.34 g, 26.9 mmol) in THF (16 mL) at 0° C. under N2, was added K+-OtBu (26.9 mL, 26.9 mmol, 1.0 M in THF).
The reaction was stirred for 20 min at 0° C. during which time a thick slurry formed. The anion solution was then poured into a solution of ethyl 2,4-difluorobenzoate (5.00 g, 26.9 mmol) in THF (16 mL) which had been cooled to −65° C. The reaction was allowed to slowly warm to room temperature and was stirred for 18 hr. The reaction was diluted with dichloromethane and washed with water. The water layer was extracted with additional dichloromethane and the dichloromethane layers combined and washed with brine, dried, and concentrated in vacuo to give a yellow oil. Purification on silica gel, eluting with a gradient of 4:1 to 3:1, hexane:EtOAc, yielded 3.82 g (43.5%) of the desired product as a colorless oil.
Ethyl 2-(2-tert-butoxycarbonylaminoethoxy)-4-fluorobenzoate (1.75 g, 5.35 mmol) and morpholine (1 mL) were heated at 90° C. in a sealed vial for 7 days. The reaction was diluted with dichloromethane (25 mL), washed with water, dried, and the solvent was removed in vacuo. Purification via silica gel chromatography, eluting with a gradient of hexane and ethyl acetate, yielded 0.791 g (37.5%) of the desired product as a colorless oil.
In a manner substantially equivalent to Example 21-D, ethyl 2-(2-tert-butoxycarbonylaminoethoxy)-4-(1-morpholino)benzoate (0.790 g, 2.00 mmol) yielded 0.617 g (84.1%) of the desired product as a white solid.
IS-MS, m/z 367.1 (m+1), 365.2 (m−1)
To a stirring solution of KMnO4 (76 g, 483 mmol) in water (1 L) was added 4-fluoro-2-nitrotoluene and the solution was heated to reflux. After 4 h, the hot mixture was filtered and the filtrate was cooled with ice, washed with diethyl ether, acidified with cone HCl, and then extracted twice with diethyl ether. The combined ether extracts were washed with brine, dried with MgSO4, filtered and concentrated in vacuo to give 12.07 g (34%) of a white solid.
1NMR
IS-MS, m/e 184.0 (m−1)-
Analysis for C7H4FNO4:
Calcd: C, 45.42; H, 2.18; N, 7.57;
Found: C, 45.63; H, 2.30; N, 7.61.
Using methods substantially equivalent to those described in Example 16-A, N-(5-chloropyridin-2-yl)-4-fluoro-2-nitrobenzamide (16.06 g, 88%) was prepared from 4-fluoro-2-nitrobenzoic acid and 2-amino-5-chloropyridine.
1NMR
IS-MS, m/e 296.2 (m+1)
Analysis for C12H7ClFN3O3:
Calcd: C, 48.75; H, 2.38; N, 14.21;
Found: C, 48.96; H, 2.66; N, 14.40.
Using methods substantially equivalent to those described in Example 2-B, N-(5-chloropyridin-2-yl)-2-amino-4-fluorobenzamide (7.98 g, 88%) was prepared from N-(5-chloropyridin-2-yl)-4-fluoro-2-nitrobenzamide.
1NMR
IS-MS, m/e 264.2 (m−1)-
Analysis for C12H9ClFN3O:
Calcd: C, 54.25; H, 3.42; N, 15.82;
Found: C, 54.45; H, 3.65; N, 15.76.
The 2-[2-(2-tert-butoxycarbonylaminoethoxy)-4-(morpholin-4-yl)benzoic acid (825 mg, 2.25 mmol) was mixed with CH2Cl2 (20 mL), cooled to 0° C. under N2, and treated with a 2 M CH2Cl2 solution of oxalyl chloride (1.2 mL) and 1 drop of DMF. The reaction was stirred at 0° C. for 1 hour, concentrated to dryness, mixed with CH2Cl2 (5 mL), and added to a cold solution of the N-(5-chloropyridin-2-yl)-2-amino-4-fluoro-benzamide in pyridine (20 mL). The reaction was stirred at 0° C. for 3 hours, then overnight at ambient temperature. The reaction was concentrated to dryness, mixed with toluene, and reconcentrated to dryness. The residue was partitioned between saturated aqueous NaHCO3 (50 mL) and EtOAc (75 mL). The aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were dried over MgSO4 and concentrated to 1 g of an oil which was purified by flash chromatrography using Hex/EtOAc to give 0.67 g (1.1 mmol, 48%) of a white solid.
1NMR
IS-MS m/e 612 (m−2)
Analysis for C30H33 ClFN5O6:
Calcd: C, 58.68; H, 5.42; N, 11.40;
Found: C, 58.83; H, 5.43; N, 11.23.
Using methods substantially equivalent to those described in Example 4-G, 2-[2-(3-amino-2,2-dimethylpropoxy)-4-(morpholin-4-yl)benzoylamino]-N-(5-chloro-pyridin-2-yl)benzamide (106 mg, 0.12 mmol, 100%) was prepared from 2-[2-(3-tert-butoxycarbonylamino-2,2-dimethylpropoxy)-4-(morpholin-4-yl)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide.
1NMR (400 MHz, DMSO-d6): δ 8.41 (d, J=2.4 Hz, 1H); 8.16 (d, J=8.0 Hz, 1H); 8.07 (d, J=9.2 Hz, 1H); 7.91 (dd, J=2.6, 9.2 Hz, 1H); 7.83 (d, J=8.0 Hz, 1H); 7.75 (br s, 1H); 7.59-7.54 (m, 2H); 7.21 (t, J=8.0 Hz, 1H); 6.60 (d, J=8.8 Hz, 1H); 6.57 (s, 1H); 3.94 (s, 2H); 3.72-3.70 (m, 4H); 3.27-3.22 (m, 4H); 2.84 (s, 2H); 0.97 (s, 6H).
IS-MS, m/e 538.4 (m+1).
Analysis for C28H32ClN5O4.CH2Cl2:
Calc: C, 56.75; H, 5.40; N, 11.03;
Found: C, 56.46; H, 5.24; N, 10.70.
Using methods substantially equivalent to those described in Example 4-G, 2-[2-(3-amino-2,2-dimethylpropoxy)-4-(pyrrolidin-1-yl)benzoylamino]-N-(5-chloro-pyridin-2-yl)benzamide (386 mg, 0.74 mmol, 100%) was prepared from 2-[2-(3-tert-butoxycarbonylamino-2,2-dimethylpropoxy)-4-(pyrrolidin-1-yl)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide.
1NMR (400 MHz, DMSO-d6): δ 8.40 (s, 1H); 8.17 (d, J=8.4 Hz, 1H); 8.08 (d, J=8.4 Hz, 1H); 7.91 (d, J=9.2 Hz, 1H); 7.79 (d, J=7.6 Hz, 1H); 7.58 (d, J=9.2 Hz, 1H); 7.51 (t, J=8.0 Hz, 1H); 7.17 (t, J=8.0 Hz, 1H); 6.19 (d, J=7.6 Hz, 1H); 6.15 (s, 1H); 3.94 (s, 2H); 3.28 (br s, 4H); 2.63 (m, 2H); 1.93 (br s, 4H); 0.89 (s, 6H).
IS-MS, m/e 522.2 (m+1).
Analysis for C28H32ClN5O3:
Calc: C, 60.75; H, 5.80; N, 12.17;
Found: C, 60.79; H, 5.61; N, 11.92.
Using methods substantially equivalent to those described in Example 4-E, 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-fluorobenzoylamino]-N-(5-chloro-pyridin-2-yl)-5-chlorobenzamide (2.28 g, 3.78 mmol, 44%) was prepared from N-(5-chloropyridin-2-yl)-2-amino-5-chlorobenzamide and 2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-4-fluorobenzoic acid.
IR(CHCl3): 1678, 1496, 1375, 1275 cm−1.
1NMR (400 MHz, DMSO-d6): δ 11.36 (s, 1H); 10.98 (s, 1H); 8.41 (d, J=2.8 Hz, 1H); 8.36 (d, J=8.8 Hz, 1H); 8.10 (d, J=8.8 Hz, 1H); 7.92-7.89 (m, 2H); 7.85 (s, 1H); 7.61 (dd, J=2.6, 9.0 Hz, 1H); 7.25 (d, J=11.6 Hz, 1H); 6.89 (t, J=8.2 Hz, 1H); 4.79 (m, 1H); 3.68 (d, J=15.2 Hz, 2H); 3.01 (m, 2H); 1.89-1.78 (m, 4H); 1.33 (s, 9H)
IS-MS, m/e 603.48 (m+1)
Analysis for C29H29Cl2 FN4O5:
Calc: C, 57.72; H, 4.84; N, 9.28;
Found: C, 57.89; H, 4.85; N, 9.47.
Using methods substantially equivalent to those described in example 4-F, 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(morpholin-4-yl)benzoylamino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide (1.3611 g, 2.03 mmol, 55%) was prepared from 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-fluorobenzoylamino]-N-(5-chloropyridin-2-yl)-5-chlorobenzamide and morpholine.
1NMR (400 MHz, DMSO-d6): δ 11.33 (s, 1H); 10.84 (s, 1H); 8.41 (s, 1H); 8.35 (d, J=9.2 Hz, 1H); 8.12 (d, J=8.8 Hz, 1H); 7.91 (d, J=8.8 Hz, 1H); 7.79-7.75 (m, 2H); 7.57 (d, J=9.2 Hz, 1H); 6.61-6.59 (m, 2H); 4.80 (br s, 1H); 3.70 (m, 4H); 3.23 (m, 6H); 2.99 (m, 2H); 1.86-1.78 (m, 4H); 1.32 (s, 9H).
IS-MS, m/e 670.4 (m+1)
Analysis for C33H37Cl2N5O6:
Calc: C, 59.11; H, 5.56; N, 10.44;
Found: C, 59.81; H, 5.58; N, 10.59.
Using methods substantially equivalent to those described in Example 4-G, 5-chloro-N-(5-chloropyridin-2-yl)-2-[4-(morpholin-4-yl)-2-(piperidin-4-yloxy)-benzoylamino]benzamide (1.17 g, 2.05 mmol, 100%) was prepared from 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(morpholin-4-yl)benzoylamino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide.
1NMR (400 MHz, DMSO-d6): δ 10.83 (s, 1H); 8.43 (d, J=2.0 Hz, 1H); 8.33 (dd, J=1.8, 9.0 Hz, 1H); 8.11 (d, J=8.8 Hz, 1H); 7.94 (d, J=9.2 Hz, 1H); 7.83 (s, 1H); 7.72 (dd, J=1.8, 8.6 Hz, 1H); 7.59 (dd, J=2.2. 11.0 Hz, 1H); 6.63 (d, J=8.8 Hz, 1H); 6.60 (s, 1H); 4.86 (br s, 1H); 4.07 (m, 2H); 3.70 (m, 2H); 3.27-2.93 (m, 8H); 2.00 (m, 2H); 1.93 (m, 2H).
IS-MS, m/e 570.3 (m+1).
Analysis for C28H29Cl2N5O4. 1.05CH2Cl2:
Calc: C, 53.78; H, 4.66; N, 10.42;
Found: C, 53.48; H, 4.41; N, 10.26.
The 2-[2-(2-tert-butoxycarbonylaminoethoxy)-4-(morpholin-4-yl)benzoylamino]-N-(5-chloropyridin-2-yl)-4-fluorobenzamide (570 mg, 0.93 mmol) was mixed with CH2Cl2 (5 mL), anisole (1 mL), and trifluoroacetic acid (2 mL). The mixture was stirred at ambient temperature for 2 hours, concentrated to dryness, mixed with diethyl ether, and sonicated for 5 minutes to give a white fluffy solid which was filtered to give 490 mg (62%) of the desired product as the trifluoroacetate salt.
1NMR
FD-MS, m/e 512 (m−1)
Analysis for C25H25 ClFN5O4.1.5C2 HF3O2:
Calcd: C, 49.10; H, 3.90; N, 10.22;
Found: C, 49.27; H, 3.95; N, 10.16.
A mixture of methyl 2-(2-tert-butoxycarbonylaminoethoxy)-4-fluorobenzoate (4.2 g, 13.4 mmol), THF (100 mL), and MeOH (50 mL) was treated with 1 M lithium hydroxide (16 mL) and stirred for 48 hours at ambient temperature. The reaction was acidified with 10% aqueous citric acid (50 mL), diluted with brine (100 mL), and extracted with EtOAc (3×100 mL). The combined organic layers were dried over MgSO4 and concentrated to give 3.93 g (13.1 mmol, 98%) of a white solid.
Using methods substantially equivalent to those described in Example 29-G, the compound was prepared in a 75% yield from N-(5-chloropyridin-2-yl)-2-amino-5-chloro-benzamide and 2-(2-tert-butoxycarbonylaminoethoxy)-4-fluorobenzoic acid.
1NMR
IS-MS, m/e 563 (m+)
Analysis for C26H25Cl2 FN4O5:
Calcd: C, 55.43; H, 4.47; N, 9.94;
Found: C, 55.35; H, 4.42; N, 9.81.
A mixture of 2-[2-(2-tert-butoxycarbonylaminoethoxy)-4-fluoroberzoylamino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide (1.4 g, 2.5 mmol), morpholine (10.1 g, 116 mmol), and K2 CO3 (0.5 g) was heated in a sealed tube at 120° C. for 16 hours. The reaction was filtered, then concentrated to dryness under vacuum. The residue was dissolved in CH2Cl2 and purified by chromatography using 30% EtOAc in hexanes to give 810 mg (51%) of product.
1NMR
IS-MS, m/e 630 (m+)
Analysis for C30H33Cl2N5O6:
Calcd: C, 57.15; H, 5.28; N, 11.11;
Found: C, 57.14; H, 5.46; N, 11.05.
The N-(5-chloropyridin-2-yl)-2-[2-(piperidin-4-yloxy)-4-(pyrrolidin-1-yl)-benzoylamino]benzamide (304 mg, 0.58 mmol) was diluted with methanol (1 mL).
Propylene oxide (81 μL, 1.16 mmol) was added and the reaction was heated at 60° C. for minutes. The reaction was concentrated and the crude residue was purified by flash column chromatography (about 35 g silica, 5% MeOH/CH2Cl2 through 10% MeOH/CH2Cl2) to give the desired product (133 mg, 0.23 mmol, 40%) as a white solid.
1NMR (400 MHz, DMSO-d6): δ 11.14 (s, 1H); 10.78 (s, 1H); 8.39 (d, J=2.4 Hz, 1H); 8.34 (d, J=8.4 Hz, 1H); 8.19 (d, J=9.6 Hz, 1H); 7.92 (d, J=9.2 Hz, 1H); 7.74-7.70 (m, 2H); 7.49 (t, J=7.8 Hz, 1H); 7.13 (t, J=7.2 Hz, 1H); 6.21 (d, J=8.8 Hz, 1H); 4.18 (s, 1H); 3.27 (m, 1H); 2.59 (m, 2H); 2.12-1.85 (m, 12H); 0.96 (d, J=6.4 Hz, 3H).
IS-MS, m/e 578.4 (m+1).
Analysis for C31H36ClN5O4.0.50H2O:
Calc: C, 63.42; H, 6.35; N, 11.93;
Found: C, 63.76; H, 6.28; N, 11.74.
Using methods substantially equivalent to those described in Example 36, 5-chloro-N-(5-chloropyridin-2-yl)-2-[2-[1-(2-hydroxypropyl)piperidin-4-yloxy]-4-(morpholin-4-yl)benzoylamino]benzamide (54 mg, 0.09 mmol, 11%) was prepared from 5-chloro-N-(5-chloropyridin-2-yl)-2-[4-(morpholin-4-yl)-2-(piperidin-4-yloxy)-benzoylamino]benzamide.
1NMR (400 MHz, DMSO-d6): δ 11.30 (s, 1H); 10.80 (s, 1H); 8.40 (s, 1H); 8.38 (d, J=9.3 Hz, 1H); 8.16 (d, J=8.7 Hz, 1H); 7.93 (dd, J=2.1, 8.7 Hz, 1H); 7.78 (s, 1H); 7.74 (d, J=8.7 Hz, 1H); 7.56 (dd, J=2.1, 9.3 Hz, 1H); 6.59 (d, J=9.3 Hz, 1H); 6.56 (s, 1H); 4.62 (br s, 1H); 4.17 (s, 1H); 3.69 (s, 4H); 3.21 (s, 8H); 2.56 (m, 2H); 2.12-1.81 (m, 4H); 0.95 (d, J=6.0 Hz, 3H).
IS-MS, m/e 629.2 (m+2).
Analysis for C31H35Cl2N5O5:
Calc: C, 59.24; H, 5.61; N, 11.14;
Found: C, 59.29; H, 5.87; N, 11.04.
Using methods substantially equivalent to those described in Example 34, 2-[2-(2-aminoethoxy)-4-(morpholin-4-yl)benzoylamino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide trifluoroacetate was prepared in a 74% yield from 2-[2-(2-tert-butoxy-carbonylaminoethoxy)-4-(morpholin-4-yl)benzoylamino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide.
1NMR
IS-MS, m/e 530 (m+)
Analysis for C25H25Cl2N5O4/1.1C2HF3O2:
Calcd: C, 49.81; H, 4.01; N, 10.81;
Found: C, 49.76; H, 3.82; N, 10.88.
Using methods substantially equivalent to those described in Example 29-G, 2-[2-(2-tert-butoxycarbonylaminoethoxy)-4-(morpholin-4-yl)benzoylamin]-4-chloro-N-(5-chloropyridin-2-yl)benzamide was prepared in a 74% yield from 2-amino-4-chloro-N-(5-chloropyridin-2-yl)benzamide and 2-(2-tert-butoxycarbonylaminoethoxy)-4-(morpholin-4-yl)benzoic acid.
1NMR
IS-MS, m/e 630 (m+)
Analysis for C30H33Cl2N5O6.0.1H2O:
Calcd: C, 56.98; H, 5.29; N, 11.08;
Found: C, 57.10; H, 5.63; N, 10.89.
Using methods substantially equivalent to those described in Example 29-G, 2-[2-(2-tert-butoxycarbonylaminoethoxy)-4-fluorobenzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide was prepared in a 69% yield from 2-(2-tert-butoxycarbonyl-aminoethoxy)-4-fluorobenzoic acid and 2-amino-N-(5-chloropyridin-2-yl)-5-fluoro-benzamide.
1NMR
IS-MS, m/e 545 (m−1)
Analysis for C26H25ClF2N4O5.0.5H2O:
Calcd: C, 56.17; H, 4.71; N, 10.08;
Found: C, 55.81; H, 4.59; N, 9.76.
A mixture of 2-[2-(2-tert-butoxycarbonylaminoethoxy)-4-fluorobenzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide (0.8 g, 1.5 mmol), morpholine (10 mL), and K2CO3 (0.2 g) was heated in a sealed tube at 100° C. for 12 hours and then 120° C. for 4 h.
The reaction was filtered, and concentrated to dryness. The residue was dissolved in CH2Cl2 and purified by chromatography to give 260 mg (28%) of product.
1NMR
FD-MS, m/e 614 (m+)
Analysis for C30H33 ClFN5O6.H2O:
Calcd: C, 56.84; H, 5.60; N, 11.05;
Found: C, 57.00; H, 5.49; N, 10.93.
Using methods substantially equivalent to those described in Example 34, 2-2-(2-aminoethoxy)-4-(morpholin-4-yl)benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide trifluoroacetate was prepared in a 74% yield from 2-[2-(2-tert-butoxy-carbonylaminoethoxy)-4-(morpholin-4-yl)benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide.
1NMR
FD-MS, m/e 514 (m+1)
Analysis for C25H25 ClFN5O4.1.1C2HF3O2:
Calcd: C, 51.09; H, 4.11; N, 10.95;
Found: C, 51.04; H, 4.31; N, 10.71.
Using methods substantially equivalent to those described in Example 4-B, methyl 4-chloro-2-hydroxybenzoate was prepared in a 84% yield from 4-chloro-2-hydroxy-benzoic acid.
1NMR
IS-MS, m/e 187 (m+1)
Analysis for C8H7ClO3.0.4H2O:
Calcd: C, 49.58; H, 4.06;
Found: C, 49.82; H, 3.87.
Using methods substantially equivalent to those described in Example 29-A, methyl 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-chlorobenzoate was prepared in a 76% yield from methyl 4-chloro-2-hydroxybenzoate and 4-hydroxy-1-tert-butoxycarbonylpiperidine.
1NMR
IS-MS, m/e 370 (m+1)
Using methods substantially equivalent to those described in Example 35-A, 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-chlorobenzoic acid was prepared in a 97% yield from methyl 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-chlorobenzoate.
1NMR
IS-MS, m/e 354 (m−1)
Using methods substantially equivalent to those described in Example 29-G, 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-chlorobenzoylamino]-N-(5-chloro-pyridin-2-yl)benzamide was prepared in a 97% yield from 2-amino-N-(5-chloropyridin-2-yl)benzamide and 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-chlorobenzoic acid.
1NMR
IS-MS M/e 585 (m+)
Using methods substantially equivalent to those described in Example 34, 2-[4-chloro-2-(piperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide trifluoroacetate was prepared in a quantitative yield from 2-[2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-4-chlorobenzoylamino]-N-(5-chloropyridin-2-yl)benzamide.
1NMR
IS-MS 485 (m+)
Using methods substantially equivalent to those described in Example 4-E, 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-fluorobenzoylamino]-4-chloro-N-(5-chloropyridin-2-yl)benzamide (3.89 g, 6.44 mmol, 86%) was prepared from 2-amino-4-chloro-N-(5-chloropyridin-2-yl)benzamide and 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-fluorobenzoic acid.
1NMR (400 MHz, DMSO-d6): δ 11.34 (s, 1H); 11.18 (s, 1H); 8.52 (s, 1H); 8.41 (d, J=2.0 Hz, 1H); 8.10 (d, J=8.8 Hz, 1H); 7.92-7.85 (m, 2H); 7.83 (d, J=8.8 Hz, 1H); 7.30-7.24 (m, 2H); 6.91 (t, J=8.2 Hz, 1H); 4.78 (s, 1H); 3.67 (d, J=12.0 Hz, 2H); 3.00 (m, 2H); 1.88 (m, 2H); 1.77 (m, 2H); 1.32 (s, 9H).
IS-MS, m/e 603.2 (m+1).
Analysis for C29H29Cl2 FN4O5:
Calc: C, 57.72; H, 4.84; N, 9.28;
Found: C, 57.80; H, 4.72; N, 9.48.
Using methods substantially equivalent to those described in Example 4-F, 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(morpholin-4-yl)benzoylamino]-4-chloro-N-(5-chloropyridin-2-yl)benzamide (1.32 g, 1.97 mmol, 42%) was prepared from 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-fluorobenzoylamino]-4-chloro-N-(5-chloropyridin-2-yl)benzamide and morpholine.
1NMR (400 MHz, DMSO-d6): δ 11.30 (s, 1H); 11.03 (s, 1H); 8.51 (s, 1H); 8.41 (s, 1H); 8.12 (d, J=8.4 Hz, 1H); 7.92 (d, J=8.8 Hz, 1H); 7.79-7.74 (m, 2H); 7.23 (d, J=8.0 Hz, 1H); 6.61 (d, J=14.8 Hz, 1H); 6.60 (s, 1H); 4.81 (m, 1H); 3.70 (m, 6H); 3.24 (m, 4H); 2.98 (m, 2H); 1.85-1.78 (m, 4H); 1.32 (s, 9H).
IS-MS, m/e 670.4 (m+1).
Analysis for C33H37Cl2N5O6:
Calc: C, 59.11; H, 5.56; N, 10.44;
Found: C, 59.39; H, 5.58; N, 10.50.
Using methods substantially equivalent to those described in Example 34, 2-[2-(2-aminoethoxy)-4-(morpholin-4-yl)benzoylamino]-4-chloro-N-(5-chloropyridin-2-yl)benzamide trifluoroacetate was prepared in a 78% yield from 2-[2-(2-tert-butoxy-carbonylaminoethoxy)-4-(morpholin-4-yl)benzoylamino]-N-(5-chloropyridin-2-yl)-4-chlorobenzamide.
1NMR
IS-MS, m/e 529 (m−1)
Using methods substantially equivalent to those described in example 4-G, 4-chloro-N-(5-chloropyridin-2-yl)-2-[4-(morpholin-4-yl)-2-(piperidin-4-yloxy)-benzoylamino]benzamide (1.06 g, 1.86 mmol, 89%) was prepared from 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(morpholin-4-yl)benzoylamino]-N-(5-chloropyridin-2-yl)-4-chlorobenzamide.
1NMR (400 MHz, DMSO-d6): δ 8.54 (d, J=2.0 Hz, 1H); 8.42 (d, J=2.0 Hz, 1H); 8.15 (d, J=9.2 Hz, 1H); 7.95 (dd, J=2.6, 9.0 Hz, 1H); 7.78 (d, J=8.8 Hz, 1H); 7.73 (d, J=8.8 Hz, 1H); 7.23 (dd, J=2.2, 8.2 Hz, 1H); 6.62 (d, J=8.8 Hz, 1H); 6.58 (s, 1H); 4.71 (m, 1H); 3.70 (m, 4H); 3.23 (m, 4H); 2.84 (m, 2H); 2.62 (m, 2H); 1.86 (m, 2H); 1.71 (m, 2H).
IS-MS, m/e 570.3 (m+1).
Analysis for C28H29Cl2N5O4.0.75H2O:
Calc: C, 57.59; H, 5.26; N, 11.99;
Found: C, 57.20; H, 4.90; N, 11.68.
Using methods substantially equivalent to those described in Example 36, 4-chloro-N-(5-chloropyridin-2-yl)-2-[4-(morpholin-4-yl)-2-[1-(2-hydroxypropyl)-piperidin-4-yloxy]benzoylamino]benzamide (132 mg, 0.21 mmol, 34%) was prepared from 4-chloro-N-(5-chloropyridin-2-yl)-2-[4-(morpholin-4-yl)-2-(piperidin-4-yloxy)-benzoylamino]benzamide and propylene oxide.
1NMR (400 MHz, DMSO-d6): δ 11.28 (s, 1H); 10.99 (s, 1H); 8.56 (s, 1H); 8.41 (d, J=2.8 Hz, 1H); 8.16 (d, J=8.8 Hz, 1H); 7.94 (dd, J=2.6, 9.0 Hz, 1H); 7.76 (m, 2H); 7.23 (dd, J=2.0, 8.4 Hz, 1H); 6.61 (d, J=9.2 Hz, 1H); 6.57 (s, 1H); 4.59 (m, 1H); 4.16 (m, 1H); 3.70 (m, 4H); 3.23 (m, 4H); 2.54 (m, 2H); 2.13-1.81 (m, 8H); 0.95 (d, J=6.4 Hz, 3H).
IS-MS, m/e 628.3 (m+1).
Analysis for C31H35Cl2N5O5:
Calc: C, 59.24; H, 5.61; N, 11.14;
Found: C, 59.35; H, 5.51; N, 11.15.
Potassium carbonate (14.17 g, 102.5 mmol) was added to a mixture of 2-methyl-allylamine hydrochloride in acetone (500 mL), followed by di-tert-butyl dicarbonate (12.18 g, 55.8 mmol). Water (200 mL) was added to get all of the solids to go into solution. After stirring overnight, the reaction was concentrated to less than 200 mL. The residue was extracted with ethyl acetate (2×). The organic layers were combined, dried over sodium sulfate, and concentrated. The crude residue was purified by flash column chromatography (5% EtOAc/hexanes) to give the desired product (7.11 g, 41.6 mmol, 89%) as a colorless oil.
IR(CHCl3): 1711, 1506, 1368, 1167 cm−1.
1NMR (300 MHz, DMSO-d6): δ 6.98 (br s, 1H); 4.69 (s, 2H); 3.40 (d, J=6.0 Hz, 2H); 1.59 (s, 3H); 1.34 (s, 9H).
The tert-butyl N-(2-methylallyl)carbamate (213 mg, 1.24 mmol) was diluted with THF (12 mL) and the mixture was cooled to 0° C. Borane-dimethylsulfide complex (0.9 mL, 1.8 mmol) was added. After 1.5 hours, the reaction was cooled to −40° C. and 1 N NaOH (5 mL) and 30% hydrogen peroxide (5 mL) were carefully added. After 15 minutes, the reaction was warmed slowly until the frozen mixture melted. Ethyl acetate (100 mL) was then added, and the mixture was washed with brine (3×10 mL). The combined aqueous layers were extracted with ethyl acetate (100 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by flash column chromatography (about 20 g silica, 10% EtOAc/CH2Cl2 through 15% EtOAc/CH2Cl2) to give the desired product (209 mg, 1.10 mmol, 89%).
IR(CHCl3): 1693, 1512, 1368, 1134 cm−1.
1NMR (300 MHz, DMSO-d6): δ 6.70 (br s, 1H); 3.17 (m, 2H); 2.87 (m, 1H); 2.70 (m, 1H); 1.56 (m, 1H); 1.33 (s, 1H); 0.74 (d, J=6.6 Hz, 3H).
FD-MS, m/e 189 (m)
Using methods substantially equivalent to those described in Example 21-C, ethyl-2-(3-tert-butoxycarbonylamino-2-methylpropoxy)-4-fluorobenzoate was prepared from ethyl-2,4-difluorobenzoate and 2-methyl-3-tert-butoxycarbonylaminopropanol. The impure material was saponified using methods substantially equivalent to those described in Example 21-D to give 2-(3-tert-butoxycarbonylamino-2-methylpropoxy)-4-fluoro-benzoic acid (554 mg, 1.69 mmol, 7% for 2 steps after RPHPLC purification).
1NMR (400 MHz, DMSO-d6): δ 7.71 (d, J=7.6 Hz, 1H); 6.95-6.78 (m, 2H); 3.88 (m, 2H); 1.97 (m, 1H); 1.33 (s, 9H); 0.92 (d, J=6.8 Hz, 3H); IS-MS, m/e 228.2 (m-BOC+1)
Analysis for C16H22 FNO5:
Calc: C, 58.71; H, 6.77; N, 4.28;
Found: C, 58.96; H, 6.90; N, 4.37.
Using methods substantially equivalent to those described in Example 4-E, 2-[2-(3-tert-butoxycarbonylamino-2-methylpropoxy)-4-fluorobenzoylamino]-N-(5-chloropyridin-2-yl)benzamide (527 mg, 0.95 mmol, 68%) was prepared from N-(5-chloropyridin-2-yl)-2-aminobenzamide and 2-(3-tert-butoxycarbonylamino-2-methylpropoxy)-4-fluorobenzoic acid.
1NMR (400 MHz, DMSO-d6): δ 11.13 (s, 1H); 11.03 (s, 1H); 8.40 (d, J=2.0 Hz, 1H); 8.32 (d, J=8.0 Hz, 1H); 8.11 (d, J=8.8 Hz, 1H); 7.94-7.87 (m, 2H); 7.78 (d, J=8.8 Hz, 1H); 7.54 (t, J=8.0 Hz, 1H); 7.21 (t, J=7.4 Hz, 1H); 7.05 (d, J=10.4 Hz, 1H); 6.89 (t, J=7.2 Hz, 1H); 6.80 (m, 1H); 4.10 (m, 1H); 3.98 (m, 1H); 2.86 (m, 2H); 2.13 (m, 1H); 1.29 (s, 9H); 0.76 (d, J=6.8 Hz, 3H).
IS-MS, m/e 557.1 (m+1)
Analysis for C28H30 ClFN4O5:
Calc: C, 60.38; H, 5.43; N, 10.06;
Found: C, 60.59; H, 5.55; N, 9.98.
Using methods substantially equivalent to those described in example 4-F, except that the reaction was heated to 80° C., 2-[2-(3-tert-butoxycarbonylamino-2-methyl-propoxy)-4-(pyrrolidin-1-yl)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (427 mg, 0.70 mmol, 83%) was prepared from 2-[2-(3-tert-butoxycarbonylamino-2-methyl-propoxy)-4-fluorobenzoylamino]-N-(5-chloropyridin-2-yl)benzamide and pyrrolidine.
1NMR (300 MHz, DMSO-d6): δ 11.11 (s, 1H); 10.94 (s, 1H); 8.39 (m, 1H); 8.14 (d, J=8.7 Hz, 1H); 7.93 (dd, J=1.8, 8.7 Hz, 1H); 7.77 (d, J=8.7 Hz, 1H); 7.70 (d, J=7.8 Hz, 1H); 7.48 (t, J=7.8 Hz, 1H); 7.12 (t, J=7.4 Hz, 1H); 6.83 (m, 1H); 6.20 (d, J=8.7 Hz, 1H); 6.05 (s, 1H); 4.15 (m, 1H); 3.92 (m, 1H); 3.29 (d, J=12.9 Hz, 4H); 2.83 (m, 2H); 2.17 (m, 1H); 1.94 (d, J=6.0 Hz, 4H); 1.31 (s, 9H); 0.74 (d, J=6.6 Hz, 1H).
IS-MS, m/e 608.2 (m+1).
Analysis for C32H38ClN5O5:
Calc: C, 63.20; H, 6.30; N, 11.52;
Found: C, 63.43; H, 6.10; N, 11.62.
Using methods substantially equivalent to those described in Example 4-G, 2-[2-(3-amino-2-methylpropoxy)-4-(pyrrolidin-1-yl)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (342 mg, 0.67 mmol, 100%) was prepared from 2-[2-(3-tert-butoxy-carbonylamino-2-methylpropoxy)-4-(pyrrolidin-1-yl)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide.
1NMR (400 MHz, DMSO-d6): δ 8.42 (d, J=2.0 Hz, 1H); 8.37 (dd, J=0.8, 8.4 Hz, 1H); 8.11 (d, J=9.2 Hz, 1H); 7.95 (dd, J=2.8, 8.8 Hz, 1H); 7.78-7.72 (m, 1H); 7.50 (t, J=7.2 Hz, 1H); 7.14 (t, J=7.4 Hz, 1H); 6.22 (d, J=8.8 Hz, 1H); 6.12 (s, 1H); 4.17 (m, 1H); 4.05 (m, 1H); 2.73 (dd, J=6.0, 12.8 Hz, 1H); 2.57 (dd, J=6.4, 12.8 Hz, 1H); 2.22 (m, 1H); 1.94 (m, 4H); 0.85 (d, J=6.8 Hz, 1H).
IS-MS, m/e 508.2 (m+1).
Analysis for C27H30ClN5O3.0.65CH2Cl2:
Calc: C, 59.53; H, 5.53; N, 12.26;
Found: C, 59.34; H, 5.46; N, 12.09.
Using methods substantially equivalent to those described in Example 29-B, methyl 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-fluoro benzoate (7.76 g, 22.0 mmol) and morpholine (40 mL) afforded, after purification by chromatography (SiO2: 25 to 40% EtOAc in hexanes), 2.43 g (26%) of the title compound.
1NMR
IS-MS, m/e=420 (m)
Using methods substantially equivalent to those described in Example 21-D, methyl 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(morpholin-4-yl)benzoate (2.40 g, 5.71 mmol), lithium hydroxide monohydrate (605 mg, 15.1 mmol), and 2:1 (10% water in tetrahydrofuran):methanol (75 mL) afforded 2.16 g (93%) of the title compound; which was used without further purification.
1NMR
IS-MS, m/e=406 (m)
Using methods substantially equivalent to those described in Example 4-E, 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(morpholin-4-yl)benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide (1.33 g, 2.03 mmol, 90%) was prepared from N-(5-chloropyridin-2-yl)-2-amino-5-fluorobenzamide and 2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-4-(morpholin-4-yl)benzoic acid.
1NMR (400 MHz, DMSO-d6): δ 11.27 (s, 1H); 10.76 (s, 1H); 8.40 (d, J=2.8 Hz, 1H); 8.28 (dd, J=5.2, 9.2 Hz, 1H); 8.13 (d, J=8.8 Hz, 1H); 7.91 (dd, J=2.2, 9.0 Hz, 1H); 7.77 (d, J=9.6 Hz, 1H); 7.59 (dd, J=3.0, 9.4 Hz, 1H); 7.39 (m, 1H); 6.60 (d, J=5.2 Hz, 1H); 6.60 (s, 1H); 4.85 (m, 1H); 3.70 (m, 4H); 3.23 (m, 4H); 3.00 (m, 2H); 2.47 (m, 2H); 1.87-1.79 (m, 4H); 1.33 (s, 9H);
IS-MS, m/e 654.2 (m+1)
Analysis for C33H37 ClFN5O6:
Calc: C, 60.59; H, 5.70; N, 10.71;
Found: C, 60.50; H, 5.86; N, 10.54.
Using methods substantially equivalent to those described in Example 4-G, N-(5-chloropyridin-2-yl)-5-fluoro-2-[4-(morpholin-4-yl)-2-(piperidin-4-yloxy)-benzoylamino]benzamide (1.123 g, 2.03 mmol, 100%) was prepared from 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(morpholin-4-yl)benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide. The salt was prepared by treatment of the free base with HCl.
1NMR (400 MHz, DMSO-d6): δ 8.41 (d, J=2.8 Hz, 1H); 8.32 (m, 1H); 8.18 (d, J=8.8 Hz, 1H); 7.94 (dd, J=2.8, 8.8 Hz, 1H); 7.76 (d, J=8.8 Hz, 1H); 7.58 (dd, J=2.8, 9.2 Hz, 1H); 7.38 (m, 1H); 6.59 (d, J=8.8 Hz, 1H); 6.57 (s, 1H); 4.64 (m, 1H); 3.69 (m, 4H); 3.21 (m, 4H); 2.77 (m, 2H); 2.46 (m, 2H); 1.81 (m, 2H); 1.60 (m, 2H).
IS-MS, m/e 554.2 (m+1).
Analysis for (free base) C28H29 ClFN5O4.0.30H2O:
Calc: C, 60.12; H, 5.33; N, 12.52;
Found: C, 60.17; H, 5.25; N, 12.13.
Using methods substantially equivalent to those described in Example 4-E, 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(morpholin-4-yl)benzoylamino]-N-(5-chloropyridin-2-yl)-4-fluorobenzamide (1.29 g, 1.97 mmol, 91%) was prepared from N-(5-chloropyridin-2-yl)-2-amino-4-fluorobenzamide and 2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-4-(morpholin-4-yl)benzoic acid.
1NMR (400 MHz, DMSO-d6): δ 11.24 (s, 1H); 11.17 (s, 1H); 8.40 (d, J=2.8 Hz, 1H); 8.31 (dd, J=2.8, 12.4 Hz, 1H); 8.11 (d, J=8.8 Hz, 1H); 7.92-7.83 (m, 1H); 7.75 (d, J=9.2 Hz, 1H); 7.01 (m, 1H); 6.61 (d, J=10.8 Hz, 1H); 6.60 (s, 1H); 4.79 (m, 1H); 3.70 (m, 4H); 3.24 (m, 4H); 2.99 (m, 2H); 2.47 (m, 2H); 1.86 (m, 2H); 1.77 (m, 2H); 1.31 (s, 9H).
IS-MS, m/e 654.2 (m+1).
Using methods substantially equivalent to those described in Example 4-G, N-(5-chloropyridin-2-yl)-4-fluoro-2-[4-(morpholin-4-yl)-2-(piperidin-4-yloxy)-benzoylamino]benzamide (1.05 g, 1.90 mmol, 99%) was prepared from 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(morpholin-4-yl)benzoylamino]-N-(5-chloropyridin-2-yl)-4-fluorobenzamide.
1NMR (400 MHz, DMSO-d6): δ 8.42 (d, J=2.4 Hz, 1H); 8.34 (dd, J=2.8, 12.4 Hz, 1H); 8.14 (d, J=8.8 Hz, 1H); 7.94 (dd, J=2.8, 8.8 Hz, 1H); 7.85 (m, 1H); 7.73 (d, J=8.8 Hz, 1H); 7.02 (m, 1H); 6.62 (d, J=10.8 Hz, 1H); 6.58 (s, 1H); 4.71 (m, 1H); 3.70 (m, 4H); 3.29 (m, 2H); 2.84 (m, 2H); 2.61 (m, 2H); 1.85 (m, 2H); 1.80 (m, 2H).
IS-MS, m/e 554.2 (m+1).
Analysis for C28H29 ClFN5O4.0.15CH2Cl2:
Calc: C, 59.78; H, 5.19; N, 12.32;
Found: C, 59.76; H, 5.04; N, 11.98.
By methods substantially equivalent to those described in Examples 16-F and 16-G, 2-[4-(tert-butyl)-2-(piperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)-4-fluorobenzamide hydrochloride (0.35 g, 11%) was prepared from N-(5-chloropyridin-2-yl)-2-amino-4-fluorobenzamide and 4-(tert-butyl)-2-(piperidin-4-yloxy)benzoyl chloride.
1 N MR
IS-MS, m/e 525.3 (m+1)
Analysis for C28H30 ClFN4O3-1.7 HCl.1.2H2O:
Calcd: C, 55.26; H, 5.65; N, 9.21; Cl, 15.73;
Found: C, 55.51; H, 5.54; N, 8.85; Cl, 15.81.
By methods substantially equivalent to those described in Example 36, N-(5-chloropyridin-2-yl)-5-fluoro-2-[2-[1-(2-hydroxypropyl)piperidin-4-yloxy]-4-(morpholin-4-yl)benzoylamino]benzamide (379 mg, 0.62 mmol, 73%) was prepared from N-(5-chloropyridin-2-yl)-5-fluoro-2-[4-(morpholin-4-yl)-2-(piperidin-4-yloxy)-benzoylamino]benzamide.
1NMR (400 MHz, DMSO-d6): δ 11.24 (s, 1H); 10.72 (s, 1H); 8.40 (d, J=2.0 Hz, 1H); 8.33-8.29 (m, 1H); 8.17 (d, J=8.4 Hz, 1H); 7.93 (dd, J=2.4, 9.2 Hz, 1H); 7.75 (d, J=8.8 Hz, 1H); 7.58 (dd, J=3.0, 9.0 Hz, 1H); 7.39 (t, J=8.8 Hz, 1H); 6.59 (d, J=9.6 Hz, 1H); 6.57 (s, 1H); 4.60 (m, 1H); 4.17 (m, 1H); 3.69 (m, 4H); 3.22-3.12 (m, 4H); 2.59 (m, 2H); 2.13-2.02 (m, 4H); 1.84 (m, 4H); 0.96 (d, J=6.0 Hz, 3H).
IS-MS, m/e 612.2 (m+1).
By methods substantially equivalent to those described in Example 36, N-(5-chloropyridin-2-yl)-4-fluoro-2-[2-[1-(2-hydroxypropyl)piperidin-4-yloxy]-4-(morpholin-4-yl)benzoylamino]benzamide (253 mg, 0.41 mmol, 49%) was prepared from N-(5-chloropyridin-2-yl)-5-fluoro-2-[4-(morpholin-4-yl)-2-(piperidin-4-yloxy)-benzoylamino]benzamide.
1NMR (300 MHz, DMSO-d6): δ 11.21 (s, 1H); 11.12 (s, 1H); 8.40 (d, J=2.4 Hz, 1H); 8.35 (dd, J=2.3, 12.5 Hz, 1H); 8.15 (d, J=9.0 Hz, 1H); 7.93 (dd, J=2.4, 8.7 Hz, 1H); 7.84 (t, J=7.5 Hz, 1H); 7.73 (d, J=8.7 Hz, 1H); 6.99 (t, J=6.8 Hz, 1H); 6.60 (d, J=9.0 Hz, 1H); 6.56 (s, 1H); 4.58 (br s, 1H); 4.16 (s, 2H); 4.06 (d, J=5.1 Hz, 1H); 3.73-3.59 (m, 4H); 3.27-3.12 (m, 4H); 2.52 (m, 2H); 2.16-1.99 (m, 4H); 1.85-1.74 (m, 4H); 0.94 (d, J=6.0 Hz, 3H).
IS-MS, m/e 612.2 (m+1).
Analysis for C31H35 ClFN5O5:
Calc: C, 60.83; H, 5.76; N, 11.44;
Found: C, 61.11; H, 5.56; N, 11.71.
To a solution of borane-trimethylamine complex (1.35 mL of a 1 M solution in tetrahydrofuran) in tetrahydrofuran (3 mL) stirring at 0° C., a solution of 4-(tert-butyl)-2-(1-Boc-piperidine-4-yloxy)benzoic acid (0.51 g, 1.35 mmol) in tetrahydrofuran (7 mL) was added slowly via cannula. After the addition was complete the reaction mixture was stirred at room temperature for 4 h, then an additional amount of borane-trimethylamine complex was added (1.35 mL of a 1 M solution in tetrahydrofuran). The reaction mixture was stirred at room temperature for another 2 h. After quenching with ice, the mixture was partitioned between brine and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane (3×). The combined organic layers were dried with magnesium sulfate, filtered, and concentrated in vacuo to a residue (0.42 g, 86%) which was identified as the title compound and used directly in the next step without further purification.
1NMR
FD-MS, m/e 364.1 (m+1).
To a solution of oxalyl chloride (0.30 mL, 3.46 mmol) in dichloromethane (5 mL) stirring at −78° C. under nitrogen atmosphere, dimethylsulfoxide was added dropwise (0.49 mL, 6.93 mmol). After 10 min, a solution of the crude 4-(tert-butyl)-2-(1-Boc-piperidine-4-yloxy)benzyl alcohol (0.42 g, 1.15 mmol) in dichloromethane (6 mL) was added slowly via cannula. After the addition was complete, the reaction mixture was stirred at −78° C. for 1 h. The reaction was then treated with triethylamine (1.6 mL, 11.5 mmol) and allowed to warm up to room temperature overnight. The reaction mixture was partitioned between brine and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried with magnesium sulfate, filtered, and concentrated in vacuo to a brown residue which was purified on a silica gel chromatotron plate. Elution with ethyl acetate-hexanes (1:5) afforded the title compound (0.42 g, 100%) as a clear oil which foamed up under vacuum.
1NMR
FD-MS, m/e 362.1 (m+1).
