WO2026027643A1 - Compounds and pharmaceutical compositions thereof for the treatment of diseases such as cancer - Google Patents

Abstract

The present invention discloses compounds according to Formula (I) or a pharmaceutically acceptable salt and/or solvate thereof, wherein X₁, X₂, X₃, X₄, 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

1 WHEN NOVEL COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF DISEASES SUCH AS CANCER. FIELD OF THE INVENTION 5 [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 10 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 15 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 & 20 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 25 and Cook, Pharmacology & Therapeutics, 2010, 125, 105-117; Turner and Grose, Nature Reviews Cancer, 2010, 10, 116-129). Large scale DNA sequencing of thousands of tumor 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 30 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, 35 breast, colorectal, endometrial, gastric, head and neck, kidney, lung, ovarian, prostate), hematopoietic malignancies (e.g., multiple myeloma, acute myelogenous leukemia, and myeloproliferative 2 neoplasms), 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 5 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. SUMMARY OF THE INVENTION [0006] The present invention provides compounds that are FGFR inhibitors. The invention also provides 10 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 15 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, the present invention provides compounds of Formula (I): 20 wherein: X1 is N or CH; X₂ is N and X₃ is C, or, alternatively, X₃ is N and X₂ is C; X₄ is N or CR⁴; 25 Y is a bond, O or NH; Y₁ is a bond, CHR⁶, CH₂-CHR⁶, CHR⁶-CH₂, CF₂, CH₂-CF₂ or CF₂-CH₂; Y₂ is CR⁴R⁵ or CF₂; 3 Y3 is CR³R⁴, CR3R4CR3R4, CH2CF2 or CF2; when X4 is N, B is a bond, -C(O)Y⁴-, -Y⁴-, -CH2Y⁴-, or -CH2CH2Y⁴-, and A is CN, R⁸R⁹C=CR¹⁰C(=O)-, R¹¹R¹²NCH2CH=CHC(=O)-, H2C=CHSO2- or R¹³C≡CC(=O)-; when X4 is CR⁴, B is a bond, and A is -NR⁴-CN, R⁸R⁹C=CR¹⁰C(=O)R⁴N-, R¹¹R¹²NCH2CH=CHC(=O)R⁴N- 5 , H2C=CHSO2-R⁴N- or R¹³C≡CC(=O)-R⁴N-; Y⁴ is a 4-7 membered heterocycloalkyl comprising a nitrogen atom or C3-7 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; 10 R¹ is 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 15 unsubstituted or independently substituted with one or more substituents independently selected from halogen, CN, hydroxyl and methoxy; R² is hydrogen, hydroxyl, C_1-4 alkyl, CN, -CONHC_1-4 alkyl, or C_1-4 haloalkyl; each R³ is independently selected from hydrogen, fluoro, hydroxyl, methoxy, C_1-3 alkyl, cyclopropyl, or a R³ is fused with R⁵ or R⁶ to form CH₂, CH₂-CH₂ or CH₂OCH₂; 20 each R⁴ is independently selected from hydrogen and C_1-3 alkyl; R⁵ is hydrogen, fluoro, hydroxyl, methoxy, C_1-3 alkyl, cyclopropyl or is fused with one R³ to form CH₂, CH₂-CH₂ or CH₂OCH₂, wherein the C_1-3 alkyl is unsubstituted or independently substituted with one or more substituents independently selected from halogen, heteroaryl (which heteroaryl is preferably pyridyl), phenyl, hydroxyl, -CO₂R⁴ or C_1-3 alkoxy; 25 R⁶ is hydrogen, fluoro, hydroxyl, methoxy, C_1-3 alkyl or is fused with one R³ to form CH₂, CH₂-CH₂ or CH₂OCH₂; each R⁸ is independently selected from hydrogen and C_1-6 alkyl; each R⁹ is independently selected from hydrogen, CF₃ and C_1-6 alkyl, which alkyl is unsubstituted or substituted with one or more substituents independently selected from fluoro, chloro, bromo, hydroxyl, and 30 C_1-6 alkoxy; and R¹⁰ is hydrogen, C_1-3 alkyl or halogen; or R⁹ and R¹⁰ together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring; each of R¹¹ and R¹² is independently hydrogen, C_1-6 alkyl, or R¹¹ and R¹² together with the nitrogen atom to 35 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; R¹³ is hydrogen, R¹⁴R¹⁵NCH2-, or C1-3 alkyl which is unsubstituted or substituted with hydroxyl; R¹⁴ and R¹⁵ are each independently hydrogen or C1-6 alkyl; 4 R¹⁶ is C1-3 alkyl-R¹⁷, C3-6 cycloalkyl-R¹⁷ or 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, -NR⁴R⁸ wherein 5 R⁴ and R⁸ are as defined above, or, alternatively, R⁴ and R⁸ together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring; R¹⁷ is 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, heteroaryl, heterocycloalkyl, and cycloalkyl are unsubstituted or substituted with one or more substituents independently selected from 10 the group consisting of halogen, CN, C1-4 alkyl, and C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; or a pharmaceutically acceptable salt and/or solvate thereof. [0008] In a second 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 15 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. [0009] 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, disorder 20 or condition that is associated with abnormal activity or expression of an FGFR enzyme, in particular cancer. [0010] 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. 25 [0011] 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. [0012] In another aspect, the invention provides methods of using/administering the compounds or a pharmaceutical composition comprising them. 30 [0013] In an additional aspect, the invention provides methods of making the compounds and compositions comprising them. [0014] Moreover, the compounds of the invention, useful in the pharmaceutical compositions and treatment methods disclosed herein, are pharmaceutically acceptable as prepared and used. [0015] In additional aspects, this invention provides methods for synthesizing the compounds of the 35 invention, with representative synthetic protocols and pathways disclosed later on herein. [0016] Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing detailed description. 5 [0017] 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. [0018] Certain compounds provided herein have superior FGFR3 potency compared to certain previously 5 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). [0019] In another aspect, the present invention provides compounds of Formula (Ia-5): 10 X1 is N or CH; X2 is N and X3 is C, or, alternatively, X3 is N and X2 is C; Y is a bond, O or NH; Y1 is a CHR⁶, CH2-CHR⁶, CHR⁶-CH2, CH2-CF2 or CF2-CH2; 15 Y₂ is CR⁴R⁵ or CF₂; Y₃ is CR³R⁴ _, CH₂CR³R⁴, CH₂CF₂ or CF₂; wherein Y₁, Y₂ and Y₃ together with N atom of N-A and the pyrazolyl ring form a 7-membered nitrogen containing ring; A is CN, R⁸R⁹C=CR¹⁰C(=O)-, R¹¹R¹²NCH₂CH=CHC(=O)-, H₂C=CHSO₂-, R¹³C≡CC(=O)- or R²³CH=CH- 20 SO₂- wherein R²³ is H or C_1-2alkyl; R¹ is hydrogen, halogen, C_1-5 alkyl, C_1-5 alkoxy, CN, C_3-10 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 25 from halogen, methyl, halomethyl, hydroxyl or methoxy and wherein the C_1-5 alkyl and C_1-5 alkoxy, are unsubstituted or independently substituted with one or more substituents independently selected from halogen, CN, hydroxyl and methoxy; R² is hydrogen, hydroxyl, C_1-4 alkyl, CN, -CONHC_1-4 alkyl, or C_1-4 haloalkyl; each R³ is independently selected from hydrogen, fluoro, hydroxyl, methoxy, C_1-3 alkyl, cyclopropyl, or a 30 R³ is fused with R⁵ or R⁶ to form CH₂, CH₂-CH₂ or CH₂OCH₂; each R⁴ is independently selected from hydrogen and C_1-3 alkyl; 6 R⁵ is hydrogen, fluoro, hydroxyl, methoxy, C1-3 alkyl, cyclopropyl or is fused with one R³ to 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, -CO2R⁴ or C1-3 alkoxy; 5 R⁶ is hydrogen, fluoro, hydroxyl, methoxy, C1-3 alkyl or is fused with one R³ to form CH2, CH2-CH2 or CH2OCH2; each R⁸ is independently selected from hydrogen and C1-6 alkyl; each R⁹ is 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 10 C1-6 alkoxy; and R¹⁰ is hydrogen, C1-3 alkyl or halogen; or R⁹ and R¹⁰ together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring; each of R¹¹ and R¹² is independently hydrogen, C1-6 alkyl, or R¹¹ and R¹² together with the nitrogen atom to 15 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; R¹³ is hydrogen, R¹⁴R¹⁵NCH₂-, or C_1-3 alkyl which is unsubstituted or substituted with hydroxyl; R¹⁴ and R¹⁵ are each independently hydrogen or C_1-6 alkyl; R¹⁶ is C_1-3 alkyl-R¹⁷, C_3-6 cycloalkyl-R¹⁷ or a 4-6 membered heterocycloalkyl comprising 1, 2 or 3 20 heteroatoms independently selected from N, O and S, wherein the C_1-3 alkyl, C_3-6 cycloalkyl and 4-6 membered heterocycloalkyl are unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, CN, C_1-4 alkyl, C_3-6 cycloalkyl, OH, OMe, -NR⁴R⁸ wherein R⁴ and R⁸ are as defined above, or, alternatively, R⁴ and R⁸ together 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 25 carbon atom are attached to the same carbon atom in the C_1-3 alkyl, C_3-6 cycloalkyl and 4-6 membered heterocycloalkyl group such that an oxygen-containing heterocyclyl forms; R¹⁷ is hydrogen, aryl, heteroaryl, 4-6 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, O and S, or C_3-8 cycloalkyl, wherein the aryl and heteroaryl are unsubstituted or substituted with one or more substituents independently selected from the group consisting 30 of halogen, CN, NH₂, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 alkoxy, and C_1-4 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, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 alkoxy, and C_1-4 haloalkoxy; or a pharmaceutically acceptable salt and/or solvate thereof. 35 [0020] In another aspect, the present invention provides compounds of Formula (Ia-6): 7 wherein: X1 is N or CH; X2 is N and X3 is C, or, alternatively, X3 is N and X2 is C; 5 Y is a bond, O or NH; Y1 is a CHR⁶; Y2 is CR⁴R⁵ or CF2; Y3 is CH2CR³R⁴; A is CN, R⁸R⁹C=CR¹⁰C(=O)-, R¹¹R¹²NCH2CH=CHC(=O)-, H2C=CHSO2- or R¹³C≡CC(=O)-; 10 R¹ is 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 15 unsubstituted or independently substituted with one or more substituents independently selected from halogen, CN, hydroxyl and methoxy; R² is hydrogen, hydroxyl, C_1-4 alkyl, CN, -CONHC_1-4 alkyl, or C_1-4 haloalkyl; each R³ is independently selected from hydrogen, fluoro, hydroxyl, methoxy, C_1-3 alkyl, cyclopropyl, or a R³ is fused with R⁵ or R⁶ to form CH₂, CH₂-CH₂ or CH₂OCH₂; 20 each R⁴ is independently selected from hydrogen and C_1-3 alkyl; R⁵ is hydrogen, fluoro, hydroxyl, methoxy, C_1-3 alkyl, cyclopropyl or is fused with one R³ to form CH₂, CH₂-CH₂ or CH₂OCH₂, wherein the C_1-3 alkyl is unsubstituted or independently substituted with one or more substituents independently selected from halogen, heteroaryl (which heteroaryl is preferably pyridyl), phenyl, hydroxyl, -CO₂R⁴ or C_1-3 alkoxy; 25 R⁶ is hydrogen, fluoro, hydroxyl, methoxy, C_1-3 alkyl or is fused with one R³ to form CH₂, CH₂-CH₂ or CH₂OCH₂; each R⁸ is independently selected from hydrogen and C_1-6 alkyl; each R⁹ is independently selected from hydrogen, CF₃ and C_1-6 alkyl, which alkyl is unsubstituted or substituted with one or more substituents independently selected from fluoro, chloro, bromo, hydroxyl, and 30 C_1-6 alkoxy; and R¹⁰ is hydrogen, C_1-3 alkyl or halogen; 8 or R⁹ and R¹⁰ together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring; each of R¹¹ and R¹² is independently hydrogen, C1-6 alkyl, or R¹¹ and R¹² together with the nitrogen atom to which they are attached form a 4-6 membered heterocycloalkyl optionally having an additional ring 5 heteroatom which is O, wherein said ring is optionally substituted with halogen; R¹³ is hydrogen, R¹⁴R¹⁵NCH2-, or C1-3 alkyl which is unsubstituted or substituted with hydroxyl; R¹⁴ and R¹⁵ are each independently hydrogen or C1-6 alkyl; R¹⁶ is C1-3 alkyl-R¹⁷, C3-6 cycloalkyl-R¹⁷ or 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 10 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, -NR⁴R⁸ wherein R⁴ and R⁸ are as defined above, or, alternatively, R⁴ and R⁸ together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring; R¹⁷ is hydrogen, aryl, heteroaryl, 4-6 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms 15 independently selected from N, O 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, C_1-4 alkyl, and C_1-4 haloalkyl, C_1-4 alkoxy, and C_1-4 haloalkoxy; or a pharmaceutically acceptable salt and/or solvate thereof. 20 [0021] In another aspect, the present invention provides compounds of Formula (Ib-3): 25 wherein: X1 is N or CH; X2 is N and X3 is C, or, alternatively, X3 is N and X2 is C; Y is a bond, O or NH; Y1 is a bond, CHR⁶, CH2-CHR⁶, CHR⁶-CH2, CF2, CH2-CF2 or CF2-CH2; 30 Y2 is CR⁴R⁵ or CF2; 9 Y3 is CR³R⁴, CR³R⁴CR³R⁴, CH2CF2 or CF2; A is -NR⁴-CN, R⁸R⁹C=CR¹⁰C(=O)R⁴N-, R¹¹R¹²NCH2CH=CHC(=O)R⁴N-, H2C=CHSO2-R⁴N- or R¹³C≡CC(=O)-R⁴N-; R¹ is hydrogen, halogen, C1-5 alkyl, C1-5 alkoxy, CN, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl 5 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 10 selected from halogen, CN, hydroxyl and methoxy; R² is hydrogen, hydroxyl, C1-4 alkyl, CN, -CONHC1-4 alkyl, or C1-4 haloalkyl; each R³ is independently selected from hydrogen, fluoro, hydroxyl, methoxy, C1-3 alkyl, cyclopropyl, or a R³ is fused with R⁵ or R⁶ to form CH2, CH2-CH2 or CH2OCH2; each R⁴ is independently selected from hydrogen and C1-3 alkyl; 15 R⁵ is hydrogen, fluoro, hydroxyl, methoxy, C1-3 alkyl, cyclopropyl or is fused with one R³ to 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, -CO₂R⁴ or C_1-3 alkoxy; R⁶ is hydrogen, fluoro, hydroxyl, methoxy, C_1-3 alkyl or is fused with one R³ to form CH₂, CH₂-CH₂ or 20 CH₂OCH₂; each R⁸ is independently selected from hydrogen and C_1-6 alkyl; each R⁹ is independently selected from hydrogen, CF₃ and C_1-6 alkyl, which alkyl is unsubstituted or substituted with one or more substituents independently selected from fluoro, chloro, bromo, hydroxyl, and C_1-6 alkoxy; and 25 R¹⁰ is hydrogen, C_1-3 alkyl or halogen; or R⁹ and R¹⁰ together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring; each of R¹¹ and R¹² is independently hydrogen, C_1-6 alkyl, or R¹¹ and R¹² together with the nitrogen atom to which they are attached form a 4-6 membered heterocycloalkyl optionally having an additional ring 30 heteroatom which is O, wherein said ring is optionally substituted with halogen; R¹³ is hydrogen, R¹⁴R¹⁵NCH₂-, or C_1-3 alkyl which is unsubstituted or substituted with hydroxyl; R¹⁴ and R¹⁵ are each independently hydrogen or C_1-6 alkyl; R¹⁶ is C_1-3 alkyl-R¹⁷, C_3-6 cycloalkyl-R¹⁷ or a 4-6 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein the C_1-3 alkyl, C_3-6 cycloalkyl and 4-6 35 membered heterocycloalkyl are unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, CN, C_1-4 alkyl, C_3-6 cycloalkyl, OH, OMe, -NR⁴R⁸ wherein R⁴ and R⁸ are as defined above, or, alternatively, R⁴ and R⁸ together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring; 10 R¹⁷ is 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, 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 C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; 5 or a pharmaceutically acceptable salt and/or solvate thereof DETAILED DESCRIPTION OF THE INVENTION Definitions [0022] The following terms are intended to have the meanings presented therewith below and are useful 10 in understanding the description and intended scope of the present invention. [0023] 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 15 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. [0024] The articles ‘a’ and ‘an’ may be used herein to refer to one or to more than one (i.e. at least one) of 20 the grammatical objects of the article. By way of example ‘an analogue’ means one analogue or more than one analogue. [0025] A dash ( - ) that 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 25 more dashes without losing their ordinary meaning. [0026] 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. 30 [0027] The prefix “C_u-v” indicates that the following group has from u to v carbon atoms. For example, “C_1-8 alkyl” indicates that the alkyl group has from 1 to 8 carbon atoms. [0028] 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%. 35 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 11 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. [0029] Unless indicated explicitly otherwise, where combinations of groups are referred to herein as one 5 moiety, e.g. arylalkyl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule. [0030] ‘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 10 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. 15 [0031] ‘Alkenyl’ refers to monovalent olefinically (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 (-CH=CH₂), n-propenyl (-CH₂CH=CH₂), isopropenyl (-C(CH₃)=CH₂) and the like. 20 [0032] 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-. [0033] ‘Alkylene’ refers to divalent alkyl radical groups having the number of carbon atoms specified, in 25 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. [0034] ‘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 30 atoms which can be straight-chained or branched. This term is exemplified by groups such as -C≡C-, -CH₂-C≡C-, and -C(CH₃)H-C≡CH-. [0035] ‘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_1-6 alkyl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 35 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. [0036] ‘Amino’ refers to the radical -NH2. 12 [0037] ‘Aryl’ 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, 5 and naphthyl. [0038] ‘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, 10 cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. [0039] ‘Cyano’ refers to the radical -CN. [0040] ‘Halo’ or ‘halogen’ refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). Particular halo groups are either fluoro or chloro. [0041] ‘Hetero’ when used to describe a compound or a group present on a compound means that one or 15 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. 20 [0042] ‘Heteroaryl’ means an aromatic ring structure, monocyclic or fused polycyclic, that includes one or more heteroatoms independently selected from O, 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 25 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 30 in the case of an indole 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. [0043] 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. 35 [0044] Examples of six membered monocyclic heteroaryl groups include but are not limited to pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl. [0045] 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. 13 [0046] 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, 5 triazolopyrimidinyl, and pyrazolopyridinyl groups. [0047] 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, 10 oxazolyl and pyrazinyl. [0048] Examples of representative heteroaryls include the following: wherein each Y is selected from >C=O, NH, O and S. [0049] ‘Heterocycloalkyl’ means a non-aromatic fully saturated ring structure, monocyclic, fused 15 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, 20 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), tetrahydrofuranyl (e.g. 1-tetrahydrofuranyl, 2- tetrahydrofuranyl and 3-tetrahydrofuranyl), tetrahydrothiophenyl (e.g. 1-tetrahydrothiophenyl, 2- tetrahydrothiophenyl and 3-tetrahydrothiophenyl), piperidinyl (e.g. 1-piperidinyl, 2-piperidinyl, 3- 25 piperidinyl and 4-piperidinyl), tetrahydropyranyl (e.g. 4-tetrahydropyranyl), tetrahydrothiopyranyl (e.g. 4-tetrahydrothiopyranyl), morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl. [0050] 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: 30 14 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. [0051] Particular examples of monocyclic rings are shown in the following illustrative examples: 5 wherein each W and Y is independently selected from -CH₂-, -NH-, -O- and –S-. [0052] Particular examples of fused bicyclic rings are shown in the following illustrative examples: wherein each W and Y is independently selected from -CH₂-, -NH-, -O- and –S-. [0053] Particular examples of bridged bicyclic rings are shown in the following illustrative examples: 10 wherein each W and Y is independently selected from -CH2-, -NH-, -O- and –S- and each Z is selected from N or CH. [0054] Particular examples of spirocyclic rings are shown in the following illustrative examples: 15 wherein each Y is selected from -CH₂-, -NH-, -O- and –S-. [0055] ‘Hydroxyl’ refers to the radical -OH. [0056] ‘Oxo’ refers to the radical =O. [0057] ‘Substituted’ refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s). 20 [0058] ‘Sulfo’ or ‘sulfonic acid’ refers to a radical such as –SO₃H. [0059] ‘Thiol’ refers to the group -SH. [0060] 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. 25 [0061] ‘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-C_1-6 alkyl. Particular thioalkoxy groups are thiomethoxy, thioethoxy, n-thiopropoxy, isothiopropoxy, n-thiobutoxy, tert-thiobutoxy, sec- thiobutoxy, n-thiopentoxy, n-thiohexoxy, and 1,2-dimethylthiobutoxy. Particular thioalkoxy groups are 15 lower thioalkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms. [0062] 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, 5 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. [0063] ‘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 10 listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans. [0064] ‘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 parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and 15 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,20 mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenesulfonic 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 25 acid, stearic acid, muconic 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 30 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. 35 [0065] ‘Pharmaceutically acceptable vehicle’ refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered. [0066] ‘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 16 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. [0067] ‘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, 5 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 10 solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates. [0068] ‘Subject’ includes humans. The terms ‘human’, ‘patient’ and ‘subject’ are used interchangeably herein. [0069] ‘Effective amount’ means the amount of a compound of the invention that, when administered to a 15 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. [0070] ‘Preventing’ or ‘prevention’ refers to a reduction in risk of acquiring or developing a disease or disorder (i.e. causing at least one of the clinical symptoms of the disease not to develop in a subject that 20 may be exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset. [0071] 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 25 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. [0072] ‘Treating’ or ‘treatment’ of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.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 30 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. 35 [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 FGFR1. For example, certain 17 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. [0074] As used herein, the term "selectivity" of a compound refers to the compound having more potent 5 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. 10 [0075] 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 15 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 20 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 25 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- 30 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 35 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 18 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) 5 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. [0076] 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 10 particularly, the term refers to acute myeloid leukaemia (AML), and acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukaemia (CLL). [0077] 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 15 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, 20 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. [0078] ‘Compound(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, 25 and the solvates, e.g. hydrates, and the solvates of the pharmaceutically acceptable salts where the context so permits. Accordingly, ‘compound(s) of the invention’ may refer to a compound according to any of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), or Formula (Ie), 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 30 permits. [0079] When ranges are referred to herein, for example but without limitation, C₁-₈ alkyl, the citation of a range should be considered a representation of each member of said range. [0080] 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 35 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 19 aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention 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 C1-8 alkyl, C2-8 alkenyl, C6-10 optionally substituted aryl, and (C6-10 aryl)-(C1-4 alkyl) esters of 5 the compounds of the invention. [0081] 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 10 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 15 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 20 forms will typically be isotopically enriched variant forms. [0082] 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 (¹¹C), 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 (³⁶Cl), chlorine-37 (³⁷Cl), fluorine-18 (¹⁸F) iodine-123 (¹²³I), 25 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. [0083] 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 30 of detection. Unnatural variant isotopic forms which incorporate deuterium i.e ²H 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 as ¹¹C, ¹⁸F, ¹⁵0 and ¹³N, and would be useful in Positron Emission Topography (PET) studies for 35 examining substrate receptor occupancy. [0084] 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’. 20 [0085] 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 5 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’. 10 [0086] ‘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 π 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 15 formed by treatment with acid or base. [0087] Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest. [0088] 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. 20 [0089] 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*. 25 [0090] 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. [0091] It will be appreciated that compounds of the invention may be metabolized to yield biologically 30 active metabolites. THE INVENTION [0092] 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 35 compound of the invention, pharmaceutical compositions comprising the compound of the invention, methods for the prophylaxis and/or treatment of diseases, disorders, or conditions that are associated 21 with abnormal activity or expression of an FGFR enzyme, in particular cancer, by administering a compound of the invention. [0093] Accordingly, in a first aspect, the invention provides compounds of Formula (I): 5 wherein: X1 is N or CH; X2 is N and X3 is C, or, alternatively, X3 is N and X2 is C; X4 is N or CR⁴; 10 Y is a bond, O or NH; Y1 is a bond, CHR⁶, CH2-CHR⁶, CHR⁶-CH2, CF2, CH2-CF2 or CF2-CH2; Y2 is CR⁴R⁵ or CF2; Y3 is CR³R⁴, CR3R4CR3R4, CH2CF2 or CF2; when X4 is N, B is a bond, -C(O)Y⁴-, -Y⁴-, -CH2Y⁴-, or -CH2CH2Y⁴-, and A is CN, R⁸R⁹C=CR¹⁰C(=O)-, 15 R¹¹R¹²NCH2CH=CHC(=O)-, H2C=CHSO2- or R¹³C≡CC(=O)-; when X4 is CR⁴, B is a bond, and A is -NR⁴-CN, R⁸R⁹C=CR¹⁰C(=O)R⁴N-, R¹¹R¹²NCH2CH=CHC(=O)R⁴N- , H2C=CHSO2-R⁴N- or R¹³C≡CC(=O)-R⁴N-; Y⁴ is a 4-7 membered heterocycloalkyl comprising a nitrogen atom or C3-7 cycloalkyl-R⁴N-, wherein the heterocycloalkyl and cycloalkyl are unsubstituted or independently substituted with one or more 20 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; R¹ is 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 25 membered heteroaryl are unsubstituted or substituted with one or more substituents independently selected from halogen, methyl, halomethyl, hydroxyl or methoxy and wherein the C_1-5 alkyl and C_1-5 alkoxy, are unsubstituted or independently substituted with one or more substituents independently selected from halogen, CN, hydroxyl and methoxy; 22 R² is hydrogen, hydroxyl, C1-4 alkyl, CN, -CONHC1-4 alkyl, or C1-4 haloalkyl; each R³ is independently selected from hydrogen, fluoro, hydroxyl, methoxy, C1-3 alkyl, cyclopropyl, or a R³ is fused with R⁵ or R⁶ to form CH2, CH2-CH2 or CH2OCH2; each R⁴ is independently selected from hydrogen and C1-3 alkyl; 5 R⁵ is hydrogen, fluoro, hydroxyl, methoxy, C1-3 alkyl, cyclopropyl or is fused with one R³ to 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, -CO2R⁴ or C1-3 alkoxy; R⁶ is hydrogen, fluoro, hydroxyl, methoxy, C1-3 alkyl or is fused with one R³ to form CH2, CH2-CH2 or 10 CH2OCH2; each R⁸ is independently selected from hydrogen and C1-6 alkyl; each R⁹ is 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 C1-6 alkoxy; and 15 R¹⁰ is hydrogen, C1-3 alkyl or halogen; or R⁹ and R¹⁰ together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring; each of R¹¹ and R¹² is independently hydrogen, C_1-6 alkyl, or R¹¹ and R¹² together with the nitrogen atom to which they are attached form a 4-6 membered heterocycloalkyl optionally having an additional ring 20 heteroatom which is O, wherein said ring is optionally substituted with halogen; R¹³ is hydrogen, R¹⁴R¹⁵NCH₂-, or C_1-3 alkyl which is unsubstituted or substituted with hydroxyl; R¹⁴ and R¹⁵ are each independently hydrogen or C_1-6 alkyl; R¹⁶ is C_1-3 alkyl-R¹⁷, C_3-6 cycloalkyl-R¹⁷ or a 4-6 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein the C_1-3 alkyl, C_3-6 cycloalkyl and 4-6 25 membered heterocycloalkyl are unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, CN, C_1-4 alkyl, C_3-6 cycloalkyl, OH, OMe, -NR⁴R⁸ wherein R⁴ and R⁸ are as defined above, or, alternatively, R⁴ and R⁸ together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring; R¹⁷ is hydrogen, aryl, heteroaryl, 4-6 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms 30 independently selected from N, O and S, or C_3-8 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, C_1-4 alkyl, and C_1-4 haloalkyl, C_1-4 alkoxy, and C_1-4 haloalkoxy; or a pharmaceutically acceptable salt and/or solvate thereof. [0094] In certain embodiments, the compound of the Formula (I) is a compound of the Formula (Ia): 23 or a pharmaceutically acceptable salt and/or solvate thereof; wherein X₁, X₂, X₃, Y, Y₁, Y₂, Y₃, R¹, R², R¹⁶ and A are as defined for Formula (I). Preferred definitions 5 of X₁, X₂, X₃, Y, Y₁, Y₂, Y₃, R¹, R², R¹⁶ and A are as defined for compounds of formula (I). [0095] In certain embodiments, the compound of the Formula (Ia) is a compound of the Formula (Ia-1): (Ia-1) wherein X₁, X₂, X₃, Y, R¹, R², R³, R⁴, R⁵, R⁶ and R¹⁶ are as defined for Formula (I). Preferred definitions 10 of X₁, X₂, X₃, Y, R¹, R², R³, R⁴, R⁵, R⁶ and R¹⁶ are as defined for compounds of formula (I). [0096] In certain embodiments, the compound of the Formula (Ia) is a compound of the Formula (Ia-2): 24 wherein X1, X2, X3, Y, R¹, R², R³, R⁴, R⁵, R⁶, R⁸, R⁹, R¹⁰ and R¹⁶ are as defined for Formula (I). Preferred definitions of X1, X2, X3, Y, R¹, R², R³, R⁴, R⁵, R⁶, R⁸, R⁹, R¹⁰ and R¹⁶ are as defined for compounds of formula (I). [0097] In certain embodiments, the compound of the Formula (Ia) is a compound of the Formula (Ia-3): 5 (Ia-3) wherein X1, X2, X3, Y, R¹, R², R³, R⁴, R⁵, R⁶ and R¹⁶ are as defined for Formula (I). Preferred definitions of X1, X2, X3, Y, R¹, R², R³, R⁴, R⁵, R⁶ and R¹⁶ are as defined for compounds of formula (I). [0098] In certain embodiments, the compound of the Formula (Ia) is a compound of the Formula (Ia-4): 10 (Ia-4) wherein X₁, X₂, X₃, Y, R¹, R², R³, R⁴, R⁵, R⁶, R⁸, R⁹, R¹⁰ and R¹⁶ are as defined for Formula (I). Preferred definitions of X₁, X₂, X₃, Y, R¹, R², R³, R⁴, R⁵, R⁶, R⁸, R⁹, R¹⁰ and R¹⁶ are as defined for compounds of formula (I). 15 [0099] In certain embodiments, the compound of the Formula (I) is a compound of the Formula (Ib): 25 or a pharmaceutically acceptable salt and/or solvate thereof; wherein X1, X2, X3, Y, Y1, Y2, Y3, R¹, R², R⁴, R¹⁶ and A are as defined for Formula (I). Preferred definitions 5 of X1, X2, X3, Y, Y1, Y2, Y3, R¹, R², R⁴, R¹⁶ and A are as defined for compounds of formula (I). [0100] In certain embodiments, the compound of the Formula (Ib) is a compound of the Formula (Ib-1): (Ib-1) wherein X1, X2, X3, Y, R¹, R², R³, R⁴, R⁵, R⁶ and R¹⁶ are as defined for Formula (I). Preferred definitions 10 of X1, X2, X3, Y, R¹, R², R³, R⁴, R⁵, R⁶ and R¹⁶ are as defined for compounds of formula (I). [0101] In certain embodiments, the compound of the Formula (Ib) is a compound of the Formula (Ib-1): wherein X1, X2, X3, Y, R¹, R², R³, R⁴, R⁵, R⁶ and R¹⁶ are as defined for Formula (I). Preferred definitions 15 of X1, X2, X3, Y, R¹, R², R³, R⁴, R⁵, R⁶ and R¹⁶ are as defined for compounds of formula (I). [0102] In certain embodiments, the compound of the Formula (I) is a compound of the Formula (Ib-3): 26 wherein X1, X2, X3, Y, Y1, Y2, Y3, R1, R2, R4, R16 and A are as defined for Formula (I). Preferred definitions of X1, X2, X3, Y, Y1, Y2, Y3, R1, R2, R4, R16 and A are as defined for compounds of formula (I). 5 [0103] 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; 10 wherein: Z is a absent, or is CO or (CH2)n; each n is independently 1 or 2; R²¹ is absent or is halogen, methyl, halomethyl, hydroxyl or methoxy; and X₁, X₂, X₃, Y, Y₁, Y₂, Y₃, R¹, R², R¹⁶ and A are as defined for Formula (I). Preferred definitions of X₁, X₂, 15 X₃, Y, Y₁, Y₂, Y₃, R¹, R², R¹⁶ and A are as defined for compounds of formula (I). [0104] In certain embodiments, the compound of the Formula (Ic) is a compound of the Formula (Ic-1): 27 (Ic-1) wherein hydrogen, methyl or halogen (preferably fluoro), and X₁, X₂, X₃, Y, Y₁, Y₂, Y₃, R¹, R², and R¹⁶ are as defined for Formula (I). Preferred definitions of X₁, X₂, X₃, Y, Y₁, Y₂, 5 Y₃, R¹, R², and R¹⁶ are as defined for compounds of formula (I). [0105] In certain embodiments, the compound of the Formula (I) is a compound of the Formula (Id): 10 or a pharmaceutically acceptable salt and/or solvate thereof; wherein: a is independently 0, 1, 2, 3, or 4; R¹⁸ is halogen; R¹⁹ is methyl, hydroxymethyl, or halomethyl (preferably fluoromethyl); 15 R²⁰ is H or methyl; and 28 X1, X2, X3, X4, Y1, Y2, Y3, R¹, R², B and A are as defined for Formula (I). Preferred definitions of X1, X2, X3, X4, Y1, Y2, Y3, R¹, R², B and 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 (Ie): 5 or a pharmaceutically acceptable salt and/or solvate thereof; wherein: a is independently 0, 1, 2, 3, or 4; 10 R¹⁸ is halogen; R¹⁹ is methyl, hydroxymethyl, or OH; R²⁰ is H or methyl; and X1, X2, X3, X4, Y1, Y2, Y3, R¹, R², B and A, are as defined for Formula (I). Preferred definitions of X1, X2, X3, X4, Y1, Y2, Y3, R¹, R², B and A are as defined for compounds of formula (I). 15 [0107] 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 20 (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. [0108] Preferred values of X₁, X₂, X₃, X₄, Y, Y₁, Y₂, Y₃, Y₄, R¹, R², R³, R⁴, R⁵, R⁶, R⁸, R⁹, R¹⁰, R¹¹, R¹², 25 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), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ib-1), (Ib-2) and (Ib-3) as well as other formulae disclosed herein. The term “compounds of the invention” refer to compounds 29 of formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), ), (Ib), (Ib-1), (Ib-2) and (Ib-3) as well as other formulae disclosed herein, in particular compounds of formula (Ia-5),(Ia-6) and (Ib-3). [0109] In some suitable compounds of the invention, X1 is N. [0110] Preferably X1 is CH. 5 [0111] In some suitable compounds of the invention, X2 is N and X3 is C. [0112] In some suitable compounds of the invention, X3 is N and X2 is C. [0113] Preferably X2 is C. [0114] Preferably X3 is N. [0115] Preferably X4 is N or CH. 10 [0116] In some suitable compounds of the invention, preferably X4 is CR⁴. [0117] In some suitable compounds of the invention, preferably X4 is N. [0118] When X4 is N, preferably B is a bond, -C(O)Y⁴-, -Y⁴- or -CH2Y⁴-, and preferably A is CN or R⁸R⁹C=CR¹⁰C(=O)-, wherein preferably Y⁴ is a 3-6 membered heterocycloalkyl comprising a nitrogen atom or C3-5 cycloalkyl-R⁴N-, wherein the heterocycloalkyl and cycloalkyl are unsubstituted or 15 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. [0119] When X₄ is N, more preferably B is a bond, or is selected from , 20 , 30 w_{herein 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; R⁴ is independently selected from hydrogen and C_1-3 alkyl; R²¹ is absent or each is independently halogen (preferably fluoro), methyl or methoxy and each R²² is independently hydrogen, halogen (preferably fluoro) or methyl. 5 [0120] When X₄ is N, most preferably B is a bond, or is selected from fluoro) and R²² is hydrogen, methyl or halogen (preferably fluoro). 10 [0121] Preferably, B is a bond, such as when X4 is N, B is a bond. [0122] Preferably, B is a bond, such as when X4 is CR⁴, B is a bond. [0123] When X4 is CH, preferably B is a bond and preferably A is -NH-CN or R⁸R⁹C=CR¹⁰C(=O) NH-. [0124] When X4 is CH, more preferably B is a bond and more preferably A is -NH-CN, 31 [0125] When X4 is CH, most preferably B is a bond and most preferably A is -NH-CN, . [0126] In one embodiment, A is CN. In a second embodiment, A is R⁸R⁹C=CR¹⁰C(=O)-. In a third embodiment, A is R¹¹R¹²NCH₂CH=CHC(=O)-. In a fourth embodiment, A is H₂C=CHSO₂-. In a fifth 5 embodiment, A is R¹³C≡CC(=O)-. In a sixth embodiment, A is R²³CH=CH-SO2- wherein R²³ is H or C_1-2alkyl. [0127] In one embodiment, A is -NR⁴-CN. In a second embodiment, A is R⁸R⁹C=CR¹⁰C(=O)R⁴N- . In a third embodiment, A is R¹¹R¹²NCH₂CH=CHC(=O)R⁴N-. In a fourth embodiment, A is H₂C=CHSO₂-R⁴N- . In a fifth embodiment, A is R¹³C≡CC(=O)-R⁴N-. In a sixth embodiment, A is CH₃CH=CH-SO₂-. 10 [0128] Preferably, A is CN or R⁸R⁹C=CR¹⁰C(=O)-, e.g. CN. [0129] In one embodiment, Y is a bond. In a second embodiment, Y is NH. In a third embodiment, Y is O. [0130] Preferably Y is O. [0131] In one embodiment, Y1 is a bond. In a second embodiment, Y1 is CHR⁶. In a third embodiment, 15 Y₁ is CH2-CHR⁶. In a fourth embodiment, Y₁ is CHR⁶-CH₂. In a fifth embodiment, Y₁ is CH₂-CF₂. In a sixth embodiment, Y₁ is CF₂-CH₂.In one embodiment, Y₁ is CHR⁶ or CF₂. [0132] In one embodiment, Y1 is CHR⁶, CH2-CHR⁶, CHR⁶-CH2, CH2-CF2 or CF2-CH2. [0133] Preferably Y1 is CHR⁶. [0134] Most preferably Y1 is CH2. 20 [0135] In one embodiment, Y2 is CR⁴R⁵. In a second embodiment, Y2 is CF2. [0136] Most preferably Y2 is CHR⁵. [0137] In one embodiment, Y3 is CR³R⁴. In a second embodiment, Y3 is CR3R4CR3R4. In a third embodiment, Y3 is CH2CF2. In a fourth embodiment, Y3 is CF2. [0138] Preferably Y3 is CR³R⁴ or CH2CR³R⁴ e.g. CH2CR³R⁴. 25 [0139] Most preferably Y3 is CH2 or CH2CH2. [0140] Even more preferably, Y3 is CR³R⁴ (e.g. CH2) or CF2. [0141] In another embodiment, Y1, Y2 and Y3 together with C atom of CR⁴-A and the pyrazolyl ring form a 6-membered ring. [0142] In another embodiment, Y1, Y2 and Y3 together with C atom of CR⁴-A and the pyrazolyl ring form 30 a 7-membered ring. [0143] In one embodiment, Y1 is CHR⁶, Y2 is CR⁴R⁵ or CF2 and Y3 is CH2CR3R4. [0144] In another embodiment, Y1 is a CHR⁶, CH2-CHR⁶, CHR⁶-CH2, CH2-CF2 or CF2-CH2; Y2 is CR⁴R⁵ or CF2; Y3 is CR³R⁴, CH2CR3R4, CH2CF2 or CF2; wherein Y1, Y2 and Y3 together with N atom of N-A and the pyrazolyl ring form a 7-membered nitrogen containing ring. 32 [0145] For example, in this embodiment Y1 is CHR⁶, Y2 is CR⁴R⁵ and Y3 is CH2CR3R4 or CH2CF2. Alternatively, Y1 is CHR⁶, Y2 is CF2 and Y3 is CH2CR3R4 or CH2CF2. Alternatively, Y1 is CH2-CHR⁶, CHR⁶-CH2, CH2-CF2 or CF2-CH2, Y2 is CR⁴R⁵ and Y3 is CR³R⁴ or CF2. Alternatively, Y1 is CH2-CHR⁶, CHR⁶-CH2, CH2-CF2 or CF2-CH2, Y2 is CF2 and Y3 is CR³R⁴ or CF2. 5 [0146] In one embodiment, R¹ is hydrogen. In a second embodiment, R¹ is halo e.g. chloro. In a third embodiment, R¹ is C1-5 alkyl. In a fourth embodiment, R¹ is C1-5 alkoxy e.g. OMe. In a fifth embodiment, R¹ is CN. In a sixth embodiment, R¹ is C3-10 cycloalkyl. In a seventh embodiment, R¹ is 4-10 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, O and S. In a eighth embodiment, R¹ is phenyl. In a nineth embodiment, R¹ is a 5-6 membered heteroaryl. 10 [0147] Preferably R¹ is 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). [0148] More preferably R¹ is hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, 15 halomethyl, haloethyl, halomethoxy, haloethoxy, cyano, CF3, CHF2, OCH3 or OCHF2. [0149] Most preferably R¹ is hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, cyano, CF3, CHF₂, OCH₃ or OCHF₂ (especially OCH₃ or OCHF₂). [0150] Even more preferably, R¹ is chloro. [0151] In one embodiment, R² is hydrogen. In a second embodiment, R² is hydroxyl. In a third 20 embodiment, R² is C_1-4 alkyl e.g. CH₃. In a fourth embodiment, R² is CN. In a fifth embodiment, R² is -CONHC_1-4 alkyl. In a sixth embodiment, R² is C_1-4 haloalkyl [0152] Preferably R² is hydrogen, hydroxyl or C_1-2 alkyl. [0153] Most preferably R² is hydrogen, methyl or ethyl. [0154] Even more preferably R² is methyl. 25 [0155] Preferably each R³ is independently selected from hydrogen, fluoro and C_1-2 alkyl. [0156] More preferably each R³ is independently selected from hydrogen, fluoro and methyl. [0157] Most preferably each R³ is independently hydrogen. [0158] Preferably each R⁴ is independently selected from hydrogen and methyl. [0159] Most preferably each R⁴ is independently hydrogen. 30 [0160] Preferably R⁵ is hydrogen, fluoro, hydroxyl, methoxy or C_1-3 alkyl, wherein the C_1-3 alkyl is unsubstituted or independently substituted with one or more substituents independently selected from halogen, pyridyl, phenyl, hydroxyl, -CO₂R⁴ or C_1-3 alkoxy. [0161] Most preferably R⁵ is hydrogen or C_1-3 alkyl, wherein the C_1-3 alkyl is unsubstituted or substituted with a substituent selected from pyridyl, phenyl, and -CO₂H. 35 [0162] Even more preferably R⁵ is hydrogen. [0163] Preferably R⁶ is hydrogen, fluoro or C_1-2 alkyl. [0164] More preferably R⁶ is hydrogen, fluoro or methyl. [0165] Most preferably R⁶ is hydrogen. 33 [0166] Preferably each R⁸ is independently selected from hydrogen and C1-2 alkyl. [0167] More preferably each R⁸ is independently selected from hydrogen and methyl. [0168] Most preferably each R⁸ is independently hydrogen. [0169] Preferably each R⁹ is independently selected from hydrogen, CF3 and C1-2 alkyl, which alkyl is 5 unsubstituted or substituted with one or more substituents independently selected from fluoro, chloro and bromo. [0170] More preferably each R⁹ is independently selected from hydrogen, CF3 and methyl. [0171] Most preferably each R⁹ is independently hydrogen. [0172] Preferably each R¹⁰ is independently selected from hydrogen, C1-2 alkyl and halogen. 10 [0173] More preferably each R¹⁰ is independently selected from hydrogen, fluoro, chloro, and methyl. [0174] Most preferably each R¹⁰ is independently selected from hydrogen, fluoro and methyl. [0175] Preferably each of R¹¹ and R¹² is independently hydrogen, C1-3 alkyl, or R¹¹ and R¹² together 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 15 with one or more halogen atoms. [0176] More preferably each of R¹¹ and R¹² is independently hydrogen, C1-2 alkyl, or R¹¹ and R¹² together 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. [0177] Most preferably each of R¹¹ and R¹² is independently hydrogen or methyl, or R¹¹ and R¹² together 20 with the nitrogen atom to which they are attached form a 4-6 membered heterocycloalkyl. [0178] Preferably each R¹³ is independently selected from hydrogen, R¹⁴R¹⁵NCH₂-, and C_1-3 alkyl, which alkyl is unsubstituted or substituted with hydroxyl. [0179] More preferably each R¹³ is independently selected from hydrogen and C_1-2 alkyl, which alkyl is unsubstituted or substituted with hydroxyl. 25 [0180] Most preferably each R¹³ is independently selected from hydrogen and methyl. [0181] Preferably R¹⁴ and R¹⁵ are each independently hydrogen or C_1-3 alkyl. [0182] More preferably R¹⁴ and R¹⁵ are each independently hydrogen or C_1-2 alkyl. [0183] Most preferably R¹⁴ and R¹⁵ are each independently hydrogen or methyl. [0184] Preferably R¹⁶ is C_1-3 alkyl-R¹⁷, wherein the C_1-3 alkyl is unsubstituted or substituted with one or 30 more substituents independently selected from the group consisting of halogen, C_1-2 alkyl, C_3-6 cycloalkyl, OH and OMe. [0185] In one embodiment, R¹⁶ is C₁ alkyl-R¹⁷, wherein the C₁ alkyl is unsubstituted or substituted with one or more substituents as defined herein. In a second embodiment, R¹⁶ is C₂ alkyl-R¹⁷, wherein the C₂ alkyl is unsubstituted or substituted with one or more substituents as defined herein. In a third 35 embodiment, R¹⁶ is C₃ alkyl-R¹⁷, wherein the C₃ alkyl is unsubstituted or substituted with one or more substituents as defined herein. [0186] In one embodiment, R¹⁶ is -CH2CH2CH2R¹⁷. Alternatively R¹⁶ is -CH2CH(R¹⁷)CH3. Alternatively R¹⁶ is -CH(R¹⁷)CH2CH3. Alternatively R¹⁶ is -CH(R¹⁷)CH3. Alternatively R¹⁶ is -CH2CH2R¹⁷. 34 [0187] Preferably, R¹⁶ is -CH2CH2R¹⁷ or -CH(R¹⁷)CH3. [0188] When R¹⁶ is C1-3 alkyl-R¹⁷ substituted 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), R¹⁶ is suitably -CH(R¹⁷)-CH2(substituent) e.g. -CH(R¹⁷)-CH2(OH). 5 [0189] In one embodiment, the C1-3 alkyl is substituted by one substituent. [0190] Suitably, the one substituent is OH. Alternatively the one substituent is methyl. [0191] 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. [0192] In one embodiment, R¹⁶ is C1-3 alkyl-R¹⁷ substituted with –O(CH2)2-4– wherein the oxygen atom10 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. [0193] Thus in one embodiment, there is suitably provided a compound of formula (Ia-7): 15 wherein all variables are as defined elsewhere herein. [0194] More preferably R¹⁶ is selected from: , wherein R¹⁹ and R²⁰ are as defined herein (above and below). 20 [0195] Even more preferably R¹⁶ is selected from: 35 [0196] Most preferably R¹⁶ is selected from: , [0197] In one embodiment, R¹⁷ is hydrogen. In a second embodiment, R¹⁷ is aryl e.g. phenyl. In a third 5 embodiment, R¹⁷ is heteroaryl e.g. 5- or 6-membered heteroaryl such as pyrazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl e.g. pyridinyl. In a fourth embodiment, R¹⁷ is 4-6 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms (such as 1 or 2 heteroatoms e.g. 1 heteroatom) independently selected from N, O and S (e.g. N or O). In a fifth embodiment, R¹⁷ is C3-8 cycloalkyl. 10 [0198] 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, C1-4 alkyl e.g. methyl, C1-4 haloalkyl e.g. C1 haloalkyl such as CHF2, C1-4 alkoxy e.g. OMe, and C1-4 haloalkoxy e.g. substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-4 alkyl, C1-4 haloalkyl, 15 C1-4 alkoxy, and C1-4 haloalkoxy. In another embodiment the heterocycloalkyl, and cycloalkyl are substituted with one or more substituents independently selected from the group consisting of halogen e.g. F, CN, NH2, oxo, C1-4 alkyl e.g. methyl, C1-4 haloalkyl e.g. C1 haloalkyl such as CHF2, C1-4 alkoxy e.g. OMe, and C1-4 haloalkoxy e.g. substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy. 20 [0199] When R¹⁷ is substituted by oxo (=O), the oxo group may be attached to a carbon atom thus forming C=O, or one or two oxo groups may be attached to a S atom in the heterocycloalkyl ring to form S=O or S(=O)2 respectively. [0200] In one embodiment, the substituents are selected from the group consisting of halogen e.g. F, CN, C1-2 alkyl e.g. Me, and C1-2 haloalkyl e.g. C1 haloalkyl such as CHF2, C1-2 alkoxy e.g. OMe, and C1-2 25 haloalkoxy. [0201] Most suitably, the substituent is F. [0202] Preferably R¹⁷ is hydrogen, phenyl, pyridyl, pyridazinyl, isoquinolinyl, tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, or C_3-7 cycloalkyl, wherein the phenyl, pyridyl, pyridazinyl, isoquinolinyl, tetrahydropyranyl, tetrahydrofuranyl, oxetanyl and cycloalkyl are unsubstituted or substituted with one 30 or more substituents independently selected from the group consisting of halogen, CN, C_1-2 alkyl, and C_1-2 haloalkyl, C_1-2 alkoxy, and C_1-2 haloalkoxy. 36 [0203] More preferably R¹⁷ is 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. [0204] More preferably still R¹⁷ is phenyl or pyridyl, wherein the phenyl or pyridyl are unsubstituted or 5 substituted with one or more substituents independently selected from halogen. [0205] Most preferably R¹⁷ is 2-pyridyl which is unsubstituted or substituted with one or two halogens (preferably fluoro). [0206] Preferably, R¹⁷ is unsubstituted heteroaryl or is heteroaryl substituted with one halogen e.g. one fluoro. 10 [0207] [0208] A preferred group of compounds according to the invention are those of formula I-1, which are compounds of formula I wherein: X1 is CH; X2 is C and X3 is N or X2 is N and X3 is C; 15 X4 is N or CH; Y is O; Y₁ is CHR⁶; Y₂ is CR⁴R⁵; Y₃ is CR³R⁴ or CH₂CR₃R₄; 20 when X₄ is N, B is a bond, -C(O)Y⁴-, -Y⁴- or -CH₂Y⁴-, and A is CN or R⁸R⁹C=CR¹⁰C(=O)-, wherein Y⁴ is a 3-6 membered heterocycloalkyl comprising a nitrogen atom or C_3-5 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 25 wherein R⁸ is independently selected from hydrogen and C_1-2 alkyl, R⁹ is independently selected from hydrogen, CF₃ and C_1-2 alkyl, which alkyl is unsubstituted or substituted with one or more substituents independently selected from fluoro, chloro and bromo, and R¹⁰ is independently selected from hydrogen, C_1-2 alkyl and halogen; when X₄ is CH, B is a bond and A is -NH-CN or R⁸R⁹C=CR¹⁰C(=O)NH-, where R⁸ is independently 30 selected from hydrogen and C_1-2 alkyl, R⁹ is independently selected from hydrogen, CF₃ and C_1-2 alkyl, which alkyl is unsubstituted or substituted with one or more substituents independently selected from fluoro, chloro and bromo, and R¹⁰ is independently selected from hydrogen, C_1-2 alkyl and halogen; R¹ is hydrogen, halogen, C_1-3 alkyl, C_1-3 alkoxy, CN, wherein the C_1-3 alkyl and C_1-3 alkoxy are unsubstituted or independently substituted with one or more substituents independently selected from 35 halogen; R² is hydrogen, hydroxyl or C_1-2 alkyl; each R³ is independently selected from hydrogen, fluoro and C1-2 alkyl; each R⁴ is independently selected from hydrogen and C1-2 alkyl; 37 R⁵ is 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, -CO2R⁴ or C1-3 alkoxy; R⁶ is hydrogen, fluoro or C1-2 alkyl; 5 R¹⁶ is 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 R¹⁷ is 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 10 independently selected from the group consisting of halogen, CN, C1-2 alkyl, and C1-2 haloalkyl, C1-2 alkoxy, and C1-2 haloalkoxy; or a pharmaceutically acceptable salt and/or solvate thereof. [0209] One group of compounds according to this embodiment are compounds of formula (I-1a) which 15 are compounds of formula (I-1) wherein X2 is C and X3 is N; each R³ is independently selected from hydrogen, fluoro and methyl; each R⁴ is independently hydrogen; R⁵ is hydrogen or C_1-3 alkyl, wherein the C_1-3 alkyl is unsubstituted or substituted with a substituent selected 20 from pyridyl, phenyl, and -CO₂H; R⁶ is hydrogen, fluoro or methyl (preferably hydrogen); and each R⁸ is independently selected from hydrogen and methyl, each R⁹ is independently selected from hydrogen, CF₃ and methyl, and each R¹⁰ is independently selected from hydrogen, fluoro, chloro, and methyl; 25 or a pharmaceutically acceptable salt and/or solvate thereof [0210] One group of compounds according to this embodiment are compounds of formula (I-1b) which are compounds of formula (I-1) wherein R¹ is OCH₃ or OCHF₂; or a pharmaceutically acceptable salt and/or solvate thereof. [0211] One group of compounds according to this embodiment are compounds of formula (I-1c) which 30 are compounds of formula (I-1) wherein R² is methyl; or a pharmaceutically acceptable salt and/or solvate thereof. [0212] One group of compounds according to this embodiment are compounds of formula (I-1d) which are compounds of formula (I-1) wherein R¹⁷ is 2-pyridyl which is unsubstituted or substituted with one or two halogens (preferably fluoro); or a pharmaceutically acceptable salt and/or solvate thereof. 35 [0213] Another preferred group of compounds according to the invention are those of formula I-2, which are compounds of formula I wherein: X1 is CH; X2 is C and X3 is N or X2 is N and X3 is C; 38 X4 is N or CH; Y is O; Y1 is CH2; Y2 is CHR⁵; 5 Y3 is CH2 or CH2CH2; when X4 is N, B is a bond or is selected from _{10 wherein Z is absent or is CO or (CH2)n; each n is independently 0, 1 or} 2; m is 0, 1 or 2; R⁴ is independently selected from hydrogen and C_1-3 alkyl; R²¹ is absent or is independently halogen (preferably fluoro), methyl or methoxy and R²² is independently hydrogen, halogen (preferably fluoro) or methyl; 39 R¹ is hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, halomethyl, haloethyl, halomethoxy, haloethoxy, cyano, CF3, CHF2, OCH3 or OCHF2; 5 R² is hydrogen, methyl or ethyl; R⁵ is hydrogen or C1-3 alkyl, wherein the C1-3 alkyl is unsubstituted or substituted with a substituent selected from pyridyl, phenyl, and -CO2H; wherein R¹⁹ is methyl, hydroxymethyl, or halomethyl (preferably fluoromethyl) ethyl; or 10 wherein R¹⁹ is methyl, hydroxymethyl, or OH and R20 is hydrogen or methyl; and R¹⁷ is 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. 15 [0214] One group of compounds according to this embodiment are compounds of formula (I-2a) which are compounds of formula (I-2) wherein X₂ is C and X₃ is N; or a pharmaceutically acceptable salt and/or solvate thereof. [0215] One group of compounds according to this embodiment are compounds of formula (I-2b) which are compounds of formula (I-2) wherein R¹ is OCH₃ or OCHF₂; or a pharmaceutically acceptable salt 20 and/or solvate thereof. [0216] One group of compounds according to this embodiment are compounds of formula (I-2c) which are compounds of formula (I-2) wherein R² is methyl; or a pharmaceutically acceptable salt and/or solvate thereof. 40 [0217] One group of compounds according to this embodiment are compounds of formula (I-2d) which are compounds of formula (I-2) wherein R¹⁷ is 2-pyridyl which is unsubstituted or substituted with one or two halogens (preferably fluoro) ; or a pharmaceutically acceptable salt and/or solvate thereof. 5 [0218] Another preferred group of compounds according to the invention are those of formula I-3, which are compounds of formula I wherein: X1 is CH; X2 is C and X3 is N or X2 is N and X3 is C; X4 is N or CH; 10 Y is O; Y1 is CH2; Y2 is CHR⁵; Y3 is CH2 or CH2CH2; when X4 is N, B is a bond or is selected from ₁₅ hydrogen, methyl or halogen (preferably fluoro); when X₄ is CH, B is a bond and A is -NH-CN, 20 R¹ is hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, cyano, CF₃, CHF₂, OCH₃ or OCHF₂; R² is hydrogen, methyl or ethyl; 41 R⁵ is hydrogen or C1-3 alkyl, wherein the C1-3 alkyl is unsubstituted or substituted with a substituent selected from pyridyl, phenyl, and -CO2H; 5 R¹⁷ is 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. [0220] One group of compounds according to this embodiment are compounds of formula Ia or Ib wherein 10 X₂ is C and X₃ is N; or a pharmaceutically acceptable salt and/or solvate thereof. [0221] One group of compounds according to this embodiment are compounds of formula Ia or Ib wherein R¹ is OCH₃ or OCHF₂; or a pharmaceutically acceptable salt and/or solvate thereof. [0222] One group of compounds according to this embodiment are compounds of formula Ia or Ib wherein R² is methyl; or a pharmaceutically acceptable salt and/or solvate thereof. 15 [0223] One group of compounds according to this embodiment are compounds of formula Ia or Ib wherein R¹⁷ is 2-pyridyl which is unsubstituted or substituted with one or two halogens (preferably fluoro) ; or a pharmaceutically acceptable salt and/or solvate thereof. [0224] In one embodiment, there is provided a compound which is selected from the group consisting of: 42 43 44 45 46 47 or a pharmaceutically acceptable salt and/or solvate thereof. [0225] In one embodiment, there is provided a compound which is selected from the group consisting of: 48 49 8- 9- 10 11 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 72 73 74 75 66 67 68 69 70 71 72 73 74 75 or a pharmaceutically acceptable salt and/or solvate thereof. [_{0226] In an embodiment, the moiety selected from: 5} wherein R⁸, R⁹ and R¹⁰ are as defined herein (above and below); each n is independently 1 or 2; R²¹ is 10 absent or is halogen, methyl, halomethyl, hydroxyl or methoxy; 76 and A is selected from [0227] In an embodiment, R² is C1-4 alkyl. In a preferred embodiment, R² is methyl. [0228] In an embodiment, R¹ is hydrogen, halogen, C1-3 alkyl, C1-3 alkoxy, CN, wherein the C1-3 alkyl 5 and C1-3 alkoxy are unsubstituted or independently substituted with one or more substituents independently selected from halogen. [0229] In a preferred embodiment, R¹ is hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, halomethyl, haloethyl, halomethoxy, haloethoxy, cyano, CF₃, CHF₂, OCH₃ or OCHF₂. [0230] In a more preferred embodiment, R¹ is hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy, 10 ethoxy, cyano, CF₃, CHF₂, OCH₃ or OCHF₂ (especially OCH₃ or OCHF₂). [0231] In an especially preferred embodiment, R¹ OCH₃ or OCHF₂. [0232] In a preferred embodiment, R⁸ is hydrogen. [0233] In a preferred embodiment, R⁹ is hydrogen. [0234] In a preferred embodiment, R¹⁰ is hydrogen. 15 [0235] In a preferred embodiment, R¹⁶ is C_1-3 alkyl-R¹⁷, wherein the C_1-3 alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of OH and OMe. [0236] In an embodiment, R¹⁶ is selected from: , wherein R¹⁹ and R²⁰ are as defined herein (above and below). [0237] In a preferred embodiment, R¹⁶ is selected from: 20 77 , [0239] In an embodiment, R¹⁷ is 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, 5 C1-4 alkoxy, and C1-4 haloalkoxy. [0240] In a preferred embodiment, R¹⁷ is selected from phenyl and pyridyl, optionally substituted with one or more halogen. [0241] In a more preferred embodiment, R¹⁷ is 2-pyridyl. [0242] In another embodiment, R¹⁷ is selected from: cyclobutyl, oxetane, and tetrahydropyran. In an 10 embodiment, R¹⁷ is selected from cyclobutyl and tetrahydropyran. [0243] In another aspect, the present invention provides compounds of Formula (Ia-5): 15 X₁ is N or CH; X₂ is N and X₃ is C, or, alternatively, X₃ is N and X₂ is C; Y is a bond, O or NH; Y₁ is a CHR⁶, CH₂-CHR⁶, CHR⁶-CH₂, CH₂-CF₂ or CF₂-CH₂; Y₂ is CR⁴R⁵ or CF₂; 20 Y₃ is CR³R⁴ _, CH₂CR³R⁴, CH₂CF₂ or CF₂ wherein Y₁, Y₂ and Y₃ together with N atom of N-A and the pyrazolyl ring form a 7-membered nitrogen containing ring; A is CN, R⁸R⁹C=CR¹⁰C(=O)-, R¹¹R¹²NCH₂CH=CHC(=O)-, H₂C=CHSO₂-, R¹³C≡CC(=O)- or R²³CH=CH- SO2- wherein R²³ is H or C1-2alkyl; 78 R¹ is 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 5 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; R² is hydrogen, hydroxyl, C1-4 alkyl, CN, -CONHC1-4 alkyl, or C1-4 haloalkyl; each R³ is independently selected from hydrogen, fluoro, hydroxyl, methoxy, C1-3 alkyl, cyclopropyl, or a 10 R³ is fused with R⁵ or R⁶ to form CH2, CH2-CH2 or CH2OCH2; each R⁴ is independently selected from hydrogen and C1-3 alkyl; R⁵ is hydrogen, fluoro, hydroxyl, methoxy, C1-3 alkyl, cyclopropyl or is fused with one R³ to 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), 15 phenyl, hydroxyl, -CO2R⁴ or C1-3 alkoxy; R⁶ is hydrogen, fluoro, hydroxyl, methoxy, C1-3 alkyl or is fused with one R³ to form CH2, CH2-CH2 or CH₂OCH₂; each R⁸ is independently selected from hydrogen and C_1-6 alkyl; each R⁹ is independently selected from hydrogen, CF₃ and C_1-6 alkyl, which alkyl is unsubstituted or 20 substituted with one or more substituents independently selected from fluoro, chloro, bromo, hydroxyl, and C_1-6 alkoxy; and R¹⁰ is hydrogen, C_1-3 alkyl or halogen; or R⁹ and R¹⁰ together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring; 25 each of R¹¹ and R¹² is independently hydrogen, C_1-6 alkyl, or R¹¹ and R¹² together 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; R¹³ is hydrogen, R¹⁴R¹⁵NCH₂-, or C_1-3 alkyl which is unsubstituted or substituted with hydroxyl; R¹⁴ and R¹⁵ are each independently hydrogen or C_1-6 alkyl; 30 R¹⁶ is C_1-3 alkyl-R¹⁷, C_3-6 cycloalkyl-R¹⁷ or a 4-6 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein the C_1-3 alkyl, C_3-6 cycloalkyl and 4-6 membered heterocycloalkyl are unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, CN, C_1-4 alkyl, C_3-6 cycloalkyl, OH, OMe, -NR⁴R⁸ wherein R⁴ and R⁸ are as defined above, or, alternatively, R⁴ and R⁸ together with the carbon atoms to which they 35 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 C_1-3 alkyl, C_3-6 cycloalkyl and 4-6 membered heterocycloalkyl group such that an oxygen-containing heterocyclyl forms; 79 R¹⁷ is 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, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy, wherein the 5 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, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; or a pharmaceutically acceptable salt and/or solvate thereof. [0244] In an further aspect, the present invention provides compounds of Formula (Ia-6): 10 wherein: X1 is N or CH; X2 is N and X3 is C, or, alternatively, X3 is N and X2 is C; 15 Y is a bond, O or NH; Y₁ is a CHR⁶; Y₂ is CR⁴R⁵ or CF₂; Y₃ is CH₂CR³R⁴; A is CN, R⁸R⁹C=CR¹⁰C(=O)-, R¹¹R¹²NCH₂CH=CHC(=O)-, H₂C=CHSO₂- or R¹³C≡CC(=O)-; 20 R¹ is hydrogen, halogen, C_1-5 alkyl, C_1-5 alkoxy, CN, C_3-10 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 C_1-5 alkyl and C_1-5 alkoxy, are 25 unsubstituted or independently substituted with one or more substituents independently selected from halogen, CN, hydroxyl and methoxy; R² is hydrogen, hydroxyl, C_1-4 alkyl, CN, -CONHC_1-4 alkyl, or C_1-4 haloalkyl; each R³ is independently selected from hydrogen, fluoro, hydroxyl, methoxy, C_1-3 alkyl, cyclopropyl, or a R³ is fused with R⁵ or R⁶ to form CH₂, CH₂-CH₂ or CH₂OCH₂; 30 each R⁴ is independently selected from hydrogen and C_1-3 alkyl; 80 R⁵ is hydrogen, fluoro, hydroxyl, methoxy, C1-3 alkyl, cyclopropyl or is fused with one R³ to 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, -CO2R⁴ or C1-3 alkoxy; 5 R⁶ is hydrogen, fluoro, hydroxyl, methoxy, C1-3 alkyl or is fused with one R³ to form CH2, CH2-CH2 or CH2OCH2; each R⁸ is independently selected from hydrogen and C1-6 alkyl; each R⁹ is 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 10 C1-6 alkoxy; and R¹⁰ is hydrogen, C1-3 alkyl or halogen; or R⁹ and R¹⁰ together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring; each of R¹¹ and R¹² is independently hydrogen, C1-6 alkyl, or R¹¹ and R¹² together with the nitrogen atom to 15 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; R¹³ is hydrogen, R¹⁴R¹⁵NCH₂-, or C_1-3 alkyl which is unsubstituted or substituted with hydroxyl; R¹⁴ and R¹⁵ are each independently hydrogen or C_1-6 alkyl; R¹⁶ is C_1-3 alkyl-R¹⁷, C_3-6 cycloalkyl-R¹⁷ or a 4-6 membered heterocycloalkyl comprising 1, 2 or 3 20 heteroatoms independently selected from N, O and S, wherein the C_1-3 alkyl, C_3-6 cycloalkyl and 4-6 membered heterocycloalkyl are unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, CN, C_1-4 alkyl, C_3-6 cycloalkyl, OH, OMe, -NR⁴R⁸ wherein R⁴ and R⁸ are as defined above, or, alternatively, R⁴ and R⁸ together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring; 25 R¹⁷ is hydrogen, aryl, heteroaryl, 4-6 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, O and S, or C_3-8 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, C_1-4 alkyl, and C_1-4 haloalkyl, C_1-4 alkoxy, and C_1-4 haloalkoxy; or a pharmaceutically acceptable salt and/or solvate thereof. 30 [0245] In another aspect, the present invention provides compounds of Formula (Ib-3): 81 (Ib-3) wherein: X₁ is N or CH; 5 X₂ is N and X₃ is C, or, alternatively, X₃ is N and X₂ is C; Y is a bond, O or NH; Y₁ is a bond, CHR⁶, CH₂-CHR⁶, CHR⁶-CH₂, CF₂, CH₂-CF₂ or CF₂-CH₂; Y₂ is CR⁴R⁵ or CF₂; Y₃ is CR³R⁴, CR₃R₄CR₃R₄, CH₂CF₂ or CF₂; 10 A is -NR⁴-CN, R⁸R⁹C=CR¹⁰C(=O)R⁴N-, R¹¹R¹²NCH₂CH=CHC(=O)R⁴N-, H₂C=CHSO₂-R⁴N- or R¹³C≡CC(=O)-R⁴N-; R¹ is hydrogen, halogen, C_1-5 alkyl, C_1-5 alkoxy, CN, C_3-10 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 15 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; R² is hydrogen, hydroxyl, C1-4 alkyl, CN, -CONHC1-4 alkyl, or C1-4 haloalkyl; 20 each R³ is independently selected from hydrogen, fluoro, hydroxyl, methoxy, C1-3 alkyl, cyclopropyl, or a R³ is fused with R⁵ or R⁶ to form CH2, CH2-CH2 or CH2OCH2; each R⁴ is independently selected from hydrogen and C1-3 alkyl; R⁵ is hydrogen, fluoro, hydroxyl, methoxy, C1-3 alkyl, cyclopropyl or is fused with one R³ to form CH2, CH2-CH2 or CH2OCH2, wherein the C1-3 alkyl is unsubstituted or independently substituted with one or 25 more substituents independently selected from halogen, heteroaryl (which heteroaryl is preferably pyridyl), phenyl, hydroxyl, -CO2R⁴ or C1-3 alkoxy; R⁶ is hydrogen, fluoro, hydroxyl, methoxy, C1-3 alkyl or is fused with one R³ to form CH2, CH2-CH2 or CH2OCH2; each R⁸ is independently selected from hydrogen and C1-6 alkyl; 82 each R⁹ is 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 C1-6 alkoxy; and R¹⁰ is hydrogen, C1-3 alkyl or halogen; 5 or R⁹ and R¹⁰ together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring; each of R¹¹ and R¹² is independently hydrogen, C1-6 alkyl, or R¹¹ and R¹² together 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; 10 R¹³ is hydrogen, R¹⁴R¹⁵NCH2-, or C1-3 alkyl which is unsubstituted or substituted with hydroxyl; R¹⁴ and R¹⁵ are each independently hydrogen or C1-6 alkyl; R¹⁶ is C1-3 alkyl-R¹⁷, C3-6 cycloalkyl-R¹⁷ or 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 15 selected from the group consisting of halogen, CN, C1-4 alkyl, C3-6 cycloalkyl, OH, OMe, -NR⁴R⁸ wherein R⁴ and R⁸ are as defined above, or, alternatively, R⁴ and R⁸ together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring; R¹⁷ is hydrogen, aryl, heteroaryl, 4-6 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, O and S, or C_3-8 cycloalkyl, wherein the aryl, heteroaryl, heterocycloalkyl, 20 and cycloalkyl are unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, CN, C_1-4 alkyl, and C_1-4 haloalkyl, C_1-4 alkoxy, and C_1-4 haloalkoxy; or a pharmaceutically acceptable salt and/or solvate thereof. 25 EMBODIMENTS [0246] Further embodiments according to the invention are provided as set out below. [0247] Embodiment 1 provides a compound of Formula (I):

83 wherein: X₁ is N or CH; 5 X2 is N and X3 is C, or, alternatively, X3 is N and X2 is C; X4 is N or CR⁴; Y is a bond, O or NH; Y1 is a bond, CHR⁶, CH2-CHR⁶, CHR⁶-CH2, CF2, CH2-CF2 or CF2-CH2; Y2 is CR⁴R⁵ or CF2; 10 Y3 is CR³R⁴, CR3R4CR3R4, CH2CF2 or CF2; when X4 is N, B is a bond, -C(O)Y⁴-, -Y⁴-, -CH2Y⁴-, or -CH2CH2Y⁴-, and A is CN, R⁸R⁹C=CR¹⁰C(=O)-, R¹¹R¹²NCH2CH=CHC(=O)-, H2C=CHSO2- or R¹³C≡CC(=O)-; when X4 is CR⁴, B is a bond, and A is -NR⁴-CN, R⁸R⁹C=CR¹⁰C(=O)R⁴N-, R¹¹R¹²NCH2CH=CHC(=O)R⁴N- , H2C=CHSO2-R⁴N- or R¹³C≡CC(=O)-R⁴N-; 15 Y⁴ is a 4-7 membered heterocycloalkyl comprising a nitrogen atom or C3-7 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; R¹ is hydrogen, halogen, C1-5 alkyl, C1-5 alkoxy, CN, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl 20 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 C_1-5 alkyl and C_1-5 alkoxy, are unsubstituted or independently substituted with one or more substituents independently selected from 25 halogen, CN, hydroxyl and methoxy; R² is hydrogen, hydroxyl, C_1-4 alkyl, CN, -CONHC_1-4 alkyl, or C_1-4 haloalkyl; each R³ is independently selected from hydrogen, fluoro, hydroxyl, methoxy, C_1-3 alkyl, cyclopropyl, or a R³ is fused with R⁵ or R⁶ to form CH₂, CH₂-CH₂ or CH₂OCH₂; 84 each R⁴ is independently selected from hydrogen and C1-3 alkyl; R⁵ is hydrogen, fluoro, hydroxyl, methoxy, C1-3 alkyl, cyclopropyl or is fused with one R³ to 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), 5 phenyl, hydroxyl, -CO2R⁴ or C1-3 alkoxy; R⁶ is hydrogen, fluoro, hydroxyl, methoxy, C1-3 alkyl or is fused with one R³ to form CH2, CH2-CH2 or CH2OCH2; each R⁸ is independently selected from hydrogen and C1-6 alkyl; each R⁹ is independently selected from hydrogen, CF3 and C1-6 alkyl, which alkyl is unsubstituted or 10 substituted with one or more substituents independently selected from fluoro, chloro, bromo, hydroxyl, and C1-6 alkoxy; and R¹⁰ is hydrogen, C1-3 alkyl or halogen; or R⁹ and R¹⁰ together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring; 15 each of R¹¹ and R¹² is independently hydrogen, C1-6 alkyl, or R¹¹ and R¹² together 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; R¹³ is hydrogen, R¹⁴R¹⁵NCH₂-, or C_1-3 alkyl which is unsubstituted or substituted with hydroxyl; R¹⁴ and R¹⁵ are each independently hydrogen or C_1-6 alkyl; 20 R¹⁶ is C_1-3 alkyl-R¹⁷, C_3-6 cycloalkyl-R¹⁷ or a 4-6 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein the C_1-3 alkyl, C_3-6 cycloalkyl and 4-6 membered heterocycloalkyl are unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, CN, C_1-4 alkyl, C_3-6 cycloalkyl, OH, OMe, -NR⁴R⁸ wherein R⁴ and R⁸ are as defined above, or, alternatively, R⁴ and R⁸ together with the carbon atoms to which they 25 are attached form a 4-8-membered carbocyclic ring; R¹⁷ is hydrogen, aryl, heteroaryl, 4-6 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, O and S, or C_3-8 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, C_1-4 alkyl, and C_1-4 haloalkyl, C_1-4 alkoxy, and C_1-4 haloalkoxy; 30 or a pharmaceutically acceptable salt and/or solvate thereof. [0248] Embodiment 2 provides a compound, or a pharmaceutically acceptable salt and/or solvate thereof, according to embodiment 1, wherein X₁ is CH. [0249] Embodiment 3 provides a compound, or a pharmaceutically acceptable salt and/or solvate thereof, according to embodiment 1 or 2, wherein X₂ is C and X₃ is N or X₂ is N and X₃ is C. 35 [0250] Embodiment 4 provides a compound, or a pharmaceutically acceptable salt and/or solvate thereof, according to embodiment 1 or 2, wherein Y is O. [0251] 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. 85 [0252] 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 Y⁴ is a 3-6 membered heterocycloalkyl comprising a nitrogen atom or C3-5 cycloalkyl-R⁴N-, wherein the heterocycloalkyl and cycloalkyl are unsubstituted or 5 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 R⁸ is independently selected from hydrogen and C1-2 alkyl, R⁹ is independently selected from hydrogen, CF3 and C1-2 alkyl, which alkyl is unsubstituted or substituted with one or more substituents independently selected from fluoro, chloro 10 and bromo, and R¹⁰ is independently selected from hydrogen, C1-2 alkyl and halogen. [0253] Embodiment 7 provides a compound, or a pharmaceutically acceptable salt and/or solvate thereof, according to embodiment 1, 2, 3, 4 or 5, wherein X4 is CH, B is a bond and A is -NH-CN or R⁸R⁹C=CR¹⁰C(=O)NH-, wherein R⁸ is independently selected from hydrogen and C1-2 alkyl, R⁹ is independently selected from hydrogen, CF3 and C1-2 alkyl, which alkyl is unsubstituted or substituted 15 with one or more substituents independently selected from fluoro, chloro and bromo, and R¹⁰ is independently selected from hydrogen, C1-2 alkyl and halogen. [0254] 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 R¹ is hydrogen, halogen, C_1-3 alkyl, C_1-3 alkoxy, CN, wherein the C_1-3 alkyl and C_1-3 alkoxy are unsubstituted or independently substituted with one or 20 more substituents independently selected from halogen. [0255] 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 R² is hydrogen, hydroxyl or C_1-2 alkyl. [0256] 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 Y₁ is CHR⁶, Y₂ is CR⁴R⁵, Y₃ is CR³R⁴ or 25 CH₂CR³R⁴, each R³ is independently selected from hydrogen, fluoro and C_1-2 alkyl, each R⁴ is independently selected from hydrogen and methyl, R⁵ is hydrogen, fluoro, hydroxyl, methoxy or C_1-3 alkyl, wherein the C_1-3 alkyl is unsubstituted or independently substituted with one or more substituents independently selected from halogen, pyridyl, phenyl, hydroxyl, -CO₂R⁴ or C_1-3 alkoxy, and R⁶ is hydrogen, fluoro or C_1-2 alkyl. 30 [0257] 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 R⁸ is independently selected from hydrogen and methyl, each R⁹ is independently selected from hydrogen, CF₃ and methyl, and each R¹⁰ is independently selected from hydrogen, fluoro, chloro, and methyl. [0258] Embodiment 12 provides a compound, or a pharmaceutically acceptable salt and/or solvate thereof, 35 according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11, wherein Y₁ is CH₂, Y₂ is CHR⁵, Y₃ is CH₂ or CH₂CH₂ and R⁵ is hydrogen or C_1-3 alkyl, wherein the C_1-3 alkyl is unsubstituted or substituted with a substituent selected from pyridyl, phenyl, and -CO2H. 86 [0259] 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 R¹⁶ is 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. 5 [0260] 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 R¹⁷ is 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 10 from the group consisting of halogen, CN, C1-2 alkyl, and C1-2 haloalkyl, C1-2 alkoxy, and C1-2 haloalkoxy. [0261] 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 15 _{wherein Z is absent or is CO or (CH2)n; each n is independently 1 or 2;} m is 0, 1 or 2; R⁴ is independently selected from hydrogen and C1-3 alkyl; R²¹ is absent or is independently 87 halogen (preferably fluoro), methyl or methoxy and R²² is independently hydrogen, halogen (preferably fluoro) or methyl. [0262] 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 5 [0263] 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 R¹ is hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, halomethyl, haloethyl, halomethoxy, haloethoxy, cyano, CF₃, CHF₂, OCH₃ or OCHF₂. 10 [0264] 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 R² is hydrogen, methyl or ethyl. [0265] 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 R³ 15 is independently hydrogen, each R⁴ is independently hydrogen and R⁶ is hydrogen. [0266] 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 R¹⁶ is wherein R¹⁹ is methyl, hydroxymethyl, or halomethyl (preferably fluoromethyl) and R20 is hydrogen or methyl, wherein R¹⁹ is methyl, hydroxymethyl, or OH and R20 is 20 hydrogen or methyl. [0267] 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 R¹⁷ is cyclobutyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl or pyridyl, wherein the phenyl or pyridyl are unsubstituted or substituted with one or more substituents independently selected from 25 halogen. 88 [0268] 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 X4 is N, B is a bond or is selected from 5 hydrogen, methyl or halogen (preferably fluoro). [0269] 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, wherein 10 X4 is CH, B is a bond and A is -NH-CN, . [0270] 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 R¹ is hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, cyano, CF3, CHF2, OCH3 or OCHF2. 15 [0271] 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 R² is methyl. [0272] 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, 20 24 or 25, wherein R¹⁶ is selected from: 89 , , and . [0273] 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 R¹⁷ is phenyl or pyridyl, wherein the phenyl or pyridyl are unsubstituted or 5 substituted with one or more substituents independently selected from halogen. [0274] 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 R¹⁷ is 2-pyridyl which is unsubstituted or substituted with one or two halogens (preferably fluoro). 10 [0275] 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 R¹ is OCH₃ or OCHF₂. [0276] Embodiment 30 provides a compound, or a pharmaceutically acceptable salt and/or solvate thereof, according to embodiment 1, wherein the compound is selected from: 15 90 91 92 93 94 95 96 97 98 99 or a pharmaceutical acceptable salt and/or solvate therof [0277] 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. 5 [0278] 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. [0279] 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 10 31, for use in the prophylaxis and/or treatment of a disease, disorder or condition that is mediated by α4β7 integrin. [0280] 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 15 disease and/or ulcerative colitis. [0281] Specific examples of compounds of Formula (I) are illustrated below: 102 [0282] Another example of a compound of Formula (I) is: 103 5 wherein R⁸, R⁹ and R¹⁰ are as defined herein (above and below); each n is independently 1 or 2; R²¹ is absent or is halogen, methyl, halomethyl, hydroxyl or methoxy; 10 [0285] In an embodiment, R² is C_1-4 alkyl. In a preferred embodiment, R² is methyl. 104 [0286] In an embodiment, R¹ is 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. [0287] In a preferred embodiment, R¹ is hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, 5 halomethyl, haloethyl, halomethoxy, haloethoxy, cyano, CF3, CHF2, OCH3 or OCHF2. [0288] In a more preferred embodiment, R¹ is hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, cyano, CF3, CHF2, OCH3 or OCHF2 (especially OCH3 or OCHF2). [0289] In an especially preferred embodiment, R¹ OCH3 or OCHF2. [0290] In a preferred embodiment, R⁸ is hydrogen. 10 [0291] In a preferred embodiment, R⁹ is hydrogen. [0292] In a preferred embodiment, R¹⁰ is hydrogen. [0293] In a preferred embodiment, R¹⁶ is 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. 15 [0294] In an embodiment, R¹⁶ is selected from: , wherein R¹⁹ and R²⁰ are as defined herein (above and below). [0295] In a preferred embodiment, R¹⁶ is selected from: 20 , [0297] In an embodiment, R¹⁷ is 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 C1-4 haloalkoxy. 105 [0298] In a preferred embodiment, R¹⁷ is selected from phenyl and pyridyl, optionally substituted with one or more halogen. [0299] In a more preferred embodiment, R¹⁷ is 2-pyridyl. [0300] In another embodiment, R¹⁷ is selected from: cyclobutyl, oxetane, and tetrahydropyran. In an 5 embodiment, R¹⁷ is selected from cyclobutyl and tetrahydropyran. [0301] In one embodiment, the compound of the invention according to Formula I is selected from: 106 107 108 109 110 111 112 113 114 115 or a pharmaceutically acceptable salt and/or solvate thereof. [0302] In one embodiment, the compound of the invention according to Formula I is a compound selected from the list comprising: 123 or a pharmaceutically acceptable salt and/or solvate thereof. [0303] The compound of Formula (I) may also be selected from: 127 or a pharmaceutically acceptable salt and/or solvate thereof. [0304] The compound of Formula (I) may be: [0305] In one embodiment, the compounds of the invention are provided in a natural isotopic form. [0306] 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. [0307] 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. [0308] 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. 128 [0309] In one aspect a compound of the invention according to any one of the embodiments herein described is present as the free base. [0310] In one aspect a compound of the invention according to any one of the embodiments herein described is a pharmaceutically acceptable salt. [0311] In one aspect a compound of the invention according to any one of the embodiments herein described is a solvate of the compound. [0312] 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. [0313] 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. [0314] 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. [0315] 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. [0316] 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. [0317] 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 ((alkoxycarbonyl)oxy)alkylesters. Particularly useful are the C₁ to C₈ alkyl, C₂-C₈ alkenyl, aryl, C₇-C₁₂ substituted aryl, and C₇-C₁₂ arylalkyl esters of the compounds of the invention. 129 PHARMACEUTICAL COMPOSITIONS [0318] 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. [0319] 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. [0320] 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 as unitary 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. [0321] 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 corn 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. [0322] 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. 130 [0323] 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. [0324] 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. [0325] The above-described components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington’s Pharmaceutical Sciences, 17^th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference. [0326] 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. [0327] 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 [0328] 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 [0329] 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 [0330] 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 131 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 [0331] 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 [0332] 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 [0333] Stearyl alcohol (250 g) and a white petrolatum (250 g) may be melted at about 75ºC 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 [0334] 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. [0335] 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. [0336] 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. [0337] 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. 132 [0338] 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, 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. 133 [0339] 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). [0340] 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), 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. [0341] 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. [0342] 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. [0343] 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. [0344] Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses. [0345] 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. [0346] 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. 134 [0347] 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. [0348] 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 or dexamethasone), cyclophosphamide, cyclosporin A, tacrolimus, mycophenolate, mofetil, muromonab- CD3 (OKT3, e.g. Orthocolone®), ATG, aspirin, acetaminophen, ibuprofen, naproxen, and piroxicam. [0349] 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, auranofin, 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). [0350] 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^TM), capecitabine, raloxifene hydrochloride, EGFR inhibitors (e.g. lressa®, 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. [0351] 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-β), TNF binding proteins (e.g. infliximab, etanercept, or adalimumab), mycophenolate, fingolimod and myriocin.. [0352] 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, 135 everolimus), anti-proliferatives (e.g. azathioprine, mycophenolic acid), corticosteroids (e.g. prednisolone, hydrocortisone), antibodies (e.g. monoclonal anti-IL-2Rα receptor antibodies, basiliximab, daclizumab), polyclonal anti-T-cell antibodies (e.g. anti-thymocyte globulin (ATG), anti- lymphocyte globulin (ALG)). [0353] 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 β2-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). [0354] 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, aminophylline, bamiphylline), inhalation anesthetics that have a bronchodilatory effect (e.g. isoflurane, halothane, enflurane), ketamine and intravenous magnesium sulfate. [0355] 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). [0356] 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. 136 [0357] 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 biologics 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)). [0358] 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 anti- leukotrienes (e.g. montelukast or zafirlukast), anti-cholinergics and decongestants. [0359] 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 PROCEDURES General [0360] 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. [0361] 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). [0362] 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. 137 [0363] 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 µm) 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. ¹H NMR spectra are recorded on a Bruker Avance 400 NMR spectrometer (400 MHz). Chemical shifts (δ) for ¹H NMR spectra are reported in parts per million (ppm) relative to tetramethylsilane (δ 0.00) or the appropriate residual solvent peak, i.e. CHCl3 (δ 7.27), 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 C181.7µm, 2.1mm ID x 50mm L, or Waters Acquity UPLC CSH C181.7µm, 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 XBRIDGE BEH C18 OBD 19 mm ID × 100 mm L columns and ACN/H₂O gradients with either 0.1% formic acid in H₂O or 0.5% NH₃ in 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+. Table I. List of abbreviations used in the experimental section: 138 139 140 141 SYNTHETIC PREPARATION OF THE COMPOUNDS OF THE INVENTION General synthesis Scheme 1 [0364] A compound of Formula (Ia), in which X4 is 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 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 (IV) can be cleaved using acidic condition, for example, in presence of HCl 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 (Ia). As an example, compounds of Formula (Ia) 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 (Ia) 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)Cl) 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 142 [0365] A compound of Formula (Ib) or (Ib-3), in which X₄ = CR⁴, can be prepared from a NHBoc intermediate of Formula (VI) as depicted in Scheme 2a or Scheme 2b respectively. 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 HCl 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 (Ib) or (Ib-3). As an example, compounds of Formula (Ib) or (Ib-3) 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 (Ib) or (Ib-3) 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)Cl) 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 3 143 [0366] A compound of Formula (Ic), in which X4is a nitrogen and Z is a linker such as a bond, CO or (CH2)n can 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 V 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 HCl 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 is an acyl moiety, can be obtained by reacting a compound of Formula (X) with an acyl chloride (such as CH2=CH-C(=O)Cl) 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 [0367] A compound of Formula Intermediate of Formula (XV) where Y3 is CH2 can 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 PPh3 in a suitable solvent afford compound a Formula (XIII). Alternatively, substitution of pyrazol (XI) by an alkyl halide (such as XY₁Y₂NHBoc) in presence of a base (such as K₂CO₃ or KOH) and a catalytic amount of an iodine 144 salt (such as NaI 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 HCl 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 [0368] 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 trimethylboroxine in presence of a suitable base and a catalyst (such as Pd(dppf)Cl2) 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 col 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 7 145 [0370] An alternative synthesis to obtain intermediate of Formula (XXIV) where Y3 is (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 DPPA) 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 PPh3 in water but also other more standardly use reducting agents such as LiAlH4 or 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 [0371] 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 9 146 [0372] An alcohol of general formula R¹⁶-OH, 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 PPh3 in 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 NaI 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-(1-(pyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carbonitrile [0373] A 40 mL vial was charged with (R)-4-(1-(pyridin-2-yl)ethoxy)-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] (193 mg, 0.497 mmol, 1.50 equiv), tert-butyl 2-bromo-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (100 mg, 0.331 mmol, 1.00 equiv), Pd(PPh3)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-(1-(pyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (80 mg, 50% yield) as a white solid. LCMS (ESI-MS) m/z = 486.2 [M+H]⁺. [0374] A 50 mL round-bottom flask was charged with tert-butyl (R)-2-(3-cyano-4-(1-(pyridin-2- yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (80 mg, 0.165 mmol, 1.00 equiv), HCl (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-(1-(pyridin-2-yl)ethoxy)-6-(4,5,6,7-tetrahydropyrazolo[1,5-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-(1-(pyridin-2-yl)ethoxy)-6-(4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyrazolo[1,5-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. 147 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, 5μm; Mobile Phase A: Water (10mmol/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-(1-(pyridin-2- yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile (33.8 mg, 40% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 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(ESI-MS) m/z = 411.3 [M+H]⁺. Example 2 (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 [0375] A 40 mL vial was charged with (R)-4-(1-(pyridin-2-yl)ethoxy)-6-(4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-2-yl)pyrazolo[1,5-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 C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10mmol/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. [0376] 1H NMR (400 MHz, Chloroform-d) δ 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(ESI-MS) m/z = 440.4 [M+H]⁺. Example 3 148 2-(3-cyano-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, Isomer 1 Example 4 2-(3-cyano-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, Isomer 2 [0377] A 1 L flask was charged with tert-butyl 3-bromo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (10 g, 33.1 mmol, 1.00 equiv), trimethyl-1,3,5,2,4,6-trioxatriborinane (16.6 g, 132 mmol, 4.00 equiv), Pd(dppf)Cl₂ (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 ℃ 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[1,5-a]pyrazine-5(4H)-carboxylate (7 g, 89% yield) as a light yellow solid. LCMS (ESIMS) m/z = 238.1 [M+H]⁺. [0378] A 500 mL flask was charged with tert-butyl 3-methyl-6,7-dihydropyrazolo[1,5-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 ℃. 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: C18 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]pyrazine-5-carboxylattert-butyl 2-bromo-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (2 g, 21% yield) as a yellow oil. LCMS (ESI-MS) m/z = 316.1 [M+H]⁺. [0379] A 100 mL flask was charged with tert-butyl 2-bromo-3-methyl-6,7-dihydropyrazolo[1,5- 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- 149 carbonitrile [which can be made according to the procedures described in WO2022187443] (1.61 g, 3.80 mmol, 1.20 equiv), Pd(PPh3)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. The above 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[1,5- a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (630 mg, 37%) as a light yellow solid. LCMS (ESI-MS) m/z = 534.2 [M+H]⁺. [0380] A 50 mL flask was charged with tert-butyl 2-(3-cyano-4-(2-(5-fluoropyridin-2-yl)-2- hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (150 mg, 0.281 mmol, 1.00 equiv) and 1,4-dioxane (5 mL). Then HCl (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[1,5-a]pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (150 mg, crude) as a light yellow solid. LCMS (ESI-MS) m/z = 434.2 [M+H]⁺. [0381] A 100 mL flask was charged with 4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-6-(3-methyl- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyrazolo[1,5-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 μm; 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[1,5-a]pyrazine-5(4H)-carbonitrile, Isomer 1 (the first elution, 11.2 mg, 15% yield) as a white solid. [0382] 1H NMR (400 MHz, DMSO-d6) δ 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]⁺. [0383] Isomer 2 (the second elution, 14.6 mg, 20% yield) as a white solid. [0384] 1H NMR (400 MHz, DMSO-d6) δ 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]⁺. 150 Example 5 6-(5-(1-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, Isomer1 Example 6 6-(5-(1-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 2 [0385] A 40 mL vial was charged with 4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-6-(3-methyl- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (250 mg, 0.577 mmol, 1.00 equiv) DMF (5 mL), DIEA (149 mg, 1.15 mmol, 2.00 equiv), 1-(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-1-carboxylate (180 mg, 51% yield) as a light yellow solid. LCMS (ESI-MS) m/z = 617.3 [M+H]⁺. [0386] 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]pyridin-6-yl)-3-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-5- carbonyl)azetidine-1-carboxylate (180 mg, 0.292 mmol, 1.00 equiv) and 1,4-dioxane (5 mL). HCl (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[1,5-a]pyrazin-2-yl)-4-(2-(5-fluoropyridin-2-yl)-2- hydroxyethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (180 mg, crude) as light yellow solid. LCMS (ESI-MS) m/z = 517.2 [M+H]⁺. [0387] 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 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- 151 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 μm; 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-(1-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-d6) δ 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]⁺. [0388] Isomer 2 (the second elution, 15.8 mg, 10% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 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 7 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[1,5-a]pyridine-3-carbonitrile, Isomer 1 Example 8 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[1,5-a]pyridine-3-carbonitrile, Isomer 2 [0389] 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). The resulting 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 μm; Mobile Phase A: Hex(0.1% FA)--HPLC, Mobile Phase B: MeOH: 152 DCM=1: 1--HPLC; 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[1,5-a]pyridine-3-carbonitrile, Isomer 1 (the first elution, 16.0 mg, 9% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 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]⁺. [0390] Isomer 2 (the second elution, 15.9 mg, 9% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 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 9 2-(3-chloro-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, Isomer 1 Example 10 2-(3-chloro-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, Isomer 2 [0391] Starting from 2-((3-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridin- 4-yl)oxy)-1-(5-fluoropyridin-2-yl)ethan-1-ol [which can be made according to the procedures described in WO2022187443] and tert-butyl 2-bromo-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine- 5(4H)-carboxylate, example 9 and 10 were synthesized following the same procedure as used for example 3. [0392] The crude product was purified by Prep-chiral-HPLC with the following conditions: Column: UniChiral OD-5H, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.1% FA)--HPLC, Mobile Phase B: MeOH: EtOH=1: 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[1,5-a]pyrazine-5(4H)-carbonitrile, Isomer 1 (the first elution) as an off- white solid. 1H NMR (400 MHz, Chloroform-d) δ 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]⁺ 153 [0393] Isomer 2, (the second elution, 15.4 mg, 7% yield) as an off-white solid. 1H NMR (400 MHz, Chloroform-d) δ 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 (ESI- MS) m/z = 468.1 [M+H]⁺. Example 11 (3-(2-(3-chloro-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-1-carbonitrile, Isomer 1 Example 12 3-(2-(3-chloro-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-1-carbonitrile, Isomer 2 [0394] Starting from 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-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. [0395] The crude product was purified by Prep-chiral-HPLC with the following conditions: Column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 μm; 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[1,5- a]pyridin-6-yl)-3-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-5-carbonyl)azetidine-1- carbonitrile, isomer 1 (the first elution, 9.9 mg, 6% yield) as an off-white solid. 1H NMR (400 MHz, Chloroform-d) δ 8.42 (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]⁺. [0396] Isomer 2 (the second elution, 9.6 mg, 6% yield) as a white solid. 1H NMR (400 MHz, Chloroform- d) δ 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 1-(3-(2-(3-chloro-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)azetidin-1-yl)prop-2-en-1-one, Isomer 1 Example 14 154 1-(3-(2-(3-chloro-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)azetidin-1-yl)prop-2-en-1-one, Isomer 2 [0397] Into a 100 mL round-bottom flask were added azetidin-3-yl(2-(3-chloro-4-(2-(5-fluoropyridin-2- yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-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 μm; Mobile Phase A: Hex(0.1% FA)--HPLC, Mobile Phase B: MeOH: DCM=1: 1--HPLC; Flow rate: 20ML/MIN mL/min; Gradient: isocratic 30; Wave Length: 254/220nm to afford 1-(3-(2-(3-chloro-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)azetidin-1-yl)prop-2-en-1-one, Isomer 1 (elution 1) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 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]⁺ [0398] Isomer 2 (2^nd elution, 23.7 mg, 10.7% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 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 15 2-(3-cyano-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, Isomer 1 155 Example 16 2-(3-cyano-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, Isomer 2 [0399] Starting from 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 and tert-butyl 2-bromo-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate, examples 15 and 16 were synthesized following the same procedure as used for example 3. [0400] The crude product was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK IE, 2*25 cm, 5 μm; 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[1,5-a]pyridin-6-yl)-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, isomer 1 (the first elution, 5.6 mg, 9% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 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]⁺. [0401] Isomer 2, (the second elution, 5.5 mg, 9% yield) as a white solid. 1H NMR (400 MHz, DMSO- d6) δ 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 (ESI- MS) m/z = 445.2 [M+H]⁺. Example 17 2-(3-chloro-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, Isomer 1 Example 18 2-(3-chloro-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, Isomer 2 156 [0402] Starting from 2-((3-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridin- 4-yl)oxy)-1-(5-fluoropyridin-2-yl)ethan-1-ol and tert-butyl 2-bromo-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate, example 17 and 18 were synthesized following the same procedure as used for example 3. [0403] The crude product was purified by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK IF, 2*25 cm, 5 μm; 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[1,5-a]pyridin-6-yl)-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, isomer 1 (the first elution, 5.1 mg, 11% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 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]⁺. [0404] Isomer 2 (the second elution, 5.9 mg, 4.5% yield) as a white solid. 1H NMR (400 MHz, DMSO- d6) δ 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 19 2-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, Isomer 1 Example 20 2-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, Isomer 2 157 [0405] 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[1,5-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 ℃ 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[1,5-a]pyridin-4-ol (3.8 g, crude) as a white solid. LCMS(ESI- MS) m/z = 213.0 [M+H]⁺. [0406] A 500 mL round-bottom flask was charged with PPh3 (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 reaction was stirred at 0°C for 0.5 h. To the mixture is added a solution 6-bromo-3-chloropyrazolo[1,5- a]pyridin-4-ol (4.1 g, 16.6 mmol, 1.00 equiv) 2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2- yl)ethan-1-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)-1- (5-fluoropyridin-2-yl)ethoxy)-3-chloropyrazolo[1,5-a]pyridine (7.5 g, 90% yield) as a yellow oil. LCMS(ESI-MS) m/z = 500.0 [M+H]⁺. 158 [0407] A 100 mL round-bottom flask was charged with 6-bromo-4-(2-((tert-butyldimethylsilyl)oxy)-1-(5- fluoropyridin-2-yl)ethoxy)-3-chloropyrazolo[1,5-a]pyridine (4 g, 7.99 mmol, 1.00 equiv), bis(pinacolato)diboron (4.06 g, 16.0 mmol, 2.00 equiv), Pd(dppf)Cl2 (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 re- crystallized from EA/ PE (1 / 10, 20 mL) to afford 4-(2-((tert-butyldimethylsilyl)oxy)-1-(5- fluoropyridin-2-yl)ethoxy)-3-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5- a]pyridine (5 g, crude) as a yellow solid. LCMS(ESI-MS) m/z = 548.2 [M+H]⁺. [0408] To a solution of tert-butyl 2-bromo-3-tert-butyl 2-bromo-3-methyl-6,7-dihydropyrazolo[1,5- 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)-1-(5- fluoropyridin-2-yl)ethoxy)-3-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5- a]pyridine (506.86 mg, 0.925 mmol, 1.5 equiv) and Pd(PPh3)4 (35.63 mg, 0.031 mmol, 0.05eq). The reaction was stirred for overnight at 100°C under N₂ atmosphere. 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)-1-(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]⁺. [0409] To a solution of tert-butyl 2-(4-{2-[(tert-butyldimethylsilyl)oxy]-1-(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 HCl (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[1,5-a]pyrazin-2-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5- fluoropyridin-2-yl)ethan-1-ol (53 mg, crude) as a white solid. LCMS(ESI-MS) m/z =443.0 [M+H]⁺. [0410] To a solution of 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)-2-(5-fluoropyridin-2-yl)ethan-1-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 μm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)-HPLC, Mobile Phase B: 159 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-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin- 6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, Isomer 1 (the first elution, 3.7 mg, 6.5% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 8.49 (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]⁺. [0411] Isomer 2 (the second elution, 3.9 mg, 7% yield) as a white solid. 1H NMR (400 MHz, Chloroform- d) δ 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 1-(2-(3-chloro-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)prop-2-en-1-one, Isomer 1 Example 22 1-(2-(3-chloro-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)prop-2-en-1-one, Isomer 2 [0412] A 100mL 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-1-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: 1mL/min mL/min; Gradient: isocratic ; Injection Volume: 1uL mL; Wave Length: 220 nm to 1- (2-(3-chloro-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)prop-2-en-1-one, isomer 1 (the first elution, 13.2 mg, 13.8% 160 yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 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 = 497.2 [M+H]⁺. [0413] Isomer 2 (the second elution, 12.3 mg, 12.9% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 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 = 497.2[M+H]⁺. Example 23 3-((S)-2-(3-chloro-4-((R)-1-(pyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-cyano-3-methyl- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-6-yl)propanoic acid [0414] To a stirred mixture of PPh3 (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-1H-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- 1-(2-((tert-butoxycarbonyl)amino)-5-methoxy-5-oxopentyl)-4-methyl-1H-pyrazole-5-carboxylate (3.7 g, 66% yield) as a light yellow oil. LCMS(ESI-MS) m/z = 462.1 [M+H]⁺. [0415] Into a 250 mL round-bottom flask were added ethyl ethyl (S)-3-bromo-1-(2-((tert- butoxycarbonyl)amino)-5-methoxy-5-oxopentyl)-4-methyl-1H-pyrazole-5-carboxylate (3.7 g, 8.00 161 mmol, 1.00 equiv), HCl (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 NaHCO3 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[1,5-a]pyrazin-6-yl)propanoate (1.1 g, 44% yield) as a white solid. LCMS(ESI-MS) m/z = 316.0 [M+H]⁺. [0416] Into a 100 mL round-bottom flask were added methyl (S)-3-(2-bromo-3-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-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[1,5-a]pyrazin- 6-yl)propan-1-ol (1 g, crude) as a white solid. LCMS(ESI-MS) m/z = 274.1 [M+H]⁺. [0417] Into a 100 mL round-bottom flask were added (S)-3-(2-bromo-3-methyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-6-yl)propan-1-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 tert- butyl (S)-2-bromo-6-(3-hydroxypropyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (650 mg, 48% yield) as a light yellow oil. LCMS(ESI-MS) m/z = 374.1 [M+H]⁺. [0418] Into a 100 mL round-bottom flask were added tert-butyl (S)-2-bromo-6-(3-hydroxypropyl)-3- methyl-6,7-dihydropyrazolo[1,5-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[1,5-a]pyrazin-6-yl)propanoic acid (400 mg, 59% yield) as a white solid. LCMS(ESI-MS) m/z = 388.1 [M+H]⁺. 162 [0419] Into a 40 mL round-bottom flask were added (S)-3-(2-bromo-5-(tert-butoxycarbonyl)-3-methyl- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-6-yl)propanoic acid (400 mg, 0.618 mmol, 1.00 equiv), (R)- 3-chloro-4-(1-(pyridin-2-yl)ethoxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5- a]pyridine (988 mg, 2.47 mmol, 4.00 equiv), Pd(PPh3)4 (35.7 mg, 0.031 mmol, 0.05 equiv), K2CO3 (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 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 3-((S)-5-(tert-butoxycarbonyl)-2-(3-chloro-4-((R)-1-(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, 39% yield) as a brown oil. LCMS(ESI-MS) m/z = 581.2 [M+H]⁺. [0420] Into a 50 mL round-bottom flask were added 3-((S)-5-(tert-butoxycarbonyl)-2-(3-chloro-4-((R)-1- (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 NH₄Cl 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)-1- (pyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-6-(3-methoxy-3-oxopropyl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (100 mg, 69.74% yield) as a colorless oil. LCMS(ESI-MS) m/z = 595.2 [M+H]⁺. [0421] Into a 50 mL round-bottom flask were added tert-butyl (S)-2-(3-chloro-4-((R)-1-(pyridin-2- yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-6-(3-methoxy-3-oxopropyl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (100 mg, 0.168 mmol, 1.00 equiv), HCl (4M in 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)-1- (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(ESI-MS) m/z = 495.2 [M+H]⁺. [0422] Into a 50 mL round-bottom flask were added methyl 3-((S)-2-(3-chloro-4-((R)-1-(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, 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 163 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)-1-(pyridin- 2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-cyano-3-methyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-6-yl)propanoate (50 mg, 68% yield) as a light brown oil. LCMS(ESI-MS) m/z = 520.2 [M+H]⁺. [0423] Into a 50 mL round-bottom flask were added methyl 3-((S)-2-(3-chloro-4-((R)-1-(pyridin-2- yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-cyano-3-methyl-4,5,6,7-tetrahydropyrazolo[1,5-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, 5μm; 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)-1-(pyridin-2- yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-cyano-3-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin- 6-yl)propanoic acid (4.3 mg, 8.6% yield) as an off-white solid. 1H NMR (400 MHz, Chloroform-d) δ 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 24 2-(3-chloro-4-((R)-1-(pyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6-(pyridin-2- ylmethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, Isomer 1 Example 25 2-(3-chloro-4-((R)-1-(pyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6-(pyridin-2- ylmethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, Isomer 2

164 [0424] A 100 mL round-bottom flask was charged with 2-amino-3-(pyridin-2-yl)propan-1-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 tert- butyl (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]⁺. [0425] A 500 mL round-bottom flask was charged with PPh3 (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 (1-hydroxy-3-(pyridin-2- yl)propan-2-yl)carbamate (0.82 g, 3.25 mmol, 1.00 equiv) and ethyl 3-bromo-4-methyl-1H-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-1-(2-((tert- butoxycarbonyl)amino)-3-(pyridin-2-yl)propyl)-4-methyl-1H-pyrazole-5-carboxylate (1.6 g, crude) as a yellow solid. LCMS(ESI-MS) m/z = 467.1 [M+H]⁺. 165 [0426] A 100 mL round-bottom flask was charged with ethyl 3-bromo-1-(2-((tert-butoxycarbonyl)amino)- 3-(pyridin-2-yl)propyl)-4-methyl-1H-pyrazole-5-carboxylate (0.8 g, 1.71 mmol, 1.00 equiv) and HCl (4M in 1,4-dioxane, 15 mL). The resulting mixture was stirred at room temperature for 2h. To the mixture is added NaHCO3 (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[1,5-a]pyrazin-4(5H)-one (0.19 g, 27% yield) as a white solid. LCMS(ESI-MS) m/z = 321.0 [M+H]⁺. [0427] A 100 mL round-bottom flask was charged with 2-bromo-3-methyl-6-(pyridin-2-ylmethyl)-6,7- dihydropyrazolo[1,5-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[1,5-a]pyrazine (300 mg, crude) as a yellow oil. LCMS(ESI-MS) m/z = 307.1 [M+H]⁺. [0428] A 100 mL round-bottom flask was charged with 2-bromo-3-methyl-6-(pyridin-2-ylmethyl)- 4,5,6,7-tetrahydropyrazolo[1,5-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 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 = 3 / 7) to afford tert-butyl 2- bromo-3-methyl-6-(pyridin-2-ylmethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (215 mg, 41% yield) as a white solid. LCMS(ESI-MS) m/z = 407.1 [M+H]⁺. [0429] A 40 mL vial was charged with tert-butyl 2-bromo-3-methyl-6-(pyridin-2-ylmethyl)-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (215 mg, 0.528 mmol, 1.00 equiv), (R)-3-chloro- 4-(1-(pyridin-2-yl)ethoxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (633 mg, 1.58 mmol, 3.00 equiv), Pd(PPh₃)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 166 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 μm; 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)-1-(pyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6-(pyridin-2-ylmethyl)-6,7- dihydropyrazolo[1,5-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]⁺. [0430] A 100 mL round-bottom flask was charged with tert-butyl 2-(3-chloro-4-((R)-1-(pyridin-2- yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6-(pyridin-2-ylmethyl)-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate, isomer 1 (120 mg, 0.200 mmol, 1.00 equiv) and HCl (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)-1-(pyridin-2- yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6-(pyridin-2-ylmethyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine, isomer 1 (120 mg, crude) as a white solid. LCMS(ESI-MS) m/z = 500.2 [M+H]⁺. [0431] A 100 mL round-bottom flask was charged with 2-(3-chloro-4-((R)-1-(pyridin-2- yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6-(pyridin-2-ylmethyl)-4,5,6,7- tetrahydropyrazolo[1,5-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 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 crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol/L NH₄CO₃H), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 33% B to 63% B in 10min; Wave Length 254nm/220nm to afford 2-(3-chloro-4-((R)-1-(pyridin-2-yl)ethoxy)pyrazolo[1,5- a]pyridin-6-yl)-3-methyl-6-(pyridin-2-ylmethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carbonitrile, isomer 1 (37.9 mg, 36% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 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]⁺. [0432] Isomer 2 was synthesized using the same procedure, starting with tert-butyl 2-(3-chloro-4-((R)-1- (pyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6-(pyridin-2-ylmethyl)-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate, isomer 2 the same procedure as used as described 167 above. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4CO3H), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 33% B to 63% B in 10min; Wave Length: 254nm/220nm to afford 2-(3-chloro-4-((R)-1-(pyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3- methyl-6-(pyridin-2-ylmethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, isomer 2 (38.2 mg, 36% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 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 26 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, Isomer 1 Example 27 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, Isomer 2 Example 28 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, Isomer 3 Example 29 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, Isomer 4

168 [0433] A 100 mL round bottom flask was charged with 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-5-amine (3.5 g, 25.5 mmol, 1.00 equiv), Boc₂O (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 / 25) to afford tert-butyl (4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-5- yl)carbamate (5.8 g, 96% yield) as a white solid. LCMS (ESI-MS) m/z = 238.2[M+H]⁺. [0434] A 40 mL vial were added tert-butyl (4,5,6,7-tetrahydropyrazolo[1,5-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[1,5-a]pyridin-5-yl)carbamate (2 g, 94% yield) as a white solid. LCMS (ESI-MS) m/z = 316.1[M+H]⁺. [0435] A 100mL round bottom 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[1,5-a]pyridin- 5-yl)carbamate (2 g, 6.33 mmol, 1.00 equiv), trimethyl-1,3,5,2,4,6-trioxatriborinane (7.94 g, 31.6 mmol, 5.00 equiv, 50%), Pd(dppf)Cl2 (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 169 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[1,5-a]pyridin- 5-yl)carbamate (850 mg, 53% yield) as a white solid. LCMS (ESI-MS) m/z = 252.2[M+H]⁺. [0436] A 8 mL vial were added tert-butyl (3-methyl-4,5,6,7-tetrahydropyrazolo[1,5-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[1,5-a]pyridin-5-yl)carbamate (350 mg, 59% yield) as a white solid. LCMS (ESI-MS) m/z = 330.1[M+H]⁺. [0437] A 40 mL vial were added tert-butyl (2-bromo-3-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin- 5-yl)carbamate (410 mg, 1.24 mmol, 1.00 equiv), 2-((3-chloro-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-1-(5-fluoropyridin-2-yl)ethan-1-ol (1067 mg, 2.48 mmol, 2.00 equiv), Pd(PPh3)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[1,5-a]pyridin]-5-yl)carbamate (150 mg, 22% yield) as a white solid. LCMS (ESI-MS) m/z = 557.2[M+H]⁺. [0438] A 100 mL round bottom 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[1,5-a]pyridin]-5-yl)carbamate (148 mg, 0.266 mmol, 1.00 equiv), 1,4-dioxane (1 mL) and HCl (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 2 2-((5-amino-3'-chloro-3-methyl-4,5,6,7-tetrahydro-[2,6'-bipyrazolo[1,5-a]pyridin]-4'-yl)oxy)-1-(5- fluoropyridin-2-yl)ethan-1-ol (148 mg, crude) as a white solid. LCMS (ESI-MS) m/z = 457.2[M+H]⁺. [0439] A 40 mL vial were added 2-((5-amino-3'-chloro-3-methyl-4,5,6,7-tetrahydro-[2,6'-bipyrazolo[1,5- a]pyridin]-4'-yl)oxy)-1-(5-fluoropyridin-2-yl)ethan-1-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 170 following conditions1: Column: CHIRALPAKAD3; Mobile Phase A: Hex(0.2%FA): EtOH=60: 40; Flow rate: 1mL/min mL/min; Gradient: isocratic; Injection Volume: 2μ 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. [0440] 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: 1mL/min mL/min; Gradient: isocratic; Injection Volume: 3μl 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-d4) δ 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]⁺. [0441] Isomer 2 (the second elution of mixture 1, 6.1 mg, 3.8% yield) as a white solid. 1H NMR (400 MHz, Methanol-d4) δ 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), 3.84-3.77 (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]⁺. [0442] 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: 1mL/min mL/min; Gradient: isocratic; Injection Volume: 1uL 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-d4) δ 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]⁺. [0443] Isomer 4 (the second elution of mixture 2, 5.5 mg, 3.4% yield) as a white solid. 1H NMR (400 MHz, Methanol-d4) δ 8.45 (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-(1-(pyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-hydroxy-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile 171 [0444] A 40 mL vial were added tert-butyl 3-bromo-4H,6H,7H-pyrazolo[1,5-a]pyrazine-5-carboxytert- butyl 3-bromo-6,7-dihydropyrazolo[1,5-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)Cl2 (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- 1,3,2-dioxaborolan-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (1 g, crude) as a colorless solid. LCMS (ESI-MS) m/z = 350.2[M+H]⁺. [0445] A 100 mL round bottom flask was charged with tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-6,7-dihydropyrazolo[1,5-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 (10 mL) 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[1,5-a]pyrazine-5(4H)-carboxylate (400 mg, 53% yield) as a white solid. LCMS (ESI-MS) m/z = 240.1[M+H]⁺. [0446] A 100 mL round bottom 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((1Z,5Z)-cycloocta-1,5-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-1,3,2-dioxaborolan-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (300 mg, crude) as a colorless solid. LCMS (ESI-MS) m/z = 366.2[M+H]⁺. 172 [0447] A 40 mL vial were added tert-butyl 3-hydroxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (300 mg, 0.821 mmol, 1.00 equiv), (R)-6- bromo-3-chloro-4-(1-(pyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridine [which can be made according to the procedures described in WO2022187443] (145 mg, 0.410 mmol, 0.50 equiv), Pd(PPh3)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 H2O (1mL). 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[1,5-a]pyrazine-5(4H)-carboxylate (100 mg, 21% yield) as a white solid. LCMS (ESI-MS) m/z = 511.2[M+H]⁺. [0448] A 100 mL round bottom flask was charged with tert-butyl (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)- carboxylate (170 mg, 0.333 mmol, 1.00 equiv), 1,4-dioxane (3 mL) and HCl (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-(1-(pyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-ol (170 mg, crude) as a white solid. LCMS (ESI-MS) m/z =411.1[M+H]⁺. [0449] A 100 mL round bottom flask was charged with (R)-2-(3-chloro-4-(1-(pyridin-2- yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-4,5,6,7-tetrahydropyrazolo[1,5-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, 5μm; Mobile Phase A: Water (10mmol/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. 1H NMR (400 MHz, DMSO- d6) δ 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 31 2-(3-chloro-4-methoxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine- 5(4H)-carbonitrile 173 [0450] Into a 100 mL round-bottom flask were added 6-bromo-3-chloro-4-methoxypyrazolo[1,5- a]pyridine (4 g, 15.3 mmol, 1.00 equiv), bis(pinacolato)diboron (5.83 g, 22.9 mmol, 1.50 equiv), Pd(dppf)Cl₂ (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- 1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (5 g, crude) as a black solid. LCMS(ESI-MS) m/z = 309.1 [M+H]⁺. [0451] Into a 40 mL round-bottom flask were added 3-chloro-4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (351 mg, 1.14 mmol, 2.00 equiv), tert-butyl 2-bromo-3- methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (180 mg, 0.569 mmol, 1.00 equiv), Pd(PPh₃)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 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-(3-chloro-4- methoxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (232 mg, 78.02% yield) as a light brown solid. LCMS(ESI-MS) m/z = 418.2 [M+H]⁺. [0452] Into a 100 mL round-bottom flask were added tert-butyl 2-(3-chloro-4-methoxypyrazolo[1,5- a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (100 mg, 0.239 mmol, 1.00 equiv), HCl (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[1,5-a]pyridin-6-yl)-3-methyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine (60 mg, crude) as a white solid. LCMS(ESI-MS) m/z = 318.1 [M+H]⁺. 174 [0453] Into a 100 mL round-bottom flask were added 2-(3-chloro-4-methoxypyrazolo[1,5-a]pyridin-6-yl)- 3-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (70 mg, 0.220 mmol, 1.00 equiv), DIEA (0.19 mL, 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, 5μm; Mobile Phase A: Water(10nmol/LNH4CO3H), 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) δ 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 32 2-(3-chloro-4-(pyridin-2-ylmethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carbonitrile [0454] Into a 500 mL round-bottom flask were added tert- tert-butyl 2-(3-chloro-4-methoxypyrazolo[1,5- a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-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[1,5-a]pyridin-6-yl)-3- methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (4.5 g, 74 %yield) as a white solid. LCMS(ESI-MS) m/z =404.1 [M+H]⁺. 175 [0455] To a stirred mixture of tert-butyl 2-(3-chloro-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-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[1,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (80 mg, 52% yield) as a light yellow solid. LCMS(ESI-MS) m/z = 495.2 [M+H]⁺. [0456] A mixture of tert-butyl 2-(3-chloro-4-(pyridin-2-ylmethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3- methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (80 mg, 0.162 mmol, 1.00 equiv) and HCl (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[1,5-a]pyridin-6- yl)-3-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (65 mg, crude) as a white solid. LCMS (ESI- MS) m/z = 395.1 [M+H]⁺. [0457] To a stirred mixture of 2-(3-chloro-4-(pyridin-2-ylmethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,6,7-tetrahydropyrazolo[1,5-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, 5μm; Mobile Phase A: Water(10nmol/LNH₄CO₃H), 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[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile (27.7 mg, 40% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 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-(1-(pyridin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile 176 [0458] Starting from tert-butyl 2-(3-chloro-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate and (S)-1-(pyridin-3-yl)ethan-1-ol, exemple 33 was synthesized following the same procedure as used for example 32. [0459] The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep Shield RP18 OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10nmol/LNH₄CO₃H), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 29% B to 59 % B in 10 min; Wave Length: 254nm/220nm to afford (R)-2-(3-chloro-4-(1-(pyridin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6- yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile (26 mg, 38% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 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 34 2-(3-chloro-4-(1-(pyridazin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, Isomer 1 Example 35 2-(3-chloro-4-(1-(pyridazin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, Isomer 2 [0460] Into a 40 mL round-bottom flask were added PPh₃ (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[1,5-a]pyridin-6-yl)-3-methyl- 6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (300 mg, 0.743 mmol, 1.00 equiv) and 1- (pyridazin-3-yl)etha1-(pyridazin-3-yl)ethan-1-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 177 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-(1- (pyridazin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine- 5(4H)-carboxylate (400 mg, crude) as a yellow solid. LCMS(ESI-MS) m/z = 510.2 [M+H]⁺. [0461] Into a 100 mL round-bottom flask were added tert-butyl 2-(3-chloro-4-(1-(pyridazin-3- yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (400 mg, 0.784 mmol, 1.00 equiv), HCl (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-(1-(pyridazin-3-yl)ethoxy)pyrazolo[1,5- a]pyridin-6-yl)-3-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (200 mg, crude) as a white solid. LCMS(ESI-MS) m/z = 410.1 [M+H]⁺. [0462] Into a 50 mL round-bottom flask were added 2-(3-chloro-4-(1-(pyridazin-3- yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,6,7-tetrahydropyrazolo[1,5-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: 1mL/min mL/min; Gradient: isocratic; Injection Volume: 1μl mL; Wave Length: 254/220nm to afford 2-(3-chloro-4-(1-(pyridazin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 6,7-dihydropyrazolo[1,5-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-d) δ 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]⁺. [0463] Isomer 2 (the second elution, 31.5 mg, 14.7% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 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-(1-(pyridin-4-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile 178 [0464] Starting from tert-butyl 2-(3-chloro-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate and (S)-1-(pyridin-4-yl)ethan-1-ol, exemple 36 was synthesized following the same procedure as used for example 32. [0465] The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep Shield RP18 OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10nmol/LNH₄CO₃H), 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-(1-(pyridin-4-yl)ethoxy)pyrazolo[1,5-a]pyridin-6- yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile (36.2 mg, 28% yield) as an off- white solid. 1H NMR (400 MHz, Chloroform-d) δ 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-(1-(tetrahydro-2H-pyran-4-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile [0466] Starting from tert-butyl 2-(3-chloro-4-hydroxypyrazolo[1,5-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. [0467] The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10nmol/LNH4CO3H), 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-(1-(tetrahydro-2H-pyran-4-yl)ethoxy)pyrazolo[1,5- a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile (61.9 mg, 29% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 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]⁺. 179 Example 38 (R)-2-(3-chloro-4-(1-cyclobutylethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile [0468] Starting from tert-butyl 2-(3-chloro-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate and (S)-1-cyclobutylethan-1-ol, exemple 38 was synthesized following the same procedure as used for example 32. [0469] The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep Shield RP18 OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10nmol/LNH₄CO₃H), 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-(1- cyclobutylethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carbonitrile (32.1 mg, 33% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 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[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile [0470] Starting from tert-butyl 2-(3-chloro-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate and (S)-tetrahydrofuran-3-ol, exemple 39 was synthesized following the same procedure as used for example 32. [0471] The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep Shield RP18 OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10nmol/LNH₄CO₃H), 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[1,5-a]pyridin- 6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile (12.7 mg, 14% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 8.27 (s, 1H), 7.82 (s, 1H), 6.78 (s, 1H), 5.17-5.11 (m, 1H), 180 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(ESI-MS) m/z = 399.1 [M+H]⁺. Example 40 (S)-2-(3-chloro-4-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile [0472] Starting from tert-butyl 2-(3-chloro-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate and (R)-tetrahydrofuran-3-ol, exemple 40 was synthesized following the same procedure as used for example 32. [0473] The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep Shield RP18 OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10nmol/LNH4CO3H), 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[1,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile (30.3 mg, 23.55% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 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 41 2-(3-chloro-4-(1-(tetrahydrofuran-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, Isomer 1 Example 42 2-(3-chloro-4-(1-(tetrahydrofuran-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, Isomer 2 Example 43 2-(3-chloro-4-(1-(tetrahydrofuran-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, Isomer 3 Example 44 181 2-(3-chloro-4-(1-(tetrahydrofuran-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, Isomer 4 [0474] Starting from tert-butyl 2-(3-chloro-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate and 1-(tetrahydrofuran-3-yl)ethan-1-ol, exemple 41 to 44 were synthesized following the same procedure as used for example 32. [0475] 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 μm; Mobile Phase A: Hex(0.1% FA)-- HPLC, Mobile Phase B: EtOH: DCM=1: 1-HPLC; Flow rate: 20ML/MIN mL/min; Gradient: isocratic [0476] 40; Wave Length: 254/220nm to afford three elution. [0477] 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 μm; 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; RT1(min): 17.357; RT2(min): 20.117; Sample Solvent: EtOH-HPLC; Injection Volume: 1.0 mL; to afford 2-(3-chloro-4-(1-(tetrahydrofuran-3- yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-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-d) δ 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(ESI-MS) m/z = 427.2 [M+H]⁺. [0478] Isomer 2 (the second elution from the mixture, 7.5 mg, 7.8% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 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]⁺. [0479] 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) δ 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]⁺. [0480] Isomer 4 (the third elution from the first prep-chiral HPLC purification, 15.4 mg, 16.1% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 8.23 (s, 1H), 7.80 (s, 1H), 6.83 (s, 1H), 4.54 (quint, 182 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 45 2-(3-chloro-4-(1-(2-cyanophenyl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, Isomer 1 Example 46 2-(3-chloro-4-(1-(2-cyanophenyl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, Isomer 2 [0481] Into a 40 mL round-bottom flask were added tert-butyl 2-(3-chloro-4-hydroxypyrazolo[1,5- a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (250 mg, 0.619 mmol, 1.00 equiv), 1-(2-bromophenyl)ethan-1-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-(1-(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]⁺. [0482] 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 NiCl2 (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-(1-(2-bromophenyl)ethoxy)-3- chloropyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate 183 (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, 5μm; 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-(1-(2-cyanophenyl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (31 mg, 42% yield) as a white solid. LCMS(ESI- MS) m/z = 533.2 [M+H]⁺. [0483] Into a 50 mL round-bottom flask were added tert-butyl 2-(3-chloro-4-(1-(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-(1-((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)benzonitrile (30 mg, crude) as a white solid. LCMS(ESI-MS) m/z = 433.2 [M+H]⁺. [0484] Into a 100 mL round-bottom flask were added 2-(1-((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)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: 1μl mL; Wave Length: 254/220nm to afford 2-(3-chloro-4-(1-(2-cyanophenyl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3- methyl-6,7-dihydropyrazolo[1,5-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) δ 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]⁺. [0485] Isomer 2, (the second elution, 3.4 mg, 11% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 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]⁺. 184 Example 47 2-(3-chloro-4-(1-(7-fluoroisoquinolin-4-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, Isomer 1 Example 48 2-(3-chloro-4-(1-(7-fluoroisoquinolin-4-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, Isomer 2 [0486] A 100 mL round bottom 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- methylisoquinoline-4-carboxamide (450 mg, 66% yield) as a yellow oil. LCMS(ESI-MS) m/z = 235.1 [M+H]⁺. [0487] A 100 mL round bottom 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 1-(7- fluoroisoquinolin-4-yl)ethan-1-one (230 mg, 51% yield) as a colorless oil. LCMS(ESI-MS) m/z = 190.1 [M+H]⁺. [0488] A 100 mL round bottom flask was charged with 1-(7-fluoroisoquinolin-4-yl)ethan-1-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, 185 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 column chromatography, eluted with (PE / EA = 1 / 5) to afford 1-(7-fluoroisoquinolin-4-yl)ethan-1-ol (180 mg, 70% yield) as a light yellow oil. LCMS(ESI-MS) m/z = 192.1 [M+H]⁺. [0489] 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(4H)- carboxylate (215 mg, 0.533 mmol, 1.00 equiv), 1-(7-fluoroisoquinolin-4-yl)ethan-1-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- (1-(7-fluoroisoquinolin-4-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate (140 mg, 41% yield) as a colorless oil. LCMS(ESI-MS) m/z = 577.2 [M+H]⁺. [0490] Into a 100 mL round-bottom flask were added tert-butyl 2-(3-chloro-4-(1-(7-fluoroisoquinolin-4- yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (140 mg, 0.243 mmol, 1.00 equiv), HCl (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-(1-((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]⁺. [0491] Into a 100 mL round-bottom flask were added 4-(1-((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: 1mL/min mL/min; Gradient: isocratic; Injection Volume: 1μl mL; Wave Length: 254/220nm to afford 2-(3-chloro-4-(1-(7-fluoroisoquinolin-4-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)- 3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, isomer 1 (the first elution, 23.1 mg, 186 12.7% yield) as an off-white solid. 1H NMR (400 MHz, Chloroform-d) δ 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]⁺. [0492] Isomer 2 (the second elution, 23.3 mg, 12.5% yield) as an off-white solid. 1H NMR (400 MHz, Chloroform-d) δ 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 49 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)-carbonitrile, Isomer 1 Example 50 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)-carbonitrile, Isomer 2 [0493] To a solution of tert-butyl 2-(3-chloro-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (300 mg, 0.743 mmol, 1 equiv) in DMSO (10 mL) was added 2-chloro-1-(5-fluoropyridin-2-yl)ethan-1-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]⁺. 187 [0494] To a solution of 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 (200 mg, 0.370 mmol, 1.00 equiv) in THF (10 mL) 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 NH4Cl 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]⁺. [0495] 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 HCl (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[1,5-a]pyrazin-2-yl)pyrazolo[1,5-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]⁺. [0496] A 8 mL reaction bottles was charged with 1-((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; Flow rate: 1mL/min mL/min; Gradient: isocratic; Injection Volume: 1μl; Wave Length: 254/220nm to afford 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)-carbonitrile, isomer 1 (the first elution, 24.6 mg, 39% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.51 (d, 1H), 8.35 (s, 1H), 8.00 (s, 1H), 7.84 (dd, 1H), 7.75 (td, 1H), 6.92 (s, 1H), 5.64 (s, 1H), 4.61 (s, 2H), 4.36 (dd, 2H), 4.25 (dd, 2H), 3.78 (dd, 2H), 2.12 (s, 3H), 1.63 (s, 3H). LCMS(ESI-MS) m/z = 482.2 [M+H]⁺. [0497] Isomer 2 (the second elution, 21.8 mg, 34% yield) as a white solid. 1H NMR (400 MHz, DMSO- d6) δ 8.51 (d, 1H), 8.35 (s, 1H), 8.00 (s, 1H), 7.84 (dd, 1H), 7.75 (td, 1H), 6.92 (s, 1H), 5.64 (s, 1H), 4.61 (s, 2H), 4.36 (dd, 2H), 4.25 (dd, 2H), 3.78 (dd, 2H), 2.12 (s, 3H), 1.63 (s, 3H). LCMS(ESI-MS) m/z = 482.2 [M+H]⁺. 188 Example 51 2-(3-chloro-4-(2-(5-fluoropyridin-2-yl)-2-hydroxybutoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, Isomer 1 Example 52 2-(3-chloro-4-(2-(5-fluoropyridin-2-yl)-2-hydroxybutoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, Isomer 2 [0498] Starting from 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 and ethylmagnesium bromide, exemple 51 and 52 were synthesized following the same procedure as used for example 49. [0499] The residue was purified by silica gel column chromatography, eluted with (PE / EA = 1 / 5) to get the product that was then purified by Pre-Chiral-HPLC: Column: CHIRAL ART Cellulose-SZ, 3*25 cm, 5 μm; Mobile Phase A: Hex(0.1% FA)--HPLC, Mobile Phase B: EtOH: DCM=1: 1--HPLC; Flow rate: 30ML/MIN mL/min; Gradient: isocratic 50; Wave Length: 254/220nm to get 2-(3-chloro-4-(2-(5- fluoropyridin-2-yl)-2-hydroxybutoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, isomer 1 (the first elution, 2.8 mg, 4.6% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 8.41 (s, 1H), 8.24 (s, 1H), 7.83-7.77 (m, 2H), 7.50 - 7.43 (m, 1H), 6.88 (s, 1H), 4.83 (s, 1H), 4.50 (s, 2H), 4.47 - 4.16 (m, 4H), 3.78-3.71 (m, 2H), 2.19 - 2.09 (m, 5H), 0.91 - 0.82 (m, 3H). LCMS(ESI-MS) m/z =496.3 [M+H]⁺. [0500] Isomer 2 (the second elution, 4.3 mg, 7.1% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 8.41 (s, 1H), 8.24 (s, 1H), 7.83-7.77 (m, 2H), 7.50 - 7.43 (m, 1H), 6.88 (s, 1H), 4.83 (s, 1H), 4.50 (s, 2H), 4.47 - 4.16 (m, 4H), 3.78-3.71 (m, 2H), 2.19 - 2.09 (m, 5H), 0.91 - 0.82 (m, 3H). LCMS(ESI-MS) m/z =496.2 [M+H]⁺. Example 53 2-(3-chloro-4-(2-cyclopropyl-2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6- yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, Isomer 1 Example 54 2-(3-chloro-4-(2-cyclopropyl-2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6- yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, Isomer 2 189 [0501] Starting from 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 and isopropylmagnesium bromide, exemple 53 and 54 were synthesized following the same procedure as used for example 49. [0502] The residue product was purified by reversed-phased flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.05% TFA), 30% to 70% gradient in 30 min; detector, UV 254 nm to afford a crude product. The crude product was purified by Prep- Chiral-HPLC with the following conditions: Column: CHIRALPAK IM, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.1% FA)--HPLC, Mobile Phase B: MeOH: DCM=1: 1--HPLC; Flow rate: 20ML/MIN mL/min; Gradient: isocratic 45; Wave Length: 254/220nm to afford 2-(3-chloro-4-(2-cyclopropyl-2- (5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, isomer 1 (the first elution, 12.5 mg, 14.1% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 8.43 (d, 1H), 8.26 (s, 1H), 7.97 (dd, 1H), 7.79 (s, 1H), 7.59 (td, 1H), 6.94 (s, 1H), 4.63 (d, 1H), 4.51 (s, 2H), 4.41 - 4.31 (m, 3H), 3.76 (dd, 2H), 2.16 (s, 3H), 1.75 - 1.67 (m, 1H), 0.83-0.76 (m, 1H), 0.59-0.46 (m, 2H), 0.41-0.33 (m, 1H). LCMS(ESI-MS) m/z =508.3 [M+H]⁺. [0503] Isomer 2 (the second elution, 14.1 mg, 16% yield). 1H NMR (400 MHz, Chloroform-d) δ 8.43 (d, 1H), 8.26 (s, 1H), 7.97 (dd, 1H), 7.79 (s, 1H), 7.59 (td, 1H), 6.94 (s, 1H), 4.63 (d, 1H), 4.51 (s, 2H), 4.37 (dd, 2H), 4.31 (d, 3H), 3.76 (dd, 2H), 2.16 (s, 3H), 1.72 - 1.65 (m, 1H), 0.81-0.75 (m, 1H), 0.58- 0.45 (m, 2H), 0.40-0.33 (m, 1H). LCMS(ESI-MS) m/z =508.3 [M+H]⁺. Example 55 N-(3-(2-(3-chloro-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)-3-fluorocyclobutyl)cyanamide, Isomer 1 Example 56 N-(3-(2-(3-chloro-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)-3-fluorocyclobutyl)cyanamide, Isomer 2 190 [0504] A 40 mL vial were added 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-1-ol (500 mg, 1.13 mmol, 1.00 equiv), 3-((tert-butoxycarbonyl)amino)-1-fluorocyclobutane-1-carboxylic acid (263 mg, 1.13 mmol, 1.00 equiv), HATU (859 mg, 2.26 mmol, 2.00 equiv), DIEA (292 mg, 2.26 mmol, 2.00 equiv) and DMF (5 mL). The resulting solution was stirred for 2 hours at room temperature. The reaction was quenched with water (50 mL). The mixture was extracted with EA (3 x 100 mL). The organic layers were combined, washed with water (3 x 50 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-(2-(3-chloro-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)-3-fluorocyclobutyl)carbamate (300 mg, 32% yield) as a colorless oil. LCMS (ESI-MS) m/z = 658.2 [M+H]⁺. [0505] A 100 mL round bottom flask was charged with tert-butyl (3-(2-(3-chloro-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)-3-fluorocyclobutyl)carbamate (350 mg, 0.532 mmol, 1.00 equiv), 1,4-dioxane (3 mL) and HCl (4M in dioxane, 3 mL). The resulting solution was stirred for 2 hours at room temperature and concentrated under reduced pressure to provide (3-amino-1-fluorocyclobutyl)(2-(3- chloro-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)methanone (400 mg, crude) as a white solid. LCMS (ESI-MS) m/z = 558.2 [M+H]⁺. [0506] A 100 mL round bottom flask was charged with (3-amino-1-fluorocyclobutyl)(2-(3-chloro-4-(2- (5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)methanone (400 mg, 0.717 mmol, 1.00 equiv), BrCN (75.9 mg, 0.717 mmol, 1.00 equiv), K2CO3 (991 mg, 7.17 mmol, 10.0 equiv) and DMF (10 mL). The resulting solution was stirred for 2 hours at room temperature. The reaction was quenched with water (50 mL). The mixture was extracted with EA (3 x 100 mL). The organic layers were washed with water (3 x 50 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: CHIRALPAKIA3; Mobile Phase A: Hex(0.2%FA): (MeOH: DCM=1: 1)=60: 40; Flow rate: 1mL/min mL/min; Gradient: isocratic; Injection Volume: 1μl mL; Wave Length: 254/220nm 191 [0507] to afford N-(3-(2-(3-chloro-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)-3-fluorocyclobutyl)cyanamide, isomer 1 (the first elution, 11.7 mg, 2.8% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 8.44 (d, 1H), 8.28 (d, 1H), 7.82 (s, 1H), 7.69 (dd, 1H), 7.49 (td, 1H), 6.92 (d, 1H), 5.28-5.23 (m, 1H), 4.77 (d, 2H), 4.54 - 4.41 (m, 3H), 4.28 (dd, 2H), 4.17 - 4.00 (m, 4H), 3.01 - 2.80 (m, 4H), 2.19 (d, 3H). LCMS (ESI-MS) m/z = 583.1 [M+H]⁺. [0508] Isomer 2 (the second elution, 14.4 mg, 3.3% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 8.44 (d, 1H), 8.28 (d, 1H), 7.82 (s, 1H), 7.69 (dd, 1H), 7.49 (td, 1H), 6.92 (s, 1H), 5.28 (t, 1H), 4.77 (d, 2H), 4.57-4.48 (m, 1H), 4.44 (d, 2H), 4.28 (dd, 2H), 4.17 - 4.00 (m, 4H), 3.01 - 2.80 (m, 4H), 2.19 (d, 3H). LCMS (ESI-MS) m/z = 583.1 [M+H]⁺. Example 57 3-(2-(3-chloro-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)azetidine-1-carbonitrile, Isomer 1 Example 58 3-(2-(3-chloro-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)azetidine-1-carbonitrile, Isomer 2 [0509] To a solution of 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-1-ol (45 mg, 0.102 mmol, 1 equiv) in DCE (2 mL) was added TEA (82.3 mg, 0.816 mmol, 8 equiv) and tert-butyl 3-oxoazetidine-1- carboxylate (26.1 mg, 0.153 mmol, 1.5 equiv). The reaction was stirred for 1 hour at room temperature. Added sodium triacetoxyborohydride (64.60 mg, 0.306 mmol, 3 equiv) in the solution. The reaction was stirred for 1 hour at room temperature. 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 silica gel column chromatography, eluted with (DCM / MeOH = 15 / 1) to afford tert-butyl 3-(2-(3-chloro-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin- 6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)azetidine-1-carboxylate (35 mg, 57.59% yield) as a yellow solid. LCMS(ESI-MS) m/z =598.2 [M+H]⁺. [0510] To a solution of tert-butyl 3-(2-(3-chloro-4-(2-(5-fluoropyridin-2-yl)-2- hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)- 192 yl)azetidine-1-carboxylate (35 mg, 0.059 mmol, 1 equiv) in 1,4-dioxane (0.5 mL) was added HCl (4 M in 1,4-dioxane, 2 mL). The reaction was stirred for 1 hour at room temperature. The reaction was concentrated under reduced pressure to afford 2-((6-(5-(azetidin-3-yl)-3-methyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-3-chloropyrazolo[1,5-a]pyridin-4-yl)oxy)-1-(5-fluoropyridin- 2-yl)ethan-1-ol (29 mg, crude) as a white solid. LCMS(ESI-MS) m/z =498.2 [M+H]⁺. [0511] To a solution of 2-((6-(5-(azetidin-3-yl)-3-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)- 3-chloropyrazolo[1,5-a]pyridin-4-yl)oxy)-1-(5-fluoropyridin-2-yl)ethan-1-ol (29 mg, 0.058 mmol, 1.00 equiv) in DCM (1 mL) was added DIEA (60.2 mg, 0.464 mmol, 8.00 equiv) and BrCN (9.25 mg, 0.087 mmol, 1.50 equiv). The reaction was stirred for 0.5 hour at room temperature. 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 silica gel column chromatography, eluted with (DCM / MeOH = 15 / 1), then purified by Prep-Chiral-HPLC: Column: CHIRAL ART Cellulose-SZ, 3*25 cm, 5 μm; Mobile Phase A: Hex(0.1% FA)--HPLC, Mobile Phase B: EtOH: DCM=1: 1--HPLC; Flow rate: 20ML/MIN mL/min; Gradient: isocratic 60; Wave Length: 254/220nm to get 3-(2-(3-chloro-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3- methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)azetidine-1-carbonitrile, isomer 1 (the first elution, 2.2 mg, 7% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 8.44 (s, 1H), 8.26 (s, 1H), 7.80 (s, 1H), 7.69 (dd, 1H), 7.48 (td, 1H), 7.28 (s, 1H), 6.92 (s, 1H), 5.26 (dd, 1H), 4.43 (d, 2H), 4.33 - 4.25 (m, 2H), 4.27 - 4.16 (m, 4H), 3.65-3.57 (m, 1H), 3.55 (s, 2H), 2.88 (dd, 2H), 2.13 (d, 3H). LCMS(ESI-MS) m/z =523.3 [M+H]⁺. [0512] Isomer 2 (the second elution, 2.1 mg, 7% yield) as a white solid. 1H NMR (400 MHz, Chloroform- d) δ 8.44 (d, 1H), 8.26 (s, 1H), 7.80 (s, 1H), 7.69 (dd, 1H), 7.48 (td, 1H), 7.28 (s, 1H), 6.92 (s, 1H), 5.26 (dd, 1H), 4.43 (d, 2H), 4.31-4.17 (m, 6H), 3.65-3.57 (m, 1H), 3.55 (s, 2H), 2.88 (dd, 2H), 2.13 (d, 3H). LCMS(ESI-MS) m/z =523.3 [M+H]⁺. Example 59 1-(3-(2-(3-chloro-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3- methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)azetidin-1-yl)prop-2-en-1-one, Isomer 1 Example 60 1-(3-(2-(3-chloro-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3- methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)azetidin-1-yl)prop-2-en-1-one, Isomer 2 193 [0513] To a solution of 2-({6-[5-(azetidin-3-yl)-3-methyl-4H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]-3- chloropyrazolo[1,5-a]pyridin-4-yl}oxy)-1-(5-fluoropyridin-2-yl)ethanol (73 mg, 0.147 mmol, 1.00 equiv) in DCM (5.5 mL) was added DIEA (114 mg, 0.882 mmol, 6.00 equiv) and prop-2-enoyl chloride (13.3 mg, 0.147 mmol, 1.00 equiv) at 0°C. The reaction was stirred for 2 hours at room temperature. 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 silica gel column chromatography, eluted with (DCM / MeOH = 15 / 1) and concentrated to afford crude product. The crude product was purified by Prep-Chiral-HPLC with the following conditions: Column: CHIRAL ART Cellulose-SZ, 3*25 cm, 5 μm; Mobile Phase A: Hex(0.1% FA)--HPLC, Mobile Phase B: MeOH: DCM=1: 1--HPLC; Flow rate: 30ML/MIN mL/min; Gradient: isocratic 50; Wave Length: 254/220nm to afford 1-(3-(2-(3-chloro-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)- 3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)azetidin-1-yl)prop-2-en-1-one, isomer 1 (the first elution, 27.7 mg, 34% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 8.46 (d, 1H), 8.28 (s, 1H), 7.81 (s, 1H), 7.71 (dd, 1H), 7.51 (td, 1H), 6.96 (s, 1H), 6.39 (dd, 1H), 6.23 (dd, 1H), 5.74 (dd, 1H), 5.28 (dd, 1H), 4.46 (d, 2H), 4.41-4.35 (m, 1H), 4.33 - 4.22 (m, 4H), 4.13-4.06 (m, 1H), 3.66 (s, 2H), 3.60 (quint, 1H), 3.02-2.91 (m, 2H), 2.16 (s, 3H). LCMS(ESIMS) m/z =552.3 [M+H]⁺. [0514] Isomer 2 (the second elution, 26.2 mg, 32% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 8.46 (d, 1H), 8.28 (s, 1H), 7.81 (s, 1H), 7.71 (dd, 1H), 7.51 (td, 1H), 6.96 (s, 1H), 6.39 (dd, 1H), 6.23 (dd, 1H), 5.74 (dd, 1H), 5.28 (dd, 1H), 4.46 (d, 2H), 4.41-4.34 (m, 1H), 4.29 - 4.12 (m, 4H), 4.13-4.06 (m, 1H), 3.66 (s, 2H), 3.60 (quint, 1H), 3.02-2.91 (m, 2H), 2.16 (s, 3H). LCMS(ESIMS) m/z =552.4 [M+H]⁺. Example 61 N-(3'-chloro-3-hydroxy-4'-((R)-1-(pyridin-2-yl)ethoxy)-4,5,6,7-tetrahydro-[2,6'-bipyrazolo[1,5- a]pyridin]-5-yl)cyanamide, Isomer 1 Example 62 194 N-(3'-chloro-3-hydroxy-4'-((R)-1-(pyridin-2-yl)ethoxy)-4,5,6,7-tetrahydro-[2,6'-bipyrazolo[1,5- a]pyridin]-5-yl)cyanamide, Isomer 2 [0515] A 40 mL vial were added tert-butyl (3-bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-5- yl)carbamate (1.50 g, 4.74 mmol, 1.00 equiv), bis(pinacolato)diboron (2.41 g, 9.49 mmol, 2.00 equiv), Pd(dppf)Cl₂ (174 mg, 0.237 mmol, 0.05 equiv), AcOK (931 mg, 9.49 mmol, 2.00 equiv) and 1,4- dioxane (5 mL). The resulting solution was stirred overnight at 80°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 to afford tert-butyl (3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-5-yl)carbamate (1.8 g, crude) as a brown solid. LCMS (ESI-MS) m/z = 364.2 [M+H]⁺. [0516] A 40 mL vial were added tert-butyl (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyridin-5-yl)carbamate (1.8 g, 4.96 mmol, 1.00 equiv), sodium perborate tetrahydrate (1.52 g, 9.91 mmol, 2.00 equiv), THF (30 mL) and H2O (10 mL). The resulting solution was stirred for 2 hours 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 to afford tert-butyl (3-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-5-yl)carbamate (170 mg, crude) as a white solid. LCMS (ESI-MS) m/z =254.1 [M+H]⁺. [0517] A 40 mL vial were added tert-butyl (3-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-5- yl)carbamate (300 mg, 1.18 mmol, 1.00 equiv), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (15.2 mg, 0.118 mmol, 0.10 equiv), bis(pinacolato)diboron (602 mg, 2.37 mmol, 2.00 equiv), dtbpy (31.8 mg, 0.118 mmol, 0.10 equiv), [Ir(COD)(OMe)]2 (39.3 mg, 0.059 mmol, 0.05 equiv) and 1,4-dioxane (2 mL). The resulting solution was stirred overnight at 100°C under nitrogen atmosphere. The resulting mixture was filtered, the filtrate was concentrated under reduced pressure to provide tert-butyl (3- hydroxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-5- yl)carbamate (200 mg, crude) as a brown solid. LCMS (ESI-MS) m/z = 380.2 [M+H]⁺. 195 [0518] A 40 mL vial were added tert-butyl (3-hydroxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-5-yl)carbamate (200 mg, 0.527 mmol, 1.00 equiv), (R)-6- bromo-3-chloro-4-(1-(pyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridine (186 mg, 0.527 mmol, 1.00 equiv), Pd(PPh3)4 (30.5 mg, 0.026 mmol, 0.05 equiv), K2CO3 (146 mg, 1.05 mmol, 2.00 equiv), H2O (5 mL) and 1,4-dioxane (1 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 = 2 / 1) to afford tert-butyl (3'-chloro-3-hydroxy-4'-((R)- 1-(pyridin-2-yl)ethoxy)-4,5,6,7-tetrahydro-[2,6'-bipyrazolo[1,5-a]pyridin]-5-yl)carbamate (80 mg, 26% yield) as a white solid. LCMS (ESI-MS) m/z = 525.2 [M+H]⁺. [0519] A 100 mL round bottom flask was charged with tert-butyl N-(2-{3-chloro-4-[(1R)-1-(pyridin-2- yl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl}-3-hydroxy-4H,5H,6H,7H-pyrazolo[1,5-a]pyridin-5- yl)carbamate (61 mg, 0.116 mmol, 1.00 equiv), 1,4-dioxane (3 mL) and HCl (4M in 1,4-dioxane, 3 mL). The resulting solution was stirred for 2 hours at room temperature and concentrated under reduced pressure to provide 5-amino-3'-chloro-4'-((R)-1-(pyridin-2-yl)ethoxy)-4,5,6,7-tetrahydro-[2,6'- bipyrazolo[1,5-a]pyridin]-3-ol (61 mg, crude) as a white solid. LCMS (ESI-MS) m/z =425.1 [M+H]⁺. [0520] A 100 mL round bottom flask was charged with 5-amino-3'-chloro-4'-((R)-1-(pyridin-2-yl)ethoxy)- 4,5,6,7-tetrahydro-[2,6'-bipyrazolo[1,5-a]pyridin]-3-ol (61 mg, 0.144 mmol, 1.00 equiv), BrCN (15.2 mg, 0.144 mmol, 1.00 equiv), K₂CO₃ (198 mg, 1.44 mmol, 10.00 equiv) and DMF (3 mL). The resulting solution was stirred for 2 hours at room temperature. The reaction was quenched by the addition of 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-Chiral-HPLC with the following conditions: Column: CHIRALARTCelluloseSZ; Mobile Phase A: Hex(0.1%DEA): (EtOH: DCM=1: 1)=70: 30; Flow rate: 1 mL/min; Gradient: isocratic; Injection Volume: 3μl; Wave Length: 254/220nm to afford N-(3'-chloro-3-hydroxy-4'-((R)-1-(pyridin-2-yl)ethoxy)-4,5,6,7-tetrahydro-[2,6'-bipyrazolo[1,5- a]pyridin]-5-yl)cyanamide, isomer 1 (the first elution, 4.1 mg, 6% yield) as an off-white solid. 1H NMR (400 MHz, Methanol-d4) δ 8.74 (d, 1H), 8.56 (dd, 1H), 7.87 (s, 1H), 7.84 (dt, 2H), 7.69 (d, 1H), 7.35 (ddd, 1H), 7.10 (d, 1H), 5.69 (q, 1H), 4.21 (dt, 1H), 4.11 (ddd, 1H), 3.74 (tdd, 1H), 3.13 (ddd, 1H), 2.76 (dd, 1H), 2.34-2.26 (m, 1H), 2.16 (ddt, 1H), 1.80 (d, 3H). LCMS (ESI-MS) m/z = 450.1 [M+H]⁺. [0521] Isomer 2, (the second elution, 4.5 mg, 7% yield) as a white solid. 1H NMR (400 MHz, Methanol- d4) δ 8.74 (d, 1H), 8.56 (dd, 1H), 7.87 (s, 1H), 7.84 (dt, 2H), 7.69 (d, 1H), 7.35 (ddd, 1H), 7.10 (d, 1H), 5.69 (q, 1H), 4.21 (td, 1H), 4.11 (ddd, 1H), 3.74 (tdd, 1H), 3.13 (dd, 1H), 2.76 (dd, 1H), 2.34-2.26 (m, 1H), 2.16 (ddt, 1H), 1.80 (d, 3H). LCMS (ESI-MS) m/z = 450.1 [M+H]⁺. Example 63 196 2-(3-chloro-4-(2-fluoro-1-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, Isomer 1 Example 64 2-(3-chloro-4-(2-fluoro-1-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, Isomer 2 [0522] A 100 mL round bottom flask was charged with 2-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2- hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carbonitrile (170 mg, 0.363 mmol, 1.00 equiv), DAST (87.9 mg, 0.544 mmol, 1.50 equiv) and DCM (5 mL). The resulting solution was stirred for 2 hours at room temperature. The reaction was quenched by the addition of 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-Chiral-HPLC with the following conditions: Column: CHIRALPAKIG3; Mobile Phase A: Hex(0.2%FA): (MeOH: DCM=1: 1)=65: 35; Flow rate: 1mL/min mL/min; Gradient: isocratic; Injection Volume: 2μl mL; Wave Length: 254/220nm to afford 2-(3-chloro-4-(2-fluoro-1-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[1,5- a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, Isomer 1 (the first elution, 6.4 mg, 3.7% yield) as an off-white solid. 1H NMR (400 MHz, Chloroform-d) δ 8.50 (d, 1H), 8.28 (s, 1H), 7.87 (s, 1H), 7.68 (dd, 1H), 7.46 (td, 1H), 6.79 (s, 1H), 5.83 (ddd, 1H), 4.99 (ddd, 1H), 4.87 (ddd, 1H), 4.47 (s, 2H), 4.32 (dd, 2H), 3.72 (dd, 2H), 2.04 (s, 3H). LCMS (ESI-MS) m/z =470.0 [M+H]⁺. [0523] Isomer 2 (the second elution, 7.2 mg, 4% yield) as an off-white solid. 1H NMR (400 MHz, Chloroform-d) δ 8.50 (d, 1H), 8.28 (s, 1H), 7.87 (s, 1H), 7.68 (dd, 1H), 7.46 (td, 1H), 6.79 (s, 1H), 5.83 (ddd, 1H), 4.99 (ddd, 1H), 4.87 (ddd, 1H), 4.47 (s, 2H), 4.32 (dd, 2H), 3.72 (dd, 2H), 2.04 (s, 3H). LCMS (ESI-MS) m/z =470.0 [M+H]⁺. Example 65 197 2-(3-chloro-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1 Example 66 2-(3-chloro-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2 [0524] A 1 L round bottom flask was charged with ethyl 3-oxopentanoate (20.0 g, 139 mmol, 1.00 equiv), [2-(dimethylamino)ethyl]dimethylamine (19.3 g, 166 mmol, 1.20 equiv) and tetrahydrofuran (300 mL). To the above mixture was added sodium hydride (6.66 g, 166 mmol, 1.20 equiv, 60% in mineral oil) in three portions at -20°C under nitrogen atmosphere. The mixture was stirred for 15 min at -20°C and n- butyllithium (83.2 mL, 208 mmol, 1.50 equiv, 2.5 M in hexane) was added dropwise at -20°C under nitrogen atmosphere. The mixture was stirred for 15 min at -20 °C. To the above solution was added rapidly methyl formate (9.16 g, 153 mmol, 1.10 equiv) in THF (50 mL) at -20°C and stirred for 15 min at -20°C. The reaction was quenched with 10 % HCl aqueous solution and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with saturated salt solution (3 x 100 mL), dried over anhydrous sodium sulfate, filtrated and concentrated under reduced pressure to afford ethyl ethyl 4-methyl-3,5-dioxopentanoate (23 g, crude) as a brown oil. LCMS(ESI-MS) m/z =173.1 [M+H]⁺. [0525] A 1000 mL round bottom flask was charged with ethyl 4-methyl-3,5-dioxopentanoate (20 g, 58.1 mmol, 1.00 equiv, 50% purity), 2-hydroxyethylhydrazine (4.42 g, 58.1 mmol, 1.00 equiv) and ethanol (300 mL). The resulting solution was stirred overnight at 80 °C. The reaction was concentrated under reduced pressure and the residue was diluted with water (500 mL). The mixture was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with saturated salt solution (3 x 50 mL), dried over anhydrous sodium sulfate, filtrated and concentrated under reduced pressure. The crude was purified by silica gel column chromatography, eluted with (DCM / MeOH =10 / 1) to afford 198 ethyl ethyl 2-(1-(2-hydroxyethyl)-4-methyl-1H-pyrazol-5-yl)acetate (8 g, crude) as a yellow oil. LCMS(ESI-MS) m/z =213.1 [M+H]⁺. [0526] A 250 mL round bottom flask was charged with ethyl 2-(1-(2-hydroxyethyl)-4-methyl-1H-pyrazol- 5-yl)acetate (4.0 g, 18.8 mmol, 1.00 equiv) and THF (100 mL) at 0 °C under nitrogen atmosphere. To the above mixture was added dropwise LiAlH4 (7.54 mL, 15.1 mmol, 0.80 equiv, 2 M in THF) dropwise at 0 °C. The resulting solution was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was quenched with water (10 mL) at 0 °C. The mixture was diluted with THF (300 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford 2,2'-(4-methyl-1H-pyrazole-1,5-diyl)bis(ethan-1-ol) (5.3 g, crude) as a brown oil. LCMS(ESI-MS) m/z =171.1 [M+H]⁺. [0527] A 250 mL round bottom flask was charged with 2,2'-(4-methyl-1H-pyrazole-1,5-diyl)bis(ethan-1- ol) l (3 g, 17.6 mmol, 1.00 equiv), p-toluenesulfonyl chloride (3 g, 15.7 mmol, 0.89 equiv), TEA (5 g, 49.4 mmol, 2.80 equiv), DMAP (0.2 g, 1.64 mmol, 0.09 equiv) and DCM (100 mL). The resulting solution was stirred for overnight at room temperature. The reaction was quenched with water (200 mL). The resulting mixture was extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude was purified by silica gel column chromatography, eluted with (PE / EA = 3 / 1) to afford (4-methyl-1H-pyrazole-1,5-diyl)bis(ethane-2,1-diyl) bis(4- methylbenzenesulfonate) (2.5 g, 30% yield) as a yellow oil. LCMS(ESI-MS) m/z = 479.1 [M+H]⁺. [0528] A 250 mL round bottom flask was charged with (4-methyl-1H-pyrazole-1,5-diyl)bis(ethane-2,1- diyl) bis(4-methylbenzenesulfonate) (2.5 g, 5.22 mmol, 1.00 equiv), ammonia solution (50 mL, 80% in water) and 1,4-dioxane (20 mL). The resulting solution was stirred overnight at 80 °C. The resulting mixture was concentrated under reduced pressure to afford 3-methyl-5,6,7,8-tetrahydro-4H- pyrazolo[1,5-d][1,4]diazepine (2.7 g, crude) as a light yellow oil. LCMS(ESI-MS) m/z =152.1 [M+H]⁺. [0529] A 100 mL round bottom flask was charged with 3-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- d][1,4]diazepine (2.7 g, 8.93 mmol, 1.00 equiv, 50% purity), di-tert-butyl dicarbonate (1.95 g, 8.93 mmol, 1.00 equiv), tetrahydrofuran (30 mL), TEA (1.81 g, 17.9 mmol, 2.00 equiv) and water (10 mL). The resulting solution was stirred for 3 h at room temperature. The reaction was quenched with water (200 mL). The resulting mixture was extracted with ethyl acetate (3 x 80 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA = 1 / 2) to afford tert-butyl 3-methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carboxylate (210 mg, 9% yield) as a white solid. LCMS(ESI-MS) m/z =252.2 [M+H]⁺. [0530] A 100 mL round bottom flask was charged with tert-butyl 3-methyl-4,5,7,8-tetrahydro-6H- pyrazolo[1,5-d][1,4]diazepine-6-carboxylate (210 mg, 0.836 mmol, 1.00 equiv), ACN (20 mL) and NBS (148.72 mg, 0.836 mmol, 1.00 equiv). The resulting solution was stirred for 2 h at 60 °C. The reaction was quenched with water (100 mL). The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous 199 sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA = 1: 2) to afford tert-butyl 2-bromo-3-methyl-4,5,7,8-tetrahydro-6H- pyrazolo[1,5-d][1,4]diazepine-6-carboxylate (160 mg, 58% yield) as a yellow oil. LCMS(ESI-MS) m/z =330.1 [M+H]⁺. [0531] A 100 mL round bottom flask was charged with tert-butyl 2-bromo-3-methyl-4,5,7,8-tetrahydro- 6H-pyrazolo[1,5-d][1,4]diazepine-6-carboxylate (160 mg, 0.485 mmol, 1.00 equiv), Pd(PPh3)4 (28.0 mg, 0.024 mmol, 0.05 equiv), 2-((3-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-1-(5-fluoropyridin-2-yl)ethan-1-ol (841 mg, 0.970 mmol, 2.00 equiv, 50% purity), potassium carbonate (135 mg, 0.970 mmol, 2.00 equiv), water (2 mL) and 1,4- dioxane (10 mL). The resulting solution was stirred overnight at 100 °C under nitrogen atmosphere. The reaction was quenched with water (100 mL). The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (2 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 2-(3-chloro-4-(2-(5-fluoropyridin-2-yl)-2- hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5- d][1,4]diazepine-6-carboxylate (121 mg, 45% yield) as a brown oil. LCMS(ESI-MS) m/z =557.2 [M+H]⁺. [0532] A 100 mL round bottom flask was charged with tert-butyl 2-(3-chloro-4-(2-(5-fluoropyridin-2-yl)- 2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5- d][1,4]diazepine-6-carboxylate (121 mg, 0.217 mmol, 1.00 equiv), HCl (4 M in 1,4-dioxane, 3 mL) and 1,4-dioxane (3 mL). The resulting solution was stirred for 2 h at room temperature. The reaction was concentrated under reduced pressure to afford 2-((3-chloro-6-(3-methyl-5,6,7,8-tetrahydro-4H- pyrazolo[1,5-d][1,4]diazepin-2-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-1-(5-fluoropyridin-2-yl)ethan-1- ol (140 mg, crude) as a brown solid. LCMS(ESI-MS) m/z =457.2 [M+H]⁺. [0533] A 100 mL round bottom flask was charged with 2-((3-chloro-6-(3-methyl-5,6,7,8-tetrahydro-4H- pyrazolo[1,5-d][1,4]diazepin-2-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-1-(5-fluoropyridin-2-yl)ethan-1- ol (105 mg, 0.230 mmol, 1.00 equiv), BrCN (26.8 mg, 0.253 mmol, 1.10 equiv), DIEA (149 mg, 1.150 mmol, 5.00 equiv) and DCM (10 mL). The resulting solution was stirred for 2 h at room temperature. The reaction was quenched with water (150 mL). The mixture was extracted with DCM (3 x 50 mL). The organic layers were combined, washed with brine (3 x 30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude was purified by Prep-TLC (EA / MeOH = 10 / 1) to afford crude product. The crude product was purified by Prep-CHRAL-HPLC with the following conditions: CHIRALPAK AD-H, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.1% FA)--HPLC, Mobile Phase B: MeOH: EtOH=1: 1--HPLC; Flow rate: 20ML/MIN mL/min; Gradient: isocratic 60; 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-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, isomer 1 (the first elution, 27.1 mg, 24% yield) as a light yellow solid. 1H NMR (400 MHz, Chloroform-d) δ 8.45 (s, 1H), 8.26 (s, 1H), 7.81 (s, 1H), 7.69 (dd, 1H), 7.49 (td, 1H), 6.91 (d, 1H), 5.26 (dd, 1H), 4.60 - 200 4.50 (m, 2H), 4.46 - 4.36 (m, 2H), 3.54 - 3.49 (m, 2H), 3.48 - 3.42 (m, 2H), 3.07 - 2.99 (m, 2H), 2.17 (s, 3H). LCMS(ESI-MS) m/z =482.1 [M+H]⁺. [0534] Isomer 2 (the second elution, 24.9 mg, 22% yield) as a light yellow solid. 1H NMR (400 MHz, Chloroform-d) δ 8.45 (d, 1H), 8.26 (s, 1H), 7.81 (s, 1H), 7.69 (dd, 1H), 7.49 (td, 1H), 6.91 (d, 1H), 5.26 (dd, 1H), 4.57 - 4.54 (m, 2H), 4.45 - 4.38 (m, 2H), 4.06 (s, 1H), 3.54 - 3.49 (m, 2H), 3.48 - 3.42 (m, 2H), 3.07 - 2.99 (m, 2H), 2.17 (s, 3H). LCMS(ESI-MS) m/z =482.1 [M+H]⁺. Example 67 2-(4-(1-(5-fluoropyridin-2-yl)ethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, Isomer 1 Example 68 2-(4-(1-(5-fluoropyridin-2-yl)ethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, Isomer 2 [0535] A 40 mL reaction bottles was charged with DIAD (2.85 g, 14.1 mmol, 1.5 equiv), PPh₃ (3.69 g, 14.1 mmol, 1.5 equiv) and THF (5 mL). The resulting solution was stirred for 0.5 hours at 0°C under nitrogen atmosphere. Then was added 6-bromopyrazolo[1,5-a]pyridin-4-ol (2 g, 9.39 mmol, 1 equiv) and 1-(5-fluoropyridin-2-yl)ethan-1-ol (1.33 g, 9.39 mmol, 1 equiv) in THF (20 mL). The resulting solution was stirred overnight at room temperature. The reaction was quenched by the addition of water (10 mL). The resulting mixture was extracted with EA (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 silica gel column chromatography, 201 eluted with (DCM / MeOH = 30 / 1) to afford 6-bromo-4-(1-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[1,5- a]pyridine (3.1 g, 88% yield) as a yellow solid. LCMS(ESI-MS) m/z = 336.0 [M+H]⁺. [0536] A 40 mL reaction bottles was charged with 6-bromo-4-(1-(5-fluoropyridin-2- yl)ethoxy)pyrazolo[1,5-a]pyridine (1.5 g, 4.46 mmol, 1 equiv), bis(pinacolato)diboron (1.70 g, 6.69 mmol, 1.5 equiv), AcOK (1.31 g, 13.4 mmol, 3 equiv), Pd(dppf)Cl2 (0.33 g, 0.446 mmol, 0.1 equiv) and 1,4-dioxane (25 mL) under nitrogen atmosphere. The resulting solution was stirred overnight at 80 °C. The reaction was quenched by the addition of water (100 mL). The resulting mixture was extracted with EA (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 to afford 4-(1-(5-fluoropyridin-2-yl)ethoxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5- a]pyridine (2 g, crude) as a yellow oil. LCMS(ESI-MS) m/z = 384.2 [M+H]⁺. [0537] A 50 mL round bottom flask was charged with tert-butyl 2-bromo-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (1.2 g, 3.80 mmol, 1.00 equiv), 4-(1-(5- fluoropyridin-2-yl)ethoxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (1.45 g, 3.80 mmol, 1.00 equiv), Pd(PPh3)4 (439 mg, 0.380 mmol, 0.10 equiv), K2CO3 (1.57 g, 11.4 mmol, 3.00 equiv), H2O (5 mL) and 1,4-dioxane (20 mL) under nitrogen atmosphere. The resulting solution was stirred 2 hours at 100°C. The reaction was quenched by the addition of water (50 mL). The resulting mixture was extracted with EA (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 reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in Water (0.1% TFA), 10% to 70% gradient in 30 min; detector, UV 254 nm to afford tert-butyl (R)-2-(4-(1-(5-fluoropyridin-2- yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (500 mg, 24% yield) as a yellow solid. LCMS(ESI-MS) m/z = 493.2 [M+H]⁺. [0538] A 25 mL round bottom flask was charged with tert-butyl (R)-2-(4-(1-(5-fluoropyridin-2- yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (300 mg, 0.609 mmol, 1 equiv), NIS (164 mg, 0.731 mmol, 1.2 equiv) and DCM (10 mL). The resulting solution was stirred overnight at room temperature. The reaction was quenched by the addition of water (50 mL). The resulting mixture was extracted with EA (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 silica gel column chromatography, eluted with (DCM / MeOH = 20 / 1) to afford tert-butyl 2-(4-(1-(5- fluoropyridin-2-yl)ethoxy)-3-iodopyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carboxylate (200 mg, 47% yield) as a yellow solid. LCMS(ESI-MS) m/z = 619.1 [M+H]⁺. [0539] A 40 mL reaction bottles was charged with tert-butyl 2-(4-(1-(5-fluoropyridin-2-yl)ethoxy)-3- iodopyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (220 mg, 0.356 mmol, 1.00 equiv), isopropylmagnesium chloride - Lithium chloride complex (77.5 202 mg, 0.534 mmol, 1.50 equiv), 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (199 mg, 1.07 mmol, 3.00 equiv) and THF (10 mL). The resulting solution was stirred 2 hours at 0 °C under nitrogen atmosphere. The reaction was quenched by the addition of water (100 mL). The resulting mixture was extracted with EA (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 to afford tert-butyl 2-(4-(1-(5-fluoropyridin-2-yl)ethoxy)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (200 mg, crude) as a yellow oil. LCMS(ESI-MS) m/z = 619.3 [M+H]⁺. [0540] A 40 mL reaction bottles was charged with tert-butyl 2-(4-(1-(5-fluoropyridin-2-yl)ethoxy)-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (200 mg, 0.323 mmol, 1.00 equiv), sodium perborate (78.6 mg, 0.969 mmol, 3.00 equiv), H2O (2 mL) and THF (2 mL). The resulting solution was stirred 2 hours at room temperature. The reaction was quenched by the addition of water (10 mL). The resulting mixture was extracted with EA (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 silica gel column chromatography, eluted with (DCM / MeOH = 15 / 1) to afford tert-butyl 2-(4-(1-(5-fluoropyridin-2-yl)ethoxy)-3- hydroxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (130 mg, 70% yield) as a yellow solid. LCMS(ESI-MS) m/z = 509.2 [M+H]⁺. [0541] A 8 mL reaction bottles was charged with tert-butyl 2-(4-(1-(5-fluoropyridin-2-yl)ethoxy)-3- hydroxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (130 mg, 0.256 mmol, 1.00 equiv), iodomethane (109 mg, 0.768 mmol, 3.00 equiv), K₂CO₃ (106 mg, 0.768 mmol, 3.00 equiv) and DMF (1 mL). The resulting solution was stirred 2 hours at 80 °C. The reaction was quenched by the addition of water (10 mL). The resulting mixture was extracted with EA (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 silica gel column chromatography, eluted with (DCM / MeOH = 20 / 1) to afford tert-butyl 2-(4-(1-(5-fluoropyridin-2-yl)ethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3- methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (80 mg, 60% yield) as a yellow solid. LCMS(ESI-MS) m/z = 523.2 [M+H]⁺. [0542] A 8 mL reaction bottles was charged with tert-butyl 2-(4-(1-(5-fluoropyridin-2-yl)ethoxy)-3- methoxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (86 mg, 0.165 mmol, 1.00 equiv), 1,4-dioxane (1 mL) and HCl (4 M in 1,4-dioxane, 0.5 mL). The resulting solution was stirred for 2 hours at room temperature and concentrated under reduced pressure to afford 2-(4-(1-(5-fluoropyridin-2-yl)ethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (70 mg, crude) as a yellow oil. LCMS(ESI-MS) m/z = 423.2 [M+H]⁺. 203 [0543] A 8 mL reaction bottles was charged with 2-(4-(1-(5-fluoropyridin-2-yl)ethoxy)-3- methoxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (50 mg, 0.118 mmol, 1 equiv), DIEA (91.8 mg, 0.708 mmol, 6 equiv), BrCN (12.5 mg, 0.118 mmol, 1 equiv) and DCM (1 mL). The resulting solution was stirred for 1 hours at room temperature. The reaction was quenched with water (10 mL). The mixture was extracted with DCM (3 x 100 mL). The organic layers were washed with water (3 x 50 mL). The residue was purified by silica gel column chromatography, eluted with (DCM / MeOH = 20 / 1) to afford a crude product. The crude product was purified by Prep- chiral-HPLC with the following conditions Column: CHIRALPAKIH3; Mobile Phase A: Hex(0.2%FA): (MeOH: DCM=1: 1)=80: 20; Flow rate: 1mL/min mL/min; Gradient: isocratic ; Injection Volume: 1μl; Wave Length: 254/220nm to afford 2-(4-(1-(5-fluoropyridin-2-yl)ethoxy)-3- methoxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carbonitrile, isomer 1 (the first elution, 9 mg, 17% yield) as a white solid. 1H NMR (400 MHz, DMSO- d6) δ 8.58 (d, 1H), 8.15 (s, 1H), 7.86 (s, 1H), 7.77 (td, 1H), 7.62 (dd, 1H), 6.56 (s, 1H), 5.67 (q, 1H), 4.56 (s, 2H), 4.20 (dd, 2H), 3.91 (s, 3H), 3.75 (dd, 2H), 1.96 (s, 3H), 1.68 (d, 3H). LCMS(ESI-MS) m/z = 448.2 [M+H]⁺. [0544] Isomer 2 (the second elution, 8 mg, 15% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.58 (d, 1H), 8.15 (s, 1H), 7.86 (s, 1H), 7.77 (td, 1H), 7.62 (dd, 1H), 6.56 (s, 1H), 5.67 (q, 1H), 4.56 (s, 2H), 4.20 (dd, 2H), 3.91 (s, 3H), 3.75 (dd, 2H), 1.96 (s, 3H), 1.68 (d, 3H). LCMS(ESI-MS) m/z = 448.2 [M+H]⁺. Example 69 2-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, Isomer 1 Example 70 2-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, Isomer 2

204 [0545] Starting from 6-bromopyrazolo[1,5-a]pyridin-4-ol and 2-((tert-butyldimethylsilyl)oxy)-1-(5- fluoropyridin-2-yl)ethan-1-ol, exemple 69 and 70 were synthesized following the same procedure as used for example 67. [0546] The crude product was purified by Prep-Chiral-HPLC with the following conditions: Column: CHIRAL ARTCelluloseSB; Mobile Phase A: Hex(0.2%FA): (MeOH: DCM=1: 1)=70: 30; Flow rate: 1mL/min mL/min; Gradient: isocratic; Injection Volume: 1μl mL; Wave Length: 254/220nm to afford 2-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, isomer 1 (the first elution, 2.4 mg, 3.2% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 8.49 (d, 1H), 8.19 (s, 1H), 7.71 (s, 1H), 7.64 (dd, 1H), 7.45 (td, 1H), 6.59 (s, 1H), 5.53 (dd, 1H), 4.46 (s, 2H), 4.30 (dd, 2H), 4.16 - 4.06 (m, 2H), 4.02 (s, 3H), 3.71 (dd, 2H), 2.03 (s, 3H). LCMS(ESI-MS) m/z =464.2 [M+H]⁺. [0547] Isomer 2 (the second elution, 2.1 mg, 2.8% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 8.49 (d, 1H), 8.19 (s, 1H), 7.71 (s, 1H), 7.64 (dd, 1H), 7.45 (td, 1H), 6.59 (s, 1H), 5.53 (dd, 1H), 4.46 (s, 2H), 4.30 (dd, 2H), 4.16 - 4.06 (m, 2H), 4.02 (s, 3H), 3.71 (dd, 2H), 2.03 (s, 3H). LCMS(ESI-MS) m/z =464.2 [M+H]⁺. Example 71 1-(2-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3- methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)prop-2-en-1-one, Isomer 1 Example 72 1-(2-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3- methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)prop-2-en-1-one, Isomer 2 205 [0548] Into a 100 mL round-bottom flask were added 2-(5-fluoropyridin-2-yl)-2-((3-methoxy-6-(3- methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethan-1-ol (160 mg, 0.365 mmol, 1.00 equiv), DIEA (236 mg, 1.83 mmol, 5.00 equiv) and DCM (20 mL) at room temperature. Then prop-2-enoyl chloride (29.7 mg, 0.329 mmol, 0.90 equiv) was added to the above mixture at 0 °C. The reaction was quenched with water (20 mL) at room temperature. The resulting mixture was extracted with DCM (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 / MeOH = 10 / 1) to afford a crude product. The crude product was purified by Prep-Chiral-HPLC with the following conditions: Column: CHIRALARTCellulose; Mobile Phase A: Hex(0.2%FA): (MeOH: DCM=1: 1) =75: 25; Flow rate: 1mL/min mL/min; Gradient: isocratic; Injection Volume: 1μL mL; Wave Length: 254/220nm to afford 1-(2-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3- methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)prop-2-en-1-one, isomer 1 (the first elution, 39.7 mg, 22% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 8.48 (d, 1H), 8.22 (s, 1H), 7.70 (s, 1H), 7.66 (dd, 1H), 7.46 (td, 1H), 6.65 (dd, 1H), 6.64 (s, 1H), 6.40 (d, 1H), 5.84 (d, 1H), 5.57 (dd, 1H), 4.78 (s, 2H), 4.24 (s, 2H), 4.14 (dd, 2H), 4.07 (dd, 2H), 4.01 (s, 3H), 2.07 (s, 3H). LCMS(ESI- MS) m/z = 493.3 [M+H]⁺. [0549] Isomer 2 (the second elution, 24.9 mg, 14% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 8.48 (d, 1H), 8.22 (s, 1H), 7.70 (s, 1H), 7.66 (dd, 1H), 7.46 (td, 1H), 6.65 (dd, 1H), 6.64 (s, 1H), 6.40 (d, 1H), 5.84 (d, 1H), 5.57 (dd, 1H), 4.78 (s, 2H), 4.24 (s, 2H), 4.14 (dd, 2H), 4.07 (dd, 2H), 4.01 (s, 3H), 2.07 (s, 3H). LCMS(ESI-MS) m/z = 493.3 [M+H]⁺. Example 73 2-fluoro-1-(2-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)- 3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)prop-2-en-1-one, Isomer 1 Example 74 206 2-fluoro-1-(2-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)- 3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)prop-2-en-1-one, Isomer 2 [0550] A 100 mL round bottom flask was charged with 2-(5-fluoropyridin-2-yl)-2-((3-methoxy-6-(3- methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethan-1-ol (100 mg, 0.228 mmol, 1.00 equiv), 2-fluoroprop-2-enoic acid (20.5 mg, 0.228 mmol, 1.00 equiv), HATU (173 mg, 0.456 mmol, 2.00 equiv), DIEA (88.4 mg, 0.684 mmol, 3.00 equiv) and DMF (5 mL). The resulting solution was stirred for 2 hours 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-Chiral-HPLC with the following conditions: Column: Chiral ART Cellulose-SA, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.1% FA)--HPLC, Mobile Phase B: MeOH: DCM=1: 1--HPLC; Flow rate: 20ML/MIN mL/min; Gradient: isocratic 40; Wave Length: 254/220nm to afford 2-fluoro-1-(2-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3- methoxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)prop-2- en-1-one, isomer 1 (the first elution, 16.9 mg, 14% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 8.49 (d, 1H), 8.22 (s, 1H), 7.71 (s, 1H), 7.66 (dd, 1H), 7.47 (dd, 1H), 6.64 (s, 1H), 5.57 (dd, 1H), 5.41 (dd, 1H), 5.33 (dd, 1H), 4.75 (s, 2H), 4.29-4.22 (m, 2H), 4.17-4.02 (m, 4H), 4.01 (d, 3H), 2.07 (s, 3H). LCMS(ESI-MS) m/z = 511.2 [M+H]⁺. [0551] Isomer 2 (the second elution, 15.8 mg, 13% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 8.49 (s, 1H), 8.22 (s, 1H), 7.71 (s, 1H), 7.66 (dd, 1H), 7.47 (dd, 1H), 6.64 (s, 1H), 5.57 (dd, 1H), 5.41 (dd, 1H), 5.32 (dd, 1H), 4.75 (s, 2H), 4.29-4.22 (m, 2H), 4.17- 4.02 (m, 4H), 4.01 (d, 3H), 2.07 (s, 3H). LCMS(ESI-MS) m/z = 511.2 [M+H]⁺. Example 75 3-((2-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3- methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)methyl)azetidine-1-carbonitrile, Isomer 1 207 Example 76 3-((2-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3- methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)methyl)azetidine-1-carbonitrile, Isomer 2 [0552] Starting from 2-(5-fluoropyridin-2-yl)-2-((3-methoxy-6-(3-methyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethan-1-ol and tert-butyl 3- formylazetidine-1-carboxylate, examples 75 and 76 were synthesized following the same procedure as used for example 57. [0553] The crude product was purified by Prep-Chiral-HPLC with the following conditions: Column: Chiral ART Cellulose-SA, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.1% FA)--HPLC, Mobile Phase B: EtOH: DCM=1: 1--HPLC; Flow rate: 20ML/MIN mL/min; Gradient: isocratic 50; Wave Length: 254/220nm to afford 3-((2-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5- a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)methyl)azetidine-1- carbonitrile, isomer 1 (the first elution, 20.9 mg, 20% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 8.47 (d, 1H), 8.19 (s, 1H), 7.69 (s, 1H), 7.64 (dd, 1H), 7.44 (td, 1H), 6.62 (s, 1H), 5.53 (dd, 1H), 4.30 (t, 2H), 4.21 - 4.03 (m, 4H), 4.01 (d, 3H), 3.91 (dd, 2H), 3.59 (s, 2H), 3.05 - 2.87 (m, 5H), 2.00 (s, 3H). LCMS(ESI-MS) m/z = 533.3 [M+H]⁺. [0554] Isomer 2 (the second elution, 30.2 mg, 28% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 8.47 (d, 1H), 8.19 (s, 1H), 7.69 (s, 1H), 7.64 (dd, 1H), 7.44 (td, 1H), 6.62 (s, 1H), 5.53 (dd, 1H), 4.30 (t, 2H), 4.21 - 4.03 (m, 4H), 4.01 (d, 3H), 3.91 (dd, 2H), 3.59 (s, 2H), 3.05 - 2.87 (m, 5H), 2.00 (s, 3H). LCMS(ESI-MS) m/z = 533.2 [M+H]⁺. Example 77 1-(3-((2-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3- methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)methyl)azetidin-1-yl)prop-2-en-1-one, Isomer 1 G2192078- Example 78 1-(3-((2-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3- methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)methyl)azetidin-1-yl)prop-2-en-1-one, Isomer 2 208 [0555] A 100 mL round bottom flask was charged with 2-({6-[5-(azetidin-3-ylmethyl)-3-methyl- 4H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]-3-methoxypyrazolo[1,5-a]pyridin-4-yl}oxy)-2-(5- fluoropyridin-2-yl)ethanol (150 mg, 0.296 mmol, 1.00 equiv), acryloyl chloride (26.8 mg, 0.296 mmol, 1.00 equiv), DIEA (115 mg, 0.888 mmol, 3.00 equiv) and DCM (10 mL). The resulting solution was stirred for 2 hours at 0 ℃. 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-Chiral-HPLC with the following conditions: Column: Chiral ART Cellulose-SA, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.1% FA)--HPLC, Mobile Phase B: MeOH: DCM=1: 1--HPLC; Flow rate: 20ML/MIN mL/min; Gradient: isocratic 40; Wave Length: 254/220nm to afford 2-((6-(5- (azetidin-3-ylmethyl)-3-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-3- methoxypyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethan-1-ol, isomer 1 (the first elution, 35.2 mg, 21% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 8.48 (d, 1H), 8.20 (s, 1H), 7.69 (s, 1H), 7.64 (dd, 1H), 7.44 (td, 1H), 6.62 (s, 1H), 6.36 (dd, 1H), 6.20 (dd, 1H), 5.70 (dd, 1H), 5.53 (dd, 1H), 4.36 (dd, 1H), 4.27 - 4.10 (m, 3H), 4.13 (dd, 1H), 4.06 (dd, 1H), 4.01 (s, 3H), 3.97 (s, 1H), 3.83-3.77 (m, 1H), 3.72-3.59 (m, 2H), 3.08-2.84 (m, 5H), 2.00 (s, 3H). LCMS(ESI-MS) m/z = 562.3 [M+H]⁺. [0556] Isomer 2 (the second elution, 33.7 mg, 20% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 8.48 (d, 1H), 8.20 (s, 1H), 7.69 (s, 1H), 7.64 (dd, 1H), 7.44 (td, 1H), 6.62 (s, 1H), 6.36 (dd, 1H), 6.20 (dd, 1H), 5.70 (dd, 1H), 5.53 (dd, 1H), 4.36 (dd, 1H), 4.27 - 4.10 (m, 3H), 4.13 (dd, 1H), 4.06 (dd, 1H), 4.01 (s, 3H), 3.97 (s, 1H), 3.83-3.77 (m, 1H), 3.68-3.59 (m, 2H), 3.08-2.85 (m, 5H), 2.00 (s, 3H). LCMS(ESI-MS) m/z = 562.3 [M+H]⁺. Example 79 (6S)-2-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3- methyl-6-(pyridin-2-ylmethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, Isomer 1 Example 80 209 (6S)-2-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3- methyl-6-(pyridin-2-ylmethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, Isomer 2 [0557] A 100 mL round-bottom flask was charged with 6-bromo-4-(2-((tert-butyldimethylsilyl)oxy)-1-(5- fluoropyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridine (2 g, 4.29 mmol, 1.00 equiv), DCM (30 mL) and NIS (0.96 g, 4.29 mmol, 1.00 equiv). The resulting mixture was stirred at room temperature for overnight. The reaction was quenched by the addition of water (300 mL) at room temperature. The resulting mixture was extracted with DCM (3 x 150 mL). The combined organic layers were washed with water (3 x 10 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 = 4 / 1) to afford 6-bromo-4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin- 2-yl)ethoxy)-3-iodopyrazolo[1,5-a]pyridine (2.04 g, 80% yield) as a yellow solid. LCMS(ESI-MS) m/z = 592.0 [M+H]⁺. [0558] A 100 mL round-bottom flask was charged with 6-bromo-4-(2-((tert-butyldimethylsilyl)oxy)-1-(5- fluoropyridin-2-yl)ethoxy)-3-iodopyrazolo[1,5-a]pyridine (2.04 g, 3.44 mmol, 1.00 equiv) and THF (15 mL). Isopropylmagnesium chloride in THF (4.31 mL, 8.61 mmol, 2.50 equiv, 2.0 M in THF) was added at 0 °C under nitrogen atmosphere. The reaction was stirred at 0 °C for 0.5 hour. To the mixture was added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.28 g, 6.89 mmol, 2.00 equiv) in THF (5 mL). The resulting mixture was stirred at room temperature for overnight under nitrogen atmosphere. The reaction was quenched by the addition of saturated NH₄Cl aqueous (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 10 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford 6-bromo-4-(2-((tert-butyldimethylsilyl)oxy)-1-(5- 210 fluoropyridin-2-yl)ethoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (2.04 g, crude) as a yellow oil. LCMS(ESI-MS) m/z = 592.2 [M+H]⁺. [0559] A 100 mL round-bottom flask was charged with 6-bromo-4-(2-((tert-butyldimethylsilyl)oxy)-1-(5- fluoropyridin-2-yl)ethoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (2.04 g, 3.44 mmol, 1.00 equiv), THF (40 mL), H2O (10 mL) and sodium perborate tetrahydrate (1.59 g, 10.3 mmol, 3.00 equiv). The resulting mixture was stirred at room temperature for overnight. The reaction was quenched by the addition of water (300 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 20 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)-1-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[1,5- a]pyridin-3-ol (1.2 g, 72% yield) as a green oil. LCMS(ESI-MS) m/z = 482.1 [M+H]⁺. [0560] A 100 mL round-bottom flask was charged with 6-bromo-4-(2-((tert-butyldimethylsilyl)oxy)-1- (5-fluoropyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-3-ol (1.2 g, 2.49 mmol, 1.00 equiv), DMF (10 mL), K2CO3 (0.69 g, 4.974 mmol, 2.00 equiv) and CH3I (0.35 g, 2.49 mmol, 1.00 equiv). The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched by the addition of water (300 mL) at room temperature. The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with water (6 x 20 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 = 4 / 1) to afford 6-bromo-4-(2-((tert- butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-methoxypyrazolo[1,5-a]pyridine (1.02 g, 83% yield) as a yellow oil. LCMS(ESI-MS) m/z = 496.1 [M+H]⁺. [0561] A 100 mL round-bottom flask was charged with 6-bromo-4-(2-((tert-butyldimethylsilyl)oxy)-1- (5-fluoropyridin-2-yl)ethoxy)-3-methoxypyrazolo[1,5-a]pyridine (1.02 g, 2.06 mmol, 1.00 equiv), bis(pinacolato)diboron (0.78 g, 3.08 mmol, 1.50 equiv), Pd(dppf)Cl₂ (0.08 g, 0.103 mmol, 0.05 equiv), AcOK (0.40 g, 4.110 mmol, 2.00 equiv) and 1,4- dioxane (20 mL). The resulting mixture was stirred at 80 °C for overnight 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 100 mL). The combined organic layers were washed with water (3 x 20 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford 4-(2-((tert- butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-methoxy-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (1.7 g, crude) as a yellow solid. LCMS(ESI-MS) m/z = 544.3 [M+H]⁺. [0562] A 100 mL round-bottom flask was charged with 4-(2-((tert-butyldimethylsilyl)oxy)-1-(5- fluoropyridin-2-yl)ethoxy)-3-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5- a]pyridine (534 mg, 0.491 mmol, 1.00 equiv, 50% purity), tert-butyl (S)-2-bromo-3-methyl-6-(pyridin- 2-ylmethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (200 mg, 0.491 mmol, 1.00 equiv), Pd(PPh3)4 (28.4 mg, 0.025 mmol, 0.05 equiv), 1,4-dioxane (12 mL), K2CO3 (136 mg, 0.982 211 mmol, 2.00 equiv) and H2O (3 mL). The resulting mixture was stirred at 100 °C for overnight under nitrogen atmosphere. The reaction was quenched by the addition of water (200 mL) at room temperature. The resulting mixture was extracted with EA (3 x 80 mL). The combined organic layers were washed with water (3 x 10 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 / 10) to afford tert-butyl (6S)-2-(4-(2-((tert- butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3- methyl-6-(pyridin-2-ylmethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (360 mg, 99% yield) as a light yellow solid. LCMS(ESI-MS) m/z = 744.4 [M+H]⁺. [0563] A 100 mL round-bottom flask was charged with tert-butyl (6S)-2-(4-(2-((tert- butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3- methyl-6-(pyridin-2-ylmethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (240 mg, 0.323 mmol, 1 equiv) and HCl (4.0 M in 1,4-dioxane, 10 mL). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure to afford 2-(5- fluoropyridin-2-yl)-2-((3-methoxy-6-((S)-3-methyl-6-(pyridin-2-ylmethyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethan-1-ol (240 mg, crude) as a white solid. LCMS(ESI-MS) m/z = 530.2 [M+H]⁺. [0564] A 100 mL round-bottom flask was charged with 2-(5-fluoropyridin-2-yl)-2-((3-methoxy-6-((S)-3- methyl-6-(pyridin-2-ylmethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyrazolo[1,5-a]pyridin- 4-yl)oxy)ethan-1-ol (240 mg, 0.453 mmol, 1.00 equiv), DCM (20 mL) and DIEA (117.15 mg, 0.906 mmol, 2.00 equiv). The BrCN (288.02 mg, 2.718 mmol, 6.00 equiv) in DCM (4 mL) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for overnight. The reaction was quenched by the addition of water (150 mL) at room temperature. The resulting mixture was extracted with DCM (3 x 80 mL). The combined organic layers were washed with water (3 x 10 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 a crude product. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: water (10mmol/L NH₄CO₃H), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 20% B to 50% B in 8min; Wave Length: 254nm/220nm nm to afford a crude product. The crude product was purified by Prep-Chiral-HPLC with the following conditions: Column: Chiral ART Cellulose-SA, 2*25 cm, 5 μm; Mobile Phase A: Hex--HPLC, Mobile Phase B: EtOH: DCM=1: 1--HPLC; Flow rate: 20ML/MIN mL/min; Gradient: isocratic 40; Wave Length: 254/220nm to afford (6S)-2-(4-(1-(5- fluoropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6-(pyridin-2- ylmethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, isomer 1 (the first elution, 30.5 mg, 12% yield) as a white solid. 1HNMR (400 MHz, Chloroform-d) δ 8.60 (ddd, 1H), 8.48 (d, 1H), 8.18 (d, 1H), 7.74 (td, 1H), 7.70 (s, 1H), 7.63 (dd, 1H), 7.44 (td, 1H), 7.35 - 7.29 (m, 2H), 6.59 (d, 1H), 5.53 212 (dd, 1H), 4.52 (d, 1H), 4.40 (d, 1H), 4.36 - 4.22 (m, 2H), 4.17 - 4.04 (m, 3H), 4.01 (s, 3H), 3.39 (dd, 1H), 3.20 (dd, 1H), 2.02 (s, 3H). LCMS(ESI-MS) m/z = 555.3 [M+H]⁺. [0565] Isomer 2 (the second elution, 30.3 mg, 12% yield) as a white solid. 1HNMR (400 MHz, Chloroform-d) δ 8.60 (ddd, 1H), 8.48 (d, 1H), 8.18 (d, 1H), 7.74 (td, 1H), 7.70 (s, 1H), 7.63 (dd, 1H), 7.44 (td, 1H), 7.35 - 7.29 (m, 2H), 6.59 (d, 1H), 5.53 (dd, 1H), 4.52 (d, 1H), 4.40 (d, 1H), 4.36 - 4.22 (m, 2H), 4.17 - 4.04 (m, 3H), 4.01 (s, 3H), 3.39 (dd, 1H), 3.20 (dd, 1H), 2.02 (s, 3H). LCMS(ESI-MS) m/z = 555.3 [M+H]⁺. Example 81 2-(4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, Isomer 1 Example 82 2-(4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile, Isomer 2 [0566] A mixture of 6-bromopyrazolo[1,5-a]pyridin-4-ol (3 g, 14.1 mmol, 1.00 equiv), KOH (1.58 g, 28.2 mmol, 2.00 equiv) and KI (2.34 g, 14.1 mmol, 1.00 equiv) in DMSO (100 mL) was stirred at room temperature for 2 hours. The reaction was quenched with water (30 mL). The resulting mixture was extracted with EA (2 x 200 mL). The combined organic layers were washed with water (6 x 50 mL), 213 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 = 5 / 1) to afford 2-((6-bromopyrazolo[1,5-a]pyridin-4-yl)oxy)-1-(5-fluoropyridin-2-yl)ethan-1-one (2.8 g, 56% yield) as a brown solid. LCMS(ESI-MS) m/z =350.0 [M+H]⁺. [0567] To a stirred solution of 2-((6-bromopyrazolo[1,5-a]pyridin-4-yl)oxy)-1-(5-fluoropyridin-2- yl)ethan-1-one (2.7 g, 7.71 mmol, 1.00 equiv) in MeOH (25 mL) was added NaBH4 (292 mg, 7.71 mmol, 1.00 equiv) in portions at 0 °C for 4 hours. The reaction was quenched with water (30 mL). The resulting mixture was extracted with EA (3 x 200 mL). The combined organic layers were washed with brine (3 x 10 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 = 5 / 1) to afford 2-((6-bromopyrazolo[1,5-a]pyridin-4-yl)oxy)-1-(5-fluoropyridin-2-yl)ethan- 1-ol (1.5 g, 50% yield) as a yellow solid. LCMS(ESI-MS) m/z =352.0 [M+H]⁺. [0568] A mixture of 2-((6-bromopyrazolo[1,5-a]pyridin-4-yl)oxy)-1-(5-fluoropyridin-2-yl)ethan-1-ol (700 mg, 1.91 mmol, 1.00 equiv), bis(pinacolato)diboron (971 mg, 3.82 mmol, 2.00 equiv), Pd(dppf)Cl2 (140 mg, 0.191 mmol, 0.10 equiv) and AcOK (375 mg, 3.82 mmol, 2.00 equiv) in 1,4-dioxane (10 mL) was stirred overnight at 80 °C under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EA (3 x 10 mL). The filtrate was concentrated under reduced pressure to afford 1-(5-fluoropyridin-2-yl)-2-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridin-4- yl)oxy)ethan-1-ol (1.85 g, crude) as a brown oil. LCMS(ESI-MS) m/z =400.2 [M+H]⁺. [0569] A mixture of 1-(5-fluoropyridin-2-yl)-2-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethan-1-ol (253 mg, 0.633 mmol, 1.00 equiv), tert-butyl 2-bromo- 3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (200 mg, 0.633 mmol, 1.00 equiv), Pd(PPh₃)₄ (73.1 mg, 0.063 mmol, 0.10 equiv) and K₂CO₃ (175 mg, 1.27 mmol, 2.00 equiv) in 1,4- dioxane (4 mL) and H₂O (1 mL) was stirred at 100 °C for 2 hours under nitrogen atmosphere. The reaction was quenched with water (10 mL). The resulting mixture was extracted with EA (2 x 20 mL). The combined organic layers were washed with water (3 x 10 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-(4-(2-(5- fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (110 mg, 31 % yield) as a brown oil. LCMS(ESI- MS) m/z =509.2 [M+H]⁺. [0570] A mixture of tert-butyl 2-(4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6- yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (200 mg, 0.393 mmol, 1.00 equiv) and NIS (106 mg, 0.472 mmol, 1.20 equiv) in DCM (5 mL) was stirred at room temperature for 1 hour. The reaction was quenched with water (10 mL). The resulting mixture was extracted with EA (2 x 20 mL). The combined organic layers were washed with water (3 x 10 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-(4- 214 (2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-iodopyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (180 mg, 69% yield) as a brown solid. LCMS(ESI- MS) m/z =635.1 [M+H]⁺. [0571] A mixture of tert-butyl 2-(4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-iodopyrazolo[1,5- a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (170 mg, 0.268 mmol, 1.00 equiv), imidazole (27.4 mg, 0.402 mmol, 1.50 equiv) and tert-butyl(chloro)dimethylsilane (52.5 mg, 0.348 mmol, 1.30 equiv) in DMF (5 mL) was stirred overnight at room temperature. The reaction was quenched with water (10 mL). The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with water (3 x 10 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 tert-butyl 2-(4-(2-((tert- butyldimethylsilyl)oxy)-2-(5-fluoropyridin-2-yl)ethoxy)-3-iodopyrazolo[1,5-a]pyridin-6-yl)-3- methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (160 mg, 76% yield) as a brown solid. LCMS(ESI-MS) m/z =749.2 [M+H]⁺. [0572] A solution of tert-butyl 2-(4-(2-((tert-butyldimethylsilyl)oxy)-2-(5-fluoropyridin-2-yl)ethoxy)-3- iodopyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (200 mg, 0.267 mmol, 1.00 equiv) in THF (5 mL) was treated with isopropylmagnesium chloride - Lithium chloride complex (58.2 mg, 0.401 mmol, 1.50 equiv) at 0 °C for 40 min under nitrogen atmosphere followed by the addition of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (149 mg, 0.801 mmol, 3.00 equiv) dropwise at 0°C. The resulting mixture was stirred for 2 hours at 0 °C. The reaction was quenched with water (10 mL). The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with water (3 x 10 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl 2-(4- (2-((tert-butyldimethylsilyl)oxy)-2-(5-fluoropyridin-2-yl)ethoxy)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (210 mg, crude) as a brown solid. LCMS(ESI-MS) m/z =749.4 [M+H]⁺. [0573] A mixture of tert-butyl 2-(4-(2-((tert-butyldimethylsilyl)oxy)-2-(5-fluoropyridin-2-yl)ethoxy)-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (210 mg, 0.280 mmol, 1.00 equiv) and sodium perborate tetrahydrate (129 mg, 0.840 mmol, 3.00 equiv) in THF (5 mL) and H₂O (5 mL) was stirred at room temperature for 2 hours. The reaction was quenched with water (10 mL). The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with water (3 x 10 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-(4-(2-((tert-butyldimethylsilyl)oxy)-2-(5-fluoropyridin-2-yl)ethoxy)-3- hydroxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (70 mg, 64% yield) as a brown solid. LCMS(ESI-MS) m/z =639.3 [M+H]⁺. 215 [0574] A mixture of tert-butyl 2-(4-(2-((tert-butyldimethylsilyl)oxy)-2-(5-fluoropyridin-2-yl)ethoxy)-3- hydroxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (70 mg, 0.110 mmol, 1.00 equiv), K2CO3 (45.4 mg, 0.330 mmol, 3.00 equiv) and iodomethane (46.7 mg, 0.330 mmol, 3.00 equiv) in DMF (5 mL) was stirred at 80 °C for 4 hours under nitrogen atmosphere. The reaction was quenched with water (10 mL). The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with water (6 x 10 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 / 2) to afford tert-butyl 2-(4-(2-((tert-butyldimethylsilyl)oxy)-2-(5-fluoropyridin-2-yl)ethoxy)-3- methoxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (60 mg, 83% yield) as a white solid. LCMS(ESI-MS) m/z =653.3 [M+H]⁺. [0575] A mixture of tert-butyl tert-butyl 2-(4-(2-((tert-butyldimethylsilyl)oxy)-2-(5-fluoropyridin-2- yl)ethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine- 5(4H)-carboxylate (60 mg, 0.092 mmol, 1.00 equiv) and TBAF (48.1 mg, 0.184 mmol, 2.00 equiv) in THF (10 mL) was stirred at room temperature for 2 hours. The reaction was quenched with water (10 mL). The resulting mixture was extracted with EA (3 x 10 mL). The combined organic layers were washed with water (3 x 10 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-(4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3- methoxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- carboxylate (50 mg, 96% yield) as a brown solid. LCMS(ESI-MS) m/z =539.2 [M+H]⁺. [0576] A solution of tert-butyl 2-(4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5- a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (50 mg, 0.093 mmol, 1.00 equiv) in 1,4-dioxane (12 mL) and HCl (4 M in 1,4-dioxane, 3 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure to afford 1-(5- fluoropyridin-2-yl)-2-((3-methoxy-6-(3-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2- yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethan-1-ol (80 mg, crude) as a yellow solid. LCMS(ESI-MS) m/z =439.2 [M+H]⁺. [0577] A solution of 1-(5-fluoropyridin-2-yl)-2-((3-methoxy-6-(3-methyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-2-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethan-1-ol (80 mg, 0.182 mmol, 1.00 equiv) in DCM (2 mL) was treated with DIEA (141.49 mg, 1.092 mmol, 6.00 equiv) at room temperature followed by the addition of BrCN (38.65 mg, 0.364 mmol, 2.00 equiv) dropwise at room temperature. The resulting mixture was quenched with water (10 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were washed with water (2 x 10 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 / 10) to afford crude product. The crude product was purified by Prep-HPLC with the following conditions: Column: CHIRALPAKIH3; Mobile Phase A: Hex(0.2%FA): (MeOH: EtOH=1: 1=1: 1)=30: 70; Flow rate: 1mL/min mL/min; Gradient: isocratic ; 216 Injection Volume: 1μl mL; Wave Length: 254/220nm to afford 2-(4-(2-(5-fluoropyridin-2-yl)-2- hydroxyethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5- a]pyrazine-5(4H)-carbonitrile, isomer 1 (the first elution, 14.5 mg, 29% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 8.48 (d, 1H), 8.23 (s, 1H), 7.80 (dd, 1H), 7.67 (s, 1H), 7.49 (td, 1H), 6.79 (s, 1H), 5.31 (dd, 1H), 4.49 (s, 2H), 4.48 - 4.40 (m, 2H), 4.35 (dd, 2H), 3.98 (s, 3H), 3.74 (dd, 2H), 2.16 (s, 3H). LCMS(ESI-MS) m/z =464.1 [M+H]⁺. [0578] Isomer 2, (the second elution, 12.2 mg, 24 % yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 8.48 (s, 1H), 8.23 (s, 1H), 7.80 (dd, 1H), 7.67 (s, 1H), 7.49 (dd, 1H), 6.79 (s, 1H), 5.31 (dd, 1H), 4.49 (s, 2H), 4.45 - 4.30 (m, 4H), 3.98 (s, 3H), 3.74 (dd, 2H), 2.16 (s, 3H). LCMS(ESI-MS) m/z =464.1 [M+H]⁺. Table II. Illustrative compounds of the invention 217 218 219 220 221 222 223 224 225 226 227 228 229 Example 3-a 2-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1 Example 4-a 2-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2

230 Into a 500 mL round-bottom flask were added NaOH (10.6 g, 264 mmol, 3 equiv), H2O (10.57 g, 587 mmol, 6.7 equiv) and 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (20 g, 88 mmol, 1 equiv), dodecane-1- thiol (63 mL, 264 mmol, 3 equiv) and DMA (50 mL). The resulting mixture was stirred for overnight at 50 °C. The reaction was quenched with water (50 mL) at room temperature. The resulting mixture was adjusted pH to 4 with formic acid. 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 precipitated solids were collected by filtration and washed with PE (3 x 30 mL). The residue was purified by trituration with EA (50 mL) to afford 6-bromopyrazolo[1,5-a]pyridin-4-ol (14 g, crude) as a yellow solid. LCMS(ESI-MS) m/z = 213.0 [M+H]+. Into a 1 L round-bottom flask were added PPh3 (14.6 g, 56 mmol, 1.5 equiv) and THF (500 mL). DIAD (11 mL, 56 mmol, 1.5 equiv) was added to the above mixture at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 hour at 0 °C. Then 6-bromopyrazolo[1,5-a]pyridin-4-ol (8 g, 38 mmol, 1 equiv) and 2-[(tertbutyldimethylsilyl) oxy]-1-(5-fluoropyridin-2-yl)ethanol (10.2 g, 38 mmol, 1 equiv) dissolved in THF (200 mL) was added to the above mixture. The resulting mixture was stirred for overnight at room temperature under nitrogen atmosphere. The reaction was quenched by the addition of water (200 mL) at room temperature. The resulting mixture was extracted with EA (3 x 100 mL). The combined 231 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 = 7 / 3) to afford 6-bromo-4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[1,5- a]pyridine (8.2 g, 47% yield) as a yellow oil. LCMS (ESI-MS) m/z = 466.1 [M+H]+. A 100 mL round-bottom flask was charged with 6-bromo-4-(2-((tert-butyldimethylsilyl)oxy)-1-(5- fluoropyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridine (2 g, 4.29 mmol, 1 equiv), DCM (30 mL) and NIS (0.96 g, 4.29 mmol, 1 equiv). The resulting mixture was stirred at room temperature for overnight. The reaction was quenched by the addition of water (300 mL) at room temperature. The resulting mixture was extracted with DCM (3 x 150 mL). The combined organic layers were washed with water (3 x 10 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 = 4 / 1) to afford 6-bromo-4-(2- ((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-iodopyrazolo[1,5-a]pyridine (2.04 g, 80% yield) as a yellow solid. LCMS (ESI-MS) m/z = 592.0 [M+H]+. A 100 mL round-bottom flask was charged with 6-bromo-4-(2-((tert-butyldimethylsilyl)oxy)-1-(5- fluoropyridin-2-yl)ethoxy)-3-iodopyrazolo[1,5-a]pyridine (2.04 g, 3.4 mmol, 1 equiv) and THF (15 mL). Isopropylmagnesium chloride in THF (4.3 mL, 8.6 mmol, 2.5 equiv, 2.0 M in THF) was added at 0 °C under nitrogen atmosphere. The reaction was stirred at 0 °C for 30 min. To the mixture was added 2- isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.28 g, 6.89 mmol, 2.00 equiv) in THF (5 mL). The resulting mixture was stirred at room temperature for overnight under nitrogen atmosphere. The reaction was quenched by the addition of saturated NH4Cl aqueous (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 10 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford 6-bromo-4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (2.04 g, crude) as a yellow oil. LCMS(ESI- MS) m/z = 592.2 [M+H]+. A 100 mL round-bottom flask was charged with 6-bromo-4-(2-((tert-butyldimethylsilyl)oxy)-1-(5- fluoropyridin-2-yl)ethoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (2.04 g, 3.4 mmol, 1 equiv), THF (40 mL), H2O (10 mL) and sodium perborate tetrahydrate (1.59 g, 10.3 mmol, 3 equiv). The resulting mixture was stirred at room temperature for overnight. The reaction was quenched by the addition of water (300 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 20 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)-1-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-3-ol (1.2 g, 72% yield) as a green oil. LCMS (ESI-MS) m/z = 482.1 [M+H]+. A 100 mL round-bottom flask was charged with 6-bromo-4-{2-[(tert-butyldimethylsilyl)oxy]-1-(5- fluoropyridin-2-yl)ethoxy}pyrazolo[1,5-a]pyridin-3-ol (1.2 g, 2.49 mmol, 1 equiv), DMF (10 mL), K2CO3 (0.69 g, 4.97 mmol, 2 equiv) and CH3I (0.35 g, 2.49 mmol, 1 equiv). The resulting mixture was stirred at 232 room temperature for 2 hours. The reaction was quenched by the addition of water (300 mL) at room temperature. The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with water (6 x 20 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 = 4 / 1) to afford 6-bromo-4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2- yl)ethoxy)-3-methoxypyrazolo[1,5-a]pyridine (1.02 g, 83% yield) as a yellow oil. LCMS (ESI-MS) m/z = 496.1 [M+H]+. A 100 mL round-bottom flask was charged with 6-bromo-4-(2-((tert-butyldimethylsilyl)oxy)-1-(5- fluoropyridin-2-yl)ethoxy)-3-methoxypyrazolo[1,5-a]pyridine (1.02 g, 2.06 mmol, 1 equiv), bis(pinacolato)diboron (0.78 g, 3.0 mmol, 1.5 equiv), Pd(dppf)Cl2 (0.08 g, 0.1 mmol, 0.05 equiv), AcOK (0.40 g, 4.1 mmol, 2 equiv) and 1,4-dioxane (20 mL). The resulting mixture was stirred at 80 °C for overnight 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 100 mL). The combined organic layers were washed with water (3 x 20 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford 4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2- yl)ethoxy)-3-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (1.7 g, crude) as a yellow solid. LCMS (ESI-MS) m/z = 544.3 [M+H]+. To a solution of tert-butyl tert-butyl 2-bromo-3-methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5- d][1,4]diazepine-6-carboxylate (230 mg, 0.70 mmol, 1 equiv) in 1,4-dioxane (6 mL) was added 4-(2-((tert- butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-methoxy-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (416 mg, 0.77 mmol, 1.1 equiv), Pd(PPh3)4 (80 mg, 0.07 mmol, 0.1 equiv), K2CO3 (289 mg, 2.1 mmol, 3 equiv) and H₂O (1.25 mL). The reaction was stirred at 100 °C for 2 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature and quenched with water (50 mL). The resulting mixture was extracted with ethyl acetate (3 x 50 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 (DCM / MeOH = 20 / 1) to tert-butyl 2-(4-(2-((tert-butyldimethylsilyl)oxy)- 1-(5-fluoropyridin-2-yl)ethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro-6H- pyrazolo[1,5-d][1,4]diazepine-6-carboxylate (320 mg, 69% yield) as a green solid. LCMS (ESI-MS) m/z=667.3[M+H]+. To a solution of tert-butyl 2-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3- methoxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6- carboxylate (320 mg, 0.48 mmol, 1 equiv) in 1,4-dioxane (6 mL) was added HCl (4 M in 1,4-dioxane, 12 mL). The mixture was stirred for 2 hours at room temperature. The resulting mixture was concentrated under reduced pressure to 2-(5-fluoropyridin-2-yl)-2-((3-methoxy-6-(3-methyl-5,6,7,8-tetrahydro-4H- pyrazolo[1,5-d][1,4]diazepin-2-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethan-1-ol (217 mg, crude) as a yellow solid. LCMS (ESI-MS) m/z=453.2[M+H]+. 233 To a solution of 2-(5-fluoropyridin-2-yl)-2-((3-methoxy-6-(3-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- d][1,4]diazepin-2-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethan-1-ol (105 mg, 0.23 mmol, 1 equiv) in DCM (6 mL) was added DIEA (180 mg, 1.39 mmol.00 equiv) and BrCN (22 mg, 0.21 mmol, 0.9 equiv) at 0 °C. The mixture was stirred for 1 hour at room temperature and quenched with water (30 mL). The resulting mixture was extracted with DCM (3 x 50 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 (DCM / MeOH = 15 / 1) to afford a crude product. The crude product was purified by Prep-Chiral-HPLC with the following conditions Column: Chiral ART Cellulose-SA, 2*25 cm, 5 μm; 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: 254/220nm to afford 2-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5- a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile (the first elution, 31.7 mg, 29% yield) as a white solid. LCMS(ESI-MS) m/z=478.3 [M+H]+; (the second elution, 31.8 mg, 29% yield) as a white solid. LCMS(ESI-MS) m/z=478.3[M+H]+. Example 5-a 1-(2-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 1 Example 6-a 1-(2-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 2 To a solution of 2-(5-fluoropyridin-2-yl)-2-((3-methoxy-6-(3-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- d][1,4]diazepin-2-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethan-1-ol (105 mg, 0.23 mmol, 1 equiv) in DCM (6 mL) was added DIEA (180 mg, 1.39 mmol, 6 equiv) and acryloyl chloride (19 mg, 0.21 mmol, 0.9 equiv) at 0 °C. The mixture was stirred for 1 hour at 0 °C and quenched with water (30 mL). The resulting mixture was extracted with DCM (3 x 50 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 (DCM / MeOH = 15 / 1) to afford a crude product. The crude product was purified by Prep-Chiral-HPLC with the following conditions Column: Chiral ART Cellulose-SA, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.1% FA)--HPLC, Mobile Phase B: MeOH: DCM=1: 1--HPLC; Flow rate: 20ML/MIN mL/min; Gradient: isocratic 30; Wave Length: 234 254/220nm to afford 1-(2-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5- a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one (the first elution, 32.6 mg, 27.57% yield) as a white solid. LCMS(ESI-MS) m/z=507.3[M+H]+; (the second elution, 31.9 mg, 26.79% yield) as a white solid. LCMS(ESI-MS) m/z=507.3[M+H]+. Example 7-a (R)-2-(3-chloro-4-(1-(pyridin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro- 6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile A 40 mL vial was charged with 6-bromo-3-chloropyrazolo[1,5-a]pyridin-4-ol (500 mg, 2 mmol, 1 equiv), (1S)-1-(pyridin-3-yl)ethanol (373 mg, 3 mmol, 1.5 equiv), CMBP (975 mg, 4 mmol, 2 equiv) and toluene (10 mL). The resulting solution was stirred for 2 hours at 100 °C under nitrogen atmosphere. The reaction was quenched with 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 / 1) to afford (R)-6-bromo-3-chloro-4-(1-(pyridin-3-yl)ethoxy)pyrazolo[1,5-a]pyridine (450 mg, 63% yield) as a white solid. LCMS (ESI-MS) m/z =352.0 [M+H]+. A 40 mL vial was charged with bis(pinacolato)diboron (389 mg, 1.53 mmol, 1.2 equiv), 3(R)-6-bromo-3- chloro-4-(1-(pyridin-3-yl)ethoxy)pyrazolo[1,5-a]pyridine (450 mg, 1.28 mmol, 1 equiv), Pd(dppf)Cl2 (47 mg, 0.06 mmol, 0.05 equiv) and 1,4-dioxane (10 mL) and AcOK (250 mg, 2.55 mmol, 2 equiv). The resulting solution 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 layers were combined, washed with water (3 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide (R)-3-chloro-4-(1-(pyridin-3-yl)ethoxy)-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (450 mg, crude) as a black solid. LCMS (ESI-MS) m/z =400.2 [M+H]+. 235 A 40 mL vial was charged with (R)-3-chloro-4-(1-(pyridin-3-yl)ethoxy)-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (131 mg, 0.33 mmol, 1.2 equiv), tert-butyl 2-bromo-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carboxylate (90 mg, 0.27 mmol, 1 equiv), Pd(PPh3)4 (16 mg, 0.014 mmol, 0.05 equiv), K2CO3 (75 mg, 0.55 mmol, 2 equiv), 1,4-dioxane (10 mL) and H2O (2 mL). The resulting solution was stirred for overnight at 100 °C under nitrogen atmosphere. The reaction was diluted with water (100 mL). The mixture was extracted with EA (3 x 100 mL). The organic layers were combined, washed with water (3 x 50 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 / 1) to afford tert-butyl 2-{3-chloro-4-[(1R)-1-(pyridin-3-yl)ethoxy]pyrazolo[1,5- a]pyridin-6-yl}-3-methyl-4H,5H,7H,8H-pyrazolo[1,5-d][1,4]diazepine-6-carboxylate (90 mg, 63.14% yield) as a white solid. LCMS(ESI-MS) m/z =523.2 [M+H]+. A solution of tert-butyl (R)-2-(3-chloro-4-(1-(pyridin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carboxylate (90 mg, 0.172 mmol, 1.00 equiv) in HCl in 1,4-dioxane (1 mL, 4 M in 1,4-dioxane) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure to afford (R)-2-(3-chloro-4-(1-(pyridin-3- yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepine (90 mg, crude) as a yellow solid. LCMS(ESI-MS) m/z =423.2 [M+H]+. A solution of (R)-2-(3-chloro-4-(1-(pyridin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-5,6,7,8- tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepine (150 mg, 0.29 mmol, 1 equiv) and DIEA (110 mg, 0.85 mmol, 4 equiv) in DCM (3 mL) was added BrCN (45 mg, 0.43 mmol, 2 equiv). The final reaction mixture was stirred at room temperature for 1 hour. The reaction was poured into water (10 mL) and extracted with DCM (3 x 5 mL). The combined organic layers were washed with water (3 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, 5μm; Mobile Phase A: water (10mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 30% B to 60% B in 8min; Wave Length: 254nm/220nm to afford (R)-2-(3- chloro-4-(1-(pyridin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro-6H- pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile (35.5 mg, 37% yield) as a white solid. LCMS (ESI-MS) m/z =448.2 [M+H]+. Example 8-a 2-(3-chloro-4-(1-(6-fluoropyridin-3-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1 Example 9-a 2-(3-chloro-4-(1-(6-fluoropyridin-3-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2 236 Starting from 2-((tert-butyldimethylsilyl)oxy)-1-(6-fluoropyridin-3-yl)ethan-1-ol and 6-bromo-3- chloropyrazolo[1,5-a]pyridin-4-ol (prepared according to the procedure described for intermediate 5-(2- ((tert-butyldimethylsilyl)oxy)-1-hydroxyethyl)picolinonitrile), examples 8-a and 9-a were synthesized using procedure described in example 3-a. Example 10-a 2-(3-chloro-4-(1-(6-cyanopyridin-3-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1 Example 11-a 2-(3-chloro-4-(1-(6-cyanopyridin-3-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2 Starting from 5-(2-((tert-butyldimethylsilyl)oxy)-1-hydroxyethyl)picolinonitrile and 6-bromo-3- chloropyrazolo[1,5-a]pyridin-4-ol, examples 10-a and 11-a were synthesized using procedure described in example 3-a. Example 12-a 2-(3-chloro-4-(1-(3-cyanophenyl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro- 6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1 Example 13-a 2-(3-chloro-4-(1-(3-cyanophenyl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro- 6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2 237 Starting from 3-(1-hydroxyethyl)benzonitrile and 6-bromo-3-chloropyrazolo[1,5-a]pyridin-4-ol, examples 12-a and 13-a were synthesized following the same procedure as used for example 7-a. Example 14-a 2-(3-chloro-4-(1-(6-cyanopyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1 Example 15-a 2-(3-chloro-4-(1-(6-cyanopyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2 Starting from 6-(1-hydroxyethyl)picolinonitrile and 6-bromo-3-chloropyrazolo[1,5-a]pyridin-4-ol, examples 14-a and 15-a were synthesized following the same procedure as used for example 7-a. Example 16-a 2-(4-(1-(6-aminopyridin-2-yl)ethoxy)-3-chloropyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1 Example 17-a 2-(4-(1-(6-aminopyridin-2-yl)ethoxy)-3-chloropyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2 238 Starting from tert-butyl (6-(1-hydroxyethyl)pyridin-2-yl)carbamate and 6-bromo-3-chloropyrazolo[1,5- a]pyridin-4-ol, examples 16-a and 17-a were synthesized following the same procedure as used for example 7-a. Example 18-a 2-(3-chloro-4-(1-(1-methyl-1H-pyrazol-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1 Example 19-a 2-(3-chloro-4-(1-(1-methyl-1H-pyrazol-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2 wi-a 2-(4-(1-(1,3,4-oxadiazol-2-yl)ethoxy)-3-chloropyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1 Example 21-a 2-(4-(1-(1,3,4-oxadiazol-2-yl)ethoxy)-3-chloropyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2 239 Starting from 2-(1-((3-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridin-4- yl)oxy)ethyl)-1,3,4-oxadiazole and tert-butyl 2-bromo-3-methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5- d][1,4]diazepine-6-carboxylate, examples 20-a and 21-a were synthesized following the same procedure as used for example 65. Example 22-a 2-(3-chloro-4-(1-(pyrimidin-5-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro- 6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1 Example 23-a 2-(3-chloro-4-(1-(pyrimidin-5-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro- 6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2 Starting from 1-(pyrimidin-5-yl)ethan-1-ol and 6-bromo-3-chloropyrazolo[1,5-a]pyridin-4-ol, examples 22-a and 23-a were synthesized following the same procedure as used for example 7-a. Example 24-a 2-(3-chloro-4-(1-(6-methylpyridazin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1 Example 25-a 2-(3-chloro-4-(1-(6-methylpyridazin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2 240 Starting from 1-(6-methylpyridazin-3-yl)ethan-1-ol and 6-bromo-3-chloropyrazolo[1,5-a]pyridin-4-ol, examples 24-a and 25-a were synthesized following the same procedure as used for example 7-a. Example 26-a 2-(3-chloro-4-(1-(6-methylpyridin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1 Example 27-a 2-(3-chloro-4-(1-(6-methylpyridin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2 Starting from 1-(6-methylpyridin-3-yl)ethan-1-ol and 6-bromo-3-chloropyrazolo[1,5-a]pyridin-4-ol, examples 26-a and 27-a were synthesized following the same procedure as used for example 7-a. Example 28-a 2-(3-chloro-4-(1-(1-methyl-1H-pyrazol-4-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1 Example 29-a 2-(3-chloro-4-(1-(1-methyl-1H-pyrazol-4-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2 241 Starting from 1-(6-methylpyridin-3-yl)ethan-1-ol and 6-bromo-3-chloropyrazolo[1,5-a]pyridin-4-ol, examples 28-a and 29-a were synthesized following the same procedure as used for example 7-a. Example 30-a 2-(3-chloro-4-(1-(pyridazin-4-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro- 6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1 Example 31-a 2-(3-chloro-4-(1-(pyridazin-4-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro- 6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2 Starting from 1-(pyridazin-4-yl)ethan-1-ol and 6-bromo-3-chloropyrazolo[1,5-a]pyridin-4-ol, examples 30-a and 31-a were synthesized following the same procedure as used for example 7-a. Example 32-a 2-(3-chloro-4-(1-(pyrimidin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro- 6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1 Example 33-a 2-(3-chloro-4-(1-(pyrimidin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro- 6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2 242 Starting from 1-(pyrimidin-2-yl)ethan-1-ol and 6-bromo-3-chloropyrazolo[1,5-a]pyridin-4-ol, examples 32-a and 33-a were synthesized following the same procedure as used for example 7-a. Example 34-a 2-(3-chloro-4-(1-(5-(difluoromethyl)pyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1 Example 35-a 2-(3-chloro-4-(1-(5-(difluoromethyl)pyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2 Starting from 1-(5-(difluoromethyl)pyridin-2-yl)ethan-1-ol and 6-bromo-3-chloropyrazolo[1,5-a]pyridin- 4-ol, examples 34-a and 35-a were synthesized following the same procedure as used for example 7-a. Example 36-a 2-(3-chloro-4-(1-(5-methoxypyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1 Example 37-a 2-(3-chloro-4-(1-(5-methoxypyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2 243 Starting from 1-(5-methoxypyridin-2-yl)ethan-1-ol and 6-bromo-3-chloropyrazolo[1,5-a]pyridin-4-ol, examples 36-a and 37-a were synthesized following the same procedure as used for example 7-a. Example 38-a 2-(3-chloro-4-(1-(isoquinolin-1-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro- 6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1 Example 39-a 2-(3-chloro-4-(1-(isoquinolin-1-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro- 6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2 Starting from 1-(isoquinolin-1-yl)ethan-1-ol and 6-bromo-3-chloropyrazolo[1,5-a]pyridin-4-ol, examples 38-a and 39-a were synthesized following the same procedure as used for example 7-a. Example 40-a 2-(3-chloro-4-(1-(5-methylpyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1 Example 41-a 2-(3-chloro-4-(1-(5-methylpyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2 244 Starting from 1-(5-methylpyridin-2-yl)ethan-1-ol and 6-bromo-3-chloropyrazolo[1,5-a]pyridin-4-ol, examples 40-a and 41-a were synthesized following the same procedure as used for example 7-a. Example 42-a 1-(2-(3-chloro-4-(1-(5-methylpyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 1 Example 43-a 1-(2-(3-chloro-4-(1-(5-methylpyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 2 Starting from 2-(3-chloro-4-(1-(5-methylpyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepine, examples 42-a and 43-a were synthesized following the same procedure as used for example 5-a. Example 44-a 2-(3-chloro-4-(1-(pyridazin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro- 6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1 Example 45-a 2-(3-chloro-4-(1-(pyridazin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro- 6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2 245 Starting from 1-(pyridazin-3-yl)ethan-1-ol and 6-bromo-3-chloropyrazolo[1,5-a]pyridin-4-ol, examples 44-a and 45-a were synthesized following the same procedure as used for example 7-a. Example 46-a 1-(2-(3-chloro-4-(1-(pyridazin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro- 6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 1 Example 47-a 1-(2-(3-chloro-4-(1-(pyridazin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro- 6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 2 Starting from 2-(3-chloro-4-(1-(pyridazin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-5,6,7,8- tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepine, examples 46-a and 47-a were synthesized following the same procedure as used for example 5-a. Example 44-a 2-(3-chloro-4-(1-(pyridazin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro- 6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1 Example 45-a 2-(3-chloro-4-(1-(pyridazin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro- 6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2 246 Starting from 1-(pyridazin-3-yl)ethan-1-ol and 6-bromo-3-chloropyrazolo[1,5-a]pyridin-4-ol, examples 44-a and 45-a were synthesized following the same procedure as used for example 7-a. Example 46-a 1-(2-(3-chloro-4-(1-(pyridazin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro- 6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 1 Example 47-a 1-(2-(3-chloro-4-(1-(pyridazin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro- 6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 2 Starting from 2-(3-chloro-4-(1-(pyridazin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-5,6,7,8- tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepine, examples 46-a and 47-a were synthesized following the same procedure as used for example 5-a. Example 48-a 2-(3-chloro-4-(1-(pyrazin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro-6H- pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1 Example 49-a 2-(3-chloro-4-(1-(pyrazin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro-6H- pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2 247 Starting from 1-(pyrazin-2-yl)ethan-1-ol and 6-bromo-3-chloropyrazolo[1,5-a]pyridin-4-ol, examples 48-a and 49-a were synthesized following the same procedure as used for example 7-a. Example 50-a 1-(2-(3-chloro-4-(1-(pyrazin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro- 6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 1 Example 51-a 1-(2-(3-chloro-4-(1-(pyrazin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro- 6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 2 Starting from 2-(3-chloro-4-(1-(pyrazin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-5,6,7,8- tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepine, examples 50-a and 51-a were synthesized following the same procedure as used for example 5-a. Example 52-a 2-(3-chloro-4-(2-hydroxy-2-(1-methyl-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1 Example 53-a 2-(3-chloro-4-(2-hydroxy-2-(1-methyl-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2 Example 54-a 2-(3-chloro-4-(2-hydroxy-2-(1-methyl-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 3 248 Example 55-a 2-(3-chloro-4-(2-hydroxy-2-(1-methyl-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 4 A 8 mL reaction bottles was charged with methyl 1-methyl-5-oxopyrrolidine-3-carboxylate (500 mg, 3.18 mmol, 1 equiv), chloroiodomethane (2.24 g, 12.7 mmol, 4 equiv) and THF (15 mL). Then was added LDA (2.04 g, 19.1 mmol, 6 equiv) at -78 °C under nitrogen atmosphere. The resulting solution was stirred for 2 hours at -78 °C and 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 100 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford 4-(2-chloroacetyl)-1- methylpyrrolidin-2-one (170 mg, crude) as a yellow oil. LCMS (ESI-MS) m/z = 175.6 [M+H]+. A 40 mL reaction bottles was charged with tert-butyl 2-(3-chloro-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)- 3-methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carboxylate (120 mg, 0.29 mmol, 1 equiv), 4-(2-chloroacetyl)-1-methylpyrrolidin-2-one (76 mg, 0.43 mmol, 1.5 equiv), K₂CO₃ (79 mg, 0.57 mmol, 2 equiv) and DMF (1 mL). The resulting solution was stirred for 3 hours at room temperature and quenched with water (50 mL). The resulting mixture was extracted with EA (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 silica gel column chromatography, eluted with (DCM / MeOH = 10 / 1) to afford tert-butyl 2-(3-chloro-4-(2-(1-methyl-5- oxopyrrolidin-3-yl)-2-oxoethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro-6H- pyrazolo[1,5-d][1,4]diazepine-6-carboxylate (77 mg, 46% yield) as a yellow solid. LCMS (ESI-MS) m/z = 557.0 [M+H]+. A 40 mL reaction bottles was charged with tert-butyl 2-(3-chloro-4-(2-(1-methyl-5-oxopyrrolidin-3-yl)-2- oxoethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6- carboxylate (77 mg, 0.14 mmol, 1 equiv), NaBH₄ (10.5 mg, 0.28 mmol, 2 equiv) and MeOH (2 mL). The resulting solution was stirred for 1 hour at room temperature and quenched with water (50 mL). The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine 249 (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 tert-butyl 2-(3-chloro-4-(2-hydroxy-2-(1-methyl-5-oxopyrrolidin-3- yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6- carboxylate (70 mg, 86% yield) as a yellow solid. LCMS(ESI-MS) m/z = 559.1 [M+H]+. A 8 mL reaction bottles was charged with tert-butyl 2-(3-chloro-4-(2-hydroxy-2-(1-methyl-5- oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5- d][1,4]diazepine-6-carboxylate (70 mg, 0.125 mmol, 1 equivHCl (4 M in 1,4-dioxane, 1 mL). The resulting solution was stirred for 1 hour at room temperature and concentrated under reduced pressure to afford 4- (2-((3-chloro-6-(3-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)pyrazolo[1,5- a]pyridin-4-yl)oxy)-1-hydroxyethyl)-1-methylpyrrolidin-2-one (57 mg, crude) as a yellow oil. LCMS (ESI- MS) m/z = 458.9 [M+H]+. A 40 mL round-bottom flask was charged with 4-(2-((3-chloro-6-(3-methyl-5,6,7,8-tetrahydro-4H- pyrazolo[1,5-d][1,4]diazepin-2-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-1-hydroxyethyl)-1-methylpyrrolidin- 2-one (50 mg, 0.11 mmol, 1 equiv), BrCN (11.5 mg, 0.11 mmol, 1 equiv), DCM (1 mL) and DIEA (42.2 mg, 0.33 mmol, 3 equiv). The resulting mixture was stirred at room temperature for 1 hour and quenched with water (50 mL). The resulting mixture was extracted with DCM (3 x 100 mL). The combined organic layers were washed with water (3 x 10 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 a crude product. The crude product was purified by Prep- Chiral-HPLC with the following conditions: Column: Column: CHIRALPAK IE3; Mobile Phase A: Hex: (MeOH: DCM=1: 1)=50: 50; Flow rate: 1 mL/min mL/min; Gradient: isocratic; Injection Volume: 1 μl mL; Wave Length: 254/220nm to afford 2-(3-chloro-4-(2-hydroxy-2-(1-methyl-5-oxopyrrolidin-3- yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6- carbonitrile (the first elution, 5.9 mg, 11% yield) as a white solid, LCMS (ESI-MS) m/z = 484.2 [M+H]+; (the second elution, 8.2 mg, 15.5% yield) as a white solid, LCMS (ESI-MS) m/z = 484.2 [M+H]+; (the third elution, 6.0 mg, 11% yield) as a white solid, LCMS (ESI-MS) m/z = 484.2 [M+H]+; (the fourth elution, 4.9 mg, 9% yield), LCMS (ESI-MS) m/z = 484.2 [M+H]+. Example 56-a 2-(3-chloro-4-(2-hydroxy-2-(tetrahydrofuran-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1 Example 57-a 2-(3-chloro-4-(2-hydroxy-2-(tetrahydrofuran-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2 Example 58-a 2-(3-chloro-4-(2-hydroxy-2-(tetrahydrofuran-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 3 250 Example 59-a 2-(3-chloro-4-(2-hydroxy-2-(tetrahydrofuran-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile Starting from tert-butyl 2-(3-chloro-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro- 6H-pyrazolo[1,5-d][1,4]diazepine-6-carboxylate and methyl 5-oxopyrrolidine-3-carboxylate 2-chloro-1- (tetrahydrofuran-3-yl)ethan-1-one, examples 56-a to 59-a were synthesized following a similar procedure as used for example 52-a. Example 60-a 2-(3-chloro-4-(2-hydroxy-2-(5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1 Example 61-a 2-(3-chloro-4-(2-hydroxy-2-(5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2 Example 62-a 2-(3-chloro-4-(2-hydroxy-2-(5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 3 Example 63-a 2-(3-chloro-4-(2-hydroxy-2-(5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 4 251 Starting from methyl 5-oxopyrrolidine-3-carboxylate, examples 60-a to 63-a were synthesized following a similar procedure as used for example 52-a. Example 64-a 2-(4-((2R)-1-(5-fluoropyridin-2-yl)-2-hydroxypropoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1 Example 65-a 2-(4-((2R)-1-(5-fluoropyridin-2-yl)-2-hydroxypropoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2 From 6-bromo-3-methoxypyrazolo[1,5-a]pyridin-4-ol and (2R)-2-((tert-butyldimethylsilyl)oxy)-1-(5- fluoropyridin-2-yl)propan-1-ol (prepared according to the procedure described for intermediate 5-(2-((tert- butyldimethylsilyl)oxy)-1-hydroxyethyl)picolinonitrile), examples 64-a and 65-a were synthesized using procedure described in example 3-a. Example 66-a 1-(2-(4-((2R)-1-(5-fluoropyridin-2-yl)-2-hydroxypropoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 1 Example 67-a 1-(2-(4-((2R)-1-(5-fluoropyridin-2-yl)-2-hydroxypropoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 2 252 Starting from (2R)-1-(5-fluoropyridin-2-yl)-1-((3-methoxy-6-(3-methyl-5,6,7,8-tetrahydro-4H- pyrazolo[1,5-d][1,4]diazepin-2-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)propan-2-ol, examples 66-a and 67-a were synthesized following the same procedure as used for example 5-a. Example 68-a 2-(4-((2S)-1-(5-fluoropyridin-2-yl)-2-hydroxypropoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1 Example 69-a 2-(4-((2S)-1-(5-fluoropyridin-2-yl)-2-hydroxypropoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2 From 6-bromo-3-methoxypyrazolo[1,5-a]pyridin-4-ol and (2S)-2-((tert-butyldimethylsilyl)oxy)-1-(5- fluoropyridin-2-yl)propan-1-ol (prepared according to the procedure described for intermediate 5-(2-((tert- butyldimethylsilyl)oxy)-1-hydroxyethyl)picolinonitrile), examples 68-a and 69-a were synthesized following the same procedure as used for example 3-a. Example 70-a 1-(2-(4-((2S)-1-(5-fluoropyridin-2-yl)-2-hydroxypropoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 1 Example 71-a 253 1-(2-(4-((2S)-1-(5-fluoropyridin-2-yl)-2-hydroxypropoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 2 Starting from (2S)-1-(5-fluoropyridin-2-yl)-1-((3-methoxy-6-(3-methyl-5,6,7,8-tetrahydro-4H- pyrazolo[1,5-d][1,4]diazepin-2-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)propan-2-ol, examples 70-a and 71-a were synthesized following the same procedure as used for example 5-a. Example 72-a 2-(3-chloro-4-((2-(5-fluoropyridin-2-yl)tetrahydrofuran-2-yl)methoxy)pyrazolo[1,5-a]pyridin-6-yl)- 3-methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1 Example 73-a 2-(3-chloro-4-((2-(5-fluoropyridin-2-yl)tetrahydrofuran-2-yl)methoxy)pyrazolo[1,5-a]pyridin-6-yl)- 3-methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2 Starting from 1-(pyridazin-3-yl)ethan-1-ol and 6-bromo-3-chloropyrazolo[1,5-a]pyridin-4-ol, examples 72-a and 73-a were synthesized following the similar procedure as used for example 7-a. Example 74-a 1-(2-(3-chloro-4-((2-(5-fluoropyridin-2-yl)tetrahydrofuran-2-yl)methoxy)pyrazolo[1,5-a]pyridin-6- yl)-3-methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 1 Example 75-a 1-(2-(3-chloro-4-((2-(5-fluoropyridin-2-yl)tetrahydrofuran-2-yl)methoxy)pyrazolo[1,5-a]pyridin-6- yl)-3-methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 2 254 Starting from 2-(3-chloro-4-((2-(5-fluoropyridin-2-yl)tetrahydrofuran-2-yl)methoxy)pyrazolo[1,5- a]pyridin-6-yl)-3-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepine, examples 74-a and 75-a were synthesized following the same procedure as used for example 5-a. Example 76-a 2-(3-(difluoromethoxy)-4-(2-(5-fluoropyridin-2-yl)-2-hydroxypropoxy)pyrazolo[1,5-a]pyridin-6-yl)- 3-methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1 Example 77-a 2-(3-(difluoromethoxy)-4-(2-(5-fluoropyridin-2-yl)-2-hydroxypropoxy)pyrazolo[1,5-a]pyridin-6-yl)- 3-methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2 Starting from 1-((3-(difluoromethoxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5- a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)propan-2-ol, examples 76-a and 77-a were synthesized following the similar procedure as used for example 65. Example 78-a 1-(2-(3-(difluoromethoxy)-4-(2-(5-fluoropyridin-2-yl)-2-hydroxypropoxy)pyrazolo[1,5-a]pyridin-6- yl)-3-methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 1 Example 79-a 1-(2-(3-(difluoromethoxy)-4-(2-(5-fluoropyridin-2-yl)-2-hydroxypropoxy)pyrazolo[1,5-a]pyridin-6- yl)-3-methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 2 255 Starting from 1-((3-(difluoromethoxy)-6-(3-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2- yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)propan-2-ol, examples 78-a and 79-a were synthesized following the same procedure as used for example 5-a. Example 80-a 2-(3-chloro-4-((2-(5-fluoropyridin-2-yl)oxetan-2-yl)methoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1 Example 81-a 2-(3-chloro-4-((2-(5-fluoropyridin-2-yl)oxetan-2-yl)methoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2 Into a 100 mL round-bottom flask were added tert-butyl 2-(3-chloro-4-hydroxypyrazolo[1,5-a]pyridin-6- yl)-3-methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carboxylate (300 mg, 0.72 mmol, 1 equiv), 2-chloro-1-(5-fluoropyridin-2-yl)ethan-1-one (162 mg, 0.93 mmol, 1.3 equiv), Na₂CO₃ (152 mg, 1.44 mmol, 2 equiv), KI (119 mg, 0.72 mmol, 1 equiv) and DMF (20 mL). The resulting mixture was stirred for overnight at room temperature. The reaction was quenched with water. The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The 256 residue was purified by Prep-TLC (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-4,5,7,8-tetrahydro-6H-pyrazolo[1,5- d][1,4]diazepine-6-carboxylate (280 mg) as a light yellow solid. LCMS(ESI-MS) m/z = 555.2 [M+H]+. Into a 40 mL round-bottom flask were added trimethylsulfoxonium iodide (268 mg, 1.22 mmol, 2.50 equiv), t-BuOK(1.0 M in THF) (1.2mL, 1.22 mmol, 2.5 equiv) and DMSO (10 mL). The solution was stirred for 30 min at room temperature under N2 atmosphere. Into an another 10 mL round-bottom flask were added tert-butyl 2-(3-chloro-4-(2-(5-fluoropyridin-2-yl)-2-oxoethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carboxylate (270 mg, 0.49 mmol, 1 equiv), THF (5 mL) and DMSO (10 mL). The first vial was added to the second vial at 0 °C. The resulting mixture was stirred for 30 min at 0 °C under N2 atmosphere, before being warmed to room temperature. The solution was stirred for 2 h under N2 atmosphere at room temperature. The mixture was further warmed to 55 °C and was stirred at this temperature for overnight. The reaction was quenched with water. The resulting mixture was extracted with EA (3 x 20 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 Prep-TLC (PE / EA = 1 / 1) to afford tert-butyl 2-(3-chloro-4-((2-(5- fluoropyridin-2-yl)oxetan-2-yl)methoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro-6H- pyrazolo[1,5-d][1,4]diazepine-6-carboxylate (78 mg, 27% yield) as a light yellow solid. LCMS(ESI-MS) m/z = 583.2 [M+H]+. Into a 100 mL round-bottom flask were tert-butyl 2-(3-chloro-4-((2-(5-fluoropyridin-2-yl)oxetan-2- yl)methoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine- 6-carboxylate (30 mg, 0.05 mmol, 1 equiv), trifluoroacetic acid (1 mL) and DCM (10 mL). The resulting mixture was stirred for 1 h at room temperature. DIEA (5 mL, 0.255 mmol) was added to the above mixture and BrCN (7.24 mg, 0.067 mmol, 1.1 equiv) dissolved in DCM (2 mL) was added to the above mixture. The resulting mixture was stirred for 2 h. The reaction was quenched with water at room temperature. 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 Prep-TLC (PE / EA = 1 / 1) to afford the crude. The crude product was purified by Prep- Chiral-HPLC with the following conditions (Column: CHIRALPAK IE, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH₃-MeOH)--HPLC, Mobile Phase B: MeOH: DCM=1: 1--HPLC; Flow rate: 20ML/MIN mL/min; Gradient (B%): isocratic 70; Wave Length: 254/220nm nm; to afford 2-(3-chloro-4-((2-(5- fluoropyridin-2-yl)oxetan-2-yl)methoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro-6H- pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile (8.9 mg, 34% yield) as a white solid, LCMS(ESI-MS) m/z = 508.4 [M+H]+; (the second elution, 7.5 mg, 29% yield) as a white solid, LCMS(ESI-MS) m/z = 508.4 [M+H]+. Example 82-a 1-(2-(3-chloro-4-((2-(5-fluoropyridin-2-yl)oxetan-2-yl)methoxy)pyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 1 257 Example 83-a 1-(2-(3-chloro-4-((2-(5-fluoropyridin-2-yl)oxetan-2-yl)methoxy)pyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 2 From tert-butyl 2-(3-chloro-4-((2-(5-fluoropyridin-2-yl)oxetan-2-yl)methoxy)pyrazolo[1,5-a]pyridin-6- yl)-3-methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carboxylate, examples 82-a and 83-a were synthesized following a similar procedure as used for example 5-a. Example 86-a 2-(3-chloro-4-(1-(1-methylpyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1 Example 87-a 2-(3-chloro-4-(1-(1-methylpyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2 Example 88-a 2-(3-chloro-4-(1-(1-methylpyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 3 Example 89-a 2-(3-chloro-4-(1-(1-methylpyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 4 258 Starting from tert-butyl 3-(1-hydroxyethyl)pyrrolidine-1-carboxylate and 6-bromo-3-chloropyrazolo[1,5- a]pyridin-4-ol, examples 86-a to 89-a were synthesized following a similar procedure as used for example 7-a. Example 90-a 2-(3-(difluoromethoxy)-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1 Example 91-a 2-(3-(difluoromethoxy)-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2 Starting from 6-bromo-3-(difluoromethoxy)pyrazolo[1,5-a]pyridin-4-ol and 2-((tert- butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethan-1-ol, examples 90-a and 91-a were synthesized following using procedure described in example 3-a. Example 92-a 1-(2-(3-(difluoromethoxy)-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6- yl)-3-methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 1 Example 93-a 1-(2-(3-(difluoromethoxy)-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6- yl)-3-methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 2 259 From 2-((3-(difluoromethoxy)-6-(3-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2- yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethan-1-ol, examples 92-a and 93-a were synthesized following a similar procedure as used for example 5-a. Example 94-a 2-(4-(1-(6-aminopyridin-2-yl)-2-hydroxyethoxy)-3-chloropyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1 Example 95-a 2-(4-(1-(6-aminopyridin-2-yl)-2-hydroxyethoxy)-3-chloropyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2 Starting from 6-bromo-3-chloropyrazolo[1,5-a]pyridin-4-ol and tert-butyl (6-(2-((tert- butyldimethylsilyl)oxy)-1-hydroxyethyl)pyridin-2-yl)carbamate (prepared according to the procedure described for intermediate 5-(2-((tert-butyldimethylsilyl)oxy)-1-hydroxyethyl)picolinonitrile), examples 94 and 95 were synthesized using procedures described in example 3-a. Example 96-a 1-(2-(4-(1-(6-aminopyridin-2-yl)-2-hydroxyethoxy)-3-chloropyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 1 Example 97-a 1-(2-(4-(1-(6-aminopyridin-2-yl)-2-hydroxyethoxy)-3-chloropyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 2 260 From 2-(6-aminopyridin-2-yl)-2-((3-chloro-6-(3-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- d][1,4]diazepin-2-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethan-1-ol, examples 96-a and 97-a were synthesized following a similar procedure as used for example 5-a. Example 100-a 2-(4-(1-(5-chloropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1 Example 101-a 2-(4-(1-(5-chloropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2 Starting from 6-bromo-3-methoxypyrazolo[1,5-a]pyridin-4-ol and 2-((tert-butyldimethylsilyl)oxy)-1-(5- chloropyridin-2-yl)ethan-1-ol (prepared according to the procedure described for intermediate 5-(2-((tert- butyldimethylsilyl)oxy)-1-hydroxyethyl)picolinonitrile), examples 100-a and 101-a were synthesized using procedure described in example 3-a. Example 102-a 1-(2-(4-(1-(5-chloropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 1 Example 103-a 1-(2-(4-(1-(5-chloropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 2 261 From 2-(5-chloropyridin-2-yl)-2-((3-methoxy-6-(3-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- d][1,4]diazepin-2-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethan-1-ol, examples 102-a and 103-a were synthesized following a similar procedure as used for example 5-a. Example 104-a 2-(3-chloro-4-(1-(1,1-dioxidotetrahydrothiophen-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1 Example 105-a 2-(3-chloro-4-(1-(1,1-dioxidotetrahydrothiophen-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2 Example 106-a 2-(3-chloro-4-(1-(1,1-dioxidotetrahydrothiophen-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 3 Example 107-a 2-(3-chloro-4-(1-(1,1-dioxidotetrahydrothiophen-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 4 Starting from 3-(1-hydroxyethyl)tetrahydrothiophene 1,1-dioxide and 6-bromo-3-chloropyrazolo[1,5- a]pyridin-4-ol, examples 104-a to 107-a were synthesized following the same procedure as used for example 7-a. 262 Example 126-a N-(2-(4-((S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3- methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-6-yl)cyanamide, Isomer 1 Example 127-a N-(2-(4-((S)-1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3- methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-6-yl)cyanamide, Isomer 2 Into a 500 mL round-bottom flask were added bromo(ethynyl)magnesium (255 mL, 127 mmol, 1.20 equiv, 0.5 M in THF) at room temperature. To the above mixture was added 3-((tert- butyldimethylsilyl)oxy)propanal (20 g, 106 mmol, 1.00 equiv) and THF (100 mL) dropwise over 3 minutes at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C for additional 30 minutes. The resulting mixture was stirred at room temperature for 2 hours under nitrogen atmosphere. The reaction was quenched with water (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted 263 with PE / EA (5 / 1) to afford 5-((tert-butyldimethylsilyl)oxy)pent-1-yn-3-ol (16.1 g, 71% yield) as a yellow oil. LCMS(ESI-MS) m/z = 215.1 [M+H]+. Into a 500 mL round-bottom flask were added NaH (2.70 g, 113 mmol, 1.50 equiv) and THF (100 mL) at room temperature. To the above mixture was added 5-((tert-butyldimethylsilyl)oxy)pent-1-yn-3-ol (16.1 g, 75.1 mmol, 1.00 equiv) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for additional 20 minutes. To the above mixture was added (bromomethyl)benzene (19.3 g, 113 mmol, 1.50 equiv) and tetrabutylazanium iodide (5.55 g, 15 mmol, 0.20 equiv) at 0 °C. The resulting mixture was stirred at room temperature for additional overnight. The reaction was quenched with sat. NH4Cl (aq.100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5 / 1) to afford ((3-(benzyloxy)pent-4-yn-1-yl)oxy)(tert-butyl)dimethylsilane (22 g, 96% yield) as a yellow oil. LCMS(ESI-MS) m/z = 305.2 [M+H]+. Into a 500 mL round-bottom flask were added ((3-(benzyloxy)pent-4-yn-1-yl)oxy)(tert- butyl)dimethylsilane (27.8 g, 91 mmol, 2.00 equiv), 5-iodo-4-methyl-1H-pyrazole (9.5 g, 45.7 mmol, 1.00 equiv), Pd(PPh3)2Cl2 (3.205 g, 4.56 mmol, 0.10 equiv), CuI (1.74 g, 9.135 mmol, 0.20 equiv), Et3N (30 mL) and DMF (300 mL) at room temperature. The resulting mixture was stirred at 60 °C for overnight under nitrogen atmosphere. The reaction was quenched with water (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (3 x 100 mL), dried over anhydrous Na₂SO₄. 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 5-(3-(benzyloxy)-5-((tert-butyldimethylsilyl)oxy)pent-1-yn-1-yl)-4-methyl-1H-pyrazole (17 g, crude) as a brown oil. LCMS(ESI-MS) m/z = 385.2 [M+H]+. Into a 500 mL round-bottom flask were added 5-(3-(benzyloxy)-5-((tert-butyldimethylsilyl)oxy)pent-1-yn- 1-yl)-4-methyl-1H-pyrazole (12 g, 31.2 mmol, 1.00 equiv), ethyl acetate (200 mL) and Pd/C (16.6 g, 156 mmol, 5.00 equiv) at room temperature. The resulting mixture was stirred at 4 0°C for 3 days under hydrogen atmosphere (20 atm). The resulting mixture was filtered, the filter cake was washed with ethyl acetate (20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (6 / 1) to afford 5-(3-(benzyloxy)-5-((tert- butyldimethylsilyl)oxy)pentyl)-4-methyl-1H-pyrazole (3.59 g, 30% yield) as a brown oil. LCMS(ESI-MS) m/z = 389.2 [M+H]+. Into a 100 mL round-bottom flask were added 5-(3-(benzyloxy)-5-((tert-butyldimethylsilyl)oxy)pentyl)-4- methyl-1H-pyrazole (3.59 g, 9.24 mmol, 1.00 equiv), HCl in 1,4-dioxane (10 mL, 4 mmol/L) and 1,4- dioxane (5 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours under air atmosphere. The resulting mixture was concentrated under reduced pressure to afford 3- (benzyloxy)-5-(4-methyl-1H-pyrazol-5-yl)pentan-1-ol (2.74 g, 91% yield) as a brown solid. LCMS(ESI- MS) m/z = 275.2 [M+H]+. 264 Into a 500 mL round-bottom flask were added 3-(benzyloxy)-5-(4-methyl-1H-pyrazol-5-yl)pentan-1-ol (2.79 g, 10.2 mmol, 1.00 equiv), 2-(tributyl-l^[5]-phosphanylidene)acetonitrile (4.91 g, 20.3 mmol, 2.00 equiv) and toluene (100 mL) at room temperature. The resulting mixture was stirred at 100 °C for 2 hours under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / MeOH (10 / 1) to afford 6-(benzyloxy)- 3-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepine (1.97 g, 76% yield) as a yellow oil. LCMS(ESI- MS) m/z = 257.2 [M+H]+. Into a 500 mL round-bottom flask were added 6-(benzyloxy)-3-methyl-5,6,7,8-tetrahydro-4H- pyrazolo[1,5-a]azepine (1.97 g, 7.68 mmol, 1.00 equiv), methanol (50 mL) and Pd/C (0.41 g, 3.842 mmol, 0.50 equiv) at room temperature. The resulting mixture was stirred at 60 °C for overnight under hydrogen atmosphere (2 atm). The resulting mixture was filtered, the filter cake was washed with methanol (3 x 10 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (12 / 1) to afford 3-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-6-ol (1.2 g, 94% yield) as a yellow oil. LCMS(ESI-MS) m/z = 167.1 [M+H]+. Into a 250 mL round-bottom flask were added 3-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-6-ol (1.2 g, 7.22 mmol, 1.00 equiv), 1-hydroxy-1-oxo-3H-1l^[5],2-benziodaoxol-3-one (6.06 g, 21.6 mmol, 3.00 equiv) and ethyl acetate (30 mL) at room temperature. The resulting mixture was stirred at 80 °C for 2 hours. The reaction was quenched with water (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂ / MeOH (12 / 1) to afford 3-methyl-4,5,7,8-tetrahydro-6H- pyrazolo[1,5-a]azepin-6-one (543 mg, 46% yield) as a yellow oil. LCMS(ESI-MS) m/z = 165.1 [M+H]+. Into a 100 mL round-bottom flask were added 3-methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-a]azepin-6- one (543 mg, 3.31 mmol, 1.00 equiv), tert-butanesulfinamide (601 mg, 4.96 mmol, 1.50 equiv), tetrakis(propan-2-yloxy)titanium (2.82 g, 9.92 mmol, 3.00 equiv) and THF (10 mL) at room temperature. The resulting mixture was stirred at 60 °C for overnight. The mixture was allowed to cool down to room temperature. To the above mixture was added MeOH (2 mL) dropwise at room temperature. To the above mixture was added NaBH₄ (5 mg, 0.132 mmol, 0.04 equiv) in portions at 0 °C. The resulting mixture was stirred at room temperature for additional 3 minutes. The reaction was quenched by water (100 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous Na₂SO₄. 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-methyl-N-(3- methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-6-yl)propane-2-sulfinamide (675 mg, 75.7% yield) as a yellow oil. LCMS(ESI-MS) m/z = 270.2 [M+H]+. Into a 100 mL round-bottom flask were added 2-methyl-N-(3-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a]azepin-6-yl)propane-2-sulfinamide (675 mg, 2.505 mmol, 1.00 equiv) and 1,4-dioxane (5 mL) at room temperature. To the above mixture was added HCl in 1,4-dioxane (10 mL, 4mmol/L) dropwise over 1 265 minutes at room temperature. The resulting mixture was stirred at room temperature for additional 2 hours. The resulting mixture was concentrated under reduced pressure. To the above mixture was added TEA (2 mL) and DCM (5 mL) at room temperature. To the above mixture was added Boc2O (634 mg, 2.91 mmol, 1.20 equiv) at room temperature. The resulting mixture was stirred at room temperature for additional 2 hours. The reaction was quenched with water (100 mL) at room temperature. The resulting mixture was extracted with CH2Cl2 (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA = 5 / 1) to afford tert-butyl (3-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-6-yl)carbamate (300 mg, 47% yield) as an off-white solid. LCMS(ESI-MS) m/z = 266.2 [M+H]+. Into a 40 mL vial were added tert-butyl (3-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-6- yl)carbamate (300 mg, 1.13 mmol, 1.00 equiv), NBS (241 mg, 1.36 mmol, 1.20 equiv) and DMF (5 mL) at room temperature. The resulting mixture was stirred at room temperature for overnight. The reaction was quenched with water (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (3 x 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA = 1 / 1) to afford tert-butyl (2-bromo-3-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-6- yl)carbamate (101 mg, 26% yield) as a white solid. LCMS(ESI-MS) m/z = 344.1 [M+H]+. Into a 40 mL vial were added (S)-4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3- methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (316 mg, 0.580 mmol, 2.00 equiv), tert-butyl (2-bromo-3-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-6-yl)carbamate (100 mg, 0.290 mmol, 1.00 equiv), Pd(PPh₃)₄ (16.8 mg, 0.014 mmol, 0.05 equiv), K₂CO₃ (80.3 mg, 0.580 mmol, 2.00 equiv), 1,4-dioxane (10 mL) and H₂O (2 mL) at room temperature. The resulting mixture was stirred at 100 °C for overnight under nitrogen atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA = 1 / 1) to afford tert-butyl (2-(4-((S)-2-((tert- butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3- methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-6-yl)carbamate (105 mg, 53% yield) as a brown oil. LCMS(ESI-MS) m/z = 681.4 [M+H]+. Into a 100 mL round-bottom flask were added tert-butyl (2-(4-((S)-2-((tert-butyldimethylsilyl)oxy)-1-(5- fluoropyridin-2-yl)ethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl-5,6,7,8-tetrahydro-4H- pyrazolo[1,5-a]azepin-6-yl)carbamate (124 mg, 0.182 mmol, 1.00 equiv) and 1,4-dioxane (5 mL) at room temperature. To the above mixture was added HCl in 1,4-dioxane (10 mL, 4 mmol/L) at room temperature. The resulting mixture was stirred at room temperature for additional 2 hours. The resulting mixture was concentrated under reduced pressure to afford (2S)-2-((6-(6-amino-3-methyl-5,6,7,8-tetrahydro-4H- pyrazolo[1,5-a]azepin-2-yl)-3-methoxypyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethan-1- ol (crude) as a brown solid. LCMS(ESI-MS) m/z = 467.2 [M+H]+. 266 Into a 100 mL round-bottom flask were added (2S)-2-((6-(6-amino-3-methyl-5,6,7,8-tetrahydro-4H- pyrazolo[1,5-a]azepin-2-yl)-3-methoxypyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethan-1- ol (90 mg, 0.193 mmol, 1.00 equiv), DIEA (125 mg, 0.965 mmol, 5.00 equiv) and DMF (5 mL) at room temperature. To the above mixture was added carbononitridic bromide (18.4 mg, 0.174 mmol, 0.90 equiv)at room temperature. The resulting mixture was stirred at room temperature for additional 2 hours. The reaction was quenched with water (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (3 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (EA / MeOH = 10 / 1) to afford crude product. The residue was purified by Prep- Chiral-HPLC with following conditions: Column: CHIRALPAK IH, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: EtOH: DCM=1: 1--HPLC; Flow rate: 20 mL/min; Gradient (B%): isocratic 25% B; Wave Length: 254/220 nm to afford the two isomers 126-a and 126-b. Isomer 1 (7.4 mg, 8% yield). LCMS(ESI-MS) m/z = 492.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.47 (d, 1H), 8.18 (s, 1H), 7.73 – 7.62 (m, 2H), 7.45 (td, 1H), 6.65 (s, 1H), 5.55 (dd, 1H), 4.52 (dd, 1H), 4.22 (d, 1H), 4.15-4.04 (m, 3H), 4.00 (d, 3H), 3.52 (s, 1H), 3.18 (s, 1H), 2.97 (dd, 1H), 2.51 (dd, 1H), 2.27-2.15 (m, 2H), 2.03 (s, 3H), 1.83 (q, 1H), 1.65 (q, 1H). Isomer 2 (9.3 mg, 10% yield). LCMS(ESI-MS) m/z = 492.2 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.47 (d, 1H), 8.18 (s, 1H), 7.68 (s, 1H), 7.65 (dd, 1H), 7.44 (td, 1H), 6.63 (s, 1H), 5.53 (dd, 1H), 4.49 (dd, 1H), 4.18 (d, 1H), 4.15-4.03 (m, 3H), 4.00 (s, 3H), 3.52 (s, 1H), 2.96 (dd, 1H), 2.51 (dd, 1H), 2.27-2.15 (m, 2H), 2.02 (s, 3H), 1.81 (q, 1H), 1.63 (q, 1H). Synthesis of 6-bromo-3-methoxypyrazolo[1,5-a]pyridin-4-ol A 500 mL round-bottom flask was charged with 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (10 g, 44 mmol, 1 equiv), dodecane-1-thiol (26.7 g, 132 mmol, 3 equiv), NaOH (5.28 g, 132 mmol, 3 equiv), H₂O (5.28 g, 293 mmol, 6.7 equiv) and DMA (200 mL).The resulting mixture was stirred for overnight at 50 °C 267 under nitrogen atmosphere. The reaction was quenched by the addition of water (400 mL) at room temperature. The residue was acidified to pH 4 with FA. The resulting mixture was extracted with EA (3 x 300 mL). The combined organic layers were washed with water (3 x 200 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford a crude product. The crude product was re-crystallized from (PE / EA = 9 / 1, 100 mL) to afford 6-bromopyrazolo[1,5-a]pyridin- 4-ol (8 g, 85% yield) as a brown yellow solid. LCMS (ESI-MS) m/z =213.0 [M+H]+. A 250 ml round-bottom flask was charged with 6-bromopyrazolo[1,5-a]pyridin-4-ol (6.9 g, 32 mmol, 1 equiv), bromo(methoxy)methane (6.1 g, 48.6 mmol, 1.50 equiv), K2CO3 (9.0 g, 64.8 mmol, 2 equiv) and acetone (100 mL). The resulting mixture was stirred for overnight at room temperature. 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 100 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to provide 6-bromo-4- (methoxymethoxy)pyrazolo[1,5-a]pyridine (6.8 g, crude) as a white solid. LCMS(ESI-MS) m/z = 257.0 [M+H]+. A 40 mL vial were added 6-bromo-4-(methoxymethoxy)pyrazolo[1,5-a]pyridine (6.8 g, 26.5 mmol, 1 equiv), NIS (7.14 g, 31.7 mmol, 1.2 equiv) and DMF (100 mL). The resulting solution was stirred for 5 hours 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 (PE / EA = 2 / 1) to afford 6-bromo-3-iodo-4- (methoxymethoxy)pyrazolo[1,5-a]pyridine (6.6 g, 65% yield) as a white solid. LCMS (ESI-MS) m/z = 382.9 [M+H]+. A 250 ml round-bottom flask was charged with 6-bromo-3-iodo-4-(methoxymethoxy)pyrazolo[1,5- a]pyridine (6.8 g, 17.8 mmol, 1 equiv), isopropylmagnesium chloride (17.8 mL, 35.5 mmol, 2 equiv, 2.0 M in diethyl ether) and THF (50 mL) . The reaction was stirred for 30 minutes at 0 °C under nitrogen atmosphere. Then 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.96 g, 26.6 mmol, 1.5 equiv) was added dropwise at 0 °C. The resulting mixture was stirred for 2 hours at 0 °C 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 100 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford 6-bromo-4-(methoxymethoxy)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (6.6 g, crude) as a colorless solid. LCMS (ESI-MS) m/z = 383.1 [M+H]+. A 100 mL round bottom flask was charged with 6-bromo-4-(methoxymethoxy)-3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (8 g, 20.9 mmol, 1 equiv), sodium perborate tetrahydrate (9.6 g, 62.7 mmol, 3 equiv), THF (200 mL) and H₂O (50 mL). The resulting solution was stirred for 4 hours 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 268 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 6-bromo-4- (methoxymethoxy)pyrazolo[1,5-a]pyridin-3-ol (4 g, 70% yield) as a white solid. LCMS(ESI-MS) m/z = 273.0 [M+H]+. A 100 mL round bottom flask was charged with 6-bromo-4-(methoxymethoxy)pyrazolo[1,5-a]pyridin-3-ol (4 g, 14.6 mmol, 1 equiv), K2CO3 (4 g, 29 mmol, 2 equiv), CH3I (1.66 g, 11.7 mmol, 0.8 equiv) and DMF (50 mL). The resulting solution was stirred for 2 hours 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 (PE / EA = 1 / 10) to afford 6-bromo-3-methoxy-4-(methoxymethoxy)pyrazolo[1,5-a]pyridine (3.5 g, 83% yield) as a white solid. LCMS (ESI-MS) m/z = 287.0 [M+H]+. A 100 mL round bottom flask was charged with 6-bromo-3-methoxy-4-(methoxymethoxy)pyrazolo[1,5- a]pyridine (4 g, 13.9 mmol, 1.00 equiv), HCl in 1,4-dioxane (5 mL, 4.0 M in 1,4-dioxane) and 1,4-dioxane (2 mL). The resulting solution was stirred for 2 hours at room temperature and concentrated under reduced pressure to provide 6-bromo-3-methoxypyrazolo[1,5-a]pyridin-4-ol (3.2 g, crude) as a white solid. LCMS (ESI-MS) m/z = 243.0 [M+H]+. Synthesis of (R)-2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethan-1-ol A 500 mL round bottom flask was charged with 2-bromo-5-fluoropyridine (20 g, 114 mmol, 1.0 equiv) and toluene (150 mL). To the mixture was added isopropylmagnesium chloride (85 mL, 170 mmol, 1.5 equiv, 2.0 M in THF) at 0 °C under N₂ atmosphere. The resulting solution was stirred for 1 h at 0 °C. A solution of 2-[(tert-butyldimethylsilyl)oxy]acetaldehyde (29.7 g, 170 mmol, 1.5 equiv) in toluene (50 mL) was added to the above mixture at 0 °C under N₂ atmosphere. The resulting solution was stirred for overnight at room temperature. The reaction was quenched with sat. NH₄Cl (aq., 300 mL) at 0 °C. The mixture was extracted with ethyl acetate (3 x 200 mL). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 2-[(tert-butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2- yl)ethanol (20 g, 64% yield) as a yellow oil. LCMS(ESI-MS) m/z =272.1 [M+H]⁺. A 500 mL round bottom flask was charged with 2-[(tert-butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2- yl)ethanol (20 g, 73.6 mmol, 1.00 equiv) and DCM (200 mL). To the mixture was added 1,1-bis(acetyloxy)- 3-oxo-3H-1l^[5],2-benziodaoxol-1-yl acetate (46.88 g, 111 mmol, 1.50 equiv) at 0 °C. The resulting solution was stirred for 3 h at room temperature. The reaction was quenched with water (300 mL) at 0 °C. The mixture was extracted with DCM (3 x 150 mL). The organic layers were combined, dried over 269 anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 2-[(tert-butyldimethylsilyl)oxy]-1-(5- fluoropyridin-2-yl)ethanone (13 g, 65% yield) as a yellow solid. LCMS(ESI-MS) m/z =270.1 [M+H]⁺. A 1000 mL round bottom flask was charged with (3aR)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2- c][1,3,2]oxazaborole (40.1 g, 145 mmol, 1.00 equiv) and THF (300 mL). To the mixture was added borane- tetrahydrofuran complex (145 mL, 145 mmol, 1.00 equiv, 1.0 M in THF) dropwise at -78 °C and keep the temperature below -70 °C. The resulting solution was stirred for 6 h at -78 °C. Then a solution of 2-[(tert- butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2-yl)ethanone (39 g, 145 mmol, 1.00 equiv) in THF (150 mL) was added to the above mixture at -78 °C. The mixture was warmed up to room temperature during two hours. The resulting solution was stirred for overnight at room temperature. The reaction was quenched by the addition of MeOH (100 mL) at 0 °C and stirred for 30 min at room temperature. The mixture was diluted with water (500 mL) and extracted with ethyl acetate (3 x 500 mL). The organic layers were combined, washed with brine (3 x 200 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3 / 1) to afford (1R)-2-[(tert-butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2-yl)ethanol (8.5 g, 20% yield, 95% purity) as a yellow oil. LCMS(ESI-MS) m/z =272.1 [M+H]⁺.

270 The following compounds depicted in table III can be prepared essentially as described in the methods above. Table III 275 BIOLOGICAL EXAMPLES Overview [0579] The FGFR3 phosphorylation assay aims at measuring the reduction of FGFR3 auto- phosphorylation, a marker for FGFR3 activity, upon treatment with potential FGFR3 inhibitors. 293T cells were transfected with a doxycycline inducible construct encoding the FGFR3 S249C+V555M double mutant fused to a C-terminal FLAG-tag. After exposing the transfected cells for two hours to potential FGFR3 inhibitors, phospho-FGFR (pFGFR) and total FGFR (tFGFR) levels were measured in a high-content microscopy assay by means of an anti-phospho-FGFR antibody and an anti-FLAG antibody. Protocol [0580] Fourteen million 293T cells (ATCC, Cat. No. CRL-3216) were transiently transfected using 75 µL JetPEI (Polyplus, Cat. No.101000020), 2.5 µg of a FGFR3 S249C+V555M FLAG construct and 22.5 µg pBluescript DNA. The transfected cells were seeded in a T175 culture flask in culture medium consisting of Dulbecco’s Modified Eagle's Medium (DMEM, Gibco, Cat. No. 41966-029) complemented with 10% heat inactivated (HI) fetal bovine serum (FBS), 2 mM L-glutamine and 1% penicillin/streptomycin (P/S) and incubated overnight (O/N) at 37°C, 5% CO2. [0581] Assay plates (384-well format) were coated with 30 µL of a 50 µg/mL poly-D-lysine solution per well, followed by a brief centrifugation at 1,000 RPM and incubated for 1 hour (h) at 37°C, 5% CO2. The coating solution was then removed by tapping the plates on sterile tissues and subsequently the plates were washed 1x with PBS and dried for 1h at room temperature (RT). [0582] The transfected 293T cells were harvested by trypsinization and resuspended in culture medium (DMEM supplemented with 10% FBS, 1% Pen/strep, 2 mM L-Glutamine and 100 ng/ml doxycycline (Sigma, Cat. No. D3072)).45 µl cell suspension, containing 20,000 transfected cells, was seeded into each well of the assay plates and the plates were incubated O/N at 37°C, 5% CO2. 276 [0583] The test compounds were prepared in compound dilution plates as a 10-point 1/5 dilution series in 100% DMSO starting from 10 mM. Control samples were added to the compound dilution plates: 100% DMSO was added to the negative control wells and 1 mM G1756296 to the positive control wells. [0584] Compounds and controls were diluted 1/33 in culture medium supplemented with 100 ng/ml doxycycline and 5 ^µL of the dilution was transferred to the assay plates containing the cells. This resulted in a final concentration of 0.3% DMSO for the negative control wells, 3 µM G1756296 for the positive control wells and a 10-point 1/5 dilution series starting at a final concentration of 30 µM for the test compounds. The plates were briefly centrifuged at 1000 rpm and incubated at 37°C, 5% CO2 for 2h. [0585] Cell fixation was performed by addition of 2.7 µL of a 37% paraformaldehyde (PFA) solution to each well of the assay plates still containing the medium (final PFA concentration: 2%), followed by a 15 min incubation at RT. Afterwards the plates were washed 3 times with PBS using a BlueWasher (BlueCatBio) device to remove the PFA. After the last wash the PBS was kept on the plates and plates were either stored at 4°C until further staining or stained immediately. [0586] PBS was removed using a BlueWasher device and 25 µL of blocking buffer (PBS containing 0.2% Triton X-100, 2% heat inactivated FBS, 3% bovine serum albumin and 1% milk) was added to each well. Plates were incubated for 1h at RT. Next, immunostaining was performed by incubating the wells for 2 h with 25 µL of 1/200 diluted anti-pFGFR antibody (Cell Signaling Technology, Cat. No.52928) and 1/1,000 diluted anti-FLAG antibody (Sigma, Cat. No. F1804) at RT. [0587] The plates were washed 2x with PBS-T and 1x with PBS and 25 µL of a solution containing secondary antibodies and nucleic acid stain was added. This solution consisted of PBS, 1/500 diluted Alex Fluor 647 conjugated goat anti-rabbit IgG (ThermoFisher Scientific, Cat. No. A-21245), 1/500 diluted Alexa Fluor 488 conjugate goat anti-mouse IgG (ThermoFisher Scientific, Cat. No. A28175) and 1/1000 diluted Hoechst 33342 (ThermoFisher Scientific, H3570). Plates were incubated for 1h at RT. [0588] After two wash steps with PBS-T and 1 wash step with PBS, plates were imaged on an automated high-content microscope (e.g., Operetta, Revvity). Table III. Biological data of the compounds A: IC50= <25 nM B: IC50= >25 to 250 nM C: IC50= >250 to 1000 nM D: IC50= >1000 nM to 10000 nM 277 278 279 280 281 282 Protocol for FGFR1 The same protocol as described above for FGFR3 inhibition was used, replacing the double-mutant FGFR3 (S249C+V555M) by the FLAG-tagged full-length FGFR1. Protocol for FGFR2 The same protocol as described above for FGFR3 inhibition was used, replacing the double-mutant FGFR3 (S249C+V555M) by the FLAG-tagged full-length FGFR2. Protocol for FGFR4 The same protocol as described above for FGFR3 inhibition was used, replacing the double-mutant FGFR3 (S249C+V555M) by the FLAG-tagged full-length FGFR4 Pharmacokinetic, ADME and Toxicity Assays 1.1. Thermodynamic solubility [0589] The thermodynamic solubility was determined in Fasted State Simulated Gastric Fluid (FaSSGF, pH 1.6), Fed State Simulated Intestine Fluid (FeSSIF v2, pH 5.8), Fasted State Simulated Intestine Fluid (FaSSIF v2, pH 6.5) and phosphate buffer (pH7.4). [0590] Approximately 1 mg of each compound was weighed into a 12 mL clear glass screw cap vial and 1 mL of medium was added (final concentration about 1mg/mL). The sample was placed in a thermodynamic water bath at 37 °C and 120 rpm of orbital shaking for 24 hours. [0591] For HPLC/DAD analysis the sample was filtered through a 0.2 µm PTFE filter mounted onto syringe and then analysed neat and accurately diluted 10 and 100 times. [0592] The same batch of test compound was used as a standard, assigning the purity of 100%, in order to prepare the calibration curve. Test compound stock solution was prepared at a concentration of 1 mg/mL in DMSO and diluted to cover the calibration range from 0.0001 – 0.1 mg/mL. [0593] The samples are analysed on HPLC system with a flow rate of 0.5 mL/min. Solvent A is 10 mM ammonium carbonate at pH10 and solvent B is acetonitrile. The sample is going through a XBridge C18 2.7µM (2.1 x 50mm) column, from Waters. The solvent gradient has a total run time of 12 min and ranges from 10% B to 90% B. [0594] Peak areas are analysed and are plotted against the standard curve to obtain the solubility of the compound. 283 [0595] Solubility values are reported in µM or µg/mL. 1.2. Aqueous Solubility [0596] This protocol describes determination of kinetic solubility by turbidimetry. [0597] Turbidimetric solubility allows rapid determination of solubility using small amounts of compound. Briefly, compound’s DMSO solutions (prepared at specific concentrations) are spiked into aqueous buffer and turbidity is measured using VIS spectrophotometry at 620 nm. Sulfaphenazole and α- naphtoflavone are used as assay controls. [0598] 10 mM DMSO stock solution is diluted in DMSO (in 96-well V-bottom polypropylene microplates) to a concentration of 1 mM. [0599] 3 µl of compound’s/control’s dilution in DMSO in triplicates were added to appropriate wells containing 297 µl of 100 mM PBS solution to the final concentration of 10 µM (1% DMSO; Table 3.; done in 96-well flat bottom microplates) [0600] The plate is incubated by gently shaking (200-300 rpm) for 45 minutes at 37°C and left at room temperature (without shaking) for 15 minutes (total incubation time = 1h). [0601] The plate absorbance at 620nm is read on a Microplate reader (Tecan, Infinite F500 or Spark) [0602] Calculation of solubility range data and resulting curves is made by Excel tools software. [0603] The absorbance is proportionally increased with concentration of insoluble particles. Compound/control samples are compared to a solvent control in aqueous buffer (DMSO 1% final concentration), where significant increase of sample absorbance is considered when its absorbance is 3- fold standard deviation of average DMSO absorbance. [0604] Results are accepted depending on solubility values obtained for assay controls: - α–naphtoflavone: <10 µM - sulfaphenazole: >10µM [0605] Results are expressed as an average of three replicas (<10 µM or >10 µM) for one concentration set-up. 1.3. Plasma Protein Binding (Equilibrium Dialysis) [0606] The binding of the test compound to plasma proteins was tested by equilibrium dialysis using a Teflon unit from HTDialysis, performed on a Freedom EVO liquid handling unit. [0607] Prior to the start of the experiment, dialysis membranes (Dialysis membranes MW cut-off 12- 14kDa – HTDialysis – Cat.No. 1101) were soaked in deionised water for 60 minutes, transferred and left overnight in 20% ethanol. On the day of experiment, compound and control stock solutions were diluted, spiked into plasma in order to achieve a final concentration of 5 µM (0.5% DMSO). [0608] Immediately after assembly of the Teflon unit, a volume of 100 µl of plasma (spiked with compound/control) was placed on one side of the well and 100 µl of blank PPB buffer (60 mM Na2HPO4, 14 mM KH2PO4, 70 mM NaCl) was added to the other side, respectively, with each compound assayed in duplicate. The test compound was incubated for 4 hours at 37℃ with gentle shaking. Thereafter, an aliquot was taken from each side of the well and matrix matched (mix of equal volumes of spiked plasma with 284 blank PPB buffer and samples from buffer compartment with blank plasma). In order to estimate the recovery an aliquot was also taken at t=0 min from spiked plasma solutions and matrix matched as described above. [0609] Matrix matched samples were further mixed with six volumes of STOP solution (acetonitrile: methanol, 2:1 v/v with an internal standard (IS)). After brief mixing and centrifugation (at 4500 rpm for 30 min, at +4ºC), the supernatant was transferred into new plates and analysed and quantified by LC-MS/MS. [0610] The percentage bound (PPB) was determined using the following equation: PPB = [(Cplasma-Cbuffer)/Cplasma]*100 Cplasma = Peak area of the compound in the plasma / Peak area of the IS in the plasma Cbuffer = Peak area of the compound in the buffer / Peak area of the IS in the buffer The recovery is a control, it allows to be sure that the compound has not a non-specific binding to the plates or it is not stable in the plasma in these conditions. % recovery = [(Buffer+Plasma)/Recovery]*100 Buffer = (ratio of the peak area of the compound/peak area of IS) in Buffer compartment after 4h Plasma = (ratio of the peak area of the compound/peak area of IS) in Plasma compartment after 4h Recovery = ratio at T0 of the peak area of the compound in the well recovery / peak area of the IS in the well recovery 1.4. Aldehyde oxidase stability [0611] An in vitro metabolic stability in human and rat liver S9 (human: 20-donor pool, mixed gender (Corning, Cat.No.452961) and rat: pooled, male Sprague-Dawley (Corning, Cat.No.452591)) was done in order to investigate the test compound as substrate of aldehyde oxidase. A 10 mM DMSO stock solution of the test compound was first diluted in DMSO (40 fold) to obtain a 250 µM working solution. Incubation mixtures were prepared by adding liver S9 suspension (final protein concentration of 2 mg/mL) to 50mM potassium phosphate buffer, pH 7.4. Hydralazine (Sigma, Cat.No.H1753) (selective inhibitor of aldehyde oxidase; final concentration of 100 µM) or miliQ water were added for incubations with and without addition of selective inhibitor, respectively. After pre-warming for 5 min at 37°C, the reaction was initiated by addition of test compound to the incubation mixture (final concentration in the incubation mixture of 1 µM, 0.4%DMSO). After 0, 3, 6, 12, 18 and 30 minutes of incubation, the reaction (aliquot of 100 µL) was terminated with 300 µL of acetonitrile:methanol (2:1) mixture with 1% acetic acid and the analytical internal standard. Samples were mixed, centrifuged and the supernatant analysed by LC-MS/MS (Table 2 and Table 3). Phthalazine (Aldrich, Cat.No. P38706) was included as a positive control. [0612] S9 stability, expressed as the percentage of remaining parent compound, was calculated from the peak area ratio of compound and internal standard following different incubation times compared to the same ratio at the t=0 min (100%). The half-life (t1/2) is calculated in GraphPadPrism software from % remaining vs. time regression using non-linear regression fit (one phase exponential decay) with following constrain parameters: Span=100, Plateau=0, K=no constraint). 285 [0613] In vitro intrinsic clearance (CLint) was calculated from the half-life value using following equation: CLint[µl/min/mg] = (ln2/t1/2)*(ml per incubation/mg S9 protein) 1.5. Liver microsomal stability [0614] The test compound was diluted from DMSO stock solution to obtain a final concentration of 1µM in the final incubation mix (final DMSO 0.03%). A NADPH generating system (Cofactor solution) was prepared by adding to a 50mM PBS pH 7.4 buffer, NADP (Sigma, N0505), G6P (Sigma, G6526), MgCl2x6H2O (Sigma, M2670) and G6P DH (Sigma, G637) to obtain in the final incubation mix NADP at 0.5mM , G6P at 5mM , MgCl2x6H2O at 0.5mM and G6P DH at 1.5 U/mL. Liver microsomes (Corning; Discovery Life Sciences) solution was prepared from 20mg/mL stock concentration to obtain a final concentration in the incubation mix of 0.5mg/mL. [0615] Test compounds were incubated at 37°C with and without cofactors and reaction was started by adding cofactors or buffer (for negative control) to incubation mix. Time points were taken at 0, 10, 25 and 40’. At the desired incubation time point, a STOP solution (acetonitrile: methanol, 2:1 v/v) was added at a ratio 3:1 to the incubation mix. Samples were then centrifuged (at 4500 rpm, at 4°C, for 30 min). The supernatant was then analyzed using a LC-MS/MS method. [0616] Metabolic stability, expressed as the percentage of remaining parent compound, is calculated from the ratio of peak area of the remaining compound and peak area of the internal standard after different time of incubation compared to the same ratio at the t=0 min (100%): [0617] % remaining = (peak area ratios of test compound vs IS at appointed time)/(peak area ratios of test compound vs IS at 0min) x 100 [0618] The half-life (t_1/2) is calculated in GraphPad Prism software from % remaining vs. time regression using non-linear regression fit (one phase exponential decay with following constrain parameters: Span=100, Plateau=0, K=no constraint). [0619] In vitro intrinsic clearance (CL_int) is calculated from half-life using following equation: [0620] CL_int = [µl/min/mg] = 0.693/t_1/2 /min ^ (mL of incubation/mg protein) x 1000 1.6. Hepatocyte stability [0621] The test compound was diluted from DMSO stock solution to obtain a final concentration of 1µM in the final incubation mix. The test compound was incubated in dog, monkey, human, mouse and rat hepatocytes (BioIVT, mouse Cat. No. M005052, rat Cat. No. M00005 , dog, Cat. No. M00205 , monkey Cat. No. M00305, human Cat. No. X008001) (final concentration: 0.5x106 cells/ml), resuspended in Krebs- Henseleit modified buffer for 3 hours (except in human – 90 minutes) at 37°. Aliquots were taken at different time points and the reaction was terminated by addition of 3 volumes of STOP solution (acetonitrile:methanol = 2:1 with an internal standard). Aliquots were then centrifuged (at 4500 rpm, at 4°C, for 30 min). The supernatant was then analysed using a LC-MS/MS method. 286 [0622] Metabolic stability, expressed as the percentage of remaining parent compound, was calculated from the ratio of peak area of the remaining compound and peak area of the internal standard after different time of incubation compared to the same ratio at the t=0 min (100%). [0623] The half-life (t1/2) was calculated in GraphPadPrism software from % remaining vs. time regression using non-linear regression fit (one phase exponential decay) with following constrain parameters: Span=100, Plateau=0, K=no constraint) [0624] In vitro intrinsic clearance (CLint) was calculated from half-life using the following equation: [0625] CLint^µl/min/106cells^ = (ln2/t1/2)*(ml per incubation/#cells per incubation) 1.7. Caco2 Permeability [0626] Bi-directional Caco-2 assays are performed as described below. Cells were seeded at 1 x 105 cells/cm2 in 96-well HTS Transwell plates (Corning). Permeability assays were performed with the cells at days 21-25 post-seeding. [0627] This assay was performed in both the apical (A) to basolateral (B) A-B or B-A direction. Compounds and the references (Propranolol, Labetalol, Ranitidine, Colchicine) were prepared at 10 μM in HBSS-MES (pH 6.5) or HBSS-HEPES (pH 7.4) with a final DMSO concentration of 1 % (v/v). The working solution was then centrifuged and the supernatant was added to the donor side. [0628] The assay plate was incubated at 37 °C for 60 min or 40 min for the A-B or B-A assay, respectively. Samples were aliquoted from the donor side at time zero and the end point, and from the receiver side at the end point. [0629] In addition, Lucifer yellow (LY), a membrane integrity marker, was co-incubated with the test compound at the start of the experiment to assess integrity of the cell layers. As LY cannot freely permeate lipophilic barriers, a high Papp of the Lucifer yellow (measured by fluorescence) indicates poor formation of the cell monolayer. [0630] Moreover, the Transepithelial electrical resistance (TEER) of each Multiscreen™ well was also evaluated prior to the initiation of the assay so as to evaluate monolayer integrity. [0631] Reference compounds namely, Propranolol (highly permeable), Labetalol (moderately permeable), Ranitidine (poorly permeable), and Colchicine (P-glycoprotein substrate) were included in this assay. Samples were analysed by LC/MS-MS. [0632] Apparent permeability (Papp) values are calculated from the relationship: P_app = [compound]_{acceptor final} ^ V_acceptor / ([compound]_{donor initial} ^ V_donor) / T_inc ^ V_donor / surface area ^ 60 ^ 10- ⁶ cm/s V = chamber volume Tinc = incubation time. Surface area = 0.33cm² The Efflux ratios, as an indication of active efflux from the apical cell surface, are calculated using the ratio of Papp B>A/ Papp A>B. 287 The following assay acceptance criteria are used: If at least 3 out of 4 control molecules are in these ranges determined by the historical data, the assay is validated. Lucifer yellow permeability: <0.510-6 cm/s Colchicine: Papp (A>B) value < 1 (x10-6 cm/s) with Efflux ratio ≥4 Labetalol: Papp (A>B) value < 6 (x10-6 cm/s) Propranolol: Papp (A>B) value < 25 (x10-6 cm/s) Ranitidine: Papp (A>B) value < 2 (x10-6 cm/s) 1.8. MDCKII-MDR1 Permeability [0633] MDCKII-MDR1 cells are Madin-Darby canine kidney epithelial cells, over-expressing human multi-drug resistance (MDR1) gene, coding for P-glycoprotein (P-gp). Cells are obtained from Netherlands Cancer Institute and used after a 3-4 day cell culture in 24-well Millicell cell culture insert plates (Millipore, PSRP010R5). Bi-directional MDCKII-MDR1 permeability assay is performed as described below. [0634] 3x105 cells/mL (1.2x105 cells/well) are seeded in plating medium consisting of DMEM + 1% Glutamax-100 + 1% Antibiotic/Antimycotic + 10% FBS (Biowest, S1810). Cells are left in CO2 incubator for 3-4 days. The medium is changed 24h after seeding and on the day of experiment. [0635] Test and reference compounds (amprenavir and propranolol) are prepared in Dulbecco’s phosphate buffer saline (D-PBS, pH7.4) and added to either the apical (400µL) or basolateral (800µL) chambers of the Millicell cell culture insert plates assembly at a final concentration of 10 µM (0.5 µM in case of amprenavir) with a final DMSO concentration of 1% [0636] 100µM Lucifer Yellow (Sigma) is added to the all donor buffer solutions, in order to assess integrity of the cell monolayers by monitoring Lucifer Yellow permeation. Lucifer yellow is a fluorescent marker for the paracellular pathway and it is used as an internal control in every monolayer to verify tight junction integrity during the assay. [0637] After a 1 h incubation at 37°C while shaking at an orbital shaker at 150rpm, 75µL aliquots are taken from both apical (A) and basal (B) chambers and added to 225µL acetonitrile:water solution (2:1) containing analytical internal standard (10 ng/mL warfarin) in a 96 well plate. Aliquoting is also performed at the beginning of the experiment from donor solutions to obtain initial (Co) concentration. [0638] Concentration of compound in the samples is measured by high performance liquid- chromatography/mass spectroscopy (LC-MS/MS). [0639] Lucifer yellow is measured with a Fluoroscan Ascent FL Thermo Scientific (Ex 485nm and Em 530nm) in a 96 well plate containing 150µL of liquid from all receiver wells (basolateral or apical side). [0640] The apparent permeability coefficient (Papp) was calculated according to the following equation: Papp = (dQ/dT)*(1/C0)*(1/A) where dQ/dT = permeability rate C0 = initial concentration in donor compartment A = surface area of the cell monolayer (0.11 cm2) “Concentration” is the ratio between compound and internal standard peak areas. 288 The Papp value has a dimension of a rate (x10-6 cm/sec). Permeability values were classified as follows: low permeability: <2x10-6 cm/sec [0001] , moderate permeability: 2-10x10-6 cm/sec, high permeability: >10x10-6 cm/sec The Efflux ratio, as an indication of active efflux from the apical cell surface, was calculated using following equation: Efflux ratio = Papp (B2A)/Papp (A2B) A compound is considered to be a possible P-gp substrate when the efflux ratio is ≥ 2. Mass balance (MB) was calculated from equation: MB = (Md+Mr)/Mo where Md = mass of drug in donor compartment at time 60 min Mr = mass of drug in receiver compartment at time 60 min Mo = mass of drug in donor compartment at time 0 min Mass of drug = Analyte/IS ratio * volume of compartment (75 µL or 250 µL) [0641] Mass balance results should be evaluated as follows: Mass balance between 80-120%: acceptable, Mass balance between 50-80% and 120-135% should be interpreted with caution, Mass balance <50% and >135% should be discarded [0642] Results were accepted based on obtained data: Lucifer yellow: all Papp values should be <3x10-6 cm/sec, Amprenavir: low permeability (PappA2B ≤2x10-6 cm/sec), efflux ratio >2, Diclofenac: high permeability (PappA2B >10x10-6 cm/sec), efflux ratio <2 a. Glutathione stability assay Solutions of test compound (10 µM, 1% final DMSO concentration) are incubated in 50 mM PBS buffer only to evaluate the buffer stability of the test compound and in 50 mM PBS buffer containing 2 mM reduced L-glutathione to determine the reactivity of the test compound. The incubation is performed in duplicate for 5h at 37°C and pH7.4. Omeprazole, Afatinib and Ibrutinib are used as positive controls. At 0, 30, 60, 180 and 300 min, aliquots are withdrawn and immediately quenched with ice-cold organic solvent (acetonitrile:methanol (2:1)) containing diclofenac and warfarin sodium as internal standard. Samples are then centrifuged to remove precipitated proteins, diluted with H₂O MilliQ:STOP solution (if needed) and the (diluted) supernatant is analysed by Liquid Chromatography-Tandem Mass Spectrometry (LC- MS/MS). GSH reactivity, expressed as the percentage of remaining parent compound, is calculated from the ratio of peak area of the remaining compound and peak area of the internal standard after different times of incubation compared to the same ratio at the t=0 min (100%). ^_{^^^^^^^ ^^^^^^^^ ^^^^^^^^^^^^ ^^^^ ^^^^^^^^ ^^^^^^^^^^^^^^^^ ^^^^. ^^^^ ^^^^ ^^^^^^^^^^^^^^^^^^ ^^^^^^^^ % ^^^^^^^^^^^^^^^^^^ = ^^^^^^^^ ^^^^^^^^ ^^^^^^^^^^^^ ^^^^ ^^^^^^^^ ^^^^^^^^^^^^^^^^ ^^^^. ^^^^ ^^^^ 0 ^^^^^^} ^^ 100. The half-life (t1/2) is calculated in GraphPad Prism software from % remaining vs. time regression using non-linear regression fit (one phase exponential decay with following constrain parameters: Span=100, Plateau=0, K=no constraint). The half-life and %remaining after 5 h is reported for the test compound and the reference compounds. For omeprazole, the % remaining at 5h should be ≤ 50% and the half-life < 5h. For Afatinib, the % remaining at 5h should be ≤ 35% and the half-life < 5h. For Ibrutinib, the % remaining 289 at 5h should be > 80% and the half-life > 5h. The % remaining in the buffer stability assay condition should be >80%. [0643] 1.9. Pharmacokinetic study in rodents 1.9.1. Animals [0644] Wistar-Han rats (male, 200-225g) are obtained from Janvier (France). [0645] CD-1 Mice (male, 25-30g) are obtained from Janvier (France). [0646] Animals are acclimatized for at least 7 days before treatment and are kept on a 12 h light/dark cycle (0700 - 1900). Temperature is maintained at approximately 22°C, and food and water are provided ad libitum. 1.9.2. Pharmacokinetic study [0647] Compounds are formulated in DMSO/10% hydroxylpropyl-β-cyclodextrine (5/95) for the intravenous route and in a suitable solution for the oral route. Test compounds are orally dosed as a single oesophageal gavage at 5 mg/kg under a dosing volume of 10 mL/kg (group of 3 animals) and intravenously dosed as a bolus via the caudal vein at 0.5 mg/kg under a dosing volume of 5 mL/kg. (groups of 2 animals). Blood samples are collected at the retro-orbital sinus with EDTA as anti-coagulant at the following time points: 0.05, 1, 3, 6 and 24 h (intravenous route), and 0.25, 1, 3, 6, and 24 h (oral route). Whole blood samples are centrifuged at 5000 rpm for 10 min and the resulting plasma samples are stored at -20°C pending analysis. 1.9.3. Quantification of compound levels in plasma [0648] Plasma concentrations of each test compound are determined by an LC-MS/MS method in which the mass spectrometer is operated in positive or negative electrospray mode. 1.9.4. Determination of pharmacokinetic parameters [0649] Pharmacokinetic parameters are calculated for each individual animal and for each analyte by non- compartmental analysis. 1.10. Liability for QT prolongation [0650] Potential for QT prolongation is assessed in the hERG manual patch clamp assay. 1.10.1. Manual patch clamp assay [0651] Single CHO cells are used for recording hERG currents at near physiological temperature (34- 35°C) using the whole-cell patch-clamp technique with an Axopatch 700A amplifier/pClamp software (Molecular Devices, Sunnyvale CA). [0652] Electrodes (5-7 MΩ resistance) are prepared from GC150-10 glass capillary tubes (Harvard Apparatus, Cambridge, UK) and filled with intracellular solution (in mM: KCl 120; Na₂ATP 4; HEPES 10; EGTA 10; MgCl₂1.75; CaCl₂5.374, pH 7.2 adjusted with KOH). 290 [0653] The patch-clamp recording chamber is perfused with control extracellular solution (in mM: NaCl 145; KCl 4; MgCl21; HEPES, 10; glucose 10; CaCl22 at pH 7.4 adjusted with NaOH). [0654] With the formation of a gigaohm seal, the cell membrane is ruptured to establish the whole-cell configuration. The minimum acceptable seal resistance is 1 gigaohm, and access resistance no greater than 20pF. [0655] The cell membrane is then voltage-clamped at a holding potential of -80 mV and depolarised to +20 mV for 2 sec followed by a negative pulse at -40mV for 1.6 sec, before returning to -80mV at a frequency of 0.1 Hz. [0656] Once the hERG current is stable, the perfusion is switched to extracellular solution containing test compounds starting from the lowest concentration. Each concentration on the 4pt concentration-response curve is tested for 4min to achieve steady state. 1.10.2. Automated patch clamp [0657] Electrophysiological recordings are made from a Chinese Hamster Ovary cell line stably expressing the full-length ion channel. Single cell ionic currents were measured in whole-cell configuration at room temperature (21-23⁰C) using a QPatch II (Sophion Bioscience). [0658] The internal solution for hERG contains (mM): 120 KCl, 20 KF, 10EGTA, 10 HEPES and is buffered to pH 7.3. [0659] The external solution (HEPES-buffered saline, HBPS) contains (mM): 138 NaCl, 4.5 KCl, 1.8 CaCl₂, 1.0 MgCl₂, 10 HEPES, 10 glucose, buffered to pH 7.4. [0660] Cells are clamped at a holding potential of -80mV before a step to +20mV for 500ms, and then - 40mV for 500ms. The test pulse is applied every 10 seconds. Currents are measured from the -40mV step and referenced to the holding current. [0661] Compounds are incubated for 120 seconds to allow stabilization of the parameters. Concentration- response curves are generated by cumulative addition of compound with concentrations low to high. FINAL REMARKS [0662] It will be appreciated by those skilled in the art that the foregoing descriptions are exemplary and explanatory in nature, and intended to illustrate the invention and its preferred embodiments. Through routine experimentation, an artisan will recognize apparent modifications and variations that may be made without departing from the spirit of the invention. All such modifications coming within the scope of the appended claims are intended to be included therein. Thus, the invention is intended to be defined not by the above description, but by the following claims and their equivalents. [0663] All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication are specifically and individually indicated to be incorporated by reference herein as though fully set forth. 291 [0664] It should be understood that factors such as the differential cell penetration capacity of the various compounds can contribute to discrepancies between the activity of the compounds in the in vitro biochemical and cellular assays. [0665] At least some of the chemical names of compound of the invention as given and set forth in this application, may have been generated on an automated basis by use of a commercially available chemical naming software program, and have not been independently verified. Representative programs performing this function include the Lexichem naming tool sold by Open Eye Software, Inc. and the Autonom Software tool sold by MDL, Inc. and Chemdraw 20 by PerkinElmer Informatics Inc. [0666] In the instance where the indicated chemical name and the depicted structure differ, the depicted structure will control.

Claims

292 CLAIMS 1. A compound of Formula (I): wherein: X1 is N or CH; X2 is N and X3 is C, or, alternatively, X3 is N and X2 is C; X4 is N or CR⁴; Y is a bond, O or NH; Y1 is a bond, CHR⁶, CH2-CHR⁶, CHR⁶-CH2, CF2, CH2-CF2 or CF2-CH2; Y2 is CR⁴R⁵ or CF2; Y3 is CR³R⁴, CR3R4CR3R4, CH2CF2 or CF2; when X4 is N, B is a bond, -C(O)Y⁴-, -Y⁴-, -CH2Y⁴-, or -CH2CH2Y⁴-, and A is CN, R⁸R⁹C=CR¹⁰C(=O)-, R¹¹R¹²NCH2CH=CHC(=O)-, H2C=CHSO2- or R¹³C≡CC(=O)-; when X4 is CR⁴, B is a bond, and A is -NR⁴-CN, R⁸R⁹C=CR¹⁰C(=O)R⁴N-, R¹¹R¹²NCH2CH=CHC(=O)R⁴N- , H2C=CHSO2-R⁴N- or R¹³C≡CC(=O)-R⁴N-; Y⁴ is a 4-7 membered heterocycloalkyl comprising a nitrogen atom or C3-7 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; R¹ is 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 C_1-5 alkyl and C_1-5 alkoxy, are unsubstituted or independently substituted with one or more substituents independently selected from halogen, CN, hydroxyl and methoxy; R² is hydrogen, hydroxyl, C_1-4 alkyl, CN, -CONHC_1-4 alkyl, or C_1-4 haloalkyl; 293 each R³ is independently selected from hydrogen, fluoro, hydroxyl, methoxy, C1-3 alkyl, cyclopropyl, or a R³ is fused with R⁵ or R⁶ to form CH2, CH2-CH2 or CH2OCH2; each R⁴ is independently selected from hydrogen and C1-3 alkyl; R⁵ is hydrogen, fluoro, hydroxyl, methoxy, C1-3 alkyl, cyclopropyl or is fused with one R³ to 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, -CO2R⁴ or C1-3 alkoxy; R⁶ is hydrogen, fluoro, hydroxyl, methoxy, C1-3 alkyl or is fused with one R³ to form CH2, CH2-CH2 or CH2OCH2; each R⁸ is independently selected from hydrogen and C1-6 alkyl; each R⁹ is 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 C1-6 alkoxy; and R¹⁰ is hydrogen, C1-3 alkyl or halogen; or R⁹ and R¹⁰ together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring; each of R¹¹ and R¹² is independently hydrogen, C_1-6 alkyl, or R¹¹ and R¹² together 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; R¹³ is hydrogen, R¹⁴R¹⁵NCH₂-, or C_1-3 alkyl which is unsubstituted or substituted with hydroxyl; R¹⁴ and R¹⁵ are each independently hydrogen or C_1-6 alkyl; R¹⁶ is C_1-3 alkyl-R¹⁷, C_3-6 cycloalkyl-R¹⁷ or a 4-6 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein the C_1-3 alkyl, C_3-6 cycloalkyl and 4-6 membered heterocycloalkyl are unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, CN, C_1-4 alkyl, C_3-6 cycloalkyl, OH, OMe, -NR⁴R⁸ wherein R⁴ and R⁸ are as defined above, or, alternatively, R⁴ and R⁸ together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring; R¹⁷ is hydrogen, aryl, heteroaryl, 4-6 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, O and S, or C_3-8 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, C_1-4 alkyl, and C_1-4 haloalkyl, C_1-4 alkoxy, and C_1-4 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 X₁ is CH. 3. The compound, or a pharmaceutically acceptable salt and/or solvate thereof, according to claim 1 or claim 2, wherein X2 is C and X3 is N.

294 4. The compound, or a pharmaceutically acceptable salt and/or solvate thereof, according to any preceding claim, wherein X4 is N or CH. 5. The compound, or a pharmaceutically acceptable salt and/or solvate thereof, according to any preceding claim, wherein X4 is N, B is a bond, -C(O)Y⁴-, -Y⁴- or -CH2Y⁴-, and A is CN or R⁸R⁹C=CR¹⁰C(=O)-, wherein Y⁴ is 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; or wherein X4 is 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 claim, wherein R¹ is 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 claim, wherein R² is hydrogen, hydroxyl or C_1-2 alkyl. 8. The compound, or a pharmaceutically acceptable salt and/or solvate thereof, according to any preceding claim, wherein Y is O. 9. The compound, or a pharmaceutically acceptable salt and/or solvate thereof, according to any preceding claim, wherein R¹⁶ is C_1-3 alkyl-R¹⁷, wherein the C_1-3 alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, C_1-2 alkyl, C_3-6 cycloalkyl, OH and OMe. 10. The compound, or a pharmaceutically acceptable salt and/or solvate thereof, according to any preceding claim, wherein R¹⁷ is hydrogen, phenyl, pyridyl, pyridazinyl, isoquinolinyl, tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, or C_3-7 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, C_1-2 alkyl, and C_1-2 haloalkyl, C_1-2 alkoxy, and C_1-2 haloalkoxy. 11. The compound, or a pharmaceutically acceptable salt and/or solvate thereof, according to any preceding claim, wherein R¹⁶ is selected from:

295 12. The compound, or a pharmaceutically acceptable salt and/or solvate thereof, according to any preceding claim, wherein X₄ is N, B is a bond or is selected from , , , 13. The compound, or a pharmaceutically acceptable salt and/or solvate thereof, according to any preceding claim, wherein R¹⁷ is 2-pyridyl which is unsubstituted or substituted with one or two halogens (preferably fluoro).

296 14. The compound, or a pharmaceutically acceptable salt and/or solvate thereof, according to any preceding claim, wherein R² is methyl. 15. The compound, or a pharmaceutically acceptable salt and/or solvate thereof, according to claim 1, wherein X1 is CH; X2 is C and X3 is N or X2 is N and X3 is C; X4 is N or CH; Y is O; Y1 is CH2; Y2 is CHR⁵; Y3 is CH2 or CH2CH2; when X4 is N, B is a bond or is selected from hydrogen, methyl or halogen (preferably fluoro); when X₄ is CH, B is a bond and A is -NH-CN, R¹ is hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, cyano, CF₃, CHF₂, OCH₃ or OCHF₂; R² is hydrogen, methyl or ethyl; R⁵ is hydrogen or C_1-3 alkyl, wherein the C_1-3 alkyl is unsubstituted or substituted with a substituent selected from pyridyl, phenyl, and -CO₂H; 297 R¹⁶ is selected from: R¹⁷ is 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 claim 1, wherein the compound is selected from:

302 . 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 claims 1-16. 18. A compound, or a pharmaceutically acceptable salt and/or solvate thereof, according to any one of claims 1-16, or a pharmaceutical composition according to claim 17, for use in medicine. 19. A compound, or a pharmaceutically acceptable salt and/or solvate thereof, according to any one of claims 1-16, or a pharmaceutical composition according to claim 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 claims 1-16, or a pharmaceutical composition according to claim 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, 303 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, 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. 21. A compound of Formula (Ia-5): 304 wherein: X1 is N or CH; X2 is N and X3 is C, or, alternatively, X3 is N and X2 is C; Y is a bond, O or NH; Y1 is a CHR⁶, CH2-CHR⁶, CHR⁶-CH2, CH2-CF2 or CF2-CH2; Y2 is CR⁴R⁵ or CF2; Y3 is CR³R⁴, CH2CR³R⁴, CH2CF2 or CF2; wherein Y1, Y2 and Y3 together with N atom of N-A and the pyrazolyl ring form a 7-membered nitrogen containing ring; A is CN, R⁸R⁹C=CR¹⁰C(=O)-, R¹¹R¹²NCH2CH=CHC(=O)-, H2C=CHSO2-, R¹³C≡CC(=O)- or R²³CH=CH- SO2- wherein R²³ is H or C1-2alkyl; R¹ is 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 C_1-5 alkyl and C_1-5 alkoxy, are unsubstituted or independently substituted with one or more substituents independently selected from halogen, CN, hydroxyl and methoxy; R² is hydrogen, hydroxyl, C_1-4 alkyl, CN, -CONHC_1-4 alkyl, or C_1-4 haloalkyl; each R³ is independently selected from hydrogen, fluoro, hydroxyl, methoxy, C_1-3 alkyl, cyclopropyl, or a R³ is fused with R⁵ or R⁶ to form CH₂, CH₂-CH₂ or CH₂OCH₂; each R⁴ is independently selected from hydrogen and C_1-3 alkyl; R⁵ is hydrogen, fluoro, hydroxyl, methoxy, C_1-3 alkyl, cyclopropyl or is fused with one R³ to form CH₂, CH₂-CH₂ or CH₂OCH₂, wherein the C_1-3 alkyl is unsubstituted or independently substituted with one or more substituents independently selected from halogen, heteroaryl (which heteroaryl is preferably pyridyl), phenyl, hydroxyl, -CO₂R⁴ or C_1-3 alkoxy; R⁶ is hydrogen, fluoro, hydroxyl, methoxy, C_1-3 alkyl or is fused with one R³ to form CH₂, CH₂-CH₂ or CH₂OCH₂; each R⁸ is independently selected from hydrogen and C_1-6 alkyl; 305 each R⁹ is 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 C1-6 alkoxy; and R¹⁰ is hydrogen, C1-3 alkyl or halogen; or R⁹ and R¹⁰ together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring; each of R¹¹ and R¹² is independently hydrogen, C1-6 alkyl, or R¹¹ and R¹² together 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; R¹³ is hydrogen, R¹⁴R¹⁵NCH2-, or C1-3 alkyl which is unsubstituted or substituted with hydroxyl; R¹⁴ and R¹⁵ are each independently hydrogen or C1-6 alkyl; R¹⁶ is C1-3 alkyl-R¹⁷, C3-6 cycloalkyl-R¹⁷ or 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, -NR⁴R⁸ wherein R⁴ and R⁸ are as defined above, or, alternatively, R⁴ and R⁸ together 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 C_1-3 alkyl, C_3-6 cycloalkyl and 4-6 membered heterocycloalkyl group such that an oxygen-containing heterocyclyl forms; R¹⁷ is hydrogen, aryl, heteroaryl, 4-6 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, O and S, or C_3-8 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, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 alkoxy, and C_1-4 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, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 alkoxy, and C_1-4 haloalkoxy; or a pharmaceutically acceptable salt and/or solvate thereof. 22. The compound according to claim 21 which is a compound of Formula (Ia-6): wherein: 306 X1 is N or CH; X2 is N and X3 is C, or, alternatively, X3 is N and X2 is C; Y is a bond, O or NH; Y1 is a CHR⁶; Y2 is CR⁴R⁵ or CF2; Y3 is CH2CR³R⁴; A is CN, R⁸R⁹C=CR¹⁰C(=O)-, R¹¹R¹²NCH2CH=CHC(=O)-, H2C=CHSO2- or R¹³C≡CC(=O)-; R¹ is 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; R² is hydrogen, hydroxyl, C1-4 alkyl, CN, -CONHC1-4 alkyl, or C1-4 haloalkyl; each R³ is independently selected from hydrogen, fluoro, hydroxyl, methoxy, C1-3 alkyl, cyclopropyl, or a R³ is fused with R⁵ or R⁶ to form CH₂, CH₂-CH₂ or CH₂OCH₂; each R⁴ is independently selected from hydrogen and C_1-3 alkyl; R⁵ is hydrogen, fluoro, hydroxyl, methoxy, C_1-3 alkyl, cyclopropyl or is fused with one R³ to form CH₂, CH₂-CH₂ or CH₂OCH₂, wherein the C_1-3 alkyl is unsubstituted or independently substituted with one or more substituents independently selected from halogen, heteroaryl (which heteroaryl is preferably pyridyl), phenyl, hydroxyl, -CO₂R⁴ or C_1-3 alkoxy; R⁶ is hydrogen, fluoro, hydroxyl, methoxy, C_1-3 alkyl or is fused with one R³ to form CH₂, CH₂-CH₂ or CH₂OCH₂; each R⁸ is independently selected from hydrogen and C_1-6 alkyl; each R⁹ is independently selected from hydrogen, CF₃ and C_1-6 alkyl, which alkyl is unsubstituted or substituted with one or more substituents independently selected from fluoro, chloro, bromo, hydroxyl, and C_1-6 alkoxy; and R¹⁰ is hydrogen, C_1-3 alkyl or halogen; or R⁹ and R¹⁰ together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring; each of R¹¹ and R¹² is independently hydrogen, C_1-6 alkyl, or R¹¹ and R¹² together 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; R¹³ is hydrogen, R¹⁴R¹⁵NCH₂-, or C_1-3 alkyl which is unsubstituted or substituted with hydroxyl; R¹⁴ and R¹⁵ are each independently hydrogen or C_1-6 alkyl; R¹⁶ is C1-3 alkyl-R¹⁷, C3-6 cycloalkyl-R¹⁷ or 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 4-6 307 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, -NR⁴R⁸ wherein R⁴ and R⁸ are as defined above, or, alternatively, R⁴ and R⁸ together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring; R¹⁷ is 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, 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 C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; or a pharmaceutically acceptable salt and/or solvate thereof. 23. The compound according to claim 21 or claim 22 wherein X1 is CH. 24. The compound according to any one of claims 21 to 23 wherein X3 is N and X2 is C. 25. The compound according to any one of claims 21 to 24 wherein Y is O. 26. The compound according to any one of claims 21 to 25 wherein Y₁ is a CH₂, Y₂ is CH₂ and Y₃ is CH₂CH₂. 27. The compound according to any one of claims 21 to 26 wherein A is CN or R⁸R⁹C=CR¹⁰C(=O)-. - 28. The compound according to claim 27 wherein A is CN. 29. The compound according to any one of claims 21 to 28 wherein R¹ is halogen e.g. chloro. - 30. The compound according to any of claims 21 to 28 wherein R¹ is C_1-5 alkoxy, wherein the C_1-5 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. 31. The compound according to any one of claims 21 to 30 wherein R² is C_1-4 alkyl e.g. methyl. 32. The compound according to any one of claims 21 to 31 wherein R³, R⁴, R⁵ and R⁶ are hydrogen. 33. The compound according to any one of claims 21 to 32 wherein R¹⁶ is C_1-3 alkyl-R¹⁷ wherein the C_1-3 alkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, CN, C_1-4 alkyl, C_3-6 cycloalkyl, OH, OMe, -NR⁴R⁸ wherein R⁴ and R⁸ are as defined above, or, alternatively, R⁴ and R⁸ together 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.

308 34. The compound according to any one of claims 21 to 33 wherein R¹⁷ is aryl, heteroaryl or 4-6 membered heterocycloalkyl. 35. The compound according to claim 34 wherein R¹⁷ is selected from the group consisting of pyrazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl e.g. pyridinyl. 36. The compound according to any one of claims 21 to 35 which is selected from the group consisting of: 2-(3-chloro-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1; 2-(3-chloro-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2; 2-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile; 1-(2-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one; 2-(3-chloro-4-(1-(6-fluoropyridin-3-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile; 2-(3-chloro-4-(1-(6-cyanopyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile; 2-(3-chloro-4-(1-(1-methyl-1H-pyrazol-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile; 2-(4-(1-(1,3,4-oxadiazol-2-yl)ethoxy)-3-chloropyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile; 2-(3-chloro-4-(1-(pyrimidin-5-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro-6H- pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile; 2-(3-chloro-4-(1-(6-methylpyridin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile; 2-(3-(difluoromethoxy)-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile; (R)-2-(3-chloro-4-(1-(pyridin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro- 6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile; 2-(3-chloro-4-(1-(6-cyanopyridin-3-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile; 2-(3-chloro-4-(1-(3-cyanophenyl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro-6H- pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile; 309 2-(3-chloro-4-(1-(1-methyl-1H-pyrazol-4-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile; 2-(4-(1-(6-aminopyridin-2-yl)ethoxy)-3-chloropyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile; 2-(3-chloro-4-(1-(pyridazin-4-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro-6H- pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile; 2-(3-chloro-4-(1-(6-methylpyridazin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile; 2-(3-(difluoromethoxy)-4-(2-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile; 2-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1; 2-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2; 1-(2-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 1; 1-(2-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 2; (R)-2-(3-chloro-4-(1-(pyridin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro- 6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile; 2-(3-chloro-4-(1-(6-fluoropyridin-3-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1; 2-(3-chloro-4-(1-(6-fluoropyridin-3-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2; 2-(3-chloro-4-(1-(6-cyanopyridin-3-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1; 2-(3-chloro-4-(1-(6-cyanopyridin-3-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2; 2-(3-chloro-4-(1-(3-cyanophenyl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro-6H- pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1; 2-(3-chloro-4-(1-(3-cyanophenyl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro-6H- pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2; 2-(3-chloro-4-(1-(3-cyanophenyl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro-6H- pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1; 2-(3-chloro-4-(1-(3-cyanophenyl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro-6H- pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2; 310 2-(4-(1-(6-aminopyridin-2-yl)ethoxy)-3-chloropyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1; 2-(4-(1-(6-aminopyridin-2-yl)ethoxy)-3-chloropyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2; 2-(3-chloro-4-(1-(1-methyl-1H-pyrazol-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1; 2-(3-chloro-4-(1-(1-methyl-1H-pyrazol-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2 2-(4-(1-(1,3,4-oxadiazol-2-yl)ethoxy)-3-chloropyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1; 2-(4-(1-(1,3,4-oxadiazol-2-yl)ethoxy)-3-chloropyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2; 2-(3-chloro-4-(1-(pyrimidin-5-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro-6H- pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1; 2-(3-chloro-4-(1-(pyrimidin-5-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro-6H- pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2; 2-(3-chloro-4-(1-(6-methylpyridazin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1; 2-(3-chloro-4-(1-(6-methylpyridazin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2; 2-(3-chloro-4-(1-(6-methylpyridin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1; 2-(3-chloro-4-(1-(6-methylpyridin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2; 2-(3-chloro-4-(1-(1-methyl-1H-pyrazol-4-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1; 2-(3-chloro-4-(1-(1-methyl-1H-pyrazol-4-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2; 2-(3-chloro-4-(1-(pyridazin-4-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro-6H- pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1; 2-(3-chloro-4-(1-(pyridazin-4-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro-6H- pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2; 2-(3-chloro-4-(1-(pyrimidin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro-6H- pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1; 2-(3-chloro-4-(1-(pyrimidin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro-6H- pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2; 311 2-(3-chloro-4-(1-(5-(difluoromethyl)pyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1; 2-(3-chloro-4-(1-(5-(difluoromethyl)pyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2 2-(3-chloro-4-(1-(5-methoxypyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1; 2-(3-chloro-4-(1-(5-methoxypyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2; 2-(3-chloro-4-(1-(isoquinolin-1-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro- 6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1; 2-(3-chloro-4-(1-(isoquinolin-1-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro- 6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2; 2-(3-chloro-4-(1-(5-methylpyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1; 2-(3-chloro-4-(1-(5-methylpyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2; 1-(2-(3-chloro-4-(1-(5-methylpyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 1; 1-(2-(3-chloro-4-(1-(5-methylpyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 2; 2-(3-chloro-4-(1-(pyridazin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro-6H- pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1; 2-(3-chloro-4-(1-(pyridazin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro-6H- pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2; 1-(2-(3-chloro-4-(1-(pyridazin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro- 6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 1; 1-(2-(3-chloro-4-(1-(pyridazin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro- 6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 2; 2-(3-chloro-4-(1-(pyrazin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro-6H- pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1; 2-(3-chloro-4-(1-(pyrazin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro-6H- pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2; 1-(2-(3-chloro-4-(1-(pyrazin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro-6H- pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 1; 1-(2-(3-chloro-4-(1-(pyrazin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8-tetrahydro-6H- pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 2; 312 2-(3-chloro-4-(2-hydroxy-2-(1-methyl-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1; 2-(3-chloro-4-(2-hydroxy-2-(1-methyl-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2; 2-(3-chloro-4-(2-hydroxy-2-(1-methyl-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 3; 2-(3-chloro-4-(2-hydroxy-2-(1-methyl-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 4; 2-(3-chloro-4-(2-hydroxy-2-(tetrahydrofuran-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1; 2-(3-chloro-4-(2-hydroxy-2-(tetrahydrofuran-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2; 2-(3-chloro-4-(2-hydroxy-2-(tetrahydrofuran-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 3; 2-(3-chloro-4-(2-hydroxy-2-(tetrahydrofuran-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 4; 2-(3-chloro-4-(2-hydroxy-2-(5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1; 2-(3-chloro-4-(2-hydroxy-2-(5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2; 2-(3-chloro-4-(2-hydroxy-2-(5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 3; 2-(3-chloro-4-(2-hydroxy-2-(5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 4; 2-(4-((2R)-1-(5-fluoropyridin-2-yl)-2-hydroxypropoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1; 2-(4-((2R)-1-(5-fluoropyridin-2-yl)-2-hydroxypropoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2; 1-(2-(4-((2R)-1-(5-fluoropyridin-2-yl)-2-hydroxypropoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 1; 1-(2-(4-((2R)-1-(5-fluoropyridin-2-yl)-2-hydroxypropoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 2; 2-(4-((2S)-1-(5-fluoropyridin-2-yl)-2-hydroxypropoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1; 2-(4-((2S)-1-(5-fluoropyridin-2-yl)-2-hydroxypropoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2; 313 1-(2-(4-((2S)-1-(5-fluoropyridin-2-yl)-2-hydroxypropoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 1; 1-(2-(4-((2S)-1-(5-fluoropyridin-2-yl)-2-hydroxypropoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 2; 2-(3-chloro-4-((2-(5-fluoropyridin-2-yl)tetrahydrofuran-2-yl)methoxy)pyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1; 2-(3-chloro-4-((2-(5-fluoropyridin-2-yl)tetrahydrofuran-2-yl)methoxy)pyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2; 1-(2-(3-chloro-4-((2-(5-fluoropyridin-2-yl)tetrahydrofuran-2-yl)methoxy)pyrazolo[1,5-a]pyridin-6-yl)- 3-methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 1; 1-(2-(3-chloro-4-((2-(5-fluoropyridin-2-yl)tetrahydrofuran-2-yl)methoxy)pyrazolo[1,5-a]pyridin-6-yl)- 3-methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 2; 2-(3-(difluoromethoxy)-4-(2-(5-fluoropyridin-2-yl)-2-hydroxypropoxy)pyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1; 2-(3-(difluoromethoxy)-4-(2-(5-fluoropyridin-2-yl)-2-hydroxypropoxy)pyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2; 1-(2-(3-(difluoromethoxy)-4-(2-(5-fluoropyridin-2-yl)-2-hydroxypropoxy)pyrazolo[1,5-a]pyridin-6-yl)- 3-methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 1; 1-(2-(3-(difluoromethoxy)-4-(2-(5-fluoropyridin-2-yl)-2-hydroxypropoxy)pyrazolo[1,5-a]pyridin-6-yl)- 3-methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 2; 2-(3-chloro-4-((2-(5-fluoropyridin-2-yl)oxetan-2-yl)methoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1; 2-(3-chloro-4-((2-(5-fluoropyridin-2-yl)oxetan-2-yl)methoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2; 1-(2-(3-chloro-4-((2-(5-fluoropyridin-2-yl)oxetan-2-yl)methoxy)pyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 1; 1-(2-(3-chloro-4-((2-(5-fluoropyridin-2-yl)oxetan-2-yl)methoxy)pyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 2; 2-(3-chloro-4-(1-(1-methylpyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1; 2-(3-chloro-4-(1-(1-methylpyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2; 2-(3-chloro-4-(1-(1-methylpyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 3; 2-(3-chloro-4-(1-(1-methylpyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 4; 314 2-(3-(difluoromethoxy)-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1; 2-(3-(difluoromethoxy)-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3- methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2; 1-(2-(3-(difluoromethoxy)-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)- 3-methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 1; 1-(2-(3-(difluoromethoxy)-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)- 3-methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 2; 2-(4-(1-(6-aminopyridin-2-yl)-2-hydroxyethoxy)-3-chloropyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1; 2-(4-(1-(6-aminopyridin-2-yl)-2-hydroxyethoxy)-3-chloropyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2; 1-(2-(4-(1-(6-aminopyridin-2-yl)-2-hydroxyethoxy)-3-chloropyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 1; 1-(2-(4-(1-(6-aminopyridin-2-yl)-2-hydroxyethoxy)-3-chloropyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 2; 2-(4-(1-(5-chloropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1; 2-(4-(1-(5-chloropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2; 1-(2-(4-(1-(5-chloropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 1; 1-(2-(4-(1-(5-chloropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one, Isomer 2; 2-(3-chloro-4-(1-(1,1-dioxidotetrahydrothiophen-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 1; 2-(3-chloro-4-(1-(1,1-dioxidotetrahydrothiophen-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 2; 2-(3-chloro-4-(1-(1,1-dioxidotetrahydrothiophen-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 3; 2-(3-chloro-4-(1-(1,1-dioxidotetrahydrothiophen-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile, Isomer 4; 2-(3-chloro-4-(2-hydroxy-1-(pyridin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile; 1-(2-(3-chloro-4-(2-hydroxy-1-(pyridin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one; 315 2-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl-7,8- dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carbonitrile; 1-(2-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)prop-2-en-1-one; 1-(2-(4-((1,3-dihydroisobenzofuran-4-yl)methoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one; 2-(4-(2-hydroxy-1-(tetrahydrofuran-3-yl)ethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile; 1-(2-(4-(2-hydroxy-1-(tetrahydrofuran-3-yl)ethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl- 4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one; 1-(2-(4-((2,2-dioxido-1,3-dihydrobenzo[c]isothiazol-4-yl)methoxy)-3-methoxypyrazolo[1,5-a]pyridin- 6-yl)-3-methyl-4,5,7,8-tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one; 1-(2-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepin-6-yl)prop-2-en-1-one; 2-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-4,5,7,8- tetrahydro-6H-pyrazolo[1,5-d][1,4]diazepine-6-carbonitrile; and (E)-2-(5-fluoropyridin-2-yl)-2-((3-methoxy-6-(3-methyl-6-(prop-1-en-1-ylsulfonyl)-5,6,7,8-tetrahydro- 4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethan-1-ol; or a pharmaceutically acceptable salt and/or solvate thereof. 37. 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 21-36. 38. A compound, or a pharmaceutically acceptable salt and/or solvate thereof, according to any one of claims 21-36, or a pharmaceutical composition according to claim 37, for use in medicine. - 39. A compound, or a pharmaceutically acceptable salt and/or solvate thereof, according to any one of claims 21-36, or a pharmaceutical composition according to claim 37, 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. 40. A compound, or a pharmaceutically acceptable salt and/or solvate thereof, according to any one of claims 21-36, or a pharmaceutical composition according to claim 37, 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 316 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, 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), 317 thyroid cancer, renal cancer (e.g. renal pelvis cancer), glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer. 41. A compound of Formula (Ib-3): (Ib-3) wherein: X1 is N or CH; X2 is N and X3 is C, or, alternatively, X3 is N and X2 is C; Y is a bond, O or NH; Y1 is a bond, CHR⁶, CH2-CHR⁶, CHR⁶-CH2, CF2, CH2-CF2 or CF2-CH2; Y2 is CR⁴R⁵ or CF2; Y3 is CR³R⁴, CR³R⁴CR³R⁴, CH2CF2 or CF2; A is -NR⁴-CN, R⁸R⁹C=CR¹⁰C(=O)R⁴N-, R¹¹R¹²NCH2CH=CHC(=O)R⁴N-, H2C=CHSO2-R⁴N- or R¹³C≡CC(=O)-R⁴N-; R¹ is 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; R² is hydrogen, hydroxyl, C_1-4 alkyl, CN, -CONHC_1-4 alkyl, or C_1-4 haloalkyl; each R³ is independently selected from hydrogen, fluoro, hydroxyl, methoxy, C_1-3 alkyl, cyclopropyl, or a R³ is fused with R⁵ or R⁶ to form CH₂, CH₂-CH₂ or CH₂OCH₂; each R⁴ is independently selected from hydrogen and C_1-3 alkyl; R⁵ is hydrogen, fluoro, hydroxyl, methoxy, C_1-3 alkyl, cyclopropyl or is fused with one R³ to form CH₂, CH₂-CH₂ or CH₂OCH₂, wherein the C_1-3 alkyl is unsubstituted or independently substituted with one or more substituents independently selected from halogen, heteroaryl (which heteroaryl is preferably pyridyl), phenyl, hydroxyl, -CO₂R⁴ or C_1-3 alkoxy; R⁶ is hydrogen, fluoro, hydroxyl, methoxy, C_1-3 alkyl or is fused with one R³ to form CH₂, CH₂-CH₂ or CH₂OCH₂; 318 each R⁸ is independently selected from hydrogen and C1-6 alkyl; each R⁹ is 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 C1-6 alkoxy; and R¹⁰ is hydrogen, C1-3 alkyl or halogen; or R⁹ and R¹⁰ together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring; each of R¹¹ and R¹² is independently hydrogen, C1-6 alkyl, or R¹¹ and R¹² together 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; R¹³ is hydrogen, R¹⁴R¹⁵NCH2-, or C1-3 alkyl which is unsubstituted or substituted with hydroxyl; R¹⁴ and R¹⁵ are each independently hydrogen or C1-6 alkyl; R¹⁶ is C1-3 alkyl-R¹⁷, C3-6 cycloalkyl-R¹⁷ or 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, -NR⁴R⁸ wherein R⁴ and R⁸ are as defined above, or, alternatively, R⁴ and R⁸ together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring; R¹⁷ is hydrogen, aryl, heteroaryl, 4-6 membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, O and S, or C_3-8 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, C_1-4 alkyl, and C_1-4 haloalkyl, C_1-4 alkoxy, and C_1-4 haloalkoxy; or a pharmaceutically acceptable salt and/or solvate thereof. 42. The compound according to claim 41 wherein X₁ is CH. 43. The compound according to claim 41 or claim 42 wherein X₃ is N and X₂ is C. 44. The compound according to any one of claims 41 to 43 wherein Y is O. 45. The compound according to any one of claims 41 to 44 wherein Y₁ is a CH₂, Y₂ is CH₂ and Y₃ is CH₂. - 46. The compound according to any one of claims 41 to 44 wherein Y₁ is a CH₂, Y₂ is CH₂ and Y₃ is CH₂CH₂. 47. The compound according to any one of claims 41 to 46 wherein A is NR⁴-CN, preferably NH-CN.

319 48. The compound according to any one of claims 41 to 47 wherein R¹ is halogen e.g. chloro. 49. The compound according to any one of claims 41 to 48 wherein R² is C1-4 alkyl e.g. methyl. 50. The compound according to any one of claims 41 to 49 wherein R³, R⁴, R⁵ and R⁶ are hydrogen. 51. The compound according to any one of claims 41 to 50 wherein R¹⁶ is unsubstituted C1-3 alkyl-R¹⁷. 52. The compound according to any one of claims 41 to 51 wherein R¹⁶ is C1-3 alkyl-R¹⁷ substituted by one OH group. 53. The compound according to any one of claims 41 to 52 wherein R¹⁷ is unsubstituted heteroaryl. - 54. The compound according to any one of claims 41 to 53 wherein R¹⁷ is heteroaryl substituted by one or more halo. 55. The compound according to claim 54 wherein R¹⁷ is pyridinyl substituted by fluoro. 56. The compound according to any one of claims 41 to 55 which is selected from the group consisting 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, Isomer 1; 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, Isomer 2; 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, Isomer 3; 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, Isomer 4; N-(3'-chloro-3-hydroxy-4'-((R)-1-(pyridin-2-yl)ethoxy)-4,5,6,7-tetrahydro-[2,6'-bipyrazolo[1,5- a]pyridin]-5-yl)cyanamide, Isomer 1; and N-(3'-chloro-3-hydroxy-4'-((R)-1-(pyridin-2-yl)ethoxy)-4,5,6,7- tetrahydro-[2,6'-bipyrazolo[1,5-a]pyridin]-5-yl)cyanamide, Isomer 2; N-(2-(4-((S)-1-(5-fluoropyridin-2- yl)-2-hydroxyethoxy)-3-methoxypyrazolo[1,5-a]pyridin-6-yl)-3-methyl-5,6,7,8-tetrahydro-4H- pyrazolo[1,5-a]azepin-6-yl)cyanamide, isomer 1 and 2; or a pharmaceutically acceptable salt and/or solvate thereof. 57. 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 41-56.

320 58. A compound, or a pharmaceutically acceptable salt and/or solvate thereof, according to any one of claims 41-56, or a pharmaceutical composition according to claim 56, for use in medicine. 59. A compound, or a pharmaceutically acceptable salt and/or solvate thereof, according to any one of claims 41-56, or a pharmaceutical composition according to claim 56, 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. 60. A compound, or a pharmaceutically acceptable salt and/or solvate thereof, according to any one of claims 41-56, or a pharmaceutical composition according to claim 56, 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 321 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, 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.