Substituted pyrazole compounds and methods of using them for treatment of hyperproliferative diseases
Disclosed are compounds useful, for example, in methods of treating hyperproliferative disorders such as cancer, methods of arresting the cell cycle in cancer cells, methods of inhibiting glutathione synthesis in cancer cells, and associated compounds for use and uses in medicaments. In certain embodiments, the methods, uses and compounds are provided with reference to compounds of the structural formulae in which R 1 , L 1 , L 2 , Q, L 3 , R 3 , L 4 , R 4 , L 5 , and R 5 are as described herein. In certain embodiments, compounds disclosed herein are especially active against cancers having a mutant KRAS gene.
1 . A compound having the structural formula (Ia):
optionally in the form of a pharmaceutically acceptable salt, N-oxide, a solvate or hydrate thereof, wherein
L 1 is —S— or a bond;
R 1 is selected from the group consisting of C 1 -C 8 alkyl, C 1 -C 8 alkenyl and C 1 -C 8 alkynyl, each unsubstituted or fluorinated,
L 2 is a bond or —CH 2 —;
Q is —C(O)OH, —C(O)OR 2A , or —C(O)NR 2B R 2A , in which
each R 2A is independently selected from H and C 1 -C 3 alkyl, and
each R 2B is independently selected from H and C 1 -C 3 alkyl;
L 3 is a bond;
R 3 is phenyl or monocyclic heteroaryl, optionally substituted with 1-5 R 3E , in which
each R 3E is independently selected from oxo, optionally-substituted C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, halogen, —CN, SF 5 , —N 3 , —C(O)R 3F , —SR 3F , —S(O) 1-2 R 3F , —OR 3F , —NR 3G R 3F , —C(O)R 3F , —C(O)NR 3G R 3F , —NR 3G C(O)R 3F , —C(S)NR 3G R 3F , —NR 3G C(S)R 3F , —C(O)OR 3F , —OC(O)R 3F , —C(O)SR 3F , —SC(O)R 3F , —C(S)OR 3F , —OC(S)R 3F , —C(S)SR 3F , —SC(S)R 3F , —S(O) 1-2 OR 3F , —OS(O) 1-2 R 3F , —S(O) 1-2 NR 3G R 3F , and —NR 3G S(O) 1-2 R 3F ;
each R 3F is independently selected from H, C 1 -C 3 alkyl and C 1 -C 3 fluoroalkyl and
each R 3G is independently selected from H, C 1 -C 3 alkyl, and C 1 -C 3 fluoroalkyl;
L 4 is a bond,
R 4 is selected from the group consisting of hydrogen, optionally substituted C 1 -C 8 alkyl, optionally-substituted C 1 -C 8 alkenyl and optionally substituted C 1 -C 8 alkynyl;
L 5 is a bond,
R 5 is cycloalkyl or heterocycloalkyl, each optionally substituted with 1-5 R 5E , in which
each R 5E is independently selected from oxo, optionally-substituted C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, halogen, —CN, —SF 5 , —N 3 , —C(O)R 5F , SR 5F , —S(O) 12 R 5F , —OR 5F , —NR SG R 5F , —C(O)R 5F , —C(O)NR 5G R 5F , —NR 5G C(O)R 5F , —C(S)NR 5G R 5F , —NR 1G C(S)R 5F , —C(O)OR 5F , —OC(O)R 5F , —C(O)SR 5F , —SC(O)R 5F , —C(S)OR 5F , —OC(S)R 5F , —C(S)SR 5F , —SC(S)R 5F , —S(O) 1-2 OR 5F , —OS(O) 1-2 R 5F , —S(O) 1-2 NR 5G R 5F and —NR 5G S(O) 1-2 R 5F ;
each R 5F is independently selected from H, C 1 -C 3 alkyl and C 1 -C 3 fluoroalkyl and
each R 5G is independently selected from H and C 1 -C 3 alkyl;
wherein
each optionally substituted alkyl, alkenyl and alkynyl is unsubstituted, fluorinated or substituted with one or two hydroxyl groups;
each cycloalkyl has 3-10 ring carbons and is saturated or partially unsaturated, and optionally has one or two fused cycloalkyl rings, each fused ring having 3-8 ring members;
each heterocylcloalkyl has 3-10 ring members and 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur and is saturated or partially unsaturated, and optionally has one or two fused cycloalkyl rings, each having 3-8 ring members;
each monocyclic heteroaryl is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.
2 . The compound according to claim 1 , wherein L 1 is —S—.
3 . The compound according to claim 1 , wherein R 1 is unsubstituted.
4 . The compound according to claim 1 , wherein R 1 is C 1 -C 8 alkyl.
5 . The compound according to claim 1 , wherein R 1 is propyl, butyl or butenyl.
6 . The compound according to claim 1 , wherein L 2 is a bond.
7 . The compound according to claim 1 , wherein Q is —C(O)OH wherein Q is —C(O)OH.
8 . The compound according to claim 1 , wherein Q is —C(O)O(C 1 -C 3 alkyl).
9 . The compound according to claim 1 , wherein R 3 is phenyl optionally substituted with 1-5 R 3E .
10 . The compound according to claim 1 , wherein R 4 is unsubstituted C 1 -C 3 alkyl.
11 . The compound according to claim 1 , wherein R 5 is heterocycloalkyl optionally substituted with 1-5 R 5E .
12 . The compound according to claim 11 , wherein the heterocycloalkyl is a monocyclic nitrogen-containing heterocycloalkyl, attached to the -L 5 - through a nitrogen atom.
13 . The compound according to claim 1 , wherein R 5 is cycloalkyl optionally substituted with 1-5 R 5E .
14 . The compound according to claim 13 , wherein the cycloalkyl of R 5 is monocyclic and is partially unsaturated.
15 . The compound according to claim 1 , wherein each optionally substituted alkyl, alkenyl and alkynyl is unsubstituted or fluorinated.
16 . The compound according to claim 1 , wherein
L 1 is —S—;
R 1 is propyl, butyl or butenyl;
L 2 is a bond;
Q is —C(O)OH;
R 3 is phenyl optionally substituted with 1-5 R 3E ;
R 4 is unsubstituted C 1 -C 3 alkyl; and
each optionally substituted alkyl, alkenyl and alkynyl is unsubstituted or fluorinated.
17 . The compound according to claim 16 , wherein R 5 is monocyclic heterocycloalkyl optionally substituted with 1-5 R 5E , the monocyclic heterocycloalkyl being attached to the -L 5 - through a nitrogen atom.
18 . The compound according to claim 16 , wherein R 5 is monocyclic cycloalkyl optionally substituted with 1-5 R 5E .
19 . The compound according to claim 18 , wherein the monocyclic cycloalkyl of R 5 is partially unsaturated.
20 . The compound according to claim 1 , wherein the compound is
4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-methylcyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;
4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;
1-(4-(4,4-dimethylcyclohex-1-en-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;
4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;
4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(piperidin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;
4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)piperidin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;
4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-morpholinothiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;
1-(4-(4,4-difluoropiperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;
methyl 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate;
4-(3-fluorophenyl)-1-(5-isobutyl-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;
4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;
1-(4-(4-cyanopiperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;
1-(4-(4-cyclopropylpiperazin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;
1-(4-(4-ethylpiperazin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;
1-(4-(4-acetylpiperazin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;
4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-methylpiperidin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;
4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-methylpiperazin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;
1-(4-(4,4-dimethylpiperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;
4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(3-(trifluoromethyl)pyrrolidin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;
1-(4-(4-(tert-butyl)piperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;
4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(6-azaspiro[2.5]octan-6-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;
4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-methoxy-4-(trifluoromethyl)piperidin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; or
4-(3-fluorophenyl)-1-(4-(4-isopropylpiperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid,
optionally in the form of a pharmaceutically acceptable salt, N-oxide, a solvate or hydrate thereof.
21 . A method for treating a hyperproliferative disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of claim 1 .
22 . A method for inhibiting cell cycle progression in, inducing apoptosis in, inducing a cytotoxic effect on, or inhibiting glutathione synthesis in a cancer cell, the method comprising contacting the cancer cell with an effective amount of a compound of claim 1 .