US 2003/0191307 A1 · 2,4-Diaminopyrimidine compounds useful as immunosuppressants

Abstract

Novel compounds according to the formula 1 and pharmaceutically acceptable salts, solvates, or hydrates thereof; wherein each occurrence of A is independently selected from CH or N; X is selected from the group consisting of —CH2—, —O—, —NH—, (C1-C6)alkylamino-, (C1-C6)alkylaminocarbonylamino-, (C1-C6)alkylcarbonylamino-, (C1-C6)alkylsulfonylamino-, phenylsulfonylamino-, carbonyl, —NH—C(O)—, —N(C1-C6)alkyl-C(O)—, —S(O)y— where y is 0, 1 or 2, and; n in —(CH2)n— is 1, 2 or 3; and R1, R2, and R3 are as described herein; pharmaceutical compositions that including these compounds, and methods for the treatment of autoimmune disease, inflammation, allergy, transplant rejection, and other circumstances where administration of an immunosuppressive agent is of therapeutic benefit.

A compound according to the formula

19
or pharmaceutically acceptable salts, solvates, or hydrates thereof;
wherein
each occurrence of A is independently selected from CH or N;
X is selected from the group consisting of —CH2—, —O—, —NH—, (C1-C6)alkylamino-, (C1-C6)alkylaminocarbonylamino-, (C1-C6)alkylcarbonylamino-, (C1-C6)alkylsulfonylamino-, phenylsulfonylamino-, carbonyl, —NH—C(O)—, —N(C1-C6)alkyl-C(O)—, —S(O)y— where y is 0, 1 or 2, and;
n in —(CH2)n— is 1, 2 or 3;
R1 is selected from the groups consisting of (C6-C10)aryl-, (C1-C9)heteroaryl-, (C6-C10)aryl(C6-C10)aryl-, (C6-C10)aryl(C1-C9) heteroaryl-, (C1-C9)heteroaryl(C1-C9)heteroaryl-, (C1-C9)heteroaryl(C6-C10)aryl-, (C6-C10)arylsulfinyl-, (C6-C10)aryl(C6-C10)arylsulfinyl-, (C1-C9)heteroaryl(C6-C10)arylsulfinyl-, (C6-C10)arylsulfonyl-, (C6-C10)aryl(C6-C10)arylsulfonyl-, (C1-C9)heteroaryl(C6-C10)arylsulfonyl-, (C1-C9)heteroarylsulfinyl-, (C1-C9)heteroaryl(C1-C9)heteroarylsulfinyl-, (C6-C10)aryl(C1-C9)heteroarylsulfinyl-, (C1-C9)heteroarylsulfonyl-, (C1-C9)heteroaryl(C1-C9)heteroarylsulfonyl-, (C6-C10)aryl(C1-C9)heteroarylsulfonyl-, (R4)sulfinyl-, (R4)sulfonyl-, (C6-C10)aryl(R4)sulfinyl-, (C6-C10)aryl(C6-C10)aryl(R4)sulfinyl-, (C1-C9)heteroaryl(C6-C10)aryl(R4)sulfinyl-, (C6-C10)aryl(R4)sulfonyl-, (C6-C10)aryl(C6-C10)aryl(R4)sulfonyl-, (C1-C9)heteroaryl(C6-C10)aryl(R4)sulfonyl-, (C1-C9)heteroaryl(R4)sulfinyl-, (C6-C10)aryl(C1-C9)heteroaryl(R4)sulfinyl-, (C1-C9)heteroaryl(C1-C9)heteroaryl(R4)sulfinyl-, (C1-C9)heteroaryl(R4)sulfonyl-, (C6-C10)aryl(C1-C9)heteroaryl(R4)sulfonyl-, (C1-C9)heteroaryl(C1-C9)heteroaryl(R4)sulfonyl-, (C6-C10)arylaminocarbonyl-, (C6-C10)aryl(C6-C10)arylaminocarbonyl-, (C1-C9)heteroaryl(C6-C10)arylaminocarbonyl-, (C1-C9)heteroarylaminocarbonyl-, (C6-C10)aryl(C1-C9)heteroarylaminocarbonyl-, (C1-C9)heteroaryl(C1-C9)heteroarylaminocarbonyl-, (C6-C10)arylcarbonyl-, (C6-C10)aryl(C6-C10)arylcarbonyl-, (C1-C9)heteroaryl(C6-C10