A solution of the 4-(tert-butyl)-2-(1-Boc-piperidine-4-yloxy)benzaldehyde (0.15 g, 0.42 mmol), N-(5-chloropyridin-2-yl)-2-amino-5-chlorobenzamide (0.12 g, 0.42 mmol) and catalytic pyridinium p-toluenesulfonate in toluene (8 mL) was treated with excess magnesium sulfate (0.5 g). The reaction mixture was then heated at 75° C. overnight. The reaction was cooled down to room temperature, filtered, and concentrated in vacuo to an oily residue which was redissolved in acetic acid (1.4 mL). The resulting solution was treated with borane-trimethylamine complex (0.2 g, 2.74 mmol) and stirred at room temperature for 3 h. The reaction mixture was then partition between 5 N aqueous sodium hydroxide and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried with magnesium sulfate, filtered, and concentrated in vacuo to a residue which was purified on a silica gel chromatotron plate. Elution with ethyl acetate-hexanes (95:5) then (9:1) provided the title compound (0.23 g, 87%) as a yellow oil which foamed up under vacuum. Recrystallization of the oil from ethyl acetate-hexanes provided analytically pure product (0.17 mg) as a pale-yellow crystalline solid.
1 NMR
mp 161.3-162.9° C.
FD-MS, m/e 627.1 (m).
Analysis for C33H40Cl2N4O4:
Calcd: C, 63.15; H, 6.42; N, 8.93;
Found: C, 63.03; H, 6.58; N, 8.86.
A solution of the 2-[4-(tert-butyl)-2-(1-Boc-piperidin-4-yloxy)benzylamino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide (0.2 g, 0.32 mmol) in trifluoroacetic acid (5 mL) was stirred at room temperature for 2 h. The mixture was poured into ice, then taken to basic pH with 5 N aqueous sodium hydroxide, and extracted with dichloromethane. The organic layer was separated, and the aqueous layer was thoroughly extracted with dichloromethane. The combined organic layers were dried with magnesium sulfate, filtered, and concentrated in vacuo to a yellow oily residue which was purified on a silica gel chromatotron plate. Elution with 9:1 dichloromethane-2 N ammonia in methanol provided the title compound as a clear oil which foamed up under vacuum (0.15 mg, 87%). Recrystallization of the oil from ethyl acetate-hexanes provided analytically pure product (0.09 mg) as a yellow-white crystalline solid.
1NMR
mp 153.6-154.5° C.
FD-MS, m/e 527.0 (m).
Analysis for C28H32Cl2 N4O2:
Calcd: C, 63.76; H, 6.11; N, 10.62;
Found: C, 63.87; H, 6.21; N, 10.65.
Using methods substantially equivalent to those described in Example 1-C, methyl 4-benzyloxy-2-hydroxybenzoate (2.0 g, 8.1 mmol), N-tert-butoxycarbonyl-4-hydroxy-piperidine (1.6 g, 8.1 mmol), triphenylphosphine (2.1 g, 8.1 mmol), and diethyl azodicarboxyalte (1.3 mL, 8.1 mmol) afforded, after purification by chromatography (SiO2: 5 to 15% EtOAc in hexanes), 2.57 g (74%) of the title compound.
1NMR
IS-MS, m/e=429 (m)
Using methods substantially equivalent to those described in Example 1-D, methyl 4-benzyloxy-2-(piperidin-4-yloxy)benzoate (2.20 g, 5.13 mmol) afforded 2.01 g (94%) of the title compound.
1NMR
IS-MS, m/e=429 (m)
Using methods substantially equivalent to those described in Example 1-F, 4-benzyloxy-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoic acid (529 mg, 1.27 mmol) and N-(5-chloropyridin-2-yl)-2-aminobenzamide (297 mg, 1.20 mmol) afforded, after purification by chromatography (SiO2: EtOAc in hexanes), 493 mg (63%) of the title compound.
1NMR
IS-MS, m/e=656 (m)
To a solution of 2-[4-(benzyloxy)-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (130 mg, 0.2 mmol) in methylene chloride (20 mL) was added trifluoroacetic acid (2 mL). The reaction was stirred for 2 h at room temperature, then it was diluted with methanol and purified by SCX column to give 112 mg (100%) of the product. The product was dissolved in methanol, and 2 M HCl in methanol (1 mL) was added. The solution was stirred for 15 minutes and then concentrated in vacuo to give 120 mg of a tan solid.
1NMR
FD-MS, m/e 648
Analysis for C31H29ClN4O4.2HCl.H20:
Calcd: C, 57.46; H, 5.13; N, 8.65;
Found: C, 57.88; H, 5.05; N, 8.70.
The N-(5-chloropyridin-2-yl)-2-[2-(piperidin-4-yloxy)-4-(pyrrolidin-1-yl)-benzoylamino]benzamide (287 mg, 0.55 mmol) was diluted with methylene chloride (6 mL) and pyridine (49 μL, 0.61 mmol). Excess trifluoroacetic anhydride (TFAA) was added. After 5 minutes, the reaction was diluted with methylene chloride (100 mL) and extracted with saturated aqueous sodium bicarbonate (3×10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by flash column chromatography (about 35 g silica, 10% EtOAc/CH2Cl2) to give the desired product (240 mg, 0.39 mmol, 71%) as a yellow solid.
1NMR (400 MHz, DMSO-d6): δ 8.42 (d, J=2.8 Hz, 1H); 8.13 (d, J=8.0 Hz, 1H); 7.87 (dd, J=3.0, 8.6 Hz, 1H); 7.71 (d, J=7.2 Hz, 1H); 7.55-7.32 (m, 3H); 6.14 (m, 2H); 4.84 (s, 1H); 3.98 (m, 2H); 3.76 (m, 2H); 3.27 (m, 4H); 1.95-1.69 (m, 8H).
N-(5-Chloropyridin-2-yl)-2-aminobenzamide (0.09 g, 0.39 mmol) was converted into the title compound (0.24 g, 100%) using the procedure described in Example 56-C. The product was obtained as a yellow oil, which was further purified by recrystallization from ethyl acetate-hexanes, giving rise to a yellow-white solid (0.14 g).
1NMR
mp 182.6-183.1° C.
FD-MS, m/e 593.6 (m)
Analysis for C33H41ClN4O4:
Calcd: C, 66.82; H, 6.97; N, 9.45;
Found: C, 67.06; H, 7.14; N, 9.56.
2-[4-(tert-butyl)-2-(1-Boc-piperidin-4-yloxy)benzylamino]-N-(5-chloropyridin-2-yl)benzamide (0.19 g, 0.32 mmol) was converted to the title compound (0.14 g, 88%) using the procedure described in Example 56-D. The product was obtained as a foam which was further purified by recrystallization from ethyl acetate-hexanes, giving rise to a white, powdery solid (0.09 g).
1NMR
mp 169.0-170.0° C.
FD-MS, m/e 493.3 (m)
Analysis for C28H33ClN4O2:
Calcd: C, 68.21; H, 6.75; N, 11.36;
Found: C, 68.29; H, 6.95; N, 11.47.
Into methylene chloride (300 mL) was dissolved 3-isopropylphenol (27.24 g, 200 mmol). After cooling the solution in an ice bath, diisopropylethyl amine (69.7 mL, 400 mmol) was added in one portion, followed by the dropwise addition of chloromethyl methyl ether (18.9 mL, 236 mmol) in methylene chloride (50 mL). The reaction mixture was gradually allowed to warm to room temperature. After 16 h, the reaction mixture was diluted with cold water (500 mL) and methylene chloride. The mixture was shaken in a separatory funnel and the layers were separated. The organic layer was extracted with cold water (2×500 mL), dried (MgSO4), and concentrated under vacuum. The product was dissolved in ether (200 mL) and stirred with 5 N NaOH (200 mL) at room temperature for 5 min. The ether layer was separated and extracted with cold 1 N HCl (200 mL), dried (MgSO4), and concentrated under vacuum. The product was chromatographed over silica (0 to 30% EtOAc in hexane gradient), giving 20.0 g (56%) of the title compound.
1NMR
FD-MS, m/e: 180 (m)
Into ether (450 mL) was dissolved 3-isopropyl-1-methoxymethoxybenzene (20.0 g, 111 mmol), and the resulting solution was cooled to −15° C. via an ice-salt-acetone-bath. Under nitrogen, 1.7 M tert-butyl lithium (78.4 mL, 133.2 mmol) was added dropwise over 10 min. and the reaction mixture was stirred for an additional 10 min. Excess carbon dioxide was bubbled in over 5 min; then the reaction mixture was poured into cold water (400 mL) and shaken in a separatory funnel. The aqueous layer was acidified with cold 1 N HCl and shaken with ether (300 mL). The ether layer was washed with water (300 mL), dried (MgSO4), and concentrated under vacuum. The product was dissolved in a minimum amount of hexanes, giving 19.5 g (78%) of the title compound as a solid on standing at room temperature.
1NMR
IS-MS, m/e: 225 (m+1), 223 (m−1)
Into methylene chloride (40 mL) was dissolved 4-isopropyl-2-methoxymethoxy-benzoic acid (6.0 g, 26.8 mmol). Methanol (10 mL) was added, followed by the dropwise addition of 2 M hexane solution of trimethylsilyldiazomethane (14.7 mL). After 2 h, HOAc (0.5 mL) was added and the solvent was removed under vacuum, giving the title compound as an oil, which was used in next step without further purification.
1NMR
Into CCl4 (50 mL) was dissolved methyl 4-isopropyl-2-methoxymethoxybenzoate (3.36 g, 14.1 mmol). To this solution was added N-bromosuccinimide (3.02 g, 16.92 mmol), followed by azobis(isobutyronitrile) (AIBN) (about 30 mg). Under nitrogen, the reaction mixture was heated and stirred at gentle reflux for 4 h. The reaction mixture was cooled to room temperature and filtered, giving the title compound as as a crude oil.
1NMR
The crude methyl 4-(1-bromo-1-methyl)ethyl-2-methoxymethoxybenzoate was dissolved in dry DMF (30 mL). To this solution was added NaN3 (1.1 g, 16.9 mmol) in one portion at room temperature. The reaction mixture was stirred for 4 h and then shaken between EtOAc (200 mL) and cold dilute HCl (200 mL). The layers were separated and the organic layer was washed with cold dilute HCl (200 mL), dried (MgSO4), and concentrated under vacuum.
The crude azide product was combined with another preparation (approx. 22.5 mmol total) and dissolved in chloroform (80 mL). To this solution was added NaN3 (4.39 g, 67.5 mmol). The mixture was cooled in an ice bath and a mixture of 80 mL CHCl3 and TFA was added dropwise over 30 min. The reaction was allowed to warm gradually to room temperature. After 48 h, the reaction mixture was washed with cold water (2×300 mL) and then with satd NaHCO3. The organic layer was dried (MgSO4) and concentrated under vacuum, giving 4.47 g (85% yield) of the title compound as an oil.
1NMR
The methyl 4-(1-azido-1-methyl)ethyl-2-hydroxybenzoate (1.05 g) was dissolved in EtOH (30 mL), then 5% BaSO4 on palladium (0.5 g) was added. At atmospheric pressure, excess hydrogen was applied for 16 h. The reaction mixture was filterd and concentrated under vacuum, giving 0.93 g (100%) of the title compound as a solid after trituration with hexanes.
1NMR
The methyl 4-(1-amino-1-methy)ethyl-2-hydroxybenzoate (0.93 g, 4.4 mmol) was dissolved in methylene chloride (30 mL), then di-tert-butyl dicarbonate (1.92 g, 8.8 mmol) and diisopropylethyl amine (1.53 mL, 8.8 mmol) were added. After 4 h, the reaction mixture was diluted with methylene chloride (100 mL) and extracted with water (2×150 mL). The product was dried (MgSO4), concentrated under vacuum, and chromatographed over silica (0 to 30% EtOAc in hexane gradient), giving 0.576 g (42% yield) of the title compound as an oil.
1NMR
Analysis for C16H23NO5:
Calcd: C, 62.12; H, 7.49; N, 4.53;
Found: C, 62.34; H, 7.27; N, 4.49.
The methyl 4-(1-tert-butoxycarbonylamino-1-methyl)ethyl-2-hydroxybenzoate (0.5 g, 1.84 mmol), 4-hydroxy-1-tert-butoxycarbonylpiperidine (0.371 g, 1.84 mmol), and triphenylphosphine (0.482 g, 0.84 mmol) were diluted with THF (20 mL). The reaction mixture was cooled in an ice bath and diisopropyl azodicarboxylate (0.372 g, 1.84 mmol) was added dropwise over 10 min. The reaction mixture was allowed to gradually warm to room temperature. After 16 h, the reaction was diluted with methylene chloride (100 mL), extracted with water (150 mL), dried (MgSO4), and concentrated under vacuum. The product was chromatographed over silica (0 to 30% EtOAc in hexane gradient), giving 321 mg (35% yield) of the title compound as an oil.
1NMR
The methyl 4-(1-tert-butyloxycarbonylamino-1-methyl)ethyl-2-(1-tert-butoxy-carbonylpiperid-4-oxy)benzoate (0.321 g, 0.65 mmol) was dissolved in THF (15 mL).
A 5 mL aqueous solution of LiOH.H2O (60 mg, 1.43 mmol) was added, and the mixture stirred at 65° C. in an oil bath for 24 h. Solvent was removed under vacuum. The product was diluted with toluene (2×35 mL) and concentrated to give the crude lithium salt of the benzoate.
The lithium benzoate was dispersed in methylene chloride (20 mL) and a catalytic amount of DMF was added. The solution was cooled in an ice bath, and oxalyl chloride (0.1 mL, 0.78 mmol) was added. After stirring for 1 h, the ice bath was removed. The reaction mixture was stirred for an additional hour, and then solvent was removed under vacuum. The benzoyl chloride product was concentrated under vacuum from toluene (2×35 mL) and was used subsequently without further purification.
The crude benzoyl chloride product in methylene chloride (10 mL) was added dropwise to a 0° C. solution of N-(5-chloropyridin-2-yl)-2-aminobenzamide (0.161 g, 0.65 mmol) and pyridine (0.11 mL, 1.3 mmol) in methylene chloride (20 mL). The reaction mixture was allowed to gradually warm to room temperature. After 16 h, the reaction mixture was diluted with methylene chloride (100 mL) and extracted with cold water (2×150 mL). The organic layer was dried (MgSO4) and concentrated. The product was chromatographed over silica (0 to 30% EtOAc in hexane gradient), giving 164 mg of the desired product.
1NMR
The 2-[4-(1-tert-butoxycarbonylamino-1-methyl)ethyl-2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)benzoylamino-N-(5-chloropyridin-2-yl)benzamide was dissolved in methylene chloride (2 mL) and TFA (2 mL). After 4 h at room temperature, the solvent was removed under vacuum and the residue was triturated with hexane and then with ether, to give 1-50 mg of the title compound as a solid.
1NMR
MS-FD, m/e: 508 (m−2TFA)
Analysis for C27H30ClN5O2.2CF3COOH:
Calcd: C, 50.59; H, 4.38; N, 9.51;
Found: C, 49.91; H, 4.21; N, 9.43.
Using methods substantially equivalent to those described in Example 36, N-(5-chloropyridin-2-yl)-2-[2-[1-(2-hydroxypropyl)piperidin-4-yloxy]-4-(methylthio)-benzoylamino]benzamide (197 mg, 0.35 mmol, 89%) was prepared from N-(5-chloro-pyridin-2-yl)-2-[4-(methylthio)-2-(piperidin-4-yloxy)benzoylamino]benzamide.
1NMR (400 MHz, DMSO-d6): δ 11.18 (s, 1H); 10.96 (s, 1H); 8.40 (s, 1H); 8.38 (d, J=9.6 Hz, 1H); 8.15 (d, J=8.4 Hz, 1H); 7.92 (dd, J=2.4, 8.8 Hz, 1H); 7.77 (d, J=7.6 Hz, 2H); 7.54 (t, J=7.8 Hz, 1H); 7.19 (t, J=7.6 Hz, 1H); 7.00 (s, 1H); 6.91 (d, J=7.6 Hz, 1H); 4.64 (m, 1H); 3.64 (m, 1H); 2.49 (s, 3H); 2.29-1.83 (m, 7H); 0.95 (d, J=6.4 Hz, 3H).
IS-MS, m/e 555.2 (m+1).
Analysis for C28H31ClN4O4S:
Calc: C, 60.59; H, 5.63; N, 10.09;
Found: C, 60.75; H, 5.60; N, 10.19.
Using methods substantially equivalent to those described in Example 58, N-(5-chloropyridin-2-yl)-2-[4-(methylthio)-2-(1-trifluoracetylpiperidin-4-yloxy)-benzoylamino]benzamide (321 mg, 0.54 mmol, 77%) was prepared from N-(5-chloro-pyridin-2-yl)-2-[4-(methylthio)-2-(piperidin-4-yloxy)benzoylamino]benzamide.
1NMR (300 MHz, DMSO-d6): δ 11.21 (s, 1H); 10.98 (s, 1H); 8.37 (m, 2H); 8.01 (d, J=9.0 Hz, 1H); 7.79 (m, 3H); 7.53 (t, J=7.7 Hz, 1H); 7.18 (t, J=7.5 Hz, 1H); 7.07 (s, 1H); 6.93 (d, J=8.4 Hz, 1H); 4.95 (m, 1H); 3.96 (m, 2H); 3.71 (m, 2H); 2.51 (s, 3H); 2.08-1.78 (m, 4H).
IS-MS, m/e 593.03 (m+1).
Analysis for C27H24ClF3N4O4S:
Calc: C, 54.69; H, 4.08; N, 9.45;
Found: C, 55.64; H, 4.75; N, 9.48.
Using methods substantially equivalent to those described in Example 4-E, 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(methylthio)benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide (837 mg, 1.36 mmol, 78%) was prepared from N-(5-chloropyridin-2-yl)-2-amino-5-fluorobenzamide and 2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-4-(methylthio)benzoic acid.
1NMR (400 MHz, DMSO-d6): δ 11.29 (s, 1H); 10.86 (s, 1H); 8.41 (d, J=2.8 Hz, 1H); 8.31 (dd, J=5.4, 9.4 Hz, 1H); 8.11 (d, J=9.2 Hz, 1H); 7.91 (dd, J=2.6, 9.4 Hz, 1H); 7.80 (d, J=8.0 Hz, 1H); 7.63 (dd, J=2.6, 9.4 Hz, 1H); 7.44-7.39 (m, 1H); 7.05 (s, 1H); 6.92 (dd, J=1.2, 8.4 Hz, 1H); 4.84 (m, 1H); 3.68 (d, J=13.6 Hz, 1H); 3.02 (m, 2H); 2.47 (s, 3H); 1.87 (m, 2H); 1.78 (m, 2H); 1.33 (s, 9H).
IS-MS, m/e 615.2 (m+1).
Analysis for C30H32 ClFN4O5S:
Calc: C, 58.28; H, 5.24; N, 9.11;
Found: C, 58.64; H, 5.44; N, 8.90.
Using methods substantially equivalent to those described in Example 4-G, N-(5-chloropyridin-2-yl)-5-fluoro-2-[4-(methylthio)-2-(piperidin-4-yloxy)benzoylamino]-benzamide (684 mg, 1.11 mmol, 84%) was prepared from 2-[2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-4-(methylthio)benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluoro-benzamide.
1NMR (300 MHz, DMSO-d6): δ 8.41 (d, J=1.8 Hz, 1H); 8.28 (m, 1H); 8.12 (d, J=8.7 Hz, 1H); 7.93 (dd, J=2.3, 8.9 Hz, 1H); 7.74 (d, J=8.4 Hz, 1H); 7.64 (d, J=9.0 Hz, 1H); 7.42 (t, J=8.6 Hz, 1H); 7.02 (s, 1H); 6.92 (d, J=8.4 Hz, 2H); 4.79 (m, 1H); 2.96 (m, 2H); 2.76 (m, 2H); 2.46 (s, 3H); 1.95 (m, 2H); 1.79 (m, 2H).
IS-MS m/e: 515.3 (m+1).
Analysis for C25H24 ClFN4O3S:
Calc: C, 54.98; H, 4.53; N, 9.86;
Found: C, 54.79; H, 4.58; N, 9.79.
To a stirring solution of 2-methoxymethyloxy-4-isopropylbenzoic acid (3.0 g, 13.4 mmol) in THF (50 mL) was added sodium ethoxide (0.91 g, 13.4 mmol). After 15 min, the solvent was removed in vacuo and the residue was suspended in dichloromethane (50 mL). To this mixture was added a couple drops of DMF followed by oxalyl chloride (1.7 g, 13.4 mmol). After another 30 min, the solvent was removed in vacuo and the residue was again suspended in dichloromethane (150 mL). To this mixture was added pyridine (2.9 g, 36.5 mmol), followed by N-(5-chloropyridin-2-yl)-2-aminobenzamide (3.02 g, 12.2 mmol). After stirring for 2 h, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate (400 mL) and water (200 mL). The organic phase was washed twice with 1 M citric acid, once with brine, twice with saturated aq sodium bicarbonate and once with brine. The organic phase was then dried with MgSO4 and filtered. To this solution was added silica gel (about 10 g) and the solvent was removed in vacuo. The resulting dry pack was loaded onto the top of a silica gel column loaded with 10% ethyl acetate in hexanes and eluted with a gradient of 10% ethyl acetate in hexanes through 30% ethyl acetate in hexanes. The clean product containing fractions were combined and concentrated in vacuo to give 2.18 g (39%) of off white solid. Another set of fractions which contained a small amount of impurity were combined and concentrated in vacuo to give 2.09 g (about 38%) of an off white solid.
1NMR
ES_MS, m/e 454.1 (m+1)
To a stirring solution of 2-[2-methoxymethyloxy-4-isopropylbenzoylamino]-N-(5-chloropyridin-2-yl)benzamide (5.74 g, 12.6 mmol) in dichloromethane (20 mL) was added TFA (100 mL) followed by water (100 mL). After stirring for 15 min, the solvents were removed in vacuo and the residue was partitioned between ethyl acetate (500 mL) and water (200 mL). At this point, the mixture was filtered to give 1.13 g (22%) of white solid. The filtrate was returned to a separatory funnel and the layers were separated. The organic phase was then washed with 1 M citric acid, once with brine, twice with saturated aq sodium bicarbonate, and once again with brine. The organic phase was then dried with MgSO4, filtered and concentrated to a volume of about 50 mL in vacuo. At this point, a significant amount of precipitate had formed; so the mixture was sonicated and filtered to give another 2.76 g (53%) of the title compound.
1NMR
ES-MS, m/e 410.3 (m+1)
Analysis for C22H20N3O3Cl:
Calcd: C, 64.47; H, 4.92; N, 10.25;
Found: C, 64.36; H, 4.92; N, 10.16.
4-Hydroxycyclohexanone-1,1-ethylene ketal (0.63 g, 4 mmol), 2-[4-isopropyl-2-hydroxybenzoylamino]-N-(5-chloropyridin-2-yl)benzamide (1.64 g, 4 mmol), triphenyl-phosphine (1.05 g, 4 mmol), and dry DMF (2 mL) were sonicated for 5 min at room temperature. DIAD (0.8 mL, 4 mmol) was added and sonication was continued for 1 h. Ether (40 mL) was added and the solution was chilled overnight in the freezer to crystallize triphenylphosphine oxide. The crystals were filtered, washed with a little ether, and the combined filtrates were evaporated to dryness to give a yellow oil.
Chromatographic purification (Merck silica gel 60, elution with hexane (100-60%) and ethyl acetate (0-40%)) gave 960 mg (44%) of the desired ketal.
1NMR
IS-MS: [m+1]+=550.3, [m−1]−=548.3
Calcd for C30H32N3O5Cl: [m+1]+=550.0, [m−1]−=548.0
D. N-(5-Chloropyridin-2-yl)-2-[2-(1,4-dioxaspiro[4.5]dec-8-yloxy)-4-isopropyl-benzoylamino]benzamide (960 mg, 1.75 mmol) was dissolved in THF (30 mL). The solution was cooled to ice-water bath temperature and 5 M HCl (5.6 mL, 28 mmol) was added dropwise. The reaction was allowed to warm to room temperature and stir for 6 h.
Water (100 mL) was added, and the pH was adjusted to 8 with 5 M NaOH. THF was removed on the rotary evaporator and the precipitated white solid was filtered, washed with water, and dried under vacuum to give 790 mg (90%) of the desired ketone as a white solid.
1NMR
Analysis for C28H28ClN3O4:
Calcd: C, 66.46; H, 5.58; N, 8.30;
Found: C, 66.65; H, 5.46; N, 8.32.
N-(5-Chloropyridin-2-yl)-2-[4-isopropyl-2-(4-oxocyclohexyloxy)benzoylamino]-benzamide (51 mg, 0.10 mmol) and benzylamine (16 mg, 0.15 mmol) were suspended in 7:1:1 dry MeOH-DMF-methylene chloride. Sodium borohydride (50 mg) was added and the reaction was agitated overnight at room temperature. Aldehyde resin (150 mg, 1 mmol aldehyde/gram, 0.15 mmol) was added to the resulting homogeneous solution, and the mixture was agitated overnight at room temperature. The mixture was filtered, the resin was washed with methylene chloride, and the filtrate was evaporated under vacuum.
The crude product was dissolved in MeOH and added to an SCX column. The column was washed thoroughly with MeOH; then the product was eluted with 2 M ammonia in MeOH. Evaporation of the methanolic ammonia eluates gave 2-[2-[4-(benzylamino)-cyclohexyloxy]-4-isopropylbenzoylamino]-N-(5-chloropyridin-2-yl)benzamide (48 mg, 81%).
1NMR
IS-MS: [m+1]+=597.1, [m−1]−=595.1
Calcd for C35H37N4O3Cl: [m+1]+=597.0, [m−1]−=595.0
Using methods substantially equivalent to those described in Example 36, N-(5-chloropyridin-2-yl)-5-fluoro-2-[2-[1-(2-hydroxypropyl)piperidin-4-yloxy]-4-(methylthio)benzoylamino]benzamide (122 mg, 0.21 mmol, 55%) was prepared from N-(5-chloropyridin-2-yl)-5-fluoro-2-[4-(methylthio)-2-(piperidin-4-yloxy)benzoylamino]-benzamide.
1NMR (300 MHz, DMSO-d6): δ 11.26 (s, 1H); 10.82 (s, 1H); 8.40 (d, J=1.2 Hz, 1H); 8.33 (m, 1H); 8.15 (d, J=9.0 Hz, 1H); 7.93 (dd, J=2.1, 9.0 Hz, 1H); 7.77 (d, J=8.4 Hz, 1H); 7.62 (dd, J=2.0, 9.5 Hz, 1H); 7.41 (t, J=8.4 Hz, 1H); 7.00 (s, 1H); 6.90 (d, J=8.1 Hz, 1H); 4.63 (m, 1H); 4.17 (s, 1H); 3.64 (m, 1H); 2.56 (m, 2H); 2.49 (s, 3H); 2.19-1.77 (m, 7H); 0.95 (d, J=6.3 Hz, 3H).
IS-MS, m/e 573.2 (m+1)
Using methods substantially equivalent to those described in Example 4-E, 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(methylthio)benzoylamino]-N-(5-chloro-pyridin-2-yl)-4-fluorobenzamide (708 mg, 1.15 mmol, 87%) was prepared from 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-(4-methylthio)benzoic acid and N-(5-chloropyridin-2-yl)-2-amino-4-fluorobenzamide.
1NMR (300 MHz, DMSO-d6): δ 11.29 (s, 1H); 11.26 (s, 1H); 8.41 (s, 1H); 8.33 (dd, J=1.5, 11.1 Hz, 1H); 8.09 (d, J=9.0 Hz, 1H); 7.89 (m, 2H); 7.78 (d, J=8.1 Hz, 1H); 7.05 (m, 2H); 6.92 (d, J=8.4 Hz, 1H); 4.82 (m, 1H); 3.63 (d, J=12.9 Hz, 2H); 3.00 (t, J=10.4 Hz, 2H); 2.50 (s, 3H); 1.88-1.73 (m, 4H); 1.31 (s, 9H).
IS-MS, m/e 615.2 (m+1).
Analysis for C30H32 ClFN4O5S:
Calc: C, 58.58; H, 5.24; N, 9.11;
Found: C, 58.89; H, 5.14; N, 9.15.
Using methods substantially equivalent to those described in Example 4-G, N-(5-chloropyridin-2-yl)-4-fluoro-2-[4-(methylthio)-2-(piperidin-4-yloxy)benzoylamino]-benzamide (554 mg, 1.08 mmol, 100%) was prepared from 2-[2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-4-(methylthio)benzoylamino]-N-(5-chloropyridin-2-yl)-4-fluoro-benzamide.
IS-MS m/e: 515.3 (m+1)
Analysis for C25H24 ClFN4O3S:
Calc: C, 58.31; H, 4.70; N, 10.88;
Found: C, 58.02; H, 4.68; N, 10.59.
Using methods substantially equivalent to those described in Example 58, N-(5-chloropyridin-2-yl)-5-fluoro-2-[4-(methylthio)-2-(1-trifluoroacetylpiperidin-4-yloxy)benzoylamino]benzamide (179 mg, 0.29 mmol, 55%) was prepared from N-(5-chloropyridin-2-yl)-5-fluoro-2-[4-(methylthio)-2-(piperidin-4-yloxy)benzoylamino]-benzamide.
1NMR (400 MHz, DMSO-d6): δ 11.29 (s, 1H); 10.84 (s, 1H); 8.41 (d, J=2.0 Hz, 1H); 8.32 (dd, J=5.2, 9.2 Hz, 1H); 8.01 (d, J=8.8 Hz, 1H); 7.82 (m, 2H); 7.63 (dd, J=2.8, 9.2 Hz, 1H); 7.42 (dt, J=2.8, 8.2 Hz, 1H); 7.08 (s, 1H); 6.94 (d, J=8.0 Hz, 1H); 4.97 (m, 1H); 3.73 (d, J=14.8 Hz, 2H); 3.41 (t, J=11.4 Hz, 2H); 2.47 (s, 3H); 2.05-1.79 (m, 4H).
IS-MS, m/e 611.0 (m+1).
Analysis for C27H23ClF4N4O4S:
Calc: C, 53.08; H, 3.79; N, 9.17;
Found: C, 52.94; H, 3.82; N, 8.92.
Using methods substantially equivalent to those described in Example 36, N-(5-chloropyridin-2-yl)-4-fluoro-2-[2-[1-(2-hydroxypropyl)piperidin-4-yloxy]-4-(methylthio)benzoylamino]benzamide (111 mg; 0.19 mmol, 50%) was prepared from N-(5-chloropyridin-2-yl)-4-fluoro-2-[4-(methylthio)-2-(piperidin-4-yloxy)benzoylamino]-benzamide.
1NMR (400 MHz, DMSO-d6): δ 11.25 (s, 2H); 8.41 (d, J=2.4 Hz, 1H); 8.37 (dd, J=2.8, 12.8 Hz, 1H); 8.14 (d, J=8.8 Hz, 1H); 7.95-7.87 (m, 2H); 7.77 (d, J=8.4 Hz, 1H); 7.05 (dt, J=2.4, 8.0 Hz, 1H); 7.00 (s, 1H); 6.92 (d, J=8.4 Hz, 1H); 4.62 (m, 1H); 4.16 (d, J=3.6 Hz, 1H); 3.62 (m, 1H); 2.53 (m, 2H); 2.47 (s, 3H); 2.12-1.77 (m, 6H); 0.94 (d, J=6.0 Hz, 3H).
IS-MS, m/e 573.2 (m+1).
Using methods substantially equivalent to those described in Example 58, N-(5-chloropyridin-2-yl)-4-fluoro-2-[4-(methylthio)-2-(1-trifluoroacetylpiperidin-4-yloxy)benzoylamino]benzamide (135 mg, 0.22 mmol, 76%) was prepared from N-(5-Chloropyridin-2-yl)-4-fluoro-2-[4-(methylthio)-2-(piperidin-4-yloxy)benzoyl-amino]benzamide.
1NMR (300 MHz, DMSO-d6): δ 11.27 (s, 2H); 8.40 (d, J=2.4 Hz, 1H); 8.34 (dd, J=2.3, 12.5 Hz, 1H); 7.98 (d, J=8.7 Hz, 1H); 7.85 (m, 3H); 7.05 (m, 2H); 6.94 (d, J=8.1 Hz, 1H); 4.94 (m, 1H); 3.94 (m, 2H); 3.66 (m, 2H); 2.51 (s, 3H); 2.09-1.81 (m, 4H).
IS-MS, m/e 611.0 (m+1).
Analysis for C27H23ClF4N4O4S:
Calc: C, 53.08; H, 3.79; N, 9.17;
Found: C, 53.14; H, 4.06; N, 8.95.
N-(5-Chloropyridin-2-yl)-2-[4-isopropyl-2-(4-oxocyclohexyloxy)benzoylamino]-benzamide (51 mg, 0.10 mmol), ammonium acetate (77 mg, 1 mmol), and sodium cyano-borohydride (6 mg, 0.1 mmol) were dissolved in 0.5 mL of dry. 1:1 MeOH-methylene chloride by brief sonication. The solution was agitated for 24 h at room temperature. The resulting mixture was filtered and the filtrate was washed with MeOH and methylene chloride. The combined filtrates were evaporated to dryness under vacuum. The residue was taken up in methylene chloride-water and the pH was adjusted to 3 with 5 M HCl.
The methylene chloride layer was washed with brine, dried over sodium sulfate, and evaporated in vacuo to give 44 mg of crude product. Chromatography (1 g silica gel column, chloroform (100-80%) and MeOH (0-20%)) gave 16 mg of 2-[2-(4-amino-cyclohexyl)-4-isopropylbenzoylamino]-N-(5-chloropyridin-2-yl)benzamide as a colorless glassy solid.
IS-MS: [m+1]+=507.1, [m−1]−=505.2
Calcd for C28H31ClN4O3: [m+1]+=507.0, [m−1]−=505.0
The methyl 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-fluorobenzoate (7.99 mmol, 22.6 mmol) was diluted with pyrrolidine (18 mL, 215.6 mmol). The resulting mixture was heated to 80° C. After 3 hours, the reaction was cooled to room temperature and quenched with water (50 mL). The mixture was extracted with dichloromethane (200 mL). The organic layer was washed with saturated aqueous citric acid (3×50 mL), dried over sodium sulfate, filtered, and concentrated to a colorless oil (9.14 g, 22.6 mmol, 100%).
1NMR (400 MHz, DMSO-d6): δ 7.59 (d, J=9.2 Hz, 1H); 6.14 (dd, J=2.2, 8.6 Hz, 1H); 6.09 (s, 1H); 4.67 (m, 1H); 3.65 (s, 3H); 3.44-3.23 (m, 8H); 1.91 (s, 4H); 1.74 (m, 2H); 1.64 (m, 2H); 1.37 (s, 9H).
FIA-MS, m/e 405.5 (m+1).
Analysis for C22H32N2O5:
Calc: C, 65.32; H, 7.97; N, 6.93;
Found: C, 65.62; H, 8.00; N, 7.14.
Using methods substantially equivalent to those described in Example 21-D, except that the reaction was heated to 60° C., 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoic acid (6.90 g, 17.7 mmol, 78%) was prepared from methyl-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoate.
1NMR (400 MHz, DMSO-d6): δ 11.47 (br s, 1H); 7.56 (d, J=8.8 Hz, 1H); 6.11 (d, J=8.4 Hz, 1H); 6.05 (s, 1H); 4.64 (m, 1H); 3.44-3.11 (m, 8H); 1.88 (m, 4H); 1.72 (m, 2H); 1.60 (m, 2H); 1.33 (s, 9H).
FIA-MS, m/e 391.3 (m+1).
Analysis for C21H30N2O5:
Calc: C, 64.60; H, 7.74; N, 7.17;
Found: C, 67.23; H, 8.13; N, 7.65.
Using methods substantially equivalent to those described in Example 4-E, methyl 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]benzoate (5.88 g, 11.23 mmol, 81%) was prepared from 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoic acid and methyl 2-aminobenzoate.
IR(CHCl3): 1604, 1515, 1448, 1266 cm−1.
1NMR (300 MHz, DMSO-d6): δ 11.37 (s, 1H); 8.56 (d, J=8.4 Hz, 1H); 7.92 (d, J=7.8 Hz, 1H); 7.72 (d, J=8.7 Hz, 1H); 7.56 (t, J=7.7 Hz, 1H); 7.11 (t, J=7.5 Hz, 1H); 6.23 (d, J=9.0 Hz, 1H); 6.17 (s, 1H); 4.77 (m, 1H); 3.79 (s, 3H); 3.67 (d, J=13.5 Hz, 2H); 3.29 (m, 4H); 3.03 (m, 2H); 1.94 (m, 4H); 1.69 (m, 2H); 1.33 (m, 2H); 1.32 (s, 9H).
IS-MS, m/e 524.5 (m+1).
Analysis for C29H37N3O3:
Calc: C, 66.52; H, 7.12; N, 8.02;
Found: C, 67.11; H, 7.07; N, 8.19.
Using methods substantially equivalent to those described in Example 21-D, 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]benzoic acid (6.34 g, 12.4 mmol, 100%) was prepared from methyl 2-[2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]benzoate.
IR(CHCl3): 1668, 1605, 1514, 1389, 1286 cm−1.
1NMR (300 MHz, DMSO-d6): δ 8.50 (d, J=8.4 Hz, 1H); 7.90 (d, J=7.8 Hz, 1H); 7.57 (d, J=8.4 Hz, 1H); 7.34 (t, J=7.4 Hz, 1H); 6.95 (t, J=7.4 Hz, 1H); 6.18 (d, J=8.7 Hz, 1H); 6.11 (s, 1H); 4.66 (m, 1H); 3.51 (m, 2H); 3.26 (m, 4H); 3.13 (m, 2H); 1.93 (m, 4H); 1.89-1.71 (m, 4H); 1.32 (s, 9H).
IS-MS m/e: 510.4 (m+1).
Analysis for C28H35N3O6:
Calc: C, 65.99; H, 6.92; N, 8.25;
Found: C, 65.76; H, 6.80; N, 8.50.
The 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)-benzoylamino]benzoic acid (about 11.23 mmol) was diluted with methylene chloride (115 mL). DMF (4 drops) and pyridine (1.1 mL, 13.6 mmol) were added, followed by oxalyl chloride (1.1 mL, 12.6 mmol). A precipitate formed immediately. After 2 hours, the reaction was filtered and the filtrate was concentrated in vacuo. The crude residue from the filtrate concentration was purified by flash column chromatography (5% EtOAc/CH2Cl2) to give the desired product (4.83 g, 9.82 mmol, 87%) as a yellow solid.
1NMR (400 MHz, DMSO-d6): δ 8.04 (dd, J=1.6, 7.6 Hz, 1H); 7.84 (t, J=8.6 Hz, 1H); 7.79 (d, J=9.2 Hz, 1H); 7.48 (m, 2H); 6.27 (dd, J=2.0, 8.8 Hz, 1H); 6.19 (s, 1H); 4.82 (m, 1H); 3.45-3.32 (m, 4H); 3.29 (m, 4H); 1.95 (m, 6H); 1.76 (m, 2H); 1.37 (s, 9H).
IS-MS m/e: 492.3 (m+1).
Analysis for C28H33N3O5:
Calc: C, 68.42; H, 6.77; N, 8.55;
Found: C, 68.51; H, 6.57; N, 8.66.
The 2-aminothiazole (245 mg, 2.45 mmol) was diluted with THF (3 mL) and the mixture was cooled to 0° C. A 3.0 M ether solution of methylmagnesium bromide (0.8 mL, 2.4 mmol) was then added. After 20 minutes, this mixture was added via syringe to a solution of 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)phenyl]-4H-3,1-benzoxazin-4-one (299 mg, 0.61 mmol) in THF (3 mL) at 0° C. The flask containing the magnesium salt of 2-aminothiazole was rinsed with THF (1 mL) and the washings were added to the reaction. The reaction was allowed to slowly warm to room temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride (1 mL), diluted with EtOAc (100 mL), and washed with water (2×10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by flash column chromatography (about 35 g silica, 20% EtOAc/CH2Cl2).
The mixed fractions were combined, concentrated, and purified again using flash column chromatography (10% EtOAc/CH2Cl2). The product containing fractions from both purifications were combined, concentrated, and triturated with toluene (3×) to give the desired product (232 mg, 0.39 mmol, 64%) as a white solid.
1NMR (300 MHz, DMSO-d6): δ 8.30 (d, J=8.1 Hz, 1H); 7.81-7.74 (m, 3H); 7.51 (m, 1H); 7.15 (m, 2H); 6.22 (d, J=9.0 Hz, 1H); 6.17 (s, 1H); 4.80 (m, 1H); 3.76 (d, J=12.3 Hz, 2H); 3.29 (m, 4H); 3.02 (m, 2H); 1.94 (m, 8H).
MS-FIA m/e: 592.6 (m+1).
Analysis for C31H37N5O5S:
Calc: C, 62.92; H, 6.30; N, 11.84;
Found: C, 63.22; H, 6.22; N, 11.77.
Using methods substantially equivalent to those described in example 4-G, 2-[2-(piperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]-N-(thiazol-2-yl)benzamide (174 mg, 0.35 mmol, 100%) was prepared from 2-[2-(1-tert-Butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]-N-(thiazol-2-yl)benzamide.
1NMR (400 MHz, DMSO-d6): δ 8.37 (d, J=8.0 Hz, 1H); 7.88 (d, J=7.2 Hz, 1H); 7.72 (t, J=8.8 Hz, 1H); 7.47 (m, 2H); 7.15 (m, 2H); 6.22 (d, J=8.0 Hz, 1H); 6.15 (s, 1H); 4.72 (m, 1H); 3.28 (m, 4H); 2.96 (m, 2H); 2.68 (m, 2H); 1.90 (m, 8H).
MS-FIA m/e: 492.3 (m+1).
Using methods substantially equivalent to those described in example 71-F, 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]-N-(4-methylthiazol-2-yl)benzamide (198 mg, 0.33 mmol, 53%) was prepared from 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)phenyl]-4H-3,1-benzoxazin-4-one and the magnesium salt of 2-amino-4-methylthiazole.
1NMR (400 MHz, DMSO-d6): δ 8.31 (m, 1H); 7.76 (d, J=8.4 Hz, 2H); 7.51 (t, J=7.6 Hz, 1H); 7.14 (t, J=7.2 Hz, 1H); 6.73 (s, 1H); 6.22 (d, J=10.0 Hz, 1H); 6.17 (s, 1H); 4.80 (m, 1H); 3.74 (m, 2H); 3.29 (m, 4H); 3.00 (m, 2H); 2.26 (s, 3H); 1.95 (m, 8H); 1.31 (s, 9H)
IS-MS m/e: 606.4 (m+1).
Analysis for C32H39N5O5S 0.25H2O:
Calc: C, 62.98; H, 6.52; N, 11.48;
Found: C, 62.64; H, 6.31; N, 11.86.
Using methods substantially equivalent to those described in example 4-G, N-(4-methylthiazol-2-yl)-2-[2-(piperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]-benzamide (149 mg, 0.29 mmol, 98%) was prepared from 2-[2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]-N-(4-methylthiazol-2-yl)benzamide.
1NMR (400 MHz, DMSO-d6): δ 8.36 (d, J=7.6 Hz, 1H); 7.88 (d, J=8.8 Hz, 1H); 7.72 (d, J=8.8 Hz, 1H); 7.52 (t, J=8.0 Hz, 1H); 7.15 (t, J=7.6 Hz, 1H); 6.78 (s, 1H); 6.25 (d, J=9.2 Hz, 1H); 6.18 (s, 1H); 4.86 (m, 1H); 3.29 (m, 4H); 3.08 (m, 2H); 2.89 (m, 2H); 2.26 (s, 3H); 2.07-1.94 (m, 8H).
IS-MS m/e: 506.2 (m+1).
Using methods substantially equivalent to those described in Example 4-E, 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(methylthio)benzoylamino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide (1.48 g, 2.35 mmol, 79%) was prepared from N-(5-chloropyridin-2-yl)-2-amino-5-chlorobenzamide and 2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-4-(methylthio)benzoic acid.
1NMR (400 MHz, DMSO-d6): δ 11.35 (s, 1H); 10.95 (s, 1H); 8.41 (d, J=2.8 Hz, 1H); 8.37 (d, J=8.8 Hz, 1H); 8.10 (d, J=9.2 Hz, 1H); 7.91 (d, J=9.2 Hz, 1H); 7.83 (d, J=2.4 Hz, 1H); 7.79 (d, J=8.0 Hz, 1H); 7.60 (d, J=6.6 Hz, 1H); 7.05 (s, 1H); 6.92 (d, J=8.4 Hz, 1H); 4.68 (m, 1H); 3.66 (d, J=13.2 Hz, 2H); 3.02 (m, 2H); 2.47 (s, 3H); 1.95 (m, 2H); 1.86 (m, 2H); 1.32 (s, 9H).
IS-MS m/e: 631.2 (m+1).
Analysis for C30H32Cl2 N4O5S:
Calc: C, 57.05; H, 5.11; N, 8.87;
Found: C, 57.33; H, 5.15; N, 8.61.
Using methods substantially equivalent to those described in Example 4-G, 5-chloro-N-(5-chloropyridin-2-yl)-2-[4-(methylthio)-2-(piperidin-4-yloxy)benzoyl-amino]benzamide (171 mg, 0.32 mmol, 100%) was prepared from 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(methylthio)benzoylamino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide.
1NMR (300 MHz, DMSO-d6): δ 8.42 (s, 1H); 8.40 (d, J=5.4 Hz, 1H); 8.14 (d, J=9.0 Hz, 1H); 7.94 (dd, J=2.6, 8.9 Hz, 1H); 7.83 (d, J=2.4 Hz, 1H); 7.77 (dd, J=2.4, 9.0 Hz, 1H); 7.00 (s, 1H); 6.91 (d, J=8.4 Hz, 1H); 4.68 (m, 1H); 2.81-2.74 (m, 2H); 2.54-2.46 (m, 2H); 2.49 (s, 3H); 1.95-1.81 (m, 2H); 1.65-1.58 (m, 2H).
