6-substituted indole-3-carboxylic acid amide compounds having sphingosine-1-phosphate (S1P) receptor antagonist biological activity

A compound represented by the formula I having sphingosine-1-phosphate receptor agonist and or antagonist biological activity:

• wherein:
• R1 is selected from the group consisting of hydrogen, straight or branched chain alkyl having 1 to 12 carbons, heterocyclic groups having up to 20 carbon atoms and at least one of oxygen, nitrogen and/or sulfur in the ring, halo, C1 to C12 haloalkyl, hydroxyl, C1 to C12 alkoxy, C1 to C12 alkylcarbonyl, formyl, C1 to C12 alkyl carboxylate, C1 to C12 alkyl amide, aminocarbonyl, amino, cyano, nitro and sulfonyl groups;
• R2 is selected from the group consisting of hydrogen and halo;
• R3 is selected from the group consisting of straight or branched chain alkyl having 3 to 12 carbons, carbocyclic hydrocarbon groups having from 3 to 20 carbon atoms, heterocyclic groups having up to 20 carbon atoms and at least one of oxygen, nitrogen and/or sulfur in the ring, C1 to C12 alkoxy, C1 to C12 alkylcarbonyl and C1 to C12 alkyl carboxylate;
• R4 is selected from the group consisting of hydrogen, halo and C1 to C12 haloalkyl;
• X is NR5;
• X1 is selected from the group consisting of NR5, O and S;
• R5 is hydrogen;
• Y is a phenyl or a pyridyl group and wherein said phenyl or pyridyl group may be bonded to A at any position;
• Z is O;
• n is 0 or an integer of from 1 to 5;
• o is an integer of from 1 to 3;
• p is 1;
• q is 1;
• r is 0 or 1;
• A is selected from the group consisting of (CH2)v wherein v is an integer of from 1 to 12;
• A1 and A2 are independently selected from the group consisting of (CN2)v wherein v is 0 or an integer of from 1 to 12, and branched chain alkyl having 3 to 12 carbons;
• B is selected from the group consisting of hydrogen, OR6, COOR7, NR8R9, CONR8R9, COR10, CH═NOR11, and CH═NNR12R13;
• and
• wherein R6, R7, R10and R11 are independently selected from the group consisting of hydrogen, straight or branched chain alkyl having 1 to 12 carbons, alkenyl having 2 to 6 carbons and 1 or 2 double bonds, alkynyl having 2 to 6 carbons and 1 or 2 triple bonds, a carbocyclic hydrocarbon group having from 3 to 20 carbon atoms, and a heterocyclic group having up to 20 carbon atoms and at least one of oxygen, nitrogen and/or sulfur in the ring, R8, R9 , R12 and R13 are independently selected from the group consisting of hydrogen, straight or branched chain alkyl having 1 to 12 carbons, alkenyl having 2 to 6 carbons and 1 or 2 double bonds, alkynyl having 2 to 6 carbons and 1 or 2 triple bonds, a carbocyclic hydrocarbon group having from 3 to 20 carbon atoms, and a heterocyclic group having up to 20 carbon atoms and at least one of oxygen, nitrogen and/or sulfur in the ring, or R8 and R9 and/or R12 and R13, together, can form a divalent carbon radical of 2 to 5 carbons to form a heterocyclic ring with nitrogen, wherein any of R6, R7, R8, R9, R10, R11, R12 or R13 may be substituted with one or more halogen, hydroxy, alkyloxy, cyano, nitro, mercapto or thiol radical;
• provided however, when v is 0, and r is 0, B is not hydrogen;
• or B is a carbocyclic hydrocarbon group having from 3 to 20 carbon atoms, or a heterocyclic group having up to 20 carbon atoms and at least one of oxygen, nitrogen and/or sulfur in the ring, and wherein when said B is a carbocyclic or heterocyclic group B may be bonded to A2 at any position, or a pharmaceutically acceptable salt of said compound.