Pyrazolopyridine and imidazopyridine derivatives useful as FGFR3 inhibitor compounds

Abstract

The present disclosure provides compounds of the formula: for use in the treatment of systemic sclerosis, fibrosis (e.g. pulmonary fibrosis), achondroplasia, thanatophoric dysplasia (e.g. type I), severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), muenke syndrome or cancer.

Description

120039.000206 (TYRA.042PCT)FGFR3 INHIBITOR COMPOUNDSCross Reference to Related Application

[0001] This application claims the benefit of U.S. Provisional Application No.63 / 739,191, filed December 27, 2024, the entirety of which is incorporated by reference herein.Background

[0002] Fibroblast growth factor (FGF) has been recognized as an important mediator of many physiological processes, such as morphogenesis during development, fibrosis, andangiogenesis. The fibroblast growth factor receptor (FGFR) family consists of five members four of which (FGFR 1-4) are glycoproteins composed of extracellular immunoglobulin (Ig)-like domains, a hydrophobic transmembrane region and a cytoplasmic part containing a tyrosine kinase domain. FGF binding leads to FGFR dimerization, followed by receptor autophosphorylation and activation of downstream signaling pathways. Receptor activation is sufficient for the recruitment and activation of specific downstream signaling partners that participate in the regulation of diverse processes such as cell growth, cell metabolism and cell survival. Thus, the FGF / FGFR signaling pathway has pleiotropic effects on many biological processes critical to tumor cell proliferation, migration, invasion, and angiogenesis.Summary

[0003] Provided herein are compounds of the formula:Formula Ior a pharmaceutically acceptable salt thereof, wherein A, X1, X2, X3, X4, Y, Y1, Y2, Y3, Y4, Z, Z1, R2and R6are as defined herein.

[0004] Provided herein are pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, with one or more120039.000206 (TYRA.042PCT)pharmaceutically acceptable carriers, diluents, or excipients. Provided herein are methods of using the compounds of formula (I), or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions thereof, to treat systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, thanatophoric dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), muenke syndrome or proliferative disorders such as cancer, particularly to treat FGFR3 -associated cancer. The methods include administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to a patient in need.Description

[0005] Provided herein are compounds believed to have clinical use for the treatment of systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, thanatophoric dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), muenke syndrome, proliferative disorders such as cancer and particularly for the treatment of FGFR3 -associated cancer.

[0006] Certain compounds provided herein have superior FGFR3 potency compared to certain previously known FGFR inhibitors. Certain compounds provided herein have superior selectivity for FGFR3 over FGFR1 compared to certain previously known FGFR inhibitors, reducing potential dose limiting toxicity caused by inhibition of FGFR1 ( e.g. hyperphosphatemia).

[0007] The compounds provided herein are of formula:Formula IwhereinA is pyrazole, triazole, thiadiazole or oxadiazole, substituted with R1 and RIA; R1is hydrogen or C1-C3 alkyl;R1Ais hydrogen, halo, CN, or C1-C3 alkyl optionally substituted with one or more substituents independently selected from halo, OH, and OCH3;X1and X2are independently selected from N and C, wherein when one of X1or X2is N the other is C;2120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)X3is N or CH;X4is N or C-R9;Y is NH, 0, S or a bond;Y1is a bond, CHR7, CH2-CHR7, CHR7-CH2, CF2, CH2-CF2 or CF2-CH2;Y2is a bond, CHR3, CH2-CHR3, CHR3-CH2, CF2, CH2-CF2 or CF2-CH2;Y3is CH2OC1-C3- alkyl, preferably CH2OCH3;Y4is CR3R4, or CF2;Z is a bond, CHR9A, CR4R4A, CR4R4A-CH2, CH2-CR4R4A, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo(l.l.l )pentane, bicyclo(2.1.1)hexane, azetidine, pyrrolidine or piperidine;Z1is a bond when Z is a bond, CR4R4A, CR4R4A-CH2, CH2-CR4R4A, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo(l.l.l )pentane, bicyclo(2.1.1 )hexane, azetidine, pyrrolidine or piperidine, or Z1is CH2 or CH2-CH2 when Z is CHR9A;Z2is a bond, C(O), SO2 or -NR4C(O);Z3is a bond, C(O), SO2 or -NR4C(O);R2is C1-C5 alkyl or R8, wherein C1-C5 alkyl is optionally substituted with one or more substituents independently selected from halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-Cs cycloalkyl, -Z2-Rnand R10, wherein C1-C4 alky and C3-C5 cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine and CN;R3is hydrogen, F, OH, OCH3, C1-C3 alkyl, cyclopropyl, or one R3is fused with R5or R7to form CH2, CH2-CH2 or CH2OCH2;R4is hydrogen or C1-C3 alkyl;R4Ais hydrogen, halo, OH, or C1-C3 alkyl;R5is hydrogen, F, OH, OCH3, C1-C3 alkyl, cyclopropyl, or is fused with one R3to form CH2, CH2-CH2 or CH2OCH2;R6is hydrogen, halo, C1-C5 alkyl, CN, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl, wherein 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered aryl and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, methyl, halomethyl, OH or OCH3 and wherein C1-C5 alkyl is optionally substituted with one or more substituents independently selected from halo, OH and OCH3;3120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)R7is hydrogen, F, OH, OCH3, C1-C3 alkyl or is fused with one R3to form CH2, CH2-CH2 or CH2OCH2;R8is 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl, optionally fused or substituted with R8A;R8Ais 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl;R9is hydrogen, C1-C3 alkyl, or is fused with R9Ato form CH2 or CH2-CH2;R10is 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl, optionally fused or substituted with R8A;R11is C1-C4 alkyl, NH2, NHC1-C3 alkyl, NHC3-C5 cycloalkyl orN(Ci-C3 alkyl)2, wherein C1-C4 alkyl, C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,Ndimethylamine and CN;R12is C1-C4 alkyl, C3-C5 cycloalkyl, NH2, NHC1-C3 alkyl, NHC3-C5 cycloalkyl or N(CI-C3 alkyl)2, wherein C1-C4 alky, C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine and CN; andR8, R10and R8Aare optionally substituted with one or more substituents independently selected from halo, OH, CN, -OC1-C4 alkyl, -OC3-C5 cycloalkyl and -Z3-R12wherein C1-C4 alky and C3-C5 cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine and CN;

[0008] or a pharmaceutically acceptable salt thereof. In the compounds of formula (I), X1can be C, and X2can be N; or X1can be N, and X2can be C.

[0009] In the compounds of formula (I), X1can be C, and X2can be N, forming:

[0010] wherein * indicates the connection to A in formula (I).

[0011] In the compounds of formula (I), XI can be N, and X2 can be C, forming:4120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)

[0012] wherein * indicates the connection point to A in formula (I).

[0013] The specific chemical naming conventions used herein are intended to be familiar to one of skill in the chemical arts. Some terms are defined specifically for additional clarity.

[0014] As used herein, the term "alkyl" refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, the term "C1-C5 alkyl" as used herein refers to saturated linear or branched chain monovalent hydrocarbon radicals of one, two, three, four or five carbon atoms. Examples of C1-C5 alkyl include, but are not limited to, methyl, ethyl, 1 -propyl, isopropyl, 1 -butyl, isobutyl, sec-butyl, tert-butyl, 2-methyl-2-propyl, pentyl, and neopentyl. Examples of Ci-C4 alkyl include, but are not limited to, methyl, ethyl, 1- propyl, isopropyl, I-butyl, isobutyl, sec-butyl, tert-butyl, and 2-methyl-2-propyl. Examples of C1-C3 alkyl include, but are not limited to, methyl, ethyl, 1-propyl or isopropyl.

[0015] As used herein, the term "cycloalkyl" means a saturated cyclic hydrocarbon group containing the indicated number of carbon atoms. For example, the term "3-6 membered cycloalkyl" as used herein refers to a saturated cyclic hydrocarbon group having three, four, five or six carbon atoms. Examples of 3-6 membered cycloalkyl include, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. As used herein, the term "heterocycloalkyl" means a saturated cyclic group containing the indicated number of atoms selected from C(0)o-i, N, O and S(0)o-2. For example, the term "5-6 membered heterocycloalkyl" as used herein refers to a saturated cyclic ring system having five or six ring atoms, one, two or three of which are selected from N, O and S(0)o-2, the remainder being C(0)o-i. Examples of 4-6 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrrolidinyl, pyrrolidin-2-onyl, dioxanyl, morpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, oxazolidinyl, isothiazolidinyl oxozolid-2-onyl and isothiazolid-2-onyl. Examples of 5-6 membered heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, pyrrolidin-2-onyl, dioxanyl, morpholinyl,5120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, oxazolidinyl, isothiazolidinyl oxozolid-2-onyl and isothiazolid-2-onyl.

[0016] As used herein, the term "aryl" refers to an aromatic cyclic hydrocarbon group having the indicated number of carbon atoms. For example, the term "5-6 membered aryl" as used herein refers to an aromatic cyclic hydrocarbon group having five or six carbon atoms. Examples of 5-6 membered aryls include cyclopentadienyl and phenyl. As used herein, the term "heteroaryl" refers to an aromatic cyclic group having the indicated number of atoms selected from C, N, O and S. For example, the term "5-6 membered heteroaryl" as used herein refers to an aromatic cyclic group having five or six ring atoms, one, two or three of which are selected from N, O and S, the remainder being C. Examples of 5-6 membered heteroaryls include, but are not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl and thiadiazolyl.Examples of 6 membered heteroaryls include, but are not limited to, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl.

[0017] As used herein the term "halogen" or "halo" refers to F (fluoro), Cl (chloro), Br (bromo) and I (iodo).

[0018] As used herein the term "halomethyl" refers to -CEE, in which one or more hydrogen atoms is / are replaced with an independently selected halo.

[0019] As used herein the term "oxo" refers to the substitution of CEE with O to form C(O).

[0020] As used herein the term "N(CI-C3 alkyl)?" allows the independent selection of each C1-C3 alkyl substituent, for example, N may be substituted by methyl and ethyl.

[0021] As used herein the substituent -NR4C(O) is connected to R2through N.

[0022] In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, 1,2,4 triazole, 1,2,3 thiadiazole, 1,2,4 thiadiazole, 1,2,5 thiadiazole, 1,3,4 thiadiazole, 1,2,3 oxadiazole, 1,2,4 oxadiazole, 1,2,5 oxadiazole, or 1,3,4 oxadiazole, substituted with R1and R1A.

[0023] In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1and R1A.6120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)

[0024] In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1and R1A, wherein R1Ais hydrogen and R1Ais C1-C3 alkyl.

[0025] In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1and R1A, wherein R1Ais hydrogen and R1is CH3.

[0026] In the compounds of formula (I), Z can be CHR9A, cyclobutyl, azetidine, pyrrolidine or piperidine.

[0027] In the compounds of formula (I), Z can be a bond,wherein * indicates the connection point to Z1and** indicates the connection point to A in formula (I).

[0028] In the compounds of formula (I), Z can be CHR9A, Z1can be selected from CH2 or CH2-CH2, and R9can be fused with R9Ato form CH2 or CH2-CH2.

[0029] In the compounds of formula (I), Z can be CHR9A, Z1can be CH2, and R9can be fused with R9Ato form CH2 or CH2-CH2.

[0030] In the compounds of formula (I), Z can be CHR9A, Z1can be CH2-CH2, and R9can be fused with R9Ato form CH2 or CH2-CH2.

[0031] In the compounds of formula (I), Z can be CHR9A, Z1can be selected from CH2 or CH2-CH2, and R9can be fused with R9Ato form CH2.

[0032] In the compounds of formula (I), Z can be CHR9A, Z1can be selected from CH2 or CH2-CH2, and R9can be fused with R9Ato form CH2-CH2.

[0033] In the compounds of formula (I), Z can be CHR9A, Z1can be CH2, and R9can be fused with R9Ato form CH2.

[0034] In the compounds of formula (I), Z can be CHR9A, Z1can be CH2-CH2, and R9can be fused with R9Ato form CH2-CH2.

[0035] In the compounds of formula (I), Z can be a bond.

[0036] In the compounds of formula (I), Z1can be a bond.

[0037] In the compounds of formula (I), Y can be NH or O.

[0038] In the compounds of formula (I), Y can be O.7120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)

[0039] In the compounds of formula (I), Y1can be a bond, CHR, CH2-CHR7or CHR7CH2, wherein R7is selected from hydrogen, F, OH and CH3; and Y2can a bond, CHR3, CH2-CHR3or CHR3-CH2, wherein R3is selected from hydrogen, F, OH and CH3.

[0040] In the compounds of formula (I), Y1can be a bond or CHR7, wherein R7is hydrogen, F, OH or CH3; and Y2can a bond or CHR3, wherein R3is hydrogen, F, OH or CH3.

[0041] In the compounds of formula (I), Y1can be a bond, CHR7, CH2-CHR7or CHR7-CH2, wherein R7is hydrogen, F, OH or CH3; and Y2can a bond, CHR3, CH2-CHR3or CHR3-CH2, wherein R3is hydrogen, F, OH or CH3, forming:wherein* indicates the connection point to Z1 in formula (I),

[0042] In the compounds of formula (I), Y1can be a bond or CHR7, wherein R7is hydrogen, F, OH or CH3; and Y2can a bond or CHR3, wherein R3is hydrogen, F, OH or CH3, forming:wherein* indicates the connection point to Z1in formula (I).8120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)

[0043] In the compounds of formula (I), R1Acan be hydrogen, or C1-C3 alkyl optionally substituted with one or more substituents independently selected from halo, OH, and OCH3.

[0044] In the compounds of formula (I), R1Acan be hydrogen or CH3.

[0045] In the compounds of formula (I), R1Acan be hydrogen.

[0046] In the compounds of formula (I), R1can be methyl, ethyl or propyl.

[0047] In the compounds of formula (I), R1can be methyl.

[0048] In the compounds of formula (I), R2can be C1-C3 alkyl optionally substituted with one, two, three or four substituents independently selected from halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z2-Rnand R10, wherein C1-C4 alkyl and C3-Cs cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine and CN.

[0049] In the compounds of formula (I), R2can be C1-C4 alkyl optionally substituted with one or more substituents independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R10.

[0050] In the compounds of formula (I), R2can be:optionally substituted with one, two, three or four substituents independently selected from halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z2-Rnand R10, wherein C1-C4 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine and CN, wherein * indicates the connection point to Y in formula (I).

[0051] In the compounds of formula (I), R2can be:9120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)optionally substituted with one, two, three or four substituents independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R10, wherein * indicates the connection point to Y in formula (I).

[0052] In the compounds of formula (I), R2can be:optionally substituted with one, two, three or four substituents independently selected from halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z2-Rnand R10, wherein C^-C4alkyl and C3-C5 cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine and CN, wherein* indicates the connection point to Yin formula (I).

[0053] In the compounds of formula (I), R2can be:10120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)optionally substituted with one, two, three or four substituents independently selected from F, OH, CN, oxo, -OCH3 and -OC3 cycloalkyl and R10, wherein * indicates the connection point to Y in formula (I).

[0054] In the compounds of formula (I), Y3is CH2OC1-C3- alkyl. In some aspects, Y3is CH2OCH3. In some aspects, Y3is CH2OCH2CH3. In some aspects, Y3is CH2O CH2CH2CH3. In some aspects, Y3is CH2O CH(CH3)CH3.

[0055] In the compounds of formula (I), X4can be N or C-R9wherein R9is hydrogen or CH3.

[0056] In the compounds of formula (I), X4can be C-R9wherein R9is fused with R9Ato form CH2 or CH2-CH2; and Z1is CH2 or CH2-CH2.

[0057] In the compounds of formula (I), X4can be N or CH.

[0058] In the compounds of formula (I), R6can be CN, F, Cl, CH3, CF3 or cyclopropyl.

[0059] In the compounds of formula (I), R6can be CN, F or Cl.

[0060] In the compounds of formula (I), R6can be CN or Cl.

[0061] In the compounds of formula (I), R6can be CN.

[0062] In the compounds of formula (I), R8can be 5-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl, optionally fused or substituted with R8A.

[0063] In the compounds of formula (I), R8can be 5-6 membered cycloalkyl, or 5-6 membered heterocycloalkyl, optionally fused with R8A.

[0064] In the compounds of formula (I), R8can be cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl or pyridinyl, optionally fused with R8A.

[0065] In the compounds of formula (I), R8can be cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl or tetrahydropyranyl, fused with R8A.

[0066] In the compounds of formula (I), R8can be cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl or tetrahydropyranyl, fused with R8A, wherein R8Acan be phenyl or 6 membered heteroaryl.

[0067] In the compounds of formula (I), R9can be hydrogen.

[0068] In the compounds of formula (I), R10can be 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl, optionally fused with R8A.11120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)

[0069] In the compounds of formula (I), R10can be 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, optionally fused with R8A.

[0070] In the compounds of formula (I), R 10 can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, pyrrolidinyl, pyrrolidin-2-onyl, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, oxazolidinyl, isothiazolidinyl, oxozolid-2-onyl, isothiazolid-2-onyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl, optionally fused with R8A.

[0071] In the compounds of formula (I), R10can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl, optionally fused with R8A.

[0072] In the compounds of formula (I), R10can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl, optionally fused with R8A.

[0073] In the compounds of formula (I), R10can be cyclopropyl, cyclobutyl, phenyl, pyridinyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl, optionally fused with R8A.

[0074] In the compounds of formula (I), R10can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, pyrrolidinyl, pyrrolidin-2-onyl, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, oxazolidinyl, isothiazolidinyl, oxozolid-2-onyl, isothiazolid-2-onyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl.

[0075] In the compounds of formula (I), R10can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl.

[0076] In the compounds of formula (I), R10can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridinyl,12120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadi azolyl.

[0077] In the compounds of formula (I), R10can be cyclopropyl, cyclobutyl, phenyl, pyridinyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl.

[0078] In the compounds of formula (I), R10can be cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl, fused with R8A.

[0079] In the compounds of formula (I), R10can be cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl or pyridinyl, fused with R8A.

[0080] In the compounds of formula (I), R10can be cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl or pyridinyl, fused with R8A.

[0081] In the compounds of formula (I), R10can be cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl or pyridinyl, fused with R8A.

[0082] In the compounds of formula (I), R10can be cyclopentyl, cyclohexyl, phenyl or pyridinyl, fused with R8A.

[0083] In the compounds of formula (I), R10can be phenyl or pyridinyl, fused with R8Awherein R8Acan be 5-6 membered heterocycloalkyl or 5-6 membered heteroaryl.