MS-FIA m/e: 531.1 (m+1).
Analysis for C25H24Cl2 N4O3S:
Calc: C, 56.50; H, 4.55; N, 10.54;
Found: C, 56.78; H, 4.53; N, 10.28.
Using methods substantially equivalent to those described in Example 23, 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(methylsulfinyl)benzoylamino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide (273 mg, 0.42 mmol, 34%) was prepared from 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(methylthio)benzoylamino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide.
1NMR (300 MHz, DMSO-d6): δ 11.35 (s, 1H); 11.02 (s, 1H); 8.41 (d, J=2.4 Hz, 1H); 8.37 (d, J=9.0 Hz, 1H); 8.09 (d, J=8.7 Hz, 1H); 7.91 (m, 3H); 7.63 (dd, J=2.3, 8.9 Hz, 1H); 7.49 (s, 1H); 7.34 (d, J=8.1 Hz, 1H); 4.84 (m, 1H); 3.69 (m, 2H); 3.07 (m, 2H); 2.77 (s, 3H); 1.84 (m, 4H); 1.32 (s, 9H).
IS-MS m/e: 647.4 (m+1).
Analysis for C30H32Cl2 N4O6S:
Calc: C, 55.64; H, 4.98; N, 8.65;
Found: C, 56.03; H, 5.07; N, 8.21.
Using methods substantially equivalent to those described in Example 4-G, 5-chloro-N-(5-chloropyridin-2-yl)-2-[4-(methylsulfinyl)-2-(piperidin-4-yloxy)-benzoylamino]-benzamide (214 mg, 0.39 mmol, 100%) was prepared from 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(methylsulfinyl)benzoylamino]-N-(5-chloropyridin-2-yl)-5-chlorobenzamide.
1NMR (300 MHz, DMSO-d6): δ 8.42 (s, 1H); 8.36 (d, J=8.7 Hz, 1H); 8.11 (d, J=9.0 Hz, 1H); 7.94 (m, 2H); 7.86 (s, 1H); 7.63 (d, J=8.7 Hz, 1H); 7.46 (s, 1H); 7.33 (d, J=8.1 Hz, 1H); 4.75 (m, 1H); 2.88 (m, 2H); 2.76 (s, 3H); 2.64 (m, 2H); 1.89 (m, 2H); 1.70 (m, 2H).
MS-FIA m/e: 547.2 (m+1).
Analysis for C25H24Cl2 N4O4S.0.25H2O:
Calc: C, 54.40; H, 4.47; N, 10.15;
Found: C, 54.34; H, 4.35; N, 9.87.
To the free amine starting material, prepared in a manner similar to that described above, (1.5 g, 2.74 mmol) dissolved in 10% MeOH/CH2Cl2 (15 mL) was added 5 N HCl (0.55 mL, 2.7 mmol). After stirring for 1 h, the mixture was concentrated and vacuum dried to give the title compound as a white solid (1.60 g, quantitative).
IS-MS, m/e: 547 (m+1).
Analysis for C25H24Cl2 N4O4S.HCl.0.25H2O:
Calcd: C, 51.03; H, 4.37; N, 9.52;
Found: C, 50.80; H, 4.09; N, 9.40.
Using methods substantially equivalent to those described in example 25, 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(methylsulfonyl)benzoylamino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide (402 mg, 0.61 mmol, 87%) was prepared from 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(methylthio)benzoylamino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide.
1NMR (400 MHz, DMSO-d6): δ 11.34 (s, 1H); 11.03 (s, 1H); 8.41 (s, 1H); 8.32 (d, J=8.8 Hz, 1H); 8.08 (d, J=8.8 Hz, 1H); 7.97-7.87 (m, 3H); 7.67-7.56 (m, 3H); 4.92 (m, 1H); 3.56 (m, 2H); 3.29 (s, 3H); 3.11 (m, 2H); 1.96-1.87 (m, 4H); 1.32 (s, 9H).
IS-MS m/e: 663.1 (m+1).
Analysis for C30H32Cl2 N4O7S:
Calc: C, 54.30; H, 4.86; N, 8.44;
Found: C, 54.45; H, 5.11; N, 8.15.
Using methods substantially equivalent to those described in Example 4-G, 5-chloro-N-(5-chloropyridin-2-yl)-2-[4-(methylsulfonyl)-2-(piperidin-4-yloxy)-benzoylamino]benzamide (291 mg, 0.52 mmol, 92%) was prepared from 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(methylsulfonyl)benzoylamino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide.
1NMR (300 MHz, DMSO-d6): δ 8.42 (d, J=1.8 Hz, 1H); 8.23 (d, J=9.0 Hz, 1H); 8.09 (d, J=8.7 Hz, 1H); 7.90 (m, 3H); 7.61 (m, 3H); 4.92 (m, 1H); 3.04 (m, 2H); 2.89 (m, 2H); 1.95 (m, 2H); 1.82 (m, 2H).
MS-FIA m/e: 563.2 (m+11).
Analysis for C25H24Cl2 N4O5S—CH2Cl2:
Calc: C, 49.11; H, 3.97; N, 8.48;
Found: C, 49.50; H, 4.06; N, 8.47.
Using methods substantially equivalent to those described in Example 60-I & J, 2-[4-(1-amino-1-methyl)ethyl-2-(piperidin-4-yloxy)benzoylamino]-5-chloro-N-(5-chloro-pyridin-2-yl)benzamide trifluoroacetate (300 mg, 0.34 mmol, 85%) was prepared from methyl 4-[1-(tert-butoxycarbonylamino)-1-methyl]ethyl-2-[1-(tert-butoxycarbonyl)-piperidin-4-yloxy]benzoate and N-(5-chloropyridin-2-yl)-2-amino-5-chlorobenzamide.
1NMR
The product was further purified by RPHPLC, giving 127 mg of the title compound as the hydrochloride salt.
1NMR
Using a procedure analagous to that described in Example 21-C, methyl 4-bromo-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoate (1.7 g, 91%) was prepared from methyl 4-bromo-2-hydroxybenzoate.
1NMR
FD-MS, m/e 416.19
To a solution of methyl 4-bromo-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-benzoate (0.207 g, 0.5 mmol) in 1,2-dimethoxyethane (3 mL) was added 4-chlorophenyl-boronic acid (0.094 g, 0.6 mmol), tetrakis(triphenylphospine)palladium(0) (0.010 g), and 1 M aq potassium phosphate (0.8 mL). The reaction mixture was heated at 80° C. overnight under a nitrogen atmosphere. The reaction was then cooled to room temperature and water (10 mL) and ethyl acetate (50 mL) were added. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×25 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by RPHPLC (ethyl acetate/hexane 1:4) to give 0.190 g (85%) of product.
1NMR
FD-MS, m/e (m+1) 446
A solution of methyl 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(4-chloro-phenyl)benzoate (0.3 g 0.67 mmol) in dioxane (10 mL) and aqueous NaOH (2 g in 10 mL H2O) was heated at reflux for 4 h. The reaction was then cooled to room temperature, acidified to pH 3 with 1 N HCl, and extracted with ethyl acetate (3×50 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 0.293 g of product (100%).
Using a procedure analogous to Example 4-E, 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(4-chlorophenyl)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (0.15 g, 34%) was prepared from 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(4-chlorophenyl)-benzoic acid and N-(5-chloropyridin-2-yl)-2-aminobenzamide.
Using a procedure analogous to Example 57-D, 2-[4-(4-chlorophenyl)-2-(piperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide trifluoroacetate (0.087 g, 69%) was prepared from 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(4-chlorophenyl)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide.
1NMR
FD-MS, m/e 563.33
To a mixture of 1-(tert-butoxycarbonyl)piperazine (11.18 g, 60 mmol) in CH2Cl2 (120 mL) at 0° C. was added 2-nitrobenzoyl chloride (8.0 mL, 60.6 mmol). The reaction was warmed to room temperature and stirred for 2 hours. A solution of 50% satd Na2 CO3 was added and the mixture was extracted with CH2Cl2. The organic layer was washed with satd citric acid and water, dried over MgSO4, and concentrated to a slurry. Ether was added to the mixture and it was filtered to give the desired product as a white solid (16.0 g, 79%).
1NMR (300 MHz, CDCl3): δ 8.21 (d, J=8.4 Hz, 1H), 7.74 (m, 1H), 7.60 (m, 1H), 7.40 (d, 1H), 3.90 (m, 1 h), 3.70 (m, 1H), 3.60 (m, 2H), 3.40 (m, 2H), 3.20 (m, 2H), 1.47 (s, 9H).
IS-MS, m/e: 336 (m+1).
Using a procedure analogous to Example 2-B, 1-(tert-butoxycarbonyl)-4-(2-nitro-benzoyl)piperazine gave 1-(2-aminobenzoyl)-4-(tert-butoxycarbonyl)piperazine as a white solid (12.07 g, 83%).
1NMR
IS-MS, m/e: 306 (m+1).
Using methods substantially equivalent to those described in Example 4-E, 1-(tert-butoxycarbonyl)-4-[2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(methylthio)-benzoylamino]benzoyl]piperazine (1.32 g, 2.02 mmol, 81%) was prepared from 1-(2-aminobenzoyl)-4-(tert-butoxycarbonyl)piperazine and 2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-(4-methylthio)benzoic acid.
1NMR (300 MHz, DMSO-d6): δ 9.98 (s, 1H); 8.03 (d, J=8.1 Hz, 1H); 7.83 (d, J=8.4 Hz, 1H); 7.43 (t, J=7.8 Hz, 1H); 7.33 (t, J=7.8 Hz, 1H); 7.18 (t, J=7.5 Hz, 1H); 7.08 (s, 1H); 6.93 (d, J=8.7 Hz, 1H); 4.83 (m, 1H); 3.78 (d, J=13.2 Hz, 2H); 3.54 (m, 2H); 3.27 (m, 6H); 3.00 (m, 2H); 2.46 (s, 3H); 1.90-1.73 (m, 4H); 1.35 (s, 18H).
IS-MS m/e: 655.5 (m+1).
Analysis for C34H46N4O7S:
Calc: C, 62.36; H, 7.08; N, 8.56;
Found: C, 62.41; H, 6.92; N, 8.31.
Using methods substantially equivalent to those described in Example 4-G, 1-[2-[4-(methylthio)-2-(piperidin-4-yloxy)benzoylamino]benzoyl]piperazine (103 mg, 0.23 mmol, 73%) was prepared from 1-(tert-butoxycarbonyl)-4-[2-[2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-4-(methylthio)benzoylamino]benzoyl]piperazine.
1NMR (300 MHz, DMSO-d6): δ 8.12 (d, J=7.8 Hz, 1H); 7.92 (t, J=8.3 Hz, 1H); 7.83 (d, J=8.4 Hz, 1H); 7.69 (d, J=8.1 Hz, 1H); 7.60 (t, J=7.4 Hz, 1H); 7.07 (s, 1H); 6.99 (d, J=8.4 Hz, 1H); 5.00 (m, 1H); 3.36-3.12 (m, 12H); 2.46 (s, 3H); 2.05 (m, 4H).
IS-MS m/e: 453.9 (m).
Using a procedure analogous to Example 77-B, methyl 2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-4-(thiophen-3-yl)benzoate (0.22 g, 88%) was prepared from methyl 4-bromo-2-(1-tert-butoxycarbonylpiperidine-4-yloxy)benzoate.
1NMR
FD-MS, m/e (+1) 418
Using a procedure analogous to Example 77-C, 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(thiophen-3-yl)benzoic acid (0.202 g, 95%) was prepared from methyl 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(thiophen-3-yl)benzoate.
Using a procedure analogous to Example 4-E, 2-[2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-4-(thiophen-3-yl)benzoylamino]-N-(5-chloropyridin-2-yl)-5-chloro-benzamide (0.220 g, 65%) was prepared from 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(thiophen-3-yl)benzoic acid and N-(5-chloropyridin-2-yl)-2-amino-5-chloro-benzamide.
1NMR
FD-MS, m/e (m+1) 667
Using a procedure analogous to Example 57-D, 5-chloro-N-(5-chloropyridin-2-yl)-2-[2-(piperidin-4-yloxy)-4-(thiophen-3-yl)benzoylamino]benzamide trifluoroacetate (0.096 g, 51%) was prepared from 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(thiophen-3-yl)benzoylamino]-N-(5-chloropyridin-2-yl)-5-chlorobenzamide. The compound was purified by RPHPLC to give the hydrochloride salt.
1NMR
FD-MS, m/e 569.31
Using a procedure analogous to Example 77-B, methyl 2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-4-(4-methoxyphenyl)benzoate (0.208 g, 100%) was prepared from methyl 4-bromo-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoate.
1NMR
FD-MS, m/e (+1) 442.1
Using a procedure analogous to Example 77-C, 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(4-methoxyphenyl)benzoic acid (0.175 g, 87%) was prepared from methyl 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(4-methoxyphenyl)benzoate.
Using a procedure analogous to Example 4-E, 2-[2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-4-(4-methoxyphenyl)benzoylamino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide (0.180 g, 65%) was prepared from 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(4-methoxyphenyl)benzoic acid and N-(5-chloropyridin-2-yl)-2-amino-5-chlorobenzamide.
1NMR
FD-MS, m/e (m+1) 691
Using a procedure analogous to Example 57-D followed by treatment with HCl, 5-chloro-N-(5-chloropyridin-2-yl)-2-[4-(4-methoxyphenyl)-2-(piperidin-4-yloxy)-benzoylamino]benzamide hydrochloride (0.112 g, 72%) was prepared from 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(4-methoxyphenyl)benzoylamino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide.
1NMR
FD-MS, m/e 591.43
Using methods substantially equivalent to those described in Example 60-I-&-J, 2-[4-(1-amino-1-methyl)ethyl-2-(piperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide trifluoroacetate (250 mg, 0.29 mmol, 72%) was prepared from methyl 4-[1-(tert-butoxycarbonylamino)-1-methylethyl]-2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)benzoate and N-(5-chloropyridin-2-yl)-2-amino-5-fluorobenzamide.
1NMR
This product was subjected to reverse phase HPLC to obtain 165 mg of the title compound as the hydrochloride salt.
1NMR
Using methods substantially equivalent to those described in Example 23, 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(methylsulfinyl)benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide (134 mg, 0.21 mmol, 21%) was prepared from 2-[2-(1-tert-butoxycarbonyl-4-(methylthio)piperidin-4-yloxy)benzoylamino]-N-(5-chloro-pyridin-2-yl)-5-fluorobenzamide.
1NMR (300 MHz, DMSO-d6): δ 11.29 (s, 1H); 10.93 (s, 1H); 8.40 (d, J=2.7 Hz, 1H); 8.30 (m, 1H); 8.10 (d, J=9.0 Hz, 1H); 7.93 (m, 3H); 7.65 (dd, J=2.9, 9.2 Hz, 1H); 7.48 (s, 1H); 7.34 (d, J=8.1 Hz, 1H); 4.84 (m, 1H); 3.63 (d, J=12.9 Hz, 2H); 3.13 (m, 2H); 2.76 (s, 3H); 1.95-1.74 (m, 4H); 1.32 (s, 9H).
IS-MS m/e: 631.3 (m+1).
Using methods substantially equivalent to those described in Example 4-G, N-(5-chloropyridin-2-yl)-5-fluoro-2-[4-(methylsulfinyl)-2-(piperidin-4-yloxy)-benzoylamino]benzamide (102 mg, 0.19 mmol, 100%) was prepared from 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(methylsulfinyl)benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide.
1NMR (300 MHz, DMSO-d6): δ 8.42 (d, J=2.1 Hz, 1H); 8.30 (m, 1H); 8.13 (d, J=8.7 Hz, 1H); 7.93 (m, 3H); 7.65 (dd, J=2.7, 9.0 Hz, 1H); 7.45 (s, 1H); 7.32 (d, J=8.1 Hz, 1H); 4.72 (m, 1H); 2.85 (m, 3H); 2.76 (s, 3H); 2.57 (m, 2H); 1.88 (m, 2H); 1.65 (m, 2H).
IS-MS m/e: 531.1 (m+1).
Analysis for C25H24 ClFN4O4S.0.2CH2Cl20.1H2O:
Calc: C, 55.25; H, 4.49; N, 10.15;
Found: C, 55.42; H, 4.81; N, 9.85.
Using a procedure analogous to Example 1-C, methyl 2-hydroxy-4-fluorobenzoate and 3-(tert-butoxycarbonylamino)propanol gave the desired product as a white solid (20.6 g, 84%).
1NMR
IS-MS, m/e: 328 (m+1).
Using a procedure analogous to Example 21-D, 4-fluoro-2-(3-tert-butoxy-carbonylaminopropoxy)benzoic acid was prepared from methyl 4-fluoro-2-(3-tert-butoxycarbonylaminopropoxy)benzoate.
Using a procedure similar to Example 4-E, 2-[4-fluoro-2-(3-tert-butoxycarbonyl-aminopropoxy)benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide (5.1 g, 77%) was prepared from 4-fluoro-2-(3-tert-butoxycarbonylaminopropoxy)benzoic acid and N-(5-chloropyridin-2-yl)-5-fluorobenzamide.
1NMR
FD-MS, m/e 561.19
Analysis for C27H27ClF2N4O5:
Calcd: C, 57.81; H, 4.85; N, 9.99;
Found: C, 58.25; H, 5.32; N, 9.71.
A solution of N-(5-chloropyridin-2-yl)-5-fluoro-2-[4-fluoro-2-(3-tert-butoxycarbonylaminopropoxy)benzoylamino]benzamide (0.4 g, 0.71 mmol) in pyrrolidine (10 mL) was heated at 80° C. for 6 hr. The reaction was concentrated in vacuo and the residue was purified by RPLC (ethyl acetate/hexane 1:4) to give pure product (0.345 g, 79%).
1NMR
FD-MS, m/e 612.23
Using a procedure analogous to Example 57-D, 2-[2-(3-aminopropoxy)-4-(pyrrolidinyl)benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide (0.240 g, 86%) was prepared from 2-[2-(3-tert-butoxycarbonylaminopropoxy)-4-(pyrrolidin-1-yl)-benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide.
1NMR
FD-MS, m/e 512.49
The 2-[4-tert-butyl-2-(piperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide (400 mg, 0.76 mmol) was placed in a screw-top vial and diluted with dry MeOH (15 mL). The vial was purged with nitrogen. Propylene oxide (0.133 mL, 1.91 mmol) was added and the vial was sealed. The reaction was heated at 65° C. for 1.5 h. More propylene oxide (0.133 mL) was added to the reaction and it was heated (sealed) at 80° C. for 2 hours longer. After cooling, the solvents were evaporated in vacuo and the residue was triturated in MeOH (15 mL), filtered, rinsed with diethyl ether, and dried to give desired product as a white solid (396.5 mg, 0.68 mmol, 89%).
1NMR (300 Hz, DMSO-d6): δ 11.25 (s, 1H); 10.83 (s, 1H); 8.4 (s, 1H); 8.35 (m, 1H), 8.13 (d, J=8.9 Hz, 1H); 7.93 (m, 1H); 7.75 (d, J=8.1 Hz, 1H); 7.63 (d, J=11.7 Hz, 1H); 7.41 (t, J=1.9 Hz, 1H), 7.1 (s, 1H); 7.04 (d, J=8.2 Hz, 1H); 4.62 (m, 1H); 4.16 (s, 1H); 3.63 (m, 1H); 2.55 (m, 2H); 2.13 (m, 2H); 2.05 (m, 2H); 1.74-1.87 (m, 4H); 1.25 (s, 9H); 0.94 (d, J=6.0 Hz, 3H) ppm.
IS-MS, 583.2 m/e
Analysis for C31H36 ClFN4O4:
Calcd: C, 63.86; H, 6.22; N, 9.61;
Found: C, 63.56; H, 6.03; N, 9.56.
By methods substantially equivalent to those described in Example 16-A, 5-chloro-N-(5-fluoropyridin-2-yl)-2-nitrobenzamide (4.27 g, 80%) was prepared from 5-chloro-2-nitrobenzoic acid and 2-amino-5-fluoropyridine.
1NMR
IS-MS, m/e 296.2 (m+1)
Analysis for C12H7ClFN3O3:
Calcd: C, 48.75; H, 2.39; N, 14.21;
Found: C, 48.97; H, 2.61; N, 14.13.
By methods substantially equivalent to those described in Example 2-B, 2-amino-5-chloro-N-(5-fluoropyridin-2-yl)benzamide (1.87 g, 88%) was prepared from 5-chloro-N-(5-fluoropyridin-2-yl)-2-nitrobenzamide.
1NMR
IS-MS, m/e 266.0 (m+1)
By methods substantially equivalent to those described in Example 16-F, 2-[4-(tert-butyl)-2-(1-Boc-piperidin-4-yloxy)benzoylamino]-5-chloro-N-(5-fluoropyridin-2-yl)benzamide (0.36 g, 41%) was prepared from 4-(tert-butyl)-2-(1-Boc-piperidin-4-yloxy)benzoyl chloride and 2-amino-5-chloro-N-(5-fluoropyridin-2-yl)benzamide.
1NMR
IS-MS, m/e 625.4 (m+1)
Analysis for C33H38 ClFN4O5:
Calcd: C, 63.40; H, 6.13; N, 8.96;
Found: C, 63.63; H, 6.26; N, 8.69.
To a stirring solution of 2-[4-(tert-butyl)-2-(1-Boc-piperidin-4-yloxy)benzoyl-amino]-5-chloro-N-(5-fluoropyridin-2-yl)benzamide (0.3 g, 0.48 mmol) and anisole (0.26 mL) in dichloromethane (10 mL) was added TFA (1 mL). After 2 h, the solvent was removed in vacuo and the residue was suspended in diethyl ether and concentrated in vacuo twice and then again suspended in diethyl ether with vigorous stirring. The solid was washed with diethyl ether, filtered and dried in vacuo to give 0.28 g (90%) of off-white solid,
1NMR
IS-MS, m/e 525.1 (m+1)
Analysis for C28H30ClFN4O3-TFA:
Calcd: C, 56.39; H, 4.89; N, 8.77; F, 11.89;
Found: C, 56.23; H, 4.90; N, 8.64; F, 12.05.
To a solution of methyl 4-benzyloxy-2-(piperidin-4-yloxy)benzoate (2 g) in methanol (50 mL) was added Pd/C (200 mg). The mixture was stirred under balloon pressure of hydrogen overnight. The catalyst was filtered off and the filtrate was concentrated to provide clean product (1.55 g, 97%).
1NMR
FD-MS, m/e (m−1) 350.1
To a solution of methyl 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-hydroxy-benzoate (0.735 g, 2.1 mmol), triphenylphosphine (0.551 g, 2.1 mmol), and isopropanol (0.158 mL, 2 mmol) in tetrahydrofuran was added diisopropyl azodicarboxylate (0.433 mL, 2.2 mmol) dropwise. The solution was sonicated for 30 minutes. The reaction mixture was purified without workup by RPLC (EtOAc/Hexane 3:7) to give 0.675 g (86%) of pure product.
1NMR
FD-MS, m/e (m+1) 394.1
Using a procedure analogous to Example 77-C, 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-isopropoxybenzoic acid (0.490 g, 100%) was prepared from methyl 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-isopropoxybenzoate.
Using a procedure analogous to Example 4-E, 2-[2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-4-isopropoxybenzoylamino]-N-(5-chloropyridin-2-yl)-5-fluoro-benzamide (0.326 g, 80%) was prepared from 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-isopropoxybenzoic acid and N-(5-chloropyridin-2-yl)-2-amino-5-fluoro-benzamide.
1NMR
FD-MS, m/e 627.34
Analysis for C32H36 ClFN4O6:
Calcd: C, 61.29; H, 5.79; N, 8.93;
Found: C, 61.57; H, 5.88; N, 8.96.
Using a procedure analogous to Example 57-D, N-(5-chloropyridin-2-yl)-5-fluoro-2-[4-isopropoxy-2-(piperidin-4-yloxy)benzoylamino]benzamide (0.246 g, 95%) was prepared from 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-isoproxy-benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide.
1NMR
FD-MS, m/e 527.2
Using a procedure analogous to Example 4-E, 2-[2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-4-(isopropoxy)benzoylamino]-5-chloro-N-(5-chloropyridin-2-yl)-benzamide (0.372 g, 91%) was prepared from 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-isopropoxybenzoic acid and 5-chloro-N-(5-chloropyridin-2-yl)benzamide.
1NMR
FD-MS, m/e 643.33
Using a procedure analogous to Example 57-D, 5-chloro-N-(5-chloropyridin-2-yl)-2-[4-(isopropoxy)-2-(piperidin-4-yloxy)benzoylamino]benzamide (0.295 g, 99%) was prepared from 2-[4-(isopropoxy)-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-benzoylamino]-N-(5-chloropyridin-2-yl)-5-chlorobenzamide.
1NMR
FD-MS, m/e 643.28
Analysis for C27H28Cl2 N4O4:
Calcd: C, 59.67; H, 5.19; N, 10.31;
Found: C, 59.93; H, 4.97; N, 10.23.
The methyl-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(methylthio)benzoate (3.65 g, 9.56 mmol) was dissolved in chloroform (100 mL). After the solution had been cooled to 0° C., mCPBA (7.68 g, 25.81 mmol, 58% purity) was added in portions. After minutes, the reaction was extracted with saturated aqueous sodium bicarbonate (2×50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude material was purified by flash column chromatography (5% EtOAc/CH2Cl2 through 10% EtOAc/CH2Cl2) to give the desired product (2.996 g, 7.25 mmol, 76%).
1NMR (300 MHz, DMSO-d6): δ 7.81 (d, J=8.1 Hz, 1H); 7.63 (s, 1H); 7.52 (d, J=8.1 Hz, 1H); 4.88 (m, 1H); 3.80 (s, 3H); 3.33 (m, 5H); 1.79 (m, 2H); 1.62 (m, 2H).
FIA-MS, m/e 414.2 (m+1).
Using methods substantially equivalent to those described in Example 21-D, 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(methylsulfonyl)benzoic acid (2.79 g, 6.98 mmol, 96%) was prepared from methyl 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(methylsulfonyl)benzoate.
1NMR (300 MHz, DMSO-d6): δ 7.16 (d, J=7.8 Hz, 1H); 7.60 (s, 1H); 7.49 (d, J=7.8 Hz, 1H); 5.72 (m, 1H); 3.39-3.30 (m, 4H); 1.80 (m, 2H); 1.62 (s, 2H).
FIA-MS, m/e 400.1 (m+1).
Analysis for C18H25NO7S:
Calc: C, 54.12; H, 6.31; N, 3.51;
Found: C, 54.13; H, 6.29; N, 3.26.
Using methods substantially equivalent to those described in Example 4-E, 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(methylsulfonyl)benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide (120 mg, 0.19 mmol, 26%) was prepared from 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(methylsulfonyl)benzoic acid and N-(5-chloropyridin-2-yl)-2-amino-5-fluorobenzamide.
1NMR (400 MHz, DMSO-d6): δ 11.28 (s, 1H); 10.94 (s, 1H); 8.41 (d, J=2.0 Hz, 1H); 8.26 (m, 1H); 8.09 (d, J=8.8 Hz, 1H); 7.96 (d, J=8.0 Hz, 1H); 7.91 (m, 1H); 7.67 (s, 1H); 7.57 (d, J=8.4 Hz, 1H); 7.45 (m, 1H); 4.91 (m, 1H); 3.57 (m, 2H); 3.26 (s, 3H); 3.12 (m, 2H); 1.95 (m, 2H); 1.75 (m, 2H); 1.33 (s, 9H).
IS-MS m/e: 647.5 (m+1).
Analysis for C30H32 ClFN4O7S.0.5H2O:
Calc: C, 54.92; H, 5.07; N, 8.54;
Found: C, 54.81; H, 5.19; N, 8.32.
Using methods substantially equivalent to those described in Example 4-G, N-(5-chloropyridin-2-yl)-5-fluoro-2-[4-(methylsulfonyl)-2-(piperidin-4-yloxy)-benzoylamino]benzamide (75 mg, 0.14 mmol, 81%) was prepared from 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(methylsulfonyl)benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide.
1NMR (400 MHz, DMSO-d6): δ 8.42 (d, J=1.8 Hz, 1H); 8.28 (dd, J=5.1, 8.7 Hz, 1H); 8.12 (d, J=9.0 Hz, 1H); 7.93 (d, J=7.8 Hz, 1H); 7.65 (m, 3H); 7.55 (d, J=8.1 Hz, 1H); 7.45 (t, J=6.3 Hz, 1H); 4.76 (m, 1H); 3.29 (s, 3H); 2.82 (m, 2H); 2.54 (m, 2H); 1.89 (m, 2H); 1.62 (m, 2H).
IS-MS m/e: 547.2 (m+1).
By methods substantially analogous to those described in Example 4-E, 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide (6.11 g, 90%) was prepared from 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoic acid and N-(5-chloro-pyridin-2-yl)-2-amino-5-fluorobenzamide.
IR(CHCl3): 1680, 1602, 1504, 1375, 1285 cm−1.
1NMR (300 MHz, DMSO-d6) δ ppm: 11.27 (s, 1H), 10.72 (s, 1H), 8.43 (d, J=2.6 Hz, 1H), 8.30 (dd, J=5.0, 9.4 Hz, 1H), 8.17 (d, J=9.0 Hz, 1H), 7.94 (dd, J=2.6, 9.0 Hz, 1H), 7.78 (d, J=9.0 Hz, 1H), 7.60 (dd, J=2.6, 9.0 Hz, 1H), 7.34 (m, 1H), 6.24 (dd, J=1.8, 9.0 Hz, 1H), 6.18 (d, J=1.8 Hz, 1H), 4.81 (m, 1H), 3.75 (m, 2H), 3.27 (m, 2H), 3.03 (m, 2H) 1.90 (m, 10H), 1.40 (s, 9H).
IS-MS, m/e: 638.2 (m+1).
Analysis for C33H37 ClFN5O5:
Calcd: C, 62.11; H, 5.84; N, 10.97;
Found: C, 61.81; H, 5.70; N, 10.67.
Using procedures described in Example 4-G, N-(5-chloropyridin-2-yl)-5-fluoro-2-[4-(pyrrolidin-1-yl)-2-(piperidin-4-yloxy)benzoylamino]benzamide (3.38 g, 66%) was prepared from 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)-benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide.
IR (CHCl3): 1602, 1504, 1374, 1286 cm−1.
1NMR (300 MHz, DMSO-d6) δ ppm: 10.7 (br s, 1H), 8.43 (d, J=2.6 Hz, 1H), 8.35 (dd, J=5.3, 9.0 Hz, 1H), 8.22 (d, J=8.7 Hz, 1H), 7.97 (dd, J=3.0, 8.7 Hz, 1H), 7.77 (d, J=9.0 Hz, 1H), 7.58 (dd, J=3.0, 9.4 Hz, 1H), 7.39 (m, 1H), 6.24 (dd, J=1.9, 8.7 Hz, 1H), 6.14 (d, J=1.9 Hz, 1H), 4.60 (m, 1H), 3.3 (m, 4H), 2.80 (m, 2H), 2.47 (m, 2H), 1.94 (m, 4H), 1.87 (m, 2H), 1.67 (m, 2H).
IS-MS, m/e: 538 (m+1).
To a solution of N-(5-chloropyridin-2-yl)-5-fluoro-2-[4-(pyrrolidin-1-yl)-2-(piperidin-4-yloxy)benzoylamino]benzamide (1.5 g, 2.74 mmol) and 10%
MeOH:CH2Cl2 (15 mL) was added 5 N HCl (0.55 mL, 2.74 mmol). The reaction was stirred for one hour. It was then concentrated to dryness to yield N-(5-chloropyridin-2-yl)-5-fluoro-2-[2-(piperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]benzamide hydrochloride as a solid (1.6 g, 100%).
IS-MS, m/e: 538.4 (m+1).
Analysis for C28H30Cl2 FN5O3:
Calcd: C, 58.54; H, 5.26; N, 12.19;
Found: C, 58.53; H, 5.35; N, 12.34.
By methods substantially analogous to those described in example 4-E, 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide (260 mg, 35%) was prepared from 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoic acid and N-(5-chloro-pyridin-2-yl)-2-amino-5-chlorobenzamide.
1NMR (300 MHz, DMSO-d6) δ ppm: 11.32 (s, 1H), 10.8 (s, 1H), 8.40 (d, J=2.4 Hz, 1H), 8.34 (d, J=8.9 Hz, 1H), 8.12 (d, J=8.9 Hz, 1H), 7.92 (dd, J=2.4, 8.90 Hz, 1H), 7.75 (m, 2H), 7.54 (dd, J=2.30, 8.9 Hz, 1H), 6.21 (d, J=8.9 Hz, 1H), 6.14 (s, 1H), 4.77 (m, 1H), 3.68 (m, 2H), 3.3 (m, 2H), 3.00 (m, 2H), 1.90 (m, 10H), 1.32 (s, 9H).
IS-MS, m/e: 654.3 (m+1).
Analysis for C33H37Cl2 N5O5:
Calcd: C, 60.55; H, 5.70; N, 10.70;
Found: C, 60.66; H, 5.79; N, 10.40.
Using the procedure described in Example 4-G, 2-[2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide gave 5-chloro-N-(5-chloropyridin-2-yl)-2-[2-(piperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]benzamide (200 mg, 98%).
1NMR (300 MHz, DMSO-d6) δ ppm: 8.40 (m, 2H), 8.18 (d, J=8.9 Hz, 1H), 7.94 (dd, J=2.4, 8.9 Hz, 1H), 7.74 (m, 2H), 7.54 (dd, J=2.4, 8.9 Hz, 1H), 6.21 (d, J=8.9 Hz, 1H), 6.11 (s, 1H), 4.59 (m, 1H), 3.26 (m, 2H), 2.75 (m, 2H), 2.46 (m, 2H), 1.95 (m, 4H), 1.84 (m, 4H), 1.60 (m, 2H).
IS-MS, m/e: 554.21 (m+1).
Analysis for C28H29Cl2 N5O3.0.5H2O:
Calcd: C, 59.69; H, 5.27; N, 12.43;
Found: C, 59.52; H, 5.33; N, 12.07.
A mixture of methyl 4-fluoro-2-hydroxybenzoate (12 g, 70.5 mmol), triphenyl-phosphine (22.2 g, 84.6 mmol), N-methyl-4-hydroxypiperidine (8.1 g, 70.3 mmol) and benzene (25 mL) was heated until all the solids dissolved. The solution was cooled to 0° C., then sonicated while adding diethyl azodicarboxylate (14.7 g, 84.6 mmol) dropwise.
After the addition was complete, the reaction was sonicated for an additional 60 minutes, and then purified by flash chromatography, eluting sequentially with 50% EtOAc in hexanes followed by 1%, 2%, 5% then 10% MeOH in CHCl3, to yield 10.8 g (40.4 mmol, 57%) of an oil.
1NMR
The methyl 4-fluoro-2-(1-methylpiperidin-4-yloxy)benzoate (10.6 g, 40 mmol) was mixed with pyrrolidine (14 g, 200 mmol) and heated at 70° C. for 3 hours, then heated at 100° C. for 1 hour before concentrating under vacuum. The residue was partitioned between EtOAc (100 mL) and saturated aqueous NaHCO3 (100 mL). The aqueous layer was saturated with NaCl and extracted with EtOAc (100 mL). The combined organic layer was dried over MgSO4 and concentrated to 12.5 g of an oil which was purified by flash chromatography, using THF/Hex/Et3 N 20/75/5 then 40/55/5 and finally 60/35/5, to give 11.9 g (37 mmol, 93%) of the desired product as an oil.
1NMR
A mixture of the methyl 2-(1-methylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)-benzoate (11.9 g, 37.4 mmol) and EtOH (100 mL) was treated with a solution of KOH (10.5 g, 187 mmol) in H2O (100 mL). The resulting mixture was heated to reflux for 3 h.
The reaction mixture was neutralized with 5 N HCl (37.4 mL) and concentrated under vacuum. It was mixed with 1 liter 50/50 THF/MeOH and filtered. The filtrate was concentrated to 9.46 g solid (83%).
1NMR
The 2-(1-methylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoic acid (9.3 mg, 30.6 mmol) was mixed with CH2Cl2 (100 mL) then treated with 2 M CH2Cl2 solution of oxalyl chloride (30 mL) at ambient temperature overnight. Subsequently, 3 drops of DMF were added and the reaction was stirred an additional 2 hours. The reaction was concentrated to dryness, mixed with CH2Cl2 (75 mL), then added to a cold solution of methyl 2-amino-5-fluorobenzoate in pyridine (100 mL) and CH2Cl2 (25 mL). The reaction was stirred at 0° C. for 3 hours, concentrated to dryness, then partitioned between water (400 mL) and EtOAc (400 mL). The aqueous layer was extracted with EtOAc (200 mL). The combined organic layer was dried over MgSO4 and concentrated to an oil which was purified by flash chromatography, using THF/Hex/Et3 N 20/75/5 then 40/55/5, to give 7.9 g (17.3 mmol, 57%) of a solid.
1NMR
IS-MS, m/e 456 (m+1)
A solution of methyl 5-fluoro-2-[2-(1-methylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]benzoate (7.8 g, 17 mmol) in EtOH (100 mL) and water (100 mL) was treated with KOH (4.8 g, 85 mmol) and stirred at 70° C. for 1 hour. The reaction was concentrated under vacuum, quenched with glacial acetic acid (5.1 g), and allowed to stand at ambient temperature for crystallization. The solid was filtered to recover 7.4 g (98%).
1NMR
IS-MS, m/e 442 (m+1)
A solution of 5-fluoro-2-[2-(1-methylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)-benzoylamino]benzoic acid (7.4 g, 16.8 mmol) in dry DMF (120 mL) was treated with S1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.42 g, 33.5 mmol). The reaction was stirred at ambient temperature overnight. The mixture was poured into brine (300 mL) and extracted with 10% MeOH in EtOAc (3×100 mL). The combined extracts were washed with water (2×400 mL), then brine (2×400 mL), dried over MgSO4, and concentrated to a solid which was purified by chromatography on silica, using 40/55/5 THF/Hex/Et3 N in hexanes, to give 3.4 g (48%) of a yellow solid.
1NMR
IS-MS 424 (m+)
Analysis for C24H26 FN3O3:
Calcd: C, 66.65; H, 6.29; N, 9.72;
Found: C, 66.73; H, 6.10; N, 9.82.
A solution of 2-fluoroaniline (22.1 mg, 0.18 mmol) in dry THF (1 mL) was treated with a 1 M diethyl ether solution of allyl magnesium bromide (0.2 mL). The reaction was stirred for 5 minutes before adding 6-fluoro-2-[4-(pyrrolidin-1-yl)-2-(1-methylpiperidin-4-yloxy)phenyl]-4H-3,1-benzoxazin-4-one (25 mg, 0.06 mmol) in THF (1 mL). The reaction was stirred overnight at ambient temperature, concentrated to dryness and mixed with saturated aqueous NaHCO3 (1 mL) and CH2Cl2 (2 mL). The mixture was filtered through a plug of diatomaceous earth and treated with an isocyanate resin (methylisocyanate polystyrene HL, 0.360 mmol) overnight. Purification consisted of applying this mixture directly onto a column of silica and eluting with 1% MeOH in CHCl3.
1NMR
IS-MS, m/e 535 (m+1)
The 2-[4-tert-butyl-2-(piperidin-4-yloxy)-benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide (450 mg, 0.86 mmol) was placed in a dry flask and diluted with dry MeOH (0.95 mL). Paraformaldehyde (54.0 mg, 1.8 mmol) and NaCNBH4 (167.0 mg, 2.7 mmol) were added, followed by acetic acid (0.5 mL). The reaction was allowed to stir for 18 h. More paraformaldehyde (54.0 mg), NaCNBH4 (107.0 mg) and acetic acid (1.0 mL) were added, and the reaction was stirred another 18 hrs under N2 at room temperature. The solvents were removed in vacuo, and the residue was diluted with H2O (5.0 mL). The flask was cooled in an ice bath while the pH was adjusted to 8 using saturated sodium bicarbonate. This solution was extracted with EtOAc (5×90 mL). The organics were combined and washed with a saturated solution of sodium bicarbonate and then brine. The organic layer was dried over MgSO4 and the solvents were removed in vacuo to obtain the desired product as a white solid (338.2 mg, 0.63 mmol, 73%).
1NMR (300 Hz, DMSO-d6): δ 11.26 (s, 1H); 10.81 (s, 1H); 8.41 (s, 1H); 8.37 (m, 1H); 8.13 (d, J=9.0 Hz, 1H); 7.92 (d, J=8.8 Hz, 1H); 7.73 (d, J=8.1 Hz, 1H); 7.61 (d, J=9.1 Hz, 1H); 7.43 (t, J=8.3 Hz, 1H); 7.09 (s, 1H); 7.05 (d, J=8.2 Hz, 1H); 4.60 (m, 1H); 2.39 (m, 2H); 1.84-2.01 (m, 5H); 1.73-1.80 (m, 4H); 1.25 (s, 9H) ppm.
IS-MS, 539.3 m/e
Analysis for C29H32 ClFN4O3:
Calcd: C, 64.62; H, 5.98; N, 10.39;
Found: C, 64.39; H, 5.94; N, 10.34.
Using methods substantially equivalent to those described in Example 4-E, 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(dimethylamino)benzoylamino]-N-(5-chloropyridin-2-yl)-5-chlorobenzamide (229 mg, 0.36 mmol, 48%) was prepared from 4-(dimethylamino)-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoic acid and N-(5-chloropyridin-2-yl)-2-amino-5-chlorobenzamide.
1NMR (400 MHz, DMSO-d6): δ 11.32 (s, 1H); 10.79 (s, 1H); 8.41 (d, J=2.4 Hz, 1H); 8.35 (d, J=8.8 Hz, 1H); 8.13 (d, J=9.2 Hz, 1H); 7.91 (dd, J=2.4, 8.8 Hz, 1H); 7.78 (d, J=2.8 Hz, 1H); 7.74 (d, J=9.6 Hz, 1H); 7.56 (d, J=8.8 Hz, 1H); 6.38 (d, J=9.6 Hz, 1H); 6.29 (s, 1H); 4.79 (m, 1H); 3.68 (d, J=12.4 Hz, 2H); 3.00 (m, 2H); 2.96 (s, 6H); 1.88 (m, 2H); 1.80 (m, 2H); 1.32 (s, 9H).
IS-MS m/e: 628.3 (m+1).
Analysis for C31H35Cl2 N5O5:
Calc: C, 59.24; H, 5.61; N, 11.14;
Found: C, 59.06; H, 5.61; N, 11.41.
Using methods substantially equivalent to those described in Example 4-G, 5-chloro-N-(5-chloropyridin-2-yl)-2-[4-(dimethylamino)-2-(piperidin-4-yloxy)-benzoylamino]benzamide (152 mg, 0.29 mmol, 99%) was prepared from 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(dimethylamino)benzoylamino]-N-(5-chlorpyridin-2-yl)-5-chlorobenzamide.
1NMR (300 MHz, DMSO-d6): δ 8.41 (s, 1H); 8.40 (d, J=9.0 Hz, 1H); 8.17 (d, J=9.0 Hz, 1H); 7.94 (dd, J=2.6, 9.3 Hz, 1H); 7.76 (d, J=2.1 Hz, 1H); 7.72 (d, J=6.3 Hz, 1H); 7.55 (dd, J=2.1, 9.0 Hz, 1H); 6.36 (d, J=9.0 Hz, 1H); 6.26 (s, 1H); 4.62 (m, 1H); 2.77 (m, 2H); 2.49 (m, 2H); 1.84 (m, 2H); 1.63 (m, 2H).
IS-MS m/e: 528.1 (m+1).
Analysis for C26H27Cl2 N5O3:
Calc: C, 56.67; H, 5.11; N, 12.47;
Found: C, 56.61; H, 5.01; N, 12.62.
Methyl 2-[2-(tert-butoxycarbonylamino)ethoxy]-4-(methylthio)benzoate was prepared (12.6 g, 76%) as described in Example 21-C from methyl 2-hyroxy-4-(methylthio)benzoate and 2-(tert-butoxycarbonylamino)ethanol.
IR(CHCl3): 1707, 1595, 1249, 1162 cm−1.
1NMR (300 MHz, DMSO-d6) δ ppm: 7.78 (d, J=8.3 Hz, 1H), 7.26 (s, 1H), 6.83 (dd, J=1.5, 8.3 Hz, 1H), 6.78 (d, J=1.5 Hz, 1H), 4.11 (m, 2H), 3.89 (s, 3H), 3.57 (m, 2H), 2.49 (s, 3H), 1.45 (s, 9H).
IS-MS, m/e: 342.1 (m+1).
The methyl 2-[2-(tert-butoxycarbonylamino)ethoxy]-4-(methylthio)benzoate was added to a solution of KOH (9.05 g, 161.2 mmol) in EtOH (200 mL) and H1120 (200 mL).
The reaction was heated to 70° C. for two hours. Ethanol was removed in vacuo, and the remaining aqueous solution was diluted with CH2Cl2 (500 mL) and saturated citric acid (200 mL). The organic layer was partitioned, dried over Na2 SO4, and concentrated to yield 2-[2-(tert-butoxycarbonylamino)ethoxy]-4-(methylthio)benzoic acid (9.1 g, 87%).
IR(CHCl3): 1711, 1597, 1412, 1162 cm−1.
1NMR (300 MHz, DMSO-d6) δ ppm: 8.05 (d, J=8.3 Hz, 1H), 7.26 (s, 1H), 6.93 (dd, J=1.5, 8.3 Hz, 1H), 6.84 (d, J=1.5 Hz, 1H), 5.05 (s, 1H), 4.28 (t, J=5.7 Hz, 2H), 3.62 (dt, J=5.7, 10.9 Hz, 2H), 2.52 (s, 3H), 1.45 (s, 9H).
IS-MS, m/e: 328.2 (m+1).
Analysis for C15H21NO5S:
Calcd: C, 55.03; H, 6.47; N, 4.28;
Found: C, 54.80; H, 6.21; N, 4.50.
2-[2-[2-(tert-Butoxycarbonylamino)ethoxy]-4-(methylthio)benzoylamino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide was prepared by methods described in example 4-E from 2-[2-(tert-butoxycarbonylamino)ethoxy]-4-(methylthio)benzoic acid and N-(5-chloropyridin-2-yl)-2-amino-5-chlorobenzamide (3 g, 92%).
IR (CHCl3): 1665, 1500, 1375, 1296 cm−1.
1 NMR (300 MHz, DMSO-d6) δ ppm: 11.28 (s, 1H), 11.25 (s, 1H), 8.44 (m, 2H), 8.20 (d, J=9.0 Hz, 1H), 7.96 (dd, J=2.6, 9.0 Hz 1H), 7.88 (m, 2H), 7.62 (dd, J=2.6, 9.0 Hz, 1H), 7.07 (s, 1H), 6.96 (dd, J=1.1, 8.3 Hz, 1H), 4.30 (t, J=6.0 Hz, 2H), 3.40 (m, 2H), 2.50 (s, 3H), 1.31 (s, 9H).
IS-MS, m/e: 591.4 (m+1).
Analysis for C27H28Cl2 N4O5S:
Calcd: C, 54.83; H, 4.77; N, 9.47;
Found: C, 54.64; H, 4.78; N, 9.49.
Using the procedure described in example 4-G, 2-[2-[2-(tert-butoxycarbonyl-amino)ethoxy]-4-(methylthio)benzoylamino]-5-chloro-N-(5-chloropyridin-2-yl)-benzamide gave 2-[2-(2-aminoethoxy)-4-(methylthio)benzoylamino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide (200 mg, 87%).
1NMR (300 MHz, DMSO-d6) δ ppm: 8.41 (d, J=1.5 Hz, 1H), 8.31 (d, J=8.9 Hz, 1H), 8.08 (d, J=8.8 Hz, 1H), 7.94 (dd, J=2.7, 9.0 Hz, 1H), 7.82 (m, 2H), 7.59 (dd, J=2.7, 9.0 Hz, 1H), 7.00 (d, J=1.2 Hz, 1H), 6.93 (dd, J=1.2, 8.23 Hz, 1H), 4.27 (m, 2H), 3.27 (s, 3H), 3.0 (m, 2H), 2.51 (s, 3H).
IS-MS, m/e: 491.2 (m+1).
To a mixture of 2-[2-(2-aminoethoxy)-4-(methylthio)benzoylamino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide (1.25 g, 2.47 mmol), paraformaldehyde (312 mg, 10.4 mmol) and methanol (30 mL) was added acetic acid to obtain a pH of 4.0. Sodium cyanoborohydride (311 mg, 4.95 mmol) was added to this mixture. After stirring overnight, the reaction was concentrated, dissolved in 10% MeOH/CHCl3, and passed through an SCX column. The eluent was concentrated and chromatographed on silica gel (1:10 EtOAc:CH2Cl2 to 1:10 MeOH:CH2Cl2) to give impure product. The impure product was dissolved in 5% MeOH/CH2Cl2 and 1 N HCl and stirred for one hour. The mixture was basified with 50% satd sodium carbonate and extracted with CH2Cl2. The organic layer was concentrated and purified by HPLC on a Vydac C18 column [preparative: gradient 20% CH3 CN/(0.01% HCl in H2O) to 80% CH3 CN/(0.01% HCl in H2O) over 6 h on a 5×25 cm column; analytical: 5% CH3 CN/(0.1% TFA in H2O) to 70% CH3 CN/(0.1% TFA in H2O) on a 0.46×25 cm column] to give the title product as a white solid (329 mg, 62%).
1NMR (300 MHz, DMSO-d6) δ ppm: 11.34 (s, 1H), 11.06 (s, 1H), 10.34 (s, 1H), 8.47 (d, J=2.6 Hz, 1H), 8.39 (d, J=9.0 Hz, 1H), 8.11 (d, J=9.0 Hz, 1H), 7.98 (dd, J=2.6, 8.7 Hz, 1H), 7.89 (d, J=2.6 Hz, 1H), 7.84 (d, J=8.3 Hz, 1H), 7.64 (dd, J=2.6, 9.0 Hz, 1H), 7.07 (d, J=1.5 Hz, 1H), 7.01 (dd, J=1.5, 8.3 Hz, 1H), 4.66 (t, J=4.9 Hz, 2H), 3.61 (m, 2H), 2.78 (s, 6H), 2.56 (s, 3H).
IS-MS, m/e: 519.2 (m+1).
Analysis for C24H25Cl2 N4O3S—HCl:
Calcd: C, 51.85; H, 4.53; N, 10.08;
Found: C, 51.82; H, 4.42; N, 9.87.
2-[2-[2-(tert-Butoxycarbonylamino)ethoxy]-4-(methylthio)benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide was prepared by methods described in Example 4-E from 2-[2-[2-(tert-butoxycarbonylamino)ethoxy]-4-(methylthio)benzoic acid and N-(5-chloropyridin-2-yl)-2-amino-5-fluorobenzamide (2.80 g, 89%).
1NMR (300 MHz, DMSO-d6) δ ppm: 11.21 (s, 1H), 11.12 (s, 1H), 8.44 (d, J=2.6 Hz, 1H), 8.36 (dd, J=4.9, 9.0 Hz, 1H), 8.21 (d, J=9.0 Hz, 1H), 7.96 (dd, 2.6, 8.7 Hz, 1H), 7.88 (d, 8.3 Hz, 1H), 7.66 (dd, J=3.0, 9.0 Hz, 1H), 6.94 (dt, J=1.5, 8.3 Hz, 1H), 7.06 (s, 1H), 6.96 (m, 2H), 4.29 (t, J=6.0 Hz, 2H), 3.42 (m, 2H), 2.55 (s, 3H), 1.31 (s, 9H).
IS-MS, m/e: 575.2 (m+1).
Analysis for C27H28 ClFN4O5S:
Calcd: C, 56.39; H, 4.91; N, 9.74;
Found: C, 56.17; H, 4.78; N, 10.02.
Using the procedure described in Example 4-G, 2-[4-methylmercapto-2-(2-tert-butoxycarbonylaminoethoxy)benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide gave 2-[2-(2-aminoethoxy)-4-(methylthio)benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide (190 mg, 85%).
1NMR
IS-MS, m/e: 475.1 (m+1).
Analysis for C22H20ClFN4O3S:
Calcd: C, 55.64; H, 4.24; N, 11.80;
Found: C, 55.62; H, 4.17; N, 11.72.
To a solution of 2-[2-[2-(tert-butoxycarbonylamino)ethoxy]-4-(methylthio)-benzoylamino]-N-(5-chloropyridin-2-yl)-5-chlorobenzamide (893 mg, 1.51 mmol), camphorsulfonic acid (92 mg, 0.40 mmol) and CHCl3 (8.5 mL) was added tert-butyl hydroperoxide (0.30 mL, 3.02 mmol). After stirring overnight, the mixture was chromatographed (10% EtOAc/CH2Cl2 to 10% MeOH/CH2Cl2) to give the desired product as a white solid (517 mg, 56%).
1NMR (300 MHz, DMSO-d6) δ ppm: 11.27 (s, 1H), 8.44 (d, J=2.6 Hz, 1H), 8.39 (d, J=8.7 Hz, 1H), 8.18 (d, J=9.0 Hz, 1H), 8.07 (d, J=8.7 Hz, 1H), 7.94 (dd, J=2.6, 8.7 Hz, 1H), 7.90 (d, J=2.2 Hz, 1H), 7.64 (dd, J=2.6, 8.7 Hz, 1H), 7.49 (d, J=1.1 Hz, 1H), 7.39 (dd, J=1.1, 8.7 Hz, 1H), 4.30 (m, 2H), 3.41 (m, 2H), 2.81 (s, 3H), 1.29 (s, 9H).
IS-MS, m/e: 607.2 (m+1).
Analysis for C27H28Cl2 N4O6S:
Calcd: C, 53.38; H, 4.65; N, 9.22;
Found: C, 53.31; H, 4.46; N, 9.31.
Using the procedure described in example 4-G, 2-[2-[2-(tert-butoxycarbonyl-amino)ethoxy)-4-methylsulfinylbenzoylamino]-N-(5-chloropyridin-2-yl)-5-chloro-benzamide gave 2-[2-(2-aminoethoxy)-4-methylsulfinylbenzoylamino]-N-(5-chloro-pyridin-2-yl)-5-chlorobenzamide (381 mg, 98%).
1NMR
IS-MS, m/e: 507.0 (m+1).
Analysis for C22H20Cl2 N4O4S:
Calcd: C, 52.08; H, 3.97; N, 11.04;
Found: C, 51.90; H, 3.93; N, 10.90.
Using a procedure analogous to Example 96-A, 2-[2-[2-(tert-butoxycarbonyl-amino)ethoxy]-4-(methylthio)benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluoro-benzamide gave 2-[2-(2-tert-butoxycarbonylaminoethoxy)-4-methylsulfinyl-benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide (485 mg, 54%).
1NMR (300 MHz, DMSO-d6) δ ppm: 11.19 (s, 1H), 11.14 (s, 1H), 8.44 (d, J=2.6 Hz, 1H), 8.31 (dd, J=5.3, 9.0 Hz, 1H), 8.19 (d, J=9.0 Hz, 1H), 8.05 (d, J=7.9 Hz, 1H), 7.94 (dd, J=2.6, 9.0 Hz, 1H), 7.69 (dd, J=2.6, 9.0 Hz, 1H), 7.48 (d, J=1.1 Hz, 1H), 7.45 (dd, J=2.6, 7.9 Hz, 1H), 7.36 (d, J=1.1 Hz, 1H), 6.95 (m, 1H), 4.30 (m, 2H), 3.42 (m, 2H), 2.80 (s, 3H), 1.29 (s, 9H).
IS-MS, m/e: 591.4 (m+1).
Analysis for C27H28 ClFN4O6S:
Calcd: C, 54.87; H, 4.77; N, 9.48;
Found: C, 54.83; H, 4.73; N, 9.62.
Using the procedure described in example 4-G, 2-[2-(2-tert-butoxycarbonylamino-ethoxy)-4-methylsulfinylbenzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide gave 2-[2-(2-aminoethoxy)-4-methylsulfinylbenzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide (330 mg, 87%).
1NMR
IS-MS, m/e: 491.2 (m+1).
Analysis for C22H20ClFN4O4S:
Calcd: C, 52.86; H, 4.23; N, 11.21;
Found: C, 52.51; H, 3.88; N, 10.99.
Using methods substantially equivalent to those described in Example 4-E & 4-G, 2-[4-(dimethylamino)-2-(piperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide (158 mg, 0.31 mmol, 100%) was prepared from 2-(1-tert-butoxy-carbonylpiperidin-4-yloxy)-4-(dimethylamino)benzoic acid and N-(5-chloropyridin-2-yl)-2-amino-5-fluorobenzamide.
1NMR (400 MHz, DMSO-d6): δ 10.67 (br s, 2H); 8.41 (d, J=2.0 Hz, 1H); 8.31 (dd, J=4.8, 9.2 Hz, 1H); 8.18 (d, J=9.2 Hz, 1H); 7.94 (dd, J=2.8, 8.8 Hz, 1H); 7.73 (d, J=9.2 Hz, 1H); 7.57 (dd, J=3.0, 9.0 Hz, 1H); 7.37 (dt, J=2.8, 9.2 Hz, 1H); 6.36 (dd, J=2.2, 9.0 Hz, 1H); 6.27 (d, J=2.0 Hz, 1H); 4.65 (m, 1H); 2.95 (s, 6H); 2.82 (m, 2H); 2.54 (m, 2H); 1.87 (m, 2H); 1.67 (m, 2H); 1.07 (s, 1H).
IS-MS m/e: 512.5 (m+1).
Analysis for C26H27 ClFN5O3.0.75H2O:
Calc: C, 59.43; H, 5.47; N, 13.33;
Found: C, 59.14; H, 5.23; N, 13.21.
A mixture of methyl 4-fluoro-2-[3-(tert-butoxycarbonylamino)propoxy]benzoate (8.148 g, 25 mmol) and pyrrolidine (20.87 mL, 250 mmol) was purged with nitrogen and heated to 80° C. for 3 hours. The reaction was concentrated in vacuo. After diluting with EtOAc, the mixture was cooled to 0° C., acidified with satd citric acid, and extracted with EtOAc. The organic layer was washed with satd citric acid and water, dried (Na2 SO4), and concentrated. The resulting residue was absorbed onto silica gel and chromatographed (20% EtOAc/hexane to 35% EtOAc/hexane). The resulting product was triturated with Et2O/hexane to give the desired product as a white solid (9.05 g, 99%).
1NMR (300 MHz, CDCl3) δ ppm: 7.85 (d, J=8.7 Hz, 1H), 6.24 (d, J=8.7 Hz, 1H), 6.20 (s, 1H), 4.19 (t, J=5.7 Hz, 0.4H), 4.12 (t, J=5.7 Hz, 1.6H), 3.90 (m, 0.7H), 3.84 (s, 2.3H), 3.77 (m, 0.8H), 3.41 (m, 3.2H), 2.25 (m, 0.8H), 2.08 (m, 3.2H), 1.45 (s, 9H).
IS-MS, m/e: 379.1 (m+1).
Using a procedure analogous to Example 21-D, methyl 2-[3-(tert-butoxycarbonyl-amino)propoxy]-4-(pyrrolidin-1-yl)benzoate gave the desired product as a white solid (7.65 g, 88%).
1NMR (300 MHz, CDCl3) δ ppm: 7.97 (d, J=8.7 Hz, 1H); 6.30 (dd, J=1.8, 8.7 Hz, 1H), 6.13 (s, 1H), 4.82 (br s, 1H), 4.24 (t, J=6.3 Hz, 2H), 3.37 (m, 6H), 2.11 (m, 6H), 1.43 (s, 9H).
IS-MS, m/e: 365.1 (m+1).
Analysis for C19H28N2O5:
Calcd: C, 61.86; H, 7.79; N, 7.59;
Found: C, 61.79; H, 7.57; N, 7.51.
Using methods substantially equivalent to those described in Example 4-E, 2-[3-(tert-butoxycarbonylamino)propoxy]-4-(pyrrolidin-1-yl)benzoylamino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide (1.60 g, 2.54 mmol, 34%) was prepared from 2-[3-(tert-butoxycarbonylamino)propoxy]-4-(pyrrolidin-1-yl)benzoic acid and N-(5-chloropyridin-2-yl)-2-amino-5-chlorobenzamide.
1NMR (400 MHz, DMSO-d6): δ 11.27 (s, 1H); 11.00 (s, 1H); 8.43 (m, 2H); 8.14 (d, J=8.4 Hz, 1H); 7.96 (d, J=8.8 Hz, 1H); 7.78 (m, 2H); 7.54 (d, J=8.8 Hz, 1H); 6.80 (m, 1H); 6.22 (d, J=8.8 Hz, 1H); 6.07 (s, 1H); 4.23 (t, J=6.2 Hz, 2H); 3.29 (m, 4H); 2.95 (m, 2H); 1.95 (m, 4H); 1.86 (m, 2H); 1.31 (s, 9H).
IS-MS m/e: 628.4 (m+1).
Analysis for C31H35Cl2 N5O5. 0.30H2O:
Calc: C, 58.73; H, 5.66; N, 11.05;
Found: C, 58.36; H, 5.25; N, 10.71.
Using methods substantially equivalent to those described in Example 4-G, 2-[2-(3-aminopropoxy)-4-(pyrrolidin-1-yl)-benzoylamino]-N-(5-chloropyridin-2-yl)-5-chlorobenzamide (1.56 g, 2.96 mmol, 100%) was prepared from 2-[3-(tert-butoxy-carbonylamino)propoxy]-4-(pyrrolidin-1-yl)benzoylamino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide.
1NMR (400 MHz, DMSO-d6): δ 8.44 (d, J=1.6 Hz, 1H); 8.41 (d, J=8.8 Hz, 1H); 8.10 (d, J=8.8 Hz, 1H); 7.96 (dd, J=2.4, 9.2 Hz, 1H); 7.78 (d, J=9.2 Hz, 1H); 7.56 (dd, J=1.6, 10.4 Hz, 1H); 6.24 (d, J=8.0 Hz, 1H); 6.11 (s, 1H); 4.32 (t, J=4.8 Hz, 2H); 3.29 (m, 4H); 2.86 (m, 2H); 2.05 (m, 2H); 1.94 (m, 4H).
Analysis for C26H27Cl2 N5O3.155CH2Cl2:
Calc: C, 51.50; H, 4.47; N, 10.32;
Found: C, 51.22; H, 4.14; N, 10.47.
The 4-isopropyl-2-methoxymethoxybenzoic acid (5.3 g, 23.6 mmol) was dissolved in methylene chloride (75 mL) and MeOH (75 mL). Acetyl chloride (1 mL) was added to generate HCl. The reaction mixture was stirred for 2 h. The reaction was washed with water (2×150 mL), dried (MgSO4), and concentrated under vacuum. The crude product was dissolved in methylene chloride (100 mL) and MeOH (30 mL), and to this solution a 2 M hexane solution of trimethylsilyldiazomethane (11.8 mL, 23.6 mmol) was added dropwise. After 1 h, the solvent was removed under vacuum, giving the title compound as an oil.
1NMR
The methyl 4-isopropyl-2-hydroxybenzoate (4.4 g, 22.7 mmol) was dissolved in THF (100 mL). Then 3-hydroxymethyl-N-tert-butoxycarbonylpiperidine (4.88 g, 22.7 mmol) and triphenylphosphine (7.14 g, 27.24 mmol) were added. The mixture was placed in an ice bath, and then diisopropyl azodicarboxylate (4.59 g, 22.7 mmol) in methylene chloride (15 mL) was added dropwise. The reaction mixture was allowed to warm gradually to room temperature. After 16 h, the solvent was removed under vacuum. The solid residue was subjected directly to flash chromatography on silica (0 to 30% EtOAc in hexane gradient), giving the title compound (3.34 g, 43% yield) as an oil.
1NMR
The methyl 2-(1-tert-butoxycarbonypiperidin-3-ylmethoxy)-4-isopropylbenzoate (1.53 g, 3.90 mmol) was dissolved in THF (15 mL) and LiOH.H2O (0.36 g, 8.58 mmol) in water (5 mL) was added. The mixture was heated at 65° C. for 24 h. The reaction mixture was concentrated in vacuo and redissolved in a mixture of EtOAc (100 mL) and cold dilute HCl. The mixture was shaken in a separatory funnel. The layers were separated and the organic layer was washed with cold water (100 mL), dried (MgSO4), and concentrated to give 1.23 g of the title compound as an oil.
1NMR
Using methods substantially equivalent to those described in Example 60-I and J, 5-chloro-N-(5-chloropyridin-2-yl)-2-[4-isopropyl-2-(piperidin-3-ylmethoxy)-benzoylamino]benzamide trifluoroacetate (150 mg, 0.20 mmol, 6%) was prepared from 2-(N-tert-butoxycarbonylpiperidin-3-yl)-4-isopropylmethoxybenzoic acid and N-(5-chloropyridin-2-yl)-2-amino-5-chlorobenzamide. This product was subjected to reverse phase HPLC to obtain 60 mg of the title compound as the hydrochloride salt.
1NMR
Using methods substantially equivalent to those described in example 60-I & J, 2-[4-isopropyl-2-(piperidin-3-yl-methoxy)benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide hydrochloride (92 mg, 0.15 mmol, 14%) was prepared from 4-isopropyl-2-(N-tert-butoxycarbonylpiperidin-3-yl)methoxybenzoic acid and N-(5-chloropyridin-2-yl)-2-amino-5-fluorobenzamide after reverse phase HPLC purification.
1NMR
To a solution of 2-[2-(2-tert-butoxycarbonylaminoethoxy)-4-(methylthio)-benzoylamino]-N-(5-chloropyridin-2-yl)-5-chlorobenzamide (414 mg, 0.70 mmol) and CHCl3 (10 mL), at 0° C., was added mCPBA (567 mg, 1.91 mmol). After stirring for 30 minutes, Ca(OH)2 (249 mg, 3.36 mmol) was added. The reaction was warmed to room temperature and filtered. The filtrate was concentrated and chromatographed (10% EtOAc/CH2Cl2) to give the desired product as a white solid (340 mg, 78%).
1NMR (300 MHz, DMSO-d6) δ ppm: 11.27 (s, 1H), 8.44 (d, 2.3 Hz, 1H), 8.35 (d, J=9.0 Hz, 1H), 8.18 (d, J=9.0 Hz, 1H), 8.07 (d, J=7.9 Hz, 1H), 7.95 (dd, J=2.6, 8.7 Hz, 1H), 7.90 (d, J=2.6 Hz, 1H), 7.70 (s, 1H), 7.67 (dd, J=2.6, 8.7 Hz, 1H), 7.61 (dd, J=1.5, 8.3 Hz, 1H), 6.94 (m, 2H), 4.34 (m, 2H), 3.42 (m, 2H), 3.29 (s, 3H), 1.29 (s, 9H).
IS-MS, m/e: 623.3 (m+1).
Analysis for C27H28Cl2 N4O7S:
Calcd: C, 52.01; H, 4.53; N, 8.99;
Found: C, 52.20; H, 4.42; N, 8.85.
Using the procedure described in Example 4-G, 2-[2-(2-tert-butoxycarbonyl-aminoethoxy)-4-methylsulfonylbenzoylamino]-5-chloro-N-(5-chloropyridin-2-yl)-benzamide gave 2-[2-(2-aminoethoxy)-4-methylsulfonylbenzoylamino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide (220 mg, 89%).
1NMR (300 MHz, DMSO-d6) δ ppm: 8.42 (d, J=2.6 Hz, 1H), 8.28 (d, J=9.0 Hz, 1H), 8.12 (d, J=9.0 Hz, 1H), 8.01 (d, J=7.9 Hz, 1H), 7.94 (dd, J=2.6, 9.0 Hz, 1H), 7.88 (d, J=2.6 Hz, 1H), 7.67 (d, J=1.5 Hz, 1H), 7.62 (m, 2H), 6.80 (br s, 2H), 4.28 (t, J=5.6 Hz, 2H), 3.28 (s, 3H), 2.94 (t, J=5.6 Hz, 2H).
S-MS, nim/e: 523.1 (m+1).
Analysis for C22H20Cl2 N4O5S:
Calcd: C, 50.49; H, 3.85; N, 10.70;
Found: C, 50.23; H, 3.73; N, 10.46.
Using a procedure analogous to Example 102-A, 2-[2-(2-tert-butoxycarbonyl-aminoethoxy)-4-(methylthio)benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide gave 2-[2-(2-tert-butoxycarbonylaminoethoxy)-4-methylsulfonylbenzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide (370 mg, 87%).
1NMR (300 MHz, DMSO-d6) δ ppm: 11.18 (s, 1H), 11.14 (s, 1H), 8.44 (d, J=2.3 Hz, 1H), 8.27 (dd, J=5.0, 9.0 Hz, 1H), 8.18 (d, J=9.0 Hz, 1H), 8.05 (d, J=7.9 Hz, 1H), 7.96 (d, J=2.3, 9.0 Hz, 1H), 7.70 (m, 2H), 7.60 (dd, J=1.5, 7.9 Hz, 1H), 7.45 (m, 1H), 6.96 (m, 1H), 4.33 (m, 2H), 3.43 (m, 2H), 3.28 (s, 3H), 1.30 (s, 9H).
IS-MS, m/e: 607.2 (m+1).
Analysis for C27H28 ClFN4O7S:
Calcd: C, 53.42; H, 4.65; N, 9.23;
Found: C, 53.30; H, 4.78; N, 9.17.
Using the procedure described in example 4-G, 2-[2-(2-tert-butoxycarbonylamino-ethoxy)-4-methylsulfonylbenzoylamino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide gave 2-[2-(2-aminoethoxy)-4-methylsulfonylbenzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide (25 mg, 88%).
1NMR
IS-MS, m/e: 507.1 (m+1).
Analysis for C22H20ClFN4O5S:
Calcd: C, 52.13; H, 3.98; N, 11.05;
Found: C, 52.20; H, 3.96; N, 10.93.
Using methods substantially equivalent to those described in Example 91-G, and isolating the product as a salt by evaporating an ethanolic HCl solution, 5-fluoro-2-[2-(1-methylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]-N-(pyridin-2-yl)-benzamide hydrochloride was prepared from 6-fluoro-2-[2-(1-methylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)phenyl]-4H-3,1-benzoxazin-4-one and 2-aminopyridine.
1NMR
IS-MS 518 (m+1)
Methyl 2-(3-tert-butoxycarbonylaminopropoxy)-4-(methylthio)benzoate (7.0 g, 82%) was obtained as described in Example 21-C from methyl 2-hydroxy-4-(methylthio)-benzoate and 3-(tert-butoxycarbonylamino)propanol.
1NMR (300 MHz, DMSO-d6) δ ppm: 7.82 (d, J=8.3 Hz, 1H), 6.80 (m, 2H), 6.0 (s, 1H), 4.11 (t, 5.3 Hz, 2H), 3.88 (s, 3H), 3.42 (m, 2H), 2.50 (s, 3H), 2.05 (m, 2H), 1.44 (s, 9H).
IS-MS, m/e: 356.4 (m+1).
Analysis for C17H25NO5S:
Calcd: C, 57.44; H, 7.09; N, 3.94;
Found: C, 57.41; H, 7.04; N, 4.24.
Using a procedure analogous to Example 94-B, methyl 2-(3-tert-butoxycarbonyl-aminopropoxy)-4-(methylthio)benzoate gave 2-(3-tert-butoxycarbonylaminopropoxy)-4-(methylthio)benzoic acid (6.04 g, 93%).
1NMR (300 MHz, DMSO-d6) δ ppm: 8.03 (d, J=8.3 Hz, 1H), 6.92 (dd, J=1.5, 8.3 Hz, 1H), 6.83 (d, 1.5 Hz, 1H), 4.85 (m, 1H), 4.27 (t, J=6.4 Hz, 2H), 3.35 (m, 2H), 2.52 (s, 3H), 2.10 (m, 2H), 1.42 (s, 9H).
IS-MS, m/e: 342.1 (m+1).
Analysis for C16H23NO5S:
Calcd: C, 56.29; H, 6.79; N, 4.10;
Found: C, 56.33; H, 6.49; N, 4.38.
2-[2-(3-tert-Butoxycarbonylaminopropoxy)-4-(methylthio)benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide was prepared by methods described in Example 4-E from 2-(3-tert-butoxycarbonylaminopropoxy)-4-(methylthio)benzoic acid and N-(5-chloropyridin-2-yl)-2-amino-5-fluorobenzamide (1.53 g, 47%).
1NMR (300 MHz, DMSO-d6).8 ppm: 11.22 (s, 1H), 11.02 (s, 1H), 8.44 (d, J=2.6 Hz, 1H), 8.36 (m, 1H), 8.15 (d, J=9.0 Hz, 1H), 7.97 (dd, J=2.6, 9.0 Hz, 1H), 7.86 (d, J=8.3 Hz, 1H), 7.65 (dd, J=3.0, 9.4 Hz, 1H), 7.44 (m, 1H), 6.95 (m, 2H), 6.82 (m, 1H), 4.27 (t, 6.4 Hz, 2H), 3.02 (m, 2H), 2.53 (s, 3H), 1.90 (m, 2H), 1.33 (s, 9H).
IS-MS, m/e: 589.2 (m+1).
Analysis for C28H30ClFN4O5S:
Calcd: C, 57.09; H, 5.13; N, 9.51;
Found: C, 56.95; H, 5.09; N, 9.45.
Using the procedure described in Example 4-G, 2-[2-(3-tert-butoxycarbonyl-aminopropoxy)-4-(methylthio)benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluoro-benzamide gave 2-[2-(3-aminopropoxy)-4-(methylthio)benzoylamino]-N-(5-chloro-pyridin-2-yl)-5-fluorobenzamide (206 mg, 92%).
1NMR
IS-MS, m/e: 489.5 (m+1).
2-[2-(3-tert-Butoxycarbonylaminopropoxy)-4-(methylthio)benzoylamino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide was prepared by methods described in Example 4-E from 2-(3-tert-butoxycarbonylaminopropoxy)-4-(methylthio)benzoic acid and N-(5-chloropyridin-2-yl)-2-amino-5-chlorobenzamide (1.63 g, 49%).
1NMR (300 MHz, DMSO-d6) 5 ppm: 11.29 (s, 1H), 11.10 (s, 1H), 8.41 (s, 1H), 8.11 (d, J=9.0 Hz, 1H), 7.94 (dd, J=2.4, 9.0 Hz, 1H), 7.83 (d, J=9.0 Hz, 1H), 7.59 (dd, J=2.4, 9.0 Hz, 1H), 7.17 (m, 2H), 6.93 (m, 2H), 6.79 (m, 1H), 4.23 (t, J=6.3 Hz, 2H), 2.94 (m, 2H), 2.50 (s, 3H), 1.84 (m, 2H), 1.29 (s, 9H).
IS-MS, m/e: 605.2 (m+1).
Analysis for C28H30Cl2 N4O5S:
Calcd: C, 55.54; H, 4.99; N, 9.25;
Found: C, 55.81; H, 5.01; N, 9.50.
Using the procedure described in Example 4-G, 2-[2-(3-tert-butoxycarbonyl-aminopropoxy)-4-(methylthio)benzoylamino]-5-chloro-N-(5-chloropyridin−2-yl)-benzamide gave 2-[2-(3-aminopropoxy)-4-(methylthio)benzoylamino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide (199 mg, 87%).
1NMR
IS-MS, m/e: 505.1 (m+1).
Analysis for C23H22Cl2 N4O3S:
Calcd: C, 54.66; H, 4.39; N, 11.09;
Found: C, 54.96; H, 4.44; N, 10.96.
Using a procedure analogous to Example 102-A, 2-[2-(3-tert-butoxycarbonyl-aminopropoxy)-4-(methylthio)benzoylamino]-5-chloro-N-(5-chloropyridin-2-yl)-benzamide gave 2-[2-(3-tert-butoxycarbonylaminopropoxy)-4-methylsulfonyl-benzoylamino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide (307 mg, 69%).
1NMR (300 MHz, DMSO-d6) δ ppm: 11.26 (s, 1H), 11.11 (s, 1H), 8.41 (d, J=1.8 Hz, 1H), 8.29 (d, J=8.7 Hz, 1H), 8.09 (d, J=8.7 Hz, 1H), 7.94 (m, 2H), 7.85 (s, 1H), 7.60 (m, 3H), 6.80 (m, 1H), 4.25 (t, J=6.0 Hz, 2H), 3.29 (s, 3H), 2.97 (m, 2H), 1.85 (m, 2H), 1.28 (s, 9H).
IS-MS, m/e: 637.1 (m+1).
Analysis for C28H30Cl2 N4O7S:
Calcd: C, 52.75; H, 4.74; N, 8.79;
Found: C, 52.63; H, 4.85; N, 8.70.
Using a procedure analogous to Example 4-G, 2-[2-(3-tert-butoxycarbonylamino-propoxy)-4-methylsulfonylbenzoylamino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide gave 2-[2-(3-aminopropoxy)-4-methylsulfonylbenzoylamino]-5-chloro-N-(5-chloro-pyridin-2-yl)benzamide (232 mg, 100%).
1NMR
IS-MS, m/e: 537.2 (m+1).
Using a procedure analogous to Example 102-A, 2-[2-(3-tert-butoxycarbonyl-aminopropoxy)-4-(methylthio)benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluoro-benzamide gave 2-[2-(3-tert-butoxycarbonylaminopropoxy)-4-methylsulfonylbenzoyl-amino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide (328 mg, 75%).
1NMR (300 MHz, DMSO-d6) 5 ppm: 11.19 (s, 1H), 11.00 (s, 1H), 8.41 (d, J=1.8 Hz, 1H), 8.21 (m, 1H), 8.10 (d, J=9.0 Hz, 1H), 7.94 (m, 2H), 7.85 (s, 1H), 7.60 (m, 3H), 7.41 (m, 1H), 6.82 (m, 1H), 4.25 (m, 1H), 3.29 (s, 3H), 2.98 (m, 2H), 1.87 (m, 2H), 1.28 (s, 9H).
IS-MS, m/e: 621.5 (m+1).
Analysis for C28H30ClFN4O7S:
Calcd: C, 54.15; H, 4.87; N, 9.02;
Found: C, 54.75; H, 5.05; N, 9.27.
Using a procedure analogous to Example 4-G, 2-[2-(3-tert-butoxycarbonylamino-propoxy)-4-methylsulfonylbenzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide gave 2-[2-(3-aminopropoxy)-4-methylsulfonylbenzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide (242 mg, 95%).
1NMR
IS-MS, m/e: 521.2 (m+1).
Using a procedure analogous to Example 96-A, 2-[2-(3-tert-butoxycarbonyl-aminopropoxy)-4-(methylthio)benzoylamino]-5-chloro-N-(5-chloropyridin-2-yl)-benzamide gave 2-[2-(3-tert-butoxycarbonylaminopropoxy)-4-methylsulfinylbenzoyl-amino]-N-(5-chloropyridin-2-yl)-5-chlorobenzamide (437 mg, 70%).
1NMR (300 MHz, DMSO-d6) δ ppm: 11.29 (s, 1H), 11.17 (s, 1H), 8.44 (d, J=2.6 Hz, 1H), 8.37 (d, J=9.0 Hz, 1H), 8.13 (d, J=9.0 Hz, 1H), 8.02 (d, J=8.3 Hz, 1H), 7.96 (dd, J=2.6, 9.0 Hz, 1H), 7.88 (d, J=2.6 Hz, 1H), 7.64 (dd, J=2.6, 8.3 Hz, 1H), 7.46 (s, 1H), 7.36 (d, J=1.5 Hz, 1H), 6.81 (m, 1H), 4.28 (t, J=6.4 Hz, 2H), 3.00 (m, 2H), 2.79 (s, 3H), 1.91 (m, 2H), 1.32 (s, 9H).
IS-MS, m/e: 621.5 (m+1).
Analysis for C28H30Cl2 N4O6S:
Calcd: C, 54.11; H, 4.87; N, 9.01;
Found: C, 54.36; H, 4.86; N, 8.97.
Using a procedure analogous to Example 4-G, 2-[2-(3-tert-butoxycarbonylamino-propoxy)-4-methylsulfinylbenzoylamino]-N-(5-chloropyridin-2-yl)-5-chlorobenzamide gave 2-[4-methylsulfinyl-2-(3-aminopropoxy)benzoylamino]-N-(5-chloropyridin-2-yl)-5-chlorobenzamide (308 mg, 92%).
1NMR
IS-MS, m/e: 521.2 (m+1).
Using a procedure analogous to Example 96-A, 2-[2-(3-tert-butoxycarbonyl-aminopropoxy)-4-(methylthio)benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluoro-benzamide gave 2-[2-(3-tert-butoxycarbonylaminopropoxy)-4-methylsulfinylbenzoyl-amino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide (519 mg, 75%).
1NMR (300 MHz, DMSO-d6) δ ppm: 11.21 (s, 1H), 11.05 (s, 1H), 8.44 (d, J=2.6 Hz, 1H), 8.30 (m, 1H), 8.15 (d, J=9.0 Hz, 1H), 8.02 (d, J=7.9 Hz, 1H), 7.96 (dd, J=2.6, 8.7 Hz, 1H), 7.67 (dd, J=3.0, 9.0 Hz, 1H), 7.46 (m, 2H), 7.36 (dd, J=1.1, 8.3 Hz, 1H), 6.80 (m, 1H), 4.27 (t, J=6.4 Hz, 2H), 3.02 (m, 2H), 2.79 (s, 3H), 1.91 (m, 2H), 1.32 (s, 9H).
IS-MS, m/e: 605.3 (m+1).
Analysis for C28H30ClFN4O6S:
Calcd: C, 55.58; H, 5.00; N, 9.26;
Found: C, 55.46; H, 4.94; N, 9.36.
Using a procedure analogous to Example 4-G, 2-[2-(3-tert-butoxycarbonylamino-propoxy)-4-methylsulfinylbenzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide gave 2-[2-(3-aminopropoxy)-4-methylsulfinylbenzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide (355 mg, 88%).
1NMR
IS-MS, m/e: 505.1 (m+1).
By methods substantially equivalent to those described in Example 16-A, N-(pyridin-2-yl)-5-chloro-2-nitrobenzamide (8.6 g, 42%) was prepared from 5-chloro-2-nitrobenzoic acid and 2-aminopyridine.
1NMR
IS-MS, m/e 278.0 (m+1)
Analysis for C12H8ClN3O3:
Calcd: C, 51.91; H, 2.90; N, 15.13;
Found: C, 52.53; H, 2.85; N, 15.05.
By methods substantially equivalent to those described in Example 2-B, N-(pyridin-2-yl)-2-amino-5-chlorobenzamide (2.4 g, 67%) was prepared from N-(pyridin-2-yl)-5-chloro-2-nitrobenzamide.
1NMR
IS-MS, m/e 248.3 (m+1)
Analysis for C12H10ClN3O:
Calcd: C, 58.19; H, 4.07; N, 16.96;
Found: C, 58.39; H, 4.07; N, 17.08.
By methods substantially equivalent to those described in Example 16-F, 2-[4-(tert-butyl)-2-(1-Boc-piperidin-4-yloxy)benzoylamino]-5-chloro-N-(pyridin-2-yl)-benzamide (0.44 g, 57%) was prepared from 4-(tert-butyl)-2-(1-Boc-piperidin-4-yloxy)-benzoyl chloride and N-(pyridin-2-yl)-2-amino-5-chlorobenzamide.
1NMR
IS-MS, m/e 607.3 (m+1)
Analysis for C33H39ClN4O5:
Calcd: C, 65.28; H, 6.47; N, 9.23;
Found: C, 65.21; H, 6.64; N, 8.93.
By methods substantially equivalent to those described in Example 85-D, 2-[4-(tert-butyl)-2-(piperidin-4-yloxy)benzoylamino]-5-chloro-N-(pyridin-2-yl)-benzamide hydrochloride (0.16 g, 73%) was prepared from 2-[4-(tert-butyl)-2-(1-Boc-piperidin-4-yloxy)benzoylamino]-5-chloro-N-(pyridin-2-yl)benzamide. The product was purified by preparative RPHPLC, eluting with a gradient of 20% through 40% acetonitrile in 0.05% aq HCl, over 180 min.
1NMR
IS-MS, m/e 507.2 (m+1)
Analysis for C28H32ClN4O3.0.7HCl.0.7TFA.H2O:
Calcd: C, 55.93; H, 5.65; N, 8.87; Cl, 9.55; F, 6.32;
Found: C, 55.53; H, 5.28; N, 8.92; Cl, 9.04; F, 6.12.
By methods substantially equivalent to those described in Example 16-A, N-(5-methylpyridin-2-yl)-5-chloro-2-nitrobenzamide (11.4 g, 53%) was prepared from 5-chloro-2-nitrobenzoic acid and 2-amino-5-methylpyridine.
IS-MS, m/e 292.0 (m+1)
Analysis for C13H10ClN3O3:
Calcd: C, 53.53; H, 3.46; N, 14.40;
Found: C, 53.76; H, 3.41; N, 14.35.
By methods substantially equivalent to those described in Example 2-B, N-(5-methylpyridin-2-yl)-2-amino-5-chlorobenzamide (2.4 g, 67%) was prepared from N-(5-methylpyridin-2-yl)-5-chloro-2-nitrobenzamide.
1NMR
IS-MS, m/e 262.0 (m+1)
Analysis for C13H12ClN3O:
Calcd: C, 59.66; H, 4.62; N, 16.06;
Found: C, 59.89; H, 4.57; N, 15.99.
By methods substantially equivalent to those described in Example 16-F, 2-[4-(tert-butyl)-2-(1-Boc-piperidin-4-yloxy)benzoylamino]-5-chloro-N-(5-methyl-pyridin-2-yl)benzamide (0.50 g, 76%) was prepared from 4-(tert-butyl)-2-(1-Boc-piperidin-4-yloxy)benzoyl chloride and N-(5-methylpyridin-2-yl)-2-amino-5-chloro-benzamide.
1NMR
IS-MS, m/e 621.5 (m+1)
Analysis for C34H41ClN4O5:
Calcd: C, 65.74; H, 6.65; N, 9.02;
Found: C, 66.00; H, 6.80; N, 8.80.
By methods substantially equivalent to those described in Example 16-G, 2-[4-(tert-butyl)-2-(piperidin-4-yloxy)benzoylamino]-5-chloro-N-(5-methylpyridin-2-yl)-benzamide hydrochloride (0.17 g, 40%) was prepared from 2-[4-(tert-butyl)-2-(1-Boc-piperidin-4-yloxy)benzoylamino]-5-chloro-N-(5-methylpyridin-2-yl)benzamide. The product was purified by preparative RPHPLC, eluting with a gradient of 20% through 40% acetonitrile in 0.05% aq HCl, over 180 min.
1NMR
IS-MS, m/e 521.3 (m+1)
Analysis for C29H34ClN4O3.1.7HCl1.5H2O:
Calcd: C, 57.00; H, 6.38; N, 9.17; Cl, 15.67;
Found: C, 57.08; H, 6.00; N, 9.29; Cl, 15.55.
To a stirred solution of 3-hydroxyacetophenone (20.40 g, 150 mmol) in CH2Cl2 (450 mL) at 0° C. under N2 was added N,N-diisopropylethylamine (52.25 mL, 300 mmol) followed by methyl chloromethyl ether (MOM chloride) (13.67 mL, 180 mmol) over a period of 30 min. The reaction was stirred at 0° C. for 30 min and then at room temperature for 2 h. The reaction was quenched with H2O (500 mL). The organic solution was separated, washed with H2O (2×500 mL), 0.5 N NaOH (2×100 mL), and again with H1120 (200 mL). The organic solution was dried (Na2 SO4) and concentrated. The resulting residue was purified by filtration through a pad of silica gel using n-hexanes through 2-5% EtOAc/n-hexanes to give the desired product (17.30 g, 64%); TLC
Rf: 0.45 (20% EtOAc/n-hexanes).
1H NMR (400 MHz, CDCl3): δ 7.62 (dd, 1H, J=1.6 and 8.4 Hz); 7.59 (d, 1H, J=1.6 Hz); 7.38 (t, 1H, J=6 Hz); 5.23 (s, 2H); 3.49 (s, 3H); 2.60 (s, 3H).
IS-MS (m/e): 180 (m)
Analysis for C10H12O3:
Calcd: C, 66.65; H, 6.71;
Found: C, 67.73; H, 6.87.
A mixture of 3-(acetyl)phenyl methoxymethyl ether (3.6 g, 20 mmol), ethylene glycol (3.72 g, 60 mmol) and pyridinium tosylate (0.075 g, 0.3 mmol, 3 mol %) in benzene (200 mL) was azeotropically refluxed for 8 h. The reaction was concentrated and the resulting residue was diluted with ethyl ether (150 mL) and washed with saturated aqueous bicarbonate (2×50 mL) and brine (100 mL). The ethyl ether solution was dried (K2 CO3) and concentrated. The residue was suspended in n-hexanes and the by-product was precipitated. The n-hexane solution was then separated and concentrated to obtain the desired product (2.69 g, 61%); TLC Rf: 0.5 (30% EtOAc/n-hexanes).
1H NMR (400 MHz, CDCl3): δ 7.33 (t, 1H, J=7.6 Hz); 7.22 (ddd, 1H, J=1.6, 2.4 and 7.6 Hz); 7.19 (bs, 1H); 7.06 (dd, 1H, J=1.2 and 8.0 Hz); 5.26 (s, 2H); 4.10 (m, 2H); 3.86 (m, 2H); 3.56 (s, 3H); 1.73 (s, 3H).
IS-MS (m/e): 225 (m+1)
Analysis for C12H1604:
Calcd: C, 64.27; H, 7.19;
Found: C, 64.46; H, 7.09.
A dry reaction flask equipped with a magnetic stirring bar and a rubber septum was charged with methoxymethyl 3-(2-methyl-1,3-dioxolan-2-yl)phenyl ether (4.75 g, 21.20 mmol) and ethyl ether (85 mL). The solution was placed under N2 and cooled to −10° C. Then tert-BuLi (1.7 M in pentane, 14.96 mL, 25.45 mmol) was added over a period of 25 min. After the reaction had stirred for 3.5 h, CO2 gas was bubbled in for 15 minutes, during which the precipitate color changed from yellow to faint yellow. The resulting reaction was stirred at room temperature for 3 h, diluted with ethyl ether (100 mL), filtered, washed with ethyl ether (2×50 mL) and dried to obtain the desired lithium salt (5.25 g, 90%).
1H NMR (400 MHz, D2O): δ 7.23 (d, 1H, J=8 Hz); 7.03 (d, 1H, J=0.8 Hz); 7.00 (d, 1H, J=8 Hz); 5.08 (s, 2H); 3.93 (m, 2H); 3.71 (m, 2H); 3.31 (s, 3H); 1.51 (s, 3H).
IS-MS (m/e): 275 (m+1)
Analysis for C13H15 LiO6:
Calcd: C, 56.95; H, 5.51;
Found: C, 55.92, H, 5.37.
To a suspension of lithium 2-(methoxymethoxy)-4-(2-methyl-1,3-dioxolan-2-yl)-benzoate (0.08 g, 0.29 mmol) in CH2Cl2 (2 mL) at 0° C. was added DMF (2 drops) followed by oxalyl chloride (0.025 mL, 0.29 mmol). Vigorous bubbling occurred. The reaction was stirred at room temperature for 30 min and then the solvent was removed under reduced pressure. The residue was suspended in CH2Cl2 (10 mL) and cooled to 0° C. Pyridine (0.07 mL, 0.87 mmol) and N-(5-chloropyridiri-2-yl)-2-aminobenzamide (0.072 g, 0.29 mmol) were added and the reaction was stirred at room temperature for 6 h. The reaction was quenched with H2O:EtOAc (10 mL each) and extracted with EtOAc (3×30 mL). The organic solution was washed with 2 NHC (cold), H2O (10 mL), 2 N NaOH (cold) and H2O (10 mL), dried (Na2 SO4), and concentrated. The resulting residue was purified by silica gel flash chromatography (n-hexanes through 30% EtOAc/n-hexanes) to obtain the desired product (0.110 g, 76%); TLC Rf: 0.42 (40% EtOAc/n-hexanes).
1H NMR (400 MHz, CDCl3): δ 11.61 (s, 1H); 8.80 (s, 1H); 8.71 (d, 1H, J=7.6 Hz); 8.25 (d, 1H, J=8.8 Hz); 8.17 (d, 2H, J=8.4 Hz); 7.70 (dd, 1H, J=2.4 and 8.8 Hz); 7.61 (dd, 1H, J=1.6 and 7.6 Hz); 7.52 (dt, 1H, J=1.6 and 7.2 Hz); 7.39 (d, 1H, 1.2 Hz); 7.21 (dd, 1H, J=1.2 and 8 Hz); 7.11 (dt, 1H, J=1.2 and 7.2 Hz); 5.49 (s, 2H); 4.03 (m, 2H); 3.77 (m, 2H); 3.51 (s, 3H); 1.64 (s, 3H).
IS-MS (m/e): 498 (m)
Analysis for C25H24ClN3O6:
Calcd: C, 60.30; H, 4.86; N, 8.44;
Found: C, 60.20; H, 5.00; N, 8.15.
To a solution of N-(5-chloropyridin-2-yl)-2-[2-(methoxymethoxy)-4-(2-methyl-1,3-dioxolan-2-yl)benzoylamino]benzamide (4.37 g, 8.78 mmol) in THF (150 mL) at 0° C. was added 5 N HCl (28 mL, 140 mmol). The resulting solution was stirred at room temperature for 6 h. The solution was concentrated to the half of its original volume, diluted with H2O (300 mL) and basified with 2 N NaOH (˜pH 9). The solid obtained was filtered, washed with H2O (3×50 mL), and dried to give the expected product (3.82 g, 96%),
TLC Rf: 0.38 (40% EtOAc/n-hexanes).
1H NMR (400 MHz, CDCl3): δ 11.79 (s, 1H); 8.75 (d, 1H, J=8.4 Hz); 8.54 (bs, 1H); 8.28 (d, 2H, J=8.4 Hz); 7.86 (d, 1H, J=1.2 Hz); 7.74-7.57 (m, 5H); 7.21 (t, 1H, J=7.2 Hz); 5.48 (s, 2H); 3.26 (s, 3H); 2.60 (s, 3H).
IS-MS (m/e):454 (m)
Analysis for C23H20ClN3O5:
Calcd: C, 60.86; H, 4.44; N, 9.26; Cl, 7.81;
Found: C, 61.04; H, 4.33; N, 9.25; Cl, 8.40.
A mixture of 2-[4-acetyl-2-(methioxymethoxy)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (2.4 g, 5.28 mmol) and 3 Å molecular sieves (5 g) was evacuated for 15 min under N2. Methanol and methylene chloride (90 mL each) were added. The reaction mixture was refluxed for 6 h and then cooled to room temperature. After the addition of NaCNBH3 (0.331 g, 5.28 mmol) the reaction mixture was stirred at 60° C. for 4-6 h and then at room temperature for 16 h. The reaction was filtered through a pad of diatomaceous earth and concentrated. The resulting residue was dissolved in CH2Cl2 (200 mL) and extracted with 2 N HCl (cold) (3×100 mL). The aqueous acidic solution was then basified with 2 N NaOH (about pH 9), extracted with EtOAc (5×100 mL), dried (Na2 SO4) and concentrated to give the requisite product (1.4 g, 60%), TLC Rf: 0.36 (2 N NH3/MeOH in CH2Cl2).
1H NMR (400 MHz, CDCl3): δ 11.62 (s, 1H); 8.73 (d, 1H, J=8 Hz); 8.55 (s, 1H); 8.24 (d, 1H, J=8.8 Hz); 8.23 (s, 1H); 8.16 (d, 1H, J=8.0 Hz); 7.70 (dd, 1H, J=2.4 and 8.8 Hz); 7.61 (dd, 1H, J=1.6 and 7.6 Hz); 7.54 (dt, 1H, J=1.6 and 8.8 Hz); 7.29 (s, 1H); 7.17-7.09 (m, 2H); 5.51 (s, 2H); 41.19 (m, 1H); 3.51 (s, 3H).
IS-MS (m/e): 454 (m)
To a solution of 2-[4-(1-aminoethyl)-2-(methoxymethoxy)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (0.205 g, 0.45 mmol) in CH2Cl2 (4.1 mL) was added trifluoroacetic acid (4.1 mL) followed by H2O (4.1 mL). The reaction was stirred at room temperature for 20-30 min. Then the volatile solvent was removed under a reduced pressure and the residue was diluted with H2O (20 mL) and carefully neutralized with solid NaHCO3. The aqueous solution was extracted with EtOAc (5×25 mL), dried (Na2 SO4) and concentrated to afford the expected product (0.180 g, 97%), TLC Rf: 0.36 (5% 2 N NH3/MeOH in CH2Cl2).
1H NMR (400 MHz, CD3OD): δ 8.44 (d, 1H, J=8.0 Hz); 8.31 (d, 1H, J=2.4 Hz); 8.23 (d, 1H, J=8.8 Hz); 7.93 (d, 1H, J=8.8 Hz); 7.86-7.82 (m, 2H); 7.59 (dt, 1H, J=2.0 and 8.8 Hz); 7.29 (dt, 1H, J=0.8 and 7.6 Hz); 7.00 (m, 2H); 4.39 (q, 1H, J=7.2 Hz); 1.58 (d, 3H, J=6.8 Hz).
IS-MS (m/e): 411 (m+1) and 409 (m−1) H. Wang's Resin-linked 2-[4-(1-aminoethyl)-2-hydroxybenzoylamino]-N-(5-chloro-pyridin-2-yl)benzamide
To a screw-capped vial was placed Wang-p-nitrophenyl carbonate resin (0.173 g, 1.43 mmol/g, 0.243 mmol), 2-[4-(1-aminoethyl)-2-hydroxybenzoylamino]-N-(5-chloro-pyridin-2-yl)benzamide (0.102 g, 0.292 mmol) and CH2Cl2:NMP (1 mL each), followed by N,N-diisopropylethylamine (0.084 mL, 0.486 mmol). The vial was capped well and shaken for 2 days. The resulting resin was filtered using a fritted funnel, washed with CH2Cl2, THF, MeOH (3×10 mL, each) and dried to afford the desired resin (0.217 g, 1.38 mmol/g).
A vial which was equipped with a sintered glass filter was charged with Wang's resin-linked 2-[4-(1-aminoethyl)-2-(hydroxy)benzoylamino]-N-(5-chloropyridin-2-yl)-benzamide (1.38 mmol/g, 0.150 g, 0.207 mmol), Ph3P (0.271 g, 1.035 mmol), 3-hydroxy-methyl-1-tert-butoxycarbonylpiperidine (0.222 g, 1.035 mmol) and THF (14 mL). The resulting mixture was shaken well and to it was added diethylisopropylamine (0.203 mL, 1.035 mmol). The vial was capped and shaken for 4 days. The resin was filtered, washed with THF, CH2Cl2 and MeOH (3×5 mL, each) and further treated with trifluoroacetic acid and CH2Cl2 (1 mL, each) at room temperature for 30 min. After the filtration, the resin was washed with CH2Cl2 (3×4 mL) and the filtrate was collected and concentrated. The resulting trifluoroacetate salt was purified by preparative RPHPLC using acetonitrile and 0.1% aqueous TFA to yield the title product (24.3 mg).
MS (m/e): 508 (m+1), 506 (m−1) 1H NMR (400 MHz, CD3OD): δ 8.40 (d, 1H, J=8.4 Hz); 8.35 (bs, 1H); 8.11 (d, 1H, J=8.8 Hz); 7.92 (d, 1H, J=8.0 Hz); 7.84 (dt, 2H, J=2.4 and 8.8 Hz); 7.60 (dt, 1H, J=1.6 and 8.4 Hz); 7.35 (bs, 1H); 7.30 (dt, 1H, J=1.2 and 7.6 Hz); 7.17 (d, 1H, J=7.6 Hz); 4.53 (m, 1H); 4.30 (m, 1H); 4.22 (m, 1H); 3.55 (m, 1H); 3.35 (m, 2H); 2.92 (m, 1H); 2.80 (m, 1H); 2.50 (m, 1H); 1.90 (m, 2H); 1.63 (d, 3H, 6.4 Hz); 1.47 (m, 1H).
Using methods substantially equivalent to those described in Example 91-G, 5-fluoro-N-(5-methylisoxazol-3-yl)-2-[2-(1-methylpiperidin-4-ylxy)-4-(pyrrlidin-1-yl)-benzoylamino]benzamide was prepared from 6-fluoro-2-[2-(1-methylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)phenyl]-4H-3,1-benzoxazin-4-one and 3-amino-5-methylisoxazole.
1NMR
IS-MS, m/e 522 (m+1)
Using methods substantially equivalent to those described in Example 4-F, methyl 2-[3-(tert-butoxycarbonylamino)propoxy]-4-(morpholin-4-yl)benzoate (2.39 g, 6.06 mmol, 16%) was prepared from methyl 2-[3-(tert-butoxycarbonylamino)propoxy]-4-fluorobenzoate and morpholine.
1NMR (300 MHz, DMSO-d6): δ 7.60 (d, J=9.0 Hz, 1H); 6.84 (m, 1H); 6.50 (d, J=9.0 Hz, 1H); 6.46 (s, 1H); 3.98 (t, J=5.9 Hz, 2H); 3.68 (m, 4H); 3.22 (m, 4H); 3.10 (q, J=6.3 Hz, 2H); 1.79 (t, J=6.3 Hz, 2H); 1.33 (s, 9H).
IS-MS, m/e 395.2 (m+1).
Analysis for C20H30N2O6:
Calc: C, 60.90; H, 7.67; N, 7.10;
Found: C, 60.61; H, 7.45; N, 7.08.
The methyl 2-[3-(tert-butoxycarbonylamino)propoxy]-4-(morpholin-4-yl)benzoate (2.34 g, 5.93 mmol) was diluted with ethanol (60 mL) and water (60 mL). Potassium hydroxide pellets (1.64 g, 29.2 mmol) were added and the resulting mixture was heated to 70° C. After 2 hours, the reaction was concentrated in vacuo. The residue was diluted with methylene chloride (200 mL) and extracted with saturated aqueous citric acid (2×50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to give the desired product (2.24 g, 5.90 mmol, 99%).
1NMR (300 MHz, DMSO-d6): δ 7.59 (d, J=8.7 Hz, 1H); 6.85 (m, 1H); 6.49 (m, 2H); 4.00 (t, J=5.9 Hz, 2H); 3.68 (m, 4H); 3.21 (m, 4H); 3.07 (m, 2H); 1.79 (t, J=6.2 Hz, 2H); 1.33 (s, 9H).
IS-MS m/e: 381.4 (m+1).
Using a procedure analogous to Example 4-C, 2-[3-(tert-butoxycarbonylamino)-propoxy]-4-(morpholin-4-yl)benzoic acid and N-(5-chloropyridin-2-yl)-2-amino-5-fluorobenzamide gave the desired product as a solid (2.56 g, 70%).
1NMR
IS-MS, m/e: 628.2 (m+1).
2-[2-(3-Aminopropoxy)-4-(morpholin-4-yl)benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide was prepared by methods described in example 4-G from 2-[2-[3-(tert-butoxycarbonylamino)propoxy]-4-(morpholin-4-yl)benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide (1.82 g, quant.).
1NMR (300 MHz, DMSO-d6) δ ppm: 8.41 (m, 2H), 8.16 (d, J=9.0 Hz, 1H), 7.98 (dd, J=2.6, 9.0 Hz, 1H), 7.83 (d, J=2.6 Hz, 1H), 7.60 (dd, J=2.6, 9.0 Hz, 1H), 7.40 (m, 1H), 6.33 (m, 2H), 4.29 (t, J=6.4 Hz, 2H), 3.73 (m, 4H), 3.27 (m, 4H), 2.57 (t, J=6.4 Hz, 2H), 1.80 (m, 2H).
IS-MS, m/e: 528.1 (m+1).
Using methods substantially equivalent to those described in Example 91-G, except using potassium t-butoxide as the base and isolating the product as a salt by evaporating an ethanolic HCl solution, N-(5-chloropyrimidin-2-yl)-5-fluoro-2-[2-(1-methylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]benzamide hydrochloride was prepared from 6-fluoro-2-[4-(pyrrolidin-1-yl)-2-(1-methylpiperidin-4-yloxy)phenyl]-4H-3,1-benzoxazin-4-one and 2-amino-5-chloropyrimidine.
1NMR
IS-MS, m/e 553 (m+1)
Using methods substantially equivalent to those described in Example 116, 5-fluoro-2-[2-(1-methylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]-N-[4-(methylthio)phenyl]benzamide hydrochloride was prepared from 6-fluoro-2-[2-(1-methylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)phenyl]-4H-3,1-benzoxazin-4-one and 4-(methylthio)aniline.
1NMR
IS-MS, m/e 563 (m+1)
Using methods substantially equivalent to those described in Example 91-G, except using potassium t-butoxide as the base; N-(3,4-dichlorophenyl)-5-fluoro-2-[2-(1-methylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]benzamide was prepared from 6-fluoro-2-[2-(1-methylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)phenyl]-4H-3,1-benzoxazin-4-one and 3,4-dichloroaniline.
1NMR
IS-MS, m/e 585 (m+)
Using methods substantially equivalent to those described in Example 116, N-(4-chloro-2-methylphenyl)-5-fluoro-2-[2-(1-methylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]benzamide hydrochloride was prepared from 6-fluoro-2-[2-(1-methyl-piperidin-4-yloxy)-4-(pyrrolidin-1-yl)phenyl]-4H-3,1-benzoxazin-4-one and 4-chloro-2-methylaniline.
1NMR
IS-MS, m/e 565 (m+)
Using methods substantially equivalent to those described in Example 116, 5-fluoro-2-[2-(1-methylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]-N-(5-trifluoromethylpyridin-2-yl)benzamide hydrochloride was prepared from 6-fluoro-2-[2-(1-methylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)phenyl]-4H-3,1-benzoxazin-4-one and 2-amino-5-(trifluoromethyl)aniline.
1NMR
IS-MS, m/e 586 (m+1)
Using methods substantially equivalent to those described in Example 118, N-(2,4-dichlorophenyl)-5-fluoro-2-[2-(1-methylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)-benzoylamino]benzamide was prepared from 6-fluoro-2-[2-(1-methylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)phenyl]-4H-3,1-benzoxazin-4-one and 2,4-dichloroaniline.
1NMR
IS-MS, m/e 585 (m+)
Using methods substantially equivalent to those described in Example 118, 5-fluoro-2-[2-(1-methylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]-N-(2,4,6-tri-chlorophenyl)benzamide was prepared from 6-fluoro-2-[2-(1-methylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)phenyl]-4H-3,1-benzoxazin-4-one and 2,3,5-trichloroaniline.
1NMR
IS-MS, m/e 621 (m+2)
Using the procedure described in Example 4-G, 2-[4-fluoro-2-(1-tert-butoxy-carbonylpiperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide yielded the title compound as a solid.
IR(CHCl3): 1675, 1504, 1374, 1177 cm−1; 1H-NMR (400 MHz, DMSO-d6): δ 11.17 (s, 1H); 10.95 (s, 1H); 8.43 (s, 1H); 8.35 (m, 1H); 8.27 (d, J=8.0 Hz, 1H); 8.10 (d, J=9.2 Hz, 1H); 7.93 (d, J=8.8 Hz, 1H); 7.81 (d, J=7.2 Hz, 2H); 7.57 (t, J=8.0 Hz, 1H); 7.25-7.21 (m, 2H); 6.93 (t, J=8.0 Hz, 1H); 4.86 (m, 1H); 3.17 (m, 2H); 3.04 (m, 2H); 2.06 (m, 2H); 1.99 (m, 2H); MS-FD m/e: 469.1 (m+1).
Analysis for C24H22 ClFN4O3CF3CO2H:
Calc: C, 53.57; H, 3.98; N, 9.61;
Found: C, 53.89; H, 3.81; N, 9.50.
A mixture of 2-[2-(3-aminopropoxy)-4-(morpholin-4-yl)benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide (400 mg, 0.76 mmol), paraformaldehyde (96 mg, 3.19 mmol) and MeOH (75 mL) was adjusted to pH 5-6 with AcOH. Sodium cyanoborohydride (96 mg, 1.57 mmol) was added. After stirring overnight, the reaction was acidified with 1 N HCl (pH=2) and stirred for 2 hours. Methylene chloride was added to the mixture and it was basified with 50% satd Na2 CO3. The organic layer was dried (Na2 SO4) and concentrated to give the desired product (418 mg, 99%). 1 NMR (300 MHz, DMSO-d6) δ ppm: 11.34 (br s, 0.7H), 11.13 (br s, 1H), 10.96 (br s, 0.3H), 8.43 (m, 2H), 8.16 (d, J=8.6 Hz, 1H), 7.98 (dd, J=2.6, 9.0 Hz, 1H), 7.83 (d, J=8.6 Hz, 1H), 7.61 (dd, J=3.0, 9.0 Hz, 1H), 7.41 (m, 1H), 6.62 (dd, J=1.5, 9.0 Hz, 1H), 6.57 (d, J=1.5 Hz, 1H), 4.25 (t, J=6.8 Hz, 2H), 3.73 (m, 4H), 3.26 (m, 4H), 2.17 (t, J=6.8 Hz, 2H), 1.98 (s, 6H), 1.86 (m, 2H).
IS-MS, m/e: 556.2 (m+1).
Analysis for C28H31ClFN5O4:
Calcd: C, 60.48; H, 5.62; N, 12.60;
Found: C, 60.18; H, 5.58; N, 12.74.
Using methods substantially equivalent to those described in Example 118, N-(1,3-dimethylpyrazol-4-yl)-5-fluoro-2-[2-(1-methylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]benzamide hydrochloride was prepared from 6-fluoro-2-[4-(pyrrolidin-1-yl)-2-(1-methylpiperidin-4-yloxy)phenyl]-4H-3,1-benzoxazin-4-one and 5-amino-1,3-dimethylpyrazole.
IS-MS, m/e 535 (m+1)
Using methods substantially equivalent to those described in Example 118, 5-fluoro-2-[2-(1-methylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]-N-(3-nitro-pyridin-2-yl)benzamide hydrochloride was prepared from 6-fluoro-2-[4-(pyrrolidin-1-yl)-2-(1-methylpiperidin-4-yloxy)phenyl]-4H-3,1-benzoxazin-4-one and 2-amino-3-nitro-pyridine.
IS-MS, m/e 563 (m+1)
Using methods substantially equivalent to those described in Example 118, 5-fluoro-2-[2-(1-methylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]-N-(4-nitro-phenyl)benzamide hydrochloride was prepared from 6-fluoro-2-[4-(pyrrolidin-1-yl)-2-(1-methylpiperidin-4-yloxy)phenyl]-4H-3,1-benzoxazin-4-one and 4-nitroaniline.
IS-MS, m/e 562 (m+1)
Using methods substantially equivalent to those described in Example 118, N-(4-acetylphenyl)-5-fluoro-2-[2-(1-methylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)-benzoylamino]benzamide trifluoroacetate was prepared from 6-fluoro-2-[4-(pyrrolidin-1-yl)-2-(1-methylpiperidin-4-yloxy)phenyl]-4H-3,1-benzoxazin-4-one and 4-acetylaniline.
IS-MS, m/e 558 (m+1)
Using methods substantially equivalent to those described in Example 118, N-(3,5-dichloropyridin-2-yl)-5-fluoro-2-[2-(1-methylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]benzamide trifluoroacetate was prepared from 6-fluoro-2-[4-(pyrrolidin-1-yl)-2-(1-methylpiperidin-4-yloxy)phenyl]-4H-3,1-benzoxazin-4-one and 3,5-dichloro-pyridine.
IS-MS, m/e 586 (m+1)
Using methods substantially equivalent to those described in Example 118, 5-fluoro-2-[2-(1-methylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]-N-(3-methylpyridin-2-yl)benzamide trifluoroacetate was prepared from 6-fluoro-2-[4-(pyrrolidin-1-yl)-2-(1-methylpiperidin-4-yloxy)phenyl]-4H-3,1-benzoxazin-4-one and 2-amino-3-methylpyridine.
IS-MS, m/e 532 (m+1)
Using methods substantially equivalent to those described in Example 118, N-(4,6-dimethylpyridin-2-yl)-5-fluoro-2-[2-(1-methylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]benzamide trifluoroacetate was prepared from 6-fluoro-2-[4-(pyrrolidin-1-yl)-2-(1-methylpiperidin-4-yloxy)phenyl]-4H-3,1-benzoxazin-4-one and 4,6-dimethyl-pyridine.
IS-MS, m/e 546 (m+1)
Using methods substantially equivalent to those described in Example 118, 5-fluoro-N-(4-methoxy-2-nitrophenyl)-2-[2-(1-methylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]benzamide trifluoroacetate was prepared from 6-fluoro-2-[4-(pyrrolidin-1-yl)-2-(1-methylpiperidin-4-yloxy)phenyl]-4H-3,1-benzoxazin-4-one and 4-methoxy-2-nitroaniline.
IS-MS, m/e 592 (m+1)
Using methods substantially equivalent to those described in Example 118, N-(4-bromo-2-chlorophenyl)-5-fluoro-2-[2-(1-methylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]benzamide trifluoroacetate was prepared from 6-fluoro-2-[4-(pyrrolidin-1-yl)-2-(1-methylpiperidin-4-yloxy)phenyl]-4H-3,1-benzoxazin-4-one and 4-bromo-2-chloroaniline.
IS-MS, m/e 631 (m+2)
Using methods substantially equivalent to those described in Example 118, N-(2-chloro-4-nitrophenyl)-5-fluoro-2-[2-(1-methylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]benzamide trifluoroacetate was prepared from 6-fluoro-2-[4-(pyrrolidin-1-yl)-2-(1-methylpiperidin-4-yloxy)phenyl]-4H-3,1-benzoxazin-4-one and 2-chloro-4-nitroaniline.
IS-MS, m/e 596 (m+1)
Using methods substantially equivalent to those described in Example 118, 5-fluoro-2-[2-(1-methylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]-N-(2-methoxyphenyl)benzamide trifluoroacetate was prepared from 6-fluoro-2-[4-(pyrrolidin-1-yl)-2-(1-methylpiperidin-4-yloxy)phenyl]-4H-3,1-benzoxazin-4-one and 2-methoxyaniline.
IS-MS, m/e 547 (m+1)
Using a procedure similar to Example 16-F, N-(5-chloropyridin-2-yl)-2-nitro-benzenesulfonamide was prepared from 2-nitrobenzenesulfonyl chloride and 2-amino-5-chloropyridine.
FD-MS, m/e (m+1) 313.9
To a solution of N-(5-chloropyridin-2-yl)-2-nitrobenzenesulfonamide in THF (300 mL) and CH3 OH (150 mL) at room temperature was added Ni(OAc)2.4H2O (9.62 g, 38.6 mmol). The mixture was stirred until all the solid dissolved. The dark green solution was then cooled to 0° C. and NaBH4 (2.92 g, 72.3 mmoles) was added portionwise. The reaction was stirred at room temperature for 10 min. The solvent was stripped away and the residue partitioned between EtOAc (300 mL) and a mixture of H2O (150 mL) and conc NH4OH (150 mL). The aqueous layer was further extracted with EtOAc (3×200 mL). The combined extracts were washed once with brine, dried (Na2 SO4), filtered and the solvent removed. Chromatography using 10-20% Et2O/CHCl3 afforded 1.6 g (5.64 mmoles, 29% yield) of product as a gray solid.
TLC (20% Et2O/CHCl3) Rf=0.31
1NMR
IS-MS, m/e 284.1
Analysis for C11H10ClN3O2S:
Calcd: C, 46.56; H, 3.55; N, 14.81;
Found: C, 46.46; H, 3.64; N, 14.59.
To a solution of 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)-benzoic acid (781 mg, 2.0 mmol), DMF (catalytic) and pyridine (178 μL, 2.2 mmol) in CH2Cl2 (20 mL) at 0° C. was added dropwise 2 M oxalyl chloride in CH2Cl2 (1.1 mL, 2.2 mmol). This mixture was allowed to warm to room temperature and stirred for 30 min. The acid chloride solution was then added to a solution of 2-amino-N-(5-chloro-pyridin-2-yl)benzenesulfonamide (624 mg, 2.2 mmol) and pyridine (178 μL, 2.2 mmol) in CH2Cl2 (20 mL). The reaction was stirred at room temperature for 6 h. The reaction mixture was partitioned between saturated NaHCO3 (200 mL) and EtOAc (3×300 mL). The extracts were washed with H2O (200 mL) and brine, dried (Na2SO4), filtered, and the solvent removed. Flash chromatography with 3-10% acetone/CHCl3 afforded 620 mg (0.945 mmol, 47% yield) of product.
TLC (10% acetone/CHCl3) Rf=0.55
1NMR
IS-MS, m/e 656.3
Analysis for C32H38ClN5O6S:
Calcd: C, 58.57; H, 5.84; N, 10.67;
Found: C, 58.15; H, 5.96; N, 10.06.
To a solution of 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]-N-(5-chloropyridin-2-yl)benzsulfonamide (620 mg, 0.945 mmol) in CH2Cl2 (15 mL) was added trifluoroacetic acid (2.5 mL). This was stirred at room temperature overnight. The solvent was removed in vacuo and the residue purified by flash chromatography using 5% 2 M NH3 in CH3OH and 15% CH3OH in CHCl3. The chromatography product crystallized from CH2Cl2 affording 120 mg (0.216 mmol, 23% yield) of product.
1NMR
IS-MS, m/e 556.3
Using a procedure analogous to Example 16-F, 4-nitroisatoic anhydride and 4-methoxyaniline gave the desired product as a greenish-yellow solid (2.73 g, 95%).
1NMR (300 MHz, DMSO-d6) δ ppm: 7.76 (d, J=8.7 Hz, 1H), 7.58 (m, 3H), 7.32 (dd, J=2.1, 8.7 Hz, 1H), 6.90 (d, J=9.3 Hz, 2H), 3.72 (s, 3H).
IS-MS, m/e: 286 (m−1).
Using a procedure similar to that in Example 21-C, methyl 2-(2-tert-butoxy-carbonylaminoethoxy)-4-methoxybenzoate was produced from methyl 2-hydroxy-4-methoxybenzoate and 2-(tert-butoxycarbonylamino)ethanol.
Using a procedure analogous to Example 21-D, methyl 2-(2-tert-butoxycarbonyl-aminoethoxy)-4-methoxy benzoate gave the desired product as a white solid (14.52 g, 99%).
1NMR (300 MHz, CDCl3) δ ppm: 8.14 (d, J=8.7 Hz, 1H), 6.66 (dd, J=2.1, 8.7 Hz, 1H), 6.54 (d, J=2.1 Hz, 1H), 5.02 (br s, 1H), 4.28 (t, J=5.1 Hz, 2H), 3.88 (s, 3H), 3.64 (m, 2H), 1.46 (s, 9H).
FD-MS, m/e: 311 (m+1)
Analysis for C15H21NO6:
Calcd: C, 57.87; H, 6.80; N, 4.50;
Found: C, 57.94; H, 6.73; N, 4.68.
Using methods substantially equivalent to those described in Example 4-E, 2-[2-[2-(tert-butoxycarbonylamino)ethoxy]-4-methoxybenzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide (833 mg, 1.43 mmol, 44%) was prepared from 2-(2-tert-butoxy-carbonylaminoethoxy)-4-methoxybenzoic acid and 2-amino-N-(4-methoxyphenyl)-4-nitrobenzamide.
IR(CHCl3): 1703, 1662, 1606, 1533, 1511, 1260 cm−1.
1NMR (300 MHz, DMSO-d6): δ 11.48 (s, 1H); 10.67 (s, 1H); 9.37 (s, 1H); 8.76 (m, 1H); 8.02-7.93 (m, 3H); 7.65 (d, J=9.0 Hz, 2H); 6.92 (d, J=9.0 Hz, 2H); 6.76 (s, 1H); 6.67 (d, J=8.7 Hz, 1H); 4.25 (t, J=5.6 Hz, 2H); 3.81 (s, 3H); 3.71 (s, 3H); 3.33 (d, J=5.7 Hz, 2H); 1.25 (s, 9H).
FD-MS m/e: 580.0 (m).
Analysis for C29H32N4O9:
Calc: C, 59.99; H, 5.56; N, 9.65;
Found: C, 59.74; H, 5.48; N, 9.62.
Using methods substantially equivalent to those described in Example 4-G except 1 N NaOH was used as the base, 2-[2-(2-aminoethoxy)-4-methoxybenzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide (262 mg, 0.55 mmol; 42%) was prepared from 2-[2-[2-(tert-butoxycarbonylamino)ethoxy]-4-methoxybenzoylamino]-N-(4-methoxy-phenyl)-4-nitrobenzamide.
1NMR (300 MHz, DMSO-d6): δ 9.32 (s, 1H); 8.02-7.92 (m, 3H); 7.62 (d, J=8.7 Hz, 2H); 6.92 (d, J=9.0 Hz, 2H); 6.71 (s, 1H); 6.67 (d, J=8.7 Hz, 2H); 4.18 (t, J=5.7 Hz, 2H); 3.80 (s, 3H); 3.71 (s, 3H); 2.88 (t, J=5.4 Hz, 2H).
IS-MS m/e: 481.2 (m+1).
Analysis for C24H24N4O7:
Calc: C, 59.96; H, 5.04; N, 11.66;
Found: C, 60.17; H, 5.13; N, 11.73.
A mixture of 2-[2-(2-aminoethoxy)-4-methoxybenzoylamino]-N-(4-methoxy-phenyl)-4-nitrobenzamide (227 mg, 0.47 mmol), P-EPC resin (2.09 g, 1.78 mmol), and thiophene-2-carboxylic acid (144 mg, 1.12 mmol) in methylene chloride (15 mL) was shaken in a screw top vial overnight. The reaction was filtered and the solids were washed with 10% methanol in chloroform. The filtrate was concentrated to yield the desired product (265 mg, 0.45 mmol, 95%) as a greenish solid.
1NMR (300 MHz, DMSO-d6): δ 11.51 (s, 1H); 10.65 (s, 1H); 9.31 (s, 1H); 8.55 (s, 1H); 8.02-7.92 (m, 3H); 7.65 (d, J=6.9 Hz, 4H); 6.97 (m, 1H); 6.90 (d, J=8.7 Hz, 2H); 6.82 (s, 1H); 6.66 (d, J=9.0 Hz, 1H); 4.41 (t, J=6.0 Hz, 2H); 3.77 (s, 3H); 3.67 (s, 3H); 3.61 (d, J=5.7 Hz, 2H).
IS-MS m/e: 591.4 (m+1).
The 2-[2-[4-methoxy-2-(thiophen-2-ylcarbonylamino)ethoxy]benzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide (258 mg, 0.44 mmol) was diluted with methanol (20 mL) and THF (20 mL). Nickel acetate tetrahydrate (220 mg, 0.88 mmol) was added and the mixture was cooled to 0° C. Sodium borohydride (72 mg, 1.90 mmol) was then added in portions. Vigorous bubbling occurred and the reaction turned black. After 15 minutes, the reaction was concentrated in vacuo. The crude residue was diluted with EtOAc (60 mL), water (20 mL), and concentrated ammonium hydroxide (10 mL). The resulting mixture was stirred for 5 minutes and then it was poured into a separatory funnel and the layers were separated. The organic layer was washed with water (20 mL) and brine (20 mL) and then dried over magnesium sulfate, filtered and concentrated to give the desired product (201 mg, 0.36 mmol, 81%) as a grey solid.
1NMR (300 MHz, DMSO-d6): δ 11.85 (s, 1H); 9.89 (s, 1H); 8.57 (s, 1H); 7.85-7.80 (m, 2H); 7.68 (d, J=4.8 Hz, 1H); 7.56-7.49 (m, 4H); 7.01 (t, J=4.2 Hz, 1H); 6.82 (d, J=8.7 Hz, 2H); 6.76 (s, 1H); 6.61 (d, J=8.4 Hz, 1H); 6.30 (d, J=7.5 Hz, 1H); 5.78 (br s, 2H); 4.33 (t, J=5.9 Hz, 2H); 3.77 (s, 3H); 3.64 (s, 3H); 3.29 (m, 2H).
IS-MS m/e: 561.2 (m+1).
Using a procedure similar to that used in Example 21-C, methyl 2-(1-tert-butoxy-carbonylpiperidin-4-yloxy)-4-methoxybenzoate (10.38 g, 71%) was prepared from methyl 2-hydroxy-4-methoxybenzoate and 4-hydroxy-1-tert-butoxycarbonylpiperidine.
Using a procedure analogous to Example 21-D, methyl 2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-4-methoxybenzoate gave the desired product as a white solid (9.95 g, 98%).
1NMR (300 MHz, CDCl3) δ ppm: 8.17 (d, J=8.7 Hz, 1H), 6.68 (dd, J=2.1, 8.7 Hz, 1H), 6.55 (d, J=2.1 Hz, 1H), 4.72 (m, 1H), 3.89 (s, 3H), 3.85 (m, 2H), 3.30 (m, 2H), 2.11 (m, 2H), 1.87 (m, 2H), 1.49 (s, 9H).
Analysis for C18H25NO6:
Calcd: C, 61.52; H, 7.17; N, 3.99;
Found: C, 61.55; H, 7.26; N, 3.80.
Using methods substantially equivalent to those described in example 4-E, 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-methoxybenzoylamino]-N-(4-methoxy-phenyl)-4-nitrobenzamide (1.64 g, 2.64 mmol, 93%) was prepared from 2-(1-tert-butoxy-carbonylpiperidin-4-yloxy)-4-methoxybenzoic acid and N-(4-methoxyphenyl)-2-amino-4-nitrobenzamide.
IR(CHCl3): 1670, 1533, 1245 cm−1.
1NMR (300 MHz, DMSO-d6): δ 11.17 (s, 1H); 10.69 (s, 1H); 9.33 (s, 1H); 8.02-7.96 (m, 2H); 7.87 (d, J=9.0 Hz, 1H); 7.62 (d, J=9.0 Hz, 2H); 6.91 (d, J=9.0 Hz, 2H); 6.74 (s, 1H); 6.67 (d, J=8.7 Hz, 1H); 4.74 (m, 1H); 3.80 (s, 3H); 3.71 (s, 3H); 3.68 (m, 2H); 2.99 (m, 2H); 1.83 (br s, 2H); 1.33 (s, 9H).
IS-MS m/e: 621.6 (m+1).
Analysis for C32H36N4O9:
Calc: C, 61.93; H, 5.85; N, 9.03;
Found: C, 62.17; H, 6.04; N, 9.03.
Using methods substantially equivalent to those described in example 4-G, except that 1 N NaOH was used as the base, 2-[4-methoxy-2-(piperidin-4-yloxy)benzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide (1.08 g, 2.07 mmol, 82%) was prepared from 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-methoxybenzoylamino]-N-(4-methoxy-phenyl)-4-nitrobenzamide.
IR(CHCl3): 1606, 1532, 1511, 1254 cm−1.
1NMR (300 MHz, DMSO-d6): δ 9.42 (s, 1H); 8.04-7.95 (m, 2H); 7.85 (d, J=8.7 Hz, 1H); 7.63 (d, J=8.7 Hz, 2H); 6.92 (d, J=8.7 Hz, 2H); 6.69-6.64 (m, 2H); 4.58 (m, 1H); 3.79 (s, 3H); 3.71 (s, 3H); 2.70 (d, J=12.3 Hz, 2H); 2.42 (m, 2H); 1.81-1.76 (m, 2H); 1.58-1.54 (m, 2H).
IS-MS m/e: 521.2 (m+1).
Analysis for C27H28N4O7:
Calc: C, 62.30; H, 5.42; N, 10.76;
Found: C, 62.09; H, 5.61; N, 10.55.
Using methods substantially equivalent to those described in Example 139-A, N-(4-methoxyphenyl)-2-[4-methoxy-2-[1-(thiophen-2-ylcarbonyl)piperidin-4-yloxy]-benzoylamino]-4-nitrobenzamide (192 mg, 0.30 mmol, 78%) was prepared from N-(4-methoxyphenyl)-2-[4-methoxy-2-(piperidin-4-yloxy)benzoylamino]-4-nitro-benzamide and thiophene 2-carboxylic acid.
1NMR (300 MHz, DMSO-d6): δ 11.19 (s, 1H); 10.68 (s, 1H); 9.34 (s, 1H); 8.04-7.95 (m, 2H); 7.90 (d, J=9.0 Hz, 1H); 7.71 (d, J=4.8 Hz, 1H); 7.57 (d, J=8.7 Hz, 2H); 7.29 (d, J=3.3 Hz, 1H); 7.07 (t, J=4.2 Hz, 1H); 6.81 (d, J=9.0 Hz, 3H); 6.68 (d, J=9.3 Hz, 1H); 4.91 (m, 1H); 3.99 (d, J=7.2 Hz, 4H); 3.81 (s, 3H); 3.66 (s, 3H); 1.95 (m, 4H).
IS-MS m/e: 631.2 (m+1).
Using methods substantially equivalent to those described in example 139-B, 4-amino-N-(4-methoxyphenyl)-2-[4-methoxy-2-[1-(thiophen-2-ylcarbonyl)piperidin-4-yloxy]benzoylamino]benzamide was prepared from N-(4-methoxyphenyl)-2-[4-methoxy-2-[1-(thiophen-2-ylcarbonyl)piperidin-4-yloxy]benzoylamino]-4-nitrobenzamide.
1NMR (300 MHz, DMSO-d6): δ 11.68 (s, 1H); 9.84 (s, 1H); 7.86 (s, 1H); 7.74-7.68 (m, 2H); 7.47 (d, J=8.7 Hz, 2H); 7.23 (s, 1H); 7.05 (s, 1H); 6.83-6.69 (m, 3H); 6.62 (d, J=8.1 Hz, 1H); 6.29 (d, J=8.4 Hz, 1H); 5.80 (s, 2H); 4.83 (m, 1H); 3.84 (m, 2H); 3.78 (s, 3H); 3.64 (s, 3H); 3.39 (m, 2H); 1.90 (br s, 4H).
IS-MS m/e: 601.4 (m+1).
Analysis for C32H32N4O6S:
Calc: C, 63.98; H, 5.37; N, 9.33;
Found: C, 64.28; H, 5.55; N, 9.03.
To a solution of methyl 4-fluoro-2-(methoxymethoxy)benzoate (10.6 g, 50 mmol) and DMSO (20 mL), under nitrogen, was added sodium ethanethiolate (5.8 g, 55 mmol) in portions. The exothermic reaction was stirred for 19 h, diluted with water, and extracted with ethyl acetate. The organic layer was concentrated; and the residue was dissolved in ether, filtered through diatomaceus earth, and concentrated to give intermediate methyl 4-(ethylthio)-2-(methoxymethoxy)benzoate.
To this intermediate was added methylene chloride (75 mL), TFA (377 mL), and water (377 mL); and the mixture was stirred for 0.5 h. The reaction was concentrated and chromatographed (silica gel, 5% ethyl acetate/hexane) to give the title compound (5.8 g, 55%).
1NMR (250 MHz, CDCl3): δ 10.87 (s, 1H); 7.71 (d, J=8.5 Hz, 1H); 6.84 (d, J=1.8 Hz, 1H); 6.76 (dd, J=1.8, 8.5 Hz, 1H); 3.96 (s, 3H); 3.02 (q, J=7.3 Hz, 2H); 1.40 (t, J=7.3 Hz, 3H).
IS-MS, m/e 213.1 (m+1).
Using a procedure analogous to Example 21-C, methyl 2-hydroxy-4-(ethylthio)-benzoate and 3-t-butoxycarbonylaminopropanol gave the title compound as a solid (10.41 g, 85%).
1NMR (250 MHz, CHCl3): δ 7.85 (d, J=8.2 Hz, 1H), 6.80 (m, 2H), 6.12 (br s, 1H), 4.14 (t, 5.8 Hz, 2H), 3.91 (s, 3H), 3.43 (m, 2H), 3.03 (q, J=7.3 Hz, 2H), 2.09 (m, 2H), 1.48 (s, 9H), 1.39 (t, J=7.3 Hz, 3H).
IS-MS, m/e: 370.1 (m+1).
Using a procedure analogous to Example 94-B, methyl 2-(3-t-butoxycarbonyl-aminopropoxy)-4-(ethylthio)benzoate gave the title compound as a solid (8.28 g, 96%).
1NMR (250 MHz, CDCl3): δ 8.04 (d, J=8.5 Hz, 1H), 6.97 (dd, J=1.5, 8.5 Hz, 1H), 6.88 (d, J=1.5 Hz, 1H), 4.94 (br s, 1H), 4.27 (t, J=6.4 Hz, 2H), 3.05 (q, J=7.3 Hz, 2H), 2.11 (m, 2H), 1.44 (s, 9H), 1.40 (t, J=7.3 Hz, 3H).
IS-MS, m/e: 356.3 (m+1).
Analysis for C17H25NO5S:
Calcd: C, 57.44; H, 7.09; N, 3.94;
Found: C, 57.60; H, 7.05; N, 4.02.
Using a procedure analogous to Example 4-E, N-(5-chloropyridin-2-yl)-4-fluoro-2-aminobenzamide and 4-(ethylthio)-2-(3-(t-butoxycarbonylamino)propyloxy)benzoic acid gave the title compound as a solid (0.93 g, 44%).
1NMR (300 MHz, CDCl3) ES-MS, m/e 603.2 (m+1).
Analysis for C29H32 ClFN4O5S:
Calcd: C, 57.75; H, 5.35; N, 9.29;
Found: C, 57.40; H, 5.23; N, 9.11.
Using a sequential procedures analogous to Example 102-A and Example 4-G, N-(5-chloropyridin-2-yl)-4-fluoro-2-[4-ethylthio-2-(3-(t-butoxycarbonyamino)-propyloxy)benzoylamino]benzamide gave the title compound as a solid (0.6 g, 54%).
1NMR (300 MHz, CD3OD) ES-MS, m/e 535.1 (m+1).
Analysis for C24H24 ClFN4O5S:
Calcd: C, 53.88; H, 4.52; N, 10.47;
Found: C, 53.48; H, 4.52; N, 10.30.
To a solution of 3-bromopropylamine hydrobromide (100 g, 457 mmol) in water (250 mL) was added a solution of di-tert-butyl dicarbonate (49.84 g, 228 mmol) in dichloromethane (600 mL). The resulting biphasic mixture was stirred vigorously, then a solution of sodium hydroxide (36.56 g, 914 mmol) in water (250 mL) was added and the mixture stirred at room temperature for 3 to 16 hours. The organic layer was washed sequentially with water, 0.2 N HCl until the pH reached 1, then again with water until the pH reached 6 to 7. The organic layer was dried over sodium sulfate and concentrated in vacuo to provide 45.18 grams (83%) of 1-tert-butoxycarbonylamino-3-bromopropane as a pale orange oil.
1NMR
FAB-MS, m/z 238.0 (m+1), 240.0 (m+1).
Analysis for C8H16 BrNO2:
Calcd: C, 40.35; H, 6.77; N, 5.88;
Found: C, 40.12; H, 6.62; N, 6.06.
To a solution of methyl 4-methoxysalicylate (11.48 g, 63 mmol) in dimethylformamide (30 mL) was added solid K2 CO3 (13.06 g, 94.5 mmol), 1-tert-butoxycarbonylamino-3-bromopropane (22.5 g, 94.5 mmol), and freshly ground potassium iodide (1.5 g). The resulting slurry was placed under a nitrogen atmosphere and stirred for 2.5 days. The slurry was diluted with water (250 mL), washed with 1 N NaOH (2×250 mL), water (250 mL), and brine (250 mL), then dried over sodium sulfate and concentrated in vacuo. The crude mixture was purified on a preparative HPLC chromatograph using two silica columns and a hexanes through 1:1 hexanes:EtOAc gradient to provide methyl 2-(3-tert-butoxycarbonylaminopropoxy)-4-methoxybenzoate (19.93 g, 93.3%) as a colorless oil.
1NMR
FAB-MS, m/z 340.2 (m+1).
Analysis for C17H25 NO6:
Calcd: C, 60.16; H, 7.43; N, 4.13;
Found: C, 59.92; H, 7.42; N, 4.18.
Methyl 2-(3-tert-butoxycarbonylaminopropoxy)-4-methoxybenzoate (18.61 g, 54.8 mmol) was suspended in 3:1 tetrahydrofuran:water (100 mL), then solid LiOH monohydrate (5.06 g, 121 mmol) was added and the mixture was stirred at 50° C. for 24 hours. The mixture was diluted with water (350 mL) and washed with diethyl ether (2×250 mL). The aqueous layer was acidified to pH 1-2 with 1 N sodium bisulfate and the resulting slurry was extracted with EtOAc (2×300 mL). The combined EtOAc layers were washed with brine, dried, then concentrated in vacuo to give a solid white mass. Recrystallization from EtOAc provided 2-(3-tert-butoxycarbonylaminopropoxy)-4-methoxybenzoic acid as white needles (15.52 g, 87%).
1NMR
FAB-MS, m/z 312.2 (m+1).
