US 6,916,809 B2Granted

Heterocyclic acridone inhibitors of IMPDH enzyme

AssigneeBristol-Myers Squibb Company

InventorsPing Chen, T.G. Murali Dhar, Edwin J. Iwanowicz, Scott H. Watterson, Henry Gu, Yufen Zhao

Life of this patent

Estimating the term…

Abstract

Compounds having the formula (I), wherein R3 is selected from H, OH and NH2; R30 is selected from ═O and ═S; W is —C(═O)—, —S(═O)—, or —S(O)2—; or W may be —CH2— if X is —C(═O)—; X is selected from —CH2—, —N(R4)—, and —O—, except that when W is —CH2—, X is —C(═O)—; Y is a bond or —C(R40)(R45)—; Q is a linker; Z is optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; and X1, X2, X3, X4, X5, X6, X7, X8, X9, X10 and X11 are selected such a tricyclic heteroaryl ring system is formed as further defined in the specification.

Claims9

Dependent claims

A compound having the formula,

or an enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt, solvate, or prodrug thereof,
wherein:
X1 is CR1;
X2 is selected from CR25 and N;
X6 is selected from CR25 and N;
X7 is CR3;
X9 is C;
Provided, however, that at least one of X2 and X6 is N;
and provided further that X1, X2, X6, X7 and X9 are selected such that a tricyclic heteroaryl ring system is formed;
W is —C(═O)—, —S(═O)—, or —S(O)2—;
Y is a bond or —C(R40)(R45)—;
Q is selected from a bond, —C(R26)(R48)—, —C(═O)—, —CH2—O—, —CH2—O—CH2—CO2—NR4—, —CH2—CO2—, —C(═O)NR4—, and —CH═C(R25)—;
Z is selected from Z1 and Z2, wherein when Y and Q are both a bond, Z is Z1;
and when Y is —C(R40)(R46)— and Q is selected from a bond, —C(R26)(R46)—, —C(═O)—, —CH2—O—CH2—, —CH2—CO2—NR4—, —CH2—CO2—, —C(═O)NR4—, and —CH═C(CR28)—, then Z is Z2;
Z1 is
wherein J and K are each independently a bond, O, NR31, or —CHR31—;
Z2 is selected from
a) C1-6alkyl optionally substituted with one to two R31;
b) piperidyl, piperazinyl, morpholinyl, or C3-7cycloalkyl optionally substituted with one to three R41;
and
c) phenyl, napthyl, benzocyclopentyl, indolyl, tetrahydroquinolyl, oxazolyl, imidazolyl, thiazolyl, pyridyl, pyridinyl, pyrimidinyl, and pyrazinyl, optionally substituted with one to three R42;
R1 is the same or different and is selected from hydrogen, halogen, cyano, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, O—R7, —(C═O)R7, —(C═O)—O—R7, NR8R9, —(C═O)NR8R9, —SR20, —S(═O)R20, —SO2R20 and —C≡C—Si(CH3)3;
R4 is selected from H and C1-4 alkyl;
R7 is selected from hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl, C(═O)alkyl, C(═O)substituted alkyl, C(═O)cycloalkyl, C(═O) substituted cycloalkyl, C(═O)aryl, C(═O)substituted aryl, C(═O)O-alkyl, C(═O)O-substituted alkyl, C(═O)heterocyclo, —C(═O)—NR8R9, C(═O)heteroaryl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, heteroaryl and substituted heteroaryl;
R8 and R9 are independently selected from hydrogen, OR7, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, C(═O)alkyl, C(═O)substituted alkyl, C(═O)cycloalkyl. C(═O)substituted cycloalkyl, C(═O)aryl, C(═O)substituted aryl, C(═O)O-alkyl, C(═O)O-substituted alkyl, C(═O)heterocyclo, C(═O)heteroaryl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl and substituted heteroaryl, or R6 and R9 are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted heterocyclic ring of 3 to 8 atoms, or substituted or unsubstituted heteroaryl ring of 5 atoms;
R20 is selected from alkyl and substituted alkyl;
R25 is the same or different and is selected from hydrogen, halogen, nitro, cyano, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, O—R7, NR8R9, SR7, S(O)R7, SO2R7, SO3R7, SO2NR8R9, —C(═O)R7, CO2R7, C(═O)NR8R9, and —C≡C—Si(CH3)3;
R28 and R46 are independently selected from hydrogen, C1-4alkyl, hydroxy, halogen, hydroxyC1-4alkyl, haloC1-4alkyl, and heterocycloC1-4alkyl, or taken together form a C3-7 cycloalkyl ring;
R40 and R45 are independently selected from hydrogen, cyano, C1-8alkyl, and C1-8alkyl substituted with hydroxy, or R40 and R45 are taken together to form a substituted or unsubstituted cycloalkyl ring of 3 to 7 atoms;
R32 is selected from cyano, OR34, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl,
R34 is selected from hydrogen, alkyl, and trifluoromethyl;
R31 and R41 are independently selected from ═O, ═CH2, halogen, trifluoromethyl, C2-4alkenyl, C2-4alkynyl, SR60, cyano, S(═O)alkyl, SO2(alkyl), CO2(alkyl), SO2NR50R51, NR50R51, OR60;
or a group R62;
or a C1-6alkyl optionally substituted with up to two groups selected from R62, NR50R51, OR50, and SO2(alkyl);
R42 is at each occurrence independently selected from halogen, trifluoromethyl, C2-4alkenyl, C2-4alkynyl, S(alkyl), cyano, S(═O)alkyl, SO2(alkyl), CO2(alkyl), SO2NR50R51, NR60R51, OR60;
or a group R62;
or a C1-6alkyl optionally substituted with up to two groups selected from R62, NH2, NH(C1-4alkyl), N(C1-4alkyl)2, OR60, and SO2(alkyl);
R50 and R51 are independently selected from hydrogen, hydroxy, —(CH2)d-cycloalkyl, —(CH2)d-heterocyclo, O(alkyl), O(SI)(C1-4alkyl)3, or R50 and R51 together form a four to six membered heterocyclo ring, wherein when R50 or R51 is a heterocyclo, said heterocyclo in turn is optionally substituted with up to two groups selected from lower alkyl, NH3, NH(C1-4alkyl), and/or N(C1-4alkyl)2;
R60 is selected from hydrogen, alkyl, pyridyl, pyrimidinyl, and C1-6alkyl substituted with O(alkyl), NH2, NH(C1-4alkyl), N(C1-4alkyl)2, or five or six membered heterocyclo, wherein each R60 in turn is optionally substituted with up to two groups selected from C1-4alkyl, S(alkyl), NH2, NH(C1-4alkyl), and/or N(C1-4alkyl)2;
R62 is selected from phenyl, five to seven membered heterocyclo, or five to six membered heteroaryl, wherein each R62 in turn is optionally substituted with one to two groups selected from OH, SO2(alkyl), CH2—OH, CH2—OCH3, NHC(═O)CH3, NH2, NH(C1-4alkyl), and/or N(C1-4alkyl)2;
d is 0, 1, 2, 3 or 4;
e is 1, 2, or 3;
and
f is 0, 1, 2, or 3.

41 more elements

A compound having the formula,

or an enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt, solvate, or prodrug thereof,
wherein:
X5 is N
X7 is CR1;
W is —C(═O)—, —S(═O)—, or —S(O)2—;
or W may be —CH2— if X is —C(═O)—, —S(═O)—, or —S(O)2—;
X is selected from —CH2—, —N(R4)—, and —O—, except that when W is —CH2, X is selected from —C(═O)—, —S(═O)—, or —S(O)2—;
or
the groups W—X taken together are —C(═O)NR4—;
Y is —C(R40)(R45)—;
Q is selected from a bond, —C(R26)(R46)—, —C(═O)—, —CH2—O—, —CH2—O—CH2, —CH2—CO2—NR4—, —CH2—CO2—, —C(═O)NR4—, and —CH═C(R26)—;
Z is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl, and when Q is a bond or —C(R26)(R46)—, Z may be CO2H or CO2alkyl;
R1 is the same or different and is selected from hydrogen, halogen, cyano, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, O—R7, —(C═O)R7, —(C═O)—O—R7, NR8R9, —(C═O)NR8R9, —SR20, —S(═O)R20, —SO2R20 and —C≡C—Si(CH3)3;
R4 is selected from H, OH and C1-4alkyl;
R7 is selected from hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl, C(═O)alkyl, C(═O)substituted alkyl, C(═O)cycloalkyl, C(═O) substituted cycloalkyl, C(═O)aryl, C(═O)substituted aryl, C(═O)O-alkyl C(═O)O-substituted alkyl, C(═O)heterocyclo, —C(═O)—NR8R9, C(═O)heteroaryl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, heteroaryl and substituted heteroaryl;
R8 and R9 are independently selected from hydrogen, OR7, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, C(═O)alkyl, C(═O)substituted alkyl, C(═O)cycloalkyl, C(═O)substituted cycloalkyl, C(═O)aryl, C(═O)substituted aryl, C(═O)O-alkyl, C(═O)O-substituted alkyl, C(═O)heterocyclo, C(═O)heteroaryl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl and substituted heteroaryl, or R8 and R9 are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted heterocyclic ring of 3 to 8 atoms, or substituted or unsubstituted heteroaryl ring of 5 atoms;
R20 is selected from alkyl and substituted alkyl;
R25 is the same or different and is selected from hydrogen, halogen, nitro, cyano, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, O—R7, NR8R9, SR7, S(O)R7, SO2R7, SO3R7, SO2NR8R9, —C(═O)R7, CO2R7, C(═O)NR8R9, and —C≡C—Si(CH3)3;
R26 and R46 are independently selected from hydrogen, C1-4alkyl, hydroxy, halogen, hydroxyC1-4alkyl, haloC1-4alkyl, and heterocycloC1-4alkyl or taken together form a C3-7cycloalkyl ring;
and
R40 and R45 are both methyl, or one of R40 and R45 is methyl and the other of R40 and R45 is cyano, or R40 and R45 together form cyclopropyl, cyclobutyl, or cyclopentyl.

18 more elements

A compound having the formula (I),

or an enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt, solvate, or prodrug thereof,
wherein:
X1 is CR1;
X2 is selected from CR25 and N;
X3 is CR1;
X4 is CR1;
X5 is CR1;
X6 is selected from CR25 and N;
X7 is CR1;
X8, X9, X10 and X11 are C;
Provided, however, that at least one of X2 and X6 is N;
and provided further that X1, X2, X3, X4, X5, X6, X7, X8, X9, X10 and X11 are selected such that a tricyclic heteroaryl ring system is formed;
W is —C(═O)—, —S(═O)—, or —S(O)2—;
or W may be —CH2— if X is —C(═O)—, —S(═O)—, or —S(O)2—;
X is selected from —CH2—, —N(R4)—, and —O—, except that when W is —CH2—, X is selected from —C(═O)—, —S(═O)—, or —S(O)2—;
Y is a bond or —C(R40)(R45)—;
Q is selected from a bond, —C(R26)(R48)—, —C(═O)—, —CH2—O—, —CH2—O—CH2—, —CH2—CO2NR4—, —CH2—CO2—, —C(═O)NR4—, and —CH═C(R26)—;
R1 is the same or different and is selected from hydrogen, halogen, cyano, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, O—R7, —(C═O)R7, —(C═O)—O—R7, NR8R9, —(CO)NR8R9, —SR20, —S(═O)R20, —SO2R20 and —C≡C—SI(CH3)3;
R3 is selected from H, OH and NH2;
R4 is selected from H, OH and C1-4alkyl;
R7 is selected from hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl, C(═O)alkyl, C(═O)substituted alkyl, C(═O)cycloalkyl, C(═O) substituted cycloalkyl, C(═O)aryl, C(═O)substituted aryl, C(═O)O-alkyl, C(═O)O-substituted alkyl, C(═O)heterocyclo, —C(═O)—NR8R9, C(═O)heteroaryl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, heteroaryl and substituted heteroaryl;
R8 and R9 are independently selected from hydrogen, OR7, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, C(═O)alkyl, C(═O)substituted alkyl, C(═O)cycloalkyl, C(═O)substituted cycloalkyl, C(═O)aryl, C(═O)substituted aryl, C(═O)O-alkyl, C(═O)O-substituted alkyl, C(═O)heterocyclo, C(═O)heteroaryl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl and substituted heteroaryl, or R8 and R9 are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted heterocyclic ring of 3 to 8 atoms, or substituted or unsubstituted heteroaryl ring of 5 atoms;
R20 is selected from alkyl and substituted alkyl;
R26 is the same or different and is selected from hydrogen, halogen, nitro, cyano, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, O—R7, NR8R9SR7, S(O)R7, SO2R7, SO3R7, SO2NR8R9, —C(═O)R7, CO2R7, C(═O)NR8R9, and —C≡C—SI(CH3)3;
R30 is selected from ═O and ═S;
R26 and R46 are independently selected from hydrogen, C1-4alkyl, hydroxy, halogen, hydroxyC1-4alkyl, haloC1-4alkyl, and heterocycloC1-4alkyl, or taken together form a C3-7cycloalkyl ring;
R40 and R45 are independently selected from hydrogen, cyano, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, heteroaryl and substituted heteroaryl, or R40 and R45 are taken together to form a substituted or unsubstituted cycloalkyl ring of 3 to 8 atoms or a substituted or unsubstituted heterocyclo ring of 3 to 8 atoms;
and
Z is selected from

26 more elements

A compound having the formula (I),

or an enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt, solvate, or prodrug thereof,
wherein:
X1 is CR1;
X2 is selected from CR25 and N;
X3 is CR1;
X4 is CR1;
X5 is CR1;
X6 is selected from CR25 and N;
X7 is CR1;
X8, X9, X10 and X11 are C;
Provided, however, that at least one of X2 and X8 is N;
and provided further that X1, X2, X3, X4, X5, X6, X7, X8, X9, X10 and X11 are selected such that a tricyclic heteroaryl ring system is formed;
W is —C(═O)—, —S(═O)—, or —S(O)2—;
or W may be —CH2— if X is —C(═O)—, —S(═O)—, or —S(O)2—;
X is selected from —CH2—, —N(R4)—, and —O—, except that when W is —CH2—, X is selected from —C(═O)—, —S(═O)—, or —S(O)2—;
Y is a bond;
Q is selected from a bond, —C(R26)(R45)—, —C(═O)—, —CH2—O—, —CH2—O—CH2—, —CH2—CO2—NR4—, —CH2CO2—, —C(═O)NR4—, and —CH═C(R26)—;
R1 is the same or different and is selected from hydrogen, halogen, cyano, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, O—R7, —(C≡O )R7, —(C═O)—O—R7, NR8R9, —(C═O)NR8R9, —SR20, —S(═O)R20, —SO2R20 and —C≡C—SI(CH3)3;
R3 is selected from H, OH and NH2;
R4 is selected from H, OH and C1-4 alkyl;
R7 is selected from hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl, C(═O)alkyl, C(═O)substituted alkyl, C(═O)cycloalkyl, C(═O) substituted cycloalkyl, C(═O)aryl, C(═O)substituted aryl, C(═O)O-alkyl, C(═O)O-substituted alkyl, C(═O)heterocyclo, —C(═O)—NR8R9, C(═O)heteroaryl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, heteroaryl and substituted heteroaryl;
R8 and R9 are independently selected from hydrogen, OR7, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, C(═O)alkyl, C(═O)substituted alkyl, C(═O)cycloalkyl, C(═O)substituted cycloalkyl, C(═O)aryl, C(═O)substituted aryl, C(═O)O-alkyl, C(═O)O-substituted alkyl, C(═O)heterocyclo, C(═O)heteroaryl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl and substituted heteroaryl, or R8 and R9 are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted heterocyclic ring of 3 to 8 atoms, or substituted or unsubstituted heteroaryl ring of 5 atoms;
R20 is selected from alkyl and substituted alkyl;
R25 is the same or different and is selected from hydrogen, halogen, nitro, cyano, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, O—R7, NR8R9, SR7, S(O)R7, SO2R7, SO3R7, SO2NR8R9, —C(═O)R7, CO2R7, C(═O)NR8R9, and —C≡C—SI(CH3)3;
R30 is selected from ═O and ═S;
R26 and R48 are independently selected from hydrogen, C1-4alkyl, hydroxy, halogen, hydroxyC1-4alkyl, haloC1-4alkyl, and heterocycloC1-4alkyl, or taken together form a C3-7cycloalkyl ring;
and
Z is selected from

25 more elements

A compound having the formula (I),

or an enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt, solvate, or prodrug thereof,
wherein:
X1 is CR1;
X2 is selected from CR25 and N;
X3 is CR1;
X4 is CR1;
X5 is CR1;
X6 is selected from CR25 and N;
X7 is CR1;
X8, X9, X10 and X11 are C;
Provided, however, that at least one of X2 and X8 is N;
and provided further that X1, X2, X3, X4, X5, X6, X7, X8, X9, X10 and X11 are selected such that a tricyclic heteroaryl ring system is formed;
the groups W—X—Y—Q—Z taken together are selected from:
R1 is the same or different and is selected from hydrogen, halogen, cyano, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, O—R7, —(C═O)R7, —(C═O)—O—R7, NR8R9, —(C═O)NR8R9, —SR20, —S(═O)R20, —SO2R20 and —C≡C—SI(CH3)3;
R3 is selected from H, OH and NH2;
R7 is selected from hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl, C(═O)alkyl, C(═O)substituted alkyl, C(═O)cycloalkyl, C(═O) substituted cycloalkyl, C(═O)aryl, C(═O)substituted aryl, C(═O)O-alkyl, C(═O)O-substituted alkyl, C(═O)heterocyclo, —C(═O)—NR8R9, C(═O)heteroaryl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, heteroaryl and substituted heteroaryl;
R8 and R9 are independently selected from hydrogen, OR7, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, C(═O)alkyl, C(═O)substituted alkyl, C(═O)cycloalkyl C(═O)substituted cycloalkyl, C(═O)aryl, C(═O)substituted aryl, C(═O)O-alkyl, C(═O)O-substituted alkyl, C(═O)heterocyclo, C(═O)heteroaryl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl and substituted heteroaryl, or R8 and R9 are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted heterocyclic ring of 3 to 8 atoms, or substituted or unsubstituted heteroaryl ring of 5 atoms;
R20 is selected from alkyl and substituted alkyl;
R25 is the same or different and is selected from hydrogen, halogen, nitro, cyano, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, O—R7, NR8R9, SR7, S(O)R7, SO2R7, SO3R7, SO2NR8R9, —C(═O)R7, CO2R7, C(═O)NR8R9, and —C≡C—Si(CH3)3;
and
R30 is selected from ═O and ═S.

18 more elements

A pharmaceutical composition comprising a compound having the formula (I),

or an enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt, solvate, or prodrug thereof,
wherein:
X1 is CR1;
X2 is selected from CR25 and N;
X3 is CR1;
X4 is CR1;
X5 is CR1;
X6 selected from CR25 and N;
X7 is CR1;
X8, X9, X10 and X11 are C;
Provided, however, that at least one of X2 and X6 is N;
and provided further that X1, X2, X3, X4, X5, X6, X7, X8, X9, X10 and X11 are selected such that a tricyclic heteroaryl ring system is formed;
W is —C(═O)—, —S(═O)—, or —S(O)2—;
or W may be —CH2— if X is —C(═O)—, —S(═O)—, or —S(O)2—;
X is selected from —CH2—, —N(R4)—, and —O—, except that when W is —CH2, X is selected from —C(═O)—, —S(═O)—, or —S(O)2—;
Y is a bond or —C(R40)(R45)—;
Q is selected from a bond, —C(R26)(R48)—, —C(═O)—, —CH2O—, —CH2—O—CH2—, —CH2—CO2NR4—, —CH2—CO2—, —C(═O)NR4—, and —CH═C(R26)—;
Z is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl, and when Y is —C(R40)(R45)— and Q is a bond or —C(R26)(R46)—, Z may be CO2H or CO2alkyl;
R1 is the same or different and is selected from hydrogen, halogen, cyano, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, O—R7, —(C═O)R7, —(C═O)—O—R7, NR8R9, —(C═O)NR8R9, —SR20, —S(═O)R20, —SO2R20 and —C≡C—Si(CH3)3;
R3 is selected from H, OH and NH2;
R4 is selected from H, OH and C1-4 alkyl;
R7 is selected from hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl, C(═O)alkyl, C(═O)substituted alkyl, C(═O)cycloalkyl, C(═O) substituted cycloalkyl, C(═O)aryl, C(═O)substituted aryl, C(═O)O-alkyl, C(═O)O-substituted alkyl, C(O)heterocyclo, —C(═O)—NR8R9, C(═O)heteroaryl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, heteroaryl and substituted heteroaryl;
R8 and R9 are independently selected from hydrogen, OR7, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, C(═O)alkyl, C(═O)substituted alkyl, C(═O)cycloalkyl, C(═O)substituted cycloalkyl, C(═O)aryl, C(═O)substituted aryl, C(═O)O-alkyl, C(═C))O-substituted alkyl, C(═O)heterocyclo, C(═O)heteroaryl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl and substituted heteroaryl, or R8 and R9 are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted heterocyclic ring of 3 to 8 atoms, or substituted or unsubstituted heteroaryl ring of 5 atoms;
R20 is selected from alkyl and substituted alkyl;
R25 is the same or different and is selected from hydrogen, halogen, nitro, cyano, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, O—R7, NR8R9, SR7, S(O)R7, SO2R7, SO3R7, SO2NR8R9, —C(═O)R7, CO2R7, C(═O)NR8R9, and —C≡C—Si(CH3)3;
R50 is selected from ═O and ═S;
R20 and R40 are independently selected from hydrogen, C1-4alkyl, hydroxy, halogen, hydroxyC1-4alkyl haloC1-4alkyl, and heterocycloC1-4alkyl, or taken together form a C3-7 cycloalkyl ring;
R40 and R45 are independently selected from hydrogen, cyano, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, heteroaryl and substituted heteroaryl, or R40 and R45 are taken together to form a substituted or unsubstituted cycloalkyl ring of 3 to 8 atoms or a substituted or unsubstituted heterocyclo ring of 3 to a atoms;
and a pharmaceutically acceptable carrier.