[0084] In the compounds of formula (I), R10can be phenyl or pyridinyl, fused with R8Awherein R8Acan be pyrrolidinyl, pyrrolidin-2-onyl, dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, oxazolidinyl, isothiazolidinyl, oxozolid-2-onyl, isothiazolid-2-onyl furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl.

[0085] In the compounds of formula (I), R10can be phenyl or pyridinyl, fused with R8Awherein R8Acan be tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, oxazolidinyl, isothiazolidinyl, oxozolid-2-onyl, isothiazolid-2-onyl, furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl.13120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)

[0086] In the compounds of formula (1), R10can be phenyl or pyridinyl, fused with R8A, wherein R8Acan be tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, oxazolidinyl, isothiazolidinyl, oxozolid-2-only or isothiazolid-2-onyl.

[0087] In the compounds of formula (I), where both Z and Z1are a bond, together they form a single bond.

[0088] In the compounds of formula (I), Z can be CHR9A, Z1can be CH2, X4can be C-R9, and R9can be fused with R9Ato form CH2, forming:wherein * indicates the connection point to A.

[0089] In the compounds of formula (I), R8can be cyclopentyl, fused with R8A, wherein R8Acan be pyridinyl, for example forming:wherein * indicates the connection point to Y.

[0090] In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1and R1A; and Y can be NH or O.

[0091] In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1and R1A, wherein R1Ais hydrogen and R1is C1-C3 alkyl; and Y can be NH or O.

[0092] In the compounds of formula (I), A can be:wherein* indicates the connection point to Z or Z' and ** indicates the other connection point from A in formula (1); R1can be C1-C3 alkyl; and Y can be NH or O.14120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)

[0093] In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1and R1A; and Y can be O.

[0094] In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1and R1A, wherein R1Ais hydrogen and R1is C1-C3 alkyl; and Y can be O.

[0095] In the compounds of formula (I), A can be:wherein* indicates the connection point to Z or Z' and ** indicates the other connection point from A in formula (I); R1can be C1-C3 alkyl; and Y can be O.

[0096] In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1and R1A; and R6can be CN, F, Cl, CH3, CF3 or cyclopropyl.

[0097] In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1and R1A, wherein R1Ais hydrogen and R1is C1-C3 alkyl; and R6can be CN, F, Cl or CF3.

[0098] In the compounds of formula (I), A can be:wherein * indicates the connection point to Z or Z' and** indicates the other connection point from A in formula (I); and R6can be CN, F, Cl, CH3, CF3 or cyclopropyl.

[0099] In the compounds of formula (I), A can be:15120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)wherein* indicates the connection point to Z or Z' and ** indicates the other connection point from A in formula (I); and R6can be CN, F, Cl or CF3.

[0100] In the compounds of formula (I), A can be:wherein * indicates the connection point to Z or Z' and ** indicates the other connection point from A in formula (I); R1can be CI-C3 alkyl; and R6can be CN or Cl.

[0101] In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1and R1A; R6can be CN, F, Cl, CH3, CF3 or cyclopropyl; and Y can be NH or O.

[0102] In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1and R1A, wherein R1Ais hydrogen and R1is C1-C3 alkyl; R6can be CN, F, Cl or CF3; and Y can be NH or O.

[0103] In the compounds of formula (I), A can be:wherein* indicates the connection point to Z or Z' and ** indicates the other connection point from A in formula (I); R6can be CN, F, Cl, CH3, CF3 or cyclopropyl; and Y can be NH or O.

[0104] In the compounds of formula (I), A can be:

[0105] wherein* indicates the connection point to Z or Z' and ** indicates the other connection point from A in formula (I); R6can be CN, F, Cl or CF3; and Y can be NH or O.16120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)

[0106] In the compounds of formula (I), A can be:wherein * indicates the connection point to Z or Z' and ** indicates the other connection point from A in formula (I); R1can be C1-C3 alkyl; R6can be CN or Cl; and Y can be NH or O.

[0107] In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1and R1A; R6can be CN, F, Cl, CH3, CF3 or cyclopropyl; and Y can be O.

[0108] In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1and R1A, wherein R1Ais hydrogen and R1is C1-C3 alkyl; R6can be CN, F, Cl or CF3; and Y can be O.

[0109] In the compounds of formula (I), A can be:wherein* indicates the connection point to Z or Z' and ** indicates the other connection point from A in formula (I); R6can be CN, F, Cl, CH3, CF3 or cyclopropyl; and Y can be O.

[0110] In the compounds of formula (I), A can be:wherein* indicates the connection point to Z or Z' and ** indicates the other connection point from A in formula (I); R6can be CN, F, Cl or CF3; and Y can be O.

[0111] In the compounds of formula (I), A can be:17120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)wherein* indicates the connection point to Z or Z' and** indicates the other connection point from A in formula (I); R1can be C1-C3 alkyl; R6can be CN or Cl; and Y can be O.

[0112] In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1and R1A; R6can be CN, F, Cl, CH3, CF3 or cyclopropyl; Y can be NH or O; and R2can be C1-C3 alkyl optionally substituted with one, two, three or four substituents independently selected from halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z2-Rnand R10, wherein C1-C4 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine and CN.

[0113] In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1and R1A; R6can be CN, F, Cl, CH3, CF3 or cyclopropyl; Y can be NH or O; and R2can be C1-C4 alkyl optionally substituted with one or more substituents independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R10.

[0114] In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1and R1A; R6can be CN, F, Cl or CF3; Y can be NH or O; and R2can be:optionally substituted with one, two, three or four substituents independently selected from halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z2-Rnand R10, wherein C1-C4 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more substituents18120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine and CN, wherein * indicates the connection point to Y in formula (I).

[0115] In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1and R1A; R6can CN, F, Cl or CF3; Y can be NH or O; and R2can be:optionally substituted with one, two, three or four substituents independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R10, wherein * indicates the connection point to Y in formula (I).

[0116] In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1and R1A; R6can be CN, F, Cl or CF3; Y can be NH or O; and R2can be:optionally substituted with one, two, three or four substituents independently selected from halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z2-Rnand R10, wherein C1-C4 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine and CN, wherein * indicates the connection point to Y in formula (I).19120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)

[0117] In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1and R1A; R6can CN, F, Cl or CF3; Y can be NH or O; and R2can be:optionally substituted with one, two, three or four substituents independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R10, wherein * indicates the connection point to Y in formula (I).

[0118] In the compounds of formula (I), A can bewherein * indicates the connection point to Z or Z' and ** indicates the other connection point from A in formula (I); R6can be CN, F, Cl, CH3, CF3 or cyclopropyl; Y can be NH or O; and R2can be C1-C3 alkyl optionally substituted with one, two, three or four substituents independently selected from halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z2-Rnand R10, wherein C1-C4 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine and CN.

[0119] In the compounds of formula (I), A can be:20120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)wherein * indicates the connection point to Z or Z' and ** indicates the other connection point from A in formula (I); R6can be CN, F, Cl, CH3, CF3 or cyclopropyl; Y can be NH or O; and R2can be C1-C4 alkyl optionally substituted with one or more substituents independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R10.

[0120] In the compounds of formula (I), A can be:wherein * indicates the connection point to Z or Z' and ** indicates the other connection point from A in formula (I); R6can be CN, F, Cl or CF3; Y can be NH or O; and R2can be:optionally substituted with one, two, three or four substituents independently selected from halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z2-Rnand R10, wherein C1-C4 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine and CN, wherein* indicates the connection point to Yin formula (I).

[0121] In the compounds of formula (I), A can be:wherein * indicates the connection point to Z or Z' and ** indicates the other connection point from A in formula (I); R6can CN, F, Cl or CF3; Y can be NH or O; and R2can be:21120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)optionally substituted with one, two, three or four substituents independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R10, wherein * indicates the connection point to Y in formula (I).

[0122] In the compounds of formula (I), A can be:wherein * indicates the connection point to Z or Z' and ** indicates the other connection point from A in formula (I); R6can be CN, F, Cl or CF3; Y can be NH or O; and R2can be:optionally substituted with one, two, three or four substituents independently selected from halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z2-Rnand R10, wherein C1-C4 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine and CN, wherein * indicates the connection point to Y in formula (I).22120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)

[0123] In the compounds of formula (I), A can be:

[0124] wherein * indicates the connection point to Z or Z' and ** indicates the other connection point from A in formula (I); R6can CN, F, Cl or CF3; Y can be NH or O; and R2can be:optionally substituted with one, two, three or four substituents independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R10, wherein * indicates the connection point to Yin formula (I).

[0125] In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1and R1A; R6can be CN, F, Cl, CH3, CF3 or cyclopropyl; Y can be NH or O; R2can be C1-C3 alkyl optionally substituted with one, two, three or four substituents independently selected from halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z2-Rnand R10, wherein C1-C4 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine and CN; and Z can be a bond,wherein * indicates the connection point to Z1and ** indicates the connection point to A in formula (I).23120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)

[0126] In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1and R1A; R6can be CN, F, Cl, CH3, CF3 or cyclopropyl; Y can be NH or O; R2can be C1-C4 alkyl optionally substituted with one or more substituents independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R10; and Z can be a bond,wherein * indicates the connection point to Z1and ** indicates the connection point to A in formula (I).

[0127] In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1and R1A; R6can be CN, F, Cl or CF3; Y can be NH or O; and R2can be:

[0128] optionally substituted with one, two, three or four substituents independently selected from halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z2-R11and R10, wherein C1-C4 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine and CN, wherein * indicates the connection point to Y in formula (I); and Z can be a bond,

[0129] wherein * indicates the connection point to Z1 and ** indicates the connection point to A in formula (I).24120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)

[0130] In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1and R1A; R6can CN, F, Cl or CF3; Y can be NH or O; and R2can be:optionally substituted with one, two, three or four substituents independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R10, wherein* indicates the connection point to Y in formula (I); and Z can be a bond,wherein * indicates the connection point to Z1and ** indicates the connection point to A in formula (I).

[0131] In the compounds of formula (I), A can be:

[0132] wherein * indicates the connection point to Z or Z' and ** indicates the other connection point from A in formula (I); R6can be CN, F, Cl, CH3, CF3 or cyclopropyl; Y can be NH or O; R2can be C1-C3 alkyl optionally substituted with one, two, three or four substituents independently selected from halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z2-Rnand R10, wherein C1-C4 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine and CN; and Z can be a bond,25120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)wherein * indicates the connection point to Z1and ** indicates the connection point to A in formula (I).

[0133] In the compounds of formula (I), A can be:wherein * indicates the connection point to Z or Z' and ** indicates the other connection point from A in formula (I); R6can be CN, F, Cl, CH3, CF3 or cyclopropyl; Y can be NH or O; R2can be C1-C4 alkyl optionally substituted with one or more substituents independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R10; and Z can be a bond,wherein * indicates the connection point to Z1and ** indicates the connection point to A in formula (I).

[0134] In the compounds of formula (I), A can be:wherein * indicates the connection point to Z or Z' and ** indicates the other connection point from A in formula (I); R6can be CN, F, Cl or CF3; Y can be NH or O; R2can be26120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)optionally substituted with one, two, three or four substituents independently selected from halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z2-Rnand R10, wherein C1-C4 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine and CN, wherein * indicates the connection point to Y in formula (I); and Z can be a bond,wherein * indicates the connection point to Z1and ** indicates the connection point to A in formula (I).

[0135] In the compounds of formula (I), A can be:wherein* indicates the connection point to Z or Z' and ** indicates the other connection point from A in formula (I); R6can CN, F, Cl or CF3; Y can be NH or O; and R2can be:27120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)optionally substituted with one, two, three or four substituents independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R10, wherein * indicates the connection point to Y in formula (I); and Z can be a bond,wherein* indicates the connection point to Z1and** indicates the connection point to A in formula (I).

[0136] In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1and R1A; R6can be CN, F, Cl, CH3, CF3 or cyclopropyl; Y can be NH or O; R2can be C1-C3 alkyl optionally substituted with one, two, three or four substituents independently selected from halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z2-Rnand R10, wherein C1-C4 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine and CN; Z can be a bond,wherein * indicates the connection point to Z1and ** indicates the connection point to A in formula (I); Y1can be a bond or CHR7, wherein R7is hydrogen, F, OH or CH3; and Y2can a bond or CHR3, wherein R3is hydrogen, F, OH or CH3.

[0137] In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R1and R1A; R6can be CN, F, Cl, CH3, CF3 or cyclopropyl; Y can be NH or O; R2can be C1-C4 alkyl optionally substituted with one or more28120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)substituents independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R10; Z can be a bond,wherein * indicates the connection point to Z1and ** indicates the connection point to A in formula (I); Y1can be a bond or CHR7, wherein R7is hydrogen, F, OH or CH3; and Y2can a bond or CHR3, wherein R3is hydrogen, F, OH or CH3.

[0138] In the compounds of formula (I), A can be:

[0139] wherein * indicates the connection point to Z or Z' and ** indicates the other connection point from A in formula (I); R6can CN, F, Cl or CF3; Y can be NH or O; and R2can be:optionally substituted with one, two, three or four substituents independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R10, wherein * indicates the connection point to Y in formula (I); Z can be a bond,29120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)wherein * indicates the connection point to Z1and ** indicates the connection point to A in formula (I); Y1can be a bond or CHR7, wherein R7is hydrogen, F, OH or CH3; and Y2can a bond or CHR3, wherein R3is hydrogen, F, OH or CH3.

[0140] In one embodiment, the compounds of Formula (I) are selected from the30120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)31120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)32120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)33120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)or a pharmaceutically acceptable salt thereof,wherein the bond at the * position is as represented,example, for the compound of formula:

[0141] In exemplary embodiments, the compounds of Formula (I) are:34120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)35120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)

[0142] In a further embodiment, the compounds of Formula (I) are selected from the group consisting of:36120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)

[0143] The compounds of formula (I), provided herein, or a pharmaceutically acceptable salt thereof, any or all hydrogens present in the compound, or in a particular group or moiety within the compound, may be replaced by a deuterium or a tritium. Thus, a recitation of alkyl includes deuterated alkyl, where from one to the maximum number of hydrogens present may be replaced by deuterium. For example, ethyl refers to both C2H5 or C2H5 where from 1 to 5 hydrogens are replaced by deuterium, such as in C2DxHs-x.

[0144] The compounds of formula (I), provided herein may form pharmaceutically acceptable salts. The Examples provided herein may form pharmaceutically acceptable salts. Such pharmaceutically acceptable salts are intended to be included. Pharmaceutically acceptable salts and common methodology for preparing them are well known in the art (see, e.g., P. Stahl, el al. Handbook of Pharmaceutical Salts: Properties, Selection and Use, 2nd Revised Edition (Wiley-VCR, 2011); S.M. Berge, etal., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, Vol. 66, No. 1, January 1977).

[0145] The compounds of formula (I), provided herein, or a pharmaceutically acceptable salt thereof, can be mixed with one or more pharmaceutically acceptable carriers, diluents, or excipients. More particularly, the compounds of formula (I), provided herein, or a pharmaceutically acceptable salt thereof, can be formulated as pharmaceutical compositions. Such pharmaceutical compositions and processes for preparing the same are38120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)well known in the art (see, e.g., Remington: The Science and Practice of Pharmacy (A Gennaro, etal., eds., 21st ed., Mack Publishing Co., 2005)).

[0146] The compounds of formula (I), provided herein, or a pharmaceutically acceptable salt thereof, and their pharmaceutical compositions can be administered by a variety of routes. Such routes of administration include oral and intravenous.

[0147] The compounds of formula (I), provided herein, or a pharmaceutically acceptable salt thereof, can be combined with one or more other therapeutic agents.

[0148] The compounds of formula (I), provided herein, or a pharmaceutically acceptable salt thereof, can be a component in a pharmaceutical composition for the treatment of systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, thanatophoric dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), muenke syndrome or cancer with one or more pharmaceutically acceptable carriers, diluents, or excipients, and optionally with one or more additional therapeutic agents.

[0149] The compounds of formula (I), provided herein, or a pharmaceutically acceptable salt thereof, can be a component in a pharmaceutical composition for the treatment of cancer with one or more pharmaceutically acceptable carriers, diluents, or excipients, and optionally with one or more additional therapeutic agents.

[0150] The compounds of formula (I), provided herein, or a pharmaceutically acceptable salt thereof, can be combined with one or more other therapeutic agents for simultaneous, separate or sequential administration.

[0151] The compounds of formula (I), provided herein, or a pharmaceutically acceptable salt thereof, and their pharmaceutical compositions can be used in the methods described herein.

[0152] The compounds of formula (I), provided herein, or a pharmaceutically acceptable salt thereof, are generally effective over a wide dosage range. For example, dosages per day normally fall within the range of about 0.5 to about 100 mg / kg of body weight. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, and therefore the above dosage range is not intended to limit the scope of the invention in any way. It will be understood that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of39120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)administration, the actual compound or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms.

[0153] Certain compounds of formula (I), or a pharmaceutically acceptable salt thereof, selectively target FGFR3. For example, certain compounds of formula (I), or a pharmaceutically acceptable salt thereof, selectively target FGFR3 over another FGFR. For example, certain compounds of formula (I), or a pharmaceutically acceptable salt thereof, selectively target FGFR3 over FGFR1. For example, certain compounds of formula (I), or a pharmaceutically acceptable salt thereof, are at least about 3 fold ( e.g. at least about 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 30-, 40-, 50-fold, or more) more selective for FGFR3 than for FGFR1.

[0154] As used herein, the term "selectivity" of a compound refers to the compound having more potent activity at the first target than the second target. A fold selectivity can be calculated by any method known in the art. For example, a fold selectivity can be calculated by dividing the ICso value of a compound for the second target ( e.g., FGFR1) by the ICso value of the same compound for the first target (e.g., FGFR3). An ICso value can be determined by any method known in the art. For example, an ICso value can be determined as described in the assays below.

[0155] As used herein, the term "cancer" refers to or describes the physiological condition in patients that is typically characterized by unregulated cell proliferation.Included in this definition are benign and malignant cancers.

[0156] As used herein, the term "FGFR3 -associated cancer" refers to cancers associated with or having a dysregulation of the FGFR3 gene, the FGFR3 kinase protein, or expression or activity, or level of any of the same. Non-limiting examples of FGFR3-associated cancer are described herein. As used herein an "FGFR3 -associated cancer" includes but is not limited to breast cancer (e.g. invasive ductal cancer, invasive lobular cancer), lung cancer (e.g. non-small-cell lung cancer, lung adenocarcinoma, squamous cell lung cancer and small-cell lung cancer), urothelial cancer, bladder cancer (e.g. urothelial bladder cancer, non-muscle invasive bladder cancer, muscle invasive bladder cancer), upper tract cancer ( e.g. urothelial upper tract cancer), urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma (e.g. cutaneous melanoma), head and neck cancer (e.g. oral cancer), thyroid cancer, renal cancer ( e.g. renal pelvis cancer), glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer.40120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)

[0157] As used herein, the term "treating" ( or "treatment") refers to restraining, slowing, stopping, or reversing the progression or severity of an existing symptom, condition or disorder.

[0158] As used herein, the term "patient" refers to a mammal, particularly a human.

[0159] Provided herein are methods of treating systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, thanatophoric dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), muenke syndrome or cancer, comprising administering to a patient in need of such treatment an effective amount of the compounds of formula (I), or a pharmaceutically acceptable salt thereof.

[0160] Provided herein are methods of treating cancer, comprising administering to a patient in need of such treatment an effective amount of the compounds of formula (I), or a pharmaceutically acceptable salt thereof.

[0161] Provided in the methods herein, the cancer is selected from the group consisting of breast cancer (e.g. invasive ductal cancer, invasive lobular cancer), lung cancer (e.g. nonsmall-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. Particularly, the cancer is selected from the group consisting of breast cancer (e.g. invasive ductal cancer, invasive lobular cancer), lung cancer (e.g. nonsmall-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, pancreatic cancer, prostate cancer, colorectal cancer, melanoma (e.g. cutaneous melanoma), renal cancer (e.g. renal pelvis cancer), glioblastoma, endometrial cancer, and ovarian cancer. More particularly, the cancer is selected from the group consisting of 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,41120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)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) and glioblastoma. Most particularly, the cancer is bladder cancer ( e.g. urothelial bladder cancer, non-muscle invasive bladder cancer, muscle invasive bladder cancer).

[0162] The compounds provided herein can be prepared as illustrated in the preparations and examples below.

[0163] Certain abbreviations are defined as follows: "ACN1refers to acetonitrile; "AcOH" refers to acetic acid; "Ac2O" refers to acetic anhydride; "aq." refers to aqueous; " AIBN" refers to azobisisobutyronitrile; "BINAP" refers to 2,2'-bis(diphenylphosphino)l,l '-binaphthyl; "Pd(DtBPF)Ch" refers to [1, 1 -Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II); NBS" refers to N-bromosuccinimide; "n-BuOH" refers ton-butyl alcohol or n-butanol; "BOC" refers to tert-butyloxycarbonyl; "BOC2O" refers to di-tert-butyl dicarbonate; "BuLi" refers to butyl lithium; "CuSC>45H2O" refers to copper sulfate pentahydrate; 'CsF" refers to cesium fluoride; "F-TEDA" refers to l-chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane; "Cui" refers to copper iodide; "DMP" refers to Dess-Martin periodinane; "DCE" refers to 1,2-dichloroethane; "DCM" refers to dichloromethane or methylene chloride; "DMEA" refers to dimethylethylamine; "NDM" refers to 1 -dodecanethiol; "DEA" refers to diethanolamine; "DEAD" refers to diethyl azodicarboxylate; "DIAD" refers to diisopropyl azodicarboxylate; "DIEA" or "DIPEA" refers to N,N-diisopropyl ethylamine; "DMA" refers to N,N-dimethylaniline; "DMAP" refers to 4-dimethylaminopyridine; "DMF" refers to N,N-dimethylformamide; "DPPA" refers to diphenylphosphoryl azide; "EAA" refers to ethyl acetoacetate; "EtOAc" refers to ethyl acetate; "FA" refers to formic acid "hr" refers to hour or hours; "i-PrMgCl" refers to isopropyl magnesium chloride; "IP A" refers to isopropyl amine; "T3P" refers to propylphosphonic anhydride; "KO Ac" refers to potassium acetate; "LiBEU" refers to lithium borohydride; "LDA" refers to lithium diisopropylamide; "MsQ" refers to methanesulfonyl chloride; "MTBE" refers to methyl tert-butyl ether; "NCS" refers toN-chlorosuccinimide; "NIS" refers to N-iodosuccinimide; 'MeMgBr" 10 refers to methyl magnesium bromide; "NMP" refers to N-methyl-2-pyrrolidone; "-OAc" refers to acetate; -"OMs" refers to methanesulfonate, also known as mesylate; "min" or "min." refers to minute or minutes; "N2" refers to nitrogen; "sat." or "sat'd" refers to saturated; "soln." refers to solution; "-OTf refers to trifluoromethanesulfonate, also known as triflate; "PCy / ' refers to tricyclohexylphosphine; "Pd(AcO)2" refers to palladium(II) acetate; "Pd( dba) / '42120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)refers to bis(dibenzylideneacetone )palladium(O); "Pd2(dba) / ' refers to tris(dibenzylideneacetone) dipalladium(O); "Pd2(dba)3.CHCb" refers to tris(dibenzylideneacetone)dipalladium-chloroform adduct; "Pd(dppf)Ch" refers to [ 1, 1' -bis( diphenylphosphino )ferrocene] dichloropalladium (II); "Pd( dppf)C12. CH2Q2" refers to 1, l'-bis(diphenylphosphino) ferrocene-palladium(II)di chloride di chloromethane complex; "PE" refers to petroleum ether; "K3PQ4" refers to potassium phosphate; "RT" refers to room temperature; "PPh / 1refers to triphenylphosphine; "Pd(PPh3) / ' refers to tetrakis(triphenylphosphine)palladium(0); "Ph" refers to phenyl; "NaH" refers to sodium hydride; "TBAF" refers to tetra-n-butylammonium fluoride; "TEA" refers to triethylamine; "TF A" refers to trifluoroacetic acid; "Tf 20" refers to trifluoromethane sulfonic anhydride; "THF" refers to tetrahydrofuran; "TsQ" referes to 4-toluenesulfonyl chloride; "TMSCFJ" refers to (trifluoromethyl)trimethyl silane; "TMSOTf refers to trimethyl silyl trifluoro methanesulfonate; "(CF 3SO2)2O" refers to trifluoromethanesulfonic anhydride; "t(R)” refers to retention time; "Xantphos" refers to 4, 5 -bi s( di phenyl phosphino )-9, 9-dimethylxanthene; "X-Phos" refers to 2-di cycl ohexyl phosphino-2,4,6-triisopropylbiphenyl; "XPhos Pd G2" refers to chloro(2-dicyclohexylphosphino-2' ,4' ,6' -triisopropyl- l,l'-biphenyl)[2-(2' -amino- 1,1'-biphenyl)]palladium(II); and "XPhos Pd G / ' refers to CAS # 1599466-81-5; "ZnCh" refers to zinc chloride.

[0164] Certain stereochemical centers have been left unspecified and certain substituents have been eliminated in the following schemes for the sake of clarity and are not intended to limit the teaching of the schemes in any way. Furthermore, individual isomers, enantiomers, and diastereomers may be separated or resolved by one of ordinary skill in the art at any convenient point in the synthesis of compounds of the invention, by methods such as selective crystallization techniques or chiral chromatography (See for example, J. Jacques, et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981, and E.L. Eliel and S.H. Wilen," Stereochemistry of Organic Compounds", Wiley-Interscience, 1994). The designations "isomer 1" and "isomer 2" refer to the compounds that elute from chiral chromatography first and second, respectively, under the conditions described herein and if chiral chromatography is initiated early in the synthesis, the same designation is applied to subsequent intermediates and examples. Where more than one chiral chromatography is conducted in the preparation, a further designation of "A" and "B" is provided where "A" refers to the compounds that elute first43120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)and "B" for those that elute second. For example "isomer 2A" refer to the first eluting compounds from the chiral chromatography of a compound previously designated "isomer 2". Additionally, the intermediates described in the following schemes contain a number of nitrogen or oxygen protecting groups. The variable protecting group may be the same or different in each occurrence depending on the particular reaction conditions and the particular transformations to be performed. The protection and deprotection conditions are well known to the skilled artisan and are described in the literature (See for example "Greene's Protective Groups in Organic Synthesis", Fourth Edition, by Peter G.M. Wuts and Theodora W. Greene, John Wiley and Sons, Inc. 2007).

[0165] Compounds of the disclosure can be made in view of U.S. 11,878,976, along with the knowledge of one of ordinary skill in the art. In the schemes below, all substituents, unless otherwise indicated, are as previously defined. "PG" refers to a protecting group developed for the amino group, such as carbamates and amides, an example being a BOC protecting group. Such protecting groups are well known and appreciated in the art. The reagents and starting materials are generally readily available to one of ordinary skill in the art. Others may be made by standard techniques of organic and heterocyclic chemistry which are analogous to the syntheses of known structurally similar compounds and the procedures described in the Preparations and Examples which follow including any novel procedures. Intermediates and processes useful for the synthesis of the compounds of formula (I), are intended to be included in this description.44120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)

[0166] Scheme I depicts the preparation of compounds of (4) and (8) that lead to compound 13 through different routes and will be further elaborated to formula (I). A person of skill in the art will recognize that alcohol (1) may react with a mesyl chloride to afford mesylate (2) that can be further reacted with (3) to provide (4). Treatment of compound ( 4) with LDA and an appropriate alkylating agent may afford compound (8). Alternatively, one skilled in the art may start with compound (3) that is substituted bromide (3) that when reacted with mesylate (2) directly affords compounds of (8).

[0167] Compound (8) can also be synthesized through an alternative route as depicted in Scheme 1. Additionally, a skilled artisan will appreciate that alcohol (1) may react under Mitsunobu conditions to provide azide (5). Azide (5) may be condensed with a beta-keto ester to afford triazole ester (6) that can undergo saponification to provide carboxylic acid (7). Treatment of carboxylic acid (7) with bromine in the presence of base affords compounds of (8).

[0168] Scheme 1 further depicts the preparation of compounds of (12) and (13) that will be further elaborated to formula (I). A skilled artisan will recognize that45120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)compounds of ( 4) and (8) may be deprotected to give (9) and (11) that when reacted with tritiate (10) result in bromide compounds of (12) and (13). Compound (12) may further be alkylated to give compounds of(13). A skilled artisan will appreciate that ketone compounds may be substituted for the tritiate compounds of ( 10). Alternatively, reacting compound (9) or (11) with an appropriate ketone under reductive amination conditions may also afford compounds (12) or (13).Scheme 2

[0169] Scheme 2 depicts an alternative preparation of compounds of (12) and (13) that will be further elaborated to formula (I). A person of skill in the art will recognize that alcohol (14) may react with mesyl chloride to afford mesylate (15) that can be further reacted with a compound (3) to provide (12). Compounds of (12) may further be alkylated to furnish compounds of (13). Alternatively, compound (3) that is substituted may be reacted with (15) to directly give compounds of (13).

[0170] Additionally, compound (13) may also be synthesized from alternative routes as depicted in Scheme 2. Alcohol (14) may react under Mitsunobu conditions to provide azide (16). Azide (16) may be condensed with a beta-keto ester to afford triazole ester (17) that can undergo saponification to provide carboxylic acid (18). Treatment of carboxylic acid (18) with bromine in the presence of base affords bromide (13).Alternatively, azide (16) may be reacted with an appropriately substituted46120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)trimethylsilylalkyne to afford trimethylsilyl analog (19). Reaction of (19) with NBS in the presence of silicon dioxide provides compounds of (13). Scheme 3Scheme 3

[0171] Scheme 3 depicts the preparation of compounds of formula (I). Reaction of (20) with chloroacetaldehyde provides heteroaryl chloride (21) that may be demethylated to give (22). Compound (22) may react with alcohol (23) via Mitsunobu conditions to provide a R2substituted heteroaryl chloride (24). A skilled artisan will recognize that when R2is methyl, it is unnecessary to demethylate (22) to arrive at a R2substituted (24). Conversion of heteroaryl chloride (24) to boronic acid (25) is achieved by treatment of (24) with bis(pinocolato)diboron under palladium catalyzed conditions.Boronic acid (25) may be reacted with bromide (13) to result in compounds of (26) through Suzuki coupling. Iodination of compounds of (26) in the presence of NIS provides47120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)(27) that may be further elaborated to provide R6substituted compounds of (28).Alternatively, as would be known to one skilled in the art, compounds of (26) may be reacted with reagents such as NCS or NBS to afford R6as chlorine or bromine directly without the intermediate iodination step to arrive at (28). Compounds of (28) are deprotected to provide compounds of (29). N-Cyanation of (29) results in N-cyanoamino compounds of formula (I).

[0172] Alternatively, a skilled artisan will appreciate that prior to conversion of (24) to boronic acid (25), compounds of (24) may first be iodinated then reacted with copper cyanide in DMF to afford a R6substituted heteroaryl chloride (24). Next, the R6substituted heteroaryl chloride (24) may be converted to a R6substituted boronic acid R6 substituted (25) that can be reacted with bromide (13) to provide compounds of (28). Deprotection of (28) followed by N-cyanation results in N-cyanoamino compounds of formula (I).Scheme 4{3748120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)

[0173] Scheme 4 depicts the preparation of compounds of (37a). Reaction of (30) in the presence of l-(chloromethyl)-4-fluoro-l,4-diazabicyclo[2.2.2]octane-l,4-diium tetrafluorob orate affords the fluorinated bi cyclic analog (31 ). Reaction of (31) with bis(pinocolato)diboron under palladium catalyzed conditions provides the boronate ester (32). Reaction of (32) with bromide (13) under palladium catalyzed conditions affords (34). Demethylation of (34) with aqueous sodium hydroxide and dodecane- 1 -thiol provides hydroxy bicyclic analog (35). Alkylation of (35) with the appropriate bromide gives compound (36). Deprotection of (36) followed by N-cyanation results in Ncyanoamino compounds of (37a).Scheme 5

[0174] Scheme 5 depicts an alternative preparation of cyanoamino compounds of Formula (I). One of ordinary skill will recognize that compounds of (30) may be demethylated to afford (38). Demethylated (38) may be reacted with alcohol (22) under Mitsunobu conditions to provide R2substituted bromide compounds (39). Alternatively,49120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)Compound (39) may be alkylated by substituting R2OH (22) with the corresponding iodo analog R2! of (22). Conversion of R2substituted bromide (39) to boronate ester ( 40) may be achieved by treating (39) with bis(pinocolato)diboron under palladium catalyzed conditions. Boronate ester ( 40) reacted with ( 13) results in compounds of (28) through Suzuki coupling. Alternatively, a skilled artisan will recognize that, as depicted in Scheme 5, methylated compounds of (30) may first be treated with bis(pinocolato)diboron under palladium catalyzed conditions to provide boronate ester ( 41 ). Boronate ester ( 41) may be reacted with (13) to give compounds of ( 42) through Suzuki coupling. A skilled artisan will recognize that compounds of (42) are also compounds of (28) where R2is methyl. Lastly, compounds of (28) may be deprotected to provide amine (29). N-Cyanation of amine (28) gives N-cyanoamino compounds of formula (I).

[0175] Scheme 6 depicts an alternative preparation of compounds of formula (I) starting with compounds (42) from Scheme 5 and compounds (28) from Schemes 3 and 5 where R2is methyl. Compounds ( 42) are demethylated to provide compounds of (43) that are reacted with alcohol (22) under Mitsunobu conditions to provide R2substituted compounds of (28) where the R2group is not methyl. R2substituted (28) may be deprotected to give compound (29) and then N-cyanated to give N-cyanoamino compounds of formula (I).50120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)

[0176] One skilled in the art will recognize alternative reactants may also result in compounds of (28). For instance, alcohol (22) may be converted to tritiate analog (R2-OTf) of (22) that may then be reacted with compounds of ( 43) to give compounds of (28). Additionally, alcohol compounds of ( 43) may first be converted to tritiate compounds of (35) that may then be reacted with R2-NH2 analogs of (22) to afford an amine-R2substituted compounds of (28).Scheme 7

[0177] Scheme 7 depicts the preparation of compounds of (47) that are further elaborated to cyanoamino compounds of Formula (I) in Scheme 8. Boronate ester (40), as prepared in Scheme 5, may be reacted with (8) to result in compounds of ( 46) through Suzuki coupling. Alternatively, a skilled artisan will recognize that boronate ester (41), as prepared in Scheme 5, may be reacted with (8) to give compounds of ( 44) through Suzuki coupling. A skilled artisan will recognize that boronic acid R6 substituted (25) as prepared in Scheme 3 may be substituted for boronic esters ( 40) and ( 41) in these reactions.Compounds of ( 44) may be demethylated to afford compounds of ( 45) that when reacted with alcohol (22) under Mitsunobu conditions afford compounds of ( 46). Lastly, compounds of (44) or (46) may be deprotected to provide amine (47).51120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)

[0178] A skilled artisan will recognize that amine ( 47) may also be prepared by replacing the R1 substituted compounds (8) with unsubstituted compounds (4) to result in amine (47) where the A group is unsubstituted.Scheme 8

[0179] Scheme 8 depicts the preparation of compounds of Formula (I).Reductive amination of compounds of (47), as prepared in Scheme 7, with ketone (48) affords compounds of Formula (I). Alternatively, alkylation of (47) with tritiate (49) gives compounds of Formula (I). A skilled artisan will also appreciate that mesylate (-OMs) compounds of (49) may be substituted for tritiate (49).

