WO2018226150A1

WO2018226150A1 - Pyrazolopyrimidine as malt-1 inhibitors

Info

Publication number: WO2018226150A1
Application number: PCT/SE2018/050587
Authority: WO
Inventors: Karolina Ersmark; Sofia KARLSTRÖM; Björn KLASSON; Stina Lundgren; Åsa ROSENQUIST; Lourdes SALVADOR ODÉN
Original assignee: Medivir AB
Current assignee: Medivir AB
Priority date: 2017-06-05
Filing date: 2018-06-05
Publication date: 2018-12-13
Anticipated expiration: 2019-12-05

Abstract

The invention provides a compound of formula (I): herein R¹, R² and R³ of series (x), (y) and (z) are as defined in the specification which are potent inhibitors of the enzyme MALT1 and are useful in an immunooncology approach to the treatment of cancer, especially bladder cancer, colon cancer, hepatocellular cancer or small cell or non-small cell lung cancer.

Description

PYRAZOLOPYRIMIDINE AS MALT-1 INHIBITORS

FIELD OF THE INVENTION

The present invention relates to compounds which are inhibitors of the protease MALT1 and pharmaceutical compositions and combinations thereof, processes for preparing the

compounds and their use in cancer therapy in mammals, including humans.

BACKGROUND TO THE INVENTION

MALT1 (mucosa associated lymphoid tissue lymphoma translocation protein 1) is an

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). The function of MALT1 is best known in the context of T cell receptor (TCR signalling), where it mediates nuclear factor κΒ (N FKB) signalling leading to T cell activation and proliferation. Accordingly 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.

Several groups have identified inhibitors of MALT1 activity as potential therapeutics. Rebaud et al. Nat. Immunol., 2008 9(3), 272-81 describes a warhead-equipped substrate analogue zVRPRfmk, while Lim et al., J. Med. Chem., 2015 58(21), 8591-8502 describes the small molecule MALT1 inhibitor MI2. Nagel et al., Cancer Cell 2012 22(6), 825-37 describes another small molecule inhibitor mepazine. Novartis has published, in international patent applications WO2015/1 181747 and WO2017/081641 , small molecule MALT1 inhibitors believed to interact with an allosteric site on the enzyme. Characteristic for these prior art inhibitors of MALT1 is that the compounds are proposed for autoimmune or inflammatory pathways, or cancers dependent on dysregulated N FKB pathway activity.

SUMMARY OF THE INVENTION

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. In addition to this, the present invention also comprises the appreciation of an activity of MALT1 inhibitors which is

independent of the direct inhibition of dysregulated N FKB pathway activity in tumour cells. It is rather a function of the effect on various components of the immune system of inhibiting MALT1.

In other words, in addition to MALT1 inhibitors acting directly on the tumour tissue, the present invention envisages that the site of MALT1 action is within specified T cell populations of a subject. This appreciation dramatically expands the range of cancers for which administration of a MALT1 inhibitor is desirable, because a MALT1 inhibitor can now additionally be used as an immunomodulatory agent to activate or augment the T cell anti-cancer response in a subject, irrespective of whether the cancer has dysregulated N FKB pathway activity.

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

dysregulated N FKB pathway activation within the cancer cells. 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:

(i) 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; and/or

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; and/or

(iii) a composition comprising a tumour antigen or immunogenic fragment thereof.

DESCRIPTION OF THE INVENTION

In accordance with the invention, there is provided compounds of the formula (I)

wherein

(x) R¹ is R^1a R² is R^2a and R³ is R^3a; or

(y) R¹ is R^1a, R² is R^2b and R³ is R^3b; or

(z) R¹ is R^{1 b}, R² is R^2b and R³ is R^3a, R^1a is H, halo, cyano, Ci-dalkyl, haloCi-dalkyl, d-dalkoxy, halod-dalkoxy or amino; R^{1 b} is H, d-Csalkoxy, halod-C₃alkoxy, S(=0)(=NRa)NH₂, S(=0)₂NH₂ or amino;

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; wherein

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;

the 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-C₆alkyl, Ci-C₆alkoxy, C₃-C₆cycloalkyl, haloCi-C₆alkyl, Het, HetCi-C₆alkyl, 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;

the 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;

Het for the purposes of 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 R¹³;

each R¹³ 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 R¹³;

each R¹³ 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;

or a pharmaceutically acceptable salt thereof;

wherein 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;

and the following definitions apply:

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. In certain embodiments R^1a or R^{1 b} are other than amino.

A first aspect the invention provides a com ound of series (x):

R¹ is H, halo, cyano, Ci-dalkyl, halod-dalkyl, d-dalkoxy or halod-dalkoxy;

R² 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; wherein

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; wherein

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

substituents each independently selected NRaRb and oxo;

R³ is phenyl, d-dcycloalkyl, heterocyclyl or heteroaryl, any of which is optionally substituted with one, two or three R¹³;

each R¹³ 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,

heterocycloxy, heteroaryl, wherein

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;

or a pharmaceutically acceptable salt and/or solvate thereof.

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. In one embodiment a compound of the invention is provided in the form of a pharmaceutically acceptable salt. In another embodiment a compound of the invention is provided in the form of a pharmaceutically acceptable solvate. In another embodiment a compound of the invention is provided in its free form.

In one embodiment of the invention, R¹ is halo, d-Csalkyl or halod-Csalkoxy, such as chloro, fluoro, methyl, difluoromethoxy or trifluoromethoxy. Typically according to this embodiment R¹ is chloro or methyl. In one embodiment of the invention R² is haloCi-Cealkoxy, CycAlk, CycAlkCi-CsalkyI or a 5 or 6 membered heteroaryl, wherein

the 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.

Representative values for R² according to this embodiment, are haloCi-Cealkoxy, CycAlk, thiazolyl and pyridinyl, wherein pyridinyl or CycAlk is substituted with one or two halo, haloCr Csalkyl or haloCi-Csalkoxy.

Typically according to this embodiment, R² is C3-C4cycloalkyl which is substituted with trifluoromethyl or with one or two halo. For example, R² is cyclopropyl which is substituted with trifluoromethyl or with one or two halo.

A representative configuration of CycAlk according to this embodiment is cyclopropyl which is substituted with chloro or fluoro, preferably cyclopropyl substituted with fluoro.

In a further representative configuration according to this embodiment CycAlk is cyclopropyl which is substituted with trifluoromethyl, thus providing a compound having the formula (II):

A favoured group of R² embodiments comprises the above depicted 1-(CF3)-cycloprop-1-yl or - CH(CH₃)-0-CHF₂.

In one embodiment of the invention R² is thiazolyl or isothiazolyl, preferably thiazolyl. In a further embodiment of the invention R² is a 5- or 6-membered heteroaryl which is substituted with halo, haloalkyl or haloalkoxy.

A typical configuration for R² according to this embodiment is pyridinyl which is substituted with fluoro, chloro or trifluoromethyl, such as pyridinyl substituted with fluoro. In one embodiment of the invention R² is halod-Cealkyl which is substituted with NRaRb. Typically according to this embodiment, one of Ra and Rb is H and the other is H or Me.

Typically, both Ra and Rb are H.

In one embodiment of the invention, R³ is pyridinyl, pyridazinyl or pyrimidinyl any of which is optionally substituted with one, two or three R¹³;

each R¹³ 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.

In one embodiment R³ is pyridinyl which is substituted with one or two R¹³;

each R¹³ 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 R³ according to this embodiment is pyridinyl which is substituted with chloro and triazolyl.

A further representative configuration for R³ according to this embodiment is pyridinyl which is substituted with chloro and pyrazolyl, wherein pyrazolyl is substituted with aminomethyl.

In one embodiment R³ is pyridinyl which is substituted with Ci-dalkyl or d-dhaloalkyl, typically methyl or trifluoromethyl. In one embodiment of the invention, R³ is optionally substituted 2-pyridinyl.

In an alternative embodiment of the invention, R³ is optionally substituted 3-pyridinyl.

In a further alternative embodiment of the invention, R³ is optionally substituted 4-pyridinyl.

In one embodiment of the invention, R³ is optionally substituted pyridazinyl. In an alternative embodiment of the invention, R³ is optionally substituted pyrimidinyl.

In one embodiment of the invention,

R¹ is chloro or methyl;

R² is cyclopropyl which is substituted with trifluoromethyl, thiazolyl or pyridinyl which is substituted with fluoro;

R³ 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.

In one embodiment of the invention,

R¹ is chloro or methyl;

R³ is pyridazinyl which is optionally substituted with one or two substituents each independently selected from chloro, trifluoromethyl, difluoromethoxy, trifluoromethoxy.

In one embodiment of the invention, R³ is optionally substituted 3-pyridinyl, thus providing compounds of the general fo

(III)

wherein R¹ , R² and R¹³ are as defined for compounds of formula (I).

In a representative configuration of this embodiment, 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.

and pharmaceutically acceptable salts thereof.

In a second aspect the invention provides a com ound of formula (ly):

R¹ is H, halo, cyano, d-Csalkyl, haloCi-CsalkyI, Ci-Csalkoxy or haloCi-Csalkoxy;

R² is Ci-C₆alkyl, Ci-C₆alkoxy, C₃-C₆cycloalkyl, haloCi-C₆alkyl, Het, HetCi-C₆alkyl, 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, 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;

R³ is pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolo[1 ,5-a]pyrimidine, thiazolyl or pyrazolyl any of which is optionally substituted with one, two or three R¹³;

each R¹³ 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-

Csalkyl, heterocycloxy, heteroaryl, wherein

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; wherein

d-dalkyl is optionally substituted with NRaRb;

or a pharmaceutically acceptable salt and/or solvate thereof.

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. In one embodiment a compound of the invention is provided in the form of a pharmaceutically acceptable salt. In another embodiment a compound of the invention is provided in the form of a pharmaceutically acceptable solvate. In another embodiment a compound of the invention is provided in its free form.

In one embodiment of the invention, R¹ is halo, d-dalkyl or halod-dalkoxy, such as chloro, fluoro or methyl. Typically according to this embodiment R¹ is chloro.

In one embodiment of the invention R² 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 R² according to this embodiment, are Ci-dsalkyl, which is optionally substituted with one or two d-dsalkoxy, Ci-C6alkoxyCi-C6alkoxy or haloCi-Cealkyl.

Typically according to this embodiment, R² is 2,2,2-trifluoroethyl, Ci-C6alkyl or Ci-C6alkyl which is substituted with one or two methoxy.

In a further typical configuration of compounds of the invention, R² 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:

Typically, the configuration at the asteriskt chiral centre of compounds of formula (la) is as shown in formula (la*):

In one embodiment of the invention R² 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. In a further embodiment of the invention R² 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.

In a representative embodiment of the invention, R³ is pyridazinyl or pyrimidinyl any of which is optionally substituted with one, two or three R¹³;

Representative values for R¹³ 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.

In one embodiment, each of the one, two or three R¹³ is independently selected from fluoro, chloro, difluoromethyl, trifluoromethyl, triazolyl and pyrazolyl; wherein

triazolyl and pyrazolyl are optionally substituted with aminomethyl.

In a further embodiment, R³ is pyridazinyl which is substituted with fluoro, chloro, cyano, methyl, difluoromethyl or trifluoromethyl.

In a further embodiment, R³ is pyridazinyl which is substituted with one or two substituents each independently selected from pyrazolyl and triazolyl, wherein pyrazolyl is optionally substituted with aminomethyl.

In one embodiment, R³ is pyridazin-4-yl which is optionally substituted with one, two or three R¹³, thus providing compound

wherein R¹ , R² and R¹³ are as defined for compounds of formula (I).

In a representative configuration of this embodiment, 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. In a representative embodiment of compounds of the invention, R³ is pyridazin-4-yl which is substituted in the 6-position with fluoro, chloro, cyano, methyl, difluoromethyl or trifluoromethyl.

In certain embodiments, R³ is other than thiazolyl or pyrazolyl.

In one embodiment, R³ is pyrazolo[1 ,5-a]pyrimidine which is optionally substituted with one, two or three R¹³. In a typical configuration of compounds according to this embodiment, the pyrazolo[1 ,5-a]pyrimidine is linked to the urea nitrogen in the 6-position, thus providing compounds of the general

(Ill)

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. In one embodiment R³ is pyrazolyl or thiazolyl, either of which is optionally substituted with fluoro, cyano, methyl, difluoromethyl or trifluoromethyl.

In one embodiment of the invention,

R¹ is fluoro, chloro or methyl;

R² is Ci-C6alkyl which is optionally substituted with one or two d-Csalkoxy;

R³ 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. In one embodiment of the invention,

R¹ is chloro or methyl;

R² is Ci-C6alkyl which is substituted with one or two methoxy;

R³ 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. In one embodiment of the invention,

R¹ is chloro or methyl;

R² is Ci-C3alkyl which is substituted with methoxy;

R³ is pyridazinyl which is optionally substituted with one or two substituents each independently selected from fluoro, chloro, cyano, methyl, difluoromethyl, trifluoromethyl.

In one embodiment of the invention,

R¹ is chloro or methyl;

R² is Ci-C6alkyl which is substituted with one or two methoxy;

R³ is pyridazin-4-yl which is optionally substituted with one or two substituents each

independently selected from fluoro, chloro, cyano, methyl, difluoromethyl or trifluoromethyl.

In one embodiment of the invention,

R¹ is chloro or methyl;

R² is Ci-C6alkyl which is substituted with one or two methoxy;

R³ is pyridazin-4-yl which is optionally substituted in the 6-position with fluoro, chloro, cyano, methyl, difluoromethyl or trifluoromethyl.

In a further aspect, the invention provides compounds of series (z) within formula (I):

R¹ is H, Ci-C₃alkoxy, haloCi-C₃alkoxy, S(=0)(=NRa)NH₂, S(=0)₂NHRa or amino;

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;

the 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;

R³ is phenyl, C3-C7cycloalkyl, heterocyclyl or heteroaryl, any of which is optionally substituted with one, two or three R¹³;

each R¹³ 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-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-C₃alkyl;

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;

with the proviso that R³ is not optionally substituted pyrimidinyl, pyridazinyl, pyrazinyl or pyrazolo[1 ,5-a]pyrimidinyl;

or a pharmaceutically acceptable salt and/or solvate thereof;

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. In one embodiment a compound of the invention is provided in the form of a pharmaceutically acceptable salt. In another embodiment a compound of the invention is provided in the form of a pharmaceutically acceptable solvate. In another embodiment a compound of the invention is provided in its free form. In one embodiment of the invention, R¹ is H, methoxy, difluoromethoxy or trifluoromethoxy. In a typical embodiment of the invention, R¹ is H.

In a further typical embodiment of the invention, R¹ is difluoromethoxy or trifluoromethoxy.

In certain embodiments, R¹ is other than amino.

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-

Csalkoxyd-Csalkyl or NRaRb.

Typically, Ra and Rb according to this embodiment are independently selected from H and d-dalkyl such as methyl. Representative values for R² according to this embodiment are Ci-dsalkyl which is optionally substituted with one or two d-dsalkoxy, Ci-C6alkoxyCi-C6alkoxy or NRaRb.

In a further typical configuration according to this embodiment, R² is Ci-C6alkyl or C3- dscycloalkyl any of which is substituted with NRaRb, wherein Ra and Rb are each

independently selected from H and Ci-dalkyl, Typically one of Ra and Rb is Me and the other is H or Me.

In a further typical configuration of compounds of the invention, R² is Ci-dsalkyl, for instance methyl, ethyl or isopropyl, typically isopropyl. In a further typical configuration of compounds of the invention, R² is Ci-C6alkyl which is substituted with one or two methoxy, representative configurations are 2-methoxyethyl and 1 ,2- dimethoxypropyl ly:

Typically, the configuration at the asteriskt chiral centre of compounds of formula la is as shown in formula la*:

In one embodiment of the invention R² 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.

In a further embodiment of the invention R² 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.

In a further embodiment of the invention R² 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.

In one embodiment of the invention, R³ is phenyl which is optionally substituted with one, two or three R¹³;

Representative values for R¹³ 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.

triazolyl and pyrazolyl are optionally substituted with aminomethyl.

In one embodiment of the invention, R³ is pyridinyl which is optionally substituted with one, two or three R¹³;

each R¹³ is independently selected from halo, cyano, Ci-dsalkyl, haloCi-Cealkyl, d- dsalkoxy, d-Cehaloalkoxy and a 5- or 6-membered heteroaryl, wherein

In one embodiment R³ is pyridinyl which is substituted with one or two R¹³; each R¹³ is independently selected from fluoro, chloro, cyano, trifluoromethyl, difluoromethoxy, trifluoromethoxy, d-Csalkyl, triazolyl and pyrazolyl, wherein

triazolyl and pyrazolyl are optionally substituted with aminomethyl. In one embodiment R³ is pyridinyl which is substituted with Ci-C3alkyl or d-Cshaloalkyl, typically methyl or trifluoromethyl.

In a further embodiment R³ is pyridinyl which is substituted with chloro and pyrazolyl, wherein pyrazolyl is substituted with aminomethyl.

A representative configuration for R³ is pyridinyl which is substituted with chloro and triazolyl. In embodiment of the invention, R³ is 2-pyridinyl which is optionally substituted with one, two or three R¹³.

In an alternative embodiment of the invention, R³ is 4-pyridinyl which is optionally substituted with one, two or three R¹³.

In an alternative embodiment of the invention, R³ is 3-pyridinyl which is optionally substituted with one, two or three R¹³ thus providing compounds of the general formula (I I):

(II) wherein R¹ , R² and R¹³ are as defined for compounds of formula (I).

In a representative configuration of this embodiment, the pyridin-3-yl is substituted with one or two R¹³ each independently selected from methyl, chloro and a 5-membered heteroaryl which is optionally substituted with aminomethyl.

In one embodiment, R³ 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

In a further representative embodiment of the invention, R³ is pyridinyl which is substituted with chloro and triazolyl. Typically according to this embodiment, R³ is pyridin-4-yl which is substituted with chloro in the 5-position and triazolyl in the 6-position.

In certain embodiments of the invention,

In one embodiment of the invention,

R¹ is H, Ci-C3alkoxy or halod-Csalkoxy;

R² is Ci-C6alkyl or C3-C6cycloalkyl any of which is optionally substituted with NRaRb;

R³ 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.

In one embodiment of the invention,

R¹ is H, Ci-C3alkoxy or halod-Csalkoxy;

R² is Ci-C6alkyl which is substituted with one or two methoxy;

R³ 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.

In one embodiment of the invention,

R¹ is H, difluoromethoxy or trifluoromethoxy;

R² is Ci-C₆alkyl;

R³ 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.

In one embodiment of the invention,

R¹ is H, Ci-C3alkoxy or haloCi-Csalkoxy;

R² is Ci-C6alkyl or C3-C6cycloalkyl any of which is substituted with one or two methoxy or with NRaRb;

R³ 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,

R¹ is H, difluoromethoxy or trifluoromethoxy;

R² is Ci-C6alkyl or C3-C4cycloalkyl any which is substituted with NRaRb; R³ 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

or pharmaceutically acceptable salts and diastereomers thereof.

In an aspect, 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

a) Fox P3 positive T-regulatory (T_reg) lymphocytes, and

b) CD4+ and CD8+ T-effector (T_efr) 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. In this embodiment, the tumoural tissue is preferably characterized by infiltration of

a) Fox P3 positive T_reg lymphocytes, and

b) CD4+ and CD8+ Tetr lymphocytes. Accordingly, the invention provides a compound of formula (I) or any subgroup thereof for use in the treatment of cancer. In an additional aspect, 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.

Further according to this aspect, the invention provides a pharmaceutical composition for use in the treatment of cancer.

Especially according to this aspect, 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.

In an additional aspect, 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. In one embodiment of this aspect, the further therapeutic agent is a chemotherapeutical agent.

In one embodiment of this aspect, the immuno-oncology agent is selected from antibodies, cytokine therapy, adoptive T-cell therapy and immunostimulatory polysaccharides.

Typically, the antibody according to this embodiment is a check point inhibitor.

In an additional aspect, 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.

In an additional aspect, the invention provides a method for the treatment of cancer comprising the administration of a compound of formula (I) or any subgroup thereof.

IMMUNE SYSTEM INVOLVEMENT IN CANCER

Accumulating evidence shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and favourable prognosis in various malignancies. In particular, the presence of CD8+ T- cells and a high ratio of CD8+ T_eff cells compared to FoxP3+ T_reg cells correlates with improved prognosis and long-term survival in solid cancers, e.g. colorectal- and ovarian cancer, hepatocellular carcinoma, bladder cancer, malignant melanoma and renal cell carcinoma. Similarly, high levels of infiltrating T_reg have been found to be associated with poor prognosis in a number of cancers, e.g. ovarian carcinoma, breast cancer, cervical and renal carcinoma, and malignant melanoma. Therapies resulting in reduction of T_reg and thereby changing the T_eff/T_reg ratio would therefore be expected to have a positive influence on cancer outcome.

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. In animal studies, 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.

Several FoxP3 recognising antibodies are commercially available, and immunohistochemistry (IHC) or flow cytometry methods are widely available for recognising FoxP3 positive T_reg lymphocytes, and the tumours which they infiltrate. 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.

CD4+ 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.

In embodiments of the third aspect of the invention, the further immuno-oncology treatment regime is selected from antibodies, cytokine therapy, adoptive T-cell therapy and immune- stimulatory polysaccharides. In a favoured embodiment the antibody is a checkpoint inhibitor, such as a PD1 inhibitor, for example BGB-A317, or more preferably nivolumab or pembrolizumab. In another embodiment the checkpoint antibody is a PD-L1 antibody, preferably atezolizemab, avelumab or durvalumab.

In another embodiment 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

In another embodiment the antibody is:

an anti-CD52 antibody such as alemtuzumab;

a CTLA4 antibody such as ipilimumab;

a CD20 antibody such as ofatumumab or rituximab. In a further embodiment of the third aspect of the invention, the cytokine therapy comprises an interferon selected from IFNa, ΙΡΝβ, IFNy and I FNA, or an interleukin, preferably IL-2.

It will thus be appreciated that the method of the invention employing a compound of formula I, as defined above, but excluding the proviso directed to compounds published in CN

103833827, may additionally comprise administering to the cancer patient a further therapeutic agent. The further therapeutic agent may be:

(i) 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; and/or

(ii) 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

(iii) a composition comprising a tumour antigen or immunogenic fragment thereof; and/or

(iv) a chemotherapeutic agent.

It will be appreciated that many conventional immuno-oncology agents for use in the third aspect of the invention, such as those illustrated above, are biologicals requiring intravenous, intraperitoneal or depot administration. In a favoured embodiment of the invention, 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. Where 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 /

intracerebral^ for glioblastoma, astrocytoma or other nerve tissue cancers. The MALT1 inhibitor may change the ratio of T_reg/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_eff cells. The ratio of T_reg/T_eff 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,

In one embodiment of the invention, the compound of the invention is orally administered. In certain forms of cancer it may be preferable to administer the compound of the invention locally, e.g. topically, or intravesically in the case of bladder cancer. Alternatively, as 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. In other embodiments, 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.

In various embodiments of the invention the cancer is selected from

bladder cancer,

colon cancer,

hepatocellular cancer, or

Small Cell or Non-Small Cell lung cancer.

In a further embodiment of the invention, 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). METHODS FOR THE PREVENTION OR TREATMENT OF CANCER

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.

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-κΒ pathway. The cancer may be characterised by the presence of both infiltrating regulatory T cells (T_reg cells) and infiltrating effector T cells (T_efr cells) in the tumour. T_reg cells are typically characterised as FOXP3+. Te_fr 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

bladder cancer,

colon cancer,

hepatocellular cancer, or small cell or non-small cell lung cancer.

In a further embodiment of the invention, 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.

COMBINATIONS

The invention may additionally comprise administering to the subject a further therapeutic agent. The further therapeutic agent may preferably be:

(v) 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; and/or

(vi) 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; and/or

(vii) a composition comprising a tumour antigen or immunogenic fragment thereof; and/or

(viii) a chemotherapeutic agent.

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.

The terms "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

administered by the same route of administration or at the same time.

The term "pharmaceutical combination" as used herein 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. The term "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. The term "non-fixed combination" means that the active ingredients, e.g. a compound of formula (I) and a co-agent, are both

administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the 2 compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of 3 or more active ingredients. In one embodiment, 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. In one embodiment, 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. Optionally, the pharmaceutical composition may comprise a pharmaceutically acceptable excipient.

It will be appreciated that many of the further therapeutic agents used in the methods of the invention may be biologicals requiring intravenous, intraperitoneal or depot administration. In a favoured embodiment the compound of the invention is orally administered and the further therapeutic agent is administered parenterally, for example intravenously, intraperitoneally or as a depot. IMMUNE SYSTEM CHECKPOINT

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. Or it might be indirect, such as the blocking or inhibition of an interaction between a ligand and a cell surface receptor which would otherwise transmit an activatory signal into the effector T cell, or an interaction which promotes the upregulation of an inhibitory molecule or cell, or the depletion by an enzyme of a metabolite required by the effector T cell, or any combination thereof.

Examples of immune system checkpoints include:

a) The interaction between indoleamine 2,3-dioxygenase (ID01) and its substrate;

b) The interaction between PD1 and PDL1 and/or PD1 and PDL2; c) The interaction between CTLA4 and CD86 and/or CTLA4 and CD80; d) The interaction between B7-H3 and/or B7-H4 and their respective ligands; e) The interaction between HVEM and BTLA; f) The interaction between GAL9 and TIM3; g) The interaction between MHC class 1 or II and LAG 3; and h) The interaction between MHC class l or II and KIR i) The interaction between OX40(CD134) and OX40L (CD252) k) The interaction between CD40 and CD40L (CD154)

1) The interaction between 4-1 BB (CD137) and ligands including 4-1 BBL

m) The interaction between GITR and ligands including GITRL

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. By blocking the interaction between PD1 and one or both of its ligands, 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

Another preferred checkpoint for the purposes of the present invention is checkpoint (c), 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. Thus, by blocking the CTLA-4 interaction with the B7 proteins, but not the CD28 interaction with the B7 proteins, one of the normal check points of the immune response may be removed, leading to augmented anti-tumour T cell responses. Therefore 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. Examples of 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.

Other suitable inhibitors include small molecule inhibitors (SMI), which are typically small organic molecules. Preferred inhibitors of ID01 include Epacadostat (INCB24360), Indoximod, GDC-0919 (NLG919) and F001287. Other inhibitors of ID01 include 1-methyltryptophan (1 MT). DIRECT STIMULATION OF IMMUNE EFFECTOR RESPONSES

As used herein, "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, ΙΡΝβ, 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. 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. 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. Alternatively 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). Preferred examples of antibodies of this type include anti-CD20 antibodies such as ofatumumab or rituximab, and anti-CD52 antibodies such as alemtuzumab.

COMPOSITIONS COMPRISING TUMOUR ANTIGENS

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

administered to a subject. The 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. These antigens are recognized and the antigen-expressing cell can be destroyed by cytotoxic T cells. Additionally, 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. Further, 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). Each of these antigens, i.e. melanocyte-specific antigens, cancer-testis antigens and tumour-specific antigens, may elicit autologous cellular and humoral immune responses. 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.

Particularly preferred 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- 1/m, coactosin-like protein, collage XXIII, COX-2, CT-9/BRD6, Cten, cyclin B1 , cyclin D1 , cyp-B, CYPB1 , DAM-10, DAM-6, DEK-CAN, EFTUD2/m, EGFR, ELF2/m, EMMPRIN, EpCam, EphA2, EphA3, ErbB3, ETV6-AML1 , EZH2, FGF-5, FN, Frau-1 , G250, GAGE-1 , GAGE-2, GAGE-3, GAGE-4, GAGE-5, GAGE-6, GAGE7b, GAGE-8, GDEP, GnT-V, gp100, GPC3, GPNMB/m, HAGE, HAST-2, hepsin, Her2/neu, HERV-K-MEL, HLA-A*0201-R17I, HLA-A11/m, HLA-A2/m, HNE, homeobox NKX3.1 , HOM-TES-14/SCP-1 , HOM-TES-85, HPV-E6, HPV-E7, HSP70-2M, HST-2, hTERT, iCE, IGF-1 R, IL-13Ra2, IL-2R, IL-5, immature laminin receptor, kallikrein-2, kallikrein-4, Ki67, KIAA0205, KIAA0205/m, KK-LC-1 , K-Ras/m, LAGE-A1 , LDLR-FUT, MAGE- A1 , MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A6, MAGE-A9, MAGE-A10, MAGE-A12, MAGE- B1 , MAGE-B2, MAGE-B3, MAGE-B4, MAGE-B5, MAGE-B6, MAGE-B10, MAGE-B16, MAGE- B17, MAGE-C1 , MAGE-C2, MAGE-C3, MAGE-D1 , MAGE-D2, MAGE-D4, MAGE-E1 , MAGE- E2, MAGE-F1 , MAGE-H1 , MAGEL2, mammaglobin A, MART-1/melan-A, MART-2, MART-2/m, matrix protein 22, MC1 R, M-CSF, ME1/m, mesothelin, MG50/PXDN, MMP11 , MN/CA IX- antigen, MRP-3, MUC-1 , MUC-2, MUM-1/m, MUM-2/m, MUM-3/m, myosin class l/m, NA88-A, N-acetylglucosaminyltransferase-V, Neo-PAP, Neo-PAP/m, NFYC/m, NGEP, NMP22,

NPM/ALK, N-Ras/m, NSE, NY-ESO-B, NY-ESO-1 , OA1 , OFA-iLRP, OGT, OGT/m, OS-9, OS- 9/m, osteocalcin, osteopontin, p15, p190 minor bcr-abl, p53, p53/m, PAGE-4, PAI-1 , PAI-2, PAP, PART-1 , PATE, PDEF, Pim-1-Kinase, Pin-1 , Pml/PARalpha, POTE, PRAME, PRDX5/m, prostein, proteinase-3, PSA, PSCA, PSGR, PSM, PSMA, PTPRK/m, RAGE-1 , RBAF600/m, RHAMM/CD168, RU1 , RU2, S-100, SAGE, SART-1 , SART-2, SART-3, SCC, SIRT2/m, Sp17, SSX-1 , SSX-2/HOM-MEL-40, SSX-4, STAMP-1 , STEAP-1 , survivin, survivin-2B, SYT-SSX-1 , SYT-SSX-2, TA-90, TAG-72, TARP, TEL-AML1 , TGFbeta, TGFbetaRII, TGM-4, TPI/m, TRAG- 3, TRG, TRP-1 , TRP-2/6b, TRP/INT2, TRP-p8, tyrosinase, UPA, VEGFR1 , VEGFR-2/FLK-1 , and WT1.

