Process for preparing pyrazole functionalized benzodiazepinones

A method of forming a compound of Formula I comprising the step of

• reacting a compound of Formula V
• with acid under conditions sufficient to cause hydrogenolysis to form the compound of Formula I;
• wherein:
• Y is benzyl or allyl;
• R″ is alkyl, alkoxy, halogen, COOH, COOAlkyl, CN, C(O)N(R6)2, or (OCH2CH2)nOCH3;
• R′ 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 with alkyl or C(O)OR6;
• each R6 is independently hydrogen or alkyl;
• each n is independently 1, 2, or 3;
• m is 2, 3, or 4;
• R7 and R8 are each independently hydrogen, alkyl, or alkoxyalkyl;
• or R7 and R8 taken together with the nitrogen to which they are attached form a 6-membered heterocycle which is optionally substituted by alkyl;
• or R′ and R″ together form a 5-membered heterocyclic ring;
• and
• R′″ is hydrogen, halogen, CN, NO2, alkyl, or alkoxy.

A compound of Formula VI

• wherein:
• R′ 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 with alkyl or C(O)OR6;
• each R6 is independently hydrogen or alkyl;
• each n is independently 1, 2, or 3;
• m is 2, 3, or 4;
• R7 and R8 are each independently hydrogen, alkyl, or alkoxyalkyl;
• or R7 and R8 taken together with the nitrogen to which they are attached form a 6-membered heterocycle which is optionally substituted by alkyl;
• Q is (Q′)2 N(Q″)r-;
• Q′ is lower alkyl, lower alkenyl, lower alkoxy, aryl, aryl alkyl, heteroaryl, heterocyclyl, or cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, OH, and alkoxy;
• Q″ is a lower alkylenyl linking group;
• and
• r is 1, 2, or 3.

A method of making a compound of Formula VI,

• comprising the step of reacting a compound of Formula I
• with Q-C(O)O-Q′″ under mild reaction conditions in the presence of a base;
• wherein:
• R″ is alkyl, alkoxy, halogen, COOH, COAlkyl, CN, C(O)N(R6)2, or (OCH2CH2)nOCH3;
• R′ 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 with alkyl or C(O)OR6;
• each R6 is independently hydrogen or alkyl;
• each n is independently 1, 2, or 3;
• m is 2, 3, or 4;
• R7 and R8 are each independently hydrogen, alkyl, or alkoxyalkyl;
• or R7 and R8 taken together with the nitrogen to which they are attached form a 6-membered heterocycle which is optionally substituted by alkyl;
• or R′ and R″ together form a 5-membered heterocyclic ring;
• R′″ is hydrogen, halogen, CN, NO2, alkyl, or alkoxy;
• Q is (Q′)2 N(Q″)r-;
• each Q′ is independently H, lower alkyl, lower alkenyl, lower alkoxy, aryl, aryl alkyl, heteroaryl, heterocyclyl, or cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, hydroxyl, and alkoxy;
• Q″ is a lower alkylenyl linking group;
• r is 1, 2, or 3;
• and
• Q′″ is lower alkyl.

A method of making a compound of Formula VII,

• comprising the step of deallylation-cyclization of a compound of Formula VI
• wherein:
• Q is (Q′)2 N(Q″)r-;
• Q″ is —CH2—;
• Q′ is allyl;
• r is 1;
• R″ is alkyl, alkoxy, halogen, COOH, COOAlkyl, CN, C(O)N(R6)2, or (OCH2CH2)nOCH3;
• R′ 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 with alkyl or C(O)OR6;
• each R6 is independently hydrogen or alkyl;
• each n is independently 1, 2, or 3;
• m is 2, 3, or 4;
• R7 and R8 are each independently hydrogen, alkyl, or alkoxyalkyl;
• or R7 and R8 taken together with the nitrogen to which they are attached form a 6-membered heterocycle which is optionally substituted by alkyl;
• or R′ and R″ together form a 5-membered heterocyclic ring;
• and
• R′″ is hydrogen, halogen, CN, NO2, alkyl, or alkoxy.

A method of making a pyrazolo[3,4-b][1,4]benzodiazepine comprising the step of converting a compound of Formula VII

• to an imidate of Formula VIIa;
• wherein
• R″ is alkyl, alkoxy, halogen, COOH, COOAlkyl, CN, C(O)N(R6)2, or (OCH2CH2)nOCH3;
• R′ 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 with alkyl or C(O)OR6;
• each R6 is independently hydrogen or alkyl;
• each n is independently 1, 2, or 3;
• m is 2, 3, or 4;
• R7 and R8 are each independently hydrogen, alkyl, or alkoxyalkyl;
• or R7 and R8 taken together with the nitrogen to which they are attached form a 6-membered heterocycle which is optionally substituted by alkyl;
• or R′ and R″ together form a 5-membered heterocyclic ring;
• and
• R′″ is hydrogen, halogen, CN, NO2, alkyl, or alkoxy.

A method of making a semicarbazone of Formula VIIc comprising the step of reacting an enamine of Formula VIIb

• with semicarbazide hydrochloride to form the semicarbazone of Formula VIIc;
• wherein
• R″ is alkyl, alkoxy, halogen, COOH, COOAlkyl, CN, C(O)N(R6)2, or (OCH2CH2)nOCH3;
• R′ 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 with alkyl or C(O)OR6;
• each R6 is independently hydrogen or alkyl;
• each n is independently 1, 2, or 3;
• m is 2, 3, or 4;
• R7 and R8 are each independently hydrogen, alkyl, or alkoxyalkyl;
• or R7 and R8 taken together with the nitrogen to which they are attached form a 6-membered heterocycle which is optionally substituted by alkyl;
• or R′ and R″ together form a 5-membered heterocyclic ring;
• and
• R′″ is hydrogen, halogen, CN, NO2, alkyl, or alkoxy.

A method of making a carbamate of Formula VIId

• comprising the step of converting a semicarbazone of Formula VIIc
• to the carbamate of Formula VIId by acid-catalyzed cyclization;
• wherein
• R″ is alkyl, alkoxy, halogen, COOH, COOAlkyl, CN, C(O)N(R6)2, or (OCH2CH2)nOCH3;
• R′ 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 with alkyl or C(O)OR6;
• each R6 is independently hydrogen or alkyl;
• each n is independently 1, 2, or 3;
• m is 2, 3, or 4;
• R7 and R8 are each independently hydrogen, alkyl, or alkoxyalkyl;
• or R7 and R8 taken together with the nitrogen to which they are attached form a 6-membered heterocycle which is optionally substituted by alkyl;
• or R′ and R″ together form a 5-membered heterocyclic ring;
• and
• R′″ is hydrogen, halogen, CN, NO2, alkyl, or alkoxy.

A compound of the formula VIIe

• wherein:
• R″ is alkyl, alkoxy, halogen, COOH, COAlkyl, CN, C(O)N(R6)2, or (OCH2CH2)nOCH3;
• R′ 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 with alkyl or C(O)OR6;
• each R6 is independently hydrogen or alkyl;
• each n is independently 1, 2, or 3;
• m is 2, 3, or 4;
• R7 and R8 are each independently hydrogen, alkyl, or alkoxyalkyl;
• or R7 and R8 taken together with the nitrogen to which they are attached form a 6-membered heterocycle which is optionally substituted by alkyl;
• or R′ and R″ together form a 5-membered heterocyclic ring;
• and
• R′″ is hydrogen, halogen, CN, NO2, alkyl, or alkoxy.

A compound of the formula VIIc

• wherein:
• R″ is alkyl, alkoxy, halogen, COOH, COOAlkyl, CN, C(O)N(R6)2, or (OCH2CH2)nOCH3;
• R′ 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 with alkyl or C(O)OR6;
• each R6 is independently hydrogen or alkyl;
• each n is independently 1, 2, or 3;
• m is 2, 3, or 4;
• R7 and R8 are each independently hydrogen, alkyl, or alkoxyalkyl;
• or R7 and R8 taken together with the nitrogen to which they are attached form a 6-membered heterocycle which is optionally substituted by alkyl;
• or R′ and R″ together form a 5-membered heterocyclic ring;
• and
• R′″ is hydrogen, halogen, CN, NO2, alkyl, or alkoxy.

A compound of the formula VIId

• wherein:
• R″ is alkyl, alkoxy, halogen, COOH, COAlkyl, CN, C(O)N(R6)2, or (OCH2CH2)nOCH3;
• R′ 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 with alkyl or C(O)OR6;
• each R6 is independently hydrogen or alkyl;
• each n is independently 1, 2, or 3;
• m is 2, 3, or 4;
• R7 and R8 are each independently hydrogen, alkyl, or alkoxyalkyl;
• or R7 and R8 taken together with the nitrogen to which they are attached form a 6-membered heterocycle which is optionally substituted by alkyl;
• or R′ and R″ together form a 5-membered heterocyclic ring;
• and
• R′″ is hydrogen, halogen, CN, NO2, alkyl, or alkoxy.

A method of making a compound of Formula VIIe,

• comprising deriving a compound of Formula VIIe from an enamine of Formula VIIb
• wherein:
• R″ is alkyl, alkoxy, halogen, COOH, COOAlkyl, CN, C(O)N(R6)2, or (OCH2CH2)nOCH3;
• R′ 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 with alkyl or C(O)OR6;
• each R6 is independently hydrogen or alkyl;
• each n is independently 1, 2, or 3;
• m is 2, 3, or 4;
• R7 and R8 are each independently hydrogen, alkyl, or alkoxyalkyl;
• or R7 and R8 taken together with the nitrogen to which they are attached form a 6-membered heterocycle which is optionally substituted by alkyl;
• or R′ and R″ together form a 5-membered heterocyclic ring;
• and
• R′″ is hydrogen, halogen, CN, NO2, alkyl, or alkoxy.

A method of making a carbamate of Formula VIId,

• comprising converting a semicarbazone of Formula VIIc
• to the carbamate of Formula VIId by acid-catalyzed cyclization
• wherein:
• R″ is alkyl, alkoxy, halogen, COOH, COOAlkyl, CN, C(O)N(R6)2, or (OCH2CH2)nOCH3;
• R′ 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 with alkyl or C(O)OR6;
• each R6 is independently hydrogen or alkyl;
• each n is independently 1, 2, or 3;
• m is 2, 3, or 4;
• R7 and R8 are each independently hydrogen, alkyl, or alkoxyalkyl;
• or R7 and R8 taken together with the nitrogen to which they are attached form a 6-membered heterocycle which is optionally substituted by alkyl;
• or R′ and R″ together form a 5-membered heterocyclic ring;
• and
• R′″ is hydrogen, halogen, CN, NO2, alkyl, or alkoxy.

A method of making a pyrazolo[3,4-b][1,4]benzodiazepine of Formula VIII,

• comprising the step of converting a carbamate of formula VIId
• to the pyrazolo[3,4-b][1,4]benzodiazepine of Formula VIII by acyl transfer to an amine wherein:
• R″ is alkyl, alkoxy, halogen, COOH, COOAlkyl, CN, C(O)N(R6)2, or (OCH2CH2)nOCH3;
• R′ 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 with alkyl or C(O)OR6;
• each R6 is independently hydrogen or alkyl;
• each n is independently 1, 2, or 3;
• m is 2, 3, or 4;
• R7 and R8 are each independently hydrogen, alkyl, or alkoxyalkyl;
• or R7 and R8 taken together with the nitrogen to which they are attached form a 6-membered heterocycle which is optionally substituted by alkyl;
• or R′ and R″ together form a 5-membered heterocyclic ring;
• and
• R′″ is hydrogen, halogen, CN, NO2, alkyl, or alkoxy.