Compounds and pharmaceutical compositions thereof for the treatment of diseases such as cancer

Abstract

The present invention discloses compounds according to Formula (Ig) or a pharmaceutically acceptable salt and / or solvate thereof, wherein X1, X2, X3, X4, Y, Y1, Y2, Y3, Y4, R1, R2, R16, B and A are as defined herein. The present invention relates to compounds that are inhibitors of FGFR enzymes, in particular FGFR3, methods for their production, pharmaceutical compositions comprising the same, and methods of treatment using the same, for the prophylaxis and / or treatment of a disease, disorder or condition that is associated with abnormal activity or expression of an FGFR enzyme, particularly FGFR3, by administering a compound of the invention.

Description

COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF DISEASES SUCH AS CANCERFIELD OF THE INVENTION

[0001] The present invention relates to novel compounds that are inhibitors of FGFR enzymes and are useful in the treatment of FGFR-associated diseases such as cancer, and prodrugs thereof. The present invention also provides methods for the manufacture of the compounds of the invention, pharmaceutical compositions comprising the compounds of the invention, methods for the prophylaxis and / or treatment of FGFR-associated diseases, such as cancer, by administering the compounds of the invention.BACKGROUND OF THE INVENTION

[0002] The Fibroblast Growth Factor Receptors (FGFR) are receptor tyrosine kinases that bind to fibroblast growth factor (FGF) ligands. There are four FGFR proteins (FGFR1-4) that are capable of binding ligands and are involved in the regulation of many physiological processes including tissue development, angiogenesis, wound healing, and metabolic regulation. Upon ligand binding, the receptors undergo dimerization and phosphorylation leading to stimulation of the protein kinase activity and recruitment of many intracellular docking proteins. These interactions facilitate the activation of an array of intracellular signaling pathways including Ras-MAPK, AKT-PI3K, and phospholipase C that are important for cellular growth, proliferation and survival (Eswarakumar et al. Cytokine & Growth Factor Reviews, 2005, 16, 139-149). Aberrant activation of this pathway either through overexpression of FGF ligands or FGFR or activating mutations in the FGFRs can lead to tumor development, progression, and resistance to conventional cancer therapies.

[0003] In human cancer, genetic alterations, including gene amplification, chromosomal translocations and somatic mutations that lead to ligand-independent receptor activation have been described (Knights and Cook, Pharmacology & Therapeutics, 2010, 125, 105-117; Turner and Grose, Nature Reviews Cancer, 2010, 10, 116-129). Large scale DNA sequencing of thousands oftumor samples has revealed that FGFR genes are altered in many cancers (Helsten et al., Clin Cancer Res., 2016, 22, 259-267). Some of these activating mutations are identical to germline mutations that lead to skeletal dysplasia syndromes (Gallo et al., Cytokine & Growth Factor Reviews, 2015, 26, 425-449). Mechanisms that lead to aberrant ligand-dependent signaling in human disease include overexpression of FGFs and changes in FGFR splicing that lead to receptors with more promiscuous ligand binding abilities. Therefore, development of inhibitors targeting FGFR may be useful in the clinical treatment of diseases that have elevated FGF or FGFR activity.

[0004] The cancer types in which FGF / FGFRs are implicated include, inter alia, carcinomas (e.g., bladder, breast, colorectal, endometrial, gastric, head and neck, kidney, lung, ovarian, prostate), hematopoietic malignancies (e.g., multiple myeloma, acute myelogenous leukemia, and myeloproliferativeneoplasms), and other neoplasms (e.g., glioblastoma and sarcomas). In addition to a role in oncogenic neoplasms, FGFR activation has also been implicated in skeletal and chondrocyte disorders including, inter alia, achondroplasia and craniosynostosis syndromes. There is a continuing need for the development of new drugs for the treatment of cancer, and the FGFR inhibitors described herein help address this need.

[0005] There is also an ongoing need for new FGFR inhibitors with improved properties for the treatment of FGFR-associated diseases, such as cancer. In the current state of the art, a variety of FGFR3 inhibitors have been explored, yet many of these compounds continue to exhibit important limitations, particularly with respect to their selectivity profde and occurrence of treatment resistance. There remains a need for FGFR3 inhibitors with improved selectivity as many known compounds exhibit insufficient discrimination between FGFR3 and other FGFR isoforms, leading to reduced efficacy and increased side effects. The selectivity index, defined as the ratio of ICA values for off-target kinases versus FGFR3, is often relatively low. As a consequence, these compounds are likely to inhibit other members of the FGFR family (e.g., FGFR1, FGFR2, or FGFR4) or unrelated kinases at therapeutically relevant concentrations. This lack of target discrimination can give rise to undesirable pharmacological effects, including toxicity and interference with unrelated signaling pathways, ultimately reducing their therapeutic window. In addition, cancer cells can develop resistance to current compounds, a.o. through mutations at the gatekeeper residue within the kinase domain. These mutations hinder the inhibitor's access to the ATP -binding pocket, reducing the drug's efficacy. It is known that acquired resistance mutations in FGFR3 can emerge in a substantial proportion of patients following relapses after treatment with FGFR inhibitors, thereby limiting the long-term efficacy of such therapies.SUMMARY OF THE INVENTION

[0006] The present invention provides compounds that are FGFR inhibitors. The invention also provides compositions comprising the compounds, in particular pharmaceutical compositions, and methods of using / administering and making the compounds and compositions. The compounds provided herein are useful in treating diseases, disorders, or conditions that are mediated by FGFRs. The invention also provides compounds for use in therapy. The invention further provides compounds for use in a method of treating a disease, disorder, or condition that is mediated by a FGFR. Moreover, the invention provides uses of the compounds in the manufacture of a medicament for the treatment of a disease, disorder or condition that is mediated by a FGFR.

[0007] Accordingly, in a first aspect, there is provided a compound of Formula (Ig):wherein:Xi is N or CH;X2is N and X3is C, or, alternatively, X3is N and X2is C;X4is N;Y is a bond, 0 or NH;Yi is a bond, CHR6, CH2-CHR6, CHR6-CH2, CF2, CH2-CF2or CF2-CH2;Y2is CR4R5or CF2;Y3is CR3R4, CR3R4CR3R4, CH2CF2or CF2; wherein Yi, Y2, Y3and X_ together with the pyrazolyl ring form a 6- to 8-membered nitrogen containing ring;B is -C(O)Y4-, -Y4-, -CH2Y4-, or -CH2CH2Y4-, and A is CN;Y4is C3-10 cycloalkyl -R4N- or a 5- to 8-membered oxygen containing heterocyclyl-NR4-, wherein the cycloalkyl or 5- to 8-membered oxygen containing heterocyclyl is unsubstituted or independently substituted with one or more substituents independently selected from halogen, methyl, halomethyl, hydroxyl or methoxy, or wherein the cycloalkyl is substituted by two groups which are attached to the same carbon atom and join to form a 4- to 6- membered oxygen containing heterocyclyl ring, and wherein the nitrogen atom of the cycloalkyl -R4N or 5- to 8-membered oxygen containing heterocyclyl-NR4- is connected to A;R1is hydrogen, halogen, C1.5 alkyl, C1.5 alkoxy, CN, C3-10 cycloalkyl, C2.4alkynyl, 4-10 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, 0 and S, phenyl or a 5- 6 membered heteroaryl, wherein the 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are unsubstituted or substituted with one or more substituents independently selected from halogen, methyl, halomethyl, hydroxyl or methoxy and wherein the C1.5 alkyl and C1.5 alkoxy, are unsubstituted or independently substituted with one or more substituents independently selected from halogen, CN, hydroxyl and methoxy;R2is hydrogen, hydroxyl, Ci.4alkyl, CN, -CONHCi.4alkyl, or Ci-4haloalkyl;each R3is independently selected from hydrogen, fluoro, hydroxyl, methoxy, C1.3 alkyl, cyclopropyl, or a R3is fused with R5or R6to form CH2, CH2-CH2 or CH2OCH2; each R4is independently selected from hydrogen and C1.3 alkyl;R5is hydrogen, fluoro, hydroxyl, methoxy, C1.3 alkyl, cyclopropyl or is fused with one R3to form CH2, CH2-CH2 or CH2OCH2, wherein the C1-3 alkyl is unsubstituted or independently substituted with one or more substituents independently selected from halogen, heteroaryl (which heteroaryl is preferably pyridyl), phenyl, hydroxyl, -CO2R4or C1-3 alkoxy;R6is hydrogen, fluoro, hydroxyl, methoxy, C1.3 alkyl or is fused with one R3to form CH2, CH2-CH2or CH2OCH2; each R8is independently selected from hydrogen and Cue alkyl; each R9is independently selected from hydrogen, CF3and Ci-e alkyl, which alkyl is unsubstituted or substituted with one or more substituents independently selected from fluoro, chloro, bromo, hydroxyl, and Cue alkoxy; andR10is hydrogen, C1.3 alkyl or halogen; or R9and R10together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring; each of R11and R12is independently hydrogen, Ci-g alkyl, or R11and R12together with the nitrogen atom to which they are attached form a 4-6 membered heterocycloalkyl optionally having an additional ring heteroatom which is O, wherein said ring is optionally substituted with halogen;R13is hydrogen, R14R15NCH2-, or C1.3 alkyl which is unsubstituted or substituted with hydroxyl;R14and R15are each independently hydrogen or Ci-g alkyl;R16is C1.3 alkyl-R17, C3-6 cycloalkyl-R17or a 4-6 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein the C1-3 alkyl, C3-6 cycloalkyl and 4-6 membered heterocycloalkyl are unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-4 alkyl optionally substituted with one or more OH, , C3-6 cycloalkyl, OH, OMe, -NR4R8wherein R4and R8are as defined above, or, alternatively, R4and R8together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring, or - O(CH2)2-4- wherein the oxygen atom and terminal carbon atom are attached to the same carbon atom in the C1-3 alkyl, C3-6 cycloalkyl and 4-6 membered heterocycloalkyl group such that an oxygen-containing heterocyclyl forms;R17is hydrogen, aryl, heteroaryl, 4-6 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, 0 and S, or C3-8 cycloalkyl, wherein the aryl and heteroaryl are unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, CN, NH2, C1-4 alkyl, and C1.4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy, wherein the heterocycloalkyl and cycloalkyl are unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, CN, NH2, oxo, C1.4 alkyl, and C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; or a pharmaceutically acceptable salt and / or solvate thereof.

[0008] Accordingly, in a second aspect, there is provided a compound of Formula (Ih):wherein:Xi is N or CH;X2is N and X3 is C, or, alternatively, X3 is N and X2is C;X4is N;Y is a bond, 0 or NH;Yi is a bond, CHR6, CH2-CHR6, CHR6-CH2, CF2, CH2-CF2or CF2-CH2;Y2is CR4R5or CF2;Y3is CR3R4, CR3R4CR3R4, CH2CF2 or CF2;B is -C(O)Y4-, -Y4-, -CH2Y4-, or -CH2CH2Y4-, and A is CN;Y4is C3-10 cycloalkyl -R4N-, wherein the cycloalkyl is unsubstituted or independently substituted with one or more substituents independently selected from halogen, methyl, halomethyl, hydroxyl or methoxy and wherein the nitrogen atom of the cycloalkyl-R4N, is connected to A;R1is hydrogen, halogen, C1.5 alkyl, C1.5 alkoxy, CN, C3-10 cycloalkyl, C2-4 alkynyl, 4-10 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, 0 and S, phenyl or a 5- 6 membered heteroaryl, wherein the 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are unsubstituted or substituted with one or more substituents independently selected from halogen, methyl, halomethyl, hydroxyl or methoxy and wherein the C1.5 alkyl and C1.5 alkoxy, are unsubstituted or independently substituted with one or more substituents independently selected from halogen, CN, hydroxyl and methoxy;R2is hydrogen, hydroxyl, C1-4 alkyl, CN, -CONHC1.4 alkyl, or C1-4 haloalkyl; each R3is independently selected from hydrogen, fluoro, hydroxyl, methoxy, C1.3 alkyl, cyclopropyl, or a R3is fused with R5or R6to form CH2, CH2-CH2or CH2OCH2; each R4is independently selected from hydrogen and C1.3 alkyl;R5is hydrogen, fluoro, hydroxyl, methoxy, C1.3 alkyl, cyclopropyl or is fused with one R3to form CH2, CH2-CH2or CH2OCH2, wherein the C1-3 alkyl is unsubstituted or independently substituted with one ormore substituents independently selected from halogen, heteroaryl (which heteroaryl is preferably pyridyl), phenyl, hydroxyl, -CO2R4or C1-3 alkoxy;R6is hydrogen, fluoro, hydroxyl, methoxy, C1.3 alkyl or is fused with one R3to form CH2, CH2-CH2 or CH2OCH2; each R8is independently selected from hydrogen and Cue alkyl; each R9is independently selected from hydrogen, CF3 and C1-6 alkyl, which alkyl is unsubstituted or substituted with one or more substituents independently selected from fluoro, chloro, bromo, hydroxyl, and Cue alkoxy; andR10is hydrogen, C1.3 alkyl or halogen; or R9and R10together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring; each of R11and R12is independently hydrogen, Cue alkyl, or R11and R12together with the nitrogen atom to which they are attached form a 4-6 membered heterocycloalkyl optionally having an additional ring heteroatom which is O, wherein said ring is optionally substituted with halogen;R13is hydrogen, R14R15NCH2-, or C1.3 alkyl which is unsubstituted or substituted with hydroxyl;R14and R15are each independently hydrogen or Cue alkyl;R16is Ci-3 alkyl-R17, C3-6 cycloalkyl-R17or a 4-6 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein the C1-3 alkyl, C3-6 cycloalkyl and 4-6 membered heterocycloalkyl are unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-4 alkyl optionally substituted with one or more OH, , C3-6 cycloalkyl, OH, OMe, -NR4R8wherein R4and R8are as defined above, or, alternatively, R4and R8together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring;R17is hydrogen, aryl, heteroaryl, 4-6 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, 0 and S, or C3 8 cycloalkyl, wherein the aryl, heteroaryl, heterocycloalkyl, and cycloalkyl are unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1.4 alkyl, and Ci.4haloalkyl, C1.4 alkoxy, and C1.4 haloalkoxy; or a pharmaceutically acceptable salt and / or solvate thereof

[0009] In a third aspect, the present invention provides compounds of Formula (I):wherein:Xi is N or CH;X2is N and X3is C, or, alternatively, X3is N and X2is C;X4is N or CR4;Y is a bond, 0 or NH;Yi is a bond, CHR6, CH2-CHR6, CHR6-CH2, CF2, CH2-CF2or CF2-CH2;Y2is CR4R5or CF2;Y3is CR3R4, CR3R4CR3R4, CH2CF2or CF2; when X4is N, B is a bond, -C(O)Y4-, -Y4-, -CH2Y4-, or -CH2CH2Y4-, and A is CN, R8R9C=CR10C(=O)-, RnR12NCH2CH=CHC(=O)-, H2C=CHSO2- or RIC =CC(=O)-: when X4is CR4, B is a bond, and A is -NR4-CN, R8R9C=CR10C(=O)R4N-, RnR12NCH2CH=CHC(=O)R4N- , H2C=CHSO2-R4N- or R13C=CC(=O)-R4N-;Y4is a 5-8 membered heterocycloalkyl -R4N comprising a nitrogen atom or C3-10 cycloalkyl-R4N-, wherein the heterocycloalkyl and cycloalkyl are unsubstituted or independently substituted with one or more substituents independently selected from halogen, methyl, halomethyl, hydroxyl or methoxy and wherein the nitrogen atom of the heterocycloalkyl and the cycloalkyl-R4N, respectively, are connected to A;R1is hydrogen, halogen, C1.5 alkyl, C1.5 alkoxy, CN, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, O and S, phenyl or a 5-6 membered heteroaryl, wherein the 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are unsubstituted or substituted with one or more substituents independently selected from halogen, methyl, halomethyl, hydroxyl or methoxy and wherein the C1-5 alkyl and C1.5 alkoxy, are unsubstituted or independently substituted with one or more substituents independently selected from halogen, CN, hydroxyl and methoxy;R2is hydrogen, hydroxyl, Ci.4alkyl, CN, -CONHCI.4alkyl, or Ci-4haloalkyl; each R3is independently selected from hydrogen, fluoro, hydroxyl, methoxy, C1.3 alkyl, cyclopropyl, or a R3is fused with R5or R6to form CH2, CH2-CH2or CH2OCH2;each R4is independently selected from hydrogen and C1.3 alkyl;R5is hydrogen, fluoro, hydroxyl, methoxy, C1.3 alkyl, cyclopropyl or is fused with one R3to form CH2, CH2-CH2 or CH2OCH2, wherein the C1-3 alkyl is unsubstituted or independently substituted with one or more substituents independently selected from halogen, heteroaryl (which heteroaryl is preferably pyridyl), phenyl, hydroxyl, -CO2R4or C1-3 alkoxy;R6is hydrogen, fluoro, hydroxyl, methoxy, C1.3 alkyl or is fused with one R3to form CH2, CH2-CH2 or CH2OCH2; each R8is independently selected from hydrogen and Ci-g alkyl; each R9is independently selected from hydrogen, CF3and Ci-e alkyl, which alkyl is unsubstituted or substituted with one or more substituents independently selected from fluoro, chloro, bromo, hydroxyl, and Ci-e alkoxy; andR10is hydrogen, C1.3 alkyl or halogen; or R9and R10together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring; each of R11and R12is independently hydrogen, Ci-g alkyl, or R11and R12together with the nitrogen atom to which they are attached form a 4-6 membered heterocycloalkyl optionally having an additional ring heteroatom which is O, wherein said ring is optionally substituted with halogen;R13is hydrogen, R14R15NCH2-, or C1.3 alkyl which is unsubstituted or substituted with hydroxyl;R14and R15are each independently hydrogen or Ci-e alkyl;R16is C1.3 alkyl-R17, C3-6 cycloalkyl-R17or a 4-6 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein the C1-3 alkyl, C3-6 cycloalkyl and 4-6 membered heterocycloalkyl are unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-4 alkyl optionally substituted with one or more OH, , C3-6 cycloalkyl, OH, OMe, -NR4R8wherein R4and R8are as defined above, or, alternatively, R4and R8together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring;R17is hydrogen, aryl, heteroaryl, 4-6 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, 0 and S, or C3-8 cycloalkyl, wherein the aryl, heteroaryl, heterocycloalkyl, and cycloalkyl are unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1.4 alkyl, and Ci.4haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; or a pharmaceutically acceptable salt and / or solvate thereof.

[0010] In a further aspect, the invention provides compositions comprising the compounds, in particular pharmaceutical compositions comprising a compound of the invention and a pharmaceutical carrier, excipient or diluent. In a particular aspect, the pharmaceutical composition may additionally comprise further therapeutically active ingredients suitable for use in combination with the compounds of the invention. In a more particular aspect, the further therapeutically active ingredient is an agent for the treatment of FGFR-associated diseases, in particular cancer.

[0011] In a further aspect, the invention provides use of the compounds, or a pharmaceutical composition comprising them, in medicine, in particular in the prophylaxis and / or treatment of a disease, disorderor condition that is associated with abnormal activity or expression of an FGFR enzyme, in particular cancer.

[0012] In another aspect, the invention provides the compounds, or a pharmaceutical composition comprising them, for use in a method of treating a disease, disorder, or condition that is associated with abnormal activity or expression of an FGFR enzyme, in particular cancer.

[0013] In a yet further aspect, the invention provides uses of the compounds in the manufacture of a medicament for the treatment of a disease, disorder or condition that is associated with abnormal activity or expression of an FGFR enzyme, in particular cancer.

[0014] In another aspect, the invention provides methods of using / administering the compounds or a pharmaceutical composition comprising them.

[0015] In an additional aspect, the invention provides methods of making the compounds and compositions comprising them.

[0016] Moreover, the compounds of the invention, useful in the pharmaceutical compositions and treatment methods disclosed herein, are pharmaceutically acceptable as prepared and used.

[0017] In additional aspects, this invention provides methods for synthesizing the compounds of the invention, with representative synthetic protocols and pathways disclosed later on herein.

[0018] Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing detailed description.

[0019] Furthermore, it has been unexpectedly demonstrated that the compounds of the invention exhibit advantageous properties for their use treating diseases, disorders, or conditions that are associated with abnormal activity or expression of an FGFR enzyme, in particular cancer.

[0020] Certain compounds provided herein have superior FGFR3 potency compared to certain previously known FGFR inhibitors. Certain compounds provided herein have superior selectivity for FGFR3 over FGFR1 compared to certain previously known FGFR inhibitors, reducing potential dose limiting toxicity caused by inhibition of FGFR1 (e.g. hyperphosphatemia).DETAILED DESCRIPTION OF THE INVENTIONDefinitions

[0021] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention.

[0022] When describing the invention, which may include compounds, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term “substituted” is to be defined as set out below. It should be further understood that the terms “groups” and “radicals” can be considered interchangeable when used herein.

[0023] The articles ‘a’ and ‘an’ may be used herein to refer to one or to more than one (z. e. at least one) of the grammatical objects of the article. By way of example ‘an analogue’ means one analogue or more than one analogue.

[0024] A dashthat is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH2 is attached through the carbon atom. A dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning.

[0025] A wavy line drawn through a line in a structure indicates a point of attachment of a group.Similarly, a squiggly line on a chemical group as shown, for example, indicates a point of attachment, i.e., it shows the broken bond by which the group is connected to another described group.

[0026] The prefix “Cu-v” indicates that the following group has from u to v carbon atoms. For example, “C1-8 alkyl” indicates that the alkyl group has from 1 to 8 carbon atoms.

[0027] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount ± 10%. In other embodiments, the term “about” includes the indicated amount ± 5%. In certain other embodiments, the term “about” includes the indicated amount ± 1%. Also, to the term “about X” includes description of “X”. Also, the singular forms "a" and "the" include plural references unless the context clearly dictates otherwise. Thus, e.g., reference to "the compound" includes a plurality of such compounds and reference to "the assay" includes reference to one or more assays and equivalents thereof known to those skilled in the art.

[0028] Unless indicated explicitly otherwise, where combinations of groups are referred to herein as one moiety, e.g. arylalkyl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule.

[0029] ‘Alkyl’ means straight or branched aliphatic hydrocarbon having the specified number of carbon atoms. Particular alkyl groups have 1 to 6 carbon atoms or 1 to 4 carbon atoms. Branched means that one or more alkyl groups such as methyl, ethyl or propyl is attached to a linear alkyl chain. Particular alkyl groups are methyl (-CH3), ethyl (-CH2-CH3), n-propyl (-CH2-CH2-CH3), isopropyl (-CH(CH3)2), n-butyl (-CH2-CH2-CH2-CH3), isobutyl (-CH2CH(CH3)2), tert-butyl (-CH2-C(CH3)3), sec-butyl (-CH2- CH(CH3)2), n-pentyl (-CH2-CH2-CH2-CH2-CH3), n-hexyl (-CH2-CH2-CH2-CH2-CH2-CH3), and 1,2- dimethylbutyl (-CHCH3)-C(CH3)H2-CH2-CH3). Particular alkyl groups have between 1 and 4 carbon atoms.

[0030] ‘Alkenyl’ refers to monovalent olefmically (unsaturated) hydrocarbon groups with the number of carbon atoms specified. Particular alkenyl has 2 to 8 carbon atoms, and more particularly, from 2 to 6 carbon atoms, which can be straight-chained or branched and having at least 1 and particularly from 1 to 2 sites of olefinic unsaturation. Particular alkenyl groups include ethenyl (-CFUCH2). n-propenyl (-CH2CFUCH2), isopropenyl (-C(CH3)=CH2) and the like.

[0031] Alkenylene’ refers to divalent alkenyl radical groups having the number of carbon atoms and the number of double bonds specified, in particular 2 to 6 carbon atoms and more particularly 2 to 4 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as -CH=CH- , -CH2-CH=CH-, -C(CH3)=CH-, -C(CH3)=CH-CH2-, -C(CH3)=C(CH3)-, and -CH2-C(CH3)=CH-.

[0032] ‘Alkylene’ refers to divalent alkyl radical groups having the number of carbon atoms specified, in particular having 1 to 6 carbon atoms and more particularly 1 to 4 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as methylene (-CH2-), ethylene (-CH2-CH2-), or -CH(CH3)- and the like.

[0033] ‘Alkynylene’ refers to divalent alkyne radical groups having the number of carbon atoms and the number of triple bonds specified, in particular 2 to 6 carbon atoms and more particularly 2 to 4 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as -C=C-, -CH2-OC-, and -C(CH3)H-C=CH-.

[0034] ‘Alkoxy’ refers to the group O-alkyl, where the alkyl group has the number of carbon atoms specified. In particular the term refers to the group -O-C i ,, alkyl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.

[0035] ‘ Amino’ refers to the radical -NH2.

[0036] ‘AryT refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system . In particular aryl refers to an aromatic ring structure, monocyclic or fused polycyclic, with the number of ring atoms specified. Specifically, the term includes groups that include from 6 to 10 ring members. Particular aryl groups include phenyl, and naphthyl.

[0037] ‘Cycloalkyl’ refers to a non-aromatic hydrocarbyl ring structure, monocyclic, fused polycyclic, bridged polycyclic, or spirocyclic, with the number of ring atoms specified. A cycloalkyl may have from 3 to 12 carbon atoms, in particular from 3 to 10, and more particularly from 3 to 7 carbon atoms. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0038] ‘Cyano’ refers to the radical -CN.

[0039] ‘ Halo’ or ‘halogen’ refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). Particular halo groups are either fluoro or chloro.

[0040] ‘ Hetero’ when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g. heterocycloalkyl, aryl, e.g. heteroaryl, and the like having from 1 to 4, and particularly from 1 to 3 heteroatoms, more typically 1 or 2 heteroatoms, for example a single heteroatom.

[0041] ‘Heteroaryl’ means an aromatic ring structure, monocyclic or fused polycyclic, that includes one or more heteroatoms independently selected from 0, N and S and the number of ring atoms specified. In particular, the aromatic ring structure may have from 5 to 10 ring members. The heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a fused bicyclic structure formed from fused five and six membered rings or two fused six membered rings or, by way of a further example, two fused five membered rings. Each ring may contain up to four heteroatoms typically selected from nitrogen, sulphur and oxygen. Typically the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an mdole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five. The term ‘heteroaryl’ also encompasses fused bicyclic systems wherein one ring is aromatic and one ring is not aromatic and one or more (e g. one or two e.g. one) ring atoms are independently selected from 0, N and S. An example is a phenyl ring fused to a non -aromatic heterocycloalkyl group, such as piperidyl, piperazinyl, morpholinyl, tetrahydrofuranyl dihydrothiophenyl, dihydroisothiazolyl, dihydrothiophenyl dioxide, dihydroisothiazolyl dioxide, thiadiazolyl dioxide, imidazolidinonyl, pyrrolidinonyl e.g. tetrahydrofuranyl or l,3-dihydrobenzo[c]isothiazolyl 2,2-dioxide.

[0042] Examples of five membered monocyclic heteroaryl groups include but are not limited to pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.

[0043] Examples of six membered monocyclic heteroaryl groups include but are not limited to pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

[0044] Particular examples of bicyclic heteroaryl groups containing a five membered ring fused to another five-membered ring include but are not limited to imidazothiazolyl and imidazoimidazolyl.

[0045] Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzofuranyl, benzothiophenyl, benzoimidazolyl, benzoxazolyl, isobenzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, purinyl (e.g. adenine, guanine), indazolyl, pyrazolopyrimidinyl, triazolopyrimidinyl, and pyrazolopyridinyl groups.

[0046] Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups. Particular heteroaryl groups are those derived from thiophenyl, pyrrolyl, benzothiophenyl, benzofuranyl, indolyl, pyridinyl, quinolinyl, imidazolyl, oxazolyl and pyrazinyl.

[0047] Examples of representative heteroaryls include the following:wherein each Y is selected from >C=O, NH, 0 and S.

[0048] ‘Heterocycloalkyl’ means a non-aromatic folly saturated ring structure, monocyclic, fused polycyclic, spirocyclic, or bridged polycyclic, that includes one or more heteroatoms independently selected from O, N and S and the number of ring atoms specified. The heterocycloalkyl ring structure may have from 4 to 12 ring members, in particular from 4 to 10 ring members and more particularly from 4 to 7 ring members. Each ring may contain up to four heteroatoms typically selected from nitrogen, sulphur and oxygen. Typically the heterocycloalkyl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. Examples of heterocyclic rings include, but are not limited to azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (e.g. 1- pyrrolidinyl, 2-pyrrolidinyl and 3 -pyrrolidinyl), tetrahydroforanyl (e.g. 1-tetrahydroforanyl, 2- tetrahydroforanyl and 3 -tetrahydroforanyl), tetrahydrothiophenyl (e.g. 1 -tetrahydrothiophenyl, 2- tetrahydrothiophenyl and 3 -tetrahydrothiophenyl), piperidinyl (e.g. 1-piperidinyl, 2-piperidinyl, 3- piperidinyl and 4-piperidinyl), tetrahydropyranyl (e.g. 4 -tetrahydropyranyl), tetrahydrothiopyranyl (e.g. 4-tetrahydrothiopyranyl), morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl. The term ‘Heterocycloalkyl’ is interchangeable with ‘Heterocyclyl’.

[0049] As used herein, the term ‘heterocycloalkenyl’ means a ‘heterocycloalkyl’, which comprises at least one double bond. Particular examples of heterocycloalkenyl groups are shown in the following illustrative examples:wherein each W is selected from CH2, NH, O and S; each Y is selected from NH, O, C(=O), SO2, and S; and each Z is selected from N or CH.

[0050] Particular examples of monocyclic rings are shown in the following illustrative examples:wherein each W and Y is independently selected from -CH2-, -NH-, -O- and -S-.

[0051] Particular examples of fused bicyclic rings are shown in the following illustrative examples:wherein each W and Y is independently selected from -CH2-, -NH-, -0- and -S-.

[0052] Particular examples of bridged bicyclic rings are shown in the following illustrative examples:wherein each W and Y is independently selected from -CH2-, -NH-, -0- and -S- and each Z is selected from N or CH.

[0053] Particular examples of spirocyclic rings are shown in the following illustrative examples:wherein each Y is selected from -CH2-, -NH-, -0- and -S-.

[0054] ‘Hydroxyl’ refers to the radical -OH.

[0055] ‘Oxo’ refers to the radical =0.

[0056] ‘ Substituted’ refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).

[0057] ‘Sulfo’ or ‘sulfonic acid’ refers to a radical such as -SO3H.

[0058] ‘ Thiol’ refers to the group -SH.

[0059] As used herein, term ‘substituted with one or more’ refers to one to four substituents. In one embodiment it refers to one to three substituents. In further embodiments it refers to one or two substituents. In a yet further embodiment it refers to one substituent.

[0060] ‘Thioalkoxy’ refers to the group -S-alkyl where the alkyl group has the number of carbon atoms specified. In particular the term refers to the group -S-C1-6 alkyl. Particular thioalkoxy groups are thiomethoxy, thioethoxy, n-thiopropoxy, isothiopropoxy, n-thiobutoxy, tert-thiobutoxy, secthiobutoxy, n-thiopentoxy, n-thiohexoxy, and 1,2-dimethylthiobutoxy. Particular thioalkoxy groups are lower thioalkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.

[0061] One having ordinary skill in the art of organic synthesis will recognize that the maximum number of heteroatoms in a stable, chemically feasible heterocyclic ring, whether it is aromatic or non -aromatic, is determined by the size of the ring, the degree of unsaturation and the valence of the heteroatoms. In general, a heterocyclic ring may have one to four heteroatoms so long as the heteroaromatic ring is chemically feasible and stable.

[0062] ‘Pharmaceutically acceptable ’ means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[0063] ‘Pharmaceutically acceptable salt’ refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parentcompound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2- hydroxyethanesulfonic acid, benzene sulfonic acid, 4 -chlorobenzene sulfonic acid, 2- naphthalenesulfonic acid, 4-toluene sulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2- ene- 1 -carboxylic acid, glucoheptonic acid, 3 -phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, mucomc acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g. an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. The term ‘pharmaceutically acceptable cation’ refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.

[0064] ‘Pharmaceutically acceptable vehicle’ refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.

[0065] ‘Prodrugs’ refers to compounds, including derivatives of the compounds of the invention, which have cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.

[0066] ‘ Solvate’ refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, EtOH, acetic acid and the like. The compounds of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. ‘Solvate’ encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates.

[0067] ‘Subject’ includes humans. The terms ‘human’, ‘patient’ and ‘subject’ are used interchangeably herein.

[0068] ‘ Effective amount’ means the amount of a compound of the invention that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The “effective amount” can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.

[0069] ‘Preventing’ or ‘prevention’ refers to a reduction in risk of acquiring or developing a disease or disorder (z. e. causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to a disease -causing agent, or predisposed to the disease in advance of disease onset.

[0070] The term ‘prophylaxis’ is related to ‘prevention’, and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease. Non-limiting examples of prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization; and the administration of an anti-malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.

[0071] ‘Treating’ or ‘treatment’ of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (z. e. arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof). In another embodiment ‘treating’ or ‘treatment’ refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, ‘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 a further embodiment, “treating” or “treatment” relates to slowing the progression of the disease.

[0072] Certain compounds of formula (I), or a pharmaceutically acceptable salt thereof, selectively target FGFR3. For example, certain compounds of formula (I), or a pharmaceutically acceptable salt thereof, selectively target FGFR3 over another FGFR. For example, certain compounds of formula (I), or a pharmaceutically acceptable salt thereof, selectively target FGFR3 over FGFR1. For example, certain compounds of formula (I), or a pharmaceutically acceptable salt thereof, are at least about 3 fold (e g. at least about 4-, 5- , 6-, 7-, 8-, 9-, 10-, 15-, 20-, 30-, 40-, 50-fold, or more) more selective for FGFR3 than for FGFR1.

[0073] Certain compounds of formula (I), or a pharmaceutically acceptable salt thereof, selectively target FGFR3. For example, certain compounds of formula (I), or a pharmaceutically acceptable salt thereof, selectively target FGFR3 over another FGFR. For example, certain compounds of formula (I), or a pharmaceutically acceptable salt thereof, selectively target FGFR3 over FGFR2. For example, certain compounds of formula (I), or a pharmaceutically acceptable salt thereof, are at least about 3 fold (e g. at least about 4-, 5- , 6-, 7-, 8-, 9-, 10-, 15-, or more) more selective for FGFR3 than for FGFR2.

[0074] Certain compounds of formula (I), or a pharmaceutically acceptable salt thereof, selectively target FGFR3. For example, certain compounds of formula (I), or a pharmaceutically acceptable salt thereof, selectively target FGFR3 over another FGFR. For example, certain compounds of formula (I), or a pharmaceutically acceptable salt thereof, selectively target FGFR3 over FGFR4. For example, certaincompounds of formula (I), or a pharmaceutically acceptable salt thereof, are at least about 3 fold (e.g. at least about 4-, 5- , 6-, 7-, 8-, 9-, 10-, 15-, or more) more selective for FGFR3 than for FGFR4.

[0075] As used herein, the term "selectivity" of a compound refers to the compound having more potent activity at the first target than the second target. A fold selectivity can be calculated by any method known in the art. For example, a fold selectivity can be calculated by dividing the IC50 value of a compound for the second target (e.g., FGFR1) by the IC50 value of the same compound for the first target (e.g., FGFR3). An IC50 value can be determined by any method known in the art. For example, an IC50 value can be determined as described in the assays below.

[0076] As used herein the term “cancer” refers to diseases caused by an uncontrolled division of abnormal cells in a part of the body. In particular, the term refers to metastatic tumour cell types (such as but not limited to, melanoma, lymphoma, leukaemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma) and types of tissue carcinoma (such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, glioblastoma, primary liver cancer, ovarian cancer, prostate cancer and uterine leiomyosarcoma). More particularly, the term refers to acute lymphoblastic leukemia, acute myeloidleukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumors, brain and spinal cord tumors, breast cancer, bronchial tumors, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T -Cell lymphoma, embryonal tumors, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, ewing sarcoma family of tumors, eye cancer, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gastrointestinal stromal cell tumor, germ cell tumor, glioma, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors (endocrine pancreas), Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, Acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, liver cancer, non- small cell lung cancer, small cell lung cancer, Burkitt lymphoma, cutaneous T-celllymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoma, Waldenstrom macroglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, mouth cancer, chronic myelogenous leukemia, myeloid leukemia, multiple myeloma, asopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, pineal parenchymal tumors of intermediate differentiation, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary tumor, plasma cell neoplasm / multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer,rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing sarcoma family of tumors, sarcoma, kaposi, Sezary syndrome, skin cancer, small cell Lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer, supratentorial primitive neuroectodermal tumors, T -cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom macroglobulinemia, and Wilms tumor.

[0077] As used herein the term “leukemia” refers to neoplastic diseases of the blood and blood forming organs. In particular, the term refers to neoplastic diseases of the blood and blood forming organs. More particularly, the term refers to acute myeloid leukaemia (AML), and acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukaemia (CLL).

[0078] As used herein, the term “FGFR3 -associated cancer” refers to cancers associated with or having a dysregulation of the FGFR3 gene, the FGFR3 kinase protein, or expression or activity, or level of any of the same. Non-limiting examples of FGFR3- associated cancer are described herein. As used herein an “FGFR3 -associated cancer” includes but is not limited to breast cancer (e.g. invasive ductal cancer, invasive lobular cancer), lung cancer (e g. non-small-cell lung cancer, lung adenocarcinoma, squamous cell lung cancer and small-cell lung cancer), urothelial cancer, bladder cancer (e.g. urothelial bladder cancer, non -muscle invasive bladder cancer, muscle invasive bladder cancer), upper tract cancer (e g. urothelial upper tract cancer), urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma (e.g. cutaneous melanoma), head and neck cancer (e.g. oral cancer), thyroid cancer, renal cancer (e.g. renal pelvis cancer), glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer.

[0079] Compoiind(s) of the invention’, and equivalent expressions, are meant to embrace compounds of the Formula(e) as herein described, which expression includes the pharmaceutically acceptable salts, and the solvates, e.g. hydrates, and the solvates of the pharmaceutically acceptable salts where the context so permits. Accordingly, 'compoLind(s) of the invention’ may refer to a compound according to any of Formula (I), Formula (la), Formula (lb), Formula (Ic), Formula (Id), or Formula (le), or a pharmaceutically acceptable salt and / or solvate thereof. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits.

[0080] When ranges are referred to herein, for example but without limitation, Ci-s alkyl, the citation of a range should be considered a representation of each member of said range.

[0081] Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but in the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (Bundgard, H, 1985). Prodrugs include acid derivatives well know to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of thisinvention are particularly useful prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy )alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Particular such prodrugs are the Ci-s alkyl, C2-8 alkenyl, Ce-io optionally substituted aryl, and (Ce-io aryl)-(Ci-4 alkyl) esters of the compounds of the invention.

[0082] The present disclosure includes all isotopic forms of the compounds of the invention provided herein, whether in a form (i) wherein all atoms of a given atomic number have a mass number (or mixture of mass numbers) which predominates in nature (referred to herein as the “natural isotopic form”) or (ii) wherein one or more atoms are replaced by atoms having the same atomic number, but a mass number different from the mass number of atoms which predominates in nature ( referred to herein as an “unnatural variant isotopic form”). It is understood that an atom may naturally exists as a mixture of mass numbers. The term “unnatural variant isotopic form” also includes embodiments in which the proportion of an atom of given atomic number having a mass number found less commonly in nature (referred to herein as an “uncommon isotope”) has been increased relative to that which is naturally occurring e.g. to the level of >20%, >50%, >75%, >90%, >95% or> 99% by number of the atoms of that atomic number (the latter embodiment referred to as an "isotopically enriched variant form"). The term “unnatural variant isotopic form” also includes embodiments in which the proportion of an uncommon isotope has been reduced relative to that which is naturally occurring. Isotopic forms may include radioactive forms (i.e. they incorporate radioisotopes) and non-radioactive forms. Radioactive forms will typically be isotopically enriched variant forms.

[0083] An unnatural variant isotopic form of a compound may thus contain one or more artificial or uncommon isotopes such as deuterium (2H or D), carbon-11 (nC), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-15 (15N), oxygen-15 (15O), oxygen-17 (17O), oxygen-18 (18O), phosphorus- 32 (32P), sulphur-35 (35S), chlorine-36 (36C1), chlorine-37 (37C1), fluorine-18 (18F) iodine-123 (123I), iodine-125 (125I) in one or more atoms or may contain an increased proportion of said isotopes as compared with the proportion that predominates in nature in one or more atoms.

[0084] Unnatural variant isotopic forms comprising radioisotopes may, for example, be used for drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e.3H, and carbon-14, i.e.14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Unnatural variant isotopic forms which incorporate deuterium i.e2H or D may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Further, unnatural variant isotopic forms may be prepared which incorporate positron emitting isotopes, such asnC,18F,150 and13N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

[0085] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed ‘isomers’. Isomers that differ in the arrangement of their atoms in space are termed ‘stereoisomers’.

[0086] Stereoisomers that are not mirror images of one another are termed ‘diastereomers’ and those that are non-superimposable mirror images of each other are termed ‘enantiomers’. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e. as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a ‘racemic mixture’.

[0087] ‘ Tautomers’ refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of n electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base . Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane, that are likewise formed by treatment with acid or base.

[0088] Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.

[0089] The compounds of the invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof.

[0090] An optical isomer with unknown absolute configuration may be depicted with an asterix (*) at the chiral center, e.g.,. Likewise, when a chemical structure possessing one or more asymmetric centers is described using its chemical name, stereocenters with unknown absolute configuration may be depicted with an asterix (*), e.g. R* and / or s*.

[0091] Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.

[0092] It will be appreciated that compounds of the invention may be metabolized to yield biologically active metabolites.THE INVENTION

[0093] The present invention relates to compounds that may be useful in the prophylaxis and / or treatment of diseases, disorders, or conditions that are associated with abnormal activity or expression of an FGFR enzyme, in particular cancer. The present invention also provides methods for the production of the compound of the invention, pharmaceutical compositions compnsing the compound of the invention, methods for the prophylaxis and / or treatment of diseases, disorders, or conditions that are associatedwith abnormal activity or expression of an FGFR enzyme, in particular cancer, by administering a compound of the invention.

[0094] Accordingly, in a first aspect, there is provided a compound of Formula (Ig):wherein:Xi is N or CH;X2is N and X3 is C, or, alternatively, X3 is N and X2is C;X4is N;Y is a bond, 0 or NH;Yi is a bond, CHR6, CH2-CHR6, CHR6-CH2, CF2, CH2-CF2or CF2-CH2;Y2is CR4R5or CF2;Y3is CR3R4, CR3R4CR3R4, CH2CF2or CF2; wherein Yi, Y2, Y3and X4together with the pyrazolyl ring form a 6- to 8-membered nitrogen containing ring;B is -C(O)Y4-, -Y4-, -CH2Y4-, or -CH2CH2Y4-, and A is CN;Y4is C3-10 cycloalkyl -R4N- or a 5- to 8-membered oxygen containing heterocyclyl-NR4-, wherein the cycloalkyl or 5- to 8-membered oxygen containing heterocyclyl is unsubstituted or independently substituted with one or more substituents independently selected from halogen, methyl, halomethyl, hydroxyl or methoxy, or wherein the cycloalkyl is substituted by two groups which are attached to the same carbon atom and join to form a 4- to 6- membered oxygen containing heterocyclyl ring, and wherein the nitrogen atom of the cycloalkyl -R4N or 5- to 8-membered oxygen containing heterocyclyl-NR4-, is connected to A;R1is hydrogen, halogen, C1-5 alkyl, C1.5 alkoxy, CN, C3-10 cycloalkyl, C2-4alkynyl, 4-10 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, 0 and S, phenyl or a 5- 6 membered heteroaryl, wherein the 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are unsubstituted or substituted with one or more substituents independently selected from halogen, methyl, halomethyl, hydroxyl or methoxy and wherein the C1.5 alkyl and C1.5 alkoxy,are unsubstituted or independently substituted with one or more substituents independently selected from halogen, CN, hydroxyl and methoxy;R2is hydrogen, hydroxyl, C1-4 alkyl, CN, -CONHC1.4 alkyl, or C1-4 haloalkyl; each R3is independently selected from hydrogen, fluoro, hydroxyl, methoxy, C1.3 alkyl, cyclopropyl, or a R3is fused with R5or R6to form CH2, CH2-CH2 or CH2OCH2; each R4is independently selected from hydrogen and C1.3 alkyl;R5is hydrogen, fluoro, hydroxyl, methoxy, C1.3 alkyl, cyclopropyl or is fused with one R3to form CHZ, CH2-CH2 or CH2OCH2, wherein the C1-3 alkyl is unsubstituted or independently substituted with one or more substituents independently selected from halogen, heteroaryl (which heteroaryl is preferably pyridyl), phenyl, hydroxyl, -CO2R4or C1-3 alkoxy;R6is hydrogen, fluoro, hydroxyl, methoxy, C1.3 alkyl or is fused with one R3to form CH2, CH2-CH2or CH2OCH2; each R8is independently selected from hydrogen and Cue alkyl; each R9is independently selected from hydrogen, CF3and C1-6 alkyl, which alkyl is unsubstituted or substituted with one or more substituents independently selected from fluoro, chloro, bromo, hydroxyl, and Cue alkoxy; andR10is hydrogen, C1.3 alkyl or halogen; or R9and R10together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring; each of R11and R12is independently hydrogen, Ci-g alkyl, or R11and R12together with the nitrogen atom to which they are attached form a 4-6 membered heterocycloalkyl optionally having an additional ring heteroatom which is O, wherein said ring is optionally substituted with halogen;R13is hydrogen, R14R15NCH2-, or C1.3 alkyl which is unsubstituted or substituted with hydroxyl;R14and R15are each independently hydrogen or Cue alkyl;R16is C1-3 alkyl-R17, C3-6 cycloalkyl-R17or a 4-6 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein the C1.3 alkyl, C3-6 cycloalkyl and 4-6 membered heterocycloalkyl are unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-4 alkyl optionally substituted with one or more OH, , C3-6 cycloalkyl, OH, OMe, -NR4R8wherein R4and R8are as defined above, or, alternatively, R4and R8together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring, or - O(CH2)2-4- wherein the oxygen atom and terminal carbon atom are attached to the same carbon atom in the C1-3 alkyl, C3-6 cycloalkyl and 4-6 membered heterocycloalkyl group such that an oxygen-containing heterocyclyl forms;R17is hydrogen, aryl, heteroaryl, 4-6 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, 0 and S, or C3-8 cycloalkyl, wherein the aryl and heteroaryl are unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, CN, NH2, C1-4 alkyl, and C1.4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy, wherein the heterocycloalkyl and cycloalkyl are unsubstituted or substituted with one or more substituentsindependently selected from the group consisting of halogen, CN, NH2, oxo, C1.4 alkyl, and Ci.4haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; or a pharmaceutically acceptable salt and / or solvate thereof.

[0095] Accordingly, in a second aspect, there is provided a compound of Formula (Ih):wherein:Xi is N or CH;X2is N and X3 is C, or, alternatively, X3 is N and X2is C;X4is N;Y is a bond, 0 or NH;Yi is a bond, CHR6, CH2-CHR6, CHR6-CH2, CF2, CH2-CF2or CF2-CH2;Y2is CR4R5or CF2;Y3is CR3R4, CR3R4CR3R4, CH2CF2or CF2;B is -C(O)Y4-, -Y4-, -CH2Y4-, or -CH2CH2Y4-, and A is CN;Y4is C3-10 cycloalkyl -R4N-, wherein the cycloalkyl is unsubstituted or independently substituted with one or more substituents independently selected from halogen, methyl, halomethyl, hydroxyl or methoxy and wherein the nitrogen atom of the cycloalkyl-R4N, is connected to A;R1is hydrogen, halogen, C1.5 alkyl, C1-5 alkoxy, CN, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, O and S, phenyl or a 5-6 membered heteroaryl, wherein the 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are unsubstituted or substituted with one or more substituents independently selected from halogen, methyl, halomethyl, hydroxyl or methoxy and wherein the C1-5 alkyl and C1.5 alkoxy, are unsubstituted or independently substituted with one or more substituents independently selected from halogen, CN, hydroxyl and methoxy;R2is hydrogen, hydroxyl, C1-4 alkyl, CN, -CONHC1.4 alkyl, or C1-4 haloalkyl; each R3is independently selected from hydrogen, fluoro, hydroxyl, methoxy, C1.3 alkyl, cyclopropyl, or a R3is fused with R5or R6to form CH2, CH2-CH2or CH2OCH2;each R4is independently selected from hydrogen and C1.3 alkyl;R5is hydrogen, fluoro, hydroxyl, methoxy, C1.3 alkyl, cyclopropyl or is fused with one R3to form CH2, CH2-CH2 or CH2OCH2, wherein the C1-3 alkyl is unsubstituted or independently substituted with one or more substituents independently selected from halogen, heteroaryl (which heteroaryl is preferably pyridyl), phenyl, hydroxyl, -CO2R4or C1-3 alkoxy;R6is hydrogen, fluoro, hydroxyl, methoxy, C1.3 alkyl or is fused with one R3to form CH2, CH2-CH2 or CH2OCH2; each R8is independently selected from hydrogen and Ci-g alkyl; each R9is independently selected from hydrogen, CF3and Ci-e alkyl, which alkyl is unsubstituted or substituted with one or more substituents independently selected from fluoro, chloro, bromo, hydroxyl, and Ci-e alkoxy; andR10is hydrogen, C1.3 alkyl or halogen; or R9and R10together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring; each of R11and R12is independently hydrogen, Ci-g alkyl, or R11and R12together with the nitrogen atom to which they are attached form a 4-6 membered heterocycloalkyl optionally having an additional ring heteroatom which is O, wherein said ring is optionally substituted with halogen;R13is hydrogen, R14R15NCH2-, or C1.3 alkyl which is unsubstituted or substituted with hydroxyl;R14and R15are each independently hydrogen or Ci-e alkyl;R16is C1.3 alkyl-R17, C3-6 cycloalkyl-R17or a 4-6 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein the C1-3 alkyl, C3-6 cycloalkyl and 4-6 membered heterocycloalkyl are unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-4 alkyl, C3-6 cycloalkyl, OH, OMe, -NR4R8wherein R4and R8are as defined above, or, alternatively, R4and R8together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring;R17is hydrogen, aryl, heteroaryl, 4-6 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, 0 and S, or C3-8 cycloalkyl, wherein the aryl, heteroaryl, heterocycloalkyl, and cycloalkyl are unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1.4 alkyl, and Ci.4haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; or a pharmaceutically acceptable salt and / or solvate thereof.

[0096] Accordingly, in a third aspect, the invention provides compounds of Formula (I):wherein:Xi is N or CH;X2is N and X3is C, or, alternatively, X3is N and X2is C;X4is N or CR4;Y is a bond, 0 or NH;Yi is a bond, CHR6, CH2-CHR6, CHR6-CH2, CF2, CH2-CF2or CF2-CH2;Y2is CR4R5or CF2;Y3is CR3R4, CR3R4CR3R4, CH2CF2or CF2; when X4is N, B is a bond, -C(O)Y4-, -Y4-, -CH2Y4-, or -CH2CH2Y4-, and A is CN, R8R9C=CR10C(=O)-, RnR12NCH2CH=CHC(=O)-, H2C=CHSO2- or RIC =CC(=O)-: when X4is CR4, B is a bond, and A is -NR4-CN, R8R9C=CR10C(=O)R4N-, RnR12NCH2CH=CHC(=O)R4N- , H2C=CHSO2-R4N- or R13C=CC(=O)-R4N-;Y4is a 5-8 membered heterocycloalkyl-R4N comprising a nitrogen atom or C3-10 cycloalkyl-R4N-, wherein the heterocycloalkyl and cycloalkyl are unsubstituted or independently substituted with one or more substituents independently selected from halogen, methyl, halomethyl, hydroxyl or methoxy and wherein the nitrogen atom of the heterocycloalkyl or the cycloalkyl-R4N is connected to A;R1is hydrogen, halogen, C1.5 alkyl, C1-5 alkoxy, CN, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, O and S, phenyl or a 5-6 membered heteroaryl, wherein the 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are unsubstituted or substituted with one or more substituents independently selected from halogen, methyl, halomethyl, hydroxyl or methoxy and wherein the C1-5 alkyl and C1.5 alkoxy, are unsubstituted or independently substituted with one or more substituents independently selected from halogen, CN, hydroxyl and methoxy;R2is hydrogen, hydroxyl, Ci.4alkyl, CN, -CONHCI.4alkyl, or Ci-4haloalkyl; each R3is independently selected from hydrogen, fluoro, hydroxyl, methoxy, C1.3 alkyl, cyclopropyl, or a R3is fused with R5or R6to form CH2, CH2-CH2or CH2OCH2;each R4is independently selected from hydrogen and C1.3 alkyl;R5is hydrogen, fluoro, hydroxyl, methoxy, C1.3 alkyl, cyclopropyl or is fused with one R3to form CH2, CH2-CH2 or CH2OCH2, wherein the C1-3 alkyl is unsubstituted or independently substituted with one or more substituents independently selected from halogen, heteroaryl (which heteroaryl is preferably pyridyl), phenyl, hydroxyl, -CO2R4or C1-3 alkoxy;R6is hydrogen, fluoro, hydroxyl, methoxy, C1.3 alkyl or is fused with one R3to form CH2, CH2-CH2 or CH2OCH2; each R8is independently selected from hydrogen and Ci-g alkyl; each R9is independently selected from hydrogen, CF3and Ci-e alkyl, which alkyl is unsubstituted or substituted with one or more substituents independently selected from fluoro, chloro, bromo, hydroxyl, and Ci-e alkoxy; andR10is hydrogen, C1.3 alkyl or halogen; or R9and R10together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring; each of R11and R12is independently hydrogen, Ci-g alkyl, or R11and R12together with the nitrogen atom to which they are attached form a 4-6 membered heterocycloalkyl optionally having an additional ring heteroatom which is O, wherein said ring is optionally substituted with halogen;R13is hydrogen, R14R15NCH2-, or C1.3 alkyl which is unsubstituted or substituted with hydroxyl;R14and R15are each independently hydrogen or Ci-e alkyl;R16is C1.3 alkyl-R17, C3-6 cycloalkyl-R17or a 4-6 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein the C1-3 alkyl, C3-6 cycloalkyl and 4-6 membered heterocycloalkyl are unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-4 alkyl, C3-6 cycloalkyl, OH, OMe, -NR4R8wherein R4and R8are as defined above, or, alternatively, R4and R8together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring;R17is hydrogen, aryl, heteroaryl, 4-6 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, 0 and S, or C3-8 cycloalkyl, wherein the aryl, heteroaryl, heterocycloalkyl, and cycloalkyl are unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1.4 alkyl, and Ci.4haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; or a pharmaceutically acceptable salt and / or solvate thereof.

[0097] In certain embodiments, the compound of the Formula (I) is a compound of the Formula (la):(la) or a pharmaceutically acceptable salt and / or solvate thereof; wherein Xi, X2, X3, Y, Yi, Y2, Y3, R1, R2, R16and A are as defined for Formula (I). Preferred definitions of Xi, X2, X3, Y, Yi, Y2, Y3, R1, R2, R16and A are as defined for compounds of formula (I).

[0098] In certain embodiments, the compound of the Formula (la) is a compound of the Formula (la-1):wherein Xi, X2, X3, Y, R1, R2, R3, R4, R5, R6and R16are as defined for Formula (I). Preferred definitions of Xi, X2, X3, Y, R1, R2, R3, R4, R5, R6and R16are as defined for compounds of formula (I).

[0099] In certain embodiments, the compound of the Formula (la) is a compound of the Formula (la-2):(la-2) wherein Xi, X2, X3, Y, R1, R2, R3, R4, R5, R6, R8, R9, R10and R16are as defined for Formula (I). Preferred definitions of Xi, X2, X3, Y, R1, R2, R3, R4, R5, R6, R8, R9, R10and R16are as defined for compounds of formula (I).

[0100] In certain embodiments, the compound of the Formula (la) is a compound of the Formula (la-3):wherein Xi, X2, X3, Y, R1, R2, R3, R4, R5, R6and R16are as defined for Formula (I). Preferred definitions of Xi, X2, X3, Y, R1, R2, R3, R4, R5, R6and R16are as defined for compounds of formula (I).

[0101] In certain embodiments, the compound of the Formula (la) is a compound of the Formula (la-4):wherein Xi, X2, X3, Y, R1, R2, R3, R4, R5, R6, R8, R9, R10and R16are as defined for Formula (I). Preferred definitions of Xi, X2, X3, Y, R1, R2, R3, R4, R5, R6, R8, R9, R10and R16are as defined for compounds of formula (I).

[0102] In certain embodiments, the compound of the Formula (I) is a compound of the Formula (lb):or a pharmaceutically acceptable salt and / or solvate thereof; wherein Xi, X2, X3, Y, Yi, Y2, Y3, R1, R2, R4, R16and A are as defined for Formula (I). Preferred definitions of Xi, X2, X3, Y, Yi, Y2, Y3, R1, R2, R4, R16and A are as defined for compounds of formula (I).

[0103] In certain embodiments, the compound of the Formula (lb) is a compound of the Formula (Ib-1):(Ib-1) wherein Xi, X2, X3, Y, R1, R2, R3, R4, R5, R6and R16are as defined for Formula (I). Preferred definitions of Xi, X2, X3, Y, R1, R2, R3, R4, R5, R6and R16are as defined for compounds of formula (I).

[0104] In certain embodiments, the compound of the Formula (lb) is a compound of the Formula (Ib-1):wherein Xi, X2, X3, Y, R1, R2, R3, R4, R5, R6and R16are as defined for Formula (I). Preferred definitions of Xi, X2, X3, Y, R1, R2, R3, R4, R5, R6and R16are as defined for compounds of formula (I).

[0105] In certain embodiments, the compound of the Formula (I) is a compound of the Formula (Ib-3):or a pharmaceutically acceptable salt and / or solvate thereof; wherein Xi, X2, X3, Y, Yi, Y2, Y3, R1, R2, R4, R16and A are as defined for Formula (I). Preferred definitions of Xi, X2, X3, Y, Yi, Y2, Y3, R1, R2, R4, R16and A are as defined for compounds of formula (I).

[0106] In certain embodiments, the compound of the Formula (I) is a compound of the Formula (Ic):or a pharmaceutically acceptable salt and / or solvate thereof; wherein:Z is a absent, or is CO or (CFb ; each n is independently 1 or 2;R21is absent or is halogen, methyl, halomethyl, hydroxyl or methoxy; andXi, X2, X3, Y, Yi, Y2, Y3, R1, R2, R16and A are as defined for Formula (I). Preferred definitions of Xi, X2, X3, Y, Yi, Y2, Y3, R1, R2, R16and A are as defined for compounds of formula (I).

[0107] In certain embodiments, the compound of the Formula (Ic) is a compound of the Formula (Ic-1):whereinhydrogen, methyl or halogen (preferably fluoro), and Xi, X2, X3,Y, Yi, Y2, Y3, R1, R2, and R16are as defined for Formula (I). Preferred definitions of Xi, X2, X3, Y, Yi, Y2, Y3, R1, R2, and R16are as defined for compounds of formula (I).

[0108] In certain embodiments, the compound of the Formula (I) is a compound of the Formula (Id):or a pharmaceutically acceptable salt and / or solvate thereof; wherein: a is independently 0, 1, 2, 3, or 4;R18is halogen;R19is methyl, hydroxymethyl, or halomethyl (preferably fluoromethyl);R20is H or methyl; andXi, X2, X3, X4, Yi, Y2, Y3, R1, R2, B and A are as defined for Formula (I) e.g. (Ig) such as (Ih). Preferred definitions of Xi, X2, X3, X4, Yi, Y2, Y3, R1, R2, B and A are as defined for compounds of formula (I) e.g. (Ig) such as (Ih).

[0109] In certain embodiments, the compound of the Formula (I) is a compound of the Formula (le):or a pharmaceutically acceptable salt and / or solvate thereof; wherein: a is independently 0, 1, 2, 3, or 4;R18is halogen;R19is methyl, hydroxymethyl, or OH;R20is H or methyl; andXi, X2, X3, X4, Yi, Y2, Y3, R1, R2, B and A, are as defined for Formula (I) e.g. (Ig) such as (Ih). Preferred definitions of Xi, X2, X3, X4, Yi, Y2, Y3, R1, R2, B and A are as defined for compounds of formula (I) e.g. (Ig) such as (Ih).

[0110] In certain embodiments, the compound of the Formula (I) is a compound of formula (Ig- 1):or a pharmaceutically acceptable salt and / or solvate thereof; andXi, X2, X3, R1, R2and B are as defined for Formula (I) e.g. (Ig) such as (Ih). Preferred definitions of Xi, X2, X3, R1, R2and B are as defined for compounds of Formula (I) e.g. (Ig) such as (Ih).[OlH] In certain embodiments, the compound of the Formula (I) is a compound of formula (Ig-2):or a pharmaceutically acceptable salt and / or solvate thereof; andXi, X2, X3, R1, R2and B are as defined for Formula (I) e.g. (Ig) such as (Ih). Preferred definitions of Xi, X2, X3, R1, R2and B are as defined for compounds of Formula (I) e.g. (Ig) such as (Ih).

[0112] In certain embodiments, the compound of the Formula (I) is a compound of formula (Ig-3):or a pharmaceutically acceptable salt and / or solvate thereof; andXi, X2, X3, R1, R2and B are as defined for Formula (I) e.g. (Ig) such as (Ih). Preferred definitions of Xi, X2, X3, R1, R2and B are as defined for compounds of Formula (I) e.g. (Ig) such as (Ih).

[0113] In certain embodiments, the compound of the Formula (I) is a compound of formula (Ig-4):or a pharmaceutically acceptable salt and / or solvate thereof; andXi, X2, X3, R1, R2and B are as defined for Formula (I) e.g. (Ig) such as (Ih). Preferred definitions of Xi, X2, X3, R1, R2and B are as defined for compounds of Formula (I) e.g. (Ig) such as (Ih).

[0114] In certain embodiments, the compound of the Formula (I) is a compound of formula (Ig-5):or a pharmaceutically acceptable salt and / or solvate thereof; andXi, X2, X3, R1, R2and B are as defined for Formula (I) e.g. (Ig) such as (Ih). Preferred definitions of Xi, X2, X3, R1, R2and B are as defined for compounds of Formula (I) e.g. (Ig) such as (Ih).

[0115] Suitably, the compound of formula (I) is a compound of formula (Ig-2) or (Ig-4).

[0116] Certain compounds according to the invention may exhibit one or more benefits including, inter alia, advantageous levels of biological activity which may be useful in the prophylaxis and / or treatment of one or more disease, improved safety characteristics (e.g. relating to hERG inhibition, drug-drug interaction (DDI) or CYP-interaction characteristics, etc), improved selectivity for one or more disease- associated biological target (e.g. reduced off-target effects, etc), improved pharmacokinetic properties (e.g. relating to dosing, solubility, absorption, etc), improved pharmacodynamic properties (e.g. relating to permeability, efflux, etc) or superior properties for use as pharmaceutical active ingredients alone or in pharmaceutical compositions (e g. stability), or advantageous physico-chemical properties useful in the manufacturability of such aforementioned pharmaceutical compositions.

[0117] Preferred values of Xi, X2, X3, X4, Y, Yi, Y2, Y3, Y4, R1, R2, R3, R4, R5, R6, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, B and A are, in any combination thereof, as set out below, and apply equally to compounds of formula (I), (Ig), (Ih) (Ig-1), (Ig-2), (Ig-3), (Ig-4), (Ig-5), and (Ig-6), as well as other formulae disclosed herein. The term “compounds of the invention” refer to compounds of formula (I), (Ig), (Ih), (Ig-1), (Ig-2), (Ig-3), (Ig-4), (Ig-5), and (Ig-6) as well as other formulae disclosed herein, in particular compounds of formula (Ig) and (Ih)

[0118] In some suitable compounds of the invention, Xi is N.

[0119] Preferably Xi is CH.

[0120] In some suitable compounds of the invention, X2is N and X3is C.

[0121] In some suitable compounds of the invention, X3is N and X2is C.

[0122] Preferably X2is C.

[0123] Preferably X3 is N.

[0124] Preferably X4 is N or CH.

[0125] In some suitable compounds of the invention, preferably X4 is N.

[0126] When X4 is N, preferably B is a bond, -C(O)Y4-, -Y4- or -CH2Y4- (such as -C(O)Y4-, -Y4- or - CH2Y4-), and preferably A is CN or R8R9C=CR10C(=O)- (such as CN), wherein preferably Y4is a 3-6 membered heterocycloalkyl comprising a nitrogen atom or C3-5 cycloalkyl-R4N- (such as C3-5 cycloalkyl-R4N-), wherein the heterocycloalkyl and cycloalkyl are unsubstituted or independently substituted with one or more substituents independently selected from halogen, methyl, halomethyl, hydroxyl or methoxy and wherein the nitrogen atom of the heterocycloalkyl and the cycloalkyl-R4N, respectively, are connected to A.

[0127] When X4is N, preferably B is a -C(O)Y4-, -Y4- or -CH2Y4-, and preferably A is CN, wherein preferably Y4is C3-10 cycloalkyl-R4N- or a 5- to 8-membered oxygen containing heterocyclyl-NR4-, wherein the cycloalkyl or 5- to 8-membered oxygen containing heterocyclyl is unsubstituted or independently substituted with one or more substituents independently selected from halogen, methyl, halomethyl, hydroxyl or methoxy, or wherein the cycloalkyl is substituted by two groups which are attached to the same carbon atom and join to form a 4- to 6- membered oxygen containing heterocyclyl ring, and wherein the nitrogen atom of the cycloalkyl-R4N or 5- to 8-membered oxygen containing heterocyclyl-NR4-, is connected to A.

[0128] When X4is N, more preferably B is a bond, or is selected fromwherein more preferably; wherein Z is a absent, or is CO or (CH2)n; each n is independently 1 or 2; m is 0, 1 or 2; R4is independently selected from hydrogen and C1-3 alkyl; R21is absent or each is independently halogen (preferably fluoro), methyl or methoxy and each R22is independently hydrogen, halogen (preferably fluoro) or methyl.

[0129] When X4is N, most preferably B is a bond, or is selected fromwherein most preferably; wherein R21is hydrogen or halogen (preferably fluoro) and R22is hydrogen, methyl or halogen (preferably fluoro).

[0130] When X4is CH, preferably B is a bond and preferably A is -NH-CN or R8R9C=CR10C(=O) NH-.

[0131] In one embodiment, B is -C(O)Y4-. In a second embodiment, B is -Y4-. In a third embodiment, B is -CH2Y4-.

[0132] When X4is CH, more preferably B is a bond and more preferably A is -NH-CN,

[0133] When X4is CH, most preferably B is a bond and most preferably A is -NH-CN,

[0134] In one embodiment, Y is a bond. In a second embodiment, Y is NH. In a third embodiment, Y is 0.

[0135] Preferably Y is 0.

[0136] In one embodiment, Yi is bond. In a second embodiment, Yi is CHR6. In a third embodiment, Yi is CH2-CHR6. In a fourth embodiment, Yi is CHR6-CH2. In a fifth embodiment, Yi is CF2. In a sixth embodiment, Yi is CH2-CF2. In a seventh embodiment, Yi is CF2-CH2.

[0137] Preferably Yi is CHR6.

[0138] Most preferably Y 1 is CH2.

[0139] In one embodiment, Y2is CR4R5. In a second embodiment, Y2is CF2.

[0140] Preferably Y2is CR4R5.

[0141] Most preferably Y2is CHR5.

[0142] In one embodiment, Y3 is CR3R4. In a second embodiment, Y3 is CR3R4CR3R4. In a third embodiment, Y3is CH2CF2. In a fourth embodiment, Y3is CF2.

[0143] Preferably Y3is CR3R4or CH2CR3R4.

[0144] Most preferably Y3is CH2or CH2CH2.

[0145] In one embodiment, Y 1 is CHR6, Y2is CR4R5or CF2and Y3is CH2CR3R4.

[0146] In another embodiment, Y 1 is CHR6, Y2is CR4R5or CF2and Y3 is CR3R4.

[0147] In one embodiment, Yi , Y2, Y3and X4together with the pyrazolyl ring form a 6-membered nitrogen containing ring. In a second embodiment, Yi, Y2, Y3and X4together with the pyrazolyl ring form a 7- membered nitrogen containing ring. In a third embodiment, Yi, Y2, Y3and X4together with the pyrazolyl ring form an 8 -membered nitrogen containing ring.

[0148] Preferably, Yi, Y2, Y3and X4together with the pyrazolyl ring form a 6- or 7-membered nitrogen containing ring.H

[0149] In one embodiment, Y4is C3-10 cycloalkyl-R4N- such as C3-7 cycloalkyl -R4N-,membered oxygen containing heterocyclyl-NR4-, such as:wherein ' '' indicates the connection to the remainder of the compound of formula (I), such as (Ig) or(Ill).

[0150] In one embodiment, the cycloalkyl of Y4is unsubstituted. In a second embodiment, the cycloalkyl of Y4is substituted by one or more (such as one, two or three, e.g. two) substituents independently selected from halogen, methyl, halomethyl, hydroxyl or methoxy, e g. is substituted by two fluoro or two methyl groups. When the cycloalkyl of Y4is substituted with two groups, the groups may be attached to the same or different ring atoms. Suitably, the two groups are attached to the same ring atom. In a third embodiment, the cycloalkyl of Y4is substituted by two groups which are attached to the same carbon atom and join to form a 4- to 6- membered oxygen containing heterocyclyl ring, such as a 4-membered oxygen containing heterocyclyl ring.

[0151] In one embodiment, the heterocyclyl of Y4is unsubstituted. In a second embodiment, the heterocyclyl of Y4is substituted by one or more (such as one, two or three, e.g. two) substituents independently selected from halogen, methyl, halomethyl, hydroxyl or methoxy, e.g. is substituted by two fluoro or two methyl groups. When the heterocyclyl of Y4is substituted with two groups, the groups may be attached to the same or different ring atoms, suitably carbon ring atoms. Suitably, the two groups are attached to the same ring atom, suitably the same carbon ring atom.

[0152] In any of the above embodiments, the nitrogen atom of the cycloalkyl -R4N or 5- to 8 -membered oxygen containing heterocyclyl -NR4-, is connected to A such as to form the group -NR4-CN.

[0153] In one embodiment, R1is hydrogen. In a second embodiment, R1is halo e.g. chloro. In a third embodiment, R1is C1-5 alkyl. In a fourth embodiment, R1is C1-5 alkoxy e.g. OMe. In a fifth embodiment, R1is CN. In a sixth embodiment, R1is C3-10 cycloalkyl. In a seventh embodiment, R1is 4-10 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, O and S . In an eighth embodiment, R1is phenyl . In a nineth embodiment, R1is a 5 -6 membered heteroaryl . In a tenth embodiment R1is a C2-4 alkynyl.

[0154] Preferably R1is hydrogen, halogen, C1-3 alkyl, C1.3 alkoxy, CN, wherein the C1-3 alkyl and C1.3 alkoxy are unsubstituted or independently substituted with one or more substituents (such as one or two e.g. two) independently selected from halogen (e.g. fluoro).

[0155] More preferably R1is hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, halomethyl, haloethyl, halomethoxy, haloethoxy, cyano, CF3, CHF2, OCH3or OCHF2.

[0156] Most preferably R1is hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, cyano, CF3, CHF2, OCH3or OCHF2(especially OCH3or OCHF2).

[0157] Preferably R2is hydrogen, hydroxyl or C1.2 alkyl.

[0158] Most preferably R2is hydrogen, methyl or ethyl.

[0159] Even more preferably R2is methyl.

[0160] Preferably each R3is independently selected from hydrogen, fluoro and C1-2 alkyl.

[0161] More preferably each R3is independently selected from hydrogen, fluoro and methyl.

[0162] Most preferably each R3is independently hydrogen.

[0163] Preferably each R4is independently selected from hydrogen and methyl.

[0164] Most preferably each R4is independently hydrogen.

[0165] Preferably R5is hydrogen, fluoro, hydroxyl, methoxy or C1.3 alkyl, wherein the C1.3 alkyl is unsubstituted or independently substituted with one or more substituents independently selected from halogen, pyridyl, phenyl, hydroxyl, -CO2R4or C1-3 alkoxy.

[0166] Most preferably R5is hydrogen or C1-3 alkyl, wherein the C1-3 alkyl is unsubstituted or substituted with a substituent selected from pyndyl, phenyl, and -CO2H.

[0167] Even more preferably R5is hydrogen.

[0168] Preferably R6is hydrogen, fluoro or C1-2 alkyl.

[0169] More preferably R6is hydrogen, fluoro or methyl.

[0170] Most preferably R6is hydrogen.

[0171] Preferably each R8is independently selected from hydrogen and C1.2 alkyl.

[0172] More preferably each R8is independently selected from hydrogen and methyl.

[0173] Most preferably each R8is independently hydrogen.

[0174] Preferably each R9is independently selected from hydrogen, CF3and C1.2 alkyl, which alkyl is unsubstituted or substituted with one or more substituents independently selected from fluoro, chloro and bromo.

[0175] More preferably each R9is independently selected from hydrogen, CF3and methyl.

[0176] Most preferably each R9is independently hydrogen.

[0177] Preferably each R10is independently selected from hydrogen, C1-2 alkyl and halogen.

[0178] More preferably each R10is independently selected from hydrogen, fluoro, chloro, and methyl.

[0179] Most preferably each R10is independently selected from hydrogen, fluoro and methyl.

[0180] Preferably each of R11and R12is independently hydrogen, C1-3 alkyl, or R11and R12together with the nitrogen atom to which they are attached form a 4-6 membered heterocycloalkyl optionally having an additional ring heteroatom which is O, wherein said heterocycloalkyl is unsubstituted or substituted with one or more halogen atoms.

[0181] More preferably each of R11and R12is independently hydrogen, C1-2 alkyl, or R11and R12together with the nitrogen atom to which they are attached form a 4-6 membered heterocycloalkyl, wherein said heterocycloalkyl is unsubstituted or substituted with one or more halogen atoms.

[0182] Most preferably each of R11and R12is independently hydrogen or methyl, or R11and R12together with the nitrogen atom to which they are attached form a 4-6 membered heterocycloalkyl.

[0183] Preferably each R13is independently selected from hydrogen, R14R15NCH2-, and C1.3 alkyl, which alkyl is unsubstituted or substituted with hydroxyl.

[0184] More preferably each R13is independently selected from hydrogen and C1.2 alkyl, which alkyl is unsubstituted or substituted with hydroxyl.

[0185] Most preferably each R13is independently selected from hydrogen and methyl.

[0186] Preferably R14and R15are each independently hydrogen or C1.3 alkyl.

[0187] More preferably R14and R15are each independently hydrogen or C1-2 alkyl.

[0188] Most preferably R14and R15are each independently hydrogen or methyl.

[0189] Preferably R16is C1-3 alkyl-R17, wherein the C1-3 alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, C1-2 alkyl, C3-6 cycloalkyl, OH and OMe.

[0190] In one embodiment, R16is Ci alkyl-R17, wherein the Ci alkyl is unsubstituted or substituted with one or more substituents as defined herein. In a second embodiment, R16is C2 alkyl-R17, wherein the C2 alkyl is unsubstituted or substituted with one or more substituents as defined herein. In a third embodiment, R16is C3 alkyl-R17, wherein the C3 alkyl is unsubstituted or substituted with one or more substituents as defined herein.

[0191] In one embodiment, R16is -CH2CH2CH2R17. Alternatively R16is -CH2CH(R17)CH3. Alternatively R16is -CH(R17)CH2CH3. Alternatively R16is -CH(R17)CH3. Alternatively R16is -CH2CH2R17.

[0192] When R16is C1-3 alkyl-R17substituted with one or more (e.g. one or two e.g. one) substituents independently selected from the group consisting of halogen, C1-2 alkyl, C3-6 cycloalkyl, OH and OMe (e.g. OH), R16is suitably -CH(R17)-CH2(substituent) e.g. -CH(R17)-CH2(OH).

[0193] In one embodiment, the C1-3 alkyl is substituted by one substituent.

[0194] Suitably, the one substituent is OH. Alternatively the one substituent is methyl.

[0195] Alternatively the C1-3 alkyl is substituted by two substituents such as OH and methyl. Suitably the two substituents are attached to the same carbon atom.

[0196] In one embodiment, R16is C1-3 alkyl-R17substituted with -O(CH2)24- wherein the oxygen atom and terminal carbon atom are attached to the same carbon atom in the C1-3 alkyl, C3-6 cycloalkyl and 4- 6 membered heterocycloalkyl group such that an oxygen-containing heterocyclyl forms i.e .:wherein '''' indicates the join to the remainder of the molecule.

[0197] Thus in one embodiment, there is suitably provided a compound of formula (Ig-6) :wherein all variables are as defined elsewhere herein.

[0198] More preferably the C1.3 alkyl moiety contained in R16is selected from:, wherein Rig is methyl, hydroxymethyl, or halomethyl (preferably fluoromethyl) and R20 is hydrogen or methyl;wherein R19is methyl, hydroxymethyl, or OH and R20is hydrogen or methyl.

[0199] Even more preferably the C1.3 alkyl moiety contained in R16is selected from:

[0200] Most preferably the C1-3 alkyl moiety contained in R16is selected from:

[0201] In one embodiment, R17is hydrogen. In a second embodiment, R17is aryl e.g. phenyl. In a third embodiment, R17is heteroaryl e.g. 5- or 6-membered heteroaryl such as pyrazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl e.g. pyridinyl. In a fourth embodiment, R17is 4-6membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms (such as 1 or 2 heteroatoms e.g. 1 heteroatom) independently selected from N, 0 and S (e.g. N or 0). In a fifth embodiment, R17is C3-8 cycloalkyl.

[0202] In one embodiment, the aryl, heteroaryl, heterocycloalkyl, and cycloalkyl are unsubstituted. In another embodiment the aryl and heteroaryl are substituted with one or more substituents independently selected from the group consisting of halogen e.g. F, CN, NH2, CM alkyl e.g. methyl, Ci-4haloalkyl e.g. Ci haloalkyl such as CHF2, Ci-4alkoxy e.g. OMe, and Ci -4 haloalkoxy e.g. substituted with one or more substituents independently selected from the group consisting ofhalogen, CN, C1.4 alkyl, Ci- 4 haloalkyl, CM alkoxy, and CM haloalkoxy. In another embodiment the heterocycloalkyl, and cycloalkyl are substituted with one or more substituents independently selected from the group consisting ofhalogen e.g. F, CN, NH2, OXO, CM alkyl e.g. methyl, CM haloalkyl e.g. Ci haloalkyl such as CHF2, CM alkoxy e.g. OMe, and C 1.4 haloalkoxy e.g. substituted with one or more substituents independently selected from the group consisting ofhalogen, CN, CMalkyl, Ci- 4 haloalkyl, CM alkoxy, and CM haloalkoxy.

[0203] When R17is substituted by oxo (=0), the oxo group may be attached to a carbon atom thus forming C=O, or one or two oxo groups may be attached to an S atom in the heterocycloalkyl ring to form S=O or S(=O)2respectively.

[0204] In one embodiment, the substituents are selected from the group consisting of halogen e.g. F, CN, Ci-2alkyl e.g. Me, and Ci-2haloalkyl e.g. Ci haloalkyl such as CHF2, Ci-2alkoxy e.g. OMe, and Ci-2haloalkoxy.

[0205] Most suitably, the substituent is F.

[0206] Preferably R17is hydrogen, phenyl, pyridyl, pyridazinyl, isoquinolinyl, tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, or C3-7 cycloalkyl, wherein the phenyl, pyridyl, pyridazinyl, isoquinolinyl, tetrahydropyranyl, tetrahydrofuranyl, oxetanyl and cycloalkyl are unsubstituted or substituted with one or more substituents independently selected from the group consisting ofhalogen, CN, CM alkyl, and Ci_2haloalkyl, CM alkoxy, and C haloalkoxy.

[0207] More preferably R17is cyclobutyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl or pyridyl, wherein the phenyl or pyridyl are unsubstituted or substituted with one or more substituents independently selected from halogen.

[0208] More preferably still R17is phenyl or pyridyl, wherein the phenyl or pyridyl are unsubstituted or substituted with one or more substituents independently selected from halogen.

[0209] Most preferably R17is 2-pyridyl which is unsubstituted or substituted with one or two halogens (preferably fluoro).

[0210] A preferred group of compounds according to the invention are those of formula 1-1, which are compounds of formula I wherein:Xi is CH;X2is C and X3is N or X2is N and X3is C;X4is N or CH;Y is O;Yi is CHR6;Y2is CR4R5;Y3is CR3R4or CH2CR3R4; when X4 is N, B is a bond, -C(O)Y4-, -Y4- or -CH2Y4-, and A is CN or R8R9C=CR10C(=O)-, wherein Y4is a 3-6 membered heterocycloalkyl comprising a nitrogen atom or C3-iocycloalkyl-R4N-, wherein the heterocycloalkyl and cycloalkyl are unsubstituted or independently substituted with one or more substituents independently selected from halogen, methyl, halomethyl, hydroxyl or methoxy and wherein the nitrogen atom of the heterocycloalkyl and the cycloalkyl -R4N-, respectively, are connected to A, and wherein R8is independently selected from hydrogen and Ci-2alkyl, R9is independently selected from hydrogen, CF3and Ci-2alkyl, which alkyl is unsubstituted or substituted with one or more substituents independently selected from fluoro, chloro and bromo, and R10is independently selected from hydrogen, C1-2 alkyl and halogen; when X4is CH, B is a bond and A is -NH-CN or R8R9C=CR10C(=O)NH-, where R8is independently selected from hydrogen and C1-2 alkyl, R9is independently selected from hydrogen, CF3and Ci-2alkyl, which alkyl is unsubstituted or substituted with one or more substituents independently selected from fluoro, chloro and bromo, and R10is independently selected from hydrogen, Ci-2alkyl and halogen;R1is hydrogen, halogen, C1-3 alkyl, C1-3 alkoxy, CN, wherein the C1-3 alkyl and C1.3 alkoxy are unsubstituted or independently substituted with one or more substituents independently selected from halogen;R2is hydrogen, hydroxyl or C1-2 alkyl; each R3is independently selected from hydrogen, fluoro and Ci-2alkyl; each R4is independently selected from hydrogen and Ci-2alkyl;R5is hydrogen, fluoro, hydroxyl, methoxy or C1-3 alkyl, wherein the C1.3 alkyl is unsubstituted or independently substituted with one or more substituents independently selected from halogen, pyridyl, phenyl, hydroxyl, -CO2R4or C1-3 alkoxy;R6is hydrogen, fluoro or C1.2 alkyl;R16is C1.3 alkyl-R17, wherein the C1.3 alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, C1-2 alkyl, C3-6 cycloalkyl, OH and OMe; and R17is hydrogen, phenyl, pyridyl, pyridazinyl, isoquinolinyl, tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, or C3.7 cycloalkyl, wherein the phenyl, pyridyl, pyridazinyl, isoquinolinyl, tetrahydropyranyl, tetrahydroforanyl, oxetanyl and cycloalkyl are unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1.2 alkyl, and Ci-2haloalkyl, Ci -2 alkoxy, and C1-2 haloalkoxy; or a pharmaceutically acceptable salt and / or solvate thereof.

[0211] One group of compounds according to this embodiment are compounds of formula (I- la) which are compounds of formula (1-1) whereinX2is C and X3is N; each R3is independently selected from hydrogen, fluoro and methyl;each R4is independently hydrogen;R5is hydrogen or C1.3 alkyl, wherein the C1-3 alkyl is unsubstituted or substituted with a substituent selected from pyridyl, phenyl, and -CO2H;R6is hydrogen, fluoro or methyl (preferably hydrogen); and each R8is independently selected from hydrogen and methyl, each R9is independently selected from hydrogen, CF3 and methyl, and each R10is independently selected from hydrogen, fluoro, chloro, and methyl; or a pharmaceutically acceptable salt and / or solvate thereof

[0212] One group of compounds according to this embodiment are compounds of formula (I- lb) which are compounds of formula (1-1) wherein R1is 0CH3or OCHF2; or a pharmaceutically acceptable salt and / or solvate thereof.

[0213] One group of compounds according to this embodiment are compounds of formula (I-lc) which are compounds of formula (1-1) wherein R2is methyl; or a pharmaceutically acceptable salt and / or solvate thereof.

[0214] One group of compounds according to this embodiment are compounds of formula (I- Id) which are compounds of formula (1-1) wherein R17is 2-pyridyl which is unsubstituted or substituted with one or two halogens (preferably fluoro); or a pharmaceutically acceptable salt and / or solvate thereof.

[0215] Another preferred group of compounds according to the invention are those of formula 1-2, which are compounds of formula I wherein:Xi is CH;X2is C and X3is N or X2is N and X3is C;X4is N or CH;Y is O;Yi is CH2;Y2is CHR5;Y3is CH2or CH2CH2; when X4 is N, B is a bond or is selected from; wherein Z is absent or is CO or (CH2)n; each n is independently 0, 1 or2; m is 0, 1 or 2; R4is independently selected from hydrogen and C1-3 alkyl; R21is absent or is independently halogen (preferably fluoro), methyl or methoxy and R22is independently hydrogen, halogen (preferably fluoro) or methyl;R1is hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, halomethyl, haloethyl, halomethoxy, haloethoxy, cyano, CF3, CHF2, OCH3or OCHF2;R2is hydrogen, methyl or ethyl;R5is hydrogen or C1.3 alkyl, wherein the C1-3 alkyl is unsubstituted or substituted with a substituent selected from pyridyl, phenyl, and -CO2H;the Ci-3 alkyl moiety containedwherein R19is methyl, hydroxymethyl, or halomethyl (preferably fluoromethyl) and R20is hydrogen or methyl; or the Ci-3 alkyl moiety contained iwherein R19is methyl, hydroxymethyl, or OH and R20is hydrogen or methyl; andR17is cyclobutyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl or pyridyl, wherein the phenyl or pyridyl are unsubstituted or substituted with one or more substituents independently selected from halogen; or a pharmaceutically acceptable salt and / or solvate thereof.

[0216] One group of compounds according to this embodiment are compounds of formula (I-2a) which are compounds of formula (1-2) wherein X2is C and X3is N; or a pharmaceutically acceptable salt and / or solvate thereof.

[0217] One group of compounds according to this embodiment are compounds of formula (I-2b) which are compounds of formula (1-2) wherein R1is OCH3or OCHF2; or a pharmaceutically acceptable salt and / or solvate thereof.

[0218] One group of compounds according to this embodiment are compounds of formula (I-2c) which are compounds of formula (1-2) wherein R2is methyl; or a pharmaceutically acceptable salt and / or solvate thereof.

[0219] One group of compounds according to this embodiment are compounds of formula (I-2d) which are compounds of formula (1-2) wherein R17is 2-pyridyl which is unsubstituted or substituted with one or two halogens (preferably fluoro) ; or a pharmaceutically acceptable salt and / or solvate thereof.

[0220] Another preferred group of compounds according to the invention are those of formula 1-3, which are compounds of formula I wherein:Xi is CH;X2is C and X3is N or X2is N and X3is C;X4is N or CH;Y is O;Yi is CH2;Y2is CHR5;Y3is CH2or CH2CH2; when X4is N, B is a bond or is selected fromwhereinwherein R21is hydrogen or halogen (preferably fluoro) and R22is hydrogen, methyl or halogen (preferably fluoro); when X4is CH, B is a bond and A is -NH-CN,R1is hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, cyano, CF3, CHF2, OCH3 or OCHF2;R2is hydrogen, methyl or ethyl;R5is hydrogen or C1.3 alkyl, wherein the C1-3 alkyl is unsubstituted or substituted with a substituent selected from pyridyl, phenyl, and -CO2H;

[0221] the C1-3 alkyl moiety contained in R16is selected from:R17is phenyl or pyridyl, wherein the phenyl or pyridyl are unsubstituted or substituted with one or more substituents independently selected from halogen; or a pharmaceutically acceptable salt and / or solvate thereof

[0222] One group of compounds according to this embodiment are compounds of formula (I-3a) which are compounds of formula (1-3) wherein X2 is C and X3 is N; or a pharmaceutically acceptable salt and / or solvate thereof.

[0223] One group of compounds according to this embodiment are compounds of formula (I-3b) which are compounds of formula (1-3) wherein R1is OCH3 or OCHF2; or a pharmaceutically acceptable salt and / or solvate thereof.

[0224] One group of compounds according to this embodiment are compounds of formula (I-3c) which are compounds of formula (1-3) wherein R2is methyl; or a pharmaceutically acceptable salt and / or solvate thereof.

[0225] One group of compounds according to this embodiment are compounds of formula (I-3d) which are compounds of formula (1-3) wherein R17is 2-pyridyl which is unsubstituted or substituted with one or two halogens (preferably fluoro) ; or a pharmaceutically acceptable salt and / or solvate thereof.

[0226] In one embodiment, there is provided a compound which is selected from the group consisting of:or a pharmaceutically acceptable salt and / or solvate thereof.

[0227] Another example of a compound of Formula (I) is:or a pharmaceutica ly acceptable salt and / or solvate thereof.

[0228] In one embodiment, there is provided a compound which is selected from the group consisting of:or a pharmaceutically acceptable salt and / or solvate thereof.EMBODIMENTS

[0229] Further embodiments according to the invention are provided as set out below.

[0230] Embodiment 1 provides a compound of Formula (I):wherein:Xi is N or CH;X2is N and X3is C, or, alternatively, X3is N and X2is C;X4is N or CR4;Y is a bond, 0 or NH;Yi is a bond, CHR6, CH2-CHR6, CHR6-CH2, CF2, CH2-CF2or CF2-CH2;Y2is CR4R5or CF2;Y3is CR3R4, CR3R4CR3R4, CH2CF2or CF2; when X4is N, B is a bond, -C(O)Y4-, -Y4-, -CH2Y4-, or -CH2CH2Y4-, and A is CN, R8R9C=CR10C(=O)-, RnR12NCH2CH=CHC(=O)-, H2C=CHSO2- or RIC =CC(=O)-: when X4is CR4, B is a bond, and A is -NR4-CN, R8R9C=CR10C(=O)R4N-, RnR12NCH2CH=CHC(=O)R4N- , H2C=CHSO2-R4N- or R13C=CC(=O)-R4N-;Y4is a 5-8 membered heterocycloalkyl-R4N comprising a nitrogen atom or C3-10 cycloalkyl-R4N-, wherein the heterocycloalkyl and cycloalkyl are unsubstituted or independently substituted with one or more substituents independently selected from halogen, methyl, halomethyl, hydroxyl or methoxy and wherein the nitrogen atom of the heterocycloalkyl and the cycloalkyl-R4N, respectively, are connected to A;R1is hydrogen, halogen, C1.5 alkyl, C1-5 alkoxy, CN, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, O and S, phenyl or a 5-6 membered heteroaryl, wherein the 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are unsubstituted or substituted with one or more substituents independently selected from halogen, methyl, halomethyl, hydroxyl or methoxy and wherein the C1-5 alkyl and C1.5 alkoxy, are unsubstituted or independently substituted with one or more substituents independently selected from halogen, CN, hydroxyl and methoxy;R2is hydrogen, hydroxyl, Ci.4alkyl, CN, -CONHCI.4alkyl, or Ci-4haloalkyl; each R3is independently selected from hydrogen, fluoro, hydroxyl, methoxy, C1.3 alkyl, cyclopropyl, or a R3is fused with R5or R6to form CH2, CH2-CH2or CH2OCH2;each R4is independently selected from hydrogen and C1.3 alkyl;R5is hydrogen, fluoro, hydroxyl, methoxy, C1.3 alkyl, cyclopropyl or is fused with one R3to form CH2, CH2-CH2 or CH2OCH2, wherein the C1-3 alkyl is unsubstituted or independently substituted with one or more substituents independently selected from halogen, heteroaryl (which heteroaryl is preferably pyridyl), phenyl, hydroxyl, -CO2R4or C1-3 alkoxy;R6is hydrogen, fluoro, hydroxyl, methoxy, C1.3 alkyl or is fused with one R3to form CH2, CH2-CH2 or CH2OCH2; each R8is independently selected from hydrogen and Ci-g alkyl; each R9is independently selected from hydrogen, CF3and Ci-e alkyl, which alkyl is unsubstituted or substituted with one or more substituents independently selected from fluoro, chloro, bromo, hydroxyl, and Ci-e alkoxy; andR10is hydrogen, C1.3 alkyl or halogen; or R9and R10together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring; each of R11and R12is independently hydrogen, Ci-g alkyl, or R11and R12together with the nitrogen atom to which they are attached form a 4-6 membered heterocycloalkyl optionally having an additional ring heteroatom which is O, wherein said ring is optionally substituted with halogen;R13is hydrogen, R14R15NCH2-, or C1.3 alkyl which is unsubstituted or substituted with hydroxyl;R14and R15are each independently hydrogen or Ci-e alkyl;R16is C1.3 alkyl-R17, C3-6 cycloalkyl-R17or a 4-6 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein the C1-3 alkyl, C3-6 cycloalkyl and 4-6 membered heterocycloalkyl are unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-4 alkyl optionally substituted with one or more OH, , C3-6 cycloalkyl, OH, OMe, -NR4R8wherein R4and R8are as defined above, or, alternatively, R4and R8together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring;R17is hydrogen, aryl, heteroaryl, 4-6 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, 0 and S, or C3-8 cycloalkyl, wherein the aryl, heteroaryl, heterocycloalkyl, and cycloalkyl are unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1.4 alkyl, and Ci.4haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; or a pharmaceutically acceptable salt and / or solvate thereof.

[0231] Embodiment 2 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, wherein Xi is CH.

[0232] Embodiment 3 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1 or 2, wherein X2is C and X3is N or X2is N and X3 is C.

[0233] Embodiment 4 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1 or 2, wherein Y is 0.

[0234] Embodiment 5 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3 or 4, wherein X4 is N or CH.

[0235] Embodiment 6 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4 or 5, wherein X4 is N, B is a bond, -C(O)Y4-, -Y4- or -CH2Y4-, and A is CN or R8R9C=CR10C(=O)-, wherein Y4is a 3-6 membered heterocycloalkyl comprising a nitrogen atom or C3-5 cycloalkyl-R4N-, wherein the heterocycloalkyl and cycloalkyl are unsubstituted or independently substituted with one or more substituents independently selected from halogen, methyl, halomethyl, hydroxyl or methoxy and wherein the nitrogen atom of the heterocycloalkyl and the cycloalkyl-R4N-, respectively, are connected to A, and wherein R8is independently selected from hydrogen and C1-2 alkyl, R9is independently selected from hydrogen, CF3and C1-2 alkyl, which alkyl is unsubstituted or substituted with one or more substituents independently selected from fluoro, chloro and bromo, and R10is independently selected from hydrogen, C1-2 alkyl and halogen.

[0236] Embodiment 7 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4 or 5, wherein X4is CH, B is a bond and A is -NH-CN or R8R9C=CR10C(=O)NH-, wherein R8is independently selected from hydrogen and C1-2 alkyl, R9is independently selected from hydrogen, CF3and C1-2 alkyl, which alkyl is unsubstituted or substituted with one or more substituents independently selected from fluoro, chloro and bromo, and R10is independently selected from hydrogen, C1-2 alkyl and halogen.

[0237] Embodiment 8 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6 or 7, wherein R1is hydrogen, halogen, C1.3 alkyl, C1-3 alkoxy, CN, wherein the C1-3 alkyl and C1-3 alkoxy are unsubstituted or independently substituted with one or more substituents independently selected from halogen.

[0238] Embodiment 9 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 7 or 8, wherein R2is hydrogen, hydroxyl or C1.2 alkyl.

[0239] Embodiment 10 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 7, 8 or 9, wherein Yi is CHR6, Y3is CR4R5, Y3is CR3R4or CH2CR3R4, each R3is independently selected from hydrogen, fluoro and C1-2 alkyl, each R4is independently selected from hydrogen and methyl, R5is hydrogen, fluoro, hydroxyl, methoxy or C1.3 alkyl, wherein the C1.3 alkyl is unsubstituted or independently substituted with one or more substituents independently selected from halogen, pyridyl, phenyl, hydroxyl, -CO2R4or C1-3 alkoxy, and R6is hydrogen, fluoro or C1-2 alkyl.

[0240] Embodiment 11 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, wherein each R8is independently selected from hydrogen and methyl, each R9is independently selected from hydrogen, CF3and methyl, and each R10is independently selected from hydrogen, fluoro, chloro, and methyl.

[0241] Embodiment 12 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11, wherein Yi is CH2, Y2 is CHR5, Y3is CH2or CH2CH2 and R5is hydrogen or C1.3 alkyl, wherein the C1.3 alkyl is unsubstituted or substituted with a substituent selected from pyridyl, phenyl, and -CO2H.

[0242] Embodiment 13 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, wherein R16is C1-3 alkyl-R17, wherein the C1-3 alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, C1-2 alkyl, C3-6 cycloalkyl, OH and OMe.

[0243] Embodiment 14 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13, wherein R17is hydrogen, phenyl, pyridyl, pyridazinyl, isoquinolinyl, tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, or C3-7 cycloalkyl, wherein the phenyl, pyridyl, pyridazinyl, isoquinolinyl, tetrahydropyranyl, tetrahydrofuranyl, oxetanyl and cycloalkyl are unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, CN, Ci-2alkyl, and C1-2 haloalkyl, Ci-2alkoxy, and C1.2 haloalkoxy.

[0244] Embodiment 15 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13 or 14, wherein X4 is N, B is a bond or is selected from; wherein Z is absent or is CO or (CH2)n; each n is independently 1 or 2; m is 0, 1 or 2; R4is independently selected from hydrogen and C1-3 alkyl; R21is absent or is independentlyhalogen (preferably fluoro), methyl or methoxy and R22is independently hydrogen, halogen (preferably fluoro) or methyl.

[0245] Embodiment 16 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13 or 14, wherein X4 is CH, B is a bond and

[0246] Embodiment 17 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16, wherein R1is hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, halomethyl, haloethyl, halomethoxy, haloethoxy, cyano, CF3, CHF2, OCH3or OCHF2.

[0247] Embodiment 18 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17, wherein R2is hydrogen, methyl or ethyl.

[0248] Embodiment 19 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18, wherein each R3is independently hydrogen, each R4is independently hydrogen and R6is hydrogen.

[0249] Embodiment 20 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19, wherein the C1-3 alkyl moiety contained in R16iswherein R19is methyl, hydroxymethyl, or halomethyl (preferably fluoromethyl) and R20is hydrogen or methyl, or the CI-3 alkyl moiety contained iwherein R19is methyl, hydroxymethyl, or OH and R20is hydrogen or methyl.

[0250] Embodiment 21 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, wherein R17is cyclobutyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl or pyridyl, wherein the phenyl or pyridyl are unsubstituted or substituted with one or more substituents independently selected from halogen.

[0251] Embodiment 22 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14, 15, 17, 18, 19, 20 or 21, wherein X4is N, B is a bond or is selected fromwhereinwherein R21is hydrogen or halogen (preferably fluoro) and R22is hydrogen, methyl or halogen (preferably fluoro).

[0252] Embodiment 23 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21 or 22, whereinX4is CH, B is a bond and A is -NH-CN,

[0253] Embodiment 24 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23, wherein R1is hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, cyano, CF3, CHF2, OCH3or OCHF2.

[0254] Embodiment 25 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24, wherein R2is methyl.

[0255] Embodiment 26 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25, wherein the C alkyl moiety contained in R16is selected from:

[0256] Embodiment 27 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26, wherein R17is phenyl or pyridyl, wherein the phenyl or pyridyl are unsubstituted or substituted with one or more substituents independently selected from halogen.

[0257] Embodiment 28 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 or 27, wherein R17is 2-pyridyl which is unsubstituted or substituted with one ortwo halogens (preferably fluoro).

[0258] Embodiment 29 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28, wherein R1is OCH3or OCHF2.

[0259] Embodiment 30 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, wherein the compound is selected from:

[0260] Embodiment 31 provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of embodiments 1-30.

[0261] Embodiment 32 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of embodiments 1-30, or a pharmaceutical composition according to embodiment 31, for use in medicine.

[0262] Embodiment 33 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of embodiments 1-30, or a pharmaceutical composition according to embodiment 31, for use in the prophylaxis and / or treatment of a disease, disorder or condition that is mediated by a4(37 integrin.

[0263] Embodiment 34 provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of embodiments 1-30, or a pharmaceutical composition according to embodiment 31, for use in the prophylaxis and / or treatment of inflammatory bowel disease, in particular Crohn’s disease and / or ulcerative colitis.FURTHER EMBODIMENTS1. A compound of F ormula (I) :wherein:Xi is N or CH;X2is N and X3is C, or, alternatively, X3is N and X2is C;X4is N or CR4;Y is a bond, O or NH;Yi is a bond, CHR6, CH2-CHR6, CHR6-CH2, CF2, CH2-CF2or CF2-CH2;Y2is CR4R5or CF2;Y3is CR3R4, CR3R4CR3R4, CH2CF2or CF2;Y4is a 5-8 membered heterocycloalkyl-R4N comprising a nitrogen atom or C3-10 cycloalkyl-R4N-, wherein the heterocycloalkyl and cycloalkyl are unsubstituted or independently substituted with one or more substituents independently selected from halogen, methyl, halomethyl, hydroxyl or methoxy and wherein the nitrogen atom of the heterocycloalkyl and the cycloalkyl-R4N, respectively, are connected to A;R1is hydrogen, halogen, C1.5 alkyl, C1-5 alkoxy, CN, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, 0 and S, phenyl or a 5-6 membered heteroaryl, wherein the 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are unsubstituted or substituted with one or more substituents independently selected from halogen, methyl, halomethyl, hydroxyl or methoxy and wherein the C1-5 alkyl and C1.5 alkoxy, are unsubstituted or independently substituted with one or more substituents independently selected from halogen, CN, hydroxyl and methoxy;R2is hydrogen, hydroxyl, Ci.4alkyl, CN, -CONHCI.4alkyl, or C1-4 haloalkyl; each R3is independently selected from hydrogen, fluoro, hydroxyl, methoxy, C1.3 alkyl, cyclopropyl, or a R3is fused with R5or R6to form CH2, CH2-CH2or CH2OCH2; each R4is independently selected from hydrogen and C1.3 alkyl;R5is hydrogen, fluoro, hydroxyl, methoxy, C1.3 alkyl, cyclopropyl or is fused with one R3to form CH2, CH2-CH2or CH2OCH2, wherein the C1-3 alkyl is unsubstituted or independently substituted with one or more substituents independently selected from halogen, heteroaryl (which heteroaryl is preferably pyridyl), phenyl, hydroxyl, -CO2R4or C1-3 alkoxy;R6is hydrogen, fluoro, hydroxyl, methoxy, C1.3 alkyl or is fused with one R3to form CH2, CH2-CH2or CH2OCH2; each R8is independently selected from hydrogen and Cue alkyl; each R9is independently selected from hydrogen, CF3 and Cue alkyl, which alkyl is unsubstituted or substituted with one or more substituents independently selected from fluoro, chloro, bromo, hydroxyl, and C1-6 alkoxy; andR10is hydrogen, C1.3 alkyl or halogen; or R9and R10together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic nng; each of R11and R12is independently hydrogen, Cue alkyl, or R11and R12together with the nitrogen atom to which they are attached form a 4-6 membered heterocycloalkyl optionally having an additional ring heteroatom which is 0, wherein said ring is optionally substituted with halogen;R13is hydrogen, R14R15NCH2-, or C1.3 alkyl which is unsubstituted or substituted with hydroxyl;R14and R15are each independently hydrogen or Cue alkyl;R16is Ci-3 alkyl-R17, C3-6 cycloalkyl-R17or a 4-6 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, 0 and S, wherein the C1-3 alkyl, C3-6 cycloalkyl and 4-6 membered heterocycloalkyl are unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-4 alkyl optionally substituted with one or more OH, , C3-6 cycloalkyl, OH, OMe, -NR4R8wherein R4and R8are as defined above, or, alternatively, R4and R8together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring;R17is hydrogen, aryl, heteroaryl, 4-6 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, 0 and S, or C3-8 cycloalkyl, wherein the aryl, heteroaryl, heterocycloalkyl, and cycloalkyl are unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-4 alkyl, and C .4haloalkvl. Ci.4alkoxy, and C1-4 haloalkoxy; or a pharmaceutically acceptable salt and / or solvate thereof..2. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, wherein Xi is CH.3. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1 or embodiment 2, wherein X2is C and X3is N.4. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any preceding embodiment, wherein X4is N or CH.5. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any preceding embodiment, wherein X4is N, B is a bond, -C(O)Y4-, -Y4- or -CH2Y4-, and A is CN or R8R9C=CR10C(=O)-, wherein Y4is a 3-6 membered heterocycloalkyl comprising a nitrogen atom or C35 cycloalkyl-R4N-, wherein the heterocycloalkyl and cycloalkyl are unsubstituted or independently substituted with one or more substituents independently selected from halogen, methyl, halomethyl, hydroxyl or methoxy and wherein the nitrogen atom of the heterocycloalkyl and the cycloalkyl -R4N, respectively, are connected to A; or wherein X4is CH, B is a bond and A is -NH-CN or R8R9C=CR10C(=O) NH- .6. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any preceding embodiment, wherein R1is hydrogen, halogen, C1.3 alkyl, C1-3 alkoxy, CN, wherein the C1.3 alkyl and C1-3 alkoxy are unsubstituted or independently substituted with one or more substituents independently selected from halogen.7. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any preceding embodiment, wherein R2is hydrogen, hydroxyl or Ci-2alkyl.8. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any preceding embodiment, wherein Y is 0.9. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any preceding embodiment, wherein R16is C1-3 alkyl-R17, wherein the C1-3 alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, C1-2 alkyl, C3-6 cycloalkyl, OH and OMe.10. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any preceding embodiment, wherein R17is hydrogen, phenyl, pyridyl, pyridazinyl, isoquinolinyl, tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, or C3-7 cycloalkyl, wherein the phenyl, pyridyl, pyridazinyl, isoquinolinyl, tetrahydropyranyl, tetrahydrofuranyl, oxetanyl and cycloalkyl are unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-2 alkyl, and Ci-2haloalkyl, C1-2 alkoxy, and C1-2 haloalkoxy.11. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any preceding embodiment, wherein the C1-3 alkyl moiety contained in R16is selected from:halogen (preferably fluoro); or X4is CH, B is a bond and A is -NH-CN,13. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any preceding embodiment, wherein R17is 2-pyridyl which is unsubstituted or substituted with one or two halogens (preferably fluoro).14. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any preceding embodiment, wherein R2is methyl.15. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, whereinXi is CH;X2is C and X3is N or X2is N and X3is C;X4is N or CH;Y is O;Yi is CH2;Y2is CHR5;Y3is CH2or CH2CH2; when X4is N, B is a bond or is selected fromwhereinwherein R21is hydrogen or halogen (preferably fluoro) and R22is hydrogen, methyl or halogen (preferably fluoro); when X4is CH, B is a bond and A is -NH-CN,R1is hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, cyano, CF3, CHF2, OCH3 or OCHF2;R2is hydrogen, methyl or ethyl;R5is hydrogen or C1.3 alkyl, wherein the C1-3 alkyl is unsubstituted or substituted with a substituent selected from pyridyl, phenyl, and -CO2H; the C1-3 alkyl moiety contained in R16is selected from:R17is phenyl or pyridyl, wherein the phenyl or pyridyl are unsubstituted or substituted with one or more substituents independently selected from halogen.16. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 1, wherein the compound is selected from:17. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of embodiments 1-16.18. A compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of embodiments 1-16, or a pharmaceutical composition according to embodiment 17, for use in medicine.19. A compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of embodiments 1-16, or a pharmaceutical composition according to embodiment 17, for use in the prophylaxis and / or treatment of a disease, disorder or condition that is associated with abnormal activity or expression of an FGFR enzyme, preferably FGFR3.20. A compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of embodiments 1-16, or a pharmaceutical composition according to embodiment 17, for use in the prophylaxis and / or treatment of a disease, disorder or condition that is selected from metastatic tumours (such as but not limited to, melanoma, lymphoma, leukaemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma) and types of tissue carcinoma (such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, glioblastoma, primary liver cancer, ovarian cancer, prostate cancer and uterine leiomyosarcoma), acute lymphoblastic leukemia, acute myeloidleukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumors, brain and spinal cord tumors, breast cancer, bronchial tumors, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T -Cell lymphoma, embryonal tumors, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, ewing sarcoma family of tumors, eye cancer, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor,gastrointestinal stromal tumor (GIST), gastrointestinal stromal cell tumor, germ cell tumor, glioma, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors (endocrine pancreas), Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, Burkitt lymphoma, cutaneous T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoma, Waldenstrom macroglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, mouth cancer, chronic myelogenous leukemia, myeloid leukemia, multiple myeloma, asopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, pineal parenchymal tumors of intermediate differentiation, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary tumor, plasma cell neoplasm / multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing sarcoma family of tumors, sarcoma, kaposi, Sezary syndrome, skin cancer, small cell Lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer, supratentorial primitive neuroectodermal tumors, T -cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom macroglobulinemia, Wilms tumor, a neoplastic disease of the blood and blood forming organs, including but not limited to: acute myeloid leukaemia (AML), and acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukaemia (CLL), breast cancer (e.g. invasive ductal cancer, invasive lobular cancer), lung cancer (e.g. non-small-cell lung cancer, lung adenocarcinoma, squamous cell lung cancer and small-cell lung cancer), urothelial cancer, bladder cancer (e.g. urothelial bladder cancer, nonmuscle invasive bladder cancer, muscle invasive bladder cancer), upper tract cancer (e.g. urothelial upper tract cancer), urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma (e g. cutaneous melanoma), head and neck cancer (e.g. oral cancer), thyroid cancer, renal cancer (e.g. renal pelvis cancer), glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer.101. A compound of F ormula (Ig) :wherein:Xi is N or CH;X2is N and X3is C, or, alternatively, X3is N and X2is C;X4is N;Y is a bond, 0 or NH;Yi is a bond, CHR6, CH2-CHR6, CHR6-CH2, CF2, CH2-CF2or CF2-CH2;Y2is CR4R5or CF2;Y3is CR3R4, CR3R4CR3R4, CH2CF2or CF2; wherein Yi, Y2, Y3and X_ together with the pyrazolyl ring form a 6- to 8-membered nitrogen containing ring;B is -C(O)Y4-, -Y4-, -CH2Y4-, or -CH2CH2Y4-, and A is CN;Y4is C3-10 cycloalkyl -R4N- or a 5- to 8-membered oxygen containing heterocyclyl-NR4-, wherein the cycloalkyl or 5- to 8-membered oxygen containing heterocyclyl is unsubstituted or independently substituted with one or more substituents independently selected from halogen, methyl, halomethyl, hydroxyl or methoxy, or wherein the cycloalkyl is substituted by two groups which are attached to the same carbon atom and join to form a 4- to 6- membered oxygen containing heterocyclyl ring, and wherein the nitrogen atom of the cycloalkyl -R4N or 5- to 8-membered oxygen containing heterocyclyl-NR4- is connected to A;R1is hydrogen, halogen, C1.5 alkyl, C1.5 alkoxy, CN, C3-10 cycloalkyl, C2.4alkynyl, 4-10 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, 0 and S, phenyl or a 5- 6 membered heteroaryl, wherein the 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are unsubstituted or substituted with one or more substituents independently selected from halogen, methyl, halomethyl, hydroxyl or methoxy and wherein the C1.5 alkyl and C1.5 alkoxy, are unsubstituted or independently substituted with one or more substituents independently selected from halogen, CN, hydroxyl and methoxy;R2is hydrogen, hydroxyl, Ci.4alkyl, CN, -CONHCi.4alkyl, or Ci-4haloalkyl;each R3is independently selected from hydrogen, fluoro, hydroxyl, methoxy, C1.3 alkyl, cyclopropyl, or a R3is fused with R5or R6to form CH2, CH2-CH2 or CH2OCH2; each R4is independently selected from hydrogen and C1.3 alkyl;R5is hydrogen, fluoro, hydroxyl, methoxy, C1.3 alkyl, cyclopropyl or is fused with one R3to form CH2, CH2-CH2 or CH2OCH2, wherein the C1-3 alkyl is unsubstituted or independently substituted with one or more substituents independently selected from halogen, heteroaryl (which heteroaryl is preferably pyridyl), phenyl, hydroxyl, -CO2R4or C1-3 alkoxy;R6is hydrogen, fluoro, hydroxyl, methoxy, C1.3 alkyl or is fused with one R3to form CH2, CH2-CH2or CH2OCH2; each R8is independently selected from hydrogen and Cue alkyl; each R9is independently selected from hydrogen, CF3and Ci-e alkyl, which alkyl is unsubstituted or substituted with one or more substituents independently selected from fluoro, chloro, bromo, hydroxyl, and Cue alkoxy; andR10is hydrogen, C1.3 alkyl or halogen; or R9and R10together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring; each of R11and R12is independently hydrogen, Ci-g alkyl, or R11and R12together with the nitrogen atom to which they are attached form a 4-6 membered heterocycloalkyl optionally having an additional ring heteroatom which is O, wherein said ring is optionally substituted with halogen;R13is hydrogen, R14R15NCH2-, or C1.3 alkyl which is unsubstituted or substituted with hydroxyl;R14and R15are each independently hydrogen or Ci-g alkyl;R16is C1.3 alkyl-R17, C3-6 cycloalkyl-R17or a 4-6 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein the C1-3 alkyl, C3-6 cycloalkyl and 4-6 membered heterocycloalkyl are unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-4 alkyl optionally substituted with one or more OH, , C3-6 cycloalkyl, OH, OMe, -NR4R8wherein R4and R8are as defined above, or, alternatively, R4and R8together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring, or - O(CH2)2-4- wherein the oxygen atom and terminal carbon atom are attached to the same carbon atom in the C1-3 alkyl, C3-6 cycloalkyl and 4-6 membered heterocycloalkyl group such that an oxygen-containing heterocyclyl forms;R17is hydrogen, aryl, heteroaryl, 4-6 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, 0 and S, or C3-8 cycloalkyl, wherein the aryl and heteroaryl are unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, CN, NH2, C1-4 alkyl, and C1.4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy, wherein the heterocycloalkyl and cycloalkyl are unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, CN, NH2, oxo, C1.4 alkyl, and C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; or a pharmaceutically acceptable salt and / or solvate thereof.102. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 101, wherein Xi is N, X3 is N and X2 is C and Y is 0.103. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 101, wherein Xi is CH, X3 is N and X2 is C and Y is O.104. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 101 to 103, wherein Yi is CHR6, Y2 is CR4R5or CF2 and Y3 is CH2CR3R4, or Yi is CHR6, Y2 is CR4R5or CF2and Y3is CR3R4.105. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 101 to 104 wherein Yi is CH2, Y2is CH2and Y3is CH2106. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 101 to 104 wherein Yi is CH2, Y2is CH2and Y3is CH2CH2.107. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of embodiments 101 to 106, wherein B is -C(O)Y4-.108. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of embodiments 101 to 106, wherein B is -Y4-.109. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of embodiments 101 to 108, wherein Y4is C3-10 cycloalkyl -R4N- wherein the cycloalkyl is unsubstituted or independently substituted with one or more substituents independently selected from halogen, methyl, halomethyl, hydroxyl or methoxy, or wherein the cycloalkyl is substituted by two groups which are attached to the same carbon atom and join to form a 4- to 6- membered oxygen containing heterocyclyl ring, and wherein the nitrogen atom of the cycloalkyl-R4N is connected to A.110. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of embodiments 101 to 109, wherein Y4is C3-10 cycloalkyl -R4N- wherein the cycloalkyl is unsubstituted or independently substituted with one or more substituents independently selected from halogen, methyl, halomethyl, hydroxyl or methoxy and wherein the nitrogen atom of the cycloalkyl -R4N, is connected to A.111. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of embodiments 101 to 110, wherein Y4is C3-10 cycloalkyl-R4N- wherein the R4is H.112. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of embodiments 101 to 108, wherein Y4is 5- to 8-membered oxygen containing heterocyclyl-NR4- wherein the 5- to 8 -membered oxygen containing heterocyclyl is unsubstituted or independently substituted with one or more substituents independently selected from halogen, methyl, halomethyl, hydroxyl or methoxy, and wherein the nitrogen atom of the 5- to 8-membered oxygen containing heterocyclyl-NR4- is connected to A.113. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of embodiments 101 to 110, wherein Y4is heterocyclyl-R4N- wherein the R4is H.114. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of embodiments 101 to 112, wherein Y4is unsubstituted.115. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of embodiments 109, 110 or 112, wherein the cycloalkyl or heterocyclyl is substituted with one or more substituents independently selected from halogen, methyl, halomethyl, hydroxyl or methoxy.116. The compound according to any one of embodiments 101 to 115 wherein R1is halogen e.g. chloro.117. The compound according to any one of embodiments 101 to 115 wherein R1is C1.5 alkoxy, wherein the C1-5 alkoxy is unsubstituted or independently substituted with one or more (e.g. one or two e.g. two) substituents independently selected from halogen, CN, hydroxyl and methoxy such as halogen e.g. F.118. The compound according to any one of embodiment 101 to 115 wherein R1is selected from OMe, OCH2F, OCHF2, or OCF3119. The compound according to any one of embodiment 101 to 115 wherein R1is OMe120. The compound according to any one of embodiment 101 to 115 wherein R1is OCHF2121. The compound according to any one of embodiments lOl to 115 wherein R2is C1.4 alkyl e.g. methyl and R3, R4, R5and R6are hydrogen.122. The compound according to any one of embodiments 101 to 121 wherein R16is C1.3 alkyl-R17wherein the C1-3 alkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-4 alkyl, C3-6 cycloalkyl, OH, OMe, -NR4R8wherein R4and R8are as defined above, or, alternatively, R4and R8together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring, such as the C1-3 alkyl group is substituted by one OH.123. The compound according to any one of embodiments 101 to 122 wherein R15is selected from C2 alkyl- R17or C3 alkyl-R17and wherein C2 alkyl or C3 is optionally substituted with at least one -OH. Preferably R16is a C2 alkyl-R17wherein C2 alkyl is substituted with one -OH. More preferably R76is Ci alkyl-R77, wherein the Ci alkyl is substituted with OH or Ci alkyl-OH.124. The compound according to any of embodiments 101 to 123 wherein R17is 2-pyridinyl optionally substituted with one or more F.125. The compound according to any one of embodiments 101 to 124 wherein R17is aryl, heteroaryl or 4-6 membered heterocycloalkyl, such as pyrazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl e.g. pyridinyl.126. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to embodiment 101, wherein the compound is selected from:127. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of embodiments 101-126.128. A compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of embodiments 101-126, or a pharmaceutical composition according to embodiment 127, for use in medicine.129. A compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of embodiments 101-126, or a pharmaceutical composition according to embodiment 127, for use in the prophylaxis and / or treatment of a disease, disorder or condition that is associated with abnormal activity or expression of an FGFR enzyme, preferably FGFR3.130. A compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of embodiments 101-126, or a pharmaceutical composition according to embodiment 127, for use in the prophylaxis and / or treatment of a disease, disorder or condition that is selected from embodiment 20.

[0264] Specific examples of compounds of Formula (I) are illustrated below:

[0265] Another specific example of a compound of Formula (I) is:wherein R8, R9and R10are as defined herein (above and below); each n is independently 1 or 2; R21is absent or is halogen, methyl, halomethyl, hydroxyl or methoxy; and A is selected from

[0267] In an embodiment, the moietyselected from:where each n is independently 1, 2, 3, 4, 5, 6, 7, 8 or 9 wherein n+n is less than or equal to 10; R21is absent or is halogen, methyl, halomethyl, hydroxyl or methoxy;

[0268] In an embodiment, R2is C1.4 alkyl. In a preferred embodiment, R2is methyl.

[0269] In an embodiment, R1is hydrogen, halogen, C1.3 alkyl, C1-3 alkoxy, CN, wherein the C1.3 alkyl and Ci -3 alkoxy are unsubstituted or independently substituted with one or more substituents independently selected from halogen.

[0270] In a preferred embodiment, R1is hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, halomethyl, haloethyl, halomethoxy, haloethoxy, cyano, CF3, CHF2, OCH3 or OCHF2.

[0271] In a more preferred embodiment, R1is hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, cyano, CF3, CHF2, OCH3 or OCHF2 (especially OCH3 or OCHF2).

[0272] In an especially preferred embodiment, R1OCH3 or OCHF2.

[0273] In a preferred embodiment, R8is hydrogen.

[0274] In a preferred embodiment, R9is hydrogen.

[0275] In a preferred embodiment, R10is hydrogen.

[0276] In a preferred embodiment, R16is C1.3 alkyl-R17, wherein the C1.3 alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of OH and OMe.

[0277] In an embodiment, the C1-3 alkyl moiety contained in R16is selected from:, wherein R19and R20are as defined herein (above and below).

[0278] In a preferred embodiment, the C1-3 alkyl moiety contained in R16is selected from:

[0279] In an embodiment, the C1-3 alkyl moiety contained in R16is selected from:

[0280] In an embodiment, R17is selected from phenyl and pyridyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-4 alkyl, and C1.4 haloalkyl, C1.4 alkoxy, and C 1.4 haloalkoxy.

[0281] In a preferred embodiment, R17is selected from phenyl and pyridyl, optionally substituted with one or more halogen.

[0282] In a more preferred embodiment, R17is 2-pyridyl.

[0283] In another embodiment, R17is selected from: cyclobutyl, oxetane, and tetrahydropyran. In an embodiment, R17is selected from cyclobutyl and tetrahydropyran.

[0284] In one embodiment, the compound of the invention according to Formula I is selected from:or a pharmaceutically acceptable salt and / or solvate thereof.

[0285] In one embodiment, the compound of the invention according to Formula I is a compound selected from the list comprising:or a pharmaceutically acceptable salt and / or solvate thereof.

[0286] The compound of Formula (I) may also be selected from:or a pharmaceutically acceptable salt and / or solvate thereof.

[0287] The compound of Formula (I) also may be:or a pharmaceutically acceptable salt and / or solvate thereof.

[0288] In one embodiment, the compounds of the invention are provided in a natural isotopic form.

[0289] In one embodiment, the compounds of the invention are provided in an unnatural variant isotopic form. In a specific embodiment, the unnatural variant isotopic form is a form in which deuterium (i.e. 2H or D) is incorporated where hydrogen is specified in the chemical structure in one or more atoms of a compound of the invention. In one embodiment, the atoms of the compounds of the invention are in an isotopic form which is not radioactive. In one embodiment, one or more atoms of the compounds of the invention are in an isotopic form which is radioactive. Suitably radioactive isotopes are stable isotopes. Suitably the unnatural variant isotopic form is a pharmaceutically acceptable form.

[0290] In one embodiment, a compound of the invention is provided whereby a single atom of the compound exists in an unnatural variant isotopic form. In another embodiment, a compound of the invention is provided whereby two or more atoms exist in an unnatural variant isotopic form.

[0291] Unnatural isotopic variant forms can generally be prepared by conventional techniques known to those skilled in the art or by processes described herein e.g. processes analogous to those described in the accompanying Examples for preparing natural isotopic forms. Thus, unnatural isotopic variant forms could be prepared by using appropriate isotopically variant (or labelled) reagents in place of the normal reagents employed in the illustrative example as examples.

[0292] In one aspect a compound of the invention according to any one of the embodiments herein described is present as the free base.

[0293] In one aspect a compound of the invention according to any one of the embodiments herein described is a pharmaceutically acceptable salt.

[0294] In one aspect a compound of the invention according to any one of the embodiments herein described is a solvate of the compound.

[0295] In one aspect a compound of the invention according to any one of the embodiments herein described is a solvate of a pharmaceutically acceptable salt of a compound.

[0296] While specified groups for each embodiment have generally been listed above separately, a compound of the invention includes one in which several or each embodiment in the above Formula, as well as other formulae presented herein, is selected from one or more of particular members or groups designated respectively, for each variable . Therefore, this invention is intended to include all combinations of such embodiments within its scope.

[0297] While specified groups for each embodiment have generally been listed above separately, a compound of the invention may be one for which one or more variables (for example, R groups) is selected from one or more embodiments according to any of the Formula(e) listed above and below. Therefore, the present invention is intended to include all combinations of variables from any of the disclosed embodiments within its scope.

[0298] Alternatively, the exclusion of one or more of the specified variables from a group or an embodiment, or combinations thereof is also contemplated by the present invention.

[0299] In certain aspects, the present invention provides prodrugs and derivatives of the compounds according to the formulae above. Prodrugs are derivatives of the compounds of the invention, which have metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention, which are pharmaceutically active, in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.

[0300] Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (Bundgard, H, 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are preferred prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy )alkyl esters or ((alkoxy carbonyl)oxy)alkylesters. Particularly useful are the Ci to C? alkyl, C2-C8 alkenyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl esters of the compounds of the invention.PHARMACEUTICAL COMPOSITIONS

[0301] When employed as a pharmaceutical, a compound of the invention is typically administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound of the invention according to Formula I. Generally, a compound of the invention is administered in a pharmaceutically effective amount. The amount of compound of the invention actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound of the invention administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like.

[0302] The pharmaceutical compositions of this invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intra-articular, intravenous, intramuscular, and intranasal. Depending on the intended route of delivery, a compound of the invention is preferably formulated as either injectable or oral compositions or as salves, as lotions or as patches all for transdermal administration.

[0303] The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term ‘unit dosage forms’ refers to physically discrete units suitable asunitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient, vehicle or carrier. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the compound of the invention according to Formula I is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.

[0304] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. Solid forms may include, for example, any of the following ingredients, or compound of the inventions of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint or orange flavoring.

[0305] Injectable compositions are typically based upon injectable sterile saline or phosphate -buffered saline or other injectable carriers known in the art. As before, the active compound of the invention according to Formula I in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like.

[0306] Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0. 1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight. When formulated as an ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base. Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope of this invention.

[0307] A compound of the invention can also be administered by a transdermal device . Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.

[0308] The above-described components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the likeare set forth in Part 8 of Remington’s Pharmaceutical Sciences, 17thedition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0309] A compound of the invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington’s Pharmaceutical Sciences.

[0310] The following formulation examples illustrate representative pharmaceutical compositions that may be prepared in accordance with this invention. The present invention, however, is not limited to the following pharmaceutical compositions.Formulation 1 - Tablets

[0311] A compound of the invention according to Formula I may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate may be added as a lubricant. The mixture may be formed into 240-270 mg tablets (80-90 mg of active compound of the invention according to Formula I per tablet) in a tablet press.Formulation 2 - Capsules

[0312] A compound of the invention according to Formula I may be admixed as a dry powder with a starch diluent in an approximate 1: 1 weight ratio. The mixture may be filled into 250 mg capsules (125 mg of active compound of the invention according to Formula I per capsule).Formulation 3 - Liquid

[0313] A compound of the invention according to Formula I (125 mg), may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) and the resultant mixture may be blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50 mg) in water. Sodium benzoate (10 mg), flavor, and color may be diluted with water and added with stirring. Sufficient water may then be added with stirring. Further sufficient water may be then added to produce a total volume of 5 mL.Formulation 4 - Tablets

[0314] A compound of the invention according to Formula I may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate may be added as a lubricant. The mixture may be formed into 450-900 mg tablets (150-300 mg of active compound of the invention according to Formula I) in a tablet press.Formulation 5 - Injection

[0315] A compound of the invention according to Formula I may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg / mL.Formulation 6 - Topical

[0316] Stearyl alcohol (250 g) and a white petrolatum (250 g) may be melted at about 75°C and then a mixture of A compound of the invention according to Formula I (50 g) methylparaben (0 25 g),propylparaben (0.15 g), sodium lauryl sulfate (10 g), and propylene glycol (120 g) dissolved in water (about 370 g) may be added and the resulting mixture may be stirred until it congeals.METHODS OF TREATMENT

[0317] In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine . In a particular embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of a disease, disorder, or condition that is associated with abnormal activity or expression of an FGFR enzyme (in particular FGFR3), in particular cancer.

[0318] In another embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention for use in the manufacture of a medicament for use in the prophylaxis and / or treatment of a disease, disorder, or condition that is associated with abnormal activity or expression of an FGFR enzyme (in particular FGFR3), in particular cancer.

[0319] In another embodiment, this invention provides methods of prophylaxis and / or treatment of a mammal afflicted with a disease, disorder, or condition that is associated with abnormal activity or expression of an FGFR enzyme, in particular cancer, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions described herein for the treatment or prophylaxis of said condition.

[0320] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent. In a particular embodiment, the other therapeutic agent is a treatment agent directed to a disease, disorder, or condition that is associated with abnormal activity or expression of an FGFR enzyme (in particular FGFR3), in particular cancer.

[0321] In a particular embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of a disease selected from: metastatic tumours (such as but not limited to, melanoma, lymphoma, leukaemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma) and types of tissue carcinoma (such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, glioblastoma, primary liver cancer, ovarian cancer, prostate cancer and uterine leiomyosarcoma), acute lymphoblastic leukemia, acute myeloidleukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumors, brain and spinal cord tumors, breast cancer, bronchial tumors, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, coloncancer, colorectal cancer, craniopharyngioma, cutaneous T -Cell lymphoma, embryonal tumors, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, ewing sarcoma family of tumors, eye cancer, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gastrointestinal stromal cell tumor, germ cell tumor, glioma, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors (endocrine pancreas), Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, Acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, Burkitt lymphoma, cutaneous T-celllymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoma, Waldenstrom macroglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, mouth cancer, chronic myelogenous leukemia, myeloid leukemia, multiple myeloma, asopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, pineal parenchymal tumors of intermediate differentiation, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary tumor, plasma cell neoplasm / multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing sarcoma family of tumors, sarcoma, kaposi, Sezary syndrome, skin cancer, small cell Lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer, supratentorial pnmitive neuroectodermal tumors, T -cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom macroglobulinemia, and Wilms tumor.

[0322] In another embodiment, the disease or condition is a neoplastic disease of the blood and blood forming organs, including but not limited to: acute myeloid leukaemia (AML), and acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukaemia (CLL) .

[0323] In another embodiment, the disease or condition is selected from breast cancer (e.g. invasive ductal cancer, invasive lobular cancer), lung cancer (e.g. non-small-cell lung cancer, lung adenocarcinoma, squamous cell lung cancer and small -cell lung cancer), urothelial cancer, bladder cancer (e.g. urothelial bladder cancer, non-muscle invasive bladder cancer, muscle invasive bladder cancer), upper tract cancer (e.g. urothelial upper tract cancer), urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma (e.g. cutaneous melanoma), headand neck cancer (e.g. oral cancer), thyroid cancer, renal cancer (e.g. renal pelvis cancer), glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer.

[0324] Injection dose levels range from about 0.1 mg / kg / h to at least 10 mg / kg / h, all for from about 1 to about 120 h and especially 24 to 96 h. A preloading bolus of from about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve adequate steady state levels . The maximum total dose is not expected to exceed about 1 g / day for a 40 to 80 kg human patient.

[0325] For the prophylaxis and / or treatment of long-term conditions, such as degenerative conditions, the regimen for treatment usually stretches over many months or years so oral dosing is preferred for patient convenience and tolerance. With oral dosing, one to four (1-4) regular doses daily, especially one to three (1-3) regular doses daily, typically one to two (1-2) regular doses daily, and most typically one (1) regular dose daily are representative regimens. Alternatively for long lasting effect drugs, with oral dosing, once every other week, once weekly, and once a day are representative regimens. In particular, dosage regimen can be every 1-14 days, more particularly 1-10 days, even more particularly 1-7 days, and most particularly 1-3 days.

[0326] Using these dosing patterns, each dose provides from about 1 to about 1000 mg of a compound of the invention, with particular doses each providing from about 10 to about 500 mg and especially about 30 to about 250 mg.

[0327] Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.

[0328] When used to prevent the onset of a condition, a compound of the invention will be administered to a patient at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above. Patients at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.

[0329] A compound of the invention can be administered as the sole active agent or it can be administered in combination with other therapeutic agents, including other compound of the inventions that demonstrate the same or a similar therapeutic activity and that are determined to be safe and efficacious for such combined administration. In a specific embodiment, co-administration of two (or more) agents allows for significantly lower doses of each to be used, thereby reducing the side effects seen.

[0330] In one embodiment, a compound of the invention or a pharmaceutical composition comprising a compound of the invention is administered as a medicament. In a specific embodiment, said pharmaceutical composition additionally comprises a further active ingredient.

[0331] In one embodiment, a compound of the invention is co -administered with another therapeutic agent for the treatment and / or prophylaxis of a disease involving inflammation, particular agents include, but are not limited to, immunoregulatory agents e.g. azathioprine, corticosteroids (e.g. prednisolone ordexamethasone), cyclophosphamide, cyclosporin A, tacrolimus, my cophenolate, mofetil, muromonab- CD3 (0KT3, e.g. Orthocolone®), ATG, aspirin, acetaminophen, ibuprofen, naproxen, and piroxicam.

[0332] In one embodiment, a compound of the invention is co -administered with another therapeutic agent for the treatment and / or prophylaxis of arthritis (e.g. rheumatoid arthritis), particular agents include but are not limited to analgesics, non-steroidal anti-inflammatory drugs (NSAIDS), steroids, synthetic DMARDS (for example but without limitation methotrexate, leflunomide, sulfasalazine, auranofm, sodium aurothiomalate, penicillamine, chloroquine, hydroxychloroquine, azathioprine, tofacitinib, baricitinib, fostamatinib, and cyclosporin), and biological DMARDS (for example but without limitation infliximab, etanercept, adalimumab, rituximab, and abatacept).

[0333] In one embodiment, a compound of the invention is co -administered with another therapeutic agent for the treatment and / or prophylaxis of proliferative disorders, particular agents include but are not limited to: methotrexate, leukovorin, adriamycin, prednisone, bleomycin, cyclophosphamide, 5- fluorouracil, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, doxorubicin, tamoxifen, toremifene, megestrol acetate, anastrozole, goserelin, anti-HER2 monoclonal antibody (e.g. Herceptin™), capecitabine, raloxifene hydrochloride, EGFR inhibitors (e.g. Iressa®, Tarceva™, Erbitux™), VEGF inhibitors (e.g. Avastin™), proteasome inhibitors (e.g. Velcade™), Glivec® and hsp90 inhibitors (e.g. 17-AAG). Additionally, the compound of the invention according to Formula I may be administered in combination with other therapies including, but not limited to, radiotherapy or surgery. In a specific embodiment the proliferative disorder is selected from cancer, myeloproliferative disease or leukaemia.

[0334] In one embodiment, a compound of the invention is co -administered with another therapeutic agent for the treatment and / or prophylaxis of autoimmune diseases, particular agents include but are not limited to: glucocorticoids, cytostatic agents (e.g. purine analogs), alkylating agents, (e.g nitrogen mustards (cyclophosphamide), nitrosoureas, platinum compound of the inventions, and others), antimetabolites (e.g. methotrexate, azathioprine and mercaptopurine), cytotoxic antibiotics (e.g. dactinomycin anthracyclines, mitomycin C, bleomycin, and mithramycin), antibodies (e.g. anti-CD20, anti-CD25 or anti-CD3 (OTK3) monoclonal antibodies, Atgam® and Thymoglobuline®), cyclosporin, tacrolimus, rapamycin (sirolimus), interferons (e.g. IFN-P), TNF binding proteins (e.g. infliximab, etanercept, or adalimumab), mycophenolate, fmgolimod and myriocin..

[0335] In one embodiment, a compound of the invention is co -administered with another therapeutic agent for the treatment and / or prophylaxis of transplant rejection, particular agents include but are not limited to: calcineurin inhibitors (e.g. cyclosporin or tacrolimus (FK506)), mTOR inhibitors (e g. sirolimus, everolimus), anti-proliferatives (e.g. azathioprine, mycophenolic acid), corticosteroids (e.g. prednisolone, hydrocortisone), antibodies (e.g. monoclonal anti-IL-2Ra receptor antibodies,basiliximab, daclizumab), polyclonal anti-T-cell antibodies (e.g. anti-thymocyte globulin (ATG), antilymphocyte globulin (ALG)).

[0336] In one embodiment, a compound of the invention is co -administered with another therapeutic agent for the treatment and / or prophylaxis of asthma and / or rhinitis and / or COPD, particular agents include but are not limited to: beta2-adrenoceptor agonists (e.g. salbutamol, levalbuterol, terbutaline and bitolterol), epinephrine (inhaled or tablets), anticholinergics (e.g. ipratropium bromide), glucocorticoids (oral or inhaled). Long-acting [32 -agonists (e.g. salmeterol, formoterol, bambuterol, and sustained -release oral albuterol), combinations of inhaled steroids and long -acting bronchodilators (e.g. fluticasone / salmeterol, budesonide / formoterol), leukotriene antagonists and synthesis inhibitors (e.g. montelukast, zafirlukast and zileuton), inhibitors of mediator release (e.g. cromoglycate and ketotifen), biological regulators of IgE response (e.g. omalizumab), antihistamines (e.g. ceterizine, cinnarizine, fexofenadine) and vasoconstrictors (e.g. oxymethazoline, xylomethazoline, nafazoline and tramazoline).

[0337] Additionally, a compound of the invention may be administered in combination with emergency therapies for asthma and / or COPD, such therapies include oxygen or heliox administration, nebulized salbutamol or terbutaline (optionally combined with an anticholinergic (e.g. ipratropium), systemic steroids (oral or intravenous, e.g. prednisone, prednisolone, methylprednisolone, dexamethasone, or hydrocortisone), intravenous salbutamol, non-specific beta-agonists, injected or inhaled (e.g. epinephrine, isoetharine, isoproterenol, metaproterenol), anticholinergics (IV or nebulized, e.g. glycopyrrolate, atropine, ipratropium), methylxanthines (theophylline, ammophylline, bamiphylline), inhalation anesthetics that have a bronchodilatory effect (e.g. isoflurane, halothane, enflurane), ketamine and intravenous magnesium sulfate.

[0338] In one embodiment, a compound of the invention is co -administered with another therapeutic agent for the treatment and / or prophylaxis of inflammatory bowel disease (IBD), particular agents include but are not limited to: glucocorticoids (e.g. prednisone, budesonide) synthetic disease modifying, immunomodulatory agents (e.g. methotrexate, leflunomide, sulfasalazine, mesalazine, azathioprine, 6- mercaptopurine and cyclosporin) and biological disease modifying, immunomodulatory agents (infliximab, adalimumab, rituximab, and abatacept).

[0339] In one embodiment, a compound of the invention is co -administered with another therapeutic agent for the treatment and / or prophylaxis of SLE, particular agents include but are not limited to: human monoclonal antibodies (belimumab (Benlysta)), Disease-modifying antirheumatic drugs (DMARDs) such as antimalarials (e.g. plaquenil, hydroxychloroquine), immunosuppressants (e.g. methotrexate and azathioprine), cyclophosphamide and mycophenolic acid, immunosuppressive drugs and analgesics, such as nonsteroidal anti-inflammatory drugs, opiates (e.g. dextropropoxyphene and co-codamol),opioids (e.g. hydrocodone, oxycodone, MS Contin, or methadone) and the fentanyl duragesic transdermal patch.

[0340] In one embodiment, a compound of the invention is co -administered with another therapeutic agent for the treatment and / or prophylaxis of psoriasis, particular agents include but are not limited to: topical treatments such as bath solutions, moisturizers, medicated creams and ointments containing coal tar, dithranol (anthralin), corticosteroids like desoximetasone (Topicort™), fluocinonide, vitamin D3 analogues (for example, calcipotriol), argan oil and retinoids (etretinate, acitretin, tazarotene), systemic treatments such as methotrexate, cyclosporine, retinoids, tioguanine, hydroxyurea, sulfasalazine, mycophenolate mofetil, azathioprine, tacrolimus, fumaric acid esters or biologies such as Amevive™, Enbrel™, Humira™, Remicade™, Raptiva™ and ustekinumab (a IL- 12 and IL-23 blocker). Additionally, a compound of the invention may be administered in combination with other therapies including, but not limited to phototherapy, or photochemotherapy (e.g. psoralen and ultraviolet A phototherapy (PUVA)).

[0341] In one embodiment, a compound of the invention is co -administered with another therapeutic agent for the treatment and / or prophylaxis of allergic reaction, particular agents include but are not limited to: antihistamines (e.g. cetirizine, diphenhydramine, fexofenadine, levocetirizine), glucocorticoids (e.g. prednisone, betamethasone, beclomethasone, dexamethasone), epinephrine, theophylline or antileukotrienes (e.g. montelukast or zafirlukast), anti-cholinergics and decongestants.

[0342] By co-administration is included any means of delivering two or more therapeutic agents to the patient as part of the same treatment regime, as will be apparent to the skilled person. Whilst the two or more agents may be administered simultaneously in a single formulation, i.e. as a single pharmaceutical composition, this is not essential. The agents may be administered in different formulations and at different times.CHEMICAL SYNTHETIC PROCEDURESGeneral

[0343] The compound of the invention can be prepared from readily available starting materials using the following general methods and procedures . It will be appreciated that where typical or preferred process conditions (i.e. reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0344] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art (Wuts & Greene 2006).

[0345] The following methods are presented with details as to the preparation of a compound of the invention as defined hereinabove and the comparative examples. A compound of the invention may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.

[0346] All reagents are of commercial grade and are used as received without further purification, unless otherwise stated. Commercially available anhydrous solvents are used for reactions conducted under inert atmosphere. Reagent grade solvents are used in all other cases, unless otherwise specified. Column chromatography is performed on silica gel 60 (35-70 pm) or with Interchim® PuriFlash® Si HC flash chromatography cartridges. Thin layer chromatography is carried out using pre-coated silica gel F-254 plates (thickness 0.25 mm). Biotage® ISOLUTE® phase separators (e.g., Cat# 120-1907-E) are used for aqueous phase separation. Biotage® ISOLUTE® SCX-3 cation exchange sorbent (e.g., Cat# 533-0100- C) is used to extract basic analytes. 'H NMR spectra are recorded on a Bruker Avance 400 NMR spectrometer (400 MHz). Chemical shifts (5) for 'H NMR spectra are reported in parts per million (ppm) relative to tetramethylsilane (80.00) or the appropriate residual solvent peak, i. e. CHCL (87.27), as internal reference. Multiplicities are given as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m) and broad (br). Electrospray MS spectra are obtained on a Waters Acquity H-Class UPLC system coupled to a to a Waters QDA Mass detector spectrometer. Columns used: Waters Acquity UPLC BEH C18 1.7pm, 2.1mm ID x 50mm L, or Waters Acquity UPLC CSH C18 1.7pm, 2.1mm ID x 50mm L. The methods are using 5-95 % MeCN / H2O gradients in either 2 or 8 minute runs. H2O contains either 0.1% formic acid (when used with CSH column) , or 15 mM NH3(when used with BEH column). Final compounds were analyzed on 8 minute runs, using either acidic conditions (analytical method A) or basic conditions (analytical method B). Preparative HPLC is performed on a Waters AutoPurification system with UV and MS detection using Waters XB RIDGE BEH Cl 8 OBD 19 mm ID x 100 mm L columns and ACN / H2O gradients with either 0. 1% formic acid in H2O or 0.5% NH3in H2O. Reversed phase column chromatography is performed using a Buchi® Pure C850 FlashPrep using the same columns as for preparative HPLC. Microwave heating is performed with a Biotage® Initiator-l-.Table I. List of abbreviations used in the experimental section:SYNTHETIC PREPARATION OF THE COMPOUNDS OF THE INVENTIONGeneral synthesisScheme 1

[0347] A compound of Formula (la), in which X4is a nitrogen, can be prepared from a Boc intermediate of Formula (III) as depicted in Scheme 1. A boronate ester or acid of Formula (II) can react with bromide intermediate of formula (III) through Suzuki coupling using a palladium catalyst (such asPd(PPh3)4) in the presence of a base (such as K2CO3) in a suitable solvent (such as dioxane). The Boc protecting group of compound of Formula (IV) can be cleaved using acidic condition, for example, in presence of HC1 in a suitable solvent (such as 1,4-dioxane). The reaction of the resulting deprotected amine of Formula (V) with a suitable agent can afford a compound of Formula (la). As an example, compounds of Formula (la) in which A is a nitrile group, can be obtained by reacting a compound of Formula (V) with BrCN in the presence of a base in a suitable solvent. Other compounds of Formula (la) in which A is an acyl moiety, can be obtained by reacting a compound of Formula (V) with an acyl chloride (such as CH2=CH-C(=O)C1) in the presence of a base in a suitable solvent or by reacting with a carboxylic acid in presence of a coupling agent (such as HATU) in the presence of a base in a suitable solvent.Scheme 2a

[0348] Reference to Formula (lb) herein means Formula (lb) or (Ib-3) e.g. (Ib). A compound of Formula (lb), in which X4= CR4, can be prepared from a NHBoc intermediate of Formula (VI) as depicted in Scheme 2. A boronate ester or acid of Formula (II) can react with bromide intermediate of formula (VI)through Suzuki coupling using a palladium catalyst (such as Pd(PPh3)4) in the presence of a base (such as K2CO3) in a suitable solvent (such as dioxane). The Boc protecting group of compound of Formula (VII) can be cleaved using acidic condition, for example, in presence of HC1 in a suitable solvent (such as 1,4-dioxane). The reaction of the resulting deprotected amine of Formula (VIII) with a suitable agent can afford a compound of Formula (lb). As an example, compounds of Formula (lb) in which A is a nitrile group, can be obtained by reacting a compound of Formula (VIII) with BrCN in the presence of a base in a suitable solvent. Other compounds of Formula (lb) in which A is an acyl moiety, can be obtained by reacting a compound of Formula (VIII) with an acyl chloride (such as CH2=CH-C(=O)C1) in the presence of a base in a suitable solvent or by reacting with a carboxylic acid in presence of a coupling agent (such as HATU) in the presence of a base in a suitable solvent.Scheme 3

[0349] A compound of Formula (Ic), in which X4is a nitrogen and Z is a linker such as a bond, CO or (CH2)ncan be prepared from an amine of Formula (V) following procedure depicted in Scheme 3. When Z is CO, compound of Formula (IX) can be synthesized by reaction between compound of Formula XX and an acyl chloride in presence of a base and a suitable solvent. Alternatively, compound of formula (IX) can be obtained from a carboxylic acid in the presence of a coupling agent (such as HATU) and a base (such as DIEA) in a suitable solvent (such as DMF or THF). When Z is a bond or (CH2)X, compound of Formula (IX) can be synthesized from an aldehyde or a ketone using a reducing agent (such as STAB) in a solvent (such as DCE). Alternatively, such compound can also be obtained from an alkyl halide in presence of a base and in a suitable solvent. The Boc protecting group of compound of Formula (IX) can be cleaved using acidic condition, for example, in presence of HC1 in a suitable solvent (such as 1,4-dioxane). The reaction of the resulting deprotected amine of Formula (X) with a suitable agent can afford a compound of Formula (Ic). As an example, compounds of Formula (Ic)in which A is a nitrile group, can be obtained by reacting a compound of Formula (X) with BrCN in the presence of a base in a suitable solvent. Other compounds of Formula (Ic) in which A isan acyl moiety, can be obtained by reacting a compound of Formula (X) with an acyl chloride (such as CH2=CH-C(=O)C1) in the presence of a base in a suitable solvent or by reacting with a carboxylic acid in presence of a coupling agent (such as HATU) in the presence of a base in a suitable solvent.Scheme 4

[0350] A compound of Formula Intermediate of Formula (XV) where Y3 is CH2can be synthesized as depicted in Scheme 4. Compound of Formula (XI) where R is an alkyl can react with an alcohol of general Formula (XII) using a Mitsunobu reaction. For example DIAD and PPh3in a suitable solvent afford compound a Formula (XIII). Alternatively, substitution of pyrazol (XI) by an alkyl halide (such as XY IY2NHBOC) in presence of a base (such as K2CO3 or KOH) and a catalytic amount of an iodine salt (such as Nal or KI) in a suitable solvent afford alkylated pyrazol (XIII). Boc deprotection of compound of Formula (XIII) using acidic condition, for example, in presence of HC1 and in a suitable solvent (such as 1,4-dioxane) followed by cyclisation in basic condition using base (such as NaHCO3) in a solvent such as water can afford compound of Formula XIV. The cyclic amide of compound of Formula XIV can react with a reducing agent (such as BH3) in a suitable solvent (such as THF) to afford an amine intermediate that can be subsequently protected using a suitable protecting group such as Boc and lead to bicycle of Formula XV.Scheme 5

[0351] Intermediate of Formula (XIX) can be synthesized as depicted in Scheme 5. Compound of Formula (XVII) where PG is a suitable protecting group (such Boc), can be synthesized by reaction between compound of Formula (XVI) with a suitable halogenating agent (such as NBS) in a suitable solvent (sur as DMF). The heteroaryl halide of formula (XVII) can undergo palladium coupling using a boronic acid, ester or other boronic species such as trimethylboroxme in presence of a suitable base and a catalyst (such as Pd(dppf)Ch) in a solvent (such as dioxane) to afford compound of Formula (XVIII). Subsequent halogenation with reagent such as NBS in presence of a solvent lead to intermediate of Formula (XIX).Scheme 6

[0352] Intermediate of Formula (XXIV) where Y3is (CH2)2 can be synthesized following protocol described in Scheme 6. And aldehyde of Formula (XX) where R is an alkyl can react with an hydrazine of Formula (XXI) by condensation in a suitable solvent to afford substituted pyrazol of Formula (XXII). Reduction of the ester of Formula (XXII) using a reducing agent (such as LiAlH4) in a suitable solvent lead to the isolation of a bis alcohol intermediate that was subsequently tosylated to afford compound of Formula (XXIII) . Other reducing agent (such as BH3) could also be used in this sequence. Compound of Formula (XXIII) can finally undergo cyclisation using ammonia in a solvent of choice to lead to the isolation of intermediate of Formula (XXIV).Scheme 7

[0353] An alternative synthesis to obtain intermediate of Formula (XXIV) where Y3is (CH2)2 is depicted in Scheme 7. The alcohol of Formula (XXII) where R is an alkyl can be substituted by an azide using reagent (such as DPP A) and standard Mitsunobu reagent in a suitable solvent to afford compound of Formula (XXV) that can then undergo a reduction and lead to the amine intermediate of Formula (XXVI). A variety of reagents could be used for the reduction of the azide into amine such as PPh3in water but also other more standardly use reducting agents such as LiAlH4or Pd / C. Compound of Formula (XXVI) can finally undergo cyclisation using a suitable base (such as K2CO3) in a solvent of choice (such as EtOH) and lead to the cyclized compound of Formula (XXVII) that can be reduced using reducing agent (such as BH3) in a suitable solvent (such as THF) and lead to the isolation of intermediate of Formula (XIV).Scheme 8

[0354] A compound of Formula (XXXI) can be prepared from an intermediate of Formula (XXVIII) where PG is a suitable protecting group (such Boc) as described in Scheme 8. Iodinated intermediate of Formula (XXVIII) can react with Turbo Grignard (such as iPrMgCl.LiCl) and a boronic ester in a suitable solvent (such as THF) to afford compound of Formula (XXIX). Oxidation of compound of Formula (XXIX) using reagent such as sodium perborate in presence of a solvent such as THF and water lead to compound of Formula (XXX). Subsequent reaction with an alkylating agent (such as methyl iodide) in presence of a base (such as K2CO3) afford intermediate compound of Formula (XXXI).Scheme 9

[0355] An alcohol of general formula R16-0H, can be introduced on the alcohol of a compound of Formula (XXXII), where PG is a suitable protecting group (such Boc), using a Mitsunobu reaction. For example DIAD and PPh3in a suitable solvent afford compound a Formula (XXXIII) as represented in Scheme 9. Alternatively, substitution of alcohol of Formula (XXXII) by an alkyl halide (such as BrCH2R17) in presence of a base (such as K2CO3 or KOH), a catalytic amount of an iodine salt (such as Nal or KI) in a suitable solvent (such as EtOH or DMSO) also afford O-substituted intermediate of Formula (XXXIII).Example 1(R)-2-(3-cyano-4-(l-(pyridin-2-yl)ethoxy)pyrazolo[l,5-a]pyridin-6-yl)-6,7-dihydropyrazolo[l,5- a] pyrazine-5(4H)-carbonitrile

[0356] A 40 mL vial was charged with (R)-4-(l-(pyridin-2-yl)ethoxy)-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile [which can be made according to the procedures described in WO2022187443] (193 mg, 0.497 mmol, 1.50 equiv), tert-butyl 2-bromo-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate (100 mg, 0.331 mmol, 1.00 equiv), Pd(PPli3)4 (19.1 mg, 0.017 mmol, 0.05 equiv), K2CO3 (91.5 mg, 0.662 mmol, 2.00 equiv), water (2 mL) and 1,4-dioxane (8 mL) was stirred for overnight at 80 °C under nitrogen atmosphere. The reaction was quenched with water (100 mL). The mixture was extracted with EA (3 x 100 mL). The organic was combined, washed with water (3 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA = 1 / 5) to afford tert-butyl (R)-2-(3-cyano- 4-(l-(pyridin-2-yl)ethoxy)pyrazolo[l,5-a]pyridin-6-yl)-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)- carboxylate (80 mg, 50% yield) as a white solid. LCMS (ESI-MS) m / z = 486.2 [M+H]+.

[0357] A 50 mL round-bottom flask was charged with tert-butyl (R)-2-(3-cyano-4-(l-(pyridm-2- yl)ethoxy)pyrazolo[l,5-a]pyndin-6-yl)-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate (80 mg, 0.165 mmol, 1.00 equiv), HC1 (4M in 1,4-dioxane, 3 mL) and 1,4-dioxane (3 mL). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure to provide (R)-4-(l-(pyridin-2-yl)ethoxy)-6-(4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2- yl)pyrazolo[ 1,5 -a] pyridine -3 -carbonitrile (64 mg, crude) as a white solid. LCMS(ESI-MS) m / z = 386.2 [M+H]+.A 50 mL round-bottom flask was charged with (R)-4-(l-(pyridin-2-yl)ethoxy)-6-(4, 5,6,7- tetrahydropyrazolo[l,5-a]pyrazin-2-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile (80 mg, 0.208 mmol, 1.00 equiv), DIEA (134 mg, 1.04 mmol, 5.00 equiv) and DCM (3 mL). The BrCN (22.0 mg, 0.208 mmol, 1.00 equiv) in DCM (1 mL) was added dropwise. The resulting solution was stirred for 2 h at room temperature. The reaction was quenched by water (100 mL). The mixture was extracted with EA (3 x 100 mL). The organic layers were combined, washed with water (3 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under pressure. The residue was purified by silica gel column chromatography, eluted with EA / MeOH (20 / 1) to afford crude product The crude product was purified by Prep-HPLC with the following conditions: Column: X Bridge Prep OBD C18 Column, 30* 150 mm, 5pm; Mobile Phase A: Water (lOmmol / L NH4CO3H), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 26% B to 51 % B in 10 min; Wave Length: 254nm to afford (R)-2-(3-cyano-4-(l-(pyridin-2-yl)ethoxy)pyrazolo[l,5-a]pyridin-6-yl)-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carbonitrile (33.8 mg, 40% yield) as a white solid. 1H NMR (400 MHz, Chloroform- ) 3 8.60 (d, 1H), 8.53 (d, 1H), 8.22 (s, 1H), 7.92 - 7.69 (m, 2H), 7.26 (t, 1H), 7.19 (s, 1H), 6.32 (s, 1H), 5.78 (q, 1H), 4.58 (s, 2H), 4.38 (t, 2H), 3.75 (dd, 2H), 1.86 (d, 3H). LCMS(ESLMS) m / z = 411.3 [M+H]+.Example 2(R)-6-(5-acryloyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2-yl)-4-(l-(pyridin-2- yl)eth oxy)py r az olo [ 1 ,5- a] py ridine-3- carb onitrile

[0358] A 40 mL vial was charged with (R)-4-(l-(pyridin-2-yl)ethoxy)-6-(4,5,6,7-tetrahydropyrazolo[l,5- a]pyrazin-2-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile (64 mg, 0.166 mmol, 1.00 equiv), DIEA (64 mg, 0.498 mmol, 3.00 equiv) and DCM (2 mL). The acryloyl chloride (18 mg, 1.20 mmol, 1.20 equiv) in DCM (1 mL) was added dropwise at room temperature. The resulting mixture was stirred for 1 h at room temperature. The reaction was quenched by water (100 mL). The mixture was extracted with EA (3 x 100 mL). The organic layers were combined, washed with water (3 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under pressure. The residue was purified by silica gel column chromatography, eluted with EA / MeOH (20 / 1) to afford crude product. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD Cl 8 Column, 30* 150 mm, 5pm; Mobile Phase A: Water (lOmmol / L NH4CO3H), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 23% B to 53% B in 7 min; Wave Length: 254nm / 220nm to afford (R)- 6-(5 -acryloyl-4,5 ,6,7-tetrahydropyrazolo[ 1 ,5 -a]pyrazin-2-yl)-4-( 1 -(pyridin-2-yl)ethoxy)pyrazolo[ 1 ,5 - a] pyridine -3 -carbonitrile (13.7 mg, 19% yield) as a white solid.

[0359] 1H NMR (400 MHz, Chlorofonn- ) 3 8.60 (d, 1H), 8.54 (s, 1H), 8.21 (s, 1H), 7.79-7.74 (m, 2H), 7.28-7.24 (m, 1H), 7.20 (s, 1H), 6.64 (dd, 1H), 6.41 (dd, 1H), 6.31 (s, 1H), 5.84 (d, 1H), 5.79 (q, 1H) 4.89 (s, 2H), 4.28 (br s, 2H), 4.12 (d, 2H), 1.86 (d, 3H). LCMS(ESLMS) m / z = 440.4 [M+H]+.Example 4 2-(3-cyano-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carbonitrile, Isomer 1Example 52-(3-cyano-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carbonitrile, Isomer 2

[0360] A I L flask was charged with tert-butyl 3-bromo-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)- carboxylate (10 g, 33.1 mmol, 1.00 equiv), trimethyl-l,3,5,2,4,6-trioxatriborinane (16.6 g, 132 mmol, 4.00 equiv), Pd(dppf)C12 (0.97 g, 1.32 mmol, 0.04 equiv), K2CO3 (9 15 g, 66.2 mmol, 2.00 equiv) and 1,4-dioxane (400 mL). The mixture was stirred overnight at 100 °C under nitrogen atmosphere. The reaction was quenched with water (300 mL). The resulting mixture was extracted with EA (3 x 300 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (1 / 3) to tert-butyl 3-methyl-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate (7 g, 89% yield) as a light yellow solid. LCMS (ESIMS) m / z = 238.1 [M+H]+.

[0361] A 500 mL flask was charged with tert-butyl 3-methyl-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)- carboxylate (7 g, 29.5 mmol, 1.00 equiv) and ACN (200 mL). NBS (6.30 g, 35.4 mmol, 1.20 equiv) was added in portions at room temperature. The mixture was stirred for 1 h. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with EA (2 x 200 mL). The combined organic layers were washed with brine (3 x50 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed -phase flash chromatography with the following conditions: column: Cl 8 silica gel; mobile phase: ACN in water (0.1% FA), 10% to 50% gradient in 10 min; detector: UV 254 nm to afford tert -butyl 2-bromo-3- methyl-4H,6H,7H-pyrazolo [ 1 ,5 -a]pyrazme-5 -carboxylattert-butyl 2-bromo-3 -methyl-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate (2 g, 21% yield) as a yellow oil. LCMS (ESI-MS) m / z = 316.1 [M+H]+.

[0362] A 100 mL flask was charged with tert-butyl 2-bromo-3-methyl-6,7-dihydropyrazolo[l,5- a]pyrazine-5(4H)-carboxylate (1 g, 3.16 mmol, 1.00 equiv), 4-(2-(5-fluoropyridin-2-yl)-2- hydroxyethoxy)-6-(4, 4,5 ,5 -tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyrazolo [ 1 ,5 -a]pyridine-3- carbonitrile [which can be made according to the procedures described in WO2022187443] (1.61 g, 3.80 mmol, 1.20 equiv), Pd(PPhg)4 (0.18 g, 0.158 mmol, 0.05 equiv), K2CO3 (0.87 g, 6.33 mmol, 2.00 equiv) and 1,4-dioxane (40 mL). The flask was evacuated and refilled with nitrogen for 3 times. Theabove mixture was stirred overnight at 100 °C. The reaction was quenched with water (100 mL). The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE(10 / 1) to afford tert-butyl 2-(3-cyano-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[l,5- a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate (630 mg, 37%) as a light yellow solid. LCMS (ESI-MS) m / z = 534.2 [M+H]+.

[0363] A 50 mL flask was charged with tert-butyl 2-(3-cyano-4-(2-(5-fluoropyridin-2-yl)-2- hydroxyethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)- carboxylate (150 mg, 0.281 mmol, 1.00 equiv) and 1,4-dioxane (5 mL). Then HC1 (4M in 1,4-dioxane, 1 mL) was added dropwise. The solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-6-(3- methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile (150 mg, crude) as a light yellow solid. LCMS (ESI-MS) m / z = 434.2 [M+H]+.

[0364] A 100 mL flask was charged with 4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-6-(3-methyl- 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile (70 mg, 0.161 mmol, 1.00 equiv), DCM (10 mL) and DIEA (41.75 mg, 0.322 mmol, 2.00 equiv). Then BrCN (25.7 mg, 0.241 mmol, 1.50 equiv) in DCM (2 mL) was added dropwise at room temperature. The above solution was stirred for 2 h at room temperature. The reaction was quenched with water (50 mL). The resulting mixture was extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (EA) to afford crude product. The crude product was purified by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK IE, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.1% FA)-HPLC, Mobile Phase B: EtOH: DCM=1: 1— HPLC; Flow rate: 20ML / MIN mL / min; Gradient: isocratic 80; Wave Length: 254 / 220nm to afford 2-(3 -cyano-4-(2-(5 -fluoropyridin -2 -yl)-2 -hydroxyethoxy )pyrazolo [ 1 ,5 -a]pyridin-6-yl)-3 - methyl-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carbonitrile, Isomer 1 (the first elution, 11.2 mg, 15% yield) as a white solid.

[0365] 1H NMR (400 MHz, DMSO-t / 6) 5 8.60 (s, 1H), 8.58 (s, 1H), 8.52 - 8.50 (m, 1H), 7.77 - 7.72 (m, 2H), 7.32 (d, 1H), 5.95 (d, 1H), 5.10 (q, 1H), 4.62 (s, 2H), 4.57 (dd, 1H), 4.49 (dd, 1H), 4.26 (t, 2H), 3.78 (t, 2H), 2.14 (s, 3H). LCMS (ESI-MS) m / z = 459.2 [M+H]+.

[0366] Isomer 2 (the second elution, 14.6 mg, 20% yield) as a white solid.

[0367] 1H NMR (400 MHz, DMSO- 6) 5 8.60 (s, 1H), 8.58 (s, 1H), 8.52-8.50 (m, 1H), 7.77 - 7.70 (m, 2H), 7.32 (d, 1H), 5.96 (d, 1H), 5.10 (q, 1H), 4.61 (s, 2H), 4.57 (dd, 1H), 4.49 (dd, 1H), 4.26 (t, 2H), 3.78 (t, 2H), 2 14 (s, 3H). LCMS (ESI-MS) m / z = 459.2 [M+H]+.Example 56-(5-(l-cyanoazetidine-3-carbonyl)-3-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2-yl)-4-(2-(5- fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[l,5-a]pyridine-3-carbonitrile, IsomerlExample 66-(5-(l-cyanoazetidine-3-carbonyl)-3-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2-yl)-4-(2-(5- fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[l,5-a]pyridine-3-carbonitrile, Isomer 2

[0368] A 40 mL vial was charged with 4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-6-(3-methyl- 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile (250 mg, 0.577 mmol, 1.00 equiv) DMF (5 mL), DIEA (149 mg, 1.15 mmol, 2.00 equiv), l-(tert- butoxycarbonyl)azetidine -3 -carboxylic acid (104 mg, 0.519 mmol, 0.90 equiv) and HATU (263 mg, 0.692 mmol, 1.20 equiv). The resulting solution was stirred for overnight at room temperature. The reaction was quenched with water (100 mL). The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (EA) to afford tert-butyl 3-(2-(3-cyano-4-(2-(5-fluoropyridin-2-yl)-2- hydroxyethoxy)pyrazolo [ 1 ,5 -a]pyridin-6-yl)-3 -methyl -4, 5 ,6,7-tetrahydropyrazolo [ 1 ,5 -a]pyrazine-5 - carbonyl)azetidine-l -carboxylate (180 mg, 51% yield) as a light yellow solid. LCMS (ESI-MS) m / z = 617.3 [M+H]+.

[0369] A 50 mL flask was charged with tert-butyl 3-(2-(3-cyano-4-(2-(5-fluoropyridin-2-yl)-2- hydroxyethoxy)pyrazolo [ 1 ,5 -a]pyridm-6-yl)-3 -methyl -4, 5 ,6,7-tetrahydropyrazolo [ 1 ,5 -a]pyrazme-5 - carbonyl)azetidine-l -carboxylate (180 mg, 0.292 mmol, 1.00 equiv) and 1,4-dioxane (5 mL). HC1 (4 M in 1,4-dioxane, 2 mL) was added dropwise. The solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 6-(5-(azetidine-3-carbonyl)- 3-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2-yl)-4-(2-(5-fluoropyridin-2-yl)-2- hydroxy ethoxy )pyrazolo[ 1,5 -a] pyridine -3 -carbonitrile (180 mg, crude) as light yellow solid. LCMS (ESI-MS) m / z = 517.2 [M+H]+.

[0370] A 100 mL flask was charged with 6-(5-(azetidine-3-carbonyl)-3-methyl-4, 5,6,7- tetrahydropyrazolo [ 1 ,5 -a]pyrazin-2-yl)-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[ 1,5- a] pyridine -3 -carbonitrile (150 mg, 0.290 mmol, 1.00 equiv), DCM (20 mL) and DIEA (75.07 mg, 0.580 mmol, 2.00 equiv). The BrCN (46. 1 mg, 0.435 mmol, 1.50 equiv) in DCM (2 mL) was added dropwise at room temperature. The above solution was stirred for 2 h at room temperature. The reaction wasquenched with water (50 mL). The resulting mixture was extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep- TLC (EA) to afford crude product. The crude product was purified by Prep -Chiral -HPLC with the following conditions: Column: CHIRALPAK IE, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.1% FA)— HPLC, Mobile Phase B: EtOH: DCM=1: 1— HPLC; Flow rate: 20ML / MIN mL / min; Gradient: isocratic 80; Wave Length: 254 / 220nm to afford 6-(5-(l-cyanoazetidine-3-carbonyl)-3-methyl-4, 5,6,7- tetrahydropyrazolo [ 1 ,5 -a]pyrazin-2-yl)-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[ 1,5- a] pyridine -3 -carbonitrile, Isomer 1 (the first elution, 9.7 mg, 6% yield) white solid. 1H NMR (400 MHz, DMSO-c / 6) 5 8.59 (s, 1H), 8.58 (s, 1H), 8.52 (s, 1H), 7.79 - 7.70 (m, 2H), 7.32 (s, 1H), 5.96 (d, 1H), 5.10 (q, 1H), 4.71 (s, 1H), 4.62 - 4.46 (m, 3H), 4.42 - 4.26 (m, 4H), 4.22 - 4.12 (m, 2H), 4.11 - 3.97 (m, 2H), 3.76 (t, 1H), 2.18 (s, 3H). LCMS (ESI-MS) m / z = 542.2 [M+H]+.

[0371] Isomer 2 (the second elution, 15.8 mg, 10% yield) as a white solid. 1H NMR (400 MHz, DMSO-c / 6) 8 8.58 (s, 1H), 8.57 (s, 1H), 8.51 (s, 1H), 7.76 - 7.71 (m, 2H), 7.31 (s, 1H), 5.96 (d, 1H), 5.10 (q, 1H), 4.70 (s, 1H), 4.61 - 4.52 (m, 2H), 4.49 (dd, 1H), 4.40 - 4.25 (m, 4H), 4.21 - 4.11 (m, 2H), 4.09 - 3.95 (m, 2H), 3.75 (t, J= 5.5 Hz, 1H), 2.17 (s, 3H). LCMS (ESI-MS) m / z = 542.2 [M+H]+.Example 76-(5-(l-acryloylazetidine-3-carbonyl)-3-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2-yl)-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[l,5-a]pyridine-3-carbonitrile, Isomer 1Example 86-(5-(l-acryloylazetidine-3-carbonyl)-3-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2-yl)-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[l,5-a]pyridine-3-carbonitrile, Isomer 2

[0372] A 50 mL flask was charged with 6-(5-(azetidine-3-carbonyl)-3-methyl-4,5,6,7- tetrahydropyrazolo [ 1 ,5 -a]pyrazin-2-yl)-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[ 1,5- a] pyridine -3 -carbonitrile (160 mg, 0.310 mmol, 1.00 equiv), DIEA (120 mg, 0.930 mmol, 3.00 equiv) and DCM (20 mL). Acryloyl chloride in DCM (1 mL) was added dropwise at room temperature. The mixture was stirred for 2 h at room temperature. The reaction was quenched with water (50 mL). Theresulting mixture was extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (EA) to afford crude product. The crude product was separated by Prep-Chiral-HPLC by the following conditions: Column: CHIRALPAK IE, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.1% FA)-HPLC, Mobile Phase B: MeOH: DCM=1: 1— EIPLC; Flow rate: 20ML / MIN mL / min; Gradient: isocratic 80; Wave Length: 254 / 220nm to afford 6-(5 -( 1 -acryloylazetidine-3-carbonyl)-3 -methyl -4, 5 ,6,7-tetrahydropyrazolo [ 1 ,5 -a]pyrazin-2- yl)-4-(2-(5-fluoropyridin-2 -yl)-2 -hydroxyethoxy )pyrazolo[ l,5-a]pyridine-3-carbonitrile, Isomer 1 (the first elution, 16.0 mg, 9% yield) as a white solid. 1H NMR (400 MHz, Chloroform -d) 8 8.43 (s, 1H), 8.35 (d, 1H), 8.18 (d, 1H), 7.87 - 7.77 (m, 1H), 7.52 (dt, 1H), 7.21 (d, 1H), 6.37 (d, 1H), 6.22 (ddd, 1H), 5.73 (d, 1H), 5.32 (s, 1H), 4.87-4.76 (m, 1H), 4.74-4.67 (m, 1H), 4.55-4.45 (m, 3H), 4.40 (t, 2H), 4.33-4.09 (m, 4H), 3.82 (s, 1H), 3.74-3.64 (m, 1H), 2.19 (s, 3H). LCMS (ESI-MS) m / z = 571.4 [M+H]+.

[0373] Isomer 2 (the second elution, 15.9 mg, 9% yield) as a white solid. 1H NMR (400 MHz, Chloroform -d) 8 8.43 (d, 1H), 8.36 (d, 1H), 8.18 (d, 1H), 7.83 (dd, 1H), 7.51 (td, 1H), 7.21 (s, 1H), 6.37 (d, 1H), 6.21 (ddd, 1H), 5.74 (dd, 1H), 5.31 (t, 1H), 4.89-4.77 (m, 1H), 4.73-4.66 (m, 1H), 4.55- 4.46 (m, 3H), 4.40 (t, 2H), 4.34 - 4.12 (m, 4H), 3.82 (s, 1H), 3.76-3.67 (m, 1H), 2.20 (s, 3H). LCMS (ESI-MS) m / z = 571.4 [M+H]+.Example 92-(3-chloro-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carbonitrile, Isomer 1Example 102-(3-chloro-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carbonitrile, Isomer 2

[0374] Starting from 2-((3-chloro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridin- 4-yl)oxy)-l-(5-fluoropyridin-2-yl)ethan-l-ol [which can be made according to the procedures described in WO2022187443] and tert-butyl 2-bromo-3-methyl-6,7-dihydropyrazolo[l,5-a]pyrazine- 5(4H)-carboxylate, example 9 and 10 were synthesized following the same procedure as used for example 3.

[0375] The crude product was purified by Prep-chiral-HPLC with the following conditions: Column: UniChiral 0D-5H, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.1% FA)— HPLC, Mobile Phase B: MeOH: EtOH=l: 1— HPLC; Flow rate: 20ML / MIN mL / min; Gradient: isocratic 30; Wave Length: 254 / 220nm to afford 2-(3 -chloro-4-(2-(5 -fluoropyridin -2 -yl)-2 -hydroxyethoxy )pyrazolo [ 1 ,5 -a]pyridin-6-yl)-3 - methyl-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carbonitrile, Isomer 1 (the first elution) as an off- white solid. 1H NMR (400 MHz, Chloroform- ) 5 8.43 (d, 1H), 8.24 (s, 1H), 7.79 (s, 1H), 7.67 (dd, 1H), 7.47 (td, 1H), 6.88 (s, 1H), 5.23 (dd, 1H), 4.47 (s, 2H), 4.41 (d, 2H), 4.32 (t, 2H), 4.04 (s, 1H), 3.72 (t, 2H), 2.13 (s, 3H). LCMS (ESI-MS) m / z = 468.2 [M+H]+

[0376] Isomer 2, (the second elution, 15.4 mg, 7% yield) as an off-white solid. 1H NMR (400 MHz, Chloroform -d) 5 8.43 (d, 1H), 8.24 (s, 1H), 7.79 (s, 1H), 7.67 (dd, 1H), 7.47 (td, 1H), 6.88 (s, 1H), 5.24 (dd, 1H), 4.47 (s, 2H), 4.41 (d, 2H), 4.32 (t, 2H), 4.05 (s, 1H), 3.72 (t, 2H), 2.13 (s, 3H). LCMS (ESIMS) m / z = 468.1 [M+H]+.Example 11(3-(2-(3-chloro-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-4,5,6,7-tetrahydropyrazolo [1 ,5-a] pyrazine-5-carbonyl)azetidine-l-carbonitrile, Isomer 1Example 123-(2-(3-chloro-4-(2-(5-fhioropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-5-carbonyl)azetidine-l-carbonitrile, Isomer 2

[0377] Starting from 2-((3-chloro-6-(3-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2- yl)pyrazolo[ l,5-a]pyridin-4-yl)oxy)- 1 -(5-fluoropyridin-2-yl)ethan- 1 -ol and 1 -(tert- butoxycarbonyl)azetidine -3 -carboxylic acid, example 11 and 12 was synthesized following the same procedure as used for example 5.

[0378] The crude product was purified by Prep-chiral-HPLC with the following conditions: Column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.1% FA)-HPLC, Mobile Phase B: MeOH: DCM=1: 1— HPLC; Flow rate: 20ML / MIN mL / min; Gradient: isocratic 25; Wave Length: 254 / 220nmto afford 3-(2-(3-chloro-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[l,5- a]pyridin-6-yl)-3-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-5-carbonyl)azetidine-l- carbonitrile, isomer 1 (the first elution, 9.9 mg, 6% yield) as an off-white solid. 1H NMR (400 MHz, Chloroform -d) 58.42 (d, 1H), 8.24 (d, 1H), 7.79 (s, 1H), 7.61-7.66 (m, 1H), 7.46 (td, 1H), 6.88 (d, 1H), 5.24 (s, 1H), 4.77 (s, 1H), 4.49 (dt, 2H), 4.44 - 4.38 (m, 3H), 4.34 (dd, 2H), 4.21 (t, 2H), 4.13 (t, 1H), 4.06 (s, 1H), 3.83 - 3.68 (m, 2H), 2.16 (d, 3H). LCMS (ESI-MS) m / z = 551.2 [M+H]+.

[0379] Isomer 2 (the second elution, 9.6 mg, 6% yield) as a white solid. 1H NMR (400 MHz, Chloroform- d) 8 8.42 (d, 1H), 8.24 (d, 1H), 7.79 (s, 1H), 7.70-7.66 (m, 1H), 7.46 (td, 1H), 6.88 (d, 1H), 5.24 (t, 1H),4.77 (s, 1H), 4.49 (dt, 2H), 4.44 - 4.38 (m, 3H), 4.34 (dd, 2H), 4.21 (t, 2H), 4.16 - 4.00 (m, 2H), 3.85-3.77 (m, 1H), 3.71 (t, 1H), 2.16 (d, 3H). LCMS (ESI-MS) m / z = 551.2 [M+H]+.Example 13 l-(3-(2-(3-chloro-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3- methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-5-carbonyl)azetidin-l-yl)prop-2-en-l-one, Isomer1Example 14 l-(3-(2-(3-chloro-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3- methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-5-carbonyl)azetidin-l-yl)prop-2-en-l-one, Isomer2

[0380] Into a 100 mL round-bottom flask were added azetidin-3-yl(2-(3-chloro-4-(2-(5-fluoropyridin-2- yl)-2-hydroxyethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[l,5-a]pyrazin- 5(4H)-yl)methanone (200 mg, 0.380 mmol, 1.00 equiv), DCM (10 mL) and DIEA (147 mg, 1.14 mmol, 3.00 equiv). Acryloyl chloride (27.5 mg, 0.304 mmol, 0.80 equiv) in DCM (1 mL) was added dropwise. The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched by the addition of water (100 mL). The resulting mixture was extracted with DCM (3 x 100 mL). The combined organic layers were washed with water (3x100 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / MEOH (20 / 1) to afford crude product. The crude product was purified by Prep-chiral-HPLC with the following conditions: Column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.1% FA)-HPLC, Mobile Phase B: MeOH: DCM=1: 1— EIPLC; Flow rate: 20ML / MIN mL / min; Gradient: isocratic 30; Wave Length: 254 / 220nm to afford l-(3-(2-(3-chloro-4-(2-(5-fluoropyridin-2 -yl)-2 -hydroxyethoxy )pyrazolo[I,5-a]pyridin-6-yl)- 3 -methyl -4, 5 ,6,7-tetrahydropyrazolo[ 1 ,5 -a]pyrazine-5 -carbonyl)azetidm- 1 -yl)prop-2-en- 1 -one, Isomer 1 (elution 1) as a white solid. 1H NMR (400 MHz, Chloroform-d) 5 8.44 (d, 1H), 8.26 (d, 1H), 7.81 (s, 1H), 7.68 (dd, 1H), 7.48 (td, 1H), 6.91 (s, 1H), 6.37 (d, 1H), 6.21 (ddd, 1H), 5.73 (d, 1H), 5.26 (s, 1H), 4.80 (dd, 1H), 4.73-4.64 (m, 1H), 4.50 (dd, 1H), 4.46 - 4.37 (m, 4H), 4.27 - 4.04 (m, 5H), 3.77 (t, 1H), 3.75-3.66 (m, 1H), 2.18 (d, 3H). LCMS (ESI-MS) m / z = 580.2 [M+H]+

[0381] Isomer 2 (2ndelution, 23.7 mg, 10.7% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) 5 8.44 (d, 1H), 8.26 (d, 1H), 7.81 (s, 1H), 7.68 (dd, 1H), 7.48 (td, 1H), 6.91 (s, 1H), 6.37 (d, 1H), 6.21(ddd, 1H), 5.73 (d, 1H), 5.26 (s, 1H), 4.80 (dd, 1H), 4.73-4.64 (m, 1H), 4.50 (dd, 1H), 4.46 - 4.37 (m, 4H), 4.27 - 4.04 (m, 5H), 3.77 (t, 1H), 3.75-3.66 (m, 1H), 2.18 (d, 3H). LCMS (ESI-MS) m / z = 580.2 [M+H]+.Example 152-(3-cyano-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[l,5-a]pyridin-6-yl)-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carbonitrile, Isomer 1Example 162-(3-cyano-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[l,5-a]pyridin-6-yl)-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carbonitrile, Isomer 2BrCN, DIEA, DCM rt, 2 hi

[0382] Starting from 4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile and tert-butyl 2-bromo-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate, examples 15 and 16 were synthesized following the same procedure as used for example 3.

[0383] The crude product was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK IE, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.1% FA)-HPLC, Mobile Phase B: MeOH: DCM=1: 1— HPLC; Flow rate: 20ML / MIN mL / min; Gradient: isocratic 65; Wave Length: 254 / 220nm to afford 2-(3-cyano-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[l,5-a]pyridin-6-yl)-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carbonitrile, isomer 1 (the first elution, 5.6 mg, 9% yield) as a white solid. 1H NMR (400 MHz, DMSO-r / 6) 5 8.94 (s, 1H), 8.56 (s, 1H), 8.53 (s, 1H), 7.80 - 7.69 (m, 2H), 7.46 (s, 1H), 6.86 (s, 1H), 5.96 (d, 1H), 5.11 (dd, 1H), 4.67 (s, 2H), 4.60 (dd, 1H), 4.52 (dd, 1H), 4.31 (t, J= 5.6 Hz, 2H), 3.80 (t, 2H). LCMS (ESI-MS) m / z = 445.2 [M+H]+.

[0384] Isomer 2, (the second elution, 5.5 mg, 9% yield) as a white solid. 1H NMR (400 MHz, DMSO- d6) 5 8.94 (s, 1H), 8.56 (s, 1H), 8.52 (d, 1H), 7.79 - 7.70 (m, 2H), 7.46 (s, 1H), 6 86 (s, 1H), 5.96 (d,1H), 5.11 (dd, 1H), 4.67 (s, 2H), 4.60 (dd, 1H), 4.51 (dd, 1H), 4.31 (t, 2H), 3.81 (t, 2H). LCMS (ESIMS) m / z = 445.2 [M+H]+.Example 172-(3-chloro-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[l,5-a]pyridin-6-yl)-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carbonitrile, Isomer 1Example 182-(3-chloro-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[l,5-a]pyridin-6-yl)-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carbonitrile, Isomer 2BrCN, DIEA, DCM rt, 2 h

[0385] Starting from 2-((3-chloro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridin- 4-yl)oxy)-l-(5-fluoropyridin-2-yl)ethan-l-ol and tert-butyl 2-bromo-6,7-dihydropyrazolo[l,5- a]pyrazine-5(4H)-carboxylate, example 17 and 18 were synthesized following the same procedure as used for example 3.

[0386] The crude product was purified by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK IF, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.1% FA)-HPLC, Mobile Phase B: MeOH: DCM=1: 1--HPLC; Flow rate: 20ML / MIN mL / min; Gradient: isocratic 50; Wave Length: 254 / 220nm to afford 2-(3-chloro-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[l,5-a]pyridin-6-yl)-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carbonitrile, isomer 1 (the first elution, 5.1 mg, 11% yield) as a white solid. 1H NMR (400 MHz, DMSO-r / 6) 5 8.70 (s, 1H), 8.53 (s, 1H), 7.99 (s, 1H), 7.75 (dd, 2H), 7.10 (s, 1H), 6.78 (s, 1H), 5.94 (d, 1H), 5.10 (s, 1H), 4.65 (s, 2H), 4.50 (d, 1H), 4.44 (d, 1H), 4.29 (s, 2H), 3.80 (d, 2H). LCMS(ESI-MS) m / z =454.2 [M+H]+.

[0387] Isomer 2 (the second elution, 5.9 mg, 4.5% yield) as a white solid. 1H NMR (400 MHz, DMSO- d6) 5 8.70 (s, 1H), 8.53 (s, 1H), 7.99 (s, 1H), 7.79-7.67 (m, 2H), 7.10 (s, 1H), 6.78 (s, 1H), 5.94 (d, 1H),5.10 (dd, 1H), 4.65 (s, 2H), 4.50 (dd, 1H), 4.44 (dd, 1H), 4.29 (t, 2H), 3.80 (t, 2H). LCMS(ESI-MS) m / z =454.2 [M+H]+.Example 192-(3-chloro-4-(l-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carbonitrile, Isomer 1Example 202-(3-chloro-4-(l-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carbonitrile, Isomer 2

[0388] A 500 mL flask was charged with NaOH (2.64 g, 66.0 mmol, 3.00 equiv), H2O (1.19 mL, 66.0 mmol, 3.00 equiv), DMA (200 mL), 6-bromo-3-chloro-4-methoxypyrazolo[l,5-a]pyridine (5 g, 22.0 mmol, 1.00 equiv) and dodecane- 1 -thiol (13.4 g, 66.0 mmol, 3.00 equiv) respectively. The above mixture was stirred for 2 hours at 60 °C under nitrogen atmosphere. The reaction was quenched with water (200 mL). The resulting mixture was extracted with EA (3 x 200 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with EA (20 mL)to afford 6-bromo-3-chloropyrazolo[l,5-a]pyridin-4-ol (3.8 g, crude) as a white solid. LCMS(ESI- MS) m / z = 213.0 [M+H]+.

[0389] A 500 mL round-bottom flask was charged with PPI13 (8.69 g, 33.1 mmol, 2.00 equiv) and THF (200 mL). DIAD (6.70 g, 33.1 mmol, 2.00 equiv) was added dropwise at 0°C under N2. The reactionwas stirred at 0°C for 0.5 h. To the mixture is added a solution 6-bromo-3-chloropyrazolo[l,5- a]pyridin-4-ol (4.1 g, 16.6 mmol, 1.00 equiv) 2-((tert-butyldimethylsilyl)oxy)-l-(5-fluoropyridin-2- yl)ethan-l-ol [which can be made according to the procedures described in WO2022187443] (4.50 g, 16.6 mmol, 1.00 equiv) in THF (50 mL). The resulting mixture was stirred for overnight at room temperature under nitrogen atmosphere. The reaction was quenched by the addition of water (500 mL) at room temperature. The resulting mixture was extracted with EA (3 x 400 mL). The combined organic layers were washed with water (3 x 100 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2 / 1) to afford 6-bromo-4-(2-((tert-butyldimethylsilyl)oxy)-l- (5-fluoropyridin-2-yl)ethoxy)-3-chloropyrazolo[l,5-a]pyridine (7.5 g, 90% yield) as a yellow oil. LCMS(ESI-MS) m / z = 500.0 [M+H]+.

[0390] A 100 mL round-bottom flask was charged with 6-bromo-4-(2-((tert-butyldimethylsilyl)oxy)-l-(5- fluoropyridin-2-yl)ethoxy)-3-chloropyrazolo[l,5-a]pyridine (4 g, 7.99 mmol, 1.00 equiv), bis(pinacolato)diboron (4.06 g, 16.0 mmol, 2.00 equiv), Pd(dppf)C12 (0.29 g, 0.400 mmol, 0.05 equiv), AcOK (1.57 g, 16.0 mmol, 2.00 equiv) and 1,4-dioxane (100 mL). The resulting mixture was stirred for overnight at 80°C under nitrogen atmosphere. The reaction was quenched by the addition of water (300 mL) at room temperature. The resulting mixture was extracted with EA (3 x 150 mL). The combined organic layers were washed with water (3 x 100 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was recrystallized from EA / PE (1 / 10, 20 mL) to afford 4-(2-((tert-butyldimethylsilyl)oxy)-l-(5- fluoropyridin-2-yl)ethoxy)-3-chloro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5- a]pyridine (5 g, crude) as a yellow solid. LCMS(ESI-MS) m / z = 548.2 [M+H]+.

[0391] To a solution of tert-butyl 2 -bromo -3 -tert-butyl 2-bromo-3-methyl-6,7-dihydropyrazolo[l,5- a]pyrazine-5(4H)-carboxylate (195 mg, 0.617 mmol, 1 equiv) in 1,4-dioxane (8 mL) and H2O(2 mL)was added K2CO3 (170.46 mg, 1.234 mmol, 2 equiv), 4-(2-((tert-butyldimethylsilyl)oxy)-l-(5- fluoropyridin-2-yl)ethoxy)-3-chloro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5- a]pyridine (506.86 mg, 0.925 mmol, 1.5 equiv) and Pd(PPhs)4 (35.63 mg, 0.031 mmol, 0.05eq). The reaction was stirred for overnight at 100°C under N2atmosphere . The reaction was quenched with water (50 mL). The resulting solution was extracted with EA (3 x 50 mL). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 1) to afford tert-butyl 2-(4-(2-((tert-butyldimethylsilyl)oxy)-l-(5-fluoropyridin-2-yl)ethoxy)-3- chloropyrazolo [ 1 ,5 -a]pyridin-6-yl)-3 -methyl-6,7-dihydropyrazolo [ 1 ,5 -a]pyrazine-5 (4H)-carboxylate (66 mg, 16% yield) as a light yellow solid. LCMS(ESI-MS) m / z =658.0 [M+H]+.

[0392] To a solution of tert-butyl 2-(4-{2-[(tert-butyldimethylsilyl)oxy]-l-(5-fluoropyridin-2-yl)ethoxy}- 3 -chloropyrazolo [ 1 ,5 -a]pyridin-6-yl)-3 -methyl -4H,6H,7H-pyrazolo[ 1 ,5 -a]pyrazine-5-carboxylate (80 mg, 0.122 mmol, 1 equiv) in 1,4-dioxane (2 mL) was added HC1 (4M in 1,4-dioxane, 2 mL). The reaction was stirred for 2h at rt and concentrated under reduced pressure to afford 2-((3-chloro-6-(3- methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2-yl)pyrazolo[l,5-a]pyridin-4-yl)oxy)-2-(5- fhioropyridin-2-yl)ethan-l-ol (53 mg, crude) as a white solid. LCMS(ESI-MS) m / z =443.0 [M+H]+.

[0393] To a solution of 2-((3-chloro-6-(3-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2- yl)pyrazolo[l,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethan-l-ol (53 mg, 0.12 mmol, 1.00 equiv) in DCM (3 mL) was added DIEA (77 mg, 0.60 mmol, 5.00 equiv) and BrCN (32 mg, 0.30 mmol, 2.50 equiv). The reaction was stirred for 2 h at rt. The reaction was quenched with water (20 mL). The mixture was extracted with DCM (3 x 50 mL). The organic layers were combined, washed with brine (3 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM / MeOH = 15 / 1) to afford crude product. The crude product was purified by Pre-chiral-HPLC with following conditions: Column: CHIRAL ART Amylose-SA, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)-HPLC, Mobile Phase B: EtOH: DCM=1: 1--HPLC; Flow rate: 20ML / MIN mL / min; Gradient: isocratic 40; Wave Length: 254 / 220nmto afford 2-(3 -chloro-4-( 1 -(5 -fluoropyri din-2 -yl)-2-hydroxyethoxy)pyrazolo [ 1 ,5 -a]pyridin- 6-yl)-3-methyl-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carbonitrile, Isomer 1 (the first elution, 3.7 mg, 6.5% yield) as a white solid. 1HNMR (4OO MHz, Chloroform-d) 58.49 (s, 1H), 8.29 (s, 1H), 7.88 (d, 1H), 7.67 (dd, 1H), 7.56 - 7.45 (m, 1H), 6.79 (s, 1H), 5.73 (t, 1H), 4.48-4.42 (m, 2H), 4.36-4.28 (m, 2H), 4.21-4.10 (m, 2H), 3.76-3.68 (m, 4H), 2.12 (s, 3H). LCMS(ESI-MS) m / z =468.2 [M+H]+.

[0394] Isomer 2 (the second elution, 3.9 mg, 7% yield) as a white solid. 1H NMR (400 MHz, Chloroform - d) 5 8.50 (s, 1H), 8.29 (s, 1H), 7.88 (d, 1H), 7.67 (dd, 1H), 7.56 - 7.45 (m, 1H), 6.79 (s, 1H), 5.73 (t, 1H), 4.48-4.42 (m, 2H), 4.36-4.28 (m, 2H), 4.21-4.10 (m, 2H), 3.76-3.68 (m, 4H), 2.12 (s, 3H). LCMS(ESI-MS) m / z =468.2 [M+H]+.Example 21 l-(2-(3-chloro-4-(2-(5-fhioropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl- 6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)prop-2-en-l-one, Isomer 1Example 22 l-(2-(3-chloro-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)prop-2-en-l-one, Isomer 2

[0395] A lOOmL round bottom flask was charged with 2-((3-chloro-6-(3-methyl-4, 5,6,7- tetrahydropyrazolo [ 1 ,5 -a]pyrazin-2-yl)pyrazolo[ 1 ,5 -a]pyridin-4-yl)oxy)- 1 -(5 -fluoropyridin-2- yl)ethan-l-ol (85 mg, 0.192 mmol, 1.00 equiv), DIEA (74.4 mg, 0.576 mmol, 3.00 equiv) and DCM (3 mL). Acryloyl chloride (17.4 mg, 0.192 mmol, 1.00 equiv) in DCM (1 mL) was added dropwise. The resulting solution was stirred for 2 h at room temperature. The reaction was quenched by water (100 mL). The mixture was extracted with EA (3 x 100 mL). The organic layers were combined, washed with water (3 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (EA / MeOH = 20 / 1) to afford crude product. The crude product was separated by Prep-Chiral -HPLC with the following conditions: Column: LuxCellulose4; Mobile Phase A: Hex(0.2%FA): EtOH=50: 50; Flow rate: ImL / min mL / min; Gradient: isocratic ; Injection Volume: luL mL; Wave Length: 220 nm to 1- (2-(3-chloro-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)prop-2-en-l-one, isomer 1 (the first elution, 13.2 mg, 13.8% yield) as a white solid. 1HNMR (400 MHz, Chloroform- ) 3 8.45 (s, 1H), 8.28 (s, 1H), 7.81 (s, 1H), 7.70 (dd, 1H), 7.50 (dt, 1H), 6.93 (s, 1H), 6.67 (dd, 1H), 6.42 (dd, 1H), 5.86 (dd, 1H), 5.27 (dd, 1H), 4.85-4.73 (m, 2H), 4.44 (d, 2H), 4.27 (s, 2H), 4.20-4.00 (m, 2H), 2.20 (s, 3H), 1.28 (s, 1H). LCMS (ESI-MS) m / z = 497.1 [M+H]+.

[0396] Isomer 2 (the second elution, 12.3 mg, 12.9% yield) as a white solid. 1H NMR (400 MHz, Chloroform -d) 3 8.46 (s, 1H), 8.28 (s, 1H), 7.81 (s, 1H), 7.72 - 7.67 (m, 1H), 7.50 (dd, 1H), 6.93 (s, 1H), 6.67 (dd, 1H), 6.42 (dd, 1H), 5.86 (dd, 1H), 5.28 (s, 1H), 4.82 (s, 2H), 4.44 (d, 2H), 4.27 (s, 2H), 4.21-4.01 (m, 2H), 2.20 (s, 3H), 1.28 (s, 1H). LCMS (ESI-MS) m / z = 497.1[M+H]+.Example 233-((S)-2-(3-chloro-4-((R)-l-(pyridin-2-yl)ethoxy)pyrazolo[l,5-a]pyridin-6-yl)-5-cyano-3-methyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazin-6-yl)propanoic acid

[0397] To a stirred mixture of PPIv, (4.77 g, 18.2 mmol, 1.50 equiv) in THF (100 mL) was added DIAD (3.61 mL, 18.2 mmol, 1.50 equiv). The resulting mixture was stirred for 1 h at 0 °C under nitrogen atmosphere. To the above mixture was added methyl methyl (S)-4-((tert-butoxycarbonyl)amino)-5- hydroxypentanoate (3 g, 12.1 mmol, 1.00 equiv) and ethyl 3-bromo-4-methyl-lH-pyrazole-5- carboxylate (3.11 g, 13.3 mmol, 1.10 equiv). The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction was quenched with water (150 mL). The resulting mixture was extracted with EA (3 x 150 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (PE / EA = 4 / 1) to afford ethyl (S)-3-bromo- l-(2-((tert-butoxycarbonyl)amino)-5-methoxy-5-oxopentyl)-4-methyl-lH-pyrazole-5-carboxylate (3.7 g, 66% yield) as a light yellow oil. LCMS(ESI-MS) m / z = 462.1 [M+EI]+.

[0398] Into a 250 mL round-bottom flask were added ethyl ethyl (S)-3-bromo-l-(2-((tert- butoxycarbonyl)amino)-5-methoxy-5-oxopentyl)-4-methyl-lH-pyrazole-5-carboxylate (3.7 g, 8.00 mmol, 1.00 equiv), HC1 (4 M in 1,4-dioxane, 20 mL) and 1,4-dioxane (20 mL). The resulting mixture was stirred for 2 h at room temperature. The mixture was basified pH to 9-10 with saturated NaHCOi aqueous solution (200 mL) at 0 °C. The resulting mixture was stirred overnight at room temperature. The reaction was quenched with water (50 mL). The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (PE / EA = 1 / 1) to afford methyl (S)-3-(2-bromo-3-methyl-4-oxo- 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-6-yl)propanoate (1.1 g, 44% yield) as a white solid. LCMS(ESI-MS) m / z = 316.0 [M+H]+.

[0399] Into a 100 mL round-bottom flask were added methyl (S)-3-(2-bromo-3-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[l,5-a]pyrazin-6-yl)propanoate (1.1 g, 3.48 mmol, 1.00 equiv) and BH3-THF (20 mL, 1.3 M in THF). The resulting mixture was stirred overnight at room temperature. The reaction was quenched with MeOH (20 mL) at 0 °C and stirred for 2 h at 60 °C. The resulting mixture was concentrated under vacuum, added water (30 mL) and extracted with EA (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford (S)-3-(2-bromo-3-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin- 6-yl)propan-l-ol (1 g, crude) as a white solid. LCMS(ESI-MS) m / z = 274.1 [M+H]+.

[0400] Into a 100 mL round-bottom flask were added (S)-3-(2-bromo-3-methyl-4,5,6,7- tetrahydropyrazolo[I,5-a]pyrazin-6-yl)propan-l-ol (1.0 g, 3.65 mmol, 1.00 equiv), TEA (2.54 mL, 18.2 mmol, 5.00 equiv), THF (20 mL) and BOC2O (1.19 mg, 5.47 mmol, 1.50 equiv). The resulting mixture was stirred for 5 h at room temperature. The reaction was quenched by the addition of water (30 mL). The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (PE / EA = 1 / 5) to tertbutyl (S)-2-bromo-6-(3-hydroxypropyl)-3-methyl-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)- carboxylate (650 mg, 48% yield) as a light yellow oil. LCMS(ESI-MS) m / z = 374.1 [M+H]+.

[0401] Into a 100 mL round-bottom flask were added tert-butyl (S)-2-bromo-6-(3-hydroxypropyl)-3- methyl-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate (650 mg, 1.74 mmol, 1.00 equiv), potassium chloride (25.9 mg, 0.347 mmol, 0.20 equiv), iron(III) nitrate nonahydrated (141 mg, 0.347 mmol, 0.20 equiv), TEMPO (54.3 mg, 0.347 mmol, 0.20 equiv) and DCE (20 mL). The resulting mixture was stirred for 3 days at room temperature under oxygen atmosphere. The reaction was quenched with water (20 mL). The resulting mixture was extracted with DCM (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (PE / EA = 1 / 10) to afford (S)-3-(2-bromo-5-(tert-butoxycarbonyl)-3-methyl-4,5,6,7- tetrahydropyrazolo[l,5-a]pyrazin-6-yl)propanoic acid (400 mg, 59% yield) as a white solid. LCMS(ESI-MS) m / z = 388.1 [M+H]+.

[0402] Into a 40 mL round-bottom flask were added (S)-3-(2-bromo-5-(tert-butoxycarbonyl)-3-methyl- 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-6-yl)propanoic acid (400 mg, 0.618 mmol, 1.00 equiv), (R)- 3-chloro-4-(l-(pyridin-2-yl)ethoxy)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5- a]pyridine (988 mg, 2.47 mmol, 4.00 equiv), Pd(PPh3)4 (35.7 mg, 0.031 mmol, 0.05 equiv), K3CO3(171 mg, 1.24 mmol, 2.00 equiv), 1,4-dioxane (15 mL) and H2O (3 mL). The resulting mixture was stirred overnight at 100 °C under nitrogen atmosphere. The reaction was quenched with water (20 mL). The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were driedover anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (PE / EA = 1 / 10) to afford 3 -(( S) -5 -(tert-butoxy carbonyl) -2-(3 -chloro-4-((R)- 1 -(pyridin-2-yl)ethoxy)pyrazolo [1,5 -a]pyridin-6- yl)-3-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-6-yl)propanoic acid (140 mg, 39% yield) as a brown oil. LCMS(ESI-MS) m / z = 581.2 [M+H]+.

[0403] Into a 50 mL round-bottom flask were added 3-((S)-5-(tert-butoxycarbonyl)-2-(3-chloro-4-((R)-l- (pyridin-2-yl)ethoxy)pyrazolo [ 1 ,5-a]pyridin-6-yl)-3 -methyl -4, 5 ,6,7-tetrahydropyrazolo [ 1 ,5 - a]pyrazin-6-yl)propanoic acid (140 mg, 0.241 mmol, 1.00 equiv), K2CO3 (66.6 mg, 0.482 mmol, 2.00 equiv), CH3I (34.2 mg, 0.241 mmol, 1.00 equiv) and DMF (30 mL). The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched by the addition of saturated NH4CI aqueous solution (30 mL) at 0 °C. The resulting mixture was extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (PE / EA = 1 / 3) to afford tert-butyl (S)-2-(3-chloro-4-((R)-l- (pyridin-2-yl)ethoxy)pyrazolo[l,5-a]pyridin-6-yl)-6-(3-methoxy-3-oxopropyl)-3-methyl-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate (100 mg, 69.74% yield) as a colorless oil. LCMS(ESI-MS) m / z = 595.2 [M+H]+.

[0404] Into a 50 mL round-bottom flask were added tert-butyl (S)-2-(3-chloro-4-((R)-l-(pyridin-2- yl)ethoxy)pyrazolo [ 1 , 5 -a] pyridin-6-yl) -6-(3 -methoxy-3 -oxopropyl)-3 -methyl-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate (100 mg, 0.168 mmol, 1.00 equiv), HC1 (4Min 1,4- dioxane, 5 mL) and 1,4-dioxane (5 mL). The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum to afford methyl 3-((S)-2-(3-chloro-4-((R)-l- (pyridin-2-yl)ethoxy)pyrazolo [ 1 ,5-a]pyridin-6-yl)-3 -methyl-4,5 ,6,7-tetrahydropyrazolo [ 1 ,5 - a]pyrazin-6-yl)propanoate (70 mg, crude) as a white solid. LCMS(ESLMS) m / z = 495.2 [M+H]+.

[0405] Into a 50 mL round-bottom flask were added methyl 3-((S)-2-(3-chloro-4-((R)-l-(pyridin-2- yl)ethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-6- yl)propanoate (70 mg, 0.141 mmol, 1.00 equiv), DIEA (91.39 mg, 0.705 mmol, 5.00 equiv) and DCM (4 mL). BrCN (15.0 mg, 0.141 mmol, 1.00 equiv) dissolved in DCM (1 mL) was added to the above mixture. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction was quenched with water (20 mL). The resulting mixture was extracted with DCM (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (PE / EA = 1 / 2) to afford methyl 3-((S)-2-(3-chloro-4-((R)-l-(pyridin- 2-yl)ethoxy)pyrazolo[l,5-a]pyridin-6-yl)-5-cyano-3-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-6-yl)propanoate (50 mg, 68% yield) as a light brown oil. LCMS(ESI-MS) m / z = 520.2 [M+H]+.

[0406] Into a 50 mL round-bottom flask were added methyl 3-((S)-2-(3-chloro-4-((R)-l-(pyridin-2- yl)ethoxy)pyrazolo[l,5-a]pyridin-6-yl)-5-cyano-3-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin- 6-yl)propanoate (50 mg, 0.096 mmol, 1.00 equiv), NaOH (7.69 mg, 0.192 mmol, 2.00 equiv), EtOH (5 mL) and H2O (5 mL). The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched with water (10 mL). The resulting mixture was extracted with EA (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by Prep-HPLC with the following conditions: Column: Xbridge Prep OBD C18 Column, 30* 150 mm, 5pm; Mobile Phase A: Water(10mmol / L NH4CO3H), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 21% B to 42 % B in 10 min; Wave Length: 254nm / 220nm to afford 3-((S)-2-(3-chloro-4-((R)-l-(pyridin-2- yl)ethoxy)pyrazolo[l,5-a]pyridin-6-yl)-5-cyano-3-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin- 6-yl)propanoic acid (4.3 mg, 8.6% yield) as an off-white solid. 1H NMR (400 MHz, Chlorofonn-c / ) <5 8.61 (d, 1H), 8.26 (s, 1H), 7.85 (s, 1H), 7.77 (t, 1H), 7.68 (d, 1H), 6.76 (s, 1H), 5.72 (q, 1H), 4.48 (d, 1H), 4.40-4.28 (m, 2H), 4.06 (dd, 1H), 3.76-3.67 (s, 1H), 2.67 (s, 2H), 2.24 - 2.06 (m, 3H), 1.97 (s, 3H), 1.81 (d, 3H). LCMS(ESI-MS) m / z = 506.2 [M+H]+.Example 242-(3-chloro-4-((R)-l-(pyridin-2-yl)ethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6-(pyri din-2- ylmethyl)-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carbonitrile, Isomer 1Example 252-(3-chloro-4-((R)-l-(pyridin-2-yl)ethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6-(pyri din-2- ylmethyl)-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carbonitrile, Isomer 2

[0407] A 100 mL round-botom flask was charged with 2-amino-3-(pyridin-2-yl)propan-l-ol (1.00 g, 6.57 mmol, 1.00 equiv), BOC2O (4.30 g, 19.7 mmol, 3.00 equiv), TEA (1.99 g, 19.7 mmol, 3.00 equiv) and DCM (30 mL). The resulting mixture was stirred at room temperature for 3h. The reaction was quenched by the addition of water (100 mL) at room temperature. The resulting mixture was extracted with DCM (3 x 100 mL). The combined organic layers were washed with water (3 x 50 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (PE / EA = 1 / 5) to afford tertbutyl (1 -hydroxy-3 -(pyridin -2 -yl)propan -2 -yl)carbamate (0.82 g, 49% yield) as a yellow oil. LCMS(ESI-MS) m / z = 253.2 [M+H]+.

[0408] A 500 mL round-botom flask was charged with PPh; (1.70 g, 6.50 mmol, 2.00 equiv) and THF (50 mL). DIAD (1.31 g, 6.50 mmol, 2.00 equiv) was added dropwise at 0°C under nitrogen atmosphere. The reaction was stirred at 0°C for 0.5 h. To the mixture is added tert -butyl (l-hydroxy-3-(pyridin-2- yl)propan-2-yl)carbamate (0.82 g, 3.25 mmol, 1.00 equiv) and ethyl 3-bromo-4-methyl-lH-pyrazole-5-carboxylate (0.76 g, 3.25 mmol, 1.00 equiv) in THF (50 mL). The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction was quenched by the addition of water (100 mL) at room temperature. The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with water (3 x 50 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (PE / EA =1 / 3) to afford ethyl 3-bromo-l-(2-((tert- butoxycarbonyl)amino)-3-(pyridin-2-yl)propyl)-4-methyl-lH-pyrazole-5-carboxylate (1.6 g, crude) as a yellow solid. LCMS(ESI-MS) m / z = 467.1 [M+H]+.

[0409] A 100 mL round-bottom flask was charged with ethyl 3-bromo-l-(2-((tert-butoxycarbonyl)amino)- 3 -(pyridin-2-yl)propyl)-4-methyl-lH-pyrazole-5 -carboxylate (0.8 g, 1.71 mmol, 1.00 equiv) and HC1 (4M in 1,4-dioxane, 15 mL). The resulting mixture was stirred at room temperature for 2h. To the mixture is added NaHCOs (100 mg, 1.19 mmol, 0.55 equiv) in H2O (1 mL). The resulting mixture was stirred overnight at room temperature. The reaction was quenched by the addition of water (150 mL) at room temperature. The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with water (3 x 50 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (EA / MeOH = 10 / 1) to afford 2-bromo-3-methyl-6-(pyridin-2- ylmethyl)-6,7-dihydropyrazolo[l,5-a]pyrazin-4(5H)-one (0.19 g, 27% yield) as a white solid. LCMS(ESI-MS) m / z = 321.0 [M+H]+.

[0410] A 100 mL round-bottom flask was charged with 2-bromo-3-methyl-6-(pyridin-2-ylmethyl)-6,7- dihydropyrazolo[l,5-a]pyrazin-4(5H)-one (330 mg, 1.03 mmol, 1.00 equiv) and BH3.THF (4.12 mL, 1.3M in THF). The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (6 mL). The resulting mixture was stirred overnight at 60°C. The reaction was quenched by the addition of water (150 mL) at room temperature. The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with water (3 x 50 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford 2-bromo- 3-methyl-6-(pyridin-2-ylmethyl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine (300 mg, crude) as a yellow oil. LCMS(ESI-MS) m / z = 307.1 [M+H]+.

[0411] A 100 mL round-bottom flask was charged with 2-bromo-3-methyl-6-(pyridin-2-ylmethyl)- 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine (400 mg, 1.30 mmol, 1.00 equiv), triethylamine (395 mg, 3.91 mmol, 3.00 equiv), di -tert-butyl dicarbonate (853 mg, 3.91 mmol, 3.00 equiv) and DCM (20 mL). The resulting mixture was stirred at room temperature for 2h. The reaction was quenched by the addition of water (150 mL) at room temperature. The resulting mixture was extracted with DCM (3 x 100 mL). The combined organic layers were washed with water (3 x 30 mL), dried over anhydroussodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (PE / EA = 3 / 7) to afford tert-butyl 2- bromo-3-methyl-6-(pyridin-2-ylmethyl)-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate (215 mg, 41% yield) as a white solid. LCMS(ESI-MS) m / z = 407.1 [M+H]+.

[0412] A 40 mL vial was charged with tert-butyl 2-bromo-3-methyl-6-(pyridin-2-ylmethyl)-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4EI)-carboxylate (215 mg, 0.528 mmol, 1.00 equiv), (R)-3-chloro- 4-(l-(pyridin-2-yl)ethoxy)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridine (633 mg, 1.58 mmol, 3.00 equiv), Pd(PPhg)4 (30.5 mg, 0.026 mmol, 0.05 equiv), 1,4-dioxane (12 mL), H2O (3 mL) and K2CO3 (146 mg, 1.06 mmol, 2.00 equiv). The resulting mixture was stirred at 100°C for 2h under nitrogen atmosphere. The reaction was quenched by the addition of water (150 mL) at room temperature. The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with water (3 x 30 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (EA / MeOH = 10 / 1) to afford crude product. The crude product was purified by Prep -Chiral -HPLC with the following conditions: Column: CHIRALPAK IG, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.1% FA)--HPLC, Mobile Phase B: EtOH: DCM=1: 1— HPLC; Flow rate: 20ML / MIN mL / min; Gradient: isocratic 40; Wave Length: 254 / 220nm to afford tert -butyl 2-(3-chloro- 4-((R)-l-(pyridin-2-yl)ethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6-(pyridin-2-ylmethyl)-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate, isomer 1 (the first elution, 120 mg, 38% yield) as a light yellow solid. LCMS(ESI-MS) m / z = 600.2 [M+H]+. And isomer 2 (the second elution, 120 mg, 38% yield) as a light yellow solid. LCMS(ESI-MS) m / z = 600.2 [M+H]+.

[0413] A 100 mL round-bottom flask was charged with tert-butyl 2-(3-chloro-4-((R)-l-(pyridm-2- yl)ethoxy)pyrazolo[l,5-a]pyndin-6-yl)-3-methyl-6-(pyridin-2-ylmethyl)-6,7-dihydropyrazolo[l,5- a]pyrazine-5(4H)-carboxylate, isomer 1 (120 mg, 0.200 mmol, 1.00 equiv) and HC1 (4M in 1,4- dioxane, 15 mL). The resulting mixture was stirred at room temperature for 2h. The resulting mixture was concentrated under reduced pressure to afford 2-(3-chloro-4-((R)-l-(pyridin-2- yl)ethoxy)pyrazolo[ l,5-a]pyridin-6-yl)-3-methyl-6-(pyri din-2 -ylmethyl)-4, 5,6,7- tetrahydropyrazolo[l,5-a]pyrazine, isomer 1 (120 mg, crude) as a white solid. LCMS(ESI-MS) m / z = 500.2 [M+H]+.

[0414] A 100 mL round-bottom flask was charged with 2-(3-chloro-4-((R)-l-(pyridin-2- yl)ethoxy)pyrazolo[ l,5-a]pyridin-6-yl)-3-methyl-6-(pyri din-2 -ylmethyl)-4, 5,6,7- tetrahydropyrazolo[l,5-a]pyrazine, isomer 1 (100 mg, 0.200 mmol, 1.00 equiv), DCM (20 mL) and DIEA (51.7 mg, 0.400 mmol, 2.00 equiv). The BrCN (21.2 mg, 0.200 mmol, 1.00 equiv) in DCM (1 mL) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 2h. The reaction was quenched by the addition of water (100 mL) at room temperature. The resultingmixture was extracted with DCM (3 x 100 mL). The combined organic layers were washed with water (3 x 50 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30* 150 mm, 5pm; Mobile Phase A: Water) lOmmol / L NH4CO3H), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 33% B to 63% B in lOmin; Wave Length 254nm / 220nm to afford 2-(3-chloro-4-((R)-l-(pyridin-2-yl)ethoxy)pyrazolo[l,5- a]pyridin-6-yl)-3-methyl-6-(pyridin-2-ylmethyl)-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)- carbonitrile, isomer 1 (37.9 mg, 36% yield) as a white solid. 1H NMR (400 MHz, Chloroform-c / ) <5 8.60 (dt, 2H), 8.24 (d, 1H), 7.84 (s, 1H), 7.73 (tt, 2H), 7.64 (d, 1H), 7.32 (d, 1H), 7.27 - 7.19 (m, 2H), 6.75 (d, 1H), 5.67 (q, 1H), 4.54 (d, 1H), 4.42 (d, 1H), 4.35 - 4.22 (m, 2H), 4.13 (dd, 1H), 3.41 (dd, 1H), 3.20 (dd, 1H), 1.99 (s, 3H), 1.81 (d, 3H). LCMS(ESI-MS) m / z = 525.2 [M+H]+.

[0415] Isomer 2 was synthesized using the same procedure, starting with tert-butyl 2-(3-chloro-4-((R)-l- (pyridin-2-yl)ethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6-(pyridin-2-ylmethyl)-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate, isomer 2 the same procedure as used as described above. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30* 150 mm, 5pm; Mobile Phase A: Water) lOmmol / L NH4CO3H), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 33% B to 63% B in lOmin; Wave Length: 254nm / 220nm to afford 2-(3-chloro-4-((R)-l-(pyridin-2-yl)ethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3- methyl-6-(pyridin-2-ylmethyl)-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carbonitrile, isomer 2 (38.2 mg, 36% yield) as a white solid. 1H NMR (400 MHz, Chloroform-fi) 8.60 (ddd, 2H), 8.24 (d, 1H), 7.84 (s, 1H), 7.73 (tt, 2H), 7.64 (d, 1H), 7.32 (d, 1H), 7.27 (dd, 1H), 7.22 (dd, 2H), 6.75 (d, 1H), 5.67 (q, 1H), 4.54 (d, 1H), 4.42 (d, 1H), 4.35 - 4.22 (m, 2H), 4.13 (dd, 1H), 3.41 (dd, 1H), 3.20 (dd, 1H), 1.99 (s, 3H), 1.81 (d, 3H). LCMS(ESI-MS) m / z = 525.2 [M+H]+.Example 26N-(3'-chloro-4'-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-methyl-4,5,6,7-tetrahydro-[2,6'- bipyrazolo[l,5-a]pyridin]-5-yl)cyanamide, Isomer 1Example 27N-(3'-chloro-4'-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-methyl-4,5,6,7-tetrahydro-[2,6'- bipyrazolo[l,5-a]pyridin]-5-yl)cyanamide, Isomer 2Example 28N-(3'-chloro-4'-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-methyl-4,5,6,7-tetrahydro-[2,6'- bipyrazolo[l,5-a]pyridin]-5-yl)cyanamide, Isomer 3Example 29N-(3'-chloro-4'-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-methyl-4,5,6,7-tetrahydro-[2,6'- bipyrazolo[l,5-a]pyridin]-5-yl)cyanamide, Isomer 4

[0416] A 100 mL round bottom flask was charged with 4,5,6,7-tetrahydropyrazolo[l,5-a]pyridin-5-amine (3.5 g, 25.5 mmol, 1.00 equiv), BoczO (11.1 g, 51.0 mmol, 2.00 equiv), DIEA (9.89 g, 76.5 mmol, 3.00 equiv) and DCM (20 mL). The resulting solution was stirred for 2 h at room temperature. The reaction was quenched by water (100 mL). The mixture was extracted with EA (3 x 100 mL). The organic layers were combined, washed with water (3 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (MeOH / DCM = 1 I 25) to afford tert-butyl (4,5,6,7-tetrahydropyrazolo[l,5-a]pyridin-5- yl)carbamate (5.8 g, 96% yield) as a white solid. LCMS (ESI-MS) m / z = 238.2[M+H]+.

[0417] A 40 mL vial were added tert-butyl (4,5,6,7-tetrahydropyrazolo[l,5-a]pyridin-5-yl)carbamate (1.6 g, 6.74 mmol, 1.00 equiv), NBS (1.20 g, 6.74 mmol, 1.00 equiv) and DMF (10 mL). The resulting solution was stirred for 2 h at room temperature. The reaction was quenched by water (100 mL). The mixture was extracted with EA (3 x 100 mL). The organic layers were combined, washed with water (3 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (MeOH / DCM = 1 / 25) to afford tert-butyl (3-bromo-4,5,6,7-tetrahydropyrazolo[l,5-a]pyridin-5-yl)carbamate (2 g, 94% yield) as a white solid. LCMS (ESI-MS) m / z = 316.1[M+H]+.

[0418] A lOOmL round botom flask was charged with tert-butyl N-{3-bromo-4H,5H,6H,7H- pyrazolo [1, 5 -a]pyridin-5-yl} carbamate tert-butyl (3-bromo-4,5,6,7-tetrahydropyrazolo[l,5-a]pyridin- 5-yl)carbamate (2 g, 6.33 mmol, 1.00 equiv), trimethyl-l,3,5,2,4,6-trioxatriborinane (7.94 g, 31.6 mmol, 5.00 equiv, 50%), Pd(dppf)C12 (231 mg, 0.316 mmol, 0.05 equiv), K2CO3 (1.75 g, 12.6 mmol, 2.00 equiv) and 1,4-dioxane (50 mL). The resulting solution was stirred for 36 h at 100°C. The reaction was quenched by water (100 mL). The mixture was extracted with EA (3 x 100 mL). The organic layers were combined, washed with water (3 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (PE / EA = 1 / 25) to afford tert-butyl (3-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyridin- 5-yl)carbamate (850 mg, 53% yield) as a white solid. LCMS (ESI-MS) m / z = 252.2[M+H]+.

[0419] A 8 mL vial were added tert-butyl (3-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyridin-5- yl)carbamate (450 mg, 1.79 mmol, 1.00 equiv), NBS (255 mg, 1.43 mmol, 0.80 equiv), SiO2 (215 mg, 3.58 mmol, 2.00 equiv) and ACN (10 mL). The resulting solution was stirred for 2 h at room temperature. The reaction was quenched by water (100 mL). The mixture was extracted with EA (3 x 100 mL). The organic layers were combined, washed with water (3 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (EA / MeOH = 1 / 25) to afford tert -butyl (2-bromo-3-methyl- 4,5,6,7-tetrahydropyrazolo[l,5-a]pyridin-5-yl)carbamate (350 mg, 59% yield) as a white solid. LCMS (ESI-MS) m / z = 330.1[M+H]+.

[0420] A 40 mL vial were added tert-butyl (2-bromo-3-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyndin- 5-yl)carbamate (410 mg, 1.24 mmol, 1.00 equiv), 2-((3-chloro-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrazolo [ 1 ,5 -a]pyridin-4-yl)oxy)- 1 -(5-fluoropyndin-2-yl)ethan- 1 -ol (1067 mg, 2.48 mmol, 2.00 equiv), Pd(PPhs)4 (71.7 mg, 0.062 mmol, 0.05 equiv), K2CO3 (343 mg, 2.48 mmol, 2.00 equiv), 1,4-dioxane (10 mL) and H2O (2 mL). The resulting solution was stirred overnight at 100°C under nitrogen atmosphere. The reaction was quenched by water (100 mL). The mixture was extracted with EA (3 x 100 mL). The organic layers were combined, washed with water (3 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (PE / EA = 1 / 5) to afford tert-butyl (3'- chloro-4,-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-methyl-4,5,6,7-tetrahydro-[2,6'- bipyrazolo[l,5-a]pyridin]-5-yl)carbamate (150 mg, 22% yield) as a white solid. LCMS (ESI-MS) m / z = 557.2[M+H]+.

[0421] A 100 mL round botom flask was charged with tert-butyl (3'-chloro-4'-(2-(5-fluoropyridin-2-yl)- 2-hydroxyethoxy)-3-methyl-4,5,6,7-tetrahydro-[2,6'-bipyrazolo[l,5-a]pyridin]-5-yl)carbamate (148 mg, 0.266 mmol, 1.00 equiv), 1,4-dioxane (1 mL) and HC1 (4M in 1,4-dioxane, 3 mL). The resulting solution was stirred for 2 h at room temperature and concentrated under reduced pressure to provide 22-((5-amino-3'-chloro-3-methyl-4,5,6,7-tetrahydro-[2,6'-bipyrazolo[l,5-a]pyridin]-4'-yl)oxy)-l-(5- fluoropyridin-2-yl)ethan-l-ol (148 mg, crude) as a white solid. LCMS (ESI-MS) m / z = 457.2[M+H]+.

[0422] A 40 mL vial were added 2-((5-amino-3'-chloro-3-methyl-4,5,6,7-tetrahydro-[2,6'-bipyrazolo[l,5- a]pyridin]-4'-yl)oxy)-l-(5-fluoropyridin-2-yl)ethan-l-ol (148 mg, 0.324 mmol, 1.00 equiv), K2CO3 (448 mg, 3.24 mmol, 10.00 equiv), BrCN (34.3 mg, 0.324 mmol, 1.00 equiv) and DMF (5 mL). The resulting solution was stirred for 2 h at room temperature. The reaction was quenched by water (100 mL). The mixture was extracted with EA (3 x 100 mL). The organic layers were combined, washed with water (3 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (EA / MeOH = 20 / 1) to afford crude product. The crude product was separated by Prep-Chiral-HPLC with the following conditions!: Column: CHIRALPAKAD3; Mobile Phase A: Hex(0.2%FA): EtOH=60: 40; Flow rate: ImL / min mL / min; Gradient: isocratic; Injection Volume: 2p mL to afford the mixture 1 and mixture 2 of N-(3'-chloro-4'-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-methyl-4,5,6,7-tetrahydro- [2,6'-bipyrazolo [ 1 ,5 -a]pyridin] -5-yl)cyanamide .

[0423] Mixture 1 was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAKIE3; Mobile Phase A: Hex(0.2%FA): (MeOH: DCM=1: 1) = 55: 45; Flow rate: ImL / min mL / min; Gradient: isocratic; Injection Volume: 3 pl mL to afford isomer 1 (the first elution of mixture 1, 6.9 mg, 4.3% yield) as a white solid. 1H NMR (400 MHz, Methanol-r / 4) 3 8.45 (d, 1H), 8.28 (s, 1H), 7.82 (s, 1H), 7.80 (dd, 2H), 7.66 (td, 1H), 6.97 (s, 1H), 5.24 (dd, 1H), 4.55 (dd, 1H), 4.46 (dd, 1H),4.30 (dt, 1H), 4.20 (ddd, 1H), 3.83-3.77 (m, 1H), 3.13 (dd, 1H), 2.78 (dd, 1H), 2.41-2.32 (m, 1H), 2.25- 2.16 (m, 4H). LCMS (ESI-MS) m / z = 482.1 [M+H]+.

[0424] Isomer 2 (the second elution of mixture 1, 6.1 mg, 3.8% yield) as a white solid. 1H NMR (400 MHz, Methanol-r / 4) 38.45 (d, 1H), 8.28 (s, 1H), 7.82 (s, 1H), 7.80 (dd, 2H), 7.66 (td, 1H), 6.97 (s, 1H), 5.24 (dd, 1H), 4.55 (dd, 1H), 4.46 (dd, 1H), 4.30 (dt, 1H), 4.20 (ddd, 1H), 3.84-3.77 (m, 1H), 3.13 (dd, 1H), 2.78 (dd, 1H), 2.41-2.32 (m, 1H), 2.25-2.16 (m, 4H). LCMS (ESI-MS) m / z = 482.2 [M+H]+.

[0425] Mixture 2 was separated by Prep-Chiral-HPLC with the following conditions: Column: LuxCellulose4; Mobile Phase A: Hex(0.2%FA): EtOH=50: 50; Flow rate: ImL / min mL / min; Gradient: isocratic; Injection Volume: luL mL; Wave Length: 254nm / 220nm to afford isomer 3 (the first elution of mixture 2, 4.5 mg, 2.9% yield) as a white solid. 1H NMR (400 MHz, Methanol-r / 4) 3 8.45 (d, 1H),8.30 (s, 1H), 7.83 (s, 1H), 7.80 (dd, 2H), 7.66 (td, 1H), 6.98 (s, 1H), 5.24 (dd, 1H), 4.55 (dd, 1H), 4.46 (dd, 1H), 4.30 (dt, 1H), 4.20 (ddd, 1H), 3.85-3.77 (m, 1H), 3.14 (dd, 1H), 2.80 (dd, 1H), 2.41-2.32 (m, 1H), 2.25-2.16 (m, 4H). LCMS (ESI-MS) m / z = 482.1 [M+H]+.

[0426] Isomer 4 (the second elution of mixture 2, 5.5 mg, 3.4% yield) as a white solid. 1H NMR (400 MHz, Methanol 4) 38.45 (d, 1H), 8.27 (s, 1H), 7.82 (s, 1H), 7.80 (dd, 2H), 7.66 (td, 1H), 6.98 (s, 1H),5.24 (dd, 1H), 4.55 (dd, 1H), 4.46 (dd, 1H), 4.30 (dt, 1H), 4.20 (ddd, 1H), 3.83-3.77 (m, 1H), 3.14 (dd, 1H), 2.80 (dd, 1H), 2.40-2.33 (m, 1H), 2.25-2.15 (m, 4H). LCMS (ESI-MS) m / z = 482.2 [M+H]+.Example 30(R)-2-(3-chloro-4-(l-(pyridin-2-yl)ethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-hydroxy-6,7- dihydr opyrazolo [1 ,5-a] pyrazine-5(4H)-carbonitrile

[0427] A 40 mL vial were added tert-butyl 3-bromo-4H,6H,7H-pyrazolo[l,5-a]pyrazine-5-carboxytert- butyl 3-bromo-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate (1 g, 3.31 mmol, 1.00 equiv), bis(pinacolato)diboron (1.68 g, 6.62 mmol, 2.00 equiv), Pd(dppf)C12 (121 mg, 0.165 mmol, 0.05 equiv), AcOK (650 mg, 6.62 mmol, 2.00 equiv) and 1,4-dioxane (5 mL). The resulting solution was stirred overnight at 80°C and concentrated under reduced pressure to afford tert-butyl 3-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate (1 g, crude) as a colorless solid. LCMS (ESI-MS) m / z = 350.2[M+H]+.

[0428] A 100 mL round bottom flask was charged with tert-butyl 3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate (1 g, 2.86 mmol, 1.00 equiv), sodium perborate (0.70 g, 8.59 mmol, 3.00 equiv), THF (lOmL) and H2O (3 mL) . The resulting solution was stirred for 5 h at room temperature. The reaction was quenched by water (100 mL). The mixture was extracted with EA (3 x 100 mL). The organic layers were combined, washed with water (3 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in H2O, 55% gradient, UV 254 nm to afford tert-butyl 3- hydroxy-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate (400 mg, 53% yield) as a white solid. LCMS (ESI-MS) m / z = 240.1[M+H]+.

[0429] A 100 mL round botom flask was charged with tert-butyl 3 -hydroxy-6, 7-dihydropyrazolo[ 1,5- a]pyrazine-5(4H)-carboxylate (200 mg, 0.836 mmol, 1.00 equiv), bis(pinacolato)diboron (425 mg, 1.67 mmol, 2.00 equiv), dtbpy (22.4 mg, 0.084 mmol, 0.10 equiv), bis((lZ,5Z)-cycloocta-l,5-diene); bis(chloroiridium) (28.1 mg, 0.042 mmol, 0.05 equiv) and 1,4-dioxane (3 mL). The resulting solution was stirred overnight at 100°C and concentrated under reduced pressure to provide tert-butyl 3- hydroxy-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)- carboxylate (300 mg, crude) as a colorless solid. LCMS (ESI-MS) m / z = 366.2[M+H]+.

[0430] A 40 mL vial were added tert-butyl 3-hydroxy-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate (300 mg, 0.821 mmol, 1.00 equiv), (R)-6- bromo-3-chloro-4-(l-(pyridin-2-yl)ethoxy)pyrazolo[l,5-a]pyridine [which can be made according to the procedures described in WO2022187443] (145 mg, 0.410 mmol, 0.50 equiv), Pd(PPhg)4 (47.5 mg, 0.041 mmol, 0.05 equiv), K2CO3 (227 mg, 1.64 mmol, 2.00 equiv), 1,4-dioxane (5 mL) and I FO (ImL). The resulting solution was stirred overnight at 100°C. The reaction was quenched by water (100 mL). The mixture was extracted with EA (3 x 100 mL). The organic layers were combined, washed with water (3 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (PE / EA = 1 / 10) to afford tert-butyl (R)-2-(3-chloro-4-( 1 -(pyridin-2-yl)ethoxy)pyrazolo [1,5 -a]pyridin-6-yl)-3 -hydroxy- 6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate (100 mg, 21% yield) as a white solid. LCMS (ESI-MS) m / z = 511 ,2[M+H]+.

[0431] A 100 mL round botom flask was charged with tert-butyl (R)-2-(3-chloro-4-(l-(pyridin-2- yl)ethoxy)pyrazolo[l,5-a]pyndin-6-yl)-3-hydroxy-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)- carboxylate (170 mg, 0.333 mmol, 1.00 equiv), 1,4-dioxane (3 mL) and HC1 (4M in 1,4-dioxane, 3 mL). The resulting solution was stirred for 2 h at room temperature and concentrated under reduced pressure to provide (R)-2-(3-chloro-4-(l-(pyridin-2-yl)ethoxy)pyrazolo[l,5-a]pyridin-6-yl)-4,5,6,7- tetrahydropyrazolo[l,5-a]pyrazin-3-ol (170 mg, crude) as a white solid. LCMS (ESI-MS) m / z =411.1[M+H]+.

[0432] A 100 mL round botom flask was charged with (R)-2-(3-chloro-4-(l-(pyridin-2- yl)ethoxy)pyrazolo[l,5-a]pyridin-6-yl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-3-ol (170 mg, 0.414 mmol, 1.00 equiv), DIEA (80.2 mg, 0.621 mmol, 1.50 equiv) and DCM (4 mL). BrCN (43.8 mg, 0.414 mmol, 1.00 equiv) in DCM (1 mL) was added dropwise. The resulting solution was stirred for 2 h at room temperature. The reaction was quenched by water (100 mL). The mixture was extracted with EA (3 x 100 mL). The organic layers were combined, washed with water (3 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column: Xbridge Prep OBD C18 Column, 30* 150 mm, 5pm; Mobile Phase A: Water (lOmmol / L NH4CO3H), Mobile Phase B: ACN; Flow rate:60 mL / min mL / min; Gradient: 29% B to54 % B in 10 min; Wave Length: 254 nm / 220 nm to (R)-2-(3- chloro-4-( 1 -(pyridin-2-yl)ethoxy)pyrazolo [ 1 ,5 -a]pyridin-6-yl)-3 -hydroxy-6, 7-dihydropyrazolo[ 1 ,5 - a]pyrazine-5(4H)-carbonitrile (9.8 mg, 5.4% yield) as an off white solid. 1HNMR(4OO MHz, DMSO- d6) 3 9.02 (s, 1H), 8.69 (s, 1H), 8.61 - 8.56 (d, 1H), 8.08 (s, 1H), 7.83 (td, 1H), 7.54 (d, 1H), 7.35 - 7.30 (ddd, 1H), 7.02 (s, 1H), 5.68 (q, 1H), 4.48 (s, 2H), 4.16-4.10 (m, 2H), 3.72 (t, 2H), 1.70 (d, 3H). LCMS (ESI-MS) m / z = 436.1 [M+H]+.Example 312-(3-chloro-4-methoxypyrazolo[l,5-a] pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carbonitrile

[0433] Into a 100 mL round-bottom flask were added 6-bromo-3-chloro-4-methoxypyrazolo[l,5- a]pyridine (4 g, 15.3 mmol, 1.00 equiv), bis(pinacolato)diboron (5.83 g, 22.9 mmol, 1.50 equiv), Pd(dppf)C12 (560 mg, 0.765 mmol, 0.05 equiv), AcOK (3.00 g, 30.6 mmol, 2.00 equiv) and 1,4-dioxane (80 mL). The resulting mixture was stirred overnight at 80 °C under nitrogen atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford 3-chloro-4-methoxy-6-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridine (5 g, crude) as a black solid. LCMS(ESI-MS) m / z = 309.1 [M+H]+.

[0434] Into a 40 mL round-bottom flask were added 3-chloro-4-methoxy-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrazolo[l,5-a]pyridine (351 mg, 1.14 mmol, 2.00 equiv), tert-butyl 2-bromo-3- methyl-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate (180 mg, 0.569 mmol, 1.00 equiv), Pd(PPli3)4 (32.9 mg, 0.028 mmol, 0.05 equiv), K2CO3 (157 mg, 1.14 mmol, 2.00 equiv), H2O (2 mL) and 1,4-dioxane (10 mL). The resulting mixture was stirred overnight at 100 °C under nitrogen atmosphere. The reaction was quenched with water (10 mL) at room temperature. The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were dried over anhydrous sodiumsulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (PE / EA = 1 / 2) to afford tert-butyl 2-(3-chloro-4- methoxypyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)- carboxylate (232 mg, 78.02% yield) as a light brown solid. LCMS(ESI-MS) m / z = 418.2 [M+H]+.

[0435] Into a 100 mL round-bottom flask were added tert-butyl 2-(3-chloro-4-methoxypyrazolo[l,5- a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4EI)-carboxylate (100 mg, 0.239 mmol, 1.00 equiv), HC1 (4.0 M in 1,4-dioxane, 10 mL) and 1,4-dioxane (10 mL). The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 2-(3-chloro-4-methoxypyrazolo[l,5-a]pyridin-6-yl)-3-methyl-4,5,6,7- tetrahydropyrazolo[l,5-a]pyrazine (60 mg, crude) as a white solid. LCMS(ESI-MS) m / z = 318.1 [M+H]+.

[0436] Into a 100 mL round-bottom flask were added 2-(3-chloro-4-methoxypyrazolo[l,5-a]pyridin-6-yl)- 3-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine (70 mg, 0.220 mmol, 1.00 equiv), DIEA (0.19mL, 1.10 mmol, 5.00 equiv) and DCM (5 mL). Then BrCN (23.3 mg, 0.220 mmol, 1.00 equiv) dissolved in DCM (1 mL) was added to the above mixture. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was quenched with water (15 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep Shield RP18 OBD C18 Column, 30* 150 mm, 5pm; Mobile Phase A: Watcri lOnmol / LNHA’CLH). Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 28% B to58 % B in 10 min; Wave Length: 254nm / 220nm to afford 2-(3-chloro-4- methoxypyrazolo[ 1 ,5 -a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[ 1 ,5 -a]pyrazine-5(4H)- carbonitrile (17.5 mg, 23% yield) as a white solid. 1H NMR (400 MHz, Chloroform-^ / ) d 8.26 (s, 1H), 7.82 (s, 1H), 6.87 (s, 1H), 4.51 (s, 2H), 4.37 (t, 2H), 4.04 (s, 3H), 3.76 (t, 2H), 2.18 (s, 3H). LCMS(ESI- MS) m / z = 343.1 [M+H]+.Example 322-(3-chloro-4-(pyridin-2-ylmethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[l,5- a] pyrazine-5(4H)-carbonitrile

[0437] Into a 500 mL round-bottom flask were added tert- tert-butyl 2-(3-chloro-4-methoxypyrazolo[l,5- a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate (6.30 g, 15.1 mmol, 1.00 equiv), N,N-dimethylacetamide (200 mL), NaOH (1.81 g, 45.2 mmol, 3.00 equiv), dodecane-1- thiol (9.15 g, 45.2 mmol, 3.00 equiv) and water (1.8 mL). The resulting mixture was stirred at 50°C for overnight. The reaction was quenched with water. The mixture was acidified to pH 4 with formic acid. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with water (5x100 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 3) to afford tert-butyl 2-(3-chloro-4-hydroxypyrazolo[l,5-a]pyridin-6-yl)-3- methyl-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate (4.5 g, 74 %yield) as a white solid. LCMS(ESI-MS) m / z =404.1 [M+H]+.

[0438] To a stirred mixture of tert-butyl 2-(3-chloro-4-hydroxypyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate (100 mg, 0.248 mmol, 1.00 equiv) and 2- pyridinemethanol (27.0 mg, 0.248 mmol, 1.00 equiv) in toluene (10 mL) was added (tributylphosphoranylidene)acetonitrile (179 mg, 0.744 mmol, 3.00 equiv). The resulting mixture was stirred at 100°C for 2 hours under nitrogen atmosphere. The reaction was quenched with water (100 mL) The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with saturated salt solution (3 x 100 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (PE / EA = 1 / 5) to afford tert-butyl 2-(3-chloro-4-(pyridin-2- ylmethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)- carboxylate (80 mg, 52% yield) as a light yellow solid. LCMS(ESI-MS) m / z = 495.2 [M+H]+.

[0439] A mixture of tert-butyl 2-(3-chloro-4-(pyridin-2-ylmethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3- methyl-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate (80 mg, 0.162 mmol, 1.00 equiv) and HC1 (4 M in 1,4-dioxane, 2 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum to afford 2-(3-chloro-4-(pyridin-2-ylmethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine (65 mg, crude) as a white solid. LCMS (ESIMS) m / z = 395.1 [M+H]+.

[0440] To a stirred mixture of 2-(3-chloro-4-(pyridin-2-ylmethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3- methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine (65 mg, 0.165 mmol, 1.00 equiv) and DIEA (64 mg, 0.495 mmol, 3.00 equiv) in DCM (10 mL) was added BrCN (26 mg, 0.247 mmol, 1.50 equiv) dropwise. The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (100 mL). The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with saturated salt solution (3 x 100 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (PE / EA = 1 / 5) to afford a crude product. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep Shield RP18 OBD C18 Column, 30* 150 mm, 5pm; Mobile Phase A: Watcr( lOnmol / LNI LCO’J I). Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 30% B to 60 % B in 10 min; Wave Length: 254nm / 220nm to afford 2-(3-chloro-4-(pyridin-2-ylmethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carbonitrile (27.7 mg, 40% yield) as a white solid. 1H NMR (400 MHz, Chloroform -d) S 8.63 (d, 1H), 8.32 (d, 1H), 7.90 - 7.78 (m, 3H), 7.28 - 7.26 (m, 1H), 7.02 (d, 1H), 5.42 (s, 2H), 4.51 (s, 2H), 4.37 (dd, 2H), 3.75 (dd, 2H), 2.14 (s, 3H). LCMS(ESI-MS) m / z = 420.1 [M+H]+.Example 33(R)-2-(3-chloro-4-(l-(pyridin-3-yl)ethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7- dihydr opyrazolo [1 ,5-a] pyrazine-5(4H)-carbonitrile

[0441] Starting from tert-butyl 2-(3-chloro-4-hydroxypyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate and (S)-l-(pyridin-3-yl)ethan-l-ol, exemple 33 was synthesized following the same procedure as used for example 32.

[0442] The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep Shield RP 18 OBD C18 Column, 30* 150 mm, 5pm; Mobile Phase A: Water Onmol / LTMLCOsH), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 29% B to 59 % B in lO min; Wave Length: 254nm / 220nm to afford (R)-2-(3-chloro-4-(l-(pyridin-3-yl)ethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carbonitrile (26 mg, 38% yield) as a white solid.1H NMR (400 MHz, Chlorofon ) d 8.75 (s, 1H), 8.57 (s, 1H), 8.23 (d, 1H), 7.90 (dt, 1H), 7.84 (s, 1H), 7.35 (dd, 1H), 6.74 (d, 1H), 5.65 (q, 1H), 4.47 (s, 2H), 4.34 (dd, 2H), 3.74 (dd, 2H), 2.03 (s, 3H), 1.80 (d, 3H). LCMS(ESI-MS) m / z = 434.1 [M+H]+.Example 342-(3-chloro-4-(l-(pyridazin-3-yl)ethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carbonitrile, Isomer 1Example 352-(3-chloro-4-(l-(pyridazin-3-yl)ethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carbonitrile, Isomer 2

[0443] Into a 40 mL round-bottom flask were added PPh; (292 mg, 1.11 mmol, 1.50 equiv) and THF (20 mL) DIAD (225 mg, 1.11 mmol, 1.5 equiv) was added to the above mixture at 0 °C. The above mixture was stirred for 1 hour at 0 °C tert-butyl 2-(3-chloro-4-hydroxypyrazolo[l,5-a]pyridin-6-yl)-3-methyl- 6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate (300 mg, 0.743 mmol, 1.00 equiv) and 1- (pyridazin-3-yl)ethal-(pyridazin-3-yl)ethan-l-olnol (101 mg, 0.817 mmol, 1.10 equiv) dissolved in THF (10 mL) were added to the above mixture at 0 °C. The resulting mixture was stirred overnight at room temperature. The reaction was quenched with water (10 mL). The resulting mixture was extracted with EA (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (EA / PE = 10 / 1) to afford ttert -butyl 2-(3-chloro-4-(l- (pyridazin-3-yl)ethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[l,5-a]pyrazine- 5 (4H) -carboxylate (400 mg, crude) as a yellow solid. LCMS(ESI-MS) m / z = 510.2 [M+H]+.

[0444] Into a 100 mL round-bottom flask were added tert-butyl 2-(3-chloro-4-(l-(pyridazin-3- yl)ethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)- carboxylate (400 mg, 0.784 mmol, 1.00 equiv), HC1 (4.0 M in 1,4-dioxane, 10 mL) and 1,4-dioxane (10 mL). The resulting mixture was stirred for 2 hours at room temperature. The resulting mixture was concentrated under reduced pressure to afford 2-(3-chloro-4-(l-(pyridazin-3-yl)ethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine (200 mg, crude) as a white solid. LCMS(ESI-MS) m / z = 410.1 [M+H]+.

[0445] Into a 50 mL round-bottom flask were added 2-(3-chloro-4-(l-(pyridazin-3- yl)ethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine (200 mg, 0.488 mmol, 1.00 equiv), DIEA (0.42 mL, 2.440 mmol, 5.00 equiv) and DCM (10 mL). BrCN (56.9 mg, 0.537 mmol, 1.10 equiv) dissolved in DCM (5 mL) was added to the above mixture The resulting mixture was stirred for 2 hours at room temperature. The reaction was quenched with water (10 mL). The resulting mixture was extracted with DCM (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford a crude product. The crude product was purified by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAKIA3; Mobile Phase A: MtBE (0.1%FA): (MeOH: DCM=1: 1) = 85: 15; Flow rate: ImL / min mL / min; Gradient: isocratic; Injection Volume: Ipl mL; Wave Length: 254 / 220nm to afford 2-(3-chloro-4-(l-(pyridazin-3-yl)ethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl- 6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carbonitrile, isomer 1 (the first elution, 24.8 mg, 11.7% yield) as an off-white solid. 1H NMR (400 MHz, Chloroform - ) 3 9.16 (d, 1H), 8.25 (s, 1H), 7.93 - 7.80 (m, 2H), 7.56 (dd, 1H), 6.85 (s, 1H), 6.02 (q, 1H), 4.47 (s, 2H), 4.33 (dd, 2H), 3.73 (dd, 2H), 2.03 (s, 3H), 1.89 (d, 3H). LCMS(ESI-MS) m / z = 435.2 [M+H]+.

[0446] Isomer 2 (the second elution, 31.5 mg, 14.7% yield) as a white solid. 1H NMR (400 MHz, Chloroform -d) 3 9.16 (dd, 1H), 8.25 (d, 1H), 7.90 (dd, 1H), 7.85 (s, 1H), 7.56 (dd, 1H), 6.85 (s, 1H), 6.02 (q, 1H), 4.47 (s, 2H), 4.33 (dd, 2H), 3.73 (dd, 2H), 2.03 (s, 3H), 1.89 (d, 3H). LCMS(ESI-MS) m / z 435. 1 [M+H]+.Example 36(R)-2-(3-chloro-4-(l-(pyridin-4-yl)ethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7- dihydr opyrazolo [1 ,5-a] pyrazine-5(4H)-carbonitrile

[0447] Starting from tert-butyl 2-(3-chloro-4-hydroxypyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate and (S)-l-(pyridin-4-yl)ethan-l-ol, exemple 36 was synthesized following the same procedure as used for example 32.

[0448] The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep Shield RP 18 OBD C18 Column, 30* 150 mm, 5pm; Mobile Phase A: Water Onmol / LbdrUCOgH), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 29% B to59 % B in 10 min; Wave Length: 254nm / 220nm to afford (R)-2-(3-chloro-4-(l-(pyridin-4-yl)ethoxy)pyrazolo[l,5-a]pyridin-6- yl)-3-methyl-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carbonitrile (36.2 mg, 28% yield) as an off- white solid. 1H NMR (400 MHz, Chloroform- ) 8 8.63 (d, 2H), 8.24 (d, 1H), 7.86 (s, 1H), 7.50 - 7.37 (m, 2H), 6.65 (d, 1H), 5.56 (q, 1H), 4.46 (s, 2H), 4.32 (dd, 2H), 3.72 (dd, 2H), 2.01 (s, 3H), 1.77 (d, 3H). LCMS(ESI-MS) m / z = 434. 1 [M+H]+.Example 37(R)-2-(3-chloro-4-(l-(tetrahydro-2H-pyran-4-yl)ethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7- dihydr opyrazolo [1 ,5-a] pyrazine-5(4H)-carbonitrile

[0449] Starting from tert-butyl 2-(3-chloro-4-hydroxypyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[ 1 ,5 -a]pyrazine-5(4H)-carboxylate and (S)- 1 -(tetrahydro-2H-pyran-4-yl)ethan- 1 -ol, exemple 37 was synthesized following the same procedure as used for example 35.

[0450] The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD Cl 8 Column, 30* 150 mm, 5pm; Mobile Phase A: Water Onmol / LNTLCOsH), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 36% B to 66 % B in 10 min; Wave Length: 254nm / 220nm to afford (R)-2-(3-chloro-4-(l-(tetrahydro-2H-pyran-4-yl)ethoxy)pyrazolo[l,5- a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carbomtrile (61.9 mg, 29% yield) as a white solid. 1H NMR (400 MHz, Chlorofonn-d) 8 8.20 (d, 1H), 7.78 (s, 1H), 6.79 (s, 1H), 4.48 (s, 2H), 4.41 (quint, 1H), 4.36 (dd, 2H), 4.05 (dd, 2H), 3.75 (dd, 2H), 3.45 (dt, 2H), 2.14 (s, 3H), 2.00 - 1.85 (m, 2H), 1.71 - 1.52 (m, 3H), 1.41 (d, 3H). LCMS (ESI-MS) m / z = 441.1 [M+H]+.Example 38(R)-2-(3-chloro-4-(l-cyclobutylethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7- dihydr opyrazolo [1 ,5-a] pyrazine-5(4H)-carbonitrile

[0451] Starting from tert-butyl 2-(3-chloro-4-hydroxypyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate and (S)-l-cyclobutylethan-l-ol, exemple 38 was synthesized following the same procedure as used for example 32.

[0452] The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep Shield RP18 OBD C18 Column, 30* 150 mm, 5pm; Mobile Phase A: Water (lOnmol / LNFLCOiH), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 48% B to78 % B in 10 min; Wave Length: 254nm / 220nm nm to afford (R)-2-(3-chloro-4-(l- cyclobutylethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)- carbonitrile (32. 1 mg, 33% yield) as a white solid. 1H NMR (400 MHz, Chloroform -d) 3 8.20 (d, 1H), 7.78 (s, 1H), 6.80 (s, 1H), 4.52 (quint, 1H), 4.51 (s, 2H), 4.35 (dd, 2H), 3.75 (dd, 2H), 2.74-2.63 (m, 1H), 2.17 - 2.05 (m, 5H), 2.01 - 1.84 (m, 4H), 1.31 (d, 3H). LCMS (ESI-MS) m / z = 411.2 [M+H]+.Example 39(R)-2-(3-chloro-4-((tetrahydrofuran-3-yl)oxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7- dihydr opyrazolo [1 ,5-a] pyrazine-5(4H)-carbonitrile

[0453] Starting from tert-butyl 2-(3-chloro-4-hydroxypyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate and (S)-tetrahydrofuran-3-ol, exemple 39 was synthesized following the same procedure as used for example 32.

[0454] The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep Shield RP 18 OBD C18 Column, 30* 150 mm, 5pm; Mobile Phase A: Water Onmol / LTMLCOsH), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 27% B to57 % B in 10 min; Wave Length: 254nm / 220nm to afford (R)-2-(3-chloro-4-((tetrahydrofuran-3-yl)oxy)pyrazolo[l,5-a]pyridin- 6-yl)-3-methyl-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carbonitrile (12.7 mg, 14% yield) as awhite solid. 1H NMR (400 MHz, Chloroform -rt) 8.27 (s, 1H), 7.82 (s, 1H), 6.78 (s, 1H), 5.17-5.11 (m, 1H),4.51 (s, 2H), 4.37 (dd, 2H), 4.17-4.11 (m, 2H), 4.11-4.04 (m, 1H), 4.00 (ddd, 1H), 3.76 (dd, 2H), 2.43 - 2.24 (m, 2H), 2.17 (s, 3H). LCMS(ESLMS) m / z = 399.1 [M+H]+.Example 40(S)-2-(3-chloro-4-((tetrahydrofuran-3-yl)oxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7- dihydr opyrazolo [1 ,5-a] pyrazine-5(4H)-carbonitrile

[0455] Starting from tert-butyl 2-(3-chloro-4-hydroxypyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate and (R)-tetrahydrofuran-3-ol, exemple 40 was synthesized following the same procedure as used for example 32.

[0456] The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep Shield RP18 OBD C18 Column, 30* 150 mm, 5pm; Mobile Phase A: Water (lOnmol / LNEUCOsH), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 27% B to 57 % B in 10 min; Wave Length: 254nm / 220nm to afford (S)-2-(3-chloro-4-((tetrahydrofuran-3- yl)oxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carbonitrile (30.3 mg, 23.55% yield) as a white solid. 1H NMR (400 MHz, Chloroform-c ) 8.27 (s, 1H), 7.82 (s, 1H), 6.78 (s, 1H), 5.17-5.11 (m, 1H), 4.51 (s, 2H), 4.37 (dd, 2H), 4.17-4.11 (m, 2H), 4.11-4.04 (m, 1H), 4.00 (ddd, 1H), 3.76 (dd, 2H), 2.43 - 2.24 (m, 2H), 2.16 (s, 3H). LCMS(ESI-MS) m / z = 399.0 [M+H]+.Example 412-(3-chloro-4-(l-(tetrahydrofuran-3-yl)ethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carbonitrile, Isomer 1Example 422-(3-chloro-4-(l-(tetrahydrofuran-3-yl)ethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carbonitrile, Isomer 2Example 432-(3-chloro-4-(l-(tetrahydrofuran-3-yl)ethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carbonitrile, Isomer 3Example 442-(3-chloro-4-(l-(tetrahydrofuran-3-yl)ethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carbonitrile, Isomer 4

[0457] Starting from tert-butyl 2-(3-chloro-4-hydroxypyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate and l-(tetrahydrofuran-3-yl)ethan-l-ol, exemple 41 to 44 were synthesized following the same procedure as used for example 32.

[0458] The residue was purified by silica gel column chromatography, eluted with (EA / MeOH = 10 / 1) to afford the crude product. The crude product was purified by Prep-Chiral-HPLC with the following conditions: Column: Chiral ART Cellulose-SA, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.1% FA)— HPLC, Mobile Phase B: EtOH: DCM=1: 1-HPLC; Flow rate: 20ML / MIN mL / min; Gradient: isocratic

[0459] 40; Wave Length: 254 / 220nm to afford three elution.

[0460] The first elution being a mixture of 2 isomers, was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK IG, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.1% FA)- HPLC, Mobile Phase B: MeOH: DCM=1: 1-HPLC; Flow rate: 20ML / MIN mL / min; Gradient: isocratic 35; Wave Length: 254 / 220nm nm; RTl(min): 17.357; RT2(min): 20.117; Sample Solvent: EtOH-HPLC; Injection Volume: 1.0 mL; to afford 2-(3-chloro-4-(l-(tetrahydrofuran-3- yl)ethoxy)pyrazolo[l,5-a]pyndin-6-yl)-3-methyl-6,7-dihydropyrazolo[l,5-a]pyrazme-5(4H)-carbonitrile, Isomer 1 (the first elution from the mixture, 17.9 mg, 18.7% yield) as a white solid. 1H NMR (400 MHz, Chloroform / ) 3 8.25 (s, 1H), 7.81 (s, 1H), 6.85 (s, 1H), 4.57 (quint, 1H), 4.51 (s, 2H), 4.38 (dd, 2H), 3.96-3.91 (m, 2H), 3.83 (dd, 1H), 3.75 (dd, 2H), 3.69 (dd, 1H), 2.70 (sext, 1H), 2.27 - 2.19 (m, 1H), 2.17 (s, 3H), 2.06 - 1.94 (m, 1H), 1.46 (d, 3H). LCMS(ESLMS) m / z = 427.2 [M+H]+.

[0461] Isomer 2 (the second elution from the mixture, 7.5 mg, 7.8% yield) as a white solid. 1H NMR (400 MHz, Chloroform-cO 3 8.23 (s, 1H), 7.80 (s, 1H), 6.83 (s, 1H), 4.54 (quint, 1H), 4.50 (s, 2H), 4.36 (dd, 2H), 4.07 (dd, 1H), 3.94 (dt, 1H), 3.84-3.73 (m, 4H), 2.70 (sext, 1H), 2.11 (s, 3H), 2.13 - 2.04 (m, 1H), 1.82 - 1.77 (m, 1H), 1.46 (d, 3H). LCMS(ESI-MS) m / z = 427.2 [M+H]+.

[0462] Isomer 3 (the second elution from the first prep-chiral HPLC purification, 20.1 mg, 20.8% yield) as a white solid. 1H NMR (400 MHz, Chloroform -d) 3 8.25 (s, 1H), 7.81 (s, 1H), 6.85 (s, 1H), 4.57 (quint, 1H), 4.50 (s, 2H), 4.36 (dd, 2H), 3.96-3.91 (m, 2H), 3.83 (dd, 1H), 3.75 (dd, 2H), 3.69 (dd, 1H), 2.70 (sext, 1H), 2.24 - 2.16 (m, 1H), 2.17 (s, 3H), 2.04 - 1.94 (m, 1H), 1.46 (d, 3H). LCMS(ESI-MS) m / z = 427.2 [M+H]+.

[0463] Isomer 4 (the third elution from the first prep-chiral HPLC purification, 15.4 mg, 16.1% yield) as a white solid. 1HNMR (400 MHz, Chloroform -d) 38.23 (s, 1H), 7.80 (s, 1H), 6.83 (s, 1H), 4.54 (quint, 1H), 4.50 (s, 2H), 4.36 (dd, 2H), 4.07 (dd, 1H), 3.94 (dt, 1H), 3.84-3.73 (m, 4H), 2.70 (sext, 1H), 2.11 (s, 3H), 2.13 - 2.04 (m, 1H), 1.82 - 1.77 (m, 1H), 1.46 (d, 3H). LCMS(ESI-MS) m / z = 427.1 [M+H]+.Example 452-(3-chloro-4-(l-(2-cyanophenyl)ethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carbonitrile, Isomer 1Example 462-(3-chloro-4-(l-(2-cyanophenyl)ethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carbonitrile, Isomer 2

[0464] Into a 40 mL round-bottom flask were added tert-butyl 2-(3-chloro-4-hydroxypyrazolo[l,5- a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate (250 mg, 0.619 mmol, 1.00 equiv), l-(2-bromophenyl)ethan-l-ol (336 mg, 1.67 mmol, 1.50 equiv), (tributylphosphoranylidene)acetonitrile (807 mg, 3.34 mmol, 3.00 equiv) and toluene (15 mL). The resulting mixture was stirred for 5 hours at 100 °C under nitrogen atmosphere. The reaction was quenched with water (10 mL) at room temperature. The resulting mixture was extracted with EA (3 x 15 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (PE / EA = 1 / 2) to afford tert-butyl 2-(4-(l-(2-bromophenyl)ethoxy)-3- chloropyrazolo [ 1 ,5 -a]pyridin-6-yl)-3 -methyl-6,7-dihydropyrazolo [ 1 ,5 -a]pyrazine-5 (4H)-carboxylate (200 mg, 27% yield) as a yellow oil. LCMS(ESI-MS) m / z = 586.1 [M+H]+.

[0465] A 100 mL round bottom flask was charged with MeCN (0.01 mL, 0.102 mmol, 0.75 equiv), triphenylphosphine (7.15 mg, 0.027 mmol, 0.20 equiv) and NiC12 (1.77 mg, 0.014 mmol, 0.10 equiv). The mixture was stirred for 30 minutes at room temperature. Zinc (44.5 mg, 0.680 mmol, 5.00 equiv) was added to above mixture. The resulting solution was stirred for 10 minutes at room temperature. To the solution was added a mixture tert-butyl 2-(4-(l-(2-bromophenyl)ethoxy)-3- chloropyrazolo [ 1 ,5 -a]pyridin-6-yl)-3 -methyl-6,7-dihydropyrazolo [ 1 ,5 -a]pyrazine-5 (4H)-carboxylate (80 mg, 0.136 mmol, 1.00 equiv) and acetic acid (8.19 mg, 0.136 mmol, 1.00 equiv) in MeCN (2 mL). The resulting solution was stirred for 48 hours at 80 °C. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtrated and concentrated under reduced pressure. The crude was purified by Prep-HPLC with the following conditions: Column: Xbridge Prep OBD C18 Column, 30* 150 mm, 5pm; Mobile Phase A: water(10mmol / L NH4CO3H), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 54% B to 84 % B in 10 min; Wave Length: 254nm / 220nm to afford tert-butyl 2-(3-chloro-4-(l-(2-cyanophenyl)ethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate (31 mg, 42% yield) as a white solid. LCMS(ESI- MS) m / z = 533.2 [M+H]+.

[0466] Into a 50 mL round -bottom flask were added tert-butyl 2-(3-chloro-4-(l-(2- cyanophenyl)ethoxy)pyrazolo [ 1 ,5 -a]pyridin-6-yl)-3 -methyl-6,7-dihydropyrazolo [ 1 , 5 -a] pyrazine - 5 (4H) -carboxylate (35 mg, 0.066 mmol, 1.00 equiv), hydrogen chloride (3.0 M in THF) (6 mL) and 1,4-dioxane (3 mL). The resulting mixture was stirred for 2 hours at room temperature. The resulting mixture was concentrated under reduced pressure to afford 2-(l-((3-chloro-6-(3-methyl-4,5,6,7- tetrahydropyrazolo[l,5-a]pyrazin-2-yl)pyrazolo[l,5-a]pyridin-4-yl)oxy)ethyl)benzonitrile (30 mg, crude) as a white solid. LCMS(ESI-MS) m / z = 433.2 [M+H]+

[0467] Into a 100 mL round-bottom flask were added 2-(l-((3-chloro-6-(3-methyl-4,5,6,7- tetrahydropyrazolo[l,5-a]pyrazin-2-yl)pyrazolo[l,5-a]pyridin-4-yl)oxy)ethyl)benzonitrile (30 mg, 0.069 mmol, 1.00 equiv), DIEA (44.8 mg, 0.345 mmol, 5.00 equiv) and DCM (10 mL). Then BrCN (8.07 mg, 0.076 mmol, 1.10 equiv) dissolved in DCM (3 mL) was added to the above mixture. The resulting mixture was stirred for 2 hours at room temperature. The reaction was quenched with water (10 mL). The resulting mixture was extracted with DCM (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (MeOH / EA = 1 / 10) to afford the crude product. The crude product was purified by Prep-Chiral -HPLC with the following conditions: Column: CHIRALPAKIH3; Mobile Phase A: Hex(0.1%DEA): (EtOH: DCM=1: 1) = 80: 20; Flow rate: 1 mL / min; Gradient: isocratic; Injection Volume: Ipl mL; Wave Length: 254 / 220nm to afford 2-(3-chloro-4-(l-(2-cyanophenyl)ethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3- methyl-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carbonitrile, Isomer 1 (the first elution, 3.4 mg, 11% yield) as a white solid. 1H NMR (400 MHz, Chloroform -d) 3 8.26 (s, 1H), 7.85 (s, 1H), 7.84 (d, 1H), 7.69 (d, 1H), 7.64 (td, 1H), 7.42 (td, 1H), 6.71 (s, 1H), 5.94 (q, 1H), 4.47 (s, 2H), 4.35 (dd, 2H), 3.73 (dd, 2H), 2.02 (s, 3H), 1.84 (d, 3H). LCMS(ESI-MS) m / z = 458.2 [M+H]+.

[0468] Isomer 2, (the second elution, 3.4 mg, 11% yield) as a white solid. 1H NMR (400 MHz, Chloroform -d) 3 8.26 (s, 1H), 7.85 (s, 1H), 7.84 (d, 1H), 7.69 (d, 1H), 7.64 (td, 1H), 7.42 (td, 1H), 6.71 (s, 1H), 5.94 (q, 1H), 4.47 (s, 2H), 4.35 (dd, 2H), 3.73 (dd, 2H), 2.02 (s, 3H), 1.84 (d, 3H). LCMS(ESI- MS) m / z - 458.2 [M+H]+.Example 472-(3-chloro-4-(l-(7-fluoroisoquinolin-4-yl)ethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carbonitrile, Isomer 1Example 482-(3-chloro-4-(l-(7-fluoroisoquinolin-4-yl)ethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carbonitrile, Isomer 2

[0469] A 100 mL round botom flask was charged with 7-fluoroisoquinoline-4-carboxylic acid (500 mg, 2.62 mmol, 1.00 equiv), HATU (1.99 g, 5.23 mmol, 2.00 equiv), DIEA (1.35 g, 10.5 mmol, 4.00 equiv), DMF (10 mL), methoxy(methyl)aminehydrochloride (306 mg, 3.14 mmol, 1.20 equiv). The resulting solution was stirred overnight at room temperature. The reaction was quenched with water (200 mL). The mixture was extracted with ethyl acetate (3 x 100 mL). The organic layers were dried over anhydrous sodium sulfate, filtrated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (EA / PE = 2 / 1) to afford 7-fluoro-N-methoxy-N- methylisoquinolme-4-carboxamide (450 mg, 66% yield) as a yellow oil. LCMS(ESI-MS) m / z = 235.1 [M+H]+.

[0470] A 100 mL round botom flask was charged with 7-fluoro-N-methoxy-N-methylisoquinoline-4- carboxamide (500 mg, 2.14 mmol, 1.00 equiv) and toluene (20 mL) at 0 °C. To the mixture was added MeMgBr (8.54 mL, 8.54 mmol, 4.00 equiv) dropwise at 0 °C. The reaction was slowly warmed to room temperature and stirred for 2 hours at room temperature. The reaction was quenched with water (200 mL) at 0 °C. The mixture was extracted with ethyl acetate (3 x 80 mL). The organic layers were dried over anhydrous sodium sulfate, filtrated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (PE / EA = 1 / 1) to afford l-(7- fluoroisoquinolin-4-yl)ethan-l-one (230 mg, 51% yield) as a colorless oil. LCMS(ESI-MS) m / z = 190.1 [M+H]+.

[0471] A 100 mL round botom flask was charged with l-(7-fluoroisoquinolin-4-yl)ethan-l-one (230 mg, 1.22 mmol, 1.00 equiv) and methanol (20 mL) at 0 °C. To the mixture was added NaBH4(92.0 mg, 2.43 mmol, 2.00 equiv) at 0 °C. The reaction was slowly warmed to room temperature and stirred overnight at room temperature. The reaction was quenched with water (200 mL) at 0 °C. The mixture was extracted with ethyl acetate (3 x 200 mL). The organic layers were dried over anhydrous sodium sulfate, filtrated and concentrated under reduced pressure. The residue was purified by silica gel columnchromatography, eluted with (PE / EA = 1 / 5) to afford l-(7-fluoroisoquinolin-4-yl)ethan-l-ol (180 mg, 70% yield) as a light yellow oil. LCMS(ESI-MS) m / z = 192.1 [M+H]+.

[0472] Into a 40 mL round -bottom flask were added tert-butyl tert-butyl 2-(3-chloro-4- hydroxypyrazolo [ 1 ,5 -a]pyridin-6-yl)-3 -methyl-6,7-dihydropyrazolo[ 1 ,5 -a]pyrazine-5 (4 H ) - carboxylate (215 mg, 0.533 mmol, 1.00 equiv), l-(7-fhioroisoquinolin-4-yl)ethan-l-ol (170 mg, 0.533 mmol, 1.00 equiv), (tributylphosphoranylidene)acetonitrile (386 mg, 1 60 mmol, 3.00 equiv) and toluene (15 mL). The resulting mixture was stirred for 5 hours at 100 °C under nitrogen atmosphere. The reaction was quenched with water (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (PE / EA = 1 / 5) to afford tert-butyl 2-(3-chloro-4- (l-(7-fluoroisoquinolin-4-yl)ethoxy)pyrazolo[L5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[L5- a]pyrazine-5(4H)-carboxylate (140 mg, 41% yield) as a colorless oil. LCMS(ESI-MS) m / z = 577.2 [M+H]+.

[0473] Into a 100 mL round-bottom flask were added tert-butyl 2-(3-chloro-4-(l-(7-fluoroisoquinolin-4- yl)ethoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)- carboxylate (140 mg, 0.243 mmol, 1.00 equiv), HC1 (4 M in 1,4-dioxane, 5 mL) and 1,4-dioxane (5 mL). The resulting mixture was stirred for 2 hours at room temperature. The resulting mixture was concentrated under reduced pressure to afford 4-(l-((3-chloro-6-(3-methyl-4, 5,6,7- tetrahydropyrazolo [ 1 ,5 -a]pyrazin-2-yl)pyrazolo[ 1 ,5 -a]pyridin-4-yl)oxy)ethyl)-7-fluoroisoquinoline (150 mg, crude) as a white solid. LCMS(ESI-MS) m / z = 477.2 [M+H]+.

[0474] Into a 100 mL round-bottom flask were added 4-(l-((3-chloro-6-(3-methyl-4, 5,6,7- tetrahydropyrazolo [ 1 ,5 -a]pyrazin-2-yl)pyrazolo[ 1 ,5 -a]pyridin-4-yl)oxy)ethyl)-7 -fluoroisoquinoline (170 mg, 0.356 mmol, 1.00 equiv), DIEA (230 mg, 1.780 mmol, 5.00 equiv) and DCM (20 mL). BrCN (41.53 mg, 0.392 mmol, 1.10 equiv) dissolved in DCM (5 mL) was added to the above mixture. The resulting mixture was stirred for 2 hours at room temperature. The reaction was quenched with water (10 mL). The resulting mixture was extracted with DCM (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (EA / MeOH = 10 / 1) to afford the crude product. The crude product was purified by Prep-HPLC with the following conditions: Column: CHIRALPAKIF3; Mobile Phase A: Hex(0.2%FA): (EtOH: DCM = 1 / 1) = 60: 40; Flow rate: ImL / min mL / min; Gradient: isocratic; Injection Volume: Ipl mL; Wave Length: 254 / 220nm to afford 2-(3-chloro-4-(l-(7-fluoroisoquinolin-4-yl)ethoxy)pyrazolo[l,5-a]pyridin-6-yl)- 3-methyl-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carbonitrile, isomer 1 (the first elution, 23.1 mg, 12.7% yield) as an off-white solid. 1H NMR (400 MHz, Chloroform -d) 8 9.17 (s, 1H), 8.71 (s, 1H),8.60 (dd, 1H), 8.19 (d, 1H), 7.84 (s, 1H), 7.68 - 7.52 (m, 2H), 6.74 (d, 1H), 6.08 (q, 1H), 4.43 (s, 2H), 4.30 (dd, 2H), 3.72 (dd, 2H), 2.02 (d, 3H), 1.90 (s, 3H). LCMS(ESI-MS) m / z = 502.2 [M+H]+.

[0475] Isomer 2 (the second elution, 23.3 mg, 12.5% yield) as an off-white solid. 1H NMR (400 MHz, Chloroform-d) 5 9.17 (s, 1H), 8.71 (s, 1H), 8.60 (dd, 1H), 8.19 (d, 1H), 7.84 (s, 1H), 7.64 - 7.52 (m, 2H), 6.74 (d, 1H), 6.08 (q, 1H), 4.43 (s, 2H), 4.30 (dd, 2H), 3.72 (dd, 2H), 2.02 (d, 3H), 1.90 (s, 3H). LCMS(ESI-MS) m / z = 502.2 [M+H]+.Example 492-(3-chloro-4-(2-(5-fluoropyridin-2-yl)-2-hydroxypropoxy)pyrazolo[l,5-a] pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carbonitrile, Isomer 1Example 502-(3-chloro-4-(2-(5-fluoropyridin-2-yl)-2-hydroxypropoxy)pyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carbonitrile, Isomer 2

[0476] To a solution of tert-butyl 2-(3-chloro-4-hydroxypyrazolo[l,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate (300 mg, 0.743 mmol, 1 equiv) in DMSO (10 mb) was added 2-chloro-l-(5-fluoropyridin-2-yl)ethan-l-one (258 mg, 1.49 mmol, 2 equiv), KOH (83 mg, 1.49 mmol, 2 equiv) and KI (123 mg, 0.743 mmol, 1 equiv). The reaction was stirred for overnight at room temperature and added water (100 mL). The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (3 x 150 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 / 1) to afford tert-butyl 2-(3-chloro-4-(2- (5 -fluoropyridin-2-yl)-2-oxoethoxy)pyrazolo[ 1 ,5 -a]pyridin-6-yl)-3 -methyl-6,7-dihydropyrazolo [1,5- a]pyrazine-5(4H)-carboxylate (334 mg, 79% yield) as a yellow solid. LCMS(ESI-MS) m / z = 541.0 [M+H]+.

[0477] To a solution of tert-butyl 2-(3-chloro-4-(2-(5-fluoropyridin-2-yl)-2-oxoethoxy)pyrazolo[l,5- a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate (200 mg, 0.370 mmol, 1.00 equiv) in THF (10 mb) was added MeMgBr (265 mg, 2.22 mmol, 6.00 equiv) at 0°C. The mixture was stirred for 3 hours at room temperature. The reaction was quenched with NH4C1 solution (10 mL). The aqueous layer was extracted with EA (3 x 15 mL). The combined organic layers were washed with brine (3 x 5 mL), dried over anhydrous sodium sulfate After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (DCM / MeOH = 25 / 1) to afford tert-butyl 2-(3-chloro-4-(2-(5-fluoropyridin-2-yl)-2- hydroxypropoxy)pyrazolo[ 1 ,5 -a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[ 1 ,5-a]pyrazine-5(4H)- carboxylate (170 mg, 83% yield) as a white solid. LCMS(ESI-MS) m / z = 557.2 [M+H]+.

[0478] A 8 mL reaction bottles was charged with tert-butyl 2-(3-chloro-4-(2-(5-fluoropyridin-2-yl)-2- hydroxypropoxy)pyrazolo[ 1 ,5 -a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[ 1 ,5-a]pyrazine-5(4H)- carboxylate (194 mg, 0.348 mmol, 1.00 equiv), 1,4 - dioxane (1 mL) and HC1 (4 M in 1,4-dioxane, 0.5 mL). The resulting solution was stirred for 2 hours at room temperature and concentrated to afford 1- ((3-chloro-6-(3-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2-yl)pyrazolo[l,5-a]pyridin-4- yl)oxy)-2-(5-fluoropyridin-2-yl)propan-2-ol (150 mg, crude) as a yellow oil. LCMS(ESI-MS) m / z = 457.2 [M+H]+.

[0479] A 8 mL reaction bottles was charged with l-((3-chloro-6-(3-methyl-4,5,6,7- tetrahydropyrazolo [ 1 ,5 -a]pyrazin-2-yl)pyrazolo[ 1 ,5 -a]pyridin-4-yl)oxy)-2-(5 -fluoropyridin-2- yl)propan-2-ol (60 mg, 0.131 mmol, 1.00 equiv), DIEA (102 mg, 0.786 mmol, 6.00 equiv), BrCN (13.9 mg, 0.131 mmol, 1.00 equiv) and DCM (1 mL). The resulting solution was stirred for 2 h at room temperature. The reaction was quenched by water (10 mL). The mixture was extracted with DCM (3 x 50 mL). The organic layers were combined, washed with water (3 x 50 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (DCM / MeOH = 20 / 1) to afford crude product. The crude product was purified by Prep-Chiral-HPLC with the following conditions Column: CHIRALART Cellulose SZ; Mobile Phase A: Hex(0.2%FA): (EtOH: DCM=1: 1)=55: 45; Fl...

Claims

CLAIMS1. A compound of F ormula (Ig) :wherein:Xi is N or CH;X2is N and X3is C, or, alternatively, X3is N and X2is C;X4is N;Y is a bond, 0 or NH;Yi is a bond, CHR6, CH2-CHR6, CHR6-CH2, CF2, CH2-CF2or CF2-CH2;Y2is CR4R5or CF2;Y3is CR3R4, CR3R4CR3R4, CH2CF2or CF2; wherein Yi, Y2, Y3and X_ together with the pyrazolyl ring form a 6- to 8-membered nitrogen containing ring;B is -C(O)Y4-, -Y4-, -CH2Y4-, or -CH2CH2Y4-, and A is CN;Y4is C3.io cycloalkyl -R4N- or a 5- to 8-membered oxygen containing heterocyclyl-NR4-, wherein the cycloalkyl or 5- to 8-membered oxygen containing heterocyclyl is unsubstituted or independently substituted with one or more substituents independently selected from halogen, methyl, halomethyl, hydroxyl or methoxy, or wherein the cycloalkyl is substituted by two groups which are attached to the same carbon atom and join to form a 4- to 6- membered oxygen containing heterocyclyl ring, and wherein the nitrogen atom of the cycloalkyl -R4N or 5- to 8-membered oxygen containing heterocyclyl-NR4- is connected to A;R1is hydrogen, halogen, C1.5 alkyl, C1.5 alkoxy, CN, C3-10 cycloalkyl, C2.4 alkynyl, 4-10 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, 0 and S, phenyl or a 5- 6 membered heteroaryl, wherein the 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are unsubstituted or substituted with one or more substituents independentlyselected from halogen, methyl, halomethyl, hydroxyl or methoxy and wherein the C1.5 alkyl and C1.5 alkoxy, are unsubstituted or independently substituted with one or more substituents independently selected from halogen, CN, hydroxyl and methoxy;R2is hydrogen, hydroxyl, C1-4 alkyl, CN, -CONHCi 4 alkyl, or C1-4 haloalkyl; each R3is independently selected from hydrogen, fluoro, hydroxyl, methoxy, C1.3 alkyl, cyclopropyl, or a R3is fused with R5or R6to form CH2, CH2-CH2 or CH2OCH2; each R4is independently selected from hydrogen and C1.3 alkyl;R5is hydrogen, fluoro, hydroxyl, methoxy, C1.3 alkyl, cyclopropyl or is fused with one R3to form CH2, CH2-CH2 or CH2OCH2, wherein the C1-3 alkyl is unsubstituted or independently substituted with one or more substituents independently selected from halogen, heteroaryl (which heteroaryl is preferably pyridyl), phenyl, hydroxyl, -CO2R4or C1-3 alkoxy;R6is hydrogen, fluoro, hydroxyl, methoxy, C1.3 alkyl or is fused with one R3to form CH2, CH2-CH2or CH2OCH2; each R8is independently selected from hydrogen and Ci-6 alkyl; each R9is independently selected from hydrogen, CF3and Cue alkyl, which alkyl is unsubstituted or substituted with one or more substituents independently selected from fluoro, chloro, bromo, hydroxyl, and Cue alkoxy; andR10is hydrogen, C1.3 alkyl or halogen; or R9and R10together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic nng; each of R11and R12is independently hydrogen, Cue alkyl, or R11and R12together with the nitrogen atom to which they are attached form a 4-6 membered heterocycloalkyl optionally having an additional ring heteroatom which is O, wherein said ring is optionally substituted with halogen;R13is hydrogen, R14R15NCH2-, or C1.3 alkyl which is unsubstituted or substituted with hydroxyl;R14and R15are each independently hydrogen or Ci-e alkyl;R16is Ci-3 alkyl-R17, C3-6 cycloalkyl-R17or a 4-6 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein the C1-3 alkyl, C3-6 cycloalkyl and 4-6 membered heterocycloalkyl are unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-4 alkyl optionally substituted with one or more OH, C3-6 cycloalkyl, OH, OMe, -NR4R8wherein R4and R8are as defined above, or, alternatively, R4and R8together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring, or - O(CH2)24- wherein the oxygen atom and terminal carbon atom are attached to the same carbon atom in the C1-3 alkyl, C3-6 cycloalkyl and 4-6 membered heterocycloalkyl group such that an oxygen-containing heterocyclyl forms;R17is hydrogen, aryl, heteroaryl, 4-6 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, O and S, or C3-8 cycloalkyl, wherein the aryl and heteroaryl are unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, CN, NH2, C1-4 alkyl, and C1.4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy, wherein the heterocycloalkyl and cycloalkyl are unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, CN, NH2, oxo, C1.4 alkyl, and C1.4 haloalkyl, C1.4 alkoxy, and C1.4 haloalkoxy; or a pharmaceutically acceptable salt and / or solvate thereof.

2. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to claim 1, wherein Xi is N, X3is N and X2is C and Y is 0.

3. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to claim 1, wherein Xi is CH, X3is N and X2is C and Y is 0.

4. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to claim 1 to 3 , wherein Y 1 is CHR6, Y2is CR4R5or CF2and Y3is CH2CR3R4, or Yi is CHR6, Y2is CR4R5or CF2and Y3is CR3R4.

5. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to claim 1 to 4 wherein Y 1 is CH2, Y2is CH2and Y3is CH26. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to claim 1 to 4 wherein Y 1 is CH2, Y2is CH2and Y3is CH2CH2.

7. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of claims 1 to 6, wherein B is -C(0)Y4-.

8. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of claims 1 to 6, wherein B is -Y4-.

9. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of claims 1 to 8, wherein Y4is C3-10 cycloalkyl-R4N- wherein the cycloalkyl is unsubstituted or independently substituted with one or more substituents independently selected from halogen, methyl, halomethyl, hydroxyl or methoxy, or wherein the cycloalkyl is substituted by two groups which are attachedto the same carbon atom and join to form a 4- to 6- membered oxygen containing heterocyclyl ring, and wherein the nitrogen atom of the cycloalkyl-R4N is connected to A.

10. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of claims 1 to 9, wherein Y4is C3-10 cycloalkyl-R4N- wherein the cycloalkyl is unsubstituted or independently substituted with one or more substituents independently selected from halogen, methyl, halomethyl, hydroxyl or methoxy and wherein the nitrogen atom of the cycloalkyl -R4N, is connected to A.

11. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of claims 1 to 10, wherein Y4is C3-10 cycloalkyl-R4N- wherein the R4is H.

12. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of claims 1 to 8, wherein Y4is 5- to 8-membered oxygen containing heterocyclyl-NR4- wherein the 5- to 8-membered oxygen containing heterocyclyl is unsubstituted or independently substituted with one or more substituents independently selected from halogen, methyl, halomethyl, hydroxyl or methoxy, and wherein the nitrogen atom of the 5- to 8-membered oxygen containing heterocyclyl-NR4- is connected to A.

13. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of claims 1 to 10, wherein Y4is heterocyclyl-R4N- wherein the R4is H.

14. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of claims 1 to 12, wherein Y4is unsubstituted.

15. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of claims 9, 10 or 12, wherein the cycloalkyl or heterocyclyl is substituted with one or more substituents independently selected from halogen, methyl, halomethyl, hydroxyl or methoxy.

16. The compound according to any one of claims 1 to 15 wherein R1is halogen e.g. chloro.

17. The compound according to any one of claims 1 to 15 wherein R1is C1.5 alkoxy, wherein the C1.5 alkoxy is unsubstituted or independently substituted with one or more (e g . one or two e g . two) substituents independently selected from halogen, CN, hydroxyl and methoxy such as halogen e.g. F.

18. The compound according to any one of claims 1 to 15 wherein R1is selected from OMe, OCH2F, OCHF2, or OCF319. The compound according to any one of claims 1 to 15 wherein R1is OMe20. The compound according to any one of claims 1 to 15 wherein R1is OCHF221. The compound according to any one of claims 1 to 15 wherein R2is C1.4 alkyl e g. methyl and R3, R4, R5and R6are hydrogen.

22. The compound according to any one of claims 1 to 21 wherein R16is C1-3 alkyl-R17wherein the Ci. alkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1.4 alkyl, C3-6 cycloalkyl, OH, OMe, -NR4R8wherein R4and R8are as defined above, or, alternatively, R4and R8together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring, such as the C1.3 alkyl group is substituted by one OH.

23. The compound according to any one of claims 1 to 22 wherein R16is selected from C2alkyl-R17or C3 alkyl-R17and wherein C2alkyl or C3 is optionally substituted with at least one -OH.

24. The compound according to any of claims 1 to 23 wherein R17is 2-pyridinyl optionally substituted with one ore more F.

25. The compound according to any one of claims 1 to 22 wherein R17is aryl, heteroaryl or 4-6 membered heterocycloalkyl, such as pyrazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pynmidinyl and pyrazinyl e.g. pyridinyl.

26. The compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to claim 1, wherein the compound is selected from:

27. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of claims 1-26.

28. A compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of claims 1-26, or a pharmaceutical composition according to claim 27, for use in medicine.

29. A compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of claims 1-26, or a pharmaceutical composition according to claim 27, for use in the prophylaxis and / or treatment of a disease, disorder or condition that is associated with abnormal activity or expression of an FGFR enzyme, preferably FGFR3.

30. A compound, or a pharmaceutically acceptable salt and / or solvate thereof, according to any one of claims 1-26, or a pharmaceutical composition according to claim 27, for use in the prophylaxis and / or treatment of a disease, disorder or condition that is selected from metastatic tumours (such as but not limited to, melanoma, lymphoma, leukaemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma) and types oftissue carcinoma (such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, glioblastoma, primary liver cancer, ovarian cancer, prostate cancer and uterine leiomyosarcoma), acute lymphoblastic leukemia, acute myeloidleukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumors, brain and spinal cord tumors, breast cancer, bronchial tumors, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T -Cell lymphoma, embryonal tumors, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, ewing sarcoma family of tumors, eye cancer, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gastrointestinal stromal cell tumor, germ cell tumor, glioma, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors (endocrine pancreas), Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, Burkitt lymphoma, cutaneous T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoma, Waldenstrom macroglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, mouth cancer, chronic myelogenous leukemia, myeloid leukemia, multiple myeloma, asopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, pineal parenchymal tumors of intermediate differentiation, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary tumor, plasma cell neoplasm / multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing sarcoma family of tumors, sarcoma, kaposi, Sezary syndrome, skin cancer, small cell Lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer, supratentorial primitive neuroectodermal tumors, T -cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom macroglobulinemia, Wilms tumor, a neoplastic disease of the blood and blood forming organs, including but not limited to: acute myeloid leukaemia (AML), and acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukaemia (CLL), breast cancer (e.g. invasive ductal cancer, invasive lobular cancer), lung cancer (e g. non-small-cell lung cancer, lung adenocarcinoma, squamous cell lungcancer and small-cell lung cancer), urothelial cancer, bladder cancer (e.g. urothelial bladder cancer, nonmuscle invasive bladder cancer, muscle invasive bladder cancer), upper tract cancer (e.g. urothelial upper tract cancer), urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma (e.g. cutaneous melanoma), head and neck cancer (e.g. oral cancer), thyroid cancer, renal cancer (e.g. renal pelvis cancer), glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer.

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