HETEROCYCLYL PYRAZOLOPYRIMIDINE ANALOGUES AS JAK INHIBITORS

• US 20120252779A1
• Filed: 10/19/2010
• Published: 10/04/2012
• Est. Priority Date: 10/20/2009
• Status: Active Grant

• Current Assignee: Cellzome Limited (GlaxoSmithKline PLC)
• Original Assignee: Cellzome Limited (GlaxoSmithKline PLC)
• Inventors: Ramsden, Nigel, Harrison, Richard John, Bell, Kathryn, Piton, Nelly, Dagostin, Claudio, Boussard, Cyrille, Oxenford, Sally, Ratcliffe, Andrew
• Granted Patent: US 9,242,987 B2
• Time in Patent Office: Days
• US Class Current: 514/210.21
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 41/00 : Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 5/38 : of the suprarenal hormones
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems

Abstract

The invention relates to compounds of formula (I)

wherein X¹ to X⁵, Y, Z¹ to Z³, and R have the meaning as cited in the description and the claims. Said compounds are useful as JAK inhibitors for the treatment or prophylaxis of immunological, inflammatory, autoimmune, allergic disorders, and immunologically-mediated diseases. The invention also relates to pharmaceutical compositions including said compounds, the preparation of such compounds as well as the use as medicaments.

Claims

1. A compound of formula (I)

2. A compound of claim 1, wherein R is H.

3. A compound of claim 1, wherein ring A is a pyrazole, an oxazole or an isoxazole.

4. A compound of claim 1, wherein 0, 1, or 2 R¹, which are the same or different, are other than H.

5. A compound of claim 1, wherein R¹ is OR² or C_1-4 alkyl, which is optionally substituted with 1 or 2 R³, which are the same or different.

6. A compound of claim 1, wherein R³ is halogen;

CN;

OR⁴;

C(O)N(R⁴R^4a);

or C(O)T¹, wherein T¹ is an unsubstituted 4 to 7 membered heterocycle containing at least one ring nitrogen atom which is attached to C(O).

7. A compound of claim 1, wherein n is 0, 1 or 2.

8. A compound of claim 1, wherein R⁵, R^5a are H.

9. A compound of claim 1, wherein none or one of X¹, X², X³, X⁴, X⁵ is N.

10. A compound of claim 1, wherein R⁶, R^6a, R^6b, R^6c, R^6d are H.

11. A compound of claim 1, wherein at least one of R⁶, R^6a, R^6b, R^6c, R^6d is other than H.

12. A compound of claim 11, wherein R⁶, R^6a, R^6b, R^6c, R^6d are independently selected from the group consisting of H;

halogen;

CN;

C(O)OR⁷;

C(O)N(R⁷R^7a);

S(O)₂NR⁷R^7a); and

N(R⁷)S(O)₂R^7a, provided that 1 or 2 of R⁶, R^6a, R^6b, R^6c, R^6d are other than H.

13. A compound of claim 11, wherein R⁷, R^7a, R^7b are independently selected from the group consisting of H;

and unsubstituted C_1-4 alkyl.

14. A compound of claim 11, wherein in formula (I) Y, X¹, X², X³, X⁴, X⁵ are selected to give formula (Ia)

15. A compound of claim 11, wherein in formula (I) Y, X¹, X², X³, X⁴, X⁵ are selected to give formula (Ib)

16. A compound of claim 11, wherein in formula (I) Y, X¹, X², X³, X⁴, X⁵ are selected to give formula (Ic)

17. A compound of claim 1 selected from the group consisting of

2-((6-(1-Methyl-1H-pyrazol-4-ylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)benzonitrile;

1-(2-Fluorobenzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

2-((6-(1-Methyl-1H-pyrazol-3-ylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)benzonitrile;

2-((6-(1H-Pyrazol-4-ylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)benzonitrile;

2-((6-(Isoxazol-4-ylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)benzonitrile;

2-((6-(1,3-Dimethyl-1H-pyrazol-4-ylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)benzonitrile;

2-((6-(1-Ethyl-3-methyl-1H-pyrazol-4-ylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)benzonitrile;

2-((6-(Isoxazol-3-ylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)benzonitrile;

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

2-((6-(1-(2-Methoxyethyl)-1H-pyrazol-4-ylamino)-1H-pyrazolo[3,4-d]pyrimidi-1-yl)methyl)benzonitrile;