Analysis for C15H21NO6:
Calcd: C, 57.87; H, 6.80; N, 4.50;
Found: C, 58.09; H, 6.88; N, 4.57.
Using methods substantially equivalent to those described in Example 4-E, 2-[2-(3-tert-butoxycarbonylaminopropoxy)-4-methoxybenzoylamino]-N-(4-methoxy-phenyl)-4-nitrobenzamide (984 mg, 1.65 mmol, 58%) was prepared from 4-methoxy-2-(3-tert-butoxycarbonylaminopropoxy)benzoic acid and N-(4-methoxyphenyl)-2-amino-4-nitrobenzamide.
IR(CHCl3): 1606, 1533, 1250 cm−1.
1NMR (300 MHz, DMSO-d6): δ 11.40 (s, 1H); 10.69 (s, 1H); 9.41 (s, 1H); 7.99 (m, 1H); 7.64 (d, J=8.7 Hz, 2H); 6.94 (d, J=9.0 Hz, 2H); 6.67 (m, 3H); 4.23 (t, J=5.9 Hz, 2H); 3.81 (s, 3H); 3.73 (s, 3H); 2.93 (m, 2H); 1.83 (m, 2H); 1.30 (s, 9H).
FD-MS m/e: 594.0 (m).
Using methods substantially equivalent to those described in example 4-G except 1 N NaOH was used as the base, 2-[2-(3-aminopropoxy)-4-methoxybenzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide (1.214 g, 2.45 mmol, 100%) was prepared from 2-[2-(3-tert-butoxycarbonylaminopropoxy)-4-methoxybenzoylamino]-N-(4-methoxy-phenyl)-4-nitrobenzamide.
IR(KBr): 1602, 1532, 1262 cm−1.
1 NMR (300 MHz, DMSO-d6): δ 11.43 (s, 1H); 10.72 (s, 1H); 9.38 (s, 1H); 8.00 (m, 3H); 7.64 (d, J=9.0 Hz, 2H); 6.95 (d, J=9.0 Hz, 2H); 6.72 (d, J=6.9 Hz, 2H); 4.34 (t, J=5.9 Hz, 2H); 3.83 (s, 3H); 3.74 (s, 3H); 2.85 (m, 2H); 2.07 (m, 2H).
IS-MS m/e: 495 (m+1).
Analysis for C27H27F3N4O9:
Calc: C, 53.29; H, 4.47; N, 9.21;
Found: C, 53.31; H, 4.23; N, 9.16.
Using methods substantially equivalent to those described in Example 139-A, 2-[4-methoxy-2-[3-(thiophen-2-ylcarbonylamino)propoxy]benzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide (162 mg, 0.27 mmol, 81%) was prepared from 2-[2-(3-aminopropoxy)-4-methoxybenzoylamino]-N-(4-methoxyphenyl)-4-nitro-benzamide and thiophene 2-carboxylic acid.
IR(CHCl3): 1606, 1511, 1258 cm−1.
1NMR (300 MHz, DMSO-d6): δ 11.43 (s, 1H); 10.67 (s, 1H); 9.39 (s, 1H); 8.40 (m, 1H); 8.04-7.94 (m, 3H); 7.67-7.61 (m, 4H); 7.05 (t, J=4.4 Hz, 2H); 6.89 (d, J=9.0 Hz, 2H); 6.69-6.65 (m, 2H); 4.29 (t, J=6.3 Hz, 2H); 3.78 (s, 3H); 3.69 (s, 3H); 3.23 (d, J=6.0 Hz, 2H); 1.98 (t, J=6.6 Hz, 2H).
IS-MS m/e: 605.2 (m+1).
Analysis for C30H28N4O8.1.0H2O:
Calc: C, 57.87; H, 4.86; N, 9.00;
Found: C, 57.77; H, 4.52; N, 8.98.
Using methods substantially equivalent to those described in Example 139-B, 4-amino-2-[4-methoxy-2-[3-(thiophen-2-ylcarbonylamino)propoxy]-benzoylamino]-N-(4-methoxyphenyl)benzamide (114 mg, 0.20 mmol, 100%) was prepared from 2-[4-methoxy-2-[3-(thiophen-2-ylcarbonylamino)propoxy]benzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide.
IR(CHCl3): 1642, 1606, 1511 cm−1.
1NMR (400 MHz, DMSO-d6): δ 11.79 (s, 1H); 9.48 (s, 1H); 8.41 (m, 1H); 7.87 (s, 1H); 7.77 (d, J=8.8 Hz, 1H); 7.67-7.63 (m, 2H); 7.52-7.48 (m, 3H); 7.04 (t, J=4.4 Hz, 1H); 6.80 (d, J=9.2 Hz, 2H); 6.62 (m, 2H); 6.28 (d, J=8.4 Hz, 1H); 5.78 (br s, 2H); 4.19 (t, J=6.6 Hz, 2H); 3.76 (s, 3H); 3.65 (s, 3H); 3.27 (m, 2H); 1.71 (m, 2H).
IS-MS m/e: 575.2 (m+1).
Using methods substantially equivalent to those described in Example 94-E, 2-[4-methoxy-2-[1-(3-methoxybenzyl)piperidin-4-yloxy]benzoylamino]-N-(4-methoxy-phenyl)-4-nitrobenzamide (62 mg, 0.097 mmol, 65%) was prepared from 2-[4-methoxy-2-(piperidin-4-yloxy)benzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide and 3-methoxybenzaldehyde.
1NMR (400 MHz, DMSO-d6): δ 11.13 (s, 1H); 10.67 (s, 1H); 8.03-7.79 (m, 2H); 7.86 (d, J=8.8 Hz, 1H); 7.63 (d, J=9.2 Hz, 2H); 7.16 (t, J=7.6 Hz, 1H); 6.91-6.64 (m, 7H); 4.59 (m, 1H); 3.79 (s, 3H); 3.66 (s, 3H); 3.65 (s, 3H); 3.27 (s, 2H); 2.51 (m, 2H); 2.07 (m, 2H); 1.83 (m, 4H).
IS-MS m/e: 641.3 (m+1).
Using methods substantially equivalent to those described in Example 94-E, 2-[2-(1-(2,6-dimethoxybenzyl)piperidin-4-yloxy)-4-methoxybenzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide (78 mg, 0.12 mmol, 78%) was prepared from 2-[4-methoxy-2-(piperidin-4-yloxy)benzoylamino]-N-(4-methoxyphenyl)-4-nitro-benzamide and 2,6-dimethoxybenzaldehyde.
1NMR (400 MHz, DMSO-d6): δ 11.10 (s, 1H); 10.63 (s, 1H); 9.32 (s, 1H); 8.04-7.96 (m, 2H); 7.83 (d, J=8.4 Hz, 1H); 7.60 (d, J=6.0 Hz, 2H); 7.15 (m, 1H); 6.83 (d, J=6.0 Hz, 2H); 6.69 (s, 1H); 6.64 (d, J=8.4 Hz, 1H); 6.56 (d, J=8.0 Hz, 2H); 4.52 (m, 1H); 3.77 (s, 3H); 3.68 (s, 3H); 3.65 (s, 6H); 3.29 (s, 2H); 2.56 (s, 2H); 2.04 (m, 2H); 1.76 (m, 4H).
IS-MS m/e: 671.6 (m+1).
Using methods substantially equivalent to those described in Example 94-E, 2-[4-methoxy-2-(1-(2-methylbenzyl)piperidin-4-yloxy)benzoylamino]-N-(4-methoxy-phenyl)-4-nitrobenzamide (66 mg, 0.11 mmol, 70%) was prepared from 2-[4-methoxy-2-(piperidin-4-yloxy)benzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide and 2-methyl-benzaldehyde.
1NMR (400 MHz, DMSO-d6): δ 11.13 (s, 1H); 10.66 (s, 1H); 9.34 (s, 1H); 8.05-7.96 (m, 2H); 7.86 (d, J=8.8 Hz, 1H); 7.61 (d, J=9.2 Hz, 2H); 7.10 (s, 4H); 6.77 (d, J=9.2 Hz, 2H); 6.71-6.64 (m, 2H); 4.60 (m, 1H); 3.79 (s, 3H); 3.64 (s, 3H); 2.52 (m, 2H); 2.23 (s, 3H); 2.10 (m, 2H); 1.83 (m, 4H).
IS-MS m/e: 625.6 (m+1).
Using methods substantially equivalent to those described in Example 94-E, 2-[4-methoxy-2-[1-(2-methoxybenzyl)piperidin-4-yloxy]benzoylamino]-N-(4-methoxy-phenyl)-4-nitrobenzamide (83 mg, 0.13 mmol, 86%) was prepared from 2-[4-methoxy-2-(piperidin-4-yloxy)benzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide and 2-methoxybenzaldehyde.
1NMR (400 MHz, DMSO-d6): δ 11.14 (s, 1H); 10.68 (s, 1H); 9.37 (s, 1H); 8.04-8.00 (m, 2H); 7.86 (d, J=8.8 Hz, 1H); 7.64 (d, J=6.4 Hz, 2H); 7.21 (m, 2H); 6.92-6.82 (m, 2H); 6.71-6.67 (m, 2H); 4.63 (m, 1H); 3.79 (s, 3H); 3.68 (s, 3H); 3.66 (s, 3H); 3.30 (s, 2H); 2.52 (m, 2H); 2.11 (m, 2H); 1.84 (m, 4H).
IS-MS m/e: 641.3 (m+1).
Using methods substantially equivalent to those described in example 94-E, 2-[2-(1-benzylpiperidin-4-yloxy)-4-methoxybenzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide (60 mg, 0.098 mmol, 65%) was prepared from 2-[4-methoxy-2-(piperidin-4-yloxy)benzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide and benzaldehyde.
1NMR (400 MHz, DMSO-d6): δ 11.14 (s, 1H); 9.38 (s, 1H); 8.06-7.98 (m, 2H); 7.86 (d, J=8.8 Hz, 1H); 7.63 (d, J=8.8 Hz, 2H); 7.28-7.19 (m, 5H); 6.81 (d, J=9.2 Hz, 2H); 6.70-6.65 (m, 2H); 4.60 (m, 1H); 3.79 (s, 3H); 3.66 (s, 3H); 3.29 (s, 2H); 2.50 (m, 2H); 2.08 (m, 2H); 1.84 (m, 4H).
IS-MS m/e: 611.3 (m+1).
Using methods substantially equivalent to those described in example 94-E, 2-[4-methoxy-2-(1-(4-methoxybenzyl)piperidin-4-yloxy)benzoylamino]-N-(4-methoxy-phenyl)-4-nitrobenzamide (69 mg, 0.11 mmol, 72%) was prepared from 2-[4-methoxy-2-(piperidin-4-yloxy)benzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide and 4-methoxybenzaldehyde.
1NMR (400 MHz, DMSO-d6): δ 11.13 (s, 1H); 10.67 (s, 1H); 9.36 (s, 1H); 8.06-7.97 (m, 2H); 7.85 (d, J=7.2 Hz, 1H); 7.63 (d, J=8.0 Hz, 2H); 7.09 (d, J=8.0 Hz, 2H); 6.83-6.64 (m, 6H); 4.59 (m, 1H); 3.78 (s, 3H); 3.67 (s, 6H); 3.29 (s, 2H); 2.46 (m, 2H); 2.04 (m, 2H); 1.82 (m, 4H).
IS-MS m/e: 641.3 (m+1).
Using methods substantially equivalent to those described in Example 94-E, 2-[2-[1-(2-fluorobenzyl)piperidin-4-yloxy]-4-methoxybenzoylamino]-N-(4-methoxy-phenyl)-4-nitrobenzamide (63 mg, 0.10 mmol, 67%) was prepared from 2-[4-methoxy-2-(piperidin-4-yloxy)benzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide and 2-fluoro-benzaldehyde.
1NMR (300 MHz, DMSO-d6): δ 11.12 (s, 1H); 10.66 (s, 1H); 9.36 (s, 1H); 8.05-7.96 (m, 2H); 7.84 (d, J=8.1 Hz, 1H); 7.62 (d, J=8.1 Hz, 2H); 7.29-7.23 (m, 2H); 7.11-7.06 (m, 2H); 6.82 (d, J=8.1 Hz, 2H); 6.70 (s, 1H); 6.64 (d, J=8.7 Hz, 1H); 4.59 (m, 1H); 3.78 (s, 3H); 3.67 (s, 3H); 3.42 (s, 2H); 2.50 (m, 2H); 2.12 (m, 2H); 1.83 (m, 4H).
IS-MS m/e: 629.3 (m+1).
Using methods substantially equivalent to those described in Example 94-E except that sodium borohydride was the reducing agent, 2-[2-[3-(2-fluorobenzyl)aminopropoxy]-4-methoxybenzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide (20 mg, 0.033 mmol, 22%) was prepared from 2-[2-(3-aminopropoxy)-4-methoxybenzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide and 2-fluorobenzaldehyde.
1NMR (400 MHz, DMSO-d6): δ 11.43 (s, 1H); 10.67 (s, 1H); 9.37 (d, J=2.4 Hz, 1H); 7.99 (m, 3H); 7.61 (d, J=8.8 Hz, 2H); 7.17 (m, 2H); 6.94 (d, J=9.2 Hz, 2H); 6.87 (d, J=8.8 Hz, 2H); 6.69 (m, 2H); 4.36 (m, 2H); 3.78 (s, 3H); 3.67 (s, 3H); 3.56 (m, 2H); 2.46 (s, 2H); 2.07 (m, 2H).
IS-MS m/e: 603.3 (m+1).
Using methods substantially equivalent to those described in example 94-E except that sodium borohydride was the reducing agent, 2-[2-[3-(2-chlorobenzyl)amino-propoxy]-4-methoxybenzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide (34 mg, 0.055 mmol, 37%) was prepared from 2-[2-(3-aminopropoxy)-4-methoxybenzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide and 2-chlorobenzaldehyde.
1NMR (400 MHz, DMSO-d6): δ 11.44 (s, 1H); 10.66 (s, 1H); 9.35 (s, 1H); 8.02 (d, J=9.2 Hz, 1H); 7.95 (d, J=8.8 Hz, 1H); 7.84 (d, J=8.0 Hz, 1H); 7.62 (d, J=8.8 Hz, 2H); 7.40 (d, J=3.6 Hz, 2H); 7.31 (m, 2H); 6.87 (d, J=8.8 Hz, 2H); 6.70 (s, 1H); 6.67 (d, J=9.2 Hz, 2H); 4.36 (m, 2H); 3.78 (s, 3H); 3.60 (s, 3H); 3.29 (s, 2H); 2.09 (m, 2H).
IS-MS m/e: 619.5 (m+1).
Using methods substantially equivalent to those described in Example 94-E except that sodium borohydride was the reducing agent, 2-[4-methoxy-2-[3-(4-methoxybenzyl)-aminopropoxy]benzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide (48 mg, 0.078 mmol, 52%) was prepared from 2-[2-(3-aminopropoxy)-4-methoxybenzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide and 4-methoxybenzaldehyde.
1NMR (300 MHz, DMSO-d6): δ 11.43 (s, 1H); 10.67 (s, 1H); 9.39 (s, 1H); 7.99 (m, 3H); 7.63 (d, J=8.8 Hz, 2H); 7.53 (d, J=8.8 Hz, 2H); 6.89 (d, J=11.6 Hz, 4H); 6.70 (m, 2H); 4.34 (m, 2H); 3.78 (s, 3H); 3.74 (s, 3H); 3.68 (s, 3H); 3.46 (s, 2H); 2.02 (m, 2H).
IS-MS m/e: 615.3 (m+1).
Using methods substantially equivalent to those described in Example 94-E except that sodium borohydride was the reducing agent, 2-[4-methoxy-2-[3-(3-methoxybenzyl)-aminopropoxy]benzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide (26 mg, 0.042 mmol, 28%) was prepared from 2-[2-(3-aminopropoxy)-4-methoxybenzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide and 3-methoxybenzaldehyde.
1NMR (400 MHz, DMSO-d6): δ 9.37 (d, J=1.8 Hz, 1H); 7.99 (m, 3H); 7.63 (d, J=9.2 Hz, 2H); 7.26 (t, J=7.8 Hz, 1H); 7.15 (m, 2H); 6.94 (m, 4H); 6.89 (d, J=8.8 Hz, 2H); 6.70 (s, 1H); 6.68 (d, J=13.6 Hz, 1H); 4.36 (m, 2H); 3.78 (s, 3H); 3.70 (s, 3H); 3.68 (s, 3H); 3.51 (m, 2H); 3.30 (s, 2H); 2.05 (m, 2H).
IS-MS m/e: 615.3 (m+1).
Using methods substantially equivalent to those described in Example 94-E except that sodium borohydride was the reducing agent, 2-[2-[3-(2,6-dimethoxybenzyl)amino-propoxy]-4-methoxybenzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide (59 mg, 0.092 mmol, 61%) was prepared from 2-[2-(3-aminopropoxy)-4-methoxybenzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide and 2,6-dimethoxybenzaldehyde.
1NMR (400 MHz, DMSO-d6): δ 9.38 (d, J=2.0 Hz, 1H); 7.98 (m, 3H); 7.62 (d, J=9.2 Hz, 2H); 6.90 (t, J=8.4 Hz, 1H); 6.61 (m, 6H); 4.28 (q, J=7.6 Hz, 2H); 3.79 (s, 3H); 3.69 (s, 3H); 3.63 (s, 6H); 3.45 (m, 2H); 2.03 (m, 2H).
IS-MS m/e: 645.5 (m+1).
Using methods substantially equivalent to those described in Example 94-E except that sodium borohydride was the reducing agent, 2-[4-methoxy-2-(3-(2-methylbenzyl)-aminopropoxy)benzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide (50 mg, 0.084 mmol, 56%) was prepared from 2-[2-(3-aminopropoxy)-4-methoxybenzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide and 2-methylbenzaldehyde.
1NMR (300 MHz, DMSO-d6): δ 11.43 (s, 1H); 10.67 (s, 1H); 9.36 (s, 1H); 7.98 (m, 3H); 7.62 (d, J=9.0 Hz, 2H); 6.87 (d, J=9.3 Hz, 2H); 6.69 (s, 1H); 6.67 (d, J=10.8 Hz, 1H); 4.35 (m, 2H); 3.77 (s, 3H); 3.67 (s, 3H); 3.63 (s, 6H); 3.54 (t, J=5.9 Hz, 2H); 3.26 (s, 2H); 2.30 (s, 3H); 2.06 (t, J=3.9 Hz, 2H).
IS-MS m/e: 599.4 (m+1).
Using methods substantially equivalent to those described in Example 94-E except that sodium borohydride was the reducing agent, 2-[4-methoxy-2-[3-(2-methoxybenzyl)-aminopropoxy]benzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide (52 mg, 0.085 mmol, 56%) was prepared from 2-[2-(3-aminopropoxy)-4-methoxybenzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide and 2-methoxybenzaldehyde.
1NMR (300 MHz, DMSO-d6): δ 11.44 (s, 1H); 10.66 (s, 1H); 9.38 (s, 1H); 7.95 (m, 3H); 7.62 (d, J=8.7 Hz, 2H); 7.08 (m, 2H); 6.88 (d, J=9.0 Hz, 2H); 6.72 (m, 4H); 4.30 (t, J=7.2 Hz, 2H); 4.26-3.68 (m, 11H); 3.50 (s, 2H); 1.86 (m, 2H).
IS-MS m/e: 615.3 (m+1).
Using methods substantially equivalent to those described in Example 94-E except that sodium borohydride was the reducing agent, 2-[2-(3-benzylaminopropoxy)-4-methoxybenzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide (45 mg, 0.077 mmol, 51%) was prepared from 2-[2-(3-aminopropoxy)-4-methoxybenzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide and benzaldehyde.
1NMR (300 MHz, DMSO-d6): δ 11.43 (s, 1H); 10.67 (s, 1H); 9.38 (s, 1H); 8.01 (d, J=8.8 Hz, 1H); 7.95 (m, 2H); 7.61 (m, 4H); 7.36 (m, 3H); 6.88 (d, J=9.2 Hz, 2H); 6.69 (s, 1H); 6.67 (d, J=8.8 Hz, 1H); 4.34 (m, 2H); 3.77 (s, 3H); 3.51 (m, 2H); 3.27 (s, 2H); 2.04 (m, 2H).
IS-MS m/e: 585.5 (m+1).
Using a procedure analogous to Example 4-E, N-(5-chloropyridin-2-yl)-4-methoxycarbonyl-2-aminobenzamide and 4-(methylthio)-2-(3-(t-butoxycarbonylamino)-propoxy)benzoic acid gave the title compound as a white solid (12 g, 50%).
1NMR (300 MHz, DMSO-d6): δ 1.32 (s, 9H), 1.87 (m, 2H), 2.54 (s, 3H), 2.97 (m, 2H), 3.91 (s, 3H), 4.28 (t, J=6.6 Hz, 2H), 6.80 (m, 1H), 6.99 (m, 2H), 7.76 (dd, J=1.5, 8.1 Hz, 1H), 7.89 (s, 1H), 7.92 (s, 1H), 7.98 (dd, J=2.6, 8.8 Hz, 1H), 8.18 (d, J=8.8 Hz, 1H), 8.45 (d, J=2.6 Hz, 1H), 9.03 (d, J=0.7 Hz, 1H), 11.15 (s, 1H), 11.38 (s, 1H).
FIA-MS, m/e 629.2 (m+1).
Analysis for C30H33ClN4O7S:
Calcd: C, 57.27; H, 5.29; N, 8.91;
Found: C, 57.36; H, 5.03; N, 9.18.
Using a procedure analogous to Example 4-G, N-(5-chloropyridin-2-yl)-4-methoxycarbonyl-2-[4-methylthio-2-(3-t-butoxycarbonylamino)propoxy)benzoylamino]-benzamide gave the title compound as a light yellow solid (680 mg, 90%).
1NMR (300 MHz, DMSO-d6): δ 1.79 (m, 2H), 2.57 (m, 5H), 3.91 (s, 3H), 4.32 (t, J=6.6 Hz, 2H), 6.96 (dd, J=1.5, 8.4 Hz, 1H), 7.02 (s, 1H), 7.74 (dd, J=1.8, 8.1 Hz, 1H), 7.91 (m, 2H), 7.98 (dd, J=2.6, 8.8 Hz, 1H), 8.17 (d, J=8.8 Hz, 1H), 8.43 (d, J=2.6 Hz, 1H), 9.06 (d, J=1.5 Hz, 1H).
FIA-MS, m/e 529.1 (m+1).
Analysis for C25H25ClN4O5S:
Calcd: C, 56.76; H, 4.76; N, 10.59;
Found: C, 56.99; H, 4.92; N, 10.74.
To a mixture of N-(5-chloropyridin-2-yl)-4-methoxycarbonyl-2-[4-methylthio-2-(3-aminopropoxy)benzoylamino]benzamide (480 mg, 0.91 mmol), MeOH (10 mL) and water (7 mL) was added LiOH (109 mg, 4.54 mmol). The reaction mixture was heated to 65° C. for 45 min and then cooled to room temperature. To the mixture was added 5N HCl (1.8 mL, 9 mmol), and the resulting solid was filtered with CH2Cl2 and 20% Et2O/hexanes washes to give the title compound as a white solid (213 mg, 55%).
1NMR (300 MHz, DMSO-d6): δ 2.13 (m, 2H), 2.55 (s, 3H), 2.93 (m, 2H), 4.39 (t, J=6.2 Hz, 2H), 6.99 (dd, J=1.1, 8.4 Hz, 1H), 7.04 (s, 1H), 7.75 (dd, J=1.5, 8.1 Hz, 1H), 7.89 (m, 3H), 8.01 (dd, J=2.6, 8.8 Hz, 1H), 8.15 (d, J=8.8 Hz, 1H), 8.46 (d, J=2.9 Hz, 1H), 8.95 (d, J=1.1 Hz, 1H), 11.14 (s, 1H), 11.36 (s, 1H), 13.30 (br s, 1H).
FIA-MS, m/e 515.3 (m+1).
Analysis for C24H23ClN4O5S.HCl:
Calcd: C, 52:27; H, 4.39; N, 10.16;
Found: C, 52.59; H, 4.73; N, 9.65.
Using a procedure analogous to Example 23, N-(5-chloropyridin-2-yl)-4-methoxycarbonyl-2-[4-methylthio-2-(3-t-butoxycarbonylamino)propoxy)benzoylamino]-benzamide gave the title compound as a white solid (1.4 g, 68%).
1NMR (300 MHz, DMSO-d6): δ 1.31 (s, 9H), 1.90 (m, 2H), 2.80 (s, 3H), 2.99 (m, 2H), 3.91 (s, 3H), 4.29 (t, J=6.2 Hz, 2H), 7.38 (d, J=8.1 Hz, 1H), 7.47 (s, 1H), 7.79 (dd, J=1.5, 8.1 Hz, 1H), 7.93 (d, J=8.1 Hz, 1H), 7.98 (dd, J=2.6, 8.8 Hz, 1H), 8.05 (d, J=8.1 Hz, 1H), 8.17 (d, J=8.8 Hz, 1H), 8.44 (d, J=2.6 Hz, 1H), 8.97 (s, 1H), 11.18 (s, 1H), 11.37 (s, 1H).
FIA-MS, m/e 645.5 (m+1).
Analysis for C30H33ClN4O8S:
Calcd: C, 55.85; H, 5.16; N, 8.68;
Found: C, 55.55; H, 4.97; N, 8.65.
Using a procedure analogous to Example 4-G, N-(5-chloropyridin-2-yl)-4-methoxycarbonyl-2-[4-methylsulfinyl-2-(3-t-butoxycarbonylamino)propyloxy)benzoyl-amino]benzamide gave the title compound as a white solid (950 mg, 83%).
1NMR (300 MHz, DMSO-d6): δ 1.84 (m, 2H), 2.65 (t, J=6.6 Hz, 2H), 2.81 (s, 3H), 3.91 (s, 3H), 4.31 (t, J=6.2 Hz, 2H), 7.36 (dd, J=1.5, 8.1 Hz, 1H), 7.46 (d, =1.5 Hz, 1H), 7.73 (dd, J=1.5, 8.1 Hz, 1H), 7.93 (dd, J=2.6, 8.8 Hz, 1H), 7.99 (d, J=8.1 Hz, 1H), 8.04 (d, J=8.1 Hz, 1H), 8.17 (d, J=8.8 Hz, 1H), 8.40 (s, 1H), 9.04 (d, J=1.5 Hz, 1H).
FIA-MS, m/e 545.2 (m+1).
Analysis for C25H25ClN4O6S:
Calcd: C, 55.10; H, 4.62; N, 10.28;
Found: C, 55.36; H, 4.65; N, 10.00.
Using a procedure analogous to Example 161, N-(5-chloropyridin-2-yl)-4-methoxycarbonyl-2-[4-methylsulfinyl-2-(3-aminopropoxy)benzoylamino]benzamide gave the title compound as a white solid (240 mg, 46%).
1NMR (300 MHz, DMSO-d6): δ 2.12 (m, 2H), 2.82 (s, 3H), 2.94 (m, 2H), 4.39 (t, J=5.9 Hz, 2H), 7.39 (dd, J=1.1, 8.1 Hz, 1H), 7.51 (d, J=1.1 Hz, 1H) 7.78 (dd, J=1.5, 8.1 Hz, 1H), 7.86 (br s, 1H), 7.92 (d, J=8.1 Hz, 1H), 8.00 (m, 2H), 8.14 (d, J=8.8 Hz, 1H), 8.46 (d, J=2.6 Hz, 1H), 8.87 (d, J=1.1 Hz, 1H), 11.15 (s, 1H), 11.34 (s, 1H), 13.4 (br s, 1H).
FIA-MS, m/e 531.1 (m+1).
Analysis for C24H23ClN4O6S—HCl.0.75H2O:
Calcd: C, 49.53; H, 4.59; N, 9.36;
Found: C, 49.27; H, 4.21; N, 9.63.
Using a procedure analogous to Example 25, N-(5-chloropyridin-2-yl)-4-methoxycarbonyl-2-[4-methylthio-2-(3-t-butoxycarbonylamino)propoxy)benzoylamino]-benzamide gave the title compound as a white solid (1.82 g, 86%).
1NMR (300 MHz, DMSO-d6): δ 1.31 (s, 9H), 1.89 (m, 2H), 3.00 (m, 2H), 3.29 (s, 3H), 3.91 (s, 3H), 4.30 (t, J=6.2 Hz, 2H), 6.81 (m, 1H), 7.64 (m, 2H), 7.81 (dd, J=1.5, 8.1 Hz, 1H), 7.96 (m, 2H), 8.05 (d, J=8.1 Hz, 1H), 8.16 (d, J=8.8 Hz, 1H), 8.45 (d, J=2.6 Hz, 1H), 8.91 (s, 1H), 11.16 (s, 1H), 11.35 (s, 1H).
FIA-MS, m/e 661.1 (m+1).
Analysis for C30H33ClN4O9S:
Calcd: C, 54.50; H, 5.03; N, 8.47;
Found: C, 55.03; H, 4.88; N, 8.37.
Using a procedure analogous to Example 4-G, N-(5-chloropyridin-2-yl)-4-methoxycarbonyl-2-[4-methylsulfonyl-2-(3-t-butoxycarbonylamino)propoxy)benzoyl-amino]benzamide gave the title compound as a white solid (1.3 g, 88%).
1NMR (300 MHz, DMSO-d6): δ 1.88 (m, 2H), 2.73 (t, J=6.2 Hz, 2H), 3.29 (s, 3H), 3.90 (s, 3H), 4.31 (t, J=6.2 Hz, 2H), 7.61 (m, 2H), 7.68 (dd, J=1.5, 8.1 Hz, 1H), 7.90 (dd, J=2.6, 8.8 Hz, 1H), 8.05 (m, 2H), 8.19 (d, J=8.8 Hz, 1H), 8.36 (d, J=2.6 Hz, 1H), 9.01 (d, J=1.5 Hz, 1H).
FIA-MS, m/e 561.2 (m+1).
Analysis for C25H25ClN4O7S:
Calcd: C, 53.52; H, 4.49; N, 9.99;
Found: C, 53.61; H, 4.57; N, 9.86.
Using a procedure analogous to Example 161, N-(5-chloropyridin-2-yl)-4-methoxycarbonyl-2-[4-methylsulfonyl-2-(3-aminopropoxy)benzoylamino]benzamide gave the title compound as a white solid (380 mg, 73%).
1NMR (300 MHz, DMSO-d6): δ 2.12 (m, 2H), 2.94 (m, 2H), 3.30 (s, 3H), 4.40 (t, J=5.9 Hz, 2H), 7.67 (m, 2H), 7.80 (dd, J=1.5, 8.1 Hz, 1H), 7.85 (br s, 1H), 7.93 (d, J=8.4 Hz, 1H), 8.00 (m, 2H), 8.14 (d, J=8.8 Hz, 1H), 8.46 (d, J=2.6 Hz, 1H), 8.82 (s, 1H), 11.14 (s, 1H), 11.32 (s, 1H), 13.35 (br s, 1H).
FIA-MS, m/e 547.1 (m+1).
Analysis for C24H23ClN4O7S.HCl.0.5H2O:
Calcd: C, 48.66; H, 4.25; N, 9.46;
Found: C, 48.63; H, 3.99; N, 9.15.
Using a procedure analogous to Example 4-E, N-(5-chloropyridin-2-yl)-4-iodo-2-aminobenzamide and 4-methylthio-2-(1-t-butoxycarbonylpiperidin-4-yloxy)benzoic acid gave the title compound as a white solid (3.03 g, 84%).
1NMR (300 MHz, DMSO-d6): δ 1.36 (s, 9H), 1.78 (m, 2H), 1.88 (m, 2H), 2.55 (s, 3H), 3.04 (m, 2H), 3.67 (m, 2H), 4.86 (m, 1H), 6.95 (dd, J=1.8, 8.4 Hz, 1H), 7.07 (s, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.92 (m, 2H), 8.11 (s, 1H), 8.12 (d, J=8.8 Hz, 1H), 8.22 (d, J=8.8 Hz, 1H), 8.43 (d, J=2.6 Hz, 1H), 10.97 (s, 1H), 11.37 (s, 1H).
ES-MS, m/e 723.28 (m+1).
Analysis for C30H32 ClIN4O5S:
Calcd: C, 49.84; H, 4.46; N, 7.75;
Found: C, 49.81; H, 4.46; N, 7.66.
Using a procedure analogous to Example 25, N-(5-chloropyridin-2-yl)-4-iodo-2-[4-methylthio-2-(1-t-butoxycarbonyl)piperidino-4-yloxy)benzoylamino]benzamide gave the title compound as a white solid (2.41 g, 82%).
1NMR (300 MHz, DMSO-d6): δ 1.36 (s, 9H), 1.72 (m, 2H), 1.87 (m, 2H), 3.13 (m, 2H), 3.29 (s, 3H), 3.55 (m, 2H), 4.91 (m, 1H), 7.60 (dd, J=1.5, 8.1 Hz, 1H), 7.69 (s, 1H), 7.93 (m, 2H), 7.98 (d, J=8.1 Hz, 1H), 8.15 (m, 3H), 8.44 (d, J=2.6 Hz, 1H), 11.07 (s, 1H), 11.36 (s, 1H).
ES-MS, m/e 755.1 (m+1).
FAB+/MS, exact m/e: calc. 755.0803 (C30H33C11N4O7S); found 755.0793.
Using a procedure analogous to Example 4-G, N-(5-chloropyridin-2-yl)-4-iodo-2-[4-methylthio-2-(1-t-butoxycarbonylpiperidin-4-yloxy)benzoylamino]benzamide gave the title compound as a white solid (207 mg, 79%).
1NMR (300 MHz, DMSO-d6): δ 1.53 (m, 2H), 1.80 (m, 2H), 2.47 (m, 2H), 2.75 (m, 2H), 3.29 (s, 3H), 4.68 (m, 1H), 7.56 (s, 1H), 7.61 (s, 1H), 7.83 (m, 2H), 7.90 (d, J=2.6 Hz, 1H), 8.13 (d, J=8.8 Hz, 1H), 8.20 (d, J=1.8 Hz, 1H), 8.27 (d, J=8.8 Hz, 1H), 8.36 (d, J=2.2 Hz, 1H).
ES-MS, m/e: 655.0 (m+1).
A mixture of N-(5-chloropyridin-2-yl)-4-iodo-2-[4-methylsulfonyl-2-(1-t-butoxy-carbonylpiperidin-4-yloxy)benzoylamino]benzamide (755 mg, 1.0 mmol), Zn(CN)2 (82 mg, 0.7 mmol), Pd(PPh3)4 (58 mg, 0.05 mmol) and DMF (3 ml) was degassed and vented with nitrogen. The mixture was heated to 80° C. for 4 h, cooled to room temperature, diluted with water and filtered. The solid was suspended in CH2Cl2, with sonication, chromatographed (60 g SiO2, CH2Cl2 to 15% EtOAc/CH2Cl2), triturated with Et2O, and filtered to give the title compound as a white solid (634 mg, 97%).
1NMR (300 MHz, DMSO-d6): δ 1.35 (s, 9H), 1.73 (m, 2H), 1.89 (m, 2 h), 3.13 (m, 2H), 3.31 (s, 3H), 3.56 (m, 2H), 4.92 (m, 1H), 7.61 (dd, J=1.1, 8.1 Hz, 1H), 7.71 (s, 1H), 7.96 (dd, J=2.6, 8.8 Hz, 1H), 8.02 (d, J=8.8 Hz, 1H), 8.05 (dd, J=1.8, 8.8 Hz, 1H), 8.11 (d, J=9.1 Hz, 1H), 8.34 (d, J=1.8 Hz, 1H), 8.46 (d, J=2.2 Hz, 1H), 8.59 (d, J=8.4 Hz, 1H), 11.34 (s, 1H), 11.44 (s, 1H).
ES-MS, m/e 654.4 (m+1).
Analysis for C31H32ClI N5O7S:
Calcd: C, 56.92; H, 4.93; N, 10.71;
Found: C, 56.61; H, 4.76; N, 10.48.
Using a procedure analogous to Example 4-G, N-(5-chloropyridin-2-yl)-4-cyano-2-[4-methylsulfonyl-2-(1-t-butoxycarbonylpiperidin-4-yloxy)benzoylamino]benzamide gave the title compound as a white solid.
1NMR (300 MHz, DMSO-d6): δ 1.41 (m, 2H), 1.74 (m, 2H), 2.41 (m, 2H), 2.80 (m, 2H), 3.27 (s, 3H), 4.47 (m, 1H), 7.49 (m, 2H), 7.65 (dd, J=0.7, 7.4 Hz, 1H), 7.76 (m, 2H), 8.18 (d, J=2.2 Hz, 1H), 8.21 (d, J=7.7 Hz, 1H), 8.35 (d, J=1.8 Hz, 1H), 8.65 (d, J=9.1 Hz, 1H).
FAB+/MS, exact m/e: calc. 554.1265 (C26H24ClN5O5S+H); found 554.1263.
5-Fluoro-2-amino-N-(5-chloropyridin-2-yl)benzamide (5.32 g, 20 mmol) was added to a solution of 2 mL dry pyridine and 2-acetoxy-4-fluorobenzoyl chloride (21 mmol) in 100 mL dry methylene chloride under dry nitrogen with magnetic stirring. The reaction was allowed to stir overnight at room temperature and then was diluted with 500 mL of methylene chloride. The methylene chloride solution was washed with cold 1 M HCl, cold saturated NaHCO3, and brine; and then was dried over sodium sulfate. The solvent was evaporated, and the crude product was crystallized from acetone to give 2:92 g of off-white product.
1H NMR
ESMS [M+H]+446.1 calcd from C21H15ClF2N3O4 446
ESMS [M−H]−444.2 calcd from C21H13ClF2N3O4 444
Analysis for C21H14ClF2N3O4:
Calcd: C, 56.58; H, 3.17; N, 9.43;
Found: C, 53.76; H, 3.08; N, 8.66.
N-(5-Chloropyridin-2-yl)-5-fluoro-2-(2-acetoxy-4-fluorobenzoylamino)-benzamide (2.75 g, 6 mmol) was dissolved in 75 mL of methanol under nitrogen. The solution was cooled in an ice-water bath and 0.5M NaOH (13 mL, 6.5 mmol) was added.
The reaction mixture was stirred overnight warming to room temperature. HCl (6.5 mL, 1M, 6.5 mmol) was added. The mixture was diluted with additional water; and the precipitated solid was filtered, washed with water, and dried over KOH in vacuo at 35° C. to give 2.15 g of white solid (89% yield).
1H NMR
ESMS [M+H]+404.4 calcd from C19H12ClF2N3O3 404
ESMS [M−H]−402.2 calcd from C19H11ClF2N3O3 402
Analysis for C21H14ClF2N3O4:
Calcd: C, 56.52; H, 3.00; N, 10.41;
Found: C, 56.34; H, 2.93; N, 9.99.
N-(5-Chloropyridin-2-yl)-5-fluoro-2-(4-fluoro-2-hydroxybenzoylamino)-benzamide (1.62 g, 4 mmol), 8-hydroxy-1,4-dioxa-spiro[4.5]decane (630 mg, 4 mmol), and triphenylphosphine (1.04 g, 4 mmol) were dissolved in 4 mL dry DMF, 2 mL dry methylene chloride, and 6 mL dry THF. The resulting slurry was sonicated for 5 min, and then diisopropyl azodicarboxylate (DIAD, 0.8 mL, 4 mmol) was added; and the mixture was sonicated for 2 h. Ether (40 mL) was added, and the mixture was cooled in the freezer overnight. Triphenylphosphine oxide was filtered off, and the resulting solution was concentrated to dryness under reduced pressure. Flash chromatography on silica gel gave the crude product (1.53 g) as a viscous, colorless oil which was used without further purification.
N-(5-Chloropyridin-2-yl)-5-fluoro-2-[4-fluoro-2-(1,4-dioxa-spiro[4.5]decan-8-yl-oxy)benzoylamino]benzamide (1.5 g, 2.8 mmol) and 1.5 mL 1-methylhexahydro-1,4-diazepine were dissolved in 1.5 mL of dry DMSO and heated overnight in a pressure tube at 100° C. under Ar. The solution was cooled and poured into 1 L of ethyl acetate. The ethyl acetate solution was washed once with brine, dried over sodium sulfate and evaporated to dryness under reduced pressure at 40° C. to give the intermediate ketal as a yellow oil which was used without further purification.
N-(5-Chloropyridin-2-yl)-5-fluoro-2-[4-(4-methylhexahydro-1,4-diazepin-1-yl)-2-(1,4-dioxa-spiro[4.5]decan-8-yloxy)benzoylamino]benzamide (2.8 mmol) in was dissolved in 48 mL THF with magnetic stirring. The solution was cooled to ice water bath temperature and 5M HCl (9 mL) was added. The reaction mixture was allowed to stir overnight, warming to room temperature. Water (160 mL) was added and the pH of the mixture was adjusted to 12. The alkaline solution was extracted with methylene chloride. The extracts were washed with brine, dried over sodium sulfate, and evaporated under reduced pressure to give 1.64 g of a yellow glass. This material was dissolved in ether. A solution of trifluoroacetic acid (0.154 mL, 2.0 mmol) in ether was added with magnetic stirring. The resulting precipitate was filtered, washed with ether, and dried in vacuo over KOH pellets at room temperature to yield 550 mg of the title product as an off-white solid TFA salt.
1 HNMR
ESMS [M+H]+ 594.5 calcd from C31H34 ClFN5O4 594
ESMS [M−H]−592.5 calcd from C31H32 ClFN5O4 592
Analysis for C31H33 ClFN5O4.C2HF3O2:
Calcd: C, 55.98; H, 4.84; N, 9.89;
Found: C, 55.15; H, 4.93; N, 9.64.
To a stirred solution of 2-acetoxy-4-fluorobenzoic acid (852 mg, 4.9 mmol) in dry dichloromethane (40 mL) under dry nitrogen were added sequentially dry DMF (8 drops), dry pyridine (0.5 mL) and oxalyl chloride (0.5 mL). After stirring 1.5 h at room temperature, the reaction mixture was evaporated to dryness to afford 2-acetoxy-4-fluoro-benzoyl chloride.
The acid chloride (4.9 mmol) was dissolved in dry dichloromethane (40 mL) and treated with dry pyridine (0.5 mL) and 2-amino-5-chloro-N-(5-chloropyridin-2-yl)-benzamide (1.27 g). The reaction mixture was stirred at room temperature overnight before it was evaporated to dryness and taken up in ethyl acetate and water. After filtration of a small amount of insoluble material, 1 M HCl was added to bring the aqueous phase to about 0.5 M HCl. After separation of the phases, the organic phase was washed with sodium bicarbonate solution, then brine, and dried over sodium sulfate. The solution was evaporated to afford a tan solid (1.72 g), which was triturated with ether to afford a first crop (0.63 g) of the title compound as a tan solid. Evaporation of the ethereal mother liquour and trituration with ether afforded a second crop (0.41 g) of the title compound as a tan solid. Combined yield (1.04 g).
1NMR
2-(2-Acetoxy-4-fluorobenzoylamino)-5-chloro-N-(5-chloropyridin-2-yl)-benzamide (1.04 g, 2.17 mmol) was dissolved in methanol (25 mL) under nitrogen. The solutions was cooled in an ice-water bath and 0.5 M NaOH (5 mL, 2.5 mmol) was added.
The reaction mixture was stirred overnight, warming to room temperature. The reaction mixture was evaporated to dryness and taken up in ethyl acetate and water, which did not afford a homogeneous mixture, but a sold precipitate and an aqueous layer. After addition of additional ethyl acetate and 1 M HCl, the separated organic phase was evaporated to a small volume. The resulting solid was filtered, washed with water and dried under vacuum over KOH, first at room temperature to afford the title phenol (870 mg, 92%) as a light tan solid (1 NMR) which was further dried under vacuum over KOH at 40° C. prior to the next step.
Using a procedure similar to that of Example 64A, part C, 5-chloro-N-(5-chloro-pyridin-2-yl)-2-(4-fluoro-2-hydroxybenzoylamino)benzamide (860 mg) was O-alkylated to afford the title compound (220 mg, 19%) as a white solid.
1NMR
5-Chloro-N-(5-chloropyridin-2-yl)-2-[2-(1,4-dioxa-spiro[4.5]decan-8-yloxy)-4-fluorobenzoylamino]benzamide (220 mg, 0.38 mmol) under nitrogen was treated with pyrrolidine (2 mL, 24 mmol), and the stirred reaction mixture was heated 3 h in an 80° C. oil bath. After cooling to room temperature, water was added, and the solid product was filtered, washed with water, and dried under vacuum over KOH overnight to afford the crude product (170 mg) as an off white solid.
ESMS: 1223.2 [M+H+M]+; 610 [M−H]−
Using a procedure similar to that of Example 64A, part D, the ketal of 5-chloro-N-(5-chloropyridin-2-yl)-2-[2-(1,4-dioxa-spiro[4.5]decan-8-yloxy)-4-(pyrrolidino-1-yl)-benzoylamino]benzamide was hydrolyzed. After the diluted, acidic reaction mixture was adjusted to pH 8, the THF was evaporated; and the resulting was filtered, washed with water and dried under vacuum over KOH at room temperature to afford a cream colored solid (144 mg). Examination by TLC showed ketal hydrolysis incomplete; to the product was resubmitted to the hydrolysis conditions for an additional 6 h, leading to the isolation of a light yellow solid (127 mg) which was triturated with ether and dried under vacuum to afford the title ketone as a white solid (91 mg).
ESMS: 567 [M+H]+; 565 [M−H]
Using a procedure similar to that of Example 60, part H, methyl 4-(1-tert-butyloxycarbonylamino-1-methyl)ethyl-2-hydroxybenzoate (0.58 g) was O-alkylated to afford the title compound.
Using a procedure similar to that of Example 60, part I, first paragraph, methyl 4-(1-tert-butyloxycarbonylamino-1-methyl)ethyl-2-(1,4-dioxa-spiro[4.5]decan-8-yloxy)-benzoate (0.635 g) was converted into lithium 4-(1-tert-butyloxycarbonylamino-1-methyl)ethyl-2-(1,4-dioxa-spiro[4.5]decan-8-yloxy)benzoate.
Using a procedure similar to that of Example 60, part I, second paragraph, the lithium benzoate was converted into the corresponding benzoyl chloride.
Using a procedure similar to that of Example 60, part I, third paragraph, and 2-amino-5-chloro-N-(5-chloropyridin-2-yl)benzamide, the benzoyl chloride was converted into the title compound.
Using a procedure similar to that of Example 64A, part D, the ketal of 2-[4-(1-tert-butyloxycarbonylamino-1-methyl)ethyl-2-(1,4-dioxa-spiro[4.5]decan-8-yloxy)benzoyl-amino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide was hydrolyzed using 5 M HCl.
Using a procedure similar to that of Example 60, part J, the BOC group was removed. The resulting salt was purified by reversed phase chromatography to provide the product as a dihydrochloride.
1NMR, MS
Using a procedure similar to that of Example 60, part I, third paragraph, and 2-amino-N-(5-chloropyridin-2-yl)-5-fluorobenzamide, 4-(1-tert-butyloxycarbonylamino-1-methyl)ethyl-2-(1,4-dioxa-spiro[4.5]decan-8-yloxy)benzoyl chloride was converted into the title compound.
Using a procedure similar to that of Example 64A, part D, the ketal of 2-[4-(1-tert-butyloxycarbonylamino-1-methyl)ethyl-2-(1,4-dioxa-spiro[4.5]decan-8-yloxy)benzoyl-amino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide was hydrolyzed using 5 M HCl.
Using a procedure similar to that of Example 60, part J, the BOC group was removed. The resulting salt was purified by reversed phase chromatography to provide the product as a dihydrochloride.
1NMR, MS
By methods substantially equivalent to those described in Example 16-F, N-(5-chloropyridin-2-yl)-2-[(2-nitrobenzoyl)amino]benzamide (0.48 g, 75%) was prepared from N-(5-chloropyridin-2-yl)-2-aminobenzamide and 2-nitrobenzoyl chloride.
1NMR
IS-MS, m/e 397.1 (m+1)
Analysis for C19H13ClN4O4:
Calcd: C, 57.51; H, 3.30; N, 14.12;
Found: C, 57.52; H, 3.47; N, 13.88.
By methods substantially equivalent to those described in Example 139-B, N-(5-chloropyridin-2-yl)-2-[(2-aminobenzoyl)amino]benzamide (0.33 g, 96%) was prepared from N-(5-chloropyridin-2-yl)-2-[(2-nitrobenzoyl)amino]benzamide.
1NMR
IS-MS, m/e 367.1 (m+1)
By methods substantially equivalent to those described in Example 16-F, N-(5-chloropyridin-2-yl)-2-[2-[1-(4-pyridinyl)piperidin-4-ylcarbonylamino]benzoyl-amino]benzamide hydrochloride (0.208 g, 46%) was prepared from N-(5-chloropyridin-2-yl)-2-[(2-aminobenzoyl)amino]benzamide and 1-(4-pyridinyl)piperidin-2-ylcarbonyl chloride.
1NMR
IS-MS, m/e 555.2 (m+1)
Analysis for C30H27ClN6O3.HCl.0.5H2O:
Calcd: C, 59.97; H, 4.87; N, 14.00;
Found: C, 59.96; H, 4.78; N, 13.97.
in which R has the indicated value of Ra were prepared according to the indicated procedure from a requisite corresponding compound of formula I and the reagents and conditions appropriate for the indicated procedure or by a procedure otherwise noted.
R═BOC; Procedure:
Under a nitrogen atmosphere, 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-tert-butyl benzoic acid (1.52 g, 4 mmol) was dissolved in dry dichloromethane (25 mL) and dimethylformamide (0.25 mL) catalyst was added. Subsequently oxalyl chloride (0.423 mL, 4.85 mmol) was added portionwise via syringe. Vigorous gas evolution took place.
The mixture was stirred at room temperature for about 10 minutes until gas evolution nearly ceased, then the volatiles were evaporated under vacuum. The resulting milky-white residue was redissolved in 4:1 dichloromethane:toluene, concentrated again in vacuo, then dissolved in amylene-stabilized chloroform (10 mL) and transferred to an addition funnel. The acid chloride solution was added dropwise to a stirring ice-cold solution of 2-amino-N-(5-chloropyridin-2-yl)benzamide (1.0 g, 4 mmol) and pyridine (1.15 g, 14.5 mmol) in amylene-stabilized chloroform (20 mL). The mixture was then allowed to warm to room temperature with stirring overnight. The mixture was diluted with dichloromethane, washed once each with saturated sodium bicarbonate solution, water, and brine, then dried and concentrated in vacuo to provide a crusty brown foam.
The foam was purified on a 6 mm Chromatotron plate using 1:1 ether:hexanes. A mass of white solid precipitated from the eluted fractions. This material was washed several times with petroleum ether, then dried under high vacuum to provide 1.75 grams (71%) of 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(tert-butyl)benzoylamino]-N-(5-chloro-pyridin-2-yl)benzamide as a white solid.
1NMR
IS-MS, m/z 607.3 (m+)
Analysis for C33H39ClN4O5:
Calcd: C, 65.28; H, 6.48; N, 9.23;
Found: C, 65.51; H, 6.78; N, 9.31.
R═H; Procedure:
The 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(tert-butyl)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (1.57 g, 2.58 mmol) was dissolved in 20 mL of a 4 N HCl in dioxane solution at room temperature, resulting in a modest evolution of gas. After 1 hour stirring at room temperature, the solvent and HCl gas were evaporated in vacuo, then the resulting white solid was resuspended in 75 mL 2:1 EtOAc:dichloromethane and evaporated a second time. The pasty white solid was dissolved in a solution of K2 CO3 (11.2 g) in water (75 mL), dichloromethane was added (75 mL), and the mixture vigorously stirred overnight. The mixture was partitioned, the aqueous layer back-extracted twice with dichloromethane, then the combined organic layers washed with brine. The organic layer was dried and concentrated in vacuo to provide 2-[4-tert-butyl)-2-(piperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (1.32 g, 100%) as an off-white crystalline solid.
1NMR
IS-MS, m/z 507.3 (m+); 505.3 (m−1).
The 2-[4-(tert-butyl)-2-(piperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (30 mg, 59 pmunol) is placed in a 4 mL screw-cap vial, then the aldehyde (180 micromoles, 3 eq) or the ketone (at least 180 micromoles, at least 3 eq) is added directly to the amine. The amine and aldehyde component mixture are then dissolved in 1 mL of freshly prepared 95:5 anhydrous MeOH:AcOH. To this solution is added 0.5 mL freshly prepared sodium cyanoborohydride solution (15.1 mg/mL in 95:5 anhydrous MeOH:AcOH, 120 micromoles, 2 equivalents). The vial is capped and shaken overnight at room temperature on an orbital platform shaker (350 rpm). The crude reaction mixture is then applied to a solid phase extraction (SPE) cartridge (strong cation exchange (SCX), 6 cc volume, 1 gram of packing material from Varian Sample Preparation Products, Harbor City, Calif.) that has been pre-washed with methanol (2×5 mL). The cartridge is next washed with methanol (3-4×5 mL). The product is eluted with 0.5 M ammonia in methanol (2×5 mL). The resulting solution is concentrated in vacuo to afford the alkylated product, generally in 60-95% yield.
R=4-Methylbenzyl; Procedure A; IS-MS m/z 611.3 (m+1), 609 (m−1).
R=2-Nitrobenzyl; Procedure A; IS-MS m/z 642.3 (m+1).
R=2,3-Methylenedioxybenzyl; Procedure A; IS-MS m/z 641.3 (m+1), 639.4 (m−1).
The 2-[4-tert-butyl)-2-(piperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (30 mg, 59 pnol) in a 4 mL screw cap vial is dissolved in amylene-stabilized chloroform (1 mL). An isocyanate or isothiocyanate (1.3 equivalents) is then added directly to the amine solution and the resulting mixture shaken for 2-20 h at room temperature on an orbital shaker (350 rpm). Excess acylating agent is scavenged by adding aminomethylated polystyrene resin (100 mg 2.25 mmol/g loading) and amylene stabilized chloroform (1 mL) to the reaction vial. This slurry is shaken overnight, then filtered through a disposable polypropylene frit. Concentration of the filtrate affords clean product.
R=(2-Fluorophenyl)aminocarbonyl; Procedure B; IS-MS m/z 644.4 (m+1).
R=Benzyl; Procedure A; IS-MS m/z 597.5 (m+1), 595.6 (m−1).
R=2-Fluorobenzyl; Procedure A; IS-MS m/z 615.3 (m+1), 613.5 (m−1).
R=2-Chlorobenzyl; Procedure A; IS-MS m/z 631.3 (m+1), 629.7 (m−1).
R=2-Methoxybenzyl; Procedure A; IS-MS m/z 627.3 (m+1), 625.5 (m−1).
R=2-Ethoxybenzyl; Procedure A; IS-MS m/z 641.3 (m+1), 639.5 (m−1).
R=2-Hydroxybenzyl; Procedure A; IS-MS m/z 613.3 (m+1), 61-1.4 (m−1).
R=2-Methylbenzyl; Procedure A; IS-MS m/z 611.3 (m+1).
R=3-Methylbenzyl; Procedure A; IS-MS m/z 611.3 (m+1), 609.4 (m−1).
R=Thien-2-ylmethyl; Procedure A; IS-MS m/z 603.3 (m+1).
R=3-Methylthien-2-ylmethyl; Procedure A; IS-MS m/z 617.4 (m+1), 615.6 (m−1).
R=Thien-3-ylmethyl; Procedure A; IS-MS m/z 603.3 (m+1).
R=Cyclopropylmethyl; Procedure A; IS-MS m/z 561.3 (m+1), 559.4 (m−1).
R=2-Carboxybenzyl; Procedure A; IS-MS m/z 641.3 (m+1), 639.4 (m−1).
R=Imidazol-2-ylmethyl; Procedure A; IS-MS m/z 587.3 (m+1), 585.3 (m−1).
R=2-Pyridinylmethyl; Procedure A; IS-MS m/z 598.4 (m+1), 596.5 (m−1).
R=2-Cyanobenzyl; Procedure A; IS-MS m/z 622.5 (m+1).
R=Thiazol-2-ylmethyl; Procedure A; IS-MS m/z 604.3 (m+1), 602.4 (m−1).
R=5-Methylimidazol-4-ylmethyl; Procedure A; IS-MS m/z 601.4 (m+1), 599.4 (m−1).
R=2-Methoxycarbonylbenzyl; Procedure A; IS-MS m/z 655.5 (m+1), 653.5 (m−1).
R=Methyl; Procedure A; IS-MS m/z 521.4 (m+1).
R=2-Methoxyethyl; Procedure A, modified such that the aqueous solution of methoxyacetaldehyde was passed over a diatomaceous earth column before addition to the amine; IS-MS m/z 562.2 (m+1), 563.3 (m−1).
To 2-[4-(tert-butyl)-2-(piperidin-4-yloxy)benzoylamino]-N-(5-chloropyrdin-2-yl)benzamide (30 mg, 59 pmnol) in a 4 mL screw cap vial is added polymer-supported carbodiimide (P-EPC, 280 mg 0.85 mmol/g, 4 eq) and a carboxylic acid of choice (120 micromoles, 2 eq), followed by 3 mL of 4:1 (amylene stabilized) chloroform:tert-butyl alcohol. Where acid hydrochloride salts are used, piperidinomethyl polystyrene resin (100 mg 2.6-2.8 mmol/g) is added to effect reaction. The vial is capped, shaken overnight at room temperature, then the mixture is filtered. Retentates are washed with amylene stabilized chloroform (3 mL), and the combined filtrate and wash are concentrated in vacuo to afford the amide derivative of the compound of Example 202.
R=2-Oxo-2-(2-thiophenyl)acetyl; Procedure C; IS-MS m/z 645.0 (m+1), 643.0 (m−1).
R=Isopropyl; Procedure A; IS-MS m/z 549.4 (m+1).
R=Propyl; Procedure A; IS-MS m/z 549.2 (m+1), 547.3 (m−1).
General Procedure D for Alkylation of Secondary Amines Such as the Compound Described in Example 202 with Epoxides:
To 2-[4-(tert-butyl)-2-(piperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (30 mg, 59 μmol) in a 4 mL screw cap vial is added a selected epoxide (120 micromoles, 2 eq) and methanol (350 microliters). The vial is capped, heated to 60° C. for 16-24 h, then the mixture is diluted with methanol and purified via SCX solid phase extraction as described in general procedure A to afford the (hydroxyethyl)alkylamine.
R=2-Hydroxypropyl; Procedure D; IS-MS m/z 565.1 (m+1), 563.1 (m−1).
R=2-Phenylpropyl; Procedure A; IS-MS m/z 625.1 (m+1), 623.1 (m−1).
R=2-Methylbutyl; Procedure A; IS-MS m/z 577.1 (m+1), 575.1 (m−1).
R=(Methoxyethyl)aminothiocarbonyl; Procedure B; IS-MS m/z 624.0 (m+1), 622.1 (m−1).
R=(3-Diethylaminopropyl)aminothiocarbonyl; Procedure B; IS-MS m/z 679.1 (m+1), 677.2 (m−1).
R=2-hydroxy-3,3,3-trifluoropropyl; Procedure D; IS-MS m/z 619.0 (m+1), 617.1 (m−1).
R=2-Phenylethyl; Procedure A; IS-MS m/z 611.1 (m+1), 609.1 (m−1).
R=(3-Dimethylaminopropyl)aminothiocarbonyl; Procedure B; IS-MS m/z 651.1 (m+1), 649.1 (m−1).
R=3-(Morpholin-4-yl)propylaminothiocarbonyl Procedure B; IS-MS m/z 693.1 (m+1), 691.1 (m−1).
R=(3-Pyridinylmethyl)aminothiocarbonyl; Procedure B; IS-MS m/z 657.0 (m+1), 655.1 (m−1).
R=2-(2-Furanyl)-2-oxoacetyl; Procedure C; IS-MS m/z 629.0 (m+1), 627.1 (m−1).
R=1-Methylpyrazol-5-ylcarbonyl; Procedure C; IS-MS m/z 615.0 (m+1), 613.1 (m−1).
R=3,3-Dimethylbutyl; Procedure A; IS-MS m/z 591.1 (m+1), 589.2 (m−1).
R=3-Carboxypropionyl; Procedure C using succinic anyhdride with polymer-supported base and without polymer-supported carbodiimide; IS-MS m/z 607.0 (m+1), 605.1 (m−1).
R=1-Methylpyrrol-2-ylcarbonyl; Procedure C; IS-MS m/z 614.2 (m+1).
R=(Dimethylamino)acetyl; Procedure C; IS-MS m/z 592.2 (m+1), 590.3 (m−1).
R=3-Methylbutyl; Procedure A; IS-MS m/z 577.2 (m+1), 575.3 (m−1).
R=Pyruvoyl; Procedure C; IS-MS m/z 577.2 (m+1), 575.3 (m−1).
R=E/Z-3-(Furan-2-yl)prop-2-enyl; Procedure A; IS-MS m/z 613.2 (m+1).
R=E/Z-3-Phenylprop-2-enyl; Procedure A; IS-MS m/z 623.2 (m+1).
R=3-Phenylpropyl; Procedure A; IS-MS m/z 625.3 (m+1).
R=n-Butyl; Procedure A; IS-MS m/z 563.2 (m+1).
R=2-(Thien-2-yl)ethylaminocarbonyl; Procedure B; IS-MS m/z 660.2 (m+1).
R=Tetrazol-1-ylacetyl; Procedure C; IS-MS m/z 617.1 (m+1), 615.2 (m−1).
R=(3-Methoxypropyl)aminothiocarbonyl; Procedure B; IS-MS m/z 638.2 (m+1).
R=2-Hydroxy-3,3-dimethylbutyl; Procedure D; IS-MS m/z 607.2 (m+1), 605.3 (m−1).
in which R has the indicated value of Ra were prepared according to the indicated procedure from a requisite corresponding compound of formula I and the reagents and conditions appropriate for the indicated procedure or by a procedure otherwise noted.
R═BOC; Procedure:
Using methods substantially equivalent to Example 21-C, except that the Mitsonobu reaction was allowed to proceed for 7 to 10 days, methyl 2-(3-tert-butoxy-carbonylamino-2,2-dimethylpropoxy)-4-(tert-butyl)benzoate (10.85 g, 39%) as a pale yellow brittle foam was prepared from methyl 4-(tert-butyl)salicylate (14.72 g, 70.8 mmol) and 3-(tert-butoxycarbonylamino)-2,2-dimethylpropanol (14.37 g, 70.8 mmol).
1NMR
IR (KBr): 3339, 1722, 1691 cm−1.
IS-MS, m/z 394.2 (m+1), 392.4 (m−1).
Analysis for C22H35NO5:
Calcd: C, 67.15; H, 8.96; N, 3.56;
Found: C, 61.13; H, 8.11; N, 3.24.
Using methods substantially equivalent to those described in Example 21-D, 2-(3-tert-butoxycarbonylamino-2,2-dimethylpropoxy)-4-(tert-butyl)benzoic acid (10.6 g, 102%) was prepared from methyl-2-(3-tert-butoxycarbonylamino-2,2-dimethylpropoxy)-4-(tert-butyl)benzoate (10.8 g, 27.4 mmol).
Using methods substantially equivalent to those described in Example 201, 2-[2-(3-tert-butoxycarbonylamino-2,2-dimethylpropoxy)-4-(tert-butyl)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide was prepared from 2-(3-tert-butoxycarbonylamino-2,2-dimethylpropoxy)-4-(tert-butyl)benzoic acid and N-(5-chloropyridin-2-yl)-2-amino-benzamide to provide, after silica gel purification, 1.98 g (80.5%) of a yellow foam.
1NMR
IS-MS, m/z 609.3 (m+1), 607.5 (m−1)
Analysis for C33H41ClN4O5:
Calcd: C, 65.07; H, 6.78; N, 9.20;
Found: C, 64.46; H, 6.63; N, 8.90.
R═H; Procedure:
2-[2-(3-tert-butoxycarbonylamino-2,2-dimethylpropoxy)-4-(tert-butyl)benzoyl-amino]-N-(5-chloropyridin-2-yl)benzamide (1.50 g, 2.48 mmol) was dissolved in TFA (5 mL) and stirred at room temperature for 3 h. The TFA was removed in vacuo to give a yellow oil. The free base was obtained from the salt by loading onto 3 SCX columns (60 cc, 10 g; prewashed with MeOH). The columns were washed with 9:1 CHCl3:MeOH, and the free amine eluted with 3:1 CHCl3:2 N NH3 in MeOH to provide 2-[2-(3-amino-2,2-dimethylpropoxy)-4-(tert-butyl)benzoylamino]-N-(5-chlropyridin-2-yl)benzamide (1.08 g, 86.4%) as a pale yellow foam.
1NMR
IS-MS m/z 504.3 (m+1), 502.4 (m−1).
R=1-Methylpyrrol-2-ylcarbonyl; Procedure C; IS-MS m/z 616.4 (m+1), 614.4 (m−1).
R=3-Methylthien-2-ylcarbonyl; Procedure C; IS-MS m/z 633.3 (m+1), 631.5 (m−1).
R=3-Thienylcarbonyl; Procedure C; IS-MS m/z 619.6 (m+1), 617.5 (m−1).
R=2-Fluorobenzoyl; Procedure C; IS-MS m/z 631.3 (m+1), 629.5 (m−1).
R=2-Oxo-2-(2-thienyl)acetyl; Procedure C; IS-MS m/z 647.5 (m+1), 645.6 (m−1).
R=(3-Thienyl)acetyl; Procedure C; IS-MS m/z 633.4 (m+1), 631.4 (m−1).
R=2-Methylbenzoyl; Procedure C; IS-MS m/z 627.4 (m+1), 625.5 (m−1).
R=3-(2-Pyridinyl)-1-oxopropyl; Procedure C; IS-MS m/z 642.3 (m+1), 640.4 (m−1).
R=2-Thienylcarbonyl; Procedure C; IS-MS m/z 642.3 (m+1), 640.4 (m−1).
R=(2-Thienyl)acetyl; Procedure C; IS-MS m/z 633.6 (m+1), 631.3 (m−1).
To an aldehyde (98 mmol, 2 eq) in a 1 mL screw cap vial is added 2-[2-(3-amino-2,2-dimethylpropoxy)-4-(tert-butyl)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (25 mg, 49 mmol) as a solution in MeOH (0.25 mL). The vial is capped and allowed to stand at room temperature. After 1 h, excess solid NaBH4 is added, and the vials are left capped at room temperature overnight. The reaction is diluted with MeOH (0.5 mL) and CHCl3 (0.5 mL) and a drop of AcOH is added. The solution is applied to a prewashed (MeOH) 10 cc, 0.5 g SCX solid phase extraction cartridge, and the cartridge is washed with 2×5 mL of CHCl3:MeOH (9:1). The product is eluted with 2×5 mL of CHCl3:2 N NH3 in MeOH, and the solvent is removed in vacuo to give the purified product.
R=2-Fluorobenzyl; Procedure G; IS-MS m/z 617.4 (m+1), 615.2 (m−1).
R=3-Methylthien-2-ylmethyl; Procedure G; IS-MS m/z 619.5 (m+1), 617.6 (m−1).
R=2,3-Dimethoxybenzyl; Procedure G; IS-MS m/z 659.4 (m+1), 657.4 (m−1).
R=2-Methoxybenzyl; Procedure G; IS-MS m/z 629.3 (m+1), 627.5 (m−1).
R=2-Methylbenzyl; Procedure G; IS-MS m/z 613.5 (m+1), 611.4 (m−1).
R=2,3-Methylenedioxybenzyl; Procedure G; IS-MS m/z 643.4 (m+1), 641.4 (m−1).
R=2-Hydroxy-6-methoxybenzyl; Procedure G; IS-MS m/z 645.6 (m+1), 643.5 (m−1).
N-(5-Chloropyridin-2-yl)-2-(2-hydroxy-4-isopropylbenzoylamino)benzamide (2.55 g, 6.23 mmol), 3-bromo-1-propanol (867 mg, 0.564 mL, 6.23 mmol) and triphenyl-phosphine (1.63 g, 6.23 mmol) were dissolved in dry THF (25 mL) under a nitrogen atmosphere, then cooled on ice. To the chilled solution was then added dropwise diisopropyl azidodicarboxylate (1.26 g, 1.23 mL, 6.23 mmol) via syringe over a 15 minute period. The mixture was stirred on ice for 15 minutes more, then it was allowed to warm to room temperature with stirring overnight. The reaction was concentrated in vacuo, redissolved in dichloromethane (200 mL), washed twice with saturated sodium bicarbonate, once with brine, then dried and concentrated to provide a yellow oil. This oil was partially purified by flash chromatography on about 250 g silica (isocratic 95:5 dichloromethane:EtOAc) to yield 2.4 g of a pale yellow oil. This material was divided in half and each portion applied to a 4 mm chromatotron plate equilibrated with dichloromethane. The product was eluted with 95:5 dichloromethane:EtOAc and the clean fractions were pooled and concentrated to provide 2.34 g (71%) of 2-[2-(3-bromo-propyl)-4-isopropylbenzoylamino]-N-(5-chloropyridin-2-yl)benzamide as a crystalline white solid.
1NMR
IS-MS, m/z 530.1/532.1 (m+1)
Analysis for C25H25 BrClN3O3:
Calcd: C, 56.57; H, 4.75; N, 7.92;
Found: C, 56.27; H, 4.73; N, 8.03.
in which R has the indicated value of NRaRb were prepared from an amine of formula HNRaRb according to the indicated procedure from the above intermediate corresponding to a compound of formula I-4 in which R is bromo and the reagents and conditions appropriate for the indicated procedure or by a procedure otherwise noted.
To 2-[2-(3-bromopropyl)-4-isopropylbenzoylamino]-N-(5-chloropyridin-2-yl)-benzamide (22 mg, 42 μmol) in a 4 mL screw cap vial is added a primary or secondary amine of choice (120 μmol, 3 equiv) and dimethylformamide (0.25 mL). The vial is capped, and the reaction mixture is heated at 60° C. for 16-36 hours and then allowed to cool to room temperature. Excess primary amines are scavenged by the addition of resin-supported aldehyde (formylmethyl polystyrene, 120 mg@about 1 mmol/g), resin-supported base (piperidinomethylpolystyrene, 100 mg@2.6-2.8 mmol/g), and amylene stabilized chloroform (3 mL). Excess secondary amines are scavenged in the same fashion, except that resin-supported isocyanate (methylisocyanate polystyrene resin, Novabiochem, San Diego, Calif., 150 mg@1 mmol/g) is used instead of aldehyde resin. The resulting slurry is shaken at room temperature on an orbital shaker (350 rpm) overnight, then applied to a pre-washed (1:1 chloroform:MeOH) 6 cc, 1 gram SCX solid phase extraction cartridge. The remaining slurry in the vial is washed with chloroform (3 mL) and the wash is added to the cartridge. The cartridge containing resin slurry is washed once with 5 mL of 1:1 chloroform:MeOH, three times with 5 mL portions of MeOH, then allowed to dry overnight. The dried resin over the SCX media is discarded and the cartridge rinsed once with MeOH (5 mL). The product is eluted with two 5 mL portions of 0.5 M NH3 in MeOH and the eluent is concentrated in vacuo. The residue is then dissolved in 4 mL 1:1 chloroform:MeOH, filtered (0.45 micron teflon filter, Gelman Sciences), and concentrated in vacuo to provide the desired product.
R=4-Morpholinyl; Procedure E; IS-MS m/z 537.0 (m+1), 535.1 (m−1).
R=4-Thiomorpholinyl; Procedure E; IS-MS m/z 553.0 (m+1), 551.1 (m−1).
R=Piperidin-1-yl; Procedure E; IS-MS m/z 535.0 (m+1), 533.1 (m−1).
R=4-Hydroxypiperidin-1-yl; Procedure E; IS-MS m/z 551.0 (m+1), 549.1 (m−1).
R=Azetidin-1-yl; Procedure E; IS-MS m/z 507.0 (m+1), 505.0 (m−1).
R=Pyrrolidin-1-yl; Procedure E; IS-MS m/z 521.0 (m+1), 519.1 (m−1).
R=3-Carbamoylpiperidin-1-yl; Procedure E; IS-MS m/z 578.0 (m+1), 576.0 (m−1).
R=Cyclopropylamino; Procedure E; IS-MS m/z 507.0 (m+1), 505.1 (m−1).
R=Cyclobutylamino; Procedure E; IS-MS m/z 521.0 (m+1), 519.1 (m−1).
R=Cyclopentylamino; Procedure E; IS-MS m/z 535.1 (m+1), 533.1 (m−1).
R=Cyclohexylamino; Procedure E; IS-MS m/z 549.1 (m+1), 547.1 (m−1).
R=(3-Methylcyclohexyl)amino; Procedure E; IS-MS m/z 563.1 (m+1), 561.2 (m−1).
R=(4-Methylcyclohexyl)amino; Procedure E; IS-MS m/z 563.1 (m+1), 561.2 (m−1).
R=(5-Hydroxy-1,3,3-trimethylcyclohexylmethyl)amino; Procedure E;
IS-MS m/z 621.1 (m+1), 619.2 (m−1).
R=Cyclooctylamino; Procedure E; IS-MS m/z 577.1 (m+1), 575.2 (m−1).
R═N-Methyl-N-(2-hydroxyethyl)amino; Procedure E; IS-MS m/z 525.0 (m+1), 523.1 (m−1).
R=(1-Ethylpyrrolidin-2-ylmethyl)amino; Procedure E; IS-MS m/z 578.1 (m+1), 576.2 (m−1).
R═N-Propyl-N-(hydroxyethyl)amino; Procedure E; IS-MS m/z 553.1 (m+1), 551.1 (m−1).
R=2-(1-Pyrrolidinyl)ethylamino; Procedure E; IS-MS m/z 564.1 (m+1), 562.1 (m−1).
R=(2-Furanylmethyl)amino; Procedure E; IS-MS m/z 547.0 (m+1), 545.1 (m−1).
R=Cycloheptylamino; Procedure E; IS-MS m/z 563.1 (m+1), 561.2 (m−1).
R=Octahydroazocin-1-yl; Procedure E; IS-MS m/z 563.1 (m+1), 561.2 (m−1).
R=1-(Hydroxymethyl)-3-(methylthio)propylamino; Procedure E; IS-MS m/z 585.0 (m+1), 583.1 (m−1).
R=1,3-Thiazolidin-1-yl; Procedure E; IS-MS m/z 539.0 (m+1), 537.1 (m−1).
R═(S)-2-(2-Hydroxyethyl)pyrrolidin-1-yl; Procedure E; IS-MS m/z 551.0 (m+1), 549.1 (m−1).
R=3-Hydroxypyrrolidin-1-yl; Procedure E; IS-MS m/z 537.0 (m+1), 535.1 (m−1).
R=(2-Tetrahydrofuranylmethyl)amino; Procedure E; IS-MS m/z 551.0 (m+1), 549.1 (m−1).
R=4-Phenylpiperazin-1-yl; Procedure E; IS-MS m/z 612.1 (m+1), 610.1 (m−1).
R=4-(4-Pyridyl)piperazin-1-yl; Procedure E; IS-MS m/z 613.1 (m+1), 611.1 (m−1).
R=4-(2-Methoxyphenyl)piperazin-1-yl; Procedure E; IS-MS m/z 642.2 (m+1), 640.1 (m−1).
R=3,4-Didehydropiperidin-1-yl; Procedure E; IS-MS m/z 533.0 (m+1), 531.1 (m−1).
R=4-Methylpiperazin-1-yl; Procedure E; IS-MS m/z 550.1 (m+1), 548.1 (m−1).
R=4-[2-(1-Pyrrolidinyl)-2-oxoethyl]piperazin-1-yl; Procedure E; IS-MS m/z 647.1 (m+1), 645.2 (m−1).
R=4-(2-Hydroxyethyl)piperazin-1-yl; Procedure E; IS-MS m/z 580.1 (m+1), 578.1 (m−1).
R=2,6-Dimethylmorpholin-4-yl; Procedure E; IS-MS m/z 565.1 (m+1), 563.1 (m−1).
R=2-Methylpiperidin-1-yl; Procedure E; IS-MS m/z 549.1 (m+1), 547.1 (m−1).
R=2,2,6,6-Tetramethylpiperidin-4-ylamino; Procedure E; IS-MS m/z 606.1 (m+1), 604.2 (m−1).
R=2-Hydroxymethylpiperidin-1-yl; Procedure E; IS-MS m/z 565.1 (m+1), 563.1 (m−1).
R=2-(2-Hydroxyethyl)piperidin-1-yl; Procedure E; IS-MS m/z 579.1 (m+1), 577.1 (m−1).
R=3,5-Dimethylpiperidin-1-yl; Procedure E; IS-MS m/z 563.1 (m+1), 561.2 (m−1).
R=3-Hydroxymethylpiperidin-1-yl; Procedure E; IS-MS m/z 565.0 (m+1), 563.1 (m−1).
R=4-Methylpiperidin-1-yl; Procedure E; IS-MS m/z 549.1 (m+1), 547.1 (m−1).
R=4-(2-Hydroxyethyl)piperidin-1-yl; Procedure E; IS-MS m/z 579.1 (m+1), 577.1 (m−1).
R=4-(2-Pyridinyl)piperazin-1-yl; Procedure A; IS-MS m/z 613.1 (m+1), 611.1 (m−1).
R=2-Pyridinylmethylamino; Procedure E; IS-MS m/z 558.0 (m+1), 556.1 (m−1).
R=3-Pyridinylmethylamino; Procedure E; IS-MS m/z 558.0 (m+1), 556.1 (m−1).
R=4-(1-Piperidinyl)piperidin-1-yl; Procedure E; IS-MS m/z 618.1 (m+1), 616.2 (m−1).
R═N-Methyl-N-(1-methylpiperidin-4-yl)amino; Procedure E; IS-MS m/z 578.1 (m+1), 576.1 (m−1).
R=2-(1-Piperidinyl)ethylamino; Procedure E; IS-MS m/z 578.1 (m+1), 576.2 (m−1).
R=Hexahydroazepin-1-yl; Procedure E; IS-MS m/z 549.1 (m+1), 547.1 (m−1).
R=2,2,5-Trimethylhexahydroazepin-1-yl; Procedure E; IS-MS m/z 591.1 (m+1), 589.1 (m−1).
R=1,1-Dimethyl-2-hydroxyethylamino; Procedure E; IS-MS m/z 539.0 (m+1), 537.1 (m−1).
R=Isopropylamino; Procedure E; IS-MS m/z 509.1 (m+1), 507.1 (m−1).
R=Benzylamino; Procedure E; IS-MS m/z 557.1 (m+1), 555.1 (m−1).
R=2-(Acetylamino)ethylamino; Procedure E; IS-MS m/z 552.1 (m+1), 550.1 (m−1).
R=2-(Dimethylamino)ethylamino; Procedure E; IS-MS m/z 538.1 (m+1), 536.2 (m−1).
R=2-Methoxyethylamino; Procedure E; IS-MS m/z 525.1 (m+1), 523.1 (m−1).
R=2-Hydroxyethylamino; Procedure E; IS-MS m/z 511.1 (m+1), 509.1 (m−1).
R=Propargylamino; Procedure E; IS-MS m/z 505.0 (m+1), 503.1 (m−1).
R=3-Hydroxypropylamino; Procedure E; IS-MS m/z 525.1 (m+1), 523.1 (m−1).
R=4-Hydroxybutylamino; Procedure E.
R═N,N-Dimethylamino; Procedure E; IS-MS m/z 495.1 (m+1), 493.1 (m−1).
R═N-Ethyl-(2-dimethylamino)ethylamino; Procedure E; IS-MS m/z 566.1 (m+1), 564.2 (m−1).
R═(S)-2-(Methoxymethyl)pyrrolidin-1-yl; Procedure E; IS-MS m/z 565.1 (m+1), 563.2 (m−1).
R=1-Hydroxymethylcyclopentylamino; Procedure E; IS-MS m/z 565.1 (m+1), 563.2 (m−1).
R=1,2-Diethylpyrazolidin-4-ylamino; Procedure E; IS-MS m/z 593.1 (m+1), 591.2 (m−1).
R═(S)-2-(1-Pyrrolidinylmethyl)pyrrolidin-1-yl; Procedure E; IS-MS m/z 604.1 (m+1), 602.2 (m−1).
R=1-Methyl-2-(dimethylamino)ethylamino; Procedure E; IS-MS m/z 552.1 (m+1), 550.2 (m−1).
R=2-(Methylthio)ethylamino; Procedure E; IS-MS m/z 541.0 (m+1), 539.1 (m−1).
R═N-Methyl-N-[2-(dimethylamino)ethyl]amino; Procedure E; IS-MS m/z 552.1 (m+1), 550.2 (m−1).
R=1-Isopropyl-2-methylpropylamino; Procedure E; IS-MS m/z 565.1 (m+1), 563.2 (m−1).
R=2-[2-(Pyrrolidin-1-yl)ethyl]piperidin-1-yl; Procedure E; IS-MS m/z 632.2 (m+1), 630.2 (m−1).
R═N-Methyl-N-(3-pyridinylmethyl)amino; Procedure E; IS-MS m/z 572.1 (m+1), 570.2 (m−1).
R═N-Ethyl-N-(4-pyridinylmethyl)amino; Procedure E; IS-MS m/z 586.1 (m+1), 584.1 (m−1).
R=4-(1-Pyrrolidinyl)piperidin-1-yl; Procedure E; IS-MS m/z 604.1 (m+1), 602.2 (m−1).
R=4-(Furan-2-ylcarbonyl)piperazin-1-yl; Procedure E; IS-MS m/z 630.1 (m+1), 628.1 (m−1).
R=4-(2-Chlorophenyl)piperazin-1-yl; Procedure E; IS-MS m/z 646.1 (m+1), 644.1 (m−1).
R=4-(3-Chlorophenyl)piperazin-1-yl; Procedure E; IS-MS m/z 646.1 (m+1), 644.1 (m−1).
R=4-(3-Methylphenyl)piperazin-1-yl; Procedure E; IS-MS m/z 626.1 (m+1), 624.2 (m−1).
R=4-(2-Pyrimidinyl)piperazin-1-yl; Procedure E; IS-MS m/z 614.1 (m+1), 612.2 (m−1).
R=4-(2-Pyrazinyl)piperazin-1-yl; Procedure E; IS-MS m/z 614.1 (m+1), 612.2 (m−1).
R=2,2-Dimethyl-3-(dimethylamino)propylamino; Procedure E; IS-MS m/z 580.2 (m+1), 578.2 (m−1).
R=2-hydroxy-1-(hydroxymethyl)ethylamino; Procedure E; IS-MS m/z 541.1 (m+1), 539.1 (m−1).
R=4-Acetylpiperazin-1-yl; Procedure E; IS-MS m/z 578.1 (m+1), 576.2 (m−1).
R=4-Methylhexahydro-1,4-diazepin-1-yl; Procedure E; IS-MS m/z 564.1 (m+1), 562.2 (m−1).
R=2,2-Dimethyl-3-hydroxypropylamino; Procedure E; IS-MS m/z 553.1 (m+1), 551.2 (m−1).
R═(R)-2-Hydroxymethylpyrrolidin-1-yl; Procedure E; IS-MS m/z 551.1 (m+1), 549.2 (m−1).
R═(S)-2-Hydroxy-1-methylethylamino; Procedure E; IS-MS m/z 525.1 (m+1), 523.2 (m−1).
R═(R)-2-Hydroxy-1-methylethylamino; Procedure E; IS-MS m/z 525.1 (m+1), 523.2 (m−1).
R═(S)-2-Hydroxymethylpropylamino; Procedure E; IS-MS m/z 539.1 (m+1), 537.2 (m−1).
R═(R)-2-Hydroxymethylpropylamino; Procedure E; IS-MS m/z 539.1 (m+1), 537.2 (m−1).
R═(S)-2-Hydroxypropylamino; Procedure E; IS-MS m/z 525.1 (m+1), 523.2 (m−1).
R═(R)-2-Hydroxypropylamino; Procedure E; IS-MS m/z 525.1 (m+1), 523.2 (m−1).
R═(S)-Hexahydro-2-oxoazepin-3-ylamino; Procedure E; IS-MS m/z 578.1 (m+1), 576.2 (m−1).
R=Cis-2,6-Dimethyl-piperidin-1-yl; Procedure E; IS-MS m/z 563.1 (m+1), 561.2 (m−1).
R=1,3,3-Trimethyl-6-azabicyclo[3.2.1]octan-6-yl; Procedure E; IS-MS m/z 603.2 (m+1), 601.2 (m−1).
R=trans-4-Hydroxycyclohexylamino; Procedure E; IS-MS m/z 565.1 (m+1), 563.2 (m−1).
R═(S)-3-(Acetylamino)pyrrolidin-1-yl; Procedure E; IS-MS m/z 578.1 (m+1), 576.2 (m−1).
R═N-Methyl-N-(2-methoxyethyl)amino; Procedure E; IS-MS m/z 539.1 (m+1), 537.2 (m−1).
R=4-Cyclopentylpiperazin-1-yl; Procedure E; IS-MS m/z 604.2 (m+1), 602.2 (m−1).
R=4-Hydroxymethylpiperidin-1-yl; Procedure E; IS-MS m/z 565.1 (m+1), 563.2 (m−1).
R═(S)-3-(Dimethylamino)pyrrolidin-1-yl; Procedure E; IS-MS m/z 564.1 (m+1), 562.2 (m−1).
R═(S)-1-Hydroxymethyl-2,2-dimethylpropylamino; Procedure E; IS-MS m/z 567.1 (m+1), 565.2 (m−1).
R═(S)-1-Hydroxmethyl-3-methylbutylamino; Procedure E; IS-MS m/z 567.1 (m+1), 565.2 (m−1).
R═(S)-1-Hydroxymethyl-2-methylpropylamino; Procedure E; IS-MS m/z 553.1 (m+1), 551.2 (m−1).
R═(R)-α-Methylbenzylamino; Procedure E; IS-MS m/z 571.1 (m+1), 569.2 (m−1).
R═(S)-α-Methylbenzylamino; Procedure E; IS-MS m/z 571.1 (m+1), 569.2 (m−1).
R═(R)-α-(Hydroxymethyl)benzylamino; Procedure E; IS-MS m/z 587.1 (m+1), 585.1 (m−1).
Using methods substantially equivalent to those described in Example 201, N-(5-chloropyridin-2-yl)-2-[2-(oxiranylmethyl)-4-isopropylbenzoylamino]benzamide was prepared from glycidol and N-(5-chloropyridin-2-yl)-2-[2-hydroxy-4-isopropyl-benzoylamino]benzamide. This compound contained diisopropyl hydrazodicarboxylate as a contaminant (about 30%) after two rounds of silica gel flash chromatography, first with hexanes through 6:4 hexanes:EtOAc, then with 95:5 dichloromethane:EtOAc. Partially purified material was carried on directly to the next transformation.
IS-MS, m/z 466.2 (m+1), 464.3 (m−1).
in which R has the indicated value of NRaRb were prepared according to the indicated procedure from a requisite amine of formula HNRaRb and the above described epoxide and the reagents and conditions appropriate for the indicated procedure or by a procedure otherwise noted.
Procedure F is substantially equivalent to that described in general procedure E, except that 2 or more equivalents of nucleophilic amine are employed and the piperidinomethylpolystyrene resin is omitted.
R=Thiomorpholin-4-yl; Procedure F; IS-MS m/z 569.0 (m+1), 567.0 (m−1).
R=1-Piperidinyl; Procedure F; IS-MS m/z 551.0 (m+1), 549.1 (m−1).
R=Morpholin-4-yl; Procedure F; IS-MS m/z 553.0 (m+1), 551.1 (m−1).
R=4-Hydroxypiperidin-1-yl; Procedure F; IS-MS m/z 567.0 (m+1), 565.1 (m−1).
R=1-Pyrrolidinyl; Procedure F; IS-MS m/z 537.0 (m+1), 535.1 (m−1).
R=1-Azetidinyl; Procedure F; IS-MS m/z 523.0 (m+1), 521.1 (m−1).
R=3-Carbamoylpiperidin-1-yl; Procedure F; IS-MS m/z 594.0 (m+1), 592.2 (m−1).
R=4-Pyridinylmethylamino; Procedure F; IS-MS m/z 574.0 (m+1), 572.1 (m−1).
R=Octahydroazocin-1-yl; Procedure F; IS-MS m/z 579.1 (m+1), 577.2 (m−1).
R=1,3-Thiazolidin-3-yl; Procedure F; IS-MS m/z 555.0 (m+1), 553.1 (m−1).
R═(S)-2-Hydroxymethylpyrrolidin-1-yl; Procedure F; IS-MS m/z 567.1 (m+1), 565.1 (m−1).
R=4-Phenylpiperazin-1-yl; Procedure F; IS-MS m/z 628.1 (m+1), 626.1 (m−1).
R=4-[2-(1-Pyrrolidinyl)-2-oxoethyl]piperazin-1-yl; Procedure F; IS-MS m/z 663.1 (m+1), 661.2 (m−1).
R=2,6-Dimethylmorpholin-4-yl; Procedure F; IS-MS m/z 581.1 (m+1), 579.1 (m−1).
R=Hexahydroazepin-1-yl; Procedure F; IS-MS m/z 565.1 (m+1), 563.2 (m−1).
R=3,3,5-Trimethylhexahydroazepin-1-yl; Procedure F; IS-MS m/z 607.1 (m+1), 605.2 (m−1).
R═(S)-2-Methoxymethylpyrrolidin-1-yl; Procedure F; IS-MS m/z 581.1 (m+1), 579.1 (m−1).
R=1-Hydroxymethylcyclopentylamino; Procedure F; IS-MS m/z 581.1 (m+1), 579.1 (m−1).
R=4-(Pyrrolidin-1-yl)piperazin-1-yl; Procedure F; IS-MS m/z 620.1 (m+1), 618.2 (m−1).
R=4-(2-Pyrimidinyl)piperazin-1-yl; Procedure F; IS-MS m/z 630.1 (m+1), 628.1 (m−1).
R=4-(2-Pyrazinyl)piperazin-1-yl; Procedure F; IS-MS m/z 630.1 (m+1), 628.1 (m−1).
R=4-Acetylpiperazin-1-yl; Procedure F; IS-MS m/z 594.1 (m+1), 592.1 (m−1).
R═(S)-1-Hydroxymethyl-2-methylpropylamino; Procedure F; IS-MS m/z 569.1 (m+1), 567.1 (m−1).
R═(S)-1-Hydroxymethylethylamino; Procedure F; IS-MS m/z 541.0 (m+1), 539.1 (m−1).
R═(R)-1-Hydroxymethylethylamino; Procedure F; IS-MS m/z 541.0 (m+1), 539.1 (m−1).
R═(S)-Hexahydro-2-oxoazepin-3-ylamino; Procedure F; IS-MS m/z 594.1 (m+1), 592.1 (m−1).
R=Cis-2,6-Dimethylpiperidin-1-yl; Procedure F; IS-MS m/z 579.1 (m+1), 577.2 (m−1).
R=4-Cyclopentylpiperazin-1-yl; Procedure F; IS-MS m/z 620.1 (m+1), 618.2 (m−1).
R=4-Hydroxymethylpiperidin-1-yl; Procedure F; IS-MS m/z 581.1 (m+1), 579.1 (m−1).
R═(S)-3-(Dimethylamino)pyrrolidin-1-yl; Procedure F; IS-MS m/z 580.1 (m+1), 578.1 (m−1).
Using methods substantially equivalent to those described in Preparation 401 except that the Mitsonobu reaction was performed with 2-bromoethanol, 2-[2-(2-bromo-ethoxy)-4-isopropylbenzoylamino]-N-(5-chloropyridin-2-yl)benzamide (2.6 g, 5 mmol, 68%) was prepared from N-(5-chloropyridin-2-yl)-2-[2-hydroxy-4-isopropylbenzoyl-amino]benzamide.
in which R has the indicated value of NRaRb were prepared according to the indicated procedure from a requisite corresponding amine of formula HNRaRb and the above bromide corresponding to a compound of formula I-7 in which R is bromo and the reagents and conditions appropriate for the indicated procedure or by a procedure otherwise noted.
R=Cyclobutylamino; Procedure E; IS-MS m/z 507.2 (m+1), 505.3 (m−1).
R=Cyclopentylamino; Procedure E; IS-MS m/z 521.2 (m+1), 519.3 (m−1).
R=Cyclohexylamino; Procedure E; IS-MS m/z 535.2 (m+1), 533.3 (m−1).
R=(3-Methyl)cyclohexylamino; Procedure E; IS-MS m/z 549.3 (m+1), 547.3 (m−1).
R=(4-Methyl)cyclohexylamino; Procedure E; IS-MS m/z 549.2 (m+1), 547.3 (m−1).
R═N-Methyl-N-(2-hydroxyethyl)amino; Procedure E; IS-MS m/z 511.2 (m+1), 509.3 (m−1).
R═N-Propyl-N-(2-hydroxyethyl)amino; Procedure E; IS-MS m/z 539.2 (m+1), 537.3 (m−1).
R=2-(1-Pyrrolidinyl)ethylamino; Procedure E; IS-MS m/z 550.2 (m+1), 548.3 (m−1).
R=2-Furanylmethylamino; Procedure E; IS-MS m/z 533.2 (m+1), 531.1 (m−1).
R=Cycloheptylamino; Procedure E; IS-MS m/z 549.3 (m+1), 547.3 (m−1).
R=Octahydroazocin-1-yl; Procedure E; IS-MS m/z 549.3 (m+1), 547.3 (m−1).
R=1-Azetidinyl; Procedure E; IS-MS m/z 493.2 (m+1), 491.3 (m−1).
R=1,3-Thiazolidin-3-yl; Procedure E; IS-MS m/z 525.2 (m+1), 523.1 (m−1).
R=1-Pyrrolidinyl; Procedure E; IS-MS m/z 507.2 (m+1), 505.3 (m−1).
R═(S)-2-Hydroxymethylpyrrolidin-1-yl; Procedure E; IS-MS m/z 537.2 (m+1), 535.3 (m−1).
R=2-Thienylmethylamino; Procedure E; IS-MS m/z 549.2 (m+1), 547.2 (m−1).
R=3,4-Didehydropiperidin-1-yl; Procedure E; IS-MS m/z 519.2 (m+1), 517.3 (m−1).
R=4-Methylpiperazin-1-yl; Procedure E; IS-MS m/z 536.2 (m+1), 534.3 (m−1).
R=4-[2-(1-Pyrrolidinyl)-2-oxoethyl]piperazin-1-yl; Procedure E; IS-MS m/z 633.3 (m+1), 631.3 (m−1).
R=4-(2-Hydroxyethyl)piperazin-1-yl; Procedure E; IS-MS m/z 566.2 (m+1), 564.3 (m−1).
R=Morpholin-4-yl; Procedure E; IS-MS m/z 523.2 (m+1), 521.3 (m−1).
R=2,6-Dimethylmorpholin-4-yl; Procedure E; IS-MS m/z 551.2 (m+1), 549.3 (m−1).
R=Thiomorpholin-4-yl; Procedure E; IS-MS m/z 539.2 (m+1), 537.3 (m−1).
R=1-Piperidinyl; Procedure E; IS-MS m/z 521.2 (m+1), 519.3 (m−1).
R=3,5-Dimethylpiperidin-1-yl; Procedure E; IS-MS m/z 549.3 (m+1), 547.3 (m−1).
R=4-Hydroxypiperidin-1-yl; Procedure E; IS-MS m/z 537.2 (m+1), 535.3 (m−1).
R=4-Methylpiperidin-1-yl; Procedure E; IS-MS m/z 535.2 (m+1), 533.3 (m−1).
R=4-(2-Hydroxyethyl)piperidin-1-yl; Procedure E; IS-MS m/z 565.2 (m+1), 563.3 (m−1).
R=4-(2-Pyridinyl)piperazin-1-yl; Procedure E; IS-MS m/z 599.3 (m+1), 597.3 (m−1).
R=2-Pyridinylmethylamino; Procedure E; IS-MS m/z 544.2 (m+1), 542.3 (m−1).
R=3-Pyridinylmethylamino; Procedure E; IS-MS m/z 544.2 (m+1), 542.3 (m−1).
R=4-(1-Piperidinyl)piperidin-1-yl; Procedure E; IS-MS m/z 604.3 (m+1), 602.4 (m−1).
R═N-Methyl-N-(1-methylpiperidin-4-yl)amino; Procedure E; IS-MS m/z 564.3 (m+1), 562.4 (m−1).
R=2-(1-Piperidinyl)ethylamino; Procedure E; IS-MS m/z 564.3 (m+1), 562.3 (m−1).
R=Hexahydroazepin-1-yl; Procedure E; IS-MS m/z 535.2 (m+1), 533.3 (m−1).
R=1,1-Dimethyl-2-hydroxyethylamino; Procedure E; IS-MS m/z 525.2 (m+1), 523.3 (m−1).
R=Isopropylamino; Procedure E; IS-MS m/z 495.2 (m+1), 493.3 (m−1).
R=Benzylamino; Procedure E; IS-MS m/z 543.2 (m+1), 541.3 (m−1).
R=2-(Acetylamino)ethylamino; Procedure E; IS-MS m/z 538.2 (m+1), 536.3 (m−1).
R=2-(N,N-Dimethylamino)ethylamino; Procedure E; IS-MS m/z 524.2 (m+1), 522.3 (m−1).
R=2-Methoxyethylamino; Procedure E; IS-MS m/z 511.2 (m+1), 509.3 (m−1).
R=2-Hydroxyethylamino; Procedure E; IS-MS m/z 497.2 (m+1), 495.3 (m−1).
R=Propargylamino; Procedure E; IS-MS m/z 491.2 (m+1), 489.2 (m−1).
R=3-Hydroxypropylamino; Procedure E; IS-MS m/z 511.2 (m+1), 509.3 (m−1).
R=4-Hydroxybutylamino; Procedure E; IS-MS m/z 525.2 (m+1), 523.3 (m−1).
R═N,N-Dimethylamino; Procedure E; IS-MS m/z 481.2 (m+1), 479.3 (m−1).
R═N-[2-(N,N-Dimethylamino)ethyl]-N-ethylamino; Procedure E;
IS-MS m/z 552.3 (m+1), 550.3 (m−1).
R═(S)-2-Methoxymethylpyrrolidin-1-yl; Procedure E; IS-MS m/z 551.2 (m+1), 549.3 (m−1).
R=1-Hydroxymethylcyclopentylamino; Procedure E; IS-MS m/z 551.2 (m+1), 549.3 (m−1).
R═(S)-2-(1-Pyrrolidinylmethyl)pyrrolidin-1-yl; Procedure E; IS-MS m/z 590.3 (m+1), 588.4 (m−1).
R=1,2-Diethylpyrazolidin-4-ylamino; Procedure E; IS-MS m/z 579.3 (m+1), 577.3 (m−1).
R=2-(Methylthio)ethylamino; Procedure E; IS-MS m/z 527.2 (m+1), 525.3 (m−1).
R═N-[2-(Dimethylamino)ethyl]-N-methylamino; Procedure E; IS-MS m/z 538.3 (m+1), 536.3 (m−1).
R=1-Isopropyl-2-methylpropylamino; Procedure E; IS-MS m/z 551.3 (m+1), 549.3 (m−1).
R═N-Methyl-N-(3-pyridinylmethyl)amino; Procedure E; IS-MS m/z 558.2 (m+1), 556.3 (m−1).
R═N-Ethyl-N-(4-pyridinylmethyl)amino; Procedure E; IS-MS m/z 572.2 (m+1), 570.3 (m−1).
R=4-(1-Pyrrolidinyl)piperidin-1-yl; Procedure E; IS-MS m/z 590.3 (m+1), 588.3 (m−1).
R=4-Carbamoylpiperidin-1-yl; Procedure E; IS-MS m/z 564.2 (m+1), 562.3 (m−1).
R=4-(2-Furoyl)piperazin-1-yl; Procedure E; IS-MS m/z 616.3 (m+1), 614.3 (m−1).
R=4-(2-Pyrimidinyl)piperazin-1-yl; Procedure E; IS-MS m/z 600.3 (m+1), 589.3 (m−1).
R=2,2-Dimethyl-(3-dimethylamino)propylamino; Procedure E; IS-MS m/z 566.3 (m+1), 564.4 (m−1).
R=2-Hydroxy-1-(hydroxymethyl)ethylamino; Procedure E; IS-MS m/z 527.2 (m+1), 525.3 (m−1).
R=2-(2-Thienyl)ethylamino; Procedure E; IS-MS m/z 563.2 (m+1), 561.3 (m−1).
R=4-Acetylpiperazin-1-yl; Procedure E; IS-MS m/z 564.2 (m+1), 562.3 (m−1).
R=4-Methylhexahydro-1,4-diazepin-1-yl; Procedure E; IS-MS m/z 550.3 (m+1), 548.3 (m−1).
R=2,2-Dimethyl-3-hydroxypropylamino; Procedure E; IS-MS m/z 539.2 (m+1), 537.3 (m−1).
R═(R)-2-Hydroxypropylamino; Procedure E; IS-MS m/z 511.2 (m+1), 509.3 (m−1).
R═(S)-2-Hydroxypropylamino; Procedure E; IS-MS m/z 511.2 (m+1), 509.3 (m−1).
R═(S)-Hexahydro-2-oxoazepin-3-ylamino; Procedure E; IS-MS m/z 564.2 (m+1), 562.3 (m−1).
R=cis-2,6-Dimethylpiperidin-1-yl; Procedure E; IS-MS m/z 549.3 (m+1).
R═(S)-3-Acetamidopyrrolidin-1-yl; Procedure E; IS-MS m/z 564.2 (m+1), 562.3 (m−1).
R═N-Methyl-N-(2-methoxyethyl)amino; Procedure E; IS-MS m/z 525.2 (m+1), 523.3 (m−1).
R=4-Cyclopentylpiperazin-1-yl; Procedure E; IS-MS m/z 590.3 (m+1), 588.4 (m−1).
R═(S)-3-Dimethylaminopyrrolidin-1-yl; Procedure E; IS-MS m/z 550.2 (m+1), 548.3 (m−1).
R=4-Hydroxymethylpiperidin-1-yl; Procedure E; IS-MS m/z 551.2 (m+1), 549.3 (m−1).
R═(R)-2-Hydroxymethylpyrrolidin-1-yl; Procedure E; IS-MS m/z 537.2 (m+1), 535.3 (m−1).
R═(S)-1-Hydroxymethyl-3-(methylthio)propylamino; Procedure E;
IS-MS m/z 571.2 (m+1), 569.3 (m−1).
R═(R)-α-(Hydroxymethyl)benzylamino; Procedure E.
R═(S)-1-Hydroxymethyl-3-methylbutylamino; Procedure E; IS-MS m/z 553.2 (m+1), 551.3 (m−1).
R═(S)-1-Hydroxymethyl-2-methylpropylamino; Procedure E; IS-MS m/z 539.2 (m+1), 537.3 (m−1).
R═(S)-α-Methylbenzylamino; Procedure E; IS-MS m/z 557.2 (m+1), 555.3 (m−1).
R═(R)-α-Methylbenzylamino; Procedure E; IS-MS m/z 557.2 (m+1), 555.3 (m−1).
R═(S)-1-Methyl-2-hydroxyethylamino; Procedure E; IS-MS m/z 511.2 (m+1), 509.3 (m−1).
R═(R)-1-Methyl-2-hydroxyethylamino; Procedure E; IS-MS m/z 511.2 (m+1), 509.3 (m−1).
R═(S)-1-Hydroxymethylpropylamino; Procedure E; IS-MS m/z 525.2 (m+1), 523.3 (m−1).
R═(R)-1-Hydroxymethylpropylamino; Procedure E; IS-MS m/z 525.2 (m+1), 523.3 (m−1).
R=trans-4-Hydroxycyclohexylamino; Procedure E; IS-MS m/z 551.2 (m+1), 549.3 (m−1).
R═(S)-1-Hydroxymethyl-2,2-dimethylpropylamino; Procedure E; IS-MS m/z 553.3 (m+1), 551.3 (m−1).
R=1-Ethylpyrrolidin-2-ylmethylamino; Procedure E; IS-MS m/z 564.3 (m+1), 562.3 (m−1).
R=3-Hydroxypyrrolidin-1-yl; Procedure E; IS-MS m/z 523.2 (m+1), 521.3 (m−1).
R=Tetrahydrofuran-2-ylmethylamino; Procedure E; IS-MS m/z 537.2 (m+1), 535.3 (m−1).
R=2-Methylpiperidin-1-yl; Procedure E; IS-MS m/z 535.2 (m+1), 533.3 (m−1).
R=2-Hydroxymethylpiperidin-1-yl; Procedure E; IS-MS m/z 551.2 (m+1), 549.3 (m−1).
R=2-(2-Hydroxyethyl)piperidin-1-yl; Procedure E; IS-MS m/z 565.3 (m+1), 563.3 (m−1).
R=3-Carbamoylpiperidin-1-yl; Procedure E; IS-MS m/z 564.2 (m+1), 562.3 (m−1).
R=3,3,5-Trimethylhexahydroazepin-1-yl; Procedure E; IS-MS m/z 577.3 (m+1), 575.3 (m−1).
R=2-(Dimethylamino)-1-methylethylamino; Procedure E; IS-MS m/z 538.3 (m+1), 536.3 (m−1).
R=2-Methylpyrrolidin-1-yl; Procedure E; IS-MS m/z 521.2 (m+1), 519.3 (m−1).
R=3-Hydroxymethylpiperidin-1-yl; Procedure E; IS-MS m/z 551.2 (m+1), 549.3 (m−1).
in which R has the indicated value of Ra were prepared according to the indicated procedure from a requisite corresponding compound of formula I and the reagents and conditions appropriate for the indicated procedure or by a procedure otherwise noted.
R═BOC; Procedure:
To a solution of methyl 2-(3-tert-butoxycarbonylamino-2,2-dimethylpropoxy)-4-tert-butylbenzoate (2.50 g, 6.35 mmol) in THF at 0° C. under N2 was added methyl iodide (4.51 g, 31.8 mmol, 5 eq), followed by sodium bis(trimethylsilyl)amide (12.7 mL, 12.7 mmol, 1.0 M in THF). The cooling bath was allowed to slowly warm to room temperature. The reaction was stirred at room temerature for 2.5 days, then diluted with dichloromethane, washed with water and brine, dried, and concentrated in vacuo to give 1.60 g (61.8%) of the desired product as a viscous oil which was used without further purification.
Using methods substantially equivalent to those described in Example 21-D, methyl 2-[3-[(tert-butoxycarbonyl)(methyl)amino]-2,2-dimethylpropoxy]-4-tert-butylbenzoate (1.60 g, 3.93 mmol) was hydrolized to give 2-[3-[(tert-butoxycarbonyl)-(methyl)amino]-2,2-dimethylpropoxy]-4-tert-butylbenzoic acid (1.34 g, 87.0%) as a white foam.
IS-MS, m/z 394.5 (m+1), 392.4 (m−1);
Analysis for C22H35NO5:
Calcd: C, 67.15; H, 8.96; N, 3.56;
Found: C, 66.86; H, 8.88; N, 3.54.
Using methods substantially equivalent to those described in Example 201, 2-[2-[3-[(tert-butoxycarbonyl)(methyl)amino]-2,2-dimethylpropoxy]-4-tert-butylbenzoyl-amino]-N-(5-chloropyridin-2-yl)benzamide was prepared from 2-[3-[(tert-butoxy-carbonyl)(methyl)amino]-2,2-dimethylpropoxy]-4-tert-butylbenzoic acid (1.30 g, 3.30 mmol) and N-(5-chloropyridin-2-yl)-2-aminobenzamide (0.817 g, 3.30 mmol) to provide, after silica gel purification, 1.57 g (76.2%) of a white foam.
1NMR
IS-MS, m/z 623.5 (m+1), 622.0 (m−1);
Analysis for C34H43ClNO5:
Calcd: C, 65.53; H, 6.95; N, 8.99;
Found: C, 65.45; H, 6.96; N, 8.78.
R═H; Procedure:
Using methods substantially equivalent to those described in Example 302, 2-[4-tert-butyl-2-(2,2-dimethyl-3-methylamino-propoxy)benzoylamino]-N-(5-chloro-pyridin-2-yl)benzamide was prepared from 2-[2-[3-[(tert-butoxycarbonyl)(methyl)-amino]-2,2-dimethylpropoxy]-4-tert-butylbenzoylamino]-N-(5-chloropyridin−2-yl)-benzamide to provide 0.806 g (96.1%) of the desired product as a white foam.
1NMR
IS-MS, m/z 523.3 (m+1), 521.4 (m−1).
R=Cyclobutyl; Procedure A, except that an additional silica gel purification was performed at the end. IS-MS, m/z 577.2 (m+1), 575.2 (m−1).
R=Cyclopentyl; Procedure A, except that an additional silica gel purification was performed at the end. IS-MS, m/z 591.2 (m+1), 589.3 (m−1).
R=2-Hydroxybenzyl; Procedure A, except that an additional silica gel purification was performed at the end. IS-MS, m/z 629.2 (m+1), 627.2 (m−1).
R=2-Methylbenzyl; Procedure A, except that an additional silica gel purification was performed at the end. IS-MS, m/z 627.2 (m+1), 625.3 (m−1).
R=2-Thienylmethyl; Procedure A, except that an additional silica gel purification was performed at the end. IS-MS, m/z 619.1 (m+1), 617.2 (m−1).
R=2-Carboxybenzyl; Procedure A, except that an additional silica gel purification was performed at the end. IS-MS, m/z 657.2 (m+1), 655.2 (m−1).
R=2-Fluorophenylaminocarbonyl; Procedure B, except that no scavenging was conducted, and the compound was purified via SCX solid phase extraction. IS-MS, m/z 660.1 (m+1), 658.2 (m−1).
R=2-Fluorophenylcarbonyl; Procedure C, except that the compound was purified via silical gel chromatography. IS-MS, m/z 645.1 (m+1), 643.2 (m−1).
R=3-Methylthiophen-2-ylcarbonyl; Procedure C, except that the compound was purified via silical gel chromatography. IS-MS, m/z 647.1 (m+1), 645.2 (m−1).
in which R has the indicated value of Ra were prepared according to the indicated procedure from a requisite corresponding compound of formula I and the reagents and conditions appropriate for the indicated procedure or by a procedure otherwise noted.
R=Boc; Procedure:
In a manner substantially equivalent to Example 21-C, methyl 4-tert-butyl-2-hydroxybezoate (2.08 g, 10.0 mmol) and 1-Boc-3-hydroxymethylpiperidine (2.15 g, 10.0 mmol) were reacted to give the desired product (1.30 g, 32.1%).
In a manner substantially equivalent to Example 21-D, methyl 2-(1-tert-butoxy-carbonylpiperidin-3-ylmethoxy)-4-tert-butylbenzoate (1.30 g, 3.21 mmol) yielded 1.25 g (99.2%) of the desired product as an off-white foam.
In a manner substantially equivalent to Example 201, 2-(1-tert-butoxycarbonyl-piperidin-3-ylmethoxy)-4-tert-butylbenzoic acid (1.25 g, 3.19 mmol) and N-(5-chloropyridin-2-yl)-2-aminobenzamide (0.791 g, 3.19 mmol) yielded 0.396 g (20%) of 2-[2-(1-tert-butoxycarbonylpiperidin-3-ylmethoxy)-4-tert-butylbenzoylamino]-N-(5-chloropyridin-2-yl)benzamide as a white foam.
1NMR
IS-MS, m/z 621.9 (m+1), 619.8 (m−1).
R═H; Procedure:
In a manner substantially equivalent to example 302, 2-[4-tert-butyl-2-(piperidin-3-ylmethoxy)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide was prepared from 2-[2-(1-tert-butoxycarbonylpiperidin-3-ylmethoxy)-4-tert-butylbenzoylamino]-N-(5-chloropyridin-2-yl)benzamide (0.375 g, 0.604 mmol) to give 0.311 g (98.7%) of the desired product as an off-white solid.
1NMR
IS-MS, m/z 521.4 (m+1), 519.4 (m−1).
R=2-Fluorophenylcarbonyl; Procedure C; IS-MS, m/z 643.2 (m+1), 641.2 (m−1).
R=2-Fluorophenylaminocarbonyl; Procedure B, except that no scavanging was conducted, and the compound was purified via SCX solid phase extraction; IS-MS, m/z 658.2 (m+1), 656.3 (m−1).
R=2-Hydroxybenzyl; Procedure A; IS-MS, m/z 627.2 (m+1), 625.3 (m−1).
R=2-Carboxybenzyl; Procedure A; IS-MS, m/z 655.2 (m+1), 653.3 (m−1).
R=2-Methylbenzyl; Procedure A; IS-MS, m/z 625.2 (m+1), 6523.3 (m−1).
R=Imidazol-2-ylmethyl; Procedure A; IS-MS, m/z 601.2 (m+1), 599.3 (m−1).
R=Thiophen-3-ylmethyl; Procedure A; IS-MS, m/z 617.2 (m+1), 615.2 (m−1).
R=Cyclopropylmethyl; Procedure A; IS-MS, m/z 575.2 (m+1), 573.3 (m−1).
in which R has the indicated value of Ra were prepared according to the indicated procedure from a requisite corresponding compound of formula I and the reagents and conditions appropriate for the indicated procedure or by a procedure otherwise noted.
R═BOC; Procedure:
In a manner substantially equivalent to Example 201, 2-(2-tert-butoxycarbonyl-aminoethoxy)-4-(4-morpholinyl)benzoic acid (0.610 g, 1.66 mmol) and N-(5-chloro-pyridin-2-yl)-2-aminobenzamide (0.411 g, 1.66 mmol) yielded 0.503 g (50.7%) of 2-[2-(2-tert-butoxycarbonylaminoethoxy)-4-(4-morpholinyl)benzoylamino]-N-(5-chloro-pyridin-2-yl)benzamide as a white solid.
1NMR
IS-MS, m/z 596.1 (m+1), 594.2 (m−1);
Analysis for C30H34N5O6 Cl:
Calcd: C, 60.45; H, 5.75; N, 11.75;
Found: C, 60.48; H, 5.58; N, 11.70.
R═H; Procedure:
In a manner substantially equivalent to Example 302, 2-[2-(2-aminoethoxy)-4-(4-morpholinyl)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide was prepared from 2-[2-(2-tert-butoxycarbonylaminoethoxy)-4-(4-morpholinyl)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (0.210 g, 0.352 mmol) to give 0.147 g (94.3%) of the desired product as a white solid.
1NMR
IS-MS, m/z 496.0 (m+1), 494.0 (m−1);
Analysis for C25H26N5O4 Cl:
Calcd: C, 60.54; H, 5.28; N, 14.12;
Found: C, 60.13; H, 5.35; N, 13.72.
in which R has the indicated value of Ra were prepared according to the indicated procedure from a requisite corresponding compound of formula I and the reagents and conditions appropriate for the indicated procedure or by a procedure otherwise noted.
R═BOC; Procedure:
In a manner substantially equivalent to Example 201, 2-(3-tert-butoxycarbonylaminopropoxy)-4-(4-morpholinylbenzoic acid (1.25 g, 3.29 mmol) and N-(5-chloropyridin-2-yl)-2-aminobenzamide (0.815 g, 3.29 mmol) yielded 0.59 g (29.5%) of 2-[2-(3-tert-butoxycarbonylaminopropoxy)-4-(4-morpholinyl)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide as a white solid.
1NMR
IS-MS, m/z 610.2 (m+1), 608.3 (m−1).
R═H; Procedure:
In a manner substantially equivalent to Example 302, 2-[2-(3-aminopropoxy)-4-(4-morpholinyl)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide was prepared from 2-[2-(3-tert-butoxycarbonylaminopropoxy)-4-(4-morpholinyl)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (0.568 g, 0.931 mmol) to give 0.445 g (93.5%) of the desired product as an off-white solid.
1NMR (300 MHz, DMSO-d6):
IS-MS, m/z 510.3 (m+1), 508.2 (m−1).
R=2-Fluorophenylaminocarbonyl; Procedure B, except the crude material was purified via SCX solid phase extraction followed by silica gel chromatography.
IS-MS, m/z 647.0 (m+1), 645.1 (m−1).
R=2-Fluorophenylaminothiocarbonyl; Procedure B, the crude material was purified via SCX solid phase extraction followed by silica gel chromatography.
IS-MS, m/z 662.9 (m+1), 661.0 (m−1).
R=3-Methylthiophen-2-ylcarbonyl; Procedure C, except the crude material was purified via SCX solid phase extraction followed by silica gel chromatography.
IS-MS, m/z 633.9 (m+1), 632.0 (m−1).
R=2-Thiophenecarbonyl; Procedure C, except the crude material was purified via SCX solid phase extraction followed by silica gel chromatography. IS-MS, m/z 619.9 (m+1), 618.0 (m−1).
R=3-Thiophenecarbonyl; Procedure C, except the crude material was purified via SCX solid phase extraction followed by silica gel chromatography. IS-MS, m/z 619.9 (m+1), 618.0 (m−1).
R=2-Methylbenzyl; Procedure A. The crude material was purified as described, followed by silica gel chromatography. IS-MS, m/z 614.0 (m+1), 612.1 (m−1).
in which R has the indicated value of NRaRb were prepared according to the indicated procedure from a requisite corresponding compound of formula I and the reagents and conditions appropriate for the indicated procedure or by a procedure otherwise noted.
R═NH—BOC; Procedure:
Methyl 4-tert-butyl-2-hydroxybenzoate (2.41 g, 11.6 mmol) was dissolved in DMF (15 mL) and K2 CO3 (2.39 g, 17.4 mmol) and N-Boc-3-bromopropylamine (4.14 g, 17.4 mmol) was added using DMF (10 mL) to aid the transfer. Potassium iodide (0.30 g) was added, and the reaction stirred at room temperature under nitrogen for 18 hr. The DMF was removed in vacuo and the residue taken up in ethyl acetate and washed with water and brine, dried, and the solvent removed in vacuo to give a viscous brown oil. Purification by chromaotgraphy over silica on a preparative scale apparatus, eluting with a gradient of hexane to hexane:ethyl acetate (70:30) gave 1.91 g (45.2%) of a viscous yellow oil.
In a manner substantially equivalent to 21-D, methyl 2-(3-tert-butoxycarbonyl-aminopropoxy)-4-tert-butylbenzoate (1.90 g, 5.20 mmol) gave the desired product (1.78 g, 97.4%) as a viscous oil.
In a manner substantially equivalent to Example 201, 2-(3-tert-butoxycarbonylaminopropoxy)-4-tert-butylbenzoic acid (1.74 g, 4.95 mmol) and N-(5-chloropyridin-2-yl)-2-aminobenzamide (1.23 g, 4.95 mmol) yielded 1.55 g (53.8%) of the desired product as a white solid.
1NMR
IS-MS, m/z 581.1 (m+1), 579.2 (m−1);
Analysis for C31H37ClN4O5:
Calcd: C, 64.07; H, 6.42; N, 9.64;
Found: C, 64.92; H, 6.30; N, 9.47.
R═NH2; Procedure:
In a manner substantially equivalent to Example 302, 2-[2-(3-tert-butoxycarbonyl-aminopropoxy)-4-tert-butylbenzoylamino]-N-(5-chloropyridin-2-yl)benzamide (1.50 g, 2.58 mmol) gave 1.18 g (95.2%) of the desired product as a white foam.
1NMR
IS-MS, m/z 481.1 (m+1), 479.2 (m−1).
Analysis for C26H29ClN4O3:
Calcd: C, 64.93; H, 6.08; N, 11.65;
Found: C, 64.58; H, 5.72; N, 11.40.
R=2-Fluorophenylcarbonylamino; Procedure C, with purification by silica gel chromatography. IS-MS, m/z 603.0 (m+1), 601.0 (m−1).
R=3-Methylthiophen-2-ylcarbonylamino; Procedure C, with purification by silica gel chromatography. IS-MS, m/z 605.0 (m+1), 603.0 (m−1).
R=2-Hydroxybenzylamino; Procedure A, with additional purification via silica gel chromatography. IS-MS, m/z 587.1 (m+1), 585.1 (m−1).
R=Bis(3-thiophenylmethyl)amino; Procedure A, except that purification was effected by recrystallization from acetonitrile. IS-MS, m/z 673.0 (m+1), 671.1 (m−1).
R=Bis(2-methylbenzyl)amino; Procedure A, with additional purification via silica gel chromatography. IS-MS, m/z 689.1 (m+1), 687.2 (m−1).
R=Bis(cyclopropylmethyl)amino; Procedure A, with additional purification via silica gel chromatography. IS-MS, m/z 589.1 (m+1), 587.2 (m−1).
R=1-(2-Pyridinyl)ethylamino; Procedure A, with additional purification via silica gel chromatography. IS-MS, m/z 586.1 (m+1), 584.1 (m−1).
in which R has the indicated value of R1 were prepared according to the indicated procedure from a requisite corresponding compound of formula I-13 in which R is H and the reagents and conditions appropriate for the indicated procedure or by a procedure otherwise noted.
R=3-pyrrolidinyl:
Wang para-nitrophenyl carbonate (Wang-PNP) resin (1 g, 1.4 mmol, 1.4 mmol/g) was weighed into a 20 mL scintillation vial, and 5 mL of 1:1 dichloromethane:NMP was added. 3-Pyrrolidinol (0.366 g, 4.2 mmol) was added, followed by N,N-(diisopropyl)-ethylamine (2 eq), and the vial was capped and placed on an orbital shaker at 200 rpm for 72 h. The reaction was transferred to a tared 30 mL fritted funnel and the resin was washed, alternating with dichloromethane and methanol (8 washes total), then washed with dichloromethane (3×), and dried in the vacuum oven at room temperature.
The above resin (40.5 mg, 61.0 mmol, 1.508 mmol/g) was weighed into a 3 mL solid phase reaction vessel and the fritted end was capped. PPh3 (19.2 mg, 73.2 mmol) was added as a solution in DMF (0.25 mL), followed by N-(5-chloropyridin-2-yl)-2-(2-hydroxy-4-isopropylbenzoylamino)benzamide (30.0 mg, 73.2 mmol) as a solution in DMF (0.5 mL). DIAD (14.8 mg, 73.2 mmol) was added and the vessel was sealed and heated in a heating block at 60° C. for 72 h. The reaction vessel was drained and the resin was washed with DMF (3×), dichloromethane (3×), THF (2×), water (2×), THF (2×) and dichloromethane (2×). The fritted end of the vessel was capped and phthalic anhydride (45.3 mg, 0.305 mmol, 5 eq) and DMF (1 mL) were added. N,N-(Diisopropyl)-ethylamine (23.7 mL, 0.120 mmol) was added and the vessel capped and placed on a 360° C. rotator for 18 h. The vessel was drained and the resin was washed as before. The vessel was capped on the fritted end and 2 mL of 95:5 TFA:water was added. The vessel was capped and placed back on the rotator for 2 h. The vessel was drained in a 20 mL scintillation vial and the resin was washed with 2 mL of water. The vial was frozen and placed on a lyophilizer for 18 h. The crude residue was purified via silica gel chromatography to give N-(5-chloropyridin-2-yl)-2-[4-isopropyl-2-(3-pyrrolidinyloxy)-benzoylamino]benzamide.
IS-MS, m/z 479.0 (m+1).
R=2-Amino-4-methylthiobutyl; Procedure H; IS-MS, m/z 527.0 (m+1).
R=2-(1-piperazinyl)ethyl; Procedure H; IS-MS, m/z 522.0 (m+1).
R=2-(2-Piperidinyl)ethyl; Procedure H; IS-MS, m/z 521.0 (m+1).
R=2-(2-Aminoethoxy)ethyl; Procedure H; IS-MS, m/z 497.0 (m+1).
R=2-Aminoethyl; Procedure H; IS-MS, m/z 453.0 (m+1).
R=4-Aminobutyl; Procedure H; IS-MS, m/z 481.0 (m+1).
R=3-Aminopropyl; Procedure H; IS-MS, m/z 467.0 (m+1).
R=4-Piperidinylmethyl; Procedure H; IS-MS, m/z 507.0 (m+1);
R=3-piperidinylmethyl; Procedure H, except that the phthalic anhydride addition was omitted and the crude material was purified by SCX solid phase extraction followed be silica gel chromatography. IS-MS, m/z 507.0 (m+1), 505.1 (m−1).
in which R has the indicated value of R2 were prepared according to the indicated procedure from a requisite corresponding compound of formula HNRsRt and the reagents and conditions appropriate for the indicated procedure or by a procedure otherwise noted.
R=Piperidin-1-yl; Procedure:
In a manner substantially aequivalent to Example 201, 2-(3-tert-butoxyaminopropoxy)-4-fluorobenzoic acid (3.29 g, 10.5 mmol) and N-(5-chloropyridin-2-yl)-2-aminobenzamide (2.60 g, 10.5 mmol) gave, after trituration of the crude product with ether, 4.1 g (71.9%) of a white solid.
General Procedure J for the NAS (nuceophilic aromatic substitution) reaction of secondary amines:
The 2-[2-(3-tert-butoxycarbonylaminopropoxy)-4-fluorobenzoylamino]-N-(5-chloropyridin-2-yl)benzamide (0.100 g, 0.184 mmol) was weighed into a 4 mL vial and piperidine (0.5 mL) was added. The capped reaction vessel was heated at 110° C. for 24 h. After cooling, the reaction was diluted with dichloromethane and washed with water and brine, dried, and the solvent was removed in vacuo to give an oil. The crude residue was purified by silica gel chromatography to give 75.9 mg of a viscous oil. The oil was transferred to a 20 mL scintillation vial, 2.5 mL of 95:5 TFA:water was added, and the vial was allowed to stand capped for 2 h. The reaction was diluted with water (2.5 mL), frozen, and lyophilized for 18 h. The crude salt was purified by SCX solid phase chromatography as described in General Procedure A to give 52.8 mg (83.3%) of the title product.
IS-MS, m/z 508.0 (m+1), 506.1 (m−1).
R=4-Thiomorpholinyl; Procedure J; IS-MS, m/z 525.9 (m+1), 524.1 (m−1).
R=Pyrrolidin-1-yl; Procedure J; IS-MS, m/z 494.0 (m+1), 492.0 (m−1).
R=4-(2-Hydroxyethyl)piperidin-1-yl; Procedure J; IS-MS, m/z 524.0 (m+1), 522.0 (m−1).
R=4-Hydroxypiperidin-1-yl; Procedure J; IS-MS, m/z 497.1 (m+1), 495.1 (m−1).
R=4-Methylpiperazin-1-yl; Procedure J; IS-MS, m/z 523.1 (m+1), 521.0 (m−1).
R═(S)-3-(Dimethylamino)pyrrolidin-1-yl; Procedure J; IS-MS, m/z 537.0 (m+1), 535.0 (m−1).
R═(S)-3-Aminopyrrolidin-1-yl; Procedure J; IS-MS, m/z 509.0 (m+1), 507.0 (m−1).
R═(S)-2-(Methoxymethyl)pyrrolidin-1-yl; Procedure J; IS-MS, m/z 538.0 (m+1), 536.0 (m−1).
R=3,4-Didehydropyridin-1-yl; Procedure J; IS-MS, m/z 606.1 (m+1), 604.1 (m−1).
R=3-Hydroxypiperidin-1-yl; Procedure J; IS-MS, m/z 624.1 (m+1), 622.2 (m−1).
R=3-Carbamoylpiperidin-1-yl; Procedure J; IS-MS, m/z 651.2 (m+1), 649.1 (m−1).
R=3-Hydroxypyrrolidin-1-yl; Procedure J; IS-MS, m/z 610.1 (m+1), 608.2 (m−1).
R=4-Methylhexahydro-1,4-diazepin-1-yl; Procedure J; IS-MS, m/z 637.2 (m+1), 635.2 (m−1).
R=4-Carbamoylpiperidin-1-yl; Procedure J; IS-MS, m/z 651.2 (m+1), 649.2 (m−1).
R=3-Methylpiperidin-1-yl; Procedure J; IS-MS, m/z 622.2 (m+1), 620.2 (m−1).
R=Hexahydro-1,4-diazepin-1-yl; Procedure J; IS-MS, m/z 622.2 (m+1), 620.1 (m−1).
in which R has the indicated value of R2 were prepared according to the indicated procedure from a requisite corresponding compound of formula HNRsRt and the reagents and conditions appropriate for the indicated procedure or by a procedure otherwise noted.
R=Piperidin-1-yl; Procedure J, except that DMSO (a volume equal to that of the amine) was added. IS-MS, m/z 552.2 (m+1).
R=4-Acetylpiperazin-1-yl; Procedure J, except that DMSO (a volume equal to that of the amine) was added. IS-MS, m/z 595.2 (m+1).
R=1-Azetidinyl; Procedure J, except that DMSO (a volume equal to that of the amine) was added. IS-MS, m/z 524.1 (m+1).
R═(S)-2-(Methoxymethyl)pyrrolidin-1-yl; Procedure J, except that DMSO (a volume equal to that of the amine) was added. IS-MS, m/z 582.2 (m+1).
R═(S)-3-(Acetylamino)pyrrolidin-1-yl; Procedure J, except that DMSO (a volume equal to that of the amine) was added. IS-MS, m/z 595.2 (m+1).
R═(R)-2-Carbamoylpyrrolidin-1-yl; Procedure J, except that DMSO (a volume equal to that of the amine) was added. IS-MS, m/z 581.2 (m+1).
R=4-Carbamoylpiperidin-1-yl; Procedure J, except that DMSO (a volume equal to that of the amine) was added. IS-MS, m/z 595.5 (m+1).
R=4-Thiomorpholinyl; Procedure J, except that DMSO (a volume equal to that of the amine) was added. IS-MS, m/z 570.4 (m+1).
R=4-Methylhexahydro-1,4-diazepin-1-yl; Procedure J, except that DMSO (a volume equal to that of the amine) was added. 1NMR; IS-MS, m/z 555.2 (m+1), 553.3 (m−1).
Methyl 2,4-dihydroxybenzoate (20.0 g, 0.119 mol) was dissolved in DMF (400 mL) and potassium carbonate (17.2 g, 0.125 mol) and benzyl bromide (21.4 g, 0.125 mol) were added using additional DMF (400 mL) to aid the transfer. Potassium iodide (3.0 g) was added, and the reaction was stirred at room temperature under nitrogen for 48 h. The DMF was removed in vacuo and the residue was dissolved in ethyl acetate, washed with water and brine, dried, and the solvent was removed in vacuo to give a white solid which was recrystallized from ethyl acetate:hexane to yield 17.9 g (61.1%) of a white solid.
Methyl 4-benzyloxy-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoate was prepared from methyl 4-benzyloxy-2-hydroxybenzoate and 1-Boc-4-hydroxypiperidine using a procedure similar to that described in Example 21-C. The crude material, in dichloromethane, was filtered and purified by chromatography over silica gel using a preparative high pressure chromatography apparatus, eluting with a gradient of 9:1 to 4:1 to 3:1 hexane:ethyl acetate to give 12.8 g of a white solid.
1NMR
Analysis for C25H31NO6:
Calcd: C, 68.01; H, 7.08; N, 3.17;
Found: C, 67.84; H, 7.12; N, 3.22.
The methyl 4-benzyloxy-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoate (12.8 g) was dissolved in EtOH (135 mL). 10% Pd/C catalyst (1.3 g) was added and the reaction was placed under an H2 atmosphere (4.1 bar) for 4 h at room temperature. The catalyst was filtered and the ethanol was removed in vacuo to give 9.15 g (89.7%) of a white foam.
Methyl 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-hydroxybenzoate (9.13 g, 26.0 mmol) was dissolved in DMF. Potassium carbonate (7.19 g, 52.0 mmol) was added, followed by methoxymethyl chloride (2.51 g, 31.2 mmol), and the reaction was stirred at room temperature under a drying tube for 24 h. An additional 1.2 eq of methoxymethyl chloride was added and the reaction stirred an additional 48 h. The DMF was removed in vacuo. The residue was dissolved in ethyl acetate, washed with water, dried, and the solvent was removed in vacuo to give 9.91 g (96.2%) of a viscous oil.
In a manner substantially equivalent to Example 21-D, methyl 2-(1-tert-butoxy-carbonylpiperidin-4-yloxy)-4-methoxymethoxy benzoate (9.90 g, 25.0 mmol) gave 8.44 g (88.4%) of the desired product as a viscous oil.
In a manner substantially equivalent to Example 201, 2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-4-methoxymethoxybenzoic acid (8.40 g, 22.0 mmol) and 2-amino-N-(5-chloropyridin-2-yl)-5-fluorobenzamide (5.85 g, 22.0 mmol) yielded 6.84 g (49.2%) of the desired product as a white solid.
2-[2-(1-tert-Butoxycarbonylpiperidin-4-yloxy)-4-(methoxymethoxy)benzoyl-amino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide (6.70 g, 10.7 mmol) was suspended in methanol (18 mL). 4 N HCl in dioxane (35 mL) was added and the resulting solution stirred at room temperature under nitrogen for 2 h. The reaction was cooled to 0° C. and cautiously quenched with saturated aqueous sodium bicarbonate. The resulting precipitate was collected and dried in a vacuum oven to give a quantitative yield of the title product as a fine white powder.
IS-MS, m/z 485.1 (m+1), 483.1 (m−1).
in which R has the indicated value of Rq were prepared according to the indicated procedure from a requisite alkylating agent and the above described phenol corresponding corresponding to a compound of formula I-16 in which R is hydrogen and the reagents and conditions appropriate for the indicated procedure or by a procedure otherwise noted.
General Procedure K for the Alkylation by Alkyl Halides of Phenols Such as that of Preparation 1601:
Wang-PNP resin (6.85 g, 10.1 mmol, 1.48 mmol/g) was weighed into a 100 mL solid phase reaction vessel and dichloromethane (15 mL) was added. N-(5-Chloro-pyridin-2-yl)-5-fluoro-2-[4-hydroxy-2-(piperidin-4-yloxy)benzoylamino]benzamide (5.16 g, 10.6 mmol) was added in 1-methylpyrrolidin-2-one (15 mL) followed by diisopropylethylamine (2.63 g, 20.3 mmol). The vessel was capped, and placed on a wrist shaker for 24 h. The reaction was poured into a tared fritted funnel, and the resin was washed with dichloromethane and methanol alternately (4 times each), followed by dichloromethane (3×). Drying in the vacuum oven at room temperature gave a quantitative yield of the desired resin (0.981 mmol/g).
The above resin (50 mmol) is weighed into a 4 mL vial and DMF (0.25 mL) was added, followed by sodium methoxide (100 mL, 100.0 mmol, 0.5 N in MeOH). The vial is capped and allowed to stand for 15 min with occasional agitation. The alkyl halide is added (catalytic tetrabutylammonium iodide was added to alkyl chlorides, and 2 eq additional sodium methoxide used for alkyl halides containing acid addition salts of amines) and the capped vial is heated at 60° C. on a 360° rotator for 48 h. The reaction mixture is transferred to a 3 mL solid phase reaction vial. The resin is washed with DMF (2×), dichloromethane (2×), THF (2×), water (2×), THF (2×), and dichloromethane (2×).
After drying briefly in the vacuum oven, 2 mL of 4:1 dichloromethane:TFA is added and the vial is placed on a 360° rotator for 2 h. The reaction is drained into a 20 mL scintillation vial and the resin is washed with 3 mL of dichloromethane. After concentrating overnight under a flow of nitrogen, the residue is taken up in dichloromethane (1 mL) and MeOH (0.25 mL) and the compound purified by SCX solid phase extraction as described in General Procedure A, followed by silica gel chromatography, eluting with a step gradient of 95:5 chloroform:MeOH to 90:10 chloroform:MeOH, to 90:9:1 chloroform:MeOH:(2 N ammonia in MeOH) to 90:5:5 chloroform:MeOH:(2 N ammonia in MeOH) to 90:10:10 chloroform:MeOH:(2 N ammonia in MeOH) to give the desired product.
R=2-Methoxyethyl; Procedure K; IS-MS, m/z 543.0 (m+1), 541.0 (m−1).
R=2-Amino-2-oxoethyl; Procedure K; IS-MS, m/z 541.9 (m+1), 540.0 (m−1).
R=2-Fluoroethyl; Procedure K; IS-MS, m/z 530.9 (m+1), 529.0 (m−1).
R=1,2,4-Oxadiazol-3-ylmethyl; Procedure K.
R=Propargyl; Procedure K; IS-MS, m/z 522.9 (m+1), 521.0 (m−1).
R=2-Ethoxy-2-oxoethyl; Procedure K; IS-MS, m/z 570.9 (m+1), 569.0 (m−1).
R=3-Methylbutyl; Procedure K; IS-MS, m/z 555.0 (m+1), 553.0 (m−1).
R=Cyclopentyl; Procedure K; IS-MS, m/z 553.0 (m+1), 551.0 (m−1).
R=Cycloheptyl; Procedure K; IS-MS, m/z 581.0 (m+), 579.1 (m−1).
R=1-Ethylpropyl; Procedure K; IS-MS, m/z 555.0 (m+1), 553.0 (m−1).
This application claims the benefit of U.S. Provisional Application No. 60/630,984, filed Nov. 24, 2004.
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/US2005/041161 | 11/10/2005 | WO | 00 | 5/16/2007 |
| Number | Date | Country | |
|---|---|---|---|
| 60630984 | Nov 2004 | US |
