Pyrazolo[3,4- d ]pyrimidine compounds

• US 8,637,529 B2
• Filed: 06/10/2011
• Issued: 01/28/2014
• Est. Priority Date: 06/11/2010
• Status: Active Grant

• Current Assignee: Abbvie Incorporated
• Original Assignee: Abbyie Incorporated
• Inventors: Woller, Kevin R., Curtin, Michael L., Frank, Kristine E., Josephsohn, Nathan S., Li, Biqin C., Wishart, Neil
• Primary Examiner(s): MURRAY, JEFFREY H
• Application Number:
  US13/157,777
• Publication Number:
  US 20120015963A1
• Time in Patent Office: 963 Days
• Field of Search: None
• US Class Current: 514/262.1
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

The present disclosure is directed to novel compounds of Formula (I)

pharmaceutically acceptable salts, pro-drugs, biologically active metabolites, stereoisomers and isomers thereof wherein the variables are as defined herein. The compounds of Formula (I) are useful as kinase inhibitors and as such would be useful in treating certain conditions and diseases, especially inflammatory conditions and diseases and proliferative disorders and conditions, for example, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, Crohn'"'"'s disease, psoriasis and asthma.

Claims

1. A compound of Formula (I)

2. The compound according to claim 1 wherein R⁴ is H.

3. The compound of claim 2 wherein

R¹ is —

W—

X—

Y wherein W is directly attached to the nitrogen of the pyrazolyl ring;

W is optionally substituted (C₁-C₆)alkylene, phenylene, (C₃-C₆)cycloalkylene, optionally substituted heterocyclylene or optionally substituted heteroarylene;

X is a bond, phenylene, optionally substituted (C₃-C₆)cycloalkylene, optionally substituted piperidinyl or optionally substituted pyridinyl;

Y is —

C(O)R^a, —

S(O)₂N(R^a)₂, —

N(R^a)S(O)₂, —

OR^a, N(R^a)S(O)₂R^a, —

C(O)N(R^a)₂, —

N(R^a)C(O)R^a, N(R^a)₂, S(O)₂R^a, CH₃ or CH₂NH₂, provided that when W and X are both bonds that Y is not oxo, —

N(R^a)S(O)₂, —

N(R^a)S(O)₂R^a, N(R^a)C(O)R^a or N(R^a)₂;

or

Y is A-D wherein A is connected to X wherein

A is a bond, C(O), C(O)R^b, R^bC(O), S(O)₂, optionally substituted (C₁-C₆)alkylene, N(R^a)S(O)₂R^b, N(R^a)C(O), C(O)N(R^a), N(R^a)S(O)₂, S(O)₂N(R^a), O, OR^b, R^bO, N(R^a)R^b, R^bN(R^a), R^bN(R^a)C(O), C(O)N(R^a)R^b, R^bN(R^a)S(O)₂, N(R^a)C(O)R^b, R^bC(O)N(R^a), R^bN(R^a), R^bN(R^a)S(O)₂, S(O)₂R^b, R^bS(O)₂, or N(R^a); and

D is —

CN, —

C(O)N(R^a)₂ or N(R^a)₂;

or

D is —

O-optionally substituted (C₁-C₆)alkyl, optionally substituted aryl, optionally substituted (C₃-C₁₀)cycloalkyl, optionally substituted heterocyclyl or optionally substituted heteroaryl;

wherein D may be optionally substituted by one or more CN, halogen, OH, —

C(O)—

(C₁-C₆)alkyl, —

C(O)N(R^a)₂, —

O—

(C₁-C₆)alkyl, —

N(R^a)S(O)₂R^a, —

S—

(C₁-C₆)alkyl, —

S(O)—

(C₁-C₆)alkyl, —

S(O)₂—

(C₁-C₆)alkyl or —

S(O)₂N(R^a)₂.

