WO2015140566A1

WO2015140566A1 - Pyrazolo-pyrimidines as inhibitors of btk

Info

Publication number: WO2015140566A1
Application number: PCT/GB2015/050819
Authority: WO
Inventors: Richard Armer; Nicolas E. S. GUISOT; Catherine Lucas
Original assignee: Redx Pharma Plc
Priority date: 2014-03-20
Filing date: 2015-03-19
Publication date: 2015-09-24
Also published as: GB201404987D0

Abstract

This invention relates to novel compounds. The compounds of the invention are tyrosine kinase inhibitors. Specifically, the compounds of the invention are useful as inhibitors of Bruton's tyrosine kinase (BTK). The invention also contemplates the use of the compounds for treating conditions treatable by the inhibition of Bruton's tyrosine kinase, for example cancer, lymphoma, leukemia and immunological diseases.

Description

PYRAZOLO-PYRIMIDINES AS INHIBITORS OF BTK

[0001] This invention relates to compounds. More specifically, the invention relates to compounds useful as kinase inhibitors, along with processes to prepare the compounds and uses of the compounds. Specifically, the invention relates to inhibitors of Bruton's tyrosine kinase (BTK).

BACKGROUND

[0002] Kinases are a class of enzyme that control the transfer of phosphate groups from phosphate donor groups, for example ATP, to specific substrates. Protein kinases are a subset of kinases and BTK is one such protein kinase.

[0003] BTK is a member of the src-related Tec family of cytoplasmic tyrosine kinases. BTK plays a key role in the signalling pathways of B-cells, affecting B-cell development, activation, signalling and survival. In certain malignancies, B-cells overexpress BTK. These malignant B-cells and the overexpression of BTK by the cells has been associated with the increased proliferation and survival of tumor cells. Inhibition of BTK affects the B-cell signalling pathways, preventing activation of B-cells and inhibiting the growth of malignant B-cells.

[0004] A number of clinical trials have shown that BTK inhibitors are affective against cancer.

[0005] BTK inhibitors that have been reported are Ibrutinib (PCI-32765) and CC-292. CC-292 is manufactured by Avila Pharmaceuticals who have filed applications for protein kinases published as WO 201 1 /090760 and WO 2009/158571 . Ibrutinib is disclosed in at least US 2008/0076921 .

Studies on Ibrutinib have found that it possesses a number of undesirable pharmacological features. For example, Ibrutinib is poorly soluble and is a weak inhibitor of hERG. Furthermore, rat pharmacokinetic data has shown that Ibrutinib has a low estimated fraction absorbed, poor bioavailability and a high clearance rate from the body, with a terminal T1 2 of 1 .5 hours.

[0006] Since Ibrutinib was first disclosed there have been a number of patent applications concerned with structures closely related to Ibrutinib, for example see WO 2012/158843, WO 2012/158764, WO 201 1/153514, WO 201 1/046964, US 2010/0254905, US 2010/0144705, US 7718662, WO, 2008/054827 and WO 2008/121742.

[0007] Most recently, WO 2013/010136 disclosed BTK inhibitors with a related structure to Ibrutinib.

[0008] Known BTK inhibitors, e.g. Ibrutinib, have presented gastrointestinal side effects. These side effects have been attributed to the EGFR inhibitory activity of the BTK inhibitors. It is therefore desirable to have a BTK inhibitor with high BTK inhibition and low EGFR inhibition to reduce or avoid the gastrointestinal side effects. Such high BTK inhibition and low EGFR inhibition is readily identified by a large "Fold Selectivity" value.

[0009] Therefore, an aim of the present invention is to provide BTK inhibitors. In addition the invention aims to provide BTK inhibitors with high selectivity for BTK inhibition over EGFR inhibition. SU M MARY OF THE DISCLOSURE

[0010] In accordance with the present invention there is provided compounds as disclosed below. Furthermore, the invention provides compounds capable of inhibiting Bruton's tyrosine kinase (BTK) and the use of these compounds in inhibiting BTK. In accordance with the invention there is provided a method of treating conditions modulated by BTK. The invention provides compounds for use in treating a condition which is modulated by BTK.

[0011] In a first aspect of the invention there is provided a compound according to formula (I):

(I)

wherein

A is N or CR^a;

D is either a substituted or unsubstituted Ci-e alkylene chain which is saturated or unsaturated and which may also contain, where chemically possible, 1 , 2 or 3 N, O, or S atoms in the chain which are independently chosen at each occurrence;

or wherein D represents a substituted or unsubstituted carbocyclic or heterocyclic moiety which is saturated or unsaturated and which contains from 3 to 8 atoms in the carbocyclic or heterocyclic ring, wherein the ring is optionally substituted with -NR^b-, wherein -NR^b- is bonded to the ring; and wherein, when substituted, the alkylene chain or the carbocyclic or heterocyclic moiety includes 1 to 5 substituents independently selected at each occurrence from the group comprising: halo, -OR^b, - SR^b, -NR^bR^c, NO, =0, -CN, acyl, Ci-₆ alkyl, Ci-₆ haloalkyl, C₃-₈ cycloalkyl, -S0₂R^b, and S0₃R^b , - C(0)R and C(0)OR ;

E is selected from:

Y is either O or NR^b; L is selected from a bond, -0-, -0(CR^dR^e)_m-, -NR^b- and -(CR^dR^e)_m-; L² represents -NR^bS02-;

n is selected from 0, 1 , 2, and 3;

m is selected from 1 , 2, 3 and 4;

R^a is selected from: H, halo, Ci-e alkyl, Ci-e haloalkyl, OH, SH, Ci-e alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C₃-s cycloalkenyl, NR^bR^c, -CN, acyl, -C(0)R^b, -C(0)OR , -S0₂R^b, and -S0₃R^b;

R^b and R^c are independently selected at each occurrence from: H, C1-4 alkyl, C1-4 haloalkyl, C1-4 acyl, C3-7 cycloalkyl, and C3-7 halocycloalkyl; R^d and R^e are independently selected at each occurrence from: H, halo, C1-4 alkyl, C1-4 haloalkyl, Ci- 4 acyl, C3-7 cycloalkyl, and C3-7 halocycloalkyl;

R is a group selected from a substituted or unsubstituted C1-8 alkyl or a substituted or unsubstituted carbocyclic or heterocyclic moiety which either contains from 3 to 8 atoms in a single ring or 7 to 14 atoms in a fused polycyclic ring system, wherein, when substituted, R contains 1 to 5 substituents independently selected at each occurrence from the group comprising: halo, -OR^b, - SR^b, -NR^bR^c, - NO2, =0, -CN, acyl, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 heterocycloalkyl, -S0₂R^b, S0₃R^b, - C(0)R^b, -C(0)OR^b, -C(0)NR^bR^c and aryl optionally substituted by 1 or 2 halo atoms;

R² is selected from H, halo, -OR^b, C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 heterocycloalkyl, C3-8 cycloalkenyl, C3-8 heterocycloalkenyl, -NR^bR^c, -C02R^b, - C(0)R and -C(0)NR R^c; and

R³, R⁴, and R⁵ are independently selected from H, halo, -OR^b, -CN, -NR^bR^c, -CH₂NR^bR^c, -C0₂R^b, - C(0)R^b, -C(0)NR^bR^c, C1-6 alkoxy, C1-6 alkyl, C1-6 alkyl substituted with C3-8 cycloalkyl, C1-6 alkyl substituted with C3-8 heterocycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 heterocycloalkyl, C3-8 cycloalkenyl, C3-8 heterocycloalkenyl, aryl, heteroaryl, alkaryl and

alkheteroaryl; or R³ and R⁴ taken together with the carbon atoms to which they are attached form a

C3-8 cycloalkene and R⁵ is independently selected as above;

or R⁴ and R⁵ taken together with the carbon atom to which they are attached form a C3-8 cycloalkyl and R³ is independently selected as above;

or R³ and R⁵ taken together with the carbon atoms to which they are attached form a C-C triple bond and R⁴ is independently selected as above.

[0012] In embodiments A is CR^a. R^a may be H, halo, e.g. fluoro or chloro, C1-6 alkyl, C1-6 haloalkyl, -OH, or C1-6 alkoxy. In particular R^a may be H, fluoro, chloro or C1-4 haloalkyl. In particular A may be CR^a and R^a may be H, fluoro, chloro or C1-4 haloalkyl, preferably H. Hence, in an embodiment A may be CH.

[0013] Thus, the compound of formula (I) may be a compound according to formula (la):

(la)

[0014] L² represents -NR^bS02-. Therefore, L² can be described as representing a sulfonamide, wherein the sulfonamide nitrogen is substituted by R^b. The sulfonamide, -NR^bS02-, may be oriented in one of two directions, as is evident to the skilled person. In other words: L² may represent a sulfonamide, -NR^bS02-, wherein the sulfonamide nitrogen is substituted by R^b and the nitrogen is bonded to (CR^dR^e)_n, or the phenyl ring when n is 0, and the sulfur is bonded to R when oriented in a first direction or the nitrogen is bonded to R and the sulfur is bonded to (CR^dR^e)_n, or the phenyl ring when n is 0, when oriented in a second direction. Thus, L² may represent -NR^bS02- or - S02NR^b-, wherein the groups are oriented in formula (I) as shown.

[0015] In all definitions of all other groups in the formulae of the invention the written

representation of the groups is not necessarily indicative of the only orientation of the group when the relevant group may be oriented in other chemically possible ways.

[0016] The groups, L and (CR^dR^e)_n-L²-R¹ , on the phenyl ring of compounds of formula (I) and (la) may be substitured in any arrangement possible. For example the groups may be in a para, ortho or meta relationship. In an embodiment, the compound of formula (I) may be a compound according to formula (Ma), having a para relationship between the groups on the phenyl ring or (Mb), having a meta relationship between the groups on the phenyl ring: (CR^dR^e),

(CR^dR^e)_n L²— R

(Ma) (lib)

[0017] The group R may be a substituted or unsubstituted: Ci-e alkyl, cycloalkyi, aryl,

heterocycloalkyi or heteroaryl, wherein the cycloalkyi and heterocycloalkyi groups may be saturated or unsaturated and the cycloalkyi, aryl, heterocycloalkyi or heteroaryl may contain either from 3 to 8 atoms in a single ring or 7 to 14 atoms in a fused polycyclic ring system, wherein, when substituted, R contains 1 to 5 substituents independently selected at each occurrence from the group comprising: halo, -OR^b, - SR^b, -NR^bR^c, NO, =0, -CN, acyl, Ci-e alkyl, Ci-e haloalkyl, C₃-s cycloalkyi, C₃-8 heterocycloalkyi, -S0₂R^b, S0₃R^b , -C(0)R^b, C(0)OR^b -C(0)NR^bR^c and aryl optionally substituted by 1 or 2 halo atoms.

[0018] The group R may be a substituted or unsubstituted: C1-6 alkyl, C3-8 cycloalkyi, Ce-u aryl, C3- 8 heterocycloalkyi or C5-14 heteroaryl, wherein the C3-8 cycloalkyi and C3-8 heterocycloalkyi groups may be saturated or unsaturated, wherein, when substituted, R contains 1 to 3 substituents independently selected at each occurrence from the group comprising: halo, -OR^b, - SR^b, -NR^bR^c, NO, =0, -CN, acyl, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyi, C3-8 heterocycloalkyi, S0₂R^b, S0₃R^b , - C(0)R^b, C(0)OR^b -C(0)NR^bR^c and aryl optionally substituted by 1 or 2 halo atoms.

[0019] The group R may be a substituted or unsubstituted: C1-6 alkyl (optionally C1-4 alkyl), C3-8 cycloalkyi (optionally C3 or C5-7 cycloalkyi), Ce-u aryl (optionally Ce Cg, or C10 aryl) or C5-14 heteroaryl (optionally C5, C6 or C10 heteroaryl), wherein the C3-8 cycloalkyi group may be saturated or unsaturated. When substituted, R contains 1 to 3 substituents independently selected at each occurrence from the group comprising: halo, -OR^b, - SR^b, -NR^bR^c, NO, =0, -CN, acyl, C1-6 alkyl, C1-6 haloalkyl, C₃-s cycloalkyi, C₃-s heterocycloalkyi, , -S0₂R^b, S0₃R^b , -C(0)R , -C(0)OR , -C(0)NR R^c and aryl optionally substituted by 1 or 2 halo atoms.

[0020] Preferably, when R is substituted it is substituted by 1 or 2 substituents independently selected at each occurrence from the group comprising: fluoro, chloro, methoxy, -CN, methyl, ethyl, trifluoromethyl, trifluoroethyl, nitrile, ethoxy, -OCF3, -NC(0)Me and -C(0)NMe2 , tetrahydrofuranyl, or phenyl.

[0021] In embodiments R may be methyl, trifluoromethyl, ethyl, fluoroethyl, difluoroethyl, trifluoroethyl, tetrafluroethyl, pentafluoroethyl, propyl, isopropyl, fluoropropyl, trifluoropropyl), butyl, tert-butyl, tetrahydrofuranyl-trifluoroethyl, cyclopropyl, cyclohexyl, unsubstituted phenyl, indanyl, napthyl, pyridyl, pyrazolyl, quinolinyl or phenyl substituted with one or two groups independently selected from fluoro, chloro, methyl, nitrile, methoxy, ethoxy, trifluoromethyl, -OCF3, -NC(0)Me and -C(0)NMe₂ or phenyl. [0022] In an embodiment, R² is hydrogen.

[0023] In an embodiment, R³, R⁴, and R⁵ may be independently selected from hydrogen, fluorine, chlorine, bromine, iodine, -CN, -CH2NR^bR^c, Ci-e alkyl, Ci-e alkyl substituted with C3-8 cycloalkyl, C1-6 alkyl substituted with C3-8 heterocycloalkyl, C1-6 haloalkyl, aryl, heteroaryl, alkaryl and alkheteroaryl. [0024] In another embodiment, R³, R⁴, and R⁵ may be independently selected from hydrogen, fluorine, chlorine, bromine, iodine, -CN, -CH2NR^bR^c and C1-6 alkyl, where R^b and R^c are

independently selected from hydrogen and C1-6 alkyl.

[0025] In a more preferred embodiment, two of R³, R⁴, and R⁵ may be hydrogen and the other may be fluorine, chlorine, bromine, iodine, -CN, -CH2NR^bR^c and C1-6 alkyl, where R^b and R^c are independently selected from hydrogen and C1-6 alkyl, e.g. R³ and R⁴ may be hydrogen; or R⁴ and R⁵ may be hydrogen; or R³ and R⁵ may be hydrogen.

[0026] In a further preferred embodiment, R³, R⁴, and R⁵ are all hydrogen.

[0027] In an embodiment, R^b and R^c are hydrogen or C1-4 alkyl, preferably H or methyl.

[0028] In an embodiment R^d and R^e are independently selected at each occurrence from: H, halo, C1-4 alkyl, C1-4 haloalkyl or C1-4 acyl. Preferably, R^d and R^e are independently selected at each occurrence from: H, halo (e.g. fluoro and chloro), C1-4 alkyl (e.g. methyl or ethyl) or Ci-4 haloalkyl (e.g. trifluoromethyl or trifluoroethyl). Further preferably R^d and R^e are H.

[0029] In embodiments n is selected from 1 , 2 or 3, preferably n is 1 .

[0030] In one embodiment E is:

, wherein Y is O or NR^b, may be selected from:

[0032] In another embodiment Ε is:

[0033] In all embodiments

†_ec| f_ro m:

,0. o o o o o o

[0034] In a further embodiment E is:

[0035] In embodiments Y is O. In alternative embodiments Y is NR^a wherein R^a is H or methyl.

[0036] In the statement of invention D may represent a substituted or unsubstituted carbocyclic or heterocyclic moiety which is saturated or unsaturated and which contains from 3 to 8 atoms in the carbocyclic or heterocyclic ring, wherein the ring is optionally substituted with -NR^b-. The group - NR^b- is bonded to two entities, as is evident to the skilled person. The two entities may be the heterocyclic or carbocyclic ring and E.

[0037] In an embodiment D is either a substituted or unsubstituted Ci-e alkylene chain which is saturated or unsaturated and which may also contain, where chemically possible, 1 , 2 or 3 N, O, or S atoms in the chain which are independently chosen at each occurrence;

or wherein D represents a substituted or unsubstituted carbocyclic or heterocyclic moiety which is saturated or unsaturated and which contains from 3 to 8 atoms in the carbocyclic or heterocyclic ring;

and wherein, when substituted, the alkylene chain or the carbocyclic or heterocyclic moiety includes 1 to 5 substituents independently selected at each occurrence from the group comprising: halo, - OR^b, - SR^b, -NR^bR^c, NO, =0, -CN, acyl, Ci_-e alkyl, Ci-₆ haloalkyl, C₃-s cycloalkyl, -S0₂R^b, and S0₃R^b , -C(0)R and C(0)OR .

[0038] In an embodiment, D is selected from a substituted or unsubstituted saturated Ci-e alkylene chain containing, where chemically possible, 1 , 2 or 3, optionally 1 or 2, N, O or S atoms in the chain which are independently chosen at each occurrence; or D represents a substituted or unsubstituted saturated heterocyclic moiety which contains from 3 to 8 atoms in the heterocyclic ring and contains, where chemically possible, 1 , 2 or 3, optionally 1 or 2, N, O or S atoms in the ring which are independently chosen at each occurrence. [0039] In an embodiment D represents a substituted or unsubstituted saturated heterocyclic moiety which contains from 3 to 8 atoms in the heterocyclic ring and contains, where chemically possible, 1 , 2 or 3, optionally 1 or 2, N, O or S atoms in the ring which are independently chosen at each occurrence. [0040] In embodiments the alkylene chain and the heterocyclic ring contain 1 heteroatom selected from N, O or S, optionally N. In embodiments the alkylene chain and the heterocyclic ring contain 1 nitrogen atom and the nitrogen atom is the point of connection with group E.

[0041] In an embodiment, D is selected from substituted or unsubstituted Ci-e heteroalkyl, substituted or unsubstituted C3-8 heterocycloalkyl and substituted or unsubstituted C3-8

heterocycloalkenyl. In embodiments D may be selected from substituted or unsubstituted C1-6 heteroalkyl, substituted or unsubstituted C3-8 heterocycloalkyl and substituted or unsubstituted C3-8 heterocycloalkenyl where N is the heteroatom and D comprises 1 or 2 nitrogen atoms. In an embodiment D is substituted or unsubstituted C3-8 heterocycloalkyl, optionally C6 heterocycloalkyl. D may be substituted or unsubsustituted piperidinyl, preferably unsubstituted. [0042] In an embodiment, D is substituted or unsubstituted C3-8 heterocycloalkyl or substituted or unsubstituted C3-8 heterocycloalkenyl. In embodiments D may be substituted or unsubstituted C3-8 heterocycloalkyl or substituted or unsubstituted C3-8 heterocycloalkenyl where N is the heteroatom and D comprises 1 or 2 nitrogen atoms.

[0043] In an embodiment D is unsubstituted. In an alternative embodiment D is substituted. In an embodiment D is substituted with halo, optionally fluoro.

[0044] In an embodiment, D may be selected from:

and D may be substituted or unsubstituted. In particular, D may be unsubstituted.

[0045] In an embodiment, D may be selected from:

[0046] In an embodiment, D may be:

Optionally, D is substituted by a halo group, for example, fluoro. [0047] In embodiments L is selected from a bond, -(CR^dR^e)_m-, -O- and -NR^b-. In embodiments m is 1 or 2, optionally m is 1 . In embodiments R^b is independently selected from hydrogen Ci-e alkyl and Ci-e haloalkyl and R^d and R^e are independently selected from hydrogen, fluorine, chlorine, bromine, iodine, Ci-e alkyl and Ci-e haloalkyl. In embodiments R^b, R^d and R^e are independently hydrogen or Ci-e alkyl. [0048] In embodiments L is selected from a bond, -CH2-, -O- and -NH-, optionally a bond or -CH2-.

[0049] The embodiments described above may be applied individually, or in any combination of one another, and independently, to the compounds of the invention, for example those compounds disclosed below.

[0050] In the case when D is:

the compound of formula (I) is a compound according to formula (III): TT~~(CR^dR^e)_n— L²— R¹

(III)

[0051] In any embodiment D may be the group shown below with the indicated stereochemistry:

[0052] Thus, the compound of formula (I) may be a compound according to formula (Ilia):

(Ilia)

[0053] In embodiments where there is a single enantiomer of the compounds of the invention, the compounds of the invention may have an enantiomeric purity of at least about 90% enantiomeric excess (ee), at least about 95% enantiomeric excess (ee), at least about 98% enantiomeric excess (ee), at least about 99% enantiomeric excess (ee), or 100% enantiomeric excess (ee). In embodiments where there is a mixture of enantiomers of the compounds of the invention, the compounds of the invention may be a racemic mixture or any other mixture of enantiomers, for example the compounds of the invention may have an enantiomeric purity of at least about 50% enantiomeric excess (ee), at least about 60% enantiomeric excess (ee), at least about 70% enantiomeric excess (ee), at least about 80% enantiomeric excess (ee), at least about 90% enantiomeric excess (ee), or at least about 95% enantiomeric excess (ee).

[0054] In an embodiment the compound of formula (I) is a compound according to formula (IVa) and (IVb):

[0055] In an embodiment the compound of formula (I) is a compound according to formula (Va) and (Vb):

[0056] In an embodiment the compound of formula (I) is a compound according to formula (Via) and (VI b):

(Via) (Vlb)

[0057] In an embodiment the compound of formula (I) is a compound according to formula (Vila) and (Vllb):

[0059] In an embodiment the compound of formula (I) is a compound according to formula (Villa) and (Vlllb):

(Villa) (Vlllb)

[0060] In an embodiment the compound of formula (I) is a compound according to formula (Vlllc) and (Vllld):





[0062] Compounds of the invention also include:

5

22





[0064] Compounds of the invention also include: 

[0065] In another aspect of the invention there is provided a compound of formula (I) for use as a medicament.

[0066] In another aspect a compound of formula (I) is for use in the treatment of a condition which is modulated by Bruton's tyrosine kinase (BTK). Usually conditions that are modulated by BTK are conditions that would be treated by the inhibition of BTK using a compound of the present invention. A compound of formula (I) may be for use in the treatment of a condition treatable by the inhibition of Bruton's tyrosine kinase (BTK).

[0067] BTK inhibition is a novel approach for treating many different human diseases associated with the inappropriate activation of B-cells, including B-cell malignancies, immunological disease for example, autoimmune and inflammatory disorders. In embodiments the condition treatable by the inhibition of BTK may be selected from: cancer, lymphoma, leukemia, autoimmune diseases and inflammatory disorders. Specific conditions treatable by the inhibition of BTK may be selected from: B-cell malignancy, B-cell lymphoma, diffuse large B cell lymphoma, chronic lymphocyte leukemia, non-Hodgkin lymphoma for example ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B-cell non-Hodgkin lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, bone cancer, bone metastasis, arthritis, multiple sclerosis osteoporosis, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease and lupus.

[0068] B-cell malignancy, B-cell lymphoma, diffuse large B cell lymphoma, chronic lymphocyte leukemia, non-Hodgkin lymphoma for example ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B-cell non-Hodgkin lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, bone cancer and bone metastasis are examples of cancer, lymphoma and leukemia treatable by BTK inhibition.

[0069] Arthritis, multiple sclerosis osteoporosis, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease and lupus are examples of immunological diseases treatable by BTK inhibition. Arthritis is an example of an inflammatory disorder treatable by BTK inhibition. Lupus is an example of an autoimmune disease treatable by BTK inhibition.

[0070] In embodiments, a compound of the invention may be for use in the treatment of: cancer, lymphoma, leukemia, immunological diseases, autoimmune diseases and inflammatory disorders. The compound of the invention may be for use in the treatment of specific conditions selected from: B-cell malignancy, B-cell lymphoma, diffuse large B cell lymphoma, chronic lymphocyte leukemia, non-Hodgkin lymphoma for example ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B-cell non-Hodgkin lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, bone cancer, bone metastasis, arthritis, multiple sclerosis osteoporosis, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease and lupus. The compounds may also be used for the treatment of disorders associated with renal transplant. [0071] In an embodiment the compound of the invention may be for use in the treatment of specific conditions selected from: B-cell malignancy, B-cell lymphoma, diffuse large B cell lymphoma, chronic lymphocyte leukemia, non-Hodgkin lymphoma for example ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B-cell non-Hodgkin lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, lupus and arthritis. [0072] In an aspect of the invention there is provided a method of treatment of a condition which is modulated by Bruton's tyrosine kinase, wherein the method comprises administering a therapeutic amount of a compound of the invention, to a patient in need thereof.

[0073] The method of treatment may be a method of treating a condition treatable by the inhibition of Bruton's tyrosine kinase. [0074] The invention also provides a method of treating a condition selected from: cancer, lymphoma, leukemia, immunological diseases autoimmune diseases and inflammatory disorders, wherein the method comprises administering a therapeutic amount of a compound of the invention, to a patient in need thereof. The invention also provides a method of treating a specific condition selected from: B-cell malignancy, B-cell lymphoma, diffuse large B cell lymphoma, chronic lymphocyte leukemia, non-Hodgkin lymphoma for example ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B-cell non-Hodgkin lymphoma, Waldenstrom's

macroglobulinemia, multiple myeloma, bone cancer, bone metastasis, arthritis, multiple sclerosis osteoporosis, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease and lupus, wherein the method comprises administering a therapeutic amount of a compound of formula (I), to a patient in need thereof. The method may also treat disorders associated with renal transplant. [0075] In an embodiment the method may be for treating a specific condition selected from: B-cell malignancy, B-cell lymphoma, diffuse large B cell lymphoma, chronic lymphocyte leukemia, non- Hodgkin lymphoma for example ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B-cell non-Hodgkin lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, arthritis and lupus. [0076] In another aspect of the invention there is provided a pharmaceutical composition, wherein the composition comprises a compound of the invention and pharmaceutically acceptable excipients.

[0077] In an embodiment the pharmaceutical composition may be a combination product comprising an additional pharmaceutically active agent. The additional pharmaceutically active agent may be an anti-tumor agent described below.

[0078]

DETAILED DESCRIPTION

[0079] Given below are definitions of terms used in this application. Any term not defined herein takes the normal meaning as the skilled person would understand the term. [0080] The term "halo" refers to one of the halogens, group 17 of the periodic table. In particular the term refers to fluorine, chlorine, bromine and iodine. Preferably, the term refers to fluorine or chlorine.

[0081] The term "Ci-e alkyl" refers to a linear or branched hydrocarbon chain containing 1 , 2, 3, 4, 5 or 6 carbon atoms, for example methyl, ethyl, n-propyl, /^'so-propyl, n-butyl, sec-butyl, fe/ -butyl, n- pentyl and n-hexyl. Alkylene groups may likewise be linear or branched and may have two places of attachment to the remainder of the molecule. Furthermore, an alkylene group may, for example, correspond to one of those alkyl groups listed in this paragraph. The alkyl and alkylene groups may be unsubstituted or substituted by one or more substituents. Possible substituents are described below. Substituents for the alkyl group may be halogen, e.g. fluorine, chlorine, bromine and iodine, OH, Ci-e alkoxy. [0082] The term "Ci-e alkoxy" refers to an alkyl group which is attached to a molecule via oxygen. This includes moieties where the alkyl part may be linear or branched and may contain 1 , 2, 3, 4, 5 or 6 carbon atoms, for example methyl, ethyl, n-propyl, /^'so-propyl, n-butyl, sec-butyl, fe/f-butyl, n- pentyl and n-hexyl. Therefore, the alkoxy group may be methoxy, ethoxy, n-propoxy, /^'so-propoxy, n- butoxy, sec-butoxy, fe/ -butoxy, n-pentoxy and n-hexoxy. The alkyl part of the alkoxy group may be unsubstituted or substituted by one or more substituents. Possible substituents are described below. Substituents for the alkyl group may be halogen , e.g. fluorine, chlorine, bromine and iodine, OH, Ci-e alkoxy.

[0083] The term "Ci-e haloalkyl" refers to a hydrocarbon chain substituted with at least one halogen atom independently chosen at each occurrence, for example fluorine, chlorine, bromine and iodine. The halogen atom may be present at any position on the hydrocarbon chain. For example, Ci-e haloalkyl may refer to chloromethyl, flouromethyl, trifluoromethyl, chloroethyl e.g. 1 -chloromethyl and 2-chloroethyl, trichloroethyl e.g. 1 ,2,2-trichloroethyl, 2,2,2-trichloroethyl, fluoroethyl e.g. 1 - fluoromethyl and 2-fluoroethyl, trifluoroethyl e.g. 1 ,2,2-trifluoroethyl and 2,2,2-trifluoroethyl, chloropropyl, trichloropropyl, fluoropropyl, trifluoropropyl.

[0084] The term "C2-6 alkenyl" refers to a branched or linear hydrocarbon chain containing at least one double bond and having 2, 3, 4, 5 or 6 carbon atoms. The double bond(s) may be present as the E or Z isomer. The double bond may be at any possible position of the hydrocarbon chain. For example, the "C2-6 alkenyl" may be ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl.

[0085] The term "C2-6 alkynyl" refers to a branded or linear hydrocarbon chain containing at least one triple bond and having 2, 3, 4, 5 or 6 carbon atoms. The triple bond may be at any possible position of the hydrocarbon chain . For example, the "C2-6 alkynyl" may be ethynyl, propynyl, butynyl, pentynyl and hexynyl. [0086] The term "C1-6 heteroalkyl" refers to a branded or linear hydrocarbon chain containing 1 , 2, 3, 4, 5, or 6 carbon atoms and at least one heteroatom selected from N, O and S positioned between any carbon in the chain or at an end of the chain. For example, the hydrocarbon chain may contain one or two heteroatoms. The C1-6 heteroalkyl may be bonded to the rest of the molecule through a carbon or a heteroatom. For example, the "C1-6 heteroalkyl" may be C1-6 /V-alkyl, C1-6 Λ/,/V-alkyl, or Ci-₆ O-alkyl.

[0087] The term "carbocyclic" refers to a saturated or unsaturated carbon containing ring system. A "carbocyclic" system may be monocyclic or a fused polycyclic ring system, for example, bicyclic or tricyclic. A "carbocyclic" moiety may contain from 3 to 14 carbon atoms, for example, 3 to 8 carbon atoms in a monocyclic system and 7 to 14 carbon atoms in a polycyclic system. "Carbocyclic" encompasses cycloalkyl moieties, cycloalkenyl moieties, aryl ring systems and fused ring systems including an aromatic portion. [0088] The term "heterocyclic" refers to a saturated or unsaturated ring system containing at least one heteroatom selected from N, O or S. A "heterocyclic" system may contain 1 , 2, 3 or 4 heteroatoms, for example 1 or 2. A "heterocyclic" system may be monocyclic or a fused polycyclic ring system, for example, bicyclic or tricyclic. A "heterocyclic" moiety may contain from 3 to 14 carbon atoms, for example, 3 to 8 carbon atoms in a monocyclic system and 7 to 14 carbon atoms in a polycyclic system. "Heterocyclic" encompasses heterocycloalkyl moieties, heterocycloalkenyl moieties and heteroaromatic moieties. For example, the heterocyclic group may be: oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran.

[0089] The term "C3-8 cycloalkyl" refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms. For example, the "C3-8 cycloalkyl" may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0090] The term "C3-8 cycloalkenyl" refers to an unsaturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms that is not aromatic. The ring may contain more than one double bond provided that the ring system is not aromatic. For example, the "C3-8 cycloalkyl" may be

cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienly, cycloheptenyl, cycloheptadiene, cyclooctenyl and cycloatadienyl.

[0091] The term "C3-8 heterocycloalkyl" refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms and at least one heteroatom within the ring selected from N, O and S. For example there may be 1 , 2 or 3 heteroatoms, optionally 1 or 2. The "C3-8 heterocycloalkyl" may be bonded to the rest of the molecule through any carbon atom or heteroatom. The "C3-8 heterocycloalkyl" may have one or more, e.g. one or two, bonds to the rest of the molecule: these bonds may be through any of the atoms in the ring. For example, the "C3-8 heterocycloalkyl" may be oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran.

[0092] The term "C3-8 heterocycloalkenyl" refers to an unsaturated hydrocarbon ring system, that is not aromatic, containing 3, 4, 5, 6, 7 or 8 carbon atoms and at least one heteroatom within the ring selected from N, O and S. For example there may be 1 , 2 or 3 heteroatoms, optionally 1 or 2. The "C3-8 heterocycloalkenyl" may be bonded to the rest of the molecule through any carbon atom or heteroatom. The "C3-8 heterocycloalkenyl" may have one or more, e.g. one or two, bonds to the rest of the molecule: these bonds may be through any of the atoms in the ring. For example, the "C3-8 heterocycloalkyl" may be tetrahydropyridine, dihydropyran, dihydrofuran, pyrroline. [0093] The term "aromatic" when applied to a substituent as a whole means a single ring or polycyclic ring system with 4n + 2 electrons in a conjugated π system within the ring or ring system where all atoms contributing to the conjugated π system are in the same plane. [0094] The term "aryl" refers to an aromatic hydrocarbon ring system. The ring system has 4n +2 electrons in a conjugated π system within a ring where all atoms contributing to the conjugated π system are in the same plane. For example, the "aryl" may be phenyl and naphthyl. The aryl system itself may be substituted with other groups. [0095] The term "heteroaryl" refers to an aromatic hydrocarbon ring system with at least one heteroatom within a single ring or within a fused ring system, selected from O, N and S. The ring or ring system has 4n +2 electrons in a conjugated π system where all atoms contributing to the conjugated π system are in the same plane. For example, the "heteroaryl" may be imidazole, thiene, furane, thianthrene, pyrrol, benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine and indole.

[0096] The term "alkaryl" refers to an aryl group, as defined above, bonded to a C1-4 alkyl, where the Ci-4 alkyl group provides attachment to the remainder of the molecule.

[0097] The term "alkheteroaryl" refers to a heteroaryl group, as defined above, bonded to a

Ci-4 alkyl, where the alkyl group provides attachment to the remainder of the molecule. [0098] The term "halogen" herein includes reference to F, CI, Br and I. Halogen may be CI.

Halogen may be F.

[0099] A bond terminating in a " " represents that the bond is connected to another atom that is not shown in the structure. A bond terminating inside a cyclic structure and not terminating at an atom of the ring structure represents that the bond may be connected to any of the atoms in the ring structure where allowed by valency.

