US 2013/0096301 A1Published application

Kinase inhibitors and method of treating cancer with same

AssigneeUniversity Health Network

InventorsGraham Cumming, Narendra Kumar B. Patel, Bryan T. Forrest, Yong Liu, Sze-Wan Li, Peter Brent Sampson, Louise G. Edwards, Heinz W. Pauls

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Abstract

The present invention is directed to novel synthetic methods for preparing a spiro cyclopropyl indolinone compound represented by Structural Formula (A): (A) or its pharmaceutically acceptable salt thereof. Also included are synthetic intermediates described herein.

Claims42

Dependent claims

A method of preparing a spiro indolinone compound represented by the following Structural Formula:

or a salt thereof, comprising the step of reacting an indolinone compound represented by the following Structural Formula:
with a base and an indazole compound represented by the following Structural Formula:
wherein:
each of Ra and Rb independently is —H, halogen, —C(O)OR1, —C(O)R1, —C(S)R1, —OC(O)R1—, —C(O)NR1R2, —C(S)NR1R2, —OC(O)NR1R2, —S(O)R1, —S(O)2R1, —SO3R1, —SO2NR1R2, —OR1, —SR1, —NR1R2, —NR2C(O)R1, —NR2S(O)R1, —NR2C(O)OR1, —NR2C(O)ONR1R2, —N(R2)C(O)NR1R2, —NR2SO2NR1R2, —NR2SO2R1;
—NO2, —CN, —NCS;
or two ortho Ra groups taken together form —O—[CH2]p—O—, —S—[CH2]p—S— or —[CH2]q—;
or
C1-10 aliphatic group optionally substituted with one or more substituents selected from the group consisting halogen, nitro, cyano, —N(R21)2, —C(O)N(R21)2, —C(O)N(R21)2, —NR21C(O)R21, —SO2R22, —SO2N(R21)2, —NR21SO2R22, —NR21C(O)OR21, —OC(O)N(R21)2, —NR21C(O)N(R21)2, —NR21C(O)ON(R21)2, —NR21SO2N(R21)2, —OR21, —SR21, C1-10 haloalkoxy, —C(O)R21, —C(O)OR21 and —OC(O)R21;
or
(C0-10 alkylene)-Ar1, wherein Ar1 is a C6-14 aryl group or a 5-14 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, C1-10 alkyl, C1-10 haloalkyl, (C1-10 haloalkoxy)C1-10 alkyl, (C1-10 alkoxy)C1-10 alkyl, C1-10 hydroxyalkyl, C1-10 aminoalkyl, (C1-10 alkylamino)C1-10 alkyl, (C1-10 dialkylamino)C1-10 alkyl, —N(R21)2, —C(O)N(R21)2, —C(O)N(R21)2, —NR21C(O)R21, —SO2R22, —SO2N(R21)2, —NR21SO2R22, —NR21C(O)N(R21)2, —NR21C(O)ON(R21)2, —NR21SO2N(R21)2, —OR21, —SR21, C1-10 haloalkoxy, —C(O)R21, —C(O)OR21, —OC(O)R21, phenyl and 5-6 membered heteroaryl, wherein said phenyl and said 5-6 membered heteroaryl are each independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy and C1-3 haloalkoxy;
each R1 independently is:
i) hydrogen;
ii) a C6-14 aryl group or a 5-14 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, —NO2, —CN, —NCS, C1-C10 aliphatic, (C1-10 alkylene)-Ar10, —C(O)OR10, —C(O)R10, —C(S)R10, —OC(O)R10, —C(O)N(R11)2, —C(S)N(R11)2, —OC(O)N(R11)2, —S(O)R12, —S(O)2R12, —SO3R12, —SO2N(R11)2, —OR10, —SR10, —N(R11)2, —NR11C(O)R10, —NR11S(O)R12, —NR11C(O)OR12, —N(R11)C(O)N(R11)2, —NR11SO2N(R11)2 and —NR11SO2R12;
or
iii) a C1-10 aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, —NO2, —CN, —NCS, Ar10, —C(O)OR10, —C(O)R10, —C(S)R10, —OC(O)R10, —C(O)N(R11)2, —C(S)N(R11)2, —OC(O)N(R11)2, —S(O)R12, —S(O)R12, —S(O)2R12, —SO3R12, —SO2N(R11)2, —OR10, —SR10, —N(R11)2, —NR11C(O)R10, —NR11S(O)R12, —NR11C(O)OR12, —N(R11)C(O)N(R11)2, —NR11SO2N(R11)2 and —NR11SO2R12,
provided that R1 is other than hydrogen when Ra or Rb is —S(O)R1, —S(O)2R1, —SO3R1, —NR2S(O)R1 or —NR2SO2R1;
and
each R2 independently is —H or C1-C6 alkyl, or, taken together with NR1, forms a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting of ═O, ═S, halogen, nitro, cyano, hydroxy, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, amino, C1-6 alkylamino, C1-6 dialkylamino, C1-6 aminoalkyl, (C1-6 alkylamino)C1-6 alkyl, (C1-6 dialkylamino)C1-6 alkyl, (phenyl)C1-6 alkyl, (5-6 membered heteroaryl)C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkylcarbonyloxy, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyl, phenyl and 5-6 membered heteroaryl;
R3 is —H, halogen, C1-6 alkyl or C1-6 haloalkyl;
R4 is —H, C1-6 alkyl, phenyl, —C(O)(C1-6 alkyl), —C(O)(phenyl), —C(O)O(C1-6 alkyl), —C(O)O(phenyl), —S(O)2(C1-6 alkyl) or —S(O)2(phenyl), wherein each alkyl in the groups represented by R4 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, —C(O)NH2, phenyl, 5-6 membered heteroaryl, C1-6 alkoxy, C1-6 alkylamino, C1-6 dialkylamino and C1-6 haloalkoxy, and wherein each phenyl in the groups represented by R4 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy and C1-6 haloalkoxy;
R6 is hydrogen, halogen, nitro, cyano, R′, —OR, —SR, —N(R)2, —C(O)R, —C(O)OR, —OC(O)R, —C(O)N(R)2, —OC(O)N(R)2, —NRC(O)R, —NRC(O)OR, —SOR′, —SO2R′, —SO3R′, —SO2N(R)2, —NRS(O)R′, —NRSO2R′, —NRC(O)N(R)2, —NRC(O)ON(R)2, or —NRSO2N(R)2;
each R10 independently is:
i) hydrogen;
ii) a C6-14 aryl group or a 5-14 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, C1-10 alkyl, C1-10 haloalkyl, (C1-10 haloalkoxy)C1-10 alkyl, (C1-10 alkoxy)C1-10 alkyl, C1-10 hydroxyalkyl, C1-10 aminoalkyl, (C1-10 alkylamino)C1-10 alkyl, (C1-10 dialkylamino)C1-10 alkyl, (phenyl)C1-10 alkyl, (5-6 membered heteroaryl)C1-10 alkyl, amino, C1-10 alkylamino, C1-10 dialkylamino, C1-10 alkoxy, C1-10 haloalkoxy, C1-10 alkylcarbonyloxy, C1-10 alkoxycarbonyl and C1-10 alkylcarbonyl;
or
iii) a C1-10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, C1-10 haloalkyl, C1-10 alkoxy, C1-10 haloalkoxy, amino, C1-10 alkylamino, C1-10 dialkylamino, C1-10 alkylcarbonyloxy, C1-10 alkoxycarbonyl, C1-10 alkylcarbonyl and phenyl, said phenyl being optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy and C1-3 haloalkoxy;
each R11 independently is R10, —CO2R10, —SO2R10 or —C(O)R10, or
—N(R11)2 taken together is a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting of ═O, ═S, halogen, nitro, cyano, hydroxy, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, amino, C1-6 alkylamino, C1-6 dialkylamino, C1-6 aminoalkyl, (C1-6 alkylamino)C1-6 alkyl, (C1-6 dialkylamino)C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkylcarbonyloxy, C1-6 alkoxycarbonyl and C1-6 alkylcarbonyl;
and
each R12 is independently is R10 provided that R12 is not hydrogen;
each R21 independently is hydrogen, C1-6 alkyl, phenyl or 5-6 membered heteroaryl, wherein each of the phenyl and heteroaryl groups represented by R21 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy and C1-3 haloalkoxy, and wherein the alkyl group represented by R21 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy and C1-3 haloalkoxy;
or
N(R21)2 forms a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, ═O, C1-3 alky, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy and amino;
and
each R22 independently C1-6 alkyl, phenyl or 5-6 membered heteroaryl, wherein each of the phenyl and heteroaryl groups represented by R22 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy and C1-3 haloalkoxy, and wherein the alkyl group represented by R22 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy and C1-3 haloalkoxy;
each R independently is hydrogen, C1-10 aliphatic, phenyl or 5-6 membered heteroaryl, wherein the aliphatic group represented by R is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, phenyl, 5-6 membered heteroaryl, C1-6 alkoxy, C1-6 haloalkoxy, and wherein each of the phenyl and heteroaryl groups represented by R, and the phenyl and heteroaryl substituents for the aliphatic group represented by R independently are optionally and independently substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, or
N(R)2 forms a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting of ═O, ═S, halogen, nitro, cyano, hydroxy, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, amino, C1-6 alkylamino, C1-6 dialkylamino, C1-6 aminoalkyl, (C1-6 alkylamino)C1-6 alkyl, (C1-6 dialkylamino)C1-6 alkyl, (phenyl)C1-6 alkyl, (5-6 membered heteroaryl)C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkylcarbonyloxy, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyl, phenyl and 5-6 membered heteroaryl;
and
each R′ independently is C1-10 aliphatic, phenyl, 5-12 membered heteroaryl or 9-12 membered heterocyclyl group, wherein the aliphatic group represented by R′ is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, phenyl, 5-12 membered heteroaryl, 9-12 membered heterocyclyl group, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-6 alkylamino, C1-6 dialkylamino, —C(O)H, —C(O)(C1-C6 alkyl), —C(O)(C1-C6 haloalkyl), —C(O)(phenyl), —C(O)(non-aromatic heterocyclic group), —C(O)O(C1-C6 alkyl), —C(O)O(C1-C6 haloalkyl), —C(O)O(phenyl), —OC(O)(C1-C6 alkyl), —OC(O)(C1-C6 haloalkyl), —OC(O)(phenyl), —S(O)2(C1-C6 alkyl), —S(O)2(C1-C6 haloalkyl) and —S(O)2(phenyl), and wherein each of the phenyl, heteroaryl and heterocyclyl groups represented by R′, and the phenyl, heteroaryl and heterocyclyl groups in the substituents for the aliphatic group represented by R′ independently are optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —SH, —C(O)H, nitro, cyano, amino, C1-6 alkylamino, C1-6 dialkylamino, (C1-6 dialkylamino)C1-6 dialkylamino, C1-C6 alkyl, C1-C6 haloalkyl, —O(C1-6 alkyl), —O-(non-aromatic heterocyclic group), —S(C1-6 alkyl), —O(C1-6 haloalkyl), (C1-6 haloalkoxy)C1-6 alkyl, (C1-6 alkoxy)C1-6 alkyl, C1-6 hydroxyalkyl, (C1-6 aminoalkyl), (C1-6 alkylamino)C1-6 alkyl, (C1-6 dialkylamino)C1-6 alkyl, (C1-6 dialkylamino)C1-6 alkoxy, (phenyl)C1-6 alkyl, (5-6 membered heteroaryl)C1-6 alkyl, (non-aromatic heterocyclic group)C1-6 alkyl (optionally substituted with halogen, —OH, C1-6 hydroxyalkyl, C1-6 alkyl, C1-6 acyl, C5-7 cycloalkyl, C1-6 alkylamino, di(C1-6 alkyl)amino or non-aromatic heterocyclic group), (5-6 membered heteroaryl)C1-6 alkoxy, (non-aromatic heterocyclic group)C1-6 alkoxy, —C(O)(C1-C6 alkyl), —C(O)(C1-C6 haloalkyl), —C(O)(phenyl), —C(O)(non-aromatic heterocyclic group), —C(O)O(C1-C6 alkyl), —C(O)O(C1-C6 haloalkyl), —C(O)O(phenyl), —OC(O)(C1-C6 alkyl), —OC(O)(C1-C6 haloalkyl), —OC(O)(phenyl), —S(O)2NH2, —S(O)2(C1-C6 alkyl), —S(O)2(C1-6 haloalkyl), and —S(O)2(phenyl);
each Ar10 independently is a C6-14 aryl group or a 5-14 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, —OH, —SH, —O(C1-10 alkyl), —S(C1-10 alkyl), C1-10 alkyl, C1-10 haloalkyl, (C1-10 haloalkoxy)C1-10 alkyl, (C1-10 alkoxy)C1-10 alkyl, C1-10 hydroxyalkyl, (C1-10 aminoalkyl, (C1-10 alkylamino)C1-10 alkyl, (C1-10 dialkylamino)C1-10 alkyl, (phenyl)C1-10 alkyl, (5-6 membered heteroaryl)C1-10 alkyl, amino, C1-10 alkylamino, C1-10 dialkylamino, C1-10 haloalkoxy, C1-10 alkylcarbonyloxy, C1-10 alkoxycarbonyl and C1-10 alkylcarbonyl;
X1 and X2 are independently a sulfonate leaving group or halogen;
P1 is —H or a nitrogen protecting group;
P2 is R4 or a nitrogen protecting group;
each p is 1, 2 or 3;
each q is 2, 3, 4 or 5;
n is 1, 2 or 3;
and
m is 1 or 2.

45 more elements

A method of preparing a halogenated indolinone compound represented by the following Structural Formula:

or a salt thereof, comprising the step of halogenating an indazole compound represented by the following Structural Formula:
with a halogenating reagent, wherein:
each of Ra and Rb independently is —H, halogen, —C(O)OR1, —C(O)R1, —C(S)R1, —OC(O)R1—, —C(O)NR1R2, —C(S)NR1R2, —OC(O)NR1R2, —S(O)R1, —S(O)2R1, —SO3R1, —SO2NR1R2, —OR1, —SR1, —NR1R2, —NR2C(O)R1, —NR2S(O)R1, —NR2C(O)OR1, —NR2C(O)ONR1R2, —N(R2)C(O)NR1R2, —NR2SO2NR1R2, —NR2SO2R1;
—NO2, —CN, —NCS;
or two ortho Ra groups taken together form —O—[CH2]p—O—, —S—[CH2]p—S— or —[CH2]q—;
or
C1-10 aliphatic group optionally substituted with one or more substituents selected from the group consisting halogen, nitro, cyano, —N(R21)2, —C(O)N(R21)2, —C(O)N(R21)2, —NR21C(O)R21, —SO2R22, —SO2N(R21)2, —NR21SO2R22, —NR21C(O)OR21, —OC(O)N(R21)2, —NR21C(O)N(R21)2, —NR21C(O)ON(R21)2, —NR21SO2N(R21)2, —OR21, —SR21, C1-10 haloalkoxy, —C(O)R21, —C(O)OR21 and —OC(O)R21;
or
(C0-10 alkylene)-Ar1, wherein Ar1 is a C6-14 aryl group or a 5-14 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, C1-10 alkyl, C1-10 haloalkyl, (C1-10 haloalkoxy)C1-10 alkyl, (C1-10 alkoxy)C1-10 alkyl, C1-10 hydroxyalkyl, C1-10 aminoalkyl, (C1-10 alkylamino)C1-10 alkyl, (C1-10 dialkylamino)C1-10 alkyl, —N(R21)2, —C(O)N(R21)2, —C(O)N(R21)2, —NR21C(O)R21, —SO2R22, —SO2N(R21)2, —NR21SO2R22, —NR21C(O)N(R21)2, —NRC(O)ON(R)2, —NR21SO2N(R21)2, —OR21, —SR21, C1-10 haloalkoxy, —C(O)R21, —C(O)OR21, —OC(O)R21, phenyl and 5-6 membered heteroaryl, wherein said phenyl and said 5-6 membered heteroaryl are each independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy and C1-3 haloalkoxy;
each R1 independently is:
i) hydrogen;
ii) a C6-14 aryl group or a 5-14 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, —NO2, —CN, —NCS, C1-C10 aliphatic, (C1-10 alkylene)-Ar10, —C(O)OR10, —C(O)R10, —C(S)R10, —OC(O)R10, —C(O)N(R11)2, —C(S)N(R11)2, —OC(O)N(R11)2, —S(O)R12, —S(O)2R12—SO2N(R11)2, —OR10, —SR10, —N(R11)2, —NR11C(O)R10, —NR11S(O)R12, —NR11C(O)OR12, —N(R11)C(O)N(R11)2, —NR11SO2N(R11)2 and —NR11SO2R12;
or
iii) a C1-10 aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, —NO2, —CN, —NCS, Ar10, —C(O)OR10, —C(O)R10, —C(S)R10, —OC(O)R10, —C(O)N(R11)2, —C(S)N(R11)2, —OC(O)N(R11)2, —S(O)R12, —S(O)2R12, —SO2N(R11)2, —OR10, —SR10, —N(R11)2, —NR11C(O)R10, —NR11S(O)R12, —NR11C(O)OR12, —N(R11)C(O)N(R11)2, —NR11SO2N(R11)2 and —NR11SO2R12,
provided that R1 is other than hydrogen when Ra or Rb is —S(O)R1, —S(O)2R1, —SO3R1, —NR2S(O)R1 or —NR2SO2R1;
and
each R2 independently is —H or C1-C6 alkyl, or, taken together with NR1, forms a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting of ═O, ═S, halogen, nitro, cyano, hydroxy, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, amino, C1-6 alkylamino, C1-6 dialkylamino, C1-6 aminoalkyl, (C1-6 alkylamino)C1-6 alkyl, (C1-6 dialkylamino)C1-6 alkyl, (phenyl)C1-6 alkyl, (5-6 membered heteroaryl)C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkylcarbonyloxy, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyl, phenyl and 5-6 membered heteroaryl;
R3 is —H, halogen, C1-6 alkyl or C1-6 haloalkyl;
R4 is —H, C1-6 alkyl, phenyl, —C(O)(C1-6 alkyl), —C(O)(phenyl), —C(O)O(C1-6 alkyl), —C(O)O(phenyl), —S(O)2(C1-6 alkyl) or —S(O)2(phenyl), wherein each alkyl in the groups represented by R4 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, —C(O)NH2, phenyl, 5-6 membered heteroaryl, C1-6 alkoxy, C1-6 alkylamino, C1-6 dialkylamino and C1-6 haloalkoxy, and wherein each phenyl in the groups represented by R4 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy and C1-6 haloalkoxy;
each R10 independently is:
i) hydrogen;
ii) a C6-14 aryl group or a 5-14 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, C1-10 alkyl, C1-10 haloalkyl, (C1-10 haloalkoxy)C1-10 alkyl, (C1-10 alkoxy)C1-10 alkyl, C1-10 hydroxyalkyl, C1-10 aminoalkyl, (C1-10 alkylamino)C1-10 alkyl, (C1-10 dialkylamino)C1-10 alkyl, (phenyl)C1-10 alkyl, (5-6 membered heteroaryl)C1-10 alkyl, amino, C1-10 alkylamino, C1-10 dialkylamino, C1-10 alkoxy, C1-10 haloalkoxy, C1-10 alkylcarbonyloxy, C1-10 alkoxycarbonyl and C1-10 alkylcarbonyl;
or
iii) a C1-10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, C1-10 haloalkyl, C1-10 alkoxy, C1-10 haloalkoxy, amino, C1-10 alkylamino, C1-10 dialkylamino, C1-10 alkylcarbonyloxy, C1-10 alkoxycarbonyl, C1-10 alkylcarbonyl and phenyl, said phenyl being optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy and C1-3 haloalkoxy;
each R11 independently is R10, —CO2R10, —SO2R10 or —C(O)R10, or
—N(R11)2 taken together is a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting of ═O, ═S, halogen, nitro, cyano, hydroxy, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, amino, C1-6 alkylamino, C1-6 dialkylamino, C1-6 aminoalkyl, (C1-6 alkylamino)C1-6 alkyl, (C1-6 dialkylamino)C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkylcarbonyloxy, C1-6 alkoxycarbonyl and C1-6 alkylcarbonyl;
and
each R12 independently is R10 provided that R12 is not hydrogen;
each R21 independently is hydrogen, C1-6 alkyl, phenyl or 5-6 membered heteroaryl, wherein each of the phenyl and heteroaryl groups represented by R21 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy and C1-3 haloalkoxy, and wherein the alkyl group represented by R21 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy and C1-3 haloalkoxy;
or
N(R21)2 forms a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, ═O, C1-3 alky, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy and amino;
and
each R22 independently is C1-6 alkyl, phenyl or 5-6 membered heteroaryl, wherein each of the phenyl and heteroaryl groups represented by R22 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy and C1-3 haloalkoxy, and wherein the alkyl group represented by R22 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy and C1-3 haloalkoxy;
each Ar10 independently is a C6-14 aryl group or a 5-14 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, —OH, —SH, —O(C1-10 alkyl), —S(C1-10 alkyl), C1-10 alkyl, C1-10 haloalkyl, (C1-10 haloalkoxy)C1-10 alkyl, (C1-10 alkoxy)C1-10 alkyl, C1-10 hydroxyalkyl, (C1-10 aminoalkyl, (C1-10 alkylamino)C1-10 alkyl, (C1-10 dialkylamino)C1-10 alkyl, (phenyl)C1-10 alkyl, (5-6 membered heteroaryl)C1-10 alkyl, amino, C1-10 alkylamino, C1-10 dialkylamino, C1-10 haloalkoxy, C1-10 alkylcarbonyloxy, C1-10 alkoxycarbonyl and C1-10 alkylcarbonyl;
X is halogen;
R102 is —H or a nitrogen protecting group;
P2 is R4 or a nitrogen protecting group;
each p is 1, 2 or 3;
each q is 2, 3, 4 or 5;
n is 1, 2 or 3;
and
m is 1 or 2.

39 more elements

A method of preparing a diol compound represented by the following Structural Formula:

comprising the step of reacting a vinyl indazole compound represented by the following Structural Formula:
with a dihydroxylation reagent, wherein:
each Rb independently is —H, halogen, —C(O)OR1, —C(O)R1, —C(S)R1, —OC(O)R1—, —C(O)NR1R2, —C(S)NR1R2, —OC(O)NR1R2, —S(O)R1, —S(O)2R1, —SO3R1, —SO2NR1R2, —OR1, —SR1, —NR1R2, —NR2C(O)R1, —NR2S(O)R1, —NR2C(O)OR1, —NR2C(O)ONR1R2, —N(R2)C(O)NR1R2, —NR2SO2NR1R2, —NR2SO2R1;
—NO2, —CN, —NCS;
or two ortho Ra groups taken together form —O—[CH2]p—O—, —S—[CH2]p—S— or —[CH2]q;
or
C1-10 aliphatic group optionally substituted with one or more substituents selected from the group consisting halogen, nitro, cyano, —N(R21)2, —C(O)N(R21)2, —C(O)N(R21)2, —NR21C(O)R21, —SO2R22, —SO2N(R21)2, —NR21SO2R22, —NR21C(O)OR21, —OC(O)N(R21)2, —NR21C(O)N(R21)2, —NR21C(O)ON(R21)2, —NR21SO2N(R21)2, —OR21, —SR21, C1-10 haloalkoxy, —C(O)R21, —C(O)OR21 and —OC(O)R21;
or
(C0-10 alkylene)-Ar1, wherein Ar1 is a C6-14 aryl group or a 5-14 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, C1-10 alkyl, C1-10 haloalkyl, (C1-10 haloalkoxy)C1-10 alkyl, (C1-10 alkoxy)C1-10 alkyl, C1-10 hydroxyalkyl, C1-10 aminoalkyl, (C1-10 alkylamino)C1-10 alkyl, (C1-10 dialkylamino)C1-10 alkyl, —N(R21)2, —C(O)N(R21)2, —C(O)N(R21)2, —NR21C(O)R21, —SO2R22, —SO2N(R21)2, —NR21SO2R22, —NR21C(O)N(R21)2, —NR21C(O)ON(R21)2, —NR21SO2N(R21)2, —OR21, —SR21, C1-10 haloalkoxy, —C(O)R21, —C(O)OR21, —OC(O)R21, phenyl and 5-6 membered heteroaryl, wherein said phenyl and said 5-6 membered heteroaryl are each independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy and C1-3 haloalkoxy;
each R1 independently is:
i) hydrogen;
ii) a C6-14 aryl group or a 5-14 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, —NO2, —CN, —NCS, C1-C10 aliphatic, (C1-10 alkylene)-Ar10, —C(O)OR10, —C(O)R10, —C(S)R10, —OC(O)R10, —C(O)N(R11)2, —C(S)N(R11)2, —OC(O)N(R11)2, —S(O)R12, —S(O)2R12, —SO2N(R11)2, —OR10, —SR10, —N(R11)2, —NR11C(O)R10, —NR11S(O)R12, —NR11C(O)OR12, —N(R11)C(O)N(R11)2, —NR11SO2N(R11)2 and —NR11SO2R12;
or
iii) a C1-10 aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, —NO2, —CN, —NCS, Ar10, —C(O)OR10, —C(O)R10, —C(S)R10, —OC(O)R10, —C(O)N(R11)2, —C(S)N(R11)2, —OC(O)N(R11)2, —S(O)R12, —S(O)2R12, —SO2N(R11)2, —OR10, —SR10, —N(R11)2, —NR11C(O)R10, —NR11S(O)R12, —NR11C(O)OR12, —N(R11)C(O)N(R11)2, —NR11SO2N(R11)2 and —NR11SO2R12,
provided that R1 is other than hydrogen when Ra or Rb is —S(O)R1, —S(O)2R1, —SO3R1, —NR2S(O)R1 or —NR2SO2R1;
and
each R2 independently is —H or C1-C6 alkyl, or, taken together with NR1, forms a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting of ═O, ═S, halogen, nitro, cyano, hydroxy, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, amino, C1-6 alkylamino, C1-6 dialkylamino, C1-6 aminoalkyl, (C1-6 alkylamino)C1-6 alkyl, (C1-6 dialkylamino)C1-6 alkyl, (phenyl)C1-6 alkyl, (5-6 membered heteroaryl)C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkylcarbonyloxy, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyl, phenyl and 5-6 membered heteroaryl;
R3 is —H, halogen, C1-6 alkyl or C1-6 haloalkyl;
each R10 independently is:
i) hydrogen;
ii) a C6-14 aryl group or a 5-14 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, C1-10 alkyl, C1-10 haloalkyl, (C1-10 haloalkoxy)C1-10 alkyl, (C1-10 alkoxy)C1-10 alkyl, C1-10 hydroxyalkyl, C1-10 aminoalkyl, (C1-10 alkylamino)C1-10 alkyl, (C1-10 dialkylamino)C1-10 alkyl, (phenyl)C1-10 alkyl, (5-6 membered heteroaryl)C1-10 alkyl, amino, C1-10 alkylamino, C1-10 dialkylamino, C1-10 alkoxy, C1-10 haloalkoxy, C1-10 alkylcarbonyloxy, C1-10 alkoxycarbonyl and C1-10 alkylcarbonyl;
or
iii) a C1-10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, C1-10 haloalkyl, C1-10 alkoxy, C1-10 haloalkoxy, amino, C1-10 alkylamino, C1-10 dialkylamino, C1-10 alkylcarbonyloxy, C1-10 alkoxycarbonyl, C1-10 alkylcarbonyl and phenyl, said phenyl being optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy and C1-3 haloalkoxy;
each R11 independently is R10, —CO2R10, —SO2R10 or —C(O)R10, or
—N(R11)2 taken together is a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting of ═O, ═S, halogen, nitro, cyano, hydroxy, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, amino, C1-6 alkylamino, C1-6 dialkylamino, C1-6 aminoalkyl, (C1-6 alkylamino)C1-6 alkyl, (C1-6 dialkylamino)C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkylcarbonyloxy, C1-6 alkoxycarbonyl and C1-6 alkylcarbonyl;
and
each R12 is independently is R10 provided that R12 is not hydrogen;
each R21 independently is hydrogen, C1-6 alkyl, phenyl or 5-6 membered heteroaryl, wherein each of the phenyl and heteroaryl groups represented by R21 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy and C1-3 haloalkoxy, and wherein the alkyl group represented by R21 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy and C1-3 haloalkoxy;
or
N(R21)2 forms a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, ═O, C1-3 alky, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy and amino;
and
each R22 independently C1-6 alkyl, phenyl or 5-6 membered heteroaryl, wherein each of the phenyl and heteroaryl groups represented by R22 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy and C1-3 haloalkoxy, and wherein the alkyl group represented by R22 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy and C1-3 haloalkoxy;
each Ar10 independently is a C6-14 aryl group or a 5-14 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, —OH, —SH, —O(C1-10 alkyl), —S(C1-10 alkyl), C1-10 alkyl, C1-10 haloalkyl, (C1-10 haloalkoxy)C1-10 alkyl, (C1-10 alkoxy)C1-10 alkyl, C1-10 hydroxyalkyl, (C1-10 aminoalkyl, (C1-10 alkylamino)C1-10 alkyl, (C1-10 dialkylamino)C1-10 alkyl, (phenyl)C1-10 alkyl, (5-6 membered heteroaryl)C1-10 alkyl, amino, C1-10 alkylamino, C1-10 dialkylamino, C1-10 haloalkoxy, C1-10 alkylcarbonyloxy, C1-10 alkoxycarbonyl and C1-10 alkylcarbonyl;
P1 is —H or a nitrogen protecting group;
each p is 1, 2 or 3;
each q is 2, 3, 4 or 5;
and
m is 1 or 2.

35 more elements

A compound represented by the following Structural Formula:

or a salt thereof, wherein:
each of Ra and Rb independently is —H, halogen, —C(O)OR1, —C(O)R1, —C(S)R1, —OC(O)R1—, —C(O)NR1R2, —C(S)NR1R2, —OC(O)NR1R2, —S(O)R1, —S(O)2R1, —SO3R1, —SO2NR1R2, —OR1, —SR1, —NR1R2, —NR2C(O)R1, —NR2S(O)R1, —NR2C(O)OR1, —NR2C(O)ONR1R2, —N(R2)C(O)NR1R2, —NR2SO2NR1R2, —NR2SO2R1;
—NO2, —CN, —NCS;
or two ortho Ra groups taken together form —O—[CH2]p—O—, —S—[CH2]p—S— or —[CH2]q—;
or
C1-10 aliphatic group optionally substituted with one or more substituents selected from the group consisting halogen, nitro, cyano, —N(R21)2, —C(O)N(R21)2, —C(O)N(R21)2, —NR21C(O)R21, —SO2R22, —SO2N(R21)2, —NR21SO2R22, —NR21C(O)OR21, —OC(O)N(R21)2, —NR21C(O)N(R21)2, —NR21C(O)ON(R21)2, —NR21SO2N(R21)2, —OR21, —SR21, C1-10 haloalkoxy, —C(O)R21, —C(O)OR21 and —OC(O)R21;
or
(C0-10 alkylene)-Ar1, wherein Ar1 is a C6-14 aryl group or a 5-14 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, C1-10 alkyl, C1-10 haloalkyl, (C1-10 haloalkoxy)C1-10 alkyl, (C1-10 alkoxy)C1-10 alkyl, C1-10 hydroxyalkyl, C1-10 aminoalkyl, (C1-10 alkylamino)C1-10 alkyl, (C1-10 dialkylamino)C1-10 alkyl, —N(R21)2, —C(O)N(R21)2, —C(O)N(R21)2, —NR21C(O)R21, —SO2R22, —SO2N(R21)2, —NR21SO2R22, —NR21C(O)N(R21)2, —NR21C(O)ON(R21)2, —NR21SO2N(R21)2, —OR21, —SR21, C1-10 haloalkoxy, —C(O)R21, —C(O)OR21, —OC(O)R21, phenyl and 5-6 membered heteroaryl, wherein said phenyl and said 5-6 membered heteroaryl are each independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy and C1-3 haloalkoxy;
each R1 independently is:
i) hydrogen;
ii) a C6-14 aryl group or a 5-14 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, —NO2, —CN, —NCS, C1-C10 aliphatic, (C1-10 alkylene)-Ar10, —C(O)OR10, —C(O)R10, —C(S)R10, —OC(O)R10, —C(O)N(R11)2, —C(S)N(R11)2, —OC(O)N(R11)2, —S(O)R12, —S(O)2R12—SO2N(R11)2, —OR10, —SR10, —N(R11)2, —NR11C(O)R10, —NR11S(O)R12, —NR11C(O)OR12, —N(R11)C(O)N(R11)2, —NR11SO2N(R11)2 and —NR11SO2R12;
or
iii) a C1-10 aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, —NO2, —CN, —NCS, Ar10, —C(O)OR10, —C(O)R10, —C(S)R10, —OC(O)R10, —C(O)N(R11)2, —C(S)N(R11)2, —OC(O)N(R11)2, —S(O)R12, —S(O)2R12, —SO3R12, —SO2N(R11)2, —OR10, —SR10, —N(R11)2, —NR11C(O)R10, —NR11S(O)R12, —NR11C(O)OR12, —N(R11)C(O)N(R11)2, —NR11SO2N(R11)2 and —NR11SO2R12,
provided that R1 is other than hydrogen when Ra or Rb is —S(O)R1, —S(O)2R1, —SO3R1, —NR2S(O)R1 or —NR2SO2R1;
and
each R2 independently is —H or C1-C6 alkyl, or, taken together with NR1, forms a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting of ═O, ═S, halogen, nitro, cyano, hydroxy, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, amino, C1-6 alkylamino, C1-6 dialkylamino, C1-6 aminoalkyl, (C1-6 alkylamino)C1-6 alkyl, (C1-6 dialkylamino)C1-6 alkyl, (phenyl)C1-6 alkyl, (5-6 membered heteroaryl)C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkylcarbonyloxy, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyl, phenyl and 5-6 membered heteroaryl;
R4 is —H, C1-6 alkyl, phenyl, —C(O)(C1-6 alkyl), —C(O)(phenyl), —C(O)O(C1-6 alkyl), —C(O)O(phenyl), —S(O)2(C1-6 alkyl) or —S(O)2(phenyl), wherein each alkyl in the groups represented by R4 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, —C(O)NH2, phenyl, 5-6 membered heteroaryl, C1-6 alkoxy, C1-6 alkylamino, C1-6 dialkylamino and C1-6 haloalkoxy, and wherein each phenyl in the groups represented by R4 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy and C1-6 haloalkoxy;
each R10 independently is:
i) hydrogen;
ii) a C6-14 aryl group or a 5-14 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, C1-10 alkyl, C1-10 haloalkyl, (C1-10 haloalkoxy)C1-10 alkyl, (C1-10 alkoxy)C1-10 alkyl, C1-10 hydroxyalkyl, C1-10 aminoalkyl, (C1-10 alkylamino)C1-10 alkyl, (C1-10 dialkylamino)C1-10 alkyl, (phenyl)C1-10 alkyl, (5-6 membered heteroaryl)C1-10 alkyl, amino, C1-10 alkylamino, C1-10 dialkylamino, C1-10 alkoxy, C1-10 haloalkoxy, C1-10 alkylcarbonyloxy, C1-10 alkoxycarbonyl and C1-10 alkylcarbonyl;
or
iii) a C1-10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, C1-10 haloalkyl, C1-10 alkoxy, C1-10 haloalkoxy, amino, C1-10 alkylamino, C1-10 dialkylamino, C1-10 alkylcarbonyloxy, C1-10 alkoxycarbonyl, C1-10 alkylcarbonyl and phenyl, said phenyl being optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy and C1-3 haloalkoxy;
each R11 independently is R10, —CO2R10, —SO2R10 or —C(O)R10, or
—N(R11)2 taken together is a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting of ═O, ═S, halogen, nitro, cyano, hydroxy, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, amino, C1-6 alkylamino, C1-6 dialkylamino, C1-6 aminoalkyl, (C1-6 alkylamino)C1-6 alkyl, (C1-6 dialkylamino)C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkylcarbonyloxy, C1-6 alkoxycarbonyl and C1-6 alkylcarbonyl;
and
each R12 is independently is R10 provided that R12 is not hydrogen;
each R21 independently is hydrogen, C1-6 alkyl, phenyl or 5-6 membered heteroaryl, wherein each of the phenyl and heteroaryl groups represented by R21 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy and C1-3 haloalkoxy, and wherein the alkyl group represented by R21 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy and C1-3 haloalkoxy;
or
N(R21)2 forms a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, ═O, C1-3 alky, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy and amino;
and
each R22 independently C1-6 alkyl, phenyl or 5-6 membered heteroaryl, wherein each of the phenyl and heteroaryl groups represented by R22 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy and C1-3 haloalkoxy, and wherein the alkyl group represented by R22 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy and C1-3 haloalkoxy;
each Ar10 independently is a C6-14 aryl group or a 5-14 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, —OH, —SH, —O(C1-10 alkyl), —S(C1-10 alkyl), C1-10 alkyl, C1-10 haloalkyl, (C1-10 haloalkoxy)C1-10 alkyl, (C1-10 alkoxy)C1-10 alkyl, C1-10 hydroxyalkyl, (C1-10 aminoalkyl, (C1-10 alkylamino)C1-10 alkyl, (C1-10 dialkylamino)C1-10 alkyl, (phenyl)C1-10 alkyl, (5-6 membered heteroaryl)C1-10 alkyl, amino, C1-10 alkylamino, C1-10 dialkylamino, C1-10 haloalkoxy, C1-10 alkylcarbonyloxy, C1-10 alkoxycarbonyl and C1-10 alkylcarbonyl;
R101 is —H or halogen;
each p is 1, 2 or 3;
each q is 2, 3, 4 or 5;
n is 0, 1, 2 or 3;
and
m is 0, 1 or 2,
provided the compound is not represented by the following structural formula:

36 more elements

A compound represented by the following Structural Formula:

wherein:
each of Rb independently is —H, halogen, —C(O)OR1, —C(O)R1, —C(S)R1, —OC(O)R1—, —C(O)NR1R2, —C(S)NR1R2, —OC(O)NR1R2, —S(O)R1, —S(O)2R1, —SO3R1, —SO2NR1R2, —OR1, —SR1, —NR1R2, —NR2C(O)R1, —NR2S(O)R1, —NR2C(O)OR1, —NR2C(O)ONR1R2, —N(R2)C(O)NR1R2, —NR2SO2NR1R2, —NR2SO2R1;
—NO2, —CN, —NCS;
or two ortho Ra groups taken together form —O—[CH2]p—O—, —S—[CH2]p—S— or —[CH2]q;
or
C1-10 aliphatic group optionally substituted with one or more substituents selected from the group consisting halogen, nitro, cyano, —N(R21)2, —C(O)N(R21)2, —C(O)N(R21)2, —NR21C(O)R21, —SO2R22, —SO2N(R21)2, —NR21SO2R22, —NR21C(O)OR21, —OC(O)N(R21)2, —NR21C(O)N(R21)2, —NR21C(O)ON(R21)2, —NR21SO2N(R21)2, —OR21, —SR21, C1-10 haloalkoxy, —C(O)R21, —C(O)OR21 and —OC(O)R21;
or
(C0-10 alkylene)-Ar1, wherein Ar1 is a C6-14 aryl group or a 5-14 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, C1-10 alkyl, C1-10 haloalkyl, (C1-10 haloalkoxy)C1-10 alkyl, (C1-10 alkoxy)C1-10 alkyl, C1-10 hydroxyalkyl, C1-10 aminoalkyl, (C1-10 alkylamino)C1-10 alkyl, (C1-10 dialkylamino)C1-40 alkyl, —N(R21)2, —C(O)N(R21)2, —C(O)N(R21)2, —NR21C(O)R21, —SO2R22, —SO2N(R21)2, —NR21SO2R22, —NR21C(O)N(R21)2, —NR21C(O)ON(R21)2, —NR21SO2N(R21)2, —OR21, —SR21, C1-10 haloalkoxy, —C(O)R21, —C(O)OR21, —OC(O)R21, phenyl and 5-6 membered heteroaryl, wherein said phenyl and said 5-6 membered heteroaryl are each independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy and C1-3 haloalkoxy;
each R1 independently is:
i) hydrogen;
ii) a C6-14 aryl group or a 5-14 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, —NO2, —CN, —NCS, C1-C10 aliphatic, (C1-10 alkylene)-Ar10, —C(O)OR10, —C(O)R10, —C(S)R10, —OC(O)R10, —C(O)N(R11)2, —C(S)N(R11)2, —OC(O)N(R11)2, —S(O)R12, —S(O)2R12—SO2N(R11)2, —OR10, —SR10, —N(R11)2, —NR11C(O)R10, —NR11S(O)R12, —NR11C(O)OR12, —N(R11)C(O)N(R11)2, —NR11SO2N(R11)2 and —NR11SO2R12;
or
iii) a C1-10 aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, —NO2, —CN, —NCS, Ar10, —C(O)OR10, —C(O)R10, —C(S)R10, —OC(O)R10, —C(O)N(R11)2, —C(S)N(R11)2, —OC(O)N(R11)2, —S(O)R12, —S(O)R12, —S(O)2R12, —SO3R12, —SO2N(R11)2, —OR10, —SR10, —N(R11)2, —NR11C(O)R10, —NR11S(O)R12, —NR11C(O)OR12, —N(R11)C(O)N(R11)2, —NR11SO2N(R11)2 and —NR11SO2R12,
provided that R1 is other than hydrogen when Ra or Rb is —S(O)R1, —S(O)2R1, —SO3R1, —NR2S(O)R1 or —NR2SO2R1;
and
each R2 independently is —H or C1-C6 alkyl, or, taken together with NR1, forms a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting of ═O, ═S, halogen, nitro, cyano, hydroxy, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, amino, C1-6 alkylamino, C1-6 dialkylamino, C1-6 aminoalkyl, (C1-6 alkylamino)C1-6 alkyl, (C1-6 dialkylamino)C1-6 alkyl, (phenyl)C1-6 alkyl, (5-6 membered heteroaryl)C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkylcarbonyloxy, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyl, phenyl and 5-6 membered heteroaryl;
R3 is —H, halogen, C1-6 alkyl or C1-6 haloalkyl;
each R10 independently is:
i) hydrogen;
ii) a C6-14 aryl group or a 5-14 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, C1-10 alkyl, C1-10 haloalkyl, (C1-10 haloalkoxy)C1-10 alkyl, (C1-10 alkoxy)C1-10 alkyl, C1-10 hydroxyalkyl, C1-10 aminoalkyl, (C1-10 alkylamino)C1-10 alkyl, (C1-10 dialkylamino)C1-10 alkyl, (phenyl)C1-10 alkyl, (5-6 membered heteroaryl)C1-10 alkyl, amino, C1-10 alkylamino, C1-10 dialkylamino, C1-10 alkoxy, C1-10 haloalkoxy, C1-10 alkylcarbonyloxy, C1-10 alkoxycarbonyl and C1-10 alkylcarbonyl;
or
iii) a C1-10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, C1-10 haloalkyl, C1-10 alkoxy, C1-10 haloalkoxy, amino, C1-10 alkylamino, C1-10 dialkylamino, C1-10 alkylcarbonyloxy, C1-10 alkoxycarbonyl, C1-10 alkylcarbonyl and phenyl, said phenyl being optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy and C1-3 haloalkoxy;
each R11 independently is R10, —CO2R10, —SO2R10 or —C(O)R10, or
—N(R11)2 taken together is a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting of ═O, ═S, halogen, nitro, cyano, hydroxy, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, amino, C1-6 alkylamino, C1-6 dialkylamino, C1-6 aminoalkyl, (C1-6 alkylamino)C1-6 alkyl, (C1-6 dialkylamino)C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkylcarbonyloxy, C1-6 alkoxycarbonyl and C1-6 alkylcarbonyl;
and
each R12 is independently is R10 provided that R12 is not hydrogen;
each R21 independently is hydrogen, C1-6 alkyl, phenyl or 5-6 membered heteroaryl, wherein each of the phenyl and heteroaryl groups represented by R21 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy and C1-3 haloalkoxy, and wherein the alkyl group represented by R21 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy and C1-3 haloalkoxy;
or
N(R21)2 forms a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, ═O, C1-3 alky, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy and amino;
and
each R22 independently C1-6 alkyl, phenyl or 5-6 membered heteroaryl, wherein each of the phenyl and heteroaryl groups represented by R22 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy and C1-3 haloalkoxy, and wherein the alkyl group represented by R22 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy and C1-3 haloalkoxy;
each Ar10 independently is a C6-14 aryl group or a 5-14 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, —OH, —SH, —O(C1-10 alkyl), —S(C1-10 alkyl), C1-10 alkyl, C1-10 haloalkyl, (C1-10 haloalkoxy)C1-10 alkyl, (C1-10 alkoxy)C1-10 alkyl, C1-10 hydroxyalkyl, (C1-10 aminoalkyl, (C1-10 alkylamino)C1-10 alkyl, (C1-10 dialkylamino)C1-10 alkyl, (phenyl)C1-10 alkyl, (5-6 membered heteroaryl)C1-10 alkyl, amino, C1-10 alkylamino, C1-10 dialkylamino, C1-10 haloalkoxy, C1-10 alkylcarbonyloxy, C1-10 alkoxycarbonyl and C1-10 alkylcarbonyl;
P1 is —H or a nitrogen protecting group;
each p is 1, 2 or 3;
each q is 2, 3, 4 or 5;
and
m is 0, 1 or 2.

34 more elements

A method of preparing a spiro cyclopropyl indolinone compound represented by the following Structural Formula:

or a salt thereof, comprising the step of reacting a halogenated indolinone compound represented by the following Structural Formula:
with R6B(OH)2 or a boronic acid ester derivative thereof in the presence of a palladium catalyst, wherein:
X is a halogen;
each of Ra and Rb independently is —H, halogen, —C(O)OR1, —C(O)R1, —C(S)R1, —OC(O)R1—, —C(O)NR1R2, —C(S)NR1R2, —OC(O)NR1R2, —S(O)R1, —S(O)2R1, —SO3R1, —SO2NR1R2, —OR1, —SW, —NR1R2, —NR2C(O)R1, —NR2S(O)R1, —NR2C(O)OR1, —NR2C(O)ONR1R2, —N(R2)C(O)NR1R2, —NR2SO2NR1R2, —NR2SO2R1;
—NO2, —CN, —NCS;
or
two ortho Ra groups taken together form —O—[CH2]p—O—, —S—[CH2]p—S— or —[CH2]q—;
or
C1-10 aliphatic group optionally substituted with one or more substituents selected from the group consisting halogen, nitro, cyano, —N(R21)2, —C(O)N(R21)2, —C(O)N(R21)2, —NR21C(O)R21, —SO2R22, —SO2N(R21)2, —NR21SO2R22, —NR21C(O)OR21, —OC(O)N(R21)2, —NR21C(O)N(R21)2, —NR21C(O)ON(R21)2, —NR2SO2N(R21)2, —OR21, —SR21, C1-10 haloalkoxy, —C(O)R21, —C(O)OR21 and —OC(O)R21;
or
(C0-10 alkylene)-Ar1, wherein Ar1 is a C6-14 aryl group or a 5-14 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, C1-10 alkyl, C1-10 haloalkyl, (C1-10 haloalkoxy)C1-10 alkyl, (C1-10 alkoxy)C1-10 alkyl, C1-10 hydroxyalkyl, C1-10 aminoalkyl, (C1-10 alkylamino)C1-10 alkyl, (C1-10 dialkylamino)C1-10 alkyl, —N(R21)2, —C(O)N(R21)2, —C(O)N(R21)2, —NR21C(O)R21, —SO2R22, —SO2N(R21)2, —NR21SO2R22, —NR21C(O)N(R21)2, —NR21C(O)ON(R21)2, —NR21SO2N(R21)2, —OR21, —SR21, C1-10 haloalkoxy, —C(O)R21, —C(O)OR21, —OC(O)R21, phenyl and 5-6 membered heteroaryl, wherein said phenyl and said 5-6 membered heteroaryl are each independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy and C1-3 haloalkoxy;
each R1 independently is:
i) hydrogen;
ii) a C6-14 aryl group or a 5-14 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, —NO2, —CN, —NCS, C1-C10 aliphatic, (C1-10 alkylene)-Ar10, —C(O)OR10, —C(O)R10, —C(S)R10, —OC(O)R10, —C(O)N(R11)2, —C(S)N(R11)2, —OC(O)N(R11)2, —S(O)R12, —S(O)2R12—SO2N(R11)2, —OR10, —SR10, —N(R11)2, —NR11C(O)R10, —NR11S(O)R12, —NR11C(O)OR12, —N(R11)C(O)N(R11)2, —NR11SO2N(R11)2 and —NR11SO2R12;
or
iii) a C1-10 aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, —NO2, —CN, —NCS, Ar10, —C(O)OR10, —C(O)R10, —C(S)R OC(O)R10, —C(O)N(R11)2, —C(S)N(R11)2, —OC(O)N(R11)2, —S(O)R12, —S(O)R12, —S(O)2R12, —SO3R12, —SO2N(R11)2, —OR10, —SR10, —N(R11)2, —NR11C(O)R10, —NR11S(O)R12, —NR11C(O)OR12, —N(R11)C(O)N(R11)2, —NR11SO2N(R11)2 and —NR11SO2R12,
provided that R1 is other than hydrogen when Ra or Rb is —S(O)R1, —S(O)2R1, —SO3R1, —NR2S(O)R1 or —NR2SO2R1;
and
each R2 independently is —H or C1-C6 alkyl, or, taken together with NR1, forms a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting of ═O, ═S, halogen, nitro, cyano, hydroxy, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, amino, C1-6 alkylamino, C1-6 dialkylamino, C1-6 aminoalkyl, (C1-6 alkylamino)C1-6 alkyl, (C1-6 dialkylamino)C1-6 alkyl, (phenyl)C1-6 alkyl, (5-6 membered heteroaryl)C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkylcarbonyloxy, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyl, phenyl and 5-6 membered heteroaryl;
R3 is —H, halogen, C1-6 alkyl or C1-6 haloalkyl;
R4 is a nitrogen protecting group or —H, C1-6 alkyl, phenyl, —C(O)(C1-6 alkyl), —C(O)(phenyl), —C(O)O(C1-6 alkyl), —C(O)O(phenyl), —S(O)2(C1-6 alkyl) or —S(O)2(phenyl), wherein each alkyl in the groups represented by R4 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, —C(O)NH2, phenyl, 5-6 membered heteroaryl, C1-6 alkoxy, C1-6 alkylamino, C1-6 dialkylamino and C1-6 haloalkoxy, and wherein each phenyl in the groups represented by R4 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy and C1-6 haloalkoxy;
R6 is C2-10 alkenyl, phenyl, 5-12 membered heteroaryl or 9-12 membered heterocyclyl group, wherein the C2-10 alkenyl group represented by R6 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, phenyl, 5-12 membered heteroaryl, 9-12 membered heterocyclyl group, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-6 alkylamino, C1-6 dialkylamino, —C(O)H, —C(O)(C1-C6 alkyl), —C(O)(C1-C6 haloalkyl), —C(O)(phenyl), —C(O)(non-aromatic heterocyclic group), —C(O)O(C1-C6 alkyl), —C(O)O(C1-C6 haloalkyl), —C(O)O(phenyl), —OC(O)(C1-C6 alkyl), —OC(O)(C1-C6 haloalkyl), —OC(O)(phenyl), —S(O)2(C1-C6 alkyl), —S(O)2(C1-C6 haloalkyl) and —S(O)2(phenyl), and wherein each of the phenyl, heteroaryl and heterocyclyl groups represented by R6, and the phenyl, heteroaryl and heterocyclyl groups in the substituents for the aliphatic group represented by R6 independently are optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —SH, —C(O)H, nitro, cyano, amino, C1-6 alkylamino, C1-6 dialkylamino, (C1-6 dialkylamino)C1-6 dialkylamino, C1-C6 alkyl, C1-C6 haloalkyl, —O(C1-6 alkyl), —O-(non-aromatic heterocyclic group), —S(C1-6 alkyl), —O(C1-6 haloalkyl), (C1-6 haloalkoxy)C1-6 alkyl, (C1-6 alkoxy)C1-6 alkyl, C1-6 hydroxyalkyl, (C1-6 aminoalkyl), (C1-6 alkylamino)C1-6 alkyl, (C1-6 dialkylamino)C1-6 alkyl, (C1-6 dialkylamino)C1-6 alkoxy, (phenyl)C1-6 alkyl, (5-6 membered heteroaryl)C1-6 alkyl, (non-aromatic heterocyclic group)C1-6 alkyl (optionally substituted with halogen, —OH, C1-6 hydroxyalkyl, C1-6 alkyl, (C1-6 alkoxy)C1-6 alkyl, C1-6 acyl, C5-7 cycloalkyl, C1-6 alkylamino, C1-6 dialkylamino or non-aromatic heterocyclic group), (5-6 membered heteroaryl)C1-6 alkoxy, (non-aromatic heterocyclic group)C1-6 alkoxy, —C(O)(C1-C6 alkyl), —C(O)(C1-C6 haloalkyl), —C(O)(phenyl), —C(O)(non-aromatic heterocyclic group), —C(O)O(C1-C6 alkyl), —C(O)O(C1-C6 haloalkyl), —C(O)O(phenyl), —OC(O)(C1-C6 alkyl), —OC(O)(C1-C6 haloalkyl), —OC(O)(phenyl), —S(O)2NH2, —S(O)2(C1-C6 alkyl), —S(O)2(C1-6 haloalkyl), and —S(O)2(phenyl);
each R10 independently is:
i) hydrogen;
ii) a C6-14 aryl group or a 5-14 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, C1-10 alkyl, C1-10 haloalkyl, (C1-10 haloalkoxy)C1-10 alkyl, (C1-10 alkoxy)C1-10 alkyl, C1-10 hydroxyalkyl, C1-10 aminoalkyl, (C1-10 alkylamino)C1-10 alkyl, (C1-10 dialkylamino)C1-10 alkyl, (phenyl)C1-10 alkyl, (5-6 membered heteroaryl)C1-10 alkyl, amino, C1-10 alkylamino, C1-10 dialkylamino, C1-10 alkoxy, C1-10 haloalkoxy, C1-10 alkylcarbonyloxy, C1-10 alkoxycarbonyl and C1-10 alkylcarbonyl;
or
iii) a C1-10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, C1-10 haloalkyl, C1-10 alkoxy, C1-10 haloalkoxy, amino, C1-10 alkylamino, C1-10 dialkylamino, C1-10 alkylcarbonyloxy, C1-10 alkoxycarbonyl, C1-10 alkylcarbonyl and phenyl, said phenyl being optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy and C1-3 haloalkoxy;
each R11 independently is R10, —CO2R10, —SO2R10 or —C(O)R10, or
—N(R11)2 taken together is a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting of ═O, ═S, halogen, nitro, cyano, hydroxy, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, amino, C1-6 alkylamino, C1-6 dialkylamino, C1-6 aminoalkyl, (C1-6 alkylamino)C1-6 alkyl, (C1-6 dialkylamino)C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkylcarbonyloxy, C1-6 alkoxycarbonyl and C1-6 alkylcarbonyl;
and
each R12 is independently is R10 provided that R12 is not hydrogen;
each R21 independently is hydrogen, C1-6 alkyl, phenyl or 5-6 membered heteroaryl, wherein each of the phenyl and heteroaryl groups represented by R21 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy and C1-3 haloalkoxy, and wherein the alkyl group represented by R21 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy and C1-3 haloalkoxy;
or
N(R21)2 forms a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, ═O, C1-3 alky, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy and amino;
and
each R22 independently C1-6 alkyl, phenyl or 5-6 membered heteroaryl, wherein each of the phenyl and heteroaryl groups represented by R22 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy and C1-3 haloalkoxy, and wherein the alkyl group represented by R22 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy and C1-3 haloalkoxy;
each Ar10 independently is a C6-14 aryl group or a 5-14 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, —OH, —SH, —O(C1-10 alkyl), —S(C1-10 alkyl), C1-10 alkyl, C1-10 haloalkyl, (C1-10 haloalkoxy)C1-10 alkyl, (C1-10 alkoxy)C1-10 alkyl, C1-10 hydroxyalkyl, (C1-10 aminoalkyl, (C1-10 alkylamino)C1-10 alkyl, (C1-10 dialkylamino)C1-10 alkyl, (phenyl)C1-10 alkyl, (5-6 membered heteroaryl)C1-10 alkyl, amino, C1-10 alkylamino, C1-10 dialkylamino, C1-10 haloalkoxy, C1-10 alkylcarbonyloxy, C1-10 alkoxycarbonyl and C1-10 alkylcarbonyl;
each p is 1, 2 or 3;
each q is 2, 3, 4 or 5;
n is 1, 2 or 3;
and
m is 1 or 2.

39 more elements

Dependencies are inferred from the claim text.

Facts

Application: 13/639,648Filed 6 Apr 2011
Priority: CA PCT/CA2010/0005186 Apr 2010
Published: 18 Apr 2013
Term ends: Not estimatedThe source records don’t support an estimate.

Classification15 codes

C07D 403/10
Containing two hetero rings: linked by a carbon chain containing aromatic rings
A61K 31/5377
1,4-Oxazines, e.g. morpholine: not condensed and containing further heterocyclic rings, e.g. timolol
A61K 45/06
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system

Family

Application61/321,332Us provisional application · filed 6 Apr 2010
Application61/321,329Us provisional application · filed 6 Apr 2010
US 8,921,545 B2Related patent
US 2013/0096301 A1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A method of preparing a spiro indolinone compound represented by the following Structural Formula:

or a salt thereof, comprising the step of reacting an indolinone compound represented by the following Structural Formula:
with a base and an indazole compound represented by the following Structural Formula:
wherein:
each of Ra and Rb independently is —H, halogen, —C(O)OR1, —C(O)R1, —C(S)R1, —OC(O)R1—, —C(O)NR1R2, —C(S)NR1R2, —OC(O)NR1R2, —S(O)R1, —S(O)2R1, —SO3R1, —SO2NR1R2, —OR1, —SR1, —NR1R2, —NR2C(O)R1, —NR2S(O)R1, —NR2C(O)OR1, —NR2C(O)ONR1R2, —N(R2)C(O)NR1R2, —NR2SO2NR1R2, —NR2SO2R1;
—NO2, —CN, —NCS;
or two ortho Ra groups taken together form —O—[CH2]p—O—, —S—[CH2]p—S— or —[CH2]q—;
or
C1-10 aliphatic group optionally substituted with one or more substituents selected from the group consisting halogen, nitro, cyano, —N(R21)2, —C(O)N(R21)2, —C(O)N(R21)2, —NR21C(O)R21, —SO2R22, —SO2N(R21)2, —NR21SO2R22, —NR21C(O)OR21, —OC(O)N(R21)2, —NR21C(O)N(R21)2, —NR21C(O)ON(R21)2, —NR21SO2N(R21)2, —OR21, —SR21, C1-10 haloalkoxy, —C(O)R21, —C(O)OR21 and —OC(O)R21;
or
(C0-10 alkylene)-Ar1, wherein Ar1 is a C6-14 aryl group or a 5-14 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, C1-10 alkyl, C1-10 haloalkyl, (C1-10 haloalkoxy)C1-10 alkyl, (C1-10 alkoxy)C1-10 alkyl, C1-10 hydroxyalkyl, C1-10 aminoalkyl, (C1-10 alkylamino)C1-10 alkyl, (C1-10 dialkylamino)C1-10 alkyl, —N(R21)2, —C(O)N(R21)2, —C(O)N(R21)2, —NR21C(O)R21, —SO2R22, —SO2N(R21)2, —NR21SO2R22, —NR21C(O)N(R21)2, —NR21C(O)ON(R21)2, —NR21SO2N(R21)2, —OR21, —SR21, C1-10 haloalkoxy, —C(O)R21, —C(O)OR21, —OC(O)R21, phenyl and 5-6 membered heteroaryl, wherein said phenyl and said 5-6 membered heteroaryl are each independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy and C1-3 haloalkoxy;
each R1 independently is:
i) hydrogen;
ii) a C6-14 aryl group or a 5-14 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, —NO2, —CN, —NCS, C1-C10 aliphatic, (C1-10 alkylene)-Ar10, —C(O)OR10, —C(O)R10, —C(S)R10, —OC(O)R10, —C(O)N(R11)2, —C(S)N(R11)2, —OC(O)N(R11)2, —S(O)R12, —S(O)2R12, —SO3R12, —SO2N(R11)2, —OR10, —SR10, —N(R11)2, —NR11C(O)R10, —NR11S(O)R12, —NR11C(O)OR12, —N(R11)C(O)N(R11)2, —NR11SO2N(R11)2 and —NR11SO2R12;
or
iii) a C1-10 aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, —NO2, —CN, —NCS, Ar10, —C(O)OR10, —C(O)R10, —C(S)R10, —OC(O)R10, —C(O)N(R11)2, —C(S)N(R11)2, —OC(O)N(R11)2, —S(O)R12, —S(O)R12, —S(O)2R12, —SO3R12, —SO2N(R11)2, —OR10, —SR10, —N(R11)2, —NR11C(O)R10, —NR11S(O)R12, —NR11C(O)OR12, —N(R11)C(O)N(R11)2, —NR11SO2N(R11)2 and —NR11SO2R12,
provided that R1 is other than hydrogen when Ra or Rb is —S(O)R1, —S(O)2R1, —SO3R1, —NR2S(O)R1 or —NR2SO2R1;
and
each R2 independently is —H or C1-C6 alkyl, or, taken together with NR1, forms a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting of ═O, ═S, halogen, nitro, cyano, hydroxy, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, amino, C1-6 alkylamino, C1-6 dialkylamino, C1-6 aminoalkyl, (C1-6 alkylamino)C1-6 alkyl, (C1-6 dialkylamino)C1-6 alkyl, (phenyl)C1-6 alkyl, (5-6 membered heteroaryl)C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkylcarbonyloxy, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyl, phenyl and 5-6 membered heteroaryl;
R3 is —H, halogen, C1-6 alkyl or C1-6 haloalkyl;
R4 is —H, C1-6 alkyl, phenyl, —C(O)(C1-6 alkyl), —C(O)(phenyl), —C(O)O(C1-6 alkyl), —C(O)O(phenyl), —S(O)2(C1-6 alkyl) or —S(O)2(phenyl), wherein each alkyl in the groups represented by R4 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, —C(O)NH2, phenyl, 5-6 membered heteroaryl, C1-6 alkoxy, C1-6 alkylamino, C1-6 dialkylamino and C1-6 haloalkoxy, and wherein each phenyl in the groups represented by R4 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy and C1-6 haloalkoxy;
R6 is hydrogen, halogen, nitro, cyano, R′, —OR, —SR, —N(R)2, —C(O)R, —C(O)OR, —OC(O)R, —C(O)N(R)2, —OC(O)N(R)2, —NRC(O)R, —NRC(O)OR, —SOR′, —SO2R′, —SO3R′, —SO2N(R)2, —NRS(O)R′, —NRSO2R′, —NRC(O)N(R)2, —NRC(O)ON(R)2, or —NRSO2N(R)2;
each R10 independently is:
i) hydrogen;
ii) a C6-14 aryl group or a 5-14 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, C1-10 alkyl, C1-10 haloalkyl, (C1-10 haloalkoxy)C1-10 alkyl, (C1-10 alkoxy)C1-10 alkyl, C1-10 hydroxyalkyl, C1-10 aminoalkyl, (C1-10 alkylamino)C1-10 alkyl, (C1-10 dialkylamino)C1-10 alkyl, (phenyl)C1-10 alkyl, (5-6 membered heteroaryl)C1-10 alkyl, amino, C1-10 alkylamino, C1-10 dialkylamino, C1-10 alkoxy, C1-10 haloalkoxy, C1-10 alkylcarbonyloxy, C1-10 alkoxycarbonyl and C1-10 alkylcarbonyl;
or
iii) a C1-10 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, C1-10 haloalkyl, C1-10 alkoxy, C1-10 haloalkoxy, amino, C1-10 alkylamino, C1-10 dialkylamino, C1-10 alkylcarbonyloxy, C1-10 alkoxycarbonyl, C1-10 alkylcarbonyl and phenyl, said phenyl being optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy and C1-3 haloalkoxy;
each R11 independently is R10, —CO2R10, —SO2R10 or —C(O)R10, or
—N(R11)2 taken together is a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting of ═O, ═S, halogen, nitro, cyano, hydroxy, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, amino, C1-6 alkylamino, C1-6 dialkylamino, C1-6 aminoalkyl, (C1-6 alkylamino)C1-6 alkyl, (C1-6 dialkylamino)C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkylcarbonyloxy, C1-6 alkoxycarbonyl and C1-6 alkylcarbonyl;
and
each R12 is independently is R10 provided that R12 is not hydrogen;
each R21 independently is hydrogen, C1-6 alkyl, phenyl or 5-6 membered heteroaryl, wherein each of the phenyl and heteroaryl groups represented by R21 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy and C1-3 haloalkoxy, and wherein the alkyl group represented by R21 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy and C1-3 haloalkoxy;
or
N(R21)2 forms a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, ═O, C1-3 alky, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy and amino;
and
each R22 independently C1-6 alkyl, phenyl or 5-6 membered heteroaryl, wherein each of the phenyl and heteroaryl groups represented by R22 is independently and optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy and C1-3 haloalkoxy, and wherein the alkyl group represented by R22 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy and C1-3 haloalkoxy;
each R independently is hydrogen, C1-10 aliphatic, phenyl or 5-6 membered heteroaryl, wherein the aliphatic group represented by R is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, phenyl, 5-6 membered heteroaryl, C1-6 alkoxy, C1-6 haloalkoxy, and wherein each of the phenyl and heteroaryl groups represented by R, and the phenyl and heteroaryl substituents for the aliphatic group represented by R independently are optionally and independently substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, or
N(R)2 forms a non-aromatic heterocyclic group optionally substituted with one or more substituents selected from the group consisting of ═O, ═S, halogen, nitro, cyano, hydroxy, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, amino, C1-6 alkylamino, C1-6 dialkylamino, C1-6 aminoalkyl, (C1-6 alkylamino)C1-6 alkyl, (C1-6 dialkylamino)C1-6 alkyl, (phenyl)C1-6 alkyl, (5-6 membered heteroaryl)C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkylcarbonyloxy, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyl, phenyl and 5-6 membered heteroaryl;
and
each R′ independently is C1-10 aliphatic, phenyl, 5-12 membered heteroaryl or 9-12 membered heterocyclyl group, wherein the aliphatic group represented by R′ is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, phenyl, 5-12 membered heteroaryl, 9-12 membered heterocyclyl group, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-6 alkylamino, C1-6 dialkylamino, —C(O)H, —C(O)(C1-C6 alkyl), —C(O)(C1-C6 haloalkyl), —C(O)(phenyl), —C(O)(non-aromatic heterocyclic group), —C(O)O(C1-C6 alkyl), —C(O)O(C1-C6 haloalkyl), —C(O)O(phenyl), —OC(O)(C1-C6 alkyl), —OC(O)(C1-C6 haloalkyl), —OC(O)(phenyl), —S(O)2(C1-C6 alkyl), —S(O)2(C1-C6 haloalkyl) and —S(O)2(phenyl), and wherein each of the phenyl, heteroaryl and heterocyclyl groups represented by R′, and the phenyl, heteroaryl and heterocyclyl groups in the substituents for the aliphatic group represented by R′ independently are optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —SH, —C(O)H, nitro, cyano, amino, C1-6 alkylamino, C1-6 dialkylamino, (C1-6 dialkylamino)C1-6 dialkylamino, C1-C6 alkyl, C1-C6 haloalkyl, —O(C1-6 alkyl), —O-(non-aromatic heterocyclic group), —S(C1-6 alkyl), —O(C1-6 haloalkyl), (C1-6 haloalkoxy)C1-6 alkyl, (C1-6 alkoxy)C1-6 alkyl, C1-6 hydroxyalkyl, (C1-6 aminoalkyl), (C1-6 alkylamino)C1-6 alkyl, (C1-6 dialkylamino)C1-6 alkyl, (C1-6 dialkylamino)C1-6 alkoxy, (phenyl)C1-6 alkyl, (5-6 membered heteroaryl)C1-6 alkyl, (non-aromatic heterocyclic group)C1-6 alkyl (optionally substituted with halogen, —OH, C1-6 hydroxyalkyl, C1-6 alkyl, C1-6 acyl, C5-7 cycloalkyl, C1-6 alkylamino, di(C1-6 alkyl)amino or non-aromatic heterocyclic group), (5-6 membered heteroaryl)C1-6 alkoxy, (non-aromatic heterocyclic group)C1-6 alkoxy, —C(O)(C1-C6 alkyl), —C(O)(C1-C6 haloalkyl), —C(O)(phenyl), —C(O)(non-aromatic heterocyclic group), —C(O)O(C1-C6 alkyl), —C(O)O(C1-C6 haloalkyl), —C(O)O(phenyl), —OC(O)(C1-C6 alkyl), —OC(O)(C1-C6 haloalkyl), —OC(O)(phenyl), —S(O)2NH2, —S(O)2(C1-C6 alkyl), —S(O)2(C1-6 haloalkyl), and —S(O)2(phenyl);
each Ar10 independently is a C6-14 aryl group or a 5-14 membered heteroaryl group, each optionally and independently substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, —OH, —SH, —O(C1-10 alkyl), —S(C1-10 alkyl), C1-10 alkyl, C1-10 haloalkyl, (C1-10 haloalkoxy)C1-10 alkyl, (C1-10 alkoxy)C1-10 alkyl, C1-10 hydroxyalkyl, (C1-10 aminoalkyl, (C1-10 alkylamino)C1-10 alkyl, (C1-10 dialkylamino)C1-10 alkyl, (phenyl)C1-10 alkyl, (5-6 membered heteroaryl)C1-10 alkyl, amino, C1-10 alkylamino, C1-10 dialkylamino, C1-10 haloalkoxy, C1-10 alkylcarbonyloxy, C1-10 alkoxycarbonyl and C1-10 alkylcarbonyl;
X1 and X2 are independently a sulfonate leaving group or halogen;
P1 is —H or a nitrogen protecting group;
P2 is R4 or a nitrogen protecting group;
each p is 1, 2 or 3;
each q is 2, 3, 4 or 5;
n is 1, 2 or 3;
and
m is 1 or 2.

45 more elements

Facts

Application

13/639,648Filed 6 Apr 2011

Priority

CA PCT/CA2010/0005186 Apr 2010

Published

18 Apr 2013

Term ends

Not estimatedThe source records don’t support an estimate.

Classification15 codes

C07D 403/10
Containing two hetero rings: linked by a carbon chain containing aromatic rings
A61K 31/5377
1,4-Oxazines, e.g. morpholine: not condensed and containing further heterocyclic rings, e.g. timolol
A61K 45/06
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system