4. The compound of claim 3 wherein

Y is A-D wherein A is connected to X wherein

A is a bond, C(O), C(O)R^b, R^bC(O), S(O)₂, optionally substituted (C₁-C₆)alkylene, N(R^a)S(O)₂R^b, N(R^a)C(O), C(O)N(R^a), N(R^a)S(O)₂, S(O)₂N(R^a), O, OR^b, R^bO, N(R^a)R^b, R^bN(R^a), R^bN(R^a)C(O), C(O)N(R^a)R^b, R^bN(R^a)S(O)₂, N(R^a)C(O)R^b, R^bC(O)N(R^a), R^bN(R^a), R^bN(R^a)S(O)₂, S(O)₂R^b, R^bS(O)₂, or N(R^a);

and

D is —

CN, —

C(O)N(R^a)₂ or —

N(R^a)₂;

or

D is, —

O-optionally substituted (C₁-C₆)alkyl, optionally substituted aryl, optionally substituted (C₃-C₁₀)cycloalkyl, optionally substituted heterocyclyl or optionally substituted heteroaryl;

wherein D may be optionally substituted by one or more —

CN, halogen, —

OH, —

C(O)—

(C₁-C₆)alkyl, —

C(O)N(R^a)₂, —

O—

(C₁-C₆)alkyl, —

N(R^a)S(O)₂R^a, —

S—

(C₁-C₆)alkyl, —

S(O)—

(C₁-C₆)alkyl, —

S(O)₂—

(C₁-C₆)alkyl or —

S(O)₂N(R^a)₂.

5. The compound of claim 3 wherein

Y is —

S(O)₂N(R^a)₂, —

N(R^a)S(O)₂, —

OR^a, —

C(O)N(R^a)₂, —

N(R^a)C(O)R^a, —

N(R^a)₂, —

CH₃ or —

CH₂NH₂;

or

Y is A-D wherein

A is a bond, C(O), S(O)₂, optionally substituted (C₁-C₆)alkylene, N(R^a)S(O)₂R^b, N(R^a)C(O), C(O)N(R^a), N(R^a)S(O)₂, S(O)₂N(R^a), O, OR^b, R^bN(R^a), R^bN(R^a)C(O), C(O)N(R^a)R^b, R^bN(R^a)S(O)₂, N(R^a)C(O)R^b, or R^bC(O)N(R^a), and

D is CN, —

C(O)N(R^a)₂, N(R^a)₂, or —

O-optionally substituted (C₁-C₆)alkyl;

or

D is optionally substituted aryl, optionally substituted (C₃-C₁₀)cycloalkyl, optionally substituted heterocyclyl or optionally substituted heteroaryl;

wherein D may be optionally substituted by one or more —

CN, halogen, —

OH, —

C(O)—

(C₁-C₆)alkyl, —

C(O)N(R^a)₂, —

O—

(C₁-C₆)alkyl, —

N(R^a)S(O)₂R^a, —

S—

(C₁-C₆)alkyl, —

S(O)—

(C₁-C₆)alkyl, —

S(O)₂—

(C₁-C₆)alkyl or —

S(O)₂N(R^a)₂.

6. The compound of claim 5 wherein

W is optionally substituted (C₁-C₆)alkylene;

X is a bond, phenylene, optionally substituted (C₃-C₆)cycloalkylene, or optionally substituted piperidinyl;

Y is —

S(O)₂N(R^a)₂, —

N(R^a)S(O)₂, —

OR^a, —

C(O)N(R^a)₂, —

N(R^a)C(O)R^a, —

N(R^a)₂, or optionally substituted (C₁-C₆)alkyl;

or

Y is A-D wherein A is connected to X wherein

A is a bond, C(O), N(R^a)C(O), or R^bN(R^a)C(O); and

D is —

CN, —

C(O)N(R^a)₂, —

N(R^a)₂, or —

O-optionally substituted (C₁-C₆)alkyl.

7. The compound of claim 6 wherein

R⁴ is H or optionally substituted (C₁-C₄)alkyl;

R⁵ is -G-J wherein G is connected to the nitrogen atom and wherein

G is a bond, pyrazole or phenylene;

wherein the phenylene is optionally substituted with CH₃; and

J is H, optionally substituted (C₁-C₃)alkyl, —

OH, —

OCH₃, —

C(O)Ra, —

C(O)N(R^a)₂, —

SR^a—

, —

S(O)₂-optionally substituted (C₁-C₃)alkyl, —

S(O)₂—

N(R^a)₂, -optionally substituted phenyl, optionally substituted thiomorpholinyl or optionally substituted piperazinyl;

wherein R^a is independently H or optionally substituted (C₁-C₆)alkyl.

8. The compound of claim 2 wherein

9. The compound of claim 8 wherein R¹¹, R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ are independently H, CN, OH, optionally substituted (C₁-C₆)alkyl, —

O-optionally substituted (C₁-C₆)alkyl or optionally substituted (C₃-C₁₀)cycloalkyl.

10. The compound of claim 8 wherein R¹³ and R¹⁶ together form an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring.

11. The compound of claim 8 wherein R¹¹ and R¹² together form an optionally substituted carbocyclic ring, an optionally substituted heterocyclic ring or an optionally substituted spirocyclic ring.

12. The compound of claim 8 wherein R¹⁶ and R¹⁷ together form an optionally substituted carbocyclic ring or optionally substituted heterocyclic ring.

13. The compound of claim 8 wherein R¹⁵ and R¹⁷ together with the nitrogen to which R¹⁷ is attached form heterocyclic ring fused to Ring 1.

14. The compound of claim 8 wherein R¹⁷ and R¹⁸ are independently H, —

S(O)₂-optionally substituted (C₃-C₁₀)cycloalkyl, —

S(O)₂-optionally substituted aryl, —

S(O)₂-optionally substituted (C₁-C₆)alkyl, —

S(O)₂, —

S(O)₂-optionally substituted heterocyclyl, —

S(O)₂-optionally substituted heteroaryl, —

C(O)-optionally substituted (C₃-C₁₀)cycloalkyl, —

C(O)-optionally substituted aryl, —

C(O)-optionally substituted (C₁-C₆)alkyl, —

C(O)-optionally substituted heterocyclyl- or —

C(O)-optionally substituted heteroaryl;

or

R¹⁷ and R¹⁸ form a heterocyclic ring together with the nitrogen to which they are attached.

15. The compound of claim 8 wherein R⁵ is -G-J wherein G is connected to the nitrogen atom and wherein

G is a bond, optionally substituted (C₃-C₁₀)cycloalkylene, pyrazole or phenylene optionally substituted with CH₃;

and

J is H, optionally substituted (C₁-C₆)alkyl, —

OR^a, —

C(O)R^a, —

SR^a—

, —

S(O)₂—

R^a, —

S(O)₂—

N(R^a)₂, —

S(O)₂—

NH—

C(O)—

R^a, optionally substituted heteroaryl, or optionally substituted morpholinyl, optionally substituted thiomorpholinyl or optionally substituted piperazinyl;

wherein R^a is independently H, deuterium, optionally substituted (C₁-C₆)alkyl, optionally substituted (C₃-C₁₀)cycloalkyl, or optionally substituted heteroaryl; and

R^b is independently optionally substituted (C₁-C₆)alkyl, optionally substituted (C₃-C₁₀)cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl.

16. The compound of claim 1 wherein the compound is

tert-butyl-cis-4-((6-(4-methyl-3-sulfamoylphenylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate;

tert-butyl((1R,4R)-4-((6-(4-(4-methylpiperazin-1-yl)phenylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexyl)methylcarbamate;

3-(1-(3-(N,N-dimethylsulfamoyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-N,N-dimethylbenzenesulfonamide;

tert-butyl ((1R,4R)-4-((6-(3-sulfamoylphenylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexyl)methylcarbamate;

tert-butyl(1R,4R)-4-((6-(4-(4-methylpiperazin-1-yl)phenylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamat;

tert-butyl 4-(6-(4-methyl-3-sulfamoylphenylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate;

tert-butyl 4-(6-(4-(4-methylpiperazin-1-yl)phenylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate;

tert-butyl 4-(6-(4-methyl-3-sulfamoylphenylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexylcarbamate;