26 more elements

A method of treating at least one inosine monophosphate dehydrogenase associated disorder, wherein the disorder is selected from psoriasis, transplant rejection, and rheumatoid arthritis, comprising administering to a subject in need of treatment thereof an effective amount of at least one compound having the formula (I),

or an enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt, solvate, or prodrug thereof,
wherein:
X1 is CR1;
X2 is selected from CR2 and N;
X3 CR1;
X4 is CR1;
X5 is CR1;
X6 is selected from CR25 and N;
X7 is CR1;
X8, X9, X10 and X11 are C;
Provided, however, that at least one of X2 and X5 is N;
and provided further that X1, X2, X3, X4, X5, X6, X7, X8, X9, X10 and X11 are selected such that a tricyclic heteroaryl ring system is formed;
W is —C(═O)—, —S(═O)—, or —S(O)2—;
or W may be —CH2— if X is —C(═O)—, —S(═O)—, or —S(O)2—;
X is selected from —CH2—, —N(R4)—, and —O—, except that when W is —CH2—, X is selected from —C(═O)—, —S(═O)—, or —S(O)2—;
Y is a bond or —C(R40)(R45)—;
Q is selected from a bond, —C(R26)(R46)—, —C(═O)—, —CH2—O—, —CH2—O—CH2—, —CH2—CO2—NR4—, —CH2—CO2—, —C(═O)NR4—, and —CH═C(R26)—;
Z is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl, and when Y is —C(R40)(R45)— and Q is a bond or —C(R28)(R46)—, Z may be CO2H or CO2alkyl;
R1 is the same or different and is selected from hydrogen, halogen, cyano, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, O—R7, —(C═O)R7, —(C═O)—O—R7, NR8R9, —(C═O)NR8R9, —SR20, —S(═O)R20, —SO2R20 and —C≡C—Si(CH3)3;
R3 is selected from H, OH and NH2;
R4 is selected from H, OH and C1-4 alkyl;
R7 is selected from hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl, C(═O)alkyl, C(═O)substituted alkyl, C(═O)cycloalkyl, C(═O) substituted cycloalkyl, C(═O)aryl, C(═O)substituted aryl, C(═O)O-alkyl, C(═O)O-substituted alkyl, C(═O)heterocyclo, —C(═O)—NR8R9, C(═O)heteroaryl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, heteroaryl and substituted heteroaryl;
R8 and R9 are independently selected from hydrogen, OR7, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, C(═O)alkyl, C(═O)substituted alkyl, C(═O)cycloalkyl, C(═O)substituted cycloalkyl, C(═O)aryl, C(═O)substituted aryl, C(═O)O-alkyl, C(═O)O-substituted alkyl, C(═O)heterocyclo, C(═O)heteroaryl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl and substituted heteroaryl, or R8 and R9 are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted heterocyclic ring of 3 to 8 atoms, or substituted or unsubstituted heteroaryl ring of 5 atoms;
R20 is selected from alkyl and substituted alkyl;
R25 is the same or different and is selected from hydrogen, halogen, nitro, cyano, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, O—R7, NR8R9, SR7, S(O)R7, SO2R7, SO3R7, SO2NR8R9, —C(═O)R7, CO2R7, C(═O)NR8R9, and —C≡O—Si(CH3)3;
R30 is selected from ═O and ═S;
R28 and R46 are independently selected from hydrogen, C1-4alkyl, hydroxy, halogen, hydroxyC1-4alkyl, haloC1-4alkyl, and heterocycloC1-4alkyl, or taken together form a C3-7 cycloalkyl ring;
and
R40 and R45 are independently selected from hydrogen, cyano, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, heteroaryl and substituted heteroaryl, or R40 and R45 are taken together to form a substituted or unsubstituted cycloalkyl ring of 3 to 8 atoms or a substituted or unsubstituted heterocyclo ring of 3 to 8 atoms.

26 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/325,009Filed 20 Dec 2002 · us provisional application
Priority: 21 Dec 2001
Published: US 2003/0181497 A125 Sep 2003
Granted: 12 Jul 2005
Term ends: Not estimatedThe source records don’t support an estimate.

Classification35 codes

C07D 401/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
A61P 1/18
Drugs for disorders of the alimentary tract or the digestive system: for pancreatic disorders, e.g. pancreatic enzymes
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics

Family

Application60/343,234Us provisional application · filed 21 Dec 2001
US 2003/0181497 A1Pre-grant publication · published 25 Sep 2003
US 6,916,809 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound having the formula,

or an enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt, solvate, or prodrug thereof,
wherein:
X1 is CR1;
X2 is selected from CR25 and N;
X6 is selected from CR25 and N;
X7 is CR3;
X9 is C;
Provided, however, that at least one of X2 and X6 is N;
and provided further that X1, X2, X6, X7 and X9 are selected such that a tricyclic heteroaryl ring system is formed;
W is —C(═O)—, —S(═O)—, or —S(O)2—;
Y is a bond or —C(R40)(R45)—;
Q is selected from a bond, —C(R26)(R48)—, —C(═O)—, —CH2—O—, —CH2—O—CH2—CO2—NR4—, —CH2—CO2—, —C(═O)NR4—, and —CH═C(R25)—;
Z is selected from Z1 and Z2, wherein when Y and Q are both a bond, Z is Z1;
and when Y is —C(R40)(R46)— and Q is selected from a bond, —C(R26)(R46)—, —C(═O)—, —CH2—O—CH2—, —CH2—CO2—NR4—, —CH2—CO2—, —C(═O)NR4—, and —CH═C(CR28)—, then Z is Z2;
Z1 is
wherein J and K are each independently a bond, O, NR31, or —CHR31—;
Z2 is selected from
a) C1-6alkyl optionally substituted with one to two R31;
b) piperidyl, piperazinyl, morpholinyl, or C3-7cycloalkyl optionally substituted with one to three R41;
and
c) phenyl, napthyl, benzocyclopentyl, indolyl, tetrahydroquinolyl, oxazolyl, imidazolyl, thiazolyl, pyridyl, pyridinyl, pyrimidinyl, and pyrazinyl, optionally substituted with one to three R42;
R1 is the same or different and is selected from hydrogen, halogen, cyano, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, O—R7, —(C═O)R7, —(C═O)—O—R7, NR8R9, —(C═O)NR8R9, —SR20, —S(═O)R20, —SO2R20 and —C≡C—Si(CH3)3;
R4 is selected from H and C1-4 alkyl;
R7 is selected from hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl, C(═O)alkyl, C(═O)substituted alkyl, C(═O)cycloalkyl, C(═O) substituted cycloalkyl, C(═O)aryl, C(═O)substituted aryl, C(═O)O-alkyl, C(═O)O-substituted alkyl, C(═O)heterocyclo, —C(═O)—NR8R9, C(═O)heteroaryl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, heteroaryl and substituted heteroaryl;
R8 and R9 are independently selected from hydrogen, OR7, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, C(═O)alkyl, C(═O)substituted alkyl, C(═O)cycloalkyl. C(═O)substituted cycloalkyl, C(═O)aryl, C(═O)substituted aryl, C(═O)O-alkyl, C(═O)O-substituted alkyl, C(═O)heterocyclo, C(═O)heteroaryl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl and substituted heteroaryl, or R6 and R9 are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted heterocyclic ring of 3 to 8 atoms, or substituted or unsubstituted heteroaryl ring of 5 atoms;
R20 is selected from alkyl and substituted alkyl;
R25 is the same or different and is selected from hydrogen, halogen, nitro, cyano, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, O—R7, NR8R9, SR7, S(O)R7, SO2R7, SO3R7, SO2NR8R9, —C(═O)R7, CO2R7, C(═O)NR8R9, and —C≡C—Si(CH3)3;
R28 and R46 are independently selected from hydrogen, C1-4alkyl, hydroxy, halogen, hydroxyC1-4alkyl, haloC1-4alkyl, and heterocycloC1-4alkyl, or taken together form a C3-7 cycloalkyl ring;
R40 and R45 are independently selected from hydrogen, cyano, C1-8alkyl, and C1-8alkyl substituted with hydroxy, or R40 and R45 are taken together to form a substituted or unsubstituted cycloalkyl ring of 3 to 7 atoms;
R32 is selected from cyano, OR34, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl,
R34 is selected from hydrogen, alkyl, and trifluoromethyl;
R31 and R41 are independently selected from ═O, ═CH2, halogen, trifluoromethyl, C2-4alkenyl, C2-4alkynyl, SR60, cyano, S(═O)alkyl, SO2(alkyl), CO2(alkyl), SO2NR50R51, NR50R51, OR60;
or a group R62;
or a C1-6alkyl optionally substituted with up to two groups selected from R62, NR50R51, OR50, and SO2(alkyl);
R42 is at each occurrence independently selected from halogen, trifluoromethyl, C2-4alkenyl, C2-4alkynyl, S(alkyl), cyano, S(═O)alkyl, SO2(alkyl), CO2(alkyl), SO2NR50R51, NR60R51, OR60;
or a group R62;
or a C1-6alkyl optionally substituted with up to two groups selected from R62, NH2, NH(C1-4alkyl), N(C1-4alkyl)2, OR60, and SO2(alkyl);
R50 and R51 are independently selected from hydrogen, hydroxy, —(CH2)d-cycloalkyl, —(CH2)d-heterocyclo, O(alkyl), O(SI)(C1-4alkyl)3, or R50 and R51 together form a four to six membered heterocyclo ring, wherein when R50 or R51 is a heterocyclo, said heterocyclo in turn is optionally substituted with up to two groups selected from lower alkyl, NH3, NH(C1-4alkyl), and/or N(C1-4alkyl)2;
R60 is selected from hydrogen, alkyl, pyridyl, pyrimidinyl, and C1-6alkyl substituted with O(alkyl), NH2, NH(C1-4alkyl), N(C1-4alkyl)2, or five or six membered heterocyclo, wherein each R60 in turn is optionally substituted with up to two groups selected from C1-4alkyl, S(alkyl), NH2, NH(C1-4alkyl), and/or N(C1-4alkyl)2;
R62 is selected from phenyl, five to seven membered heterocyclo, or five to six membered heteroaryl, wherein each R62 in turn is optionally substituted with one to two groups selected from OH, SO2(alkyl), CH2—OH, CH2—OCH3, NHC(═O)CH3, NH2, NH(C1-4alkyl), and/or N(C1-4alkyl)2;
d is 0, 1, 2, 3 or 4;
e is 1, 2, or 3;
and
f is 0, 1, 2, or 3.

41 more elements

Facts

Application

10/325,009Filed 20 Dec 2002 · us provisional application

Priority

21 Dec 2001

Published

US 2003/0181497 A125 Sep 2003

Granted

12 Jul 2005

Term ends

Not estimatedThe source records don’t support an estimate.

Classification35 codes

C07D 401/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
A61P 1/18
Drugs for disorders of the alimentary tract or the digestive system: for pancreatic disorders, e.g. pancreatic enzymes
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics