GB2516303A

GB2516303A - Compounds

Info

Publication number: GB2516303A
Application number: GB1312901.0A
Authority: GB
Inventors: Fred Elustondo; Richard Armer; Angus Morrison; Tilly Bingham; Emma Carswell
Original assignee: Redx Pharna PLC
Current assignee: Redx Pharna PLC
Priority date: 2013-07-18
Filing date: 2013-07-18
Publication date: 2015-01-21
Also published as: GB201312901D0

Abstract

A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof: wherein R1 is a substituent; L is a bond or a linker; A is selected from an optionally substituted- phenyl, pyridinyl and pyrazolyl; R2a and R2b are independently selected from hydrogen and a substituent; Ra and Rb independently selected from hydrogen and a substituent; m is 1, 2, 3 or 4; het is is selected from an optionally substituted- pyrrolidinylene, piperidinylene and azepanylene; R4 is selected from hydrogen and C(=Y)C(-R5)=CR6R7 wherein R5, R6 and R7 are independently selected from hydrogen and a substituent and Y is selected from oxyygen and NRc where Rc is selected from hydrogen and a substituent. These compounds are tyrosine kinase inhibitors. More specifically, the compounds are inhibitors of Brutons tyrosine kinase (BTK) and are useful for treating conditions treatable by the inhibition of BTK, for example cancer, lymphoma, leukemia and immunological diseases.

Description

Compounds [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 AlP, 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 2011/090760 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 hERO. 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 11,2 of 1.5 hours.

[0006] Since Ibrutinib was first disclosed there have been a number of patent applications concerned with structures closely related to Ibrutinib, for example see WO 2012/156843, wa 2012/158764, WO 2011/153514, wa 2011/046964, US 201 0/0254905, US 2010/01 44705, US 7718662, wa, 2008/054827 and WO 2008/121742.

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

SUMMARY OF THE DISCLOSURE

[0008] 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.

[0009] In a first aspect of the invention there is provided a compound according to formula (I) and pharmaceutically acceptable salts and solvates thereof:

N N

-L N N N -het -R28 R2b (I) wherein het" is selected from substituted or unsubstituted: pyrrolidinylene, piperidinylene and azapanylene; A is selected from substituted or unsubstituted: phenyl, pyridinyl and pyrazolyl, and wherein the ring may be optionally substituted by 1 to 4 R3; L is selected from a bond, -0-, 0(CRaRb)0, NR° C(O)NRc and (CRaRb)0, wherein o is selected from 1, 2 or 3; R1 is -NR8R°, -OR10, or a substituted or unsubstituted carbocyclic or heterocyclic moiety which is saturated, unsaturated or aromatic and which either contains from 3 to 8 atoms in a single ring or 7 to 14 atoms in a fused polycyclic ring system; R2 and R2b independently selected at each occurrence from: H, C14 alkyl, C14 haloalkyl, C14 acyl, C37 cycloalkyl, and C37 halocycloalkyl; R3 is independently selected at each occurrence from the group comprising: H, halo, C16 alkyl, haloalkyl, ORc, SRc, C16 alkoxy, C26 alkenyl, C26 alkynyl, C38 cycloalkyl, C33 cycloalkenyl, NRCRd, -CN, acyl, C(O)RC, C(O)ORC, -S02R°, and SO3RC; t is H or C(O)ORC or t is represented by: Y is either 0 or NRC; R5, R6 and R' are independently selected from H, halo, 0RC, -ON, NRcRd, CH2NRcRd, -CO2R°, C(O)RC, C(O)NR0Rd, C16 alkoxy, C16 alkyl, 016 alkyl substituted with cycloalkyl, C16 alkyl substituted with 03-3 heterocycloalkyl, 016 alkyl substituted with C56 heteroaryl, C26 alkenyl, C26 alkynyl, haloalkyl, C38 cycloalkyl, heterocycloalkyl, 038 cycloalkenyl, 038 heterocycloalkenyl, aryl, heteroaryl, alkaryl and alkheteroaryl; or R5 and R6 taken together with the carbon atoms to which they are attached form a C38 cycloalkene and R7 is independently selected as above; or R6 and R7 taken together with the carbon atom to which they are attached form a C38 cycloalkyl and R5 is independently selected as above; or R5 and R7 taken together with the carbon atoms to which they are attached form a C-C triple bond and R6 is independently selected as above; R8, R9 and R1° may be independently selected from H, substituted or unsubstituted C16 alkyl, C16 haloalkyl, substituted or unsubstituted C cycloalkyl, (CRaRb)aryl and -SO2R°, wherein n is 0, 1 or 2; m is selected from 1, 2, 3 and 4.

R and Rb are independently selected at each occurrence from: H, halo, 014 alkyl, C14 haloalkyl, C14 acyl, C37 cycloalkyl, and 037 halocycloalkyl; R° and Rd are independently selected at each occurrence from: H, 01-4 alkyl, 01-4 haloalkyl, C14 acyl, 037 cycloalkyl, and C37 halocycloalkyl; and wherein, when substituted, the substituted moiety includes 1 to 5 substituents independently selected at each occurrence from the group comprising: halo, 0Rc, -SRC, - NRCRd, NO, =0, -ON, acyl, 016 alkyl, 016 haloalkyl, cycloalkyl, SO2Rd, and SO3RC, -C(0)R' and C(O)OR°.

-L

[0010] In embodiments is selected from: R1L R1L R1L N_N (R3)/N / [0011] In embodiments is selected from: R1 L R1L R1L NN HNN (R/ CRV/ R1L 3 LR1 (R3)4 (R) R1 L R1 (R)3 [0012] In certain embodiments the group R1 may be a substituted or unsubstituted carbocyclic or heterocyclic moiety which is saturated, unsaturated or aromatic 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, when substituted, R1 contains 1 to 5 substituents independently selected at each occurrence from the group comprising: halo, -OR°, -SR°, NR0Rd, NO, =0, -ON, acyl, O16 alkyl, C16 haloalkyl, C38 cycloalkyl, S02Rc, and SO3RC, C(0)RC and C(0)0R.

[0013] In certain embodiments R1 is a substituted or unsubstituted carbocyclic or heterocyclic moiety and which is saturated, unsaturated or aromatic which contains from 3 to 8 atoms in a single ring, wherein, when substituted, R1 contains 1 to 5 substituents independently selected at each occurrence from the group comprising: -OR°, -SR°, - NRCRd, NO, =0, -CN, acyl, C16 alkyl, C16 haloalkyl, C38 cycloalkyl, SO2Rc, and SO3RC, -C(O)RC and C(O)ORC.

[0014] In an alternative embodiment R1 is a substituted or unsubstituted carbocyclic or heterocyclic moiety which is saturated, unsaturated or aromatic and which contains 7 to 14 atoms in a fused polycyclic ring system, wherein, when substituted, R1 contains 1 to 5 substituents independently selected at each occurrence from the group comprising: ORc, -SRC, NRcRd, NO, =0, -CN, acyl, C16 alkyl, C16 haloalkyl, C38 cycloalkyl, SO2Rc, and S03Rc, C(O)Rc and C(O)ORC.

[0015] In embodiments R1 is a substituted or unsubstituted carbocyclic moiety which is saturated, unsaturated or aromatic. In alternative embodiments R1 is a substituted or unsubstituted heterocyclic moiety which is saturated, unsaturated or aromatic.

[0016] In any embodiment the carbocyclic moiety may be cycloalkyl, cycloalkenyl or aryl.

Carbocyclic rings generally contain from 3 to 7 carbon atoms in a single ring or 7 to 14 atoms in a fused polycyclic ring system. In any embodiment the heterocyclic moiety may be heterocycloalkyl, heterocycloalkenyl or heteroaryl. Heterocyclic rings generally contain from 3 to 7 carbon atoms in a single ring or 7 to 14 atoms in a fused polycyclic ring system [0017] In an embodiment R1 is a substituted or unsubstituted heterocyclic moiety which is saturated, unsaturated or aromatic and the heteroatom is N. In an embodiment R1 is a substituted or unsubstituted heterocycloalkyl, heterocycloalkenyl or heteroaryl, wherein the heteroatom is N. The heterocycloalkyl, heterocycloalkenyl or heteroaryl may have 1, 2 or 3 nitrogen atoms, optionally 1 or 2.

[0018] In any embodiment the carbocyclic moiety may be selected from substituted or unsubstituted: cycloheptanyl, cyclohexanyl, cyclohexenyl, cyclopentanyl, cyclopentenyl, cyclobutanyl, cyclopropanyl, indenyl, phenyl, tetralin and naphthyl.

[0019] In any embodiment the heterocyclic moiety may be selected from substituted or unsubstituted: piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, pyrolidinyl, imidazolidinyl, succinimidyl, pyrazolidinyl, tetrahydrofuranyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, oxetanyl, azetidinyl, oxiranyl, aziridinyl, oxepanyl, azepane, oxazepane, diazepanyl, furanyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl indolyl, isoindolyl, indolinyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl, dihydroindazolyl, dihydrobenzimidazolyl, qiunolinyl, isoquinolinyl, tetrahydroqiunolinyl, tetrahydroisoquinolinyl,phtalazinyl, tetrahydrophthalazinyl, quinazolinyl, tetrahydroquinazolinyl, chromanyl and isochromanyl.

[0020] In a further embodiment R1 may be a substituted or unsubstituted ring selected from: piporidinyl, piperazinyl, totrahydropyranyl, 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 L through either a N atom or a C atom.

may be a substituted or unsubstituted ring selected from: furanyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl, wherein the ring may be bound to [through either a N atom or a C atom. R1 may be a substituted or unsubstituted ring selected from: indolyl, isoindolyl, indolinyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl, dihydroindazolyl, dihydrobenzimidazolyl, qiunolinyl, isoquinolinyl, tetrahydroqiunolinyl, tetrahydroisoquinolinyl,phtalazinyl, tetrahydrophthalazinyl, quinazolinyl, tetrahydroquinazolinyl, chromanyl and isochromanyl.

(0021] In an embodiment, R1 may be a substituted or unsubstituted ring selected from: cycloheptanyl, cyclohexanyl, cyclohexenyl, cyclopentanyl, cyclopentenyl, cyclobutanyl, cyclopropanyl, indenyl. R1 may be a substituted or unsubstituted ring selected from phenyl, tetralin or naphthyl.

[0022] In a further embodiment P1 may be a substituted or unsubstituted ring selected from: phenyl, pyridinyl, 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 L through either a N atom or a C atom.

[0023] In an embodiment R1 is selected from substituted or unsubstituted: -001-4 alkyl, phenyl, morpholinyl, pyridinyl, benzosuccinimidyl, tetrahydroquinolinyl and tetrahydroisoquinolinyl.

[0024] In an embodiment R1 is selected from substituted or unsubstituted: -0C14 alkyl, phenyl, morpholinyl and pyridinyl.

[0025] In a preferred embodiment R1 morpholinyl, phenyl, or methoxy.

[0026] In a further embodiment, the group defined by R1 in any of the compounds of the invention may be selected from substituted or unsubstituted:

ONH

N\-c N >1

N

CF3 Ph

N N

H

O CO

[0027] In a preferred embodiment, the group defined by R1 in any of the compounds of the invention may be selected from substituted or unsubstituted: >1 CF3 Ph oJ a a

N N \

[0028] In an embodiment R1 may be selected from substituted or unsubstituted: Pg Pg pg pg pg Rg pg pg wherein two R groups form a 04-8 ring with the carbon atoms to which they are attached, wherein the C43 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, orB carbon atoms and 1, 2 or 3 heteroatoms.

[0029] In an embodiment, R1 is selected from substituted or unsubstituted: F OMe [0030] In an embodiment R1 is selected from substituted or unsubstituted: [0031] In an embodiment, the group defined by R1 in any of the compounds of the invention may be selected from substituted or unsubstituted: qqccoo [0032] In an embodiment R1 is -NR8R9.

[0033] In embodiments R6 and Fl9 are independently selected from: H, C1-6 alkyl, C16 haloalkyl, (CR8Rb). -aryl and SO2RG. wherein n is 0, 1 or 2.

[0034] In embodiments Fl8 is C16 alkyl and Fl9 is C16 alkyl, Cl_fl haloalkyl, wherein n is 0, 1 or 2.

[0035] In embodiments Fl8 is methyl, ethyl or propyl and Fl9 is methyl, ethyl or propyl. In embodiments R° is methyl or ethyl and Fl9 is C16 haloalkyl, optionally Cl_fl fluoroalkyl. In embodiments R8 is methyl, ethyl or propyl and R9 is -(CH2) -phenyl wherein n is 0 or 1. In embodiments R8 is H and R9 is -SO2R°, wherein Rb is methyl, ethyl orfluoromethyl.

[0036] In an embodiment, the group defined by Fl1 in any of the compounds of the invention may be selected from substituted or unsubstituted: ___ 0*-/ rh

-N N HN

[0037] In an embodiment R1 is -OR10.

[0038] In embodiments Fl1° is independently selected from: H, C16 alkyl, C15haloalkyl, (CFlaFlb)naryl and SO2Flc, wherein n is 0, 1 or 2.

[0039] In embodiments R1° is alkyl, optionally methyl.

[0040] In an embodiment "het" is unsubstituted. In an alternative embodiment "het" is substituted. In an embodiment "het" is substituted with halo, optionally fluoro.

[0041] In an embodiment, "het" may be selected from:

HQH

and met" may be substituted or unsubstituted. In particular, met" may be unsubstituted.

[0042] In an embodiment, "het' may be selected from: NH oytt 6H [0043] In an embodiment, "het' may be: o or [0044] Optionally, "het" is substituted by a halo group for example fluoro, methyl or trifluoromethyl.

[0045] In an embodiment R2 and R2b are independently selected from: H, C14 alkyl and C14 haloalkyl. In an embodiment R2 and p2b are both H. [0046] In an embodiment R4 may be any substituent, for example a substituted or unsubstituted hydrocarbyl group which may optionally comprise one or more heteroatoms. R6

In an embodiment the substituent is C(O)ORC or Y R7. In an embodiment R4 is not H. [0047] In one embodiment R4 is: 7.

[0048] In embodiments Y is 0. In alternative embodiments Y is NRC wherein RC is H or methyl.

[0049] In an embodiment, R5, R6 and iI may be independently selected from hydrogen, fluorine, chlorine, bromine, iodine, -CN, CH2NRGRd, C16 alkyl, C16 alkyl substituted with C38 cycloalkyl, 01-6 alkyl substituted with C38 heterocycloalkyl, 01-6 haloalkyl, aryl, heteroaryl, alkaryl and alkheteroaryl.

[0050] In another embodiment, R5, R° and R7 may be independently selected from hydrogen, fluorine, chlorine, bromine, iodine, -ON, 0H2NR0Rd and 01-6 alkyl, where R° and are independently selected from hydrogen and alkyl.

[0051] In an embodiment, two of R5, R6 and R7 may be hydrogen and the other may be fluorine, chlorine, bromine, iodine, -ON, CH2NRCRd and 016 alkyl, where RC and Rd are independently selected from hydrogen and C alkyl, e.g. R5 and R6 may be hydrogen; or R6 and R7 may be hydrogen; or R5 and R' may be hydrogen.

[0052] In a preferred embodiment, R5, R6, and R' are all hydrogen. R6

[0053] In all embodiments Y R7, wherein Y is 0 or NRC, may be selected from: °

H HN

!=rNy!=y2%> rN [0054] In an embodiment m is 1 or 2, optionally m is 1. In an embodiment _(CRaRb)m is -CH2-or -CH2CH2-.

[0055] In an embodiment, R and Rb are independently selected from hydrogen 01-4 alkyl and halo, optionally hydrogen, methyl or fluoro. Optionally, R and Rb may be hydrogen.

[0056] In an embodiment, R° and Rd are independently selected from hydrogen or methyl. Optionally, RC and Rd may be hydrogen. In an embodiment Rb is H or methyl and R° is H. [0057] In embodiments L is selected from a bond, _O(CRtRb)0 -(crnt)0-, NRc and -C(O)NR°-. In embodiments o is 1 or 2, optionally o is 1. In embodiments R and Rb are independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C16 alkyl and C16 haloalkyl and R° is selected from hydrogen, 01-6 alkyl and baloalkyl. In embodiments R, Rb and RC are independently hydrogen or C alkyl.

[0058] In embodiments L is selected from a bond, -00H2-, -OH2-, -0-, -NH-and C(O)NH-, optionally -OH2-, -0-or -NH2-.

[0059] The embodiments and definitions of the various substituents, R1 etc, described above may be applied individually, or in any combination of one another, and independently, to the compounds of the invention.

[0060] In embodiments the compound of formula (I) is a compound according to formula (lIa) or a compound according to formula (lIb) and pharmaceutically acceptable salts and solvates thereof:

N N

Rl_LAab4 R2b (ha)

N N

-L)L N (C RH Rb) (hib) [0061] In embodiments the compound of formula (I) may be a compound according to formula (lila) or a compound according to formula (hlIb) and pharmaceutically acceptable salts and solvates thereof:

N N

R1-L A N (CR2Rb) N (lila)

N N

Rl_LAx(Cab) R5 R2b (Ihib) Y" )__R6 [0062] In embodiments the compound of formula (I) is a compound according to formula (IVa) or a compound according to formula (lVb) and pharmaceutically acceptable salts and solvates thereof:

N N

RlLfl4 (IVa)

N N

R1LQAQ (IVb) [0063] In all embodiments, the group represented by:

-L

may be selected from: LR1 [0064] In all embodiments R3 may be selected from H, halo, C6 alkyl, C6 haloalkyl, OH and C alkoxy. In particular, R3 may be H. [0065] In particular, the group represented by: may be [0066] In embodiments, the compound of formula (I) is a compound according to formula (Va) or a compound according to formula (Vb): R1LLR3 R3 R2a R2b (Va) R1LR3 NN R3 N -L NL. R3 R2 (Vb)

[0067] In all embodiments L may be selected from a bond, -0-, -NH2-and -OH2-. L may be -0-or -OH2-.

[0068] In embodiments, the compound of formula (I) is a compound according to formula (VIa) or a compound according to formula (VIb): RILR3 NN R3 R2 R2b (VIa) R1LR3 NN P3 P2 p2b (VIb) [0069] Compounds of the invention include: N N r'Y' y' N N ) L)N)NNVfl

H

-

I NNN NNN t

[0070] Preferred compounds of the invention are:

NN -NN

NNLNt NXNNQ t o [0071] In another aspect of the invention there is provided a compound of formula (I) for use as a medicament.

(0072] 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 BIK 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).

[0073] 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.

[0074] 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.

[0075] Arthritis, multiple sclerosis osteoporosis, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease and lupus are examples of immunological diseases treatable by 31K inhibition. Arthritis is an example of an inflammatory disorder treatable by 31K inhibition. Lupus is an example of an autoimmune disease treatable by BIK inhibition.

[0076] 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.

[0077] In an embodiment the compound of the invention may be for use in the treatment of specific conditions selected from: 3-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.

[0078] 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.

[0079] The method of treatment may be a method of treating a condition treatable by the inhibition of Bruton's tyrosine kinase.

[0080] 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, bore 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.

[0081] 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.

[0082] 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.

[0083] 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.

[0084] In an aspect of the invention there is provided a use of a compound of formula (I) in the manufacture of a medicament for the treatment of a condition which is modulated by Bruton's tyrosine kinase (BTK). The condition may be any of the conditions mentioned above.

DETAILED DESCRIPTION

[0085] 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.

[0086] 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.

[0087] The term 016 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. Substiuents for the alkyl group may be halogen, e.g. fluorine, chlorine, bromine and iodine, OH, 016 alkoxy.

[0088] The term "C16 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, 016 alkoxy.

[0089] The term "016 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, C16 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.

[0090] The term "026 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 For Zisomer. The double bond may be at any possible position of the hydrocarbon chain. For example, the C26 alkenyl" may be ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl.

[0091] The term "026 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 "C26 alkynyl" may be ethynyl, propynyl, butynyl, pentynyl and hexynyl.

[0092] The term 016 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, 0 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 C16 heteroalkyl may be bonded to the rest of the molecule through a carbon or a heteroatom. For example, the "C16 heteroalkyl" may be C16 N-alkyl, N,N-alkyl, or C16 O-alkyl.

[0093] The term "carbocyclic" refers to a saturated or unsaturated carbon containing ring system. A "carbocyclic" system may be rnonocyclic 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.

"Carbocyclic" may be 03-8 cycloalkyl or C610 aryl.

[0094] The term "heterocyclic" refers to a saturated or unsaturated ring system containing at least one heteroatom selected from N, 0 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. "Heterocyclic" may be C38 heterocycloalkyl or C510 heteroaryl.

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.

[0095] The term "C38 cycloalkyl" refers to a saturated hydrocarbon ring system containing 3,4, 5, 6, 7 or 8 carbon atoms. For example, the "C33 cycloalkyl" may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0096] The term "C 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 "C cycloalkyl" may be cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienly, cycloheptenyl, cycloheptadiene, cyclooctenyl and cycloatadienyl.

[0097] The term 038 heterocycloalkyl" refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7 orB carbon atoms and at least one heteroatom within the ring selected from N, 0 and S. For example there may be 1, 2 or 3 heteroatoms, optionally 1 or 2. The "Ca-B 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.

[0098] The term "Ca_B 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, 0 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.

[0099] 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 ii system within the ring or ring system where all atoms contributing to the conjugated yr system are in the same plane.

[00100] The term "aryl" refers to an aromatic hydrocarbon ring system. The ring system has 4n +2 electrons in a conjugated u system within a ring where all atoms contributing to the conjugated u system are in the same plane. "Aryl" may be aryl. For example, the "aryl" may be phenyl and napthyl. The aryl system itself may be substituted with other groups.

[00101] 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 0, N and S. The ring or ring system has 4n +2 electrons in a conjugated u system where all atoms contributing to the conjugated u system are in the same plane. "Heteroaryl" may be C510 heteroaryl. For example, the "heteroaryl" may be imidazole, thiene, furane, thianthrene, pyrrol, benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine and indole.

[00102] The term "alkaryl" refers to an awl group, as defined above, bonded to a C14 alkyl, where the C14 alkyl group provides attachment to the remainder of the molecule.

[00103] The term "alkheteroaryl" refers to a heteroaryl group, as defined above, bonded to a C14 alkyl, where the alkyl group provides attachment to the remainder of the molecule.

[00104] The term "halogen" herein includes reference to F, Cl, Br and I. Halogen may be Cl. Halogen may be F. [00105] 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.

[00106] 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, =0, NHR, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, C(O)H, acyl, acyloxy, carboxy, sulfo, sulfamoyl, carbamoyl, cyano, azo, nitro, halo, 01-6 alkyl, 01-6 alkoxy, C16 haloalkyl, 03-8 cycloalkyl, C26 alkenyl, C26 alkynyl, awl, heteroaryl or alkaryl. Where the moiety is substituted with two or more substituents and two of the substituents are adjacent the adjacent substituents may form a C48 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.

[00107] 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.

[00108] 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, C16 alkyl, C3.8 cycloalkyl, phenyl, benzyl or phenethyl group, eg R is H or Cl_s 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.

[00109] The invention contemplates pharmaceutically acceptable salts of the compounds of formula (I). Those may include the acid addition and base salts of the compounds.

[00110] 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.

[00111] 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).

[00112] 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.

[00113] 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.

[00114] 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.

[00115] 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), 1269-1 288 by Haleblian (August 1975).

[00116] Hereinafter all references to compounds of any formula include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.

[00117] The compounds of the invention include compounds of a number of formula as herein defined, including all polymcrphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labeled compounds of the invention.

[00118] 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.

[00119] 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-lnterscience 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.

[00120] 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.

[00121] 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. Optionally, the additional active agent may be an anti-tumour agent selected from the list below.

[00122] 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 specific anti-tumour agents listed below or anti-tumour agents from one or more of the categories of listed below:- (i) antiproliferative/antineoplastic drugs and combinations thereof, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, bendamustin, melphalan, chlorambucil, busulphan,capecitabine temozolamide ifosamide, mitobronitol, carboquone, thiotepa, ranimustine, nimustine, AMD-473, altretamine, AP-5280, apaziquone, brostallicin, carmustine, estramustine, fotemustine, gulfosfamide, KW-21 70, mafosfamide, mitolactol, etaplatin, lobaplatin, nedaplatin, strrplatin and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, pemetrexed, cytosine arabinoside, 6-mercaptopurine riboside, leucovarin, UFT, doxifluridine, carmoflur, cytarabine, enocitabine S-i, 5-azacitidine, cepecitabine, clofarabine, decitabine, eflornithine, ethynlcytidine, TS-1, nelarabine, nolatrexed, ocosfate, pelitrexol, triapine, trimetrexate, vidarabine, and hydroxyurea); antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, mithramycin, aclarubicin, actinomycin D, amrubicin, annamycin, elsamitrucin, galarubicin, nemorubicin, neocarzinostatin, peplomycin, piarubicin, rebeccamycin, stimalamer, streptozocin, valrubicin and zinostatin); antimitotic agents (for example ymca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol, docetaxol (Taxotere), and paclitaxel and polokinase inhibitors); proteasome inhibitors, for example carfilzomib and bortezomib; interferon therapy; and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, aclarubicin, amonafide, belotecan, 1 0-hydroxycamptothecin, 9-aminocamptothecin, diflomotecan, edotecarin, exatecan, gimatecan, lurtotecan, pirarubicin, pixantrone, rubitecan, sobuzoxane, SN-38, tafluposide, amsacrine, topotecan, mitoxantrone and camptothecin) and adjuvants used in combination with these therapies, for example folinic acid; (ii) cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, lasofoxifeneand iodoxyfene), antiandrogens (for example bicalutamide, mifepristone, flutamide, nilutamide, casodex 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 Siz-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 [HerceptinTM], the anti-EGER antibody panitumurriab, the anti-erbBl 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-N-(3-chloro-4-fluoropheny-7-(3-morpholinopropoxy) -quinazolin-4-amine (Cl 1033), erbB2 tyrosine kinase inhibitors such as lapatinib); ErbB2 inhibitors (for example GW-28297, Herceptin, 204, pertuzumab, TAK-165, GW-572016, AR-209, and 2B-1); 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 (AMN1O7); 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 AKI kinases, c-kit inhibitors, abl kinase inhibitors, P13 kinase inhibitors, P1t3 kinase inhibitors, CSF-1 R kinase inhibitors, IOF 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 (AvastinlM); COXII inhibitors (for example Arcoxia (etoricoxib), Bextra (valdecoxib), Celebrex (celecoxib), Paracoxib Vioxx (rofecoxib)); MMP inhibitors (for example MMP-2 inhibitors, MMP-9 inhibitors, AG-3340, RO 32-3555, and IRS 13- 0830); thalidomide; lenalidomide; and for example, a VEOF receptor (for example SU- 11248, SU-541 6, SU-6668, and angiozyme) tyrosine kinase inhibitor (such as vandetanib, vatalanib, sunitinib, axitinib and pazopanib); acitretin; fenretinide; zoledronic acid; angiostatin; aplidine; cilengtide; A-4; endostatin; halofuginome; rebimastat; removab; revlimid; squalamine; ukrain; and vitaxincombretastatin; (vi) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2; (vU) 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); interferons, such as interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma-la, and interferon gamma-n; PF3S1 2676; Filgrastim (Neupogen); lentinan; sizofilan; TheraCys; ubenimex; WF-l0; BAM-002; dacarbazine; daclizumab; denileukin; gemtuzumab; ozogamicin; imiquimod; lenograstim; melanoma vaccine (Corixa); molgramostim; OncoVAX-CL; sargramostim; tasonermin; tecleukin; thymalasin; tositumomab; Virulizin; 7-100; epratuzumab; mitumomab; oregovomab; pemtumoniab; and toll-like receptor modulators for example TLR-7 or TLR-9 agonists; and (viii) cytotoxic agents for example fludaribine (fludara), cladribine, pentostatin (NipentTM), edotecarin, SU-l 1248, paclitaxel, Erbitux, and irinotecan; (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, fluoromotholone, fluprednidene, fluprednidene acetate, flurandrenolone, fluticasone, fluticasone propionate, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone valerate, icomethasone, icomethasone enbutate, meprednisone, methylprednisolone, mometasone paramethasone, mometasone furoate monohydrate, prednicarbate, prednisolone, prednisone, tixocortol, tixocortol pivalate, triamcinolone, triamcinolone acetonide, triamcinolone alcohol and their respective pharmaceutically acceptable derivatives. A combination of steroids may be used, for example a combination of two or more steroids mentioned in this paragraph; (x) targeted therapies, for example PI3Kd inhibitors, for example idelalisib and perifosine; (xi) and additional active agents such as estramustine phosphate, fludarabine phosphate, farnesyl transferase inhibitors, PDGFr, streptozocin, strontium-89, suramin, hormonal therapies (for example Lupron, doxercalciferol, fadrozole, formestane and trelstar), supportive care products (for example, Filgrastim (Neupogen), ondansetron (Zofran), Fragmin, Procrit, Aloxi and Emend), biological response modifiers (e.g. Krestin, lentinan, sizofiran, picibanil and ubenimex), alitretinoin, ampligen, atrasenten, bexarotene, bosentan, calcitriol, exisulind, fotemustine, ibandronic acid, miltefosine, 1-asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pegaspargase, tazarotne, TLK-286, Velcade, Tarceva, tretinoin.

[00123] 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 rnineralocorticoids, for example aclometasone, aclometasone dipropionate, aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasol propionate, cloprednol, cortisone, cortisone acetate, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate, difluorocortolone, fluclorolone, flumethasone, flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluorocortisone, fluorocortolone, fluocortolone caproate, fluocortolone pivalate, fluorometholone, fluprednidene, fluprednidene acetate, flurandrenolone, fluticasone, fluticasone propionate, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone valerate, icomethasone, icomethasone enbutate, meprednisone, methylprednisolone, mometasone paramethasone, mometasone furoate monohydrate, prednicarbate, prednisolone, prednisone, tixocortol, tixocortol pivalate, triamcinolone, triamcinolone acetonide, triamcinolone alcohol and their respective pharmaceutically acceptable derivatives. A combination of steroids may be used, for example a combination of two or more steroids mentioned in this paragraph; (ii) TNF inhibitors for example etanercept; monoclonal antibodies (e.g. infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi)); fusion proteins (e.g. etanercept (Enbrel)); and 5-HT2A agonists (e.g. 2,5-dimethoxy-4-iodoamphetamine, TCB-2, lysergic acid diethylamide ([SD), 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.

[00124] 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.

[00125] 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.

[00126] 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.

[00127] 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.

[00128] 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.

[00129] 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.

(00130] 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.

EXAMPLES AND SYNTHESIS

(00131] As used herein the following terms have the meanings given: "Boc" refers to tert- butoxycarbonyl; "DCM" refers to dichloromethane; "DIFEA" refers to N,N-Diisopropylethylamine; "LCMS" refers to liquid chromatography/mass spectrometry; "MIM" refers to monoisotopic mass; "mm" refers to minutes; "NMP" refers to N-methylpyrrolidinone; "TLC" refers to thin layer chromatography; "Rf" refers to Retention factor; "RT" refers to retention time; "SCX" refers to strong cation exchange; "TFA" refers to trifluoroacetic acid; "THF" refers to tetrahydrofuran; and "TBME" refers to tert-Butyl methyl ether.

(00132] All LCMS analysis was carried out on a Waters Acquity SQ Detector 2 with two 0.2pm guard filters using a UPLC Column (Cia, 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 mI/mm, back pressure ca <8000 psi. Injection volume was 2 pL. Temperature was 40 °C. Run time was B Mins. The Gradient was: Time (mm) %A %B 0 95 5 1.1 95 5 6.1 5 95 7 5 95 7.5 95 5 8 95 5 [00133] ExamDle 1 [00134] The compounds of the present invention may be synthesised by analogy with the following reaction route shown in Route A. [00135] Route A Amine I Amine 2 N'N DIPEA NN DIPEA LtJ MeCN NH2 H2N Boc Amine I Amine 2 [flr'CuJ N_ LN_0, .:: dioxane (1'cJL NININNY acrylic acid EDCI, DIPEA NN

II I I II II

DCM

H H

[00136] Protecting groups may be present or absent as necessary. For example, a nitrogen atom may be protected or unprotected.

[00137] A synthesis of representative compounds of the invention is given below.

4-Chloro-N-(4-phenoxyphenyl)-1,3,5-triazin-2-amine KK° T1"l N N

L NXNACI

2,4-Dichloro-1,3,5-triazine (445.33mg, 2.97mmol) and 4-phenoxyaniline (0.5g, 2.7mmol) were weighed in a vial. MeCN (5mL) was added followed by N,N-diisopropylethylamine (0.71mL, 4.Obmmol). The reaction was allowed to stir for 30 minutes. The reaction was concentrated to dryness and the residue was taken up in DCM (20 ml) and washed with 1 x 25 ml saturated brine solution. The organics were then separated and dried (MgSO4) before being concentrated to dryness. The crude material was then purified by flash column chromatography eluting with 0% to 100% EtOAc in heptanes resulting in 4-chloro-N-(4-phenoxyphenyl)-1,3,5-triazin-2-amine(SSOmg,1.9416mmo1, 71.923%yield) as a white solid.

NMR (CDCI3): 8.65 (1 H, s), 7.55 (2H, m), 7.45 (2H, m), 7.11 (SH, m) (ES, short acidic): 1.81 mm, m/z 299 [M--H] 100% tert-Butyl 4-[[4-(4-phenoxyanilino)-1,3,5-triazin-2-yl]amino]methyl]piperidine-1 -carboxylate

N N

ft NXNXNt 4-Chloro-N-(4-phenoxypheny-1,3,5-triazin-2-amine (298.mg, 1 mmol) and tert-butyl 4- (aminomethyl)piperidine-1 -carboxylate (250mg, 1.1 7mmol) were weighed into a vial.

MeCN (3mL) and N,N-diisopropylethylamine (0.35mL, 2mmol) were added. The vial was closed and the reaction was stirred for 6 hours. The solution was added to a SNAP column (50g) and was then purified by flash column chromatography eluting 0 to 100% EtOAc in heptanes to provide tert-butyl 4-[[4-(4-phenoxyanilino)-1,3,5-triazin-2-yl]amino]methyl]piperidine-1 -carboxylate (400mg, 0.83 mmol, 84.1% yield).

NMR (CDCI3): 8.25 (1 H, s), 7.55 (2H, m), 7.42 (2H, m), 7.11(1 H, m), 7.02 (4H, m), 4.21 (3H, m), 3.35 (2H, m), 2.75 (2H, m), 1.75 (2H, m), 1.52 (9H, s), 1.21 (2H, m) LCMS (ES, short acidic): 2.02 mm, mlz 477 [M+H] 97% purity N2-(4-Phenoxyphenyl)-N4-(4-piperidylmethyl)-1,3,5-triazine-2,4-diamine r<'Th"Th N N 4M HCI in dioxane (4.mL, 0.4200mmol) and tert-butyl 4-[[4-(4-phenoxyanilino)-1 3,5-triazin-2-yl]amino]methyl]piperidine-1 -carboxylate (200mg, 0.4200mmo1) were weighed into a vial. Further 1,4-dioxane (3mL) was added and the vial was closed and the reaction was stirred for 6 hours. EtOAc (1 OmL) was added. A solid precipitate was recovered by filtration. N2-(4-phenoxyphenyl)-N4-(4-piperidylmethyl)-1,3,5-triazine-2,4-diamine (l4Omg,0.3719mmo1, 88.617% yield) was recovered as an off white solid.

(ES+, short acidic): 0.65 mm, m/z 377 [M+H]+ N-[4-[[4-(4-Phenoxyanilino)-1,3,5-triazin-2-yl]amino]methyl]-1-piperidyl] prop-2-en-1 -one

N N t

3-(Ethyliminomethyleneamino)propyl-dimethyl-ammonium chloride (38.19mg, 0.2000mmol) was weighed into a vial. DCM (2mL) was added followed by triethylamine (26.88mg, 0.2700mmol) and acrylic acid (1 4.35mg, 0.2000mmol). The vial was closed and the reaction was stirred for 30 minutes. N-(4-phenoxyphenyl)-N4-(4-piperidylmethyl)-1,3,5-triazine-2,4-diamine (50mg, 0.1 300mmol) was then added in one portion. The reaction was allowed to stir for 1 hour. The crude material was purified by flash column chromatography eluting with 0 to 40% MeOH in EtOAc and resulting in N-[4-[[4-(4-phenoxyanilino)-1,3,5-triazin-2-yl]amino]methyl]-1 -piperidyl]prop-2-en-1-one (8.4mg,0.Olg5mmol, 14.693% yield) LCMS (ES+, short acidic): 1.21 mi m/z 340 [M+H]+ NMR (CDCI3) 8.21 (1 H, s), 7.58 (2H, m), 7.31 (2H, m), 7.22 (1 H, m), 7.12 (4H, m), 6.67 (1 H, m), 6.32 1 H, m), 5.64 (1 H, m), 4.82(1 H, m), 4.02 (1 H, m), 3.32 (2H, m), 3.11(1 H, m), 2.75 (2H, m), 1.765(3H, m)1.21 (2H, m).

[00138] Example 2

[00139] BTK Binding Activity [00140] 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 LanthascreenlM Eu anti-His Antibody and l5nM Kinase Tracer 236 was incubated in lx LanthascreenTM Kinase Buffer A for five hours. Recombinant BIK kinase and all LanthasceenTM components were purchased from Invitrogen. Measurements were performed in a reaction volume of 30p1 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 1050 from log[lnhibitor] vs response using the Variable Slope model in Graphpad prism from Graphpad software (SanDiego, Calif).

[00141] Table 1 below shows the BTK binding as an 1050 value in nM, as determined by the assay described above, for certain compounds of formula (I).

Table 1

Compound 1C50 (nM) 0 -NN I NXNLN%() 1349

N N

NLNXNQ 31.6

N N

LJ 1435

H H___

N N

L NLNLNt 16.7 t ___ [00142] The following assays may be used by the skilled person to investigate the efficacy of BTK inhibitors.

Off-Rate Assay [00143] The irreversible nature of compounds was determined using an off-rate assay utilising the TR-FRET based LanthascreenTM binding assay (Invitrogen) described above.

5nM Recombinant BTK kinase, inhibitor and 2nM LanthascreenTM Eu anti-His Antibody were incubated in a total volume of 30pl in lx LanthascreenTM Kinase Buffer A for one hour. The reaction was then diluted 33-fold into a saturating concentration of Kinase Tracer 236 in a half-area 96-well assay plate and the TR-FRET signal was measured at regular intervals over three hours. The concentration of inhibitor to be incubated with kinase was determined by calculating 40X Ki, where the Ki for each compound was calculated using the IC50 from the LanthascreenlM binding assay in the following equation, /(= (IC50)! (1+([Tracer]!Kd)) [00144] Controls were performed in the absence of inhibitor and in the absence of kinase and positive controls consisted of using 40X Ki of known reversible and irreversible BTK kinase inhibitors. The no kinase control values were then subtracted from each value for each time point and these values were calculated as a percentage of the no inhibitor control at each time point.

BTK In Vitro Inhibitory Activity [00145] The BTK kinase activity was determined using the Omnia® assay (Invitrogen) that utilises a chelation enhanced fluorophore (CHEF) incorporated into a peptide substrate.

Phosphorylation of the peptide by a kinase results in increased fluorescence and so the increase in fluorescence can be used as a measure of kinase activity. 1 5OnM recombinant BTK kinase (Invitrogen) and inhibitor were pre-incubated for 30mm in 1X Kinase Reaction Buffer before transferring lOpI of this into 3Oiil of Omnia master mix to give final concentrations of 37.5nM BTK, 0.2mM DII, 1 0jiM Omnia® peptide and 0.1mM ATP (KmATP = 0.15mM). Measurements were performed in half-area 96-well assay plate and the fluorescence was read in a kinetic manner on a plate reader with an excitation wavelength of 360nm and detection wavelength of 485nm.Controls were performed in the absence of kinase and the fluorescence values from these wells were subtracted from each of the test wells at each time point. The initial velocity (0-1 5mm) was then determined from the slope of a plot of relative fluorescence units plotted against time (in seconds) and the velocities were then 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).

BTK Cellular Assay [00146] Compounds were assayed in Ramos human Burkitt Lymphoma cells. Ramos cells were grown in suspension in T225 flasks, centrifuged and re-suspended in serum-free media. Cells were then plated at 1.5x1 0°/mI in serum-free media and varying concentrations of compound and incubated for 2 hours at 37°C. Cells were then stimulated for 10 mm in 5pg/ml goat F(ab')2 Anti-Human 1gM (Invitrogen) to activate B-cell receptor signalling. The cells were then washed once in ice cold PBS and lysed on ice in lysis buffer consisting of 150mM NaCI, 50mM Iris pH8 containing freshly added Halt Protease and Phosphatase Inhibitor Cocktails (Pierce). 1 5pg total protein from lysates was loaded onto gels and blots were probed for Total BTK and phosphorylation of BTK at Y223 using antibodies from Cell signalling Technology #3533 and #5082.

[00147] 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.

[00148] 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.

[00149] 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

CLAIMS1. A compound according to formula (I) and pharmaceutically acceptable salts and solvates thereof:N NR1_LACabhR4 R2b (I) wherein "het" is selected from substituted or unsubstituted: pyrrolidinylene, piperidinylene and azapanylene; A is selected from substituted or unsubstituted: phenyl, pyridinyl and pyrazolyl, and wherein the ring may be optionally substituted by 1 to 4 R3; L is selected from a bond, -0-, c(crnRb)0, NRc, C(0)NRc and (CRaRb)0, wherein o is selected from 1,
2 or 3; fl1 is -NR8R9, -CR10, or a substituted or unsubstituted carbocyclic or heterocyclic moiety which is saturated, unsaturated or aromatic and which either contains from
3 to 8 atoms in a single ring or 7 to 14 atoms in a fused polycyclic ring system; R2 and R2b independently selected at each occurrence from: H, 01-4 alkyl, 01-4 haloalkyl, 014 acyl, 03-7 cycloalkyl, and 03-7 halocycloalkyl; R3 is independently selected at each occurrence from the group comprising: H, halo, 01-6 alkyl, 016 haloalkyl, -OR°, -SR°, C6 alkoxy, C26 alkenyl, C26 alkynyl, C38 cycloalkyl, cycloalkenyl, NRCRd, -CN, acyl, C(0)Rc, C(C)0Rc, S02Rc, and S0sRc; R4 is H or C(0)ORC or R4 is represented by: Y is either 0 or NRC; R5, R6 and R' are independently selected from H, halo, ORC, -CN, NR0Rd, CH2NR0Rd, -CO2RC, C(0)RC, C(0)NRcRd, 01-6 alkoxy, C16 alkyl, C16 alkyl substituted with cycloalkyl, Ci alkyl substituted with C3-8 heterocycloalkyl, 016 alkyl substituted with Cs-fl heteroaryl, C26 alkenyl, C2-6 alkynyl, C16 haloalkyl, 038 cycloalkyl, C33 heterocycloalkyl, C35 cycloalkenyl, C38 heterocycloalkenyl, aryl, heteroaryl, alkaryl and alkheteroaryl; or R5 and R6 taken together with the carbon atoms to which they are attached form a C38 cycloalkene and it is independently selected as above; or R6 and R7 taken together with the carbon atom to which they are attached form a C38 cycloalkyl and 112 is independently selected as above; or fl5 and R taken together with the carbon atoms to which they are attached form a C-C triple bond and R is independently selected as above: 118, R and 1110 may be independently selected from H, substituted or unsubstituted C16 alkyl, 016 haloalkyl, substituted or unsubstituted C33 cycloalkyl, and S02RC, wherein n is 0, 1 or 2; m is selected from 1, 2, 3 and 4.

R and 11b are independently selected at each occurrence from: H, halo, 01-4 alkyl, 01-4 haloalkyl, 01-4 acyl, C37 cycloalkyl, and 037 halocycloalkyl; flO and Rd are independently selected at each occurrence from: H, 01-4 alkyl, 01-4 haloalkyl, 01-4 acyl, C37 cycloalkyl, and 03-7 halocycloalkyl; and wherein, when substituted, the substituted moiety includes 1 to 5 substituents independently selected at each occurrence from the group comprising: halo, -OR°, -SR°, - NRCRd, NO, =0, -CN, acyl, C16 alkyl, C16 haloalkyl, C38 cycloalkyl, SO2Rd, and SO3R°, -C(O)R' and C(O)ORC.

-L -(1 2. A compound of claim 1 wherein, is selected from: R1 L R1L R1L NN HNN (RP (Rc (R// R1L 3 LR1 (R3)4 (R) R1 L R1 (R3)3t 3. The compound of claims 1 or 2, wherein R1 may be a substituted or unsubstituted carbocyclic or heterocyclic moiety which is saturated, unsaturated or aromatic and which either contains from 3 to 8 atoms in a single ring or 7 to 14 atoms in a fused polycyclic ring system.
4. The compound of claim 3, wherein the carbocyclic moiety may be cycloalkyl, cycloalkenyl or aryl and the heterocyclic moiety may be heterocycloalkyl, heterocycloalkenyl or heteroaryl.
5. The compound of any preceding claim, wherein R1 is selected from substituted or unsubstituted: phenyl, morpholinyl and pyridinyl.
6. The compound of claim 5, wherein R1 is phenyl.
7. The compound of any preceding claim, wherein "het" may be selected from: 6NH
8. The compound of any preceding claim, wherein R2 and R2b are independently selected from: H, C14 alkyl and 01-4 haloalkyl.
9. The compound of claim 8, wherein R2 and R2b are both H.
10. The compound of any preceding claim, wherein R4 is:
ii. The compound of any preceding claim, wherein R5, R6 and R7 may be independently selected from hydrogen, fluorine, chlorine, bromine, iodine, -CN, CH2NR0Rd and C16 alkyl, where flC and Rd are independently selected from hydrogen and C16 alkyl.
12. The compound of claim 9, wherein R5, R6 and Ware hydrogen.
13. The compound of any preceding claim, wherein L is selected from -0-, O(CRaRb)0 and (CRLRb)0 and o is 1 or 2.
14. The compound of any of claims ito 10, wherein L is selected from a bond, -OCH2- -CH2-, -0-, -NH-and C(0)NH-.
15. The compound of any preceding claim, wherein m is 1 or 2.
16. The compound of any preceding claim, wherein R and Rb are independently selected from hydrogen, methyl and fluoro.
17. The compound of any preceding claim, wherein _(CR2Rb)m is -CH2-or -CH2CH2-.
18. The compound of any preceding claim, wherein Y isO.
19. The compound of claim i,wherein the compound of formula (I) is a compound selected from:N N N N LNXN*LNQ NXNNQ H o N N r°"t1Th N N NXNXN NXNXNH H H H LNH20. A compound of any preceding claim for use as a medicament.21. A compound of any or claims 1 to 19 for use in the treatment of a condition which is modulated by BTK.22. A compound of claim 21 wherein the condition modulated by BIK is cancer, lymphoma, leukemia, immunological disease, autoimmune diseases and inflammatory disorders.23. A compound of claims 21 or claim 22, wherein the condition modulated by BIK 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, bore metastasis, arthritis, multiple sclerosis osteoporosis, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease and lupus.24. A compound of any of claims 1 to 19 for use simultaneously, sequentially or separately with an additional anti-tumour agent, in the treatment of cancer, lymphoma, leukemia or immunological diseases.25. A pharmaceutical composition, wherein the composition comprises a compound of any of claims 1 to 19 and pharmaceutically acceptable excipients.26. A pharmaceutical composition of claim 25 wherein the composition is a combination product and comprises an additional pharmaceutically active agent.27. 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 ito 19, to a patient in need thereof.28. The method of claim 27 wherein the condition modulated by BIK is cancer, lymphoma, leukemia, immunological disease, autoimmune diseases and inflammatory disorders.29. A compound of claims 27 or claim 28, wherein the condition modulated by BIK 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, bore metastasis, arthritis, multiple sclerosis osteoporosis, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease and lupus.30. A method of treatment of a condition selected from cancer, lymphoma, leukemia or immunological diseases comprising administering a therapeutically effective amount of a compound any of claims 1 to 19, simultaneously, sequentially or separately with an additional anti-tumour agent to a patient in need thereof.31. A method of providing a combination product, wherein the method comprises providing a compound of any of claims 1 to 19 simultaneously, sequentially or separately with an anti-tumour agent.32. Use of a compound of any of claims 1 to 19 in the manufacture of a medicament for the treatment of a condition which is modulated by Bruton's tyrosine kinase.33. Use of a compound of any of claims 1 to 19 in combination with an anti-tumour agent.