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US 2006/0079511 A1Published application
7,8-Disubstituted pyrazolobenzodiazepines
AssigneeHoffmann-La Roche Inc.
InventorsJin-Jun Liu, Kin-Chun Luk, Giacomo Pizzolato, Yi Ren, Kshitij Thakkar, Peter Wovkulich, Zhuming Zhang
Life of this patent
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Abstract
The present invention provides compounds of formula I wherein R1, R2, R3, R4, and R5 are described herein. The invention also provides syntheses for preparation of such compounds and pharmaceutical compositions containing them. The invention further provides methods for inhibiting kinases, in particular CDK2, for inhibiting angiogenesis, and for treating cancers, in particular breast, colon, prostate, and lung cancer.
Claims63
A compound of formula IV
- wherein
- R1 is alkyl, alkoxy, halogen, COOH, COOAlkyl, CN, C(O)N(R6)2, or (OCH2CH2)nOCH3;
- R2 is alkyl, halogen, alkyl substituted by halogen, OH, alkoxy, alkoxy substituted by halogen, phenyl, N(R6)2, (OCH2CH2)nOCH3, O(CH2)mNR7R8, or
- is a 6-membered heterocycle optionally substituted by alkyl or C(O)OR6;
- or R1 and R2 together form a 5-membered heterocyclic ring;
- R3 is hydrogen or alkyl;
- R4 is hydrogen, halogen, CN, NO2, alkyl, or alkoxy;
- each R6 is independently hydrogen or alkyl;
- R7 and R8 are each independently hydrogen, alkyl, or alkoxyalkyl, or R7 and R8 taken together with the nitrogen atom to which they are attached form a 6-membered heterocycle which is optionally substituted by alkyl;
- each n is independently 1, 2, or 3;
- and
- m is 2, 3, or 4;
- or a pharmaceutically acceptable salt thereof.
10 more elements
A method of inhibiting angiogenesis in a patient having a tumor comprising administering a therapeutically effective amount of a compound of formula IV
- wherein
- R1 is alkyl, alkoxy, halogen, COOH, COOAlkyl, CN, C(O)N(R6)2, or (OCH2CH2)nOCH3;
- R2 is alkyl, halogen, alkyl substituted by halogen, OH, alkoxy, alkoxy substituted by halogen, phenyl, N(R6)2, (OCH2CH2)nOCH3, O(CH2)mNR7R8, or
- is a 6-membered heterocycle optionally substituted by alkyl or C(O)OR6;
- or R1 and R2 together form a 5-membered heterocyclic ring;
- R3 is hydrogen or alkyl;
- R4 is hydrogen, halogen, CN, NO2, alkyl, or alkoxy;
- each R6 is independently hydrogen or alkyl;
- R7 and R8 are each independently hydrogen, alkyl, or alkoxyalkyl, or R7 and R8 taken together with the nitrogen atom to which they are attached form a 6-membered heterocycle which is optionally substituted by alkyl;
- each n is independently 1, 2, or 3;
- m is 2, 3, or 4;
- or a pharmaceutically acceptable salt thereof.
9 more elements
A method of treating breast cancer in a patient comprising administering a therapeutically effective amount of a compound of formula IV
- wherein
- R1 is alkyl alkoxy, halogen, COOH, COOAlkyl, CN, C(O)N(R6)2, or (OCH2CH2)nOCH3;
- R2 is alkyl, halogen, alkyl substituted by halogen, OH, alkoxy, alkoxy substituted by halogen, phenyl, N(R6)2, (OCH2CH2)nOCH3, O(CH2)mNR7R8, or
- is a 6-membered heterocycle optionally substituted by alkyl or C(O)OR6;
- or R1 and R2 together form a 5-membered heterocyclic ring;
- R3 is hydrogen or alkyl;
- R4 is hydrogen, halogen, CN, NO2, alkyl, or alkoxy;
- each R6 is independently hydrogen or alkyl;
- R7 and R8 are each independently hydrogen, alkyl, or alkoxyalkyl, or R7 and R8 taken together with the nitrogen atom to which they are attached form a 6-membered heterocycle which is optionally substituted by alkyl;
- each n is independently 1, 2, or 3;
- and
- m is 2, 3, or 4;
- or a pharmaceutically acceptable salt thereof.
10 more elements
A method of treating prostate cancer in a patient comprising administering a therapeutically effective amount of a compound of formula IV
- wherein
- R1 is alkyl, alkoxy, halogen, COOH, COOAlkyl, CN, C(O)N(R6)2, or (OCH2CH2)nOCH3;
- R2 is alkyl, halogen, alkyl substituted by halogen, OH, alkoxy, alkoxy substituted by halogen, phenyl, N(R6)2, (OCH2CH2)nOCH3, O(CH2)mNR7R8, or
- is a 6-membered heterocycle optionally substituted by alkyl or C(O)OR6;
- or R1 and R2 together form a 5-membered heterocyclic ring;
- R3 is hydrogen or alkyl;
- R4 is hydrogen, halogen, CN, NO2, alkyl, or alkoxy;
- each R6 is independently hydrogen or alkyl;
- R7 and R8 are each independently hydrogen, alkyl, or alkoxyalkyl, or R7 and R8 taken together with the nitrogen atom to which they are attached form a 6-membered heterocycle which is optionally substituted by alkyl;
- each n is independently 1, 2, or 3;
- and
- m is 2, 3, or 4;
- or a pharmaceutically acceptable salt thereof.
10 more elements
A method of treating colon cancer in a patient comprising administering a therapeutically effective amount of a compound of formula IV
- wherein
- R1 is alkyl, alkoxy, halogen, COOH, COOAlkyl, CN, C(O)N(R6)2, or (OCH2CH2)nOCH3;
- R2 is alkyl, halogen, alkyl substituted by halogen, OH, alkoxy, alkoxy substituted by halogen, phenyl, N(R6)2, (OCH2CH2)nOCH3, O(CH2)mNR7R8, or
- is a 6-membered heterocycle optionally substituted by alkyl or C(O)OR6;
- or R1 and R2 together form a 5-membered heterocyclic ring;
- R3 is hydrogen or alkyl;
- R4 is hydrogen, halogen, CN, NO2, alkyl, or alkoxy;
- each R6 is independently hydrogen or alkyl;
- R7 and R8 are each independently hydrogen, alkyl, or alkoxyalkyl, or R7 and R8 taken together with the nitrogen atom to which they are attached form a 6-membered heterocycle which is optionally substituted by alkyl;
- each n is independently 1, 2, or 3;
- and
- m is 2, 3,or 4;
- or a pharmaceutically acceptable salt thereof.
10 more elements
A method of treating lung cancer in a patient comprising administering a therapeutically effective amount of a compound of formula IV
- wherein
- R1 is alkyl, alkoxy, halogen, COOH, COOAlkyl, CN, C(O)N(R6)2, or (OCH2CH2)nOCH3;
- R2 is alkyl, halogen, alkyl substituted by halogen, OH, alkoxy, alkoxy substituted by halogen, phenyl, N(R6)2, (OCH2CH2)nOCH3, O(CH2)mNR7R8, or
- is a 6-membered heterocycle optionally substituted by alkyl or C(O)OR6;
- or R1 and R2 together form a 5-membered heterocyclic ring;
- R3 is hydrogen or alkyl;
- R4 is hydrogen, halogen, CN, NO2, alkyl, or alkoxy;
- each R6 is independently hydrogen or alkyl;
- R7 and R8 are each independently hydrogen, alkyl, or alkoxyalkyl, or R7 and R8 taken together with the nitrogen atom to which they are attached form a 6-membered heterocycle which is optionally substituted by alkyl;
- each n is independently 1, 2, or 3;
- and
- m is 2, 3, or 4;
- or a pharmaceutically acceptable salt thereof.
10 more elements
A process for preparing a compound of formula IV
- wherein
- R1 is alkyl, alkoxy, halogen, COOH, COOAlkyl, CN, C(O)N(R6)2, or (OCH2CH2)nOCH3;
- R2 is alkyl, halogen, alkyl substituted by halogen, OH, alkoxy, alkoxy substituted by halogen, phenyl, N(R6)2, (OCH2CH2)nOCH3, O(CH2)mNR7R8, or
- is a 6-membered heterocycle optionally substituted by alkyl or C(O)OR6;
- or R1 and R2 together form a 5-membered heterocyclic ring;
- R3 is hydrogen or alkyl;
- R4 is hydrogen, halogen, CN, NO2, alkyl, or alkoxy;
- each R6 is independently hydrogen or alkyl;
- R7 and R8 are each independently hydrogen, alkyl, or alkoxyalkyl, or R7 and R8 taken together with the nitrogen atom to which they are attached form a 6-membered heterocycle which is optionally substituted by alkyl;
- each n is independently 1, 2, or 3;
- and
- m is 2, 3 , or 4;
- said process comprising
- (a) converting a benzodiazepine lactam of formula I
- to a thiolactam of formula II
- (b) reacting the thiolactam of formula II with the dimethyl acetal of N,N-dimethyl acetamide to form a compound of formula III
- (c) reacting the compound of formula III with hydrazine to form a compound of formula IV.
14 more elements
A process for preparing a compound of formula IV
- wherein
- R1 is alkyl, alkoxy, halogen, COOH, COOAlkyl, CN, C(O)N(R6)2, or (OCH2CH2)nOCH3;
- R2 is alkyl, halogen, alkyl substituted by halogen, OH, alkoxy, alkoxy substituted by halogen, phenyl, N(R6)2, (OCH2CH2)nOCH3, O(CH2)mNR7R8, or
- is a 6-membered heterocycle optionally substituted by alkyl or C(O)OR6;
- or R1 and R2 together form a 5-membered heterocyclic ring;
- R3 is hydrogen or alkyl;
- R4 is hydrogen, halogen, CN, NO2, alkyl, or alkoxy;
- each R6 is independently hydrogen or alkyl;
- R7 and R8 are each independently hydrogen, alkyl, or alkoxyalkyl, or R7 and R8 taken together with the nitrogen atom to which they are attached form a 6-membered heterocycle which is optionally substituted by alkyl;
- each n is independently 1, 2, or 3;
- and
- m is 2, 3, or 4;
- said process comprising
- (a) converting of a benzodiazepine lactam of formula I
- to the corresponding O-methyl ether of formula V
- (b) reacting the ether of formula V with the dimethyl acetal of N,N-dimethyl acetamide to form a compound of formula VI
- (c) reacting a compound of formula VI with hydrazine to form a compound of formula IV.
14 more elements
A process of preparing a compound of formula IV
- wherein
- R1 is alkyl, alkoxy, halogen, COOH, COOAlkyl, CN, C(O)N(R6)2, or (OCH2CH2)nOCH3;
- R2 is alkyl halogen, alkyl substituted by halogen, OH, alkoxy, alkoxy substituted by halogen, phenyl, N(R6)2, (OCH2CH2)nOCH3, O(CH2)mNR7R8, or
- is a 6-membered heterocycle optionally substituted by alkyl or C(O)OR6;
- or R1 and R2 together form a 5-membered heterocyclic ring;
- R3 is hydrogen or alkyl;
- R4 is hydrogen, halogen, CN, NO2, alkyl, or alkoxy;
- each R6 is independently hydrogen or alkyl;
- R7 and R8 are each independently hydrogen, alkyl, or alkoxyalkyl, or R7 and R8 taken together with the nitrogen atom to which they are attached form a 6-membered heterocycle which is optionally substituted by alkyl;
- each n is independently 1, 2, or 3;
- and
- m is 2, 3, or 4;
- said process comprising
- (a) reacting a compound of formula X
- with an amino-chloro-pyrazole derivative of formula XIII
- to form a compound of formula XIV
- (b) reacting the compound of formula XIV is reacted in the presence of diisobutyl aluminum hydride and a nickel catalyst to produce a compound of formula IV.
14 more elements
A compound of formula XIV
- wherein
- R1 is alkyl, alkoxy, halogen, COOH, COOAlkyl, CN, C(O)N(R6)2, or (OCH2CH2)nOCH3;
- R2 is alkyl, halogen, alkyl substituted by halogen, OH, alkoxy, alkoxy substituted by halogen, phenyl, N(R6)2, (OCH2CH2)nOCH3, O(CH2)mNR7R8, or
- is a 6-membered heterocycle optionally substituted by alkyl or C(O)OR6;
- or R1 and R2 together form a 5-membered heterocyclic ring;
- R4 is hydrogen, halogen, CN, NO2, alkyl, or alkoxy;
- each R6 is independently hydrogen or alkyl;
- R7 and R8 are each independently hydrogen, alkyl, or alkoxyalkyl, or R7 and R8 taken together with the nitrogen atom to which they are attached form a 6-membered heterocycle which is optionally substituted by alkyl;
- each n is independently 1, 2, or 3;
- and
- m is 2, 3, or 4.
8 more elements
Dependencies are inferred from the claim text.