)arylcarbonyl-, (C1-C9)heteroarylcarbonyl-, (C6-C10)aryl(C1-C9)heteroarylcarbonyl-, (C1-C9)heteroaryl(C1-C9)heteroarylcarbonyl-, (C6-C10)aryloxycarbonyl-, (C6-C10)aryl(C6-C10)aryloxycarbonyl-, (C1-C9)heteroaryl(C6-C10)aryloxycarbonyl-, (C1-C9)heteroaryloxycarbonyl-, (C6-C10)aryl(C1-C9)heteroaryloxycarbonyl-, (C1-C9)heteroaryl(C1-C9)heteroaryloxycarbonyl-, (R4)carbonyl-, (R4)oxycarbonyl-, (R4)aminocarbonyl-, (C6-C10)aryl(R4)carbonyl-, (C6-C10)aryl(R4)oxycarbonyl-, (C6-C10)aryl(R4)aminocarbonyl-, (C1-C9)heteroaryl(R4)carbonyl-, (C1-C9)heteroaryl(R4)oxycarbonyl-, and (C1-C9)heteroaryl(R4) aminocarbonyl-;
wherein R4 is selected from the groups consisting of
(a) (C1-C6)alkyl-, (C2-C6)alkenyl-, or (C2-C6)alkynyl-, wherein the alkyl-, alkenyl- and alkynyl-groups are optionally substituted by hydroxy, halo, amino, trifluoromethyl, hydroxy(C2-C6)alkyl-, (C1-C6)alkoxy-, (C1-C6)acyloxy-, (C1-C6)alkylamino-, ((C1-C6)alkyl)2amino-, (C1-C6)acylamino-, cyano, nitro, (C1-C6)alkyl-, (C2-C6)alkenyl-, (C2-C6)alkynyl-, (C1-C6)acylamino-, cyano(C1-C6)alkyl-, trifluoromethyl(C1-C6)alkyl-, (C1-C3)alkyl(difluoromethylene)(C1-C3)alkyl-, or nitro(C1-C6)alkyl-;
(b) (C3-C10)cycloalkyl-, wherein the cycloalkyl-group is optionally substituted by hydroxy, halo, amino, trifluoromethyl, hydroxy(C2-C6)alkyl-, (C1-C6)alkoxy-, (C1-C6)acyloxy-, (C1-C6)alkylamino-, ((C1-C6)alkyl)2amino-, (C1-C6)acylamino-, cyano, nitro, (C1-C6)alkyl-, (C2-C6)alkenyl-, (C2-C6)alkynyl-, (C1-C6)acylamino-, cyano(C1-C6)alkyl-, trifluoromethyl(C1-C6)alkyl-, (C1-C3)alkyl(difluoromethylene)(C1-C3)alkyl-, or nitro(C1-C6)alkyl-;
or
(c) (C3-C10)heterocycloalkyl-, wherein the heterocycloalkyl-group is optionally substituted by hydroxy, halo, amino, trifluoromethyl, hydroxy(C2-C6)alkyl-, (C1-C6)alkoxy-, (C1-C6)acyloxy-, (C1-C6)alkylamino-, ((C1-C6)alkyl)2amino-, (C1-C6)acylamino-, cyano, nitro, (C1-C6)alkyl-, (C2-C6)alkenyl-, (C2-C6)alkynyl-, (C1-C6)acylamino-, cyano(C1-C6)alkyl-, trifluoromethyl(C1-C6)alkyl-, (C1-C3)alkyl(difluoromethylene)(C1-C3)alkyl-, or nitro(C1-C6)alkyl-;
and
wherein any of said of (C6-C10)aryl- or (C1-C9)heteroaryl-groups of R1 may be optionally substituted by one to five groups selected from
(a) deuterium, hydroxy, halo, amino, trifluoromethyl, carboxy, (C1-C6)alkoxy-, (C1-C6)acyloxy-, (C1-C6)alkylamino-, ((C1-C6)alkyl)2amino-, (C1-C6)acylamino-, cyano, nitro, (C1-C6)alkyl-, (C2-C6)alkenyl-, (C2-C6)alkynyl-, (C1-C6)acylamino-, cyano(C1-C6)alkyl-, trifluoromethyl(C1-C6)alkyl-, or nitro(C1-C6)alkyl-, (C1-C3)alkyl(difluoromethylene)(C1-C3)alkyl-, (C1-C6)acylamino(C1-C6)alkyl-, (C1-C6)alkoxy(C1-C6)acylamino-, amino(C1-C6)acyl-, amino(C1-C6)acyl(C1-C6)alkyl-, (C1-C6)alkylamino(C1-C6)acyl-, ((C1-C6)alkyl)2amino(C1-C6)acyl-, (C3-C10)cycloalkyl(C1-C6)alkyl-, (C1-C6)acyloxy(C1-C6)alkyl-, (C2-C6)alkoxy(C1-C6)alkyl-, piperazinyl(C1-C6)alkyl-, (C1-C6)acylamino(C1-C6)alkyl-, (C6-C10)aryl(C1-C6)alkoxy(C1-C6)alkyl-, (C5-C9)heteroaryl(C1-C6)alkoxy(C1-C6)alkyl-, (C1-C6)alkylthio(C1-C6)alkyl-, (C6-C10)arylthio(C1-C6)alkyl-, (C1-C6)alkylsulfinyl(C1-C6)alkyl-, (C6-C10)arylsulfinyl(C1-C6)alkyl-, (C1-C6)alkylsulfonyl(C1-C6)alkyl-, (C6-C10)arylsulfonyl(C1-C6)alkyl-, amino(C1-C6)alkyl-, (C1-C6)alkylamino(C1-C6)alkyl-, (C1-C6)alkyl(difluoromethylene)-, (C1-C3)alkyl(difluoromethylene)(C1-C3)alkyl-, (C1-C6)alkoxy(C1-C6)acyl-, (C1-C6)alkylamino(C1-C6)acyl-, ((C1-C6)alkyl)2amino(C1-C6)acyl-, (C6-C10)aryl-, (C1-C9)heteroaryl-, (C6-C10)aryl(C1-C6)alkyl-, (C1-C9)heteroaryl(C1-C6)alkyl-, (C6-C10)aryl(C6-C10)aryl-, (C6-C10)aryl(C6-C10)aryl(C1-C6)alkyl-, (C3-C10)cycloalkyl-, (C3-C6)cycloalkyl(C1-C6)alkyl-, (C3-C10)heterocycloalkyl-, (C3-C10)heterocycloalkyl(C1-C6)alkyl-, hydroxy(C2-C6)alkyl-, (C1-C6)acyloxy(C2-C6)alkyl-, (C1-C6)alkoxy(C2-C6)alkyl-, piperazinyl(C1-C6)alkyl-, (C1-C6)acylamino(C1-C6)alkyl-, (C6-C10)aryl(C1-C6)alkoxy(C1-C6)alkyl-, (C1-C9)heteroaryl(C1-C6)alkoxy(C1-C6)alkyl-, (C1-C6)alkylthio(C1-C6)alkyl-, (C6-C10)arylthio(C1-C6)alkyl-, (C1-C6)alkylsulfinyl(C1-C6)alkyl-, (C6-C10)arylsulfinyl(C1-C6)alkyl-, (C1-C6)alkylsulfonyl(C1-C6)alkyl-, (C6-C10)arylsulfonyl(C1-C6)alkyl-, amino(C1-C6)alkyl-, (C1-C6)alkylamino(C1-C6)alkyl-, ((C1-C6)alkyl)2amino(C1-C6)alkyl-;
(b) R5OCO(C1-C6)alkyl-, wherein R5 is selected from the group consisting of hydrogen, (C1-C6)alkyl-, (C6-C10)aryl(C1-C6)alkyl-, (C1-C9)heteroaryl(C1-C6)alkyl-;
or
(c) R6(C0-C6)alkyl-, wherein R6 is selected from the group consisting of piperazino, (C1-C6)acylpiperazino-, (C6-C10)arylpiperazino-, (C5-C9)heteroarylpiperazino-, (C1-C6)alkylpiperazino-, (C6-C10)aryl(C1-C6)alkylpiperazino-, (C1-C9)heteroaryl(C1-C6)alkylpiperazino-, morpholino-, (C1-C6)acylmorpholino-, (C6-C10)arylmorpholino-, (C1-C9)heteroarylmorpholino-, (C1-C6)alkylmorpholino-, (C6-C10)aryl(C1-C6)alkylmorpholino-, (C1-C9)heteroaryl(C1-C6)alkylmorpholino-, thiomorpholino-, (C1-C6)acylthiomorpholino-, (C6-C10)arylthiomorpholino-, (C1-C9)heteroarylthiomorpholino-, (C1-C6)alkylthiomorpholino-, (C6-C10)aryl(C1-C6)alkylthiomorpholino-, (C1-C9)heteroaryl(C1-C6)alkylthiomorpholino-, piperidino-, (C1-C6)acylpiperidino-, (C6-C10)arylpiperidino-, (C1-C9)heteroarylpiperidino-, (C1-C6)alkyl piperidino-, (C6-C10)aryl(C1-C6)piperidino-, (C1-C9)heteroaryl(C1-C6)alkylpiperidino-, pyrrolidino-, (C1-C6)acylpyrrolidino-, (C6-C10)aryl-pyrrolidino-, (C1-C9)heteroaryl-pyrrolidino-, (C1-C6)alkylpyrrolidino-, (C6-C10)aryl(C1-C6)pyrrolidino-, (C1-C9)heteroaryl(C1-C6)alkylpyrrolidino-, (C1-C6)alkoxy(C1-C6)acyl-, (C1-C6)alkylamino(C6-C10)aryl-, and ((C1-C6)alkyl2amino(C1-C6)acyl-;
R2 represents one to four optional substituents, each being independently selected from the members of groups (a) to (f)