[00100] Where a moiety is substituted, it may be substituted at any point on the moiety where chemically possible and consistent with atomic valency requirements. The moiety may be substituted by one or more substituents, e.g. 1 , 2, 3 or 4 substituents; optionally there are 1 or 2 substituents on a group. Where there are two or more substituents, the substituents may be the same or different. The substituent(s) may be selected from: OH, NHR⁹, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, C(0)H, acyl, acyloxy, carboxy, sulfo, sulfamoyl, carbamoyl, cyano, azo, nitro, halo, Ci-e alkyl, Ci-e alkoxy, Ci-e haloalkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl or alkaryl. Where the group to be substituted is an alkyl group the substituent may be =0. Where the moiety is substituted with two or more substituents and two of the substituents are adjacent the adjacent substituents may form a C4-8 ring along with the atoms of the moiety on which the substituents are substituted, wherein the C4-8 ring is a saturated or unsaturated hydrocarbon ring with 4, 5, 6, 7, or 8 carbon atoms or a saturated or unsaturated hydrocarbon ring with 4, 5, 6, 7, or 8 carbon atoms and 1 , 2 or 3 heteroatoms. [00101] Substituents are only present at positions where they are chemically possible, the person skilled in the art being able to decide (either experimentally or theoretically) without inappropriate effort which substitutions are chemically possible and which are not.

[00102] Ortho, meta and para substitution are well understood terms in the art. For the absence of doubt, "ortho" substitution is a substitution pattern where adjacent carbons possess a substituent, whether a simple group, for example the fluoro group in the example below, or other portions of the molecule, as indicated by the bond ending in " ".

[00103] "Meta" substitution is a substitution pattern where two substituents are on carbons one carbon removed from each other, i.e with a single carbon atom between the substituted carbons. In other words there is a substituent on the second atom away from the atom with another substituent. For example the groups below are meta substituted.

[00104] "Para" substitution is a substitution pattern where two substituents are on carbons two carbons removed from each other, i.e with two carbon atoms between the substituted carbons. In other words there is a substituent on the third atom away from the atom with another substituent. For example the groups below are para substituted.

[00105] By "acyl" is meant an organic radical derived from, for example, an organic acid by the removal of the hydroxyl group, e.g. a radical having the formula R-C(O)-, where R may be selected from H, Ci-6 alkyl, C3-8 cycloalkyl, phenyl, benzyl or phenethyl group, eg R is H or C1-3 alkyl. In one embodiment acyl is alkyl-carbonyl. Examples of acyl groups include, but are not limited to, formyl, acetyl, propionyl and butyryl. A particular acyl group is acetyl.

[00106] Throughout the description the disclosure of a compound also encompasses

pharmaceutically acceptable salts, solvates and stereoisomers thereof. Where a compound has a stereocentre, both (R) and (S) stereoisomers are contemplated by the invention, equally mixtures of stereoisomers or a racemic mixture are completed by the present application. Where a compound of the invention has two or more stereocentres any combination of (R) and (S) stereoisomers is contemplated. The combination of (R) and (S) stereoisomers may result in a diastereomeric mixture or a single diastereoisomer. The compounds of the invention may be present as a single stereoisomer or may be mixtures of stereoisomers, for example racemic mixtures and other enantiomeric mixtures, and diasteroemeric mixtures. Where the mixture is a mixture of enantiomers the enantiomeric excess may be any of those disclosed above. Where the compound is a single stereoisomer the compounds may still contain other diasteroisomers or enantiomers as impurities. Hence a single stereoisomer does not necessarily have an enantiomeric excess (e.e.) or diastereomeric excess (d.e.) of 100% but could have an e.e. or d.e. of about at least 85%

[00107] The invention contemplates pharmaceutically acceptable salts of the compounds of formula (I). These may include the acid addition and base salts of the compounds. These may be acid addition and base salts of the compounds. In addition the invention contemplates solvates of the compounds. These may be hydrates or other solvated forms of the compound.

[00108] Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 1 ,5- naphthalenedisulfonate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts. [00109] Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts. For a review on suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[00110] Pharmaceutically acceptable salts of compounds of formula (I) may be prepared by one or more of three methods:

(i) by reacting the compound of formula (I) with the desired acid or base;

(ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of formula (I) or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or

(iii) by converting one salt of the compound of formula (I) to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column.

[0011 1] All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised. [00112] The compounds of the invention may exist in both unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water. [00113] Included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non- stoichiometric amounts. The resulting complexes may be ionised, partially ionised, or non- ionised. For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975).

[00114] Hereinafter all references to compounds of any formula include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.

[00115] The compounds of the invention include compounds of a number of formula as herein defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labeled compounds of the invention.

[00116] Before purification, the compounds of the present invention may exist as a mixture of enantiomers depending on the synthetic procedure used. The enantiomers can be separated by conventional techniques known in the art. Thus the invention covers individual enantiomers as well as mixtures thereof.

[00117] For some of the steps of the process of preparation of the compounds of formula (I), it may be necessary to protect potential reactive functions that are not wished to react, and to cleave said protecting groups in consequence. In such a case, any compatible protecting radical can be used. In particular methods of protection and deprotection such as those described by T.W.

GREENE (Protective Groups in Organic Synthesis, A. Wiley- Interscience Publication, 1981) or by P. J. Kocienski (Protecting groups, Georg Thieme Verlag, 1994), can be used. All of the above reactions and the preparations of novel starting materials used in the preceding methods are conventional and appropriate reagents and reaction conditions for their performance or preparation as well as procedures for isolating the desired products will be well-known to those skilled in the art with reference to literature precedents and the examples and preparations hereto.

[00118] Also, the compounds of the present invention as well as intermediates for the preparation thereof can be purified according to various well-known methods, such as for example

crystallization or chromatography.

[00119] The method of treatment or the compound for use in the treatment of cancer, lymphoma, leukemia or immunological diseases as defined hereinbefore may be applied as a sole therapy or be a combination therapy with an additional active agent. [00120] The method of treatment or the compound for use in the treatment of cancer, lymphoma or leukemia may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumor agents:

(i) antiproliferative/antineoplastic drugs and combinations thereof, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, bendamustin, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, pemetrexed, cytosine arabinoside, and hydroxyurea); antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere and polokinase inhibitors); proteasome inhibitors, for example carfilzomib and bortezomib; interferon therapy; and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan, mitoxantrone and camptothecin);

(ii) cytostatic agents such as antiestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a-reductase such as finasteride;

(iii) anti-invasion agents, for example dasatinib and bosutinib (SKI-606), and metalloproteinase inhibitors, inhibitors of urokinase plasminogen activator receptor function or antibodies to

Heparanase;

(iv) inhibitors of growth factor function: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies, for example the anti-erbB2 antibody trastuzumab [Herceptin™], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab, tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as gefitinib, erlotinib and 6-acrylamido-/V-(3-chloro-4- fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; modulators of protein regulators of cell apoptosis (for example Bcl-2 inhibitors); inhibitors of the platelet-derived growth factor family such as imatinib and/or nilotinib (AMN107); inhibitors of serine/threonine kinases (for example Ras/Raf signalling inhibitors such as farnesyl transferase inhibitors, for example sorafenib , tipifarnib and lonafarnib), inhibitors of cell signalling through MEK and/or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1 R kinase inhibitors, IGF receptor, kinase inhibitors; aurora kinase inhibitors and cyclin dependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors; (v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab

(Avastin™); thalidomide; lenalidomide; and for example, a VEGF receptor tyrosine kinase inhibitor such as vandetanib, vatalanib, sunitinib, axitinib and pazopanib;

(vi) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2;

(vii) immunotherapy approaches, including for example antibody therapy such as alemtuzumab, rituximab, ibritumomab tiuxetan (Zevalin®) and ofatumumab; interferons such as interferon a; interleukins such as IL-2 (aldesleukin); interleukin inhibitors for example IRAK4 inhibitors; cancer vaccines including prophylactic and treatment vaccines such as HPV vaccines, for example

Gardasil, Cervarix, Oncophage and Sipuleucel-T (Provenge); and toll-like receptor modulators for example TLR-7 or TLR-9 agonists; and

(viii) cytotoxic agents for example fludaribine (fludara), cladribine, pentostatin (Nipent™);

(ix) steroids such as corticosteroids, including glucocorticoids and mineralocorticoids, for example aclometasone, aclometasone dipropionate, aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasol propionate, cloprednol, cortisone, cortisone acetate, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate, difluorocortolone, fluclorolone, flumethasone, flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluorocortisone, fluorocortolone, fluocortolone caproate, fluocortolone pivalate, fluorometholone, fluprednidene, fluprednidene acetate, flurandrenolone, fluticasone, fluticasone propionate, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone valerate, icomethasone, icomethasone enbutate, meprednisone, methylprednisolone, mometasone paramethasone, mometasone furoate monohydrate, prednicarbate, prednisolone, prednisone, tixocortol, tixocortol pivalate, triamcinolone, triamcinolone acetonide, triamcinolone alcohol and their respective pharmaceutically acceptable derivatives. A combination of steroids may be used, for example a combination of two or more steroids mentioned in this paragraph;

(x) targeted therapies, for example PI3Kd inhibitors, for example idelalisib and perifosine.

[00121] The method of treatment or the compound for use in the treatment of immunological diseases may involve, in addition to the compound of the invention, additional active agents. The additional active agents may be one or more active agents used to treat the condition being treated by the compound of formula (I) and additional active agent. The additional active agents may include one or more of the following active agents:-

(i) steroids such as corticosteroids, including glucocorticoids and mineralocorticoids, for example aclometasone, aclometasone dipropionate, aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasol propionate, cloprednol, cortisone, cortisone acetate, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate, difluorocortolone, fluclorolone, flumethasone, flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluorocortisone, fluorocortolone, fluocortolone caproate, fluocortolone pivalate, fluorometholone, fluprednidene, fluprednidene acetate, flurandrenolone, fluticasone, fluticasone propionate, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone valerate, icomethasone, icomethasone enbutate, meprednisone, methylprednisolone, mometasone paramethasone, mometasone furoate monohydrate, prednicarbate, prednisolone, prednisone, tixocortol, tixocortol pivalate, triamcinolone, triamcinolone acetonide, triamcinolone alcohol and their respective pharmaceutically acceptable derivatives. A combination of steroids may be used, for example a combination of two or more steroids mentioned in this paragraph;

(ii) TNF inhibitors for example etanercept; monoclonal antibodies (e.g. infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi)); fusion proteins (e.g. etanercept (Enbrel)); and 5-ΗΪ2Α agonists (e.g. 2,5-dimethoxy-4-iodoamphetamine, TCB-2, lysergic acid diethylamide (LSD), lysergic acid dimethylazetidide);

(iii) anti-inflammatory drugs, for example non-steroidal anti-inflammatory drugs;

(iv) dihydrofolate reductase inhibitors/antifolates, for example methotrexate, trimethoprim, brodimoprim, tetroxoprim, iclaprim, pemetrexed, ralitrexed and pralatrexate; and

(v) immunosuppressants for example cyclosporins, tacrolimus, sirolimus pimecrolimus, angiotensin II inhibitors (e.g. Valsartan, Telmisartan, Losartan, Irbesatan, Azilsartan, Olmesartan, Candesartan, Eprosartan) and ACE inhibitors e.g. sulfhydryl-containing agents (e.g. Captopril, Zofenopril), dicarboxylate-containing agents (e.g. Enalapril, Ramipril, Quinapril, Perindopril, Lisinopril, Benazepril, Imidapril, Zofenopril, Trandolapril), phosphate-containing agents (e.g.

Fosinopril), casokinins, lactokinins and lactotripeptides.

[00122] Such combination treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention within a therapeutically effective dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.

[00123] According to a further aspect of the invention there is provided a pharmaceutical product comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof as defined hereinbefore and an additional active agent. The additional active agent may be an anti- tumour agent as defined hereinbefore for the combination treatment of a condition modulated by BTK.

[00124] According to a further aspect of the invention there is provided a method of treatment a condition modulated by BTK comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof simultaneously, sequentially or separately with an additional anti-tumor agent, as defined hereinbefore, to a patient in need thereof.

[00125] According to a further aspect of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof for use simultaneously, sequentially or separately with an additional anti-tumour agent as defined hereinbefore, in the treatment of a condition modulated by BTK.

[00126] According to another aspect of the invention there is provided a use of the compound of formula (I) in combination with an anti-tumor agent as hereinbefore described. The compound of formula (I) may be used simultaneously, sequentially or separately with the additional anti-tumor agent The use may be in a single combination product comprising the compound of formula (I) and the anti-tumor agent.

[00127] According to a further aspect there is provided a method of providing a combination product, wherein the method comprises providing a compound of formula (I) simultaneously, sequentially or separately with an anti-tumor agent, as defined hereinbefore. The method may comprise combining the compound of formula (I) and the anti-tumor agent in a single dosage form. Alternatively the method may comprise providing the anti-tumor agent as separate dosage forms.

[00128] According to a further aspect there is provided a method of providing a combination product, wherein the method comprises providing a compound of formula (I) simultaneously, sequentially or separately with an anti-tumor agent, as defined hereinbefore. The method may comprise combining the compound of formula (I) and the anti-tumor agent in a single dosage form. Alternatively the method may comprise providing the anti-tumor agent as separate dosage forms.

[00129] The condition modulated by BTK described above may be cancer, leukemia or cancer. More specifically the condition modulated by BTK may be selected from: B-cell malignancy, B-cell lymphoma, diffuse large B cell lymphoma, chronic lymphocyte leukemia, non-Hodgkin lymphoma for example ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B-cell non- Hodgkin lymphoma, Waldenstrom's macroglobulinemia and multiple myeloma.

[00130] Compounds of the invention may exist in a single crystal form or in a mixture of crystal forms or they may be amorphous. Thus, compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, or spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.

[00131] For the above-mentioned compounds of the invention the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. For example, if the compound of the invention is administered orally, then the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight ( g/kg) to 100 milligrams per kilogram body weight (mg/kg). [00132] A compound of the invention, or pharmaceutically acceptable salt thereof, may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the compounds of the invention, or pharmaceutically acceptable salt thereof, is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example,

"Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.

[00133] Depending on the mode of administration of the compounds of the invention, the pharmaceutical composition which is used to administer the compounds of the invention will preferably comprise from 0.05 to 99 %w (per cent by weight) compounds of the invention, more preferably from 0.05 to 80 %w compounds of the invention, still more preferably from 0.10 to 70 %w compounds of the invention, and even more preferably from 0.10 to 50 %w compounds of the invention, all percentages by weight being based on total composition.

[00134] The pharmaceutical compositions may be administered topically (e.g. to the skin) in the form, e.g., of creams, gels, lotions, solutions, suspensions, or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of a sterile solution, suspension or emulsion for injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion); by rectal administration in the form of suppositories; or by inhalation in the form of an aerosol.

[00135] For oral administration the compounds of the invention may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.

Alternatively, the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.

[00136] For the preparation of soft gelatine capsules, the compounds of the invention may be admixed with, for example, a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the compound using either the above-mentioned excipients for tablets. Also liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules. Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, sweetening agents (such as saccharine), preservative agents and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art. [00137] For intravenous (parenteral) administration the compounds of the invention may be administered as a sterile aqueous or oily solution.

[00138] The size of the dose for therapeutic purposes of compounds of the invention will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.

[00139] Dosage levels, dose frequency, and treatment durations of compounds of the invention are expected to differ depending on the formulation and clinical indication, age, and co-morbid medical conditions of the patient. The standard duration of treatment with compounds of the invention is expected to vary between one and seven days for most clinical indications. It may be necessary to extend the duration of treatment beyond seven days in instances of recurrent infections or infections associated with tissues or implanted materials to which there is poor blood supply including bones/joints, respiratory tract, endocardium, and dental tissues.

[00140]

EXAMPLES AND SYNTHESIS

[00141] As used herein the following terms have the meanings given: "Boc" refers to tert- butoxycarbonyl; "DCM" refers to dichloromethane; "DIPEA" refers to A/,/V-Diisopropylethylamine; "LCMS" refers to liquid chromatography/mass spectrometry; "MIM" refers to monoisotopic mass; "min" refers to minutes; "NMP" refers to /V-methylpyrrolidinone; "TLC" refers to thin layer chromatography; "Rf refers to Retention factor; "RT" refers to retention time; "SCX" refers to strong cation exchange; "TFA" refers to trifluoroacetic acid; "THF" refers to tetrahydrofuran; and "TBME" refers to fe/f-Butyl methyl ether.

[00142] All LCMS analyses were carried out on a Waters Acquity SQ Detector 2 with two 0.2 μηι guard filters using a UPLC Column (C18, 50 x 2.1 mm, < 2μη-ι). Mobile phase A was 0.1 % (v/v) formic acid in water and mobile phase B was 0.1 % (v/v) formic acid in acetonitrile. Flow rate was 0.6 ml/min, back pressure ca <8000 psi. Injection volume was 2 and temperature was 40 °C. Run time was 3 min for short acidic and 8 min for lon acidic. The Gradient was:

[00143] The compounds of the present invention may be synthesised by analogy with the following reaction route.

[00144] General procedure A: Synthesis of pinacol boronate esters

[00145] To a solution of 4-aminomethylphenylboronic acid pinacol ester (1.1 eq.), DMAP (0.4 eq.), and DIPEA (1.0 eq.) in DCM (0.16 M), cooled to 0 °C under a nitrogen atmosphere, was added dropwise the corresponding sulfonyl chloride (1.0 eq.). The reaction mixture was stirred at 0 °C for 20 min, then allowed to return to room temperature and stirred overnight. The mixture was concentrated and the residue was dissolved in ethyl acetate and then washed with hydrochloric acid solution (0.5 M) and the organic washed with brine. The organic layer was dried over Na2S04, filtered and then concentrated under reduced pressure to afford the desired boronate ester. No further purification was attempted and the product was used directly in the next step.

[00146] General procedure B: Synthesis of boronic acids

[00147] To a suspension of [4-(aminomethyl)phenyl]boronic acid hydrochloride (1.1 eq.) and N,N- diisopropylethylamine (2.0 eq.) in anhydrous THF (0.1 M) , cooled to 0 °C, was added dropwise the corresponding sulfonyl chloride (1.0 eq.) under a nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 1 h, then at room temperature for 2 h. The reaction was quenched with hydrochloric acid solution (0.5 M) and extracted with EtOAc (3 ^χ). The combined organic extracts were washed with brine (1 ^χ), then dried over Na2S04, filtered, and concentrated under reduced pressure to afford the desired boronic acid. No further purification was attempted and the product was used as such in the next step.

[00148] General procedure C: Suzuki cross-coupling (Thermal)

[00149] A mixture of fe/f-butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-rf]pyrimidin-1-yl)piperidine-1- carboxylate (1 .0 eq.), boronic acid or pinacol ester (1.5 eq.) and potassium carbonate (2.0 eq.) in 1 ,4-dioxane and water (3: 1 , 0.1 M) was degassed by bubbling nitrogen through it for 25 min. 1 ,1 '- Jb/^'s(Diphenylphosphino)ferrocene-palladium(ll) dichloride dichloromethane complex (0.05 eq.) was added and the mixture was degassed again by bubbling nitrogen through it for 30 min. The mixture was then heated under reflux for 14 h. The reaction mixture was filtered over Celite®. The residue was rinsed with DCM. Water was added to the filtrate and the layers were partitioned. The aqueous layer was extracted with DCM (2 χ) . The combined organic extracts were filtered using a phase separator and concentrated under reduced pressure to give a residue which was further purified by flash column chromatography (DCM/MeOH 1 00:0 to 90:1 0) to give the desired compound.

[00150] General procedure D: Suzuki cross-coupling (Microwave irradiation)

[00151] A mixture of fe/f-butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-rf]pyrimidin-1 -yl)piperidine-1 - carboxylate (1 .0 eq.), boronic acid or pinacol ester (1 .5 eq.) and potassium carbonate (2.0 eq.) in 1 ,4-dioxane and water (3: 1 , 0.1 M) was degassed by bubbling nitrogen through it for 1 5 min. 1 ,1 '- Jb/^'s(diphenylphosphino)ferrocene-palladium(ll) dichloride dichloromethane complex (0.05 eq.) was added and the mixture was degassed again by bubbling nitrogen through it for 15 min. The mixture was then heated under microwave irradiation for 90 min. The reaction mixture was filtered over Celite® and the residue was rinsed with DCM. Water was added to the filtrate and the layers were partitioned. The aqueous layer was extracted with DCM (2 χ) . The combined organic extracts were filtered over a phase separator and then concentrated under reduced pressure and the residue further purified by flash column chromatography (DCM/MeOH 100:0 to 90:10) to give the desired compound.

[00152] General procedure E: Boc-Removal

[00153] To a solution of Boc-protected amine (1 .0 eq.) in dry methanol (0.7 M) under a nitrogen atmosphere was added hydrogen chloride solution (4.0 M in 1 ,4-dioxane, 20-30 eq.). The reaction mixture was stirred at room temperature overnight, and concentrated under reduced pressure to give the crude product. Further purification by flash column chromatography (DCM/7N ammonia in MeOH 100:0 to 95:5) gave, after further drying, the desired compound.

[00154] General procedure F: Final coupling

[00155] To a suspension of deprotected amine (1 .0 eq.) and acrylic acid (1 .0 eq.) in anhydrous THF (0.3 M) under a nitrogen atmosphere were added successively A/,/V-diisopropylethylamine (3.0 eq.) and propylphosphonic anhydride (≥50 wt. % in EtOAc, 1 .5 eq.). The reaction mixture was stirred overnight at room temperature, then diluted with water and DCM. The layers were partitioned and the aqueous layer further extracted with DCM (2 χ) . The combined organic extracts were filtered over a phase separator and concentrated to give a foam which was further purified by flash column chromatography (EtOAc/MeOH 100:0 to 90: 10) to give, after further drying , the title compound.

[00156] Example 1 : Af-[[4-[4-Amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- o(|pyrimidin-3-yl]phenyl]methyl]methanesulfonamide [00157] fe/f-Butyl (3 ?)-3-[4-amino-3-[4-(methanesulfonamidomethyl)phenvnpyrazolo [3,4- tflpyrimidin-1 -yllpiperidine-1 -carboxylate

[00158] Following general procedure D, fe/f-butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-rf]pyrimidin- 1 -yl)piperidine-1 -carboxylate (200.0 mg , 0.45 mmol) and [4- (methanesulfonamidomethyl)phenyl]boronic acid (134.1 mg , 0.59 mmol) afforded fe/f-butyl (3R)-3- [4-amino-3-[4-(methanesulfonamidomethyl)phenyl]pyrazolo[3,4-rf]pyrimidin-1 -yl]piperidine-1 - carboxylate (218.0 mg, 0.43 mmol, 97% yield) as a brown gum.

UPLC-MS (ES⁺, Short acidic): 1 .46 min, m/z 502.4 [M+H]⁺

[00159] /V-[[4-[4-Amino-1 -[(3f?)-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3-yllphenyllmethyll methanesulfonamide

[00160] Following general procedure E, fe/f-butyl (3R)-3-[4-amino-3-[4- (methanesulfonamidomethyl)phenyl]pyrazolo[3,4-rf]pyrimidin-1 -yl]piperidine-1 -carboxylate

(217.0 mg, 0.43 mmol) afforded /V-[[4-[4-amino-1 -[(3f?)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3- yl]phenyl]methyl]methanesulfonamide (1 1 1 .0 mg, 0.25 mmol, 58% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 0.91 min, m/z 402.3 [M+H]⁺

[00161] /V-[[4-[4-Amino-1 -[(3f?)-1 -prop-2-enoyl-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3- yllphenyllmethyllmethanesulfonamide

[00162] Following general procedure F, A/-[[4-[4-amino-1 -[(3R)-3-piperidyl]pyrazolo[3,4- rf]pyrimidin-3-yl]phenyl]methyl]methanesulfonamide (1 1 1 .0 mg , 0.25 mmol) gave, after purification by preparative HPLC /V-[[4-[4-amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4-rf]pyrimidin-3- yl]phenyl]methyl]methanesulfonamide (4.0 mg, 0.01 mmol, 3% yield).

[00163] UPLC-MS (ES⁺, Short acidic): 1 .15 min, m/z 456.3 [M+H]⁺

[00164] UPLC-MS (ES⁺, Long acidic): 2.55 min, m/z 456.4 [M+H]⁺

[00165] H-NMR (400 MHz, DMSO-d₆) δ (ppm, 1 :1 mixture of conformers) 8.27 (s, 1 H, ArH), 7.69- 7.61 (m, 3H, NH + 2 ArH), 7.52 (d, ³ J 8.3 Hz, 2H, 2 ArH), 7.35-6.63 (m, 2H), 6.86 (dd, ¾_rans 16.5, ^zJcis 10.5 Hz, 0.5H), 6.71 (dd, ¾_rans 16.4, ¼_s 10.4 Hz, 0.5H), 6.13 (d, ¾_rans 16.4 Hz, 0.5H), 6.06 (d, ^zJtrans 16.4 Hz, 0.5H), 5.71 (d, ³J_C(S 10.4 Hz, 0.5H), 5.59 (d, ³J_C(S 10.4 Hz, 0.5H), 4.78-4.64 (m, 1 H, CH), 4.59-4.50 (m, 0.5H), 4.25 (d, ³J 6.4 Hz, 2H, CH₂), 4.24-4.15 (m, 1 H), 4.1 1 -4.03 (m, 0.5H), 3.76-3.66 (m, 0.5H), 3.27-3.14 (m, 1 H), 3.07-2.94 (m, 0.5H), 2.91 (s, 3H, CH₃) 2.34-2.21 (m, 1 H), 2.17-2.07 (m, 1 H), 1 .98-1 .88 (m, 1 H), 1 .71 -1 .50 (m, 1 H).

[00166] Example 2: Af-[[4-[4-Amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- o(|pyrimidin-3-yl]phenyl]methyl]ethanesulfonamide

[00167] /V-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyll ethanesulfonamide

[00168] Following general procedure A, 4-aminomethylphenylboronic acid, pinacol ester

(299.1 mg, 1 .28 mmol) and ethanesulfonyl chloride (0.1 1 mL, 1 .17 mmol) afforded Λ/-[[4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]ethanesulfonamide (320.0 mg, 0.98 mmol, 84% yield) as an orange oil.

[00169] UPLC-MS (ES⁺, Short acidic): 1.71 min, m/z 348.3 [M+Na]⁺

[00170] fe/f-Butyl (3f?)-3-[4-amino-3-[4-[(ethylsulfonylamino)methyllphenyll pyrazolo[3,4- tflpyrimidin-1 -yllpiperidine-1 -carboxylate

[00171] Following general procedure D, A/-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]ethanesulfonamide (170.1 mg, 0.52 mmol) and fe/f-butyl (3R)-3-(4-amino-3-iodo- pyrazolo[3,4-rf]pyrimidin-1-yl)piperidine-1-carboxylate (193.7 mg, 0.44 mmol) gave fe/f-butyl (3R)-3- [4-amino-3-[4-[(ethylsulfonylamino)methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1-yl]piperidine-1- carboxylate (200.0 mg, 0.34 mmol, 78% yield) as a brown solid.

[00172] UPLC-MS (ES⁺, Short acidic): 1.51 min, m/z 516.4 [M+H]⁺

[00173] /V-[[4-[4-Amino-1-[(3f?)-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3-yllphenyll

methyllethanesulfonamide

[00174] Following general procedure E, fe/f-butyl (3R)-3-[4-amino-3-[4- [(ethylsulfonylamino)methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1 -yl]piperidine-1 -carboxylate (147.0 mg , 0.29 mmol) gave A/-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-rf]pyrimidin-3- yl]phenyl]methyl]ethanesulfonamide (92.2 mg, 0.20 mmol, 71 % yield) as a white solid.

[00175] UPLC-MS (ES⁺, Short acidic): 0.95 min, m/z 416.3 [M+H]⁺

[00176] /V-[[4-[4-Amino-1-[(3f?)-1-prop-2-enoyl-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3- yllphenyllmethyllethanesulfonamide

[00177] Following general procedure F, A/-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4- rf]pyrimidin-3-yl]phenyl]methyl]ethanesulfonamide (90.0 mg, 0.22 mmol) afforded A/-[[4-[4-amino-1- [(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-rf]pyrimidin-3-yl]phenyl]methyl]ethanesulfonamide (35.0 mg, 0.07 mmol, 34% yield).

[00178] UPLC-MS (ES⁺, Short acidic): 1.20 min, m/z 470.4 [M+H]⁺

[00179] H-NMR (400 MHz, CDCI₃) δ (ppm, 1 :1 mixture of conformers) 11.47 (s, 1 H), 8.29 (s, 1 H, ArH), 7.62 (d, ³ J 8.2 Hz, 2H, ArH), 7.57 (d, ³ J 8.2 Hz, 2H, ArH), 6.67-6.22 (m, 3H), 5.80-5.65 (m, 1 H), 5.46-5.27 (m, 1 H), 4.97-4.84 (m, 1 H, CH), 4.83-4.73 (m, 1 H), 4.61-4.46 (m, 0.5H), 4.38 (s, 2H, CH₂), 4.25-4.13 (m, 0.5H), 4.08-3.96 (m, 1 H), 3.84-3.70 (m, 0.5H), 3.49-3.38 (m, 0.5H), 3.32-3.21 (m, 2H), 3.06 (q, J 7.3 Hz, 2H, CH₂), 3.04-2.88 (m, 1 H), 2.46-2.21 (m, 2H), 2.11 -1.97 (m, 1 H), 1.80- 1.65 (m, 1 H), 1.38 (t, J 7.3 Hz, 3H, CH₃).

[00180] Example 3: Af-[[4-[4-Amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- o(|pyrimidin-3-yl]phenyl]methyl]cyclohexanesulfonamide

[00181] /V-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyllcyclohexanesulfonamide [00182] Following general procedure A, 4-aminomethylphenylboronic acid pinacol ester

(140.4 mg, 0.60 mmol), and cyclohexanesulfonyl chloride (0.07 ml_, 0.55 mmol) yielded Λ/-[[4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]cyclohexanesulfonamide (126.0 mg, 0.33 mmol, 61 % yield) as an orange solid.

[00183] UPLC-MS (ES⁺, Short acidic): 1 .96 min, m/z 380.3 [M+H]⁺, 403.3 [M+Na]⁺

[00184] fe/f-Butyl (3 ?)-3-[4-amino-3-[4-[(cvclohexylsulfonylamino)methyllphenyllpyrazolo[3,4- clpyrimidin-1 -yllpiperidine-1 -carboxylate

[00185] Following general procedure D, A/-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]cyclohexanesulfonamide (179.3 mg, 0.47 mmol) and fe/f-butyl (3R)-3-(4-amino-3- iodo-pyrazolo[3,4-c]pyrimidin-1 -yl)piperidine-1 -carboxylate (175.0 mg , 0.39 mmol) gave fe/f-butyl (3R)-3-[4-amino-3-[4-[(cyclohexylsulfonylamino)methyl]phenyl]pyrazolo[3,4-c]pyrimidin-1 - yl]piperidine-1 -carboxylate (185.0 mg, 0.32 mmol, 82% yield) as a brown oil.

[00186] UPLC-MS (ES⁺, Short acidic): 1 .74 min, m/z 570.5 [M+H]⁺

[00187] /V-[[4-[4-Amino-1 -[(3f?)-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3- yllphenyllmethyllcyclohexanesulfonamide

[00188] Following general procedure E, fe/f-butyl (3R)-3-[4-amino-3-[4- [(cyclohexylsulfonylamino)methyl]phenyl]pyrazolo[3,4-c]pyrimidin-1 -yl]piperidine-1 -carboxylate (180.0 mg, 0.32 mmol) gave A/-[[4-[4-amino-1 -[(3f?)-3-piperidyl]pyrazolo[3,4-c]pyrimidin-3- yl]phenyl]methyl]cyclohexanesulfonamide (25.0 mg, 0.05 mmol, 17% yield) as a clear film.

[00189] UPLC-MS (ES⁺, Short acidic): 1 .18 min, m/z 470.4 [M+H]⁺

[00190] /V-[[4-[4-Amino-1 -[(3f?)-1 -prop-2-enoyl-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3- yllphenyllmethyllcyclohexanesulfonamide

[00191] Following general procedure F, A/-[[4-[4-amino-1 -[(3R)-3-piperidyl]pyrazolo[3,4- c]pyrimidin-3-yl]phenyl]methyl]cyclohexanesulfonamide (25.0 mg, 0.05 mmol) afforded, after purification by preparative HPLC, A/-[[4-[4-amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- c]pyrimidin-3-yl]phenyl]methyl]cyclohexanesulfonamide (3.8 mg , 0.01 mmol, 13% yield) as an off- white gum.

[00192] UPLC-MS (ES⁺, Short acidic): 1 .43 min, m/z 524.5 [M+H]⁺

[00193] UPLC-MS (ES⁺, Long acidic): 3.24 min, m/z 524.5 [M+H]⁺

[00194] H-NMR (400 MHz, DMSO-c₆) δ (ppm, 1 :1 mixture of conformers) 8.27 (s, 1 H, ArH), 7.65 (d, ³J 8. 1 Hz, 2H, 2 ArH), 7.64 (dd, J 1 1 .2, 6.4 Hz, 1 H), 7.52 (d, ³J 8.3 Hz, 2H, 2 ArH), 6.87 (dd, ^zJtrans 16.7, ¼_s 10.6 Hz, 0.5H), 6.71 (dd, ¾._a„s 16.4, ³J_C(S 10.3 Hz, 0.5H), 6.1 3 (d, ¾_rans 16.4 Hz, 0.5H), 6.13 (~d, ^zJtrans 16.9 Hz, 0.5H), 5.71 (~d, ¼_s 10.6 Hz, 0.5H), 5.58 (d, ³J_C(S 10.4 Hz, 0.5H), 4.80-4.63 (m, 1 H, CH), 4.60-4.49 (m, 0.5H), 4.24 (d, J 6.1 Hz, 2H, CH₂), 4.24-4.15 (m, 1 H), 4.12- 4.02 (m, 0.5H), 3.77-3.66 (m, 0.5H), 3.52-3.14 (m, 4H), 3.08-2.96 (m, 0.5H), 2.88 (tt, J 1 1 .7, 3.2 Hz, 1 H), 2.32-2.20 (m, 1 H), 2.18-2.08 (m, 1 H), 2.06-2.00 (m, 2H), 1.97-1.89 (m, 1 H), 1 .82-1.72 (m, 2H), 1.67-1.51 (m, 2H), 1.44-1.28 (m, 2H), 1 .27-1.04 (m, 3H).

[00195] Example 4: Af-[[4-[4-Amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- o(|pyrimidin-3-yl]phenyl]methyl]benzenesulfonamide

[00196] A/-[[4-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyllbenzenesulfonamide

[00197] Following general procedure A, 4-aminomethylphenylboronic acid pinacol ester

(264.0 mg, 1.13 mmol) and benzenesulfonyl chloride (0.14 ml_, 1.13 mmol) gave Λ/-[[4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]benzenesulfonamide (181.0 mg,0.48 mmol, 43% yield).

[00198] UPLC-MS (ES⁺, short acidic): 1.94 min, m/z 396.3 [M+Na]⁺

[00199] fe/f-Butyl (3 ?)-3-[4-amino-3-[4-(benzenesulfonamidomethyl)phenyllpyrazolo[3,4- tflpyrimidin-1 -yllpiperidine-1 -carboxylate

[00200] Following general procedure D, fe/f-butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-rf]pyrimidin- 1-yl)piperidine-1-carboxylate (190.0 mg, 0.43 mmol), and A/-[[4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl]methyl]benzenesulfonamide (191 .6 mg, 0.51 mmol) gave fe/f-butyl (3R)-3- [4-amino-3-[4-(benzenesulfonamidomethyl)phenyl]pyrazolo[3,4-rf]pyrimidin-1-yl]piperidine-1- carboxylate (210.0 mg, 0.37 mmol, 87% yield) as a brown oil.

[00201] UPLC-MS (ES⁺, short acidic): 1.69 min, m/z 564.4 [M+H]⁺

[00202] /V-[[4-[4-Amino-1-[(3f?)-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3-yllphenyllmethyll benzenesulfonamide

[00203] Following general procedure E, fe/f-butyl (3R)-3-[4-amino-3-[4- (benzenesulfonamidomethyl)phenyl]pyrazolo[3,4-rf]pyrimidin-1-yl]piperidine-1-carboxylate

(210.0 mg, 0.37 mmol) gave A/-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-rf]pyrimidin-3- yl]phenyl]methyl]benzenesulfonamide (80.0 mg, 0.17 mmol, 46% yield) as a brown solid.

[00204] UPLC-MS (ES⁺, short acidic): 1.09 min, m/z 464.3 [M+H]⁺

[00205] /V-[[4-[4-Amino-1-[(3f?)-1-prop-2-enoyl-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3- yllphenyllmethyllbenzenesulfonamide

[00206] Following general procedure F, A/-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4- rf]pyrimidin-3-yl]phenyl]methyl]benzenesulfonamide (80.0 mg, 0.17 mmol) afforded, after purification, A/-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-rf]pyrimidin-3- yl]phenyl]methyl]benzenesulfonamide (26.0 mg, 0.05 mmol, 29% yield).

[00207] UPLC-MS (ES⁺, Short acidic): 1.38 min, m/z 518.4 [M+H]⁺

[00208] UPLC-MS (ES⁺, Long acidic): 3.14 min, m/z 518.4 [M+H]⁺

[00209] H-NMR (400 MHz, DMSO-d₆) δ (ppm, 1 :1 mixture of conformers) 8.31-8.23 (m, 1 H, NH), 8.26 (s, 1 H, ArH), ) 7.84-7.80 (m, 2H, 2 χ ArH), 7.66-7.53 (m, 5H, 5 χ ArH), 7.40 (d, ³ J 8.3 Hz, 2H, 2 ArH), 6.85 (dd, ¾_ra„s 16.9, ³J_C(S 10.6 Hz, 0.5H), 6.70 (dd, ¾_rans 16.9, ³J_C/S 10.6 Hz, 0.5H), 6.13 (d, ^zJtrans 16.5 Hz, 0.5H), 6.06 (d, ^zJtrans 16.5 Hz, 0.5H), 5.71 (d, ³Jcfc 10.5 Hz, 0.5H), 5.59 (d, ¼_s 10.5 Hz, 0.5H), 4.77-4.63 (m, 1 H, CH), 4.58-4.49 (m, 0.5H), 4.26-4.15 (m, 1 H), 4.09 (d, ³ J 5.6 Hz, 2H, CH₂), 3.74-3.65 (m, 0.5H), 3.25-3.15 (m, 1 H), 3.06-2.97 (m, 0.5H), 2.29-2.19 (m, 1 H), 2.16-2.07 (m, 1 H), 1 .97-1 .87 (m, 1 H), 1 .65-1 .50 (m, 1 H).

[00210] Example 5: Af-[[4-[4-Amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- d]pyrimidin-3-yl]p enyl]met yl]-4-fluoro-benzenesulfonamide

[0021 1] 4-Fluoro-/V-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- vDphenyllmethyllbenzenesulfonamide

[00212] Following general procedure A, 4-aminomethylphenylboronic acid pinacol ester

(395.3 mg, 1 .70 mmol) and and 4-fluorobenzene sulfonyl chloride (300.0 mg, 1 .54 mmol) afforded 4-fluoro-/V-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]benzenesulfonamide (482.0 mg, 1 .23 mmol, 80% yield) as an orange solid.

[00213] UPLC-MS (ES⁺, short acidic): 1 .92 min, m/z 392.4 [M+H]⁺

[00214] fe/f-Butyl (3f?)-3-[4-amino-3-[4-[[(4-fluorophenyl)sulfonylaminolmethyllphenyllpyrazolo[3,4- tflpyrimidin-1 -yllpiperidine-1 -carboxylate

[00215] Following general procedure D, 4-fluoro-/V-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]benzenesulfonamide (21 1 .4 mg, 0.54 mmol) and fe/f-butyl (3R)-3-(4-amino-3-iodo- pyrazolo[3,4-rf]pyrimidin-1 -yl)piperidine-1 -carboxylate (200.0 mg, 0.45 mmol) gave fe/f-butyl (3R)-3- [4-amino-3-[4-[[(4-fluorophenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1 -yl]piperidine- 1 -carboxylate (235.0 mg, 0.40 mmol, 90% yield) as a brown solid.

[00216] UPLC-MS (ES⁺, short acidic): 1 .71 min, m/z 582.5 [M+H]⁺

[00217] /V-[[4-[4-Amino-1 -[(3f?)-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3-yllphenyllmethyll-4-fluoro- benzenesulfonamide

[00218] Following general procedure E, fe/f-butyl (3f?)-3-[4-amino-3-[4-[[(4- fluorophenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1 -yl]piperidine-1 -carboxylate (235.0 mg, 0.40 mmol) gave A/-[[4-[4-amino-1 -[(3R)-3-piperidyl]pyrazolo[3,4-rf]pyrimidin-3- yl]phenyl]methyl]-4-fluoro-benzenesulfonamide (153.0 mg, 0.32 mmol, 79% yield) as a brown solid.

[00219] UPLC-MS (ES⁺, short acidic): 1 .12 min, m/z 482.3 [M+H]⁺

[00220] /V-[[4-[4-Amino-1 -[(3f?)-1 -prop-2-enoyl-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3- yllphenyllmethyll-4-fluoro-benzenesulfonamide

[00221] Following general procedure F, A/-[[4-[4-amino-1 -[(3R)-3-piperidyl]pyrazolo[3,4- rf]pyrimidin-3-yl]phenyl]methyl]-4-fluoro-benzenesulfonamide (150.0 mg, 0.31 mmol) afforded Λ/-[[4- [4-amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4-rf]pyrimidin-3-yl]phenyl]methyl]-4-fluoro- benzenesulfonamide (28.0 mg, 0.05 mmol, 16%) as an off-white solid after purification by preparative HPLC. [00222] UPLC-MS (ES⁺, short acidic): 1.41 min, m/z 536.4 [M+H]⁺

[00223] UPLC-MS (ES⁺, long acidic): 3.20 min, m/z 536.4 [M+H]⁺

[00224] H-NMR (400 MHz, DMSO-d₆) δ (ppm, 1 :1 mixture of conformers) 8.30 (t, J 6.3 Hz, 1 H, NH), 8.26 (s, 1 H, ArH), 7.90-7.85 (m, 2H, 2 ArH), 7.58 (d, ³J 8.2 Hz, 2H, 2 ArH), 7.90-7.85 (m, 4H, 4 ArH), 6.86 (dd, ³J_ira„s 16.6, ³J_C/S 10.5 Hz, 0.5H), 6.71 (dd, ¾_ra„s 16.6, ³J_C(S 10.5 Hz, 0.5H), 6.13 (d, Jtrans 16.5 Hz, 0.5H), 6.05 (d, ³J,_ra„s 16.5 Hz, 0.5H), 5.70 (d, ³J_CS 10.5 Hz, 0.5H), 5.58 (d, ^zJcis 10.5 Hz, 0.5H), 4.78-4.63 (m, 1 H, CH), 4.59-4.48 (m, 0.5H), 4.27-4.13 (m, 1 H), 4.09 (d, ³J 6.2 Hz, 2H, CH₂), 4.08-4.02 (m, 0.5H), 3.75-3.65 (m,1 H, 0.5H), 3.27-3.14 (m, 1 H), 3.07-2.97 (m, 0.5H), 2.32-2.20 (m, 1 H), 2.16-2.06 (m, 1 H), 1 .98-1.87 (m, 1 H), 1.67-1.49 (m, 1 H).

[00225] Example 6: Ai-[[4-[4-Amino-1-[(3/?)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4- d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-5-(trifluoromethyl)benzenesulfonamide

[00226] 2-Fluoro-/V-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyll-5- (trifluoromethyl)benzenesulfonamide

[00227] Following general method A, 4-aminomethylphenylboronic acid pinacol ester (292.9 mg, 1.26 mmol) and 2-fluoro-5-(trifluoromethyl)benzenesulfonyl chloride (0.19 ml_, 1.14 mmol) gave 2- fluoro-/V-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]-5- (trifluoromethyl)benzenesulfonamide (413.0 mg, 0.90 mmol, 79% yield) as an orange gum.

[00228] UPLC-MS (ES-, Short acidic): 2.03 min, m/z 458.3 [M-H]-

[00229] fe/f-Butyl (3f?)-3-[4-amino-3-[4-[[[2-fluoro-5-(trifluoromethyl)phenyllsulfonylaminol methyllphenyllpyrazolo[3,4-Qlpyrimidin-1-yllpiperidine-1 -carboxylate

[00230] Following general procedure D, 2-fluoro-/V-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]-5-(trifluoromethyl)benzenesulfonamide (294.6 mg, 0.51 mmol) and fe/ -butyl-(3R)- 3-(4-amino-3-iodo-pyrazolo[3,4-rf]pyrimidin-1-yl)piperidine-1 -carboxylate (152.0 mg, 0.34 mmol) afforded fe/f-butyl (3f?)-3-[4-amino-3-[4-[[[2-fluoro-5- (trifluoromethyl)phenyl]sulfonylamino]methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1-yl]piperidine-1- carboxylate (197.8 mg, 0.21 mmol, 62% yield) as a brown oil.

[00231] UPLC-MS (ES⁺, Short acidic): 1.84 min, m/z 650.4 [M+H]⁺

[00232] /V-[[4-[4-Amino-1-[(3f?)-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3-yllphenyllmethyll-2-fluoro-5- (trifluoromethyl)benzenesulfonamide

[00233] Following general procedure E, fe/f-butyl (3f?)-3-[4-amino-3-[4-[[[2-fluoro-5-

(trifluoromethyl)phenyl]sulfonylamino]methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1-yl]piperidine-1- carboxylate (197.8 mg, 0.30 mmol) gave /V-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-rf]pyrimidin- 3-yl]phenyl]methyl]-2-fluoro-5-(trifluoromethyl)benzenesulfonamide (116.6 mg, 0.17 mmol, 56% yield) as a yellow solid.

[00234] UPLC-MS (ES⁺, Short acidic): 1.26 min, m/z 550.3 [M+H] [00235] A/-[[4-[4-Amino-1 -[(3 ?V1 -prop-2-enoyl-3-piperidyllpyrazolo[3,4-Qlpyrim yllphenyllmethyll-2-11uoro-5-(tri11uoromethyl)benzenesulfonamide

[00236] Following general procedure F, A/-[[4-[4-amino-1 -[(3R)-3-piperidyl]pyrazolo[3,4- <^pyrimidin-3-yl]phenyl]methyl]-2-fluoro-5-(trifluoromethyl)benzenesulfonamide (1 16.6 mg,

0.21 mmol) gave, after purification by preparative HPLC, A/-[[4-[4-amino-1 -[(3R)-1 -prop-2-enoyl-3- piperidyl]pyrazolo[3,4-rf]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-5-

(trifluoromethyl)benzenesulfonamide (23.8 mg, 0.04 mmol, 18% yield) as an off-white solid.

[00237] UPLC-MS (ES⁺, Short acidic): 1 .53 min, m/z 604.4 [M+H]⁺

[00238] UPLC-MS (ES⁺, Long acidic): 3.53 min, m/z 604.4 [M+H]⁺

[00239] H-NMR (400 MHz, DMSO-d₆): δ (ppm, 1 :1 mixture of conformers) 8.89 (t, J 6.2 Hz, 1 H, NH), 8.27 (s, 1 H, ArH), 8.09-8.03 (m, 1 H, ArH), 7.98-7.94 (m, 1 H, ArH), 7.66-7.59 (m, 1 H, ArH), 7.55-7.48 (m, 2H, ArH), 7.38 (d, ³J 8.2 Hz, 2H, 2 ArH), 6.87 (dd, ¾_ra„s 16.5, ³J_C(S 10.4 Hz, 0.5H), 6.70 (dd, ^zJtrans 16.5, ³Jcfc 10.4 Hz, 0.5H), 6.13 (d, ¾._a„s 16.5 Hz, 0.5H), 6.05 (d, ¾_rans 16.5 Hz, 0.5H), 5.71 (d, ³Jcfc 10.4 Hz, 0.5H), 5.58 (d, ¼_s 10.4 Hz, 0.5H), 4.78-4.63 (m, 1 H, CH), 4.59-4.49 (m, 0.5H), 4.27 (d, ³J 6.2 Hz, 2H, CH₂), 4.23-4.14 (m, 1 H), 4.12-4.04 (m, 0.5H), 3.75-3.66 (m, 0.5H), 3.26-3.18 (m, 1 H), 3.10-2.99 (m, 0.5H), 2.30-2.20 (m, 1 H), 2.17-2.07 (m, 1 H), 1 .98-1 .89 (m, 1 H), 1 .67-1 .51 (m, 1 H).

[00240] Example 7: Af-[[4-[4-Amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-benzenesulfonamide

[00241] [4-[[(2-Fluorophenyl)sulfonylaminolmethyllphenyllboronic acid

[00242] Following general procedure B, 4-(aminomethyl)phenyl]boronic acid hydrochloride (5.19 g, 27.13 mmol) and 2-fluorobenzenesulfonyl chloride (3.3 mL, 24.66 mmol) afforded [4-[[(2- fluorophenyl)sulfonylamino]methyl]phenyl]boronic acid (5.75 g, 18.60 mmol, 75% yield) as an off- white solid.

[00243] UPLC-MS (ES⁺, Short acidic): 1 .31 min, m/z 307.2, 308.1 [M+H]⁺

[00244] te/f-Butyl (3 ?)-3-[4-amino-3-[4-[[(2-fluorophenyl)sulfonylaminolmethyllphenyllpyrazolo[3,4- tflpyrimidin-1 -yllpiperidine-1 -carboxylate

[00245] Following general procedure C, a mixture of fe/f-butyl (3R)-3-(4-amino-3-iodo- pyrazolo[3,4-rf]pyrimidin-1 -yl)piperidine-1 -carboxylate (4.04 g, 9.09 mmol) and [4-[[(2- fluorophenyl)sulfonylamino]methyl]phenyl]boronic acid (4.35 g, 13.64 mmol) gave fe/ -butyl (3R)-3- [4-amino-3-[4-[[(2-fluorophenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1 -yl]piperidine- 1 -carboxylate (4.03 g, 6.93 mmol, 76% yield) as a thick oil.

[00246] UPLC-MS (ES⁺, Short acidic): 2.06 min, m/z 582.4 [M+H]⁺

[00247] /V-[[4-[4-Amino-1 -[(3f?)-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3-yllphenyllmethyll-2-fluoro- benzenesulfonamide [00248] Following general procedure E, fe/f-butyl (3f?)-3-[4-amino-3-[4-[[(2- fluorophenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-^

(4.03 g, 6.93 mmol) afforded /V-[[4-[4-amino-1-[(3f?)-3-piperidyl]pyrazolo[3,4-rf]pyrimidin-3- yl]phenyl]methyl]-2-fluoro-benzenesulfonamide (2.23 g, 4.63 mmol, 79% yield) as an off-white foam.

[00249] UPLC-MS (ES⁺, Short acidic): 1.10 min, m/z 482.3 [M+H]⁺

[00250] /V-[[4-[4-Amino-1-[(3f?)-1-prop-2-enoyl-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3- yllphenyllmethyll-2-fluoro-benzenesulfonamide

[00251] Following general procedure F, A/-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4- rf]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-benzenesulfonamide (2.23 g, 4.63 mmol) and acrylic acid (0.32 ml_, 4.63 mmol) gave A/-[[4-[4-amino-1-[(3f?)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4- rf]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-benzenesulfonamide (1.51 g, 2.81 mmol, 61 %) as a white solid.

[00252] UPLC-MS (ES⁺, Short acidic): 1.37 min, m/z 536.4 [M+H]⁺

[00253] UPLC-MS (ES⁺, Long acidic): 3.12 min, m/z 536.3 [M+H]⁺

[00254] H-NMR (400 MHz, DMSO-d₆): δ (ppm, 1 :1 mixture of conformers) 8.60 (t, J 5.4 Hz, 1 H, NH), 8.27 (s, 1 H, ArH), ) 7.77 (td, J 7.7, J 1.7 Hz, 1 H, ArH), 7.68-7.62 (m, 1 H, ArH), 7.53 (d, J 8.2 Hz, 2H, 2 ArH), 7.39 (d, J 8.2 Hz, 2H, 2 ArH), 7.39-7.30 (m, 2H, 2 ArH), 6.90-6.81 (m, 0.5H), 6.75-6.66 (m, 0.5H), 6.16-6.03 (m, 1 H), 5.73-5.57 (m, 1 H), 4.77-4.63 (m, 1 H, CH), 4.57-4.48 (m, 0.5H), 4.21 (d, J 5.4Hz, 2H, CH₂), 4.21-4.13 (m, 1 H), 4.12-4.01 (m, 0.5H), 3.75-3.65 (m, 0.5H), 3.26-3.14 (m, 1 H), 3.08-2.97 (m, 0.5H), 2.31-2.18 (m, 1 H), 2.17-2.06 (m, 1 H), 1.98-1.86 (m, 1 H), 1.67-1.49 (m, 1 H).

[00255] Example 8: Af-[[4-[4-Amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- o(|pyrimidin-3-yl]phenyl]methyl]naphthalene-2 -sulfonamide

[00256] [4-[(2-Naphthylsulfonylamino)methyllphenyllboronic acid

[00257] Following general procedure B, 4-aminomethylphenylboronic acid hydrochloride

(219.8 mg, 1.46 mmol) and 2-naphthalenesulfonyl chloride (300.0 mg, 1 .32 mmol) afforded [4-[(2- naphthylsulfonylamino)methyl]phenyl]boronic acid (264.0 mg, 0.77 mmol, 58% yield) as an off-white powder.

[00258] fe/f-Butyl (3f?)-3-[4-amino-3-[4-[(2-naphthylsulfonylamino)methyllphenyllpyrazolo[3,4- tflpyrimidin-1 -yllpiperidine-1 -carboxylate

[00259] Following general procedure D, [4-[(2-naphthylsulfonylamino)methyl]phenyl]boronic acid (170.5 mg, 0.50 mmol) and fe/f-butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-rf]pyrimidin-1- yl)piperidine-1-carboxylate (185.0 mg, 0.42 mmol) afforded fe/f-butyl (3R)-3-[4-amino-3-[4-[(2- naphthylsulfonylamino)methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1-yl]piperidine-1-carboxylate (140.0 mg, 0.23 mmol, 55% yield) as an off-white solid.

[00260] UPLC-MS (ES⁺, Short acidic): 1.82 min, m/z 614.5 [M+H]⁺ [00261] A/-[[4-[4-Amino-1 -[(3 ?V3-piperidyllpyrazolo[3,4-Qlpyrimidin-3-yllph

naphthalene-2-sulfonamide

[00262] Trifluoroacetic acid (0.35 mL, 4.56 mmol) was added dropwise to a solution of fe/ -butyl (3R)-3-[4-amino-3-[4-[(2-naphthylsulfonylamino)methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1 - yl]piperidine-1 -carboxylate (140.0 mg, 0.23 mmol) in DCM (5 mL) at 20 °C under an inert atmosphere. The reaction mixture was then stirred at this temperature for 3 h, quenched with a saturated solution of ammonium chloride (10 mL) and extracted with DCM (2 x 10 mL). The organics were washed with a saturated solution of NhUCI (10 mL). The combined aqueous extracts were basified to pH 10 with solid K2CO3. The basic aqueous layer was extracted with DCM (x 5) and these combined organic washings were dried over Na2S04, filtered, and concentrated in vacuo to afford A/-[[4-[4-amino-1 -[(3R)-3-piperidyl]pyrazolo[3,4-rf]pyrimidin-3-yl]phenyl]methyl]naphthalene- 2-sulfonamide (34.0 mg, 0.07 mmol, 29% yield) as a white solid.

[00263] UPLC-MS (ES⁺, Short acidic): 1 .28 min, m/z 514.4 [M+H]⁺

[00264] /V-[[4-[4-Amino-1 -[(3f?)-1 -prop-2-enoyl-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3- yllphenyllmethyllnaphthalene-2-sulfonamide

[00265] Following general procedure F, A/-[[4-[4-amino-1 -[(3R)-3-piperidyl]pyrazolo[3,4- rf]pyrimidin-3-yl]phenyl]methyl]naphthalene-2-sulfonamide (34.0 mg, 0.07 mmol) afforded, after purification by preparative HPLC and salt removal by SCX cartridge, A/-[[4-[4-amino-1 -[(3R)-1 -prop- 2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]naphthalene-2-sulfonamide (9.5 mg, 0.06 mmol, 24% yield).

[00266] UPLC-MS (ES⁺, Short acidic): 1 .52 min, m/z 568.4 [M+H]⁺

[00267] UPLC-MS (ES⁺, Long acidic): 3.51 min, m/z 568.4 [M+H]⁺

[00268] H-NMR (400 MHz, DMSO-d₆) δ (ppm, 1 :1 mixture of conformers) 8.48 (d, J 1 .3 Hz, 1 H, ArH), 8.34 (t, J 6.4 Hz, 1 H, NH), 8.26 (s, 1 H, ArH), ) 8.18-8.12 (m, 2H, 2 ^χ ArH), 8.07-8.03 (m, 1 H, ArH), 7.87 (dd, J 8.7, 2.0 Hz, 1 H, ArH), 7.72-7.64 (m, 2H, 2 ArH), 7.56 (d, ³ J 8.0 Hz, 2H, 2 ^χ ArH), 7.43 (d, ³ J 8.0 Hz, 2H, 2 ^χ ArH), 6.86 (dd, ¾_rans 16.6, ³J_C(S 10.5 Hz, 0.5H), 6.71 (dd, ¾_rans 16.6, ³J_C(S 10.5 Hz, 0.5H), 6.13 (d, ¾_rans 16.6 Hz, 0.5H), 6.05 (d, ³J,_ra„s 16.6 Hz, 0.5H), 5.70 (d, ³J_C(S 10.5 Hz, 0.5H), 5.58 (d, Jcis 10.5 Hz, 0.5H), 4.77-4.62 (m, 1 H, CH), 4.57-4.49 (m, 0.5H), 4.25-4.14 (m, 1 H), 4.1 1 (d, ³J 6.4 Hz, 2H, CH₂), 4.09-4.02 (m, 0.5H), 3.75-3.62 (m, 0.5H), 3.26-3.13 (m, 1 H), 3.07-2.95 (m, 0.5H), 2.31 -2.16 (m, 1 H), 2.16-2.06 (m, 1 H), 1 .94-1 .86 (m, 1 H), 1 .67-1 .48 (m, 1 H).

[00269] Example 9: Af-[[4-[4-Amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- o(|pyrimidin-3-yl]phenyl]methyl]-4-fluoro-3-(trifluoromethyl)benzenesulfonamide

[00270] [4-[[[4-Fluoro-3-(trifluoromethyl)phenyllsulfonylaminolmethyllphenyllboronic acid

[00271] Following general procedure B, 4-aminomethylphenylboronic acid hydrochloride

(189.7 mg, 1 .26 mmol) and 4-fluoro-3-trifluoromethylbenzenesulfonyl chloride (0.19 mL, 1 .14 mmol) afforded [4-[[[4-fluoro-3-(trifluoromethyl)phenyl]sulfonylamino]methyl]phenyl]boronic acid (308.0 mg, 0.82 mmol, 71 % yield) as an orange gum. [00272] fe/f-Butyl (3ffl-3-[4-amino-3-[4-[[[4-fluoro-3-

(trifluoromethyl)phenyllsulfonylaminolmethyllphenyllpyrazolo[3,4-(^pyrim

carboxylate

[00273] Following general procedure C, fe/f-butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-rf]pyrimidin- 1 -yl)piperidine-1 -carboxylate (1 71 .7 mg , 0.39 mmol) and [4-[[[4-fluoro-3-

(trifluoromethyl)phenyl]sulfonylamino]methyl]phenyl]boronic acid (279.3 mg, 0.50 mmol) gave fe/f- butyl (3R)-3-[4-amino-3-[4-[[[4-fluoro-3-

(trifluoromethyl)phenyl]sulfonylamino]methyl]phenyl]pyrazolo[3,4-(^pyrimidin-1 -yl]piperidine-1 - carboxylate (236.5 mg, 0.36 mmol, 94% yield) as brown foam.

[00274] UPLC-MS (ES⁺, short acidic): 1 .85 min, m/z 650.4 [M+H]⁺

[00275] /V-[[4-[4-Amino-1 -[(3f?)-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3-yllphenyllmethyll-4-fluoro-3- (trifluoromethyl)benzenesulfonamide

[00276] Following general procedure E, fe/f-butyl (3R)-3-[4-amino-3-[4-[[[4-fluoro-3- (trifluoromethyl)phenyl]sulfonylamino]methyl]phenyl]pyrazolo[3,4-(^pyrimidin-1 -yl]piperidine-1 - carboxylate (236.5 mg, 0.36 mmol) afforded A/-[[4-[4-amino-1 -[(3f?)-3-piperidyl]pyrazolo[3,4- rf]pyrimidin-3-yl]phenyl]methyl]-4-fluoro-3-(trifluoromethyl)benzenesulfonamide (assumed quantitative) as a brown foam.

[00277] UPLC-MS (ES⁺, short acidic): 1 .29 min, m/z 550.3 [M+H]⁺

[00278] /V-[[4-[4-Amino-1 -[(3f?)-1 -prop-2-enoyl-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3- yllphenyllmethyll-4-fluoro-3-(trifluoromethyl)benzenesulfonamide

[00279] Following general procedure F, A/-[[4-[4-amino-1 -[(3R)-3-piperidyl]pyrazolo[3,4- d]pyrimidin-3-yl]phenyl]methyl]- 4-fluoro-3-(trifluoromethyl)benzenesulfonamide (235.7 mg , 0.43 mmol) afforded A/-[[4-[4-amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4-rf]pyrimidin-3- yl]phenyl]methyl]-4-fluoro-3-(trifluoromethyl)benzenesulfonamide (59.2 mg, 0.10 mmol, 23% yield) as a white foam.

[00280] UPLC-MS (ES⁺, Short acidic): 1 .55 min, m/z 604.4 [M+H]⁺

[00281] UPLC-MS (ES⁺, Long acidic): 3.58 min, m/z 604.3 [M+H]⁺

[00282] H-NMR (400 MHz, DMSO-d₆) δ (ppm, 1 : 1 mixture of conformers) 8.52 (t, J 6.2 Hz, 1 H, NH), 8.26 (s, 1 H, ArH), ) 8.18-8.12 (m, 1 H, ArH), 8.10-8.05 (m, 1 H, ArH), 7.72 (dd, J 10.0, 9.2 Hz, 1 H, ArH), 7.56 (d, ³ J 8.1 Hz, 2H, 2 ArH), 7.39 (d, ³ J 8.1 Hz, 2H, 2 ArH), 6.92-6.63 (m, 1 H), 6.16- 6.01 m, 1 H), 5.75-5.55 (m, 1 H), 4.77-4.63 (m, 1 H, CH), 4.58-4.49 (m, 0.5H), 4.26-4.12 (m, 1 H), 4.15 (d, ³J 6.2 Hz, 2H, CH₂), 4.13-4.04 (m, 0.5H), 3.74-3.65 (m, 0.5H), 3.26-3.13 (m, 1 H), 3.06-2.97 (m, 0.5H), 2.30-2.18 (m, 1 H), 2.16-2.07 (m, 1 H), 2.01 -1 .98 (m, 1 H), 1 .66-1 .51 (m, 1 H).

[00283] Example 10: Af-[[4-[4-Amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- o(|pyrimidin-3-yl]phenyl]methyl]-2,6-difluoro-benzenesulfonamide

[00284] [4-[[(2,6-Difluorophenyl)sulfonylaminolmethyllphenyllboronic acid [00285] Following general procedure B, [4-(aminomethyl)phenyl]boronic acid hydrochloride (290.9 mg, 1.55 mmol) and 2,6-difluorobenzenesulfonyl chloride (0.19 ml_, 1.41 mmol) gave [4- [[(2,6-difluorophenyl)sulfonylamino]methyl]phenyl]boronic acid (292.0 mg, 0.89 mmol, 63% yield) as a pale yellow oil which solidified upon standing.

[00286] UPLC-MS (ES-, Short acidic): 1.30 min, m/z 326.2 [M-H]-

[00287] fe/f-Butyl (3ffl-3-[4-amino-3-[4-[[(2.6- difluorophenyl)sulfonylaminolmethyllphenyllpyrazolo[3,4-Qlpyrimidin-1-yllpiperidine-1-carboxylate

[00288] Following general procedure D, [4-[[(2,6- difluorophenyl)sulfonylamino]methyl]phenyl]boronic acid (262.6 mg, 0.64 mmol) and fe/f-butyl (3R)- 3-(4-amino-3-iodo-pyrazolo[3,4-rf]pyrimidin-1-yl)piperidine-1-carboxylate (190.0 mg, 0.43 mmol) afforded fe/f-butyl (3R)-3-[4-amino-3-[4-[[(2,6- difluorophenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1-yl]piperidine-1-carboxylate (206.1 mg, 0.28 mmol, 64% yield) as a brown oil.

[00289] UPLC-MS (ES⁺, Short acidic): 1.68 min, m/z 600.4 [M+H]⁺

[00290] /V-[[4-[4-Amino-1-[(3f?)-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3-yllphenyllmethyll-2,6- difluoro-benzenesulfonamide

[00291 ] Following general procedure E, fe/f-butyl (3f?)-3-[4-amino-3-[4-[[(2,6- difluorophenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1-yl]piperidine-1-carboxylate (206.1 mg, 0.27 mmol) gave A/-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-rf]pyrimidin-3- yl]phenyl]methyl]-2,6-difluoro-benzenesulfonamide (152.0 mg, 0.27 mmol, 99% yield) as a brown foam.

[00292] UPLC-MS (ES⁺, Short acidic): 1.11 min, m/z 500.3 [M+H]⁺

[00293] /V-[[4-[4-Amino-1-[(3f?)-1-prop-2-enoyl-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3- yllphenyllmethyll-2,6-difluoro-benzenesulfonamide

[00294] Following general procedure F, A/-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4- rf]pyrimidin-3-yl]phenyl]methyl]-2,6-difluoro-benzenesulfonamide (65.7 mg, 0.13 mmol) afforded Λ/- [[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,6- difluoro-benzenesulfonamide (12.0 mg, 0.02 mmol, 16% yield)

[00295] UPLC-MS (ES⁺, Short acidic): 1.37 min, m/z 554.4 [M+H]⁺

[00296] UPLC-MS (ES⁺, Long acidic): 3.10 min, m/z 554.3 [M+H]⁺

[00297] H-NMR (400 MHz, DMSO-d₆): δ (ppm, 1 :1 mixture of conformers) 8.90 (s, 1 H, NH), 8.27 (s, 1 H, ArH), 7.66-7.56 (m, 1 H, ArH), 7.53 (d, ³ J 7.9 Hz, 2H, 2 ArH), 7.41 (d, ³ J 7.9 Hz, 2H, 2 ArH), 7.17 (dd, ³J 9.0, ³J 9.0 Hz, 2H, 2 ArH), 6.87 (dd, ¾_rans 16.5, ³J_CS 10.5 Hz, 0.5H), 6.70 (dd, Jtrans 16.5, ³J_C(S 10.5 Hz, 0.5H), 6.13 (d, ³J_ira„s 16.5 Hz, 0.5H), 6.05 (d, ³J_ira„s 16.5 Hz, 0.5H), 5.71 (d, Jcis 10.5 Hz, 0.5H), 5.58 (d, ³J_CS 10.5 Hz, 0.5H), 4.79-4.62 (m, 1 H, CH), 4.58-4.48 (m,

0.5H), 4.32-4.25 (bs, 2H, CH₂), 4.23-4.14 (m, 1 H), 4.11-4.03 (m, 0.5H), 3.76-3.05 (m, 0.5H), 3.28- 3.14 (m, 1 H), 3.10-2.97 (m, 0.5H), 2.30-2.20 (m, 1 H), 2.17-2.07 (m, 1 H), 1 .96-1 .88 (m, 1 H), 1 .67- 1 .51 (m, 1 H).

[00298] Example 11 : Af-[[4-[4-Amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- d]pyrimidin-3-yl]p enyl]met yl]-2,4-difluoro-benzenesulfonamide

[00299] [4-[[(2,4-Difluorophenyl)sulfonylaminolmethyllphenyllboronic acid

[00300] Following general procedure B, [4-(aminomethyl)phenyl]boronic acid hydrochloride (290.9 mg, 1 .55 mmol) and 2,4-difluorobenzenesulfonyl chloride (0.19 ml_, 1 .41 mmol) afforded [4- [[(2,4-difluorophenyl)sulfonylamino]methyl]phenyl]boronic acid (420.0 mg , 1 .28 mmol, 91 % yield) as a yellow oil, which solidified to a white solid upon standing.

[00301] UPLC-MS (ES-, Short acidic): 1 .36 min, m/z 326.1 [M-H]-

[00302] fe/f-Butyl (3ffl-3-[4-amino-3-[4-[[(2.4- difluorophenyl)sulfonylaminolmethyllphenyllpyrazolo[3,4-Qlpyrimidin-1 -yllpiperidine-1 -carboxylate

[00303] Following general procedure D, [4-[[(2,4- difluorophenyl)sulfonylamino]methyl]phenyl]boronic acid (308.9 mg, 0.64 mmol) and fe/f-butyl (3R)- 3-(4-amino-3-iodo-pyrazolo[3,4-rf]pyrimidin-1 -yl)piperidine-1 -carboxylate (1 90.0 mg, 0.43 mmol) afforded fe/f-butyl (3R)-3-[4-amino-3-[4-[[(2,4- difluorophenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1 -yl]piperidine-1 -carboxylate (169.5 mg, 0.23 mmol, 53% yield) as a brown oil .