2-((6-(1-Ethyl-1H-pyrazol-4-ylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)benzonitrile;

2-((6-(1-Isopropyl-1H-pyrazol-4-ylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)benzonitrile;

2-(4-(1-(2-Cyanobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-1H-pyrazol-1-yl)-N-methylacetamide;

2-((6-(1-(2-Morpholino-2-oxo ethyl)-1H-pyrazol-4-ylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)benzonitrile;

2-((6-(1-(2-Cyano ethyl)-1H-pyrazol-4-ylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)benzonitrile;

2-((6-(1-Methyl-1H-pyrazol-4-ylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)benzamide;

N-Methyl-N-(4-(6-(1-methyl-1H-pyrazol-4-ylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)methanesulfonamide;

N-(4-(6-(1-Methyl-1H-pyrazol-4-ylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)methanesulfonamide;

2-((6-(1-Isopropyl-1H-pyrazol-3-ylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)benzonitrile;

2-((6-(1-(3-Cyanopropyl)-1H-pyrazol-4-ylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)benzonitrile;

2-((6-(3-Methyl-1-propyl-1H-pyrazol-4-ylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)benzonitrile;

2-((6-(1-(2,2-Difluoroethyl)-3-methyl-1H-pyrazol-4-ylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)benzonitrile;

2-((6-(1-(2-methoxyethyl)-3-methyl-1H-pyrazol-4-ylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)benzonitrile;

2-((6-(1-(2,2-Difluoroethyl)-3-methoxy-1H-pyrazol-4-ylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)benzonitrile;

2-((6-(1-(2-Hydroxyethyl)-1H-pyrazol-4-ylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)benzonitrile;

1-(1-(2-Fluorophenyl)ethyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(2-Chlorobenzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(2-fluorobenzyl)-N-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(2,6-Difluorobenzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(2,5-Difluorobenzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(2,3-Difluorobenzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

2-(4-(1-(2,5-Difluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-1H-pyrazol-1-yl)ethanol;

2-(4-(1-(2,3-Difluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-1H-pyrazol-1-yl)ethanol;

2-(4-(1-(2-Fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-1H-pyrazol-1-yl)ethanol;

4-(6-(1-Methyl-1H-pyrazol-4-ylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzenesulfonamide;

2-((6-(1-(2,2-difluoroethyl)-3-methoxy-1H-pyrazol-4-ylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)benzamide;

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

2-((6-(3-methoxy-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-ylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)benzonitrile;

2-((6-(1-(2,2-Difluoroethyl)-1H-pyrazol-4-ylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)benzonitrile;

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

2-((6-(1-Methyl-1H-pyrazol-4-ylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)benzoic acid;

2-((6-(1-(2,2-Difluoroethyl)-1H-pyrazol-4-ylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)benzamide;

2-((6-(1-(2,2-Difluoroethyl)-3-methyl-1H-pyrazol-4-ylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)benzamide;

2-((6-(1-(2-Hydroxyethyl)-3-methoxy-1H-pyrazol-4-ylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)benzonitrile;

1-((2-Fluoropyridin-3-yl)methyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

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

1-(2,4-Difluorobenzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

N-(1-Methyl-1H-pyrazol-4-yl)-1-phenethyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

2-(4-(1-(2-Fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-3-methoxy-1H-pyrazol-1-yl)ethanol;

2-(4-(1-(2,3-Difluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-3-methoxy-1H-pyrazol-1-yl)ethanol;

2-(4-(1-(2,5-Difluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-3-methoxy-1H-pyrazol-1-yl)ethanol;

4-Fluoro-2-((6-(1-methyl-1H-pyrazol-4-ylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)benzonitrile;

4-fluoro-2-((6-(1-methyl-1H-pyrazol-4-ylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)benzamide;

N-(6-(6-(1-methyl-1H-pyrazol-4-ylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyridin-3-yl)methanesulfonamide;

N-(2-methyl-6-(6-(1-methyl-1H-pyrazol-4-ylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyridin-3-yl)methanesulfonamide;

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

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

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

(R)—

N-(1-methyl-1H-pyrazol-4-yl)-1-((6-(3-methylmorpholino)pyridin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

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

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

1-(2-chloro-5-fluorobenzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(2-chloro-6-fluorobenzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(5-chloro-2-fluorobenzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

N-(1-methyl-1H-pyrazol-4-yl)-1-(2-(trifluoromethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

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

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

3-((6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)benzonitrile;

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

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

4-(6-((1-(2,2-difluoroethyl)-3-methoxy-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzenesulfonamide;

1-(3-chloro-2-fluorobenzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

2-(4-((1-(2,6-difluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrazol-1-yl)ethanol;

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

N-(2-((6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)methanesulfonamide;

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

1-(2-fluorophenethyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

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

1-(3,5-difluorobenzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

3-((6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)benzamide;

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

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

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

N-(1-methyl-1H-pyrazol-4-yl)-1-(2-methylbenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

N-(1-methyl-1H-pyrazol-4-yl)-1-(2-(trifluoromethoxy)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

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

1-(2-methoxybenzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(2-fluorobenzyl)-N-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(4-((1-(2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrazol-1-yl)propan-2-ol;

1-(2-fluoro-6-methoxybenzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(5-fluoro-2-methoxybenzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

(2-((6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)methanol;

1-(2-fluoro-3-methoxybenzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(2-fluoro-5-methoxybenzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(4-((1-(2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrazol-1-yl)ethanone;

1-(2-fluorobenzyl)-N-(1-(methylsulfonyl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

N-(3-chloro-1H-pyrazol-4-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

N-(1-methyl-1H-pyrazol-4-yl)-1-(2,3,6-trifluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

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

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

1-(2-isopropylbenzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(2-(2-methoxyethoxy)benzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

4-((1-(2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrazole-1-carboxamide;

1-(3-fluoro-5-methoxybenzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

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

2-(4-((1-benzyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3-methoxy-1H-pyrazol-1-yl)ethanol;

2-fluoro-3-((6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)benzonitrile;

2-fluoro-6-((6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)benzonitrile;

1-benzyl-N-(1,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-benzyl-N-(1,3-dimethyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(2-cyclopropylbenzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(4-((1-(2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrazol-1-yl)-2-methylpropan-2-ol;

2-(4-((1-benzyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3-methyl-1H-pyrazol-1-yl)ethanol;

1-(2-(benzyloxy)benzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(3-fluoro-2-methylbenzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(5-fluoro-2-methylbenzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(2-fluoro-6-methylbenzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-benzyl-N-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-benzyl-N-(1-(2,2-difluoroethyl)-3-methoxy-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-benzyl-N-(1-(2,2-difluoroethyl)-3-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

4-(6-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzenesulfonamide;

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

N-(1-(2-(diethylamino)ethyl)-1H-pyrazol-4-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(2-fluorobenzyl)-N-(1-(2-morpholino ethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

N-(1-(3-(dimethylamino)propyl)-1H-pyrazol-4-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

N-(2-((6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)propane-2-sulfonamide;

4-(6-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzenesulfonamide;

N-(1-(2,2-difluoro ethyl)-1H-pyrazol-4-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(2,5-difluorobenzyl)-N-(1-(2,2-difluoro ethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

2-((6-((1-(2,2-difluoro ethyl)-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-4-fluorobenzonitrile;

N-(2-((6-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)methanesulfonamide hydrochloride;

1-(3-(2-methoxyethoxy)benzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

2-(4-((1-benzyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrazol-1-yl)-N-methylacetamide;

2,2,2-trifluoro-N-(2-((6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)ethanesulfonamide;

4-(6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzamide;

N-methyl-4-(6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzamide;

(4-(6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)(morpholino)methanone;

2-fluoro-4-(6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzenesulfonamide;

N-(2-hydroxyethyl)-4-(6((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzenesulfonamide;

N-(3-((6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)methanesulfonamide;

N-(3-((6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)propane-2-sulfonamide;

N-(3-fluoro-2-((6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)methanesulfonamide;

1-(2-fluorobenzyl)-N-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(2-fluorobenzyl)-N-(1-(3-(piperidin-1-yl)propyl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(2-fluorobenzyl)-N-(1-(3-morpholinopropyl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

(3-(6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)(morpholino)methanone;

N-(2-hydroxyethyl)-3-(6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzamide;

N-(2-hydroxyethyl)-4-(6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzamide;

(4-(6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)(4-methylpiperazin-1-yl)methanone;

1-(2,5-difluorobenzyl)-N-(1-(2,2-difluoroethyl)-3-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

2-((6-((1-(2,2-difluoroethyl)-3-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-4-fluorobenzonitrile;

1-(2,5-difluorobenzyl)-N-(1-(2,2-difluoroethyl)-3-methoxy-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

2-((6-((1-(2,2-difluoroethyl)-3-methoxy-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-4-fluorobenzonitrile;

N-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-1-(3-fluoro-2-methylbenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(2,3-difluorobenzyl)-N-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(3-chloro-2-fluorobenzyl)-N-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

N-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-1-(2,3,6-trifluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

N-(1-methyl-1H-pyrazol-4-yl)-1-(2,3,5-trifluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(2,6-difluoro-3-methoxybenzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(2,6-difluorobenzyl)-N-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(2-cyclopropylbenzyl)-N-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

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

N-(1-methyl-1H-pyrazol-4-yl)-1-(2,3,5,6-tetrafluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(2-fluoro-6-(trifluoromethyl)benzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(2-fluorobenzyl)-N-(1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

2-(3-((6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenoxy)ethanol;

N-(1-methyl-1H-pyrazol-4-yl)-1-(3-(2-(piperidin-1-yl)ethoxy)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

2-(2-((6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenoxy)ethanol;

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

1-((6-fluoropyridin-2-yl)methyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

(S)-1-(3-(2-methoxypropoxy)benzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

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

1-(2-(cyclopropylmethoxy)benzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

N-(1-methyl-1H-pyrazol-4-yl)-1-((6-morpholinopyridin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(3-((2S,6R)-2,6-dimethylmorpholino)benzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

N-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-1-(3-(2-methoxyethoxy)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

N-(1-(3-(azetidin-1-yl)propyl)-1H-pyrazol-4-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(2,3-dichlorobenzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

2-methyl-3-((6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenol;

N-(1-methyl-1H-pyrazol-4-yl)-1-(2-morpholinobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

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

1-(2-fluorobenzyl)-N-(1-(2-(piperazin-1-yl)ethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-((6-(dimethylamino)pyridin-2-yl)methyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

N-(1-(3-(dimethylamino)propyl)-1H-pyrazol-4-yl)-1-(3-(2-methoxyethoxy)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(3-(2-methoxyethoxy)-2-methylbenzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

N-(1-(3-(dimethylamino)propyl)-1H-pyrazol-4-yl)-1-(3-morpholinobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

(R)—

N-(1-methyl-1H-pyrazol-4-yl)-1-((6-((tetrahydrofuran-3-yl)amino)pyridin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

N-(1-methyl-1H-pyrazol-4-yl)-1-((6-(pyrrolidin-1-yl)pyridin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

4-methyl-3-((6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenol;

2-(4-((1-(3-morpholinobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrazol-1-yl)ethanol;

(3-((6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)(morpholino)methanone;

1-(2-fluorobenzyl)-N-(1-((1-methylpiperidin-3-yl)methyl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

(R)—

N-(1-methyl-1H-pyrazol-4-yl)-1-((6-((tetrahydrofuran-2-yl)methoxy)pyridin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(2-fluorobenzyl)-N-(1-(3-(4-methylpiperazin-1-yl)propyl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

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

2-(4-((1-(2,3,5,6-tetrafluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrazol-1-yl)ethanol;

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

N-(1-methyl-1H-pyrazol-4-yl)-1-(3-(tetrahydro-2H-pyran-4-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

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

N-(2-methoxyethyl)-3-((6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)benzamide;

N-(1-methyl-1H-pyrazol-4-yl)-1-(2-methyl-3-morpholinobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

N-methyl-2-(4-((1-(3-morpholinobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrazol-1-yl)acetamide;

ethyl 1-(3-((6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)piperidine-3-carboxylate;

3-(4-((1-(3-morpholinobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrazol-1-yl)propanamide;

1-(2-fluoro-5-morpholinobenzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(3-(2-aminopyridin-4-yl)benzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

N,N-dimethyl-3-(4-((1-(3-morpholinobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrazol-1-yl)propanamide;

(R)-1-(6-((6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyridin-2-yl)pyrrolidin-3-ol;

2-(3-((6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenoxy)acetamide;

N-(1-methyl-1H-pyrazol-4-yl)-1-(2,3,6-trifluoro-5-morpholinobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

3-(4-((1-(3-morpholinobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrazol-1-yl)propan-1-ol;

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

3-(4-((1-(3-morpholinobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrazol-1-yl)-1-(piperidin-1-yl)propan-1-one;

1-(2-fluoro-3-morpholinobenzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

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

N-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-1-(3-morpholinobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

N-methyl-3-(4-((1-(3-morpholinobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrazol-1-yl)propanamide;

1-(3-(3,6-dihydro-2H-pyran-4-yl)benzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

6-(6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2H-benzo[1)][1,4]oxazin-3(4H)-one;

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

1-(2-(2-(benzyloxy)ethoxy)benzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(3-(2-(benzyloxy)ethoxy)benzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

4-(3-((6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)thiomorpholine 1,1-dioxide;

N-(1-methyl-1H-pyrazol-4-yl)-1-(2-phenoxybenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(2-(3-((6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenoxy)ethyl)pyrrolidin-2-one;

1-(3-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)benzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

4-(3-((6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)morpholin-3-one;

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

1-((2,3-dihydrobenzo[b][1,4]dioxin-5-yl)methyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

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

4-(3-((6-((1-(3-(dimethylamino)propyl)-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)morpholin-3-one;

4-(3-((6-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)morpholin-3-one;

1-(3-(4-((1-(3-morpholinobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrazol-1-yl)propyl)pyrrolidin-2-one;

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

4-(3-((6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)morpholin-3-ol;

3-((1-(2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1-methyl-1H-pyrazole-5-carboxylic acid;

1-(2-fluorobenzyl)-N-(1-methyl-1H-imidazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

2-(3-((1-(2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrazol-1-yl)ethanol;

4-((1-(2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-N-methyl-1H-pyrrole-2-carboxamide;

2-(4-((1-(2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-imidazol-1-yl)ethanol;

1-(2-fluorobenzyl)-N-(1-methyl-1H-pyrrol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

4-((1-(2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-N,1-dimethyl-1H-pyrrole-2-carboxamide;

4-((1-(2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1-methyl-N42-morpholinoethyl)-1H-pyrrole-2-carboxamide;

(4-((1-(2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1-methyl-1H-pyrrol-2-yl)(morpholino)methanone;

N-(cyanomethyl)-4-((1-(2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1-methyl-1H-pyrrole-2-carboxamide;

4-((1-(2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-N,N,1-trimethyl-1H-pyrrole-2-carboxamide;

2-(3-((1-(2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrrol-1-yl)ethanol;

(1-methyl-4-((1-(3-morpholinobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrrol-2-yl)(morpholino)methanone;

N-(1-(3-(dimethylamino)-2-methylpropyl)-1H-pyrazol-4-yl)-1-(3-morpholinobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(dimethylamino)-3-(4-((1-(3-morpholinobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrazol-1-yl)propan-2-ol;

N-(1-(3-aminopropyl)-1H-pyrazol-4-yl)-1-(3-morpholinobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

N-cyclopropyl-3-(4-((1-(3-morpholinobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrazol-1-yl)propanamide;

1-(3-((6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)piperazin-2-one;

2-(4-((1-(2,3,6-trifluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrazol-1-yl)ethanol;

1-(2,3-difluoro-5-morpholinobenzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(2,6-difluoro-3-morpholinobenzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

2-(4-((1-(2-fluoro-3-morpholinobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrazol-1-yl)ethanol;

4-(2-fluoro-3-((6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)morpholin-3-one;

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

2-(4-((1-(2-cyclopropylbenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrazol-1-yl)ethanol;

2-(4-((1-(2-fluoro-6-(trifluoromethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrazol-1-yl)ethanol;

N-(1-(3-(dimethylamino)propyl)-1H-pyrazol-4-yl)-1-(2,3,6-trifluoro-5-morpholinobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

N-(1-(3-(dimethylamino)propyl)-1H-pyrazol-4-yl)-1-(2-fluoro-3-morpholinobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

2-(4-((1-(2-fluoro-5-morpholinobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrazol-1-yl)ethanol;

2-(4-((1-(2,3,6-trifluoro-5-morpholinobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrazol-1-yl)ethanol;

4-(2-fluoro-3-((6-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)morpholin-3-one;

2-(4-((1-(3-(piperazin-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrazol-1-yl)ethanol;

1-(3-morpholinobenzyl)-N-(1-(piperidin-3-ylmethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(3-fluoro-5-morpholinobenzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

4-(3-((6-((1-(3-(dimethylamino)propyl)-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-2-fluorophenyl)morpholin-3-one;

2-(4-((1-(3-fluoro-5-morpholinobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrazol-1-yl)ethanol;

4-(3-fluoro-5-((6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)morpholin-3-one;

4-(3,4-difluoro-5-((6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)morpholin-3-one;

1-(2-fluoro-3-((6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)piperazin-2-one;

1-(2-fluoro-3-((6-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)piperazin-2-one;

2-(4-((1-(2,3-difluoro-5-morpholinobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrazol-1-yl)ethanol;

1-(3-((6-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)piperazin-2-one;

4-(3-fluoro-5-((6-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)morpholin-3-one;

4-(3,4-difluoro-5-((6-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)morpholin-3-one;

1-(3-morpholinobenzyl)-N-(1-(pyrrolidin-3-ylmethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

4-(2,4,5-trifluoro-3-((6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)morpholin-3-one;

4-(2,4,5-trifluoro-3-((6-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)morpholin-3-one;

2-(4-((1-(2,3,6-trifluoro-5-(piperazin-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrazol-1-yl)ethanol;

1-(3-fluoro-5-((6-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)piperazin-2-one;

1-(3-fluoro-5-((6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)piperazin-2-one;

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

N-(1-methyl-1H-pyrazol-4-yl)-1-(2,3,6-trifluoro-5-(piperazin-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(2-fluoro-3-(piperazin-1-yl)benzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

2-(4-((1-(3-fluoro-5-(3-oxomorpholino)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrazol-1-yl)-N-methylacetamide;

2-(4-((1-(2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrazol-1-yl)-N-methylacetamide;

2-(4-((1-((6-fluoropyridin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrazol-1-yl)-N-methylacetamide;

4-(2,4-difluoro-3-((6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)morpholin-3-one;

4-(2,4-difluoro-3-((6-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)morpholin-3-one;

4-(3-((6-((1-(3-(dimethylamino)propyl)-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-2,4,5-trifluorophenyl)morpholin-3-one;

1-(3,4-difluoro-5-((6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)piperazin-2-one;

1-(3,4-difluoro-5-((6-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)piperazin-2-one;

4-(2,5-difluoro-3-((6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)morpholin-3-one;

4-(2,5-difluoro-3-((6-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)morpholin-3-one;

4-(3-((6-((1-(3-(dimethylamino)propyl)-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-2,4-difluorophenyl)morpholin-3-one;

1-(2,4-difluoro-3-((6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)piperazin-2-one;

1-(2,6-difluoro-3-(piperazin-1-yl)benzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(2,4-difluoro-3-((6-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)piperazin-2-one;

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

2-(4-((1-(2,6-difluoro-3-(piperazin-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrazol-1-yl)ethanol;

2-(4-((1-(2,3-difluoro-5-(piperazin-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrazol-1-yl)ethanol;

1-(2-fluorobenzyl)-N-(1-(pyrrolidin-3-ylmethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

(3-fluoro-5-((6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)(morpholino)methanone;

(3-fluoro-5-((6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)(piperazin-1-yl)methanone;

N-(1H-pyrazol-4-yl)-1-(2,3,6-trifluoro-5-morpholinobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

2-(4-((1-(2,6-difluoro-3-morpholinobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrazol-1-yl)ethanol;

2-(4-((1-(2-fluoro-3-(piperazin-1-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrazol-1-yl)ethanol;

4-(3-((6-((1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-fluorophenyl)morpholin-3-one;

(2-Fluoro-3-((6-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)(morpholino)methanone;

2-(4-((1-((6-fluoropyridin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrazol-1-yl)ethanol;

1-(2,3-difluoro-5-(piperazin-1-yl)benzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

and

(2-fluoro-3-((6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)(morpholino)methanone.

18. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof of claim 1 together with a pharmaceutically acceptable carrier, optionally in combination with one or more other pharmaceutical compositions.

23. A method for treating, controlling, delaying or preventing in a mammalian patient in need thereof one or more conditions selected from the group consisting of diseases and disorders associated with JAK, wherein the method comprises the administration to said patient of a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

24. A method for the preparation of a compound of claim 1 comprising the steps of

(a) reacting a compound of formula (II)

25. A method for treating, controlling, delaying or preventing in a mammalian patient in need thereof one or more conditions selected from the group consisting of an immunological, inflammatory, autoimmune, or allergic disorder or disease of a transplant rejection or a Graft-versus host disease, wherein the method comprises the administration to said patient of a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

26. A method for treating, controlling, delaying or preventing in a mammalian patient in need thereof, a proliferative disease, wherein the method comprises the administration to said patient of a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

19. (canceled)

20. (canceled)

21. (canceled)

22. (canceled)