US2018327401A1PendingUtilityA1
Imidazolin-5-one derivative useful as fasn inhibitors for the treatment of cancer
Est. expirySep 7, 2032(~6.1 yrs left)· nominal 20-yr term from priority
Inventors:Peter J. ConnollyGilles BignanTianbao LuMichael H. ParkerDonald LudoviciChristophe MeyerLieven MeerpoelKarine SmansChristian Rocaboy
A61P 5/00A61P 35/00A61P 3/10A61P 43/00A61P 3/06C07D 491/107C07D 401/06C07D 403/06C07D 405/14C07D 471/04C07D 417/14C07D 409/14C07D 401/14C07D 498/04C07D 471/10C07D 403/14C07D 487/10A61P 3/04C07D 413/14
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Claims
Abstract
wherein L1, a, b, m, n, R1, R2, R3, R4, and R5 are defined herein.
Claims
exact text as granted — not AI-modified1 - 17 . (canceled)
18 . A method of treating a disorder mediated by inhibition of fatty acid synthase (FASN) enzyme, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of formula (I)
wherein
R 1 and R 2 are taken together to form an optionally substituted ring structure selected from the group consisting of
C 3-6 cycloalkyl and 4 to 6-membered, saturated heterocyclyl; wherein the 4 to 6-membered saturated heterocyclyl contains NR 10 ; provided that the NR 10 is not present at the 2-position relative to the carbon atom of the imidazolidin-5-one;
wherein R 10 is selected from the group consisting of hydrogen, C 1-4 alkyl, C 2-4 alkenyl, —CH 2 -(hydroxy substituted C 1-2 alkyl), —CH 2 -(phenyl), —(C 2 alkyl)-O-(C 1-2 alkyl), —C(O)—(C 1-4 alkyl), —C(O)-(fluorinated C 1-2 alkyl), —C(O)-(cyclopropyl), —C(O)O—(C 1-4 alkyl), —C(O)—NR A R B , and —SO 2 —(C 1-2 alkyl), wherein R A and R B are each independently selected from the group consisting of hydrogen and methyl;
m is an integer from 0 to 1; and n is an integer from 0 to 2 provide that when n is 2, then m is 0;
such that
is selected from the group consisting of azetidin-3-yl, pyrrolidin-3-yl, pyrrolidin-3R-yl, pyrrolidin-3S-yl, piperidin-3-yl, piperidin-3R-yl, piperidin-3S-yl, and piperidin-4-yl;
a is 1;
L 1 is selected from the group consisting of —C(O)—, —C(O)O—, and —SO 2 —;
R 3 is selected from the group consisting of C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, fluorinated C 1-2 alkyl, C 2-4 alkenyl, C 3-5 cycloalkyl, 4 to 5-membered, saturated heterocyclyl, 5 to 6-membered heteroaryl, and NR V R W ; wherein the C 3-5 cycloalkyl, 4 to 5-membered, saturated heterocyclyl or 5 to 6-membered heteroaryl are each optionally substituted with a substituent selected from the group consisting of halogen, hydroxy, C 1-2 alkyl, (C 1-2 alkyl)-OH, fluorinated C 1-2 alkyl, cyano, and NH 2 ; and wherein R V and R W are each independently selected from the group consisting of hydrogen and methyl;
is selected from the group consisting of
b is an integer from 0 to 1;
R 4 is selected from the group consisting of halogen, C 1-2 alkyl, and C 1-2 alkoxy;
R 5 is selected from the group consisting of
wherein
selected from the group consisting of phenyl, naphthyl, 5 to 6-membered heteroaryl, 9 to 10-membered heteroaryl, and partially unsaturated 9 to 10-membered heterocyclyl;
c is an integer from 0 to 2;
each R 6 is independently selected from the group consisting of hydroxy, oxo, halogen, cyano, C 1-4 alkyl, fluorinated C 1-2 alkyl, hydroxy substituted C 1-4 alkyl, cyano-substituted C 1-2 alkyl, —(C 1-2 alkyl)—O—(C 1-2 alkyl), C 1-4 alkoxy, fluorinated C 1-2 alkoxy, —SO 2 —(C 1-4 alkyl), —CO 2 H, —C(O)O—(C 1-2 alkyl), —C(O)—(C 1-2 alkyl), —C(O)-(fluorinated C 1-2 alkyl), —C(O)—NR M R N , —NR M R N , —NR M —C(O)H,—NR M —SO 2 —(C 1-2 alkyl), C 3-5 cycloalkyl, 1-cyano-cyclopropyl, —(C 1-2 alkyl)-(C 3-5 cycloalkyl), —S—(C 3-5 cycloalkyl), —SO 2 —(C 3-5 cycloalkyl), —NH—C(O)—(C 3-5 cycloalkyl) —NH—SO 2 —(C 3-5 cycloalkyl), and oxetan-3-yl; and wherein R M and R N are each independently selected from the group consisting of hydrogen and C 1-2 alkyl;
wherein
is selected from the group consisting of phenyl and 6-membered, nitrogen containing heteroaryl;
wherein
is selected from the group consisting of phenyl, 5 to 6-membered, saturated, nitrogen containing heterocylyl and 5 to 6-membered, nitrogen containing heteroaryl;
e is an integer from 0 to 1;
R 8 is selected from the group consisting of halogen, C 1-4 alkyl, C 3-5 cycloalkyl, —(C 1-2 alkyl)-(C 3-5 cycloalkyl), and oxetanyl;
provided that the
is bound at the 3- or 4-position of the
relative to the point of attachment of
to the
provided that when R 1 and R 2 are taken together with the carbon atom to which they are bound to form 1-(methoxycarbonyl)-azetidin-3-yl, m is 1 and n is 0 or m is 0 and n is 1;
is pyrrolidin-3R-yl; -(L 1 ) a -R 3 is selected from the group consisting of —C(O)—CF, —C(O)-cyclopropyl, —C(O)-(thiazol-2-yl); —C(O)OCH, and —SO 2 —CH 3 ,
and b=0; then R 5 is other than quinolin-7-yl, benzofuran-5-yl, 1-methyl-indazol-5-yl, 1-methyl-pyrazol-4-yl, 4-(1-methyl-pyrazol-4-yl)-phenyl, 1,2,3,4,4a,8a-hexahydro-2-methyl-carbonyl-isoquinolin-6-yl), or 1,2,3,4-trihydro-2-methylcarbonyl-isoquinolin-2-yl;
provided further that when R 1 and R 2 are taken together with the carbon atom to which they are bound to form cyclopentyl; m is 1 and n is 0 or m is 0 and m is 1;
is pyrrolidin-3R-yl; -(L 1 ) a -R 3 is —C(O)-cyclopropyl;
b=0 or (R 4 ) b is 2-methyl; then R 5 is other than 1-methyl-pyrazol-4-yl, 4-methyl-3,4-dihydro-pyrido[2,3-b]oxazon-7-yl, 2-(piperazin-1-yl)-pyridin-4-yl, or 2-(4-methyl-piperazin-1-yl)-pyridin-4-yl;
provided further that when R 1 and R 2 are taken together with the carbon atom to which they are bound to form cyclopentyl; m is 1 and n is 0 or m is 0 and m is 1;
is pyrrolidin-3R-yl; -(L 1 ) a -R 3 is —SO 2 -pyrrolidin-1-yl;
b=0 or (R 4 )b is 2-methyl; then R 5 is other than benzofuran-5-yl;
provided further that when R 1 and R 2 are taken together with the carbon atom to which they are bound to form cyclopropyl; m is 0, n is 0,
is azetidin-3-yl; -(L 1 ) a -R 3 is selected from the group consisting of —C(O)-cyclopropyl, —C(O)-(1-methyl-cyclopropyl), and —C(O)-(1-hydroxy-cyclopropyl);
b=0 or (R 4 ) b is selected from the group consisting of 2-fluoro and 2-methyl; then R 5 is other than 1-isopropylsulfonyl-phenyl, 1-methyl-indazol-5-yl, 1-isopropyl-indazol-5-yl, 1-oxetan-3-yl, indazol-5-yl, 1-methyl-pyrazol-4-yl, 4-methyl-7-bromo-quinolin-2-yl, 5-(2-hydroxy-2-methyl-propyl)-pyridin-2-yl, 6-isopropyl-pyridin-3-yl, 6-(1-cyanomethyl)-pyridin-3-yl, 6-(2-hydroxy-2-methyl-propyl)-pyridin-3-yl, 1,5-naphthyridin-3-yl, 3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl, 4-(1-isobutyl-pyrazol-5-yl)-phenyl, or 6-(morpholin-4-yl)-pyridin-3-yl;
provided further that when R 1 and R 2 are taken together with the carbon atom to which they are bound to form cyclopropyl; m is 0, n is 0,
is azetidin-3-yl; -(L 1 ) a -R 3 is —C(O)-(1-hydroxy-cyclopropyl);
and (R 4 ) b is 2-methyl; then R 5 is other 1-methyl-indazol-5-yl;
provided further that when R 1 and R 2 are taken together with the carbon atom to which they are bound to form cyclopropyl; m is 0, n is 0,
is azetidin-3-yl; -(L 1 ) a -R 3 is —C(O)-pyridin-3-yl;
(R 4 )b is 2-methyl; then R 5 is other than 1-methyl-indazol-5-yl;
provided further that when R 1 and R 2 are taken together with the carbon atom to which they are bound to form cyclopropyl; m is 0, n is 2.
is piperidin-3R-yl or piperidin-3S-yl; -(L 1 ) a -R 3 is —C(O)-cyclopropyl;
and b=0; then R 5 is other than indazol-5-yl, benzofuran-5-yl, benzothien-5-yl, 1-methyl-indazol-5-yl, 4-(4-methylphenyl)phenyl, or 4-(3-chlorophenyl)-phenyl;
provided further that when R 1 and R 2 are taken together with the carbon atom to which they are bound to form cyclopropyl; m is 1, n is 1,
is piperidin-4-yl; -(L 1 ) a -R 3 is —C(O)-cyclopropyl;
and b=0; then R 5 is other than 4-trifluoromethyl-phenyl, 1-methyl-pyrazol-4-yl, benzoxazol-5-yl, pyridin-4-yl, or 4-(1-methyl-pyrazol-4-yl)-phenyl;
provided further that when R 1 and R 2 are taken together with the carbon atom to which they are bound to form cyclopropyl; m is 0 and n is 1 or m is 1 and n is 0;
is pyrrolidin-3R-yl; -(L 1 ) a -R 3 is —C(O)-cyclopropyl;
and b=0; then R 5 is other than 5-chloro-pyridin-3-yl, 2-oxo-3,4-dihydro-quinolin-7-yl, or 6-(4-methyl-piperazin-1-yl)-pyridin-3-yl;
provided further that when R 1 and R 2 are taken together with the carbon atom to which they are bound to form tetrahydrofuran-3,3-diyl or tetrahydropyran-4,4-diyl; m is an integer from 0 to 1 and n is 0 or m is 0 and n is an integer from 0 to 1;
is selected from the group consisting of azetidin-3-yl, pyrrolidin-3R-yl and pyrrolidin-3-yl; -(L 1 ) a -R 3 is selected from the group consisting of —C(O)-thiazol-2-yl, —C(O)—CF, —C(O)OCH 3 and —SO 2 —CH 3 ;
and b=0; then R 5 is other than quinolin-7-yl, 1-methyl-indazol-5-yl, benzofuran-5-yl, or 4-(1-methyl-pyrazol-4-yl)-phenyl;
or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.
19 . The method of claim 18 , wherein the disorder mediated by inhibition of fatty acid synthase (FASN) enzyme is selected from the group consisting of cancer of the breast, prostate, head, neck, skin, lung, ovary, endometrium, thyroid, colon, rectum, esophagus, stomach, kidney, liver, bladder, pancreas, brain, spinal cord, blood, and bone.
20 . The method of claim 18 , wherein the disorder mediated by inhibition of fatty acid synthase (FASN) enzyme is selected from the group consisting of obesity, overweight, weight gain, Type II diabetes mellitus, Syndrome X, and appetite or satiety modulation.
21 . The method of claim 18 , wherein the disorder mediated by inhibition of fatty acid synthase (FASN) enzyme is selected from the group consisting of dyslipidemia, elevated cholesterol levels, elevated LDL, decreased HDL, elevated triglycerides, fatty liver, non-alcoholic steatohepatitis (NASH), fatty liver, and non-alcoholic fatty liver disease (NAFLD).
