WO2014188173A1

WO2014188173A1 - Pyrazolopyrimidine derivatives useful as inhibitors of bruton's tyrosine kinase

Info

Publication number: WO2014188173A1
Application number: PCT/GB2014/051542
Authority: WO
Inventors: Richard Armer; Matilda Bingham; Angus Morrison; Emma Carswell; Fred ELUSTONDO; Rolf WALKER; Nicolas GUISOT; Catherine Lucas
Original assignee: Redx Pharma Limited
Priority date: 2013-05-20
Filing date: 2014-05-20
Publication date: 2014-11-27
Also published as: GB201309085D0

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

PYRAZOLOPYRIMIDINE DERIVATIVES USEFUL AS INHIBITORS OF

BRUTON'S TYROSINE KINASE

[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 AVL-292. AVL-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 T_V2 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] It is an aim of certain embodiments of this invention to provide new cancer treatments. In particular, it is an aim of certain embodiments of this invention to provide compounds which have comparable activity to existing cancer treatments, ideally better activity. Certain embodiments of the invention also aim to provide improved solubility compared to prior art compounds and existing therapies. It is particularly attractive for certain compounds of the invention to provide better activity and better solubility over known compounds. Reduced side effects compared to known therapies are also an aim.

[0009] It is an aim of certain embodiments of this invention to provide compounds which exhibit reduced cytotoxicity relative to prior art compounds and existing therapies. [0010] Another aim of certain embodiments of this invention is to provide compounds having a convenient pharmacokinetic profile and a suitable duration of action following dosing. A further aim of certain embodiments of this invention is to provide compounds in which the metabolised fragment or fragments of the drug after absorption are GRAS (Generally Regarded As Safe).

[0011] Certain embodiments of the present invention satisfy some or all of the above aims.

SUM MARY OF THE DISCLOSURE

[0012] 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.

[0013] In a first aspect of the invention there is provided a compound according to formula (I) and pharmaceutically acceptable salts and solvates thereof:

wherein

one of A¹ , A², A³, A⁴ and A⁵ is CL²R¹ and the remaining A¹ , A², A³, A⁴ and A⁵ are independently selected from N or CR^a;

or wherein A¹ , A², A³, A⁴ and A⁵ are independently selected from N or CR^a and any two CR^a on adjacent A groups form an additional fused ring which is a non-aromatic carbocyclic or heterocyclic ring wherein the non-aromatic ring contains 5 to 7 atoms, and wherein the ring may be substituted by 1 to 4 groups independently selected at each occurrence from halo, C_1- alkyl, C_1- haloalkyl and C₃.₆ cycloalkyl;

D is either a substituted or unsubstituted C_1-6 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 the rest of the molecule; 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, d_₆ alkyl, d_₆ haloalkyl, C₃-₈ cycloalkyl, -S0₂R^b, and S0₃R^b , - C(0)R^b and C(0)OR^b;

E is selected from:

Y is either O or NR^b;

R^a is selected from the group comprising: H, halo, C_1-6 alkyl, C_1-6 haloalkyl, OH, SH, C_1-6 alkoxy, C₂_₆ alkenyl, C₂-₆ alkynyl, C₃-₈ cycloalkyl, C₃-₈ 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, C_1- alkyl, C_1- haloalkyl, C_1- acyl, C₃_7 cycloalkyl, and C₃.₇ halocycloalkyl;

R is -NR⁶R⁷ or a substituted or unsubstituted carbocyclic or heterocyclic moiety which is saturated or unsaturated and which either contains from 3 to 8 atoms in a single ring or 7 to 14 atoms in a fused polycyclic ring system, wherein the group R as a whole is not aromatic, and 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, C_1-6 alkyl, C_1-6 haloalkyl, C₃.₈ cycloalkyl, - S0₂R^b, and S0₃R^b , -C(0)R^b and C(0)OR^b;

R², R³, and R⁴ 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, C_1-6 alkoxy, C_1-6 alkyl, C_1-6 alkyl substituted with C₃.₈ cycloalkyl, C_1-6 alkyl substituted with C₃.₈ heterocycloalkyl, C₂.₆ alkenyl, C₂.₆ alkynyl, C_1-6 haloalkyl, C₃.₈ cycloalkyl, C₃.₈ heterocycloalkyl, C₃.₈ cycloalkenyl, C₃.₈ heterocycloalkenyl, aryl, heteroaryl, alkaryl and alkheteroaryl; or R² and R³ taken together with the carbon atoms to which they are attached form a C₃.₈ cycloalkene and R⁴ is independently selected as above;

or R³ and R⁴ taken together with the carbon atom to which they are attached form a C₃.₈ cycloalkyl and R² is independently selected as above;

or R² and R⁴ taken together with the carbon atoms to which they are attached form a C-C triple bond and R³ is independently selected as above;

R⁵ is selected from H, halo, -OR^b, C_1-6 alkoxy, C_1-6 alkyl, C₂.₆ alkenyl, C₂.₆ alkynyl, C_1-6 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;

R⁶ and R⁷ may be independently be selected from H, substituted or unsubstituted C_1-6 alkyl, C_1-6 haloalkyl, substituted or unsubstituted C₃.₈ cycloalkyl, -(CR^dR^e)_n-aryl, wherein n is 0, 1 or 2; L and L² are independently selected from a bond, -0-, -0(CR^dR^e)_m-, -NR^b- and -(CR^dR^e)_m-, wherein Rd and Re are independently selected at each occurrence from: H, halo, C_1- alkyl, C_1- haloalkyl, C_1- acyl, C3.7 cycloalkyl, and C₃.₇ halocycloalkyl; and

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

[0014] The invention also provides a compound according to formula (I) and pharmaceutically acceptable salts and solvates thereof:

(I)

wherein

or wherein A¹ , A², A³, A⁴ and A⁵ are independently selected from N or CR^a and any two CR^a on adjacent A groups form an additional fused ring which is a non-aromatic carbocyclic or heterocyclic ring wherein the non-aromatic ring contains 5 to 7 atoms, and wherein the ring may be substituted by 1 to 4 groups independently selected at each occurrence from halo, C_1- alkyl, C_1- haloalkyl and C₃.₆ cycloalkyl, provided that the heterocyclic ring does not comprise 2 oxygen atoms;

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 the rest of the molecule;

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, d_₆ alkyl, d_₆ haloalkyl, C₃-₈ cycloalkyl, -S0₂R^b, and S0₃R^b, -C(0)R^b and C(0)OR^b;

E

Y is either O or NR^b;

X is selected from chloro, fluoro, bromo or iodo;

0 is 0, 1 or 2 R^a is selected from the group comprising: H, halo, C_1-6 alkyl, C_1-6 haloalkyl, OH, SH, C_1-6 alkoxy, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃-₈ cycloalkyl, C₃-₈ 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, C_1- alkyl, C_1- haloalkyl, C_1- acyl, C3.7 cycloalkyl, and C₃.₇ halocycloalkyl;

R is -NR⁶R⁷ or a substituted or unsubstituted carbocyclic or heterocyclic moiety which is saturated or unsaturated and which either contains from 3 to 8 atoms in a single ring or 7 to 14 atoms in a fused polycyclic ring system, wherein the group R as a whole is not aromatic, and 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, C_1-6 alkyl, C_1-6 haloalkyl, C₃.₈ cycloalkyl, C₆_ ₁₀ aryl, -S0₂R^b, S0₃R^b, -C(0)R^b and C(0)OR^b;

or R² and R⁴ taken together jointly contribute to a bond so that the carbon atoms to which they are attached form a C-C triple bond and R³ is independently selected as above;

R⁶ and R⁷ may be independently be selected from H, substituted or unsubstituted C_1-6 alkyl, C_1-6 haloalkyl, substituted or unsubstituted C₃.₈ cycloalkyl, -(CR^dR^e)_n-aryl, wherein n is 0, 1 or 2, when substituted, R⁶ and R⁷ independently contain 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, C_1-6 alkyl, C_1-6 haloalkyl, C₃.₈ cycloalkyl, C₆.₁₀ aryl, -S0₂R^b, S0₃R^b, -C(0)R^b and C(0)OR^b;

L is selected from a bond, -0-, -0(CR^dR^e)_m-, -NR^b- and -(CR^dR^e)_m-, wherein R^d and R^e are independently selected at each occurrence from: H, halo, C_1- alkyl, C_1- haloalkyl, C_1- acyl,

C₃_7 cycloalkyl, and C₃.₇ halocycloalkyl;

L² is selected from -0-, -0(CR^dR^e)_m-, -NR^b- and -(CR^dR^e)_m-, wherein R^d and R^e are independently selected at each occurrence from: H, halo, C_1- alkyl, C_1- haloalkyl, C_1- acyl, C₃.₇ cycloalkyl, and C₃.₇ halocycloalkyl;and

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

[0015] In embodiments one of A¹ , A², A³, A⁴ and A⁵ is CL²R¹ and the remaining A¹, A², A³, A⁴ and A⁵ are independently selected from N or CR^a. A³

[0016] The group R is a substituent on the ring A ^" ^ in embodiments where one of A , A², A³, A⁴ and A⁵ is CL²R¹ and the remaining A¹ , A², A³, A⁴ and A⁵ are independently selected from N or CR^a. This R group is an important part of the molecule and may be a carbocyclic or heterocyclic moiety. This group may be saturated or unsaturated and, when unsaturated may also contain an aromatic ring i.e. an aromatic portion as part of a fused or substituted ring system. However, it is important that the group as a whole does not have aromatic character. R does not encompass wholly aromatic bicyclic groups, for example R does not encompass:

However, R does encompass, amongst other things:

A --A⁴ _N

A³

[0017] The ring represented by A 1 - A²

("the A-ring") is also an important part of the molecule.

[0018] In an embodiment, one of A¹, A², A³, A⁴ and A⁵ is CL²R¹ , one of A¹ , A², A³, A⁴ and A⁵ is N and the remaining A¹ , A², A³, A⁴ and A⁵ are CR^a. In this embodiment, the A ring is a pyridyl ring which may have the N at any position. In an embodiment, one of A¹, A², A³, A⁴ and A⁵ is CL²R¹ and the remaining A¹ , A², A³, A⁴ and A⁵ are all CR^a. In this case, the A ring is a phenyl ring.

[0019] The group R in CL²R¹ which is attached to one of the A groups in the A ring can be a substituted or unsubstituted carbocyclic or heterocyclic moiety which is saturated or unsaturated and which either contains from 3 to 8 atoms in a single ring or 7 to 14 atoms in a fused polycyclic ring system, wherein the group R as a whole is not aromatic, and 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, d_₆ alkyl, d_₆ haloalkyl, C₃-₈ cycloalkyl, -S0₂R^b, and S0₃R^b , - C(0)R^b and C(0)OR^b. Optionally, the heterocyclic moiety comprises 1 , 2 or 3 heteroatoms selected from N, O or S.

[0020] The carbocyclic moiety may be saturated or unsaturated and contain 7 to 14 atoms in a fused polycyclic ring system. The fused ring will usually have 2 rings, one of which is aromatic, e.g. phenyl. Optionally, the carbocyclic moiety of R is not a substituted or unsubstituted carbocyclic moiety which is saturated or unsaturated and which contains from 3 to 8 atoms in a single ring. Thus, in an embodiment R is a substituted or unsubstituted carbocyclic moiety which is saturated or unsaturated and which contains 7 to 14 atoms in a fused polycyclic ring system or a substituted or unsubstituted heterocyclic moiety which is saturated or unsaturated and which either contains from 3 to 8 atoms in a single ring or 7 to 14 atoms in a fused polycyclic ring system, wherein the group R as a whole is not aromatic, and wherein, when substituted, R is substituted as described elsewhere herein.

[0021] In an embodiment R is a substituted or unsubstituted carbocyclic or heterocyclic moiety and which is saturated or unsaturated which contains from 3 to 8 atoms in a single ring, wherein R as a whole is not aromatic, and wherein, when substituted, R contains 1 to 5 substituents independently selected at each occurrence from the group comprising: -OR^b, - SR^b, -NR^bR^c, NO, =0, -CN, acyl, C_1-6 alkyl, d_₆ haloalkyl, C₃-₈ cycloalkyl, -S0₂R^b, and S0₃R^b , -C(0)R^b and C(0)OR^b.

[0022] In an alternative embodiment R is a substituted or unsubstituted carbocyclic or heterocyclic moiety which is saturated or unsaturated and which contains 7 to 14 atoms in a fused polycyclic ring system wherein R as a whole is not aromatic, and wherein, when substituted, R contains 1 to 5 substituents independently selected at each occurrence from the group comprising: -OR^b, - SR^b, - NR^bR^c, NO, =0, -CN, acyl, d_₆ alkyl, d_₆ haloalkyl, C₃-₈ cycloalkyl, -S0₂R^b, and S0₃R^b, -C(0)R^b and C(0)OR^b. Optionally, the heterocyclic moiety contains 9, 10 or 1 1 atoms in a fused bicyclic ring system. Optionally, the heterocyclic moiety may comprise at least one nitrogen atom.

[0023] In embodiments R is a substituted or unsubstituted carbocyclic moiety which is saturated or unsaturated. In alternative embodiments R is a substituted or unsubstituted heterocyclic moiety which is saturated or unsaturated.

[0024] The heterocyclic moiety may comprise 1 , 2 or 3 heteroatoms selected from N, O or S.

Optionally, the heterocyclic moiety comprises at least one N atom. Further optionally, the heterocyclic moiety comprises at least an N atom and an O atom.

[0025] In an embodiment R may be a substituted or unsubstituted ring selected from: piperidinyl, piperazinyl, piperidinyl, tetrahydropyranyl, morpholinyl, pyrolidinyl, imidazolidinyl, succinimidyl, pyrazolidinyl, tetrahydrofuranyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, oxetanyl, azetidinyl, oxiranyl, aziridinyl, oxepanyl, azepanyl, diazepanyl, oxazepanyl, diazepanyl, cycloheptanyl, cyclohexanyl, cyclohexenyl, cyclopentanyl, cyclopentenyl, cyclobutanyl, cyclopropanyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, hexahydroquinolinyl, hexahydroisoquinolinyl, octahydroquinolinyl, octahydroisoquinolinyl, dihydroisoquinolinyl, dihydroquinolinyl

tetrahydrobenzazepinyl, dioxobenzothiazolidinyl, tetrahydronaphthyridinyl, dihydronaphthyridinyl, hexahydronaphthyridinyl, octahydronaphthyridinyl, dihydrobenzothiazinyl,

tetrahydrobenzothiazinyl.dihydropyrido-oxazinyl, tetrahydropyrido-oxazinyl, oxazabicycloheptanyl (for example oxazabicyclo[2.2.1 ]heptanyl), oxazabicyclo-octanyl (for example,

oxazabicyclo[3.2.1 .Joctanyl), octahydrobenzoxazinyl and dihydrobenzoxazinyl.

[0026] In a further embodiment R may be a substituted or unsubstituted ring selected from:

piperidinyl, piperazinyl, piperidinyl, tetrahydropyranyl, morpholinyl, pyrolidinyl, imidazolidinyl, succinimidyl, pyrazolidinyl, tetrahydrofuranyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, oxetanyl, azetidinyl, oxiranyl, aziridinyl, oxepanyl, azepanyl, oxazepanyl and diazepanyl, wherein the ring may be bound to L² through either a N atom or a C atom. [0027] In an embodiment R may be a substituted or unsubstituted ring selected from: indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, hexahydroquinolinyl, hexahydroisoquinolinyl, octahydroquinolinyl, octahydroisoquinolinyl, dihydroisoquinolinyl, dihydroquinolinyl

oxazabicyclo[3.2.1 .Joctanyl), octahydrobenzoxazinyl and dihydrobenzoxazinyl.

[0028] Where R is a group comprising a nitrogen atom the group R may be bonded to L² through the nitrogen atom.

[0029] In a further embodiment R may be a substituted or unsubstituted ring selected from:

cycloheptanyl, cyclohexanyl, cyclohexenyl, cyclopentanyl, cyclopentenyl, cyclobutanyl, cyclopropanyl.

[0030] In a further embodiment R may be a substituted or unsubstituted ring selected from:

piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, pyrolidinyl, imidazolidinyl, succinimidyl, pyrazolidinyl, tetrahydrofuranyl, oxazolidinyl, isoxazolidinyl, azetidinyl, oxetanyl, aziridinyl, azepane, oxazepane and diazepane, wherein the ring may be bound to L² through either a N atom or a C atom.

[0031] In an alternative embodiment R is a substituted or unsubstituted ring selected from:

piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, pyrolidinyl, pyrazolidinyl, tetrahydrofuranyl, oxazolidinyl, isoxazolidinyl, azetidinyl, aziridinyl, oxetanyl, azepanyl, oxazepanyl and diazepanyle, wherein the ring may be bound to L² through either a N atom or a C atom.

[0032] In a preferred embodiment R is a substituted or unsubstituted ring selected from: piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, pyrolidinyl, tetrahydrofuranyl, oxazolidinyl and

isoxazolidinyl, wherein the ring may be bound to L² through either a N atom or a C atom.

[0033] In a preferred embodiment R is piperazinyl. In a preferred embodiment R is morpholinyl. In a preferred embodiment R is oxazolidinyl. In a preferred embodiment R is morpholinyl. In a preferred embodiment R is piperidinyl. In a preferred embodiment R is morpholinyl. In a preferred embodiment R is morpholinyl.

[0034] In an embodiment R is a substituted or unsubstituted ring selected from: -N(C_1-6alkyl)₂, morpholinyl, diazepanyl, pyrolidinyl, tetrahydrofuranyl, piperidinyl, indolinyl, isoindolinyl,

tetrahydroquinolinyl, tetrahydroisoquinolinyl, hexahydroquinolinyl, hexahydroisoquinolinyl,

octahydroquinolinyl, octahydroisoquinolinyl, dihydroisoquinolinyl, dihydroquinolinyl

oxazabicyclo[3.2.1 .Joctanyl), octahydrobenzoxazinyl and dihydrobenzoxazinyl. [0035] In an embodiment R is a substituted or unsubstituted ring selected from: indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydronaphthyridinyl and

dihydronaphthyridinyl.

[0036] In a preferred embodiment R is substituted piperazinyl. In a preferred embodiment R is substituted morpholinyl. In a preferred embodiment R is substituted oxazolidinyl. In a preferred embodiment R is unsubstituted morpholinyl. In a preferred embodiment R is substituted piperidinyl. In a preferred embodiment R is unsubstituted or substituted indolinyl. In a preferred embodiment R is unsubstituted or substituted isoindolinyl. In a preferred embodiment R is unsubstituted or substituted tetrahydroquinolinyl. In a preferred embodiment R is unsubstituted or substituted

tetrahydroisoquinolinyl. In a preferred embodiment R is unsubstituted or substituted

dihydrobenzoxazinyl. In a preferred embodiment R is unsubstituted or substituted

dihydronaphthyridinyl. In a preferred embodiment R is unsubstituted or substituted

tetrahydronaphthyridinyl.

[0037] When substituted, R may contain 1 to 5 (optionally 1 to 3, further optionally 1 or 2) substituents independently selected at each occurrence from the group comprising: halo (optionally fluoro or chloro), C_1-6 haloalkyl (optionally C_1- haloalkyl, further optionally C^₂ haloalkyl), C_1-6 alkyl (optionally C_{1 4} alkyl, further optionally C_1-2 alkyl), -CN, -OR^b, =0, -C(0)OR^b and C_6-10 aryl (optionally phenyl).

[0038] When substituted, R may contain 1 to 3 (optionally 1 or 2) substituents independently selected at each occurrence from the group comprising: fluoro, chloro, methoxy, ethoxy, methyl, ethyl, trifluoromethyl, -CN, =0, -C(0)0'Bu and phenyl.

[0039] In a further embodiment, the group defined by R in any of the compounds of the invention may be selected from substituted or unsubstituted:

[0040] In a preferred embodiment, the group defined by R in any of the compounds of the invention may be selected from substituted or unsubstituted:

[0041] In an embodiment, R is substituted or unsubstituted:

wherein the two R' groups form a C₄.₈ ring with the carbon atoms to which they are attached, 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.

[0042] In an embodiment, R is:

[0043] Optionally, the two R' groups form a substituted or unsubstituted C₆ ring with the carbon atoms to which they are attached, wherein the C₆ ring is an unsaturated hydrocarbon ring with 6 carbon atoms or a unsaturated hydrocarbon ring with 5 carbon atoms and 1 nitrogen atom. The C₆ ring may be a phenyl ring or a pyridyl ring. Preferably, the two R' groups form a substituted or unsubstituted C₆ ring with the carbon atoms to which they are attached, wherein the C₆ ring is a phenyl ring.

[0044] In an alternative embodiment, R is selected from substituted or unsubstituted:

[0046] In an embodiment R is selected from substituted or unsubstituted:

[0048] In an embodiment R is selected from substituted or unsubstituted:

[0049] In an embodiment, the group defined by R in any of the compounds of the invention may be selected from substituted or unsubstituted:

[0050] In an embodiment R is -NR⁶R⁷.

[0051] In embodiments R⁶ and R⁷ are independently selected from: H, C_1-6 alkyl, C_1-6 alkyl substituted with =0, haloalkyl, -(CR^dR^e)_n -aryl, wherein n is 0, 1 or 2. In embodiments R⁶ and R⁷ are independently selected from: H, C_1-6 alkyl, haloalkyl, -(CR^dR^e)_n -aryl, wherein n is 0, 1 or 2.

[0052] In embodiments R⁶ is C_1-6 alkyl and R⁷ is C_1-6 alkyl, C_1-6 haloalkyl, -(CR^dR^e)_n -aryl, wherein n is 0, 1 or 2.

[0053] In embodiments R⁶ is methyl, ethyl or propyl and R⁷ is methyl, ethyl or propyl. In embodiments R⁶ is methyl, ethyl or propyl substituted with and R⁷ is methyl, ethyl or propyl. In embodiments R⁶ is methyl or ethyl and R⁷ is C_1-6 haloalkyl, optionally C_1-6 fluoroalkyl. In embodiments R⁶ is methyl, ethyl or propyl and R⁷ is -(CH₂)_n -phenyl wherein n is 0 or 1 . In embodiments R⁶ is methanoyl, ethanoyl or propanoyl and R⁷ is H or methyl.

[0054] In an embodiment, the group defined by R in any of the compounds of the invention may be selected from substituted or unsubstituted:

—

[0055] In an embodiment, the group defined by R is selected from substituted or unsubstituted

[0056] In an embodiment R is selected from an unsubstituted group from the preceding paragraph or a group from the preceding paragraph substituted with 1 to 5 (optionally 1 to 3, further optionally 1 or 2) substituents independently selected at each occurrence from the group comprising: halo

(optionally fluoro or chloro), C_1-6 haloalkyl (optionally C_1- haloalkyl, further optionally C^₂ haloalkyl), C_1-6 alkyl (optionally C_{1 4} alkyl, further optionally C_1-2 alkyl), -CN, -OR^b, =0, -C(0)OR^b and C_6-10 aryl (optionally phenyl). Optionally, the group is substituted with 1 to 3 (further optionally 1 or 2) substituents independently selected at each occurrence from the group comprising: fluoro, chloro, methoxy, ethoxy, methyl, ethyl, trifluoromethyl, -CN, =0, -C(0)0'Bu and phenyl. [0057] In an embodiment, the group defined by R is selected from substituted or unsubstituted:

wherein the group may be substituted as described above.

[0058] In an embodiment R is indolinyl substituted with 1 to 3 (further optionally 1 or 2) substituents independently selected at each occurrence from the group comprising: fluoro, chloro, methoxy, ethoxy, methyl, ethyl, trifluoromethyl, -CN, =0, -C(0)0'Bu and phenyl. Optionally, the indolinyl group is attached to the rest of the molecule by the nitrogen atom.

[0059] In embodiments, A¹ , A², A³, A⁴ and A⁵ are independently selected from N or CR^a and any two CR^a groups represented by adjacent A groups form an additional fused ring which is a non- aromatic carbocyclic or heterocyclic ring, wherein the ring contains 5 to 7 atoms of which 1 or 2 atoms of the ring formed by the adjacent A groups are heteroatoms, wherein the carbocylic or heterocyclic rings may be substituted by 1 to 4 groups independently selected at each occurrence from halo, C_1- alkyl, C_1- haloalkyl and C₃.₆ cycloalkyl. The heteroatoms may be N, O, S or a combination. Where there are two heteroatoms they may both be N or may be N and O. In embodiments there is 1 heteroatom in the ring formed by the adjacent CR^a groups. In embodiments the heteroatom is N. Optionally, provided that the heterocyclic ring does not comprise 2 oxygen atoms.

[0060] In an embodiment, R², R³, and R⁴ may be independently selected from hydrogen, fluorine, chlorine, bromine, iodine, -CN, -CH₂NR^bR^c, C_1-6 alkyl, C_1-6 alkyl substituted with C₃.₈ cycloalkyl, C_1-6 alkyl substituted with C₃.₈ heterocycloalkyl, C_1-6 haloalkyl, aryl, heteroaryl, alkaryl and alkheteroaryl.

[0061] In another embodiment, R², R³, and R⁴ may be independently selected from hydrogen, fluorine, chlorine, bromine, iodine, -CN, -CH₂NR^bR^c and C_1-6 alkyl, where R^b and R^c are independently selected from hydrogen and C_1-6 alkyl.

[0062] In a more preferred embodiment, two of R², R³, and R⁴ may be hydrogen and the other may be fluorine, chlorine, bromine, iodine, -CN, -CH₂NR^bR^c and C_1-6 alkyl, where R^b and R^c are independently selected from hydrogen and C_1-6 alkyl, e.g. R² and R³ may be hydrogen; or R³ and R⁴ may be hydrogen; or R² and R⁴ may be hydrogen.

[0063] In a further preferred embodiment, R², R³, and R⁴ are all hydrogen.

[0064] In an embodiment, R⁵ is hydrogen.

[0065] In an embodiment, R^a is hydrogen.

[0066] In an embodiment, R^b and R^c are hydrogen.

[0067] In an embodiment, R^d and R^e are hydrogen. [0068] In embodiments E is

[0069] In one embodiment E is:

[0070] In all embodiments E may

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

[0071] In another embodiment E is: [0072] In all embodiments E is

and it may be selected from:

[0

In a further embodiment E is

[0074] In embodiments E is , optionally wherein X is chloro.

[0075] In embodiments E is

, optionally 0 is 1 . [0076] In embodiments E is

, optionally o is 1 .

[0077] In embodiments o is 1 or 2, optionally o is 1 .

[0078] In an embodiment D is either a substituted or unsubstituted C_1-6 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, d_₆ alkyl, d_₆ haloalkyl, C₃-₈ cycloalkyl, -S0₂R^b, and S0₃R^b, -C(0)R^b and C(0)OR^b.

[0079] In an embodiment, D is selected from a substituted or unsubstituted saturated C_1-6 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. 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.

[0080] In an embodiment, D is selected from substituted or unsubstituted C_1-6 heteroalkyl, substituted or unsubstituted C₃.₈ heterocycloalkyl and substituted or unsubstituted C₃.₈

heterocycloalkenyl. In embodiments A may be selected from substituted or unsubstituted C_1-6 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.

[0081] In an embodiment D is unsubstituted. In an alternative embodiment D is substituted. In an embodiment D is substituted with halo, optionally fluoro.

[0082] In an embodiment, D may be selected from:

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

Additionally, D may be

[0083] In an embodiment, D may be selected from:

[0084] In an embodiment, D may be:

optionally, D is substituted by a halo group, for example, fluoro.

[0085] In embodiments Y is O. In alternative embodiments Y is NR^a wherein R^a is H or methyl.

[0086] In embodiments L² is selected from -(CR^dR^e)_m-, -O- and -NR^b-. In embodiments m is 1 or 2, optionally m is 1 . In embodiments R^b, R^d and R^e are independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C_1-6 alkyl and C_1-6 haloalkyl. In embodiments R^b, R^d and R^e are

independently hydrogen or C_1-6 alkyl.

[0087] In embodiments L² is selected from -CH₂-, -O- and -NH-, optionally -CH₂- or -0-.

[0088] 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, R^d and R^e are independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C_1-6 alkyl and C_1-6 haloalkyl. In embodiments R^b, R^d and R^e are independently hydrogen or C_1-6 alkyl.

[0089] In embodiments L is selected from a bond, -CH₂-, -O- and -NH-, optionally a bond or -CH₂-.

[0090] The embodiments described above may be applied individually, or in any combination of one another, and independently, to the compounds of the invention.

[0091] In embodiments the compound of formula (I) is a compound according to formula (la) and pharmaceutically acceptable salts and solvates thereof:

(la)

wherein A¹ , A², A³, A⁴, A⁵, Y, R^a, R^b, R^c, R^d, R^e, R¹ , R², R³, R⁴, R⁵, R⁶, R⁷, L , L², n and m, are as described above for formula (I).

[0092] In the case when D is:

the compound of formula (I) is a compound according to formula (II) and pharmaceutically acceptable salts and solvates thereof:

(II)

wherein A¹ , A², A³, A⁴, A⁵, E, Y, R^a, R^b, R^c, R^d, R^e, R¹ , R², R³, R⁴, R⁵, R⁶, R⁷, L , L², n and m, are as described above for formula (I). [0093] In embodiments the compound of formula (I) is a compound according to formula (Ma) and pharmaceutically acceptable salts and solvates thereof:

(Ha) wherein A¹ , A², A³, A⁴, A⁵, Y, R^a, R^b, R^c, R^d, R^e, R¹ , R², R³, R⁴, R⁵, R⁶, R⁷, L1 , L², n and m, are as described above for formula (I).

[0094] In all embodiments one of A¹ , A², A³, A⁴ and A⁵ is CL²R¹ and the remaining A¹, A², A³, A⁴ and A⁵ may be independently selected from N, or CR^a at each occurrence and one or two, optionally one, of A¹ to A⁵ are N, the remainder being CR^a, wherein R^a is as described above for formula (I).

[0095] In all embodiments, the group represented by:

may be selected from:

wherein one of A¹, A², A³, A⁴ and A⁵ is N and the remaining A¹ , A², A³, A⁴ and A⁵ are CR^a.

[0096] In an embodiment one of A¹ , A², A³, A⁴ and A⁵ is CL²R¹ and the remainder are CR^a

[0097] In all embodiments, the group represented by:

may be selected from:

[0098] In all embodiments, the group represented by:

may be selected from:

[0099] In all embodiments R^a may be selected from H, halo, C_1-6 alkyl, C_1-6 haloalkyl, OH alkoxy. In particular, R^a may be H.

[00100] In particular, the group represented by:

R

may be R

[00101] In embodiments, the compound of formula (I) is a compound according to formula (III) or (Ilia) and pharmaceutically acceptable salts and solvates thereof:

(III) (Ilia) wherein E, Y, R^a, R^b, R^c, R^d, R^e, R¹ , R², R³, R⁴, R⁵, R⁶, R⁷, L , L², n and m are as described above for formula (I).

[00102] In embodiments, the compound of formula (I) is a compound according to formula (IVa), (IVb) or (IVc) and pharmaceutically acceptable salts and solvates thereof:

(IVa) (IVb) (IVc)

wherein Y, R^a, R^b, R^c, R^d, R^e, R , R⁵, L , L² and m are as described above for formula (I).

[00103] The compound of formula (I) may be a compound according to formula (Va), (Vb), (Vc) or (Vd) and pharmaceutically acceptable salts and solvates thereof:

(Va) (Vb)

(Vc) (Vd)

wherein R^a, R^b, R^c, R^d, R^e, R , L , L² and m are as described above for formula (I). [00104] The compound of formula (I) may be a compound according to formula (Ve), (Vf) or (Vg) and pharmaceutically acceptable salts and solvates thereof:

(Ve) (Vf) (Vg) wherein R^a, R^b, R^c, R^d, R^e, R , L , L² and m are as described above for formula (I).

[00105] In all embodiments L may be selected from a bond, -0-, -NH₂- and -CH₂-. In all embodiments L² may be selected from a bond, -0-, -NH₂- and -CH₂-. L may be a bond. L² may be -O- or -CH₂-. In embodiments L is a bond and L² is -0-. In embodiments L is a bond and L² is -CH₂.

[00106] In embodiments the compound of formula (I) may be a compound according to formula (VI) or (Via) and pharmaceutically acceptable salts and solvates thereof:

(VI) (Via)

wherein A¹ , A², A³, A⁴, A⁵, D, E, Y, R^a, R^b, R^c, R^d, R^e, R¹ , R², R³, R⁴, R⁵, R⁶, R⁷, L², n and m are as described above for formula (I).

[00107] In all embodiments where L is a bond, the group represented by:

may be selected from:

[00108] In particular, the group represented by:

[00109] Therefore, the compound of formula (I) may be a compound according to formula (VII) or (Vila) and pharmaceutically acceptable salts and solvates thereof:

(VII) (Vila)

wherein D, E, Y, R^a, R^b, R^c, R^d, R^e, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, L², n and m are as described above for formula (I).

[00110] The compound of formula (I) may be a compound according to formulae (Villa), (Vlllb), (Vlllc) or (Vllld) and pharmaceutically acceptable salts and solvates thereof:

O NR

(Villa) (Vlllb)

(Vlllc) (Vllld) wherein D, R^a, R^u, R^c, R^u, R^e, R , R⁵, L² and m are as described above for formula (I) and Z¹ , Z , Ζ^ό, Z⁴, Z⁵ and Z⁶ are as described above for formula (IV).

[001 11] In compounds of any of formulae (Villa), (Vlllb), (Vlllc) or (Vllld) R⁵ may be hydrogen, R^b and R^c may be independently selected from hydrogen or methyl, and R^d, R^e may be independently selected from hydrogen, methyl or fluoro. In compounds of formula (Villa), (Vlllb), (Vlllc) or (Vlllb) R^b may be H or methyl and R^c may be H.

[001 12] In embodiments, L may be a bond and D may be:

[001 13] The compounds of formula (I) may be a compound according to formula (IX) or (IXa) and pharmaceutically acceptable salts and solvates thereof:

(IX) (IXa)

wherein A¹ , A², A³, A⁴, A⁵, E, Y, R^a, R^b, R^c, R^d, R^e, R¹ , R², R³, R⁴, R⁵, R⁶, R⁷, L², n and m are as described above for formula (I).

[00114] The compounds of formula (I) may be a compound according to formula (X) or (Xa) and pharmaceutically acceptable salts and solvates thereof:

(X) (Xa)

wherein E, Y, R^a, R^b, R^c, R^d, R^e, R¹ , R², R³, R⁴, R⁵, R⁶, R⁷, L², n and m are as described above for formula (I).

[00115] The compounds of formula (I) may be a compound according to formulae (XIa), (Xlb), (Xlc) or (Xld) and pharmaceutically acceptable salts and solvates thereof:

(Xlc) (Xld)

wherein R^a, R^b, R^c, R^d, R^e, R , R⁵, L² and m are as described above for formula (I).

[00116] In compounds of formulae (XIa), (Xlb), (Xlc) and (Xld) R⁵ may be hydrogen, R^b and R^c may be independently selected from hydrogen or methyl, and R^d, R^e may be independently selected from hydrogen, methyl or fluoro. In compounds of formulae (XIa), (Xlb), (Xlc) and (Xld) R^b may be hydrogen or methyl and R^c may be hydrogen.

[00117] The compounds of formula (I) may be a compound according to formulae (Xle) or (Xlf) and pharmaceutically acceptable salts and solvates thereof:

(Xle) (Xlf) (Xlg) wherein R^a, R^b, R^c, R^d, R^e, R , R⁵, L² and m are as described above for formula (I).

[00118] In compounds of formulae (Xle) and (Xlf) R⁵ may be hydrogen, R^b and R^c may be independently selected from hydrogen or methyl, and R^d, R^e may be independently selected from hydrogen, methyl or fluoro. In compounds of formulae (Xle) and (Xlf) R^b may be hydrogen or methyl and R^c may be hydrogen. In the compounds of this paragraph L² may be -CH₂-.

[00119] In embodiments, the compound of formula (I) is a compound according to formula (XII) or (Xlla) and pharmaceutically acceptable salts and solvates thereof:

(XII) (Xlla)

wherein E, Y, R^a, R^b, R^c, R^d, R^e, R², R³, R⁴, R⁵, R⁶, R⁷, L , L², n and m are as described above for formula (I).

[00120] In embodiments, the compound of formula (I) is a compound according to formula (XIII) (Xllla) and pharmaceutically acceptable salts and solvates thereof:

(XIII) (Xllla) wherein D, E, Y, R^a, R^b, R^c, R^d, R^e, R², R³, R⁴, R⁵, R⁶, R⁷, L², n and m are as described above for formula (I).

[00121] In embodiments, the compound of formula (I) is a compound according to formula (XIV) or (XlVa) and pharmaceutically acceptable salts and solvates thereof: e

(XIV) wherein E, Y, R^a, R^b, R^c, R^d, R^e, R², R³, R⁴, R⁵, R⁶, R⁷, L², n and m are as described above for formula (I).

[00122] In embodiments, the compound of formula (I) is a compound according to formula (XV) or (XVI) and pharmaceutically acceptable salrs and solvates thereof:

(XV) (XVI)

wherein A¹ , A², A³, A⁴, A⁵, Y, R^a, R^b, R^c, R^d, R^e, R¹ , R², R³, R⁴, R⁶, R⁷, L , L², n and m, are as described above for formula (I).

[00123] In embodiments, the compound of the invention may be a compound of any formula described above (for example formula (I), formula (XV) or formula (XVI), wherein D is piperidinyl and E

is

preferably Y is O; optionally R², R³, and R⁴ may be all hydrogen The compound of the invention may be a compound of any formula described above (for example formula (I), formula

(XV) or formula (XVI), wherein D is piperidinyl and E is

, optionally wherein R², R³, and R⁴ are all hydrogen. The compound of the invention may be a compound of any formula described above (for example formula (I), formula (XV) or formula (XVI), wherein D is piperidinyl and E is

. The compound of the invention may be a compound of any formula described above (for

example formula (I), formula (XV) or formula (XVI), wherein D is piperidinyl and E is

preferably X is chloro. The compound of the invention may be a compound of any formula described above (for example formula (I), formula (XV) or formula (XVI), wherein D is piperidinyl and E is

compound of the invention may be a compound of any formula described above (for example formula (I), formula (XV) or formula (XVI), wherein D is piperidinyl and E is

[00124] The compound of the invention may be a compound of any formula described above (for example formula (I), formula (XV) or formula (XVI), wherein L² is -CH₂-, D is piperidinyl and E is

, preferably Y is O; optionally R², R³, and R⁴ are all hydrogen. The compound of the invention may be a compound of any formula described above (for example formula (I), formula (XV)

or formula (XVI), wherein L² is -CH₂-, D is piperidinyl and E is

optionally wherein R², R³, and R⁴ are all hydrogen. The compound of the invention may be a compound of any formula described above (for example formula (I), formula (XV) or formula (XVI), wherein L² is -CH₂-, D is piperidinyl and E is N . The compound of the invention may be a compound of any formula described above (for example formula (I), formula (XV) or formula (XVI), wherein L² is -CH₂-, D is

piperidinyl and E

, preferably X is chloro. The compound of the invention may be a compound of any formula described above (for example formula (I), formula (XV) or formula (XVI),

,o

wherein L² is -CH₂-, D is piperidinyl and E is ^x ' ^u . The compound of the invention may be a compound of any formula described above (for example formula (I), formula (XV) or formula (XVI),

wherein L² is -CH₂-, D is piperidinyl and E is

[00125] In another aspect of the invention there is provided a compound of formula (I) for use as a medicament.

[00126] 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).

[00127] 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- Hodgkins lymphoma for example ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B-cell non-Hodgkins 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.

[00128] B-cell malignancy, B-cell lymphoma, diffuse large B cell lymphoma, chronic lymphocyte leukemia, non-Hodgkins lymphoma for example ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B-cell non-Hodgkins lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, bone cancer and bone metastasis are examples of cancer, lymphomas and leukemias treatable by BTK inhibition.

[00129] 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.

[00130] In embodiments, a compound of the invention may be for use in the treatment of: cancer, lymphoma, leukemia and immunological diseases. 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-Hodgkins lymphoma for example ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B-cell non-Hodgkins 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.

[00131] 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-Hodgkins lymphoma for example ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B-cell non-Hodgkins lymphoma, Waldenstrom's

macroglobulinemia, multiple myeloma, lupus and arthritis.

[00132] 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.

[00133] The method of treatment may be a method of treating a condition treatable by the inhibition of Bruton's tyrosine kinase.

[00134] The invention also provides a method of treating a condition selected from: cancer, lymphoma, leukemia and immunological diseases, 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-Hodgkins lymphoma for example ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B-cell non-Hodgkins 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.

[00135] 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- Hodgkins lymphoma for example ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B-cell non-Hodgkins lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, arthritis and lupus.

[00136] 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.

[00137] 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.

DETAILED DESCRIPTION

[00138] 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.

[00139] 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.

[00140] The term "C_1-6 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, iso-propyl, n-butyl, sec-butyl, tert-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, C_1-6 alkoxy.

[00141] The term "C_1-6 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, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. Therefore, the alkoxy group may be methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, tert-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, C_1-6 alkoxy.

[00142] The term "C_1-6 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, C_1-6 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.

[00143] 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.

[00144] 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.

[00145] The term "C_1-6 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 C_1-6 heteroalkyl may be bonded to the rest of the molecule through a carbon or a heteroatom. For example, the "C_1-6 heteroalkyl" may be C_1-6 /V-alkyl, C_1-6 Λ/,/V-alkyl, or C_1-6 O-alkyl.

[00146] 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.

[00147] 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.

[00148] 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.

[00149] 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.

[00150] 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.

[00151] 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.

[00152] 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.

[00153] 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 napthyl. The aryl system itself may be substituted with other groups.

[00154] 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.

[00155] The term "alkaryl" refers to an aryl group, as defined above, bonded to a C_1- alkyl, where the C_1- alkyl group provides attachment to the remainder of the molecule.

[00156] The term "alkheteroaryl" refers to a heteroaryl group, as defined above, bonded to a

C_1- alkyl, where the alkyl group provides attachment to the remainder of the molecule.

[00157] The term "halogen" herein includes reference to F, CI, Br and I. Halogen may be CI.

Halogen may be F. [00158] 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.

[00159] Within the specification, A¹ , A², A³, A⁴ and A⁵ may collectively be referred to as "A groups". One of the "A groups" may generally be described as an "A group".

[00160] Within the specification, Z , Z², Z³, Z⁴, Z⁵ and Z⁶ may collectively be referred to as "Z groups". One of the "Z groups" may generally be described as a "Z group".

[00161] 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 substitutuents, 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, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 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.

[00162] 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.

[00163] 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, C_1-6 alkyl, C₃.₈ cycloalkyl, phenyl, benzyl or phenethyl group, eg R is H or C_1-3 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.

[00164] The invention contemplates pharmaceutically acceptable salts of the compounds of formula (I). These may include the acid addition and base salts of the compounds.

[00165] Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, 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.

[00166] 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, hemisulphate 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).

[00167] 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.

[00168] 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.

[00169] 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.

[00170] 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).

[00171] Hereinafter all references to compounds of any formula include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.

[00172] 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, for example compounds of the invention comprising dueterium.

[00173] 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.

[00174] 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.

[00175] 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.

[00176] 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.

[00177] 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-tumour 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 antioestrogens (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 ΡΙ3Κδ inhibitors, for example idelalisib and perifosine.

[00178] 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,

(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-HT_2A 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. [00179] 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.

[00180] 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.

[00181] 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 of formula (I), or a pharmaceutically acceptable salt thereof simultaneously, sequentially or separately with an additional anti-tumour agent, as defined hereinbefore, to a patient in need thereof.

[00182] 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.

[00183] According to another aspect of the invention there is provided a use of the compound of formula (I) in combination with an anti-tumour agent as hereinbefore described. The compound of formula (I) may be used simultaneously, sequentially or separately with the additional anti-tumour agent The use may be in a single combination product comprising the compound of formula (I) and the anti-tumour agent.

[00184] 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-tumour agent, as defined hereinbefore. The method may comprise combining the compound of formula (I) and the anti-tumour agent in a single dosage form. Alternatively the method may comprise providing the anti-tumour agent as separate dosage forms.

[00185] 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-Hodgkins lymphoma for example ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B-cell non- Hodgkins lymphoma, Waldenstrom's macroglobulinemia and multiple myeloma.

[00186] The compound of formula (I) may be a compound according to formula (III) or (Ilia) as defined above and, in embodiments where R^a is H, the compound of formula (III) or (Ilia) is then a compound of formula (1Mb) or (lllc) respectively:

(Hlbi (Hlc) wherein E, R^b, R^c, R^d, R^e, R , R², R³, R⁴, R⁵, L , L², n and m are as defined above for formula (I).

[00187] The compound of formula (I) may be a compound according to formulae (IVa), (IVb) or (IVc) as defined above and, in embodiments where R^a is H, the compound of formulae (IVa), (IVb) or (IVc) is then a compound of formulae (IVd), (IVe) or (IVf) respectively :

(IVd) (IVe) (IVf)

wherein Y, R^b, R^c, R^d, R^e, R , R⁵, L , L² and m are as described above for formula (I).

[00188] The compound of formula (I) may be a compound according to formulae (Va), (Vb), (Vc) or (Vd) as defined above and, in embodiments where R^a is H, the compound of formulae (Va), (Vb), (Vc) or (Vd) is then a compound of formulae (Vh), (Vi), (Vj) or (Vk) respectively:

(Vh) (Vi)

(Vj) (Vk)

wherein R^a, R^b, R^c, R^d, R^e, L , L² and m are as described above for formula (I).

[00189] The compound of formula (I) may be a compound according to formulae (Ve) or (Vf) or (Vg) as defined above and R^a may be H.

[00190] The compound of formula (I) may be a compound according to formulae (VII) or (Vila) as defined above and, in embodiments where R^a is H, the compound of formulae (VII) or (Vila) are then a compound according to formulae (Vllb) or (Vile) respectively:

(Vllb) (Vile)

wherein E, D, Y, R^b, R^c, R^d, R^e, R , R², R³, R⁴, R⁵, R⁶, R⁷, L², n and m are as described above for formula (I).

[00191] The compound of formula (I) may be a compound according to formulae (Villa), (Vlllb), (Vlllc) or (Vllld) as defined above and, in embodiments where R^a is H, the compound of formulae (Villa), (Vlllb), (Vlllc) or (Vllld) is then a compound according to formulae (Vllle), (Vlllf), (Vlllg) or (Vlllh):

(Vlllg)

wherein D, R^a, R^b, R°, R^d, R^e, R , R⁵, L² and m are as described above for formula (I).

[00192] The compound of formula (I) may be a compound according to formulae (X) or (Xa) as defined above and, in embodiments where R^a is H, the compound of formulae (X) or (Xa) are then a compound according to formula (Xb) or (Xc) respectively:

(Xb) (Xc)

wherein E, Y, R^b, R^c, R^d, R^e, R , R², R³, R⁴, R⁵, L², n and m are as described above for formula (I). [00193] The compound of formula (I) may be a compound according to formulae (XIa), (Xlb), (Xlc) or (Xld) as defined above and, in embodiments where R^a is H, the compound of formulae (XIa), (Xlb), (Xlc) or (Xld) are then a compound according to formula (Xlh), (Xli), (Xlj) or (Xlk) respectively:

(Xlh) (Xli)

wherein R^a, R^b, R^c, R^d, R^e, R , R⁵, L² and m are as described above for formula (I) and Z , Z², Z³, Z⁴, Z⁵ and Z⁶ are as described above for formula (IV).

[00194] The compound of formula (I) may be a compound according to formulae (Xle) or (Xlf) or (Xlg) as defined above and R^a may be H.

[00195] Preferred compounds of the invention include:

51

EXAMPLES AND SYNTHESIS

[00199] Example 1 : The compounds of the present invention may be synthesised by analogy with the following reaction routes shown in Scheme A or Scheme B.

[00200] Scheme A

[00201] Scheme B

[00202] Protecting groups may be present or absent as necessary. For example, a nitrogen atom may be protected or unprotected. [00203] The synthesis of representative compounds of the invention is given below.

[00204] All LCMS analysis was carried out on a Waters Acquity SQ Detector 2 with two 0.2μηι guard filters using a UPLC Column (C18, 50 x 2.1 mm, < 2pm). 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 pL. Temperature was 40 °C. Run time was 8 Mins. The Gradient was:

[00205] 3-iodo-1 H-pyrazolo[3,4-d]pyrimidin-4-amine

1 H-Pyrazolo[3,4-d]pyrimidin-4-amine (20. Og, 148.01 mmol) and /V-iodosuccinimide (60.61 g,

222.01 mmol) were combined in DMF (200mL) and the mixture heated to 80°C, under nitrogen, overnight. The bulk of the solvent was removed under reduced pressure and the residue was allowed to cool and stand for a couple of hours. The resultant material was stirred in warm water (250 ml), filtered off and washed with methanol (3 x 150 ml) to give 3-iodo-1 /-/-pyrazolo[3,4-c ]pyrimidin-4-amine (20.92g, 80.147mmol, 54.1 % yield)

LCMS (ES⁺, short acidic): ~0.35-0.65 min, m/z 262 [M+H]⁺

NMR (d6 DMSO): 13.8 (s, 1 H), 8.21 (s, 1 H), 7.20 (bs, 2H).

[00206] There are two possible routes to the compounds of the invention when following Scheme A. The Scheme A shows Route A in which the piperidine nitrogen is protected. An alternative pathway is Route B where no protecting groups are used. Exemplary compounds produced by Route A and Route B are given below.

[00207] Scheme A, Route A

[00208] tert-Butyl 3-(4-amino-3-iodo-pyrazolo[3,4-c ]pyrimidin-1 -yl)piperidine-1 -carboxylate

3-lodo-1 H-pyrazolo[3,4-<^pyrimidin-4-amine (6.5g, 24.9mmol) was added drop wise to a cooled (ice bath) mixture of DIAD (5.88ml_, 29.88mmol), triphenylphosphine (7.84g, 29.88mmol) and te/ -butyl (3S)-3-hydroxypiperidine-1 -carboxylate (5.01 g, 24.9mmol) in THF (45ml_). The temperature of the reaction mixture was not allowed to exceed 5°C. A solution was obtained immediately following the addition. The solution was stirred for a further 0.5 hrs with cooling. The mixture was allowed to stir overnight at ambient temperature. The bulk of the solvent was removed under reduced pressure. The crude material was subjected to flash chromatography (EtOAc in heptane) to yield fe/ -butyl 3-(4- amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1 -yl)piperidine-1 -carboxylate (3.87 g, 35%)

NMR (d6 DMSO): 8.20 (s, 1 H), 4.53 (m, 1 H), 3.85 (m, 2H), 2.98 (m, 1 H), 2.01 (m, 2H), 1 .73 (m, 1 H), 1 .51 (m, 1 H), 1 .31 (m, 10H).

LCMS (ES⁺, short acidic): 1 .58min, m/z 445.1 [M+H]⁺

[00209] fert-Butyl 3-[(1S)-4-amino-3-[4-(morpholinomethyl)phenyl]pyrazolo[3,4-c lpyrimidin-1 - yl]piperidine-1 -carboxylate

A mixture of fe/ -butyl 3-[(1 S)-4-amino-3-iodo-pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (1 OO.Omg, 0.23mmol), 4-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholine (102.37mg, 0.34mmol), potassium carbonate (62.22mg, 0.45mmol), and

tetrakis(triphenylphosphine)palladium(0) (15.61 mg, 0.01 mmol) catalyst in water (1 ml_) and 1 ,4-dioxane (6ml_) was degassed and filled with nitrogen. The reaction mixture was put under microwave irradiation at 300W for 60 mins at 100°C. The solvent was removed under reduced pressure. The crude product was purified by column chromatography in silica gel eluting with 1 % MeOH in DCM to provide tert-butyl 3-[(1 S)-4-amino-3-[4-(morpholinomethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-1 - yl]piperidine-1 -carboxylate (1 1 1 mg, 100%).