5-(1-((cis-4-aminocyclohexyl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-2-methylbenzenesulfonamide;

5-(1-(((1R,4R)-4-(aminomethyl)cyclohexyl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-2-methylbenzenesulfonamide;

1-(((1R,4R)-4-(aminomethyl)cyclohexyl)methyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(((1R,4R)-4-aminocyclohexyl)methyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

N-(4-(4-methylpiperazin-1-yl)phenyl)-1-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

5-(1-(4-aminocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-2-methylbenzenesulfonamide;

1-(((1S,4S)-4-aminocyclohexyl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(((1R,4R)-4-aminocyclohexyl)methyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

2-(4-(1-(((1R,4R)-4-aminocyclohexyl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-1H-pyrazol-1-yl)propan-1-ol;

N-(cis-4-((6-(4-Methyl-3-sulfamoylphenylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexyl)acetamide;

N-(5-1-(((1S,4S)-4-(3,3-dimethylbutanamido)cyclohexyl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-2-methylphenylsulfonyl)-3,3-dimethylbutanamide;

3,3-dimethyl-N-((1S,4S)-4-((6-(4-methyl-3-sulfamoylphenylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexyl)butanamide;

3-((1-(cyclohexylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)methyl)benzenesulfonamide;

3-((1-(cyclohexylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)methyl)benzenesulfonamide;

N-(1-cyclohexylmethyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3-(1-cyclohexylmethyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylmethyl)-benzenesulfonamide;

1-(cyclohexylmethyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

tert-butyl((1R,4R)-4-((6-(4-cyclohexylphenylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexyl)methylcarbamate;

1-(((1R,4R)-4-(aminomethyl)cyclohexyl)methyl)-N-(4-cyclohexylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

4-(1-(((1R,4R)-4-aminocyclohexyl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-N,N-dimethylbenzenesulfonamide;

4-(1-(((1R,4R)-4-aminocyclohexyl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-N-cyclopropylbenzenesulfonamide;

3-(1-(((1R,4R)-4-aminocyclohexyl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)benzamide;

[1-(4-amino-cyclohexylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-[4-(1,1-dioxo-thiomorpholin-4-yl)-phenyl]-amine;

1-(((1R,4R)-4-aminocyclohexyl)methyl)-N-(4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

2-(4-(1-(((1R,4R)-4-aminocyclohexyl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)phenylsulfonyl)ethanol;

4-(1-(((1R,4R)-4-aminocyclohexyl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-N-(pyridin-3-ylmethyl)benzenesulfonamide;

4-(1-(((1R,4R)-4-aminocyclohexyl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-N-(4-methoxyphenyl)benzenesulfonamide;

4-(1-(pyridin-3-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)benzene sulfonamide;

N-(4-(4-methylpiperazin-1-yl)phenyl)-1-(pyridin-3-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

[4-(1,1-dioxo-thiomorpholin-4-yl)-phenyl]-(1-pyridin-3-ylmethyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-amine;

N1-(3-chlorophenyl)-N4-(1-(pyridin-3-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)benzene-1,4-diamine;

N1-(2-methoxyphenyl)-N4-(1-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)benzene-1,4-diamine;

2-(6-(4-(2-methoxyphenylamino)phenylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-N-methylbenzene sulfonamide;

N1-(1-(cyclohexylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N4-phenylbenzene-1,4-diamine;

1-(cyclohexylmethyl)-N-(4-(morpholinosulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

or

N1-(1-(cyclohexylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N4,N4-dimethylbenzene-1,4-diamine.

17. The compound

2-methyl-5-(4-(1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)phenylamino)benzenesulfonamide;

2-methyl-5-(1-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)benzenesulfonamide;

N-(2-methoxyphenyl)-1-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine.