Combinatorial library of 3-aryl-1H-indole-2-carboxylic acid amides

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;
• R2 is a substituents selected from the group consisted of hydrogen, lower alkyl containing from 1 to 7 carbon atoms, lower alkenyl containing from 2 to 7 carbon atoms, lower alkynyl containing from 3 to 7 carbon atoms, mono and bicycloaliphatic ring with each ring having from 3 to 7 carbon atoms, aryl containing from 1 to 3 fused aromatic rings each ring consisting of 6 carbon atoms, heterocyloaliphatic containing 1 to 2 fused rings with each ring containing from 3 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 3 to 6 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 are 1 or 2 hetero atoms in the ring and when the hetero atoms 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 an cycloaliphatic ring which ring substituent may be substituted or unsubstituted and R1 is an amino protecting group or anyone of the substituents given for R2.

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;
• R1 and R2 are individually hydrogen, lower alkyl containing from 1 to 7 carbon atoms, lower alkenyl containing from 2 to 7 carbon atoms, lower alkynyl containing from 3 to 7 carbon atoms, mono and bicycloaliphatic ring with each ring having from 3 to 7 carbon atoms, aryl containing from 1 to 3 fused aromatic rings each ring consisting of 6 carbon atoms, heterocyloaliphatic containing 1 to 2 fused rings with each ring containing from 3 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 3 to 6 carbon atoms with 1 to 4 hetero atoms which can be N, S or O and when the hetero atom is S or O, there are 1 or 2 hetero atoms in the ring and when the hetero atoms 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 cyloaliphatic 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 with the proviso that R1 is other than hydrogen;
• and R3 is 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 on a solid support an amine of the formula:
• R2NH2
• wherein R2 is as above
• to produce an immobilized amine of the formula:
• wherein ● is the solid support, and R2 is as above
• b) coupling said immobilized amine to an organic acid of the formula:
• wherein P is as above, and R13 is a leaving group,
• to produce an immobilized amide of the formula:
• wherein ●, P, R2, and R13 is a leaving group
• c) reacting the product of step (d) with a halide of the formula
• R1 halo
• wherein R1 is as above and halo is a halide
• wherein ●, P, R1, R2, and R13 are as above
• to produce a protected indole of the formula
• d) reacting said protected indole produced in step (c) 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 an immobilized compound of the formula I;
• and
• when ●, P, R1, R2, and R3 are as above, and
• f) cleaving said immobilized compound of formula I from said solid support to produce the compounds of formula I.

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;
• R2 is individually is hydrogen, lower alkyl containing from 1 to 7 carbon atoms, lower alkenyl containing from 2 to 7 carbon atoms, lower alkynyl containing from 3 to 7 carbon atoms, mono and bicycloaliphatic ring with each ring having from 3 to 7 carbon atoms, aryl containing from 1 to 3 fused aromatic rings each ring consisting of 6 carbon atoms, heterocycloaliphatic containing 1 to 2 fused rings with each ring containing from 3 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 3 to 6 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 are 1 or 2 hetro atoms in the ring and when the hetero atoms 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 cyloaliphatic 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 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 on a solid support an amine of the formula
• R2NH2
• wherein R2 is as above
• to produce an immobilized amine of the formula:
• wherein ● is the solid support, and R2 is as above
• b) coupling said immobilized amine to an organic acid of the formula:
• where P is as above, and R13 is a leaving group,
• to produce an immobilized amide having a free amino group of the formula:
• where ●, P, R2, and R13 is a leaving group
• c) reacting the product of step b) with an amino protecting group:
• to produce an immobilized amine of the formula
• wherein, P, R2, R13 and ● are as above;
• and R16 is a hydrolyzable amino protecting group
• d) reacting said protected immobilized amide 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, R2, and R3 is as above and R16 is hydrolyzable amino protecting group
• e) and cleaving by hydrolysis 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, 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, lower alkyl containing from 1 to 7 carbon atoms, lower alkenyl containing from 2 to 7 carbon atoms, lower alkynyl containing from 3 to 7 carbon atoms, mono and bicycloaliphatic ring with each ring having from 3 to 7 carbon atoms, aryl containing from 1 to 3 fused aromatic rings each ring consisting of 6 carbon atoms, heterocycloaliphatic containing 1 to 2 fused rings with each ring containing from 3 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 3 to 6 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 are 1 or 2 hetro atoms in the ring and when the hetero atoms 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 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 amide of the formula
• wherein P, R2, as above and R13 is a leaving group, and R16 is a hydrolyzable amino protecting group
• b) reacting said immobilized amide 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 alkylene bridge between their attached oxygen atoms,
• to produce said immobilized indole.

A method of preparing a combinatorial library comprising a plurality of 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;
• R1 and R2 are individually hydrogen, lower alkyl containing from 1 to 7 carbon atoms, lower alkenyl containing from 2 to 7 carbon atoms, lower alkynyl containing from 3 to 7 carbon atoms, mono and bicycloaliphatic ring with each ring having from 3 to 7 carbon atoms, aryl containing from 1 to 3 fused aromatic rings each ring consisting of 6 carbon atoms, heterocyloaliphatic containing 1 to 2 fused rings with each ring containing from 3 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 3 to 6 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 are 1 or 2 hetro atoms in the ring and when the hetero atoms 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 with the further proviso that R1 is other than hydrogen, and 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;
• comprising:
• a) providing an immobilized amine of the formula:
• wherein ●, P, and R2, are as above and R13 is a leaving group
• b) reacting the product of step (a) with a halide of the formula
• R1 halo
• wherein R1 is as above and halo is a halide
• 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 ● 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;
• R2 is a substituent selected from the group consisting of hydrogen, lower alkyl containing from 1 to 7 carbon atoms, lower alkenyl containing from 2 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 each ring consisting of 6 carbon atoms, heterocyloaliphatic containing 1 to 2 fused rings with each ring containing from 3 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 3 to 6 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 are 1 or 2 hetro atoms in the ring and when the hetero atoms 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 cyloaliphatic 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 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, R14 is an amino protecting group or a substituent selected from those substituents set forth for R2 except hydrogen,
• comprising reacting a compound of the formula:
• wherein ● is a solid support, R13 is a leaving group;
• R14 is an amino protecting group, R14, R2, 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 amide.