LCMS (ES⁺,short acidic): 1 .13 min, m/z 494.4 [M+H]⁺ [00210] (1 S)-3-[4-(Morpholinomethyl)phenyl]-1 -(3-piperidyl)pyrazolo[3,4-c |pyrimidin-4-amine hydrochloride

tert-Butyl 3-[(1 S)-4-amino-3-[4-(morpholinomethyl)phenyl]pyrazolo[3,4-d]pyrimidin

carboxylate (400mg,0.93mmol) was stirred / suspended in 4M HCI in dioxane (0.42ml_, 12.16mmol) for 4 hrs. Solvent was removed under reduced pressure to give a pale brown gum - (1 S)-3-[4- (morpholinomethyl)phenyl]-1 -(3-piperidyl)pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride

(400mg,0.93mmol, 1 14.8% yield). Used without further purification.

LCMS (ES⁺, short acidic): 0.52 min, m/z 394.3 [M+H]⁺

[00211 ] 1 -[3-[(1 S)-4-Amino-3-[4-(morpholinomethyl)phenyl]pyrazolo[3,4-c lpyrimidin-1 -yl]-1 - piperidyl]prop-2-en-1 -one

Triethylamine (0.21 mL, 1 .52mmol) was added to a solution of (1 S)-3-[4-(morpholinomethyl)phenyl]-1 - (3-piperidyl)pyrazolo[3,4-c ]pyrimidin-4-amine (200. mg, 0.51 mmol) in DCM (5ml_) followed by the addition of acryloyl chloride (45.43uL, 0.56mmol). The reaction mixture was then left to stir at room temperature for 2 hrs. Mixture concentrated and purified by column chromatography (DCM in EtOAc ) to give the desired product as a pale brown gum 1 -[3-[(1 S)-4-amino-3-[4-(morpholinomethyl)phenyl]- pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one (12.1 mg,0.027mmol, 5.32% yield).

LCMS (ES⁺, short acidic): 0.89 min, m/z 448.3 [M+H]⁺

NMR (CDCI₃): 8.29 (s,1 H), 7.53 (d, J 8.3Hz, 2H), 7.41 (d, J 8.3 Hz, 2H), 6.52 (m, 1 H), 6.20 (m, 1 H), 5.60 (m, 3H), 4.78 (m, 1 H), 4.02 (m, 1 H), 3.91 (m, 1 H), 1 .98 (m, 17H).

[00212] Scheme A, Route B [00213] 3-iodo-1 -(3-piperidyl)pyrazolo amine

To a suspension of 3-iodo-1 H-pyrazolo[3,4-c ]pyrimidin-4-amine (5.g, 19.16mmol) in THF (500mL) was added fe/ -butyl (3S)-3-hydroxypiperidine-1 -carboxylate (5.78g, 28.73mmol), then triphenylphosphine (9.03g, 34.48mmol) followed by the dropwise addition of DIAD (6.79ml_, 34.48mmol). The temperature of the reaction mixture was not allowed to exceed 5°C. The ice bath was removed and the mixture was allowed to warm up to ambient temperature, at which it was stirred for 3 days. The solvent was removed under vacuum. 4M HCI (40 ml) in dioxane was then added to the mixture and stirred for 6 hrs. The solvent was concentrated in vacuo. The crude material was then purified by flash column chromatography (water in acetonitrile) to give a brown solid, 3-iodo-1 -(3-piperidyl)pyrazolo[3,4- c ]pyrimidin-4-amine (1 .3g, 3.8mmol, 19.7% yield).

LCMS (ES⁺, short acidic): 0.796 min, m/z 345.1 [M+H]⁺

NMR (d6-DMSO): 8.43 (s, 1 H), 5.1 1 (m, 1 H), 3.31 (m, 1 H), 3.27 (m, 2H), 2.93 (m, 1 H), 2.03 (m, 2H), 1 .91 (2H, m).

[00214] 1 -[3-[4-amino-3-[4-(1 -piperidylmethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 - piperidyl]prop-2-en-1 -one

4-(Piperidinomethyl)phenylboronic acid pinacol ester (131 .29mg, 0.44mmol) was added to a degassed solution of 3-iodo-1 -(3-piperidyl)pyrazolo[3,4-c ]pyrimidin-4-amine (l OO.Omg, 0.29mmol), potassium carbonate (80.32mg, 0.58mmol), and 1 ,1 '-bis(diphenylphosphino)ferrocene-palladium(ll) dichloride dichloromethane complex (1 1 .87mg, O.OI OOmmol) in water (1 ml_) and 1 ,4-dioxane (6ml_). The reaction mixture was heated under microwave irradiation at 300W for 90 min at 120°C. Upon completion, the solvent was removed under vacuum. The crude 1 -(3-piperidyl)-3-[4-(1 - piperidylmethyl)phenyl]pyrazolo[3,4-d]pyrimidin-4-amine (1 13.77mg, 0.29mmol) was added to a solution of acrylic acid (0.04ml_, 0.58mmol), /V-(3-dimethylaminopropyl)-/V-ethylcarbodiimide hydrochloride (EDCI) (1 1 1 .42mg, 0.58mmol), and triethylamine (0.12mL, 0.87mmol) in DCM (3ml_). The reaction mixture was left under constant stirring overnight at room temperature. The product was isolated and purified by prep LCMS (dissolved in 8:1 :1 DMSO:CH₃CN:H₂0 in the presence of a strong acid modifier, which was TFA).

LCMS (ES⁺, short acidic) 0.99 min, m/z 446.3 [M+H]⁺

NMR: 8.32 (bs, 1 H), 8.25 (s, 1 H), 7.75 (d, J 8.1 Hz, 2H), 7.19 (d, J, 8.1 Hz, 2H), 6.60 ( m, 1 H), 6.31 (m, 1 H), 5.51 (m, 1 H), 4.90 (m, 1 H), 4.51 (m, 1 H), 4.21 (s, 2H), 4.01 (m, 1 H), 3.78 (m, 2H), 3.43 (m, 1 H), 3.15 (m, 5H), 2.31 (m, 2H), 1 .48 (m, 5H), 1 .17 (m, 2H).

[00215] The table below shows a range of boronic acids which may be used to introduce the groups attached to the boronic acid into the compounds of the invention by the Suzuki coupling shown in Scheme A. The Suzuki coupling can be carried out by following Route A or Route B as described above. The LCMS data is for the final product, the compound of the invention.

[00216] Scheme B

[00217] iert-Butyl 3-(4-amino-3-iodo-pyrazolo[3,4-c ]pyrimidin-1 -yl)piperidine-1 -carboxylate

3-lodo-1 /-/-pyrazolo[3,4-c ]pyrimidin-4-amine (6.5g, 24.9mmol) was added drop wise to a cooled (ice bath) mixture of DIAD (5.88ml_, 29.88mmol), triphenylphosphine (7.84g, 29.88mmol) and te/ -butyl (3S)-3-hydroxypiperidine-1 -carboxylate (5.01 g, 24.9mmol) in THF (45ml_). The temperature of the reaction mixture was not allowed to exceed 5°C. A solution was obtained immediately following the addition. The solution was stirred for a further 0.5 hrs with cooling. The mixture was allowed to stir overnight at ambient temperature. The bulk of the solvent was removed under reduced pressure. The crude material was subjected to flash chromatography (EtOAc in heptane ) to yield fe/ -butyl 3-(4- amino-3-iodo-pyrazolo[3,4-c ]pyrimidin-1 -yl)piperidine-1 -carboxylate (3.87 g, 35%)

LCMS (ES⁺, short acidic): 1 .58min, m/z 445.1 [M+H]⁺

[00218] fert-Butyl 3-[4-amino-3-(4-hydroxyphenyl)pyrazolo[3,4-c lpyrimidin-1 -yl] pipe rid ine-1 - carboxylate

fe/f-Butyl 3-(4-amino-3-iodo-pyrazolo[3,4-c ]pyrimidin-1 -yl)piperidine-1 -carboxylate (600mg, 1 .35mmol) and (4-hydroxyphenyl)boronic acid (280.01 mg, 2.03mmol) were combined in 1 ,4-dioxane (36ml_) and the solution was degassed. Palladium acetate, 0.05 equivalents, 1 ,1 '-Bis(di- tertbutylphosphino)ferrocene, 0.1 equivalents and potassium phosphate tribasic, 3 equivalents (156 mg) were added to a tube. The tube was degassed by alternative applications of vacuum and nitrogen. The reaction was stirred under nitrogen at 100 °C. Upon completion the reaction was diluted with DCM (25 ml_) and then washed with brine. The organic phase was extracted with 1 M HCI aqueous solution diluted to pH 3. The aqueous phase was neutralised with 5 M NaOH aqueous solution then extracted with ethyl acetate. The organic phase was dried over anhydrous MgS0₄ then the solvent was removed in vacuo to afford fe/ -butyl 3-[4-amino-3-(4-hydroxyphenyl)pyrazolo[3,4- c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (78 mg, 0.190 mmol, 84% yield).

LCMS (ES⁺, short acidic): 1 .41 min, m/z 41 1 [M+H]⁺

NMR (d6 DMSO): 8.35 (bs, 1 H), 7.52 (bs, 2H), 6.91 (ds, 2H), 5.52 (bs, 2H), 4.52 (m, 2H), 4.15 (m, 1 H), 3.1 1 (m, 1 H), 2.59 (m, 1 H), 2.00 (m, 2H), 1 .87 (m, 2H), 1 .61 (m, 2H), 1 .43 (s, 9H).

[00219] fert-Butyl 3-[4-amino-3-(4 etrahydrofuran-3-yloxyphenyl)pyrazolo[3,4-c lpyrimidin-1 - yl]piperidine-1 -carboxylate

fe/ -Butyl 3-[4-amino-3-(4-hydroxyphenyl)pyrazolo[3,4-^

(279. mg, 0.68mmol), triphenylphosphine (214.01 mg, 0.82mmol) and 3-hydroxytetrahydrofuran (54.94uL, 0.68mmol) were combined in THF (3.4ml_). The solution was cooled to 0 °C then DIAD (161 .0 uL, 0.82mmol) was added. The reaction was stirred over 2 nights. LCMS indicated almost complete conversion and the presence of the desired product. The reaction was diluted with ethyl acetate and washed with brine. The combined organic phases were dried over anhydrous MgS0₄ then the solvent was removed in vacuo. The residue obtained was purified by column chromatography (eluted with 25-100% ethyl acetate in DCM) to afford the desired product as a cream solid.

LCMS (ES⁺, short acidic): 1 .59 min, m/z 481 [M+H]⁺

[00220] 1 -(3-Piperidyl)-3-(4 etrahydrofuran-3-yloxyphenyl)pyrazolo[3,4-d]pyrimidin-4-amine

fe/ -Butyl 3-[4-amino-3-(4-tetrahydrofuran-3-yloxyphenyl)pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 - carboxylate (40. mg, 0.08mmol) was dissolved in DCM (0.50ml_) then trifluoroacetic acid (120.0uL, 1 .69mmol) was added. The reaction was stirred at room temperature for 5 hours. Upon completion the reaction was dried in vacuo, the residue obtained was dissolved in MeOH and 0.05 ml_ of HCI in dioxane was added. The resultant was eluted through a preconditioned SCX cartridge (2 g), followed by MeOH then eluted with 7 N ammonia in MeOH. The fraction containing the product was determined by TLC and the solvent removed in vacuo to afford a colourless glass. The compound was used without further purification.

LCMS (ES⁺, short acidic): 0.98 min, m/z 381 [M+H]⁺

[00221] 1 -[3-[(1 S)-4-Amino-3-(4 etrahydrofuran-3-yloxyphenyl)pyrazolo[3,4-c lpyrimidin-1 -yl]- 1 -piperidyl]prop-2-en-1 -one

1 -(3-Piperidyl)-3-(4-tetrahydrofura^ (21 .mg,

0.06mmol) was dissolved in THF (0.75ml_) and the solution cooled to -78 °C. DIPEA (4.48uL, 0.03mmol) and acryloyl chloride (4.48uL, 0.06mmol) were added and the reaction was stirred for 1 hour. The reaction was dried in vacuo and the residue obtained was dissolved in DCM and washed with brine. The aqueous was extracted with DCM twice. The combined organic extracts were dried. The solvent was removed in vacuo. The residue obtained was purified by column chromatography (0- 9% MeOH in DCM to afford 1 -[3-[(1 S)-4-amino-3-(4-tetrahydrofuran-3-yloxyphenyl)pyrazolo[3,4- c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one as a brown solid.

LCMS (ES⁺, short acidic): 1 .24 min, m/z 435 [M+H]⁺

NMR (d6 DMSO): 8.91 (bs, 2H), 8.21 (s, 1 H), 7.65 (m, 2H), 7.06 (d, J 8.1 Hz, 2H), 6.53 (m, 1 H), 6.83 (m, 1 H), 6.63 (m, 1 H), 6.01 (m, 1 H), 5.61 (m, 1 H), 5.08 (m, 1 H), 4.65 (m, 1 H), 4.12 (m, 1 H), 4.06 (m, 1 H), 3.55 (m, 1 H), 2.15 (m, 4H), 1 .93 (m, 1 H), 1 .86 (m, 1 H), 1 .79 (m, 2H), 1 .43 (m, 2H).

[00222] An intermediate in Scheme A and the starting material in Scheme B, fe/ -butyl 3-(4-amino-3- iodo-pyrazolo[3,4-d]pyrimidin-1 -yl)piperidine-1 -carboxylate, can be synthesised as discussed above in Scheme A, Route A or it can be synthesised with the following procedure.

[00223] tert-Butyl 3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1 -yl)piperidine-1 -carboxylate

[00224] fe/f-Butyl (3S)-3-methylsulfonyloxypiperidine-1 -carboxylate

To a solution of (S)-1 -Boc-3-hydroxypiperidine (10.0 g, 49.7 mmol) and triethylamine (7.82 mL, 54.7 mmol in DCM (60 mL) under a nitrogen atmosphere, cooled at 0 °C, was added dropwise

methanesulfonyl chloride (4.23 mL, 54.7 mmol). The mixture stirred for 1 h, diluted with water (60 mL) before being passed through a hydrophobic frit. The organic layer was concentrated under reduced pressure to afford fe/ -butyl (3S)-3-methylsulfonyloxypiperidine-1 -carboxylate (13.9 g, 49.7 mmol,

100% yield) as a colourless solid.

H-NMR (400 MHz, DMSO-c/₆): δ (ppm) 4.76-4.71 (m, 1 H, CH), 3.69-3.66 (m 1 H), 3.65-3.60 (m, 1 H),

3.49-3.43 (m, 1 H), 3.37-3.31 (m, 1 H), 3.07 (s, 3H, CH₃), 2.02-1 .96 (m, 1 H), 1 .94-1 .91 (m, 1 H), 1 .87-

1 .80 (m, 1 H), 1 .59-1 .53, 1 .48-1 .45 (m, 9H)

[00225] fe/f-Butyl (3 ?)-3-(4-amino-3-iodo-pyrazolo[3,4-c lpyrimidin-1 -yl)piperidine-1 -carboxylate To a suspension of fe/ -butyl (3S)-3-methylsulfonyloxypiperidine-1 -carboxylate (13.88 g, 49.7 mmol) and 3-iodo-1 H-pyrazolo[3,4-d]pyrimidin-4-amine (1 1 .47 g, 43.9 mmol) in DMF (240 mL) was added cesium carbonate (36.22 g, 1 1 1 .2 mmol) under a nitrogen atmosphere. The reaction was then heated to 80 °C for 16 h, cooled and concentrated to dryness. The residue was taken up in ethyl acetate (200 ml_), the mixture was sonicated before being filtered giving a dark orange filtrate. The filtrate was washed with water (2 ^χ 150 ml_), brine (2 ^χ 150 ml_), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a dark orange film. Further purification by flash column chromatography (DCM/EtOAc 1 :1) afforded the crude product as a light yellow powder. Trituration with methanol gave fe/ -butyl (3R)-3-(4-amino-3-iodo^yrazolo[3,4-c ]pyrimidin-1 -yl)piperidine-1 -carboxylate (2.12 g, 4.77 mmol, 10% yield) as an off white solid.

UPLC-MS (ES⁺, Short acidic): 1 .60 min, m/z 445.2 [M+H]⁺

H-NMR (400 MHz, DMSO-c/₆): δ (ppm) 8.22 (s, 1 H, ArH), 4.66-4.53 (m, 1 H, CH), 4.15-3.65 (m, 2H), 3.55-3.36 (m, 0.5H), 3.21 -3.08 (m, 0.5H), 3.05-2.92 (m, 1 H), 2.20-2.08 (m, 1 H), 2.07-1 .99 (m, 1 H), 1 .96-1 .80 (m, 1 H), 1 .60-1 .47 (m, 1 H), 1 .45-1 .24 (m, 9H)

[00226] Below there are given general procedures which may be utilised in the synthesis of compounds of the invention. After the general procedures, processes for the synthesis of the invention are disclosed with reference back to appropriate general procedures.

[00227] General procedure A

A solution of 4-bromomethylphenylboronic acid pinacol ester (1 .0 eq.), amine (1 .2 eq) and DIPEA (2.5- 3.0 eq.) in anhydrous THF (0.2 M) under a nitrogen atmosphere was heated to 80 °C overnight. The mixture was concentrated under reduced pressure to afford the desired boronate ester. No further purification was attempted and the product was used as such in the next step. [00228] General procedure B

A mixture of fe/ -butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-c ]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 (6:1 , 0.08 M) was degassed by bubbling nitrogen through it for 15 min.

Tetrakis(triphenylphosphine)palladium(0) (0.06 eq.) was added and the mixture degassed by bubbling nitrogen through for 15 min. The mixture was then heated under microwave irradiation at 100 °C for 60 minutes. The mixture was then concentrated under reduced pressure and purified by flash column chromatography to afford the desired compound.

[00229] General procedure C

A mixture of fe/ -butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-c ]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 '- B/^'s(diphenylphosphino)ferrocene-palladium(ll) dichloride dichloromethane complex (0.05 eq.) was added and the mixture was degassed again by bubbling nitrogen through for 30 min. The mixture was then heated at 120 °C for 14 h. The reaction mixture was filtered over Celite^® and the cake was rinsed with DCM. Water was added to the filtrate and the layers were partitioned. The aqueous layer was extracted with DCM (2 x). The combined organic extracts were filtered over phase separator and then concentrated under reduced pressure to give a dark solid. Further purification by flash column chromatography (dry loading, DCM/MeOH 100:0 to 90:10 over 10 cVs) gave the desired compound. [00230] General procedure D

A mixture of fe/ -butyl (3R)-3-(4-amino-3-iodo^yrazolo[3,4-(^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 for 15 min. 1 ,1 '- B/^'s(diphenylphosphino)ferrocene-palladium(ll) dichloride dichloromethane complex (0.05 eq.) was added and the mixture was degassed again by bubbling nitrogen through for 15 min. The mixture was then heated under microwave irradiation at 120-140 °C for 60-90 minutes. The reaction mixture was either purified by SCX and used as such or purified using the following procedure, unless stated used crude. The mixture was filtered over Celite^® and the cake was rinsed with DCM. Water was added to the filtrate and the layers were partitioned. The aqueous layer was extracted with DCM (2 x). The combined organic extracts were filtered over phase separator and then concentrated under reduced pressure to give a dark solid. Further purification by flash column chromatography (DCM/MeOH 100:0 to 90:10) gave the desired compound.

[00231] General procedure E

Trifluoroacetic acid (2.0 eq.) was added dropwise to a solution of Boc-protected amine (1 .0 eq.) in

DCM (0.06 M) at room temperature under an inert atmosphere. The reaction mixture was stirred at this temperature for 2 h, quenched with a saturated NH₄CI solution and extracted with DCM (x2). The organics were back-washed with a saturated NH₄CI solution then the combined aqueous washings were basified to pH 10 with solid K₂C0₃. The basified aqueous layer was extracted with DCM (x5) and the combined organic washings were dried over Na₂S0₄, filtered, and concentrated under reduced pressure to afford the title compound.

[00232] General procedure F

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

[00233] General procedure G

To a stirred solution of EDCI (1 .2 eq.), triethylamine (3.0 eq.) and acrylic acid (1 .5 eq.) in DCM (0.1 M) was added the corresponding amine (1 .0 eq.) in DCM (0.1 M). The reaction mixture was stirred at room temperature until completion, and then concentrated under reduced pressure. Further purification by flash chromatography afforded the title product.

[00234] General procedure H

To a solution of the corresponding amine (1 .0 eq) and Λ/,/V-diisopropylethylamine (3.0 eq.) in anhydrous DCM (0.05 M), cooled to -78 °C under a nitrogen atmosphere, was added dropwise a solution of acryloyl chloride (1 .0 eq, 0.05 M) in anhydrous DCM at -78 °C. The reaction mixture was stirred at the same temperature for 2 h. The reaction mixture was then quenched with a saturated aqueous solution of ammonium chloride, allowed to return to 0 °C and partitioned. The aqueous layer was extracted with DCM (2x). The combined organic extracts were washed with a saturated aqueous solution of sodium bicarbonate, brine, filtered over hydrophobic frit and concentrated under reduced pressure to give the crude product. Further purification by flash column chromatography gave, after further drying under reduced pressure, title compound.

[00235] General procedure I

To a suspension of amine (1 .0 eq.) and acrylic acid (1 .0 eq.) in anhydrous THF (0.3 M) were added successively Λ/,/V-diisopropylethylamine (3.0 eq.) and propylphosphonic anhydride (1 .5 eq.). The reaction mixture was stirred overnight at room temperature, diluted with water and DCM. The layers were partitioned. The aqueous layer was extracted with DCM (2 x). The combined organic extracts were filtered over phase separator and concentrated to give a foam. Further purification by flash column chromatography (liquid loading, EtOAc/MeOH 100:0 to 90:10) gave, after drying under reduced pressure, title compound. [00236] General procedure J

(a) To a solution of the corresponding 2-methyl-1 -nitro-benzene derivative (1 eq.) in DMF (0.8 M) was added Λ/,/V-dimethylformamide dimethyl acetal (4.8 eq.) . The reaction was heated at 120 °C for 6 h, poured onto ice/water and then extracted with EtOAc (x3). The combined organic extracts were washed successively with a saturated aqueous solution of sodium bicarbonate, a saturated aqueous solution of ammonium chloride and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the desired /V,/V-dimethyl-2-[2-nitro-phenyl]ethenamine (Assumed quantitative yield and used crude in next step.)

(b) To a solution of previously prepared /V,/V-dimethyl-2-[2-nitro-phenyl]ethenamine (1 eq.) in acetic acid (0.16 M) was added iron (3.2 eq.). The reaction was heated at 120 °C under nitrogen for 22 h. Upon cooling, the reaction mixture was diluted with 1 M HCI and the aqueous phase was extracted with EtOAc. The organic layer was neutralised with potassium carbonate and extracted with EtOAc (x3). The organic layers were combined, washed with a saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude product. Further purification by flash column chromatography gave the desired indole. [00237] General procedure K

To a solution of the corresponding 2-nitro-benzene derivative (1 .0 eq.) in THF (0.45 M) under a nitrogen atmosphere and cooled to -50 °C, was added dropwise vinylmagnesium bromide (3.5 eq) while ensuring that the reaction temperature did not exceed -40 °C. The reaction mixture was stirred for 3 h, poured onto a saturated solution of ammonium chloride and then, was extracted with ethyl acetate (x3). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness to give a black oil. Further purification by flash column chromatography gave the desired indole. [00238] General procedure L

To a borane tetrahydrofuran complex solution (1 .0 M, 1 .5 eq), cooled to 0 °C, was added the corresponding indole (1 .0 eq) portionwise. The reaction mixture was stirred at 0 °C for 30 min.

Trifluoroacetic acid (19.5 eq) was then added dropwise. Once addition was complete, the reaction mixture was stirred for a further 30 minutes before being basified to pH 1 1 using a 5.0 M aqueous solution of sodium hydroxide. The mixture was extracted with DCM (x3). The combined organic extracts were dried (hydrophobic frit) and concentrated to dryness to give crude indoline, which was used as such for the next steps.

[00239] General procedure M

Triethylsilane (2.0 eq.) was slowly added to a solution of indole (1 .0 eq.) in trifluoroacetic acid (1 .4 M), cooled to 0 °C. The reaction mixture was stirred at 0 °C for 1 h, then at r.t. for 1 h. Upon completion (monitored by TLC), the reaction was basified to pH 1 1 with NaOH (5.0 M) and extracted with EtOAc (x3). The organic layers were combined, washed with brine, dried over Na₂S0₄ and concentrated under reduced pressure. The crude product was purified by flash chromatography to give the desired indoline.

[00240] Example 2: 1 -[(3R)-3-[4-Amino-3-(4-tetrahydrofuran-3-yloxyphenyl)pyrazolo[3,4- cflpyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

1 -[(3 ?)-3-Piperidyll-3-(4-tetrahvdrofuran-3-yloxyphenyl)pyrazolo[3,4-c lpyrimidin-4-amine

fe/ -Butyl-(3R)-3-[4-amino-3-(4-hydroxyphenyl)pyrazolo[3,4-(^pyrimidin-1 -yl]piperidine-1 -carboxylate (279.0 mg, 0.68 mmol), triphenylphosphine (214.0 mg, 0.82 mmol) and 3- hydroxytetrahydrofuran (55 μΙ_, 0.68 mmol) were combined in THF (3.4 mL). The solution was cooled to 0 °C then DIAD (161 μΙ_, 0.82 mmol) was added. The reaction was stirred for 2d, diluted with ethyl acetate (20 mL) and washed with brine (20 mL). The organic phase was diluted with 1 M HCI aqueous solution and stirred for 30 min. The aqueous phase was neutralised with 5 M NaOH then extracted with ethyl acetate (3 x 10 mL). The combined organic phases were dried (MgS0₄) and the organics removed in vacuo. The residue obtained was purified by flash column chromatography (25-100% EtOAc in DCM, then 0-10% MeOH) to afford 1 -[(3R)-3-piperidyl]-3-(4-tetrahydrofuran-3-yloxyphenyl)pyrazolo[3,4-c ]pyrimidin-4- amine (40.0 mg, 0.083 mmol, 12% yield) as a cream solid.

UPLC-MS (ES⁺, Short acidic): 1 .59 min, m/z 481 .4 [M+H]⁺

[00241] 1 -[(3 ?)-3-Piperidyll-3-(4-tetrahvdrofuran-3-yloxyphenyl)pyrazolo[3,4-c lpyrimidin-4-amine Following general procedure E, 1 -[(3R)-3-piperidyl]-3-(4-tetrahydrofuran-3-yloxyphenyl)pyrazolo[3,4- c ]pyrimidin-4-amine (40.0 mg, 0.083 mmol) gave 1 -[(3R)-3-piperidyl]-3-(4-tetrahydrofuran-3- yloxyphenyl)pyrazolo[3,4-c ]pyrimidin-4-amine (23.3 mg, 0.061 mmol, 74% yield) as a colourless solid. UPLC-MS (ES⁺, Short acidic): 0.98 min, m/z 381 .3 [M+H]⁺

[00242] 1 -[(3f?)-3-[4-Amino-3-(4-tetrahvdrofuran-3-yloxyphenyl)pyrazolo[3,4-c lpyrimidin-1 -yll-1 - piperidyllprop-2-en-1 -one

Following general procedure H, 1 -[(3R)-3-piperidyl]-3-(4-tetrahydrofuran-3-yloxyphenyl)pyrazolo[3,4- c ]pyrimidin-4-amine (21 .0 mg, 0.055 mmol) afforded 1 -[(3R)-3-[4-amino-3-(4-tetrahydrofuran-3- yloxyphenyl)pyrazolo[3,4-(^pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one (5.9 mg, 0.014 mmol, 25% yield).

UPLC-MS (ES⁺, Short acidic): 1 .24 min, m/z 435.3 [M+H]⁺

H-NMR (400 MHz, DMSO-c/₆) δ (ppm) 8.93 (br. s, 2H), 8.24 (s, 1 H, ArH), 7.58 (d, ³ 8.2 Hz, 2H, ArH), 7.08 (d, ³J 8.2 Hz, 2H, ArH), 6.92-6.82 (m, 0.5H), 6.75-6.65 (m, 0.5H), 6.17-6.01 (m, 1 H), 5.74-5.67 (m, 0.5H), 5.63-5.55 (m, 0.5H), 5.13-5.07 (m, 1 H), 4.75-4.62 (m, 1 H), 4.59-4.50 (m, 0.5H), 4.25-4.14 (m, 0.5H), 4.14-4.04 (m, 1 H), 3.95-3.90 (m, 1 H), 3.88-3.82 (m, 2H), 3.81 -3.75 (m, 1 H), 3.74-3.65 (m, 0.5H), 3.25-3.18 (m, 1 H), 3.05-2.97 (m, 0.5H), 2.30-2.20 (m, 2H), 2.16-2.07 (m, 1 H), 2.06-1 .98 (m, 1 H), 1 .97-1 .88 (m, 1 H), 1 .66-1 .51 (m, 1 H).

[00243] Example 3: 1 -[(3R)-3-[4-amino-3-[4-[(dimethylamino)methyl]phenyl]pyrazolo[3,4- cflpyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00244] 3-[4-[(Dimethylamino)methyllphenyll-1 -[(3R)-3-piperidyllpyrazolo[3,4-dlpyrimidin-4-amine Following general procedure D, a mixture of 3-iodo-1 -[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-4- amine (100.0 mg, 0.29 mmol), /V,/V-dimethyl-1 -[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methanamine (1 13.8 mg, 0.44 mmol) gave, after concentration under reduced pressure, 3- [4-[(dimethylamino)methyl]phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c/]pyrimidin-4-amine (102.1 mg, 0.29 mmol, assumed quantitative).

UPLC-MS (ES⁺, Short acidic): 0.41 min, m/z 352.3 [M+H]⁺

[00245] 1 -[(3f?)-3-[4-Amino-3-[4-[(dimethylamino)methyllphenyllpyrazolo[3,4-c lpyrimidin-1 -yll-1 - piperidyllprop-2-en-1 -one

Following general procedure G, crude 3-[4-[(dimethylamino)methyl]phenyl]-1 -[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (102.1 mg, 0.29 mmol) gave, after further purification by preparative HPLC, 1 -[(3R)-3-[4-amino-3-[4-[(dimethylamino)methyl]phenyl]pyrazolo[3,4-c/]pyrimidin-1 - yl]-1 -piperidyl]prop-2-en-1 -one (15.8 mg, 0.04 mmol, 13% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 0.93 min, m/z 406.3 [M+H]⁺

[00246] Example 4: 1 -[3-[(1 R)-4-Amino-3-[4-(pyrrolidin-1 -ylmethyl)phenyl]pyrazolo[3,4- cflpyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00247] 1 -[(3 ?)-3-piperidyll-3-[4-(pyrrolidin-1 -ylmethyl)phenyllpyrazolo[3,4-c/lpyrimidin-4-amine

Following general procedure D, a mixture of 3-iodo-1 -[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-4- amine (100.0 mg, 0.29 mmol) and 4-(pyrrolidin-1 -ylmethyl)phenylboronic acid, pinacol ester (125.2 mg, 0.44 mmol) afforded 1 -[(3R)-3-piperidyl]-3-[4-(pyrrolidin-1 -ylmethyl)phenyl]pyrazolo[3,4- c ]pyrimidin-4-amine (109.7 mg, 0.29 mmol, assumed quantitative).

UPLC-MS (ES⁺, Short acidic): 0.38 min, m/z 378.3 [M+H]⁺

[00248] 1 -[3-[(1 f?)-4-amino-3-[4-(pyrrolidin-1 -ylmethyl)phenyllpyrazolo[3,4-c lpyrimidin-1 -yll-1 - piperidyllprop-2-en-1 -one

Following general procedure G, crude 1 -[(3R)-3-piperidyl]-3-[4-(pyrrolidin-1 - ylmethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-4-amine (109.7 mg, 0.29 mmol) gave, after further purification by preparative HPLC, 1 -[3-[(1 R)-4-amino-3-[4-(pyrrolidin-1 -ylmethyl)phenyl]pyrazolo[3,4- c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one (15.3 mg, 0.04 mmol, 12% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 0.95 min, m/z 432.3 [M+H]⁺ [00249] Example 5: 1 -[3-[(1 R)-4-Amino-3-[4-(1 -piperidylmethyl)phenyl]pyrazolo[3,4- cflpyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00250] 1 -[(3 ?V3-Piperidyll-3-[4-n-piperidylmethyl)phenyllpyrazolo[3,4-(^pyrim

Following general procedure D, a mixture of 3-iodo-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c/]pyrimidin-4- amine (100.0 mg, 0.29 mmol) and 4-(piperidinomethyl)phenylboronic acid, pinacol ester (131 .3 mg, 0.44 mmol) afforded 1 -[(3R)-3-piperidyl]-3-[4-(1 -piperidylmethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-4- amine (1 13.8 mg, 0.27 mmol, 92% yield).

UPLC-MS (ES⁺, Short acidic): 0.75 min, m/z 392.3 [M+H]⁺

[00251] 1 -[3-[(1 f?)-4-Amino-3-[4-(1 -piperidylmethyl)phenyllpyrazolo[3,4-c lpyrimidin-1 -yll-1 - piperidyllprop-2-en-1 -one

Following general procedure G, crude 1 -[(3R)-3-piperidyl]-3-[4-(1 -piperidylmethyl)phenyl]pyrazolo[3,4- c ]pyrimidin-4-amine (1 13.8 mg, 0.29 mmol) afforded, after further purification by preparative HPLC, 1 -

[3-[(1 R)-4-amino-3-[4-(1 -piperidylmethyl)phenyl]pyra^

one (29.2 mg, 0.07 mmol, 23% yield) as a grey solid.

UPLC-MS (ES⁺, Short acidic): 0.99 min, m/z 446.3 [M+H]⁺

[00252] Example 6: 1 -[(3R)-3-[4-Amino-3-[4-(diethylaminomethyl)phenyl]pyrazolo[3,4- cflpyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00253] 3-[4-(Diethylaminomethyl)phenyll-1 -[(3 ?)-3-piperidyllpyrazolo[3,4-c lpyrimidin-4-amine

Following general procedure D, [4-(diethylaminomethyl)phenyl]boronic acid (90.0 mg, 0.43 mmol) and 3-iodo-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine (100.0 mg, 0.29 mmol), gave 3-[4-

(diethylaminomethyl)phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine (1 10.3 mg, 0.29 mmol, 100% yield) as a brown solid. This was used in the next reaction without further purification, assumed quantitative.

UPLC-MS (ES⁺, Short acidic): 0.98 min, m/z 381 .3 [M+H]⁺

[00254] 1 -[(3f?)-3-[4-Amino-3-[4-(diethylaminomethyl)phenyllpyrazolo[3,4-c lpyrimidin-1 -yll-1 - piperidyllprop-2-en-1 -one

Following general procedure G, 3-[4-(diethylaminomethyl)phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4- c ]pyrimidin-4-amine (1 10.3 mg, 0.29 mmol) afforded 1 -[(3f?)-3-[4-amino-3-[4- (diethylaminomethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one (26.7 mg, 0.062 mmol, 21 % yield).

UPLC-MS (ES⁺, Short acidic): 0.98 min, m/z 434.3 [M+H]⁺

H-NMR (400 MHz, CDCI₃) δ (ppm) 8.38 (s, 1 H, ArH), 7.63 (d, ³J 8.2 Hz, 2H, ArH), 7.53 (d, ³J 8.2 Hz, 2H, ArH), 6.68-6.53 (m, 1 H), 6.35-6.24 (m, 1 H), 5.76-5.62 (m, 1 H), 5.53 (br. s, 2H), 4.95-4.82 (m, 1 .5H), 4.67-4.58 (m, 0.5H), 4.26-4.17 (m, 0.5H), 4.08-3.99 (m, 0.5H), 3.85-3.72 (m, 0.5H), 3.65 (br. s, 2H), 3.46-3.35 (m, 0.5H), 3.25-3.14 (m, 0.5H), 2.95-2.83 (m, 0.5H), 2.58 (q, ³J 7.1 Hz, 4H, 2 x CH₂), 2.47-2.36 (m, 1 H), 2.31 -2.23 (m, 1 H), 2.04-1 .97 (m, 1 H), 1 .80-1 .72 (m, 1 H), 1 .08 (t, ³J 7.1 Hz, 6H, 2 x CH₃).

[00255] Example 7: fert-Butyl 4-[[4-[4-amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- c ]pyrimidin-3-yl]phenyl]methyl]-1 ,4-diazepane-1 -carboxylate [00256] fe/f-Butyl 4-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyll-1 ,4-diazepane-1- carboxylate ethylbis(propan-2-vDamine hydrobromide

Following general procedure A, fe/f-butyl 1 ,4-diazepane-1-carboxylate (242.7 mg, 1.01 mmol) afforded fe/f-butyl 4-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]-1 ,4-diazepane-1- carboxylate ethylbis(propan-2-yl)amine hydrobromide (537.0 mg, 0.86 mmol) as a brown gum.

UPLC-MS (ES⁺, Short acidic): 1.46 min, m/z 417.2 [M+H]+

[00257] fe/f-Butyl 4-[[4-[4-amino-1-[(3f?)-3-piperidyllpyrazolo[3,4-c lpyrimidin-3-yllphenyllmethyll-1 ,4- diazepane-1 -carboxylate

Following general procedure D, a mixture of 3-iodo-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-4- amine (112.0 mg, 0.33 mmol) and fe/f-butyl 4-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]-1 ,4-diazepane-1 -carboxylate (203.2 mg, 0.49 mmol) gave, after further purification by flash column chromatography (DCM/MeOH 100:0 to 90:10), fe/f-butyl 4-[[4-[4-amino-1-[(3f?)-3- piperidyl]pyrazolo[3,4-c/]pyrimidin-3-yl]phenyl]methyl]-1 ,4-diazepane-1 -carboxylate (127.1 mg,

0.25 mmol, 77% yield) as a brown solid.

UPLC-MS (ES⁺, Short acidic) 0.92 min, m/z 507.4 [M+H]⁺

[00258] fe/f-Butyl 4-[[4-[4-amino-1-[(3f?)-1-prop-2-enoyl-3-piperidyllpyrazolo[3,4-c/lpyrimidin-3- yllphenyllmethyll-1 ,4-diazepane-1 -carboxylate

Following general procedure I, 3-[4-(2,3-dihydropyrido[3,2-£>][1 ,4]oxazin-4-ylmethyl)phenyl]-1-[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (124.1 mg, 0.32 mmol) gave, after further purification by preparative HPLC, fe/f-butyl 4-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- piperidyl]pyrazolo[3,4-c/]pyrimidin-3-yl]phenyl]methyl]-1 ,4-diazepane-1 -carboxylate (67.1 mg, 0.12 mmol, 59% yield).

UPLC-MS (ES⁺, Short acidic) 1.12 min, m/z 561.4 [M+H]⁺

[00259] Example 8: 1-[(3 ?)-3-[4-Amino-3-[4-(thiomorpholinomethyl)phenyl]pyrazolo[3,4- cflpyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00260] 1-[(3 ?)-3-Piperidyll-3-[4-(thiomorpholinomethyl)phenyllpyrazolo[3,4-c lpyrimidin-4-amine Following general procedure D, [4-(thiomorpholinomethyl)phenyl]boronic acid (103.0 mg, 0.43 mmol) and 3-iodo-1-[(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine (100.0 mg, 0.29 mmol), gave 1-[(3R)- 3-piperidyl]-3-[4-(thiomorpholinomethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-4-amine (119.0 mg, 0.29 mmol, 100% yield) as a brown solid. This was used in the next reaction without further purification, assumed quantitative.

UPLC-MS (ES⁺, Short acidic): 0.76 min, m/z 410.2 [M+H]⁺

[00261] 1 -[(3f?)-3-[4-Amino-3-[4-(thiomorpholinomethyl)phenyllpyrazolo[3,4-c lpyrimidin-1 -yll-1 - piperidyllprop-2-en-1 -one

Following general procedure G, 1-[(3R)-3-piperidyl]-3-[4-(thiomorpholinomethyl)phenyl]pyrazolo[3,4- c ]pyrimidin-4-amine (119.0 mg, 0.29 mmol) afforded 1-[(3f?)-3-[4-amino-3-[4- (thiomorpholinomethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-1-yl]-1-piperidyl]prop-2-en-1-one (10.4 mg, 0.022 mmol, 8% yield).

UPLC-MS (ES⁺, Short acidic): 0.98 min, m/z 464.3 [M+H]⁺

H-NMR (400 MHz, CDCI₃) δ (ppm) 8.39 (s, 1 H, ArH), 7.65 (d, ³ J 8.2 Hz, 2H, ArH), 7.50 (d, ³ J 8.2 Hz, 2H, ArH), 6.68-6.52 (m, 1 H), 6.38-6.23 (m, 1 H), 5.76-5.62 (m, 1 H), 5.47 (br. s, 2H), 4.96-4.83 (m, 1 .5H), 4.66-4.54 (m, 0.5H), 4.26-4.16 (m, 0.5H), 4.10-3.99 (m, 0.5H), 3.83-3.72 (m, 0.5H), 3.60 (br. s, 2H), 3.45-3.36 (m, 0.5H), 3.25-3.14 (m, 0.5H), 2.96-2.85 (m, 0.5H), 2.79-2.74 (m, 4H, 2 x CH₂), 2.73- 2.66 (m, 4H, 2 x CH₂), 2.46-2.33 (m, 1 H), 2.31 -2.23 (m, 1 H), 2.05-1 .96 (m, 1 H), 1 .81 -1 .72 (m, 1 H).

[00262] Example 9: 1 -[(3R)-3-[4-Amino-3-[4-(morpholinomethyl)phenyl]pyrazolo[3,4- cflpyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00263] 3-[4-(Morpholinomethyl)phenyl1-1 -[(3^

Following general procedure C, 4-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]morpholine hydrochloride (1 .526 g, 4.4 mmol) and 3-iodo-1 -[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (1 .000 g, 2.9 mmol), gave 3-[4-(morpholinomethyl)phenyl]- 1 -[(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine (1 .143 g, 2.9 mmol, 100% yield) as a brown gum. This was used in the next reaction without further purification, assumed quantitative.

UPLC-MS (ES⁺, Short acidic): 0.29 min & 0.54 min, m/z 394.3 [M+H]⁺

[00264] 1 -[(3f?)-3-[4-Amino-3-[4-(morpholinomethyl)phenyllpyrazolo[3,4-c lpyrimidin-1 -yll-1 - piperidyllprop-2-en-1 -one

Following general procedure H, 3-[4-(morpholinomethyl)phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4- c ]pyrimidin-4-amine (2.220 g, 5.64 mmol) afforded 1 -[(3f?)-3-[4-amino-3-[4- (morpholinomethyl)phenyl]pyrazolo[3,4-c/]pyrimidin-1 -yl]-1 -piperidyl] prop-2-en-1 -one (1 .920 g, 4.30 mmol, 76% yield).

UPLC-MS (ES⁺, Short acidic): 0.93 min, m/z 448.3 [M+H]⁺

H-NMR (400 MHz, DMSO-c/₆) δ (ppm) 8.27 (s, 1 H, ArH), 7.63 (d, ³J 7.8 Hz, 2H, ArH), 7.48 (d, ³J 7.8 Hz, 2H, ArH), 6.92-6.82 (m, 0.5H), 6.76-6.66 (m, 0.5H), 6.18-6.02 (m, 1 H), 5.75-5.68 (m, 0.5H), 5.63- 5.55 (m, 0.5H), 4.78-4.63 (m, 1 H), 4.61 -4.51 (m, 0.5H), 4.28-4.15 (m, 1 H), 4.14-4.04 (m, 0.5H), 3.76- 3.65 (m, 0.5H), 3.64-3.57 (m, 4H, CH₂), 3.54 (s, 2H, CH₂), 3.27-3.14 (m, 1 H), 3.08-2.97 (m, 0.5H), 2.46-2.36 (m, 4H, CH₂), 2.32-2.21 (m, 1 H), 2.18-2.08 (m, 1 H), 1 .99-1 .88 (m, 1 H), 1 .67-1 .52 (m, 1 H).

[00265] Example 10: 1 -[(3R)-3-[4-amino-3-[3-(morpholinomethyl)phenyl]pyrazolo[3,4- cflpyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00266] 3-[3-(Morpholinomethyl)phenyll-1 -[(3 ?)-3-piperidyllpyrazolo[3,4-c lpyrimidin-4-amine

Following general procedure D, [3-(morpholinomethyl)phenyl]boronic acid (96.4 mg, 0.44 mmol) and 3-iodo-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine (100.0 mg, 0.29 mmol), gave 3-[3- (morpholinomethyl)phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine (1 14.3 mg, 0.29 mmol, 100% yield) as a brown gum. This was used in the next reaction without further purification, assumed quantitative.

UPLC-MS (ES⁺, Short acidic): 0.29 min & 0.59 min, m/z 394.2 [M+H]⁺

[00267] 1 -[(3f?)-3-[4-Amino-3-[3-(morpholinomethyl)phenyllpyrazolo[3,4-c lpyrimidin-1 -yll-1 - piperidyllprop-2-en-1 -one

Following general procedure G, 3-[3-(morpholinomethyl)phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4- c ]pyrimidin-4-amine (1 14.3 mg, 0.29 mmol) afforded 1 -[(3f?)-3-[4-amino-3-[3- (morpholinomethyl)phenyl]pyrazolo[3,4-c/]pyrimidin-1 -yl]-1 -piperidyl] prop-2-en-1 -one (32.0 mg, 0.072 mmol, 25% yield).

UPLC-MS (ES⁺, Short acidic): 0.93 min, m/z 448.3 [M+H]⁺ H-NMR (400 MHz, DMSO-c/₆) δ (ppm) 8.28 (s, 1 H, ArH), 7.61 (s br., 1 H, ArH), 7.57 (d, ³J 7.6 Hz, 1 H, ArH), 7.51 (t, ³J 7.6 Hz, 1 H, ArH), 7.42 (d, ³J 7.6 Hz, 1 H, ArH), 6.93-6.83 (m, 0.5H), 6.79-6.68 (m, 0.5H), 6.18-6.04 (m, 1 H), 5.75-5.68 (m, 0.5H), 5.64-5.58 (m, 0.5H), 4.79-4.65 (m, 1 H), 4.59-4.51 (m, 0.5H), 4.27-4.17 (m, 1 H), 4.14-4.03 (m, 2H), 3.78-3.68 (m, 0.5H), 3.62-3.57 (m, 4H, 2 x CH₂), 3.55 (s, 2H, CH₂), 3.28-3.14 (m, 1 H), 3.21 -3.13 (m, 0.5H), 3.07-2.98 (m, 0.5H), 2.45-2.36 (m, 4H, 2 x CH₂), 2.32-2.21 (m, 1 H), 2.19-2.09 (m, 1 H), 1 .99-1 .88 (m, 1 H), 1 .67-1 .52 (m, 1 H).

[00268] Example 11 : 1 -[(3R)-3-[4-amino-3-[3-fluoro-4-(morp olinomet yl)p enyl]pyrazolo[3,4- cflpyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00269] 3-[3-Fluoro-4-(morpholinomethyl)phenvn^

amine

Following general procedure D, 3-iodo-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c/]pyrimidin-4-amine (200.0 mg, 0.58 mmol) and 3-fluoro-4-(n-morpholinomethyl)phenylboronic acid, pinacol ester (280.0 mg, 0.87 mmol) afforded 3-[3-fluoro-4-(morpholinomethyl)phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4- amine (239.1 mg, 0.58 mmol, 100% yield). This was used in the next reaction without further purification, assumed quantitative.

UPLC-MS (ES⁺, Short acidic): 0.59 min, m/z 412.2 [M+H]⁺

[00270] 1 -[(3f?V3-[4-Amino-3-[3-fluoro-4-(morpholinomethyl)phenyllpyrazolo[3,4-c lpyrimidin-1 -yll-1 - piperidyllprop-2-en-1 -one

Following general procedure G, crude 3-[3-fluoro-4-(morpholinomethyl)phenyl]-1 -[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (239.1 mg, 0.58 mmol) gave, after purification by flash column chromatography (DCM/(0.1 % 7N NH₃ in MeOH) 100:0 to 90:10), 1 -[(3f?)-3-[4-amino-3-[3- fluoro-4-(morpholinomethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one (52.0 mg , 0.1 1 mmol, 19% yield) as a brown solid.

UPLC-MS (ES⁺, Short acidic): 0.97 min, m/z 466.3 [M+H]⁺

[00271] Example 12: 1 -[(3R)-3-[4-Amino-3-[2-fluoro-4-(morpholinomethyl)phenyl]pyrazolo[3,4- cflpyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00272] S-^-Fluoro^-^orpholinomethvOphenyll-l -fOffl-S-piperidyllpyrazolofS^-c lpyrimidin^- amine

Following general procedure D, 3-iodo-1 -[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (200.0 mg, 0.58 mmol) and 2-fluoro-4-(morpholinomethyl)phenylboronic acid pinacol ester (280.0 mg, 0.87 mmol) afforded 3-[2-fluoro-4-(morpholinomethyl)phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine (239.1 mg, 0.58 mmol, 100% yield). This was used in the next reaction without further purification, assumed quantitative.

UPLC-MS (ES⁺, Short acidic): 0.40 min, m/z 412.2 [M+H]⁺

[00273] 1 -[(3f?V3-[4-Amino-3-[2-fluoro-4-(morpholinomethyl)phenyllpyrazolo[3,4-c lpyrimidin-1 -yll-1 - piperidyllprop-2-en-1 -one

Following general procedure G, crude 3-[2-fluoro-4-(morpholinomethyl)phenyl]-1 -[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (239.1 mg, 0.58 mmol) gave, after purification by flash column chromatography (DCM/(0.1 % 7N NH₃ in MeOH) 100:0 to 90:10), 1 -[(3f?)-3-[4-amino-3-[2- fluoro-4-(morpholinomethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one (32.0 mg , 0.07 mmol, 1 1 % yield) as a black solid. UPLC-MS (ES⁺, Short acidic): 0.95 min, m/z 466.3 [M+H]⁺

[00274] Example 13: 1 -[(3R)-3-[4-Amino-3-[4-(1 -morpholinoethyl)phenyl]pyrazolo[3,4- cflpyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00275] 3-[4-n -Morpholinoethyl)phenvn-1 -[(3 ?)-3-piperidvnpyrazolo[3,4-(^pyrimidin-4-ami

Following general procedure D, 3-iodo-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c/]pyrimidin-4-amine (200.0 mg, 0.58 mmol) and 4-[1 -[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]ethyl]morpholine (276.5 mg, 0.87 mmol) afforded 3-[4-(1 -morpholinoethyl)phenyl]-1 -[(3R)-3^iperidyl]pyrazolo[3,4-c ]pyrimidin- 4-amine (236.8 mg, 0.58 mmol, 100% yield). This was used in the next reaction without further purification, assumed quantitative.