[0180] Additionally, a skilled artisan will recognize that N-protected ketone compounds of (50) and tritiate compounds of ( 10) may also be used instead of N-cyanoamino compounds (48) and (49). Reductive amination of compounds of ( 47), as prepared in Scheme 7, with N-protected ketone (50) affords N-protected (28). Alkylation of compounds of (47) with N-protected tritiate (10) also affords N-protected (28).Protected (28) may be deprotected to give compounds of (29) that when reacted with cyanogen bromide result in N-cyanoamino compounds of formula (I).52120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)Scl '-'fi

[0181] Scheme 9 depicts the preparation of compounds of (54a). Compounds of R10, where RIO is a 5-6 membered aryl or a 5-6-membered heteroaryl substituted with, but not limited to a halogen, may undergo a halogen-magnesium exchange with reagents such as iPrMgCl. The resultant Grignard reagent is reacted with the TBDMS protected alcohol R2aldehyde (51) to convert the aldehyde into the alcohol (52). Protecting groups other than TBDMS may be used to protect the R2alcohol in this step. Reacting the alcohol (52) under Mitsunobu conditions provides compounds (53). Treatment of (53) under acidic conditions affords the double deprotected compound (54). Reacting (54) with cyanogen bromide results in N-cyanoamino compounds of (54a).53120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)Scheme 1<&&&)

[0182] Scheme 10 depicts the preparation of compounds of (60a). 4,6-dichloropyridin-2- amine is reacted with a solution of 2-bromo-l, 1 -dimethoxypropane previously treated with aq. HC1 in EtOH to afford 5,7-dichloro-3-methylimidazo[l,2-a]pyridine. The 5,7-dichloro intermediate is treated with sodium methoxide to yield 7-chloro-5-methoxy-3-methylimidazo[l,2-a]pyridine. The boronate ester (55) is formed by Pd catalyzed reaction of 7-chloro-5-methoxy-3-methylimidazo[ l,2-a]pyridine with bis(pinacolato )di boron. Suzuki coupling of boronate ester (55) with bromide (56) affords compound (57). Hydrolysis of (57) with NaOH gives hydroxy compound (58). Alkylation of(58) with mesylate (59) provides compound (60). Deprotection of (60) affords (61) with is cyanogen bromide to afford the N-cyanoamino compounds of (60a).54120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)S ie-iw i I

[0183] Scheme 11 depicts the preparation of (65a). Treatment of R2OH in the presence of base followed by the addition of 4,6-dichloropyridin-2-amine affords compound (61). The boronate ester ( 62) is formed by the Pd catalyzed reaction of compound ( 61) with bis(pinacolato)diboron. Suzuki coupling of boronate ester (62) and compound (13) provides compound (63). Chlorination of (63) with l,3-dichloro-5,5-dimethyl -imidazolidine-2, 4-dione affords compound (64) which is then deprotected under acidic conditions to give compound (65). Subsequent treatment of (65) with cyanogen bromide affords the N-cyanoamino compounds of (65a).55120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)Scheme 171) (71s)

[0184] Scheme 12 depicts the preparation of (71a). Treatment of 7-chloro-6Himidazo[l,2-c]pyrimidin-5-one with the boronate ester (67) under palladium catalyzed conditions provides (68). Reaction of (68) under Mitsunobu conditions affords (70).Halogenation of (70) in the presence of NCS yields ( 69). Deprotection of ( 69) affords (71). Subsequent treatment of (71) with cyanogen bromide affords compounds of (71a).

[0185] The compounds of the present invention, or pharmaceutically acceptable salts thereof, may be prepared according to the following Preparations and Examples by methods well known and appreciated in the art. Suitable reaction conditions for the steps of these Preparations and Examples are well known in the art and appropriate substitutions of solvents and co-reagents are within the skill of the art. Likewise, it will be appreciated by those skilled in the art that synthetic intermediates may be isolated and / or purified by various well known techniques as needed or desired, and that frequently, it will be possible to use various intermediates directly in subsequent synthetic steps with little or no purification. As an illustration, compounds of the preparations and examples can be isolated, for example, by silica gel purification, isolated directly by filtration, or crystallization. Furthermore, the skilled artisan will appreciate that in some circumstances,56120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)the order in which moi eties are introduced is not critical. The particular order of steps required to produce the compounds of the present invention is dependent upon the particular compound being synthesized, the starting compound, and the relative liability of the substituted moieties, as is well appreciated by the skilled chemist. All substituents, unless otherwise indicated, are as previously defined, and all reagents are well known and appreciated in the art.Preparations and Examples

[0186] Compounds and intermediates described herein can be prepared in view of U.S. 11,878,976. Representative procedures are summarized, herein.Scheme 1357120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)

[0187] Scheme 13 depicts the preparation of Examples 1 and 2, as further described below.

[0188] Example 1. (2S,4S)-4-(4-(3-chloro-4-((R)-l-(5-fluoropyridin-2-yl)-2-hydroxy ethoxy )pyrazolo[ 1 ,5 -a]pyridin-6-yl)-5-methyl- 1H- 1 ,2,3 -tri azol- 1 -yl)-2-(methoxymethyl)piperidine-l -carbonitrile and Example 2 (2S,4S)-4-(4-(3-chloro-4-((S)-l-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[l,5-a]pyridin-6-yl)-5-methyl-lH-l,2,3-triazol- 1 -yl)-2-(methoxymethyl)piperidine- 1 -carbonitrile.

[0189] Step 1. 6-bromo-3-chloro-4-methoxy-pyrazolo[l,5-a]pyridine. To a solution of 6-bromo-4-methoxy-pyrazolo[l,5-a]pyridine (24.00 g, 105.70 mmol, 1.0 eq) in DCM (1000 mL) was added PPTS (2.66 g, 10.57 mmol, 0.1 eq) and NCS (14.82 g, 110.9958120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)mmol, 1.05 eq). The reaction mixture was stirred for 48 h at rt. After the reaction was completed, the mixture was diluted with di chloromethane (1000 mL) and washed with brine (400 mL x 2). The organic layer was dried over Na2SC>4 and concentrated. The crude product was purified by silica gel column (petroleum ether / ethyl acetate = 10 / 1) to give a light-yellow solid (25.0 g, 90% yield). LCMS m / z = 261.6 (M+l).

[0190] Step 2. 6-bromo-3-chloro-pyrazolo[l,5-a]pyridin-4-ol. To a solution of 6-bromo-3-chloro-4-methoxy-pyrazolo[l,5-a]pyridine (9.00 g, 34.42 mmol, 1.0 eq) in DMA (150 mL) was added NaOH (50% aq., 19.27 g, 240.93 mmol, 7.0 eq) and NDM (34.83 g, 172.08 mmol, 5.0 eq). The reaction mixture was stirred for 6 h at 60 °C. After the reaction was completed, the pH of the mixture was adjusted to 5-6 by addition of formic acid, and then extracted with ethyl acetate (200 mL x 2). The combined organic layers were washed with brine (200 mL x 3), dried over Na2SC>4 and concentrated. The crude product was purified by silica gel column (petroleum ether / ethyl acetate = 5 / 1) to give a yellow solid (7.3 g, 86% yield). LCMS m / z = 247.5 (M+l).

[0191] Step 3. 2-[tert-butyl(dimethyl)silyl]oxy-l-(5-fluoro-2-pyridyl)ethanol. To a solution of 2-bromo-5-fluoro-pyridine (10.0 g, 56.82 mmol, 1.0 eq) in dry THF (150 mL) was added z-PrMgCl (11.7 g, 113.65 mmol, 2.0 eq) dropwise under N2 atmosphere at 0°C. The reaction mixture was stirred at 25 °C for 2 h. Then a solution of 2-[tert-butyl(dimethyl)silyl]oxyacetaldehyde (19.8 g, 113.65 mmol, 2.0 eq) in dry THF (10 mL) was added at 0 °C and the mixture was stirred for further 2 h. After the reaction completion, the reaction mixture was quenched with 80 mL of saturated aqueous NH4Q and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SC>4, the solid was filtered out and the filtrate was concentrated in vacuum. The crude product was purified by silica gel chromatography (Petroleum Ether / EtOAc = 10 / 1) to give a yellow oil (6.0 g, 39% yield). LCMS m / z = 272.2 (M+l).

[0192] Step 4. [2-[tert-butyl(dimethyl)silyl]oxy-l-(5-fluoro-2-pyridyl)ethyl] methanesulfonate. To a solution of 2-[tert-butyl(dimethyl)silyl]oxy-l-(5-fluoro-2-pyridyl)ethanol (3.0 g, 11.05 mmol, 1.0 eq) and TEA (2.2 g, 22.11 mmol, 2.0 eq) in DCM (50 mL) was added MsCl (1.6 g, 14.37 mmol, 1.3 eq) at 0°C. The mixture was stirred for 2 h at rt. After the reaction was completed, the mixture was poured into H2O (30 mL) and extracted with DCM (50 mL x 3). The combined organic layer was washed with brine,59120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)dried over Na2SC>4, and concentrated to give a yellow oil (4.5 g, crude yield). LCMS m / z = 350.2 (M+l).

[0193] Step 5. [2-(6-bromo-3-chloro-pyrazolo[l,5-a]pyridin-4-yl)oxy-2-(5-fluoro-2-pyridyl)ethoxy]-tert-butyl-dimethyl-silane. To a solution of 6-bromo-3-chloro-pyrazolo[l,5-a]pyridin-4-ol (2.7 g, 10.91 mmol, 1.0 eq) and [2-[tert-butyl(dimethyl)silyl]oxy-l-(5-fluoro-2-pyridyl)ethyl] methanesulfonate (4.2 g, 12.0 mmol, 1.1 eq) in DMF (30 mL) was added K2CO3 (4.5 g, 32.73 mmol, 3.0 eq). The reaction mixture was stirred for 2 h at 70 °C. After the reaction was completed, the mixture was poured into water (20 mL) which was extracted with EtOAc (40 mL x 3). The combined organic layer was washed with brine, dried over Na2SC>4, and concentrated, the crude product was purified by silica gel chromatography eluted with (Petroleum Ether / EtOAc = 5 / 1) to give a yellow solid (2.7 g, 49% yield). LCMS m / z = 500.3 (M+l).

[0194] Step 6. tert-butyl-[tert-butyl(diphenyl)silyl](2S,4R)-4-[tert-butyl(diphenyl)silyl]oxypiperidine-l,2-dicarboxylate. To a solution of (2S,4R)-l-tert-butoxycarbonyl-4-hydroxy-piperidine-2-carboxylic acid (9.00 g, 36.69 mmol, 1.0 eq) in DCM (150 mL) were added imidazole (12.49 g, 183.47 mmol, 5.0 eq) and TBDPSC1 (25.21 g, 91.74 mmol, 2.5 eq) at 0°C, the resulting mixture was stirred at rt for 12 h. After the reaction was completed, the reaction mixture was poured into cold H2O (500 mL) and extracted with DCM (500 mL x 3). The combined organic phases were washed with brine (1000 mL), dried and concentrated in vacuum to give a colorless oil (34.0 g, crude yield).

[0195] Step 7. (2S,4R)-1 -tert-butoxycarbonyl -4-[tert-butyl(diphenyl)silyl]oxy-piperidine-2-carboxylic acid. To a solution of tert-butyl-[tert-butyl(diphenyl)silyl](2S,4R)-4-[tert-butyl(diphenyl)silyl]oxypiperidine-l,2-dicarboxylate j (26.5 g, crude yield) in MeOH (250 mL) and THF (150 mL) was slowly added the solution of K2CO3 (10.14 g, 73.40 mmol, 2.0 eq) in H2O (150 mL) at 0 °C. The resulting mixture was stirred at 25°C for 3 h. After the reaction was completed, the reaction mixture was poured into cold H2O (500 mL) and extracted with EtOAc (500 mL x 3). The combined organic phases were washed with brine (1000 mL), dried and concentrated in vacuum to give a colorless oil (33.00 g, crude yield). LCMS m / z = 384.3 (M-100).

[0196] Step 8. tert-butyl (2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-2-(hydroxymethyl)piperidine-l -carboxylate. To a solution of (2S,4R)-l-tert-butoxycarbonyl-4-[tert-butyl(diphenyl)silyl]oxy-piperidine-2-carboxylic acid (30.00 g, crude yield) in THF (250 mL) was slowly added BH3 / THF (1 M, 434 mL, 434.18 mmol, 7.0 eq) at 0°C. The60120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)resulting mixture was stirred at rt for 12 h. After the reaction was completed, the reaction mixture was quenched with MeOH (50 mL) slowly, and then poured into cold H2O (500 mL), extracted with EtOAc (600 mL x 3). The combined organic phases were washed with brine (1000 mL), dried and concentrated. The crude was purified by silica gel column (PE / EA=7 / 1) to give a colorless oil (12.00 g, 41% yield for 3 steps). LCMS m / z = 370.3 (M-100).

[0197] Step 9. tert-butyl (2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-2-(methoxymethyl)piperidine-l -carboxylate. To a solution of tert-butyl (2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-2-(hydroxymethyl)piperidine-l-carboxylate (12.00 g, 25.55 mmol, 1.0 eq) and CH3I (54.40 g, 383.23 mmol, 15.0 eq) in THF (120 mL) was added t-BuOK (1 M in THF, 127 mL, 127.74 mmol, 5.0 eq) dropwise at -70 °C under N2 protection. The resulting mixture was stirred at -70 °C for 1 h under N2 protection. After the reaction was completed, the reaction mixture was poured into cold H2O (500 mL) and extracted with EtOAc (500 mL x 3). The combined organic phases were washed with brine (1000 mL), dried and concentrated in vacuum. The crude was purified by silica gel column (PE / EA=10 / l) to give a light-yellow oil (11.2 g, 91% yield). LCMS m / z = 484.4 (M+l).

[0198] Step 10. tert-butyl (2S,4R)-4-hydroxy-2-(methoxymethyl)piperidine-l-carboxylate. A solution of tert-butyl (2S,4R)-4-[tert-butyl(diphenyl)silyl]oxy-2-(methoxymethyl)piperidine-l -carboxylate (11.00 g, 22.74 mmol, 1.0 eq) in TBAF (IM in THF, 150 mL) was stirred at 30 °C for 12 h. After the reaction was completed, the reaction mixture was diluted with H2O (300 mL) and extracted with EtOAc (300 mL x 3). The combined organic phases were washed with brine (500 mL), dried and concentrated in vacuum. The crude material was purified by silica gel column (PE / EA=1 / 1) to give a colorless oil (5.10 g, 91% yield). LCMS m / z = 246.2 (M+l).

[0199] Step 11. tert-butyl (2S,4R)-2-(methoxymethyl)-4-methylsulfonyloxy-piperidine-1 -carboxylate. To a solution of tert-butyl (2S,4R)-4-hydroxy-2-(methoxymethyl)piperidine-l -carboxylate (3.40 g, 13.86 mmol, 1.0 eq) and TEA (7.01 g, 69.30 mmol, 5.0 eq) in DCM (60 mL) was added the solution of MsCl (4.76 g, 41.58 mmol, 3.0 eq) in DCM (5 mL) at 0°C. The resulting mixture was stirred at 25°C for 2 h. After the reaction was completed, the reaction mixture was poured into H2O (150 mL) and extracted with DCM (150 mL x 2). The combined organic phases were washed with61120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)aqueous NaHCCh solution (150 mL), dried and concentrated in vacuum to give a lightyellow oil (5.0 g, crude yield). LCMS m / z = 224.1 (M-100).

[0200] Step 12. tert-butyl (2S,4S)-4-azido-2-(methoxymethyl)piperidine-l-carboxylate. To a solution of tert-butyl (2S,4R)-2-(methoxymethyl)-4-methylsulfonyloxy-piperidine-1 -carboxylate (4.48 g, crude yield) in DMF (100 mL) was added NaNs (4.50 g, 69.26 mmol, 5.0 eq) at rt. The resulting mixture was stirred at 100°C for 2 h under N2 protection. After the reaction was completed, the reaction mixture was poured into H2O (150 mL) and extracted with EtOAc (150 mL x 2). The combined organic phases were washed with brine (150 mL), dried and concentrated in vacuum to give a light-yellow oil (3.74 g, crude yield). LCMS m / z = 215.2 (M-56).

[0201] Step 13. tert-butyl (2S,4S)-4-(4-ethoxycarbonyl-5-methyl-triazol-l-yl)-2-(methoxymethyl)piperidine-l -carboxylate. To a solution of tert-butyl (2S,4S)-4-azido-2-(methoxymethyl)piperidine-l -carboxylate (3.74 g, crude yield) and ethyl 3-oxobutanoate (2.70 g, 20.75 mmol, 1.5 eq) in DMSO (60 mL) was added K2CO3 (5.74 g, 41.51 mmol, 3.0 eq) at rt. The resulting mixture was stirred at 80°C for 16 h under N2 protection. After the reaction was completed, the reaction mixture was poured into H2O (200 mL) and extracted with EtOAc (200 mL x 2). The combined organic phases were washed with brine (200 mL), dried and concentrated in vacuum. The crude was purified by silica gel column (PE / EA=1 / 1) to give a light-yellow oil (3.78 g, 71% yield for 3 steps). LCMS m / z = 383.3 (M+l).

[0202] Step 14. l-[(2S,4S)-l-tert-butoxycarbonyl-2-(methoxymethyl)-4-piperidyl]-5-methyl-triazole-4-carboxylic acid. To a solution of tert-butyl (2S,4S)-4-(4-ethoxycarbonyl-5-methyl-triazol-l-yl)-2-(methoxymethyl)piperidine-l-carboxylate (3.48 g, 9.10 mmol, 1.0 eq) in MeOH (35 mL) was added the solution of KOH (2.55 g, 45.50 mmol, 5.0 eq) in H2O (35 mL), which was stirred at 50°C for 2 h. After the reaction was completed, the reaction mixture was concentrated in vacuum to give a light-yellow oil (3.22 g, crude yield). LCMS m / z = 355.3 (M+l).

[0203] Step 15. tert-butyl (2S,4S)-4-(4-bromo-5-methyl-triazol-l-yl)-2-(methoxymethyl)piperidine-l -carboxylate. To a solution of l-[(2S,4S)-l-tert-butoxycarbonyl-2-(methoxymethyl)-4-piperidyl]-5-methyl-triazole-4-carboxylic acid (3.22 g, 9.09 mmol, 1.0 eq) and KOH (2.55 g, 45.43 mmol, 5.0 eq) in H2O (40 mL) was added Br2 (5.08 g, 31.80 mmol, 3.0 eq) at 0 °C, and was stirred at 25 °C for 2 h. Then KOH (764 mg, 13.63 mmol, 1.5 eq) and Bn (1.45 g, 9.09 mmol, 1.0 eq) was added to the reaction62120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)mixture, and stirred at 25 °C for another 1 h. After the reaction was completed, the reaction mixture was quenched with aqueous NaHCCh solution (60 mL) and extracted with EtOAc (100 mL x 2). The combined organic phases were washed with brine (100 mL), dried and concentrated in vacuum. The crude material was purified by silica gel column (PE / EA=1 / 1) to give a light-yellow solid (3.40 g, 96% yield for 2 steps). LCMS m / z = 389.2 (M+l).

[0204] Step 16. tert-butyl-[2-[3-chloro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridin-4-yl]oxy-2-(5-fluoro-2-pyridyl)ethoxy]-dimethyl-silane. To a solution of 2-(6-bromo-3-chloro-pyrazolo[l,5-a]pyridin-4-yl)oxy-2-(5-fluoro-2-pyridyl)ethoxy]-tert-butyl-dimethyl-silane (300 mg, 0.60 mmol, 1.0 eq) in dioxane (4 mL) was added KO Ac (293 mg, 2.99 mmol, 5.0 eq), BPD (228 mg, 0.90 mmol, 1.5 eq) and Pd(dppf)C12 (50 mg, 0.06 mmol, 0.1 eq) at rt. The resulting mixture was stirred at 85 °C for 5 h under N2 protection. After the reaction was completed, the reaction mixture was used directly in the next step without further purification. LCMS m / z = 548.2 (M+l).

[0205] Step 17. tert-butyl (2S,4S)-4-[4-[4-[2-[tert-butyl(dimethyl)silyl]oxy-l-(5-fluoro-2-pyridyl)ethoxy]-3-chloro-pyrazolo[l,5-a]pyridin-6-yl]-5-methyl-triazol-l-yl]-2-(hydroxymethyl)piperidine-l -carboxylate. To a solution of tert-butyl-[2-[3-chloro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridin-4-yl]oxy-2-(5-fluoro-2-pyridyl)ethoxy]-dimethyl-silane and tert-butyl (2S,4S)-4-(4-bromo-5-methyl-triazol-l-yl)-2-(methoxymethyl)piperidine-l -carboxylate (163 mg, 0.42 mmol, 1.0 eq) in dioxane (4 mL) and H2O (0.4 mL) was added K2CO3 (206 mg, 1.49 mmol, 3.5 eq) and Pd(dppf)C12 (60 mg, 0.07 mmol, 0.17 eq) at rt. The resulting mixture was stirred at 85 °C for 5 h under N2 protection. After the reaction was completed, the reaction mixture was filtered, and the filtrate was concentrated in vacuum to give a solid. The crude solid was purified by silica gel column (PE / EA=1 / 1) to give a light-yellow solid (123 mg, 40% yield for 2 steps). LCMS m / z = 730.4 (M+l).

[0206] Step 18. 2-[3-chloro-6-[l-[(2S,4S)-2-(methoxymethyl)-4-piperidyl]-5-methyl-triazol-4-yl]pyrazolo[l,5-a]pyridin-4-yl]oxy-2-(5-fluoro-2-pyridyl)ethanol. To a solution of tert-butyl (2S,4S)-4-[4-[4-[2-[tert-butyl(dimethyl)silyl]oxy-l-(5-fluoro-2-pyridyl)ethoxy]-3-chloro-pyrazolo[l,5-a]pyridin-6-yl]-5-methyl-triazol-l-yl]-2-(hydroxymethyl)piperidine-l -carboxylate (550 mg, 0.75 mmol, 1.0 eq) in DCM (10 mL) was added HCl / dioxane (4 mL) at rt. The resulting mixture was stirred at rt for 2 h and63120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)then was concentrated in vacuum to give an off-white solid (416 mg, HC1 salt). LCMS m / z = 516.3 (M+l).

[0207] Step 19. (2S,4S)-4-[4-[3-chloro-4-[l-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]pyrazolo[l,5-a]pyridin-6-yl]-5-methyl-triazol-l-yl]-2-(methoxymethyl)piperidine-1 -carbonitrile. To a solution of 2-[3-chloro-6-[l-[(2S,4S)-2-(methoxymethyl)-4-piperidyl]-5-methyl-triazol-4-yl]pyrazolo[l,5-a]pyridin-4-yl]oxy-2-(5-fluoro-2-pyridyl)ethanol (1.20 g, 2.17 mmol, 1.0 eq, HC1 salt) and DIEA (1.32 g, 13.03 mmol, 6.0 eq) in DCM (20 ml) was added CNBr (231 mg, 2.17 mmol, 1.0 eq) at 0 °C. The resulting mixture was stirred at 0°C for 1 h. After the reaction was completed, the mixture was quenched with H2O (30 mL) and extracted with DCM (30 mL x 2). The combined organic phases were washed with brine (30 mL), dried and concentrated in vacuum. The crude solid was initially purified by Pre-TLC (dichloromethane / methanol=15 / l) and then by Prep-HPLC (Prep-C18, 5 pM Triart column, 20 * 150 mm, YMC-Actus; gradient elution of 63% MeCN in water to 83% MeCN in water over a 18 min period, where both solvents contain 0.05% NH3.H2O) to give a white solid (730 mg, 51% yield). LCMS m / z = 541.1 (M+l).

[0208] Step 20. Example 1 andExample2. Racemic (2S,4S)-4-[4-[3-chloro-4-[l-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]pyrazolo[l,5-a]pyridin-6-yl]-5-methyl-triazol-l-yl]-2-(methoxymethyl)piperidine-l -carbonitrile (730 mg) was separated using chiral HPLC to give peak 1 (Example 1, white solid; rt = 4.8 min; 334.2 mg). LCMS m / z = 541.1 (M+H); 1HNMR (400 MHz, DMSO-d6) 88.60 (d, J = 2.8 Hz, 1H), 8.43 (s, 1H), 8.11 (s, 1H), 7.79-7.74 (m, 1H), 7.65-7.61 (m, 1H), 6.90 (s, 1H), 5.63 (t, J = 5.2 Hz, 1H), 5.15 (t, J = 6.0 Hz, 1H), 4.81-4.71 (m, 1H), 3.95 (t, J = 5.2 Hz, 2H), 3.89-3.83 (m, 1H), 3.79-3.74 (m, 1H), 3.58-3.52 (m, 1H), 3.49 (t, J = 6.0 Hz, 2H), 3.34 (s, 3H), 2.38 (s, 3H), 2.26-2.17 (m, 1H), 2.17-1.90 (m, 3H). Peak 2 (Example 2, white solid, rt = 6.03 min; 331.6 mg). LCMS m / z = 541.1 (M+H); 1HNMR (400 MHz, DMSO-d6) 68.60 (d, J = 3.2 Hz, 1H), 8.43 (s, 1H), 8.11 (s, 1H), 7.79-7.74 (m, 1H), 7.65-7.61 (m, 1H), 6.90 (s, 1H), 5.63 (t, J = 5.2 Hz, 1H), 5.15 (t, J = 6.0 Hz, 1H), 4.81-4.72 (m, 1H), 3.95 (t, J = 5.2 Hz, 2H), 3.89-3.83 (m, 1H), 3.79-3.74 (m, 1H), 3.58-3.52 (m, 1H), 3.49 (t, J = 6.0 Hz, 2H), 3.34 (s, 3H), 2.38 (s, 3H), 2.26-2.18 (m, 1H), 2.18-1.97 (m, 3H).

[0209] Chiral Separation Method:

[0210] Instrument Model: Prep- HPLC-Flash Brix 1860

[0211] Column Name: Phenomenex lux 5um i-Amylose-1250*21.2mm64120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)

[0212] Mobile Phase: A: n-Hexane; B: EtOH

[0213] Isocratic elution: A:B=25:85 (V / V)

[0214] Total Flow: 20 mL / min

[0215] Column temp.: RT

[0216] RT(min) 9 min; 20 min

[0217] Running Time: 30 minScheme 1465120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)

[0218] Scheme 14 depicts the preparation of Examples 3 and 4, as further described below.

[0219] Example 3. (2R,4S)-4-(4-(3-chloro-4-((R)-l-(5-fluoropyridin-2-yl)-2-hydroxy ethoxy )pyrazolo[ 1 ,5 -a]pyridin-6-yl)-5-methyl- 1H- 1 ,2,3 -tri azol- 1 -yl)-2-(methoxymethyl)piperidine-l -carbonitrile and Example 4 (2R,4S)-4-(4-(3-chloro-4-((S)-l-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[l,5-a]pyridin-6-yl)-5-methyl-lH-l,2,3-triazol- 1 -yl)-2-(methoxymethyl)piperidine- 1 -carbonitrile.Example 3

[0220] Step 1. tert-butyl -methyl (2R,4R)-4-[tert-butyl(diphenyl)silyl]oxypiperidine-l,2-dicarboxylate. To a solution of tert-butyl, methyl66120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)(2R,4R)-4-hydroxypiperidine-l,2-dicarboxylate (7.0 g, 27.0 mmol, 1.0 eq) and imidazole (3.68 g, 53.99 mmol, 2.0 eq) in DCM (90 mL) was added TBDPSC1 (4.71 g, 40.49 mmol, 1.5 eq) at 0 °C. The resulting mixture was stirred at rt for 16 h. After the reaction was completed, the reaction mixture was poured into cold water (500 mL) and extracted with DCM (500 mL x 3). The combined organic layers were washed with brine (1000 mL) and concentrated in vacuum to give a colorless oil (10.0 g). LCMS m / z = 498.3 (M+l).

[0221] Step 2. tert-butyl (2R,4R)-4-[tert-butyl(diphenyl)silyl]oxy-2-(hydroxymethyl)piperidine-l -carboxylate. To a solution of tert-butyl -methyl (2R,4R)-4-[tert-butyl(diphenyl)silyl]oxypiperidine-l,2-dicarboxylate (10.0 g, 20.09 mmol, 1.0 eq) in THF (100 mL) and MeOH (25 mL) was slowly added LiBJL (2.21 g, 100.46 mmol, 5.0 eq) at 0 °C. The resulting mixture was stirred at rt for 16 h. After the reaction was completed, the reaction mixture was quenched with MeOH (50 mL) slowly, then poured into cold water (500 mL) and extracted with DCM (600 mL x 3). The combined organic layers were washed with brine (1000 mL), dried and concentrated in vacuum. The crude was purified by silica gel column (petroleum ether / EtOAc =7 / 1) to give a yellow oil (6.5 g, 69% yield). LCMS m / z = 470.4 (M+l).

[0222] Step 3. tert-butyl (2R,4R)-4-[tert-butyl(diphenyl)silyl]oxy-2-(methoxymethyl)piperidine-l -carboxylate. To a solution of tert-butyl (2R,4R)-4-[tert-butyl(diphenyl)silyl]oxy-2-(hydroxymethyl)piperidine-l-carboxylate (6.5 g, 13.84 mmol, 1.0 eq) and CH3I (29.46 g, 207.59 mmol, 15.0 eq) in THF (90 mL) was added t-BuOK (1 M in THF, 69.2 mL, 69.20 mmol, 5.0 eq) dropwise at -70 °C. The resulting solution was stirred at -65 °C for 0.5 h under N2. After the reaction was completed, the reaction mixture was poured into cold water (500 mL) and extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with brine (500 mL) and concentrated in vacuum. The crude was purified by silica gel column (Petroleum ether / EtOAc =10 / 1) to give yellow oil (6.5 g, 97% yield). LCMS m / z = 4884.4 (M+l).

[0223] Step 4. tert-butyl (2R,4R)-4-hydroxy-2-(methoxymethyl)piperidine-l-carboxylate. A solution of tert-butyl (2R,4R)-4-[tert-butyl(diphenyl)silyl]oxy-2-(methoxymethyl)piperidine-l -carboxylate (6.5 g, 13.44 mmol, 1.0 eq) in TBAF (IM in THF, 80 mL) was stirred at rt for 16 h. After the reaction was completed, the reaction mixture was diluted with H2O (300 mL) and extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine (500 mL), dried and concentrated in67120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)vacuum. The crude material was purified by silica gel column (petroleum ether / EtOAc =1 / 1) to give colorless oil (2.8 g, 85% yield). LCMS m / z = 246.3 (M+l).

[0224] Step 5. tert-butyl (2R,4R)-2-(methoxymethyl)-4-methylsulfonyloxy-piperidine-1 -carboxylate. To a solution of tert-butyl (2R,4R)-4-hydroxy-2-(methoxymethyl)piperidine-l -carboxylate (2.8 g, 11.41 mmol, 1.0 eq) and TEA (3.46 g, 34.24 mmol, 3.0 eq) in DCM (30 mL) was added the solution of MsCl (1.96 g, 17.12 mmol, 1.5 eq) in DCM (5 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 2 h. After the reaction was completed, the reaction mixture was poured into H2O (150 mL) and extracted with DCM (150 mL x 3). The combined organic layers were washed with the saturated NaHCCh solution, dried and concentrated in vacuum to give yellow oil (3.5 g, crude yield). LCMS m / z = 324.2 (M+l).

[0225] Step 6. tert-butyl (2R,4S)-4-azido-2-(methoxymethyl)piperidine-l-carboxylate. To a solution of tert-butyl (2R,4R)-2-(methoxymethyl)-4-methylsulfonyloxy-piperidine-1 -carboxylate (3.5 g, 10.82 mmol, 1.0 eq) in DMF (50 mL) was added NaNs (1.06 g, 14.07 mmol, 1.3 eq) at rt. The resulting mixture was stirred at 100 °C for 2 h under N2 protection. After the reaction was completed, the reaction mixture was poured into H2O (150 mL) and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (150 mL), dried and concentrated in vacuum to give a yellow oil (2.93 g, crude yield). LCMS m / z = 271.3 (M+l).

[0226] Step 7. tert-butyl (2R,4S)-4-(4-ethoxycarbonyl-5-methyl-triazol-l-yl)-2-(methoxymethyl)piperidine-l -carboxylate. To a solution of tert-butyl (2R,4S)-4-azido-2-(methoxymethyl)piperidine-l -carboxylate (2.93 g, 10.84 mmol, 1.0 eq) and ethyl 3-oxobutanoate (2.12 g, 16.26 mmol, 1.5 eq) in DMSO (40 mL) was added K2CO3 (4.49 g, 32.52 mmol, 3.0 eq) at rt. The resulting mixture was stirred at 80 °C for 16 h under N2 protection. After the reaction was completed, the reaction mixture was poured into H2O (200 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried and concentrated in vacuum. The crude material was purified by silica gel column (Petroleum ether / EtOAc =1 / 1) to give a yellow oil (3.30 g, 79.6% yield). LCMS m / z = 383.3 (M+l); 1H-NMR (400 MHz, CDCh-d) 84.44-4.38 (m, 3H), 4.13-4.06 (m, 1H), 3.92-3.87 (m, 1H), 3.66-3.58 (m, 1H), 3.48-3.45 (m, 1H), 3.38-3.33 (m, 1H), 3.23 (s, 3H), 2.58 (s, 3H), 2.49-2.41 (m, 1H), 2.33-2.56 (m, 1H), 2.22-2.20 (m, 1H), 2.14-2.08 (m, 1H), 1.47 (s, 9H), 1.41 (t, J = 6.8 Hz, 3H).68120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)

[0227] Step 8. l-[(2R,4S)-l-tert-butoxycarbonyl-2-(methoxymethyl)-4-piperidyl]-5-methyl-triazole-4-carboxylic acid. To a solution of tert-butyl (2R,4S)-4-(4-ethoxycarbonyl-5-methyl-triazol-l-yl)-2-(methoxymethyl)piperidine-l-carboxylate (3.3 g, 8.63 mmol, 1.0 eq) in MeOH (15 mL) and H2O (15 mL) was added KOH (968 mg, 17.26 mmol, 2.0 eq). The reaction mixture was stirred at 50 °C for 2 h. After the reaction was completed, the pH of the mixture was adjusted to 5 by addition of hydrochloric acid solution (1 M) and extracted with DCM (300 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated in vacuum to give a white solid (3.0 g, 98% yield). LCMS m / z = 355.3 (M+l).

[0228] Step 9. tert-butyl (2R,4S)-4-(4-bromo-5-methyl-triazol-l-yl)-2-(methoxymethyl)piperidine-l -carboxylate. To a solution of l-[(2R,4S)-l-tert-butoxycarbonyl-2-(methoxymethyl)-4-piperidyl]-5-methyl-triazole-4-carboxylic acid (3.0 g, 8.47 mmol, 1.0 eq) and KOH (950 g, 16.93 mmol, 2.0 eq) in H2O (40 mL) was added Br2 (1.76 g, 11.0 mmol, 1.3 eq) at 0 °C, and then stirred at 25 °C for 2 h. After the reaction was completed, the reaction mixture was diluted with aqueous NaHCOi solution (60 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried and concentrated in vacuum. The crude product was purified by silica gel column (petroleum ether / EtOAc =1 / 1) to give a yellow solid (2.6 g, 79% yield). LCMS m / z = 389.2 (M+l).

[0229] Step 10. tert-butyl (2R,4S)-4-[4-[4-[2-[tert-butyl(dimethyl)silyl]oxy-l-(5-fluoro-2-pyridyl)ethoxy]-3-chloro-pyrazolo[l,5-a]pyridin-6-yl]-5-methyl-triazol-l-yl]-2-(methoxymethyl)piperidine-l -carboxylate. To a solution of tert-butyl-[2-[3-chloro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridin-4-yl]oxy-2-(5-fluoro-2-pyridyl)ethoxy]-dimethyl-silane (457 mg, 0.83 mmol, 1.3 eq) and tert-butyl (2R,4S)-4-(4-bromo-5-methyl-triazol-l-yl)-2-(methoxymethyl)piperidine-l -carboxylate (250 mg, 0.64 mmol, 1.0 eq) in dioxane (4 mL) and H2O (0.4 mL) was added K2CO3 (266 mg, 1.93 mmol, 3.0 eq) and Pd(dppf)C12 (52 mg, 0.06 mmol, 0.1 eq) at rt. The resulting mixture was stirred at 90 °C for 16 h under N2. After the reaction was completed, the reaction mixture was filtered, and then concentrated in vacuum. The crude product was purified by silica gel column (petroleum ether / EtOAc =1 / 1) to give a yellow solid (280 mg, 60% yield for 2 steps). LCMS m / z = 730.4 (M+l).

[0230] Step 11. 2-[3-chloro-6-[l-[(2R,4S)-2-(methoxymethyl)-4-piperidyl]-5-methyl-triazol-4-yl]pyrazolo[l,5-a]pyridin-4-yl]oxy-2-(5-fluoro-2-pyridyl)ethanol. To a69120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)solution of tert-butyl (2R,4S)-4-[4-[4-[2-[tert-butyl(dimethyl)silyl]oxy-l-(5-fluoro-2-pyridyl)ethoxy]-3-chloro-pyrazolo[l,5-a]pyridin-6-yl]-5-methyl-triazol-l-yl]-2-(methoxymethyl)piperidine-l -carboxylate (280 mg, 0.38 mmol, 1.0 eq) in DCM (4 mL) was added HCl / dioxane (2 mL) at rt. The resulting solution was stirred at rt for 2 h. After the reaction was completed, the reaction mixture was concentrated in vacuum to give a yellow solid (200 mg, HC1 salt). LCMS m / z = 516.3 (M+l).

[0231] Step 12. (2R,4S)-4-[4-[3-chloro-4-[l-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]pyrazolo[l,5-a]pyridin-6-yl]-5-methyl-triazol-l-yl]-2-(methoxymethyl)piperidine-1 -carbonitrile. To a solution of 2-[3-chloro-6-[l-[(2R,4S)-2-(methoxymethyl)-4-piperidyl]-5-methyl-triazol-4-yl]pyrazolo[l,5-a]pyridin-4-yl]oxy-2-(5-fluoro-2-pyridyl)ethanol (70 mg, 0.14 mmol, 1.0 eq, HC1 salt) and DIEA (70 mg, 0.54 mmol, 4.0 eq) in DCM (4 ml) was added BrCN (30 mg, 0.27 mmol, 2.0 eq) at 0 °C. The resulting mixture was stirred at 0°C for 2 h. After the reaction was completed, the mixture was quenched with water (30 mL) and extracted with DCM (30 mL x 2). The combined organic phases were washed with brine (30 mL), dried and concentrated in vacuum. The crude was purified by Pre-TLC (dichloromethane / methanol=15 / l) to give a white solid (65 mg, 89% yield). LCMS m / z = 541.1 (M+l).

[0232] Step 13. (2R,4S)-4-(4-(3-chloro-4-((R)-l-(5-fluoropyridin-2-yl)-2-hydroxy ethoxy )pyrazolo[ 1 ,5 -a]pyridin-6-yl)-5-methyl- 1H- 1 ,2,3 -tri azol- 1 -yl)-2-(methoxymethyl)piperidine-l -carbonitrile and (2R,4S)-4-(4-(3-chloro-4-((S)-l-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[l,5-a]pyridin-6-yl)-5-methyl-lH-l,2,3-triazol-l-yl)-2-(methoxymethyl)piperidine-l -carbonitrile. The racemate (65 mg) was separated by Prep-Chiral-HPLC.

[0233] Chiral Separation Method:

[0234] Instrument Model: Prep- HPLC-Flash Brix 1860-01

[0235] Column Name: YMC CHIRAL ART Cellulose-SC, 250*20mm, 5um

[0236] Mobile Phase: A: n-Hexane; B: EtOH

[0237] Isocratic elution: A:B=70:70 (V / V)

[0238] Total Flow: 20 mL / min

[0239] Column temp.: RT

[0240] RT (min) 15 min;35 min

[0241] Running Time: 30 min70120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)

[0242] Example 3 Peak 1 (2R,4S)-4-(4-(3-chloro-4-((R)-l-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[ 1 , 5-a]pyridin-6-yl)-5-methyl- 1H- 1 ,2,3 -tri azol- 1 -yl)-2-(methoxymethyl)piperidine-l-carbonitrile (white solid; rt = 3.6 min.; 13.0 mg, 20% yield). LCMS m / z = 541.2 (M+H); 1H NMR (400 MHz, DMSO-d6) 68.59 (d, J = 2.8 Hz, 1H), 8.43 (s, 1H), 8.11 (s, 1H), 7.76 (dt, J = 8.8 Hz, 2.8 Hz, 1H), 7.65-7.63 (m, 1H), 6.89 (s, 1H), 5.63 (t, J = 5.2 Hz, 1H), 5.14 (t, J = 5.6 Hz, 1H), 4.72-4.64 (m, 1H), 3.94 (t, J = 5.2 Hz, 2H), 3.64-3.60 (m, 1H), 3.56-3.54 (m, 2H), 3.49-3.45 (m, 1H), 3.38-3.35 (m, 1H), 3.30 (s, 3H), 2.39 (s, 3H), 2.14-2.03 (m, 3H), 1.97-1.88 (m, 1H).

[0243] Example 4 Peak 2 (white solid; rt = 4.43 min.; 12.5 mg, 19% yield). LCMS m / z = 542.1 (M+H); 1H NMR (400 MHz, DMSO-d6) 6 8.59 (d, J = 2.8 Hz, 1H), 8.43 (s, 1H), 8.11 (s, 1H), 7.76 (dt, J = 8.8 Hz, 2.8 Hz, 1H), 7.65-7.62 (m, 1H), 6.89 (s, 1H), 5.63 (t, J = 5.2 Hz, 1H), 5.14 (t, J = 5.6 Hz, 1H), 4.72-4.64 (m, 1H), 3.94 (t, J = 5.2 Hz, 2H), 3.64-3.60 (m, 1H), 3.56-3.53 (m, 2H), 3.48-3.45 (m, 1H), 3.38-3.36 (m, 1H), 3.30 (s, 3H), 2.39 (s, 3H), 2.14-2.03 (m, 3H), 1.97-1.88 (m, 1H).Scheme 15

[0244] Scheme 15 depicts the preparation of Example 5, as further described below.71120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)

[0245] Example 5. (2S,4S)-4-(4-(3-chloro-5-((R)-l-(pyridin-2-yl)ethoxy)imidazo[ 1 ,2-a]pyridin-7-yl)-5-methyl- 1H- 1 ,2,3 -tri azol- 1 -yl)-2-(methoxymethyl)piperidine- 1 -carbonitrile.Example 5

[0246] Step 1. 5-[(lR)-l-(2-pyridyl)ethoxy]-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)imidazo[l,2-a]pyridine. To a solution of 7-chloro-5-[(lR)-l-(2-pyridyl)ethoxy]imidazo[l,2-a]pyridine (150 mg, 0.55 mmol, 1.0 eq) and BPD (278 mg, 1.10 mmol, 2.0 eq) in dioxane (6 mL) was added Pd2(dba)3 (50 mg, 0.05 mmol, 0.1 eq), X-Phos (52 mg, 0.11 mmol, 0.2 eq) and KO Ac (158 mg, 1.65 mmol, 3.0 eq). The reaction mixture was stirred for 16 h at 80 °C under N2. After the reaction was completed, the mixture was concentrated under vacuum to give a brown oil (150 mg, crude yield). LCMS m / z = 284.2 (M-82).

[0247] Step 2. tert-butyl (2S,4S)-2-(methoxymethyl)-4-[5-methyl-4-[5-[(lR)-l-(2-pyridyl)ethoxy]imidazo[ 1 ,2-a]pyridin-7-yl]triazol- 1 -yl]piperidine- 1 -carboxylate. To a solution of 5-[(lR)-l-(2-pyridyl)ethoxy]-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)imidazo[l,2-a]pyridine (150 mg, 0.53 mmol) and tert-butyl (2S,4S)-4-(4-bromo-5-methyl-triazol-l-yl)-2-(methoxymethyl)piperidine-l -carboxylate (186 mg, 0.48 mmol, 0.9 eq) in dioxane (6 mL) and H2O (0.6 mL) was added Pd(dtbpf)C12 (51 mg, 0.08 mmol, 0.15 eq) and K2CO3 (219 mg, 1.59 mmol, 3.0 eq). The reaction mixture was stirred for 2 h at 80 °C under N2 protection. After the reaction was completed, the mixture was concentrated. The crude product was purified by silica gel column (dichloromethane / methanol = 10 / 1) to give a yellow solid (110 mg, 37% yield for 2 steps). LCMS m / z = 548.3 (M+l) = 548.3.72120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)

[0248] Step 3. tert-butyl (2S,4S)-4-[4-[3-chloro-5-[(lR)-l-(2-pyridyl)ethoxy]imidazo[l,2-a]pyridin-7-yl]-5-methyl-triazol-l-yl]-2-(methoxymethyl)piperidine-l -carboxylate. To a solution of tert-butyl (2S,4S)-2-(methoxymethyl)-4-[5-methyl-4-[5-[(lR)-l-(2-pyridyl)ethoxy]imidazo[l,2-a]pyridin-7-yl]triazol-l-yl]piperidine-l-carboxylate (40 mg, 0.07 mmol) in ACN (3 mL) was added NCS (15 mg, 0.10 mmol, 1.5 eq) at 0 °C. The reaction mixture was stirred for 16 h at rt. After the reaction was completed, the solution was concentrated and the crude was purified by silica gel column (dichloromethane / methanol = 10 / 1) to give a yellow solid (30 mg, 56% yield). LCMS m / z = 582.2 (M+l).

[0249] Step 4. 3-chloro-7-[l-[(2S,4S)-2-(methoxymethyl)-4-piperidyl]-5-methyl-triazol-4-yl]-5-[(lR)-l-(2-pyridyl)ethoxy]imidazo[l,2-a]pyridine. To a solution of tert-butyl (2S,4S)-4-[4-[3-chloro-5-[(lR)-l-(2-pyridyl)ethoxy]imidazo[l,2-a]pyridin-7-yl]-5-methyl-triazol-l-yl]-2-(methoxymethyl)piperidine-l -carboxylate (30 mg, 0.05 mmol, 1.0 eq) in DCM (1 mL) was added HCl / dioxane (4M, 0.5 mL) and stirred at rt for 2 h. After the reaction was completed, the mixture was concentrated to give a yellow solid (30 mg, crude yield, HC1 salt). LCMS m / z = 482.1 (M+l).

[0250] Step 5. (2S,4S)-4-(4-(3-chloro-5-((R)-l-(pyridin-2-yl)ethoxy)imidazo[ 1 ,2-a]pyridin-7-yl)-5-methyl- 1H- 1 ,2,3 -tri azol- 1 -yl)-2-(methoxymethyl)piperidine-l -carbonitrile. To a solution of3-chloro-7-[l-[(2S,4S)-2-(methoxymethyl)-4-piperidyl]-5-methyl-triazol-4-yl]-5-[(lR)-l-(2-pyridyl)ethoxy]imidazo[l,2-a]pyridine (30 mg, 0.06 mmol, 1.0 eq) and BrCN (7 mg, 0.06 mmol, 1.0 eq) in DCM (1 mL) was added DIEA (40 mg, 0.31 mmol, 5.0 eq). The reaction mixture was stirred at rt for 2 h. After the reaction was completed, the solution was diluted with H2O (20 mL) and extracted with dichloromethane (50 mL x 2). The combined organic layers were washed with brine (25 mL), dried over Na2SC>4 and concentrated. The residue was purified by Prep-HPLC (Prep-C18, 5 pM Triart column, 20 * 150 mm, YMC-Actus; gradient elution of 30% MeCN in water to 50% MeCN in water over a 9 min period, where both solvents contain 0.05% NH3.H2O -10MMOL / L NH4HCO3-CAN) to give a white solid (2.2 mg, 8.4% yield for 2 steps). LCMS m / z = 507.2 (M+H); 1H NMR (400 MHz, DMSO-d6) 88.59 (d, J = 4.4 Hz, 1H), 7.87-7.83 (m, 1H), 7.61-7.59 (m, 2H), 7.37-7.33 (m, 2H), 6.55 (s, 1H), 5.86-5.81(m, 1H), 4.80-4.74 (m, 1H), 3.89-3.83 (m, 1H), 3.79-3.75 (m, 1H), 3.56-3.52 (m, 1H), 3.49-3.47 (m, 2H), 3.34 (s, 3H), 2.40 (s, 3H), 2.25-2.18 (m, 1H), 2.11-1.98 (m, 3H), 1.76 (d, J = 6.4 Hz, 3H).73120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)Scheme 16

[0251] Scheme 16 depicts the preparation of Example 6, as further described below.

[0252] Example 6. (2R,4S)-4-(4-(3-chloro-4-((R)-l-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[ 1 ,5 -a]pyridin-6-yl)-5-methyl- 1H- 1 ,2,3 -tri azol- 1 -yl)-2-(methoxymethyl)piperidine-l -carbonitrile. Step 1. 3-chloro-4-[(lR)-l-(5-fhioro-2-pyridyl)ethoxy]-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridine.Example 6

[0253] Step 1. 3-chloro-4-[(lR)-l-(5-fluoro-2-pyridyl)ethoxy]-6-(4, 4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridine. To a solution of 6-bromo-3-chloro-4-[(lR)-l-(5-fluoro-2-pyridyl)ethoxy]pyrazolo[l,5-a]pyridine (280 mg, 0.75 mmol, 1.0 eq) in dioxane (10 mL) was added KO Ac (145 mg, 1.51 mmol, 2.0 eq), BPD (384 mg, 1.51 mmol, 2.0 eq) and Pd(dppf)C12 (62 mg, 0.075 mmol, 0.1 eq) at rt. The resulting mixture was stirred at 80 °C for 4 h under N2. After the reaction was completed, the74120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)reaction mixture was used directly for the next step without further purification (250 mg, crude yield). LCMS m / z = 336.2 (M+l).

[0254] Step 2. tert-butyl (2R,4S)-4-[4-[3-chloro-4-[(lR)-l-(5-fluoro-2-pyridyl)ethoxy]pyrazolo[l,5-a]pyridin-6-yl]-5-methyl-triazol-l-yl]-2-(methoxymethyl)piperidine-l -carboxylate. To a solution of 3-chloro-4-[(lR)-l-(5-fluoro-2-pyridyl)ethoxy]-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridine (250 mg, 0.75 mmol, 1.0 eq, crude) and tert-butyl (2R,4S)-4-(4-bromo-5-methyl-triazol-l-yl)-2-(methoxymethyl)piperidine-l -carboxylate (232 mg, 0.60 mmol, 0.8 eq) in dioxane (4 mL) and H2O (0.4 mL) were added K2CO3 (308 mg, 2.24 mmol, 3.0 eq) and Pd(dtbpf)C12 (76 mg, 0.07 mmol, 0.1 eq) at rt. The resulting mixture was stirred at 80 °C for 6 h under N2. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated. The crude product was purified by silica gel column (DCM / MeOH = 20 / 1) to give a yellow oil (230 mg, 51.4% yield). LCMS m / z = 600.1 (M+l).

[0255] Step 3. 3-chloro-4-[(lR)-l-(5-fluoro-2-pyridyl)ethoxy]-6-[l-[(2R,4S)-2-(methoxymethyl)-4-piperidyl]-5-methyl-triazol-4-yl]pyrazolo[l,5-a]pyridine HC1. To a solution of tert-butyl (2R,4S)-4-[4-[3-chloro-4-[(lR)-l-(5-fluoro-2-pyridyl)ethoxy]pyrazolo[l,5-a]pyridin-6-yl]-5-methyl-triazol-l-yl]-2-(methoxymethyl)piperidine-l -carboxylate (230 mg, 0.38 mmol, 1.0 eq) in DCM (4 mL) was added HCl / dioxane (2 mL) and stirred at rt for 2 h. After the reaction was completed, the mixture was concentrated to give a yellow solid (200 mg, crude yield). LCMS m / z = 500.1 (M+l).

[0256] Step 4. (2R,4S)-4-(4-(3-chloro-4-((R)-l-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[ 1 ,5 -a]pyridin-6-yl)-5-methyl- 1H- 1 ,2,3 -tri azol- 1 -yl)-2-(methoxymethyl)piperidine-l -carbonitrile. To a solution of3-chloro-4-[(lR)-l-(5-fluoro-2-pyridyl)ethoxy]-6-[l-[(2R,4S)-2-(methoxymethyl)-4-piperidyl]-5-methyl-triazol-4-yl]pyrazolo[l,5-a]pyridine HC1 (60 mg, 0.12 mmol, 1.0 eq) and DIEA (62 mg, 0.48 mmol, 4.0 eq) in DCM (3 ml) was added CNBr (26 mg, 0.24 mmol, 2.0 eq) at 0 °C. The resulting mixture was stirred at 0 °C for 2 h. After the reaction was completed, the mixture was quenched with water (30 mL) and extracted with DCM (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried and concentrated. The residue was purified by Prep-HPLC (Prep-C18, 5 pM Triart column, 20 * 150 mm, YMC-Actus; gradient elution of 40% MeCN in water to 50% MeCN in water over a 15 min period, where both solvents contain 0.05% NH3.H2O) to give a white solid (23.4 mg, 37% yield).75120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)LCMS m / z = 525.1 (M+H); 8.59 (d, J = 2.8 Hz, 1H), 8.43 (s, 1H), 8.12 (s, 1H), 7.78 (dt, J = 3.2 Hz, 8.8 Hz, 1H), 7.66-7.63 (m, 1H), 6.85 (s, 1H), 5.77 (q, J = 6.4 Hz, 1H), 4.72-4.64 (m, 1H), 3.64-3.61 (m, 1H), 3.55-3.54 (m, 2H), 3.49-3.43 (m, 1H), 3.36-3.32 (m, 1H), 3.30 (s, 3H), 2.39 (s, 3H), 2.14-2.03 (m, 3H), 1.97-1.87 (m, 1H), 1.70 (d, J = 6.4 Hz, 3H).Scheme 17

[0257] Scheme 17 depicts the preparation of Example 7, as further described below.

[0258] Example 7. (2R,4S)-4-(4-(3-chloro-4-((R)-l-(pyridin-2-yl)ethoxy)pyrazolo[ 1 ,5 -a]pyridin-6-yl)-5-methyl- 1H- 1 ,2,3 -tri azol- 1 -yl)-2-(methoxymethyl)-piperidine- 1 -carbonitrile.Example 7

[0259] Step 1. 3-chloro-4-[(lR)-l-(2-pyridyl)ethoxy]-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridine. To a solution of 6-bromo-3-chloro-4-[(lR)-l-(2-pyridyl)ethoxy]pyrazolo[l,5-a]pyridine (250 mg, 0.71 mmol, 1.0 eq) and BPD (270 mg, 1.06 mmol, 1.5 eq) in dioxane (5 mL) was added KO Ac (264 mg, 2.70 mmol, 3.0 eq) and Pd(dppf)C12 (58 mg, 0.07 mmol, 0.1 eq). The reaction mixture was stirred for76120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)2 h at 85 °C under N2. After the reaction was completed, the solid was filtered out, the filtrate was concentrated to give an oil (250 mg, crude yield). LCMS m / z = 400.3 (M+l).

[0260] Step 2. tert-butyl (2R,4S)-4-[4-[3-chloro-4-[(lR)-l-(2-pyridyl)ethoxy]pyrazolo[l,5-a]pyridin-6-yl]-5-methyl-triazol-l-yl]-2-(methoxymethyl)piperidine-l -carboxylate. To a solution of 3-chloro-4-[(lR)-l-(2-pyridyl)ethoxy]-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridine (230 mg, 0.58 mmol, 1.5 eq) and tert-butyl (2R,4S)-4-(4-bromo-5-methyl-triazol-l-yl)-2-(methoxymethyl)piperidine-l -carboxylate (150 mg, 0.38 mmol, 1.0 eq) in dioxane (5 mL) and water (0.5 mL) was added CS2CO3 (250 mg, 0.77 mmol, 2.0 eq) and Pd(dtbpf)C12 (25 mg, 0.04 mmol, 0.1 eq). The reaction mixture was stirred for 3h at 85 °C under N2. After the reaction was completed, the solid was filtered out and the filtrate was concentrated. The crude product was purified by silica gel (petroleum Ether / EtOAc = 1 / 1) to give a brown solid (200 mg, 89% yield). LCMS m / z = 582.3 (M+l).

[0261] Step 3. 3-chloro-6-[l-[(2R,4S)-2-(methoxymethyl)-4-piperidyl]-5-methyl-triazol-4-yl]-4-[(lR)-l-(2-pyridyl)ethoxy]pyrazolo[l,5-a]pyridine HC1. To a solution of tert-butyl (2R,4S)-4-[4-[3-chloro-4-[(lR)-l-(2-pyridyl)ethoxy]pyrazolo[l,5-a]pyridin-6-yl]-5-methyl-triazol-l-yl]-2-(methoxymethyl)piperidine-l-carboxylate (190 mg, 0.33 mmol, 1.0 eq) in DCM (3 mL) was added HCl / dioxane (1.5 mL). The reaction mixture was stirred for 5 h at rt. After the reaction was completed, the mixture was concentrated to give a brown solid (180 mg, crude yield). LCMS m / z = 482.3 (M+l).

[0262] Step 4. (2R,4S)-4-(4-(3-chloro-4-((R)-l-(pyridin-2-yl)ethoxy)pyrazolo[ 1 ,5 -a]pyridin-6-yl)-5-methyl- 1H- 1 ,2,3 -tri azol- 1 -yl)-2-(methoxymethyl)-piperidine-l -carbonitrile. To a solution of 3-chloro-6-[l-[(2R,4S)-2-(methoxymethyl)-4-piperidyl]-5-methyl-triazol-4-yl]-4-[(lR)-l-(2-pyridyl)ethoxy]pyrazolo[l,5-a]pyridine HC1 (40 mg, 0.08 mmol, 1.0 eq) and DIEA (54 mg, 0.41 mmol, 5.0 eq) in DCM (2 mL) was added BrCN (14 mg, 0.12 mmol, 1.5 eq) at 0 °C and stirred at rt for 5 h. After the reaction completion, the mixture was diluted with DCM (20 mL) and washed with water (10 mL x 2). The organic layer was dried over Na2SC>4 and concentrated. The crude product was purified by Pre-HPLC (Prep-C18, 5pMTriart column, 20 * 150 mm, YMC-Actus; gradient elution of 50% MeCN in water to 60% MeCN in water over a 4 min period, where both solvents contain 0.05% NH3.H2O) to give a white solid (11.4 mg, 27% yield). LCMS m / z = 507.2 (M+H); 1H NMR (400 MHz, DMSO-d6) 6 8.58 (d, J = 4.0 Hz, 1H), 8.42 (d, J = 0.8 Hz, 1H), 8.12 (s, 1H), 7.86-7.8277120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)(m, 1H), 7.57-7.55 (m, 1H), 7.34-7.31 (m, 1H), 6.83 (s, 1H), 5.72 (q, J = 6.0 Hz, 1H), 4.71-4.63 (m, 1H), 3.64-3.60 (m, 1H), 3.54 (d, J = 5.2 Hz, 2H), 3.49-3.43 (m, 1H), 3.35-3.32 (m, 1H), 3.30 (s, 3H), 2.37 (s, 3H), 2.13-2.02 (m, 3H), 1.96-1.87 (m, 1H), 1.70 (d, J = 6.4 Hz, 3H).Scheme 18Example 8

[0263] Scheme 18 depicts the preparation of Example 8, as further described below.

[0264] Example 8. (2R,4S)-4-(4-(3-chloro-5-((R)-l-(pyridin-2-yl)ethoxy)imidazo[ 1 ,2-a]pyridin-7-yl)-5-methyl- 1H- 1 ,2,3 -tri azol- 1 -yl)-2-(methoxymethyl)piperidine- 1 -carbonitrile.78120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)Example 8

[0265] Step 1. 7-chloro-5-[(lR)-l-(2-pyridyl)ethoxy]imidazo[l,2-a]pyridine. To a solution of (lS)-l-(2-pyridyl)ethanol (600 mg, 4.88 mmol, 1.0 eq) and PPhi (2.55 g, 9.76 mmol, 2.0 eq) in DMF (10 mL) was added DBAD (1.68 g, 7.32 mmol, 1.5 eq) at 0 °C under N2 protection, then a solution of 7-chloroimidazo[l,2-a]pyridin-5-ol (820 mg, 4.88 mmol, 1.0 eq) in DMF (8 mL) was added dropwise at 0 °C. The reaction mixture was stirred at rt for 16 h. After the reaction was completed, the mixture was diluted with EtOAc (80 mL) and washed with brine (30 mL x 3). The organic layer was dried over Na2SC>4 and concentrated. The crude product was purified by silica gel column (MeOH / DCM = 1 / 10) to give a crude product. The crude product was purified by reverse phase preparative MPLC (Prep-C18, 20-45 pM, 120 g, Tianjin Bonna-Agela Technologies; gradient elution of 5% MeCN in water to 30% MeCN in water over a 30 min period, where both solvents contain 0.1% formic acid) to give a yellow solid (350 mg, 26% yield). LCMS m / z = 274.2 (M+l).

[0266] Step 2. 5-[(lR)-l-(2-pyridyl)ethoxy]-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)imidazo[l,2-a]pyridine. To a solution of 7-chloro-5-[(lR)-l-(2-pyridyl)ethoxy]imidazo[l,2-a]pyridine (280 mg, 1.02 mmol, 1.0 eq), KOAc (300 mg, 3.06 mmol, 3.0 eq) and BPD (389 mg, 1.53 mmol, 1.5 eq) in dioxane (5 mL) was added X-Phos (97 mg, 0.20 mmol, 0.2 eq) and Pd2(dba)s (103 mg, 0.1 mmol, 0.1 eq). The reaction mixture was stirred for 16 h at 85 °C under N2. After the reaction was completed, the solid was filtered out, the filtrate was concentrated to give a brown solid (350 mg, crude yield). LCMS m / z = 366.2 (M+l).79120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)

[0267] Step 3. tert-butyl (2R,4S)-2-(methoxymethyl)-4-[5-methyl-4-[5-[(lR)-l-(2-pyridyl)ethoxy]imidazo[ 1 ,2-a]pyridin-7-yl]triazol- 1 -yl]piperidine- 1 -carboxylate. To a solution of tert-butyl (2R,4S)-4-(4-bromo-5-methyl-triazol-l-yl)-2-(methoxymethyl)piperidine-l -carboxylate (200 mg, 0.51 mmol, 1.0 eq) and 5-[(lR)-l-(2-pyridyl)ethoxy]-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)imidazo[l,2-a]pyridine (282 mg, 0.77 mmol, 1.5 eq) in dioxane (5 mL) and water (0.5 mL) was added K2CO3 (213 mg, 1.54 mmol, 3.0 eq) and Pd(dtbpf)C12 (33 mg, 0.05 mmol, 0.1 eq). The reaction mixture was stirred for 2 h at 85 °C under N2. After the reaction was completed, the solid was filtered out and the filtrate was concentrated. The crude product was purified by silica gel chromatography (DCM / MeOH = 20 / 1) to give a brown solid (120 mg, 43% yield). LCMS m / z = 548.2 (M+l).

[0268] Step 4. tert-butyl (2R,4S)-4-[4-[3-chloro-5-[(lR)-l-(2-pyridyl)ethoxy]imidazo[l,2-a]pyridin-7-yl]-5-methyl-triazol-l-yl]-2-(methoxymethyl)piperidine-l -carboxylate. To a solution of tert-butyl (2R,4S)-2-(methoxymethyl)-4-[5-methyl-4-[5-[(lR)-l-(2-pyridyl)ethoxy]imidazo[l,2-a]pyridin-7-yl]triazol-l-yl]piperidine-l-carboxylate (70 mg, 0.13 mmol, 1.0 eq) in ACN (5 mL) was added NCS (26 mg, 0.19 mmol, 1.5 eq) at 0 °C. The reaction mixture was stirred for 16 h at rt. After the reaction was completed, the crude product was purified by prep-TLC (DCM / MeOH = 20 / 1) to give a yellow solid (45 mg, 61% yield). LCMS m / z = 582.2 (M+l).

[0269] Step 5. 3-chloro-7-[l-[(2R,4S)-2-(methoxymethyl)-4-piperidyl]-5-methyl-triazol-4-yl]-5-[(lR)-l-(2-pyridyl)ethoxy]imidazo[l,2-a]pyridine. To a solution of tert-butyl (2R,4S)-4-[4-[3-chloro-5-[(lR)-l-(2-pyridyl)ethoxy]imidazo[l,2-a]pyridin-7-yl]-5-methyl-triazol-l-yl]-2-(methoxymethyl)piperidine-l -carboxylate (45 mg, 0.08 mmol, 1.0 eq) in DCM (2 mL) and HCl / dioxane (4M, 2 mL). The reaction mixture was stirred for 2 h at rt. After the reaction was completed, the reaction was concentrated to give a white solid (40 mg, crude yield, HC1 salt). LCMS m / z = 482.3 (M+l).

[0270] Step 6. (2R,4S)-4-(4-(3-chloro-5-((R)-l-(pyridin-2-yl)ethoxy)imidazo[ 1 ,2-a]pyridin-7-yl)-5-methyl- 1H- 1 ,2,3 -tri azol- 1 -yl)-2-(methoxymethyl)piperidine-l -carbonitrile. To a solution of3-chloro-7-[l-[(2R,4S)-2-(methoxymethyl)-4-piperidyl]-5-methyl-triazol-4-yl]-5-[(lR)-l-(2-pyridyl)ethoxy]imidazo[l,2-a]pyridine (40 mg, 0.08 mmol, 1.0 eq) and DIEA (64 mg, 0.50 mmol, 6.0 eq) in DCM (2 mL) at 0 °C, was added BrCN (18 mg, 0.17 mmol, 2.0 eq).80120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)The resulting mixture was stirred at rt for 2 h. After the reaction completion, the mixture was diluted with DCM (10 mL) and washed with water (5 mL x 2). The organic layer was dried over Na2SC>4 and concentrated in vacuum. The crude product was purified by Pre-HPLC (Prep-C18, 5pMTriart column, 20 * 150 mm, YMC-Actus; gradient elution of 35% MeCN in water to 50% MeCN in water over a 5 min period, where both solvents contain 0.05% NH3.H2O) to give a white solid (3.0 mg, 7.1% yield). LCMS m / z = 507.1 (M+H); 1H NMR (400 MHz, DMSO-d6) 88.59 (d, J = 5.2 Hz, 1H), 7.88-7.83 (m, 1H), 7.61-7.59 (m, 2H), 7.37-7.33 (m, 2H), 6.55 (s, 1H), 5.84 (q, J = 6.4 Hz, 1H), 4.69-4.67 (m, 1H), 3.63-3.60 (m, 1H), 3.54-3.53 (m, 2H), 3.49-3.44 (m, 2H), 3.29 (s, 3H), 2.41 (s, 3H), 2.08-2.02 (m, 3H), 1.90-1.90 (m, 1H), 1.76 (d, J = 6.4 Hz, 3H).Scheme 19

[0271] Scheme 19 depicts the preparation of Example 9, as further described below.

[0272] Example 9. (2S,4S)-4-(4-(3-chloro-5-((R)-l-(5-fluoropyridin-2-yl)ethoxy)imidazo[ 1 ,2-a]pyridin-7-yl)-5-methyl- 1H- 1 ,2,3 -tri azol- 1 -yl)-2-(methoxymethyl)-piperidine- 1 -carbonitrile.

[0273] Step 1. 5,7-dichloroimidazo[l,2-a]pyridine. To a solution of 4,6-dichloropyridin-2-amine (50.0 g, 309 mmol, 1.0 eq) in EtOH (1000 mL) was added 2-bromo- 1,1 -dimethoxy-ethane (62.2 g, 370 mmol, 1.2 eq) and HBr aq. (52 mL, 309 mmol, 1.0 eq). The reaction mixture was stirred for 4 h at 80 °C. After the reaction was completed, the mixture was concentrated. The crude product was purified by silica gel column (petroleum ether / DCM = 3 / 1) to give a brown solid (50.0 g, 87% yield). LCMS m / z = 187.1 (M+l).81120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)

[0274] Step 2. 7-chloro-5-methoxy-imidazo[l,2-a]pyridine. To a solution of 5,7-dichloroimidazo[l,2-a]pyridine (50.0 g, 269 mmol, 1.0 eq) in MeOH (1000 mL) was added MeONa / MeOH (242 g, 1.34 mol, 5.0 eq, 30%wt in MeOH). The reaction mixture was stirred at 50 °C for 5 h. After the reaction was completed, the mixture was concentrated in vacuum. The residual was diluted with water (500 mL) and extracted with EtOAc (500 mL x 3). The organic layers were dried over Na2SO4 and concentrated in vacuum. The crude product was purified by silica gel column (petroleum ether / DCM = 1 / 2) to give a brown solid (45.0 g, 92% yield). LCMS m / z = 183.1 (M+l).

[0275] Step 3. 7-chloroimidazo[l,2-a]pyridin-5-ol. To a solution of 7-chloro-5-methoxy-imidazo[l,2-a]pyridine (10.0 g, 54.9 mmol, 1.0 eq) in DMA (100 mL) was added 50% NaOH aq. (11.0 g, 275 mmol, 5.0 eq) and NDM (22.2 g, 110 mmol, 2.0 eq). The reaction mixture was stirred for 5 h at 60 °C under N2 protection. After the reaction was completed, the pH value of the reaction mixture was adjusted to 5-6 by addition of FA. The mixture was purified by reverse phase preparative MPLC (Prep-C18, 20-45 pM, 120 g, Tianjin Bonna-Agela Technologies; gradient elution of 5% MeCN in water to 30% MeCN in water over a 30 min period, where both solvents contain 0.1% formic acid) to give a yellow solid (3.5 g, 38% yield). LCMS m / z = 169.2 (M+l).

[0276] Step 4. 7-chloro-5-[(lR)-l-(5-fluoro-2-pyridyl)ethoxy]imidazo[l,2-a]pyridine. To a solution of (lS)-l-(5-fluoro-2-pyridyl)ethanol (300 mg, 2.11 mmol, 1.0 eq) and PPF13 (1.11 g, 4.23 mmol, 2.0 eq) in DMF (5 mL) was added the solution of DBAD (729 mg, 3.17 mmol, 1.5 eq) at 0°C under N2 protection. Then the solution of 7-chloroimidazo[l,2-a]pyridin-5-ol (355 mg, 2.11 mmol, 1.0 eq) in DMF (4 mL) was added dropwise to the reaction solution at 0 °C. The reaction mixture was stirred at rt for 16 h. After the reaction was completed, the mixture was diluted with EtOAc (50 mL) and washed with brine (30 mL x 3). The organic layer was dried over Na2SO4 and concentrated. The crude product was purified by silica gel column (MeOH / DCM = 1 / 10) to give a crude solid. The product was purified by reverse phase preparative MPLC (Prep-Ci 8, 20-45 pM, 120 g, Tianjin Bonna-Agela Technologies; gradient elution of 5% MeCN in water to 30% MeCN in water over a 30 min period, where both solvents contain 0.1% formic acid) to give a yellow solid (150 mg, 24.3% yield). LCMS m / z = 292.2 (M+l).

[0277] Step 5. 5-[(lR)-l-(5-fluoro-2-pyridyl)ethoxy]-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)imidazo[l,2-a]pyridine. To a solution of 7-chloro-5-[(lR)-l-(5-fluoro-2-pyridyl)ethoxy]imidazo[l,2-a]pyridine (70 mg, 0.24 mmol, 1.0 eq) and BPD (11082120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)mg, 0.43 mmol, 1.8 eq) in dioxane (2 mL) was added Pd2(dba)3 (22 mg, 0.02 mmol, 0.1 eq), X-Phos (23 mg, 0.05 mmol, 0.2 eq) and KO Ac (70 mg, 0.72 mmol, 3.0 eq). The reaction mixture was stirred for 12 h at 85 °C under N2 protection. After the reaction was completed, the reaction mixture was used directly in the next step without further purification. LCMS m / z = 302.2 (M-82).

[0278] Step 6. tert-butyl (2S,4S)-4-[4-[5-[(lR)-l-(5-fluoro-2-pyridyl)ethoxy]imidazo[l,2-a]pyridin-7-yl]-5-methyl-triazol-l-yl]-2-(methoxymethyl)piperidine-l -carboxylate. To a solution of 5-[(lR)-l-(5-fluoro-2-pyridyl)ethoxy]-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)imidazo[l,2-a]pyridine (72 mg, 0.19 mmol, 1.6 eq) and tert-butyl (2S,4S)-4-(4-bromo-5-methyl-triazol-l-yl)-2-(methoxymethyl)piperidine-l -carboxylate (47 mg, 0.12 mmol, 1.0 eq) in dioxane (2 mL) and H2O (0.2 mL) was added Pd(dtbpf)C12 (10 mg, 0.01 mmol, 0.1 eq) and K2CO3 (45 mg, 0.36 mmol, 3.0 eq). The reaction mixture was stirred for 2 h at 85 °C under N2. After the reaction was completed, the mixture was concentrated. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give a brown solid (44 mg, 65% yield for 2 steps). LCMS m / z = 566.4 (M+l).

[0279] Step 7. tert-butyl (2S,4S)-4-[4-[3-chloro-5-[(lR)-l-(5-fluoro-2-pyridyl)ethoxy]imidazo[l,2-a]pyridin-7-yl]-5-methyl-triazol-l-yl]-2-(methoxymethyl)piperidine-l -carboxylate. To a solution of tert-butyl (2S,4S)-4-[4-[5-[(lR)-l-(5-fluoro-2-pyridyl)ethoxy]imidazo[l,2-a]pyridin-7-yl]-5-methyl-triazol-l-yl]-2-(methoxymethyl)piperidine-l -carboxylate (40 mg, 0.07 mmol) in ACN (3 mL) was added NCS (17 mg, 0.13 mmol, 1.8 eq) at 0 °C. The reaction solution was stirred for 12 h at rt. After the reaction was completed, the solution was purified by Pre-TLC (dichloromethane / methanol = 20 / 1) to give a light-yellow solid (35 mg, 83% yield).LCMS m / z = 600.3 (M+l).

[0280] Step 8. 3-chloro-5-[(lR)-l-(5-fluoro-2-pyridyl)ethoxy]-7-[l-[(2S,4S)-2-(methoxymethyl)-4-piperidyl]-5-methyl-triazol-4-yl]imidazo[l,2-a]pyridine. To a solution of tert-butyl (2S,4S)-4-[4-[3-chloro-5-[(lR)-l-(5-fluoro-2-pyridyl)ethoxy]imidazo[l,2-a]pyridin-7-yl]-5-methyl-triazol-l-yl]-2-(methoxymethyl)piperidine-l-carboxylate (35 mg, 0.06 mmol, 1.0 eq) in DCM (3 mL) was added HCl / dioxane (4M, 1 mL), which was stirred at rt for Ih. After the reaction was completed, the mixture was concentrated under vacuum to give a light-yellow solid (31 mg, HC1 salt, crude yield). LCMS m / z = 500.3 (M+l).83120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)

[0281] Step 9. (2S,4S)-4-(4-(3-chloro-5-((R)-l-(5-fluoropyridin-2-yl)ethoxy)imidazo[ 1 ,2-a]pyridin-7-yl)-5-methyl- 1H- 1 ,2,3 -tri azol- 1 -yl)-2-(methoxymethyl)-piperidine-l-carbonitrile. To a solution of3-chloro-5-[(lR)-l-(5-fluoro-2-pyridyl)ethoxy]-7-[l-[(2S,4S)-2-(methoxymethyl)-4-piperidyl]-5-methyl-triazol-4-yl]imidazo[l,2-a]pyridine (31 mg, 0.06 mmol, 1.0 eq) and DIEA (37 mg, 0.29 mmol, 5.0 eq) in DCM (2 mL) was added BrCN (7 mg, 0.06 mmol, 1.1 eq). The reaction mixture was stirred at rt for 2h. After the reaction was completed, the reaction mixture was diluted with H2O (20 mL) and extracted with Di chloromethane (20 mL x 2). The combined organic layers were washed with brine (25 mL), dried over Na2SC>4 and concentrated under vacuum. The residue was purified by Prep-HPLC (Prep-C18, 5 pM Triart column, 20 x 150 mm, YMC-Actus; gradient elution of 38% MeCN in water to 58% MeCN in water over a 9 min period, where both solvents contain 0.05% NH3.H2O -10MMOL / L NH4HCO3-CAN) to give a white solid (3.1 mg, 10.2% yield for 2 steps). LCMS m / z = 525.2 (M+H); 1HNMR (400 MHz, DMSO-d6) 88.46 (d, J = 2.8 Hz, 1H), 7.61-7.58 (m, 1H), 7.46-7.37 (m, 3H), 6.71 (s, 1H), 5.78 (q, J = 6.4 Hz, 1H), 4.79-4.75 (m, 1H), 3.92-3.87 (m, 1H), 3.79-3.57 (m, 4H), 3.44 (s, 3H), 2.46 (s, 3H), 2.39-2.14 (m, 4H), 1.85 (d, J = 6.4 Hz, 3H).Kinase Assays

[0282] Kinase-tagged T7 phage strains were prepared in an E. coli host derived from the BL21 strain. E. coli were grown to log -phase and infected with T7 phage and incubated with shaking at 32°C until lysis. The lysates were centrifuged and filtered to remove cell debris. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays. The liganded beads were blocked with excess biotin and washed with blocking buffer SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT to remove unbound ligand and to reduce non-specific binding. Binding reactions were assembled by combining kinases, liganded affinity beads, and test compounds in lx binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT).

[0283] Test compounds were prepared as 11 IX stocks in 100% DMSO. Kds were determined using an 11 -point 3-fold compound dilution series with three DMSO control points. All compounds for Kd measurements are distributed by acoustic transfer (non-contact dispensing) in 100% DMSO. The compounds were then diluted directly into the assays such that the final concentration of DMSO was 0.9%. All reactions performed 84120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)in polypropylene 384-well plate. Each was a final volume of 0.02 ml. The assay plates were incubated at room temperature with shaking for 1 hour and the affinity beads were washed with wash buffer (lx PBS, 0.05% Tween 20). The beads were then re-suspended in elution buffer (lx PBS, 0.05% Tween 20, 0.5 pM non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The kinase concentration in the eluates was measured by qPCR.

[0284] Binding constants (Kds)

[0285] Binding constants were calculated with a standard dose-response curve using the Hill equation:

[0286] The Hill Slope was set to -1. Curves were fitted using a non-linear least square fit with the Levenberg-Marquardt algorithm.Table 1. FGFR Binding data (Kd, nM)A= 1-50 nMB= >50 to 300 nMC= >300 to 1000 nMD= >1000 nMCell Viability AssaysBa / F3 Cell Viability Assay

[0287] Experimental Purpose: Recombinant kinase fusions are transduced into parental Ba / F3, which becomes dependent upon this constitutive kinase activity for IL3-85120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)independent survival. Inhibition of kinase activity leads to cell death, which is monitored using CellTiter-Glo® 2.0 (Promega) which measures intracellular ATP concentration that in turn serves as a marker for viability. BCR-FGFR1 Ba / F3, BCR-FGFR2 and FGFR3-BAIAP2L1 Ba / F3 were obtained from Advanced Cellular Dynamics (Seattle, WA).ETV6-FGFR4 was obtained from Kyinno (Waltham, MA).

[0288] Cell Viability Assay Procedure: Cell Titer-Gio® 2.0 Luminescent cell viability assay reagent was purchased from Promega (Madison, WI). Ba / F3 cell lines were cultured in RPMI1640 media supplemented with 10% fetal bovine serum. Cultures were maintained at 37°C in a humidified atmosphere of 5% CO2 and 95% air. Cells were plated in 96-well clear bottom / white plates (Corning #3903) at 10,000 cells / well in lOOpl of media, incubated overnight. The next day, test compound DMSO stock solutions were made at 10 mM and 2 pM final concentration. Compounds were then added to cells in a 9-dose, 10-fold dilution series starting at 30 pM with an HP 300e Digital Dispenser (each dose was applied in triplicate). DMSO was backfilled to each well up to 301 nL total volume of test compound + DMSO, and a total of 301 nL DMSO was added to a control / no test compound well in triplicate. The cells in cell culture plates were incubated with the compounds at 37 °C and 5% CO2 for 48 hours. Then 50 pl of Cell Titer Gio 2.0 reagent was added to each well of the cell culture plates. The contents were covered from light and mixed on an orbital shaker at room temperature for 10 min. Luminescence was recorded by a Synergy Hl Microplate Reader (Biotek, Winooski, VT ). Cells were assessed as a percentage of DMSO only treated control cells. Curves were plotted and IC50 values were calculated using the GraphPad Prism 8 program based on a sigmoidal doseresponse equation (4 parameter).Table 2. Ba / Fr3 Cell data (IC50, nM); NT = not testedA = 0.1 - 50 nMB = >50 - 200nMC = >200 - 1000 nMD = > 1000 nMCancer Cell Line Cell Viability Assays86120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)

[0289] Experimental Purpose: To detect the change of intracellular ATP by Cell Titer-Gio® and to evaluate the inhibitory effect of the compounds on cancer cell lines by determining the in vitro IC50 value of the compounds.

[0290] Cell Titer-Gio® 2.0 Luminescent cell viability assay reagent was purchased from Promega (Madison, WI). KG-1, KATO-III, and MDA-MB-453 cell lines were purchased from American Type Culture Collection (Manassas, VA). RT112 / 84 cell line was purchased from Millipore- Sigma (St. Louis, MO). HuH7 cells were purchased from Seikisui Xenotech (Kansas City, KS). RT112 / 84 and MDA-MB-453 cells were cultured in RPMI1640 media supplemented with 10% fetal bovine serum. KG-1 and KATO-III cell lines were cultured in IMDM media supplemented with 20% FBS. HuH7 cells were cultured in IMDM media supplemented with 10% FBS. Cultures were maintained at 37°C in a humidified atmosphere of 5% CO2 and 95% air.

[0291] Cell Viability Assay Procedure: Cells were plated in 96-well clear bottom / white plates (Corning #3903) at a range of densities depending on the optimal assay window (5,000-20,000 cells / well in lOOpl of media), incubated overnight. The next day, test compound DMSO stock solutions were made at 10 mM and 2 pM final concentration. Compounds were then added to cells in a 9-dose, 4-fold dilution series starting at 3 pM with an HP 300e Digital Dispenser (each dose was applied in triplicate). DMSO was backfilled to each well up to 301 nL total volume of test compound + DMSO, and a total of 301 nL DMSO was added to a control / no test compound well in triplicate. The cells in cell culture plates were incubated with the compounds at 37 °C and 5% CO2 for 72 hours-120 hours depending on the cell line. Then 50 pl of Cell Titer Gio 2.0 reagent was added to each well of the cell culture plates. The contents were covered from light and mixed on an orbital shaker at room temperature for minimum of 10 min. Luminescence87120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)was recorded by a Clariostar Plus Microplate Reader (BMG Labtech, Cary, NC ). Cells were assessed as a percentage of DMSO only treated control cells. Curves were plotted and IC50 values were calculated using the GraphPad Prism 9 program based on a sigmoidal dose-response equation (log (inhibitor) vs. response - Variable slope, 4-parameter).Table 3. Cancer Cell Data (IC50, nM), NT = not testedA = 0.1 - 50 nMB = >50 - 200nMC = >200 - 1000 nMD = > 1000 nM88120039.000206\4906-8907-1992.1

Claims

120039.000206 (TYRA.042PCT)What is claimed:

1. A compound of Formula I:Formula I or a pharmaceutically acceptable salt thereof, whereinA is a pyrazole, triazole, thiadiazole, or a oxadiazole, optionally substituted with R1and R1A;R1is hydrogen or C1-C3 alkyl;R1Ais hydrogen, halogen, CN, or C1-C3 alkyl optionally substituted with one or more substituents independently selected from halogen, OH, and OCH3; X1and X2are independently selected from N and C, wherein when one of X1or X2is N the other is C;X3is N or CH;X4is N or C-R9;Y is NH, O, S, or a bond;Y1is a bond, CHR7, CH2-CHR7, CHR7-CH2, CF2, CH2-CF2 or CF2-CH2;Y2is a bond, CHR3, CH2-CHR3, CHR3-CH2, CF2, CH2-CF2 or CF2-CH2;Y3is CH2OCH3;Y4is CR3R4, or CF2;Z is a bond, CHR9A, CR4R4A, CR4R4A-CH2, CH2-CR4R4A, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo(l.l.l)pentane, bicyclo(2.

1. l)hexane, azetidine, pyrrolidine, or piperidine;Z1is a bond when Z is a bond, CR4R4A, CR4R4A-CH2, CH2-CR4R4A, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo(l ,l.l)pentane, bicyclo(2.

1. l)hexane, azetidine, pyrrolidine, or piperidine, or Z1is CH2 or CH2-CH2 when Z is CHR9A;89120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)Z2is a bond, C(O), SO2 or -NR4C(O);Z3is a bond, C(O), SO2 or -NR4C(O);R2is C1-C5 alkyl or R8, wherein C1-C5 alkyl is optionally substituted with one or more substituents independently selected from halo, OH, CN, oxo, -OC1-C4 alkyl, OC3-C5 cycloalkyl, -Z2-Rnand R10, wherein C1-C4 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N- dimethylamine, and CN;R3is hydrogen, F, OH, OCH3, C1-C3 alkyl, cyclopropyl, or one R3is fused with R5or R7to form CH2, CH2-CH2 or CH2OCH2;R4is hydrogen or C1-C3 alkyl;R4Ais hydrogen, halo, OH, or C1-C3 alkyl;R5is hydrogen, F, OH, OCH3, C1-C3 alkyl, cyclopropyl, or is fused with one R3to form CH2, CH2-CH2 or CH2OCH2;R6is hydrogen, halo, C1-C5 alkyl, CN, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered aryl, or 5-6 membered heteroaryl, wherein 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered aryl and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, methyl, halomethyl, OH, or OCH3 and wherein C1-C5 alkyl is optionally substituted with one or more substituents independently selected from halo, OH, and OCH3;R7is hydrogen, F, OH, OCH3, C1-C3 alkyl or is fused with one R3to form CH2, CH2-CH2 or CH2OCH2;R8is 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl, optionally fused or substituted with R8A; R8Ais 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl;R9is hydrogen, C1-C3 alkyl, or is fused with R9Ato form CH2 or CH2-CH2;R10is 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl, any of which is optionally fused or substituted with R8A;R11is C1-C4 alkyl, NH2, NHC1-C5 alkyl, NHC3-C5 cycloalkyl orN(Ci-C3 alkyl)2, wherein C1-C4 alkyl, C1-C3 alkyl and C3-C5 cycloalkyl are optionally90120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine, and CN;R12is C1-C4 alkyl, C3-C5 cycloalkyl, NH2, NHC1-C3 alkyl, NHC3-C5 cycloalkyl or N(CI-C3 alkyl)2, wherein C1-C4 alky, C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine and CN; and R8, R10and R8Aare optionally substituted with one or more substituents independently selected from halo, OH, CN, -OC1-C4 alkyl, -OC3-C5 cycloalkyl and -Z3-R12wherein C1-C4 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine, and CN; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 wherein X1is C and X2is N; or X1is N and X2is C.

3. The compound according to any preceding claim of the formula:or a pharmaceutically acceptable salt thereof.

4. The compound according to any preceding claim of the formula:91120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)or a pharmaceutically acceptable salt thereof.

5. The compound according to any preceding claims, wherein X3is CH, or a pharmaceutically acceptable salt thereof.

6. The compound according to any preceding claims, wherein R1is methyl, or a pharmaceutically acceptable salt thereof.

7. The compound according to any preceding claims, wherein R1Ais hydrogen or Ci-C3 alkyl optionally substituted with one or more substituents independently selected from halo, OH, and OCH3, or a pharmaceutically acceptable salt thereof.

8. The compound according to any one of claim 1 to 6, wherein R1Ais hydrogen, or a pharmaceutically acceptable salt thereof.

9. The compound according to any preceding claim, wherein R9is hydrogen or is fused with R9Ato form CH2 or CH2-CH2, or a pharmaceutically acceptable salt thereof.

10. The compound according to any preceding claims, wherein R6is CN, F, Cl, CH3, CF3 or cyclopropyl, or a pharmaceutically acceptable salt thereof.

11. The compound according to any one of claims 1 to 9, wherein R6is CN, F, or Cl, or a pharmaceutically acceptable salt thereof.

12. The compound according to any one of claims 1 to 9, wherein R6is CN or Cl, or a pharmaceutically acceptable salt thereof.

13. The compound according to any preceding claim, wherein A is pyrazole or triazole, substituted with R1and R1A, or a pharmaceutically acceptable salt thereof.92120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)14. The compound according to any preceding claim, wherein Z is a bond, cyclobutyl, bicyclo(l.l.l)pentane, bicyclo(2.1.1)hexane, azetidine or piperidine, or a pharmaceutically acceptable salt thereof.

15. The compound according to any one of claims 1 to 13, wherein Z is a bond, cyclobutyl, azetidine or piperidine, or a pharmaceutically acceptable salt thereof.

16. The compound according to any preceding claims, wherein R2is C1-C3 alkyl optionally substituted with one, two, three or four substituents independently selected from halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z2-Rnand R10, wherein C1-C4 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine and CN, or a pharmaceutically acceptable salt thereof.

17. The compound according to any one of claims 1 to 15, wherein R2is selected from:optionally substituted with one, two, three or four substituents independently selected from halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z2-Rnand R10, wherein C1-C4 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine and CN, wherein * indicates the connection point to Y, or a pharmaceutically acceptable salt thereof18. The compound according to claim 17, wherein R2is optionally substituted with one, two, three or four substituents independently selected from F, OH, CN, oxo, -OCH3 and-OCscycloalkyl, or a pharmaceutically acceptable salt thereof.93120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)19. The compound according to any preceding claim, wherein R10is 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl, optionally fused with R8A, or a pharmaceutically acceptable salt thereof.

20. The compound according to any one of claims 1 to 18, wherein R10is 5-6 membered heteroaryl, optionally fused with R8A, or a pharmaceutically acceptable salt thereof.

21. The compound according to claim 19 or claim 20, wherein R10and R8Aare optionally substituted with one, two or three substituents independently selected from halo, OH, CN, -OC1-C4 alkyl, -OC3-C5 cycloalkyl and -Z3-R12wherein C1-C4 alkyl and C3-C5 cycloalkyl are optionally substituted with one, two or three substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine and CN, or a pharmaceutically acceptable salt thereof.

22. The compound according to any preceding claim, wherein Y1is a bond, CHR7, CH2-CHR7or CHR7-CH2, wherein R7is selected from hydrogen, F, OH and CH3, or a pharmaceutically acceptable salt thereof.

23. The compound according to any preceding claim, wherein Y2is a bond, CHR3, CH2-CHR3 or CHR3-CH2, wherein R3is selected from hydrogen, F, OH and CH3, or a pharmaceutically acceptable salt thereof.

24. The compound according to any preceding claim, wherein Z is a bond, azetidine or piperidine, or a pharmaceutically acceptable salt thereof.

25. The compound according to any preceding claim, wherein Z1is a bond, or a pharmaceutically acceptable salt thereof.

26. The compound according to any preceding claim, wherein Z is CHR9A, Z1is CH2 and R9is fused with R9Ato form CH2, or a pharmaceutically acceptable salt thereof.

27. The compound according to claim 1, selected from the group consisting of:94120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)95120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)96120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)97120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)28. A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 27, and a pharmaceutically acceptable carrier, diluent or excipient.

29. A method of treating cancer, comprising administering to a patient in need of such treatment an effective amount of a compound of any one of claims 1 to 27, or pharmaceutically acceptable salt thereof.

30. The method of claim 29, wherein the cancer is selected from the group consisting of breast cancer, invasive ductal breast cancer, invasive lobular breast cancer, lung cancer, non-small-cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, small-cell lung cancer, urothelial cancer, bladder cancer, urothelial bladder cancer, nonmuscle invasive bladder cancer, muscle invasive bladder cancer, upper tract cancer, urothelial upper tract cancer, urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma, cutaneous melanoma, head and neck cancer, oral cancer, thyroid cancer, renal cancer, renal pelvis cancer, glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer.

31. The method of claim 30, wherein the cancer is selected from the group consisting of breast cancer, invasive ductal breast cancer, invasive lobular breast cancer, lung cancer, non-small-cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, small-cell lung cancer, urothelial cancer, bladder cancer, urothelial bladder cancer, nonmuscle invasive bladder cancer, muscle invasive bladder cancer, upper tract cancer, urothelial upper tract cancer, and glioblastoma.

32. The method of claim 31, wherein the cancer is selected from the group consisting of bladder cancer, urothelial bladder cancer, non-muscle invasive bladder cancer and muscle invasive bladder cancer.98120039.000206\4906-8907-1992.1120039.000206 (TYRA.042PCT)33. The method of claim 32, wherein the cancer is a FGFR3 -associated cancer.99120039.000206\4906-8907-1992.1

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