US 6,617,323 B2 · Amino-substituted compounds useful as inhibitors of IMPDH enzyme

Abstract

The present invention discloses compounds useful in treating or preventing IMPDH-associated disorders, such as transplant rejection and autoimmune diseases, having the formula (I), wherein X is —C(O)—, —C(S)—, or —S(O)2—; A is an optionally-substituted saturated or unsaturated monocyclic or bicyclic ring; B is a saturated or unsaturated monocyclic or bicyclic ring system having at least one substituent Q which is selected from R7 and R8; R7 is selected from (C0-C6)alkyl, (C2-C6)alkenyl and (C2-C6)alkynyl and R7 is substituted with R8 is selected from (C0-C6)alkyl, (C2-C6)alkenyl and (C2-C6)alkynyl and R8 is substituted with and Z1 through Z5 are as defined in the specification.

A compound having the formula,

or a pharmaceutically acceptable salt thereof, in which
U2 is selected from R10 and R11;
Z3 is selected from OR2 and NR3R4;
R1 is oxazolyl optionally substituted with oxo (═O);
and optionally having up to 3 substituents selected from R2 and R3;
R2 is selected from halogen, CN, NO2, CF3, —(C0-C4 alkyl)OR3, OCF3, OC(O)R3, OC(O)OR3, OC(O)NR3R4, —(C0-C4 alkyl)C(O)R3, —(C0-C4alkyl)C(O)OR3, —(C0-C4alkyl)C(O)NR3R4, —(C0-C4alkyl)SR3, —(C0-C4 alkyl)S(O)R5, —(C0-C4alkyl)S(O)2R5, —(C0-C4 alkyl)S(O)2NR3R4, —(C0-C4alkyl)NR3R4, —(C0-C4 alkyl)NR3C(O)NR4, —(C0-C4 alkyl)NR3C(O)R4, —(C0-C4 alkyl)NR3C(O)OR5, and —(C0-C4 alkyl)NR3S(O)2R5;
R2a is selected from hydrogen, halogen, CN, NO2, CF3, —(C0-C4 alkyl)OR3, OCF3, OC(O)R3, OC(O)OR3, OC(O)NR3R4, —(C0-C4 alkyl)C(O)R3, —(C0-C4alkyl)C(O)OR3, —(C0-C4alkyl)C(O)NR3R4, —(C0-C4 alkyl)SR3, —(C0-C4 alkyl)S(O)R5, —(C0-C4alkyl)S(O)2R5, —(C0-C4alkyl)S(O)2NR3R4, —(C0-C4alkyl)NR3R4, —(C0-C4 alkyl)NR3C(O)NR4, —(C0-C4 alkyl)NR3C(O)R4, —(C0-C4 alkyl)NR3C(O)OR5, and —(C0-C4 alkyl)NR3S(O)2R5;
R3 is selected from hydrogen, (C1-C4)alkyl, (C2-C4)alkenyl, aryl(C0-C4)alkyl, heterocycle(C0-C4)alkyl, and cycloalkyl(C0-C4)alkyl, wherein said groups are substituted with 0-2 substituents independently selected from R6;
R4 is selected from hydrogen, (C1-C4)alkyl, (C2-C4)alkenyl, aryl(C0-C4)alkyl, heterocycle(C0-C4)alkyl, and cycloalkyl(C0-C4)alkyl, wherein said groups are substituted with 0-2 substituents independently selected from R6;
alternatively, R3 and R4, when both substituents are on the same nitrogen atom, as in (—NR3R4), can be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from the group consisting of 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, and 1-piperazinyl, said heterocycle being optionally substituted with 0-3 groups selected from the group consisting of oxo, R6, (C1-C6)alkyl, C3-C7 cycloalkyl(C0-C4alkyl), (C1-C6)alkylcarbonyl, C3-C7cycloalkyl(C0-C5alkyl)carbonyl, C1-C6alkoxycarbonyl, C3-C7cycloalkyl(C0-C5 alkoxy)carbonyl, aryl(C0-C5alkyl), heterocycle(C0-C5 alkyl), aryl(C1-C5 alkoxy)carbonyl, heterocycle(C1-C5 alkoxy)carbonyl, (C1-C6)alkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl;
R5 is selected from (C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, aryl(C0-C4) alkyl, heterocycle(C0-C4)alkyl, and cycloalkyl(C0-C4)alkyl, and each R5 optionally comprises up to 2 substituents independently selected from R6;
R6 is selected from hydrogen, halogen, NO2, CN, C1-C4alkyl, C3-C10 cycloalkyl, C2-C6alkenyl, haloalkyl, haloalkoxy, OH, hydroxyC1-C4alkyl, C1-C4 alkoxy, (C1-C4alkyl)carbonyl, NH2, (C1-C4alkyl)1-2alkylamino, C0-C4alkylthio, and (C1-C4alkyl)sulfonyl;
R10 is selected from hydrogen, (C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, aryl, heterocycle, and cycloalkyl, and each R10 optionally comprises up to 3 substituents selected from R11 and R12;
R11 is selected from hydrogen, halogen, NO2, CN, (C1-C4)alkyl, C3-C10 cycloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, haloalkyl, haloalkoxy, OH, C1-C4alkoxy, C1-C4alkylcarbonyl, NH2, (C1-C4alkyl)1-2alkylamino—, C0-C4alkylthio-, and C1-C4 alkylsulfonyl;
R12 is selected from hydrogen, alkyl, (C1-C6)alkoxy, C3-C6cycloalkyl, heterocycle and aryl;
and
x is 0, 1 or 2.

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Amino-substituted compounds useful as inhibitors of IMPDH enzyme

Life of this patent

Amino-substituted compounds useful as inhibitors of IMPDH enzyme

Life of this patent

Abstract

Claims10