22 . A method of treating
(a) cancer, selected from the group consisting of breast, prostate, head, neck, skin, lung, ovary, endometrium, thyroid, colon, rectum, esophagus, stomach, kidney, liver, bladder, pancreas, brain, spinal cord, blood, and bone; (b) obesity or a related disorder selected from the group consisting of overweight, weight gain, Type II diabetes mellitus, Syndrome X, and appetite, and satiety modulation; or (c) a liver related disorder selected from the group consisting of dyslipidemia, elevated cholesterol levels, elevated LDL, decreased HDL, elevated triglycerides, fatty liver, non-alcoholic steatohepatitis (NASH), fatty liver, and non-alcoholic fatty liver disease (NAFLD); comprising administering to a subject in need thereof a therapeutically effective amount of the compound of formula (I)
wherein
R 1 and R 2 are taken together to form an optionally substituted ring structure selected from the group consisting of
C 3-6 cycloalkyl and 4 to 6-membered, saturated heterocyclyl; wherein the 4 to 6-membered saturated heterocyclyl contains NR 10 ; provided that the NR 10 is not present at the 2-position relative to the carbon atom of the imidazolidin-5-one;
wherein R 10 is selected from the group consisting of hydrogen, C 1-4 alkyl, C 2-4 alkenyl, —CH 2 -(hydroxy substituted C 1-2 alkyl), —CH 2 -(phenyl), —(C 2 alkyl)-O—(C 1-2 alkyl), —C(O)—(C 1-4 alkyl), —C(O)-(fluorinated C 1-2 alkyl), —C(O)-(cyclopropyl), —C(O)O—(C 1-4 alkyl), —C(O)—NR A R B , and —SO 2 -(C 1-2 alkyl), wherein R A and R B are each independently selected from the group consisting of hydrogen and methyl;
m is an integer from 0 to 1; and n is an integer from 0 to 2 provide that when n is 2, then m is 0;
such that
is selected from the group consisting of azetidin-3-yl, pyrrolidin-3-yl, pyrrolidin-3R-yl, pyrrolidin-3S-yl, piperidin-3-yl, piperidin-3R-yl, piperidin-3S-yl, and piperidin-4-yl;
a is 1;
L 1 is selected from the group consisting of —C(O)—, —C(O)O—, and —SO 2 —;
R 3 is selected from the group consisting of C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, fluorinated C 1-2 alkyl, C 2-4 alkenyl, C 3-5 cycloalkyl, 4 to 5-membered, saturated heterocyclyl, 5 to 6-membered heteroaryl, and NR V R W ; wherein the C 3-5 cycloalkyl, 4 to 5-membered, saturated heterocyclyl or 5 to 6-membered heteroaryl are each optionally substituted with a substituent selected from the group consisting of halogen, hydroxy, C 1-2 alkyl, (C 1-2 alkyl)—OH, fluorinated C 1-2 alkyl, cyano, and NH 2 ; and wherein R V and R W are each independently selected from the group consisting of hydrogen and methyl;
is selected from the group consisting of
b is an integer from 0 to 1;
R 4 is selected from the group consisting of halogen, C 1-2 alkyl, and C 1-2 alkoxy;
R 5 is selected from the group consisting of
wherein
selected from the group consisting of phenyl, naphthyl, 5 to 6-membered heteroaryl, 9 to 10-membered heteroaryl, and partially unsaturated 9 to 10-membered heterocyclyl;
c is an integer from 0 to 2;
each R 6 is independently selected from the group consisting of hydroxy, oxo, halogen, cyano, C 1-4 alkyl, fluorinated C 1-2 alkyl, hydroxy substituted C 1-4 alkyl, cyano-substituted C 1-2 alkyl, —(C 1-2 alkyl)-O—(C 1-2 alkyl), C 1-4 alkoxy, fluorinated C 1-2 alkoxy, —SO 2 —(C 1-4 alkyl), —CO 2 H, —C(O)O—(C 1-2 alkyl), —C(O)—(C 1-2 alkyl), —C(O)-(fluorinated C 1-2 alkyl), —C(O)—NR M R N , —NR M R N , —NR M —C(O)H,—NR M —SO 2 —(C 1-2 alkyl), C 3-5 cycloalkyl, 1-cyano-cyclopropyl, —(C 1-2 alkyl)-(C 3-5 cycloalkyl), —S—(C 3-5 cycloalkyl), —SO 2 —(C 3-5 cycloalkyl), —NH—C(O)—(C 3-5 cycloalkyl) —NH—SO 2 -(C 3-5 cycloalkyl), and oxetan-3-yl; and wherein R M and R N are each independently selected from the group consisting of hydrogen and C 1-2 alkyl;
wherein
is selected from the group consisting of phenyl and 6-membered, nitrogen containing heteroaryl;
wherein
is selected from the group consisting of phenyl, 5 to 6-membered, saturated, nitrogen containing heterocylyl and 5 to 6-membered, nitrogen containing heteroaryl;
e is an integer from 0 to 1;
R 8 is selected from the group consisting of halogen, C 1-4 alkyl, C 3-5 cycloalkyl, —(C 1-2 alkyl)-(C 3-5 cycloalkyl), and oxetanyl;
provided that the
is bound at the 3- or 4-position of the
relative to the point of attachment of the
to the
provided that when R 1 and R 2 are taken together with the carbon atom to which they are bound to form 1-(methoxycarbonyl)-azetidin-3-yl, m is 1 and n is 0 or m is 0 and n is 1;
is pyrrolidin-3R-yl; -(L 1 ) a -R 3 is selected from the group consisting of —C(O)—CF 3 , —C(O)-cyclopropyl, —C(O)-(thiazol-2-yl), —C(O)OCH, and —SO 2 —CH,
and b=0; then R 5 is other than quinolin-7-yl benzofuran-5-yl, 1-methyl-indazol-5-yl, 1-methyl-pyrazol-4-yl, 4-(1-methyl-pyrazol-4-yl)-phenyl, 1,2,3,4,4a,8a-hexahydro-2-methyl-carbonyl-isoquinolin-6-yl), or 1,2,3,4-trihydro-2-methylcarbonyl-isoquinolin-2-yl;
provided further that when R 1 and R 2 are taken together with the carbon atom to which they are bound to form cyclopentyl; m is 1 and n is 0 or m is 0 and m is 1;
is pyrrolidin-3R-yl; -(L 1 ) a -R 3 is —C(O)-cyclopropyl:
b=0 or (R 4 ) b is 2-methyl; then R 5 is other than 1-methyl-pyrazol-4-yl, 4-methyl-3,4-dihydro-pyrido[2,3-b]oxazon-7-yl, 2-(piperazin-1-yl)-pyridin-4-yl, or 2-(4-methyl-piperazin-1-yl)-pyridin-4-yl;
provided further that when R 1 and R 2 are taken together with the carbon atom to which they are bound to form cyclopentyl; m is 1 and n is 0 or m is 0 and m is 1;
is pyrrolidin-3R-yl; -(L 1 ) a -R 3 is —SO 2 -pyrrolidin-1-yl;
b=0 or (R 4 )b is 2-methyl; then R 5 is other than benzofuran-5-yl;
provided further that when R 1 and R 2 are taken together with the carbon atom to which they are bound to form cyclopropyl; m is 0, n is 0,
is azetidin-3-yl; -(L 1 ) a -R 3 is selected from the group consisting of —C(O)-cyclopropyl, —C(O)-(1-methyl-cyclopropyl), and —C(O)—(1-hydroxy-cyclopropyl);
b=0 or (R 4 ) b is selected from the group consisting of 2-fluoro and 2-methyl; then R 5 is other than 1-isopropylsulfonyl-phenyl, 1-methyl-indazol-5-yl, 1-isopropyl-indazol-5-yl, 1-oxetan-3-yl, indazol-5-yl, 1-methyl-pyrazol-4-yl, 4-methyl-7-bromo-quinolin-2-yl, 5-(2-hydroxy-2-methyl-propyl)-pyridin-2-yl, 6-isopropyl-pyridin-3-yl, 6-(1-cyanomethyl)-pyridin-3-yl, 6-(2-hydroxy-2-methyl-propyl)-pyridin-3-yl, 1,5-naphthyridin-3-yl, 3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl, 4-(1-isobutyl-pyrazol-5-yl)-phenyl, or 6-(morpholin-4-yl)-pyridin-3-yl;
provided further that when R 1 and R 2 are taken together with the carbon atom to which they are bound to form cyclopropyl; m is 0, n is 0,
is azetidin-3-yl; -(L 1 ) a -R 3 is —C(O)-(1-hydroxy-cyclopropyl);
and (R 4 ) b is 2-methyl; then R 5 is other 1-methyl-indazol-5-yl;
provided further that when R 1 and R 2 are taken together with the carbon atom to which they are bound to form cyclopropyl; m is 0, n is 0,
is azetidin-3-yl; -(L 1 ) a -R 3 is —C(O)-pyridin-3-yl;
(R 4 ) b is 2-methyl; then R 5 is other than 1-methyl-indazol-5-yl;
provided further that when R 1 and R 2 are taken together with the carbon atom to which they are bound to form cyclopropyl; m is 0, n is 2.
is piperidin-3R-yl or piperidin-3S-yl; -(L 1 ) a -R 3 is —C(O)-cyclopropyl;
and b=0; then R 5 is other than indazol-5-yl, benzofuran-5-yl, benzothien-5-yl, 1-methyl-indazol-5-yl, 4-(4-methylphenyl)phenyl, or 4-(3-chlorophenyl)-phenyl;
provided further that when R 1 and R 2 are taken together with the carbon atom to which they are bound to form cyclopropyl; m is 1, n is 1,
is piperidin-4-yl; -(L 1 ) a -R 3 is —C(O)-cyclopropyl;
and b=0; then R 5 is other than 4-trifluoromethyl-phenyl, 1-methyl-pyrazol-4-yl, benzoxazol-5-yl, pyridin-4-yl, or 4-(1-methyl-pyrazol-4-yl)-phenyl;
provided further that when R 1 and R 2 are taken together with the carbon atom to which they are bound to form cyclopropyl; m is 0 and n is 1 or m is 1 and n is 0;
is pyrrolidin-3R-yl; -(L 1 ) a -R 3 is —C(O)-cyclopropyl;
and b=0; then R 5 is other than 5-chloro-pyridin-3-yl, 2-oxo-3,4-dihydro-quinolin-7-yl, or 6-(4-methyl-piperazin-1-yl)-pyridin-3-yl;
provided further that when R 1 and R 2 are taken together with the carbon atom to which they are bound to form tetrahydrofuran-3,3-diyl or tetrahydropyran-4,4-diyl; m is an integer from 0 to 1 and n is 0 or m is 0 and n is an integer from 0 to 1;
is selected from the group consisting of azetidin-3-yl, pyrrolidin-3R-yl and pyrrolidin-3-yl; -(L 1 ) a -R 3 is selected from the group consisting of —C(O)-thiazol-2-yl, —C(O)—CF 3 , —C(O)OCH 3 and —SO 2 —CH 3 ;
and b=0; then R 5 is other than quinolin-7-yl, 1-methyl-indazol-5-yl, benzofuran-5-yl, or 4-(1-methyl-pyrazol-4-yl)-phenyl;
or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.
23 . A method of treating
(a) cancer selected from the group consisting of breast, prostate, head, neck, skin, lung, ovary, endometrium, thyroid, colon, rectum, esophagus, stomach, kidney, liver, bladder, pancreas, brain, spinal cord, blood, and bone; (b) obesity or a related disorder selected from the group consisting of overweight, weight gain, Type II diabetes mellitus, Syndrome X, and appetite or satiety modulation; or (c) a liver related disorders selected from the group consisting of dyslipidemia, elevated cholesterol levels, elevated LDL, decreased HDL, elevated triglycerides, fatty liver, non-alcoholic steatohepatitis (NASH), fatty liver, and non-alcoholic fatty liver disease (NAFLD); comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula (I)
wherein
R 1 and R 2 are taken together to form an optionally substituted ring structure selected from the group consisting of
C 3-6 cycloalkyl and 4 to 6-membered, saturated heterocyclyl; wherein the 4 to 6-membered saturated heterocyclyl contains NR 10 ; provided that the NR 10 is not present at the 2-position relative to the carbon atom of the imidazolidin-5-one;
wherein R 10 is selected from the group consisting of hydrogen, C 1-4 alkyl, C 2-4 alkenyl, —CH 2 -(hydroxy substituted C 1-2 alkyl), —CH 2 -(phenyl); —(C2alkyl)-O—(C 1-2 alkyl), —C(O)—(C 1-4 alkyl), —C(O)-(fluorinated C 1-2 alkyl), —C(O)-(cyclopropyl), —C(O)O—(C 1-4 alkyl), —C(O)—NR A R B , and —SO 2 —(C 1-2 alkyl), wherein R A and R B are each independently selected from the group consisting of hydrogen and methyl;
m is an integer from 0 to 1; and n is an integer from 0 to 2 provide that when n is 2, then m is 0;
such that
is selected from the group consisting of azetidin-3-yl, pyrrolidin-3-yl, pyrrolidin-3R-yl, pyrrolidin-3S-yl, piperidin-3-yl, piperidin-3R-yl, piperidin-3S-yl, and piperidin-4-yl;
a is 1;
L 1 is selected from the group consisting of —C(O)—, —C(O)O—, and —SO 2 —;
R 3 is selected from the group consisting of C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, fluorinated C 1-2 alkyl, C 2-4 alkenyl, C 3-5 cycloalkyl, 4 to 5-membered, saturated heterocyclyl, 5 to 6-membered heteroaryl, and NR V R W ; wherein the C 3-5 cycloalkyl, 4 to 5-membered, saturated heterocyclyl or 5 to 6-membered heteroaryl are each optionally substituted with a substituent selected from the group consisting of halogen, hydroxy, C 1-2 alkyl, (C 1-2 alkyl)-OH, fluorinated C 1-2 alkyl, cyano, and NH 2 ; and wherein R V and R W are each independently selected from the group consisting of hydrogen and methyl;
is selected from the group consisting of
b is an integer from 0 to 1;
R 4 is selected from the group consisting of halogen, C 1-2 alkyl, and C 1-2 alkoxy;
R 5 is selected from the group consisting of
wherein
selected from the group consisting of phenyl, naphthyl, 5 to 6-membered heteroaryl, 9 to 10-membered heteroaryl, and partially unsaturated 9 to 10-membered heterocyclyl;
c is an integer from 0 to 2;
each R 6 is independently selected from the group consisting of hydroxy, oxo, halogen, cyano, C 1-4 alkyl, fluorinated C 1-2 alkyl, hydroxy substituted C 1-4 alkyl, cyano-substituted C 1-2 alkyl, —(C 1-2 alkyl)-O—(C 1-2 alkyl), C 1-4 alkoxy, fluorinated C 1-2 alkoxy, —SO 2 -(C 1-4 alkyl), —CO 2 H, —C(O)O—(C 1-2 alkyl), —C(O)—(C 1-2 alkyl), —C(O)-(fluorinated C 1-2 alkyl), —C(O)—NR M R N , —NR M R N , —NR M —C(O)H,—NR M —SO 2 —(C 1-2 alkyl), C 3-5 cycloalkyl, 1-cyano-cyclopropyl, —(C 1-2 alkyl)-(C 3-5 cycloalkyl), —S—(C 3-5 cycloalkyl), —SO 2 —(C 3-5 cycloalkyl), —NH—C(O)—(C 3-5 cycloalkyl) —NH—SO 2 —(C 3-5 cycloalkyl), and oxetan-3-yl; and wherein R M and R N are each independently selected from the group consisting of hydrogen and C 1-2 alkyl;
wherein
is selected from the group consisting of phenyl and 6-membered, nitrogen containing heteroaryl;
wherein
is selected from the group consisting of phenyl, 5 to 6-membered, saturated, nitrogen containing heterocylyl and 5 to 6-membered, nitrogen containing heteroaryl;
e is an integer from 0 to 1;
R 8 is selected from the group consisting of halogen, C 1-4 alkyl, C 3-5 cycloalkyl, —(C 1-2 alkyl)-(C 3-5 cycloalkyl), and oxetanyl;
provided that the
is bound at the 3- or 4-position of the
relative to the point of attachment of the
to the
provided that when R 1 and R 2 are taken together with the carbon atom to which they are bound to form 1-(methoxycarbonyl)-azetidin-3-yl, m is 1 and n is 0 or m is 0 and n is 1;
is pyrrolidin-3R-yl; -(L 1 ) a -R 3 is selected from the group consisting of —C(O)—CF 3 , —C(O)-cyclopropyl, —C(O)-(thiazol-2-yl), —C(O)OCH, and —SO 2 —CH 3 ,
and b=0; then R 5 is other than quinolin-7-yl, benzofuran-5-yl, 1-methyl-indazol-5-yl, 1-methyl-pyrazol-4-yl, 4-(1-methyl-pyrazol-4-yl)-phenyl, 1,2,3,4,4a,8a-hexahydro-2-methyl-carbonyl-isoquinolin-6-yl), or 1,2,3,4-trihydro-2-methylcarbonyl-isoquinolin-2-yl;
provided further that when R 1 and R 2 are taken together with the carbon atom to which they are bound to form cyclopentyl; m is 1 and n is 0 or m is 0 and m is 1;
is pyrrolidin-3R-yl; -(L 1 ) a -R 3 is —C(O)-cyclopropyl;
b=0 or (R 4 ) b is 2-methyl; then R 5 is other than 1-methyl-pyrazol-4-yl, 4-methyl-3,4-dihydro-pyrido[2,3-b]oxazon-7-yl, 2-(piperazin-1-yl)-pyridin-4-yl, or 2-(4-methyl-piperazin-1-yl)-pyridin-4-yl;
provided further that when R 1 and R 2 are taken together with the carbon atom to which they are bound to form cyclopentyl; m is 1 and n is 0 or m is 0 and m is 1;
is pyrrolidin-3R-yl; -(L 1 ) a -R 3 is —SO 2 -pyrrolidin-1-yl;
b=0 or (R 4 ) b is 2-methyl; then R 5 is other than benzofuran-5-yl;
provided further that when R 1 and R 2 are taken together with the carbon atom to which they are bound to form cyclopropyl; m is 0, n is 0,
is azetidin-3-yl; -(L 1 ) a -R 3 is selected from the group consisting of —C(O)-cyclopropyl, —C(O)-(1-methyl-cyclopropyl), and —C(O)-(1-hydroxy-cyclopropyl);
b=0 or (R 4 ) b is selected from the group consisting of 2-fluoro and 2-methyl; then R 5 is other than 1-isopropylsulfonyl-phenyl, 1-methyl-indazol-5-yl, 1-isopropyl-indazol-5-yl, 1-oxetan-3-yl, indazol-5-yl, 1-methyl-pyrazol-4-yl, 4-methyl-7-bromo-quinolin-2-yl, 5-(2-hydroxy-2-methyl-propyl)-pyridin-2-yl, 6-isopropyl-pyridin-3-yl, 6-(1-cyanomethyl)-pyridin-3-yl, 6-(2-hydroxy-2-methyl-propyl)-pyridin-3-yl, 1,5-naphthyridin-3-yl, 3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl, 4-(1-isobutyl-pyrazol-5-yl)-phenyl, or 6-(morpholin-4-yl)-pyridin-3-yl;
provided further that when R 1 and R 2 are taken together with the carbon atom to which they are bound to form cyclopropyl; m is 0, n is 0,
is azetidin-3-yl; -(L 1 ) a -R 3 is —C(O)-(1-hydroxy-cyclopropyl);
and (R 4 ) b is 2-methyl; then R 5 is other 1-methyl-indazol-5-yl;
provided further that when R 1 and R 2 are taken together with the carbon atom to which they are bound to form cyclopropyl; m is 0, n is 0,
is azetidin-3-yl; -(L 1 ) a -R 3 is —C(O)-pyridin-3-yl;
(R 4 ) b is 2-methyl; then R 5 is other than 1-methyl-indazol-5-yl;
provided further that when R 1 and R 2 are taken together with the carbon atom to which they are bound to form cyclopropyl; m is 0, n is 2,
is piperidin-3R-yl or piperidin-3S-yl; -(L 1 ) a -R 3 is —C(O)-cyclopropyl;
and b=0; then R 5 is other than indazol-5-yl, benzofuran-5-yl, benzothien-5-yl, 1-methyl-indazol-5-yl, 4-(4-methylphenyl)phenyl, or 4-(3-chlorophenyl)-phenyl;
provided further that when R 1 and R 2 are taken together with the carbon atom to which they are bound to form cyclopropyl; m is 1, n is 1,
is piperidin-4-yl; -(L 1 ) a-R 3 is —C(O)-cyclopropyl;
and b=0; then R 5 is other than 4-trifluoromethyl-phenyl, 1-methyl-pyrazol-4-yl, benzoxazol-5-yl, pyridin-4-yl, or 4-(1-methyl-pyrazol-4-yl)-phenyl;
provided further that when R 1 and R 2 are taken together with the carbon atom to which they are bound to form cyclopropyl; m is 0 and n is 1 or m is 1 and n is 0;
is pyrrolidin-3R-yl; -(L 1 ) a -R 3 is —C(O)-cyclopropyl;
and b=0; then R 5 is other than 5-chloro-pyridin-3-yl, 2-oxo-3,4-dihydro-quinolin-7-yl, or 6-(4-methyl-piperazin-1-yl)-pyridin-3-yl;
provided further that when R 1 and R 2 are taken together with the carbon atom to which they are bound to form tetrahydrofuran-3,3-diyl or tetrahydropyran-4,4-diyl; m is an integer from 0 to 1 and n is 0 or m is 0 and n is an integer from 0 to 1;
is selected from the group consisting of azetidin-3-yl, pyrrolidin-3R-yl and pyrrolidin-3-yl; —(L 1 ) a -R 3 is selected from the group consisting of —C(O)-thiazol-2-yl, —C(O)-CF 3 , —C(O)OCH 3 and —SO 2 —CH 3 ;
and b=0; then R 5 is other than quinolin-7-yl, 1-methyl-indazol-5-yl, benzofuran-5-yl, or 4-(1-methyl-pyrazol-4-yl)-phenyl;
or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.
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