(a) deuterium, halo, hydroxy, carboxy, amino, trifluoromethyl, (C1-C6) alkyl-, (C2-C6)alkenyl-, (C2-C6)alkynyl-, (C1-C6)alkylamino-, ((C1-C6)(alkyl)2amino-, cyanoalkyl-, (C3-C10)cycloalkyl-, (C3-C10)heterocycloalkyl-, (C3-C10)cycloalkoxy-, (C1-C6)alkylthio-, (C1-C6)alkylsulfinyl-, (C1-C6)alkylsulfonyl-, amino-CO—NH—, (C1-C6)alkoxy-CO—NH—, (C1-C6)alkyl-CO—NH—, (C1-C6)alkyl-CO—NH—(C1-C6)alkyl-, (C1-C6)alkyl-CO—NH—(C1-C6)alkoxy-, (C1-C6)alkoxycarbonyl(C1-C6)alkoxy-, (C1-C6)alkoxy-CO—NH—(C1-C6)alkoxy-, (C1-C6)alkylamino-CO—NH—, (C1-C6)alkylamino-CO—NH—(C1-C6)alkyl-, ((C1-C6)alkyl)2amino-CO—NH—(C1-C6)alkyl-, ((C1-C6)alkyl)2amino-CO—NH-carboxy, carboxy(C1-C6)alkyl-, carboxy(C1-C6)alkoxy-, benzyloxycarbonyl(C1-C6)alkoxy-, (C1-C6)alkylamino-CO—, (C1-C6)acylamino-, (C1-C6)alkoxy-, (C1-C6)acyl-, (C1-C6)acyloxy-, (C1-C6)acyl(C1-C6)alkylamino-, (C1-C6)alkoxyacyl-, (C1-C6)alkylaminoacyl-, ((C1-C6)alkyl)2aminoacyl-, amino(C1-C6)acyl-, amino(C1-C6)alkyl-, (C1-C6)alkoxycarbonylamino-, (C1-C6)alkoxycarbonyl(C1-C6)alkyl-, (C6-C10)aryl(C1-C6)alkoxycarbonylamino-, trihalomethyl-, trihalomethyl(C1-C6)alkyl-, (C1-C6)alkyldihalomethylene-, (C1-C3)alkyl(dihalomethylene)(C1-C3)alkyl-, (C3-C6)cycloalkyl-, (C3-C6)cycloalkyl(C1-C6)alkyl-, hydroxy(C1-C6)alkyl-, (C1-C6)acyloxy(C1-C6)alkyl-, (C1-C6)alkoxy(C1-C6)alkyl-, (C1-C6)acylamino(C1-C6)alkyl-, (C1-C6)alkylthio(C1-C6)alkyl-, (C1-C6)alkoxycarbonyl-, (C1-C6)alkylsulfinyl(C1-C6)alkyl-, (C1-C6)alkylsulfonyl(C1-C6)alkyl-, (C1-C6)alkylsulfonyl-, (C1-C6)alkylsulfonylamino-, (C1-C6)alkylsulfonylamino(C1-C6)alkyl-, amino(C1-C6)alkyl-, (C1-C6)alkylamino(C1-C6)alkyl-, ((C1-C6)alkyl)2amino(C1-C6)alkyl-, (C1-C6)CO(C1-C6)alkyl-;
(b) (C6-C10)aryl-, (C1-C9)heteroaryl-, (C6-C10)aryl(C6-C10)aryl-, (C6-C10)aryl(C1-C9) heteroaryl-, (C1-C9)heteroaryl(C1-C9)heteroaryl-, (C1-C9)heteroaryl(C6-C10)aryl-, (C6-C10)arylsulfinyl-, (C6-C10)aryl(C6-C10)arylsulfinyl-, (C1-C9)heteroaryl(C6-C10)arylsulfinyl-, (C6-C10)arylsulfonyl-, (C6-C10)aryl(C6-C10)arylsulfonyl-, (C1-C9)heteroaryl(C6-C10)arylsulfonyl-, (C1-C9)heteroarylsulfinyl-, (C1-C9)heteroaryl(C1-C9)heteroarylsulfinyl-, (C6-C10)aryl(C1-C9)heteroarylsulfinyl-, (C1-C9)heteroarylsulfonyl-, (C1-C9)heteroaryl(C1-C9)heteroarylsulfonyl-, (C6-C10)aryl(C1-C9)heteroarylsulfonyl-, (R4)sulfinyl-, (R4)sulfonyl-, (C6-C10)aryl(R4)sulfinyl-, (C6-C10)aryl(C6-C10)aryl(R4)sulfinyl-, (C1-C9)heteroaryl(C6-C10)aryl(R4)sulfinyl-, (C6-C10)aryl(R4)sulfonyl-, (C6-C10)aryl(C6-C10)aryl(R4)sulfonyl-, (C1-C9)heteroaryl(C6-C10)aryl(R4)sulfonyl-, (C1-C9)heteroaryl(R4)sulfinyl-, (C6-C10)aryl(C1-C9)heteroaryl(R4)sulfinyl-, (C1-C9)heteroaryl(C1-C9)heteroaryl(R4)sulfinyl-, (C1-C9)heteroaryl(R4)sulfonyl-, (C6-C10)aryl(C5-C9)heteroaryl(R4)sulfonyl-, (C1-C9)heteroaryl(C1-C9)heteroaryl(R4)sulfonyl-, (C6-C10)arylaminocarbonyl-, (C6-C10)aryl(C6-C10)arylaminocarbonyl-, (C1-C9)heteroaryl(C6-C10)arylaminocarbonyl-, (C1-C9)heteroarylaminocarbonyl-, (C6-C10)aryl(C1-C9)heteroarylaminocarbonyl-, (C1-C9)heteroaryl(C1-C9)heteroarylaminocarbonyl-, (C6-C10)arylcarbonyl-, (C6-C10)aryl(C6-C10)arylcarbonyl-, (C1-C9)heteroaryl(C6-C10)arylcarbonyl-, (C1-C9)heteroarylcarbonyl-, (C6-C10)aryl(C1-C9)heteroarylcarbonyl-, (C1-C9)heteroaryl(C1-C9)heteroarylcarbonyl-, (C6-C10)aryloxycarbonyl-, (C6-C10)aryl(C6-C10)aryloxycarbonyl-, (C1-C9)heteroaryl(C6-C10)aryloxycarbonyl-, (C1-C9)heteroaryloxycarbonyl-, (C6-C10)aryl(C1-C9)heteroaryloxycarbonyl-, (C1-C9)heteroaryl(C1-C9)heteroaryloxycarbonyl-, (R4)carbonyl-, (R4)oxycarbonyl-, (R4)aminocarbonyl-, (C6-C10)aryl(R4)carbonyl-, (C6-C10)aryl(R4)oxycarbonyl-, (C6-C10)aryl(R4)aminocarbonyl-, (C1-C9)heteroaryl(R4)carbonyl-, (C5-C9)heteroaryl(R4)oxycarbonyl-, (C1-C9)heteroaryl(R4)aminocarbonyl-, wherein R4 is defined as above, and wherein any of said of (C6-C10)aryl- or (C1-C9)heteroaryl-R2 groups may be optionally substituted by one to five groups independently selected from:
(i) hydroxy, halo, amino, trifluoromethyl, carboxy, (C1-C6)alkoxy-, (C1-C6)acyloxy-, (C1-C6)alkylamino-, ((C1-C6)alkyl)2amino-, (C1-C6)acylamino-, cyano, nitro, (C1-C6)alkyl-, (C2-C6)alkenyl-, (C2-C6)alkynyl-, (C1-C6)acylamino-, cyano(C1-C6)alkyl-, trifluoromethyl(C1-C6)alkyl-, or nitro(C1-C6)alkyl-, (C1-C3)alkyl(difluoromethylene)(C1-C3)alkyl-, (C1-C6)acylamino(C1-C6)alkyl-, (C1-C6)alkoxy(C1-C6)acylamino-, amino(C1-C6)acyl-, amino(C1-C6)acyl(C1-C6)alkyl-, (C1-C6)alkylamino(C1-C6)acyl-, ((C1-C6)alkyl)2amino(C1-C6)acyl-, (C3-C10)cycloalkyl(C1-C6)alkyl-, (C1-C6)acyloxy(C1-C6)alkyl-, (C2-C6)alkoxy(C1-C6)alkyl-, piperazinyl(C1-C6)alkyl-, (C1-C6)acylamino(C1-C6)alkyl-, (C6-C10)aryl(C1-C6)alkoxy(C1-C6)alkyl-, (C1-C9)heteroaryl(C1-C6)alkoxy(C1-C6)alkyl-, (C1-C6)alkylthio(C1-C6)alkyl-, (C6-C10)arylthio(C1-C6)alkyl-, (C1-C6)alkylsulfinyl(C1-C6)alkyl-, (C6-C10)arylsulfinyl(C1-C6)alkyl-, (C1-C6)alkylsulfonyl(C1-C6)alkyl-, (C6-C10)arylsulfonyl(C1-C6)alkyl-, amino(C1-C6)alkyl-, (C1-C6)alkylamino(C1-C6)alkyl-, (C1-C6)alkyl(difluoromethylene)-, (C1-C3)alkyl(difluoromethylene)(C1-C3)alkyl-, (C1-C6)alkoxy(C1-C6)acyl-, (C1-C6)alkylamino(C1-C6)acyl-, ((C1-C6)alkyl)2amino(C1-C6)acyl-, (C6-C10)aryl-, (C1-C9)heteroaryl-, (C6-C10)aryl(C1-C6)alkyl-, (C1-C9)heteroaryl(C1-C6)alkyl-, (C6-C10)aryl(C6-C10)aryl-, (C6-C10)aryl(C6-C10)aryl(C1-C6)alkyl-, (C3-C10)cycloalkyl-, (C3-C6)cycloalkyl(C1-C6)alkyl-, (C3-C10)heterocycloalkyl-, (C3-C10)heterocycloalkyl(C1-C6)alkyl-, hydroxy(C2-C6)alkyl-, (C1-C6)acyloxy(C2-C6)alkyl-, (C1-C6)alkoxy(C2-C6)alkyl-, piperazinyl(C1-C6)alkyl-, (C1-C6)acylamino(C1-C6)alkyl-, (C6-C10)aryl(C1-C6)alkoxy(C1-C6)alkyl-, (C1-C9)heteroaryl(C1-C6)alkoxy(C1-C6)alkyl-, (C1-C6)alkylthio(C1-C6)alkyl-, (C6-C10)arylthio(C1-C6)alkyl-, (C1-C6)alkylsulfinyl(C1-C6)alkyl-, (C6-C10)arylsulfinyl(C1-C6)alkyl-, (C1-C6)alkylsulfonyl(C1-C6)alkyl-, (C6-C10)arylsulfonyl(C1-C6)alkyl-, amino(C1-C6)alkyl-, (C1-C6)alkylamino(C1-C6)alkyl-, ((C1-C6)alkyl)2amino(C1-C6)alkyl-;
(ii) R5OCO(C1-C6)alkyl—wherein R5 is selected from the group consisting of hydrogen, (C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl-, (C1-C9)heteroaryl(C1-C6)alkyl-;
(iii) R6(C2-C6)alkyl—wherein R6 is selected from the group consisting of piperazino, (C1-C6)acylpiperazino-, (C6-C10)arylpiperazino-, (C5-C9)heteroarylpiperazino-, (C1-C6)alkylpiperazino-, (C6-C10)aryl(C1-C6)alkylpiperazino-, (C1-C9)heteroaryl(C1-C6)alkylpiperazino-, morpholino-, (C1-C6)acylmorpholino-, (C6-C10)arylmorpholino-, (C1-C9)heteroarylmorpholino-, (C1-C6)alkylmorpholino-, (C6-C10)aryl(C1-C6)alkylmorpholino-, (C1-C9)heteroaryl(C1-C6)alkylmorpholino-, thiomorpholino-, (C1-C6)acylthiomorpholino-, (C6-C10)arylthiomorpholino-, (C1-C9)heteroarylthiomorpholino-, (C1-C6)alkylthiomorpholino-, (C6-C10)aryl(C1-C6)alkylthiomorpholino-, (C1-C9)heteroaryl(C1-C6)alkylthiomorpholino-, piperidino-, (C1-C6)acylpiperidino-, (C6-C10)arylpiperidino-, (C1-C9)heteroarylpiperidino-, (C1-C6)alkyl piperidino-, (C6-C10)aryl(C1-C6)piperidino-, (C1-C9)heteroaryl(C1-C6)alkylpiperidino-, pyrrolidino-, (C1-C6)acylpyrrolidino-, (C6-C10)arylpyrrolidino-, (C1-C9)heteroarylpyrrolidino, (C1-C6)alkylpyrrolidino-, (C6-C10)aryl(C1-C6)alkylpyrrolidino-, (C1-C9)heteroaryl(C1-C6)alkylpyrrolidino-, (C1-C6)alkoxy(C1-C6)acyl-, (C1-C6)alkylamino(C6-C10)aryl-, and ((C1-C6)alkyl2amino(C1-C6)acyl-;
(c) R7, or R7Y-, where R7 is selected from the group consisting of piperazino-, (C6-C10)arylpiperazino-, (C1-C9)heteroarylpiperazino-, (C1-C6)alkylpiperazino-, (C6-C10)aryl(C1-C6)alkylpiperazino-, (C1-C9)heteroaryl(C1-C6)alkylpiperazino-, morpholino-, (C6-C10)arylmorpholino-, (C1-C9)heteroarylmorpholino-, (C1-C6)alkylmorpholino-, (C6-C10)aryl(C1-C6)alkylmorpholino-, (C1-C9)heteroaryl(C1-C6)alkylmorpholino-, thiomorpholino-, (C6-C10)arylthiomorpholino-, (C1-C9)heteroarylthiomorpholino-, (C1-C6)alkylthiomorpholino-, (C6-C10)aryl(C1-C6)alkylthiomorpholino-, (C1-C9)heteroaryl(C1-C6)alkylthiomorpholino-, piperidino-, (C6-C10)arylthiopiperidino-, (C1-C9)heteroarylthiopiperidino-, (C1-C6)alkylthiopiperidino-, (C6-C10)aryl(C1-C6)alkylthiopiperidino-, (C1-C9)heteroaryl(C1-C6)alkylthiopiperidino-, pyrolidino-, (C6-C10)arylthiopyrolidino-, (C1-C9)heteroarylthiopyrolidino-, (C1-C6)alkylthiopyrolidino-, (C6-C10)aryl(C1-C6)alkylthiopyrolidino-, (C1-C9)heteroaryl(C1-C6)alkylthiopyrolidino-, and Y, if present, is selected from the group consisting of (C1-C6)alkyl-, (C2-C6)alkenyl-, (C2-C6)alkynyl-, amino, oxygen, thio, sulfinyl, sulfonyl, halo(C1-C6)alkyl-, and hydroxy(C2-C6)alkyl-;
(d) ZR8—, where R8 is selected from the group consisting of piperazino-, (C6-C10)arylpiperazino-, (C1-C9)heteroarylpiperazino-, (C1-C6)alkylpiperazino-, (C6-C10)aryl(C1-C6)alkylpiperazino-, (C1-C9)heteroaryl(C1-C6)alkylpiperazino-, morpholino-, (C6-C10)arylmorpholino-, (C1-C9)heteroarylmorpholino-, (C1-C6)alkylmorpholino-, (C6-C10)aryl(C1-C6)alkylmorpholino-, (C1-C9)heteroaryl(C1-C6)alkylmorpholino-, thiomorpholino-, (C6-C10)arylthiomorpholino-, (C1-C9)heteroarylthiomorpholino-, (C1-C6)alkylthiomorpholino-, (C6-C10)aryl(C1-C6)alkylthiomorpholino-, (C1-C9)heteroaryl(C1-C6)alkylthiomorpholino-, piperidino-, (C6-C10)arylthiopiperidino-, (C1-C9)heteroarylthiopiperidino-, (C1-C6)alkylthiopiperidino-, (C6-C10)aryl(C1-C6)alkylthiopiperidino-, (C1-C9)heteroaryl(C1-C6)alkylthiopiperidino-, pyrolidino-, (C6-C10)arylthiopyrolidino-, (C1-C9)heteroarylthiopyrolidino-, (C1-C6)alkylthiopyrolidino-, (C6-C10)aryl(C1-C6)alkylthiopyrolidino-, (C1-C9)heteroaryl(C1-C6)alkylthiopyrolidino-, and Z is selected from the group consisting of (C1-C6)alkyl-, (C2-C6)alkenyl-, (C2-C6)alkynyl-, amino, oxygen, thio, sulfinyl, sulfonyl, halo(C1-C6)alkyl-, and hydroxy(C2-C6)alkyl-;
(e) two or more of R2, when vicinal, together to form one or more further rings of 4, 5, 6 or 7 member atoms selected from the group consisting of phenyl-, naphthyl-, furyl-, thienyl-, thiazolyl-, pyrazolyl-, isothiazolyl-, oxazolyl-, isoxazolyl-, pyrrolyl-, triazolyl-, tetrazolyl-, imidazolyl-, 1,3,5-oxadiazolyl-, 1,2,4-oxadiazolyl-, 1,2,3-oxadiazolyl-, 1,3,5-thiadiazolyl,-1,2,3-thiadiazolyl-, 1,2,4-thiadiazolyl-, pyridyl-, pyrimidyl-, pyrazinyl-, pyridazinyl-, 1,2,4-triazinyl-, 1,2,3-triazinyl-, 1,3,5-triazinyl-, pyrazolo[3,4-b]pyridinyl-, cinnolinyl-, pteridinyl-, purinyl-, 6,7-dihydro-5H-[1]pyrindinyl-, benzo[b]thiophenyl-, 5, 6, 7, 8-tetrahydro-quinolin-3-yl, benzoxazolyl-, benzothiazolyl-, benzisothiazolyl-, benzisoxazolyl-, benzimidazolyl-, thianaphthenyl-, isothianaphthenyl-, benzofuranyl-, isobenzofuranyl-, isoindolyl-, indolyl-, indolizinyl-, indazolyl-, isoquinolyl-, quinolyl-, phthalazinyl-, quinoxalinyl-, quinazolinyl-, benzoxazinyl-, and wherein said ring(s) are optionally substituted by one or more (C1-C6)alkyl-, (C2-C6)alkenyl-, (C2-C6)alkynyl-, amino-, halo-, hydroxy-, carboxy-, thiol-, nitro-, cyano-, sulfonic-, halo(C1-C6)alkyl-, and hydroxy(C2-C6)alkyl-;
and
(f) two or more of R2 when vicinal, together to form one or more further rings of 3, 4, 5, 6 or 7 member atoms selected from the groups consisting of:
(i) (C3-C10)cycloalkyl-, containing zero to two levels of unsaturation, selected from the group consisting of cyclopropyl-, cyclobutyl-, cyclopentyl-, cyclohexyl-, cycloheptyl-, cyclopropenyl-, cyclobutenyl-, cyclopentenyl-, cyclohexenyl-, cycloheptenyl-, 1,3-cyclobutadienyl-, 1,3-cyclopentadienyl-, 1,3-cyclohexadienyl-, 1,4-cyclohexadienyl-, 1,3-cycloheptadienyl-, 1,4-cycloheptadienyl-, bicyclo[3.2.1]octane-, bicyclo [2.2.1] heptane, the norborn-2-ene unsaturated form thereof, and the like, wherein said ring is optionally substituted by hydroxy-, halo-, amino-, trifluoromethyl-, hydroxy(C2-C6)alkyl-, (C1-C6)alkoxy-, (C1-C6)acyloxy-, (C1-C6)alkylamino-, ((C1-C6)alkyl)2amino-, (C1-C6)acylamino-, cyano-, nitro-, carboxy-, thiol-, sulfonyl-, (C1-C6)alkyl-, (C2-C6)alkenyl-, (C2-C6)alkynyl-, (C1-C6)acylamino-, cyano(C1-C6)alkyl-, trifluoromethyl(C1-C6)alkyl-, (C1-C3)alkyl(difluoromethylene)(C1-C3)alkyl-, halo(C1-C6)alkyl- or nitro(C1-C6)alkyl-;
and
(ii) (C3-C10)heterocycloalkyl—selected from the group consisting of pyrrolidinyl-, tetrahydrofuranyl-, dihydrofuranyl-, tetrahydropyranyl-, pyranyl-, thiopyrany-l, aziridinyl-, oxiranyl-, methylenedioxyl-, isoxazolidinyl,- 1,3-oxazolidin-3-yl-, isothiazolidinyl-, 1,3-thiazolidin-3-yl-, 1,2-pyrazolidin-2-yl-, 1,3-pyrazolidin-1-yl-, piperidinyl-, thiomorpholinyl-, 1,2-tetrahydrothiazin-2-yl-, 1,3-tetrahydrothiazin-3-yl-, tetrahydrothiadiazinyl-, morpholinyl-, 1,2-tetrahydrodiazin-2-yl-, 1,3-tetrahydrodiazin-1-yl-, tetrahydroazepinyl-, piperazinyl-, chromenyl-, chromanyl-, where said ring is optionally substituted by hydroxy-, halo-, amino-, trifluoromethyl-, hydroxy(C2-C6)alkyl-, (C1-C6)alkoxy-, (C1-C6)acyloxy-, (C1-C6)alkylamino-, ((C1-C6)alkyl)2amino-, (C1-C6)acylamino-, cyano-, nitro-, carboxy-, thiol-, sulfonyl-, (C1-C6)alkyl-, (C2-C6)alkenyl-, (C2-C6)alkynyl-, (C1-C6)acylamino-, cyano(C1-C6)alkyl-, trifluoromethyl(C1-C6)alkyl-, (C1-C3)alkyl(difluoromethylene)(C1-C3)alkyl-, halo(C1-C6)alkyl- or nitro(C1-C6)alkyl-;
wherein any (C1-C6)alkyl-, (C2-C6)alkenyl-, (C2-C6)alkynyl-, (C3-C10)cycloalkyl- or (C3-C10)heterocycloalkyl-groups that are, or comprise a portion of, said one to four optional R2 substituents are themselves optionally substituted by deuterium-, hydroxy-, amino-, trifluoromethyl-, cyano-, nitro-, carboxy-, (C1-C4)alkoxy-, (C1-C6)acyloxy-, (C1-C6)alkylamino-, ((C1-C6)alkyl)2amino-, (C1-C6)alkyl-(C2-C6)alkenyl-, (C2-C6)alkynyl-, (C1-C6)acylamino-, (C3-C10)cycloalkyl-, (C3-C10)heterocycloalkyl-, cyano(C1-C6)alkyl-, trifluoromethyl(C1-C6)alkyl-, nitro(C1-C6)alkyl-, and (C1-C6)acylamino;
and.
R3 represents one or more optional substituents on a ring carbon atom, including at X where X is —CH2—, selected from the groups consisting of (C1-C6)alkyl-, trihalo(C1-C6)alkyl—that is preferably trifluoromethyl-, deuterium, and fluorine.

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2,4-Diaminopyrimidine compounds useful as immunosuppressants

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2,4-Diaminopyrimidine compounds useful as immunosuppressants

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Abstract

Claims33