Patent Grant
9266835
The present invention is directed to quinoline derivatives, pharmaceutical compositions containing said derivatives and their use in the treatment of disorders and conditions mediated by the CB-1 receptor; more particularly, in the treatment of disorders and conditions responsive to inverse agonism of the CB-1 receptor. For example, the compounds of the present invention are useful in the treatment of metabolic disorders.
Centrally penetrant cannabanoid-1 receptor (CB1) inverse agonist compounds are efficacious for weight loss, glycemic control and treatment of cardiovascular risk factors associated with obesity and/or Type II diabetes mellitus. However such compounds are also associated serious adverse effects such as anxiety, depression, suicidal ideation, and others, which adverse effects preclude their use. Peripherally restricted cannabanoid-1 receptor (CB1R) inverse agonists aim to selectively inhibit the CB1R in organs/tissues outside the blood-brain barrier, for example in the liver, adipose tissue and/skeletal muscle, to avoid the adverse effects.
Thus there remains a need for peripherally restricted cannabanoid-1 receptor (CB1R) inverse agonists for the treatment of, for example metabolic disorders, such as obesity, Type II diabetes mellitus, Syndrome X.
The present invention is directed to CB-1 inverse agonists, more particularly quinoline and quinolone derivatives, compounds of formula (A)
and stereoisomers, tautomers and pharmaceutically acceptable salts thereof; and compounds of formula (B)
and stereoisomers, tautomers and pharmaceutically acceptable salts thereof.
In an embodiment, the present invention is directed to compounds of formula (I)
and stereoisomers, tautomers and pharmaceutically acceptable salts thereof. In another embodiment, the present invention is directed to compounds of formula (II)
and stereoisomers, tautomers and pharmaceutically acceptable salts thereof. In another embodiment, the present invention is directed to compounds of formula (III)
and stereoisomers, tautomers and pharmaceutically acceptable salts thereof. In another embodiment, the present invention is directed to compounds of formula (IV)
and stereoisomers, tautomers and pharmaceutically acceptable salts thereof.
The present invention is directed to compounds of formula (A)
wherein
U1 is selected from the group consisting of
and
R0 is selected from the group consisting of
and
provided that when U1 is
then R0 is
is selected from the group consisting of phenyl, furyl, thienyl, thiazolyl, pyridyl, benzothiazolyl and benzo[d][1,3]dioxolyl;
wherein the phenyl, furyl, thienyl, thiazolyl, pyridyl, benzothiazolyl or benzo[d][1,3]dioxolyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-4alkyl, fluorinated C1-4alkyl, C1-4alkoxy, fluorinated C1-4alkoxy, cyano, —C(O)OH, C(O)O—C1-4alkyl and NRARB; wherein RA and RB are each independently selected from the group consisting of hydrogen, C1-4alkyl and —(C2-4alkyl)-O—(C1-4alkyl); provided that each substituent is bound to a carbon atom of the ring;
L1 is selected from the group consisting of
and
wherein the azetidin-1,3-diyl, piperidin-1,4-diyl or piperazin-1,4-diyl group is bound to the —CH— portion of the core structure of the compounds of formula (I) at the 1-position;
is phenyl; wherein the phenyl is optionally substituted with one or more substituents, independently selected from the group consisting of halogen, —OH, —CN, C1-4alkyl, fluorinated C1-2alkyl, C1-4alkoxy and fluorinated C1-2alkoxy:
is selected from the group consisting of phenyl, furyl, thienyl, thiazolyl, pyridyl, benzothiazolyl and benzo[d][1,3]dioxolyl;
R1 is selected from the group consisting of hydrogen, halogen, —(C1-4alkyl)-O—(C1-2alkyl), —(C1-4alkyl)-OH, —(C3-4alkenyl)-O—(C1-2alkyl), —(C3-4alkenyl)-OH, —OH, —C1-4alkyl, —O—(C1-4alkyl), —O—(C1-4alkyl)-CO2H, —O—(C1-4alkyl)-C(O)O—(C1-4alkyl), —O—(C2-4alkyl)-NH2, —O—(C1-4alkyl)-C(O)—NH2, —O—(C2-4alkyl)-NH—C(O)—(C1-2alkyl), —O—(C2-4alkyl)-NH—C(O)O—(C1-4alkyl) and —NRERF;
wherein RE and RF are each independently selected from the group consisting of hydrogen, C1-4alkyl, —(C1-4alkyl)-OH, —(C1-4alkyl)-CO2H, —(C1-4alkyl)-C(O)O—(C1-4alkyl), —(C1-4alkyl)-O—(C1-4alkyl) —(C1-4alkyl)-NH2 and 1-((halogenated C1-2alkyl)-sulfonyl))-piperidin-4-yl; alternatively, RE and RF are taken together with the nitrogen atom to which they are bound to form a 5 to 6 membered, saturated ring selected from the group consisting of pyrrolidin-1-yl, 1-(pyrrolidin-2-one), piperidin-1-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl and morpholin-4-yl;
is selected from the group consisting of
and
R2 is selected from the group consisting of hydrogen, —(C1-4alkyl), —(C2-4alkyl)-O—(C1-4alkyl), —(C1-4alkyl)-CO2H, —(C1-4alkyl)-C(O)O—(C1-4alkyl) and —(C1-4alkyl)-C(O)—NRLRM; wherein RL and RM are each independently selected from the group consisting of hydrogen and C1-4alkyl;
R3 is selected from the group consisting of hydrogen and —OR4;
wherein R4 is selected from the group consisting of —C1-12alkyl, -(hydroxy substituted C2-12alkyl), —(C1-12alkyl)-N3, —(C2-12alkyl)-NRJRK, —(C2-12alkyl)-O—(C1-12 alkyl), —(C2-12alkyl)-O—(C1-12alkyl)-CN, —(C2-12alkyl)-O—(C1-12alkyl)-CO2H, —(C2-12alkyl)-O—(C1-12alkyl)-C(O)—O—(C1-6alkyl), —(C2-12alkyl)-O—(C1-12alkyl)-C(O)—NRJRK, —(C1-12alkyl)-CO2H, —(C1-12alkyl)-C(O)O—(C1-6alkyl), —(C2-12alkyl)-OC(O)—(C1-6alkyl), —(C2-12alkyl)-OC(O)—NRJRK, —(C1-12alkyl)-C(O)—NRJRK, —(C2-12alkyl)-NRJ—C(O)—(C1-6alkyl), —(C2-12alkyl)-NRJ—C(O)—(C1-12alkyl)-OH, —(C2-12alkyl)-NRJ—SO2—(C1-6alkyl), and —SO2-(halogenated C1-6alkyl); wherein RJ and RK are each independently selected from the group consisting of hydrogen, C1-6alkyl and hydroxy substituted C2-6alkyl;
provided that when R1 is selected from the group consisting of —(C1-4alkyl)-O—(C1-2alkyl), —(C1-4alkyl)-OH, —(C3-4alkenyl)-O—(C1-2alkyl), —(C3-4alkenyl)-OH, —O—(C1-4alkyl)-CO2H, —O—(C1-4alkyl)-C(O)O—(C1-4alkyl), —O—(C2-4alkyl)-NH2, —O—(C1-4alkyl)-C(O)—NH2, —O—(C2-4alkyl)-NH—C(O)—(C1-2alkyl), —O—(C2-4alkyl)-NH—C(O)O—(C1-4alkyl) and —NRERF; and wherein RE and RF are other than hydrogen or C1-4alkyl, then R3 is selected from the group consisting of hydrogen and —O—C1-4alkyl;
provided further that when R1 is other than hydrogen, then R2 is hydrogen;
R5 is selected from the group consisting of hydrogen and C1-4alkyl;
b is an integer from 0 to 1;
L2 is selected from the group consisting of —CH2—, —CH2CH2—, —CH(CH3)— and cycloprop-1,2-diyl;
R6 is selected from the group consisting of azetidin-3-yl, pyrrolidin-3-yl, piperidin-4-yl, piperazin-1-yl, morpholin-4-yl, phenyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, thien-2-yl, thien-3-yl, furan-2-yl, furan-3-yl, pyrimidin-2-yl, pyrazin-2-yl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;
wherein any of the R6 ring structures is optionally substituted with one substituent selected from the group consisting of halogen, hydroxy, cyano, C1-4alkyl, halogenated C1-4alkyl, hydroxy substituted C1-12alkyl, C1-4alkoxy, halogenated C1-4alkoxy, —(C1-4alkyl)-O—(C1-4alkyl), —(C1-4alkyl)-CO2H, —(C1-4alkyl)-C(O)O—(C1-4alkyl), —(C1-4alkyl)-C(O)—NRPRQ, —O—(C1-4alkyl)-O—(C1-4alkyl), —O—(C1-4alkyl)-CO2H, —O—(C1-4alkyl)-C(O)O—(C1-4alkyl), —O—(C1-4alkyl)-C(O)—NRPRQ, —C(O)—(C1-4alkyl), —C(O)-(halogenated C1-4alkyl), —C(O)—(C1-4alkyl)-CO2H, —C(O)—(C1-4alkyl)-C(O)O—(C1-4alkyl), —C(O)—NRPRQ, —C(O)—(C1-4alkyl)-C(O)—NRPRQ, —CO2H, —C(O)O—(C1-4alkyl), —C(O)O—(C1-4alkyl)-OC(O)O—(C1-4alkyl), —C(═NRP)—NRQ—C(O)O—(C1-4alkyl), —C(═NH)—NH2, —C(═N-Boc)-NH(Boc), —NRPRQ, —NRP—C(O)—(C1-4alkyl), —NR4—SO2—(C1-4alkyl), —SO2—(C1-4alkyl), —SO2-(halogenated C1-4alkyl), —SO2—(C1-4alkyl)-OH, —SO2—(C1-4alkyl)-C(O)O—(C1-4alkyl), —SO2—NRPRQ and —SO2—(C1-4alkyl)-C(O)—NRPRQ; and wherein RP and RQ are each independently selected from the group consisting of hydrogen and C1-4alkyl;
and wherein R6 is phenyl; the phenyl is further optionally substituted with an additional substituent selected from the group consisting of halogen, hydroxy, cyano, C1-4alkyl, halogenated C1-4alkyl, C1-4alkoxy and halogenated C1-4alkoxy;
provided that when R6 is piperazin-1-yl or morpholin-4-yl, then b is 1 and L2 is —CH2CH2—;
is selected from the group consisting of
and
wherein Z1 is C or N, respectively; and wherein the
is optionally substituted at the ortho-position relative to Z1 with a substituent selected from the group consisting of halogen and C1-4alkyl;
c is an integer from 0 to 1;
L3 is selected from the group consisting of —CH2—, —CH(CH3)—, —CH(CH2CH3)—, —C(O)— and —SO2—;
R7 is selected from the group consisting of azetidin-3-yl, pyrrolidin-1-yl, piperidin-4-yl, piperazin-1-yl, morpholin-4-yl, phenyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, thien-2-yl, thien-3-yl, furan-2-yl, furan-3-yl, pyrimidin-2-yl, pyrazin-2-yl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;
wherein any of the R7 ring structures is optionally substituted with one substituent selected from the group consisting of halogen, hydroxy, cyano, C1-4alkyl, halogenated C1-4alkyl, hydroxy substituted C1-12alkyl, C1-4alkoxy, halogenated C1-4alkoxy, —(C1-4alkyl)-O—(C1-4alkyl), —(C1-4alkyl)-CO2H, —(C1-4alkyl)-C(O)O—(C1-4alkyl), —(C1-4alkyl)-C(O)—NRPRQ, —O—(C1-4alkyl)-O—(C1-4alkyl), —O—(C1-4alkyl)-CO2H, —O—(C1-4alkyl)-C(O)O—(C1-4alkyl), —O—(C1-4alkyl)-C(O)—NRPRQ, —C(O)—(C1-4alkyl), —C(O)-(halogenated C1-4alkyl), —C(O)—(C1-4alkyl)-CO2H, —C(O)—(C1-4alkyl)-C(O)O—(C1-4alkyl), —C(O)—NRPRQ, —C(O)—(C1-4alkyl)-C(O)—NRPRQ, —CO2H, —C(O)O—(C1-4alkyl), —C(O)O—(C1-4alkyl)-OC(O)O—(C1-4alkyl), —C(═NRP)—NRQ—C(O)O—(C1-4alkyl), —C(═NH)—NH2, —C(═N-Boc)-NH(Boc), —NRPRQ, —NRP—C(O)—(C1-4alkyl), —NR4—SO2—(C1-4alkyl), —SO2—(C1-4alkyl), —SO2-(halogenated C1-4alkyl), —SO2—(C1-4alkyl)-OH, —SO2—(C1-4alkyl)-C(O)O—(C1-4alkyl), —SO2—NRPRQ and —SO2—(C1-4alkyl)-C(O)—NRPRQ; and wherein RP and RQ are each independently selected from the group consisting of hydrogen and C1-4alkyl;
and wherein R7 is phenyl; the phenyl is further optionally substituted with an additional substituent selected from the group consisting of halogen, hydroxy, cyano, C1-4alkyl, halogenated C1-4alkyl, C1-4alkoxy and halogenated C1-4alkoxy;
provided that when
is
and c is 0 (i.e L3 is absent); then R7 is phenyl;
provided that when
is
c is an integer from 0 to 1, and L3 is —CH2—, then R7 is selected from the group consisting of azetidin-3-yl, piperidin-4-yl, phenyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, thien-2-yl, thien-3-yl, furan-2-yl, furan-3-yl, pyrimidin-2-yl, pyrazin-2-yl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;
and stereoisomers, tautomers and pharmaceutically acceptable salts thereof.
The present invention is further directed to compounds of formula (B)
wherein
U2 is selected from the group consisting of
and
is selected from the group consisting of phenyl, furyl, thienyl, thiazolyl, pyridyl, benzothiazolyl and benzo[d][1,3]dioxolyl;
wherein the phenyl, furyl, thienyl, thiazolyl, pyridyl, benzothiazolyl or benzo[d][1,3]dioxolyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-4alkyl, fluorinated C1-4alkyl, C1-4alkoxy, fluorinated C1-4alkoxy, cyano, —C(O)OH, C(O)O—C1-4alkyl and NRARB; wherein RA and RB are each independently selected from the group consisting of hydrogen, C1-4alkyl and —(C2-4alkyl)-O—(C1-4alkyl); provided that each substituent is bound to a carbon atom of the ring;
is selected from the group consisting of phenyl, furyl, thienyl, thiazolyl, pyridyl, benzothiazolyl and benzo[d][1,3]dioxolyl;
wherein the phenyl, furyl, thienyl, thiazolyl, pyridyl, benzothiazolyl or benzo[d][1,3]dioxolyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-4alkyl, fluorinated C1-4alkyl, C1-4alkoxy, fluorinated C1-4alkoxy, cyano, —C(O)OH, C(O)O—C1-4alkyl and NRCRD; wherein RC and RD are each independently selected from the group consisting of hydrogen, C1-4alkyl and —(C2-4alkyl)-O—(C1-4alkyl); provided that each substituent is bound to a carbon atom of the ring;
R15 is selected from the group consisting of hydrogen, halogen, —OH, —C1-4alkyl, —O—(C1-4alkyl), —NH2, —NH(C1-4alkyl) and —N(C1-4alkyl)2;
provided that when U2 is
then R15 is selected from the group consisting of hydrogen and —O—(C1-4alkyl);
is selected from the group consisting of
and
R2 is selected from the group consisting of hydrogen, —(C1-4alkyl), —(C2-4alkyl)-O—(C1-4alkyl), —(C1-4alkyl)-CO2H, —(C1-4alkyl)-C(O)O—(C1-4alkyl) and —(C1-4alkyl)-C(O)—NRLRM; wherein RL and RM are each independently selected from the group consisting of hydrogen and C1-4alkyl;
R3 is selected from the group consisting of hydrogen and —OR4;
wherein R4 is selected from the group consisting of —C1-12alkyl, -(hydroxy substituted C2-12alkyl), —(C1-12alkyl)-N3, —(C2-12alkyl)-NRJRK, —(C2-12alkyl)-O—(C1-12alkyl), —(C2-12alkyl)-O—(C2-12alkyl)-CN, —(C2-12alkyl)-O—(C1-12alkyl)-CO2H, —(C2-12alkyl)-O—(C1-12alkyl)-C(O)—O—(C1-6alkyl), —(C1-12alkyl)-O—(C1-12alkyl)-C(O)—NRJRK, —(C1-12alkyl)-CO2H, —(C2-12alkyl)-OC(O)—(C1-6alkyl), —(C2-12alkyl)-OC(O)—NRJRK, —(C1-12alkyl)-C(O)—NRJRK, —(C2-12alkyl)-NRJ—C(O)—(C1-6alkyl), —(C2-12alkyl)-NRJ—C(O)—(C1-12alkyl)-OH, —(C2-12alkyl)-NRJ—SO2—(C1-6alkyl), and —SO2-(halogenated C1-12alkyl); wherein RJ and RK are each independently selected from the group consisting of hydrogen, C1-6alkyl and hydroxy substituted C2-6alkyl;
provided that when that when R15 is other than hydrogen, then R2 is hydrogen;
L4 is selected from the group consisting of —CH2—, —CH2CH2— and —CH═CH—;
d is an integer from 0 to 2; and each R8 is independently selected from the group consisting of halogen, cyano, C1-4alkyl, halogenated C1-4alkyl, C1-4alkoxy and halogenated C1-4alkoxy;
is selected from the group consisting of
and
wherein Z2 is N and “” represents a single bond or alternatively, Z2 is C and “
” represents a double bond;
R9 is selected from the group consisting of hydrogen, —C(O)O—(C1-4alkyl), —C(O)—(C1-4alkyl), —C(O)-(halogenated C1-4alkyl) and —SO2-(halogenated C1-4alkyl);
provided that when
is piperazin-1-yl, then R9 is other than hydrogen;
and stereoisomers, tautomers and pharmaceutically acceptable salts thereof.
In an embodiment, the present invention is directed to compounds of formula (I)
wherein
R0 is selected from the group consisting of
and
is selected from the group consisting of phenyl, furyl, thienyl, thiazolyl, pyridyl, benzothiazolyl and benzo[d][1,3]dioxolyl;
wherein the phenyl, furyl, thienyl, thiazolyl, pyridyl, benzothiazolyl or benzo[d][1,3]dioxolyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-4alkyl, fluorinated C1-4alkyl, C1-4alkoxy, fluorinated C1-4alkoxy, cyano, —C(O)OH, C(O)O—C1-4alkyl and NRARB; wherein RA and RB are each independently selected from the group consisting of hydrogen, C1-4alkyl and —(C2-4alkyl)-O—(C1-4alkyl); provided that each substituent is bound to a carbon atom of the ring;
L1 is selected from the group consisting of —O—, —CH2—,
and
wherein the azetidin-1,3-diyl, piperidin-1,4-diyl or piperazin-1,4-diyl group is bound to the —CH— portion of the core structure of the compounds of formula (I) at the 1-position;
is phenyl; wherein the phenyl is optionally substituted with one or more substituents, independently selected from the group consisting of halogen, —OH, —CN, C1-4alkyl, fluorinated C1-2alkyl, C1-4alkoxy and fluorinated C1-2alkoxy;
is selected from the group consisting of phenyl, furyl, thienyl, thiazolyl, pyridyl, benzothiazolyl and benzo[d][1,3]dioxolyl;
wherein the phenyl, furyl, thienyl, thiazolyl, pyridyl, benzothiazolyl or benzo[d][1,3]dioxolyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-4alkyl, fluorinated C1-4alkyl, C1-4alkoxy, fluorinated C1-4alkoxy, cyano, —C(O)OH, C(O)O—C1-4alkyl and NRCRD; wherein RC and RD are each independently selected from the group consisting of hydrogen, C1-4alkyl and —(C2-4alkyl)-O—(C1-4alkyl); provided that each substituent is bound to a carbon atom of the ring;
R1 is selected from the group consisting of hydrogen, halogen, —(C1-4alkyl)-O—(C1-2alkyl), —(C1-4alkyl)-OH, —(C3-4alkenyl)-O—(C1-2alkyl), —(C3-4alkenyl)-OH, —OH, —C1-4alkyl, —O—(C1-4alkyl), —O—(C1-4alkyl)-CO2H, —O—(C1-4alkyl)-C(O)O—(C1-4alkyl), —O—(C2-4alkyl)-NH2, —O—(C1-4alkyl)-C(O)—NH2, —O—(C2-4alkyl)-NH—C(O)—(C1-2alkyl), —O—(C2-4alkyl)-NH—C(O)O—(C1-4alkyl) and —NRERF;
wherein RE and RF are each independently selected from the group consisting of hydrogen, C1-4alkyl, —(C1-4alkyl)-OH, —(C1-4alkyl)-CO2H, —(C1-4alkyl)-C(O)O—(C1-4alkyl), —(C1-4alkyl)-O—(C1-4alkyl) —(C1-4alkyl)-NH2 and 1-((halogenated C1-2alkyl)-sulfonyl))-piperidin-4-yl; alternatively, RE and RF are taken together with the nitrogen atom to which they are bound to form a 5 to 6 membered, saturated ring selected from the group consisting of pyrrolidin-1-yl, 1-(pyrrolidin-2-one), piperidin-1-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl and morpholin-4-yl;
is selected from the group consisting of
and
and;
R2 is selected from the group consisting of hydrogen, —(C1-4alkyl), —(C2-4alkyl)-O—(C1-4alkyl), —(C1-4alkyl)-CO2H, —(C1-4alkyl)-C(O)O—(C1-4alkyl) and —(C1-4alkyl)-C(O)—NRLRM; wherein RL and RM are each independently selected from the group consisting of hydrogen and C1-4alkyl;
R3 is selected from the group consisting of hydrogen and —OR4;
wherein R4 is selected from the group consisting of —C1-12alkyl, -(hydroxy substituted C2-12alkyl), —(C1-12alkyl)-N3, —(C2-12alkyl)-NRJRK, —(C2-12alkyl)-O—(C1-12alkyl), —(C2-12alkyl)-O—(C1-12alkyl)-CN, —(C2-12alkyl)-O—(C1-12alkyl)-CO2H, —(C2-12alkyl)-O—(C1-12alkyl)-C(O)—O—(C1-6alkyl), —(C2-12alkyl)-O—(C1-12alkyl)-C(O)—NRJRK, —(C1-12alkyl)-CO2H, —(C1-12alkyl)-C(O)O—(C1-6alkyl), —(C2-12alkyl)-OC(O)—(C1-6alkyl), —(C2-12alkyl)-OC(O)—NRJRK, —(C1-12alkyl)-C(O)—NRJRK, —(C2-12alkyl)-NRJ—C(O)—(C1-6alkyl), —(C2-12alkyl)-NRJ—C(O)—(C1-12alkyl)-OH, —(C2-12alkyl)-NRJ—SO2—(C1-6alkyl), and —SO2-(halogenated C1-6alkyl); wherein RJ and RK are each independently selected from the group consisting of hydrogen, C1-6alkyl and hydroxy substituted C2-6alkyl;
provided that when R1 is selected from the group consisting of —(C1-4alkyl)-O—(C1-2alkyl), —(C1-4alkyl)-OH, —(C3-4alkenyl)-O—(C1-2alkyl), —(C3-4alkenyl)-OH, —O—(C1-4alkyl)-CO2H, —O—(C1-4alkyl)-C(O)O—(C1-4alkyl), —O—(C2-4alkyl)-NH2, —O—(C1-4alkyl)-C(O)—NH2, —O—(C2-4alkyl)-NH—C(O)—(C1-2alkyl), —O—(C2-4alkyl)-NH—C(O)O—(C1-4alkyl) and —NRERF; and wherein RE and RF are other than hydrogen or C1-4alkyl, then R3 is selected from the group consisting of hydrogen and —O—C1-4alkyl;
provided further that when R1 is other than hydrogen, then R2 is hydrogen;
R5 is selected from the group consisting of hydrogen and C1-4alkyl;
b is an integer from 0 to 1;
L2 is selected from the group consisting of —CH2—, —CH2CH2—, —CH(CH3)— and cycloprop-1,2-diyl;
R6 is selected from the group consisting of azetidin-3-yl, pyrrolidin-3-yl, piperidin-4-yl, piperazin-1-yl, morpholin-4-yl, phenyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, thien-2-yl, thien-3-yl, furan-2-yl, furan-3-yl, pyrimidin-2-yl, pyrazin-2-yl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;
wherein any of the R6 ring structures is optionally substituted with one substituent selected from the group consisting of halogen, hydroxy, cyano, C1-4alkyl, halogenated C1-4alkyl, hydroxy substituted C1-12alkyl, C1-4alkoxy, halogenated C1-4alkoxy, —(C1-4alkyl)-O—(C1-4alkyl), —(C1-4alkyl)-CO2H, —(C1-4alkyl)-C(O)O—(C1-4alkyl), —(C1-4alkyl)-C(O)—NRPRQ, —O—(C1-4alkyl)-O—(C1-4alkyl), —O—(C1-4alkyl)-CO2H, —O—(C1-4alkyl)-C(O)O—(C1-4alkyl), —O—(C1-4alkyl)-C(O)—NRPRQ, —C(O)—(C1-4alkyl), —C(O)-(halogenated C1-4alkyl), —C(O)—(C1-4alkyl)-CO2H, —C(O)—(C1-4alkyl)-C(O)O—(C1-4alkyl), —C(O)—NRPRQ, —C(O)—(C1-4alkyl)-C(O)—NRPRQ, —CO2H, —C(O)O—(C1-4alkyl), —C(O)O—(C1-4alkyl)-OC(O)O—(C1-4alkyl), —C(═NRP)—NRQ—C(O)O—(C1-4alkyl), —C(═NH)—NH2, —C(═N-Boc)-NH(Boc), —NRPRQ, —NRP—C(O)—(C1-4alkyl), —NR4—SO2—(C1-4alkyl), —SO2—(C1-4alkyl), —SO2-(halogenated C1-4alkyl), —SO2—(C1-4alkyl)-OH, —SO2—(C1-4alkyl)-C(O)O—(C1-4alkyl), —SO2—NRPRQ and —SO2—(C1-4alkyl)-C(O)—NRPRQ; and wherein RP and RQ are each independently selected from the group consisting of hydrogen and C1-4alkyl;
and wherein R6 is phenyl; the phenyl is further optionally substituted with an additional substituent selected from the group consisting of halogen, hydroxy, cyano, C1-4alkyl, halogenated C1-4alkyl, C1-4alkoxy and halogenated C1-4alkoxy;
provided that when R6 is piperazin-1-yl or morpholin-4-yl, then b is 1 and L2 is —CH2CH2—;
and stereoisomers, tautomers and pharmaceutically acceptable salts thereof.
In another embodiment, the present invention is directed to compounds of formula (II)
wherein
is selected from the group consisting of phenyl, furyl, thienyl, thiazolyl, pyridyl, benzothiazolyl and benzo[d][1,3]dioxolyl;
wherein the phenyl, furyl, thienyl, thiazolyl, pyridyl, benzothiazolyl or benzo[d][1,3]dioxolyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-4alkyl, fluorinated C1-4alkyl, C1-4alkoxy, fluorinated C1-4alkoxy, cyano, —C(O)OH, C(O)O—C1-4alkyl and NRARB; wherein RA and RB are each independently selected from the group consisting of hydrogen, C1-4alkyl and —(C2-4alkyl)-O—(C1-4alkyl); provided that each substituent is bound to a carbon atom of the ring;
is selected from the group consisting of phenyl, furyl, thienyl, thiazolyl, pyridyl, benzothiazolyl and benzo[d][1,3]dioxolyl;
wherein the phenyl, furyl, thienyl, thiazolyl, pyridyl, benzothiazolyl or benzo[d][1,3]dioxolyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-4alkyl, fluorinated C1-4alkyl, C1-4alkoxy, fluorinated C1-4alkoxy, cyano, —C(O)OH, C(O)O—C1-4alkyl and NRCRD; wherein RC and RD are each independently selected from the group consisting of hydrogen, C1-4alkyl and —(C2-4alkyl)-O—(C1-4alkyl); provided that each substituent is bound to a carbon atom of the ring;
R1 is selected from the group consisting of hydrogen, halogen, —(C1-4alkyl)-O—(C1-2alkyl), —(C1-4alkyl)-OH, —(C3-4alkenyl)-O—(C1-2alkyl), —(C3-4alkenyl)-OH, —OH, —C1-4alkyl, —O—(C1-4alkyl), —O—(C1-4alkyl)-CO2H, —O—(C1-4alkyl)-C(O)O—(C1-4alkyl), —O—(C2-4alkyl)-NH2, —O—(C1-4alkyl)-C(O)—NH2, —O—(C2-4alkyl)-NH—C(O)—(C1-2alkyl), —O—(C2-4alkyl)-NH—C(O)O—(C1-4alkyl) and —NRERF;
wherein RE and RF are each independently selected from the group consisting of hydrogen, C1-4alkyl, —(C2-4alkyl)-OH, —(C1-4alkyl)-CO2H, —(C1-4alkyl)-C(O)O—(C1-4alkyl), —(C2-4alkyl)-O—(C1-4alkyl) —(C1-4alkyl)-NH2 and 1-((halogenated C1-2alkyl)-sulfonyl))-piperidin-4-yl; alternatively, RE and RF are taken together with the nitrogen atom to which they are bound to form a 5 to 6 membered, saturated ring selected from the group consisting of pyrrolidin-1-yl, 1-(pyrrolidin-2-one), piperidin-1-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl and morpholin-4-yl;
is selected from the group consisting of
and
and;
R2 is selected from the group consisting of hydrogen, —(C1-4alkyl), —(C2-4alkyl)-O—(C1-4alkyl), —(C1-4alkyl)-CO2H, —(C1-4alkyl)-C(O)O—(C1-4alkyl) and —(C1-4alkyl)-C(O)—NRLRM; wherein RL and RM are each independently selected from the group consisting of hydrogen and C1-4alkyl;
R3 is selected from the group consisting of hydrogen and —OR4;
wherein R4 is selected from the group consisting of —C1-12alkyl, -(hydroxy substituted C2-12alkyl), —(C1-12alkyl)-N3, —(C2-12alkyl)-NRJRK, —(C2-12alkyl)-O—(C1-12alkyl), —(C2-12alkyl)-O—(C1-12alkyl)-CN, —(C2-12alkyl)-O—(C1-12alkyl)-CO2H, —(C2-12alkyl)-O—(C1-12alkyl)-C(O)—O—(C1-6alkyl), —(C6-12alkyl)-O—(C1-12alkyl)-C(O)—NRJRK, —(C1-12alkyl)-CO2H, —(C1-12alkyl)-C(O)O—(C1-6alkyl), —(C2-12alkyl)-OC(O)—(C1-6alkyl), —(C2-12alkyl)-OC(O)—NRJRK, —(C1-12alkyl)-C(O)—NRJRK, —(C2-12alkyl)-NRJ—C(O)—(C1-6alkyl), —(C2-12alkyl)-NRJ—C(O)—(C1-12alkyl)-OH, —(C2-12alkyl)-NRJ—SO2—(C1-6alkyl), and —SO2-(halogenated C1-12alkyl); wherein RJ and RK are each independently selected from the group consisting of hydrogen, C1-6alkyl and hydroxy substituted C2-6alkyl;
provided that when R1 is selected from the group consisting of —(C1-4alkyl)-O—(C1-2alkyl), —(C1-4alkyl)-OH, —(C3-4alkenyl)-O—(C1-2alkyl), —(C3-4alkenyl)-OH, —O—(C1-4alkyl)-CO2H, —O—(C1-4alkyl)-C(O)O—(C1-4alkyl), —O—(C2-4alkyl)-NH2, —O—(C1-4alkyl)-C(O)—NH2, —O—(C2-4alkyl)-NH—C(O)—(C1-2alkyl), —O—(C2-4alkyl)-NH—C(O)O—(C1-4alkyl) and —NRERF; and wherein RE and RF are other than hydrogen or C1-4alkyl, then R3 is selected from the group consisting of hydrogen and —O—C1-4alkyl;
provided further that when R1 is other than hydrogen, then R2 is hydrogen;
R5 is selected from the group consisting of hydrogen and C1-4alkyl;
is selected from the group consisting of
and
wherein Z1 is C or N, respectively; and wherein the
is optionally substituted at the ortho-position relative to Z1 with a substituent selected from the group consisting of halogen and C1-4alkyl;
c is an integer from 0 to 1;
L3 is selected from the group consisting of —CH2—, —CH(CH3)—, —CH(CH2CH3)—, —C(O)— and —SO2—;
R7 is selected from the group consisting of azetidin-3-yl, pyrrolidin-1-yl, piperidin-4-yl, piperazin-1-yl, morpholin-4-yl, phenyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, thien-2-yl, thien-3-yl, furan-2-yl, furan-3-yl, pyrimidin-2-yl, pyrazin-2-yl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;
wherein any of the R7 ring structures is optionally substituted with one substituent selected from the group consisting of halogen, hydroxy, cyano, C1-4alkyl, halogenated C1-4alkyl, hydroxy substituted C1-12alkyl, C1-4alkoxy, halogenated C1-4alkoxy, —(C1-4alkyl)-CO2H, C(O)O—(C1-4alkyl), —(C1-4alkyl)-C(O)—NRPRQ, —O—(C1-4alkyl)-CO2H, —O—(C1-4alkyl)-C(O)O—(C1-4alkyl), —O—(C1-4alkyl)-C(O)—NRPRQ, —C(O)—(C1-4alkyl), —C(O)-(halogenated C1-4alkyl), —C(O)—(C1-4alkyl)-CO2H, —C(O)—(C1-4alkyl)-C(O)O—(C1-4alkyl), —C(O)—NRPRQ, —C(O)—(C1-4alkyl)-C(O)—NRPRQ, —CO2H, —C(O)O—(C1-4alkyl), —C(O)O—(C1-4alkyl)-OC(O)O—(C1-4alkyl), —C(═NRP)—NR4—C(O)O—(C1-4alkyl), —C(═NH)—NH2, —C(═N-Boc)-NH(Boc), —NRPRQ, —NRP—C(O)—(C1-4alkyl), —NR4—SO2—(C1-4alkyl), —SO2—(C1-4alkyl), —SO2-(halogenated C1-4alkyl), —SO2—(C1-4alkyl)-OH, —SO2—(C1-4alkyl)-C(O)O—(C1-4alkyl), —SO2—NRPRQ and —SO2—(C1-4alkyl)-C(O)—NRPRQ; and wherein RP and RQ are each independently selected from the group consisting of hydrogen and C1-4alkyl;
and wherein R7 is phenyl; the phenyl is further optionally substituted with an additional substituent selected from the group consisting of halogen, hydroxy, cyano, C1-4alkyl, halogenated C1-4alkyl, C1-4alkoxy and halogenated C1-4alkoxy;
provided that when
is
and c is 0 (i.e L3 is absent); then R7 is phenyl;
provided that when
is
c is an integer from 0 to 1, and L3 is —CH2—, then R7 is selected from the group consisting of azetidin-3-yl, piperidin-4-yl, phenyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, thien-2-yl, thien-3-yl, furan-2-yl, furan-3-yl, pyrimidin-2-yl, pyrazin-2-yl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;
and stereoisomers, tautomers and pharmaceutically acceptable salts thereof.
In another embodiment, the present invention is directed to compounds of formula (III)
wherein
is selected from the group consisting of phenyl, furyl, thienyl, thiazolyl, pyridyl, benzothiazolyl and benzo[d][1,3]dioxolyl;
wherein the phenyl, furyl, thienyl, thiazolyl, pyridyl, benzothiazolyl or benzo[d][1,3]dioxolyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-4alkyl, fluorinated C1-4alkyl, C1-4alkoxy, fluorinated C1-4alkoxy, cyano, —C(O)OH, C(O)O—C1-4alkyl and NRARB; wherein RA and RB are each independently selected from the group consisting of hydrogen, C1-4alkyl and —(C2-4alkyl)-O—(C1-4alkyl); provided that each substituent is bound to a carbon atom of the ring;
is selected from the group consisting of phenyl, furyl, thienyl, thiazolyl, pyridyl, benzothiazolyl and benzo[d][1,3]dioxolyl;
wherein the phenyl, furyl, thienyl, thiazolyl, pyridyl, benzothiazolyl or benzo[d][1,3]dioxolyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-4alkyl, fluorinated C1-4alkyl, C1-4alkoxy, fluorinated C1-4alkoxy, cyano, —C(O)OH, C(O)O—C1-4alkyl and NRCRD; wherein RC and RD are each independently selected from the group consisting of hydrogen, C1-4alkyl and —(C2-4alkyl)-O—(C1-4alkyl); provided that each substituent is bound to a carbon atom of the ring;
R13 is selected from the group consisting of hydrogen and —O—(C1-4alkyl);
is selected from the group consisting of
and
and;
R2 is selected from the group consisting of hydrogen, —(C1-4alkyl), —(C2-4alkyl)-O—(C1-4alkyl), —(C1-4alkyl)-CO2H, —(C1-4alkyl)-C(O)O—(C1-4alkyl) and —(C1-4alkyl)-C(O)—NRLRM; wherein RL and RM are each independently selected from the group consisting of hydrogen and C1-4alkyl;
R3 is selected from the group consisting of hydrogen and —OR4;
wherein R4 is selected from the group consisting of —C1-12alkyl, -(hydroxy substituted C2-12alkyl), —(C1-12alkyl)-N3, —(C2-12alkyl)-NRJRK, —(C2-12alkyl)-O—(C1-12alkyl), —(C2-12alkyl)-O—(C1-12alkyl)-CN, —(C2-12alkyl)-O—(C1-12alkyl)-CO2H, —(C2-12alkyl)-O—(C1-12alkyl)-C(O)—O—(C1-6alkyl), —(C2-12alkyl)-O—(C1-12alkyl)-C(O)—NRJRK, —(C1-12alkyl)-CO2H, —(C1-12alkyl)-C(O)O—(C1-6alkyl), —(C2-12alkyl)-OC(O)—(C1-6alkyl), —(C2-12alkyl)-OC(O)—NRJRK, —(C1-12alkyl)-C(O)—NRJRK, —(C2-12alkyl)-NRJ—C(O)—(C1-6alkyl), —(C2-12alkyl)-NRJ—C(O)—(C1-12alkyl)-OH, —(C2-12alkyl)-NRJ—SO2—(C1-6alkyl), and —SO2-(halogenated C1-12alkyl); wherein RJ and RK are each independently selected from the group consisting of hydrogen, C1-6alkyl and hydroxy substituted C2-6alkyl;
provided that when R13 is —O—(C1-4alkyl), then R2 is hydrogen;
L4 is selected from the group consisting of —CH2—, —CH2CH2— and —CH═CH—;
d is an integer from 0 to 2;
each R8 is independently selected from the group consisting of halogen, cyano, C1-4alkyl, halogenated C1-4alkyl, C1-4alkoxy and halogenated C1-4alkoxy;
and stereoisomers, tautomers and pharmaceutically acceptable salts thereof.
In another embodiment, the present invention is directed to compounds of formula (IV)
wherein
is selected from the group consisting of phenyl, furyl, thienyl, thiazolyl, pyridyl, benzothiazolyl and benzo[d][1,3]dioxolyl;
wherein the phenyl, furyl, thienyl, thiazolyl, pyridyl, benzothiazolyl or benzo[d][1,3]dioxolyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-4alkyl, fluorinated C1-4alkyl, C1-4alkoxy, fluorinated C1-4alkoxy, cyano, —C(O)OH, C(O)O—C1-4alkyl and NRARB; wherein RA and RB are each independently selected from the group consisting of hydrogen, C1-4alkyl and —(C2-4alkyl)-O—(C1-4alkyl); provided that each substituent is bound to a carbon atom of the ring;
is selected from the group consisting of phenyl, furyl, thienyl, thiazolyl, pyridyl, benzothiazolyl and benzo[d][1,3]dioxolyl;
wherein the phenyl, furyl, thienyl, thiazolyl, pyridyl, benzothiazolyl or benzo[d][1,3]dioxolyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-4alkyl, fluorinated C1-4alkyl, C1-4alkoxy, fluorinated C1-4alkoxy, cyano, —C(O)OH, C(O)O—C1-4alkyl and NRCRD; wherein RC and RD are each independently selected from the group consisting of hydrogen, C1-4alkyl and —(C2-4alkyl)-O—(C1-4alkyl); provided that each substituent is bound to a carbon atom of the ring;
R14 is selected from the group consisting of hydrogen, halogen, —OH, —C1-4alkyl, —O—(C1-4alkyl), —NH2, —NH(C1-4alkyl) and —N(C1-4alkyl)2;
is selected from the group consisting of
and
and;
R2 is selected from the group consisting of hydrogen, —(C1-4alkyl), —(C2-4alkyl)-O—(C1-4alkyl), —(C1-4alkyl)-CO2H, —(C1-4alkyl)-C(O)O—(C1-4alkyl) and —(C1-4alkyl)-C(O)—NRLRM; wherein RL and RM are each independently selected from the group consisting of hydrogen and C1-4alkyl;
R3 is selected from the group consisting of hydrogen and —OR4;
wherein R4 is selected from the group consisting of —C1-12alkyl, -(hydroxy substituted C2-12alkyl), —(C1-12alkyl)-N3, —(C2-12alkyl)-NRJRK, —(C2-12alkyl)-O—(C1-12alkyl), —(C2-12alkyl)-O—(C2-12alkyl)-CN, —(C2-12alkyl)-O—(C1-12alkyl)-CO2H, —(C2-12alkyl)-O—(C1-12alkyl)-C(O)—O—(C1-6alkyl), —(C1-12alkyl)-O—(C1-12alkyl)-C(O)—NRJRK, —(C1-12alkyl)-CO2H, —(C1-12alkyl)-C(O)O—(C1-6alkyl), —(C2-12alkyl)-OC(O)—(C1-6alkyl), —(C2-12alkyl)-OC(O)—NRJRK, —(C1-12alkyl)-C(O)—NRJRK, —(C2-12alkyl)-NRJ—C(O)—(C1-6alkyl), —(C2-12alkyl)-NRJ—C(O)—(C1-12alkyl)-OH, —(C2-12alkyl)-NRJ—SO2—(C1-6alkyl), and —SO2-(halogenated C1-12alkyl); wherein RJ and RK are each independently selected from the group consisting of hydrogen, C1-6alkyl and hydroxy substituted C2-6alkyl;
provided that when R14 is other than hydrogen, then R2 is hydrogen;
is selected from the group consisting of
and
wherein Z2 is N and “” represents a single bond or alternatively, Z2 is C and “
” represents a double bond;
R9 is selected from the group consisting of hydrogen, —C(O)O—(C1-4alkyl), —C(O)—(C1-4alkyl), —C(O)-(halogenated C1-4alkyl) and —SO2-(halogenated C1-4alkyl);
provided that when
is piperazin-1-yl, then R9 is other than hydrogen;
and stereoisomers, tautomers and pharmaceutically acceptable salts thereof.
The present invention is further directed to processes for the preparation of the compounds of formula (I). The present invention is further directed to processes for the preparation of the compounds of formula (II). The present invention is further directed to processes for the preparation of the compounds of formula (III). The present invention is further directed to processes for the preparation of the compounds of formula (IIV). The present invention is further directed to a product prepared according to any of the process(es) described herein.
The present invention is further directed to intermediate compounds useful in the synthesis of the compounds of formula (I), as described and defined in the synthesis schemes and examples which follow herein. The present invention is further directed to intermediate compounds useful in the synthesis of the compounds of formula (II), as described and defined in the synthesis schemes and examples which follow herein. The present invention is further directed to intermediate compounds useful in the synthesis of the compounds of formula (III), as described and defined in the synthesis schemes and examples which follow herein. The present invention is further directed to intermediate compounds useful in the synthesis of the compounds of formula (IV), as described and defined in the synthesis schemes and examples which follow herein.
Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the product prepared according to the process described herein. An illustration of the invention is a pharmaceutical composition made by mixing the product prepared according to the process described herein and a pharmaceutically acceptable carrier. Illustrating the invention is a process for making a pharmaceutical composition comprising mixing the product prepared according to the process described herein and a pharmaceutically acceptable carrier.
Exemplifying the invention are methods of treating a disorder mediated by the CB-1 receptor (selected from the group consisting of obesity, Type I diabetes, Type II diabetes, gestational diabetes, latent autoimmune diabetes of adults (LADA), pre-diabetes, insulin resistance, inadequate glucose tolerance, dyslipidemias (including, but not limited to elevated triglycerides and LDL, and low HDL), nonalcoholic steatohepatitis (NASH), cirrhosis, fatty liver disease, atherosclerosis, hypertension, inflammatory bowel disease, Alzheimer's disease, osteoporosis, multiple sclerosis, traumatic brain injury, arthritis, and neuropathic pain) comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.
In an embodiment, the present invention is directed to a compound of formula (I) or a compound of formula (II) for use as a medicament. In another embodiment, the present invention is directed to a compound of formula (I) or a compound of formula (II) for use in the treatment of a disorder mediated by the CB-1 receptor (selected from the group consisting of obesity, Type I diabetes, Type II diabetes, gestational diabetes, latent autoimmune diabetes of adults (LADA), pre-diabetes, insulin resistance, inadequate glucose tolerance, dyslipidemias (including, but not limited to elevated triglycerides and LDL, and low HDL), nonalcoholic steatohepatitis (NASH), cirrhosis, fatty liver disease, atherosclerosis, hypertension, inflammatory bowel disease, Alzheimer's disease, osteoporosis, multiple sclerosis, traumatic brain injury, arthritis, and neuropathic pain). In another embodiment, the present invention is directed to a composition comprising a compound of formula (I) for the treatment of a disorder mediated by the CB-1 receptor (selected from the group consisting of obesity, Type I diabetes, Type II diabetes, gestational diabetes, latent autoimmune diabetes of adults (LADA), pre-diabetes, insulin resistance, inadequate glucose tolerance, dyslipidemias (including, but not limited to elevated triglycerides and LDL, and low HDL), nonalcoholic steatohepatitis (NASH), cirrhosis, fatty liver disease, atherosclerosis, hypertension, inflammatory bowel disease, Alzheimer's disease, osteoporosis, multiple sclerosis, traumatic brain injury, arthritis, and neuropathic pain
Another example of the invention is the use of any of the compounds described herein in the preparation of a medicament for treating: (a) obesity, (b) Type I diabetes, (c) Type II diabetes, (d) gestational diabetes, (e) latent autoimmune diabetes of adults (LADA), (f) pre-diabetes, (g) insulin resistance, (h) inadequate glucose tolerance, (i) dyslipidemia (including, but not limited to elevated triglycerides and LDL, and low HDL), (j) nonalcoholic steatohepatitis (NASH), (k) cirrhosis, (l) fatty liver disease, (m) atherosclerosis, (n) hypertension, (o) inflammatory bowel disease, (p) Alzheimer's disease, (q) osteoporosis, (r) multiple sclerosis, (s) traumatic brain injury, (t) arthritis, or (u) neuropathic pain, in a subject in need thereof. In another example, the present invention is directed to a compound as described herein for use in method for treating a disorder selected from the group consisting of obesity, Type I diabetes, Type II diabetes, gestational diabetes, latent autoimmune diabetes of adults (LADA), pre-diabetes, insulin resistance, inadequate glucose tolerance, dyslipidemias (including, but not limited to elevated triglycerides and LDL, and low HDL), nonalcoholic steatohepatitis (NASH), cirrhosis, fatty liver disease, atherosclerosis, hypertension, inflammatory bowel disease, Alzheimer's disease, osteoporosis, multiple sclerosis, traumatic brain injury, arthritis, and neuropathic pain, in a subject in need thereof.
In additional embodiments the present invention is as described herein.
The present invention is directed to compounds of formula (A)
wherein R0, R1, R5, U1,
and
are as herein defined, and stereoisomers, tautomers and pharmaceutically acceptable salts thereof. The present invention is further directed to compounds of formula (B)
wherein R15, U2.
and
are as herein defined, and stereoisomers, tautomers and pharmaceutically acceptable salts thereof.
The compounds of formula (A) and the compounds of formula (B) of the present invention are CB-1 receptor inverse agonists, useful in the treatment of metabolic disorders, including but not limited to obesity, Type I diabetes, Type II diabetes, gestational diabetes, latent autoimmune diabetes of adults (LADA), pre-diabetes, insulin resistance, inadequate glucose tolerance, dyslipidemias (including, but not limited to elevated triglycerides and LDL, and low HDL), nonalcoholic steatohepatitis (NASH), cirrhosis, fatty liver disease, atherosclerosis, hypertension, inflammatory bowel disease, Alzheimer's disease, osteoporosis, multiple sclerosis, traumatic brain injury, arthritis, and neuropathic pain.
In an embodiment, the present invention is directed to compounds of formula (I)
wherein
R0, R1,
R5, b, L2 and R6 are as herein defined, and stereoisomers, tautomers and pharmaceutically acceptable salts thereof.
In another embodiment, the present invention is directed to compounds of formula (II)
wherein
R1,
R5,
c, L3 and R7 are as herein defined, and stereoisomers, tautomers and pharmaceutically acceptable salts thereof.
In another embodiment, present invention is directed to compounds of formula (III)
wherein
R13,
L4, d and R8 are as herein defined, and stereoisomers, tautomers and pharmaceutically acceptable salts thereof.
In another embodiment, present invention is directed to compounds of formula (IV)
wherein
R14,
and R9 are as herein defined, and stereoisomers, tautomers and pharmaceutically acceptable salts thereof.
The compounds of formula (I), the compounds of formula (II), the compounds of formula (III) and the compounds of formula (IV) of the present invention are CB-1 receptor inverse agonists, useful in the treatment of metabolic disorders including, but not limited to obesity, Type I diabetes, Type II diabetes, gestational diabetes, latent autoimmune diabetes of adults (LADA), pre-diabetes, insulin resistance, inadequate glucose tolerance, dyslipidemias (including, but not limited to elevated triglycerides and LDL, and low HDL), nonalcoholic steatohepatitis (NASH), cirrhosis, fatty liver disease, atherosclerosis, hypertension, inflammatory bowel disease, Alzheimer's disease, osteoporosis, multiple sclerosis, traumatic brain injury, arthritis, and neuropathic pain.
One skilled in the art will recognize that wherein the compounds of formula (A), (B), (I), (II), (Ill) and/or (IV) of the present invention,
is
and R2 is hydrogen, said compounds may exists as tautomers. More particularly, the quinoline/quinolone core may be present in either of the following keto/enol tautomeric forms or as a mixture of said keto/enol tautomeric forms:
One skilled in the art will further recognize that some variables (e.g.
R1,
R2, R3, etc.) appear in the definition of two or more of the compounds of formula (A), compounds of formula (B), compounds of formula (I), compounds of formula (II), compounds of formula (III) and compounds of formula (IV). One skilled in the art will further recognize that the selection of substituent(s) for any particularly variable in any compound of formula (A), compound of formula (B), compound of formula (I), compound of formula (II), compound of formula (III) and/or compound of formula (IV), is not intended to limit said variable in any of the others of the compounds of formula (A), compounds of formula (B), compounds of formula (I), compounds of formula (II), compounds of formula (III) and/or compounds of formula (IV).
More particularly, one skilled in the art will recognize that wherein a particular substituent or group of substituents is selected for a given variable for a compound of formula (A), said selection is not intended to limit the scope of said variable for compounds of formula (B), compounds of formula (I), compounds of formula (II), compounds of formula (III) and/or compounds of formula (IV). Similarly, the selection of a particular substituent for a given variable for a compound of formula (B), is not intended to limit the scope of said variable for compounds of formula (A), compounds of formula (I), compounds of formula (II), compounds of formula (III) and/or compounds of formula (IV). Similarly, the selection of a particular substituent for a given variable for a compound of formula (I), is not intended to limit the scope of said variable for compounds of formula (A), compounds of formula (B), compounds of formula (II), compounds of formula (III) and/or compounds of formula (IV). Similarly, the selection of a particular substituent for a given variable for a compound of formula (II), is not intended to limit the scope of said variable for compounds of formula (A), compounds of formula (B), compounds of formula (I), compounds of formula (III) and/or compounds of formula (IV). Similarly, the selection of a particular substituent for a given variable for a compound of formula (III), is not intended to limit the scope of said variable for compounds of formula (A), compounds of formula (B), compounds of formula (I), compounds of formula (II) and/or compounds of formula (IV). Similarly, the selection of a particular substituent for a given variable for a compound of formula (IV), is not intended to limit the scope of said variable for compounds of formula (A), compounds of formula (B), compounds of formula (I), compounds of formula (II) and/or compounds of formula (III).
In an embodiment of the present invention,
is selected from the group consisting of phenyl, thiazolyl and benzothiazolyl; wherein the phenyl or thiazolyl is optionally substituted with one to two substituents independently selected from the group consisting of halogen, hydroxy, C1-4alkyl, fluorinated C1-2alkyl, C1-4alkoxy, fluorinated C1-2alkoxy, and NRARB; wherein RA and RB are each independently selected from the group consisting of hydrogen, C1-4alkyl and —(C2alkyl)-O—(C1-2alkyl); provided that each substituent is bound to a carbon atom of the ring. In another embodiment of the present invention,
is selected from the group consisting of phenyl and thiazolyl; wherein the phenyl is substituted with a halogen. In another embodiment of the present invention,
is phenyl; wherein the phenyl is substituted with a substituent selected from the group consisting of halogen and C1-2alkoxy. In another embodiment of the present invention,
is phenyl; wherein the phenyl is substituted with a halogen.
In an embodiment of the present invention,
is selected from the group consisting of 4-chlorophenyl and 4-methoxyphenyl. In another embodiment of the present invention,
is selected from the group consisting of phenyl, 4-chlorophenyl and 4-fluorophenyl. In another embodiment of the present invention,
is 4-chlorophenyl.
In an embodiment of the present invention, L1 is selected from the group consisting of —O—, —CH2—,
and
wherein the azetidin-1,3-diylor piperidin-1,4-diylgroup is bound to the —CH— portion of the core structure of the compounds of formula (I) at the 1-position.
In another embodiment of the present invention, L1 is selected from the group consisting in —O—, —CH2— and
wherein the piperidin-1,4-diyl group is bound to the —CH— portion of the core structure of the compounds of formula (I) at the 1-position.
In another embodiment of the present invention, L1 is selected from the group consisting in —O— and
wherein the piperidin-1,4-diyl group is bound to the —CH— portion of the core structure of the compounds of formula (I) at the 1-position.
In an embodiment of the present invention,
is phenyl; wherein the phenyl is optionally substituted with one to two substituents, independently selected from the group consisting of halogen, —OH, C1-4alkyl, fluorinated C1-2alkyl, C1-4alkoxy and fluorinated C1-2alkoxy. In another embodiment of the present invention,
is phenyl; wherein the phenyl is substituted with a halogen.
In another embodiment of the present invention,
is selected from the group consisting of phenyl, 4-fluorophenyl and 4-chlorophenyl. In another embodiment of the present invention,
is selected from the group consisting of phenyl and 4-chlorophenyl.
In another embodiment of the present invention, L1 is —O—; and
is 4-chlorophenyl.
In an embodiment of the present invention,
is selected from the group consisting of phenyl, thiazolyl, pyridyl and benzothiazolyl; wherein the phenyl, thiazolyl or pyridyl is optionally substituted with one to two substituents independently selected from the group consisting of halogen, hydroxy, C1-4alkyl, fluorinated C1-2alkyl, C1-4alkoxy, fluorinated C1-2alkoxy, and NRCRD; wherein RC and RD are each independently selected from the group consisting of hydrogen, C1-4alkyl and —(C2-2alkyl)-O—(C1-2alkyl); provided that each substituent is bound to a carbon atom of the ring. In another embodiment of the present invention,
is selected from the group consisting of phenyl, thiazolyl, pyridyl and benzothiazolyl; wherein the phenyl or pyridyl is optionally substituted with one to two substituents independently selected from the group consisting of halogen, hydroxy, C1-2alkoxy, fluorinated C1-2alkyl and —NRCRD; wherein RC and RD are each independently selected from the group consisting of hydrogen and —(C2alkyl)-O—(C1-2alkyl). In an embodiment of the present invention,
is selected from the group consisting of phenyl, thiazolyl and thienyl; wherein the phenyl or thienyl is optionally substituted with a substituent selected from the group consisting of halogen and C1-2alkoxy.
In another embodiment of the present invention,
is selected from the group consisting of 4-chlorophenyl, 4-fluorophenyl, 3,4-dichlorophenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 4-(methoxyethylamino)-phenyl, thiazol-2-yl, 4-chloro-pyridyl, benzothiazol-2-yl and benzo[d][1,3]dioxol-5-yl. In another embodiment of the present invention,
is selected from the group consisting of 4-chlorophenyl, 3,4-dichlorophenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 4-(methoxyethylamino)-phenyl, thiazol-2-yl, 6-chloro-pyrid-3-yl, benzothiazol-2-yl and benzo[d][1,3]dioxol-5-yl. In another embodiment of the present invention,
is selected from the group consisting of 4-chlorophenyl, 3,4-dichlorophenyl, 4-hydroxyphenyl, 4-trifluoromethylphenyl, 4-(methoxyethylamino)-phenyl, thiazol-2-yl, 6-chloro-pyrid-3-yl, benzothiazol-2-yl and benzo[d][1,3]dioxol-5-yl. In another embodiment of the present invention,
is selected from the group consisting of 4-chlorophenyl, 3,4-dichlorophenyl, 4-hydroxyphenyl, 4-trifluoromethylphenyl, 4-(methoxyethylamino)-phenyl, thiazol-2-yl, 6-chloro-pyrid-3-yl and benzo[d][1,3]dioxol-5-yl. In another embodiment of the present invention,
is selected from the group consisting of 4-chlorophenyl and thiazol-2-yl.
In an embodiment of the present invention,
is selected from the group consisting of phenyl, 4-chlorophenyl, 4-methoxyphenyl, thiazol-2-yl, thiazol-4-yl, thien-2-yl, thien-3-yl and 5-chloro-thien-2-yl. In an embodiment of the present invention,
is selected from the group consisting of phenyl, 4-chlorophenyl, 4-methoxyphenyl, thiazol-2-yl, thiazol-4-yl, thien-2-yl and thien-3-yl. In an embodiment of the present invention,
is selected from the group consisting of 4-chlorophenyl, thiazol-2-yl, thiazol-4-yl and thien-3-yl. In an embodiment of the present invention,
is selected from the group consisting of 4-chlorophenyl, thiazol-2-yl, thien-2-yl and thien-3-yl.
In another embodiment of the present invention,
is phenyl; wherein the phenyl is substituted with a halogen. In another embodiment of the present invention,
is 4-chlorophenyl.
In an embodiment of the present invention, R1 is selected from the group consisting of hydrogen, halogen, —(C1-4alkyl)-O—(C1-2alkyl), —(C1-4alkyl)-OH, —(C3-4alkenyl)-O—(C1-2alkyl), —(C3-4alkenyl)-OH, —OH, —C1-4alkyl, —O—(C1-4alkyl), —O—(C1-4alkyl)-CO2H, —O—(C1-4alkyl)-C(O)O—(C1-4alkyl), —O—(C2-4alkyl)-NH2, —O—(C1-4alkyl)-C(O)—NH2, —O—(C2-4alkyl)-NH—C(O)—(C1-2alkyl), —O—(C2-4alkyl)-NH—C(O)O—(C1-4alkyl) and —NRERF; wherein RE and RF are each independently selected from the group consisting of hydrogen, C1-4alkyl, —(C2-4alkyl)-OH, —(C1-4alkyl)-CO2H, —(C1-4alkyl)-C(O)O—(C1-4alkyl), —(C2-4alkyl)-O—(C1-4alkyl), —(C1-4alkyl)-NH2 and 1-((fluorinated C1-2alkyl)-sulfonyl))-piperidin-4-yl; alternatively, RE and RF are taken together with the nitrogen atom to which they are bound to form a 5 to 6 membered, saturated ring selected from the group consisting of pyrrolidin-1-yl, 1-(pyrrolidin-2-one), piperidin-1-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl and morpholin-4-yl.
In another embodiment of the present invention, R1 is selected from the group consisting of hydrogen, halogen, —(C1-4alkyl)-O—(C1-2alkyl), —(C1-4alkyl)-OH, —(C3-4alkenyl)-O—(C1-2alkyl), —(C3-4alkenyl)-OH, —OH, —O—(C1-2alkyl), —O—(C1-4alkyl)-CO2H, —O—(C1-4alkyl) —C(O)O—(C1-4alkyl), —O—(C1-4alkyl) —C(O)—NH2, —O—(C2-4alkyl)-NH2, —O—(C2-4alkyl)-NH—C(O)—(C1-2alkyl), —O—(C2-4alkyl)-NH—C(O)O(C1-4alkyl), and —NRERF; wherein RE and RF are each independently selected from the group consisting of hydrogen, C1-4alkyl, —(C2-2alkyl)-O—(C1-2alkyl), —(C1-4alkyl)-CO2H, —(C1-2alkyl)-C(O)O—(C1-2alkyl), —(C1-4alkyl)-NH2, and 1-(fluorinated C1-2alkyl)-sulfonyl))-piperidin-4-yl; alternatively, RE and RF are taken together with the nitrogen atom to which they are bound to form 1-pyrrolidin-2-one.
In an embodiment of the present invention, R1 is selected from the group consisting of hydrogen, halogen, —C1-4alkyl, —O—(C1-4alkyl), —O—(C1-2alkyl)-CO2H, —O—(C1-2alkyl)-C(O)O—(C1-4alkyl), —O—(C2alkyl)-NH2 and —NRERF; wherein RE and RF are each independently selected from the group consisting of hydrogen, C1-4alkyl, —(C1-2alkyl)-CO2H, —(C1-2alkyl)-C(O)O—(C1-4alkyl), —(C2alkyl)-O—(C1-2alkyl) and 1-((fluorinated C1-2alkyl)-sulfonyl))-piperidin-4-yl; alternatively, RE and RF are taken together with the nitrogen atom to which they are bound to form a 5 to 6 membered, saturated ring selected from the group consisting of pyrrolidin-1-yl, 1-(pyrrolidin-2-one), piperidin-1-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl and morpholin-4-yl.
In another embodiment of the present invention, R1 is selected from the group consisting of hydrogen, bromo, —CH2CH2CH2—OCH3, —CH2CH2CH2—OH, —CH═CH—CH2—OCH3, —CH═CH—CH2—CH2OH, —OH, —OCH3, —O—CH2CH2CH2CH2—CO2H, —O—CH2CH2CH2CH2—C(O)O—C(CH3)3, —O—CH2CH2CH2CH2—C(O)NH2, —O—CH2CH2CH2CH2—NH2, —O—CH2CH2CH2CH2—NH—C(O)—CH3, —O—CH2CH2CH2CH2—NH—C(O)—O—C(CH3)3, —O—CH2—CO2H, —O—CH2—C(O)O—CH2CH3, —O—CH2CH2CH2CH2—C(O)O—CH2CH3, —NH—CH2CH2CH2CH3, —NH—CH2CH2—OCH3, —NH—CH2CH2CH2—CO2H, —NH—CH2CH2CH2—C(O)O—CH2CH3, —NH—CH2CH2CH2CH2—NH2, —NH-(1-trifluoromethyl-sulfonyl-piperidin-4-yl) and 1-pyrrolidin-2-one.
In another embodiment of the present invention, R1 is selected from the group consisting of hydrogen, bromo, —CH2CH2CH2—OCH3, —CH2CH2CH2—OH, —CH═CH—CH2—OCH3, —CH═CH—CH2—CH2OH, —OH, —OCH3, —O—CH2CH2CH2CH2—CO2H, —O—CH2CH2CH2CH2—C(O)NH2, —O—CH2CH2CH2CH2—NH2, —O—CH2CH2CH2CH2—NH—C(O)—CH3, —O—CH2CH2CH2CH2—NH—C(O)—O—C(CH3)3, —O—CH2—C(O)O—CH2CH3, —O—CH2CH2CH2CH2—C(O)O—CH2CH3, —NH—CH2CH2—OCH3, —NH—CH2CH2CH2—CO2H, and 1-pyrrolidin-2-one. In another embodiment of the present invention, R1 is selected from the group consisting of hydrogen, bromo, —CH2CH2CH2—OCH3, —CH2CH2CH2—OH, —CH═CH—CH2—OCH3, —CH═CH—CH2—CH2OH, —OH, —OCH3, —O—CH2CH2CH2CH2—CO2H, —O—CH2CH2CH2CH2—C(O)NH2, —O—CH2CH2CH2CH2—NH2, —O—CH2CH2CH2CH2—NH—C(O)—CH3, —O—CH2CH2CH2CH2—NH—C(O)—O—C(CH3)3, —O—CH2—C(O)O—CH2CH3, —O—CH2CH2CH2CH2—C(O)O—CH2CH3, —NH—CH2CH2—OCH3 and 1-pyrrolidin-2-one. In another embodiment of the present invention, R1 is selected from the group consisting of hydrogen, bromo, —CH2CH2CH2—OCH3, —CH2CH2CH2—OH, —CH═CH—CH2—OCH3 and —NH—CH2CH2—OCH3. In another embodiment of the present invention, R1 is hydrogen.
In an embodiment of the present invention
is
In another embodiment of the present invention,
is
In another embodiment of the present invention,
is
In another embodiment of the present invention,
is
In an embodiment of the present invention, R2 is selected from the group consisting of hydrogen, —(C1-4alkyl), —(C2-4alkyl)-O(C1-4alkyl), —(C1-2alkyl)-CO2H, —(C1-2alkyl)-C(O)O—(C1-4alkyl) and —(C1-4alkyl)-C(O)—NRLRM; wherein RL and RM are each independently selected from the group consisting of hydrogen and C1-2alkyl. In another embodiment of the present invention, R2 is selected from the group consisting of hydrogen, C1-2alkyl, —(C2-4alkyl)-O—(C1-2alkyl) and —(C1-2alkyl)-C(O)NH2. In an embodiment of the present invention, R2 is selected from the group consisting of hydrogen and C1-2alkyl.
In another embodiment of the present invention, R2 is selected from the group consisting of hydrogen, methyl, —CH2CH2CH2—OCH3 and —CH2—C(O)NH2. In another embodiment of the present invention, R2 is selected from the group consisting of hydrogen, methyl and —CH2CH2CH2—OCH3. In another embodiment of the present invention, R2 is selected from the group consisting of hydrogen and methyl. In another embodiment of the present invention, R2 is hydrogen.
In an embodiment of the present invention, R3 is hydrogen. In another embodiment of the present invention, R3 is —OR4. In an embodiment of the present invention, R3 is selected from the group consisting of hydrogen and —OR4; wherein R4 is selected from the group consisting of C1-4alkyl. In another embodiment of the present invention, R3 is —O—C1-4alkyl. In another embodiment of the present invention, R3 is selected from the group consisting of hydrogen and —OR4; wherein R4 is —SO2-(fluorinated C1-2alkyl). In another embodiment of the present invention, R3 is selected from the group consisting hydrogen and —O—SO2—CF3.
In another embodiment of the present invention, R3 is selected from the group consisting of hydrogen, —OCH3, —O—CH2CH2—OCH3, —O—CH2—CO2H, —O—CH2—C(O)O—C(CH3)3, —O—CH2CH2CH2CH2CH2—CO2H, —O—CH2CH2CH2CH2CH2—C(O)OCH3 and —O—CH2—C(O)—NH—CH3. In another embodiment of the present invention, R3 is selected from the group consisting of hydrogen, —OCH3, —O—CH2CH2—OCH3, —O—CH2CH2CH2CH2CH2—CO2H, and —O—CH2—C(O)—NH—CH3. In another embodiment of the present invention, R3 is selected from the group consisting of hydrogen, —OCH3, —O—CH2CH2—OCH3, and —O—CH2—C(O)—NH—CH3.
In an embodiment of the present invention, R4 is selected from the group consisting of —C1-6alkyl, -(hydroxy substituted C2-4alkyl), —(C1-4alkyl)-NRJRK, —(C2-4alkyl)-O—(C1-4alkyl), —(C2-4alkyl)-O—(C1-4alkyl)-CO2H, —(C2-4alkyl)-O—(C1-4alkyl)-C(O)—O—(C1-4alkyl), —(C2-4alkyl)-O—(C1-4alkyl)-C(O)—NRJRK, —(C1-6alkyl)-CO2H, —(C1-6alkyl)-C(O)O—(C1-4alkyl), —(C1-4alkyl)-C(O)—NRJRK, —(C2-4alkyl)-NRJ—C(O)—(C1-4alkyl) and —SO2-(fluorinated C1-2alkyl); wherein RJ and RK are each independently selected from the group consisting of hydrogen, C2-6alkyl. In another embodiment of the present invention, R4 is selected from the group consisting of —C1-4alkyl, —(C2-2alkyl)-O—(C1-2alkyl), —(C2-6alkyl)-CO2H, —(C1-6alkyl)-C(O)O—(C1-4alkyl) and —(C1-2alkyl)-C(O)—NH—(C1-2alkyl).
In an embodiment of the present invention, R5 is selected from the group consisting of hydrogen and C1-4alkyl. In an embodiment of the present invention, R5 is selected from the group consisting of hydrogen and C1-2alkyl. In another embodiment of the present invention, R5 is hydrogen.
In an embodiment of the present invention, b is an integer from 0 to 1. In another embodiment of the present invention b is 1. In another embodiment of the present invention is 0.
In an embodiment of the present invention, L2 is selected from the group consisting of —CH2—, —CH2CH2— and —CH(CH3)—. In another embodiment of the present invention, L2 is selected from the group consisting of —CH2— and —CH(CH3)—.
In an embodiment of the present invention, R6 is selected from the group consisting of azetidin-3-yl, pyrrolidin-3-yl, piperidin-4-yl, piperazin-1-yl, phenyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, thien-2-yl, thien-3-yl, furan-2-yl, furan-3-yl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; wherein any of the R6 ring structures is optionally substituted with one substituent selected from the group consisting of halogen, hydroxy, C1-4alkyl, fluorinated C1-4alkyl, C1-4alkoxy, fluorinated C1-4alkoxy, —(C1-4alkyl)-O—(C1-4alkyl), —(C1-4alkyl)-CO2H, —(C1-4alkyl)-C(O)O—(C1-4alkyl), —(C1-4alkyl)-C(O)—NRPRQ, —O—(C1-4alkyl)-O—(C1-4alkyl), —O—(C1-4alkyl)-CO2H, —O—(C1-4alkyl)-C(O)O—(C1-4alkyl), —O—(C1-4alkyl)-C(O)—NRPRQ, —C(O)—(C1-4alkyl), —C(O)-(fluorinated C1-4alkyl), —C(O)—(C1-4alkyl)-CO2H, —C(O)—(C1-4alkyl)-C(O)O—(C1-4alkyl), —C(O)—NRPRQ, —C(O)—(C1-4alkyl)-C(O)—NRPRQ, —CO2H, —C(O)O—(C1-4alkyl), —C(═NH)—NH2, —C(═N-Boc)-NH(Boc), —NRPRQ, —NRP—C(O)—(C1-4alkyl), —NR4—SO2—(C1-4alkyl), —SO2—(C1-4alkyl), —SO2-(fluorinated C1-4alkyl), —SO2—(C1-4alkyl)-C(O)O—(C1-4alkyl), —SO2—NRPRQ and —SO2—(C1-4alkyl)-C(O)—NRPRQ; and wherein RP and RQ are each independently selected from the group consisting of hydrogen and C1-4alkyl; and wherein R6 is phenyl; the phenyl is further optionally substituted with an additional substituent selected from the group consisting of halogen, hydroxy, C1-4alkyl, fluorinated C1-4alkyl, C1-4alkoxy and fluorinated C1-4alkoxy.
In another embodiment of the present invention, R6 is selected from the group consisting of azetidin-3-yl, pyrrolidin-3-yl, piperidin-4-yl, phenyl, pyrid-2-yl, pyrid-3-yl, and cyclohexyl; wherein any of the R6 ring structures is optionally substituted with one substituent selected from the group consisting of halogen, C1-4alkyl, fluorinated C1-4alkyl, —(C1-4alkyl)-O—(C1-4alkyl), —(C1-4alkyl)-CO2H, —(C1-4alkyl)-C(O)O—(C1-4alkyl), —(C1-4alkyl)-C(O)—NRPRQ, —O—(C1-4alkyl)-O—(C1-4alkyl), —O—(C1-4alkyl)-CO2H, —O—(C1-4alkyl)-C(O)O—(C1-4alkyl), —O—(C1-4alkyl)-C(O)—NRPRQ, —C(O)-(fluorinated C1-4alkyl), —C(O)—(C1-4alkyl)-CO2H, —C(O)—(C1-4alkyl)-C(O)O—(C1-4alkyl), —C(O)—NRPRQ, —C(O)—(C1-4alkyl)-C(O)—NRPRQ, —CO2H, —C(O)O—(C1-4alkyl), —C(═NH)—NH2, —C(═N-Boc)-NH(Boc), —SO2—(C1-4alkyl), —SO2-(fluorinated C1-4alkyl) and —SO2—(C1-4alkyl)-C(O)O—(C1-4alkyl); and wherein RP and RQ are each hydrogen; and wherein R6 is phenyl; the phenyl is further optionally substituted with an additional halogen.
In another embodiment of the present invention, R6 is selected from the group consisting of cyclohexyl, 4-(trifluoromethyl)-cyclohexyl, 4-(trifluoromethyl-sulfonyl)-cyclohexyl, 3-chloro-4-fluoro-phenyl, 3-fluoro-4-chloro-phenyl, 3-(trifluoromethyl)-phenyl, 4-(trifluoromethyl)-phenyl, 4-(methoxy-ethoxy)-phenyl, 4-(carboxy)-phenyl, 4-(methoxycarbonyl)-phenyl, 4-(t-butoxycarbonyl-methoxy)-phenyl, 4-(ethoxycarbonyl-n-propyloxy)-phenyl, 4-(carboxy-methoxy)-phenyl, 4-(carboxy-n-propyloxy)-phenyl, 4-(carboxy-methyl)-phenyl, 4-(methoxycarbonyl-methyl)-phenyl, 4-(aminocarbonyl)-phenyl, 4-(aminocarbonyl-methoxy)-phenyl, 4-(aminocarbonyl-n-propoxy)-phenyl, 4-(aminocarbonyl-methyl)-phenyl, 5-(trifluoromethyl)-pyrdi-2-yl, 5-(trifluoromethyl)-pyrdi-3-yl, 6-(trifluoromethyl)-pyrid-3-yl, 6-(methyl)-pyrid-3-yl, azetidin-3-yl, 1-(t-butoxycarbonyl)-azetidin-3-yl, S-(1-(t-butoxycarbonyl)-pyrrolidin-3-yl), R-(1-(t-butoxycarbonyl)-pyrrolidin-3-yl), S-(1-(trifluoromethyl-sulfonyl)-pyrrolidin-3-yl), R-(1-(trifluoromethyl-sulfonyl)-pyrrolidin-3-yl), piperidin-4-yl, 1-(1,1,1-trifluoroethyl)-piperidin-4-yl, 1-(ethoxycarbonyl)-piperidin-4-yl, 1-(methyl-sulfonyl)piperidin-4-yl, 1-(ethyl-sulfonyl)-piperidin-4-yl, 1-(isopropyl-sulfonyl)-piperidin-4-yl, 1-(trifluoromethyl-sulfonyl)-piperidin-4-yl, 1-(1,1,1-trifluoroethyl-carbonyl)piperidin-4-yl, 1-(carboxy-methyl)-piperidin-4-yl, 1-(carboxy-ethyl)-piperidin-4-yl, 1-(t-butoxycarbonyl-methyl)-piperidin-4-yl, 1-(t-butoxycarbonyl-ethyl)piperidin-4-yl, 1-(carboxy-ethylcarbonyl)-piperidin-4-yl, 1-(carboxy-methylcarbonyl)-piperidin-4-yl, 1-(ethoxycarbonyl-methylcarbonyl)-piperidin-4-yl, 1-(ethoxycarbonyl-ethylcarbonyl)-piperidin-4-yl, 1-(aminocarbonyl-methylcarbonyl)-piperidin-4-yl, 1-(aminocarbonyl-ethylcarbonyl)-piperidin-4-yl, 1-(ethoxycarbonyl-methylsulfonyl)-piperidin-4-yl, 1-(ethoxycarbonyl-ethylsulfonyl)-piperidin-4-yl, 1-(amino-carboimido)-piperidin-4-yl and 1-(t-butoxycarbonyl-amino)-t-butoxycarbonyl-carboimido)-piperidin-4-yl.
In another embodiment of the present invention, R6 is selected from the group consisting of cyclohexyl, 4-(trifluoromethyl)-cyclohexyl, 3-fluoro-4-chloro-phenyl, 3-(trifluoromethyl)-phenyl, 4-(trifluoromethyl)-phenyl, 4-(methoxy-ethoxy)-phenyl, 4-(methoxycarbonyl)-phenyl, 4-(t-butoxycarbonyl-methoxy)-phenyl, 4-(ethoxycarbonyl-n-propyloxy)-phenyl, 4-(methoxycarbonyl-methyl)-phenyl, 4-(aminocarbonyl-methoxy)-phenyl, 4-(aminocarbonyl-n-propoxy)-phenyl, 4-(aminocarbonyl-methyl)-phenyl, 5-(trifluoromethyl)-pyrdi-2-yl, 5-(trifluoromethyl)-pyrdi-3-yl, 6-(trifluoromethyl)-pyrid-3-yl, 6-(methyl)-pyrid-3-yl, S-(1-(trifluoromethyl-sulfonyl)-pyrrolidin-3-yl), R-(1-(trifluoromethyl-sulfonyl)-pyrrolidin-3-yl), 1-(1,1,1-trifluoroethyl)-piperidin-4-yl, 1-(ethoxycarbonyl)-piperidin-4-yl, 1-(methyl-sulfonyl)piperidin-4-yl, 1-(ethyl-sulfonyl)piperidin-4-yl, 1-(isopropyl-sulfonyl)-piperidin-4-yl, 1-(trifluoromethyl-sulfonyl)piperidin-4-yl, 1-(1,1,1-trifluoroethyl-carbonyl)piperidin-4-yl, 1-(t-butoxycarbonyl-methyl)-piperidin-4-yl, 1-(t-butoxycarbonyl-ethyl)piperidin-4-yl, 1-(carboxy-ethylcarbonyl)-piperidin-4-yl, 1-(ethoxycarbonyl-methylcarbonyl)-piperidin-4-yl, 1-(ethoxycarbonyl-ethylcarbonyl)-piperidin-4-yl, 1-(aminocarbonyl-ethylcarbonyl)-piperidin-4-yl, 1-(ethoxycarbonyl-methylsulfonyl)-piperidin-4-yl, and 1-(t-butoxycarbonyl-amino)-t-butoxycarbonyl-carboimido)-piperidin-4-yl.
In another embodiment of the present invention, R6 is selected from the group consisting of cyclohexyl, 4-(trifluoromethyl)-cyclohexyl, 3-fluoro-4-chloro-phenyl, 3-(trifluoromethyl)-phenyl, 4-(trifluoromethyl)-phenyl, 4-(methoxy-ethoxy)-phenyl, 4-(methoxycarbonyl)-phenyl, 4-(t-butoxycarbonyl-methoxy)-phenyl, 4-(ethoxycarbonyl-n-propyloxy)-phenyl, 4-(methoxycarbonyl-methyl)-phenyl, 4-(aminocarbonyl-methoxy)-phenyl, 4-(aminocarbonyl-methyl)-phenyl, 5-(trifluoromethyl)-pyrdi-2-yl, 5-(trifluoromethyl)-pyrdi-3-yl, 6-(trifluoromethyl)-pyrid-3-yl, S-(1-(trifluoromethyl-sulfonyl)-pyrrolidin-3-yl), 1-(1,1,1-trifluoroethyl)-piperidin-4-yl, 1-(ethoxycarbonyl)-piperidin-4-yl, 1-(methyl-sulfonyl)-piperidin-4-yl, 1-(ethyl-sulfonyl)piperidin-4-yl, 1-(trifluoromethyl-sulfonyl)piperidin-4-yl, 1-(1,1,1-trifluoroethyl-carbonyl)-piperidin-4-yl, 1-(t-butoxycarbonyl-methyl)-piperidin-4-yl, 1-(t-butoxycarbonyl-ethyl)piperidin-4-yl, 1-(ethoxycarbonyl-methylcarbonyl)-piperidin-4-yl, 1-(ethoxycarbonyl-ethylcarbonyl)-piperidin-4-yl, 1-(ethoxycarbonyl-methylsulfonyl)-piperidin-4-yl, and 1-(t-butoxycarbonyl-amino)-t-butoxycarbonyl-carboimido)-piperidin-4-yl.
In another embodiment of the present invention, R6 is selected from the group consisting of cyclohexyl, 3-fluoro-4-chloro-phenyl, 3-(trifluoromethyl)-phenyl, 4-(trifluoromethyl)-phenyl, 4-(methoxycarbonyl-methyl)-phenyl, 6-(trifluoromethyl)-pyrid-3-yl, 1-(1,1,1-trifluoroethyl)-piperidin-4-yl, 1-(ethoxycarbonyl)-piperidin-4-yl, 1-(ethyl-sulfonyl)piperidin-4-yl, 1-(trifluoromethyl-sulfonyl)-piperidin-4-yl, 1-(1,1,1-trifluoroethyl-carbonyl)-piperidin-4-yl, 1-(t-butoxycarbonyl-methyl)piperidin-4-yl, 1-(ethoxycarbonyl-methylcarbonyl)-piperidin-4-yl, 1-(ethoxycarbonyl-ethylcarbonyl)-piperidin-4-yl and 1-(ethoxycarbonyl-methylsulfonyl)-piperidin-4-yl. In another embodiment of the present invention, R6 is 1-(trifluoromethyl-sulfonyl)piperidin-4-yl.
In an embodiment of the present invention,
is selected from the group consisting of
and
In another embodiment of the present invention,
is selected from the group consisting of
and
In another embodiment of the present invention,
is
In another embodiment of the present invention,
is
In an embodiment of the present invention, c is an integer from 0 to 1. In another embodiment of the present invention, c is 1. In another embodiment of the present invention, c is 0.
In an embodiment of the present invention, L3 is selected from the group consisting of —CH2—, —C(O)— and —SO2—. In an embodiment of the present invention, L3 is —CH2—. In an embodiment of the present invention, L3 is selected from the group consisting of —C(O)— and —SO2—.
In an embodiment of the present invention, R7 is selected from the group consisting of azetidin-3-yl, pyrrolidin-1-yl, piperidin-4-yl, phenyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, thien-2-yl, thien-3-yl, furan-2-yl, furan-3-yl, pyrimidin-2-yl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; wherein any of the R7 ring structures is optionally substituted with one substituent selected from the group consisting of halogen, hydroxy, C1-4alkyl, fluorinated C1-4alkyl, C1-4alkoxy, fluorinated C1-4alkoxy, —(C1-4alkyl)-O—(C1-4alkyl), —(C1-4alkyl)-CO2H, —(C1-4alkyl)-C(O)O—(C1-4alkyl), —(C1-4alkyl)-C(O)—NRPRQ, —O—(C1-4alkyl)-O—(C1-4alkyl), —O—(C1-4alkyl)-CO2H, —O—(C1-4alkyl)-C(O)O—(C1-4alkyl), —O—(C1-4alkyl)-C(O)—NRPRQ, —C(O)—(C1-4alkyl), —C(O)-(fluorinated C1-4alkyl), —C(O)—(C1-4alkyl)-CO2H, —C(O)—(C1-4alkyl)-C(O)O—(C1-4alkyl), —C(O)—NRPRQ, —C(O)—(C1-4alkyl)-C(O)—NRPRQ, —CO2H, —C(O)O—(C1-4alkyl), —C(═NH)—NH2, —C(═N-Boc)-NH(Boc), —NRPRQ, —NRP—C(O)—(C1-4alkyl), —NR4—SO2—(C1-4alkyl), —SO2—(C1-4alkyl), —SO2-(fluorinated C1-4alkyl), —SO2—(C1-4alkyl)-C(O)O—(C1-4alkyl), —SO2—NRPRQ and —SO2—(C1-4alkyl)-C(O)—NRPRQ; and wherein RP and RQ are each independently selected from the group consisting of hydrogen and C1-4alkyl; and wherein R7 is phenyl; the phenyl is further optionally substituted with an additional substituent selected from the group consisting of halogen, hydroxy, C1-4alkyl, fluorinated C1-4alkyl, C1-4alkoxy and fluorinated C1-4alkoxy.
In another embodiment of the present invention, R7 is selected from the group consisting of cyclopropyl, phenyl, pyrrolidin-1-yl, pyrimidin-2-yl, pyrid-2-yl, furan-2-yl and thien-2-yl; wherein the phenyl, furanyl or thienyl is optionally substituted with a substituent selected from the group consisting of halogen, —CO2H, —C(O)O—(C1-2alkyl). In another embodiment of the present invention, R7 is selected from the group consisting of cyclopropyl, phenyl, 3-fluorophenyl, 3-carboxy-phenyl, 4-carboxy-phenyl, 4-(methoxycarbonyl)-phenyl, pyrrolidin-1-yl, pyrimidin-2-yl, pyrid-2-yl, 5-carboxy-furan-2-yl and 5-carboxy-thien-2-yl. In another embodiment of the present invention, R7 is selected from the group consisting of cyclopropyl, phenyl, 3-fluorophenyl, 3-carboxy-phenyl, 4-carboxy-phenyl, 4-(methoxycarbonyl)-phenyl, pyrrolidin-1-yl, pyrimidin-2-yl, pyrid-2-yl and 5-carboxy-thien-2-yl. In another embodiment of the present invention, R7 is selected from the group consisting of cyclopropyl, phenyl, 3-fluorophenyl, 4-(methoxycarbonyl)-phenyl, pyrrolidin-1-yl, pyrimidin-2-yl and pyrid-2-yl. In another embodiment of the present invention, R7 is selected from the group consisting of cyclopropyl, phenyl, 4-(methoxycarbonyl)-phenyl, pyrrolidin-1-yl, pyrimidin-2-yl and pyrid-2-yl.
In an embodiment of the present invention, R13 is selected from the group consisting of hydrogen and —O—(C1-2alkyl). In an embodiment of the present invention, R13 is hydrogen.
In an embodiment of the present invention, L4 is selected from the group consisting of —CH2—, —CH2CH2— and —CH═CH—. In an embodiment of the present invention, L4 is selected from the group consisting of —CH2—, —CH2CH2—, —CH═CH—, cis-CH═CH— and trans-CH═CH—. In an embodiment of the present invention, L4 is selected from the group consisting of —CH2CH2—, —CH═CH—, cis-CH═CH— and trans-CH═CH—.
In an embodiment of the present invention, d is an integer from 0 to 1. In another embodiment of the present invention, d is 1. In another embodiment of the present invention, d is 0.
In an embodiment of the present invention, each R8 is independently selected from the group consisting of halogen, cyano, C1-4alkyl, fluorinated C1-2alkyl, C1-4alkoxy and fluorinated C1-2alkoxy. In an embodiment of the present invention, R8 is selected from the group consisting of halogen, C1-2alkyl, fluorinated C1-2alkyl and fluorinated C1-2alkoxy.
In an embodiment of the present invention, R8 is selected from the group consisting of 3-fluoro, 3-chloro, 4-chloro, 4-methyl, 3-trifluoromethyl, 4-trifluoromethyl and 4-trifluoromethoxy. In an embodiment of the present invention, R8 is selected from the group consisting of 3-fluoro, 3-chloro, 4-methyl, 3-trifluoromethyl, 4-trifluoromethyl and 4-trifluoromethoxy. In an embodiment of the present invention, R8 is selected from the group consisting of 3-fluoro, 3-chloro and 3-trifluoromethyl.
In an embodiment of the present invention, R14 is selected from the group consisting of hydrogen, halogen, —C1-2alkyl, —NH2, —NH(C1-2alkyl) and —N(C1-2alkyl)2. In another embodiment of the present invention, R14 is selected from the group consisting of hydrogen, halogen and C1-4alkyl. In another embodiment of the present invention, R14 is hydrogen.
In an embodiment of the present invention,
is selected from the group consisting of
and
wherein Z2 is N and “” represents a single bond or alternatively, Z2 is C and “
” represents a double bond.
In an embodiment of the present invention, R9 is selected from the group consisting of hydrogen, —C(O)O—(C1-4alkyl), —C(O)—(C1-4alkyl), —C(O)-(fluorinated C1-2alkyl) and —SO2-(fluorinated C1-2alkyl). In another embodiment of the present invention, R9 is selected from the group consisting of hydrogen, —C(O)O—(C1-4alkyl), —C(O)—(C1-2alkyl), —C(O)-(fluorinated C1-2alkyl) and —SO2-(fluorinated C1-2alkyl).
In another embodiment of the present invention, R9 is selected from the group consisting of hydrogen, —C(O)O-t-butyl, —C(O)-methyl, —C(O)—CF3 and —SO2—CF3. In another embodiment of the present invention, R9 is selected from the group consisting of —C(O)O-t-butyl, —C(O)—CF3 and —SO2—CF3.
Additional embodiments of the present invention, include those wherein the substituents selected for one or more of the variables defined herein (e.g. U1, U2,
a, b, c, d, L1, L2, L3, L4, Z1, Z2, R0, R1, R2, R3, R4, R5, R6, R7, R8, R9, R13, R14, R15, etc.) are independently selected to be any individual substituent or any subset of substituents selected from the complete list as defined herein. Additional embodiments of the present invention, include those wherein the substituents selected for one or more of the variables defined herein (e.g.
a, b, c, d, L1, L2, L3, L4, Z1, Z2, R0, R1, R2, R3, R4, R5, R6, R7, R8, R9, R13, R14, R15, U1, U2, etc.) are independently selected to be individual substituent or subset of substituents selected from those exemplified in the Tables which follow herein.
In additional embodiments, the present invention is directed to any single compound or subset of compounds, independently selected from the representative compounds of formula (I), compounds of formula (II), compounds of formula (III) and compounds formula (IV), listed in the Tables which follow herein.
In the Tables which follow herein, unless otherwise noted, wherein a stereogenic center is present in the listed compound, the compound was prepared as a mixture of enantiomers. Where a stereogenic center is present, and the compound was prepared in an enantiomeric or diastereomeric excess, the S*- and R* designations are intended to indicate relative stereo-configuration (where the exact stereo-configuration of the stereogenic center has not been determined).
Representative compounds of formula (I) of the present invention are as listed in Tables (I-1), (I-2) and (I-3), below.
Representative compounds of formula (II) of the present invention are as listed in Tables (II-1) and (II-2), below.
Representative compounds of formula (III) of the present invention are as listed in Tables (III-1) and (III-2), below.
Representative compounds of formula (IV) of the present invention are as listed in Tables (IV-1) and (IV-2), below.
Representative intermediates in the synthesis of the compounds of formula (I), compounds of formula (II), compounds of formula (III) and/or compounds of formula (IV) of the present invention are as listed in Table (INT) below.
As used herein, “halogen” shall mean chlorine, bromine, fluorine and iodine.
As used herein, the term “alkyl” whether used alone or as part of a substituent group, include straight and branched chains. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl and the like. Unless otherwise noted, “CX-Yalkyl” wherein X and Y are integers, shall mean a carbon chain composition of between X and Y carbon atoms. For example, “C1-4alkyl” shall mean any straight or branched chain composition of between 1 and 4 carbon atoms (including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl).
