INTERMEDIATES USEFUL IN THE SYNTHESIS OF ALKYLQUINOLINE AND ALKYLQUINAZOLINE KINASE MODULATORS, AND RELATED METHODS OF SYNTHESIS

• US 20070021436A1
• Filed: 06/06/2006
• Published: 01/25/2007
• Est. Priority Date: 06/10/2005
• Status: Active Grant

• Current Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: Xu, Guozhang, Gaul, Michael, Baindur, Nand, Kreutter, Kevin
• Granted Patent: US 7,825,244 B2
• Time in Patent Office: Days
• US Class Current: 514/252.170
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/14 containing three or more hetero rings

Abstract

The invention is directed to alkylquinoline and alkylquinazoline compounds of Formula C:
wherein R₁, R₂, R₉₉, and X are as defined herein, the use of such compounds in the sysnthesis of protein tyrosine kinase inhibitors, particularly inhibitors of FLT3 and/or c-kit and/or TrkB.

Claims

1. A compound of Formula C:

2. A compound of claim 1, wherein:

R_w and R_x are independently selected from;

hydrogen, alkyl, alkenyl, aralkyl, or heteroaralkyl, or R_w and R_x may optionally be taken together to form a ring selected from the group consisting of;

3. A compound of claim 1, wherein R₉₉ is hydrogen, —

CO₂-tert-butyl, —

CO₂CH₂Ph, —

CO₂CH₂-9H-fluoren-9-yl, —

SO₂Ph, or —

SO₂toluyl).

4. A compound of claim 1, wherein:

R_bb is hydrogen provided that both R₁ and R₂ are not hydrogen;

or R_bb is alkoxy provided that both R₁ and R₂ are not alkoxy;

or R_bb is selected from the group consisting of;

halogen, dialkylamino, phenyl, heteroaryl, piperazinyl-2-one optionally substituted with R₆, imidazolidinyl-2-one optionally substituted with R₆, oxazolidinyl-2-one optionally substituted with R₆, or heterocyclyl optionally substituted with R₆.

5. A compound of claim 4, wherein:

Y is a direct bond, O, or NH;

R_a is alkoxy, heteroaryl optionally substituted with R₅, hydroxyl, alkylamino, dialkylamino, oxazolidinonyl optionally substituted with R₅, pyrrolidinonyl optionally substituted with R₅, piperidinonyl optionally substituted with R₅, piperazinyl-2-one optionally substituted with R₅, cyclic heterodionyl optionally substituted with R₅, heterocyclyl optionally substituted with R₅, squaryl optionally substituted with R₅, —

CONR_wR_x, —

N(R_y)CON(R_w)(R_x), —

N(R_w)C(O)OR_x, —

N(R_w)COR_y, —

SR_y, —

SOR_y, —

SO₂R_y, or —

NR_wSO₂R_y; and

R_bb is hydrogen provided that both R₁ and R₂ are not hydrogen;

or R_bb is alkoxy provided that both R₁ and R₂ are not alkoxy;

or R_bb is selected from the group consisting of;

halogen, piperazinyl-2-one optionally substituted with R₆, imidazolidinyl-2-one optionally substituted with R₆, oxazolidinyl-2-one optionally substituted with R₆, or heterocyclyl optionally substituted with R₆.

6. A compound of claim 5, wherein:

R₁ and R₂ are independently selected from;

Y is O or NH;

R_a is alkoxy, heteroaryl optionally substituted with R₅, hydroxyl, alkylamino, dialkylamino, oxazolidinonyl optionally substituted with R₅, pyrrolidinonyl optionally substituted with R₅, piperidinonyl optionally substituted with R₅, piperazinyl-2-one optionally substituted with R₅, heterocyclyl optionally substituted with R₅, squaryl optionally susbstituted with R₅, —

CONR_wR_x, —

N(R_y)CON(R_w)(R_x), —

N(R_w)C(O)OR_x, —

N(R_w)COR_y, —

SO₂R_y, or —

NR_wSO₂R_y;

R₅ is one or two substituents selected from;

—

C(O)alkyl, —

SO₂alkyl, —

C(O)NH(alkyl), —

C(O)N(alkyl)₂, —

C(O)C(_1-4)alkyl-N(alkyl)₂, alkyl, —

C(_1-4)alkyl-OH, —

C(_1-4)alkyl-OCH₃, —

C(O)C(_1-4)alkyl-OH, fluoren-9-yl-methyl-oxy carbonyl, or —

C(O)C(_1-4)alkyl-OCH_3,;

provided that the same R₅ substituent is not present more than once, unless said R₅ substituent is alkyl;

R₆ is one or two substituents independently selected from;

halogen, hydroxyl, heteroaryl, alkoxy, —

C(O)alkyl, —

SO₂alkyl, —

C(O)NH(alkyl), —

C(O)N(alkyl)₂, —

C(O)C(_1-4)alkyl-N(alkyl)₂, alkyl, —

C(_1-4)alkyl-OH, —

C(_1-4)alkyl-OCH₃, —

C(O)C(_1-4)alkyl-OH, or —

C(O)C(_1-4)alkyl-OCH₃;

provided that the same R₆ substituent is not present more than once, unless said R₆ substituent is halogen, hydroxyl, or alkyl;

R_c is heterocyclyl optionally substituted with R₇; and

R₇ is one substituent selected from;

hydroxyl, —

C(O)alkyl, —

SO₂alkyl, alkyl, or —

C(O)N(alkyl)₂.

7. A compound of claim 6, wherein:

R₁ and R₂ are independently selected from;

Y is O;

R_a is alkoxy, heteroaryl optionally substituted with R₅, hydroxyl, alkylamino, dialkylamino, oxazolidinonyl optionally substituted with R₅, pyrrolidinonyl optionally substituted with R₅, piperazinyl-2-one optioanlly substituted with R₅, heterocyclyl optionally substituted with R₅, —

CONR_wR_x, —

N(R_y)CON(R_w)(R_x), —

SO₂R_y, or —

NR_wSO₂R_y;

R₅ is one substituent selected from;

—

C(O)alkyl, —

SO₂alkyl, —

C(O)NH(alkyl), —

C(O)N(alkyl)₂, —

C(O)C_1-4alkyl-N(alkyl)₂, alkyl, —

C(_1-4)alkyl-OH, —

C(_1-4)alkyl-OCH₃, —

C(O)C(_1-4)alkyl-OH, fluoren-9-yl-methyl-oxy carbonyl, or —

C(O)C(_1-4)alkyl-OCH_3,;

R₆ is one substituent selected from;

hydroxyl, alkoxy, —

C(O)alkyl, —

SO₂alkyl, —

C(O)NH(alkyl), —

C(O)N(alkyl)₂, —

C(O)C_1-4alkyl-N(alkyl)₂, alkyl, —

C(_1-4)alkyl-OH, —

C(_1-4)alkyl-OCH₃, —

C(O)C(_1-4)alkyl-OH, or —

C(O)C(_1-4)alkyl-OCH₃; and

R₇ is one substituent selected from —

C(O)alkyl, —

SO₂alkyl, or alkyl.

11. A compound of claim 2, wherein:

R_bb is hydrogen provided that both R₁ and R₂ are not hydrogen;

or R_bb is alkoxy provided that both R₁ and R₂ are not alkoxy;

or R_bb is selected from the group consisting of;

halogen, dialkylamino, phenyl, heteroaryl, piperazinyl-2-one optionally substituted with R₆, imidazolidinyl-2-one optionally substituted with R₆, oxazolidinyl-2-one optionally substituted with R₆, or heterocyclyl optionally substituted with R₆.

12. A compound of claim 3, wherein:

R_bb is hydrogen provided that both R₁ and R₂ are not hydrogen;

or R_bb is alkoxy provided that both R₁ and R₂ are not alkoxy;

or R_bb is selected from the group consisting of;

halogen, dialkylamino, phenyl, heteroaryl, piperazinyl-2-one optionally substituted with R₆, imidazolidinyl-2-one optionally substituted with R₆, oxazolidinyl-2-one optionally substituted with R₆, or heterocyclyl optionally substituted with R₆.

13. A compound of claim 2, wherein R₉₉ is hydrogen, —

CO₂-tert-butyl, —

CO₂CH₂Ph, —

CO₂CH₂-9H-fluoren-9-yl, —

SO₂Ph, or —

SO₂toluyl).

8. A compound selected from the group consisting of:

9. A compound selected from the group consisting of:

10. A compound that is: