WO2018226150A1 - Pyrazolopyrimidine utilisés en tant qu'inhibiteurs de malt-1 - Google Patents

Pyrazolopyrimidine utilisés en tant qu'inhibiteurs de malt-1 Download PDF

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Publication number
WO2018226150A1
WO2018226150A1 PCT/SE2018/050587 SE2018050587W WO2018226150A1 WO 2018226150 A1 WO2018226150 A1 WO 2018226150A1 SE 2018050587 W SE2018050587 W SE 2018050587W WO 2018226150 A1 WO2018226150 A1 WO 2018226150A1
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mmol
dalkyl
optionally substituted
independently selected
nrarb
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PCT/SE2018/050587
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English (en)
Inventor
Karolina Ersmark
Sofia KARLSTRÖM
Björn KLASSON
Stina Lundgren
Åsa ROSENQUIST
Lourdes SALVADOR ODÉN
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Medivir Aktiebolag
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Publication of WO2018226150A1 publication Critical patent/WO2018226150A1/fr

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    • 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
    • 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

Definitions

  • the present invention relates to compounds which are inhibitors of the protease MALT1 and pharmaceutical compositions and combinations thereof, processes for preparing the
  • MALT1 (mucosa associated lymphoid tissue lymphoma translocation protein 1) is an
  • MALT1 intracellular signalling protein, known from innate (natural killer cells NK, dendritic cells DC, and mast cells) and adaptive immune cells (T cells and B cells).
  • TCR signalling T cell receptor
  • N FKB nuclear factor ⁇
  • MALT1 was of interest in the mechanism of autoimmune and inflammatory pathologies. Additionally, it was noted that constitutive (dysregulated) MALT1 activity is associated with MALT lymphoma and activated B cell-like diffuse large B Cell lymphoma (ABC-DLBCL).
  • MALT1 is a paracaspase with both scaffold functions (contributing to the assembly of other signalling complexes) and protease functions cleaving a limited repertoire of proteins.
  • the MALT1 proteolytic activity appears essential for T cell activation and also the B cell lymphomas identified above.
  • MALT1 inhibitors have previously been proposed for treatment of cancers in which the N FKB pathway is overactive (e.g. ABC-DLBCL). Blockade/inhibition of MALT1 directly down-regulates the N FKB pathway in such cancers, resulting in treatment.
  • the present invention also comprises the appreciation of an activity of MALT1 inhibitors which is
  • the present invention envisages that the site of MALT1 action is within specified T cell populations of a subject.
  • the invention thus provides a MALT1 inhibitor of formula I or any subgroup thereof.
  • the invention further provides a compound of formula I or any subgroup thereof for use as an immunomodulatory agent in the prevention or treatment of cancer, independently of
  • the present invention further provides a method for the prevention or treatment of cancer in a subject, the method comprising administering to said subject a compound of formula I or any subgroup thereof as an immunomodulatory agent.
  • the method may additionally comprise administering to the subject a further therapeutic agent.
  • the further therapeutic agent may be:
  • checkpoint which checkpoint may or may not be a component of the N FKB pathway.
  • an agent which directly stimulates an immune effector response such as a cytokine, or a tumour specific adoptively transferred T cell population, or an antibody specific for a protein expressed by a tumour cell;
  • composition comprising a tumour antigen or immunogenic fragment thereof.
  • R 1 is R 1a
  • R 2 is R 2a and R 3 is R 3a ;
  • R 1 is R 1a
  • R 2 is R 2b and R 3 is R 3b ;
  • R 2a is H, haloCi-CealkyI, halod-dsalkoxy, haloCi-CealkoxyCi-Cealkyl, thiazolyl, isothiazolyl, CycAlk, CycAlkCi-CealkyI, 5-6-het, 5-6-hetCi-C6alkyl, a 5- or 6-membered heteroaryl or phenyl which is substituted with halo, haloCi-CealkyI or haloCi-Cealkoxy, wherein
  • haloCi-dsalkyl is substituted with one, two or three substituents each independently selected from hydroxy, NRaRb, d-Cecycloalkyl and 5-6-het;
  • C3-C6cycloalkyl and 5-6-het are optionally substituted with one two or three substituents each independently selected from halo, d-dhaloalkyl, NRaRb and aminoCi-dalkyl;
  • Ci-C6alkyl of CycAlkCi-CealkyI and 5-6-hetCi-C6alkyl is optionally substituted with NRaRb;
  • thiazolyl or isothiazolyl is optionally substituted with one or two substituents each independently selected from Ci-C6alkyl, hydroxyCi-dsalkyl, d-dsalkoxy, halo, halod- dsalkyl, halod-dsalkoxy;
  • heteroaryl is substituted with one, two or three substituents each independently selected from halo, haloCi-CealkyI, halod-dsalkoxy and optionally substituted with NRaRb; and
  • 5-6-het is substituted with one or two substituents each independently selected from halo, d-dshaloalkyl and d-dshaloalkoxy, and optionally substituted with one or two substituents each independently selected NRaRb and oxo;
  • R 2b is Ci-C 6 alkyl, Ci-C 6 alkoxy, C 3 -C 6 cycloalkyl, haloCi-C 6 alkyl, Het, HetCi-C 6 alkyl, Het-O, phenyl, a 5- or 6-membered heteroaryl, phtalimido or carbamoyl wherein
  • Ci-C6alkyl is optionally substituted with one, two or three substituents each independently selected from hydroxy, alkenyl, NRaRb, d-Cecycloalkyl, d-dsalkoxy, Ci-C6alkoxyCi-C6alkoxy, Het-O, Het or phenyl; wherein
  • C3-C6cycloalkyl is optionally substituted with one two or three substituents each independently selected from, Ci-C6alkyl, d-dsalkoxy, Ci-C6alkoxyCi-C6alkyl, NRaRb and aminoCi-dalkyl;
  • d-dsalkoxy is optionally substituted with d-dsalkoxy
  • Ci-C6alkyl of Hetd-Cealkyl is optionally substituted with NRaRb;
  • phenyl or heteroaryl is optionally substituted with one, two or three substituents each independently selected from Ci-C6alkyl, hydroxy, hydroxyCi-dsalkyl, aminod-Cealkyl and NRaRb;
  • R 2b is optionally substituted with one or two substituents each independently selected from Ci-C6alkyl, Ci-C6alkoxyCi-C6alkyl, Ci-C6alkoxycarbonyl, NRaRb, and oxo;
  • R 3a is phenyl, C3-C7cycloalkyl, heterocyclyl or heteroaryl, any of which is optionally substituted with one, two or three R 13 ;
  • each R 13 is independently selected from halo, hydroxy, cyano, NRaRb, Ci- Csalkoxycarbonyl, d-dsalkoxy, d-dshaloalkoxy, d-Cealkyl, d-Cehaloalkyl, C3- Cecycloalkyl, phenyl, phenyld-dalkyl, heterocyclyl, heterocyclylCi-dalkyl, heterocycloxy, heteroaryl, wherein
  • Ci-dsalkyl is optionally substituted with NRaRb;
  • C3-C6cycloalkyl, heterocyclyl or heteroaryl is optionally substituted with one, two or three substituents each independently selected from Ci-C6alkyl, d-dsalkoxy, hydroxy, hydroxyCi-Cealkyl, halo, haloCi-dsalkyl, haloCi-dsalkoxy, oxo, NRaRb, and carbamoyl; wherein
  • Ci-C6alkyl is optionally substituted with NRaRb;
  • R 3b is pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolo[1 ,5-a]pyrimidine, thiazolyl or pyrazolyl any of which is optionally substituted with one, two or three R 13 ;
  • each R 13 is independently selected from halo, hydroxy, cyano, NRaRb, carbamoyl, d-dalkoxycarbonyl, d-dsalkoxy, haloCi-dsalkoxy, Ci-CealkoxyCi-dsalkoxy, Ci- Cealkyl, haloCi-dsalkyl, C3-C6cycloalkyl, phenyl, phenyld-dalkyl, heterocyclyl, heterocyclylCi-C3alkyl, heterocycloxy, heteroaryl, wherein
  • Ci-C6alkyl and Ci-C6alkoxy are optionally substituted with one or two substituents each independently selected from hydroxy, d-dalkoxy and NRaRb;
  • C3-C6cycloalkyl, phenyl, heterocyclyl, heterocycloxy and heteroaryl are optionally substituted with one, two or three substituents each independently selected from Ci-C6alkyl, d-dsalkoxy, hydroxy, hydroxyCi-Cealkyl, halo, haloCi-dsalkyl, haloCi-Cealkoxy, oxo, NRaRb, and carbamoyl; wherein
  • Ci-C6alkyl is optionally substituted with NRaRb;
  • Ra and Rb for the purposes of series (x) and (y) are each independently selected from H, Ci-C6alkyl, haloCi-Cealkyl and d-dcycloalkyl, or Ra and Rb together with the nitrogen atom to which they are attached form a 4-, 5- or 6- membered ring which ring may contain a further nitrogen atom or an oxygen atom and is optionally substituted with one or two fluoro; or for the purposes of series (z) Ra is H, d-dalkyl;
  • Rb is H, Ci-C6alkyl, haloCi-dsalkyl and d-dcycloalkyl, or Ra and Rb together with the nitrogen atom to which they are attached form a 4-, 5- or 6-membered ring which ring may contain a further nitrogen atom or an oxygen atom and is optionally substituted with one or two fluoro; and wherein for the purposes of series (z), with the proviso that R 3a is not optionally substituted pyrimidinyl, pyridazinyl, pyrazinyl or pyrazolo[1 ,5-a]pyrimidinyl;
  • CycAlk is, unless otherwise specified, C3-C6cycloalkyl which is substituted with one, two or three substituents each independently selected from halo, haloCi-dalkyl and halod- dalkoxy;
  • 5-6-het is, unless otherwise specified, a 5-or 6-membered saturated or partly unsaturated ring containing 1 , 2 or 3 heteroatoms each independently selected from N, O and S;
  • heterocyclyl is, unless otherwise specified, a 4-to 11-membered mono-, bi- or spirocyclic saturated or partly unsaturated ring containing 1 , 2, 3 or 4 heteroatoms each independently selected from N, O and S;
  • heteroaryl is, unless otherwise specified, a 5-to 11-membered mono- or bicyclic aromatic ring containing 1 , 2, 3 or 4 heteroatoms each independently selected from N, O and S; and Het is, unless otherwise specified, a 5-or 6-membered saturated or partly unsaturated ring containing 1 , 2 or 3 heteroatoms each independently selected from N, O and S.
  • R 1a or R 1 b are other than amino.
  • a first aspect the invention provides a com ound of series (x):
  • R 1 is H, halo, cyano, Ci-dalkyl, halod-dalkyl, d-dalkoxy or halod-dalkoxy;
  • R 2 is H, haloCi-C6alkyl, halod-dalkoxy, haloCi-C6alkoxyCi-C6alkyl, thiazolyl, isothiazolyl,
  • CycAlk CycAlkCi-CealkyI, 5-6-het, 5-6-hetCi-C6alkyl, a 5- or 6-membered heteroaryl or phenyl which is substituted with halo, haloCi-Cealkyl or haloCi-Cealkoxy;
  • haloCi-C6alkyl is substituted with one, two or three substituents each independently selected from hydroxy, NRaRb, C3-C6cycloalkyl and a 5- or 6-membered heterocyclyl;
  • C3-C6cycloalkyl and 5 or 6 membered heterocyclyl are optionally substituted with one two or three substituents each independently selected from halo, Ci- dhaloalkyl, NRaRb and aminoCi-dalkyl; the Ci-C6alkyl of CycAlkd-dalkyl and 5-6-hetCi-C6alkyl is optionally substituted with NRaRb;
  • thiazolyl or isothiazolyl is optionally substituted with one or two substituents each independently selected from d-dalkyl, hydroxyd-dalkyl, d-dalkoxy, halo, halod- dalkyl, halod-dalkoxy;
  • heteroaryl is substituted with one, two or three substituents each independently selected from halo, halod-dalkyl, halod-dalkoxy and optionally substituted with NRaRb; and 5-6-het is substituted with one or two substituents each independently selected from halo, d-dhaloalkyl and d-dhaloalkoxy, and optionally substituted with one or two
  • R 3 is phenyl, d-dcycloalkyl, heterocyclyl or heteroaryl, any of which is optionally substituted with one, two or three R 13 ;
  • each R 13 is independently selected from halo, hydroxy, cyano, NRaRb, Ci- dalkoxycarbonyl, d-dalkoxy, d-dhaloalkoxy, d-dalkyl, d-dhaloalkyl, d- Cecycloalkyl, phenyl, phenyld-dalkyl, heterocyclyl, heterocyclyld-dalkyl,
  • d-dalkyl is optionally substituted with NRaRb;
  • d-dcycloalkyl, heterocyclyl or heteroaryl is optionally substituted with one, two or three substituents each independently selected from d-dalkyl, d-dalkoxy, hydroxy, hydroxyd-dalkyl, halo, halod-dalkyl, halod-dalkoxy, oxo, NRaRb, and carbamoyl; wherein
  • d-dalkyl is optionally substituted with NRaRb;
  • Ra and Rb are each independently selected from H, d-dalkyl, halod-dalkyl and d- dcycloalkyl, or Ra and Rb together with the nitrogen atom to which they are attached form a 4-, 5- or 6-membered ring which ring may contain a further nitrogen atom or an oxygen atom and is optionally substituted with one or two fluoro;
  • CycAlk is d-dcycloalkyl which is substituted with one, two or three substituents each independently selected from halo, halod-dalkyl and halod-dalkoxy;
  • 5-6-het is a 5-or 6-membered saturated or partly unsaturated ring containing 1 , 2 or 3 heteroatoms each independently selected from N, O and S;
  • heterocyclyl is, unless otherwise specified, a 4- to 11-membered mono-, bi- or spirocyclic saturated or partly unsaturated ring containing 1 , 2, 3 or 4 heteroatoms each independently selected from N, O and S;
  • heteroaryl is, unless otherwise specified, a 5- to 11-membered mono- or bicyclic aromatic ring containing 1 , 2, 3 or 4 heteroatoms each independently selected from N, O and S.
  • the compounds of Formula (I) or any subgroup thereof may optionally be provided in the form of a pharmaceutically acceptable salt and/or solvate.
  • a compound of the invention is provided in the form of a pharmaceutically acceptable salt.
  • a compound of the invention is provided in the form of a pharmaceutically acceptable solvate.
  • a compound of the invention is provided in its free form.
  • R 1 is halo, d-Csalkyl or halod-Csalkoxy, such as chloro, fluoro, methyl, difluoromethoxy or trifluoromethoxy. Typically according to this embodiment R 1 is chloro or methyl.
  • R 2 is haloCi-Cealkoxy, CycAlk, CycAlkCi-CsalkyI or a 5 or 6 membered heteroaryl, wherein
  • Ci-C3alkyl of C3-C6cycloalkylCi-C3alkyl is optionally substituted with amino
  • heteroaryl or CycAlk is substituted with one or two substituents independently selected from halo, haloCi-C3alkyl, haloCi-Csalkoxy and optionally with amino.
  • R 2 are haloCi-Cealkoxy, CycAlk, thiazolyl and pyridinyl, wherein pyridinyl or CycAlk is substituted with one or two halo, haloCr Csalkyl or haloCi-Csalkoxy.
  • R 2 is C3-C4cycloalkyl which is substituted with trifluoromethyl or with one or two halo.
  • R 2 is cyclopropyl which is substituted with trifluoromethyl or with one or two halo.
  • CycAlk is cyclopropyl which is substituted with chloro or fluoro, preferably cyclopropyl substituted with fluoro.
  • CycAlk is cyclopropyl which is substituted with trifluoromethyl, thus providing a compound having the formula (II):
  • a favoured group of R 2 embodiments comprises the above depicted 1-(CF3)-cycloprop-1-yl or - CH(CH 3 )-0-CHF 2 .
  • R 2 is thiazolyl or isothiazolyl, preferably thiazolyl.
  • R 2 is a 5- or 6-membered heteroaryl which is substituted with halo, haloalkyl or haloalkoxy.
  • R 2 is pyridinyl which is substituted with fluoro, chloro or trifluoromethyl, such as pyridinyl substituted with fluoro.
  • R 2 is halod-Cealkyl which is substituted with NRaRb.
  • Ra and Rb is H and the other is H or Me.
  • both Ra and Rb are H.
  • R 3 is pyridinyl, pyridazinyl or pyrimidinyl any of which is optionally substituted with one, two or three R 13 ;
  • each R 13 is independently selected from halo, d-Cealkyl, haloCi-Cealkyl, d-dsalkoxy, Ci- dshaloalkoxy and a 5- or 6-membered heteroaryl, wherein
  • heteroaryl is optionally substituted with one or two substituents each independently selected from Ci-dalkyl, halo, trifluoromethyl and aminoCi-dalkyl.
  • R 3 is pyridinyl which is substituted with one or two R 13 ;
  • each R 13 is independently selected from fluoro, chloro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, Ci-dalkyl, triazolyl and pyrazolyl, wherein
  • triazolyl and pyrazolyl are optionally substituted with aminomethyl.
  • a representative configuration for R 3 according to this embodiment is pyridinyl which is substituted with chloro and triazolyl.
  • a further representative configuration for R 3 according to this embodiment is pyridinyl which is substituted with chloro and pyrazolyl, wherein pyrazolyl is substituted with aminomethyl.
  • R 3 is pyridinyl which is substituted with Ci-dalkyl or d-dhaloalkyl, typically methyl or trifluoromethyl. In one embodiment of the invention, R 3 is optionally substituted 2-pyridinyl.
  • R 3 is optionally substituted 3-pyridinyl.
  • R 3 is optionally substituted 4-pyridinyl.
  • R 3 is optionally substituted pyridazinyl. In an alternative embodiment of the invention, R 3 is optionally substituted pyrimidinyl.
  • R 1 is chloro or methyl
  • R 2 is cyclopropyl which is substituted with trifluoromethyl, thiazolyl or pyridinyl which is substituted with fluoro;
  • R 3 is pyridinyl which is substituted with one, two or three substituents each independently selected from chloro, trifluoromethyl, difluoromethoxy, trifluoromethoxy and optionally substituted 5-membered heteroaryl.
  • R 1 is chloro or methyl
  • R 2 is cyclopropyl which is substituted with trifluoromethyl, thiazolyl or pyridinyl which is substituted with fluoro;
  • R 3 is pyridazinyl which is optionally substituted with one or two substituents each independently selected from chloro, trifluoromethyl, difluoromethoxy, trifluoromethoxy.
  • R 3 is optionally substituted 3-pyridinyl, thus providing compounds of the general fo
  • R 1 , R 2 and R 13 are as defined for compounds of formula (I).
  • the 3-pyridinyl is substituted with one or two substituents selected from methyl, chloro and a 5-membered heteroaryl which is optionally substituted with aminomethyl.
  • R 1 is H, halo, cyano, d-Csalkyl, haloCi-CsalkyI, Ci-Csalkoxy or haloCi-Csalkoxy;
  • R 2 is Ci-C 6 alkyl, Ci-C 6 alkoxy, C 3 -C 6 cycloalkyl, haloCi-C 6 alkyl, Het, HetCi-C 6 alkyl, Het-O, phenyl, a 5- or 6-membered heteroaryl, phtalimido or carbamoyl wherein
  • Ci-C6alkyl is optionally substituted with one, two or three substituents each
  • C3-C6cycloalkyl independently selected from hydroxy, alkenyl, NRaRb, C3-C6cycloalkyl, Ci-C6alkoxy, Ci- C6alkoxyCi-C6alkoxy, Het-O, Het or phenyl; wherein C3-C6cycloalkyl is optionally substituted with one two or three substituents each independently selected from, d-dalkyl, d-dalkoxy, Ci-C6alkoxyCi-C6alkyl, NRaRb and aminod-dalkyl;
  • Ci-C6alkoxy is optionally substituted with d-dalkoxy
  • the d-dalkyl of Hetd-dalkyl is optionally substituted with NRaRb;
  • phenyl or heteroaryl is optionally substituted with one, two or three substituents each independently selected from d-dalkyl, hydroxy, hydroxyd-dalkyl, aminod-dalkyl and NRaRb;
  • Het is optionally substituted with one or two substituents each independently selected from d-dalkyl, Ci-C6alkoxyCi-C6alkyl, d-dalkoxycarbonyl, NRaRb, and oxo;
  • R 3 is pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolo[1 ,5-a]pyrimidine, thiazolyl or pyrazolyl any of which is optionally substituted with one, two or three R 13 ;
  • each R 13 is independently selected from halo, hydroxy, cyano, NRaRb, carbamoyl, d- dalkoxycarbonyl, d-dalkoxy, halod-dalkoxy, Ci-C6alkoxyCi-C6alkoxy, Ci-C6alkyl, halod-dalkyl, C3-C6cycloalkyl, phenyl, phenyld-dalkyl, heterocyclyl, heterocyclyld-
  • d-dalkyl and Ci-C6alkoxy are optionally substituted with one or two substituents each independently selected from hydroxy, d-dalkoxy and NRaRb;
  • C3-C6cycloalkyl, phenyl, heterocyclyl, heterocycloxy and heteroaryl are optionally substituted with one, two or three substituents each independently selected from d-dalkyl, d-dalkoxy, hydroxy, hydroxyd-dalkyl, halo, halod-dalkyl, halod-dalkoxy, oxo, NRaRb, and carbamoyl;
  • d-dalkyl is optionally substituted with NRaRb;
  • Ra and Rb are each independently selected from H, d-dalkyl, halod-dalkyl and d- dcycloalkyl, or Ra and Rb together with the nitrogen atom to which they are attached form a 4-, 5- or 6-membered ring which ring may contain a further nitrogen atom or an oxygen atom and is optionally substituted with one or two fluoro;
  • Het is, unless otherwise specified, a 5-or 6-membered saturated or partly unsaturated ring containing 1 , 2 or 3 heteroatoms each independently selected from N, O and S;
  • heterocyclyl is, unless otherwise specified, a 4-to 11-membered mono- or bicyclic saturated or partly unsaturated ring containing 1 , 2, 3 or 4 heteroatoms each independently selected from N, O and S; heteroaryl is, unless otherwise specified, a 5-to 11-membered mono- or bicyclic aromatic ring containing 1 , 2, 3 or 4 heteroatoms each independently selected from N, O and S.
  • the compounds of Formula (I) or any subgroup thereof may optionally be provided in the form of a pharmaceutically acceptable salt and/or solvate.
  • a compound of the invention is provided in the form of a pharmaceutically acceptable salt.
  • a compound of the invention is provided in the form of a pharmaceutically acceptable solvate.
  • a compound of the invention is provided in its free form.
  • R 1 is halo, d-dalkyl or halod-dalkoxy, such as chloro, fluoro or methyl. Typically according to this embodiment R 1 is chloro.
  • R 2 is Ci-CealkyI, halod-Cealkyl, heterocyclyl or C3- Cecycloalkyl, wherein
  • Ci-CealkyI or haloCi-Cealkyl is optionally substituted with one, two or three substituents each independently selected from d-dsalkoxy, Ci-C6alkoxyCi-C6alkoxy, NRaRb and C3- dscycloalkyl;
  • heterocyclyl or d-Cecycloalkyl is optionally substituted with Ci-dalkyl, d-dalkoxy or Ci- C3alkoxyCi-C3alkyl.
  • Representative values for R 2 according to this embodiment, are Ci-dsalkyl, which is optionally substituted with one or two d-dsalkoxy, Ci-C6alkoxyCi-C6alkoxy or haloCi-Cealkyl.
  • R 2 is 2,2,2-trifluoroethyl, Ci-C6alkyl or Ci-C6alkyl which is substituted with one or two methoxy.
  • R 2 is Ci-C6alkyl which is substituted with one or two methoxy, representative configurations are 2-methoxyethyl and 1 ,2- dimethoxypropyl, thus providing compounds of the formulae la and lb respectively:
  • R 2 is C3-C6cycloalkyl which is optionally substituted with Ci- Csalkyl or Ci-Csalkoxy.
  • Typical configurations according to this embodiment include cyclopropyl and cyclopropyl which is substituted with methyl or methoxy.
  • R 2 is a 5- or 6-membered heterocyclyl which is optionally substituted with d-dalkyl or Ci-C3alkoxyCi-C3alkyl.
  • Typical configurations according to this embodiment include tetrahydrofuranyl and tetrahydropyranyl any of which is optionally substituted with methyl, methoxy or methoxymethyl.
  • R 3 is pyridazinyl or pyrimidinyl any of which is optionally substituted with one, two or three R 13 ;
  • R 13 Representative values for R 13 include cyano, chloro, fluoro, d-Cealkyl, halod-Cealkyl, Ci- dsalkoxy, d-dshaloalkoxy, heterocycloxy and a 5- or 6-membered heteroaryl; wherein heteroaryl and heterocycloxy are optionally substituted with one or two substituents each independently selected from Ci-dalkyl, halo, trifluoromethyl and aminod- CsalkyI.
  • each of the one, two or three R 13 is independently selected from fluoro, chloro, difluoromethyl, trifluoromethyl, triazolyl and pyrazolyl; wherein
  • triazolyl and pyrazolyl are optionally substituted with aminomethyl.
  • R 3 is pyridazinyl which is substituted with fluoro, chloro, cyano, methyl, difluoromethyl or trifluoromethyl.
  • R 3 is pyridazinyl which is substituted with one or two substituents each independently selected from pyrazolyl and triazolyl, wherein pyrazolyl is optionally substituted with aminomethyl.
  • R 3 is pyridazin-4-yl which is optionally substituted with one, two or three R 13 , thus providing compound wherein R 1 , R 2 and R 13 are as defined for compounds of formula (I).
  • the pyridazin-4-yl is substituted with one or two substituents each independently selected from methyl, chloro and a 5-membered heteroaryl which is optionally substituted with aminomethyl.
  • R 3 is pyridazin-4-yl which is substituted in the 6-position with fluoro, chloro, cyano, methyl, difluoromethyl or trifluoromethyl.
  • R 3 is other than thiazolyl or pyrazolyl.
  • R 3 is pyrazolo[1 ,5-a]pyrimidine which is optionally substituted with one, two or three R 13 .
  • the pyrazolo[1 ,5-a]pyrimidine is linked to the urea nitrogen in the 6-position, thus providing compounds of the general
  • Typical substituents to the right hand side pyrazolo[1 ,5-a]pyrimidine of compounds of formula (III) include chloro and Ci-C3alkoxyCi-C6alkyl, such as 1-methoxyethyl.
  • R 3 is pyrazolyl or thiazolyl, either of which is optionally substituted with fluoro, cyano, methyl, difluoromethyl or trifluoromethyl.
  • R 1 is fluoro, chloro or methyl
  • R 2 is Ci-C6alkyl which is optionally substituted with one or two d-Csalkoxy;
  • R 3 is pyridazinyl or pyrimidinyl which is optionally substituted with one or two substituents each independently selected from fluoro, chloro, cyano, d-Csalkyl, halod-Csalkyl and optionally substituted 5-membered heteroaryl.
  • substituents each independently selected from fluoro, chloro, cyano, d-Csalkyl, halod-Csalkyl and optionally substituted 5-membered heteroaryl.
  • R 1 is chloro or methyl
  • R 2 is Ci-C6alkyl which is substituted with one or two methoxy
  • R 3 is pyridazinyl or pyrimidinyl which is optionally substituted with one or two substituents each independently selected from fluoro, chloro, cyano, methyl, difluoromethyl, trifluoromethyl and optionally substituted 5-membered heteroaryl.
  • substituents each independently selected from fluoro, chloro, cyano, methyl, difluoromethyl, trifluoromethyl and optionally substituted 5-membered heteroaryl.
  • R 1 is chloro or methyl
  • R 2 is Ci-C3alkyl which is substituted with methoxy
  • R 3 is pyridazinyl which is optionally substituted with one or two substituents each independently selected from fluoro, chloro, cyano, methyl, difluoromethyl, trifluoromethyl.
  • R 1 is chloro or methyl
  • R 2 is Ci-C6alkyl which is substituted with one or two methoxy
  • R 3 is pyridazin-4-yl which is optionally substituted with one or two substituents each
  • R 1 is chloro or methyl
  • R 2 is Ci-C6alkyl which is substituted with one or two methoxy
  • R 3 is pyridazin-4-yl which is optionally substituted in the 6-position with fluoro, chloro, cyano, methyl, difluoromethyl or trifluoromethyl.
  • the invention provides compounds of series (z) within formula (I):
  • R 2 is Ci-C 6 alkyl, Ci-C 6 alkoxy, C 3 -C 6 cycloalkyl, haloCi-C 6 alkyl, Het, HetCi-C 6 alkyl, Het-O, phenyl, a 5- or 6-membered heteroaryl, phtalimido or carbamoyl wherein
  • Ci-C6alkyl is optionally substituted with one, two or three substituents each independently selected from hydroxy, alkenyl, NRaRb, C3-C6cycloalkyl, d-dsalkoxy, d-Cealkoxyd- Cealkoxy, Het-O, Het or phenyl; wherein
  • C3-C6cycloalkyl is optionally substituted with one two or three substituents each independently selected from, d-Cealkyl, d-dsalkoxy, Ci-C6alkoxyCi-C6alkyl, NRaRb and aminoCi-dalkyl;
  • d-dsalkoxy is optionally substituted with d-dsalkoxy
  • Ci-C6alkyl of Hetd-Cealkyl is optionally substituted with NRaRb;
  • phenyl or heteroaryl is optionally substituted with one, two or three substituents each independently selected from Ci-C6alkyl, hydroxy, hydroxyCi-Cealkyl, aminod-Cealkyl and NRaRb; Het is optionally substituted with one or two substituents each independently selected from Ci-C6alkyl, Ci-C6alkoxyCi-C6alkyl, d-Cealkoxycarbonyl, NRaRb, and oxo;
  • R 3 is phenyl, C3-C7cycloalkyl, heterocyclyl or heteroaryl, any of which is optionally substituted with one, two or three R 13 ;
  • each R 13 is independently selected from halo, hydroxy, cyano, NRaRb, Ci-
  • Ci-dsalkyl is optionally substituted with NRaRb;
  • C3-C6cycloalkyl, heterocyclyl or heteroaryl is optionally substituted with one, two or three substituents each independently selected from Ci-dsalkyl, d-dsalkoxy, hydroxy, hydroxyd-dsalkyl, halo, haloCi-dsalkyl, haloCi-dsalkoxy, oxo, NRaRb, and carbamoyl; wherein
  • Ci-C6alkyl is optionally substituted with NRaRb;
  • Ra is H, Ci-C 3 alkyl
  • Rb is H, Ci-C6alkyl, haloCi-dsalkyl and C3-C4cycloalkyl, or Ra and Rb together with the nitrogen atom to which they are attached form a 4-, 5- or 6- membered ring which ring may contain a further nitrogen atom or an oxygen atom and is optionally substituted with one or two fluoro;
  • R 3 is not optionally substituted pyrimidinyl, pyridazinyl, pyrazinyl or pyrazolo[1 ,5-a]pyrimidinyl;
  • Het is, unless otherwise specified, a 5-or 6-membered saturated or partly unsaturated ring containing 1 , 2 or 3 heteroatoms each independently selected from N, O and S;
  • heterocyclyl is, unless otherwise specified, a 4-to 1 1-membered mono-, bi- or spirocyclic saturated or partly unsaturated ring containing 1 , 2, 3 or 4 heteroatoms each independently selected from N, O and S;
  • heteroaryl is, unless otherwise specified, a 5-to 11-membered mono- or bicyclic aromatic ring containing 1 , 2, 3 or 4 heteroatoms each independently selected from N, O and S;
  • the compounds of Formula (I) or any subgroup thereof may optionally be provided in the form of a pharmaceutically acceptable salt and/or solvate.
  • a compound of the invention is provided in the form of a pharmaceutically acceptable salt.
  • a compound of the invention is provided in the form of a pharmaceutically acceptable solvate.
  • a compound of the invention is provided in its free form.
  • R 1 is H, methoxy, difluoromethoxy or trifluoromethoxy. In a typical embodiment of the invention, R 1 is H.
  • R 1 is difluoromethoxy or trifluoromethoxy.
  • R 1 is other than amino
  • R 2 is Ci-CealkyI, halod-Cealkyl, heterocyclyl or C3- Cecycloalkyl, wherein
  • Ci-CealkyI and haloCi-Cealkyl are optionally substituted with one, two or three substituents each independently selected from d-dsalkoxy, Ci-C6alkoxyCi-C6alkoxy, NRaRb and C3- Cecycloalkyl;
  • heterocyclyl or C3-C6cycloalkyl is optionally substituted with Ci-dalkyl, d-dalkoxy, Ci-
  • Ra and Rb according to this embodiment are independently selected from H and d-dalkyl such as methyl.
  • Representative values for R 2 according to this embodiment are Ci-dsalkyl which is optionally substituted with one or two d-dsalkoxy, Ci-C6alkoxyCi-C6alkoxy or NRaRb.
  • R 2 is 2,2,2-trifluoroethyl, Ci-C6alkyl or Ci-C6alkyl which is substituted with one or two methoxy.
  • R 2 is Ci-C6alkyl or C3- dscycloalkyl any of which is substituted with NRaRb, wherein Ra and Rb are each
  • Ra and Rb are independently selected from H and Ci-dalkyl, Typically one of Ra and Rb is Me and the other is H or Me.
  • R 2 is Ci-dsalkyl, for instance methyl, ethyl or isopropyl, typically isopropyl.
  • R 2 is Ci-C6alkyl which is substituted with one or two methoxy, representative configurations are 2-methoxyethyl and 1 ,2- dimethoxypropyl ly:
  • R 2 is C3-C6cycloalkyl which is optionally substituted with Ci- Csalkyl or d-dalkoxy.
  • Typical configurations according to this embodiment include cyclopropyl and cyclopropyl which is substituted with methyl or methoxy.
  • R 2 is a 5- or 6-membered heterocyclyl which is optionally substituted with Ci-dalkyl or Ci-C3alkoxyCi-C3alkyl.
  • Typical configurations according to this embodiment include tetrahydrofuranyl and tetrahydropyranyl any of which is optionally substituted with methyl, methoxy or methoxymethyl.
  • R 2 is a 5- or 6-membered heteroaryl which is optionally substituted with Ci-C3alkyl or Ci-C3alkoxyCi-C3alkyl.
  • Typical configurations according to this embodiment include pyridazinyl and pyrimidinyl.
  • R 3 is phenyl which is optionally substituted with one, two or three R 13 ;
  • R 13 Representative values for R 13 include chloro, fluoro, cyano, d-Cealkyl, halod-Cealkyl, d- dsalkoxy, haloCi-dsalkoxy, heterocycloxy and a 5- or 6-membered heteroaryl; wherein heteroaryl and heterocycloxy are optionally substituted with one or two substituents each independently selected from Ci-dalkyl, halo, trifluoromethyl and aminod- dalkyl.
  • each of the one, two or three R 13 is independently selected from fluoro, chloro, difluoromethyl, trifluoromethyl, triazolyl and pyrazolyl; wherein
  • triazolyl and pyrazolyl are optionally substituted with aminomethyl.
  • R 3 is pyridinyl which is optionally substituted with one, two or three R 13 ;
  • each R 13 is independently selected from halo, cyano, Ci-dsalkyl, haloCi-Cealkyl, d- dsalkoxy, d-Cehaloalkoxy and a 5- or 6-membered heteroaryl, wherein
  • heteroaryl is optionally substituted with one or two substituents each independently selected from Ci-dalkyl, halo, trifluoromethyl and aminoCi-dalkyl.
  • R 3 is pyridinyl which is substituted with one or two R 13 ; each R 13 is independently selected from fluoro, chloro, cyano, trifluoromethyl, difluoromethoxy, trifluoromethoxy, d-Csalkyl, triazolyl and pyrazolyl, wherein
  • R 3 is pyridinyl which is substituted with Ci-C3alkyl or d-Cshaloalkyl, typically methyl or trifluoromethyl.
  • R 3 is pyridinyl which is substituted with chloro and pyrazolyl, wherein pyrazolyl is substituted with aminomethyl.
  • R 3 is pyridinyl which is substituted with chloro and triazolyl.
  • R 3 is 2-pyridinyl which is optionally substituted with one, two or three R 13 .
  • R 3 is 4-pyridinyl which is optionally substituted with one, two or three R 13 .
  • R 3 is 3-pyridinyl which is optionally substituted with one, two or three R 13 thus providing compounds of the general formula (I I):
  • the pyridin-3-yl is substituted with one or two R 13 each independently selected from methyl, chloro and a 5-membered heteroaryl which is optionally substituted with aminomethyl.
  • R 3 is pyridin-3-yl or pyridin-4-yl any of which is substituted in the 5-position with fluoro, chloro, cyano, methyl, difluoromethyl or trifluoromethyl, and in the 6-position with methoxy or triazolyl
  • R 3 is pyridinyl which is substituted with chloro and triazolyl.
  • R 3 is pyridin-4-yl which is substituted with chloro in the 5-position and triazolyl in the 6-position.
  • R 1 is H, Ci-C3alkoxy or halod-Csalkoxy
  • R 2 is Ci-C6alkyl or C3-C6cycloalkyl any of which is optionally substituted with NRaRb;
  • R 3 is pyridinyl which is substituted with one or two substituents each independently selected from fluoro, chloro, cyano, d-Csalkyl, halod-Csalkyl and optionally substituted 5-membered heteroaryl;
  • Ra and Rb are independently H or Ci-C3alkyl.
  • R 1 is H, Ci-C3alkoxy or halod-Csalkoxy
  • R 2 is Ci-C6alkyl which is substituted with one or two methoxy
  • R 3 is pyridinyl which is substituted with one or two substituents each independently selected from fluoro, chloro, cyano, methyl, difluoromethyl, tnfluoromethyl and optionally substituted 5- membered heteroaryl.
  • R 1 is H, difluoromethoxy or trifluoromethoxy
  • R 2 is Ci-C 6 alkyl
  • R 3 is pyridin-3-yl or pyridin-4-yl which is substituted with one or two substituents each independently selected from fluoro, chloro, cyano, methyl, tnfluoromethyl, triazolyl and pyrazolyl optionally substituted with aminomethyl.
  • R 1 is H, Ci-C3alkoxy or haloCi-Csalkoxy
  • R 2 is Ci-C6alkyl or C3-C6cycloalkyl any of which is substituted with one or two methoxy or with NRaRb;
  • R 3 is pyridin-3-yl or pyridin-4-yl which is substituted with one or two substituents each independently selected from fluoro, chloro, cyano, methyl, difluoromethyl, tnfluoromethyl, triazolyl or aminomethylpyrazolyl;
  • Ra and Rb are independently H or Ci-C3alkyl. In one embodiment of the invention,
  • R 1 is H, difluoromethoxy or trifluoromethoxy
  • R 2 is Ci-C6alkyl or C3-C4cycloalkyl any which is substituted with NRaRb;
  • R 3 is pyridin-3-yl which is substituted with fluoro or chloro and with triazolyl; one of Ra and Rb is Me and the other is H or Me.
  • Preferred compounds of series (z) include
  • the invention provides a compound of formula I or any subgroup or series thereof for use as a medicament.
  • a second aspect of the invention provides a compound of formula I or any subgroup or series thereof for use in the treatment of cancer, wherein the tumoural tissue is characterized by infiltration of
  • T reg Fox P3 positive T-regulatory lymphocytes
  • a third aspect of the invention provides the use of a compound of formula I or any subgroup or series thereof in the treatment of cancer, in combination with a treatment regime comprising at least one further immuno-oncology agent.
  • the tumoural tissue is preferably characterized by infiltration of
  • the invention provides a compound of formula (I) or any subgroup thereof for use in the treatment of cancer.
  • the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or any subgroup or series thereof in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the invention provides a pharmaceutical composition for use in the treatment of cancer.
  • the invention provides a pharmaceutical composition for use in the treatment of bladder cancer, colon cancer, hepatocellular cancer or Small Cell or Non- Small Cell lung cancer.
  • the invention additionally provides a pharmaceutical composition for use in the treatment of glioblastoma, cutaneous T-cell lymphoma or head and neck cancers.
  • the invention provides a pharmaceutical combination comprising a therapeutically effective amount of compound of formula (I) or any subgroup thereof, further comprising one or more additional therapeutic agent(s) selected from the group consisting of chemotherapeutical agent, multi-drug resistance reversing agent and immuno-oncology agent.
  • the further therapeutic agent is a chemotherapeutical agent.
  • the immuno-oncology agent is selected from antibodies, cytokine therapy, adoptive T-cell therapy and immunostimulatory polysaccharides.
  • the antibody according to this embodiment is a check point inhibitor.
  • the invention provides the use of a compound of formula (I) or any subgroup thereof in the manufacture of a medicament for the treatment of cancer.
  • the invention provides a method for the treatment of cancer comprising the administration of a compound of formula (I) or any subgroup thereof.
  • FoxP3 (forkhead box P3), also known as scurfin, is a protein involved in immune system responses and appears to function as a master regulator of the regulatory pathway in the development and function of regulatory T cells. While the precise control mechanism has not yet been established, Fox proteins belong to the forkhead/winged-helix family of transcriptional regulators and are presumed to exert control via similar DNA binding interactions during transcription. In regulatory T cell model systems, the FoxP3 transcription factor occupies the promoters for genes involved in regulatory T-cell function. FoxP3 is a specific marker for natural T regulatory cells (nT reg , a lineage of T cells) and adaptive/induced T regulatory cells (a/iT reg ), also identified by other less specific markers such as CD25 or CD45RB.
  • nT reg a lineage of T cells
  • a/iT reg adaptive/induced T regulatory cells
  • T reg that express FoxP3 are critical in the transfer of immune tolerance, especially self-tolerance.
  • the induction or administration of FoxP3 positive T cells has, in animal studies, led to marked reductions in autoimmune disease severity in models of diabetes, MS, asthma, inflammatory bowel disease and renal disease.
  • Human trials using regulatory T cells to treat graft versus host disease have shown efficacy.
  • CD8+ T effector lymphocytes also known as cytotoxic T lymphocyte or CTL bearing the CD8 glycoprotein, which binds to the constant portion of the class 1 MHC molecule during antigen recognition and apoptosis. CD8+ T effector lymphocytes are readily identified by IHCor by flow cytometry.
  • T effector lymphocytes also known as T helper cells, express the surface protein CD4, a co-receptor of the TCR complex which binds to a different location on the class II MHC molecule.
  • the further immuno-oncology treatment regime is selected from antibodies, cytokine therapy, adoptive T-cell therapy and immune- stimulatory polysaccharides.
  • the antibody is a checkpoint inhibitor, such as a PD1 inhibitor, for example BGB-A317, or more preferably nivolumab or pembrolizumab.
  • the checkpoint antibody is a PD-L1 antibody, preferably atezolizemab, avelumab or durvalumab.
  • the antibody is an immune-stimulatory antibody, such as a 4-1 BB (CD137) antibody, such as Utomilumab. a GITR antibody, an OX40 (CD134) antibody, or a CD40 antibody
  • an anti-CD52 antibody such as alemtuzumab
  • CTLA4 antibody such as ipilimumab
  • the cytokine therapy comprises an interferon selected from IFNa, ⁇ , IFNy and I FNA, or an interleukin, preferably IL-2.
  • the further therapeutic agent may be:
  • an additional immunomodulatory agent which blocks or inhibits an immune system checkpoint, which checkpoint may or may not be a component of the N FKB pathway;
  • an agent which directly stimulates an immune effector response such as a cytokine or chemokine (or an agent which stimulates production of either), a tumour specific adoptively transferred T cell population, or an antibody specific for a protein expressed by a tumour cell; and/or
  • composition comprising a tumour antigen or immunogenic fragment thereof;
  • the MALT1 inhibitor is an orally administered small molecule inhibitor and the further immune-oncology treatment regime is administered parenterally, for example intravenously, intraperitoneally or as a depot.
  • the subject receives other medicaments, whether as part of a method of the invention or otherwise, it may be convenient to administer the MALT1 inhibitor by the same route as the other medicaments.
  • Such routes may include parenterally in the case of many immunomodulatory agents, or as TACE for hepatocellular cancer or intrathecally /
  • the MALT1 inhibitor may change the ratio of T re g/Teff cells infiltrating a tumour in favour of the Teff cells. This may typically be achieved by reducing the number of infiltrating T reg cells whilst maintaining or increasing the level of infiltrating T e ff cells.
  • the ratio of T re g/T e ff cells in a tumour may be determined by any suitable method, but typically involves the quantification of each cell type in a tumour sample or a sample from a tumour draining lymph node. Suitable methods include flow cytometry,
  • the compound of the invention is orally administered.
  • the patient may also be receiving further parenteral medicaments, for example the further immune-oncology agent of the third aspect of the invention, it may be convenient to deliver the compound of the invention by the same route.
  • the patient may be receiving other medicaments by still further routes, such as TACE for hepatocellular cancer or
  • intrathecally/intracerebrally for glioblastoma, astrocytoma or other nerve tissue cancers. It may be convenient to co-administer the MALT1 inhibitor by the same route.
  • the cancer is selected from B-cell malignancies such as
  • B-cell lymphoma e.g. Diffuse large cell B-cell lymphoma (DLBCL) and Mantle cell lymphoma (MCL), and
  • Leukemias e.g. chronicle lymphatic leukemia (CLL).
  • CLL chronicle lymphatic leukemia
  • the invention concerns preventing or treating cancer.
  • the cancer is preferably of a type which is not characterised by abnormally high activity in the NF- ⁇ pathway.
  • the cancer may be characterised by the presence of both infiltrating regulatory T cells (T reg cells) and infiltrating effector T cells (T ef r cells) in the tumour.
  • T reg cells are typically characterised as FOXP3+.
  • Te f r cells are typically characterised as CD4+ or CD8+.
  • the number of T reg and T eff cells in a tumour may be determined by any suitable method, but typically this involves the quantification of each cell type in a tumour sample or a sample from a tumour draining lymph node. Suitable methods for the quantification of cells include flow cytometry, which may be performed in accordance with the protocols set out in the Examples.
  • the cancer may be prostate cancer, brain cancer, breast cancer, colorectal cancer, pancreatic cancer, ovarian cancer, lung cancer, cervical cancer, liver cancer, head/neck/throat cancer, skin cancer, bladder cancer or a hematologic cancer.
  • the cancer may take the form of a tumour or a blood born cancer.
  • the tumour may be solid.
  • the tumour is typically malignant and may be metastatic.
  • the tumour may be an adenoma, an adenocarcinoma, a blastoma, a carcinoma, a desmoid tumour, a desmopolastic small round cell tumour, an endocrine tumour, a germ cell tumour, a lymphoma, a leukaemia, a sarcoma, a Wilms tumour, a lung tumour, a colon tumour, a lymph tumour, a breast tumour or a melanoma.
  • Types of blastoma include hepatoblastoma, glioblastoma, neuroblastoma or retinoblastoma.
  • Types of carcinoma include colorectal carcinoma or heptacellular carcinoma, pancreatic, prostate, gastric, esophegal, cervical, and head and neck carcinomas, and adenocarcinoma.
  • Types of sarcoma include Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, or any other soft tissue sarcoma.
  • Types of melanoma include Lentigo maligna, Lentigo maligna melanoma, Superficial spreading melanoma, Acral lentiginous melanoma, Mucosal melanoma, Nodular melanoma, Polypoid melanoma, Desmoplastic melanoma, Amelanotic melanoma, Soft-tissue melanoma, Melanoma with small nevus-like cells, Melanoma with features of a Spitz nevus and Uveal melanoma.
  • Types of lymphoma and leukaemia include Precursor T-cell
  • leukemia/lymphoma acute myeloid leukaemia, chronic myeloid leukaemia, acute lymphcytic leukaemia, Follicular lymphoma, Diffuse large B cell lymphoma, Mantle cell lymphoma, chronic lymphocytic leukemia/lymphoma, MALT lymphoma, Burkitt's lymphoma, Mycosis fungoides, Peripheral T-cell lymphoma, Nodular sclerosis form of Hodgkin lymphoma, Mixed-cellularity subtype of Hodgkin lymphoma.
  • Types of lung tumour include tumours of non-small-cell lung cancer (adenocarcinoma, squamous-cell carcinoma and large-cell carcinoma) and small-cell lung carcinoma.
  • the cancer may preferably be selected from
  • hepatocellular cancer or small cell or non-small cell lung cancer.
  • the compounds of formula I or any subgroup thereof are proposed for autoimmune or inflammatory pathways, or cancers dependent on dysregulated N FKB pathway activity.
  • the invention may additionally comprise administering to the subject a further therapeutic agent.
  • the further therapeutic agent may preferably be:
  • an additional immunomodulatory agent which blocks or inhibits an immune system checkpoint, which checkpoint may or may not be a component of the N FKB pathway;
  • an agent which directly stimulates an immune effector response such as a cytokine, or a tumour specific adoptively transferred T cell population, or an antibody specific for a protein expressed by a tumour cell;
  • composition comprising a tumour antigen or immunogenic fragment thereof;
  • the compound of the invention may be administered either simultaneously with, or before or after, the further therapeutic agent.
  • the MALT1 inhibitor may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the further therapeutic agent.
  • co-administration or “combined administration” or the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily
  • pharmaceutical combination means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • fixed combination means that the active ingredients, e.g. a compound of formula (I) and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that the active ingredients, e.g. a compound of formula (I) and a co-agent, are both
  • the Invention provides a product comprising a compound of the invention, such as a compound of formula (I) or any subgroup thereof and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy.
  • Products provided as a combined preparation include a composition comprising the compound of the invention such as a compound of formula (I) or any subgroup thereof and the other therapeutic agent(s) together in the same pharmaceutical composition, or the compound of formula (I) or any subgroup thereof and the other therapeutic agent(s) in separate form, e.g. in the form of a kit.
  • the invention provides a pharmaceutical composition for use in therapy comprising a compound of formula (I) or any subgroup thereof and an additional immunomodulatory agent or a composition comprising a tumour antigen or immunogenic fragment thereof.
  • the pharmaceutical composition may comprise a pharmaceutically acceptable excipient.
  • the further therapeutic agents used in the methods of the invention may be biologicals requiring intravenous, intraperitoneal or depot administration.
  • the compound of the invention is orally administered and the further therapeutic agent is administered parenterally, for example intravenously, intraperitoneally or as a depot.
  • Effector T cell activation is normally triggered by the T cell receptor recognising antigenic peptide presented by the MHC complex. The type and level of activation achieved is then determined by the balance between signals which stimulate and signals which inhibit the effector T cell response.
  • the term "immune system checkpoint" is used herein to refer to any molecular interaction which alters the balance in favour of inhibition of the effector T cell response. That is, a molecular interaction which, when it occurs, negatively regulates the activation of an effector T cell. Such an interaction might be direct, such as the interaction between a ligand and a cell surface receptor which transmits an inhibitory signal into an effector T cell.
  • immune system checkpoints examples include:
  • a preferred checkpoint for the purposes of the present invention is checkpoint (b), namely the interaction between PD1 and either of its ligands PD-L1 and PD-L2.
  • PD1 is expressed on effector T cells. Engagement with either ligand results in a signal which downregulates activation.
  • the ligands are expressed by some tumours.
  • PD-L1 in particular is expressed by many solid tumours, including melanoma. These tumours may therefore down regulate immune mediated anti-tumour effects through activation of the inhibitory PD-1 receptors on T cells.
  • a checkpoint of the immune response may be removed, leading to augmented anti-tumour T cell responses. Therefore PD1 and its ligands are examples of components of an immune system checkpoint which may preferably be targeted in the method of the invention
  • checkpoint namely the interaction between the T cell receptor CTLA-4 and its ligands, the B7 proteins (B7-1 and B7-2).
  • CTLA-4 is ordinarily upregulated on the T cell surface following initial activation, and ligand binding results in a signal which inhibits further/continued activation.
  • CTLA-4 competes for binding to the B7 proteins with the receptor CD28, which is also expressed on the T cell surface but which upregulates activation.
  • CTLA4 and its ligands are examples of components of an immune system checkpoint which may preferably be targeted in the method of the invention IMMUNOMODULATORY AGENT
  • an “immunomodulatory agent” is used herein to mean any agent which, when administered to a subject, blocks or inhibits the action of an immune system checkpoint, resulting in the upregulation of an immune effector response in the subject, typically a T cell effector response, which preferably comprises an anti-tumour T cell effector response.
  • the immunomodulatory agent used in the method of the present invention may block or inhibit any of the immune system checkpoints described above.
  • the agent may be an antibody or any other suitable agent which results in said blocking or inhibition.
  • the agent may thus be referred to generally as an inhibitor of a said checkpoint.
  • An "antibody” as used herein includes whole antibodies and any antigen binding fragment (i.e., "antigen-binding portion") or single chains thereof.
  • An antibody may be a polyclonal antibody or a monoclonal antibody and may be produced by any suitable method.
  • binding fragments encompassed within the term "antigen-binding portion" of an antibody include a Fab fragment, a F(ab')2 fragment, a Fab' fragment, a Fd fragment, a Fv fragment, a dAb fragment and an isolated complementarity determining region (CDR).
  • Single chain antibodies such as scFv and heavy chain antibodies such as VHH and camel antibodies are also intended to be encompassed within the term "antigen-binding portion" of an antibody.
  • Preferred antibodies which block or inhibit the CTLA-4 interaction with B7 proteins include ipilumumab, tremelimumab, or any of the antibodies disclosed in WO2014/207063.
  • Other molecules include polypeptides, or soluble mutant CD86 polypeptides. Ipilumumab is most preferred.
  • Preferred antibodies which block or inhibit the PD1 interaction with PD-L1 include Nivolumab, Pembrolizumab, Lambrolizumab, Pidilzumab, BGB-A317 and AMP-224. Nivolumab or pembrolizumab is most preferred.
  • Anti-PD-L1 antibodies include atezolizemab, avelumab or durvalumab, MEDI-4736 and MPDL3280A.
  • Preferred antibodies which block or inhibit the interaction between 4-1 BB and its ligand include utomilumab.
  • SMI small molecule inhibitors
  • Preferred inhibitors of ID01 include Epacadostat (INCB24360), Indoximod, GDC-0919 (NLG919) and F001287.
  • Other inhibitors of ID01 include 1-methyltryptophan (1 MT).
  • an agent which directly stimulates an immune effector response means any suitable agent, but typically refers to a cytokine or chemokine (or an agent which stimulates production of either), a tumour specific adoptively transferred T cell population, or an antibody specific for a protein expressed by a tumour cell.
  • the cytokine may be an interferon selected from IFNa, ⁇ , IFNy and IFNA, or an interleukin, preferably IL-2.
  • the chemokine may be an inflammatory mediator, for example selected from CXCL9, 10, and 1 1 , which attract T cells expressing CXCR3.
  • the agent which stimulates production of a cytokine or chemokine may be an adjuvant suitable for administration to humans.
  • a preferred example is Bacille Calmette-Guerin (BCG), which is typically administered intravesical ⁇ (i.e. urethral catheter) for treatment of bladder cancer.
  • BCG Bacille Calmette-Guerin
  • a typical dosage regime of BCG for bladder cancer is once per week for six weeks, but given its long safety history it is also administered indefinitely as maintenance.
  • BCG has been shown to stimulate immune responses to bladder cancer.
  • BCG has also been used as an adjuvant in combination with compositions which comprise tumour antigens (i.e. with cancer vaccines), particularly for colon cancer when it is administered typically intradermally.
  • tumour antigens i.e. with cancer vaccines
  • Such uses of BCG are also envisaged in the present invention.
  • the tumour specific adoptively transferred T cell population directly increases the size of the tumour specific T cell population in an individual, and may be generated by any suitable means. However, typically the process involves isolating tumour specific T cells from a tumour sample taken from a patient, and selectively culturing those cells before returning the expanded population of tumour-specific T cells to the patient.
  • a tumour specific T cell population may be produced by genetic engineering of the T cell receptor locus, followed by expansion of the altered cell.
  • Antibodies specific for proteins expressed by a tumour cell typically stimulate immune activity by binding to the tumour cell and promoting destruction of the cell via antibody-dependent cell- mediated cytotoxicity (ADCC).
  • ADCC antibody-dependent cell- mediated cytotoxicity
  • Preferred examples of antibodies of this type include anti-CD20 antibodies such as ofatumumab or rituximab, and anti-CD52 antibodies such as alemtuzumab.
  • a composition of the invention may comprise any tumour antigen or any antigenic fragment thereof. Such a composition may alternatively be described as a vaccine against the said tumour antigen, which stimulates an adaptive immune response to the antigen when
  • tumour antigen or fragment may be present in the composition in polypeptide (or peptide) form, or may be encoded by a nucleic acid, for example an RNA or DNA molecule, or may be present as whole cells (e.g. an autologous tumour cell vaccine).
  • Tumour antigens are typically molecules which are located on the surface of the tumour cell. Tumour antigens may be selected from proteins which are overexpressed in tumour cells compared to a normal, non-cancerous cell. Tumour antigens include antigens expressed in cells which are not cancerous but are associated with a tumour. Antigens which are connected with tumour-supplying vessels or formation thereof, in particular those antigens which are associated with neo-vascularization, e.g. VEGF, bFGF, are also included herein. Antigens associated with a tumour furthermore include antigens from cells or tissues, typically embedding the tumour.
  • Tumour antigens can be divided further into tumour-specific antigens (TSAs) and tumour- associated-antigens (TAAs).
  • TSAs can only be expressed by tumour cells and not by normal "healthy" cells. They typically result from a tumour specific mutation.
  • TAAs which are more common, may be expressed by both tumour and healthy cells.
  • TAAs which are more common, may be expressed by both tumour and healthy cells.
  • tumour antigens can also occur on the surface of the tumour in the form of, e.g., a mutated receptor. In this case, they can be recognized by antibodies.
  • tumour associated antigens may be classified as tissue-specific antigens, examples of which include melanocyte-specific antigens, cancer-testis antigens and tumour-specific antigens.
  • Cancer-testis antigens are typically understood to be peptides or proteins of germ-line associated genes which may be activated in a wide variety of tumours.
  • Human cancer-testis antigens may be further subdivided into antigens which are encoded on the X chromosome, so-called CT-X antigens, and those antigens which are not encoded on the X chromosome, the so-called non-X CT antigens.
  • Cancer-testis antigens which are encoded on the X-chromosome comprise, for example, the family of melanoma antigen genes, the so-called MAGE-family.
  • the genes of the MAGE-family may be characterised by a shared MAGE homology domain (MHD).
  • MHD MAGE homology domain
  • Preferred tumour antigens of the invention include a melanocyte-specific antigen, a cancer-testis antigen or a tumour-specific antigen, preferably a CT-X antigen, a non-X CT-antigen, a binding partner for a CT-X antigen or a binding partner for a non-X CT-antigen or a tumour-specific antigen, more preferably a CT-X antigen, a binding partner for a non-X CT-antigen or a tumour-specific antigen.
  • tumour antigens are selected from 5T4, 707-AP, 9D7, AFP, AlbZIP HPG1 , alpha-5-beta-1-integrin, alpha-5-beta-6-integrin, alpha-actinin-4/m, alpha-methylacyl-coenzyme A racemase, ART-4, ARTC1/m, B7H4, BAGE-1 , BCL-2, bcr/abl, beta-catenin/m, BING-4, BRCA1/m, BRCA2/m, CA 15-3/CA 27-29, CA 19-9, CA72-4, CA125, calreticulin, CAMEL, CASP-8/m, cathepsin B, cathepsin L, CD19, CD20, CD22, CD25, CDE30, CD33, CD4, CD52, CD55, CD56, CD80, CDC27/m, CDK4/m, CDKN2A/m, CEA, CLCA2, CML28, CML66, COA-
  • tumour antigens are selected from p53, CAI25, EGFR, Her2/neu, hTERT, PAP, MAGE-A1 , MAGE-A3, Mesothelin, MUC-1 , GP100, MART-1 , Tyrosinase, PSA, PSCA, PSMA, STEAP-1 , VEGF, VEGFR1 , VEGFR2, Ras, CEA or WT1.
  • Tumour antigens also may encompass idiotypic antigens associated with a cancer or tumour disease, particularly lymphoma or a lymphoma associated disease, wherein said idiotypic antigen is an immunoglobulin idiotype of a lymphoid blood cell or a T cell receptor idiotype of a lymphoid blood cell.
  • a method for the treatment of bladder cancer comprising the administration of a MALT1 inhibitor and at least one of BCG and a chemotherapeutic agent selected from mitomycin, valrubicin, docataxel, thiotepa and gemcitabine, wherein at least the BCG and the chemotherapeutic agent are preferably administered intravesically, i.e.
  • a method for the treatment of colon cancer comprising the administration of a MALT1 inhibitor and at least one of BCG and a composition comprising a tumour antigen, preferably an autologous tumor cell vaccine. At least the BCG and the composition comprising a tumour antigen are preferably administered parenterally, optionally as a single combined preparation.
  • Ci- C 4 alkyl means an alkyl radical having from 1 to 4 carbon atoms and includes methyl, ethyl, n- propyl, isopropyl, t-butyl, n-butyl and isobutyl, similarly, d-Cealkyl means a straight or branched alkyl radical having from 1 to 6 carbon atoms, including also all straight and branched chain isomers of pentyl and hexyl.
  • C2-C n alkenyl' as a group or part of a group denotes a straight or branched chain hydrocarbon radical having saturated carbon-carbon bonds and at least one carbon-carbon double bond, and having the number of carbon atoms indicated wherein n is an integer ⁇ 1 , e.g. C2-C6alkenyl means an alkenyl group having from 2 to 6 carbon atoms.
  • Exemplary alkenyl groups include, but are not limited to, ethenyl (or vinyl), 1-propenyl, 2-propenyl (or allyl), isopropenyl, butenyl, and the like.
  • C2-C n alkynyl' as a group or part of a group denoted s a straight or branched chain hydrocarbon radical having saturated carbon-carbon bonds and at least one carbon-carbon triple bond, and having the number of carbon atoms indicated wherein n is an integer > 1 , e.g. C2-C6alkynyl means an alkynyl group having from 2 to 6 carbon atoms.
  • Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, propynyl, butynyl, and the like.
  • 'C3-C n cycloalkyr as a group or part of a group denotes a saturated cyclic hydrocarbon radical having the number of carbon atoms indicated wherein n is an integer ⁇ 3, e.g. C3- Cecycloalkyl means a cycloalkyl group having 3, 4, 5 or 6, carbon atoms.
  • Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl cyclopentyl, cyclohexyl and the like, especially cyclopropyl.
  • 'C3-C n 'CycloalkylCm-C n alkyr denotes a C m -C n alkyl radical which is substituted with a d-d cycloalkyl moiety, wherein d-d cycloalkyl and C m -C n alkyl are as defined above for d- Cncycloalkyl and C m -C n alkyl respectively.
  • Exemplary C3-C n 'CycloalkylC m -C n alkyl groups include, but are not limited to, C3-C7cycloalkylCi-C3alkyl, i.e. the cycloalkyl moiety is bonded through a methyl, ethyl, n-propyl or isopropyl group.
  • C3-C6cycloalkenyl means a cycloalkenyl group having 3, 4, 5 or 6, carbon atoms.
  • Exemplary cycloalkenyl groups include, but are not limited to, cyclobutenyl cyclopentenyl, cyclohexenyl and the like.
  • 'CyclAlk' as a group or part of a group denotes a C3-C6cycloalkyl which is substituted with one, two or three substituents each independently selected from halo, halod-dalkyl and haloCrCealkoxy.
  • 'CycAlkC m -C n alkyr denotes a C m -C n alkyl radical which is substituted with a CycAlk moiety, wherein CycAlk and C m -C n alkyl are as defined above.
  • CycAlkC m -C n alkyl groups include, but are not limited to, CycAlkd-dalkyl, i.e. the CycAlk moiety is bonded through a methyl, ethyl, n-propyl or isopropyl group.
  • 'Ci-C n alkoxy' defines a radical 0-Ci-C n alkyl wherein Ci-C n alkyl is as defined for C m - dalkyl above.
  • Preferred alkoxy groups for use in the invention are d-dalkoxy, i.e. alkoxy groups having from 1 to 6 carbon atoms.
  • Exemplary alkoxy groups include but are not limited to methoxy, ethoxy n-propoxy and isopropoxy, and the like.
  • Me means methyl and “MeO” means methoxy.
  • 'halo' or 'halogen' is generic to fluoro, chloro, bromo and iodo.
  • the term 'haloCm-dalkyl' as a group or part of a group represents a C m -C n alkyl wherein at least one C-atom is substituted with one or more halogen atom(s), in particular d-dalkyl substituted with one, two, three, four, five, six, or more halo atoms, such as methyl or ethyl with one or more fluoro atoms, for example, difluoromethyl, trifluoromethyl, trifluoroethyl.
  • halogen atom is attached to an alkyl group within the definition of
  • the halogen atoms may be the same or different.
  • 'haloC n -C m alkoxy' represents a C n -C m alkoxy having the number of carbon atoms indicated, wherein at least one C-atom is substituted with one or more halogen atom(s), typically chloro or fluoro.
  • halogen atom(s) typically chloro or fluoro.
  • Ci-Cehaloalkoxy In many cases trifluoromethyl is preferred.
  • 'amino' means NH2.
  • 'aminoC m -C n alkyr and 'amino(C m -C n alkyl)2' denotes an amino group wherein one or two of the hydrogen atoms respectively is replaced by C m -C n alkyl wherein C m -C n alkyl is as defined above and wherein the m and n in the (C m -C n alkyl)2 are selected independently of each other.
  • alkoxyamido refers to such as tert.butoxycarbonylamino.
  • aryl' as a group or part of a group as applied herein represents an aryl moiety such as a phenyl or naphthyl or a phenyl fused to a C4-C6cycloalkyl (for example indanyl), or a C 4 - Cecycloalkenyl.
  • suitable aryl groups include but are not limited to phenyl, biphenyl, naphthyl, tetrahydronaphthyl, indenyl and indanyl.
  • arylCm-C n alkyl' represents a C m -C n alkyl which is substituted with aryl, wherein aryl and Cm-C n alkyl are as defined above.
  • Preferred arylC m -C n alkyl groups for use in the invention are aryld-Csalkyl, i.e. the aryl moiety is bonded through a methyl, ethyl, n-propyl or isopropyl group.
  • heterocyclyl', 'heterocyclic' or heterocycle denotes a saturated or partially unsaturated mono- or bicyclic ring system composed of 4-10 atoms, whereof 1 , 2, 3 or 4 are heteroatoms each independently selected from S, O and N.
  • suitable heterocyclyl groups include but are not limited to pyranyl, tetrahydropyranyl,
  • heterocyclyl group is optionally substituted with one, two or three substituents.
  • heterocyclylC m -C n alkyr represents a C m -C n alkyl which is substituted with heterocyclyl, wherein heterocyclyl and C m -C n alkyl are as defined above.
  • Preferred heterocyclylC m -C n alkyl groups for use in the invention are heterocyclylCi-CsalkyI, i.e. the heterocyclyl moiety is bonded through a methyl, ethyl, n-propyl or isopropyl group.
  • heteroaryl as applied herein means an aromatic heterocyclyl moiety.
  • suitable heteroaryl groups include but are not limited to pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, tetrahydroquinazolinyl, quinoxalinyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazinolyl, benzisothiazinolyl, benzothiazolyl, benzoxadiazolyl, benzo-1 ,2,3-triazolyl, benzo
  • heteroarylC m -C n alkyr represents a C m -C n alkyl which is substituted with heteroaryl, wherein heterocyclyl and C m -C n alkyl are as defined above.
  • Preferred heteroarylC m -C n alkyl groups for use in the invention are heteroaryld-Csalkyl, i.e. the heteroaryl moiety is bonded through a methyl, ethyl, n-propyl or isopropyl group.
  • aryl, heterocyclyl and heteroaryl moieties within the scope of the above definitions are thus a monocyclic ring with 5 or especially 6 ring atoms, or a bicyclic ring structure comprising a 6 membered ring fused to a 5 or 6 membered ring.
  • radical position(s) on any moiety used in the definitions may be anywhere on such a moiety as long as it is chemically stable.
  • Radicals used in the definitions of the variables include all possible isomers unless otherwise indicated.
  • pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl.
  • the term “optionally substituted” as used herein, means that substitution is optional, i.e. there may or may not be substitution.
  • the expression “alkyl group optionally substituted with one or more substituents” means that the alkyl group is substituted by zero, one or more substituents.
  • substituted refers to a molecule wherein at least one hydrogen atom is replaced with a substituent.
  • salt refers to an acid addition or base addition salt of a compound.
  • Salts include in particular “pharmaceutically acceptable salts”.
  • “pharmaceutically acceptable salts” refers to salts that retain the biological effectiveness and properties of the compounds of this invention and, which typically are not biologically or otherwise undesirable, in many cases, the compounds are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide,
  • chlortheophyllonate citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isothionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen
  • phosphate/dihydrogen phosphate poiygalacturonate, propionate, stearate, succinate, subsalicylate, tartrate, tosylate and trifluoroacetate salts.
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,
  • compositions can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table.
  • the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include
  • the pharmaceutically acceptable salts can be synthesized from a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable. Lists of additional suitable salts can be found, e.g., in "Remington's
  • the term "pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.
  • a therapeutically effective amount refers to an amount of a substance that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc.
  • the term "a therapeutically effective amount” refers to the amount of a compound of the invention that, when administered to a subject, is sufficient to achieve an immunomodulatory effect which at least partially alleviates, inhibits, prevents and/or ameliorates a cancerous condition, independently of dysregulated NFkB pathway activation within the cancer cells.
  • chemotherapeutic agent means any agent which has been approved for use as a chemotherapy for cancer. Examples include but are not limited to: all-trans retinoic acid, actimide, azacitidine, azathioprine, bleomycin, carboplatin, capecitabine, cisplatin, chlorambucil, cyclophosphamide, cytarabine, daunorubicin, docetaxel, doxifluridine, doxorubicin, epirubicin, etoposide, fludarabine, fluorouracil, gemcitabine, hydroxyurea, idarubicin, irinotecan, lenalidomide, leucovorin, mechlorethamine, melphalan, mercaptopurine, methotrexate, mitomycin, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, revlimid, temozolomide,
  • a chemotherapeutic agent for use in the combinations described herein may, itself, be a combination of different chemotherapeutic agents.
  • Suitable combinations include a combination of 5-fluorouracil (5-FU), leucovorin, and oxaliplatin (may be referred to as FOLFOX), or a combination of irinotecan, 5-FU, and leucovorin (may be referred to as IFL).
  • the term "subject” refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like, in certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human. As used herein, the term “inhibit”, “inhibition” or “inhibiting” refers to the reduction or
  • the term “treat”, “treating” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof), in another embodiment “treat”, “treating” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In yet another embodiment, “treat”, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment, “treat”, “treating” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.
  • a subject is "in need of” a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
  • the present invention includes unlabelled compounds as well compounds wherein one or more of the atom(s) is/are replaced by an isotope of that atom(s), i.e. an atom having the same atomic number but an atomic mass different from the one(s) typically found in nature.
  • isotopes examples include but are not limited to isotopes of hydrogen, such as 2 H and 3 H (also denoted D for deuterium and T for tritium, respectively), carbon, such as 11 C, 13 C and 14 C, nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 0 and 18 0, phosphorus, such as 31 P and 32 P, fluorine, such as 18 F, chlorine, such as 36 CI and bromine such as 75 Br, 76 Br, 77 Br and 82 Br.
  • isotopically labelled compounds include for example those wherein radioactive isotopes, such as 3 H and 14 C are present, or those wherein non-radioactive isotopes, such as 2 H and 13 C are present.
  • isotope included in an isotope-containing compound will depend on the specific application of that compound. For example, for drug or substrate tissue distribution assays or in metabolic studies compounds wherein a radioactive isotope such as 3 H or 14 C is incorporated, will generally be most useful. For radio-imaging applications, for example positron emission tomography (PET) a positron emitting isotope such as 11 C, 18 F, 13 N or 15 0 will be useful.
  • PET positron emission tomography
  • a heavier isotope such as deuterium, i.e. 2 H, may provide certain therapeutic advantages resulting from greater metabolic stability to a compound of the invention, which may result in, for example, an increased in vivo half life of the compound, reduced dosage requirements or an improvement in therapeutic index.
  • Isotopically-labelled compounds of formula (I) or any subgroup thereof can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Schemes and/or Examples herein by using the appropriate isotopically-labelled reagents or starting material instead of the corresponding non-isotopically- labelled reagent or starting material.
  • solvates include those wherein the solvent of crystallization may be isotopically substituted, e.g. D2O, d6-acetone, d6-DMSO.
  • Compounds of formula (I) or any subgroup thereof that contain groups capable of acting as donors and/or acceptors for hydrogen bonds may be capable of forming co-crystals with suitable co-crystal formers. These co-crystals may be prepared from compounds of formula (I) or any subgroup thereof by known co-crystal forming procedures.
  • Such procedures include grinding, heating, co-subliming, co-melting, or contacting in solution compounds of formula (I) or any subgroup thereof with the co-crystal former under crystallization conditions and isolating co- crystals thereby formed.
  • Suitable co-crystal formers include those described in WO
  • any asymmetric atom (e.g., carbon or the like) of a compound of the invention can be present in racemic or enantiomerically enriched, for example the (R)-, (S)- or (R,S)- configuration.
  • each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or (S)- configuration.
  • Substituents at atoms with unsaturated double bonds may, if possible, be present in cis-(Z)-or trans-(E)- form.
  • a compound of the invention can be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (c/s or trans) isomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof. Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
  • any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound.
  • a basic moiety may thus be employed to resolve the compounds of the present invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di- ⁇ , ⁇ '- ⁇ -toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid.
  • Racemic products can also be resolved by chiral chromatography, e.g., high pressure liquid
  • compound of the invention can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.
  • a compound of the invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, it is intended that a compound of the invention embrace both solvated and unsolvated forms.
  • solvate refers to a molecular complex of a compound of the invention (including pharmaceutically acceptable salts thereof) with one or more solvent molecules. Such solvent molecules are those commonly used in the
  • hydrate refers to the complex where the solvent molecule is water.
  • a compound of the invention including salts, hydrates and solvates thereof, may inherently or by design form polymorphs.
  • a compound of the invention is presented as a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration, and rectal administration, etc.
  • the pharmaceutical compositions can be made up in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including without limitation solutions, suspensions or emulsions).
  • compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc.
  • the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders, e.g., magnesium aluminium silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners. Tablets may be either film coated or enteric coated according to methods known in the art.
  • compositions for oral administration include an effective amount of a compound of the invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use are prepared according to any method known in the art for the manufacture of
  • compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets may contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
  • Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
  • compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions.
  • Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.
  • Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1-75%, or contain about 1-50%, of the active ingredient.
  • compositions for transdermal application include an effective amount of a compound of the invention with a suitable carrier.
  • Carriers suitable for transdermal delivery include
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and
  • compositions for intravesical administration include nanocarriers such as solid lipid nanoparticles, protein nanoparticles with targeted ligands grafted on the surface, branched polymeric dendrimers, mucoadhesive biopolymers (such as chitosan), mucoadhesive nanogels or synthetic polymers, magnetic particles, gold nanoshells, and in situ gelling systems.
  • nanocarriers such as solid lipid nanoparticles, protein nanoparticles with targeted ligands grafted on the surface, branched polymeric dendrimers, mucoadhesive biopolymers (such as chitosan), mucoadhesive nanogels or synthetic polymers, magnetic particles, gold nanoshells, and in situ gelling systems.
  • thermosensitive hydrogels such as aqueous solutions of poly (ethylene glycol-b-[di- lactic acid-co-glycolic acidj ⁇ -ethyleneglycol) triblock copolymers that form a free-flowing solution at room temperature and become a viscous gel at body temperature of 37 °C.
  • liposomal vesicles shown to enhance the therapeutic index of chemotherapeutic agents may be used.
  • a reservoir-based intravesical devices that can be inserted and remain in the bladder may also be used. The drug is then released from the device in a controlled and extended manner.
  • the device can be either biodegradable or nondegradable.
  • compositions for topical application include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, e.g., for delivery by aerosol or the like.
  • topical delivery systems will in particular be appropriate for dermal application, e.g., for the treatment of skin cancer, e.g., for prophylactic use in sun creams, lotions, sprays and the like. They are thus particularly suited for use in topical, including cosmetic, formulations well-known in the art.
  • Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • a topical application may also pertain to an inhalation or to an intranasal application. They may be conveniently delivered in the form of a dry powder (either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids) from a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomizer or nebuliser, with or without the use of a suitable propellant.
  • a dry powder either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids
  • Anhydrous pharmaceutical compositions and dosage forms comprising a compound of the invention as active ingredients, since water may facilitate the degradation of certain compounds.
  • Anhydrous pharmaceutical compositions and dosage forms can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
  • An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained.
  • anhydrous compositions are packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e. g., vials), blister packs, and strip packs.
  • compositions and dosage forms may comprise one or more agents that reduce the rate by which a compound of the present invention as an active ingredient will decompose.
  • agents which are referred to herein as “stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers, etc. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. "such as”) provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed.
  • any functional groups are present on any of the building blocks that may interfere in reactions, these are suitably protected during the reaction in order to avoid undesired side reactions, and deprotected at the end of the synthesis.
  • Appropriate protecting groups that can be used are extensively described in the literature, e.g. in Greene, "Protective Groups in Organic Chemistry", John Wiley & Sons, New York (1981)
  • the acid 1A used in the first step is chiral, and depending on the substitution pattern, partial racemization may occur during the reaction sequence.
  • the final product may be purified to high enantiomeric purity by chiral chromatography typically as described in example 1 19 of WO2015/181747.
  • Hydrolysis of the ester using the appropriate conditions according to the protecting group used provides acid 1 E.
  • an ethyl ester treatment with LiOH or equivalent in a solvent like THF and/or MeOH or the like is suitable, whereas in the case of a t.Bu-ester treatment with acid is typically appropriate.
  • a Curtius rearrangement of the afforded acid 1 E i.e.
  • aminopyrazole 3A under Sandmeyer conditions, i.e. reaction of the amine with a nitrite salt such as t.butyl nitrite or the like, a Cu(l) salt such as CuCI or CuBr and an acid e.g. HCI, provides 3-chloropyrazole 3B.
  • Nitration effected by reaction with HNO3 provides the N- nitropyrazole, which upon heating rearranges to the desired 3-chloro-5-nitropyrazole.
  • Reduction of the nitro group using any suitable reduction conditions such as iron, tin or tin chloride finally provides the desired 3-amino-5-chloropyrazole 3E.
  • R 3 -amines to be used in the preparation of compounds of formula I wherein R 3 is optionally substituted phenyl or pyridinyl can be prepared using the route illustrated in Scheme 4.
  • an optionally substituted halo e.g. chloro derivative 4A with a protonated nucleophile (R 13 -H) in the presence of a base such as NaH, K2CO3 or the like an inert solvent like DMF, provides the substitution product 4B.
  • the nucleophile R 13 in this case can be a deprotonated alcohol, amine, lactam or heterocycle, e.g. the anion of 1 ,2,3 triazole.
  • Reduction of the nitro substituent using any suitable reduction conditions such as tin or iron in acidic media provides the desired R 13 -substituted amine 4C.
  • R 3 -amines can be prepared via Curtius rearrangement of the corresponding acid as shown in Scheme 5:
  • Certain substituted anilines and aminoheteroaryls can be prepared by palladium-catalyzed coupling with a boronic acid derivative of the desired substituent R 13 .
  • the method is illustrated with aniline or aminopyridine in Scheme 6.
  • 6A A is CH or N 6B
  • R 3 -amines to be used in the preparation of compounds of the invention wherein R 13 is alkoxy or haloalkoxy are generally prepared by alkylation of the corresponding hydroxy, nitro compound followed by reduction of the nitro group to the amine. This strategy is generally depicted in Scheme 7.
  • the alkoxy or haloalkoxy substituent R 13 is typically introduced on the ring R 3 by reaction of the corresponding hydroxy compound 7A with the halide of the desired substituent R 13 effected by treatment with a base such as NaH or potassium carbonate or similar, thus providing alkoxy or haloalkoxy derivative 7B.
  • compound 7B may be obtained by using Mitsunobu conditions, i.e. reaction of the hydroxy compound 7A with the alcohol of the desired substituent R 13 using an azodicarboxylate like DEAD or similar in the presence of triphenylphosphine.
  • the nitro group is then reduced using any suitable reduction method, for instance an iron or tin mediated reduction method to provide the amino derivative 7C.
  • reaction are performed in an inert atmosphere (including but not limited to nitrogen or argon) where necessary to protect reaction components from air or moisture. Temperatures are given in degrees Celsius (°C). Solution percentages and ratios express a volume to volume relationship, unless stated otherwise.
  • the reactants used in the examples below may be obtained from commercial sources or they may be prepared from commercially available starting materials as described herein or by methods known in the art.
  • Tin(ll) chloride (30.0 g, 158 mmol) was added portion wise at rt to a solution of compound 1-1 a (7.0 g, 31 mmol) in 1 M HCI in MeOH (158 mL). The resulting mixture was stirred at rt for 3 h, then concentrated under reduced pressure. The residue was diluted with DCM (100 mL) and the mixture was basified with 1 N aqueous NaOH solution (50 mL). The phases were separated and the organic phase was dried over sodium sulphate, filtered and concentrated, which gave the title compound (5.0 g, 77%) as a solid MS (ES+) 196.02 [M+H] + .
  • Step a J step b
  • Fuming nitric acid 14.00 ml, 329 mmol was added at 0 °C over a period of 10 min to a solution of 5-chloro-1 H-pyrazole (10.0 g, 97.5 mmol) in acetic acid (14.0 ml, 245 mmol). The resulting mixture was stirred at 0 °C for 2 h, then acetic anhydride (33.0 ml, 349 mmol) was added and the reaction mixture was stirred at rt.
  • Iron powder 410 mg, 7.34 mmol
  • acetic acid 5 mL
  • the resulting mixture was heated to 80 °C for 10 min, then the reaction was quenched with NaHCC>3 solution (30 mL) and the mixture was extracted with EtOAc (50 mL). The organic phase was separated and the aqueous phase was extracted with EtOAc (50 mL).
  • N,N'-carbonyldiimidazole (1.2 g, 7.08 mmol) was added at 0 °C to a stirred solution of 1- (trifluoromethyl)cyclopropanecarboxylic acid (1.0 g, 6.49 mmol) in THF. The reaction mixture was stirred at rt for 3 h.
  • N,N'-carbonyldiimidazole (3.79 g, 23.4 mmol) was added at 0 °C to a stirred solution of 3- fluoroisonicotinic acid (3.0 g, 21.3mmol) in THF (60 mL). The reaction mixture was stirred at rt for 3 h.
  • Solution B was then added dropwise at 0 °C to solution A and the resulting mixture was stirred at rt for 1 h.
  • the aqueous layer was extracted with EtOAc (2 x 200 mL) and the combined organic layers were washed with saturated sodium bicarbonate solution, dried (Na2S0 4 ), filtered and concentrated under reduced pressure.
  • the obtained crude was purified by column chromatography on silica gel eluted with 15% EtOAc in p.ether which gave the title compound (1.2 g, 20%).
  • N,N'-carbonyldiimidazole (1.3 g, 8.46 mmol) was added at 0 °C to a stirred solution of thiazole- 5-carboxylic acid (1.0 g, 7.74 mmol) in THF (20 mL). The reaction mixture was stirred at rt for 3 h.
  • N,N'-carbonyldiimidazole (2.05 g, 12.6 mmol) was added at 0 °C to a stirred solution of 2- fluorocyclopropanecarboxylic acid (1.2 g, 11.5 mmol) in THF (20 mL). The reaction mixture was stirred at rt for 3 h.
  • Solution B was then added dropwise at 0 °C to solution A and the resulting mixture was stirred at rt for 1 h.
  • 10% Aqueous citric acid (aq., 25 mL) was added and the mixture was extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with saturated sodium bicarbonate solution, dried (Na2S0 4 ), filtered and concentrated under reduced pressure, which gave the title compound (1.2 g, 51 %).
  • Step b) Tert-butyl 2-chloro-7-((1 S,2S)-2-fluorocvclopropyl)pyrazolo[1 ,5-alpyrimidine-6- carboxylate(l-9b)
  • Compound 1-10a (2 g, 6.94 mmol) was reacted with 5-methyl-1 H-pyrazol-3-amine (680 mg, 6.94 mmol) using the procedure described for Intermediate 9 step b, which gave the title compound (1.3 g, 55%).
  • Iron powder (1.62 g, 29.1 mmol) was added in portions at rt to a stirred solution of l-12a
  • 1-13a 1.0 g, 1.90 mmol
  • EtOH 10 mL
  • 1 H-pyrazol-3-amine 154 mg, 1.90 mmol
  • the reaction mixture was heated at 100 °C for 16 h, then concentrated under reduced pressure.
  • the afforded crude was purified by column chromatography on silica gel, eluted with 15% ethyl acetate / pet ether which gave the title compound (400 mg, 60%) as a solid.
  • Lithium hydroxide (1.5 g, 35.75 mmol) was added at rt to a stirred solution of 1-15a (1.4 g, 8.24 mmol) in THF (20.0 ml_), acetonitrile (10 ml_) and water (10 ml_). The resulting reaction mixture was stirred at rt for 18 h. Progress of the reaction was monitored by 1 HNMR, then concentrated under reduced pressure at 30 °C bath temperature. The afforded crude was diluted with ice water (50 ml_) and acidified with 1 N HCI up to pH 3, and extracted with EtOAc (2 x 150 ml_). The combined organic layers were washed with brine, dried (Na2S0 4 ), filtered and concentrated under reduced pressure at 30 °C bath temperature, which gave the title compound (500 mg) as liquid. The compound was used in next step without further purification.
  • N,N'-carbonyldiimidazole (4.5 g, 27.75 mmol) was added at 0 °C to a stirred solution of compound 1-15b (3.0 g, 21.42 mmol) in THF (60 ml_). The reaction mixture was stirred at rt for 3 h.
  • Solution B was then added dropwise at 0 °C to solution A and the resulting mixture was stirred at rt until TLC indicated completion of the reaction (1 h).
  • 10% aqueous citric acid was added and the mixture was diluted with water.
  • the aqueous layer was extracted with EtOAc and the combined organic layers were washed with saturated sodium bicarbonate solution, dried (Na2S0 4 ), filtered and concentrated under reduced pressure at 30 °C bath temperature, which gave the title compound (3 g) as liquid. The compound was used in next step without further purification.
  • Step a) (S)-tert-butyl 7-(1-(difluoromethoxy)ethyl)pyrazolo[1 ,5-alpyrimidine-6-carboxylate (1-16a)
  • 1-15d 1.3 g, 4.43 mmol
  • EtOH 40 mL
  • 1 H-pyrazol-3-amine 600 mg, 7.08 mmol
  • the reaction mixture was heated at 85 °C for 2 h, then concentrated under reduced pressure.
  • Iron powder (685 mg, 12.27 mmol) was added portion-wise at room temperature to a solution of compound 1-17a (1 g, 2.44 mmol) in acetic acid (10 mL). The resulting mixture was stirred at rt for 16 h, then concentrated and the residue was diluted with EtOAc (50 mL) and filtered through the celite bed, the filtrate was washed with NaHC03 solution (30 mL) and the mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (20 mL), dried over Na2S0 4 , filtered and concentrated under reduced pressure.
  • DPPA (0.9 mL, 4.00 mmol) and Et 3 N (1.1 mL, 8.01 mmol) were added to a solution of l-6c (500 mg, 1.60 mmol) in 1 ,4-dioxane (5 mL) and t-butanol (5 mL). The solution was stirred at rt for 30 min, the mixture was stirred for 8 h at 100 °C. The reaction mixture was cooled to rt, water (10 mL) was added and the mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with aqueous saturated sodium bicarbonate (5 mL) and brine (5 mL), dried (Na2S0 4 ), filtered and concentrated.
  • DPPA (1.5 mL, 7.00 mmol) and Et 3 N (3.0 mL, 21.5 mmol) were added to a solution of l-20b (1 g, 3.5 mmol) in t-butanol (20 mL). The solution was stirred at rt for 30 min, the mixture was stirred for 16 h at 100 °C. The reaction mixture was cooled to rt, water (10 mL) was added and the mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with aqueous saturated sodium bicarbonate (5 mL) and brine (5 mL), dried (Na2S04), filtered and concentrated.
  • N,N'-carbonyldiimidazole 360 mg, 2.20 mmol was added at 0 °C to a stirred solution of compound 1-21 b (500 mg, 1.90 mmol) in THF (10 mL). The reaction mixture was stirred at rt for 3 h.
  • Step f) 7-((2S,4R)-4-fluoro-1-(4-methoxybenzyl)-5-oxopyrrolidin-2-yl)-2-methylpyrazolo[1 ,5- alpyrimidine-6-carboxylic acid (1-21 f)
  • N,N'-carbonyldiimidazole (2.4 g, 14.8 mmol) was added at 0 °C to a stirred solution of (1 R,2S)- 2-fluorocyclopropanecarboxylic acid (1.4 g, 13.5 mmol) in THF (30 mL). The reaction mixture was stirred at rt for 3 h.
  • Solution B was then added dropwise at 0 °C to solution A and the resulting mixture was stirred at rt for 1 h.
  • 10% aqueous citric acid 25 mL was added and the mixture was extracted with EtOAc (2 x 40 mL).
  • the combined organic layers were washed with saturated sodium bicarbonate solution, dried (Na2S0 4 ), filtered and concentrated under reduced pressure.
  • the crude was purified by column chromatography on silica gel and eluted with 20% EtOAc in pet ether, which gave the title compound (1.35 g, 50%) as a liquid. The compound was used in next step without further purification.
  • Lithium hydroxide (1.0 g, 23.83 mmol) was added at rt to a stirred solution of l-23a (1.1 g, 6.55 mmol) in THF (20.0 mL), acetonitrile (15 mL) and water (15 mL). The resulting reaction mixture was stirred at rt for 18 h. Progress of the reaction was monitored by 1 HNMR, then concentrated under reduced pressure at 30 °C bath temperature. The afforded crude was diluted with ice water (50 ml_) and acidified with 1 N HCI up to pH 3, and extracted with EtOAc (2 x 150 ml_). The combined organic layers were washed with brine, dried (Na2S0 4 ), filtered and concentrated under reduced pressure at 30 °C bath temperature, which gave the title compound (900 mg) as liquid. The compound was used in next step without further purification.
  • N,N'-carbonyldiimidazole (1.2 g, 7.1 mmol) was added at 0 °C to a stirred solution of compound l-23b (800 mg, 5.30 mmol) in THF (25 ml_). The reaction mixture was stirred at rt for 3 h.
  • EtOH 50 mL
  • Step b ( '- 28a .
  • R t Bu
  • Zinc powder 50 g, 765 mmol was added portion-wise at 0 °C to a solution of ethyl 5-nitro-1 H- pyrazole-3-carboxylate (10 g, 53.5 mmol) in acetic acid (100 mL) and water (20 mL). The resulting mixture was stirred to rt for 3 h, then filtered and the pH of the filtrate was adjusted to 8 with ammonium hydroxde and extracted with EtOAc (2 x 500 mL). The combined organic layers dried over Na2S0 4 and concentrated which gave the title compound (6 g, 53%) as a solid. The compound was used in next step without further purification. MS (ES+) 156.11 [M+H] + .
  • 6-chloro-3-methoxy-4-(trifluoromethyl)pyridazine 500 mg, 2.30 mmol was added to a stirred solution of tert-butyl carbamate (344 mg, 2.93 mmol) in 1 ,4-dioxane (10 mL) in a sealed tube.
  • the reaction mixture was degassed for 10 minutes with argon, then CS2CO3 (1.47g, 4.51 mmol), Xantphos (131 mg, 0.23 mmol) and Pd(OAc)2 (51 mg, 0.23 mmol) were added and the resulting reaction mixture was stirred at 100 °C for 16 h in a sealed tube.
  • the reaction mixture was filtered through Celite and concentrated.
  • Step b) (S)-2-chloro-7-(1-(difluoromethoxy)ethyl)pyrazolo[1 ,5-alpyrimidin-6-amine (l-34b) 4M HCI in MeOH (2 mL) was added at 0 °C to a solution of l-34a (210 mg, 0.50 mmol) in MeOH (5 mL). The reaction mixture was stirred at rt for 4h, then concentrated under reduced pressure and basified with saturated sodium bicarbonate (15 mL). The aqueous layer was extracted with EtOAc (2 x 30 mL), the organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure.
  • Fuming nitric acid 14.00 ml, 329 mmol was added at 0 °C over a period of 10 min to a solution of 5-chloro-1 H-pyrazole (10.0 g, 97.5 mmol) in acetic acid (14.0 ml, 245 mmol). The resulting mixture was stirred at 0 °C for 2 h, then acetic anhydride (33.0 ml, 349 mmol) was added and the reaction mixture was stirred at rt.
  • Solution 2 2M isopropyl magnesium chloride in THF (140 mL, 280 mmol) was added dropwise at 0 °C to a solution of 3-tert-butoxy-3-oxopropanoic acid (15 g, 93.6 mmol) in THF (200 mL) and the reaction mixture was stirred for 3 h at rt.
  • Step e) (S)-tert-butyl 2-chloro-7-(1-methoxyethyl)pyrazolo[1 ,5-alpyrimidine-6-carboxylate
  • 1-1 e A mixture of 1-1 d (25 g, 87 mmol) and 1 , 1-dimethoxy-N,N-dimethylmethanamine (9.5 g, 80 mmol) was heated at 120 °C for 90 min, then a solution of 1-1 c (10 g, 80 mmol) in ethanol (20 mL) was added and the mixture was heated to 85 °C for 2 h.
  • Tin(ll) chloride (30.0 g, 158 mmol) was added portion wise at rt to a solution of compound 1-1 a (7.0 g, 31 mmol) in 1 M HCI in MeOH (158 mL). The resulting mixture was stirred at rt for 3 h, then concentrated under reduced pressure. The residue was diluted with DCM (100 mL) and the mixture was basified with 1 N aqueous NaOH solution (50 mL). The phases were separated and the organic phase was dried over sodium sulphate, filtered and concentrated, which gave the title compound (5.0 g, 77%) as a solid MS (ES+) 196.02 [M+H] + .
  • Solution 2 2M isopropyl magnesium chloride in THF (140 mL, 280 mmol) was added dropwise at 0 °C to a solution of 3-tert-butoxy-3-oxopropanoic acid (15 g, 93.6 mmol) in THF (200 mL) and the reaction mixture was stirred for 3 h at rt.
  • Lithium hydroxide monohydrate (0.12 g, 2.84 mmol, Aldrich) was added at 0 °C to a stirred solution of l-3a (0.45 g, 1.42 mmol) in THF (5 mL) and water (5 mL). The reaction mixture was stirred at rt for 3 h, then concentrated under reduced pressure. 1 N HCI was added to the obtained solid until to pH 2 was reached. The solid was filtered and dried under vacuum which gave the title compound (300 mg, 69.81) as a solid. LCMS (MS+) m/z 272.20 [M+H] + .
  • a mixture of (R)-tert-butyl 3-((tert-butoxycarbonyl)(methyl)amino)-2-methyl-3-oxopropanoate ( 10 g, 19.86 mmol) and 1 , 1-dimethoxy-N,N-dimethylmethanamine (2.4 g, 20.14 mmol) was heated at 120 °C for 90 min, then a solution of 1 H-pyrazol-3-amine (1.7 g, 20.5 mmol,) in EtOH (100 mL) was added and the reaction mixture was heated to 85 °C for 2 h.
  • Solution 1 CDI (3.92 g, 24.2 mmol) was added at 0 °C to a solution of pyridazine-4-carboxylic acid (3.0 g, 24.2 mmol) in DMF (50.0 mL). The reaction mixture was stirred at rt for 3 h.
  • Solution 2 In a separate flask, 2M isopropyl magnesium chloride in THF (37.5 mL) was added dropwise at 0 °C to a solution of mono-tert-butyl malonate (3.87 g,24.2 mmol) in THF (50.0 mL). The reaction was stirred for 3 h at rt.
  • Solution 1 CDI (10.0 g, 61.6 mmol) was added at 0 °C to l-6a (10.0 g, 40.1 mmol) in dry THF (60 ml_) and stirred at rt for 3 h.
  • Solution 2 iPrMgCI (60.0 ml_) was added to (3-tert-butoxy-3-oxopropanoic acid ( 10.0 g, 62.43 mmol) in dry THF (60 ml_) at 0 °C and the solution was stirred at 20 °C for 3 h.
  • Solution 1 CDI (7.0 g, 43.2 mmol) was added at 0 °C to l-7a (4.0 g, 31.0 mmol) in dry DMF (20 ml_) and stirred at rt for 3 h.
  • Solution 2 iPrMgCI (60.0 ml_) was added to (3-tert-butoxy-3-oxopropanoic acid (10.0 g, 62.4 mmol) in dry THF (60 ml_) at 0 °C and the solution was stirred at 20 °C for 3 h.
  • DPPA 0.1 17 mL, 0.545 mmol
  • Et 3 N 0.3 mL, 2.1 mmol
  • l-8c 150 mg, 0.449 mmol
  • 1 ,4-dioxane 10 mL
  • the solution was stirred at rt for 30 min, then 1-1 b (135 mg, 0.673 mmol) was added and the mixture was stirred at 100 °C for 2 h.
  • the reaction mixture was diluted with ice cold water and extracted with EtOAc (2 x 10 mL).
  • DPPA (0.43 mL, 2.00 mmol) and Et 3 N (0.9 ml_, 6.46 mmol) were added at rt under nitrogen to a stirred solution of l-9c (365 mg, 0.99 mmol) in 1 ,4 dioxane(10 mL). The mixture was stirred at rt for 30 min, then 1-1 b (210 mg, 1.00 mmol) was added. The mixture was heated to 100 °C and stirred at this temp for 3h, then diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were dried (Na2S0 4 ), filtered and concentrated.
  • DPPA (0.35 ml_, 1.63 mmol) and Et 3 N (1.2 ml_, 8.61 mmol) were added at rt to a stirred solution of l-6c (300 mg, 0.94 mmol) and 1-1 1 b (300 mg, 1.46 mmol) in toluene (20 ml_).
  • the reaction mixture was heated by microwave irradiation and stirred at 120 °C for 2 h.
  • the reaction mixture was diluted with water (50 ml_) and extracted with EtOAc (2 x 60 ml_). The combined organic layers were washed with NaHCOs (aq), dried (Na2S0 4 ), filtered and concentrated.

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Abstract

L'invention concerne un composé de formule (I) : dans laquelle, R1, R2 et R3 des séries (x), (y) et (z) sont tels que définis dans la description qui sont des inhibiteurs puissants de l'enzyme MALT1 et sont utiles dans une approche immuno-oncologique pour le traitement du cancer, en particulier du cancer de la vessie, du cancer du côlon, du cancer hépatocellulaire ou du cancer du poumon à petites cellules ou non à petites cellules.
PCT/SE2018/050587 2017-06-05 2018-06-05 Pyrazolopyrimidine utilisés en tant qu'inhibiteurs de malt-1 WO2018226150A1 (fr)

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CN111686111A (zh) * 2020-06-09 2020-09-22 南方医科大学 Malt1蛋白酶抑制剂在制备非小细胞肺癌治疗药物中的应用
WO2020208222A1 (fr) 2019-04-11 2020-10-15 Janssen Pharmaceutica Nv Cycles pyridine contenant des dérivés servant d'inhibiteurs de malt1
WO2021000855A1 (fr) * 2019-07-01 2021-01-07 Qilu Regor Therapeutics Inc. Inhibiteurs de malt1 et leurs utilisations
WO2021134004A1 (fr) * 2019-12-27 2021-07-01 Schrodinger, Inc. Composés cycliques et leurs procédés d'utilisation
WO2021216949A1 (fr) 2020-04-24 2021-10-28 Vanderbilt University Hydropyrroles substitués condensés utilisés en tant qu'antagonistes du récepteur muscarinique m4 de l'acétylcholine
WO2021216951A1 (fr) 2020-04-24 2021-10-28 Vanderbilt University Hydropyrroles substitués condensés en tant qu'antagonistes du récepteur muscarinique m4 de l'acétylcholine
WO2022106857A1 (fr) * 2020-11-23 2022-05-27 Exscientia Limited Modulateurs de malt-1
WO2022164789A1 (fr) * 2021-01-26 2022-08-04 Schrödinger, Inc. Composés tricycliques utiles dans le traitement du cancer, des troubles auto-immuns et des troubles inflammatoires
WO2023051759A1 (fr) * 2021-09-30 2023-04-06 上海拓界生物医药科技有限公司 Composé tricyclique et son procédé de préparation
WO2023139479A1 (fr) * 2022-01-18 2023-07-27 Aurigene Oncology Limited Hétérocycles bicycliques substitués utilisés en tant qu'inhibiteurs de malt-1
WO2023148501A1 (fr) 2022-02-03 2023-08-10 C4X Discovery Limited Dérivés hétérocycliques en tant qu'inhibiteurs de malt1
WO2023192913A1 (fr) 2022-03-31 2023-10-05 Abbvie Inc. Inhibiteurs de thiazolo[5,4-b]pyridine malt-1
WO2023218203A1 (fr) 2022-05-13 2023-11-16 C4X Discovery Limited Dérivés de dihydro-indène en tant qu'inhibiteurs de malt1
US11827640B2 (en) 2020-10-23 2023-11-28 Ildong Pharmaceutical Co., Ltd. Substituted pyrazolo[1,5-a]pyrimidines as CFTR modulators

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WO2017081641A1 (fr) * 2015-11-13 2017-05-18 Novartis Ag Nouveaux dérivés de pyrazolo-pyrimidine
WO2018141749A1 (fr) * 2017-02-01 2018-08-09 Medivir Ab Applications thérapeutiques d'inhibiteurs de malt1

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WO2016061142A1 (fr) * 2014-10-14 2016-04-21 Novartis Ag Molécules d'anticorps de pd-l1 et leurs utilisations
WO2017081641A1 (fr) * 2015-11-13 2017-05-18 Novartis Ag Nouveaux dérivés de pyrazolo-pyrimidine
WO2018141749A1 (fr) * 2017-02-01 2018-08-09 Medivir Ab Applications thérapeutiques d'inhibiteurs de malt1

Cited By (17)

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Publication number Priority date Publication date Assignee Title
WO2020208222A1 (fr) 2019-04-11 2020-10-15 Janssen Pharmaceutica Nv Cycles pyridine contenant des dérivés servant d'inhibiteurs de malt1
CN113677674A (zh) * 2019-04-11 2021-11-19 詹森药业有限公司 含有吡啶环的作为malt1抑制剂的衍生物
WO2021000855A1 (fr) * 2019-07-01 2021-01-07 Qilu Regor Therapeutics Inc. Inhibiteurs de malt1 et leurs utilisations
WO2021134004A1 (fr) * 2019-12-27 2021-07-01 Schrodinger, Inc. Composés cycliques et leurs procédés d'utilisation
CN114945571A (zh) * 2019-12-27 2022-08-26 薛定谔公司 环状化合物及其使用方法
WO2021216949A1 (fr) 2020-04-24 2021-10-28 Vanderbilt University Hydropyrroles substitués condensés utilisés en tant qu'antagonistes du récepteur muscarinique m4 de l'acétylcholine
WO2021216951A1 (fr) 2020-04-24 2021-10-28 Vanderbilt University Hydropyrroles substitués condensés en tant qu'antagonistes du récepteur muscarinique m4 de l'acétylcholine
CN111686111A (zh) * 2020-06-09 2020-09-22 南方医科大学 Malt1蛋白酶抑制剂在制备非小细胞肺癌治疗药物中的应用
US11827640B2 (en) 2020-10-23 2023-11-28 Ildong Pharmaceutical Co., Ltd. Substituted pyrazolo[1,5-a]pyrimidines as CFTR modulators
WO2022106857A1 (fr) * 2020-11-23 2022-05-27 Exscientia Limited Modulateurs de malt-1
WO2022164789A1 (fr) * 2021-01-26 2022-08-04 Schrödinger, Inc. Composés tricycliques utiles dans le traitement du cancer, des troubles auto-immuns et des troubles inflammatoires
WO2023051759A1 (fr) * 2021-09-30 2023-04-06 上海拓界生物医药科技有限公司 Composé tricyclique et son procédé de préparation
WO2023139479A1 (fr) * 2022-01-18 2023-07-27 Aurigene Oncology Limited Hétérocycles bicycliques substitués utilisés en tant qu'inhibiteurs de malt-1
WO2023148501A1 (fr) 2022-02-03 2023-08-10 C4X Discovery Limited Dérivés hétérocycliques en tant qu'inhibiteurs de malt1
WO2023192913A1 (fr) 2022-03-31 2023-10-05 Abbvie Inc. Inhibiteurs de thiazolo[5,4-b]pyridine malt-1
US11993613B2 (en) 2022-03-31 2024-05-28 Abbvie Inc. Thiazolo[5,4-b]pyridine MALT-1 inhibitors
WO2023218203A1 (fr) 2022-05-13 2023-11-16 C4X Discovery Limited Dérivés de dihydro-indène en tant qu'inhibiteurs de malt1

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