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US 2008/0287682 A1Published application
Substituted benzimidazoles and methods of preparation
AssigneeNovartis AG
InventorsMartin Dimitroff, Bridget R. Miller, Brady S. Stillwell, David A. Siesel, Tyson Swiftney, Brian Diaz, Danlin Gu, Jonathan P. van Dyck, David Ryckman, Daniel J. Poon, Teresa E. Pick
Life of this patent
Estimating the term…
Abstract
Methods for preparing new substituted benzimidazole compounds having formula (I) useful for treating kinase mediated disorders are provided wherein R1, R2, R3, R4, a, b, and c are defined herein
Claims17
A method for preparing a compound of Formula (I) or a tautomer, stereoisomer, ester, metabolite, prodrug, or pharmaceutically acceptable salt thereof
- wherein,
- each R1 is independently selected from hydroxy, halo, C1-6 alkyl, C1-6 alkoxy, (C1-6 alkyl)sulfanyl, (C1-6 alkyl)sulfonyl, cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl;
- R2 is C1-6 alkyl or halo(C1-6 alkyl);
- each R3 is independently selected from halo, C1-6 alkyl, and C1-6 alkoxy;
- each R4 is independently selected from hydroxy, C1-6 alkyl, C1-6 alkoxy, halo, heterocycloalkylcarbonyl, carboxyl, (C1-6 alkoxy)carbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, carbonitrile, cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl;
- wherein R1, R2, R3, and R4 may be optionally substituted with one or more substituents independently selected from hydroxy, halo, C1-6 alkyl, halo(C1-6 alkyl), C1-6 alkoxy, and halo(C1-6 alkoxy);
- a is 1, 2, 3, 4, or 5;
- b is 0, 1, 2, or 3;
- c is 1 or 2;
- the method comprising:
- (a) reacting a compound of Formula (II) with a compound of Formula (III) to provide a compound of Formula (IV)
- wherein Q is NH2 or NO2;
- one of L1 or L2 is halo and the other of L1 or L2 is OH or an anion thereof;
- Z is cyano, COOR5, CH2OR5, CHO, or imidazol-2-yl substituted with one or two R4 groups and wherein R5 is hydrogen or a hydroxy protecting group;
- (b) when in the compound of Formula (IV) Z is cyano, COOR5 or CH2OR5, converting said compound to a compound of Formula (IV) wherein Z is CHO;
- (c) when in the compound of Formula (IV) Z is cyano, converting the cyano functionality to an amidino functionality and reacting said amidino functionality with a compound of Formula (Va) under imidazole ring forming conditions;
- or when in the compound of Formula (IV) Z is CHO, reacting said compound with a compound of Formula (Vb) to provide a compound of Formula (VI).
- wherein Xa in Formula (Va) is a leaving group and R4p and R4q in Formula (Vb) are independently H or R4, provided that at least one of R4p and R4q is R4 and Xb is ═O or ═NHOH and provided that c is 1 when a compound of Formula (VI) is prepared from a compound of Formula (Va);
- (d) when in the compound of Formula (VI) Q is NO2, converting said compound to a compound of Formula (VI) wherein Q is NH2;
- (e) reacting the compound of Formula (VI) wherein Q is NH2 with a compound of Formula (VII) to provide a compound of Formula (VIII) or a tautomer thereof.
- (f) reacting the compound of Formula (VIII) or a tautomer thereof with a desulfurizing agent to provide a compound of Formula (I);
- (g) optionally reacting the compound of Formula (I) or a tautomer thereof with an acid to give a first pharmaceutically acceptable salt;
- (h) optionally converting the first pharmaceutically acceptable salt of a compound of Formula (I) or a tautomer thereof to a second pharmaceutically acceptable salt;
- and
- (i) optionally converting a compound of Formula (I) or a tautomer or pharmaceutically acceptable salt thereof to an ester, metabolite, or prodrug of Formula (I).
22 more elements
A method for preparing a pharmaceutically acceptable salt of a compound of Formula (I) or tautomer thereof
- wherein,
- each R1 is independently selected from hydroxy, halo, C1-6 alkyl, C1-6 alkoxy, (C1-6 alkyl)sulfanyl, (C1-6 alkyl)sulfonyl, cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl;
- R2 is C1-6 alkyl or halo(C1-6 alkyl);
- each R3 is independently selected from halo, C1-6 alkyl, and C1-6 alkoxy;
- each R4 is independently selected from hydroxy, C1-6 alkyl, C1-6 alkoxy, halo, heterocycloalkylcarbonyl, carboxyl, (C1-6 alkoxy)carbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, carbonitrile, cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl;
- wherein R1, R2, R3, and R4 may be optionally substituted with one or more substituents independently selected from hydroxy, halo, C1-6 alkyl, halo(C1-6 alkyl), C1-6 alkoxy, and halo(C1-6 alkoxy);
- a is 1, 2, 3, 4, or 5;
- b is 0, 1, 2, or 3;
- c is 1 or 2;
- the method comprising:
- (a) reacting a compound of Formula (I) or a tautomer thereof with an acid to give a first pharmaceutically acceptable salt;
- or
- (b) converting the first pharmaceutically acceptable salt of a compound of Formula (I) or a tautomer thereof to a second pharmaceutically acceptable salt.
10 more elements
A method for preparing a compound of Formula (I) or a tautomer, stereoisomer, ester, metabolite, prodrug, or pharmaceutically acceptable salt thereof
- wherein,
- each R1 is independently selected from hydroxy, halo, C1-6 alkyl, C1-6 alkoxy, (C1-6 alkyl)sulfanyl, (C1-6 alkyl)sulfonyl, cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl;
- R2 is C1-6 alkyl or halo(C1-6 alkyl);
- each R3 is independently selected from halo, C1-6 alkyl, and C1-6 alkoxy;
- each R4 is independently selected from hydroxy, C1-6 alkyl, C1-6 alkoxy, halo, heterocycloalkylcarbonyl, carboxyl, (C1-6 alkoxy)carbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, carbonitrile, cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl;
- wherein R1, R2, R3, and R4 may be optionally substituted with one or more substituents independently selected from hydroxy, halo, C1-6 alkyl, halo(C1-6 alkyl), C1-6 alkoxy, and halo(C1-6 alkoxy);
- a is 1, 2, 3, 4, or 5;
- b is 0, 1, 2, or 3;
- c is 1 or 2;
- the method comprising:
- reacting a compound of Formula (XIII) with a compound of Formula (XIV) to provide a compound of Formula (I)
- wherein one of L3 or L4 is halo and the other of L3 or L4 is OH or an anion thereof;
- or
- reacting a compound of Formula (XV) with a compound of Formula (Vb) to provide a compound of Formula (I)
- wherein R4p and R4q are independently H or R4, provided that at least one of R4p and R4q is R4;
- and Xb is ═O or ═NHOH;
- or
- reacting the compound of Formula (VIII) or a tautomer thereof with a desulfurizing agent to provide a compound of Formula (I)
15 more elements
Dependencies are inferred from the claim text.