Combinatorial library of 3-aryl-1h-indole-2-carboxylic acid

The combinatorial library comprising a library containing a plurality of different compounds having the formula immobilized on a solid support as follows:

• wherein ● is a solid support, wherein P is a fused ring substituent, which ring substituent is an aromatic ring, a heteroaromatic ring or a cycloaliphatic ring which may be substituted or unsubstituted;
• R1 is an amino protecting group, hydrogen lower alkyl containing from 1 to 7 carbon atoms, lower alkenyl containing from 3 to 7 carbon atoms, lower alkynyl containing from 3 to 7 carbon atoms, mono or bicycloaliphatic ring with each ring having from 3 to 7 carbon atoms, aryl containing from 1 to 3 fused aromatic rings with at least one of said rings containing 6 carbon atoms and the other rings containing 5, 6 or 7 carbon atoms, heterocyloaliphatic containing 1 to 2 fused rings with each ring containing from 2 to 6 carbon atoms with one or two hetero atoms selected from the group consisting of O, S and N, monocyclic or bicyclic heteroaryl rings each containing from 1 to 5 carbon atoms with 1 to 4 hetero atoms which can be N, S or O with the proviso that when the hetero atom is S or O there is 1 hetero atom in the ring and when the hetero atom is N there are from 1 to 4 N atoms in the ring, and wherein the hetero ring in the heterocycloaliphatic ring or monocyclic or bicyclic heteroaryl rings can be condensed with an aryl or cycloaliphatic ring and wherein any of the heteroaryl, aryl, cycloaliphatic or heteroaliphatic rings in the cycloaliphatic, aryl, heteroaryl or heteroaliphatic substituents may be connected to the formula I by a lower alkylene chain containing from 1 to 7 carbon atoms and R3 is a ring substituent selected from the group consisting of an aromatic ring, a heteroaromatic ring and a cycloaliphatic ring which ring substituent may be substituted or unsubstituted.

A method of preparing a combinatorial library containing a plurality of different compounds having the formula:

• wherein P is a fused ring substituent, which ring substituent is an aromatic ring, a heteroaromatic ring or a cycloaliphatic ring which may be substituted or unsubstituted;
• R2 is hydrogen, R1 lower alkyl containing from 1 to 7 carbon atoms, lower alkenyl containing from 3 to 7 carbon atoms, lower alkynyl containing from 3 to 7 carbon atoms, mono or bicycloaliphatic ring with each ring having from 3 to 7 carbon atoms, aryl containing from 1 to 3 fused aromatic rings with at least one of said rings containing 6 carbon atoms and the other rings containing 5, 6 or 7 carbon atoms, heterocyloaliphatic containing 1 to 2 fused rings with each ring containing from 2 to 6 carbon atoms with one or two hetero atoms selected from the group consisting of O, S and N, monocyclic or bicyclic heteroaryl rings each containing from 1 to 5 carbon atoms with 1 to 4 hetero atoms which can be N, S or O with the proviso that when the hetero atom is S or O there is 1 hetero atom in the ring and when the hetero atom is N there are from 1 to 4 N atoms in the ring, and wherein the hetero ring in the heterocycloaliphatic ring or monocyclic or bicyclic heteroaryl rings can be condensed with an aryl or cycloaliphatic ring and wherein any of the heteroaryl, aryl, cycloaliphatic or heteroaliphatic rings in the cycloaliphatic, aryl, heteroaryl or heteroaliphatic substituents may be connected to the formula I by a lower alkylene chain containing from 1 to 7 carbon atoms and R3 is a ring substituent selected from the group consisting of an aromatic ring, a heteroaromatic ring and a cycloaliphatic ring which ring substituent may be substituted or unsubstituted:
• a) coupling said organic acid of the formula:
• wherein P is as above, and R13 is Cl, Br, I, or mesyloxy, to produce an immobilized ester of the formula:
• wherein ●, P, and R13 is Cl, Br, I or mesyloxy
• b) reacting the product of step (a) with a substituent reagent of the formula
• R1-LG
• wherein R1 is as above and LG is a leaving group to produce a protected indole of the formula
• wherein ●, P, R1, and R13 are as above
• c) reacting said protected indole produced in step (b) with a boronic acid of the formula
• wherein R3 is as above R1 and R1 are individually lower alkyl or taken together form a lower alkylene bridge between their attached oxygen atoms to produce an immobilized compound of the formula I;
• and
• when ●, P, R1, and R3 are as above
• d) cleaving said immobilized compound of formula I from said solid support to produce the compounds of formula I-A.

A method of preparing a combinatorial library which comprises a plurality of different indoles having the formula:

• wherein P is a fused ring substituent, which ring substituent is an aromatic ring, a heteroaromatic ring or a cycloaliphatic ring which may be substituted or unsubstituted;
• R3 is a ring substituent selected from the group consisting of an aromatic ring, a heteroaromatic ring and a cycloaliphatic ring which ring substituent may be substituted or unsubstituted, comprising:
• a) immobilizing an organic acid of the formula:
• where P is as above, and R13 is Cl, Br, I or mesyloxy,
• on a solid support to produce a immobilized ester having a free amino group of the formula:
• where ●, P, and R13 are as above
• b) reacting the product of step a) with an amino protecting group:
• to produce an immobilized ester of the formula
• wherein, P, R13 and ● are as above;
• and R16 is a eliminatable or hydrolyzable amino protecting group
• c) reacting said protected immobilized ester of step b) with a boronic acid of the formula:
• wherein R3 is as above R1 and R11 are individually lower alkyl or taken together form a lower alkylene bridge between their attached oxygen atoms
• to produce a protected immobilized indole of the formula:
• wherein ●, P and R3 is as above and R16 is amino protecting group
• d) and cleaving by acidic elimination the immobilized indole from said solid support to produce the indole of formula I-A.

A method of preparing a combinatorial library which contains a plurality of different immobilized indoles having the formula:

• wherein ● is a solid support, wherein P is a fused ring substituent, which ring substituent is an aromatic ring, a heteroaromatic ring or a cycloaliphatic ring which may be substituted or unsubstituted;
• wherein P is a fused ring substituent, which ring substituent is an aromatic ring, a heteroaromatic ring or a cycloaliphatic ring which may be substituted or unsubstituted;
• R3 is ring substituent selected from the group consisting of an aromatic ring, a heteroaromatic ring and an cycloaliphatic ring which ring substituent may be substituted or unsubstituted;
• and R16 is an amino protecting group, comprising:
• a) providing on a solid support an immobilized ester of the formula
• wherein R16 and P are above and R13 is a Cl, Br, I or mesyloxy, is a amino protecting group
• b) reacting said immobilized ester with a boronic acid of the formula
• when R3 is as above R1 and R11 are individually lower alkyl or taken together form a lower alklylene bridge between their attached oxygen atoms,
• to produce said immobilized indole.

A method of preparing a combinatorial library comprising a plurality of indoles of the formula:

• wherein ● is a solid support, wherein P is a fused ring substituent, which ring substituent is an aromatic ring, a heteroaromatic ring or a cycloaliphatic ring which may be substituted or unsubstituted;
• R1 is lower alkyl containing from 1 to 7 carbon atoms, lower alkenyl containing from 3 to 7 carbon atoms, lower alkynyl containing from 3 to 7 carbon atoms, mono or bicycloaliphatic ring with each ring having from 3 to 7 carbon atoms, aryl containing from 1 to 3 fused aromatic rings with at least one of said rings containing 6 carbon atoms and the other rings containing 5, 6 or 7 carbon atoms, heterocyloaliphatic containing 1 to 2 fused rings with each ring containing from 2 to 6 carbon atoms with one or two hetero atoms selected from the group consisting of O, S and N, monocyclic or bicyclic heteroaryl rings each containing from 1 to 5 carbon atoms with 1 to 4 hetero atoms which can be N, S or O with the proviso that when the hetero atom is S or O there is 1 hetero atom in the ring and when the hetero atom is N there are from 1 to 4 N atoms in the ring, and wherein the hetero ring in the heterocycloaliphatic ring or monocyclic or bicyclic heteroaryl rings can be condensed with an aryl or cycloaliphatic ring and wherein any of the heteroaryl, aryl, cycloaliphatic or heteroaliphatic rings in the cycloaliphatic, aryl, heteroaryl or heteroaliphatic substituents may be connected to the formula I by a lower alkylene chain containing from 1 to 7 carbon atoms and R3 is a ring substituent selected from the group consisting of an aromatic ring, a heteroaromatic ring and a cycloaliphatic ring which ring substituent may be substituted or unsubstituted, comprising:
• a) providing an immobilized ester of the formula:
• wherein ●, P, is as above and R13 is a leaving group.
• b) reacting the product of step (a) with a halide of the formula
• R1-LG
• wherein R1 is as above and LG is a leaving group such as chlorine, bromine or iodine.
• to produce an immobilized indole product of the formula
• wherein ●, P, R1, and R13 are as above
• c) reacting said protected immobilized indole product of step (b) with a boronic acid of the formula:
• wherein R3 is as above R1 and R11 are individually lower alkyl or taken together form a lower alkylene bridge between their attached oxygen atoms
• to produce said indole of formula IB-1.

A method of producing an immobilized indole of the formula:

• wherein ● is a solid support, P is a fused ring substituent, which ring substituent is an aromatic ring, a heteroaromatic ring or a cycloaliphatic ring which may be substituted or unsubstituted;
• R14 is an amino protecting group, lower alkyl containing from 1 to 7 carbon atoms, lower alkenyl containing from 3 to 7 carbon atoms, lower alkynyl containing from 3 to 7 carbon atoms, mono or bi-cycloaliphatic ring with each ring having from 3 to 7 carbon atoms, aryl containing from 1 to 3 fused aromatic rings with at least one of said rings containing 6 carbon atoms and the other rings containing 5, 6 or 7 carbon atoms, heterocyloaliphatic containing 1 to 2 fused rings with each ring containing from 2 to 6 carbon atoms with one or two hetero atoms selected from the group consisting of O, S and N, monocyclic or bicyclic heteroaryl rings each containing from 1 to 5 carbon atoms with 1 to 4 hetero atoms which can be N, S or O with the proviso that when the hetero atom is S or O there is 1 hetero atom in the ring and when the hetero atom is N there are from 1 to 4 N atoms in the ring, and wherein the hetero ring in the heterocycloaliphatic ring or monocyclic or bicyclic heteroaryl rings can be condensed with an aryl or cycloaliphatic ring and wherein any of the heteroaryl, aryl, cycloaliphatic or heteroaliphatic rings in the cycloaliphatic, aryl, heteroaryl or heteroaliphatic substituents may be connected to the formula I by a lower alkylene chain containing from 1 to 7 carbon atoms and R3 is a ring substituent selected from the group consisting of an aromatic ring, a heteroaromatic ring and a cycloaliphatic ring which ring substituent may be substituted or unsubstituted,
• comprising reacting a compound of the formula:
• wherein is a solid support, R13 is a leaving group;
• and, R14, and P are as above,
• with a boronic acid of the formula:
• wherein R3 is as above R1 and R11 are individually lower alkyl or taken together form a lower alkylene bridge between their attached oxygen atoms,
• to produce said immobilized indole of formula IV.