WO2014188173A1 - Dérivés pyrazolopyrimidine utiles comme inhibiteurs de la tyrosine kinase de bruton - Google Patents

Dérivés pyrazolopyrimidine utiles comme inhibiteurs de la tyrosine kinase de bruton Download PDF

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Publication number
WO2014188173A1
WO2014188173A1 PCT/GB2014/051542 GB2014051542W WO2014188173A1 WO 2014188173 A1 WO2014188173 A1 WO 2014188173A1 GB 2014051542 W GB2014051542 W GB 2014051542W WO 2014188173 A1 WO2014188173 A1 WO 2014188173A1
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mmol
compound
phenyl
pyrazolo
methyl
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PCT/GB2014/051542
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English (en)
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Richard Armer
Matilda Bingham
Angus Morrison
Emma Carswell
Fred ELUSTONDO
Rolf WALKER
Nicolas GUISOT
Catherine Lucas
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Redx Pharma Limited
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Publication of WO2014188173A1 publication Critical patent/WO2014188173A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • 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
  • 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.
  • 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.
  • Ibrutinib PCI-32765
  • 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.
  • Ibrutinib is poorly soluble and is a weak inhibitor of hERG.
  • 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.
  • WO 2013/010136 disclosed BTK inhibitors with a related structure to Ibrutinib.
  • Another aim of certain embodiments of this invention is to provide compounds which exhibit reduced cytotoxicity relative to prior art compounds and existing therapies.
  • 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).
  • the invention provides compounds capable of inhibiting Bruton's tyrosine kinase (BTK) and the use of these compounds in inhibiting BTK.
  • BTK Bruton's tyrosine kinase
  • a method of treating conditions modulated by BTK The invention provides compounds for use in treating a condition which is modulated by BTK.
  • a 1 , A 2 , A 3 , A 4 and A 5 is CL 2 R 1 and the remaining A 1 , A 2 , A 3 , A 4 and A 5 are independently selected from N or CR a ;
  • a 1 , A 2 , A 3 , A 4 and A 5 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 C 3 . 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;
  • 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, C 2 _ 6 alkenyl, C 2 - 6 alkynyl, C 3 - 8 cycloalkyl, C 3 - 8 cycloalkenyl, NR b R c , -CN, acyl, -C(0)R b , -C(0)OR b , -S0 2 R b , and -S0 3 R b ;
  • R b and R c are independently selected at each occurrence from: H, C 1- alkyl, C 1- haloalkyl, C 1- acyl, C 3 _7 cycloalkyl, and C 3 . 7 halocycloalkyl;
  • R 2 , R 3 , and R 4 are independently selected from H, halo, -OR b , -CN, -NR b R c , -CH 2 NR b R c , -C0 2 R b , - C(0)R b , -C(0)NR b R c , C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkyl substituted with C 3 . 8 cycloalkyl, C 1-6 alkyl substituted with C 3 . 8 heterocycloalkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 1-6 haloalkyl, C 3 . 8 cycloalkyl, C 3 .
  • R 3 and R 4 taken together with the carbon atom to which they are attached form a C 3 . 8 cycloalkyl and R 2 is independently selected as above;
  • R 2 and R 4 taken together with the carbon atoms to which they are attached form a C-C triple bond and R 3 is independently selected as above;
  • R 5 is selected from H, halo, -OR b , C 1-6 alkoxy, C 1-6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 1-6 haloalkyl, C 3 . 8 cycloalkyl, C 3 . 8 heterocycloalkyl, C 3 . 8 cycloalkenyl, C 3 . 8 heterocycloalkenyl, -NR b R c , -C0 2 R b , -C(0)R b and -C(0)NR b R c ;
  • R 6 and R 7 may be independently be selected from H, substituted or unsubstituted C 1-6 alkyl, C 1-6 haloalkyl, substituted or unsubstituted C 3 . 8 cycloalkyl, -(CR d R e ) n -aryl, wherein n is 0, 1 or 2; L and L 2 are independently selected from a bond, -0-, -0(CR d R e ) m -, -NR b - and -(CR d R 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 C 3 . 7 halocycloalkyl; and
  • n is selected from 1 , 2, 3 and 4.
  • the invention also provides a compound according to formula (I) and pharmaceutically acceptable salts and solvates thereof:
  • a 1 , A 2 , A 3 , A 4 and A 5 is CL 2 R 1 and the remaining A 1 , A 2 , A 3 , A 4 and A 5 are independently selected from N or CR a ;
  • a 1 , A 2 , A 3 , A 4 and A 5 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 C 3 . 6 cycloalkyl, provided that the heterocyclic ring does not comprise 2 oxygen atoms;
  • 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;
  • 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;
  • Y is either O or NR b ;
  • X is selected from chloro, fluoro, bromo or iodo
  • R a is selected from the group comprising: H, halo, C 1-6 alkyl, C 1-6 haloalkyl, OH, SH, C 1-6 alkoxy, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3 - 8 cycloalkyl, C 3 - 8 cycloalkenyl, NR b R c , -CN, acyl, -C(0)R b , -C(0)OR b , -S0 2 R b , and -S0 3 R 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 C 3 . 7 halocycloalkyl;
  • R 2 , R 3 , and R 4 are independently selected from H, halo, -OR b , -CN, -NR b R c , -CH 2 NR b R c , -C0 2 R b , - C(0)R b , -C(0)NR b R c , C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkyl substituted with C 3 . 8 cycloalkyl, C 1-6 alkyl substituted with C 3 . 8 heterocycloalkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 1-6 haloalkyl, C 3 . 8 cycloalkyl, C 3 .
  • R 3 and R 4 taken together with the carbon atom to which they are attached form a C 3 . 8 cycloalkyl and R 2 is independently selected as above;
  • R 2 and R 4 taken together jointly contribute to a bond so that the carbon atoms to which they are attached form a C-C triple bond and R 3 is independently selected as above;
  • R 5 is selected from H, halo, -OR b , C 1-6 alkoxy, C 1-6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 1-6 haloalkyl, C 3 . 8 cycloalkyl, C 3 . 8 heterocycloalkyl, C 3 . 8 cycloalkenyl, C 3 . 8 heterocycloalkenyl, -NR b R c , -C0 2 R b , -C(0)R b and -C(0)NR b R c ;
  • L is selected from a bond, -0-, -0(CR d R e ) m -, -NR b - and -(CR d R 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,
  • L 2 is selected from -0-, -0(CR d R e ) m -, -NR b - and -(CR d R 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, C 3 . 7 cycloalkyl, and C 3 . 7 halocycloalkyl;and
  • n is selected from 1 , 2, 3 and 4.
  • one of A 1 , A 2 , A 3 , A 4 and A 5 is CL 2 R 1 and the remaining A 1 , A 2 , A 3 , A 4 and A 5 are independently selected from N or CR a .
  • the group R is a substituent on the ring A " ⁇ in embodiments where one of A , A 2 , A 3 , A 4 and A 5 is CL 2 R 1 and the remaining A 1 , A 2 , A 3 , A 4 and A 5 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:
  • R does encompass, amongst other things:
  • the A-ring is also an important part of the molecule.
  • one of A 1 , A 2 , A 3 , A 4 and A 5 is CL 2 R 1
  • one of A 1 , A 2 , A 3 , A 4 and A 5 is N and the remaining A 1 , A 2 , A 3 , A 4 and A 5 are CR a
  • the A ring is a pyridyl ring which may have the N at any position.
  • one of A 1 , A 2 , A 3 , A 4 and A 5 is CL 2 R 1 and the remaining A 1 , A 2 , A 3 , A 4 and A 5 are all CR a .
  • the A ring is a phenyl ring.
  • the heterocyclic moiety comprises 1 , 2 or
  • 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.
  • 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.
  • 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.
  • the heterocyclic moiety contains 9, 10 or 1 1 atoms in a fused bicyclic ring system.
  • the heterocyclic moiety may comprise at least one nitrogen atom.
  • R is a substituted or unsubstituted carbocyclic moiety which is saturated or unsaturated.
  • R is a substituted or unsubstituted heterocyclic moiety which is saturated or unsaturated.
  • the heterocyclic moiety may comprise 1 , 2 or 3 heteroatoms selected from N, O or S.
  • the heterocyclic moiety comprises at least one N atom. Further optionally, the heterocyclic moiety comprises at least an N atom and an O atom.
  • 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, in
  • 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 L 2 through either a N atom or a C atom.
  • R may be a substituted or unsubstituted ring selected from: indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, hexahydroquinolinyl, hexahydroisoquinolinyl, octahydroquinolinyl, octahydroisoquinolinyl, dihydroisoquinolinyl, dihydroquinolinyl
  • R is a group comprising a nitrogen atom the group R may be bonded to L 2 through the nitrogen atom.
  • R may be a substituted or unsubstituted ring selected from:
  • cycloheptanyl cyclohexanyl, cyclohexenyl, cyclopentanyl, cyclopentenyl, cyclobutanyl, cyclopropanyl.
  • R may be a substituted or unsubstituted ring selected from:
  • R is a substituted or unsubstituted ring selected from:
  • 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 L 2 through either a N atom or a C atom.
  • 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.
  • R is a substituted or unsubstituted ring selected from: -N(C 1-6 alkyl) 2 , morpholinyl, diazepanyl, pyrolidinyl, tetrahydrofuranyl, piperidinyl, indolinyl, isoindolinyl,
  • R is a substituted or unsubstituted ring selected from: indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydronaphthyridinyl and
  • 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
  • R is unsubstituted or substituted
  • R is unsubstituted or substituted
  • R is unsubstituted or substituted
  • the group defined by R in any of the compounds of the invention may be selected from substituted or unsubstituted:
  • the group defined by R in any of the compounds of the invention may be selected from substituted or unsubstituted:
  • R is substituted or unsubstituted:
  • the two R' groups form a C 4 . 8 ring with the carbon atoms to which they are attached, wherein the C 4 _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.
  • R is:
  • the two R' groups form a C 4 . 8 ring with the carbon atoms to which they are attached, wherein the C 4 _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.
  • the two R' groups form a substituted or unsubstituted C 6 ring with the carbon atoms to which they are attached, wherein the C 6 ring is an unsaturated hydrocarbon ring with 6 carbon atoms or a unsaturated hydrocarbon ring with 5 carbon atoms and 1 nitrogen atom.
  • the C 6 ring may be a phenyl ring or a pyridyl ring.
  • the two R' groups form a substituted or unsubstituted C 6 ring with the carbon atoms to which they are attached, wherein the C 6 ring is a phenyl ring.
  • R is selected from substituted or unsubstituted:
  • R is selected from substituted or unsubstituted:
  • R is selected from substituted or unsubstituted:
  • the group defined by R in any of the compounds of the invention may be selected from substituted or unsubstituted:
  • R is -NR 6 R 7 .
  • R 6 and R 7 are independently selected from: H, C 1-6 alkyl, haloalkyl, -(CR d R e ) n -aryl, wherein n is 0, 1 or 2.
  • R 6 is C 1-6 alkyl and R 7 is C 1-6 alkyl, C 1-6 haloalkyl, -(CR d R e ) n -aryl, wherein n is 0, 1 or 2.
  • R 6 is methyl, ethyl or propyl and R 7 is methyl, ethyl or propyl.
  • R 6 is methyl, ethyl or propyl substituted with and R 7 is methyl, ethyl or propyl.
  • R 6 is methyl or ethyl and R 7 is C 1-6 haloalkyl, optionally C 1-6 fluoroalkyl.
  • R 6 is methyl, ethyl or propyl and R 7 is -(CH 2 ) n -phenyl wherein n is 0 or 1 .
  • R 6 is methanoyl, ethanoyl or propanoyl and R 7 is H or methyl.
  • the group defined by R in any of the compounds of the invention may be selected from substituted or unsubstituted:
  • the group defined by R is selected from substituted or unsubstituted
  • 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
  • the indolinyl group is attached to the rest of the molecule by the nitrogen atom.
  • a 1 , A 2 , A 3 , A 4 and A 5 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 C 3 . 6 cycloalkyl.
  • the heteroatoms may be N, O, S or a combination.
  • heteroatoms 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.
  • R 2 , R 3 , and R 4 may be independently selected from hydrogen, fluorine, chlorine, bromine, iodine, -CN, -CH 2 NR b R c , C 1-6 alkyl, C 1-6 alkyl substituted with C 3 . 8 cycloalkyl, C 1-6 alkyl substituted with C 3 . 8 heterocycloalkyl, C 1-6 haloalkyl, aryl, heteroaryl, alkaryl and alkheteroaryl.
  • R 2 , R 3 , and R 4 may be independently selected from hydrogen, fluorine, chlorine, bromine, iodine, -CN, -CH 2 NR b R c and C 1-6 alkyl, where R b and R c are independently selected from hydrogen and C 1-6 alkyl.
  • two of R 2 , R 3 , and R 4 may be hydrogen and the other may be fluorine, chlorine, bromine, iodine, -CN, -CH 2 NR b R c and C 1-6 alkyl, where R b and R c are independently selected from hydrogen and C 1-6 alkyl, e.g. R 2 and R 3 may be hydrogen; or R 3 and R 4 may be hydrogen; or R 2 and R 4 may be hydrogen.
  • R 2 , R 3 , and R 4 are all hydrogen.
  • R 5 is hydrogen
  • R a is hydrogen
  • R b and R c are hydrogen.
  • R d and R e are hydrogen.
  • E is
  • E is:
  • E may herein Y is O or NR b , may be selected from:
  • E is: [0072] In all embodiments E is and it may be selected from:
  • E is , optionally 0 is 1 .
  • E is , optionally o is 1 .
  • o is 1 or 2, optionally o is 1 .
  • 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;
  • 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.
  • the alkylene chain and the heterocyclic ring contain 1 heteroatom selected from N, O or S, optionally N.
  • the alkylene chain and the heterocyclic ring contain 1 nitrogen atom and the nitrogen atom is the point of connection with group E.
  • D is selected from substituted or unsubstituted C 1-6 heteroalkyl, substituted or unsubstituted C 3 . 8 heterocycloalkyl and substituted or unsubstituted C 3 . 8
  • heterocycloalkenyl In embodiments A may be selected from substituted or unsubstituted C 1-6 heteroalkyl, substituted or unsubstituted C 3 . 8 heterocycloalkyl and substituted or unsubstituted C 3 . 8 heterocycloalkenyl where N is the heteroatom and D comprises 1 or 2 nitrogen atoms.
  • D is unsubstituted. In an alternative embodiment D is substituted. In an embodiment D is substituted with halo, optionally fluoro.
  • D may be selected from:
  • D may be substituted or unsubstituted.
  • D may be unsubstituted.
  • D may be
  • D may be selected from:
  • D may be:
  • D is substituted by a halo group, for example, fluoro.
  • Y is O. In alternative embodiments Y is NR a wherein R a is H or methyl.
  • L 2 is selected from -(CR d R e ) m -, -O- and -NR b -.
  • m is 1 or 2, optionally m is 1 .
  • 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.
  • 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.
  • L 2 is selected from -CH 2 -, -O- and -NH-, optionally -CH 2 - or -0-.
  • L is selected from a bond, -(CR d R e ) m -, -O- and -NR b -.
  • m is 1 or 2, optionally m is 1 .
  • 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.
  • R b , R d and R e are independently hydrogen or C 1-6 alkyl.
  • L is selected from a bond, -CH 2 -, -O- and -NH-, optionally a bond or -CH 2 -.
  • the compound of formula (I) is a compound according to formula (la) and pharmaceutically acceptable salts and solvates thereof:
  • a 1 , A 2 , A 3 , A 4 , A 5 , Y, R a , R b , R c , R d , R e , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , L , L 2 , n and m, are as described above for formula (I).
  • the compound of formula (I) is a compound according to formula (II) and pharmaceutically acceptable salts and solvates thereof:
  • one of A 1 , A 2 , A 3 , A 4 and A 5 is CL 2 R 1 and the remaining A 1 , A 2 , A 3 , A 4 and A 5 may be independently selected from N, or CR a at each occurrence and one or two, optionally one, of A 1 to A 5 are N, the remainder being CR a , wherein R a is as described above for formula (I).
  • a 1 , A 2 , A 3 , A 4 and A 5 is N and the remaining A 1 , A 2 , A 3 , A 4 and A 5 are CR a .
  • one of A 1 , A 2 , A 3 , A 4 and A 5 is CL 2 R 1 and the remainder are CR a
  • R a may be selected from H, halo, C 1-6 alkyl, C 1-6 haloalkyl, OH alkoxy.
  • R a may be H.
  • the compound of formula (I) is a compound according to formula (III) or (Ilia) and pharmaceutically acceptable salts and solvates thereof:
  • the compound of formula (I) is a compound according to formula (IVa), (IVb) or (IVc) and pharmaceutically acceptable salts and solvates thereof:
  • the compound of formula (I) may be a compound according to formula (Va), (Vb), (Vc) or (Vd) and pharmaceutically acceptable salts and solvates thereof:
  • the compound of formula (I) may be a compound according to formula (Ve), (Vf) or (Vg) and pharmaceutically acceptable salts and solvates thereof:
  • L may be selected from a bond, -0-, -NH 2 - and -CH 2 -.
  • L 2 may be selected from a bond, -0-, -NH 2 - and -CH 2 -.
  • L may be a bond.
  • L 2 may be -O- or -CH 2 -.
  • L is a bond and L 2 is -0-.
  • L is a bond and L 2 is -CH 2 .
  • the compound of formula (I) may be a compound according to formula (VI) or (Via) and pharmaceutically acceptable salts and solvates thereof:
  • a 1 , A 2 , A 3 , A 4 , A 5 , D, E, Y, R a , R b , R c , R d , R e , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , L 2 , n and m are as described above for formula (I).
  • the compound of formula (I) may be a compound according to formula (VII) or (Vila) and pharmaceutically acceptable salts and solvates thereof:
  • the compound of formula (I) may be a compound according to formulae (Villa), (Vlllb), (Vlllc) or (Vllld) and pharmaceutically acceptable salts and solvates thereof:
  • R 5 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.
  • R b may be H or methyl and R c may be H.
  • L may be a bond and D may be:
  • the compounds of formula (I) may be a compound according to formula (IX) or (IXa) and pharmaceutically acceptable salts and solvates thereof:
  • a 1 , A 2 , A 3 , A 4 , A 5 , E, Y, R a , R b , R c , R d , R e , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , L 2 , n and m are as described above for formula (I).
  • the compounds of formula (I) may be a compound according to formula (X) or (Xa) and pharmaceutically acceptable salts and solvates thereof:
  • the compounds of formula (I) may be a compound according to formulae (XIa), (Xlb), (Xlc) or (Xld) and pharmaceutically acceptable salts and solvates thereof:
  • R a , R b , R c , R d , R e , R , R 5 , L 2 and m are as described above for formula (I).
  • R 5 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.
  • R b may be hydrogen or methyl and R c may be hydrogen.
  • the compounds of formula (I) may be a compound according to formulae (Xle) or (Xlf) and pharmaceutically acceptable salts and solvates thereof:
  • R 5 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.
  • R b may be hydrogen or methyl and R c may be hydrogen.
  • L 2 may be -CH 2 -.
  • the compound of formula (I) is a compound according to formula (XII) or (Xlla) and pharmaceutically acceptable salts and solvates thereof:
  • the compound of formula (I) is a compound according to formula (XIII) (Xllla) and pharmaceutically acceptable salts and solvates thereof:
  • the compound of formula (I) is a compound according to formula (XIV) or (XlVa) and pharmaceutically acceptable salts and solvates thereof: e
  • the compound of formula (I) is a compound according to formula (XV) or (XVI) and pharmaceutically acceptable salrs and solvates thereof:
  • a 1 , A 2 , A 3 , A 4 , A 5 , Y, R a , R b , R c , R d , R e , R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , L , L 2 , n and m, are as described above for formula (I).
  • 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
  • the compound of the invention may be a compound of any formula described above (for example formula (I), formula
  • 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 .
  • 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
  • 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
  • the compound of the invention may be a compound of any formula described above (for example formula (I), formula (XV) or formula (XVI), wherein L 2 is -CH 2 -, D is piperidinyl and E is , preferably Y is O; optionally R 2 , R 3 , and R 4 are all hydrogen.
  • the compound of the invention may be a compound of any formula described above (for example formula (I), formula (XV)
  • the compound of the invention may be a compound of any formula described above (for example formula (I), formula (XV) or formula (XVI), wherein L 2 is -CH 2 -, 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 L 2 is -CH 2 -, D is
  • the compound of the invention may be a compound of any formula described above (for example formula (I), formula (XV) or formula (XVI),
  • the compound of the invention may be a compound of any formula described above (for example formula (I), formula (XV) or formula (XVI),
  • L 2 is -CH 2 -
  • D is piperidinyl
  • E is
  • a compound of formula (I) is for use in the treatment of a condition which is modulated by Bruton's tyrosine kinase (BTK).
  • BTK Bruton's tyrosine kinase
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • a method of treatment of a condition which is modulated by Bruton's tyrosine kinase comprising administering a therapeutic amount of a compound of the invention, to a patient in need thereof.
  • the method of treatment may be a method of treating a condition treatable by the inhibition of Bruton's tyrosine kinase.
  • 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 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.
  • 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.
  • composition comprising a compound of the invention and pharmaceutically acceptable excipients.
  • 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.
  • halo refers to one of the halogens, group 17 of the periodic table.
  • the term refers to fluorine, chlorine, bromine and iodine.
  • the term refers to fluorine or chlorine.
  • 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.
  • 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.
  • 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.
  • 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.
  • C 2 - 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.
  • the "C 2 - 6 alkenyl” may be ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl.
  • C 2 - 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.
  • the "C 2 - 6 alkynyl” may be ethynyl, propynyl, butynyl, pentynyl and hexynyl.
  • 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.
  • 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.
  • the "C 1-6 heteroalkyl” may be C 1-6 /V-alkyl, C 1-6 ⁇ /,/V-alkyl, or C 1-6 O-alkyl.
  • 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.
  • 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.
  • the heterocyclic group may be: oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran.
  • C 3 . 8 cycloalkyl refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms.
  • the "C 3 . 8 cycloalkyl” may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • C 3 . 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.
  • the "C 3 . 8 cycloalkyl” may be cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienly, cycloheptenyl, cycloheptadiene, cyclooctenyl and cycloatadienyl.
  • C 3 . 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 "C 3 . 8 heterocycloalkyl” may be bonded to the rest of the molecule through any carbon atom or heteroatom.
  • the "C 3 . 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.
  • the "C 3 . 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.
  • 8 heterocycloalkyl may be oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran.
  • C 3 . 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 "C 3 _ 8 heterocycloalkenyl” may be bonded to the rest of the molecule through any carbon atom or heteroatom.
  • the “C 3 . 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.
  • the "C 3 . 8 heterocycloalkyl” may be tetrahydropyridine, dihydropyran, dihydrofuran, pyrroline.
  • aromatic when applied to a substituent as a whole means a single ring or polycyclic ring system with 4n + 2 electrons in a conjugated ⁇ system within the ring or ring system where all atoms contributing to the conjugated ⁇ system are in the same plane.
  • aryl refers to an aromatic hydrocarbon ring system.
  • the ring system has 4n +2 electrons in a conjugated ⁇ system within a ring where all atoms contributing to the conjugated ⁇ system are in the same plane.
  • the "aryl” may be phenyl and napthyl.
  • the aryl system itself may be substituted with other groups.
  • 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 ⁇ system where all atoms contributing to the conjugated ⁇ system are in the same plane.
  • the "heteroaryl” may be imidazole, thiene, furane, thianthrene, pyrrol, benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine and indole.
  • 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.
  • heteroaryl refers to a heteroaryl group, as defined above, bonded to a
  • halogen herein includes reference to F, CI, Br and I. Halogen may be CI.
  • Halogen may be F.
  • 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.
  • a 1 , A 2 , A 3 , A 4 and A 5 may collectively be referred to as "A groups".
  • One of the "A groups” may generally be described as an "A group”.
  • Z , Z 2 , Z 3 , Z 4 , Z 5 and Z 6 may collectively be referred to as "Z groups".
  • Z groups One of the "Z groups” may generally be described as a "Z group”.
  • a moiety 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, NHR 9 , 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, C 3 . 8 cycloalkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, aryl, heteroaryl or alkaryl.
  • the moiety is substituted with two or more substituents and two of the substituents are adjacent the adjacent substituents may form a C 4 . 8 ring along with the atoms of the moiety on which the substituents are substituted, wherein the C 4 . 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.
  • 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, C 3 . 8 cycloalkyl, phenyl, benzyl or phenethyl group, eg R is H or C 1-3 alkyl.
  • R may be selected from H, C 1-6 alkyl, C 3 . 8 cycloalkyl, phenyl, benzyl or phenethyl group, eg R is H or C 1-3 alkyl.
  • 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.
  • the invention contemplates pharmaceutically acceptable salts of the compounds of formula (I). These may include the acid addition and base salts of the compounds.
  • 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,
  • 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.
  • suitable salts see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
  • 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.
  • the compounds of the invention may exist in both unsolvated and solvated forms.
  • '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.
  • solvent molecules for example, ethanol.
  • 'hydrate' is employed when said solvent is water.
  • 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.
  • 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.
  • references to compounds of any formula include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.
  • 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.
  • 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.
  • the invention covers individual enantiomers as well as mixtures thereof.
  • any compatible protecting radical can be used.
  • 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.
  • 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.
  • 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.
  • 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.
  • chemotherapy may include one or more of the following categories of anti-tumour agents:-
  • 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
  • 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 activ
  • inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies, for example the anti-erbB2 antibody trastuzumab [HerceptinTM], 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;
  • growth factor antibodies and growth factor receptor antibodies for example the anti-erbB2 antibody trastuzumab [HerceptinTM], the anti
  • 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;
  • 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 (AvastinTM); thalidomide; lenalidomide; and for example, a VEGF receptor tyrosine kinase inhibitor such as vandetanib, vatalanib, sunitinib, axitinib and pazopanib;
  • vascular endothelial growth factor for example the anti-vascular endothelial cell growth factor antibody bevacizumab (AvastinTM); thalidomide; lenalidomide; and for example, a VEGF receptor tyrosine kinase inhibitor such as vandetanib, vatalanib, sunitinib, axitinib and pazopanib;
  • 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
  • cytotoxic agents for example fludaribine (fludara), cladribine, pentostatin (NipentTM);
  • steroids such as corticosteroids, including glucocorticoids and mineralocorticoids, for example aclometasone, aclometasone dipropionate, aldosterone, amcinonide, beclomethasone,
  • (x) targeted therapies, for example ⁇ 3 ⁇ inhibitors, for example idelalisib and perifosine.
  • 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:-
  • steroids such as corticosteroids, including glucocorticoids and mineralocorticoids, for example aclometasone, aclometasone dipropionate, aldosterone, amcinonide, beclomethasone,
  • 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);
  • 5-HT 2A agonists e.g. 2,5-dimethoxy-4-iodoamphetamine, TCB-2, lysergic acid diethylamide (LSD), lysergic acid dimethylazetidide
  • anti-inflammatory drugs for example non-steroidal anti-inflammatory drugs
  • dihydrofolate reductase inhibitors/antifolates for example methotrexate, trimethoprim, brodimoprim, tetroxoprim, iclaprim, pemetrexed, ralitrexed and pralatrexate; and
  • immunosuppressants for example cyclosporins, tacrolimus, sirolimus pimecrolimus, angiotensin II inhibitors (e.g. Valsartan, Telmisartan, Losartan, Irbesatan, Azilsartan, Olmesartan, Candesartan,
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a method of providing a combination product comprising 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.
  • the method may comprise providing the anti-tumour agent as separate dosage forms.
  • 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.
  • 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:
  • 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 :
  • 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:
  • R a , R b , R c , R d , R e , L , L 2 and m are as described above for formula (I).
  • 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.
  • 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:
  • 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):
  • 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:
  • 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:
  • R a , R b , R c , R d , R e , R , R 5 , L 2 and m are as described above for formula (I) and Z , Z 2 , Z 3 , Z 4 , Z 5 and Z 6 are as described above for formula (IV).
  • 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.
  • Preferred compounds of the invention include: 51
  • 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.
  • Protecting groups may be present or absent as necessary. For example, a nitrogen atom may be protected or unprotected.
  • the synthesis of representative compounds of the invention is given below.
  • 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.
  • 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.
  • 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 tube was degassed by alternative applications of vacuum and nitrogen.
  • the reaction was stirred under nitrogen at 100 °C.
  • 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.
  • 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.
  • Trifluoroacetic acid (2.0 eq.) was added dropwise to a solution of Boc-protected amine (1 .0 eq.) in
  • 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.
  • 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 Na 2 S0 4 and concentrated under reduced pressure. The crude product was purified by flash chromatography to give the desired indoline.
  • 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
  • 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 (MgS0 4 ) 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.
  • 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
  • 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
  • Example 6 1 -[(3R)-3-[4-Amino-3-[4-(diethylaminomethyl)phenyl]pyrazolo[3,4- cflpyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one
  • 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
  • Example 8 1-[(3 ?)-3-[4-Amino-3-[4-(thiomorpholinomethyl)phenyl]pyrazolo[3,4- cflpyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one
  • Example 9 1 -[(3R)-3-[4-Amino-3-[4-(morpholinomethyl)phenyl]pyrazolo[3,4- cflpyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one
  • Example 10 1 -[(3R)-3-[4-amino-3-[3-(morpholinomethyl)phenyl]pyrazolo[3,4- cflpyrimidin-1 -yl]-1 -piperidyl]prop-2-en-1 -one
  • 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
  • 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
  • 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
  • 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
  • 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
  • Example 16 1-[(3R)-3-[4-Amino-3-[4-[[2-(trifluoromethyl)morpholin-4- yl]methyl]phenyl]pyrazolo[3,4-c
  • Example 17 1-[(3R)-3-[4-Amino-3-[4-[(2,3-dimethylmorpholin-4- yl)methyl]phenyl]pyrazolo[3,4-c
  • 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
  • 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
  • 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
  • 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)
  • Example 22 1 -[(3R)-3-[4-Amino-3-[4-[(2,6-dimethylmorpholin-4- yl)methyl]phenyl]pyrazolo[3,4-c
  • Example 23 1 -[(3R)-3-[4-Amino-3-[4-(8-oxa-3-azabicyclo[3.2.1]octan-3- ylmethyl)phenyl]pyrazolo[3,4-c
  • Example 24 1 -[(3R)-3-[4-Amino-3-[4-(morpholinomethyl)phenyl]pyrazolo[3,4- cflpyrimidin-1 -yl]-1 -piperidyl]-2-chloro-ethanone
  • 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 ⁇
  • Example 26 3-[4-(morpholinomethyl)phenyl]-1 -[(3R)-1 -vinylsulfonyl-3- piperidyl]pyrazolo[3,4-c ]pyrimidin-4-amine
  • 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
  • 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.
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • Example 37 3-[4-(3,4-Dihydro-1 H-isoquinolin-2-ylmethyl)phenyl]-1 -[(3R)-1 - vinylsulfonyl-3-piperidyl]pyrazolo[3,4-c
  • Example 38 (3R)-3-[4-Amino-3-[4-(3,4-dihydro-1 H-isoquinolin-2- ylmethyl)phenyl]pyrazolo[3,4-c
  • 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
  • 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
  • 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
  • Example 42 1 -[3-[4-Amino-3-[4-(3,4-dihydro-2H-quinolin-1 - ylmethyl)phenyl]pyrazolo[3,4-c
  • Example 43 1 -[(3R)-3-[4-Amino-3-[4-(3,4-dihydro-2H-quinolin-1 - ylmethyl)phenyl]pyrazolo[3,4-c
  • 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
  • Example 45 1 -[(3R)-3-[4-Amino-3-[4-[(6-chloro-3,4-dihydro-2H-quinolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c
  • Example 46 1 -[(3R)-3-[4-Amino-3-[4-[(6-methoxy-3,4-dihydro-2H-quinolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c
  • Example 47 1 -[(3R)-3-[4-Amino-3-[4-[(2-methyl-3,4-dihydro-2H-quinolin-1 - yl)methyl]phenyl]pyrazolo[3,4-c
  • 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

Abstract

La présente invention concerne de nouveaux composés. Les composés selon l'invention sont des inhibiteurs de tyrosine kinase. Plus particulièrement, les composés selon l'invention sont utiles comme inhibiteurs de la tyrosine kinase de Bruton (BTK). L'invention concerne également l'utilisation des composés pour traiter des états pathologiques qui peuvent être traités par l'inhibition de la tyrosine kinase de Bruton, par exemple le cancer, des lymphomes, la leucémie et des maladies immunologiques.
PCT/GB2014/051542 2013-05-20 2014-05-20 Dérivés pyrazolopyrimidine utiles comme inhibiteurs de la tyrosine kinase de bruton WO2014188173A1 (fr)

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