[00304] UPLC-MS (ES⁺, Short acidic): 1 .71 min, m/z 600.4 [M+H]⁺

[00305] /V-[[4-[4-Amino-1 -[(3 ?)-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3-yllphenyllmethyll-2,4- difluoro-benzenesulfonamide

[00306] Following general procedure E, fe/f-butyl (3f?)-3-[4-amino-3-[4-[[(2,4- difluorophenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1 -yl]piperidine-1 -carboxylate (169.5 mg, 0.24 mmol) gave A/-[[4-[4-amino-1 -[(3R)-3-piperidyl]pyrazolo[3,4-rf]pyrimidin-3- yl]phenyl]methyl]-2,4-difluoro-benzenesulfonamide (130.0 mg, 0.23 mmol, 97% yield) as a brown foam.

[00307] UPLC-MS (ES⁺, Short acidic): 1 .13 min, m/z 500.3 [M+H]⁺

[00308] /V-[[4-[4-Amino-1 -[(3f?)-1 -prop-2-enoyl-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3- yllphenyllmethyll-2,4-difluoro-benzenesulfonamide

[00309] Following general procedure F, A/-[[4-[4-amino-1 -[(3R)-3-piperidyl]pyrazolo[3,4- rf]pyrimidin-3-yl]phenyl]methyl]-2,4-difluoro-benzenesulfonamide (107.6 mg , 0.22 mmol) gave Λ/-[[4- [4-amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4-rf]pyrimidin-3-yl]phenyl]methyl]-2,4- difluoro-benzenesulfonamide (22.0 mg, 0.04 mmol, 17% yield).

[00310] UPLC-MS (ES⁺, Short acidic): 1 .41 min, m/z 554.4 [M+H]⁺

[0031 1] UPLC-MS (ES⁺, Long acidic): 3.19 min, m/z 554.3 [M+H]⁺ [00312] H-NMR (400 MHz, DMSO-c₆): δ (ppm, 1 :1 mixture of conformers) 8.68-8.61 (bs, 1 H, NH), 8.27 (s, 1 H, ArH), 7.82 (td, J 8.7, 6.5 Hz, 1 H, ArH), 7.55 (d, ³ J 8.0 Hz, 2H, 2 ArH), 7.49-7.43 (m, 1 H, ArH), 7.40 (d, ³J 8.0 Hz, 2H, 2 ArH), 7.21 (td, J 8.7, 2.3 Hz, 1 H, ArH), 6.87 (dd, ¾_rans 16.5, Jcis 10.5 Hz, 0.5H), 6.71 (dd, ¾_ra„s 16.5, ³J_C(S 10.5 Hz, 0.5H), 6.13 (d, ¾_ra„s 16.5 Hz, 0.5H), 6.06 (d, ³Jtrans 16.5 Hz, 0.5H), 5.71 (d, ³J_C(S 10.5 Hz, 0.5H), 5.58 (d, ³J_C(S 10.5 Hz, 0.5H), 4.77-4.63 (m, 1 H, CH), 4.58-4.50 (m, 0.5H), 4.25-4.13 (m, 3H), 4.12-4.03 (m, 0.5H), 3.76-3.66 (m, 1 H, 0.5H), 3.27- 3.14 (m, 1 H), 3.08-2.97 (m, 0.5H), 2.30-2.21 (m, 1 H), 2.17-2.07 (m, 1 H), 1 .98-1 .88 (m, 1 H), 1 .66- 1 .51 (m, 1 H).

[00313] Example 12: Af-[[4-[4-Amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- o(|pyrimidin-3-yl]phenyl]methyl]-4-phenyl-benzenesulfonamide

[00314] [4-[[(4-Phenylphenyl)sulfonylaminolmethyllPhenyllboronic acid

[00315] Following general procedure B, 4-aminomethylphenylboronic acid hydrochloride

(197.1 mg, 1 .31 mmol) and biphenyl-4-sulfonyl chloride (300.0 mg, 1 .19 mmol) afforded crude [4- [[(4-phenylphenyl)sulfonylamino]methyl]phenyl]boronic acid (304.0 mg, 0.49 mmol, 41 % yield) as a cream solid.

[00316] UPLC-MS (ES⁺, Short acidic): 1 .62 min, m/z 412.3 [M+2Na-H]⁺

[00317] fe/f-Butyl (3ffl-3-[4-amino-3-[4-[[(4- phenylphenyl)sulfonylaminolmethyllphenyllpyrazolo[3,4-Qlpyrimidin-1 -yllpiperidine-1 -carboxylate

[00318] Following general procedure D, [4-[[(4-phenylphenyl)sulfonylamino]methyl]phenyl]boronic acid (304.0 mg, 0.52 mmol) and fe/f-butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-c]pyrimidin-1 - yl)piperidine-1 -carboxylate (192.9 mg, 0.43 mmol) gave fe/ -butyl (3R)-3-[4-amino-3-[4-[[(4- phenylphenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-c]pyrimidin-1 -yl]piperidine-1 -carboxylate (275.0 mg, 0.32 mmol, 74% yield) as a brown solid film.

[00319] UPLC-MS (ES⁺, Short acidic): 1 .88 min, m/z 640.5 [M+H]⁺

[00320] /V-[[4-[4-Amino-1 -[(3f?)-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3-yllphenyllmethyll-4-phenyl- benzenesulfonamide

[00321] Following general procedure E, fe/f-butyl (3f?)-3-[4-amino-3-[4-[[(4- phenylphenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-c]pyrimidin-1 -yl]piperidine-1 -carboxylate (275.0 mg, 0.32 mmol) afforded /V-[[4-[4-amino-1 -[(3f?)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3- yl]phenyl]methyl]-4-phenyl-benzenesulfonamide (247.9 mg, assumed quantitative) as a brown solid.

[00322] UPLC-MS (ES⁺, Short acidic): 1 .32 min, m/z 540.4 [M+H]⁺

[00323] /V-[[4-[4-Amino-1 -[(3f?)-1 -prop-2-enoyl-3-piperidyllpyrazolo[3,4-dlpyrimidin-3- yllphenyllmethyll-4-phenyl-benzenesulfonamide

[00324] Following general procedure F, A/-[[4-[4-amino-1 -[(3R)-3-piperidyl]pyrazolo[3,4- c]pyrimidin-3-yl]phenyl]methyl]-4-phenyl-benzenesulfonamide (247.9 mg, 0.40 mmol) gave, after purification by preparative HPLC, A/-[[4-[4-amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- <^pyrimidin-3-yl]phenyl]methyl]-4-phenyl-benzenesulfonamide (10.0 mg, 0.02 mmol, 4% yield) as a white powder.

[00325] UPLC-MS (ES⁺, short acidic): 1 .58 min, m/z 594.4 [M+H]⁺

[00326] UPLC-MS (ES⁺, long acidic): 3.65 min, m/z 594.4 [M+H]⁺

[00327] H-NMR (400 MHz, DMSO-d₆) δ (ppm, 1 : 1 mixture of conformers) 8.30 (t, J 6.4 Hz, 1 H, NH), 8.26 (s, 1 H, ArH), 7.88 (d, J 8.5 Hz, 2H, 2 ArH), 7.85 (d, J 8.5 Hz, 2H, 2 ArH), 7.71 -7.65 (m, 2H), 7.58 (d, ³ J 8.1 Hz, 2H, 2 ArH), 7.71 -7.65 (m, 5H), 6.86 (dd, ¾_rans 16.5, ³J_C(S 10.5 Hz, 0.5H), 6.74-6.66 (m, 0.5H), 6.13 (d, ¾_rans 16.5 Hz, 0.5H), 6.06 (d, ¾_rans 16.5 Hz, 0.5H), 5.71 (d, ³J_C(S 10.5 Hz, 0.5H), 5.58 (d, ¼_s 10.5 Hz, 0.5H), 4.77-4.62 (m, 1 H, CH), 4.58-4.49 (m, 0.5H), 4.24-4.14 (m, 1 H), 4.12 (d, ³J 6.2 Hz, 2H, CH₂), 4.09-4.03 (m, 0.5H), 3.73-3.64 (m, 0.5H), 3.25-3.13 (m, 1 H), 3.07-2.96 (m, 0.5H), 2.31 -2.1 7 (m, 1 H), 2.16-2.06 (m, 1 H), 1 .97-1 .87 (m, 1 H), 1 .68-1 .50 (m, 1 H) .

[00328] Example 13: Af-[[4-[4-Amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- o(|pyrimidin-3-yl]phenyl]methyl]naphthalene-1 -sulfonamide

[00329] /V-[[4-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyllnaphthalene-1 - sulfonamide

[00330] Following general method A, 4-aminomethylphenylboronic acid pinacol ester (339.4 mg , 1 .46 mmol) and naphthalene-1 -sulfonyl chloride (0.19 ml_, 1 .32 mmol) gave Λ/-[[4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]naphthalene-1 -sulfonamide (397.0 mg ,

0.94 mmol, 71 % yield) as an orange gum.

[00331] UPLC-MS (ES⁺, Short acidic): 2.01 min, m/z 424.4 [M+H]⁺

[00332] fe/f-Butyl (3f?)-3-[4-amino-3-[4-[(1 -naphthylsulfonylamino)methyllphenyllpyrazolo[3,4- tflpyrimidin-1 -yllpiperidine-1 -carboxylate

[00333] Following general procedure D, fe/f-butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-rf]pyrimidin- 1 -yl)piperidine-1 -carboxylate (200.0 mg , 0.45 mmol) gave fe/f-butyl (3R)-3-[4-amino-3-[4-[(1 - naphthylsulfonylamino)methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1 -yl]piperidine-1 -carboxylate (255.0 mg, 0.42 mmol, 92% yield) as a brown solid.

[00334] UPLC-MS (ES⁺, Short acidic): 1 .81 min, m/z 614.5 [M+H]⁺

[00335] /V-[[4-[4-Amino-1 -[(3f?)-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3- yllphenyllmethyllnaphthalene-1 -sulfonamide

[00336] Following general procedure E, fe/f-butyl (3f?)-3-[4-amino-3-[4-[(1 - naphthylsulfonylamino)methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1 -yl]piperidine-1 -carboxylate (255.0 mg, 0.42 mmol) afforded /V-[[4-[4-amino-1 -[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3- yl]phenyl]methyl]naphthalene-1 -sulfonamide (85.0 mg, 0.17 mmol, 40% yield) as a white powder.

[00337] UPLC-MS (ES⁺, Short acidic): 1 .26 min, m/z 614.5 [M+H]⁺ [00338] A/-[[4-[4-Amino-1 -[(3/?yi -prop-2-enoyl-3-pi^^

yllphenyllmethyllnaphthalene-1 -sulfonamide

[00339] Following general procedure F, A/-[[4-[4-amino-1 -[(3R)-3-piperidyl]pyrazolo[3,4- rf]pyrimidin-3-yl]phenyl]methyl]naphthalene-1 -sulfonamide (85.0 mg , 0.17 mmol) gave, after purification by preparative HPLC, A/-[[4-[4-amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- rf]pyrimidin-3-yl]phenyl]methyl]naphthalene-1 -sulfonamide (14.0 mg , 0.02 mmol, 15% yield).

[00340] UPLC-MS (ES⁺, short acidic): 1 .50 min, m/z 568.5 [M+H]⁺

[00341] UPLC-MS (ES⁺, long acidic): 3.45 min, m/z 568.5 [M+H]⁺

[00342] H-NMR (400 MHz, DMSO-d₆) δ (ppm, 1 : 1 mixture of conformers) 8.69 (d, J 8.6 Hz, 1 H, ArH), 8.63 (t, J 6.2 Hz, 1 H, NH), 8.27 (s, 1 H, ArH), ) 8.19 (d, J 8.2 Hz, 1 H, ArH), 8.14 (m, 1 H, ArH), 8.06 (dd, J 8.3, 1 .0 Hz, 1 H , ArH), 7.72 (ddd, J 8.4, 6.8, 1 .5 Hz, 1 H, ArH), 7.66 (m, 1 H , ArH), 7.61 (dd, J 8.2, 7.5 Hz, 1 H , ArH), 7.44 (d, ³ J 8.2 Hz, 2H, 2 ArH), 7.28 (d, ³ J 8.2 Hz, 2H, 2 ArH), 6.85 (dd, ^zJtrans 16.5, ³J_C(S 10.5 Hz, 0.5H), 6.70 (dd, ¾._a„s 16.5, ³J_C(S 10.5 Hz, 0.5H), 6.12 (d, ¾_rans 16.5 Hz, 0.5H), 6.05 (d, ¾_rans 16.5 Hz, 0.5H), 5.70 (d, ³J_C(S 10.5 Hz, 0.5H), 5.57 (d, ³J_C(S 10.5 Hz, 0.5H), 4.77-4.61 (m, 1 H, CH), 4.58-4.48 (m, 0.5H), 4.26-4.09 (m, 1 H), 4.13 (d, ³J 6.2 Hz, 2H, CH₂), 4.09- 3.99 (m, 0.5H), 3.69 (dd, J 12.1 , 10.5 Hz, 0.5H), 3.27-3.12 (m, 1 H), 3.09-2.94 (m, 0.5H), 2.31 -2.18 (m, 1 H), 2.16-2.03 (m, 1 H), 1 .97-1 .84 (m, 1 H), 1 .67-1 .48 (m, 1 H) .

[00343] Example 14: Af-[[4-[4-Amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- o(|pyrimidin-3-yl]phenyl]methyl]-2 -methyl-be nzenesulfonamide

[00344] [4-[(o-Tolylsulfonylamino)methyllphenyllboronic acid

[00345] Following general procedure B, [4-(aminomethyl)phenyl]boronic acid hydrochloride (300.0 mg, 1 .6 mmol) and 2-methylbenzenesulfonyl chloride (610.3 mg, 3.20 mmol) afforded [4-[(o- tolylsulfonylamino)methyl]phenyl]boronic acid (320.0 mg, 0.79 mmol, 49% yield) as a pale brown solid .

[00346] UPLC-MS (ES⁺, short acidic): 1 .39 min, m/z 306.2 [M+H]⁺

[00347] fe/f-Butyl (3ffl-3-[4-amino-3-[4-[[(2- methylphenyl)sulfonylaminolmethyllphenyllpyrazolo[3,4-Qlpyrimidin-1 -yllpiperidine-1 -carboxylate

[00348] Following general procedure D, a mixture of [4-[(o- tolylsulfonylamino)methyl]phenyl]boronic acid (206.1 mg, 0.68 mmol) and fe/f-butyl (3R)-3-(4- amino-3-iodo-pyrazolo[3,4-rf]pyrimidin-1 -yl)piperidine-1 -carboxylate (200.0 mg, 0.45 mmol) afforded fe/f-butyl (3R)-3-[4-amino-3-[4-[[(2-methylphenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4- rf]pyrimidin-1 -yl]piperidine-1 -carboxylate (278.0 mg , 0.46 mmol, 86% yield) as a pale brown solid.

[00349] UPLC-MS (ES⁺, short acidic): 1 .75 min, m/z 578.5 [M+H]⁺

[00350] /V-[[4-[4-Amino-1 -[(3f?)-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3-yllphenyllmethyll-2-methyl- benzenesulfonamide [00351] Following general procedure E, fe/r-butyl (3f?)-3-[4-amino-3-[4-[[(2- methylphenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-<^^

(250.0 mg, 0.43 mmol) afforded /V-[[4-[4-amino-1-[(3f?)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3- yl]phenyl]methyl]-2-methyl-benzenesulfonamide (103.0 mg, 0.19 mmol, 45% yield).

[00352] UPLC-MS (ES⁺, short acidic): 1.16 min, m/z 478.3 [M+H]⁺

[00353] /V-[[4-[4-Amino-1-[(3f?)-1-prop-2-enoyl-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3- yllphenyllmethyll-2-methyl-benzenesulfonamide

[00354] Following general procedure F, A/-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4- rf]pyrimidin-3-yl]phenyl]methyl]-2-methyl-benzenesulfonamide (103.0 mg, 0.22 mmol) gave, after purification by preparative HPLC and salt removal by SCX cartridge, A/-[[4-[4-amino-1-[(3R)-1-prop- 2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methyl-benzenesulfonamide (15.4 mg. 0.03 mmol, 13% yield).

[00355] UPLC-MS (ES⁺, short acidic): 1.43 min, m/z 532.5 [M+H]⁺

[00356] UPLC-MS (ES⁺, long acidic): 3.26 min, m/z 532.5 [M+H]⁺

[00357] H-NMR (400 MHz, DMSO-d₆) δ (ppm, 1 :1 mixture of conformers) 8.33 (t, J 6.3 Hz, 1 H, NH), 8.27 (s, 1 H, ArH), 7.85-7.81 (m, 1 H, ArH), 7.54 (d, ³ J 7.8 Hz, 2H, 2 ArH), 7.49 (dt, J 7.5, J 1.2 Hz, 1 H), 7.39-7.32 (m, 2H, 2 ArH), 7.37 (d, ³J 7.8 Hz, 2H, 2 ArH), 6.87 (dd, ¾_ra„s 16.5, ³J_C(S 10.5 Hz, 0.5H), 6.71 (dd, ³J_ira„s 16.5, ³J_CS 10.5 Hz, 0.5H), 6.13 (d, ³J,_ra„s 16.5 Hz, 0.5H), 6.06 (d, ^zJtrans 16.5 Hz, 0.5H), 5.71 (d, ^zJcis 10.5 Hz, 0.5H), 5.59 (d, ³J_C(S 10.5 Hz, 0.5H), 4.80-4.63 (m, 1 H, CH), 4.59-4.48 (m, 0.5H), 4.26-4.15 (m, 1 H), 4.12 (d, ³J 6.3 Hz, 2H, CH₂), 4.10-4.02 (m, 0.5H),

3.77-3.64 (m, 0.5H), 3.27-3.18 (m, 1 H), 3.09-2.96 (m, 0.5H), 2.58 (s, 3H, CH₃), 2.32-2.20 (m, 1 H), 2.17-2.07 (m, 1 H), 1.98-1.87 (m, 1 H), 1 .68-1.49 (m, 1 H).

[00358] Example 15: Af-[[4-[4-Amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- o(|pyrimidin-3-yl]phenyl]methyl]-5-chloro-2-fluoro-benzenesulfonamide

[00359] [4-[[(5-Chloro-2-fluoro-phenyl)sulfonylaminolmethyllphenyllboronic acid

[00360] Following general procedure B, [4-(aminomethyl)phenyl]boronic acid hydrochloride (270.0 mg, 1.44 mmol) and 5-chloro-2-fluorobenzenesulfonyl chloride (0.19 mL, 1.31 mmol) afforded [4-[[(5-chloro-2-fluoro-phenyl)sulfonylamino]methyl]phenyl]boronic acid (294.0 mg, 0.76 mmol, 58% yield) as a white solid.

[00361] UPLC-MS (ES-, short acidic): 1.45 min, m/z 342.1 [M-H]-

[00362] fe/f-Butyl (3ffl-3-[4-amino-3-[4-[[(5-chloro-2-fluoro- phenyl)sulfonylaminolmethyllphenyllpyrazolo[3,4-Qlpyrimidin-1-yllpiperidine-1-carboxylate

[00363] Following general procedure D, [4-[[(5-chloro-2-fluoro- phenyl)sulfonylamino]methyl]phenyl]boronic acid (185.6 mg, 0.54 mmol), fe/r-butyl (3R)-3-(4-amino- 3-iodo-pyrazolo[3,4-rf]pyrimidin-1-yl)piperidine-1-carboxylate (200.0 mg, 0.45 mmol) gave fe/r-butyl (3R)-3-[4-amino-3-[4-[[(5-chloro-2-fluoro-phenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4- rf]pyrimidin-1 -yl]piperidine-1 -carboxylate (229.0 mg, 0.37 mmol, 83% yield) as an orange/brown solid.

[00364] UPLC-MS (ES⁺, short acidic): 1 .80 min, m/z 616.0 [M+H]⁺

[00365] A/-[[4-[4-Amino-1 -[(3 ?)-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3-yllphenyllmethyll-5-chloro-2- fluoro-benzenesulfonamide

[00366] Following general procedure E, fe/f-Butyl (3R)-3-[4-amino-3-[4-[[(5-chloro-2-fluoro- phenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1 -yl]piperidine-1 -carboxylate

(229.0 mg, 0.37 mmol) afforded /V-[[4-[4-amino-1 -[(3f?)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3- yl]phenyl]methyl]-5-chloro-2-fluoro-benzenesulfonamide (24.0 mg, 0.04 mmol, 1 1 % yield) as a cream solid.

[00367] UPLC-MS (ES⁺, short acidic): 1 .19 min, m/z 516.0 [M+H]⁺

[00368] /V-[[4-[4-Amino-1 -[(3f?)-1 -prop-2-enoyl-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3- yllphenyllmethyll-5-chloro-2-fluoro-benzenesulfonamide

[00369] Following general procedure F, A/-[[4-[4-Amino-1 -[(3R)-3-piperidyl]pyrazolo[3,4- rf]pyrimidin-3-yl]phenyl]methyl]-5-chloro-2-fluoro-benzenesulfonamide (24.0 mg , 0.04 mmol) afforded, after purification by preparative HPLC and salt removal by SCX cartridge, A/-[[4-[4-amino- 1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4-(^pyrimidin-3-yl]phenyl]methyl]-5-chloro-2-fluoro- benzenesulfonamide (8.1 mg , 0.01 mmol, 31 % yield).

[00370] UPLC-MS (ES⁺, short acidic): 1 .48 min, m/z 571 .0 [M+H]⁺

[00371] UPLC-MS (ES⁺, long acidic): 3.40 min, m/z 570.1 [M]⁺

[00372] H-NMR (400 MHz, DMSO-d₆) δ (ppm, 1 : 1 mixture of conformers) 8.79 (t, J 6.2 Hz, 1 H, NH), 8.27 (s, 1 H, ArH), 7.75-7.66 (m, 2H, 2 ArH), 7.58-7.52 (m, 2H, 2 ArH), 7.44 (dd, J 9.3, 9.2 Hz, 1 H, ArH), 7.40 (d, ³J 8.1 Hz, 2H, 2 ArH), 6.87 (dd, ¾_ra„s 16.5, ³J_C(S 10.5 Hz, 0.5H), 6.71 (dd, Jtrans 16.5, ²J_cis 10.5 Hz, 0.5H), 6.13 (d, ³J_ira„s 16.5 Hz, 0.5H), 6.06 (d, ³J_ira„s 16.5 Hz, 0.5H), 5.71 (d, ^zJcis 10.5 Hz, 0.5H), 5.58 (d, ³J_C(S 10.5 Hz, 0.5H), 4.79-4.62 (m, 1 H, CH), 4.59-4.49 (m, 0.5H), 4.25 (d, ³J 6.2 Hz, 2H, CH₂), 4.22-4.14 (m, 1 H), 4.13-4.02 (m, 0.5H), 3.77-3.65 (m, 0.5H), 3.29-3.19 (m, 1 H), 3.12-2.96 (m, 0.5H), 2.32-2.19 (m, 1 H), 2.17-2.05 (m, 1 H), 2.00-1 .87 (m, 1 H), 1 .69-1 .49 (m, 1 H) .

[00373] Example 16: Af-[[4-[4-Amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- o(|pyrimidin-3-yl]phenyl]methyl]-3,5-difluoro-benzenesulfonamide

[00374] [4-[[(3,5-Difluorophenyl)sulfonylaminolmethyllphenyllboronic acid

[00375] Following general procedure B, [4-(aminomethyl)phenyl]boronic acid hydrochloride (290.9 mg, 1 .55 mmol) and 3,5-difluorobenzenesulfonyl chloride (300.0 mg, 1 .41 mmol) gave [4- [[(3,5-difluorophenyl)sulfonylamino]methyl]phenyl]boronic acid (326.0 mg , 0.74 mmol, 52% yield) as an off-white solid.

[00376] UPLC-MS (ES⁺, Short acidic): 1 .42 min, m/z 328.1 [M+H]⁺ [00377] fe/f-Butyl (3ffl-3-[4-amino-3-[4-[[(3.5- difluorophenyl)sulfonylaminolmethyllphenyllpyrazolo[3,4-(^pyrimidi

[00378] Following general procedure D, [4-[[(3,5- difluorophenyl)sulfonylamino]methyl]phenyl]boronic acid (176.7 mg, 0.54 mmol) and fe/f-butyl (3R)- 3-(4-amino-3-iodo-pyrazolo[3,4-rf]pyrimidin-1-yl)piperidine-1-carboxylate (200.0 mg, 0.45 mmol) gave fe/f-butyl (3R)-3-[4-amino-3-[4-[[(3,5-difluorophenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4- rf]pyrimidin-1-yl]piperidine-1-carboxylate (232.0 mg, 0.39 mmol, 86% yield) as a brown solid.

[00379] UPLC-MS (ES⁺, Short acidic): 1.76 min, m/z 600.4 [M+H]⁺

[00380] /V-[[4-[4-Amino-1-[(3f?)-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3-yllphenyllmethyll-3,5- difluoro-benzenesulfonamide

[00381] Following general procedure E, fe/f-butyl (3f?)-3-[4-amino-3-[4-[[(3,5- difluorophenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-(^pyrimidin-1-yl]piperidine-1-carboxylate (225.0 mg, 0.38 mmol) afforded /V-[[4-[4-amino-1-[(3f?)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3- yl]phenyl]methyl]-3,5-difluoro-benzenesulfonamide (136.0 mg, 0.27 mmol, 73% yield) as a pale brown powder.

[00382] UPLC-MS (ES⁺, Short acidic): 1.19 min, m/z 500.3 [M+H]⁺

[00383] /V-[[4-[4-Amino-1-[(3f?)-1-prop-2-enoyl-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3- yllphenyllmethyll-3,5-difluoro-benzenesulfonamide

[00384] Following general procedure F, A/-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4- rf]pyrimidin-3-yl]phenyl]methyl]-3,5-difluoro-benzenesulfonamide (136.0 mg, 0.27 mmol) gave, after purification by preparative HPLC and salt removal by SCX cartridge, A/-[[4-[4-amino-1-[(3R)-1-prop- 2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3,5-difluoro-benzenesulfonamide (30.0 mg, 0.05 mmol, 19% yield) as a colourless oil.

[00385] UPLC-MS (ES⁺, short acidic): 1.45 min, m/z 554.4 [M+H]⁺

[00386] UPLC-MS (ES⁺, long acidic): 3.33 min, m/z 554.4 [M+H]⁺

[00387] H-NMR (400 MHz, DMSO-d₆) δ (ppm, 1 :1 mixture of conformers) 8.52 (t, J 6.2 Hz, 1 H, NH), 8.27 (s, 1 H, ArH), 7.62-7.56 (m, 3H, 3 ArH), 7.52-7.46 (m, 2H, 2 ArH), 7.41 (d, ³J 8.2 Hz, 2H, 2 ArH), 6.86 (dd, ³J_ira„s 16.5, ³J_C/S 10.5 Hz, 0.5H), 6.71 (dd, ¾_ra„s 16.5, ³J_C(S 10.5 Hz, 0.5H), 6.13 (d, Jtrans 16.5 Hz, 0.5H), 6.06 (d, ³J,_ra„s 16.5 Hz, 0.5H), 5.71 (d, ³J_CS 10.5 Hz, 0.5H), 5.58 (d, Jcis 10.5 Hz, 0.5H), 4.78-4.63 (m, 1 H, CH), 4.60-4.49 (m, 0.5H), 4.26-4.12 (m, 1 H), 4.17 (d, ³J 6.2 Hz, 2H, CH₂), 4.12-3.99 (m, 0.5H), 3.78-3.65 (m, 0.5H), 3.27-3.14 (m, 1 H), 3.10-2.96 (m, 0.5H), 2.34-2.19 (m, 1 H), 2.17-2.04 (m, 1 H), 1 .99-1.83 (m, 1 H), 1.68-1.47 (m, 1 H).

[00388] Example 17: Af-[[4-[4-Amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- o(|pyrimidin-3-yl]phenyl]methyl]-2-fluoro-5-methyl-benzenesulfonamide

[00389] [4-[[(2-Fluoro-5-methyl-phenyl)sulfonylaminolmethyllphenyllboronic acid [00390] Following general procedure B, [4-(aminomethyl)phenyl]boronic acid hydrochloride (296.5 mg, 1.58 mmol) and 2-fluoro-5-methylbenzenesulfonylchloride (300.0 mg, 1 .44 mmol) gave [4-[[(2-fluoro-5-methyl-phenyl)sulfonylamino]methyl]phenyl]boronic acid (212.0 mg, 0.40 mmol, 28% yield) as an off-white solid.

[00391 ] UPLC-MS (ES⁺, Short acidic): 1.41 min, m/z 324.2 [M+H]⁺

[00392] fe/f-Butyl (3ffl-3-[4-Amino-3-[4-[[(2-fluoro-5-methyl- phenyl)sulfonylaminolmethyllphenyllpyrazolo[3,4-Qlpyrimidin-1-yllpiperidine-1-carboxylate

[00393] Following general procedure D, [4-[[(2-fluoro-5-methyl- phenyl)sulfonylamino]methyl]phenyl]boronic acid (174.6 mg, 0.54 mmol) and fe/f-butyl (3R)-3-(4- amino-3-iodo-pyrazolo[3,4-rf]pyrimidin-1-yl)piperidine-1-carboxylate (200.0 mg, 0.45 mmol) gave fe/ -butyl (3f?)-3-[4-amino-3-[4-[[(2-fluoro-5-methyl- phenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1-yl]piperidine-1-carboxylate

(151 .0 mg, 0.25 mmol, 56% yield) as a white solid.

[00394] UPLC-MS (ES⁺, Short acidic): 1.75 min, m/z 596.4 [M+H]⁺

[00395] /V-[[4-[4-Amino-1-[(3f?)-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3-yllphenyllmethyll-2-fluoro-5- methyl-benzenesulfonamide

[00396] Following general procedure E, fe/f-butyl (3R)-3-[4-amino-3-[4-[[(2-fluoro-5-methyl- phenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1-yl]piperidine-1-carboxylate

(150.0 mg, 0.25 mmol) afforded /V-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3- yl]phenyl]methyl]-2-fluoro-5-methyl-benzenesulfonamide (110.0 mg, 0.22 mmol, 88% yield) as a white solid.

[00397] UPLC-MS (ES⁺, Short acidic): 1.19 min, m/z 496.3 [M+H]⁺

[00398] /V-[[4-[4-Amino-1-[(3f?)-1-prop-2-enoyl-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3- yllphenyllmethyll-2-fluoro-5-methyl-benzenesulfonamide

[00399] Following general procedure F, A/-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4- rf]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-5-methyl-benzenesulfonamide (110.0 mg, 0.22 mmol) yielded, after purification by preparative HPLC and salt removal by SCX , A/-[[4-[4-amino-1-[(3R)-1- prop-2-enoyl-3-piperidyl]pyrazolo[3,4-rf]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-5-methyl- benzenesulfonamide (50.0 mg, 0.09 mmol, 40% yield) as a colourless oil.

[00400] UPLC-MS (ES⁺, short acidic): 1.44 min, m/z 550.5 [M+H]⁺

[00401 ] UPLC-MS (ES⁺, long acidic): 3.31 min, m/z 550.5 [M+H]⁺

[00402] H-NMR (400 MHz, DMSO-d₆) δ (ppm, 1 :1 mixture of conformers) 8.53 (t, J 6.3 Hz, 1 H, NH), 8.27 (s, 1 H, ArH), 7.55-7.52 (m, 3H, 3 ArH), 7.45-7.22 (m, 1 H, ArH), 7.40 (d, ³J 8.2 Hz, 2H, 2 ArH), 7.25 (dd, J 10.3, 8.4 Hz, 1 H, ArH), 6.86 (dd, ¾_ra„s 16.5, ³J_C/S 10.5 Hz, 0.5H), 6.71 (dd, Jtrans 16.5, ²J_cis 10.5 Hz, 0.5H), 6.13 (d, ³J_ira„s 16.5 Hz, 0.5H), 6.06 (d, ³J_ira„s 16.5 Hz, 0.5H), 5.71 (d, Jcis 10.5 Hz, 0.5H), 5.58 (d, ³J_C(S 10.5 Hz, 0.5H), 4.78-4.63 (m, 1 H, CH), 4.60-4.49 (m, 0.5H), 4.26- 4.13 (m, 1 H), 4.20 (d, ³J 6.2 Hz, 2H, CH₂), 4.12-4.02 (m, 0.5H), 3.77-3.64 (m, 0.5H), 3.27-3.14 (m, 1 H), 3.10-2.96 (m, 0.5H), 2.35-2.28 (m, 2H), 2.30 (s, 3H, CH₃), 2.28-2.20 (m, 1 H), 2.16-2.07 (m, 1 H).

[00403] Example 18: Af-[[4-[4-Amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- o(|pyrimidin-3-yl]phenyl]methyl]-3-methoxy-benzenesulfonamide

[00404] [4-[[(3-Methoxyphenyl)sulfonylaminolmethyllphenyllboronic acid

[00405] Following general procedure B, [4-(aminomethyl)phenyl]boronic acid hydrochloride (300.0 mg, 1.60 mmol) and 3-methoxybenzenesulfonyl chloride (0.25 ml_, 1.76 mmol) gave [4-[[(3- methoxyphenyl)sulfonylamino]methyl]phenyl]boronic acid (462.0 mg, 1.44 mmol, 90% yield) as a white solid.

[00406] UPLC-MS (ES^", Short acidic): 1.35 min, m/z 320.2 [M-H]-

[00407] fe/f-Butyl (3ffl-3-[4-Amino-3-[4-[[(3- methoxyphenyl)sulfonylaminolmethyllphenyllpyrazolo[3,4-Qlpyrimidin-1-yllpiperidine-1-carboxylate

[00408] Following general procedure D, [4-[[(3- methoxyphenyl)sulfonylamino]methyl]phenyl]boronic acid (216.9 mg, 0.68 mmol), fe/f-butyl (3R)-3- (4-amino-3-iodo-pyrazolo[3,4-rf]pyrimidin-1-yl)piperidine-1-carboxylate (200.0 mg, 0.45 mmol) afforded fe/f-butyl (3R)-3-[4-amino-3-[4-[[(3- methoxyphenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1-yl]piperidine-1-carboxylate (240.0 mg,0.40 mmol, 90% yield) as a pale brown solid.

[00409] UPLC-MS (ES⁺, Short acidic): 1.69 min, m/z 594.4 [M+H]⁺

[00410] /V-[[4-[4-Amino-1-[(3f?)-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3-yllphenyllmethyll-3-methoxy- benzenesulfonamide

[00411] Following general procedure E, fe/f-butyl (3R)-3-[4-amino-3-[4-[[(3- methoxyphenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1-yl]piperidine-1-carboxylate (240.0 mg, 0.40 mmol) afforded /V-[[4-[4-amino-1-[(3f?)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3- yl]phenyl]methyl]-3-methoxy-benzenesulfonamide (126.0 mg, 0.26 mmol, 63% yield) as a pale yellow foam.

[00412] UPLC-MS (ES⁺, Short acidic): 1.13 min, m/z 494.3 [M+H]⁺

[00413] /V-[[4-[4-Amino-1-[(3f?)-1-prop-2-enoyl-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3- yllphenyllmethyll-3-methoxy-benzenesulfonamide

[00414] Following general procedure F, A/-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4- rf]pyrimidin-3-yl]phenyl]methyl]-3-methoxy-benzenesulfonamide (126.0 mg, 0.26 mmol) gave, after purification by preparative HPLC and salt removal by SCX column, A/-[[4-[4-amino-1-[(3R)-1-prop-2- enoyl-3-piperidyl]pyrazolo[3,4-rf]pyrimidin-3-yl]phenyl]methyl]-3-methoxy-benzenesulfonamide (23.0 mg, 0.04 mmol, 16% yield).

[00415] UPLC-MS (ES⁺, Short acidic): 1.39min, m/z 548.5 [M+H]⁺ [00416] UPLC-MS (ES⁺, Long acidic): 3.20 min, m/z 548.2 [M+H]⁺

[00417] H-NMR (400 MHz, DMSO-d₆) δ (ppm, 1 :1 mixture of conformers) 8.27 (s, 1 H, ArH), 8.25 (t, J 6.4 Hz, 1 H, NH), 7.57 (d, J 7.7 Hz, 2H, 2 ArH), 7.50 (dd, J 8.0 Hz, 2H, 2 ArH), 7.43-7.38 (m, 3H, 3x ArH), 7.32-7.29 (m, 1 H, ArH), 7.19 (ddd, ³J 8.3, 2.6, 1.0 Hz, 1 H, ArH), 6.86 (dd, ¾_ra„s 16.6, Jcis 10.5 Hz, 0.5H), 6.71 (dd, ¾_ra„s 16.6, ³J_C(S 10.5 Hz, 0.5H), 6.13 (d, ¾_ra„s 16.6 Hz, 0.5H), 6.06 (d, Jtrans 16.6 Hz, 0.5H), 5.71 (d, Jcis 10.5 Hz, 0.5H), 5.58 (d, ³J_C(S 10.5 Hz, 0.5H), 4.81 -4.63 (m, 1 H, CH), 4.60-4.47 (m, 0.5H), 4.29-4.13 (m, 1 H), 4.14-4.03 (m, 0.5H), 4.08 (d, ³J 6.4 Hz, 2H, CH₂), 2.35-2.28 (m, 2H), 3.80 (s, 3H, CH₃), 3.74-3.66 (m, 0.5H), 3.26-3.16 (m, 1 H), 3.08-2.95 (m, 0.5H), 2.31-2.20 (m, 1 H), 2.17-2.06 (m, 1 H), 1 .98-1.86 (m, 1 H), 1.67-1.49 (m, 1 H).

[00418] Example 19: Ai-[[4-[4-Amino-1-[(3/?)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4- d]pyrimidin-3-yl]p enyl]met yl]-4-et oxy-benzenesulfonamide

[00419] [4-[[(4-Ethoxyphenyl)sulfonylaminolmethyllPhenyllboronic acid

[00420] Following general procedure B, [4-(aminomethyl)phenyl]boronic acid hydrochloride (300.0 mg, 1.60 mmol) and 4-ethoxybenzenesulfonyl chloride (388.5 mg, 1.76 mmol) afforded [4- [[(4-ethoxyphenyl)sulfonylamino]methyl]phenyl]boronic acid (386.0 mg, 1.15 mmol, 72% yield) as a white solid.

[00421] UPLC-MS (ES⁺, Short acidic): 1.43 min, m/z 357.9 [M+Na]⁺

[00422] fe/f-Butyl (3ffl-3-[4-amino-3-[4-[[(4- ethoxyphenyl)sulfonylaminolmethyllphenyllpyrazolo[3,4-Qlpyrimidin-1-yllpiperidine-1-carboxylate

[00423] Following general procedure D, [4-[[(4-ethoxyphenyl)sulfonylamino]methyl]phenyl]boronic acid (226.3 mg, 0.68 mmol) and fe/f-butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-rf]pyrimidin-1- yl)piperidine-1-carboxylate (200.0 mg, 0.45 mmol) gave fe/ -butyl (3R)-3-[4-amino-3-[4-[[(4- ethoxyphenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1-yl]piperidine-1-carboxylate (330.0 mg, 0.54 mmol, 86% yield) as a pale brown solid.

[00424] UPLC-MS (ES⁺, Short acidic): 1 .76 min, m/z 608.7 [M+H]⁺

[00425] /V-[[4-[4-Amino-1-[(3f?)-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3-yllphenyllmethyll-4-ethoxy- benzenesulfonamide

[00426] Following general procedure E, fe/f-butyl (3R)-3-[4-amino-3-[4-[[(4- ethoxyphenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1-yl]piperidine-1-carboxylate (330.0 mg, 0.54 mmol) afforded /V-[[4-[4-amino-1-[(3f?)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3- yl]phenyl]methyl]-4-ethoxy-benzenesulfonamide (168.0 mg, 0.33 mmol, 61 % yield) as a pale foam.

[00427] UPLC-MS (ES⁺, Short acidic): 1.18 min, m/z 508.1 [M+H]⁺

[00428] /V-[[4-[4-Amino-1-[(3f?)-1-prop-2-enoyl-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3- yllphenyllmethyll-4-ethoxy-benzenesulfonamide

[00429] Following general procedure F, A/-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4- rf]pyrimidin-3-yl]phenyl]methyl]-4-ethoxy-benzenesulfonamide (168.0 mg, 0.33 mmol) gave, after purification by preparative HPLC and salt removal by SCX cartridge, A/-[[4-[4-amino-1-[(3R)-1-prop- 2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-ethoxy-benzenesulfonamide (12.0 mg, 0.02 mmol, 7% yield).

[00430] UPLC-MS (ES⁺, Short acidic): 1.45 min, m/z 562.2 [M+H]⁺

[00431] UPLC-MS (ES⁺, Long acidic): 3.36 min, m/z 562.2 [M+H]⁺

[00432] H-NMR (400 MHz, DMSO-d₆) δ (ppm, 1 :1 mixture of conformers) 8.27 (s, 1 H, ArH), 8.07 (t, J 6.4 Hz, 1 H, NH), 7.74 (d, ³ J 8.9 Hz, 2H, 2 ArH), 7.59 (d, ³ J 8.2 Hz, 2H, 2 ArH), 7.42 (d, ³ J 8.2 Hz, 2H, 2 ArH), 7.08 (d, ³J 8.9 Hz, 2H, 2 χ ArH), 6.87 (dd, ¾_rans 16.9, ³J_C(S 10.4 Hz, 0.5H), 6.72 (dd, ^zJtrans 16.9, ³J_C(S 10.4 Hz, 0.5H), 6.13 (d, ¾_rans 16.9 Hz, 0.5H), 6.06 (d, ¾_rans 16.9 Hz, 0.5H), 5.71 (d, Jcis 10.4 Hz, 0.5H), 5.59 (d, ³J_CS 10.4 Hz, 0.5H), 4.79-4.64 (m, 1 H, CH), 4.60-4.50 (m,

0.5H), 4.27-4.15 (m, 1 H), 4.12-4.02 (m, 0.5H), 4.09 (q, ²J 7.0 Hz, 2H, CH₂),4.03 (d, ³J 6.4 Hz, 2H, CH₂), 3.76-3.66 (m, 0.5H), 3.27-3.18 (m, 1 H), 3.07-2.96 (m, 0.5H), 2.32-2.21 (m, 1 H), 2.18-2.07 (m, 1 H), 1.99-1.88 (m, 1 H), 1 .69-1.50 (m, 1 H), 1.32 (t, ²J 7.0 Hz, 3H, CH₃).

[00433] Example 20: Af-[[4-[4-Amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- d]pyrimidin-3-yl]phenyl]methyl]-3-chloro-benzenesulfonamide

[00434] [4-[[(3-Chlorophenyl)sulfonylaminolmethyllphenyllboronic acid

[00435] Following general procedure B, [4-(aminomethyl)phenyl]boronic acid hydrochloride (300.0 mg, 1.6 mmol) and 3-chlorobenzenesulfonyl chloride (371 .6 mg, 1.76 mmol) afforded [4-[[(3- chlorophenyl)sulfonylamino]methyl]phenyl]boronic acid (414.0 mg, 1.27 mmol, 79% yield) as an off white solid.

[00436] UPLC-MS (ES-, Short acidic): 1.44 min, m/z 324.2 [M-H]-

[00437] fe/f-Butyl (3ffl-3-[4-amino-3-[4-[[(3- chlorophenyl)sulfonylaminolmethyllphenyllpyrazolo[3,4-Qlpyrimidin-1-yllpiperidine-1-carboxylate

[00438] Following general procedure D, [4-[[(3-chlorophenyl)sulfonylamino]methyl]phenyl]boronic acid (249.2 mg,, 0.77 mmol) and fe/f-butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-rf]pyrimidin-1- yl)piperidine-1-carboxylate (200.0 mg, 0.45 mmol) gave fe/f-butyl (3R)-3-[4-amino-3-[4-[[(3- chlorophenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1-yl]piperidine-1-carboxylate (258.0 mg, 0.39 mmol, 86% yield) as a brown foam.

[00439] UPLC-MS (ES⁺, Short acidic): 1.78 min, m/z 599.1 [M+H]⁺

[00440] /V-[[4-[4-Amino-1-[(3f?)-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3-yllphenyllmethyll-3-chloro- benzenesulfonamide

[00441] Following general procedure E, fe/f-butyl (3fi)-3-[4-amino-3-[4-[[(3- chlorophenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1-yl]piperidine-1-carboxylate (258.0 mg, 0.43 mmol) afforded /V-[[4-[4-amino-1-[(3f?)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3- yl]phenyl]methyl]-3-chloro-benzenesulfonamide (168.0 mg, 0.30 mmol, 70% yield) as a brown foam.

[00442] UPLC-MS (ES⁺, Short acidic): 1.17 min, m/z 499.0 [M+H]⁺ [00443] A/-[[4-[4-Amino-1 -[(3 ?V1 -prop-2-enoyl-3-piperidyllpyrazolo[3,4-clpyrim yllphenyllmethyll-3-chloro-benzenesulfonamide

[00444] Following general procedure F, A/-[[4-[4-amino-1 -[(3R)-3-piperidyl]pyrazolo[3,4- c]pyrimidin-3-yl]phenyl]methyl]-3-chloro-benzenesulfonamide (168.0 mg, 0.34 mmol) afforded, after purification by preparative HPLC A/-[[4-[4-amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- c]pyrimidin-3-yl]phenyl]methyl]-3-chloro-benzenesulfonamide (20.8 mg, 0.04 mmol, 1 1 % yield) as an off white foam.

[00445] UPLC-MS (ES⁺, short acidic): 1 .47 min, m/z 552.1 [M+H]⁺

[00446] UPLC-MS (ES⁺, long acidic): 3.37 min, m/z 552.1 [M+H]⁺

[00447] H-NMR (400 MHz, DMSO-de) δ (ppm, 1 :1 mixture of conformers) 8.46-8.36 (bs, 1 H, NH), 8.27 (s, 1 H), 7.79-7.75 (m, 2H), 7.73-7.68 (m, 1 H), 7.64-7.59 (m, 1 H), 7.59-7.52 (m, 2H), 7.40 (d, J 8 Hz, 1 H), 6.87 (dd, ³J_trans 16.4 Hz, ³J_C(S 10.4 Hz, 0.5H) 6.71 (dd, ³J_trans 16.4 Hz, ³J_C(S 10.4 Hz, 0.5H), 6.13 (d, ³J_trans 16.4 Hz, 0.5H), 6.06 (d, ³J_trans 16.4 Hz, 0.5H), 5.71 (d, ³J_cis 10.40 Hz, 0.5H), 5.58 (d, ³Jds 10.4 Hz, 0.5H), 4.77-4.63 (m, 1 H, CH), 4.58-4.51 (m, 0.5H), 4.25-4.15 (m, 1 H), 4.25 (d, ³J 4.0 Hz, 2H, CH₂), 4.12-4.03 (m, 0.5H), 3.75-3.66 (m, 0.5H), 3.28-3.14 (m, 1 H), 3.08-2.97 (m, 0.5H), 2.31 -2.20 (m, 1 H), 2.17-2.06 (m, 1 H), 1 .98-1 .88 (m, 1 H), 1 .67-1 .51 (m, 1 H).

[00448] Example 21 : Af-[[4-[4-Amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- cflpyrimidin-3-yl]phenyl]methyl]-2-fluoro-W-methyl-benzenesulfonamide

[00449] [4-[[(2-Fluorophenyl)sulfonyl-methyl-aminolmethyllphenyllboronic acid

[00450] To a cooled solution of [4-[[(2-fluorophenyl)sulfonylamino]methyl]phenyl]boronic acid (500.0 mg, 1 .62 mmol) in DMF (1 1 ml_) under a nitrogen atmosphere was added portionwise sodium hydride (200.6 mg, 5.0 mmol) . The solution was stirred at room temperature for 1 hour under nitrogen, lodomethane (0.31 ml_, 5.0 mmol) was then added dropwise, and the mixture was stirred overnight at room temperature. The reaction was diluted with saturated ammonium chloride (100 ml_) before being extracted using ethyl acetate (2 ^χ 100 ml_). The combined organic layers were then washed with 0.1 M NaOH (100 ml_), water (100 mL) and brine (2 100 ml_). The yellow/brown solution was then dried over Na2S04, filtered and concentrated under reduced pressure to give [4-[[(2-fluorophenyl)sulfonyl-methyl-amino]methyl]phenyl]boronic acid (587.0 mg, 1 .09 mmol, 67% yield) as a yellow oil.

[00451] UPLC-MS (ES⁺, Short acidic): 1 .47 min, m/z 323.8 [M+H]⁺

[00452] fe/f-Butyl (3 ?)-3-[4-amino-3-[4-[[(2-fluorophenyl)sulfonyl-methyl- aminolmethyllphenyllpyrazolo[3,4-Qlpyrimidin-1 -yllpiperidine-1 -carboxylate

[00453] Following general procedure D, [4-[[(2-fluorophenyl)sulfonyl-methyl- amino]methyl]phenyl]boronic acid (584.5 mg, 1 .08 mmol) and fe/f-butyl (3R)-3-(4-amino-3-iodo- pyrazolo[3,4-c]pyrimidin-1 -yl)piperidine-1 -carboxylate (260.0 mg, 0.59 mmol) gave fe/f-butyl (3R)-3- [4-amino-3-[4-[[(2-fluorophenyl)sulfonyl-methyl-amino]methyl]phenyl]pyrazolo[3,4-c]pyrimidin-1 - yl]piperidine-1 -carboxylate (408.0 mg, 0.55 mmol, 94% yield) as a brown foam. [00454] UPLC-MS (ES⁺, Short acidic): 1.82 min, m/z 596.5 [M+H]⁺

[00455] A/-[[4-[4-Amino-1-[(3/?)-3-piperidyllpyrazo

methyl-benzenesulfonamide

[00456] Following general procedure E, fe/f-butyl (3R)-3-[4-amino-3-[4-[[(2-fluorophenyl)sulfonyl- methyl-amino]methyl]phenyl]pyrazolo[3,4-(^pyrimidin-1-yl]piperidine-1-carboxylate (408.0 mg,

0.55 mmol) afforded A/-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-<^pyrimidin-3-yl]phenyl]methyl]- 2-fluoro-/V-methyl-benzenesulfonamide (197.0 mg, 0.40 mmol, 69% yield) as a brown/orange foam.

[00457] UPLC-MS (ES⁺, Short acidic): 1.20 min, m/z 496.4 [M+H]⁺

[00458] /V-[[4-[4-Amino-1-[(3f?)-1-prop-2-enoyl-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3- yllphenyllmethyll-2-fluoro-/V-methyl-benzenesulfonamide

[00459] Following general procedure F, A/-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4- rf]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-/V-methyl-benzenesulfonamide (197.0 mg, 0.40 mmol) afforded, after purification by preparative HPLC A/-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- piperidyl]pyrazolo[3,4-rf]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-/V-methyl-benzenesulfonamide (13.0 mg, 0.02 mmol, 6% yield) as an off white foam.

[00460] UPLC-MS (ES⁺, short acidic): 1.50 min, m/z 550.4 [M+H]⁺

[00461] UPLC-MS (ES⁺, long acidic): 3.45 min, m/z 550.5 [M+H]⁺

[00462] H-NMR (400 MHz, DMSO-d₆) δ (ppm, 1 A mixture of conformers) 8.27 (s, 1 H), 7.91 (td, J 7.5, 1 .7 Hz, 1 H), 7.83-7.76 (m, 1 H), 7.69-7.63 (m, 2H), 7.54 (ddd, J 10.8, 8.3, 1.0 Hz, 1 H), 7.50-7.44 (m, 3H), 6.87 (dd, ¾_rans 16.4, ¼_s 10.8 Hz, 0.5H), 6.72 (dd, ¾_rans 16.4, ³J_C(S 10.8 Hz, 0.5H), 6.13 (d, Jtrans 16.4 Hz, 0.5H), 6.06 (d, Jtrans 16.4 Hz, 0.5H), 5.71 (d, Jcis 10.8 Hz, 0.5H), 5.59 (d, ³J_CS 10.8 Hz, 0.5H), 4.79-4.63 (m, 1 H, CH), 4.59-4.50 (m, 0.5H), 4.34 (s, 2H, CH₂), 4.25-4.15 (m, 1 H), 4.12- 4.03 (m, 0.5H), 3.75-3.65 (m, 0.5H), 3.26-3.16 (m, 1 H), 3.07-2.96 (m, 0.5H), 2.74 (s, 3H, CH₃), 2.30- 2.20 (m, 1 H), 2.17-2.07 (m, 1 H), 1 .98-1.88 (m, 1 H), 1 .67-1.51 (m, 1 H).

[00463] Example 22: Ai-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4- o(|pyrimidin-3-yl]phenyl]methyl]-3-fluoro-benzenesulfonamide

[00464] 3-Fluoro-/V-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- vDphenyllmethyllbenzenesulfonamide

[00465] Following general procedure A, 4-aminomethylphenylboronic acid, pinacol ester

(395.3 mg, 1.70 mmol) and 3-fluorobenzenesulfonyl chloride (0.2 mL, 1 .54 mmol) afforded 3-fluoro- A/-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]benzenesulfonamide (570.0 mg, 1.46 mmol, 95% yield) as an orange solid.

[00466] UPLC-MS (ES⁺, short acidic): 1.92 min, m/z 414.3 [M+Na]⁺

[00467] te/f-Butyl (3 ?)-3-[4-amino-3-[4-[[(3-fluorophenyl)sulfonylaminolmethyllphenyllpyrazolo[3,4- tflpyrimidin-1 -yllpiperidine-1 -carboxylate [00468] Following general procedure D, 3-fluoro-/V-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]benzenesulfonamide (279.0 mg, 0.71 mmol) and fe/f-butyl (3R)-3-(4-amino-3-iodo- pyrazolo[3,4-rf]pyrimidin-1-yl)piperidine-1-carboxylate (264.0 mg, 0.59 mmol) gave fe/f-butyl (3R)-3- [4-amino-3-[4-[[(3-fluorophenyl)sulfonylamino]methyl]phenyl]py^

1-carboxylate (386.7 mg, assumed quantitative) as an orange oil.

[00469] ULPC-MS (ES⁺, short acidic): 1.71 min, m/z 582.5 [M+H]⁺

[00470] /V-[[4-[4-Amino-1-[(3f?)-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3-yllphenyllmethyll-3-fluoro- benzenesulfonamide

[00471] Following general procedure E, fe/f-butyl (3fi)-3-[4-amino-3-[4-[[(3- fluorophenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1 -yl]piperidine-1 -carboxylate (386.7 mg, 0.58 mmol) afforded /V-[[4-[4-amino-1-[(3f?)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3- yl]phenyl]methyl]-3-fluoro-benzenesulfonamide (262.0 mg, 0.54 mmol, 94% yield) as a fluffy orange solid.

[00472] UPLC-MS (ES⁺, short acidic): 1.17min, m/z 482.3 [M+H]⁺

[00473] /V-[[4-[4-Amino-1-[(3f?)-1-prop-2-enoyl-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3- yllphenyllmethyll-3-fluoro-benzenesulfonamide

[00474] Following general procedure F, A/-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4- rf]pyrimidin-3-yl]phenyl]methyl]-3-fluoro-benzenesulfonamide (262.0 mg, 0.54 mmol) afforded, after purification by preparative HPLC and salt removal by SCX cartridge, A/-[[4-[4-amino-1-[(3R)-1-prop- 2-enoyl-3^iperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-fluoro-benzenesulfonamide (17.4 mg, 0.03 mmol, 5% yield).

[00475] UPLC-MS (ES⁺, short acidic): 1.40 min, m/z 536.5 [M+H]⁺

[00476] UPLC-MS (ES⁺, long acidic): 3.20 min, m/z 536.4 [M+H]⁺

[00477] H-NMR (400 MHz, DMSO-d₆) δ (ppm, 1 :1 mixture of conformers) 8.46-8.36 (bs, 1 H, NH), 8.27 (s, 1 H), 7.69-7.62 (m, 2H), 7.61 -7.54 (m, 3H), 7.53-7.47 (m, 1 H), 7.40 (d, J 8.3 Hz, 1 H), 6.93- 6.63 (m, 1 H), 6.17-6.01 (m, 1 H), 5.74-5.55 (m, 1 H), 4.78-4.62 (m, 1 H, CH), 4.57-4.48 (m, 0.5H), 4.25-4.14 (m, 1 H), 4.16-4.10 (bs, 2H, CH₂), 4.11-4.03 (m, 0.5H), 3.76-3.65 (m, 0.5H), 3.27-3.14 (m, 1 H), 3.08-2.96 (m, 0.5H), 2.31-2.20 (m, 1 H), 2.17-2.06 (m, 1 H), 1.99-1.86 (m, 1 H), 1 .67-1.50 (m, 1 H).

[00478] Example 23: Ai-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4- o(|pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzenesulfonamide

[00479] [4-[[(2-Methoxyphenyl)sulfonylaminolmethyllphenyllboronic acid

[00480] Following general procedure B, [4-(aminomethyl)phenyl]boronic acid hydrochloride (299.3 mg, 1.60 mmol) and 2-methoxybenzenesulfonyl chloride (363.0 mg, 1 .76 mmol) afforded [4- [[(2-methoxyphenyl)sulfonylamino]methyl]phenyl]boronic acid (217.0 mg, 0.68 mmol, 42% yield) as a yellow gum. [00481] UPLC-MS (ES⁺, short acidic): 1 .29 min, m/z 321 .8 [M+H]⁺

[00482] fe/f-Butyl (3ffl-3-[4-amino-3-[4-[[(2- methoxyphenyl)sulfonylaminolmethvnphenvnpyrazolo[3,4-(^pyrimidin-1 -yllpiperid

[00483] Following general procedure D, fe/f-butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-rf]pyrimidin- 1 -yl)piperidine-1 -carboxylate (200.0 mg, 0.45 mmol), [4-[[(2- methoxyphenyl)sulfonylamino]methyl]phenyl]boronic acid (216.9 mg, 0.68 mmol) gave fe/f-butyl (3R)-3-[4-amino-3-[4-[[(2-methoxyphenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1 - yl]piperidine-1 -carboxylate (210.0 mg, 0.35 mmol, 79% yield) as a yellow solid.

[00484] UPLC-MS (ES⁺, short acidic): 1 .68 min, m/z 594.5 [M+H]⁺

[00485] /V-[[4-[4-Amino-1 -[(3f?)-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3-yllphenyllmethyll-2-methoxy- benzenesulfonamide

[00486] Following general procedure E, fe/f-butyl (3f?)-3-[4-amino-3-[4-[[(2- methoxyphenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1 -yl]piperidine-1 -carboxylate (210.0 mg, 0.35 mmolj afforded /V-[[4-[4-amino-1 -[(3f?)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3- yl]phenyl]methyl]-2-methoxy-benzenesulfonamide (81 .0 mg, 0.16 mmol, 46% yield) as a pale yellow gum

[00487] UPLC-MS (ES⁺, short acidic): 1 .10 min, m/z 494.3 [M+H]⁺

[00488] /V-[[4-[4-Amino-1 -[(3f?)-1 -prop-2-enoyl-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3- yllphenyllmethyll-2-methoxy-benzenesulfonamide

[00489] Following general procedure F, A/-[[4-[4-amino-1 -[(3R)-3-piperidyl]pyrazolo[3,4- rf]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzenesulfonamide (81 .0 mg, 0.16 mmol) afforded, after purification by preparative HPLC and salt removal by SCX cartridge, A/-[[4-[4-amino-1 -[(3R)-1 - prop-2-enoyl-3-piperidyl]pyrazolo[3,4-rf]pyrimidin-3-yl]phenyl]methyl]-2-methoxy- benzenesulfonamide (15.0 mg, 0.03 mmol, 17% yield) as a colourless gum.

[00490] UPLC-MS (ES⁺, Short acidic): 1 .36 min, m/z 548.5 [M+H]⁺

[00491] UPLC-MS (ES⁺, Long acidic): 3.10 min, m/z 548.5 [M+H]⁺

[00492] H-NMR (400 MHz, DMSO-d₆) δ (ppm, 1 :1 mixture of conformers) 8.27 (s, 1 H, ArH), 7.90 (t, J 6.5 Hz, 1 H, NH), 7.70 (dd, J 7.7, 1 .7 Hz, 1 H, ArH), 7.58-7.46 (m, 3H), 7.35 (d, J 8.2 Hz, 1 H, ArH), 7.08 (d, J 8.2 Hz, 2H, 2 ArH), 7.01 (td, J 7.7, 0.9 Hz, 1 H, ArH), 6.86 (dd, ³J,_ra„s 16.7, ³J_C/S 10.5 Hz, 0.5H), 6.70 (dd, ³J_ira„s 16.7, ³J_C/S 10.5 Hz, 0.5H), 6.13 (d, ³J,_ra„s 16.7 Hz, 0.5H), 6.05 (d, ^zJtrans 16.7 Hz, 0.5H), 5.71 (d, ^zJcis 10.5 Hz, 0.5H), 5.58 (d, ³J_C(S 10.5 Hz, 0.5H), 4.78-4.62 (m, 1 H, CH), 4.58-4.48 (m, 0.5H), 4.25-4.1 1 (m, 1 H), 4.13 (d, ³J 6.5 Hz, 2H, CH₂), 4.10-4.01 (m, 0.5H), 3.85 (s, 3H, CH₃), 3.75-3.65 (m, 0.5H), 3.27-3.15 (m, 1 H), 3.08-2.98 (m, 0.5H), 2.32-2.19 (m, 1 H), 2.17- 2.06 (m, 1 H), 1 .98-1 .88 (m, 1 H), 1 .67-1 .50 (m, 1 H).

[00493] Example 24: Ai-[[4-[4-Amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- o(|pyrimidin-3-yl]phenyl]methyl]-2-chloro-benzenesulfonamide [00494] [4-[[(2-Chlorophenyl)sulfonylaminolmethyllphenyllboronic acid

[00495] Following general procedure B, [4-(aminomethyl)phenyl]boronic acid hydrochloride (293.0 mg, 1 .56 mmol) and 2-chlorobenzenesulfonyl chloride (363.0 mg, 1 .72 mmol) afforded crude [4-[[(2-chlorophenyl)sulfonylamino]methyl]phenyl]boronic acid (220.0 mg, 0.68 mmol, 43% yield) as a yellow gum.

[00496] UPLC-MS (ES-, short acidic): 1 .36 min, m/z 324.2 [M-H]-

[00497] fe/f-Butyl (3ffl-3-[4-amino-3-[4-[[(2- chlorophenyl)sulfonylaminolmethyllphenyllpyrazolo[3,4-Qlpyrimidin-1 -yllpiperidine-1 -carboxylate

[00498] Following general procedure D, fe/f-butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-rf]pyrimidin- 1 -yl)piperidine-1 -carboxylate (200.0 mg, 0.45 mmol) and [4-[[(2- chlorophenyl)sulfonylamino]methyl]phenyl]boronic acid (219.9 mg, 0.68 mmol) gave fe/f-butyl (3R)- 3-[4-amino-3-[4-[[(2-chlorophenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1 - yl]piperidine-1 -carboxylate (330.0 mg, assumed quantitative) as a yellow solid.

[00499] UPLC-MS (ES⁺, short acidic): 1 .73 min, m/z 599.0 [M+H]⁺

[00500] /V-[[4-[4-Amino-1 -[(3f?)-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3-yllphenyllmethyll-2-chloro- benzenesulfonamide

[00501] Following general procedure E, fe/f-butyl (3f?)-3-[4-amino-3-[4-[[(2- chlorophenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1 -yl]piperidine-1 -carboxylate (330.0 mg, 0.55 mmol) afforded /V-[[4-[4-amino-1 -[(3f?)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3- yl]phenyl]methyl]-2-chloro-benzenesulfonamide (178.0 mg, 0.36 mmol, 65% yield) as an off-white solid.

[00502] UPLC-MS (ES⁺, Short acidic): 1 .13 min, m/z 499.0 [M+H]⁺

[00503] /V-[[4-[4-Amino-1 -[(3f?)-1 -prop-2-enoyl-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3- yllphenyllmethyll-2-chloro-benzenesulfonamide

[00504] Following general procedure F, A/-[[4-[4-amino-1 -[(3R)-3-piperidyl]pyrazolo[3,4- rf]pyrimidin-3-yl]phenyl]methyl]-2-chloro-benzenesulfonamide (178.0 mg, 0.36 mmol) afforded Λ/-[[4- [4-amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4-rf]pyrimidin-3-yl]phenyl]methyl]-2-chloro- benzenesulfonamide (71 .9 mg, 0.12 mmol, 33% yield) as a white solid.

[00505] UPLC-MS (ES⁺, Short acidic): 1 .41 min, m/z 552.9 [M+H]⁺

[00506] UPLC-MS (ES⁺, Long acidic): 3.22 min, m/z 553.0 [M+H]⁺

[00507] H-NMR (400 MHz, DMSO-d₆) δ (ppm, 1 :1 mixture of conformers) 8.55 (t, J 6.2 Hz, 1 H, NH), 8.27 (s, 1 H, ArH), 7.94 (dt, J 7.7, 0.9 Hz, 1 H, ArH), 7.59-7.55 (m, 2H, 2 ArH), 7.53-7.49 (m, 2H, 2 ArH), 7.49-7.43 (m, 1 H), 7.38 (d, ³J 8.2 Hz, 2H, 2 ArH), 6.86 (dd, ¾_rans 16.8, ³J_C/S 10.5 Hz, 0.5H), 6.70 (dd, ¾_rans 16.8, ³J_C(S 10.5 Hz, 0.5H), 6.13 (d, ¾_ra„s 16.8 Hz, 0.5H), 6.06 (d, ¾_rans 16.8 Hz, 0.5H), 5.70 (d, ³J_C/S 10.5 Hz, 0.5H), 5.58 (d, ³J_C(S 10.5 Hz, 0.5H), 4.79-4.63 (m, 1 H, CH), 4.59- 4.48 (m, 0.5H), 4.24-4.13 (m, 1 H), 4.20 (d, ³J 6.2 Hz, 2H, CH₂), 4.1 1 -4.01 (m, 0.5H), 3.74-3.64 (m, 0.5H), 3.27-3.13 (m, 1 H), 3.08-2.96 (m, 0.5H), 2.31 -2.19 (m, 1 H), 2.16-2.06 (m, 1 H), 1 .98-1.85 (m, 1 H), 1.67-1.48 (m, 1 H).

[00508] Example 25: Af-[[4-[4-Amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- d]pyrimidin-3-yl]p enyl]met yl]-3,4-difluoro-benzenesulfonamide

[00509] 4-[[(3,4-Difluorophenyl)sulfonylaminolmethyllphenyllboronic acid

[00510] Following general procedure B, [4-(aminomethyl)phenyl]boronic acid hydrochloride (300.0 mg, 1.60 mmol) and 3,4-difluorobenzenesulfonyl chloride (374.3 mg, 1.76 mmol) afforded crude 4-[[(3,4-difluorophenyl)sulfonylamino]methyl]phenyl]boronic acid (315.0 mg, 0.96 mmol, 60% yield) as an off white solid.

[00511] UPLC-MS (ES-, short acidic): 1.41 min, m/z 326.2 [M-H]-

[00512] fe/f-Butyl (3ffl-3-[4-amino-3-[4-[[(3.4- difluorophenyl)sulfonylaminolmethyllphenyllpyrazolo[3,4-Qlpyrimidin-1-yllpiperidine-1-carboxylate

[00513] Following general procedure D, [4-[[(3,4- difluorophenyl)sulfonylamino]methyl]phenyl]boronic acid (220.9 mg, 0.68 mmol) andfe/f-butyl (3R)- 3-(4-amino-3-iodo-pyrazolo[3,4-rf]pyrimidin-1-yl)piperidine-1-carboxylate (200.0 mg, 0.45 mmol) gave fe/f-butyl (3R)-3-[4-amino-3-[4-[[(3,4-difluorophenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4- rf]pyrimidin-1-yl]piperidine-1-carboxylate (135.0 mg, 0.23 mmol, 50% yield).

[00514] UPLC-MS (ES⁺, short acidic): 1.74 min, m/z 600.5 [M+H]⁺

[00515] /V-[[4-[4-Amino-1-[(3f?)-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3-yllphenyllmethyll-3,4- difluoro-benzenesulfonamide

[00516] Following general procedure E, fe/f-butyl (3f?)-3-[4-amino-3-[4-[[(3,4- difluorophenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1-yl]piperidine-1-carboxylate (110.0 mg, 0.18 mmol) afforded /V-[[4-[4-amino-1-[(3f?)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3- yl]phenyl]methyl]-3,4-difluoro-benzenesulfonamide (19.0 mg, 0.04 mmol, 21 % yield) as a pale yellow solid.

[00517] UPLC-MS (ES⁺, Short acidic): 1.17 min, m/z 500.2 [M+H]⁺

[00518] /V-[[4-[4-Amino-1-[(3f?)-1-prop-2-enoyl-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3- yllphenyllmethyll-3,4-difluoro-benzenesulfonamide

[00519] Following general procedure F, A/-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4- rf]pyrimidin-3-yl]phenyl]methyl]-3,4-difluoro-benzenesulfonamide (19.0 mg, 0.04 mmol) afforded, after purification by preparative HPLC and salt removal by SCX cartridge, A/-[[4-[4-amino-1-[(3R)-1- prop-2-enoyl-3-piperidyl]pyrazolo[3,4-rf]pyrimidin-3-yl]phenyl]methyl]-3,4-difluoro- benzenesulfonamide (4.6 mg, 0.01 mmol, 20% yield) as a white gummy solid.

[00520] UPLC-MS (ES⁺, Short acidic): 1.44 min, m/z 554.3 [M+H]⁺

[00521] UPLC-MS (ES⁺, Long acidic): 3.30 min, m/z 554.3 [M+H]⁺ [00522] H-NMR (400 MHz, DMSO-d₆) δ (ppm, 1 :1 mixture of conformers) 8.41 (t, J 6.2 Hz, 1 H, NH), 8.27 (s, 1 H, ArH), 7.87-7.81 (m, 1 H), 7.71-7.63 (m, 2H), 7.61-7.55 (m, 2H), 7.41 (d, ³J 8.1 Hz, 2H, 2 ArH), 6.87 (dd, ¾_rans 16.3, ¼_s 10.4 Hz, 0.5H), 6.71 (dd, ¾_rans 16.3, ³J_C(S 10.4 Hz, 0.5H), 6.13 (d, Jtrans 16.3 Hz, 0.5H), 6.06 (d, ¾_ra„s 16.3 Hz, 0.5H), 5.71 (d, ³J_C/S 10.4 Hz, 0.5H), 5.58 (d, Jcis 10.4 Hz, 0.5H), 4.79-4.64 (m, 1 H, CH), 4.59-4.49 (m, 0.5H), 4.26-4.14 (m, 1 H), 4.13 (d, ³J 6.2 Hz, 2H, CH₂), 4.11-4.02 (m, 0.5H), 3.76-3.66 (m, 0.5H), 3.26-3.14 (m, 1 H), 3.08-2.96 (m, 0.5H), 2.29-2.19 (m, 1 H), 2.17-2.06 (m, 1 H), 2.01 -1.86 (m, 1 H), 1.68-1.50 (m, 1 H).

[00523] Example 26: Af-[[4-[4-Amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- d]pyrimidin-3-yl]p enyl]met yl]-4-fluoro-3-met oxy-benzenesulfonamide

[00524] [4-[[(4-Fluoro-3-methoxy-phenyl)sulfonylaminolmethyllphenyllboronic acid

[00525] Following general procedure B, [4-(aminomethyl)phenyl]boronic acid hydrochloride (300.0 mg, 1.6 mmol) and 4-fluoro-3-methoxybenzenesulfonyl chloride (395.5 mg, 1 .76 mmol) afforded crude [4-[[(4-fluoro-3-methoxy-phenyl)sulfonylamino]methyl]phenyl]boronic acid (505.0 mg, 1.49 mmol, 93% yield) as an off-white solid.

[00526] UPLC-MS (ES⁺, short acidic): 1.37 min, m/z 339.9 [M+H]⁺

[00527] fe/f-Butyl (3ffl-3-[4-amino-3-[4-[[(4-fluoro-3-methoxy- phenyl)sulfonylaminolmethyllphenyllpyrazolo[3,4-Qlpyrimidin-1-yllpiperidine-1-carboxylate

[00528] Following general procedure D, [4-[[(4-fluoro-3-methoxy- phenyl)sulfonylamino]methyl]phenyl]boronic acid (183.2 mg, 0.54 mmol), fe/r-butyl (3R)-3-(4-amino- 3-iodo-pyrazolo[3,4-rf]pyrimidin-1-yl)piperidine-1-carboxylate (200.0 mg, 0.45 mmol) gave fe/r-butyl (3R)-3-[4-amino-3-[4-[[(4-fluoro-3-methoxy-phenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4- rf]pyrimidin-1-yl]piperidine-1-carboxylate (135.0 mg, 0.22 mmol, 49% yield).

[00529] UPLC-MS (ES⁺, short acidic): 1.71 min, m/z 612.3 [M+H]⁺

[00530] /V-[[4-[4-Amino-1-[(3f?)-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3-yllphenyllmethyll-4-fluoro-3- methoxy-benzenesulfonamide

[00531] Following general procedure E, fe/r-butyl (3R)-3-[4-amino-3-[4-[[(4-fluoro-3-methoxy- phenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1-yl]piperidine-1-carboxylate

(145.0 mg, 0.24 mmol) afforded /V-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3- yl]phenyl]methyl]-4-fluoro-3-methoxy-benzenesulfonamide (95.0 mg, 0.13 mmol, 56% yield) as a pale yellow solid.

[00532] UPLC-MS (ES⁺, short acidic): 1.14 min, m/z 512.4 [M+H]⁺

[00533] /V-[[4-[4-Amino-1-[(3f?)-1-prop-2-enoyl-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3- yllphenyllmethyll-4-fluoro-3-methoxy-benzenesulfonamide

[00534] Following general procedure F, A/-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4- rf]pyrimidin-3-yl]phenyl]methyl]-4-fluoro-3-methoxy-benzenesulfonamide (95.0 mg, 0.19 mmol) afforded, after purification by preparative HPLC and salt removal by SCX cartridge, A/-[[4-[4-amino- 1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4-<^pyrimidin-3-yl]phenyl]meth benzenesulfonamide (36.4 mg , 0.06 mmol, 34% yield) as a white gummy solid.

[00535] UPLC-MS (ES⁺, Short acidic): 1 .42 min, m/z 566.4 [M+H]⁺

[00536] UPLC-MS (ES⁺, Long acidic): 3.24 min, m/z 566.5 [M+H]⁺

[00537] H-NMR (400 MHz, DMSO-c₆) δ (ppm, 1 A mixture of conformers) 8.27 (s, 1 H, ArH), 7.62- 7.56 (m, 2H, 2 ArH), 7.54-7.50 (m, 1 H, ArH), 7.45-7.39 (m, 4H, 4 ArH), 6.86 (dd, ¾_rans 16.7, ³J_CS 10.4 Hz, 0.5H), 6.71 (dd, ¾_rans 16.7, ¼_s 10.4 Hz, 0.5H), 6.1 3 (d, ¾_rans 16.7 Hz, 0.5H), 6.06 (d, ^zJtrans 16.7 Hz, 0.5H), 5.71 (d, ^zJcis 10.4 Hz, 0.5H), 5.58 (d, ³J_C(S 10.4 Hz, 0.5H), 4.80-4.63 (m, 1 H, CH), 4.60-4.49 (m, 0.5H), 4.27-4.12 (m, 1 H), 4.09 (s, 2H, CH₂), 4.08-4.02 (m, 0.5H), 3.90 (s, 3H, CH₃), 3.76-3.65 (m, 0.5H), 3.28-3.13 (m, 1 H), 3.08-2.96 (m, 0.5H), 2.32-2.20 (m, 1 H), 2.17-2.06 (m, 1 H), 1 .98-1 .86 (m, 1 H), 1 .68-1 .49 (m, 1 H).

[00538] Example 27: Af-[[4-[4-Amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- o(|pyrimidin-3-yl]phenyl]methyl]-2-fluoro-4-methyl-benzenesulfonamide

[00539] [4-[[(2-Fluoro-4-methyl-phenyl)sulfonylaminolmethyllphenyllboronic acid

[00540] Following general procedure B, [4-(aminomethyl)phenyl]boronic acid hydrochloride (300.0 mg, 1 .6 mmol) and 2-fluoro-4-methylbenzenesulfonylchloride (367.3 mg, 1 .76 mmol) afforded crude [4-[[(2-fluoro-4-methyl-phenyl)sulfonylamino]methyl]phenyl]boronic acid (451 .0 mg , 1 .40 mmol, 87% yield) as an off white solid.

[00541] UPLC-MS (ES^", short acidic): 1 .40 min, m/z 322.2 [M-H]- [00542] fe/f-Butyl (3ffl-3-[4-amino-3-[4-[[(2-fluoro-4-methyl- phenyl)sulfonylaminolmethyllphenyllpyrazolo[3,4-Qlpyrimidin-1 -yllpiperidine-1 -carboxylate

[00543] Following general procedure D, [4-[[(2-fluoro-4-methyl- phenyl)sulfonylamino]methyl]phenyl]boronic acid (216.9 mg , 0.68 mmol), fe/r-butyl (3R)-3-(4-amino- 3-iodo-pyrazolo[3,4-c]pyrimidin-1 -yl)piperidine-1 -carboxylate (200.0 mg, 0.45 mmol) gave fe/r-butyl (3R)-3-[4-amino-3-[4-[[(2-fluoro-4-methyl-phenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4- c]pyrimidin-1 -yl]piperidine-1 -carboxylate (200.0 mg , 0.24 mmol, 54% yield) as an orange oil.

[00544] UPLC-MS (ES⁺, short acidic): 1 .75 min, m/z 596.5 [M+H]⁺

[00545] /V-[[4-[4-Amino-1 -[(3f?)-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3-yllphenyllmethyll-2-fluoro-4- methyl-benzenesulfonamide

[00546] Following general procedure E, fe/r-butyl (3R)-3-[4-amino-3-[4-[[(2-fluoro-4-methyl- phenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-c]pyrimidin-1 -yl]piperidine-1 -carboxylate

(200.0 mg, 0.34 mmol) afforded /V-[[4-[4-amino-1 -[(3f?)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3- yl]phenyl]methyl]-2-fluoro-4-methyl-benzenesulfonamide (1 17.0 mg, 0.24 mmol, 70% yield) as a pale foam.

[00547] UPLC-MS (ES⁺, short acidic): 1 .17 min, m/z 496.2 [M+H]⁺ [00548] A/-[[4-[4-Amino-1-[(3 ?V1-prop-2-enoyl-3-piperidyllpyrazolo[3,4-Qlpyrim yllphenyllmethyll-2-fluoro-4-methyl-benzenesulfonamide

[00549] Following general procedure F, A/-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4- <^pyrimidin-3-yl]phenyl]methyl]-2-fluoro-4-methyl-benzenesulfonamide (117.0 mg, 0.24 mmol) afforded, after purification by preparative HPLC and salt removal by SCX cartridge, A/-[[4-[4-amino- 1-[(3R)-1^rop-2-enoyl-3^iperidyl]pyrazolo[3,4-(^pyrimidin-3-yl]phenyl]methyl]-2-fluoro-4-methyl- benzenesulfonamide (3.0 mg, 0.05 mmol, 3% yield) as a thin film.

[00550] UPLC-MS (ES⁺, Short acidic): 1.43 min, m/z 550.2 [M+H]⁺

[00551] UPLC-MS (ES⁺, Long acidic): 3.30 min, m/z 550.1 [M+H]⁺

[00552] H-NMR (400 MHz, DMSO-d₆) δ (ppm, 1 :1 mixture of conformers) 8.48 (t, J 64 Hz, 1 H, NH), 8.27 (s, 1 H, ArH), 7.64 (dd, J 7.9, 7.9 Hz, 1 H, ArH), 7.55 (bd, ³ J 8.1 Hz, 2H, 2 ArH), 7.40 (d, ³J 8.1 Hz, 2H, 2 x ArH), 7.20 (d, ³J 11.5 Hz, 1 H, ArH), 7.13 (d, ³J 7.9 Hz, 1 H, ArH), 6.87 (dd, ¾_rans 16.5, ^zJcis 10.5 Hz, 0.5H), 6.71 (dd, ¾_rans 16.5, ³J_CS 10.5 Hz, 0.5H), 6.13 (d, ¾_rans 16.5 Hz, 0.5H), 6.06 (d, ^zJtrans 16.5 Hz, 0.5H), 5.71 (d, ³J_C(S 10.5 Hz, 0.5H), 5.58 (d, ³J_C(S 10.5 Hz, 0.5H), 4.78-4.63 (m, 1 H, CH), 4.58-4.49 (m, 0.5H), 4.26-4.13 (m, 1 H), 4.17 (d, ³J 6.4 Hz, 2H, CH₂), 4.12-4.03 (m, 1 H), 3.76-3.66 (m, 0.5H), 3.26-3.13 (m, 1 H), 3.07-2.96 (m, 0.5H), 2.33 (s, 3H, CH₃), 2.32-2.19 (m, 1 H), 2.15-2.06 (m, 1 H), 1 .98-1.87 (m, 1 H), 1.70-1.49 (m, 1 H).

[00553] Example 28: Af-[[4-[4-Amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- o(|pyrimidin-3-yl]phenyl]methyl]-2,4-dimethyl-benzenesulfonamide

[00554] [4-[[(2,4-Dimethylphenyl)sulfonylaminolmethyllphenyllboronic acid

[00555] Following general procedure B, [4-(aminomethyl)phenyl]boronic acid hydrochloride (300.0 mg, 1.60 mmol) and 2,4-dimethylbenzenesulfonyl chloride (360.4 mg, 1 .76 mmol) afforded crude [4-[[(2,4-dimethylphenyl)sulfonylamino]methyl]phenyl]boronic acid (340.0 mg, 1.07 mmol, 67% yield) as an off white solid.

[00556] UPLC-MS (ES⁺, Short acidic) 1.48 min, m/z 319.9 [M+H]⁺

[00557] fe/f-Butyl (3ffl-3-[4-amino-3-[4-[[(2.4- dimethylphenyl)sulfonylaminolmethyllphenyllpyrazolo[3,4-Qlpyrimidin-1-yllpiperidine-1-carboxylate

[00558] Following general procedure D, [4-[[(2,4- dimethylphenyl)sulfonylamino]methyl]phenyl]boronic acid (323.3 mg, 1.01 mmol) (300.0 mg, 0.68 mmol), fe/f-butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-rf]pyrimidin-1-yl)piperidine-1-carboxylate gave fe/f-butyl (3f?)-3-[4-amino-3-[4-[[(2,4- dimethylphenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1-yl]piperidine-1-carboxylate (70.0 mg, 0.12 mmol, 18% yield) as a brown foam.

[00559] UPLC-MS (ES+, Short acidic): 1.80 min, m/z 592.3 [M+H]+

[00560] /V-[[4-[4-Amino-1-[(3f?)-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3-yllphenyllmethyll-2,4- dimethyl-benzenesulfonamide Following general procedure E, fe/ -butyl (3R)-3-[4-amino-3-[4-[[(2,4- dimethylphenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-^

(70.0 mg, 0.12 mmol) afforded /V-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-c]pyrimidin-3- yl]phenyl]methyl]-2,4-dimethyl-benzenesulfonamide (60.0 mg, assumed quantitative) as a pale foam.

[00561] UPLC-MS (ES⁺, Short acidic): 1.22 min, m/z 492.2 [M+H]⁺

[00562] /V-[[4-[4-Amino-1-[(3f?)-1-prop-2-enoyl-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3- yllphenyllmethyll-2,4-dimethyl-benzenesulfonamide

[00563] Following general procedure F, A/-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4- c]pyrimidin-3-yl]phenyl]methyl]-2,4-dimethyl-benzenesulfonamide (63.0 mg, 0.13 mmol) afforded, after purification by preparative HPLC and salt removal by SCX cartridge, A/-[[4-[4-amino-1-[(3R)-1- prop-2-enoyl-3-piperidyl]pyrazolo[3,4-c]pyrimidin-3-yl]phenyl]methyl]-2,4-dimethyl- benzenesulfonamide (3.0 mg, 0.01 mmol, 4% yield) as a thin film.

[00564] UPLC-MS (ES⁺, Short acidic) 1.49 min, m/z 546.2 [M+H]⁺

[00565] UPLC-MS (ES⁺, Long acidic) 3.45 min, m/z 546.2 [M+H]⁺

[00566] H NMR (400 MHz, DMSO-c₆, δ) (ppm, 1 :1 mixture of conformers) 8.27 (s, 1 H, ArH), 8.25 (t, J 6.2 Hz, 1 H, NH), 7.61 (d, J 1.1 Hz, 1 H), 7.56-7.50 (m, 2H), 7.36 (d, ³ J 8.1 Hz, 2H, 2 ArH), 7.29 (dd, J 7.7, 1.1 Hz, 1 H), 7.22 (d, J 7.7 Hz, 1 H), 6.87 (dd, ¾_ra„_s 16.5, ³J_C/S 10.5 Hz, 0.5H), 6.71 (dd, Jtrans 16.5, ³J_C(S 10.5 Hz, 0.5H), 6.13 (d, ³J_ira„s 16.5 Hz, 0.5H), 6.06 (d, ³J_ira„s 16.5 Hz, 0.5H), 5.71 (d, ^zJcis 10.5 Hz, 0.5H), 5.58 (d, ³J_{C S} 10.5 Hz, 0.5H), 4.78-4.62 (m, 1 H), 4.59-4.48 (m, 0.5H),

4.25-4.14 (m, 1 H), 4.1 1 (d, ³J 6.2 Hz, 2H, CH₂), 4.11 -4.01 (m, 0.5H), 3.76-3.64 (m, 0.5H), 3.26-3.13 (m, 1 H), 3.08-2.96 (m, 0.5H), 2.52 (s, 3H, CH₃), 2.29 (s, 3H, CH₃), 2.29-2.20 (m, 1 H), 2.17-2.07 (m, 1 H), 1.97 -1.87 (m, 1 H), 1.67-1.49 (m, 1 H).

[00567] Example 29: Af-[[4-[4-Amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- o(|pyrimidin-3-yl]phenyl]methyl]-2-methoxy-5-methyl-benzenesulfonamide

[00568] [4-[[(2-Methoxy-5-methyl-phenyl)sulfonylaminolmethyllphenyllboronic acid

[00569] Following general procedure B, [4-(aminomethyl)phenyl]boronic acid hydrochloride (300.0 mg, 1.60 mmol) and 2-methoxy-5-methylbenzene-1-sulfonyl chloride (388.5 mg, 1.76 mmol) afforded crude [4-[[(2-methoxy-5-methyl-phenyl)sulfonylamino]methyl]phenyl]boronic acid

(495.0 mg, 1.48 mmol, 92% yield).

[00570] UPLC-MS (ES⁺, Short acidic) 1.39 min, m/z 335.8 [M+H]⁺

[00571] fe/f-Butyl (3ffl-3-[4-amino-3-[4-[[(2-methoxy-5-methyl- phenyl)sulfonylaminolmethyllphenyllpyrazolo[3,4-Qlpyrimidin-1-yllpiperidine-1-carboxylate

[00572] Following general procedure D, [4-[[(2-methoxy-5-methyl- phenyl)sulfonylamino]methyl]phenyl]boronic acid (226.3 mg, 0.68 mmol) and fe/f-butyl (3R)-3-(4- amino-3-iodo-pyrazolo[3,4-c]pyrimidin-1-yl)piperidine-1-carboxylate (200 mg, 0.45 mmol) gave tert- butyl (3R)-3-[4-amino-3-[4-[[(2-methoxy-5-methyl^henyl)sulfonylamino]methyl]phen

rf]pyrimidin-1 -yl]piperidine-1 -carboxylate (248.0 mg, 0.41 mmol, 91 % yield) as a brown foam.

[00573] UPLC-MS (ES⁺, Short acidic): 1 .74 min, m/z 608.5 [M+H]⁺

[00574] A/-[[4-[4-Amino-1 -[(3/?)-3-piperidyllpyrazolore

5-methyl-benzenesulfonamide

[00575] Following general procedure E, fe/f-butyl (3R)-3-[4-amino-3-[4-[[(2-methoxy-5-methyl- phenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1 -yl]piperidine-1 -carboxylate

(180.0 mg, 0.30 mmol) afforded /V-[[4-[4-amino-1 -[(3f?)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3- yl]phenyl]methyl]-2-methoxy-5-methyl-benzenesulfonamide (130.0 mg, 0.26 mmol, 86 % yield) as a colourless solid.

[00576] UPLC-MS (ES⁺, Short acidic): 1 .16 min, m/z 508.1 [M+H]⁺

[00577] /V-[[4-[4-Amino-1 -[(3f?)-1 -prop-2-enoyl-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3- yllphenyllmethyll-2-methoxy-5-methyl-benzenesulfonamide

[00578] Following general procedure F, A/-[[4-[4-amino-1 -[(3R)-3-piperidyl]pyrazolo[3,4- rf]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-5-methyl-benzenesulfonamide (150.0 mg, 0.30 mmol) afforded, after purification by preparative HPLC and salt removal by SCX cartridge, A/-[[4-[4-amino- 1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4-rf]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-5-methyl- benzenesulfonamide (22 mg, 0.04 mmol, 13% yield).

[00579] UPLC-MS (ES⁺, Short acidic) 1 .43 min, m/z 562.2 [M+H]⁺

[00580] UPLC-MS (ES⁺, Long acidic) 3.29 min, m/z 562.2 [M+H]⁺

[00581] H NMR (400 MHz, DMSO-d₆, δ) (ppm, 1 :1 mixture of conformers): 8.27 (s, 1 H, ArH), 7.82 (t, J 64 Hz, 1 H, NH), 7.55-7.47 (m, 3H), 7.39-7.31 (m, 3H), 7.00 (d, ³J 8.6 Hz, 1 H), 6.92-6.64 (m, 1 H), 6.18-6.00 (m, 1 H), 5.76-5.54 (m, 1 H), 4.79-4.62 (m, 1 H), 4.59-4.48 (m, 0.5H), 4.26-4.14 (m, 1 H), 4.1 1 (d, ³J 6.4 Hz, 2H, CH₂), 4.08-4.01 (m, 0.5H), 3.81 (s, 3H, CH₃), 3.75-3.65 (m, 0.5H), 3.27- 3.13 (m, 1 H), 3.10-2.97 (m, 0.5H), 2.31 -2.20 (m, 1 H), 2.26 (s, 3H, CH₃), 2.16-2.06 (m, 1 H), 1 .98- 1 .87 (m, 1 H), 1 .67-1 .49 (m, 1 H).

[00582] Example 30: Af-[[4-[4-Amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- o(|pyrimidin-3-yl]phenyl]methyl]-2,5-difluoro-benzenesulfonamide

[00583] [4-[[(2,5-Difluorophenyl)sulfonylaminolmethyllphenyllboronic acid

[00584] Following general procedure B, [4-(aminomethyl)phenyl]boronic acid hydrochloride (300.0 mg, 1 .60 mmol) and 2,5-difluorobenzene sulfonyl chloride (0.24 mL, 1 .76 mmol) afforded crude [4- [[(2,5-difluorophenyl)sulfonylamino]methyl]phenyl]boronic acid (462.0 mg, 1 .41 mmol, 88% yield) as a yellow solid.

[00585] UPLC-MS (ES-, short acidic): 1 .36 min, m/z 326.2 [M-H]- [00586] fe/f-Butyl (3ffl-3-[4-amino-3-[4-[[(2.5- difluorophenyl)sulfonylaminolmethyllphenyllpyrazolo[3,4-(^pyrimidi

[00587] Following general procedure D, fe/f-butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-rf]pyrimidin- 1-yl)piperidine-1-carboxylate (200.0 mg, 0.45 mmol) and [4-[[(2,5- difluorophenyl)sulfonylamino]methyl]phenyl]boronic acid (220.9 mg, 0.68 mmol) gave, after purification by flash column chromatography (DCM/MeOH 100:0 to 90:10), fe/f-butyl (3f?)-3-[4- amino-3-[4-[[(2,5-difluorophenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1- yl]piperidine-1-carboxylate (130.0 mg, 0.22 mmol, 48% yield) as a pale yellow solid.

[00588] UPLC-MS (ES⁺, Short acidic): 1 .71 min, m/z 600.3 [M+H]⁺

[00589] /V-[[4-[4-Amino-1-[(3f?)-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3-yllphenyllmethyll-2,5- difluoro-benzenesulfonamide

[00590] Following general procedure E, fe/f-butyl (3f?)-3-[4-amino-3-[4-[[(2,5- difluorophenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1-yl]piperidine-1-carboxylate (130.0 mg, 0.22 mmol) gave A/-[[4-[4-amino-1-[(3f?)-3-piperidyl]pyrazolo[3,4-rf]pyrimidin-3- yl]phenyl]methyl]-2,5-difluoro-benzenesulfonamide (96.0 mg, 0.19 mmol, 89% yield) as a white solid.

[00591] UPLC-MS (ES⁺, Short acidic): 1.13 min, m/z 500.2 [M+H]⁺

[00592] /V-[[4-[4-Amino-1-[(3f?)-1-prop-2-enoyl-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3- yllphenyllmethyll-2,5-difluoro-benzenesulfonamide

[00593] Following general procedure F, A/-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4- rf]pyrimidin-3-yl]phenyl]methyl]-2,5-difluoro-benzenesulfonamide (96.0 mg, 0.19 mmol) gave, after purification by preparative LC-MS and salt removal by SCX cartridge, A/-[[4-[4-amino-1-[(3R)-1- prop-2-enoyl-3-piperidyl]pyrazolo[3,4-rf]pyrimidin-3-yl]phenyl]methyl]-2,5-difluoro- benzenesulfonamide (17.0 mg, 0.03 mmol, 16% yield) as a thin white film.

[00594] UPLC-MS (ES⁺, Short acidic): 1.42 min, m/z 554.4 [M+H]⁺

[00595] UPLC-MS (ES⁺, Long acidic): 3.22 min, m/z 554.4 [M+H]⁺

[00596] H NMR (400 MHz, DMSO-d₆, δ) (ppm, 1 :1 mixture of conformers): 8.79 (t, ³J 5.6 Hz, 1 H, NH), 8.33 (s, 1 H, ArH), 7.59-7.51 (m, 4H, 4 χ ArH), 7.50-7.44 (m, 1 H, ArH), 7.41 (d, ³ J 8.4 Hz, 2H, 2 x ArH), 7.50 (d, ³ J 7.9 Hz, 2H, 2 χ ArH), 6.87 (dd, ³J_trans 16.7, ³J_cis 10.3 Hz, 0.5H), 6.70 (dd, ³Jtrans 15.9, ^zJcis 10.3 Hz, 0.5H), 6.13 (d, ³Jtrans 15.9 Hz, 0.5H), 6.06 (d, ³Jtrans 15.9 Hz, 0.5H), 5.71 (d, ³J_cis 10.3 Hz, 0.5H), 5.58 (d, ³J_cis 10.3 Hz, 0.5H), 4.76-4.68 (m, 1 H), 4.57-5.42 (m, 0.5H), 4.25 (d, ³J 5.8 Hz, 2H, CH₂), 4.22-4.17 (m, 0.5H), 4.09-4.05 (m, 0.5H), 3.75-3.68 (m, 1 H), 3.26-3.18 (m, 1 H), 3.08- 3.01 (m, 0.5H), 2.30-2.22 (m, 1 H), 2.16-2.1 1 (m, 1 H), 1.97-1.91 (m, 1 H), 1.66-1.56 (m, 1 H).

[00597] Example 31 : Af-[[4-[4-Amino-1 -[(3R)-1 -prop-2-enoyl-piperidyl]pyrazolo[3,4- o(|pyrimidin-3-yl]phenyl]methyl]-4-methyl-benzenesulfonamide

[00598] [4-[(p-Tolylsulfonylamino)methyllphenyllboronic acid [00599] Following general procedure B, [4-(aminomethyl)phenyl]boronic acid hydrochloride (300.0 mg, 1.60 mmol) and p-toluenesulfonyl chloride (335.7 mg, 1.76 mmol) afforded crude [4-[(p- tolylsulfonylamino)methyl]phenyl]boronic acid (515.0 mg, assumed quantitative) as an off-white solid.

[00600] UPLC-MS (ES⁺, Short acidic): 1.40 min, m/z 305.8 [M+H]⁺

[00601 ] fe/f-Butyl (3f?)-3-[4-amino-3-[4-[(p-tolylsulfonylamino)methyllphenyllpyrazolo[3,4- tflpyrimidin-1 -yllpiperidine-1 -carboxylate

[00602] Following general procedure D, [4-[[(4-methylphenyl)sulfonylamino]methyl]phenyl]boronic acid (329.8 mg, 1.01 mmol) and fe/f-butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-rf]pyrimidin-1- yl)piperidine-1-carboxylate (200.0 mg, 0.45 mmol) gave crude fe/ -butyl (3R)-3-[4-amino-3-[4-[(p- tolylsulfonylamino)methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1-yl]piperidine-1-carboxylate (750.0 mg, assumed quantitative) as a brown solid.

[00603] UPLC-MS (ES⁺, Short acidic): 1.73 min, m/z 578.5 [M+H]⁺

[00604] /V-[[4-[4-Amino-1-[(3f?)-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3-yllphenyllmethyll-4-methyl- benzenesulfonamide

[00605] Following general procedure E, fe/f-butyl (3R)-3-[4-amino-3-[4-[(p- tolylsulfonylamino)methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1-yl]piperidine-1-carboxylate (300.0 mg, 0.52 mmol) afforded A/-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-rf]pyrimidin-3-yl]phenyl]methyl]- 4-methyl-benzenesulfonamide (120.0 mg, 0.25 mmol, 48% yield) as a pale foam.

[00606] UPLC-MS (ES⁺, Short acidic): 1.16 min, m/z 478.3 [M+H]⁺

[00607] /V-[[4-[4-Amino-1-[(3f?)-1-prop-2-enoyl-piperidyllpyrazolo[3,4-Qlpyrimidin-3- yllphenyllmethyll-4-methyl- benzenesulfonamide

[00608] Following general procedure F, A/-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4- rf]pyrimidin-3-yl]phenyl]methyl]-4-methyl-benzenesulfonamide (120.0 mg, 0.25 mmol) afforded, after purification by preparative LC-MS and salt removal by SCX cartridge, A/-[[4-[4-amino-1-[(3R)-1- prop-2-enoyl-piperidyl]pyrazolo[3,4-rf]pyrimidin-3-yl]phenyl]methyl]-4-methyl-benzenesulfonamide (15.0 mg, 0.03 mmol, 11 % yield) as a thin film.

[00609] UPLC-MS (ES⁺, Short acidic): 1.46 min, m/z 532.3 [M+H]⁺

[0061 0] UPLC-MS (ES⁺, Long acidic): 3.29 min, m/z 532.2 [M+H]⁺

[0061 1 ] H NMR (400 MHz, DMSO-d₆, δ) (ppm, 1 :1 mixture of conformers): 8.27 (s, 1 H, ArH), 8.17 (t, ³ J 7.0 Hz, 1 H, NH), 7.72 (d, ³ J 8.3 Hz, 2H, 2 ArH), 7.59 (d, 2H, ³ J 8.3 Hz, 2 ArH), 7.43 - 7.38 (m, 4H, 4 ArH), 6.89 (dd, ¾_rans 16.4, ³J_C(S 10.4 Hz, 0.5H), 6.72 (dd, 0.5H, ¾_rans 16.0, ³J_CS 10.4 Hz, 0.5H), 6.14 (d, ^zJtrans 16.4 Hz, 0.5H), 6.07 (d, ¾_rans 16.8 Hz, 0.5H), 5.71 (d, ³J_C(S 10.8 Hz, 0.5H), 5.59 (d, ^zJcis 10.0 Hz, 0.5H), 4.79-4.64 (m, 1 H), 4.57-4.54 (m, 0.5H), 4.19-4.12 (m, 1 H), 4.11-4.08 (m, 0.5H), 4.05 (d, ²J 6.0 Hz, 2H, CH₂), 3.74-3.68 (m, 0.5H), 3.26-3.18 (m, 1 H), 3.05-3.00 (m, 0.5H), 2.38 (s, 3H, CH₃), 2.32-2.21 (m, 1 H), 2.15-2.10 (m, 1 H), 1 .96-1.91 (m, 1 H), 1.65-1.55 (m, 1 H). [00612] Example 32: Af-[[4-[4-Amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- o(|pyrimidin-3-yl]phenyl]methyl]-4-methoxy-benzenesulfonamide

[00613] [4-[[(4-Methoxyphenyl)sulfonylaminolmethyllphenyllboronic acid

[00614] Following general procedure B, [4-(aminomethyl)phenyl]boronic acid hydrochloride (300.0 mg, 1.60 mmol) and p-anisylsulfonyl chloride (363.8 mg, 1.76 mmol) afforded crude [4-[[(4- methoxyphenyl)sulfonylamino]methyl]phenyl]boronic acid (580.0 mg, assumed quantitative) as an off-white solid.

[00615] UPLC-MS (ES⁺, Short acidic): 1.33 min, m/z 321.7 [M+H]⁺

[00616] fe/f-Butyl (3ffl-3-[4-amino-3-[4-[[(4- methoxyphenyl)sulfonylaminolmethyllphenyllpyrazolo[3,4-Qlpyrimidin-1-yllpiperidine-1-carboxylate

[00617] Following general procedure D, [4-[[(4- methoxyphenyl)sulfonylamino]methyl]phenyl]boronic acid (325.3 mg, 1.01 mmol) and fe/f-butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-rf]pyrimidin-1-yl)piperidine-1-carboxylate (200.0 mg,

0.45 mmol) gave fe/f-butyl (3f?)-3-[4-amino-3-[4-[[(4- methoxyphenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1 -yl]piperidine-1 -carboxylate (200.0 mg, 0.34 mmol, 50% yield) as an orange oil.

[00618] UPLC-MS (ES⁺, Short acidic): 1.68 min, m/z 594.5 [M+H]⁺

[00619] /V-[[4-[4-Amino-1-[(3f?)-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3-yllphenyllmethyll-4-methoxy- benzenesulfonamide

[00620] Following general procedure E, fe/f-butyl (3R)-3-[4-amino-3-[4-[[(4- methoxyphenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1-yl]piperidine-1-carboxylate (200.0 mg, 0.34 mmol) afforded /V-[[4-[4-amino-1-[(3f?)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3- yl]phenyl]methyl]-4-methoxy-benzenesulfonamide (110.0 mg, 0.23 mmol, 66% yield) as a pale foam.

[00621] UPLC-MS (ES⁺, Short acidic): 1.11 min, m/z 494.2 [M+H]⁺

[00622] /V-[[4-[4-Amino-1-[(3f?)-1-prop-2-enoyl-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3- yllphenyllmethyll-4-methoxy-benzenesulfonamide

[00623] Following general procedure F, A/-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4- rf]pyrimidin-3-yl]phenyl]methyl]-4-methoxy-benzenesulfonamide (110.0 mg, 0.22 mmol) afforded, after purification by preparative LC-MS and salt removal by SCX cartridge, A/-[[4-[4-amino-1-[(3R)-1- prop-2-enoyl-3-piperidyl]pyrazolo[3,4-rf]pyrimidin-3-yl]phenyl]methyl]-4-methoxy- benzenesulfonamide (19.0 mg, 0.03 mmol, 16% yield) as a thin film.

[00624] UPLC-MS (ES⁺, Short acidic) 1.37min, m/z 548.1 [M+H]⁺

[00625] UPLC-MS (ES⁺, Long acidic): 3.15 min, m/z 548.2 [M+H] [00626] H NMR (400 MHz, DMSO-d₆, δ) (ppm, 1 :1 mixture of conformers): 8.27 (s, 1 H, ArH), 8.08 (t, ³ J 6.7 Hz, 1 H, NH), 7.78 (d, ³ J 6.7 Hz, 2H, 2 x ArH), 7.59 (d, ³ J 8.2 Hz, 2H, 2 x ArH), 7.42 (d, ³ J 8.2 Hz, 2H, 2 x ArH), 7.12 (d, ³J 8.2 Hz, 2H, 2 x ArH), 6.87 (dd, ¾_rans 16.3, ³J_C(S 10.4 Hz, 0.5H), 6.72 (dd, ^zJtrans 16.3, ³J_C(S 10.4 Hz, 0.5H), 6.13 (d, ¾._a„s 17.0 Hz, 0.5H), 6.06 (d, ¾._a„s 17.0 Hz, 0.5H), 5.72 (d, Jcis 10.4 Hz, 0.5H), 5.59 (d, ³J_CS 10.4 Hz, 0.5H), 4.76-4.66 (m, 1 H), 4.57-4.53 (m, 0.5H), 4.22-4.18 (m, 1 H), 4.10-4.06 (m, 0.5H), 4.03 (d, ³J 5.9 Hz, 2H, CH₂), 3.83 (s, 3H, OCH₃), 3.74-3.68 (m, 0.5H), 3.25-3.17 (m, 1 H), 3.05-2.98 (m, 0.5H), 2.29-2.21 (m, 1 H), 2.15-2.10 (m, 1 H), 1.97-1.91 (m, 1 H), 1.66-1.55 (m, 1 H).

[00627] Example 33: Af-[[4-[4-Amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- d]pyrimidin-3-yl]p enyl]met yl]-4-c loro-benzenesulfonamide

[00628] [4-[[(4-Chlorophenyl)sulfonylaminolmethyllphenyllboronic acid

[00629] Following general procedure B, [4-(aminomethyl)phenyl]boronic acid hydrochloride (300.0 mg, 1.60 mmol) and 4-chlorobenzene sulfonyl chloride (371.6 mg, 1.76 mmol) afforded crude [4-[[(4-chlorophenyl)sulfonylamino]methyl]phenyl]boronic acid (500.0 mg, 1 .54 mmol, 96% yield) as an off-white solid.

[00630] UPLC-MS (ES⁺, Short acidic): 1.45 min, m/z 325.9 [M+H]⁺

[00631] te/f-Butyl(3 ?)-3-[4-amino-3-[4-[[(4-chlorophenyl)sulfonylaminolmethyllphenyllpyrazolo[3,4- tflpyrimidin-1 -yllpiperidine-1 -carboxylate

[00632] Following general procedure D, 4-[[(4-chlorophenyl)sulfonylamino]methyl]phenyl]boronic acid (329.8 mg, 1 .01 mmol) and fe/f-butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-rf]pyrimidin-1- yl)piperidine-1-carboxylate (200.0 mg, 0.45 mmol) gave fe/ -butyl (3R)-3-[4-amino-3-[4-[[(4- chlorophenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1-yl]piperidine-1-carboxylate (700.0 mg, assumed quantitative) as an orange oil.

[00633] UPLC-MS (ES⁺, Short acidic): 1.77 min, m/z 599.1 [M+H]⁺

[00634] /V-[[4-[4-Amino-1-[(3f?)-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3-yllphenyllmethyll-4-chloro- benzenesulfonamide

[00635] Following general procedure E, fe/f-butyl (3R)-3-[4-amino-3-[4-[[(4- chlorophenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1-yl]piperidine-1-carboxylate (300.0 mg, 0.50 mmol) afforded crude /V-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-rf]pyrimidin-3- yl]phenyl]methyl]-4-chloro-benzenesulfonamide (260.0 mg, assumed quantitative) as a pale foam.

[00636] UPLC-MS (ES⁺, Short acidic): 1.18 min, m/z 498.1 [M+H]⁺

[00637] /V-[[4-[4-Amino-1-[(3f?)-1-prop-2-enoyl-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3- yllphenyllmethyll-4-chloro-benzenesulfonamide

[00638] Following general procedure F, A/-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- piperidyl]pyrazolo[3,4-rf]pyrimidin-3-yl]phenyl]methyl]-4-chloro-benzenesulfonamide (263.0 mg, 0.53 mmol) afforded, after purification by preparative LC-MS and salt removal by SCX cartridge, Λ/-[[4-[4- amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-<^pyrim^

benzenesulfonamide (13.0 mg, 0.02 mmol, 4% yield) as a colourless gum.

[00639] UPLC-MS (ES⁺, Short acidic): 1.47 min, m/z 552.1 [M+H]⁺

[00640] UPLC-MS (ES⁺, Long acidic): 3.38 min, m/z 552.1 [M+H]⁺

[00641] H NMR (400 MHz, DMSO-d₆, δ) (ppm, 1 :1 mixture of conformers): 8.36 (t, ³ J 6.3 Hz, 1 H, NH), 8.27 (s, 1 H, ArH), 7.82 (d, ³J 10.1 Hz, 2H, 2 x ArH), 7.66 (d, ³J 10.1 Hz, 2H, 2 x ArH), 7.59 (d, ³J 7.6 Hz, 2H, 2 x ArH), 7.42 (d, ³J 7.6 Hz, 2H, 2 x ArH), 6.87 (dd, ¾_rans 16.4, ³J_CS 10.1 Hz, 0.5H), 6.72 (dd, ^zJtrans 16.4, ^zJcis 10.1 Hz, 0.5H), 6.14 (d, ¾._a„s 16.4 Hz, 0.5H), 6.06 (d, ¾_rans 16.4 Hz, 0.5H), 5.71 (d, ^zJcis 10.1 Hz, 0.5H), 5.59 (d, ³J_CS 10.1 Hz, 0.5H), 4.76-4.66 (m, 1 H), 4.57-4.53 (m, 0.5H), 4.22-4.18 (m, 1 H), 4.10 (d, ³J 6.3 Hz, 2H, CH₂), 4.08-4.05 (m, 0.5H), 3.74-3.69 (m, 0.5H), 3.26-3.18 (m, 1 H), 3.06-2.99 (m, 0.5H), 2.32-2.23 (m, 1 H), 2.15-2.11 (m, 1 H), 1.97-1.91 (m, 1 H), 1.66-1.56 (m, 1 H).

[00642] Example 34: Af-[[4-[4-Amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- d]pyrimidin-3-yl]phenyl]methyl]-2,5-cfimethyl-benzenesulfonamide

[00643] [4-[[(2,5-Dimethylphenyl)sulfonylaminolmethyllphenyllboronic acid

[00644] Following general procedure B, [4-(aminomethyl)phenyl]boronic acid hydrochloride (300.0 mg, 1.60 mmol) and 2,5-dimethylbenzenesulfonyl chloride (0.28 mL, 1.76 mmol) afforded [4-[[(2,5- dimethylphenyl)sulfonylamino]methyl]phenyl]boronic acid (381.0 mg, 1.19 mmol, 75% yield) as an off-white solid.

[00645] UPLC-MS (ES-, short acidic): 1 .48 min, m/z 318.2 [M-H]- [00646] fe/f-Butyl (3ffl-3-[4-amino-3-[4-[[(2.5- dimethylphenyl)sulfonylaminolmethyllphenyllpyrazolo[3,4-Qlpyrimidin-1-yllpiperidine-1-carboxylate (72. mg, 0.1200mmol)

[00647] Following general procedure D, fe/f-butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-rf]pyrimidin- 1-yl)piperidine-1-carboxylate (200.0 mg, 0.45 mmol) and [4-[[(2,5- dimethylphenyl)sulfonylamino]methyl]phenyl]boronic acid (215.5 mg, 0.68 mmol) afforded, after purification by flash column chromatography (DCM/MeOH 100:0 to 90:10), fe/f-butyl (3f?)-3-[4- amino-3-[4-[[(2,5-dimethylphenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1- yl]piperidine-1-carboxylate (72.0 mg, 0.12 mmol, 27% yield).

[00648] UPLC-MS (ES⁺, Short acidic,): 1.80 min, m/z 592.5 [M+H]⁺

[00649] /V-[[4-[4-Amino-1-[(3f?)-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3-yllphenyllmethyll-2,5- dimethyl-benzenesulfonamide

[00650] Following general procedure E, fe/f-butyl (3f?)-3-[4-amino-3-[4-[[(2,5- dimethylphenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1-yl]piperidine-1-carboxylate (72.0 mg, 0.12 mmol) gave /V-[[4-[4-amino-1-[(3f?)-3-piperidyl]pyrazolo[3,4-rf]pyrimidin-3- yl]phenyl]methyl]-2,5-dimethyl-benzenesulfonamide (30 mg, 0.06 mmol, 50% yield) as a yellow solid.

[00651] UPLC-MS (ES⁺, Short acidic): 1 .22 min, m/z 492.1 [M+H]⁺

[00652] /V-[[4-[4-Amino-1 -[(3f?)-1 -prop-2-enoyl-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3- yllphenyllmethyll-2,5-dimethyl-benzenesulfonamide

[00653] Following general procedure F, A/-[[4-[4-amino-1 -[(3R)-3-piperidyl]pyrazolo[3,4- rf]pyrimidin-3-yl]phenyl]methyl]-2,5-dimethyl-benzenesulfonamide (30.0 mg, 0.06 mmol) gave, after purification by preparative LC-MS and removal of salt by SCX, A/-[[4-[4-amino-1 -[(3R)-1 -prop-2- enoyl-3^iperidyl]pyrazolo[3,4-rf]pyrimidin-3-yl]phenyl]methyl]-2,5-dimethyl-benzenesulfonamide (12.0 mg, 0.02 mmol, 32% yield) as a colourless solid.

[00654] UPLC-MS (ES⁺, Short acidic): 1 .50 min, m/z 546.3 [M+H]⁺

[00655] UPLC-MS (ES⁺, Long acidic): 3.44 min, m/z 546.5 [M+H]⁺

[00656] H NMR (400 MHz, DMSO-d₆) δ (ppm, 1 :1 mixture of conformers): 8.27 (s, 1 H, ArH), 8.25 (t, ³ J 6.2 Hz, 1 H, NH), 7.60 (m, 1 H, ArH), 7.53 (d, ³ J 7.8 Hz, 2H, 2 ArH), 7.36 (d, ³ J 7.8 Hz, 2H, 2 ArH), 7.30-7.27 (m, 1 H, ArH), 7.22 (d, ³J 8.2 Hz, 1 H, ArH), 6.86 (dd, ¾_rans 17.6, ³J_C(S 1 1 .4 Hz, 0.5H), 6.71 (dd, Jtrans 17.6, Jcis 1 1 .4 Hz, 0.5H), 6.12 (d, ³J_ira„s 17.6 Hz, 0.5H), (dd, ³J_ira„s 17.6 Hz, 0.5H), 5.71 (d, Jcis 1 1 .4 Hz, 0.5H), 5.58 (d, ³J_C(S 1 1 .4 Hz, 0.5H), 4.75-4.4.64 (m, 1 H), 4.53 (m, 0.5H), 4.26- 4.04 (m, 1 H), 4.10 (d, ³J 6.2 Hz, 2H, CH₂), 3.73-3.66 (m, 0.5H), 3.36-3.27 (m, 1 H), 3.32 (s, 3H, CH₃), 3.27-3.15 (m, 1 H), 3.07-2.98 (m, 0.5H), 2.29 (s, 3H, CH₃), 2.25-2.20 (m, 0.5H), 2.15-2.09 (m, 1 H), 1 .96-1 .89 (m, 1 H), 1 .66-1 .53 (m, 1 H).

[00657] Example 35: Af-[[4-[4-Amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- o(|pyrimidin-3-yl]phenyl]methyl]-2-(trifluoromethoxy)benzenesulfonamide

[00658] [4-[[[2-(Trifluoromethoxy)phenyllsulfonylaminolmethyllphenyllboronic acid

[00659] Following general procedure B, [4-(aminomethyl)phenyl]boronic acid hydrochloride (300.0 mg, 1 .60 mmol) and 2-(trifluoromethoxy)benzenesulfonyl chloride (0.29 mL, 1 .76 mmol) afforded [4-[[[2-(trifluoromethoxy)phenyl]sulfonylamino]methyl]phenyl]boronic acid (445.0 mg, 1 .19 mmol, 74% yield) as a yellow oil that solidified upon standing.

[00660] UPLC-MS (ES-, short acidic): 1 .47 min, m/z 374.1 [M-H]-

[00661] fe/f-Butyl (3ffl-3-[4-amino-3-[4-[[[2- (trifluoromethoxy)phenyllsulfonylaminolmethyllphenyllpyrazolo[3,4-Qlpyrimidin-1 -yllpiperidine-1 - carboxylate

[00662] Following, general procedure D, fe/f-butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4- d]pyrimidin-1 -yl)piperidine-1 -carboxylate (200.0 mg, 0.45 mmol) and [4-[[[2- (trifluoromethoxy)phenyl]sulfonylamino]methyl]phenyl]boronic acid (253.3 mg, 0.68 mmol) gave, after purification by flash column chromatography (DCM/MeOH 100:0 to 90:10), fe/ -butyl (3f?)-3-[4- amino-3-[4-[[[2-(trifluoromethoxy)phenyl]sulfonylamino]methyl]phenyl]^

yl]piperidine-1 -carboxylate (249.0 mg, 0.38 mmol, 85% yield) as a white solid.

[00663] UPLC-MS (ES⁺, Short acidic): 1.80 min, m/z 648.5 [M+H]⁺

[00664] /V-[[4-[4-Amino-1-[(3f?)-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3-yllphenyllmethyll-2- (trifluoromethoxy)benzenesulfonamide

[00665] Following general procedure E, fe/f-butyl (3f?)-3-[4-amino-3-[4-[[[2- (trifluoromethoxy)phenyl]sulfonylamino]methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1-yl]piperidine-1- carboxylate (249.0 mg, 0.38 mmol) gave /V-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-rf]pyrimidin- 3-yl]phenyl]methyl]-2-(trifluoromethoxy)benzenesulfonamide (140.0 mg, 0.26 mmol, 67% yield) as an off-white solid.

[00666] UPLC-MS (ES⁺, Short acidic): 1.24 min, m/z 548.0 [M+H]⁺

[00667] /V-[[4-[4-Amino-1-[(3f?)-1-prop-2-enoyl-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3- yllphenyllmethyll-2-(trifluoromethoxy)benzenesulfonamide

[00668] Following general procedure F, A/-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4- rf]pyrimidin-3-yl]phenyl]methyl]-2-(trifluoromethoxy)benzenesulfonamide (140.0 mg, 0.26 mmol) afforded, after purification by preparative LC-MS and salt removal by SCX cartridge, A/-[[4-[4-amino- 1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-rf]pyrimidin-3-yl]phenyl]methyl]-2- (trifluoromethoxy)benzenesulfonamide (150.0 mg, 0.24 mmol, 95% yield).

[00669] UPLC-MS (ES⁺, Short acidic): 1.52 min, m/z 602.1 [M+H]⁺

[00670] UPLC-MS (ES+, Long acidic): 3.47 min, m/z 602.3 [M+H]+

[00671] H NMR (400 MHz, DMSO-d₆, δ) (ppm, 1 :1 mixture of conformers): 8.53 (t, ³J 6.0 Hz, 1 H, NH), 8.27 (s, 1 H, ArH), 7.90 (dd, ³ J 8.0, ³ J 1.6 Hz, 1 H, ArH), 7.72-7.70 (m, 1 H, ArH), 7.55-7.47 (m, 4H, 4 ArH), 7.39 (d, ³J 8.0 Hz, 2H, 2 ArH), 6.86 (dd, ¾_rans 17.0, ³J_{C S} 10.0 Hz, 0.5H), 6.71 (dd, Jtrans 17.0, ³J_{C S} 10.0 Hz, 0.5H), 6.13 (d, ³J_ira„s 17.0 Hz, 0.5H), 6.06 (d, ³J_ira„s 17.0 Hz, 0.5H), 5.70 (d, Jcis 10.0 Hz, 0.5H), 5.58 (d, ³J_C(S 10.0 Hz, 0.5H), 4.71 (m, 1 H), 4.57-4.50 (m, 0.5H), 4.25-4.15 (m, 1 H), 4.24 (d, 2H, ³J 6.0 Hz, CH₂), 4.11-4.03 (m, 0.5H), 3.75-.366 (m, 0.5H), 3.25-3.18 (m, 1 H), 3.03 (m, 0.5H), 2.30-2.21 (m, 1 H), 2.13-2.1 1 (m, 1 H), 1.95-1.91 (m, 1 H), 1 .61-1.55 (m, 1 H).

[00672] Example 36: Af-[[4-[4-Amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- o(|pyrimidin-3-yl]phenyl]methyl]indane-5-sulfonamide

[00673] [4-[(lndan-5-ylsulfonylamino)methyllphenyllboronic acid

[00674] Following general procedure B, [4-(aminomethyl)phenyl]boronic acid hydrochloride (300.0 mg, 1.60 mmol) and indan-5-sulfonyl chloride (0.25 mL, 1.76 mmol) afforded [4-[(indan-5- ylsulfonylamino)methyl]phenyl]boronic acid (414.0 mg,1.25 mmol, 78% yield) as a pale brown solid.

[00675] UPLC-MS (ES-, Short acidic): 1.50 min, m/z 330.2 [M-H]- [00676] fe/f-Butyl (3 ?V3-[4-amino-3-[4-[0ndan-5-ylsulfonylamino)methyllphenyllpyrazolo[3,4- tflpyrimidin-1 -yllpiperidine-1 -carboxylate

[00677] Following general procedure D, fe/f-butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-rf]pyrimidin- 1-yl)piperidine-1-carboxylate (200.0 mg, 0.45 mmol) and [4-[(indan-5- ylsulfonylamino)methyl]phenyl]boronic acid (223.7 mg, 0.68 mmol) gave, after purification by flash column chromatography (DCM:MeOH 100:0 to 95:10), fe/f-butyl (3f?)-3-[4-amino-3-[4-[(indan-5- ylsulfonylamino)methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1-yl]piperidine-1-carboxylate (185.0 mg, 0.31 mmol, 68% yield) as a pale yellow solid.

[00678] UPLC-MS (ES⁺, Short acidic): 1.83 min, m/z 604.6 [M+H]⁺

[00679] /V-[[4-[4-Amino-1-[(3f?)-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3-yllphenyllmethyllindane-5- sulfonamide

[00680] Following general procedure E, fe/f-butyl (3R)-3-[4-amino-3-[4-[(indan-5- ylsulfonylamino)methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1-yl]piperidine-1-carboxylate (185.0 mg, 0.31 mmol) gave A/-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-rf]pyrimidin-3- yl]phenyl]methyl]indane-5-sulfonamide (119.0 mg, 0.24 mmol, 77% yield) as a pale cream foam.

[00681] UPLC-MS (ES⁺, Short acidic): 1.20 min, m/z 504.6 [M+H]⁺

[00682] /V-[[4-[4-Amino-1-[(3f?)-1-prop-2-enoyl-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3- yllphenyllmethyllindane-5-sulfonamide

[00683] Following general procedure F, A/-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4- rf]pyrimidin-3-yl]phenyl]methyl]indane-5-sulfonamide (119.0 mg, 0.24 mmol) gave, after purification by preparative LC-MS and salt removal by SCX cartridge, A/-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- piperidyl]pyrazolo[3,4-rf]pyrimidin-3-yl]phenyl]methyl]indane-5-sulfonamide (30.0 mg, 0.05 mmol, 22% yield) as a white solid.

[00684] UPLC-MS (ES⁺, Short acidic): 1.52 min, m/z 558.4 [M+H]⁺

[00685] UPLC-MS (ES⁺, Long acidic): 3.51 min, m/z 558.4 [M+H]⁺

[00686] H NMR (400 MHz, DMSO-d₆, δ) (ppm, 1 :1 mixture of conformers): 8.26 (s, 1 H, ArH), 8.11 (t, ³ J 6.5 Hz, 1 H, NH), 7.63-7.59 (m, 2H, 2 ArH), 7.57 (d, ³ J 8.1 Hz, 2H, 2 ArH), 7.41 -7.39 (m, 3H, 3 ArH), 6.87 (dd, ³J_ira„s 17.4, ³J_C/S 10.6 Hz, 0.5H), 6.71 (dd, ³J,_ra„s 17.4, ³J_C(S 10.6 Hz, 0.5H), 6.13 (d, Jtrans 17.4 Hz, 0.5H), 6.06 (d, ³J,_ra„s 17.4 Hz, 0.5H), 5.71 (d, ³J_{C S} 10.6 Hz, 0.5H), 5.59 (d, Jcis 10.6 Hz, 0.5H), 4.76-4.65 (m, 1 H), 4.57-4.51 (m, 0.5H), 4.24-4.17 (m, 1 H), 4.11 -4.05 (m, 0.5H), 4.04 (d, ³J 6.5 Hz, 2H, CH₂), 3.74-3.67 (m, 0.5H), 3.26-3.17 (m, 1 H), 3.09-2.96 (m, 0.5H), 2.90 (t, ³ J 7.4 Hz, 4H, 2 x CH₂), 2.91-2.02 (m, 1 H), 2.15-2.09 (m, 1 H), 2.03 (p, ³J 7.4 Hz, 2H, CH₂), 1.98-1.90 (m, 1 H), 1 .63-1.55 (m, 1 H).

[00687] Example 37: Af-[[4-[4-Amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- d]pyrimidin-3-yl]phenyl]methyl]-3-fluoro-5-(trifluoromethyl)benzenesulfonamide

[00688] [4-[[[3-Fluoro-5-(trifluoromethyl)phenyllsulfonylaminolmethyllphenyllboronic acid [00689] Following general procedure B, [4-(aminomethyl)phenyl]boronic acid hydrochloride (300.0 mg, 1.60 mmol) and 3-fluoro-5-(trifluoromethyl)benzenesulfonyl chloride (0.29 ml_, 1.76 mmol) afforded [4-[[[3-fluoro-5-(trifluoromethyl)phenyl]sulfonylamino]methyl]phenyl]boronic acid (559.0 mg, 1.48 mmol, 93% yield) as a yellow solid.

[00690] UPLC-MS (ES-, Short acidic): 1.55 min, m/z 376.2 [M-H]-

[00691] fe/f-Butyl (3ffl-3-[4-amino-3-[4-[[[3-fluoro-5-

(trifluoromethyl)phenyllsulfonylaminolmethyllphenyllpyrazolo[3,4-Qlpyrimidin-1-yllpiperidine-1- carboxylate

[00692] Following general procedure D, a mixture of fe/f-butyl (3R)-3-(4-amino-3-iodo- pyrazolo[3,4-rf]pyrimidin-1-yl)piperidine-1 -carboxylate (200.0 mg, 0.45 mmol) and [4-[[[3-fluoro-5- (trifluoromethyl)phenyl]sulfonylamino]methyl]phenyl]boronic acid (254.7 mg, 0.68 mmol) afforded, after purification by flash column chromatography (DCM:MeOH 100:0 to 90:10), fe/ -butyl (3f?)-3-[4- amino-3-[4-[[[3-fluoro-5-(trifluoromethyl)phenyl]sulfonylamino]methyl]phenyl]pyrazolo[3,4- d]pyrimidin-1 -yl]piperidine-1 -carboxylate (240.0 mg, 0.37 mmol, 82% yield) as a pale yellow solid.

[00693] UPLC-MS (ES⁺, Short acidic): 1.86 min, m/z 650.6 [M+H]⁺

[00694] /V-[[4-[4-Amino-1-[(3f?)-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3-yllphenyllmethyll-3-fluoro-5- (trifluoromethyl)benzenesulfonamide

[00695] Following general procedure E, fe/f-butyl (3R)-3-[4-amino-3-[4-[[[3-fluoro-5- (trifluoromethyl)phenyl]sulfonylamino]methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1-yl]piperidine-1- carboxylate (240.0 mg, 0.37 mmol) gave /V-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-rf]pyrimidin- 3-yl]phenyl]methyl]-3-fluoro-5-(trifluoromethyl)benzenesulfonamide (159.0 mg, 0.29 mmol, 78% yield) as a pale yellow foam.

[00696] UPLC-MS (ES⁺, Short acidic): 1.25 min, m/z 550.4 [M+H]⁺

[00697] /V-[[4-[4-Amino-1-[(3f?)-1-prop-2-enoyl-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3- yllphenyllmethyll-3-fluoro-5-(trifluoromethyl)benzenesulfonamide

[00698] Following general procedure F, A/-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4- rf]pyrimidin-3-yl]phenyl]methyl]-3-fluoro-5-(trifluoromethyl)benzenesulfonamide (159.0 mg, 0.29 mmol) gave, after purification by preparative LC-MS and removal of the salt by SCX cartridge, Λ/-[[4- [4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-rf]pyrimidin-3-yl]phenyl]methyl]-3-fluoro-5- (trifluoromethyl)benzenesulfonamide (26.0 mg, 0.04 mmol, 14% yield) as a colourless oil.

[00699] UPLC-MS (ES⁺, Short acidic): 1.57 min, m/z 604.2 [M+H]⁺

[00700] UPLC-MS (ES⁺, Long acidic): 3.61 min, m/z 604.2 [M+H]⁺

[00701] H NMR (400 MHz, DMSO-d₆, δ) (ppm, 1 :1 mixture of conformers): 8.63 (t, ³J 6.2 Hz, 1 H, NH), 8.26 (s, 1 H, ArH), 8.03-8.01 (m, 1 H, ArH), 7.93-7.90 (m, 2H, 2 ArH), 7.56 (d, ³ J 7.6 Hz, 2H, 2 ArH), 7.39 (d, ³ J 8.0 Hz, 2H, 2 ArH), 6.86 (dd, ³J_ira„s 16.6, ³J_{C S} 10.6 Hz, 0.5H), 6.70 (dd, ³J,_ra„s 16.6, Jcis 10.6 Hz, 0.5H), 6.13 (d, ³J,_ra„s 16.6 Hz, 0.5H), 6.05 (d, ¾_rans 16.6 Hz, 0.5H), 5.71 (d, ³J_C(S 10.6 Hz, 0.5H), 5.57 (d, ³J_CS 10.6 Hz, 0.5H), 4.77-4.65 (m, 1 H), 4.75-4.51 (m, 0.5H), 4.26-4.11 (m, 1 H), 4.19 (d, ³J 6.2 Hz, 2H, CH₂), 4.13-4.05 (m, 0.5H), 3.75-3.68 (m, 0.5H), 3.27-3.17 (m, 1 H), 3.08- 3.00 (m, 0.5H), 2.29-2.22 (m, 1 H), 2.15-2.2.10 (m, 1 H), 1.97-1.91 (m, 1 H), 1.63-1.54 (m, 1 H).

[00702] Example 38: Af-[[4-[4-Amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- d]pyrimidin-3-yl]phenyl]methyl]-3-methyl-benzenesulfonamide

[00703] [4-[(m-Tolylsulfonylamino)methyllphenyll boronic acid

[00704] Following general procedure B, 4-aminomethylphenylboronic acid hydrochloride (300.0 mg, 1.60 mmol), DIPEA (0.71 mL, 4.00 mmol), and m-toluenesulfonyl chloride (0.26 mL, 1.76 mmol) afforded [4-[(m-tolylsulfonylamino)methyl]phenyl] boronic acid (379.0 mg, 1.24 mmol, 78%) as an off-white solid.

[00705] UPLC-MS (ES⁺, short acidic): 1 .40 min, m/z 305.8 [M+H]⁺

[00706] fe/f-Butyl (3f?)-3-[4-amino-3-[4-[(m-tolylsulfonylamino)methyllphenyllpyrazolo[3,4- tflpyrimidin-1 -yllpiperidine-1 -carboxylate

[00707] Following general procedure D, fe/f-butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-rf]pyrimidin- 1-yl)piperidine-1-carboxylate (200.0 mg, 0.45 mmol) and [4-[(m- tolylsulfonylamino)methyl]phenyl]boronic acid (206.1 mg, 0.68 mmol) gave, after purification by flash column chromatography (DCM:MeOH 100:0 to 90:10), fe/f-butyl (3f?)-3-[4-amino-3-[4-[(m- tolylsulfonylamino)methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1-yl]piperidine-1-carboxylate (231.7 mg, 0.40 mmol, 89% yield) as a yellow oil.

[00708] UPLC-MS (ES⁺, Short acidic): 1.74 min, m/z 578.5 [M+H]⁺

[00709] /V-[[4-[4-Amino-1-[(3f?)-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3-yllphenyllmethyll-3-methyl- benzenesulfonamide

[00710] Following general procedure E, fe/f-butyl (3R)-3-[4-amino-3-[4-[(m- tolylsulfonylamino)methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (231.7 mg, 0.40 mmol) gave A/-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-rf]pyrimidin-3-yl]phenyl]methyl]-3- methyl-benzenesulfonamide (126.3 mg, 0.26 mmol, 66% yield) as an pale yellow oil.

[00711] UPLC-MS (ES⁺, Short acidic): 1.17 min, m/z 478.2 [M+H]⁺

[00712] /V-[[4-[4-Amino-1-[(3f?)-1-prop-2-enoyl-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3- yllphenyllmethyll-3-methyl-benzenesulfonamide

[00713] Following general procedure F, A/-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4- rf]pyrimidin-3-yl]phenyl]methyl]-3-methyl-benzenesulfonamide (126.3 mg, 0.26 mmol) afforded, after purification by preparative HPLC and salt removal by SCX cartridge, A/-[[4-[4-amino-1-[(3R)-1-prop- 2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-methyl-benzenesulfonamide (13.2 mg, 0.02 mmol, 9% yield) as a white solid.

[00714] UPLC-MS (ES⁺, Short acidic): 1.44 min, m/z 532.3 [M+H]⁺ [00715] UPLC-MS (ES⁺, Long acidic): 3.28 min, m/z 532.4 [M+H]⁺

[00716] H-NMR (400 MHz, DMSO-c₆, δ) (ppm, 1 :1 mixture of conformers): 8.27 (s, 1 H, ArH), 8.21 (t, J 64 Hz, 1 H), 7.64-7.59 (m, 2H), 7.59-7.54 (m, 2H), 7.49-7.43 (m, 2H), 7.43-7.37 (m, 2H), 6.91- 6.80 (m, 0.5H), 6.77-6.64 (m, 0.5H), 6.18-6.01 (m, 1 H), 5.74-5.55 (m, 1 H), 4.78-4.63 (m, 1 H), 4.56- 4.49 (m, 0.5H), 4.25-4.14 (m, 1 H), 4.08 (d, J 6.4 Hz, 2H, CH₂), 4.10-4.05 (m, 0.5H), 3.76-3.65 (m, 0.5H), 3.27-3.15 (m, 1 H), 3.07-2.96 (m, 0.5H), 2.37 (s, 3H), 2.30-2.18 (m, 1 H), 2.17-2.06 (m, 1 H), 2.00-1.88 (m, 1 H), 1.69-1.50 (m, 1 H).

[00717] Example 39: Af-[[4-[4-Amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- o(|pyrimidin-3-yl]phenyl]methyl]-2-methoxy-4-methyl-benzenesulfonamide

[00718] [4-[[(2-Methoxy-4-methyl-phenyl)sulfonyl aminolmethyllphenyllboronic acid

[00719] Following general procedure B, 4-aminomethylphenylboronic acid hydrochloride (300.0 mg, 1.60 mmol) and 2-methoxy-4-methylbenzenesulfonyl chloride (389.0 mg, 1.76 mmol) afforded [4-[[(2-methoxy-4-methyl-phenyl)sulfonyl amino]methyl]phenyl]boronic acid (419.0 mg, 1.25 mmol, 78%) as a yellow oil.

[00720] UPLC-MS (ES⁺, short acidic): 1.37 min, m/z 335.8 [M+H]⁺

[00721] fe/f-Butyl (3ffl-3-[4-amino-3-[4-[[(2-methoxy-4-methyl- phenyl)sulfonylaminolmethyllphenyllpyrazolo[3,4-Qlpyrimidin-1-yllpiperidine-1-carboxylate

[00722] Following general procedure D, fe/f-butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-c]pyrimidin- 1-yl)piperidine-1-carboxylate (200.0 mg, 0.45 mmol) and [4-[[(2-methoxy-4-methyl- phenyl)sulfonylamino]methyl]phenyl]boronic acid (226.3 mg, 0.68 mmol) gave, after purification by flash column chromatography (DCM:MeOH 100:0 to 95:5), fe/f-butyl (3f?)-3-[4-amino-3-[4-[[(2- methoxy-4-methyl-phenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-c]pyrimidin-1-yl]piperidine-1- carboxylate (99.8 mg, 0.16 mmol, 36% yield) as a pale yellow oil.

[00723] UPLC-MS (ES⁺, Short acidic): 1.73 min, m/z 608.5 [M+H]⁺

[00724] /V-[[4-[4-Amino-1-[(3f?)-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3-yllphenyllmethyll-2-methoxy- 4-methyl-benzenesulfonamide

[00725] Following general procedure E, fe/f-butyl (3R)-3-[4-amino-3-[4-[[(2-methoxy-4-methyl- phenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-c]pyrimidin-1-yl]piperidine-1 -carboxylate (99.8 mg, 0.16 mmol) afforded A/-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-c]pyrimidin-3-yl]phenyl]methyl]- 2-methoxy-4-methyl-benzenesulfonamide (62.4 mg, 0.12 mmol, 75% yield) as a thin clear film.

[00726] UPLC-MS (ES⁺, Short acidic): 1.15 min, m/z 508.4 [M+H]⁺

[00727] /V-[[4-[4-Amino-1-[(3f?)-1-prop-2-enoyl-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3- yllphenyllmethyll-2-methoxy-4-methyl-benzenesulfonamide

[00728] Following general procedure F, A/-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4- c]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-4-methyl-benzenesulfonamide (62.4 mg, 0.12 mmol), afforded, after purification by preparative HPLC and salt removal by SCX cartridge, A/-[[4-[4-amino- 1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-<^pyrimidin-3-yl]phenyl]meth

benzenesulfonamide (15.9 mg, 0.03 mmol, 23% yield) as a white powder.

[00729] UPLC-MS (ES⁺, Short acidic): 1.43 min, m/z 562.3 [M+H]⁺

[00730] UPLC-MS (ES⁺, Long acidic): 3.25 min, m/z 562.3 [M+H]⁺

[00731] H-NMR (400 MHz, DMSO-c₆, δ) (ppm, 1 :1 mixture of conformers): 8.27 (s, 1 H, ArH), 7.79 (t, J 6.2 Hz, 1 H), 7.58 (d, J 8.0, 1 H), 7.52 (d, J 8.0, 2H), 7.38 (d, J 8.2, 2H), 6.94 (s, 1 H), 6.92-6.85 (m, 0.5H), 6.85-6.80 (m, 1 H), 6.75-6.66 (m, 0.5H), 6.18-6.00 (m, 1 H), 5.74-5.54 (m, 1 H), 4.79-4.63 (m, 1 H), 4.59-4.50 (m, 0.5H), 4.26-4.14 (m, 1 H), 4.09 (d, J 5.5 Hz, 2H, CH₂), 3.86 (s, 3H), 3.75-3.66 (m, 0.5H), 3.27-3.15 (m, 1 H), 3.08-2.96 (m, 0.5H), 2.35-2.21 (m, 1 H), 2.31 (s, 3H), 2.17-2.08 (m, 1 H), 2.01 -1.89 (m, 1 H), 1 .67-1.51 (m, 1 H).

[00732] Example 40: Af-[[4-[4-amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- o(|pyrimidin-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzenesulfonamide

[00733] [4-[[(5-Fluoro-2-methoxy-phenyl)sulfonyl aminolmethyllphenyllboronic acid

[00734] Following general procedure B, 4-aminomethylphenylboronic acid hydrochloride (300.0 mg, 1.60 mmol) and 5-fluoro-2-methoxy benzenesulfonyl chloride (396.0 mg, 1.76 mmol) afforded [4-[[(5-fluoro-2-methoxy-phenyl)sulfonyl amino]methyl]phenyl]boronic acid (337.0 mg, 0.99 mmol, 62% yield) as a yellow oil.

[00735] UPLC-MS (ES⁺, short acidic): 1.34 min, m/z 339.9 [M+H]⁺.

[00736] fe/f-Butyl (3ffl-3-[4-amino-3-[4-[[(5-fluoro-2-methoxy- phenyl)sulfonylaminolmethyllphenyllpyrazolo[3,4-Qlpyrimidin-1-yllpiperidine-1-carboxylate

[00737] Following general procedure D, fe/f-butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-c]pyrimidin- 1-yl)piperidine-1-carboxylate (200.0 mg, 0.45 mmol) and [4-[[(5-fluoro-2-methoxy- phenyl)sulfonylamino]methyl]phenyl]boronic acid (229.0 mg, 0.68 mmol), gave, after purification by flash column chromatography (DCM:MeOH 100:0 to 90:10), fe/f-butyl (3f?)-3-[4-amino-3-[4-[[(5- fluoro-2-methoxy-phenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-c]pyrimidin-1-yl]piperidine-1- carboxylate (80.2 mg, 0.13 mmol, 29% yield) as a yellow oil.

[00738] UPLC-MS (ES⁺, Short acidic): 1.69 min, m/z 612.5 [M+H]⁺

[00739] /V-[[4-[4-Amino-1-[(3f?)-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3-yllphenyllmethyll-5-fluoro-2- methoxy-benzenesulfonamide

[00740] Following general procedure E, fe/f-butyl (3R)-3-[4-amino-3-[4-[[(5-fluoro-2-methoxy- phenyl)sulfonylamino]methyl]phenyl]pyrazolo[3,4-c]pyrimidin-1-yl]piperidine-1 -carboxylate (80.2 mg, 0.13 mmol) afforded A/-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-c]pyrimidin-3-yl]phenyl]methyl]- 5-fluoro-2-methoxy-benzenesulfonamide (74.4 mg, assumed quantitative) as an orange oil.

[00741] UPLC-MS (ES⁺, Short acidic): 1.13 min, m/z 512.3 [M+H] [00742] A/-[[4-[4-Amino-1 -[(3 ?V1 -prop-2-enoyl-3-piperidyllpyrazolo[3,4-clpyri yllphenyllmethyll-5-fluoro-2-methoxy-benzenesulfonamide

[00743] Following general procedure F, A/-[[4-[4-amino-1 -[(3R)-3-piperidyl]pyrazolo[3,4- <^pyrimidin-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzenesulfonamide (74.4 mg, 0.15 mmol) afforded, after purification by preparative HPLC and salt removal by SCX cartridge, A/-[[4-[4-amino- 1 -[(3R)-1 ^rop-2-enoyl-3^iperidyl]pyrazolo[3,4-<^pyrimidin-3-yl]phenyl]methyl]-5-fluoro-2-methoxy- benzenesulfonamide (1 1 .8 mg, 0.02 mmol, 14% yield) as a white solid.

[00744] UPLC-MS (ES⁺, Short acidic): 1 .42 min, m/z 566.3 [M+H]⁺

[00745] UPLC-MS (ES⁺, Long acidic): 3.21 min, m/z 566.3 [M+H]⁺

[00746] H-NMR (400 MHz, DMSO-c₆, δ) (ppm, 1 :1 mixture of conformers): 8.28 (s, 1 H, ArH), 8.1 1 (t, J 64 Hz, 1 H), 7.55-7.48 (m, 2H), 7.47-7.31 (m, 4H), 7.13 (dd, J 9.0, 4.0 Hz, 1 H), 6.93-6.81 (m, 0.5H), 6.76-6.63 (m, 0.5H), 6.18-6.01 (m, 1 H), 5.75-5.54 (m, 1 H), 4.79-4.63 (m, 1 H), 4.59-4.49 (m, 0.5H), 4.23-4.13 (m, 1 H), 4.17 (d, J 6.4 Hz, 2H, CH₂), 4.1 1 -4.03 (m, 0.5 H), 3.84 (s, 3H), 3.76-3.65 (m, 0.5H), 3.27-3.14 (m, 1 H), 3.10-2.99 (m, 0.5H), 2.30-2.19 (m, 1 H), 2.18-2.07 (m, 1 H), 1 .99-1 .87 (m, 1 H), 1 .69-1 .51 (m, 1 H).

[00747]

[00748] Example 41 : Af-[[4-[4-Amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- o(|pyrimidin-3-yl]phenyl]methyl]-2-(trifluoromethyl)benzenesulfonamide

[00749] [4-[[[2-(Trifluoromethyl)phenyllsulfonylaminolmethyllphenyllboronic acid

[00750] Following general procedure B, [4-(aminomethyl)phenyl]boronic acid hydrochloride (300.0 mg, 1 .60 mmol) and 2-(trifluoromethyl)benzenesulfonyl chloride (0.27 mL, 1 .76 mmol) afforded crude [4-[[[2-(trifluoromethyl)phenyl]sulfonylamino]methyl]phenyl]boronic acid (592.6 mg, 1 .65 mmol, quantitative) as a white powder.

[00751] UPLC-MS (ES-, Short acidic): 1 .45 min, m/z 358.2 [M-H]- [00752] fe/f-Butyl (3ffl-3-[4-amino-3-[4-[[[2-

(trifluoromethyl)phenyllsulfonylaminolmethyllphenyllpyrazolo[3,4-Qlpyrimidin-1 -yllpiperidine-1 - carboxylate

[00753] Following general procedure D, fe/f-butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-c]pyrimidin- 1 -yl)piperidine-1 -carboxylate (200.0 mg, 0.45 mmol) and [4-[[[2- (trifluoromethyl)phenyl]sulfonylamino]methyl]phenyl]boronic acid (242.5 mg, 0.68 mmol) afforded, after purification by flash column chromatography, fe/f-butyl (3R)-3-[4-amino-3-[4-[[[2- (trifluoromethyl)phenyl]sulfonylamino]methyl]phenyl]pyrazolo[3,4-rf]pyrimidin-1 -yl]piperidine-1 - carboxylate (356.7 mg, assumed quantitative) as a yellow oil.

[00754] UPLC-MS (ES⁺, Short acidic): 1 .77 min, m/z 632.5 [M+H]⁺ [00755] A/-[[4-[4-Amino-1 -[(3 ?V3-piperidyllpyrazolo[3,4-Qlpyrimidin-3-yllph

(trifluoromethyl)benzenesulfonamide

[00756] Following general procedure E, fe/f-butyl (3f?)-3-[4-amino-3-[4-[[[2- (trifluoromethyl)phenyl]sulfonylamino]methyl]phenyl]pyrazo^

carboxylate (356.7 mg, 0.56 mmol) afforded A/-[[4-[4-amino-1 -[(3R)-3-piperidyl]pyrazolo[3,4- rf]pyrimidin-3-yl]phenyl]methyl]-2-(trifluoromethyl)benzenesulfonamide (145.5 mg, 0.27 mmol, 48% yield) as a light brown oil.

[00757] UPLC-MS (ES⁺, Short acidic): 1 .20 min, m/z 532.3 [M+H]⁺

[00758] /V-[[4-[4-Amino-1 -[(3f?)-1 -prop-2-enoyl-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3- yllphenyllmethyll-2-(trifluoromethyl)benzenesulfonamide

[00759] Following general procedure F, A/-[[4-[4-amino-1 -[(3R)-3-piperidyl]pyrazolo[3,4- rf]pyrimidin-3-yl]phenyl]methyl]-2-(trifluoromethyl)benzenesulfonamide (145.5 mg, 0.27 mmol), afforded, after purification by preparative LC-MS and salt removal by SCX cartridge, A/-[[4-[4-amino- 1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4-rf]pyrimidin-3-yl]phenyl]methyl]-2- (trifluoromethyl)benzenesulfonamide (15.9 mg, 0.03 mmol, 10% yield) as a white solid.

[00760] UPLC-MS (ES⁺, Short acidic): 1 .50 min, m/z 586.4 [M+H]⁺

[00761] UPLC-MS (ES⁺, Long acidic): 3.43 min, m/z 586.4 [M+H]⁺

[00762] H-NMR (400 MHz, DMSO-d₆, δ) (ppm, 1 :1 mixture of conformers): 8.63 (t, J 6.2 Hz, 1 H), 8.28 (s, 1 H, ArH), 8.12-8.06 (m, 1 H), 7.99-7.95 (m, 1 H), 7.87-7.77 (m, 2H), 7.61 -7.53 (m, 2H), 7.43 (d, J 8.2 Hz, 2H), 6.94-6.82 (m, 0.5H), 6.78-6.63 (m, 0.5H), 6.20-6.00 (m, 1 H), 5.78-5.53 (m, 1 H), 4.81 -4.63 (m, 1 H), 4.59-4.47 (m, 0.5H), 4.25 (d, J 6.2 Hz, 2H, CH₂), 4.25-4.15 (m, 1 H), 4.13-4.03 (m, 0.5H), 3.77-3.66 (m, 0.5H), 3.28-3.16 (m, 1 H), 3.09-2.97 (m, 0.5H), 2.31 -2.20 (m, 1 H), 2.18-2.08 (m, 1 H), 2.00-1 .89 (m, 1 H), 1 .69-1 .51 (m, 1 H).

[00763] Example 42: Af-[[4-[4-amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- o(|pyrimidin-3-yl]phenyl]methyl]-3,3,3-trifluoro-propane-1 -sulfonamide

[00764] [4-[(3,3,3-Trifluoropropylsulfonylamino)methyllphenyllboronic acid

[00765] Following general procedure B, [4-(aminomethyl)phenyl]boronic acid hydrochloride (300.0 mg, 1 .60 mmol) and 3,3,3-trifluoropropane-1 -sulfonyl chloride (0.22 mL, 1 .76 mmol) afforded crude [4-[(3,3,3-trifluoropropylsulfonylamino)methyl]phenyl]boronic acid (290.6 mg, 0.93 mmol, 58% yield) as a fine pale yellow powder.

[00766] UPLC-MS (ES-, Short acidic): 1 .29 min, m/z 310.2 [M-H]-

[00767] fe/f-Butyl (3ffl-3-[4-amino-3-[4-[(3.3.3- trifluoropropylsulfonylamino)methyllphenyllpyrazolo[3,4-Qlpyrimidin-1 -yllpiperidine-1 -carboxylate

[00768] Following general procedure D, fe/ -butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-rf]pyrimidin- 1 -yl)piperidine-1 -carboxylate (200.0 mg, 0.45 mmol) and [4-[(3,3,3- trifluoropropylsulfonylamino)methyl]phenyl]boronic acid (210.1 mg, 0.68 mmol) gave, after purification by flash column chromatography (DCM:MeOH 100:0 to 90:10), fe/ -butyl (3f?)-3-[4- amino-3-[4-[(3,3,3-trifluoropropylsulfonylamino)methyl]phenyl]pyrazolo[3,4-c]pyrimidin-1 - yl]piperidine-1 -carboxylate (172.0 mg, 0.29 mmol, 65% yield) as a pale yellow oil.

[00769] UPLC-MS (ES⁺, Short acidic): 1 .66 min, m/z 584.5 [M+H]⁺

[00770] /V-[[4-[4-Amino-1 -[(3f?)-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3-yllphenyllmethyll-3,3,3- trifluoro-propane-1 -sulfonamide

[00771] Following general procedure E, fe/f-butyl (3f?)-3-[4-amino-3-[4-[(3,3,3- trifluoropropylsulfonylamino)methyl]phenyl]pyrazolo[3,4-(^pyrimidin-1 -yl]piperidine-1 -carboxylate (172.0 mg, 0.29 mmol) afforded /V-[[4-[4-amino-1 -[(3f?)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3- yl]phenyl]methyl]-3, 3, 3-trifluoro-propane-1 -sulfonamide (107.5 mg, 0.22 mmol, 75% yield) as a light brown film.

[00772] UPLC-MS (ES⁺, Short acidic): 1 .09 min, m/z 484.3 [M+H]⁺

[00773] /V-[[4-[4-Amino-1 -[(3f?)-1 -prop-2-enoyl-3-piperidyllpyrazolo[3,4-Qlpyrimidin-3- yllphenyllmethyll-3, 3, 3-trifluoro-propane-1 -sulfonamide

[00774] Following general procedure F, A/-[[4-[4-amino-1 -[(3R)-3-piperidyl]pyrazolo[3,4- c]pyrimidin-3-yl]phenyl]methyl]-3, 3, 3-trifluoro-propane-1 -sulfonamide (107.5 mg, 0.22 mmol) gave, after purification by preparative LC-MS and salt removal by SCX cartridge, A/-[[4-[4-amino-1 -[(3R)-1 - prop-2-enoyl-3-piperidyl]pyrazolo[3,4-c]pyrimidin-3-yl]phenyl]methyl]-3,3,3-trifluoro-propane-1 - sulfonamide (40.1 mg, 0.07 mmol, 34% yield) as a white solid.

[00775] UPLC-MS (ES⁺, Short acidic): 1 .38 min, m/z 538.4 [M+H]⁺

[00776] UPLC-MS (ES⁺, Long acidic): 3.1 1 min, m/z 538.4 [M+H]⁺

[00777] H-NMR (400 MHz, DMSO-c₆, δ) (ppm, 1 :1 mixture of conformers): 8.28 (s, 1 H, ArH), 7.99 (t, J 6.2 Hz, 1 H), 7.71 -7.64 (m, 2H), 7.53 (d, J 8.0 Hz, 2H), 6.93-6.81 (m, 0.5H), 6.78-6.66 (m, 0.5H), 6.19-6.01 (m, 1 H), 5.76-5.54 (m, 1 H), 4.80-4.65 (m, 1 H), 4.60-4.49 (m, 0.5H), 4.29 (d, J 6.2 Hz, 2H, CH₂), 4.25-4.16 (m, 1 H), 4.14-4.03 (m, 0.5H), 3.78-3.65 (m, 0.5H), 3.32-3.25 (m, 2H), 3.25-3.15 (m, 1 H), 3.08-2.97 (m, 0.5H), 2.77-2.61 (m, 2H), 2.34-2.22 (m, 1 H), 2.18-2.08 (m, 1 H), 1 .99-1 .89 (m, 1 H), 1 .68-1 .51 (m, 1 H).

[00778] Example 43: Af-[[4-[4-Amino-1 -[(3R)-1 -cyano-3-piperidyl]pyrazolo[3,4-c lpyrimidin-3- yl]phenyl]methyl]-3-chloro-benzenesulfonamide

[00779] To a solution of A/-[[4-[4-amino-1 -[(3f?)-3-piperidyl]pyrazolo[3,4-c]pyrimidin-3- yl]phenyl]methyl]-3-chloro-benzenesulfonamide (99.6 mg, 0.20 mmol) in DCM (8 mL) at 0 °C was added triethylamine (0.08 mL, 0.60 mmol), followed by cyanogen bromide (10.6 mg, 0.10 mmol) and left to stir for 3 h at 0 °C. The reaction was quenched with 1 M aqueous NaOH and the layers partitioned. The aqueous layer was extracted with DCM. The combined organic extracts were dried over sodium sulfate, concentrated. Further purification by flash column chromatography afforded N- [[4-[4-amino-1 -[(3R)-1 -cyano-3-piperidyl]pyrazolo[3,4-(^pyrimidin-3-yl]ph

benzenesulfonamide (38.0 mg, 0.07 mmol, 73% yield) as a white powder.

[00780] UPLC-MS (ES⁺, Short acidic): 1 .51 min, m/z 523.9 [M+H]⁺

[00781] H NMR (400 MHz, DMSO-d₆, δ): 8.43 (t, J 64 Hz, 1 H, NH), 8.28 (s, 1 H, ArH), 7.80-7.75 (m, 2H, 2 x ArH), 7.73-7.69 (m, 1 H, ArH), 7.64-7.60 (m, 1 H, ArH), 7.60-7.55 (m, 2H, 2 χ ArH), 7.43- 7.38 (m, 2H, 2 χ ArH), 4.92-4.82 (m, 1 H, CH), 4.13 (d, J 6.1 Hz, 2H, CH₂), 3.63 (dd, J 12.3, 4.3 Hz, 1 H), 3.52 (dd, J 12.3, 10.4 Hz, 1 H), 3.44-3.36 (m, 1 H), 3.16 (dt, J 12.3, 3.1 Hz, 1 H), 2.23-2.04 (m, 2H), 1 .95-1 .86 (m, 1 H), 1 .86-1 .72 (m, 1 H).

[00782] Example 44: Af-[[4-[4-Amino-1 -[(3R)-1 -cyano-3-piperidyl]pyrazolo[3,4-c lpyrimidin-3- yl]phenyl]methyl]-3-fluoro-benzenesulfonamide

[00783] To a solution of A/-[[4-[4-amino-1 -[(3f?)-3-piperidyl]pyrazolo[3,4-rf]pyrimidin-3- yl]phenyl]methyl]-3-fluoro-benzenesulfonamide (96.3 mg, 0.20 mmol) in DCM (8 ml_) at 0 °C was added triethylamine (0.08 ml_, 0.60 mmol), followed by cyanogen bromide (10.6 mg, 0.10 mmol) and left to stir for 3 h at 0 °C. The reaction was quenched with 1 M aqueous NaOH and the layers partitioned. The aqueous layer was extracted with DCM. The combined organic extracts were dried over sodium sulfate and concentrated. Further purification by column chromatography afforded Λ/- [[4-[4-amino-1 -[(3R)-1 -cyano-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-fluoro- benzenesulfonamide (40.0 mg,0.08 mmol, 79% yield) as a white powder.

[00784] UPLC-MS (ES⁺, Short acidic): 1 .44 min, m/z 507.4 [M+H]⁺

[00785] H NMR (400 MHz, DMSO-d₆, δ): 8.29 (s, 1 H, ArH), 7.69-7.63 (m, 2H, 2 χ ArH), 7.62-7.56 (m, 3H), 7.54-7.48 (m, 1 H, ArH), 7.44-7.39 (m, 2H, 2 χ ArH), 4.92-4.83 (m, 1 H, CH), 4.15-4.06 (m, 2H), 3.66-3.60 (m, 1 H), 3.52 (dd, J 12.3, 10.4 Hz, 1 H), 3.44-3.37 (m, 1 H), 3.22-3.1 1 (m, 1 H), 2.22- 2.05 (m, 2H), 1 .96-1 .74 (m, 2H).

[00786] Example 45: Af-[[4-[4-Amino-1 -[(3R)-1 -cyano-3-piperidyl]pyrazolo[3,4-cGpyrimidin-3- yl]phenyl]methyl]-2-fluoro-benzenesulfonamide

[00787] To a solution of A/-[[4-[4-amino-1 -[(3f?)-3-piperidyl]pyrazolo[3,4-rf]pyrimidin-3- yl]phenyl]methyl]-2-fluoro-benzenesulfonamide (96.3 mg, 0.20 mmol) in DCM (8 ml_) at 0 °C was added triethylamine (0.08 ml_, 0.60 mmol), followed by cyanogen bromide (10.6 mg, 0.10 mmol) and left to stir for 3 h at 0 °C. The reaction was quenched with 1 M aqueous NaOH and the layers partitioned. The aqueous layer was extracted with DCM. The combined organic extracts were dried over sodium sulfate and concentrated. Further purification by flash column chromatography afforded /V-[[4-[4-amino-1 -[(3R)-1 -cyano-3-piperidyl]pyrazolo[3,4-rf]pyrimidin-3-yl]phenyl]methyl]-2- fluoro-benzenesulfonamide (23.0 mg, 0.05 mmol, 45% yield) as a white powder.

[00788] UPLC-MS (ES⁺, Short acidic): 1 .41 min, m/z 507.1 [M+H]⁺

[00789] UPLC-MS (ES⁺, Long acidic): 3.17 min, m/z 507.4 [M+H]⁺ [00790] H NMR (400 MHz, DMSO-d₆, δ): 8.61 (t, J 6.4 Hz, 1 H, NH), 8.29 (s, 1 H, ArH), 7.78 (td, J 7.6, 1 .8 Hz, 1 H, ArH), 7.70-7.62 (m, 1 H), 7.57-7.52 (m, 2H), 7.42-7.38 (m, 2H), 7.38-7.30 (m, 2H), 4.92-4.82 (m, 1 H, CH), 4.22 (d, J 6.2 Hz, 2H, CH₂), 3.64 (dd, J 12.4, 4.3 Hz, 1 H), 3.52 (dd, J 12.4, 10.4 Hz, 1 H), 3.44-3.36 (m, 1 H), 3.22-3.1 1 (m, 1 H), 2.23-2.05 (m, 2H), 1 .96-1 .87 (m, 1 H), 1 .87-1 .74 (m, 1 H).

[00791] Example 46: BTK Binding Affinity

[00792] BTK binding affinity of each compound tested was determined using a time-resolved fluorescence resonance energy transfer (TR-FRET) methodology. 2.5 nM Recombinant BTK kinase, varying concentrations of inhibitor, 2 nM Lanthascreen™ Eu anti-His Antibody and 15 nM Kinase Tracer 236 was incubated in 1X Lanthascreen™ Kinase Buffer A for five hours.

Recombinant BTK kinase and all Lanthasceen™ components were purchased from Invitrogen. Measurements were performed in a reaction volume of 30 μΙ_ using half-area 96-well assay plates. The TR-FRET signal was read on a plate reader with an excitation wavelength of 340 nm and detection wavelengths of 615 and 665 nm. Binding affinity was determined for each compound by measuring TR-FRET activity at various concentrations of compound and plotting the relative fluorescence units against the inhibitor concentration to estimate the IC50 from log[lnhibitor] vs response using the Variable Slope model in Graphpad prism from Graphpad software (SanDiego, Calif).

[00793] Results of the BTK Binding Affinity are shown below in Table 1 .

[00794] Example 47: EGFR Binding Affinity

[00795] EGFR binding affinity was determined using a time-resolved fluorescence resonance energy transfer (TR-FRET) methodology. 2.5 nM Recombinant EGFR, varying concentrations of inhibitor, 2 nM Lanthascreen™ Eu anti-GST Antibody and 3nM Kinase Tracer 199 was incubated in 1X Lanthascreen™ Kinase Buffer A for five hours. Recombinant EGFR and all Lanthasceen™ components were purchased from Invitrogen. Measurements were performed in a reaction volume of 30 μί using half-area 96-well assay plates. The TR-FRET signal was read on a plate reader with an excitation wavelength of 340 nm and detection wavelengths of 615 and 665 nm. Binding affinity was determined for each compound by measuring TR-FRET activity at various concentrations of compound and plotting the relative fluorescence units against the inhibitor concentration to estimate the IC50 from log[lnhibitor] vs response using the Variable Slope model in Graphpad prism from Graphpad software (SanDiego, Calif).

[00796] Results of the EGFR Binding Affinity are shown in Table 1 below.

[00797] Example 48: TMD8 Growth Inhibition Assay

[00798] Compounds were assayed for effects on the growth of TMD8 human ABC-DLBCL cells that are dependent on NFKB signalling. TMD8 cells were grown in suspension in T225 flasks, centrifuged and re-suspended in 2.5% FBS containing media. Cells were then plated at 1 .0x10⁴ cells per well in 96-well plates in varying concentrations of compound and incubated for 72 h at 37 °C. An additional plate of cells to be used as the Day 0 read was seeded without compound addition, Resazurin was added to each well, incubated for 5 hours and the fluorescence measured at 590 nm. After 72 h of compound treatment, Resazurin was added to each well of the compound treated plates, incubated for 5 h and the fluorescence measured at 590 nm. The IC50 was then calculated but subtracting the average Day 0 value from each well value from the treated plates, each treatment was then calculated as a percentage of the DMSO control and the percentages plotted against the inhibitor concentration to estimate the ICso from log[lnhibitor] vs response using the Variable Slope model in Graphpad prism from Graphpad software (SanDiego, Calif).

[00799] The results of the TMD8 growth inhibition assay are shown in Table 1 below.

Table 1

Compound of ICso (nM) ICso (nM) ICso (nM) Example Binding BTK Binding EGFR TMD8

29 0.4 350.7 5.0

28 0.5 249.5 2.8

27 0.7 174.0 4.0

26 1 .0 >300 10.0

25 1.4 >300 8.6

24 0.6 167.7 3.2

23 1 .4 >300 21 .7

22 0.3 81 .7 1 .5

21 1.3 78.8 6.1

20 0.2 45.7 0.5

19 0.5 371 .1 6.9

18 0.5 290.5 9.6

17 0.6 64.6 5.1

16 0.2 120.2 2.9

15 0.6 120.2 7.6

14 0.4 91 .8 3.6

13 0.2 58.1 2.0

12 0.4 73.0 7.3

1 1 0.4 124.3 11 .5

10 0.5 95.7 9.4

9 0.4 199.4 3.6

8 0.1 98.7 2.8

7 0.3 41 .0 2.1

6 0.2 150.6 3.6 5 0.6 363.1 1 1 .2

3 1.0 265.3 10.7

4 0.5 45.0 9.0

2 5.3 132.4 NA

1 4.3 1 12.2 300.6

30 4.0 >100 27.5

31 0.4 90.7 3.0

32 0.4 129.0 4.7

33 0.3 60.5 3.7

34 0.3 194.0 1 .1

35 0.5 452.5 1 .8

36 0.4 73.3 3.6

37 0.6 97.7 7.8

38 0.5 86.2 20.2

39 0.8 322.9 53.0

40 1 .1 163.1 50.9

41 0.5 86.3 5.6

42 0.9 276.8 28.9

43 1.3 571 .5 48.5

44 2.4 271 .7 1 19.2

45 4.6 >100 139.3

[00800] Throughout the description and claims of this specification, the words "comprise" and "contain" and variations of them mean "including but not limited to", and they are not intended to (and do not) exclude other moieties, additives, components, integers or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

[00801] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

[00802] The reader's attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.

Claims

1. A compound according to formula (I):

(I)

wherein

A is N or CR^a;

or wherein D represents a substituted or unsubstituted carbocyclic or heterocyclic moiety which is saturated or unsaturated and which contains from 3 to 8 atoms in the carbocyclic or heterocyclic ring, wherein the ring is optionally substituted with -NR^b-, wherein -NR^b- is bonded to the ring; and wherein, when substituted, the alkylene chain or the carbocyclic or heterocyclic moiety includes 1 to 5 substituents independently selected at each occurrence from the group comprising: halo, -OR^b, - SR^b, -NR^bR^c, NO, =0, -CN, acyl, Ci-₆ alkyl, Ci-₆ haloalkyl, C₃-s cycloalkyl, -S0₂R^b, and S0₃R^b , - C(0)R and C(0)OR ;

E is selected from:

Y is either O or NR^b;

L is selected from a bond, -0-, -0(CR^dR^e)_m-, -NR^b- and -(CR^dR^e),

L² represents -NR^bS02-; n is selected from 1 , 2, and 3;

m is selected from 1 , 2, 3 and 4;

R^a is selected from: H, halo, Ci-e alkyl, Ci-e haloalkyl, OH, SH, Ci-e alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C₃-s cycloalkenyl, NR^bR^c, -CN, acyl, -C(0)R^b, -C(0)OR^b, -S0₂R^b, and -S0₃R^b;

R^b and R^c are independently selected at each occurrence from: H, C1-4 alkyl, C1-4 haloalkyl, C1-4 acyl, C3-7 cycloalkyl, and C3-7 halocycloalkyl;

R^d and R^e are independently selected at each occurrence from: H, halo, C1-4 alkyl, C1-4 haloalkyl, Ci- 4 acyl, C3-7 cycloalkyl, and C3-7 halocycloalkyl;

R² is selected from H, halo, -OR^b, C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 heterocycloalkyl, C3-8 cycloalkenyl, C3-8 heterocycloalkenyl, -NR^bR^c, -C02R^b, - C(0)R^b and -C(0)NR^bR^c; and

alkheteroaryl;

or R³ and R⁴ taken together with the carbon atoms to which they are attached form a

C3-8 cycloalkene and R⁵ is independently selected as above;

or R⁴ and R⁵ taken together with the carbon atom to which they are attached form a C3-8 cycloalkyl and R³ is independently selected as above; or R³ and R⁵ taken together with the carbon atoms to which they are attached form a C-C triple bond and R⁴ is independently selected as above.

2. A compound of claim 1 , wherein A is CR^a and R^a is H, fluoro, chloro or C1-4 haloalkyl, preferably H.

3. A compound of claim 1 or claim 2, wherein R is a substituted or unsubstituted: Ci-e alkyl, cycloalkyi, aryl, heterocycloalkyi or heteroaryl, wherein the cycloalkyi and heterocycloalkyi groups may be saturated or unsaturated and the cycloalkyi, aryl, heterocycloalkyi or heteroaryl may contain either from 3 to 8 atoms in a single ring or 7 to 14 atoms in a fused polycyclic ring system, wherein, when substituted, R contains 1 to 5 substituents independently selected at each occurrence from the group comprising: halo, -OR^b, - SR^b, -NR^bR^c, NO, =0, -CN, acyl, Ci-e alkyl, Ci-e haloalkyl, C₃-₈ cycloalkyi, C₃-₈ heterocycloalkyi, -S0₂R^b, S0₃R^b , -C(0)R^b, C(0)OR^b -C(0)NR^bR^c and aryl optionally substituted by 1 or 2 halo atomsD

4. A compound of any preceding claim, wherein R is methyl, trifluoromethyl, ethyl, fluoroethyl, difluoroethyl, trifluoroethyl, tetrafluroethyl, pentafluoroethyl, propyl, isopropyl, fluoropropyl, trifluoropropyl), butyl, fe/ -butyl, tetrahydrofuranyl-trifluoroethyl, cyclopropyl, cyclohexyl, unsubstituted phenyl, indanyl, napthyl, pyridyl, pyrazolyl, quinolinyl or phenyl substituted with one or two groups independently selected from fluoro, chloro, methyl, nitrile, methoxy, ethoxy, trifluoromethyl, -OCF₃, -NC(0)Me and -C(0)NMe₂ or phenyl.

5. A compound of any preceding claim, wherein n is 1

6. A compound of any preceding claim, wherein R² is hydrogen.

7. A compound of any preceding claim, wherein R³, R⁴, and R⁵ are independently selected from hydrogen, fluorine, chlorine, bromine, iodine, -CN, -CH2NR^bR^c and Ci-e alkyl, where R^b and R^c are independently selected from hydrogen and Ci-e alkyl.

8. A compound of any preceding claim, wherein R³, R⁴, and R⁵ are all hydrogen.

9. A compound of any preceding claim, wherein E is:

10. A compound of any preceding claim, wherein D is substituted or unsubstituted C₃-8 heterocycloalkyi, preferably C6 heterocycloalkyi.

11 . A compound of claim 10, wherein D is

12. A compound of any preceding claim, wherein L is selected from a bond, -CH2-, -O- and -NH- , optionally a bond or -CH2-.

13. A compound of claim 1 , wherein the compound of formula (I) is a compound according to formulae (Vila), (Vllb), (Vile) or (Vlld):

(Vile) (Vlld)

14. A compound of claim 1 , wherein the compound of formula (I) is a compound selected from:

105

106

108

109

111

15. A compound of any preceding claim for use as a medicament

16. A compound of any of claims 1 to 14 for use in the treatment of a condition which is modulated by BTK.

17. A compound of claim 16, wherein the condition modulated by BTK is cancer, lymphoma, leukemia, immunological disease, autoimmune diseases and inflammatory disorders.

18. A compound of claim 16 or claim 17, wherein the condition modulated by BTK is selected from: B-cell malignancy, B-cell lymphoma, diffuse large B cell lymphoma, chronic lymphocyte leukemia, non-Hodgkin lymphoma for example ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B-cell non-Hodgi lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, bone cancer, bone metastasis, arthritis, multiple sclerosis osteoporosis, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease and lupus

19. A compound of any of claims 1 to 14 for use in the treatment of: cancer, lymphoma, leukemia, immunological diseases, autoimmune diseases and inflammatory disorders.

20. A compound of any of for use in the treatment of specific conditions selected from: B-cell malignancy, B-cell lymphoma, diffuse large B cell lymphoma, chronic lymphocyte leukemia, non- Hodgkin lymphoma for example ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B-cell non-Hodgkin lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, bone cancer, bone metastasis, arthritis, multiple sclerosis osteoporosis, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, lupus and disorders associated with renal transplant

21 . A compound of any of claims 1 to 14 for use simultaneously, sequentially or separately with an additional anti-tumour agent, in the treatment of cancer, lymphoma, leukemia, immunological diseases autoimmune diseases or inflammatory disorders.

22. A pharmaceutical composition, wherein the pharmaceutical composition comprises a compound of any of claims 1 to 14 and pharmaceutically acceptable excipients.

23. A pharmaceutical composition of claim 23 wherein the composition is a combination product and comprises an additional pharmaceutically active agent.

24. A method of treatment of a condition which is modulated by Bruton's tyrosine kinase, wherein the method comprises administering a therapeutic amount of a compound of claims 1 to 14, to a patient in need thereof.

25. A method of claim 24 wherein the condition modulated by BTK is cancer, lymphoma, leukemia, immunological disease, autoimmune diseases and inflammatory disorders.

26. A method of treating a condition selected from: cancer, lymphoma, leukemia, immunological diseases, autoimmune diseases and inflammatory disorders, wherein the method comprises administering a therapeutic amount of a compound of any of claims 1 to 14, to a patient in need thereof.

27. A method of claim 26, wherein the condition is selected from: B-cell malignancy, B-cell lymphoma, diffuse large B cell lymphoma, chronic lymphocyte leukemia, non-Hodgkin lymphoma for example ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B-cell non- Hodgkin lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, bone cancer, bone metastasis, arthritis, multiple sclerosis osteoporosis, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, lupus, and disorders associated with renal transplant.

28. A method of treatment of a condition selected from cancer, lymphoma, leukemia, immunological diseases, autoimmune diseases or inflammatory disorders comprising administering a therapeutically effective amount of a compound of any of claims 1 to 14, simultaneously, sequentially or separately with an additional anti-tumour agent to a patient in need thereof.

29. A method of claim 28, wherein the condition is selected from: B-cell malignancy, B-cell lymphoma, diffuse large B cell lymphoma, chronic lymphocyte leukemia, non-Hodgkin lymphoma for example ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B-cell non- Hodgkin lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, bone cancer, bone metastasis, arthritis, multiple sclerosis osteoporosis, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, lupus and disorders associated with renal transplant.

30. A method of providing a combination product, wherein the method comprises providing a compound of any of claims 1 to 14 simultaneously, sequentially or separately with an anti-tumor agent.

31 . Use of a compound of any of claims 1 to 14 in the manufacture of a medicament for the treatment of a condition which is modulated by Bruton's tyrosine kinase.

32. Use of a compound of any of claims 1 to 14 in combination with an anti-tumor agent.