Most preferred 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. In a particular embodiment, provided herein is 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. via urethral catheter. In another embodiment, provided herein is 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.

DEFINITIONS

As used in the foregoing and hereinafter, the scientific and technological terms and

nomenclature have the same meaning as commonly understood by a person of ordinary skill in the art, in addition, the following definitions apply unless otherwise noted. The term 'C_m-C_nalkyr as a group or part of a group such as C_m-C_nhaloalkyl, C_m-C_nalkylcarbonyl, Cm-C_nalkylamine, etc. wherein m and n are integers≥ 0, and m < n, denotes a saturated straight or branched chain hydrocarbon radical having the number of carbon atoms indicated, e.g. Ci- C₄alkyl 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.

The term 'C2-C_nalkenyl' 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.

The term 'C2-C_nalkynyl' 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.

The term 'C3-C_ncycloalkyr 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.

The term 'C3-C_n'CycloalkylCm-C_nalkyr denotes a C_m-C_nalkyl radical which is substituted with a d-d cycloalkyl moiety, wherein d-d cycloalkyl and C_m-C_nalkyl are as defined above for d- Cncycloalkyl and C_m-C_nalkyl respectively. Exemplary C3-C_n'CycloalkylC_m-C_nalkyl 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.

The term 'C3-C_ncycloalkenyr as a group or part of a group defines a cyclic hydrocarbon radical having the number of carbon atoms designated and one double bond, e.g. 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.

The term '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. The term 'CycAlkC_m-C_nalkyr denotes a C_m-C_nalkyl radical which is substituted with a CycAlk moiety, wherein CycAlk and C_m-C_nalkyl are as defined above. Exemplary CycAlkC_m-C_nalkyl 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.

The term 'Ci-C_nalkoxy' defines a radical 0-Ci-C_nalkyl wherein Ci-C_nalkyl 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.

The term "Me" means methyl and "MeO" means methoxy.

The term '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_nalkyl 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. In case more than one halogen atom is attached to an alkyl group within the definition of

haloCm-dalkyl, the halogen atoms may be the same or different.

The term 'haloC_n-C_malkoxy' represents a C_n-C_malkoxy 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. Of particular interest is Ci-Cehaloalkoxy. In many cases trifluoromethyl is preferred.

The term Όχο' or '(=0)' represents double bonded oxygen atom, i.e. forms a carbonyl moiety when attached to a carbon atom, a sulphoxide moiety when attached to a sulphur atom and a sulphonyl moiety when two of said terms are attached to the same sulphur atom. It should be noted that an atom can only be substituted with an oxo group when the valency of that atom so permits.

The term 'amino' means NH2.

The terms 'aminoC_m-C_nalkyr and 'amino(C_m-C_nalkyl)2' denotes an amino group wherein one or two of the hydrogen atoms respectively is replaced by C_m-C_nalkyl wherein C_m-C_nalkyl is as defined above and wherein the m and n in the (C_m-C_nalkyl)2 are selected independently of each other. Included are also radicals wherein the two C_m-C_nalkyl groups of the -N(C_m-C_nalkyl)2 together with the nitrogen atom to which they are attached form a saturated 3 to 6 membered cyclic amine such as pyrrolidinyl, piperidinyl, piperazinyl. The term 'amido' as a group or part of a group includes the radicals NHC(=0)H, NH(C=0)C_m- dalkyl, N(C_m-C_nalkyl)(C=0)H and N(Cm-C_nalkyl)(C=0)Cm-C_nalkyl wherein C_m-C_nalkyl is as defined above and wherein the m and n in the (C_m-C_nalkyl)2 are selected independently of each other.

The term 'alkoxyamido' refers to

such as tert.butoxycarbonylamino. The term 'carbamoyl' denotes C(=0)NH₂, C(=0)NHC_m-C_nalkyl, C(=0)N(Cm-C_nalkyl)₂, wherein Cm-C_nalkyl is as defined above and wherein the m and n in the (C_m-C_nalkyl)2 are selected independently of each other. Included are also radicals wherein the two C_m-C_nalkyl groups of C(=0)N(Cm-C_nalkyl)2, together with the nitrogen atom to which they are attached form a saturated 3 to 6 membered cyclic amine such as pyrrolidinyl, piperidinyl, piperazinyl. The term '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 C₄- Cecycloalkenyl. Examples of suitable aryl groups include but are not limited to phenyl, biphenyl, naphthyl, tetrahydronaphthyl, indenyl and indanyl.

The term 'arylCm-C_nalkyl' represents a C_m-C_nalkyl which is substituted with aryl, wherein aryl and Cm-C_nalkyl are as defined above. Preferred arylC_m-C_nalkyl 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. The term 'heterocyclyl', 'heterocyclic' or heterocycle as applied herein 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. Examples of suitable heterocyclyl groups include but are not limited to pyranyl, tetrahydropyranyl,

tetrahydrothiopyranyl, thiopyranyl, furanyl, tetrahydrofuranyl, piperidinyl, piperazinyl,

morpholinyl, pyrazolinyl, pyrazolidinyl, thiazolidinyl, thiadiazolyl, pyrrolinyl, pyrrolidinyl, azetidinyl etc. Unless otherwise indicated the heterocyclyl group is optionally substituted with one, two or three substituents.

The term 'heterocylylC_m-C_nalkyr represents a C_m-C_nalkyl which is substituted with heterocyclyl, wherein heterocyclyl and C_m-C_nalkyl are as defined above. Preferred heterocyclylC_m-C_nalkyl 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.

The term 'heteroaryl' as applied herein means an aromatic heterocyclyl moiety. Examples of 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-1 ,2,4-triazolyl, benzotetrazolyl, benzofuranyl, benzothienyl, benzopyridyl, benzopyrimidinyl, benzopyridazinyl, benzopyrazolyl, indolyl, isoindolyl indolinyl, isoindolinyl, indanyl, pyrrolopyridinyl, pyrazolopyridinyl etc. Unless otherwise indicated the heteroaryl group is optionally substituted with one, two or three substituents.

The term 'heteroarylC_m-C_nalkyr represents a C_m-C_nalkyl which is substituted with heteroaryl, wherein heterocyclyl and C_m-C_nalkyl are as defined above. Preferred heteroarylC_m-C_nalkyl 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.

Typically 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. It should be noted that the 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. For instance 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. For instance, the expression "alkyl group optionally substituted with one or more substituents" means that the alkyl group is substituted by zero, one or more substituents. The term "substituted" refers to a molecule wherein at least one hydrogen atom is replaced with a substituent.

When any variable occurs more than one time in any constituent, each definition is

independent.

As used herein, the terms "salt" or "salts" refers to an acid addition or base addition salt of a compound. "Salts" include in particular "pharmaceutically acceptable salts". The term

"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,

bicarbonate/carbonate, bisulfafe/sulfafe, camphorsulfonate, chloride/hydrochloride,

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,

toluenesulfonic acid, sulfosalicylic acid, and the like. Pharmaceutically acceptable base addition salts 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. In certain embodiments, 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

isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.

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

Pharmaceutical Sciences", 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley- VCH, Weinheim, Germany, 2002).

As used herein, 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. The term "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. In one non-limiting embodiment, 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.

As used herein, "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, teniposide, thioguanine, thiotepa, valrubicin, vinblastine, vincristine, vindesine and vinorelbine. 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).

As used herein, 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

suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

As used herein, 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.

As used herein, a subject is "in need of" a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.

As used herein, the term "a," "an," "the" and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context.

ISOTOPES

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. Examples of isotopes that may be incorporated into the compounds of the invention, include but are not limited to isotopes of hydrogen, such as ²H and ³H (also denoted D for deuterium and T for tritium, respectively), carbon, such as ¹¹C, ¹³C and ¹⁴C, nitrogen, such as ¹³N and ¹⁵N, oxygen, such as ¹⁵0, ¹⁷0 and ¹⁸0, phosphorus, such as ³¹ P and ³²P, fluorine, such as ¹⁸F, chlorine, such as ³⁶CI and bromine such as ⁷⁵Br, ⁷⁶Br, ⁷⁷Br and ⁸²Br. Isotopically labelled compounds include for example those wherein radioactive isotopes, such as ³H and ¹⁴C are present, or those wherein non-radioactive isotopes, such as ²H and ¹³C are present.

The choice of 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 ³H or ¹⁴C is incorporated, will generally be most useful. For radio-imaging applications, for example positron emission tomography (PET) a positron emitting isotope such as ¹¹C, ¹⁸F, ¹³N or ¹⁵0 will be useful. The incorporation of a heavier isotope, such as deuterium, i.e. ²H, 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.

Pharmaceutically acceptable 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

2004/078163,

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. In certain embodiments, 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.

Accordingly, as used herein 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. In particular, 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- Ο,Ο'-ρ-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

chromatography (HPLC) using a chiral stationary phase.

Furthermore, compound of the invention, including their salts, 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. The term "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

pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, and the like. The term "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. In another aspect, 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. In addition, 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). The pharmaceutical 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.

Typically, for oral administration 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.

Suitable 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

pharmaceutical 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. These 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. For example, 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. Certain injectable 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.

Suitable compositions for transdermal application include an effective amount of a compound of the invention with a suitable carrier. Carriers suitable for transdermal delivery include

absorbable pharmacologically acceptable solvents to assist passage through the skin of the host. For example, 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

predetermined rate over a prolonged period of time, and means to secure the device to the skin. Suitable 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. A review is found at Zacche et al, Research and Reports in Urology 2015:7 169-178. A suitable approach is the use of hydrogels as depot formulations on the bladder walls. An example is 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.

Additionally, 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.

Suitable compositions for topical application, e.g., to the skin and eyes, include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, e.g., for delivery by aerosol or the like. Such 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. As used herein 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.

Another embodiment presents 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. Accordingly, 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.

The pharmaceutical 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. Such 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.

GENERAL SYNTHESIS OF COMPOUNDS OF THE INVENTION

Compounds of the present invention and intermediates useful for the synthesis of these compounds may be prepared by a variety of methods and techniques known to those skilled in the art. The general synthetic schemes and preparative examples shown and described below illustrate typical synthetic routes to the compounds of the invention and intermediates to these compounds, but as will be readily apparent to the ordinary skilled organic chemist, alternative routes may also be used for the preparation of the entire compounds or to various portions of the compounds. Starting materials and reagents used are available from commercial suppliers or can be prepared according to literature procedures using methods well known to those skilled in the art.

In the case 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)

Compounds of the invention are typically obtained by preparing a pyrazolopyrimidine moiety carrying the desired groups R¹ and R², and subsequently couple it to an amine R³-NH2. A general route is illustrated in Scheme 1.

Scheme 1

Activation of acid 1A carrying the desired R²-group or a group that subsequently can be transferred to R², for instance by treatment with carbonyl diimidazole (CDI) to provide the corresponding imidazolid, followed by reaction with the dianion of a suitably protected malonate 1 B or similar provides the β-ketoester 1 C. Subsequent condensation with a C1 equivalent, e.g. dimethylformamide-dimethylacetal or triethyl orthoformiate or the like, followed by cyclo- condensation with an aminopyrazole carrying the desired R¹-group in an organic solvent like ethanol or similar typically at elevated temperature provides the substituted pyrazolo-pyrimidine 1 D. In case the acid 1A used in the first step is chiral, and depending on the substitution pattern, partial racemization may occur during the reaction sequence. In this case 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. In the case of 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. reaction with diphenylphosphryl azide (DPPA) in the presence of a base like triethylamine or similar provides the intermediate isocyanate 1 F which then is reacted with the appropriate amine or aniline H2N-R³ to form the compound of formula I.

Compounds of formula I wherein R² is H can be prepared from commercially available protected 2-formyl-3-oxopropanoic acid as illustrated in Scheme 2.

Scheme 2

Reaction of protected 2-formyl-3-oxopropanoic acid e.g. ethyl 2-formyl-3-oxopropanoate with the appropriate aminopyrazole in a solvent like ethanol or similar typically at elevated temperature provides pyrazolo-pyrimidine 2B. Removal of the protecting group, followed by Curtius rearrangement and reaction with the amine or aniline H2N-R³ then provides the compound of formula I.

The synthesis of aminopyrazoles, like 3-amino-5-chloropyrazole can be conducted as described in J. Med. Chem., 2012, 55(7), 3036-3048 and schematically shown in Scheme 3.

Scheme 3

Treatment of 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. R³-amines to be used in the preparation of compounds of formula I wherein R³ is optionally substituted phenyl or pyridinyl can be prepared using the route illustrated in Scheme 4.

4A 4B 4C

Scheme 4

Treatment of an optionally substituted halo e.g. chloro derivative 4A with a protonated nucleophile (R¹³-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 R¹³ 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 R¹³-substituted amine 4C.

Alternatively, R³-amines can be prepared via Curtius rearrangement of the corresponding acid as shown in Scheme 5:

5A 5B 5C

Scheme 5

Treatment of acid 5A with DPPA and a base like triethylamine or similar in t-butanol provides the Boc-protected amino compound 5B. Removal of the Boc group under acidic conditions using e.g. HCI or TFA provides the desired aniline or aminopyridine 5C.

Certain substituted anilines and aminoheteroaryls can be prepared by palladium-catalyzed coupling with a boronic acid derivative of the desired substituent R¹³. The method is illustrated with aniline or aminopyridine in Scheme 6.

6A A is CH or N 6B

Scheme 6

Coupling of halo substituted aniline or aminopyridine with a boronic acid or ester of the desired group R¹³ in the presence of a Pd-catalyst such as PdCl2(PPh3)2 or similar and a base like K2CO3 or the like, typically at elevated temperature provides the diaryl compound 6B.

R³-amines to be used in the preparation of compounds of the invention wherein R¹³ 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.

Scheme 7 Ph₃P

The alkoxy or haloalkoxy substituent R¹³ is typically introduced on the ring R³ by reaction of the corresponding hydroxy compound 7A with the halide of the desired substituent R¹³ effected by treatment with a base such as NaH or potassium carbonate or similar, thus providing alkoxy or haloalkoxy derivative 7B. Alternatively, compound 7B may be obtained by using Mitsunobu conditions, i.e. reaction of the hydroxy compound 7A with the alcohol of the desired substituent R¹³ 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.

In addition to the definitions above, the following abbreviations are used in the synthetic schemes above and the examples below. If an abbreviation used herein is not defined it has its generally accepted meaning.

Bn Benzyl

BOP-CI Bis(2-oxo-3-oxazolidinyl)phosphinic chloride

COMU (1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino- carbenium hexafluorophosphate

DCC Dicyclohexylcarbodiimide

DCM Dichloromethane

DIEA Diisopropylethylamine

DMAP 4-Dimethylaminopyridine

DMF A/,A/-Dimethylformamide

EDAC A/-ethyl-/V-[(3-dimethylamino) propyl] carbodiimide

EtOAc Ethyl acetate

Et₃N Triethylamine

EtOH Ethanol

Et₂0 Diethyl ether

LC Liquid chromatography

HATU 0-(7-Azabenzotrizol-1-yl)-/V, Ν,Ν', Λ/'-tetramethyluronium hexafluorophosphate

HBTU 0-(Benzotriazol-1-yl)-/\/,A/,A/',A/'-tetramethyluronium hexafluorophosphate

HOAc Acetic acid

HOAt 1 -Hydroxy-7-azabenzotriazole HOBt 1 -Hydroxybenzotriazole

HPLC High performance liquid chromatography

MeCN Acetonitrile

MeOH Methanol

on Over night

Pg Protecting group

Ph Phenyl

PyBOP (Benzotriazol-1 -yloxy) tris-(dimethylamino) phosphonium hexafluorophosphate rt Room temperature

THF Tetrahydrofuran

TFA Trifluoroacetic acid

TFAA Trifluoroacetic anhydride

TI PS Triisopropylsilyl

DETAILED DESCRIPTION OF THE EMBODIMENTS

Various embodiments of the compounds invention and intermediates therefore will now be illustrated by the following examples. The Examples are just intended to further illustrate the invention and are by no means limiting the scope of the invention. The compound names were generated by ChemDraw Ultra software, Cambridgesoft, version 12.0.2.

As is well known to a person skilled in the art, reactions 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.

The compounds of the invention including intermediates are prepared as described in the Examples and in the general schemes herein. It will be apparent to a skilled person that analogous synthetic routes may be used, with appropriate modifications, to prepare the compounds of the invention as described herein. The progress of the reactions described herein were followed as appropriate by e.g. LC, GC or TLC, and as the skilled person will readily realise, reaction times and temperatures may be adjusted accordingly.

Intermediate 1

Step a) 3-Chloro-5-nitro-2-(2H-1 ,2,3-triazol-2-yl)pyridine (1-1 a)

Potassium carbonate (14.0 g, 101.35 mmol) was added to solution of 2,3-dichloro-5- nitropyridine (10.0 g, 51.82 mmol) in THF (60 mL) followed by addition of 2H-1 ,2,3-triazole (3.4 mL, 58.7 mmol). The resulting mixture was stirred at rt until reaction was deemed completed as judged by TLC (-16 h), then diluted with water (300 mL). The aqueous layer was extracted with EtOAc (2 x 300 mL), the organic layer was dried over sodium sulphate, filtered and

concentrated under reduced pressure. The crude product was purified by column

chromatography on silica (100-200 mesh), eluted at 20% EtOAc in p. ether which gave the title compound (7.0 g, 60%) as a solid with 99.42% LCMS purity. MS (ES+) 226.03 [M+H]⁺.

Step b) 5-chloro-6-(2H-1 ,2,3-triazol-2-yl)pyridin-3-amine (1-1 b)

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]⁺.

Intermediate 2

HOAc

H HN0₃ . . H

j ' k V^{CI (} ,^AC0)2° anisole N _r. SnCI_o

0 υ₂₂NΝ.-_Ν" γ. _Cο_|ι _ _ΔΔ_→ N ^>yj -^Cl S HCTI

Step a =J step b

0,N

l-2a l-2b Step c

H₂N _{| 2c} Step d , |-2d, R .- H

b^teP ^e |-2e, R = H

Step a) 5-Chloro-1-nitro-1 H-pyrazole (l-2a)

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. Progress of the reaction was monitored by TLC and LCMS and when starting material was deemed completely consumed (after 4h), the reaction mixture was poured into ice-water (70 mL) and basified with Na2C03 (60 g) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with aqueous saturated sodium bicarbonate (100 mL) and brine (50 mL), dried over Na2S0₄ and concentrated. The afforded solid was washed with n-pentane which gave the title compound (7.0 g, 6.2%) as a solid. MS (ES+) 147.93 [M+H]⁺.

Step b) 5-Chloro-3-nitro-1 H-pyrazole (l-2b)

Compound l-2a (7.0 g, 47.4 mmol) was dissolved in anisole (150 ml) in a steal bomb. The vessel was sealed and the mixture heated at 140 °C. The progress of the reaction was monitored by TLC and stopped after 16 h even though starting material was not completely consumed. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by column chromatography on silica gel (100-200 mesh) eluted with 20% EtOAc in p.ether which gave the title compound (4.0 g, 56 %) as a solid. MS (ES-) 145.99 [M-H]^"

Step c) 5-Chloro-1 H-pyrazol-3-amine (l-2c)

Aqueous HCI (16.8 mL, 544 mmol) was added over a period of 10 min to a solution of compound l-2b (4.0 g, 27.1 mmol) in MeOH (200 mL). The reaction mixture was cooled to 0 °C and tin(ll) chloride (30.0 g, 158 mmol) was added portion wise and the resulting reaction mixture was stirred at rt. The progress of the reaction was monitored by TLC and after 16 h, when starting material was deemed consumed, the solvent was evaporated. The residue was diluted with EtOAc (100 mL) and 30% aqueous NaOH solution (120 mL) was added dropwise at 0 °C until basic pH, then stirred at 0 °C for 2h. Solid precipitates were filtered off through a pad of Celite and the cake was rinsed with EtOAc (50 mL) and water (50 mL). The organic phase was separated and the aqueous phase was extracted with EtOAc (50 mL). The combined organic layers were washed with brine (50 mL), dried (Na2S0₄), filtered and concentrated under vacuum which gave the title compound (3.5 g, 93 %). The compound was used in next step without further purification. MS (ES+) 1 18.04 [M+H]⁺. Step d) Ethyl 2-chloropyrazolo[1 ,5-alpyrimidine-6-carboxylate (l-2d)

l-2c (1.10 g, 9.36 mmol) was added at rt to a stirred solution of ethyl 2-formyl-3-oxopropanoate (1.30 g, 9.02 mmol) in EtOH (15 mL). The resulting solution was heated at 80 °C for 2 h under nitrogen, then cooled to rt. The formed solid was isolated by filtration and dried under vacuum, which gave the title compound (1.40 g, 67%). LCMS (ES+) M/z = 226.12 [M+H]⁺. The compound was used in the next step without further purification.

Step e) 2-Chloropyrazolo[1 ,5-alpyrimidine-6-carboxylic acid (l-2e)

To a stirred solution of l-2d (0.3 g, 1.29 mmol) in THF (2 mL) & MeOH (5 mL) was added LiOH'hbO (0.110 g, 2.62 mmol) in water (2 mL). The resulting solution was stirred at rt for 2 h, then concentrated under reduced pressure. A solution of citric acid was added until pH 2-3 and the mixture was extracted with 10% MeOH in DCM (2 x 40 mL). The organic layer was washed with brine (20 mL), dried (Na2S0₄), filtered and concentrated under reduced pressure which gave the title compound (170 mg, 64%) as a solid. LCMS (ES+) M/z = 198.02 [M+H]⁺. The compound was used as such without further purification.

Intermediate 3

⁺ FV _F ^Ap OH — Step a

l-3a l-3b

Step a) 3-Chloro-2-(difluoromethoxy)-5-nitropyridine (l-3a)

Sodium hydride (60%, 4.3 g, 0.1 1 mol) was added portion wise at rt under nitrogen to a stirred solution of 3-chloro-5-nitropyridin-2-ol (7.0 g, 40.1 mmol) in acetonitrile (700 mL). After 10 min 2,2-difluoro-2-(fluorosulfonyl)acetic acid (12.5 g, 70.2 mmol) was added and the reaction was stirred for 20 min at rt. The reaction mixture was cooled to 0 °C, ice water (300 mL) was added dropwise and the mixture was extracted with EtOAc (2 x 300 mL). The organic layer was dried (Na2S0₄), filtered and concentrated under reduced pressure. The afforded crude material was purified by column chromatography on silica gel eluted with 10% EtOAc in p. ether. Appropriate fractions were combined and concentrated which gave the title compound (1.9 g, 21 %).

Step b) 5-Chloro-6-(difluoromethoxy)pyridin-3-amine (l-3b)

Fe (4.8 g, 85.95 mmol) was added at rt to a stirred solution of l-2a (1.9 g, 8.46 mmol) in HOAc (27.1 mL, 474 mmol). The resulting reaction mixture was stirred at rt for 3 h, then concentrated under reduced pressure, diluted with DCM (50 mL) and filtered through Celite The filtrate was washed with saturated sodium bicarbonate solution (2 x 50 mL), dried (Na2S0₄), filtered and concentrated which gave the title compound (1.4 g, 83%) as a solid. LCMS (ES+) m/z 195.08 [M+H]⁺.

Intermediate 4

Step a) Ethyl 2-methylpyrazolo[1 ,5-alpyrimidine-6-carboxylate (l-4a)

3-Methyl-1 H-pyrazol-5-amine ( 3.8 g, 35.0 mmol) was added at rt to a stirred solution of ethyl 2- formyl-3-oxopropanoate (5.0 g, 34.7 mmol) in EtOH (50.0 mL). The resulting reaction mixture was stirred at 80 ° C under nitrogen for 2 h. The formed solid was filtered off and dried under vacuum which gave the title compound (4.0 g, 56%) as a solid. LCMS (ES+) M/z 206.25

[M+H]⁺. Step b) 2-Methylpyrazolo[1 ,5-alpyrimidine-6-carboxylic acid (l-4b)

Lithium hydroxide (1.6 g, 39 mmol) was added at rt to a stirred solution of l-4a (4.0 g, 19.5 mmol) in THF (20.0 mL) and water (20.0 mL). The resulting reaction mixture was stirred at rt for 2 h, then concentrated under reduced pressure. The afforded crude was diluted with ice water (50 mL) and acidified with 1 N HCI up to pH 2 and the thus formed solid was filtered off and dried under vacuum which gave the title compound (3.0 g, 85.96%) as a solid. LCMS (ES+) M/z =

178.07 [M+H]⁺. Intermediat

Step a) tert-butyl ((1-(3-chloro-5-nitropyridin-2-yl)-1 H-pyrazol-4-yl)methyl)carbamate (l-5a) To solution of 2,3-dichloro-5-nitropyridine (400 mg, 2.07 mmol) in DMF (10 mL) was added potassium carbonate (350 mg, 2.53 mmol) followed by tert-butyl ((1 H-pyrazol-4- yl)methyl)carbamate (410 mg, 2.08 mmol), the resulting mixture was stirred at room

temperature for 6 h, then diluted with Water (20 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column

chromatography on silica gel eluted with 10-20% EtOAc in p. ether which gave the title compound (520 mg, 66% yield) a solid. MS (ES+) 354.10 [M+H]⁺.

Step b) tert-butyl ((1-(5-amino-3-chloropyridin-2-yl)-1 H-pyrazol-4-yl)methyl)carbamate (l-5b) Iron powder (410 mg, 7.34 mmol) was added portion-wise at room temperature to a solution of compound 1 b (520 mg, 1.47 mmol) in 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). The combined organic layers were washed with brine (20 mL), dried over Na2S0₄ and concentrated which gave the title compound (450 mg, 85%) as a solid. The compound was used in next step without further purification. MS (ES+) 324.32 [M+H]⁺. Intermediate 6

Step a) Tert-butyl 3-oxo-3-(1-(trifluoromethyl)cyclopropyl)propanoate (l-6a)

Solution A

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.

Solution B

2M Isopropyl magnesium chloride in THF (9.5 ml_, 18.9 mmol) was added drop wise to a solution of 3-tert-butoxy-3-oxopropanoic acid (1.03 g, 6.49 mmol) in THF at 0 °C. 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 complete reaction (1 h). 10% aqueous citric acid (aq) 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 (Na2S0₄), filtered and concentrated under reduced pressure. The obtained crude compound was purified by column chromatography on silica eluted with 5% EtOAc:p. ether which gave the title compound (600 mg, 29%). Step b) Tert-butyl 2-chloro-7-(1-(trifluoromethyl)cyclopropyl)pyrazolo[1 ,5-alpyrimidine-6- carboxylate (l-6b)

Compound l-6a (0.63 g, 2.0 mmol) and DMF-DMA (0.24 g, 1.99 mmol) was heated at 120 °C for 90 min, then cooled to rt and a solution of l-2c (250 mg, 2.0 mmol) in EtOH (2 ml_) was added. The reaction mixture was again heated to 85 °C for 2 h, then concentrated under reduced pressure. The obtained crude material was purified by column chromatography on silica eluting with 0 - 10% EtOAc in p. ether which gave the title compound (230 mg, 31 %) as a solid. LCMS (ES+) m/z 362.35 [M+H]⁺. Step c) 2-Chloro-7-(1-(trifluoromethyl)cvclopropyl)pyrazolo[1 ,5-alpyrirriidine-6-carboxylic acid (I- 6c)

TFA (0.9 ml, 9.4 mmol) at RT under nitrogen was added to a stirred solution of l-6b (180 mg, 0.13 mmol) in DCM . The reaction mixture was stirred at rt for 16 h, then concentrated under reduced pressure, to get light brown colour liquid. Diethyl ether (6 mL) was added to the crude compound and the mixture was concentrated and dried. The crude compound was triturated with diethyl ether (10 mL) which gave the title compound (120 mg, 80%) as a solid. LCMS (ES+) m/z 306.09 [M+H]⁺. Intermediate 7

l-7b, R t.Bu

Step c (

l-7c, R H

Step a) tert-butyl 3-(3-fluoropyridin-4-yl)-3-oxopropanoate (l-7a)

Solution A

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

2M Isopropyl magnesium chloride in THF (30.8 mL, 103 mmol) was added dropwise at 0 °C to a solution of 3-tert-butoxy-3-oxopropanoic acid (5.1 1 g, 31.9 mmol) in THF (40 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, 50 mL) and water (100 mL) was added. The aqueous layer was extracted with EtOAc (2 x 200 mL) and the combined organic layers were washed with saturated sodium bicarbonate solution, dried (Na2S0₄), 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%). LC-MS (ES+) m/z 240.1 [M+H]⁺.

Step b) tert-butyl 7-(3-fluoropyridin-4-yl)-2-methylpyrazolo[1 ,5-alpyrimidine-6-carboxylate (l-7b)

A mixture of l-7a (1.20 g, 5.02 mmol) and 1 , 1-dimethoxy-N,N-dimethylmethanamine (0.598 g, 5.02 mmol) was heated at 120 °C for 90 min, then a solution of 5-methyl-1 H-pyrazol-3-amine (0.487 g, 5.02 mmol) in EtOH (10 mL) was added and the mixture was heated to 85 °C for 1 h The mixture was concentrated under reduced pressure and the obtained crude material was purified by column chromatography on silica gel eluting with 15% EtOAc in p. ether which gave the title compound (450 mg, 25%). LC-MS (ES+) m/z 329.30 [M+H]⁺. Step c) 7-(3-fluoropyridin-4-yl)-2-methylpyrazolo[1 ,5-alpyrimidine-6-carboxylic acid (l-7c)

TFA (0.31 mL, 4.1 mmol) was added at 0 °C to a stirred solution of l-7b (450 mg, 1.37 mmol) in DCM (20 mL). The reaction mixture was stirred at 50 °C for 48 h, then concentrated under reduced pressure. Water and aq. sat. NaHCC>3 was added and the mixture was extracted with EtOAc (2x100 mL). The water layer was acidified with 1 N HCI then extracted with EtOAc (2x100 mL). The combined organic layers were washed with brine, dried (Na2S0₄) and concentrated, which gave the title compound (340 mg, 83%) as a solid. LC-MS (ES+) m/z = 273.21 [M+H]⁺. The compound was used as such without further purification in the next step.

Intermediate 8

Step a) Tert-butyl 3-oxo-3-(thiazol-5-yl)propanoate (l-8a)

Solution A

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.

Solution B

2M Isopropyl magnesium chloride in THF (1 1 mL, 22.6 mmol) was added dropwise at 0 °C to a solution of 3-tert-butoxy-3-oxopropanoic acid (1.24 g, 7.74 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, 50 mL) and water (100 mL) was added. The aqueous layer was extracted with EtOAc (2 x 200 mL) and the combined organic layers were washed with saturated sodium bicarbonate solution, dried (Na2S0₄), filtered and concentrated under reduced pressure. The obtained crude was purified by column chromatography on silica gel eluted with 20% EtOAc in p.ether which gave the title compound (600 mg, 29%). LC-MS (ES+) m/z 228 [M+H]⁺. Step b) Tert-butyl 2-chloro-7-(thiazol-5-yl)pyrazolo[1 ,5-alpyrimidine-6-carboxylate (l-8b)

A mixture of l-8a (2.0 g, 8.36 mmol) and 1 , 1-dimethoxy-N,N-dimethylmethanamine (1.0 g, 8.36 mmol) was heated at 120 °C for 90 min, then a solution of l-2c (1.31 g, 8.36 mmol) in EtOH (10 mL) was added and the mixture was heated to 85 °C for 2 h. The mixture was concentrated under reduced pressure and the obtained crude material was purified by column

chromatography on silica gel eluting with 0 - 10% EtOAc in p. ether which gave the title compound (500 mg, 14%). LC-MS (ES+) m/z 337 [M+H]⁺.

Step c) 2-Chloro-7-(thiazol-5-yl)pyrazolo[1 ,5-alpyrimidine-6-carboxylic acid (l-8c)

TFA (0.45 mL, 5.9 mmol) was added at 0 °C to a stirred solution of l-8b (500 mg, 1.17 mmol) in DCM. The reaction mixture was stirred at rt for 16 h, then concentrated under reduced pressure. The residue was dissolved in water and the pH was adjusted to 3-4 with citric acid whereafter the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2S0₄) and concentrated, which gave the title compound (250 mg, 63%) as a solid. LC- MS (ES+) m/z = 281 [M+H]⁺. The compound was used as such without further purification in the next step.

Intermediate 9

Step a) Tert-butyl 3-((1 R,2R)-2-fluorocvclopropyl)-3-oxopropanoate (l-9a)

Solution A

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

2M Isopropyl magnesium chloride in THF (1 1 mL, 22.6 mmol) was added dropwise at 0 °C to a solution of 3-tert-butoxy-3-oxopropanoic acid (2.77 g, 17.3 mmol) in THF (17 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 (Na2S0₄), 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)

A mixture of l-9a (600 mg, 2.97 mmol) and1 , 1-dimethoxy-N,N-dimethylmethanamine (424 mg, 3.56 mmol) was heated at 120 °C for 90 min, then a solution of l-2c (400 mg, 3.00 mmol) in EtOH (10 ml_) was added and the mixture was heated to 85 °C for 1 h. The reaction mixture was concentrated and the afforded crude compound was purified by column on silica gel eluted with 0 - 20% EtOAc in p. ether, which gave the title compound (0.5 g, 52%) as a solid LCMS (ES+) m/z 312 [M+H]⁺.

Step c) 2-Chloro-7-((1S,2S)-2-fluorocvclopropyl)pyrazolo[1 ,5-alpyrimidine-6-carboxylic acid (I- 9c)

TFA (1.5 ml_, 20.2 mmol) was added to a solution of l-9b (450 mg, 1.44 mmol) in DCM (8 ml_). The mixture was stirred art rt for 16 h, then concentrated. The obtained solid was triturated with n-pentane (2 x 10 ml_) and dried which gave the title compound (365 mg, 70%) as a solid.

LCMS (ES+) m/z 256.1 [M+H]⁺.

Intermediate 10

Step a) tert-butyl 3-(5-fluoropyridin-2-yl)-3-oxopropanoate (1-10a)

The title compound was prepared from 5-fluoropicolinic acid (5 g, 35.44 mmol) using the procedure described for Intermediate 8 step a. Yield 2.0 g, 19%. LCMS (ES-) m/z 237.89 [M-H]^"

Step b) tert-butyl 7-(5-fluoropyridin-2-yl)-2-methylpyrazolo[1 ,5-alpyrimidine-6-carboxylate (1-10b) 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%). LCMS (ES+) m/z 329.3 [M+H]⁺.

Step c) 7-(5-fluoropyridin-2-yl)-2-methylpyrazolo[1 ,5-alpyrimidine-6-carboxylic acid (1-10c)

Compound 1-10b (1.3 g, 3.8 mmol) was treated with TFA (1.45 mL, 19 mmol) as described for Intermediate 9 step c, which gave the title compound (1.04 g, 56%). LCMS (ES+) m/z 273.21 [M+H]⁺.

Intermediate 11

Step a) 3-chloro-5-nitro-2-(1 H-1 ,2,3-triazol-1-yl)pyridine (1-1 1 a)

Potassium carbonate (7.0 g, 50.6 mmol) and 1 H-1 ,2,3-triazole (2.0 g, 29.0 mmol) were added to a stirred solution of 2,3-dichloro-5-nitropyridine (5 g, 25.9 mmol) in THF (30 mL). The resulting mixture was stirred at rt for 16 h, then diluted with water (50 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL) and the combined organic layers were dried (Na2S0₄), filtered and concentrated under reduced pressure. The afforded crude compound was stirred with 10% MeOH in DCM (50 mL) for 20 min, then filleted, which gave the title compound (2.0 g, 32%) as a solid. LCMS (ES+) m/z 226.20 [M+H]. Step b) 5-chloro-6-(1 H-1 ,2,3-triazol-1-yl)pyridin-3-amine (1-1 1 b)

Tin(ll)chloride (8.5 g, 44.8 mmol) was added in portions at rt to a stirred solution of 1-1 1 b (2.0 g, 8.77 mmol) in 3M HCI in MeOH (50 mL). The resulting mixture was stirred at rt for 16 h, then concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL), basified with 1 N aqueous sodium hydroxide (100 mL). The organic layer was dried (Na2S0₄), filtered and concentrated. The crude compound was purified by column chromatography using on silica gel eluted with a gradient of EtOAc : p. ether. Fractions containing the title compound were pooled and concentrated which gave the title compound (400 mg, 22.18%) as a solid. LCMS (ES+) m/z 196.22 [M+H]⁺. Intermediate 12

Step a) 3-methyl-5-nitro-2-(1 H-1 ,2,3-triazol-1-yl)pyridine (1-12a)

K2CO3 (2.02 g, 14.49 mmol) and 2H-1 ,2,3-triazole (480 mg, 6.95 mmol) were added at 0°C to a stirred solution of 2-chloro-3-methyl-5-nitropyridine (1 g, 5.79 mmol) in DMF. The mixture was stirred at rt for 16 h, then poured into the ice water and stirred for 1 h. The obtained solids were filtered, washed with hexane and dried which gave the title compound mixed with inseparable isomers. Step b) 5-methyl-6-(2H-1 ,2,3-triazol-1-yl)pyridin-3-amine (l-12b)

Iron powder (1.62 g, 29.1 mmol) was added in portions at rt to a stirred solution of l-12a

(mixture of isomers)(1.2 g, 5.8 mmol) in acetic acid. The resulting mixture was stirred at rt for 16 h, then concentrated. The residue was dissolved in water and filtered through Celite. The filtrate was basified and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2S04), filtered and concentrated. The obtained crude compound was purified by column chromatography on silica gel and eluted with 30% EtOAc : p. ether which gave the title compound mixed with isomers. LCMS (ES+) m/z 176.24 [M+H]⁺.

Intermediate 13

Step a) (Z)-tert-butyl 3-(dimethylamino)-2-(1-(trifluoromethyl)cvclopropanecarbonyl)acrylate (I- 13a)

Compound l-6a (2 g, 7.93 mmol) and DMF-DMA (1.90 g, 15.86 mmol) were heated at 90 °C for 2 h, then concentrated under reduced pressure which gave the crude title compound (2.45 g, 35%). LCMS (ES+) m/z 308.19 [M+H]⁺. The compound was used in next step without further purification. Step b) tert-butyl 7-(1-(trifluoromethyl)cvclopropyl)pyrazolo[1 ,5-alpyrimidine-6-carboxylate (1-13a) To a stirred solution of 1-13a (1.0 g, 1.90 mmol) in EtOH (10 mL) was added 1 H-pyrazol-3-amine (154 mg, 1.90 mmol) at rt. 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. LCMS (ES+) m/z 328.25 [M+H]⁺.

Step c) 7-(1-(trifluoromethyl)cvclopropyl)pyrazolo[1 ,5-alpyrimidine-6-carboxylic acid (l-13c)

TFA (0.84 mL, 1 1.4 mmol) was added at rt under nitrogen to a stirred solution of 1-13a (400 mg, 1.14 mmol) in DCM (5 mL) at 0 °C. The reaction mixture was stirred at rt for 16 h, then concentrated under reduced pressure. The crude was triturated with diethyl ether (10 mL) followed by n-pentane (10 mL) which gave the title compound (250 mg, 79%) as a solid. LCMS (ES+) m/z 272.16 [M+H]⁺. Intermediate 14

Step a) 5-nitro-2-(2H-1 ,2,3-triazol-2-yl)nicotinonitrile (1-14a)

Potassium carbonate (8.0 g, 59 mmol) was added to a stirred solution of 2-chloro-5- nitronicotinonitrile (5.0 g, 27.24 mmol) in THF (50 mL) followed by addition of 1 H-1 ,2,3-triazole (2.2 g, 31.85 mmol). The resulting mixture was stirred at rt until reaction was deemed completed as judged by TLC (-18 h), then diluted with water (100 mL) and stirred at rt for 10 min. The precipitated solid was filtered, washed with water followed by diethyl ether and dried under vacuum. The crude product was purified by column chromatography on silica (100-200 mesh), eluted with 50% ethyl acetate in pet ether which gave the title compound (3.6 g, 57%) as a solid with 94% LCMS purity. MS (ES+) 217.19 [M+H]⁺.

Step b) 5-amino-2-(2H-1 ,2,3-triazol-2-yl)nicotinonitrile (1-14b)

Iron powder (2.8 g, 50 14 mmol) was added portion-wise at room temperature to a solution of I- 14a (2.4 g, 10 mmol) in acetic acid (75 mL). The resulting mixture was heated to 80 °C for 1 h, then concentrated and the residue was diluted with EtOAc (50 mL) and filtered through the celite bed. The filtrate was washed with NaHCC>3 solution (30 mL) and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (20 mL), dried over Na2S0₄ and concentrated which gave the title compound (700 mg, 29%) as a solid. The compound was used in next step without further purification. MS (ES+) 187.25 [M+H]⁺.

Intermediate 15

Step a) (S)-ethyl 2-(difluoromethoxy)propanoate (1-15a)

Copper (I) iodide (2.0 g, 10.50 mmol) and triethylamine (6.0 mL, 44 mmol) were added to a stirred solution of (S)-ethyl 2-hydroxypropanoate (6.0 g, 50.79 mmol) in acetonitrile (200 mL) at rt in a sealed tube. 2-fluorosulfonyl-2,2-difluoroacetic acid (45.0 g, 252.69 mmol) was added at 50 °C and stirred at 50 °C for 16 h, then concentrated under reduced pressure at 30 °C bath temperature. Water (100 ml_) was added to the residue and extracted with EtOAc (2 x 150 ml_). The combined organic layers were washed with brine, dried (Na2S0₄), filtered and concentrated under reduced pressure at 30 °C bath temperature which gave the title compound (4.0 g) as liquid. The compound was used in next step without further purification.

Step b) (S)-2-(difluoromethoxy)propanoic acid (1-15b)

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 (Na2S0₄), 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.

Step c) (S)-tert-butyl 4-(difluoromethoxy)-3-oxopentanoate (1-15c)

Solution A

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

2M Isopropyl magnesium chloride in THF (30 ml_, 60 mmol) was added drop wise to a solution of 3-tert-butoxy-3-oxopropanoic acid (4.1 g, 25.60 mmol) in THF (60 ml_) at 0 °C. 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 (Na2S0₄), 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 d) (S,Z)-tert-butyl 4-(difluoromethoxy)-2-((dimethylamino)methylene)-3-oxopentanoate (I- 15d)

Compound l-15c (1.5 g, 6.17 mmol) and DMF-DMA (1.0 g, 8.40 mmol) were heated at 120 °C for 90 min, then concentrated under reduced pressure which gave the crude title compound (1.6 g). The compound was used in next step without further purification. Step e) (S)-tert-butyl2-chloro-7-(1-(difluoromethoxy)ethyl)pyrazolo[1 ,5-alpyrirTiidine-6- carboxylate (1-15e)

To a stirred solution of 1-15d (1.6 g, 5.5 mmol) in EtOH (50 mL) was added l-2c (800 mg, 6.70 mmol) at rt. The reaction mixture was heated at 85 °C for 16 h, then concentrated under reduced pressure. The afforded crude was purified by column chromatography on silica gel, eluted with 20% ethyl acetate / pet ether which gave the title compound (900 mg) as a solid with 47% LCMS purity. MS (ES+) m/z 348.30 [M+H]⁺. The compound was used in next step without further purification. Step f) (S)-2-chloro-7-(1-(difluoromethoxy)ethyl)pyrazolo[1 ,5-alpyrimidine-6-carboxylic acid (I- 15f)

TFA (4 mL, 44.80 mmol) was added under nitrogen to a stirred solution of 1-15e (900 mg, 1.22 mmol) in DCM (20 mL) at 0 °C. The reaction mixture was stirred at rt for 6 h, then concentrated under reduced pressure. The crude was triturated with diethyl ether (10 mL) followed by n- pentane (10 mL) which gave the title compound (650 mg) as a solid with 46% LCMS purity. MS (ES+) m/z 292.21 [M+H]⁺. The compound was used in next step without further purification.

Intermediate 16

s_tep b [ l-16a, R = t.Bu

μ ^ 1-16b, R = H

Step a) (S)-tert-butyl 7-(1-(difluoromethoxy)ethyl)pyrazolo[1 ,5-alpyrimidine-6-carboxylate (1-16a) To a stirred solution of 1-15d (1.3 g, 4.43 mmol) in EtOH (40 mL) was added 1 H-pyrazol-3-amine (600 mg, 7.08 mmol) at rt. The reaction mixture was heated at 85 °C for 2 h, then concentrated under reduced pressure. The afforded crude was purified by column chromatography on silica gel, eluted with 20% ethyl acetate / pet ether which gave the title compound (1.2 g) as a solid with 78% LCMS purity.MS (ES+) m/z 314.32 [M+H]⁺. The compound was used in next step without further purification.

Step b) (S)-7-(1-(difluoromethoxy)ethyl)pyrazolo[1 ,5-alpyrimidine-6-carboxylic acid (1-16b)

TFA (6 mL, 67.0 mmol) was added under nitrogen to a stirred solution of l-16a (1.2 g, 3.01 mmol) in DCM (20 mL) at 0 °C. The reaction mixture was stirred at rt for 3 h, then concentrated under reduced pressure. The crude was triturated with diethyl ether (10 mL) followed by n-pentane (10 mL) which gave the title compound (750 mg, 89%) as a solid with 92% LCMS purity.MS (ES+) m/z 258.27 [M+H]⁺. ntermediate 17

Step a) tert-butyl 3-(3-chloro-5-nitropyridin-2-yloxy)pyrrolidine-1-carboxylate (1-17a)

Sodium hydride (100%, 274 mg, 1 1.40 mmol) was added portion wise at 0 °C under nitrogen to a stirred solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1.2 g, 6.21 mmol) in THF (50 mL). After 30 min 2,3-dichloro-5-nitropyridine (1.0 g, 5.2 mmol) was added at 0 °C and the reaction was stirred for 16 h at rt. The reaction mixture was cooled to 0 °C, ice water (300 mL) was added dropwise and the mixture was extracted with EtOAc (2 x 300 mL). The organic layer was dried (Na2S0₄), filtered and concentrated under reduced pressure. The afforded crude material was purified by column chromatography on silica gel, eluted with 20-30% EtOAc in pet ether. Appropriate fractions were combined and concentrated which gave the title compound (1.2 g, 56%) as a solid with 84% LCMS purity.MS (ES+) m/z 344.13 [M+H]⁺.

Step b) tert-butyl 3-(5-amino-3-chloropyridin-2-yloxy)pyrrolidine-1-carboxylate (1-17b)

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 Na2S0₄, filtered and concentrated under reduced pressure. The afforded crude material was purified by column chromatography on silica gel, eluted with 30-50% EtOAc in pet ether. Appropriate fractions were combined and concentrated which gave the title compound (150 mg, 8%) as a solid. The compound was used in next step without further purification. MS (ES+) 314.32 [M+H]⁺.

Intermediate 18

Step a) tert-butyl 2-chloro-7-(1-(trifluoromethyl)cyclopropyl)pyrazolo[1 ,5-alpyrimidin-6- ylcarbamate(l-18a)

DPPA (0.9 mL, 4.00 mmol) and Et₃N (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 (Na2S0₄), filtered and concentrated. The afforded crude was purified by column chromatography on silica gel and eluted with 10-15% EtOAc in pet ether. Fractions containing the desired compound were combined and concentrated which gave the title compound (250 mg, 35%) as a solid. LCMS (ES+) m/z 377.18 [M+H]⁺. Step b) 2-chloro-7-(1-(trifluoromethyl)cyclopropyl)pyrazolo[1 ,5-alpyrimidin-6-amine (1-18b)

TFA (0.67 mL, 9.02 mmol) was added at rt under nitrogen to a stirred solution of compound 1-18a (200 mg, 0.50 mmol) in DCM (2 mL). The mixture was stirred at rt for 5 h, then concentrated under reduced pressure. Diethyl ether (6 mL) was added to the residue and the mixture was concentrated then dried. The crude compound was triturated with diethyl ether (10 mL) and vacuum dried which gave the title compound (120 mg, 94%) as a solid. MS (ES+) 277.15 [M+H]⁺.

Intermediate 19

Step a) (S)-tert-butyl7-(1-(difluoromethoxy)ethyl)-2-methylpyrazolo[1 ,5-alpyrimidine-6- carboxylate (1-19a)

To a stirred solution of 1-15d (1.6 g, 5.50 mmol) in EtOH (50 mL) was added 5-methyl-1 H-pyrazol- 3-amine (650 mg, 6.60 mmol) at rt. The reaction mixture was heated at 85 °C for 16 h, then concentrated under reduced pressure. The afforded crude was purified by column chromatography on silica gel, eluted with 20% ethyl acetate / pet ether which gave the title compound (600 mg, 18%) as a solid with 54% LCMS purity.MS (ES+) m/z 328.33 [M+H]⁺. The compound was used in next step without further purification.

Step b) (S)-7-(1-(difluoromethoxy)ethyl)-2-methylpyrazolo[1 ,5-alpyrimidine-6-carboxylic acid (I- 19b)

TFA (4.0 mL, 45 mmol) was added under nitrogen to a stirred solution of 1-19a (600 mg, 1.00 mmol) in DCM (20 mL) at 0 °C. The reaction mixture was stirred at rt for 6 h, then concentrated under reduced pressure. The crude was triturated with diethyl ether (10 mL) followed by n- pentane (10 mL) which gave the title compound (420 mg, 76%) as a solid with 49% LCMS purity. MS (ES+) m/z 272.28 [M+H]⁺.The compound was used in next step without further purification.

Intermediate 20

i l-20a, R ^ l-20c, R = Boc

Step b I l-20b, R = H Step d ^ I l-20d, R = H

Step a) tert-butyl2-methyl-7-(1-(trifluoromethyl)cvclopropyl)pyrazolo[1 ,5-alpyrimidine-6- carboxylatete (l-20a)

To a stirred solution of 1-13a (5.3 g, 16.60 mmol) in EtOH (50 mL) was added 5-methyl-1 H-pyrazol- 3-amine (2.20 g, 16.60 mmol) at rt. The reaction mixture was heated at 90 °C for 4 h, then concentrated under reduced pressure. The afforded crude was purified by column chromatography on silica gel, eluted with 10% ethyl acetate / pet ether which gave the title compound (3.5 g, 61 %) as a solid. LCMS (ES+) m/z 342.1 1 [M+H]⁺. Step b) 2-methyl-7-(1-(trifluoromethyl)cvclopropyl)pyrazolo[1 ,5-alpyrimidine-6-carboxylic acid (I- 20b)

TFA (18 mL, 198.50 mmol) was added at rt under nitrogen to a stirred solution of l-20a (3.5 g, 10.0 mmol) in DCM (50 mL) at 0 °C. The reaction mixture was stirred at rt for 48 h, then concentrated under reduced pressure. The crude was triturated with diethyl ether (10 mL) followed by n-pentane (10 mL) which gave the title compound (2.2 g, 76%) as a solid. LCMS (ES+) m/z 286.32 [M+H]⁺.

Step c) tert-butyl 2-methyl-7-(1-(trifluoromethyl)cyclopropyl)pyrazolo[1 ,5-alpyrimidin-6- ylcarbamate (l-20c)

DPPA (1.5 mL, 7.00 mmol) and Et₃N (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. The afforded crude was purified by column chromatography on silica gel eluted, with 2% MeOH in DCM. Fractions containing the desired compound were combined and concentrated which gave the title compound (600 mg, 45%) as a solid. LCMS (ES+) m/z 357.34 [M+H]⁺. Step d) 2-methyl-7-(1-(trifluoromethyl)cyclopropyl)pyrazolo[1 ,5-alpyrimidin-6-amine (l-20d)

TFA (2.0 mL, 27.0 mmol) was added at rt under nitrogen to a stirred solution of compound l-20c (500 mg, 1.40 mmol) in DCM (10 mL). The mixture was stirred at rt for 16 h, then concentrated under reduced pressure. The afforded crude was purified by column chromatography on silica gel, eluted with 2% MeOH in DCM. Fractions containing the desired compound were combined and concentrated which gave the title compound (220 mg, 51 %) as a solid. MS (ES+) 257.27 [M+H]⁺.

Intermediate 21

Step a) (2S,4R)-methyl 4-fluoro-1-(4-methoxybenzyl)-5-oxopyrrolidine-2-carboxylate (1-21 a) To a stirred solution of (2S,4R)-methyl 4-fluoro-5-oxopyrrolidine-2-carboxylate (1 g, 5.0 mmol) in acetonitrile (30 mL) was added cesium carbonate (6 g, 18.30 mmol) and stirred at rt for 30 min, then 1-(chloromethyl)-4-methoxy benzene (1 mL, 7.301 mmol) was added and the resulting solution was stirred at 45 °C for 4 h. 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 which gave the title compound (1.5 g) as a solid with 22.74% LCMS purity. MS (ES+) 282.28 [M+H]⁺.The compound was used in next step without further purification.

Step b) (2S,4R)-4-fluoro-1-(4-methoxybenzyl)-5-oxopyrrolidine-2-carboxylic acid (1-21 b)

Lithium hydroxide (0.45 g, 10.70 mmol) was added at rt to a stirred solution of l-21a (1.5 g, 5.33 mmol) in THF (16.0 mL) and water (4.0 mL). The resulting reaction mixture was stirred at rt for 3 h, then concentrated under reduced pressure. The afforded crude was diluted with ice water (50 mL) and acidified with 1 N HCI up to pH 2 and was extracted with EtOAc (2 x 20 mL). The combined organic layer was washed with brine (5 mL), dried (Na2S0₄), filtered and concentrated which gave the title compound which gave the title compound (600 mg, 35%) as a solid. LCMS (ES+) M/z = 268.28 [M+H]⁺.

Step c) tert-butyl 3-((2S,4R)-4-fluoro-1-(4-methoxybenzyl)-5-oxopyrrolidin-2-yl)-3-oxopropanoate (l-21 c)

Solution A

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.

Solution B

2M Isopropyl magnesium chloride in THF (5 mL, 6.5 mmol) was added drop wise to a solution of 3-tert-butoxy-3-oxopropanoic acid (450 mg, 2.81 mmol) in THF (10 mL) at 0 °C. 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 (Na2S0₄), filtered and concentrated under reduced pressure at 30 °C bath temperature, which gave the title compound (700 mg) as liquid. The compound was used in next step without further purification. LCMS (ES+) m/z 366.38 [M+H]⁺.

Step d) (Z)-tert-butyl 3-(dimethylamino)-2-((2S,4R)-4-fluoro-1-(4-methoxybenzyl)-5- oxopyrrolidine-2-carbonyl)acrylate (1-21 d)

Compound l-21c (700 mg, 1.22 mmol) and DMF-DMA (0.7 mL, 5.30 mmol) were heated at 120 °C for 30 min, then concentrated under reduced pressure which gave the crude title compound (700 mg). LCMS (ES+) m/z 421.42 [M+H]⁺. The compound was used in next step without further purification.

Step e) tert-butyl 7-((2S,4R)-4-fluoro-1-(4-methoxybenzyl)-5-oxopyrrolidin-2-yl)-2- methylpyrazolo[1 ,5-alpyrimidine-6-carboxylate (1-21 e)

To a stirred solution of 1-21 d (700 mg, 1.04 mmol) in EtOH (20 mL) was added 5-methyl-1 H- pyrazol-3-amine (150 mg, 1.54 mmol) at rt. The reaction mixture was heated at 80 °C for 90 min, 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 (450 mg, 90%) as a solid. LCMS (ES+) m/z 455.26 [M+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)

TFA (1.5 mL, 16.80 mmol) was added at rt under nitrogen to a stirred solution of compound l-21e (450 mg, 1.00 mmol) in DCM (20 mL). The mixture was stirred at rt for 16 h, then concentrated under reduced pressure. The afforded crude was purified by column chromatography on silica gel, eluted with 2% MeOH in DCM. Fractions containing the desired compound were combined and concentrated which gave the title compound (325 mg, 80%) as a solid. MS (ES+) 399.19 [M+H]⁺. Intermediate 22

p Step c |._{22Ci R = H}

Step a) tert-butyl 3-((1 R,2S)-2-fluorocvclopropyl)-3-oxopropanoate (l-22a)

Solution A

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

2M Isopropyl magnesium chloride in THF (19.6 mL, 39.2 mmol) was added dropwise at 0 °C to a solution of 3-tert-butoxy-3-oxopropanoic acid (3.23 g, 20.5 mmol) in THF (40 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 (Na2S0₄), 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.

Step b) tert-butyl 2-chloro-7-((1 R,2S)-2-fluorocvclopropyl)pyrazolo[1 ,5-alpyrimidine-6- carboxylate (l-22b)

A mixture of l-22a (700 mg, 3.50 mmol) and1 , 1-dimethoxy-N,N-dimethylmethanamine (500 mg, 4.20 mmol) was heated at 120 °C for 90 min, then a solution of l-2c (430 mg, 3.50 mmol) in EtOH (10 mL) was added and the mixture was heated to 85 °C for 1 h. The reaction mixture was concentrated and the afforded crude compound was purified by column on silica gel, eluted with 0 - 20% EtOAc in p. ether, which gave the title compound (500 mg, 44%) as a solid LCMS (ES+) m/z 312.20 [M+H]⁺.

Step c) 2-chloro-7-((1 R,2S)-2-fluorocvclopropyl)pyrazolo[1 ,5-alpyrimidine-6-carboxylic acid (I- 22c)

TFA (2.0 mL, 27 mmol) was added to a solution of l-22b (500 mg, 1.60 mmol) in DCM (8 mL). The mixture was stirred art rt for 16 h, then concentrated. The obtained solid was triturated with n-pentane (2 x 10 mL) and dried which gave the title compound (350 mg, 56%) as a solid.

LCMS (ES+) m/z 256.10 [M+H]⁺.

Intermediate 23

Step a) methyl 1-(difluoromethoxy)cvclopropanecarboxylate (l-23a)

Copper (I) iodide (650 mg, 3.41 mmol) and triethylamine (3.0 mL, 22 mmol) were added to a stirred solution of methyl 1-hydroxycyclopropanecarboxylate (2.0 g, 17.22 mmol) in acetonitrile (60 mL) at rt in a sealed tube. The reaction mixture was heated to 50 °C and 2-fluorosulfonyl-2,2- difluoroacetic acid (15.0 g, 84.23 mmol) was added and stirred at 50 °C at 18 h, then concentrated under reduced pressure at 30 °C bath temperature. To the residue water (100 mL) was added and extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with brine, dried (Na2S04), filtered and concentrated under reduced pressure at 30 °C bath temperature which gave the title compound (1.1 g) as liquid. The compound was used in next step without further purification.

Step b) 1-(difluoromethoxy)cvclopropanecarboxylic acid (l-23b)

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 (Na2S0₄), 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.

Step c) tert-butyl 3-(1-(difluoromethoxy)cvclopropyl)-3-oxopropanoate (l-23c)

Solution A

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.

Solution B

2M Isopropyl magnesium chloride in THF (8 ml_, 16 mmol) was added drop wise to a solution of 3-tert-butoxy-3-oxopropanoic acid (1.0 g, 6.24 mmol) in THF (25 ml_) at 0 °C. 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 (2 h). 10% aqueous citric acid (aq) 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 (Na2S0₄), filtered and concentrated under reduced pressure at 30 °C bath temperature, which gave the title compound (600 mg. 43%) as liquid. MS (ES+) m/z 251.16 [M+H

Step d) (Z)-tert-butyl 2-(1-(difluoromethoxy)cvclopropanecarbonyl)-3-(dimethylamino)acrylate (I- 23d)

Compound l-23c (550 mg, 2.10 mmol) and DMF-DMA (1.0 g, 8.40 mmol) were heated at 120 °C for 90 min, then concentrated under reduced pressure which gave the title compound (750 mg) with 65% LCMS purity.MS (ES+) m/z 306.33 [M+H]⁺. The compound was used in next step without further purification.

Stepe)tert-butyl2-chloro-7-(1-(difluoromethoxy)cvclopropyl)pyrazolo[1 ,5-alpyrimidine-6- carboxylate (l-23e)

To a stirred solution of l-23d (750 mg, 1.60 mmol) in EtOH (40 ml_) was added l-2c (300 mg, 2.50 mmol) at rt. The reaction mixture was heated at 85 °C for 16 h, then concentrated under reduced pressure. The afforded crude was purified by column chromatography on silica gel, eluted with 20% ethyl acetate / pet ether which gave the title compound (600 mg) as a solid with 50% LCMS purity.MS (ES+) m/z 360.25 [M+H]⁺. The compound was used in next step without further purification. Step f) 2-chloro-7-(1-(difluoromethoxy)cvclopropyl)pyrazolo[1 ,5-alpyrirnidine-6-carboxylic acid (I- 23f)

TFA (2 mL, 22.40 mmol) was added under nitrogen to a stirred solution of 1-15e (600 mg, 8.44 mmol) in DCM (20 mL) at 0 °C. The reaction mixture was stirred at rt for 4 h, then concentrated under reduced pressure. The crude was triturated with diethyl ether (10 mL) followed by n- pentane (10 mL) which gave the title compound (350 mg) as a solid with 72% LCMS purity. MS (ES+) m/z 304.20 [M+H]⁺. The compound was used in next step without further purification.

Intermediate 24

Step a) (S)-6-tert-butyl 2-methyl 7-(1-(difluoromethoxy)ethyl)pyrazolo[1 ,5-alpyrimidine-2,6- dicarboxylate (l-24a)

To a stirred solution of 1-15d (450 mg, 1.50 mmol) in EtOH (30 mL) was added methyl 5-amino- 1 H-pyrazole-3-carboxylate (450 mg, 1.90 mmol) at rt. The reaction mixture was heated at 85 °C for 4 h, then concentrated under reduced pressure. The afforded crude was purified by column chromatography on silica gel, eluted with 20% ethyl acetate / pet ether which gave the title compound (300 mg) as a solid with 65% LCMS purity.MS (ES+) m/z 372.33 [M+H]⁺. The compound was used in next step without further purification. Step b) (S)-7-(1-(difluoromethoxy)ethyl)-2-(methoxycarbonyl)pyrazolo[1 ,5-alpyrimidine-6- carboxylic acid (l-24b)

TFA (2.0 mL, 22 mmol) was added under nitrogen to a stirred solution of l-24a (250 mg, 0.63 mmol) in DCM (20 mL) at 0 °C. The reaction mixture was stirred at rt for 6 h, then concentrated under reduced pressure. The crude was triturated with diethyl ether (10 mL) followed by n- pentane (10 mL) which gave the title compound (200 mg) as a solid with 68% LCMS purity.MS (ES+) m/z 316.23 [M+H]⁺.The compound was used in next step without further purification.

Intermediate 25

Step a) (2S,4S)-tert-butyl 2-(2,2-dimethyl-4,6-dioxo-1 ,3-dioxane-5-carbonyl)-4-fluoropyrrolidine- 1-carboxylate( l-25a)

To a stirred solution of (2S,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (3 g, 13 mmol) and 2,2-dimethyl-1 ,3-dioxane-4,6-dione (1.9 g, 13 mmol) in DCM (60 mL) were added Ν,Ν'-Dicyclohexylcarbodiimide (2.7g, 13 mmol) and DMAP (3.2g, 26 mmol) at rt. The reaction mixture was stirred at rt for 18 h, then filtered through the Celite bed. The filtrate was washed with 3M citric acid solution, brine and dried (Na2S0₄), filtered and concentrated under reduced pressure which gave the title compound (5 g) as a solid with 62% LCMS purity. MS (ES+) m/z 360.37 [M+H]⁺.The compound was used in next step without further purification.

Step b) (2S,4S)-tert-butyl 2-(3-ethoxy-3-oxopropanoyl)-4-fluoropyrrolidine-1-carboxylate(l-25b) A stirred solution of l-25a (5 g, 8.7 mmol) in EtOH (50 mL) was heated to 90 °C for 4 h, then concentrated under reduced pressure which gave the crude title compound (4.2 g) as a solid. The compound was used in next step without further purification.

Step c) (2S,4S)-tert-butyl 2-((Z)-3-(dimethylamino)-2-(ethoxycarbonyl)acryloyl)-4- fluoropyrrolidine-1-carboxylate (l-25c)

Compound l-25b (4.2 g, 7.0 mmol) and DMF-DMA (4.0 mL, 30.11 mmol) were heated at 120 °C for 30 min, then concentrated under reduced pressure which gave the crude title compound (4.35 g) with 57% LCMS purity.MS (ES+) m/z 359.40 [M+H]⁺. The compound was used in next step without further purification.

Step d) ethyl 7-((2S,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-2-yl)-2-chloropyrazolo[1 ,5- alpyrimidine-6-carboxylate(l-25d)

To a stirred solution of l-25c (4.35 g, 6.90 mmol) in EtOH (60 mL) was added l-2c (1.1 g, 6.90 mmol) at rt. The reaction mixture was heated at 85 °C for 2 h, then concentrated under reduced pressure. The afforded crude was purified by column chromatography on silica gel, eluted with 10% ethyl acetate / pet ether which gave the title compound (1.2 g, 42%) as a solid. MS (ES+) m/z 413.16 [M+H]⁺.

Step e) 7-((2S,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-2-yl)-2-chloropyrazolo[1 ,5- alpyrimidine-6-carboxylic acid (l-25e)

Lithium hydroxide (305 mg, 7.3 mmol) was added at rt to a stirred solution of l-25d (1.2 g, 3.00 mmol) in THF (15.0 mL) and water (2 mL). The resulting reaction mixture was stirred at rt for 3 h, 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, the precipitated solid was filtered and vacuum dried which gave the title compound (1 g, 84%) as a solid. MS (ES+) m/z 385.31 [M+H]⁺.

Intermediate 26

Step a) (2S,4R)-tert-butyl 2-(2,2-dimethyl-4,6-dioxo-1 ,3-dioxane-5-carbonyl)-4-fluoropyrrolidine- 1-carboxylate (l-26a)

To a stirred solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (2 g, 8.6 mmol) and 2,2-dimethyl-1 ,3-dioxane-4,6-dione ( 1.24 g, 8.60 mmol) in DCM (40 mL) were added N,N'-Dicyclohexylcarbodiimide (1.8 g, 8.6 mmol) and DMAP (2.1 g, 17.19 mmol) at rt. The reaction mixture was stirred at rt for 13h, then filtered through the Celite bed. The filtrate was washed with 3M citric acid solution, brine and dried (Na2S0₄), filtered and concentrated under reduced pressure which gave the title compound (3 g) as a solid with 60% LCMS purity.MS (ES+) m/z 358.31 [M-H]^".The compound was used in next step without further purification. Step b) (2S,4R)-tert-butyl 2-(3-ethoxy-3-oxopropanoyl)-4-fluoropyrrolidine-1-carboxylate (l-26b) A stirred solution of l-26a (3 g, 8.34 mmol) in EtOH (50 mL) was heated to 90 °C for 3 h, then then concentrated under reduced pressure which gave the crude title compound (2 g) as a solid. The compound was used in next step without further purification. Step c) (2S,4R)-tert-butyl 2-((Z)-3-(dimethylamino)-2-(ethoxycarbonyl)acryloyl)-4- fluoropyrrolidine-1-carboxylate (l-26c)

Compound l-26b (2 g, 6.6 mmol) and DMF-DMA (3.0 mL, 22.6 mmol) were heated at 120 °C for 30 min, then concentrated under reduced pressure which gave the crude title compound (2.3 g) with 63% LCMS purity.MS (ES+) m/z 359.36 [M+H]⁺. The compound was used in next step without further purification.

Step d) ethyl 7-((2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-2-yl)-2-chloropyrazolo[1 ,5- alpyrimidine-6-carboxylate (l-26d)

To a stirred solution of l-26c (2.3 g, 6.41 mmol) in EtOH (40 mL) was added l-2c (760 mg, 6.50 mmol) at rt. The reaction mixture was heated at 85 °C for 3 h, then concentrated under reduced pressure. The afforded crude was purified by column chromatography on silica gel, eluted with 10% ethyl acetate / pet ether which gave the title compound (1.0 g, 37%) as a solid. MS (ES+) m/z 413.31 [M+H]⁺. Step e) 7-((2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-2-yl)-2-chloropyrazolo[1 ,5- alpyrimidine-6-carboxylic acid (l-26e)

Lithium hydroxide (160 mg, 3.81 mmol) was added at rt to a stirred solution of l-26d (1.0 g, 2.42 mmol) in THF (15.0 ml_) and water (5 ml_). The resulting reaction mixture was stirred at rt for 4 h, 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, the precpitated solid was filtered and vacuum dried which gave the title compound (500 mg, 52%) as a solid. MS (ES+) m/z 385.31 [M+H]⁺. Intermediate 27

Step a) 5-(difluoromethoxy)-1 H-pyrazol-3-amine (l-27a)

To a stirred solution of 2-(5-hydroxy-1 H-pyrazol-3-yl)isoindoline-1 ,3-dione (4 g, 14 mmol) in DMF (40 ml_) and water (10 ml_) were added sodium chlorodifluoroacetate (5 g, 33 mmol) and cesium carbonate (9 g, 27.62 mmol) at rt. The reaction mixture was heated at 110 °C for 22 h, then quenched with saturated sodium bicarbonate (50 ml_) and extracted with DCM (2 x 100ml_). The combined organic layers were washed with brine (50 ml_), dried (Na2S0₄), filtered and concentrated under reduced pressure. The afforded crude was purified by column chromatography on silica gel, eluted with 10% ethyl acetate / pet ether which gave the title compound (400 mg) as a liquid with 45% LCMS purity.MS (ES+) m/z 150.16 [M-H]\The compound was used in next step without further purification.

Step b) (S)-tert-butyl 2-(difluoromethoxy)-7-(1-(difluoromethoxy)ethyl)pyrazolo[1 ,5-alpyrimidine- 6-carboxylate (l-27b)

To a stirred solution of 1-15d (500 mg, 1.70 mmol) in EtOH (30 ml_) was added l-27a (500 mg, 2.00 mmol) at rt. The reaction mixture was heated at 85 °C for 2 h, then concentrated under reduced pressure. The afforded crude was purified by column chromatography on silica gel, eluted with 20% ethyl acetate / pet ether which gave the title compound (200 mg, 29%) as a solid.MS (ES+) m/z 380.17 [M+H]⁺.

Step c) (S)-2-(difluoromethoxy)-7-(1-(difluoromethoxy)ethyl)pyrazolo[1 ,5-alpyrimidine-6- carboxylic acid (l-27c) TFA (2.1 mL, 23 mmol) was added under nitrogen to a stirred solution of l-27b (200 mg, 0.50 mmol) in DCM (20 mL) at 0 °C. The reaction mixture was stirred at rt for 6 h, then concentrated under reduced pressure. The crude was triturated with diethyl ether (10 mL) followed by n- pentane (10 mL) which gave the title compound (150 mg, 80%) as a solid. MS (ES+) m/z 324.14 [M+H]⁺.

Intermediate 2

Step b ( '-^28a. ^R = ^{t Bu}

|-28b, R = H

Step a) tert-butyl 2-(difluoromethoxy)-7-(1-(trifluoromethyl)cvclopropyl)pyrazolo[1 ,5-alpyrimidine- 6-carboxylate (l-28a)

A mixture of l-6a (2 g, 5.00 mmol) and 1 ,1-dimethoxy-N,N-dimethylmethanamine (1 g, 8.22 mmol) was heated at 120 °C for 90 min, then a solution of l-27a (1.8 g, 3.93 mmol) in EtOH (60 mL) was added and the mixture was heated at 85 °C for 4 h. The reaction mixture was concentrated and the afforded crude compound was purified by column on silica gel, eluted with 0 - 20% EtOAc in p. ether, which gave the title compound (800 mg, 40%) as a solid LCMS (ES+) m/z 394.30 [M+H]⁺.

Step b) 2-(difluoromethoxy)-7-(1-(trifluoromethyl)cyclopropyl)pyrazolo[1 ,5-alpyrimidine-6- carboxylic acid (l-28b)

TFA (5.0 mL, 56 mmol) was added to a solution of l-28a (800 mg, 2.00 mmol) in DCM (30 mL). The mixture was stirred art rt for 4 h, then concentrated. The obtained solid was triturated with n-pentane (2 x 10 mL) and dried which gave the title compound (550 mg, 81 %) as a solid.

LCMS (ES+) m/z 338.20 [M+H]⁺.

Intermediate 29

l-29a Step c [ l-29b = t.Bu

μ l-29c = H

Step a) ethyl 5-amino-1 H-pyrazole-3-carboxylate (l-29a)

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 Na2S0₄ 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]⁺.

Step b) 6-tert-butyl 2-ethyl 7-(1-(trifluoromethyl)cyclopropyl)pyrazolo[1 ,5-alpyrimidine-2,6- dicarboxylate (l-29b)

To a stirred solution of 1-13a (4 g, 13.02 mmol) in EtOH (50 mL) was added l-29a (2 g, 12.90 mmol) at rt. The reaction mixture was heated at 85 °C for 4 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 (2 g, 38%) as a solid. MS (ES+) m/z 400.31 [M+H]⁺. Step c) 2-(ethoxycarbonyl)-7-(1-(trifluoromethyl)cyclopropyl)pyrazolo[1 ,5-alpyrimidine-6- carboxylic acid (l-29c)

TFA (2.3 mL, 25.8 mmol) was added under nitrogen to a stirred suspension of l-29b (1 g, 2.50 mmol) in DCM (20 mL) at 0 °C. The reaction mixture was stirred at rt for 14 h, then concentrated under reduced pressure. The crude was triturated with diethyl ether (10 mL) followed by n- pentane (10 mL) which gave the title compound (700 mg, 80%) as a solid. MS (ES+) m/z 344.30 [M+H]⁺.

Intermedia

Step a) 2-(5-(trifluoromethoxy)-1 H-pyrazol-3-yl)isoindoline-1 ,3-dione (l-30a)

To a stirred solution of 2-(5-hydroxy-1 H-pyrazol-3-yl)isoindoline-1 ,3-dione (2 g, 8.72 mmol) in DMF (30 mL) was added 1-trifluoromethyl-3,3-dimethyl-1 ,2-benziodoxole (2.5 g, 7.60 mmol) at rt. The reaction mixture was heated at 70 °C for 16 h, then ice cold water (50 mL) was added and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (50 mL), dried (Na2S0₄), filtered and concentrated under reduced pressure. The afforded crude was purified by column chromatography on silica gel, eluted with 30-50% ethyl acetate / pet ether, which gave the title compound (250 mg) as a solid with 77% LCMS purity.MS (ES+) m/z 298.14 [M+H]⁺.The compound was used in next step without further purification.

Step b) 5-(trifluoromethoxy)-1 H-pyrazol-3-amine (l-30b)

Hydrazine hydrate (500 mg, 10 mmol) was added at rt to a solution of l-30a (250 mg, 0.65 mmol) in EtOH (10.0 mL). The resulting mixture was stirred at rt for 4 h, then diluted with water (10 mL) extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (20 mL), dried (Na2S0₄), filtered and concentrated under reduced pressure. The afforded crude was purified by column chromatography on silica gel, eluted with 50-70% ethyl acetate / pet ether, which gave the title compound (100 mg) as a liquid with 79% LCMS purity. LCMS (ES+) m/z 168.10 [M+H]⁺. The compound was used in next step without further purification. Step c) (S)-tert-butyl 7-(1-(difluoromethoxy)ethyl)-2-(trifluoromethoxy)pyrazolo[1 ,5-alpyrimidine- 6-carboxylate (l-30c)

A mixture of 1-15c (200 mg, 0.70 mmol) and 1 , 1-dimethoxy-N,N-dimethylmethanamine (100 mg, 0.84 mmol) was heated at 120 °C for 90 min, then a solution of l-30b (90 mg, 0.54 mmol) in EtOH (15 mL) was added and the mixture was heated to 85 °C for 4 h. The mixture was concentrated under reduced pressure and the obtained crude material was purified by column chromatography on silica gel eluting with 20% EtOAc in pet ether, which gave the title compound (130 mg, 47%). LC-MS (ES+) m/z 398.33 [M+H]⁺.

Step d) (S)-7-(1-(difluoromethoxy)ethyl)-2-(trifluoromethoxy)pyrazolo[1 ,5-alpyrimidine-6- carboxylic acid (l-30d)

TFA (0.5 mL, 6.00 mmol) was added under nitrogen to a stirred suspension of l-30c (130 mg, 0.32 mmol) in DCM (5 mL) at 0 °C. The reaction mixture was stirred at rt for 4 h, then concentrated under reduced pressure. The crude was triturated with diethyl ether (10 mL) followed by n- pentane (10 mL) which gave the title compound (90 mg, 77%) as a solid. MS (ES+) m/z 342.24 [M+H]⁺.

Intermediate 31

Step a) tert-butyl 6-methoxy-5-(trifluoromethyl)pyridazin-3-ylcarbamate (1-31 a)

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. The crude compound was purified by column chromatography on silica gel, eluted with 5-10% EtOAc in pet ether, which gave the title compound (90 mg, 13%) as a solid. LCMS (ES+) 294.39 [M+H]⁺.

Step b) 6-methoxy-5-(trifluoromethyl)pyridazin-3-amine (1-31 b)

TFA (0.22 mL, 3.00 mmol) was added under nitrogen to a stirred suspension of l-31a (90 mg, 0.30 mmol) in DCM (5 mL) at 0 °C. The reaction mixture was stirred at rt for 4 h, then concentrated under reduced pressure. The crude was triturated with diethyl ether (10 mL) followed by n- pentane (10 mL) which gave the title compound (95 mg, 99%) as a solid. MS (ES+) m/z 194.26 [M+H]⁺.

Intermediate 32

Step a) (1 E,2E)-2-(2-(3-chloropyridin-2-yl)hvdrazono)propanal oxime (l-32a)

To a suspension of 3-chloro-2-hydrazinylpyridine (1 g, 7 mmol) in EtOH (20 mL) was added 2- oxopropanal oxime (730 mg, 8.40 mmol) at rt. The reaction mixture was heated at 85 °C for 3 h, then reaction was cooled to rt. The precipitated solid was filtered and dried, which gave the title compound (900 mg, 60%) as a solid. MS (ES+) m/z 213.21 [M+H]⁺.

Step b) 3-chloro-2-(4-methyl-2H-1 ,2,3-triazol-2-yl)pyridine (l-32b)

A mixture of l-32a (900 mg, 4.23 mmol) and acetic anhydride (10 mL, 105.8 mmol) was heated at 120 °C for 2 h, then concentrated, which gave the title compound (800 mg) as a semi solid. MS (ES+) m/z 195.16 [M+H]⁺. The compound was used in next step without further purification.

Step c) 2-(3-chloropyridin-2-yl)-2H-1 ,2, 3-triazole-4-carboxylic acid (l-32c)

To a stirred solution of l-32b (500 mg, 2.57 mmol) in sulphuric acid (66%, aq) (10 mL) was added sodium dichromate dihydrate (1.53 g, 5.13 mmol) portion wise maintaining the temperature of the reaction below 90 °C. The reaction mixture was heated at 80 °C for 30 min, then reaction mixture was poured into crushed ice and allowed to stand at rt for 16 h. The precipitated solid was filtered and dried, which gave the title compound (200 mg, 32%) as a solid. MS (ES+) m/z 225.20 [M+H]⁺.

Intermediate 33

Step a) 6-chloro-4-methoxy-3-(2H-1 ,2,3-triazol-2-yl)pyridazine (l-33a)

DIPEA (3.9 mL, 22.4 mmol) was added to solution of 3,6-dichloro-4-methoxypyridazine (2.0 g, 1 1.2 mmol) in DMSO (6 mL) followed by addition of 1 H-1 ,2,3-triazole (930 mg, 13 mmol). The resulting mixture was heated at 180 °C for 2 h in a microwave, until reaction was deemed completed as judged by TLC (~2 h), then diluted with water (30 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. The crude product was purified by column chromatography on silica (100-200 mesh), eluted at 3-5% MeOH in DCM which gave the title compound (1.0 g, 41 %) as a solid with 97.13% LCMS purity. MS (ES+) 212.16 [M+H]⁺.

Step b) tert-butyl 5-methoxy-6-(2H-1 ,2,3-triazol-2-yl)pyridazin-3-ylcarbamate (l-33b)

l-33a (1 g, 4.60 mmol) was added to a stirred solution of tert-butyl carbamate (700 mg, 6.00 mmol) in 1 ,4-dioxane (10 mL) in a sealed tube. The reaction mixture was degassed for 10 min with argon, then Cs₂C0₃ (3 g, 9.20 mmol), Xantphos (265 mg, 0.50 mmol) and Pd(OAc)₂ (103 mg, 0.50 mmol) were added and the resulting reaction mixture was stirred at 120 °C for 16 h in a sealed tube. The reaction mixture was filtered through Celite and concentrated, which gave the title compound (1.3 g) as a solid. LCMS (ES+) 293.27 [M+H]⁺. The compound was used in next step without further purification.

Step c) 5-methoxy-6-(2H-1 ,2,3-triazol-2-yl)pyridazin-3-amine (l-33c)

BBr3 (1 M in DCM) (4.2 mL, 4.20 mmol) was added under nitrogen to a stirred solution of l-33b (1.3 g, 3.82 mmol) in DCM (50 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, then diluted with water (30 mL). The aqueous layer was extracted with DCM (2 x 30 mL), the organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica (100-200 mesh), eluted at 3- 8% MeOH in DCM which gave the title compound (800 mg, 94%) as a solid with 87.13% LCMS purity. MS (ES+) 193.22 [M+H]⁺.

Intermediate 34

I -34a I -34b

Step a) (S)-tert-butyl 2-chloro-7-(1-(difluoromethoxy)ethyl)pyrazolo[1 ,5-alpyrimidin-6- ylcarbamate (l-34a)

DPPA (0.3 mL, 1.40 mmol) and Et₃N (1.0 mL, 7.2 mmol) were added to a solution of l-15f (220 mg, 0.60 mmol) in t-butanol (15 mL). 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. The afforded crude was purified by column chromatography on silica gel eluted, with 10% EtOAc in pet ether. Fractions containing the desired compound were combined and concentrated which gave the title compound (210 mg) as a solid. LCMS (ES+) m/z 363.32 [M+H]⁺.The compound was used in next step without further purification.

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. The crude product was purified by column chromatography on silica (100-200 mesh), eluted at 60% EtOAc in pet ether, which gave the title compound (80 mg, 61 %) as a solid with 97.04% LCMS purity. MS (ES+) 263.25 [M+H]⁺. Intermediate 35

Step a) 6-chloro-5-(trifluoromethyl)pyridazin-3-amine (l-35a)

To a stirred solution of 3,6-dichloro-4-(trifluoromethyl)pyridazine (900 mg, 4.14 mmol) in 1 ,4- dioxane (10 ml_) was added ammonium hydroxide (4.52 ml_, 29 mmol) in a steel bomb. The reaction mixture was heated at 100 °C for 16 h in a sealed tube. 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. The crude product was purified by column chromatography on silica (100-200 mesh), eluted at 10-15% EtOAc in pet ether, which gave the title compound (250 mg) as a solid with 75% LCMS purity. MS (ES+) 198.23 [M+H]⁺. The compound was used in next step without further purification.

Step b) 6-(2H-1 ,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridazin-3-amine l-35b)

K2CO3 (395 g, 2.90 mmol) and Kl (158 mg, 0.95 mmol) were added at 0 °C to a stirred solution of 1 H-1 ,2,3-triazole (66 mg, 0.95 mmol) in DMF (5 ml_). To the above reaction mixture was added l-35a (250 mg, 0.95 mmol) and the mixture was stirred at 180 °C for 2 h in microwave, then poured into the ice water and extracted with EtOAc (2 x 30 ml_), the organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica (100-200 mesh), eluted at 20-30% EtOAc in pet ether, which gave the title compound (120 mg) as a solid with 40% LCMS purity. MS (ES+) 231.32 [M+H]⁺. The compound was used in next step without further purification.

Intermediate 36

I -36a _. l-36b, R

S^teP ^c ( I-36C, R

Step a) (Z)-ethyl 3-(dimethylamino)-2-(pyrimidine-5-carbonyl)acrylate (l-36a)

To a suspension of pyrimidine-5-carboxylic acid (5 g, 40.3 mmol) in toluene (70 mL) were added (E)-ethyl 3-(dimethylamino)acrylate (6.0 mL, 40.3 mmol), trimethylacetyl chloride (8.9 mL, 93.80 mL) and EtzN (20 mL, 143.5 mmol) at rt. The resulting reaction mixture was stirred at 100 ⁰ C under nitrogen for 16 h, then ice cold water was added. The aqueous layer was extracted with EtOAc (2 x 100 mL), the organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica (100-200 mesh), eluted at 3% MeOH in DCM which gave the title compound (2.0 g, 60%) as a semi solid with 62.16% LCMS purity. MS (ES+) 250.1 1 [M+H]⁺. The compound was used in next step without further purification.

Step b) ethyl 7-(pyrimidin-5-yl)pyrazolo[1 ,5-alpyrimidine-6-carboxylate (l-36b)

To a stirred solution of l-36a (2.0 g, 5.00 mmol) in EtOH (30 mL) was added 1 H-pyrazol-5-amine (620 mg, 7.50 mmol) at rt. The reaction mixture was heated at 85 °C for 16 h, then concentrated under reduced pressure. The afforded crude was triturated with diethyl ether (2 x 10 mL) which gave the title compound (800 mg, 59%) as a solid. LCMS (ES+) m/z 270.17 [M+H]⁺.

Step c) 7-(pyrimidin-5-yl)pyrazolo[1 ,5-alpyrimidine-6-carboxylic acid (l-36c)

Lithium hydroxide (247 mg, 5.90 mmol) was added at rt to a stirred solution of l-36b (800 mg, 3.00 mmol) in THF (10.0 mL) and water (10.0 mL). The resulting reaction mixture was stirred at rt for 3 h, then concentrated under reduced pressure. The afforded crude was diluted with ice water (10 mL) and acidified with 1 N HCI (aq) solution up to pH 2 and precipitated solid was filtered and dried under vacuum which gave the title compound (600 mg, 78%) as a solid. LCMS (ES+) M/z = 242.26 [M+H]⁺.

Intermediates of series (y)

Intermediate 1y

1-1 e 1-1 f

Step a) 5-Chloro-1-nitro-1 H-pyrazole (1-1 a)

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. Progress of the reaction was monitored by TLC and LCMS and when starting material was deemed completely consumed (after 4h), the reaction mixture was poured into ice-water (70 mL) and basified with Na2C03 (60 g) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with aqueous saturated sodium bicarbonate (100 mL) and brine (50 mL), dried over Na2S0₄ and concentrated. The afforded solid was washed with n-pentane which gave the title compound (7.0 g, 6.2%) as a solid. LCMS (ES+) 147.93 [M+H]⁺. Step b) 5-Chloro-3-nitro-1 H-pyrazole (1-1 b)

Compound 1-1 a (7.0 g, 47.4 mmol) was dissolved in anisole (150 ml) in a steal bomb. The vessel was sealed and the mixture heated at 140 °C. The progress of the reaction was monitored by TLC and stopped after 16 h even though starting material was not completely consumed. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by column chromatography on silica gel (100-200 mesh) eluted with 20% EtOAc in p.ether which gave the title compound (4.0 g, 56 %) as a solid. LCMS (ES-) 145.99 [M-H]-. Step c) 5-Chloro-1 H-pyrazol-3-amine (1-1 c)

Aqueous HCI (16.8 mL, 544 mmol) was added over a period of 10 min to a solution of compound 1-1 b (4.0 g, 27.1 mmol) in MeOH (200 mL). The reaction mixture was cooled to 0 °C and tin(ll) chloride (30.0 g, 158 mmol) was added portion wise and the resulting reaction mixture was stirred at rt. The progress of the reaction was monitored by TLC and after 16 h, when starting material was deemed consumed, the solvent was evaporated. The residue was diluted with EtOAc (100 mL) and 30% aqueous NaOH solution (120 mL) was added dropwise at 0 °C until basic pH, then stirred at 0 °C for 2h. Solid precipitates were filtered off through a pad of Celite and the cake was rinsed with EtOAc (50 mL) and water (50 mL). The organic phase was separated and the aqueous phase was extracted with EtOAc (50 mL). The combined organic layers were washed with brine (50 mL), dried (Na2S0₄), filtered and concentrated under vacuum which gave the title compound (3.5 g, 93 %). The compound was used in next step without further purification. MS (ES+) 1 18.04 [M+H]⁺.

Step d) (S)-tert-butyl 4-methoxy-3-oxopentanoate (1-1 d)

Solution 1 : N,N'-carbonyldiimidazole (17.0 g, 104.84 mmol) was added at 0 °C to a stirred solution of (S)-2-methoxypropanoic acid (10 g, 96.1 mmol) in THF (200 mL) and the mixture was stirred at rt for 3 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.

Solution 2 was then added drop wise at 0 °C to solution 1 and the resulting mixture was stirred at rt for 1 h. The reaction was quenched by addition of 10% aqueous citric acid solution (50 mL) and the mixture was diluted with water (100 mL). The aqueous layer was extracted with EtOAc (2 x 200 ml). The organic layer was washed with saturated sodium bicarbonate solution (100 mL), dried (Na2S0₄), filtered and concentrated under reduced pressure which gave the title compound (25 g, 57%). LCMS (ES+) m/z 203.3 [M+H]⁺. 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.

The mixture was concentrated under reduced pressure and the obtained crude material was purified by column chromatography on silica gel eluting with a gradient of 0 - 10% EtOAc in p. ether, which gave the title compound (11 g, 33%) as a solid. LCMS (ES+) m/z 312.21 [M+H]⁺ .

Step f) (S)-2-chloro-7-(1-methoxyethyl)pyrazolo[1 ,5-alpyrimidine-6-carboxylic acid (l-1f)

To a stirred solution of 1-1 e (11 g, 27 mmol) in DCM (20 mL) was added TFA (47 mL, 526 mmol) at rt under nitrogen. The reaction mixture was stirred at rt for 16 h, then concentrated under reduced pressure. Diethyl ether (20 mL) was added to the crude compound and the mixture was concentrated. The crude compound was triturated in diethyl ether (10 mL) which gave the title compound (7.5 g,98 %) as a solid. LCMS (ES+) shows 90% purity of the desired product with m/z 256.10 [M+H]⁺.

Intermediate 2y

1-1 f l-2a l-2b

(S)-Tert-butyl (2-chloro-7-(1-methoxyethyl)pyrazolo[1 ,5-alpyrimidin-6-yl)carbamate (l-2a)

DPPA (3.5 mL, 16.2 mmol) and Et₃N (5.5 mL, 39.6 mmol) were added at rt to a solution of l-1f (1.0 g, 3.9 mmol) in t-butanol and the mixture was stirred at rt for 30 min then at 100 °C for 16 h. The reaction mixture was diluted with water and extracted with EtOAc, the combined organic layers were washed with aqueous saturated sodium bicarbonate, dried (Na2S0₄), filtered and concentrated. The crude material was purified by column chromatography on silica gel eluted with 5-10% EtOAc in p. ether, which gave the title compound (1.0 g, 76%) as a solid. LCMS (ES+) m/z 327.24 [M+H]⁺.

Step b) (S)-2-Chloro-7-(1-methoxyethyl)pyrazolo[1 ,5-alpyrimidin-6-amine (l-2b)

A 4 M solution of HCI in dioxane (5 mL, 17.1 mmol) was added to a stirred solution of l-2b (1.0 g, 2.9 mmol) in DCM (10 mL). The solution was stirred at rt for 2 h, then concentrated under reduced pressure. The crude compound was diluted with saturated sodium bicarbonate (70 mL) and extracted with EtOAc (2x50 mL), dried (Na2S0₄), filtered and concentrated. The afforded residue was washed with diethyl ether in pentane, the solid was filtered and dried, which gave the title compound (0.53 g, 77%) as a solid. LCMS (ES+) m/z 227.21 [M+H]⁺. Intermediat

ο÷_Ω ( l-3a, R = CI , . / l-3c, R = Me

^{St8P b} ί |-3b, R = I ^SteP ^d ( |-3d, R = H

Step a) methyl 6-chloropyridazine-4-carboxylate (l-3a)

2M TMSCH2N2 in hexane (18.92 ml) was added at 0 °C to a stirred solution of 6- chloropyridazine-4-carboxylic acid (5.0 g, 31.5 mmol) in DCM:MeOH. The mixture was stirred at 0 °C for 2 h, then poured in to water and extracted with DCM. The organic layers were combined and washed with NaHCC>3 (aq) and brine, dried (Na2S0₄), filtered and concentrated. The crude compound was washed with the pentane, which gave the title compound (2.7 g, 42%) as a solid. LCMS (ES+) m/z 173.06 [M+H]⁺.

Step b) methyl 6-iodopyridazine-4-carboxylate (l-3b)

Nal (2.56 g, 17.09 mmol) was added to a stirred solution of l-3a (2.7 g, 13 mmol) in HCI. The solution was heated to 40°C for 16 h, then poured into water and extracted with EtOAc. The combined organic layers were washed with saturated NaCI (aq), dried (Na2S0₄), filtered and concentrated. The crude compound was purified by column chromatography on silica gel eluted with a gradient of 5-10% EtOAc in p. ether which gave the title compound (1.0 g, 3.5%) as a solid. LCMS (ES+) m/z 265.02 [M+H]⁺.

Step c) methyl 6-(trifluoromethyl)pyridazine-4-carboxylate (l-3c)

A solution of l-3b (1.0 g, 3.29 mmol) in dry DMF was vacuum de-gassed for 10 min then [1 , 10- Phenanthroline(CuCF3)] (1.54 g, 4.94 mmol) was added and the mixture was stirred in dark, under N2 at rt for 16 h. The reaction mixture was diluted with the diethyl ether and filtered through the Celite. The organic layer was washed with water, brine and concentrated. The crude compound was purified by flash column chromatography eluted with a gradient of 5-10% EtOAc in p.ether which gave the title compound as solid (210 mg, 23%). LCMS (ES+) m/z 207.15 [M+H]⁺.

Step d) 6-(trifluoromethyl)pyridazine-4-carboxylic acid (l-3d)

LiOhM-bO (107 mg, 2.55 mmol) was added to a stirred solution of compound l-3c (210 mg, 1.02 mmol) in THFihbO. The reaction was stirred at rt for 3 h, then concentrated, diluted with water and washed with ether. The aqueous layer was acidified and extracted with EtOAc, The EtOAc layers were combined and washed with saturated NaCI (aq), dried (Na2S0₄), filtered and concentrated. The crude compound was washed with the pentane which gave the title compound (190 mg, 82%) as a solid. LCMS (ES-) m/z 191.10 [M-H]\ ntermediate 4y

l-4a

Step a) 2-(Difluoromethoxy)-5-nitropyrimidine (l-4a)

NaH (60%, 1.4 g, 35 mmol) was added portion wise at rt under nitrogen to a stirred solution of 5-nitropyrimidin-2-ol (3.5 g, 25 mmol) in acetonitrile (200 mL). After 10 min, 2,2-difluoro-2-

(fluorosulfonyl)acetic acid (4.5 mL, 43 mmol) was added and the mixture was stirred for 20 min at rt. The reaction mixture was cooled the reaction to 0 °C and of ice water (50 mL) was added dropwise. The mixture was extracted with EtOAc (2 x 100 mL) and the combined organic layers were dried (Na2S0₄), filtered and concentrated. The obtained crude material was purified by column chromatography on silica gel eluted with 10% EtOAc in p. ether, which gave the title compound (130 mg, 2.6%).

Step b) 2-(Difluoromethoxy)pyrimidin-5-amine (l-4b)

Fe (0.38 g, 6.8 mmol) was added at rt to a stirred solution of l-4a (20 mg, 0.1 mmol) in HOAc (2.2 mL, 38.4 mmol). The resulting mixture was stirred at rt for 3 h, then concentrated under reduced pressure, diluted with EtOAc (30 mL) and filtered through Celite. The organic layer was washed with saturated sodium bicarbonate solution (2 x 20 mL), dried (Na2S0₄), filtered and concentrated which gave the title compound (75 mg, 67.6%) as a solid. LC-MS (ES+) m/z 162.1 1 [M+H]⁺.

Intermediate 5y

I-5

N-methyl-2-(trifluoromethyl)pyridin-4-amine (I-5)

NaH (60%, 320 mg, 8.0 mmol) was added portion wise at rt to a stirred solution of 2- (trifluoromethyl) pyridin-4-amine (1.0 g, 6.17 mmol) in THF (20 mL). The mixture was stirred at rt for 3h, then cooled to 0 °C and iodomethane (0.4 mL, 6.4 mmol) was added. Thejnixture was stirred at 50 °C for 16 h, then_diluted with cold water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried (Na2S0₄), filtered and and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel eluted with a gradient of 20-25% EtOAc in p. ether, which gave the title compound (120 mg, 7.8%). LC-MS (ES+) m/z 177.11 [M+H]⁺. Intermediates of series (z)

Intermediate 1z

Step a) 3-Chloro-5-nitro-2-(2H-1 ,2,3-triazol-2-yl)pyridine (1-1 a)

concentrated under reduced pressure. The crude product was purified by column

chromatography on silica gel eluted at 20% EtOAc in p. ether which gave the title compound (7.0 g, 60%) as a solid with 99.42% LC-MS purity. MS (ES+) 226.03 [M+H]⁺.

Step b) 5-chloro-6-(2H-1 ,2,3-triazol-2-yl)pyridin-3-amine (1-1 b)

Intermediate 2z

Step a) (S)-tert-butyl 4-methoxy-3-oxopentanoate (l-2a)

Solution 2 was then added drop wise at 0 °C to solution 1 and the resulting mixture was stirred at rt for 1 h. The reaction was quenched by addition of 10% aqueous citric acid solution (50 mL) and the mixture was diluted with water (100 mL). The aqueous layer was extracted with EtOAc (2 x 200 ml). The organic layer was washed with saturated sodium bicarbonate solution (100 mL), dried (Na2S0₄), filtered and concentrated under reduced pressure which gave the title compound (25 g, 57%). LC-MS (ES+) m/z 203.3 [M+H]⁺.

Step b) (S)-tert-butyl 7-(1-methoxyethyl)pyrazolo[1 ,5-alpyrimidine-6-carboxylate (l-2b)

A mixture of l-2a (500 mg, 2.373 mmol) and 1 , 1-dimethoxy-N,N-dimethylmethanamine (283 mg, 2.37 mmol) was heated at 120 °C for 90 min, then a solution of 1 H-pyrazol-3-amine (197 mg, 2.37 mmol) in EtOH (10 mL) was added and the mixture was heated at 85 °C for 2 h. The reaction mixture was concentrated under reduced pressure and the obtained crude material was purified by column chromatography on silica gel eluted with a gradient of 0 - 10% EtOAc in p. ether, which gave the title compound (400 mg, 59%). LC-MS (ES+) m/z 278.24 [M+H]⁺. Step c) (S)-7-(1-methoxyethyl)pyrazolo[1 ,5-alpyrimidine-6-carboxylic acid (l-2c)

TFA ( 2.5 mL, 27.9 mmol) was added at rt under nitrogen to a stirred solution of l-2b (400 mg, 1.41 mmol) in DCM (4 mL). The reaction mixture was stirred at rt for 16 h, then concentrated under reduced pressure. The obtained residue was triturated in diethyl ether (10 mL) which gave the title compound (200 mg, 63%) as a solid. LC-MS (ES+) m/z 222.21 [M+H]⁺.

Intermediate 3z

Step a) (S)-ethyl 2-(Difluoromethoxy)-7-(1-methoxyethyl)pyrazolo[1 ,5-alpyrimidine-6-carboxylate Ma)

A mixture of (Z)-ethyl 2-(ethoxymethylene)-4-methyl-3-oxopentanoate (0.33 g, 1.5 mmol) and 5- (difluoromethoxy)-1 H-pyrazol-3-amine (2.12 g, 3 mmol) in EtOH (20 mL) was stirred at 85 °C for 16 h, then concentrated under reduced pressure. The afforded residue was poured into water (20 mL) and extracted with EtOAc (2 x 20 mL). The organic layers were combined, washed with brine, dried (Na2S0₄), filtered and concentrated.

The crude was purified by column chromatography on silica gel using a gradient of 5-7% EtOAc in p. ether, which gave the title compound (450 mg, 95%). LC-MS (ES+) m/z 300.20 [M+H]⁺. Step b) (S)-2-(Difluoromethoxy)-7-(1-methoxyethyl)pyrazolo[1 ,5-alpyrirTiidine-6-carboxylic acid Mb)

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]⁺.

Intermediate 4z

'-^4a Step c '^"4b' ^R = ^H

^ l-4c, R = Boc

Step a) (S)-Tert-butyl 7-(1-(methylamino)ethyl)pyrazolo[1 ,5-alpyrimidine-6-carboxylate (l-4a 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. The reaction mixture was concentrated under reduced pressure and the obtained crude was purified by column chromatography on silica gel using a gradient of 0 - 10% EtOAc in p. ether as eluent, which gave the title compound (4.0 g, 46%) as a solid. LC-MS (ES+) m/z 377.36 [M+H]⁺. Step b) (S)-7-(1-(Methylamino)ethyl)pyrazolo[1 ,5-alpyrimidine-6-carboxylic acid (l-4b)

TFA (17 mL, 190.39 mmol) was added under nitrogen at rt to a stirred solution of l-4a (4 g, 9.5 mmol) in DCM (20 mL). The reaction mixture was stirred at rt for 16 h, then concentrated. The obtained crude compound was dissolved in DCM (100 mL) and concentrated twice and the final crude was then triturated in diethyl ether (50 mL) which gave the title compound (2.0 g, 86 %). LC-MS (ES+) m/z 221.35 [M+H]⁺.

Step c) (S)-7-(1-((tert-butoxycarbonyl)(methyl)amino)ethyl)pyrazolo[1 ,5-alpyrimidine-6- carboxylic acid (l-4c)

Di-tert-butyl dicarbonate (3 mL, 13 mmol) and 1 M (aq.) sodium carbonate (50 mL, 5.3 mmol) were added at rt under nitrogen to a stirred solution of l-4b (2.0 g, 8.2 mmol) in THF (50 mL). The reaction mixture was stirred at room temperature for 16 h, then concentrated under reduced pressure. The residue was dissolved in water (30 mL) and extracted with EtOAc (2 X50 mL). The aqueous layer was acidified with 1 N aqueous HCI (to pH 4-5) and extracted with EtOAc (2 X50 mL). The organic layers were combined dried (Na2S0₄), filtered and concentrated, which gave the title compound (2.0 g, 65%) as a solid. LC-MS (ES-) m/z 319.33

[M-H]-. Intermediate 5z

l-5b, R = t.Bu S^{tep c} V |-5c, R = H

Step a) tert-butyl 3-oxo-3-(pyridazin-4-yl)propanoate (l-5a)

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 2 was then added to Solution 1 at 0 °C and the resulting solution was stirred at rt for 1 h, then concentrated. The crude was diluted with EtOAc (200 mL), washed with water (500 mL) and brine (500 mL). The organic layer was dried (Na2S0₄), filtered and concentrated. The crude compound was purified by combi flash chromatography on silica gel using 30 % EtOAc in p. ether as eluent, which gave the title compound (2.5 g, 45%) as a solid. LC-MS (ES+) m/z 223.14 [M+H]⁺. Step b) tert-butyl 7-(pyridazin-4-yl)pyrazolo[1 ,5-alpyrimidine-6-carboxylate (l-5b)

A mixture of DMA-DMF (1.414 g, 11.88 mmol) and l-5a (2.2 g, 9.9 mmol) was stirred at 120 °C for 1.5 h, then a solution of 1 H-pyrazol-3-amine (0.823 g, 19.9 mmol) in EtOH (30 mL) was added and resulting mixture was stirred fori h at 85 °C, then concentrated. The obtained residue was purified by column chromatography on silica gel using 15% EtOAc in p. ether as eluent, which gave the title compound (1.2 g, 39%) as a solid .

LC-MS (ES+) m/z 298.14 [M+H]⁺.

Step c) 7-(pyridazin-4-yl)pyrazolo[1 ,5-alpyrimidine-6-carboxylic acid (l-5c)

TFA (0.450 mL, 6.05 mmol) was added at rt to a solution of l-5b (0.6 g, 0.2.02 mmol) in DCM (10 mL). The reaction mixture was stirred at rt for 24 h, then concentrated, basified with sat. NaHC03, and washed with EtOAc (2 X 300 mL). The aqueous layer was acidified with 1 N HCI, then extracted into EtOAc (2 X 500 mL). The organic layers were combined and washed with brine (300 ml_), dried (Na2S0₄), filtered and concentrated, which gave the title compound (400 mg, 65%) as a solid. LC-MS (ES+) m/z 242.37 [M+H]⁺. The crude was used without further purification in the next step.

Intermediate 6z

Step a) 1-(((Benzyloxy)carbonyl)(methyl)amino)cvclopropanecarboxylic acid (l-6a)

NaH (3.0 g, 75 mmol) was added in portions at 0 °C to a solution of 1- (methylamino)cyclopropanecarboxylic acid (10.0 g, 42.5 mmol) in THF (50 ml_). The mixture was stirred for 10 min, then Mel (8.0 g, 56.3 mmol) was added and stirring was continued for 10 h. A few drops of water was added and the mixture was concentrated under vacuum. Water and diethyl ether was added and the ether layer was washed with NaHCC>3. The aqueous layer was adjusted to pH 3 by addition of citric acid, then extracted with EtOAc and concentrated, which gave the title compound (9.20 g, 64%). LC-MS (ES+) m/z 250.25 [M+H]⁺.

Step b) tert-butyl 3-(1-(((benzyloxy)carbonyl)(methyl)amino)cvclopropyl)-3-oxopropanoate (l-6b) 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 2 was added to Solution 1 at 0 °C and whereafter the reaction mixture was stirred at rt for 1 h. 10% citric acid (aq.) was added and the mixture was extracted with EtOAc and washed with sat. NaHCC>3. The organic layer was dried (Na2S0₄), filtered and concentrated. The obtained residue was purified by column chromatography on silica gel using 15% EtOAc in p. ether as eluent, which gave the title compound (10.5 g, 64%). LC-MS (ES+) m/z 348.38

[M+H]⁺.

Step c) tert-butyl 7-(1-(((benzyloxy)carbonyl)(methyl)amino)cyclopropyl)pyrazolo[1 ,5- alpyrimidine-6-carboxylate (l-6c)

A mixture of 1 , 1-dimethoxy-N,N-dimethylmethanamine (5.0 g, 42.0 mmol) and l-6b (10.0 g, 28.8 mmol) was stirred at 120 °C for 1.5 h, then a solution of 1 H-pyrazol-3-amine (3.50 g, 42.1 mmol) in EtOH (5 mL) was added and the resulting mixture was stirred at 85 °C for 12 h.

The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel using 10% EtOAc in p. ether as eluent, which gave the title compound (3.85 g, 30%). LC-MS (ES+) m/z 423.36 [M+H]⁺.

Step d) 7-(1-(((benzyloxy)carbonyl)(methyl)amino)cvclopropyl)pyrazolo[1 ,5-alpyrimidine-6- carboxylic acid (l-6d)

TFA (3.0 ml_, 40.3 mmol) was added at rt to a solution of l-6c (1.70 g, 4.02 mmol) in DCM (10 ml_),. The reaction mixture was stirred for 12 h at rt then concentrated. Et20 was added to residue and the suspension was concentrated which gave the title compound (700 mg, 44%). LC-MS (ES+) m/z 367.31 [M+H]⁺.

Intermediate

l-7b, R = t.Bu

Step c (

l-7c, R = H

Step a) Tert-butyl 3-(1-(dimethylamino)cvclopropyl)-3-oxopropanoate (l-7a)

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.

Solution 2 was added to Solution 1 at 0 °C and whereafter the reaction mixture was stirred at rt for 1 h. 10% citric acid (aq.) was added and the mixture was extracted with EtOAc and washed with sat. NaHCC>3. The organic layer was dried (Na2S0₄), filtered and concentrated. The obtained residue was purified by column chromatography on silica gel using 15% EtOAc in p. ether as eluent, which gave the title compound (5.4 g, 49%). LC-MS (ES+) m/z 228.25

[M+H]⁺. Step b) Tert-butyl 7-(1-(dimethylamino)cvclopropyl)pyrazolo[1 ,5-alpyrimidine-6-carboxylate (I- m

A mixture of 1 , 1-dimethoxy-N,N-dimethylmethanamine (1.80 g, 15.11 mmol) and l-7a (2.80 g, 12.3 mmol) were stirred at 120 °C for 5 h, then a solution of 1 H-pyrazol-3-amine (1.30 g, 15.6 mmol) in EtOH (5 mL) was added and resulting mixture was stirred at 85 °C for 1 h. The reaction mixture was concentrated and the obtained residue was purified by column chromatography on silica gel using 10% EtOAc in p. ether as eluent, which gave the title compound (3.7 g, 89%) as a solid. LC-MS (ES+) m/z 303.31 [M+H]⁺. Step c) 7-(1-(Dimethylamino)cvclopropyl)pyrazolo[1 ,5-alpyrirriidine-6-carboxylic acid (l-7c)

TFA (2.0 g, 17.5 mmol) was added at rt to a solution of l-7c (0.70 g, 2.31 mmol) in DCM (5 mL). The reaction mixture was stirred for 16 h, then concentrated. Et20 was added to the residue and the suspension was concentrated to dryness which gave the title compound as a solid. LC-MS (ES+) m/z 247.25 [M+H]⁺.

Compounds of the invention

Example 1

1-(5-Chloro-6-(2H-1 ,2,3-triazol-2-yl)pyridin-3-yl)-3-(2-chloropyrazolori ,5-alpyrimidin-6-yl)urea (1) DPPA (0.190 g, 0.690 mmol) and Et₃N (0.4 mL, 2.87 mmol) were added to a solution of l-2e (0.120 g, 0.588 mmol) in 1 ,4-dioxane (5 mL). The solution was stirred at rt for 30 min, then 1-1 b (0.179 g, 0.885 mmol) was added and the mixture was stirred for 2 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. The afforded crude was purified by column chromatography on silica gel eluted with 2% MeOH in DCM. Fractions containing the desired compound were combined and concentrated and further purified by SFC. Appropriate fractions were collected, concentrated under lyophilized. The afforded solid was suspended in water (5 mL), stirred for 4 h at 40 °C and filtered. The solid was dried under vacuum which gave the title compound (20 mg, 8.6%) as a solid.

Conditions for preparative SFC

Column/dimensions : Chiralpak IC (250 X 30 ) Γπηι,δμ

% C0₂ : 50.0%

% Co solvent : 50.0% (100% MeOH)

Total Flow : 70.0 g/min

Back Pressure : 100.0 bar

UV : 266 nm

Stack time : 18.0 min

Load/inj. : 10.4 mg xam le 2

l-2e l-3b 2

1-(5-chloro-6-(difluoromethoxy)pyridin-3-yl)-3-(2-chloropyrazolo[1 ,5-alpyrimidin-6-yl)urea (2) DPPA (0.45 mL, 2.08 mmol) and Et₃N (1.1 mL, 7.61 mmol) were added at rt to a stirred solution of l-2e (300 mg, 1.52 mmol) in 1 ,4-dioxane (10 mL). The reaction mixture was stirred at rt for 50 minutes, then l-3b (450 mg, 2.31 mmol) was added and the reaction mixture was stirred at 100 °C for 2 h. When TLC indicated consumption of starting material the reaction mixture was cooled to rt, diluted with water (30 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (30 mL), dried (Na2S0₄), filtered and concentrated. The crude material was purified by CombiFlash® on a silica gel column eluted with 8% MeOH in DCM. Appropriate fractions were combined and concentrated and the afforded solid was triturated in MeCN (2x 5 mL) The afforded solid was again triturated in EtOH which gave the title compound (40 mg, 6.4%) as a solid. LCMS (ES+) m/z 389.14 [M+H]⁺. Example 3

l-4b l-3b 3

1-(5-chloro-6-(difluoromethoxy)pyridin-3-yl)-3-(2-methylpyrazolo[1 ,5-alpyrimidin-6-yl)urea (3) DPPA (0.5 mL, 2.31 mmol) and Et₃N (1.2 mL, 8.3 mmol) were added at rt to a stirred solution of l-4b (300 mg, 1.69 mmol) in 1 ,4-dioxane (10 mL). The resulting reaction mixture was stirred at rt for 50 min, then l-3b (500 mg, 2.57 mmol) was added and the reaction mixture was stirred at 100 °C for 2 h. When TLC indicated consumption of starting material the reaction mixture was cooled to rt, diluted in water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (50 mL), dried (Na2S0₄), filtered and concentrated. The crude material was purified by CombiFlash® (silica gel) eluted with 8% MeOH in DCM.

Fractions containing compound were combined and concentrated and the resulting solid was triturated in MeCN (2 x 5 mL) followed by trituration in EtOH (15 mL). and dried which gave the title compound (100 mg, 15%) as a solid. LCMS (ES+) m/z 369.20 [M+H]⁺. xam le 4

1-(5-chloro-6-(2H-1 ,2,3-triazol-2-yl)pyridin-3-yl)-3-(2-chloro-7-(1- (trifluoromethyl)cvclopropyl)pyrazolo[1 ,5-alpyrimidin-6-yl)urea (4)

DPPA (210 mg, 0.76 mmol) was added at rt to a stirred solution of l-6c (120 mg, 0.38 mmol) in 1 ,4 dioxane followed by addition of EtzN (210 mg, 2.08 mmol). The resulting mixture was stirred at rt for 30 min then compound 1-1 b (89.8 mg, 0.38 mmol) was added and the mixture was stirred at 100 °C for 2 h. After completion of the reaction as judged by LC-MS, the mixture was concentrated under reduced pressure, the residue was dissolved in water and extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2S0₄), filtered and concentrated. The crude compound was purified by column chromatography on silica gel eluted with 70% EtOAc : p. ether. Appropriate fractions were pooled, concentrated and purified by prep C18 HPLC eluted with a gradient of 10 mM NH₄HC0₃ in H₂0 : MeCN which gave the title compound as a solid. LCMS (ES+) m/z 498.15 [M+H]⁺.

Example 5

1-(6-(4-(aminomethyl)-1 H-pyrazol-1-yl)-5-chloropyridin-3-yl)-3-(2-chloro-7-(1- (trifluoromethyl)cvclopropyl)pyrazolo[1 ,5-alpyrimidin-6-yl)urea (5a)

DPPA (349 mg, 1.26 mmol) and Et₃N (351 mg, 3.46 mmol) were added at rt to a stirred solution of l-6c (200 mg, 0.63 mmol) in 1 ,4-dioxane. The resulting mixture was stirred at rt for 30 min, then compound l-5b (212 mg, 0.63 mmol) was added. The reaction mixture was stirred at 100 °C for 2 h, then concentrated under reduced pressure, dissolved in water and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2S0₄) and concentrated. The crude compound was purified by flash column chromatography eluted with 0.1 % HCOOH in MeCN which gave the title compound as a solid. LCMS (ES+) 626.17 [M+H]⁺.

1-(6-(4-(aminomethyl)-1 H-pyrazol-1-yl)-5-chloropyridin-3-yl)-3-(2-chloro-7-(1-

(trifluoromethyl)cvclopropyl)pyrazolo[1 ,5-alpyrimidin-6-yl)urea (5b) TFA (0.9 ml, 9.4 mmol) was added at rt under nitrogen to a stirred solution of compound 5a (180 mg, 0.13 mmol) in DCM . The mixture was stirred at rt for 16 h, then concentrated under reduced pressure. Diethyl ether (6 mL) was added to the residue and the mixture was concentrated then dried. The crude compound was triturated with diethyl ether (10 mL) which gave the title compound (120 mg, 80%) as a solid. MS (ES+) 526.21 [M+H]⁺.

Example 6

1-(5-chloro-6-(2H-1 ,2,3-triazol-2-yl)pyridin-3-yl)-3-(7-(3-fluoropyridin-4-yl)-2-methylpyrazolori ,5- alpyrimidin-6-yl)urea (9)

DPPA (0.52 mL, 2.41 mmol) and Et₃N (1.13 mL, 8.1 1 mmol) were added under nitrogen at rt to a stirred solution of l-7c (0.34 g, 1.25 mmol) in 1 ,4 dioxane (15 mL). The mixture was stirred at rt for 30 min, then 1-1 b (0.25 g, 1.28 mmol) was added and the reaction mixture was stirred at 100 °C for 3 h. The mixture was concentrated and the residue dissolved in EtOAc (200 mL). The organic layer was washed with saturated NaHCC>3 and brine, dried (Na2S0₄), filtered and concentrated under reduced pressure. The crude product was purified by column

chromatography on silica gel eluting with 10% MeOH in DCM. Appropriate fractions were pooled and concentrated and the residue was purified by prep. HPLC using a gradient of 10 mM NH₄HC03 in H2O : MeCN as mobile phase which gave the title compound (0.055 g, 9.5%) as a solid. MS (ES+) m/z 465.18 [M+H]⁺.

Example 7

1-(5-Chloro-6-(2H-1 ,2,3-triazol-2-yl)pyridin-3-yl)-3-(2-chloro-7-(thiazol-5-yl)pyrazolori ,5- alpyrimidin-6-yl)urea (7)

DPPA (0.1 17 mL, 0.545 mmol) and Et₃N (0.3 mL, 2.1 mmol) were added to a stirred solution of l-8c (150 mg, 0.449 mmol) in 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). The combined organic layers were washed with brine, dried (Na2S0₄), filtered and concentrated and the afforded crude compound was purified by column chromatography on silica gel eluted with 3-4% MeOH in DCM. The afforded solid was purified by prep HPLC on a Kromasil® C18 column using 10 mM NH4HCO3 in H2O : MeCN as mobile phase, which gave the title compound (45 mg, 21 %), MS (ES+) m/z 473.13 [M+H]⁺.

Example 8

I -6c 8

1-(2-chloro-7-(1-(trifluoromethyl)cvclopropyl)pyrazolo[1 ,5-alpyrimidin-6-yl)-3-(5-methylpyridin-3- vDurea (8)

DPPA (0.2 mL, 0.93 mmol) and Et₃N (0.8 mL, 5.74 mmol) were added at rt to a solution of l-6c (200 mg, 0.63 mmol) and 5-methylpyridin-3-amine (100 mg, 0.91 mmol) in toluene (15 mL). The resulting mixture was heated by microwave irradiation to 120 °C and stirred for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2x60 mL), the combined organic layers were washed with aqueous saturated sodium bicarbonate (20 mL), dried

(Na2S0₄), filtered and concentrated. The afforded crude material was purified by CombiFlash ® on a silica gel column eluted with EtOAc in p. ether. The afforded residue was purified by prep HPLC on a Kromasil® C18 column using 10 mM NH₄HC0₃ in H₂0 : MeCN as mobile phase, which gave the title compound (50 mg, 19%) as a solid. MS (ES+) m/z 41 1.14 [M+H]⁺.

Example 9

1-(5-Chloro-6-(2H-1 ,2,3-triazol-2-yl)pyridin-3-yl)-3-(2-chloro-7-((1 S.2S)-2- fluorocvclopropyl)pyrazolo[1 ,5-alpyrimidin-6-yl)urea (9-1)

& 1-(5-Chloro-6-(2H-1 ,2,3-triazol-2-yl)pyridin-3-yl)-3-(2-chloro-7-((1 R,2R)-2- fluorocvclopropyl)pyrazolo[1 ,5-alpyrimidin-6-yl)urea (9-2)

DPPA (0.43 mL, 2.00 mmol) and Et₃N (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 (Na2S0₄), filtered and concentrated. The residue was purified by CombiFlash ® on a silica gel column eluted with 0 - 3% MeOH in DCM. Pure fractions were pooled, concentrated and purified by prep C18HPLC. Pure fractions were pooled and concentrated which gave the two stereoisomers of the title compound (85 mg) as a solid with enantiomeric ratio 52:47. LCMS (ES+) 448.08 [M+H]⁺.

The stereoisomers were separated by SFC using a Chiralpak-IG (4.6*250)mm, 5 μ column, which gave the two stereoisomers, 9-1 (29 mg, 6.0%) and 9-2 (28 mg, 6,2%) Example 10

1-(5-chloro-6-(2H-1 ,2,3-triazol-2-yl)pyridin-3-yl)-3-(7-(5-fluoropyridin-2-yl)-2-methylpyrazolori ,5- alpyrimidin-6-yl)urea (10)

DPPA (0.27 mL, 1.28 mmol) and Et₃N (0.69 mL, 4.950 mmol), were added to a stirred solution of 1-10c (300 mg, 1.058 mmol) in toluene (15 mL) followed by addition of 1-1 b (317 mg, 1.59 mmol). The reaction mixture was heated by microwave irradiation and stirred at 100 °C for 1 h. The reaction mixture was diluted with ice cold water and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried (Na2S0₄), filtered and concentrated. The obtained crude compound was purified by column chromatography on silica gel eluting with 3-4% MeOH in DCM. Pure fractions were pooled and concentrated and the residue was purified by prep. HPLC on a on a Kromasil® C18 (25X150) mm 10 μ column using 10 mM NH₄HC0₃ in H2O : MeCN as mobile phase. Pure fractions were collected and concentrated and subjected to SFC, which gave the title compound (8 mg) as a solid. LC-MS (ES+) m/z 465 [M+H]⁺. xample 11

l-6c 11

1-(2-chloro-7-(1-(trifluoromethyl)cvclopropyl)pyrazolo[1 ,5-alpyrimidin-6-yl)-3-(5-chloropyrid vDurea (11)

DPPA (0.04 g, 0.15 mmol) and Et₃N (0.04 g, 0.42 mmol) were added at rt to a stirred solution of l-6c (25 mg, 0.08 mmol) in 1 ,4 dioxane. The resulting mixture was stirred at rt for 30 min then 5- chloropyridin-3-amine (11.9 mg, 0.08 mmol) was added. The mixture was heated to 100 °C and stirred at this temp for 4h, then concentrated, dissolved in water and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2S0₄), filtered and concentrated. The residue was purified by column chromatography on a silica gel. Fractions containing the title compound were pooled, concentrated and the residue purified by prep C18 HPLC eluted with a gradient of 10 mM NH₄HCC>3 in H2O: MeCN. Pure fractions were pooled and

concentrated and the residue purified by prep C18 HPLC eluted with a gradient of 10 mM NH₄HC0₃ in H₂0: MeCN which gave the title compound (50 mg, 25%) as a solid. LCMS (ES+) 431.08 [M+H]⁺.

Example 12

1-(5-chloro-6-(1 H-1 ,2,3-triazol-1-yl)pyridin-3-yl)-3-(2-chloro-7-(1- (trifluoromethvDcvclopropyDpyrazoloH ,5-alpyrimidin-6-yl)urea (13)

DPPA (0.35 ml_, 1.63 mmol) and Et₃N (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 (Na2S0₄), filtered and concentrated. The obtained crude compound was purified by column chromatography on silica gel eluting with EtOAc : p. ether 1 : 1. Pure fractions were pooled and concentrated and the residue was purified by prep. C18 HPLC using 10 mM NH HC03 in H₂0 : MeCN as mobile phase. Pure fractions were collected and concentrated, which gave the title compound (76 mg, 16) as a solid. LC-MS (ES+) m/z 498.06 [M+H]⁺. xample 13

1-(2-chloro-7-(1-(trifluoromethyl)cvclopropyl)pyrazolo[1 ,5-alpyrimidin-6-yl)-3-(5-methyl-6-(2H- 1 ,2,3-triazol-2-yl)pyridin-3-yl)urea (13)

DPPA (0.59 g, 2.15 mmol) and Et₃N (0.59 g, 5.88 mmol) were added at rt to a stirred solution of l-6c (25 mg, 0.08 mmol) in 1 ,4 dioxane. The resulting mixture was stirred at rt for 30 min then I- 12b (mix. of isomers, 227 mg, 1.07 mmol) was added. The mixture was stirred heated at 100 °C for 4h, then concentrated, dissolved in water and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2S0₄), filtered and concentrated. The residue was purified by prep C18 HPLC eluted with a gradient of 10 mM NH₄HC0₃ in H₂0: MeCN. Pure fractions were pooled and concentrated, which gave the title compound together with isomers (130 mg, 25%) as a solid. The isomers were separated by prep SFC, which gave the title compound (25 mg, 4.8%) as a solid. LCMS (ES+) 478.25 [M+H]⁺.

SFC Conditions

Column/dimensions : Chiralpak AD-H ( 30x250 mm ), 5μ

% C0₂ : 60.0%

% Co solvent (MeOH) : 40.0%

Total Flow : 60.0 g/min

Back Pressure : 90.0 bar

UV : 254 nm

Stack time : 6.0 min

Load/I nj 12.1 mg

Example 14

1-(5-chloro-6-(2H-1 ,2,3-triazol-2-yl)pyridin-3-yl)-3-(7-(1-(trifluoromethyl)cyclopropyl)pyrazolo[1 ,5- alpyrimidin-6-yl)urea

DPPA (0.24 mL, 1.08 mmol) and Et₃N (0.30 mL, 2.20 mmol) were added under nitrogen at rt to a stirred solution of 1-13c (150 mg, 0.54 mmol) in 1 ,4 dioxane (5 mL). The mixture was stirred at rt for 30 min, then 1-1 b (1 12 mg, 0.54 mmol) was added and the reaction mixture was stirred at 110 °C for 16 h. The mixture was diluted with water (30 ml_) and extracted with EtOAc (50 ml). The organic layer was washed with brine, dried (Na2S0₄), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel and eluted with 3% MeOH in DCM. Appropriate fractions were pooled and concentrated and the residue was purified by prep. HPLC using a gradient of 10 mM NH₄HCC in water: acetonitrile as mobile phase which gave the title compound (70 mg, 27%) as a solid. MS (ES+) m/z 464.10 [M+H]⁺.

1 H NMR (500 MHz, DMSO): δ 10.14 (s, 1 H), 8.79 (s, 1 H), 8.55 (s, 1 H), 8.50 (s, 1 H), 8.32 (s, 1 H), 8.28 (s, 1 H), 8.16 (s, 2H), 6.86 (s, 1 H), 1.77 (s, 2H), 1.49 (s, 2H).

The compounds listed in TABLE A were prepared according to the general method described in example 14 using the indicated building blocks

Compound l-18bwas coupled with 5-chloro-2-(1-methylpyrrolidin-3-yloxy)-6-(2H-1 ,2,3-triazol-2- yl)pyridin-3-amine using triphosgene and triethylamine.

²5-chloro-2-(1-methylpyrrolidin-3-yloxy)-6-(2H-1 ,2,3-triazol-2-yl)pyridin-3-amine was synthesized

according to PCT Int. Appl., 2015181747.

3Note: structure was not confirmed because correlation was not observed in NOE, HSQC and HMBC techniques.

treatment with 4M HCI after prep. HPLC purification,

treatment with TFA before prep. HPLC purification. Example15:

¹H NMR (500 MHz, DMSO): δ 10.17 (s, 1H), 8.85 (s, 1H), 8.78 (s, 1H), 8.69 (s, 1H), 8.37 (s, 1H), 8.28 (s, 2H), 6.86 (s, 1H), 1.76 (s, 2H), 1.49 (s, 2H).

Example 16:

¹H NMR (500 MHz, DMSO): δ 10.19 (s, 1H), 8.76 (s, 1H), 8.48 (d, J = 5.5 Hz, 1H), 8.31 (s, 1H), 8.26 (s, 1H), 7.89 (s, 1H), 7.51 (d, J = 5.4 Hz, 1H), 6.89 (m, J= 27.5 Hz, 2H), 1.75 (s, 2H), 1.47 (s, 2H).

SFC Conditions

Column/dimensions : (R,R) Whelk-01 (4.6x250 mm), 5 μ

C0₂ : 70.0%

Co-solvent : 30.0% (100% Methanol)

Total Flow : 3.0 g/min

Back Pressure : 100.0 bar

Example 17:

¹H NMR (500 MHz, DMSO): δ 9.97 (s, 1H), 8.74 (s, 1H), 8.69 (s, 1H), 8.58 (d, J= 2.3Hz, 1H), 8.46 (d, J = 2.3Hz, 1H), 8.15 (s, 1H), 7.02 (s, 1H), 6.83 (t, J=74.4 Hz, 1H),6.09 (q, J = 6.8 Hz, 1H), 1.80 (d, J = 6.8 Hz, 3H).

Example 17-1:

1H NMR (500 MHz, DMSO): δ 9.98 (s, 1H), 8.74 (s, 1H), 8.69 (s, 1H), 8.58 (s, 1H), 8.46 (s, 1H), 8.15 (s, 2H), 7.02 (s, 1H), 6.83 (t, J = 74.4 Hz, 1H), 6.09 (q, J = 6.7 Hz, 1H), 1.80 (d, J = 6.7 Hz, 3H).

Example 17-2:

¹H NMR (500 MHz, DMSO) δ 9.97 (s, 1H), 8.74 (s, 1H), 8.69 (s, 1H), 8.58 (s, 1H), 8.46 (s, 1H), 8.15 (s, 2H), 7.02 (s, 1H), 6.83 (t, J = 74.4 Hz, 1H), 6.09 (q, J = 6.7 Hz, 1H), 1.80 (d, J = 6.7 Hz, 3H).

Preparative SFC Conditions

Column/dimensions : Chiralcel OD-H (21 x250 mm), 5μ

% C0₂ : 80.0% % Co solvent 20.0% (100% MeOH)

Total flow 60.0 g/min

Back pressure 90.0 bar

UV 214 nm

Stack time 9.5 min

Load/I nj. 6.0 mg

Example 18

¹H NMR (500 MHz, DMSO): δ 10.02 (s, 1H), 8.87 (s, 1H), 8.76 (s, 1H), 8.74 (s, 1H), 8.66 (s, 1H) 8.28 (s, 2H), 7.02 (s, 1H), 6.83 (t, J = 74.5 Hz, 1H), 6.09 (q, J= 6.7 Hz, 1H), 1.80 (d, J = 6.7 Hz, 3H).

Preparative NP-HPLC Conditions

Column/dimensions: Pyridyl Amide (250 X30) mm, 5 u

Mobile Phase: n-Hexane: Ethanol (45:55)

Flow: 44.0 ml /min

Temperature: Ambient

Wave length: 288nm

Run time: 30min

Solubility: Ethanol+THF+ACN

Load ability/lnj: 10.0mg/lnj

Total No of injections:04

Example 19

¹H NMR (500 MHz, DMSO): δ 10.09 (s, 1H), 8.72 (s, 1H), 8.66 (s, 1H), 8.56 (d, J =5.6 Hz, 1H), 8.06 (d, J= 1.9 Hz, 1H), 7.64 (q, J= 2.5 Hz, 1H), 7.01 (s, 1H), 6.82 (t, J= 74.5 Hz, 1H), 6.08 (q, J = 6.8 Hz, 1H), 1.78 (d, J= 6.8 Hz, 3H).

Example 20

¹H NMR (500 MHz, DMSO): δ 10.85 (s, 1H), 9.36 (d, J = 1.7 Hz, 2H), 8.81 (s, 1H), 8.35 (s, 6.93 (d, J = 79.1 Hz, 1H), 6.70 (s, 1H), 6.17 (q, J = 6.8 Hz, 1H), 1.76 (d, J = 6.8 Hz, 3H).

Example 21

¹H NMR (500 MHz, DMSO): δ 9.97 (s, 1H), 8.87 (s, 1H), 8.67 (s, 2H), 8.65 (s, 1H), 8.29 (s, 8.28 (s, 2H), 6.83 (q, J = 49.7 Hz, 2H), 6.20 (d, J = 6.8 Hz, 1H), 1.82 (d, J = 6.7 Hz, 3H). Example 22

¹ H NMR (500 MHz, DMSO): δ 10.01 (s, 1 H), 8.70 (s, 1 H), 8.65 (s, 1 H), 8.58 (s, 1 H), 8.47 (s, 1 8.29 (s, 1 H), 8.15 (s, 2H), 6.83 (q, J = 49.7 Hz, 2H), 6.20 (q, J = 6.5 Hz, 1 H), 1.82 (d, J = 6.5 3H).

Preparative NP-HPLC Conditions

Column/dimensions : Chiralpak IC (250 X30) mm, 5u

Mobile Phase : Acetonitrile (100%)

Flow : 38.0ml /min

Temperature : Ambient

Wave length : 262 nm

Run time 16 min

Solubility Acetonitrile

Load ability/lnj : 5.75 mg/lnj

Total No of injections : 04

Example 23

¹ H NMR (500 MHz, DMSO): δ 9.92 (s, 1 H), 8.64 (s, 1 H), 8.48 (t, J = 8.0 Hz, 2H), 8.28 (d, J = 2.4 Hz, 1 H), 7.87 (d, J = 2.0 Hz, 1 H), 7.54 (q, J = 2.5 Hz, 1 H), 6.83 (m, J = 23.5 Hz, 3H), 6.19 (q, J = 6.8 Hz, 1 H), 1.80 (d, J = 6.8 Hz, 3H).

Preparative SFC Conditions

Column/dimensions : Chiralpak AD-H (30x250 mm), 5μ

C0₂ : 90.0%

Co solvent : 10.0% (100% Ethanol)

Total Flow : 70.0 g/min

Back Pressure : 100.0 bar

UV : 214 nm

Stack time : 7.3 min

Load/I nj : 4.0 mg Example 24

¹ H NMR (500 MHz, DMSO): δ 9.57 (s, 1 H), 8.88 (s, 1 H), 8.13 (m, J = 7.9 Hz, 3H), 6.99 (s, 1 H), 3.91 (s, 3H), 1.76 (s, 2H), 1.46 (t, J = 1 1.7 Hz, 2H).

Preparative SFC Conditions

Column/dimensions : Lux Cellulose-2 (30x250 mm), 5μ

C0₂ : 80.0%

Co solvent : 20.0% (0.5% DEA in Methanol)

Total Flow : 60.0 g/min BackPressure : 100.0 bar

UV : 214 nm

Stack time : 3.7 min

Load/I nj. : 17.0 mg

Example 25

¹H NMR (500 MHz, DMSO): δ 10.18 (s, 1H), 8.86 (d, J

8.28 (s, 2H), 7.02 (s, 1H), 1.77 (s, 2H), 1.50 (s, 2H) Example 26

¹H NMR (500 MHz, DMSO): δ 10.75 (s, 1H), 10.32 (s, 1H), 9.10 (t, J = 4.5 Hz, 2H), 7.92 (s, 1H), 7.00 (s, 1H), 1.81 (q, J = 2.1 Hz, 2H), 1.52 (s, 2H).

Example 27

H NMR (500 MHz, DMSO): δ 10.34 (s, 1H), 8.87 (s, 1H), 8.14 (s, 1H), 7.27 (s, 1H), 6.99 (s, 1H), 2.51 (s, 3H), 1.75 (s, 2H), 1.45 (s, 2H).

Example 28

¹H NMR (500 MHz, DMSO): δ 9.95 (s, 1H), 8.91 (s, 2H), 8.86 (s, 1H), 8.27 (t, J= 10.5Hz, 2H), 8.15 (d, J = 2.4 Hz, 1H), 6.99 (s, 1 H), 3.37 (m, 4H), 3.23 (m, 4H), 1.77 (s, 2H), 1.46 (s,2H).

Example 29

¹H NMR (500 MHz, DMSO): δ 9.94 (s, 1H), 9.14 (s, 2H), 8.86 (s, 1H), 8.25 (s, 1H),8.17 (s, 2H), 6.99 (s, 1H),5.57 (t, =5.0 Hz, 1H), 3.56 (q, J=6.1 Hz, 1H), 3.40 (s, 2H), 2.30 (m, =5.8 Hz, 1H), 2.17 (q, J = 4.5Hz, 1H), 1.77 (s, 2H), 1.46 (s, 2H).

Example 30

¹H NMR (500 MHz, DMSO): δ 10.96 (s, 1H), 9.97 (s, 1H), 9.37 (d, J = 1.8 Hz, 1H), 9.08 (s, 1H), 8.19 (s, 1H), 7.00 (s, 1H), 1.81 (d, J = 1.6 Hz, 2H), 1.52 (s, 2H).

Example 31

¹H NMR (500 MHz, DMSO): δ 9.89 (s, 1H), 8.89 (s, 1H), 8.53 (t, J= 3.8 Hz, 2H), 8.21(s, 1H), 8.12 (d, J= 1.6 Hz, 1H), 7.94 (s, 1H), 6.98 (s, 1H), 2.30 (s, 3H), 1.78 (s, 2H),1.49 (s, 2H).

Preparative SFC Conditions

Column/dimensions : Chiralpak AD-H (30x250 mm), 5 μ

C0₂ : 60.0%

Co solvent : 40.0% (100% Methanol) Total Flow 60.0 g/min

Back Pressure 90.0 bar

UV 254 nm

Stack time 6.0 min

Load/I nj. 12.1 mg

Example 32

¹H NMR (500 MHz, DMSO): δ 10.48 (s, 1H), 9.38 (d, J = 2.5 Hz, 1H), 8.84 (s, 1H), 8.59 (s, 1H), 8.33 (d, J = 2.5 Hz, 1H), 7.04 (s, 1H), 1.75 (s, 2H), 1.50 (s, 2H).

Example 33

¹H NMR (500 MHz, DMSO): δ 9.25 (s, 1H), 8.74 (s, 1H), 8.68 (s, 1H), 8.43 (s, 1H),8.26 (s, 1H), 6.97 (s, 1H), 5.33 (d, J =3.1 Hz, 1H), 2.78 (q, J =5.6 Hz, 1H), 2.69 (m, J = 4.3 Hz, 2H), 2.32 (q, J = 5.3 Hz, 2H), 2.26 (s, 4H), 1.87 (d, J = 2.1 Hz, 1H), 1.71(s, 2H), 1.44 (s, 2H).

Example 34-1

¹H NMR (500 MHz, DMSO): δ 9.93 (s, 1H), 8.57 (t, J= 3.5 Hz, 3H), 8.46 (d, J= 2.3Hz, 1H),8.15 (s, 2H),6.82 (t, J= 74.5 Hz, 1H),6.62 (s, 1H), 6.18 (q, J = 6.7 Hz, 1H),2.47 (s, 3H), 1.79 (d, J = 6.8 Hz, 3H).

Example 34-2

¹H NMR (500 MHz, DMSO): δ 9.98 (s, 1H), 8.57 (t, J = 4.1 Hz, 3H), 8.46 (d, J= 1.8Hz, 1H), 8.15 (s, 2H), 6.83 (t, J = 74.5 Hz, 1H), 6.62 (s, 1H), 6.18 (q, J = 6.6 Hz, 1H),2.48 (d, J= 5.5 Hz, 3H), 1.79 (d, J = 6.7 Hz, 3H).

Example 35

¹H NMR (500 MHz, DMSO): δ 10.09 (s, 1H), 8.68 (s, 1H), 8.54 (d, J= 2.3 Hz, 1H),8.49 (d, J = 2.4 Hz, 1H), 8.24 (s, 1H), 8.16 (s, 2H), 6.64 (s, 1H), 2.47 (s, 3H), 1.76 (s,2H), 1.47 (s, 2H). Example 36

¹H NMR (500 MHz, DMSO): δ 10.48 (s, 1H), 9.37 (d, J = 2.4 Hz, 1H), 8.64 (s, 1H), 8.49 (s, 1H), 8.32 (d, J = 2.5 Hz, 1 H), 6.65 (s, 1 H), 2.47 (s, 3H), 1.73 (s, 2H), 1.47 (s, 2H).

Example 37-1

1H NMR (500 MHz, DMSO): δ 9.64 (d, J= 381.7 Hz, 1H), 8.60 (d, J= 1.6 Hz, 1H),8.44 (d, J = 20.4 Hz, 2H), 8.15 (s, 2H), 6.86 (d, J = 7.9 Hz, 2H), 6.45 (s, 3H), 5.71 (d,J= 57.3 Hz, 1H), 5.40 (d, J= 10.1 Hz, 1H), 4.24 (d, J= 14.6 Hz, 1H), 3.96 (d, =13.1 Hz, 1H), 3.55 (s, 3H), 2.72 (m, J = 9.1 Hz, 2H), 2.39 (s, 3H), 1.24 (d, J= 8.7 Hz,1H).

Example 37-2

¹H NMR (500 MHz, DMSO): δ 9.93 (s, 1H), 8.54 (t, J= 16.2 Hz, 1H), 8.46 (s, 2H),8.14 (s, 2H), 6.85 (d, J= 7.6 Hz, 2H), 6.48 (d, J= 8.2 Hz, 2H), 6.41 (s, 1H), 5.41 (m, = 14.0 Hz, 1H), 5.26 (s, 1H), 4.25 (d, J= 14.5 Hz, 1H), 3.68 (m, J= 11.6 Hz, 1H),3.53 (s, 3H), 2.80 (m, J= 14.3 Hz, 2H), 2.34 (s, 3H), 1.19 (m, J= 12.6 Hz, 1H).

Preparative SFC Conditions

Column/dimensions : Chiralpak IC (21 x250 mm), 5 μ

C0₂ : 70.0%

Co solvent : 30.0% (100% EtOH)

Total flow : 60.0 g/min

Back pressure : 80.0 bar

UV : 210 nm

Stack time : 5.5 min

Load/I nj. : 3.7 mg

Example 38-1

¹H NMR (500 MHz, DMSO): 59.37 (s, 2H), 8.60 (t, = 6.6 Hz, 2H), 8.46 (d, =2.3Hz, 1H), 8.15 (s, 2H), 6.91 (s, 1H), 5.58 (m, J= 8.4 Hz, 1H), 2.85 (m, J= 3.9 Hz,1H), 1.84 (m, J= 3.8 Hz, 2H).

Example 38-2

¹H NMR (500 MHz, DMSO): δ 9.51 (s, 2H), 8.61 (t, J= 12.6 Hz, 2H), 8.47 (d, J= 1.8Hz, 1H), 8.14 (s, 2H), 6.88 (s, 1H), 5.60 (d, J = 64.9 Hz, 1H), 2.87 (m, J= 7.3 Hz,1H), 1.82 (m, J = 4.7 Hz, 2H).

Preparative SFC Conditions

Column/dimensions : Chiralpak-IG (4.6*250) mm, 5 μ

C0₂ : 50.0%

Co solvent : 100% MeOH

Flow rate : 4.0 mL/min

Back pressure : 100.0 bar

Injected volume : 10 μΙ

Example 39

¹H NMR (500 MHz, DMSO): δ 10.07 (s, 1H), 8.96 (s, 1H), 8.80 (s, 1H), 8.56 (d, J =2.3 Hz, 1H), 8.49 (d, J = 2.3 Hz, 1H), 8.16 (s, 2H), 7.00 (d, J= 18.4 Hz, 2H), 1.77 (s,2H), 1.36 (d, J= 1.2 Hz, 2H). Preparative SFC Conditions

Column/dimensions : Chiralpak IC (21 x250 mm), 5 μ

C0₂ : 65.0%

Co solvent : 35.0% (100% MeOH)

Total flow : 60.0 g/min

Back pressure : 100.0 bar

UV 254 nm

Stack time 3.8 min

Load/I nj. 7.3 mg

Example 40

¹H NMR (500 MHz, DMSO): δ 10.09 (s, 1H), 8.84 (s, 1H), 8.77 (s, 1H), 8.58 (d, J =2.4 Hz, 1H), 8.48 (d, J = 2.2, Hz, 1H), 8.16 (s, 2H), 7.32 (s, 1H), 6.86 (t, J = 74.4 Hz,1H), 6.22 (q, J = 6.8 Hz, 1 H), 3.93 (s, 3H), 1.82 (d, J = 6.8 Hz, 3H).

Example 41

¹H NMR (500 MHz, DMSO): δ 10.97 (t, J = 7.6 Hz, 1H), 10.40 (s, 1H), 9.02 (s, 1H),8.58 (d, J = 2.3 Hz, 1H), 8.46 (d, J = 2.3 Hz, 1H), 8.15 (s, 2H), 6.88 (s, 1H), 5.40 (m, J= 13.4 Hz, 2H), 4.18 (t, J= 19.4 Hz, 1H), 3.39 (s, 2H), 2.70 (m, J= 7.9 Hz, 2H),1.97 (m, J= 7.8 Hz, 1H).

Example 42

¹H NMR (500 MHz, DMSO): δ 11.00 (t, J = 6.3 Hz, 1H), 10.42 (s, 1H), 9.02 (s, 1H),8.58 (d, J = 2.3 Hz, 1H), 8.47 (d, J= 2.3 Hz, 1H), 8.15 (s, 2H), 6.88 (s, 1H), 5.40 (t, J= 26.9 Hz, 2H), 4.19 (m, J=20.6 Hz, 1H), 3.37 (s, 1H), 3.29 (s, 1H),2.68 (m, = 6.4Hz, 1H), 1.97 (m, =6.4 Hz, 1H).

Example 43

¹H NMR (500 MHz, DMSO): δ 9.71 (s, 1H), 8.86 (d, J= 2.5 Hz, 1H), 8.63 (d, J= 1.8Hz, 1H), 8.53 (s, 1H), 8.47 (s, 1H), 8.40 (t, J= 2.1 Hz, 1H), 6.81 (t, J = 74.5 Hz, 1H),6.62 (s, 1H), 6.16 (q, J = 6.7 Hz, 1 H), 2.46 (s, 3H), 1.77 (d, J = 6.8 Hz, 3H).

Preparative normal phase HPLC Conditions

Column/dimensions : Chiralcel OJ-H (21 x250 mm), 5μ

Mobile Phase : n-Hexane: Isopropanol (75:25)

Flow : 18.0 ml /min

Temperature : Ambient

Wave length : 260 nm

Runtime : 10 min

Solubility : Ethanol Load ability/ : 1.43mg/lnj

Total No of injections : 78

Example 44

1H NMR (500 MHz, DMSO): δ 9.93 (s, 1H), 8.86 (D, J=3.5Hz, 1H), 8.73 (d, J = 2.3Hz, 1 H),8.55 (s, 1H),8.26 (s, 2H), 6.82 (t, J= 74.5 Hz, 1H),6.62 (s, 1H), 6.18 (q, J = 6.7 Hz, 1H),2.47 (s,4H), 1.79 (d, J = 6.8 Hz, 3H).

Preparative NP-HPLC Conditions

Column/dimensions : Pyridyl Amide (250 X30) mm, 5u

Mobile Phase : n-Hexane: Ethanol (45:55)

Flow : 44.0 ml /min

Temperature : Ambient

Wave length : 288 nm

Run time : 30 min

Solubility : Ethanol+DCM+ACN

Load ability : 10.0mg/lnj

Total No of injections : 04

Example 45

¹H NMR (500 MHz, DMSO): δ 9.97 (s, 1H), 8.68 (s, 2H), 8.58 (d, J = 2.3 Hz, 1H), 8.46 (d, J = 2.3 Hz, 1H), 8.15 (s, 2H), 7.55 (t, J = 72.6 Hz, 1H), 6.82 (t, J = 74.5 Hz, 1H), 6.61 (s, 1H), 6.05 (q, J = 6.7 Hz, 1H) , 1.80 (d, J = 6.8 Hz, 3H).

Example 46:

1H NMR (500 MHz, DMSO) δ 10.15 (s, 1H), 8.83 (s, 1H), 8.55 (d, J = 2.4 Hz, 1H), 8.49 (d, J = 2.3 Hz, 1H), 8.36 (s, 1H), 8.16 (s, 2H), 7.52 (t, J = 72.7 Hz, 1H), 6.62 (s, 1H), 1.75 (s, 2H), 1.50 (s, 2H).

Example 47:

1H NMR (500 MHz, DMSO) δ 11.07 (d, J = 2.8 Hz, 1H), 8.86 (s, 1H), 8.53 (s, 1H), 7.73 (s, 1H), 7.03 (s, 1H), 1.74 (s, 2H), 1.49 (s, 2H).

Example 48

¹H NMR (500 MHz, DMSO) δ 11.89 (s, 1H), 8.91 (s, 1H), 8.49 (s, 1H), 8.05 (d, J= 1.4 Hz, 1H), 7.03 (s, 1 H), 1.76 (s, 2H), 1.49 (s, 2H). Preparative SFC Conditions

Column/dimensions Lux Cellulose-2 (30x250 mm), 5 μ

60.0%

Co solvent 40.0% (0.5% DEA in Methanol)

Total Flow 90.0 g/min

Back Pressure 100.0 bar

UV 240 nm

Stack time 6.5 min

Load/I nj 10.0 mg

Example 49

¹H NMR (500 MHz, DMSO): δ 10.22 (s, 1H), 8.76 (s, 1H), 8.57 (d, J = 5.6 Hz, 1H), 8.28 (d, J = 2.4 Hz, 2H), 8.07 (d, J = 1.9 Hz, 1H), 7.60 (q, J = 2.5 Hz, 1H), 6.86 (d, J = 2.4 Hz, 1H), 1.75 (s, 2H), 1.47 (s, 2H).

Example 50

¹H NMR (500 MHz, DMSO): δ 13.36 (s, 1H), 10.05 (s, 1H), 8.85 (s, 1H), 8.30 (s, 1H), 7.00 (s, 1H), 6.41 (s, 1H), 1.76 (s, 2H), 1.46 (s, 2H). Example 51

¹H NMR (500 MHz, DMSO):69.94 (s, 1H), 8.78 (s, 2H), 8.73 (d, J = 7.2 Hz, 1H), 8.58 (d, J = 2.4 Hz, 1H), 8.46 (d, J = 2.3 Hz, 1H), 8.15 (s, 2H), 6.82 (m, J = 37.2 Hz, 2H), 6.05 (q, J = 6.8 Hz, 1H), 1.80 (d, J = 6.8 Hz, 3H). Example 52

¹H NMR (500 MHz, DMSO): δ 10.70 (s, 1H), 9.81 (s, 1H), 9.06 (s, 1H), 8.23 (s, 1H), 7.00 (s, 1H), 4.13 (s, 3H), 1.82 (q, J = 2.1 Hz, 2H), 1.50 (s, 2H).

Example 53

¹H NMR (500 MHz, DMSO): δ 10.23 (s, 1H), 8.80 (s, 1H), 8.57 (d, J = 5.6 Hz, 1H), 8.32 (s, 8.07 (d, J = 1.9 Hz, 1H), 7.52 (m, J = 24.2 Hz, 2H), 6.62 (s, 1H), 1.73 (s, 2H), 1.48 (s, 2H).

Example 54

Ή NMR (500 MHz, DMSO): δ 10.55 (s, 1H), 8.98 (s, 1H), 8.61 (q, J= 2.1 Hz, 1H), 8.31 (q, J 3.2 Hz, 2H), 8.16 (s, 1H), 7.69 (q, J= 4.2 Hz, 1H), 7.00 (s, 1H), 1.77 (s, 2H), 1.47 (s, 2H). Example 55

¹H NMR (500 MHz, DMSO): δ 9.23 (s, 1H), 8.92 (s, 1H), 7.86 (s, 1H), 7.76 (d, J= 0.3 Hz, 1H), 7.40 (d, J= 0.7 Hz, 1H), 6.96 (s, 1H), 3.78 (s, 3H), 1.75 (s, 2H), 1.42 (d, J = 67.3 Hz, 2H). Example 56

H NMR (500 MHz, DMSO): δ 9.68 (s, 1H), 9.31 (s, 1H), 8.82 (s, 1H), 8.39 (s, 2H), 7.01 (s, 1H), 6.65 (s, 1H), 3.75 (s, 3H), 1.79 (s, 2H), 1.48 (s, 2H).

Preparative SFC Conditions

Column/dimensions : Chiralcel OD-H (250 x30 mm), 5μ

C0₂ : 75.0%

Co solvent : 25.0% (100% MeOH)

Total flow : 70.0 g/min

Back pressure : 90.0 bar

UV : 254 nm

Stack time : 5.5 min

Load/I nj. : 6.0 mg

Example 57

Ή NMR (500 MHz, DMSO) δ 10.35 (s, 1H), 9.42 (d, J= 2.5 Hz, 1H), 8.92 (s, 1H), 8.71 (s, 1H), 8.30 (d, J = 2.5 Hz, 1 H), 7.03 (s, 1 H), 6.81 (t, J = 74.4 Hz, 1 H), 6.08 (q, J = 6.8 Hz, 1 H), 1.78 (d, J= 6.8 Hz, 3H).

Preparative SFC Conditions

Column/dimensions : Chiralcel- OX-H (250X30) mm, 5μ

C0₂ : 85.0%

CCoo ssoollvveenntt : 15.0% MeOH

Total flow : 60.0 g/min

Back pressure : 90.0 bar

UV : 254 nm

Stack time : 8.0 min

LLooaadd//lInnji.. : 1.3 mg

Example 58

¹H NMR (500 MHz, DMSO): δ 9.38 (s, 1H), 9.02 (s, 1H), 8.64 (s, 1H), 8.30 (s, 2H), 7.03 (s, 1H), 1.80 (s, 2H), 1.53 (s, 2H). Example 59

¹ H NMR (500 MHz, DMSO): δ 9.85 (s, 1 H), 9.37 (s, 1 H), 9.19 (s, 2H), 9.03 (s, 1 H),8.86 (s, 1 H), 8.49 (d, J = 2.2, Hz, 1 H), 8.36 (d, J = 2.2 Hz, 1 H), 8.22 (d, J = 2.4 Hz, 1 H), 8.14 (s, 2H), 6.90 (d, J = 2.4 Hz, 1 H).

Preparative SFC Conditions (done twice)

Column/dimensions : Chiralpak IC (30 x250 mm), 5μ

C0₂ : 50.0%

Co solvent : 50.0% (100% MeOH)

Total flow : 60.0 g/min

Back pressure : 90.0 bar

UV : 214 nm

Stack time : 6.7 min

Load/I nj. : 5.5 mg Example 60

Step a) ethyl6-(3-(5-chloro-6-(2H-1 ,2,3-triazol-2-yl)pyridin-3-yl)ureido)-7-(1-

(trifluoromethyl)cvclopropyl)pyrazolo[1 ,5-alpyrimidine-2-carboxylate(60a)

DPPA (0.5 mL, 2.32 mmol) and Et₃N (1.3 mL, 9.32 mmol) were added under nitrogen at rt to a stirred solution of l-29c (600 mg, 1.75 mmol) in toluene (10 mL). The mixture was stirred at rt for 30 min, then 1-1 b (345 mg, 1.76 mmol) was added and the reaction mixture was stirred at 100 °C for 2 h. The mixture was concentrated and the residue was dissolved in EtOAc (50 mL). The organic layer was washed with saturated NaHC03 and brine, dried (Na2S04), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel and eluted with 60-100% EtOAc in pet ether. Appropriate fractions were pooled and concentrated, which gave the title compound (650 mg, 64%) as a solid. MS (ES+) m/z 536.37 [M+H]⁺. Step b) 6-(3-(5-chloro-6-(2H-1 ,2,3-triazol-2-yl)pyridin-3-yl)ureido)-7-(1- (trifluoromethyl)cvclopropyl)pyrazolo[1 ,5-alpyrimidine-2-carboxylic acid (60b)

Lithium hydroxide (30 mg, 1.25 mmol) was added at rt to a stirred solution of 60a (300 mg, 0.56 mmol) in THF (20.0 mL) and water (4.0 mL). The resulting reaction mixture was stirred at rt for 14 h, then concentrated under reduced pressure. The afforded crude was diluted with ice water (50 mL) and acidified with 10% citric acid (aq) solution up to pH 2 and precipitated solid was filtered and dried under vacuum which gave the title compound (250 mg, 84%) as a solid. LCMS

(ES+) M/z = 508.30 [M+H]⁺. Step c) tert-butyl 6-(3-(5-chloro-6-(2H-1 ,2,3-triazol-2-yl)pyridin-3-yl)ureido)-7-(1- (trifluoromethyl)cvclopropyl)pyrazolo[1 ,5-alpyrimidin-2-ylcarbamate (60c)

DPPA (0.1 mL, 0.37 mmol) and Et₃N (0.25 mL, 1.80 mmol) were added under nitrogen at rt to a stirred solution of 60b (150 mg, 0.30 mmol) in t-butanol (15 mL). The mixture was stirred at 80 °C for 15 h. The mixture was concentrated and the residue was dissolved in EtOAc (50 mL). The organic layer was washed with saturated NaHCC>3 and brine, dried (Na2S0₄), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel and eluted with 70-100% EtOAc in pet ether. Appropriate fractions were pooled and concentrated, which gave the title compound (220 mg) as a solid. MS (ES+) m/z 579.38 [M+H]⁺. The compound was used in next step without further purification.

Step d) 1-(2-amino-7-(1-(trifluoromethyl)cvclopropyl)pyrazolo[1 ,5-alpyrimidin-6-yl)-3-(5-chloro-6- (2H-1 ,2,3-triazol-2-yl)pyridin-3-yl)urea (60d)

TFA (0.35 mL, 3.92 mmol) at rt under nitrogen was added to a stirred solution of 60c (220 mg, 0.38 mmol) in DCM (10.0 mL). The reaction mixture was stirred at rt for 15 h, then concentrated under reduced pressure. The residue was basified with cold saturated NaHCC>3 solution. The aqueous layer was extracted with EtOAc (2 x 25 mL). The organic layer was washed with saturated NaHCOs and brine, dried (Na2S0₄), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel and eluted with 5-8% MeOH in DCM. The impure compound was purified by prep. HPLC using a gradient of 10 mM NH₄HC03 in water: acetonitrile as mobile phase. The impure compound was further purified by SFC, which gave the title compound (12 mg, 6%) as a solid. MS (ES+) m/z 479.39 [M+H]⁺. ¹ H NMR (500 MHz, DMSO): δ 10.01 (s, 1 H), 8.53 (d, J = 2.4 Hz, 1 H), 8.47 (d, J = 2.3 Hz, 1 H), 8.34 (s, 1 H), 8.15 (s, 3H), 5.83 (d, J = 12.4 Hz, 3H), 1.66 (s, 2H), 1.43 (s, 2H).

Preparative SFC Conditions

Column/dimensions : Chiralcel- OX-H (250X30) mm, 5 μ

C0₂ : 55.0% Co solvent : 45% MeOH

Total Flow : 70.0 g/min

Back Pressure : 95.0 bar

UV : 265 nm

Stack time : 2.6 min

Load/I nj : 1.0 mg

Example 61

1-(5-chloro-6-(2H-1 ,2,3-triazol-2-yl)pyridin-3-yl)-3-(2-(hvdroxymethyl)-7-(1- (trifluoromethyl)cvclopropyl)pyrazolo[1 ,5-alpyrimidin-6-yl)urea

Diisobutylaluminum hydride (1 M solution in Hexane) (2.0 ml_, 2.0 mmol) was added at -78 °C to a solution of 60a (200 mg, 0.37 mmol) in THF (15 ml) and stirred at -40 °C for 2 h.

Saturated ammonium chloride solution (aq) (1 ml_) was added at -40 °C, dried (Na2S0₄), filtered and concentrated under reduced pressure. The crude was combined with another batch and purified by column chromatography on silica gel and eluted with 9-10% MeOH in DCM. Appropriate fractions were pooled and concentrated and the residue was purified by prep. HPLC using a gradient of 10 mM NH₄HC03 in water: acetonitrile as mobile phase. The impure compound was further purified by SFC which gave the title compound (15 mg, 8%) as a solid. MS (ES+) m/z 494.33 [M+H]⁺.

¹ H NMR (500 MHz, DMSO): δ 10.17 (s, 1 H), 8.73 (s, 1 H), 8.52 (t, J = 10.5 Hz, 2H), 8.35 (s, 1 H), 8.15 (s, 2H), 6.75 (s, 1 H), 5.43 (s, 1 H), 4.68 (s, 2H), 1.75 (s, 2H), 1.47 (s, 2H).

Preparative SFC Conditions

Column/dimensions : Chiralpak-IG (250*30) mm, 5μ

C0₂ : 65.0%

Co solvent : 35% MeOH

Total Flow 70.0 g/min

Back Pressure 90.0 bar

UV 214 nm

Stack time 22.0 min

Load/inj. 3 mg

Total No of injections 30 Example 62

6-(3-(5-chloro-6-(2H-1 ,2,3-triazol-2-yl)pyridin-3-yl)ureido)-7-(1- (trifluoromethyl)cvclopropyl)pyrazolo[1 ,5-alpyrimidine-2-carboxamide

To a stirred solution of compound 60b (100 mg, 0.2 mmol) in THF (15.0 mL) were added N H4CI (30 mg, 0.56 mmol), HATU (60 mg, 0.16 mmol) followed by Et₃N (0.17 mL, 1.22 mmol) at 0 °C under nitrogen. The mixture was stirred at rt for 2 h, then concentrted and ice cold water was added. The precipitated solid was filtered, washed with water and dried. The obtained solid was triturated with diethyl ether (2 x 5 mL) and dried. The impure compound was further purified by prep. HPLC using a gradient of 10 mM NH4HCO3 in water: acetonitrile as mobile phase, which gave the title compound (40 mg, 40%). MS (ES+) 507.37 [M+H]⁺.

¹ H NMR (500 MHz, DMSO): δ 10.19 (s, 1 H), 8.91 (s, 1 H), 8.55 (d, J = 2.4 Hz, 1 H), 8.50 (d, J = 2.4 Hz, 1 H), 8.36 (s, 1 H), 8.16 (s, 2H), 7.70 (d, J = 19.2 Hz, 2H), 7.17 (s, 1 H), 1.81 (s, 2H), 1.53 (s, 2H).

Compounds of series

Example 1y

DPPA (194 mg, 0.7 mmol) and by Et₃N (195 mg, 1.92 mmol) were added at rt to a stirred solution of l-1f (100 mg, 0.35 mmol) in 1 ,4 dioxane (10 mL). The resulting mixture was stirred at rt for 30 min then pyridazin-4-amine (34 mg, 0.35 mmol) was added and the mixture was stirred at 100 °C for 2 h. The mixture was concentrated, diluted with water (25 mL) and extracted with EtOAc (2x50 mL). The organic layers were combined and washed with brine, dried (NaaSCU), filtered and concentrated. The obtained crude compound was purified by reverse phase column chromatography then further purified by prep. HPLC on a Kromasil ® C18 column using a gradient of 10 mM NH4HCO3 in H20:MeCN as mobile phase, followed by a second prep. HPLC purification on an Atlantis™ T3 column using a gradient of 10 mM NH4HCO3 in hbOiMeCN as mobile phase, which gave the title compound (40 mg, 33%). LCMS (ES+) m/z 348.34 [M+H]⁺.

Example 2y

(S)-1-(2-chloro-7-(1-methoxyethyl)pyrazolo[1 ,5-alpyrimidin-6-yl)-3-(pyrimidin-5-yl)urea (2)

DPPA (0.4 mL, 1.74 mmol) and EtzN (0.7 mL, 5.26 mmol) were added at rt to a stirred solution of l-1f (300 mg, 1.06 mmol) in 1 ,4 dioxane (5 mL). The resulting mixture was stirred at rt for 30 min, then pyrimidin-5-amine (100 mg, 1.05 mmol) was added and the reaction mixture was stirred at 100 °C for 2 h. The mixture was diluted with water (25 mL) and extracted with EtOAc (2x50 mL). The organic layers were combined and washed with aqueous saturated sodium bicarbonate (50 mL), dried (Na2S0₄), filtered and concentrated. The obtained crude compound was purified by column chromatography on silica gel eluted with 0 - 30% EtOAc in p. ether. Fractions containing the pure compound was concentrated and dried under vacuum. The residue was purified by prep. HPLC on a Kromasil^® C18 column using a gradient of 10 mM NH₄HCC>3 in hbOiMeCN as mobile phase, which gave the title compound (120 mg, 33%) as a solid. LCMS (ES+) m/z 348.34 [M+H]⁺. Example 3y

(S)-1-(2-chloro-7-(1-methoxyethyl)pyrazolo[1 ,5-alpyrimidin-6-yl)-3-(5-(trifluoromethyl)pyridazin- 3-yl)urea (3)

The title compound was prepared from l-1f (105 mg, 0.41 mmol) and 5- (trifluoromethyl)pyridazin-3-amine (67.0 mg, 0.41 mmol) using the procedure described in Example 2. LCMS (ES+) m/z 416.19 [M+H]⁺.

Example 4y

(S)-1-(2-Chloro-7-(1-methoxyethyl)pyrazolo[l

4-yl)urea (4)

DPPA (0.46 g, 1.66 mmol) and EtzN (0.46 g, 4.54 mmol) were added at rt to a stirred solution of l-3d (190 mg, 0.83 mmol) in 1 ,4 dioxane. The resulting mixture was stirred at tr for 30 min then compound amine l-2b (93%, 202.49 mg, 0.83 mmol) was added. The reaction mixture was stirred at 100 °C for 4 h, then concentrated under reduced pressure. The residue was dissolved in water and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2S0₄), filtered and concentrated. The obtained crude compound was purified by prep HPLC on a Kromasil ^® C18 column using a gradient of 10 mM NH HCC>3 in H₂0:MeCN as mobile phase, which gave the title compound (11 mg, 3.2%) as a solid. LCMS (ES-) m/z 414.25 [M-H]\

Example 5y

(S)-1-(2-Chloro-7-(1-methoxyethyl)pyrazolori ,5-alpyrimidin-6-yl)-3-(2- (difluoromethoxy)pyrimidin-5-yl)urea (5)

The title compound was prepared from 1-1 f (1 10 mg, 0.39 mmol) and l-4b (65 mg, 0.30 mmol) using the procedure described in Example 2. Yield 40 mg, 25%. LCMS (ES+) m/z 414.22

[M+H]⁺.

Example 6y

(S)-1-(2-Chloro-7-(1-methoxyethyl)pyrazolo[1 ,5-alpyrimidin-6-yl)-3-(6-(trifluoromethyl)pyrimidin- 4-yl)urea (6)

DPPA (0.35 mL, 1.62 mmol) and Et₃N (1.0 mL, 7.16 mmol) were added at rt to a solution of l-2b (300 mg, 1.02 mmol) and 6-(trifluoromethyl)pyrimidine-4-carboxylic acid (98%, 200 mg, 1.02 mmol) in toluene (20 mL). The mixture was stirred and heated by microwave irradiation at 120 °C for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2x60 mL), the organic layers were combined and washed with aqueous saturated sodium bicarbonate (20 mL), dried (Na2S0₄), filtered and concentrated. The afforded crude material was purified using a combiflash silica gel column eluted with EtOAc : p. ether 1 : 1. Fractions containing pure compound were combined and concentrated and purified by prep HPLC on a Kromasil ^® C18 column using a gradient of 10 mM NH₄HCC>3 in hbOiMeCN as mobile phase, which gave the title compound (106 mg, 25%) as a solid. LCMS (ES+) m/z 416.07 [M+H]⁺. Example 7y

1 ,3-Bis(2-chloro-7-((S)-1-methoxyethyl)pyrazolo[1 ,5-alpyrimidin-6-yl)urea (7)

Triphosgene (0.35 mL, 1.62 mmol) and EtzN (1.0 mL, 7.16 mmol) were added in portions at 0 °C to a solution of I-5 (100 mg, 0.568 mmol) in DCM (5 mL). The resulting mixture was stirred at rt for 30 min, then l-2b (129 mg, 0.568 mmol) was and the mixture and stirred at rt for 1 h. The reaction mixture was poured into ice cold water (30 mL) and extracted with EtOAc (2 x 30 mL).The organic layers were combined and washed with aqueous saturated sodium

bicarbonate and brine, dried (Na2S0₄), filtered and concentrated. The afforded crude material was purified by prep HPLC on a Kromasil ^® C18 column using a gradient of 10 mM NH₄OAC in hbOiMeCN as mobile phase, which gave the title compound (20 mg, 7.2%) as a solid. LCMS (ES+) m/z 4179.25 [M+H]⁺. Compounds of series (z)

Example 1z

(S)-1-(5-chloro-6-(2H-1 ,2,3-triazol-2-yl)pyridin-3-yl)-3-(7-(1-methoxyethyl)pyrazolori ,5- alpyrimidin-6-yl)urea (1)

DPPA (0.231 mL, 1.08 mmol) and by Et₃N (0.589 mL, 4.15 mmol) were added at rt to a stirred solution of l-2c (200 mg, 0.886 mmol) in 1 ,4 dioxane (5 mL). The resulting mixture was stirred at rt for 30 min then 1-1 b (265 mg, 1.33 mmol) was added and the mixture was stirred at 100 °C for 2 h. The mixture was diluted with ice cold water (25 mL) and extracted with EtOAc (2x20 mL). The organic layers were combined and washed with brine, dried (Na2S0₄), filtered and concentrated. The obtained crude compound was purified by column chromatography on silica gel eluted with a gradient of 70-80% EtOAc in p. ether. The compound was triturated in diethyl ether then dried under high vacuum, which gave the title compound (45 mg, 12%). LC-MS (ES+) m/z 414.22 [M+H]⁺.

Exam le 2z

DPPA (0.13 mL, 0.60 mmol) and Et₃N (0.35 mL, 2.5 mmol) were added at rt to a stirred solution of l-3b (150 mg, 0.496 mmol) in 1 ,4 dioxane (10 mL). The resulting mixture was stirred at rt for 30 min, then 1-1 b (1 17 mg, 0.595 mmol) was added and the reaction mixture was stirred at 100 °C for 2 h. The mixture was diluted with water (15 mL) and extracted with EtOAc (2x20 mL). The organic layers were combined and washed with brine, dried (Na2S0₄), filtered and concentrated. The obtained crude compound was purified by prep. HPLC on a Kromasil^® C18 column using a gradient of 10 mM NH₄HCC>3 in hbOiMeCN as mobile phase. Pure fractions were collected and concentrated and the residue purified by prep. HPLC on a Kromasil^® C18 column using a gradient of 10 mM NH₄OAc in hbOiMeCN as mobile phase. Pure fractions were collected and concentrated and the residue purified by SFC, which gave the pure title compound (30 mg, 13%) as a solid. LC-MS (ES+) m/z 464.21 [M+H]⁺.

Preparative SFC Conditions

Column/dimensions : R,R WHELK ( 30x250 mm ), 5μ

% C0₂ : 50.0%

% Co-solvent : 50.0% (100% Methanol )

Total Flow : 60.0 g/min

Back Pressure : 90.0 bar

UV : 212 nm

Stack time : 5.5 min

Load/I nj : 3.0 mg

Example 3z

Step a) (S)-Tert-butyl (1-(6-(3-(5-chloro-6-(2H-1 ,2,3-triazol-2-yl)pyridin-3-yl)ureido)pyrazolori ,5- alpyrimidin-7-yl)ethyl)(methyl)carbamate (3a)

DPPA (0.80 mL, 3.72 mmol) and Et₃N (2.20 mL, 15.8 mmol) were added at rt to a stirred solution of l-4c (1.0 g, 3.12 mmol) in 1 ,4 dioxane (10 mL). The resulting mixture was stirred at rt for 30 min, then 1-1 b (611 mg, 3.12 mmol) was added and the reaction mixture was stirred at 100 °C for 2 h. The mixture was diluted with NaHCOs (aq. 30 mL) and extracted with EtOAc (2x50 mL). The organic layers were combined and washed with water and brine, dried

(Na2S0₄), filtered and concentrated. The obtained crude compound was purified by silica gel Combiflash^® eluted with 1 % MeOH in DCM, which gave the title compound (450 mg, 19%) as a solid. LC-MS (ES+) m/z 513.32 [M+H]⁺.

Step b) (S)-1-(5-Chloro-6-(2H-1 ,2,3-triazol-2-yl)pyridin-3-yl)-3-(7-(1- (methylamino)ethyl)pyrazolo[1 ,5-alpyrimidin-6-yl)urea (3b)

4 M HCI in dioxane (1 mL) was added to a stirred solution of compound 3a (450 mg, 0.656 mmol) in 1 ,4 dioxane (2 mL). The solution was stirred at rt for 2 h, then concentrated under reduced pressure. The crude compound was washed with diethyl ether in pentane (30 mL). The formed solid was filtered, dried and washed with MeCN. Saturated NaHCC>3 solution (30 mL) was added to the solid, the mixture was stirred for 10 min, then the solid was filtered, washed with water (2x10 mL) and dried under vacuum which gave the title compound (150 mg, 54.76%) as a solid. LC-MS (ES+) m/z 413.16 [M+H]⁺.

Example 4z

(S)-1-(5-Chloro-6-(2H-1 ,2,3-triazol-2-yl)pyridin-3-yl)-3-(7-(1-(dimethylamino)ethyl)pyrazolori ,5- alpyrimidin-6-yl)urea (4)

Potassium carbonate (75 mg, 0.543 mmol) and methyl iodide (0.05 mL, 0.803 mmol) were added at 0 °C to a stirred solution of compound 3 (100 mg, 0.181 mmol) in DMF (2 mL). The mixture was stirred at rt for 1 h, then concentrated under reduced pressure. The afforded crude compound was diluted with cold water (20 mL), the solid was filtered and washed with water (2x10 mL), and pentane (30 mL) then dried under high vacuum which gave the title compound (40 mg, 51.37%) as a solid. LC-MS (ES-) m/z 427.32 [M-H]⁺.

Example

1-(5-Chloro-6-(2H-1 ,2,3-triazol-2-yl)pyridin-3-yl)-3-(7-(pyridazin-4-yl)pyrazolori ,5-alpyrimidin-6- vDurea (5)

DPPA (0.70 mL, 3.25 mmol) and Et₃N (1.51 mL, 10.8 mmol) were added at rt to a stirred solution of l-5c (400 mg, 1.66 mmol) in 1 ,4 dioxane (15 mL). The resulting mixture was stirred at rt for 30 min, then 1-1 b (333 mg, 1.70 mmol) was added and the reaction mixture was stirred at 100 °C for 3 h. The mixture was concentrated and the residue dissolved in EtOAc and washed with NaHCC>3 (aq. 30 mL) and brine. The organic layers were combined, dried (Na2S0₄), filtered and concentrated. The obtained crude compound was purified by prep HPLC on a Kromasil^® C18 column using a gradient of 10 mM NH₄OAc in HbOiMeCN as mobile phase, which gave the title compound (75 mg, 10%) as a solid. LC-MS (ES+) m/z 434.22 [M+H]⁺.

Example 6z

Step a) Benzyl (1-(6-(3-(5-chloro-6-(2H-1 ,2,3-triazol-2-yl)pyridin-3-yl)ureido)pyrazolori ,5- alpyrimidin-7-yl)cvclopropyl)(methyl)carbamate (6a)

Et₃N (0.60 mL, 4.30 mmol) was added at rt to a solution of l-6d (0.40 g, 1.09 mmol) in dry DMF (1 mL), followed by addition of DPPA (0.50 mL, 2.30 mmol). The mixture was stirred at rt for 30 min, then 1-1 b (0.30 g, 1.53 mmol) was added and stirring was continued at 100 °C for 8 h. NaHCC>3 (sat, aq) was added and the mixture was extracted with DCM. The organic layer was dried (Na2S0₄ ), filtered, concentrated and purified by column chromatography on silica gel twice, first eluted with 2% MeOH in DCM, second eluted with 50% EtOAc in p. ether which gave the title compound (200 mg, 20%) as a solid. LC-MS (ES+) m/z 559.29 [M+H]⁺. Step b) 1-(5-Chloro-6-(2H-1 ,2,3-triazol-2-yl)pyridin-3-yl)-3-(7-(1- (methylamino)cvclopropyl)pyrazolo[1 ,5-alpyrimidin-6-yl)urea (6b)

HBr in acetic acid (1.0 g) was added to compound 6a (100 mg, 0.179 mmol) at 0 °C. The solution was stirred at rt for 1 h, then concentrated. The residue was dissolved in EtOAc (20 ml_), washed with saturated NaHCC>3, brine, dried (Na2S0₄ ), filtered and concentrated. The residue was purified by column chromatography on silica gel eluted with 5% MeOH in DCM followed by prep HPLC on an X-Select™ C18 column using a gradient of 10 mM NH HCC>3 in H₂0:MeCN as mobile phase, which gave the title compound (28 mg, 37%). LC-MS (ES+) m/z 425.26 [M+H]⁺.

Example 7z

1-(5-Chloro-6-(2H-1 ,2,3-triazol-2-yl)pyridin-3-yl)-3-(7-(1- (dimethylamino)cvclopropyl)pyrazolo[1 ,5-alpyrimidin-6-yl)urea (7)

ΕίβΝ (0.50 ml_, 3.58 mmol) was added at rt under nitrogen to a stirred solution of l-7c (0.40 g, 1.62 mmol) in DMF (2 ml_), followed by addition of DPPA (0.60 ml_, 2.76 mmol). The mixture was stirred at rt for 30 min, then 1-1 b (0.40 g, 2.04 mmol) was added and the resulting mixture was stirred at 100 °C for 12 h. The mixture was concentrated and the residue dissolved in EtOAc (20 ml_), washed with saturated NaHCC>3 and brine, dried (Na2S0₄). filtered and concentrated. The crude product was purified by column chromatography on silica gel using 5% MeOH in DCM as eluent, followed by further purification by prep HPLC_on an XBridge C18 column using a gradient of 10 mM NH₄HC03 in HbOiMeCN as mobile phase, which gave the title compound (50 mg, 7.0%). LC-MS (ES+) m/z 439.30 [M+H]⁺. GENERAL BIOLOGY METHODS MALT1 BIOCHEMICAL ASSAY

Full-length MALT1 enzyme at 2 nM was assayed in 50 mM HEPES, 100 mM NaCI, 0.9 M NaCitrate, 1 mM EDTA, pH 7.5, with 50 μΜ Ac-Leu-Arg-Ser-Arg-AMC as substrate. Compound was added in an 1 1 -point concentration series from 100 μΜ to 1 nM in half-log dilution.

Compounds were distributed in 384 well plates by Echo550, and the assay was run with fluorescence readings at 460 nm, every 2 minutes for 60 minutes.

BIOLOGY EXAMPLE 1 Compounds of the invention were evaluated for inhibition of MALT1 using the above described MALT1 biochemical assay. The resulting Ki values are listed in TABLE 1.

TABLE 1

Compounds of series (y)

Compounds of series (z)

MALT1 CELL-BASED ACTIVITY ASSAY

Jurkat clone E6-1 cells (ATCC) were grown in standard cell culture conditions (RPMI 1640 with 10% fetal bovine serum, Penicillin 100 U/mL, Streptomycin 0.1 mg/mL). In-cell MALT1 protease activity, was measured as inhibition of PMA/lonomycin-induced cleavage of HOIL1. Day 1 0.75x10⁶ cells/well were seeded in a 48 well plate. Day 2 cells were stimulated by

PMA/lonomycin (1 :500 dilution) with addition of vehicle or compound in a 5-point concentration series, 1 :3 dilution. After 60 minutes cells were washed in PBS and then lysed on ice in CelLytic MT cell lysis reagent (Sigma) with protease and phosphatase inhibitors (2% Protease Inhibitor Cocktail, 10 μΜ MG-132, 1 % Phosphatase Inhibitor Cocktail 1 , 1 % Phosphatase Inhibitor Cocktail 2, 1 % Phosphatase Inhibitor Cocktail 3 (all from Sigma). After a quick centrifugation, supernatant was recovered. Samples were analysed by Protein Simple using the Peggy Sue Master kit for size separation with anti-HOIL1 antibody at 1 :200 dilution (Santa Cruz). The approx. 50 kDa cleavage fragment of HOIL1 was used for quantification of protease activity. Down-stream MALT1 activity was measured by PMA/lonomycin-induced expression of IL-2 in Jurkat (E6-1) cells. Compounds were distributed in a 96 well plate, 8-point concentration series, 1 :3 dilution. Jurkat clone E6-1 , 4x10⁴ cells/well, were added, and stimulated by PMA/lonomycin (1 :500 dilution) for 24 hours at 37 °C. Measurement was performed using a MesoScale Sector S600 with the Human IL-2 Tissue Culture kit according to the manufacturers recommendation. QUANTIFICATION OF T CELL POPULATIONS Evaluation of T_reg and T_eff cell numbers was performed by flow cytometry. From a tumour sample (resected piece or biopsy), tumour cells and TILs are dispersed into single cell suspension. Cells are then washed with PBS and stained by antibodies. Samples were stained with antibodies to identify T-cell subpopulations; CD3-BV421 (Biolegend 100228), CD8-FITC (Biolegend 100706), CD4-PE (Biolegend 116005), CD25-PerCP Cy5.5 (Biolegend 101912, clone 3C7), for 15 minutes at room temperature, followed by addition of erythrocyte lysis buffer (cat no. 349202, BD Biosciences, Franklin Lakes, NJ, USA) for 8 minutes. Cells were permeabilized with FoxP3 fix/Perm (cat no. 421401 , Biolegend San Diego, CA, USA), washed with FoxP3 Perm buffer (Cat no. 421402, Biolegend) and stained with an Alexa Fluor® 647 labelled FoxP3 antibody (Cat no. 320013, Biolegend) according to the manufacturer's instructions. The cells were washed twice in PBS with 1 % BSA and analyzed on a FACSCanto II (BD Biosciences). Data analysis was performed using FlowJo software (TreeStar, Ashland, OR, USA). For intracellular staining of cytokines, inclusion of transport inhibitors e.g. Monensin or Brefeldin A. Alternatively, immunohistochemical (IHC) evaluation of CD3, CD8, CD4, CD25 and FoxP3 expressing cells is done in Formalin-fixed, paraffin-embedded (FFPE) blocks of biopsies or tumour samples from cancer patients. IHC staining of CD3, CD8, CD4 and FoxP3 is performed with a horseradish-peroxidase technique using a DAKO Autostainer. Antigen retrieval is carried out by the pretreatment of microscope slides with an Epitope Retrieval Solution (Trilog, Cell Marque, Rocklin, CA, USA) for 30 min. Following that, staining is conducted with standardized Dako EnVision FLEX Peroxidase Blocking reagent (K800, DAKO) and polyclonal antibodies for CD3, CD8, CD4 (dilution 1 : 50; Dako) and FoxP3 (dilution 1 : 100: Sigma) following incubation for 120 min at room temperature. Dextran polymer-conjugated horseradish-peroxidase and 3,3'- diaminobenzidine (DAB) chromogen is used for visualisation followed by counterstaining with hematoxylin solution (Gill 3, Sigma). Negative control slides in the absence of primary antibodies are included for each staining.

TIL scoring of tumours by IHC is performed semi-quantitatively by measuring the densities of CD3+, CD8+, CD4+ and FoxP3+ cells, with scores from (1) no, or sporadic cells; (2) moderate numbers of cells; (3) abundant occurrence of cells; to (4) highly abundant occurrence of cells. TILs are evaluated in the following three different areas of the tumour: the intra-epithelial compartment (cells within tumour cell nests); the stroma (cells within the intratumoural stroma) and the tumour periphery (cells localized in tumour periphery). Three random fields are examined, whereas necrotic areas are excluded from the measurements. The total score for CD3, CD8, CD4 and FoxP3 is calculated as the sum of the individual scores from the three tumour areas (intra-epithelial compartment, stroma and tumour periphery), respectively. The total score ranges from 3 to 12, and the median value was used as a cutoff point. The ratios of CD3 and CD8 to both CD4 and FoxP3 (CD3 : CD4; CD8 : CD4; CD3 : FoxP3; and CD8 : FoxP3 ratio, respectively) are calculated for each individual tumour based on the cutoff value of each TIL marker.

DEVELOPMENT AND FUNCTION OF HUMAN T-REGULATORY CELLS

Naive CD4 T cell sorting and stimulation for regulatory T cell development

A flat-bottom 48 well plate was coated with 250 μΙ of purified functional grade anti-human CD3 at 2 μg/ml in PBS. The plate was sealed and incubated at 37 °C for one hour. Peripheral blood mononuclear cells (PBMC) were isolated from human leucocyte reduction system cones by differential density centrifugation using Ficoll-PLUS (GE Healthcare). Cells were washed three times in RPMI + 1 % HI-FCS + 1 % penicillin/streptomycin (P/S) (1 % RPMI), then resuspended at a concentration of 200x10⁶/ml of 1 % RPMI. An aliquot of cells was set aside for single colour controls, and the sample was stained at a dilution of 1 :20 with anti-human CD4, anti-human CD45RA, anti-human CD25, and anti-human CD127 (antibodies from BioLegend and eBioscience) for 20 minutes on ice. Following the incubation, the stained PBMC were washed and resuspended at 50x10⁶/ml in PBS + 1 % HI-FCS. Cells were sorted on a BD FACSARIA high speed cell sorter for the phenotype CD4+CD45RA+CD127+CD25-. Following the sort, cells were resuspended at 4x106/ml in pre-warmed cRPMI containing 4x 400 U/ml human IL-2 (final concentration 100 U/ml). In each well of the washed anti-CD3-coated 48 well plate, 250 μΙ of 4x 8.0 μg/ml anti-CD28 (eBioscience) and 250 μΙ of appropriate 4x concentration of compound were added. Either 250 μΙ of cRPMI or 250 μΙ of 4x 4.0 ng/ml TGFfi were added per well, as appropriate. Finally, 250 μΙ of cells were added per well. The plate was incubated for 5 days at 37 °C with 5% C02. After five days, cells were transferred to polypropylene 5 ml tubes and washed twice with cRPMI. Cells were then resuspended in IL-2 ± TGF with the appropriate vehicle control or compound. The plate was incubated for an additional 5 days at 37 °C with 5% C0₂.

STAINING REGULATORY T CELL CULTURES

Induced regulatory T cell cultures were washed and counted. Aliquots were stained with Fixable Viability Dye eFluor® 780 (eBioscience) for 30 minutes at 4 °C. Then cells were washed with PBS and stained for surface expression of CD25 for 15 minutes at 4 °C. After the staining, cells were fixed, permeabilised and stained for intracellular expression of Foxp3 per manufacturer's instructions (Human Foxp3 Buffer set and anti-human Foxp3 antibody from BD Pharmingen). Following staining, cells were washed and resuspended in PBS + 1 % HI-FCS (FACS buffer). Samples were run within four hours on a CyAn™ ADP Analyzer.

CD4+ naive T cells cultured for 10 days were analysed for their expression of FoxP3 and CD25. In the IL-2 + TGF condition, promoting in vitro differentiation of T_reg cells, there was a clear induction of a population of viable FoxP3+CD25+ T cells in all three donors (Figure 1 ; vehicle). TREG SUPPRESSIVE ACTIVITY

PBMC were isolated from fresh blood by differential density centrifugation using Ficoll-PLUS (GE Healthcare). Cells were washed three times in RPMI + 1 % heat-inactivated foetal calf serum (HI-FCS) + 1 % penicillin/streptomycin (P/S) (1 % RPMI), then resuspended in PBS + 2% heat inactivated foetal calf serum (HI-FCS) + 2.0 mM EDTA (isolation buffer). CD4+CD25- and CD4+CD25+ T cells were isolated, per the manufacturer's instructions (Miltenyi CD4+CD25+ Regulatory T cell Isolation Kit, human). Isolated CD4+CD25- T cells were then labeled with Cell Proliferation Dye eFluor® 450 per manufacturer's instructions (eBioscience). An aliquot of cells was stained with anti-CD3 and anti-CD4 (BioLegend and eBioscience) to assess cell purity and dye labeling by flow cytometry. Cultures were plated in cRPMI, with 2.5x104 CD4+CD25- cells per well. Cells from the regulatory T cell cultures were added to achieve ratios of 1 effector: 4 regulatory cells (donors 2-3), 1 :2, 1 : 1 , 2: 1 , 4:1 and 8: 1. Anti-CD3/CD28 beads (Dynabeads® T Activator CD3/CD28 beads) were added at a 1 : 1 ratio with the total number of cells per well. Unstimulated CD4+CD25- T cells and stimulated without regulatory T cells were plated as controls. Cells were incubated for four days at 37 °C with 5% CO2. After four days, cells were stained with Fixable Viability Dye eFluor® 780 (eBioscience) for 30 minutes at 4 °C. Following staining, cells were washed and resuspended in PBS + 1 % HI-FCS (FACS buffer). Samples were run within four hours on a CyAn™ ADP Analyzer. Immediately prior to acquisition, cells were transferred to FACS tubes with an exact volume of CountBright™ Absolute Counting Beads (ThermoFisher Scientific).

IMPACT ON T-EFFECTOR CELLS IN HUMAN WHOLE BLOOD

Freshly drawn whole blood from healthy volunteers (2 ml_) in a tube was incubated under rotation at 37 °C for 6 hours. Directly after blood sampling, vehicle, 4 μΜ Example 2, ^g/ml of CMV-lysate or combinations thereof were added. After 2 hours Brefeldin-A was added to allow intra-cellular analysis of cytokines (IFNy and TNFa). Antigen-specific CD8+ T-cells were identified by fluorescence-conjugated tetrameric complexes of HLA-A2 molecules loaded with the NLV peptide epitope (NLVPMVATV) of CMV pp65.

IN VIVO EFFECTS ON M B49 MOUSE BLADDER CANCER

The murine bladder urothelial carcinoma cell line Mouse Bladder (MB) -49 is a C57BL/6-derived cell line cultured at 37 °C and 5% C0₂ in DM EM + GlutaMax supplemented with 10% FBS, 0.1 mM sodium pyruvate, 100 U/ml Penicillin-Streptomycin. For determining the effects of MALT1 inhibitor on the presence of T-effector and T-regulatory cells in vivo, 3x10⁵ MB49 cells were injected s.c. on the right flank of female C57BL/6 mice. MALT1 inhibitor therapy was

administered p.o. once daily on day 8, 9, 10, 1 1 , example 2 at two doses 3 μΓΤΐοΙ/kg (1.34 mg/kg) or 30 μΓΤΐοΙ/kg (13.4 mg/kg). As reference 200 μg of anti-CD25 antibody (clone PC61) in 100 μΙ_ PBS was administered i.v. on day 8 and 1 1. The levels of T_reg and T_eff cells were analyzed by flow cytometry in the tumour (T) and in tumour-draining lymph nodes (TDLN) on

IMPACT ON T-EFFECTOR CELLS IN HUMAN WHOLE BLOOD STIMULATED WITH CMV-VACCINE

Freshly drawn whole blood from healthy volunteers (2 ml_) in a tube was incubated under rotation at 37 °C for 6 hours. Directly after blood sampling, vehicle, 30 μΜ A-8c dia-B of

Example A-8, 120 nM of a peptide conjugate, minimal tetanus toxin epitope (MTTE)3-CMV or combinations thereof were added. After 2 hours Brefeldin-A was added to allow intra-cellular analysis of cytokines (IFNy and TNFa) by flow-cytometry. Antigen-specific CD8+ T-cells were identified by fluorescence-conjugated tetrameric complexes of HLA-A2 molecules loaded with the NLV peptide epitope (NLVPMVATV) of CMV pp65.

Claims

1. A compound of formula (I)

wherein

(x) R¹ is R^1a, R² is R^2a and R³ is R^3a; or

(y) R¹ is R^1a, R² is R^2b and R³ is R^3b; or

(z) R¹ is R^{1 b}, R² is R^2b and R³ is R^3a,

R^1a is H, halo, cyano, Ci-dalkyl, haloCi-dalkyl, d-dalkoxy, halod-dalkoxy or amino; R^{1 b} is H, Ci-C₃alkoxy, haloCi-C₃alkoxy, S(=0)(=NRa)NH₂, S(=0)₂NH₂ or amino;

R^2a is H, haloCi-CealkyI, haloCi-dsalkoxy, haloCi-CealkoxyCi-CealkyI, 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-CealkyI is substituted with one, two or three substituents each independently selected from hydroxy, NRaRb, C3-C6cycloalkyl and 5-6-het; wherein

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-C3alkyl;

thiazolyl or isothiazolyl is optionally substituted with one or two substituents each independently selected from d-Cealkyl, hydroxyCi-dsalkyl, d-dsalkoxy, halo, halod- Cealkyl, halod-dsalkoxy;

heteroaryl is substituted with one, two or three substituents each independently selected from halo, haloCi-CealkyI, haloCi-Cealkoxy and optionally substituted with

NRaRb; and

5-6-het is substituted with one or two substituents each independently selected from halo, Ci-dihaloalkyl and d-dshaloalkoxy, and optionally substituted with one or two substituents each independently selected NRaRb and oxo;

R^2b is O-Cealkyl, Ci-C₆alkoxy, C₃-C₆cycloalkyl, haloCi-C₆alkyl, Het, HetCi-C₆alkyl, 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-dalkyl, d-dalkoxy, Ci-C6alkoxyCi-C6alkyl, NRaRb and aminoCi-dalkyl;

Ci-C6alkoxy is optionally substituted with d-dalkoxy;

the Ci-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 Ci-dalkyl, hydroxy, hydroxyd-dalkyl, aminoCi-dalkyl and NRaRb;

Het for the purposes of R^2b is optionally substituted with one or two substituents each independently selected from Ci-dalkyl, Ci-C6alkoxyCi-C6alkyl, d-dalkoxycarbonyl, NRaRb, and oxo;

R^3a is phenyl, d-dcycloalkyl, heterocyclyl or heteroaryl, any of which is optionally substituted with one, two or three R¹³;

each R¹³ is independently selected from halo, hydroxy, cyano, NRaRb, Ci- dalkoxycarbonyl, d-dalkoxy, d-dhaloalkoxy, Ci-dalkyl, d-dhaloalkyl, d- Cecycloalkyl, phenyl, phenyld-dalkyl, heterocyclyl, heterocyclyld-dalkyl, heterocycloxy, heteroaryl, wherein

Ci-dalkyl is optionally substituted with NRaRb;

C3-C6cycloalkyl, heterocyclyl or heteroaryl is optionally substituted with one, two or three substituents each independently selected from Ci-dalkyl, d-dalkoxy, hydroxy, hydroxyd-dalkyl, halo, halod-dalkyl, halod-dalkoxy, oxo, NRaRb, and carbamoyl; wherein

Ci-dalkyl is optionally substituted with NRaRb;

each R¹³ is independently selected from halo, hydroxy, cyano, NRaRb, carbamoyl, d-dalkoxycarbonyl, d-dalkoxy, halod-dalkoxy, Ci-C6alkoxyCi-C6alkoxy, Ci- dalkyl, halod-dalkyl, C3-C6cycloalkyl, phenyl, phenyld-dalkyl, heterocyclyl, heterocyclyld-dalkyl, heterocycloxy, heteroaryl, wherein

Ci-dalkyl and Ci-C6alkoxy are optionally substituted with one or two substituents each independently selected from hydroxy, d-dalkoxy and NRaRb;

d-dcycloalkyl, phenyl, heterocyclyl, heterocycloxy and heteroaryl are optionally substituted with one, two or three substituents each independently selected from Ci-dalkyl, d-dalkoxy, hydroxy, hydroxyd-dalkyl, halo, halod-dalkyl, halod-dalkoxy, oxo, NRaRb, and carbamoyl; wherein

d-dalkyl is optionally substituted with NRaRb; or a pharmaceutically acceptable salt thereof;

wherein Ra and Rb for the purposes of series (x) and (y) are each independently selected from H, d-Cealkyl, haloCi-dalkyl 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; or for the purposes of series (z):

Ra is H, Ci-C₃alkyl;

Rb is 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; 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;

and the following definitions apply:

CycAlk is, unless otherwise specified, Cs-dcycloalkyl which is substituted with one, two or three substituents each independently selected from halo, haloCi-dalkyl and halod- dalkoxy;

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;

A compound of series (x) according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R¹ is R^1a, R² is R^2a and R₃ is R^3a.

A compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein R^1a is halo, d-dalkyl or halod-dalkoxy.

4. A compound according to claim 2 or 3, or a pharmaceutically acceptable salt thereof, wherein R^1a is fluoro, chloro, methyl, difluoromethoxy or trifluoromethoxy, preferably chloro or methyl. 5. A compound according to any of claims 2 to 4, or a pharmaceutically acceptable salt

thereof, wherein R^2a is halod-dsalkoxy, CycAlk, CycAlkCi-dalkyl or a 5 or 6 membered heteroaryl, wherein

heteroaryl or CycAlk is substituted with one or two substituents independently selected from halo, haloCi-dalkyl, halod-dalkoxy and optionally with amino.

6. A compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein R^2a is haloCi-dsalkoxy, CycAlk, thiazolyl or pyridinyl, wherein

pyridinyl or CycAlk is substituted with one or two halo, halod-dalkyl or halod- dalkoxy, preferably where R^2a is cyclopropyl which is substituted with trifluoromethyl or with one or two halo.

7. A compound according to any one of claims 2 to 4, wherein R^2a is 1-(CF3)-cycloprop-1-yl or -CH(CH₃)-0-CHF₂.

8. A compound according to any of claims 2 to 7, or a pharmaceutically acceptable salt

thereof, wherein R^3a is pyridinyl, pyridazinyl or pyrimidinyl any of which is optionally substituted with one, two or three R¹³; wherein

each R¹³ is independently selected from halo, Ci-dsalkyl, haloCi-dsalkyl, d-dsalkoxy, d-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 aminod- C₃alkyl. 9. A compound according to any of claims 2 to 7 or a pharmaceutically acceptable salt

thereof, wherein R^3a is pyridinyl which is substituted with one or two R¹³; wherein

each R¹³ is independently selected from fluoro, chloro, trifluoromethyl,

difluoromethoxy, trifluoromethoxy, Ci-dalkyl, triazolyl and pyrazolyl; wherein triazolyl and pyrazolyl are optionally substituted with aminomethyl.

10. A compound according to claim 2, selected from the group consisting of:

pharmaceutically acceptable salt or diastereomer thereof.

A compound of series (y) as claimed in claim 1 , or a pharmaceutically acceptable salt thereof, wherein

R¹ is R^1a, R² is R^2b and R³ is R^3b;

A compound according to claim 11 , or a pharmaceutically acceptable salt thereof, wherei R^1a is halo, d-Csalkyl or halod-Csalkoxy.

13. A compound according to claim 12, or a pharmaceutically acceptable salt thereof, wherein R^1a is fluoro, chloro, methyl, preferably chloro.

14 A compound according to any one of claims 11 to 13, or a pharmaceutically acceptable salt thereof wherein R^2b is d-Cealkyl, haloCi-dalkyl, heterocyclyl or C3-C6cycloalkyl, wherein

Ci-C6alkyl and haloCi-Cealkyl are optionally substituted with one, two or three substituents each independently selected from d-dalkoxy, Ci-C6alkoxyCi-C6alkoxy, NRaRb and Cs-dcycloalkyl;

heterocyclyl or Cs-dcycloalkyl is optionally substituted with Ci-dalkyl, d-dalkoxy or d-C₃alkoxyd-C₃alkyl;

A compound according to claim 14, or a pharmaceutically acceptable salt thereof, wherei R^2b is Ci-dalkyl, wherein

Ci-dalkyl is optionally substituted with one or two d-dalkoxy, Ci-C6alkoxyCi- dalkoxy or haloCi-Cealkyl.

A compound according claim 15, or a pharmaceutically acceptable salt thereof, wherein R^2t is 2,2,2-trifluoroethyl, Ci-dalkyl or Ci-C6alkyl which is substituted with one or two methoxy. 17. A compound according to any one of claims 11 to 15, or a pharmaceutically acceptable salt thereof, wherein R^3b is pyridazinyl or pyrimidinyl any of which is optionally substituted with one, two or three R¹³; wherein

each R¹³ is independently selected from cyano, chloro, fluoro, d-Cealkyl, halod- dalkyl, d-dalkoxy, d-dhaloalkoxy, 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 aminoCi-dalkyl. 18. A compound according to claim 17, or a pharmaceutically acceptable salt thereof, wherein each of the one, two or three R¹³

is independently selected from fluoro, chloro, difluoromethyl, trifluoromethyl, triazolyl and pyrazolyl; wherein

triazolyl and pyrazolyl are optionally substituted with aminomethyl.

19. A compound according to any one of claims 1 1 to 15, wherein R^3b is pyrazolyl or thiazolyl, either of which is optionally substituted with fluoro, cyano, methyl, difluoromethyl or trifluoromethyl.

A compound according to claim 18, wherein R^3b is pyridazin-4-yl which is substituted in the 6-position with fluoro, chloro, cyano, methyl, difluoromethyl or trifluoromethyl.

A compound of series (z) as claimed in claim 1 , or a pharmaceutically acceptable salt thereof, wherein R¹ is R^{1 b}, R² is R^2b and R³ is R^3a.

A compound according to claim 21 , or a pharmaceutically acceptable salt thereof, wherein R^{1 b} is H, methoxy, difluoromethoxy or trifluoromethoxy, preferably H.

23. A compound according to 21 or 22, or a pharmaceutically acceptable salt thereof, wherein R^2b is Ci-C6alkyl, haloCi-Cealkyl, heterocyclyl or C3-C6cycloalkyl, wherein

Ci-C6alkyl and haloCi-Cealkyl are optionally substituted with one, two or three substituents each independently selected from d-dsalkoxy, d-Cealkoxyd-Cealkoxy, NRaRb and C3-C6cycloalkyl;

heterocyclyl and C3-C6cycloalkyl are optionally substituted with Ci-dalkyl, Ci- dalkoxy, Ci-C₃alkoxyCi-C₃alkyl or NRaRb;

24. A compound according to claim 23, or a pharmaceutically acceptable salt thereof, wherein R^2b is Ci-dsalkyl which is optionally substituted with one or two d-dsalkoxy, Ci-C6alkoxyCi- dsalkoxy or NRaRb.

25. A compound according to claim 24, or a pharmaceutically acceptable salt thereof, wherein R^2b is Ci-C6alkyl or C₃-C6cycloalkyl, which is substituted with NRaRb, wherein Ra and Rb are independently selected from H and Ci-C₃alkyl.

A compound according to claim 24, or a pharmaceutically acceptable salt thereof, wherein R^2b is -CH(OMe)CH(CH₃)₂ or CH(OMe)CH₃.

27. A compound according to any one of claims 21 to 26, or a pharmaceutically acceptable salt thereof, wherein R^3a is pyridinyl which is optionally substituted with one, two or three R¹³; wherein

each R¹³ is independently selected from halo, cyano, Ci-C6alkyl, haloCi-Cealkyl, Ci- dsalkoxy, halod-dsalkoxy and a 5- or 6-membered heteroaryl; wherein heteroaryl is optionally substituted with one or two substituents each independently selected from d-Csalkyl, halo, trifluoromethyl and aminoCr C₃alkyl.

28. A compound according to any one of claims 21 to 26, or a pharmaceutically acceptable salt thereof, wherein R^3a is pyridinyl which is substituted with one or two R¹³; wherein

each R¹³ is independently selected from fluoro, chloro, cyano, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, triazolyl, imidazolyl and pyrazolyl;

wherein

triazolyl, imidazolyl and pyrazolyl are optionally substituted with methyl or aminomethyl.

29. A compound according to any one of claims 21 to 26, or a pharmaceutically acceptable salt thereof wherein R^3a 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. lt

A compound according to claim 21 , selected from the group consisting of:

A compound according to anyone of claims 1 to 31 , for use in the treatment of cancer.

33. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 31 in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

34. A pharmaceutical composition according to claim 33 for use in the treatment of bladder cancer, colon cancer, hepatocellular cancer or small cell or non-small cell lung cancer.

35. A method for the treatment of cancer comprising the administration of an effective amount of a compound according to any one of claims 1 to 31 to a patient afflicted with cancer.