UPLC-MS (ES⁺, Short acidic): 0.39 min, m/z 408.2 [M+H]⁺

[00276] 1 -[(3f?)-3-[4-Amino-3-[4-(1 -morpholinoethyl)phenyllpyrazolo[3,4-c lpyrimidin-1 -yll-1 - pipe ridyllprop-2-en-1 -one

Following general procedure G, crude 3-[4-(1 -morpholinoethyl)phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4- c ]pyrimidin-4-amine (1 18.3 mg, 0.29 mmol) gave, after purification by flash column chromatography (DCM/(0.1 % 7N NH₃ in MeOH) 100:0 to 90:10), 1 -[(3f?)-3-[4-amino-3-[4-(1 - morpholinoethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1-piperidyl]prop-2-en-1 -one (53.1 mg, 0.1 1 mmol, 39% yield) as a black solid.

UPLC-MS (ES⁺, Short acidic): 0.94 min, m/z 462.3 [M+H]⁺

[00277] Example 14: 1 -[(3R)-3-(4-Amino-3-(4-[(3-methylmorpholin-4-yl)methyl]phenyl)-1 H- pyrazolo[3,4-c ]pyrimidin-1 -yl)piperidin-1 -yl]prop-2-en-1 -one

[00278] 3-Methyl-4-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyllmorpholine

To a stirred solution of 2-[4-(bromomethyl)phenyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (300.0 mg, 1 .01 mmol) and Λ/,/V-diisopropylethylamine (0.18 mL, 1 .01 mmol) in THF (5.0 mL) under nitrogen was added 3-methylmorpholine (102.2 mg, 1 .01 mmol) dropwise, and the reaction was stirred at room temperature for 22 h. The reaction mixture was concentrated under reduced pressure to give 3- methyl-4-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholine (320.4 mg, 1 .01 mmol, 100% yield) as a mixture with Λ/,/V-diisopropylethylamine. This mixture was used in the next reaction without further purification, assumed quantitative.

UPLC-MS (ES⁺, Short acidic): 1 .24 min, m/z 318.1 [M+H]⁺

[00279] 3-[4-[(3-Methylmorpholin-4-yl)methyllphenyll-1 -[(3f?)-3-piperidyllpyrazolo[3,4-c/lpyrimidin-4- amine

Following general procedure D, 3-methyl-4-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]morpholine (320.4 mg, 1 .01 mmol) and 3-iodo-1 -[(3R)-3-piperidyl]pyrazolo[3,4- c ]pyrimidin-4-amine (120.0 mg, 0.35 mmol), gave 3-[4-[(3-methylmorpholin-4-yl)methyl]phenyl]-1 - [(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine (142.6 mg, 0.35 mmol, 100% yield) as a pale brown solid. This mixture was used in the next reaction without further purification, assumed quantitative. UPLC-MS (ES⁺, Short acidic): 0.73 min, m/z 408.3 [M+H]⁺

[00280] 1 -[(3f?)-3-(4-Amino-3-(4-[(3-methylmorpholin-4-yl)methyllphenyl)-1 H-pyrazolo[3,4- c lpyrimidin-1 -yl)piperidin-1 -yllprop-2-en-1 -one

Following general procedure G, 3-[4-[(3-methylmorpholin-4-yl)methyl]phenyl]-1 -[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (142.6 mg, 0.35 mmol) afforded 1 -[(3R)-3-(4-amino-3-(4-[(3- methylmorpholin-4-yl)methyl]ph^

(81 .4 mg, 0.18 mmol, 51 % yield) as a pale green solid.

UPLC-MS (ES⁺, Short acidic): 0.96 min, m/z 462.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.1 1 min, m/z 462.4 [M+H]⁺

H-NMR (400 MHz, CDCI₃) δ (ppm) 8.41 (br. s, 0.5H, ArH), 7.84-7.74 (br. s, 0.5H, ArH), 7.78 (d, ³J 7.8 Hz, 1 H, ArH), 7.66 (d, ³J 7.8 Hz, 1 H, ArH), 7.54 (d, ³J 7.8 Hz, 1 H, ArH), 7.36 (d, ³J 7.8 Hz, 1 H, ArH), 6.69-6.53 (m, 0.5H), 6.39-6.27 (m, 0.5H), 5.77-5.65 (m, 0.5H), 5.54-5.41 (m, 1 H), 4.95-4.85 (m, 0.5H), 4.18-4.06 (m, 1 H), 3.81 -3.68 (m, 4H, CH₂ + 2H), 3.68-3.54 (m, 2H), 3.44-3.16 (3H, m), 2.72-2.47 (m, 2H), 2.32-2.16 (m, 2H), 1 .26 (s, 3H, CH₃), 1 .17-1 .06 (m, 4H).

[00281] Example 15: 1 -[(3R)-3-[4-Amino-3-[4-[(2-methylmorpholin-4- yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00282] 2-Methyl-4-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyllmorpholine

To a stirred solution of 2-[4-(bromomethyl)phenyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (300.0 mg,

1 .01 mmol) and Λ/,/V-diisopropylethylamine (0.39 ml_, 2.22 mmol) in THF (5.0 ml_) under nitrogen was added 2-methylmorpholine hydrochloride (152.9 mg, 1 .1 1 mmol), and the reaction was stirred at room temperature for 22 h. The reaction mixture was concentrated to dryness under reduced pressure to give 2-methyl-4-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholine (320.4 mg, 1 .01 mmol, 100% yield) as a mixture with Λ/,/V-diisopropylethylamine. This mixture was used in the next reaction without further purification, assumed quantitative.

UPLC-MS (ES⁺, Short acidic): 1 .26 min, m/z 318.1 [M+H]⁺

[00283] 3-[4-[(2-Methylmorpholin-4-yl)methyllphenyll-1 -[(3f?)-3-piperidyllpyrazolo[3,4-c/lpyrimidin-4- amine

Following general procedure D, 2-methyl-4-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]morpholine (320.4 mg, 1 .01 mmol) and 3-iodo-1 -[(3R)-3-piperidyl]pyrazolo[3,4- c ]pyrimidin-4-amine (120.0 mg, 0.35 mmol), gave 3-[4-[(2-methylmorpholin-4-yl)methyl]phenyl]-1 -

[(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine (142.6 mg, 0.35 mmol, 100% yield) as a pale brown solid. This mixture was used in the next reaction without further purification, assumed quantitative. UPLC-MS (ES⁺, Short acidic): 0.75 min, m/z 408.3 [M+H]⁺

[00284] 1 -[(3f?)-3-[4-Amino-3-[4-[(2-methylmorpholin-4-yl)methyllphenyllpyrazolo[3,4-c lpyrimidin-1 - yll-1 -piperidyllprop-2-en-1 -one

Following general procedure G, 3-[4-[(2-methylmorpholin-4-yl)methyl]phenyl]-1 -[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (142.6 mg, 0.35 mmol) afforded 1 -[(3R)-3-(4-amino-3-(4-[(2- methylmorpholin-4-yl)methyl]phenyl)-1 H-pyrazolo[3,4-c/]pyrimidin-1 -yl)piperidin-1 -yl]prop-2-en-1 -one (59.4 mg, 0.13 mmol, 37% yield) as a pale brown solid.

UPLC-MS (ES⁺, Short acidic): 0.98 min, m/z 462.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.14 min, m/z 462.4 [M+H]⁺

H-NMR (400 MHz, DMSO-c/₆) δ (ppm) 8.27 (s, 1 H, ArH), 7.63 (d, ³J 8.2 Hz, 2H, ArH), 7.48 (d, ³J 8.2 Hz, 2H, ArH), 6.93-6.83 (m, 0.5H), 6.77-6.67 (m, 0.5H), 6.18-6.03 (m, 1 H), 5.74-5.69 (m, 0.5H), 5.63- 5.57 (m, 0.5H), 4.80-4.65 (m, 1 H), 4.59-4.52 (m, 0.5H), 4.26-4.16 (m, 1 H), 4.14-4.05 (m, 0.5H), 3.79- 3.73 (m, 1 H), 3.60-3.48 (m, 4H, CH₂ + 2H), 3.26-3.16 (1 H, m), 2.78-2.72 (m, 1 H), 2.71 -2.66 (m, 1 H), 2.32-2.20 (m, 2H), 2.18-2.03 (m, 3H), 1.98-1.90 (m, 1 H), 1.80-1.75 (m, 1 H), 1.04 (d, ³ J 6.3 Hz, 3H, CH₃).

[00285] Example 16: 1-[(3R)-3-[4-Amino-3-[4-[[2-(trifluoromethyl)morpholin-4- yl]methyl]phenyl]pyrazolo[3,4-c |pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00286] 4-[[4-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyll-2- (trifluoromethvQmorpholine

To a stirred solution of 2-[4-(bromomethyl)phenyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (300.0 mg, 1.01 mmol) and Λ/,/V-diisopropylethylamine (0.39 ml_, 2.22 mmol) in THF (5.0 ml_) under nitrogen was added 2-(trifluoromethyl)morpholine hydrochloride (212.9 mg, 1.11 mmol), and the reaction was stirred at room temperature for 22 h. The reaction mixture was concentrated under reduced pressure to give 4-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]-2-(trifluoromethyl)morpholine (375.0 mg, 1.01 mmol, 100% yield) as a mixture with Λ/,/V-diisopropylethylamine. This mixture was used in the next reaction without further purification, assumed quantitative.

UPLC-MS (ES⁺, Short acidic): 1.87 min, m/z 371.9 [M+H]⁺

[00287] 1-[(3f?)-3-Piperidyll-3-[4-[[2-(trifluoromethyl)morpholin-4-yllmethyllphenyllpyrazolo[3,4- c lPyrimidin-4-amine

Following general procedure D, 4-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]-2- (trifluoromethyl)morpholine (375.0 mg, 1.01 mmol) and 3-iodo-1-[(3R)-3-piperidyl]pyrazolo[3,4- c/]pyrimidin-4-amine (120.0 mg, 0.35 mmol), gave 1-[(3f?)-3-piperidyl]-3-[4-[[2- (trifluoromethyl)morpholin-4-yl]methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-4-amine (161.5 mg, 0.35 mmol, 100% yield) as a pale brown solid. This mixture was used in the next reaction without further purification, assumed quantitative.

UPLC-MS (ES⁺, Short acidic): 1.00 min, m/z 462.3 [M+H]⁺

[00288] 1-[(3f?)-3-[4-Amino-3-[4-[[2-(trifluoromethyl)morpholin-4-yllmethyllphenyllpyrazolo[3,4- c lpyrimidin-1 -yll-1 -pipe ridyllprop-2-en-1 -one

Following general procedure G, 1-[(3R)-3-piperidyl]-3-[4-[[2-(trifluoromethyl)morpholin-4- yl]methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-4-amine (161.5 mg, 0.35 mmol) afforded 1-[(3R)-3-[4-amino- 3-[4-[[2-(trifluoromethyl)morpholin-4-yl]m

en-1-one (31.0 mg, 0.060 mmol, 17% yield) as a pale brown solid.

UPLC-MS (ES⁺, Short acidic): 1.27 min, m/z 516.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.85 min, m/z 516.4 [M+H]⁺

H-NMR (400 MHz, DMSO-c/₆) δ (ppm) 8.27 (s, 1 H, ArH), 7.65 (d, ³J 7.8 Hz, 2H, ArH), 7.49 (d, ³J 7.8 Hz, 2H, ArH), 6.93-6.83 (m, 0.5H), 6.77-6.67 (m, 0.5H), 6.18-6.03 (m, 1 H), 5.74-5.69 (m, 0.5H), 5.62- 5.56 (m, 0.5H), 4.78-4.65 (m, 1 H), 4.60-4.52 (m, 0.5H), 4.26-4.16 (m, 1 H), 4.14-4.05 (m, 0.5H), 3.99- 3.91 (m, 1 H), 3.72-3.60 (m, 3.5H, CH₂ + 1 H + 0.5 H), 3.28-3.16 (1 H, m), 3.07-2.97 (m, 0.5H), 2.95 (d, ³ J 11.2 Hz, 1 H), 2.74 (d, ³ 11.2 Hz, 1 H), 2.29-2.08 (m, 4H), 1.99-1.90 (m, 1 H), 1.66-1.53 (m, 1 H), 1.29-1.22 (m, 1 H).

[00289] Example 17: 1-[(3R)-3-[4-Amino-3-[4-[(2,3-dimethylmorpholin-4- yl)methyl]phenyl]pyrazolo[3,4-c |pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00290] 2,3-Dimethyl-4-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyllmorpholine To a stirred solution of 2-[4-(bromomethyl)phenyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (300.0 mg, 1 .01 mmol) and Λ/,/V-diisopropylethylamine (0.36 ml_, 2.02 mmol) in THF (5.0 ml_) under nitrogen was added 2,3-dimethylmorpholine (139.6 mg, 1 .21 mmol), and the reaction was stirred at room temperature for 22 h. The reaction mixture was concentrated under reduced pressure to give 2,3- dimethyl-4-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholine (334.6 mg, 1 .01 mmol, 100% yield) as a mixture with Λ/,/V-diisopropylethylamine. This mixture was used in the next reaction without further purification, assumed quantitative.

UPLC-MS (ES⁺, Short acidic): 1 .25 min, m/z 331 .9 [M+H]⁺

[00291] 3-[4-[(2,3-Dimethylmorpholin-4-yl)methyllphenyll-1 -[(3f?)-3-piperidyllpyrazolo[3,4-c lpyrimidin- 4-amine

Following general procedure D, 2,3-dimethyl-4-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]morpholine (334.6 mg, 1 .01 mmol) and 3-iodo-1 -[(3R)-3-piperidyl]pyrazolo[3,4- c ]pyrimidin-4-amine (120.0 mg, 0.35 mmol), gave 3-[4-[(2,3-dimethylmorpholin-4-yl)methyl]phenyl]-1 - [(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine (147.5 mg, 0.35 mmol, 100% yield) as a pale brown solid. This mixture was used in the next reaction without further purification, assumed quantitative. UPLC-MS (ES⁺, Short acidic): 0.77 min, m/z 422.3 [M+H]⁺

[00292] 1 -[(3f?)-3-[4-Amino-3-[4-[(2,3-dimethylmorpholin-4-yl)methyllphenyllpyrazolo[3,4-c/lpyrimidin- 1 -yll-1 -piperidyllprop-2-en-1 -one

Following general procedure G, 3-[4-[(2,3-dimethylmorpholin-4-yl)methyl]phenyl]-1 -[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (147.5 mg, 0.35 mmol) afforded 1 -[(3R)-3-[4-amino-3-[4- [(2,3-dimethylmorpholin-4-yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one (40.5 mg, 0.084 mmol, 24% yield) as a pale green solid.

UPLC-MS (ES⁺, Short acidic): 1 .00 min, m/z 476.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.20 min, m/z 476.4 [M+H]⁺

H-NMR (400 MHz, DMSO-c/₆) δ (ppm) 8.27 (s, 1 H, ArH), 7.66-7.60 (m, 2H, ArH), 7.50-7.44 (d, 2H, ArH), 6.93-6.83 (m, 0.5H), 6.77-6.67 (m, 0.5H), 6.18-6.03 (m, 1 H), 5.74-5.69 (m, 0.5H), 5.63-5.57 (m, 0.5H), 4.81 -4.64 (m, 1 H), 4.60-4.51 (m, 0.5H), 4.27-4.16 (m, 1 H), 4.14-4.05 (m, 0.5H), 3.76-3.63 (m, 2.5H), 3.56-3.43 (m, 1 .5H), 3.26-3.13 (2H, m), 2.64-2.55 (m, 2H), 2.36-2.22 (m, 2H), 2.21 -2.10 (m, 2H), 2.08-2.00 (m, 1 H), 2.00-1 .90 (m, 1 H), 1 .17-1 .09 (m, 3H), 1 .00-0.89 (m, 3H).

[00293] Example 18: 1 -[(3R)-3-[4-Amino-3-[4-[(2,5-dimethylmorpholin-4- yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00294] 2,3-Dimethyl-4-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyllmorpholine To a stirred solution of 2-[4-(bromomethyl)phenyl]-4, 4,5, 5-tetramethyl-1 ,3,2-dioxaborolane (300.0 mg, 1 .01 mmol) and Λ/,/V-diisopropylethylamine (0.36 mL, 2.02 mmol) in THF (5.0 mL) under nitrogen was added 2,5-dimethylmorpholine (139.6 mg, 1 .21 mmol), and the reaction was stirred at room temperature for 22 h. The reaction mixture was concentrated under reduced pressure to give 2,5- dimethyl-4-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholine (334.6 mg, 1 .01 mmol, 100% yield) as a mixture with Λ/,/V-diisopropylethylamine. This mixture was used in the next reaction without further purification, assumed quantitative.

UPLC-MS (ES⁺, Short acidic): 1 .29 min, m/z 332.0 [M+H]⁺ [00295] 3-[4-[(2,5-Dimethylmorpholin-4-yl)methyllphenyll-1 -[(3 ?V3-piperidyllp

4-amine

Following general procedure D, 2,5-dimethyl-4-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]morpholine (334.6 mg, 1 .01 mmol) and 3-iodo-1 -[(3R)-3-piperidyl]pyrazolo[3,4- c ]pyrimidin-4-amine (120.0 mg, 0.35 mmol), gave 3-[4-[(2,5-dimethylmorpholin-4-yl)methyl]phenyl]-1 - [(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine (147.5 mg, 0.35 mmol, 100% yield) as a pale brown solid. This mixture was used in the next reaction without further purification, assumed quantitative. UPLC-MS (ES⁺, Short acidic): 0.35 min, m/z 422.3 [M+H]⁺

[00296] 1 -[(3f?)-3-[4-Amino-3-[4-[(2,5-dimethylmorpholin-4-yl)methyllphenyllpyrazolo[3,4-c/lpyrimidin- 1 -yll-1 -piperidyllprop-2-en-1 -one

Following general procedure G, 3-[4-[(2,5-dimethylmorpholin-4-yl)methyl]phenyl]-1 -[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (147.5 mg, 0.35 mmol) afforded 1 -[(3R)-3-[4-amino-3-[4- [(2,5-dimethylmorpholin-4-yl)methyl]phenyl]pyrazolo[3,4-(^pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one (54.6 mg, 0.12 mmol, 33% yield) as a pale brown solid.

UPLC-MS (ES⁺, Short acidic): 1 .00 min, m/z 476.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.20 min, m/z 476.4 [M+H]⁺

H-NMR (400 MHz, DMSO-c/₆) δ (ppm) 8.27 (s, 1 H, ArH), 7.66-7.59 (m, 2H, ArH), 7.53-7.44 (m, 2H, ArH), 6.93-6.82 (m, 0.5H), 6.77-6.67 (m, 0.5H), 6.18-6.03 (m, 1 H), 5.74-5.69 (m, 0.5H), 5.63-5.56 (m, 0.5H), 4.80-4.65 (m, 1 H), 4.60-4.51 (m, 0.5H), 4.26-4.16 (m, 1 H), 4.14-4.05 (m, 1 .5H), 3.72-3.45 (m, 5H), 3.26-3.05 (m, 2H), 2.83-2.73 (m, 1 H), 2.69-2.60 (m, 1 H), 2.42-2.20 (m, 2H), 2.18-2.09 (m, 1 H), 1 .99-1 .88 (m, 1 H), 1 .81 -1 .72 (m, 1 H), 1 .65-1 .53 (m, 1 H), 1 .08-0.98 (m, 6H).

[00297] Example 19: 1 -[(3R)-3-[4-Amino-3-[4-[(2,2-dimethylmorpholin-4- yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00298] 2,2-Dimethyl-4-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyllmorpholine To a stirred solution of 2-[4-(bromomethyl)phenyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (300.0 mg, 1 .01 mmol) and Λ/,/V-diisopropylethylamine (0.36 mL, 2.02 mmol) in THF (5.0 mL) under nitrogen was added 2,2-dimethylmorpholine (139.6 mg, 1 .21 mmol), and the reaction was stirred at room temperature for 22 h. The reaction mixture was concentrated under reduced pressure to give 2,2- dimethyl-4-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholine (334.6 mg, 1 .01 mmol, 100% yield) as a mixture with Λ/,/V-diisopropylethylamine. This mixture was used in the next reaction without further purification, assumed quantitative.

UPLC-MS (ES⁺, Short acidic): 1 .32 min, m/z 332.0 [M+H]⁺

[00299] 3-[4-[(2,2-Dimethylmorpholin-4-yl)methyllphenyll-1 -[(3f?)-3-piperidyllpyrazolo[3,4-c lpyrimidin- 4-amine

Following general procedure D, 2,2-dimethyl-4-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]morpholine (334.6 mg, 1 .01 mmol) and 3-iodo-1 -[(3R)-3-piperidyl]pyrazolo[3,4- c ]pyrimidin-4-amine (120.0 mg, 0.35 mmol), gave 3-[4-[(2,2-dimethylmorpholin-4-yl)methyl]phenyl]-1 - [(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine (147.5 mg, 0.35 mmol, 100% yield) as a pale brown solid. This mixture was used in the next reaction without further purification, assumed quantitative. UPLC-MS (ES⁺, Short acidic): 0.79 min, m/z 422.3 [M+H]⁺ [00300] 1 -[(3/?y3-[4-Amino-3-[4-[(2,2-dimethylmo

1 -yll-1 -piperidyllprop-2-en-1 -one

Following general procedure G, 3-[4-[(2,2-dimethylmorpholin-4-yl)methyl]phenyl]-1 -[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (147.5 mg, 0.35 mmol) afforded 1 -[(3R)-3-[4-amino-3-[4- [(2,2-dimethylmorpholin-4-yl)methyl]phenyl]pyrazo

(62.1 mg, 0.13 mmol, 38% yield) as a pale brown solid.

UPLC-MS (ES⁺, Short acidic): 1 .01 min, m/z 476.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.22 min, m/z 476.4 [M+H]⁺

H-NMR (400 MHz, DMSO-c/₆) δ (ppm) 8.27 (s, 1 H, ArH), 7.63 (d, ³J 7.8 Hz, 2H, ArH), 7.49 (d, ³J 7.8 Hz, 2H, ArH), 6.93-6.82 (m, 0.5H), 6.77-6.67 (m, 0.5H), 6.18-6.03 (m, 1 H), 5.74-5.69 (m, 0.5H), 5.63- 5.56 (m, 0.5H), 4.78-4.65 (m, 1 H), 4.60-4.51 (m, 0.5H), 4.26-4.16 (m, 1 H), 4.10-4.05 (m, 1 .5H), 3.75- 3.66 (m, 0.5H), 3.66-3.62 (m, 2H), 3.51 (m, 2H), 3.27-3.20 (m, 1 H), 3.25-3.15 (m, 3H), 3.07-2.98 m, 0.5H) 2.31 -2.23 (m, 1 H), 2.17-2.09 (m, 1 H), 1 .99-1 .89 (m, 1 H), 1 .68-1 .52 (m, 1 H), 1 .18 (s, 6H).

[00301] Example 20: 1 -[(3R)-3-[4-Amino-3-[4-[(2-phenylmorpholin-4- yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00302] 2-Phenyl-4-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyllmorpholine

To a stirred solution of 2-[4-(bromomethyl)phenyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (300.0 mg, 1 .01 mmol) and Λ/,/V-diisopropylethylamine (0.36 ml_, 2.02 mmol) in THF (5.0 ml_) under nitrogen was added 2-phenylmorpholine (197.8 mg, 1 .21 mmol), and the reaction was stirred at room temperature for 22 h. The reaction mixture was concentrated to dryness under reduced pressure to give 2-phenyl- 4-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholine (383.1 mg, 1 .01 mmol, 100% yield) as a mixture with Λ/,/V-diisopropylethylamine. This mixture was used in the next reaction without further purification, assumed quantitative.

UPLC-MS (ES⁺, Short acidic): 1 .48 min, m/z 380.4 [M+H]⁺ & 1 .03 min, m/z 298.2 [RB(OH)₂+H]⁺

[00303] 3-[4-[(2-Phenylmorpholin-4-yl)methyllphenyll-1 -[(3f?)-3-piperidyllpyrazolo[3,4-c/lpyrimidin-4- amine

Following general procedure D, 2-phenyl-4-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]morpholine (383.1 mg, 1 .01 mmol) and 3-iodo-1 -[(3R)-3-piperidyl]pyrazolo[3,4- c ]pyrimidin-4-amine (120.0 mg, 0.35 mmol), gave 3-[4-[(2-phenylmorpholin-4-yl)methyl]phenyl]-1 - [(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine (164.4 mg, 0.35 mmol, 100% yield) as a pale brown solid. This mixture was used in the next reaction without further purification, assumed quantitative. UPLC-MS (ES⁺, Short acidic): 0.92 min, m/z 470.3 [M+H]⁺

[00304] 1 -[(3f?)-3-[4-Amino-3-[4-[(2-phenylmorpholin-4-yl)methyllphenyllpyrazolo[3,4-c lpyrimidin-1 - yll-1 -piperidyllprop-2-en-1 -one

Following general procedure G, 3-[4-[(2-phenylmorpholin-4-yl)methyl]phenyl]-1 -[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (164.4 mg, 0.35 mmol) afforded 1 -[(3R)-3-[4-amino-3-[4-[(2- phenylmorpholin-4-yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one (56.2 mg, 0.1 1 mmol, 31 % yield) as a pale brown solid.

UPLC-MS (ES⁺, Short acidic): 1 .15 min, m/z 524.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.61 min, m/z 524.4 [M+H]⁺ H-NMR (400 MHz, DMSO-c/₆) δ (ppm) 8.27 (s, 1 H, ArH), 7.64 (d, ³J 7.8 Hz, 2H, ArH), 7.50 (d, ³J 7.8 Hz, 2H, ArH), 7.39-7.25 (m, 5H, ArH), 6.93-6.82 (m, 0.5H), 6.77-6.67 (m, 0.5H), 6.18-6.03 (m, 1 H), 5.75-5.69 (m, 0.5H), 5.63-5.56 (m, 0.5H), 4.78-4.65 (m, 1 H), 4.60-4.40 (m, 1 .5H), 4.26-4.16 (m, 1 H), 4.10-4.05 (m, 0.5H), 4.00-3.90 (m, 1 .5H), 3.76-3.66 (m, 1 .5H), 3.66-3.56 (m, 2H), 3.27-3.15 (m, 1 H), 3.07-3.00 (m, 0.5H), 2.99-2.89 (m, 2H), 2.87-2.81 (m, 0.5H), 2.82-2.75 (m, 1 H), 2.30-2.18 (m, 1 H), 2.17-2.09 (m, 1 H), 1 .98-1 .88 (m, 1 H), 1 .68-1 .56 (m, 1 H).

[00305] Example 21 : 1 -[(3R)-3-[3-[4-((irans-Octahydro-2H-[1 ,4]-benzoxazin-4-yl)methyl)phenyl]- 4-amino-pyrazolo[3,4-c lpyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one (frans-stereoisomers at morpholine)

[00306] 4-[[4-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyll-frans-octahvdro-2H- [1 ,41benzoxazine

To a stirred solution of 2-[4-(bromomethyl)phenyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (300.0 mg, 1 .01 mmol) and Λ/,/V-diisopropylethylamine (0.36 mL, 2.02 mmol) in THF (5.0 mL) under nitrogen was added frans-octahydro-2/-/-1 ,4-benzoxazine (197.8 mg, 1 .21 mmol), and the reaction was stirred at room temperature for 22 h. The reaction mixture was concentrated under reduced pressure to give 4- [[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]-frans-octahydro-2/-/-[1 ,4]benzoxazine (360.9 mg, 1 .01 mmol, 100% yield) as a mixture with Λ/,/V-diisopropylethylamine. This mixture was used in the next reaction without further purification, assumed quantitative.

UPLC-MS (ES⁺, Short acidic): 1 .35 min, m/z 358.0 [M+H]⁺ & 0.89 min, m/z 276.2 [RB(OH)₂+H]⁺

[00307] 3-r4-((frans-Octahvdro-2H-ri .4l-benzoxazin-4-yl)methyl)phenyll-1 -[(3f?)-3- piperidyllpyrazolo[3,4-c/lpyrimidin-4-amine

Following general procedure D, 4-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]- frans-octahydro-2H-[1 ,4]benzoxazine (360.9 mg, 1 .01 mmol) and 3-iodo-1 -[(3f?)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (120.0 mg, 0.35 mmol), gave 3-[4-((frans-octahydro-2/-/- [1 ,4]-benzoxazin-4-yl)methyl)phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine (156.7 mg, 0.35 mmol, 100% yield) as a pale brown solid. This mixture was used in the next reaction without further purification, assumed quantitative.

UPLC-MS (ES⁺, Short acidic): 0.82 min, m/z 448.3 [M+H]⁺

[00308] 1 -[(3ft)-3-[3-[4-((frans-Octahvdro-2H-[1 ,41-benzoxazin-4-yl)methyl)phenyll-4-amino- pyrazolo[3,4-c lpyrimidin-1 -yll-1 -piperidyllprop-2-en-1 -one (trans-stereoisomers at morpholine)

Following general procedure G, 3-[4-((frans-octahydro-2/-/-[1 ,4]-benzoxazin-4-yl)methyl)phenyl]-1 - [(3f?)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine (156.7 mg, 0.35 mmol) afforded 1 -[(3f?)-3-[3-[4- ((frans-octahydro-2/-/-[1 ,4]-benzoxazin-4-yl)methyl)phenyl]-4-amino-pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 - piperidyl]prop-2-en-1 -one (frans-stereoisomers at morpholine) (8.3 mg, 0.016 mmol, 5% yield) as a colourless solid.

UPLC-MS (ES⁺, Short acidic): 1 .05 min, m/z 502.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.37 min, m/z 502.4 [M+H]⁺

H-NMR (400 MHz, DMSO-c/₆) δ (ppm) 8.28 (s, 2H, ArH + HC0₂H), 7.73 (d, ³J 7.8 Hz, 2H, ArH), 7.58 (d, ³J 7.8 Hz, 2H, ArH), 6.89-6.79 (m, 0.5H), 6.72-6.62 (m, 0.5H), 6.26-6.10 (m, 1 H), 5.81 -5.75 (m, 0.5H), 5.67-5.61 (m, 0.5H), 4.67-4.60 (m, 1 H), 4.43-4.35 (m, 1 H), 4.29-4.19 (m, 1 H), 4.17-4.09 (m,

0.5H), 3.96-3.88 (m, 0.5H), 3.88-3.82 (m, 1 H), 3.77-3.68 (m, 1 .5H), 3.58-3.53 (m, 0.5H), 3.48-3.41 (m, 1 H), 2.87-2.80 (m, 1 H), 2.58-2.48 (m, 1 H), 2.48-2.34 (m, 2H), 2.17-2.07 (m, 1 H), 1 .98-1 .90 (m, 1 H), 1 .90-1 .84 (m, 1 H), 1 .83-1 .71 (m, 2H), 1 .41 -1 .34 (m, 2H), 1 .34-1 .23 (m, 2H).

[00309] Example 22: 1 -[(3R)-3-[4-Amino-3-[4-[(2,6-dimethylmorpholin-4- yl)methyl]phenyl]pyrazolo[3,4-c |pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00310] 2,6-Dimethyl-4-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyllmorphoN

To a stirred solution of 2-[4-(bromomethyl)phenyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (300.0 mg, 1 .01 mmol) and Λ/,/V-diisopropylethylamine (0.21 ml_, 1 .21 mmol) in THF (5.0 ml_) under nitrogen was added 2,6-dimethylmorpholine (137 μΙ_, 1 .1 1 mmol), and the reaction was stirred at room temperature for 4 d. The reaction mixture was concentrated to dryness under reduced pressure to give 2,6- dimethyl-4-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholine (334.6 mg, 1 .01 mmol, 100% yield) as a mixture with Λ/,/V-diisopropylethylamine and unreacted morpholine. This mixture was used in the next reaction without further purification, assumed quantitative.

UPLC-MS (ES⁺, Short acidic): 1 .27 min, m/z 331 .9 [M+H]⁺

[00311] 3-[4-[(2,6-Dimethylmorpholin-4-yl)methyllphenyll-1 -[(3f?)-3-piperidyllpyrazolo[3,4-c lpyrimidin- 4-amine

Following general procedure D, 2,6-dimethyl-4-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]morpholine (334.6 mg, 1 .01 mmol) and 3-iodo-1 -[(3R)-3-piperidyl]pyrazolo[3,4- c ]pyrimidin-4-amine (120.0 mg, 0.35 mmol), gave 3-[4-[(2,6-dimethylmorpholin-4-yl)methyl]phenyl]-1 - [(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine (147.0 mg, 0.35 mmol, 100% yield) as a pale brown solid. This mixture was used in the next reaction without further purification, assumed quantitative. UPLC-MS (ES⁺, Short acidic): 0.79 min, m/z 422.3 [M+H]⁺

[00312] 1 -[(3f?)-3-[4-Amino-3-[4-[(2,6-dimethylmorpholin-4-yl)methyllphenyllpyrazolo[3,4-c/lpyrimidin- 1 -yll-1 -piperidyllprop-2-en-1 -one

Following general procedure G, 3-[4-[(2,6-dimethylmorpholin-4-yl)methyl]phenyl]-1 -[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (147.0 mg, 0.35 mmol) afforded 1 -[(3R)-3-[4-amino-3-[4- [(2,6-dimethylmorpholin-4-yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one (27.7 mg, 0.058 mmol, 17% yield) as a pale yellow solid.

UPLC-MS (ES⁺, Short acidic): 1 .02 min, m/z 476.4 [M+H]⁺

H-NMR (400 MHz, DMSO-c/₆) δ (ppm) 8.27 (s, 1 H, ArH), 7.63 (d, ³J 7.8 Hz, 2H, ArH), 7.47 (d, ³J 7.8 Hz, 2H, ArH), 6.93-6.82 (m, 0.5H), 6.78-6.67 (m, 0.5H), 6.18-6.03 (m, 1 H), 5.75-5.68 (m, 0.5H), 5.63- 5.57 (m, 0.5H), 4.78-4.65 (m, 1 H), 4.60-4.52 (m, 0.5H), 4.27-4.16 (m, 1 H), 4.13-4.05 (m, 0.5H), 3.77- 3.65 (m, 0.5H), 3.65-3.55 (m, 2H), 3.56-3.48 (m, 2H), 3.26-3.14 (m, 1 H), 3.08-2.97 (m, 0.5H), 2.74 (d, ³ J 10.5 Hz, 2H), 2.33-2.20 (m, 1 H), 2.18-2.08 (m, 1 H), 2.02-1 .89 (m, 1 H), 1 .69 (t, ³J 10.5 Hz, 2H), 1 .64-1 .54 (m, 1 H), 1 .06-1 .02 (m, 6H).

[00313] Example 23: 1 -[(3R)-3-[4-Amino-3-[4-(8-oxa-3-azabicyclo[3.2.1]octan-3- ylmethyl)phenyl]pyrazolo[3,4-c |pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00314] 3-[[4-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyll-8-oxa-3- azabicyclo[3.2.1 loctane

To a stirred solution of 2-[4-(bromomethyl)phenyl]-4, 4,5, 5-tetramethyl-1 ,3,2-dioxaborolane (300.0 mg, 1 .01 mmol) and Λ/,/V-diisopropylethylamine (0.39 mL, 2.22 mmol) in THF (5.0 mL) under nitrogen was added 8-oxa-3-azabicyclo[3.2.1 ]octane hydrochloride (166.2 mg, 1 .1 1 mmol), and the reaction was stirred at room temperature for 4 d. The reaction mixture was concentrated under reduced pressure to give 3-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]-8-oxa-3-azabicyclo[3.2.1 ]octane (332.5 mg, 1 .01 mmol, 100% yield) as a mixture with Λ/,/V-diisopropylethylamine and unreacted amine. This mixture was used in the next reaction without further purification, assumed quantitative.

UPLC-MS (ES⁺, Short acidic): 1 .28 min, m/z 330.2 [M+H]⁺

[00315] 3-[4-(8-Oxa-3-azabicvclo[3.2.1 loctan-3-ylmethyl)phenyll-1 -[(3f?)-3-piperidyllpyrazolo[3,4- c lPyrimidin-4-amine

Following general procedure D, 3-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]-8- oxa-3-azabicyclo[3.2.1 ]octane (332.5 mg, 1 .01 mmol) and 3-iodo-1 -[(3R)-3-piperidyl]pyrazolo[3,4- c ]pyrimidin-4-amine (120.0 mg, 0.35 mmol), gave 3-[4-(8-oxa-3-azabicyclo[3.2.1 ]octan-3- ylmethyl)phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine (146.3 mg, 0.35 mmol, 100% yield) as a pale brown solid. This mixture was used in the next reaction without further purification, assumed quantitative.

UPLC-MS (ES⁺, Short acidic): 0.75 min, m/z 420.3 [M+H]⁺

[00316] 1 -[(3f?)-3-[4-Amino-3-[4-(8-oxa-3-azabicvclo[3.2.1 loctan-3-ylmethyl)phenyllpyrazolo[3,4- c lpyrimidin-1 -yll-1 -pipe ridyllprop-2-en-1 -one

Following general procedure G, 3-[4-(8-oxa-3-azabicyclo[3.2.1 ]octan-3-ylmethyl)phenyl]-1 -[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (146.3 mg, 0.35 mmol) afforded 1 -[(3R)-3-[4-amino-3-[4-(8- oxa-3-azabicyclo[3.2.1 ]octan-3-ylmethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 - one (30.7 mg, 0.065 mmol, 19% yield) as a pale green solid.

UPLC-MS (ES⁺, Short acidic): 0.95 min, m/z 474.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.1 1 min, m/z 474.4 [M+H]⁺

H-NMR (400 MHz, DMSO-c/₆) δ (ppm) 8.27 (s, 1 H, ArH), 7.63 (d, ³J 7.8 Hz, 2H, ArH), 7.47 (d, ³J 7.8 Hz, 2H, ArH), 6.93-6.82 (m, 0.5H), 6.77-6.66 (m, 0.5H), 6.18-6.03 (m, 1 H), 5.75-5.68 (m, 0.5H), 5.64- 5.55 (m, 0.5H), 4.78-4.64 (m, 1 H), 4.60-4.51 (m, 0.5H), 4.28-4.14 (m, 2.5H), 4.14-4.05 (m, 0.5H), 3.75- 3.65 (m, 0.5H), 3.56-3.49 (m, 2H), 3.26-3.15 (m, 1 H), 3.06-2.97 (m, 0.5H), 2.61 -2.53 (m, 2H), 2.33- 2.19 (m, 3H), 2.18-2.09 (m, 1 H), 2.02-1 .89 (m, 1 H), 1 .98-1 .88 (m, 2.5H), 1 .79-1 .70 (m, 2H), 1 .66-1 .53 (m, 1 H).

[00317] Example 24: 1 -[(3R)-3-[4-Amino-3-[4-(morpholinomethyl)phenyl]pyrazolo[3,4- cflpyrimidin-1 -yl]-1 -piperidyl]-2-chloro-ethanone

[00318] 3-[4-(Morpholinomethyl)phenyll-1 -[(3 ?)-3-piperidyllpyrazolo[3,4-c lpyrimidin-4-amine

To a stirred solution of 3-[4-(morpholinomethyl)phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4- amine (1 12.5 mg, 0.29 mmol) and Λ/,/V-diisopropylethylamine (60 pL, 0.34 mmol) in DCM (5 mL) was added chloroacetyl chloride (24 pL, 0.30 mmol). The reaction mixture was then stirred at room temperature overnight. Purification by flash chromatography (DCM/MeOH 95:5 to 80:20) gave 1 -[(3R)- 3-[4-amino-3-[4-(morpholinomethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]-2-chloro- ethanone (56.6 mg, 0.12 mmol, 42% yield) as a brown foam.

UPLC-MS (ES⁺, Short acidic) 0.95 min, m/z 470.3 [M+H]⁺

[00319] Example 25: 1 -[(3R)-3-[4-amino-3-[4-(2-oxa-5-azabicyclo[2.2.1]heptan-5- ylmethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one [00320] 3-[4-(2-Oxa-5-azabicyclo[2.2.11heptan-5-ylme^

c lPyrimidin-4-amine

Following general procedure D, 5-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]-2- oxa-5-azabicyclo[2.2.1 ]heptane hydrochloride (306.5 mg, 0.87 mmol) and 3-iodo-1 -[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (200.0 mg, 0.58 mmol), gave 3-[4-(2-oxa-5- azabicyclo[2.2.1 ]heptan-5-ylmethyl)phenyl]-1 -[(3R)-3^iperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine (76.0 mg, 0.19 mmol, 32% yield) as a brown foam.

UPLC-MS (ES⁺, Short acidic): 0.49 min, m/z 406.3 [M+H]⁺

[00321] 1 -[(3f?)-3-[4-Amino-3-[4-(2-oxa-5-azabicvclo[2.2.1 lheptan-5-ylmethyl)phenyllpyrazolo[3,4- c lpyrimidin-1 -yll-1 -pipe ridyllprop-2-en-1 -one

Following general procedure I, 3-[4-(2-oxa-5-azabicyclo[2.2.1 ]heptan-5-ylmethyl)phenyl]-1 -[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (76.0 mg, 0.19 mmol) afforded 1 -[(3R)-3-[4-amino-3-[4-(2- oxa-5-azabicyclo[2.2.1 ]heptan-5-ylmethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en- 1 -one (26.4 mg, 0.057 mmol, 31 % yield) as an off-white solid following preparative mass-directed reverse phase chromatography.

UPLC-MS (ES⁺, Short acidic): 0.92 min, m/z 460.3 [M+H]⁺

H NMR (400 MHz, CD₃OD) δ (ppm) 8.32-8.28 (m, 1 H, ArH), 8.15 (s, 0.24H, HC0₂H), 7.86-7.77 (m, 4H, ArH), 6.90-6.80 (m, 0.5H), 6.69-6.60 (m, 0.5H), 6.26-6.08 (m, 1 H), 5.82-5.75 (m, 0.5H), 5.65-5.59 (m, 0.5H), 4.98-4.90 (m, 0.5H), 4.75-4.70 (m, 1 H), 4.66-4.59 (m, 0.5H), 4.63-4.55 (m, 1 H), 4.49-4.42 (m, 1 H), 4.42-4.37 (m, 1 H), 4.32-4.26 (m, 1 H), 4.24-4.16 (m, 1 H), 4.16-4.09 (m, 0.5H), 3.97-3.89 (m, 0.5H), 3.88-3.82 (m, 1 H), 3.59-3.51 (m, 0.5H), 3.49-3.36 (m, 3.5H), 2.47-2.41 (m, 1 H), 2.44-2.31 (m, 1 H), 2.29-2.22 (m, 1 H), 2.22-2.17 (m, 1 H), 2.16-2.06 (m, 1 H), 1 .84-1 .78 (m, 1 H).

[00322] Example 26: 3-[4-(morpholinomethyl)phenyl]-1 -[(3R)-1 -vinylsulfonyl-3- piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine

[00323] 3-[4-(Morpholinomethyl)phenyll-1 -[(3 ?)-3-piperidyllpyrazolo[3,4-c lpyrimidin-4-amine

Following general procedure C, 3-iodo-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c/]pyrimidin-4-amine (1 .10 g, 3.20 mmol), 4-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholine hydrochloride (1 .68 g, 4.79 mmol) afforded 3-[4-(morpholinomethyl)phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4- c ]pyrimidin-4-amine (845.8 mg, 2.15 mmol, 67% yield) as a brown foam.

UPLC-MS (ES⁺, Short acidic): 0.28 min, m/z 394.3 [M+H]⁺

[00324] 3-[4-(Morpholinomethyl)phenyll-1 -[(3 ?)-1 -vinylsulfonyl-3-piperidyllpyrazolo[3,4-c/lpyrimidin-4- amine

To a solution of 3-[4-(morpholinomethyl)phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine (121 .8 mg, 0.31 mmol) and triethylamine (62.6 mg, 0.62 mmol) in DCM (4 mL), cooled to 0 °C under a nitrogen atmosphere, was added dropwise a 1 M solution of 2-chloroethanesulfonyl chloride (0.32 mL, 0.32 mmol) in DCM. The reaction mixture was allowed to return slowly to room temperature and stirred overnight. The reaction mixture was diluted with DCM (50mL), washed with a saturated aqueous solution of NaHC0₃ (25 mL), 1 M HCI (25 mL), and brine (25 mL). Purification by flash

chromatography (DCM/MeOH 95:5 to 80:20) gave 3-[4-(morpholinomethyl)phenyl]-1 -[(3f?)-1 - vinylsulfonyl-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine (8.8 mg, 0.02 mmol, 6% yield).

UPLC-MS (ES⁺, Short acidic) 1 .01 min, m/z 484.3 [M+H]⁺ H NMR (400 MHz, CD₃OD) δ (ppm) 8.27 (s, 1 H, ArH), 8.25-8.20 (bs, 1 H), 7.70 (d, J 8.2 Hz, 2H), 7.58 (d, J 8.2 Hz, 2H), 6.69 (dd, ³J_trans 16.5, ³J_CS 10.0 Hz, 1 H), 6.18 (d, ³J_trans 16.5 Hz, 1 H), 6.10 (d, ³J_trans 16.5 Hz, 1 H), 4.99-4.87 (m, 1 H), 3.90-3.84 (m, 1 H), 3.79 (s, 2H, CH₂), 3.78-3.68 (m, 5H), 3.38-3.20 (m, 1 H), 2.79 (dt, J 12.1 , 2.9 Hz, 1 H), 2.72-2.65 (m, 4H), 2.29-2.12 (m, 2H), 2.08-2.00 (m, 1 H), 1 .92- 1 .78 (m, 1 H).

[00325] Example 27: 1 -[(3R)-3-[4-Amino-3-[4-(3,4-dihydro-1H-isoquinolin-2- ylmethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00326] 2-[[4-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyll-3,4-dihydro-1 H- isoquinoline; hydro-bromide

Following general procedure A, 4-bromomethylphenylboronic acid pinacol ester (5.00 g, 16.8 mmol) and 1 ,2,3,4-tetrahydroisoquinoline (2.69 g, 20.2 mmol) gave crude 2-[[4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl]methyl]-3,4-dihydro-1 /-/-isoquinoline; hydrobromide (8.97 g, 16.8 mmol, 100% yield) as a yellow paste. This mixture was used in the next reaction without further purification, assumed quantitative.

UPLC-MS (ES⁺, Short acidic): 1 .48 min, m/z 350.3 [M+H]⁺

[00327] fe/f-Butyl (3f?)-3-[4-amino-3-[4-(3,4-dihvdro-1 H-isoquinolin-2-ylmethyl)phenyllpyrazolo[3,4- c lPyrimidin-1 -yllpiperidine-1 -carboxylate

Following general procedure C, fe/ -butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1 - yl)piperidine-1 -carboxylate (3.98 g, 8.95 mmol) and 2-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]-3,4-dihydro-1 /-/-isoquinoline; hydrobromide (7.75 g, 13.43 mmol) gave, after purification by flash column chromatography (DCM/MeOH 100:0 to 90:10), fe/ -butyl (3R)-3-[4-amino-

3-[4-(3,4-dihydro-1 H-isoquinolin-2-ylmethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 - carboxylate (4.96 g, 9.19 mmol, 103% yield).

UPLC-MS (ES⁺, Short acidic): 1 .34 min, m/z 540.5 [M+H]⁺

[00328] 3-[4-(3,4-Dihvdro-1 H-isoquinolin-2-ylmethyl)phenyll-1 -[(3f?)-3-piperidyllpyrazolo[3,4- c lPyrimidin-4-amine

Following general procedure F, fe/ -butyl (3R)-3-[4-amino-3-[4-(3,4-dihydro-1 /-/-isoquinolin-2- ylmethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (5.31 g, 8.37 mmol) gave, after purification by flash column chromatography (DCM/7N ammonia in MeOH 100:0 to 90:10) 3-[4-(3,4- dihydro-1 H-isoquinolin-2-ylmethyl)phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine (3.24 g, 7.37 mmol, 88% yield).

UPLC-MS (ES⁺, Short acidic): 0.89 min, m/z 440.4 [M+H]⁺

[00329] 1 -[(3f?)-3-[4-Amino-3-[4-(3,4-dihvdro-1 H-isoquinolin-2-ylmethyl)phenyllpyrazolo[3,4- c lpyrimidin-1 -yll-1 -pipe ridyllprop-2-en-1 -one

Following general procedure H, 3-[4-(3,4-dihydro-1 /-/-isoquinolin-2-ylmethyl)phenyl]-1 -[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (2.02 g, 4.60 mmol) gave, after further purification by flash column chromatography (DCM/MeOH 100:0 to 80:20), 1 -[(3f?)-3-[4-amino-3-[4-(3,4-dihydro-1 H- isoquinolin-2-ylmethyl)phenyl]pyrazolo[3,4-c/]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one (1 .60 g,

3.24 mmol, 70% yield) as an off-white foam/powder.

UPLC-MS (ES⁺, Short acidic): 1 .1 1 min, m/z 494.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.49 min, m/z 494.4 [M+H]⁺ [00330] Example 28: 1 -[(3R)-3-[4-Amino-3-[4-[(6-ethoxy-3,4-dihydro-1 H-isoquinolin-2- yl)methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00331] 6-Ethoxy-2-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyll-3,4-dihyd isoquinoline ethylbis(propan-2-vDamine hydrobromide

Following general procedure A, 6-ethoxy-1 ,2,3,4-tetrahydroisoquinoline (214.8 mg, 1 .01 mmol) afforded crude 6-ethoxy-2-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]-3,4-dihydro- 1 /-/-isoquinoline ethyl£>/s(propan-2-yl)amine hydrobromide (548.0 mg, 0.919 mmol, 91 % yield) as a cream powder.

UPLC-MS (ES⁺, Short acidic): 1 .50 min, m/z 394.1 [M+H]⁺

[00332] 3-[4-[(6-Ethoxy-3.4-dihvdro-1 H-isoquinolin-2-yl)methyllphenyll-1 -[(3f?)-3- piperidyllpyrazolo[3,4-cflpyrimidin-4-amine

Following general procedure D, 3-iodo-1 -[(3/?)-3-piperidyl]pyrazolo[3,4-c/]pyrimidin-4-amine (124.6 mg, 0.36 mmol) and 6-ethoxy-2-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]-3,4- dihydro-1 /-/-isoquinoline (213.6 mg, 0.54 mmol) gave, after purification by flash column

chromatography (EtOAc/MEOH 95:5 5 to 80:20) 3-[4-[(6-ethoxy-3,4-dihydro-1 H-isoquinolin-2- yl)methyl]phenyl]-1 -[(3/?)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine (123.2 mg, 0.25 mmol, 70% yield) as a brown solid.

UPLC-MS (ES⁺, Short acidic): 0.94 min, m/z 484.4 [M+H]⁺

[00333] 1 -[(3f?)-3-[4-Amino-3-[4-[(6-ethoxy-3,4-dihydro-1 H-isoquinolin-2- yl)methyllphenyllpyrazolo[3,4-c lpyrimidin-1 -yll-1 -piperidyllprop-2-en-1 -one

Following general procedure G, 3-[4-[(6-ethoxy-3,4-dihydro-1 /-/-isoquinolin-2-yl)methyl]phenyl]-1 -[(3/?)- 3-piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (123.3 mg, 0.25 mmol) gave, after purification by flash chromatography (EtOAc/MeOH 95:5 to 70:30), 1 -[(3f?)-3-[4-amino-3-[4-[(6-ethoxy-3,4-dihydro-1 H- isoquinolin-2-yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one (100.0 mg, 0.19 mmol, 73% yield) as a brown foam.

UPLC-MS (ES⁺, Short acidic): 1 .19 min, m/z 538.7 [M+H]⁺

H NMR (400 MHz, CDCI₃), δ (ppm): 9.46-8.82 (m, 2H), 8.32-8.23 (bs, 1 H, ArH), 7.66 (d, J 7.8 Hz, 2H, ArH), 7.60 (d, J 7.8 Hz, 2H, ArH), 6.92 (d, J 8.4 Hz, 1 H), 6.71 (dd, J 8.4, 2.6 Hz, 1 H), 6.66 (d, J 2.6 Hz, 1 H), 6.64-6.49 (m, 1 H), 6.41 (d, J 17.4 Hz, 2H), 6.35-6.23 (m, 1 H), 6.13 (dd, J 17.4, 10.4 Hz, 2H), 5.85 (d, J 10.4 Hz, 1 H), 5.76-5.61 (m, 1 H), 4.95-4.80 (m, 1 .5H), 4.66.4.54 (m, 0.5H), 4.25-4.12 (m,

0.5H), 4.07-3.98 (m, 0.5H), 4.00 (q, J 7.0 Hz, 2H), 3.89 (s, 2H), 3.80-3.66 (m, 0.5H), 3.75 (s, 2H), 3.46- 3.31 (m, 0.5H), 3.25-3.09 (m, 0.5H), 2.98-2.83 (m, 2.5H), 2.46-2.30 (m, 1 H), 2.29-2.21 (m, 1 H), 2.04- 1 .94 m, 1 H), 1 .81 -1 .64 (m, 1 H).

[00334] Example 29: 1 -[3-[4-Amino-3-[4-[(6,7-dimethoxy-3,4-dihydro-1 H-isoquinolin-2- yl)methyl]phenyl]pyrazolo[3,4-c |pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00335] 6,7-Dimethoxy-2-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyll-3,4-dihydro- 1 /-/-isoquinoline ethylbis(propan-2-yl)amine hydrobromide

Following general procedure A, 6, 7-dimethoxy-1 ,2,3,4-tetrahydroisoquinoline; hydrochloride (278.4 mg, 1 .01 mmol) afforded 6, 7-dimethoxy-2-[[4-(4, 4,5, 5-tetramethyl-1 ,3, 2-dioxaborolan-2- yl)phenyl]methyl]-3,4-dihydro-1 /-/-isoquinoline ethyl£>/s(propan-2-yl)amine hydrobromide (761 .7 mg, 1 .24 mmol, 123% yield) as a cream powder. UPLC-MS (ES⁺, Short acidic): 1 .40 min, m/z 410.3 [M+H]⁺

[00336] 3-[4-[(3-Methyl-3.4-dihvdro-1 H-isoquinolin-2-yl)methyllphenyll-1 -[(3R)-3- piperidyllpyrazolo[3,4-dlpyrimidin-4-amine

Following general procedure D, 3-iodo-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c/]pyrimidin-4-amine (124.7 mg, 0.36 mmol) and 6,7-dimethoxy-2-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]-3,4- dihydro-1 /-/-isoquinoline (222.5 mg, 0.54 mmol) gave 3-[4-[(6,7-dimethoxy-3,4-dihydro-1 /-/-isoquinolin-

2- yl)methyl]phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c/]pyrimidin-4-amine (270.3 mg, 0.54 mmol, 100% yield). This mixture was used in the next reaction without further purification, assumed quantitative. UPLC-MS (ES⁺, Short acidic): 0.87 min, m/z 500.3 [M+H]⁺

[00337] 1 -[(3f?)-3-[4-Amino-3-[4-[(3-methyl-3.4-dihvdro-1 H-isoquinolin-2- yl)methyllphenyllpyrazolo[3,4-c lpyrimidin-1 -yll-1 -piperidyllprop-2-en-1 -one

Following general procedure G, 3-[4-[(6,7-dimethoxy-3,4-dihydro-1 /-/-isoquinolin-2-yl)methyl]phenyl]-1 - [(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine (270.3 mg, 0.54 mmol) gave, after purification by flash column chromatography (EtOAc/MeOH 95:5 to 70:30), 1 -[(3f?)-3-[4-amino-3-[4-[(6,7-dimethoxy- 3,4-dihydro-1 H-isoquinolin-2-yl)methyl]phenyl]pyrazolo[3,^

one (98.7 mg, 0.18 mmol, 33% yield).

UPLC-MS (ES⁺, Short acidic): 1 .07 min, m/z 554.3 [M+H]⁺

[00338] Example 30: 1 -[3-[4-Amino-3-[4-[(3-methyl-3,4-dihydro-1 H-isoquinolin-2- yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00339] 3-Methyl-2-[[4-(4.4.5.5-tetramethyl-1 .3.2-dioxaborolan-2-yl)phenyllmethyll-3.4-dihvdro-1 H- isoquinoline ethylbis(propan-2-yl)amine hydrobromide

Following general procedure A, 3-methyl-1 ,2,3,4-tetrahydroisoquinoline (178.4 mg, 1 .01 mmol) afforded 3-methyl-2-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]-3,4-dihydro-1 /-/- isoquinoline ethyl£>/^'s(propan-2-yl)amine hydrobromide (582.8 mg, 1 .03 mmol, 101 .9% yield) as a white powder.

UPLC-MS (ES⁺, Short acidic): 1 .46 min, m/z 364.2 [M+H]⁺

[00340] 3-[4-[(3-Methyl-3.4-dihvdro-1 H-isoquinolin-2-yl)methyllphenyll-1 -[(3f?)-3- piperidyllpyrazolo[3,4-c/lpyrimidin-4-amine

Following general procedure D, 3-iodo-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c/]pyrimidin-4-amine (125.0 mg, 0.36 mmol) and 3-methyl-2-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]-3,4- dihydro-1 /-/-isoquinoline (197.9 mg, 0.54 mmol) gave, after concentration under reduced pressure, a dark residue which was taken up into DCM (30 mL) and washed with water (2 x 10 mL). The organic layer was then filtered over phase separator and concentrated under reduced pressure to give 3-[4- [(3-methyl-3,4-dihydro-1 H-isoquinolin-2-yl)methyl]phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4-(^pyrimidin- 4-amine (206.5 mg, 0.36 mmol, 100% yield). This mixture was used in the next reaction without further purification, assumed quantitative.

UPLC-MS (ES+, Short acidic): 0.91 min, m/z 454.3 [M+H]⁺

[00341] 1 -[(3f?)-3-[4-Amino-3-[4-[(3-methyl-3.4-dihvdro-1 H-isoquinolin-2- yl)methyllphenyllpyrazolo[3,4-c lpyrimidin-1 -yll-1 -pipe ridyllprop-2-en-1 -one

Following general procedure G, 3-[4-[(3-methyl-3,4-dihydro-1 /-/-isoquinolin-2-yl)methyl]phenyl]-1 -[(3R)-

3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (206.5 mg, 0.46 mmol) gave, after purification by flash column chromatography (EtOAc/MeOH 95:5 to 70:30), 1 -[(3f?)-3-[4-amino-3-[4-[(3-methyl-3,4-dihydro- 1 /-/-isoquinolin-2-yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

(100.9 mg, 0.19 mmol, 41 % yield).

UPLC-MS (ES⁺, Short acidic): 1 .14 min, m/z 508.3 [M+H]⁺

[00342] Example 31 : 1 -[(3R)-3-[4-Amino-3-[4-[(1 -methyl-3,4-dihydro-1 H-isoquinolin-2- yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00343] 1 -Methyl-2-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyll-3,4-dihydro-1 H- isoquinoline ethylbis(propan-2-yl)amine hydrobromide

Following general procedure A, 1 -methyl-1 ,2,3,4-tetrahydroisoquinoline (178.4 mg, 1 .01 mmol) afforded 1 -methyl-2-{[4-(tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl}-1 ,2,3,4- tetrahydroisoquinoline ethylJb/^'s(propan-2-yl)amine hydrobromide (548 mg, 1 .04 mmol, 95% yield) as a cream powder.

UPLC-MS (ES⁺, Short acidic): 1 .40 min, m/z 363.9 [M+H]⁺

[00344] 3444(1 -Methyl-3.4-dihvdro-1 H-isoquinolin-2-yl)methyllphenyll-14(3f?)-3- piperidyllpyrazolo[3,4-c/lpyrimidin-4-amine

Following general procedure D, 3-iodo-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c/]pyrimidin-4-amine (125.7 mg, 0.37 mmol) and 1 -methyl-2-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]-3,4- dihydro-1 /-/-isoquinoline (199.0 mg, 0.55 mmol) gave, after filtration over Celite^®, and concentration under reduced pressure, 3-[4-[(1 -methyl-3,4-dihydro-1 H-isoquinolin-2-yl)methyl]phenyl]-1 -[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (322.9 mg, 0.50 mmol, 136% yield) as a dark residue. This mixture was used in the next reaction without further purification, assumed quantitative.

UPLC-MS (ES⁺, Short acidic): 0.91 min, m/z 454.4 [M+H]⁺

[00345] 1 -[(3f?)-3-[4-Amino-3-[4-[(1 -methyl-3.4-dihvdro-1 H-isoquinolin-2- yl)methyllphenyllpyrazolo[3,4-c lpyrimidin-1 -yll-1 -piperidyllprop-2-en-1 -one

Following general procedure G, 3-[4-[(1 -methyl-3,4-dihydro-1 /-/-isoquinolin-2-yl)methyl]phenyl]-1 -[(3R)- 3-piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (322.9 mg, 0.71 mmol) gave, after purification by flash chromatography (DCM/MeOH 100:0 to 95:5) gave 1 -[(3f?)-3-[4-amino-3-[4-[(1 -methyl-3,4-dihydro-1 H- isoquinolin-2-yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one (63.2 mg, 0.12 mmol, 17% yield) as a brown gum.

UPLC-MS (ES⁺, Short acidic): 1 .13 min, m/z 508.4 [M+H]⁺

H NMR (400 MHz, CDCI₃), δ (ppm) 8.37 (s, 1 H, ArH), 7.64 (d, J 8.1 Hz, 2H, ArH), 7.57 (d, J 8.1 Hz, 2H, ArH), 7.18-7.03 (m, 4H, ArH), 6.67-6.50 (m, 1 H), 6.35-6.22 (m, 1 H), 5.78-5.58 (m, 3H), 4.95-4.81 (m, 1 H), 4.66-4.55 (m, 0.5H), 4.26-4.16 (m, 0.5H), 4.08-3.98 (m, 0.5H), 3.93 (q, J 6.7 Hz, 1 H), 3.89 (d, J 13.9 Hz, 1 H), 3.78 (d, J 13.9 Hz, 1 H), 3.44-3.35 (m, 0.5H), 3.24-3.06 (m, 1 .5H), 2.99-2.82 (m, 1 .5H), 2.80-2.66 (m, 2H), 2.47-2.20 (m, 2H), 2.05-1 .94 (m, 1 H), 1 .83-1 .65 (m, 2H), 1 .41 (d, J 6.7 Hz, 3H, CH₃).

[00346] Example 32: 1 -[(3R)-3-[3-[4-(3,4,4a,5,6,7,8,8a-Octahydro-1 H-isoquinolin-2- ylmethyl)phenyl]-4-amino-pyrazolo[3,4-c |pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00347] 2-[[4-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyll-3,4,4a,5,6,7,8,8a- octahydro-1 /-/-isoquinoline Following general procedure A, decahydroisoquinoline (168.8 mg, 1 .01 mmol) and 2-[4- (bromomethyl)phenyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (300.0 mg, 1 .01 mmol) afforded 2-[[4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]-3,4,4a,5,6,7,8,8a-octahydro-1 /-/- isoquinoline (496.0 mg, 1 .39 mmol, 138% yield) as a cream solid. This mixture was used in the next reaction without further purification.

UPLC-MS (ES⁺, Short acidic): 1 .46 min, m/z 356.0 [M+H]⁺

[00348] 3-[4-(3.4.4a.5.6.7.8.8a-Octahvdro-1 H-isoquinolin-2-ylmethyl)phenyll-1 -[(3f?)-3- piperidyllpyrazolo[3,4-c/lpyrimidin-4-amine

Following general procedure D, 2-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]- 3,4,4a, 5,6,7, 8, 8a-octahydro-1 H-isoquinoline (185.8 mg, 0.52 mmol) and of 3-iodo-1 -[(3f?)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (120.0 mg, 0.35 mmol) gave, after purification by flash column chromatography (DCM/MeOH (0.1 % NH₃ in MeOH) 100:0 to 0:100) 3-[4-(3,4,4a,5,6,7,8,8a- octahydro-1 H-isoquinolin-2-ylmethyl)phenyl]-1 -[(3R)-3^iperidyl]pyrazolo[3,4-(^pyrimidin-4-amine (96.4 mg, 0.19 mmol, 53% yield), as a brown solid.

UPLC-MS (ES⁺, Short acidic): 0.96 min, m/z 446.4 [M+H]⁺

[00349] 1 -[(3f?)-3-[3-[4-(3,4,4a,5,6,7,8,8a-Octahvdro-1 H-isoquinolin-2-ylmethyl)phenyll-4-amino- pyrazolo[3,4-c lpyrimidin-1 -yll-1 -piperidyllprop-2-en-1 -one

Following general procedure I, 3-[4-(3, 4,4a, 5, 6,7,8, 8a-octahydro-1 H-isoquinolin-2-ylmethyl)phenyl]-1 - [(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine (96.4 mg, 0.22 mmol) gave, after purification by preparative mass-directed reverse phase chromatography, 1 -[(3R)-3-[3-[4-(3,4,4a,5,6,7,8,8a- octahydro-1 H-isoquinolin-2-ylmethyl)phenyl]-4-amino-pyrazolo[3,4-(^pyrimidin-1 -yl]-1 -piperidyl]prop-2- en-1 -one (32.9 mg, 0.06 mmol, 29% yield) as a colourless gum.

UPLC-MS (ES⁺, Short acidic): 1 .15 min, m/z 500.4 [M+H]⁺

[00350] Example 33: 2-[[4-[4-amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- cflpyrimidin-3-yl]phenyl]methyl]-3,4-dihydro-1 H-isoquinoline-7-carbonitrile

[00351] 2-[[4-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyll-3,4-dihydro-1 H- isoquinoline-7-carbonitrile

Following general procedure A, 7-cyano-1 ,2,3,4-tetrahydroisoquinoline (191 .7 mg, 1 .01 mmol) and 2- [4-(bromomethyl)phenyl]-4, 4, 5, 5-tetramethyl-1 ,3,2-dioxaborolane (300.0 mg, 1 .01 mmol) afforded crude 2-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]-3,4-dihydro-1 /-/-isoquinoline-7- carbonitrile (571 .8 mg, 1 .53 mmol, 151 % yield) as an orange solid. This mixture was used in the next reaction without further purification.

UPLC-MS (ES⁺, Short acidic): 1 .40 min, m/z 375.1 [M+H]⁺

[00352] 2-[[4-[4-Amino-1 -[(3f?)-3-piperidyllpyrazolo[3,4-c lpyrimidin-3-yllphenyllmethyll-3,4-dihvdro- 1 /-/-isoquinoline-7-carbonitrile

Following general procedure D, 2-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]-3,4- dihydro-1 /-/-isoquinoline-7-carbonitrile (195.8 mg, 0.52 mmol) and 3-iodo-1 -[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (120.0 mg, 0.35 mmol) gave, after purification by flash column chromatography (DCM/MeOH 100:0 to 90:10), 2-[[4-[4-amino-1 -[(3f?)-3-piperidyl]pyrazolo[3,4- c ]pyrimidin-3-yl]phenyl]methyl]-3,4-dihydro-1 /-/-isoquinoline-7-carbonitrile (121 .3 mg, 0.26 mmol, 73% yield) as a brown solid. UPLC-MS (ES⁺, Short acidic): 0.84 min, m/z 465.4 [M+H]⁺

[00353] 2-[[4-[4-Amino-1 -[(3 ?)-1 -prop-2-enoyl-3-piperidvnpyrazolo[3,4-c lpyrimidin-3

yllphenyllmethyll-3,4-dihydro-1 /-/-isoquinoline-7-carbonitrile

Following general procedure G, 2-[[4-[4-amino-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c/]pyrimidin-3- yl]phenyl]methyl]-3,4-dihydro-1 /-/-isoquinoline-7-carbonitrile (121 .3 mg, 0.26 mmol) gave, after purification by flash column chromatography (DCM/MeOH (0.1 % 7N NH₃ in MeOH) 100:0 to 90:10), 2- [[4-[4-amino-1 -[(3R)-1 ^rop-2-enoyl-3^iperidyl]pyrazolo[3,4-c ]pyrimidin-3-yl]phenyl]methyl]-3,4- dihydro-1 /-/-isoquinoline-7-carbonitrile (52.5 mg, 0.10 mmol, 37% yield) as a yellow solid.

UPLC-MS (ES⁺, Short acidic): 1 .10 min, m/z 519.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.47 min, m/z 519.5 [M+H]⁺

[00354] Example 34: 1 -[(3R)-3-[4-Amino-3-[4-[[6-(trifluoromethyl)-3,4-dihydro-1 H-isoquinolin-2- yl]methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00355] /V-Ethyl-/V-isopropyl-propan-2-amine; 2-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyllmethyll-6-(trifluoromethyl)-3,4-dihvdro-1 /-/-isoquinoline: hydrobromide

Following general procedure A, 4-bromomethylphenylboronic acid pinacol ester (303.5 mg,

1 .02 mmol) and 6-(trifluoromethyl)-1 ,2,3,4-tetrahydroisoquinoline (246.7 mg, 1 .23 mmol) afforded crude /V-ethyl-/V-isopropyl-propan-2-amine; 2-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]-6-(trifluoromethyl)-3,4-dihydro-1 /-/-isoquinoline; hydrobromide (550.0 mg, 0.88 mmol, 86% yield) as a cream solid. This mixture was used in the next reaction without further purification. UPLC-MS (ES⁺, Short acidic): 1 .56 min, m/z 418.4 [M+H]⁺

[00356] fe/f-Butyl (3f?)-3-[4-amino-3-[4-[[6-(trifluoromethyl)-3,4-dihydro-1 H-isoquinolin-2- yllmethyllphenyllpyrazolo[3,4-c lpyrimidin-1 -yllpiperidine-1 -carboxylate

Following general procedure D, /V-ethyl-/V-isopropyl-propan-2-amine; 2-[[4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl]methyl]-6-(trifluoromethyl)-3,4-dihydro-1 /-/-isoquinoline; hydrobromide (339.0 mg, 0.54 mmol) and fe/ -butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-c ]pyrimidin-1 -yl)piperidine- 1 -carboxylate (200.0 mg, 0.45 mmol) afforded, after purification by SCX cartridge, fe/ -butyl (3R)-3-[4- amino-3-[4-[[6-(trifluoromethyl)-3,4-dihydro-1 H-iso

1 -yl]piperidine-1 -carboxylate (186.0 mg, 0.31 mmol, 68% yield) as a crystalline off-white solid.

UPLC-MS (ES⁺, Short acidic): 1 .49 min, m/z 608.5 [M+H]⁺

[00357] 1 -(3-Piperidyl)-3-[4-[[6-(trifluoromethyl)-3,4-dihydro-1 H-isoquinolin-2- yllmethyllphenyllpyrazolo[3,4-c lpyrimidin-4-amine

Following general procedure E, fe/ -butyl 3-[4-amino-3-[4-[[6-(trifluoromethyl)-3,4-dihydro-1 /-/- isoquinolin-2-yl]methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (186.0 mg, 0.31 mmol) gave 1 -(3-piperidyl)-3-[4-[[6-(trifluoromethyl)-3,4-dihydro-1 /-/-isoquinolin-2- yl]methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-4-amine (121 .0 mg, 0.24 mmol, 78% yield).

UPLC-MS (ES⁺, Short acidic): 1 .06 min, m/z 508.4 [M+H]⁺

[00358] 1 -[(3f?)-3-[4-Amino-3-[4-[[6-(trifluoromethyl)-3,4-dihydro-1 H-isoquinolin-2- yllmethyllphenyllpyrazolo[3,4-c lpyrimidin-1 -yll-1 -piperidyllprop-2-en-1 -one

Following general procedure I, 1 -[(3R)-3-piperidyl]-3-[4-[[6-(trifluoromethyl)-3,4-dihydro-1 /-/-isoquinolin- 2-yl]methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-4-amine (120.6 mg, 0.24 mmol) gave, after purification by SCX cartridge, 1 -[(3f?)-3-[4-amino-3-[4-[[6-(trifluoromethyl)-3,4-dihydro-1 H-isoquinolin-2- yl]methyl]phenyl]pyrazolo[3,4-<^pyri (88.0 mg, 0.15 mmol, 65% yield) as a crystalline white solid.

UPLC-MS (ES⁺, Short acidic): 1 .26 min, m/z 562.5 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.79 min, m/z 562.5 [M+H]⁺

[00359] Example 35: 1 -[(3R)-3-[4-Amino-3-[4-[[8-(trifluoromethyl)-3,4-dihydro-1 H-isoquinolin-2- yl]methyl]phenyl]pyrazolo[3,4-c |pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00360] /V-Ethyl-/V-isopropyl-propan-2-amine: 2-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyllmethyll-8-(trifluoromethyl)-3,4-dihydro-1 /-/-isoquinoline: hydrobromide

Following general procedure A, 4-bromomethylphenylboronic acid pinacol ester (209.0 mg,

0.70 mmol) and 8-(trifluoromethyl)-1 ,2,3,4-tetrahydroisoquinoline (1 18.mg, 0.59 mmol) afforded N- ethyl-N-isopropyl-propan-2-amine; 2-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]-8- (trifluoromethyl)-3,4-dihydro-1 /-/-isoquinoline; hydrobromide (363.0 mg,0.58 mmol, 99% yield) as a cream solid.

UPLC-MS (ES⁺, Short acidic): 1 .57 min, m/z 418.4 [M+H]⁺

[00361] fe/f-Butyl (3f?)-3-[4-amino-3-[4-[[8-(trifluoromethyl)-3,4-dihydro-1 H-isoquinolin-2- yllmethyllphenyllpyrazolo[3,4-c lpyrimidin-1 -yllpiperidine-1 -carboxylate

Following general procedure D, /V-ethyl-/V-isopropyl-propan-2-amine; 2-[[4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl]methyl]-8-(trifluoromethyl)-3,4-dihydro-1 /-/-isoquinoline; hydrobromide (67.8 mg, 0.1 1 mmol) and fe/ -butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-c ]pyrimidin-1 -yl)piperidine-1 - carboxylate (40.0 mg, 0.09 mmol) gave, after purification by flash column chromatography (DCM/10% 1 M NH₃ in MeOH 100:0 to 0:100) ferf-butyl (3f?)-3-[4-amino-3-[4-[[8-(trifluoromethyl)-3,4-dihydro-1 H- isoquinolin-2-yl]methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (55.0 mg, 0.09 mmol, 100% yield) as a cream solid.

UPLC-MS (ES⁺, Short acidic): 1 .51 min, m/z 608.5 [M+H]⁺

[00362] 1 -(3-Piperidyl)-3-[4-[[8-(trifluoromethyl)-3,4-dihvdro-1 H-isoquinolin-2- yllmethyllphenyllpyrazolo[3,4-c lpyrimidin-4-amine

Following general procedure E, fe/ -butyl 3-[4-amino-3-[4-[[8-(trifluoromethyl)-3,4-dihydro-1 /-/- isoquinolin-2-yl]methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (56.0 mg, 0.09 mmol) gave 1 -(3-piperidyl)-3-[4-[[8-(trifluoromethyl)-3,4-dihydro-1 /-/-isoquinolin-2- yl]methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-4-amine (50.0 mg, 0.099 mmol, 100% yield). This mixture was used in the next reaction without further purification, assumed quantitative.

UPLC-MS (ES⁺, Short acidic): 1 .01 min, m/z 508.4 [M+H]⁺

[00363] 1 -[(3f?)-3-[4-Amino-3-[4-[[8-(trifluoromethyl)-3,4-dihydro-1 H-isoquinolin-2- yllmethyllphenyllpyrazolo[3,4-c lpyrimidin-1 -yll-1 -piperidyllprop-2-en-1 -one

Following general procedure I, 1 -[(3R)-3-piperidyl]-3-[4-[[8-(trifluoromethyl)-3,4-dihydro-1 /-/-isoquinolin- 2-yl]methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-4-amine (0.02 mL, 0.04 mmol) gave after purification by preparative mass-directed reverse phase chromatography, followed by salt removal by SCX cartridge, 1 -[(3f?)-3-[4-amino-3-[4-[[8-(trifluoromethyl)-3,4-dihydro-1 H-isoquinolin-2- yl]methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one (1 1 .7 mg, 0.02 mmol, 59% yield).

UPLC-MS (ES⁺, Short acidic): 1 .21 min, m/z 562.4 [M+H]⁺ UPLC-MS (ES⁺, Long acidic): 2.77 min, m/z 562.4 [M+H]⁺

[00364] Example 36: 1 -[(3R)-3-[4-Amino-3-[4-[(6-methoxy-3,4-dihydro-1 H-isoquinolin-2- yl)methyl]phenyl]pyrazolo[3,4-c |pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00365] 6-Methoxy-2-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenvnmethyll-3,4-dihydro-1 H- isoquinoline

Following general procedure A, 2-[4-(bromomethyl)phenyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (300.0 mg, 1 .01 mmol) and /V-[(4-methoxy-2-methyl-phenyl)methyl]ethanamine hydrochloride (261 .5 mg, 1 .21 mmol) gave, after purification by column chromatography (DCM:MeOH 100:0 to 80:20 with 0.1 % NH₃) 6-methoxy-2-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]-3,4-dihydro- 1 /-/-isoquinoline (540.4 mg, 0.54 mmol, 54% yield) as a yellow solid.

UPLC-MS (ES⁺, Short acidic): 1 .45 min, m/z 380.4 [M+H]⁺

[00366] fe/f-Butyl (3f?)-3-[4-amino-3-[4-[(6-methoxy-3,4-dihydro-1 H-isoquinolin-2- yl)methyllphenyllpyrazolo[3,4-c lpyrimidin-1 -yllpiperidine-1 -carboxylate

Following general procedure D, 6-methoxy-2-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]-3,4-dihydro-1 /-/-isoquinoline (256.1 mg, 0.68 mmol) and fe/f-butyl (3R)-3-(4-amino-3- iodo-pyrazolo[3,4-c ]pyrimidin-1 -yl)piperidine-1 -carboxylate (200.0 mg, 0.45 mmol) gave, after purification by flash column chromatography (DCM/MeOH 100:0 to 80:20), fe/f-butyl (3f?)-3-[4-amino- 3-[4-[(6-methoxy-3,4-dihydro-1 H-isoquinolin-2-yl)methyl]phenyl]pyrazolo[3,4-c/]pyrimidin-1 - yl]piperidine-1 -carboxylate (210.5 mg, 0.28 mmol, 62% yield) as a brown solid.

UPLC-MS (ES⁺, Short acidic): 1 .39 min, m/z 570.5 [M+H]⁺

[00367] 3-[4-[(6-Methoxy-3,4-dihvdro-1 H-isoquinolin-2-yl)methyllphenyll-1 -[(3f?)-3- piperidyllpyrazolo[3,4-c/lpyrimidin-4-amine

Following general procedure F, fe/f-butyl (3R)-3-[4-amino-3-[4-[(6-methoxy-3,4-dihydro-1 /-/-isoquinolin- 2-yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (210.5 mg, 0.37 mmol) gave, after purification by flash column chromatography (DCM/7N NH₃ in MeOH 100:0 to 90:10), 3-[4-[(6- methoxy-3,4-dihydro-1 H-isoquinolin-2-yl)methyl]phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4-(^pyrimidin-4- amine (83.0 mg, 0.16 mmol, 43% yield) as a light brown solid.

UPLC-MS (ES⁺, Short acidic): 0.93 min, m/z 470.4 [M+H]⁺

[00368] 1 -[(3f?)-3-[4-Amino-3-[4-[(6-methoxy-3,4-dihydro-1 H-isoquinolin-2- yl)methyllphenyllpyrazolo[3,4-c lpyrimidin-1 -yll-1 -piperidyllprop-2-en-1 -one

Following general procedure I, 3-[4-[(6-methoxy-3,4-dihydro-1 /-/-isoquinolin-2-yl)methyl]phenyl]-1 - [(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine (83.0 mg, 0.18 mmol), after purification by preparative mass-directed reverse phase chromatography, gave 1 -[(3R)-3-[4-amino-3-[4-[(6-methoxy- 3,4-dihydro-1 H-isoquinolin-2-yl)methyl]phenyl]pyrazolo[3,4-(^pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 - one (5.4 mg, 0.01 mmol, 5% yield) as a pale yellow solid.

UPLC-MS (ES⁺, Short acidic): 1 .16 min, m/z 524.5 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.54 min, m/z 524.5 [M+H]⁺

[00369] Example 37: 3-[4-(3,4-Dihydro-1 H-isoquinolin-2-ylmethyl)phenyl]-1 -[(3R)-1 - vinylsulfonyl-3-piperidyl]pyrazolo[3,4-c |pyrimidin-4-amine

To a solution of 3-[4-(3,4-dihydro-1 /-/-isoquinolin-2-ylmethyl)phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4- c ]pyrimidin-4-amine (50.0 mg, 0.1 1 mmol) and triethylamine (0.05 mL, 0.38 mmol) in DCM (1 mL) was added 2-chloroethanesulfonyl chloride (0.02 mL, 0.15 mmol). The reaction was stirred at room temperature overnight, diluted with DCM (5 mL), washed with water, dried (Na₂S0₄) and concentrated to give a brown solid. Further purification by preparative mass-directed reverse phase chromatography gave 3-[4-(3,4-dihydro-1 /-/-isoquinolin-2-ylmethyl)phenyl]-1 -[(3R)-1 -vinylsulfonyl-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (6.0 mg, 0.010 mmol, 9% yield)

UPLC-MS (ES⁺, Short acidic): 1 .19 min, m/z 530.2 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.68 min, m/z 530.3 [M+H]⁺

[00370] Example 38: (3R)-3-[4-Amino-3-[4-(3,4-dihydro-1 H-isoquinolin-2- ylmethyl)phenyl]pyrazolo[3,4-c |pyrimidin-1 -yl]piperidine-1 -carbonitrile

To a solution of 3-[4-(3,4-dihydro-1 /-/-isoquinolin-2-ylmethyl)phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4- c ]pyrimidin-4-amine (87.9 mg, 0.20 mmol) in DCM (3 mL) was added cyanogen bromide (20.0 μί, 0.40 mmol), followed by triethylamine (60.0 μί, 0.40 mmol). After 45 minutes stirring at room temperature, further cyanogen bromide (1 1 .0 μί, 0.21 mmol) was added, followed by triethylamine (60.0 μί, 0.40 mmol). After 15 minutes, the reaction mixture was quenched with a saturated aqueous solution of NaHC0₃ and then diluted with DCM (5 mL). The reaction mixture was filtered through a hydrophobic frit, and the filtrate concentrated under reduced pressure. Purification by preparative mass-directed reverse phase chromatography, followed by salt removal by SCX column, yielded (3R)- 3-[4-amino-3-[4-(3,4-dihydro-1 H-isoquinolin-2-ylmethyl)phenyl]pyrazolo[3,4-(^pyrimidin-1 -yl]piperidine- 1 -carbonitrile (20.0 mg, 0.04 mmol, 22% yield).

UPLC-MS (ES⁺, Long acidic): 2.45 min, m/z 465.3 [M+H]⁺

UPLC-MS (ES⁺, Short acidic): 1 .1 1 min, m/z 465.2 [M+H]⁺

[00371] Example 39: 3-[4-(3,4-Dihydro-1 H-isoquinolin-2-ylmethyl)phenyl]-1 -[(3R)-1 -[[(2R)- oxiran-2-yl]methyl]-3-piperidyl]pyrazolo[3,4-c |pyrimidin-4-amine

To a solution of 3-[4-(3,4-dihydro-1 /-/-isoquinolin-2-ylmethyl)phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4- c ]pyrimidin-4-amine (50.0 mg, 0.1 1 mmol) and (S)-glycidyl nosylate (32.4 mg, 0.13 mmol) in DMF (0.50 mL) was added Λ/,/V-diisopropylethylamine (0.02 mL, 0.13 mmol). The reaction mixture was heated to 60 °C under nitrogen for 2 h, and then allowed to cool. The mixture was taken up in dilute sodium bicarbonate solution (20 mL) and extracted with EtOAc (x3). The combined organic extracts were concentrated under reduced pressure and the residue purified by column chromatography (1 -5% 7N NH₃ in MeOH/EtOAc) to give 3-[4-(3,4-dihydro-1 H-isoquinolin-2-ylmethyl)phenyl]-1 -[(3f?)-1 -[[(2f?)- oxiran-2-yl]methyl]-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine (35.0 mg, 0.07 mmol, 62% yield). UPLC-MS (ES⁺, Short acidic): 0.90 min, m/z 496.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 1 .92 min, m/z 496.3 [M+H]⁺

[00372] Example 40: 1 -[(3R)-3-[4-Amino-3-[4-(2,3-dihydropyrido[3,2-ft][1 ,4]oxazin-4- ylmethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00373] /V-Ethyl-/V-isopropyl-propan-2-amine; 4-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyllmethyll-2,3-dihydropyrido[3,2-)bl[1 ,41oxazine: hvdrobromide

Following general procedure A, 4-bromomethylphenylboronic acid pinacol ester (1 .00 g, 3.37 mmol) and 3,4-dihydro-2/-/-pyrido[3,2-Jb][1 ,4]oxazine (0.52 mL, 4.04 mmol) gave /V-ethyl-/V-isopropyl-propan- 2-amine; 4-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]-2,3-dihydropyrido[3,2- Jb][1 ,4]oxazine; hydrobromide (1 .82 g, 3.24 mmol, 96% yield). UPLC-MS (ES⁺, Short acidic): 1 .33 min, m/z 353.4 [M+H]⁺

[00374] ferf-Butyl (3ffl-3-[4-amino-3-[4-(2.3-dihvdropyrido[3.2-)bl[1 .41oxazin-4- ylmethyl)phenvnpyrazolo[3,4-(^pyrimidin-1 -yllPiperidine-1 -carboxylate

Following general procedure C, fe/ -butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-c/]pyrimidin-1 - yl)piperidine-1 -carboxylate (3.40 g, 7.65 mmol) and /V-ethyl-/V-isopropyl-propan-2-amine; 4-[[4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]-2,3-dihydropyrido[3,2-Jb][1 ,4]oxazine (5.52 g, 1 1 .47 mmol) gave, after purification by flash column chromatography (DCM/MeOH 100:0 to 90:10 then to 0:100 DCM/10% NH₃ in MeOH), ferf-butyl (3f?)-3-[4-amino-3-[4-(2,3-dihydropyrido[3,2- £>][1 ,4]oxazin-4-ylmethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (4.83 g, 7.57 mmol, 99% yield).

UPLC-MS (ES⁺, Short acidic): 1 .31 min, m/z 543.5 [M+H]⁺

[00375] 3-[4-(2,3-Dihydropyrido[3,2-)bl[1 ,4loxazin-4-ylmethyl)phenyll-1 -[(3f?)-3-piperidyllpyrazolo[3,4- c lPyrimidin-4-amine

Following general procedure F, fe/ -butyl (3R)-3-[4-amino-3-[4-(2,3-dihydropyrido[3,2-£>][1 ,4]oxazin-4- ylmethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (4.83 g, 8.91 mmol) gave, after purification by flash column chromatography (DCM/7N ammonia in MeOH 100:0 to 90:10), 3-[4-(2,3- dihydropyrido[3,2-Jb][1 ,4]oxazin-4-ylmethyl)phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine (2.30 g, 5.18 mmol, 58% yield).

UPLC-MS (ES⁺, Short acidic): 0.83 min, m/z 443.3 [M+H]⁺

[00376] 1 -[(3f?)-3-[4-Amino-3-[4-(2,3-dihydropyrido[3,2-)bl[1 ,4loxazin-4-ylmethyl)phenyllpyrazolo[3,4- c lpyrimidin-1 -yll-1 -pipe ridyllprop-2-en-1 -one

Following general procedure H, 3-[4-(2,3-dihydropyrido[3,2-£>][1 ,4]oxazin-4-ylmethyl)phenyl]-1 -[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (1 .32 g, 2.98 mmol) afforded, after purification by flash column chromatography (DCM/MeOH 100:0 to 80:20 then 80:20:5% 7N ammonia in MeOH) 1 -[(3f?)-3- [4-amino-3-[4-(2,3-dihydropyrido[3,2-Jb][1 ,4]oxazin-4-ylmethyl)phenyl]pyrazolo[3,4-c/]pyrimidin-1 -yl]-1 - piperidyl]prop-2-en-1 -one (795.2 mg, 1 .60 mmol, 54% yield) as a as a pale yellow foam.

UPLC-MS (ES⁺, Short acidic): 1 .08 min, m/z 497.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.36 min, m/z 497.4 [M+H]⁺

[00377] Example 41 : 1 -[3-[4-Amino-3-[4-[(1 ,1 -dioxo-1 ,4-thiazinan-4- yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00378] /V-Ethyl-/V-isopropyl-propan-2-amine; 4-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyllmethyll-2,3-dihydropyrido[3,2-)bl[1 ,41oxazine: hydrobromide

Following general procedure A, 4-bromomethylphenylboronic acid pinacol ester (1 .00 g, 3.37 mmol) and 3,4-dihydro-2/-/-pyrido[3,2-Jb][1 ,4]oxazine (0.52 mL, 4.04 mmol) gave /V-ethyl-/V-isopropyl-propan- 2-amine; 4-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]-2,3-dihydropyrido[3,2- Jb][1 ,4]oxazine; hydrobromide (1 .82 g, 3.24 mmol, 96% yield).

UPLC-MS (ES⁺, Short acidic): 1 .33 min, m/z 353.4 [M+H]⁺

[00379] fe/f-Butyl (3f?)-3-[4-amino-3-[4-(2,3-dihydro-1 ,4-benzoxazin-4-ylmethyl)phenyllpyrazolo[3,4- c lPyrimidin-1 -yllpiperidine-1 -carboxylate

Following general procedure C, fe/ -butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-c/]pyrimidin-1 - yl)piperidine-1 -carboxylate (1 .59 g, 3.59 mmol), 4-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]-2,3-dihydro-1 ,4-benzoxazine (2.59 g, 5.38 mmol) gave, after purification by flash column chromatography (DCM/MeOH 100:0 to 95:5), te/ -butyl (3f?)-3-[4-amino-3-[4-(2,3-dihydro-1 ,4- benzoxazin-4-ylmethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (2.35 g,

3.47 mmol, 97% yield) as a brown foam.

UPLC-MS (ES⁺, Short acidic): 1 .86 min, m/z 542.5 [M+H]⁺

[00380] 3-[4-(2,3-Dihvdro-1 ,4-benzoxazin-4-ylmethyl)phenyll-1 -[(3f?)-3-piperidyllpyrazolo[3,4- c lPyrimidin-4-amine

Following general procedure F, fe/ -butyl (3R)-3-[4-amino-3-[4-(2,3-dihydro-1 ,4-benzoxazin-4- ylmethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (2.35 g, 4.34 mmol) gave, after purification by flash column chromatography (DCM/ 7N NH₃ in MeOH 100:0 to 90:10), 3-[4-(2,3- dihydro-1 ,4-benzoxazin-4-ylmethyl)phenyl]-1 -[(3R)-3^iperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine (1 .41 g, 2.87 mmol, 66% yield).

UPLC-MS (ES⁺, Short acidic): 1 .27 min, m/z 442.3 [M+H]⁺

[00381] 1 -[(3f?)-3-[4-Amino-3-[4-(2,3-dihvdro-1 ,4-benzoxazin-4-ylmethyl)phenyllpyrazolo[3,4- c lpyrimidin-1 -yll-1 -pipe ridyllprop-2-en-1 -one

Following general procedure H, 3-[4-(3,4-dihydro-2/-/-quinolin-1 -ylmethyl)phenyl]-1 -[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (1 .31 g, 2.97 mmol) gave, after purification by flash column chromatography (DCM/MeOH 100:0 to 80:20), 1 -[(3f?)-3-[4-amino-3-[4-(2,3-dihydro-1 ,4-benzoxazin-4- ylmethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one (1 .22 g, 2.46 mmol, 77% yield).

UPLC-MS (ES⁺, Short acidic): 1 .63 min, m/z 496.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.72 min, m/z 496.4 [M+H]⁺

H NMR (400 MHz, DMSO-d₆₎, δ (ppm) 8.26 (s, 1 H, ArH), 7.64 (d, J 8.1 Hz, 2H, ArH), 7.47 (d, J 8.1 Hz, 2H, ArH), 6.92-6.63 (m, 3H), 6.59-6.49 (m, 1 H), 6.18-6.00 (m, 1 H), 5.74-5.53 (m, 1 H), 4.80-4.63 (m, 1 H), 4.60-4.48 (m, 0.5H), 4.55 (s, 2H), 4.24 (t, J 4.4 Hz, 2H), 4.23-4.14 (m, 1 H), 4.12-4.03 (m,

0.5H), 3.75-3.64 (m, 0.5H), 3.43 (t, J 4.4 Hz, 2H), 3.28-3.12 (m, 1 H), 2.35-2.18 (m, 1 H), 2.17-2.04 (m, 1 H), 1 .98-1 .85 (m, 1 H), 1 .66-1 .48 (m, 1 H).

[00382] Example 42: 1 -[3-[4-Amino-3-[4-(3,4-dihydro-2H-quinolin-1 - ylmethyl)phenyl]pyrazolo[3,4-c |pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00383] 3444(1 -Methyl-3.4-dihvdro-1 H-isoquinolin-2-yl)methyllphenyll-14(3f?)-3- piperidyllpyrazolo[3,4-c/lpyrimidin-4-amine

Following general procedure D, 3-iodo-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c/]pyrimidin-4-amine (124.7 mg, 0.36 mmol) and 1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]-3,4-dihydro-2H- quinoline (189.8 mg, 0.54 mmol) was heated at 140 °C for 90 min. The reaction mixture was then concentrated to dryness. The residue was taken up into DCM (30 mL) and washed with water (2 x 10 mL). The organic layer was then filtered over phase separator and concentrated under reduced pressure to give 3-[4-(3,4-dihydro-2/-/-quinolin-1 -ylmethyl)phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4- c ]pyrimidin-4-amine (238.0 mg, 0.35 mmol, 97% yield). This mixture was used in the next reaction without further purification.

UPLC-MS (ES⁺, Short acidic): 1 .39 min, m/z 440.3 [M+H]⁺ [00384] 1 -ff3ffl-3-f4-Amino-3-f4 n-methYl-3.4-dihvdro-1 H-isoQuinolin-2- yl)methyllphenyllpyrazolo[3,4-(^pyrimidin-1 -yll-1 -piperidyllprop-^^

Following general procedure G, acrylic acid (55.7 μΙ_, 0.81 mmol) and 3-[4-(3,4-dihydro-2/-/-quinolin-1 - ylmethyl)phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine (238.0 mg, 0.54 mmol) gave 1 - [(3R)-3-[4-amino-3-[4-(3,4-dihydro-2H-quinolin-1 -ylmethy^

piperidyl]prop-2-en-1 -one (34.6 mg, 0.07 mmol, 13% yield) as an off-white foam after purification by preparative mass-directed reverse phase chromatography.

UPLC-MS (ES⁺, Short acidic): 1 .74 min, m/z 494.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 4.05 min, m/z 494.4 [M+H]⁺

H NMR (400 MHz, CDCI₃), δ (ppm) 8.38 (s, 1 H, ArH), 7.64 (d, J 8.2 Hz, 2H, ArH), 7.45 (d, J 8.2 Hz, 2H, ArH), 7.04-6.94 (m, 2H, ArH), 6.69-6.50 (m, 1 H), 6.61 (d, J 7.2 Hz, 1 H, ArH), 6.50 (d, J 7.2 Hz, 1 H, ArH), 6.36-6.22 (m, 1 H), 5.76-5.61 (m, 1 H), 5.59-5.44 (bs, 2H), 4.95-4.80 (m, 1 H), 4.66-4.55 (m, 0.5H), 4.55 (s, 2H), 4.25-4.14 (m, 0.5H), 4.09-3.97 (m, 0.5H), 3.82-3.70 (m, 0.5H), 3.42 (t, J 6.0 Hz, 2H), 3.42-3.33 (m, 0.5H), 3.25-3.12 (m, 0.5H), 2.95-2.85 (m, 0.5H), 2.85 (t, J 6.0 Hz, 2H), 2.47-2.19 (m, 2H), 2.06 (p, J 6.0 Hz, 2H), 2.03-1 .94 (m, 1 H), 1 .82-1 .61 (m, 2H).

[00385] Example 43: 1 -[(3R)-3-[4-Amino-3-[4-(3,4-dihydro-2H-quinolin-1 - ylmethyl)phenyl]pyrazolo[3,4-c |pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00386] fe/f-Butyl (3f?)-3-[4-amino-3-[4-(3,4-dihvdro-2H-quinolin-1 -ylmethyl)phenyllpyrazolo[3,4- c lPyrimidin-1 -yllpiperidine-1 -carboxylate

Following general procedure C, fe/ -butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1 - yl)piperidine-1 -carboxylate (2.80 g, 6.29 mmol) and 1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]-3,4-dihydro-2/-/-quinoline (3.40 g, 9.44 mmol) gave, after purification by flash column chromatography (DCM/MeOH 100:0 to 90:10), te/ -butyl (3f?)-3-[4-amino-3-[4-(3,4-dihydro-2H- quinolin-1 -ylmethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (3.98 g, 7.38 mmol, 1 17% yield) as a brown foam.

UPLC-MS (ES⁺, Short acidic): 2.13 min, m/z 540.5 [M+H]⁺

[00387] 3-[4-(3,4-Dihvdro-2H-quinolin-1 -ylmethyl)phenyll-1 -[(3f?)-3-piperidyllpyrazolo[3,4-c lpyrimidin- 4-amine

Following general procedure F, fe/ -butyl (3R)-3-[4-amino-3-[4-(3,4-dihydro-2/-/-quinolin-1 - ylmethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (3.98 g, 7.38 mmol) gave, after purification by flash column chromatography (DCM/50% 7N NH₃ in MeOH 100:0 to 90:10), 3-[4-(3,4- dihydro-2H-quinolin-1 -ylmethyl)phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c/]pyrimidin-4-amine (2.46 g,

5.60 mmol, 76% yield) as a brown foam.

UPLC-MS (ES⁺, Short acidic): 1 .39 min, m/z 440.4 [M+H]⁺

[00388] 1 -[(3f?)-3-[4-Amino-3-[4-(3,4-dihvdro-2H-quinolin-1 -ylmethyl)phenyllpyrazolo[3,4-c lpyrimidin-

1 -yll-1 -piperidyllprop-2-en-1 -one

Following general procedure H, 3-[4-(3,4-dihydro-2/-/-quinolin-1 -ylmethyl)phenyl]-1 -[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (1 .31 g, 2.97 mmol) gave, after purification by flash column chromatography (DCM/MeOH 100:0 to 80:20), 1 -[(3f?)-3-[4-amino-3-[4-(3,4-dihydro-2H-quinolin-1 - ylmethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one (1 .22 g, 2.47 mmol, 83% yield) as pale pink foam. UPLC-MS (ES⁺, Long acidic): 4.08 min, m/z 494.5 [M+H]⁺

H NMR (400 MHz, DMSO-d₆), δ (ppm) 8.26 (s, 1 H, ArH), 7.63 (d, J 8.2 Hz, 2H, ArH), 7.42 (d, J 8.2 Hz, 2H, ArH), 6.94-6.87 (m, 2H, ArH), 6.88-6.65 (m, 1 H), 6.52-6.44 (m, 2H), 6.18-6.01 (m, 1 H), 5.74- 5.55 (m, 1 H), 4.78-4.63 (m, 1 H), 4.56 (s, 2H), 4.58-4.50 (m, 0.5H), 4.26-4.15 (m, 1 H), 4.12-4.01 (m, 0.5H), 3.75-3.64 (m, 0.5H), 3.42 (t, J 5.6 Hz, 2H), 3.26-3.13 (m, 1 H), 2.76 (t, J 5.6 Hz, 2H), 2.32-2.19 (m, 1 H), 2.17-2.07 (m, 1 H), 2.00-1 .87 (m, 3H), 1 .66-1 .50 (m, 2H).

[00389] Example 44: 1 -[(3R)-3-[4-Amino-3-[4-[(3-methyl-3,4-dihydro-2H-quinolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00390] 3-Methyl-1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenvnmethyll-3,4-dihydro-2H- quinoline

Following general procedure A, 4-bromomethylphenylboronic acid pinacol ester (300.0 mg, 1 .01 mmol) and 6-(trifluoromethyl)indoline (226.9 mg, 1 .21 mmol) afforded, after purification by flash chromatography, 3-methyl-1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]-3,4- dihydro-2/-/-quinoline (333.0 mg, 0.92 mmol, 91 % yield) as an orange crystalline solid.

UPLC-MS (ES⁺, Short acidic): 2.41 min, m/z 364.3 [M+H]⁺

[00391] fe/f-Butyl (3f?)-3-[4-amino-3-[4-[(3-methyl-3,4-dihydro-2H-quinolin-1 - yl)methyllphenyllpyrazolo[3,4-c lpyrimidin-1 -yllpiperidine-1 -carboxylate

Following general procedure D, 3-methyl-1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]-3,4-dihydro-2H-quinoline (333.0 mg, 0.92 mmol) and te/ -butyl 3-[(3f?)-4-amino-3- bromo-pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (150.0 mg, 0.38 mmol), gave fe/ -butyl

(3R)-3-[4-amino-3-[4-[(3-methyl-3,4-dihydro-2H-quinolin-1 -yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 - yl]piperidine-1 -carboxylate (209.1 mg, 0.38 mmol, 100% yield). This mixture was used in the next reaction without further purification, assumed quantitative.

UPLC-MS (ES⁺, Short acidic): 2.17 min, m/z 554.5 [M+H]⁺

[00392] 3-[4-[(3-Methyl-3,4-dihvdro-2H-quinolin-1 -yl)methyllphenyll-1 -[(3f?)-3-piperidyllpyrazolo[3,4- c lPyrimidin-4-amine

Following general procedure F, fe/ -butyl (3R)-3-[4-amino-3-[4-[(3-methyl-3,4-dihydro-2/-/-quinolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (209.1 mg, 0.38 mmol) afforded 3-[4-[(3-methyl-3,4-dihydro-2/-/-quinolin-1 -yl)methyl]phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4- c ]pyrimidin-4-amine (172.3 mg, 0.38 mmol, 100% yield) as a dark green solid, assumed quantitative. UPLC-MS (ES⁺, Short acidic): 1 .40 min, m/z 454.4 [M+H]⁺

[00393] 1 -[(3f?)-3-[4-Amino-3-[4-[(3-methyl-3,4-dihvdro-2H-quinolin-1 -yl)methyllphenyllpyrazolo[3,4- c lpyrimidin-1 -yll-1 -pipe ridyllprop-2-en-1 -one

Following general procedure G, 3-[4-[(3-methyl-3,4-dihydro-2/-/-quinolin-1 -yl)methyl]phenyl]-1 -[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (172.3 mg, 0.38 mmol) afforded 1 -[(3R)-3-[4-amino-3-[4-[(3- methyl-3,4-dihydro-2H-quinolin-1 -yl)methyl]phenyl]pyrazolo[3,4-(^pyrimidin-1 -yl]-1 -piperidyl]prop-2-en- 1 -one (18.1 mg, 0.036 mmol, 9% yield) as an off-white solid following preparative mass-directed reverse phase chromatography.

UPLC-MS (ES⁺, Short acidic): 1 .85 min, m/z 508.5 [M+H]⁺

H NMR (400 MHz, CDCI₃) δ (ppm) 8.39 (s, 1 H, ArH), 7.66 (d, ³ J 8.0 Hz, 2H, ArH), 7.46 (d, ³ J 8.0 Hz, 2H, ArH), 7.05-6.97 (m, 2H, ArH), 6.63 (dt, ³ 7.3, 0.9 Hz, 1 H, ArH), 6.66-6.54 (m, 1 H), 6.53 (d, ³ 8.0 Hz, 1 H, ArH), 6.37-6.25 (m, 1 H), 5.77-5.64 (m, 1 H), 5.54 (s, 2H), 4.96-4.83 (m, 1 .5H), 4.66-4.55 (m, 0.5H), 4.57 (s, 2H), 4.26-4.17 (m, 0.5H), 4.10-3.98 (m, 0.5H), 3.83-3.74 (m, 0.5H), 3.45-3.32 (m, 0.5H), 3.38-3.32 (m, 1 H), 3.26-3.12 (m, 0.5H), 3.1 1 (t, ³J 10.4 Hz, 1 H), 2.96-2.87 (m, 0.5H), 2.93-2.83 (m, 1 H), 2.60-2.51 (m, 1 H), 2.47-2.32 (m, 1 H), 2.32-2.18 (m, 2H), 2.07-1 .97 (m, 1 H), 1 .82-1 .68 (m, 1 H), 1 .10 (d, ³J 6.6 Hz, 3H, CH₃).

[00394] Example 45: 1 -[(3R)-3-[4-Amino-3-[4-[(6-chloro-3,4-dihydro-2H-quinolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c |pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00395] 6-Chloro-1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyll-3,4-dihydro-2H- quinoline

Following general procedure A, 4-bromomethylphenylboronic acid pinacol ester (300.0 mg, 1 .01 mmol) and 6-chloro-1 ,2,3,4-tetrahydroquinoline (203.2 mg, 1 .21 mmol) afforded 6-chloro-1 -[[4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]-3,4-dihydro-2/-/-quinoline (387.6 mg, 1 .01 mmol, 100% yield), which was used without further purification, assumed quantitative.

UPLC-MS (ES⁺, Short acidic): 2.43 min, m/z 384.3 & 386.3 [M+H]⁺

[00396] fe/f-Butyl (3f?)-3-[4-amino-3-[4-[(6-chloro-3,4-dihydro-2H-quinolin-1 - yl)methyllphenyllpyrazolo[3,4-c lpyrimidin-1 -yllpiperidine-1 -carboxylate

Following general procedure D, 6-chloro-1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]-3,4-dihydro-2H-quinoline (387.6 mg, 1 .01 mmol) and te/ -butyl 3-[(3f?)-4-amino-3- bromo-pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (150.0 mg, 0.38 mmol), gave fe/ -butyl (3R)-3-[4-amino-3-[4-[(6-chloro-3,4-dihydro-2H-quinolin-1 -yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 - yl]piperidine-1 -carboxylate (216.8 mg, 0.38 mmol, 100% yield), assumed quantitative.

UPLC-MS (ES⁺, Short acidic): 2.17 min, m/z 574.4 & 576.4 [M+H]⁺

[00397] 3-[4-[(6-Chloro-3,4-dihvdro-2H-quinolin-1 -yl)methyllphenyll-1 -[(3f?)-3-piperidyllpyrazolo[3,4- c lPyrimidin-4-amine

Following general procedure F, fe/ -butyl (3R)-3-[4-amino-3-[4-[(6-chloro-3,4-dihydro-2/-/-quinolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (216.8 mg, 0.38 mmol) afforded 3-[4-[(6-chloro-3,4-dihydro-2/-/-quinolin-1 -yl)methyl]phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4- c ]pyrimidin-4-amine (180.0 mg, 0.38 mmol, 100% yield) as an orange crystalline solid, assumed quantitative.

UPLC-MS (ES⁺, Short acidic): 1 .44 min, m/z 474.4 & 476.4 [M+H]⁺

[00398] 1 -[(3f?)-3-[4-Amino-3-[4-[(6-chloro-3,4-dihvdro-2H-quinolin-1 -yl)methyllphenyllpyrazolo[3,4- c lpyrimidin-1 -yll-1 -pipe ridyllprop-2-en-1 -one

Following general procedure G, 3-[4-[(6-chloro-3,4-dihydro-2/-/-quinolin-1 -yl)methyl]phenyl]-1 -[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (180.0 mg, 0.38 mmol) afforded 1 -[(3R)-3-[4-amino-3-[4-[(6- chloro-3,4-dihydro-2H-quinolin-1 -yl)methyl]phenyl]pyrazolo[3,4-(^pyrimidin-1 -yl]-1 -piperidyl]prop-2-en- 1 -one (24.0 mg, 0.046 mmol, 12% yield) as an off-white solid following preparative mass-directed reverse phase chromatography.

UPLC-MS (ES⁺, Short acidic): 1 .84 min, m/z 528.4 & 530.4 [M+H]⁺

H NMR (400 MHz, CDCI₃) δ (ppm) 8.40 (s, 1 H, ArH), 7.66 (d, ³J 8.1 Hz, 2H, ArH), 7.43 (d, ³J 8.1 Hz, 2H, ArH), 7.00-6.97 (m, 1 H, ArH), 6.93 (dd, ³ J 8.7, 2.7 Hz, 1 H, ArH), 6.69-6.54 (m, 1 H), 6.40 (d, ³ 8.7 Hz, 1 H, ArH), 6.37-6.26 (m, 1 H), 5.77-5.64 (m, 1 H), 5.55-5.40 (m, 2H, NH₂), 4.96-4.83 (m, 1 .5H), 4.66- 4.49 (m, 0.5H), 4.55 (s, 2H, CH₂), 4.26-4.17 (m, 0.5H), 4.10-4.01 (m, 0.5H), 3.83-3.74 (m, 0.5H), 3.45- 3.32 (m, 0.5H), 3.48-3.38 (m, 2H), 3.28-3.12 (m, 0.5H), 2.97-2.78 (m, 0.5H), 2.88-2.79 (m, 2H), 2.45- 2.32 (m, 1 H), 2.32-2.22 (m, 1 H), 2.13-1 .97 (m, 3H), 1 .82-1 .68 (m, 1 H).

[00399] Example 46: 1 -[(3R)-3-[4-Amino-3-[4-[(6-methoxy-3,4-dihydro-2H-quinolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c |pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00400] 3-[4-[(6-Methoxy-3.4-dihvdro-2H-quinolin-1 -yl)methyllphenyll-1 -[(3ffl-3- piperidyllpyrazolo[3,4-c/lpyrimidin-4-amine

Following general procedure D, 6-methoxy-1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]-3,4-dihydro-2H-quinoline (248.0 mg, 0.65 mmol) and 3-iodo-1 -[(3f?)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (150.0 mg, 0.44 mmol) gave, after purification by flash column chromatography (DCM/MeOH (0.1 % 7N NH₃ in MeOH) 100:0 to 90:10), 3-[4-[(6-methoxy-3,4- dihydro-2H-quinolin-1 -yl)methyl]phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c/]pyrimidin-4-amine (253.9 mg, 0.48 mmol, 1 10% yield), as a brown solid.

UPLC-MS (ES⁺, Short acidic): 1 .28 min, m/z 470.4 [M+H]⁺

[00401] 1 -[(3f?)-3-[4-Amino-3-[4-[(6-methoxy-3.4-dihvdro-2H-quinolin-1 - yl)methyllphenyllpyrazolo[3,4-c lpyrimidin-1 -yll-1 -piperidyllprop-2-en-1 -one

Following general procedure I, 3-[4-[(6-methoxy-3,4-dihydro-2/-/-quinolin-1 -yl)methyl]phenyl]-1 -[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (253.9 mg, 0.54 mmol) gave, after purification by preparative mass-directed reverse phase chromatography, 2-[[4-[4-amino-1 -[(3R)-1 -prop-2-enoyl-3- piperidyl]pyrazolo[3,4-(^pyrimidin-3-yl]phenyl]methyl]-3,4-dihydro-1 /-/-isoquinoline-7-carbonitrile (52.5 mg, 0.10 mmol, 37% yield) as a yellow solid.

UPLC-MS (ES⁺, Short acidic): 1 .60 min, m/z 524.4 [M+H]⁺

[00402] Example 47: 1 -[(3R)-3-[4-Amino-3-[4-[(2-methyl-3,4-dihydro-2H-quinolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c |pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00403] 2-Methyl-1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyll-3,4-dihydro-2H- quinoline

Following general procedure A, 2-[4-(bromomethyl)phenyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (300.0 mg, 1 .01 mmol) gave crude 2-methyl-1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]-3,4-dihydro-2H-quinoline (236.0 mg, 0.65 mmol, 64% yield).

UPLC-MS (ES⁺, short acidic): 2.39 min, m/z 364.4 [M+H]⁺

[00404] 3-[4-[(2-Methyl-3,4-dihvdro-2H-quinolin-1 -yl)methyllphenyll-1 -[(3f?)-3-piperidyllpyrazolo[3,4- c lPyrimidin-4-amine

Following general procedure D, 2-methyl-1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]-3,4-dihydro-2H-quinoline (237.5 mg, 0.65 mmol) and 3-iodo-1 -[(3f?)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (150.0 mg, 0.44 mmol) gave, after purification by SCX cartridge, 3-[4-[(2-methyl-3,4-dihydro-2/-/-quinolin-1 -yl)methyl]phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4- c ]pyrimidin-4-amine (69.0 mg, 0.15 mmol, 34% yield).

UPLC-MS (ES⁺, short acidic): 1 .42 min, m/z 454.5 [M+H]⁺

[00405] 1 -[(3f?)-3-[4-Amino-3-[4-[(2-methyl-3,4-dihvdro-2H-quinolin-1 -yl)methyllphenyllpyrazolo[3,4- c lpyrimidin-1 -yll-1 -pipe ridyllprop-2-en-1 -one Following general procedure I, 3-[4-[(2-methyl-3,4-dihydro-2/-/-quinolin-1 -yl)methyl]phenyl]-1 -[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (69.0 mg, 0.15 mmol) afforded, after purification by preparative mass-directed reverse phase chromatography, 1 -[(3R)-3-[4-amino-3-[4-[(2-methyl-3,4- dihydro-2H-quinolin-1 -yl)methyl]phenyl]pyrazolo[3,4-(^pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one (29.0 mg, 0.05 mmol, 34% yield).

UPLC-MS (ES⁺, Short acidic): 1 .72 min, m/z 508.5 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 4.24 min, m/z 508.5 [M+H]⁺

[00406] Example 48: 1 -[(3R)-3-[4-Amino-3-[4-[(8-methyl-3,4-dihydro-2H-quinolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00407] 8-Methyl-1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyll-3,4-dihydro-2H- quinoline

Following general procedure A, 2-[4-(bromomethyl)phenyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (300.0 mg, 1 .01 mmol) gave 8-methyl-1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]- 3,4-dihydro-2/-/-quinoline (272.0 mg, 0.75 mmol, 91 % yield), which was used without further purification.

UPLC-MS (ES⁺, short acidic): 2.41 min, m/z 364.3 [M+H]⁺

[00408] 3-[4-[(8-Methyl-3,4-dihvdro-2H-quinolin-1 -yl)methyllphenyll-1 -[(3f?)-3-piperidyllpyrazolo[3,4- c lPyrimidin-4-amine

Following general procedure D, 8-methyl-1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]-3,4-dihydro-2H-quinoline (237.5 mg, 0.65 mmol) and 3-iodo-1 -[(3f?)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (150.0 mg, 0.44 mmol) gave, after purification by SCX cartridge, 3-[4-[(8-methyl-3,4-dihydro-2/-/-quinolin-1 -yl)methyl]phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4- c ]pyrimidin-4-amine (130.0 mg, 0.29 mmol, 66% yield).

UPLC-MS (ES⁺, Short acidic): 1 .31 min, m/z 454.5 [M+H]⁺

[00409] 1 -[(3f?)-3-[4-Amino-3-[4-[(8-methyl-3,4-dihvdro-2H-quinolin-1 -yl)methyllphenyllpyrazolo[3,4- c lpyrimidin-1 -yll-1 -pipe ridyllprop-2-en-1 -one

Following general procedure G, 3-[4-[(8-methyl-3,4-dihydro-2/-/-quinolin-1 -yl)methyl]phenyl]-1 -[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (130.0 mg, 0.29 mmol) gave, after purification by preparative mass-directed reverse phase chromatography, 1 -[(3R)-3-[4-amino-3-[4-[(8-methyl-3,4- dihydro-2H-quinolin-1 -yl)methyl]phenyl]pyrazolo[3,4-c/]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one (13.3 mg, 0.026 mmol, 9% yield).

UPLC-MS (ES⁺, Short acidic): 1 .72 min, m/z 508.5 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.89 min, m/z 508.5 [M+H]⁺

[00410] Example 49: 1 -[(3R)-3-[4-Amino-3-[4-[[5-(trifluoromethyl)-3,4-dihydro-2H-quinolin-1 - yl]methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00411] 7-Methyl-1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyll-3,4-dihydro-2H- quinoline

Following procedure A, 2-[4-(bromomethyl)phenyl]-4, 4, 5, 5-tetramethyl-1 ,3,2-dioxaborolane (330.0 mg, 1 .1 1 mmol) and 7-methyl-1 ,2,3,4-tetrahydroquinoline hydrochloride (244.9 mg, 1 .33 mmol) gave, after purification by column chromatography (DCM/0.1 % NH₃ in MeOH 100:0 to 95:5), 4-[[4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]-2,3-dihydro-1 ,4-benzothiazine (540.4 mg, 0.56 mmol, 55% yield) as a pale yellow solid.

UPLC-MS (ES⁺, Short acidic): 2.46 min, m/z 364.4 [M+H]⁺

[00412] ferf-Butyl (3f?)-3-[4-amino-3-[4-[(7-methyl-3.4-dihvdro-2H-quinolin-1 - yl)methyllphenyllpyrazolo[3,4-c lpyrimidin-1 -yllpiperidine-1 -carboxylate

Following general procedure D, 7-methyl-1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]-3,4-dihydro-2H-quinoline (245.3 mg, 0.68 mmol) and te/ -butyl (3f?)-3-(4-amino-3- iodo-pyrazolo[3,4-c ]pyrimidin-1 -yl)piperidine-1 -carboxylate (200.0 mg, 0.45 mmol) gave, after purification by flash column chromatography (DCM/MeOH 100:0 to 90:10), fe/ -butyl (3R)-3-[4-amino- 3-[4-[(7-methyl-3,4-dihydro-2H-quinolin-1 -yl)methyl]phenyl]pyrazolo[3,4-(^pyrimidin-1 -yl]piperidi carboxylate (304.0 mg, 0.55 mmol, 122% yield) as a yellow brown oil.

UPLC-MS (ES⁺, Short acidic): 2.17 min, m/z 554.6 [M+H]⁺

[00413] 3-[4-[(7-Methyl-3,4-dihvdro-2H-quinolin-1 -yl)methyllphenyll-1 -[(3f?)-3-piperidyllpyrazolo[3,4- c lPyrimidin-4-amine

Following general procedure F, fe/ -butyl (3R)-3-[4-amino-3-[4-[(7-methyl-3,4-dihydro-2/-/-quinolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (304.0 mg, 0.55 mmol) gave, after purification by flash column chromatography (DCM/0.1 % 7N NH₃ in MeOH 80:20 to 0:100), 3-[4- [(7-methyl-3,4-dihydro-2H-quinolin-1 -yl)methyl]phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4-(^pyrimidin-4- amine (144.7 mg, 0.32 mmol, 58% yield) as a yellow solid.

UPLC-MS (ES⁺, Short acidic): 1 .30 min, m/z 454.4 [M+H]⁺

[00414] 1 -[(3f?)-3-[4-Amino-3-[4-[[5-(trifluoromethyl)-3.4-dihvdro-2H-quinolin-1 - yllmethyllphenyllpyrazolo[3,4-c lpyrimidin-1 -yll-1 -piperidyllprop-2-en-1 -one

Following general procedure I, 1 -[(3R)-3-piperidyl]-3-[4-[[5-(trifluoromethyl)-3,4-dihydro-2/-/-quinolin-1 - yl]methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-4-amine (141 .2 mg, 0.28 mmol) gave, after purification by preparative mass-directed reverse phase chromatography, 1 -[(3R)-3-[4-amino-3-[4-[[5-

(trifluoromethyl)-3,4-dihydro-2H-quinolin-1 -yl]methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 - piperidyl]prop-2-en-1 -one (3.0 mg, 0.005mmol, 2% yield) as a pale yellow solid.

UPLC-MS (ES⁺, Short acidic): 1 .90 min, m/z 562.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 4.42 min, m/z 562.4 [M+H]⁺

[00415] Example 50: 1 -[(3R)-3-[4-Amino-3-[6-(3,4-dihydro-2H-quinolin-1 -ylmethyl)-3- pyridyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00416] (5-Bromo-2-pyridyl)methyl methanesulfonate

To a solution of (5-bromo-2-pyridyl)methanol (1 .46 g, 7.75 mmol) , cooled to -10 °C under a nitrogen atmosphere, were added successively triethylamine (1 .4 mL, 10.07mmol) and methanesulfonyl chloride (0.66 mL, 8.52 mmol). The reaction mixture was allowed to warm to room temperature whilst stirring for 1 h. The mixture was quenched with water (15 mL) and then extracted with DCM (3 ^χ 15 mL). The organic phase was separated, dried using a phase separator and then concentrated under reduced pressure to provide (5-bromo-2-pyridyl)methyl methanesulfonate (2.06 g, 7.73 mmol, 100% yield) as a red oil, which was used as such immediately for the next step. This mixture was used in the next reaction without further purification, assumed quantitative.

[00417] 1 -[(5-Bromo-2-pyridyl)methyll-3,4-dihydro-2H-quinoline To a solution of (5-bromo-2-pyridyl)methyl methanesulfonate (514.2 mg, 1 .93 mmol) in THF (6 ml_) and DIPEA (0.69 ml_, 3.86 mmol) was added to the corresponding amine (1 .2 eq). The reaction mixture was heated under reflux overnight, cooled and concentrated under reduced pressure.

Purification by flash column chromatography (DCM/MeOH 100:0 to 80:20) afforded 1 -[(5-bromo-2- pyridyl)methyl]-3,4-dihydro-2H-quinoline (533.9 mg, 1 .76mmol, 91 % yield), as a yellow oil.

UPLC-MS (ES⁺, Short acidic): 2.07 min, m/z 303.1 [M+H]⁺

[00418] [6-(3,4-Dihydro-2H-quinolin-1 -ylmethyl)-3-pyridyllboronic acid

A solution of 1 -[(5-bromo-2-pyridyl)methyl]-3,4-dihydro-2H-quinoline (533.9 mg, 1 .76 mmol), bis(pinacolato)diboron (670.7 mg, 2.64 mmol) and potassium acetate (864.1 mg, 8.80 mmol) in 1 ,4- dioxane (15 ml_) was degassed with nitrogen. [1 ,1 '-Bis(diphenylphosphino)ferrocene]palladium(ll) chloride dichloromethane complex (71 .9 mg, 0.09 mmol) was added, and the solution was refluxed at 80 °C overnight. The reaction mixture was then cooled and concentrated under reduced pressure. Further purification by column chromatography (DCM/MeOH 100:0 to 80:20 then 80:20 DCM/MeOH containing 1 N NH₃ in MeOH) gave [6-(3,4-dihydro-2/-/-quinolin-1 -ylmethyl)-3-pyridyl]boronic acid (407.8 mg,1 .22 mmol, 69% yield) as a brown solid.

UPLC-MS (ES⁺, Short acidic): 1 .22 min, m/z 268.9 [M+H]⁺

[00419] fe/f-Butyl (3f?)-3-[4-amino-3-[6-(3,4-dihvdro-2H-quinolin-1 -ylmethyl)-3-pyridyllpyrazolo[3,4- c lPyrimidin-1 -yllpiperidine-1 -carboxylate

Following general procedure D, fe/ -butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1 - yl)piperidine-1 -carboxylate (247.8 mg, 0.75 mmol) and [6-(3,4-dihydro-2H-quinolin-1 -ylmethyl)-3- pyridyl]boronic acid (407.8 mg,1 .22 mmol), gave te/ -butyl (3f?)-3-[4-amino-3-[6-(3,4-dihydro-2H- quinolin-1 -ylmethyl)-3-pyridyl]pyrazolo[3,4-c ]pyrimidin-1-yl]piperidine-1 -carboxylate.

UPLC-MS (ES⁺, Short acidic): 1 .94 min, m/z 541 .5 [M+H]⁺

[00420] 3-[6-(3,4-Dihvdro-2H-quinolin-1 -ylmethyl)-3-pyridyll-1 -[(3R)-3-piperidyllpyrazolo[3,4- dlpyrimidin-4-amine

Following general procedure F, fe/ -butyl (3R)-3-[4-amino-3-[6-(3,4-dihydro-2/-/-quinolin-1 -ylmethyl)-3- pyridyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (407.0 mg, 0.75 mmol) afforded 3-[6-(3,4- dihydro-2H-quinolin-1 -ylmethyl)-3-pyridyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine

(272.8 mg, 0.62 mmol, 82% yield).

UPLC-MS (ES⁺, Short acidic): 1 .27 min, m/z 442.3 [M+H]⁺

[00421] 1 -[(3f?)-3-[4-Amino-3-[6-(3,4-dihvdro-2H-quinolin-1 -ylmethyl)-3-pyridyllpyrazolo[3,4- c lpyrimidin-1 -yll-1 -pipe ridyllprop-2-en-1 -one

Following general procedure I, 3-[6-(3,4-dihydro-2/-/-quinolin-1 -ylmethyl)-3-pyridyl]-1 -[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (241 .5 mg, 0.55 mmol) afforded, after purification by following preparative mass-directed reverse phase chromatography.

and salt removal by SCX cartridge, 1 -[(3R)-3-[4-amino-3-[6-(3,4-dihydro-2/-/-quinolin-1 -ylmethyl)-3- pyridyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one (39.9 mg, 0.08 mmol, 14% yield).

UPLC-MS (ES⁺, Short acidic): 1 .57 min, m/z 495.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.59 min, m/z 495.4 [M+H]⁺

H NMR (400 MHz, DMSO-c/₆) δ (ppm) 8.79 (s, 1 H, ArH), 8.27 (s, 1 H, ArH), 8.00-7.93 (m, 1 H), 7.36 (d,

J 8.3 Hz, 1 H), 7.24-6.92 (m, 2H), 6.91 (dd, J 7.3, 1 .5 Hz, 1 H), 6.87 (dd, J 7.3, 1 .5 Hz, 1 H), 6.87-6.64 (m, 1 H), 6.49 (dd, J 7.3, 0.9 Hz, 1 H), 6.45 (d, J 8.3 Hz, 1 H), 6.17-6.01 (m, 1 H), 5.74-5.54 (m, 1 H), 4.80-4.64 (m, 1 H), 4.61 (s, 2H, CH₂), 4.57-4.49 (m, 0.5H), 4.23-4.12 (m, 1 H), 4.10-4.01 (m, 0.5H), 3.76-3.66 (m, 0.5H), 3.51 (t, J 6.0 Hz, 2H, CH₂), 3.27-3.13 (m, 1 H), 3.10-2.98 (m, 1 H), 2.77 (t, J 6.0 Hz, 2H, CH₂), 2.29-2.19 (m, 1 H), 2.17-2.07 (m, 1 H), 1 .98 (p, J 6.0 Hz, 2H, CH₂), 1 .95 -1 .88 (m, 1 H), 1 .68-1 .49 (m, 1 H).

[00422] Example 51 : 1 -[(3R)-3-[4-Amino-3-[6-(2,3-dihydropyrido[3,2-ft][1 ,4]oxazin-4-ylmethyl)-3- pyridyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00423] 4-[(5-Bromo-2-pyridyl)methyll-2,3-dihydropyrido[3,2-)bl[1 ,4loxazine

To a solution of (5-bromo-2-pyridyl)methyl methanesulfonate (514.2 mg, 1 .93 mmol) in THF (6 ml_) and DIPEA (0.69 ml_, 3.86 mmol) was added to the corresponding amine (1 .2 eq). The reaction mixture was heated under reflux overnight, cooled and concentrated under reduced pressure. Further purification by flash column chromatography (DCM/MeOH containing 3% 7N NH₃ in MeOH 100:0 to 90:10) afforded 4-[(5-bromo-2-pyridyl)methyl]-2,3-dihydropyrido[3,2-Jb][1 ,4]oxazine (520.6 mg, 1 .70 mmol, 88% yield) as a brown oil.

UPLC-MS (ES⁺, Short acidic): 1 .04 min, m/z 308.1 [M+H]⁺

[00424] [6-(2,3-Dihydropyrido[3,2-)bl[1 ,41oxazin-4-ylmethyl)-3-pyridyllboronic acid

A solution of 4-[(5-bromo-2-pyridyl)methyl]-2,3-dihydropyrido[3,2-Jb][1 ,4]oxazine (520.6 mg,

1 .70 mmol), £>/^'s(pinacolato)diboron (647.7 mg, 2.55 mmol) and potassium acetate (834.4 mg, 8.50 mmol) in 1 ,4-dioxane (15ml_) was degassed with nitrogen. [1 ,1 - Bis(diphenylphosphino)ferrocene]palladium(ll) chloride dichloromethane complex (69.4 mg, 0.09 mmol) was added, and the solution was refluxed at 80 °C overnight. The reaction mixture was then cooled and concentrated under reduced pressure. Further purification by flash column

chromatography (DCM/MeOH 100:0 to 80:20 then 80:20 DCM/MeOH containing 1 N NH₃ in MeOH) gave [6-(2,3-dihydropyrido[3,2-£>][1 ,4]oxazin-4-ylmethyl)-3-pyridyl]boronic acid (124.7 mg, 0.46 mmol, 27% yield) as a brown film.

UPLC-MS (ES⁺, Short acidic): 0.48 min, m/z 272.2 [M+H]⁺

[00425] fe/f-Butyl (3f?)-3-[4-amino-3-[6-(2,3-dihydropyrido[3,2-)bl[1 ,41oxazin-4-ylmethyl)-3- pyridyllpyrazolo[3,4-c lpyrimidin-1 -yllpiperidine-1 -carboxylate

Following general procedure D, a mixture of [6-(2,3-dihydropyrido[3,2-£>][1 ,4]oxazin-4-ylmethyl)-3- pyridyl]boronic acid (124.7 mg, 0.46 mmol) and fe/ -butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4- c ]pyrimidin-1 -yl)piperidine-1 -carboxylate (136.3 mg, 0.31 mmol) gave, after purification by flash column chromatography (DCM/ MeOH containing 3% 7N NH₃ in MeOH 100:0 to 80:20), te/ -butyl (3f?)-3-[4-amino-3-[6-(2,3-dihydropyrido[3,2-Jb][1 ,4]oxazin-4-ylmethyl)-3-pyridyl]pyrazolo[3,4- c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (103.9 mg, 0.19 mmol, 62% yield) as a brown film.

UPLC-MS (ES⁺, Short acidic): 1 .28 min, m/z 544.5 [M+H]⁺

[00426] 3-[6-(2.3-Dihvdropyrido[3.2-)bl[1 .4loxazin-4-ylmethyl)-3-pyridyll-1 -[(3f?)-3- piperidyllpyrazolo[3,4-c/lpyrimidin-4-amine

Following general procedure F, fe/ -butyl (3R)-3-[4-amino-3-[6-(2,3-dihydropyrido[3,2-£>][1 ,4]oxazin-4- ylmethyl)-3-pyridyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (103.9 mg, 0.19 mmol) afforded, after purification by SCX cartridge, 3-[6-(2,3-dihydropyrido[3,2-£>][1 ,4]oxazin-4-ylmethyl)-3- pyridyl]-1 -[(3R)-3^iperidyl]pyrazolo[3,4-(^pyrimidin-4-amine (72.0 mg, 0.16 mmol, 85% yield) as a brown film.

UPLC-MS (ES⁺, Short acidic): 0.80 min, m/z 444.4 [M+H]⁺

[00427] 1 -[(3f?)-3-[4-Amino-3-[6-(2.3-dihvdropyrido[3.2-)bl[1 .4loxazin-4-ylmethyl)-3- pyridyllpyrazolo[3,4-c lpyrimidin-1 -yll-1 -piperidyllprop-2-en-1 -one

Following general procedure I, 3-[6-(2,3-dihydropyrido[3,2-£>][1 ,4]oxazin-4-ylmethyl)-3-pyridyl]-1 -[(3R)- 3-piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (72.0 mg, 0.16 mmol) afforded 1 -[(3R)-3-[4-amino-3-[6- (2,3-dihydropyrido[3,2-Jb][1 ,4]oxazin-4-ylmethyl)-3-pyridyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 - piperidyl]prop-2-en-1 -one (14.8 mg, 0.03 mmol, 18% yield) as a cream solid following preparative mass-directed reverse phase chromatography.

UPLC-MS (ES⁺, Short acidic): 0.99 min, m/z 498.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.15 min, m/z 498.4 [M+H]⁺

[00428] Example 52: 1 -[(3R)-3-[4-Amino-3-[4-(2,3,4,5-tetrahydro-1 -benzazepin-1 - ylmethyl)phenyl]pyrazolo[3,4-c |pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00429] l -[[4-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyll-2,3,4,5-tetrahydro-1 - benzazepine

Following general procedure A, 2-[4-(bromomethyl)phenyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (300.0 mg, 1 .01 mmol) and 2,3,4,5-tetrahydro-1 H-benzo[Jb]azepine (178.5 mg, 1 .21 mmol) afforded 1 - [[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]-2,3,4,5-tetrahydro-1 -benzazepine (279.7 mg, 0.62 mmol, 61 % yield) as a yellow solid.

UPLC-MS (ES⁺, Short acidic): 2.51 min, m/z 364.4 [M+H]⁺

[00430] 1 -[(3f?)-3-Piperidyll-3-[4-(1 ,2,4,5-tetrahvdro-3-benzazepin-3-ylmethyl)phenyllpyrazolo[3,4- c lPyrimidin-4-amine

Following general procedure D, 1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]- 2,3,4,5-tetrahydro-1 -benzazepine (237.5 mg, 0.65 mmol) and fe/ -butyl (3R)-3-(4-amino-3-iodo- pyrazolo[3,4-c ]pyrimidin-1 -yl)piperidine-1 -carboxylate (150.0 mg, 0.45 mmol) gave, after purification by flash column chromatography (DCM/MeOH containing 0.1 % 7N NH₃ in MeOH 100:0 to 80:20), 1 - [(3R)-3-piperidyl]-3-[4-(2,3,4,5-tetrahydro-1 -benzazepin-1 -ylmethyl)phenyl]pyrazolo[3,4-c/]pyrimidin-4- amine (1 15.9 mg, 0.25 mmol, 57% yield) as a brown solid.

UPLC-MS (ES⁺, Short acidic): 1 .45 min, m/z 454.4 [M+H]⁺

[00431] 1 -[(3f?)-3-[4-Amino-3-[4-(2,3,4,5-tetrahvdro-1 -benzazepin-1 -ylmethyl)phenyllpyrazolo[3,4- c lpyrimidin-1 -yll-1 -pipe ridyllprop-2-en-1 -one

Following general procedure I, 1 -[(3R)-3-piperidyl]-3-[4-(2,3,4,5-tetrahydro-1 -benzazepin-1 - ylmethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-4-amine (1 15.9 mg, 0.26 mmol) gave, after purification by flash column chromatography (DCM/MeOH containing 0.1 % 7N NH₃ in MeOH 100:0 to 90:10), 1 -

[(3R)-3-[4-amino-3-[4-(2,3,4,5-tetrahydro-1 -benzazepin-1 -ylmethyl)phenyl]pyrazolo[3,4-c/]pyrimidin-1 - yl]-1 -piperidyl]prop-2-en-1 -one (21 .2 mg, 0.04 mmol, 15% yield) as a yellow solid.

UPLC-MS (ES⁺, Short acidic): 1 .85 min, m/z 508.5 [M+H]+

UPLC-MS (ES⁺, Long acidic): 4.22 min, m/z 508.5 [M+H]⁺

H NMR (400 MHz, DMSO-d₆) δ (ppm) 8.26 (s, 1 H, ArH), 7.64 (d, J 8.0 Hz, 2H, ArH), 7.50 (d, J 8.0 Hz,

2H, ArH), 7.14-7.05 (m, 2H, ArH), 7.03-6.97 (m, 1 H), 6.91 -6.65 (m, 1 H), 6.83 (dt, J 7.3, 1 .2 Hz, 1 H, ArH), 6.17-6.01 (m, 1 H), 5.74-5.54 (m, 1 H), 4.78-4.62 (m, 1 H), 4.59-4.49 (m, 0.5H), 4.39 (s, 2H), 4.27- 4.14 (m, 1 H), 4.1 1 -4.02 (m, 0.5H), 3.75-3.63 (m, 0.5H), 3.25-3.12 (m, 0.5H), 3.07-2.95 (m, 0.5H), 2.93- 2.79 (m, 4H), 2.30-2.20 (m, 1 H), 2.17-2.04 (m, 1 H), 1 .98-1 .86 (m, 1 H), 1 .68-1 .48 (m, 6H).

[00432] Example 53: 1 -[(3R)-3-[4-Amino-3-[4-(1 ,2,4,5-tetrahydro-3-benzazepin-3- ylmethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00433] 3-[[4-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyll-1 ,2,4,5-tetrahydro-3- benzazepine

Following general procedure A, 2-[4-(bromomethyl)phenyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (300.0 mg, 1 .01 mmol) and 2,3,4,5-tetrahydro-1 H-benzo[c ]azepine (178.5 mg, 1 .21 mmol) gave, after purification by flash column chromatography (DCM/MeOH containing 0.1 % 7N NH₃ in MeOH 100:0 to 10:90), afforded 3-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]-1 ,2,4,5-tetrahydro-3- benzazepine (387.4 mg, 1 .07 mmol, 106% yield) as a yellow solid.

UPLC-MS (ES⁺, Short acidic): 1 .44 min, m/z 364.2 [M+H]⁺

[00434] 1 -[(3f?)-3-Piperidyll-3-[4-(1 ,2,4,5-tetrahvdro-3-benzazepin-3-ylmethyl)phenyllpyrazolo[3,4- c lpyrimidin-4-amine

Following general procedure D, 3-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]- 1 ,2,4,5-tetrahydro-3-benzazepine (237.5 mg, 0.65 mmol) and fe/ -butyl (3R)-3-(4-amino-3-iodo- pyrazolo[3,4-c ]pyrimidin-1 -yl)piperidine-1 -carboxylate (200.0 mg, 0.45 mmol) gave, after purification by flash column chromatography (DCM/MeOH containing 0.1 % 7N NH₃ in MeOH 100:0 to 80:20), 1 - [(3R)-3-piperidyl]-3-[4-(1 ,2,4,5-tetrahydro-3-benzazepin-3-ylmethyl)phenyl]pyrazolo[3,4-c/]pyrimidin-4- amine (101 .7 mg, 0.22 mmol, 50% yield) as a brown solid.

UPLC-MS (ES⁺, Short acidic): 0.96 min, m/z 454.4 [M+H]⁺

[00435] 1 -[(3f?)-3-[4-Amino-3-[4-(1 ,2,4,5-tetrahvdro-3-benzazepin-3-ylmethyl)phenyllpyrazolo[3,4- c lpyrimidin-1 -yll-1 -pipe ridyllprop-2-en-1 -one

Following general procedure I, 1 -[(3R)-3-piperidyl]-3-[4-(1 ,2,4,5-tetrahydro-3-benzazepin-3- ylmethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-4-amine (101 .7 mg, 0.22 mmol) gave, after purification by flash column chromatography (DCM/MeOH containing 0.1 % 7N NH₃ in MeOH 100:0 to 90:10), 1 - [(3R)-3-[4-amino-3-[4-(1 ,2,4,5-tetrahydro-3-benzazepin-3-ylmethyl)phenyl]pyrazolo[3,4-c/]pyrimidin-1 - yl]-1 -piperidyl]prop-2-en-1 -one (7.8 mg, 0.01 mmol, 6% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1 .17 min, m/z 508.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.64 min, m/z 508.5 [M+H]⁺

H NMR (400 MHz, DMSO-d₆) δ (ppm) 8.28-8.25 (bs, 1 H, ArH), 7.66-7.60 (m, 2H, ArH), 7.51 (d, J 8.2 Hz, 2H, ArH), 7.13-7.05 (m, 4H, ArH), 6.93-6.55 (m, 1 H), 6.17-6.02 (m, 1 H), 5.74-5.55 (m, 1 H), 4.78- 4.63 (m, 1 H), 4.58-4.50 (m, 0.5H), 4.26-4.14 (m, 1 H), 4.13-4.02 (m, 0.5H), 3.76-3.63 (m, 0.5H), 3.68 (s, 2H), 3.25-3.13 (m, 0.5H), 3.06-2.96 (m, 0.5H), 2.93-2.83 (m, 4H), 2.63-2.54 (m, 4H), 2.30-2.20 (m, 1 H), 2.18-2.07 (m, 1 H), 2.01 -1 .88 (m, 1 H), 1 .67-1 .49 (m, 1 H).

[00436] Example 54: 1 -[(3R)-3-[4-Amino-3-[4-(1 ,3,4,5-tetrahydro-2-benzazepin-2- ylmethyl)phenyl]pyrazolo[3,4-c |pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00437] 2-[[4-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyll-1 ,3,4,5-tetrahydro-2- benzazepine Following general procedure A, 2-[4-(bromomethyl)phenyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (300.0 mg, 1 .01 mmol) and 2,3,4,5-tetrahydro-1 H-2-benzazepine hydrochloride (222.6 mg, 1 .21 mmol) gave 2-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]-1 ,3,4,5-tetrahydro-2- benzazepine (757.6 mg, 2.09 mmol, 100% yield) as a yellow solid. This mixture was used in the next reaction without further purification, assumed quantitative.

UPLC-MS (ES⁺, Short acidic): 1 .43 min, m/z 364.4 [M+H]⁺

[00438] fe/f-Butyl (3f?)-3-[4-amino-3-[4-(1 ,3,4,5-tetrahydro-2-benzazepin-2- ylmethyl)phenyllpyrazolo[3,4-c lpyrimidin-1 -yllpiperidine-1 -carboxylate

Following general procedure D, /V-ethyl-/V-isopropyl-propan-2-amine; 2-[[4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl]methyl]-1 ,3,4,5-tetrahydro-2-benzazepine (332.6 mg, 0.68 mmol) and fe/f- butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-c ]pyrimidin-1-yl)piperidine-1 -carboxylate (200.0 mg, 0.45 mmol) gave, after purification by flash chromatography (DCM/MeOH 100:0 to 90:10), fe/f-butyl (3R)-3- [4-amino-3-[4-(1 ,3,4,5-tetrahydro-2-benzazepin-2-ylmethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-1 - yl]piperidine-1 -carboxylate (187.4 mg, 0.30 mmol, 68% yield) as a yellow oil.

UPLC-MS (ES⁺, Short acidic): 1 .39 min, m/z 554.5 [M+H]⁺

[00439] 1 -[(3f?)-3-Piperidyll-3-[4-(1 ,3,4,5-tetrahvdro-2-benzazepin-2-ylmethyl)phenyllpyrazolo[3,4- c lPyrimidin-4-amine

Following general procedure F, fe/f-butyl (3R)-3-[4-amino-3-[4-(1 ,3,4,5-tetrahydro-2-benzazepin-2- ylmethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (187.5 mg, 0.34 mmol) gave, after purification by flash column chromatography (DCM/7N NH₃ in MeOH 100:0 to 90:10), 1 -[(3f?)-3- piperidyl]-3-[4-(1 ,3,4,5-tetrahydro-2-benzazepin-2-ylmethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-4-amine (1 17.6 mg, 0.23 mmol, 69% yield) as a brown solid.

UPLC-MS (ES⁺, Short acidic): 1 .44 min, m/z 554.5 [M+H]⁺

[00440] 1 -[(3f?)-3-[4-Amino-3-[4-(1 ,3,4,5-tetrahvdro-2-benzazepin-2-ylmethyl)phenyllpyrazolo[3,4- c lpyrimidin-1 -yll-1 -pipe ridyllprop-2-en-1 -one

Following general procedure I, 1 -[(3R)-3-piperidyl]-3-[4-(1 ,3,4,5-tetrahydro-2-benzazepin-2- ylmethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-4-amine (1 17.6 mg, 0.26 mmol) gave, after purification by flash chromatography (DCM/MeOH 100:0 to 80:20), 1 -[(3f?)-3-[4-amino-3-[4-(1 ,3,4,5-tetrahydro-2- benzazepin-2-ylmethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one (17.2 mg, 0.03 mmol, 12% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1 .14 min, m/z 508.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.59 min, m/z 508.4 [M+H]⁺

H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.26 (s, 1 H, ArH), 7.64-7.57 (m, 2H, ArH), 7.42 (d, J 8.2 Hz, 2H, ArH), 7.21 -7.12 (m, 2H, ArH), 7.09 (dt, J 7.1 , 2.0 Hz, 1 H, ArH), 7.00-6.95 (m, 1 H), 6.92-6.66 (m, 1 H), 6.19-6.01 (m, 1 H), 5.74-5.55 (m, 1 H), 4.79-4.63 (m, 1 H), 4.60-4.50 (m, 0.5H), 4.28-4.16 (m, 1 H), 4.13-4.03 (m, 0.5H), 3.86 (s, 2H), 3.76-3.65 (m, 0.5H), 3.56 (s, 2H), 3.41 -3.35 (m, 0.5H), 3.26-3.17 (m, 0.5H), 3.12-2.94 (m, 2.5H), 2.93-2.86 (m, 2H), 2.30-2.21 (m, 1 H), 2.17-2.07 (m, 1 H), 1 .97-1 .88 (m, 1 H), 1 .73-1 .65 (m, 2H), 1 .65-1 .50 (m, 1 H).

[00441] Example 55: 1 -[(3R)-3-[4-Amino-3-[4-(indolin-1 -ylmethyl)phenyl]pyrazolo[3,4- cflpyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one [00442] fe/f-Butyl (3/?y3-[4-amino-3-[4-findolin-1 -ylmet^

yllpiperidine-1 -carboxylate

Following general procedure C, fe/f-butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1 - yl)piperidine-1 -carboxylate (4.13 g, 9.30 mmol) and /V-ethyl-/V-isopropyl-propan-2-amine; 1 -[[4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]indoline; hydrobromide (7.85 g,

13.95 mmol) gave, after purification by flash column chromatography (DCM/MeOH 100:0 to 90:10), fe/f-butyl (3R)-3-[4-amino-3-[4-(indolin-1 -ylmethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 - carboxylate (5.18 g, 8.37 mmol, 100% yield).

UPLC-MS (ES⁺, Short acidic): 2.04 min, m/z 526.5 [M+H]⁺

[00443] 3-[4-(lndolin-1 -ylmethyl)phenyll-1 -[(3 ?)-3-piperidyllpyrazolo[3,4-c lpyrimidin-4-amine

Following general procedure F, fe/f-butyl (3R)-3-[4-amino-3-[4-(indolin-1 -ylmethyl)phenyl]pyrazolo[3,4- c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (5.18 g, 8.37 mmol) afforded, after purification by flash column chromatography (DCM/7N ammonia in MeOH 100:0 to 90:10) 3-[4-(indolin-1 -ylmethyl)phenyl]- 1 -[(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine (3.41 g, 8.01 mmol, 96% yield).

UPLC-MS (ES⁺, Short acidic): 1 .21 min, m/z 426.4 [M+H]⁺

[00444] 1 -[(3f?)-3-[4-Amino-3-[4-(indolin-1 -ylmethyl)phenyllpyrazolo[3,4-c lpyrimidin-1 -yll-1 - piperidyllprop-2-en-1 -one

Following general procedure H, 3-[4-(indolin-1 -ylmethyl)phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4- c ]pyrimidin-4-amine (2.1 1 g, 4.95 mmol) gave, after purification by flash column chromatography (DCM/MeOH 100:0 to 80:20) 1 -[(3f?)-3-[4-amino-3-[4-(indolin-1 -ylmethyl)phenyl]pyrazolo[3,4- c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one (2.04 g, 4.26 mmol, 86% yield) as an off-white foam. UPLC-MS (ES⁺, Short acidic): 1 .67 min, m/z 480.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.84 min, m/z 480.4 [M+H]⁺

[00445] Example 56: 1 -[(3R)-3-[4-Amino-3-[4-[(4-chloroindolin-1 -yl)methyl]phenyl]pyrazolo[3,4- cflpyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00446] 4-Chloro-1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyllindoline: Λ/.Λ/- diisopropylpropan-2-amine; hydrobromide

Following method A, 4-bromomethylphenylboronic acid pinacol ester (300.0 mg, 1 .01 mmol) and 4- chloroindoline (0.18 mL, 1 .21 mmol) afforded 4-chloro-1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]indoline; /V,/V-diisopropylpropan-2-amine; hydrobromide (571 .8 mg, 0.77 mmol, 76% yield) as a brown oil. This mixture was used in the next reaction without further purification.

UPLC-MS (Short acidic): 2.44 min, m/z 370.4 [M+H]⁺

[00447] fe/f-Butyl (3 ?)-3-[4-amino-3-[4-[(4-chloroindolin-1 -yl)methyllphenyllpyrazolo[3,4-c/lpyrimidin- 1 -yllpiperidine-1 -carboxylate

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-chloro-1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl]methyl]indoline; /V,/V-diisopropylpropan-2-amine; hydrobromide (571 .8 mg, 0.77 mmol) afforded fe/f-butyl (3R)-3-[4-amino-3-[4-[(4-chloroindolin-1 -yl)methyl]phenyl]pyrazolo[3,4- c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (294.3 mg, 0.42 mmol, 93% yield) as a brown oil.

UPLC-MS (ES⁺, Short acidic): 2.19 min, m/z 560.5 [M+H]⁺ [00448] 3-[4-[(4-Chloroindolin-1-yl)methyllp^

amine

Following general procedure F, fe/ -butyl (3R)-3-[4-amino-3-[4-[(4-chloroindolin-1- yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1-yl]piperidine-1-carboxylate (294.3 mg, 0.53 mmol) afforded 3-[4-[(4-chloroindolin-1-yl)methyl]phenyl]-1-[(3R)-3^

(152.1 mg, 0.31 mmol, 60% yield) as a brown foam.

UPLC-MS (ES⁺, Short acidic): 1.42 min, m/z 460.4 [M+H]⁺

[00449] 1 -[(3 ?)-3-[4-Amino-3-[4-[(4-chloroindolin-1 -yl)methyllphenyllpyrazolo[3,4-c lpyrimidin-1 -yll-1 - piperidyllprop-2-en-1 -one

Following general procedure I, 3-[4-[(4-chloroindolin-1-yl)methyl]phenyl]-1-[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (152.1 mg, 0.33 mmol) afforded 1-[(3R)-3-[4-amino-3-[4-[(4- chloroindolin-1-yl)methyl]phenyl]pyrazolo[3,4-(^pyrimidin-1-yl]-1-piperidyl]prop-2-en-1-one (43.1 mg, 0.08 mmol, 23% yield) as an off white solid.

UPLC-MS (ES⁺, Short acidic): 1.84 min, m/z 514.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 4.27 min, m/z 514.4 [M+H]⁺

[00450] Example 57: 1-[(3R)-3-[4-Amino-3-[4-[(5-chloroindolin-1-yl)methyl]phenyl]pyrazolo[3,4- d]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00451] 5-Chloro-1-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyllindoline

Following general procedure A, 5-chloroindoline (186.2 mg, 1.21 mmol) and 2-[4- (bromomethyl)phenyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (300.0 mg, 1.01 mmol) afforded 5- chloro-1-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]indoline (563.1 mg, 1.21 mmol, 100% yield) as a yellow solid. This mixture was used in the next reaction without further purification, assumed quantitative.

UPLC-MS (ES⁺, Short acidic): 2.42 min, m/z 460.4 [M+H]⁺

[00452] fe/f-Butyl (3 ?)-3-[4-amino-3-[4-[(5-chloroindolin-1-yl)methyllphenyllpyrazolo[3,4-c/lpyrimidin- 1 -yllpiperidine-1 -carboxylate

Following general procedure D, 5-chloro-1-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]indoline (249.7 mg, 0.68 mmol) and fe/ -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/ -butyl (3R)-3-[4-amino-3-[4- [(5-chloroindolin-1-yl)methyl]phenyl]pyrazolo[3,4-c/]pyrimidin-1-yl]piperidine-1 -carboxylate (314.9 mg, 0.45 mmol, 100% yield) as a brown solid.

UPLC-MS (ES⁺, Short acidic): 2.17 min, m/z 560.5 [M+H]⁺

[00453] 3-[4-[(5-Chloroindolin-1-yl)methyllphenyll-1-[(3f?)-3-piperidyllpyrazolo[3,4-c lpyrimidin-4- amine

Following general procedure F, fe/ -butyl (3R)-3-[4-amino-3-[4-[(5-chloroindolin-1- yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1-yl]piperidine-1 -carboxylate (314.9 mg, 0.56 mmol) afforded 3-[4-[(5-chloroindolin-1-yl)methyl]phenyl]-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine

(140.3 mg, 0.31 mmol, 54% yield) as a pink-brown solid.

UPLC-MS (ES⁺, Short acidic): 1.44 min, m/z 460.4 [M+H]⁺

[00454] 1 -[(3f?)-3-[4-Amino-3-[4-[(5-chloroindolin-1 -yl)methyllphenyllpyrazolo[3,4-c lpyrimidin-1 -yll-1 - piperidyllprop-2-en-1 -one Following general procedure I, 3-[4-[(5-chloroindolin-1-yl)methyl]phenyl]-1-[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (140.3 mg, 0.31 mmol) gave 1-[(3R)-3-[4-amino-3-[4-[(5- chloroindolin-1 -yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one (73.6 mg , 0.13 mmol, 42% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1 .82 min, m/z 514.4 [M]⁺

UPLC-MS (ES⁺, Long acidic): 4.24 min, m/z 514.4 [M]⁺

H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.27 (s, 1 H, ArH), 7.70-7.61 (m, 2H, ArH), 7.51 (d, J 8.3 Hz, 2H, ArH), 7.10-7.08 (m, 1 H, ArH), 7.02 (dd, J 8.4, 2.3 Hz, 1 H, ArH), 6.92-6.65 (m, 1 H), 6.61 (d, J 8.4 Hz, 1 H, ArH), 6.18-6.01 (m, 1 H), 5.75-5.55 (m, 1 H), 4.78-4.63 (m, 1 H), 4.59-4.50 (m, 0.5H), 4.36 (s, 2H), 4.26-4.17 (m, 1 H), 4.12-4.03 (m, 0.5H), 3.77-3.65 (m, 0.5H), 3.38 (t, J 8.5 Hz, 2H), 3.26-3.16 (m, 0.5H), 3.08-2.97 (m, 0.5H), 2.95 (t, J 8.5 Hz, 2H), 2.58-2.54 (m, 1 H), 2.31-2.20 (m, 1 H), 2.17-2.08 (m, 1 H), 1.99-1.89 (m, 1 H), 1.68-1.52 (m, 1 H).

[00455] Example 58: 1-[(3R)-3-[4-Amino-3-[4-[(2-methylindolin-1-yl)methyl]phenyl]pyrazolo[3,4- cflpyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00456] 2-Methyl-1-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyllindoline

Following general procedure A, 4-bromomethylphenylboronic acid pinacol ester (300.0 mg,

1.01 mmol) and 2-methylindoline (158.3 μΙ_, 1.21 mmol) gave 2-methyl-1-[[4-(4,4,5,5-tetramethyl-

1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]indoline (277.5 mg, 0.79 mmol, 79% yield) as a clear oil.

UPLC-MS (ES⁺, Short acidic): 2.39 min, m/z 350.4 [M+H]⁺

[00457] fe/f-Butyl (3f?)-3-[4-amino-3-[4-[(2-methylindolin-1-yl)methyllphenyllpyrazolo[3,4-c/lpyrimidin-

1 -yllpiperidine-1 -carboxylate

Following general procedure D, 2-methyl-1-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]indoline (277.5 mg, 0.79 mmol) and fe/ -butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4- c ]pyrimidin-1-yl)piperidine-1 -carboxylate (294.1 mg, 0.66 mmol) gave, after filtration over Celite^® and concentration under reduced pressure, fe/ -butyl (3R)-3-[4-amino-3-[4-[(2-methylindolin-1- yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1-yl]piperidine-1 -carboxylate (568.2 mg, 0.66 mmol, 100% yield) as a brown solid. This mixture was used in the next reaction without further purification, assumed quantitative.

UPLC-MS (ES⁺, Short acidic): 2.14 min, m/z 540.5 [M+H]⁺

[00458] 3-[4-[(2-Methylindolin-1-yl)methyllphenyll-1-[(3f?)-3-piperidyllpyrazolo[3,4-c lpyrimidin-4- amine

Following general procedure F, fe/ -butyl (3R)-3-[4-amino-3-[4-[(2-methylindolin-1- yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1-yl]piperidine-1 -carboxylate (568.2 mg, 0.66 mmol) gave, after purification by flash column chromatography (DCM/7M NH₃ in MeOH 100:0 to 90:10), 3-[4-[(2- methylindolin-1-yl)methyl]phenyl]-1-[(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine (207.1 mg, 0.47 mmol, 71 % yield) as a cream solid.

UPLC-MS (ES⁺, Short acidic): 1.37 min, m/z 440.4 [M+H]⁺

[00459] 1 -[(3f?)-3-[4-Amino-3-[4-[(2-methylindolin-1 -yl)methyllphenyllpyrazolo[3,4-c lpyrimidin-1 -yll-1 - piperidyllprop-2-en-1 -one

Following general procedure I, 3-[4-[(2-methylindolin-1-yl)methyl]phenyl]-1-[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (207.1 mg, 0.47 mmol) afforded, after purification by preparative HPLC, 1-[(3R)-3-[4-amino-3-[4-[(2-methylindolin-1-yl)methyl]phenyl]pyrazolo[3,4- c ]pyrimidin-1-yl]-1-piperidyl]prop-2-en-1-one (49.3 mg, 0.10 mmol, 21 % yield) as a cream solid.

UPLC-MS (ES⁺, Short acidic): 1.77 min, m/z 494.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 4.07 min, m/z 494.4 [M+H]⁺

[00460] Example 59: 1-[(3R)-3-[4-Amino-3-[4-[(5-fluoroindolin-1-yl)methyl]phenyl]pyrazolo[3,4- cflpyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00461] 5-Fluoro-1-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyllindoline

Following method A, 4-bromomethylphenylboronic acid pinacol ester (300.0 mg, 1.01 mmol) and 5- fluoroindoline (0.16 mL, 1 .21 mmol) afforded 5-fluoro-1-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]indoline (492.0 mg,0.61 mmol, 61 % yield) as an off-white solid.

UPLC-MS (ES⁺, Short acidic): 2.31 min, m/z 354.4 [M+H]⁺

[00462] fe/f-Butyl (3f?)-3-[4-amino-3-[4-[(5-fluoroindolin-1-yl)methyllphenyllpyrazolo[3,4-c lpyrimidin- 1 -yllpiperidine-1 -carboxylate

Following general procedure D, fe/ -butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1- yl)piperidine-1 -carboxylate (140 mg, 0.32 mmol) and 5-fluoro-1-[[4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl]methyl]indoline; hydrobromide (87.11 mg, 0.63 mmol) afforded fe/ -butyl

(3R)-3-[4-amino-3-[4-[(5-fluoroindolin-1-yl)methyl]phenyl]pyrazolo[3,4-(^pyrimidin-1-yl]piperidine-1- carboxylate (198.2 mg, 0.29 mmol, 93% yield) as a brown oil.

UPLC-MS (ES⁺, Short acidic): 2.04 min, m/z 544.4 [M+H]⁺

[00463] 3-[4-[(5-Fluoroindolin-1-yl)methyllphenyll-1-[(3f?)-3-piperidyllpyrazolo[3,4-c lpyrimidin-4- amine

Following general procedure F, fe/ -butyl (3R)-3-[4-amino-3-[4-[(5-fluoroindolin-1- yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1-yl]piperidine-1 -carboxylate (198.2 mg, 0.31 mmol) afforded 3-[4-[(5-fluoroindolin-1-yl)methyl]phenyl]-1-[(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine

(125.9 mg, 0.26 mmol, 82% yield) as a brown foam.

UPLC-MS (ES⁺, Short acidic): 1.34 min, m/z 444.3 [M+H]⁺

[00464] 1 -[(3f?)-3-[4-Amino-3-[4-[(5-fluoroindolin-1 -yl)methyllphenyllpyrazolo[3,4-c lpyrimidin-1 -yll-1 - piperidyllprop-2-en-1 -one

Following general procedure I, 3-[4-[(5-fluoroindolin-1-yl)methyl]phenyl]-1-[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (125.9 mg, 0.28 mmol) gave, after purification by preparative mass-directed reverse phase chromatography, 1-[(3R)-3-[4-amino-3-[4-[(5-fluoroindolin-1- yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1-yl]-1-piperidyl]prop-2-en-1-one (15.2 mg, 0.03 mmol, 10% yield) as an off white solid.

UPLC-MS (ES⁺, Short acidic): 1.64 min, m/z 498.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.88 min, m/z 498.4 [M+H]⁺

H-NMR (400 MHz, DMSO-d₆) δ (ppm) 8.27 (s, 1 H, ArH), 7.67-7.65 (d, J = 7.6 Hz, 2H, ArH), 7.54-7.52 (d, J = 8.0 Hz, 2H. ArH), 6.95-6.93 (d, J = 8.8 Hz, 2H), 6.91-6.86 (dd, _is 10.4 Hz, ³J_trans 16.4 Hz, 0.5H) 6.75-6.68 (dd, ³J_CS 10.4 Hz, ³J_trans 16.4 Hz, 0.5H) 6.84-6.78 (m, 1 H), 6.59-6.56 (m, 1 H), 6.16- 6.11 (d, ³J_trans 16.4 Hz, 0.5H), 6.09-6.05 (d, ³J_trans 16.4 Hz, 0.5H), 5.73-5.58 (d, _is 10.4 Hz, 0.5H), 5.61-5.58 (d, ³J_CS 10.4 Hz, 0.5H), 4.72 (s, 1 H), 4.57-4.54 (m, 0.5H), 4.30 (s, 2H), 4.22-4.19 (m, 1 H), 4.10-4.06 (m, 0.5H), 3.74-3.68 (m, 0.5H), 3.34-3.30 (t, J = 8.3 Hz, 2H), 3.25-3.19 (m, 1 H), 3.04-2.99 (m, 0.5H), 2.94-2.90 (t, J = 8.24 Hz, 2H), 2.29-2.23 (m, 1 H), 2.14-2.1 1 (m, 1 H), 1 .95-1 .92 (m, 1 H), 1 .62-1 .56 (m, 1 H).

[00465] Example 60: 1 -[(3R)-3-[4-Amino-3-[4-[(6-chloroindolin-1 -yl)methyl]phenyl]pyrazolo[3,4- cflpyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00466] 6-Chloro-1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyllindoline

Following general procedure A, 6-chloroindoline (186.2 mg, 1 .21 mmol) and 2-[4- (bromomethyl)phenyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (300.0 mg, 1 .01 mmol) afforded 6- chloro-1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]indoline (705.9 mg, 1 .34 mmol, 132% yield) as a yellow solid. This mixture was used in the next reaction without further purification. UPLC-MS (ES⁺, Short acidic): 2.42 min, m/z 370.3 [M+H]⁺

[00467] fe/f-Butyl (3 ?)-3-[4-amino-3-[4-[(6-chloroindolin-1 -yl)methyllphenyllpyrazolo[3,4-c/lpyrimidin- 1 -yllpiperidine-1 -carboxylate

Following general procedure D, 6-chloro-1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]indoline (249.6 mg, 0.68 mmol) and fe/ -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/ -butyl (3R)-3-[4-amino-3-[4- [(6-chloroindolin-1 -yl)methyl]phenyl]pyrazolo[3,4-c/]pyrimidin-1 -yl]piperidine-1 -carboxylate (299.0 mg, 0.43 mmol, 95% yield) as a brown oil.

UPLC-MS (ES⁺, Short acidic): 2.15 min, m/z 560.4 [M]⁺

[00468] 3-[4-[(6-Chloroindolin-1 -yl)methyllphenyll-1 -[(3f?)-3-piperidyllpyrazolo[3,4-c lpyrimidin-4- amine

Following general procedure F, fe/ -butyl (3R)-3-[4-amino-3-[4-[(6-chloroindolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (299.1 mg, 0.43 mmol) afforded 3-[4-[(6-chloroindolin-1 -yl)methyl]phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine

(126.5 mg, 0.25 mmol, 46% yield) as a brown solid.

UPLC-MS (ES⁺, Short acidic): 1 .41 min, m/z 460.4 [M+H]⁺

[00469] 1 -[(3f?)-3-[4-Amino-3-[4-[(6-chloroindolin-1 -yl)methyllphenyllpyrazolo[3,4-dlpyrimidin-1 -yll-1 - piperidyllprop-2-en-1 -one

Following general procedure I, 3-[4-[(6-chloroindolin-1 -yl)methyl]phenyl]-1 -[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (126.5 mg, 0.28 mmol) gave, after purification by preparative mass-directed reverse phase chromatography, 1 -[(3R)-3-[4-amino-3-[4-[(6-chloroindolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one (51 .3 mg, 0.09 mmol, 33% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1 .80 min, m/z 514.3 [M]⁺

UPLC-MS (ES⁺, Long acidic): 4.17 min, m/z 514.3 [M]⁺

H NMR (400 MHz, DMSO-d₆) δ (ppm) 8.26 (s, 1 H, ArH), 7.70-7.62 (m, 2H, ArH), 7.50 (d, J 8.1 Hz,

2H, ArH), 7.02 (d, J 7.7 Hz 1 H, ArH), 6.92-6.66 (m, 1 H), 6.65 (d, J 1 .7 Hz 1 H, ArH), 6.57 (dd, J 7.7, 1 .7 Hz, 1 H, ArH), 6.18-6.02 (m, 1 H), 5.75-5.54 (m, 1 H), 4.78-4.62 (m, 1 H), 4.60-4.50 (m, 0.5H), 4.39 (s, 2H), 4.26-4.15 (m, 1 H), 4.12-4.02 (m, 0.5H), 3.75-3.64 (m, 0.5H), 3.40 (t, J 8.4 Hz, 2H), 3.26-3.12 (m, 1 H), 3.06-2.96 (m, 0.5H), 2.92 (t, J 8.4 Hz, 2H), 2.30-2.20 (m, 1 H), 2.17-2.07 (m, 1 H), 1 .98-1 .88 (m, 1 H), 1 .68-1 .50 (m, 1 H). [00470] Example 61 : 1 -[(3R)-3-[4-Amino-3-[4-[(4-fluoroindolin-1 -yl)methyl]phenyl]pyrazolo[3,4- cflpyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00471] 4-Fluoro-1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yr)phenvnmethvnindoline

Following method A, 4-bromomethylphenylboronic acid pinacol ester (300 mg, 1 .01 mmol) and 4- fluoroindoline (0.16 ml_, 1 .21 mmol) afforded /V-ethyl-/V-isopropyl-propan-2-amine; 4-fluoro-1 -[[4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]indoline; hydrobromide (546.4 mg, 0.68 mmol, 67% yield) as a red solid.

UPLC-MS (ES⁺, Short acidic): 2.34 min, m/z 354.3 [M+H]⁺

[00472] fe/f-Butyl (3f?)-3-[4-amino-3-[4-[(4-fluoroindolin-1 -yl)methyllphenyllpyrazolo[3,4-c lpyrimidin- 1 -yllpiperidine-1 -carboxylate

Following general procedure D, fe/ -butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1 - yl)piperidine-1 -carboxylate (150 mg, 0.34 mmol) and /V-ethyl-/V-isopropyl-propan-2-amine; 4-fluoro-1 - [[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]indoline; hydrobromide (93.33 mg, 0.68 mmol) afforded fe/ -butyl (3R)-3-[4-amino-3-[4-[(4-fluoroindolin-1 -yl)methyl]phenyl]pyrazolo[3,4- cf]pyrimidin-1 -yl]piperidine-1 -carboxylate (216.4 mg, 0.32 mmol, 94% yield) as a brown/orange oil. UPLC-MS (ES⁺, Short acidic): 2.07 min, m/z 544.5 [M+H]⁺

[00473] 3-[4-[(4-Fluoroindolin-1 -yl)methyllphenyll-1 -[(3 ?)-3-piperidyllpyrazolo[3,4-c lpyrimidin-4- amine

Following general procedure F, fe/ -butyl (3R)-3-[4-amino-3-[4-[(4-fluoroindolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (21 1 .0 mg, 0.33 mmol) afforded 3-[4-[(4-fluoroindolin-1 -yl)methyl]phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine

(102.6 mg, 0.21 mmol, 63% yield) as a brown foam.

UPLC-MS (ES⁺, Short acidic): 1 .34 min, m/z 444.4 [M+H]⁺

[00474] 1 -[(3f?)-3-[4-Amino-3-[4-[(4-fluoroindolin-1 -yl)methyllphenyllpyrazolo[3,4-c lpyrimidin-1 -yll-1 - piperidyllprop-2-en-1 -one

Following general procedure I, 3-[4-[(4-fluoroindolin-1 -yl)methyl]phenyl]-1 -[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (102.6 mg, 0.22 mmol) gave, after purification by preparative mass-directed reverse phase chromatography, 1 -[(3R)-3-[4-amino-3-[4-[(4-fluoroindolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one (28.8 mg, 0.05 mmol, 24% yield) as an off white foam.

UPLC-MS (ES⁺, Short acidic): 1 .72 min, m/z 498.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.97 min, m/z 498.4 [M+H]⁺

H-NMR (400 MHz, DMSO-d₆) δ (ppm) 8.27 (s, 1 H, ArH), 7.66-7.64 (m, 2H, ArH), 7.52-7.50 (d, J = 8Hz, 2H, ArH), 7.06-7.01 (m, 2H, ArH), 6.48-6.46 (d, J = 7.6 Hz, 1 H, ArH), 6.41 -6.37 (m, 1 H), 6.91 - 6.86 (dd, _is 10.4 Hz, ³J_trans 16.4 Hz, 0.5H), 6.75-6.68 (dd, ³J_CS 10.4 Hz, ³J_trans 16.4 Hz, 0.5H), 6.16- 6.1 1 (d, ³J_trans 16.4 Hz, 0.5H), 6.09-6.05 (d, ³J_trans 16.4 Hz, 0.5H), 5.73-5.70 (d, _is 10.4 Hz, 0.5H), 5.61 -5.58 (d, _is 10.4 Hz, 0.5H), 4.71 (s, 1 H), 4.57-4.54 (m, 0.5H), 4.40 (s, 2H), 4.22-4.19 (m, 1 H), 4.10-4.07 (m, 0.5H), 3.74-3.68 (m, 0.5H), 3.47-3.43 (t, J = 8.6 Hz, 2H), 3.25-3.17 (m, 1 H), 3.05-3.02 (m, 0.5H), 3.00-2.96 (t, J = 8.40 Hz, 2H), 2.29-2.22 (m, 1 H), 2.14-2.1 1 (m, 1 H), 1 .95-1 .92 (m, 1 H), 1 .62-1 .56 (m, 1 H). [00475] Example 62: 1 -[(3R)-3-[4-Amino-3-[4-[(5-methoxyindolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c |pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00476] /V-Ethyl-/V-isopropyl-propan-2-amine; 5-methoxy-1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan^-vOphenyllmethyllindoline; hydrobromide .

A mixture of 4-bromomethylphenylboronic acid pinacol ester (300.0 mg, 1 .01 mmol) and 5- methoxyindoline (0.16 mL, 1 .21 mmol) afforded /V-ethyl-/V-isopropyl-propan-2-amine; 5-methoxy-1 -[[4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]indoline; hydrobromide (548.5 mg, 0.67 mmol, 66% yield) as a brown solid/foam.

UPLC-MS (ES⁺, Short acidic): 2.14 min, m/z 364.4 [M+H]⁺

[00477] fe/f-Butyl (3f?)-3-[4-amino-3-[4-[(5-methoxyindolin-1 -yl)methyllphenyllpyrazolo[3,4- c lPyrimidin-1 -yllpiperidine-1 -carboxylate

Following general procedure D, fe/ -butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-c/]pyrimidin-1 - yl)piperidine-1 -carboxylate (150 mg, 0.34 mmol) and /V-ethyl-/V-isopropyl-propan-2-amine; 5-methoxy- 1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]indoline; hydrobromide (0.47 mL, 0.64 mmol) gave fe/ -butyl (3R)-3-[4-amino-3-[4-[(5-methoxyindolin-1 -yl)methyl]phenyl]pyrazolo[3,4- c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (193.2 mg, 0.30 mmol, 88% yield) as an oily brown residue. UPLC-MS (ES⁺, Short acidic): 1 .89 min, m/z 556.5 [M+H]⁺

[00478] 3-[4-[(5-Methoxyindolin-1 -yl)methyllphenyll-1 -[(3f?)-3-piperidyll-2,3-dihydropyrazolo[3,4- c lPyrimidin-4-amine

Following general procedure F, fe/ -butyl (3R)-3-[4-amino-3-[4-[(5-methoxyindolin-1 -yl)methyl]phenyl]- 2,3-dihydropyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (189.2 mg, 0.29 mmol) afforded 3-[4- [(5-methoxyindolin-1 -yl)methyl]phenyl]-1 -[(3R)-3-piperidyl]-2,3-dihydropyrazolo[3,4-c ]pyrimidin-4- amine (100.5 mg, 0.22 mmol, 76% yield) as a brown foam.

UPLC-MS (ES⁺, Short acidic): 1 .16 min, m/z 456.4 [M+H]⁺

[00479] 1 -[(3f?)-3-[4-Amino-3-[4-[(5-methoxyindolin-1 -yl)methyllphenyllpyrazolo[3,4-c lpyrimidin-1 -yll- 1 -piperidyllprop-2-en-1 -one

Following general procedure I, 3-[4-[(5-methoxyindolin-1 -yl)methyl]phenyl]-1 -[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (100.5 mg, 0.21 mmol) gave, after purification by preparative mass-directed reverse phase chromatography, 1 -[(3R)-3-[4-amino-3-[4-[(5-methoxyindolin- 1 -yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one (5.5 mg, 0.01 mmol, 5% yield) as an off white foam.

UPLC-MS (ES⁺, short acidic): 1 .48 min, m/z 510.3 [M+H]⁺

UPLC-MS (ES⁺, long acidic): 3.36 min, m/z 510.4 [M+H]⁺

H-NMR (400 MHz, DMSO-d₆) δ (ppm) 8.27 (s, 1 H, ArH), 7.66-7.64 (m, 2H, ArH), 7.54-7.52 (d, J = 8Hz, 2H, ArH), 6.75 (s, 1 H, ArH), 6.91 -6.84 (dd, ³J_{C S} 10.4 Hz, ³J_trans 16.4 Hz, 0.5H), 6.73-6.65 (dd, ³J_{C S} 10.4 Hz, ³J_trans 16.4 Hz, 0.5H), 6.61 -6.58 (m, 1 H), 6.55-6.53 (d, J = 8.4 Hz, 1 H), 6.16-6.1 1 (d, ³J_trans = 16.4 Hz, 0.5H), 6.09-6.05 (d, ³J_trans = 16.4 Hz, 0.5H), 5.73-5.70 (d, ³J_{C S} = 10.4 Hz, 0.5H), 5.61 -5.58 (d, ³J_CS 10.4 Hz, 0.5H), 4.72 (s, 1 H), 4.57-4.54 (m, 0.5H), 4.25 (s, 2H), 4.21 -4.19 (m, 1 H), 4.10-4.07 (m, 0.5H), 3.74-3.71 (m, 0.5H), 3.66 (s, 3H), 3.26-3.22 (t, J = 8.14 Hz, 2H), 3.20-3.17 (m, 1 H), 3.04- 2.99 (m, 0.5H), 2.90-2.86 (t, J = 8 Hz, 2H), 2.29-2.23 (m, 1 H), 2.14-2.1 1 (m, 1 H), 1 .95-1 .92 (m, 1 H), 1 .62-1 .56 (m, 1 H). [00480] Example 63: 1 -[(3R)-3-[4-Amino-3-[4-[(6-met ylindolin-1 -yl)met yl]p enyl]pyrazolo[3,4- cflpyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00481] /V./V-Diisopropylpropan-2-amine; 3,3-dimethyl-1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl^')phenyllmethyllindoline; hydrobromide

1 .01 mmol) and 6-methyl-2,3-dihydro-1 /-/-indole hydrochloride (0.18 ml_, 1 .1 1 mmol) gave crude 6- methyl-1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]indoline (334.8 mg, 0.86 mmol, 85% yield) as a yellow oil. This mixture was used in the next reaction without further purification, assumed quantitative.

UPLC-MS (ES⁺, Short acidic): 2.40 min, m/z 350.4 [M+H]⁺

[00482] fe/f-Butyl (3f?)-3-[4-amino-3-[4-[(6-methylindolin-1 -yl)methyllphenyllpyrazolo[3,4-cflpyrimidin- 1 -yllpiperidine-1 -carboxylate

Following general procedure D, 6-methyl-1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]indoline (209.6 mg, 0.54 mmol) and fe/ -butyl (3/?)-3-(4-amino-3-iodo-pyrazolo[3,4- c ]pyrimidin-1 -yl)piperidine-1 -carboxylate (200.0 mg, 0.45 mmol) gave, after purification by flash column chromatography (DCM/MeOH 100:0 to 90:10), te/ -butyl (3f?)-3-[4-amino-3-[4-[(6- methylindolin-1 -yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (432.0 mg,

0.58 mmol, 100% yield) as a brown solid.

UPLC-MS (ES⁺, Short acidic): 2.15 min, m/z 540.5[M+H]⁺

[00483] 3-[4-[(6-Methylindolin-1 -yl)methyllphenyll-1 -[(3f?)-3-piperidyllpyrazolo[3,4-c lpyrimidin-4- amine

Following general procedure F, fe/ -butyl (3/?)-3-[4-amino-3-[4-[(3-methylindolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (335.5 mg, 0.54 mmol) gave, after purification by flash column chromatography (DCM/7N ammonia in MeOH 100:0 to 90:10), 3-[4- [(6-methylindolin-1 -yl)methyl]phenyl]-1 -[(3/?)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine (179.4 mg, 0.41 mmol, 70% yield) as a brown powdery solid.

UPLC-MS (ES⁺, Short acidic): 1 .39 min, m/z 440.4 [M+H]⁺

[00484] 1 -[(3f?)-3-[4-Amino-3-[4-[(6-methylindolin-1 -yl)methyllphenyllpyrazolo[3,4-c/lpyrimidin-1 -yll-1 - piperidyllprop-2-en-1 -one

Following general procedure I, 3-[4-[(6-methylindolin-1 -yl)methyl]phenyl]-1 -[(3/?)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (179.4 mg, 0.41 mmol) gave, after purification by preparative mass-directed reverse phase chromatography, 1 -[(3/?)-3-[4-amino-3-[4-[(6-methylindolin-

1 -yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one (37.0 mg, 0.08 mmol,

18% yield) as a fluffy cream solid.

UPLC-MS (ES⁺, Short acidic): 1 .76 min, m/z 494.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 4.04 min, m/z 494.3 [M+H]⁺

[00485] Example 64: 1 -[(3R)-3-[4-Amino-3-[4-[(6-fluoroindolin-1 -yl)methyl]phenyl]pyrazolo[3,4- cflpyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00486] 6-Fluoro-1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyllindoline

Following general procedure A, 6-fluorindoline (166.2 mg, 1 .21 mmol) and 2-[4-(bromomethyl)phenyl]- 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (300.0 mg, 1 .01 mmol) afforded 6-fluoro-1 -[[4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]indoline (756.8 mg, 1 .50 mmol, 148% yield) as a red-orange solid. This mixture was used in the next reaction without further purification.

UPLC-MS (ES⁺, Short acidic): 2.33 min, m/z 354.3[M+H]⁺

[00487] fe/f-Butyl (3f?)-3-[4-amino-3-[4-[(6-fluoroindolin-1 -yl)methyllphenyllpyrazolo[3,4-c lpyrimidin- 1 -yllpiperidine-1 -carboxylate

Following general procedure D, /V-ethyl-/V-isopropyl-propan-2-amine; 6-fluoro-1 -[[4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]indoline (325.8 mg, 0.67 mmol) and fe/ -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/ -butyl (3R)-3-[4-amino-3-[4-[(6-fluoroindolin-1 -yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 - yl]piperidine-1 -carboxylate (31 1 .1 mg, 0.46 mmol, 101 %) as a light brown solid.

UPLC-MS (ES⁺, Short acidic): 2.06 min, m/z 544.5 [M+H]⁺

[00488] 3-[4-[(6-Fluoroindolin-1 -yl)methyllphenyll-1 -[(3f?)-3-piperidyllpyrazolo[3,4-c lpyrimidin-4- amine

Following general procedure F, fe/ -butyl (3R)-3-[4-amino-3-[4-[(6-fluoroindolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (31 1 .1 mg, 0.57 mmol) afforded 3-[4-[(6-fluoroindolin-1 -yl)methyl]phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine (144.4 mg, 0.29 mmol, 51 % yield) as a light brown solid.

UPLC-MS (ES⁺, Short acidic): 1 .37 min, m/z 444.4 [M+H]⁺

[00489] 1 -[(3f?)-3-[4-Amino-3-[4-[(6-fluoroindolin-1 -yl)methyllphenyllpyrazolo[3,4-c lpyrimidin-1 -yll-1 - piperidyllprop-2-en-1 -one

Following general procedure I, 3-[4-[(6-fluoroindolin-1 -yl)methyl]phenyl]-1 -[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (144.4 mg, 0.33 mmol) gave, after purification by preparative mass-directed reverse phase chromatography, 1 -[(3R)-3-[4-amino-3-[4-[(6-fluoroindolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one (42.2 mg, 0.08 mmol, 23% yield).

UPLC-MS (ES⁺, Short acidic): 1 .71 min, m/z 498.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.96 min, m/z 498.4 [M+H]⁺

H NMR (400 MHz, DMSO-d₆) δ (ppm) 8.26 (s, 1 H, ArH), 7.71 -7.60 (m, 2H, ArH), 7.50 (d, J 8.3 Hz, 2H, ArH), 7.03-6.96 (m, 1 H), 6.92-6.67 (m, 1 H), 6.47 (dd, J 10.9, 2.3 Hz 1 H, ArH), 6.31 (ddd, J 9.8, 7.9, 2.3 Hz, 1 H, ArH), 6.17-6.02 (m, 1 H), 5.74-5.55 (m, 1 H), 4.79-4.63 (m, 1 H), 4.59-4.50 (m, 0.5H), 4.37 (s, 2H), 4.26-4.15 (m, 1 H), 4.12-4.02 (m, 0.5H), 3.75-3.64 (m, 0.5H), 3.40 (t, J 8.5 Hz, 2H), 3.26- 3.15 (m, 1 H), 3.06-2.96 (m, 0.5H), 2.90 (t, J 8.4 Hz, 2H), 2.30-2.20 (m, 1 H), 2.17-2.07 (m, 1 H), 1 .99- 1 .88 (m, 1 H), 1 .67-1 .50 (m, 1 H).

[00490] Example 65: 1 -[(3R)-3-[4-Amino-3-[4-[(3-methylindolin-1 -yl)methyl]phenyl]pyrazolo[3,4- cflpyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00491] /V./V-Diisopropylpropan-2-amine; 3,3-dimethyl-1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)phenyllmethyllindoline: hvdrobromide

1 .01 mmol) and 3-methyl-2,3-dihydro-1 H-indole (0.15 mL, 1 .21 mmol) gave crude N,N- diisopropylpropan-2-amine; 3-methyl-1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]indoline; hydrobromide (491 .0 mg, 0.60 mmol, 59% yield) as a brown foam/solid. This mixture was used in the next reaction without further purification.

[00492] fe/f-Butyl (3f?)-3-[4-amino-3-[4-[(3-methylindolin-1 -yl)methyllphenyllpyrazolo[3,4-c/lpyrimidin- 1 -yllpiperidine-1 -carboxylate

Following general procedure D, /V-ethyl-/V-isopropyl-propan-2-amine; 3-methyl-1 -[[4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]indoline; hydrobromide (431 .7 mg, 0.54 mmol) and fe/ -butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-c ]pyrimidin-1 -yl)piperidine-1 -carboxylate (200.0 mg, 0.45 mmol) gave, after purification by flash column chromatography (DCM/MeOH 100:0 to 90:10), tert- butyl (3R)-3-[4-amino-3-[4-[(3-methylindolin-1 -yl)methyl]phenyl]pyrazolo[3,4-c/]pyrimidin-1 - yl]piperidine-1 -carboxylate (335.5 mg, 0.54 mmol, 120% yield) as a brown gum.

UPLC-MS (ES⁺, Short acidic): 2.15 min, m/z 540.5[M+H]⁺

[00493] 3-[4-[(3-Methylindolin-1 -yl)methyllphenyll-1 -[(3f?)-3-piperidyllpyrazolo[3,4-c lpyrimidin-4- amine

Following general procedure F, fe/ -butyl (3R)-3-[4-amino-3-[4-[(3-methylindolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (335.5 mg, 0.54 mmol) gave, after purification by flash column chromatography (DCM/7N ammonia in MeOH 100:0 to 90:10), 3-[4-

[(3-methylindolin-1 -yl)methyl]phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine (179.9 mg,

0.41 mmol, 76% yield) as a brown solid.

UPLC-MS (ES⁺, Short acidic): 1 .36 min, m/z 440.4 [M+H]⁺

[00494] 1 -[(3f?)-3-[4-Amino-3-[4-[(3-methylindolin-1 -yl)methyllphenyllpyrazolo[3,4-c lpyrimidin-1 -yll-1 - piperidyllprop-2-en-1 -one

Following general procedure I, 3-[4-[(3-methylindolin-1 -yl)methyl]phenyl]-1 -[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (179.9 mg, 0.41 mmol) gave, after purification by preparative mass-directed reverse phase chromatography, 1 -[(3R)-3-[4-amino-3-[4-[(3-methylindolin- 1 -yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one (31 .1 mg, 0.06 mmol, 15% yield) as a cream solid.

UPLC-MS (ES⁺, Short acidic): 1 .76 min, m/z 494.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 4.07 min, m/z 494.2 [M+H]⁺

[00495] Example 66: 1 -[(3R)-3-[4-Amino-3-[4-[(7-fluoroindolin-1 -yl)methyl]phenyl]pyrazolo[3,4- cflpyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00496] 7-Fluoro-1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyllindoline

1 .01 mmol) and 7-fluoroindoline (166.2 mg, 1 .21 mmol) afforded 7-fluoro-1 -[[4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]indoline (573.1 mg, 0.81 mmol, 80% yield) as a light purple solid. This mixture was used in the next reaction without further purification.

UPLC-MS (ES⁺, Short acidic): 2.35 min, m/z 353.8 [M+H]⁺

[00497] fe/f-Butyl (3f?)-3-[4-amino-3-[4-[(7-fluoroindolin-1 -yl)methyllphenyllpyrazolo[3,4-c lpyrimidin- 1 -yllpiperidine-1 -carboxylate

Following general procedure D, /V-ethyl-/V-isopropyl-propan-2-amine; 7-fluoro-1 -[[4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]indoline (325.8 mg, 0.68 mmol) and te/ -butyl (3f?)- 3-(4-amino-3-iodo-pyrazolo[3,4-c ]pyrimidin-1 -yl)piperidine-1 -carboxylate (200.0 mg, 0.45 mmol) gave fe/f-butyl (3R)-3-[4-amino-3-[4-[(7-fluoroindolin-1 -yl)methyl]phenyl]pyra^

yl]piperidine-1 -carboxylate (301 .4 mg, 0.44 mmol, 99% yield) as a yellow-brown oil.

UPLC-MS (ES⁺, Short acidic): 2.08 min, m/z 544.4 [M+H]⁺

[00498] 3-[4-[(7-Fluoroindolin-1 -yl)methyllphenyll-1 -[(3f?)-3-piperidyllpyrazolo[3,4-c lpyrimidin-4- amine

Following general procedure F, fe/f-butyl (3R)-3-[4-amino-3-[4-[(7-fluoroindolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (301 .4 mg, 0.55 mmol) afforded 3-[4-[(7-fluoroindolin-1 -yl)methyl]phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine

(145.7 mg, 0.26 mmol, 47% yield) as a pale brown solid.

UPLC-MS (ES⁺, Short acidic): 1 .32 min, m/z 444.4 [M+H]⁺

[00499] 1 -[(3f?)-3-[4-Amino-3-[4-[(7-fluoroindolin-1 -yl)methyllphenyllpyrazolo[3,4-c lpyrimidin-1 -yll-1 - piperidyllprop-2-en-1 -one

Following general procedure I, 3-[4-[(7-fluoroindolin-1 -yl)methyl]phenyl]-1 -[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (145.7 mg, 0.33 mmol) gave, after purification by flash column chromatography (DCM/MeOH 100:0 to 90:10) afforded 1 -[(3f?)-3-[4-amino-3-[4-[(7- fluoroindolin-1 -yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one (34.1 mg,

0.06 mmol, 19% yield) as a white foam/solid.

UPLC-MS (ES⁺, Short acidic): 1 .72 min, m/z 498.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.96 min, m/z 498.4 [M+H]⁺

H NMR (400 MHz, DMSO-d₆₎ δ (ppm) 8.26 (s, 1 H, ArH), 7.68-7.62 (m, 2H, ArH), 7.50 (d, J 8.2 Hz, 2H, ArH), 6.94-6.86 (m, 2H), 6.86-6.66 (m, 1 H), 6.63 (ddd, J 8.2, 7.3, 4.2 Hz 1 H, ArH), 6.17-6.02 (m, 1 H), 5.74-5.53 (m, 1 H), 4.77-4.64 (m, 1 H), 4.59-4.48 (m, 0.5H), 4.54 (s, 2H), 4.26-4.14 (m, 1 H), 4.12- 4.01 (m, 0.5H), 3.75-3.62 (m, 0.5H), 3.35 (t, J 8.7 Hz, 2H), 3.25-3.10 (m, 1 H), 3.06-2.89 (m, 0.5H), 2.97 (t, J 8.4 Hz, 2H), 2.31 -2.20 (m, 1 H), 2.16-2.06 (m, 1 H), 1 .98-1 .86 (m, 1 H), 1 .66-1 .51 (m, 1 H).

[00500] Example 67: 1 -[(3R)-3-[4-Amino-3-[4-[(3,3-dimethylindolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00501] /V./V-Diisopropylpropan-2-amine; 3,3-dimethyl-1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-

2-yl)phenyllmethyllindoline: hydrobromide

1 .01 mmol) and 3,3-dimethylindoline (0.17 mL, 1 .21 mmol) gave /V,/V-diisopropylpropan-2-amine; 3,3- dimethyl-1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]indoline; hydrobromide (508.9 mg, 0.61 mmol, 60% yield) as an orange solid. This mixture was used in the next reaction without further purification.

[00502] fe/f-Butyl (3f?)-3-[4-amino-3-[4-[(3,3-dimethylindolin-1 -yl)methyllphenyllpyrazolo[3,4- c lpyrimidin-1 -yllpiperidine-1 -carboxylate

Following general procedure D, 3,3-dimethyl-1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]indoline; /V-ethyl-/V-isopropyl-propan-2-amine; hydrobromide (442.6 mg, 0.54 mmol) and 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) gave, after purification by flash column chromatography (DCM/MeOH 100:0 to 90:10), tert- butyl (3R)-3-[4-amino-3-[4-[(3,3-dimethylindolin-1 -yl)methyl]phenyl]pyrazolo[3,4-c/]pyrimidin-1 - yl]piperidine-1 -carboxylate (288.1 mg, 0.48 mmol, 106% yield) as a brown solid-oil. UPLC-MS (ES⁺, Short acidic): 2.22 min, m/z 554.5[M+H]⁺

[00503]

amine

Following general procedure F, fe/f-butyl (3R)-3-[4-amino-3-[4-[(3,3-dimethylindolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (288.1 mg, 0.48 mmol) gave, after purification by flash column chromatography (DCM/7N ammonia in MeOH 100:0 to 90:10), 3-[4- [(3,3-dimethylindolin-1 -yl)methyl]phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine (1 16.7 mg, 0.23 mmol, 49% yield) as a fluffy cream solid.

UPLC-MS (ES⁺, Short acidic): 1 .47 min, m/z 454.4 [M+H]⁺

[00504] 1 -[(3f?)-3-[4-Amino-3-[4-[(3,3-dimethylindolin-1 -yl)methyllphenyllpyrazolo[3,4-c lpyrimidin-1 - yll-1 -piperidyllprop-2-en-1 -one

Following general procedure I, 3-[4-[(3,3-dimethylindolin-1 -yl)methyl]phenyl]-1 -[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (1 16.7 mg, 0.23 mmol) gave, after purification by preparative mass-directed reverse phase chromatography, 1 -[(3R)-3-[4-amino-3-[4-[(3,3- dimethylindolin-1 -yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one (6.5 mg, 0.01 mmol, 5% yield) as a yellow solid.

UPLC-MS (ES⁺, Short acidic): 1 .84 min, m/z 508.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 4.27 min, m/z 508.3 [M+H]⁺

1 H NMR (400 MHz, DMSO-d₆) δ (ppm) 8.29-8.22 (bs, 1 H, ArH), 7.69-7.62 (m, 2H, ArH), 7.51 (d, J 8.1 Hz, 2H, ArH), 7.05-6.97 (m, 2H), 6.91 -6.67 (m, 1 H), 6.66-6.58 (m, 2H), 6.18-6.01 (m, 1 H), 5.75-5.54 (m, 1 H), 4.77-4.63 (m, 1 H), 4.59.4.49 (m, 0.5H), 4.35 (s, 2H), 4.25-4.14 (m, 1 H), 4.12-4.03 (m, 0.5H), 3.76-3.64 (m, 0.5H), 3.25-3.15 (m, 1 H), 3.10 (s, 2H), 2.46-2.30 (m, 1 H), 2.30-2.20 (m, 1 H), 2.17-2.05 (m, 1 H), 2.01 -1 .87 (m, 1 H), 1 .68-1 .52 (m, 1 H).

[00505] Example 68:1 -[(3R)-3-[4-Amino-3-[4-[(4-methoxyindolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00506] 4-Methoxy-1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyllindoline

Following general procedure A, 4-methoxyindoline (180.8 mg, 1 .21 mmol) and 2-[4- (bromomethyl)phenyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (300.0 mg, 1 .01 mmol) afforded 4- methoxy-1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]indoline (816.1 mg, 1 .1 1 mmol, 1 1 1 % yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 2.30 min, m/z 366.0 [M+H]⁺

[00507] fe/f-Butyl (3f?)-3-[4-amino-3-[4-[(4-methoxyindolin-1 -yl)methyllphenyllpyrazolo[3,4- c lPyrimidin-1 -yllpiperidine-1 -carboxylate

Following general procedure D, /V-ethyl-/V-isopropyl-propan-2-amine; 4-methoxy-1 -[[4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]indoline (334.0 mg, 0.68 mmol) and fe/f-butyl (3R)- 3-(4-amino-3-iodo-pyrazolo[3,4-c ]pyrimidin-1 -yl)piperidine-1 -carboxylate (200.0 mg, 0.45 mmol) gave fe/f-butyl (3R)-3-[4-amino-3-[4-[(4-methoxyindolin-1 -yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 - yl]piperidine-1 -carboxylate (359.0 mg, 0.56 mmol, 123% yield) as a brown oil.

UPLC-MS (ES⁺): 2.01 min, m/z 556.5 [M+H]⁺

[00508] 3-[4-[(4-Methoxyindolin-1 -yl)methyllphenyll-1 -[(3f?)-3-piperidyllpyrazolo[3,4-c lpyrimidin-4- amine Following general procedure F, fe/ -butyl (3R)-3-[4-amino-3-[4-[(4-methoxyindolin-1- yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1-yl]piperidine-1-carboxylate (359.0 mg, 0.65 mmol) afforded 3-[4-[(4-methoxyindolin-1 -yl)methyl]phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine (151.3 mg, 0.27 mmol, 41 % yield) as a brown solid.

UPLC-MS (ES⁺, Short acidic): 1.30 min, m/z 456.2 [M+H]⁺

[00509] 1-[(3 ?)-3-[4-Amino-3-[4-[(4-methoxyindolin-1-yl)methyllphenyllpyrazolo[3,4-c lpyrimidin-1-yll- 1 -piperidyllprop-2-en-1 -one

Following general procedure I, 3-[4-[(4-methoxyindolin-1-yl)methyl]phenyl]-1-[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (151.3 mg, 0.33 mmol) gave, after purification by preparative mass-directed reverse phase chromatography, 1-[(3R)-3-[4-amino-3-[4-[(4-methoxyindolin- 1-yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1-yl]-1-piperidyl]prop-2-en-1-one (22.0 mg, 0.04 mmol, 12% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.65 min, m/z 510.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.80 min, m/z 510.3 [M+H]⁺

H NMR (400 MHz, DMSO-d₆, δ (ppm) 8.26 (s, 1 H, ArH), 7.67-7.61 (m, 2H, ArH), 7.50 (d, J 8.2 Hz, 2H, ArH), 6.99 (dd, J 8.1 , 8.1 Hz, 1 H), 6.92-6.65 (m, 1 H), 6.63 (d, J 8.1 Hz 1 H, ArH), 6.17-6.00 (m, 1 H), 5.74-5.54 (m, 1 H), 4.77-4.62 (m, 1 H), 4.59-4.49 (m, 0.5H), 4.33 (s, 2H), 4.25-4.14 (m, 1 H), 4.11- 4.03 (m, 0.5H), 3.74 (s, 3H), 3.74-3.64 (m, 0.5H), 3.38-3.26 (m, 2H), 3.26-3.12 (m, 1 H), 3.07-2.95 (m, 0.5H), 2.83 (t, J 8.5 Hz, 2H), 2.30-2.20 (m, 1 H), 2.17-2.07 (m, 1 H), 1.98-1.87 (m, 1 H), 1.67-1.50 (m, 1 H).

[00510] Example 69: 1-[(3R)-3-[4-Amino-3-[4-[(4-methylindolin-1-yl)methyl]phenyl]pyrazolo[3,4- cflpyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00511] 4-Methyl-1-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyllindoline

Following general procedure A, 4-methylindoline (161.4 mg, 1 .21 mmol) and 2-[4- (bromomethyl)phenyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (300.0 mg, 1.01 mmol) afforded 4- methyl-1-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]indoline (334.3 mg, 0.86 mmol,

85% yield) as a yellow-orange solid.

UPLC-MS (ES⁺, Short acidic): 2.39 min, m/z 349.9 [M+H]⁺

[00512] fe/f-Butyl (3f?)-3-[4-amino-3-[4-[(4-methylindolin-1-yl)methyllphenyllpyrazolo[3,4-c/lpyrimidin- 1 -yllpiperidine-1 -carboxylate

Following general procedure D, 4-methyl-1-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]indoline (235.9 mg, 0.68 mmol) and fe/ -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/ -butyl (3R)-3-[4-amino-3-[4- [(4-methylindolin-1-yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1-yl]piperidine-1 -carboxylate (280.4 mg, 0.47 mmol, 104% yield) as a yellow gum. This mixture was used in the next reaction without further purification.

UPLC-MS (ES⁺, Short acidic): 2.11 min, m/z 540.4 [M+H]⁺

[00513] 3-[4-[(4-Methylindolin-1-yl)methyllphenyll-1-[(3f?)-3-piperidyllpyrazolo[3,4-c lpyrimidin-4- amine

Following general procedure F, fe/ -butyl (3R)-3-[4-amino-3-[4-[(4-methylindolin-1- yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1-yl]piperidine-1-carboxylate (280.4 mg, 0.52 mmol) afforded 3-[4-[(4-methylindolin-1 -yl)methyl]phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4-<^pyrimidin-4-amine (154.5 mg, 0.28 mmol, 54% yield) as a light brown solid.

UPLC-MS (ES⁺, Short acidic): 1.34 min, m/z 440.3 [M+H]⁺

[00514] 1 -[(3f?)-3-[4-Amino-3-[4-[(4-methylindolin-1 -yl)methyllphenyllpyrazolo[3,4-c lpyrimidin-1 -yll-1 - piperidyllprop-2-en-1 -one

Following general procedure I, 3-[4-[(4-methylindolin-1-yl)methyl]phenyl]-1-[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (154.5 mg, 0.35 mmol) gave 1-[(3R)-3-[4-amino-3-[4-[(4- methylindolin-1 -yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one (90.3 mg, 0.16 mmol, 47% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.75 min, m/z 494.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 4.01 min, m/z 494.2 [M+H]⁺

H NMR (400 MHz, DMSO-d₆) δ (ppm) 8.26 (s, 1 H, ArH), 7.67-7.61 (m, 2H, ArH), 7.51 (d, J 8.3 Hz, 2H, ArH), 6.90 (dd, J 7.8, 7.8 Hz, 1 H), 6.91-6.65 (m, 1 H), 6.46-6.41 (m, 2H), 6.17-6.01 (m, 1 H), 5.74- 5.54 (m, 1 H), 4.78-4.63 (m, 1 H), 4.58-4.50 (m, 0.5H), 4.32 (s, 2H), 4.25-4.14 (m, 1 H), 4.12-4.00 (m, 0.5H), 3.74 (s, 3H), 3.76-3.64 (m, 0.5H), 3.40-3.30 (m, 2H), 3.25-3.12 (m, 1 H), 3.06-2.94 (m, 0.5H),

2.85 (t, J 8.3 Hz, 2H), 2.29-2.19 (m, 1 H), 2.17-2.08 (m, 1 H), 2.14 (s, 2H), 1.98-1.89 (m, 1 H), 1.67-1.52 (m, 1 H).

[00515] Example 70: 1-[(3R)-3-[4-Amino-3-[4-[(7-chloroindolin-1-yl)methyl]phenyl]pyrazolo[3,4- cflpyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00516] 7-Chloro-1-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyllindoline

Following general procedure A, 7-chloroindoline (186.2 mg, 1.21 mmol) and 2-[4-

(bromomethyl)phenyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (300.0 mg, 1.01 mmol) afforded 7- chloro-1-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]indoline (384.7 mg, 0.88 mmol,

88% yield) as a dark yellow-orange solid.

UPLC-MS (ES⁺, Short acidic): 2.41 min, m/z 370.6 [M+H]⁺

[00517] tert- Butyl (3 ?)-3-[4-amino-3-[4-[(7-chloroindolin-1-yl)methyllphenyllpyrazolo[3,4-c/lpyrimidin-

1 -yllpiperidine-1 -carboxylate

Following general procedure D, 7-chloro-1-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]indoline (249.7 mg, 0.68 mmol) and fe/ -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/ -butyl (3R)-3-[4-amino-3-[4- [(7-chloroindolin-1-yl)methyl]phenyl]pyrazolo[3,4-c/]pyrimidin-1-yl]piperidine-1 -carboxylate (288.7 mg, 0.46 mmol, 103% yield) as a yellow gum.

UPLC-MS (ES⁺, Short acidic): 2.15 min, m/z 561 .0 [M+H]⁺

[00518] 3-[4-[(7-Chloroindolin-1-yl)methyllphenyll-1-[(3f?)-3-piperidyllpyrazolo[3,4-c lpyrimidin-4- amine

Following general procedure F, fe/ -butyl (3R)-3-[4-amino-3-[4-[(7-chloroindolin-1- yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1-yl]piperidine-1-carboxylate (288.7 mg, 0.52 mmol) afforded 3-[4-[(7-chloroindolin-1 -yl)methyl]phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine (153.2 mg, 0.27 mmol, 52% yield) as light brown solid.

UPLC-MS (ES⁺, Short acidic): 1 .37min, m/z 460.2 [M+H]⁺ [00519] 1 -[(3f?V3-[4-Amino-3-[4-[(7-chloroindolin-1 -yl)methyllphenyllpyrazolo[3,4-c lpyrimidin-1 -yll-1 - piperidyllprop-2-en-1 -one

Following general procedure I, 3-[4-[(7-chloroindolin-1-yl)methyl]phenyl]-1-[(3R)-3- piperidyl]pyrazolo[3,4-c/]pyrimidin-4-amine (153.2 mg, 0.33 mmol) gave 1-[(3R)-3-[4-amino-3-[4-[(7- chloroindolin-1 -yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one (72.2 mg, 0.13 mmol, 38% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1 .78 min, m/z 514.1 [M]⁺

UPLC-MS (ES⁺, Long acidic): 4.09 min, m/z 514.1 [M]⁺

H NMR (400 MHz, DMSO-d₆) δ (ppm) 8.26 (s, 1 H, ArH), 7.67-7.61 (m, 2H, ArH), 7.49 (d, J 8.3 Hz, 2H, ArH), 7.08-7.01 (m, 2H), 6.92-6.67 (m, 1 H), 6.65 (dd, J 8.1 , 7.2 Hz, 1 H), 6.17-6.01 (m, 1 H), 5.74- 5.54 (m, 1 H), 4.80 (s, 2H), 4.76-4.62 (m, 1 H), 4.58-4.50 (m, 0.5H), 4.26-4.14 (m, 1 H), 4.12-4.02 (m, 0.5H), 3.74-3.64 (m, 0.5H), 3.44 (t, J 8.8 Hz, 2H), 3.25-3.12 (m, 1 H), 3.06-3.00 (m, 0.5H), 2.99 (t, J 8.8 Hz, 2H), 2.29-2.20 (m, 1 H), 2.16-2.07 (m, 1 H), 1.98-1.87 (m, 1 H), 1.66-1.51 (m, 1 H).

[00520] Example 71 : 1-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4- c |pyrimidin-3-yl]phenyl]methyl]indoline-5-carbonitrile

[00521] lndoline-5-carbonitrile

Following general procedure M, 5-cyanoindole (600.0 mg, 4.22 mmol) afforded indoline-5-carbonitrile (340.0 mg, 2.36 mmol, 56% yield) as a light yellow solid.

UPLC-MS (ES⁺, Short acidic): 1 .30 min, m/z 289.0 [2M+H]⁺.

[00522] 1-[[4-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyllindoline-5-carbonitrile

Following general procedure A, 4-bromomethylphenylboronic acid pinacol ester (513.8 mg, 1.73 mmol) and indoline-5-carbonitrile (340.0 mg, 2.36 mmol) afforded 1-[[4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl]methyl]indoline-5-carbonitrile (450.0 mg, 1.25 mmol, 72% yield) as a yellow- orange solid.

UPLC-MS (ES⁺, Short acidic): 2.14 min, m/z 361.0 [M+H]⁺.

[00523] fe/f-Butyl (3 ?)-3-[4-amino-3-[4-[(5-cvanoindolin-1-yl)methyllphenyllpyrazolo[3,4-c/lpyrimidin- 1 -yllpiperidine-1 -carboxylate

Following general procedure D, fe/f-butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1- yl)piperidine-1 -carboxylate (300.0 mg, 0.68 mmol) and 1-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]indoline-5-carbonitrile (450.0 mg, 1 .25 mmol) afforded fe/f-butyl (3R)-3-[4-amino-3-[4- [(5-cyanoindolin-1-yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1-yl]piperidine-1 -carboxylate (340.0 mg , 0.62 mmol, 91 % yield) as a yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.88 min, m/z 551.5 [M+H]⁺.

[00524] 1-[[4-[4-Amino-1-[(3 ?)-3-piperidyllpyrazolo[3,4-c lpyrimidin-3-yllphenyllmethyllindoline-5- carbonitrile

Following general procedure F, fe/f-butyl (3R)-3-[4-amino-3-[4-[(5-cyanoindolin-1- yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1-yl]piperidine-1-carboxylate (340.0 mg, 0.62 mmol) afforded 1-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-(^pyrimidin-3-yl]phenyl]methyl]indoline-5-carbonitrile (180.0 mg, 0.40 mmol, 65% yield) as a light brown solid.

UPLC-MS (ES⁺, Short acidic): 1.39 min, m/z 451.2 [M+H]⁺ [00525] 1 -[[4-[4-Amino-1 -[(3f?)-1 -prop-2-enoyl-3-piperidyllpyrazolo[3,4-c lpyrimidin-3- yllphenyllmethyllindoline-5-carbonitrile

Following general procedure I, 1 -[[4-[4-amino-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-3- yl]phenyl]methyl]indoline-5-carbonitrile (180.0 mg, 0.40 mmol) afforded 1 -[[4-[4-amino-1 -[(3R)-1 -prop- 2-enoyl-3-piperidyl]pyrazolo[3,4-(^pyrimidin-3-yl]phenyl]methyl]indoline-5-carbonitrile (15.2 mg, 0.029 mmol, 7% yield) as a white solid following preparative mass-directed reverse phase chromatography. UPLC-MS (ES⁺, Short acidic): 1 .55 min, m/z 505.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.56 min, m/z 505.3 [M+H]⁺

H NMR (400 MHz, DMSO-d₆) δ (ppm) 8.27 (s, 1 H, ArH), 7.68-7.63 (m, 2H, ArH), 7.51 -7.46 (m, 2H, ArH), 7.45-7.41 (m, 1 H, ArH), 7.37-7.34 (m, 1 H ArH), 6.92-6.81 (m, 0.5H), 6.76-6.65 (m, 1 .5H, ArH +

0.5CH), 6.17-6.02 (m, 1 H), 5.75-5.68 (m, 0.5H), 5.61 -5.55 (m, 0.5H), 4.78-4.64 (m, 1 H), 4.59-4.47 (m,

0.5H), 4.52 (s, 2H, CH₂), 4.27-4.03 (m, 1 .5H), 3.75-3.65 (m, 0.5H), 3.57 (t, ³J = 8.7 Hz, 2H, CH₂), 3.35-

3.30 (m, 0.5H), 3.26-3.15 (m, 1 H), 3.03 (t, ³ = 8.7 Hz, 2H, CH₂), 2.32-2.20 (m, 1 H), 2.18-2.07 (m, 1 H),

1 .98-1 .89 (m, 1 H), 1 .68-1 .53 (m, 1 H).

[00526] Example 72: 1 -[(3R)-3-[4-Amino-3-[4-[[6-(trifluoromethyl)indolin-1 - yl]methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00527] 6-(Trifluoromethyl)indoline

Following general procedure M, 6-(trifluoromethyl)-1 /-/-indole (500.0 mg, 2.70 mmol) gave 6- (trifluoromethyl)indoline (226.9 mg, 1 .21 mmol, 45% yield) as an orange oil. This mixture was used in the next reaction without further purification.

UPLC-MS (ES⁺, Short acidic): 1 .53 min, m/z 187.9 [M+H]⁺

[00528] 1 -[[4-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyll-6-(trifluoromethyl)indoline Following general procedure A, 4-bromomethylphenylboronic acid pinacol ester (300.0 mg, 1 .01 mmol) and 6-(trifluoromethyl)indoline (226.9 mg, 1 .21 mmol) afforded 1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl]methyl]-6-(trifluoromethyl)indoline (407.3 mg, 1 .01 mmol, 100% yield) as a brown film and as a mixture with Λ/,/V-diisopropylethylamine. This mixture was used in the next reaction without further purification, assumed quantitative.

UPLC-MS (ES⁺, Short acidic): 2.38 min, m/z 404.0 [M+H]⁺

[00529] fe/f-Butyl (3f?)-3-[4-amino-3-[4-[[6-(trifluoromethyl)indolin-1 -yllmethyllphenyllpyrazolo[3,4- c lpyrimidin-1 -yllpiperidine-1 -carboxylate

Following general procedure D, 1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]-6- (trifluoromethyl)indoline (407.3 mg, 1 .01 mmol) and fe/ -butyl (3/?)-3-(4-amino-3-iodo-pyrazolo[3,4- c ]pyrimidin-1 -yl)piperidine-1 -carboxylate (200.0 mg, 0.45 mmol) afforded fe/ -butyl (3/?)-3-[4-amino-3- [4-[[6-(trifluoromethyl)indolin-1 -yl]methyl]ph

(236 mg, 0.40 mmol, 88% yield) as a light brown film.

UPLC-MS (ES⁺, Short acidic): 2.16 min, m/z 594.5 [M+H]+

[00530] 1 -[(3f?)-3-Piperidyll-3-[4-[[6-(trifluoromethyl)indolin-1 -yllmethyllphenyllpyrazolo[3,4- c lPyrimidin-4-amine

Following general procedure F, fe/ -butyl (3/?)-3-[4-amino-3-[4-[[6-(trifluoromethyl)indolin-1 - yl]methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (236.0 mg, 0.40 mmol) afforded 1 -[(3R)-3-piperidyl]-3-[4-[[6-(trifluoromethyl)indolin-1 -yl]methyl]pheny^

c ]pyrimidin-4-amine (156.3 mg, 0.32 mmol, 80% yield) as a brown film.

UPLC-MS (ES⁺, Short acidic): 1 .50 min, m/z 494.3 [M+H]⁺

[00531] 1 -[(3 ?)-3-[4-Amino-3-[4-[[6-(trifluoromethyl)indolin-1 -yllmethyllphenyllpyrazol^

c lpyrimidin-1 -yll-1 -pipe ridyllprop-2-en-1 -one

Following general procedure I, 1 -[(3R)-3-piperidyl]-3-[4-[[6-(trifluoromethyl)indolin-1 - yl]methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-4-amine (156.3 mg, 0.32 mmol) afforded 1 -[(3R)-3-[4-amino- 3-[4-[[6-(trifiuoromethyl)indolin-1 -yl]methyl]phenyl]pyrazolo[3,4-(^pyrimidin-1 -yl]-1 -piperidy

1 -one (45.6 mg, 0.08 mmol, 26% yield) as a white crystalline powder.

UPLC-MS (ES⁺, Short acidic): 1 .85 min, m/z 548.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 4.29 min, m/z 548.3 [M+H]⁺

H NMR (400 MHz, DMSO-d₆) δ (ppm) 8.26 (s, 1 H, ArH), 7.66 (d, J 7.9 Hz, 2H, ArH), 7.51 (d, J 7.9 Hz, 2H, ArH), 7.22 (d, J 7.6 Hz, 1 H, ArH), 6.92-6.85 (d, J 7.6 Hz, 2H, ArH), 6.90-6.81 (m, 0.5H), 6.76-6.65 (m, 0.5H), 6.18-6.02 (m, 1 H), 5.75-5.67 (m, 0.5H), 5.62-5.55 (m, 0.5H), 4.77-4.64 (m, 1 H), 4.59-4.50 (m, 0.5H), 4.46 (s, 2H, CH₂), 4.25-4.15 (m, 1 H), 4.1 1 -4.03 (m, 0.5H), 3.74-3.65 (m, 0.5H), 3.43 (t, J 8.3 Hz, 2H, CH₂), 3.37-3.26 (m, 0.5H), 3.26-3.15 (m, 1 H), 3.02 (t, J 8.3 Hz, 2H, CH₂), 2.32-2.20 (m, 1 H), 2.16-2.08 (m, 1 H), 1 .97-1 .89 (m, 1 H), 1 .66-1 .52 (m, 1 H).

[00532] Example 73: 1 -[(3R)-3-[4-Amino-3-[4-[(4,6-difluoroindolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00533] 4,6-Difluoroindoline

Following general procedure L, 4,6-difluoroindole (500.0 mg, 3.27 mmol) afforded 4,6-difluoroindoline (506.6 mg, 3.27 mmol, 100% yield) as a light brown oil. This mixture was used in the next reaction without further purification, assumed quantitative.

UPLC-MS (ES⁺, Short acidic): 1 .53 min, m/z 155.9 [M+H]⁺

[00534] 4,6-Difluoro-1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyllindoline

Following general procedure A, 4-bromomethylphenylboronic acid pinacol ester (300.0 mg, 1 .01 mmol) and 6-(trifluoromethyl)indoline (226.9 mg, 1 .21 mmol) afforded 4,6-difluoro-1 -[[4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]indoline (374.9 mg, 1 .01 mmol, 100% yield) as a brown film and as a mixture with Λ/,/V-diisopropylethylamine. This mixture was used in the next reaction without further purification, assumed quantitative.

UPLC-MS (ES⁺, Short acidic): 2.34 min, m/z 372.0 [M+H]⁺

[00535] fe/f-Butyl (3f?)-3-[4-amino-3-[4-[(4,6-difluoroindolin-1 -yl)methyllphenyllpyrazolo[3,4- c lPyrimidin-1 -yllpiperidine-1 -carboxylate

Following general procedure D, fe/ -butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1 - yl)piperidine-1 -carboxylate (200.0 mg, 0.45 mmol) and 4,6-difluoro-1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl]methyl]indoline (374.9 mg, 1 .01 mmol) afforded fe/ -butyl (3R)-3-[4-amino-3-

[4-[(4,6-difluoroindolin-1 -yl)methyl]phenyl]pyrazolo[3,4-(^pyrimidin-1 -yl]piperidine-1 -carboxylate (248.0 mg, 0.44 mmol, 98% yield) as a light brown film.

UPLC-MS (ES⁺, Short acidic): 2.10 min, m/z 562.4 [M+H]⁺

[00536] 3-[4-[(4,6-Difluoroindolin-1 -yl)methyllphenyll-1 -[(3f?)-3-piperidyllpyrazolo[3,4-c/lpyrimidin-4- amine Following general procedure F, fe/ -butyl (3R)-3-[4-amino-3-[4-[(4,6-difluoroindolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (248.0 mg, 0.44 mmol) afforded 3-[4-[(4,6-difluoroindolin-1 -yl)methyl]phenyl]-1 - ^

(199.0 mg, 0.43 mmol, 98% yield) as a brown film.

UPLC-MS (ES⁺, Short acidic): 1 .41 min, m/z 462.4 [M+H]⁺

[00537] 1 -[(3f?)-3-[4-Amino-3-[4-[(4,6-difluoroindolin-1 -yl)methyllphenyllpyrazolo[3,4-c/lpyrimidin-1 - yll-1 -piperidyllprop-2-en-1 -one

Following general procedure I, 3-[4-[(4,6-difluoroindolin-1 -yl)methyl]phenyl]-1 -[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (199.0 mg, 0.43 mmol) afforded 1 -[(3R)-3-[4-amino-3-[4- [(4,6-difluoroindolin-1 -yl)methyl]phenyl]pyrazolo[3,4-(^pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -on (39.3 mg, 0.077 mmol, 18% yield) as an off-white crystalline powder.

UPLC-MS (ES⁺, Short acidic): 1 .78 min, m/z 516.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 4.12 min, m/z 516.4 [M+H]⁺

H NMR (400 MHz, DMSO-d₆) δ (ppm) 8.27 (s, 1 H, ArH), 7.66 (d, J 7.8 Hz, 2H, ArH), 7.49 (d, J 7.8 Hz, 2H, ArH), 6.81 -6.92 (m, 0.5H), 6.76-6.65 (m, 0.5H), 6.40 (dd, J 10.0, 2.1 Hz, 1 H, ArH), 6.28 (dd, J

10.0, 2.1 Hz, 1 H, ArH), 6.18-6.02 (m, 1 H), 5.74-5.67 (m, 0.5H), 5.62-5.55 (m, 0.5H), 4.78-4.64 (m, 1 H), 4.58-4.50 (m, 0.5H), 4.42 (s, 2H, CH₂), 4.24-4.15 (m, 1 H), 4.12-4.04 (m, 0.5H), 3.75-3.65 (m, 0.5H), 3.50 (t, J 8.3 Hz, 2H, CH₂), 3.26-3.15 (m, 1 H), 2.98-2.87 (m, 0.5H), 2.95 (t, J 8.3 Hz, 2H, CH₂), 2.32- 2.20 (m, 1 H), 2.16-2.08 (m, 1 H), 1 .97-1 .89 (m, 1 H), 1 .66-1 .52 (m, 1 H).

[00538] Example 74: 1 -[(3R)-3-[4-Amino-3-[4-[(5-methylindolin-1 -yl)methyl]phenyl]pyrazolo[3,4- cflpyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00539] 5-Methyl-1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyllindoline

Following general procedure A, 5-methylindoline (161 .4 mg, 1 .21 mmol) and 2-[4- (bromomethyl)phenyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (300.0 mg, 1 .01 mmol) afforded 5- methyl-1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]indoline (334.3 mg, 0.86 mmol, 85% yield) as a yellow solid.

UPLC-MS (ES⁺, Short acidic): 2.39 min, m/z 349.7 [M+H]⁺

[00540] fe/f-Butyl (3f?)-3-[4-amino-3-[4-[(5-methylindolin-1 -yl)methyllphenyllpyrazolo[3,4-c/lpyrimidin-

1 -yllpiperidine-1 -carboxylate

Following general procedure D, 5-methyl-1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]indoline (235.9 mg, 0.68 mmol) and fe/ -butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4- c ]pyrimidin-1 -yl)piperidine-1 -carboxylate (200 mg, 0.45 mmol) gave fe/ -butyl (3R)-3-[4-amino-3-[4-[(5- methylindolin-1 -yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (273.4 mg , 0.43 mmol, 96% yield) as a brown oil.

UPLC-MS (ES⁺, Short acidic): 2.12 min, m/z 540.1 [M+H]⁺

[00541] 3-[4-[(5-Methylindolin-1 -yl)methyllphenyll-1 -[(3f?)-3-piperidyllpyrazolo[3,4-c lpyrimidin-4- amine

Following general procedure F, fe/ -butyl (3R)-3-[4-amino-3-[4-[(5-methylindolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (273.4 mg, 0.51 mmol) afforded 3-[4-[(5-methylindolin-1 -yl)methyl]phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine (153.5 mg, 0.31 mmol, 62% yield) as a pale brown solid. UPLC-MS (ES⁺, Short acidic): 1 .37 min, m/z 440.2 [M+H]⁺

[00542] 1 -[(3f?)-3-[4-Amino-3-[4-[(5-methylindolin-1 -yl)methyllPhenyllPyrazolo[3,4-c lpyrimidin-1 -yll-1 - piperidyllprop-2-en-1 -one

Following general procedure I, 3-[4-[(5-methylindolin-1 -yl)methyl]phenyl]-1 -[(3R)-3- piperidyl]pyrazolo[3,4-c/]pyrimidin-4-amine (153.5 mg, 0.35 mmol), after preparative mass-directed reverse phase chromatography, gave 1 -[(3R)-3-[4-amino-3-[4-[(5-methylindolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one (48.4 mg, 0.09 mmol, 25% yield) as a yellow solid.

UPLC-MS (ES⁺, Short acidic): 1 .75 min, m/z 494.1 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 4.01 min, m/z 494.1 [M+H]⁺

H NMR (400 MHz, DMSO-c/₆, δ): 8.27 (s, 1 H, ArH), 7.69-7.62 (m, 2H, ArH), 7.52 (d, J 8.3 Hz, 2H, ArH), 6.90 (s, 1 H), 6.90-6.66 (m, 2H), 6.52 (d, J 7.8 Hz 1 H, ArH), 6.18-6.02 (m, 1 H), 5.75-5.54 (m, 1 H), 4.78-4.64 (m, 1 H), 4.60-4.51 (m, 0.5H), 4.29 (s, 2H), 4.26-4.15 (m, 1 H), 4.13-4.03 (m, 0.5H), 3.76-3.64 (m, 0.5H), 3.36-3.13 (m, 3H), 3.09-2.96 (m, 0.5H), 2.88 (t, J 8.2 Hz, 2H), 2.32-2.20 (m, 1 H), 2.18 (s, 3H), 2.17-2.07 (m, 1 H), 1 .98-1 .88 (m, 1 H), 1 .68-1 .50 (m, 1 H).

[00543] Example 75: 1 -[(3R)-3-[4-Amino-3-[4-[[5-(trifluoromethyl)indolin-1 - yl]methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00544] 5-(Trifluoromethyl)indoline

Following general procedure L, 5-(trifluoromethyl)-1 /-/-indole (400.0 mg, 2.16 mmol) afforded 5- (trifluoromethyl)indoline (404.3 mg, 2.16 mmol, 100% yield) as a yellow oil. This mixture was used in the next reaction without further purification, assumed quantitative.

UPLC-MS (ES⁺, Short acidic): 1 .66 min, m/z 187.8 [M+H]⁺

[00545] 1 -[[4-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyll-5-(trifluoromethyl)indoline Following general procedure A, 4-bromomethylphenylboronic acid pinacol ester (300.0 mg, 1 .01 mmol) and 6-(trifluoromethyl)indoline (226.9 mg, 1 .21 mmol) afforded 1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl]methyl]-5-(trifluoromethyl)indoline (487.9 mg, 1 .21 mmol, 100% yield) as a brown film and as a mixture with Λ/,/V-diisopropylethylamine. This mixture was used in the next reaction without further purification, assumed quantitative.

UPLC-MS (ES⁺, Short acidic): 2.38 min, m/z 404.0 [M+H]⁺ & 1 .83 min, m/z 321 .9 [RB(OH)₂+H]⁺

[00546] fe/f-Butyl (3f?)-3-[4-amino-3-[4-[[5-(trifluoromethyl)indolin-1 -yllmethyllphenyllpyrazolo[3,4- c lPyrimidin-1 -yllpiperidine-1 -carboxylate

Following general procedure D, fe/f-butyl (3/?)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1 - yl)piperidine-1 -carboxylate (200.0 mg, 0.45 mmol) 1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]-5-(trifluoromethyl)indoline (487.9 mg, 1 .21 mmol) afforded fe/f-butyl (3/?)-3-[4-amino- 3-[4-[[5-(trifluoromethyl)indolin-1 -yl]methyl]phenyl]pyrazolo[3,4-(^pyrimidin-1 -yl]piperidine-1 - carboxylate (245.0 mg, 0.41 mmol, 92% yield) as a light brown film.

UPLC-MS (ES⁺, Short acidic): 2.15 min, m/z 594.5 [M+H]⁺

[00547] 1 -[(3f?)-3-Piperidyll-3-[4-[[5-(trifluoromethyl)indolin-1 -yllmethyllphenyllpyrazolo[3,4- c lPyrimidin-4-amine

Following general procedure F, fe/f-butyl (3/?)-3-[4-amino-3-[4-[[5-(trifluoromethyl)indolin-1 - yl]methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (245.0 mg, 0.41 mmol) afforded 1 -[(3R)-3-piperidyl]-3-[4-[[5-(trifluoromethyl)m^

(193.0 mg, 0.39 mmol, 95% yield) as a brown film.

UPLC-MS (ES⁺, Short acidic): 1 .49 min, m/z 494.4 [M+H]⁺

[00548] 1 -[(3 ?)-3-[4-Amino-3-[4-[[5-(trifluoromethyl)indolin-1 -yllmethyllphenyllpyrazolo[3,4- c/lpyrimidin-1 -yll-1 -pipe ridyllprop-2-en-1 -one

Following general procedure I, 1 -[(3R)-3-piperidyl]-3-[4-[[5-(trifluoromethyl)indolin-1 - yl]methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-4-amine (193.0 mg, 0.39 mmol) afforded 1 -[(3R)-3-[4-amino- 3-[4-[[5-(trifluoromethyl)indolin-1 -yl]methyl]phenyl]pyrazolo[3,4-(^pyrimidin-1 -yl]-1 -piperi

1 -one (40.7 mg, 0.074 mmol, 19% yield; 1 :0.14 product:formic acid) as a white crystalline solid following preparative mass-directed reverse phase chromatography.

UPLC-MS (ES⁺, Short acidic): 1 .85 min, m/z 548.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 4.30 min, m/z 548.4 [M+H]⁺

1 H NMR (400 MHz, DMSO-d₆) δ (ppm) 8.32 (s, 0.14H, HC0₂H), 8.27 (s, 1 H, ArH), 7.66 (d, J 7.6 Hz,

2H, ArH), 7.50 (d, J 7.6 Hz, 2H, ArH), 7.36-7.29 (m, 2H, ArH), 6.92-6.81 (m, 0.5H), 6.77-6.65 (m, 0.5H), 6.72-6.66 (m, 1 H, ArH), 6.18-6.02 (m, 1 H), 5.75-5.67 (m, 0.5H), 5.62-5.55 (m, 0.5H), 4.77-4.64

(m, 1 H), 4.59-4.51 (m, 0.5H), 4.48 (s, 2H, CH₂), 4.25-4.15 (m, 1 H), 4.13-4.04 (m, 0.5H), 3.75-3.65 (m,

0.5H), 3.52 (t, J 8.5 Hz, 2H, CH₂), 3.40-3.27 (m, 0.5H), 3.26-3.15 (m, 1 H), 3.03 (t, J 8.5 Hz, 2H, CH₂),

2.32-2.20 (m, 1 H), 2.19-2.08 (m, 1 H), 1 .99-1 .89 (m, 1 H), 1 .67-1 .51 (m, 1 H).

[00549] Example 76: 1 -[[4-[4-Amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- c |pyrimidin-3-yl]phenyl]methyl]indoline-4-carbonitrile

[00550] lndoline-4-carbonitrile

Following general procedure M, 1 /-/-indole-4-carbonitrile (500.0 mg, 3.52 mmol) afforded indoline-4- carbonitrile (355.0 mg, 2.46 mmol, 70% yield) as a light yellow oil that solidified on standing.

UPLC-MS (ES⁺, Short acidic): 1 .13 min, m/z 289.0 [2M+H]⁺ & 186.0 [M+MeCN+H]⁺

[00551] 1 -[[4-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyllindoline-4-carbonitrile

Following general procedure A, 4-bromomethylphenylboronic acid pinacol ester (300.0 mg, 1 .01 mmol) and indoline-4-carbonitrile (355.0 mg, 2.46 mmol) afforded 1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl]methyl]indoline-4-carbonitrile (363.9 mg, 1 .01 mmol, 100% yield) as a yellow- orange solid. This was used in the next reaction without further purification, assumed quantitative. UPLC-MS (ES⁺, Short acidic): 2.22 min, m/z 361 .0 [M+H]⁺

[00552] fe/f-Butyl (3 ?)-3-[4-amino-3-[4-[(4-cvanoindolin-1 -yl)methyllphenyllpyrazolo[3,4-c/lpyrimidin- 1 -yllpiperidine-1 -carboxylate

Following general procedure D, fe/f-butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1 - yl)piperidine-1 -carboxylate (250.0 mg, 0.56 mmol) and 1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]indoline-4-carbonitrile (484.4 mg, 1 .34 mmol) afforded fe/f-butyl (3R)-3-[4-amino-3-[4- [(4-cyanoindolin-1 -yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (252.0 mg , 0.46 mmol, 81 % yield) as an orange solid.

UPLC-MS (ES⁺, Short acidic): 1 .96 min, m/z 551 .4 [M+H]⁺

[00553] 1 -[[4-[4-Amino-1 -[(3 ?)-3-piperidyllpyrazolo[3,4-c lpyrimidin-3-yllphenyllmethyllindoline-4- carbonitrile Following general procedure F, fe/ -butyl (3R)-3-[4-amino-3-[4-[(4-cyanoindolin-1- yl)methyl]phenyl]pyrazolo[3,4-c]pyrimidin-1-yl]piperidine-1-carboxylate (252.0 mg, 0.46 mmol) afforded 1-[[4-[4-amino-1-[(3R)-3^iperidyl]pyrazolo[3,4-(^pyrimidin-3-yl]phenyl]methyl]indoline-4-ca

(200.0 mg, 0.44 mmol, 97% yield) as an off-white solid.

UPLC-MS (ES⁺, Short acidic): 1.32 min, m/z 451.4 [M+H]⁺

[00554] [[4-[4-Amino-1-[(3?)-1-prop-2-enoyl-3-piperidyllpyrazolo[3,4-clpyrimidin-3- yllphenyllmethyllindoline-4-carbonitrile

Following general procedure I, 1-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-c]pyrimidin-3- yl]phenyl]methyl]indoline-4-carbonitrile (200.0 mg, 0.44 mmol) afforded 1-[[4-[4-amino-1-[(3R)-1-prop- 2-enoyl-3-piperidyl]pyrazolo[3,4-c]pyrimidin-3-yl]phenyl]methyl]indoline-4-carbonitrile (104.3 mg, 0.20 mmol, 44 % yield) as an off-white solid.

UPLC-MS (ES⁺, Short acidic): 1.62 min, m/z 505.4 [M+H]⁺ (100%)

UPLC-MS (ES⁺, Long acidic): 3.73 min, m/z 505.4 [M+H]⁺ (100%)

H NMR (400 MHz, DMSO-d₆) δ (ppm) 8.27 (s, 1 H, ArH), 7.66 (d, ³J 7.9 Hz, 2H, ArH), 7.51 (d, ³J 7.9 Hz, 2H, ArH), 7.18 (t, ³J 7.9 Hz, 1H, ArH), 6.95-6.87 (m, 2H, ArH), 6.91-6.81(m, 0.5H), 6.77-6.66 (m, 0.5H), 6.18-6.01 (m, 1H), 5.75-5.67 (m, 0.5H), 5.63-5.55 (m, 0.5H), 4.79-4.64 (m, 1H), 4.59-4.51 (m, 0.5H), 4.44 (s, 2H, CH₂), 4.25-4.15 (m, 1H), 4.13-4.03 (m, 0.5H), 3.76-3.65 (m, 0.5H), 3.51 (t, ³J8.4 Hz, 2H, CH₂), 3.27-3.17 (m, 1H), 3.14 (t, ³J8.4 Hz, 2H, CH₂), 3.08-2.97 (m, 0.5H), 2.33-2.20 (m, 1H), 2.18-2.08 (m, 1H), 2.00-1.87 (m, 1H), 1.68-1.51 (m, 1H).

[00555] Example 77: (3R)-3-[4-Amino-3-[4-[(5-fluoroindolin-1-yl)methyl]phenyl]pyrazolo[3,4- cflpyrimidin-1 -yl]piperidine-1 -carbonitrile

Following general procedure G, 3-[4-[(5-fluoroindolin-1-yl)methyl]phenyl]-1-[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (89.0 mg, 0.20 mmol) afforded (3R)-3-[4-amino-3-[4-[(5- fluoroindolin-1-yl)methyl]phenyl]pyrazolo[3,4-c]pyrimidin-1-yl]piperidine-1 -carbonitrile (61.0 mg, 0.13 mmol, 65% yield).

UPLC-MS (ES⁺, Long acidic): 3.93 min, m/z 469.1 [M+H]⁺

H NMR (400 MHz, DMSO-d₆) δ (ppm) 8.28 (s, 1H, ArH), 7.65 (d, ³J8.2 Hz, 2H, ArH), 7.52 (d, ³J8.2 Hz, 2H, ArH), 6.96-6.91 (m, 1 H), 6.84-6.77 (m, 1 H), 6.56 (dd, J 8.5, 4.4 Hz, 1 H, ArH), 4.92-4.82 (m, 1H), 4.29 (2H, s), 3.63 (dd, ²J12.5 Hz, ³J4.3 Hz, 1H), 3.52 (dd, ²J12.5 Hz, ³J10.3 Hz, 1H), 3.44-3.36 (m, 1H), 3.32 (t, ³J8.4 Hz, 2H), 3.20-3.12 (m, 1H) 2.92 (t, ³J8.4 Hz, 2H), 2.23-2.04 (m, 2H), 1.96-1.74 (m, 2H).

[00556] Example 78: (3R)-3-[4-Amino-3-[4-(indolin-1-ylmethyl)phenyl]pyrazolo[3,4-c]pyrimidin- 1 -yl]piperidine-1 -carbonitrile

Following general procedure G, 3-[4-(indolin-1-ylmethyl)phenyl]-1-[(3R)-3-piperidyl]pyrazolo[3,4- c]pyrimidin-4-amine (85.0 mg, 0.20 mmol) afforded (3R)-3-[4-amino-3-[4-(indolin-1- ylmethyl)phenyl]pyrazolo[3,4-c]pyrimidin-1-yl]piperidine-1-carbonitrile (73.0 mg, 0.16 mmol, 81% yield).

UPLC-MS (ES⁺, Long acidic): 3.89 min, m/z 451.1 [M+H]⁺

H-NMR (400 MHz, DMSO-d₆) δ (ppm) 8.28 (s, 1H, ArH), 7.65 (d, ³J8.2 Hz, 2H, ArH), 7.52 (d, ³J8.2 Hz, 2H, ArH), 7.07-7.04 (m, 1 H, ArH) 7.02-6.96 (m, 1 H, ArH), 6.63-6.57 (m, 2H, ArH), 4.92-4.82 (m, 1H), 4.34 (2H, s), 3.63 (dd, ²J 12.5 Hz, ³J4.3Hz, 1 H), 3.52 (dd, ² J 12.5 Hz, ³J 10.3 Hz, 1H), 3.44- 3.36 (m, 1 H), 3.32 (t, ³J 8.4 Hz, 2H), 3.20-3.12 (m, 1 H) 2.92 (t, ³J 8.4 Hz, 2H), 2.23-2.04 (m, 2H), 1 .96- 1 .74 (m, 2H).

[00557] Example 79: (3R)-3-[4-Amino-3-[4-(indolin-1 -ylmethyl)phenyl]pyrazolo[3,4-cqpyrimidin- 1 -yl]piperidine-1 -carbonitrile

Following general procedure G, 3-[4-[(6-chloroindolin-1-yl)methyl]phenyl]-1 -[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (92.0 mg, 0.20 mmol) afforded (3R)-3-[4-amino-3-[4-[(6- chloroindolin-1 -yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carbonitrile (52.0 mg, 0.1 1 mmol, 54% yield).

UPLC-MS (ES⁺, Long acidic): 4.25 min, m/z 483.1 [M+H]⁺

H-NMR (400 MHz, DMSO-d₆) δ (ppm) 8.28 (s, 1 H, ArH), 7.66 (d, ³J 8.2 Hz, 2H, ArH), 7.50 (d, ³J 8.2 Hz, 2H, ArH), 7.02 (d, J 7.7 Hz, 1 H, ArH), 6..64 (d, J 1 .9 Hz, 1 H, ArH), 6.57 (dd, J 7.7, 1 .9 Hz, 1 H, ArH), 4.92-4.82 (m, 1 H), 4.38 (2H, s), 3.63 (dd, ² J 12.5 Hz, ³J 4.3 Hz, 1 H), 3.52 (dd, ² J 12.5 Hz, ³J 10.3 Hz, 1 H), 3.44-3.36 (m, 1 H), 3.32 (t, ³J 8.4 Hz, 2H), 3.20-3.12 (m, 1 H) 2.92 (t, ³J 8.4 Hz, 2H), 2.23- 2.04 (m, 2H), 1 .96-1 .74 (m, 2H).

[00558] Example 80: 1 -[(3R)-3-[4-Amino-3-[4-(isoindolin-2-ylmet yl)p enyl]pyrazolo[3,4- cflpyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00559] 2-[[4-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyllisoindoline

Following method A, 4-bromomethylphenylboronic acid pinacol ester (300.0 mg, 1 .01 mmol) and isoindoline (0.14 mL, 1 .21 mmol) afforded 2-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]isoindoline (209.0 mg, 0.53 mmol, 52% yield) as an off-white solid.

UPLC-MS (ES⁺, Short acidic): 2.19 min, m/z 334.4 [M+H]⁺

[00560] fe/f-Butyl (3f?)-3-[4-amino-3-[4-(isoindolin-2-ylmethyl)phenyllpyrazolo[3,4-c lpyrimidin-1 - yllpiperidine-1 -carboxylate

Following general procedure D, fe/f-butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1 - yl)piperidine-1 -carboxylate (170.0 mg, 0.38 mmol) and 2-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]isoindoline (0.2 mL, 0.62 mmol) afforded fe/f-butyl (3R)-3-[4-amino-3-[4-(isoindolin-2- ylmethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (212.8 mg, 0.34 mmol, 90% yield) as a brown oil.

UPLC-MS (ES⁺, Short acidic): 1 .36 min, m/z 526.5 [M+H]⁺

[00561] 3-[4-(lsoindolin-2-ylmethyl)phenyll-1 -[(3f?)-3-piperidyllpyrazolo[3,4-c/lpyrimidin-4-amine

Following general procedure F, fe/f-butyl (3R)-3-[4-amino-3-[4-(isoindolin-2- ylmethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (207.3 mg, 0.39 mmol) afforded 3-[4-(isoindolin-2-ylmethyl)phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c/]pyrimidin-4-amine (125.9 mg, 0.27 mmol, 68% yield) as a brown foam.

UPLC-MS (ES⁺, Short acidic): 0.88 min, m/z 426.4 [M+H]⁺

[00562] 1 -[(3f?)-3-[4-Amino-3-[4-(isoindolin-2-ylmethyl)phenyllpyrazolo[3,4-c/lpyrimidin-1 -yll-1 - piperidyllprop-2-en-1 -one

Following general procedure I, 3-[4-(isoindolin-2-ylmethyl)phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4- c ]pyrimidin-4-amine (125.9 mg, 0.30 mmol) gave, after purification by preparative mass-directed reverse phase chromatography, 1 -[(3R)-3-[4-amino-3-[4-(isoindolin-2-ylmethyl)phenyl]pyrazolo[3,4- c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one (61 .2 mg, 0.12 mmol, 41 % yield) as a white solid. UPLC-MS (ES⁺, Short acidic): 0.96 min, m/z 480.5 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.41 min, m/z 480.4 [M+H]⁺

H NMR (400 MHz, DMSO-c/₆) δ (ppm) 8.28 (s, 1 H, ArH), 7.67-7.65 (m, 2H, ArH), 7.57-7.55 (d, J = 8.4 Hz, 2H, ArH), 7.25-7.18 (m, 4H, ArH), 6.91 -6.84 (dd, _is 10.4 Hz, ³J_trans 16.4 Hz, 0.5H), 6.16-6.1 1 (d, ³J_trans 16.4 Hz, 0.5H),), 6.09-6.05 (d, ³J_trans 16.4 Hz, 0.5H), 5.73-5.70 (d, _is 10.4 Hz, 0.5H), 5.61 -5.58 (d, ³J_CS 10.4 Hz, 0.5H), 4.73 (s, 1 H), 4.10-4.08 (t, J = 5.2 Hz, 2H), 3.96 (s, 2H), 3.91 (s, 4H), 3.32 (s, 6H).

[00563] Example 81 : 1 -[(3R)-3-[4-Amino-3-[4-[(1 ,1 -dioxo-3H-1 ,2-benzothiazol-2- yl)methyl]phenyl]pyrazolo[3,4-c |pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00564] 2-[[4-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyll-3H-1 ,2-benzothiazole 1 ,1 - dioxide

Following general procedure A, 2,3-dihydro-1 ,1 -dioxo-1 ,2-benzisothiazole (0.19 mL, 1 .21 mmol) and 2-[4-(bromomethyl)phenyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (300.0 mg, 1 .01 mmol) gave, after purification by flash column chromatography (DCM/MeOH 100:0 to 90:10), 2-[[4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]-3H-1 ,2-benzothiazole 1 ,1 -dioxide (296.4 mg, 0.62 mmol, 61 % yield) as a yellow oil.

[00565] ferf-Butyl (3f?)-3-[4-amino-3-[4-[(1 ,1 -dioxo-3H-1 ,2-benzothiazol-2- yl)methyllphenyllpyrazolo[3,4-c lpyrimidin-1 -yllpiperidine-1 -carboxylate

Following general procedure D, 2-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]-3/-/- 1 ,2-benzothiazole 1 ,1 -dioxide (296.4 mg, 0.62 mmol), te/ -butyl (3f?)-3-(4-amino-3-iodo-pyrazolo[3,4- c ]pyrimidin-1 -yl)piperidine-1 -carboxylate (227.8 mg, 0.51 mmol) gave, after purification by flash chromatography (DCM/MeOH 100:0 to 90:10), ferf-butyl (3f?)-3-[4-amino-3-[4-[(1 ,1 -dioxo-3H-1 ,2- benzothiazol-2-yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (342.6 mg,0.48 mmol, 93% yield) as an orange oil.

UPLC-MS (ES⁺, Short acidic): 1 .70 min, m/z 576.4 [M+H]⁺

[00566] 3-[4-[(1 ,1 -Dioxo-3H-1 ,2-benzothiazol-2-yl)methyllphenyll-1 -[(3f?)-3-piperidyllpyrazolo[3,4- c lPyrimidin-4-amine

Following general procedure F, fe/ -butyl (3R)-3-[4-amino-3-[4-[(1 ,1 -dioxo-3/-/-1 ,2-benzothiazol-2- yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (342.6 mg, 0.48 mmol) gave, after purification by flash column chromatography (DCM/7N NH₃ in MeOH 100:0 to 90:10), 3-[4-[(1 ,1 - dioxo-3H-1 ,2-benzothiazol-2-yl)methyl]phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c/]pyrimidin-4-amine (166.0 mg, 0.35 mmol, 73% yield) as a fluffy cream solid.

UPLC-MS (ES⁺, Short acidic): 1 .12 min, m/z 476.3 [M+H]⁺

[00567] 1 -[(3f?)-3-[4-Amino-3-[4-[(1 ,1 -dioxo-3tf-1 ,2-benzothiazol-2-yl)methyllphenyllpyrazolo[3,4- c lpyrimidin-1 -yll-1 -pipe ridyllprop-2-en-1 -one

Following general procedure I, 3-[4-[(1 ,1 -dioxo-3H-1 ,2-benzothiazol-2-yl)methyl]phenyl]-1 -[(3R)-3- piperidyl]pyrazolo[3,4-c/]pyrimidin-4-amine (166.0 mg, 0.35 mmol) gave, after purification by flash column chromatography (DCM/MeOH 100:0 to 90:10), 1 -[(3f?)-3-[4-amino-3-[4-[(1 ,1 -dioxo-3H-1 ,2- benzothiazol-2-yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one (46.2 mg, 0.09 mmol, 25% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1 .38 min, m/z 530.4 [M+H]⁺ UPLC-MS (ES⁺, Long acidic): 3.13 min, m/z 530.4 [M+H]⁺

[00568] Example 82: 1 -[(3R)-3-[4-Amino-3-[4-(2,3-dihydro-1 ,4-benzothiazin-4- ylmethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00569] 4-[[4-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyll-2,3-dihydro-1 ,4- benzothiazine

Following general procedure A, 2-[4-(bromomethyl)phenyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (300.0 mg, 1 .01 mmol) and 3,4-dihydro-2H-1 ,4-benzothiazine (183.3 mg, 1 .21 mmol) gave, after purification by flash column chromatography (DCM/MeOH 100: to 95:5), 4-[[4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]-2,3-dihydro-1 ,4-benzothiazine (328.9 mg, 0.62 mmol, 61 % yield) as a white solid.

UPLC-MS (ES⁺, short acidic): 2.31 min, m/z 368.3 [M+H]⁺

[00570] fe/f-Butyl (3f?)-3-[4-amino-3-[4-(2,3-dihydro-1 ,4-benzothiazin-4-ylmethyl)phenyllpyrazolo[3,4- c lPyrimidin-1 -yllpiperidine-1 -carboxylate

Following general procedure D, 4-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]-2,3- dihydro-1 ,4-benzothiazine (329.0 mg, 0.62 mmol), fe/f-butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4- c ]pyrimidin-1 -yl)piperidine-1 -carboxylate (183.0 mg, 0.41 mmol) gave, after purification by flash column chromatography (DCM/MeOH 100:0 to 90:10), fe/f-butyl (3f?)-3-[4-amino-3-[4-(2,3-dihydro-1 ,4- benzothiazin-4-ylmethyl)phenyl]pyrazolo[3,4-c/]pyrimidin-1 -yl]piperidine-1 -carboxylate (255.6 mg, 0.27 mmol, 66% yield) as a brown crystalline solid.

UPLC-MS (ES⁺, Short acidic): 2.08 min, m/z 558.5 [M+H]⁺

[00571] 3-[4-(2,3-Dihvdro-1 ,4-benzothiazin-4-ylmethyl)phenyll-1-[(3f?)-3-piperidyllpyrazolo[3,4- c lPyrimidin-4-amine

Following general procedure F, fe/f-butyl (3R)-3-[4-amino-3-[4-(2,3-dihydro-1 ,4-benzothiazin-4- ylmethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (255.6 mg, 0.27 mmol) gave, after purification by column chromatography (DCM /7N NH₃ in MeOH 100:0 to 90:10), 3-[4-(2,3- dihydro-1 ,4-benzothiazin-4-ylmethyl)phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c/]pyrimidin-4-amine (124.8 mg, 0.21 mmol, 78% yield) as a brown solid.

UPLC-MS (ES⁺, Short acidic): 1 .38 min, m/z 458.5 [M+H]⁺

[00572] 1 -[(3f?)-3-[4-Amino-3-[4-(2,3-dihvdro-1 ,4-benzothiazin-4-ylmethyl)phenyllpyrazolo[3,4- c lpyrimidin-1 -yll-1 -pipe ridyllprop-2-en-1 -one

Following general procedure I, 3-[4-(2,3-dihydro-1 ,4-benzothiazin-4-ylmethyl)phenyl]-1 -[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (124.8 mg, 0.21 mmol) gave, after further purification by preparative mass-directed reverse phase chromatography, 1 -[(3R)-3-[4-amino-3-[4-(2,3-dihydro-1 ,4- benzothiazin-4-ylmethyl)phenyl]pyrazolo[3,4-c/]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one (14.6 mg, 0.03 mmol, 14% yield) as a cream solid.

UPLC-MS (ES⁺, Short acidic): 1 .70 min, m/z 512.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.97 min, m/z 512.4 [M+H]⁺

[00573] Example 83: 1 -[(3R)-3-[4-Amino-3-[4-[(5-fluoro-2,3-dihydro-1 ,4-benzoxazin-4- yl)methyl]phenyl]pyrazolo[3,4-c |pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00574] 5-Fluoro-4-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyll-2,3-dihydro-1 ,4- benzoxazine Following general procedure A, 5-fluoro-3,4-dihydro-2/-/-1 ,4-benzoxazine (247.5 mg, 1 .62 mmol) and

2- [4-(bromomethyl)phenyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (400.0 mg, 1 .35 mmol) gave 5- fluoro-4-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]-2,3-dihydro-1 ,4-benzoxazine (881 .4 mg, 1 .69 mmol, 100% yield) as a yellow brown solid. This mixture was used in the next reaction without further purification, assumed quantitative.

UPLC-MS (ES⁺, short acidic): 2.27 min, m/z 370.3 [M+H]⁺

[00575] fe/f-Butyl (3f?)-3-[4-amino-3-[4-[(5-fluoro-2,3-dihydro-1 ,4-benzoxazin-4- yl)methyllphenyllpyrazolo[3,4-c lpyrimidin-1 -yllpiperidine-1 -carboxylate

Following general procedure D, 5-fluoro-4-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]-2,3-dihydro-1 ,4-benzoxazine (351 .2 mg, 0.68 mmol) and fe/f-butyl (3R)-3-(4-amino-

3- iodo-pyrazolo[3,4-c ]pyrimidin-1 -yl)piperidine-1 -carboxylate (200.0 mg, 0.45 mmol) gave, after purification by column chromatography (DCM/MeOH 100:0 to 90:10), fe/f-butyl (3f?)-3-[4-amino-3-[4- [(5-fluoro-2,3-dihydro-1 ,4-benzoxazin-4-yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 - carboxylate (379.2 mg, 0.30 mmol, 66% yield) as a golden-brown film.

UPLC-MS (ES⁺, Short acidic): 2.03 min, m/z 560.5 [M+H]⁺

[00576] 3-[4-[(5-Fluoro-2,3-dihvdro-1 ,4-benzoxazin-4-yl)methyllphenyll-1 -[(3f?)-3- piperidyllpyrazolo[3,4-c/lpyrimidin-4-amine

Following general procedure F, fe/f-butyl (3R)-3-[4-amino-3-[4-[(5-fluoro-2,3-dihydro-1 ,4-benzoxazin-4- yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (379.2 mg, 0.30 mmol) gave, after purification by flash column chromatography (DCM/7N NH₃ in MeOH 100:0 to 90:10), 3-[4-[(5- fluoro-2,3-dihydro-1 ,4-benzoxazin-4-yl)methyl]phenyl]-1-[(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4- amine (77.1 mg, 0.13 mmol, 45% yield) as a fluffy cream solid.

UPLC-MS (ES⁺, Short acidic): 1 .32 min, m/z 460.4 [M+H]⁺

[00577] 1 -[(3f?)-3-[4-Amino-3-[4-[(5-fluoro-2,3-dihydro-1 ,4-benzoxazin-4- yl)methyllphenyllpyrazolo[3,4-c lpyrimidin-1 -yll-1 -piperidyllprop-2-en-1 -one

Following general procedure I, 3-[4-[(5-fluoro-2,3-dihydro-1 ,4-benzoxazin-4-yl)methyl]phenyl]-1 -[(3R)- 3-piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (77.1 mg, 0.13 mmol) gave, after purification by preparative mass-directed reverse phase chromatography, 1 -[(3R)-3-[4-amino-3-[4-[(5-fluoro-2,3- dihydro-1 ,4-benzoxazin-4-yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one (9.9 mg, 0.02 mmol, 15% yield) as a cream solid.

UPLC-MS (ES⁺, Short acidic): 1 .66 min, 514.5 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.83 min, m/z 514.4 [M+H]⁺

[00578] Example 84: 1 -[(3R)-3-[4-Amino-3-[4-[(7-methyl-3,4-dihydro-2H-1 ,8-naphthyridin-1 - yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00579] 7-Methyl-1 -[[4-(4.4.5.5-tetramethyl-1 .3.2-dioxaborolan-2-yl)phenyllmethyll-3.4-dihvdro-2H- 1 ,8-naphthyridine

Following general procedure A, 2-[4-(bromomethyl)phenyl]-4, 4, 5, 5-tetramethyl-1 ,3,2-dioxaborolane (300.0 mg, 1 .01 mmol) gave 7-methyl-1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]-3,4-dihydro-2/-/-1 ,8-naphthyridine (169.0 mg, 0.46 mmol, 46% yield) as a black film. UPLC-MS (ES⁺, short acidic): 1 .41 min, m/z 365.1 [M+H]⁺ [00580] 3-[4-[(7-Methyl-3.4-dihvdro-2H-1 .8-naphthyridin-1 -yl)methyllphenyll-1 -f(3f?)-3- piperidyllpyrazolo[3,4-c/lpyrimidin-4-amine

Following general procedure D, 3-iodo-1 -[(3R)-3^iperidyl]pyrazolo[3,4-c/7pyrirnidin-4-amine (77.5 mg, 0.23 mmol) and 7-methyl-1 -[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]-3,4- dihydro-2H-1 ,8-naphthyridine (169.2 mg, 0.45 mmol) gave, after purification by preparative mass- directed reverse phase chromatography, 3-[4-[(7-methyl-3,4-dihydro-2/-/-1 ,8-naphthyridin-1 - yl)methyl]phenyl]-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine (36.2 mg, 0.07 mmol, 32% yield) as a white film.

UPLC-MS (ES⁺, Short acidic): 0.92 min, 455.5 [M+H]⁺

[00581] 1 -[(3f?)-3-[4-Amino-3-[4-[(7-methyl-3.4-dihvdro-2H-1 .8-naphthyridin-1 - yl)methyllphenyllpyrazolo[3,4-c lpyrimidin-1 -yll-1 -piperidyllprop-2-en-1 -one

Following general procedure I, 3-[4-[(7-methyl-3,4-dihydro-2/-/-1 ,8-naphthyridin-1 -yl)methyl]phenyl]-1 - [(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine (36.2 mg, 0.08 mmol) gave, after purification by preparative mass-directed reverse phase chromatography, 1 -[(3R)-3-[4-amino-3-[4-[(7-methyl-3,4- dihydro-2H-1 ,8-naphthyridin-1 -yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 - one (3.3 mg, 0.006 mmol, 8% yield) as a brown film.

UPLC-MS (ES⁺, Short acidic): 1 .16 min, 509.5 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.62 min, m/z 509.5 [M+H]⁺

[00582] Example 85: 1 -[(3R)-3-[4-Amino-3-[4-[[2-(trifluoromethyl)-7,8-dihydro-5H-1 ,6- naphthyridin-6-yl]methyl]phenyl]pyrazolo[3,4-c |pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one

[00583] 6-Benzyl-2-(trifluoromethyl)-7,8-dihvdro-5H-1 ,6-naphthyridine

N-Benzyl-4-piperidine (0.98 mL, 5.28 mmol) and pyrrolidine (0.66 mL, 7.93 mmol), were dissolved in toluene (12 mL) and heated to 140 °C under Dean-Stark conditions for 2 h. The mixture was cooled, concentrated under reduced pressure, and the residue dissolved in 1 ,4-dioxane (24 mL). (E)-4- Ethoxy-1 ,1 ,1 -trifluoro-but-3-en-2-one (0.71 mL, 4.95 mmol) was added and the reaction mixture stirred at room temperature for 16 h under nitrogen. Ammonium acetate (0.76 g, 9.90 mmol) was added and the reaction mixture was heated to reflux for 4 d. A further two equivalents of ammonium acetate (0.76 g, 4.95 mmol) were added and the reaction mixture heated to 120 °C for 6 h, then 150 °C for 6 h under microwave irradiation. The reaction mixture was acidified to pH 1 -2 with 10% aqueous hydrochloric acid and extracted into DCM (3 x 20 mL). The combined organics were dried (Na₂S0₄), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (DCM/MeOH 0:100 to 10:90) gave 6-benzyl-2-(trifluoromethyl)-7,8-dihydro-5H-1 ,6-naphthyridine (165.0 mg, 0.55 mmol, 1 1 % yield) as a pale yellow oil.

UPLC-MS (ES⁺, short acidic): 1 .12 min, m/z 293 [M+H]⁺

[00584] 2-(Trifluoromethyl)-5,6,7,8-tetrahvdro-1 ,6-naphthyridine

A stirred solution of 6-benzyl-2-(trifluoromethyl)-7,8-dihydro-5/-/-1 ,6-naphthyridine (165.0 mg, 0.56 mmol) in methanol (8.0 mL) was evacuate and back-filled with nitrogen. To this, was added palladium on carbon (10 wt%; 30.0 mg, 0.03 mmol) and the flask was re-evacuated and back-filled with nitrogen (x 3). Following evacuation and back-filling, the reaction mixture was stirred under a hydrogen atmosphere at room temperature for 20 h. A further sample of palladium on carbon (10 wt%; 10.0 mg, 0.01 mmol) was added and the reaction mixture was stirred for a further 4 h. The reaction mixture was filtered through Celite^®, washed with MeOH, DCM and EtOAc. The combined washes were concentrated under reduced pressure and the residue purified by flash column chromatography (heptane/EtOAc 80:20 to 0:100, then DCM/7N NH₃ in MeOH 20:80) to afford 2-(trifluoromethyl)- 5,6,7,8-tetrahydro-1 ,6-naphthyridine (106.0 mg, 0.5 mmol, 93% yield) as a colourless oil.

H NMR (400 MHz, CD₃OD) δ 7.76 (d, ³J 8.0 Hz, 1 H ArH), 7.61 (d, ³J 8.0 Hz, 1 H, ArH), 4.25 (s, 2H, CH₂), 3.30 (t, ³J 6.0 Hz, 2H, CH₂), 3.06 (t, ³ = 6.0 Hz, 2H, CH₂).

[00585] /V-Ethyl-/V-isopropyl-propan-2-amine; 6-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyllmethyll-2-(trifluoromethyl)-7,8-dihydro-5/-/-1 ,6-naphthyridine: hydrobromide

Following General Procedure A, 4-bromomethylphenylboronic acid pinacol ester (106.9 mg, 0.36 mmol) and 2-(trifluoromethyl)-5, 6, 7, 8-tetrahydro-1 ,6-naphthyridine (80.1 mg, 0.40 mmol) afforded N- ethyl-/V-isopropyl-propan-2-amine; 6-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]-2- (trifluoromethyl)-7,8-dihydro-5/-/-1 ,6-naphthyridine; hydrobromide (214 mg,0.34 mmol, 95% yield) as a cream solid.

UPLC-MS (ES⁺, short acidic): 1 .49 min, m/z 419.4 [M+H]⁺

[00586] fe/f-Butyl (3f?)-3-[4-amino-3-[4-[[2-(trifluoromethyl)-7.8-dihvdro-5H-1 .6-naphthyridin-6- yllmethyllphenyllpyrazolo[3,4-c lpyrimidin-1 -yllpiperidine-1 -carboxylate

Following General Procedure D, /V-ethyl-/V-isopropyl-propan-2-amine; 6-[[4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl]methyl]-2-(trifluoromethyl)-7,8-dihydro-5/-/-1 ,6-naphthyridine; hydrobromide (203.7 mg, 0.32 mmol) , fe/ -butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4-c ]pyrimidin-1 -yl)piperidine-1 - carboxylate (120.0 mg, 0.27 mmol) were reacted in a microwave vial under the conditions specified. Further purification by SCX column, followed by flash column chromatography, eluting with 0 - 100% (20:80 1 N NH₃ in MeOH: DCM), afforded te/ -butyl (3f?)-3-[4-amino-3-[4-[[2-(trifluoromethyl)-7,8- dihydro-5H-1 ,6-naphthyridin-6-yl]methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (134.0 mg, 0.22 mmol, 82% yield) as an off white solid.

UPLC-MS (ES⁺, short acidic): 1 .42 min, m/z 609.5 [M+H]⁺

[00587] 1 -[(3R)-3-piperidyll-3-[4-[[2-(trifluoromethyl)-7.8-dihvdro-5H-1 .6-naphthyridin-6- yllmethyllphenyllpyrazolo[3,4-dlpyrimidin-4-amine

Following General Procedure E, fe/ -butyl (3R)-3-[4-amino-3-[4-[[2-(trifluoromethyl)-7,8-dihydro-5/-/- 1 ,6-naphthyridin-6-yl]methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (134.0 mg, 0.22 mmol) afforded 1 -[(3f?)-3-piperidyl]-3-[4-[[2-(trifluoromethyl)-7,8-dihydro-5H-1 ,6-naphthyridin-6- yl]methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-4-amine (70.0 mg, 0.13 mmol, 58% yield) as an off-white solid.

UPLC-MS (ES+, short acidic): 0.93 min, m/z 509.4 [M+H]+

[00588] 1 -[(3R)-3-[4-Amino-3-[4-[[2-(trifluoromethyl)-7.8-dihvdro-5H-1 .6-naphthyridin-6- yllmethyllphenyllpyrazolo[3,4-c lpyrimidin-1 -yll-1 -piperidyllprop-2-en-1 -one

Following General Procedure I, 1 -[(3f?)-3-piperidyl]-3-[4-[[2-(trifluoromethyl)-7,8-dihydro-5H-1 ,6- naphthyridin-6-yl]methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-4-amine (70.0 mg, 0.14 mmol) afforded 1 - [(3f?)-3-[4-amino-3-[4-[[2-(trifluoromethyl)-7,8-dihydro-5H-1 ,6-naphthyridin-6- yl]methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one (32.2 mg, 0.057 mmol, 41 % yield).

UPLC-MS (ES⁺, short acidic): 1 .13 min, m/z 563.5 [M+H]⁺ UPLC-MS (ES⁺, long acidic): 2.50 min, m/z 563.5 [M+H]⁺

1 H NMR (400 MHz, DMSO-c/₆) δ (ppm, 1 :1 mixture of conformers) 8.27 (s, 1 H, ArH), 7.77 (d, ³J = 7.6 Hz, 1 H, ArH), 7.67-7.64 (m, 3H, ArH), 7.54 (d, ³J = 8.1 Hz, 2H, ArH), 6.87 (dd, ³J_trans = 16.6 Hz, ³J_cis = 10.6 Hz, 0.5H), 6.72 (dd, ³J_trans = 16.6 Hz, ³J_cis = 10.6 Hz, 0.5H), 6.14 (d, ³J_trans = 16.6 Hz, 0.5H), 6.07 (d, ³J_trans = 16.6 Hz, 0.5H), 5.72 (d, ³J_cis = 10.6 Hz, 0.5H), 5.59 (d, ³J_cis = 10.6 Hz, 0.5H), 4.75-4.67 (m, 1 H, CH), 4.57 (d, ³J = 10.8 Hz, 0.5H), 4.21 (d, ³J = 10.8 Hz, 1 H), 4.09 (d, ³J = 13.9 Hz, 0.5H), 3.79 (s, 2H), 3.74 (s, 2H), 3.21 (q, ³J = 10.8 Hz, 1 H), 3.02 (t, ³J = 5.7 Hz, 2H), 2.89 (t, ³J = 5.7 Hz, 2H), 2.32- 2.22 (m, 1 H), 2.16-2.10 (m, 1 H), 1.96-1.91 (m, 1 H), 1.66-1.56 (m, 1 H).

[00589] Example 86: 2-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4- c |pyrimidin-3-yl]phenyl]methyl]isoindolin-1 -one

[00590] 2-[[4-[4-amino-1 -[(3f?)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-3- yl]phenyl]methyl]tetrahydoisoquinoiln-1-one can be similarly produced.

[00591] 2-[[4-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyllisoindolin-1-one

Following general procedure A; 4-bromomethylphenylboronic acid pinacol ester (200.0 mg, 0.67 mmol) and isoindolinone (89.7 mg, 0.67 mmol) afforded 2-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-

2- yl)phenyl]methyl]isoindolin-1-one (211.0 mg, 0.60 mmol, 90% yield) as an off-white waxy solid. UPLC-MS (ES⁺, Short acidic): 1.88 min, m/z 349.9 [m/z]⁺

[00592] fe/f-Butyl (3f?)-3-[4-amino-3-[4-[(1-oxoisoindolin-2-yl)methyllphenyllpyrazolo[3,4-c/lpyrimidin-

1 -yllpiperidine-1 -carboxylate

Following general procedure D; 2-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]isoindolin-1-one (176.9 mg, 0.51 mmol), fe/f-butyl (3R)-3-(4-amino-3-iodo- pyrazolo[3,4-c ]pyrimidin-1-yl)piperidine-1 -carboxylate (150.0 mg, 0.34 mmol) gave fe/f-butyl (3R)-3-[4- amino-3-[4-[(1-oxoisoindolin-2-yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1-yl]piperidine-1 -carboxylate

(70.0 mg, 0.13 mmol, 38% yield) as a pale yellow oil.

UPLC-MS (ES⁺, Short acidic): 1.67 min, m/z 540.5 [M+H]⁺

[00593] 2-[[4-[4-Amino-1-[(3 ?)-3-piperidyllpyrazolo[3,4-c lpyrimidin-3-yllphenyllmethyllisoindolin-1- one

Following general procedure E; fe/f-butyl (3R)-3-[4-amino-3-[4-[(1-oxoisoindolin-2- yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1-yl]piperidine-1-carboxylate (70.0 mg, 0.13 mmol) afforded 2-[[4-[4-amino-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-3-yl]phenyl]methyl]isoindolin-1 -one (53.0 mg,0.22 mmol, 93% yield) as a yellow oil.

UPLC-MS (ES⁺, Short acidic): 1.13 min, m/z 440.2 [M+H]⁺

[00594] 2-[[4-[4-Amino-1-[(3f?)-1-prop-2-enoyl-3-piperidyllpyrazolo[3,4-c lpyrimidin-3- yllphenyllmethyllisoindolin-1-one

Following general procedure F, 2-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-c/]pyrimidin-3- yl]phenyl]methyl]isoindolin-1-one (53.0 mg, 0.12 mmol) afforded 2-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-

3- piperidyl]pyrazolo[3,4-c/]pyrimidin-3-yl]phenyl]methyl]isoindolin-1-one (38.0 mg, 0.07 mmol, 62% yield) as a clear film.

UPLC-MS (ES⁺, Short acidic): 1.35 min, m/z 494.4 [M+H]⁺; UPLC-MS (ES⁺, Long acidic): 3.03 min, m/z 494.4 [M+H]⁺ H-NMR (400 MHz, DMSO-c/₆) δ (ppm, 1 :1 mixture of conformers): 8.26 (s, 1 H, ArH), 7.74 (d, 1 H, ³J = 7.5 Hz, ArH), 7.63 (d, 2H, ³J = 8.4 Hz, ArH), 7.60-7.56 (m, 2H, ArH), 7.50 (dt, 1 H, ³J = 7.5 Hz, ⁴J = 1 .6 Hz, ArH), 7.44 (d, 2H, ³J = 8.4 Hz, ArH), 6.85 (dd, 0.5H, ³J_frans = 16.7 Hz, ³J_{C S} = 10.9 Hz, C=CH), 6.69 (dd, 0.5H, ³J_trans = 16.7 Hz, ³J_{C S} = 10.9 Hz, C=CH), 6.1 1 (d, 0.5H, ³J_trans = 16.7 Hz, C=CH), 6.04 (d, 0.5H, ³J_trans = 16.7 Hz, C=CH), 5.69 (d, 0.5H, ³J_{C S} = 10.9 Hz, C=CH), 5.57 (d, 0.5H, ³J_CS = 10.9 Hz, C=CH), 4.81 (s, 2H, CH₂), 4.74-4.63 (m, 1 H, CH), 4.55-4.49 (m, 0.5H, CH), 4.44 (s, 2H, CH₂), 4.21 - 4.15 (m, 1 H, CH), 4.08-4.02 (m, 0.5H, CH), 3.71 -3.64 (m, 0.5H, CH), 3.22-3.15 (m, 1 H, CH), 3.03-2.95 (m, 0.5H, CH), 2.29-2.19 (m, 1 H, CH), 2.13-2.07 (m, 1 H, CH), 1 .94-1 .88 (m, 1 H, CH), 1 .63-1 .53 (m, 1 H, CH).

[00595] Example 87: 2-[[4-[4-amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- c |pyrimidin-3-yl]phenyl]methyl]-3,4-dihydroisoquinolin-1 -one

[00596] 2-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyllmethyll-3,4-dihydroisoquinolin-1 - one

3,4-Dihydro-1 (2/-/)-isoquinolinone (89.2 mg, 0.61 mmol) was added to a stirring solution of sodium hydride (40.4 mg, 1 .01 mmol) in DMF (5 ml_) under nitrogen at 0 °C. The reaction mixture was stirred for 1 h at this temperature before 4-bromomethylphenylboronic acid pinacol ester (150.0 mg, 0.51 mmol) was added. The reaction mixture was allowed to warm to rt overnight. The reaction mixture was quenched with water (10 ml_) and extracted into DCM (3 x 10 ml_). The organics were combined, dried over Na₂S0₄, filtered and concentrated in vacuo to afford 2-[[4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl]methyl]-3,4-dihydroisoquinolin-1 -one (21 1 .0 mg, 0.58 mmol, 1 15% yield) as a cream solid.

UPLC-MS (ES⁺, Short acidic): 1 .97 min, m/z 364.0 [M+H]⁺

[00597] fe/f-Butyl (3f?)-3-[4-amino-3-[4-[(1 -oxo-3,4-dihydroisoquinolin-2- yl)methyllphenyllpyrazolo[3,4-c lpyrimidin-1 -yllpiperidine-1 -carboxylate

Following general procedure D; 2-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]-3,4- dihydroisoquinolin-1 -one (208.0 mg, 0.57 mmol), fe/ -butyl (3R)-3-(4-amino-3-iodo-pyrazolo[3,4- c ]pyrimidin-1 -yl)piperidine-1 -carboxylate (170.0 mg, 0.38 mmol) gave fe/ -butyl (3R)-3-[4-amino-3-[4-

[(1 -oxo-3, 4-dihydroisoquinolin-2-yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 - carboxylate (202.0 mg, 0.37 mmol, 95% yield) as a dark yellow oil.

UPLC-MS (ES⁺, Short acidic): 1 .73 min, m/z 554.5 [M+H]⁺

[00598] 2-[[4-[4-amino-1 -[(3f?)-3-piperidyllpyrazolo[3,4-c lpyrimidin-3-yllphenyllmethyll-3,4- dihydroisoquinolin-1 -one

Following general procedure E; fe/ -butyl (3R)-3-[4-amino-3-[4-[(1 -oxo-3, 4-dihydroisoquinolin-2- yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]piperidine-1 -carboxylate (200.0 mg, 0.36 mmol) afforded 2-[[4-[4-amino-1 -[(3R)-3-piperidyl]pyrazolo[3,4-(^pyrimidin-3-yl]phenyl]methyl]-3,4-dihydroisoquinolin- 1 -one (90.0 mg, 0.20 mmol, 55% yield) as a yellow oil.

UPLC-MS (ES⁺, Short acidic): 1 .19 min, m/z 454.3 [M+H]⁺

[00599] 2-[[4-[4-amino-1 -[(3f?)-1 -prop-2-enoyl-3-piperidyllpyrazolo[3,4-c lpyrimidin-3- yllphenyllmethyll-3,4-dihydroisoquinolin-1 -one

Following general procedure F; afforded 2-[[4-[4-amino-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-3- yl]phenyl]methyl]-3,4-dihydroisoquinolin-1 -one (90.0 mg, 0.20 mmol) afforded 2-[[4-[4-amino-1 -[(3R)-1 - prop-2-enoyl-3-piperidyl]pyrazolo[3,4-<^pyrimidin-3-yl]phenyl]m

(15.0 mg, 0.03 mmol, 15% yield) as a clear film.

UPLC-MS (ES⁺, Short acidic): 1 .43 min, m/z 508.3 [M+H]⁺ UPLC-MS (ES⁺, Short acidic): 1 .43 min, m/z 506.4 [M-H]^~ UPLC-MS (ES⁺, Long acidic): 3.22 min, m/z 508.5 [M+H]⁺

H-NMR (400 MHz, DMSO-c/₆) δ (ppm, 1 :1 mixture of conformers): 8.26 (s, 1 H, ArH), 7.96 (d, 1 H, ³J = 7.3 Hz, ArH), 7.65 (d, 2H, ³J = 7.8 Hz, ArH), 7.52-7.49 (m, 3H, ArH), 7.38 (t, 1 H, ³J = 7.3 Hz, ArH), 7.31 (d, 1 H, ³J = 7.3 Hz, ArH), 6.87 (dd, 0.5H, ³J_irans = 16.5 Hz, ³J_{C S} = 10.4 Hz), 6.72 (dd, 0.5H, _3η5 = 16.5 Hz, ³J_{C S} = 10.4 Hz), 6.14 (d, 0.5H, ³J_frans = 16.5 Hz), 6.07 (d, 0.5H, ³J_frans = 16.5 Hz, C=CH), 5.71 (d, 0.5H, ³J_CS = 10.4 Hz), 5.59 (d, 0.5H, ³J_CS = 10.4 Hz), 4.81 (s, 2H, CH₂), 4.76-4.66 (m, 1 H, CH), 4.58-4.66 (m, 0.5H, CH), 4.23-4.18 (m, 1 H, CH), 4.1 1 -4.06 (m, 0.5H, CH), 3.74-3.67 (m, 0.5H, CH), 3.57 (t, 2H, ³J = 6.3 Hz, CH₂), 3.25-3.17 (m, 1 H, CH), 3.01 (t, 2H, ³J = 6.3 Hz, CH₂), 2.56-2.42 (m, 0.5H), 2.31 -2.22 (m, 1 H, CH), 2.16-2.10 (m, 1 H, CH), 1 .97-1 .91 (m, 1 H, CH), 1 .65-1 .55 (m, 1 H, CH).

[00600] Example 88: W-[[4-[4-Amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- c ]pyrimidin-3-yl]phenyl]methyl]acetamide

[00601] /V-[[4-[4-Amino-1 -[(3f?)-3-piperidyllpyrazolo[3,4-c lpyrimidin-3-yllphenyllmethyllacetamide Following general procedure D, A mixture of 3-iodo-1 -[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-4- amine (200.0 mg, 0.58 mmol) and 4-acetamidomethylphenylboronic acid (168.2 mg, 0.87 mmol) was heated under microwaves irradiation at 120 °C for 90 minutes. The solvent was then removed under reduced pressure and the dried crude product was carried through the next reaction without purification, assumed quantitative.

UPLC-MS (ES⁺, Short acidic): 0.80 min, m/z 366.2 [M+H]⁺

[00602] /V-[[4-[4-amino-1 -[(3f?)-1 -prop-2-enoyl-3-piperidyllpyrazolo[3,4-c lpyrimidin-3- yllphenyllmethyllacetamide

To a suspension of crude /V-[[4-[4-amino-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-3- yl]phenyl]methyl]acetamide (212.4 mg, 0.58 mmol) and acrylic acid (0.05 mL, 0.70 mmol) in anhydrous DCM (3 mL) were added successively triethylamine (0.2 mL, 1 .74 mmol) and Λ/-(3- dimethylaminopropyl)-/V'-ethylcarbodiimide hydrochloride) (167.1 mg, 0.87 mmol). The reaction mixture was stirred overnight at room temperature and then the solvent was removed under reduced pressure. Further purification by flash column chromatography (DCM/MeOH + 0.1 % 7N NH₃ in MeOH additive 100:0 to 90:10) gave /V-[[4-[4-amino-1 -[(3f?)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- c ]pyrimidin-3-yl]phenyl]methyl]acetamide (48.0 mg, 0.11 mmol, 19% yield) as a brown solid.

UPLC-MS (ES⁺, Short acidic): 1 .06 min, m/z 420.3 [M+H]⁺

H NMR (400 MHz): 8.40 (s, 1 H, ArH), 7.68 (d, J 8.1 Hz, 2H, ArH), 7.48 (d, J 8.1 Hz, 2H, ArH), 6.69- 6.53 (m, 1 H), 6.36-6.25 (m, 1 H), 5.97-5.88 (m, 1 H, NH), 5.77-5.63 (m, 1 H). 5.51 (br. s, 2H, NH₂), 4.96- 4.83 (m, 1 .5H), 4.64-4.56 (m, 0.5H), 4.55 (d, J 5.9 Hz, 2H), 4.26-4.17 (m, 0.5H), 4.10-4.00 (m, 0.5H), 3.85-3.74 (m, 0.5H), 3.46-3.36 (m, 0.5H), 3.28-3.17 (m, 1 H), 2.49-2.32 (m, 1 H), 2.32-2.23 (m, 1 H), 2.10 (s, 3H, CH₃), 2.08-1 .96 (m, 2H).

[00603] Example 89: 2-[[4-[4-Amino-1 -[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4- c |pyrimidin-3-yl]phenyl]methyl]isoindoline-1 ,3-dione

[00604] 2-[[4-[4-Amino-1 -[(3f?)-3-piperidyllpyrazolo[3,4-c lpyrimidin-3-yllphenyllmethyllisoindoline-1 ,3- dione Following general procedure D, a mixture of 3-iodo-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c/]pyrimidin-4- amine (200.0 mg, 0.58 mmol) and 2-[[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl]isoindoline-1 ,3-dione (316.6 mg, 0.87 mmol) gave 2-[[4-[4-amino-1 -[(3R)-3- piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]isoindoline-1 ,3-dione (263.5 mg, 0.38 mmol, 66%) as a crude black solid.

UPLC-MS (ES⁺, Short acidic): 1 .14 min, m/z 454.2 [M+H]⁺

[00605] 2-[[4-[4-Amino-1 -[(3f?)-1 -prop-2-enoyl-3-piperidyllpyrazolo[3,4-c lpyrimidin-3- yllphenyllmethyllisoindoline-1 ,3-dione

Following general procedure G, crude 2-[[4-[4-amino-1 -[(3R)-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-3- yl]phenyl]methyl]isoindoline-1 ,3-dione (131 .7 mg, 0.29 mmol) gave, further purification by flash column chromatography (DCM/MeOH + 0.1 % 7N NH₃ in MeOH additive 100:0 to 90:10), 2-[[4-[4-amino-1 -

[(3R)-1 -prop-2-enoyl-3-piperidyl]pyrazolo[3,4-c ]pyrimidin-3-yl]phenyl]methyl]isoindoline-1 ,3-dione (5.5 mg, 0.01 mmol, 4% yield) as a brown solid.

UPLC-MS (ES⁺, Short acidic): 1 .43 min, 508.3 m/z [M+H]⁺

[00606] Example 90: BTK Binding Activity

[00607] BTK binding activity of each compound tested was determined using a time-resolved fluorescence resonance energy transfer (TR-FRET) methodology. 2.5nM Recombinant BTK kinase, varying concentrations of inhibitor, 2nM Lanthascreen™ Eu anti-His Antibody and 15nM 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 30μΙ using half-area 96-well assay plates. The TR-FRET signal was read on a plate reader with an excitation wavelength of 340nm and detection wavelengths of 615 and 665nm. Binding activity 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).

[00608] The Table 1 below shows the BTK binding, as determined by the assay described above, for certain compounds of formula (I), characterised based on the BTK IC50 value of the compound as "+", "++" and "+++". The category "+" refers to compounds with a BTK IC50 of 150 nM to 550 nM. The category "++" refers to compounds with a BTK IC50 of 15 nM to 150 nM. The category "+++" refers to compounds with a BTK IC50 of 0.1 nM to 15 nM.

Table 1

STRUCTURE ASSAY TYPE CATEGORY

[00609] Examples of compounds of the invention with values for the BTK IC50 are given in Table 2 below.

Table 2

[00610] Example 91 : BTK Binding Activity

[00611] BTK binding activity 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 activity 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).

[00612] Results of the BTK Binding Activity are shown below in Table 3.

[00613] Table 3 shows the BTK Binding Activity, as determined by the assay described above, for compounds of formula (I), categorised based on the BTK IC50 value of the compound as "+", "++" and "+++". The category "+" refers to compounds with a BTK IC50 of 40 nM to 550 nM. The category "++" refers to compounds with a BTK IC50 of 8 nM to 40 nM. The category "+++" refers to compounds with a BTK IC50 of 0.1 nM to 8 nM.

[00614] Example 92: EGFR Binding Activity

[00615] EGFR binding activity 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 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 activity 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).

[00616] Results of the EGFR binding activity are shown in Table 3 below.

[00617] Table 3 shows the EGFR Binding Activity, as determined by the assay described above, for compounds of formula (I), categorised based on the EGFR IC50 value of the compound as "*", "**" and "***". The category "*" refers to compounds with an EGFR IC50 of 80 to 500 nM. The category "**" refers to compounds with an EGFR IC50 of 25 to 80 nM. The category "***" refers to compounds with an EGFR IC50 of <25 nM.

[00618] Example 93: TMD8 Growth Assay

[00619] Compounds were assayed for effects on the growth of TMD8 human 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 hours 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 72hrs of compound treatment, Resazurin was added to each well of the compound treated plates, incubated for 5 hours 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 IC₅₀ from log[lnhibitor] vs response using the Variable Slope model in Graphpad prism from Graphpad software (SanDiego, Calif).

[00620] The results of the TMD8 growth assay are shown in Table 3 below.

[00621] Table 3 shows the TMD8 Binding Activity, as determined by the assay described above, for compounds of formula (I), categorised based on the TMD8 IC50 value of the compound as "x", "xx" and "xxx". The category "x" refers to compounds with a TMD8 IC50 of 100 to 500 nM. The category "xx" refers to compounds with a TMD8 IC50 of 25 to 100 nM. The category "xxx" refers to compounds with a TMD8 IC50 of <25 nM.

Table 3

EGFR BTK

TMD8 IC50

Name Binding Binding

(nM) IC50 (nM) IC50 (nM)

1 -[(3f?)-3-[4-amino-3-[4-[[5-(trifluoromethyl)indolin-1 - yl]methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 - _* +++ - piperidyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4-[(5-methylindolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 - _*** +++ XX

piperidyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4-[(4,6-difluoroindolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 - _*** +++ XX

piperidyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4-[[6-(trifluoromethyl)indolin-1 - yl]methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 - _** +++ XXX

piperidyl]prop-2-en-1 -one

1 -[[4-[4-amino-1 -[(3f?)-1 -prop-2-enoyl-3- piperidyl]pyrazolo[3,4-c/]pyrimidin-3- _*** +++ XXX yl]phenyl]methyl]indoline-5-carbonitrile

(3f?)-3-[4-amino-3-[4-(indolin-1 - ylmethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-1 - _* +++ X

yl]piperidine-1 -carbonitrile

(3f?)-3-[4-amino-3-[4-[(5-fluoroindolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 - _* +++ X

yl]piperidine-1 -carbonitrile

(3f?)-3-[4-amino-3-[4-(indolin-1 - ylmethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-1 - _** +++ XX

yl]piperidine-1 -carbonitrile

1 -[(3f?)-3-[4-amino-3-[4-[(7-chloroindolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 - _*** +++ n.d.

piperidyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4-[(4-methylindolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 - _*** +++ n.d.

piperidyl]prop-2-en-1 -one 3-[4-(3,4-dihydro-1 H-isoquinolin-2-ylmethyl)phenyl]-1 - [(3f?)-1 -[[(2f?)-oxiran-2-yl]methyl]-3- _* ++ X piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine

1 -[(3f?)-3-[4-amino-3-[4-[(4-methoxyindolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 - _** +++ XXX

piperidyl]prop-2-en-1 -one

(3f?)-3-[4-amino-3-[4-(3,4-dihydro-1 H-isoquinolin-2- ylmethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-1 - - ++ - yl]piperidine-1 -carbonitrile

3-[4-(3,4-dihydro-1 H-isoquinolin-2-ylmethyl)phenyl]-1 - [(3R)-1 -vinylsulfonyl-3-piperidyl]pyrazolo[3,4- _*** +++ XXX

c ]pyrimidin-4-amine

1 -[(3f?)-3-[4-amino-3-[4-[(3,3-dimethylindolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 - _* +++ XX

piperidyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4-[(7-fluoroindolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 - _*** +++ XXX

piperidyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4-[(3-methylindolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 - _*** +++ XXX

piperidyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4-[(6-fluoroindolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 - _*** +++ XXX

piperidyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4-(1 ,3,4,5-tetrahydro-2- benzazepin-2-ylmethyl)phenyl]pyrazolo[3,4- _* +++ XX c ]pyrimidin-1 -yl]-1 -pipe ridyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4-[(6-methylindolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 - n.d. +++ XXX

piperidyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4-[(5-methoxyindolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 - _** +++ XX

piperidyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4-[(1 ,1 -dioxo-3H-1 ,2- benzothiazol-2-yl)methyl]phenyl]pyrazolo[3,4- _*** +++ XXX c ]pyrimidin-1 -yl]-1 -pipe ridyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4-[(4-fluoroindolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 - _*** +++ XXX

piperidyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4-[(6-chloroindolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 - _** +++ XXX

piperidyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4-[(6-methoxy-3,4-dihydro-1 H- isoquinolin-2-yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin- _* +++ XX

1 -yl]-1 -piperidyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4-[[5-(trifluoromethyl)-3,4- dihydro-2/-/-quinolin-1 -yl]methyl]phenyl]pyrazolo[3,4- n.d. ++ - c ]pyrimidin-1 -yl]-1 -pipe ridyl]prop-2-en-1 -one 1 -[(3f?)-3-[4-amino-3-[4-[[8-(trifluoromethyl)-3,4- dihydro-1 /-/-isoquinolin-2-yl]methyl]phenyl]pyrazolo[3,4- n.d. +++ XXX c ]pyrimidin-1 -yl]-1 -pipe ridyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4-[[2-(trifluoromethyl)-7,8- dihydro-5/-/-1 ,6-naphthyridin-6- n.d. ++ - yl]methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 - piperidyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4-[(5-fluoroindolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 - _*** +++ XXX

piperidyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4-[(2-methylindolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 - _** +++ XXX

piperidyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4-[(5-chloroindolin-1 - yl)methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1 -yl]-1 - _*** +++ XXX

piperidyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4-(2,3-dihydro-1 ,4-benzothiazin- 4-ylmethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 - _*** +++ XXX

piperidyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4-[(4-chloroindolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 - _*** +++ XXX

piperidyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4-(isoindolin-2- ylmethyl)phenyl]pyrazolo[3,4-c]pyrimidin-1 -yl]-1 - n.d. + - piperidyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[6-(2,3-dihydropyrido[3,2- Jb][1 ,4]oxazin-4-ylmethyl)-3-pyridyl]pyrazolo[3,4- n.d. + - c ]pyrimidin-1 -yl]-1 -pipe ridyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4-(isoindolin-2- ylmethyl)phenyl]pyrazolo[3,4-c]pyrimidin-1 -yl]-1 - _*** +++ XXX

piperidyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4-[[6-(trifluoromethyl)-3,4- dihydro-1 /-/-isoquinolin-2-yl]methyl]phenyl]pyrazolo[3,4- _* +++ XXX c ]pyrimidin-1 -yl]-1 -pipe ridyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[6-(3,4-dihydro-2H-quinolin-1 - ylmethyl)-3-pyridyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 - _** +++ XX

piperidyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4-(1 ,2,4,5-tetrahydro-3- benzazepin-3-ylmethyl)phenyl]pyrazolo[3,4- _* +++ XX c ]pyrimidin-1 -yl]-1 -pipe ridyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4-(2,3,4,5-tetrahydro-1 - benzazepin-1 -ylmethyl)phenyl]pyrazolo[3,4- _** +++ XX c ]pyrimidin-1 -yl]-1 -pipe ridyl]prop-2-en-1 -one

-[(3f?)-3-[4-amino-3-[4-(indolin-1 - ylmethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 - _*** +++ XXX

piperidyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4-[(8-methyl-3,4-dihydro-2H- quinolin-1 -yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 - n.d. +++ - yl]-1 -piperidyl]prop-2-en-1 -one 1 -[(3f?)-3-[4-amino-3-[4-[(7-methyl-3,4-dihydro-2H-1 ,8- naphthyridin-1 -yl)methyl]phenyl]pyrazolo[3,4- n.d. +++ XXX c ]pyrimidin-1 -yl]-1 -pipe ridyl]prop-2-en-1 -one

2-[[4-[4-amino-1 -[(3f?)-1 -prop-2-enoyl-3- piperidyl]pyrazolo[3,4-c/]pyrimidin-3-yl]phenyl]methyl]- _* +++ XX

3,4-dihydro-1 /-/-isoquinoline-7-carbonitrile

1 -[(3f?)-3-[4-amino-3-[4-[(6-methoxy-3,4-dihydro-2H- quinolin-1 -yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 - _* +++ XX

yl]-1 -piperidyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4-[(6-chloro-3,4-dihydro-2H- quinolin-1 -yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 - n.d. +++ X

yl]-1 -piperidyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4-[(3-methyl-3,4-dihydro-2H- quinolin-1 -yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 - _* +++ XX

yl]-1 -piperidyl]prop-2-en-1 -one

1 -[(3f?)-3-[3-[4-(3,4,4a,5,6,7,8,8a-octahydro-1 H- isoquinolin-2-ylmethyl)phenyl]-4-amino-pyrazolo[3,4- n.d. +++ X c ]pyrimidin-1 -yl]-1 -pipe ridyl]prop-2-en-1 -one

3-[4-(morpholinomethyl)phenyl]-1 -[(3R)-1 -vinylsulfonyl- _** +++ XX

3-piperidyl]pyrazolo[3,4-c/]pyrimidin-4-amine

1 -[(3f?)-3-[4-amino-3-[4-(2-oxa-5- azabicyclo[2.2.1 ]heptan-5- n.d. + - ylmethy phenyllpyrazolotS^-Qlpyrimidin-l -yl]-1 - piperidyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4- (morpholinomethyl)phenyl]pyrazolo[3,4-c/]pyrimidin-1 - _** +++ XX

yl]-1 -piperidyl]-2-chloro-ethanone

te/ -butyl 4-[[4-[4-amino-1 -[(3f?)-1 -prop-2-enoyl-3- piperidyl]pyrazolo[3,4-c/]pyrimidin-3-yl]phenyl]methyl]- - +++ XX

1 ,4-diazepane-1 -carboxylate

1 -[(3f?)-3-[4-amino-3-[4-(8-oxa-3- azabicyclo[3.2.1 ]octan-3-ylmethyl)phenyl]pyrazolo[3,4- n.d. ++ - c ]pyrimidin-1 -yl]-1 -pipe ridyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4-[(2,6-dimethylmorpholin-4- yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 - n.d. ++ - piperidyl]prop-2-en-1 -one

1 -[(3f?)-3-[3-[4-((frans-octahydro-2H-[1 ,4]-benzoxazin- 4-yl)methyl)phenyl]-4-amino-pyrazolo[3,4-c ]pyrimidin- n.d. + X 1 -yl]-1 -piperidyl]prop-2-en-1 -one (frans-stereoisomers

at morpholine)

1 -[(3f?)-3-[4-amino-3-[4-[(1 -methyl-3,4-dihydro-1 H- isoquinolin^-y methyllphenyllpyrazolotS^-Qlpyrimidin- n.d. +++ - 1 -yl]-1 -piperidyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4- (thiomorpholinomethyl)phenyl]pyrazolo[3,4-c ]pyrimidin- n.d. +++ X

1 -yl]-1 -piperidyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4-[(2-phenylmorpholin-4- yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 - _** +++ XX

piperidyl]prop-2-en-1 -one 1 -[(3f?)-3-[4-amino-3-[4-[(2,2-dimethylmorpholin-4- yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 - n.d. ++ - piperidyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4-[(2,5-dimethylmorpholin-4- yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 - n.d. + - piperidyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4-[(2,3-dimethylmorpholin-4- yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 - n.d. + - piperidyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4-[[2-(trifluoromethyl)morpholin- 4-yl]methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 - n.d. +++ - piperidyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4-[(2-methylmorpholin-4- yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 - n.d. +++ X

piperidyl]prop-2-en-1 -one

1 -[(3f?)-3-(4-amino-3-(4-[(3-methylmorpholin-4- yl)methyl]phenyl)-1 /-/-pyrazolo[3,4-c/]pyrimidin-1 - n.d. ++ - yl)piperidin-1 -yl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4- (diethylaminomethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-1 - n.d. + - yl]-1 -piperidyl]prop-2-en-1 -one

1 -[3-[4-amino-3-[4-(3,4-dihydro-2H-quinolin-1 - ylmethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 - _*** +++ XXX

piperidyl]prop-2-en-1 -one

1 -[3-[4-amino-3-[4-[(1 ,1 -dioxo-1 ,4-thiazinan-4- yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 - _*** +++ XXX

piperidyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4-(2,3-dihydropyrido[3,2- £>][1 ,4]oxazin-4-ylmethyl)phenyl]pyrazolo[3,4- _*** +++ XXX rf]pyrimidin-1 -yl]-1 -pipe ridyl]prop-2-en-1 -one

1 -[3-[4-amino-3-[4-[(3-methyl-3,4-dihydro-1 H- isoquinolin-2-yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin- n.d. +++ - 1 -yl]-1 -piperidyl]prop-2-en-1 -one

1 -[3-[4-amino-3-[4-[(6,7-dimethoxy-3,4-dihydro-1 H- isoquinolin-2-yl)methyl]phenyl]pyrazolo[3,4-rf]pyrimidin- n.d. ++ - 1 -yl]-1 -piperidyl]prop-2-en-1 -one

1 -[(3R)-3-[4-amino-3-[4-[(6-ethoxy-3,4-dihydro-1 H- isoquinolin-2-yl)methyl]phenyl]pyrazolo[3,4-d]pyrimidin- n.d. +++ - 1 -yl]-1 -piperidyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4-(1 - morpholinoethyl)phenyl]pyrazolo[3,4-rf]pyrimidin-1 -yl]- n.d. + - 1 -piperidyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[2-fluoro-4- (morpholinomethyl)phenyl]pyrazolo[3,4-c/]pyrimidin-1 - n.d. ++ X

yl]-1 -piperidyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[3-fluoro-4- (morpholinomethyl)phenyl]pyrazolo[3,4-c/]pyrimidin-1 - n.d. + X

yl]-1 -piperidyl]prop-2-en-1 -one 1 -[(3f?)-3-[4-amino-3-[4-(3,4-dihydro-1 H-isoquinolin-2- ylmethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 - _*** +++ XXX

piperidyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[3- (morpholinomethyl)phenyl]pyrazolo[3,4-c/]pyrimidin-1 - n.d. + - yl]-1 -piperidyl]prop-2-en-1 -one

1 -[3-[(1 f?)-4-amino-3-[4-(1 - piperidylmethyl)phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 - n.d. ++ X

piperidyl]prop-2-en-1 -one

1 -[3-[(1 f?)-4-amino-3-[4-(pyrrolidin-1 - ylmethyl)phenyl]pyrazolo[3,4-a]pyrimidin-1 -yl]-1 - n.d. ++ X

piperidyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4- [(dimethylamino)methyl]phenyl]pyrazolo[3,4- n.d. ++ X c ]pyrimidin-1 -yl]-1 -pipe ridyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4- (morpholinomethyl)phenyl]pyrazolo[3,4-c/]pyrimidin-1 - n.d. ++ X

yl]-1 -piperidyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-(4-tetrahydrofuran-3- yloxyphenyl)pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 - n.d. ++ - piperidyl]prop-2-en-1 -one

1 -[(3R)-3-[4-amino-3-[4-[(2-methyl-3,4-dihydro-2H- quinolin-1 -yl)methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1 - _** +++ XXX

yl]-1 -piperidyl]prop-2-en-1 -one

1 -[[4-[4-amino-1 -[(3f?)-1 -prop-2-enoyl-3- piperidyl]pyrazolo[3,4-c/]pyrimidin-3- n.d. +++ XXX yl]phenyl]methyl]indoline-4-carbonitrile

1 -[(3f?)-3-[4-amino-3-[4-[(5-fluoro-2,3-dihydro-1 ,4- benzoxazin-4-yl)methyl]phenyl]pyrazolo[3,4- _*** +++ XXX c ]pyrimidin-1 -yl]-1 -pipe ridyl]prop-2-en-1 -one

n.d. = not determined; - = affinity or activity >500 nM or no activity

[00622] The following table, Table 4, provides values of the BTK binding efficacy of a selection of compounds of the invention from each category.

Table 4

BTK

ID

Name Binding

No.

IC50 (nM)

1 -[(3f?)-3-[4-amino-3-[4-[[8-(trifluoromethyl)-3,4-

27 dihydro-1 H-isoquinolin-2-yl]methyl]phenyl]pyrazolo[3,4- 1 .25

c ]pyrimidin-1 -yl]-1 -pipe ridyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4-[(5-fluoroindolin-1 -

29 yl)methyl]phenyl]pyrazolo[3,4-c ]pyrimidin-1 -yl]-1 - 0.53

piperidyl]prop-2-en-1 -one 1 -[(3f?)-3-[4-amino-3-[6-(2,3-dihydropyrido[3,2-

35 £>][1 ,4]oxazin-4-ylmethyl)-3-pyridyl]pyrazolo[3,4- 84.1

c ]pyrimidin-1 -yl]-1 -pipe ridyl]prop-2-en-1 -one

1 -[(3R)-3-[4-amino-3-[6-(3,4-dihydro-2H-quinolin-1 -

38 ylmethyl)-3-pyridyl]pyrazolo[3,4-d]pyrimidin-1 -yl]-1 - 1 .39

piperidyl]prop-2-en-1 -one

1 -[(3f?)-3-[4-amino-3-[4-(8-oxa-3- azabicyclo[3.2.1 ]octan-3-ylmethyl)phenyl]pyrazolo[3,4-

53 1 1 .53

c ]pyrimidin-1 -yl]-1 -pipe ridyl]prop-2-en-1 -one

[00623] 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.

[00624] 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.

[00625] 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

A compound according to formula (I) and pharmaceutically acceptable salts and solvates

wherein

E

Y is either O or NR^b;

X is selected from chloro, fluoro, bromo or iodo;

o is 0, 1 or 2 R^a is selected from the group comprising: H, halo, C_1-6 alkyl, C_1-6 haloalkyl, OH, SH, C_1-6 alkoxy, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃-₈ cycloalkyl, C₃-₈ cycloalkenyl, NR^bR^c, -CN, acyl, -C(0)R^b, -C(0)OR^b, -S0₂R^b, and -S0₃R^b;

C₃_7 cycloalkyl, and C₃.₇ halocycloalkyl;

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

2. A compound of claim 1 wherein one of A¹, A², A³, A⁴ and A⁵ is CL²R¹ and the remaining A¹ , A², A³, A⁴ and A⁵ are independently selected from N or CR^a.

3. A compound of claim 1 or claim 2 wherein one of A , A², A³, A⁴ and A⁵ is CL²R¹ and the remaining A¹ , A², A³, A⁴ and A⁵ are all CR^a.

4. A compound of any preceding claim wherein R is a substituted or unsubstituted carbocyclic or heterocyclic moiety which is saturated or unsaturated and which either contains from 3 to 8 atoms in a single ring or 7 to 14 atoms in a fused polycyclic ring system, wherein the group R as a whole is not aromatic.

5. A compound of any preceding claim wherein R is a substituted or unsubstituted heterocyclic moiety which is saturated or unsaturated and which either contains from 3 to 8 atoms in a single ring or 7 to 14 atoms in a fused polycyclic ring system, wherein the group R as a whole is not aromatic.

6. A compound of claim 5 wherein R contains from 7 to 14 atoms in a fused polycyclic ring system, wherein the group R as a whole is not aromatic.

7. A compound of any preceding claim wherein R is a substituted or unsubstituted ring selected from: piperidinyl, piperazinyl, piperidinyl, tetrahydropyranyl, morpholinyl, pyrolidinyl, imidazolidinyl, succinimidyl, pyrazolidinyl, tetrahydrofuranyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, oxetanyl, azetidinyl, oxiranyl, aziridinyl, oxepanyl, azepanyl, diazepanyl, oxazepanyl, diazepanyl, cycloheptanyl, cyclohexanyl, cyclohexenyl, cyclopentanyl, cyclopentenyl, cyclobutanyl, cyclopropanyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, hexahydroquinolinyl,

hexahydroisoquinolinyl, octahydroquinolinyl, octahydroisoquinolinyl, dihydroisoquinolinyl, dihydroquinolinyl tetrahydrobenzazepinyl, dioxobenzothiazolidinyl, tetrahydronaphthyridinyl, dihydronaphthyridinyl, hexahydronaphthyridinyl, octahydronaphthyridinyl, dihydrobenzothiazinyl, tetrahydrobenzothiazinyl.dihydropyrido-oxazinyl, tetrahydropyrido-oxazinyl, oxazabicycloheptanyl (for example oxazabicyclo[2.2.1 ]heptanyl), oxazabicyclo-octanyl (for example,

oxazabicyclo[3.2.1 .Joctanyl), octahydrobenzoxazinyl and dihydrobenzoxazinyl.

8. A compound of claim 7 wherein R is a substituted or unsubstituted ring selected from:

indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydronaphthyridinyl and dihydronaphthyridinyl.

9. A compound of any of claims 1 to 3 wherein R is selected from substituted or unsubstituted:

10. A compound of any of claims 1 to 3 wherein R is -NR⁶R⁷.

1 1 . A compound of any of claims 1 to 3 or 10 wherein:

R⁶ is substituted or unsubstituted C_1-6 alkyl and R⁷ is C_1-6 alkyl, C_1-6 haloalkyl, - (CR^dR^e)_n -aryl, wherein n is 0, 1 or 2.

R⁶ is methyl, ethyl or propyl and R⁷ is methyl, ethyl or propyl.

R⁶ is methyl or ethyl and R⁷ is C_1-6 haloalkyl, optionally C_1-6 fluoroalkyl.

R⁶ is methyl, ethyl or propyl and R⁷ is -(CH₂)_n -phenyl wherein n is 0 or 1 .

12. A compound of any of claims 1 -3, 10 or 1 1 wherein R is selected from:

/— Ph / /— CF₃

— N — ,— N

/ y / y

13. A compound of claim 1 wherein A¹ , A², A³, A⁴ and A⁵ are independently selected from N or CR^a and any two CR^a groups represented by adjacent A groups form an additional fused ring which is a non-aromatic carbocyclic or heterocyclic ring, wherein the ring contains 5 to 7 atoms of which 1 or 2 atoms of the ring formed by the adjacent A groups are heteroatoms, wherein the carbocylic or heterocyclic rings may be substituted by 1 to 4 groups independently selected at each occurrence from halo, C_1- alkyl, C_1- haloalkyl and C₃.₆ cycloalkyl.

14. A compound of any preceding claim wherein R², R³, and R⁴ may be independently selected from hydrogen, fluorine, chlorine, bromine, iodine, -CN, -CH₂NR^bR^c, C_1-6 alkyl, C_1-6 alkyl substituted with C₃_8 cycloalkyl, C_1-6 alkyl substituted with C₃.₈ heterocycloalkyl, C_1-6 haloalkyl, aryl, heteroaryl, alkaryl and alkheteroaryl.

15. A compound of any preceding claim wherein two of R², R³, and R⁴ may be hydrogen and the other may be fluorine, chlorine, bromine, iodine, -CN, -CH₂NR^bR^c and C_1-6 alkyl, where R^b and R^c are independtley selected from hydrogen and C_1-6 alkyl, e.g. R² and R³ may be hydrogen; or R³ and R⁴ may be hydrogen; or R² and R⁴ may be hydrogen.

16. A compound of any preceding claim wherein R², R³, and R⁴ are all hydrogen

17. A compound of any preceding claim wherein R⁵ is hydrogen.

18. A compound of any preceding claim wherein R^a is hydrogen.

19. A compound of any preceding claim wherein R^b and R^c are hydrogen.

20. A compound of any preceding claim wherein E is:

21 . A compound of claim 20 wherein Y is O.

22. A compound of any preceding claim wherein D is selected from a substituted or unsubstituted saturated C_1-6 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. In embodiments the alkylene chain and the heterocyclic ring contain 1 heteroatom selected from N, O or S, optionally N.

23. A compound of claim 22 wherein the alkylene chain and the heterocyclic ring contain 1 nitrogen atom and the nitrogen atom is the point of connection with group E.

24. A compound of claim 22 wherein D is:

25. A compound of any preceding claim wherein L² is selected from -(CR^dR^e)_m-, -O- and -NR^b-, wherein m is 1 or 2.

26. A compound of claim 25 wherein L² is selected from -CH₂-, -O- and -NH-, optionally -CH₂- or - O-.

27. A compound of any preceding claim wherein L is a bond.

28. A compound of claim 1 wherein the compound of formula (I) is a compound according to formula (III) or (Ilia):

(III) (Ilia) wherein E, Y, R^a, R^b, R^c, R , R², R³, R⁴, R⁵, R⁶, R⁷, L , L², n and m are as described in any of claims 1 - 31 .

claim 1 wherein the compound is selected from

30. A compound of claim 1 wherein the compound is selected from: 159

160

161

162

31 . A compound of any preceding claim for use as a medicament.

32. A compound of any of claim 1 to 30 for use in the treatment of a condition which is modulated by BTK.

33. A compound of claim 32 wherein the condition modulated by BTK cancer, lymphoma, leukemia, immunological disease, autoimmune diseases and inflammatory disorders.

34. A compound of claim 32 or claim 33 wherein the condition modulated by BTK is selected from: B-cell malignancy, B-cell lymphoma, chronic lymphocyte leukemia, non-Hodgkins lymphoma for example ABC-DLBCL, mantle cell lymphoma, and follicular lymphoma, B-cell non-Hodgkins lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, arthritis and lupus.

35. A compound of any of claims 1 -30, or a pharmaceutically acceptable salt thereof for use simultaneously, sequentially or separately with an additional anti-tumour agent, in the treatment of cancer, lymphoma, leukemia or immunological diseases.

36. A compound of claim 35 wherein the treatment may be of conditions treatable by the inhibition of BTK selected from: B-cell malignancy, B-cell lymphoma, diffuse large B cell lymphoma, chronic lymphocyte leukemia, non-Hodgkins lymphoma for example ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B-cell non-Hodgkins 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.

37. A pharmaceutical composition, wherein the composition comprises a compound of any of claims 1 -30 and pharmaceutically acceptable excipients.

38. A pharmaceutical composition of claim 37 wherein the composition is a combination product and comprises an additional pharmaceutically active agent.

39. 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 any of claims 1 to 30, to a patient in need thereof.

40. A method of treatment of claim 39 wherein the condition which is modulated by Bruton's tyrosine kinase is selected from: cancer, lymphoma, leukemia and immunological diseases, wherein the method comprises administering a therapeutic amount of a compound of the invention, to a patient in need thereof.

41 . A method of treatment of claim 39 or claim 40 wherein the condition is selected from: B-cell malignancy, B-cell lymphoma, diffuse large B cell lymphoma, chronic lymphocyte leukemia, non- Hodgkins lymphoma for example ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B-cell non-Hodgkins 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.

42. A method of treatment of a condition selected from cancer, lymphoma, leukemia or immunological diseases comprising administering a therapeutically effective amount of a compound of any of claims 1 to 30, or a pharmaceutically acceptable salt thereof simultaneously, sequentially or separately with an additional anti-tumour agent to a patient in need thereof.

43. A method of providing a combination product, wherein the method comprises providing a compound of any of claim 1 to 30 simultaneously, sequentially or separately with an anti-tumour agent.

44. Use of a compound of any of claims 1 to 30 in combination with an anti-tumour agent.