One skilled in the art will recognize that the term “—(CX-Yalkyl)-” shall denote any CX-Yalkyl straight or branched chain composition as defined above, wherein said CX-Yalkyl straight or branched chain composition is divalent and is therefore bound through two points of attachment, preferably through two terminal carbon atoms.
As used herein, unless otherwise noted, the term “halogenated C1-4alkyl” shall mean any C1-4alkyl group as defined above substituted with at least one halogen atom, preferably substituted with a least one fluoro atom. Suitable examples include but are not limited to —CH2F, —CH2I, —CH2Br, —CH2Cl, —CF3, —CCl3, —CH2—CF3, CH2—CCl3, —CF2—CF2—CF2—CF3, and the like. Similarly, the term “fluorinated C1-4alkyl” shall mean any C1-4alkyl group as defined above substituted with at least one fluoro atom, preferably one to three fluoro atoms. Suitable examples include but are not limited to —CF3, —CH2—CF3, —CF2—CF2—CF2—CF3, and the like.
As used herein, unless otherwise noted, the term “hydroxy substituted CX-Yalkyl” shall mean any CX-Yalkyl group as defined above, substituted with at least one hydroxy group, preferably one to two hydroxy groups, more preferably one hydroxy group; provided that when the “hydroxy substituted CX-Yalkyl” is bound to a N or O atom of a substituent group as defined herein, then the hydroxy group(s) on the “hydroxy substituted CX-Yalkyl” are not bound to C-1 carbon atom of the CX-Yalkyl portion of the “hydroxy substituted CX-Yalkyl” (i.e. the hydroxy group(s) are not bound to the carbon atom which is directly bound to the N or O atom of said substituent group). Suitable examples include but are not limited to —CH2OH, —CH2CH2OH, —CH(OH)CH3, —CH2CH2CH2OH, —CH2CH(OH)CH3, —CH2CH2CH2CH2OH, —C(CH2CH2OH)2—CH2CH2OH, and the like. In an embodiment, the CX-Yalkyl is substituted with the hydroxy group(s) at terminal carbon atom(s).
As used herein, unless otherwise noted, the term “CX-Y alkenyl” wherein X and Y are integers, shall mean a carbon chain composition of between X and Y carbon atoms wherein the carbon chain contains at least one, preferably one, double bond. For example, “C3-4alkenyl” shall mean a 3 to 4 carbon chain composition containing at least one, preferably one, double bond. Suitable example include, but are not limited to —CH2—CH═CH2, —CH═CH—CH2 and the like.
One skilled in the art will recognize that the term “—(CX-Y alkenyl)-” shall denote any CX-Y alkenyl carbon chain composition as defined above, wherein said CX-Y alkenyl is divalent and is therefore bound through two points of attachment, preferably through two terminal carbon atoms. For example, the term “—(C2-4alkenyl)-” shall mean any 2 to 4 carbon atom chain containing at least one, preferably one double bond. Suitable examples include, but are not limited to —CH═CH—, —CH2—CH═CH—, —CH═CH—CH2—, —CH═CH—CH(CH3)— and the like.
As used herein, unless otherwise noted, “alkoxy” shall denote an oxygen ether radical of the above described straight or branched chain alkyl groups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy and the like. Unless otherwise noted, “CX-Yalkoxy” wherein X and Y are integers, shall mean an oxygen ether radical of the above described straight or branched chain carbon chain composition of between X and Y carbon atoms. For example, “C1-4alkoxy” shall mean any oxygen ether radical of the above described straight or branched chain composition of between 1 and 4 carbon atoms.
As used herein, unless otherwise noted, the term “halogenated C1. 4alkoxy” shall mean any C1-4alkoxy group as defined above substituted with at least one halogen atom, preferably substituted with a least one fluoro atom. Suitable examples include but are not limited to —OCH2F, —OCH2I, —OCH2Br, —OCH2Cl, —OCF3, —OCCl3, —OCH2—CF3, —OCH2—CCl3, —OCF2—CF2—CF2—CF3, and the like. Similarly, the term “fluorinated C1-4alkoxy” shall mean any C1-4alkoxy group as defined above substituted with at least one fluoro atom, preferably one to three fluoro atoms. Suitable examples include but are not limited to —OCF3, —OCH2—CF3, —OCF2—CF2—CF2—CF3, and the like.
When a particular group is “substituted” (e.g., alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, etc.), that group may have one or more substituents, preferably from one to five substituents, more preferably from one to three substituents, most preferably from one to two substituents, independently selected from the list of substituents.
With reference to substituents, the term “independently” means that when more than one of such substituents is possible, such substituents may be the same or different from each other.
As used herein, the notation “*” shall denote the presence of a stereogenic center.
Where the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Preferably, wherein the compound is present as an enantiomer, the enantiomer is present at an enantiomeric excess of greater than or equal to about 80%, more preferably, at an enantiomeric excess of greater than or equal to about 90%, more preferably still, at an enantiomeric excess of greater than or equal to about 95%, more preferably still, at an enantiomeric excess of greater than or equal to about 98%, most preferably, at an enantiomeric excess of greater than or equal to about 99%. Similarly, wherein the compound is present as a diastereomer, the diastereomer is present at a diastereomeric excess of greater than or equal to about 80%, more preferably, at a diastereomeric excess of greater than or equal to about 90%, more preferably still, at a diastereomeric excess of greater than or equal to about 95%, more preferably still, at a diastereomeric excess of greater than or equal to about 98%, most preferably, at a diastereomeric excess of greater than or equal to about 99%.
Furthermore, some of the crystalline forms for the compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
Under standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. Thus, for example, a “phenylC1-C6alkylaminocarbonylC1-C6alkyl” substituent refers to a group of the formula
Abbreviations used in the specification, particularly the Schemes and Examples, are as follows:
The compounds of the present invention are CB-1 inverse agonists useful for the treatment and/or prevention of metabolic disorders, including obesity, Type I diabetes, Type II diabetes, gestational diabetes, latent autoimmune diabetes of adults (LADA), pre-diabetes, insulin resistance, inadequate glucose tolerance, dyslipidemias (including, but not limited to elevated triglycerides and LDL, and low HDL), nonalcoholic steatohepatitis (NASH), cirrhosis, fatty liver disease, atherosclerosis, hypertension, inflammatory bowel disease, Alzheimer's disease, osteoporosis, multiple sclerosis, traumatic brain injury, arthritis, and neuropathic pain. Preferably, the metabolic disorder is selected from the group consisting of obesity, Type II diabetes, and dyslipidemias. More preferably, the metabolic disorder is obesity or Type II diabetes.
As used herein, unless otherwise noted, the terms “treating”, “treatment” and the like, shall include the management and care of a subject or patient (preferably mammal, more preferably human) for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present invention to prevent the onset of the symptoms or complications, alleviate the symptoms or complications, or eliminate the disease, condition, or disorder.
As used herein, unless otherwise noted, the term “prevention” shall include (a) reduction in the frequency of one or more symptoms; (b) reduction in the severity of one or more symptoms; (c) the delay or avoidance of the development of one or more additional symptoms; and/or (d) delay or avoidance of the development or progression of the disorder or condition.
One skilled in the art will recognize that wherein the present invention is directed to methods of prevention, a subject in need of thereof (i.e. a subject in need of prevention) shall include any subject or patient (preferably a mammal, more preferably a human) who has experienced or exhibited at least one symptom of the disorder, disease or condition to be prevented. Further, a subject in need thereof may additionally be a subject (preferably a mammal, more preferably a human) who has not exhibited any symptoms of the disorder, disease or condition to be prevented, but who has been deemed by a physician, clinician or other medical profession to be at risk of developing said disorder, disease or condition. For example, the subject may be deemed at risk of developing a disorder, disease or condition (and therefore in need of prevention or preventive treatment) as a consequence of the subject's medical history, including, but not limited to, family history, pre-disposition, co-existing (comorbid) disorders or conditions, genetic testing, and the like.
The term “subject” as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. Preferably, the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented.
The term “therapeutically effective amount” as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term “about”. It is understood that whether the term “about” is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to the experimental and/or measurement conditions for such given value.
To provide a more concise description, some of the quantitative expressions herein are recited as a range from about amount X to about amount Y. It is understood that wherein a range is recited, the range is not limited to the recited upper and lower bounds, but rather includes the full range from about amount X through about amount Y, or any amount or range therein.
As more extensively provided in this written description, terms such as “reacting” and “reacted” are used herein in reference to a chemical entity that is any one of: (a) the actually recited form of such chemical entity, and (b) any of the forms of such chemical entity in the medium in which the compound is being considered when named. One skilled in the art will recognize that, where not otherwise specified, the reaction step(s) is performed under suitable conditions, according to known methods, to provide the desired product. One skilled in the art will further recognize that, in the specification and claims as presented herein, wherein a reagent or reagent class/type (e.g. base, solvent, etc.) is recited in more than one step of a process, the individual reagents are independently selected for each reaction step and may be the same or different from each other. For example wherein two steps of a process recite an organic or inorganic base as a reagent, the organic or inorganic base selected for the first step may be the same or different than the organic or inorganic base of the second step. Further, one skilled in the art will recognize that wherein a reaction step of the present invention may be carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems. Examples of suitable solvents, bases, reaction temperatures, and other reaction parameters and components are provided in the detailed descriptions which follow herein. One skilled in the art will recognize that the listing of said examples is not intended, and should not be construed, as limiting in any way the invention set forth in the claims which follow thereafter.
As used herein, unless otherwise noted, the term “aprotic solvent” shall mean any solvent that does not yield a proton. Suitable examples include, but are not limited to DMF, 1,4-dioxane, THF, acetonitrile, pyridine, dichloroethane, dichloromethane, MTBE, toluene, acetone, and the like.
As used herein, unless otherwise noted, the term “leaving group” shall mean a charged or uncharged atom or group which departs during a substitution or displacement reaction. Suitable examples include, but are not limited to, Br, Cl, I, mesylate, tosylate, and the like.
During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
As used herein, unless otherwise noted, the term “nitrogen protecting group” shall mean a group which may be attached to a nitrogen atom to protect said nitrogen atom from participating in a reaction and which may be readily removed following the reaction. Suitable nitrogen protecting groups include, but are not limited to carbamates—groups of the formula —C(O)O—R wherein R is for example methyl, ethyl, t-butyl, benzyl, phenylethyl, CH2═CH—CH2—, and the like; amides—groups of the formula —C(O)—R′ wherein R′ is for example methyl, phenyl, trifluoromethyl, and the like; N-sulfonyl derivatives—groups of the formula —SO2—R″ wherein R″ is for example tolyl, phenyl, trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-, 2,3,6-trimethyl-4-methoxybenzene, and the like. Other suitable nitrogen protecting groups may be found in texts such as T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.
Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (−)-di-p-toluoyl-D-tartaric acid and/or (+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
Additionally, chiral HPLC against a standard may be used to determine percent enantiomeric excess (% ee). The enantiomeric excess may be calculated as follows
[(Rmoles−Smoles)/(Rmoles+Smoles)]×100%
where Rmoles and Smoles are the R and S mole fractions in the mixture such that Rmoles+Smoles=1. The enantiomeric excess may alternatively be calculated from the specific rotations of the desired enantiomer and the prepared mixture as follows:
ee=([α-obs]/[α-max])×100.
The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.
For use in medicine, the salts of the compounds of this invention refer to non-toxic “pharmaceutically acceptable salts.” Other salts may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate.
Representative acids which may be used in the preparation of pharmaceutically acceptable salts include, but are not limited to, the following: acids including acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, a-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (−)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid.
Representative bases which may be used in the preparation of pharmaceutically acceptable salts include, but are not limited to, the following: ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.
Compounds of formula (I) wherein R0 is
and wherein
is
may be prepared according to the process outlined in Scheme (I-1), below. Preferably, in Scheme (I-1) below, R1 is selected from the group consisting of hydrogen, halogen, C1-4alkyl and —O—(C1-4alkyl).
Accordingly, a suitably substituted compound of formula (INT-1), (a compound prepared for example, as described in Scheme A, which follows herein), is reacted with a suitably substituted compound of formula (X), a known compound or compound prepared by known methods; in the presence of a suitably selected catalyst such as Pd2(dba)3, Pd(OAc)2, and the like; in the presence of a suitably selected ligand such as dppf, XantPhos, XPhos, and the like; in the presence of a suitably selected base such as Cs2CO3, K2CO3, K3PO4, and the like; in a suitably selected organic solvent such as 1,4-dioxane, toluene, DME, THF, and the like; to yield the corresponding compound of formula (Ia).
The compound of formula (Ia) is further, optionally reacted with a suitably substituted compound of formula (XI), wherein LG1 is a suitably selected leaving group such as Cl, Br, I, tosylate, mesylate, and the like; in the presence of a suitably selected base such as Cs2CO3, K2CO3, NaH, and the like; in a suitably selected organic solvent such as acetonitrile, DMF, THF, and the like; to yield the corresponding compound of formula (Ib), in a mixture with the corresponding compound of formula (XII).
One skilled in the art will recognize that compounds of formula (Ib) may alternatively be prepared by reacting a suitably substituted compound of formula (INT-1) with a suitably substituted compound of formula (XI), as described in Scheme (I-1) above, to functionalize (with the desired R2 group) the nitrogen atom at the 1-position of quinol-2-one core; and then further reacting the resulting compound with a suitably substituted compound of formula (X), as described in Scheme (I-1) above, to yield the corresponding compound of formula (Ib).
Compounds of formula (I) wherein R0 is
and wherein
is
and wherein R3 is hydrogen may be similarly prepared according to the process outlined in Scheme (I-1) above, by selecting a suitably substituted compound of formula (INT-4)
(a known compound or compound prepared for example, as described in Scheme C, which follows herein), substituting said compound of formula (INT-4) for the compound of formula (INT-1) in Scheme (I-1) above, and reacting as described therein (converting the compound of formula (INT-1) to the corresponding compound of formula (I)).
Compounds of formula (I) wherein R0 is
and wherein
is
wherein R3 is —OR4 may be prepared according to the process outlined in Scheme (I-2), below.
Accordingly, a suitably substituted compound of formula (Ia), prepared for example, as described in Scheme (I-1) above, is reacted with a suitably substituted compound of formula (XIII), wherein LG2 is a suitably selected leaving group such as Br, Cl, I, mesylate, tosylate, and the like, a known compound or compound prepared by known methods; according to known methods (for example in the presence of a suitably selected base such as Cs2CO3, K2CO3, and the like; in a suitably selected solvent such as acetonitrile, DMF, THF, and the like), to yield the corresponding compound of formula (Ic), in a mixture with the corresponding compound of formula (XIV).
Compounds of formula (I) wherein R0 is
wherein
is
R3 is hydrogen; and R1 is NRERF may prepared according to the procedure as described in Scheme (I-3), below.
Accordingly, a suitably substituted compound of formula (Id); prepared for example, as described herein (e.g. Scheme (I-1)) is reacted with a suitably substituted compound of formula (XV), a known compound or compound prepared by known methods; in the presence of a suitably selected catalyst such as Pd2(dba)3, Pd(OAc)2, and the like; in the presence of a suitably selected ligand such as dppf, XantPhos, XPhos, and the like; in the presence of a suitably selected base such as Cs2CO3, K2CO3, K3PO4, and the like; in a suitably selected organic solvent such as 1,4-dioxane, toluene, DME, THF, and the like; to yield the corresponding compound of formula (Ie).
Compounds of formula (I) wherein R0 is
wherein
is
and R1 is NRERF are preferably prepared according to the procedure as described in Scheme (I-4), below.
Accordingly, a suitably substituted compound of formula (INT-2) wherein R1 is Br, and wherein A5 is selected from C1-4alkyl, preferably A1 is methyl or t-butyl, prepared for example as described in Scheme B which follows herein, is reacted with a suitably substituted compound of formula (X), a known compound or compound prepared by known methods; in the presence of a suitably selected catalyst such as Pd2(dba)3, Pd(OAc)2, and the like; in the presence of a suitably selected ligand such as dppf, XantPhos, XPhos, and the like in the presence of a suitably selected base such as Cs2CO3, K2CO3, K3PO4, and the like; in a suitably selected organic solvent such as 1,4-dioxane, toluene, DME, THF, and the like; to yield the corresponding compound of formula (XVI). Preferably, the compound of formula (INT-2) is reacted with the compound (X) in the presence of Pd2(dba)3 in combination with dppf; to yield the corresponding compound of formula (XVI).
The compound of formula (XVI) is reacted with a suitably substituted compound of formula (XV), a known compound or compound prepared by known methods; in the presence of a suitably selected catalyst such as Pd2(dba)3, Pd(OAc)2, and the like; in the presence of a suitably selected ligand such as dppf, XantPhos, XPhos, and the like; in the presence of a suitably selected base such as Cs2CO3, K2CO3, K3PO4, and the like; in a suitably selected organic solvent such as 1,4-dioxane, toluene, DME, THF, and the like; to yield the corresponding compound of formula (XVII). Preferably, the compound of formula (XVI) is reacted with the compound of formula (XV) in the presence of Pd2(dba)3 in combination with XantPhos; to yield the corresponding compound of formula (XVII).
The compound of formula (XVII) is reacted with Et3SiH in combination with TFA or SnCl2 in combination with HCl or TiCl4 in combination with Et3SiH; in a suitably selected organic solvent such as DCM, DCE, and the like; to yield the corresponding compound of formula (If).
One skilled in the art will recognize that the compound of formula (If) may be further optionally reacted with a suitably substituted compound of formula (XI) and/or with a suitably substituted compound of formula (XIII) to further functionalize the compound of formula (If), as described herein; more particularly, to attach a desired R2 and/or R4 substituent group.
Compounds of formula (I) wherein R0 is
and
is
are preferably prepared according to the procedure as outlined in Scheme (I-5), below.
Accordingly, a suitably substituted compound or formula (INT-3), prepared for example as described in Scheme A which follows herein, is reacted with a suitably substituted compound of formula (X), a known compound or compound prepared according to known methods; in the presence of a suitably selected catalyst such as Pd2(dba)3, Pd(OAc)2, and the like; in the presence of a suitably selected ligand such as dppf, XantPhos, XPhos, and the like in the presence of a suitably selected base such as Cs2CO3, K2CO3, K3PO4, and the like; in a suitably selected organic solvent such as 1,4-dioxane, toluene, DME, THF, and the like; to yield the corresponding compound of formula (XVIII).
The compound of formula (XVIII) is reacted with a suitably substituted compound of formula (XIX), a known compound or compound prepared by known methods, under Grignard conditions, in a suitably selected anhydrous organic solvent such as THF, diethyl ether, and the like; to yield the corresponding compound of formula (XX).
The compound of formula (XX) is reacted with a suitably selected acid such as TFA, HCl, p-toluene sulfonic acid, and the like, in a suitably selected solvent such as DCM, methanol, toluene, and the like; to yield the corresponding compound of formula (XXI).
The compound of formula (XXI) is reacted with H2(g) or a suitably selected source of hydrogen; in the presence of a suitably selected catalyst such as PtO2, Wilkinson's catalyst, and the like; in a suitably selected solvent such as methanol, ethanol, and the like; to yield the corresponding compound of formula (Ig).
The compound of formula (Ig) may be further, optionally substituted with desired R1, R2 and/or R4 substituent groups, according to the procedures as described herein.
Compounds of formula (I) wherein R0 is
and wherein is selected from the group consisting of —O—,
and
and wherein
is
may be prepared according to the procedure as described in Scheme (I-6), below.
Accordingly, a suitably substituted compound of formula (INT-3), prepared for example as described in Scheme A, which follows herein, is reacted with a suitably substituted compound of formula (X), a known compound or compound prepared according to known methods; in the presence of a suitably selected coupling agent such as Pd2(dba)3, Pd(OAc)2, and the like; in the presence of a suitably selected ligand such as dppf, XantPhos, XPhos, and the like in the presence of a suitably selected base such as Cs2CO3, K2CO3, K3PO4, and the like; in a suitably selected organic solvent such as 1,4-dioxane, toluene, DME, THF, and the like; to yield the corresponding compound of formula (XVIII).
The compound of formula (XVIII) is reacted with a suitably selected reducing agent such as NaBH4, LiBH4, and the like; in a suitably selected organic solvent such as methanol, THF, and the like; to yield the corresponding compound of formula (XXII).
The compound of formula (XXII) is reacted with a suitably selected chlorinating agent, such as SOCl2, CCl4 in combination with PPh3, mesyl chloride, and the like; neat or in a suitably selected solvent such as DCM, and the like; to yield the corresponding compound of formula (XXIII).
The compound of formula (XXIII) is reacted with a suitably substituted compound of formula (XXIV), a known compound or compound prepared by known methods; in the presence of a suitably selected base such as Cs2CO3, K2CO3, Na2CO3, and the like; in a suitably selected solvent such as DMF, acetonitrile, DCM, THF, and the like; to yield the corresponding compound of formula (Ih).
Alternatively, the compound of formula (XXIII) is reacted with a suitably substituted compound of formula (XXV), wherein L1 is selected from the group consisting of
and
a known compound or compound prepared by known methods, in the presence of a suitably selected organic base such as TEA, DIPEA, DBU, and the like; in a suitably selected solvent such as acetonitrile, DMF, and the like; to yield the corresponding compound of formula (Ij).
One skilled in the art will further recognize that the compound of formula (XXII) may alternatively be reacted with a suitably substituted compound of formula (XXIV) directly; under Mitsunobu conditions (for example in the presence of a mixture of DEAD and PPh3, in THF); to yield the corresponding compound of formula (Ih).
Compounds of formula (I) wherein R0 is
and wherein L1 is selected from the group consisting of —O—,
and
and wherein
is
may be prepared from the corresponding compound of formula (ID or compound of formula (Ih) (prepared as described in Scheme (I-6) above) by reacting under acid hydrolysis conditions; more particularly, reacting with a suitably selected acid such as TFA, HCl, aqueous phosphoric acid, and the like; in a suitably selected solvent such as DCM, methanol, toluene, and the like.
One skilled in the art will further recognize that the compound of formula (Ih) and/or the compound of formula (ID (or the corresponding quinolone compounds) may be further, optionally substituted with desired R1, R2 and/or R4 substituent groups, according to the procedures as described herein.
One skilled in the art will further recognize that compounds of formula (I) wherein R0 is
wherein
is
and wherein R3 is hydrogen may be prepared by selecting a suitably substituted compound of formula (INT-6)
prepared for example as described in Scheme which follows herein, and substituting said compound of formula (INT-6) for the compound of formula (INT-3) in Scheme (I-5) or Scheme (I-6) and reacting as described therein.
Additional substitutions and/or substituent transformations to yield the desired compound(s) of formula (I) may be effected according to the procedures as described herein (in the general synthesis schemes and examples) or according to methods known to those skilled in the art.
One skilled in the art will further recognize that compounds of formula (I) wherein R1 is selected from the group consisting of —O—(C1-4alkyl)-CO2H, —O—(C1-4alkyl)-C(O)O—(C1-4alkyl), —O—(C2-4alkyl)-NH2, —O—(C1-4alkyl)-C(O)—NH2, —O(C2-4alkyl)-NH—C(O)—(C1-2alkyl) may be prepared from a suitably protected precursor to the compound of formula (I), for example, a suitably substituted compound of formula (XVIII), wherein R1 is OH, by reacting with a suitably substituted compound of formula LGx-(C1-4alkyl)-CO2(C1-4alkyl), LGx-(C2-4alkyl)-NH—(C(O)O—C(CH3)3), or LGx-(C2-4alkyl)-NPhth, wherein LGx is a suitably selected leaving group such as Br, Cl, I, mesylate, tosylate, and the like, a known compound or compound prepared by known methods; according to known methods (for example in the presence of a suitably selected base such as Cs2CO3, K2CO3, and the like; in a suitably selected solvent such as acetonitrile, DMF, THF, and the like), followed by appropriate functional group manipulations known to those skilled in the art, to yield the corresponding compound of formula (I).
One skilled in the art will further recognize that compounds of formula (I) wherein R1 is selected from the group consisting of —(C1-4alkyl)-O—(C1-2alkyl), —(C3-4alkenyl)-O—(C1-2alkyl), —(C3-4alkenyl)-OH, —C1-4alkyl, —O—(C1-4alkyl) may be prepared from a suitably protected precursor to the compound of formula (I), for example, a suitably substituted compound of formula (XVI) or a compound of formula (XVIII), wherein R1 is Br, by reacting with a suitably substituted alkene, a known compound or compound prepared by known methods; according to known methods (for example in the presence of a suitably selected catalyst such as Pd(OAc)2; in the presence of a suitably selected ligand such as P(o-tol)3; in the presence of a suitably selected base such as DIEA; in a suitably selected solvent such as DMF), followed by appropriate functional group manipulations known to those skilled in the art, to yield the corresponding compound of formula (I).
Alternatively, compounds of formula (I) wherein R1 is selected from the group consisting of —(C1-4alkyl)-O—(C1-2alkyl), —(C3-4alkenyl)-O—(C1-2alkyl), —(C3-4alkenyl)-OH, —C1-4alkyl, —O—(C1-4alkyl) may be prepared from a suitably protected precursor to the compound of formula (I), for example, a suitably substituted compound of formula (XVI) or compound of formula (XVIII), wherein R1 is Br, by reacting with a suitably substituted vinylboronate derivative, a known compound or compound prepared by known methods; according to known methods (for example in the presence of a suitably selected catalyst such as Pd(dppf)Cl2; in the presence of a suitably selected base such as Cs2CO3, K2CO3, and the like; in a suitably selected solvent such as 1,4-dioxane, water, and the like), followed by appropriate functional group manipulations known to those skilled in the art, to yield the corresponding compound of formula (I).
Compounds of formula (II) wherein
is
and wherein
is
may be prepared according to the process outlined in Scheme (II-1), below.
Accordingly, a suitably substituted compound of formula (INT-1), a known compound or compound prepared for example as described in Scheme A, which follows herein, is reacted with a suitably substituted compound of formula (XXVI), wherein PG1 is a suitably selected nitrogen protecting group such as Boc, Cbz, ethoxy-carbonyl-, and the like, a known compound or compound prepared by known methods; in the presence of a suitably selected catalyst such as Pd2(dba)3, Pd(OAc)2, and the like; in the presence of a suitably selected ligand such as dppf, XantPhos, XPhos, and the like; in the presence of a suitably selected base such as Cs2CO3, K2CO3, K3PO4, and the like; in a suitably selected organic solvent such as 1,4-dioxane, toluene, THF, DME, and the like; to yield the corresponding compound of formula (XXVII).
The compound of formula (XXVII) is de-protected according to known methods, to yield the corresponding compound of formula (XXVIII). For example, wherein PG1 is Boc, the compound of formula (XXVII) is de-protected by reacting with a suitably selected acid such as HCl, TFA, and the like; alternatively, wherein PG1 is ethoxy-carbonyl, the compound of formula (XXVII) is de-protected by reacting with HBr in a suitably selected solvent such as water, acetic acid, and the like.
The compound of formula (XXVIII) is reacted with a suitably selected compound of formula (XXIX), to yield the corresponding compound of formula (IIa).
In an example, the compound of formula (XXVIII) is reacted with a suitably substituted compound of formula (XXIX) wherein L3 is selected from the group consisting of —CH2—, —CH(CH3)— and —CH(CH2CH3)—, and wherein LG3 is a suitably selected leaving group such as Cl, Br, I, tosylate, mesylate, and the like; in the presence of a suitably selected base such as TEA, Hunig's base, Na2CO3, and the like; in a suitably selected solvent such as DMF, acetonitrile, DCM, and the like; to yield the corresponding compound of formula (IIa) wherein L3 is the corresponding —CH2—, —CH(CH3)— or —CH(CH2CH3)—.
One skilled in the art will recognize that the compound of formula (IIa) wherein L3 is selected from the group consisting of —CH2—, —CH(CH3)— and —CH(CH2CH3)— may alternatively be prepared by reacting the compound of formula (XXVIII) with a compound of the formula R7—C(O)H or compound of formula R7—C(O)—CH3 or compound of formula R7—C(O)—CH2CH3; in the presence of a suitably selected reducing agent such as NaCNBH3, sodium triacetoxyborohydride, and the like; in a suitably selected organic solvent such as DCE, methanol, ethanol, and the like; to yield the corresponding compound of formula (IIa) wherein L3 is the corresponding —CH2—, —CH(CH3)— or —CH(CH2CH3)—.
In another example, the compound of formula (XXVIII) is reacted with a suitably substituted compound of formula (XXIX) wherein L3 is —C(O)— or —SO2— and wherein LG3 is for example, Cl; in the presence of a suitably selected tertiary organic base such as TEA, Hunig's base, and the like; in a suitably selected solvent such as DCM, THF, and the like; to yield the corresponding compound of formula (IIa) wherein L3 is the corresponding —C(O)— or —SO2—.
Preferably, wherein R7-L3 is CF3—SO2—, the compound of formula (XXVIII) is reacted with triflic anhydride, a known compound, in the presence of TEA, in methylene chloride; to yield the corresponding compound of formula (IIa) wherein L3 is —SO2—.
In another example, the compound of formula (XXVIII) is reacted with a suitably substituted compound of formula (XXIX) wherein L3 is —C(O)— and wherein LG3 is —OH; in the presence of a suitably selected peptide coupling agent such as DCC, HATU, HBTU, EDCI, and the like; optionally in the presence of a suitably selected base such as Hunig's base, TEA, and the like; in a suitably selected solvent such as DMF, DCM, and the like; to yield the corresponding compound of formula (IIa) wherein L3 is —C(O)—.
In another example, wherein L3 is absent (c is 0) and R7 is selected from the group consisting of phenyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, thien-2-yl, thien-3-yl, furan-2-yl, furan-3-yl, pyrimidin-2-yl and pyrazin-2-yl; the compound of formula (XXVIII) is reacted with a suitably substituted compound of formula (XXIX) wherein L3 is absent (i.e. c is 0) and wherein LG3 is suitably selected group such as Cl, Br, I, triflate, and the like; in the presence of a suitably selected catalyst such as Pd2(dba)3, Pd(OAc)2, and the like; in the presence of a suitably selected ligand such as BINAP, dppf, XantPhos, XPhos, and the like; in the presence of a suitably selected base such as Cs2CO3, K2CO3, K3PO4, and the like; in a suitably selected organic solvent such as 1,4-dioxane, toluene, THF, DME, and the like; to yield the corresponding compound of formula (IIa) wherein L3 is absent (i.e. c is 0).
In another example, wherein L3 is absent (c is 0) and R7 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; the compound of formula (XXVIII) is reacted with a suitably substituted compound of formula (XXIX), wherein L3 is absent (i.e. c is 0) and wherein LG3 is suitably selected group such as Cl, Br, I, mesylate, tosylate, and the like; in the presence of a suitably selected base such as TEA, Hunig's base, Na2CO3, and the like; in a suitably selected solvent such as DMF, acetonitrile, DCM, and the like; to yield the corresponding compound of formula (IIa) wherein L3 is absent (i.e. c is 0).
Alternatively, wherein L3 is absent (c is 0) and R7 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; the compound of formula (XXVIII) is reacted with cyclobutanone, cyclopentanone or cyclohexanone, respectively; in the presence of a suitably selected reducing agent such as NaCNBH3, sodium triacetoxyborohydride, and the like; in a suitably selected organic solvent such as DCE, methanol, ethanol, and the like; to yield the corresponding compound of formula (IIa) wherein L3 is absent (i.e. c is 0).
The compound of formula (IIa) is further, optionally, reacted with a suitably substituted compound of formula (XI), wherein LG1 is a suitably selected leaving group such as Cl, Br, I, tosylate, mesylate, and the like; in the presence of a suitably selected base such as Cs2CO3, K2CO3, NaH, and the like; in a suitably selected organic solvent such as acetonitrile, DMF, THF, and the like; to yield the corresponding compound of formula (IIb), in a mixture with the corresponding compound of formula (XXX).
Compounds of formula (II) wherein
is
and wherein
is
and may be prepared according to the process outlined in Scheme (II-2), below.
Accordingly, a suitably substituted compound of formula (INT-1), a known compound or compound prepared for example as described in Scheme A, which follows herein, is reacted with a suitably substituted compound of formula (XXXI), a known compound or compound prepared by known methods; in the presence of a suitably selected catalyst such as Pd2(dba)3, Pd(OAc)2, and the like; in the presence of a suitably selected ligand such as dppf, XantPhos, XPhos, and the like; in the presence of a suitably selected base such as Cs2CO3, K2CO3, K3PO4, and the like; in a suitably selected organic solvent such as 1,4-dioxane, toluene, THF, DME, and the like; to yield the corresponding compound of formula (IIc).
One skilled in the art will recognize that the compound of formula (IIc) may be further, optionally reacted with a suitably substituted compound of formula (XI), as described in Scheme (II-1) above (i.e. by substituting the compound of formula (IIc) for the compound of formula (IIa) in Scheme (II-1) above), to yield the corresponding compound of formula (IId), in a mixture with the corresponding compound of formula (XXXII).
One skilled in the art will further recognize that compounds of formula (II) wherein
is
and wherein R3 is hydrogen may be similarly prepared according to the processes outlined in Scheme (II-1) and Scheme (II-2) above, by selecting a suitably substituted compound of formula (INT-4)
a compound prepared for example, as described in Scheme C, which follows herein, and substituting said compound of formula (INT-4) for the compound of formula (INT-1) in Scheme (II-1) or Scheme (II-2) above, and reacting as described therein.
Compounds of formula (II) wherein
is
and wherein R3 is —OR4, may be prepared according to the process described in Scheme (II-3) below.
Accordingly, a suitably substituted compound of formula (IId) wherein R1 is other than hydroxy, prepared for example as described in Scheme (II-1) or Scheme (II-2) above, is reacted with a suitably substituted compound of formula (XIII), wherein LG2 is a suitably selected leaving group such as Br, Cl, I, mesylate, tosylate, and the like, a known compound or compound prepared by known methods; according to known methods (for example in the presence of a suitably selected base such as Cs2CO3, K2CO3, and the like; in a suitably selected solvent such as acetonitrile, DMF, THF, and the like), to yield the corresponding compound of formula (IIe), in a mixture with the corresponding compound of formula (XXXII).
Compounds of formula (II) wherein
is
wherein R3 is hydrogen, and wherein R1 is selected from the group consisting of NRERF may be prepared by selecting a suitably substituted compound of formula (IIf)
prepared for example as described in Scheme (II-1) or Scheme (II-2) above; substituting said compound of formula (IIf) for the compound of formula (Id) in Scheme (I-3) above, and reacting with a suitably substituted compound of formula (XV), as described therein.
Compounds of formula (II) wherein
is
and wherein R1 is selected from the group consisting of NRERF are preferably prepared according to the procedure as described in Scheme (II-4), below.
Accordingly, a suitably substituted compound of formula (INT-2) wherein R1 is Br, and wherein A5 is selected from the group consisting of C1-4alkyl, preferably methyl or t-butyl, prepared for example as described in Scheme B, which follows herein, is reacted with a suitably substituted compound of formula (XXXIV), a known compound or compound prepared by known methods; in the presence of a suitably selected catalyst such as Pd2(dba)3, Pd(OAc)2, and the like; in the presence of a suitably selected ligand such as dppf, XantPhos, XPhos, and the like; in the presence of a suitably selected base such as Cs2CO3, K2CO3, K3PO4, and the like; in a suitably selected organic solvent such as 1,4-dioxane, toluene, THF, DME, and the like; to yield the corresponding compound of formula (XXXV).
The compound of formula (XXXV) is reacted with a suitably substituted compound of formula (XV), a known compound or compound prepared by known methods; in the presence of a suitably selected catalyst such as Pd2(dba)3, Pd(OAc)2, and the like; in the presence of a suitably selected ligand such as dppf, XantPhos, XPhos, and the like; in the presence of a suitably selected base such as Cs2CO3, K2CO3, K3PO4, and the like; in a suitably selected organic solvent such as 1,4-dioxane, toluene, DME, THF, and the like; to yield the corresponding compound of formula (XXXVI). Preferably, the compound of formula (XXXV) is reacted with the compound of formula (XV) in the presence of Pd2(dba)3 in combination with XantPhos; to yield the corresponding compound of formula (XXXVI).
The compound of formula (XXXVI) is reacted with Et3SiH in combination with TFA or SnCl2 in combination with HCl or TiCl4 in combination with Et3SiH; in a suitably selected organic solvent such as DCM, DCE, and the like; to yield the corresponding compound of formula (IIg).
The compound of formula (IIg) is reacted under acid hydrolysis conditions, for example with a suitably selected acid such as HCl, TFA, aqueous phosphoric acid, and the like; in a suitably selected organic solvent such as DCM, methanol, toluene, and the like; to yield the corresponding compound of formula (IIh).
One skilled in the art will further recognize that compounds of formula (II) wherein R1 is selected from the group consisting of —O—(C1-4alkyl)-CO2H, —O—(C1-4alkyl)-C(O)O—(C1-4alkyl), —O—(C1-4alkyl)-NH2, —O—(C1-4alkyl)-C(O)—NH2, —O(C1-4alkyl)-NH—C(O)—(C1-2alkyl) may be prepared from a suitably protected precursor to the compound of formula (II), for example, a suitably substituted compound of formula (XXXV), wherein R1 is OH, by reacting with a suitably substituted compound of formula LGx-(C1-4alkyl)-CO2(C1-4alkyl), LGx-(C2-4alkyl)-NH—(C(O)O—C(CH3)3), or LGx-(C2-4alkyl)-NPhth wherein LGx is a suitably selected leaving group such as Br, Cl, I, mesylate, tosylate, and the like, a known compound or compound prepared by known methods; according to known methods (for example in the presence of a suitably selected base such as Cs2CO3, K2CO3, and the like; in a suitably selected solvent such as acetonitrile, DMF, THF, and the like), followed by appropriate functional group manipulations known to those skilled in the art, to yield the corresponding compound of formula (II).
One skilled in the art will further recognize that compounds of formula (II) wherein R1 is selected from the group consisting of —(C1-4alkyl)-O—(C1-2alkyl), —(C3-4alkenyl)-O—(C1-2alkyl), —(C3-4alkenyl)-OH, —C1-4alkyl, —O—(C1-4alkyl) may be prepared from a suitably protected precursor to the compound of formula (II), for example, a suitably substituted compound of formula (XXXV), wherein R1 is Br, by reacting with a suitably substituted alkene, a known compound or compound prepared by known methods; according to known methods (for example in the presence of a suitably selected catalyst such as Pd(OAc)2; in the presence of a suitably selected ligand such as P(o-tol)3; in the presence of a suitably selected base such as DIEA; in a suitably selected solvent such as DMF), followed by appropriate functional group manipulations known to those skilled in the art, to yield the corresponding compound of formula (II).
Alternatively, compounds of formula (II) wherein R1 is selected from the group consisting of —(C1-4alkyl)-O—(C1-2alkyl), —(C3-4alkenyl)-O—(C1-2alkyl), —(C3-4alkenyl)-OH, —C1-4alkyl, —O—(C1-4alkyl) may be prepared from a suitably protected precursor to the compound of formula (II), for example, a suitably substituted compound of formula (XXXV), wherein R1 is Br, by reacting with a suitably substituted vinylboronate derivative, a known compound or compound prepared by known methods; according to known methods (for example in the presence of a suitably selected catalyst such as Pd(dppf)Cl2; in the presence of a suitably selected base such as Cs2CO3, K2CO3, and the like; in a suitably selected solvent such as 1,4-dioxane, water, and the like), followed by appropriate functional group manipulations known to those skilled in the art, to yield the corresponding compound of formula (II).
Compounds of formula (III) wherein
is
and wherein L4 is —CH═CH— may be prepared according to the procedure as outlined in Scheme (III-1), below.
Accordingly, a suitably substituted compound of formula (INT-3a) (a compound of formula (INT-3) wherein R1 is selected from the group consisting of hydrogen and —O—C1-4alkyl), prepared for example as described in Scheme A, is reacted with a suitably substituted compound of formula (XXXVII) (i.e. a suitably selected boronic acid or boronic ester), a known compound or compound prepared by known methods, to yield the corresponding compound of formula (XXXVIII).
In an example, the compound of formula (INT-3a) is reacted with the compound of formula (XXXVII), wherein both R groups are the same and are hydrogen (i.e. a suitably selected boronic acid); in the presence of a suitably selected catalyst such as Pd(OAc)2, Pd(PPh3)4, Pd2(dba)3.CH2Cl2, and the like; in the presence of a suitably selected ligand such as SPhos, PPh3, dppf, and the like; in the presence of a suitably selected base such as Cs2CO3, K2CO3, K3PO4, and the like; in a suitably selected organic solvent such as 1,4-dioxane, toluene, DME, THF, and the like; to yield the corresponding compound of formula (XXXVIII).
In another example, the compound of formula (INT-3a) is reacted with a suitably substituted compound of formula (XXXVII) wherein both R groups are the same and are C1-2alkyl, or are taken together with the oxygen atoms to which they are bound to form
(i.e. a suitably selected boronic ester); in the presence of a suitably selected catalyst such as Pd(OAc)2, Pd(PPh3)4, Pd2(dba)3.CH2Cl2, and the like; in the presence of a suitably selected ligand such as SPhos, PPh3, dppf, and the like; in the presence of a suitably selected base such as Cs2CO3, K2CO3, K3PO4, and the like; in a suitably selected organic solvent such as 1,4-dioxane, toluene, DME, THF, and the like; to yield the corresponding compound of formula (XXXVIII).
The compound of formula (XXXVIII) is reacted with a suitably substituted compound of formula (XXXIX), a known compound or compound prepared by known methods, under Grignard conditions (i.e. in a suitably selected anhydrous solvent such as diethyl ether, THF, and the like), to yield the corresponding compound of formula (XL).
The compound of formula (XL) is reacted with Et3SiH in combination with TFA or SnCl2 in combination with HCl or TiCl4 in combination with Et3SiH; in a suitably selected organic solvent such as DCM, DCE, and the like; to yield the corresponding compound of formula (IIIa).
The compound of formula (IIIa) is further, optionally, reacted with a suitably substituted compound of formula (XI), wherein LG1 is a suitably selected leaving group such as Cl, Br, I, tosylate, mesylate, and the like; in the presence of a suitably selected base such as Cs2CO3, K2CO3, NaH, and the like; in a suitably selected organic solvent such as acetonitrile, DMF, THF, and the like; to yield the corresponding compound of formula (IIIb), in a mixture with the corresponding compound of formula (XLI).
One skilled in the art will recognize that compounds of formula (III) wherein
is
and wherein L4 is —CH═CH— may alternatively be prepared by reacting a suitably substituted compound of formula (INT-1a)
(a compound of formula (INT-1) wherein R1 is selected from the group consisting of hydrogen and —O—C1-4alkyl (i.e. wherein R1 is limited to the subset of substituents as in R13)), prepared for example as describe in Scheme A which follows herein, with a suitably substituted compound of formula (XXXVII), as described in Scheme (III-1) above; to yield the corresponding compound of formula (III) wherein
is
wherein R2 is hydrogen and wherein L4 is —CH═CH—; and then further, optionally reacted with a suitably substituted compound of formula (XI), as described in Scheme (III-1) above.
Compounds of formula (III) wherein
is
and wherein L4 is —CH2— may be prepared according to the procedure as outlined in Scheme (III-2), below.
Accordingly, a suitably substituted compound of formula (INT-2a), (a compound of formula (INT-2) wherein R1 is selected from the group consisting of hydrogen and —O—C1-4alkyl (i.e. wherein R1 is limited to the subset of substituents as in R13)), prepared for example as described in Scheme B above, is reacted with a suitably substituted compound of formula (XLII), to yield the corresponding compound of formula (XLIII).
In an example, the compound of formula (INT-2a) is reacted with the compound of formula (XLII), wherein both R groups are the same and are hydrogen (i.e. a suitably selected boronic acid); in the presence of a suitably selected coupling agent such as Pd(OAc)2, Pd(PPh3)4, Pd2(dba)3.CH2Cl2, and the like; in the presence of a suitably selected ligand such as SPhos, PPh3, dppf, and the like; in the presence of a suitably selected base such as Cs2CO3, K2CO3, K3PO4, and the like; in a suitably selected organic solvent such as 1,4-dioxane, toluene, DME, THF, and the like; to yield the corresponding compound of formula (XLIII).
In another example, the compound of formula (INT-2a) is reacted with a suitably substituted compound of formula (XLII) wherein both R groups are the same and are C1-2alkyl, or are taken together with the oxygen atoms to which they are bound to form
(i.e. a suitably selected boronic ester); in the presence of a suitably selected catalyst such as Pd(OAc)2, Pd(PPh3)4, Pd2(dba)3.CH2Cl2, and the like; in the presence of a suitably selected ligand such as SPhos, PPh3, dppf, and the like; in the presence of a suitably selected base such as Cs2CO3, K2CO3, K3PO4, and the like; in a suitably selected organic solvent such as 1,4-dioxane, toluene, DME, THF, and the like; to yield the corresponding compound of formula (XLIII).
The compound of formula (XLIII) is reacted with Et3SiH in combination with TFA or SnCl2 in combination with HCl or TiCl4 in combination with Et3SiH; in a suitably selected organic solvent such as DCM, DCE, and the like; to yield the corresponding compound of formula (IIIc).
One skilled in the art will recognize that the compound of formula (IIIc) may be substituted for the compound of formula (IIIa) in Scheme (III-1), above and then reacted with a suitably substituted compound of formula (XI), wherein LG1 is a suitably selected leaving group such as Cl, Br, I, tosylate, mesylate, and the like; as described therein (in the presence of a suitably selected base such as Cs2CO3, K2CO3, NaH, and the like; in a suitably selected organic solvent such as acetonitrile, DMF, THF, and the like); to yield the corresponding compound of formula (IIId), in a mixture with the corresponding compound of formula (XLIV).
Compounds of formula (III) wherein
is
and wherein L4 is —CH2CH2— may be prepared according to the procedure as outlined in Scheme (III-3), below.
Accordingly, a suitably substituted compound of formula (XLV), a known compound or compound prepared by known methods (e.g. ANGIBAUD, P. R., et al., PCT Publication WO2002/051835 A1, published 4 Jul. 2002), is reacted with a suitably substituted compound of formula (XLVI), a known compound or compound prepared by known methods, under Grignard conditions; to yield the corresponding compound of formula (XLVII).
The compound of formula (XLVII) is reacted with Et3SiH in combination with TFA or SnCl2 in combination with HCl or TiCl4 in combination with Et3SiH; in a suitably selected organic solvent such as DCM, DCE, and the like; to yield the corresponding compound of formula (Ille).
The compound of formula (Ille) is further optionally reacted with a suitably substituted compound of formula (XI), wherein LG1 is a suitably selected leaving group such as Cl, Br, I, tosylate, mesylate, and the like; as described therein (in the presence of a suitably selected base such as Cs2CO3, K2CO3, NaH, and the like; in a suitably selected organic solvent such as acetonitrile, DMF, THF, and the like); to yield the corresponding compound of formula (IIIf), in a mixture with the corresponding compound of formula (XLVIII).
Compounds of formula (III) wherein
is
wherein R3 is —OR4 may be prepared according to the process outlined in Scheme (III-4), below.
Accordingly, a suitably substituted compound of formula (IIIg), prepared for example as described in Scheme (III-1), Scheme (III-2) or Scheme (III-3) above, is reacted with a suitably substituted compound of formula (XIII), wherein LG2 is a suitably selected leaving group such as Br, Cl, I, mesylate, tosylate, and the like, a known compound or compound prepared by known methods; according to known methods (for example in the presence of a suitably selected base such as Cs2CO3, K2CO3, and the like; in a suitably selected solvent such as acetonitrile, DMF, THF, and the like), to yield the corresponding compound of formula (IIIh), in a mixture with the corresponding compound of formula (XLIX).
Compounds of formula (III) wherein
is
wherein R3 is hydrogen and L4 is —CH═CH— may be similarly prepared according to the procedures as described above, by selecting and substituting a suitably substituted compound of formula (INT-6a)
(a compound of formula (INT-6) wherein R1 is selected from the group consisting of hydrogen and —O—C1-4alkyl (i.e. wherein R1 is limited to the subset of substituents as in R13)), for the compound of formula (INT-3a), in Scheme (III-1) and reacting as therein described.
Compounds of formula (III), wherein
is
and wherein R3 is hydrogen and wherein L4 is —CH2CH2— may be similarly prepared according to the procedures as described above, by selecting and substituting a suitably substituted compound of formula (LX)
a compound prepared for example, as described in ANGIBAUD, P. R., et al., PCT Publication WO2002/051835 A1, published 4 Jul. 2002, and reacting as described in Scheme (III-3), above.
Compounds of formula (III) wherein
is
and wherein R3 is hydrogen and wherein L4 is —CH2— may be similarly prepared according to the procedures as described above, by selecting and substituting a suitably substituted compound of formula (INT-5a)
(a compound of formula (INT-5a) wherein R1 is selected from the group consisting of hydrogen and —O—C1-4alkyl), prepared for example as described in Scheme C, for the compound of formula (INT-2a), in Scheme (III-2), and reacting as therein described.
Compounds of formula (IV) wherein
is
and wherein
is
may be prepared according to the process outlined in Scheme (IV-1), below.
Accordingly, a suitably substituted compound of formula (INT-2b), (a compound of formula (INT-2) wherein R1 is selected from the group consisting of hydrogen, hydroxy, halogen, C1-4alkyl, —O—C1-4alkyl, —NH2, —NH(C1-4alkyl) and —N(C1-4alkyl)2), prepared for example as described in Scheme B, is reacted with a suitably substituted compound of formula (L), wherein PG1 is a suitably selected nitrogen protecting group such as Boc, Cbz, ethoxy-carbonyl-, and the like, a known compound or compound prepared by known methods; in the presence of a suitably selected catalyst such as Pd2(dba)3, Pd(OAc)2, and the like; in the presence of a suitably selected ligand such as dppf, XantPhos, XPhos, and the like; in the presence of a suitably selected base such as Cs2CO3, K2CO3, K3PO4, and the like; in a suitably selected organic solvent such as 1,4-dioxane, toluene, THF, DME, and the like; to yield the corresponding compound of formula (LI).
The compound of formula (LI) is de-protected according to known methods, to yield the corresponding compound of formula (LII). For example, wherein PG1 is Boc, the compound of formula (LI) is de-protected by reacting with a suitably selected acid such as HCl, TFA, and the like; alternatively, wherein PG1 is ethoxy-carbonyl, the compound of formula (LI) is de-protected by reacting with HBr in a suitably selected solvent such as water, acetic acid, and the like.
The compound of formula (LII) is reacted with a suitably selected compound of formula (LIII), to yield the corresponding compound of formula (IVa).
In an example, wherein R9 is selected from the group consisting of —C(O)O—(C1-4alkyl), —C(O)—(C1-4alkyl), —C(O)-(halogenated C1-4alkyl) and —SO2-(halogenated C1-4alkyl), the compound of formula (LII) is reacted with a suitably substituted compound of formula (LIII), wherein LG4 is, for example, Cl; in the presence of a suitably selected tertiary organic base such as TEA, Hunig's base, and the like; in a suitably selected solvent such as DCM, THF, and the like; to yield the corresponding compound of formula (IVa).
In another example, wherein R9 is —C(O)—(C1-4alkyl), the compound of formula (LII) is reacted with a suitably substituted compound of formula (LIII), wherein LG3 is —OH; in the presence of a suitably selected peptide coupling agent such as DCC, HATU, HBTU, EDCI, and the like; optionally in the presence of a suitably selected base such as Hunig's base, TEA, and the like; in a suitably selected solvent such as DMF, DCM, and the like; to yield the corresponding compound of formula (IVa).
Preferably, wherein R9 is CF3—SO2—, the compound of formula (LII) is reacted with triflic anhydride, a known compound, in the presence of TEA, in methylene chloride; to yield the corresponding compound of formula (IVa).
Compounds of formula (IV) wherein
is
and wherein
is
may alternatively be prepared according to the process outlined in Scheme (IV-1) above, by selecting an substituting a suitably substituted compound of formula (LXI)
for the compound of formula (L) and reacting as described therein (i.e. reacting under palladium-catalyzed cross-coupling conditions to yield an intermediate, which is then further reacted to remove the —OH and -t-butyl groups).
Compounds of formula (IV) wherein
is
and wherein
is
may be prepared according to the process outlined in Scheme (IV-3), below.
Accordingly, a suitably substituted compound of formula (INT-1b), (a compound of formula (INT-1) wherein R1 is selected from the group consisting of hydrogen, hydroxy, halogen, C1-4alkyl, —O—C1-4alkyl, —NH2, —NH(C1-4alkyl) and —N(C1-4alkyl)2), prepared for example as described in Scheme A, is reacted with a suitably substituted compound of formula (LV) (i.e. a suitably substituted boronic acid or boronic ester), and wherein PG3 is a suitably selected nitrogen protecting group such as Boc, Cbz, ethoxy-carbonyl-, and the like, to yield the corresponding compound of formula (LVI).
In an example, the compound of formula (INT-1b) is reacted with the compound of formula (LV), wherein both R groups are the same and are hydrogen (i.e. a suitably selected boronic acid); in the presence of a suitably selected catalyst such as Pd(OAc)2, Pd(PPh3)4, Pd2(dba)3.CH2Cl2, and the like; in the presence of a suitably selected ligand such as SPhos, PPh3, dppf, and the like; in the presence of a suitably selected base such as Cs2CO3, K2CO3, K3PO4, and the like; in a suitably selected organic solvent such as 1,4-dioxane, toluene, DME, THF, and the like; to yield the corresponding compound of formula (LVI).
In another example, the compound of formula (INT-1b) is reacted with a suitably substituted compound of formula (LV) wherein both R groups are the same and are C1-2alkyl, or are taken together with the oxygen atoms to which they are bound to form
(i.e. a suitably selected boronic ester); in the presence of a suitably selected catalyst such as Pd(OAc)2, Pd(PPh3)4, Pd2(dba)3.CH2Cl2, and the like; in the presence of a suitably selected ligand such as SPhos, PPh3, dppf, and the like; in the presence of a suitably selected base such as Cs2CO3, K2CO3, K3PO4, and the like; in a suitably selected organic solvent such as 1,4-dioxane, toluene, DME, THF, and the like; to yield the corresponding compound of formula (LVI).
The compound of formula (LVI) is de-protected according to known methods, to yield the corresponding compound of formula (IVc). For example, wherein PG3 is Boc, the compound of formula (LVI) is de-protected by reacting with a suitably selected acid such as HCl, TFA, and the like; alternatively, wherein PG3 is ethoxy-carbonyl, the compound of formula (LVI) is de-protected by reacting with HBr in a suitably selected solvent such as water, acetic acid, and the like. (One skilled in the art will recognize that the compound of formula (IVc) corresponds to the compound of formula (IV) wherein
is
and wherein R9 is hydrogen.)
The compound of formula (IVc) is reacted with a suitably selected compound of formula (LIII), to yield the corresponding compound of formula (IVd).
In an example, wherein R9 is selected from the group consisting of —C(O)O—(C1-4alkyl), —C(O)—(C1-4alkyl), —C(O)-(halogenated C1-4alkyl) and —SO2-(halogenated C1-4alkyl), the compound of formula (IVc) is reacted with a suitably substituted compound of formula (LIII), wherein LG4 is, for example, Cl; in the presence of a suitably selected tertiary organic base such as TEA, Hunig's base, and the like; in a suitably selected solvent such as DCM, THF, and the like; to yield the corresponding compound of formula (IVd).
In another example, wherein R9 is —C(O)—(C1-4alkyl), the compound of formula (IVc) is reacted with a suitably substituted compound of formula (LIII), wherein LG3 is —OH; in the presence of a suitably selected peptide coupling agent such as DCC, HATU, HBTU, EDCI, and the like; optionally in the presence of a suitably selected base such as Hunig's base, TEA, and the like; in a suitably selected solvent such as DMF, DCM, and the like; to yield the corresponding compound of formula (IVd).
Preferably, wherein R9 is CF3—SO2—, the compound of formula (IVc) is reacted with triflic anhydride, a known compound, in the presence of TEA, in methylene chloride; to yield the corresponding compound of formula (IVd).
The compound formula (IVd) is further, optionally, reacted with a suitably substituted compound of formula (XI), wherein LG1 is a suitably selected leaving group such as Cl, Br, I, tosylate, mesylate, and the like; in the presence of a suitably selected base such as Cs2CO3, K2CO3, NaH, and the like; in a suitably selected organic solvent such as acetonitrile, DMF, THF, and the like; to yield the corresponding compound of formula (IVe), in a mixture with the corresponding compound of formula (LVII).
Compounds of formula (IV) wherein
is
and wherein
is
may alternatively be prepared according to the process outlined in Scheme (IV-2) above, by selecting an substituting a suitably substituted compound of formula (LXII)
for the compound of formula (L) and reacting as described therein (i.e. reacting under palladium-catalyzed cross-coupling conditions).
Compounds of formula (IV) wherein
is
may be prepared as described in Scheme (IV-3), below.
Accordingly, a suitably substituted compound of formula (IVf) wherein R14 is hydrogen, is reacted with a suitably substituted compound of formula (XI), wherein LG1 is a suitably selected leaving group such as Cl, Br, I, tosylate, mesylate, and the like; in the presence of a suitably selected base such as Cs2CO3, K2CO3, NaH, and the like; in a suitably selected organic solvent such as acetonitrile, DMF, THF, and the like; to yield the corresponding compound of formula (IVb), in a mixture with the corresponding compound of formula (LIV).
Compounds of formula (IV) wherein
is
wherein R3 is —OR4, may be prepared according to the procedure described in Scheme (IV-4), below.
Accordingly, a suitably substituted compound of formula (IVf), prepared for example, as described herein, is reacted with a suitably substituted compound of formula (XIII), wherein LG2 is a suitably selected leaving group such as Br, Cl, I, mesylate, tosylate, and the like, a known compound or compound prepared by known methods; according to known methods (for example in the presence of a suitably selected base such as Cs2CO3, K2CO3, and the like; in a suitably selected solvent such as acetonitrile, DMF, THF, and the like), to yield the corresponding compound of formula (IVg), in a mixture with the corresponding compound of formula (LVIII).
Compounds of formula (IV) wherein
is
and wherein R3 is hydrogen and wherein
is
may be similarly prepared according to the procedures as described above, by selecting and substituting a suitably substituted compound of formula (INT-5b)
(a compound of formula (INT-5) wherein R1 is selected from the group consisting of hydrogen, halogen, —OH, —O—(C1-4alkyl), —NH2, —NH(C1-4alkyl) and —N(C1-4alkyl)2), prepared for example as described in Scheme C, for the compound of formula (INT-2b), in Scheme (IV-1), and reacting as therein described.
Compounds of formula (III) wherein
is
and wherein R3 is hydrogen and wherein
is
may be similarly prepared according to the procedures as described above, by selecting and substituting a suitably substituted compound of formula (INT-4b)
(a compound of formula (INT-4) wherein R1 is selected from the group consisting of hydrogen, halogen, —OH, —C1-4alkyl, —O—(C1-4alkyl), —NH2, —NH(C1-4alkyl) and —N(C1-4alkyl)2), prepared for example as described in Scheme C, for the compound of formula (INT-1b), in Scheme (IV-2), and reacting as therein described.
One skilled in the art will recognize that in the synthesis of the compounds of formula (I), the compounds of formula (II), the compounds of formula (III) and the compounds of formula (IV) of the present invention, additional substitutions and/or substituent transformations may be effected according to the procedures as described herein (in the general synthesis schemes and examples) or according to methods known to those skilled in the art, to yield additional desired compounds of the present invention. One skilled in the art will further recognize that the reaction steps and processes described herein may be adapted and/or applied to the synthesis of any of the compounds of the present invention.
Compounds of formula (INT-1), compounds of formula (INT-2) and compounds of formula (INT-3) may be prepared according to the procedure as outlined in Scheme A, below.
Accordingly, a suitably compound of formula (C), wherein R1 is selected from the group consisting of hydrogen, halogen (preferably bromo), —C1-4alkyl and —O—(C1-4alkyl), a known compound or compound prepared by known methods, is reacted with ethyl 3-chloro-3-oxopropanoate, a known compound; in the presence of a suitably selected organic base such as TEA, DIPEA, pyridine, and the like; in a suitably selected organic solvent such as DCM, THF, 1,4-dioxane, and the like; to yield the corresponding compound of formula (CI).
The compound of formula (CI) is reacted with a suitably selected base such as LiOH, NaOH, and the like; in a suitably selected solvent or mixture of solvents such as 1,4-dioxane/water, THF/water, ethanol/water, and the like; to yield the corresponding compound of formula (CII).
The compound of formula (CII) is subjected to ring closure, by reacting with CH3SO3H; in the presence of P2O5; optionally, in a suitably selected solvent such as toluene, benzene, chlorobenzene, and the like; to yield the corresponding compound of formula (CIII).
The compound of formula (CIII) is reacted with a suitably selected brominating agent such as PBr3, POBr3, PPh3Br2, and the like; neat or in a suitably selected solvent such as toluene, benzene, DMF, and the like; to yield the corresponding compound of formula (CIV).
The compound of formula (CIV) is reacted with a suitably selected reagent such as KOt-Bu, NaOt-Bu, and the like; in a suitably selected organic solvent such as toluene, THF, 1,4-dioxane, o-dichlorobenzene and the like; to yield the corresponding compound of formula (INT-3).
The compound of formula (INT-3) is reacted with a suitably substituted compound of formula (XXXIX), a known compound or compound prepared by known methods, under Grignard conditions, more particularly, in the presence in a suitably selected anhydrous organic solvent such as diethyl ether, THF, and the like; to yield the corresponding compound of formula (INT-2).
The compound of formula (INT-2) is reacted with Et3SiH in combination with TFA, or SnCl2 in combination with HCl, or TiCl4 in combination with Et3SiH; in a suitably selected organic solvent such as DCM, DCE, and the like; to yield the corresponding compound of formula (INT-1).
One skilled in the art will recognize that the compound of formula (CIV) may alternatively be reacted with a suitably selected sodium or potassium C1-4alkoxide, such as for example, NaOCH3 or NaOCH2CH3, to yield the corresponding compound of formula (INT-3) wherein the —O-t-butyl group at the 2-position of the quinoline core is replaced with the corresponding —O—C1-4alkyl, for example —OCH3 or —OCH2CH3 The resulting compound is then reacted with a suitably substituted compound of formula (XXXIX), a known compound or compound prepared by known methods, under Grignard conditions, as described above; and then de-protected by reacting with a suitably selected acid such as HCl, HBr, and the like.
Compounds of formula (INT-2) wherein R1 is wherein R1 is selected from the group consisting of hydrogen, halogen (preferably bromo), —C1-4alkyl and —O—(C1-4alkyl), may alternatively be prepared according to the procedure as outlined in Scheme B, below.
Accordingly, a suitably substituted compound of formula (CV), a known compound or compound prepared by known methods is protected at the terminal amine group according to known methods, to yield the corresponding compound of formula (CVI), wherein PG1 is a suitably selected nitrogen protecting group such as Boc, Cbz, and the like. For example, wherein PG1 is Boc, the methyl 4-amino-3-bromobenzoate is reacted with Boc-anhydride, in the presence of TEA, in THF.
The compound of formula (CVI) is reacted with at least two moles of a suitably substituted compound of formula (XXXIX), a known compound or compound prepared by known methods, under Grignard conditions; in a suitably selected anhydrous organic solvent such as diethyl ether, THF, and the like; to yield the corresponding compound of formula (CVII) wherein
and
are the same.
The compound of formula (CVII) is de-protected according to known methods, to yield the corresponding compound of formula (CIX). For example, wherein PG1 is Boc, the compound of formula (CVII) is de-protected by reacting with a suitably selected acid such as TFA, and the like; in a suitably selected organic solvent such as 1,4-dioxane, and the like.
The compound of formula (CIX) is reacted with ethyl 3-chloro-3-oxopropanoate, a known compound; in the presence of a suitably selected organic base such as TEA, DIPEA, pyridine, and the like; in a suitably selected organic solvent such as DCM, THF, 1,4-dioxane, and the like; to yield the corresponding compound of formula (CX).
The compound of formula (CX) is reacted with a suitably selected base such as LiOH, NaOH, and the like; in a suitably selected solvent or mixture of solvents such as 1,4-dioxane/water, THF/water, ethanol/water, and the like; to yield the corresponding compound of formula (CXI).
The compound of formula (CXI) is subjected to ring closure, by reacting with CH3SO3H; in the presence of P2O5; in a suitably selected solvent such as toluene, benzene, chlorobenzene, and the like; to yield the corresponding compound of formula (CXII).
The compound of formula (CXII) is reacted with a suitably selected brominating agent such as PBr3, POBr3, PPh3Br2, and the like; neat or in a suitably selected solvent such as toluene, benzene, DMF, and the like; to yield the corresponding compound of formula (CXIII).
The compound of formula (CXIII) is reacted with a suitably selected reagent such as KOt-Bu, NaOt-Bu, and the like; in a suitably selected organic solvent such as toluene, THF, 1,4-dioxane, o-dichlorobenzene and the like; to yield the corresponding compound of formula (INT-2).
Compounds of formula (INT-4) and (INT-5), wherein R1 is selected from the group consisting of hydrogen, halogen (preferably bromo), —C1-4alkyl and —O—(C1-4alkyl), and wherein
and
are the same, may be prepared according to the procedure as outlined in Scheme C, below.
Accordingly, a suitably substituted compound of formula (CXIV), a known compound or compound prepared by known methods, is reacted with 2,2-dimethyl-1,3-dioxane-4,6-dione, a known compound; in the presence of a suitably selected reagent such as CH(OEt)3, DMF-dimethylacetal, and the like; neat or in a suitably selected solvent such as ethanol, isopropanol, and the like; preferably at an elevated temperature in the range of from about 75° C. to about 120° C., for example, at about 100° C.; to yield the corresponding compound of formula (CXV).
The compound of formula (CXV) is subjected to ring-closure, by reacting in DOWTHERM™; to yield the corresponding compound of formula (CXVI).
The compound of formula (CXVI) is reacted with a suitably selected brominating agent such as PBr3, POBr3, PPh3Br2, and the like; neat or in a suitably selected solvent such as toluene, benzene, DMF, and the like; to yield the corresponding compound of formula (CXVII).
The compound of formula (CXVII) is reacted with at least two moles of a suitably substituted compound of formula (XXXIX), a known compound or compound prepared by known methods, under Grignard conditions; in a suitably selected anhydrous organic solvent such as diethyl ether, THF, and the like; to yield the corresponding compound of formula (INT-5), wherein
and
are the same.
The compound of formula (INT-5) is reacted with Et3SiH in combination with TFA, or SnCl2 in combination with HCl or TiCl4 in combination with Et3SiH; in a suitably selected organic solvent such as DCM, DCE, and the like; to yield the corresponding compound of formula (INT-4).
Compounds of formula (INT-4) wherein
and
are different may be prepared according to the procedure as described in Scheme D, below.
Accordingly, a suitably substituted compound of formula (CXVII), prepared for example as described in Scheme C above, is hydrolyzed by reacting with a suitably selected base such as LiOH, NaOH, and the like; in a suitably selected solvent or mixture of solvents such as 1,4-dioxane/water, THF/water, ethanol/water, and the like; to yield the corresponding compound of formula (CXL).
The compound of formula (CXL), is reacted with N,O-dimethylhydroxylamine (also known as Weinreb amide), under peptide coupling conditions, as would be known to those skilled in the art; to yield the corresponding compound of formula (CXLI).
The compound of formula (CXLI) is reacted with a suitably substituted compound of formula (LIX), a known compound or compound prepared by known methods, under Grignard conditions; in a suitably selected anhydrous organic solvent such as diethyl ether, THF, and the like; to yield the corresponding compound of formula (CXLII).
The compound of formula (CXLII) is reacted with a suitably substituted compound of formula (XXXIX), a known compound or compound prepared by known methods, under Grignard conditions; in a suitably selected anhydrous organic solvent such as diethyl ether, THF, and the like; to yield the corresponding compound of formula (INT-5).
The compound of formula (INT-5) is reacted with Et3SiH in combination with TFA, or SnCl2 in combination with HCl or TiCl4 in combination with Et3SiH; in a suitably selected organic solvent such as DCM, DCE, and the like; to yield the corresponding compound of formula (INT-4).
One skilled in the art will recognize that in the process as described in Scheme D above, the
and
groups may be incorporated into the desired compound in either order. Accordingly, the compound of formula (CXLI) may alternatively be reacted first with a suitably substituted compound of formula (XXXIX) and the resulting intermediate then reacted with a suitably substituted compound of formula (LIX), as described above, to yield the corresponding compound of formula (INT-5).
One skilled in the art will recognize that compounds of formula (INT-4) (INT-5) and/or (INT-6) may alternatively be prepared by substituting a suitably substituted compound of formula (CXVIII)
for the compound of formula (CXIV); and reacting said compound of formula (CXVIII) as described in Scheme C above, more particularly reacting sequentially with (a) 2,2-dimethyl-1,3-dioxane-4,6-dione, (b) under ring-closure conditions, (c) with a suitably selected brominating agent (to yield the corresponding compound of formula (INT-6), (d) with about one mole of a suitably selected compound of formula (XXXIX) or about one mole of a suitably selected compound of formula (LIX) (as appropriate to yield the desired intermediate compound), and (e) with for example, with Et3SiH in combination with TFA (to yield the corresponding compound of formula (INT-4) or compound of formula (INT-5)).
Compounds of formula (INT-4) wherein R1 is hydrogen, halogen (preferably bromo), C1-4alkyl and —O—(C1-4alkyl), may alternatively be prepared similarly to the process outlined in Scheme C above. More particularly, a suitably substituted compound of formula (CXIX)
is substituted for the compound of formula (CXIV) in Scheme C above and reacted sequentially as follows: (a) with 2,2-dimethyl-1,3-dioxane-4,6-dione, (b) under ring-closure conditions; (c) with a brominating agent; and (d) with for example, with Et3SiH in combination with TFA, as described in Scheme C above.
One skilled in the art will further recognize that compounds of formula (INT-1) may alternatively be prepared from the corresponding compound of formula (INT-4), as described in Scheme E, below.
Accordingly, a suitably substituted compound of formula (INT-4), prepared for example as described in Scheme C above, may be further optionally reacted with a suitably selected oxidizing agent such as MCPBA, and the like; in a suitably selected organic solvent such as DCM, chloroform, and the like; to yield the corresponding compound of formula (CXX), which compound is not isolated.
The compound of formula (CXX) is reacted with a suitably selected reagent such as tosyl chloride, mesyl chloride, and the like; in the presence of a suitably selected base such as K2CO3, Na2CO3, and the like; in a suitably selected organic solvent such as DCM, chloroform, and the like; to yield the corresponding compound of formula (INT-1).
Compounds of formula (INT-4) wherein
is
and R1 is hydrogen are preferably prepared according to the process outlined in Scheme F, below.
Accordingly, 1-fluoro-4-nitrobenzene, a known compound, is reacted with a suitably substituted compound of formula (CXXI), a known compound or compound prepared by known methods; in the presence of a suitably selected reagent such as KOt-Bu, NaOt-Bu, and the like; in a suitably selected solvent such as a mixture of isopropanol/THF, and the like; to yield the corresponding compound of formula (CXXII).
The compound of formula (CXXII) is reacted with a suitably selected reagent such as P2S5, and the like; in a suitably selected solvent such as toluene, ethanol, and the like; preferably at an elevated temperature in the range of from about 60° C. to about 120° C., for example, at about 110° C.; to yield the corresponding compound of formula (CXXII
The compound of formula (CXXIII) is reacted with 2-bromo-1,1-diethoxyethane, a known compound in the presence of acetic acid; in a suitably selected solvent such as water, ethanol, and the like; to yield the corresponding compound of formula (CXXIV).
The compound of formula (CXXIV) is reacted with a suitably selected reagent such as SnCl2 in the presence of HCl; in a suitably selected solvent such as methanol, and the like; to yield the corresponding compound of formula (CXXV).
The compound of formula (CXXV) is then reacted as described in Scheme C above, to yield the desired intermediate compound. More particularly, the compound of formula (CXXV) is substituted for the compound of formula (CXIV) in Scheme C above, and reacted sequentially with: (a) with 2,2-dimethyl-1,3-dioxane-4,6-dione, (b) a under ring closure conditions, for example DOWTHERM™, and (c) a suitably selected brominating agent; to yield the corresponding compound of formula (INT-4c).
The boronic acid compounds of the formula Q-B(OR)2, hereinafter referred to as compounds of formula (CXXX), wherein Q is selected from the group consisting of
and
and
wherein each R is the same and are selected from the group consisting of hydrogen and C1-4alkyl; or are taken together with the oxygen atoms to which they are bound to form
are intermediates used in the synthesis of the compounds of formula (I) of the present invention (i.e. the boronic acids of formula (CXXX) including compounds of formula (XXXVII), compounds of formula (XLII) and compounds of formula (LV)).
Compounds of formula (CXXX) are known compound or compounds that may be prepared according to methods as would be readily recognized by those skilled in the art. In an example, boronic acid compounds of the formula (CXXX) wherein Q is
and wherein each R is the same and is selected from the group consisting of hydrogen and C1-4alkyl, may be prepared according to the process described in Scheme G below.
Accordingly, a suitably substituted compound of formula (CXXVI), wherein Hal1 is selected from the group consisting of Cl, Br and I, a known compound or compound prepared by known methods is converted to the corresponding Grignard reagent (e.g. by reacting with Mg, according to known methods); to yield the corresponding compound of formula (CXXVII). The compound of formula (CXXVII) is then reacted with a suitably selected compound of formula (CXXVIII), wherein each R is the same and is C1-4alkyl, a known compound or compound prepared by known methods; to yield the corresponding boronic acid compound of formula (CXXXa). The compound of formula (CXXXa) is further optionally reacted under acid hydrolysis condition, known to those skilled in the art, to yield the corresponding compound of formula (CXXXb).
In another example, compounds of formula (CXXX) wherein the two R groups are taken together with the oxygen atoms to which they are bound to form
may be prepared according to the process described in Scheme H below.
Accordingly, a suitably substituted compound of formula (CXXIX), wherein Hal2 is selected from the group consisting of Br and I, a known compound or compound prepared by known methods, is reacted with bis(pinacolato)diboron (also known as 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)), a known compound, according to known methods (e.g. reacting with Pd2(dba)3, in the presence of PPh3 and a suitably selected base such as Cs2CO3), to yield the corresponding compound of formula (CXXXc).
One skilled in the art will recognize that in any of the processes described herein, the
and
rings (as substituent groups or in reagents containing said substituent groups) may be interchanged, and the synthesis completed as described, to yield the corresponding desired compound.
One skilled in the art will further recognize that additional substitutions and/or substituent transformations (to yield the desired intermediates or compound(s) of the present invention) may be effected according to the procedures as described herein (in the general synthesis schemes and examples) or according to methods known to those skilled in the art.
The present invention further comprises pharmaceutical compositions containing one or more compounds of formula (A) and/or one or more compounds of formula (B) and/or one or more compounds of formula (I) and/or one or more compounds of formula (II) and/or one or more compounds of formula (III) and/or one or more compounds of formula (IV) with a pharmaceutically acceptable carrier. Pharmaceutical compositions containing one or more of the compounds of the invention described herein as the active ingredient can be prepared by intimately mixing the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral). Thus for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like; for solid oral preparations, such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Solid oral preparations may also be coated with substances such as sugars or be enteric-coated so as to modulate major site of absorption. For parenteral administration, the carrier will usually consist of sterile water and other ingredients may be added to increase solubility or preservation. Injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives.
To prepare the pharmaceutical compositions of this invention, one or more compounds of the present invention as the active ingredient is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral preparations such as, for example, powders, capsules, caplets, gelcaps and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, through other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. The pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above. The pharmaceutical compositions herein will contain, per unit dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the like, of from about 0.01 mg to about 1000 mg or any amount or range therein, and may be given at a dosage of from about 0.01 mg/kg/day to about 300 mg/kg/day, or any amount or range therein, preferably from about 0.1 mg/kg/day to about 50 mg/kg/day, or any amount or range therein, preferably from about 0.5 mg/kg/day to about 15 mg/kg/day, or any amount or range therein. The dosages, however, may be varied depending upon the requirement of the patients, the severity of the condition being treated and the compound being employed. The use of either daily administration or post-periodic dosing may be employed.
Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the composition may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from about 0.01 mg to about 1,000 mg, or any amount or range therein, of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of material can be used for such enteric layers or coatings, such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include, aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions, include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
The method of treating disorders described herein may also be carried out using a pharmaceutical composition comprising any of the compounds as defined herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may contain between about 0.01 mg and about 1000 mg of the compound, or any amount or range therein; preferably from about 1.0 mg to about 500 mg of the compound, or any amount or range therein, and may be constituted into any form suitable for the mode of administration selected. Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings. Compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), granules, and powders, and liquid forms, such as solutions, syrups, elixirs, emulsions, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions and suspensions.
Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders; lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
The liquid forms may contain suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
To prepare a pharmaceutical composition of the present invention, a compound of formula (I) as the active ingredient is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration (e.g. oral or parenteral). Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers may be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.
Methods of formulating pharmaceutical compositions have been described in numerous publications such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3, edited by Lieberman et al; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al; published by Marcel Dekker, Inc.
Compounds of the present invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever treatment of metabolic disorders is required.
The daily dosage of the products may be varied over a wide range from about 0.01 mg to about 1,000 mg per adult human per day, or any amount or range therein. For oral administration, the compositions are preferably provided in the form of tablets containing, 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.01 mg/kg to about 300 mg/kg of body weight per day, or any amount or range therein. Preferably, the range is from about 0.01 to about 50.0 mg/kg of body weight per day, or any amount or range therein. More preferably, from about 0.05 to about 15.0 mg/kg of body weight per day, or any amount or range therein. More preferably, from about 0.07 to about 7.5 mg/kg of body weight per day, or any amount or range therein. The compounds may be administered on a regimen of 1 to 4 times per day.
Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.
One skilled in the art will recognize that, both in vivo and in vitro trials using suitable, known and generally accepted cell and/or animal models are predictive of the ability of a test compound to treat or prevent a given disorder.
One skilled in the art will further recognize that human clinical trials including first-in-human, dose ranging and efficacy trials, in healthy patients and/or those suffering from a given disorder, may be completed according to methods well known in the clinical and medical arts.
The following Examples are set forth to aid in the understanding of the invention, and are not intended and should not be construed to limit in any way the invention set forth in the claims which follow thereafter.
In the Synthesis Examples which follow, some synthesis products are listed as having been isolated as a residue. It will be understood by one of ordinary skill in the art that the term “residue” does not limit the physical state in which the product was isolated and may include, for example, a solid, an oil, a foam, a gum, a syrup, and the like.
A 2-L 4-neck flask equipped with a thermocouple controller, a mechanical stirrer, a condenser, and a nitrogen inlet/outlet adapter was charged with DCE (480.8 mL), chlorobenzene (1) (90.4 mL, 888.5 mmol) and 4-nitrobenzoylchloride (111.4 g, 600.3 mmol), and the resulting mixture stirred and warmed to 40° C. Aluminum trichloride (97.0 g, 720.4 mmol) was added portionwise over 1 h and then the reaction was heated to 60° C. and stirred for 10 h. The reaction was cooled to 20° C., poured into ice-water (2 L) and stirred for 10 min. The resulting aqueous mixture was extracted with DCM (600 mL×2). The combined organic extracts were was washed with deionized water (1 L×3). The solvent was concentrated at 40° C. to remove DCM and then at 66° C. to yield a pale to slight yellowish solid, which was dissolved in hot EtOH (500 mL) at 76° C., stirred for 30 min, and then gradually cooled to 4° C. over 1 h. The resulting solid was collected by filtration to yield (4-chlorophenyl)(4-nitrophenyl)methanone as a slightly yellowish crystalline solid. (ES, m/z) 262 (M+H)+, 284, 286 (M+Na)+
A 3-L 3-neck flask equipped with a thermocouple controller, a mechanical stirrer, a condenser, and a nitrogen inlet/outlet adapter was charged with (4-chlorophenyl)(4-nitrophenyl)methanone (132.0 g, 504.5 mmol), concentrated aqueous HCl (693.3 mL, 8.1 mol), and SnCl2 (313.3 g, 1.62 mol). The yellowish suspension was carefully heated to 36° C. with fast agitation (1000 rmp). The electric power to the heating mantle was turned off at 36° C. A moderate exotherm was observed, which gradually increased to 77° C. over 1 h with gas evolution to form a foamy suspension. The electric power was turned on at 77° C. again and gradually heated to 100° C. over 30 min and refluxed for 2 h. The reaction was cooled to 10° C., slowly poured into a mixture of ice (1 L) and 33% NaOH (1 L, 8.25 M) with fast stirring in an ice-water bath. The resulting yellowish slurry (pH=2-3) was adjusted to pH=9-10 with 50% NaOH. The resulting solid was collected by filtration and washed with deionized water (100 mL). The filtration cake was dried under air-suction at 20° C. overnight and then in a vacuum oven at 60° C. for 24 h to yield a yellowish solid. The yellowish solid (322 g) was suspended in deionized water (2 L) and extracted with EtOAc (2 L×3). The combined organic phases were washed with brine (1 L/each). The solvent was concentrated at 60° C. to yield (4-aminophenyl)(4-chlorophenyl)methanone as a slightly yellowish crystalline solid. (ES, m/z) 232, 234 (M+H)+
A 5-L 4-neck flask equipped with a thermocouple controller, a mechanical stirrer, a condenser, and a nitrogen inlet/outlet adapter was charged with (4-aminophenyl)(4-chlorophenyl)methanone (86.6 g, 370.1 mmol), DCM (2.61 L), and Et3N (70.3 mL, 499.6 mmol). After the solution was cooled to 5° C. in an ice-bath, ethyl 3-chloro-3-oxopropanoate (64.5 mL, 407.1 mmol) was added dropwise over 60 min. The resulting mixture was stirred at 0° C. for 1 h. Additional ethyl 3-chloro-3-oxopropanoate (12.9 mL) was added dropwise and the mixture was stirred at 0° C. for an additional 2 h. The reaction was cooled to 0° C. and ice-water (2 L) was added, followed by solid K2CO3 (60 g) until the solution was basic (pH=9-10). After phase separation, the organic layer was concentrated at 40° C. (to remove DCM) and then at 60° C. (to remove ex Et3N) to yield ethyl 3-((4-(4-chlorobenzoyl)phenyl)amino)-3-oxopropanoate as a slightly yellowish solid, which was used in the next step without further purification. (ES, m/z) 346, 348 (M+H)+
A 3-L 4-neck flask equipped with a thermocouple controller, a mechanical stirrer, a dropping funnel, and a nitrogen inlet/outlet adapter was charged with ethyl 3-((4-(4-chlorobenzoyl)phenyl)amino)-3-oxopropanoate (128.0 g, 370.2 mmol), EtOH (1.29 L), and KOH (27.7 g, 1444.2 mmol). The resulting mixture was stirred at 20° C. for 24 h. Additional KOH (1.12 g, 0.04 eq.) was added and the reaction was stirred for an additional 6 h. The resulting yellowish thick slurry was dissolved in deionized water (1.2 L) and then poured into a 12-L 4-neck flask equipped with an overhead stirrer that contained ice-water (6 L) in an ice-water bath. The aqueous pH was adjusted to pH 2-3 using 2 N aqueous HCl solution with fast stirring at 8-10° C. for 20 min. The solid in the resulting milky slurry was collected by filtration, washed with deionized water (100 mL), dried under air-suction for 20 h and then in a vacuum oven at 60° C. under hi-vacuum (20 mmHg) for 72 h to yield 3-((4-(4-chlorobenzoyl)phenyl)amino)-3-oxopropanoic acid as a yellowish solid, which was used in the next step without further purification. (ES, m/z) 318, 320 (M+H)+
A 2-L 4-neck flask equipped with a thermocouple controller, a mechanical stirrer, and a nitrogen inlet/outlet adapter was charged with CH3SO2OH (236.0 mL, 3.60 mol), P2O5 (34.6 g, 241.1 mmol) was added and the mixture was vigorously stirred at 80° C. for 90 min. Solid 3-((4-(4-chlorobenzoyl)phenyl)amino)-3-oxopropanoic acid (111.0 g, 321.4 mmol) was added portionwise over 3 min at 80° C., and the resulting mixture was stirred at 80° C. for 2 h. The hot mixture was poured slowly into ice-water (5 L) and vigorously agitated for 1 h. The resulting solid was collected by filtration, washed with deionized water (2 L×2), and dried by air-suction for 20 h to yield a slightly yellowish solid. The solid was suspended in acetone (990 mL) at 53° C. and sonicated for 30 min. The resulting yellowish slurry was stirred at 20° C. for 10 min. The solid was collected by filtration, washed with acetone (50 mL), dried by air-suction for 1 h and then under high vacuum (22 mmHg) at 60° C. for 20 h to yield 6-(4-chlorobenzoyl)-4-hydroxyquinolin-2(1H)-one as a light beige-yellowish solid. Elemental analysis: Calculated for C16H10ClNO5+0.1H2O+0.21CH3COCH3; MW=313.72. Theoretical: C, 63.67; H, 3.68; Cl, 11.30; N, 4.46; % H2O, 0.60; Measured: C, 63.58; H, 3.23; Cl, 11.53; N, 4.64; % H2O, 0.53
To a suspension of 6-(4-chlorobenzoyl)-4-hydroxyquinolin-2(1H)-one (7 g) in toluene (120 mL) was added phosphorus oxybromide (3 eq., 20 g) and the resulting mixture was refluxed until LCMS indicated consumption of starting material. After cooling in an ice bath, the reaction mixture was carefully hydrolyzed by addition of ice/water (200 mL) and neutralized using 6 N solution of NaOH. The precipitates were collected by filtration, washed with water (3×100 ml) and dried under vacuum to yield (4-chlorophenyl)(2,4-dibromoquinolin-6-yl)methanone. (ES, m/z) 426, 428 (M+H)+
A mixture of (4-chlorophenyl)(2,4-dibromoquinolin-6-yl)methanone (5 g) and KOBut (1.1 eq. 12.93 mmol) in dry toluene (60 mL) was heated at 70° C. for 2 hr. and then cooled to room temperature. The reaction was diluted with EtOAc and water. The aqueous layer was extracted with ethyl acetate. The organics were combined and then washed with water, concentrated and subjected to chromatography (5-15% EtOAc/hexanes silica column) to yield (4-bromo-2-(tert-butoxy)quinolin-6-yl)(4-chlorophenyl)methanone.
1H NMR (DMSO-d6) δ: 8.35 (s, 1H), 8.07 (d, J=8.8 Hz, 1H), 7.92 (d, J=8.6 Hz, 1H), 7.79-7.88 (m, J=8.3 Hz, 2H), 7.63-7.74 (m, J=8.1 Hz, 2H), 7.45 (s, 1H), 1.69 (s, 9H).
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of thiazole (255 mg, 3.00 mmol, 2.00 equip) in tetrahydrofuran (15 mL). To the resulting mixture was then added n-BuLi (1 mL, 1.70 equip, 2.5 M) dropwise with stirring at −78° C. The resulting solution was stirred for 50 min at −78° C. To the resulting mixture was added a solution of (4-bromo-2-tert-butoxyquinolin-6-yl) (4-chlorophenyl) methanone (630 mg, 1.50 mmol, 1.00 equip) in tetrahydrofuran (5 mL) dropwise with stirring at −78° C. The resulting solution was allowed to react, with stirring, for an additional 40 min at −78° C. The resulting solution was stirred for 30 min at 0° C. The reaction was then quenched by the addition of water. The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined. The resulting mixture was washed with water (2×50 mL) and brine (1×50 mL). The resulting mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate:petroleum ether (1:4) to yield (4-bromo-2-tert-butoxyquinolin-6-yl)(4-chlorophenyl)(thiazol-2-yl)methanol as a white solid. (ES, m/z): [M+H]+ 505
Into a 250-mL round-bottom flask, was placed [4-bromo-2-(tert-butoxy)quinolin-6-yl](4-chlorophenyl)1,3-thiazol-2-ylmethanol (5.5 g, 10.92 mmol, 1.00 equip), AcOH (78 mL), hydrogen chloride (13 mL), and SnCl2.2 H2O (7.4 g, 32.80 mmol, 3.00 equip). The resulting solution was stirred for 40 min at 100° C. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with water (200 mL). The resulting solution was extracted with DCM (3×200 mL) and the organic layers combined. The resulting mixture was washed with water (2×200 mL). The resulting mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with dichloromethane:methanol (10:1) to yield 4-bromo-6-[(4-chlorophenyl)(1,3-thiazol-2-yl)methyl]quinolin-2-ol as a white solid. (ES, m/z): [M+N]+ 433
Into a 20-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed 4-bromo-6-[(4-chlorophenyl)(1,3-thiazol-2-yl)methyl]quinolin-2-ol (648 mg, 1.50 mmol, 1.00 equip), Cs2CO3 (978 mg, 2.00 equip), 1-(trifluoromethane)sulfonylpiperidin-4-amine hydrochloride (138 mg, 0.51 mmol, 0.10 equip), 1,4-dioxane (20 ml), Pd2(dba)3 (155.25 mg, 0.10 equip), DPPF (293.62 mg, 0.53 mmol, 0.35 equip), t-BuOK (420 mg, 3.75 mmol, 2.5 equip). The resulting solution was stirred overnight at 100° C. The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined. The resulting mixture was washed with water (2×50 mL) and brine (1×50 mL). The resulting mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1) to yield 6-((4-chlorophenyl)(thiazol-2-yl)methyl)-4-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)amino)quinolin-2(1H)-one as a yellow solid.
(ES, m/z): [M+H]+ 583; 1H-NMR (300 MHz, DMSO-d6) δ 10.829 (s, 1H), 8.056 (s, 1H), 7.827 (d, J=3.3 Hz, 1H), 7.698 (d, J=3.0 Hz, 1H), 7.304-7.436 (m, 5H), 7.223 (d, J=8.7 Hz, 1H), 6.571 (d, J=7.5 Hz, 1H), 5.915 (s, 1H), 5.502 (s, 1H), 3.881 (d, J=12.6 Hz, 2H), 3.765 (br, 1H), 3.417-3.457 (2H), 2.102 (d, J=12.6 Hz, 2H), 1.601-1.638 (m, 2H)
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of (4-bromo-2-tert-butoxyquinolin-6-yl)(4-chlorophenyl)methanone (4 g, 9.55 mmol, 1.00 equip) in tetrahydrofuran (65 mL). To the resulting mixture was then added (4-chlorophenyl)magnesium bromide (8.2 mL, 1.30 equip, 1 M) dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at 0° C. The reaction was then quenched by the addition of water. The resulting solution was extracted with ethyl acetate (3×150 mL) and the organic layers combined. The resulting mixture was washed with water (2×100 mL) of water and brine (1×100 mL). The resulting mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate:petroleum ether (1:4) to yield (4-bromo-2-tert-butoxyquinolin-6-yl)bis(4-chlorophenyl)methanol as white solid. (ES, m/z): [M+H]+ 532
Into a 100-mL round-bottom flask, was placed a solution of [4-bromo-2-(tert-butoxy)quinolin-6-yl]bis(4-chlorophenyl)methanol (1.5 g, 2.82 mmol, 1.00 equip) in dichloromethane (55 mL), Et3SiH (1.3 g, 4.00 equip), and trifluoroacetic acid (8 g, 70.77 mmol, 25.00 equip). The resulting solution was stirred overnight at room temperature. The pH value of the solution was adjusted to 7-8 with sodium bicarbonate. The resulting solution was extracted with DCM (3×50 ml) and the organic layers combined. The resulting mixture was washed with water (2×50 mL). The resulting mixture was washed with brine (1×50 mL). The resulting mixture was dried over anhydrous sodium sulfate and concentrated to yield 6-[bis(4-chlorophenyl)methyl]-4-bromoquinolin-2-ol as a white solid. (ES, m/z): [M+H]+ 433
Into a 100-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-[bis(4-chlorophenyl)methyl]-4-bromoquinolin-2-ol (3.4 g, 7.40 mmol, 1.00 equip), 1-(trifluoromethane)sulfonylpiperidin-4-amine hydrochloride (3.4 g, 12.65 mmol, 1.70 equip), Pd(dba)3 (680 mg, 0.10 equip), dppf (1.44 g, 2.60 mmol, 0.35 equip), Cs2CO3 (6.05 g, 2.50 equip), KOt-Bu (1.5 g, 1.80 equip), and 1,4-dioxane (35 mL). The resulting solution was stirred overnight at 100° C. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (3×150 mL) and the organic layers combined. The resulting mixture was washed with water (2×100 mL) and brine (1×100 mL). The resulting mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1). The resulting residue was purified by re-crystallization from CH3CN to yield 6-[bis(4-chlorophenyl)methyl]-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]quinolin-2-ol as a white.
(ES, m/z): [M+H]+ 610; 1H-NMR (300 MHz, DMSO-d6) δ 10.786 (s, 1H), 7.930 (s, 1H), 7.390-7.418 (m, 4H), 7.128-7.222 (m, 6H), 6.542 (d, J=7.8 Hz, 1H), 5.629 (s, 1H), 5.490 (s, 1H), 3.872 (d, J=13.2 Hz, 2H), 3.373 (br, 1H), 3.411-3.452 (m, 2H), 2.069-2.107 (m, 2H), 1.556-1.663 (m, 2H)
Into a 8-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-[bis(4-chlorophenyl)methyl]-4-bromoquinolin-2-ol (150 mg, 0.33 mmol, 1.00 equip), 4-(trifluoromethyl)aniline (78.9 mg, 0.49 mmol, 1.50 equip), Pd2(dba)3 (30 mg, 0.03 mmol, 0.10 equip), dppf (63.4 mg, 0.11 mmol, 0.35 equip), Cs2CO3 (266 mg, 0.82 mmol, 2.50 equip), and 1,4-dioxane (3 mL). The resulting solution was stirred overnight at 100° C. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). The resulting residue was recrystallized from ethyl acetate:petroleum ether in the ratio of 1:10 to yield 6-[bis(4-chlorophenyl)methyl]-4-[[4-(trifluoromethyl)phenyl]amino]quinolin-2-ol as a light yellow solid.
LCMS (ES, m/z) 539 [M+H]+; 1H-NMR (300 MHz, DMSO-d6) δ 11.277 (s, 1H), 8.871 (s, 1H), 7.886 (s, 1H), 7.715 (d, J=8.4 Hz, 2H), 7.443-7.384 (m, 6H), 7.291 (s, 2H), 7.162 (d, J=6.0 Hz, 4H), 5.995 (s, 1H), 5.700 (brs, 1H)
Into a 8-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-[bis(4-chlorophenyl)methyl]-4-bromoquinolin-2-ol (150 mg, 0.33 mmol, 1.00 equip), 1-phenylpiperidin-4-amine (86 mg, 0.49 mmol, 1.49 equip), Pd2(dba)3 (30 mg, 0.03 mmol, 0.10 equip), dppf (63.4 mg, 0.11 mmol, 0.35 equip), Cs2CO3 (266 mg, 0.82 mmol, 2.50 equip), and 1,4-dioxane (3 mL). The resulting solution was stirred overnight at 100° C. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). The resulting residue was recrystallized from ethyl acetate:petroleum ether in the ratio of 1:10 to yield 6-[bis(4-chlorophenyl)methyl]-4-[(1-phenylpiperidin-4-yl)amino]quinolin-2-ol as an off-white solid.
LCMS (ES, m/z) 554 [M+H]+; 1H-NMR (300 MHz, DMSO-d6) δ10.713 (s, 1H), 7.946 (s, 1H), 7.372 (d, J=8.1 Hz, 4H), 7.229-7.103 (m, 8H), 6.957 (d, J=8.1 Hz, 2H), 6.756-6.708 (m, 1H), 6.471 (d, J=7.8 Hz, 1H), 5.588 (s, 1H), 5.421 (s, 1H), 3.776 (d, J=12.6 Hz, 2H), 3.604-3.586 (br, 1H), 2.929-2.848 (m, 2H), 1.975 (d, J=9.3 Hz, 4H), 1.694-1.624 (m, 2H)
Into a 8-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-[bis(4-chlorophenyl)methyl]-4-bromoquinolin-2-ol (150 mg, 0.33 mmol, 1.00 equip), [3-(trifluoromethyl)phenyl]methanamine (85.78 mg, 0.49 mmol, 1.50 equip), Pd2(dba)3 (30 mg, 0.03 mmol, 0.10 equip), dppf (63.4 mg, 0.11 mmol, 0.35 equip), Cs2CO3 (266 mg, 0.82 mmol, 2.50 equip), and 1,4-dioxane (3 mL). The resulting solution was stirred overnight at 100° C. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). The resulting residue was recrystallized from ethyl acetate:petroleum ether in the ratio of 1:10 to yield 6-(bis(4-chlorophenyl)methyl)-4-((3-(trifluoromethyl)benzyl)amino)quinolin-2(1H)-one as an off-white solid.
(ES, m/z) 553 [M+H]+; 1H-NMR (300 MHz, DMSO-d6) δ10.786 (s, 1H), 7.927 (s, 1H), 7.723 (s, 1H), 7.632-7.597 (m, 4H), 4.319 (d, J=8.4 Hz, 4H), 7.211-7.184 (m, 6H), 5.673 (s, 1H), 5.164 (s, 1H), 4.533 (d, J=5.1 Hz, 2H)
Into a 8-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-[bis(4-chlorophenyl)methyl]-4-bromoquinolin-2-ol (150 mg, 0.33 mmol, 1.00 equip), [6-(trifluoromethyl)pyridin-3-yl]methanamine (86 mg, 0.49 mmol, 1.49 equip), Pd2(dba)3 (30 mg, 0.03 mmol, 0.10 equip), dppf (63.4 mg, 0.11 mmol, 0.35 equip), Cs2CO3 (266 mg, 0.82 mmol, 2.50 equip), and 1,4-dioxane (3 mL). The resulting solution was stirred overnight at 100° C. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). The resulting residue was recrystallized from ethyl acetate:petroleum ether in the ratio of 1:10 to yield 6-(bis(4-chlorophenyl)methyl)-4-(((6-(trifluoromethyl)pyridin-3-yl)methyl)amino)quinolin-2(1H)-one as an off-white solid.
(ES, m/z) 554 [M+H]+; 1H-NMR (300 MHz, DMSO-D6) δ10.808 (s, 1H), 8.767 (s, 1H), 7.980 (d, J=8.1 Hz, 1H), 7.889-7.818 (m, 2H), 7.777-7.543 (m, 1H), 7.477-7.385 (m, 4H), 7.324-7.152 (m, 6H), 5.643 (s, 1H), 5.261 (s, 1H), 4.569 (s, 2H)
Into a 8-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-[bis(4-chlorophenyl)methyl]-4-bromoquinolin-2-ol (150 mg, 0.33 mmol, 1.00 equip), 1,4-dioxane (3 mL), cyclohexanamine (48.5 mg, 0.49 mmol, 1.50 equip), Pd2(dba)3 (30 mg, 0.03 mmol, 0.10 equip), dppf (63.4 mg, 0.11 mmol, 0.35 equip), and Cs2CO3 (266 mg, 0.82 mmol, 2.50 equip). The resulting solution was stirred overnight at 100° C. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). The resulting residue was recrystallized from ethyl acetate:petroleum ether in the ratio of 1:10 to yield 6-(bis(4-chlorophenyl)methyl)-4-(cyclohexylamino)quinolin-2(1H)-one as an off-white solid.
(ES, m/z) 477 [M+H]+; 1H-NMR (300 MHz, DMSO-D6) δ10.681 (s, 1H), 7.958 (s, 1H), 7.380 (d, J=8.4 Hz, 4H), 7.181-7.077 (m, 6H), 6.392 (d, J=7.8 Hz, 1H), 5.601 (s, 1H), 5.291 (s, 1H), 1.969-1.938 (m, 2H), 1.761-1.621 (m, 3H), 1.391-1.217 (m, 6H)
Into a 500-mL flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-bromo-2-(tert-butoxy)-6-[(4-chlorophenyl)carbonyl]quinoline (20 g, 47.77 mmol, 1.00 equip) in 1,4-dioxane (200 ml), 1-(trifluoromethane)sulfonylpiperidin-4-amine hydrochloride (22 g, 81.88 mmol, 1.70 equip), Pd2(dba)3 (4.92 g, 0.10 equip), dppf (9.2 g, 16.60 mmol, 0.35 equip), Cs2CO3 (38.8 g, 119.08 mmol, 2.50 equip), and KOt-Bu (9.6 g, 85.55 mmol, 1.80 equip). The resulting solution was stirred for 2 hr at 100° C. The reaction was then quenched by the addition of water (200 mL). The resulting solution was extracted with ethyl acetate (3×500 mL) and the organic layers combined. The resulting mixture was washed with water (2×300 mL) and brine (1×300 mL). The resulting mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1) to yield 2-(tert-butoxy)-6-[(4-chlorophenyl)carbonyl]-N-[1-(trifluoromethane)sulfonylpiperidin-4-yl]quinolin-4-amine as a yellow solid. LCMS (ES, m/z) 570 [M+H]+
Into a 25-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 5-bromo-2-chloropyridine (250 mg, 1.30 mmol, 3.00 equip) in tetrahydrofuran (10 mL). To the resulting mixture was then added n-BuLi (1.1 mL, 2.50 equip, 1 M) dropwise with stirring at −78° C. The resulting solution was stirred for 0.5 h at −78° C. To this was added a solution of 2-(tert-butoxy)-6-[(4-chlorophenyl)carbonyl]-N-[1-(trifluoromethane)sulfonylpiperidin-4-yl]quinolin-4-amine (250 mg, 0.44 mmol, 1.00 equip) in tetrahydrofuran (5 mL) dropwise with stirring at −78° C. The resulting solution was allowed to react, with stirring, for an additional 0.5 h at −78° C. The resulting solution was allowed to react, with stirring, for an additional 2 h at room temperature. The reaction was then quenched by the addition of water (30 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined. The resulting mixture was washed with water (2×30 mL) and brine (1×30 mL). The resulting mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting residue was used in the next step without further purification. LCMS (ES, m/z) 683 [M+H]+
Into a 25-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed [2-(tert-butoxy)-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]quinolin-6-yl](4-chlorophenyl)(6-chloropyridin-3-yl)methanol (350 mg, 0.51 mmol, 1.00 equip), SnCl2 (380 mg, 2.00 mmol, 4.00 equip), hydrogen chloride (1 mL, 37%), and AcOH (10 mL). The resulting solution was stirred for 1 h at 100° C. The pH value of the solution was adjusted to 8-9 with sodium bicarbonate. The resulting solution was extracted with ethyl acetate (3×100 mL) and the organic layers combined. The resulting mixture was washed with water (2×50 mL) and brine (1×50 mL). The resulting mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with DCM:MeOH (20:1). The product was recrystallized from ethyl acetate:n-hexane in the ratio of 1:5 to yield 6-[(4-chlorophenyl)(6-chloropyridin-3-yl)methyl]-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]-1,2-dihydroquinolin-2-one as a light-yellow solid.
(ES, m/z) 611 [M+H]+; 1H-NMR (300 MHz, DMSO-D6) δ10.791 (s, 1H), 8.225 (s, 1H), 7.900 (s, 1H), 7.607-7.572 (m, 1H), 7.500-7.472 (m, 1H), 7.419-7.391 (m, 2H), 7.223-7.139 (m, 4H), 6.528-6.502 (m, 1H), 5.686 (s, 1H), 5.479 (s, 1H), 3.877-3.832 (m, 2H), 3.721 (br, 1H), 3.434-3.395 (m, 2H), 2.094-2.053 (m, 2H), 1.638-1.531 (m, 2H).
Into a 25-mL round-bottom flask, was placed a solution of 2-(tert-butoxy)-6-[(4-chlorophenyl)carbonyl]-N-[1-(trifluoromethane)sulfonylpiperidin-4-yl]quinolin-4-amine (150 mg, 0.26 mmol, 1.00 equip) in tetrahydrofuran (15 ml). To the resulting mixture was then added (3,4-dichlorophenyl)magnesium bromide (2 mL, 8.00 equip) dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of water (30 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined. The resulting mixture was washed with water (2×50 mL). The resulting mixture was washed with brine (1×50 mL). The resulting mixture was dried over sodium sulfate and concentrated under vacuum to yield (2-tert-butoxy-4-(1-(trifluoromethylsulfonyl)piperidin-4-ylamino)quinolin-6-yl)(4-chlorophenyl)(3,4-dichlorophenyl)methanol as a yellow oil. (ES, m/z) 718 [M+H]+
Into a 25-mL round-bottom flask, was placed a solution of [2-(tert-butoxy)-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]quinolin-6-yl](4-chlorophenyl)(3,4-dichlorophenyl)methanol (200 mg, 0.28 mmol, 1.00 equip) in dichloromethane (15 ml), Et3SiH (130 mg, 1.12 mmol, 4.02 equip), and trifluoroacetic acid (850 mg, 7.52 mmol, 26.96 equip). The resulting solution was stirred overnight at room temperature. The pH value of the solution was adjusted to 8-9 with sodium bicarbonate. The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined. The resulting mixture was washed with water (2×50 mL). The resulting mixture was washed with brine (1×50 mL). The resulting mixture was dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (30:1) to yield 6-[(4-chlorophenyl)(3,4-dichlorophenyl)methyl]-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]-1,2-dihydroquinolin-2-one as a white solid.
(ES, m/z) 646 [M+H]+; 1H-NMR (300 MHz, DMSO-D6) δ 10.790 (s, 1H), 7.900 (s, 1H), 7.591 (d, J=8.4 Hz, 1H), 7.348-7.414 (m, 3H), 7.084-7.215 (m, 5H), 6.526 (d, J=7.5 Hz, 1H), 5.649 (s, 1H), 5.475 (s, 1H), 3.829-3.873 (m, 2H), 3.731 (br, 1H), 3.347-3.433 (m, 2H), 2.052-2.089 (m, 2H), 1.534-1.639 (m, 2H)
Into a 25-mL round-bottom flask, was placed a solution of 2-(tert-butoxy)-6-[(4-chlorophenyl)carbonyl]-N-[1-(trifluoromethane)sulfonylpiperidin-4-yl]quinolin-4-amine (300 g, 526.29 mmol, 1.00 equip) in tetrahydrofuran (15 ml). To the resulting mixture was then added (4-methoxyphenyl)magnesium bromide (2 mL, 4.00 equip) dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of water (30 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined. The resulting mixture was washed with water (2×50 mL). The resulting mixture was washed with saturated brine (1×50 mL). The resulting mixture was dried over sodium sulfate and concentrated under vacuum to yield [2-(tert-butoxy)-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]quinolin-6-yl](4-chlorophenyl)(4-methoxyphenyl)methanol as a yellow solid. (ES, m/z): [M+H]+ 678
Into a 25-mL round-bottom flask, was placed a solution of [2-(tert-butoxy)-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]quinolin-6-yl](4-chlorophenyl)(4-methoxyphenyl)methanol (200 mg, 0.29 mmol, 1.00 equip) in dichloromethane (15 ml), Et3SiH (840 mg, 25.00 equip), and trifluoroacetic acid (137 mg, 1.21 mmol, 4.00 equip). The resulting solution was stirred overnight at room temperature. The pH value of the solution was adjusted to 8-9 with NaHCO3 (sat.). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined. The resulting mixture was washed with water (2×50 mL). The resulting mixture was washed with brine (1×50 mL). The resulting mixture was dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (30:1) to yield 6-((4-chlorophenyl)(4-methoxyphenyl)methyl)-4-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)amino)quinolin-2(1H)-one as a white solid.
(ES, m/z): [M+H]+ 606; 1H-NMR (300 MHz, DMSO-D6) δ10.756 (s, 1H), 7.914 (s, 1H), 7.372 (d, J=8.4 Hz, 2H), 7.194-7.007 (m, 6H), 6.887 (d, J=8.7 Hz, 2H), 6.536 (d, J=7.2 Hz, 1H), 5.538 (s, 1H), 5.470 (s, 1H), 3.878-3.837 (m, 2H), 3.600-3.800 (m, 4H), 3.439-3.351 (m, 2H), 2.094-2.056 (m, 2H), 1.614-1.582 (m, 2H)
Into a 25-mL round-bottom flask, was placed a solution of [2-(tert-butoxy)-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]quinolin-6-yl](4-chlorophenyl)(4-methoxyphenyl)methanol (400 mg, 0.59 mmol, 1.00 equip) in dichloromethane (10 ml), and trifluoroacetic acid (1 mL, 10.00 equip). The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of water (30 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined. The resulting mixture was washed with water (2×50 mL). The resulting mixture was washed with brine (1×50 mL). The resulting mixture was dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (30:1) to yield 6-[(4-chlorophenyl)(hydroxy)(4-methoxyphenyl)methyl]-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]-1,2-dihydroquinolin-2-one as a white solid.
(ES, m/z) 622 [M+H]+; 1H-NMR (300 MHz, DMSO-D6) δ 10.741 (s, 1H), 8.111 (s, 1H), 7.348-7.377 (m, 2H), 7.217-7.246 (d, J=9.3 Hz, 2H), 7.003-7.117 (m, 4H), 6.867 (d, J=8.7 Hz, 2H), 6.582 (d, J=8.1 Hz, 1H), 6.409 (s, 1H), 5.472 (s, 1H), 3.843 (d, J=12.6 Hz, 2H), 3.700-3.820 (m, 1H), 3.735 (s, 3H), 3.388-3.429 (m, 2H), 2.040 (d, J=12.6 Hz, 2H), 1.589-1.700 (m, 2H)
Into a 8-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-[bis(4-chlorophenyl)methyl]-4-bromoquinolin-2-ol (150 mg, 0.33 mmol, 1.00 equip), 1-(pyrimidin-2-yl)piperidin-4-amine dihydrochloride (122.5 mg, 0.49 mmol, 1.49 equip), Pd2(dba)3 (30 mg, 0.03 mmol, 0.10 equip), dppf (63.4 mg, 0.11 mmol, 0.35 equip), Cs2CO3 (266 mg, 0.82 mmol, 2.50 equip), KOt-Bu (73 mg, 0.65 mmol, 2.00 equip), and 1,4-dioxane (3 mL). The resulting solution was stirred overnight at 100° C. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). The resulting residue was recrystallized from ethyl acetate:petroleum ether in the ratio of 1:10 to yield 6-[bis(4-chlorophenyl)methyl]-4-[[1-(pyrimidin-2-yl)piperidin-4-yl]amino]quinolin-2-ol as a white solid.
(ES, m/z) 556 [M+H]+; 1H-NMR (300 MHz, DMSO-D6) δ10.746 (s, 1H), 8.385 (d, J=4.5 Hz, 2H), 7.925 (s, 1H), 7.375-7.403 (m, 4H), 7.212-7.117 (m, 6H), 6.642-6.611 (m, 1H), 6.454 (d, J=7.8 Hz, 1H), 5.598 (s, 1H), 5.484 (s, 1H), 4.715-4.671 (m, 2H), 3.755 (br, 1H), 3.126-3.043 (m, 2H), 2.020-1.983 (d, J=11.1 Hz, 2H), 1.539-1.470 (m, 2H)
Into a 8-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-[bis(4-chlorophenyl)methyl]-4-bromoquinolin-2-ol (150 mg, 0.33 mmol, 1.00 equip), 1-(ethanesulfonyl)piperidin-4-amine (94.12 mg, 0.49 mmol, 1.50 equip), Pd2(dba)3 (30 mg, 0.03 mmol, 0.10 equip), dppf (63.4 mg, 0.11 mmol, 0.35 equip), Cs2CO3 (266 mg, 0.82 mmol, 2.50 equip), and 1,4-dioxane (3 mL). The resulting solution was stirred overnight at 100° C. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). The resulting residue was recrystallized from ethyl acetate:petroleum ether in the ratio of 1:10 to yield 6-[bis(4-chlorophenyl)methyl]-4-[[1-(ethanesulfonyl)piperidin-4-yl]amino]quinolin-2-ol as an off-white solid.
(ES, m/z) 570 [M+H]+; 1H-NMR (300 MHz, DMSO-D6) δ10.740 (s, 1H), 7.934 (s, 1H), 7.389 5 (d, J=8.4 Hz, 4H), 7.200-7.099 (m, 6H), 6.499 (d, J=7.5 Hz, 6H), 5.614 (s, 1H), 5.417 (s, 1H), 3.672-3.588 (m, 3H), 3.109-2.963 (m, 4H), 2.019-1.985 (m, 2H), 1.616-1.539 (m, 2H), 1.253 (t, J=7.5 Hz, 3H)
Into a 50-mL 3-necked round-bottom flask, was placed tert-butyl N-(piperidin-4-yl)carbamate (2 g, 9.99 mmol, 1.00 equip), tetrahydrofuran (20 mL), To this was added sodium hydride (480 mg, 20.00 mmol, 2.00 equip) at 0° C. The resulting solution was stirred for 0.5 h at 0° C., and 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.784 g, 11.99 mmol, 1.20 equip) was added. The resulting solution was stirred for 2 h at 0° C. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The filtrate was concentrated under vacuum to yield tert-butyl N-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]carbamate as yellow oil. LCMS (ES, m/z) 283 [M+H]+
Into a 50-mL round-bottom flask, was placed tert-butyl N-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]carbamate (2.0 g, 7.08 mmol, 1.00 equip), dichloromethane (20 mL), and CF3COOH (4 mL). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum to yield 1-(2,2,2-trifluoroethyl)piperidin-4-amine 2,2,2-trifluoroacetate as a yellow oil. (ES, m/z) 183 [M+H]+
Into a 8-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-[bis(4-chlorophenyl)methyl]-4-bromoquinolin-2-ol (200 mg, 0.44 mmol, 1.00 equip), 1,4-dioxane (5 mL), 1-(2,2,2-trifluoroethyl)piperidin-4-amine 2,2,2-trifluoroacetate (193 mg, 0.65 mmol, 1.50 equip), Pd2(dba)3 (40 mg, 0.04 mmol, 0.10 equip), dppf (84.5 mg, 0.15 mmol, 0.35 equip), Cs2CO3 (355 mg, 1.09 mmol, 2.50 equip), and KOt-Bu (97.6 mg, 0.87 mmol, 2.00 equip). The resulting solution was stirred overnight at 100° C. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were removed by filtration. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). The resulting residue was recrystallized from ethyl acetate:petroleum ether in the ratio of 1:10 to yield 6-[bis(4-chlorophenyl)methyl]-4-[[1-(2,2,2-trifluoroethyl)piperidin-4-yl]amino]quinolin-2-ol as a white solid.
(ES, m/z) 560 [M+H]+, 1H-NMR (400 MHz, DMSO-D6) δ10.712 (s, 1H), 7.929 (s, 1H), 7.388 (d, J=8.4 Hz, 4H), 7.189-7.106 (m, 6H), 6.404 (d, J=7.6 Hz, 1H), 5.612 (s, 1H), 5.343 (s, 1H), 3.290 (br, 1H), 3.219-3.142 (m, 2H), 2.950-2.922 (m, 2H), 2.470-2.500 (m, 2H), 1.912-1.884 (m, 2H), 1.635-1.583 (m, 2H)
Into a 25-mL round-bottom flask, was placed a solution of 6-[(4-chlorophenyl)(4-methoxyphenyl)methyl]-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]-1,2-dihydroquinolin-2-one (120 mg, 0.20 mmol, 1.00 equip) in dichloromethane (10 ml), and BBr3 (60 g, 1.20 equip) was added. The resulting solution was stirred overnight at room temperature. The pH value of the solution was adjusted to 8-9 with sodium bicarbonate. The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined. The resulting mixture was washed with water (2×50 mL) and with brine (1×50 mL). The resulting mixture was dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1) to yield 6-[(4-chlorophenyl)(4-hydroxyphenyl)methyl]-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]-1,2-dihydroquinolin-2-one as a yellow solid.
(ES, m/z) 592 [M+H]+, 1H-NMR (300 MHz, DMSO-D6) δ 10.734 (s, 1H), 9.312 (s, 1H), 7.894 (s, 1H), 7.352 (d, J=8.7 Hz, 2H), 7.180-7.082 (m, 4H), 6.887 (d, J=8.4 Hz, 2H), 6.693 (d, J=8.4 Hz, 2H), 6.525 (d, J=7.5 Hz, 1H), 5.466 (s, 2H), 3.874-3.723 (m, 3H), 3.430-3.389 (m, 2H), 2.086-2.047 (m, 2H), 1.647-1.540 (m, 2H)
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-[bis(4-chlorophenyl)methyl]-4-bromoquinolin-2-ol (500 mg, 1.09 mmol, 1.00 equip), tert-butyl 4-aminopiperidine-1-carboxylate (326.8 mg, 1.63 mmol, 1.50 equip), Pd2(dba)3 (99.8 mg, 0.11 mmol, 0.10 equip), dppf (211 mg, 0.38 mmol, 0.35 equip), Cs2CO3 (882.35 mg, 2.71 mmol, 2.50 equip), and 1,4-dioxane (10 mL). The resulting solution was stirred overnight at 100° C. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). The resulting residue was recrystallized from ethyl acetate:petroleum ether in the ratio of 1:10 to yield tert-butyl 4-([6-[bis(4-chlorophenyl)methyl]-2-hydroxyquinolin-4-yl]amino)piperidine-1-carboxylate as an off-white solid. (ES, m/z) 578 [M+H]+
Into a 25-mL round-bottom flask, was placed tert-butyl 4-([6-[bis(4-chlorophenyl)methyl]-2-hydroxyquinolin-4-yl]amino)piperidine-1-carboxylate (570 mg, 0.99 mmol, 1.00 equip), dichloromethane (8 mL), and CF3COOH (2 mL). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The resulting residue was recrystallized from ethyl acetate:petroleum ether in the ratio of 1:10 to yield 6-[bis(4-chlorophenyl)methyl]-4-[(piperidin-4-yl)amino]quinolin-2-ol as an off-white solid. LCMS-(ES, m/z) 478 [M+H]+
Into a 8-mL round-bottom flask, was placed 6-[bis(4-chlorophenyl)methyl]-4-[(piperidin-4-yl)amino]quinolin-2-ol (70 mg, 0.15 mmol, 1.00 equip), dichloromethane (3 mL), pyrrolidine-1-sulfonyl chloride (37.2 mg, 0.22 mmol, 1.50 equip), and triethylamine (44.6 mg, 0.44 mmol, 3.01 equip). The resulting solution was stirred for 2 h at room temperature. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). The resulting residue was recrystallized from ethyl acetate:petroleum ether in the ratio of 1:10 to yield 6-[bis(4-chlorophenyl)methyl]-4-[[1-(pyrrolidine-1-sulfonyl)piperidin-4-yl]amino]quinolin-2-ol as an off-white solid.
LCMS (ES, m/z) 611 [M+H]+, 1H-NMR (300 MHz, DMSO-D6) δ 10.736 (s, 1H), 7.937 (s, 1H), 7.378 (d, J=8.4 Hz, 4H), 7.094-7.196 (m, 6H), 6.485 (d, J=7.5 Hz, 1H), 5.604 (s, 1H), 5.422 (s, 1H), 3.586-3.628 (m, 3H), 3.214 (t, J=6.6 Hz, 4H), 2.938-3.014 (m, 2H), 1.973 (d, J=11.4 Hz), 1.847 (t, J=6.6 Hz, 4H), 1.510-1.615 (m, 2H)
Into a 50-mL round-bottom flask, was placed tert-butyl N-(piperidin-4-yl)carbamate (2 g, 9.99 mmol, 1.20 equip), dichloromethane (20 mL) and triethylamine (2.53 g, 25.00 mmol, 3.00 equip). To the resulting mixture was then slowly added benzoyl chloride (1.17 g, 8.32 mmol, 1.00 equip). The resulting solution was stirred for 2 h at room temperature. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The filtrate was concentrated under vacuum to yield tert-butyl N-(1-benzoylpiperidin-4-yl)carbamate as a white solid. (ES, m/z) 305 [M+H]+
Into a 50-mL round-bottom flask, was placed tert-butyl N-(1-benzoylpiperidin-4-yl)carbamate (2.6 g, 8.54 mmol, 1.00 equip), dichloromethane (20 mL), and CF3COOH (5 mL). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum to yield 1-benzoylpiperidin-4-amine, trifluoroacetic acid salt as a yellow oil. LCMS (ES, m/z) 205 [M+H]+
Into a 8-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-[bis(4-chlorophenyl)methyl]-4-bromoquinolin-2-ol (150 mg, 0.33 mmol, 1.00 equip), 1-benzoylpiperidin-4-amine hydrochloride (118 mg, 0.49 mmol, 1.50 equip), Pd2(dba)3 (30.0 mg, 0.03 mmol, 0.10 equip), dppf (63.4 mg, 0.11 mmol, 0.35 equip), Cs2CO3 (266 mg, 0.82 mmol, 2.50 equip), KOt-Bu (73 mg, 0.65 mmol, 2.00 equip), and 1,4-dioxane (3 mL). The resulting solution was stirred overnight at 100° C. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were removed by filtration. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). The resulting residue was recrystallized from ethyl acetate:petroleum ether in the ratio of 1:10 to yield 4-[(1-benzoylpiperidin-4-yl)amino]-6-[bis(4-chlorophenyl)methyl]quinolin-2-ol as an off-white solid.
LCMS (ES, m/z) 582 [M+H]+, 1H-NMR (300 MHz, DMSO-D6) δ10.744 (s, 1H), 7.937 (s, 1H), 7.486-7.465 (m, 3H), 7.414-7.377 (m, 6H), 7.210-7.109 (m, 6H), 6.472 (d, J=7.5 Hz, 1H), 5.619 (s, 1H), 5.465 (s, 1H), 4.495 (br, 1H), 3.738 (br, 1H), 3.612 (brs, 1H), 3.230 (br, 1H), 2.985 (br, 1H), 2.006-1.925 (m, 1H), 1.600-1.450 (br, 1H)
Into a 100-mL round-bottom flask, was placed a solution of 2-(tert-butoxy)-6-[(4-chlorophenyl)carbonyl]-N-[1-(trifluoromethane)sulfonylpiperidin-4-yl]quinolin-4-amine (1.14 g, 2.00 mmol, 1.00 equip) in methanol (40 ml), and NaBH4 (60 mg, 1.59 mmol, 1.50 equip) was added. The resulting solution was stirred for 2 h at room temperature. The reaction was then quenched by the addition of water (50 mL). The resulting solution was extracted with ethyl acetate (3×100 mL) and the organic layers combined. The resulting mixture was washed with water (2×50 mL). The resulting mixture was washed with brine (1×50 mL). The resulting mixture was dried over sodium sulfate and concentrated under vacuum to yield [2-(tert-butoxy)-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]quinolin-6-yl](4-chlorophenyl)methanol as a light yellow solid. LCMS (ES, m/z) 572 [M+H]+
Into a 25-mL round-bottom flask, was placed a solution of [2-(tert-butoxy)-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]quinolin-6-yl](4-chlorophenyl)methanol (250 mg, 0.44 mmol, 1.00 equip) in dichloromethane (6 ml), 4-chlorophenol (60 mg, 0.47 mmol, 1.10 equip), PPh3 (150 mg, 1.30 equip), and DEAD (100 mg, 0.57 mmol, 1.30 equip). The resulting solution was stirred for 3 h at room temperature. The reaction was then quenched by the addition of water (30 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined. The resulting mixture was washed with water (2×30 mL). The resulting mixture was washed with brine (1×30 mL). The resulting mixture was dried over sodium sulfate and concentrated under vacuum and the resulting residue was used in the next step directly. LCMS (ES, m/z) 682 [M+H]+
Into a 25-mL round-bottom flask, was placed 2-(tert-butoxy)-6-[4-chlorophenoxy(4-chlorophenyl)methyl]-N-[1-(trifluoromethane)sulfonylpiperidin-4-yl]quinolin-4-amine (250 mg, 0.37 mmol, 1.00 equip), dichloromethane (10 mL), and trifluoroacetic acid (1 mL). The resulting solution was stirred overnight at room temperature. The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined. The resulting mixture was washed with water (2×30 mL). The resulting mixture was washed with saturated brine (1×30 mL). The resulting mixture was dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1) to yield 6-[4-chlorophenoxy(4-chlorophenyl)methyl]-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]-1,2-dihydroquinolin-2-one as a white solid.
LCMS (ES, m/z) 626 [M+H]+ H-NMR (300 MHz, DMSO) δ 10.749 (s, 1H), 8.069 (s, 1H), 7.443-7.379 (m, 5H), 7.239-7.210 (m, 2H), 7.143-7.114 (m, 1H), 6.973-6.945 (m, 2H), 6.557-6.531 (m, 1H), 6.384 (s, 1H), 5.417 (s, 1H), 3.838-3.788 (m, 2H), 3.684 (br, 1H), 3.460-3.360 (m, 2H), 2.034-1.918 (m, 2H), 1.587-1.549 (m, 2H).
Into a 25-mL round-bottom flask, was placed a solution of 2-(tert-butoxy)-6-[(4-chlorophenyl)carbonyl]-N-[1-(trifluoromethane)sulfonylpiperidin-4-yl]quinolin-4-amine (150 mg, 0.26 mmol, 1.00 equip) in tetrahydrofuran (10 ml). To the resulting mixture was then added [(4-fluorophenyl)methyl]magnesium bromide (2 mL, 8.00 equip) dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of water (30 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined. The resulting mixture was washed with water (2×50 mL) and brine (1×50 mL). The resulting mixture was dried over sodium sulfate and concentrated under vacuum. The resulting residue was used in the next step without further purification. LCMS (ES, m/z) 680 [M+H]+
Into a 25-mL round-bottom flask, was placed a solution of 1-[2-(tert-butoxy)-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]quinolin-6-yl]-1-(4-chlorophenyl)-2-(4-fluorophenyl)ethan-1-ol (150 mg, 0.22 mmol, 1.00 equip) in dichloromethane (15 ml), Et3SiH (100 mg, 4.00 equip), and trifluoroacetic acid (600 mg, 5.31 mmol, 25.00 equip). The resulting solution was stirred for 3 h at room temperature. The pH value of the solution was adjusted to 8-9 with sodium bicarbonate. The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined. The resulting mixture was washed with water (2×50 mL) and brine (1×50 mL). The resulting mixture was dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (30:1) to yield a white solid. LCMS (ES, m/z) 606 [M+H]+
In an evacuated 25-mL round-bottom flask was placed a solution of 6-[(E)-1-(4-chlorophenyl)-2-(4-fluorophenyl)ethenyl]-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]-1,2-dihydroquinolin-2-one (150 mg, 0.25 mmol, 1.00 equip) in methanol (15 ml), PtO2 (150 mg), and the flask was charged with an atmosphere of H2. The resulting solution was stirred overnight at room temperature. The solids were filtered out. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1) to yield 6-[1-(4-chlorophenyl)-2-(4-fluorophenyl)ethyl]-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]-1,2-dihydroquinolin-2-one as a white solid.
LCMS (ES, m/z) 608 [M+H]+, H-NMR (400 MHz, DMSO) δ10.704 (s, 1H), 7.920 (s, 1H), 7.437 (d, J=8.4 Hz, 1H), 7.390-7.270 (m, 4H), 7.198-7.119 (m, 3H), 7.023-6.980 (m, 2H), 6.520 (d, J=7.6 Hz, 1H), 5.457 (s, 1H), 4.337-4.298 (m, 1H), 3.907-3.876 (m, 2H), 3.762 (br, 1H), 3.475-3.306 (m, 4H), 2.134-2.104 (m, 2H), 1.655-1.626 (m, 2H).
Into a 50-mL round-bottom flask, was placed a solution of 6-[bis(4-chlorophenyl)methyl]-4-bromo-1,2-dihydroquinolin-2-one (700 mg, 1.52 mmol, 1.00 equip) in N,N-dimethylformamide (15 mL), potassium carbonate (630 mg, 4.56 mmol, 3.00 equip), and CH3I (0.33 g, 1.50 equip). The resulting solution was stirred for 1 h at room temperature. The reaction was then quenched by the addition of water (30 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined. The resulting mixture was washed with water (2×50 mL) and saturated brine (1×50 mL). The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10) to yield 6-[bis(4-chlorophenyl)methyl]-4-bromo-1-methyl-1,2-dihydroquinolin-2-one as a yellow solid. (ES, m/z): [M+H]+ 474
Into a 20-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 6-[bis(4-chlorophenyl)methyl]-4-bromo-1-methyl-1,2-dihydroquinolin-2-one (120 mg, 0.25 mmol, 1.00 equip) in 1,4-dioxane (2 ml), 1-(trifluoromethane)sulfonylpiperidin-4-amine hydrochloride (114 mg, 0.42 mmol, 1.70 equip), Pd(dba)3 (23 mg, 0.10 equip), dppf (48 mg, 0.09 mmol, 0.35 equip), Cs2CO3 (204 mg, 0.63 mmol, 2.50 equip), and KOt-Bu (50 mg, 0.45 mmol, 1.80 equip). The resulting solution was stirred overnight at 100° C. The reaction was then quenched by the addition of water (20 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined. The resulting mixture was washed with water (2×50 mL) and brine (1×50 mL). The resulting mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). The resulting residue was recrystallized from ethyl acetate:n-hexane in the ratio of 1:5 to yield 6-[bis(4-chlorophenyl)methyl]-1-methyl-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]-1,2-dihydroquinolin-2-one as an off-white solid.
(ES, m/z): [M+H]+ 624; 1H-NMR (300 MHz, DMSO-D6) δ 8.017 (s, 1H), 7.380-7.407 (m, 5H), 7.119-7.226 (m, 5H), 6.584 (d, J=7.5 Hz, 1H), 5.661-5.670 (m, 2H), 3.837-3.880 (m, 2H), 3.761 (br, 1H), 3.557 (s, 3H), 3.440-3.475 (m, 2H), 2.078 (d, J=12.3 Hz, 2H), 1.545-1.653 (m, 2H)
Into a 25-mL round-bottom flask, was placed 6-[bis(4-chlorophenyl)methyl]-4-bromo-1,2-dihydroquinolin-2-one (300 mg, 0.65 mmol, 1.00 equip), N,N-dimethylformamide (10 mg, 0.14 mmol, 0.21 equip) and sodium hydride (52.3 mg, 1.31 mmol, 2.00 equip, 60%). To the resulting mixture was then added 2-bromoacetamide (108 mg, 0.78 mmol, 1.20 equip). The resulting solution was stirred for 2 h at room temperature. The reaction was then quenched by the addition of water (200 mL). The resulting solution was extracted with ethyl acetate (3×100 mL) and the organic layers combined and dried over sodium sulfate. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with DCM: MeOH (20:1) to yield 2-[6-[bis(4-chlorophenyl)methyl]-4-bromo-2-oxo-1,2-dihydroquinolin-1-yl]acetamide as a white solid. LCMS (ES, m/z) 517 [M+H]+
Into a 8-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-[6-[bis(4-chlorophenyl)methyl]-4-bromo-2-oxo-1,2-dihydroquinolin-1-yl]acetamide (160 mg, 0.31 mmol, 1.00 equip), 1,4-dioxane (3 mL), 1-(trifluoromethane)sulfonylpiperidin-4-amine hydrochloride (124.6 mg, 0.46 mmol, 1.50 equip), Pd2(dba)3 (28.4 mg, 0.03 mmol, 0.10 equip), dppf (60 mg, 0.11 mmol, 0.35 equip), Cs2CO3 (253 mg, 0.78 mmol, 2.51 equip), and t-BuOK (69.5 mg, 0.62 mmol, 2.00 equip). The resulting solution was stirred overnight at 100° C. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). The resulting residue was recrystallized from ethyl acetate:petroleum ether in the ratio of 1:10 to yield 2-[6-[bis(4-chlorophenyl)methyl]-2-oxo-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]-1,2-dihydroquinolin-1-yl]acetamide as a gray solid.
LCMS (ES, m/z) 667 [M+H]+
Into a 25-mL round-bottom flask, was placed 4-bromo-6-[(4-chlorophenyl)(1,3-thiazol-2-yl)methyl]-1,2-dihydroquinolin-2-one (370 mg, 0.86 mmol, 1.00 equip), potassium carbonate (355 mg, 2.57 mmol, 3.00 equip), and N,N-dimethylformamide (10 mL). To the resulting mixture was then added CH3I (182 mg, 1.28 mmol, 1.50 equip) dropwise with stirring. The resulting solution was stirred for 2 h at room temperature. The reaction was then quenched by the addition of water (200 mL). The resulting solution was extracted with ethyl acetate (3×100 mL) and the organic layers combined and concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1) to yield 4-bromo-6-[(4-chlorophenyl)(1,3-thiazol-2-yl)methyl]-1-methyl-1,2-dihydroquinolin-2-one as a yellow solid. LCMS (ES, m/z) 447 [M+H]+
Into a 8-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-bromo-6-[(4-chlorophenyl)(1,3-thiazol-2-yl)methyl]-1-methyl-1,2-dihydroquinolin-2-one (200 mg, 0.45 mmol, 1.00 equip), 1,4-dioxane (3 mL), 1-(trifluoromethane)sulfonylpiperidin-4-amine hydrochloride (180 mg, 0.67 mmol, 1.49 equip), Pd2(dba)3 (41 mg, 0.04 mmol, 0.10 equip), dppf (87 mg, 0.16 mmol, 0.35 equip), Cs2CO3 (365 mg, 1.12 mmol, 2.50 equip), and t-BuOK (100 mg, 0.88 mmol, 1.96 equip). The resulting solution was stirred overnight at 100° C. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). The resulting residue was recrystallized from ethyl acetate:petroleum ether in the ratio of 1:10 to yield 6-[(4-chlorophenyl)(1,3-thiazol-2-yl)methyl]-1-methyl-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]-1,2-dihydroquinolin-2-one as an off-white solid.
LCMS (ES, m/z) 597 [M+H]+; 1H-NMR (300 MHz, DMSO-D6) δ 8.111 (s, 1H), 7.814 (d, J=3.3 Hz, 1H), 7.685 (d, J=3.3 Hz, 4H), 7.469-7.395 (m, 4H), 7.305 (d, J=8.7 Hz, 2H), 6.564 (d, J=7.8 Hz, 1H), 5.951 (s, 1H), 5.649 (s, 1H), 3.877-3.685 (m, 3H), 3.547 (s, 3H), 3.469-3.396 (m, 2H), 2.101-2.062 (m, 2H), 1.654-1.537 (m, 2H)
Into a 25-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed 6-[bis(4-chlorophenyl)methyl]-4-bromoquinolin-2-ol (300 mg, 0.65 mmol, 1.00 equip, 99%), ethyl 4-(4-aminopiperidin-1-yl)-4-oxobutanoate (295.1 mg, 0.97 mmol, 1.50 equip), Pd2(dba)3 (60 mg, 0.06 mmol, 0.10 equip, 99%), dppf (126.7 mg, 0.23 mmol, 0.35 equip, 99%), Cs2CO3 (532.7 mg, 1.62 mmol, 2.50 equip, 99%), t-BuOK (146.4 mg, 1.29 mmol, 2.00 equip, 99%), and 1,4-dioxane (9 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting solution was diluted with water (80 mL). The resulting solution was extracted with ethyl acetate (3×80 mL) and the organic layers combined. The resulting mixture was washed with water (1×80 mL) and brine (1×80 mL). The resulting mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The resulting residue was purified by Prep-HPLC with the following conditions: Column, Sunfire Prep C18 OBD 5 μm, 19×150 mm; mobile phase, Phase A: water (0.05% NH4HCO3), Phase B:CH3CN (20% CH3CN up to 80% in 8 min, up to 100% for 0.1 min, hold 100% in 1.9 min, down to 20% in 0.1 min, hold 20% in 1.9 min); Detector, UV 220 & 254 nm to yield ethyl 4-[4-([6-[bis(4-chlorophenyl)methyl]-2-hydroxyquinolin-4-yl]amino)piperidin-1-yl]-4-oxobutanoate as a white solid.
LCMS (ES, m/z) 606 [M+H]+
Into a 25-mL round-bottom flask, was placed ethyl 4-[4-([6-[bis(4-chlorophenyl)methyl]-2-hydroxyquinolin-4-yl]amino)piperidin-1-yl]-4-oxobutanoate (60 g, 96.94 mmol, 1.00 equip, 98%), ethanol (15 mL), and sodium hydroxide (3 mL). The resulting solution was stirred for 4 h at room temperature. The resulting mixture was concentrated and acidified to pH3-4 with 1N HCl. The solids were collected by filtration. The resulting residue was purified by re-crystallization from methanol to yield 4-[4-([6-[bis(4-chlorophenyl)methyl]-2-oxo-1,2-dihydroquinolin-4-yl]amino)piperidin-1-yl]-4-oxobutanoic acid as a white solid.
LCMS (ES, m/z) 578 [M+H]+
Into a 8-mL vial, was placed 3-[4-([6-[bis(4-chlorophenyl)methyl]-2-hydroxyquinolin-4-yl]amino)piperidin-1-yl]-3-oxopropanoic acid (20 mg, 0.03 mmol, 1.00 equip, 98%), NH4Cl (9.48 mg, 0.18 mmol, 5.00 equip), DIEA (45.7 mg, 0.35 mmol, 10.00 equip, 99%), HATU (20.2 mg, 0.05 mmol, 1.50 equip, 99%), and N,N-dimethylformamide (3 mL). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with water (20 mL). The resulting solution was extracted with ethyl acetate (3×20 mL) and the organic layers combined. The resulting mixture was washed with water (1×20 mL) and brine (1×20 mL). The resulting mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1) to yield 3-[4-([6-[bis(4-chlorophenyl)methyl]-2-hydroxyquinolin-4-yl]amino)piperidin-1-yl]-3-oxopropanamide as a white solid.
LCMS (ES, m/z) 563 [M+H]+
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-nitrophenol (1 g, 7.12 mmol, 1.00 equip, 99%), tert-butyl 2-bromoacetate (1.68 g, 8.53 mmol, 1.00 equip), potassium carbonate (1.49 g, 10.60 mmol, 1.50 equip, 99%), and tetrahydrofuran (50 mL). The resulting solution was stirred for 4 h at 70° C. in an oil bath. The resulting solution was diluted with water (150 mL). The resulting solution was extracted with ethyl acetate (3×100 mL) and the organic layers combined. The resulting mixture was washed with water (1×100 mL) and brine (1×100 mL). The resulting mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20) to yield tert-butyl 2-(4-nitrophenoxy)acetate as a yellow solid.
Into a 100-mL round-bottom flask, was placed tert-butyl 2-(4-nitrophenoxy)acetate (2 g, 7.74 mmol, 1.00 equip, 98%), Palladium on carbon (200 mg), and methanol (50 mL). To the above hydrogen was introduced. The resulting solution was stirred for 18 h at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10) to yield tert-butyl 2-(4-aminophenoxy)acetate as a reddish oil.
Into a 25-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-[bis(4-chlorophenyl)methyl]-4-bromoquinolin-2-ol (300 mg, 0.65 mmol, 1.00 equip), tert-butyl 2-(4-aminophenoxy)acetate (220.8 mg, 0.98 mmol, 1.50 equip, 99%), Pd2(dba)3 (60 mg, 0.06 mmol, 0.10 equip, 99%), dppf (126.7 mg, 0.23 mmol, 0.35 equip, 99%), Cs2CO3 (532.7 mg, 1.62 mmol, 2.50 equip, 99%), and 1,4-dioxane (9 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting solution was diluted with water (60 mL). The resulting solution was extracted with ethyl acetate (3×60 mL) and the organic layers combined. The resulting mixture was washed with water (1×60 mL) and brine (1×60 mL). The resulting mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (30:1). The resulting residue was recrystallized from EtOAc:n-hexane in the ratio of 1:20 to yield tert-butyl 2-(4-((6-(bis(4-chlorophenyl)methyl)-2-oxo-1,2-dihydroquinolin-4-yl)amino)phenoxy)acetate as a white solid.
LCMS (ES, m/z) 601 [M+H]+; 1H-NMR (300 MHz, DMSO-D6) δ 10.922 (s, 1H), 8.442 (s, 1H), 7.985 (s, 1H), 7.407-7.379 (m, 4H), 7.469-7.395 (m, 4H), 7.7.227-7.159 (m, 8H), 6.7.966 (d, J=12 Hz, 1H), 5.646 (s, 1H), 5.366 (s, 1H), 4.665 (s, 2H), 1.433 (s, 9H)
Into a 100-mL round-bottom flask, was placed tert-butyl 2-[4-([6-[bis(4-chlorophenyl)methyl]-2-oxo-1,2-dihydroquinolin-4-yl]amino)phenoxy]acetate (200 mg, 0.33 mmol, 1.00 equip, 98%), trifluoroacetic acid (379 mg, 3.32 mmol, 10.00 equip), and dichloromethane (20 mL). The resulting solution was stirred for 3 h at room temperature. The resulting mixture was concentrated under vacuum. The resulting residue was purified by re-crystallization from methanol to yield 2-[4-([6-[bis(4-chlorophenyl)methyl]-2-oxo-1,2-dihydroquinolin-4-yl]amino)phenoxy]acetic acid as an off-white solid.
LCMS (ES, m/z) 545 [M+H]+
Into a 25-mL round-bottom flask, was placed 2-[4-([6-[bis(4-chlorophenyl)methyl]-2-hydroxyquinolin-4-yl]amino)phenoxy]acetic acid (30 g, 53.90 mmol, 1.00 equip, 98%), NH4Cl (14.72 mg, 0.27 mmol, 5.00 equip, 98%), DIPEA (71 mg, 0.54 mmol, 10.00 equip, 98%), HATU (31.37 mg, 0.08 mmol, 1.50 equip, 98%), and N,N-dimethylformamide (5 mL). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with water (50 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined. The resulting mixture was washed with water (1×50 mL) and brine (1×50 mL). The resulting mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The resulting residue was recrystallized from ethyl acetate:n-hexane in a ratio of 1:20 to yield 2-[4-([6-[bis(4-chlorophenyl)methyl]-2-hydroxyquinolin-4-yl]amino)phenoxy]acetamide as an off-white solid.
LCMS (ES, m/z) 544 [M+H]+
Into a 25-mL round-bottom flask, was placed 6-[bis(4-chlorophenyl)methyl]-4-[(piperidin-4-yl)amino]-1,2-dihydroquinolin-2-one (150 mg, 0.31 mmol, 1.00 equip, 98%), 4-(chlorosulfonyl)benzoic acid (103.77 mg, 0.47 mmol, 1.50 equip), triethylamine (98.28 mg, 0.95 mmol, 3.00 equip, 98%), dichloromethane (3 g, 35.32 mmol, 114.96 equip). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The resulting residue was purified by Prep-HPLC with the following conditions: Column, Sunfire Prep C18 OBD 5 um, 19×150 mm; mobile phase, Phase A: water (0.05% NH4HCO3), Phase B:CH3CN (20% CH3CN up to 65% in 8 min, up to 100% in 0.1 min, hold 100% for 1.9 min, down to 20% in 0.1 min, hold 20% for 1.9 min); Detector, UV 220 & 254 nm to yield 4-[4-([6-[bis(4-chlorophenyl)methyl]-2-oxo-1,2-dihydroquinolin-4-yl]amino)piperidine-1-sulfonyl]benzoic acid as an off-white solid.
LCMS (ES, m/z) 662 [M+H]+
Into a 25-mL round-bottom flask, was placed 6-[bis(4-chlorophenyl)methyl]-4-[(piperidin-4-yl)amino]quinolin-2-ol (100 mg, 0.21 mmol, 1.00 equip), methyl 3-formylbenzoate (68 mg, 0.41 mmol, 2.00 equip), methanol (10 mL), NaBH3CN (66 mg, 1.03 mmol, 5.00 equip), and acetic acid (0.1 mL). The resulting solution was stirred overnight at 25° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1) to yield methyl 3-[[4-([6-[bis(4-chlorophenyl)methyl]-2-hydroxyquinolin-4-yl]amino)piperidin-1-yl]methyl]benzoate as a yellow solid. LCMS (ES, m/z) 626 [M+H]+
Into a 100-mL round-bottom flask, was placed methyl 3-[[4-([6-[bis(4-chlorophenyl)methyl]-2-hydroxyquinolin-4-yl]amino)piperidin-1-yl]methyl]benzoate (80 mg, 0.13 mmol, 1.00 equip), methanol (20 mL), and 1M sodium hydroxide (20 mL). The resulting solution was stirred overnight at 30° C. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 5-6 with 10% HCl. The solids were collected by filtration to yield 3-[[4-([6-[bis(4-chlorophenyl)methyl]-2-hydroxyquinolin-4-yl]amino)piperidin-1-yl]methyl]benzoic acid as a white solid.
LCMS (ES, m/z) 612 [M+H]+
Into a 50-mL round-bottom flask, was placed 6-[bis(4-chlorophenyl)methyl]-4-[(piperidin-4-yl)amino]quinolin-2-ol (150 mg, 0.31 mmol, 1.00 equip), dichloromethane (20 mL), triethylamine (0.5 mL), and methyl 5-(chlorosulfonyl)thiophene-2-carboxylate (76 mg, 0.32 mmol, 1.00 equip). The resulting solution was stirred for 1 h at 25° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1) to yield methyl 5-[4-([6-[bis(4-chlorophenyl)methyl]-2-hydroxyquinolin-4-yl]amino)piperidine-1-sulfonyl]thiophene-2-carboxylate as a yellow solid. LCMS (ES, m/z) 682 [M+H]+
Into a 100-mL round-bottom flask, was placed methyl 5-[4-([6-[bis(4-chlorophenyl)methyl]-2-hydroxyquinolin-4-yl]amino)piperidine-1-sulfonyl]thiophene-2-carboxylate (100 mg, 0.15 mmol, 1.00 equip), methanol (20 mL), and 1M sodium hydroxide (20 mL). The resulting solution was stirred overnight at 50° C. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 5-6 with 10% HCl. The solids were collected by filtration. The resulting residue was purified by Prep-HPLC with the following conditions: water with 0.05% TFA and MeOH (60% MeOH up to 85% in 10 min, hold 95% for 1 min, down to 60% in 1 min) to yield 5-[4-([6-[bis(4-chlorophenyl)methyl]-2-hydroxyquinolin-4-yl]amino)piperidine-1-sulfonyl]thiophene-2-carboxylic acid; trifluoroacetic acid salt as an off-white solid.
LCMS (ES, m/z) 668 [M+H]+
Into a 1-L round-bottom flask, was placed a solution of 4-amino-3-bromobenzoic acid (50 g, 231.45 mmol, 1.00 equip) in N,N-dimethylformamide (500 mL), TEA (128 mL, 4.00 equip), HATU (106 g, 278.78 mmol, 1.20 equip), and methoxy(methyl)amine hydrochloride (45 g, 461.33 mmol, 2.00 equip). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with water (1 L). The resulting solution was extracted with ethyl acetate (1 L) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2) to yield 4-amino-3-bromo-N-methoxy-N-methylbenzamide as a yellow solid. LCMS (ES, m/z) 259 [M+H]+
Into a 2-L round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-amino-3-bromo-N-methoxy-N-methylbenzamide (59 g, 227.71 mmol, 1.00 equip) in 1,4-dioxane (1500 mL), and Boc2O (351 g, 1.61 mol, 7.00 equip). The resulting solution was stirred overnight at 100° C. The resulting mixture was concentrated under vacuum. The residue was suspended in saturated sodium chloride (200 mL). The resulting solution was extracted with ethyl acetate (2×300 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2) to yield tert-butyl N-[2-bromo-4-[methoxy(methyl)carbamoyl]phenyl]carbamate as a yellow solid. LCMS (ES, m/z) 359 [M+H]+
Into a 1-L round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl N-[2-bromo-4-[methoxy(methyl)carbamoyl]phenyl]carbamate (30 g, 83.52 mmol, 1.00 equip) in tetrahydrofuran (400 mL). To the resulting mixture was then added (4-chlorophenyl)magnesium bromide (250 mL, 3.00 equip, 1 M) dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with saturated sodium chloride (200 mL). The resulting solution was extracted with ethyl acetate (400 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The resulting residue was recrystallized from ethyl acetate:petroleum ether in a ratio of 1:20. The solids were collected by filtration. The mother liquor was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10) to yield additional tert-butyl N-[2-bromo-4-[(4-chlorophenyl)carbonyl]phenyl]carbamate as a light yellow solid. LCMS (ES, m/z) 410 [M+H]+
Into a 500-mL round-bottom flask, was placed a solution of tert-butyl N-[2-bromo-4-[(4-chlorophenyl)carbonyl]phenyl]carbamate (20 g, 48.70 mmol, 1.00 equip) in dichloromethane (300 mL). To the resulting mixture was then added trifluoroacetic acid (38 mL, 10.00 equip) dropwise with stirring. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of saturated sodium bicarbonate (500 mL). The resulting solution was extracted with DCM (500 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The resulting residue was recrystallized from ethyl acetate:petroleum ether in the ratio of 1:15 to yield 2-bromo-4-[(4-chlorophenyl)carbonyl]aniline as a light yellow solid. LCMS (ES, m/z) 310 [M+H]+
Into a 1-mL round-bottom flask, was placed a solution of 2-bromo-4-[(4-chlorophenyl)carbonyl]aniline (28.62 g, 92.15 mmol, 1.00 equip) in toluene (400 mL), and 2,2-dimethyl-1,3-dioxane-4,6-dione (25.92 g, 179.84 mmol, 2.00 equip). The resulting solution was stirred overnight at 88° C. The solution was cooled to room temperature and the solids were collected by filtration to yield 2-([2-bromo-4-[(4-chlorophenyl)carbonyl]phenyl]carbamoyl)acetic acid as a yellow solid. LCMS (ES, m/z) 396 [M+H]+
Into a 250-mL 3-necked round-bottom flask, was placed P2O5 (8.95 g, 63.03 mmol, 1.00 equip), and MSA (80.55 g). The resulting solution was stirred for 1 h at 80° C. and then the temperature was raised to 99° C. To the resulting mixture was then added 2-([2-bromo-4-[(4-chlorophenyl)carbonyl]phenyl]carbamoyl) acetic acid (25 g, 63.03 mmol, 1.00 equip) in several batches. The resulting solution was stirred for 3 h at 99° C. The resulting solution was cooled to room temperature and added dropwise into saturated sodium chloride (500 mL). The solids were collected by filtration and then dissolved in ethyl acetate (200 mL). And the un-dissolved solids were collected by filtration to yield 8-bromo-6-[(4-chlorophenyl)carbonyl]-4-hydroxy-1,2-dihydroquinolin-2-one as a yellow solid. The filtrate was concentrated under vacuum and was applied onto a silica gel column with ethyl acetate first and then dichloromethane/methanol (8:2) to yield additional 8-bromo-6-[(4-chlorophenyl)carbonyl]-4-hydroxy-1,2-dihydroquinolin-2-one as a yellow solid. LCMS (ES, m/z) 378 [M+H]+
Into a 500-mL round-bottom flask, was placed a solution of 8-bromo-6-[(4-chlorophenyl)carbonyl]-4-hydroxy-1,2-dihydroquinolin-2-one (9 g, 23.77 mmol, 1.00 equip) in 1,4-dioxane (100 mL), and phosphoroyl tribromide (20.7 g, 72.20 mmol, 3.00 equip). The resulting solution was stirred for 12 h at 92° C. The reaction was cooled to room temperature and then quenched by the addition of water/ice (200 mL). The solids were collected by filtration. The solid was washed with methanol (100 mL) and petroleum ether (100 mL). The remaining solid was dissolved with ethyl acetate (2 L) and the resulting mixture filtered and the ethyl acetate phase isolated. The resulting mixture was concentrated under vacuum. The resulting residue was recrystallized from ethyl acetate:petroleum ether in the ratio of 1:10 to yield 2,4,8-tribromo-6-[(4-chlorophenyl)carbonyl]quinoline as a gray solid. LCMS (ES, m/z) 506 [M+H]+
Into a 100-mL round-bottom flask, was placed 2,4,8-tribromo-6-[(4-chlorophenyl)carbonyl]quinoline (2 g, 3.97 mmol, 1.00 equip), toluene (20 mL), and tetrahydrofuran (2 mL). To the resulting mixture was then added NaOCH3 (642 mg, 11.89 mmol, 3.00 equip). The resulting solution was stirred for 2 h at 66° C. Then another batch of NaOCH3 (642 mg, 11.89 mmol, 3.00 equip) was added to the solution. The resulting solution was allowed to react, with stirring, for an additional 2 h at 66° C. And then a final batch of NaOCH3 (642 mg, 11.89 mmol, 3.00 equip) was added to the solution. The resulting solution was allowed to react, with stirring, for an additional 2 h at 66° C. The reaction was then quenched by the addition of saturated sodium bicarbonate (200 mL). The resulting solution was extracted with DCM (2×100 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum to yield 4,8-dibromo-6-[(4-chlorophenyl)carbonyl]-2-methoxyquinoline as a yellow solid. LCMS (ES, m/z) 456 [M+H]+
Into a 100-mL round-bottom flask, was placed a solution of 4,8-dibromo-6-[(4-chlorophenyl)carbonyl]-2-methoxyquinoline (1.5 g, 3.29 mmol, 1.00 equip) in tetrahydrofuran (30 mL). To the resulting mixture was then added (4-chlorophenyl)magnesium bromide (9.87 mL, 3.00 equip, 1 M) dropwise with stirring at 0° C. The resulting solution was stirred for 3 h at room temperature. The reaction was then quenched by the addition of saturated sodium bicarbonate (100 mL). The solids were filtered out and washed with ethyl acetate (100 mL), and the ethyl acetate was combined with the filtrate. The resulting solution was extracted with ethyl acetate (100 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:9) to yield bis(4-chlorophenyl)(4,8-dibromo-2-methoxyquinolin-6-yl)methanol as a yellow solid. LCMS (ES, m/z) 568 [M+H]+
Into a 50-mL round-bottom flask, was placed bis(4-chlorophenyl)(4,8-dibromo-2-methoxyquinolin-6-yl)methanol (1.3 g, 2.29 mmol, 1.00 equip), dppf (216 mg, 0.39 mmol, 0.17 equip), Pd2(dba)3.CHCl3 (114 mg, 0.11 mmol, 0.05 equip), Cs2CO3 (2.99 g, 9.18 mmol, 4.00 equip), 1,4-dioxane (10 mL), and 1-(trifluoromethane)sulfonylpiperidin-4-amine hydrochloride (1.23 g, 4.58 mmol, 2.00 equip). The resulting solution was stirred overnight at 84° C. The resulting solution was diluted with saturated sodium bicarbonate (100 mL). The resulting solution was extracted with ethyl acetate (2×100 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:9) to yield (8-bromo-2-methoxy-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]quinolin-6-yl)bis(4-chlorophenyl)methanol as a yellow solid. LCMS (ES, m/z) 720 [M+H]+
Into a 50-mL round-bottom flask, was placed (8-bromo-2-methoxy-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]quinolin-6-yl)bis(4-chlorophenyl)methanol (900 mg, 1.25 mmol, 1.00 equip), Pd(OAc)2 (56 mg, 0.25 mmol, 0.20 equip), P(o-tol)3 (152 mg, 0.50 mmol, 0.40 equip), DIEA (1.61 g, 12.46 mmol, 10.00 equip), N,N-dimethylformamide (10 mL), and prop-2-en-1-yl acetate (1.25 g, 12.49 mmol, 10.00 equip). The resulting solution was stirred for 3 days at 129° C. under nitrogen. The resulting solution was diluted with saturated sodium bicarbonate (50 mL). The resulting solution was extracted with ethyl acetate (2×100 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4) to yield (2E)-3-[6-[bis(4-chlorophenyl)(hydroxy)methyl]-2-methoxy-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]quinolin-8-yl]prop-2-en-1-yl acetate as a yellow solid. LCMS (ES, m/z) 738 [M+H]+
Into a 100-mL round-bottom flask, was placed a solution of (2E)-3-[6-[bis(4-chlorophenyl)(hydroxy)methyl]-2-methoxy-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]quinolin-8-yl]prop-2-en-1-yl acetate (270 mg, 0.37 mmol, 1.00 equip) in dichloromethane (mL) and nitrogen was bubbled into the solution for 30 min. To the resulting mixture was then added Et3SiH (5.90 mL, 100.00 equip) dropwise with stirring. To this was added trifluoroacetic acid (0.56 mL, 20.00 equip) dropwise with stirring. The resulting solution was stirred for 3 h at room temperature. The reaction was then quenched by the addition of saturated sodium bicarbonate (50 mL). The resulting solution was extracted with DCM (2×50 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were collected by filtration. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (9:1) to yield (2E)-3-[6-[bis(4-chlorophenyl)methyl]-2-methoxy-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]quinolin-8-yl]prop-2-en-1-yl acetate as a yellow solid. LCMS (ES, m/z) 722 [M+H]+
Into a 50-mL round-bottom flask, was placed (2E)-3-[6-[bis(4-chlorophenyl)methyl]-2-methoxy-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]quinolin-8-yl]prop-2-en-1-yl acetate (230 mg, 0.32 mmol, 1.00 equip), sodium hydroxide (88 mg, 2.20 mmol, 2.00 equip), methanol (3 mL), water (2 mL), and tetrahydrofuran (1 mL). The resulting solution was stirred for 3 h at room temperature. The resulting solution was diluted with saturated sodium chloride (20 mL). The resulting solution was extracted with ethyl acetate (50 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were removed by filtration. The resulting mixture was concentrated under vacuum. The resulting residue was purified by Prep-HPLC with the following conditions (waters 2767-1): Column, X-Bridge Prep C18, 5 um, 19×100 mm; mobile phase, Phase A, water with 0.05% NH4HCO3, Phase B, CH3CN (35% CH3CN up to 95% in 12 min); Detector, UV 254 to yield (2E)-3-[6-[bis(4-chlorophenyl)methyl]-2-methoxy-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]quinolin-8-yl]prop-2-en-1-ol as an off-white solid.
LCMS (ES, m/z) 680 [M+H]+; 1H-NMR: (400 MHz, DMSO-D6) δ: 7.969 (s, 1H), 7.561-7.389 (m, 6H), 7.177 (d, J=8.4 Hz, 4H), 6.656 (d, J=7.8 Hz, 1H), 6.383-6.329 (m, 1H), 6.062 (s, 1H), 5.700 (s, 1H), 4.833-4.796 (m, 1H), 4.153-4.121 (m, 2H), 3.915-3.838 (m, 6H), 3.436-3.321 (m, 2H), 2.105-2.069 (m, 2H), 1.621-1.588 (m, 2H).
Into a 100-mL round-bottom flask, was placed (8-bromo-2-methoxy-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]quinolin-6-yl)bis(4-chlorophenyl)methanol (300 mg, 0.42 mmol, 1.00 equip), dichloromethane (50 mL), Et3SiH (0.3 mL), and trifluoroacetic acid (0.9 mL). The resulting solution was stirred overnight at 25° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10) to yield 6-[bis(4-chlorophenyl)methyl]-8-bromo-2-methoxy-N-[1-(trifluoromethane)sulfonylpiperidin-4-yl]quinolin-4-amine as a yellow solid.
LCMS (ES, m/z) 704 [M+H]+; 1H-NMR (400 MHz, DMSO-D6) δ: 8.103 (s, 1H), 7.551 (s, 1H), 7.412 (d, J=6.3 Hz, 4H), 7.165 (d, J=6.3 Hz, 2H), 6.812 (d, J=8.0 Hz, 1H), 6.117 (s, 1H), 5.731 (s, 1H), 3.992 (s, 3H), 3.938-3.803 (m, 3H), 3.424-3.362 (m, 2H), 2.100-2.072 (m, 2H), 1.639-1.548 (m, 2H).
Into a 10-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-[bis(4-chlorophenyl)methyl]-8-bromo-2-methoxy-N-[1-(trifluoromethane)sulfonylpiperidin-4-yl]quinolin-4-amine (50 mg, 0.07 mmol, 1.00 equip), 2-[(1E)-3-methoxyprop-1-en-1-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (16 mg, 0.08 mmol, 1.10 equip), Pd(dppf)Cl2(5 mg), potassium carbonate (30 mg, 0.22 mmol, 3.00 equip), 1,4-dioxane (2 mL), and water (0.5 mL). The resulting solution was stirred overnight at 80° C. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate:petroleum ether (1:4) to yield 6-[bis(4-chlorophenyl)methyl]-2-methoxy-8-[(1E)-3-methoxyprop-1-en-1-yl]-N-[1-(trifluoromethane)sulfonylpiperidin-4-yl]quinolin-4-amine as a white solid.
LCMS (ES, m/z) 694 [M+H]+, 1H-NMR (400 MHz, DMSO-D6) δ: 7.922 (s, 1H), 7.509-7.419 (m, 2H), 7.433 (d, J=8.4 Hz, 4H), 7.117 (d, J=8.4 Hz, 4H), 6.650-6.600 (m, 1H), 6.380-6.260 (m, 1H), 6.002 (s, 1H), 5.629 (s, 1H), 4.012-4.009 (m, 2H), 3.845-3.772 (m, 6H), 3.340-3.328 (m, 2H), 3.215 (s, 3H), 2.080-1.980 (m, 2H), 1.650-1.520 (m, 2H).
Into a 100-mL round-bottom flask, was placed 6-[bis(4-chlorophenyl)methyl]-2-methoxy-8-[(1E)-3-methoxyprop-1-en-1-yl]-N-[1-(trifluoromethane)sulfonylpiperidin-4-yl]quinolin-4-amine (100 mg, 0.14 mmol, 1.00 equip), methanol (20 mL), PtO2 (5 mg), and the flask was charged with H2. The resulting solution was stirred overnight at 25° C. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate:petroleum ether (1:4) to yield 6-[bis(4-chlorophenyl)methyl]-2-methoxy-8-(3-methoxypropyl)-N-[1-(trifluoromethane)sulfonylpiperidin-4-yl]quinolin-4-amine as a light yellow solid.
LCMS (ES, m/z) 696 [M+H]+, 1H-NMR (400 MHz, DMSO-D6) δ: 7.912 (d, J=0.8 Hz, 1H), 7.390 (d, J=8.2 Hz, 4H), 7.142 (d, J=8.2 Hz, 4H), 7.705 (s, 1H), 6.606 (d, J=8.0 Hz, 1H), 6.034 (s, 1H), 5.661 (s, 1H), 3.883 (s, 3H), 3.842-3.747 (m, 3H), 3.429-3.397 (m, 2H), 3.290-3.194 (m, 2H), 3.118 (s, 3H), 2.991-2.955 (m, 2H), 2.094-2.067 (m, 2H), 1.873-1.804 (m, 2H), 1.658-1.624 (m, 2H)
Into a 10-mL round-bottom flask, was placed 6-[bis(4-chlorophenyl)methyl]-2-methoxy-8-(3-methoxypropyl)-N-[1-(trifluoromethane)sulfonylpiperidin-4-yl]quinolin-4-amine (8 mg, 0.01 mmol, 1.00 equip), 1,4-dioxane (2 mL), and 4N hydrogen chloride (2 mL). The resulting solution was stirred overnight at 100° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate:petroleum ether (1:2) to yield 6-(bis(4-chlorophenyl)methyl)-8-(3-methoxypropyl)-4-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)amino)quinolin-2(1H)-one as a white solid.
LCMS (ES, m/z) 682 [M+H]+; 1H-NMR (300 MHz, DMSO-D6) δ: 9.819 (s, 1H), 7.730 (s, 1H), 7.319 (d, J=8.4 Hz, 4H), 7.056 (d, J=8.4 Hz, 4H), 6.862 (s, 1H), 6.457 (d, J=10.5 Hz, 1H), 5.527 (s, 1H), 5.431 (s, 1H), 3.850-3.762 (m, 3H), 3.324-3.261 (m, 2H), 3.132-3.054 (m, 5H), 2.750-2.698 (m, 2H), 2.050-1.980 (m, 2H), 1.588-1.544 (m, 4H).
and
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2,4,8-tribromo-6-[(4-chlorophenyl)carbonyl]quinoline (1.0 g, 1.98 mmol, 1.00 equip) in toluene (30 mL), and KOt-Bu (2.18 mL, 1.10 equip). The resulting solution was stirred for 1.5 h at 65° C. The resulting solution was diluted with saturated sodium chloride (50 mL). The resulting solution was extracted with ethyl acetate (2×100 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (5:95) to yield 4,8-dibromo-2-(tert-butoxy)-6-[(4-chlorophenyl)carbonyl]quinoline as a yellow solid. LCMS (ES, m/z) 498 [M+H]+
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4,8-dibromo-2-(tert-butoxy)-6-[(4-chlorophenyl)carbonyl]quinoline (440 mg, 0.88 mmol, 1.00 equip) in tetrahydrofuran (30 mL). To the resulting mixture was then added (4-chlorophenyl)magnesium bromide (2.67 mL, 3.00 equip, 1 M) dropwise with stirring at 0° C. The resulting solution was stirred for 3 h at room temperature. The reaction was then quenched by the addition of saturated sodium bicarbonate (50 mL). The resulting solution was extracted with ethyl acetate (100 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:9) to yield bis(4-chlorophenyl)[4,8-dibromo-2-(tert-butoxy)quinolin-6-yl]methanol as a yellow solid. LCMS (ES, m/z) 610 [M+H]+
Into a 25-mL round-bottom flask, was placed a solution of 1-(trifluoromethane)sulfonylpiperidin-4-amine hydrochloride (244 mg, 0.91 mmol, 1.05 equip) in 1,4-dioxane (13 mL), bis(4-chlorophenyl)[4,8-dibromo-2-(tert-butoxy)quinolin-6-yl]methanol (530 mg, 0.87 mmol, 1.00 equip), Pd2(dba)3.CHCl3 (46 mg, 0.04 mmol, 0.05 equip), dppf (83 mg, 0.15 mmol, 0.17 equip), and Cs2CO3 (851 mg, 2.61 mmol, 3.00 equip). The resulting solution was stirred overnight at 85° C. The reaction was cooled to room temperature and then quenched by the addition of saturated sodium bicarbonate (50 mL). The resulting solution was extracted with ethyl acetate (100 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:9) to yield [8-bromo-2-(tert-butoxy)-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]quinolin-6-yl]bis(4-chlorophenyl)methanol as a yellow solid. LCMS (ES, m/z) 762 [M+H]+
A mixture of (8-bromo-2-(tert-butoxy)-4-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)amino) quinolin-6-yl)bis(4-chlorophenyl)methanol (58 mg, 0.0762 mmol), 2-methoxyethanamine, Pd2(dba)3 (6.98 mg, 0.0076 mmol), XPhos (15.98 mg, 0.0335 mmol), and Cs2CO3 (74.45 mg, 0.229 mmol) in 1,4-dioxane (0.7 mL) was heated to 100° C. for 5 hr under the Ar2. The reaction was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organics were concentrated and purified by silica column (15% EtOAc/hexanes) to yield (2-(tert-butoxy)-8-((2-methoxyethyl)amino)-4-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)amino)quinolin-6-yl)bis(4-chlorophenyl)methanol and (25-35% EtOAc/hexanes) (2-(tert-butoxy)-8-((2-methoxyethyl)amino)-4-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)amino)quinolin-6-yl)(4-chlorophenyl)(4-((2-methoxyethyl)amino)phenyl)methanol. (M+H)+: 755, 757, respectively.
To solution of (2-(tert-butoxy)-8-((2-methoxyethyl)amino)-4-((1-((trifluoromethyl) sulfonyl)piperidin-4-yl)amino)quinolin-6-yl)bis(4-chlorophenyl)methanol (12 mg, 0.0159 mmol) and triethylsilane (0.0152 mL, 0.0953 mmol) in CH2Cl2 (1 mL) was added slowly TFA (0.03 mL, 0.392 mmol). The resulting mixture was stirred for 4 hr at room temperature. The reaction was diluted with CH2Cl2 and washed with Na2CO3 to make the aqueous layer basic. The organics were washed with water, dried over anhydrous Na2SO4 and concentrated. The resulting residue was triturated from Et2O/hexanes (1:3) to yield 6-(bis(4-chlorophenyl)methyl)-8-((2-methoxyethyl)amino)-4-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)amino)quinolin-2(1H)-one.
(M+H)+: 683, 685. 1H NMR (CDCl3): 11.59 (br. s., 1H), 7.21-7.36 (m, 4H), 7.03 (d, J=8.1 Hz, 4H), 6.45 (s, 1H), 6.47 (s, 1H), 5.61 (s, 2H), 5.49 (s, 1H), 4.54 (d, J=6.6 Hz, 1H), 3.97 (m, 2H), 3.51-3.70 (m, 3H), 3.36 (s, 3H), 3.11-3.31 (m, 4H), 2.25 (m, 2H), 1.53-1.74 (m, 2H)
6-((4-chlorophenyl)(4-((2-methoxyethyl)amino)phenyl)methyl)-8-((2-methoxyethyl)amino)-4-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)amino)quinolin-2(1H)-one was similarly prepared by reacting (2-(tert-butoxy)-8-((2-methoxyethyl)amino)-4-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)amino)quinolin-6-yl)(4-chlorophenyl)(4-((2-methoxyethyl)amino)phenyl)methanol (prepared as described in Step 4 above) according to the procedure as described in Step 5 above.
(ES, m/z) [M+H]+ : 722. 1H NMR (CDCl3) δ: 11.25 (br. s., 1H), 7.24-7.38 (m, 3H), 7.15-7.24 (m, 2H), 6.95-7.09 (m, 3H), 6.48-6.60 (m, 3H), 5.47 (s, 1H), 5.28 (br. s., 1H), 4.86 (d, J=6.1 Hz, 1H), 4.10 (br. s., 1H), 3.90 (m, 2H), 3.59 (m, 5H), 3.38 (s, 3H), 3.32 (s, 3H), 3.21 (m, 2H), 3.25 (m, 4H), 2.17 (m, 2H), 1.66 (m, 2H)
Into a 25-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of [8-bromo-2-(tert-butoxy)-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]quinolin-6-yl]bis(4-chlorophenyl)methanol (200 mg, 0.26 mmol, 1.00 equip) in 1,4-dioxane (2 mL), tert-butyl N-(4-aminobutyl)carbamate (98 mg, 0.52 mmol, 2.00 equip), Pd2(dba)3.CHCl3 (13 mg, 0.01 mmol, 0.05 equip), Cs2CO3 (254 mg, 0.78 mmol, 3.00 equip), and XANTPHOS (25 mg, 0.04 mmol, 0.17 equip). The resulting solution was stirred overnight at 89° C. The reaction was then quenched by the addition of saturated sodium bicarbonate (50 mL). The resulting solution was extracted with ethyl acetate (100 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:6) to yield tert-butyl N-[4-([6-[bis(4-chlorophenyl)(hydroxy)methyl]-2-(tert-butoxy)-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]quinolin-8-yl]amino)butyl]carbamate as a yellow solid. LCMS (ES, m/z) 868 [M+H]+
Into a 50-mL round-bottom flask, was placed tert-butyl N-[4-([6-[bis(4-chlorophenyl)(hydroxy)methyl]-2-(tert-butoxy)-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]quinolin-8-yl]amino)butyl]carbamate (200 mg, 0.23 mmol, 1.00 equip) and dichloromethane (10 mL). The solution was bubbled with nitrogen for 30 min to remove air. To this solution was added Et3SiH (3.66 mL, 100.00 equip). To the resulting mixture was then added trifluoroacetic acid (0.351 mL, 20.00 equip) dropwise with stirring in 5 min. The resulting solution was stirred for 2 h at room temperature. To this was added trifluoroacetic acid (0.351 mL, 20.00 equip) dropwise with stirring in 5 min. The resulting solution was allowed to react, with stirring, for an additional 5.5 h at room temperature. The resulting solution was diluted with saturated sodium bicarbonate (50 mL). The resulting solution was extracted with ethyl acetate (100 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The resulting residue was purified by Prep-HPLC with the following conditions (Waters2767-1): Column, X-Bridge Prep C18, 5 um, 19×100 mm; mobile phase, Phase A: water with 0.05% TFA Phase B: CH3CN (35% CH3CN up to 95% in 12 min); Detector, UV 254 to yield 8-[(4-aminobutyl)amino]-6-[bis(4-chlorophenyl)methyl]-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]-1,2-dihydroquinolin-2-one TFA salt as a white solid.
LCMS (ES, m/z) 696 [M+H]+; 1H-NMR (400 MHz, CD3OD) δ: 7.226-7.190 (m, 5H), 7.021 (d, J=8.4 Hz, 4H), 6.410 (s, 1H), 5.562 (s, 1H), 5.514 (s, 1H), 3.889-3.857 (m, 2H), 3.676-3.622 (m, 1H), 3.264-3.217 (m, 2H), 3.032-2.973 (m, 2H), 2.858-2.799 (m, 2H), 2.073-2.041 (m, 2H), 1.648-1.528 (m, 6H).
Into a 100-mL round-bottom flask, was placed bis(4-chlorophenyl)[4,8-dibromo-2-(tert-butoxy)quinolin-6-yl]methanol (500 mg, 0.82 mmol, 1.00 equip), dichloromethane (50 mL), triethylsilane (1 mL), and trifluoroacetic acid (2 mL). The resulting solution was stirred overnight at 25° C. The resulting solution was diluted with DCM (100 mL). The resulting mixture was washed with saturated sodium bicarbonate (3×100 mL) and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum to yield 6-[bis(4-chlorophenyl)methyl]-4,8-dibromoquinolin-2-ol as a yellow solid. LCMS (ES, m/z) 538 [M+H]+
Into a 25-mL round-bottom flask, was placed 6-[bis(4-chlorophenyl)methyl]-4,8-dibromoquinolin-2-ol (360 mg, 0.67 mmol, 1.00 equip), N,N-dimethylformamide (15 mL), Cs2CO3 (654 mg, 2.01 mmol, 3.00 equip), and CH3I (190 mg, 1.34 mmol, 2.00 equip). The resulting solution was stirred overnight at 80° C. The resulting solution was diluted with water (80 mL). The solids were collected by filtration to yield 6-[bis(4-chlorophenyl)methyl]-4,8-dibromo-1-methyl-1,2-dihydroquinolin-2-one as a yellow solid. LCMS (ES, m/z) 552 [M+H]+
Into a 10-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-[bis(4-chlorophenyl)methyl]-4,8-dibromo-1-methyl-1,2-dihydroquinolin-2-one (80 mg, 0.14 mmol, 1.00 equip), 1-(trifluoromethane)sulfonylpiperidin-4-amine hydrochloride (40 mg, 0.15 mmol, 1.05 equip), Pd2(dba)3 (8 mg, 0.01 mmol, 0.05 equip), dppf (14 mg, 0.03 mmol, 0.17 equip), Cs2CO3 (142 mg, 0.44 mmol, 3.00 equip), and 1,4-dioxane (5 mL). The resulting solution was stirred overnight at 75° C. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate:petroleum ether (1:10) to yield 6-[bis(4-chlorophenyl)methyl]-8-bromo-1-methyl-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]-1,2-dihydroquinolin-2-one as a yellow solid. LCMS (ES, m/z) 704 [M+H]+
Into a 10-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-[bis(4-chlorophenyl)methyl]-8-bromo-1-methyl-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]-1,2-dihydroquinolin-2-one (100 mg, 0.14 mmol, 1.00 equip), butan-1-amine (20 mg, 0.27 mmol, 2.00 equip), Pd2(dba)3 (7 mg, 0.01 mmol, 0.05 equip), XANTPHOS (12 mg, 0.02 mmol, 0.15 equip), Cs2CO3 (138 mg, 0.42 mmol, 3.00 equip), 1,4-dioxane (3 mL). The resulting solution was stirred overnight at 75° C. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1) to yield 6-[bis(4-chlorophenyl)methyl]-8-(butylamino)-1-methyl-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]-1,2-dihydroquinolin-2-one as a light yellow solid.
LCMS (ES, m/z) 695 [M+H]+
To a suspension of methyl 4-amino-3-bromobenzoate (2 g, 8.69 mmol) in isopropanol (10 mL) was added Meldrum's acid (1.63 g, 11 mmol) and triethyl orthoformate (5.26 mL, 31.6 mmol). The resulting mixture was heated at 100° C. for 4 hr and cooled to room temperature. The resulting precipitates were filtered off and washed with 10% Et2O/hexanes to yield methyl 3-bromo-4-(((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl)amino)benzoate. (M+Na)+: 408.
To a flask with DOWTHERM (35 mL) at 210° C. was added methyl 3-bromo-4-(((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl)amino)benzoate (3.3 g, 8.59 mmol) in portions. The resulting solution was heated for 20 min and cooled down to room temperature. Solids were precipitated from the solution. To the reaction mixture was then added hexanes and the precipitate filtered. The solids were washed thoroughly with Et2O and hexanes and dried under vacuum to yield methyl 8-bromo-4-oxo-1,4-dihydroquinoline-6-carboxylate. (M+H)+: 282, 284
To a suspension of methyl 8-bromo-4-oxo-1,4-dihydroquinoline-6-carboxylate (272 mg, 0.964 mmol) in DMF (5 mL) at room temperature was added slowly phosphorous tribromide (0.1 mL, 1.06 mmol). The resulting mixture was stirred under argon for 30 min. The reaction mixture was made basic by the addition of solid NaHCO3 until the pH was greater than 10, and then the reaction mixture was diluted with water and the solid collected by filtration. The product was washed with several portion of water and dried to yield methyl 4,8-dibromoquinoline-6-carboxylate. (M+H)+: 344, 346, 348.
A solution of (4-chlorophenyl)magnesium bromide (2.02 mL, 1.0 M in THF) was dropwise added to a suspension of methyl 4,8-dibromoquinoline-6-carboxylate (0.2 g, 0.58 mmol) in THF (5 mL) at room temperature. The resulting mixture was slowly dissolved and became a clear solution after 30 min. During this period of time, cooling was needed, when the temperature of the reaction mixture rose above room temperature. After 2 hr, the reaction was quenched with ice water and saturated NH4Cl followed by EtOAc. The aqueous layer was extracted with EtOAc. The combined organics were concentrated and purified by silica column (25-30% EtOAc/hexanes) chromatography to yield bis(4-chlorophenyl)(4,8-dibromoquinolin-6-yl)methanol. (M+H)+: 536, 540, 541
To solution of bis(4-chlorophenyl)(4,8-dibromoquinolin-6-yl)methanol (175 mg, 0.325 mmol) and triethylsilane (0.208 mL, 1.3 mmol) in CH2Cl2 was added slowly TFA (0.35 mL, 4.57 mmol). The resulting mixture was stirred for 4 hr at room temperature. The reaction was diluted with CH2Cl2 and washed with Na2CO3 to make the aqueous layer basic. The organics were concentrated and purified by silica column (15% EtOAc/hexanes) chromatography to yield 6-(bis(4-chlorophenyl)methyl)-4,8-dibromoquinoline. (M+H)+: 520, 523, 528.
A mixture of 6-(bis(4-chlorophenyl)methyl)-4,8-dibromoquinoline (40 mg, 0.0766 mmol), 1-((trifluoromethyl)sulfonyl)piperidin-4-amine (22.6 mg, 0.0843 mmol), Pd2(dba)3 (3.5 mg, 0.00383 mmol), dppf (7.2 mg, 0.013 mmol), Cs2CO3 (62.4 mg, 0.192 mmol) and 1,4-dioxane (0.9 mL) was heated under argon to 95° C. overnight. The reaction was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organics were concentrated and purified by silica column (45% EtOAc/hexanes) chromatography to yield 6-(bis(4-chlorophenyl)methyl)-8-bromo-N-(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)quinolin-4-amine.
(M+H)+: 674, 676; 1H NMR (CDCl3): δ 8.64 (d, J=5.14 Hz, 1H), 7.73 (s, 1H), 7.40 (s, 1H), 7.30 (d, J=8.31 Hz, 4H), 7.03 (d, J=8.31 Hz, 4H), 6.49 (d, J=5.38 Hz, 1H), 5.63 (s, 1H), 4.78 (d, J=6.60 Hz, 1H), 4.01 (m, 2H), 3.64-3.81 (m, 1H), 3.18-3.38 (m, 2H), 2.28 (m, 2H), 1.61-1.77 (m, 2H)
A mixture of 6-(bis(4-chlorophenyl)methyl)-4,8-dibromoquinolin-2(1H)-one (48 mg, 0.0892 mmol), 1-((trifluoromethyl)sulfonyl)piperidin-4-amine (26.4 mg, 0.0981 mmol), Pd2(dba)3 (8.2 mg, 0.00892 mmol), dppf (14.8 mg, 0.0268 mmol), Cs2CO3 (72.7 mg, 0.223 mmol) and 1,4-dioxane (0.9 mL) was heated under argon to 95° C. overnight. The reaction was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organics were concentrated and purified by silica column (40-50% EtOAc/hexanes) chromatography to yield 6-(bis(4-chlorophenyl)methyl)-8-bromo-4-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)amino)quinolin-2(1H)-one.
(ES, m/z) 688, 690 [M+H]+. 1H NMR (CDCl3) δ: 8.57 (br. s., 1H), 7.38 (s, 1H), 7.31 (d, J=8.6 Hz, 4H), 7.13 (s, 1H), 7.00 (d, J=8.6 Hz, 4H), 5.63 (s, 1H), 5.55 (s, 1H), 4.52 (d, J=6.6 Hz, 1H), 4.01 (m, 2H), 3.49-3.65 (m, 1H), 3.21 (m, 2H), 2.26 (m, 2H), 1.60-1.71 (m, 2H)
Into a 250-mL round-bottom flask, was placed methyl 4-amino-3-methoxybenzoate (10 g, 55.19 mmol, 1.00 equip), 2,2-dimethyl-1,3-dioxane-4,6-dione (9.5 g, 65.91 mmol, 1.20 equip), (CH3O)3CH (100 mL). The resulting solution was stirred overnight at 100° C. The reaction mixture was cooled with a water/ice bath. The solids were collected by filtration to yield methyl 4-[[(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl]amino]-3-methoxybenzoate as a light yellow solid. LCMS (ES, m/z) 336 [M+H]+
Into a 500-mL round-bottom flask, was placed methyl 5-[[(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl]amino]-4-methoxypyridine-2-carboxylate (25 g, 74.34 mmol, 1.00 equip), and (Ph)2O (200 mL). The resulting solution was stirred for 1 h at 200° C. The reaction mixture was cooled with a water/ice bath. The solids were collected by filtration to yield methyl 8-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxylate as a yellow solid. LCMS (ES, m/z) 234 [M+H]+
Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed methyl 8-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxylate (14 g, 60.03 mmol, 1.00 equip), and N,N-dimethylformamide (200 mL). To the resulting mixture was then added PBr3 (17.8 g, 65.76 mmol, 1.10 equip) dropwise with stirring. The resulting solution was stirred for 3 h at 25° C. The reaction was then quenched by the addition of water (1000 mL). The pH value of the solution was adjusted to 8-9 with sodium bicarbonate. The solids were collected by filtration to yield methyl 4-bromo-8-methoxyquinoline-6-carboxylate as a yellow solid. LCMS (ES, m/z) 296 [M+H]+
Into a 1000-mL 3-necked round-bottom flask, was placed methyl 4-bromo-8-methoxyquinoline-6-carboxylate (13 g, 43.90 mmol, 1.00 equip), tetrahydrofuran (500 mL), and (4-chlorophenyl)magnesium bromide (220 mL, 5.00 equip). The resulting solution was stirred for 3 hr at reflux temperature. The reaction was then quenched by the addition of water (400 mL). The resulting solution was extracted with ethyl acetate (3×300 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:1) to yield (4-bromo-8-methoxyquinolin-6-yl)bis(4-chlorophenyl)methanol as a yellow solid. LCMS (ES, m/z) 490 [M+H]+
Into a 500-mL 3-necked round-bottom flask, was placed (4-bromo-8-methoxyquinolin-6-yl)bis(4-chlorophenyl)methanol (6 g, 12.27 mmol, 1.00 equip), dichloromethane (200 mL), triethylsilane (8 mL), and trifluoroacetic acid (24 mL). The resulting solution was stirred overnight at 25° C. The resulting solution was diluted with DCM (100 mL). The resulting mixture was washed with saturated sodium bicarbonate (3×100 mL) and dried over anhydrous sodium sulfate. The solids were filtered out. The residue was applied onto a silica gel column with ethyl acetate:petroleum ether (1:1) to yield 6-[bis(4-chlorophenyl)methyl]-4-bromo-8-methoxyquinoline as a yellow solid. LCMS (ES, m/z) 474 [M+H]+
Into a 25-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-[bis(4-chlorophenyl)methyl]-4-bromo-8-methoxyquinoline (500 mg, 1.06 mmol, 1.00 equip), 1-(trifluoromethane)sulfonylpiperidin-4-amine hydrochloride (425 mg, 1.58 mmol, 1.50 equip), Pd2(dba)3 (55 mg, 0.05 mmol, 0.05 equip), dppf (100 mg, 0.18 mmol, 0.17 equip), Cs2CO3(1000 mg, 3.07 mmol, 3.00 equip), and 1,4-dioxane (10 mL). The resulting solution was stirred overnight at 80° C. The resulting solution was diluted with ethyl acetate (100 mL). The organic layer was washed with water (3×50 mL) and dried over anhydrous sodium sulfate. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (5:1) to yield 6-[bis(4-chlorophenyl)methyl]-8-methoxy-N-[1-(trifluoromethane)sulfonylpiperidin-4-yl]quinolin-4-amine as a yellow solid.
LCMS (ES, m/z) 624 [M+H]+; 1H-NMR (300 MHz, DMSO-D6) δ: 8.336 (d, J=5.4 Hz, 1H), 7.715 (s, 1H), 7.393 (d, J=8.4 HZ, 4H), 7.216 (d, J=8.4 HZ, 4H), 6.801 (s, 1H), 6.758 (d, J=7.8 Hz, 1H), 6.637 (d, J=5.7 Hz, 1H), 5.693 (s, 1H), 3.897-3.853 (m, 3H), 3.772 (s, 3H), 3.435-3.321 (m, 2H), 2.111-2.073 (m, 2H), 1.705-1.655 (m, 2H), 1.301-1.274 (m, 2H).
Into a 250-mL round-bottom flask, was placed 6-[bis(4-chlorophenyl)methyl]-8-methoxy-N-[1-(trifluoromethane)sulfonylpiperidin-4-yl]quinolin-4-amine (1 g, 1.60 mmol, 1.00 equip), and dichloromethane (100 mL). To the resulting mixture was then added BBr3 (1.6 g, 6.40 mmol, 4.00 equip) dropwise with stirring at −78° C. The resulting solution was stirred overnight at 25° C. The reaction was then quenched by the addition of water (100 mL). The resulting mixture was concentrated under vacuum. The solids were collected by filtration. The residue was applied onto a silica gel column with dichloromethane:CH3OH (10:1) to yield 6-[bis(4-chlorophenyl)methyl]-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]quinolin-8-ol as a yellow solid.
LCMS (ES, m/z) 610 [M+H]+;
Into a 25-mL round-bottom flask, was placed 6-[bis(4-chlorophenyl)methyl]-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]quinolin-8-ol (200 mg, 0.33 mmol, 1.00 equip), N,N-dimethylformamide (10 mL), Cs2CO3 (320 mg, 0.98 mmol, 3.00 equip), and 2-(4-bromobutyl)-2,3-dihydro-1H-isoindole-1,3-dione (140 mg, 0.50 mmol, 1.10 equip). The resulting solution was stirred overnight at 60° C. The reaction was then quenched by the addition of water (100 mL). The solids were collected by filtration to yield 2-[4-([6-[bis(4-chlorophenyl)methyl]-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]quinolin-8-yl]oxy)butyl]-2,3-dihydro-1H-isoindole-1,3-dione as a yellow solid. LCMS (ES, m/z) 811 [M+H]+
Into a 100-mL round-bottom flask, was placed 2-[4-([6-[bis(4-chlorophenyl)methyl]-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]quinolin-8-yl]oxy)butyl]-2,3-dihydro-1H-isoindole-1,3-dione (200 mg, 0.25 mmol, 1.00 equip), ethanol (20 mL), and H2N—NH2 (0.2 mL). The resulting solution was stirred overnight at 60° C. The resulting mixture was concentrated under vacuum. The resulting residue was purified by Prep-HPLC with the following conditions (waters2767-5): Column, SunFire Prep C18, 19×150 mm 5 umH; mobile phase, Phase A: water with 0.05% CF3COOH Phase B: CH3CN (35% CH3CN up to 70% for 12 min, hold 95% for 1 min, down to 35% in 1 min, hold 35% in 1 min); Detector, UV220&254 nm to yield 8-(4-aminobutoxy)-6-[bis(4-chlorophenyl)methyl]-N-[1-(trifluoromethane)sulfonylpiperidin-4-yl]quinolin-4-amine, trifluoroacetic acid salt as a white solid.
LCMS (ES, m/z) 681 [M+H]+; 1H-NMR (300 MHz, DMSO-D6) δ: 8.401 (d, J=7.2 Hz, 1H), 8.405 (s, 1H), 7.432 (d, J=8.4 Hz, 4H), 7.250-7.222 (m, 5H), 7.085 (d, J=7.2 Hz, 1H), 5.794 (s, 1H), 4.189-4.153 (m, 3H), 3.962-3.920 (m, 2H), 3.443-3.362 (m, 2H), 2.888-2.841 (m, 2H), 2.130-2.092 (m, 2H), 1.846-1.771 (m, 6H).
Into a 25-mL round-bottom flask, was placed 8-(4-aminobutoxy)-6-[bis(4-chlorophenyl)methyl]-N-[1-(trifluoromethane)sulfonylpiperidin-4-yl]quinolin-4-amine (130 mg, 0.19 mmol, 1.00 equip), acetic acid (17 mg, 0.28 mmol, 1.50 equip), N,N-dimethylformamide (10 mL), HATU (108 mg, 0.28 mmol, 1.50 equip), and DIPEA (0.1 mL). The resulting solution was stirred overnight at 25° C. The resulting solution was diluted with water (100 mL). The solids were collected by filtration and purified by Prep-HPLC with the following conditions (waters2767-5): Column, SunFire Prep C18, 19×150 mm 5 umH; mobile phase, Phase A: water with 0.05% CF3COOH Phase: CH3CN (35% CH3CN up to 70% in 12 min, hold 95% for 1 min, down to 35% in 1 min, hold 35% for 1 min); Detector, UV220&254 nm to yield N-[4-([6-[bis(4-chlorophenyl)methyl]-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]quinolin-8-yl]oxy)butyl]acetamide, trifluoroacetic acid salt as a white solid.
LCMS (ES, m/z) 723 [M+H]+; 1H-NMR (300 MHz, DMSO-D6) δ: 8.350 (d, J=7.2 Hz, 1H), 7.973 (s, 1H), 7.427 (d, J=8.4 Hz, 4H), 7.242-7.214 (m, 5H), 7.052 (d, J=6.0 Hz, 1H), 5.785 (s, 1H), 4.185-4.163 (m, 3H), 3.947-3.878 (m, 2H), 3.428-3.345 (m, 2H), 3.125-3.079 (m, 2H), 2.136-2.094 (m, 2H), 1.818-1.759 (m, 7H), 1.601-1.552 (m, 2H).
Into a 50-mL round-bottom flask, was placed 6-[bis(4-chlorophenyl)methyl]-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]quinolin-8-ol (200 mg, 0.33 mmol, 1.00 equip), N,N-dimethylformamide (20 mL), Cs2CO3 (320 mg, 0.98 mmol, 3.00 equip), and tert-butyl N-(4-bromobutyl)carbamate (88 mg, 0.35 mmol, 1.10 equip). The resulting solution was stirred for 3 h at 60° C. The resulting solution was diluted with water (150 mL). The solids were collected by filtration. The residue was applied onto a silica gel column with dichloromethane:CH3OH (10:1) to yield tert-butyl N-[4-([6-[bis(4-chlorophenyl)methyl]-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]quinolin-8-yl]oxy)butyl]carbamate as a light brown solid.
LCMS (ES, m/z) 781 [M+H]+; 1H-NMR (400 MHz, DMSO-D6) δ: 8.364 (d, J=5.6 Hz, 1H), 7.789 (s, 1H), 7.410 (d, J=8.4 Hz, 4H), 7.211 (d, J=8.4 Hz, 4H), 7.043-6.700 (brm, 2H), 5.709 (s, 1H), 4.010-3.880 (m, 5H), 3.436-3.312 (m, 2H), 2.998-2.951 (m, 2H), 2.111-2.080 (m, 2H), 1.756-1.656 (m, 6H), 1.369 (s, 9H).
Into a 100-mL round-bottom flask, was placed 6-[bis(4-chlorophenyl)methyl]-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]quinolin-8-ol (100 mg, 0.16 mmol, 1.00 equip), N,N-dimethylformamide (20 mL), Cs2CO3 (160 mg, 0.49 mmol, 3.00 equip), and ethyl 5-bromopentanoate (38 mg, 0.18 mmol, 1.10 equip). The resulting solution was stirred for 3 h at 60° C. The resulting solution was diluted with water (150 mL). The solids were collected by filtration. The residue was applied onto a silica gel column with dichloromethane:CH3OH (10:1) to yield ethyl 5-([6-[bis(4-chlorophenyl)methyl]-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]quinolin-8-yl]oxy)pentanoate as a light yellow solid.
LCMS (ES, m/z) 738 [M+H]+; 1H-NMR (300 MHz, DMSO-D6) δ: 8.345 (d, J=5.1 Hz, 1H), 7.699 (s, 1H), 7.395 (d, J=8.4 Hz, 4H), 7.204 (d, J=8.4 Hz, 4H), 6.770 (s, 1H), 6.673-6.608 (m, 2H), 5.674 (s, 1H), 4.069-3.851 (m, 7H), 3.437-3.351 (m, 2H), 2.380-2.334 (m, 2H), 2.111-2.057 (m, 4H), 1.708-1.613 (m, 6H), 1.161 (t, J=7.2 Hz, 3H).
Into a 100-mL round-bottom flask, was placed ethyl 5-([6-[bis(4-chlorophenyl)methyl]-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]quinolin-8-yl]oxy)pentanoate (100 mg, 0.14 mmol, 1.00 equip), ethanol (20 mL), and 1M sodium hydroxide (20 mL). The resulting solution was stirred overnight at 25° C. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 3-4 with 10% HCl. The solids were collected by filtration to yield 5-([6-[bis(4-chlorophenyl)methyl]-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]quinolin-8-yl]oxy)pentanoic acid as an off-white solid.
LCMS (ES, m/z) 710 [M+H]+; 1H-NMR (300 MHz, DMSO-D6) δ: 8.340 (d, J=5.4 Hz, 1H), 7.720 (s, 1H), 7.392 (d, J=8.4 Hz, 4H), 7.203 (d, J=8.4 Hz, 4H), 6.796-6.720 (m, 2H), 6.649 (d, J=5.7 Hz, 1H), 5.682 (s, 1H), 3.995-3.857 (m, 5H), 3.554-3.351 (m, 2H), 2.340-2.265 (m, 2H), 2.113-2.078 (m, 2H), 1.741-1.570 (m, 6H).
Into a 25-mL round-bottom flask, was placed 5-([6-[bis(4-chlorophenyl)methyl]-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]quinolin-8-yl]oxy)pentanoic acid (100 mg, 0.14 mmol, 1.00 equip), NH4Cl (38 mg, 0.71 mmol, 5.00 equip), HATU (80 mg, 0.21 mmol, 1.50 equip), N,N-dimethylformamide (10 mL), and DIEA (0.5 mL). The resulting solution was stirred overnight at 25° C. The resulting solution was diluted with water (100 mL). The solids were collected by filtration. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1) to yield 5-([6-[bis(4-chlorophenyl)methyl]-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]quinolin-8-yl]oxy)pentanamide as an off-white solid.
LCMS (ES, m/z) 709 [M+H]+; 1H-NMR (300 MHz, DMSO-D6) δ: 8.342 (d, J=6.9 Hz, 1H), 7.914 (s, 1H), 7.428 (d, J=8.4 Hz, 4H), 7.230 (d, J=8.4 Hz, 4H), 7.130 (s, 1H), 6.983 (d, J=6.9 Hz, 1H), 5.767 (s, 1H), 4.121-4.103 (m, 3H), 3.948-3.845 (m, 4H), 3.429-3.345 (m, 2H), 2.188-2.097 (m, 4H), 1.803-1.680 (m, 6H).
and
A mixture of 6-(bis(4-chlorophenyl)methyl)-4-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)amino)quinolin-2(1H)-one (66.7 mg, 0.109 mmol), and 1-bromo-2-methoxyethane (0.0123 mL, 0.131 mmol) in CH3CN (2 mL) was heated at 75° C. overnight. Additional 1-bromo-2-methoxyethane (0.006 mL) was added and the reaction mixture stirred for another 24 h. The reaction mixture was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc twice. The combined organics were concentrated and purified by silica column (25% EtOAc/hexanes) to yield 6-(bis(4-chlorophenyl)methyl)-2-(2-methoxyethoxy)-N-(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)quinolin-4-amine and (80% EtOAc/hexanes) 6-(bis(4-chlorophenyl)methyl)-1-(2-methoxyethyl)-4-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)amino)quinolin-2(1H)-one.
(M+H)+: 668, 670. 1H NMR (CDCl3) δ: 7.68 (d, J=8.6 Hz, 1H), 7.29 (d, J=8.1, 4H), 7.25 (m, 2H), 7.04 (d, J=8.1 Hz, 4H), 6.02 (s, 1H), 5.64 (s, 1H), 4.56-4.67 (m, 2H), 4.46 (d, J=7.1 Hz, 1H), 4.00 (m, 2H), 3.71-3.85 (m, 2H), 3.62 (m, 1H), 3.46 (s, 3H), 3.11-3.33 (m, 2H), 2.27 (m, 2H), 1.59-1.70 (m, 2H).
To a solution of thiazole (195 mg, 2.292 mmol, 2.00 equip) in THF (10 mL) at −78° C. was added n-butyllithium (1.6 M in hexanes, 1.447 mL, 2.315 mmol, 2.02 equip) dropwise. After 30 minutes, a solution of 6-(4-chlorobenzoyl)-4-(3-chlorophenethyl)-1-methylquinolin-2(1H)-one (500 mg, 1.146 mmol, 1 equip, prepared as described in ANGIBAUD, P. R., et al., PCT Publication WO2002/051835 A1, published 4 Jul. 2002) in HMPA (8 mL) was added dropwise and the reaction mixture was warmed to room temperature. The reaction was stirred overnight, then quenched with water and the resulting mixture extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated. The residue was purified by MPLC using methanol-dichloromethane as the eluent to yield 4-(3-chlorophenethyl)-6-((4-chlorophenyl)(hydroxy)(thiazol-2-yl)methyl)-1-methylquinolin-2(1H)-one as a tan solid.
To a solution of tin(II) chloride dihydrate (268 mg, 1.189 mmol, 4 equip) and concentrated HCl (0.373 ml) in AcOH (4 ml) was added 4-(3-chlorophenethyl)-6-((4-chlorophenyl)(hydroxy)(thiazol-2-yl)methyl)-1-methylquinolin-2(1H)-one (160 mg, 0.307 mmol, 1 equip). The resulting solution was heated to 110° C. for 45 minutes. The reaction was cooled to room temperature and concentrated. The residue was purified by MPLC using dichloromethane-methanol as the eluent to yield 4-(3-chlorophenethyl)-6-((4-chlorophenyl)(thiazol-2-yl)methyl)-1-methylquinolin-2(1H)-one.
1H NMR (400 MHz, d6-DMSO) δ 7.85 (2H, d), 7.70 (1H, d), 7.60-7.53 (2H, m), 7.43-7.27 (7H, m), 7.16 (1H, d), 6.56 (1H, s), 6.23 (1H, s), 3.58 (3H, s), 3.05-3.01 (2H, m), 2.87-2.83 (2H, m); ES, m/z) 505, 507 [M+H]+
To a solution of thiazole (201 mg, 2.368 mmol, 4.00 equip) in THF (10 mL) at −78° C. was added n-butyllithium (1.6 M in hexanes, 1.495 mL, 2.392 mmol, 4.04 equip) dropwise. After 30 minutes, a solution of 6-(4-chlorobenzoyl)-4-(3-chlorophenethyl)quinolin-2(1H)-one (250 mg, 0.592 mmol, 1 equip, prepared as described in ANGIBAUD, P. R., et al., PCT Publication WO2002/051835 A1, published 4 Jul. 2002) in HMPA (4 mL) was added dropwise and the reaction mixture was warmed to room temperature. The reaction was stirred overnight, then quenched with water and the resulting mixture extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated. The residue was purified by MPLC using methanol-dichloromethane as the eluent to yield 4-(3-chlorophenethyl)-6-((4-chlorophenyl)(hydroxy)(thiazol-2-yl)methyl)quinolin-2(1H)-one as a tan solid.
(ES, m/z) 507, 509 [M+H]+
To a solution of tin(II) chloride dihydrate (121 mg, 0.536 mmol, 4 equip) and concentrated HCl (0.168 ml) in AcOH (4 ml) was added 4-(3-chlorophenethyl)-6-((4-chlorophenyl)(hydroxy)(thiazol-2-yl)methyl)-1-methylquinolin-2(1H)-one (68 mg, 0.134 mmol, 1 equip). The resulting solution was heated to 110° C. for 45 minutes. The reaction was cooled to room temperature and concentrated. The residue was taken up in dichloromethane, washed with saturated NaHCO3, dried (Na2SO4), and concentrated. The residue was purified by MPLC using dichloromethane-methanol as the eluent to yield a tacky, off-white solid. The solid was triturated repeatedly with ethyl ether to yield 4-(3-chlorophenethyl)-6-((4-chlorophenyl)(thiazol-2-yl)methyl)quinolin-2(1H)-one as a white solid.
1H NMR (400 MHz, d6-DMSO) δ 7.84 (1H, d), 7.76 (1H, d), 7.69 (1H, d), 7.48-7.27 (7H, m), 7.16 (1H, d), 6.42 (1H, s), 6.16 (1H, s), 3.02-2.98 (2H, m), 2.87-2.83 (2H, m); (ES, m/z) 491, 493 [M+H]+
(E)-6-((4-chlorophenyl)(thiazol-2-yl)methyl)-4-styrylquinolin-2(1H)-one
To a solution of 4-chlorobenzylcyanide (5.909 g, 38.979 mmol, 1.1 equip) in THF (100 mL) was added potassium t-butoxide (9.941 g, 88.589 mmol, 2.5 equip) and the solution was stirred for 10 minutes. 4-Fluoronitrobenzene (5.000 g, 35.435 mmol, 1 equip) was added and the reaction mixture stirred at room temperature overnight. The resulting mixture was acidified to pH 7 with 1N HCl, ethyl acetate and water were added, and the layers were separated. The aqueous layer was extracted 1× with ethyl acetate, and the organic layers were combined, dried (Na2SO4), and concentrated. The residue was purified by MPLC using an ethyl acetate-heptane gradient to yield 2-(4-chlorophenyl)-2-(4-nitrophenyl)acetonitrile as an orange-yellow solid.
A solution of 2-(4-chlorophenyl)-2-(4-nitrophenyl)acetonitrile (1.000 g, 3.667 mmol, 1 equip) and phosphorus pentasulfide (1.63 g, 7.334 mmol, 2 equip) in EtOH (20 mL) was heated at reflux temperature for 20 h. The reaction mixture was cooled to room temperature and concentrated. The residue was triturated with hot ethyl ether to yield 2-(4-chlorophenyl)-2-(4-nitrophenyl)ethanethioamide as a yellow solid.
A solution of 2-(4-chlorophenyl)-2-(4-nitrophenyl)ethanethioamide (800 mg, 2.608 mmol, 1 equip) and bromoacetaldehyde diethyl acetal (2.055 g, 10.431 mmol, 4 equip) in acetic acid (12.09 mL) and water (0.47 mL) was heated at 100° C. for 45 minutes. The reaction mixture was poured into water and extracted with ethyl acetate (3×). The combined organic extracts were washed with water, saturated sodium bicarbonate, and then dried over Na2SO4, filtered, and concentrated. The residue was purified by MPLC using ethyl acetate-heptane as eluent to yield 2-((4-chlorophenyl)(4-nitrophenyl)methyl)thiazole as a viscous brown oil.
A solution of 2-((4-chlorophenyl)(4-nitrophenyl)methyl)thiazole (550 mg, 1.663 mmol, 1 equip) and tin(II) chloride dihydrate (2.321 g, 9.976 mmol, 6 equip) in MeOH (11 mL) and concentrated HCl (1 ml) was heated at reflux temperature until analytical HPLC showed conversion to the desired product. The reaction mixture was made basic with excess triethylamine. The resulting thick precipitate was filtered through CELITE and the filter pad washed thoroughly with methanol. The filtrate was concentrated and the residue was purified by MPLC using ethyl acetate-heptane as the eluent to yield 4-((4-chlorophenyl)(thiazol-2-yl)methyl)aniline as a white solid (250 mg, 50%). (ES, m/z) 301, 303 [M+H]+
To a suspension of 4-((4-chlorophenyl)(thiazol-2-yl)methyl)aniline (220 mg, 0.731 mmol, 1 equip) in isopropanol (6 mL) was added 2,2-dimethyl-1,3-dioxane-4,6-dione (140 mg, 0.951 mmol, 1.3 equip) and triethyl orthoformate (443 mg, 2.925 mmol, 4 equip) and the resulting mixture was heated at 100° C. for 3 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by MPLC using dichloromethane-methanol as eluent to yield 5-(((4-((4-chlorophenyl)(thiazol-2-yl)methyl)phenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione as a pale yellow foam. 1H NMR (400 MHz, d6-DMSO) δ 11.25 (1H, d), 8.55 (1H, d), 7.82 (1H, d), 7.69 (1H, d), 7.52 (2H, d), 7.38 (2H, d), 7.38-7.30 (4H, m), 6.19 (1H, s), 1.67 (6H, s).
5-(((4-((4-Chlorophenyl)(thiazol-2-yl)methyl)phenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (1.8 g, 3.957 mmol) was added as a solid portionwise over 3-4 minutes to DOWTHERM (75 mL) at 220° C. The resulting mixture was heated for 20 minutes, cooled to room temperature, and treated with excess heptane (30 mL) with stirring. After allowing the solid to settle, the supernatant was decanted and the process repeated 3 times. After concentrating to remove heptane, the residue was purified by MPLC using a dichloromethane-methanol gradient to yield 6-((4-chlorophenyl)(thiazol-2-yl)methyl)quinolin-4-ol. (ES, m/z) 352, 354 [M+H]+
6-((4-chlorophenyl)(thiazol-2-yl)methyl)quinolin-4-ol (500 mg, 1.417 mmol, 1 equip) was dissolved in DMF (4 mL) and phosphorus tribromide (766 mg, 2.834 mmol, 2 equip) was added dropwise. A red-brown precipitate formed immediately and was collected to yield 2-((4-bromoquinolin-6-yl)(4-chlorophenyl)methyl)thiazole which was used in the next step without purification.
A solution of 2-((4-bromoquinolin-6-yl)(4-chlorophenyl)methyl)thiazole (900 mg, 2.165 mmol, 1 equip) and meta-chloroperoxybenzoic acid (578 mg, 3.247 mmol, 1.5 equip) in dichloromethane (30 mL) was stirred at room temperature for 1 h, at which point additional meta-chloroperoxybenzoic acid (578 mg, 3.247 mmol, 1.5 equip) was added and the solution stirred for an additional 3 h. The reaction mixture was washed with 10% Na2CO3 and the aqueous layer extracted with dichloromethane (2×). The combined organic extracts were washed with water, dried over Na2SO4, and concentrated to yield 4-bromo-6-((4-chlorophenyl)(thiazol-2-yl)methyl)quinoline 1-oxide as a pale yellow semi-solid.
p-Toluenesulfonyl chloride (628 mg, 3.293 mmol, 1.5 equip) was added to a biphasic mixture of 4-bromo-6-((4-chlorophenyl)(thiazol-2-yl)methyl)quinoline 1-oxide in dichloromethane (6 mL) and 10% Na2CO3 (42 mL) and the resulting mixture stirred for 1 h. The reaction mixture was diluted with dichloromethane and water, the layers were separated, and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by MPLC to yield 4-bromo-6-((4-chlorophenyl)(thiazol-2-yl)methyl)quinolin-2(1H)-one as a white solid.
4-Bromo-6-((4-chlorophenyl)(thiazol-2-yl)methyl)quinolin-2(1H)-one (50 mg, 0.116 mol, 1 equip), trans-beta-styreneboronic acid (35 mg, 0.232 mmol, 2 equip), SPhos (9.7 mg, 0.023 mmol, 0.2 equip), tripotassium phosphate (49.2 mg, 0.232 mmol, 2 equip), and palladium acetate (2.6 mg, 0.012 mmol, 0.1 equip) were added to 1,4-dioxane (5 mL) and the resulting mixture stirred for 2 h. Additional trans-beta-styreneboronic acid (35 mg, 0.232 mmol, 2 equip), SPhos (9.7 mg, 0.023 mmol, 0.2 equip), tripotassium phosphate (49.2 mg, 0.232 mmol, 2 equip), and palladium acetate (2.6 mg, 0.012 mmol, 0.1 equip) were added and the resulting mixture was stirred overnight. The reaction mixture was diluted with water and ethyl acetate and the layers were separated. The organic phase was washed with saturated sodium bicarbonate, then water, dried over Na2SO4, filtered and concentrated. The residue was purified by MPLC using a dichloromethane-methanol gradient to yield (E)-6-((4-chlorophenyl)(thiazol-2-yl)methyl)-4-styrylquinolin-2(1H)-one.
1H NMR (400 MHz, d6-DMSO) δ 8.10 (1H, d), 7.83 (1H, d), 7.74-7.60 (4H, m), 7.52-7.32 (10H, m), 6.80 (1H, s), 6.15 (1H, s); (ES, m/z) 455, 457 [M+H]+
4-Bromo-6-((4-chlorophenyl)(thiazol-2-yl)methyl)quinolin-2(1H)-one (80 mg, 0.185 mol, 1 equip), trans-2-[4-(trifluoromethyl)phenyl]vinylboronic acid (80 mg, 0.371 mmol, 2 equip), SPhos (15.5 mg, 0.037 mmol, 0.2 equip), tripotassium phosphate (78.7 mg, 0.371 mmol, 2 equip), and palladium acetate (4.2 mg, 0.019 mmol, 0.1 equip) were added to 1,4-dioxane (5 mL) and the resulting mixture stirred for 2 h. Additional trans-2-[4-(trifluoromethyl)phenyl]vinylboronic acid (80 mg, 0.371 mmol, 2 equip), SPhos (15.5 mg, 0.037 mmol, 0.2 equip), tripotassium phosphate (78.7 mg, 0.371 mmol, 2 equip), and palladium acetate (4.2 mg, 0.019 mmol, 0.1 equip) were added and the resulting mixture was stirred overnight. The reaction mixture was diluted with water and ethyl acetate and the layers were separated. The organic phase was washed with saturated sodium bicarbonate, then water, dried over Na2SO4, filtered and concentrated. The residue was purified by RP-HPLC to yield (E)-6-((4-chlorophenyl)(thiazol-2-yl)methyl)-4-(4-(trifluoromethyl)styryl)quinolin-2(1H)-one.
1H NMR (600 MHz, d6-DMSO) δ 7.98 (1H, d), 7.86 (2H, d), 7.77-7.70 (4H, m), 7.59 (1H, d), 7.50 (1H, d), 7.40-7.35 (4H, m), 7.32 (2H, d), 6.80 (1H, s), 6.10 (1H, s); (ES, m/z) 522, 524 [M+H]+
4-Bromo-6-((4-chlorophenyl)(thiazol-2-yl)methyl)quinolin-2(1H)-one (80 mg, 0.185 mol, 1 equip), trans-2-(3-fluorophenyl)vinylboronic acid (61.5 mg, 0.371 mmol, 2 equip), SPhos (15.5 mg, 0.037 mmol, 0.2 equip), tripotassium phosphate (78.7 mg, 0.371 mmol, 2 equip), and palladium acetate (4.2 mg, 0.019 mmol, 0.1 equip) were added to 1,4-dioxane (5 mL) and the resulting mixture stirred for 72 h. The reaction mixture was diluted with water and ethyl acetate and the layers were separated. The organic phase was washed with saturated sodium bicarbonate, then water, dried over Na2SO4, filtered and concentrated. The residue was purified by RP-HPLC and the fractions were lyophilized. The lyophilized product was washed with hot hexanes to remove residual SPhos, filtered, and dried under vacuum to yield (E)-6-((4-chlorophenyl)(thiazol-2-yl)methyl)-4-(3-fluorostyryl)quinolin-2(1H)-one as an off-white solid.
1H NMR (400 MHz, d6-DMSO) δ 8.15 (1H, d), 7.80 (1H, d), 7.74-7.62 (3H, m), 7.56-7.32 (9H, m), 7.21 (1H, m), 6.80 (1H, s), 6.12 (1H, s); (ES, m/z) 473, 475 [M+H]+
A mixture of 2-((4-bromoquinolin-6-yl)(4-chlorophenyl)methyl)thiazole (28 mg, 0.0674 mmol), (E)-styrylboronic acid (19.9 mg, 0.135 mmol), Pd(OAc)2 (1.5 mg, 0.00674 mmol), SPhos (5.5 mg, 0.022 mmol) and K3PO4 (28.6 mg, 0.135 mmol) was stirred at room temperature overnight under argon. The reaction was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc twice. The organic layers combined were concentrated and the crude material was purified by silica column chromatography (25% EtOAc/hexanes) to yield (E)-2-((4-chlorophenyl)(4-styrylquinolin-6-yl)methyl)thiazole.
(M+H)+: 439, 440, 442.
A solution of Meldtrum's acid (0.467 g, 3.24 mmol) and triethylorthoformate (2 mL) was heated in a sealed tube to 145° C. After 1 h, the solution was allowed to cool to 50° C. and (4-aminophenyl)(4-chlorophenyl)methanone in (0.5 g, 2.16 mmol) was added at once. The reaction mixture was heated to 145° C. for 2 hr, and then cooled to room temperature. The white precipitates were filtered and washed with hexanes to yield 5-(((4-(4-chlorobenzoyl)phenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione. (M+Na)+: 408.
To a flask with DOWTHERM at 245° C. was added 5-(((4-(4-chlorobenzoyl)phenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (3.3 g, 8.55 mmol) in portions. The resulting solution was heated for 10 min and cooled down to room temperature. Solids were precipitated from the solution. To the reaction mixture was added hexanes and the solids filtered. The solids were washed thoroughly with Et2O and hexanes and dried under vacuum to yield 6-(4-chlorobenzoyl)quinolin-4(1H)-one. (M+H)+: 284, 286.
To a suspension of 6-(4-chlorobenzoyl)quinolin-4(1H)-one (1.26 g, 4.45 mmol) in DMF (8 mL) at room temperature was added slowly phosphorous tribromide. The resulting mixture was stirred under argon for 30 min. The reaction mixture was made basic by the addition of solid NaHCO3 until pH was greater than 10, diluted with water and filtered. The product was washed with several portion of water and dried to yield (4-bromoquinolin-6-yl)(4-chlorophenyl)methanone. (M+H)+: 346, 348.
To a solution of (4-bromoquinolin-6-yl)(4-chlorophenyl)methanone (0.25 g, 0.72 mmol) in THF (5 mL) was slowly added (4-chlorophenyl)magnesium bromide (1.08 mL, 1 M in THF) at 0° C. under the argon. The resulting solution was kept at 0° C. for 3 hr. The reaction was quenched with saturated NH4Cl at 0° C. and the aqueous mixture was extracted with EtOAc 2 times. The combined organics were concentrated and purified by silica column chromatography (20-30% EtOAc/hexanes) to yield (4-bromoquinolin-6-yl)bis(4-chlorophenyl)methanol. (M+H)+: 458, 460.
A mixture of (4-bromoquinolin-6-yl)bis(4-chlorophenyl)methanol (50 mg, 0.109 mmol), (E)-styrylboronic acid (25.8 mg, 0.17 mmol), Pd(OAc)2 (2.44 mg, 0.0109 mmol), SPhos (8.9 mg, 0.022 mmol) and K3PO4 (46 mg, 0.218 mmol) was warmed to 30° C. for 7 hr under argon and then stirred at room temperature overnight. The reaction was quenched with water. The solids were filtered. The aqueous layer was extracted with EtOAc twice. The organic layers and solids (which were dissolved in EtOAc) together were concentrated and the crude material was purified by silica column chromatography (35% EtOAc/hexanes) to yield (E)-bis(4-chlorophenyl)(4-styrylquinolin-6-yl)methanol. (M+H)+: 482, 484.
To a suspension of (E)-bis(4-chlorophenyl)(4-styrylquinolin-6-yl)methanol (18 mg, 0.0373 mmol) and triethylsilane (0.0238 mL, 0.149 mmol) in CH2Cl2 (1 mL) at −78° C. was dropwise added titanium chloride (0.0102 mL, 0.0933 mmol). The resulting mixture was warmed to 0° C. for 20 min. To the reaction was slowly added aq. NaHCO3, ice at 0° C. and CH2Cl2. 1N NaOH was added until the aqueous solution was basic. The aqueous layer was extracted with CH2Cl2 twice. The organics were concentrated and purified by silica column chromatography (20-25% EtOAc/hexanes). The product was found to contain ˜7% cis-isomer based on NMR. The resulting mixture was recrystallized from EtOAc/hexanes to remove the Cis isomer.
(M+H)+: 466, 468
A mixture of 2-((4-bromoquinolin-6-yl)(4-chlorophenyl)methyl)thiazole (28 mg, 0.0674 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (37.5 mg, 0.121 mmol), Pd(dppf)Cl2.CH2Cl2 (5.5 mg, 0.00674), Na2CO3 (14.3 mg, 0.135 mmol) in 1,4-dioxane (0.8 mL) and water (0.4 mL) was heated at 95° C. for 5 hr under argon. The reaction was cooled to room temperature and diluted with EtOAc and water. The aqueous layer was extracted with EtOAc once. The combined organics were concentrated and purified by silica column chromatography (50% EtOAc/hexanes) to yield tert-butyl 4-(6-((4-chlorophenyl)(thiazol-2-yl)methyl)quinolin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate.
(M+H)+: 518, 519, 520
A mixture of (4-bromo-2-(tert-butoxy)quinolin-6-yl)(4-chlorophenyl)(thiazol-2-yl)methanol (79 mg, 0.157 mmol) and 4,4,5,5-tetramethyl-2-(4-(trifluoromethoxy)benzyl)-1,3,2-dioxaborolane (80.5 mg, 0.267 mmol) in the presence of Pd(dppf)Cl2.CH2Cl2 (512 mg, 0.0157 mmol), Na2CO3 (33 mg, 0.314 mmol) in 1,4-dioxane (1 mL) and water (0.25 mL) was heated at 80° C. overnight. The reaction was diluted with EtOAc and water. The organics were concentrated and purified by silica column (80% EtOAc/hexanes) chromatography to yield (2-(tert-butoxy)-4-(4-(trifluoromethoxy)benzyl)quinolin-6-yl)(4-chlorophenyl)(thiazol-2-yl)methanol.
(M−But)+: 543, 546; (M+H)+: 599, 601.
(2-(tert-Butoxy)-4-(4-(trifluoromethoxy)benzyl)quinolin-6-yl)(4-chlorophenyl)(thiazol-2-yl)methanol (55 mg, 0.0918 mmol) and tin(II) chloride dihydrate (83 mg, 0.367 mmol) were combined in AcOH (2 mL). HCl (conc. 36%, 0.115 mL) was then added. The solution was heated to 110° C. After 45 min the reaction was cooled to room temperature and concentrated. The residue was taken up in CH2Cl2 and washed with NaHCO3 (satd), dried (Na2SO4) and concentrated. The resulting residue was purified by silica column (70-80% EtOAc/hexanes) chromatography to yield 6-((4-chlorophenyl)(thiazol-2-yl)methyl)-4-(4-(trifluoromethoxy)benzyl)quinolin-2(1H)-one.
(M+H)+: 527, 528, 530
To a mixture of 4-bromoquinoline-6-carboxylic acid (5 g), CH3ONH(CH3) hydrochloride salt (1.8 eq. 3.5 g), and HATU (1.15 eq. 8.67 g) in CH2Cl2 (100 mL) was slowly added triethylamine (4 eq. 11 mL) at 0° C. and the resulting reaction mixture was stirred at room temperature overnight. The reaction was diluted with CH2Cl2 and water. The combined organics were washed with water several times, concentrated and then purified by chromatography (60-70% EtOAc/hexanes) to yield 4-bromo-N-methoxy-N-methylquinoline-6-carboxamide as a white solid.
A mixture of 4-bromo-N-methoxy-N-methylquinoline-6-carboxamide (155 mg, 0.525 mmol), (E)-styrylboronic acid (155 mg, 1.05 mmol), Pd(OAc)2 (11.8 mg, 0.053 mmol), SPhos (43 mg, 0.105 mmol) and K3PO4.H2O (334 mg, 1.58 mmol) in anhydrous THF (5 mL) was heated at 35° C. overnight. The reaction was diluted with DCM and water. The organics were washed with water and concentrated. The resulting residue was purified by silica column chromatography (40-55% EtOAc/hexanes) to yield (E)-N-methoxy-N-methyl-4-styrylquinoline-6-carboxamide. (ES, m/z) 319.0 [M+H]+
To a solution of (E)-N-methoxy-N-methyl-4-styrylquinoline-6-carboxamide (150 mg, 0.47 mmol) in anhydrous THF (2 mL) was dropwise added dropwise (4-chlorophenyl)magnesium bromide (0.5 M, 1.23 mL, 0.61 mmol) at 0° C. under N2 and the resulting reaction mixture was stirred at 0° C. for 3 hr. The reaction was diluted with CH2Cl2 and water. The aqueous layer was extracted with CH2Cl2 and the combined organics were concentrated and purified by chromatography (15-20% EtOAc/hexanes) to yield (E)-(4-methoxyphenyl)(4-styrylquinolin-6-yl)methanone. (ES, m/z) 366.0 [M+H]+
To a solution of thiazole (0.021 mL, 0.288 mmol) in anhydrous THF (1.5 mL) was added dropwise n-BuLi (1.6M in hexane, 0.18 mmol) at −78° C. under the argon. The resulting yellow mixture was stirred at this temperature for 30 min and then a solution of (E)-(4-methoxyphenyl)(4-styrylquinolin-6-yl)methanone (52.7 mg, 0.144 mmol) in THF (0.5 mL) was added dropwise.
The reaction was slowly warmed to room temperature and continuously stirred for 1.5 hr. The reaction was quenched with saturated NH4Cl2 and extracted with CH2Cl2. The combined organics were concentrated and purified by chromatography (60% EtOAc/hexanes) to yield (E)-(4-methoxyphenyl)(4-styrylquinolin-6-yl)(thiazol-2-yl)methanol as a white solid.
(ES, m/z) 451.0 [M+H]+
To a solution of (E)-(4-methoxyphenyl)(4-styrylquinolin-6-yl)(thiazol-2-yl)methanol (33 mg, 0.0732 mmol) and triethylsilane (0.035 mL, 0.22 mmol) in CH2Cl2 (2 mL) at −78° C. was added dropwise TiCl4 (0.22 mL, 0.22 mmol). The resulting mixture (turned to dark green suspension) was kept at −78° C. for 20 min and then warmed to 0° C. The reaction was maintained at 0° C. for 1 hr and then quenched with ice, CH2Cl2 and aqueous NaOH until the aqueous layer became basic. The aqueous layer was extracted with CH2Cl2 twice. The combined organics were concentrated and purified by chromatography (silica column, 25% EtOAc/CH2Cl2) to yield (E)-2-((4-methoxyphenyl)(4-styrylquinolin-6-yl)methyl)thiazole.
(ES, m/z) 435.0, 437.1 [M+H]+
A mixture of (4-bromo-2-(tert-butoxy)quinolin-6-yl)(4-chlorophenyl)(4-methoxyphenyl)methanol (107 mg, 0.203 mmol), (E)-styrylboronic acid (60 mg, 0.406 mmol), Pd(OAc)2 (4.56 mg, 0.0203 mmol), SPhos (16.7 mg, 0.0406 mmol) and K3PO4.H2O (86.2 mg, 0.406 mmol) in anhydrous THF (1 mL) was heated at 35° C. overnight. The reaction was diluted with DCM and water. The organics were washed with water and concentrated. The crude material was purified by silica column (40-55% EtOAc/hexanes) to yield (E)-(2-(tert-butoxy)-4-styrylquinolin-6-yl)(4-chlorophenyl)(4-methoxyphenyl)methanol.
(ES, m/z) 550, 551 [M+H]+ ; 494, 495 (M−But)+.
To a solution of (E)-(4-methoxyphenyl)(4-styrylquinolin-6-yl)(thiazol-2-yl)methanol (50 mg, 0.0909 mmol) and triethylsilane (0.029 mL, 0.182 mmol) in CH2Cl2 (2 mL) at −78° C. was added dropwise TiCl4 (0.27 mL, 0.273 mmol). The resulting mixture (turned to dark green suspension) was kept at −78° C. for 20 min and then warmed to 0° C. The reaction was continued at 0° C. for 1 hr and then quenched with ice, CH2Cl2 and aq. NaOH until the aqueous layer became basic. The aqueous layer was extracted with CH2Cl2 twice. The combined organics were concentrated and purified by chromatography (silica column, 75% EtOAc/CH2Cl2) to yield (E)-6-((4-chlorophenyl)(4-methoxyphenyl)methyl)-4-styrylquinolin-2(1H)-one.
(ES, m/z) 478.0, 480.1 [M+H]+
To a solution of tert-butyl 4-(6-(bis(4-chlorophenyl)methyl)-2-oxo-1,2-dihydroquinolin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate (80 mg, 0.142 mmol) in DCM (1 mL) was added TFA (0.35 mL) and the resulting mixture was stirred at room temperature for 2 hr. The reaction was concentrated and dried under the high vacuum to yield 6-(bis(4-chlorophenyl)methyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)quinolin-2(1H)-one, which was used in the next step without further purification. (ES, m/z) 461, 463 [M+H]+
To a solution of 6-(bis(4-chlorophenyl)methyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)quinolin-2 (1H)-one (41 mg, 0.0713 mmol) in CH2Cl2 (1 mL) was added TEA (0.06 mL, 0.428 mmol) at 0° C. under argon followed by addition of trifluoroacetic anhydride (0.093 mL, 0.093 mmol, 1M in CH2Cl2 solution). The reaction mixture was stirred for 3 hr at room temperature. A saturated NaHCO3 solution was added and the resulting mixture was stirred for 2 min. The organics were concentrated and purified (65% EtOAc/hexanes) to yield 6-(bis(4-chlorophenyl)methyl)-4-(1-(2,2,2-trifluoroacetyl)-1,2,3,6-tetrahydropyridin-4-yl)quinolin-2(1H)-one.
(ES, m/z) 557, 559 [M+H]+
and
A mixture of 6-(bis(4-chlorophenyl)methyl)-4-(1-(2,2,2-trifluoroacetyl)-1,2,3,6-tetrahydropyridin-4-yl)quinolin-2(1H)-one (23 mg, 0.041 mmol), Na2CO3 (22.8 mg, 0.165 mmol) in THF (0.8 mL), MeOH (0.5 mL) and a couple of drops of water was stirred at 30° C. for 3 hr. The solvent was evaporated and to the residue was added DCM and water. The organics were dried over anhydrous Na2SO4, filtered and concentrated to yield 6-(bis(4-chlorophenyl)methyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)quinolin-2(1H)-one. (ES, m/z) [M+H]+ 461.1, 463.0.
To a solution of 6-(bis(4-chlorophenyl)methyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)quinolin-2(1H)-one (15.4 mg, 0.033 mmol) in CH2Cl2 90.8 mL) was added TEA (0.0139 mL, 0.1 mmol) at 0° C. under Argon followed by triflic anhydride (0.0434 mL, 0.0434 mmol, 1 M in CH2Cl2). The reaction mixture was stirred for 3 hr at room temperature. A saturated NaHCO3 solution was added and the resulting mixture was stirred for 2 min. The organics were concentrated and purified by silica gel chromatography (eluent of 30% EtOAc/hexanes) to yield 6-(bis(4-chlorophenyl)methyl)-4-(1-((trifluoromethyl)sulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)quinolin-2-yl trifluoromethanesulfonate
1H NMR (CDCl3) δ: 8.01 (d, J=8.8 Hz, 1H), 7.60 (dd, J=8.8, 2.0 Hz, 1H), 7.27-7.38 (m, 5H), 6.96-7.07 (m, 5H), 5.75-5.83 (m, 1H), 5.69 (s, 1H), 4.01-4.29 (m, 2H), 3.62 (m, 2H), 2.49 (m, 2H)
followed by 75% EtOAc/hexanes to yield 6-(bis(4-chlorophenyl)methyl)-4-(1-((trifluoromethyl)sulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)quinolin-2(1H)-one.
(ES, m/z) [M+H]+ 595, 597; 1H NMR (CDCl3) d: 11.55 (br. s., 1H), 7.27-7.39 (m, 6H), 6.94-7.07 (m, 5H), 6.48 (s, 1H), 5.73 (m, 1H), 5.55 (s, 1H), 3.95-4.24 (m, 2H), 3.57 (m, 2H), 2.40 (m, 2H);
and
To a mixture of thiazole-4-carboxylic acid (1 g, 7.74 mmol), N,O-dimethylhydroxylamine (1.51 g, 15.5 mmol), and HATU (3.83 g, 10.07 mmol) in CH2Cl2 (25 mL) was added TEA (4.84 mL, 34.85 mmol). The reaction was stirred at room temperature overnight. The reaction was diluted with CH2Cl2 and water. The organics were concentrated and purified by chromatography (60-70% EtOAc/hexanes) to yield N-methoxy-N-methylthiazole-4-carboxamide as a clear oil. 1H NMR (CDCl3) δ: 8.83 (s, 1H), 8.10 (s, 1H), 3.79 (s, 3H), 3.46 (s, 3H)
To a solution of 6-bromo-4-chloroquinoline (0.459 g, 1.89 mmol) in THF (8 mL) was added n-BuLi (1.12 mL, 1.80 mmol, 1.6M in hexane) at −78° C. under argon and the resulting mixture was stirred for 2 hr. A solution of N-methoxy-N-methylthiazole-4-carboxamide (0.39 g, 2.27 mmol) in THF (2 mL) was added and the resulting mixture was allowed to warm to room temperature and stirred at room temperature for 2 hr. The reaction mixture was quenched with ice and saturated NH4Cl. The aqueous layer was extracted with CH2Cl2. The combined organics were concentrated and purified by column chromatography (40-50% EtOAc/hexanes) to yield (4-chloroquinolin-6-yl)(thiazol-4-yl)methanone. (ES, m/z) [M+H]+ 275, 277.
To a solution of (4-chloroquinolin-6-yl)(thiazol-4-yl)methanone (52 mg, 0.189 mmol) in THF (2 mL) was slowly added (4-chlorophenyl)magnesium bromide (0.246 mL, 0.246 mmol, 1M in THF) and the resulting solution was kept at 0° C. for 2 hr. The reaction was quenched with saturated NH4Cl at 0° C. and the aqueous mixture was extracted with EtOAc twice. The combined organics were concentrated and purified by silica column (40% EtOAc/hexanes) chromatography to yield (4-chlorophenyl)(4-chloroquinolin-6-yl)(thiazol-4-yl)methanol. (ES, m/z) [M+H]+ 387, 389.
A mixture of (4-chlorophenyl)(4-chloroquinolin-6-yl)(thiazol-4-yl)methanol (65 mg, 0.168 mmol), (E)-styrylboronic acid (39.74 mg, 0.269 mmol), Pd(OAc)2 (3.77 mg, 0.0168 mmol), SPhos (13.8 mg, 0.0336 mmol), and K3PO4.H2O (71.25 mg, 0.336 mmol) in anhydrous THF (1.5 mL) was stirred at 30° C. overnight. The reaction was diluted with EtOAc and water. The organics were concentrated and purified by REDSEP GOLD silica column (40% EtOAc/heptanes) to yield (Z)-(4-chlorophenyl)(4-styrylquinolin-6-yl)(thiazol-4-yl)methanol
(ES, m/z) [M+H]+ 455, 457; 1H NMR (CDCl3) δ: 8.85-8.92 (m, 2H), 8.22 (d, J=2.2 Hz, 1H), 8.07 (d, J=8.8 Hz, 1H), 7.58-7.70 (m, 3H), 7.54 (d, J=7.1 Hz, 2H), 7.39-7.46 (m, 2H), 7.28-7.39 (m, 6H), 6.89 (d, J=2.0 Hz, 1H), 4.23 (s, 1H)
and (E)-(4-chlorophenyl)(4-styrylquinolin-6-yl)(thiazol-4-yl)methanol.
(ES, m/z) [M+H]+ 455, 457; 1H NMR (CDCl3) δ: 8.84-8.90 (m, 2H), 8.21 (d, J=2.0 Hz, 1H), 8.06 (d, J=8.8 Hz, 1H), 7.56-7.68 (m, 3H), 7.49-7.56 (m, 2H), 7.41 (t, J=7.5 Hz, 2H), 7.28-7.37 (m, 5H), 7.23-7.27 (m, 1H), 6.90 (d, J=2.0 Hz, 1H), 4.42 (s, 1H).
A mixture of (4-bromo-2-(tert-butoxy)quinolin-6-yl)(4-chlorophenyl)methanone (157 mg, 0.375 mmol), (E)-(3-fluorostyryl)boronic acid (105.8 mg, 0.637 mmol), Pd(OAc)2 (8.42 mg, 0.0375 mmol), SPhos (30.79 mg, 0.0375 mmol), and K3PO4.H2O (159 mg, 0.75 mmol) in anhydrous THF (2.5 mL) was stirred at 30° C. overnight. The reaction was diluted with EtOAc and water. The organics were concentrated and purified by silica column chromatography (20% EtOAc/heptanes) to yield (E)-(2-(tert-butoxy)-4-styrylquinolin-6-yl)(4-chlorophenyl)methanone. (ES, m/z) [M-tBu]+ 404, 405, 407
To a solution of (E)-(2-(tert-butoxy)-4-(3-fluorostyryl)quinolin-6-yl)(4-chlorophenyl)methanone (90 mg, 0.196 mmol) in THF (2 mL) was slowly added thiophen-3-ylmagnesium bromide (1.04 mL, 0.313 mmol, 0.3M in toluene) and the resulting solution was kept at 0° C. for 3 hr. The reaction was quenched with saturated NH4Cl at 0° C. and the aqueous layer was extracted with EtOAc. The combined organics were purified by silica column chromatography (20-30% EtOAc/hexanes) to yield (E)-(2-(tert-butoxy)-4-(3-fluorostyryl)quinolin-6-yl)(4-chlorophenyl)(thiophen-3-yl)methanol.
(ES, m/z) [M-tBu]+ 488, 490; [M+H]+ 544, 545, 547.
Ethyl 4-((6-((4-chlorophenyl)(thiazol-2-yl)methyl)-2-oxo-1,2-dihydroquinolin-4-yl)amino)piperidine-1-carboxylate (114 mg) was dissolved in concentrated HBr solution (48%) and the resulting mixture was heated to ˜100° C. for 2 hr. The reaction mixture was cooled to room temperature and concentrated to a yellow/orange slurry. The residue was neutralized carefully with aq. NaOH (3 N). The resulting precipitates were filtered to yield 6-((4-chlorophenyl)(thiazol-2-yl)methyl)-4-(piperidin-4-ylamino)quinolin-2(1H)-one as the corresponding HBr salt as a tan solid.
(ES, m/z) [M+H]+ 451, 453. 1H NMR (CH3OD) δ: 8.05 (s, 1H), 7.80 (d, J=3.4 Hz, 1H), 7.55 (d, J=3.4 Hz, 1H), 7.18-7.43 (m, 6H), 5.97 (s, 1H), 5.59 (s, 1H), 3.50-3.67 (m, 1H), 2.98-3.19 (m, 2H), 2.66-2.83 (m, 2H), 2.07 (d, J=12.7 Hz, 2H), 1.47-1.65 (m, 2H).
A mixture of 6-(bis(4-chlorophenyl)methyl)-4,8-dibromoquinoline (50 mg, 0.0958 mmol), 1-((trifluoromethyl)sulfonyl)piperidin-4-amine (38.6 mg, 0.144 mmol), Pd2(dba)3 (8.77 mg, 0.00958 mmol), dppf (18.58 mg, 0.0335 mmol), and NaOt-Bu (23.01 mg, 0.239 mmol) in 1,4-dioxane (0.9 mL) was heated to 85° C. for 4 hr. No more starting materials remained and the reaction was cooled to room temperature and diluted with EtOAc and water. The organics were concentrated and purified by silica column chromatography (35% EtOAc/hexanes) to yield 6-(bis(4-chlorophenyl)methyl)-N4,N8-bis(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)quinoline-4,8-diamine.
(ES, m/z) [M+H]+ 824.7, 826.7.
and
To a solution of ethyl 4-((6-(bis(4-chlorophenyl)methyl)-2-oxo-4-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)amino)-1,2-dihydroquinolin-8-yl)amino)butanoate (20 mg, 0.027 mmol) in THF (1 mL) was added 1N NaOH solution (0.12 mL) and mixture was stirred at room temperature for 3.5 hr. No more starting material was observed. The reaction was concentrated and neutralized to pH=5 with 1N HCl aqueous solution. The solid was extracted with EtOAc three times. The organics were concentrated and purified by chromatography (silica gel column, 100% EtOAc to yield 6-(bis(4-chlorophenyl)methyl)-8-(2-oxopyrrolidin-1-yl)-4-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)amino)quinolin-2(1H)-one.
(ES, m/z) [M+H]+ 693, 695; 1H NMR (CDCl3) δ: 9.11 (br. s., 1H), 7.20-7.35 (m, 4H), 7.12 (s, 1H), 6.91-7.06 (m, 5H), 5.61 (s, 1H), 5.56 (s, 1H), 4.56 (d, J=6.6 Hz, 1H), 3.97 (m, 2H), 3.67 (t, J=6.6 Hz, 2H), 3.57 (m, 1H), 3.12-3.30 (m, 2H), 2.61 (t, J=7.8 Hz, 2H), 2.19-2.36 (m, 4H), 1.61 (m, 2H)
and 10% MeOH/EtOAc to yield 4-((6-(bis(4-chlorophenyl)methyl)-2-oxo-4-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)amino)-1,2-dihydroquinolin-8-yl)amino)butanoic acid.
(ES, m/z) [M+H]+ 711.2, 713; 1H NMR (DMSO-d6) δ: 10.01 (br. s., 1H), 7.37 (d, J=8.1 Hz, 4H), 7.10-7.23 (m, 5H), 6.40 (d, J=8.1 Hz, 1H), 6.31 (s, 1H), 5.51 (s, 1H), 5.47 (s, 1H), 3.83-3.86 (m, 2H), 3.70 (br. s., 1H), 3.36-3.40 (m, 2H) 2.93 (br. s., 2H), 2.24-2.38 (m, 2H), 2.04 (m, 2H), 1.69-1.82 (m, 2H), 1.60 (m, 2H)
To a mixture of 6-(bis(4-chlorophenyl)methyl)-4-(piperidin-4-ylamino)quinolin-2(1H)-one (250 mg, 0.523 mmol0, N,N′-bis-tert-butoxycarbonylthiourea (158.8 mg, 0.575 mmol) and triethylamine (0.22 mL, 1.57 mmol) in 3 mL DMF was added mercuric chloride (170.2 mg, 0.63 mmol) at 0° C. The reaction was stirred for 3 h at 0° C. and then quenched with EtOAc. The reaction was filtered through CELITE. The filtrate was washed two times with water, then dried over anhydrous Na2SO4, filtered and concentrated. The resulting residue was purified on ISCO with MeOH—CH2Cl2 and re-purified on HPLC (40-90% CH3CN (0.1% TFA)/H2O (0.1% TFA)) to yield (Z)-tert-butyl ((4-((6-(bis(4-chlorophenyl)methyl)-2-oxo-1,2-dihydroquinolin-4-yl)amino)piperidin-1-yl)((tert-butoxycarbonyl)imino)methyl)carbamate.
(ES, m/z) [M+H]+ 720, [M+Na]+ 743
(Z)-tert-butyl ((4-((6-(bis(4-chlorophenyl)methyl)-2-oxo-1,2-dihydroquinolin-4-yl)amino)piperidin-1-yl)((tert-butoxycarbonyl)imino)methyl)carbamate was combined (154 mg, 0.21 mmol) with 30% TFA in CH2Cl2 (7 mL) at room temperature and the resulting mixture was stirred for 0.5 hr. The solvent was removed and the residue was triturated with diethyl ether. The white solid was collected and purified on a Gilson (20-90% CH3CN (0.1% TFA)/H2O) (0.1% TFA)) to yield 4-((6-(bis(4-chlorophenyl)methyl)-2-oxo-1,2-dihydroquinolin-4-yl)amino)piperidine-1-carboximidamide as a white solid.
(ES m/z) [M+H]+ 521
To a 500-mL three-neck round bottom flask with stir bar, heating mantel, reflux condenser with N2 outlet, septa with N2 inlet (needle) and temperature probe was added 6-(bis(4-chlorophenyl)methyl)-4-(1-(trifluoromethylsulfonyl)piperidin-4-ylamino)quinolin-2(1H)-one (6.06 g; 9.93 mmol) and THF (120 mL). To this solution was added LAH (pellets, 1.48 g; 38.99 mmol) at room temperature and the resulting mixture was heated to reflux while stirring for 8 hr and cooled room temperature overnight. A 2nd charge of LAH (0.45 g; 11.86 mmol) was added and the resulting mixture was maintained at 60° C. for 6 hr. A 3rd charge of LAH (0.45 g; 11.86 mmol) was added and the resulting mixture was maintained at 60° C. for additional 3 h. The reaction was stopped and cooled to 0° C. with ice bath. Water (2.6 mL) (Note: highly exothermic) was added, then 15% NaOH (2.6 mL), then water (7.5 mL). The resulting mixture was stirred for 15 min and then Na2SO4 and THF was added. The reaction solution was filtered through CELITE. The filtrate was concentrated and the resulting solid residue was triturated with DCM (10 mL)/diethyl ether (25 mL) in an ice bath for 20 min to yield 6-(bis(4-chlorophenyl)methyl)-4-(piperidin-4-ylamino)quinolin-2(1H)-one as a pink solid.
To a 25-mL one-neck round bottom flask with stir bar was added 6-(bis(4-chlorophenyl)methyl)-4-(piperidin-4-ylamino)quinolin-2(1H)-one (0.1 g, 0.209 mmol), pyridine (0.02 mL; 0.247 mmol) and THF (3 mL) at 0° C. To the resulting solution was added a solution of ethyl 2-(chlorosulfonyl)acetate (43 mg; 0.23 mmol) in dichloromethane (1 mL) over 10 min. The reaction was then warmed to room temperature. The reaction was quenched with 1N HCl (10 mL) and DCM (10 mL). The aqueous layer was extracted with DCM and the organics were concentrated. The resulting residue was purified by silica gel column chromatography (0-10% MeOH/DCM) to yield ethyl 2-((4-((6-(bis(4-chlorophenyl)methyl)-2-oxo-1,2-dihydroquinolin-4-yl)amino)piperidin-1-yl)sulfonyl)acetate as an orange oil.
LCMS (ESI): 628.2 (M+H)+1H NMR (400 MHz, CDCl3): δ 1.33 (t, J=7.07 Hz, 3H), 1.70 (m, 2H), 2.01 (s, 2H), 2.21 (d, J=10.61 Hz, 2H), 3.09 (br. t., 2H), 3.46-3.63 (m, 1H), 3.86 (d, J=12.63 Hz, 2H), 3.96 (s, 2H), 4.27 (q, J=7.07 Hz, 2H), 4.55 (s, 1H), 5.56 (s, 1H), 5.65 (s, 1H), 7.01 (d, J=8.59 Hz, 4H), 7.09-7.20 (m, 2H), 7.21-7.32 (m, 5H), 10.64-10.80 (m, 1H).
To a mixture of 6-(bis(4-chlorophenyl)methyl)-4-(piperidin-4-ylamino)quinolin-2(1H)-one (0.1 g 0.209 mmol) and cesium carbonate (80 mg; 0.245 mmol) in acetone (2 mL) was added a solution of chloroacetic acid, 1,1-dimethylethyl ester (0.04 mL; 0.279 mmol) in dichloromethane (0.1 mL) by syringe. The reaction mixture was stirred at 40° C. in a sand bath for 16 h, cooled to room temperature and concentrated. The reaction was diluted with DCM and water. The organics were concentrated and purified by ISCO (0-10% MeOH/DCM) to yield tert-butyl 2-(4-((6-(bis(4-chlorophenyl)methyl)-2-oxo-1,2-dihydroquinolin-4-yl)amino)piperidin-1-yl)acetate.
LCMS: 593 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 1.47 (s, 9H) 1.59 (s, 2H) 2.03-2.16 (m, 2H) 2.26-2.43 (m, 2H) 2.84-2.99 (m, 2H) 3.14 (s, 2H) 3.35-3.50 (m, 1H) 4.42-4.54 (m, 1H) 5.57 (s, 1H) 5.65 (s, 1H) 6.96-7.11 (m, 4H) 7.20 (s, 2H) 7.24-7.34 (m, 5H) 10.27-10.40 (m, 1H)
To a solution of 6-(bis(4-chlorophenyl)methyl)-4-(piperidin-4-ylamino)quinolin-2(1H)-one (200 mg) in methanol (0.3 mL) and dichloromethane (0.3 mL) was added a solution of t-butyl acrylate (1.80 mL; 1.57 g) in methanol (0.8 mL) and dichloromethane (0.4 mL) in 1 min. The reaction was heated to 70° C. for 24 hr. The reaction was cooled to room temperature and concentrated. The resulting residue was purified by silica column (ISCO) (5% MeOH/CH2Cl2) to yield tert-butyl 3-(4-((6-(bis(4-chlorophenyl)methyl)-2-oxo-1,2-dihydroquinolin-4-yl)amino)piperidin-1-yl)propanoate.
LCMS: 606 (M+); 1H NMR (400 MHz, CDCl3) δ ppm 1.42-1.49 (m, 9H) 1.49-1.60 (m, 2H) 2.04-2.13 (m, 2H) 2.19 (br. s., 2H) 2.36-2.48 (m, 2H) 2.62-2.72 (m, 2H) 2.75-2.90 (m, 2H) 3.34-3.47 (m, 1H) 4.41-4.52 (m, 1H) 5.56 (s, 1H) 5.65 (s, 1H) 6.97-7.10 (m, 4H) 7.17 (d, J=2.02 Hz, 2H) 7.20-7.36 (m, 5H) 10.77-10.93 (m, 1H).
Into a 25-mL round-bottom flask, was placed (8-bromo-2-methoxy-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]quinolin-6-yl)bis(4-chlorophenyl)methanol (500 mg, 0.70 mmol, 1.00 equip), Pd(dppf)Cl2.CH2Cl2 (29 mg, 0.04 mmol, 0.05 equip), potassium carbonate (290 mg, 2.10 mmol, 3.00 equip), tert-butyldimethyl[(2E)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-yl]oxysilane (250 mg, 0.84 mmol, 1.20 equip), 1,4-dioxane (10 mL) and water (4 mL). The resulting solution was stirred overnight at 80° C. The reaction was then quenched by the addition of saturated sodium bicarbonate (50 mL). The resulting solution was extracted with ethyl acetate (100 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4) to yield [8-[(1E)-3-[(tert-butyldimethylsilyl)oxy]prop-1-en-1-yl]-2-methoxy-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]quinolin-6-yl]bis(4-chlorophenyl)methanol as a yellow solid. LCMS (ES, m/z) 810 [M+H]+
Into a 100-mL round-bottom flask, was placed a solution of [8-[(1E)-3-[(tert-butyldimethylsilyl)oxy]prop-1-en-1-yl]-2-methoxy-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]quinolin-6-yl]bis(4-chlorophenyl)methanol (380 mg, 0.47 mmol, 1.00 equip) in dichloromethane (30 mL). To the resulting mixture was then added 2-nitrobenzene-1-sulfonohydrazide (2.04 g, 9.39 mmol, 20.00 equip), in portions. To this was added TEA (1 mL) dropwise with stirring. The resulting solution was stirred for 5 h at room temperature. The resulting solution was diluted with DCM (100 mL). The resulting mixture was washed with water (2×50 mL). The organic phase was separated and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2) to yield (8-[3-[(tert-butyldimethylsilyl)oxy]propyl]-2-methoxy-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]quinolin-6-yl)bis(4-chlorophenyl)methanol as a yellow solid. LCMS (ES, m/z) 812 [M+H]+
Into a 100-mL round-bottom flask, was placed a solution of (8-[3-[(tert-butyldimethylsilyl)oxy]propyl]-2-methoxy-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]quinolin-6-yl)bis(4-chlorophenyl)methanol (370 mg, 0.46 mmol, 1.00 equip) in dichloromethane (30 mL). The solution was bubbled with nitrogen for 30 min to remove air. To the resulting mixture was then added Et3SiH (5.3 g, 45.58 mmol, 100.00 equip), in portions under a nitrogen atmosphere. To the resulting mixture was added trifluoroacetic acid (1 g, 8.85 mmol, 20.00 equip) dropwise with stirring at 0° C.
The resulting solution was stirred for 4 h at room temperature. The reaction was then quenched by the addition of saturated sodium bicarbonate (50 mL). The resulting solution was extracted with DCM (100 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The resulting residue was purified by Prep-TLC with ethyl acetate:petroleum ether=1:2 to yield 3-[6-[bis(4-chlorophenyl)methyl]-2-methoxy-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]quinolin-8-yl]propan-1-ol as an off-white solid.
LCMS (ES, m/z) 682 [M+H]+
Into a 100-mL round-bottom flask, was placed a solution of 6-[chloro(4-chlorophenyl)methyl]-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]-1,2-dihydroquinolin-2-one (200 mg, 0.37 mmol, 1.00 equip) in dichloromethane (30 mL). To the resulting mixture was then added thionyl dichloride (450 mg, 3.78 mmol, 10.00 equip) dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at 45° C. The reaction was then quenched by the addition of saturated sodium bicarbonate (100 mL). The resulting solution was extracted with ethyl acetate (2×100 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The resulting residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2), to yield 0.1 g (50%) of 6-[chloro(4-chlorophenyl)methyl]-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]-1,2-dihydroquinolin-2-one as a yellow solid. LCMS (ES, m/z) 534 [M+H]+
Into a 25-mL round-bottom flask, was placed a solution of 6-[chloro(4-chlorophenyl)methyl]-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]-1,2-dihydroquinolin-2-one (100 mg, 0.19 mmol, 1.00 equip) in dichloromethane (10 ml), 1-phenylpiperazine (55 mg, 0.34 mmol, 2.00 equip) and TEA (51 mg, 0.50 mmol, 3.00 equip). The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of water (30 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined. The resulting mixture was washed with water (2×30 mL) and then with brine (1×30 mL). The resulting mixture was dried over sodium sulfate and concentrated under vacuum. The resulting residue was applied onto a silica gel column with dichloromethane/methanol (20:1), to yield 30 mg (24%) of 6-[(4-chlorophenyl)(4-phenylpiperazin-1-yl)methyl]-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]-1,2-dihydroquinolin-2-one as an off-white solid.
LCMS (ES, m/z) 660 [M+H]+, H-NMR (300 MHz, DMSO) δ 10.750 (s, 1H), 7.987 (s, 1H), 7.551-7.512 (m, 3H), 7.405-7.377 (m, 2H), 7.218-7.167 (m, 3H), 6.907-6.879 (m, 2H), 6.784-6.735 (m, 1H), 6.557 (d, J=7.5 Hz, 1H), 5.461 (s, 1H), 4.317 (s, 1H), 3.907-3.864 (m, 2H), 3.745 (br, 1H), 3.450-3.316 (m, 2H), 3.220-3.155 (m, 4H), 2.448-2.350 (m, 4H), 2.190-2.088 (br, 2H), 1.700-1.623 (m, 2H)
Additional representative compounds of the present invention were similarly prepared according to the procedures as in the Examples above, selecting and substituting suitably substituted reagents as would be readily recognized by those skilled in the art. Table EX below lists the names and structures of the compounds thus prepared, along with measured physical properties as noted.
6-[(4-Chlorophenyl)(thiophen-3- yl)methyl]-4-[(E)-2-phenylethenyl]quinoline
6-[(4-Chlorophenyl)(thiophen-3- yl)methyl]-4-[(E)-2-(3- fluorophenyl)ethenyl]quinolin-2(1H)-one
6-[(4-Chlorophenyl)(thiophen-2- yl)methyl]-4-{(Z)-2-[4- (trifluoromethyl)phenyl]-ethenyl}quinolin-2(1H)-one
6-[(4-Chlorophenyl)(thiophen-2- yl)methyl]-4-{(E)-2-[4- (trifluoromethyl)phenyl]-ethenyl}quinolin-2(1H)-one
6-[(4-Chlorophenyl)(5- chlorothiophen-2-yl)methyl]- 4-{(E)-2-[4-(trifluoromethyl)phenyl]- ethenyl}quinolin-2(1H)-one
6-[(4-Chlorophenyl)(1,3- thiazol-2-yl)methyl]-4-{4- [(trifluoromethyl)sulfonyl]- piperazin-1-yl}quinolin-2(1H)-one
Ethyl 4-({6-[(4-chlorophenyl)(1,3-thiazol-2- yl)methyl]-2-oxo-1,2-dihydroquinolin-4- yl}amino)piperidine-1-carboxylate
6-[(4-Chlorophenyl)(1,3- thiazol-2-yl)methyl]-4-({(3R)- 1-[(trifluoromethyl)sulfonyl]- pyrrolidin-3-yl}amino)quinolin-2(1H)-one
6-[(4-Chlorophenyl)(4- fluorophenyl)methyl]-4-({1- [(trifluoromethyl)sulfonyl]- piperidin-4-yl}amino)quinolin-2(1H)-one
6[1,3-Benzodioxo1-5-yl(4- chlorophenyl)methyl]-4-({1- [(trifluoromethyl)sulfonyl]- piperidin-4-yl}amino)quinolin-2(1H)-one
6-[Bis(4-chlorophenyl)methyl]-4-{[4- (trifluoromethyl)benzyl]amino}-quinolin-2(1H)-one
6-{(4-Chlorophenyl)[4- (trifluoromethyl)phenyl]methyl}- 4-({1-[(trifluoromethyl)sulfonyl]- piperidin-4-yl}amino)quinolin-2(1H)-one
6-[Bis(4-chlorophenyl)methyl]-4-{[1- (methylsulfonyl)piperidin-4- yl]amino}quinolin-2(1H)-one
6-[1,3-Benzothiazol-2-yl(4- chlorophenyl)methyl]-4-({1- [(trifluoromethyl)sulfonyl]- piperidin-4-yl}amino)quinolin-2(1H)-one
6-[Bis(4-chlorophenyl)methyl]-4-{[1- (cyclopropylsulfonyl)piperidin- 4-yl]amino}quinolin-2(1H)-one
6-[Bis(4-chlorophenyl)methyl]-4-[(1- pyridin-2-ylpiperidin-4- yl)amino]quinolin-2(1H)-one
6-[Bis(4-chlorophenyl)methyl]-4-{[1- (3,3,3-trifluoropropanoyl)piperidin- 4-yl]amino}quinolin-2(1H)-one
6-[Bis(4-chlorophenyl)methyl]-4-({1- [3-(trifluoromethyl)phenyl]ethyl} amino)quinolin-2(1H)-one
6-[Bis(4-chlorophenyl)methyl]-4-{[3- (trifluoromethyl)phenyl]amino}-quinolin-2(1H)-one
6-[Bis(4-chlorophenyl)methyl]-4-[(3- chloro-4-fluorophenyl)amino]quinolin-2(1H)-one
6-[Bis(4-chlorophenyl)methyl]-4-({[5- (trifluoromethyl)pyridin-3- yl]methyl}amino)quinolin-2(1H)-one
6-[Bis(4-chlorophenyl)methyl]-4-{[1- (phenylsulfonyl)piperidin-4- yl]amino}quinolin-2(1H)-one
6-[Bis(4-chlorophenyl)methyl]-4-({1- [(3-fluorophenyl)sulfonyl]- piperidin-4-yl}amino)quinolin-2(1H)-one
6-[Bis(4-chlorophenyl)methyl]-4-[(4- chloro-3-fluorophenyl)amino]quinolin-2(1H)-one
Methyl 4-({6-[bis(4-chlorophenyl)methyl]-2-oxo- 1,2-dihydroquinolin-4-yl}amino)benzoate
6-[Bis(4-chlorophenyl)methyl]-4-{[4- (2-methoxyethoxy)phenyl]-amino}quinolin-2(1H)-one
Ethyl 3-[4-({6-[bis(4-chlorophenyl)methyl]-2-oxo- 1,2-dihydroquinolin-4- yl}amino)piperidin-1-yl]-3-oxopropanoate
Methyl 4-{[4-({6-[bis(4-chlorophenyl)methyl]-2-oxo- 1,2-dihydroquinolin-4- yl}amino)piperidin-1-yl]carbonyl}benzoate
2-({6-[Bis(4-chlorophenyl)methyl]-4-({1- [(trifluoromethyl)sulfonyl]-piperidin- 4-yl}amino)quinolin-2-yl}oxy)-N-methylacetamide
Methyl [4-({6-[bis(4-chlorophenyl)methyl]-2-oxo- 1,2-dihydroquinolin-4-yl}amino)phenyl]acetate
CB1 and CB2 receptors are Gi-coupled GPCR. Activation of CB1 and CB2 receptors results in a decrease in cAMP production. An inverse agonist of the CB1 or CB2 receptor results in the opposite effect, an increase of cAMP production. The principle of this assay is based on HTRF® technology (Homogeneous Time-Resolved Fluorescence). The method is a competitive immunoassay between native cAMP produced by cells and the cAMP labeled with the fluorophore d2. The tracer binding is quantified by a Mab anti-cAMP labeled with Eu3+TBP-NHS Cryptate (supplied as part of the assay kit). The specific signal (i.e. energy transfer) is inversely proportional to the concentration of cAMP in the standard or sample.
Preparation of Cells
Human CB1R (Cannabinoid receptor 1) was stably transfected in HEK-293 cells (DiscoveRx, cat: 93-0200C1). Human CB2R (Cannabinoid receptor 2) was stably transfected in HEK-293 cells (DiscoveRx, cat: 93-0201C1). Cell cultures were maintained in media: DMEM (Invitrogen Cat#12430-054) supplemented with 10% HI FBS (Invitrogen Cat#16140-071), 1% L-glutamine (Invitrogen Cat#25030-081), 0.2 mg/ml Hygromycin B (Invitrogen Cat#10687-010), 600 μg/mL G418 (Invitrogen Cat#10131-035), and 1X Penn/Strep (Invitrogen 15140-122). After cell expansion, aliquots were cryo-stored in media containing 5% DMSO (Pierce Cat#20684).
Plating Cells from Cryostore
One day prior to experiments media was warmed to 37° C. and the cryo-stored cells were thawed in a 37° C. water bath. The cells were then added to media (10× volume) and the mixture was centrifuged at 1000 RPM for 5 min. The supernate was removed and the cells were re-suspended in media. A sample of the cell suspension was evaluated on a Cedex XS automated cell counter (Innovatis Systems) to determine viable cells/ml. Additional media was added to the cells to achieve a final cell density of 4E5 cells/mL. The cells were then plated into 384 well PDL white solid bottom plates (Greiner, Cat#781945) at 20 μL per well using a Multidrop (Thermo Scientific). Cells were removed from Row P (location of cAMP standards). Two columns of cells were plated into a clear bottom 384 well PDL coated plate (Greiner, Cat#781944) to view confluence the day of the assay. The cell plates were lidded and stored for 15 minutes in a hood, then transferred to an incubator (37° C., 5% CO2, 95% humidity) overnight.
Preparation of Compound Plates
DMSO was added to all wells of 384 well V bottom polystyrene plate (Greiner, Cat#781280) except to columns 1 and 13, rows 0 and P and wells M13-M23 and N13-N23. Test compounds (60 μL, 10 mM) were added to Column 1 and 13 (A1 through N1 and A13 through L13). Test compounds were serially diluted 1/3 by transferring and mixing 20 μl sample with 40 μL DMSO. This process resulted in a plate of 26 compounds, 11 doses per compound, 10 mM to 0.5 μM.
Preparation of Control Plate
DMSO (40 μL) was added to wells of 384 well V bottom polystyrene plate: O2 through O11, M14 through M23, N14 through N23, and O14 through O23. AM630 (also known as [6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl)-methanone, Cayman Chemical, Cat#10006974) (60 μL, 10 mM) was added to 01; and 1-(2,4-dichlorophenyl)-7-[(4-fluorophenyl)methylene]-4,5,6,7-tetrahydro-N-1-piperidinyl-1H-indazole-3-carboxamide (60 μL, 10 mM) was added to N13. The control was serially diluted 1/3 by transferring and mixing 20 μl sample with 40 μL DMSO. This process resulted 11 doses per control, 10 mM to 0.5 μM.
cAMP Assay Protocol
Cells plated the day prior to the assay in clear bottom plates were viewed on an inverse microscope to ensure confluency in the range of 60-75%.
The following mixtures and buffer solutions were prepared: (a) Buffer 1: HBSS (Mediatech Cat#21-023-CV) with 5 mM HEPES (1 mM stock, Gibco BRL Cat#15630-056) and 0.1% BSA (7.5% stock, Invitrogen Cat#15260-037); (b) Buffer 2: 0.5 mM IBMX (200 mM stock in DMSO, Sigma 15879) in Buffer 1; (c) 1 μM cAMP Standard (50 μM stock, Perkin Elmer Cat# AD0262) diluted in Buffer 2 and serially diluted in Buffer 2, 12 doses @ ½ dilutions resulting in a dose range of 1 μM to 0.5 nM; (d) d2 labelled cAMP (CisBio HTRF Detection Kit Cat #62AM4PEB reconstituted with 6 ml dH2O) diluted 1/20 with lysis buffer (CisBio HTRF Detection Kit Cat #62AM4PEB); (e) anti-cAMP (CisBio HTRF Detection Kit Cat #62AM4PEB reconstituted with 5 ml dH2O) diluted 1/20 with lysis buffer (CisBio HTRF Detection Kit Cat #62AM4PEB); and (f) Forskolin (Sigma Cat# F6886, 10 mM in DMSO) diluted first in DMSO to 1 mM and then to 1.5 μM in Buffer 2.
A FLEXDROP (Perkin Elmer) was cleaned with ethanol then water, and primed with Buffer 2. A 384 well V bottom polypropylene plate containing d2 labelled cAMP and a second 384 well V bottom polypropylene plate containing anti-cAMP was prepared (50 μl per well). Media as “dumped” from the cell plate and 30 μL Buffer 1 was added to each well using a Multidrop. The content of the cell plate was again “dumped” and 10 μL Buffer 2 was added to each well using a Flexdrop. 12.5 nL test compound dilutions or control compound dilutions (10 mM to 0.5 μM) were added to the cell plate using an ECHO 555 (Labcyte). The cell plate was mixed (Speed 6, Lab-Line Instruments Titer Plate Shaker) and centrifuged (1000 RPMs, 1 min). Using the Flexdrop, 2 μl additions were made into the cell plate: Buffer 2 was added to Column 24; and, 1.5 μM Forskolin was added to columns 1 through 23. Final volume of the cell plate was 12 μl with 250 nM Forskolin in all wells except column 12, and serial dilutions of test compound or control ranging from 10 μM to 0.5 nM. The cell plate was again mixed (speed 6) and centrifuged (1000 RPMs, 1 min). The cell plate was incubated for 30 minutes at room temperature (˜27° C.). The contents of row P were removed and the cAMP standard dilutions were added in duplicate to Row P (P1-12 and P13-24). After incubation, 6 μL d2 labelled cAMP and 6 μL of Anti-cAMP were added to all wells of the cell plate using a BioMek FX (Beckman Coulter). The cell plate was again mixed (speed 6) and centrifuged (1000 RPMs, 1 min) and was incubated for 60 minutes in the dark at room Temp (˜27° C.).
After this final incubation, the cell plate was read in HTRF mode (fluorescence at 665 nm and 620 nm) on an Envision plate Reader (Perkin Elmer). The Envision reader outputs a ratio of channel 1/channel 2 fluorescence×10,000 (Normalized signal (NS)). Amount of cAMP in nM was calculated for each well (based on NS) from a cAMP standard curve located on each plate (at P1-12 and P13-24). EC50 values were determined from a 4-point fit (Hill equation) of a single 11-point compound dosing. Hill slope was fixed at 1.0. The bottom of the dose response curve was fixed because it was always the same as that of the control wells containing vehicle (DMSO) instead of compound. The top of the dose response curve was floated unless a plateau was not reached.
Representative compounds of formula (I), compounds of formula (II), compounds of formula (III) and compounds of formula (IV) of the present invention were tested for activity against the CB-1 and CB-2 receptors, according to assay protocol as outlined in Biological Example 1, with EC50 results (in micromolar) as listed in Tables BIO-1, below. Where a compound was tested more than once, the result presented below represents a mean of the individual measurements.
Experimental Procedure CB-1 Membrane Binding:
Into Greiner V bottom polypropylene plates, hCB1-CHO-K1 membranes (2 μg/well final concentration) in assay buffer (50 mM Tris-HCl pH 7.4, 5 mM MgCl2 and 0.5 mg/ml (0.05%) Ultra fatty acid free BSA) were dispensed. Membranes were purchased from Perkin Elmer. Test compounds were then added to each well and then [3H] CP 55, 940 (0.4 nM final well concentration) in assay buffer (50 mM Tris-HCl pH 7.4, 5 mM MgCl2 and 0.5 mg/ml (0.05%) Ultra fatty acid free BSA) was added. Samples were mixed and incubated for 90 min at 30° C. in the Greiner V Bottom Polypropylene plate. After incubation, assay reagents were transferred to a blocked 384 well polypropylene filter plates. The binding reaction was stopped by filtration and washed seven times with ice cold rinse buffer. Filter plates were then dried overnight at room temperature. The next day, plate bottoms were sealed with plate tape and 15 μl MicroScint 20 was added to each well. Plates were incubated for 2 h and radioactivity was measured by Topcount.
Experimental Procedure CB-2 Membrane Binding:
Into Greiner V bottom polypropylene plates, hCB2-HEK293 membranes (2 μg/well final concentration) in assay buffer (50 mM Tris-HCl pH 7.4, 5 mM MgCl2 and 0.5 mg/ml (0.05%) Ultra fatty acid free BSA) were dispensed. Membranes were prepared as described in FELDER, C. C., et al., Molecular Pharmacology, 1992, pp 838-845, Vol. 42. Test compounds were then added to each well and then [3H] CP 55, 940 (0.5 nM final well concentration) in assay buffer (50 mM Tris-HCl pH 7.4, 5 mM MgCl2 and 0.5 mg/ml (0.05%) Ultra fatty acid free BSA) was added. Samples were mixed and incubated for 90 min at 30° C. in the Greiner V Bottom Polypropylene plate. After incubation, assay reagents were transferred to a blocked 384 well polypropylene filter plates. The binding reaction was stopped by filtration and washed nine times with ice cold rinse buffer. Filter plates were then dried overnight at room temperature. The next day, plate bottoms were sealed with plate tape and 15 ul MicroScint 20 was added to each well. Plates were incubated for 2 h and radioactivity was measured by Topcount.
Total Binding:
Total Binding levels were achieved by combining membrane, DMSO, and [3H] CP-55,940 (also known as 5-(1,1-dimethylheptyl)-2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]-phenol).
Non-Specific Binding (NSB):
Non-Specific Binding (NSB) levels were achieved by combining membrane, 10 μM final concentration WIN-55,212 (also known as (R)-(+)-[2,3-Dihydro-5-methyl-3[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate, Tocris Biosciences Cat#1038), and [3H] CP-55,940 (also known as 5-(1,1-dimethylheptyl)-2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]-phenol).
Data Analysis:
Top Count raw data files were used for data analysis as follows:
Non-specific binding (NSB=10 μM WIN-55,212+Membrane+[3H] CP-55,940) was used as the negative control, while the Total Binding (TB=DMSO+Membrane+[3H] CP-55,940) was used as the positive control.
Excel data file reports were generated by the PE TopCount and imported into Excel for calculations or were imported into a macro driven Excel template maintained by Lead Generation—Biology.
IC50 data was calculated using raw CPM values. Curves were fitted individually from singlet 11 point dosing curves+1% DMSO Control. IC50 values were fit appropriately and calculated using the following equation:
Vmin, CPM at maximum inhibition; Vo, CPM at zero inhibition; IC50, inhibitor concentration at 50% inhibition; h, Hill coefficient.
Maximal compound % inhibition of control treated wells was also noted since some compounds exhibited values suitable for calculating IC50's.
% Inhibition of Total Binding=(1−(CPM Compound Treated Well/CPM Control Treated Well))*100
Representative compounds of formula (I), compounds of formula (II), compounds of formula (III) and compounds of formula (IV) of the present invention were tested for activity against the CB-1 and CB-2 receptors, according to assay protocol as outlined in Biological Example 2, with IC50 results (in micromolar) as listed in Tables BIO-2, below. Where a compound was tested more than once, the result presented below represents a mean of the individual measurements.
Animals, Diets and Test Compound:
Male 14-20-week old diet-induced obese mice were ordered from Taconic. Mice were started on a 60% fat diet (D12492, Research Diets, New Brunswick, N.J.) at 6 weeks of age. Mice were single-housed.
Male Sprague Dawley rats were ordered from Charles River (225-250 gm upon arrival). They were fed standard chow diet (Purina 5001) and housed 2 per cage. Male C57bl/6j mice were ordered from Charles River at 22-25 g and housed 3 per cage. They were fed standard chow (Purina 5001). All animals were housed in a temperature-controlled room with 12-hour light/dark cycle. Animals were given food and water ad libitum, except as noted.
Test compounds were formulated in 10% PEG400 and 10% solutol. Test compounds were administered by oral gavage (5 ml kg−1).
Male C57bl/6j mice were dosed with test compounds at 30 mg/kg. Plasma was collected via retro-orbital bleeding at 1 hr and 4 hrs after dosing. Whole brain without cerebellum was collected at 4 hrs after dosing. Wet brain weight was recorded before freezing. Brains were homogenized in saline and sent for analysis for determination of concentration of test compound.
Table BIO-3 below present results for representative compounds of the present invention, tested according to the procedure as described above. Each compound was tested in three animals (N=3) and administered PA at 20 mg/kg
The test compound was formulated in 10% PEG400 and 10% solutol. DIO mice received vehicle, test compound (@ 1, 3 and 10 mg/kg) daily for 26 days. At the end of the experiment, the mice were euthanized and blood and tissues were collected.
Body weight and food weight (food intake) were monitored daily for days 1-5 and twice weekly thereafter. Fed blood glucose was measured weekly.
An insulin tolerance test (0.5 U/kg Humulin, ip) was performed on day 19 after a 4 hour food removal. Blood glucose was measured at 0, 15, 30, 60 and 120 minutes after insulin. After an overnight fast, an oral glucose tolerance test (2 g/kg glucose) was performed on day 23. Blood glucose was measured at 0, 30, 60 and 120 minutes after glucose challenge.
Blood glucose was measured from the tail vein with a Lifescan glucometer. Plasma insulin was measured with an ELISA or HTRF kit (Cisbio). Plasma parameters were measured with an Olympus clinical chemistry analyzer.
Compound #44 was tested according to the procedure as described above, with results as listed in Table BIO-4A through Table BIO4-G, below.
In a second study, Compound #44 was tested according to the procedure as described above, with results as listed in Tables BIO-5A through 5G, below.
Male SD rats were weighed and transferred to the Activity Chambers with access to water. After a 2-hr acclimation period, the rats were dosed with vehicle or test compound (@ 3 and 10 mg/kg). The Activity Chamber monitoring software program was initiated and automatically recorded rat activity in each chamber for a period of 4 hours. At the end of the 4 hour monitoring period, the software was stopped and the rats were removed from the activity chambers. The rats were anesthetized and blood samples were obtained via retro-orbital puncture to determine plasma concentration of compounds. The rats were immediately euthanized with CO2 and the brains removed, washed with PBS, frozen on dry ice and stored at −80° C. for receptor occupancy (RO) analysis.
Satellite groups of 3 rats were dosed with test compound at 3 mg/kg and 10 mg/kg respectively. Four hours later, the rats were anesthetized. Blood was collected from these rats and then they were perfused with 400 ml heparinized saline through the left ventricle of the heart. The brains were removed and homogenized in PBS (4 ml/gm tissue). The samples were submitted for determination of plasma and brain compound levels.
Compound #44 was tested in n=8 animals, according to the procedure as described above, with stereotypic counts as listed in Table BIO-5A; and plasma and brain drug levels as listed in Table BIO-5B, below.
As a specific embodiment of an oral composition, 100 mg of the Compound 44, prepared as in Example 2, is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gel capsule.
While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents.
This application claims the benefit of U.S. Provisional Application 61/945,197, filed on Feb. 27, 2014, which is incorporated by reference herein in its entirety.
| Number | Name | Date | Kind |
|---|---|---|---|
| 8871756 | Chen et al. | Oct 2014 | B2 |
| Number | Date | Country |
|---|---|---|
| 02051834 | Jul 2002 | WO |
| 2005007111 | Jan 2005 | WO |
| Entry |
|---|
| International Search Report dated Apr. 1, 2015 for Appln. No. PCT/US2015/014712. |
| Lee, et al., The Current Status and Future Perspectivies of Studies of Cannabinoid Receptor 1 Antagonists as Anti-Obesity Agents, Current Topics in Medicinal Chemistry, 2009, pp. 482-503, vol. 9. |
| Number | Date | Country | |
|---|---|---|---|
| 20150239844 A1 | Aug 2015 | US |
| Number | Date | Country | |
|---|---|---|---|
| 61945197 | Feb 2014 | US |
